EP3515919A1

EP3515919A1 - N3-cyclically substituted thienouraciles and use thereof

Info

Publication number: EP3515919A1
Application number: EP17765199.9A
Authority: EP
Inventors: Michael Härter; Dirk Kosemund; Yolanda Cancho Grande; Martina Delbeck; Bernd Kalthof; Klemens Lustig; Frank SÜSSMEIER
Original assignee: Bayer AG; Bayer Pharma AG
Current assignee: Bayer AG; Bayer Pharma AG
Priority date: 2016-09-23
Filing date: 2017-09-18
Publication date: 2019-07-31
Also published as: PE20190474A1; WO2018054846A1; KR20190053242A; IL265531A; MX2019003351A; CN109963858A; SG11201902588PA; US20200016159A1; UY37415A; AU2017329677A1; RU2019111357A; TW201825497A; CA3037642A1; BR112019005795A2; JP2019529452A

Abstract

The invention relates to novel, in position 3, cyclically substituted thieno[2,3-d]pyrimidine-2,4-dione ("thienouracil")-derivatives, to methods for the production thereof, to the use thereof alone or in combinations for treating and/or preventing diseases, and to the use thereof for producing medicaments for treating and/or for preventing diseases, in particular for treating and/or preventing pulmonary and cardiovascular disorders and cancers.

Description

A ^ -cvclisch substituted thienouracils and their use

The present application relates to novel 3-position cyclically substituted thieno [2,3-d] pyrimidine-2,4-dione ("thienouracil") derivatives, processes for their preparation, their use alone or in combinations for the treatment and / or prevention of diseases and their use for the manufacture of medicaments for the treatment and / or prevention of diseases, in particular for the treatment and / or prevention of diseases of the lung and the cardiovascular system and of cancers.

The endogenous purine nucleoside adenosine is ubiquitously formed and modulates a variety of physiological and pathophysiological processes as an important signaling molecule. It is mainly caused by the intracellular and extracellular degradation of adenine nucleotides and, to a lesser extent, by the intracellular hydrolysis of S-adenosyl homocysteine. Under physiological conditions, extracellular adenosine can be re-phosphorylated by adenosine kinase to adenosine monophosphate (AMP) or converted into inosine by adenosine deaminase. The extracellular concentration is between 30 and 300 nM. In case of tissue damage, conditionally e.g. Hypoxia, inflammatory reactions and oxidative stress lead to an increased formation and accumulation of adenosine, so that the extracellular concentration can rise to 15 μΜ.

The biological effects of adenosine are mediated via G-protein coupled plasma membrane-bound receptors. Currently, four adenosine receptor subtypes are detected: Al adenosine receptor (AIR), A2a adenosine receptor (A2aR), A2b adenosine receptor (A2bR) and A3 adenosine receptor (A3R). The A2b receptor has the weakest affinity for adenosine among the four adenosine receptors mentioned above. For this reason, unlike the other adenosine receptors, it is not activated under normal physiological conditions. AI and A3 receptors are coupled to Gi proteins that inhibit adenylate cyclase, whereas A2a and A2b receptors via Gs proteins stimulate adenylate cyclase and thus an intracellular increase in cAMP. Through Gq proteins, both the AI, A3 and A2b receptors activate phospholipase C, which breaks down membrane-bound phosphatidyl inositol 4,5-bisphosphate into inositol-1, 4,5-triphosphate and diacylglycerol. This in turn leads to an increase in the intracellular calcium concentration and activation of further target proteins, such as protein kinase C and MAP kinases.

A2b receptors are expressed on pulmonary epithelial and smooth muscle cells, vascular endothelial and smooth muscle cells, fibroblasts and inflammatory cells. The expression of the A2b receptor on the cell surface is a dynamic process and is greatly increased, for example, by hypoxia, inflammatory factors and free radicals. The adenosine-activated A2b- Receptors lead to the formation and release of proinflammatory and pro-fibrotic cytokines such as IL-6, IL-4 and IL-8. Studies have shown that the A2b receptor plays an important role in the chronic stage of lung diseases in tissue remodeling and, inter alia, promotes the differentiation of fibroblasts into myofibroblasts, which leads to an increased synthesis and deposition of collagen.

In lung tissue samples from patients with idiopathic pulmonary fibrosis, COPD and pulmonary hypertension associated with COPD [Zhou et al, PLoS One 5, e9224 (2010); Selmann et al., PLoS One 2, e482 (2007)] as well as in various animal models of fibro-proliferative lung diseases [Karmouty-Quintana et al, Am. J. Respir. Cell Mol. Biol. 49 (6), 1038-1047 (2013); Karmouty-Quintana et al, FASEB J. 26, 2546-2557 (2012); Sun et al, J. Clin. Invest. 116, 2173-2182 (2006)], an increased expression of the A2b receptor was found. In the animal model of bleomycin-induced pulmonary fibrosis and pulmonary hypertension in the mouse, a genetic knock-out of the A2b receptor inhibited the progression of pulmonary fibrosis as well as pulmonary vascular remodeling and the resulting pulmonary hypertension [Karmouty-Quintana et al. Faseb J. 26, 2546-2557 (2012)]. In the development of pulmonary hypertension associated with pulmonary fibrosis, the release of, inter alia, endothelin-1 (ET-1) and interleukin-6 (IL-6) from the vascular cells modulated by the A2b receptor is thought to play a role. Stimulation of human pulmonary arterial endothelial and smooth muscle cells with 5 '- (N-ethylcarboxamido) adenosine (NECA), an adenosine analog, results in the release of ET-1 and IL-6, which are prevented by A2b receptor inhibition [Karmouty-Quintana et al., Faseb J. 26, 2546-2557 (2012)]. Increased levels of endothelin-1 and IL-6 have been found in the lung tissue and serum of patients with pulmonary hypertension [Giaid et al, N. Engl. J. Med. 329, 1967-1968 (1993); Steiner et al, Circ. Res. 104. 236-244 (2009)]. Furthermore, A2b receptor mediated release of inter alia IL-6 and other profibrotic mediators, as well as stimulation of fibroblast differentiation into myofibroblasts in the lung, is believed to induce fibrosis. Stimulation of human fibroblasts with NECA results in release of IL-6, which is hypoxia enhanced and can be prevented by A2b receptor inhibition. In patients with idiopathic pulmonary fibrosis and in animal models of pulmonary fibrosis, increased IL-6 expression has been demonstrated [Zhong et al, Am. J. Respir. Cell Mol. Biol. 32: 2-8 (2005); Cavarra et al, Am. J. Physiol. Lung Cell. Mol. Physiol. 287, LI 186-L1192 (2004)].

The A2b receptor also plays an important role in tissue remodeling after myocardial infarction. In the animal model of permanent ligation of the coronary artery in the mouse, inhibition of the A2b receptor led to a reduction of caspase-1 activity and of the immigrated inflammatory cells in the heart tissue as well as the cytokines and adhesion molecules in the plasma and to an improvement in systolic and diastolic cardiac function [Toldo et al, J. Pharmacol. Exp. Ther. 343, 587-595 (2012)].

In tumors and tumor-surrounding tissues, local adenosine concentration is due to hypoxia, necrotic processes, or genetic and epigenetic alterations of tumor cells leading to increased extracellular production of adenosine, with concomitant reduced degradation and decreased adenosine cell uptake. often greatly increased [J. Blay et al, Cancer Res. 57 (13), 2602-2605 (1997); G. Schulte, B.B. Fredholm, Cell Signal. 15 (9), 813-827 (2003)]. This leads to activation of the previously described adenosine receptors on tumor cells, tumor-associated cells and cells of the tumor-surrounding tissue. The signal chains initiated thereby trigger various processes, the majority of which favor tumor growth and its spread to other locations in the organism. Thus, inhibition of adenosine signaling pathways is a valuable strategy for treating cancers. For example, inhibition of the A2b receptor-mediated adenosine signaling pathway with the A2b receptor antagonist MRS1754 results in decreased growth of colon cancer cell lines [D .-F. Ma et al, Hum. Pathol. 4J_ (11), 1550-1557 (2010)]. The A2b receptor antagonist PSB603 reduces the growth of several prostate cancer cell lines [Q. Wei et al, purinergic signal. 9 (2), 271-280 (2013)].

The influence of adenosine on tumor metastasis seems to be greater than the direct influence on the proliferation of tumor cells. In particular, A2b receptor-mediated adenosine signaling chains are involved, and blockade of the A2b receptor - both genetically and pharmacologically with A2b receptor antagonists - results in reduced migration of tumor cells in vitro and reduced metastasis formation in animal models [J. Stagg et al, Proc. Natl. Acad. Be. USA 107 (4), 1547-1552 (2010); C.J. Desmet et al, Proc. Natl. Acad. Be. USA HO (13), 5139-5144 (2013); E. Nantie et al., Sei. Signal. 6 (277), ra39 (2013)]. Adenosine also has an influence on the tumor-associated vascular endothelium: A2b-receptor-mediated adenosine signaling chains lead to the release of pro-angiogenic factors from various human tumor cell lines, but also from tumor-associated immune cells, thus stimulating tumor growth promoting neovascularization [S. Ryzhov et al, Neoplasia 10 (9), 987-995 (2008); S. Merighi et al, Mol. Pharmacol. 72 (2), 395-406 (2007); S. Merighi et al, Neoplasia U (10), 1064-1073 (2009)].

Increasingly better understood is the importance of the immune system in the suppression of tumorigenesis, tumor growth and metastasis. It shows that adenosine is able to reduce the immune response [S. Gessi et al, Biochim. Biophys. Acta Biomembranes 1808 (5), 1400-1412 (2011); J. Stagg et al, Proc. Natl. Acad. Be. USA 107 (4), 1547-1552 (2010); D. Jin et al, Cancer Res. 70 (6), 2245-2255 (2010); SFM Häusler et al, Cancer Immunol. Immunother. 60 (10), 1405-1418 (2011); J. Spychala, Pharmacol. Ther. 87 (2-3), 161-173 (2000)]. In contrast, the inhibition of the A2b receptor-mediated adenosine signaling pathway with the A2b receptor antagonist PSB603 leads to a reduction in tumor growth and metastasis in animal melanoma models, which is attributed to an inhibition of the tumor-induced suppression of the immune system [W. Kaji et al, J. Toxicol. Be. 39 (2), 191-198 (2014)]. This improvement is due to the fact that the proportion of regulatory T cells that reduce the immune response is reduced in total immune cell infiltrate in the presence of the A2b receptor antagonist. At the same time, the populations of cytotoxic CD8 + T cells and CD4 + T helper cells are increased. In addition, immunosuppressive effects of adenosine on other cells of the immune system are described (Ml and M2 macrophages, dendritic cells, myeloid suppressor cells), some of which are mediated via the A2b receptor [B. Csoka et al, FASEB J. 26 (1), 376-386 (2012); SV Novitskiy et al, Blood 112 (5), 1822-1831 (2008); M. Yang et al, Immunol. Cell Biol. 88 (2), 165-171 (2010); S. Ryzhov et al., J. Immunol. 187 (11), 6120-6129 (2011)]. In animal models of bladder and breast tumors, the A2b receptor antagonist ATL801 causes a slowing of tumor growth and a marked reduction in metastasis [C. Cekic et al, J. Immunol. 188 (1), 198-205 (2012)]. These effects are associated with an ATL801-induced increase in the number of tumor antigen-presenting dendritic cells as well as a strong increase in interferon-y levels and, consequently, increased concentrations of the chemokine CXCLIO, which in turn activates CXCR3 + T cells and ultimately leads to an improved immune defense of tumor growth and metastasis.

Thus, it is believed that the A2b receptor plays an important role in many diseases, injuries and pathological changes whose genesis and / or progression is associated with inflammatory events and / or proliferative and fibro-proliferative tissue and vascular remodeling , These may be, in particular, diseases and / or damage to the lung, the cardiovascular system or the kidney, or it may be a blood disorder, a cancerous disease or other inflammatory diseases.

In particular, idiopathic pulmonary fibrosis, pulmonary hypertension, bronchiolitis obliterans syndrome (BOS), chronic obstructive pulmonary disease (COPD), asthma and cystic fibrosis are diseases and disorders of the lung to be named in this connection. Diseases and damages of the cardiovascular system in which the A2b receptor is involved are, for example, tissue changes after a myocardial infarction and in heart failure. Renal diseases include renal insufficiency and kidney failure. A disease of the blood is, for example, sickle cell anemia. Examples of one Tissue degradation and remodeling in cancerous processes involve the invasion of cancer cells into the healthy tissue (metastasis) and the rebuilding of supplying blood vessels (neo-angiogenesis). Another inflammatory disease in which the A2b receptor plays a role is, for example, multiple sclerosis. Idiopathic pulmonary fibrosis or idiopathic pulmonary fibrosis (IPF) is a progressive lung disease that, if left untreated, leads to an average death within 2.5 to 3.5 years after diagnosis. Patients are usually older than 60 years of age at the time of diagnosis, and men are more likely to be affected than women. The onset of the disease is gradual and characterized by an increased shortness of breath and dry, irritating cough. IPF belongs to the group of idiopathic interstitial pneumonias (IIP), a heterogeneous group of lung diseases characterized by varying degrees of fibrosis and inflammation, which are distinguished by clinical, imaging and histologic criteria. Within this group, idiopathic pulmonary fibrosis is of particular importance due to its frequency and its aggressive nature [Ley et al, Am. J. Respir. Crit. Care Med. 183. 431-440 (2011)]. IPF can be either sporadic or familial. The causes are currently not clear. In recent years, however, numerous indications have been found that chronic damage to the alveolar epithelium results in the release of profibrotic cytokines / mediators, followed by increased fibroblast proliferation and increased collagen fiber formation, resulting in a patchy fibrosis and the typical honeycomb-like Structure of the lung comes [Strieter et al., Chest 136, 1364-1370 (2009)]. The clinical consequences of fibrosis are a decrease in the elasticity of the lung tissue, a reduction in the diffusion capacity and the development of severe hypoxia. Pulmonary functionally a deterioration of the forced vital capacity (FVC) and the diffusion capacity (DLCO) can be detected. Significant and prognostically important comorbidities of IPF are acute exacerbation and pulmonary hypertension [Beck et al., Pneumologe 10, 105-111 (2013)]. The prevalence of pulmonary hypertension in interstitial lung disease is 10-40% [Lettieri et al, Chest 129, 746-752 (2006); Behr et al, Eur. Respir. J. 31, 1357-1367 (2008)]. There is currently no curative treatment for IPF, except for lung transplantation. Pulmonary hypertension (PH) is a progressive lung disease that, if left untreated, leads to death on average within 2.8 years of diagnosis. By definition, chronic pulmonary hypertension has a pulmonary arterial mean pressure (mPAP) of> 25 mmHg at rest or> 30 mmHg under exercise (normal value <20 mmHg). The pathophysiology of pulmonary hypertension is characterized by vasoconstriction and remodeling of the pulmonary vessels. Chronic PH causes neo-muscularization primarily non-muscularized pulmonary vessels, and the vascular musculature of the already muscularized vessels increases in size. As a result of this increasing obstruction of the pulmonary circulation, there is a progressive load on the right heart, which leads to a reduced output of the right heart and ultimately ends in right heart failure [M. Humbert et al., J. Am. Coli. Cardiol. 2004, 43, 13S-24S]. Although idiopathic (or primary) pulmonary arterial hypertension (IPAH) is a very rare disease, secondary pulmonary hypertension (non-PAH PH, NPAHPH) is widespread and it is currently believed that PH is the third most common cardiovascular disease Disease group after coronary heart disease and systemic hypertension is [Naeije, in: AJ Peacock et al. (Eds.), Pulmonary Circulation. Diseases and Their treatment, 3 ^rd edition, Hodder Arnold Publ., 2011, p 3]. The classification of pulmonary hypertension into different groups according to the respective etiology has been carried out since 2008 according to the Dana Point classification [D. Montana and G. Simonneau, in: AJ Peacock et al. (Eds.), Pulmonary Circulation. Diseases and Their treatment, 3 ^rd edition, Hodder Arnold Publ., 2011, pp 197-206]. Despite advances in PH treatment, there is no prospect of healing for this serious condition. Marketed therapies (eg, prostacyclin analogues, endothelin receptor antagonists, phosphodiesterase inhibitors) are able to improve the quality of life, exercise tolerance, and prognosis of patients. These are systemically applied, primarily hemodynamically acting therapeutic principles that influence vascular tone. The applicability of these drugs is determined by the z. T. serious side effects and / or complicated application forms limited. The period of time during which the clinical situation of patients can be stabilized or improved under a specific monotherapy is limited (eg due to tolerance development). Finally, there is a therapy escalation and thus a combination therapy in which several medications have to be given at the same time. At present, these standard therapies are only approved for the treatment of pulmonary arterial hypertension (PAH). In secondary forms of PH, such as PH-COPD, failed these therapeutic principles (eg sildenafil, bosentan) in clinical trials, as they led to a decrease (desaturation) of the arterial oxygen content in patients as a result of unselective vasodilation. The reason for this is probably an unfavorable influence on the ventilation-perfusion adaptation within the lungs in heterogeneous lung diseases due to the systemic administration of unselective vasodilators [I. Blanco et al, Am. J. Respir. Crit. Care Med. 2010, 181, D. Stolz et al., Eur. Respir. J.

2008, 32, 619-628].

New combination therapies are one of the most promising future treatment options for the treatment of pulmonary hypertension. In this context, the exploration is newer pharmacological mechanisms for the treatment of PH of particular interest [Ghofrani et al., Herz 2005, 30, 296-302; EB Rosenzweig, Expert Opinion. Emerging Drugs 2006, 11, 609-619; T. Ito et al., Curr. Med. Chem. 2007, 14, 719-733]. Above all, such new therapeutic approaches, which can be combined with the therapy concepts already on the market, could be the basis of a more efficient treatment and thus bring a great advantage for the patients.

For the purposes of the present invention, the term pulmonary hypertension includes both primary and secondary subforms (NPAHPH) as defined by the Dana Point classification according to their respective etiology [D. Montana and G. Simonneau, in: AJ Peacock et al. (Eds.), Pulmonary Circulation. Diseases and Their treatment, ^3rd edition, Hodder Arnold Publ, 2011, pp 197-206. Hoeper et al., J. Am. Coli. Cardiol, 2009, 54 (1), Suppl. S, S85-S96]. In particular, group 1 includes pulmonary arterial hypertension (PAH), which includes idiopathic and familial forms (IPAH and FPAH, respectively). PAH also includes persistent pulmonary hypertension in neonates and associated pulmonary arterial hypertension (AP AH), which is associated with collagenosis, congenital systemic pulmonary shunt veins, portal hypertension, HIV infection, use of certain drugs and medications (eg of appetite suppressants), with diseases with a significant venous / capillary involvement such as pulmonary veno-occlusive disease and pulmonary capillary hemangiomatosis, or with other diseases such as thyroid disorders, glycogen storage diseases, Gaucher disease, hereditary telangiectasia, hemoglobinopathies, myeloproliferative disorders and splenectomy. Group 2 of the Dana Point classification summarizes PH patients with causative left ventricular disease, such as ventricular, atrial or valvular disease. Group 3 includes forms of pulmonary hypertension associated with a lung disease such as chronic obstructive pulmonary disease (COPD), interstitial lung disease (ILD), pulmonary fibrosis (IPF), and / or hypoxemia (eg sleep apnea syndrome, alveolar hypoventilation, chronic altitude sickness , plant-related malformations) are associated. Group 4 includes PH patients with chronic thrombotic and / or embolic diseases, eg in thromboembolic obstruction of proximal and distal pulmonary arteries (CTEPH) or in non-thrombotic embolization (eg as a result of tumor diseases, parasites, foreign bodies). Rarer forms of pulmonary hypertension, such as in patients with sarcoidosis, histiocytosis X or lymphangiomatosis, are summarized in Group 5.

Bronchiolitis obliterans syndrome (BOS) is a chronic rejection reaction after lung transplantation. Within the first five years after lung transplantation, approximately 50-60% of all patients are affected and over 90% of patients within the first nine years [Estenne et al, Am. J. Respir. Crit. Care Med. 166, 440-444 (2003)]. The cause of the Disease is not clear. Despite many advances in the treatment of transplant patients, BOS case numbers have barely changed in recent years. BOS is the most important long-term complication of lung transplantation and is considered the main reason that survival rates are still significantly lower than those of other organ transplants. BOS is an inflammatory event associated with changes in the lung tissue, especially those affecting the small airways. The damage and inflammatory changes of the epithelial cells as well as the subepithelial structures of the smaller airways lead to an excessive fibroproliferation due to an inadequate regeneration of the epithelium and an aberrant tissue repair. There is scarring and eventually destruction of the bronchioles as well as grafting of granulation tissue in the small airways and alveoli, sometimes with vascular involvement. The diagnosis is made on the basis of lung function. BOS worsens FEV1 compared to the average of the two best measured postoperatively. At present, there is no curative treatment for BOS. Some of the patients improve under intensified immunosuppression, in the non-responsive patients there is a persistent deterioration, so that a new transplantation (retransplantation) is indicated.

Chronic obstructive pulmonary disease (COPD) is a slowly progressive lung disease characterized by obstruction of respiratory flow, which is caused by pulmonary emphysema and / or chronic bronchitis. The first symptoms of the disease usually appear from the fourth to fifth decade of life. In the following years, the shortness of breath is often aggravated and it manifests cough, associated with an extensive and sometimes purulent sputum and a stenosis breathing to a dyspnea. COPD is primarily a disease of smokers: smoking is responsible for 90% of all COPD cases and 80-90% of all COPD deaths. COPD is a major medical problem and is the sixth most common cause of death worldwide. About 4-6% of over 45's are affected. Although the obstruction of the respiratory flow can be only partially and temporally limited, COPD is not curable. The aim of the treatment is thus to improve the quality of life, alleviate the symptoms, prevent acute deterioration and slow down the progressive impairment of lung function. Existing pharmacotherapies, which have barely changed over the past two to three decades, include the use of bronchodilators to open blocked airways and, in certain situations, corticosteroids to control the inflammation of the lungs [PJ Barnes, N. Engl. J Med. 343. 269-280 (2000)]. The chronic inflammation of the lungs, caused by cigarette smoke or other irritants, is the driving force of disease development. The underlying mechanism involves immune cells, which in the course of the inflammatory reaction of the lung release proteases and various cytokines which lead to pulmonary emphysema and remodeling of the bronchi.

The object of the present invention is to provide new substances which act as potent and selective antagonists of the adenosine A2b receptor and, as such, for the treatment and / or prevention, in particular of diseases of the lung and of the cardiovascular system and of cancers suitable.

WO-2009/037468-A1 discloses 2-aminothieno [3,2-d] pyrimidine-4-carboxamides as adenosine A2b antagonists for the treatment of asthma, COPD, diabetes and cancer. As antagonists of the adenosine A2a receptor, which are particularly suitable for the treatment of CNS and addictive diseases, in WO 2007/103776-A2, 6-heteroaryl-substituted and in WO 2008/070529-A2 6-styryl-substituted Thieno [2,3-d] pyrimidine-2,4-diones described. WO 98/54690 A1, WO 00/12514 A1, GB 2 363 377 A and US 2004/0122028 A1 disclose various thieno [2,3-d] pyrimidine-2,4-diones which are disclosed in U.S. Pat be used for other treatment of inflammatory and proliferative diseases. From US Pat. No. 6,140,325, carboxylate-substituted thieno [2,3-d] pyrimidine-2,4-diones are known as endothelin receptor antagonists. WO 00/61583-A1 claims xanthine analogs which are suitable for the treatment of inflammatory, neurodegenerative and autoimmune diseases. WO 02/64598-A1 and WO 2004/014916-A1 describe bicyclic pyrimidinediones as inhibitors of matrix metalloproteinases (MMPs), in particular of MMP-13. WO 2013/071169-A1, WO 2014/182943-A1 and WO 2014/182950-A1 disclose thieno [2,3-d] pyrimidine-2,4-diones as ACC inhibitors for the treatment of infections and metabolic diseases. WO 2015/052065-A1 has recently described cyclic thienouracil-6-carboxamides as adenosine A2b receptor antagonists for the treatment of diseases of the lung and the cardiovascular system, and WO-A-2016/023832-A1 discloses 3- (hydroxyalkyl ) -substituted thieno [2,3-d] pyrimidine-2,4-diones are disclosed as TRPC5 modulators for the treatment of neurological diseases. In the meantime, various 6- (heterocyclylmethyl) -substituted thienouracils have been published in WO 2016/150901-A1 as adenosine A2b receptor antagonists, and in WO 2017/075056-A1 further thieno [2,3-d] pyrimidine-2 4-dione derivatives have been disclosed as ACC inhibitors for the treatment of infections and metabolic diseases. The present invention relates to compounds of the general formula (I) in which the ring A is an aza-heterocycle of the formula

in which ^* the linkage to the adjacent C (R) (R) group is labeled, identical or different and independently of one another denote hydrogen or (C 1 -C 10) -alkyl,

Is hydrogen or (Ci-C i) -alkyl, and

XO, S or N (R ⁷ ) means in which

R ^{7 represents} cyano, methoxycarbonyl or ethoxycarbonyl, independently of one another represent hydrogen or deuterium, represents methyl or ethyl,

R ^{3 is} cyclopropyl, cyclobutyl, cyclopentyl, spiro [3.3] hept-2-yl, 3-oxetanyl or 3-tetrahydrofuranyl, wherein cyclopropyl, cyclobutyl, cyclopentyl and spiro [3.3] hept-2-yl may be substituted up to two times, identically or differently, by a radical selected from fluoro, methyl, ethyl, trifluoromethyl and methoxy, and wherein 3-oxetanyl and 3-tetrahydrofuranyl may be substituted up to two times, identically or differently, by a radical selected from fluorine and methyl, and

R ^{4 is} methyl, ethyl, 2-fluoroethyl, 2,2-difluoroethyl, 2,2,2-trifluoroethyl, n-propyl, 3-cyano-propyl, 3-fluoropropyl, 3,3-difluoropropyl, 3,3,3 Trifluoropropyl, n-butyl, 4-fluorobutyl, 4,4,4-trifluorobutyl, 3,3,4,4-tetrafluorobutyl, n-pentyl, z o -pentyl or n -hexyl, or

R ^{4 is} a group of formula -CH 2 -R ⁸ wherein

R ^{8 is} cyano, cyclopropyl, cyclobutyl, cyclopentyl, 2-oxetanyl, 3-oxetanyl, 2-tetrahydrofuranyl or 3-tetrahydrofuranyl, where cyclopropyl, cyclobutyl and cyclopentyl may be substituted up to two times by fluorine, or

R ^{4 is} a group of the formula -CH ₂ -CH ₂ -OR ⁹ or -CH ₂ -CH ₂ -SR ¹⁰ wherein R ^{9 is} methyl, trifluoromethyl, ethyl or z o -propyl and

R ^{10 is} methyl or trifluoromethyl, and their solvates.

Compounds of the invention are the compounds of formula (I) and their solvates comprising the compounds of formula (I) of the formulas (1-1), (I-la), (Tlb), (I-1c), (I -ld), (I-le), (1-2), (1-3), (1-4), (1-5), (1-6), (1-7) and (1-8 ) and their solvates, as well as those of formula (I), hereinafter described as exemplary embodiments compounds and their solvates, insofar as the compounds listed below are not already solvates.

In the context of the invention, solvates are those forms of the compounds according to the invention which form a complex in the solid or liquid state by coordination with solvent molecules. Hydrates are a special form of solvates that coordinate with water. As solvates, hydrates are preferred in the context of the present invention.

The compounds of the invention may exist in different stereoisomeric forms depending on their structure, i. in the form of configurational isomers or, if appropriate, also as conformational isomers (enantiomers and / or diastereomers, including those in the case of atropisomers; is / Z double bond isomers). The present invention therefore includes the enantiomers, diastereomers and double bond isomers as well as their respective mixtures. From such mixtures, the stereoisomerically uniform constituents can be isolated in a known manner; Preferably, chromatographic methods are used for this, in particular HPLC chromatography on achiral or chiral phase.

If the compounds according to the invention can occur in tautomeric forms, the present invention encompasses all tautomeric forms.

In the context of the present invention, unless otherwise specified, the substituents and radicals have the following meanings: (C 1 -C 4) -alkyl in the context of the invention represents a straight-chain or branched alkyl radical having 1 to 4 carbon atoms. Ethyl, n-propyl, isopropyl, n -butyl, isobutyl, ec-butyl and tert -butyl.

In the context of the present invention, the meaning is independent of each other for all radicals which occur repeatedly. If radicals are substituted in the compounds according to the invention, the radicals can, unless otherwise specified, be monosubstituted or polysubstituted. Substitution with one or two identical or different substituents is preferred. Particularly preferred is the substitution with a substituent.

A specific embodiment of the present invention comprises compounds of the formula (I) in which the ring A is an aza-heterocycle of the formula

wherein ^* denotes the linkage to the adjacent C (R ^1A ) (R ^1B ) group,

R ^5A and R ^{5B are} identical or different and independently of one another are hydrogen or (C 1 -C 12) -alkyl, R ^{6 is} hydrogen or (C 1 -C ₄ ) -alkyl, and

XO, S or N (R ⁷ ) means in which

R ^{7 represents} cyano, methoxycarbonyl or ethoxycarbonyl,

R ^1A and R ^1B independently of one another are hydrogen or deuterium, R ^{2 is} methyl or ethyl,

R ^{3 is} cyclopropyl, cyclobutyl, cyclopentyl, spiro [3.3] hept-2-yl, 3-oxetanyl or 3-tetrahydrofuranyl, with cyclopropyl, cyclobutyl, cyclopentyl and spiro [3.3] hept-2-yl up to twice, may be the same or different, may be substituted by a radical selected from fluorine, methyl, ethyl, trifluoromethyl and methoxy, and wherein 3-oxetanyl and 3-tetrahydrofuranyl substituted up to two times, identically or differently, by a radical selected from fluorine and methyl can be, and R ^{4 is} methyl, ethyl, n-propyl, 3-fluoropropyl, 3,3-difluoropropyl, 3,3,3-trifluoropropyl, n-butyl, n-pentyl, z o -pentyl or n-hexyl, or

R ^{4 is} a group of formula -CH 2 -R ⁸ wherein

R ^{4 is} a group of formula -CH 2 -CH 2 -OR ⁹ wherein

R ^{9 is} methyl, trifluoromethyl, ethyl or z o-propyl, and their solvates.

Preferred in the context of the present invention are compounds of the formula (I) in which the ring A is an aza-heterocycle of the formula

wherein ^* denotes the linkage to the adjacent C (R ^1A ) (R ^1B ) group,

R ^5A and R ^{5B are} identical or different and independently of one another are hydrogen or methyl, R ^{6 is} hydrogen or methyl, and

X is O or N (R ⁷ ), in which

R ^{7 is} cyano or methoxycarbonyl, and R ^1B both are hydrogen or both are deuterium, is methyl, cyclopropyl, cyclobutyl, cyclopentyl or spiro [3.3] hept-2-yl, where cyclopropyl, cyclobutyl, cyclopentyl and spiro [ 3.3] hept-2-yl up to twice, identically or differently, may be substituted by a radical selected from fluoro, methyl and methoxy, and

R ^{4 is} methyl, ethyl, 2-fluoroethyl, 2,2-difluoroethyl, 2,2,2-trifluoroethyl, n-propyl, 3-fluoro-propyl, 3,3-difluoropropyl, 3,3,3-trifluoropropyl, n Butyl, 4,4,4-trifluorobutyl, n-pentyl or n-hexyl, or R ^{4 is} a group of the formula -CH ₂ -R ⁸ , wherein

R ^{8 is} cyclopropyl, cyclobutyl or 2-tetrahydrofuranyl, where cyclopropyl and cyclobutyl may be substituted up to two times by fluorine, or R ^{4 is} a group of the formula -CH 2 -CH 2 -OR ⁹ , wherein R ^{9 is} methyl or trifluoromethyl, and their solvates.

A further preferred embodiment of the present invention comprises compounds of the formula (I) in which the ring A is an aza-heterocycle of the formula

wherein ^* denotes the linkage to the adjacent C (R ^1A ) (R ^1B ) group,

R ^5A and R ^{5B are the} same or different and are independently hydrogen or methyl, R ^{6 is} hydrogen or methyl, and

X is O or N (R ⁷ ), in which

R ^{7 represents} cyano or methoxycarbonyl,

R ^1A and R ^{1B are} both hydrogen or both are deuterium, R ^{2 is} methyl,

R ^{3 is} cyclopropyl, cyclobutyl, cyclopentyl or spiro [3.3] hept-2-yl, wherein cyclopropyl, cyclobutyl, cyclopentyl and spiro [3.3] hept-2-yl are up to twice, the same or different, selected from fluoro , Methyl and methoxy, and

R ^{4 is} n-propyl, 3-fluoropropyl, 3,3-difluoropropyl, 3,3,3-trifluoropropyl, n-butyl, n-pentyl or n-hexyl, or

R ^{4 is} a group of formula -CH 2 -R ⁸ wherein R ^{8 is} cyclopropyl, cyclobutyl or 2-tetrahydrofuranyl, or

R ^{4 is} a group of the formula -CH 2 -CH 2 -OR ⁹ , wherein R ^{9 is} methyl or trifluoromethyl, and their solvates.

A particular Ausführungsfomi of the present invention relates to compounds of Fomiel (I), in which the ring A for an aza heterocycle of the formula x;

HN ^is > in which ^* the linkage to the adjacent C (R ^1A ) (R ^1B ) group is marked and

X is O or N (R ⁷ ), in which

R ^{7 represents} cyano or methoxycarbonyl, and their solvates. Another particular embodiment of the present invention relates to compounds of the formula (I) in which the ring A is an aza-heterocycle of the formula

stands,

wherein ^* denotes the linkage to the adjacent C (R ^1A ) (R ^1B ) group and R ^5A and R ^{5B are} each hydrogen, and their solvates.

Another particular embodiment of the present invention relates to compounds of the formula (I) in which the ring A is an aza-heterocycle of the formula

stands,

wherein ^* denotes the linkage to the adjacent C (R ^1A ) (R ^1B ) group and

R ^5A and R ^{5B are} each hydrogen, and their solvates.

Another particular embodiment of the present invention relates to compound of formula (I) in which ring A is an aza-heterocycle of the formula

wherein ^* denotes the linkage to the adjacent C (R ^1A ) (R ^1B ) group and

R ^{6 is} hydrogen, and their solvates.

Another particular embodiment of the present invention relates to compounds of the formula (I) in which the ring A for an aza-heterocycle of the formula

stands, where ^* denotes the linkage to the adjacent C (R ^1A ) (R ^1B ) group, as well as their solvates. Another particular embodiment of the present invention relates to compounds of the formula (I) in which

R ^1A and R ^{1B are} both hydrogen and their solvates.

Another particular embodiment of the present invention relates to compounds of the formula (I) in which

R ^{2 is} methyl, and their solvates.

A further particular embodiment of the present invention relates to compounds of the formula (I) in which R ^{3 is} cyclopropyl, cyclobutyl or cyclopentyl, where cyclopropyl, cyclobutyl and cyclopentyl are substituted up to twice, identically or differently, by a radical selected from fluorine and methyl and their solvates.

R ^{4 is} 3-fluoropropyl, 3,3,3-trifluoropropyl or n-butyl, and their solvates. Another particular embodiment of the present invention relates to compounds of the formula (I) in which

R ^{4 is} methyl, ethyl, 2-fluoroethyl, 2,2-difluoroethyl, 2,2,2-trifluoroethyl or n-propyl, and their solvates. Another particular embodiment of the present invention relates to compounds of the formula (I) in which

R ^{4 is} a group of formula -CH 2 -R ⁸ wherein

R ^{8 is} cyclopropyl or cyclobutyl, where cyclopropyl and cyclobutyl may be substituted up to two times by fluorine, and their solvates.

Particularly preferred in the context of the present invention are compounds of the formula (I) in which the ring A is an aza-heterocycle of the formula

stands, wherein ^* denotes the linkage to the adjacent C (R ^1A ) (R ^1B ) group, R ^5A and R ^{5B are} each hydrogen, R ^{6 is} hydrogen, and

X is O or N (R ⁷ ), in which

R ^{7 represents} cyano or methoxycarbonyl,

R ^1A and R ^{1B are} both hydrogen or both are deuterium, R ^{2 is} methyl,

R ^{3 is} cyclopropyl, cyclobutyl or cyclopentyl, where cyclopropyl, cyclobutyl and cyclopentyl may be substituted up to two times, identically or differently, by a radical selected from fluoro and methyl, and R ^{4 is} methyl, ethyl, 2-fluoroethyl, 2, 2-difluoroethyl, 2,2,2-trifluoroethyl, n-propyl, 3-fluoro-propyl, 3,3,3-trifluoropropyl or n-butyl, or

R ^{4 is} a group of formula -CH 2 -R ⁸ wherein

R ^{8 is} cyclopropyl or cyclobutyl, where cyclopropyl and cyclobutyl may be substituted up to two times by fluorine, or

R ^{4 is} a group of formula -CH 2 -CH 2 -OR ⁹ wherein

R ^{9 is} methyl or trifluoromethyl, and their solvates.

Another particularly preferred embodiment of the present invention comprises compounds of the formula (I) in which the ring A is an aza-heterocycle of the formula H VN stands,

wherein ^* denotes the linkage to the adjacent C (R ^1A ) (R ^1B ) group,

R ^5A and R ^{5B are} each hydrogen,

R ^{6 is} hydrogen, and

X is O or N (R ⁷ ), in which

R ^{7 represents} cyano or methoxycarbonyl,

R ^1A and R ^{1B are} both hydrogen or both are deuterium,

R ^{2 is} methyl, R ^{3 is} cyclopropyl, cyclobutyl or cyclopentyl, wherein cyclopropyl, cyclobutyl and cyclopentyl may be substituted up to two times, identically or differently, by a radical selected from fluoro and methyl, and

R ^{4 is} 3-fluoropropyl, 3, 3, 3-trifluoropropyl or n-butyl, or

R ^{4 is} a group of formula -CH 2 -R ⁸ wherein R ^{8 is} cyclopropyl or cyclobutyl, or

R ^{4 is} a group of the formula -CH 2 -CH 2 -OR ⁹ , wherein R ^{9 is} methyl or trifluoromethyl, and their solvates. The residue definitions given in detail in the respective combinations or preferred combinations of residues are also replaced by residue definitions of other combinations, regardless of the particular combinations of the residues indicated.

Very particular preference is given to combinations of two or more of the abovementioned preferred ranges.

The present invention also includes all suitable isotopic variants of the compounds of the invention. An isotopic variant of a compound according to the invention is understood to mean a compound in which at least one atom within the compound according to the invention is exchanged for another atom of the same atomic number but with a different atomic mass than the atomic mass that usually or predominantly occurs in nature. Examples of isotopes which can be incorporated into a compound of the invention are those of hydrogen, carbon, nitrogen, oxygen, phosphorus, sulfur, fluorine, chlorine, bromine and iodine, such as Ή (deuterium), Ή (tritium), ¹³ C, ¹⁴ C, ¹⁵ N, ¹⁷ 0, ¹⁸ 0, ³² P, ³³ P, ³³ S, ³⁴ S, ³⁵ S, ³⁶ S, ¹⁸ F, ³⁶ C1, ⁸² Br, ¹²³ I, ¹²⁴ I, ¹²⁹ I and ¹³¹ I Certain isotopic variants of a compound of the invention, such as those in which one or more radioactive isotopes are incorporated, may be useful, for example, for the study of the mechanism of action or drug distribution in the body; Due to the comparatively easy production and detectability, compounds labeled with ³ H or ¹⁴ C isotopes in particular are suitable for this purpose. In addition, the incorporation of isotopes such as deuterium may result in certain therapeutic benefits as a result of greater metabolic stability of the compound, such as prolonging the body's half-life or reducing the required effective dose; Such modifications of the compounds of the invention may therefore optionally also constitute a preferred embodiment of the present invention. Isotopic variants of the compounds according to the invention can be prepared by generally customary processes known to the person skilled in the art, for example by the methods described below and the rules reproduced in the exemplary embodiments by using corresponding isotopic modifications of the respective reagents and / or starting compounds.

In addition, the present invention also comprises prodrugs of the compounds according to the invention. The term "prodrugs" here denotes compounds which may themselves be biologically active or inactive, but are converted during their residence time in the body by, for example, metabolic or hydrolytic routes to compounds of the invention. Depending on the particular type of aza heterocycle A, the compounds of the formula (I) according to the invention can be prepared in different, in some cases also alternative ways.

Thus, compounds of the formula (1-1) according to the invention

in which the ring A ¹ for an aza-heterocycle of the formula

stands,

wherein ^* denotes the linkage to the adjacent C (R ^1A ) (R ^1B ) group and X has the meaning given above,

R ^1A and R ^{1B are} both hydrogen, and

R ² , R ³ and R ^{4 have} the meanings given above, are prepared by a general method according to the following Reaction Scheme 1:

Thienouracil carbaldehydes of the formula (1) are first reacted with 1,2-diaminoethane (2) in a reductive amination to give the diamino compounds of the formula (3). In particular, sodium cyanoborohydride or sodium borohydride is suitable in each case as reducing agent. were from acetic acid. A suitable solvent is methanol or ethanol, optionally mixed with dichloromethane, and the reaction is preferably carried out in a temperature range between RT and + 70 ° C. It may be advantageous in this reaction in terms of yield and ease of product isolation, instead of the free diamine (2), a carbamate-protected derivative such as tert-butyl (2-aminoethyl) carbamate or benzyl (2-aminoethyl) carbamate to use and then cleave the protective group (teri.-butoxycarbonyl or benzyloxycarbonyl) in the resulting, to (3) analogous amination product by conventional methods again.

The target compounds of the formulas (I-la) and (I-Ib) are obtained by subsequent reaction of the diamino compounds (3) with NN'-carbonyldiimidazole (4) [for (I-la)] or N, N'-thiocarbonyldiimidazole (5 ) [for (I-lb)]. The reactions are preferably carried out at RT and in solvents such as tetrahydrofuran (THF), 1,4-dioxane or dimethyl sulfoxide (DMSO), if appropriate in the presence of a tertiary amine base such as triethylamine. The products of the formula (I-Ic) are obtained by reaction of the diamino compounds (3) with dimethyl N-cyanodithioimino carbonate (6). The reaction is preferably carried out in N, N-dimethylformamide (DMF) as a solvent in the presence of alkali metal carbonates, for example potassium carbonate, as a base at elevated temperatures of + 80 ° C. The products of the formula (I-1d) are obtained by reaction of the diamino compounds (3) with methyl or ethyl (dichloromethylene) carbamate (7). The reaction is preferably carried out in dichloromethane as solvent in the presence of a tertiary amine base, such as triethylamine, at RT. Finally, the products of formula (I-le) are obtained by reaction of diamino compounds (3) with diethyl oxalate (8). The reaction is preferably carried out in ethanol as a solvent at elevated temperatures by + 80 ° C.

Alternatively, compounds of the formula (1-2) according to the invention

in which the ring A ² for an aza-heterocycle of the formula stands,

wherein * denotes the linkage to the adjacent C (R ^1A ) (R ^1B ) group and R ^{7 has} the meaning given above,

R ^1A and R ^{1B are} both hydrogen or both are deuterium, and

R, R and R have the meanings given above, prepared by a general method according to the following Reaction Scheme 2:

Scheme 2

SOCI ₂

ΔΤ, microwave

In the "one pot" variant of this process, an alcohol of formula (9) is first reacted with a chlorinating agent, such as preferably thionyl chloride, in the presence of a tertiary amine base, such as N, N-diisopropylethylamine or triethylamine, into the corresponding chloro compound [corresponding to formula (1 1)] This chlorine compound is not isolated, but in the same reaction vessel with a solution of the deprotonated aza-heterocycle of the formula (10). so as to obtain the target compound of the formula (1-2) in one step. For the deprotonation of the heterocycle (10), strong bases are suitable, such as, for example, alkali metal hydrides or alkali metal amides; Preferably, sodium hydride or lithium hexamethyldisilazide is used. The chlorination step is usually carried out in a halogenated hydrocarbon as inert solvent - preferably dichloromethane here - in the temperature range around 0 ° C. At the same temperature, the solution of the deprotonated heterocycle (10) is added. The substitution reaction to (1-2) then takes place preferably at RT. Suitable solvents for the preparation of the deprotonated heterocycle (10) are in particular N, N-dimethylformamide (DMF), tetrahydrofuran (THF) or mixtures thereof. The deprotonation itself is preferably carried out in a temperature range between 0 ° C and + 60 ° C.

Less hydrolysis-sensitive chlorine compounds of formula (11) can be prepared and also isolated by reacting alcohols of formula (9) with a chlorinating agent, preferably thionyl chloride, in an inert solvent such as chloroform or dichloromethane, as before become. The reaction is preferably carried out in a temperature range between RT and + 80 ° C, wherein for the heating above the boiling point of the particular solvent, the use of a microwave oven, using sealed reaction vessels, has proven to be particularly advantageous. In a subsequent, separate reaction step, the isolated chlorine compounds of the formula (11) are then reacted under similar conditions, as explained above, with a solution of the deprotonated heterocycle (10).

In the process described above, the subject aza-heterocycles of formula (10) can also be used in protected form using a suitable amide protecting group which masks one of the two NH groups, if appropriate or necessary to avoid side reactions , Such amide-protecting groups are familiar to the person skilled in the art [for the suitability, introduction and removal of amide-protecting groups see, for example, US Pat. T.W. Greene and P.G.M. Wuts, Protective Groups in Organic Synthesis, Wiley, New York, 1999].

In a further alternative method, compounds of the formula

(1-3)

in which the ring A ^{3 is} a cyclic urea derivative of the formula

stands,

wherein ^* denotes the linkage to the adjacent C (R ^1A ) (R ^1B ) group, R ^1A and R ^1B both represent hydrogen, and

R ² , R ³ and R ^{4 have} the meanings given above, are prepared according to the following reaction scheme 3: Scheme 3

(14) (9a) Here, aldehydes of the formula (1) are first converted with hydroxylamine into the corresponding oximes of the formula (12). The reaction is preferably carried out at RT using an aqueous hydroxylamine solution in a water-miscible ether, such as tetrahydrofuran (THF), as solvent. The subsequent reduction to the aminomethyl compounds (13) can be achieved by hydrogenation in the presence of a noble metal catalyst. Preferred reaction conditions are 1 bar hydrogen pressure at RT in the presence of a catalytic amount of palladium (5-10% on carbon) in methanol or ethanol as solvent. The hydrogenation is preferably carried out in the presence of aqueous mineral acid, for example concentrated hydrochloric acid. Alternatively, the reduction to the aminomethyl compounds (13) can also be carried out with sodium borohydride in the presence of suitable metal salts, such as nickel or cobalt chloride. Preferred reaction conditions here are the use of sodium borohydride in combination with nickel (II) chloride hexahydrate in methanol as solvent at RT. Another route to the aminomethyl compounds of the formula (13) starts from the alcohols of the formula (9a). These are first converted into the corresponding azides of formula (14) by reacting with Phosphorsäurediphenylesterazid in the presence of an amine base, such as 1,8-diazabicyclo [5.4.0] undec-7-ene (DBU), at 0 ° C to RT in tetrahydrofuran (THF) are reacted. The reduction of the azides (14) to the aminomethyl compounds (13) can then be carried out, for example, by reaction with trimethylphosphine in tetrahydrofuran (THF) and concentrated ammonia water at RT. The aminomethyl compounds of the formula (13) obtained in one of these ways are then reacted in a one-pot process with chloroethyl isocyanate (15), initially forming an open-chain urea derivative. The reaction is preferably carried out at RT in a solvent mixture of N, N-dimethylformamide (DMF) and tetrahydrofuran (THF), or in toluene in the temperature range between + 60 ° C and the boiling point of the solvent. By subsequent addition of a strong base, such as, for example, potassium tert-butoxide, to the reaction mixture, the ring closure then takes place at RT to give the target compounds of the formula (1-3).

Compounds of the formula (1-4) according to the invention

in which the ring A ⁴ for a l, 3-dihydroimidazol-2-one derivative of the formula

wherein ^* denotes the linkage to the adjacent C (R ^1A ) (R ^1B ) group and R ^; have the meanings given above,

R ^1A and R ^{1B are} both hydrogen, and

R ² , R ³ and R ^{4 have} the meanings given above, can be prepared according to the following reaction scheme 4: Scheme 4

Aldehydes of the formula (1) are heated here with aminoacetals or aminoketals of the formula (16) in the sense of a reductive amination first in a suitable solvent, such as methanol or dichloromethane, to reflux and then at RT with sodium triacetoxyborohydride to the compounds of formula (17) reduced. These are then converted with potassium cyanate and aqueous perchloric acid in methanol at RT into the urea derivatives of the formula (18). In the last reaction step acid-catalyzed simultaneous acetal or ketal cleavage and ring closure to the target compounds of formula (1-4). The reaction is carried out in methanol at RT with hydrochloric acid of different concentration (from 0.5 mol / L to concentrated hydrochloric acid).

In formula (16) and the following intermediates (17) and (18) the dimethyl acetal / ketal is shown; However, it is also possible to use other customary acetals or ketals in this process, in particular cyclic ones such as, for example, 1,3-dioxolane or 1,3-dioxane derivatives.

Compounds of the formula (1-5) according to the invention

in which the ring A ^{5 is} a 2,4-dihydro-l, 2,4-triazol-3-one derivative of the formula

stands,

wherein ^* denotes the linkage to the adjacent C (R ^1A ) (R ^1B ) group and is hydrogen,

R ^1A and R are both hydrogen, and R ² , R ³ and R ^{4 have} the meanings given above can be prepared in the general way according to Scheme 5: Scheme 5

[BOC = teri. Butyloxycarbonyl].

Aldehydes of formula (1) are converted by reaction with BOC-protected hydrazine in ethanol and in the presence of a catalytic amount of concentrated hydrochloric acid at RT in the hydrazones of formula (19), which then with sodium cyanoborohydride in methanol at + 65 ° C to the hydra - Zinc derivatives of the formula (20) can be reduced. In the latter reaction, precise control of the pH value plays a major role: in the presence of bromocresol green as an indicator, a pH of about 3-4 is maintained throughout the reaction time by addition of acetic acid in portions. The compounds of formula (20) are then reacted with trimethylsilyl isocyanate to form urea derivatives of formula (21). The reaction is carried out in an alcohol as a solvent, preferably in isopropanol, at elevated temperature, preferably at about + 50 ° C. At the same time, cleavage of the trimethylsilyl group takes place under these conditions. Ring closure to the target compounds of formula (1-5) is achieved by acid-mediated reaction with trimethyl orthoformate. For this purpose, the compounds of formula (21) in the presence of hydrogen chloride with an excess of trimethyl orthoformate in methanol. This reaction is preferably carried out at room temperature.

Compounds of the formula (1-6) according to the invention

in which the ring A ^{6 is} a 2,4-dihydro-l, 2,4-triazol-3-one of the formula

stands,

wherein ^* denotes the linkage to the adjacent C (R ^1A ) (R ^1B ) group and R ^{6 is} as defined above, R ^1A and R ^{1B are} both hydrogen, and

R ² , R ³ and R ^{4 have} the meanings given above can be prepared according to the following Reaction Scheme 6:

Scheme 6

[BOC = tert. Butyloxycarbonyl].

In this process, the protected hydrazine derivative of the formula (20) (see Scheme 5) is first converted with trifluoroacetic acid in dichloromethane into the free hydrazine of the formula (22). The BOC cleavage takes place in a temperature range between 0 ° C and RT, preferably at 0 ° C. In order to avoid a decomposition of the product, no longer reaction time should be selected here than necessary, in addition, subsequent work-up and cleaning operations should be carried out at maximum at RT. In analogy to a previously described, two-stage process [see US Pat. No. 6,077,814, Referential Production Examples 1 -4], the hydrazine of the formula (22) is first reacted with glyoxylic acid (23) [R ⁶ = H] under acid Catalysis to the hydrazone of formula (24) condensed. The reaction is carried out in water in the presence of hydrochloric acid in a temperature range between 0 ° C and RT, preferably at + 10 ° C to + 20 ° C. Subsequently, the hydrazonocarboxylic acid (24) is converted with diphenylphosphoryl azide (DPPA) into the corresponding carboxylic acid azide, which then yields the corresponding isocyanate in situ in the sense of a Curtius rearrangement, which spontaneously cyclizes to the triazolone derivative of the formula (1-6). The reaction is carried out in an inert solvent such as toluene and in the presence of a tertiary amine base such as triethylamine. The reaction is initially carried out in a temperature range between about + 40 ° C and + 80 ° C; in the further course, the reaction temperature is then raised to + 100 ° C to + 110 ° C. By using corresponding 2-oxocarboxylic acids (23), in principle those compounds of the formula (1-6) according to the invention in which R ^{6 is} (C 1 -C ₄ ) -alkyl can also be prepared by this process.

Alternatively, compounds of the formula (1-7) according to the invention

in which the ring A ^{7 is} a 2,4-dihydro-l, 2,4-triazol-3-one of the formula

stands,

wherein ^* denotes the linkage to the adjacent C (R ^1A ) (R ^1B ) group and R ^{6 has} the meaning given above,

R ^1A and R ^{1B are} both hydrogen or both are deuterium, and

R ² , R ³ and R ^{4 have} the meanings given above, are prepared according to the following reaction scheme 7: Scheme 7

Alcohols of the formula (9) are reacted here in the sense of a Mitsunobu reaction directly with an aza heterocycle of the formula (25) to give the target compounds of the formula (1-7). Suitable reagents for this transformation are, for example, triphenylphosphine, polymer-bound triphenylphosphine, tributylphosphine or trimethylphosphine, in each case in combination with diethyl azodicarboxylate (DEAD), diisopropyldiazodicarboxylate (DIAD) or azodicarboxylic acid dipiperidide (ADDP) [cf. z. BDL Hughes, Org. Reactions 42, 335 (1992); DL Hughes, Org. Prep. Proced. Int. 28 (2), 127 (1996)]. The reaction is preferably carried out in tetrahydrofuran (THF) or dichloromethane as solvent in a temperature range between 0 ° C and RT. In this process, the aza heterocycle (25) may also be used in protected form using a suitable amide protecting group which masks the N ⁴ atom of the l, 2,4-triazol-3-one, if desired for avoidance of side reactions is appropriate or necessary. Such amide-protecting groups are familiar to the person skilled in the art [for the suitability, introduction and removal of amide-protecting groups see, for example, US Pat. BTW Greene and PGM Wuts, Protective Groups in Organic Synthesis, Wiley, New York, 1999].

Compounds of the formula (1-8) according to the invention

in which the ring A ⁸ for a l, 2-dihydropyrazol-3-one derivative of the formula

stands,

wherein ^* denotes the linkage to the adjacent C (R ^1A ) (R ^1B ) group and R ^5A and R have the meanings given above, both represent hydrogen, and

R ² , R ³ and R ^{4 have} the meanings given above can be prepared according to the following Reaction Scheme 8:

Scheme 8

The reaction of the hydrazine derivatives of the formula (20) (see Scheme 5) with the acrylic acid chlorides of the formula (26) is carried out under customary conditions, for example in dichloromethane as solvent in a temperature range between 0 ° C. and RT and in the presence of a tertiary amine base such as N, N-diisopropylethylamine. The final acid catalyzed removal of the Boc protecting group and subsequent ring closure to the target compounds of formula (1-8) is carried out at RT in either pure concentrated sulfuric acid or in dichloromethane to which is added a catalytic amount of concentrated sulfuric acid.

The synthesis of the thieno-uracil intermediates of the formulas (1) and (9) [see Schemes 1, 2, 3, 4, 5 and 7] used for the preparation of the compounds according to the invention is shown in the following Reaction Schemes 9-13: Scheme 9

NaOEt

20 ° -50 ° C

s ₂ C0 ₃

[Y = Cl, Br, I or OTs (tosylate)].

2-aminothiophene-3-carboxylic esters of the formula (28) are hereby reacted either with isocyanates of the formula (29) or, after activation with NN'-carbonyldiimidazole (CDI), by reaction with amines of the formula (30) in the ureas of the formula (II) 31). The reaction with the isocyanates (29) is preferably carried out in an ethereal solvent, for example in tetrahydrofuran (THF), and in the presence of a tertiary amine base, for example triethylamine, under reflux conditions, or in pyridine as solvent and base at a temperature of approx + 50 ° C. Activation of the 2-aminothiophene-3-carboxylic acid esters (28) with CDI is also carried out in the presence of a tertiary amine base, such as triethylamine, in an inert solvent, preferably in tetrahydrofuran (THF) or dichloromethane, at RT, and sometimes requires longer reaction times several days. After addition of the amine component (30) to the CDI-activated 2-aminothiophene-3-carboxylic acid ester, rapid further reaction generally takes place at RT to give the ureas of the formula (31). By subsequent treatment with alkali metal alcoholates in the corresponding alcohol as solvent (for example and preferably sodium ethoxide in ethanol), the ring closure to the thieno-uracils of the formula (32) is achieved in a clean reaction. Depending on the substituent R ³ , the reaction takes place already at RT or it requires slightly elevated temperature by + 50 ° C.

Subsequent alkylation with the compounds of formula (33) is carried out in the presence of an inorganic base such as potassium or cesium carbonate in an inert solvent such as, for example and preferably N, N-dimethylformamide (DMF), tetrahydrofuran (THF), acetonitrile or mixtures thereof, carried out. The reaction temperature is usually between RT and about + 100 ° C. In the case of volatile alkylating agents (33), the use of sealed reaction vessels and heating by means of a microwave oven proves to be helpful. Depending on the nature of the leaving group Y, it may be advantageous to carry out the alkylation in the presence of a catalytic amount of potassium iodide. The compounds of the formula (34) thus obtained are then converted in a Vilsmeier-Haack reaction with a mixture of phosphorus oxychloride and N, N-dimethylformamide (DMF) in an exothermic reaction into the aldehydes of the formula (1). Usually, the heat released during the reaction is sufficient to achieve complete conversion. Sometimes, however, it may be necessary to heat the mixture to about + 90 ° C for some time after the reaction heat has subsided.

The above reaction sequence from Alkylierang and formylation can also be carried out in a reversed order by the thienouracils of formula (32) are first under the already described conditions of the Vilsmeier-Haack reaction in the formyl derivatives of the formula (35) are transferred and then the conditions already described with the compounds of formula (33) to the target aldehydes of the formula (1) are alkylated.

Alternatively, the aldehydes of formula (1) may be prepared from the thienouracil derivatives (32) or (34) [see Scheme 9] also by the following general procedure:

Scheme 10

(36)

R-Y (33)

K ₂ C0 ₃ or Cs ₂ C0 ₃

20 ° C-100 ° C

The thienouracils (32) or (34) are in this case firstly converted with a brominating agent into the brominated derivatives of the formula (36) or (37). By alkylation with a compound of formula (33), the brominated thienouracils (36) can be converted into the derivatives of formula (37). At the end of the synthesis sequence, a halogen-metal exchange takes place. Reaction of the thus generated in situ metallated species with a formamide yields the aldehydes of formula (1). Suitable brominating agents are, for example, N-bromosuccinimide (NBS) or elemental bromine; preferred is NBS. The reaction takes place in an inert solvent, for example and preferably in dichloromethane or chloroform, in the temperature range between about 0 ° C. and room temperature. The alkylation of the compounds (36) to the compounds (37) takes place under the same conditions as described above [see Scheme 9: Reaction of (35) to (1) or from (32) to (34)]. The metallation of 6-Bromthienouracile (37) is preferably carried out with tert. Butyllithium in an ethereal solvent, such as preferably tetrahydrofuran, at low temperature of about -78 ° C. At the same temperature, by adding a formamide, preferably N, N-dimethylformamide (DMF), the aldehydes of the formula (1) are obtained.

Instead of the bromine derivatives in the above reaction sequence and the corresponding chlorine or iodine derivatives can be run through, from the compounds of formula (32) or (34), for example by use of N-chlorosuccinimide (NCS), N-iodosuccinimide (NIS) or the elemental halogens (instead of NBS or bromine) are accessible.

Scheme 1 1

NaOEt

20 ° -50 ° C

TFA

or

HCI (gf) / dioxane

[Y = Cl, Br, I or

From 5-aminothiophene-2,4-dicarboxylic esters of the formula (38), the thienouracil-tertiary-butyl esters of the formula (41) can be obtained in a completely analogous manner to the reactions described in Scheme 9 for the preparation of the intermediates (34). Subsequent treatment of the tert. Butyl ester (41) at RT with either trifluoroacetic acid in dichloromethane or a solution of hydrogen chloride in 1,4-dioxane affords the carboxylic acids of formula (42). These can then be prepared either directly by reduction with lithium aluminum hydride [for R ^1A = R ^1B = H] or lithium aluminum deuteride [for R ^1A = R ^1B = D] at about 0 ° C. in an inert solvent such as, for example, and preferably tetrahydrofuran ( THF) into which alcohols of formula (9) are converted, or after prior conversion to the corresponding methyl esters of formula (43). The latter can be obtained in a one-pot process by first converting the carboxylic acids of the formula (42) at RT with oxalyl chloride in dichloromethane in the presence of a catalytic amount of N, N-dimethylformamide (DMF) into the corresponding acid chlorides, which are then quenched with methanol Methyl esters of the formula (43) result.

Scheme 12

LiAlH ₄ or LiAID

THF,

-40 ° C to 0 ° C

[Y = C1, Br, I or OTs].

From diethyl 5-aminothiophene-2,4-dicarboxylates of the formula (44), the thieno-uracilethyl esters of the formula (47) can also be obtained in a completely analogous manner to the reactions described in Scheme 9 for the preparation of the intermediates (34). Subsequent reduction with a complex metal hydride, such as, for example, and preferably lithium aluminum hydride [for R ^1A = R ^1B = H] or lithium aluminum deuteride [for R ^1A = R ^1B = D] then provides in a similar manner as previously described in Scheme 1 1, the alcohols of the formula (9). The reaction is typically carried out in a temperature range between -40 ° C and 0 ° C in an inert solvent, such as by way of example and preferably tetrahydrofuran (THF). Scheme 13

LiAlH ₄ or LiAID ₄

The aldehydes of the formula (1) and alcohols of the formula (9) obtained by one of the processes described above can, if it appears desirable for synthetic purposes, be converted into one another by a number of methods known to the person skilled in the art. Thus, for example, the alcohols of the formula (9) can be oxidized with manganese dioxide in dichloromethane or with sulfur trioxide-pyridine complex in dimethylsulfoxide (DMSO) in each case at RT to form the aldehydes of the formula (1). Conversely, the aldehydes of formula (1) can be reduced to the alcohols of formula (9) with complex hydrides such as lithium aluminum hydride, lithium aluminum deuteride, sodium borohydride or sodium bordeutide. The reduction with lithium aluminum hydride or lithium aluminum deuteride is preferably carried out in tetrahydrofuran (THF) at -78 ° C, while the reduction can be carried out with sodium borohydride or sodium bordeuteride, for example in ethanol at RT. In this way, both the deuterated version of the aldehydes of the formula (1) [R ^1A = D] and alcohols of the formula (9) in which one of the radicals R ^1A and R ^{1B is} hydrogen ( ^ι Ή and the other is deuterium ( ² H) stands, accessible.

Furthermore, compounds of the general formula (I) according to the invention in which R ^1A and / or R ^{1B are} deuterium can be obtained by reacting deuterated aldehydes of the formula (1) [Schemes 1, 3, 4 and 5] or correspondingly deuterated alcohols of the formula (9) [Schemes 2, 3 and 7] or the corresponding deuterated intermediate (20) [Schemes 6 and 8] obtainable therefrom, and the corresponding deuterium variants of the complex metal hydrides listed there (sodium borohydride, sodium triacetoxyborohydride or sodium - Cyanoborhydrid) are used or deuterium is used instead of hydrogen for hydrogenation [Scheme 3].

Alkyl-substituted 2-aminothiophene-3-carboxylic acid esters, such as the compounds of the formula (28) [Scheme 9, where R ² = methyl or ethyl], and alkyl-substituted 5-aminothiophene-2,4-dicarboxylic acid esters, such as the compounds of the formulas (38) and (44) [Schemes 11 and 12, with R ² = methyl or ethyl] can be prepared by a known method via the 3-component reaction of Acetone or 2-butanone or an acetoacetic acid or β-keto-valeric acid ester with an α-cyanoacetic acid ester and elemental sulfur ["Gewald reaction"; see, for example, BP McKibben et al., Tetrahedron Lett. 40, 5471-5474 (1999) and further references cited therein].

The compounds of the above-mentioned formulas (2), (4), (5), (6), (7), (8), (10), (15), (16), (23), (25), (26), (29), (30) and (33) are either commercially available or described as such in the literature or, starting from other commercially available compounds, can be prepared by methods known to those skilled in the art. Numerous detailed regulations and further references are also contained in the Experimental Section in the section on the Preparation of Starting Compounds and Intermediates. The compounds according to the invention have valuable pharmacological properties and can be used for the prevention and treatment of diseases in humans and animals.

The compounds according to the invention are potent and selective antagonists of the adenosine A2b receptor and are therefore suitable for the treatment and / or prevention of diseases and pathological processes, in particular those in which in the course of an inflammatory event and / or a tissue or vascular remodeling of A2b Receptor is involved.

For the purposes of the present invention, these include, in particular, diseases such as the group of interstitial idiopathic pneumonia, including idiopathic pulmonary fibrosis (IPF), acute interstitial pneumonia, non-specific interstitial pneumonia, lymphoid interstitial pneumonia, respiratory bronchiolitis with interstitial lung disease, cryptogenic organizing pneumonia Pneumonia, desquamative interstitial pneumonia, and non-classifiable idiopathic interstitial pneumonia, granulomatous interstitial lung disease, interstitial lung disease of known cause, and other interstitial lung diseases of unknown cause, pulmonary arterial hypertension (PAH), and other forms of pulmonary hypertension (PH) Bronchiolitis obliterans syndrome (BOS), chronic obstructive pulmonary disease (COPD), acute respiratory tract syndrome (ARDS), acute lung injury (ALI), alpha-1-antitrypsin deficiency (AATD), Lu respiratory (e.g. cigarette smoke-induced pulmonary emphysema), cystic fibrosis (CF), inflammatory and fibrotic kidney diseases, chronic enteritis (IBD, Crohn's disease, ulcerative colitis), peritonitis, peritoneal fibrosis, rheumatoid diseases, multiple sclerosis, inflammatory and fibrotic skin diseases, sickle cell anemia, and inflammatory and fibrotic eye diseases.

The compounds according to the invention can furthermore be used for the treatment and / or prevention of asthmatic diseases of different degrees of severity with intermittent tensive or persistent course (refractive asthma, bronchial asthma, allergic asthma, intrinsic asthma, extrinsic asthma, medication or dust-induced asthma), various forms of bronchitis (chronic bronchitis, infectious bronchitis, eosinophilic bronchitis), bronchiectasis, pneumonia, Farmer's lung and related diseases, cough and cold sores (chronic inflammatory cough, iatrogenic cough), nasal mucosal inflammations (including medicinal rhinitis, vasomotor rhinitis and season-dependent allergic rhinitis, eg hay fever) and polyps.

The compounds of the invention may also be used for the treatment and / or prevention of cardiovascular diseases, such as hypertension, heart failure, coronary heart disease, stable and unstable angina, renal hypertension, peripheral and cardial vascular diseases, arrhythmias, atrial arrhythmia and of the ventricles as well as conduction disorders such as atrio-ventricular blockades of grade I-III, supraventricular tachyarrhythmia, atrial fibrillation, atrial flutter, ventricular fibrillation, ventricular flutter, ventricular tachyarrhythmia, torsades de pointes tachycardia, extrasystoles of the atrium and ventricle, atrioventricular extrasystoles, Sick sinus syndrome, syncope, AV nodal reentry tachycardia, Wolff-Parkinson-White syndrome, acute coronary syndrome (ACS), autoimmune heart disease (pericarditis, endocarditis, valvolitis, aortitis, cardiomyopathy), boxer cardiomyopathy, aneurysms, Sch for the treatment and / or prevention of thromboembolic disorders and ischaemias, such as myocardial ischemia, myocardial infarction, stroke, cardiac hypertrophy, transitory and ischemic attacks, preeclampsia, inflammatory cardiovascular diseases, spasms of the coronary arteries and peripheral arteries, edema such as pulmonary edema, cerebral edema, renal edema or congestive heart failure edema, peripheral circulatory disorders, reperfusion injury, arterial and venous thrombosis, microalbuminuria, myocardial insufficiency, endothelial dysfunction, microvascular and macrovascular lesions (vasculitis), and prevention of Restenoses, for example, after thrombolytic therapies, percutaneous transluminal angioplasties (PTAs), percutaneous transluminal coronary angioplasties (PTCAs), heart transplants and bypass surgeries. For the purposes of the present invention, the term cardiac insufficiency includes both acute and chronic manifestations of heart failure, as well as specific or related forms thereof, such as acute decompensated heart failure, right heart failure, left heart failure, global insufficiency, ischemic cardiomyopathy, dilated cardiomyopathy, hypertrophic cardiomyopathy, idiopathic cardiomyopathy, congenital heart defects Heart valve failure, cardiac insufficiency in heart valve defects, mitral valve stenosis, mitral valve Insufficiency, aortic valve stenosis, aortic valve insufficiency, tricuspid stenosis, tricuspid insufficiency, pulmonary valve stenosis, pulmonary valvular insufficiency, combined heart valve defects, myocarditis, chronic myocarditis, acute myocarditis, viral myocarditis, diabetic cardiac insufficiency, alcoholic cardiomyopathy, cardiac storage disorders and diastolic and systolic heart failure ,

The compounds according to the invention are also suitable for the treatment and / or prevention of kidney diseases, in particular renal insufficiency and kidney failure. For the purposes of the present invention, the terms renal insufficiency and renal failure include both acute and chronic manifestations thereof as well as underlying or related renal diseases such as renal hypoperfusion, intradialytic hypotension, obstructive uropathy, glomerulopathies, glomerulonephritis, acute glomerulonephritis, glomerulosclerosis, tubulointerstitial disorders, nephropathic disorders such as primary and congenital kidney disease, nephritis, renal immunological disorders such as renal transplant rejection and immune complex-induced kidney disease, toxicology-induced nephropathy, contrast-induced nephropathy, diabetic and nondiabetic nephropathy, pyelonephritis, renal cysts, nephrosclerosis, hypertensive nephrosclerosis, and nephrotic syndrome. which diagnostically, for example, by abnormally reduced creatinine and / or water excretion, abnormally increased blood concentration urea, nitrogen, potassium and / or creatinine, altered activity of renal enzymes such as e.g. Glutamyl synthase, altered urinary or urine output, increased microalbuminuria, macro albuminuria, glomerular and arteriolar lesions, tubular dilatation, hyperphosphatemia, and / or the need for dialysis. The present invention also encompasses the use of the compounds of the invention for the treatment and / or prevention of sequelae of renal insufficiency, such as hypertension, pulmonary edema, heart failure, uremia, anemia, electrolyte imbalances (e.g., hyperkalemia, hyponatremia) and disorders in bone and carbohydrate metabolism.

In addition, the compounds according to the invention are suitable for the treatment and / or prevention of diseases of the urogenital system, such as benign prostatic syndrome (BPS), benign prostatic hyperplasia (BPH), benign prostate enlargement (BPE), bladder emptying disorders (BOO), lower urinary tract syndromes ( LUTS), neurogenic overactive bladder (OAB), incontinence such as mixed, urgency, stress or overflow incontinence (MUI, UUI, SUI, OUI), pelvic pain, as well as erectile dysfunction and female sexual dysfunction.

In addition, the compounds according to the invention have anti-inflammatory action and can therefore be used as anti-inflammatory agents for the treatment and / or prevention of sepsis (SIRS), multiple organ failure (MODS, MOF), inflammatory kidney disease, chronic enteritis (IBD, Crohn's disease, ulcerative colitis), pancreatitis, peritonitis, cystitis, urethritis, prostatitis, epidymitis, oophoritis, salpingitis, vulvovaginitis, rheumatoid diseases, inflammatory diseases of the central nervous system , Multiple Sclerosis, Inflammatory Skin Diseases and Inflammatory Eye Diseases are used.

The compounds according to the invention are furthermore suitable for the treatment and / or prevention of fibrous diseases of the internal organs, such as, for example, the lung, the heart, the kidney, the bone marrow and in particular the liver, as well as dermatological fibroses and fibroid diseases of the eye , For the purposes of the present invention, the term fibrotic disorders includes in particular such diseases as liver fibrosis, liver cirrhosis, pulmonary fibrosis, endomyocardial fibrosis, nephropathy, glomerulonephritis, interstitial kidney fibrosis, fibrotic damage as a result of diabetes, bone marrow fibrosis, peritoneal fibrosis and similar fibrotic disorders, scleroderma, Morphaea, keloids, hypertrophic scarring, nevi, diabetic retinopathy, proliferative vitroretinopathy and connective tissue diseases (eg sarcoidosis). The compounds of the invention may also be used to promote wound healing, to combat postoperative scarring, e.g. after glaucoma surgery, and for cosmetic purposes on aging or keratinizing skin.

Also, the compounds of the invention may be used for the treatment and / or prevention of anemias, such as hemolytic anemias, especially hemoglobinopathies such as sickle cell anemia and thalassemias, megaloblastic anemias, iron deficiency anemias, acute blood loss anemia, crowding anaemias and aplastic anemias.

The compounds according to the invention are furthermore suitable for the treatment of cancers, such as, for example, skin cancer, brain tumors, head and neck tumors, esophageal cancer, breast cancer, bone marrow tumors, leukemias, liposarcomas, carcinomas of the gastrointestinal tract, liver, pancreas, lung, kidney, Ureter, prostate and genital tract, bladder cancer and malignant tumors of the lymphoproliferative system, such as Hodgkin's and Non-Hodgkin's Lymphoma.

In addition, the compounds according to the invention can be used for the treatment and / or prevention of arteriosclerosis, lipid metabolism disorders and dyslipidemias (hypolipoproteinemia, hypertriglyceridemia, hyperlipidemia, combined hyperlipidemias, hypercholesterolemia, abetalipoproteinemia, sitosterolemia), xanthomatosis, Tangier's disease, obesity (obesity ), Obesity, metabolic disorders (metabolic syndrome, hyperglycemia, insulin-dependent diabetes, non-insulin-dependent diabetes, gestational diabetes, hyperinsulinemia, insulin resistance, glucose intolerance and diabetic sequelae such as Retinopathy, nephropathy and neuropathy), diseases of the gastrointestinal tract and the abdomen (glossitis, gingivitis, periodontitis, esophagitis, eosinophilic gastroenteritis, mastocytosis, Crohn's disease, colitis, proctitis, pruritis ani, diarrhea, celiac disease, hepatitis, liver fibrosis, liver cirrhosis, Pancreatitis and cholecystitis), diseases of the central nervous system and neurodegenerative disorders (stroke, Alzheimer's disease, Parkinson's disease, dementia, epilepsy, depression, multiple sclerosis), immune diseases, thyroid disorders (hyperthyroidism), skin diseases ( Psoriasis, acne, eczema, neurodermatitis, multiple forms of dermatitis such as abacribus dermatitis, dermatitis actinica, dermatitis allergica, ammoniacal dermatitis, dermatitis artefacta, autogenica dermatitis, dermatitis atrophicans, dermatitis calorica, dermatitis, congestion, dermatitis cosmetica, dermatitis escharotica, dermatit is exfoliativa, dermatitis gangrenous, dermatitis haemostatica, dermatitis herpetiformis, dermatitis lichenoides, dermatitis linearis, malignant dermatitis, median catosis, palmaris et plantaris, dermatitis parasitaria, dermatitis photoallergica, dermatitis phototoxica, dermatitis pustularis, dermatitis seborrhoica, dermatitis solaris, dermatitis toxica, ulcerative colitis, dermatitis veneata, infectious dermatitis, pyogenic dermatitis and rosacea-like dermatitis, as well as keratitis, bullosis, vasculitis, cellulitis, panniculitis, lupus erythematosus, erythema, lymphoma, skin cancer, Sweet syndrome, Weber-Christian syndrome, scarring , Wart formation, chilblains), inflammatory eye diseases (saccoidosis, blepharitis, conjunctivitis, iritis, uveitis, choroiditis, ophthalmitis), viral diseases (by influenza, adeno and coronaviruses, such as HPV, HCMV, HIV, SARS), diseases of skeletal bone and joints and skeletal muscle (much multiple forms of arthritis such as arthritis alcaptonurica, arthritis ankylosans, arthritis dysenterica, arthritis exsudativa, arthritis fungosa, arthritis gonorrhoica, arthritis mutilans, psoriatic arthritis, arthritis purulenta, arthritis rheumatica, arthritis serosa, arthritis syphilitica, arthritis tuberculosa, arthritis urica Arthritis villonodularis pigmentosa, atypical arthritis, hemophilic arthritis, juvenile chronic arthritis, rheumatoid arthritis and metastatic arthritis, in addition to the Still syndrome, Felty syndrome, Sjörgen syndrome, Clutton syndrome, Poncet syndrome, Pott syndrome and Reiter syndrome , various forms of arthropathies such as arthropathy deformans, arthropathy neuropathica, ovarian arthropod, arthropathy psoriatica and arthropathy tabica, systemic sclerosis, multiple forms of inflammatory myopathies such as myopathy epidemica, myopathy fibrosa, myopathy myoglobinurica, myopathy ossificans, myopathy ossificans neurot ica, myopathy ossificans progressiva multiplex, myopathy purulenta, myopathy rheumatica, myopathy trichinosa, myopathy tropica and myopathy typhosa, as well as the Günther syndrome and the Münchmeyer syndrome), of inflammatory arterial changes (various forms of arteritis such as endarteritis, mesarteritis, periarteritis, Panarteritis, Rheumatoid Arteritis, Arteritis deformans, Temporal Arteritis, Cranial Arteritis, Giant Arteritis cellularis and granulomatous arteritis, as well as Horton's syndrome, Churg-Strauss syndrome and Takayasu's arteritis), muckle-well syndrome, Kikuchi's disease, polychondritis, scleroderma and other diseases with an inflammatory or immunological component, such as cataracts, cachexia, osteoporosis, gout, incontinence, leprosy, Sezary syndrome and paraneoplastic syndrome, rejection reactions after organ transplantation, and wound healing and angiogenesis especially in chronic wounds.

Because of their property profile, the compounds of the invention are particularly suitable for the treatment and / or prevention of interstitial lung diseases, especially idiopathic pulmonary fibrosis (IPF), as well as pulmonary hypertension (PH), bronchiolitis obliterans syndrome (BOS), chronic obstructive pulmonary diseases (COPD), asthma, cystic fibrosis (CF), myocardial infarction, heart failure, hemoglobinopathies, especially sickle cell anemia, and cancers.

The aforementioned well-characterized human diseases of similar etiology may also be present in other mammals and also be treated there with the compounds of the present invention.

For the purposes of the present invention, the term "treatment" or "treating" includes inhibiting, delaying, arresting, alleviating, attenuating, restraining, reducing, suppressing, restraining or curing a disease, a disease, a disease, an injury or a medical condition , the unfolding, the course or progression of such conditions and / or the symptoms of such conditions. The term "therapy" is understood to be synonymous with the term "treatment".

The terms "prevention", "prophylaxis" or "prevention" are used interchangeably in the context of the present invention and denote the avoidance or reduction of the risk, a disease, a disease, a disease, an injury or a health disorder, a development or a Progression of such conditions and / or to get, experience, suffer or have the symptoms of such conditions.

The treatment or the prevention of a disease, a disease, a disease, an injury or a health disorder can be partial or complete.

Another object of the present invention is thus the use of erfmdungsgemäßen compounds for the treatment and / or prevention of diseases, in particular the aforementioned diseases. Another object of the present invention is the use of the compounds of the invention for the manufacture of a medicament for the treatment and / or prevention of diseases, in particular the aforementioned diseases.

Another object of the present invention is a pharmaceutical composition containing at least one of the compounds of the invention, for the treatment and / or prevention of diseases, in particular the aforementioned diseases.

Another object of the present invention is the use of the compounds of the invention in a method for the treatment and / or prevention of diseases, in particular the aforementioned diseases. Another object of the present invention is a method for the treatment and / or prevention of diseases, in particular the aforementioned diseases, using an effective amount of at least one of the compounds of the invention.

The compounds according to the invention can be used alone or as needed in combination with one or more other pharmacologically active substances, as long as this combination does not lead to undesired and unacceptable side effects. Another object of the present invention are therefore pharmaceutical compositions containing at least one of the compounds of the invention and one or more other active ingredients, in particular for the treatment and / or prevention of the aforementioned diseases. Examples of suitable combination active ingredients include: organic nitrates and NO donors, such as, for example, sodium nitroprusside, nitroglycerin, isosorbide mononitrate, isosorbide dinitrate, molsidomine or SIN-1, and inhaled NO;

Compounds which inhibit the degradation of cyclic guanosine monophosphate (cGMP) and / or cyclic adenosine monophosphate (cAMP), for example inhibitors of phosphodiesterases (PDE) 1, 2, 3, 4 and / or 5, in particular PDE 5 inhibitors such as sildenafil, Vardenafil, Tadalafil, Udenafil, Dasantafil, Avanafil, Mirodenafil or Lodenafil;

• NO- and heme-independent activators of soluble guanylate cyclase (sGC), in particular the compounds described in WO 01/19355, WO 01/19776, WO 01/19778, WO 01/19780, WO 02/070462 and WO 02/070510 ;

NO-independent, but heme-dependent stimulators of soluble guanylate cyclase (sGC), in particular riociguat, nelociguat and vericiguat and those described in WO 00/06568, WO 00 / 06569, WO 02/42301, WO 03/095451, WO 2011/147809, WO 2012/004258, WO 2012/028647 and WO 2012/059549 described compounds;

Prostacyclin analogs and IP receptor agonists, such as by way of example and preferably iloprost, beraprost, treprostinil, epoprostenol or selexipag; Endothelin receptor antagonists such as, by way of example and by way of preference, bosentan, darusentan, ambrisentan or sitaxsentan;

Compounds that inhibit human neutrophilic ecstasy (HNE), such as by way of example, and preferably Sivelestat or DX-890 (Reltran);

The signal transduction cascade inhibiting compounds, by way of example and preferably from the group of kinase inhibitors, in particular from the group of tyrosine kinase and / or

Serine / threonine kinase inhibitors such as, by way of example and by way of illustration, nintedanib, dasatinib, nilotinib, bosutinib, regorafenib, sorafenib, sunitinib, cediranib, axitinib, telatinib, imatinib, brivanib, pazopanib, vatalanib, gefitinib, erlotinib, lapatinib, canertinib, lestaurtinib, Pelitinib, semaxanib or tandutinib; Compounds which inhibit the degradation and remodeling of the extracellular matrix, by way of example and preferably inhibitors of matrix metalloproteases (MMPs), in particular inhibitors of stromelysin, collagenases, gelatinases and aggrecanases (in this case in particular MMP-1, MMP-3, MMP) 8, MMP-9, MMP-10, MMP-11 and MMP-13) and metallo-elastase (MMP-12); Compounds which block the binding of serotonin to its receptor, by way of example and preferably antagonists of the 5-HT2B receptor such as PRX-08066;

Antagonists of growth factors, cytokines and chemokines, by way of example and preferably antagonists of TGF-β, CTGF, IL-1, IL-4, IL-5, IL-6, IL-8, IL-13 and integrins;

The Rho kinase inhibiting compounds, such as by way of example and preferably Fasudil, Y-27632, SLx-2119, BF-66851, BF-66852, BF-66853, KI-23095 or BA-1049;

Compounds which inhibit the soluble epoxide hydrolase (sEH), such as NN'-dicyclohexylurea, 12- (3-adamantan-1-yl-ureido) -dodecanoic acid or 1-adamantan-1-yl-3- {5- [2- (2-ethoxyethoxy) ethoxy] pentyl} urea; the energy metabolism of the heart affecting compounds, such as by way of example and etomoxir, dichloroacetate, ranolazine or trimetazidine; • anti-obstructive agents, such as those used for the treatment of chronic obstructive pulmonary disease (COPD) or bronchial asthma, by way of example and preferably from the group of inhaled or systemically applied beta-adrenergic receptor agonists (beta-mimetics) and the inhaled anti-muscarinergen substances; Anti-inflammatory, immunomodulatory, immunosuppressant and / or cytotoxic agents, by way of example and preferably from the group of systemic or inhaled corticosteroids, and acetylcysteine, montelukast, tipelukast, azathioprine, cyclophosphamide, hydroxycarbamide, azithromycin, IFN-γ, pirfenidone or etanercept;

Antifibrotic agents such as by way of example and preferably pirfenidone, lysophosphatidic acid receptor 1 (LPA-1) antagonists, sphingosine 1-phosphate receptor 3 (SlP3) antagonists, autotaxine inhibitors, FP receptor antagonists , Lysyl oxidase (LOX) inhibitors, lysyl oxidase-like 2 inhibitors, vasoactive intestinal peptide (VIP), VIP analogs, α _v β6 integrin antagonists, interferons, KCa3.1 blockers, CTGF inhibitors, IL 4-antagonists, IL-13 antagonists, TGF-β antagonists, inhibitors of the WNT signaling pathway or CCR2 antagonists; · Therapeutic antibodies as well as antibody-drug conjugates, such as by way of example and preferably bevacizumab, cetuximab, trastuzumab, trastuzumab emtansine, brentuximab ve-dotin or anetumab ravtansine;

Immunotherapeutic antibodies such as, by way of example and by way of limitation, ipilimumab, nivolumab, pembrolizumab (lambrolizumab), PF-06801591, pidilizumab, BMS-936559 (MDX-1105), atezolizumab, durvalumab, avelumab, MEDI-0680 or AMP-224;

Antithrombotic agents, by way of example and preferably from the group of platelet aggregation inhibitors, anticoagulants and profibrinolytic substances;

Antihypertensive agents, by way of example and preferably from the group of calcium antagonists, angiotensin AII antagonists, ACE inhibitors, vasopeptidase inhibitors, endothelin antagonists, renin inhibitors, alpha-receptor blockers, beta-receptors

Blockers, mineralocorticoid receptor antagonists and diuretics;

Lipid metabolizing agents, by way of example and preferably from the group of thyroid receptor agonists, cholesterol synthesis inhibitors such as by way of example and preferably HMG-CoA reductase or squalene synthesis inhibitors, ACAT inhibitors, CETP inhibitors, MTP inhibitors, PPAR inhibitors alpha, PPAR gamma and / or PPAR delta agonists,

Cholesterol absorption inhibitors, lipase inhibitors, polymeric bile acid adsorbents, bile acid reabsorption inhibitors, and lipoprotein (a) antagonists; and or • Chemotherapeutic agents, such as those used for the treatment of neoplasms (neoplasms) of the lungs or other organs.

In a preferred embodiment of the invention, the compounds according to the invention are administered in combination with a beta-adrenergic receptor agonist such as, for example and preferably, albuterol, isoproterenol, metaproterenol, terbutaline, fenoterol, formoterol, repro sterol, salbutamol or salmeterol.

In a preferred embodiment of the invention, the compounds according to the invention are administered in combination with an anti-muscarinergic substance, such as by way of example and preferably ipratropium bromide, tiotropium bromide or oxitropium bromide. In a preferred embodiment of the invention, the compounds according to the invention are administered in combination with a corticosteroid, such as by way of example and preferably prednisone, prednisolone, methylprednisolone, triamcinolone, dexamethasone, beclomethasone, betamethasone, flunisolide, budesonide or fluticasone.

Antithrombotic agents are preferably understood as meaning compounds from the group of platelet aggregation inhibitors, anticoagulants and profibrinolytic substances.

In a preferred embodiment of the invention, the compounds according to the invention are administered in combination with a platelet aggregation inhibitor, such as, by way of example and by way of preference, aspirin, clopidogrel, ticlopidine or dipyridamole. In a preferred embodiment of the invention, the compounds according to the invention are administered in combination with a thrombin inhibitor, such as, by way of example and by way of preference, ximelagatran, melagatran, dabigatran, bivalirudin or Clexane.

In a preferred embodiment of the invention, the compounds according to the invention are administered in combination with a GPIIb / IIIa antagonist, such as, by way of example and by way of preference, tirofiban or abciximab.

In a preferred embodiment of the invention, the compounds according to the invention are used in combination with a factor Xa inhibitor, such as by way of example and preferably rivaraban, apixaban, fidexaban, razaxaban, fondaparinux, idraparinux, DU-176b, PMD-3112, YM-150, KFA -1982, EMD-503982, MCM-17, MLN-1021, DX 9065a, DPC 906, JTV 803, SSR-126512 or SSR-128428. In a preferred embodiment of the invention, the compounds according to the invention are administered in combination with heparin or a low molecular weight (LMW) heparin derivative.

In a preferred embodiment of the invention, the compounds according to the invention are administered in combination with a vitamin K antagonist, such as by way of example and preferably coumarin.

Among the antihypertensive agents are preferably compounds from the group of calcium antagonists, angiotensin AII antagonists, ACE inhibitors, endothelin antagonists, renin inhibitors, alpha-receptor blocker, beta-receptor blocker, mineralocorticoid receptor - understood antagonists and diuretics.

In a preferred embodiment of the invention, the compounds according to the invention are administered in combination with a calcium antagonist, such as, by way of example and by way of preference, nifedipine, amlodipine, verapamil or diltiazem.

In a preferred embodiment of the invention, the compounds according to the invention are administered in combination with an alpha-1-receptor blocker, such as by way of example and preferably prazosin.

In a preferred embodiment of the invention, the compounds according to the invention are used in combination with a beta-receptor blocker, such as by way of example and preferably propranolol, atenolol, timolol, pindolol, alprenolol, oxprenolol, penbutolol, bupranolol, metipropanol, nadolol, mepindolol, carazalol, Sotalol, metoprolol, betaxolol, celiprolol, bisoprolol, Carteolol, esmolol, labetalol, carvedilol, adaprolol, landiolol, nebivolol, epanolol or bucine dolol administered.

In a preferred embodiment of the invention, the compounds according to the invention are administered in combination with an angiotensin AII antagonist, such as by way of example and preferably losartan, candesartan, valsartan, telmisartan, irbesartan, olmesartan, eprosartan or azilsartan.

In a preferred embodiment of the invention, the compounds according to the invention are administered in combination with an ACE inhibitor, such as by way of example and preferably enalapril, captopril, lisinopril, ramipril, delapril, fosinopril, quinopril, perindopril or trandopril. In a preferred embodiment of the invention, the compounds according to the invention are administered in combination with an endothelin antagonist such as, by way of example and by way of preference, bosentan, darusentan, ambrisentan or sitaxsentan.

In a preferred embodiment of the invention, the compounds according to the invention are administered in combination with a renin inhibitor, such as by way of example and preferably aliskiren, SPP-600 or SPP-800.

In a preferred embodiment of the invention, the compounds according to the invention are administered in combination with a mineralocorticoid receptor antagonist, such as by way of example and preferably spironolactone, eplerenone or finerenone. In a preferred embodiment of the invention, the compounds according to the invention are used in combination with a diuretic, such as by way of example and preferably furosemide, bumetanide, torsemide, bendroflumethiazide, chlorothiazide, hydrochlorothiazide, hydroflumethiazide, methyclothiazide, polythiazide, trichloromethiazide, chlorthalidone, indapamide, metolazone, quinethazone, Acetazolamide, dichlorophenamide, methazolamide, glycerol, isosorbide, mannitol, amiloride or triamterene.

Among the lipid metabolizing agents are preferably compounds from the group of CETP inhibitors, thyroid receptor agonists, cholesterol synthesis inhibitors such as HMG-CoA reductase or squalene synthesis inhibitors, the ACAT inhibitors, MTP inhibitors, PPAR alpha , PPAR gamma and / or PPAR delta agonists, cholesterol absorption inhibitors, polymeric bile acid adsorbers, bile acid reabsorption inhibitors, lipase inhibitors and the lipoprotein (a) antagonists understood.

In a preferred embodiment of the invention, the compounds according to the invention are administered in combination with a CETP inhibitor, such as by way of example and preferably torcetrapib (CP-529 414), JJT-705 or CETP vaccine (Avant). In a preferred embodiment of the invention, the compounds of the invention are administered in combination with a thyroid receptor agonist such as, by way of example and by way of preference, D-thyroxine, 3,5,3'-triiodothyronine (T3), CGS 23425 or axitirome (CGS 26214).

In a preferred embodiment of the invention, the compounds according to the invention are administered in combination with an HMG-CoA reductase inhibitor from the class of statins, such as by way of example and preferably lovastatin, simvastatin, pravastatin, fluvastatin, atorvastatin, rosuvastatin or pitavastatin. In a preferred embodiment of the invention, the compounds according to the invention are administered in combination with a squalene synthesis inhibitor, such as by way of example and preferably BMS-188494 or TAK-475.

In a preferred embodiment of the invention, the compounds according to the invention are administered in combination with an AC AT inhibitor such as, for example and preferably, avasimibe, melinamide, pactimibe, eflucimibe or SMP-797.

In a preferred embodiment of the invention, the compounds according to the invention are administered in combination with an MTP inhibitor such as, for example and preferably, implitapide, BMS-201038, R-103757 or JTT-130. In a preferred embodiment of the invention, the compounds of the invention are administered in combination with a PPAR-gamma agonist such as, by way of example and by way of preference, pioglitazone or rosiglitazone.

In a preferred embodiment of the invention, the compounds according to the invention are administered in combination with a PPAR delta agonist, such as by way of example and preferably GW 501516 or BAY 68-5042.

In a preferred embodiment of the invention, the compounds according to the invention are administered in combination with a cholesterol absorption inhibitor, such as by way of example and preferably ezetimibe, tiqueside or pamaqueside.

In a preferred embodiment of the invention, the compounds according to the invention are administered in combination with a lipase inhibitor, such as, for example and preferably, orlistat.

In a preferred embodiment of the invention, the compounds of the invention are administered in combination with a polymeric bile acid adsorbent such as, by way of example and by way of preference, cholestyramine, colestipol, colesolvam, cholesta gel or colestimide. In a preferred embodiment of the invention, the compounds of the invention are used in combination with a bile acid reabsorption inhibitor such as, by way of example and preferably, ASBT (= IBAT) inhibitors such as e.g. AZD-7806, S-8921, AK-105, BARI-1741, SC-435 or SC-635.

In a preferred embodiment of the invention, the compounds according to the invention are administered in combination with a lipoprotein (a) antagonist, such as, for example and preferably, gemcabene calcium (CI-1027) or nicotinic acid. Particular preference is given to combinations of the compounds according to the invention with one or more further active compounds selected from the group consisting of PDE 5 inhibitors, sGC activators, sGC stimulators, prostacyclin analogues, IP receptor agonists, endothelin antagonists, antifibrotic agents, anti-inflammatory, immunomodulatory, immunosuppressive and / or cytotoxic agents and signal transduction cascade inhibiting compounds.

Another object of the present invention are pharmaceutical compositions containing at least one compound of the invention, usually together with one or more inert, non-toxic, pharmaceutically suitable excipients, as well as their use for the purposes mentioned above.

The compounds according to the invention can act systemically and / or locally. For this purpose, they may be applied in a suitable manner, e.g. oral, parenteral, pulmonary, intrapulmonary (inhalation), nasal, intranasal, pharyngeal, lingual, sublingual, buccal, rectal, dermal, transdermal, conjunctival, otic, or as an implant or stent. For these administration routes, the compounds according to the invention can be administered in suitable administration forms.

For the oral administration are according to the prior art functioning, the eriindungsgemäßen compounds rapidly and / or modified donating application forms containing the compounds according to the invention in crystalline and / or amorphized and / or dissolved form, such as. Tablets (uncoated or coated tablets, for example with enteric or delayed-release or insoluble coatings which control the release of the compound of the invention), tablets or films / wafers rapidly breaking down in the oral cavity, films / lyophilisates, capsules (e.g. Soft gelatin capsules), dragees, granules, pellets, powders, emulsions, suspensions, aerosols or solutions.

Parenteral administration may be by circumvention of an absorption step (e.g., intravenous, intraarterial, intracardiac, intraspinal, or intralumbar) or by absorption (e.g., inhalation, intramuscular, subcutaneous, intracutaneous, percutaneous, or intraperitoneal). For parenteral administration are suitable as application forms u.a. Injection and infusion preparations in the form of solutions, suspensions, emulsions, lyophilisates or sterile powders.

For other routes of administration are, for example, inhalant medicines (including powder inhalers, nebulizers, metered aerosols), nasal drops, solutions or sprays, throat sprays, lingual, sublingual or buccal tablets to be applied, films / wafers or capsules, suppositories, eye drops, ointments or baths, ocular inserts, ear drops, sprays, powders, rinses or tampons, vaginal capsules, aqueous suspensions (lotions, shake mixtures), lipophilic suspensions, emulsions, microemulsions, ointments, creams, transdermal therapeutic systems (eg patches), milk, pastes, foams, powdered powders, implants or stents.

Preference is given to oral and parenteral administration, in particular oral, intravenous and intrapulmonary (inhalative) administration.

The compounds of the invention can be converted into the mentioned application forms. This can be done in a manner known per se by mixing with inert, non-toxic, pharmaceutically suitable excipients. These adjuvants include, among others.

• fillers and carriers (for example, cellulose, microcrystalline cellulose such as Avicel ^®, lactose, mannitol, starch, calcium phosphates such as di-Cafos ^®);

Ointment bases (for example Vaseline, paraffins, triglycerides, waxes, wool wax, wool wax alcohols, lanolin, hydrophilic ointment, polyethylene glycols); · Suppository bases (for example, polyethylene glycols, cocoa butter, hard fat);

Solvents (e.g., water, ethanol, isopropanol, glycerol, propylene glycol, medium chain triglycerides, fatty oils, liquid polyethylene glycols, paraffins);

• surfactants, emulsifiers, dispersants or wetting agents (for example sodium dodecyl sulphate, lecithin, phospholipids, fatty alcohols such as Lanette ^®, sorbitan fatty acid esters such as clamping ^®, polyoxyethylene sorbitan fatty acid ester such as Tween ^®, polyoxyethylene fatty acid glycerides such as Cremophor ^®, polyoxyethylene fatty acid ester, polyoxyethylene fatty alcohol ethers, glycerol fatty acid ester, poloxamers such as Pluronic ^®);

Buffer substances and acids and bases (for example phosphates, carbonates, citric acid, acetic acid, hydrochloric acid, sodium hydroxide solution, ammonium carbonate, trometamol, triethanolamine); · Isotonizing agents (for example, glucose, sodium chloride);

Adsorbents (for example highly dispersed silicas);

• viscosity-increasing agents, gelling agents, thickeners or binding agents (e.g., polyvinylpyrrolidone, methyl cellulose, hydroxypropyl cellulose, hydroxypropyl methylcellulose, carboxymethylcellulose sodium, starch, carbomers, polyacrylic acids such as Carbopol ^®, alginates, gelatin); • disintegrants (for example, modified starch, carboxymethylcellulose sodium, sodium stärkeglycolat such as Explotab ^®, cross-linked polyvinylpyrrolidone, croscarmellose sodium, such as AcDiSol ^®);

• flow regulators, lubricants, glidants and mold release agents (for example magnesium stearate, stearic acid, talc, colloidal silicas such as Aerosil ^®);

• coating agent (for example, sugar, shellac,) as well as film-forming agent modified for fast or resolution movies or diffusion membranes (for example, polyvinyl pyrrolidones such as Kollidon ^®, polyvinyl alcohol, ethyl cellulose, hydroxypropyl cellulose, methyl cellulose hydroxypropyl, hydroxypropyl methyl cellulose phthalate, cellulose acetate, Celluloseacetatphtha- lat, polyacrylates, polymethacrylates such as for example, Eudragit ^®);

Capsule materials (e.g., gelatin, hydroxypropyl methylcellulose);

Natural polymers (for example albumins);

• synthetic polymers (for example polylactides, polyglycolides, polyacrylates, polymethacrylates such as Eudragit ^®, polyvinylpyrrolidones such as Kollidon ^®, polyvinyl alcohols, poly vinyl acetates, polyethylene oxides, polyethylene glycols and copolymers thereof and block copolymers);

Plasticizers (for example, polyethylene glycols, propylene glycol, glycerol, triacetin, triacetyl citrate, dibutyl phthalate);

• penetration enhancer; Stabilizers (e.g., antioxidants such as ascorbic acid, sodium ascorbate, ascorbyl palmitate, butylhydroxyanisole, butylhydroxytoluene, propyl gallate);

Preservatives (for example, parabens, sorbic acid, sodium benzoate, thiomersal, benzalkonium chloride, chlorhexidine acetate);

Dyes (e.g., inorganic pigments such as iron oxides, titanium dioxide); · Flavors, sweeteners, flavor and / or smell remedies.

In general, it has proven to be advantageous, when administered parenterally, to administer amounts of active substance of about 0.001 to 1 mg / kg, preferably about 0.01 to 0.5 mg / kg of body weight, in order to achieve effective results. When administered orally, the dosage is about 0.01 to 100 mg / kg, preferably about 0.01 to 20 mg / kg and most preferably 0.1 to 10 mg / kg of body weight. For intrapulmonary administration, the amount of active ingredient is generally about 0.1 to 50 mg per inhalation. Nevertheless, it may be necessary to deviate from the stated amounts of active ingredient, depending on body weight, route of administration, individual behavior towards the active ingredient, type of preparation and time or interval at which the application is carried out. Thus, in some cases it may be sufficient to manage with less than the aforementioned minimum amount, while in other cases, the said upper limit must be exceeded. In the case of the application of larger quantities, it may be advisable to distribute these in several single doses throughout the day.

The following embodiments illustrate the invention. The invention is not limited to the examples.

A. Examples

Abbreviations and acronyms:

Section. absolutely

Ac acetyl

aq. aqueous, aqueous solution

Boc tert. butoxycarbonyl

BPR back pressure regulator (SFC-HPLC)

br wide (at NMR signal)

Example. Example

Bu Butyl

c concentration

about circa, about

cat. catalytic

CDI NN'-carbonyldiimidazole

CI chemical ionization (in MS)

conc. concentrated, concentrated solution

d doublet (by NMR)

d day (s)

TLC thin layer chromatography

DCI direct chemical ionization (in MS)

DCM dichloromethane

dd doublet of doublet (by NMR)

ddd doublet of doublet by doublet (by NMR) de Diastereomeric excess

DIPEA N, N-diisopropylethylamine

the doublet of multiplet (by NMR)

DME 1,2-dimethoxyethane

DMF N, N-dimethylformamide

DMSO dimethyl sulfoxide

dq doublet by quartet (by NMR)

dquin doublet by quintet (by NMR)

dt doublet of triplet (by NMR)

ΔΤ temperature increase, heating (of a reaction mixture) dtd doublet of triplet of doublet (in NMR)

d. Th. Of theory (in chemical yield)

ee enantiomeric excess

EI electron impact ionization (in MS)

eq. Equivalent (s)

ESI electrospray ionization (in MS)

Et ethyl

GC gas chromatography

GC / MS gas chromatography-coupled mass spectrometry

h hour (s)

HPLC high pressure, high performance liquid chromatography

iPr isopropyl

conc. concentrated (at solution)

LC liquid chromatography

LC / MS liquid chromatography-coupled mass spectrometry

Literature (position)

m multiplet (by NMR)

M mol / L (concentration)

Me methyl

min minute (s)

MPLC medium pressure liquid chromatography (over silica gel; also "flash"

Called chromatography ")

MS mass spectrometry

MWD multi-wavelength detector

NBS N-bromosuccinimide

Neg negative, negative ionization in MS NMM N-methylmorpholine

NMO N-methylmorpholine N-oxide

NMP N-methyl-2-pyrrolidinone

NMR nuclear magnetic resonance spectrometry

Pd / C palladium on charcoal

PEG polyethylene glycol

Ph phenyl

pos positive, positive ionization in MS

Pr Propyl

q quartet (by NMR)

quant. quantitative (in chemical yield) quinquint (in NMR)

Rf Retention Index (at DC)

RP reverse phase (reversed phase, for HPLC)

RT room temperature

R _t retention time (for HPLC, LC / MS)

s singlet (by NMR)

sept septet (by NMR)

sext sextet (by NMR)

SFC supercritical liquid chromatography t triplet (by NMR)

TB ME tert. Butyl methyl ether

tBu tert. butyl

td triplet of doublet (by NMR)

TFA trifluoroacetic acid

THF tetrahydrofuran

TMS tetramethylsilane

tq triplet of quartet (by NMR)

Ts / jarotoluenesulfonyl

tt triplet of triplet (by NMR)

UV ultraviolet spectrometry

Vol. Volume

v / v volume to volume ratio (of a solution) together HPLC. LC / MS and GC / MS methods:

Method 1 (LC MS):

Instrament MS: Thermo Scientific FT-MS; UHPLC device: Thermo Scientific UltiMate 3000; Column: Waters HSST3 C18 1.8 μιη, 75 mm x 2.1 mm; Eluent A: 1 liter of water + 0.01% of formic acid; Eluent B: 1 liter acetonitrile + 0.01% formic acid; Gradient: 0.0 min 10%> B-> 2.5 min 95% B -> 3.5 min 95% B; Temperature: 50 ° C; Flow: 0.90 ml / min; UV detection: 210-300 nm.

Method 2 (LC MS):

Instrument: Waters Acquity SQD UPLC System; Column: Waters Acquity UPLC HSS T3 1.8 μιη, 50 mm x 1 mm; Eluent A: 1 l of water + 0.25 ml of 99% strength formic acid, eluent B: 1 l of acetonitrile + 0.25 ml of 99% formic acid; Gradient: 0.0 min 90% A -> 1.2 min 5% A -> 2.0 min 5% A; Temperature: 50 ° C; Flow: 0.40 ml / min; UV detection: 210-400 nm.

Method 3 (LC MS):

Instrument: Waters Acquity SQD UPLC System; Column: Waters Acquity UPLC HSS T3 1.8 μιη, 50 mm x 1 mm; Eluent A: 1 l of water + 0.25 ml of 99% strength formic acid, eluent B: 1 l of acetonitrile + 0.25 ml of 99% formic acid; Gradient: 0.0 min 95% A -> 6.0 min 5% A -> 7.5 min 5% A; Temperature: 50 ° C; Flow: 0.35 ml / min; UV detection: 210-400 nm.

Method 4 (LC / MS):

Instrument: Waters Acquity UPLC-MS SingleQuad; Column: Waters Acquity UPLC BEH C18 1.7 μιη, 50 mm x 2.1 mm; Eluent A: water + 0.1% by volume of formic acid (99%), eluent B: acetonitrile; Gradient: 0.0-1.6 min 1 -99% B, 1.6-2.0 min 99% B; Flow: 0.8 ml / min; Temperature: 60 ° C; DAD scan: 210-400 nm.

Method 5 (LC / MS):

Instrument: Micromass Quattro Premier with Waters UPLC Acquity; Column: Thermo Hypersil GOLD 1.9 μιη, 50 mm x 1 mm; Eluent A: 1 l of water + 0.5 ml of 50% strength formic acid, eluent B: 1 l of acetonitrile + 0.5 ml of 50% strength formic acid; Gradient: 0.0 min 97% A -> 0.5 min 97% A-> 3.2 min 5% A -> 4.0 min 5% A; Temperature: 50 ° C; Flow: 0.30 ml / min; UV detection: 210 nm.

Method 6 (LC / MS):

Instrument: Agilent MS Quad 6150 with HPLC Agilent 1290; Column: Waters Acquity UPLC HSS T3 1.8 μιη, 50 mm x 2.1 mm; Eluent A: 1 l of water + 0.25 ml of 99% formic acid, eluent B: 1 l of acetonitrile + 0.25 ml of 99% formic acid; Gradient: 0.0 min 90% A -> 0.3 min 90% A -> 1.7 min 5% A -> 3.0 min 5% A; Flow: 1.20 ml / min; Temperature: 50 ° C; UV detection: 205-305 nm.

Method 7 (LC MS):

Instrument: Waters Micromass Quattro Micro with HPLC Waters UPLC Acquity; Column: Waters BEH C18 1.7 μιη, 50 mm x 2.1 mm; Eluent A: 1 l of water + 0.01 mol of ammonium formate, eluent B: 1 l of acetonitrile; Gradient: 0.0 min 95% A -> 0.1 min 95% A -> 2.0 min 15% A -> 2.5 min 15% A -> 2.51 min 10% A -> 3.0 min 10% A; Flow: 0.5 ml / min; Temperature: 40 ° C; UV detection: 210 nm.

Method 8 (LC / MS):

Instrument: Waters Single Quad MS System with Waters UPLC Acquity; Column: Waters BEH C18 1.7 μιη, 50 mm x 2.1 mm; Eluent A: 1 l of water + 1.0 ml of ammonia water (25%) / l, eluent B: 1 l of acetonitrile; Gradient: 0.0 min 92% A -> 0.1 min 92% A -> 1.8 min 5% A -> 3.5 min 5% A; Temperature: 50 ° C; Flow: 0.45 ml / min; UV detection: 210 nm (208-400 nm).

Method 9 iGC / MS):

Instrument: Thermo DFS, Trace GC Ultra; Column: Restek RTX-35, 15 m × 200 μιη x 0.33 μιη; constant flow with helium: 1.20 ml / min; Oven: 60 ° C; Inlet: 220 ° C; Gradient: 60 ° C, 30 ° C / min -> 300 ° C (hold for 3.33 min).

Method 10 (preparative HPLC):

Column: Chromatorex C18, 10 μm, 125 mm × 30 mm; Eluent: acetonitrile / water with 0.1% formic acid; Gradient: 30: 70-> 95: 5 within 20 min.

Method 11 (preparative HPLC):

Column: Chromatorex C18, 10 μm, 125 mm × 30 mm; Eluent: acetonitrile / water with 0.1% formic acid; Gradient: 20: 80-> 95: 5 within 20 min.

Method 12 (preparative HPLC):

Column: Chromatorex C18, 10 μm, 125 mm × 30 mm; Eluent: acetonitrile / water with 0.1% formic acid; Gradient: 15: 85-> 95: 5 within 20 min.

Method 13 (preparative HPLC):

Column: Chromatorex C18, 10 μm, 250 mm × 30 mm; Eluent: acetonitrile / water with 0.1% trifluoroacetic acid; Gradient: 10: 90-> 95: 5 within 30 min. Method 14 Preparative HPLC:

Column: Chromatorex C18, 10 μm, 125 mm × 30 mm; Eluent: acetonitrile / water with 0.1% formic acid; Gradient: 10: 90-> 100: 0 within 10 min.

Method 15 Preparative HPLC:

Column: Phenomenex Kinetex C18, 5 μm, 100 mm × 30 mm; Eluent A: water with 2% formic acid, eluent B: acetonitrile; Gradient profile: 0 to 2 minutes 10% B, 2 to 2.2 minutes to 30%> B, 2.2 to 7 minutes to 70% B, 7 to 7.5 minutes to 92% B, 7.5 to 9 minutes 92% B; Flow: 65 ml / min; Room temperature; Wavelength: 200-400 nm.

Method 16 Preparative HPLC:

Column: Reprosil-Pur C18, 10 μm, 250 mm × 30 mm; Eluent A: acetonitrile, eluent B: water with 0.05% trifluoroacetic acid; Gradient: 0.0 min 10% A -> 4.25 min 10% A -> 4.5 min 40% A -> 11.5 min 60% A -> 12.0 min 100% A -> 14.5 min 100% A -> 14.75 min 20% A - > 18.0 min 20% A.

Method 17 preparative HPLC):

Instrument: Waters Prep LC / MS system; Column: Phenomenex Kinetex C18, 5 μm, 100 mm × 30 mm; Eluent A: water with 5 ml of 2% formic acid per 1 L of water, eluent B: acetonitrile; Flow: 65 ml / min; Gradient profile: 0 to 2 minutes 10% B, 2 to 2.2 minutes to 20% B, 2.2 to 7 minutes to 60% B, 7 to 7.5 minutes to 92% B, 7.5 to 9 minutes 92% B; Room temperature; Wavelength: 200-400 nm.

Method 18 preparative HPLC):

Instrument: Waters Prep LC / MS system; Column: XBridge C18, 5 μm, 100 mm × 30 mm; Eluent A: water with 5 ml of 2% formic acid per 1 L of water, eluent B: acetonitrile; Flow: 65 ml / min; Gradient profile: 0 to 2 minutes 10% B, 2 to 2.2 minutes to 20% B, 2.2 to 7 minutes to 60% B, 7 to 7.5 minutes to 92% B, 7.5 to 9 minutes 92% B; Room temperature; Wavelength: 200-400 nm.

More information:

The following descriptions of the coupling patterns of 'H-NMR signals are based on the visual appearance of the signals concerned and do not necessarily correspond to a rigorous, physically correct interpretation. In general, the indication of the chemical shift refers to the center of the relevant signal; In the case of broad multiplets, an interval is usually specified. Melting points and melting ranges, where indicated, are not corrected. In cases in which reaction products were obtained by stirring, stirring or recrystallization, it was often possible to isolate further product quantities from the respective mother liquor by chromatography. The description of this chromatography is omitted below, however, because a large part of the total yield could only be isolated in this step.

For all reactants or reagents, the preparation of which is not explicitly described below, it is true that they were obtained commercially from generally available sources. For all other reactants or reagents, the preparation of which is also not described below, and which were not commercially available or obtained from sources that are not generally available, reference is made to the published literature in which their preparation is described.

Starting Compounds and Intermediates: Example 1A Ethyl 2 - [(cyclopropylcarbamoyl) amino] -4-methylthiophene-3-carboxylate

Method A:

A solution of 3.0 g (15.7 mmol, 97% purity) of ethyl 2-amino-4-methylthiophene-3-carboxylate and 8.8 ml (62.8 mmol) of triethylamine in 80 ml of dichloromethane was treated with 5.09 g (31.4 mmol) of NN-carbonyldiimidazole ( CDI) and stirred for 2 days at RT. Then 2.2 ml (31.4 mmol) of cyclopropylamine were added. After a further 4 h at RT, the reaction mixture was transferred to a separating funnel and washed successively with approximately 50 ml of water and saturated sodium chloride solution. After drying over anhydrous magnesium sulfate, it was filtered and concentrated to dryness. The remaining crude product was purified by MPLC (Biotage Isolera One, cartridge SNAP KP-Sil, 100 g of silica gel, eluent cyclohexane / ethyl acetate 1: 1). After evaporation of the product fractions and drying in a high vacuum, 4.05 g (96% of theory) of the title compound were obtained. 'H-NMR (400 MHz, DMSO-de, δ / ρρηι): 10.34 (broad, 1H), 7.90 (broad, 1H), 6.45 (s, 1H), 4.28 (q, 2H), 2.59-2.63 (m , 1H, partially masked by the DMSO signal), 2.27 (s, 3H), 1.31 (t, 3H), 0.69 (br, m, 2H), 0.46 (br, m, 2H).

LC / MS (Method 2, ESIpos): R _t = 0.99 min, m / z = 269 [M + H] ⁺ . Method B:

A solution of 1.50 g (7.85 mmol, 97% purity) of ethyl 2-amino-4-methylthiophene-3-carboxylate in 7.5 ml of pyridine was treated with 1.31 g (15.7 mmol) of cyclopropyl isocyanate and stirred at 50 ° C for 40 h. It was then concentrated to dryness. The remaining residue was taken up in a little dichloromethane and evaporated again to dryness. This procedure was repeated twice more. After concluding drying in a high vacuum, 2.25 g (100% of theory, 95% purity) of the title compound were obtained, which were used for subsequent reactions without further purification.

Example 2A

Ethyl 4-methyl-2- {[(1-methylcyclopropyl) carbamoyl] amino} thiophene-3-carboxylate

A solution of 4.44 g (23.2 mmol) of ethyl 2-amino-4-methylthiophene-3-carboxylate in 133 ml of dichloromethane was treated with 7.54 g (46.5 mmol) of Ι, Γ-carbonyldiimidazole (CDI) and 13 ml (9.41 mmol) of triethylamine mixed and stirred for 3 days at RT. Then, 5.0 g (46.5 mmol) of 1-methylcyclopropanamine hydrochloride was added to the mixture, and the reaction mixture was further stirred at RT for 4.5 h. The mixture was then washed successively with water and saturated sodium chloride solution. After drying over anhydrous magnesium sulfate, it was filtered and concentrated. There were obtained 6.87 g (98% of theory, 93% purity) of the title compound.

LC / MS (Method 2, ESIpos): R _t = 1.04 min, m / z = 283 [M + H]

Example 3A Ethyl 4-methyl-2- ({[1- (trifluoromethyl) cyclopropyl] carbamoyl} amino) thiophene-3-carboxylate

Analogously to the process described under Example 1A, Method A, from 2.96 g (16.0 mmol) of ethyl 2-amino-4-methylthiophene-3-carboxylate, 5.18 g (32.0 mmol) of CDI and 5.0 g (40.0 mmol) of 1 -Amino-l- (trifluoromethyl) cyclopropane 2.13 g (39% of th.) Of the title compound.

'H-NMR (600 MHz, DMSO-de, δ / ppm): 10.41 (br.s, 1H), 8.76 (br.s, 1H), 6.51 (s, 1H), 4.29 (q, 2H), 2.28 (d, 3H), 1.31 (t, 3H), 1.27 (br, s, 2H), 1.13 (br, s, 2H).

LC / MS (Method 1, ESIpos): R _t = 2.05 min, m / z = 337.08 [M + H] ⁺ .

Example 4A Ethyl 4-methyl-2- {[(2-methylcyclopropyl) carbamoyl] amino} thiophene-3-carboxylate

(Trans-racemate)

A solution of 1.5 g (7.85 mmol) of ethyl 2-amino-4-methylthiophene-3-carboxylate in 7.5 ml of pyridine was admixed with 1.61 g (15.7 mmol) of 1-isocyanato-2-methylcyclopropane (iran-y-racemate). The reaction mixture was stirred at 50 ° C for 15 h. It was then concentrated to dryness on a rotary evaporator. The remaining residue was dissolved in dichloromethane and again concentrated to dryness. This material was then chromatographed on a silica gel cartridge (Biotage, 340 g silica gel, eluent hexane / ethyl acetate 95: 5 → 60:40). 2.16 g (97% of theory) of the title compound were obtained. 'H-NMR (400 MHz, DMSO-d _6, δ / ppm): 11:10 to 10:07 (m, 1H), 8:10 to 7:26 (m, 1H), 6:44 (s, 1H), 4.27 (q, 2H), 2.31-2.21 (m, 4H), 1.30 (t, 3H), 1.13-0.96 (m, 3H), 0.81 (br, s, 1H), 0.60 (br, s, 1H), 0.46 (br, s, 1H ).

LC / MS (Method 4, ESIpos): R _t = 1.29 min, m / z = 282 [M + H] ⁺ . Example 5A

Ethyl 2- {[(2,2-dimethylcyclopropyl) carbamoyl] amino} -4-methylthiophene-3-carboxylate (racemate)

A solution of 1.5 g (7.85 mmol) of ethyl 2-amino-4-methylthiophene-3-carboxylate in 7.5 ml of pyridine was admixed with 1.84 g (15.71 mmol) of racemic 2-isocyanato-1,1-dimethylcyclopropane. The reaction mixture was stirred at 50 ° C for 15 h. It was then concentrated to dryness on a rotary evaporator. The remaining residue was dissolved in dichloromethane and again concentrated to dryness. This material was then chromatographed on a silica gel cartridge (Biotage, 100 g of silica gel, eluent hexane / ethyl acetate 95: 5 → 60:40). 2.32 g (96% of theory) of the title compound were obtained.

'H-NMR (400 MHz, DMSO-de, δ / ppm): 10.35 (br, s, 1H), 7.89 (br, s, 1H), 6.44 (br, s, 1H), 4.27 (q, 2H) , 2.40-2.31 (m, 1H), 2.27 (s, 3H), 1.31 (t, 3H), 1.24-0.95 (m, 6H), 0.65 (br, s, 1H), 0.28 (br, s, 1H) ,

LC / MS (Method 4, ESIpos): R _t = 1.36 min, m / z = 297 [M + H] ⁺ . Example 6A

Ethyl 2- {[(1-ethylcyclopropyl) carbamoyl] amino} -4-methylthiophene-3-carboxylate

Analogously to the process described under Example 1A, Method A, from 1.09 g (5.87 mmol) of ethyl 2-amino-4-methylthiophene-3-carboxylate, 1.33 g (8.22 mmol) of CDI and 1.0 g (8.22 mmol) of 1 -Ethylcyclopropanamine hydrochloride 1.74 g (99% of theory) of the title compound. The reaction time after the addition of the amine was in this case 30 min. On a chromatographic purification could be omitted here; for purification, the crude product was stirred after the aqueous work-up and evaporation with 20 ml of ethyl acetate at RT. 'H-NMR (400 MHz, DMSO-de, δ / ρρηι): 10.21 (br.s, 1H), 8.10 (br.s, 1H), 6.43 (s, 1H), 4.28 (q, 2H), 2.27 (s, 3H), 1.52 (q, 2H), 1.31 (t, 3H), 0.89 (t, 3H), 0.64 (br, s, 4H).

LC / MS (Method 1, ESIpos): R _t = 2.10 min, m / z = 297.13 [M + H] ⁺ .

Example 7A Ethyl 2 - [(cyclobutylcarbamoyl) amino] -4-methylthiophene-3-carboxylate

A solution of 6.31 g (33.0 mmol, 97% purity) of ethyl 2-amino-4-methylthiophene-3-carboxylate and 18.4 ml (132 mmol) of triethylamine in 150 ml of dichloromethane was treated with 10.72 g (66.1 mmol) of CDI and 2 Days at RT stirred. Then 4.70 g (66.1 mmol) of cyclobutylamine were added. After a further 4 h at RT, the reaction mixture was transferred to a separating funnel and washed successively with approximately 100 ml of water and saturated sodium chloride solution. After drying over anhydrous magnesium sulfate, it was filtered and concentrated to dryness. The remaining crude product was purified by MPLC (Biotage Isolera One, cartridge SNAP KP-Sil, 340 g silica gel, eluent cyclohexane / ethyl acetate 5: 1). Evaporation of the product fractions and drying under high vacuum gave 9.30 g (99% of theory) of the title compound.

'H-NMR (400 MHz, DMSO-de, δ / ppm): 10.25 (s, 1H), 8.13 (br.d, 1H), 6.42 (s, 1H), 4.28 (q, 2H), 4.09 (sec , 1H), 2.26 (d, 3H), 2.24-2.15 (m, 2H), 1.94-1.79 (m, 2H), 1.72-1.54 (m, 2H), 1.31 (t, 3H). LC / MS (Method 2, ESIpos): R _t = 1.06 min, m / z = 283 [M + H] ⁺ . Example 8A

Ethyl 2- {[(3,3-difluorocyclobutyl) carbamoyl] amino} -4-methylthiophene-3-carboxylate

A solution of 4.79 g (25.1 mmol, 97% purity) of ethyl 2-amino-4-methylthiophene-3-carboxylate in 144 ml of dichloromethane was treated with 8.13 g (50.2 mmol) of CDI and 14 ml (100 mmol) of triethylamine and 3 Days at RT stirred. Then, 7.20 g (50.2 mmol) of 3,3-difluorocyclobutanamine hydrochloride was added, and the reaction mixture was further stirred at RT overnight. The mixture was then washed successively with about 200 ml each of water and saturated sodium chloride solution. After drying over anhydrous magnesium sulfate, it was filtered and concentrated. The crude product was purified by MPLC (Biotage Isolera One, cartridge SNAP KP-Sil, silica gel, eluent cyclohexane / ethyl acetate 2: 1). After combining the product fractions, concentrating and drying in a high vacuum, 4.96 g (62% of theory) of the title compound were obtained.

'H-NMR (400 MHz, DMSO-de, δ / ppm): 10.37 (s, 1H), 8.37 (d, 1H), 6.46 (s, 1H), 4.29 (q, 2H), 4.09-3.96 (m , 1H), 3.01-2.90 (m, 2H), 2.27 (s, 3H), 1.32 (t, 3H).

LC / MS (Method 1, ESIpos): R _t = 1.99 min, m / z = 319 [M + H] ⁺ . Example 9A

Ethyl 4-methyl-2 - [(oxetan-3-ylcarbamoyl) amino] thiophene-3-carboxylate

Analogously to the process described under Example 7A, 3.0 g (16.2 mmol) of ethyl 2-amino-4-methylthiophene-3-carboxylate, 5.25 g (32.4 mmol) of CDI and 2.37 g (32.4 mmol) of oxetan-3-amine were added to 4.39 g (94% of theory) of the title compound.

'H-NMR (400 MHz, DMSO-de, δ / ppm): 10.39 (s, 1H), 8.62 (br.d, 1H), 6.45 (s, 1H), 4.83-4.69 (m, 3H), 4.46 -4.37 (m, 2H), 4.29 (q, 2H), 2.27 (s, 3H), 1.32 (t, 3H).

LC / MS (Method 1, ESIpos): R _t = 1.61 min, m / z = 285.09 [M + H] Example 10A

Ethyl 4-methyl-2- {[(1-methylcyclobutyl) carbamoyl] amino} thiophene-3-carboxylate

Analogously to the process described under Example 7A, from 4.0 g (21.6 mmol) of ethyl 2-amino-4-methylthiophene-3-carboxylate, 5.25 g (32.4 mmol) of CDI and 3.68 g (43.2 mmol) of 1-methylcyclobutanamine 6.23 g (97% of theory) of the title compound. The reaction time after addition of the amine was 1 h here.

'H-NMR (400 MHz, DMSO-de, δ / ppm): 10.23 (s, 1H), 7.99 (s, 1H), 6.41 (s, 1H), 4.28 (q, 2H), 2.32-2.20 (m , 2H), 2.26 (s, 3H), 1.95-1.84 (m, 2H), 1.84-1.70 (m, 2H), 1.39 (s, 3H), 1.31 (t, 3H). LC / MS (Method 1, ESIpos): R _t = 2.16 min, m / z = 297.13 [M + H] ⁺ .

Example IIA

Ethyl 2- {[(trans-3-methoxycyclobutyl) carbamoyl] amino} -4-methylthiophene-3-carboxylate

A solution of 3.36 g (18.2 mmol) of ethyl 2-amino-4-methylthiophene-3-carboxylate in 105 ml of dichloromethane was admixed with 4.42 g (27.3 mmol) of CDI and 10 ml (72.7 mmol) of triethylamine and kept for 4 days RT stirred. Then, 5.0 g (36.34 mmol) of ira «, γ-3-methoxycyclobutanamine hydrochloride was added to the mixture, and the reaction mixture was further stirred at RT for 2 h. The mixture was then washed successively with water and saturated sodium chloride solution. After drying over anhydrous magnesium sulfate, it was filtered and evaporated. There were obtained 5.61 g (99% of theory) of the title compound. 'H-NMR (400 MHz, DMSO-de, δ / ρρηι): 10.30 (s, 1H), 8.18 (br.s, 1H), 6.42 (s, 1H), 4.28 (q, 2H), 4.18-4.07 (m, 1H), 3.98-3.93 (m, 1H), 3.14 (s, 3H), 2.54 (s, 3H), 2.28-2.19 (m, 2H), 2.13-2.05 (m, 2H), 1.31 (t , 3H).

LC / MS (Method 1, ESIpos): R _t = 1.84 min, m / z = 313 [M + H] ⁺ . Example 12A

Ethyl 2- {[(cis-3-methoxycyclobutyl) carbamoyl] amino} -4-methylthiophene-3-carboxylate

A solution of 3.37 g (18.2 mmol) of ethyl 2-amino-4-methylthiophene-3-carboxylate in 105 ml of dichloromethane was admixed with 4.42 g (27.3 mmol) of CDI and 10 ml (73.0 mmol) of triethylamine and kept for 5 days RT stirred. Then 5.0 g (36.3 mmol) of cw-3-methoxycyclobutanamine hydrochloride were added to the mixture, and the reaction mixture was further stirred at RT for 2 h. The mixture was then washed successively with water and saturated sodium chloride solution. After drying over anhydrous magnesium sulfate, it was filtered and evaporated. There were obtained 5.89 g (100% of theory) of the title compound. 'H-NMR (400 MHz, DMSO-d _6, δ / ppm): 10.27 (s, 1H), 8.10 6:42 (s, 1H), 4.28 (q, 2H), 3.76- (br s, 1H). 3.63 (m, 1H), 3.59-3.52 (m, 1H), 3.13 (s, 3H), 2.61-2.57 (m, 2H), 2.26 (d, 3H), 1.74-1.67 (m, 2H), 1.31 (1.31) t, 3H).

LC / MS (Method 2, ESIpos): R _t = 0.97 min, m / z = 313 [M + H] ⁺ . Example 13A Ethyl 2- {[(3,3-dimethylcyclobutyl) carbamoyl] amino} -4-methylthiophene-3-carboxylate

A solution of 3.41 g (18.4 mmol) of ethyl 2-amino-4-methylthiophene-3-carboxylate in 105 ml of dichloromethane was admixed with 4.48 g (27.7 mmol) of CDI and 10 ml (74.0 mmol) of triethylamine and kept for 3 days RT stirred. Then 5 g (36.9 mmol) of 3,3-dimethylcyclobutanamine hydrochloride were added to the mixture, and the reaction mixture was further stirred at RT for 2 h. The mixture was then washed successively with water and saturated sodium chloride solution. After drying over anhydrous magnesium sulfate, it was filtered and evaporated. There was obtained 6.93 g (100% of T, 86% purity) of the title compound.

'H-NMR (400 MHz, DMSO-de, δ / ppm): 10.26 (s, 1H), 8.08 (br.s, 1H), 6.41 (s, 1H), 4.28 (q, 2H), 4.14-4.04 (m, 1H), 2.26 (s, 3H), 2.11 -2.06 (m, 2H), 1.69-1.64 (m, 2H), 1.31 (t, 3H), 1.12 (s, 3H), 1.10 (s, 3H ).

LC / MS (Method 1, ESIpos): R _t = 2.29 min, m / z = 311 [M + H] ⁺ .

Example 14A

Ethyl 4-methyl-2 - [(spiro [3.3] hept-2-ylcarbamoyl) amino] thiophene-3-carboxylate

Analogously to the process described under Example 7A, from 3.14 g (16.9 mmol) of ethyl 2-amino-4-methylthiophene-3-carboxylate, 4.12 g (25.4 mmol) of CDI and 5.0 g (33.9 mmol) of spiro [3.3] heptan-2-amine hydrochloride 5.35 g (98% of theory) of the title compound. The reaction time after addition of the amine hydrochloride was 1 h here.

'H-NMR (400 MHz, DMSO-de, δ / ppm): 10.24 (s, 1H), 8.06 (brd, 1H), 6.41 (s, 1H), 4.28 (q, 2H), 3.94 (sec , 1H), 2.36-2.28 (m, 2H), 2.26 (d, 3H), 2.04-1.96 (m, 2H), 1.94-1.87 (m, 2H), 1.86-1.72 (m, 4H), 1.31 (t , 3H).

LC / MS (Method 2, ESIpos): R _t = 1.24 min, m / z = 323 [M + H] ⁺ .

Example 15A

Ethyl 2 - [(cyclopentylcarbamoyl) amino] -4-methylthiophene-3-carboxylate

A solution of 4.0 g (21.6 mmol) of ethyl 2-amino-4-methylthiophene-3-carboxylate and 12 ml (86.4 mmol) of triethylamine in 120 ml of dichloromethane was treated with 5.25 g (32.4 mmol) of CDI and

Stirred for 2 days at RT. Then 4.3 ml (43.2 mmol) of cyclo-ethylamine were added. After another hour of stirring at RT, the reaction mixture was transferred to a separating funnel and washed successively with about 100 ml of water and saturated sodium chloride solution. After drying over anhydrous magnesium sulfate, it was filtered and concentrated to dryness. The remaining crude product was purified by MPLC (Biotage Isolera One, cartridge SNAP KP-Sil, 340 g silica gel, eluent cyclohexane / ethyl acetate 2: 1). After evaporation of the product fractions and drying in a high vacuum, 5.96 g (93% of theory) of the title compound were obtained.

'H-NMR (400 MHz, DMSO-de, δ / ppm): 10.26 (s, 1H), 7.86 (br.d, 1H), 6.40 (s, 1H), 4.27 (q, 2H), 3.93 (sec , 1H), 2.26 (s, 3H), 1.82 (dq, 2H), 1.71-1.59 (m, 2H), 1.58-1.47 (m, 2H), 1.45-1.35 (m, 2H), 1.31 (t, 3H ). LC / MS (Method 2, ESIpos): R _t = 1.13 min, m / z = 297 [M + H] ⁺ . Example 16A

3-cyclopropyl-5-methylthieno [2,3-d] pyrimidine-2,4 (lH, 3H) -dione

13.51 g (50.3 mmol) of the compound from Ex. 1A were dissolved in 160 ml of ethanol and admixed with 37.6 ml (101 mmol) of a 21% solution of sodium ethoxide in ethanol. The reaction mixture was stirred initially at RT for 15 h and then at 50 ° C. for 2 h. Thereafter, the reaction mixture was made acidic by addition of 1 M hydrochloric acid. The product failed. It was filtered off with suction, washed neutral with water and dried under high vacuum. This gave 10.95 g (97% of theory) of the title compound. 'H-NMR (400 MHz, DMSO-de, δ / ρρηι): 11.92 (s, 1H), 6.64 (d, 1H), 2.56-2.50 (m, 1H, partially covered by the DMSO signal), 2.33 (i.e. , 3H), 1.09-0.90 (m, 2H), 0.76-0.60 (m, 2H).

LC / MS (method 2 ESIpos): R _t = 0.60 min, m / z = 223 [M + H] ^+.

Example 17A 5-Methyl-3- (1-methylcyclopropyl) thieno [2,3-d] pyrimidine-2,4 (1H, 3H) -dione

6.87 g (22.7 mmol, purity 93%) of the compound from Ex. 2A were dissolved in 214 ml of ethanol and treated with 12.7 ml (34.0 mmol) of sodium ethoxide solution (21 wt .-% in ethanol). The reaction mixture was stirred initially at RT for 16 h and then at 50 ° C. for 16 h. The mixture was then added to ice-water and adjusted to pH 5 with acetic acid. The precipitated solid was filtered off, washed neutral with water and sucked dry (= 1st fraction of the title compound). The mother liquor was extracted with ethyl acetate, and the organic phase was washed with saturated sodium chloride solution. After drying over anhydrous magnesium sulfate, it was filtered and evaporated (= 2nd fraction of the title compound). This gave a total of 4.30 g (77% of theory, 95% purity) of the title compound.

Ή-NMR (400 MHz, DMSO-de, δ / ppm): 11.90 (br.s, 1H), 6.64 (d, 1H), 2.34 (d, 3H), 1.32 (s, 3H), 0.90-0.78 ( m, 4H).

LC / MS (Method 2, ESIpos): R _t = 0.67 min, m / z = 237 [M + H] ⁺ . Example 18A 5-Methyl-3- [1- (trifluoromethyl) cyclopropyl] thieno [2,3-d] pyrimidine-2,4 (1H, 3H) -dione

2.12 g (6.30 mmol) of the compound from Ex. 3A were dissolved in 30 ml of ethanol and treated with 4.7 ml (12.6 mmol) of a 21% strength solution of sodium ethoxide in ethanol. The reaction mixture was stirred at RT for about 16 h. Thereafter, it became acidic by addition of 1 M hydrochloric acid posed. The product failed. It was filtered off with suction, washed neutral with water and dried under high vacuum. 1.67 g (91% of theory) of the title compound were obtained.

Ή-ΝΜΡ (400 MHz, DMSO-d ₆ , δ / ppm): 12.16 (s, 1H), 6.70 (d, 1H), 2.34 (d, 3H), 1.65-1.46 (m, 2H), 1.41-1.26 (m, 2H). LC / MS (Method 2, ESIpos): R _t = 1.43 min, m / z = 291 [M + H] ⁺ .

Example 19A

5-Methyl-3- (2-methylcyclopropyl) thieno [2,3-d] pyrimidine-2,4 (1H, 3H) -dione (trans-racemate)

2.15 g (7.63 mmol) of the compound from Ex. 4A were dissolved in 25 ml of ethanol and treated with 5.7 ml (15.3 mmol) of a 21% solution of sodium ethoxide in ethanol. After the mixture had been stirred at RT for about 20 h, 17.5 ml of 1 M hydrochloric acid were added. The resulting precipitate was filtered off with suction, washed neutral with water and dried. 1.72 g (95% of theory) of the title compound were obtained.

Ή-NMR (400 MHz, DMSO-de, δ / ppm): 11.93 (br.s, 1H), 6.68-6.59 (m, 1H), 2.33 (d, 3H), 2.17 (dt, 1H), 1.14 ( d, 3H), 1.05-0.92 (m, 1H), 0.89-0.74 (m, 2H).

LC / MS (Method 4, ESIpos): R _t = 0.89 min, m / z = 237 [M + H] ⁺ .

Example 20A

3- (2,2-Dimethylcyclopropyl) -5-methylthieno [2,3-d] pyrimidine-2,4 (1H, 3H) -dione (racemate)

2.31 g (7.81 mmol) of the compound from Ex. 5A were dissolved in 21.3 ml of ethanol and admixed with 5.8 ml (15.6 mmol) of a 21% strength solution of sodium ethoxide in ethanol. After the mixture was stirred at RT for 62 h, it was added with 18 ml of 1 M hydrochloric acid. The thereby fallen precipitate was filtered off with suction, washed neutral with water and dried. 1.69 g (84% of theory) of the title compound were obtained.

'H-NMR (400 MHz, DMSO-de, δ / ppm): 11.95 (br.s, 1H), 6.64 (d, 1H), 2.36-2.29 (m, 4H), 1.16 (s, 3H), 1.01 (dd, 1H), 0.86 (s, 3H), 0.78-0.72 (m, 1H). LC / MS (Method 4, ESIpos): R _t = 0.99 min, m / z = 251 [M + H] ⁺ .

Example 21A

3- (l-ethylcyclopropyl) -5-methylthieno [2,3-d] pyrimidine-2,4 (lH, 3H) -dione

1.73 g (5.84 mmol) of the compound from Ex. 6A were dissolved in 20 ml of ethanol and admixed with 3.9 ml (10.5 mmol) of a 21% solution of sodium ethoxide in ethanol. The reaction mixture was stirred at 50 ° C for about 16 h. Thereafter, it was first concentrated to about half of the original volume and then made acidic by addition of 1 M hydrochloric acid. The product failed. It was filtered off with suction, washed neutral with water and dried under high vacuum. 1.27 g (86% of theory) of the title compound were obtained. Ή-NMR (400 MHz, DMSO-d _6, δ / ppm): 11.88 (s, 1H), 6.63 (d, 1H), 2:33 (d, 3H), 1.68 (qd, 2H), 0.98-0.91 (m , 1H), 0.91-0.86 (m, 1H), 0.85-0.77 (m, 2H), 0.81 (t, 3H).

LC / MS (Method 1, ESIpos): R _t = 1.43 min, m / z = 251.08 [M + H] ⁺ .

Example 22A

3-cyclobutyl-5-methylthieno [2,3-d] pyrimidine-2,4 (lH, 3H) -dione

920 g (32.6 mmol) of the compound from Ex. 7A were dissolved in 90 ml of ethanol and admixed with 24.3 ml (65.2 mmol) of a 21% solution of sodium ethoxide in ethanol. The reaction mixture was stirred initially at RT for 15 h and then at 50 ° C. for 1 h. Thereafter, the reaction tion mixture acidified by addition of 1 M hydrochloric acid. The product failed. It was filtered off with suction, washed neutral with water and dried under high vacuum. There were obtained 6.48 g (84% of theory) of the title compound.

Ή-ΝΜΡ (400 MHz, DMSO-d ₆ , δ / ppm): 12.00 (s, 1H), 6.65 (d, 1H), 5.23 (quin, 1H), 2.98-2.80 (m, 2H), 2.34 (i.e. , 3H), 2.12 (qt, 2H), 1.88-1.61 (m, 2H).

LC / MS (Method 2, ESIpos): R _t = 0.80 min, m / z = 237 [M + H] ⁺ .

Example 23A

3- (3,3-difluorocyclobutyl) -5-methylthieno [2,3-d] pyrimidine-2,4 (lH, 3H) -dione

4.96 g (14.5 mmol) of the compound from Ex. 8A were dissolved in 137 ml of ethanol and admixed with 7 ml of sodium ethoxide solution (21% by weight in ethanol). The reaction mixture was stirred for 3 h at RT and then added to ice-water and adjusted to pH 5 with acetic acid. The precipitated solid was filtered off, washed neutral with water and sucked dry. There was obtained 3.92 g (99% of theory) of the title compound. 'H-NMR (400 MHz, DMSO-d _6, δ / ppm) 12.15 (s, 1H), 6.69 (d, 1H), 5.14 (q, 1H), 3:58 to 3:46 (m, 2H), 2.86- 2.76 (m, 2H), 2.34 (d, 3H).

LC / MS (Method 1, ESIpos): R _t = 1.56 min, m / z = 273 [M + H] ⁺ . Example 24A

5-methyl-3- (oxetan-3-yl) thieno [2,3-d] pyrimidine-2,4 (lH, 3H) -dione

Analogously to the process described under Example 18A, from 4.30 g (15.1 mmol) of the compound from Ex. 9A, 3.04 g (84% of theory) of the title compound were prepared. The reaction time was 1 h here. 'H-NMR (400 MHz, DMSO-de, δ / ρρηι): 12.14 (s, 1H), 6.69 (s, 1H), 5.07-4.94 (m, 1H), 4.78-4.71 (m, 2H), 4.70 -4.64 (m, 2H), 2.32 (s, 3H).

LC / MS (Method 1, ESIpos): R _t = 0.96 min, m / z = 239.05 [M + H] ⁺ . Example 25A 5-Methyl-3- (1-methylcyclobutyl) thieno [2,3-d] pyrimidine-2,4 (1H, 3H) -dione

Analogously to the process described in Example 16A, from 6.23 g (21.0 mmol) of the compound from Example 10A, 4.51 g (86% of theory) of the title compound were prepared.

Ή-NMR (400 MHz, DMSO-de, δ / ppm): 11.83 (s, 1H), 6.63 (d, 1H), 2.39-2.20 (m, 4H), 2.31 (d, 3H), 1.80-1.57 ( m, 2H), 1.51 (s, 3H).

LC / MS (Method 1, ESIpos): R _t = 1.54 min, m / z = 251.08 [M + H] ⁺ .

Example 26A

3- (irani'-3-Methoxycyclobutyl) -5-methylthieno [2,3-d] pyrimidm-2,4 (lH, 3H) -dione

5.61 g (18.0 mmol) of the compound from Ex. 11A were dissolved in 170 ml of ethanol and admixed with 10 ml of sodium ethoxide solution (21% by weight in ethanol). The reaction mixture was stirred at RT overnight, then added to ice-water, adjusted to pH 5 with acetic acid and extracted with dichloromethane. The organic phase was washed with water and saturated sodium chloride solution. After drying over anhydrous magnesium sulfate, the mixture was filtered and concentrated. There were obtained 4.48 g (92% of theory) of the title compound.

'H-NMR (400 MHz, DMSO-de, δ / ppm): 12.06 (s, 1H), 6.67 (d, 1H), 5.51-5.43 (m, 1H), 4.15-4.08 (m, 1H), 3.16 (s, 3H), 2.98-2.91 (m, 2H), 2.34 (d, 3H), 2.23-2.17 (m, 2H). LC / MS (Method 2, ESIpos): R _t = 0.71 min, m / z = 267 [M + H] ⁺ .

Example 27A

-dione -3-Methoxycyclobutyl) -5-methylthieno [2,3-d] pyrimidine-2,4 (lH, 3H)

5.89 g (18.9 mmol) of the compound from Ex. 12A were dissolved in 180 ml of ethanol and treated with 11 ml of sodium ethoxide solution (21 wt .-% in ethanol). The reaction mixture was stirred at RT overnight, then added to ice-water, adjusted to pH 5 with acetic acid and extracted with dichloromethane. The organic phase was washed with water and saturated sodium chloride solution. After drying over anhydrous magnesium sulfate, the mixture was filtered and concentrated. There were obtained 4.65 g (92% of theory) of the title compound.

Ή-NMR (400 MHz, DMSO-de, δ / ppm): 12.01 (s, 1H), 6.67 (d, 1H), 4.75-4.66 (m, 1H), 3.67-3.60 (m, 1H), 3.16 ( s, 3H), 2.83-2.76 (m, 2H), 2.54 (s, 3H), 2.52-2.44 (m, 2H).

LC / MS (Method 2, ESIpos): R _t = 1.27 min, m / z = 267 [M + H] ⁺ .

Example 28A 3- (3,3-Dimethylcyclobutyl) -5-methylthieno [2,3-d] pyrimidine-2,4 (1H, 3H) -dione

6.92 g (19.2 mmol, 86% purity) of the compound from Example 13A were dissolved in 181 ml of ethanol and treated with 11 ml of sodium ethoxide solution (21 wt .-% in ethanol). Since the reaction after stirring overnight at RT was not complete, the mixture was stirred for a further 5 h at 50 ° C. The reaction mixture was then added to ice-water and adjusted to pH 5 with acetic acid. The precipitated solid was filtered off, washed neutral with water and sucked dry. There were obtained 5.66 g (100% of theory, 92% purity) of the title compound, which were used without further purification for subsequent reactions. LC / MS (Method 1, ESIpos): R _t = 1.85 min, m / z = 265 [M + H] ⁺ . Example 29A

5-methyl-3- (spiro [3.3] hept-2-yl) thieno [2,3-d] pyrimidine-2,4 (lH, 3H) -dione

Analogously to the process described under Example 16A, from 5.32 g (16.5 mmol) of the compound from Example 14A, 4.33 g (94% of theory) of the title compound were prepared.

'H-NMR (400 MHz, DMSO-de, δ / ppm): 11.97 (s, 1H), 6.65 (d, 1H), 5.06 (quin, 1H), 2.94-2.81 (m, 2H), 2.33 (s , 3H), 2.20 (td, 2H), 2.10-2.02 (m, 2H), 2.01-1.93 (m, 2H), 1.86-1.75 (m, 2H).

LC / MS (Method 1, ESIpos): R _t = 1.93 min, m / z = 277.10 [M + H] ⁺ . Example 30A

3-cyclopentyl-5-methylthieno [2,3-d] pyrimidine-2,4 (lH, 3H) -dione

5.96 g (20.1 mmol) of the compound from Ex. 15A were dissolved in 60 ml of ethanol and admixed with 15 ml (40.2 mmol) of a 21% solution of sodium ethoxide in ethanol. The reaction mixture was stirred at 50.degree. C. for about 16 h. Thereafter, it was acidified by the addition of 1 M hydrochloric acid. The product failed. It was filtered off with suction, washed neutral with water and dried under high vacuum. 4.86 g (96% of theory) of the title compound were obtained.

Ή-NMR (400 MHz, DMSO-de, δ / ppm): 12.01 (s, 1H), 6.66 (d, 1H), 5.25 (quin, 1H), 2.34 (d, 3H), 2.12-1.98 (m, 2H), 1.95-1.81 (m, 2H), 1.79-1.65 (m, 2H), 1.61-1.47 (m, 2H). LC / MS (Method 2, ESIpos): R _t = 0.87 min, m / z = 251 [M + H] ⁺ . Example 31A

3-cyclopropyl-5-methyl-2,4-dioxo-l, 2,3,4-tetrahydrothieno [2,3-d] pyrimidine-6-carbaldehyde

A solution of 10.95 g (49.3 mmol) of the compound from Ex. 16A in 37.9 ml (493 mmol) of DMF was cautiously admixed with 55.1 ml (591 mmol) of phosphorus oxychloride. After the strongly exothermic reaction had subsided, the mixture was stirred for a further 15 min. Thereafter, the reaction mixture was carefully stirred into 1.5 liters of water. After about 15 h stirring at RT, the precipitated product was filtered off with suction, washed neutral with water and dried under high vacuum. 12.32 g (99% of theory) of the title compound were obtained. 'H-NMR (400 MHz, DMSO-d _6, δ / ppm): 12:41 (s, 1H), 5.10 (s, 1H), 2.74 (s, 3H), 2:58 to 2:52 (m, 1H, partially obscured by DMSO signal), 1.08-0.91 (m, 2H), 0.78-0.62 (m, 2H).

LC / MS (Method 1, ESIpos): R _t = 1.04 min, m / z = 251.05 [M + H] ⁺ .

Example 32A

5-Methyl-3- (1-methylcyclopropyl) -2,4-dioxo-1,2,3,4-tetrahydrothieno [2,3-d] pyrimidine-6-carbaldehyde

A solution of 10.0 g (42.3 mmol) of the compound from Ex. 17A in 32.6 ml (423 mmol) of DMF was carefully mixed with 47.3 ml (508 mmol) of phosphorus oxychloride. After the strongly exothermic reaction had subsided, the mixture was stirred for a further 15 min. Then it was carefully stirred into 1.5 liters of water. After about 15 h stirring at RT, the precipitated product was filtered off with suction, washed neutral with water and dried under high vacuum. There were obtained 10.50 g (94% of theory) of the title compound.

Ή-NMR (400 MHz, DMSO-de, δ / ppm): 12.40 (s, 1H), 10.05 (s, 1H), 2.75 (s, 3H), 1.33 (s, 3H), 0.91-0.82 (m, 4H). LC / MS (Method 1, ESIpos): R _t = 1.21 min, m / z = 265.06 [M + H] ⁺ . Example 33A

5-Methyl-2,4-dioxo-3- [1- (trifluoromethyl) cyclopropyl] -1,3,3,4-tetrahydrothieno [2,3-d] pyrimidine-6-carbaldehyde

Analogously to the process described under Example 31A, 1.66 g (5.72 mmol) of the compound from Ex. 18A, 6.4 ml (68.6 mmol) of phosphorus oxychloride and 4.4 ml (57.2 mmol) of DMF were admixed with 1.80 g (99% of theory) of Title compound prepared. The product was stirred with water for only 1 h. Ή-NMR (400 MHz, DMSO-d _6, δ / ppm): 12.66 (br s, 1H.), 7.10 (s, 1H), 2.75 (s, 3H), 1.68-1.46 (m, 2H), 1:42 -1.27 (m, 2H).

LC / MS (Method 2, ESIpos): R _t = 0.76 min, m / z = 319 [M + H] ⁺ . Example 34A

5-Methyl-3- (2-methylcyclopropyl) -2,4-dioxo-1,2,3,4-tetrahydrothieno [2,3-d] pyrimidine-6-carbaldehyde (trans-racemate)

A solution of 1.67 g (7.09 mmol) of the compound from Ex. 19A in 67 ml of DMF was carefully mixed with 6.6 ml (70.9 mmol) of phosphorus oxychloride while cooling with an ice bath. The mixture was stirred for 1 h at 70 ° C and then concentrated as much as possible on a rotary evaporator. The resulting residue was added to ice-water and stirred. The precipitated product was filtered off with suction, washed neutral with water and dried. 1.46 g (72% of theory) of the title compound were obtained.

'H-NMR (400 MHz, DMSO-de, δ / ppm): 12.42 (br.s, 1H), 10.04 (s, 1H), 2.73 (s, 3H), 2.19 (dt, 1H), 1.14 (i.e. , 3H), 1.05-0.94 (m, 1H), 0.89-0.77 (m, 2H). LC / MS (Method 4, ESIpos): R _t = 0.88 min, m / z = 265 [M + H] ⁺ . Example 35A

3- (2,2-Dimethylcyclopropyl) -5-methyl-2,4-dioxo-1,2,3,4-tetrahydrothieno [2,3-d] pyrimidine aldehyde (racemate)

A solution of 1.64 g (6.4 mmol) of the compound from Ex. 20A in 60 ml of DMF was cautiously combined with 6 ml (64.1 mmol) of phosphorus oxychloride while cooling with an ice bath. The mixture was stirred for 1 h at 70 ° C and then concentrated as much as possible on a rotary evaporator. The resulting residue was added to ice-water and stirred. The precipitated product was filtered off with suction, washed neutral with water and dried. There were obtained 1.57 g (88% of theory) of the title compound.

Ή-NMR (400 MHz, DMSO-de, δ / ppm): 12.45 (br.s, 1H), 10.05 (s, 1H), 2.74 (s, 3H), 2.34 (dd, 1H), 1.16 (s, 3H), 1.03 (dd, 1H), 0.88 (s, 3H), 0.79-0.69 (m, 1H).

LC / MS (Method 4, ESIpos): R _t = 0.97 min, m / z = 279 [M + H] ⁺ . Example 36A

3- (1-Ethylcyclopropyl) -5-methyl-2,4-dioxo-1,2,3,4-tetrahydrothieno [2,3-d] pyrimidine-6-carbaldehyde

Analogously to the process described under Example 31A, from 1.26 g (5.03 mmol) of the compound from Ex 21A, 4.7 ml (50.3 mmol) phosphorus oxychloride and 4.7 ml (60.4 mmol) DMF 1.30 g (92% of theory) of Title compound prepared. The product was stirred with water only for 2 h.

'H-NMR (400 MHz, DMSO-de, δ / ppm): 12.38 (br.s, 1H), 10.04 (s, 1H), 2.74 (s, 3H), 1.74-1.62 (m, 2H), 1.01 -0.75 (m, 4H), 0.82 (t, 3H). LC / MS (Method 1, ESIpos): R _t = 1.39 min, m / z = 279.08 [M + H] ⁺ .

Example 37A

3-cyclobutyl-5-methyl-2,4-dioxo-l, 2,3,4-tetrahydrothieno [2,3-d] pyrimidine-6-carbaldehyde

A solution of 6.40 g (27.1 mmol) of the compound from Ex. 22A in 20.8 ml (271 mmol) of DMF was carefully mixed with 30.3 ml (325 mmol) of phosphorus oxychloride. After the strongly exothermic reaction had subsided, the mixture was stirred for a further 15 min. Thereafter, the reaction mixture was carefully stirred into 1 liter of water. After about 1 h stirring at RT, the precipitated product was filtered off with suction, washed neutral with water and dried in a high vacuum. There were obtained 7.11 g (99% of theory) of the title compound.

Ή NMR (400 MHz, DMSO-de, δ / ppm): 12.47 (s, 1H), 10.05 (s, 1H), 5.16 (quin, 1H), 2.91-2.78 (m, 2H), 2.74 (s, 3H), 2.15 (qt, 2H), 1.90-1.62 (m, 2H).

LC / MS (Method 2, ESIpos): R _t = 0.79 min, m / z = 265 [M + H] ⁺ .

Example 38A 3- (3,3-Difluorocyclobutyl) -5-methyl-2,4-dioxo-1,2,3,4-tetrahydrothieno [2,3-d] pyrimidine-6-carbaldehyde

A solution of 3.92 g (14.4 mmol) of the compound from Ex. 23A in 11 ml of DMF was treated with 12.7 ml (137 mmol) of phosphorus oxychloride. After the strongly exothermic reaction subsided, the mixture was stirred for 45 minutes without further heat. Then, the reaction mixture was carefully stirred into 1200 ml of ice-cold water. After stirring for 16 h, the precipitated product was filtered off with suction, washed neutral with water and dried. 4.20 g (97% of theory) of the title compound were obtained. LC / MS (Method 1, ESIpos): R _t = 1.46 min, m / z = 301 [M + H] ⁺ .

Example 39A

5-Methyl-3- (1-methylcyclobutyl) -2,4-dioxo-1,2,3,4-tetrahydrothieno [2,3-d] pyrimidine-6-carbaldehyde

Analogously to the process described under Ex. 37A, 5.56 g (22.2 mmol) of the compound from Ex. 25A, 24.8 ml (267 mmol) phosphorus oxychloride and 17.1 ml (222 mmol) DMF were converted into 5.96 g (96% of theory) of the Title compound prepared.

Ή-NMR (400 MHz, DMSO-de, δ / ppm): 12.34 (s, 1H), 10.05 (s, 1H), 2.72 (s, 3H), 2.42-2.18 (m, 4H), 1.82-1.58 ( m, 2H), 1.51 (s, 3H).

LC / MS (Method 2, ESIpos): R _t = 0.83 min, m / z = 279 [M + H] ⁺ .

Example 40A

3 - (trans -methoxycyclobutyl) -5-methyl-2,4-dioxo-1,2,3,4-tetrahydrothieno [2,3-d] pyrimidine-6-carbaldehyde

A solution of 4.43 g (16.6 mmol) of the compound from Ex. 26A in 13 ml of DMF was admixed with 15 ml (160 mmol) of phosphorus oxychloride. After the strongly exothermic reaction had subsided, the mixture was stirred for 1 h without further heat. Then, the reaction mixture was carefully stirred into 1200 ml of ice-cold water. After stirring for 16 h, the precipitated product was filtered off with suction, washed neutral with water and dried. There were obtained 4.47 g (85% of theory, 94% purity) of the title compound, which were used without further purification for subsequent reactions.

'H-NMR (400 MHz, DMSO-de, δ / ppm): 12.53 (s, 1H), 10.06 (s, 1H), 5.48-5.37 (m, 1H), 4.13-4.10 (m, 1H), 3.16 (s, 3H), 2.96-2.89 (m, 2H), 2.75 (s, 3H), 2.25-2.19 (m, 2H). LC / MS (Method 2, ESIpos): R _t = 0.69 min, m / z = 295 [M + H] ⁺ . Example 41A

3- (di'-3-methoxycyclobutyl) -5-methyl-2,4-dioxo-1,2,3,4-tetrahydrothieno [2,3-d] pyrimidine-6-carbaldehyde

A solution of 4.66 g (17.1 mmol) of the compound from Ex. 27A in 13 ml of DMF was admixed with 15 ml (162 mmol) of phosphorus oxychloride. After the strongly exothermic reaction had subsided, the mixture was stirred for another 30 minutes without further heat. Then, the reaction mixture was carefully stirred into 1.7 liters of ice-cold water. After stirring for 16 h, the precipitated product was filtered off with suction, washed neutral with water and dried. There were obtained 3.99 g (60% of theory, 76% purity) of the title compound, which were used without further purification for subsequent reactions.

LC / MS (Method 1, ESIpos): R _t = 1.21 min, m / z = 295 [M + H] ⁺ .

Example 42A 3- (3,3-Dimethylcyclobutyl) -5-methyl-2,4-dioxo-1,2,3,4-tetrahydrothieno [2,3-d] pyrimidine-6-carbaldehyde

A solution of 5.50 g (19.0 mmol, 92% purity) of the compound from Ex. 28A in 15 ml of DMF was admixed with 17 ml (181 mmol) of phosphorus oxychloride. After the strongly exothermic reaction had subsided, the mixture was stirred for another 30 minutes without further heat. Then, the reaction mixture was carefully stirred into 2 liters of ice-cold water. After stirring for 16 h, the precipitated product was filtered off with suction, washed neutral with water and dried. There were 4.80 g (87%) d. Th.) Of the title compound, which were used without further purification for subsequent reactions. LC / MS (Method 1, ESIpos): R _t = 1.80 min, m / z = 293 [M + H] ⁺ . Example 43A

5-Methyl-2,4-dioxo-3- (spiro [3.3] hept-2-yl) -1,3,3,4-tetrahydrothieno [2,3-d] pyrimidine-6-carbaldehyde

Analogously to the process described under Ex. 37A, 4.32 g (15.6 mmol) of the compound from Ex. 29A, 14.5 ml (188 mmol) of phosphorus oxychloride and 12 ml (156 mmol) of DMF were converted to 4.73 g (99% of theory) of Title compound prepared.

'H-NMR (400 MHz, DMSO-de, δ / ppm): 12.45 (br.s, 1H), 10.04 (s, 1H), 5.07-4.92 (m, 1H), 2.88-2.78 (m, 2H) , 2.73 (s, 3H), 2.28-2.18 (m, 2H), 2.11-2.02 (m, 2H), 2.02-1.93 (m, 2H), 1.88-1.74 (m, 2H).

LC / MS (Method 2, ESIpos): R _t = 1.00 min, m / z = 305 [M + H] ⁺ . Example 44A

3-cyclopentyl-5-methyl-2,4-dioxo-l, 2,3,4-tetrahydrothieno [2,3-d] pyrimidine-6-carbaldehyde

A solution of 4.85 g (19.4 mmol) of the compound from Ex. 30A in 14.9 ml (194 mmol) of DMF was added carefully with 21.7 ml (233 mmol) of phosphorus oxychloride. After the strongly exothermic reaction had subsided, the mixture was stirred for a further 15 min. Thereafter, the reaction mixture was carefully stirred into 1.5 liters of water. After about 1 h stirring at RT, the precipitated product was filtered off with suction, washed neutral with water and dried under high vacuum. There was obtained 5.11 g (91% of theory, 97% purity) of the title compound.

Ή NMR (400 MHz, DMSO-de, δ / ppm): 12.49 (s, 1H), 10.06 (s, 1H), 5.23 (quin, 1H), 2.75 (s, 3H), 2.11-1.96 (m, 2H), 1.95-1.82 (m, 2H), 1.81-1.68 (m, 2H), 1.62-1.47 (m, 2H). LC / MS (Method 6, ESIpos): R _t = 1.14 min, m / z = 279 [M + H] ⁺ . Example 45A 1- (2-Methoxyethyl) -5-methyl-3- (1-methylcyclopropyl) thieno [2,3-d] pyrimidine-2,4 (1H, 3H) -dione

33.0 g (140 mmol) of the compound of Ex. 17A and 48.25 g (349 mmol) of potassium carbonate were stirred for 30 min at RT in 400 ml of anhydrous DMF before 26.3 ml (279 mmol) of (2-bromoethyl) methyl ether were added. Then the reaction mixture was stirred at RT for about 16 h. It was then mixed with water and stirred for 30 min at RT. The precipitated product was filtered off, washed with water and dried under high vacuum. There were obtained 33.54 g (81% of theory) of the title compound.

Ή NMR (400 MHz, DMSO-de, δ / ppm): 6.76 (d, 1H), 4.20-3.81 (m, 2H), 3.62 (t, 2H), 3.24 (s, 3H), 2.36 (d, 3H), 1.34 (s, 3H), 1.01-0.72 (m, 4H).

LC / MS (Method 1, ESIpos): R _t = 1.62 min, m / z = 295.11 [M + H] ⁺ .

Example 46A 5-Methyl-3- (oxetan-3-yl) -1- (3,3,3-trifluorophenyl) thieno [2,3-d] pyrimidine-2,4 (1H, 3H) -dione

Analogously to the process described under Example 45A, from 1.42 g (5.96 mmol) of the compound from Ex. 24A and 4.0 g (17.9 mmol) of 1,1'-trifluoro-3-iodopropane were dissolved 1.75 g (87% of theory). ) of the title compound. 'H-NMR (400 MHz, DMSO-de, δ / ρρηι): 6.89 (d, 1H), 5.04 (quin, 1H), 4.79-4.64 (m, 4H), 4.08 (t, 2H), 2.75 (qt , 2H), 2.35 (d, 3H).

LC / MS (Method 1, ESIpos): R _t = 1.63 min, m / z = 335.07 [M + H] ⁺ . Example 47A 6-Bromo-5-methyl-3- (oxetan-3-yl) -1- (3,3,3-trifluorophenyl) thieno [2,3-d] pyrimidine-2,4 (1H, 3H ) -dione

A solution of 1.75 g (5.24 mmol) of the compound from Ex. 46A in 30 ml of dichloromethane was admixed at 0 ° C. with 978 mg (5.50 mmol) of N-bromosuccinimide (NBS). The cold bath was removed and the reaction mixture was stirred at RT for 1 h. It was then concentrated to dryness on a rotary evaporator. The remaining residue was taken up in ethyl acetate and washed successively with water and saturated sodium chloride solution. After drying over anhydrous magnesium sulfate, it was filtered and concentrated again. There were obtained 2.17 g (96% of theory, 96% purity) of the title compound.

Ή-NMR (400 MHz, DMSO-de, δ / ppm): 5.04 (quin, 1H), 4.83-4.58 (m, 4H), 4.05 (t, 2H), 2.75 (qt, 2H), 2.32 (s, 3H).

LC / MS (Method 1, ESIpos): R _t = 1.99 min, m / z = 412.98 / 414.98 [M + H] ⁺ .

Example 48A

3-cyclopropyl-l, 5-dimethyl-2,4-dioxo-l, 2,3,4-tetrahydrothieno [2,3-d] pyrimidine-6-carbaldehyde

500 mg (2.0 mmol) of the compound from Example 31A and 976 mg (3.0 mmol) of cesium carbonate were stirred for 10 min at RT in 10 ml of anhydrous DMF, before 284 μΐ (3.0 mmol) of dimethyl sulfate were added. were added. Then the reaction mixture was heated in a microwave oven (Biotage Initiator with dynamic control of the Einstrahlleistung) for 1 h at 60 ° C. After cooling to RT, the reaction mixture was mixed with water and stirred at RT for 30 min. The precipitated product was filtered off, washed with water and dried under high vacuum. 440 mg (83% of theory) of the title compound were obtained.

'H-NMR (400 MHz, DMSO-de, δ / ppm): 10.07 (s, 1H), 3.43 (s, 3H), 2.77 (s, 3H), 2.61 (tt, 1H), 1.10-0.94 (m , 2H), 0.78-0.63 (m, 2H).

LC / MS (Method 1, ESIpos): R _t = 1.27 min, m / z = 265.06 [M + H] ⁺ . Example 49A 1-Butyl-3-cyclopropyl-5-methyl-2,4-dioxo-1,2,3,4-tetrahydrothieno [2,3-d] pyrimidine-6-carbaldehyde

Analogously to the process described under Example 45A, from 500 mg (2.00 mmol) of the compound from Example 31A and 735 mg (4.00 mmol) of n-butyl iodide 515 mg (84% of theory) of the title compound were prepared. Ή-NMR (400 MHz, DMSO-d ₆ , δ / ppm): 10.07 (s, 1H), 3.89 (t, 2H), 2.77 (s, 3H), 2.66-2.57 (m, 1H), 1.65 (quin , 2H), 1.35 (sext, 2H), 1.07-0.97 (m, 2H), 0.91 (t, 3H), 0.75-0.65 (m, 2H).

LC / MS (Method 1, ESIpos): R _t = 1.83 min, m / z = 307.11 [M + H] ⁺ .

Example 50A

3-Cyclopropyl-1- (3-fluoropropyl) -5-methyl-2,4-dioxo-1,2,3,4-tetrahydrothieno [2,3-d] pyrimidine-6-carbaldehyde

A solution of 390 mg (1.56 mmol) of the compound from Ex. 31A in 16.2 ml of DMF was admixed with 538 mg (3.89 mmol) of potassium carbonate and stirred at RT for 15 min. Then, 879 mg (4.67 mmol) of 1-fluoro-3-iodopropane was added, and the mixture was stirred at 50 ° C for 17 hours. The DMF was distilled off as far as possible and the residue obtained was partitioned between half-saturated sodium chloride solution (100 ml) and ethyl acetate (50 ml). The water phase was extracted with ethyl acetate. The combined organic phases were dried over sodium sulfate, filtered and concentrated. The resulting residue was chromatographed on a silica gel cartridge (Biotage, 50 g of silica gel, eluent hexane / ethyl acetate 92: 8 → 34:66). There were obtained 391 mg (80% of theory) of the title compound.

Ή-NMR (400 MHz, DMSO-de, δ / ppm): 10.08 (s, 1H), 4.60 (t, 1H), 4.48 (t, 1H), 4.00 (t, 2H), 2.77 (s, 3H) , 2.65-2.56 (m, 1H), 2.14-2.06 (m, 1H), 2.06-1.99 (m, 1H), 1.05-0.98 (m, 2H), 0.73-0.66 (m, 2H).

LC / MS (Method 4, ESIpos): R _t = 0.95 min, m / z = 311 [M + H] ⁺ . Example 51A

3-Cyclopropyl-5-methyl-2,4-dioxo-1- (3,3,3-trifluoropropyl) -l, 2,3,4-tetrahydrothieno [2,3-d] pyrimidine-6-carbaldehyde

900 mg (3.60 mmol) of the compound from Example 31A and 1.24 g (9.0 mmol) of potassium carbonate were stirred for 15 min at RT in 30 ml of anhydrous DMF before 1.3 ml (10.8 mmol) of 1,1-trifluoro-3-iodo - propane were added. The reaction mixture was then stirred for 2 h at RT and then ßend stirred at 50 ° C for about 16 h. After cooling to RT, water was added and extracted with ethyl acetate. The organic extract was concentrated and the residue was purified by MPLC (Biotage Isolera One, cartridge SNAP KP-Sil, 10 g silica gel, eluent cyclohexane / ethyl acetate 2: 1). After evaporation of the product fractions and drying in a high vacuum, 1.07 g (85% of theory) of the title compound were obtained.

'H-NMR (400 MHz, DMSO-de, δ / ppm): 10.09 (s, 1H), 4.13 (t, 2H), 2.87-2.69 (m, 2H), 2.78 (s, 3H), 2.63 (t , 1H), 1.09-0.96 (m, 2H), 0.75-0.65 (m, 2H).

LC / MS (Method 2, ESIpos): R _t = 0.89 min, m / z = 347 [M + H] ⁺ .

Example 52A 1- (Cyclobutylmethyl) -3-cyclopropyl-5-methyl-2,4-dioxo-1,2,3,4-tetrahydrothieno [2,3-d] pyrimidine-6-carbaldehyde

500 mg (2.00 mmol) of the compound from Example 31A and 690 mg (5.00 mmol) of potassium carbonate were stirred for 15 min at RT in 10 ml of anhydrous DMF before 449 μΐ (4.00 mmol) (bromomethyl) cyclobutane were added. Then the reaction mixture was stirred at 50 ° C for about 16 h. After cooling to RT, water was added and extracted with ethyl acetate. The organic extract was washed with saturated sodium chloride solution, dried over anhydrous magnesium sulfate, filtered and concentrated. The product was isolated by MPLC (Biotage Isolera One, cartridge SNAP KP-Sil, 50 g silica gel, eluent cyclohexane / ethyl acetate 2: 1). Evaporation of the product fractions and drying under high vacuum gave 486 mg (76% of theory) of the title compound.

'H-NMR (400 MHz, DMSO-de, δ / ppm): 10.07 (s, 1H), 3.96 (d, 2H), 2.82-2.69 (m, 1H), 2.76 (s, 3H), 2.66-2.58 (m, 1H), 2.04-1.91 (m, 2H), 1.89-1.74 (m, 4H), 1.07-0.96 (m, 2H), 0.73-0.64 (m, 2H).

LC / MS (Method 1, ESIpos): R _t = 1.89 min, m / z = 319.11 [M + H] Example 53A

3-Cyclopropyl-l - [(2,2-difluorocyclopropyl) methyl] -5-methyl-2,4-dioxo-1,2,3,4-tetrahydrothieno [2,3-d] pyrimidine-6-carbaldehyde ( racemate)

Analogously to the process described under Example 52A, from 1.0 g (4.00 mmol) of the compound from Ex. 31A and 1.02 g (6.00 mmol) of racemic 2- (bromomethyl) -1,3-difluorocyclopropane 980 mg (72% of theory) Th.) Of the title compound. The reaction was in this case not at 50 ° C, but at RT.

'H-NMR (400 MHz, DMSO-de, δ / ppm): 10.09 (s, 1H), 4.17 (ddd, 1H), 3.95 (dd, 1H), 2.78 (s, 3H), 2.67-2.58 (m , 1H), 2.30-2.12 (m, 1H), 1.78-1.62 (m, 1H), 1.49 (dtd, 1H), 1.10-0.94 (m, 2H), 0.79-0.64 (m, 2H).

LC / MS (Method 1, ESIpos): R _t = 1.68 min, m / z = 341.08 [M + H] ⁺ . Example 54A

(3-Cyclopropyl-6-formyl-5-methyl-2,4-dioxo-3,4-dihydro-thieno [2,3-d] pyrimidin-1 (2H) -yl) acetonitrile

Analogously to the process described under Example 52A, from 500 mg (2.00 mmol) of the compound from Ex. 31A and 479 mg (4.00 mmol) of bromoacetonitrile 240 mg (40% of theory) of the title compound were prepared. The reaction was in this case not at 50 ° C, but at RT. 'H-NMR (400 MHz, DMSO-d _6, δ / ppm): 10.10 (s, 1H), 5.18 (s, 2H), 2.78 (s, 3H), 2.69-2.59 (m, 1H), 1.12- 0.94 (m, 2H), 0.81-0.63 (m, 2H). LC / MS (Method 1, ESIpos): R _t = 1.30 min, m / z = 290.06 [M + H] ⁺ . Example 55A

3-Cyclopropyl-1- (2-methoxyethyl) -5-methyl-2,4-dioxo-1,2,3,4-tetrahydrothieno [2,3-d] pyrimidine-6-carbaldehyde

1.0 g (4.00 mmol) of the compound of Ex. 31A and 1.38 g (10.0 mmol) of potassium carbonate were stirred for 15 min at RT in 35 ml of anhydrous DMF before 751 μΐ (8.00 mmol) of (2-bromoethyl) methyl ether were added. Then the reaction mixture was stirred at 50 ° C for about 16 h. After cooling to RT, water was added and extracted with ethyl acetate. The organic extract was washed successively with water and saturated sodium chloride solution, dried over anhydrous magnesium sulfate, filtered and concentrated. The product was isolated by MPLC (Biotage Isolera One, cartridge SNAP KP-Sil, 100 g silica gel, eluent cyclohexane / ethyl acetate 2: 1). After evaporation of the product fractions and drying in a high vacuum, a first fraction of 942 mg of the title compound was obtained. A likewise obtained mixed fraction was concentrated and the residue was purified by preparative HPLC (Method 11). This gave, after evaporation of the product fractions and drying under high vacuum, a second fraction of 120 mg of the title compound. Overall, 1.06 g (86% of theory) of the title compound were thus obtained.

Ή-NMR (500 MHz, DMSO-de, δ / ppm): 10.07 (s, 1H), 4.06 (t, 2H), 3.64 (t, 2H), 3.24 (s, 3H), 2.76 (s, 3H) , 2.67-2.58 (m, 1H), 1.07-0.97 (m, 2H), 0.75-0.68 (m, 2H).

LC / MS (Method 1, ESIpos): R _t = 1.36 min, m / z = 309.09 [M + H] ⁺ .

Example 56A

3-Cyclopropyl-1- (2-ethoxyethyl) -5-methyl-2,4-dioxo-1,2,3,4-tetrahydrothieno [2,3-d] pyrimidine-6-carbaldehyde

500 mg (2.00 mmol) of the compound of Ex. 31A and 690 mg (5.00 mmol) of potassium carbonate were stirred for 15 min at RT in 10 ml of anhydrous DMF before 611 mg (4.00 mmol) of (2-bromoethyl) ethyl ether were added. Then the reaction mixture was stirred at 50 ° C for about 16 h. Subsequently, it was mixed with water and stirred at RT for 30 min. The precipitated product was filtered off, washed with water and dried under high vacuum. This gave a first fraction of 222 mg of the title compound. The filtrate was extracted with ethyl acetate. The organic extract was washed successively with water and saturated sodium chloride solution, dried over anhydrous magnesium sulfate, filtered and concentrated. From this residue, a second fraction of 232 mg of the title compound was isolated by MPLC (Biotage Isolera One, cartridge SNAP KP-Sil, 50 g of silica gel, eluent cyclohexane / ethyl acetate 2: 1). In total, 454 mg (70% of theory) of the title compound were thus obtained.

'H-NMR (400 MHz, DMSO-de, δ / ppm): 10.07 (s, 1H), 4.05 (t, 2H), 3.67 (t, 2H), 3.44 (q, 2H), 2.76 (s, 3H ), 2.62 (tt, 1H), 1.09-0.96 (m, 2H), 1.03 (t, 3H), 0.76-0.66 (m, 2H). LC / MS (Method 1, ESIpos): R _t = 1.55 min, m / z = 232.11 [M + H] ⁺ .

Example 57A

3-Cyclopropyl-1- (2-isopropoxyethyl) -5-methyl-2,4-dioxo-1,2,3,4-tetrahydrothieno [2,3-d] pyrimidine-6-carbaldehyde

Analogously to the process described in Example 52A, from 500 mg (2.00 mmol) of the compound from Example 31A and 667 mg (4.00 mmol) of (2-bromoethyl) -isopropyl ether, 513 mg (74% of theory) of the title compound were obtained ,

'H-NMR (400 MHz, DMSO-de, δ / ppm): 10.07 (s, 1H), 4.02 (t, 2H), 3.66 (t, 2H), 3.56 (sept, 1H), 2.76 (s, 3H ), 2.63 (tt, 1H), 1.07-0.97 (m, 2H), 1.01 (d, 6H), 0.74-0.65 (m, 2H).

LC / MS (Method 1, ESIpos): R _t = 1.71 min, m / z = 337.12 [M + H] ⁺ .

Example 58A

3-Cyclopropyl-5-methyl-2,4-dioxo-1- [2- (trifluoromethoxy) ethyl] -1,2,3,4-tetrahydrothieno [2,3-d] pyrimidine-6-carbaldehyde

500 mg (2.00 mmol) of the compound of Ex. 31A and 690 mg (5.00 mmol) of potassium carbonate were stirred for 15 min at RT in 10 ml of anhydrous DMF before 771 mg (4.00 mmol) of 1-bromo-2- (trifluoromethoxy) ethane [commercially available; Ref: PE Aldrich, WA Sheppard, J. Org. Chem. 29 (1), 11-15 (1964)]. Then, the reaction mixture was first stirred for about 16 h at RT and then at 50 ° C for about 24 h. After cooling to RT, water was added and extracted with ethyl acetate. The organic extract was washed successively with water and saturated sodium chloride solution, dried over anhydrous magnesium sulfate, filtered and concentrated. After drying the residue under high vacuum, 592 mg (81% of theory) of the title compound were obtained. Ή-NMR (400 MHz, DMSO-d _6, δ / ppm): 8.10 (s, 1H), 4:45 to 4:35 (m, 2H), 4:30 to 4:18 (m, 2H), 2.77 (s, 3H), 2.67 -2.59 (m, 1H), 1.08-0.97 (m, 2H), 0.77-0.65 (m, 2H).

LC / MS (Method 2, ESIpos): R _t = 0.90 min, m / z = 363 [M + H] ⁺ .

Example 59A

3-Cyclopropyl-5-methyl-2,4-dioxo-1 - (tetrahydrofuran-2-ylmethyl) -1,2,3,4-tetrahydrothieno [2,3-d] pyrimidine-6-carbaldehyde (racemate)

628 mg (2.51 mmol) of the compound from Example 31A and 867 mg (6.27 mmol) of potassium carbonate were stirred for 15 min at RT in 23 ml of anhydrous DMF before 570 .mu.l (5.02 mmol) of racemic 2- (bromomethyl) tetrahydrofuran were added. Then, the reaction mixture was stirred at 70 ° C for about 16 h. After this time, the same amount of racemic 2- (bromomethyl) tetrahydrofuran was again added and stirring continued at 70 ° C for 7 days. After cooling to RT, water was added to the reaction mixture and extracted with ethyl acetate. The organic extract was washed with saturated sodium chloride solution, dried over anhydrous magnesium sulfate, filtered and concentrated. The product was isolated by MPLC (Biotage Isolera One, cartridge SNAP KP-Sil, 100 g silica gel, eluent cyclohexane / ethyl acetate 1: 1). Evaporation of the product fractions and drying under high vacuum gave 730 mg (84% of theory, 97% purity) of the title compound.

'H-NMR (400 MHz, DMSO-de, δ / ppm): 10.07 (s, 1H), 4.26-4.17 (m, 1H), 4.10 (dd, 1H), 3.79-3.68 (m, 2H), 3.66 -3.55 (m, 1H), 2.76 (s, 3H), 2.66-2.59 (m, 1H), 2.06-1.74 (m, 3H), 1.73-1.59 (m, 1H), 1.09-0.94 (m, 2H) , 0.76-0.64 (m, 2H).

LC / MS (Method 1, ESIpos): R _t = 1.48 min, m / z = 335.1 1 [M + H] ⁺ .

Example 60A

3-Cyclopropyl-5-methyl-2,4-dioxo-1 - [(2R) -tetrahydrofuran-2-ylmethyl] -1,2,3,4-tetrahydrothieno [2,3-d] pyrimidine-6-carbaldehyde

Analogously to the process described under Example 59A, from 500 mg (2.00 mmol) of the compound from Example 31A and 989 mg (6.00 mmol) of (2R) -2- (bromomethyl) tetrahydrofuran 382 mg (56% of theory) the title compound. 'H-NMR (400 MHz, DMSO-de, δ / ρρηι): 10.07 (s, 1H), 4.26-4.16 (m, 1H), 4.10 (dd, 1H), 3.79-3.68 (m, 2H), 3.66 -3.57 (m, 1H), 2.76 (s, 3H), 2.67-2.58 (m, 1H), 2.06-1.75 (m, 3H), 1.72-1.60 (m, 1H), 1.07-0.97 (m, 2H) , 0.75-0.65 (m, 2H).

LC / MS (Method 1, ESIpos): R _t = 1.53 min, m / z = 335.11 [M + H] ⁺ . Example 61A

3-Cyclopropyl-5-methyl-2,4-dioxo-1 - [(2S) -tetrahydrofuran-2-ylmethyl] -1,3,3,4-tetrahydrothieno [2,3-d] pyrimidine-6-carbaldehyde

Analogously to the process described under Ex. 59A, from 500 mg (2.00 mmol) of the compound from Ex. 31 A and 989 mg (6.00 mmol) of (2S) -2- (bromomethyl) tetrahydrofuran 330 mg (48% of theory) were obtained. Th.) Of the title compound.

'H-NMR (400 MHz, DMSO-de, δ / ppm): 10.07 (s, 1H), 4.26-4.16 (m, 1H), 4.10 (dd, 1H), 3.79-3.68 (m, 2H), 3.66 -3.57 (m, 1H), 2.76 (s, 3H), 2.67-2.59 (m, 1H), 2.06-1.74 (m, 3H), 1.72-1.61 (m, 1H), 1.07-0.97 (m, 2H) , 0.76-0.66 (m, 2H). LC / MS (Method 1, ESIpos): R _t = 1.53 min, m / z = 335.11 [M + H] ⁺ .

Example 62A 1, 5-Dimethyl-3- (1-methylcyclopropyl) -2,4-dioxo-1,2,3,4-tetrahydrothieno [2,3-d] pyrimidine-6-carbaldehyde

Analogously to the process described under Example 48A, from 500 mg (1.89 mmol) of the compound from Example 32A and 269 μΐ (2.84 mmol) of dimethyl sulfate, 465 mg (85% of theory, 97% purity) of the title compound were prepared.

'H-NMR (400 MHz, DMSO-de, δ / ppm): 10.07 (s, 1H), 3.43 (s, 3H), 2.78 (s, 3H), 1.34 (s, 3H), 1.01-0.76 (m , 4H).

LC / MS (Method 1, ESIpos): R _t = 1.46 min, m / z = 279.08 [M + H] ⁺ .

Example 63A 1-Butyl-5-methyl-3- (1-methylcyclopropyl) -2,4-dioxo-1,2,3,4-tetrahydrothieno [2,3-d] pyrimidine-6-carbaldehyde

500 mg (1.89 mmol) of the compound of Ex. 32A and 654 mg (4.73 mmol) of potassium carbonate were stirred for 15 min at RT in 10 ml of anhydrous DMF before 696 mg (3.78 mmol) of n-butyl iodide were added. Then the reaction mixture was stirred at RT for about 16 h. It was then treated with water and extracted with ethyl acetate. The organic extract was washed successively with water and saturated sodium chloride solution, dried over anhydrous magnesium sulfate and concentrated. The residue was purified by MPLC (Biotage Isolera One, cartridge SNAP KP-Sil, 100 g silica gel, eluent cyclohexane / ethyl acetate 2: 1). After evaporation of the product fractions and drying in a high vacuum, 557 mg (91% of theory) of the title compound were obtained. Ή-NMR (400 MHz, DMSO-d ₆ , δ / ppm): 10.08 (s, 1H), 4.01-3.76 (m, 2H), 2.77 (s, 3H), 1.65 (quin, 2H), 1.43-1.28 (m, 2H), 1.34 (s, 3H), 0.99-0.77 (m, 4H), 0.92 (t, 3H).

LC / MS (Method 1, ESIpos): R _t = 2.02 min, m / z = 321.13 [M + H] ⁺ .

Example 64A

5-Methyl-3- (1-methylcyclopropyl) -2,4-dioxo-1 - (3,3,3-trifluoropropyl) -1,2,3,4-tetrahydrothieno [2,3-d] pyrimidine-6 carbaldehyde

A solution of 2.36 g (8.94 mmol) of the compound from Example 32A in 47 ml of DMF was admixed with 3.10 g (22.4 mmol) of potassium carbonate and stirred at RT for 15 min. Then 3.1 ml (26.8 mmol) of 1,1,1-trifluoro-3-iodopropane were added. The mixture was stirred at 50 ° C overnight. After cooling to RT, water was added to the mixture and extracted with dichloromethane. The organic phase was washed with saturated sodium chloride solution. After drying over anhydrous magnesium sulfate, it was filtered and concentrated. There were obtained 2.57 g (75% of theory, 94% purity) of the title compound.

LC / MS (Method 2, ESIpos): R _t = 0.97 min, m / z = 361 [M + H] ⁺ . Example 65A 1- (Cyclobutylmethyl) -5-methyl-3- (1-methylcyclopropyl) -2,4-dioxo-1,2,3,4-tetrahydrothieno [2,3-d] pyrimidine-6-carbaldehyde

500 mg (1.89 mmol) of the compound of Ex. 32A and 654 mg (4.73 mmol) of potassium carbonate were stirred for 15 min at RT in 10 ml of anhydrous DMF before 564 mg (3.78 mmol) (bromomethyl) cyclobutane were added. Then, the reaction mixture was first stirred for about 16 h at RT and then at 50 ° C for 8 h. Thereafter, it was added with water and extracted with ethyl acetate. The organic extract was washed successively with water and saturated sodium chloride solution, dried over anhydrous magnesium sulfate and concentrated. The residue was purified by MPLC (Biotage Isolera One, cartridge SNAP KP-Sil, 100 g silica gel, eluent cyclohexane / ethyl acetate 2: 1). Evaporation of the product fractions and drying under high vacuum gave 478 mg (76% of theory) of the title compound. 'H-NMR (400 MHz, DMSO-de, δ / ρρηι): 10.07 (s, 1H), 4.14-3.78 (m, 2H), 2.84-2.69 (m, 1H), 2.77 (s, 3H), 2.05 -1.90 (m, 2H), 1.89-1.73 (m, 4H), 1.34 (s, 3H), 0.99-0.72 (m, 4H).

LC / MS (Method 1, ESIpos): R _t = 2.08 min, m / z = 333.13 [M + H] ⁺ . Example 66A l - [(2,2-Difluorocyclopropyl) methyl] -5-methyl-3- (1-methylcyclopropyl) -2,4-dioxo-1,2,3,4-tetrahydrothieno [2,3-d ] pyrimidine-6-carbaldehyde (racemate)

1.0 g (3.78 mmol) of the compound of Ex. 32A and 1.85 g (5.68 mmol) of cesium carbonate were stirred for 15 min at RT in 25 ml of anhydrous DMF before 970 mg (5.68 mmol) of racemic 2- (bromomethyl) -1, l- difluorocyclopropane were added. Then the reaction mixture was stirred at RT for about 16 h. It was then treated with water and extracted with ethyl acetate. The organic extract was washed successively with water and saturated sodium chloride solution, dried over anhydrous magnesium sulfate and concentrated. The residue was purified by MPLC (Biotage Isolera One, cartridge SNAP KP-Sil, 100 g of silica gel, eluent cyclohexane / ethyl acetate 2: 1). Evaporation of the product fractions and drying under high vacuum gave 1.17 g (85% of theory) of the title compound.

'H-NMR (400 MHz, DMSO-de, δ / ppm): 10.09 (s, 1H), 4.32-3.79 (m, 2H), 2.78 (s, 3H), 2.30-2.13 (m, 1H), 1.78 -1.63 (m, 1H), 1.54-1.44 (m, 1H), 1.35 (s, 3H), 1.02-0.75 (m, 4H).

LC / MS (Method 1, ESIpos): R _t = 1.82 min, m / z = 355.09 [M + H] ⁺ . Example 67A

[6-Formyl-5-methyl-3- (1-methylcyclopropyl) -2,4-dioxo-3,4-dihydro-thieno [2,3-d] pyrimidin-1 (2H) -ylacetonitrile

Analogously to the process described in Example 63A, from 500 mg (1.89 mmol) of the compound from Example 32A and 454 mg (3.78 mmol) of bromoacetonitrile 455 mg (63% of theory, 80% purity) of the title compound were prepared. 'H-NMR (400 MHz, DMSO-d _6, δ / ppm): 10.10 (s, 1H), 5.18 2.79 (s, 3H), 1:36 (s, 3H), 0.96- (br d, 2H). 0.84 (m, 4H).

LC / MS (Method 2, ESIpos): R _t = 0.78 min, m / z = 304 [M + H] ⁺ . Example 68A 1- (2-Methoxyethyl) -5-methyl-3- (1-methylcyclopropyl) -2,4-dioxo-1,2,3,4-tetrahydrothieno [2,3-d] pyrimidine-6-carbaldehyde

Method A:

2.36 g (8.94 mmol) of the compound from Ex. 32A were dissolved in 47 ml of anhydrous DMF and admixed with 3.09 g (22.4 mmol) of potassium carbonate. It was stirred for 15 min at RT. Then, 2.5 ml (26.8 mmol) of (2-bromoethyl) methyl ether was added. The reaction mixture was stirred at 50 ° C for about 16 h. After cooling to RT, water was added, whereupon a portion of the product precipitated, which was filtered off, washed with a little water and dried under high vacuum. This gave a first fraction of 1.60 g (49% of theory, 89% purity) of the title compound. The filtrate and washings were combined and extracted with dichloromethane. The organic extract was washed with saturated sodium chloride solution and concentrated to dryness. Thus, a further 940 mg (23% of theory, 71% purity) of the product were isolated. Total were thus 2.54 g (73% of theory, 83% purity) of the title compound, which were used without further purification for subsequent reactions.

Method B:

A solution of 33.5 g (114 mmol) of the compound from Ex. 45A in 88 ml (1.14 mol) of DMF was added carefully with 127 ml (1.37 mol) of phosphorus oxychloride. After the strongly exothermic reaction had subsided, the mixture was stirred for a further 15 min. Then it was carefully stirred into 3.5 liters of water. After about 15 h stirring at RT, the precipitated solid was filtered off with suction, washed neutral with water and dried under high vacuum. The product was isolated therefrom by means of MPLC (Biotage Isolera One, cartridge SNAP KP-Sil, 340 g of silica gel, mobile phase cyclohexane / ethyl acetate 2: 1). After evaporation, a first fraction of the title compound (13.2 g) was obtained in pure form and a second, contaminated fraction. The contaminated fraction was stirred at RT for 16 h with ethyl acetate. The solid was filtered off with suction to give, after drying, a second fraction of the title compound (11.0 g) in pure form. In total, 24.2 g (66% of theory) of the title compound were thus obtained. 'H-NMR (400 MHz, DMSO-d _6, δ / ppm): 7.10 (s, 1H), 4.25-3.88 (m, 2H), 3.64, 3.24 (s, 3H), (br t, 2H). 2.77 (s, 3H), 1.35 (s, 3H), 1.02-0.74 (m, 4H).

LC / MS (Method 2, ESIpos): R _t = 0.82 min, m / z = 323 [M + H] ⁺ .

Example 69A

5-Methyl-3- (1-methylcyclopropyl) -2,4-dioxo-1- [2- (trifluoromethoxy) ethyl] -1,3,3,4-tetrahydrothieno [2,3-d] pyrimidine-6 carbaldehyde

500 mg (1.89 mmol) of the compound of Ex. 32A and 654 mg (4.73 mmol) of potassium carbonate were stirred for 15 min at RT in 10 ml of anhydrous DMF before 730 mg (3.78 mmol) of 1-bromo-2- (trifluoromethoxy) ethane [commercially available; Ref .: PE Aldrich, WA Sheppard, J. Org. Chem. 29 (1), 11-15 (1964)]. The reaction mixture was then stirred at RT for 2.5 days and then at 50 ° C. for a further 5 hours. Then it was mixed with water and with Extracted ethyl acetate. The organic extract was washed successively with water and saturated sodium chloride solution, dried over anhydrous magnesium sulfate and concentrated. After drying under high vacuum, 668 mg (93% of theory) of the title compound were obtained.

'H-NMR (400 MHz, DMSO-de, δ / ppm): 10.08 (s, 1H), 4.43-4.38 (m, 2H), 4.36-4.10 (m, 2H), 2.78 (s, 3H), 1.35 (s, 3H), 0.99-0.78 (m, 4H).

LC / MS (Method 1, ESIpos): R _t = 1.88 min, m / z = 377.08 [M + H] ⁺ .

Example 70A 1- (2-Ethoxyethyl) -5-methyl-3- (1-methylcyclopropyl) -2,4-dioxo-1,2,3,4-tetrahydrothieno [2,3-d] pyrimidine-6-carbaldehyde

Analogously to the process described under Example 65A, from 500 mg (1.89 mmol) of the compound from Example 32A and 579 mg (3.78 mmol) of (2-bromoethyl) ethyl ether, 448 mg (70% of theory) of the title compound were prepared ,

'H-NMR (400 MHz, DMSO-de, δ / ppm): 10.07 (s, 1H), 4.22-3.89 (m, 2H), 3.67 (t, 2H), 3.44 (q, 2H), 2.77 (s , 3H), 1.35 (s, 3H), 0.98-0.77 (m, 4H).

LC / MS (Method 1, ESIpos): R _t = 1.73 min, m / z = 337.12 [M + H] ⁺ .

Example 71A 1- (2-Isopropoxyethyl) -5-methyl-3- (1-methylcyclopropyl) -2,4-dioxo-1,2,3,4-tetrahydrothieno [2,3-d] pyrimidine-6-carbaldehyde

500 mg (1.89 mmol) of the compound of Ex. 32A and 523 mg (3.78 mmol) of potassium carbonate were stirred for 15 min at RT in 10 ml of anhydrous DMF before 474 mg (2.84 mmol) of (2-bromoethyl) isopropyl ether were added. The reaction mixture was then stirred at RT for 2.5 days and then at 50 ° C. for 8 hours. Since the conversion was not complete, an additional 131 mg (0.946 mmol) of potassium carbonate and 158 mg (0.946 mmol) of (2-bromoethyl) isopropyl ether were added and stirring continued at 50 ° C for about 16 h. Subsequently, the reaction mixture was admixed with water after cooling to RT and stirred at RT for 30 min. The precipitated product was filtered off, washed with water and dried under high vacuum. 485 mg (73% of theory) of the title compound were obtained.

Ή-NMR (400 MHz, DMSO-de, δ / ppm): 10.07 (s, 1H), 4.20-3.86 (m, 2H), 3.66 (t, 2H), 3.56 (sept, 1H), 2.77 (s, 3H), 1.35 (s, 3H), 1.00 (d, 6H), 0.96-0.78 (m, 4H).

LC / MS (Method 1, ESIpos): R _t = 1.87 min, m / z = 351.14 [M + H] ⁺ .

Example 72A 5-Methyl-3- (1-methylcyclopropyl) -2,4-dioxo-1 - [(2R) -tetrahydrofuran-2-ylmethyl] -1,2,3,4-tetrahydrothieno [2,3- d] pyrimidine-6-carbaldehyde

500 mg (1.89 mmol) of the compound of Ex. 32A and 654 mg (4.73 mmol) of potassium carbonate were stirred for 15 min at RT in 10 ml of anhydrous DMF before 624 mg (3.78 mmol) of (2R) -2- (bromomethyl) tetrahydrofuran were added. Then the reaction mixture was first stirred for 2.5 days at RT. Since the conversion was only slight, the mixture was then stirred at 50 ° C for about 20 h. There the conversion was still low, the reaction mixture was transferred to a microwave oven (Biotage initiator with dynamic control of the irradiation power) and heated there at 100 ° C for 9 h. After cooling to RT, water was added to the reaction mixture and extracted with ethyl acetate. The organic extract was washed successively with water and saturated sodium chloride solution, dried over anhydrous magnesium sulfate and concentrated. The residue was purified by MPLC (Biotage Isolera One, cartridge SNAP KP-Sil, 100 g silica gel, eluent cyclohexane / ethyl acetate 2: 1). Evaporation of the product fractions and drying under high vacuum gave 397 mg (57% of theory, 96% purity) of the title compound. 'H-NMR (400 MHz, DMSO-d _6, δ / ppm): 7.10 (s, 1H), 4.30-3.94 (m, 2H), 3.88-3.54 (m, 3H), 2.77 (s, 3H), 2.06-1.74 (m, 3H), 1.73-1.59 (m, 1H), 1.35 (s, 3H), 0.98-0.75 (m, 4H).

LC / MS (Method 1, ESIpos): R _t = 1.70 min, m / z = 349.12 [M + H] ⁺ .

Example 73A

5-Methyl-3- (1-methylcyclopropyl) -2,4-dioxo-1 - [(2S) -tetrahydrofuran-2-ylmethyl] -1,3,3,4-tetrahydrothieno [2,3-d] pyrimidine-6-carbaldehyde

Analogously to the process described under Example 65A, from 500 mg (1.89 mmol) of the compound from Example 32A and 624 mg (3.78 mmol) of (2S) -2- (bromomethyl) tetrahydrofuran, 527 mg (75% of theory, 95% purity) of the title compound.

'H-NMR (400 MHz, DMSO-de, δ / ppm): 10.07 (s, 1H), 4.30-3.96 (m, 2H), 3.89-3.56 (m, 3H), 2.77 (s, 3H), 2.06 -1.75 (m, 3H), 1.72-1.60 (m, 1H), 1.35 (s, 3H), 1.00-0.77 (m, 4H).

LC / MS (Method 1, ESIpos): R _t = 1.70 min, m / z = 349.12 [M + H] ⁺ .

Example 74A 1- (2-methoxyethyl) -5-methyl-2,4-dioxo-3- [1- (trifluoromethyl) cyclopropyl] -1,2,3,4-tetrahydrothieno [2,3-d] pyrimidine -6-carbaldehyde

1.80 g (5.66 mmol) of the compound of Ex. 33A and 1.95 g (14.1 mmol) of potassium carbonate were stirred for 15 min at RT in 30 ml of anhydrous DMF before 1 ml (11.3 mmol) of (2-bromoethyl) methyl ether was added. Then the reaction mixture was stirred at 50 ° C for about 16 h. After this time, a further 782 mg (5.66 mmol) of potassium carbonate and 531 μΐ (5.66 mmol) of (2-bromoethyl) methyl ether were added and stirring continued at 50 ° C for 7 h. After cooling to RT, water was added and extracted with ethyl acetate. The organic extract was washed successively with water and saturated sodium chloride solution, dried over anhydrous magnesium sulfate, filtered and concentrated. The product was isolated by MPLC (Biotage Isolera One, cartridge SNAP KP-Sil, 100 g silica gel, eluent cyclohexane / ethyl acetate 2: 1). After evaporation of the product fractions and drying in a high vacuum, 1.50 g (70% of theory) of the title compound were obtained.

Ή-NMR (400 MHz, DMSO-de, δ / ppm): 10.09 (s, 1H), 4.19-3.99 (m, 2H), 3.64 (t, 2H), 3.25 (s, 3H), 2.77 (s, 3H), 1.68-1.52 (m, 2H), 1.45-1.30 (m, 2H). LC / MS (Method 1, ESIpos): R _t = 1.71 min, m / z = 377.08 [M + H] ⁺ .

Example 75A 1- (3-fluoropropyl) -5-methyl-3- (2-methylcyclopropyl) -2,4-dioxo-1,2,3,4-tetrahydrothieno [2,3-d] pyrimidine-6-carbaldehyde (trans-racemate)

A solution of 479 mg (1.68 mmol) of the compound from Ex. 34A in 20 ml of DMF was admixed with 582 mg (4.21 mmol) of potassium carbonate and stirred at RT for 15 min. Then, 951 mg (5.05 mmol) of 1-fluoro-3-iodopropane was added, and the mixture was stirred at 50 ° C for 20 hours. The DMF was distilled off as much as possible and the residue obtained was partitioned between half-saturated sodium chloride solution (100 ml) and ethyl acetate (50 ml). The water phase was extracted with ethyl acetate. The combined organic phases were dried over sodium sulfate, filtered and concentrated. The residue obtained was chromatographed on a silica gel cartridge (biotage, 100 g of silica gel, eluent hexane / ethyl acetate 92: 8 → 34:66). 462 mg (82% of theory) of the title compound were obtained.

'H-NMR (400 MHz, DMSO-de, δ / ppm): 10.08 (s, 1H), 4.60 (t, 1H), 4.48 (t, 1H), 4.07-3.94 (m, 2H), 2.77 (s , 3H), 2.28-2.22 (m, 1H), 2.14-2.06 (m, 1H), 2.03 (t, 1H), 1.15 (d, 3H), 1.07-0.96 (m, 1H), 0.89-0.80 (m , 2H). LC / MS (Method 4, ESIpos): R _t = 1.09 min, m / z = 325 [M + H] ⁺ .

Example 76A

5-Methyl-3- (2-methylcyclopropyl) -2,4-dioxo-1- (3,3,3-trifluoropropyl) -l, 2,3,4-tetrahydrothieno [2,3-d] pyrimidine-6 Carbaldehyde (trans-racemate)

A solution of 479 mg (1.68 mmol) of the compound from Ex. 34A in 20 ml of DMF was admixed with 582 mg (4.21 mmol) of potassium carbonate and stirred at RT for 15 min. Then 1.17 g (5.05 mmol) of 1,1'-trifluoro-3-iodopropane were added and the mixture was stirred at 50 ° C. for 20 h. The DMF was distilled off as far as possible and the residue obtained was partitioned between half-saturated sodium chloride solution (100 ml) and ethyl acetate (50 ml). The water phase was extracted with ethyl acetate. The combined organic phases were dried over sodium sulfate, filtered and concentrated. The obtained residue was chromatographed over a silica gel cartridge (Biotage 100 g silica gel, eluent hexane / ethyl acetate 94: 6- ^"■ 50:50). This gave 517 mg (85% of theory) of the title compound.

Ή-NMR (400 MHz, DMSO-de, δ / ppm): 10.09 (s, 1H), 4.13 (d, 2H), 2.84-2.69 (m, 5H), 2.30-2.23 (m, 1H), 1.15 ( d, 3H), 1.07-0.95 (m, 1H), 0.90-0.81 (m, 2H).

LC / MS (Method 4, ESIpos): R _t = 1.2 min, m / z = 361 [M + H] ⁺ . Example 77A 1- (2-methoxyethyl) -5-methyl-3- (2-methylcycloproe

pyrimidine-6-carbaldehyde (trans-racemate)

A solution of 479 mg (1.68 mmol) of the compound from Ex. 34A in 17 ml of DMF was admixed with 582 mg (4.21 mmol) of potassium carbonate and stirred at RT for 15 min. Then 703 mg (5.05 mmol) of (2-bromoethyl) methyl ether were added and the mixture was stirred at 50 ° C. for 70 h. The DMF was distilled off as far as possible and the residue obtained was partitioned between half-saturated sodium chloride solution (100 ml) and ethyl acetate (50 ml). The water phase was extracted with ethyl acetate. The combined organic phases were dried over sodium sulfate, filtered and concentrated. The residue obtained was chromatographed on a silica gel cartridge (Biotage, 100 g of silica gel, eluent hexane / ethyl acetate 92: 8- ^{> ■} 34:66). This gave 317 mg (58% of theory) of the title compound. In addition, 136 mg (21% of theory, purity 86%) of a second fraction of the title compound were isolated. Ή-NMR (400 MHz, DMSO-d ₆ , δ / ppm): 10.07 (s, 1H), 4.11-3.99 (m, 2H), 3.63 (t, 2H), 3.23 (s, 3H), 2.76 (s , 3H), 2.26 (dt, 1H), 1.15 (d, 3H), 1.07-0.96 (m, 1H), 0.90-0.80 (m, 2H).

LC / MS (Method 4, ESIpos): R _t = 1.05 min, m / z = 323 [M + H] ⁺ .

Example 78A

3- (2,2-Dimethylcyclopropyl) -1- (3-fluoropropyl) -5-methyl-2,4-dioxo-1,2,3,4-tetrahydrothieno [2,3-d] pyrimidine-6-carbaldehyde (racemate)

Analogously to Ex. 75A, 565 mg (1.68 mmol) of the compound from Ex. 35A in 24 ml of DMF were reacted with 701 mg (5.07 mmol) of potassium carbonate and 1.14 g (6.09 mmol) of 1-fluoro-3-iodopropane. There were obtained 609 mg (87% of theory) of the title compound.

'H-NMR (400 MHz, DMSO-de, δ / ppm): 10.08 (s, 1H), 4.60 (t, 1H), 4.48 (t, 1H), 4.03 (br, d, 2H), 2.77 (s , 3H), 2.40 (dd, 1H), 2.15-1.99 (m, 2H), 1.17 (s, 3H), 1.05 (dd, 1H), 0.88 (s, 3H), 0.72 (dd, 1H).

LC / MS (Method 4, ESIpos): R _t = 1.22 min, m / z = 339 [M + H] ⁺ . Example 79A

3- (2,2-Dimethylcyclopropyl) -5-methyl-2,4-dioxo-1- (3,3,3-trifluoropropyl) -l, 2,3,4-tetrahydrothieno [2,3-d] pyrimidine 6-carbaldehyde (racemate)

A solution of 500 mg (1.79 mmol) of the compound from Ex. 35A in 22 ml of DMF was admixed with 620 mg (4.49 mmol) of potassium carbonate and stirred at RT for 15 min. Then 1.24 g (5.39 mmol) of 1,1'-trifluoro-3-iodopropane were added and the mixture was stirred at 50 ° C. for 15 h. The DMF was distilled off as far as possible and the residue obtained was partitioned between half-saturated sodium chloride solution (100 ml) and ethyl acetate (50 ml). The water phase was extracted with ethyl acetate. The combined organic phases were dried over sodium sulfate, filtered and concentrated. The obtained residue was through a silica gel cartridge chromatographic graphiert (Biotage 100 g silica gel, eluent hexane / ethyl acetate 94: 6- ^"■ 50:50). This gave 600 mg (88% of theory) of the title compound.

Ή-NMR (400 MHz, DMSO-de, δ / ppm): 10.09 (s, 1H), 4.15 (br d, 2H), 2.85-2.71 (m, 5H), 2.42 (dd, 1H), 1.17 ( s, 3H), 1.06 (dd, 1H), 0.87 (s, 3H), 0.73 (dd, 1H).

LC / MS (Method 4, ESIpos): R _t = 1.32 min, m / z = 375 [M + H] ⁺ . Example 80A

3- (2,2-Dimethylcyclopropyl) -1- (2-methoxyethyl) -5-methyl-2,4-dioxo-1,2,3,4-tetrahydrothieno [2,3-d] pyrimidine-6-carbaldehyde (racemate)

Analogously to Ex. 77A, 500 mg (1.79 mmol) of the compound from Ex. 35A in 18 ml of DMF were reacted with 621 mg (4.49 mmol) of potassium carbonate and 749 mg (5.39 mmol) of (2-bromoethyl) methyl ether. 485 mg (77% of theory) of the title compound were obtained.

Ή-NMR (400 MHz, DMSO-de, δ / ppm): 10.07 (s, 1H), 4.19-4.09 (m, 1H), 4.06-3.95 (m, 1H), 3.69- 3.57 (m, 2H), 3.22 (s, 3H), 2.76 (s, 3H), 2.42 (dd, 1H), 1.17 (s, 3H), 1.06 (dd, 1H), 0.87 (s, 3H), 0.73 (dd, 1H).

LC / MS (Method 4, ESIpos): R _t = 1.17 min, m / z = 337 [M + H] ⁺ .

Example 81A

3- (1-Ethylcyclopropyl) -5-methyl-2,4-dioxo-1- (3,3,3-trifluoropropyl) -l, 2,3,4-tetrahydrothieno [2,3-d] pyrimidine-6 carbaldehyde

Analogously to the process described under Example 52A, from 430 mg (1.54 mmol) of the compound from Example 36A and 692 mg (3.09 mmol) of 1,1,3-trifluoro-3-iodopropane 345 mg (59% of theory) were obtained. ) of the title compound. The reaction was not carried out at 50 ° C, but at 60 ° C, and the reaction time was 26 h. 'H-NMR (400 MHz, DMSO-de, δ / ρρηι): 10.09 (s, 1H), 4.23-4.04 (m, 2H), 2.86-2.70 (m, 2H), 2.78 (s, 3H), 1.70 (q, 2H), 1.04-0.84 (m, 4H), 0.83 (t, 3H).

LC / MS (Method 1, ESIpos): R _t = 2.02 min, m / z = 375.10 [M + H] ⁺ . Example 82A 3 - (1-Ethylcyclopropyl) -1- (2-methoxyethyl) -5-methyl-2,4-dioxo-1,2,3,4-tetrahydrothieno [2,3-d] pyrimidine-6-carbaldehyde

Analogously to the process described under Example 52A, 428 mg (80% of theory) of the title compound were prepared from 430 mg (1.54 mmol) of the compound from Example 36A and 644 mg (4.64 mmol) (2-bromoethyl) methyl ether , The reaction was in this case not at 50 ° C, but at 60 ° C.

Ή-NMR (400 MHz, DMSO-de, δ / ppm): 10.07 (s, 1H), 4.17-3.94 (m, 2H), 3.63 (t, 2H), 3.24 (s, 3H), 2.76 (s, 3H), 1.70 (q, 2H), 1.03-0.77 (m, 4H), 0.83 (t, 3H).

LC / MS (Method 1, ESIpos): R _t = 1.77 min, m / z = 337.12 [M + H] ⁺ . Example 83A

3-Cyclobutyl-5-methyl-2,4-dioxo-1- (3,3,3-trifluoropropyl) -l, 2,3,4-tetrahydrothieno [2,3-d] pyrimidine-6-carbaldehyde

2.50 g (9.46 mmol) of the compound from Example 37A and 3.27 g (23.6 mmol) of potassium carbonate were stirred for 15 min at RT in 50 ml of anhydrous DMF before 3.3 ml (28.4 mmol) of 1,1-trifluoro-3-iodo - propane were added. The reaction mixture was then stirred initially at RT for 16 h and then at 50 ° C. for 4 h. After cooling to RT, it was mixed with water and stirred at RT for 30 min. The precipitated product was filtered off, washed with water and dried under high vacuum. 2.90 g (85% of theory) of the title compound were obtained.

'H-NMR (400 MHz, DMSO-de, δ / ppm): 10.10 (s, 1H), 5.17 (quin, 1H), 4.14 (t, 2H), 2.88-2.70 (m, 4H), 2.78 (s , 3H), 2.27-2.11 (m, 2H), 1.90-1.64 (m, 2H).

LC / MS (Method 1, ESIpos): R _t = 2.07 min, m / z = 361.08 [M + H] ⁺ . Example 84A

3-Cyclobutyl-1- (2-methoxyethyl) -5-methyl-2,4-dioxo-1,2,3,4-tetrahydrothieno [2,3-d] pyrimidine-6-carbaldehyde

2.50 g (9.46 mmol) of the compound from Example 37A and 3.27 g (23.6 mmol) of potassium carbonate were stirred for 15 min at RT in 50 ml of anhydrous DMF before 1.8 ml (28.4 mmol) of (2-bromoethyl) methyl ether were added. The reaction mixture was then stirred initially at RT for 16 h and then at 50 ° C. for 24 h. After cooling to RT, it was mixed with water and stirred at RT for 30 min. The precipitated solid was filtered off, washed with water and dried under high vacuum. The product was isolated therefrom by MPLC (Biotage Isolera One, cartridge SNAP KP-Sil, 100 g silica gel, eluent cyclohexane / ethyl acetate 2: 1). Evaporation of the product fractions and drying under high vacuum gave 2.25 g (73% of theory) of the title compound.

Ή-NMR (400 MHz, DMSO-de, δ / ppm): 10.08 (s, 1H), 5.17 (quin, 1H), 4.07 (t, 2H), 3.65 (t, 2H), 3.25 (s, 3H) , 2.88-2.74 (m, 2H), 2.76 (s, 3H), 2.26-2.13 (m, 2H), 1.89-1.65 (m, 2H). LC / MS (Method 2, ESIpos): R _t = 0.96 min, m / z = 323 [M + H] Example 85A

3- (3,3-difluorocyclobutyl) -5-methyl-2,4-dioxo-l- (3,3,3-M

pyrimidine-6-carbaldehyde [2,3-d]

A solution of 2.0 g (6.60 mmol) of the compound from Ex. 38A in 35 ml of DMF was admixed with 2.30 g (16.6 mmol) of potassium carbonate and stirred at RT for 15 min. Then, 2.3 ml (20.0 mmol) of 1,1,1-trifluoro-3-iodopropane was added. Since after 3 days stirring at RT, the conversion was not complete, the mixture was first stirred for 4.5 h at 50 ° C and then with another 0.92 g (6.60 mmol) of potassium carbonate and 0.78 ml (6.60 mmol) l, l, l trifluoro 3-iodopropane. The reaction mixture was then stirred at 60 ° C overnight. After cooling to rt, the mixture was diluted with water and stirred for 30 min. The precipitated product was filtered off with suction, washed neutral with water and dried. There were obtained 2.15 g (78% of theory) of the title compound, which were used without further purification for subsequent reactions. LC / MS (Method 2, ESIpos): R _t = 1.08 min, m / z = 397 [M + H] ⁺ . Example 86A

3- (3,3-Difluorocyclobutyl) -1- (2-methoxyethyl) -5-methyl-2,4-dioxo-1,2,3,4-tetrahydrothieno [2,3-d] pyrimidine-6-carbaldehyde

A solution of 2.0 g (6.60 mmol) of the compound from Ex. 38A in 35 ml of DMF was admixed with 2.30 g (16.6 mmol) of potassium carbonate and stirred at RT for 15 min. Then, 1.9 ml (20.0 mmol) of (2-bromoethyl) methyl ether was added. Since the reaction was not complete at RT after stirring for 3 days, the mixture was stirred initially at 50 ° C. for 4.5 h, then with a further 0.92 g (6.60 mmol) of potassium carbonate and 0.78 ml (6.60 mmol) of (2-bromoethyl) methyl ether and stirring is then continued overnight at 60 ° C. After cooling to rt, the mixture was diluted with water and stirred for 30 min. The precipitated product was filtered off with suction, washed neutral with water and dried. There were obtained 2.15 g (78% of theory, 87% purity) of the title compound, which were used without further purification for subsequent reactions. LC / MS (Method 2, ESIpos): R _t = 0.96 min, m / z = 359 [M + H] ⁺ .

Example 87A

5-Methyl-3- (oxetan-3-yl) -2,4-dioxo-1- (3,3,3-trifluoropropyl) -l, 2,3,4-tetrahydrothieno [2,3-d] pyrimidine -6-carbaldehyde

A solution of 2.16 g (5.23 mmol) of the compound from Ex. 47A in 50 ml of anhydrous THF was added dropwise at -78 ° C with 6.3 ml (10.7 mmol) of a 1.7 M solution of tert. Butyllithium added in pentane. After 1 h, further at -78 ° C, a solution of 2 mL (26.1 mmol) DMF in 10 mL THF was added. After a further hour at -78 ° C., saturated aqueous ammonium chloride solution was added and the mixture was then warmed to RT. It was extracted with diethyl ether. The organic extract was dried over anhydrous magnesium sulfate, filtered and concentrated. The product was isolated by MPLC (Biotage Isolera One, cartridge SNAP KP-Sil, 100 g silica gel, eluent cyclohexane / ethyl acetate 2: 1). Evaporation of the product fractions and drying under high vacuum gave 785 mg (41% of theory) of the title compound. Ή-NMR (400 MHz, DMSO-d ₆ , δ / ppm): 10.10 (s, 1H), 5.05 (quin, 1H), 4.78-4.66 (m, 4H), 4.14 (t, 2H), 2.85-2.70 (m, 2H), 2.76 (s, 3H).

LC / MS (Method 1, ESIpos): R _t = 1.54 min, m / z = 363.06 [M + H] Example 88A

5-Methyl-3- (l-methylcyclobutyl) -2, ^

pyrimidine-6-carbaldehyde [2,3-d]

2.95 g (10.6 mmol) of the compound from Ex. 39A and 3.66 g (26.5 mmol) of potassium carbonate were stirred for 15 min at RT in 60 ml of anhydrous DMF before 3.7 ml (31.8 mmol) of 1,1-trifluoro-3-iodo - propane were added. Then the reaction mixture was stirred at 50 ° C for about 16 h. After cooling to RT, water was added and extracted with ethyl acetate. The organic extract was washed with saturated sodium chloride solution, dried over anhydrous magnesium sulfate, filtered and concentrated. The product was purified by stirring with pentane / dichloromethane (25: 1) at RT. After suctioning off the solid and drying in a high vacuum, 3.25 g (77% of theory, 95% purity) of the title compound were obtained.

Ή NMR (400 MHz, DMSO-de, δ / ppm): 10.09 (s, 1H), 4.12 (t, 2H), 2.85-2.69 (m, 2H), 2.76 (s, 3H), 2.40-2.21 ( m, 4H), 1.84-1.57 (m, 2H), 1.53 (s, 3H). LC / MS (Method 1, ESIpos): R _t = 2.11 min, m / z = 375.10 [M + H] ⁺ .

Example 89A

1- (2-Methoxyethyl) -5-methyl-3- (1-methylcyclobutyl) -2,4-dioxo-1,2,3,4-tetrahydrothieno [2,3-d] pyrimidine-6-carbaldehyde

3.0 g (10.8 mmol) of the compound of Ex. 39A and 3.72 g (26.9 mmol) of potassium carbonate were stirred for 15 min at RT in 60 ml of anhydrous DMF before 2 ml (21.6 mmol) of (2-bromoethyl) methyl ether were added. Then the reaction mixture was stirred at 50 ° C for about 16 h. After cooling to RT, it was mixed with water and stirred at RT for 30 min. The precipitated solid was filtered off with suction, washed with a little water and dried under high vacuum. This gave a first fraction of 2.27 g of the title compound. The filtrate combined with the washings was extracted with ethyl acetate. The organic extract was washed with saturated sodium chloride solution, dried over anhydrous magnesium sulfate, filtered and concentrated. From the residue, a second fraction of 0.73 g of the title compound was isolated by MPLC (Biotage Isolera One, cartridge SNAP KP-Sil, 100 g silica gel, eluent cyclohexane / ethyl acetate 2: 1). Overall, 3.0 g (82% of theory) of the title compound were thus obtained.

'H-NMR (400 MHz, DMSO-de, δ / ppm): 10.07 (s, 1H), 4.04 (t, 2H), 3.63 (t, 2H), 3.25 (s, 3H), 2.74 (s, 3H ), 2.40-2.20 (m, 4H), 1.82-1.58 (m, 2H), 1.53 (s, 3H).

LC / MS (Method 1, ESIpos): R _t = 1.88 min, m / z = 337.12 [M + H] ⁺ . Example 90A

3 - (trans-3-methoxycyclobutyl) -5-methyl-2,4-dioxo-1 - (3, 3, 3-trifluoropropyl) -1,2,3,4-tetrahydrothieno [2,3-d] pyrimidine-6-carbaldehyde

A solution of 2.23 g (7.09 mmol, 94%> purity) of the compound from Example 40A in 37 ml of DMF was treated with 2.45 g (17.7 mmol) of potassium carbonate and stirred at RT for 15 min. Then, 2.5 ml (21.3 mmol) of 1,1,1-trifluoro-3-iodopropane was added. Since the reaction was not complete after stirring for 16 h at RT, the mixture was stirred at 50 ° C. for a further 2 days. After cooling to rt, the mixture was diluted with water and stirred for 30 min. The precipitated product was filtered off with suction, washed neutral with water and dried. There were obtained 2.26 g (74%> D. Th., 91) purity of the title compound, which were used without further purification for subsequent reactions. 'H-NMR (400 MHz, DMSO-de, δ / ρρηι): 10.10 (s, 1H), 5.48-5.39 (m, 1H), 4.18-4.10 (m, 3H), 3.17 (s, 3H), 2.96 -2.87 (m, 2H), 2.85-2.71 (m, 5H), 2.29-2.22 (m, 2H).

LC / MS (Method 2, ESIpos): R _t = 1.01 min, m / z = 391 [M + H] ⁺ . Example 91A 3- (1α'-3-Methoxycyclobutyl) -1- (2-methoxyethyl) -5-methyl-2,4-dioxo-1,2,3,4-tetrahydrothieno [2,3-d] pyrimidine-6-carbaldehyde

A solution of 2.23 g (7.09 mmol, 94% purity) of the compound from Example 40A in 37 ml of DMF was admixed with 2.45 g (17.7 mmol) of potassium carbonate and stirred at RT for 15 min. Then, 2.0 ml (21.3 mmol) of (2-bromoethyl) methyl ether was added. Since the reaction was not complete after stirring at RT for 16 h, the mixture was stirred at 50 ° C. for a further 24 h. After cooling to RT, the mixture was diluted with water and extracted with dichloromethane. The organic phase was washed with water and saturated sodium chloride solution. After drying over anhydrous magnesium sulfate, it was filtered and concentrated. There were obtained 2.50 g (81% of theory, 81%) of the pure title compound, which were used without further purification for subsequent reactions.

LC / MS (Method 2, ESIpos): R _t = 0.84 min, m / z = 353 [M + H] ⁺ .

Example 92A

3- (di'-3-methoxycyclobutyl) -5-methyl-2,4-dioxo-1- (3,3,3-trifluoropropyl) -l, 2,3,4-tetrahydrothieno [2,3-d] pyrimidine-6-carbaldehyde

A solution of 1.99 g (5.14 mmol, 76% purity) of the compound from Example 41A in 36 ml of DMF was admixed with 2.34 g (16.9 mmol) of potassium carbonate and stirred at RT for 15 min. Then, 2.4 ml (20.0 mmol) of 1,1,1-trifluoro-3-iodopropane was added and the reaction mixture was stirred at 50 ° C for 16 h. After cooling to rt, the mixture was diluted with water and stirred for 30 min. The precipitate was filtered off, washed with water and dried. 2.26 g (82% of theory) of the title compound were obtained.

LC / MS (Method 2, ESIpos): R _t = 0.95 min, m / z = 391 [M + H] ⁺ .

Example 93A 3 - (cis -3-methoxycyclobutyl) -1- (2-methoxyethyl) -5-methyl-2,4-dioxo-1,2,3,4-tetrahydrothieno [2,3-d] pyrimidine-6 carbaldehyde

A solution of 2.40 g (8.15 mmol, 76% purity) of the compound from Example 41A in 43 ml of DMF was admixed with 2.82 g (20.4 mmol) of potassium carbonate and stirred at RT for 15 min. Then 2.4 ml (24.0 mmol) of (2-bromoethyl) -methyl ether were added and the reaction mixture was stirred at 50 ° C for 16 h. After cooling to rt, the mixture was diluted with water and stirred for 30 min. The precipitate was filtered off, washed with water and dried. There were 2.12 g (64%) d. Th., 87% purity) of the title compound, which were used without further purification for subsequent reactions. LC / MS (Method 2, ESIpos): R _t = 0.85 min, m / z = 353 [M + H] ⁺ . Example 94A

3 - (3,3-Dimethylcyclobutyl) -5-methyl-2,4-dioxo-1 - (3,3,3-trifluoropropyl) -1,2,3,4-tetrahydrothieno [2,3-d] pyrimidine -6-carbaldehyde

A solution of 2.40 g (8.21 mmol, 87% purity) of the compound from Example 42A in 44 ml of DMF was admixed with 2.84 g (20.5 mmol) of potassium carbonate and stirred at RT for 15 min. Then 2.9 ml (24.6 mmol) of 1,1,1-trifluoro-3-iodopropane were added. Since after 3 days of stirring at RT, the conversion was not complete, the mixture was stirred for 20 h at 50 ° C. After cooling to rt, the mixture was diluted with water and stirred for 30 min. The precipitated product was filtered off with suction, washed neutral with water and dried. 2.83 g (84% of theory, 95% purity) of the title compound were obtained.

LC / MS (Method 1, ESIpos): R _t = 1.23 min, m / z = 389 [M + H] ⁺ .

Example 95A

3- (3,3-Dimethylcyclobutyl) -1- (2-methoxyethyl) -5-methyl-2,4-dioxo-1,2,3,4-tetrahydrothieno [2,3-d] pyrimidine-6-carbaldehyde

A solution of 2.4 g (8.21 mmol, 87% purity) of the compound from Example 42A in 44 ml of DMF was admixed with 2.84 g (20.5 mmol) of potassium carbonate and stirred at RT for 15 min. Then 2.4 ml (24.6 mmol) of (2-bromoethyl) methyl ether were added. Since after 3 days of stirring at RT, the conversion was not complete, the mixture was stirred for 20 h at 50 ° C. After this After cooling to RT, the mixture was diluted with water and stirred for 30 minutes. The precipitated product was filtered off with suction, washed neutral with water and dried. This gave 2.55 g (81% of theory, 91%) of the pure title compound, which were used without further purification for subsequent reactions. LC / MS (Method 1, ESIpos): R _t = 2.17 min, m / z = 351 [M + H] ⁺ .

Example 96A

5-methyl-2,4-dioxo-3- (spiro [3.3] hept-2-yl) -1- (3,3,3-trifluoropropyl) -1,3,3,4-tetrahydrothieno [2,3 d] pyrimidine-6-carbaldehyde

Analogously to the process described under Example 52A, from 2.35 g (7.72 mmol) of the compound from Example 43A and 2.7 ml (23.2 mmol) of 1,1'-trifluoro-3-iodopropane were added 2.70 g (83% of theory). , 96% purity) of the title compound.

'H-NMR (400 MHz, DMSO-de, δ / ppm): 10.09 (s, 1H), 5.07-4.93 (m, 1H), 4.12 (t, 2H), 2.86-2.70 (m, 4H), 2.77 (s, 3H), 2.33-2.22 (m, 2H), 2.12-2.03 (m, 2H), 2.02-1.94 (m, 2H), 1.88-1.75 (m, 2H). LC / MS (Method 1, ESIpos): R _t = 2.43 min, m / z = 401.11 [M + H] ⁺ .

Example 97A 1- (2-Methoxyethyl) -5-methyl-2,4-dioxo-3- (spiro [3.3] hept-2-yl) -1,2,3,4-tetrahydrothieno [2,3-d] - pyrimidine-6-carbaldehyde

Analogously to the process described under Example 45A, 2.35 g (7.72 mmol) of the compound from Example 43A and 1.5 ml (15.4 mmol) (2-bromoethyl) methyl ether were used to prepare 2.51 g (89% of theory) of the title compound , The reaction was in this case not at RT, but at 50 ° C. 'H-NMR (400 MHz, DMSO-d _6, δ / ppm): 7.10 (s, 1H), 5.01, (quin, 1H), 4:05 (t, 2H), 3.63 (t, 2H), 3.24 (s, 3H), 2.86-2.72 (m, 2H), 2.75 (s, 3H), 2.27 (td, 2H), 2.07 (t, 2H), 2.02-1.94 (m, 2H), 1.88- 1.74 (m, 2H) ,

LC / MS (Method 1, ESIpos): R _t = 2.28 min, m / z = 363.14 [M + H] ⁺ . Example 98A 3-Cyclopentyl-5-methyl-2,4-dioxo-1- (3,3,3-trifluoropropyl) -l, 2,3,4-tetrahydrothieno [2,3-d] pyrimidine-6-carbaldehyde

Analogously to the process described under Example 52A, from 2.55 g (8.89 mmol, 97%> purity) of the compound from Ex. 44A and 3.1 ml (26.7 mmol) 1,1,1-trifluoro-3-iodopropane 3.30 g (93 % of theory, 94% purity) of the title compound.

Ή-NMR (400 MHz, DMSO-de, δ / ppm): 10.10 (s, 1H), 5.35-5.22 (m, 1H), 4.15 (t, 2H), 2.87-2.72 (m, 2H), 2.79 ( s, 3H), 2.09-1.96 (m, 2H), 1.95-1.83 (m, 2H), 1.82-1.71 (m, 2H), 1.62-1.50 (m, 2H).

LC / MS (Method 2, ESIpos): R _t = 1.15 min, m / z = 375 [M + H] Example 99A

3-Cyclopentyl-1- (2-methoxyethyl) -5-methyl-2,4-dioxo-1,2,3,4-tetrahydrothieno [2,3-d] pyrimidine-6-carbaldehyde

Analogously to the process described under Example 52A, 2.55 g (8.89 mmol, 97% purity) of the compound from Example 44A and 2.6 ml (27.5 mmol) (2-bromoethyl) methyl ether were mixed with 2.78 g (88% of theory). , 96% purity) of the title compound.

Ή-NMR (400 MHz, DMSO-de, δ / ppm): 10.08 (s, 1H), 5.28 (quin, 1H), 4.08 (t, 2H), 3.65 (t, 2H), 3.24 (s, 3H) , 2.77 (s, 3H), 2.08-1.96 (m, 2H), 1.95-1.83 (m, 2H), 1.82-1.71 (m, 2H), 1.62-1.49 (m, 2H).

LC / MS (Method 1, ESIpos): R _t = 1.97 min, m / z = 337.12 [M + H] ⁺ . Example 100A

6- {[(2-Aminoethyl) amino] methyl} -3-cyclopropyl-l, 5-dimethylthieno [2,3-d] pyrimidine-2,4 (1H, 3H) -dione

200 mg (0.757 mmol) of the compound from Ex. 48A were dissolved in a mixture of 5 ml of methanol and 2 ml of dichloromethane. Subsequently, 304 μΐ (4.54 mmol) of 1,2-diaminoethane and 173 μΐ (3.03 mmol) of acetic acid were added at RT. After 30 minutes, 109 mg (3.03 mmol) of sodium cyanoborohydride were added. Thereafter, the mixture was stirred at 60 ° C for 2 days. After cooling to RT, 2M sodium hydroxide solution was added and the mixture was extracted with ethyl acetate. The organic extract was washed with saturated sodium chloride solution, dried over anhydrous magnesium sulfate, filtered and concentrated. The crude product thus obtained yielded Drying under high vacuum 290 mg (99% of theory, 80%> purity) of the title compound, which were used without further purification for subsequent reactions.

LC / MS (Method 8, ESIpos): R _t = 1.14 min, m / z = 307 [M + HH ₂ ] ⁺ .

Example 101A 6 - {[(2-Aminoethyl) amino] methyl} -1-butyl-3-cyclopropyl-5-methylthieno [2,3-d] pyrimidine-2,4 (1H, 3H) -dione

Analogously to the process described under Example 100A, from 210 mg (0.685 mmol) of the compound from Ex. 49A, 275 μΐ (4.11 mmol) of 1,2-diaminoethane and 172 mg (2.74 mmol) of sodium cyanoborohydride 250 mg (98%> d Th., 95% purity) of the title compound. The reaction time was approx. 16 h.

LC / MS (Method 1, ESIpos): R _t = 0.71 min, m / z = 291.12 [M + HC ₂ H ₈ N ₂ ] ⁺ . Example 102A

6 - {[(2-aminoethyl) amino] methyl} -3-cyclopropyl-l- (3-fluoropropyl) -5-methylthieno

pyrimidine-2,4 (lH, 3H) -dione

Analogously to the process described under Example 100A, 385 mg (1.24 mmol) of the compound of Ex. 50A and 1,2-diaminoethane were used to prepare 585 mg (94% of theory, 71% purity) of the title compound. The reaction time was 69 h here.

LC / MS (Method 4, ESIpos): R _t = 0.51 min, m / z = 355 [Μ + Η] Example 103A

6 - {[(2-Aminoethyl) amino] methyl} -3-cyclopropyl-5-methyl-1- (3,3,3-trifluoropropyl) thieno-pyrimidine-2,4 (1H, 3H) -dione

250 mg (0.722 mmol) of the compound from Ex. 51 A were dissolved in a mixture of 5.5 ml of methanol and 2.5 ml of dichloromethane. Subsequently, 290 μΐ (4.33 mmol) of 1,2-diaminoethane and 165 μΐ (2.89 mmol) of acetic acid were added at RT. After 30 minutes, 181 mg (2.89 mmol) of sodium cyanoborohydride were added. Thereafter, the mixture was stirred at 60 ° C for about 16 h. After cooling to RT, 2M sodium hydroxide solution was added and the mixture was extracted with ethyl acetate. The organic extract was washed with saturated sodium chloride solution, dried over anhydrous magnesium sulfate, filtered and concentrated. The crude product thus obtained gave, after drying in a high vacuum, 312 mg (77% of theory, 70% purity) of the title compound, which were used without further purification for subsequent reactions.

LC / MS (Method 7, ESIpos): R _t = 1.21 min, m / z = 331 [M + HC ₂ H ₈ N ₂ ] ⁺ . Example 104A

6- {[(2-Aminoethyl) amino] methyl} -1- (cyclobutylmethyl) -3-cyclopropyl-5-methylthieno-pyrimidine-2,4 (1H, 3H) -dione

200 mg (0.628 mmol) of the compound from Ex. 52A were dissolved in a mixture of 5 ml of methanol and 2 ml of dichloromethane. Subsequently, 252 μΐ (3.77 mmol) of 1,2-diaminoethane and 144 μΐ (2.51 mmol) of acetic acid were added at RT. After 30 minutes, 158 mg (2.51 mmol) of sodium cyanoborohydride were added. Thereafter, the mixture was stirred at 60 ° C for about 16 h. After cooling to RT, 2M sodium hydroxide solution was added and the mixture was extracted with ethyl acetate. The organic extract was washed with saturated sodium chloride solution, dried over anhydrous magnesium sulfate, filtered and concentrated. The crude product thus obtained gave, after drying under high vacuum, 240 mg (98% of theory, 93% purity) of the title compound, which were used without further purification for subsequent reactions.

LC / MS (Method 8, ESIpos): R _t = 1.63 min, m / z = 303 [M + HC ₂ H ₈ N ₂ ] ⁺ .

Example 105A

6 - {[(2-Aminoethyl) amino] methyl} -3-cyclopropyl-l - [(2,2-difluorocyclopropyl) methyl] -5-methylthieno [2,3-d] pyrimidine-2,4 (1H , 3H) -dione (racemate)

Analogously to the process described under Example 103A, 400 mg (1.17 mmol) of the compound from Ex. 53A, 471 μΐ (7.05 mmol) of 1,2-diaminoethane and 295 mg (4.70 mmol) of sodium cyanoborohydride were converted into 490 mg (99% of theory). Th., 92% purity) of the title compound.

Example 106A

6 - {[(2-aminoethyl) amino] methyl} -3-cyclopropyl-l- (2-methoxyethyl) -5-methylthieno

pyrimidine-2,4 (lH, 3H) -dione

1.0 g (3.24 mmol) of the compound from Ex. 55A were dissolved in a mixture of 25 ml of methanol and 11 ml of dichloromethane. Subsequently, at RT, 1.3 ml (19.5 mmol) of 1,2-diaminoethane and 743 μΐ (13.0 mmol) of acetic acid were added. After 30 minutes, 815 mg (13.0 mmol) of sodium cyanoborohydride were added. Thereafter, the mixture was stirred at 60 ° C for about 16 h. After cooling to RT, 2M sodium hydroxide solution was added and the mixture was extracted with ethyl acetate. The organic extract was washed with saturated sodium chloride solution, dried over anhydrous magnesium sulfate, filtered and concentrated. The crude product thus obtained gave, after drying under high vacuum, 1.23 g (86% of theory, 80% purity) of the title compound, which were used without further purification for subsequent reactions.

LC / MS (Method 2, ESIpos): R _t = 0.24 min, m / z = 293 [M + HC ₂ H ₈ N ₂ ] ⁺ .

Example 107A

6 - {[(2-aminoethyl) amino] methyl} -3-cyclopropyl-l- (2-ethoxyethyl) -5-methylthieno

pyrimidine-2,4 (lH, 3H) -dione

Analogously to the process described under Ex. 103A, from 200 mg (0.620 mmol) of the compound from Ex. 56A, 249 μΐ (3.72 mmol) of 1,2-diaminoethane and 156 mg (2.48 mmol) of sodium cyanoborohydride 280 mg (98% of theory). Th., 80% purity) of the title compound.

LC / MS (Method 1, ESIpos): R _t = 0.58 min, m / z = 307.11 [M + HC ₂ H ₈ N ₂ ] ⁺ . Example 108A

6 - {[(2-Aminoethyl) amino] methyl} -3-cyclopropyl-1- (2-isopropoxyethyl) -5-methylthieno [2,3-d] pyrimidine-2,4 (1H, 3H) -dione

CH ₃ 200 mg (0.595 mmol) of the compound from Ex. 57A, 238 μΐ (3.57 mmol) of 1,2-diaminoethane and 149 mg (2.38 mmol) of sodium cyanoborohydride gave, in analogy to the process described in Example 103A, 242 mg (90% of theory). Th., 85% purity) of the title compound.

LC / MS (Method 1, ESIpos): R _t = 0.61 min, m / z = 321.13 [M + HC ₂ H ₈ N ₂ ] ⁺ . Example 109A

6 - {[(2-Aminoethyl) amino] methyl} -3-cyclopropyl-5-methyl-1- [2- (trifluoromethoxy) ethyl] thieno [2,3-d] pyrimidine-2,4 (1H, 3H ) -dione

240 mg (0.662 mmol) of the compound from Ex. 58A were dissolved in a mixture of 4 ml of methanol and 1.5 ml of dichloromethane. Then 266 μΐ (3.97 mmol) of 1,2-diaminoethane and 152 μΐ (2.65 mmol) of acetic acid were added at RT. After 30 minutes, 167 mg (2.65 mmol) of sodium cyanoborohydride were added. Thereafter, the mixture was stirred at 60 ° C for about 16 h. After cooling to RT, 2M sodium hydroxide solution was added and the mixture was extracted with ethyl acetate. The organic extract was washed with saturated sodium chloride solution, dried over anhydrous magnesium sulfate, filtered and concentrated. The crude product thus obtained gave, after drying under high vacuum, 330 mg (98% of theory, 80% purity) of the title compound, which were used without further purification for subsequent reactions.

LC / MS (Method 1, ESIpos): R _t = 0.73 min, m / z = 347.07 [M + HC ₂ H ₈ N ₂ ] ⁺ .

Example 110A 6 - {[(2-Aminoethyl) amino] methyl} -3-cyclopropyl-5-methyl-1- (tetrahydrofuran-2-ylmethyl) thieno [2,3-d] pyrimidine-2,4 (1H, 3H) -dione (racemate) H ₂ N

400 mg (1.20 mmol) of the compound from Ex. 59A were dissolved in a mixture of 10 ml of methanol and 4 ml of dichloromethane. Subsequently, 480 μΐ (7.18 mmol) of 1,2-diaminoethane and 274 μΐ (4.79 mmol) of acetic acid were added at RT. After 30 minutes, 301 mg (4.79 mmol) of sodium cyanoborohydride were added. Thereafter, the mixture was stirred at 50 ° C for about 16 h. After cooling to RT, 2M sodium hydroxide solution was added and the mixture was extracted with ethyl acetate. The organic extract was washed with saturated sodium chloride solution, dried over anhydrous magnesium sulfate, filtered and concentrated. The crude product thus obtained gave, after drying under high vacuum, 570 mg (100% of theory, 80% purity) of the title compound, which were used without further purification for subsequent reactions.

LC / MS (Method 1, ESIpos): R _t = 0.56 min, m / z = 319.11 [M + HC ₂ H ₈ N ₂ ] ⁺ .

Example 111A

6 - {[(2-Aminoethyl) amino] methyl} -3-cyclopropyl-5-methyl-1 - [(2R) -tetrahydrofuran-2-ylmethyl] thieno [2,3-d] pyrimidine-2,4 ( lH, 3H) -dione

Analogously to the process described under Example 100A, 150 mg (0.449 mmol) of the compound from Ex. 60A, 180 μΐ (2.69 mmol) 1,2-diaminoethane and 113 mg (1.79 mmol) sodium cyanoborohydride were admixed with 170 mg (90%) Th., 90%> purity) of the title compound.

LC / MS (Method 1, ESIpos): R _t = 0.56 min, m / z = 319.11 [M + HC ₂ H ₈ N ₂ ] Example 112A

6 - {[(2-Aminoethyl) amino] methyl} -3-cyclopropyl-5-methyl-1 - [(2S) -tetrahydrofuran-2-ylmethyl] thieno [2,3-d] pyrimidine-2,4 ( lH, 3H) -dione

Analogously to the process described under Example 100A, 125 mg (0.374 mmol) of the compound from Ex. 61A, 150 μΐ (2.24 mmol) of 1,2-diaminoethane and 94 mg (1.50 mmol) of sodium cyanoborohydride were admixed with 150 mg (95% of theory). Th., 90% purity) of the title compound.

LC / MS (Method 1, ESIpos): R _t = 0.53 min, m / z = 319.11 [M + HC ₂ H ₈ N ₂ ] ⁺ . Example 113A 6 - {[(2-Aminoethyl) amino] methyl} -1, 5-dimethyl-3- (1-methylcyclopropyl) thieno [2,3-d] pyrimidine-2,4 (1H, 3H) -dione

Analogously to the process described in Example 103A, 200 mg (0.719 mmol) of the compound from Ex. 62A, 288 μΐ (4.31 mmol) of 1,2-diaminoethane and 181 mg (2.87 mmol) of sodium cyanoborohydride gave 248 mg (96%> d Th., 90%> purity) of the title compound.

LC / MS (Method 1, ESIpos): R _t = 0.45 min, m / z = 263.08 [M + HC ₂ H ₈ N ₂ ] ⁺ .

Example 114A

6 - {[(2-Aminoethyl) amino] methyl} -1-butyl-5-methyl-3- (1-methylcyclopropyl) thieno [2,3-d] pyrimidine-2,4 (1H, 3H) -dione

235 mg (0.733 mmol) of the compound from Ex. 63A were dissolved in a mixture of 5 ml of methanol and 2 ml of dichloromethane. Subsequently, 294 μΐ (4.40 mmol) of 1,2-diaminoethane and 176 μΐ (2.93 mmol) of acetic acid were added at RT. After 30 min, 184 mg (2.93 mmol) of sodium cyanoborohydride were added. Thereafter, the mixture was stirred at 60 ° C for about 16 h. After cooling to RT, 2M sodium hydroxide solution was added and the mixture was extracted with ethyl acetate. The organic extract was washed with saturated sodium chloride solution, dried over anhydrous magnesium sulfate, filtered and concentrated. The crude product thus obtained gave, after drying under high vacuum, 298 mg (100% of theory, 90% purity) of the title compound, which were used without further purification for subsequent reactions.

LC / MS (Method 1, ESIpos): R _t = 0.78 min, m / z = 305.13 [M + HC ₂ H ₈ N ₂ ] ⁺ .

Example 115A

6 - {[(2-aminoethyl) amino] methyl} -5-methyl-3- (1-methylcyclopropyl) -1- (3,3,3-trifluoropropyl) thieno [2,3-d] pyrimidine-2, 4 (lH, 3H) -dione

1.35 g (3.52 mmol, 94%> purity) of the compound from Ex. 64A were dissolved in a mixture of 31 ml of methanol and 13 ml of dichloromethane. Then 1.4 ml (21 mmol) of 1,2-diaminomethane and 0.8 ml (14.0 mmol) of acetic acid were added at RT. The mixture was stirred at RT for 30 min, after which 886 mg (14.1 mmol) of sodium cyanoborohydride were added. After the reaction mixture was stirred for 16 h at 60 ° C, was diluted with 14 ml of water, treated with 10 ml of 1 M sodium hydroxide solution (pH about 9) and extracted with ethyl acetate. The organic extract was washed with saturated sodium chloride solution, dried over anhydrous magnesium sulfate, filtered. truncated and concentrated. The crude product obtained after drying under high vacuum gave 1.30 g (78% of theory, 86% purity) of the title compound, which were used without further purification for subsequent reactions.

LC / MS (Method 2, ESIpos): R _t = 0.47 min, m / z = 405 [M + H] ⁺ . Example 116A

6- {[(2-Aminoethyl) amino] methyl} -1- (cyclobutylmethyl) -5-methyl-3- (1-methylcyclopropyl) thieno [2,3-d] pyrimidine-2,4 (1H, 3H) -dione

180 mg (0.541 mmol) of the compound from Ex. 65A were dissolved in a mixture of 3.5 ml of methanol and 1.5 ml of dichloromethane. Then 217 μΐ (3.25 mmol) of 1,2-diaminoethane and 124 μΐ (2.17 mmol) of acetic acid were added at RT. After 30 minutes, 136 mg (2.17 mmol) of sodium cyanoborohydride were added. Thereafter, the mixture was stirred at 60 ° C for about 16 h. After cooling to RT, 2M sodium hydroxide solution was added and the mixture was extracted with ethyl acetate. The organic extract was washed with saturated sodium chloride solution, dried over anhydrous magnesium sulfate, filtered and concentrated. The crude product thus obtained gave, after drying under high vacuum, 240 mg (100% of theory, 85% purity) of the title compound, which were used without further purification for subsequent reactions.

LC / MS (Method 2, ESIpos): R _t = 0.56 min, m / z = 317 [M + HC ₂ H ₈ N ₂ ] ⁺ .

Example 117A 6- {[(2-Aminoethyl) amino] methyl} -1 - [(2,2-difluorocyclopropyl) methyl] -5-methyl-3- (1-methylcyclopropyl) thieno [2,3-d] pyrimidine-2,4 (1H, 3H) -dione (racemate) H ₂ N

F F

500 mg (1.41 mmol) of the compound from Ex. 66A were dissolved in a mixture of 10 ml of methanol and 4 ml of dichloromethane. Then 566 μΐ (8.47 mmol) of 1,2-diaminoethane and 323 μΐ (5.64 mmol) of acetic acid were added at RT. After 30 minutes, 355 mg (5.64 mmol) of sodium cyanoborohydride were added. Thereafter, the mixture was stirred at 60 ° C for about 16 h. After cooling to RT, 2M sodium hydroxide solution was added and the mixture was extracted with ethyl acetate. The organic extract was washed with saturated sodium chloride solution, dried over anhydrous magnesium sulfate, filtered and concentrated. The crude product thus obtained gave, after drying under high vacuum, 568 mg (89% of theory, 89% purity) of the title compound, which were used without further purification for subsequent reactions.

LC / MS (Method 1, ESIpos): R _t = 0.73 min, m / z = 330.10 [M + HC ₂ H ₈ N ₂ ] ⁺ .

Example 118A

6 - {[(2-aminoethyl) amino] methyl} -1- (2-methoxyethyl) -5-methyl-3- (1-methylcyclopropyl) thieno [2,3-d] pyrimidine-2,4 (1H, 3H) -dione

13.2 g (40.9 mmol) of the compound from Ex. 68A were dissolved in a mixture of 300 ml of methanol and 140 ml of dichloromethane. Subsequently, 16.4 ml (246 mmol) of 1,2-diaminoethane and 9.4 ml (164 mmol) of acetic acid were added at RT. After 30 minutes, 10.3 g (164 mmol) of sodium cyanoborohydride were added. Thereafter, the mixture was stirred at 60 ° C for about 16 h. After cooling to RT, 2M sodium hydroxide solution was added and the mixture was extracted with ethyl acetate. The organic extract was washed with saturated sodium chloride solution, dried over anhydrous magnesium sulfate, filtered and concentrated. The crude product thus obtained gave, after drying in High vacuum 19.1 g (100% of theory, 79% purity) of the title compound, which were used without further purification for subsequent reactions.

Example 119A

6- {[(2-Aminoethyl) amino] methyl} -5-methyl-3- (1-methylcyclopropyl) -1- [2- (trifluoromethoxy) ethyl] thieno [2,3-d] pyrimidine-2,4 (lH, 3H) -dione

300 mg (0.797 mmol) of the compound from Ex. 69A were dissolved in a mixture of 5 ml of methanol and 2 ml of dichloromethane. Then 320 μΐ (4.78 mmol) of 1,2-diaminoethane and 183 μΐ (3.19 mmol) of acetic acid were added at RT. After 30 minutes, 200 mg (3.19 mmol) of sodium cyanoborohydride were added. Thereafter, the mixture was stirred at 60 ° C for about 16 h. After cooling to RT, 2M sodium hydroxide solution was added and the mixture was extracted with ethyl acetate. The organic extract was washed with saturated sodium chloride solution, dried over anhydrous magnesium sulfate, filtered and concentrated. The crude product thus obtained gave, after drying under high vacuum, 359 mg (99% of theory, 93% purity) of the title compound, which were used without further purification for subsequent reactions.

LC / MS (Method 1, ESIpos): R _t = 0.81 min, m / z = 361.08 [M + HC ₂ H ₈ N ₂ ] ⁺ . Example 120A

6 - {[(2-aminoethyl) amino] methyl} -1- (2-ethoxyethyl) -5-methyl-3- (1-methylcyclopropyl) thieno [2,3-d] pyrimidine-2,4 (1H, 3H) -dione

Analogously to the process described in Example 103A, from 195 mg (0.580 mmol) of the compound from Ex. 70A, 233 μΐ (3.48 mmol) of 1,2-diaminoethane and 146 mg (2.32 mmol) of sodium cyanoborohydride 240 mg (95% of theory). Th., 88% purity) of the title compound.

LC / MS (Method 2, ESIpos): R _t = 0.43 min, m / z = 321 [M + HC ₂ H ₈ N ₂ ] ⁺ . Example 121A

6 - {[(2-aminoethyl) amino] methyl} -1- (2-isopropoxyethyl) -5-methyl-3- (1-methylcyclopropyl) thieno [2,3-d] pyrimidine-2,4 (1H, 3H) -dione

Analogously to the process described under Ex. 103A, 200 mg (0.571 mmol) of the compound from Ex. 71A, 229 μΐ (3.42 mmol) of 1,2-diaminoethane and 143 mg (2.28 mmol) of sodium cyanoborohydride gave 250 mg (99% of theory). Th., 90% purity) of the title compound.

LC / MS (Method 1, ESIpos): R _t = 0.76 min, m / z = 335.14 [M + HC ₂ H ₈ N ₂ ] ⁺ .

Example 122A

6- {[(2-Aminoethyl) amino] methyl} -5-methyl-3- (1-methylcyclopropyl) -1 - [(2R) -tetrahydrofuran-2-ylmethyl] thieno [2,3-d] pyrimidine-2 , 4 (lH, 3H) -dione

190 mg (0.545 mmol) of the compound from Ex. 72A were dissolved in a mixture of 4 ml of methanol and 1.5 ml of dichloromethane. Subsequently, 219 μΐ (3.27 mmol) of 1,2-diaminoethane and 125 μΐ (2.18 mmol) of acetic acid were added at RT. After 30 minutes, 137 mg (2.18 mmol) of sodium cyanoborohydride were added. Thereafter, the mixture was stirred at 60 ° C for about 16 h. After cooling to RT, 2M sodium hydroxide solution was added and the mixture was extracted with ethyl acetate. The organic extract was washed with saturated sodium chloride solution, dried over anhydrous magnesium sulfate, filtered and concentrated. The crude product thus obtained gave, after drying under high vacuum, 220 mg (97% of theory, 95% purity) of the title compound, which were used without further purification for subsequent reactions.

LC / MS (Method 1, ESIpos): R _t = 0.63 min, m / z = 333.13 [M + HC ₂ H ₈ N ₂ ] ⁺ .

Example 123A

6- {[(2-Aminoethyl) amino] methyl} -5-methyl-3- (1-methylcyclopropyl) -1 - [(2S) -tetrahydrofuran-2-ylmethyl] thieno [2,3-d] pyrimidine-2 , 4 (lH, 3H) -dione

Analogously to the procedure described under Ex. 103A, from 250 mg (0.718 mmol) of the compound from Ex. 73A, 288 μΐ (4.31 mmol) of 1,2-diaminoethane and 180 mg (2.87 mmol) of sodium cyanoborohydride, 308 mg (98% of theory) were obtained. Th., 90% purity) of the title compound.

LC / MS (Method 1, ESIpos): R _t = 0.63 min, m / z = 333.13 [M + HC ₂ H ₈ N ₂ ] ⁺ . Example 124A

6 - {[(2-aminoethyl) amino] methyl} -1- (2-methoxyethyl) -5-methyl-3- [1- (trifluoromethyl) cyclopropyl] thieno [2,3-d] pyrimidine-2, 4 (lH, 3H) -dione

Analogously to the process described under Example 103A, from 1.10 g (2.92 mmol) of the compound from Ex. 74A, 1.2 ml (17.5 mmol) of 1,2-diaminoethane and 735 mg (11.7 mmol) of sodium cyanoborohydride 1.28 g (98%) of theory , Th., 95% purity) of the title compound. LC / MS (Method 2, ESIpos): R _t = 0.44 min, m / z = 421 [M + H] ⁺ . Example 125A

6 - {[(2-aminoethyl) amino] methyl} -1- (3-fluoropropyl) -5-methyl-3- (2-methylcyclopropyl) thieno [2,3-d] pyrimidine-2,4 (1H, 3H) -dione {trans-racemate)

430 mg (1.28 mmol) of the compound from Ex. 75A were dissolved in a mixture of 26 ml of methanol and 12.4 ml of dichloromethane. Then 860 μΐ (12.8 mmol) of 1,2-diaminoethane and 294 μΐ (5.14 mmol) of acetic acid were added at RT. It was stirred at RT for 30 min, after which 340 mg (5.14 mmol) of sodium cyanoborohydride were added. After the reaction mixture had been stirred for 95 hours at 60 ° C., 100 ml of water were added (pH about 9) and extracted with ethyl acetate. The organic extract was washed with saturated sodium chloride solution, dried over anhydrous sodium sulfate, filtered and concentrated. The crude product obtained gave, after drying under high vacuum, 510 mg (73% of theory, 68% purity) of the title compound, which were used without further purification for subsequent reactions. LC / MS (Method 4, ESIpos): R _t = 0.57 min, m / z = 369 [M + H] ⁺ .

Example 126A

6 - {[(2-aminoethyl) amino] methyl} -5-methyl-3- (2-methylcyclopropyl) -1- (3,3,3-trifluoropropyl) thieno [2,3-d] pyrimidine-2, 4 (1H, 3H) -dione (trans-racemate)

487 mg (1.35 mmol) of the compound from Ex. 76A were dissolved in a mixture of 27.4 ml of methanol and 13 ml of dichloromethane. Then 903 μΐ (13.5 mmol) of 1,2-diaminoethane and 309 μΐ (5.4 mmol) of acetic acid were added at RT. The mixture was stirred at RT for 30 min, after which 357 mg (5.4 mmol) of sodium cyanoborohydride were added. After the reaction mixture had been stirred for 95 hours at 60 ° C., 100 ml of water were added (pH about 9) and extracted with ethyl acetate. The organic extract was washed with saturated sodium chloride solution, dried over anhydrous sodium sulfate, filtered and concentrated. The crude product obtained after drying in a high vacuum gave 610 mg (91% of theory, 82% purity) of the title compound, which were used without further purification for subsequent reactions. LC / MS (Method 4, ESIpos): R _t = 0.65 min, m / z = 405 [M + H] ⁺ .

Example 127A

6- {[(2-aminoethyl) amino] methyl} -1- (2-methoxyethyl) -5-methyl-3- (2-methylcyclopropyl) thieno [2,3-d] pyrimidine-2,4 (1H, 3H) -dione (trans-racemate)

397 mg (1.23 mmol) of the compound from Ex. 77A were dissolved in a mixture of 25 ml of methanol and 12 ml of dichloromethane. Then 825 μΐ (12.3 mmol) of 1,2-diaminoethane and 282 μΐ (4.93 mmol) of acetic acid were added at RT. It was stirred at RT for 30 min, after which 326 mg (4.93 mmol) of sodium cyanoborohydride were added. After the reaction mixture was stirred for 95 h at 60 ° C, 100 ml of water was added (pH about 9) and extracted with ethyl acetate. The organic extract was washed with saturated sodium chloride solution, dried over anhydrous sodium sulfate, filtered and concentrated. The crude product obtained gave, after drying under high vacuum, 504 mg (90% of theory, 81% purity) of the title compound, which were used without further purification for subsequent reactions.

LC / MS (Method 4, ESIpos): R _t = 0.55 min, m / z = 367 [M + H] ⁺ . Example 128A

6 - {[(2-Aminoethyl) amino] methyl} -3- (2,2-dimethylcyclopropyl) -1- (3-fluorophenyl) -5-methylthieno [2,3-d] pyrimidine-2,4 (lH, 3H) -dione {racemate)

Analogously to the process described in Example 126A, 566 mg (1.65 mmol) of the compound of Ex. 78A and 1,2-diaminoethane were used to produce 869 mg (67% of theory, 49% purity) of the title compound. The reaction time was 81 h here.

LC / MS (Method 4, ESIpos): R _t = 0.64 min, m / z = 383 [M + H] ⁺ .

Example 129A 6 - {[(2-Aminoethyl) amino] methyl} -3- (2,2-dimethylcyclopropyl) -5-methyl-1- (3,3,3-trifluoropropyl) thieno [2,3-d] pyrimidine-2,4 (1H, 3H) -dione (racemate)

557 mg (1.47 mmol) of the compound from Ex. 79A were dissolved in a mixture of 30 ml of methanol and 14 ml of dichloromethane. Then 984 μΐ (14.7 mmol) of 1,2-diaminoethane and 337 μΐ (5.89 mmol) of acetic acid were added at RT. The mixture was stirred at RT for 30 min, after which 390 mg (5.89 mmol) of sodium cyanoborohydride were added. After the reaction mixture was stirred at 60 ° C for 81 h, 100 ml of water (pH about 9) and extracted with ethyl acetate. The organic extract was washed with saturated sodium chloride solution, dried over anhydrous sodium sulfate, filtered and concentrated. The crude product obtained after drying in a high vacuum gave 699 mg (95% of theory, 84% purity) of the title compound, which were used without further purification for subsequent reactions. LC / MS (Method 4, ESIpos): R _t = min, m / z = 419 [M + H]

Example 130A

6 - {[(2-Aminoethyl) amino] methyl} -3- (2,2-dimethylcyclopropyl) -1- (2-methoxyethyl) -5-methylthieno [2,3-d] pyrimidine-2,4 ( 1H, 3H) -dione (racemate)

Analogously to the procedure described in Example 127A, 455 mg (1.29 mmol) of the compound of Ex. 80A and 1,2-diaminoethane were used to prepare 465 mg (84% of theory, 90% purity) of the title compound. The reaction time in this case was 94 h.

LC / MS (method 4, ESIpos): R _t = 0.63 min, m / z = 381 [M + ⁺ FFJ. Example 131A

6 - {[(2-aminoethyl) amino] methyl} -3- (1-ethylcyclopropyl) -5-methyl-1- (3,3,3-trifluoropropyl) thieno [2,3-d] pyrimidine-2, 4 (lH, 3H) -dione

Analogously to the process described under Ex. 103A, from 164 mg (0.428 mmol) of the compound from Ex. 81A, 176 μΐ (2.63 mmol) of 1,2-diaminoethane and 110 mg (1.75 mmol) of sodium cyanoborohydride were dissolved 159 mg (78% of theory). Th., 90% purity) of the title compound.

LC / MS (Method 2, ESIpos): R _t = 0.52 min, m / z = 359 [M + HC ₂ H ₈ N ₂ ] Example 132A

6- {[(2-Aminoethyl) amino] methyl} -3- (1-ethylcyclopropyl) -1- (2-methoxyethyl) -5-methylthieno [2,3-d] pyrimidine-2,4 (1H, 3H ) -dione

Analogously to the process described under Ex. 103A, 212 mg (0.616 mmol) of the compound from Ex. 82A, 247 μΐ (3.70 mmol) of 1,2-diaminoethane and 155 mg (2.47 mmol) of sodium cyanoborohydride gave 247 mg (94% of theory). Th., 90% purity) of the title compound.

LC / MS (Method 2, ESIpos): R _t = 0.44 min, m / z = 321 [M + HC ₂ H ₈ N ₂ ] ⁺ .

Example 133A 6 - {[(2-Aminoethyl) amino] methyl} -3-cyclobutyl-5-methyl-1- (3,3,3-trifluoropropyl) thieno [2,3-d] pyrimidine-2,4 ( lH, 3H) -dione

2.85 g (7.91 mmol) of the compound from Ex. 83A were dissolved in a mixture of 50 ml of methanol and 25 ml of dichloromethane. Subsequently, 3.2 ml (47.5 mmol) of 1,2-diaminoethane and 1.8 ml (31.6 mmol) of acetic acid were added at RT. After 30 minutes, 1.99 g (31.6 mmol) of sodium cyanoborohydride were added. Thereafter, the mixture was stirred at 60 ° C for about 16 h. After cooling to RT, 2M sodium hydroxide solution was added and the mixture was extracted with ethyl acetate. The organic extract was washed with saturated sodium chloride solution, dried over anhydrous magnesium sulfate, filtered and concentrated. The crude product thus obtained gave, after drying under high vacuum, 4.0 g (100%) d. Th., 80% purity) of the title compound, which were used without further purification for subsequent reactions. LC / MS (Method 2, ESIpos): R _t = min, m / z = 405 [M + H]

Example 134A

6- {[(2-aminoethyl) amino] methyl} -3-cyclobutyl-1- (2-methoxyethyl) -5-methylthieno

pyrimidine-2,4 (lH, 3H) -dione

2.24 g (6.95 mmol) of the compound from Ex. 84A were dissolved in a mixture of 50 ml of methanol and 25 ml of dichloromethane. Subsequently, 2.8 ml (41.7 mmol) of 1,2-diaminoethane and 1.6 ml (27.8 mmol) of acetic acid were added at RT. After 30 min, 1.75 g (27.8 mmol) of sodium cyanoborohydride were added. Thereafter, the mixture was stirred at 60 ° C for about 16 h. After cooling to RT, 2M sodium hydroxide solution was added and the mixture was extracted with ethyl acetate. The organic extract was washed with saturated sodium chloride solution, dried over anhydrous magnesium sulfate, filtered and concentrated. The crude product thus obtained gave, after drying under high vacuum, 2.70 g (84% of theory, 80% purity) of the title compound, which were used without further purification for subsequent reactions. LC / MS (Method 2, ESIpos): R _t = 0.45 min, m / z = 307 [M + HC ₂ H ₈ N ₂ ] ⁺ .

Example 135A

6 - {[(2-Aminoethyl) amino] methyl} -3- (3,3-difluorocyclobutyl) -5-methyl-1- (3,3,3-trifluoropropyl) thieno [2,3-d] pyrimidine 2,4 (lH, 3H) -dione

1.0 g (2.52 mmol) of the compound from Ex. 85A was dissolved in a mixture of 22 ml of methanol and 9 ml of dichloromethane. Then 1.0 ml (15.1 mmol) of 1,2-diaminoethane and 0.6 ml (10.1 mmol) of acetic acid were added at RT. The mixture was stirred at RT for 30 min, after which 634 mg (10.1 mmol) of sodium cyanoborohydride were added. After the reaction mixture was stirred for 16 h at 60 ° C, was diluted with 10 ml of water, treated with 7.5 ml of 1 M sodium hydroxide solution (pH about 9) and extracted with ethyl acetate. The organic extract was washed with saturated sodium chloride solution, dried over anhydrous magnesium sulfate, filtered and concentrated. The crude product obtained gave, after drying under high vacuum, 1.26 g (98% of theory, 87% purity) of the title compound, which were used without further purification for subsequent reactions.

LC / MS (Method 2, ESIpos): R _t = 0.59 min, m / z = 441 [M + H] ⁺ . Example 136A

6 - {[(2-Aminoethyl) amino] methyl} -3- (3,3-difluorocyclobutyl) -1- (2-methoxyethyl) -5-methylthieno [2,3-d] pyrimidine-2,4 (1H , 3H) -dione

1.10 g (2.67 mmol, 87%> purity) of the compound from Ex. 86A were dissolved in a mixture of 24 ml of methanol and 10 ml of dichloromethane. Then 1.1 ml (16.1 mmol) of 1,2-diaminoethane and 0.6 ml (10.7 mmol) of acetic acid were added at RT. It was stirred at RT for 30 min, after which 673 mg (10.70 mmol) of sodium cyanoborohydride were added. After the reaction mixture was stirred for 16 h at 60 ° C, was diluted with 11 ml of water, treated with 8 ml of 1 M sodium hydroxide solution (pH about 9) and extracted with ethyl acetate. The organic extract was washed with saturated sodium chloride solution, dried over anhydrous magnesium sulfate, filtered and concentrated. The crude product obtained after drying under high vacuum gave 1.22 g (78% of theory, 69% purity) of the title compound, which were used without further purification for subsequent reactions.

LC / MS (Method 2, ESIpos): R _t = 0.59 min, m / z = 359 [M + HC ₂ H ₈ N ₂ ] Example 137A

6 - {[(2-Aminoethyl) amino] methyl} -5-methyl-3- (oxetan-3-yl) -1- (3,3,3-trifluoropropyl) thieno-pyrimidine-2,4 (1H, 3H) - dion

Analogously to the process described under Example 103A, 402 mg (1.03 mmol, 93% purity) of the compound from Example 87A, 414 μΐ (6.19 mmol) of 1,2-diaminoethane and 259 mg (4.13 mmol) of sodium cyanoborohydride were admixed with 540 mg ( 100%) d. Th., 78% purity) of the title compound.

LC / MS (Method 2, ESIpos): R _t = 0.33 min, m / z = 407 [M + H] ⁺ . Example 138A

6 - {[(2-aminoethyl) amino] methyl} -5-methyl-3- (1-methylcyclobutyl) -1- (3,3,3-trifluoropropyl) thieno [2,3-d] pyrimidine-2, 4 (lH, 3H) -dione

Analogously to the process described in Example 103A, 1.20 g (3.21 mmol) of the compound from Ex. 88A, 1.3 ml (19.2 mmol) 1,2-diaminoethane and 806 mg (12.8 mmol) sodium cyanoborohydride were mixed with 1.36 g (81%). d. Th., 80% purity) of the title compound.

LC / MS (Method 2, ESIpos): R _t = 0.54 min, m / z = 359 [M + HC ₂ H ₈ N ₂ ] ⁺ . Example 139A

6 - {[(2-aminoethyl) amino] methyl} -1- (2-methoxyethyl) -5-methyl-3- (1-methylcyclobutyl) thieno [2,3-d] pyrimidine-2,4 (1H, 3H) -dione

Analogously to the process described under Example 103A, 1.20 g (3.57 mmol) of the compound from Ex. 89A, 1.4 ml (21.4 mmol) of 1,2-diaminoethane and 897 mg (14.3 mmol) of sodium cyanoborohydride were admixed with 1.30 g (76%). d., Th, 80% purity) of the title compound.

LC / MS (Method 1, ESIpos): R _t = 0.72 min, m / z = 321.13 [M + HC ₂ H ₈ N ₂ ] ⁺ .

Example 140A 6 - {[(2-Aminoethyl) amino] methyl} -3- (irani'-3-methoxycyclobutyl) -5-methyl-1- (3,3,3-trifluoropropyl) thieno [2,3- d] pyrimidine-2,4 (lH, 3H) -dione

1.60 g (3.80 mmol, 91%> purity) of the compound from Ex. 90A were dissolved in a mixture of 34 ml of methanol and 14 ml of dichloromethane. Then 1.5 ml (22.8 mmol) of 1,2-diaminomethane and 0.9 ml (15.2 mmol) of acetic acid were added at RT. The mixture was stirred at RT for 30 min, after which 953 mg (15.2 mmol) of sodium cyanoborohydride were added. After the reaction mixture was stirred for 16 h at 60 ° C, was diluted with 16 ml of water, treated with 12.5 ml of 1 M sodium hydroxide solution (pH about 9) and extracted with ethyl acetate. The organic extract was washed with saturated sodium chloride solution, dried over anhydrous magnesium sulfate, filtered and concentrated. The crude product obtained after drying under high vacuum 1.66 g (61% of theory, 61% purity) of the title compound, which were used without further purification for subsequent reactions.

LC / MS (Method 2, ESIpos): R _t = 0.48 min, m / z = 375 [M + HC ₂ H ₈ N ₂ ] ⁺ . Example 141A 6 - {[(2-Aminoethyl) amino] methyl} -3- (irani'-3-methoxycyclobutyl) -1- (2-methoxyethyl) -5-methylthieno [2,3-d] pyrimidine-2 , 4 (lH, 3H) -dione

1.60 g (3.69 mmol, 81% purity) of the compound from Ex. 91A were dissolved in a mixture of 33 ml of methanol and 14 ml of dichloromethane. Then 1.5 ml (22.1 mmol) of 1,2-diaminomethane and 0.8 ml (14.8 mmol) of acetic acid were added at RT. It was stirred at RT for 30 min, after which 928 mg (14.8 mmol) of sodium cyanoborohydride were added. After the reaction mixture was stirred for 16 h at 60 ° C, was diluted with 16 ml of water, treated with 12.5 ml of 1 M sodium hydroxide solution (pH about 9) and extracted with ethyl acetate. The organic extract was washed with saturated sodium chloride solution, dried over anhydrous magnesium sulfate, filtered and concentrated. The crude product obtained after drying under high vacuum 1.54 g (67%) d. Th., 63% purity) of the title compound, which were used without further purification for subsequent reactions.

LC / MS (Method 2, ESIpos): R _t = 0.39 min, m / z = 338 [M + HC ₂ H ₈ N ₂ ] ⁺ . Example 142A 6 - {[(2-Aminoethyl) amino] methyl} -3- (di'-3-methoxycyclobutyl) -5-methyl-1- (3,3,3-trifluoropropyl) thieno [2,3-d ] pyrimidine-2,4 (lH, 3H) -dione

1.0 g (2.48 mmol) of the compound from Ex. 92A were dissolved in a mixture of 22 ml of methanol and 9.2 ml of dichloromethane. Then 1.0 ml (14.9 mmol) of 1,2-diaminoethane and 0.6 ml (9.94 mmol) of acetic acid were added at RT. It was stirred at RT for 30 min, after which 625 mg (9.94 mmol) of sodium cyanoborohydride were added. After the reaction mixture was stirred for 16 h at 60 ° C, was diluted with 40 ml of water, treated with 7 ml of 1 M sodium hydroxide solution (pH about 9) and extracted with ethyl acetate. The organic extract was washed with saturated sodium chloride solution, dried over anhydrous magnesium sulfate, filtered and concentrated. The crude product obtained, after drying in a high vacuum, yielded 1.01 g (76% of theory, 81% purity) of the title compound, which were used without further purification for subsequent reactions.

LC / MS (Method 1, ESIpos): R _t = 0.76 min, m / z = 375 [M + HC ₂ H ₈ N ₂ ] ⁺ . Example 143A

6 - {[(2-aminoethyl) amino] methyl} -3- (cz, y-3-methoxycyclobutyl) -1- (2-methoxyethyl) -5-methylthieno [2,3-d] pyrimidine-2, 4 (lH, 3H) -dione

1.38 g (3.41 mmol, 87%> purity) of the compound from Ex. 93 A were dissolved in a mixture of 30 ml of methanol and 13 ml of dichloromethane. Then 1.4 ml (20.4 mmol) of 1,2-diaminomethane and 13 ml (0.78 mmol) of acetic acid were added at RT. The mixture was stirred at RT for 30 min, after which 856 mg (13.6 mmol) of sodium cyanoborohydride were added. After the reaction mixture was stirred for 16 h at 60 ° C, was diluted with 40 ml of water, with 7 ml of 1 M Sodium hydroxide solution (pH about 9) and extracted with ethyl acetate. The organic extract was washed with saturated sodium chloride solution, dried over anhydrous magnesium sulfate, filtered and concentrated. The crude product obtained gave, after drying under high vacuum, 1.29 g (95% of theory, 69% purity) of the title compound, which were used without further purification for subsequent reactions.

LC / MS (Method 2, ESIpos): R _t = 0.56 min, m / z = 337 [M + HC ₂ H ₈ N ₂ ] ⁺ .

Example 144A

6 - {[(2-aminoethyl) amino] methyl} -3- (3,3-dimethylcyclobutyl) -5-methyl-1- (3,3,3-trifluoropropyl) thieno [2,3-d] pyrimidine 2,4 (lH, 3H) -dione

1.0 g (2.34 mmol, 95% pure) of the compound from Ex. 94A was dissolved in a mixture of 21 ml of methanol and 9 ml of dichloromethane. Then 0.9 ml (14.1 mmol) of 1,2-diaminomethane and 0.5 ml (9.37 mmol) of acetic acid were added at RT. The mixture was stirred at RT for 30 min, after which 589 mg (9.37 mmol) of sodium cyanoborohydride were added. After the reaction mixture had been stirred at 60 ° C. for 16 h, it was diluted with 40 ml of water, admixed with 7 ml of 1 M sodium hydroxide solution (pH about 9) and extracted with ethyl acetate. The organic extract was washed with saturated sodium chloride solution, dried over anhydrous magnesium sulfate, filtered and concentrated. The crude product obtained gave, after drying under high vacuum, 1.01 g (91% of theory, 92% purity) of the title compound, which were used without further purification for subsequent reactions.

LC / MS (Method 1, ESIpos): R _t = 1.13 min, m / z = 373 [M + HC ₂ H ₈ N ₂ ] ⁺ . Example 145A

6 - {[(2-Aminoethyl) amino] methyl} -3- (3,3-dimethylcyclobutyl) -1- (2-methoxyethyl) -5-methylthieno [2,3-d] pyrimidine-2,4 ( lH, 3H) -dione

1.0 g (2.48 mmol, 91% purity) of the compound from Ex. 95A was dissolved in a mixture of 22 ml of methanol and 9 ml of dichloromethane. Then 1.0 ml (14.9 mmol) of 1,2-diaminomethane and 0.6 ml (9.93 mmol) of acetic acid were added at RT. It was stirred at RT for 30 min, after which 624 mg (9.93 mmol) of sodium cyanoborohydride were added. After the reaction mixture was stirred for 16 h at 60 ° C, was diluted with 40 ml of water, treated with 7 ml of 1 M sodium hydroxide solution (pH about 9) and extracted with ethyl acetate. The organic extract was washed with saturated sodium chloride solution, dried over anhydrous magnesium sulfate, filtered and concentrated. The resulting crude product was taken up in acetonitrile. It was decanted from the undissolved and the solution was concentrated and the residue dried under high vacuum. This gave 1.78 g (88% of theory, 48% purity) of the title compound, which were used without further purification for subsequent reactions.

LC / MS (method 2 ESIpos): R _t = 0:55 min, m / z = 395 [M + H] ^+.

Example 146A 6 - {[(2-Aminoethyl) amino] methyl} -5-methyl-3- (spiro [3.3] hept-2-yl) -1- (3,3,3-trifluoropropyl) thieno [2, 3-d] pyrimidine-2,4 (lH, 3H) -dione

Analogously to the process described in Example 103A, from 1.20 g (3.0 mmol) of the compound from Example 96A, 1.2 ml (18.0 mmol) of 1,2-diaminoethane and 753 mg (12.0 mmol) of sodium cyanoborohydride 1.46 g (89%) of theory , Th., 82% purity) of the title compound. LC / MS (Method 1, ESIpos): R _t = 1.11 min, m / z = 385.12 [M + HC ₂ H ₈ N ₂ ] ⁺ . Example 147A

6 - {[(2-aminoethyl) amino] methyl} -1- (2-methoxyethyl) -5-methyl-3- (spiro [3.3] hept-2-yl) thieno [2,3-d] pyrimidine 2,4 (lH, 3H) -dione

Analogously to the process described in Example 103A, 1.20 g (3.31 mmol) of the compound from Example 97A, 1.3 ml (19.9 mmol) of 1,2-diaminoethane and 832 mg (13.2 mmol) of sodium cyanoborohydride were mixed with 1.38 g (83%). Th., 81% purity) of the title compound.

LC / MS (Method 1, ESIpos): R _t = 0.89 min, m / z = 347.14 [M + HC ₂ H ₈ N ₂ ] ⁺ . Example 148A

6 - {[(2-aminoethyl) amino] methyl} -3-cyclopentyl-5-methyl-1- (3,3,3-trifluoropropyl) thieno [2,3-d] pyrimidine-2,4 (1H, 3H) -dione

1.60 g (4.27 mmol) of the compound from Ex. 98A were dissolved in a mixture of 29 ml of methanol and 15 ml of dichloromethane. Subsequently, 1.7 ml (25.6 mmol) of 1,2-diaminoethane and 979 μΐ (17.1 mmol) of acetic acid were added at RT. After 30 min, 1.07 g (17.1 mmol) of sodium cyanoborohydride were added. Thereafter, the mixture was stirred at 60 ° C for about 16 h. After cooling to RT, 2M sodium hydroxide solution was added and the mixture was extracted with ethyl acetate. The organic extract was washed with saturated sodium chloride solution, dried over anhydrous magnesium sulfate, filtered and concentrated. The crude product thus obtained gave, after drying in High vacuum 1.0 g (31% of theory, 56% purity) of the title compound, which were used without further purification for subsequent reactions.

LC / MS (Method 2, ESIpos): R _t = 0.56 min, m / z = 419 [M + H] ⁺ .

Example 149A 6 - {[(2-Aminoethyl) amino] methyl} -3-cyclopentyl-1- (2-methoxyethyl) -5-methylthieno [2,3-d] pyrimidine-2,4 (1H, 3H) - dion

Analogously to the process described under Example 103A, 1.60 g (4.76 mmol) of the compound from Ex. 99A, 1.9 ml (28.5 mmol) of 1,2-diaminoethane and 1.20 g (19.0 mmol) of sodium cyanoborohydride were admixed with 1.84 g (83%). d., Th, 82% purity) of the title compound.

Example 150A

3-Cyclopropyl-6- {[(2,2-dimethoxyethyl) amino] methyl} -5-methyl-1- (3,3,3-trifluoropropyl) thieno [2,3-d] pyrimidine-2,4 ( lH, 3H) -dione

1.03 g (2.87 mmol) of the compound from Ex. 51 A were dissolved in 65 ml of dichloromethane and admixed with 0.46 ml (4.31 mmol) of 2,2-dimethoxyethanamine. The mixture was heated to 35 ° C for 1 h. After cooling to RT, 1.83 g (8.62 mmol) of sodium triacetoxyborohydride was added. It was stirred further at RT. After 18 h, it was diluted with dichloromethane and washed successively with saturated sodium bicarbonate solution and saturated sodium chloride. Solution washed. After drying over anhydrous magnesium sulfate, it was filtered and the filtrate was concentrated to dryness. The crude product was purified by preparative HPLC (Method 13). After combining the product fractions, concentrating and drying under high vacuum, 795 mg (63% of theory) of the title compound were obtained. LC / MS (Method 1, ESIpos): R _t = 0.97 min, m / z = 436 [M + H] ⁺ .

Example 151A

3-Cyclopropyl-6- {[(2,2-dimethoxyethyl) amino] methyl} -1- (2-methoxyethyl) -5-methylthieno [2,3-d] pyrimidine-2,4 (1H, 3H) - dion

888 g (2.50 mmol) of the compound from Ex. 55A were dissolved in 57 ml of dichloromethane and admixed with 0.41 ml (3.76 mmol) of 2,2-dimethoxyethanamine. The mixture was heated to 35 ° C for 1 h. After cooling to RT, 1.60 g (7.52 mmol) of sodium triacetoxyborohydride were added. It was stirred further at RT. After 18 h, it was diluted with dichloromethane and washed successively with saturated sodium bicarbonate solution and saturated sodium chloride solution. After drying over anhydrous magnesium sulfate, it was filtered and the filtrate was concentrated to dryness. There was obtained 1.10 g (93%> d. Th., 85%> purity) of the title compound, which were used without further purification for subsequent reactions.

LC / MS (Method 2, ESIpos): R _t = 0.78 min, m / z = 294 [M + HC ₄ HnNO ₂ ] ⁺ .

Example 152A 3-Cyclopropyl-6- {[(2,2-dimethoxyethyl) amino] methyl} -5-methyl-1- (tetrahydrofuran-2-ylmethyl) thieno [2,3-d] pyrimidine-2,4 ( 1H, 3H) -dione (racemate) N

o H

H ₃ C o

1.07 g (2.82 mmol) of the compound from Ex. 59A were dissolved in 63 ml of dichloromethane and admixed with 0.5 ml (4.24 mmol) of 2,2-dimethoxyethanamine. The mixture was heated to 35 ° C for 1 h. After cooling to RT, 1.80 g (8.47 mmol) of sodium triacetoxyborohydride were added. It was stirred further at RT. After 40 h, it was diluted with dichloromethane and washed successively with saturated sodium bicarbonate solution and saturated sodium chloride solution. After drying over anhydrous magnesium sulfate, it was filtered and the filtrate was concentrated to dryness. There were obtained 1.24 g (62% of theory, 60% purity) of the title compound, which were used without further purification for subsequent reactions. LC / MS (Method 7, ESIpos): R _t = 1.41 min, m / z = 320 [M + HC ₄ HnNO ₂ ] ⁺ .

Example 153A l - {[3-Cyclopropyl-5-methyl-2,4-dioxo-1- (3,3,3-trifluoropropyl) -l, 2,3,4-tetrahydrothieno [2,3-d] pyrimidine -6-yl] methyl} -1- (2,2-dimethoxyethyl) urea

A solution of 795 mg (1.83 mmol) of the compound from Ex. 150A in 19 ml of methanol was initially treated at RT with 341 mg (4.20 mmol) of potassium cyanate and then with 268 μΐ (3.10 mmol) perchloric acid (70%) in water). After 1 h, the reaction mixture was treated with water and with aqueous sodium bicarbonate solution and then extracted with ethyl acetate. The organic extract was washed successively with aqueous sodium hydrogencarbonate solution and saturated sodium chloride solution, dried over anhydrous magnesium sulfate, filtered and concentrated. After drying the residue under high vacuum 631 mg (51% d. Th., 71% purity) of the title compound, which were used without further purification for subsequent reactions.

LC / MS (Method 1, ESIpos): R _t = 1.44 min, m / z = 332 [M + HC ₅ Hi ₂ N ₂ O 3] ⁺ . Example 154A l - {[3-Cyclopropyl-1- (2-methoxyethyl) -5-methyl-2,4-dioxo-1,2,3,4-tetrahydrothieno [2,3-d] pyrimidin-6-yl ] methyl} -1- (2,2-dimethoxyethyl) urea

A solution of 1.10 g (2.35 mmol, 85% purity) of the compound from Ex. 151 A in 24 ml of methanol was initially treated with 439 mg (5.41 mmol) of potassium cyanate and then with 345 μΐ (4.0 mmol) perchloric acid (70% in Water). After 1 h, the reaction mixture was treated with water and with aqueous sodium bicarbonate solution and then extracted with ethyl acetate. The organic extract was washed successively with aqueous sodium hydrogencarbonate solution and saturated sodium chloride solution, dried over anhydrous magnesium sulfate, filtered and concentrated. After drying the residue under high vacuum, 1.06 g (67%) d. Th., 66%) purity of the title compound, which were used without further purification for subsequent reactions.

LC / MS (Method 1, ESIpos): R _t = 1.18 min, m / z = 293 [M + HC ₅ Hi ₂ N ₂ O 3] ⁺ .

Example 155A

1 - {[3-Cyclopropyl-5-methyl-2,4-dioxo-1 - (tetrahydrofuran-2-ylmethyl) -1,2,3,4-tetrahydrothieno [2,3-d] pyrimidin-6-yl ] methyl} -1- (2,2-dimethoxyethyl) urea (racemate)

A solution of 1.22 g (1.73 mmol, 60% purity) of the compound from Ex. 152A in 18 ml of methanol was initially treated with 324 mg (3.99 mmol) of potassium cyanate and then with 254 μΐ (2.95 mmol) perchloric acid (70% in water ). After 2 h, the reaction mixture was treated with water and with aqueous sodium bicarbonate solution and then extracted with ethyl acetate. The organic extract was washed successively with aqueous sodium hydrogencarbonate solution and saturated sodium chloride solution, dried over anhydrous magnesium sulfate, filtered and concentrated. Drying of the residue in a high vacuum gave 1.07 g (79% of theory, 60% purity) of the title compound, which were used for subsequent reactions without further purification.

Example 156A tert-Butyl 2 - [(3-cyclopropyl-l, 5-dimethyl-2,4-dioxo-1,2,3,4-tetrahydrothieno [2,3-d] pyrimidin-6-yl) -methylene ] hydrazine carboxylate

A solution of 235 mg (0.889 mmol) of the compound from Example 48A in 10 ml of ethanol was first tert with 176 mg (1.33 mmol). Butylhydrazincarboxylat and then mixed with 3 drops of concentrated hydrochloric acid. After the reaction mixture had been stirred for about 18 h at RT, most of the ethanol was removed on a rotary evaporator. The remaining residue was diluted with 150 ml of water and neutralized by the addition of saturated aqueous sodium bicarbonate solution. The precipitated solid was filtered off, washed with a little water and dried under high vacuum. There were obtained 328 mg (97% of theory) of the title compound. 'H-NMR (400 MHz, DMSO-de, δ / ppm): 10.82 (br.s, 1H), 8.28 (s, 1H), 3.42 (s, 3H), 2.63-2.56 (m, 1H), 2.44 (s, 3H), 1.45 (s, 9H), 1.06-0.95 (m, 2H), 0.73-0.63 (m, 2H).

LC / MS (Method 1, ES Ineg): R _t = 1.68 min, m / z = 377.13 [MH] ^" Example 157A tert-butyl 2 - [(1-butyl-3-cyclopropyl-5-methyl-2, 4-dioxo-1,2,3,4-tetrahydrothieno [2,3-d] pyrimidin-6-yl) methylene] hydrazinecarboxylate

Analogously to the process described under Example 156A, from 300 mg (0.979 mmol) of the compound from Ex. 49A and 194 mg (1.47 mmol) of tert. Butylhydrazinecarboxylate 406 mg (93% of theory, 95% purity) of the title compound.

Ή-NMR (400 MHz, DMSO-de, δ / ppm): 10.84 (br.s, 1H), 8.28 (s, 1H), 3.86 (br.t, 2H), 2.63-2.56 (m, 1H), 2.43 (s, 3H), 1.66 (quin, 2H), 1.45 (s, 9H), 1.36 (dq, 2H), 1.04-0.96 (m, 2H), 0.92 (t, 3H), 0.73-0.63 (m, 2H).

LC / MS (Method 2, ES Ineg): R _t = 1.10 min, m / z = 419 [MH]. ^" Example 158A tert -butyl-2 - {[3-cyclopropyl-5-methyl-2,4-dioxo -l - (3,3,3-trifluoropropyl) -1,2,3,4-tetrahydrothieno [2,3-d] pyrimidin-6-yl] methylene} hydrazinecarboxylate

A solution of 500 mg (1.44 mmol) of the compound from Example 51A in 13 ml of ethanol was first with 286 mg (2.17 mmol) tert. Butyl hydrazinecarboxylate and then mixed with 2 drops of concentrated hydrochloric acid. After the reaction mixture had been stirred for about 18 h at RT, most of the ethanol was removed on a rotary evaporator. The remaining residue was diluted with 150 ml of water and neutralized by the addition of saturated aqueous sodium bicarbonate solution. The precipitated solid was filtered off, washed with a little water and dried under high vacuum. 663 mg (99% of theory) of the title compound were obtained.

'H-NMR (400 MHz, DMSO-de, δ / ppm): 10.86 (br.s, 1H), 8.29 (s, 1H), 4.10 (t, 2H), 2.85-2.69 (m, 2H), 2.65 -2.56 (m, 1H), 2.44 (s, 3H), 1.45 (s, 9H), 1.06-0.96 (m, 2H), 0.73-0.64 (m, 2H).

LC / MS (Method 1, ES Ineg): R _t = 1.97 min, m / z = 459.13 [MH] -.

Example 159A tert-Butyl 2 - {[1- (cyclobutylmethyl) -3-cyclopropyl-5-methyl-2,4-dioxo-1,2,3,4-tetrahydrothieno [2,3-d] pyrimidine 6-yl] methylene} hydrazinecarboxylate

Analogously to the process described under Example 156A, from 284 mg (0.892 mmol) of the compound from Ex. 52A and 177 mg (1.34 mmol) of tert. Butylhydrazinecarboxylate 350 mg (90% of theory) of the title compound.

'H-NMR (400 MHz, DMSO-de, δ / ppm): 10.84 (br.s, 1H), 8.28 (s, 1H), 3.93 (d, 2H), 2.83-2.69 (m, 1H), 2.60 (tt, 1H), 2.43 (s, 3H), 2.04-1.92 (m, 2H), 1.88-1.75 (m, 4H), 1.45 (s, 9H), 1.06-0.94 (m, 2H), 0.73-0.60 (m, 2H).

LC / MS (Method 1, ES Ineg): R _t = 2.15 min, m / z = 431.18 [MH] -. Example 160A tert. Butyl 2- ({3-cyclopropyl-l - [(2,2-difluorocyclopropyl) methyl] -5-methyl-2,4-dioxo-l, 2,3,4-tetrahydrothieno [2,3- d] pyrimidin-6-yl} methylene) hydrazinecarboxylate (racemate)

Analogously to the process described under Example 156A, from 575 mg (1.69 mmol) of the compound from Ex. 53A and 335 mg (2.53 mmol) of tert. Butylhydrazinecarboxylate 743 mg (96% of theory) of the title compound. 'H-NMR (400 MHz, DMSO-d _6, δ / ppm): 10.84, 29.08 (s, 1H), 4.13 (ddd, 1H), 3.95 (dd, 1H), 2.61 ((br s, 1H). t, 1H), 2.44 (s, 3H), 2.29-2.13 (m, 1H), 1.77-1.64 (m, 1H), 1.54-1.37 (m, 1H), 1.45 (s, 9H), 1.09-0.92 ( m, 2H), 0.78-0.62 (m, 2H).

LC / MS (Method 1, ES Ineg): R _t = 1.98 min, m / z = 453.14 [MH] ^" Example 161A tert -Butyl 2- {[1- (cyanomethyl) -3-cyclopropyl-5-methyl] 2,4-dioxo-1,2,3,4-tetrahydrothieno [2,3-d] pyrimidin-6-yl] methylene} hydrazinecarboxylate

Analogously to the process described under Example 156A, from 235 mg (0.796 mmol) of the compound from Ex. 54A and 158 mg (1.19 mmol) of tert. Butylhydrazinecarboxylate 308 mg (95% of theory) of the title compound.

'H-NMR (400 MHz, DMSO-de, δ / ppm): 10.89 (br.s, 1H), 8.30 (s, 1H), 5.15 (s, 2H), 2.63 (tt, 1H), 2.45 (s , 3H), 1.46 (s, 9H), 1.10-0.92 (m, 2H), 0.81-0.63 (m, 2H).

LC / MS (Method 2, ESIneg): R _t = 0.89 min, m / z = 402 [MH] ^" Example 162A tert. Butyl 2- {[3-cyclopropyl-1 - (2-methoxyethyl) -5-methyl-2,4-dioxo-1,2,3,4-tetrahydrothieno [2,3-d] pyrimidine-6 yl] methylene} hydrazinecarboxylate

Analogously to the process described under Example 156A, 383 mg (1.16 mmol, 93% purity) of the compound from Ex. 55A and 229 mg (1.73 mmol) of tert. Butylhydrazinecarboxylate 498 mg (98% of T, 97% purity) of the title compound.

Ή NMR (400 MHz, DMSO-de, δ / ppm): 10.83 (br, s, 1H), 8.27 (s, 1H), 4.11-3.95 (m, 2H), 3.63 (t, 2H), 3.25 ( s, 3H), 2.65-2.56 (m, 1H), 2.43 (s, 3H), 1.45 (s, 9H), 1.07-0.94 (m, 2H), 0.75-0.63 (m, 2H).

LC / MS (Method 1, ES Ineg): R _t = 1.72 min, m / z = 421.16 [MH] -. Example 163A tert. Butyl 2- {[3-cyclopropyl-1- (2-ethoxyethyl) -5-methyl-2,4-dioxo-1,2,3,4-tetrahydrothieno [2,3-d] pyrimidine-6- yl] methylene} hydrazinecarboxylate

Analogously to the process described under Example 156A, from 250 mg (0.775 mmol) of the compound from Ex. 56A and 154 mg (1.16 mmol) of tert. Butylhydrazinecarboxylate 328 mg (96% of theory) of the title compound. 'H-NMR (400 MHz, DMSO-de, δ / ρρηι): 10.83 (br.s, 1H), 8.28 (s, 1H), 4.02 (t, 2H), 3.66 (t, 2H), 3.45 (q , 2H), 2.64-2.56 (m, 1H), 2.43 (s, 3H), 1.45 (s, 9H), 1.05 (t, 3H), 1.03-0.95 (m, 2H), 0.75-0.62 (m, 2H ).

LC / MS (Method 1, ES Ineg): R _t = 1.87 min, m / z = 435.17 [MH] ^" Example 164A tert -butyl-2- {[3-cyclopropyl-l - (2-isopropoxyethyl) -5- methyl 2,4-dioxo-1,2,3,4-tetrahydrothieno [2,3-d] pyrimidin-6-yl] methylene} hydrazinecarboxylate

Analogously to the process described under Example 156A, from 305 mg (0.907 mmol) of the compound from Ex. 57A and 180 mg (1.36 mmol) of tert. Butylhydrazinecarboxylate 381 mg (93% of theory) of the title compound.

Ή NMR (400 MHz, DMSO-de, δ / ppm): 10.82 (br.s, 1H), 8.28 (s, 1H), 3.99 (t, 2H), 3.65 (t, 2H), 3.56 (sept. 1H), 2.65-2.56 (m, 1H), 2.43 (s, 3H), 1.45 (s, 9H), 1.06-0.96 (m, 2H), 1.02 (d, 6H), 0.72-0.63 (m, 2H) , LC / MS (Method 1, ES Ineg): R _t = 1.98 min, m / z = 449.19 [MH] -.

Example 165A tert. Butyl 2- ({3-cyclopropyl-5-methyl-2,4-dioxo-1- (2- (trifluoromethoxy) ethyl] -1,3,3,4-tetrahydrothieno [2,3-d] pyrimidin-6-yl} methylene) hydrazinecarboxylate

A solution of 350 mg (0.966 mmol) of the compound from Ex. 58A in 10 ml of ethanol was first tert with 191 mg (1.45 mmol). Butylhydrazincarboxylat and then mixed with 3 drops of concentrated hydrochloric acid. After the reaction mixture had been stirred for about 18 h at RT, most of the ethanol was removed on a rotary evaporator. The remaining residue was diluted with 150 ml of water and neutralized by the addition of saturated aqueous sodium bicarbonate solution. The precipitated solid was filtered off, washed with a little water and dried under high vacuum. There were obtained 442 mg (96% of theory) of the title compound. Ή-NMR (400 MHz, DMSO-d ₆ , δ / ppm): 10.85 (br.s, 1H), 8.28 (s, 1H), 4.40 (t, 2H), 4.24-4.17 (m, 2H), 2.65 -2.57 (m, 1H), 2.44 (s, 3H), 1.45 (s, 9H), 1.07-0.97 (m, 2H), 0.73-0.65 (m, 2H).

LC / MS (method 1, ESIneg): R _t = 2.00 min, m / z = 475.13 [MH] -.

Example 166A tert. Butyl-2- {[3-cyclopropyl-5-methyl-2,4-dioxo-1 - (tetrahydrofuran-2-ylmethyl) -1,2,3,4-tetrahydrothieno [2,3-d] pyrimidine -6-yl] methylene} hydrazinecarboxylate (racemate)

Analogously to the process described under Example 156A, from 722 mg (2.01 mmol, 93% purity) of the compound from Ex. 59A and 398 mg (3.01 mmol) of tert. Butylhydrazinecarboxylate 861 mg (95% of theory) of the title compound. 'H-NMR (400 MHz, DMSO-de, δ / ρρηι): 10.83 (br.s, 1H), 8.28 (s, 1H), 4.27-4.15 (m, 1H), 4.06 (dd, 1H), 3.83 -3.68 (m, 2H), 3.66-3.57 (m, 1H), 2.65-2.56 (m, 1H), 2.43 (s, 3H), 2.06-1.75 (m, 3H), 1.72-1.59 (m, 1H) , 1.45 (s, 9H), 1.06-0.95 (m, 2H), 0.75-0.62 (m, 2H).

LC / MS (Method 1, ESIneg): R _t = 1.84 min, m / z = 447.17 [MH] ^" Example 167A tert -butyl-2- ({3-cyclopropyl-5-methyl-2,4-dioxo) 1 - [(2R) -tetrahydrofuran-2-ylmethyl] -1,3,3,4-tetrahydrothieno [2,3-d] pyrimidin-6-yl} methylene) hydrazinecarboxylate

Analogously to the process described under Example 156A, from 230 mg (0.688 mmol) of the compound from Ex. 60A and 137 mg (1.03 mmol) of tert. Butylhydrazinecarboxylate 278 mg (90% of theory) of the title compound.

'H-NMR (400 MHz, DMSO-de, δ / ppm): 10.83 (br.s, 1H), 8.28 (s, 1H), 4.27-4.14 (m, 1H), 4.06 (dd, 1H), 3.82 -3.67 (m, 2H), 3.67-3.57 (m, 1H), 2.64-2.57 (m, 1H), 2.43 (s, 3H), 2.06-1.74 (m, 3H), 1.72-1.59 (m, 1H) , 1.45 (s, 9H), 1.06-0.96 (m, 2H), 0.74-0.63 (m, 2H). LC / MS (Method 1, ES Ineg): R _t = 1.87 min, m / z = 447.17 [MH] -.

Example 168A tert. Butyl-2- ({3-cyclopropyl-5-methyl-2,4-dioxo-1 - [(2S) -tetrahydrofuran-2-ylmethyl] -1,3,3,4-tetrahydrothieno [2,3-d ] pyrimidin-6-yl} methylene) hydrazinecarboxylate

200 mg (0.598 mmol) of the compound from Example 61A and 119 mg (0.897 mmol) of tert-butyl acetate were prepared analogously to the process described under Example 156A. Butylhydrazinecarboxylate 241 mg (89% of theory) of the title compound.

'H-NMR (400 MHz, DMSO-de, δ / ppm): 10.83 (br.s, 1H), 8.28 (s, 1H), 4.26-4.15 (m, 1H), 4.06 (dd, 1H), 3.82 -3.67 (m, 2H), 3.66-3.57 (m, 1H), 2.65-2.56 (m, 1H), 2.43 (s, 3H), 2.06-1.74 (m, 3H), 1.71-1.58 (m, 1H) , 1.45 (s, 9H), 1.06-0.94 (m, 2H), 0.74-0.64 (m, 2H).

LC / MS (Method 1, ESIneg): R _t = 1.87 min, m / z = 447.17 [MH] ^"

Example 169A tert-Butyl 2 - {[l, 5-dimethyl-3- (1-methylcyclopropyl) -2,4-dioxo-l, 2,3,4-tetrahydrothieno [2,3-d] pyrimidine 6-yl] methylene} hydrazinecarboxylate

Analogously to the process described under Example 156A, from 257 mg (0.923 mmol) of the compound from Ex. 62A and 183 mg (1.39 mmol) of tert. Butylhydrazinecarboxylate 362 mg (99% of theory) of the title compound. 'H-NMR (400 MHz, DMSO-d _6, δ / ppm): 10.82, 28.08 (s, 1H), 3:42 (s, 3H), 2:45 (s, 3H), 1:45 ((br s, 1H). s, 9H), 1.33 (s, 3H), 0.97-0.76 (m, 4H).

LC / MS (Method 2, ES Ineg): R _t = 0.96 min, m / z = 391 [MH] ^" .

Example 170A tert. Butyl-2 - {[1-butyl-5-methyl-3- (1-methylcyclopropyl) -2,4-dioxo-1,2,3,4-tetrahydrothieno [2,3-d] pyrimidine-6 yl] methylene} hydrazinecarboxylate

Analogously to the process described under Example 156A, from 300 mg (0.936 mmol) of the compound from Ex. 63A and 185 mg (1.40 mmol) of tert. Butylhydrazinecarboxylate 397 mg (97% of theory) of the title compound. Ή NMR (400 MHz, DMSO-d ₆ , δ / ppm): 10.84 (br.s, 1H), 8.28 (s, 1H), 4.01 -3.71 (m, 2H), 2.44 (s, 3H), 1.66 (quin, 2H), 1.45 (s, 9H), 1.41-1.28 (m, 2H), 1.33 (s, 3H), 0.98-0.75 (m, 4H), 0.92 (t, 3H).

LC / MS (Method 1, ES Ineg): R _t = 2.26 min, m / z = 433.19 [MH] -.

Example 171A tert. Butyl-2- {[5-methyl-3- (1-methylcyclopropyl) -2,4-dioxo-1- (3,3,3-trifluoropropyl) -l, 2,3,4-tetrahydrothieno [2 , 3-d] pyrimidin-6-yl] methylene} hydrazinecarboxylate

A solution of 1.07 g (2.80 mmol, 94% purity) of the compound from Example 64A in 34 ml of ethanol was first tert with 555 mg (4.20 mmol). Butylhydrazincarboxylat and then mixed with 3 drops of concentrated hydrochloric acid. After the reaction mixture had been stirred at RT for about 18 h, most of the ethanol was removed on a rotary evaporator. The remaining residue was diluted with water and neutralized by the addition of saturated aqueous sodium bicarbonate solution. The precipitated solid was filtered off, washed with a little water and dried under high vacuum. There were obtained 1.34 g (94% of theory, 94% purity) of the title compound, which were used without further purification for subsequent reactions. 'H-NMR (400 MHz, DMSO-de, δ / ρρηι): 10.86 (br.s, 1H), 8.29 (s, 1H), 4.28-4.09 (m, 2H), 2.81- 2.73 (m, 2H) , 2.45 (s, 3H), 1.45 (s, 9H), 1.34 (s, 3H), 0.95-0.80 (m, 4H).

LC / MS (Method 2, ESIpos): R _t = 1.11 min, m / z = 475 [M + H] ⁺ . Example 172A tert. Butyl-2- {[1- (cyclobutylmethyl) -5-methyl-3- (1-methylcyclopropyl) -2,4-dioxo-1,2,3,4-tetrahydrothieno [2,3-d] pyrimidine -6-yl] methylene} hydrazinecarboxylate

Analogously to the process described under Example 156A, from 290 mg (0.872 mmol) of the compound from Ex. 65A and 173 mg (1.31 mmol) of tert. Butylhydrazinecarboxylate 362 mg (92% of theory) of the title compound.

'H-NMR (400 MHz, DMSO-de, δ / ppm): 10.84 (br.s, 1H), 8.27 (s, 1H), 4.12-3.76 (m, 2H), 2.83- 2.70 (m, 1H) , 2.43 (s, 3H), 2.06-1.91 (m, 2H), 1.89-1.75 (m, 4H), 1.45 (s, 9H), 1.33 (s, 3H), 0.97-0.72 (m, 4H).

LC / MS (method 2, ES Ineg): R _t = 1.20 min, m / z = 445 [MH] ^" . Example 173A tert -butyl-2- ({1 - [(2,2-difluorocyclopropyl) methyl] - 5-methyl-3- (1-methylcyclopropyl) -2,4-dioxo l, 2,3,4-tetrahydrothieno [2,3-d] pyrimidin-6-yl} methylene) hydrazinecarboxylate (racemate)

Analogously to the process described under Example 156A, from 660 mg (1.86 mmol) of the compound from Ex. 66A and 369 mg (2.79 mmol) of tert. Butylhydrazinecarboxylate 820 mg (91% of theory, 97% purity) of the title compound.

'H-NMR (400 MHz, DMSO-de, δ / ppm): 10.85 (br.s, 1H), 8.29 (s, 1H), 4.28-3.81 (m, 2H), 2.45 (s, 3H), 2.30 -2.14 (m, 1H), 1.79-1.64 (m, 1H), 1.52-1.41 (m, 1H), 1.45 (s, 9H), 1.34 (s, 3H), 0.98-0.77 (m, 4H).

LC / MS (Method 1, ES Ineg): R _t = 2.09 min, m / z = 467.16 [MH] ^" Example 174A tert-butyl-2 - {[1- (cyanomethyl) -5-methyl-3- (l -methylcyclopropyl) -2,4-dioxo-l, 2,3,4-tetrahydrothieno [2,3-d] pyrimidin-6-yl] methylene} hydrazinecarboxylate

Analogously to the process described under Example 156A, 250 mg (0.824 mmol) of the compound from Ex. 67A and 163 mg (1.24 mmol) of tert. Butyl hydrazinecarboxylate 290 mg (75% of theory, 90% purity) of the title compound. 'H-NMR (400 MHz, DMSO-d _6, δ / ppm): 10.89 (br s, 1H.), 8.30 (s, 1H), 5.14 2:45 (s, 3H), (br d, 2H). 1.46 (s, 9H), 1.34 (s, 3H), 0.92-0.85 (m, 4H).

LC / MS (method 1, ESIneg): R _t = 1.81 min, m / z = 416.14 [MH] ^"

Example 175A tert. Butyl-2 - {[1- (2-methoxyethyl) -5-methyl-3- (1-methylcyclopropyl) -2,4-dioxo-1,2,3,4-tetrahydrothieno [2,3-d ] pyrimidin-6-yl] methylene} hydrazinecarboxylate

A solution of 932 mg (2.10 mmol, 72% purity) of the compound from Ex. 68A in 25 ml of ethanol was first treated with 412 mg (3.12 mmol) of tert-butyl-hydrazinecarboxylate and then with 3 drops of concentrated hydrochloric acid. After the reaction mixture had been stirred at RT for about 18 h, most of the ethanol was removed on a rotary evaporator. The remaining residue was diluted with water and neutralized by the addition of saturated aqueous sodium bicarbonate solution. The precipitated solid was filtered off, washed with a little water and dried under high vacuum. There were obtained 1.17 g (95% of theory, 74% purity) of the title compound, which were used without further purification for subsequent reactions.

LC / MS (Method 2, ESIpos): R _t = 0.99 min, m / z = 437 [M + H] ⁺ .

Example 176A tert-Butyl 2- ({5-methyl-3- (1-methylcyclopropyl) -2,4-dioxo-1- [2- (trifluoromethoxy) ethyl] -1,3,3,4-tetrahydrothieno [ 2,3-d] pyrimidin-6-yl} methylene) hydrazinecarboxylate

A solution of 360 mg (0.957 mmol) of the compound from Example 69A in 10 ml of ethanol was first tert with 190 mg (1.44 mmol). Butylhydrazincarboxylat and then mixed with 3 drops of concentrated hydrochloric acid. After the reaction mixture had been stirred for about 18 h at RT, most of the ethanol was removed on a rotary evaporator. The remaining residue was diluted with 150 ml of water and neutralized by the addition of saturated aqueous sodium bicarbonate solution. The precipitated solid was filtered off with suction, with little water. washed and dried under high vacuum. There were obtained 432 mg (73% of theory, 80% purity) of the title compound.

'H-NMR (400 MHz, DMSO-de, δ / ppm): 10.84 (br.s, 1H), 8.28 (s, 1H), 4.43-4.38 (m, 2H), 4.34-4.07 (m, 2H) , 2.44 (s, 3H), 1.45 (s, 9H), 1.34 (s, 3H), 0.98-0.78 (m, 4H). LC / MS (method 1, ESIneg): R _t = 2.11 min, m / z = 489.14 [MH] ^"

Example 177A tert -Butyl 2 - {[1- (2-ethoxyethyl) -5-methyl-3- (1-methylcyclopropyl) -2,4-dioxo-1,2,3,4-tetrahydrothieno [2 , 3-d] pyrimidin-6-yl] methylene} hydrazinecarboxylate

Analogously to the process described under Example 156A, 250 mg (0.743 mmol) of the compound from Ex. 70A and 147 mg (1.11 mmol) of tert. Butylhydrazinecarboxylate 316 mg (66% of theory, 70% purity) of the title compound. In this case, the product was additionally purified by means of MPLC (Biotage Isolera One, cartridge SNAP KP-Sil, 50 g of silica gel, mobile phase cyclohexane / ethyl acetate 2: 1). 'H-NMR (400 MHz, DMSO-d _6, δ / ppm): (br. S, 1H) 10.83, 28.08 (s, 1H), 4.22-3.87 (m, 2H), 3.70- 3.61 (m, 2H ), 3.45 (q, 2H), 2.44 (s, 3H), 1.45 (s, 9H), 1.34 (s, 3H), 1.05 (t, 3H), 0.96-0.78 (m, 4H).

LC / MS (Method 1, ESIneg): R _t = 2.00 min, m / z = 449.19 [MH] ^"

Example 178A tert. Butyl-2 - {[1- (2-isopropoxyethyl) -5-methyl-3- (1-methylcyclopropyl) -2,4-dioxo-1,2,3,4-tetrahydrothieno [2,3-d ] pyrimidin-6-yl] methylene} hydrazinecarboxylate

Analogously to the process described under Example 156A, from 280 mg (0.799 mmol) of the compound from Ex. 71A and 158 mg (1.20 mmol) of tert. Butylhydrazinecarboxylate 370 mg (99% of theory) of the title compound. The product was additionally purified by MPLC (Biotage Isolera One, cartridge SNAP KP-Sil, 50 g silica gel, mobile phase cyclohexane / ethyl acetate 2: 1).

Ή-NMR (400 MHz, DMSO-d ₆ , δ / ppm): 10.83 (br.s, 1H), 8.28 (s, 1H), 4.14-3.85 (m, 2H), 3.66 (t, 2H), 3.56 (1.45 (s, 3H), 1.33 (s, 3H), 1.01 (d, 6H), 0.96-0.75 (m, 4H).

LC / MS (Method 1, ES Ineg): R _t = 2.13 min, m / z = 463.20 [MH] -. Example 179A tert-Butyl 2- ({5-methyl-3- (1-methylcyclopropyl) -2,4-dioxo-1 - [(2R) -tetrahydrofuran-2-ylmethyl] -1,3,3,4 -tetrahydrothieno [2,3-d] pyrimidin-6-yl} methylene) hydrazinecarboxylate

200 mg (0.574 mmol) of the compound from Ex. 72A and 114 mg (0.861 mmol) of tert. Butylhydrazinecarboxylate 240 mg (90% of theory) of the title compound.

Ή-NMR (400 MHz, DMSO-d ₆ , δ / ppm): 10.83 (br.s, 1H), 8.28 (s, 1H), 4.34-3.92 (m, 2H), 3.89- 3.53 (m, 3H) , 2.44 (s, 3H), 2.07-1.75 (m, 3H), 1.73-1.59 (m, 1H), 1.45 (s, 9H), 1.34 (s, 3H), 0.96-0.78 (m, 4H). LC / MS (Method 1, ES Ineg): R _t = 2.00 min, m / z = 461.19 [MH] -. Example 180A tert-Butyl 2- ({5-methyl-3- (1-methylcyclopropyl) -2,4-dioxo-1 - [(2S) -tetrahydrofuran-2-ylmethyl] -1,3,3,4 -tetrahydrothieno [2,3-d] pyrimidin-6-yl} methylene) hydrazinecarboxylate

Analogously to the process described under Example 156A, from 275 mg (0.789 mmol) of the compound from Ex. 73A and 156 mg (1.18 mmol) of tert. Butylhydrazinecarboxylate 342 mg (93% of theory) of the title compound.

'H-NMR (400 MHz, DMSO-de, δ / ppm): 10.83 (br.s, 1H), 8.28 (s, 1H), 4.33-3.92 (m, 2H), 3.87- 3.54 (m, 3H) , 2.44 (s, 3H), 2.06-1.74 (m, 3H), 1.73-1.58 (m, 1H), 1.45 (s, 9H), 1.34 (s, 3H), 0.99-0.72 (m, 4H).

LC / MS (Method 1, ESIneg): R _t = 2.00 min, m / z = 461.19 [MH] ^"

Example 181A tert. Butyl 2- ({1- (2-methoxyethyl) -5-methyl-2,4-dioxo-3- [1- (trifluoromethyl) cyclopropyl] -1,3,3,4-tetrahydrothieno [2,3- d] pyrimidin-6-yl} methylene) hydrazinecarboxylate

Analogously to the process described under Example 156A, from 365 mg (0.970 mmol) of the compound from Ex. 74A and 192 mg (1.46 mmol) of tert. Butylhydrazinecarboxylate 450 mg (94% of theory) of the title compound.

Ή-NMR (400 MHz, DMSO-de, δ / ppm): 10.87 (br.s, 1H), 8.28 (s, 1H), 4.15-3.96 (m, 2H), 3.64 (t, 2H), 3.26 ( s, 3H), 2.43 (s, 3H), 1.66-1.51 (m, 2H), 1.45 (s, 9H), 1.39-1.32 (m, 2H). LC / MS (Method 1, ESIneg): R _t = min, m / z = 489.14 [MH] ^"

Example 182A tert -Butyl 2 - {[3- (1-ethylcyclopropyl) -5-methyl-2,4-dioxo-1- (3,3,3-trifluoropropyl) -l, 2,3,4-tetra - hydrothieno [2,3-d] pyrimidin-6-yl] methylene} hydrazinecarboxylate

Analogously to the process described under Example 156A, 166 mg (0.443 mmol) of the compound from Ex. 81A and 88 mg (0.665 mmol) of tert. -Butyl-hydrazinecarboxylate 201 mg (74% of theory, 80%) of the title compound, which were used without further purification for subsequent reactions. Ή-NMR (400 MHz, DMSO-d ₆ , δ / ppm): 10.86 (br.s, 1H), 8.29 (s, 1H), 4.11 (q, 2H), 2.85-2.69 (m, 2H), 2.44 (s, 3H), 1.69 (q, 2H), 1.45 (s, 9H), 1.01-0.88 (m, 2H), 0.87-0.78 (m, 2H), 0.82 (t, 3H).

LC / MS (method 1, ESIneg): R _t = 2.23 min, m / z = 487.16 [MH] -.

Example 183A tert. Butyl-2- {[3- (1-ethylcyclopropyl) -1- (2-methoxyethyl) -5-methyl-2,4-dioxo-1,2,3,4-tetrahydrothieno [2,3-d ] pyrimidin-6-yl] methylene} hydrazinecarboxylate

Analogously to the process described under Example 156A, from 212 mg (0.616 mmol) of the compound from Ex. 82A and 122 mg (0.924 mmol) of tert. -Butyl-hydrazinecarboxylate 274 mg (86% of theory, 88% purity) of the title compound, which were used without further purification for subsequent reactions. 'H-NMR (400 MHz, DMSO-de, δ / ρρηι): 10.83 (br.s, 1H), 8.27 (s, 1H), 4.12-3.93 (m, 2H), 3.63 (t, 2H), 3.25 (s, 3H), 2.43 (s, 3H), 1.70 (q, 2H), 1.45 (s, 9H), 1.01-0.76 (m, 4H), 0.82 (t, 3H).

LC / MS (Method 1, ES Ineg): R _t = 2.05 min, m / z = 449.19 [MH] ^" Example 184A tert-butyl 2 - {[3-cyclobutyl-5-methyl-2,4-dioxo] 1- (3,3,3-trifluoropropyl) -1,3,3,4-tetrahydrothieno [2,3-d] pyrimidin-6-yl] methylene} hydrazinecarboxylate

A solution of 357 mg (0.991 mmol) of the compound from Example 83A in 9 ml of ethanol was first tert with 196 mg (1.49 mmol). Butylhydrazincarboxylat and then mixed with 2 drops of concentrated hydrochloric acid. After the reaction mixture had been stirred for about 18 h at RT, most of the ethanol was removed on a rotary evaporator. The remaining residue was diluted with 150 ml of water and neutralized by the addition of saturated aqueous sodium bicarbonate solution. The precipitated solid was filtered off, washed with a little water and dried under high vacuum. There were obtained 451 mg (92% of theory, 96% purity) of the title compound.

Ή-NMR (400 MHz, DMSO-de, δ / ppm): 10.87 (br.s, 1H), 8.29 (s, 1H), 5.19 (quin, 1H), 4.11 (br.t, 2H), 2.90- 2.69 (m, 4H), 2.44 (s, 3H), 2.17 (q, 2H), 1.88-1.65 (m, 2H), 1.45 (s, 9H).

LC / MS (Method 1, ES Ineg): R _t = 2.31 min, m / z = 473.15 [MH] -.

Example 185A tert. Butyl 2- {[3 -cyclobutyl-1- (2-methoxyethyl) -5-methyl-2,4-dioxo-1,2,3,4-tetrahydrothieno [2,3-d] pyrimidine-6- yl] methylene} hydrazinecarboxylate

A solution of 280 mg (0.869 mmol) of the compound from Ex. 84A in 9 ml of ethanol was first tert with 172 mg (1.30 mmol). Butyl hydrazinecarboxylate and then mixed with 2 drops of concentrated hydrochloric acid. After the reaction mixture had been stirred for about 18 h at RT, most of the ethanol was removed on a rotary evaporator. The remaining residue was diluted with 150 ml of water and neutralized by the addition of saturated aqueous sodium bicarbonate solution. The precipitated solid was filtered off, washed with a little water and dried under high vacuum. There were obtained 354 mg (91% of theory) of the title compound. Ή-NMR (400 MHz, DMSO-d ₆ , δ / ppm): 10.84 (br.s, 1H), 8.28 (s, 1H), 5.20 (quin, 1H), 4.04 (t, 2H), 3.64 (t , 2H), 3.25 (s, 3H), 2.91-2.76 (m, 2H), 2.43 (s, 3H), 2.17 (dtd, 2H), 1.88-1.65 (m, 2H), 1.45 (s, 9H).

LC / MS (Method 1, ES Ineg): R _t = 2.12 min, m / z = 435.17 [MH] -. Example 186A tert-Butyl 2 - {[3- (3,3-difluorocyclobutyl) -5-methyl-2,4-dioxo-1- (3,3,3-trifluoropropyl) -l, 2,3,4 tetrahydro- thieno [2,3-d] pyrimidin-6-yl] methylene} hydrazinecarboxylate

A solution of 519 mg (1.26 mmol) of the compound from Ex. 85A in 15 ml of ethanol was first tert with 250 mg (1.89 mmol). Butylhydrazincarboxylat and then added with 5 drops of concentrated hydrochloric acid. After the reaction mixture had been stirred for about 18 h at RT, most of the ethanol was removed on a rotary evaporator. The remaining residue was diluted with water and neutralized by the addition of saturated aqueous sodium bicarbonate solution. The precipitated solid was filtered off, washed with water and dried under high vacuum. 670 mg (97% of theory, purity 93%) of the title compound were obtained, which were used without further purification for subsequent reactions. LC / MS (Method 2, ESIpos): R _t = 1.17 min, m / z = 511 [M + H] ⁺ .

Example 187A tert -Butyl 2 - {[3- (3,3-difluorocyclobutyl) -1- (2-methoxyethyl) -5-methyl-2,4-dioxo-1,2,3,4-tetrahydrothieno [2,3-d] pyrimidin-6-yl] methylene} hydrazinecarboxylate

A solution of 574 mg (1.40 mmol, 87% purity) of the compound from Example 86A in 17 ml of ethanol was first tert with 277 mg (2.10 mmol). Butylhydrazincarboxylat and then added with 5 drops of concentrated hydrochloric acid. After the reaction mixture had been stirred for about 18 h at RT, most of the ethanol was removed on a rotary evaporator. The remaining residue was diluted with water and neutralized by the addition of saturated aqueous sodium bicarbonate solution. The precipitated solid was filtered off, washed with a little water and dried under high vacuum. 697 mg (91% of theory, 86% purity) of the title compound were obtained, which were used without further purification for subsequent reactions.

LC / MS (Method 2, ESIpos): R _t = 1.10 min, m / z = 473 [M + H] ⁺ . Example 188A tert. Butyl-2- {[5-methyl-3 - (1-methylcyclobutyl) -2,4-dioxo-1 - (3, 3, 3-trifluoropropyl) -1,2,3,4-tetrahydrothieno [2 , 3-d] pyrimidin-6-yl] methylene} hydrazinecarboxylate

Analogously to the process described under Example 156A, from 300 mg (0.761 mmol, 95% purity) of the compound from Ex. 88A and 151 mg (1.14 mmol) of tert. Butylhydrazinecarboxylate 346 mg (93% of theory) of the title compound. Ή NMR (400 MHz, DMSO-d ₆ , δ / ppm): 10.86 (br.s, 1H), 8.29 (s, 1H), 4.09 (t, 2H), 2.84-2.69 (m, 2H), 2.42 (s, 3H), 2.36-2.22 (m, 4H), 1.82-1.57 (m, 2H), 1.52 (s, 3H), 1.45 (s, 9H).

LC / MS (Method 1, ES Ineg): R _t = 2.32 min, m / z = 487.16 [MH] -.

Example 189A tert. Butyl-2- {[1- (2-methoxyethyl) -5-methyl-3- (1-methylcyclobutyl) -2,4-dioxo-1,2,3,4-tetrahydrothieno [2,3-d ] pyrimidin-6-yl] methylene} hydrazinecarboxylate

Analogously to the process described under Example 156A, from 300 mg (0.892 mmol) of the compound from Ex. 89A and 177 mg (1.34 mmol) of tert. Butylhydrazinecarboxylate 400 mg (99% of theory) of the title compound. 'H-NMR (400 MHz, DMSO-d _6, δ / ppm): 10.83 (br s, 1H.), 8.27 (s, 1H), 4.06-3.96 (m, 2H), 3.62 (t, 2H); 3.26 (s, 3H), 2.41 (s, 3H), 2.37-2.22 (m, 4H), 1.80-1.57 (m, 2H), 1.52 (s, 3H), 1.45 (s, 9H).

LC / MS (method 1, ESIneg): R _t = 2.13 min, m / z = 449.19 [MH] ^" Example 190A ferric butyl-2 - {[3- (3-methoxycyclobutyl) -5-m

tetrahydrothieno [2,3-d] pyrimidin-6-yl] methylene} hydrazinecarboxylate

A solution of 778 mg (1.80 mmol, 91% purity) of the compound from Example 90A in 15 ml of ethanol was first treated with 358 mg (2.71 mmol) of tert-butyl hydrazinecarboxylate and then with 3 drops of concentrated hydrochloric acid. After the reaction mixture had been stirred for about 18 h at RT, most of the ethanol was removed on a rotary evaporator. The remaining residue was mixed with water and neutralized with saturated aqueous sodium bicarbonate solution. The precipitated solid was filtered off, washed with water and dried under high vacuum. There were obtained 0.95 g (86% of theory, 82% purity) of the title compound, which were used without further purification for subsequent reactions.

LC / MS (Method 2, ESIpos): R _t = 1.13 min, m / z = 505 [M + H] ⁺ .

Example 191A tert. Butyl-2- {[3 - (iranyl-3-methoxycyclobutyl) -1- (2-methoxyethyl) -5-methyl-2,4-dioxo-1,2,3,4-tetrahydrothieno [2,3 -d] pyrimidin-6-yl] methylene} hydrazinecarboxylate

A solution of 815 mg (1.89 mmol, 81% purity) of the compound from Example 91A in 22 ml of ethanol was first treated with 373 mg (2.82 mmol) of tert-butyl hydrazinecarboxylate and then with 3 drops of concentrated hydrochloric acid. After the reaction mixture had been stirred for about 18 h at RT, most of the ethanol was removed on a rotary evaporator. The remaining The residue was combined with water and ethyl acetate. The organic phase was washed with saturated aqueous sodium bicarbonate solution, water and saturated aqueous sodium chloride solution. After drying over anhydrous magnesium sulfate, it was filtered and concentrated to dryness. There were obtained 1.08 g (88% of theory, purity 71%) of the title compound, which were used without further purification for subsequent reactions.

LC / MS (Method 2, ESIpos): R _t = 1.02 min, m / z = 467 [M + H] ⁺ .

Example 192A tert. Butyl-2 - {[3- (di-3-methoxycyclobutyl) -5-methyl-2,4-dioxo-l - (3,3,3-trifluoropropyl) -l, 2,3,4-tetrahydrothieno] 2,3-d] pyrimidin-6-yl] methylene} hydrazinecarboxylate

A solution of 500 mg (1.23 mmol) of the compound from Example 92A in 15 ml of ethanol was first tert with 244 mg (1.84 mmol). Butylhydrazincarboxylat and then mixed with 3 drops of concentrated hydrochloric acid. After the reaction mixture had been stirred for about 18 h at RT, most of the ethanol was removed on a rotary evaporator. The remaining residue was diluted with water and ethyl acetate and neutralized by the addition of saturated aqueous sodium bicarbonate solution. The organic phase was washed with water and saturated sodium chloride solution, dried over anhydrous magnesium sulfate, filtered and concentrated. The crude product obtained gave, after drying under high vacuum, 0.53 g (81% of theory, 95% purity) of the title compound, which were used without further purification for subsequent reactions.

LC / MS (Method 2, ESIpos): R _t = 1.11 min, m / z = 505 [M + H] ⁺ . Example 193A tert. Butyl-2- {[3- (cis -3-methoxycyclobutyl) -1- (2-methoxyethyl) -5-methyl-2,4-dioxo-1,2,3,4-tetrahydrothieno [2,3 -d] pyrimidin-6-yl] methylene} hydrazinecarboxylate

A solution of 500 mg (1.35 mmol, 87% purity) of the compound from Example 93A in 16 ml of ethanol was first mixed with 267 mg (2.02 mmol) of tert-butyl hydrazinecarboxylate and then with 3 drops of concentrated hydrochloric acid. After the reaction mixture had been stirred at RT for about 18 h, most of the ethanol was removed on a rotary evaporator. The remaining residue was diluted with water and ethyl acetate and neutralized by the addition of saturated aqueous sodium bicarbonate solution. The organic phase was washed with water and saturated sodium chloride solution, dried over anhydrous magnesium sulfate, filtered and concentrated. The crude product obtained after drying in a high vacuum gave 0.84 g (100% of theory, 80% purity) of the title compound, which were used without further purification for subsequent reactions.

LC / MS (Method 2, ESIpos): R _t = 1.00 min, m / z = 467 [M + H] ⁺ . Example 194A tert-Butyl 2 - {[3- (3,3-dimethylcyclobutyl) -5-methyl-2,4-dioxo-1- (3,3,3-trifluoropropyl) -l, 2,3,4 - tetrahydrothieno [2,3-d] pyrimidin-6-yl] methylene} hydrazinecarboxylate

A solution of 500 mg (1.18 mmol, 95% purity) of the compound of Example 94A in 14 ml of ethanol was first treated with 235 mg (1.78 mmol) of tert-butyl hydrazinecarboxylate and then with 3 drops of concentrated hydrochloric acid. After the reaction mixture had been stirred for about 18 h at RT, most of the ethanol was removed on a rotary evaporator. The remaining residue was added with water and ethyl acetate. The organic phase was saturated aqueous sodium bicarbonate solution, water and saturated aqueous sodium chloride solution. After drying over anhydrous magnesium sulfate, it was filtered and concentrated to dryness. There were obtained 0.42 g (71% of theory, purity 87%) of the title compound, which were used without further purification for subsequent reactions. LC / MS (Method 2, ESIpos): R _t = 1.34 min, m / z = 503 [M + H] ⁺ .

Example 195A tert-Butyl 2 - {[3- (3,3-dimethylcyclobutyl) -1- (2-methoxyethyl) -5-methyl-2,4-dioxo-1,2,3,4-tetrahydrothieno [2,3-d] pyrimidin-6-yl] methylene} hydrazinecarboxylate

A solution of 500 mg (1.43 mmol, 91% purity) of the compound from Example 95A in 17 ml of ethanol was first tert with 283 mg (2.14 mmol). Butylhydrazincarboxylat and then mixed with 3 drops of concentrated hydrochloric acid. After the reaction mixture had been stirred for about 18 h at RT, most of the ethanol was removed on a rotary evaporator. The remaining residue was added with water and ethyl acetate. The organic phase was washed with saturated aqueous sodium bicarbonate solution, water and saturated aqueous sodium chloride solution. After drying over anhydrous magnesium sulfate, it was filtered and concentrated to dryness. There were obtained 0.74 g (64% of theory, 81% purity) of the title compound, which were used without further purification for subsequent reactions.

LC / MS (Method 2, ESIpos): R _t = 1.25 min, m / z = 467 [M + H] ⁺ . Example 196A tert. Butyl-2 - {[5-methyl-2,4-dioxo-3- (spiro [3.3] hept-2-yl) -1- (3,3,3-trifluoropropyl) -l, 2,3,4 tetrahydro- thieno [2,3-d] pyrimidin-6-yl] methylene} hydrazinecarboxylate

Analogously to the process described under Example 156A, from 400 mg (0.999 mmol) of the compound from Ex. 96A and 198 mg (1.50 mmol) of tert. -Butyl-hydrazinecarboxylate 498 mg (96% of theory) of the title compound. 'H-NMR (400 MHz, DMSO-d _6, δ / ppm): 10.86, 29.08 (s, 1H), 5:03 (quin, 1H), 4.10 (t, 2H), 2.89- (br s, 1H). 2.69 (m, 4H), 2.43 (s, 3H), 2.31-2.19 (m, 2H), 2.11-2.03 (m, 2H), 2.01-1.94 (m, 2H), 1.87-1.74 (m, 2H), 1.45 (s, 9H).

LC / MS (Method 1, ES Ineg): R _t = 2.58 min, m / z = 513.18 [MH] ^" Example 197A tert -butyl-2 - {[1- (2-methoxyethyl) -5-methyl-2, 4-dioxo-3- (spiro [3.3] hept-2-yl) -1,2,3,4-tetrahydrothieno [2,3-d] pyrimidin-6-yl] methylene} hydrazinecarboxylate

Analogously to the process described under Example 156A, from 400 mg (1.10 mmol) of the compound from Ex. 97A and 219 mg (1.66 mmol) of tert. -Butyl-hydrazinecarboxylate 510 mg (96% of theory) of the title compound.

'H-NMR (400 MHz, DMSO-de, δ / ppm): 10.84 (br.s, 1H), 8.27 (s, 1H), 5.04 (quin, 1H), 4.03 (t, 2H), 3.63 (t , 2H), 3.25 (s, 3H), 2.90-2.77 (m, 2H), 2.42 (s, 3H), 2.24 (td, 2H), 2.06 (t, 2H), 2.01 - 1.93 (m, 2H), 1.86-1.73 (m, 2H), 1.45 (s, 9H).

LC / MS (Method 1, ESIneg): R _t = 2.45 min, m / z = 475.20 [MH] ^" Example 198A feri. Butyl-2- {[3-cyclopentyl-5-methyl-2 _^

[2,3-d] pyrimidin-6-yl] methylene} hydrazinecarboxylate

Analogously to the process described under Example 156A, from 400 mg (1.07 mmol) of the compound from Ex. 98A and 212 mg (1.60 mmol) of tert. -Butyl-hydrazinecarboxylate 477 mg (83% of theory, 91%) of the title compound, which were used without further purification for subsequent reactions.

Ή-NMR (400 MHz, DMSO-de, δ / ppm): 10.87 (br.s, 1H), 8.30 (s, 1H), 5.29 (quin, 1H), 4.12 (t, 2H), 2.85-2.72 ( m, 2H), 2.45 (s, 3H), 2.08-1.97 (m, 2H), 1.95-1.83 (m, 2H), 1.81-1.69 (m, 2H), 1.63-1.49 (m, 2H), 1.45 ( s, 9H).

LC / MS (Method 2, ES Ineg): R _t = 1.27 min, m / z = 487 [MH] ^" . Example 199A tert -butyl-2- {[3-cyclopentyl-1- (2-methoxyethyl) -5 -methyl-2,4-dioxo-1,2,3,4-tetrahydrothieno [2,3-d] pyrimidin-6-yl] methylene} hydrazinecarboxylate

Analogously to the process described under Example 156A, from 400 mg (1.19 mmol) of the compound from Example 99A and 236 mg (1.78 mmol) of tert. -Butyl-hydrazinecarboxylate 505 mg (88% of theory, 93%) of the title compound, which were used without further purification for subsequent reactions. Ή-ΝΜΡν (400 MHz, DMSO-d ₆ , δ / ρρηι): 10.84 (br.s, 1H), 8.28 (s, 1H), 5.29 (quin, 1H), 4.05 (t, 2H), 3.64 (t , 2H), 3.25 (s, 3H), 2.44 (s, 3H), 2.09-1.96 (m, 2H), 1.94-1.82 (m, 2H), 1.80-1.69 (m, 2H), 1.62-1.49 (m , 2H), 1.45 (s, 9H).

LC / MS (Method 2, ES Ineg): R _t = 1.17 min, m / z = 449 [MH]. ^" Example 200A tert-butyl 2 - [(3-cyclopropyl-1,5-dimethyl-2,4 dioxo-1,2,3,4-tetrahydrothieno [2,3-d] pyrimidin-6-yl) methyl] hydrazinecarboxylate

To a solution of 325 mg (0.859 mmol) of the compound of Ex. 156A in 18 ml of methanol was added 270 mg (4.29 mmol) of sodium cyanoborohydride and some bromocresol green. Subsequently, enough titrated with acetic acid that the indicator color just turned from blue to yellow. Then the reaction mixture was heated to 65 ° C. After 1 h, an additional 135 mg (2.15 mmol) of sodium cyanoborohydride was added. During the entire reaction time, the pH value was adjusted again and again by adding further acetic acid, so that the indicator dye remained just yellow. After a total of 3 h, the volatile constituents of the reaction mixture were largely removed on a rotary evaporator. The remaining residue was taken up in ethyl acetate and washed successively with saturated aqueous sodium bicarbonate solution, water and saturated aqueous sodium chloride solution. After drying over anhydrous magnesium sulfate, it was filtered and concentrated to dryness. The crude product was purified by MPLC (Biotage Isolera One, cartridge SNAP KP-Sil, 50 g silica gel, eluent cyclohexane / ethyl acetate 2: 1). The product fractions were combined and concentrated. After drying under high vacuum, 232 mg (71% of theory) of the title compound were obtained.

'H-NMR (400 MHz, DMSO-de, δ / ppm): 8.24 (br, s, 1H), 4.96 (br, s, 1H), 3.96 (br, d, 2H), 3.38 (s, 3H) , 2.62-2.56 (m, 1H), 2.31 (s, 3H), 1.38 (s, 9H), 1.06-0.96 (m, 2H), 0.71-0.63 (m, 2H). LC / MS (Method 1, ES Ineg): R _t = 1.53 min, m / z = 379.14 [MH] -. Example 201A tert-Butyl 2 - [(1-butyl-3-cyclopropyl-5-methyl-2,4-dioxo-1,2,3,4-tetrahydrothieno [2,3-d] pyrimidine-6 yl) methyl] hydrazinecarboxylate

Analogously to the process described under Example 200A, from 400 mg (0.951 mmol) of the compound from Ex. 157A and a total of 448 mg (7.13 mmol) of sodium cyanoborohydride 318 mg (72% of theory, 92% purity) of the title compound were prepared , which were used without further purification for subsequent reactions.

Ή-NMR (400 MHz, DMSO-de, δ / ppm): 8.23 (br.s, 1H), 4.99 (br.d, 1H), 3.96 (br.d, 2H), 3.83 (t, 2H), 2.63-2.56 (m, 1H), 2.31 (s, 3H), 1.65 (quin, 2H), 1.38 (s, 9H), 1.38-1.29 (m, 2H), 1.05-0.96 (m, 2H), 0.92 ( t, 3H), 0.71-0.61 (m, 2H).

LC / MS (method 1, ESIneg): R _t = 1.98 min, m / z = 421.19 [MH] -.

Example 202A tert-Butyl 2 - {[3-cyclopropyl-5-methyl-2,4-dioxo-1- (3,3,3-trifluoropropyl) -l, 2,3,4-tetrahydrothieno- [2, 3-d] pyrimidin-6-yl] methyl} hydrazinecarboxylate

A solution of 655 mg (1.42 mmol) of the compound from Ex. 158A in 30 ml of methanol was treated with 447 mg (7.11 mmol) of sodium cyanoborohydride and a little bromocresol green. Then enough titrated acetic acid was added that the indicator color turned from blue to yellow. Then the reaction mixture was heated to 65 ° C. After 1 h and after 3 h each because another 224 mg (3.55 mmol) of sodium cyanoborohydride was added. During the entire reaction time, the pH value was adjusted again and again by adding further acetic acid, so that the indicator color remained just yellow. After a total of 7 h, the volatile constituents of the reaction mixture were largely removed on a rotary evaporator. The remaining residue was taken up in ethyl acetate and washed successively with saturated aqueous sodium bicarbonate solution, water and saturated aqueous sodium chloride solution. After drying over anhydrous magnesium sulfate, it was filtered and concentrated to dryness. The crude product was purified by MPLC (Biotage Isolera One, cartridge SNAP KP-Sil, 50 g silica gel, eluent cyclohexane / ethyl acetate 1: 2). The product fractions were combined and evaporated. After drying under high vacuum, 570 mg (86% of theory) of the title compound were obtained.

'H-NMR (400 MHz, DMSO-de, δ / ppm): 8.24 (br.s, 1H), 5.04 (br.d, 1H), 4.08 (t, 2H), 3.97 (d, 2H), 2.82 -2.68 (m, 2H), 2.64-2.56 (m, 1H), 2.31 (s, 3H), 1.38 (s, 9H), 1.06-0.96 (m, 2H), 0.70-0.62 (m, 2H). LC / MS (Method 1, ES Ineg): R _t = 1.86 min, m / z = 461.15 [MH] ^" Example 203A tert -butyl 2 - {[1- (cyclobutylmethyl) -3-cyclopropyl-5-methyl] 2,4-dioxo-1,2,3,4-tetrahydrothieno [2,3-d] pyrimidin-6-yl] methyl} hydrazinecarboxylate

Analogously to the process described in Example 200A, 350 mg (0.809 mmol) of the compound from Ex. 159A and a total of 381 mg (6.07 mmol) of sodium cyanoborohydride were used to produce 378 mg (97% of theory, 90% purity) of the title compound, which were used without further purification for subsequent reactions.

'H-NMR (400 MHz, DMSO-de, δ / ppm): 8.24 (br.s, 1H), 4.99 (br.d, 1H), 3.95 (br.d, 2H), 3.90 (d, 2H) , 2.85-2.71 (m, 1H), 2.59 (t, 1H), 2.30 (s, 3H), 2.03-1.91 (m, 2H), 1.89-1.74 (m, 4H), 1.38 (s, 9H), 1.03 -0.98 (m, 2H), 0.69-0.60 (m, 2H).

LC / MS (Method 1, ESIpos): R _t = 2.02 min, m / z = 303.12 [M + HC ₅ Hi ₂ N ₂ O ₂ ] ⁺ . Example 204A tert. Butyl 2- ({3-cyclopropyl-l - [(2,2-difluoro ^

hydrothieno [2,3-d] pyrimidin-6-yl} methyl) hydrazinecarboxylate (racemate)

Analogously to the process described under Example 200A, from 740 mg (1.63 mmol) of the compound of Ex. 160A and a total of 767 mg (12.2 mmol) of sodium cyanoborohydride 690 mg (80% of theory, 86% purity) of the title compound were prepared , which were used without further purification for subsequent reactions.

'H-NMR (400 MHz, DMSO-de, δ / ppm): 8.27 (br.s, 1H), 5.03 (br.s, 1H), 4.10-3.89 (m, 2H), 3.97 (s, 2H) , 2.65-2.57 (m, 1H), 2.31 (s, 3H), 2.20 (td, 1H), 1.76-1.62 (m, 1H), 1.53-1.42 (m, 1H), 1.38 (s, 9H), 1.06 -0.98 (m, 2H), 0.71-0.64 (m, 2H).

LC / MS (method 1, ESIneg): R _t = 1.87 min, m / z = 455.16 [MH] -.

Example 205A tert. Butyl 2- {[1- (cyanomethyl) -3-cyclopropyl-5-methyl-2,4-dioxo-1,2,3,4-tetrahydrothieno [2,3-d] pyrimidin-6-yl] methyl} hydrazinecarboxylate

Analogously to the process described under Ex. 200A, from 305 mg (0.756 mmol) of the compound from Ex. 161A and a total of 356 mg (5.67 mmol) of sodium cyanoborohydride were added 222 mg (80%) of theory. Th.) Of the title compound. 'H-NMR (400 MHz, DMSO-de, δ / ρρηι): 8.27 (br.s, 1H), 5.06 (s, 2H), 5.04 (br.s, 1H), 3.99 (br. D, 2H) , 2.67-2.59 (m, 1H), 2.32 (s, 3H), 1.39 (s, 9H), 1.07-0.96 (m, 2H), 0.74-0.65 (m, 2H).

LC / MS (Method 1, ES Ineg): R _t = 1.58 min, m / z = 404.14 [MH] ^" Example 206A tert -butyl-2- {[3-cyclopropyl-1 - (2-methoxyethyl) -5- methyl 2,4-dioxo-1,2,3,4-tetrahydrothieno [2,3-d] pyrimidin-6-yl] methyl} hydrazinecarboxylate

Analogously to the process described under Example 202A, 369 mg (72% of theory) of the title compound were prepared from 305 mg (0.756 mmol) of the compound from Example 162A and a total of 736 mg (2.34 mmol) of sodium cyanoborohydride. The total reaction time in this case was approx.

20 h.

Ή-NMR (400 MHz, DMSO-de, δ / ppm): 8.24 (br, s, 1H), 4.96 (br, d, 1H), 3.99 (t, 2H), 3.95 (br, d, 2H), 3.62 (t, 2H), 3.25 (s, 3H), 2.64-2.55 (m, 1H), 2.31 (s, 3H), 1.38 (s, 9H), 1.05-0.96 (m, 2H), 0.71-0.61 ( m, 2H). LC / MS (Method 1, ES Ineg): R _t = 1.58 min, m / z = 423.17 [MH] -.

Example 207A tert. Butyl 2- {[3-cyclopropyl-1- (2-ethoxyethyl) -5-methyl-2,4-dioxo-1,2,3,4-tetrahydrothieno [2,3-d] pyrimidine-6- yl] methyl} hydrazinecarboxylate

H ₃

Analogously to the process described under Example 200A, from 325 mg (0.745 mmol) of the compound from Ex. 163A and a total of 227 mg (3.61 mmol) of sodium cyanoborohydride, 233 mg (71% of theory) of the title compound were prepared.

'H-NMR (400 MHz, DMSO-de, δ / ppm): 8.23 (br, s, 1H), 4.96 (br, s, 1H), 3.98 (t, 2H), 3.96 (br, d, 2H) , 3.65 (t, 2H), 3.45 (q, 2H), 2.64-2.56 (m, 1H), 2.31 (s, 3H), 1.38 (s, 9H), 1.06 (t, 3H), 1.04-0.98 (m , 2H), 0.71-0.60 (m, 2H).

LC / MS (Method 1, ESIpos): R _t = 1.73 min, m / z = 307.11 [M + HC ₅ Hi ₂ N ₂ O ₂ ] ⁺ . Example 208A tert -butyl 2 - {[3-cyclopropyl-1- (2-isopropoxyethyl) -5-methyl-2,4-dioxo-1,2,3,4-tetrahydrothieno [2,3-d] pyrimidin-6-yl] methyl} hydrazinecarboxylate

Analogously to the process described under Example 200A, 377 mg (98% of theory) of the title compound were prepared from 380 mg (0.843 mmol) of the compound from Example 164A and a total of 227 mg (3.61 mmol) of sodium cyanoborohydride. Ή-NMR (400 MHz, DMSO-d ₆ , δ / ppm): 8.22 (br.s, 1H), 4.95 (br.d, 1H), 4.01-3.88 (m, 4H), 3.64 (t, 2H) , 3.56 (dt, 1H), 2.60 (t, 1H), 2.31 (s, 3H), 1.38 (s, 9H), 1.04-0.98 (m, 2H), 1.03 (d, 6H), 0.71-0.60 (m , 2H).

LC / MS (Method 2, ES Ineg): R _t = 0.98 min, m / z = 497 [M-H + HCOOH] -. Example 209A tert. Butyl 2- ({3-cyclopropyl-5-methyl-2,4-dioxo-1- (2- (trifluoromethoxy) ethyl] -1,3,3,4-tetrahydrothieno [2,3-d] pyrimidin-6-yl} methyl) hydrazinecarboxylate

A solution of 440 mg (0.923 mmol) of the compound from Ex. 165A in 20 ml of methanol was treated with 290 mg (4.62 mmol) of sodium cyanoborohydride and a little bromocresol green. Then enough titrated acetic acid was added that the indicator color turned from blue to yellow. Then the reaction mixture was heated to 65 ° C. After 1 h, an additional 145 mg (2.31 mmol) of sodium cyanoborohydride were added. During the entire reaction time, the pH value was adjusted again and again by adding further acetic acid, so that the indicator color remained just yellow. After a total of 3 h, the volatile constituents of the reaction mixture were largely removed on a rotary evaporator. The remaining residue was taken up in ethyl acetate and washed successively with saturated aqueous sodium bicarbonate solution, water and saturated aqueous sodium chloride solution. After drying over anhydrous magnesium sulfate, it was filtered and concentrated to dryness. The crude product was purified by MPLC (Biotage Isolera One, cartridge SNAP KP-Sil, 50 g silica gel, eluent cyclohexane / ethyl acetate 2: 1). The product fractions were combined and concentrated. After drying under high vacuum, 339 mg (72% of theory, 95% purity) of the title compound were obtained, which were used without further purification for subsequent reactions.

Ή-NMR (400 MHz, DMSO-de, δ / ppm): 8.23 (br.s, 1H), 4.98 (br.d, 1H), 4.39 (t, 2H), 4.16 (t, 2H), 3.96 ( br, d, 2H), 2.65-2.57 (m, 1H), 2.31 (s, 3H), 1.38 (s, 9H), 1.04-0.99 (m, 2H), 0.70-0.61 (m, 2H).

LC / MS (Method 1, ES Ineg): R _t = 1.90 min, m / z = 477.14 [MH] -.

Example 210A tert. Butyl-2- {[3-cyclopropyl-5-methyl-2,4-dioxo-1 - (tetrahydrofuran-2-ylmethyl) -1,3,3,4-tetrahydrothieno [2,3-d] pyrimidine -6-yl] methyl} hydrazinecarboxylate (racemate)

Analogously to the process described under Example 202A, 809 mg (1.80 mmol) of the compound from Ex. 166A and a total of 959 mg (15.3 mmol) of sodium cyanoborohydride were used to produce 619 mg (76% of theory) of the title compound. 'H-NMR (400 MHz, DMSO-d _6, δ / ppm): (br. S, 1H) (br. S, 1H) 8.24, 4.95, 4:29 to 4:18 (m, 1H), 4.02- 3.88 (m , 3H), 3.80-3.74 (m, 1H), 3.70 (dd, 1H), 3.65-3.57 (m, 1H), 2.60 (td, 1H), 2.31 (s, 3H), 2.01-1.76 (m, 3H ), 1.72-1.60 (m, 1H), 1.39 (s, 9H), 1.07-0.96 (m, 2H), 0.70-0.62 (m, 2H).

LC / MS (Method 1, ES Ineg): R _t = 1.69 min, m / z = 449.19 [MH] ^"

Example 211A tert. Butyl 2- ({3-cyclopropyl-5-methyl-2,4-dioxo-1 - [(2R) -tetrahydrofuran-2-ylmethyl] -1,3,3,4-tetrahydrothieno [2,3-d ] pyrimidine-6-yl} methyl) hydrazinecarboxylate

Analogously to the process described under Example 200A, from 275 mg (0.613 mmol) of the compound from Ex. 167A and a total of 289 mg (4.60 mmol) of sodium cyanoborohydride 223 mg (80% of theory) of the title compound were prepared.

'H-NMR (400 MHz, DMSO-de, δ / ppm): 8.24 (br, s, 1H), 4.95 (br, s, 1H), 4.32-4.17 (m, 1H), 4.03- 3.89 (m, 3H), 3.81-3.74 (m, 1H), 3.70 (dd, 1H), 3.65-3.57 (m, 1H), 2.60 (tt, 1H), 2.31 (s, 3H), 2.03-1.75 (m, 3H) , 1.72-1.60 (m, 1H), 1.39 (s, 9H), 1.06-0.95 (m, 2H), 0.71-0.60 (m, 2H).

LC / MS (Method 1, ES Ineg): R _t = 1.70 min, m / z = 449.19 [MH] ^" Example 212A feri. Butyl-2- ({3-cyclopropyl-5-methyl-2, ^^

tetrahydrothieno [2,3-d] pyrimidin-6-yl} methyl) hydrazinecarboxylate

Analogously to the process described under Example 200A, 178 mg (74% of theory) of the title compound were prepared from 235 mg (0.524 mmol) of the compound from Example 168A and a total of 247 mg (3.93 mmol) of sodium cyanoborohydride.

'H-NMR (400 MHz, DMSO-de, δ / ppm): 8.24 (br, s, 1H), 4.95 (br, s, 1H), 4.31 -4.16 (m, 1H), 4.04- 3.89 (m, 3H), 3.81-3.74 (m, 1H), 3.70 (dd, 1H), 3.65-3.57 (m, 1H), 2.64-2.56 (m, 1H), 2.31 (s, 3H), 2.03-1.74 (m, 3H), 1.72-1.59 (m, 1H), 1.39 (s, 9H), 1.07-0.94 (m, 2H), 0.72-0.60 (m, 2H).

LC / MS (Method 1, ES Ineg): R _t = 1.70 min, m / z = 449.19 [MH] -.

Example 213A teri. Butyl-2- {[l, 5-dimethyl-3- (1-methylcyclopropyl) -2,4-dioxo-1,2,3,4-tetrahydrothieno [2,3-d] pyrimidin-6-yl] methyl} hydrazinecarboxylate

Analogously to the process described under Example 200A, 357 mg (0.905 mmol) of the compound from Ex. 169A and a total of 426 mg (6.78 mmol) of sodium cyanoborohydride were converted into 267 mg (71) of theory. Th., 95% purity) of the title compound, which were used without further purification for subsequent reactions. 'H-NMR (400 MHz, DMSO-d _6, δ / ppm): 8.23, 4.96 (br d, 1H.), 3.96 (d, 2H), 3:38 (s, 3H), (br s, 1H). 2.32 (s, 3H), 1.38 (s, 9H), 1.33 (s, 3H), 0.99-0.76 (m, 4H). LC / MS (Method 2, ES Ineg): R _t = 0.89 min, m / z = 439 [M-H + HCOOH] -. Example 214A tert -Butyl 2 - {[1-butyl-5-methyl-3- (1-methylcyclopropyl) -2,4-dioxo-1,2,3,4-tetrahydrothieno [2,3-d] pyrimidin-6-yl] methyl} hydrazinecarboxylate

Analogously to the process described under Example 200A, 393 mg (0.902 mmol) of the compound from Example 170A and a total of 253 mg (4.03 mmol) of sodium cyanoborohydride were used to prepare 353 mg (89% of theory) of the title compound.

Ή-NMR (400 MHz, DMSO-de, δ / ppm): 8.22 (br, s, 1H), 4.98 (br, s, 1H), 3.95 (br, d, 2H), 3.90- 3.70 (m, 2H ), 2.31 (s, 3H), 1.65 (quin, 2H), 1.44-1.23 (m, 2H), 1.38 (s, 9H), 1.33 (s, 3H), 1.02-0.66 (m, 2H), 0.92 ( t, 3H).

LC / MS (Method 1, ES Ineg): R _t = 2.14 min, m / z = 435.21 [MH] -. Example 215A tert. Butyl-2- {[5-methyl-3- (1-methylcyclopropyl) -2,4-dioxo-1- (3,3,3-trifluoropropyl) -l, 2,3,4-tetrahydrothieno [2 , 3-d] pyrimidin-6-yl] methyl} hydrazinecarboxylate

A solution of 1.33 g (2.64 mmol, 94% purity) of the compound from Ex. 171A in 25 ml of methanol was treated with 830 mg (13.21 mmol) of sodium cyanoborohydride and a little bromocresol green. Subsequently, so much acetic acid was titrated that the indicator color turned from blue to yellow. Then the reaction mixture was heated to 65 ° C. After total 16 h, the volatile constituents of the reaction mixture were largely removed on a rotary evaporator. The remaining residue was taken up in ethyl acetate and washed successively with saturated aqueous sodium bicarbonate solution, water and saturated aqueous sodium chloride solution. After drying over anhydrous magnesium sulfate, it was filtered and concentrated to dryness. There were obtained 1.28 g (80% of theory, purity 79%) of the title compound, which were used without further purification for subsequent reactions.

LC / MS (Method 2, ES Ineg): R _t = 1.05 min, m / z = 521 [M-H + HCOOH] -.

Example 216A tert -Butyl 2 - {[1- (cyclobutylmethyl) -5-methyl-3- (1-methylcyclopropyl) -2,4-dioxo-1,2,3,4-tetrahydrothieno [2,3 -d] pyrimidin-6-yl] methyl} hydrazinecarboxylate

Analogously to the process described under Ex. 200A, 360 mg (0.806 mmol) of the compound from Ex. 172A and a total of 380 mg (6.05 mmol) of sodium cyanoborohydride gave 249 mg (68%) of theory. Th.) Of the title compound. 'H-NMR (400 MHz, DMSO-d _6, δ / ppm): 8.23, 4.98, 4.05-3.73 (m, 2H), 3.95 (d, 2H (br s, 1H). (Br d, 1H). ), 2.83-2.72 (m, 1H), 2.31 (s, 3H), 2.03-1.90 (m, 2H), 1.89-1.75 (m, 4H), 1.38 (s, 9H), 1.32 (s, 3H), 1.00-0.66 (m, 4H).

LC / MS (method 1, ESIneg): R _t = 2.19 min, m / z = 447.21 [MH] ^"

Example 217A tert. Butyl 2- ({1 - [(2,2-difluorocyclopropyl) methyl] -5-methyl-3- (1-methylcyclopropyl) -2,4-dioxo-l, 2,3,4-tetrahydrothieno [2, 3-d] pyrimidin-6-yl} methyl) hydrazinecarboxylate (racemate)

Analogously to the procedure described under Example 200A, from 810 mg (1.73 mmol) of the compound from Ex. 173A and a total of 485 mg (7.72 mmol) of sodium cyanoborohydride 682 mg (76% of theory, 91%) of the pure title compound were prepared , which were used without further purification for subsequent reactions.

'H-NMR (400 MHz, DMSO-de, δ / ppm): 8.23 (br.s, 1H), 5.01 (br.s, 1H), 4.18-3.84 (m, 2H), 3.97 (br. D, 2H), 2.32 (s, 3H), 2.27-2.12 (m, 1H), 1.78-1.62 (m, 1H), 1.52-1.42 (m, 1H), 1.38 (s, 9H), 1.34 (s, 3H) , 1.00-0.75 (m, 4H).

LC / MS (Method 1, ESIneg): R _t = 2:00 min, m / z = 469.17 [MH] ^'Example 218A tert-butyl-2 - {[l - (cyanomethyl) -5-methyl-3- (l -methylcyclopropyl) -2,4-dioxo-l, 2,3,4-tetrahydrothieno [2,3-d] pyrimidin-6-yl] methyl} hydrazinecarboxylate

Analogously to the process described under Example 200A, from 285 mg (0.478 mmol, 70% purity) of the compound from Ex. 174A and a total of 225 mg (3.58 mmol) sodium cyanoborohydride 204 mg (94% of theory, 92% purity ) of the title compound, which were used without further purification for subsequent reactions.

'H-NMR (400 MHz, DMSO-de, δ / ppm): 8.26 (br.s, 1H), 5.09-5.01 (m, 3H), 3.99 (br.d, 2H), 2.33 (s, 3H) , 1.39 (s, 9H), 1.35 (s, 3H), 1.02-0.77 (m, 4H). LC / MS (Method 2, ES Ineg): R _t = 0.90 min, m / z = 418 [MH] ^" Example 219A tert-Butyl 2 - {[1- (2-methoxyethyl) -5-methyl-3- (1-methylcyclopropyl) -2,4-dioxo-1,2,3,4-tetrahydrothieno [2 , 3-d] pyrimidin-6-yl] methyl} hydrazinecarboxylate

A solution of 1.17 g (1.98 mmol, 73% purity) of the compound from Ex. 175A in 19 ml of methanol was admixed with 620 mg (9.87 mmol) of sodium cyanoborohydride and a little bromocresol green. Subsequently, so much acetic acid was titrated that the indicator color turned from blue to yellow. Then the reaction mixture was heated to 65 ° C. After 2 h, the volatile constituents of the reaction mixture were largely removed on a rotary evaporator. The remaining residue was taken up in ethyl acetate and washed successively with saturated aqueous sodium bicarbonate solution, water and saturated aqueous sodium chloride solution. After drying over anhydrous magnesium sulfate, it was filtered and concentrated to dryness. 660 mg (69% of theory, purity 91%) of the title compound were obtained, which were used without further purification for subsequent reactions. LC / MS (Method 2, ESIpos): R _t = 0.91 min, m / z = 439 [M + H] ⁺ .

Example 220A tert-Butyl 2- ({5-methyl-3- (1-methylcyclopropyl) -2,4-dioxo-1- (2- (trifluoromethoxy) ethyl] -1,3,3,4-tetrahydrothieno [ 2,3-d] pyrimidin-6-yl} methyl) hydrazinecarboxylate

A solution of 420 mg (0.685 mmol, 80% purity) of the compound from Ex. 176A in 15 ml of methanol was treated with 215 mg (3.43 mmol) of sodium cyanoborohydride and some bromocresol green. puts. Subsequently, enough titrated with acetic acid that the indicator color just turned from blue to yellow. Then the reaction mixture was heated to 65 ° C. After 1 h, an additional 108 mg (1.72 mmol) of sodium cyanoborohydride was added. During the entire reaction time, the pH value was adjusted again and again by adding further acetic acid, so that the indicator color remained just yellow. After a total of 3 h, the volatile constituents of the reaction mixture were largely removed on a rotary evaporator. The remaining residue was taken up in ethyl acetate and washed successively with saturated aqueous sodium bicarbonate solution, water and saturated aqueous sodium chloride solution. After drying over anhydrous magnesium sulfate, it was filtered and concentrated to dryness. The crude product was purified by MPLC (Biotage Isolera One, cartridge SNAP KP-Sil, 50 g silica gel, eluent cyclohexane / ethyl acetate 2: 1). The product fractions were combined and concentrated. After drying under high vacuum, 292 mg (74% of theory, 86% purity) of the title compound were obtained, which were used without further purification for subsequent reactions.

'H-NMR (400 MHz, DMSO-de, δ / ppm): 8.23 (br.s, 1H), 4.98 (br.d, 1H), 4.46-4.33 (m, 2H), 4.30-4.04 (m, 2H), 3.96 (br d, 2H), 2.32 (s, 3H), 1.38 (s, 9H), 1.33 (s, 3H), 0.97-0.75 (m, 4H).

LC / MS (Method 1, ES Ineg): R _t = 2.03 min, m / z = 537.16 [M-H + HCOOH] -.

Example 221A tert -Butyl 2 - {[1- (2-ethoxyethyl) -5-methyl-3- (1-methylcyclopropyl) -2,4-dioxo-1,2,3,4-tetrahydrothieno [2 , 3-d] pyrimidin-6-yl] methyl} hydrazinecarboxylate

Analogously to the process described under Example 200A, from 310 mg (0.482 mmol, 70%> purity) of the compound from Ex. 177A and a total of 227 mg (3.61 mmol) of sodium cyanoborohydride 202 mg (76% of theory, 82%). > Purity) of the title compound, which were used without further purification for subsequent reactions.

'H-NMR (400 MHz, DMSO-de, δ / ppm): 8.22 (br.s, 1H), 4.96 (br.d, 1H), 4.15-3.80 (m, 2H), 3.95 (br. D, 2H), 3.65 (t, 2H), 3.45 (q, 2H), 2.31 (s, 3H), 1.38 (s, 9H), 1.33 (s, 3H), 1.05 (t, 3H), 0.96-0.76 (m , 4H). LC / MS (Method 1, ES Ineg): R _t = 1.88 min, m / z = 451.20 [MH] ^" Example 222A tert -butyl 2 - {[1- (2-isopropoxyethyl) -5-methyl-3- (1-methylcyclopropyl) -2,4-dioxo-1,2,3,4-tetrahydrothieno [2,3-d] pyrimidin-6-yl] methyl} hydrazinecarboxylate

Analogously to the process described under Example 200A, 365 mg (0.786 mmol) of the compound from Ex. 178A and a total of 227 mg (3.61 mmol) of sodium cyanoborohydride were used to produce 284 mg (77% of theory) of the title compound.

Ή-NMR (400 MHz, DMSO-de, δ / ppm): 8.21 (br.s, 1H), 4.95 (br.d, 1H), 4.08-3.82 (m, 2H), 3.95 (br. D, 2H ), 3.64 (t, 2H), 3.56 (sept, 1H), 2.31 (s, 3H), 1.38 (s, 9H), 1.33 (s, 3H), 1.03 (d, 6H), 0.96-0.74 (m, 4H).

LC / MS (Method 1, ESIneg): R _t = 2.01 min, m / z = 465.22 [MH] -. Example 223A tert -Butyl 2- ({5-methyl-3- (1-methylcyclopropyl) -2,4-dioxo-1 - [(2R) -tetrahydrofuran-2-ylmethyl] -1,3,3,4 -tetrahydrothieno [2,3-d] pyrimidin-6-yl} methyl) hydrazinecarboxylate

Analogously to the process described in Example 200A, 152 mg (64% of theory) of the title compound were prepared from 235 mg (0.508 mmol) of the compound from Ex. 179A and a total of 239 mg (3.81 mmol) of sodium cyanoborohydride. 'H-NMR (400 MHz, DMSO-de, δ / ρρηι): 8.23 (br.s, 1H), 4.94 (br.s, 1H), 4.32-3.85 (m, 4H), 3.84- 3.53 (m, 3H), 2.31 (s, 3H), 2.02-1.76 (m, 3H), 1.72-1.60 (m, 1H), 1.38 (s, 9H), 1.33 (s, 3H), 0.97-0.71 (m, 4H) ,

LC / MS (Method 1, ES Ineg): R _t = 1.86 min, m / z = 509.21 [M-H + HCOOH] -. Example 224A tert. Butyl-2- ({5-methyl-3- (1-methylcyclopropyl) -2,4-dioxo-1 - [(2S) -tetrahydrofuran-2-ylmethyl] -1,2,3,4-tetrahydrothieno [2 , 3-d] pyrimidin-6-yl} methyl) hydrazinecarboxylate

Analogously to the process described under Example 200A, 270 mg (79% of theory) of the title compound were prepared from 340 mg (0.735 mmol) of the compound from Ex. 180A and a total of 346 mg (5.51 mmol) of sodium cyanoborohydride.

'H-NMR (400 MHz, DMSO-de, δ / ppm): 8.23 (br, s, 1H), 4.94 (br, s, 1H), 4.30-3.85 (m, 4H), 3.83- 3.53 (m, 3H), 2.31 (s, 3H), 2.03-1.75 (m, 3H), 1.73-1.59 (m, 1H), 1.38 (s, 9H), 1.33 (s, 3H), 0.98-0.72 (m, 4H) , LC / MS (Method 1, ES Ineg): R _t = 1.86 min, m / z = 509.21 [M-H + HCOOH] -. Example 225A tert. Butyl 2- ({1- (2-methoxyethyl) -5-methyl-2,4-dioxo-3- [1- (trifluoromethyl) cyclopropyl] -1,3,3,4-tetrahydrothieno [2,3- d] pyrimidin-6-yl} methyl) hydrazinecarboxylate

Analogously to the process described under Example 200A, 405 mg (87% of theory, 96% purity) of the title compound were prepared from 445 mg (0.907 mmol) of the compound from Example 181A and a total of 428 mg (6.80 mmol) of sodium cyanoborohydride.

'H-NMR (400 MHz, DMSO-de, δ / ppm): 8.24 (br.s, 1H), 5.00 (br.d, 1H), 4.05-3.99 (m, 2H), 3.97 (br. D, 2H), 3.63 (t, 2H), 3.25 (s, 3H), 2.31 (s, 3H), 1.65-1.51 (m, 2H), 1.38 (s, 9H), 1.35-1.31 (m, 2H).

LC / MS (Method 1, ES Ineg): R _t = 1.88 min, m / z = 491.16 [MH] ^" Example 226A tert -butyl-2- {[3- (1-ethylcyclopropyl) -5-methyl-2, 4-dioxo-l - (3,3,3-trifluoropropyl) -l, 2,3,4-tetrahydrothieno [2,3-d] pyrimidin-6-yl] methyl} hydrazinecarboxylate

200 mg (0.328 mmol, 80% purity) of the compound from Example 182A and a total of 154 mg (2.46 mmol) of sodium cyanoborohydride gave 146 mg (90%) of theory, analogously to the process described under Example 200A. Th.) Of the title compound. LC / MS (Method 1, ES Ineg): R _t = 2.17 min, m / z = 535.18 [M-H + HCOOH] -.

Example 227A tert. Butyl-2- {[3- (1-ethylcyclopropyl) -1- (2-methoxyethyl) -5-methyl-2,4-dioxo-1,2,3,4-tetrahydrothieno [2,3-d ] pyrimidin-6-yl] methyl} hydrazinecarboxylate

Analogously to the process described under Example 200A, 270 mg (0.527 mmol, 88% purity) of the compound from Ex. 183A and a total of 249 mg (3.96 mmol) of sodium cyanoborohydride gave 146 mg (61% of theory) of the title compound produced.

LC / MS (Method 1, ESIneg): R _t = 1.91 min, m / z = 451.20 [MH] ^" Example 228A tert -butyl-2- {[3 -cyclobutyl-5-methyl-2,4-dioxo] 1 - (3, 3, 3-trifluoropropyl) -1,2,3,4-tetrahydrothieno [2,3-d] pyrimidin-6-yl] methyl} hydrazinecarboxylate

A solution of 450 mg (0.948 mmol) of the compound from Ex. 184A in 9.5 ml of methanol was admixed with 298 mg (4.74 mmol) of sodium cyanoborohydride and a little bromocresol green. Subsequently, enough titrated with acetic acid that the indicator color just turned from blue to yellow. Then the reaction mixture was heated to 65 ° C. After 1 h and after 3 h each additional 149 mg (2.37 mmol) of sodium cyanoborohydride were added. During the entire reaction time, the pH value was adjusted again and again by adding further acetic acid, so that the indicator color remained just yellow. After a total of 7 h, the volatile constituents of the reaction mixture were largely removed on a rotary evaporator. The remaining residue was taken up in ethyl acetate and washed successively with saturated aqueous sodium bicarbonate solution, water and saturated aqueous sodium chloride solution. After drying over anhydrous magnesium sulfate, it was filtered and concentrated to dryness. The crude product was stirred with acetonitrile at RT. After suctioning off the product and drying in a high vacuum, 402 mg (85% of theory, 96% purity) of the title compound were obtained.

Ή-NMR (400 MHz, DMSO-de, δ / ppm): 8.25 (br.s, 1H), 5.22 (quin, 1H), 5.05 (br.d, 1H), 4.09 (t, 2H), 3.98 ( d, 2H), 2.91-2.69 (m, 4H), 2.31 (s, 3H), 2.22-2.10 (m, 2H), 1.87-1.64 (m, 2H), 1.38 (s, 9H). LC / MS (Method 1, ES Ineg): R _t = 2.22 min, m / z = 475.16 [MH] -. Example 229A tert. Butyl 2- {[3 -cyclobutyl-1- (2-methoxyethyl) -5-methyl-2,4-dioxo-1,2,3,4-tetrahydrothieno [2,3-d] pyrimidine-6- yl] methyl} hydrazinecarboxylate

A solution of 350 mg (0.802 mmol) of the compound from Ex. 185A in 8 ml of methanol was treated with 252 mg (4.01 mmol) of sodium cyanoborohydride and a little bromocresol green. Subsequently, enough titrated with acetic acid that the indicator color just turned from blue to yellow. Then the reaction mixture was heated to 65 ° C. After 1 h and after 3 h each additional 126 mg (2.00 mmol) of sodium cyanoborohydride were added. During the entire reaction time, the pH value was adjusted again and again by addition of further acetic acid in such a way that the indicator color remained just yellow. After a total of 7 h, the volatile constituents of the reaction mixture were largely removed on a rotary evaporator. The remaining residue was taken up in ethyl acetate and washed successively with saturated aqueous sodium bicarbonate solution, water and saturated aqueous sodium chloride solution. After drying over anhydrous magnesium sulfate, it was filtered and concentrated to dryness. The crude product was stirred with acetonitrile at RT. After suctioning off the product and drying in a high vacuum, 266 mg (75% of theory) of the title compound were obtained.

Ή NMR (400 MHz, DMSO-de, δ / ppm): 8.25 (br, s, 1H), 5.23 (quin, 1H), 4.97 (br, d, 1H), 4.00 (t, 2H), 3.96 ( br, d, 2H), 3.64 (t, 2H), 3.25 (s, 3H), 2.91-2.78 (m, 2H), 2.31 (s, 3H), 2.16 (dtd, 2H), 1.87-1.63 (m, 2H), 1.39 (s, 9H).

LC / MS (Method 1, ES Ineg): R _t = 1.99 min, m / z = 483.19 [M-H + HCOOH] -.

Example 230A tert. Butyl-2- {[3- (3,3-difluorocyclobutyl) -5-methyl-2,4-dioxo-1- (3,3,3-trifluoropropyl) -l, 2,3,4-tetrahydrothieno] [2,3-d] pyrimidin-6-yl] methyl} hydrazinecarboxylate

A solution of 670 mg (1.22 mmol, 93% purity) of the compound from Ex. 186A in 12 ml of methanol was admixed with 384 mg (6.11 mmol) of sodium cyanoborohydride and a little bromocresol green. Subsequently, so much acetic acid was titrated that the indicator color turned from blue to yellow. Then the reaction mixture was heated to 65 ° C. After 2 h and after 4 h each additional 192 mg (2.50 mmol) of sodium cyanoborohydride were added. After a total of 16 h at 65 ° C, the volatiles of the reaction mixture were largely removed on a rotary evaporator. The remaining residue was taken up in ethyl acetate and washed successively with saturated aqueous sodium bicarbonate solution, water and saturated aqueous sodium chloride solution. After drying over anhydrous magnesium sulfate, it was filtered and concentrated to dryness. 630 mg (83% of theory, purity 82%) of the title compound were obtained, which were used without further purification for subsequent reactions.

LC / MS (Method 2, ESIpos): R _t = 1.18 min, m / z = 405 [M + H] ⁺ .

Example 231A tert. Butyl-2- {[3- (3,3-difluorocyclobutyl) -1- (2-methoxyethyl) -5-methyl-2,4-dioxo-1,2,3,4-tetrahydrothieno [2,3 -d] pyrimidin-6-yl] methyl} hydrazinecarboxylate

A solution of 697 mg (1.27 mmol, 86% purity) of the compound from Ex. 187A in 12 ml of methanol was mixed with 400 mg (6.37 mmol) of sodium cyanoborohydride and a little bromocresol green. Subsequently, so much acetic acid was titrated that the indicator color turned from blue to yellow. Then the reaction mixture was heated to 65 ° C. After a total of 2 h the volatile constituents of the reaction mixture were largely removed on a rotary evaporator. The remaining residue was taken up in ethyl acetate and washed successively with saturated aqueous sodium bicarbonate solution, water and saturated aqueous sodium chloride solution. After drying over anhydrous magnesium sulfate, it was filtered and concentrated to dryness. The crude product was purified by preparative HPLC (Method 13). After combining the product fractions, concentrating and drying under high vacuum, 194 mg (32% of theory) of the title compound were obtained.

LC / MS (Method 2, ES Ineg): R _t = 1.07 min, m / z = 473 [MH] ^" .

Example 232A tert. Butyl-2- {[5-methyl-3 - (1-methylcyclobutyl) -2,4-dioxo-1 - (3, 3, 3-trifluoropropyl) -1,2,3,4-tetrahydrothieno [2 , 3-d] pyrimidin-6-yl] methyl} hydrazinecarboxylate

Analogously to the process described under Example 200A, 330 mg (95% of theory) of the title compound were prepared from 345 mg (0.706 mmol) of the compound from Example 188A and a total of 333 mg (5.30 mmol) of sodium cyanoborohydride.

Ή-NMR (400 MHz, DMSO-de, δ / ppm): 8.23 (br.s, 1H), 5.03 (br.d, 1H), 4.06 (br.t, 2H), 3.97 (br. D, 2H ), 2.82-2.65 (m, 2H), 2.35-2.23 (m, 4H), 2.29 (s, 3H), 1.81-1.57 (m, 2H), 1.51 (s, 3H), 1.38 (s, 9H).

LC / MS (Method 2, ES Ineg): R _t = 1.21 min, m / z = 489 [MH] -. Example 233A tert. Butyl-2- {[1- (2-methoxyethyl) -5-methyl-3- (1-methylcyclobutyl) -2,4-dioxo-1,2,3,4-tetrahydrothieno [2,3-d ] pyrimidine-6-yl] methyl} hydrazinecarboxylate

200 mg (0.888 mmol) of the compound from Ex. 189A and a total of 418 mg (6.66 mmol) of sodium cyanoborohydride were used to prepare 305 mg (75% of theory) of the title compound analogously to the process described under Example 200A. Ή-NMR (400 MHz, DMSO-d ₆ , δ / ppm): 8.23 (br, s, 1H), 4.95 (br, s, 1H), 4.00-3.91 (m, 4H), 3.61 (t, 2H) , 3.25 (s, 3H), 2.36-2.21 (m, 4H), 2.28 (s, 3H), 1.79-1.57 (m, 2H), 1.51 (s, 3H), 1.39 (s, 9H).

Example 234A tert. Butyl-2- {[3 - (trans-3-methoxycyclobutyl) -5-methyl-2,4-dioxo-1 - (3,3,3-trifluoropropyl) -1,2,3,4-tetrahydrothieno [2 , 3-d] pyrimidin-6-yl] methyl} hydrazinecarboxylate

A solution of 946 mg (1.53 mmol, 82%> purity) of the compound from Ex. 190A in 18 ml of methanol was admixed with 482 mg (7.67 mmol) of sodium cyanoborohydride and a little bromocresol green. Subsequently, so much acetic acid was titrated that the indicator color turned from blue to yellow. Then the reaction mixture was heated to 65 ° C. After a total of 24 h, 240 mg of sodium cyanoborohydride were again added and the mixture was stirred further at RT for 18 h. The volatile constituents of the reaction mixture were then largely removed on a rotary evaporator. The remaining residue was taken up in ethyl acetate and washed successively with saturated aqueous sodium bicarbonate solution, water and saturated aqueous sodium chloride solution. After drying over anhydrous magnesium sulfate, it was filtered and concentrated to dryness. There were 1.11 g (90%> d. Th., Purity 63%) of the title compound, which were used without further purification for subsequent reactions.

LC / MS (Method 2, ES Ineg): R _t = 1.08 min, m / z = 551 [M-H + HCOOH] -. Example 235A tert. Butyl-2- {[3 - (iranyl-3-methoxycyclobutyl) -1- (2-methoxyethyl) -5-methyl-2,4-dioxo-1,2,3,4-tetrahydrothieno [2,3 -d] pyrimidin-6-yl] methyl} hydrazinecarboxylate

A solution of 1.07 g (1.64 mmol, 71% purity) of the compound from Ex. 191A in 22 ml of methanol was admixed with 514 mg (8.18 mmol) of sodium cyanoborohydride and some bromocresol green. Subsequently, so much acetic acid was titrated that the indicator color turned from blue to yellow. Then the reaction mixture was heated to 65 ° C. After a total of 18 h, the volatile constituents of the reaction mixture were largely removed on a rotary evaporator. The remaining residue was taken up in ethyl acetate and washed successively with saturated aqueous sodium bicarbonate solution, water and saturated aqueous sodium chloride solution. After drying over anhydrous magnesium sulfate, it was filtered and concentrated to dryness. There were obtained 1.02 g (98% of theory, purity 74%) of the title compound, which were used without further purification for subsequent reactions.

LC / MS (Method 2, ES Ineg): R _t = 0.94 min, m / z = 513 [M-H + HCOOH] -.

Example 236A tert. Butyl 2- {[3- (d -3-methoxycyclobutyl) -5-methyl-2,4-dioxo-l - (3,3,3-trifluoropropyl) -l, 2,3,4-tetrahydrothieno [2 , 3-d] pyrimidin-6-yl] methyl} hydrazinecarboxylate

A solution of 0.53 g (1.05 mmol) of the compound of Ex. 192A in 14 ml of methanol was treated with 330 mg (5.25 mmol) of sodium cyanoborohydride and a little bromocresol green. Subsequently, so much acetic acid was titrated that the indicator color turned from blue to yellow. Then the reaction mixture was heated to 65 ° C. After a total of 20 h, the volatile constituents of the reaction mixture were largely removed on a rotary evaporator. The remaining residue was taken up in ethyl acetate and washed successively with saturated aqueous sodium bicarbonate solution, water and saturated aqueous sodium chloride solution. After drying over anhydrous magnesium sulfate, it was filtered and concentrated to dryness. There were obtained 0.51 g (73% of theory, purity 76%) of the title compound, which were used without further purification for subsequent reactions.

LC / MS (Method 1, ES Ineg): R _t = 2.02 min, m / z = 505 [M-H + HCOOH] -.

Example 237A tert. Butyl-2- {[3- (cis -3-methoxycyclobutyl) -1- (2-methoxyethyl) -5-methyl-2,4-dioxo-1,2,3,4-tetrahydrothieno [2,3 -d] pyrimidin-6-yl] methyl} hydrazinecarboxylate

A solution of 0.84 g (1.45 mmol, 80% purity) of the compound from Ex. 193A in 20 ml of methanol was treated with 454 mg (7.23 mmol) of sodium cyanoborohydride and a little bromocresol green. Subsequently, so much acetic acid was titrated that the indicator color turned from blue to yellow. Then the reaction mixture was heated to 65 ° C. After a total of 20 h, the volatile constituents of the reaction mixture on the rotary evaporator were largely away. The remaining residue was taken up in ethyl acetate and washed successively with saturated aqueous sodium bicarbonate solution, water and saturated aqueous sodium chloride solution. After drying over anhydrous magnesium sulfate, it was filtered and concentrated to dryness. There were obtained 0.48 g (71% of theory, purity 60%) of the title compound, which were used without further purification for subsequent reactions.

LC / MS (Method 1, ES Ineg): R _t = 1.75 min, m / z = 513 [M-H + HCOOH] -.

Example 238A tert -Butyl 2 - {[3- (3,3-dimethylcyclobutyl) -5-methyl-2,4-dioxo-1- (3,3,3-trifluoropropyl) -l, 2,3,4 - tetrahydrothieno [2,3-d] pyrimidin-6-yl] methyl} hydrazinecarboxylate

A solution of 425 mg (0.85 mmol, 87% purity) of the compound from Ex. 194A in 11 mL of methanol was added 266 mg (4.23 mmol) of sodium cyanoborohydride and some bromocresol green. Subsequently, so much acetic acid was titrated that the indicator color turned from blue to yellow. Then the reaction mixture was heated to 65 ° C. After a total of 24 h, the reaction mixture was concentrated. The remaining residue was taken up in ethyl acetate and washed successively with saturated aqueous sodium bicarbonate solution, water and saturated aqueous sodium chloride solution. After drying over anhydrous magnesium sulfate, it was filtered and concentrated to dryness. There were obtained 0.40 g (92% of theory, purity 83%) of the title compound, which were used without further purification for subsequent reactions.

LC / MS (Method 1, ES Ineg): R _t = 2.46 min, m / z = 549 [M-H + HCOOH] -.

Example 239A tert-Butyl 2 - {[3- (3,3-dimethylcyclobutyl) -1- (2-methoxyethyl) -5-methyl-2,4-dioxo-1,2,3,4-tetrahydrothieno [2,3-d] pyrimidin-6-yl] methyl} hydrazinecarboxylate

To a solution of 745 mg (1.30 mmol, 81% purity) of the compound of Ex. 195A in 17 ml of methanol was added 408 mg (6.49 mmol) of sodium cyanoborohydride and a little bromocresol green. Subsequently, so much acetic acid was titrated that the indicator color turned from blue to yellow. Then the reaction mixture was heated to 65 ° C. After a total of 24 h, the reaction mixture was treated with saturated aqueous sodium bicarbonate solution and concentrated. The remaining residue was taken up in ethyl acetate and washed successively with saturated aqueous sodium bicarbonate solution, water and saturated aqueous sodium chloride solution. After drying over anhydrous magnesium sulfate, it was filtered and concentrated to dryness. There were obtained 0.59 g (98% of theory, purity 56%) of the title compound, which were used without further purification for subsequent reactions.

LC / MS (Method 1, ES Ineg): R _t = 2.28 min, m / z = 511 [M-H + HCOOH] -.

Example 240A tert -Butyl 2 - {[5-methyl-2,4-dioxo-3- (spiro [3.3] hept-2-yl) -1- (3,3,3-trifluoropropyl) -1, 2 , 3,4-tetrahydrothieno [2,3-d] pyrimidin-6-yl] methyl} hydrazinecarboxylate

Analogously to the process described under Ex. 200A, 487 mg (86%) of 485 mg (0.943 mmol) of the compound from Ex. 196A and a total of 444 mg (7.07 mmol) of sodium cyanoborohydride were added. Th., 96%) purity) of the title compound. 'H-NMR (400 MHz, DMSO-de, δ / ρρηι): 8.24 (br.s, 1H), 5.11-4.96 (m, 2H), 4.07 (br.t, 2H), 3.97 (br. D, 2H), 2.89-2.62 (m, 4H), 2.30 (s, 3H), 2.23 (td, 2H), 2.10-2.03 (m, 2H), 2.01 -1.93 (m, 2H), 1.86-1.74 (m, 2H), 1.38 (s, 9H).

LC / MS (Method 2, ES Ineg): R _t = 1.33 min, m / z = 561 [M-H + HCOOH] -. Example 241A tert -Butyl 2 - {[1- (2-methoxyethyl) -5-methyl-2,4-dioxo-3- (spiro [3.3] hept-2-yl) -1,3,3,4 tetrahydro thieno [2,3-d] pyrimidin-6-yl] methyl} hydrazinecarboxylate

Analogously to the process described under Example 200A, from 500 mg (1.05 mmol) of the compound from Example 197A and a total of 494 mg (7.87 mmol) of sodium cyanoborohydride, 392 mg (78% of theory) of the title compound were prepared.

'H-NMR (400 MHz, DMSO-de, δ / ppm): 8.23 (br.s, 1H), 5.07 (quin, 1H), 4.96 (br.s, 1H), 3.99 (t, 2H), 3.95 (br d, 2H), 3.62 (t, 2H), 3.25 (s, 3H), 2.91-2.78 (m, 2H), 2.30 (s, 3H), 2.23 (td, 2H), 2.11-2.03 (m , 2H), 2.01-1.94 (m, 2H), 1.86-1.74 (m, 2H), 1.38 (s, 9H). LC / MS (Method 2, ES Ineg): R _t = 1.24 min, m / z = 523 [M-H + HCOOH] -.

Example 242A tert -Butyl 2 - {[3-cyclopentyl-5-methyl-2,4-dioxo-l- (3,3,3-trifluoropropyl) -l, 2,3,4-tetrahydrothieno- [2, 3-d] pyrimidin-6-yl] methyl} hydrazinecarboxylate

Analogously to the process described under Example 200A, 437 mg (80% of theory, 88% purity) of the title compound were prepared from 477 mg (0.976 mmol) of the compound from Example 198A and a total of 460 mg (7.32 mmol) of sodium cyanoborohydride , which were used without further purification for subsequent reactions. 'H-NMR (400 MHz, DMSO-d _6, δ / ppm): 8.24 (br s, 1H.), 5.30 (quin, 1H), 5:05 (br d, 1H.), 4.10 (t, 2H), 3.98 (br d, 2H), 2.86-2.69 (m, 2H), 2.32 (s, 3H), 2.09-1.97 (m, 2H), 1.93-1.84 (m, 2H), 1.80- 1.66 (m, 2H ), 1.62-1.48 (m, 2H), 1.38 (s, 9H).

LC / MS (Method 2, ES Ineg): R _t = 1.23 min, m / z = 489 [MH] ^" .

Example 243A tert. Butyl 2- {[3 -cyclopentyl-1- (2-methoxyethyl) -5-methyl-2,4-dioxo-1,2,3,4-tetrahydrothieno [2,3-d] pyrimidine-6 yl] methyl} hydrazinecarboxylate

Analogously to the process described under Example 200A, 504 mg (1.05 mmol, 94% purity) of the compound from Example 199A and a total of 497 mg (7.90 mmol) of sodium cyanoborohydride were mixed with 494 mg (91% of theory, 88%). Purity) of the title compound. On a purification of the product by MPLC was omitted here.

Ή-NMR (400 MHz, DMSO-de, δ / ppm): 8.24 (br.s, 1H), 5.30 (quin, 1H), 4.98 (br.s, 1H), 4.01 (t, 2H), 3.96 ( br, d, 2H), 3.64 (t, 2H), 3.25 (s, 3H), 2.32 (s, 3H), 2.08-1.96 (m, 2H), 1.95-1.82 (m, 2H), 1.80-1.68 ( m, 2H), 1.62-1.48 (m, 2H), 1.39 (s, 9H). LC / MS (Method 2, ES Ineg): R _t = 1.11 min, m / z = 497 [M-H + HCOOH] -.

Example 244A tert. Butyl 2-carbamoyl-2 - [(3-cyclopropyl-l, 5-dimethyl-2,4-dioxo-1,2,3,4-tetrahydrothieno [2,3-d] pyrimidin-6-yl) methyl] hydrazinecarboxylate

A solution of 230 mg (0.605 mmol) of the compound from Ex. 200A in 15 ml of isopropanol was treated with 162 .mu.l (1.21 mmol) of trimethylsilyl isocyanate and stirred at RT for 2.5 days. Thereafter, the reaction mixture was concentrated to dryness. The remaining residue was taken up in ethyl acetate and washed successively with saturated sodium bicarbonate solution and saturated sodium chloride solution. After drying over anhydrous magnesium sulfate, it was filtered and concentrated. The residue was purified by MPLC (Biotage Isolera One, cartridge SNAP KP-Sil, 50 g of silica gel, eluent cyclohexane / ethyl acetate 1: 2). Concentration of the product fractions and drying of the residue under high vacuum gave 130 mg (50% of theory) of the title compound.

'H-NMR (400 MHz, DMSO-de, δ / ppm): 8.91 (br.s, 1H), 6.16 (br.s, 2H), 5.17-3.93 (broad, 2H), 3.38 (s, 3H) , 2.64-2.56 (m, 1H), 2.32 (s, 3H), 1.38 (br, s, 9H), 1.07-0.95 (m, 2H), 0.68-0.62 (m, 2H).

LC / MS (Method 2, ESIpos): R _t = 0.73 min, m / z = 424 [M + H] ⁺ . Example 245A tert -Butyl 2 - [(1-butyl-3-cyclopropyl-5-methyl-2,4-dioxo-1,2,3,4-tetrahydrothieno [2,3-d] pyrimidine-6 yl) methyl] -2-carbamoylhydrazincarboxylat

Analogously to the process described under Example 244A, from 316 mg (0.688 mmol, 92% purity) of the compound from Example 201 A and 185 μΐ (1.38 mmol) of trimethylsilyl isocyanate, 375 mg (99% of theory, 85% of purity ) of the title compound. On a purification of the product by MPLC was omitted here. LC / MS (Method 1, ES Ineg): R _t = 1.62 min, m / z = 464.20 [MH] ^"

Example 246A tert -Butyl 2-carbamoyl-2- {[3-cyclopropyl-5-methyl-2,4-dioxo-1- (3,3,3-trifluoropropyl) -l, 2,3,4-tetrahydrothieno [2,3-d] pyrimidin-6-yl] methyl} hydrazinecarboxylate

A solution of 150 mg (0.324 mmol) of the compound from Ex. 202A in 10 ml of isopropanol was treated with 130 .mu.l (0.973 mmol) of trimethylsilyl isocyanate and stirred at 50.degree. C. for 5 h. Thereafter, the reaction mixture was concentrated to dryness. The remaining residue was purified directly by MPLC (Biotage Isolera One, cartridge SNAP KP-Sil, 10 g silica gel, eluent cyclohexane / ethyl acetate 1: 1-> dichloromethane / methanol 20: 1). After evaporation of the product fractions and drying in a high vacuum, 181 mg (92% of theory, 84% purity) of the title compound were obtained, which were used without further purification for subsequent reactions.

'H-NMR (400 MHz, DMSO-de, δ / ppm): 8.91 (br, s, 1H), 6.19 (s, 2H), 5.12-4.18 (broad, 2H), 4.08 (br, t, 2H) , 2.80-2.65 (m, 2H), 2.61 (tt, 1H), 2.33 (s, 3H), 1.38 (brs s, 9H), 1.07-0.97 (m, 2H), 0.71-0.57 (m, 2H) , LC / MS (Method 1, ES Ineg): R _t = 1.58 min, m / z = 504.15 [MH] ^" . Example 247A tert -butyl-2-carbamoyl-2- {[1- (cyclobutylmethyl) -3-cyclopropyl -5-methyl-2,4-dioxo-l, 2,3,4-tetrahydrothieno [2,3-d] pyrimidin-6-yl] methyl} hydrazinecarboxylate H 3C CH 3

Analogously to the process described under Ex. 244A, 375 mg (0.781 mmol, 90% purity) of the compound from Example 203A and 209 μΐ (1.56 mmol) of trimethylsilyl isocyanate were used to prepare 372 mg (99% of theory) of the title compound. The reaction time was approx. 16 h. LC / MS (Method 1, ESIneg): R _t = 1.68 min, m / z = 476.20 [MH] ^"

Example 248A tert. Butyl 2-carbamoyl-2- ({3-cyclopropyl-1 - [(2,2-difluorocyclopropyl) methyl] -5-methyl-2,4-dioxo l, 2,3,4-tetrahydrothieno [2, 3-d] pyrimidin-6-yl} methyl) hydrazinecarboxylate (racemate)

Analogously to the process described under Ex. 244A, from 685 mg (1.35 mmol, 90%> purity) of the compound from Ex. 204A and 362 μΐ (2.70 mmol) of trimethylsilyl isocyanate 660 mg (90%) of theory. Th., 93% purity) of the title compound. The reaction time in this case was 7 days.

'H-NMR (400 MHz, DMSO-de, δ / ppm): 8.91 (br, s, 1H), 6.18 (br, s, 2H), 5.03-4.13 (broad, 2H), 4.12-3.88 (m, 2H), 2.66-2.58 (m, 1H), 2.33 (s, 3H), 2.18 (td, 1H), 1.76-1.63 (m, 1H), 1.52-1.43 (m, 1H), 1.38 (br. S, 9H), 1.08-0.94 (m, 2H), 0.68-0.63 (m, 2H).

LC / MS (method 1, ESIneg): R _t = 1.54 min, m / z = 498.16 [MH] ^" Example 249A tert-Butyl 2-carbamoyl-2- {[1- (cyanomethyl) -3-cyclopropyl-5-methyl-2,4-dioxo-1,2,3,4-tetrahydrothieno [2,3 -d] pyrimidin-6-yl] methyl} hydrazinecarboxylate

Analogously to the process described under Example 244A, 230 mg (89% of theory, 95% purity) of the title compound were prepared from 220 mg (0.543 mmol) of the compound from Example 205A and 146 μM (1.09 mmol) of trimethylsilyl isocyanate. The reaction time was approx. 16 h.

LC / MS (Method 1, ES Ineg): R _t = 1.31 min, m / z = 447.15 [MH] ^"

Example 250A tert-Butyl 2-carbamoyl-2- {[3-cyclopropyl-1- (2-methoxyethyl) -5-methyl-2,4-dioxo-1,2,3,4-tetrahydrothieno [2 , 3-d] pyrimidin-6-yl] methyl} hydrazinecarboxylate

A solution of 365 mg (0.860 mmol) of the compound from Ex. 206A in 30 ml of isopropanol was mixed with 353 μΐ (2.58 mmol) of trimethylsilyl isocyanate and stirred at 50 ° C for about 16 h. Thereafter, the reaction mixture was concentrated to about one third of the original volume. A part of the product precipitated, which was sucked off. The mother liquor was further evaporated and then separated into its components by preparative HPLC (Method 11). The product fractions were evaporated, combined with the previously separated solid and subjected to high vacuum. dried. 259 mg (59% of theory, 93% purity) of the title compound were obtained, which were used without further purification for subsequent reactions.

'H-NMR (400 MHz, DMSO-de, δ / ppm): 8.91 (br, s, 1H), 6.17 (br, s, 2H), 5.19-4.10 (broad, 2H), 3.99 (t, 2H) , 3.62 (t, 2H), 3.24 (s, 3H), 2.61 (tt, 1H), 2.31 (s, 3H), 1.38 (br, s, 9H), 1.07-0.94 (m, 2H), 0.70-0.58 (m, 2H).

LC / MS (Method 1, ES Ineg): R _t = 1.31 min, m / z = 466.18 [MH] ^"

Example 251A tert -Butyl 2-carbamoyl-2- {[3-cyclopropyl-1- (2-ethoxyethyl) -5-methyl-2,4-dioxo-1,2,3,4-tetrahydrothieno [2 , 3-d] pyrimidin-6-yl] methyl} hydrazinecarboxylate

Analogously to the process described under Example 244A, 230 mg (0.524 mmol) of the compound from Example 207A and 141 μΐ (1.05 mmol) of trimethylsilyl isocyanate were used to prepare 262 mg (98% of theory, 95% purity) of the title compound. The reaction time was approx. 16 h.

LC / MS (Method 2, ESIneg). R _t = 0.78 min, m / z = 480 [MH] ^'Example 252A tert-butyl-2-carbamoyl-2- {[3-cyclopropyl-l- (2- isopropoxyethyl) -5-methyl-2,4-dioxo-1,2,3,4-tetrahydrothieno [2,3-d] pyrimidin-6-yl] methyl} hydrazinecarboxylate

Analogously to the process described under Example 244A, 410 mg (99% of theory) of the title compound were prepared from 375 mg (0.829 mmol) of the compound from Ex. 208A and 222 μΐ (1.66 mmol) of trimethylsilyl isocyanate. The reaction time was approx. 16 h.

LC / MS (Method 1, ES Ineg): R _t = 1.56 min, m / z = 494.21 [MH] ^" Example 253A tert -butyl-2-carbamoyl-2 - ({3-cyclopropyl-5-methyl-2, 4-dioxo-1- [2- (trifluoromethoxy) ethyl] -1,2,3,4-tetrahydrothieno [2,3-d] pyrimidin-6-yl} methyl) hydrazinecarboxylate

A solution of 335 mg (0.665 mmol, 95% purity) of the compound from Ex. 209A in 15 ml of isopropanol was admixed with 178 μl (1.33 mmol) of trimethylsilyl isocyanate and stirred at RT for 2.5 days. Thereafter, the reaction mixture was concentrated to dryness. The remaining residue was taken up in ethyl acetate and washed successively with saturated sodium bicarbonate solution and saturated sodium chloride solution. After drying over anhydrous magnesium sulfate, it was filtered and concentrated. After drying under high vacuum, 360 mg (98% of theory, 95% purity) of the title compound were obtained.

LC / MS (Method 1, ESIpos): R _t = 1.60 min, m / z = 520.15 [M + H] ⁺ .

Example 254A tert -Butyl 2-carbamoyl-2- {[3-cyclopropyl-5-methyl-2,4-dioxo-1- (tetrahydrofuran-2-ylmethyl) -1,2,3,4-tetrahydrothieno [2 , 3-d] pyrimidin-6-yl] methyl} hydrazinecarboxylate (racemate) H 3C CH 3

Analogously to the process described under Ex. 250A, 365 mg (0.810 mmol) of the compound of Ex. 210A and 333 μΐ (2.43 mmol) of trimethylsilyl isocyanate were used to prepare 358 mg (85% of theory, 95% purity) of the title compound. 'H-NMR (400 MHz, DMSO-d _6, δ / ppm): (br. S, 1H) 8.94, 6.17 (s, 2H), 5:14 to 4:29 (broad, 2H), 4.29- 4.16 (m, 1H ), 3.96 (dd, 1H), 3.81-3.66 (m, 2H), 3.61 (q, 1H), 2.65-2.57 (m, 1H), 2.31 (s, 3H), 2.02-1.75 (m, 3H), 1.72-1.59 (m, 1H), 1.38 (brs s, 9H), 1.09-0.94 (m, 2H), 0.71-0.55 (m, 2H).

LC / MS (Method 1, ESIneg): R _t = 1.40 min, m / z = 492.19 [MH] ^"

Example 255A tert. Butyl 2-carbamoyl-2- ({3-cyclopropyl-5-methyl-2,4-dioxo-1 - [(2R) -tetrahydrofuran-2-ylmethyl] -1,3,3,4-tetrahydrothieno [2,3-d] pyrimidin-6-yl} methyl) hydrazinecarboxylate

Analogously to the process described under Ex. 244A, from 220 mg (0.488 mmol) of the compound from Example 211A and 131 μΐ (0.977 mmol) of trimethylsilyl isocyanate, 260 mg (97% of theory, 90%) of the pure title compound were prepared. The reaction time was approx. 16 h.

LC / MS (Method 1, ESIneg): R _t = 1.42 min, m / z = 492.19 [MH] ^" Example 256A tert. Butyl 2-carbamoyl-2- ({3-cyclopropyl-5-methyl-2,4-dioxo-l - [(2S) -tetrahydrofuran-2-yl-methyl] -l, 2,3,4-tetrahydrothieno [2,3-d] pyrimidin-6-yl} methyl) hydrazinecarboxylate

Analogously to the process described under Example 244A, from 175 mg (0.388 mmol) of the compound from Ex. 212A and 104 μΐ (0.777 mmol) of trimethylsilyl isocyanate, 212 mg (99% of theory, 90%) of purity of the title compound were prepared. The reaction time was approx. 16 h.

LC / MS (Method 1, ES Ineg): R _t = 1.40 min, m / z = 492.19 [MH] ^" Example 257A tert -butyl-2-carbamoyl-2- {[1, 5-dimethyl-3 - (1 -methylcyclopropyl) -2,4-dioxo-1,2,3,4-tetrahydrothieno [2,3-d] pyrimidin-6-yl] methyl} hydrazinecarboxylate

Analogously to the process described under Ex. 244A, from 265 mg (0.638 mmol, 95% purity) of the compound from Ex. 213A and 171 μΐ (1.28 mmol) of trimethylsilyl isocyanate 280 mg (95%) of theory. Th., 95% purity) of the title compound. The reaction time was approx. 16 h.

'H-NMR (400 MHz, DMSO-de, δ / ppm): 8.89 (br.s, 1H), 6.16 (br.s, 2H), 5.13-4.10 (broad, 2H), 3.38 (s, 3H) , 2.33 (s, 3H), 1.38 (brs s, 9H), 1.33 (s, 3H), 0.97-0.74 (m, 4H).

LC / MS (method 1, ESIneg): R _t = 1.40 min, m / z = 436.17 [MH] ^" Example 258A tert-Butyl 2 - {[1-butyl-5-methyl-3- (1-methylcyclopropyl) -2,4-dioxo-1,2,3,4-tetrahydrothieno [2,3-d] pyrimidin-6-yl] methyl} -2-carbamoylhydrazinecarboxylate

Analogously to the process described under Example 244A, from 350 mg (0.802 mmol) of the compound from Ex. 214A and 215 μΐ (1.60 mmol) of trimethylsilyl isocyanate 322 mg (74% of theory, 89% purity) of the title compound were prepared. The reaction time was approx. 16 h.

LC / MS (method 1, ESIneg): R _t = 1.77 min, m / z = 478.21 [MH] ^"

Example 259A tert. Butyl 2-carbamoyl-2- {[5-methyl-3 - (1-methylcyclopropyl) -2,4-dioxo-1 - (3,3,3-trifluoropropyl) -1,2,3,4-tetrahydrothieno [2,3-d] pyrimidin-6-yl] methyl} hydrazinecarboxylate

A solution of 1.28 g (2.11 mmol, 79% purity) of the compound from Ex. 215A in 27 ml of isopropanol was admixed with 487 mg (4.22 mmol) of trimethylsilyl isocyanate. After a total of 24 h at RT, the volatile constituents of the reaction mixture were largely removed on a rotary evaporator. There were 1.55 g (100%) d. Th., Purity 74%) of the title compound, which were used without further purification for subsequent reactions.

LC / MS (Method 2, ESIpos): R _t = 0.89 min, m / z = 520 [M + H] ⁺ . Example 260A tert-Butyl 2-carbamoyl-2- {[1- (cyclobutylmethyl) -5-methyl-3- (1-methylcyclopropyl) -2,4-dioxo-1,2,3,4-tetrahydrothieno [2 , 3-d] pyrimidin-6-yl] methyl} hydrazinecarboxylate

Analogously to the process described under Example 244A, 255 mg (85% of theory, 90% purity) of the title compound were prepared from 245 mg (0.546 mmol) of the compound from Ex. 216A and 147 μΐ (1.09 mmol) of trimethylsilyl isocyanate. The reaction time was approx. 16 h.

'H-NMR (400 MHz, DMSO-de, δ / ppm): 8.88 (br, s, 1H), 6.18 (br, s, 2H), 4.95-4.13 (broad, 2H), 4.07-3.75 (m, 2H), 2.83-2.69 (m, 1H), 2.31 (s, 3H), 2.04-1.89 (m, 2H), 1.87-1.74 (m, 4H), 1.38 (br s, 9H), 1.32 (s, 3H), 0.99-0.70 (m, 4H).

LC / MS (Method 2, ES Ineg): R _t = 0.96 min, m / z = 490 [MH] ^" .

Example 261A tert. Butyl 2-carbamoyl-2- ({1 - [(2,2-difluorocyclopropyl) methyl] -5-methyl-3 - (1-methylcyclopropyl) -2,4-dioxo-1, 2,3, 4-tetrahydrothieno [2,3-d] pyrimidin-6-yl} methyl) hydrazinecarboxylate (racemate)

Analogously to the process described under Ex. 244A, from 680 mg (1.32 mmol, 91%> purity) of the compound from Ex. 217A and 353 μΐ (2.63 mmol) of trimethylsilyl isocyanate were added 670 mg (91) of theory. Th., 92% purity) of the title compound. The reaction time was approx. 16 h. LC / MS (Method 1, ES Ineg): R _t = 1.69 min, m / z = 512.18 [MH] ^" Example 262A tert -butyl-2-carbamoyl-2- {[1- (cyanomethyl) -5-methyl] 3- (1-methylcyclopropyl) -2,4-dioxo-1,2,3,4-tetrahydrothieno [2,3-d] pyrimidin-6-yl] methyl} hydrazinecarboxylate

Analogously to the process described under Example 244A, from 200 mg (0.439 mmol, 92% purity) of the compound from Example 218A and 118 μΐ (0.877 mmol) of trimethylsilyl isocyanate, 125 mg (56% of theory, 92% of purity ) of the title compound. The reaction time was approx. 16 h.

'H-NMR (400 MHz, DMSO-de, δ / ppm): 8.92 (br, s, 1H), 6.20 (br, s, 2H), 5.08 (br, s, 2H), 4.59 (broad, 2H) , 2.34 (br s, 3H), 1.39 (br s, 9H), 1.35 (s, 3H), 1.04-0.71 (m, 4H).

LC / MS (Method 1, ESIneg): R _t = 1.46 min, m / z = 461.16 [MH] ^"

Example 263A tert. Butyl 2-carbamoyl-2- {[1- (2-methoxyethyl) -5-methyl-3- (1-methylcyclopropyl) -2,4-dioxo-1,2,3,4-tetrahydrothieno [2,3 -d] pyrimidin-6-yl] methyl} hydrazinecarboxylate

A solution of 660 mg (1.36 mmol, 91%> purity) of the compound from Ex. 219A in 17 ml of isopropanol was admixed with 314 mg (2.72 mmol) of trimethylsilyl isocyanate. After 24 h at RT, the volatile constituents of the reaction mixture were largely removed on a rotary evaporator. learns. There were obtained 808 mg (100% of theory, 83% purity) of the title compound, which were used without further purification for subsequent reactions.

LC / MS (method 2 ESIpos): R _t = 0.77 min, m / z = 482 [M + H] ^+.

Example 264A tert. Butyl 2-carbamoyl-2- ({5-methyl-3- (1-methylcyclopropyl) -2,4-dioxo-l - [2- (trifluoromethoxy) ethyl] -1,3,3,4-tetrahydrothieno [2,3-d] pyrimidin-6-yl} methyl) hydrazinecarboxylate

A solution of 290 mg (0.509 mmol, 86% purity) of the compound from Ex. 220A in 10 ml of isopropanol was admixed with 137 μM (1.02 mmol) of trimethylsilyl isocyanate and stirred at RT for about 16 h. Thereafter, the reaction mixture was concentrated to dryness. The remaining residue was taken up in ethyl acetate and washed successively with saturated sodium bicarbonate solution and saturated sodium chloride solution. After drying over anhydrous magnesium sulfate, it was filtered and concentrated. The residue was purified by MPLC (Biotage Isolera One, cartridge SNAP KP-Sil, 50 g of silica gel, eluent cyclohexane / ethyl acetate 1: 1). After evaporation of the product fractions and drying in a high vacuum, 236 mg (81) d. Th., 94%) purity) of the title compound.

'H-NMR (400 MHz, DMSO-de, δ / ppm): 8.88 (br, s, 1H), 6.17 (br, s, 2H), 4.57 (broad, 2H), 4.39 (t, 2H), 4.30 -4.04 (m, 2H), 2.33 (s, 3H), 1.37 (brs s, 9H), 1.33 (s, 3H), 0.99-0.72 (m, 4H).

LC / MS (Method 1, ES Ineg): R _t = 1.74 min, m / z = 534.16 [MH] ^" Example 265A tert -butyl-2-carbamoyl-2- {[1- (2-ethoxyethyl) -5- Methyl 3 - (1-methylcyclopropyl) -2,4-dioxo l, 2,3,4-tetrahydrothieno [2,3-d] pyrimidin-6-yl] methyl} hydrazinecarboxylate H ₃ CCH

Analogously to the process described under Ex. 264A, 200 mg (0.442 mmol) of the compound from Example 221A and 119 μΐ (0.884 mmol) of trimethylsilyl isocyanate were used to prepare 159 mg (72% of theory) of the title compound. 'H-NMR (400 MHz, DMSO-d _6, δ / ppm): (br. S, 1H) 8.88, 6.16 (s, 2H), 5:00 to 4:18 (broad, 2H), 4.14- 3.84 (m, 2H ), 3.64 (t, 2H), 3.44 (q, 2H), 2.32 (s, 3H), 1.38 (brs s, 9H), 1.33 (s, 3H), 1.05 (t, 3H), 0.99-0.73 ( m, 4H).

LC / MS (Method 2, ESIneg): R _t = 0.85 min, m / z = 494 [MH] ^'Example 266A tert-butyl-2-carbamoyl-2- {[l- (2-isopropoxyethyl) -5. -methyl-3- (1-methylcyclopropyl) -2,4-dioxol, 2,3,4-tetrahydrothieno [2,3-d] pyrimidin-6-yl] methyl} hydrazinecarboxylate

Analogously to the process described under Example 264A, 280 mg (0.600 mmol) of the compound from Ex. 222A and 161 μΐ (1.20 mmol) of trimethylsilyl isocyanate were used to produce 258 mg (84% of theory) of the title compound.

'H-NMR (400 MHz, DMSO-de, δ / ppm): 8.87 (br, s, 1H), 6.16 (br, s, 2H), 5.14-4.14 (broad, 2H), 4.10-3.81 (m, 2H), 3.64 (t, 2H), 3.60-3.50 (sept, 1H), 2.32 (s, 3H), 1.38 (br, s, 9H), 1.33 (s, 3H), 1.02 (d, 6H), 0.97 -0.73 (m, 4H). LC / MS (Method 1, ESIneg): R _t = min, m / z = 508.22 [MH] ^"

Example 267A tert. Butyl 2-carbamoyl-2- ({5-methyl-3- (1-methylcyclopropyl) -2,4-dioxo-l - [(2R) -tetrahydrofuran-2-ylmethyl] -l, 2,3,4 -tetrahydrothieno [2,3-d] pyrimidin-6-yl} methyl) hydrazinecarboxylate

Analogously to the process described under Ex. 264A, 150 mg (0.323 mmol) of the compound of Ex. 223 A and 87 μΐ (0.646 mmol) of trimethylsilyl isocyanate were used to produce 157 mg (83% of theory, 87% purity) of the title compound.

LC / MS (Method 1, ES Ineg): R _t = 1.56 min, m / z = 506.21 [MH] ^" Example 268A tert -butyl-2-carbamoyl-2- ({5-methyl-3- (1-methylcyclopropyl ) -2,4-dioxo-l - [(2S) -tetrahydrofuran-2-ylmethyl] -1,3,3,4-tetrahydrothieno [2,3-d] pyrimidin-6-yl} methyl) hydrazinecarboxylate

Analogously to the process described under Ex. 264A, from 265 mg (0.570 mmol) of the compound from Ex. 224A and 153 μΐ (1.14 mmol) of trimethylsilyl isocyanate 300 mg (98% of theory, 95%) of purity of the title compound were prepared.

LC / MS (method 1, ESIneg): R _t = 1.55 min, m / z = 506.21 [MH] ^" Example 269 A tert. Butyl 2-carbamoyl-2- ({1- (2-methoxyethyl) -5-methyl-2,4-dioxo-3- [1- (trifluoromethyl) cyclopropyl] -1,3,3,4- tetrahydrothieno [2,3-d] pyrimidin-6-yl} methyl) hydrazinecarboxylate

Analogously to the process described under Example 264A, from 400 mg (0.812 mmol) of the compound from Example 269A and 218 μΐ (1.62 mmol) of trimethylsilyl isocyanate 492 mg (98% of theory, 87% purity) of the title compound were prepared. On a purification of the product by MPLC was omitted here.

LC / MS (Method 2, ES Ineg): R _t = 0.87 min, m / z = 534 [MH]. ^" Example 270A tert -butyl-2-carbamoyl-2- {[3- (1-ethylcyclopropyl) -5 -methyl-2,4-dioxo-l - (3,3,3-trifluoropropyl) -1,2,3,4-tetrahydrothieno [2,3-d] pyrimidin-6-yl] methyl} hydrazinecarboxylate

Analogously to the process described under Example 264A, 119 mg (93% of theory) of the title compound were prepared from 146 mg (0.238 mmol, 80%> purity) of the compound of Ex. 226A and 64 μΐ (0.476 mmol) of trimethylsilyl isocyanate ,

'H-NMR (400 MHz, DMSO-de, δ / ppm): 8.89 (br, s, 1H), 6.19 (br, s, 2H), 4.57 (broad, 2H), 4.09 (br, t, 2H) , 2.82-2.63 (m, 2H), 2.33 (s, 3H), 1.69 (q, 2H), 1.38 (br, s, 9H), 1.03-0.87 (m, 2H), 0.84-0.75 (m, 2H) , 0.81 (t, 3H). Example 271A tert-Butyl 2-carbamoyl-2- {[3- (1-ethylcyclopropyl) -1- (2-methoxyethyl) -5-methyl-2,4-dioxol, 2,3,4-tetrahydrothieno [2,3-d] pyrimidin-6-yl] methyl} hydrazinecarboxylate

Analogously to the process described under Ex. 244A, from 146 mg (0.323 mmol) of the compound from Ex. 227A and 87 μΐ (0.645 mmol) of trimethylsilyl isocyanate 168 mg (99% of theory, 95% purity) of the title compound were prepared. On a purification of the product by MPLC was omitted here.

LC / MS (Method 1, ES Ineg): R _t = 1.62 min, m / z = 494.21 [MH] ^" Example 272A tert-butyl-2-carbamoyl-2- {[3-cyclobutyl-5-methyl-2, 4-dioxo-1- (3,3,3-trifluoropropyl) -l, 2,3,4-tetrahydrothieno [2,3-d] pyrimidin-6-yl] methyl} hydrazinecarboxylate

A solution of 150 mg (0.302 mmol, 96%> purity) of the compound from Example 228A in 9 ml of isopropanol was admixed with 124 μl (0.907 mmol) of trimethylsilyl isocyanate and stirred at 50 ° C. for about 16 h. Thereafter, the reaction mixture was evaporated and the residue was then separated by preparative HPLC (Method 11) into its components. The combined product fractions were concentrated and the residue was dried under high vacuum. 121 mg (75% of theory) of the title compound were obtained. 'H-NMR (400 MHz, DMSO-de, δ / ρρηι): 8.91 (br.s, 1H), 6.20 (br.s, 2H), 5.21 (quin, 1H), 5.07-4.20 (broad, 2H) , 4.09 (t, 2H), 2.89-2.64 (m, 4H), 2.33 (s, 3H), 2.23-2.10 (m, 2H), 1.88-1.63 (m, 2H), 1.38 (brs s, 9H) ,

LC / MS (Method 1, ES Ineg): R _t = 1.90 min, m / z = 518.17 [MH] ^" Example 273A tert -butyl-2-carbamoyl-2- {[3-cyclobutyl-l - (2-methoxyethyl ) -5-methyl-2,4-dioxo-1,2,3,4-tetrahydrothieno [2,3-d] pyrimidin-6-yl] methyl} hydrazinecarboxylate

A solution of 150 mg (0.342 mmol) of the compound from Ex. 229A in 10 ml of isopropanol was admixed with 141 .mu.l (1.03 mmol) of trimethylsilyl isocyanate and stirred at 50.degree. C. for about 16 h. Thereafter, the reaction mixture was evaporated and the residue was then separated by preparative HPLC (Method 11) into its components. The combined product fractions were concentrated and the residue was dried under high vacuum. 113 mg (68% of theory) of the title compound were obtained. 'H-NMR (400 MHz, DMSO-d _6, δ / ppm): 8.91 (br s, 1H.), 6.18 (s, 2H), 5.22 (quin, 1H), 5:05 to 4:17 (broad, 2H); 4.00 (t, 2H), 3.63 (t, 2H), 3.25 (s, 3H), 2.90-2.76 (m, 2H), 2.32 (s, 3H), 2.16 (qt, 2H), 1.87-1.63 (m, 2H), 1.48-1.16 (brs s, 9H).

LC / MS (Method 1, ES Ineg): R _t = 1.70 min, m / z = 480.19 [MH] ^" Example 274A tert -butyl-2-carbamoyl-2- {[3- (3,3-difluorocyclobutyl) -] 5-methyl-2,4-dioxo-l - (3,3,3-trifluoropropyl) -1,2,3,4-tetrahydrothieno [2,3-d] pyrimidin-6-yl] methyl} hydrazinecarboxylate

A solution of 630 mg (1.23 mmol, 82% purity) of the compound from Ex. 230A in 16 ml of isopropanol was admixed with 283 mg (2.46 mmol) of trimethylsilyl isocyanate. After a total of 30 h at RT, the volatile constituents of the reaction mixture were largely removed on a rotary evaporator. There were obtained 756 mg (87% of theory, purity 79%) of the title compound, which were used without further purification for subsequent reactions.

LC / MS (Method 2, ESIpos): R _t = 1.00 min, m / z = 556 [M + H] ⁺ .

Example 275A tert -Butyl 2-carbamoyl-2- {[3- (3,3-difluorocyclobutyl) -1- (2-methoxyethyl) -5-methyl-2,4-dioxo] l, 2,3,4 -tetrahydrothieno [2,3-d] pyrimidin-6-yl] methyl} hydrazinecarboxylate

A solution of 195 mg (0.41 mmol) of the compound from Ex. 231A in 5 ml of isopropanol was admixed with 94 mg (0.82 mmol) of trimethylsilyl isocyanate. After a total of 30 h at RT, the volatile constituents of the reaction mixture were largely removed on a rotary evaporator. There was obtained 232 mg (94% of theory, 86% purity) of the title compound, which were used without further purification for subsequent reactions.

LC / MS (Method 2, ESIpos): R _t = 0.90 min, m / z = 518 [M + H] ⁺ . Example 276A tert. Butyl 2-carbamoyl-2- {[5-methyl-3 - (1-methylcyclobutyl) -2,4-dioxo-1 - (3,3,3-trifluoropropyl) -1,3,3,4-tetrahydrothieno [2,3-d] pyrimidin-6-yl] methyl} hydrazinecarboxylate

Analogously to the process described under Ex. 264A, from 325 mg (0.663 mmol) of the compound of Ex. 232A and 178 μΐ (1.33 mmol) of trimethylsilyl isocyanate 415 mg (99% of theory, 85% purity) of the title compound were prepared. On a purification of the product by MPLC was omitted here.

LC / MS (Method 1, ES Ineg): R _t = 1.95 min, m / z = 532.18 [MH] -. Example 277A tert-Butyl 2-carbamoyl-2- {[1- (2-methoxyethyl) -5-methyl-3- (1-methylcyclobutyl) -2,4-dioxol, 2,3,4-tetrahydrothieno [2,3-d] pyrimidin-6-yl] methyl} hydrazinecarboxylate

Analogously to the process described under Ex. 264A, from 300 mg (0.663 mmol) of the compound from Example 233A and 178 μΐ (1.33 mmol) of trimethylsilyl isocyanate 388 mg (96% of theory, 82% purity) of the title compound were prepared , On a purification of the product by MPLC was omitted here.

LC / MS (Method 1, ES Ineg): R _t = 1.72 min, m / z = 494.21 [MH] ^" Example 278A tert -Butyl 2-carbamoyl-2- {[3- (irara-3-methoxycyclobutyl) -5-methyl-2,4-dioxo-1- (3,3,3-trifluoropropyl) -l, 2,3,4-tetrahydrothieno [2,3-d] pyrimidin-6-yl] methyl} hydrazinecarboxylate

A solution of 1.11 g (1.38 mmol, 63% purity) of the compound from Ex. 234A in 17 ml of isopropanol was admixed with 317 mg (2.80 mmol) of trimethylsilyl isocyanate. After a total of 72 h at RT, the volatile constituents of the reaction mixture were largely removed on a rotary evaporator. There were obtained 1.09 g (89% of theory, purity 62%) of the title compound, which were used without further purification for subsequent reactions. LC / MS (Method 2, ESIpos): R _t = 0.94 min, m / z = 550 [M + H] ⁺ .

Example 279A tert-Butyl 2-carbamoyl-2- {[3- (irano-3-methoxycyclobutyl) -1- (2-methoxyethyl) -5-methyl-2,4-dioxo-1, 2,3, 4-tetrahydrothieno [2,3-d] pyrimidin-6-yl] methyl} hydrazinecarboxylate

A solution of 1.02 g (1.60 mmol, 74% purity) of the compound from Ex. 235A in 20 ml of isopropanol was admixed with 369 mg (3.20 mmol) of trimethylsilyl isocyanate. After a total of 72 h at RT, the volatile constituents of the reaction mixture were largely removed on a rotary evaporator. There were obtained 1.21 g (79% of theory, purity 54%) of the title compound, which were used without further purification for subsequent reactions. LC / MS (Method 2, ESIpos): R _t = min, m / z = 512 [M + H]

Example 280A tert. Butyl 2-carbamoyl-2- {[3- (cis-3-methoxycyclobutyl) -5-methyl-2,4-dioxo-1 - (3, 3, 3-trifluoropropyl) -l, 2,3 , 4-tetrahydrothieno [2,3-d] pyrimidin-6-yl] methyl} hydrazinecarboxylate

A solution of 0.51 g (0.77 mmol, 76% purity) of the compound from Ex. 236A in 10 ml of isopropanol was admixed with 177 mg (1.54 mmol) of trimethylsilyl isocyanate. After a total of 32 h at RT, the volatile constituents of the reaction mixture were largely removed on a rotary evaporator. There were obtained 0.62 g (78% of theory, purity 53%) of the title compound, which were used without further purification for subsequent reactions.

Example 281A tert. Butyl 2-carbamoyl-2- {[3- (cz -3-methoxycyclobutyl) -1- (2-methoxyethyl) -5-methyl-2,4-dioxo-1,2,3,4-tetrahydrothieno [2 , 3-d] pyrimidin-6-yl] methyl} hydrazinecarboxylate

A solution of 0.48 g (0.83 mmol, 60% purity) of the compound from Ex. 237A in 10 ml of isopropanol was admixed with 190 mg (1.65 mmol) of trimethylsilyl isocyanate. After a total of 72 h at RT, a further 50 μΐ (0.37 mmol) of trimethylsilyl isocyanate were added, and the reaction mixture was stirred for another 16 h at RT. The volatile constituents of the reaction mixture were then largely removed on a rotary evaporator. 0.48 g (60% of theory, pure 52%) of the title compound, which were used without further purification for subsequent reactions.

Example 282A tert. Butyl 2-carbamoyl-2- {[3- (3,3-dimethylcyclobutyl) -5-methyl-2,4-dioxo-1 - (3, 3, 3-trifluoropropyl) -l, 2,3 , 4-tetrahydrothieno [2,3-d] pyrimidin-6-yl] methyl} hydrazinecarboxylate

A solution of 395 mg (0.64 mmol, 83% purity) of the compound from Ex. 238A in 8 ml of isopropanol was admixed with 148 mg (1.28 mmol) of trimethylsilyl isocyanate. After a total of 72 h at RT, the volatile constituents of the reaction mixture were largely removed on a rotary evaporator. There were obtained 0.39 g (95% of theory, purity 85%) of the title compound, which were used without further purification for subsequent reactions.

Example 283A tert-Butyl 2-carbamoyl-2- {[3- (3,3-dimethylcyclobutyl) -1- (2-methoxyethyl) -5-methyl-2,4-dioxo] l, 2,3,4 -tetrahydrothieno [2,3-d] pyrimidin-6-yl] methyl} hydrazinecarboxylate

A solution of 595 mg (1.0 mmol, 56% purity) of the compound from Ex. 239A in 13 ml of isopropanol was admixed with 229 mg (2.0 mmol) of trimethylsilyl isocyanate. After a total of 72 h at RT, the volatile constituents of the reaction mixture were largely removed on a rotary evaporator. walking away. There were obtained 0.59 g (70% of theory, purity 59%) of the title compound, which were used without further purification for subsequent reactions.

Example 284A tert-Butyl 2-carbamoyl-2- {[5-methyl-2,4-dioxo-3- (spiro [3.3] hept-2-yl) -1- (3,3,3-trifluoropropyl) - l, 2,3,4-tetrahydrothieno [2,3-d] pyrimidin-6-yl] methyl} hydrazinecarboxylate

Analogously to the process described under Example 264A, 425 mg (0.823 mmol) of the compound from Ex. 240A and 221 μΐ (1.65 mmol) of trimethylsilyl isocyanate were used to prepare 460 mg (99% of theory) of the title compound. 'H-NMR (400 MHz, DMSO-d _6, δ / ppm): 8.90, 6.20, 5:05 (quin, 1H), 4.93- 4.17 (broad, 2H (br s, 1H). (Br s, 2H). ), 4.08 (t, 2H), 2.87-2.63 (m, 4H), 2.32 (s, 3H), 2.29-2.20 (m, 2H), 2.07 (t, 2H), 2.01-1.93 (m, 2H), 1.87-1.74 (m, 2H), 1.38 (brs s, 9H).

LC / MS (Method 2, ES Ineg): R _t = 1.17 min, m / z = 558 [MH] ^" .

Example 285A tert-Butyl 2-carbamoyl-2- {[1- (2-methoxyethyl) -5-methyl-2,4-dioxo-3- (spiro [3.3] hept-2-yl) -1,2 , 3,4-tetrahydrothieno [2,3-d] pyrimidin-6-yl] methyl} hydrazinecarboxylate

Analogously to the process described under Example 264A, 380 mg (0.794 mmol) of the compound from Example 241A and 213 μΐ (1.59 mmol) of trimethylsilyl isocyanate were used to prepare 380 mg (91% of theory) of the title compound.

'H-NMR (400 MHz, DMSO-de, δ / ppm): 8.90 (br.s, 1H), 6.17 (br.s, 2H), 5.06 (quin, 1H), 4.55 (broad, 2H), 3.99 (t, 2H), 3.62 (t, 2H), 3.24 (s, 3H), 2.83 (td, 2H), 2.30 (s, 3H), 2.24 (td, 2H), 2.10- 2.03 (m, 2H), 2.02-1.93 (m, 2H), 1.88-1.75 (m, 2H), 1.38 (br, s, 9H).

LC / MS (Method 2, ES Ineg): R _t = 1.07 min, m / z = 520 [MH] ^" .

Example 286A tert -Butyl 2-carbamoyl-2- {[3-cyclopentyl-5-methyl-2,4-dioxo-1- (3,3,3-trifluoropropyl) -l, 2,3,4-tetrahydrothieno [2,3-d] pyrimidin-6-yl] methyl} hydrazinecarboxylate

A solution of 435 mg (0.782 mmol, 88% purity) of the compound of Ex. 242A in 20 ml of isopropanol was treated with 212 .mu.l (1.56 mmol) of trimethylsilyl isocyanate and stirred at RT for 2.5 days. Thereafter, the reaction mixture was concentrated to dryness. The remaining residue was stirred with a little methanol at RT. The solid was separated to give, after drying under high vacuum, 290 mg (69% of theory) of the title compound.

'H-NMR (400 MHz, DMSO-de, δ / ppm): 8.90 (br.s, 1H), 6.20 (s, 2H), 5.30 (t, 1H), 5.11 -4.17 (broad, 1H), 4.10 (t, 2H), 2.81-2.69 (m, 2H), 2.33 (s, 3H), 2.06-1.96 (m, 2H), 1.96-1.84 (m, 2H), 1.79-1.69 (m, 2H), 1.59 -1.51 (m, 2H), 1.38 (brs s, 9H). LC / MS (Method 1, ES Ineg): R _t = 2.02 min, m / z = 532.18 [MH] ^" .

Example 287A tert -Butyl 2-carbamoyl-2- {[3-cyclopentyl-1- (2-methoxyethyl) -5-methyl-2,4-dioxo-1,2,3,4-tetrahydrothieno [2 , 3-d] pyrimidin-6-yl] methyl} hydrazinecarboxylate

Analogously to the process described under Ex. 244A, from 494 mg (0.967 mmol, 88% purity) of the compound of Ex. 243A and 259 μΐ (1.93 mmol) of trimethylsilyl isocyanate 460 mg (87% of theory, 91%) of purity) the title compound. 'H-NMR (400 MHz, DMSO-d _6, δ / ppm): 8.90 (br s, 1H.), 6.18 (s, 2H), 5.30 (quin, 1H), 4.98-4.17 (broad, 2H); 4.01 (t, 2H), 3.63 (t, 2H), 3.24 (s, 3H), 2.32 (s, 3H), 2.07-1.96 (m, 2H), 1.95-1.83 (m, 2H), 1.81-1.67 ( m, 2H), 1.62-1.49 (m, 2H), 1.39 (br, s, 9H).

LC / MS (Method 1, ES Ineg): R _t = 1.78 min, m / z = 494.21 [MH] ^"

Example 288A Diethyl 5 - [(cyclopropylcarbamoyl) amino] -3-methylthiophene-2,4-dicarboxylate

A solution of 3.0 g (11.3 mmol, 97% purity) of diethyl 5-amino-3-methylthiophene-2,4-dicarboxylate in 12 ml of pyridine was treated with 3.2 ml (45.2 mmol, 98%> purity) of cyclopropyl isocyanate and heated to 80 ° C for about 16 h. Subsequently, the reaction mixture was concentrated to dryness. The remaining residue was taken up in dichloromethane three times and evaporated again. Then the residue was taken up in ethyl acetate and washed with water. After renewed concentration, the resulting solid was stirred for 2 h at RT in a mixture of 200 ml of diisopropyl ether, 20 ml of ethyl acetate and 20 ml of dichloromethane. Thereafter, the solid was filtered off with suction and dried under high vacuum. This gave a first fraction of 3.05 g of the title compound. The mother liquor from the stirring was concentrated, and an additional 0.8 g of the title compound was isolated from the residue by means of MPLC (Biotage Isolera One, cartridge SNAP KP-Sil, 10 g silica gel, mobile phase cyclohexane / ethyl acetate 2: 1). A total of 3.85 g (99% of theory) of the title compound was thus obtained.

Ή-ΝΜΡ (400 MHz, DMSO-d ₆ , δ / ppm): 10.52 (br s, 1H), 8.21 (br s, 1H), 4.32 (q, 2H), 4.23 (q, 2H), 2.66 (s, 3H), 2.62-2.55 (m, 1H, partially covered by the DMSO signal), 1.32 (t, 3H), 1.28 (t, 3H), 0.76-0.62 (m, 2H), 0.52-0.41 (m , 2H).

LC / MS (Method 1, ESIpos): R _t = 2.05 min, m / z = 341.12 [M + H] ⁺ .

Example 289A

Ethyl 3-cyclopropyl-5-methyl-2,4-dioxo-l, 2,3,4-tetrahydrothieno [2,3-d] pyrimidine-6-carboxylate

3.85 g (11.3 mmol) of the compound from Ex. 288A were dissolved in 96 ml of ethanol and treated with 7.5 ml (20.1 mmol) of a 21% solution of sodium ethoxide in ethanol. The reaction mixture was stirred at RT for about 15 h. Thereafter, the mixture was concentrated to about half of the original volume and then made acidic by addition of 1 M hydrochloric acid. The product failed. It was filtered off with suction, washed neutral with water and dried under high vacuum. 3.06 g (91% of theory) of the title compound were obtained.

'H-NMR (400 MHz, DMSO-de, δ / ppm): 12.25 (s, 1H), 4.25 (q, 2H), 2.72 (s, 3H), 2.58-2.51 (m, 1H, partially covered by DMSO Signal), 1.28 (t, 3H), 1.03-0.95 (m, 2H), 0.73-0.65 (m, 2H).

LC / MS (Method 1, ESIpos): R _t = 1.48 min, m / z = 295.07 [M + H] ⁺ .

Example 290A Ethyl 3-cyclopropyl-5-methyl-2,4-dioxo-1- (3,3,3-trifluoropropyl) -l, 2,3,4-tetrahydrothieno [2,3-d] pyrimidine-6 carboxylate

1.0 g (3.40 mmol) of the compound from Ex. 289A and 1.17 g (8.49 mmol) of potassium carbonate were stirred for 15 min at RT in 25 ml of anhydrous DMF before 2.28 g (10.2 mmol) of 1,1,1-trifluoro-3-iodo - propane were added. Then the reaction mixture was stirred at 50 ° C for about 16 h. After cooling to RT, it was mixed with water and stirred at RT for 30 min. The precipitated product was filtered off, washed with a little water and dried under high vacuum. 1.23 g (91% of theory) of the title compound were obtained.

Ή-NMR (400 MHz, DMSO-de, δ / ppm): 4.29 (q, 2H), 4.12 (t, 2H), 2.87-2.68 (m, 2H), 2.76 (s, 3H), 2.65-2.58 ( m, 1H), 1.30 (t, 3H), 1.08-0.98 (m, 2H), 0.73-0.64 (m, 2H). LC / MS (Method 1, ESIpos): R _t = 2.06 min, m / z = 391.09 [M + H] ⁺ .

Example 291A

Ethyl 3-cyclopropyl-1- (2-methoxyethyl) -5-methyl-2,4-dioxo-1,2,3,4-tetrahydrothieno [2,3-d] pyrimidine-6-carboxylate

Analogously to the process described under Example 290A, 1.13 g (92% of theory) of the title compound were prepared from 1.0 g (3.40 mmol) of the compound from Ex. 289A and 1.89 g (13.6 mmol) (2-bromoethyl) methyl ether ,

'H-NMR (400 MHz, DMSO-de, δ / ppm): 4.27 (q, 2H), 4.04 (t, 2H), 3.63 (t, 2H), 3.24 (s, 3H), 2.75 (s, 3H ), 2.65-2.58 (m, 1H), 1.29 (t, 3H), 1.06-0.97 (m, 2H), 0.74-0.65 (m, 2H). LC / MS (Method 1, ESIpos): R _t = 1.83 min, m / z = 353.12 [M + H] ⁺ . Example 292A

3-Cyclopropyl-6- [dideutero (hydroxy) methyl] -5-methyl-1- (3,3,3-trifluoropropyl) thieno

pyrimidine-2,4 (lH, 3H) -dione

A solution of 1.20 g (3.01 mmol) of the compound from Ex. 290A in 27 ml of THF was added dropwise at -78 ° C with 2.71 ml (2.71 mmol) of a 1 M solution of lithium aluminum deuteride in THF. Subsequently, the reaction mixture was stirred at 0 ° C for 1 h. Then, 1.2 ml of water, 9 ml of 1 M sodium hydroxide solution and a little diatomaceous earth were added, and the cold bath was removed. The resulting precipitate was filtered off with suction and washed thoroughly with THF. The combined with the wash liquid filtrate was concentrated to dryness. The remaining residue was taken up in ethyl acetate and washed successively with water and saturated aqueous sodium chloride solution. After drying over anhydrous magnesium sulfate, it was filtered and concentrated. The crude product was stirred at RT with a little dichloromethane. The solid was separated and dried in vacuo. The mother liquor was evaporated and the residue was purified by MPLC (Biotage Isolera One, cartridge SNAP KP-Sil, 50 g of silica gel, mobile phase cyclohexane / ethyl acetate 9: 1 → 0: 1). The product fraction was evaporated and combined with the previously isolated solid. This gave a total of 723 mg (65% of theory, 95% purity) of the title compound.

Ή-NMR (400 MHz, DMSO-de, δ / ppm): 5.54 (s, 1H), 4.08 (t, 2H), 2.74 (qt, 2H), 2.60 (tt, 1H), 2.32 (s, 3H) , 1.06-0.96 (m, 2H), 0.73-0.63 (m, 2H).

LC / MS (Method 1, ESIpos): R _t = 1.39 min, m / z = 351.09 [M + H] ⁺ .

Example 293A

3-Cyclopropyl-6- [dideutero (hydroxy) methyl] -1- (2-methoxyethyl) -5-methylthieno [2,3-d] pyrimidine-2,4 (1H, 3H) -dione

Analogously to the method described under Ex. 292A, 1.12 g (3.12 mmol) of the compound from Example 291A and 3.8 ml (3.80 mmol) of 1 M lithium aluminum deuteride solution 570 mg (58% of theory) of the title compound were prepared. Ή-NMR (400 MHz, DMSO-d _6, δ / ppm): 5:48 (s, 1H), 4.00 (t, 2H), 3.62 (t, 2H), 3.24 (s, 3H), 2.64- 2:56 (m , 1H), 2.30 (s, 3H), 1.05-0.96 (m, 2H), 0.71-0.63 (m, 2H).

LC / MS (Method 2, ESIpos): R _t = 0.66 min, m / z = 313 [M + H] ⁺ .

Example 294A

Ethyl 4-methyl-2- {[(2-methylcyclopropyl) carbamoyl] amino} thiophene-3-carboxylate (mixture of trans and cz racemate)

1-isocyanato-2-methylcyclopropane: A solution of 16.05 g (157 mmol, 98% purity) of commercially available 2-methylcyclopropanecarboxylic acid, which is typically about 85% from trans-racemat and about 15% from cz-racemate and 22 ml (157 mmol) of triethylamine in 300 ml of toluene was added dropwise with 34 ml (157 mmol) of diphenylphosphorazidate (DPPA). After completion of the dropwise addition, the mixture was heated to reflux for 2 h and then cooled to RT.

Title compound: In a second reaction vessel, 10.0 g (52.4 mmol, 97% purity) of ethyl 2-amino-4-methylthiophene-3-carboxylate were dissolved in 67 ml of pyridine, and the toluene was added to the above-prepared isocyanate solution. Subsequently, the reaction mixture was stirred at 80 ° C for about 18 h. After cooling to RT was diluted with 1.2 liters of ethyl acetate and washed successively with water, 0.5 M hydrochloric acid, 5% ammonia water, water and saturated aqueous Sodium chloride solution washed. After drying over anhydrous magnesium sulfate, it was filtered and evaporated. The remaining residue was purified by suction filtration over 350 g of silica gel (mobile phase cyclohexane / ethyl acetate 9: 1-> 2: 1). After combining the product fractions, concentrating and drying the residue in a high vacuum, 14.26 g (94% of theory, 98% purity) of the title compound were obtained as a mixture of about 85% trans racemate and about 15% cis racemate.

LC / MS (Method 2, ESIpos): R _t = 1.01 min, m / z = 283 [M + H] ⁺ , 15.2% area; R _t = 1.04 min, m / z = 283 [M + H] ⁺ , 82.8% area.

Example 295A 5-Methyl-3- (2-methylcyclopropyl) thieno [2,3-d] pyrimidine-2,4 (1H, 3H) -dione (trans-racemate)

4.80 g (17.0 mmol) of the compound from Ex. 294A were dissolved in 54 ml of ethanol and treated with 12.7 ml (34.0 mmol) of a solution of sodium ethoxide (21%) in ethanol. After the mixture was stirred for about 16 h at RT, it was diluted with 65 ml of water and brought to pH 3 with vigorous stirring with 1 M hydrochloric acid. The resulting precipitate was filtered off with suction, washed neutral with 50 ml of water and dried. Subsequently, the solid was stirred with 125 ml of acetonitrile for about 18 h at RT. After aspirating and drying in a high vacuum, 3.08 g (74% of theory, 97% purity, residue: d-racemate) of the title compound were obtained, which is identical to the compound from Ex. Ή-NMR (400 MHz, DMSO-d ₆ , δ / ppm): 11.91 (s, 1H), 6.63 (d, 1H), 2.33 (d, 3H), 2.17 (dt, 1H), 1.14 (d, 3H ), 1.04-0.92 (m, 1H), 0.88-0.75 (m, 2H).

LC / MS (Method 1, ESIpos): R _t = 1.32 min, m / z = 237.07 [M + H] ⁺ .

Example 296A

5-Methyl-3- (2-methylcyclopropyl) thieno [2,3-d] pyrimidine-2,4 (1H, 3H) -dione (d-racemate)

The aqueous filtrate from the preparation of the compound from Ex. 295A was extracted with ethyl acetate. The organic extract was dried over anhydrous magnesium sulfate, filtered and concentrated. After drying the residue in a high vacuum, 0.90 g (21% of theory, 95% purity, residue: racaro racemate) of the title compound were obtained.

Ή-NMR (400 MHz, DMSO-de, δ / ppm): 11.95 (br.s, 1H), 6.64 (d, 1H), 2.60-2.53 (m, 1H, partially covered by the DMSO signal), 2.33 (br d, 3H), 1.26-1.16 (m, 2H), 0.85 (d, 3H), 0.63-0.48 (m,

1H).

LC / MS (Method 1, ESIpos): R _t = 1.27 min, m / z = 237.07 [M + H] ⁺ . Example 297A

5-methyl-3- (2-methylcyclopropyl) -2,4-dioxo-l, 2,3,4-tetrahydrothieno [2,3-d] pyrimidine

aldehyde (cz racemate)

Analogously to the process described under Ex. 37A, from 780 mg (3.30 mmol) of the compound from Ex. 296A, 3.7 ml (39.6 mmol) phosphorus oxychloride and 3.6 ml (46.2 mmol) DMF 688 mg (74%) d. Th., 95% purity) of the title compound. Notwithstanding, the reaction time after the addition of phosphorus oxychloride here was 60 min.

'H-NMR (400 MHz, DMSO-de, δ / ppm): 12.44 (s, 1H), 10.05 (s, 1H), 2.74 (s, 3H), 2.58 (td, 1H), 1.28-1.16 (m , 2H), 0.87 (d, 3H), 0.60-0.49 (m, 1H). LC / MS (Method 1, ESIpos): R _t = 1.20 min, m / z = 265.06 [M + H] ⁺ .

Example 298A

(2R) -l-hydroxy-3-phenylpropan-2-aminium (7S, 2S) -2-methyl cyclopropanecarboxylate

Analogously to a known process [see WO 2008/103185-A2], 660 g (6.59 mol) of commercially available 2-methylcyclopropanecarboxylic acid, which typically comprises about 85% of trans-racemate and about 15% of cz-racemate, placed in 6.6 liters of ethyl acetate and with 508 g (3.36 mol) of (2R) -2-amino-3-phenylpropan-l-ol (R-phenylalaninol) was added. It flocculated a thick white precipitate. The heterogeneous mixture was heated to 70 ° C and stirred for 2 h at this temperature. The precipitation was almost completely dissolved. The heater was turned off and the mixture slowly cooled to RT with stirring. After about 16 h, the precipitate which precipitated out again was filtered off with suction and washed twice with 500 ml of ethyl acetate each time. The precipitate was dried in vacuo and then divided into two equal portions, which were treated in exactly the same manner as described below: Each of the two portions of solid was taken up in 5.1 liters of ethyl acetate and heated to reflux for 2 h. The solid again went almost completely into solution. Then the heating was switched off again and the mixture slowly cooled with stirring to RT. After about 16 h, the precipitate which had precipitated out again was filtered off with suction and washed twice with 250 ml of ethyl acetate each time. The precipitate was again dried in vacuo. This recrystallization was repeated a further time: the solid was suspended in 2.6 liters of ethyl acetate and heated again to reflux for 2 hours. Here, a significant amount of the solid remained unsolved. The mixture was again cooled slowly and with stirring to RT. After 2 days, the solid was filtered off, washed twice with 210 ml of ethyl acetate and then dried in vacuo. The two thus treated solid fractions were combined to give 309 g (18% of theory) of the title compound.

Ή-NMR (400 MHz, DMSO-de, δ / ppm): 7.33-7.25 (m, 2H), 7.24-7.14 (m, 3H), 5.50 (broad, ca. 4H), 3.39-3.29 (m, 1H ), 3.27-3.17 (m, 1H), 2.97 (br s, 1H), 2.77-2.65 (m, 1H), 2.61-2.52 (m, 1H), 1.21-1.06 (m, 2H), 1.02 (i.e. , 3H), 0.87 (dt, 1H), 0.53-0.47 (m, 1H).

LC / MS (Method 8, ESIpos): R _t = 0.98 min, m / z = 152 [M + H] ⁺ (phenylalaninol).

Example 299A

(S, 2S) -2-methylcyclopropanecarboxylic acid 2.46 liters of 1 M hydrochloric acid were mixed with 309 g (1.23 mol) of the compound from Ex. 298A. It was stirred for about 10 min at RT. It was then extracted twice with 1.22 liters of ethyl acetate. The combined organic extracts were washed once with water and dried over anhydrous magnesium sulfate. After filtration, the mixture was concentrated and the residue was dried briefly in a high vacuum. 115 g (93% of theory) of the title compound were obtained.

'H-NMR (400 MHz, DMSO-de, δ / ppm): 11.94 (s, 1H), 1.27-1.15 (m, 2H), 1.05 (d, 3H), 0.99-0.92 (m, 1H), 0.65 (ddd, 1H).

LC / MS (Method 8, ESIneg): R _t = 0.26 min, m / z = 99 [MH] -. Specific optical rotation: [O,] D ²⁰ = + 95.9 ° -ml-dm ^{~ 1} -g ^{~ 1} (ethanol). Example 300A

-Isocyanato-2-methyl cyclopropane

156 g (1.56 mol) of the compound from Ex. 299A were initially charged in 2.1 liters of toluene and admixed with 206 ml (1.48 mol) of triethylamine. Then the reaction vessel was immersed in an oil bath preheated to 85 ° C. When the internal temperature reached 60 ° C, the dropwise addition of 407 g (1.48 mol) of diphenylphosphorazidate (DPPA) was started. From about 75 ° C began a controlled evolution of nitrogen, and the reaction mixture warmed by the exothermic reaction to 95 ° C. The oil bath on a lift was turned down and the dropping speed of the DPPA adjusted so that the internal temperature to about 95-100 ° C stabilized. After completion of the dropwise addition, the oil bath was turned up again and the reaction mixture stirred for a further 15 min at 85 ° C. After cooling to about 40 ° C, the resulting solution of the title compound was used for further reactions (see Ex. 301A).

Example 301A

Ethyl 4-methyl-2- ({[(7S, 2S) -2-methylcyclopropyl] carbamoyl} amino) thiophene-3-carboxylate

A solution of 211 g (1.14 mol) of ethyl 2-amino-4-methylthiophene-3-carboxylate in 1.37 liters of pyridine was heated to 50 ° C and over a period of 15 min with the isocyanate solution of Ex. 300A (1.48 mol, assuming 100% conversion). Subsequently, the reaction mixture was stirred at 80 ° C for about 18 h. After cooling to RT, it was diluted with 1.2 liters of ethyl acetate and extracted successively with the following aqueous phases: 4 times 2 liters of hydrochloric acid, 4 liters of 5% ammonia water, 4 liters of 10% sodium chloride solution. After drying over anhydrous magnesium sulfate, it was filtered and evaporated. The remaining residue was purified by chromatography on silica gel (0.063-0.2 mm, 12 kg) with dichloromethane / acetone (98: 2, 120 liters) as eluent. After evaporation of the product fractions and drying in a high vacuum, 293 g (91% of theory) of the title compound were obtained.

'H-NMR (400 MHz, DMSO-de, δ / ppm): 11.00-10.00 (broad, 1H), 8.24-7.49 (m, 1H), 6.44 (s, 1H), 4.28 (q, 2H), 2.27 (s, 3H), 2.27-2.24 (m, 1H), 1.31 (t, 3H), 1.05 (br d, 3H), 0.92-0.72 (m, 1H), 0.70-0.55 (m, 1H), 0.52 -0.42 (m, 1H). LC / MS (Method 1, ESIpos): R _t = 2.04 min, m / z = 283.11 [M + H] ⁺ .

Example 302A

5-Methyl-3 - -dione [(7S, 2S) -2-methylcyclopropyl] thieno [2,3-d] pyrimidine-2,4 (lH, 3H)

A suspension of 293 g (1.04 mol) of the compound from Ex. 301 A in 2.9 liters of ethanol was admixed with 2.1 liters of a 21% strength solution of sodium ethanolate in ethanol. The resulting clear solution was stirred at 50 ° C for 2.5 days. It was then cooled to RT and diluted with 2.9 liters of water. By adding 2.3 liters of 1 M hydrochloric acid, the mixture was brought to about pH 3, whereupon the product precipitated. It was filtered off, washed with 2 liters of water and then dried over phosphorus pentoxide in vacuo. This gave 205 g (83% of theory) of the title compound. Ή-ΝΜΡν (500 MHz, DMSO-d ₆ , δ / ρρηι): 11.90 (s, 1H), 6.63 (d, 1H), 2.33 (d, 3H), 2.17 (dt, 1H), 1.14 (d, 3H ), 1.03-0.94 (m, 1H), 0.87-0.75 (m, 2H).

LC / MS (Method 1, ESIpos): R _t = 1.28 min, m / z = 237.07 [M + H] ⁺ . Example 303A 5-Methyl-3 - [(S, 2S) -2-methylcyclopropyl] -2,4-dioxo-1,2,3,4-tetrahydrothieno [2,3-d] pyrimidine-6-carbaldehyde

A solution of 205 g (0.870 mol) of the compound from Ex. 302A was initially introduced into 2 liters (26.1 mol) of DMF at 60 ° C. and treated with 405 ml (4.35 mol) of phosphorus oxychloride over a period of 30 min. Due to the exothermic reaction, the internal temperature rose to 80 ° C. The heating bath was turned down and the dropping rate of the phosphorus oxychloride adjusted so that the internal temperature was maintained at about 80 ° C. After completion of the dropwise addition, the heating bath was turned up again and the stirring continued at 80 ° C for a further 30 min. The mixture was then cooled to about 35 ° C and poured with stirring into 12.1 liters of 35 ° C warm water. The mixture was stirred at RT for about 2 h during which time the product slowly precipitated. The solid was filtered off, washed three times with 1.5 liters of water and then dried over phosphorus pentoxide in vacuo. There were obtained 187 g (81% of theory) of the title compound.

Ή-NMR (400 MHz, DMSO-de, δ / ppm): 12.40 (s, 1H), 10.04 (s, 1H), 2.74 (s, 3H), 2.19 (dt, 1H), 1.14 (d, 3H) , 1.07-0.95 (m, 1H), 0.90-0.75 (m, 2H).

LC / MS (Method 6, ESIpos): R _t = 0.96 min, m / z = 265 [M + H] ⁺ .

Example 304A

Ethyl 4-methyl-2- ({[2- (trifluoromethyl) cyclopropyl] carbamoyl} amino) thiophene-3-carboxylate (trans -Race at)

A solution of 1.0 g (5.63 mmol) of ethyl 2-amino-4-methylthiophene-3-carboxylate and 3.1 ml (22.5 mmol) of triethylamine in 18 ml of dichloromethane was mixed with 1.14 g (7.03 mmol) of NN'-carbonyldiimidazole (CDI ) and stirred for 4 days at RT. Then 1.0 g (6.19 mmol) of racemic iraft -2- (trifluoromethyl) cyclopropanamine hydrochloride was added. After a further 2 h at RT, the reaction mixture was transferred to a separating funnel and washed successively with approximately 50 ml of water, 10% aqueous citric acid solution and saturated sodium chloride solution. After drying over anhydrous magnesium sulfate, it was filtered and concentrated to dryness. The remaining crude product was purified by MPLC (Biotage Isolera One, cartridge SNAP KP-Sil, 50 g of silica gel, cyclohexane / ethyl acetate 5: 1). Concentration of the product fractions and drying of the residue under high vacuum gave 1.23 g (63% of theory, 97% purity) of the title compound.

'H-NMR (400 MHz, DMSO-de, δ / ppm): 10.36 (br.s, 1H), 8.25 (br.s, 1H), 6.47 (s, 1H), 4.28 (q, 2H), 3.01 -2.93 (m, 1H), 2.27 (s, 3H), 2.05-1.92 (m, 1H), 1.31 (t, 3H), 1.21-1.14 (m, 1H), 1.14-1.06 (m, 1H).

LC / MS (Method 1, ESIpos): R _t = 2.09 min, m / z = 337.08 [M + H] ⁺ . Example 305A

5-Methyl-3- [2- (trifluoromethyl) cyclopropyl] thieno [2,3-d] pyrimidine-2,4 (1H, 3H) -dione (trans racemate)

1.23 g (3.55 mmol, 97% purity) of the compound from Ex. 304A were dissolved in 12 ml of ethanol and treated with 2.7 ml (7.10 mmol) of a 21% solution of sodium ethoxide in ethanol. The reaction mixture was stirred at RT for 3 h. Thereafter, the reaction mixture was acidified by the addition of 1 M hydrochloric acid (about pH 3). The product failed. It was sucked off, with Washed water until neutral and dried under high vacuum. 1.04 g (97% of theory, 96%> purity) of the title compound were obtained.

'H-NMR (400 MHz, DMSO-de, δ / ppm): 12.04 (s, 1H), 6.67 (d, 1H), 2.93 (ddd, 1H), 2.34 (d, 3H), 2.24 (dtd, 1H ), 1.50-1.42 (m, 1H), 1.34 (dt, 1H). LC / MS (Method 1, ESIpos): R _t = 1.51 min, m / z = 291.04 [M + H] ⁺ .

Example 306A

5-Methyl-2,4-dioxo-3- [2- (trifluoromethyl) cyclopropyl] -1,3,3,4-tetrahydrothieno [2,3-d] pyrimidine

6-carbaldehyde (trans -Rac at)

A solution of 1.04 g (3.58 mmol) of the compound from Ex. 305A in 3.9 ml (50.2 mmol) of DMF was cautiously admixed with 4.0 ml (43.0 mmol) of phosphorus oxychloride. After the strongly exothermic reaction had subsided, the mixture was stirred for a further 30 min. Thereafter, the reaction mixture was stirred carefully at RT in 400 ml of water. After about 60 min stirring at RT, the precipitated product was filtered off with suction, washed neutral with water and dried under high vacuum. 1.03 g (90% of theory) of the title compound were obtained.

Ή NMR (400 MHz, DMSO-de, δ / ppm): 12.53 (br.s, 1H), 10.06 (s, 1H), 2.93 (ddd, 1H), 2.75 (s, 3H), 2.31-2.18 ( m, 1H), 1.49 (q, 1H), 1.40-1.30 (m, 1H).

LC / MS (Method 2, ESIpos): R _t = 0.79 min, m / z = 319 [M + H] ⁺ .

Example 307A Ethyl 2- {[(2-ethylcyclopropyl) carbamoyl] amino} -4-methylthiophene-3-carboxylate (trans-racemate)

Analogously to the procedure described under Ex. 304A, 1.39 g (7.48 mmol) of ethyl 2-amino-4-methylthiophene-3-carboxylate, 1.52 g (9.34 mmol) of NN'-carbonyldiimidazole (CDI) and 1.0 g (8.22 mmol ) racemic 2-ethylcyclopropanamine hydrochloride 2.0 g (86% of theory, 96% purity) of the title compound. 'H-NMR (400 MHz, DMSO-d _6, δ / ppm): 10.27 (broad, 1H), 7.91 (broad, 1H), 6:44 (s, 1H), 4.27 (q, 2H), 2.27 (s, 3H), 1.31 (t, 3H), 1.26-1.11 (m, 1H), 0.95 (t, 3H), 0.88-0.71 (m, 1H), 0.65-0.41 (m, 2H).

LC / MS (Method 1, ESIpos): R _t = 2.15 min, m / z = 297.13 [M + H] ⁺ . Example 308A 3- (2-Ethylcyclopropyl) -5-methylthieno [2,3-d] pyrimidine-2,4 (1H, 3H) -dione (trans-racemate)

Analogously to the process described under Example 305A, 2.04 g (6.55 mmol, 96% purity) of the compound from Example 307A gave 1.54 g (90% of theory, 96% purity) of the title compound. Notwithstanding, the reaction time was about 16 h here. Ή-NMR (400 MHz, DMSO-d ₆ , δ / ppm): 11.88 (s, 1H), 6.63 (d, 1H), 2.33 (d, 3H), 2.25 (dt, 1H), 1.69-1.55 (m , 1H), 1.28-1.14 (m, 1H), 1.07-0.93 (m, 1H), 0.99 (t, 3H), 0.84-0.75 (m, 2H).

LC / MS (Method 1, ESIpos): R _t = 1.50 min, m / z = 251.08 [M + H] ⁺ .

Example 309A

3- (2-Ethylcyclopropyl) -5-methyl-2,4-dioxo-1,2,3,4-tetrahydrothieno [2,3-d] pyrimidine-6-carbaldehyde (trans-racemate)

H Analogously to the process described under Example 306A, from 1.54 g (5.91 mmol, 96% purity) of the compound from Ex. 308A, 6.6 ml (86.3 mmol) of DMF and 6.9 ml (74.0 mmol) of phosphorus oxychloride 1.64 g (98%). > d. Th.) of the title compound.

'H-NMR (400 MHz, DMSO-de, δ / ppm): 12.38 (s, 1H), 10.04 (s, 1H), 2.74 (s, 3H), 2.30-2.22 (m, 1H), 1.68-1.50 (m, 1H), 1.30-1.15 (m, 1H), 1.09-0.92 (m, 1H), 1.00 (t, 3H), 0.86-0.76 (m, 2H).

LC / MS (Method 1, ESIpos): R _t = 1.47 min, m / z = 279.08 [M + H] ⁺ .

Example 310A

Ethyl 2- {[(2-methoxycyclopropyl) carbamoyl] amino} -4-methylthiophene-3-carboxylate (trans racemate)

Analogously to the procedure described under Example 304A, from 1.39 g (7.48 mmol) of ethyl 2-amino-4-methylthiophene-3-carboxylate, 1.52 g (9.34 mmol) of NN'-carbonyldiimidazole (CDI) and 1.02 g (8.22 mmol ) racemic iraft 2-methoxycyclopropanamine hydrochloride 1.90 g (85% of theory) of the title compound. 'H-NMR (400 MHz, DMSO-d _6, δ / ppm): 10:37 (broad, 1H), 7.94 (broad, 1H), 6:44 (s, 1H), 4.28 (q, 2H), 3.29 (s, 3H), 3.23-3.16 (m, 1H), 2.66-2.59 (m, 1H), 2.27 (d, 3H), 1.31 (t, 3H), 0.99-0.83 (m, 1H), 0.57-0.43 (m, 1H).

LC / MS (Method 2, ESIpos): R _t = 0.92 min, m / z = 299 [M + H] ⁺ . Example 311A 3- (2-methoxycyclopropyl) -5-methylthieno [2,3-d] pyrimidine-2,4 (1H, 3H) -dione (iroro-racemate)

Η Analogously to the process described under Example 305A, 1.5 g (96% of theory) of the title compound were obtained from 1.9 g (6.37 mmol) of the compound from Example 310A. Notwithstanding, the reaction time was about 16 h here.

'H-NMR (400 MHz, DMSO-de, δ / ppm): 11.94 (s, 1H), 6.66 (d, 1H), 3.45-3.36 (m, 1H), 3.23 (s, 3H), 2.59-2.52 (m, 1H), 2.33 (d, 3H), 1.28 (td, 1H), 0.95 (ddd, 1H).

LC / MS (Method 2, ESIpos): R _t = 0.57 min, m / z = 253 [M + H] ⁺ .

Example 312A

3- (2-methoxycyclopropyl) -5-methyl-2,4-dioxo-1,2,3,4-tetrahydrothieno [2,3-d] pyrimidine-6-carbaldehyde (iroro racemate)

1.35 g (5.35 mmol) of the compound from Ex. 311A were dissolved in 21 ml of anhydrous DMF and slowly mixed at 0 ° C. with 5 ml (53.5 mmol) of phosphorus oxychloride. The mixture was stirred for about 30 min at 0 ° C, then the reaction mixture was stirred at 50 ° C for 1 h and at 70 ° C for a further hour. After cooling to RT, the reaction mixture was carefully poured into 200 ml of water. It was extracted with ethyl acetate, and the organic extract was washed with water and saturated aqueous sodium chloride solution. After drying over anhydrous magnesium sulfate, it was filtered and concentrated. Drying of the residue in a high vacuum gave 1.26 g (83% of theory) of the title compound.

Ή-NMR (400 MHz, DMSO-de, δ / ppm): 12.45 (s, 1H), 10.05 (s, 1H), 3.47-3.38 (m, 1H), 3.23 (s, 3H), 2.74 (s, 3H), 2.58 (dt, 1H), 1.30 (td, 1H), 0.94 (ddd, 1H).

LC / MS (method 2 ESIpos): R _t = 0:55 min, m / z = 281 [M + H] ^+.

Example 313A

(2,2-difluorocyclopentyl) methanol (racemate) 1.0 g (5.61 mmol) of racemic ethyl 2,2-difluorocyclopentanecarboxylate was dissolved in 20 ml of anhydrous THF and treated dropwise at -78 ° C with 5.6 ml (5.61 mmol) of a 1 M solution of lithium aluminum hydride in THF. After 30 minutes, the cold bath was removed and stirring continued at RT. After 1 h at RT, the mixture was carefully added with saturated ammonium chloride solution and extracted with ethyl acetate. The organic extract was dried over anhydrous magnesium sulfate, filtered and evaporated. There were obtained 755 mg (96% of theory, 97% purity) of the title compound.

'H-NMR (400 MHz, DMSO-de, δ / ppm): 4.61 (t, 1H), 3.57 (dt, 1H), 3.41-3.33 (m, 1H), 2.32-2.16 (m, 1H), 2.12 -1.85 (m, 3H), 1.78-1.58 (m, 2H), 1.58-1.44 (m, 1H). Example 314A

(3,3-Difluorocyclopentyl) methanol (racemate)

Analogously to the process described under Ex. 313A, 2.0 g (11.2 mmol) of racemic ethyl 3,3-difluorocyclopentanecarboxylate and 11.2 ml (11.2 mmol) of a 1 M solution of lithium aluminum hydride in THF were mixed with 1.34 g (83% of theory) of th. , 95%> purity) of the title compound.

'H-NMR (400 MHz, DMSO-de, δ / ppm): 4.63 (t, 1H), 3.40-3.26 (m, 2H), 2.28-1.91 (m, 4H), 1.89-1.72 (m, 2H) , 1.48 (dq, 1H).

Example 315A (2,2-Difluorocyclobutyl) methyl 4-methylbenzenesulfonate (racemate)

A solution of 1.0 g (7.94 mmol, 97% purity) of racemic (2,2-difluorocyclobutyl) methanol in 15 ml of dichloromethane was admixed with 1.9 ml (23.8 mmol) of pyridine and cooled to 0 ° C. 1.67 g (8.74 mmol) / jaran-toluenesulfonyl chloride were added in portions at this temperature. Then the reaction mixture was stirred at RT for about 18 h. It was then diluted with dichloromethane, washed with water, dried over anhydrous magnesium sulfate, filtered and evaporated. 2.19 g (99% of theory) of the title compound were obtained. 'H-NMR (400 MHz, DMSO-de, δ / ρρηι): 7.79 (d, 2H), 7.50 (d, 2H), 4.24-3.99 (m, 2H), 3.24-2.99 (m, 1H), 2.48 -2.33 (m, 2H), 2.43 (s, 3H), 1.93-1.73 (m, 1H), 1.53-1.31 (m, 1H).

GC / MS (Method 9, EI): R _t = 6.20 min, m / z = 276 [M] ⁺ .

Example 316A (3,3-difluorocyclobutyl) methyl 4-methylbenzenesulfonate

A solution of 4.0 g (31.1 mmol, 95% purity) of (3,3-difluorocyclobutyl) methanol in 60 ml of dichloromethane was admixed with 7.6 ml (93.4 mmol) of pyridine and cooled to 0 ° C. At this temperature, 6.53 g (34.2 mmol) / jaran-toluenesulfonyl chloride were added in portions. Then the reaction mixture was stirred at RT for about 18 h. It was then diluted with dichloromethane, washed with water, dried over anhydrous magnesium sulfate, filtered and evaporated. There were obtained 8.65 g (98% of theory, 97% purity) of the title compound.

Ή-NMR (400 MHz, DMSO-de, δ / ppm): 7.80 (d, 2H), 7.50 (d, 2H), 4.09 (d, 2H), 2.67-2.56 (m, 2H), 2.43 (s, 3H), 2.37-2.21 (m, 3H). GC / MS (Method 9, EI): R _t = 6.13 min, m / z = 276 [M] ⁺ .

Example 317A

(2,2-Difluorocyclopentyl) methyl-4-methylbenzenesulfonate (racemate)

A solution of 670 mg (4.43 mmol, 90% purity) of the compound from Ex. 313A in 10 ml of dichloromethane was admixed with 1.1 ml (13.3 mmol) of pyridine and cooled to 0 ° C. At this temperature, 929 mg (4.87 mmol) / jaran-toluenesulfonyl chloride were added portionwise. Then the reaction mixture was stirred at RT for about 18 h. It was then diluted with dichloromethane, washed with water, dried over anhydrous magnesium sulfate, filtered and evaporated. The remaining residue was purified by MPLC (Biotage Isolera One, Cartridge SNAP KP-Sil, 50 g silica gel, cyclohexane / ethyl acetate 5: 1). Evaporation of the product fractions gave 1.23 g (95% of theory) of the title compound.

Ή-ΝΜΡ (400 MHz, DMSO-d ₆ , δ / ppm): 7.79 (d, 2H), 7.49 (d, 2H), 4.11-3.99 (m, 2H), 2.62-2.53 (m, 1H), 2.43 (s, 3H), 2.19-1.82 (m, 3H), 1.74-1.55 (m, 2H), 1.46-1.32 (m, 1H).

Example 318A

(3,3-Difluorocyclopentyl) methyl-4-methylbenzenesulfonate (racemate)

Analogously to the process described under Example 317A, from 1.33 g (9.28 mmol, 95% purity) of the compound from Example 314A and 1.95 g (10.2 mmol) / jaran-toluenesulfonyl chloride, 2.55 g (94% of theory) of the title compound were obtained receive.

Ή-NMR (400 MHz, DMSO-de, δ / ppm): 7.80 (d, 2H), 7.49 (d, 2H), 3.99 (d, 2H), 2.48-2.35 (m, 1H), 2.43 (s, 3H), 2.24-1.90 (m, 3H), 1.89-1.67 (m, 2H), 1.42 (dq, 1H).

GC / MS (Method 9, EI): R _t = 6.66 min, m / z = 290 [M] ⁺ .

Example 319A 3-Cyclopropyl-1-ethyl-5-methyl-2,4-dioxo-1,2,3,4-tetrahydrothieno [2,3-d] pyrimidine-6-carbaldehyde

Analogously to the process described under Example 63A, 130 mg (0.519 mmol) of the compound from Example 31A and 162 mg (1.04 mmol) of ethyl iodide 129 mg (89% of theory) of the title compound were prepared. The reaction time at RT was 2.5 days and the purification of the product by MPLC was omitted.

Ή NMR (400 MHz, DMSO-de, δ / ppm): 10.08 (s, 1H), 3.93 (q, 2H), 2.77 (s, 3H), 2.65-2.57 (m, 1H), 1.24 (t, 3H), 1.07-0.97 (m, 2H), 0.76-0.66 (m, 2H). LC / MS (Method 1, ESIpos): R _t = 1.48 min, m / z = 279.08 [M + H] ⁺ . Example 320A

3-Cyclopropyl-5-methyl-2,4-dioxo-1-propyl-1,2,3,4-tetrahydrothieno [2,3-d] pyrimidine-6-carbaldehyde

Analogously to the process described under Example 52A, 130 mg (0.519 mmol) of the compound from Example 31A and 177 mg (1.04 mmol) of propyl iodide 135 mg (88% of theory) of the title compound were prepared. The purification of the product by means of MPLC was omitted here.

'H-NMR (400 MHz, DMSO-de, δ / ppm): 10.08 (s, 1H), 3.91-3.79 (m, 2H), 2.77 (s, 3H), 2.65-2.58 (m, 1H), 1.70 (sext, 2H), 1.06-0.97 (m, 2H), 0.92 (t, 3H), 0.75-0.66 (m, 2H).

LC / MS (Method 1, ESIpos): R _t = 1.67 min, m / z = 293.10 [M + H] ⁺ .

Example 321A

3-Cyclopropyl-1- (2-fluoroethyl) -5-methyl-2,4-dioxo-1,2,3,4-tetrahydrothieno [2,3-d] pyrimidine-6-carbaldehyde

Analogously to the process described under Example 58A, from 130 mg (0.519 mmol) of the compound from Example 31A and 181 mg (1.04 mmol) of 1-fluoro-2-iodoethane, 84 mg (51% of theory, 94% purity ) of the title compound. The reaction time was 2.5 days at RT and 2 hours at 50 ° C. 'H-NMR (400 MHz, DMSO-de, δ / ρρηι): 10.08 (s, 1H), 4.74 (dt, 2H), 4.24 (dt, 2H), 2.77 (s, 2.66-2.58 (m, 1H) , 1.06-0.97 (m, 2H), 0.77-0.68 (m, 2H).

LC / MS (method 2 ESIpos): R _t = 0.72 min, m / z = 297 [M + H] ^+. Example 322A

3-Cyclopropyl-1- (4-fluorobutyl) -5-methyl-2,4-dioxo-1,2,3,4-tetrahydrothieno [2,3-d] pyrimidine-carbaldehyde

Analogously to the process described under Example 45A, from 130 mg (0.519 mmol) of the compound from Ex. 31A and 161 mg (1.04 mmol) of 1-bromo-4-fluorobutane 129 mg (76% of theory) of the title compound were prepared , The reaction time at RT was about 2.5 days, then was heated to 50 ° C for about 24 h.

'H-NMR (400 MHz, DMSO-de, δ / ppm): 10.08 (s, 1H), 4.57-4.49 (m, 1H), 4.41 (t, 1H), 3.94 (t, 2H), 2.77 (s , 3H), 2.61 (tt, 1H), 1.85-1.61 (m, 4H), 1.08-0.95 (m, 2H), 0.75-0.65 (m, 2H).

LC / MS (Method 1, ESIpos): R _t = 1.63 min, m / z = 325.10 [M + H] ⁺ . Example 323A

3-Cyclopropyl-1- (2,2-difluoroethyl) -5-methyl-2,4-dioxo-1,2,3,4-tetrahydrothieno [2,3-d] pyrimidine-6-carbaldehyde

150 mg (0.599 mmol) of the compound from Example 31A and 207 mg (1.50 mmol) of potassium carbonate were stirred for 15 min at RT in 4 ml of anhydrous DMF before 219 μΐ (2.40 mmol) of 1,1-difluoro-2-iodoethane were added , Then, the reaction mixture was stirred at 80 ° C for 5 days. To it was cooled to RT and water was added and extracted with ethyl acetate. The organic extract was washed successively with water and saturated sodium chloride solution, dried over anhydrous magnesium sulfate, filtered and evaporated. The product was purified by preparative HPLC (Method 11). This gave, after evaporation of the product fractions and drying under high vacuum, 94 mg (49% of theory) of the title compound.

Ή-ΝΜΡ (400 MHz, DMSO-d _6, δ / ppm): 10.09 (s, 1H), 6:34 (dd, 1H), 4:38 (td, 2H), 2.77 (s, 3H), 2.69-2.59 (m , 1H), 1.08-0.97 (m, 2H), 0.77-0.68 (m, 2H).

LC / MS (Method 1, ESIpos): R _t = 1.51 min, m / z = 315.06 [M + H] ⁺ .

Example 324A 3-Cyclopropyl-5-methyl-2,4-dioxo-1- (4,4,4-trifluorobutyl) -1,3,3,4-tetrahydrothieno [2,3-d] pyrimidin-6 carbaldehyde

Analogously to the process described under Example 52A, 130 mg (0.519 mmol) of the compound from Example 31A and 371 mg (1.56 mmol) of 1,1'-trifluoro-4-iodobutane 171 mg (88% of theory) were used. , 97% purity) of the title compound. Chromatographic purification of the product was omitted here.

Ή-NMR (400 MHz, DMSO-de, δ / ppm): 10.08 (s, 1H), 3.98 (t, 2H), 2.77 (s, 3H), 2.61 (tt, 1H), 2.51-2.34 (m, 2H, partially covered by the DMSO signal), 1.90 (dt, 2H), 1.07-0.95 (m, 2H), 0.76-0.64 (m, 2H). LC / MS (Method 1, ESIpos): R _t = 1.80 min, m / z = 361.08 [M + H] ⁺ . Example 325A

3-Cyclopropyl-l - [(2,2-difluorocyclobutyl) methyl] -5-methyl-2,4-dioxo-1,2,3,4-tetrahydrothieno [2,3-d] pyrimidine-6-carbaldehyde ( racemate)

400 mg (1.60 mmol) of the compound of Ex. 31A and 552 mg (4.00 mmol) of potassium carbonate were stirred for 10 min at RT in 10 ml of anhydrous DMF before 883 mg (3.20 mmol) of the compound from Ex. 315A were added. The reaction mixture was then heated in a microwave oven (Biotage Initiator with dynamic control of the irradiation power) at 80 ° C. for 12 hours and then at 100 ° C. for a further 3 hours. After cooling to RT, the reaction mixture was diluted with ethyl acetate and washed successively twice with water and once with saturated sodium chloride solution. After drying over anhydrous magnesium sulfate, filtration and concentration, the remaining residue was purified by MPLC (Biotage Isolera One, cartridge SNAP Ultra, 50 g of silica gel, cyclohexane / ethyl acetate 2: 1). After evaporation of the product fractions, 364 mg (64% of theory) of the title compound were obtained.

Ή-NMR (400 MHz, DMSO-de, δ / ppm): 10.08 (s, 1H), 4.08 (dd, 2H), 3.37-3.21 (m, 2H, partially covered by the water signal), 2.77 (s, 3H), 2.62 (tt, 1H), 2.53-2.40 (m, 1H, partially masked by the DMSO signal), 2.02-1.87 (m, 1H), 1.64 (quin, 1H), 1.08-0.96 (m, 2H) , 0.76-0.62 (m, 2H). LC / MS (Method 1, ESIpos): R _t = 1.74 min, m / z = 355.09 [M + H] ⁺ .

Example 326A

3-Cyclopropyl-l - [(2,2-difluorocyclobutyl) methyl] -5-methyl-2,4-dioxo-1,2,3,4-tetrahydrothieno [2,3-d] pyrimidine-6-carbaldehyde ( Enantiomer 1)

355 mg of the racemic compound from Ex. 325A were dissolved in 5 ml of acetonitrile / ethanol (1: 1) and separated into the enantiomers in 100 portions by preparative HPLC on a chiral phase [Column: Daicel Chiralpak IE, 5 μm, 250 mm × 20 mm; Eluent: n-heptane / ethanol 60:40; Flow: 30 ml / min; Temperature: 25 ° C; Detection: 220 um]. The product fractions were each concentrated on a rotary evaporator, mixed with acetonitrile and water and freeze-dried. 131 mg (90% of theory, 97.9% ee) of the title compound (enantiomer 1) and 117 mg (65% of theory, 96.3%) of the enantiomer 2 (see Example 327A) were obtained.

'H-NMR (400 MHz, DMSO-de, δ / ppm): 10.08 (s, 1H), 4.18-3.98 (m, 2H), 3.39-3.18 (m, 2H, partially covered by the water signal), 2.77 (s, 3H), 2.62 (tt, 1H), 2.55-2.40 (m, 1H, partially masked by the DMSO signal), 2.02-1.87 (m, 1H), 1.72-1.56 (m, 1H), 1.08-0.97 (m, 2H), 0.76-0.62 (m, 2H). LC / MS (Method 1, ESIpos): R _t = 1.76 min, m / z = 355.09 [M + H] ⁺ .

Chiral analytical HPLC [column: Daicel Chiraltek IE, 3 μιη, 100 mm x 4.6 mm; Eluent: isohexane / ethanol 1: 1; Flow: 1.0 ml / min; Temperature: 30 ° C; Injection: 5 μΐ; DAD 220 nm]: R _t = 4.64 min.

Example 327A

3-Cyclopropyl-l - [(2,2-difluorocyclobutyl) methyl] -5-methyl-2,4-dioxo-1,2,3,4-tetrahydrothieno [2,3-d] pyrimidine-6-carbaldehyde ( Enantiomer 2)

From 355 mg of the racemic compound from Ex. 325A, 117 mg (65% of theory, 96.3% ee) of the title compound (enantiomer 2) and 131 mg (90%) of the chiral phase were purified by preparative HPLC on a chiral phase described in Example 326A %> d.Th., 97.9% ee) of enantiomer 1 (see Ex. 326A).

Ή-NMR (400 MHz, DMSO-de, δ / ppm): 10.08 (s, 1H), 4.16-4.00 (m, 2H), 3.35-3.20 (m, 2H, partially covered by the water signal), 2.77 ( s, 3H), 2.62 (tt, 1H), 2.55-2.40 (m, 1H, partially covered by the DMSO signal), 2.02-1.85 (m, 1H), 1.64 (quin, 1H), 1.08-0.96 (m, 2H), 0.75-0.63 (m, 2H). LC / MS (Method 1, ESIpos): R _t = 1.76 min, m / z = 355.09 [M + H] ⁺ . Chiral analytical HPLC [column: Daicel Chiraltek IE, 3 μηι, 100 mm x 4.6 mm; Eluent: isohexane / ethanol 1: 1; Flow: 1.0 ml / min; Temperature: 30 ° C; Injection: 5 μΐ; DAD 220 nm]: R _t = 5.34 min.

Example 328A

3-Cyclopropyl-1 - [(3,3-difluorocyclobutyl) methyl] -5-methyl-2,4-dioxo-1,2,3,4-tetrahydrothieno [2,3-d] pyrimidine-6-carbaldehyde

300 mg (1.20 mmol) of the compound of Ex. 31A and 415 mg (3.00 mmol) of potassium carbonate were stirred for 10 min at RT in 12 ml of anhydrous DMF before 662 mg (2.40 mmol) of the compound from Ex. 316A were added. Then, the reaction mixture was heated to 80 ° C in a microwave oven (Biotage Initiator with dynamic control of the irradiation power) for 16 hours. After cooling to RT, the reaction mixture was diluted with ethyl acetate and washed successively twice with water and once with saturated sodium chloride solution. After drying over anhydrous magnesium sulfate, filtration and evaporation, the remaining residue was purified by MPLC (Biotage Isolera One, cartridge SNAP Ultra, 50 g of silica gel, cyclohexane / ethyl acetate 2: 1). After evaporation of the product fractions, 248 mg (58% of theory) of the title compound were obtained.

'H-NMR (500 MHz, DMSO-de, δ / ppm): 10.08 (s, 1H), 4.09 (d, 2H), 2.77 (s, 3H), 2.73-2.57 (m, 4H), 2.57-2.46 (m, 2H, partially masked by the DMSO signal), 1.06-0.96 (m, 2H), 0.74-0.64 (m, 2H). LC / MS (Method 6, ESIpos): R _t = 1.22 min, m / z = 355 [M + H] ⁺ . Example 329A

3-Cyclopropyl-l - [(2,2-difluorocyclopentyl) methyl] -5-methyl-2,4-dioxo-1,2,3,4-tetrahydrothieno [2,3-d] pyrimidine-6-carbaldehyde ( racemate)

300 mg (1.20 mmol) of the compound of Ex. 31A and 415 mg (3.00 mmol) of potassium carbonate were stirred for 10 min at RT in 12 ml of anhydrous DMF before 696 mg (2.40 mmol) of the compound from Ex. 317A were added. The reaction mixture was then heated in a microwave oven (Biotage Initiator with dynamic control of the irradiation power) at 80 ° C. for 20 hours and then at 100 ° C. for a further 5 hours. After cooling to RT, the reaction mixture was diluted with ethyl acetate and washed successively twice with water and once with saturated sodium chloride solution. After drying over anhydrous magnesium sulfate, filtration and evaporation, the remaining residue was purified by MPLC (Biotage Isolera One, cartridge SNAP Ultra, 50 g of silica gel, cyclohexane / ethyl acetate 2: 1). Evaporation of the product fractions gave 270 mg (61% of theory) of the title compound.

Ή NMR (400 MHz, DMSO-de, δ / ppm): 10.08 (s, 1H), 4.11-3.91 (m, 2H), 2.84-2.66 (m, 1H), 2.77 (s, 3H), 2.66- 2.58 (m, 1H), 2.23-2.02 (m, 2H), 2.01-1.88 (m, 1H), 1.84-1.51 (m, 3H), 1.09-0.95 (m, 2H), 0.79-0.61 (m, 2H ). LC / MS (Method 1, ESIpos): R _t = 1.87 min, m / z = 369.11 [M + H] ⁺ .

Example 330A

3-Cyclopropyl-l - [(2,2-difluorocyclopentyl) methyl] -5-methyl-2,4-dioxo-1,2,3,4-tetrahydrothieno [2,3-d] pyrimidine-6-carbaldehyde ( Enantiomer 1)

268 mg of the racemic compound from Example 329A were dissolved in 8 ml of acetonitrile and separated into the enantiomers in 18 portions by preparative HPLC on a chiral phase [column: Daicel Chiralpak AD-H, 5 μηι, 250 mm x 30 mm; Eluent: n-heptane / ethanol 30:70; Flow: 40 ml / min; Temperature: 25 ° C; Detection: 220 um]. The product fractions were each concentrated on a rotary evaporator, mixed with acetonitrile and water and freeze-dried. 120 mg (89% of theory,> 99% ee) of the title compound (enantiomer 1) and 118 mg (88% of theory,> 99% ee) of enantiomer 2 (see example 331A) were obtained.

'H-NMR (400 MHz, DMSO-de, δ / ppm): 10.08 (s, 1H), 4.10-3.91 (m, 2H), 2.83-2.66 (m, 1H), 2.77 (s, 3H), 2.66 -2.58 (m, 1H), 2.23-2.02 (m, 2H), 2.01-1.88 (m, 1H), 1.84-1.50 (m, 3H), 1.09-0.94 (m, 2H), 0.77-0.59 (m, 2H).

LC / MS (Method 2, ESIpos): R _t = 0.97 min, m / z = 369 [M + H] ⁺ . Chiral analytical HPLC [column: Daicel Chiraltek AD-3, 3 μm, 100 mm × 4.6 mm; Eluent: n-heptane / ethanol 1: 1; Flow: 3.0 ml / min; Temperature: 30 ° C; Injection: 5 μΐ; DAD 220 nm]: R _t = 3.61 min.

Example 331A

3-Cyclopropyl-l - [(2,2-difluorocyclopentyl) methyl] -5-methyl-2,4-dioxo-1,2,3,4-tetrahydrothieno [2,3-d] pyrimidine-6-carbaldehyde ( Enantiomer 2)

From 268 mg of the racemic compound from Example 329A, 118 mg (88% of theory,> 99% ee) of the title compound (enantiomer 2) and 120 mg (89% of the chiral phase, preparative HPLC described in Example 330A were used. Th.,> 99% ee) of the enantiomer 1 (see Ex. 330A).

Ή NMR (400 MHz, DMSO-de, δ / ppm): 10.08 (s, 1H), 4.10-3.91 (m, 2H), 2.82-2.66 (m, 1H), 2.77 (s, 3H), 2.66- 2.58 (m, 1H), 2.24-2.02 (m, 2H), 2.01-1.88 (m, 1H), 1.84-1.48 (m, 3H), 1.12-0.94 (m, 2H), 0.77-0.60 (m, 2H ).

LC / MS (Method 2, ESIpos): R _t = 0.96 min, m / z = 369 [M + H] ⁺ . Chiral analytical HPLC [column: Daicel Chiraltek AD-3, 3 μm, 100 mm × 4.6 mm; Eluent: "heptane / ethanol 1: 1; Flow: 3.0 ml / min; Temperature: 30 ° C; Injection: 5 μΐ; DAD 220 nm]: R _t = 8.94 min.

Example 332A 3-Cyclopropyl-l - [(3,3-difluorocyclopentyl) methyl] -5-methyl-2,4-dioxo-1,2,3,4-tetrahydrothieno [2,3-d] pyrimidine-6 carbaldehyde (racemate)

Analogously to the process described under Example 328A, 300 mg (1.20 mmol) of the compound from Example 31A and 696 mg (2.40 mmol) of the compound from Ex. 318A gave 295 mg (66% of theory) of the title compound.

Ή NMR (400 MHz, DMSO-de, δ / ppm): 10.08 (s, 1H), 4.05-3.81 (m, 2H), 2.77 (s, 3H), 2.69-2.56 (m, 2H), 2.38- 1.83 (m, 5H), 1.60 (dq, 1H), 1.08-0.96 (m, 2H), 0.77-0.63 (m, 2H).

LC / MS (Method 6, ESIpos): R _t = 1.27 min, m / z = 369 [M + H] ⁺ .

Example 333A 4- (3-Cyclopropyl-6-formyl-5-methyl-2,4-dioxo-3,4-dihydro-thieno [2,3-d] pyrimidin-1 (2H) -yl) butanitrile

Analogously to the process described under Example 66A, 143 mg (86% of theory) of the title compound were prepared from 130 mg (0.519 mmol) of the compound from Example 31A and 154 mg (1.04 mmol) of 4-bromobutyronitrile. The chromatography was omitted here. 'H-NMR (400 MHz, DMSO-de, δ / ρρηι): 10.08 (s, 1H), 3.99 (t, 2H), 2.77 (s, 3H), 2.67-2.56 (m, 3H), 1.99 (quin , 2H), 1.08-0.96 (m, 2H), 0.76-0.66 (m, 2H).

LC / MS (Method 1, ESIpos): R _t = 1.35 min, m / z = 318.09 [M + H] ⁺ . Example 334A 3-Cyclopropyl-5-methyl-2,4-dioxo-1- {2 - [(trifluoromethyl) sulfanyl] ethyl} -1,3,3,4-tetrahydrothieno [2,3-d] pyrimidine-6 carbaldehyde

Analogously to the process described under Ex. 69A, 130 mg (0.519 mmol) of the compound from Ex. 31A and 217 mg (1.04 mmol) 1-bromo-2 - [(trifluoromethyl) sulfanyl] ethane were admixed with 172 mg (85% of theory). Th., 98%> purity) of the title compound. Notwithstanding, stirring was carried out at 60 ° C. for 3 h.

Ή-NMR (400 MHz, DMSO-de, δ / ppm): 10.08 (s, 1H), 4.17 (t, 2H), 3.34 (t, 2H), 2.77 (s, 3H), 2.66-2.57 (m, 1H), 1.08-0.97 (m, 2H), 0.75-0.63 (m, 2H).

LC / MS (Method 2, ESIpos): R _t = 0.98 min, m / z = 379 [M + H] ⁺ . Example 335A l - [(3,3-Difluorocyclobutyl) methyl] -5-methyl-3- (1-methylcyclopropyl) -2,4-dioxo-1,2,3,4-tetrahydrothieno [2,3-d ] pyrimidine-6-carbaldehyde

400 mg (1.51 mmol) of the compound of Ex. 32A and 314 mg (2.27 mmol) of potassium carbonate were stirred for 10 min at RT in 15 ml of anhydrous DMF before 627 mg (2.27 mmol) of the compound were stirred. from example 316A. Then, the reaction mixture was heated to 80 ° C in a microwave oven (Biotage Initiator with dynamic control of the irradiation power) for 15 hours. After cooling to RT, the reaction mixture was diluted with ethyl acetate and washed successively twice with water and once with saturated sodium chloride solution. After drying over anhydrous magnesium sulfate, filtration and evaporation, the remaining residue was purified by MPLC (Biotage Isolera One, cartridge SNAP Ultra, 50 g of silica gel, cyclohexane / ethyl acetate 2: 1). Evaporation of the product fractions gave 380 mg (68% of theory) of the title compound.

'H-NMR (400 MHz, DMSO-de, δ / ppm): 10.08 (s, 1H), 4.25-3.90 (m, 2H), 2.77 (s, 3H), 2.73-2.58 (m, 3H), 1.34 (s, 3H), 1.01-0.74 (m, 4H).

LC / MS (Method 1, ESIpos): R _t = 1.89 min, m / z = 369.11 [M + H] ⁺ .

Example 336A 1, 5-Dimethyl-3- (2-methylcyclopropyl) -2,4-dioxo-1,2,3,4-tetrahydrothieno [2,3-d] pyrimidine-6-carbaldehyde (iroro racemate)

200 mg (0.8 mmol) of the compound from Example 34A and 261 mg (1.9 mmol) of potassium carbonate were initially charged in 2.9 ml of anhydrous DMF, treated with 141 .mu.l (2.3 mmol) of methyl iodide and stirred for 1 h at RT. The reaction mixture was then treated with 3 ml of water and stirred for 10 min at RT. The precipitated product was filtered off, washed with water and then dried under high vacuum. 160 mg (76% of theory) of the title compound were obtained.

Ή-NMR (400 MHz, DMSO-de, δ / ppm): 10.07 (s, 1H), 3.43 (s, 3H), 2.77 (s, 3H), 2.25 (m, 1H), 1.16 (d, 3H) , 1.07-0.96 (m, 1H), 0.90-0.80 (m, 2H).

LC / MS (Method 1, ESIpos): R _t = 1.52 min, m / z = 279.08 [M + H] ⁺ .

Example 337A 1-Ethyl-5-methyl-3- (2-methylcyclopropyl) -2,4-dioxo-1,2,3,4-tetrahydrothieno [2,3-d] pyrimidine-6-carbaldehyde (trans -Race at )

200 mg (0.8 mmol) of the compound of Example 34A and 261 mg (1.9 mmol) of potassium carbonate were initially charged in 2.9 ml of anhydrous DMF, treated with 354 mg (2.3 mmol) of ethyl iodide and in the microwave (Biotage Initiator) to 80 for 1 h ° C heated. The reaction mixture was then treated with water and stirred at RT for 10 min. The precipitated product was filtered off, washed with water and then dried under high vacuum. There were obtained 241 mg (99% of theory, 91% purity) of the title compound.

Ή-NMR (400 MHz, DMSO-de, δ / ppm): 10.08 (s, 1H), 3.93 (q, 2H), 2.77 (s, 3H), 2.26 (m, 1H), 1.24 (t, 3H) , 1.15 (d, 3H), 1.07-0.96 (m, 1H), 0.90-0.80 (m, 2H). LC / MS (Method 2, ESIpos): R _t = 0.88 min, m / z = 293.2 [M + H] ⁺ .

Example 338A

5-Methyl-3- (2-methylcyclopropyl) -2,4-dioxo-1-propyl-1,2,3,4-tetrahydrothieno [2,3-d] pyrimidine

6-carbaldehyde (trans -Race at)

200 mg (0.8 mmol) of the compound from Example 34A and 261 mg (1.9 mmol) of potassium carbonate were initially charged in 2.9 ml of anhydrous DMF, combined with 221 μΐ (2.3 mmol) of 1-iodopropane and stirred at RT for 15 h. The reaction mixture was then treated with 3 ml of water and stirred for 10 min at RT. From the sticky residue was decanted and the residue was added again with water and stirred. It was decanted again and the remaining residue dried under high vacuum. 210 mg (83% of theory, 92% purity) of the title compound were obtained.

Ή-NMR (400 MHz, DMSO-de, δ / ppm): 10.07 (s, 1H), 3.86 (m, 2H), 2.77 (s, 3H), 2.26 (m, 1H), 1.15 (d, 3H) , 1.07-0.96 (m, 1H), 0.92 (t, 3H), 0.88-0.80 (m, 2H). LC / MS (Method 2, ESIpos): R _t = 0.97 min, m / z = 307.1 [M + H] ⁺ . Example 339A 1-Butyl-5-methyl-3 - [(S, 2S) -2-methylcyclopropyl] -2,4-dioxo-1,2,3,4-tetrahydrothieno [2,3-d] pyrimidine-6 carbaldehyde

300 mg (1.14 mmol) of the compound from Ex. 303A were dissolved in 2.9 ml of anhydrous DMF, mixed with 555 mg (1.70 mmol) of cesium carbonate and stirred at RT for 10 min. Then, 388 μΐ (3.41 mmol) of 1-iodobutane was added. After the reaction mixture had been stirred for 60 minutes at 100 ° C. in a microwave oven (Biotage Initiator with dynamic control of the irradiation power), it was poured into water and made acidic by addition of 1 M hydrochloric acid. The product failed. After 1 h stirring at RT was filtered off with suction, washed with a little water and dried under high vacuum. There were obtained 345 mg (92% of theory) of the title compound.

Ή-NMR (500 MHz, DMSO-de, δ / ppm): 10.07 (s, 1H), 3.95-3.82 (m, 2H), 2.77 (s, 3H), 2.29-2.22 (m, 1H), 1.65 ( quin, 2H), 1.41-1.30 (m, 2H), 1.15 (d, 3H), 1.06-0.96 (m, 1H), 0.91 (t, 3H), 0.88-0.81 (m, 2H).

LC / MS (Method 1, ESIpos): R _t = 2.06 min, m / z = 321.13 [M + H] ⁺ .

Example 340A 1- (2-Fluoroethyl) -5-methyl-3- (2-methylcyclopropyl) -2,4-dioxo-1,2,3,4-tetrahydrothieno [2,3-d] pyrimidine-6-carbaldehyde (trans-racemate)

200 mg (0.8 mmol) of the compound from Ex. 34A and 261 mg (1.9 mmol) of potassium carbonate were initially charged in 2.9 ml of anhydrous DMF, treated with 403 mg (2.31 mmol) of 1-fluoro-2-iodoethane and 1 h in the microwave (Biotage initiator) heated to 80 ° C. The reaction mixture was then added with water and extracted with ethyl acetate. The organic phase was washed with water and saturated aqueous sodium chloride solution, dried over sodium sulfate, filtered and evaporated on a rotary evaporator to dryness. The remaining residue was reacted without further purification in subsequent reactions. There was obtained 212 mg (90% of theory, 90% purity) of the title compound.

'H-NMR (400 MHz, DMSO-de, δ / ppm): 10.08 (s, 1H), 4.73 (dt, 2H), 4.23 (dm, 2H), 2.77 (s, 3H), 2.26 (m, 1H ), 1.15 (d, 3H), 1.09-0.98 (m, 1H), 0.91-0.82 (m, 2H).

LC / MS (Method 2, ESIpos): R _t = 0.83 min, m / z = 311.2 [M + H] ⁺ . Example 341A 1- (2,2-Difluoroethyl) -5-methyl-3- (2-methylcyclopropyl) -2,4-dioxo-1,2,3,4-tetrahydrothieno [2,3-d] pyrimidine-6 Carbaldehyde (trans-racemate)

200 mg (0.8 mmol) of the compound from Example 34A and 261 mg (1.9 mmol) of potassium carbonate were initially charged in 2.9 ml of anhydrous DMF, treated with 435 mg (2.26 mmol) of 1, 1-difluoro-2-iodoethane and in the microwave ( Biotage initiator) is first heated to 80 ° C for 1 h. The mixture was then heated at 100 ° C. for a further 3 hours and then at 120 ° C. for a further 1 hour. The reaction mixture was then separated directly into its components by preparative HPLC (Method 16). 169 mg (68% of theory) of the title compound were obtained. 'H-NMR (400 MHz, DMSO-d _6, δ / ppm): 10.09 (s, 1H), 6:34 (dd, 1H), 4:38 (dd, 2H), 2.77 (s, 3H), 2.28 (m, 1H), 1.15 (d, 3H), 1.09-0.98 (m, 1H), 0.91-0.82 (m, 2H).

Example 342A

5-Methyl-3- (2-methylcyclopropyl) -2,4-dioxo-1- (2,2,2-trifluoroethyl) -1,2,3,4-tetrahydrothieno [2,3-d] pyrimidine-6 carbaldehyde (iroro racemate)

200 mg (0.8 mmol) of the compound from Example 34A and 261 mg (1.9 mmol) of potassium carbonate were initially charged in 2.9 ml of anhydrous DMF, 476 mg (2.27 mmol) of 1,1,1-trifluoro-2-iodoethane were added and the mixture was stirred for 3 h long in the microwave (Biotage initiator) heated to 140 ° C. The reaction mixture was then filtered and the filtrate was separated into its components by preparative HPLC (Method 16). 105 mg (39% of theory) of the title compound were obtained.

'H-NMR (400 MHz, DMSO-de, δ / ppm): 10.10 (s, 1H), 4.91 (m, 2H), 2.77 (s, 3H), 2.31 (m, 1H), 1.16 (d, 3H ), 1.09-0.98 (m, 1H), 0.89-0.83 (m, 2H).

LC / MS (Method 1, ESIpos): R _t = 1.84 min, m / z = 347.07 [M + H] ⁺ . Example 343A

5-Methyl-3- (2-methylcyclopropyl) -2,4-dioxo-1- (4,4,4-trifluorobutyl) -1,2,3,4-tetrahydrothieno [2,3-d] pyrimidine-6 carbaldehyde (iroro racemate)

200 mg (0.8 mmol) of the compound from Example 34A and 261 mg (1.9 mmol) of potassium carbonate were initially charged in 2.9 ml of anhydrous DMF, admixed with 540 mg (2.27 mmol) of 1,1,1-trifluoro-4-iodobutane and 1 h long in the microwave (Biotage initiator) heated to 80 ° C. The reaction mixture was then treated with water and stirred at RT for 10 min. The precipitated product was filtered off, washed with water and then dried under high vacuum. 250 mg (81% of theory, 92% purity) of the title compound were obtained. 'H-NMR (400 MHz, DMSO-d _6, δ / ppm): 8.10 (s, 1H), 3.99 (m, 2H), 2.77 (s, 3H), 2:44 (m, 2H), 2.25 (m, 1H), 1.89 (m, 2H), 1.15 (d, 3H), 1.07-0.97 (m, 1H), 0.90-0.80 (m, 2H). LC / MS (Method 1, ESIpos): R _t = min, m / z = 375.1 [M + H]

Example 344A

5-Methyl-3- (2-methylcyclopropyl) -2,4-dioxo-1- (3,3,4,4-tetrafluorobutyl) -1,2,3,4-tetrahydrothieno [2,3-d] pyrimidine -6-carbaldehyde (trans-racemate)

200 mg (0.8 mmol) of the compound from Example 34A and 261 mg (1.9 mmol) of potassium carbonate were initially charged in 2.9 ml of anhydrous DMF, treated with 499 mg (2.27 mmol) l -Brom-3,3,4,4-tetrafluorobutane and stirred overnight at RT. Thereafter, the mixture was stirred for a further 16 h at 35 ° C. and finally at 60 ° C. for 6 h. The reaction mixture was then treated with 5 ml of water and extracted with ethyl acetate. The organic phase was dried with sodium sulfate, filtered and concentrated on a rotary evaporator. The remaining residue was chromatographed on a silica gel cartridge (Biotage, 10 g SNAP Ultra, eluent cyclohexane / 0-100% ethyl acetate). This gave 193 mg (59% of theory, 90% purity) of the title compound.

Ή-NMR (400 MHz, DMSO-de, δ / ppm): 10.09 (s, 1H), 6.55 (tt, 1H), 4.13 (m, 2H), 2.78 (s, 3H), 2.57-2.44 (m, 2H), 2.26 (m, 1H), 1.15 (d, 3H), 1.07-0.98 (m, 1H), 0.89-0.82 (m, 2H).

LC / MS (Method 1, ESIpos): R _t = 1.93 min, m / z = 393.1 [M + H] ⁺ .

Example 345A 1- (cyclobutylmethyl) -5-methyl-3 - [(S, 2S) -2-methylcyclopropyl] -2,4-dioxo-1,2,3,4-tetrahydrothieno [2,3-d] pyrimidine-6-carbaldehyde

A solution of 300 mg (1.14 mmol) of the compound from Ex. 303A in 5 ml of anhydrous DMF was admixed with 392 mg (2.84 mmol) of potassium carbonate and stirred at RT for 15 min. Then, 507 mg (3.41 mmol) of (bromomethyl) cyclobutane was added, and the reaction mixture was stirred at 50 ° C for about 16 hours. After cooling to RT, it was diluted with 200 ml of ethyl acetate and washed successively with water and saturated sodium chloride solution. After drying over anhydrous magnesium sulfate, it was filtered and evaporated. The remaining residue was purified by MPLC (Biotage Isolera One, cartridge SNAP Ultra, 25 g silica gel, cyclohexane / ethyl acetate gradient). Evaporation of the product fraction and drying under high vacuum gave 335 mg (89% of theory) of the title compound. 'H-NMR (500 MHz, DMSO-d _6, δ / ppm): 7.10 (s, 1H), 4.02-3.89 (m, 2H), 2.82-2.70 (m, 1H), 2.76 (s, 3H), 2.26 (dt, 1H), 2.03-1.93 (m, 2H), 1.88-1.74 (m, 4H), 1.15 (d, 3H), 1.06-0.95 (m, 1H), 0.89-0.80 (m, 2H).

LC / MS (Method 1, ESIpos): R _t = 2.09 min, m / z = 333.13 [M + H] ⁺ . Example 346A l - [(2,2-Difluorocyclopropyl) methyl] -5-methyl-3 - [(S, 2S) -2-methylcyclopropyl] -2,4-dioxo-1,2,3,4-tetrahydrothieno [2 , 3-d] pyrimidine-6-carbaldehyde {diastereomer mixture)

258 mg (0.975 mmol) of the compound from Ex. 303A were dissolved in 5 ml of anhydrous DMF, admixed with 337 mg (2.44 mmol) of potassium carbonate and stirred at RT for 15 min. Then 250 mg (1.46 mmol) of racemic 2- (bromomethyl) -1,1-difluorocyclopropane were added. After the reaction mixture was stirred for about 16 h at 50 ° C, it was poured onto water. The product failed. After 30 min stirring at RT was filtered off with suction, washed with a little water and dried under high vacuum. There were obtained 328 mg (91% of theory, 96%> purity) of the title compound.

'H-NMR (500 MHz, DMSO-de, δ / ppm): 10.09 (s, 1H), 4.23-4.11 (m, 1H), 3.95 (ddd, 1H), 2.78 (s, 3H), 2.27 (eng , 1H), 2.25-2.15 (m, 1H), 1.76-1.64 (m, 1H), 1.49 (dtd, 1H), 1.16 (d, 3H), 1.07-0.98 (m, 1H), 0.90-0.81 (m , 2H). LC / MS (Method 2, ESIpos): R _t = 1.00 min, m / z = 355 [M + H] ⁺ . Example 347A l - [(3,3-Difluorocyclobutyl) methyl] -5-methyl-3- (2-methylcyclopropyl) -2,4-dioxo-1,2,3,4-tetrahydrothieno [2,3-d ] pyrimidine-6-carbaldehyde (trans-racemate)

319 mg (1.21 mmol) of the compound from Example 34A and 250 mg (1.81 mmol) of potassium carbonate were initially charged in 4.5 ml of anhydrous DMF, combined with 500 mg (1.81 mmol) of the compound from Example 316A and in the microwave (Biotage Initiator) Heated to 80 ° C for 1 h. The reaction mixture was then treated with 10 ml of water and stirred for 10 min at RT. The precipitated product was filtered off with suction, washed with water and then dried under high vacuum. There were obtained 390 mg (75% of theory, 85% purity) of the title compound.

Ή-NMR (400 MHz, DMSO-de, δ / ppm): 10.08 (s, 1H), 4.09 (m, 2H), 2.77 (s, 3H), 2.65 (m, 4H), 2.26 (m, 1H) , 1.15 (d, 3H), 1.06-0.96 (m, 1H), 0.88-0.81 (m, 2H).

LC / MS (Method 1, ESIpos): R _t = 1.92 min, m / z = 369.1 [M + H] ⁺ . Example 348A l - [(3,3-Difluorocyclopentyl) methyl] -5-methyl-3 - [(S, 2S) -2-methylcyclopropyl] -2,4-dioxo-1,2,3,4-tetrahydrothieno [2 , 3-d] pyrimidine-6-carbaldehyde {diastereomer mixture)

300 mg (1.14 mmol) of the compound from Example 303A and 925 mg (2.84 mmol) of cesium carbonate were initially charged in 3 ml of anhydrous DMF, with 659 mg (2.27 mmol) of the compound from Ex. 318A and heated in the microwave (Biotage Initiator) for 18 h at 80 ° C. Subsequently, another 165 mg (0.57 mmol) of the compound from Example 318A were added and the mixture was heated at 80 ° C. for a further 6 h. The reaction mixture was then taken up in ethyl acetate and washed with water and saturated aqueous sodium chloride solution. The organic phase was dried over magnesium sulfate, filtered and concentrated on a rotary evaporator. The remaining residue was chromatographed on a silica gel cartridge (Biotage, 100 g SNAP Ultra, cyclohexane / ethyl acetate 2: 1). There were obtained 92 mg (21% of theory) of the title compound.

'H-NMR (400 MHz, DMSO-de, δ / ppm): 10.08 (s, 1H), 4.03-3.89 (m, 2H), 2.77 (s, 3H), 2.67-2.55 (m, 1H), 2.37 -1.86 (m, 6H), 1.59 (m, 1H), 1.16 (d, 3H), 1.06-0.96 (m, 1H), 0.88-0.81 (m, 2H). LC / MS (Method 1, ESIpos): R _t = 1.99 min, m / z = 383.1 [M + H] ⁺ .

Example 349A 1- (2-methoxyethyl) -5-methyl-3- (2-methylcyclopropyl) -2,4-dioxo-1,2,3,4-tetrahydrothieno [2,3-d] pyrimidine-6-carbaldehyde (cz racemate)

From 685 mg (2.59 mmol) of the compound from Example 297A and 1.08 g (7.77 mmol) (2-bromoethyl) methyl ether, 538 mg (64% of theory) of the title compound were prepared analogously to the process described under Example 63 A. produced. The reaction time was 2.5 days.

Ή-NMR (400 MHz, DMSO-de, δ / ppm): 10.07 (s, 1H), 4.21-4.10 (m, 1H), 4.06-3.93 (m, 1H), 3.72- 3.56 (m, 2H), 3.23 (s, 3H), 2.76 (s, 3H), 2.66 (td, 1H), 1.29-1.20 (m, 2H), 0.86 (d, 3H), 0.57-0.48 (m, 1H).

LC / MS (Method 1, ESIpos): R _t = 1.58 min, m / z = 323.11 [M + H] ⁺ . Example 350A 1- (2-methoxyethyl) -5-methyl-3 - [(S, 2S) -2-methylcyclopropyl] -2,4-dioxo-1,2,3,4-tetrahydrothieno [2,3-d ] pyrimidine-6-carbaldehyde

A suspension of 32.50 g (123 mmol) of the compound from Ex. 303A in 450 ml of DMF was treated with 42.49 g (307 mmol) of potassium carbonate and stirred for 15 min at RT before 51.27 g (369 mmol) of (2-bromoethyl) methyl ether were added. The reaction mixture was stirred at RT for 4 days. Then 2.25 liters of water were added and it was extracted with 1 liter of ethyl acetate. After phase separation, the solid contained in the water phase was filtered off with suction, washed with a little ethyl acetate and dried in vacuo (10.70 g of product). The filtrate was extracted with 1 liter of ethyl acetate. The combined ethyl acetate layers were washed with 500 ml of 10% sodium chloride solution, dried over anhydrous magnesium sulfate, filtered and concentrated. The remaining residue was stirred with 145 ml of ethyl acetate at RT. The solid was filtered off with suction, washed with a little ethyl acetate and dried in vacuo (19.70 g of product). The mother liquor was concentrated by evaporation and the residue was chromatographed on silica gel (500 g of silica gel 0.04-0.063 mm, petroleum ether / ethyl acetate 7: 3). The product fractions were combined and concentrated, and the residue was dried in vacuo (3.16 g of product). In total, 33.56 g (84% of theory) of the title compound were obtained in this way.

Ή-NMR (500 MHz, DMSO-de, δ / ppm): 10.07 (s, 1H), 4.14-3.98 (m, 2H), 3.63 (t, 2H), 3.24 (s, 3H), 2.76 (s, 3H), 2.30-2.23 (m, 1H), 1.15 (d, 3H), 1.08-0.96 (m, 1H), 0.90-0.80 (m, 2H).

LC / MS (Method 6, ESIpos): R _t = 1.16 min, m / z = 323 [M + H] ⁺ .

Example 351A 5-Methyl-3- (2-methylcyclopropyl) -2,4-dioxo-1- [2- (trifluoromethoxy) ethyl] -1,3,3,4-tetrahydrothieno [2,3-d] pyrimidine 6-carbaldehyde (iroro racemate)

1.21 g (4.58 mmol) of the compound of Ex. 34A and 1.33 g (9.61 mmol) of potassium carbonate were stirred for 15 min at RT in 20 ml of anhydrous DMF before 972 mg (5.04 mmol) of 1-bromo-2- (trifluoromethoxy) ethane [commercially available; Ref: PE Aldrich, WA Sheppard, J. Org. Chem. 29 (1), 11-15 (1964)]. The reaction mixture was then stirred at RT for 2.5 days and then at 50 ° C. for 6 h. After standing at RT for a further 2.5 days, water was added to the mixture and extracted with ethyl acetate. The organic extract was washed successively with water and saturated sodium chloride solution, dried over anhydrous magnesium sulfate and concentrated. The residue was purified by MPLC (Biotage Isolera One, cartridge SNAP Ultra, 100 g silica gel, cyclohexane / ethyl acetate gradient). Evaporation of the product fractions and drying under high vacuum gave 1.17 g (67% of theory) of the title compound.

'H-NMR (400 MHz, DMSO-de, δ / ppm): 10.08 (s, 1H), 4.45-4.35 (m, 2H), 4.32-4.17 (m, 2H), 2.77 (s, 3H), 2.31 -2.24 (m, 1H), 1.16 (d, 3H), 1.09-0.95 (m, 1H), 0.90-0.80 (m, 2H).

LC / MS (Method 1, ESIpos): R _t = 1.93 min, m / z = 377.08 [M + H] ⁺ .

Example 352A

5-Methyl-3- (2-methylcyclopropyl) -2,4-dioxo-1- {2 - [(trifluoromethyl) sulfanyl] ethyl} -1,3,3,4-tetrahydrothieno [2,3-d] pyrimidine-6-carbaldehyde (iroro-racemate)

200 mg (0.76 mmol) of the compound from Ex. 34A and 261 mg (1.89 mmol) of potassium carbonate were initially charged in 2.9 ml of anhydrous DMF, 456 mg (2.12 mmol) of 1-bromo-2 - [(trifluoromethyl) - sulfanyljethan added and The microwave (Biotage initiator) for 1 h at 80 ° C heated. The reaction mixture was then treated with water and stirred at RT for 10 min. The precipitated product was filtered off, washed with water and then dried under high vacuum. There were obtained 267 mg (82% of theory, 91> purity) of the title compound. Ή-NMR (400 MHz, DMSO-d ₆ , δ / ppm): 10.08 (s, 1H), 4.17 (m, 2H), 3.34 (t, 2H), 2.77 (s, 3H), 2.26 (m, 1H ), 1.15 (d, 3H), 1.05-0.95 (m, 1H), 0.89-0.83 (m, 2H).

LC / MS (Method 2, ESIpos): R _t = 1.06 min, m / z = 393.0 [M + H] Example 353A

5-methyl-3 - [(S, 2S) -2-methylcyclopropyl] -1- (oxetan-2-ylmethyl) -2,4-dioxo-1,2,3,4-tetrahydrothieno [2,3- d] pyrimidine-6-carbaldehyde {diastereomer mixture)

400 mg (1.52 mmol) of the compound from Example 303A and 523 mg (1.89 mmol) of potassium carbonate were initially charged in 5.7 ml of anhydrous DMF, admixed with 686 mg (4.54 mmol) of 2- (bromomethyl) oxetane and in the microwave (Biotage Initiator) initially for 1 h at 80 ° C and then heated to 100 ° C for 2 h. The reaction mixture was then treated with 100 ml of water and stirred for 10 min at RT. It was extracted three times with 50 ml of ethyl acetate, and the combined organic phases were washed twice with saturated aqueous sodium chloride solution, dried over sodium sulfate, filtered and concentrated on a rotary evaporator. The residue was washed with water, then taken up in a methanol / dichloromethane mixture, reconcentrated on a rotary evaporator and finally dried under high vacuum. 470 mg (85% of theory, 91% purity) of the title compound were obtained. 'H-NMR (400 MHz, DMSO-d _6, δ / ppm): 7.10 (s, 1H), 5.00 (m, 1H), 4:46 (m, 2H), 4.18 (m, 2H), 2.76 (s, 3H), 2.70 (m, 2H), 2.27 (m, 1H), 1.15 (d, 3H), 1.07-0.99 (m, 1H), 0.88-0.83 (m, 2H).

LC / MS (Method 1, ESIpos): R _t = 1.55 min, m / z = 335.1 [M + H] ⁺ .

Example 354A

5-Methyl-3 - [(S, 2S) -2-methylcyclopropyl] -1- (oxetan-3-ylmethyl) -2,4-dioxo-1,2,3,4-tetrahydrothieno [2,3- d] pyrimidine-6-carbaldehyde

100 mg (0.38 mmol) of the compound from Example 303A and 131 mg (0.47 mmol) of potassium carbonate were initially charged in 1.4 ml of anhydrous DMF, 122 mg (1.15 mmol) of 3- (chloromethyl) oxetane and in the microwave (Biotage initiator) initially for 1 h at 80 ° C and then heated at 100 ° C for 5 h. The reaction mixture was then treated with 10 ml of water and stirred for 10 min at RT. The precipitate present was filtered off, washed with water, then taken up in a methanol / dichloromethane mixture, reconcentrated on a rotary evaporator and dried under high vacuum. The aqueous filtrate was extracted twice with 10 ml of ethyl acetate, and the combined organic phases were washed with saturated aqueous sodium chloride solution, dried over sodium sulfate, filtered and concentrated on a rotary evaporator. The product thus obtained was combined with the product obtained from the filtration. A total of 102 mg (81% of theory) of the title compound were obtained.

Example 355A

5-Methyl-3- (2-methylcyclopropyl) -2,4-dioxo-1 - [(2R) -tetrahydrofuran-2-ylmethyl] -1,2,3,4-tetrahydrothieno [2,3-d] pyrimidine-6-carbaldehyde (iran diastereomer mixture)

200 mg (0.76 mmol) of the compound from Example 34A and 261 mg (1.89 mmol) of potassium carbonate were initially charged in 2.9 ml of anhydrous DMF, treated with 394 mg (2.28 mmol) of (2R) -2- (bromomethyl) tetrahydrofuran and treated in The microwave (Biotage initiator) heated to 100 ° C for 5.5 h. The reaction mixture was then added with water and extracted with ethyl acetate. The organic phase was washed with water and with saturated aqueous sodium chloride solution, dried over sodium sulfate, filtered and concentrated on a rotary evaporator. There was obtained 210 mg (64% of theory, 80% purity) of the title compound.

LC / MS (Method 6, ESIpos): R _t = 1.22 min, m / z = 349.2 [M + H] ⁺ .

Example 356A 5-Methyl-3- (2-methylcyclopropyl) -2,4-dioxo-1- (tetrahydrofuran-3-ylmethyl) -1,2,3,4-tetrahydrothieno [2,3-d] pyrimidine 6-carbaldehyde (mixture of all iroro stereoisomers)

200 mg (0.76 mmol) of the compound from Example 34A and 261 mg (1.89 mmol) of potassium carbonate were initially charged in 3 ml of anhydrous DMF, treated with 374 mg (2.27 mmol) of racemic 3- (bromomethyl) -tetrahydrofuran and in the microwave (Biotage Initiator) for 2 h at 100 ° C heated. The reaction mixture was then treated with about 15 ml of water and extracted three times with 5 ml of ethyl acetate. The organic phase was dried over sodium sulfate, filtered and concentrated on a rotary evaporator. There were obtained 279 mg (96% of theory, 91% purity) of the title compound.

Ή-NMR (400 MHz, DMSO-de, δ / ppm): 10.08 (s, 1H), 3.91 (m, 1H), 3.80 (m, 1H), 3.64 (m, 1H), 3.50 (m, 1H) , 2.77 (s, 3H), 2.72 (m, 1H), 2.26 (m, 1H), 1.97 (m, 1H), 1.67 (m, 1H), 1.16 (d, 3H), 1.07-0.97 (m, 1H ), 0.89-0.81 (m, 2H).

LC / MS (Method 1, ESIpos): R _t = 1.59 min, m / z = 349.1 [M + H] ⁺ . Example 357A 1- (2-methoxyethyl) -5-methyl-2,4-dioxo-3- [2- (trifluoromethyl) cyclopropyl] -1,3,3,4-tetrahydrothieno [2,3-d] pyrimidine 6-carbaldehyde (trans-racemate)

1.03 g (3.22 mmol) of the compound of Ex. 306A and 1.11 g (8.05 mmol) of potassium carbonate were stirred for 15 min at RT in 15 ml of anhydrous DMF before 1.34 g (9.66 mmol) of (2-bromoethyl) methyl ether were added. The reaction mixture was then stirred at RT for 2.5 days and then at 55 ° C. for 4 h. After cooling to RT, it was diluted with 30 ml of ethyl acetate and washed successively with water and saturated sodium chloride solution, dried over anhydrous magnesium sulfate and evaporated. The residue was purified by MPLC purified (Biotage Isolera One, cartridge SNAP Ultra, 50 g of silica gel, cyclohexane / ethyl acetate gradient). After evaporation of the product fractions, the solid obtained was stirred in a mixture of 100 ml of cyclohexane and 10 ml of dichloromethane at RT. The purified solid was filtered off with suction and dried under high vacuum. 608 mg (50% of theory) of the title compound were obtained.

'H-NMR (400 MHz, DMSO-de, δ / ppm): 10.08 (s, 1H), 4.15-3.99 (m, 2H), 3.64 (t, 2H), 3.25 (s, 3H), 2.99 (ddd , 1H), 2.77 (s, 3H), 2.27 (dtd, 1H), 1.52 (q, 1H), 1.40-1.31 (m, 1H).

LC / MS (Method 2, ESIpos): R _t = 0.90 min, m / z = 377 [M + H] ⁺ .

Example 358A 3- (2-Ethylcyclopropyl) -1- (2-methoxyethyl) -5-methyl-2,4-dioxo-1,2,3,4-tetrahydrothieno [2,3-d] pyrimidine-6-carbaldehyde (trans-racemate)

820 mg (2.95 mmol) of the compound of Ex. 309A and 1.02 g (7.37 mmol) of potassium carbonate were stirred for 15 min at RT in 12 ml of anhydrous DMF before 1.23 g (8.84 mmol) of (2-bromoethyl) methyl ether were added. Then, the reaction mixture was stirred for 4 hours at 100 ° C in a microwave oven (biotage initiator with dynamic control of the irradiation power). After cooling to RT, it was diluted with 30 ml of ethyl acetate and washed successively with water and saturated sodium chloride solution, dried over anhydrous magnesium sulfate and evaporated. The residue was purified by MPLC (Biotage Isolera One, cartridge SNAP Ultra, 50 g silica gel, cyclohexane / ethyl acetate gradient). After evaporation of the product fractions, the solid obtained was dried under high vacuum. 867 mg (87% of theory) of the title compound were obtained.

'H-NMR (400 MHz, DMSO-de, δ / ppm): 10.07 (s, 1H), 4.12-3.99 (m, 2H), 3.63 (t, 2H), 3.24 (s, 3H), 2.76 (s , 3H), 2.38-2.29 (m, 1H), 1.61 (dquin, 1H), 1.25 (dquin, 1H), 1.11-0.95 (m, 1H), 1.00 (t, 3H), 0.90-0.77 (m, 2H ).

LC / MS (Method 1, ESIpos): R _t = 1.82 min, m / z = 337.12 [M + H] Example 359A

3- (2-Methoxycyclopropyl) -1- (2-methoxyethyl) -5-methyl-2,4-dioxo-1,2,3,4-tetrahydrothieno [2,3-d] pyrimidine-6-carbaldehyde (trans racemate)

817 mg (2.92 mmol) of the compound of Ex. 312A and 1.01 g (7.29 mmol) of potassium carbonate were stirred for 15 min at RT in 14 ml of anhydrous DMF before 1.22 g (8.74 mmol) of (2-bromoethyl) methyl ether were added. Subsequently, the reaction mixture was stirred for 3 days at RT. Thereafter, it was mixed with 400 ml of water. A part of the product precipitated, which was isolated by suction. The filtrate was extracted with ethyl acetate. The organic extract was washed successively with water and saturated aqueous sodium chloride solution. After drying over anhydrous magnesium sulfate, it was filtered and evaporated. The remaining residue was combined with the previously isolated product and purified by MPLC (Biotage Isolera One, cartridge SNAP Ultra, 50 g silica gel, cyclohexane / ethyl acetate gradient). After evaporation of the product fractions, the product was dried under high vacuum. There were obtained 676 mg (66% of theory, 96% purity) of the title compound.

Ή-NMR (400 MHz, DMSO-de, δ / ppm): 10.07 (s, 1H), 4.18-3.98 (m, 2H), 3.70-3.57 (m, 2H), 3.49-3.41 (m, 1H), 3.24 (s, 3H), 3.23 (s, 3H), 2.76 (s, 3H), 2.64 (dt, 1H), 1.33 (td, 1H), 0.91 (ddd, 1H).

LC / MS (Method 1, ESIpos): R _t = 1.29 min, m / z = 339.10 [M + H] ⁺ .

Example 360A tert. Butyl {2 - [({1- (2-methoxyethyl) -5-methyl-3 - [(7S, 2S) -2-methylcyclopropyl] -2,4-dioxo-1,2,3,4-tetrahydrothieno [2,3-d] pyrimidin-6-yl} methyl) amino] ethyl} carbamate

A solution of 208.7 g (647 mmol) of the compound from Ex. 350A in 5 liters of ethanol was treated at RT with 155.6 g (971 mmol) of tert-butyl (2-aminoethyl) carbamate and 55.6 ml (971 mmol) of acetic acid and then stirred at 55 ° C for 15 h. After cooling to RT, the reaction mixture was added in three portions over 90 minutes with a total of 44.1 g (1.17 mol) of solid sodium borohydride. This resulted in a violent evolution of gas. One hour after the last addition of sodium borohydride, 417 ml of water were added to the reaction mixture and the mixture was stirred vigorously at RT for 10 min. The mixture was then concentrated on a rotary evaporator to dryness. The remaining residue was taken up in a mixture of 2.14 liters of toluene and 856 ml of I M sodium hydroxide solution and stirred at RT. After phase separation, the aqueous phase was extracted with 1 liter of toluene. The combined toluene phases were then washed twice with 800 ml of water, dried over anhydrous magnesium sulfate and evaporated. The residue was chromatographed on silica gel (10 kg of silica gel 0.063-0.2 mm, dichloromethane / methanol 97: 3). After evaporation of the product fractions and drying in vacuo, 291 g (96% of theory) of the title compound were obtained.

Ή-NMR (400 MHz, DMSO-de, δ / ppm): 6.84-6.61 (m, 1H), 4.06-3.89 (m, 2H), 3.78-3.74 (m, 2H), 3.61 (t, 2H), 3.24 (s, 3H), 3.01 (q, 2H), 2.59-2.53 (m, 2H), 2.42-2.33 (m, 1H), 2.26-2.19 (m, 1H), 1.37 (s, 9H), 1.15 ( d, 3H), 1.06-0.91 (m, 1H), 0.87-0.77 (m, 2H).

Example 361A 6 - {[(2-Aminoethyl) amino] methyl} -3-cyclopropyl-l - [(3,3-difluorocyclobutyl) methyl] -5-methylthieno [2,3-d] pyrimidine-2,4 (lH, 3H) -dione

150 mg (0.423 mmol) of the compound from Ex. 328A were dissolved in a mixture of 4 ml of methanol and 2 ml of dichloromethane. Then 170 μΐ (2.54 mmol) of 1,2-diaminomethane and 97 μΐ (1.69 mmol) of acetic acid were added at RT. After 30 minutes, 106 mg (1.69 mmol) of sodium cyanoborohydride were added. The mixture was subsequently stirred at 60.degree. C. for about 16 h. After cooling to RT, 2M sodium hydroxide solution was added and the mixture was extracted with ethyl acetate. The organic extract was washed with saturated sodium chloride solution, dried over anhydrous magnesium sulfate, filtered and evaporated. The crude product thus obtained gave, after drying under high vacuum, 189 mg (95% of theory, 85% purity) of the title compound, which were used without further purification for subsequent reactions. LC / MS (Method 1, ESIpos): R _t = 0.73 min, m / z = 399.17 [M + H] ⁺ .

Example 362A 1, 5-Dimethyl-3 - [(S, 2S) -2-methylcyclopropyl] -2,4-dioxo-1,2,3,4-tetrahydrothieno [2,3-d] pyrimidin-6 carbaldehyde

300 mg (1.14 mmol) of the compound from Ex. 303A were dissolved in 5 ml of anhydrous DMF, combined with 392 mg (2.84 mmol) of potassium carbonate and stirred at RT for 15 min. Then, 212 μΐ (3.41 mmol) of methyl iodide was added. After the reaction mixture was stirred for 1 h at 50 ° C, it was poured into water and acidified with 1 M hydrochloric acid. The product failed. After stirring for 1 h at RT, the solid was filtered off with suction, washed with a little water and dried under high vacuum. 313 mg (99% of theory) of the title compound were obtained.

Ή-NMR (500 MHz, DMSO-de, δ / ppm): 10.07 (s, 1H), 3.43 (s, 3H), 2.77 (s, 3H), 2.29-2.22 (m, 1H), 1.15 (d, 3H), 1.06-0.95 (m, 1H), 0.90-0.81 (m, 2H).

LC / MS (Method 1, ESIpos): R _t = 1.54 min, m / z = 279.08 [M + H] ⁺ .

Example 363A 6 - {[(2-Aminoethyl) amino] methyl} -1, 5-dimethyl-3- (2-methylcyclopropyl) thieno [2,3-d] pyrimidine-2,4 (1H, 3H) -dione ( trans-racemate) N

H ₂ NH

CH ₃

130 μΐ (2.3 mmol) of acetic acid and 230 μΐ (3.45 mmol) of 1,2-ethylenediamine were added to a solution of 160 mg (0.58 mmol) of the compound from Ex. 336A in 4 ml of methanol and 1 ml of dichloromethane. The mixture was then stirred at RT for 30 min. The reaction was then diluted with 4 ml of methanol and 145 mg (2.3 mmol) of sodium cyanoborohydride were added. The reaction mixture was stirred at 60 ° C. for 8 h and then at RT for a further 60 h. The mixture was then combined with 2 M sodium hydroxide solution and a little sodium chloride and extracted three times with ethyl acetate. The combined organic phases were washed with saturated aqueous sodium chloride solution, dried over sodium sulfate, filtered and concentrated on a rotary evaporator. The residue was taken up in 5 ml of ethyl acetate, washed with a mixture of 1 ml of saturated aqueous sodium chloride solution and 1 M sodium hydroxide solution, dried over sodium sulfate, filtered and concentrated again on a rotary evaporator. After drying the residue in a high vacuum, 173 mg (93% of theory) of the title compound were obtained, which were used further without further purification. Example 364A

6 - {[(2-aminoethyl) amino] methyl} -1-ethyl-5-methyl-3- (2-methylcyclopropyl) thieno [2,3-d] pyrimidine-2,4 (1H, 3H) - dion (trans-racemate)

To a solution of 220 mg (94% purity, 0.71 mmol) of the compound from Example 337A in 3.8 ml of methanol and 0.9 ml of dichloromethane was added 160 μΐ (2.83 mmol) of acetic acid and 280 μΐ (4.25 mmol) of 1,2-ethylenediamine. The mixture was then stirred at RT for 30 min. Thereafter, 178 mg (2.83 mmol) of sodium cyanoborohydride were added and the reaction mixture was stirred overnight at 60 ° C. The mixture was then admixed with 3 ml of 1 M sodium hydroxide solution and 3 ml of saturated aqueous sodium chloride solution and extracted three times with 5 ml of ethyl acetate each time. The combined organic phases were washed with saturated aqueous sodium chloride solution, dried over sodium sulfate, filtered and concentrated on a rotary evaporator. Of the Residue was dried under high vacuum. 317 mg (> 100% of theory) of the crude title compound were obtained, which were used without further purification.

Example 365A

6 - {[(2-Aminoethyl) amino] methyl} -5-methyl-3- (2-methylcyclopropyl) -1-propylthieno [2,3-d] pyrimidine-2,4 (1H, 3H) -dione ( trans-racemate)

To a solution of 205 mg (0.67 mmol) of the compound from Ex. 338A in 4.6 ml of methanol and 1.2 ml of dichloromethane were added 150 μΐ (2.68 mmol) of acetic acid and 270 μΐ (4.02 mmol) of 1,2-ethylenediamine. The mixture was then stirred at RT for 30 min. Thereafter, 168 mg (2.66 mmol) of sodium cyanoborohydride was added and the reaction mixture was stirred overnight at 60 ° C. The mixture was then admixed with 6 ml of 1 M sodium hydroxide solution and 6 ml of saturated aqueous sodium chloride solution and extracted three times with 10 ml of ethyl acetate each time. The combined organic phases were washed with saturated aqueous sodium chloride solution, dried over sodium sulfate, filtered and concentrated on a rotary evaporator. After drying the residue in a high vacuum, 266 mg (> 100% of theory) of the crude title compound were obtained, which were used further without further purification.

Example 366A

6 - {[(2-Aminoethyl) amino] methyl} -1-butyl-5-methyl-3 - [(S, 2S) -2-methylcyclopropyl] thieno [2,3-d] pyrimidine-2,4 ( lH, 3H) -dione

To a solution of 96 mg (0.26 mmol, 87% purity) of the compound from Ex. 339A in 1.8 ml of methanol and 0.5 ml of dichloromethane was added 60 .mu.l (1.05 mmol) of acetic acid and 110 .mu.l (1.57 mmol) of 1,2-ethylenediamine. The mixture was then stirred at RT for 30 min. There- After 66 mg (1.05 mmol) of sodium cyanoborohydride was added and the reaction mixture was stirred at 60 ° C overnight. The mixture was then admixed with 3 ml of 1 M sodium hydroxide solution and 3 ml of saturated aqueous sodium chloride solution and extracted three times with 5 ml of ethyl acetate each time. The combined organic phases were washed with saturated aqueous sodium chloride solution, dried over sodium sulfate, filtered and concentrated on a rotary evaporator. After drying the residue in a high vacuum, 150 mg (> 100% of theory) of the crude title compound were obtained, which were used further without further purification.

Example 367A

6- {[(2-aminoethyl) amino] methyl} -1- (2-fluoroethyl) -5-methyl-3- (2-methylcyclopropyl) thieno [2,3-d] pyrimidine-2,4 (1H, 3H) -dione (trans-racemate)

To a solution of 210 mg (0.68 mmol) of the compound of Ex. 340A in 4 ml of methanol and 1 ml of dichloromethane were added 160 μΐ (2.72 mmol) of acetic acid and 270 μΐ (4.01 mmol) of 1,2-ethylenediamine. The mixture was then stirred at RT for 30 min. Thereafter, 170 mg (2.72 mmol) of sodium cyanoborohydride was added and the reaction mixture was stirred overnight at 60 ° C. The mixture was then admixed with 3 ml of 1 M sodium hydroxide solution and 3 ml of saturated aqueous sodium chloride solution and extracted three times with 5 ml of ethyl acetate each time. The combined organic phases were washed with saturated aqueous sodium chloride solution, dried over sodium sulfate, filtered and concentrated on a rotary evaporator. After drying the residue under high vacuum, 300 mg (> 100% of theory) of the crude title compound were obtained, which were used further without further purification.

Example 368A

6- {[(2-Aminoethyl) amino] methyl} -1- (2,2-difluoroethyl) -5-methyl-3- (2-methylcyclopropyl) thieno [2,3-d] pyrimidine-2,4 ( 1H, 3H) -dione (trans-racemate)

To a solution of 167 mg (0.51 mmol) of the compound of Ex. 341A in 3.9 ml of methanol and 1 ml of dichloromethane were added 120 μΐ (2.03 mmol) of acetic acid and 200 μΐ (3.05 mmol) of 1,2-ethylenediamine. The mixture was then stirred at RT for 30 min. Thereafter, 128 mg (2.03 mmol) of sodium cyanoborohydride was added and the reaction mixture was stirred overnight at 60 ° C. The mixture was then admixed with 3 ml of 1 M sodium hydroxide solution and 3 ml of saturated aqueous sodium chloride solution and extracted three times with 5 ml of ethyl acetate each time. The combined organic phases were washed with saturated aqueous sodium chloride solution, dried over sodium sulfate, filtered and concentrated on a rotary evaporator. After drying the residue in a high vacuum, 279 mg (> 100% of theory) of the crude title compound were obtained, which were used further without further purification.

Example 369A

6- {[(2-aminoethyl) amino] methyl} -5-methyl-3- (2-methylcyclopropyl) -1- (2,2,2-trifluoroethyl) thieno [2,3-d] pyrimidine-2, 4 (1H, 3H) -dione (trans-racemate)

To a solution of 100 mg (0.28 mmol) of the compound of Ex. 342A in 1.6 ml of methanol and 0.4 ml of dichloromethane were added 60 .mu.l (1.12 mmol) of acetic acid and 110 .mu.l (1.68 mmol) of 1,2-ethylenediamine. The mixture was then stirred at RT for 30 min. Thereafter, 70 mg (1.12 mmol) of sodium cyanoborohydride was added and the reaction mixture was stirred overnight at 60 ° C. The mixture was then admixed with 3 ml of 1 M sodium hydroxide solution and 3 ml of saturated aqueous sodium chloride solution and extracted three times with 5 ml of ethyl acetate each time. The combined organic phases were washed with saturated aqueous sodium chloride solution, dried over sodium sulfate, filtered and concentrated on a rotary evaporator. After drying the Residue under high vacuum gave 158 mg (> 100% of theory) of the crude title compound, which were used without further purification.

Example 370A

6- {[(2-aminoethyl) amino] methyl} -5-methyl-3- (2-methylcyclopropyl) -1- (4,4,4-trifluorobutyl) thieno [2,3-d] pyrimidine-2, 4 (1H, 3H) -dione (trans-racemate)

To a solution of 250 mg (0.67 mmol) of the compound of Ex. 343A in 3.7 ml of methanol and 0.9 ml of dichloromethane were added 140 μΐ (2.46 mmol) of acetic acid and 250 μΐ (3.70 mmol) of 1,2-ethylenediamine. The mixture was then stirred at RT for 30 min. Thereafter, 154 mg (2.45 mmol) of sodium cyanoborohydride were added and the reaction mixture was stirred overnight at 60 ° C. The mixture was then admixed with 3 ml of 1 M sodium hydroxide solution and 3 ml of saturated aqueous sodium chloride solution and extracted three times with 5 ml of ethyl acetate each time. The combined organic phases were washed with saturated aqueous sodium chloride solution, dried over sodium sulfate, filtered and concentrated on a rotary evaporator. After drying the residue in a high vacuum, 457 mg (> 100% of theory) of the crude title compound were obtained, which were used further without further purification.

Example 371A

6 - {[(2-aminoethyl) amino] methyl} -5-methyl-3- (2-methylcyclopropyl) -1- (3,3,4,4-tetrafluorobutyl) thieno [2,3-d] pyrimidine 2,4 (1H, 3H) -dione (trans-racemate)

To a solution of 190 mg (0.48 mmol) of the compound of Ex. 344A in 4 ml of methanol and 1 ml of dichloromethane were added 110 μΐ (1.93 mmol) of acetic acid and 190 μΐ (2.91 mmol) of 1,2-ethylenediamine. The mixture was then stirred at RT for 30 min. Thereafter, 122 mg (1.94 mmol) of sodium cyanoborohydride was added and the reaction mixture was stirred overnight at 60 ° C. The mixture was then admixed with 5 ml of 1 M sodium hydroxide solution and 5 ml of saturated aqueous sodium chloride solution and extracted three times with 5 ml of ethyl acetate each time. The combined organic phases were washed with saturated aqueous sodium chloride solution, dried over sodium sulfate, filtered and concentrated on a rotary evaporator. After drying the residue in a high vacuum, 245 mg (> 100% of theory) of the crude title compound were obtained, which were used further without further purification.

LC / MS (Method 1, ESIpos): R _t = 0.84 min, m / z = 437.1 [M + H] ⁺ .

Example 372A

6- {[(2-aminoethyl) amino] methyl} -1- (cyclobutylmethyl) -5-methyl-3 - [(S, 2S) -2-methylcyclopropyl] thieno [2,3-d] pyrimidine-2 , 4 (lH, 3H) -dione

To a solution of 100 mg (0.30 mmol) of the compound of Ex. 345A in 2.1 ml of methanol and 0.5 ml of dichloromethane was added 70 μΐ (1.20 mmol) of acetic acid and 120 μΐ (1.80 mmol) of 1,2-ethylenediamine. The mixture was then stirred at RT for 30 min. Thereafter, 75 mg (1.20 mmol) of sodium cyanoborohydride was added and the reaction mixture was stirred overnight at 60 ° C. The mixture was then admixed with 3 ml of 1 M sodium hydroxide solution and 3 ml of saturated aqueous sodium chloride solution and extracted three times with 5 ml of ethyl acetate each time. The combined organic phases were washed with saturated aqueous sodium chloride solution, dried over sodium sulfate, filtered and concentrated on a rotary evaporator. After drying the residue under high vacuum, 148 mg (> 100% of theory) of the crude title compound were obtained, which were used further without further purification.

Example 373A

6 - {[(2-aminoethyl) amino] methyl} -1- [(2,2-difluorocyclopropyl) methyl] -5-methyl-3 - [(S, 2S) -2-methylcyclopropyl] thieno [2,3- d] pyrimidine-2,4 (1H, 3H) -dione (mixture of diastereomers)

To a solution of 100 mg (0.28 mmol) of the compound of Ex. 346A in 2 ml of methanol and 0.5 ml of dichloromethane were added 70 .mu.l (1.20 mmol) of acetic acid and 110 .mu.l (1.70 mmol) of 1,2-ethylenediamine. The mixture was then stirred at RT for 30 min. Thereafter, 71 mg (1.13 mmol) of sodium cyanoborohydride was added and the reaction mixture was stirred overnight at 60 ° C. The mixture was then admixed with 3 ml of 1 M sodium hydroxide solution and 3 ml of saturated aqueous sodium chloride solution and extracted three times with 5 ml of ethyl acetate each time. The combined organic phases were washed with saturated aqueous sodium chloride solution, dried over sodium sulfate, filtered and concentrated on a rotary evaporator. After drying the residue in a high vacuum, 153 mg (> 100% of theory) of the crude title compound were obtained, which were used further without further purification.

Example 374A

6 - {[(2-Aminoethyl) amino] methyl} -1 - [(3,3-difluorocyclobutyl) methyl] -5-methyl-3- (2-methylcyclopropyl) thieno [2,3-d] pyrimidine 2,4 (1H, 3H) -dione (trans-racemate)

To a solution of 200 mg (0.46 mmol, 85% purity) of the compound of Ex. 347A in 2.7 ml of methanol and 0.7 ml of dichloromethane was added 110 μΐ (1.85 mmol) of acetic acid and 190 μΐ (2.77 mmol) of 1,2-ethylenediamine. The mixture was then stirred at RT for 30 min. Thereafter, 116 mg (1.84 mmol) of sodium cyanoborohydride was added and the reaction mixture was stirred overnight at 60 ° C. The mixture was then admixed with 3 ml of 1 M sodium hydroxide solution and 3 ml of saturated aqueous sodium chloride solution and extracted three times with 5 ml of ethyl acetate each time. The combined organic phases were washed with saturated aqueous sodium chloride solution, dried over sodium sulfate, filtered and concentrated on a rotary evaporator. To Drying of the residue in a high vacuum gave 210 mg (> 100% of theory) of the crude title compound, which were used further without further purification.

Example 375A

6 - {[(2-aminoethyl) amino] methyl} -1- [(3,3-difluorocyclopentyl) methyl] -5-methyl-3 - [(S, 2S) -2-methylcyclopropyl] thieno [2,3- d] pyrimidine-2,4 (1H, 3H) -dione (mixture of diastereomers)

Analogously to the process described under Example 374A, from 90 mg (0.24 mmol) of the compound from Example 348A, 102 mg (> 100% of theory) of the crude title compound were obtained, which were used further without further purification. Example 376A

6- {[(2-aminoethyl) amino] methyl} -1- (2-methoxyethyl) -5-methyl-3- (2-methylcyclopropyl) thieno [2,3-d] pyrimidine-2,4 (1H, 3H) -dione (d-racemate)

Analogously to the procedure described under Ex. 103A, from 510 mg (1.58 mmol) of the compound from Ex. 349A, 635 μΐ (9.49 mmol) of 1,2-diaminoethane and 419 mg (6.33 mmol) of sodium cyanoborohydride were added 604 mg (91% of theory). Th., 88% purity) of the title compound.

LC / MS (Method 1, ESIpos): R _t = 0.58 min, m / z = 307.11 [M + HC ₂ H ₈ N ₂ ] Example 377A

6 - {[(2-aminoethyl) amino] methyl} -1- (2-methoxyethyl) -5-methyl-3 - [(S, 2S) -2-methylcyclopropyl] thieno [2,3-d] pyrimidine 2,4 (lH, 3H) -dione dihydrochloride

290 g (621 mmol) of the compound from Example 360A were dissolved in 1 liter of dioxane and treated at RT with 2.9 liters of a 4 M solution of hydrogen chloride in dioxane. The reaction mixture was stirred at RT for 16 h. It was then diluted with 2.5 liters of toluene and then concentrated. The residue obtained was taken up twice in 2.5 liters of toluene and concentrated again. Thereafter, the product was freed of solvent residues in a high vacuum. 273 g (99% of theory) of the title compound were obtained.

Ή-NMR (400 MHz, DMSO-de, δ / ppm): 9.82 (br, s, 2H), 8.42 (br, s, 3H), 4.37 (br, s, 2H), 4.08- 3.91 (m, 2H ), 3.64 (t, 2H), 3.29-3.20 (m, 4H), 3.25 (s, 3H), 2.48 (s, 3H), 2.30-2.22 (m, 1H), 1.15 (d, 3H), 1.06- 0.93 (m, 1H), 0.90-0.77 (m, 2H).

LC / MS (Method 2, ESIpos): R _t = 0.40 min, m / z = 367 [M + H] ⁺ . Example 378A

6- {[(2-Aminoethyl) amino] methyl} -5-methyl-3- (2-methylcyclopropyl) -1- [2- (trifluoromethoxy) ethyl] thieno [2,3-d] pyrimidine-2,4 (lH, 3H) -dione (iroro racemate)

870 mg (2.31 mmol) of the compound from Ex. 351A were dissolved in a mixture of 20 ml of methanol and 7.5 ml of dichloromethane. Subsequently, 927 μΐ (13.9 mmol) of 1,2-diaminomethane and 529 μΐ (9.25 mmol) of acetic acid were added at RT. After 30 min, 612 mg (9.25 mmol) sodium cyanoborohydride. Subsequently, the mixture was stirred at 60 ° C for about 16 h. After cooling to RT, 2M sodium hydroxide solution was added and the mixture was extracted with ethyl acetate. The organic extract was washed with saturated sodium chloride solution, dried over anhydrous magnesium sulfate, filtered and evaporated. The remaining residue was purified by MPLC (Biotage Isolera One, cartridge SNAP Ultra, 50 g of silica gel, dichloromethane / methanol gradient). Evaporation of the product fractions and drying under high vacuum gave 550 mg (53% of theory, 94% purity) of the title compound.

'H-NMR (400 MHz, DMSO-de, δ / ppm): 6.35 (broad, 3H), 4.39 (t, 2H), 4.24-4.07 (m, 2H), 3.81 (s, 2H), 2.93-2.82 (m, 2H), 2.77-2.68 (m, 2H), 2.35 (s, 3H), 2.29-2.22 (m, 1H), 1.15 (d, 3H), 1.04-0.92 (m, 1H), 0.89-0.77 (m, 2H).

LC / MS (Method 1, ESIpos): R _t = 0.83 min, m / z = 421.15 [M + H] ⁺ .

Example 379A

6 - {[(2-Aminoethyl) amino] methyl} -5-methyl-3- (2-methylcyclopropyl) -1- {2 - [(trifluoromethyl) sulfanyl] ethyl} thieno [2,3-d] pyrimidine 2,4 (1H, 3H) -dione (iroro-racemate)

To a solution of 265 mg (0.68 mmol) of the compound of Ex. 352A in 6 ml of methanol and 2 ml of dichloromethane were added 160 μΐ (2.70 mmol) of acetic acid and 270 μΐ (4.07 mmol) of 1,2-ethylenediamine. The mixture was then stirred at RT for 30 min. Thereafter, 170 mg (2.70 mmol) of sodium cyanoborohydride was added and the reaction mixture was stirred overnight at 60 ° C. The mixture was then admixed with 3 ml of 1 M sodium hydroxide solution and 3 ml of saturated aqueous sodium chloride solution and extracted three times with 5 ml of ethyl acetate each time. The combined organic phases were washed with saturated aqueous sodium chloride solution, dried over sodium sulfate, filtered and concentrated on a rotary evaporator. Drying of the residue in a high vacuum gave 360 mg (> 100% of theory) of the crude title compound, which were used further without further purification. Example 380A

6 - {[(2-Aminoethyl) amino] methyl} -5-methyl-3 - [(S, 2S) -2-methylcyclopropyl] -1- (oxetan-2-ylmethyl) thieno [2,3-d ] pyrimidine-2,4 (1H, 3H) -dione {diastereomer mixture)

To a solution of 470 mg (1.41 mmol) of the compound from Ex. 353A in 10 mL of methanol and 3 mL of dichloromethane was added 320 μΐ (5.63 mmol) of acetic acid and 560 μΐ (8.45 mmol) of 1,2-ethylenediamine. The mixture was then stirred at RT for 30 min. Thereafter, 353 mg (5.62 mmol) of sodium cyanoborohydride was added and the reaction mixture was stirred overnight at 60 ° C. The mixture was then admixed with 5 ml of 1 M sodium hydroxide solution and 5 ml of saturated aqueous sodium chloride solution and extracted three times with 10 ml of ethyl acetate each time. The combined organic phases were washed with saturated aqueous sodium chloride solution, dried over sodium sulfate, filtered and concentrated on a rotary evaporator. Drying of the residue under high vacuum gave 460 mg (86% of theory) of the crude title compound, which were used without further purification. Example 381A

6 - {[(2-Aminoethyl) amino] methyl} -5-methyl-3 - [(S, 2S) -2-methylcyclopropyl] -1- (oxetan-3-ylmethyl) thieno [2,3-d ] pyrimidine-2,4 (lH, 3H) -dione

To a solution of 100 mg (0.30 mmol) of the compound from Ex. 354A in 2 ml of methanol and 0.5 ml of dichloromethane were added 70 μΐ (1.20 mmol) of acetic acid and 120 μΐ (1.80 mmol) of 1,2-ethylenediamine. The mixture was then stirred at RT for 30 min. Thereafter, 75 mg (1.19 mmol) of sodium cyanoborohydride was added and the reaction mixture was stirred overnight at 60 ° C. The mixture was then washed with 3 ml of 1 M sodium hydroxide solution and 3 ml of saturated aqueous Sodium chloride solution and extracted three times with 5 ml of ethyl acetate. The combined organic phases were washed with saturated aqueous sodium chloride solution, dried over sodium sulfate, filtered and concentrated on a rotary evaporator. After drying the residue in a high vacuum, 150 mg (> 100% of theory) of the crude title compound were obtained, which were used further without further purification.

Example 382A

6- {[(2-Aminoethyl) amino] methyl} -5-methyl-3- (2-methylcyclopropyl) -1 - [(2R) -tetrahydrofuran-2-ylmethyl] thieno [2,3-d] pyrimidine-2 , 4 (lH, 3H) -dione (ira, y-diastereomer mixture)

To a solution of 210 mg (0.48 mmol, 80% purity) of the compound of Ex. 355A in 4.2 ml of methanol and 1 ml of dichloromethane was added 110 μΐ (1.93 mmol) of acetic acid and 190 μΐ (2.90 mmol) of 1,2-ethylenediamine. The mixture was then stirred at RT for 30 min. The reaction was then diluted with an additional 4 ml of methanol and 121 mg (1.93 mmol) of sodium cyanoborohydride were added. The reaction mixture was stirred at 60 ° C. for 8 h and then at RT overnight. The mixture was then admixed with 6 ml of 1 M sodium hydroxide solution and 6 ml of saturated aqueous sodium chloride solution and extracted three times with 10 ml of ethyl acetate each time. The combined organic phases were washed with saturated aqueous sodium chloride solution, dried over sodium sulfate, filtered and concentrated on a rotary evaporator. After drying the residue in a high vacuum, 233 mg (> 100% of theory) of the crude title compound were obtained, which were used further without further purification.

Example 383A

6 - {[(2-Aminoethyl) amino] methyl} -5-methyl-3- (2-methylcyclopropyl) -1- (tetrahydrofuran-3-ylmethyl) thieno [2,3-d] pyrimidine-2,4 (lH, 3H) -dione (mixture of all iraro stereoisomers)

Analogously to the process described under Example 374A, from 264 mg (0.69 mmol, 91% purity) of the compound from Ex. 356A, 372 mg (> 100% of theory) of the crude title compound were obtained, which were used further without further purification. Example 384A

6 - {[(2-aminoethyl) amino] methyl} -1- (2-methoxyethyl) -5-methyl-3- [2- (trifluoromethyl) cyclopropyl] thieno [2,3-d] pyrimidine-2, 4 (1H, 3H) -dione (trans-racemate)

Analogously to the process described under Example 103A, 300 mg (0.797 mmol) of the compound from Ex. 357A, 320 μΐ (4.78 mmol) of 1,2-diaminoethane and 211 mg (3.19 mmol) of sodium cyanoborohydride were admixed with 411 mg (99% of theory). Th., 80%> purity) of the title compound.

LC / MS (Method 1, ESIpos): R _t = 0.74 min, m / z = 421.15 [M + H] ⁺ .

Example 385A

6- {[(2-Aminoethyl) amino] methyl} -3- (2-ethylcyclopropyl) -1- (2-methoxyethyl) -5-methylthieno [2,3-d] pyrimidine-2,4 (1H, 3H ) -dione (trans-racemate)

Analogously to the process described in Example 103A, from 275 mg (0.817 mmol) of the compound from Ex. 358A, 328 μΐ (4.91 mmol) of 1,2-diaminoethane and 216 mg (3.27 mmol) of sodium cyanoborohydride 323 mg (86% of theory). Th., 83% purity) of the title compound. LC / MS (Method 1, ESIpos): R _t = 0.73 min, m / z = 321.13 [M + HC ₂ H ₈ N ₂ ] ⁺ .

Example 386A

6- {[(2-Aminoethyl) amino] methyl} -3- (2-methoxycyclopropyl) -1- (2-methoxyethyl) -5-methylthieno [2,3-d] pyrimidine-2,4 (1H, 3H ) -dione (trans-racemate)

Analogously to the process described under Ex. 103A, from 320 mg (0.946 mmol) of the compound from Ex. 359A, 379 μΐ (5.67 mmol) of 1,2-diaminoethane and 250 mg (3.78 mmol) of sodium cyanoborohydride were added 509 mg (98% of theory). Th., 70% purity) of the title compound.

Example 387A

3-Cyclopropyl-1 - [(3,3-difluorocyclobutyl) methyl] -6- {[(2,2-dimethoxyethyl) amino] methyl} -5-methylthieno [2,3-d] pyrimidine-2,4 (1H , 3H) -dione

200 mg (0.564 mmol) of the compound from Ex. 328A were dissolved in 10 ml of dichloromethane and treated with 92 .mu.l (0.847 mmol) of 2,2-dimethoxyethanamine. The mixture was heated to 35 ° C for 1 h. After cooling to RT, 378 mg (1.69 mmol) of sodium triacetoxyborohydride were added. It was stirred further at RT. After 2 days, it was diluted with dichloromethane and washed successively with saturated sodium bicarbonate solution and saturated sodium chloride solution. After drying over anhydrous magnesium sulfate, it was filtered and the filtrate was concentrated to dryness. The crude product was purified by MPLC (Biotage Isolera One, cartridge SNAP Ultra, 10 g silica gel, cyclohexane / ethyl acetate 1: 1). After combining the product fractions, concentrating and drying under high vacuum, 193 mg (77% of theory) of the title compound were obtained.

'H-NMR (400 MHz, DMSO-de, δ / ppm): 4.40 (t, 1H), 4.02 (d, 2H), 3.81 (d, 2H), 3.26 (s, 6H), 2.74-2.55 (m , 7H), 2.31 (s, 3H), 2.29-2.20 (m, 1H), 1.05-0.94 (m, 2H), 0.73-0.59 (m, 2H).

LC / MS (Method 1, ESIpos): R _t = 1.02 min, m / z = 444.18 [M + H] ⁺ .

Example 388A

6- {[(2,2-Dimethoxyethyl) amino] methyl} -5-methyl-3- (1-methylcyclopropyl) -1- (3,3,3-trifluoropropyl) thieno [2,3-d] pyrimidine -2,4 (lH, 3H) -dione

300 mg (0.833 mmol) of the compound from Ex. 64A were dissolved in 17 ml of dichloromethane and treated with 135 μΐ (1.25 mmol) of 2,2-dimethoxyethanamine. The mixture was heated to 35 ° C for 1 h. After cooling to RT, 557 mg (2.50 mmol) of sodium triacetoxyborohydride were added. added. It was stirred further at RT. Since the conversion was not complete after 16 h, the mixture was heated again to 35 ° C. for 16 h. After cooling to RT, it was diluted with dichloromethane and washed successively with saturated sodium bicarbonate solution and saturated sodium chloride solution. After drying over anhydrous magnesium sulfate, it was filtered and the filtrate was concentrated to dryness. The crude product was purified by MPLC (Biotage Isolera One, cartridge SNAP Ultra, 25 g silica gel, cyclohexane / ethyl acetate 2: 1). After combining the product fractions, concentrating and drying in a high vacuum, 300 mg (80% of theory) of the title compound were obtained.

'H-NMR (400 MHz, DMSO-de, δ / ppm): 4.40 (t, 1H), 4.21-3.94 (m, 2H), 3.82 (s, 2H), 3.26 (s, 6H), 2.82-2.68 (m, 2H), 2.62 (br d, 2H), 2.33-2.24 (broad, 1H), 2.32 (s, 3H), 1.33 (s, 3H), 1.01-0.70 (m, 4H).

LC / MS (Method 1, ESIpos): R _t = 1.11 min, m / z = 450.17 [M + H] ⁺ . Example 389A l - [(3,3-Difluorocyclobutyl) methyl] -6 - {[(2,2-dimethoxyethyl) amino] methyl} -5-methyl-3- (1-methylcyclopropyl) thieno [2,3- d] pyrimidine-2,4 (lH, 3H) -dione

360 mg (0.977 mmol) of the compound from Ex. 335A were dissolved in 20 ml of dichloromethane and treated with 158 .mu.l (154 mmol) of 2,2-dimethoxyethanamine. The mixture was heated to 35 ° C for 1 h. After cooling to RT, 654 mg (2.93 mmol) of sodium triacetoxyborohydride were added. It was stirred further at RT. Since the conversion was not complete after 16 h, the mixture was heated again to 35 ° C. for 16 h. After cooling to RT, it was diluted with dichloromethane and washed successively with saturated sodium bicarbonate solution and saturated sodium chloride solution. After drying over anhydrous magnesium sulfate, it was filtered and the filtrate was concentrated to dryness. The crude product was purified by MPLC (Biotage Isolera One, cartridge SNAP Ultra, 25 g silica gel, cyclohexane / ethyl acetate 1: 2). After combining the product fractions, concentrating and drying under high vacuum, 324 mg (68% of theory, 95% purity) of the title compound were obtained. 'H-NMR (400 MHz, DMSO-de, δ / ρρηι): 4.40 (t, 1H), 4.17-3.90 (m, 2H), 3.81 (s, 2H), 3.26 (s, 6H), 2.77-2.57 (m, 5H), 2.31 (s, 3H), 2.28 (br, s, 1H), 1.32 (s, 3H), 0.99-0.71 (m, 4H).

LC / MS (Method 1, ESIpos): R _t = 1.20 min, m / z = 458.19 [M + H] ⁺ . Example 390A 6 - {[(2,2-Dimethoxyethyl) amino] methyl} -1- (2-methoxyethyl) -5-methyl-3- (1-methylcyclopropyl) thieno [2,3-d] pyrimidine-2, 4 (lH, 3H) -dione

Analogously to the process described under Ex. 389A, 300 mg (0.931 mmol) of the compound from Ex. 68A, 151 μΐ (1.40 mmol) 2,2-dimethoxyethanamine and 623 mg (2.79 mmol) sodium triacetoxyborohydride were mixed with 305 mg (74% of theory). Th., 94%> purity) of the title compound.

'H-NMR (400 MHz, DMSO-de, δ / ppm): 4.40 (t, 1H), 4.14-3.86 (m, 2H), 3.80 (s, 2H), 3.68-3.57 (m, 2H), 3.26 (s, 6H), 3.24 (s, 3H), 2.61 (d, 2H), 2.31 (s, 3H), 1.33 (s, 3H), 0.97-0.74 (m, 4H).

LC / MS (Method 1, ESIpos): R _t = 0.88 min, m / z = 307.11 [M + HC ₄ HnNO ₂ ] ⁺ .

Example 391A 6 - {[(2,2-Dimethoxyethyl) amino] methyl} -5-methyl-3- (2-methylcyclopropyl) -1- [2- (trifluoromethoxy) ethyl] thieno [2,3-d] pyrimidine-2,4 (1H, 3H) -dione (iroro-racemate)

400 mg (1.02 mmol, 95%> purity) of the compound from Ex. 351A were dissolved in 20 ml of dichloromethane and treated with 164 μΐ (1.52 mmol) of 2,2-dimethoxyethanamine. The mixture was heated to 35 ° C for 1 h. After cooling to RT, 645 mg (3.04 mmol) of sodium triacetate oxyborohydride added. It was stirred further at RT. Since the conversion was not complete after 16 h, stirring was continued for a further 5 days at RT. Thereafter, another 55 μΐ (0.507 mmol) of 2,2-dimethoxyethanamine and 215 mg (1.01 mmol) of sodium triacetoxyborohydride were added and stirring continued at RT for 20 h. The reaction mixture was then diluted with dichloromethane and washed successively with saturated sodium bicarbonate solution and saturated sodium chloride solution. After drying over anhydrous magnesium sulfate, it was filtered and the filtrate was concentrated to dryness. The crude product was purified by MPLC (Biotage Isolera One, cartridge SNAP Ultra, 25 g silica gel, cyclohexane / ethyl acetate 1: 1). After combining the product fractions, concentrating and drying under high vacuum, 365 mg (74% of theory, 96% purity) of the title compound were obtained.

'H-NMR (400 MHz, DMSO-de, δ / ppm): 4.40-4.36 (m, 3H), 4.25-4.06 (m, 2H), 3.81 (s, 2H), 3.25 (s, 6H), 2.60 (d, 2H), 2.31 (s, 3H), 2.27-2.21 (m, 1H), 1.15 (d, 3H), 1.02-0.92 (m, 1H), 0.88-0.78 (m, 2H).

LC / MS (Method 1, ESIpos): R _t = 1.17 min, m / z = 466.16 [M + H] ⁺ . Example 392A

1 - ({3-Cyclopropyl-1 - [(3,3-difluorocyclobutyl) methyl] -5-methyl-2,4-dioxo-1,2,3,4-tetrahydrothieno [2,3-d] pyrimidine 6-yl} methyl) -l- (2,2-dimethoxyethyl) urea

A solution of 190 mg (0.428 mmol) of the compound from Ex. 387A in 5 ml of methanol was initially treated at RT with 80 mg (0.985 mmol) of potassium cyanate and then with 63 μΐ (0.728 mmol) of perchloric acid (70%) in water). After 16 h, the reaction mixture was treated with water and with aqueous sodium bicarbonate solution and then extracted with ethyl acetate. The organic extract was washed with saturated sodium chloride solution, dried over anhydrous magnesium sulfate, filtered and concentrated. Drying of the remaining residue in a high vacuum gave 223 mg (87% of theory, 82% purity) of the title compound, which were used without further purification for subsequent reactions.

LC / MS (Method 1, ESIpos): R _t = 1.53 min, m / z = 487.18 [M + H] ⁺ . Example 393A 1- (2,2-Dimethoxyethyl) -1 - [[5-methyl-3- (1-methylcyclopropyl) -2,4-dioxo-1- (3,3,3-trifluoropropyl) -1,3,3 , 4-tetrahydrothieno [2,3-d] pyrimidin-6-yl] methyl} urea

A solution of 295 mg (0.656 mmol) of the compound from Ex. 388A in 7 ml of methanol was initially treated at RT with 122 mg (1.51 mmol) of potassium cyanate and then with 96 μΐ (1.12 mmol) perchloric acid (70% in water). After 16 h, the reaction mixture was treated with water and saturated sodium bicarbonate solution and then extracted with ethyl acetate. The organic extract was washed with saturated sodium chloride solution, dried over anhydrous magnesium sulfate, filtered and concentrated. Drying of the remaining residue in a high vacuum gave 310 mg (84% of theory, 89% purity) of the title compound, which were used for subsequent reactions without further purification.

LC / MS (Method 2, ESIpos): R _t = 0.85 min, m / z = 493 [M + H] ⁺ .

Example 394A 1- ({1 - [(3,3-difluorocyclobutyl) methyl] -5-methyl-3- (1-methylcyclopropyl) -2,4-dioxo-1,2,3,4-tetrahydrothieno [2 , 3-d] pyrimidin-6-yl} methyl) -l- (2,2-dimethoxyethyl) urea

A solution of 320 mg (0.699 mmol) of the compound from Ex. 389A in 7 ml of methanol was initially treated at RT with 130 mg (1.61 mmol) of potassium cyanate and then with 103 .mu.l (1.19 mmol) of perchloric acid (70%) in water. added. After 16 h, the reaction mixture was washed with water and with saturated sodium bicarbonate solution and then extracted with ethyl acetate. The organic extract was washed with saturated sodium chloride solution, dried over anhydrous magnesium sulfate, filtered and concentrated. Drying of the remaining residue in a high vacuum gave 350 mg (83% of theory, 83% purity) of the title compound, which were used for subsequent reactions without further purification.

LC / MS (Method 1, ESIpos): R _t = 1.65 min, m / z = 501.20 [M + H] ⁺ .

Example 395A

1 - (2,2-Dimethoxyethyl) -1 - {[1- (2-methoxyethyl) -5-methyl-3- (1-methylcyclopropyl) -2,4-dioxo, 2,3,4-tetrahydrothieno [ 2,3-d] pyrimidin-6-yl] methyl} urea

Analogously to the process described under Ex. 392A, 300 mg (0.685 mmol, 94% purity) of the compound from Ex. 390A, 128 mg (1.58 mmol) potassium cyanate and 100 μΐ (1.17 mmol) perchloric acid (70% in water) were used mg (81% of theory, 81% purity) of the title compound, which were used without further purification for subsequent reactions. LC / MS (Method 3, ESIpos): R _t = 2.05 min, m / z = 455 [M + H] ⁺ .

Example 396A 1- (2,2-Dimethoxyethyl) -1- {5-methyl-3- (2-methylcyclopropyl) -2,4-dioxo-1- [2- (trifluoromethoxy) ethyl] -1, 2, 3,4-tetrahydrothieno [2,3-d] pyrimidin-6-yl} methyl) urea (trans-racemate)

A solution of 445 mg (0.918 mmol, 96% purity) of the compound from Ex. 391A in 10 ml of methanol was initially at RT with 171 mg (2.11 mmol) of potassium cyanate and then with 134 μΐ (1.56 mmol) perchloric acid (70% in water ). Since the conversion was not complete after 16 h, an additional 86 mg (1.06 mmol) of potassium cyanate were added. After a further 23 h, the reaction mixture was treated with water and saturated sodium bicarbonate solution and then extracted with ethyl acetate. The organic extract was washed with saturated sodium chloride solution, dried over anhydrous magnesium sulfate, filtered and concentrated. After drying the remaining residue under high vacuum, 542 mg (96% of theory, 83%) of the pure title compound were obtained, which were used for subsequent reactions without further purification.

LC / MS (Method 1, ESIpos): R _t = 1.67 min, m / z = 509.17 [M + H] ⁺ . Example 397A tert -Butyl 2 - [(3-cyclopropyl-1-ethyl-5-methyl-2,4-dioxo-1,2,3,4-tetrahydrothieno [2,3-d] pyrimidin-6-yl ) methylene] hydrazine carboxylate

Analogously to the process described under Example 156A, from 129 mg (0.463 mmol) of the compound from Ex. 319A and 92 mg (0.695 mmol) of tert. -Butyl-hydrazinecarboxylate 177 mg (97% of theory) of the title compound.

'H-NMR (400 MHz, DMSO-de, δ / ppm): 10.84 (br.s, 1H), 8.28 (s, 1H), 3.91 (q, 2H), 2.63-2.56 (m, 1H), 2.44 (s, 3H), 1.45 (s, 9H), 1.25 (t, 3H), 1.05-0.96 (m, 2H), 0.73-0.64 (m, 2H).

LC / MS (Method 1, ES Ineg): R _t = 1.84 min, m / z = 391.14 [MH] ^~ .

Example 398A tert. Butyl-2 - [(3-cyclopropyl-5-methyl-2,4-dioxo-1-propyl-1,2,3,4-tetrahydrothieno [2,3-d] pyrimidin-6-yl) methylene ] hydrazine carboxylate H 3C CH 3 CH -

Analogously to the process described under Example 156A, from 133 mg (0.455 mmol) of the compound from Ex. 320A and 90 mg (0.682 mmol) of tert. Butylhydrazinecarboxylate 178 mg (92% of theory, 96% purity) of the title compound. The reaction time in this case was 3 h. 'H-NMR (400 MHz, DMSO-d _6, δ / ppm): 10.84, 28.08 (s, 1H), 3.83 (t, 2H), 2.60 (dd, 1H), 2:44 ((br s, 1H). s, 3H), 1.70 (sext, 2H), 1.45 (s, 9H), 1.04-0.97 (m, 2H), 0.92 (t, 3H), 0.73-0.64 (m, 2H).

LC / MS (Method 1, ES Ineg): R _t = 1.98 min, m / z = 405.16 [MH].

Example 399A tert-Butyl 2 - {[3-cyclopropyl-1- (2-fluoroethyl) -5-methyl-2,4-dioxo-1,2,3,4-tetrahydrothieno [2,3-d] - pyrimidin-6-yl] methylene} hydrazinecarboxylate

Analogously to the process described under Example 156A, from 80 mg (0.270 mmol) of the compound from Example 321A and 54 mg (0.405 mmol) of tert. Butylhydrazinecarboxylate 102 mg (92% of theory) of the title compound. 'H-NMR (400 MHz, DMSO-d _6, δ / ppm): 10.84, 28.08 (s, 1H), 4.73 (dt, 2H), 4.21 (dt, 2H), 2.65- (br s, 1H). 2.57 (m, 1H), 2.44 (s, 3H), 1.45 (s, 9H), 1.06-0.95 (m, 2H), 0.76-0.66 (m, 2H).

LC / MS (Method 1, ES Ineg): R _t = 1.76 min, m / z = 409.13 [MH].

Example 400A tert-Butyl 2 - {[3-cyclopropyl-1- (3-fluoropropyl) -5-methyl-2,4-dioxo-1,2,3,4-tetrahydrothieno [2,3-d] pyrimidin-6-yl] methylene} hydrazinecarboxylate

Analogously to the process described under Example 156A, from 144 mg (0.455 mmol, 98% purity) of the compound from Ex. 50A and 90 mg (0.682 mmol) of tert. Butylhydrazinecarboxylate 169 mg (87% of theory) of the title compound. The reaction time was 3 h here. Ή-NMR (400 MHz, DMSO-d _6, δ / ppm): 10.84 (br s, 1H.), 8.29 (s, 1H), 4:54 (dt, 2H), 3.98 (t, 2H), 2.63-2.56 (m, 1H), 2.44 (s, 3H), 2.15-1.99 (m, 2H), 1.45 (s, 9H), 1.05-0.95 (m, 2H), 0.74-0.64 (m, 2H).

LC / MS (Method 1, ES Ineg): R _t = 1.85 min, m / z = 423.15 [MH] -. Example 401A tert-Butyl 2 - {[3-cyclopropyl-1- (4-fluorobutyl) -5-methyl-2,4-dioxo-1,2,3,4-tetrahydrothieno [2,3-d] - pyrimidin-6-yl] methylene} hydrazinecarboxylate

Analogously to the process described under Example 156A, from 127 mg (0.392 mmol) of the compound from Example 322A and 78 mg (0.587 mmol) of tert. Butylhydrazinecarboxylate 167 mg (94% of theory, 97% purity) of the title compound. The reaction time was 3 h here.

Ή-NMR (400 MHz, DMSO-de, δ / ppm): 10.84 (br.s, 1H), 8.29 (s, 1H), 4.59-4.48 (m, 1H), 4.42 (t, 1H), 3.91 ( t, 2H), 2.63-2.56 (m, 1H), 2.44 (s, 3H), 1.84-1.63 (m, 4H), 1.45 (s, 9H), 1.05-0.95 (m, 2H), 0.73- 0.65 (m, 2H).

LC / MS (method 2, ESIneg): R _t = 1.01 min, m / z = 437 [MH] -. Example 402A tert. Butyl 2- {[3-cyclopropyl-1 - (2,2-difluoroethyl) -5-methyl-2,4-dioxo-1,2,3,4-tetrahydrothieno [2,3-d] pyrimidine 6-yl] methylene} hydrazinecarboxylate

Analogously to the process described under Example 156A, from 145 mg (0.452 mmol, 98% purity) of the compound from Ex. 323A and 90 mg (0.678 mmol) of tert. Butylhydrazinecarboxylate 183 mg (94% of theory) of the title compound.

'H-NMR (400 MHz, DMSO-de, δ / ppm): 10.86 (br.s, 1H), 8.28 (s, 1H), 6.33 (tt, 1H), 4.34 (td, 2H), 2.66-2.57 (m, 1H), 2.44 (s, 3H), 1.45 (s, 9H), 1.07-0.95 (m, 2H), 0.77-0.66 (m, 2H). LC / MS (Method 1, ES Ineg): R _t = 1.84 min, m / z = 427.13 [MH] ^~ .

Example 403A tert. Butyl 2- {[3-cyclopropyl-5-methyl-2,4-dioxo-1 - (4,4,4-trifluorobutyl)-1,2,3,4-tetrahydrothieno [2,3-d] pyrimidin-6-yl] methylene} hydrazinecarboxylate

Analogously to the process described under Example 156A, from 168 mg (0.452 mmol, 97% purity) of the compound from Example 324A and 90 mg (0.678 mmol) of tert. Butylhydrazinecarboxylate 210 mg (94%) d. Th., 97% purity) of the title compound. The reaction time was here

3 h.

'H-NMR (400 MHz, DMSO-de, δ / ppm): 10.84 (br.s, 1H), 8.29 (s, 1H), 3.96 (br.t, 2H), 2.62-2.55 (m, 1H) , 2.48-2.35 (m, 2H), 2.44 (s, 3H), 1.90 (quin, 2H), 1.45 (s, 9H), 1.05-0.94 (m, 2H), 0.74-0.65 (m, 2H). LC / MS (Method 1, ES Ineg): R _t = 2.07 min, m / z = 473.15 [MH] ^"

Example 404A tert. Butyl 2- ({3-cyclopropyl-l - [(2,2-difluorocyclobutyl) methyl] -5-methyl-2,4-dioxo-1,2,3,4-tetrahydrothieno [2,3- d] pyrimidin-6-yl} methylene) hydrazinecarboxylate {enantiomer 1)

Analogously to the process described under Example 156A, from 130 mg (0.367 mmol) of the compound from Ex. 326A and 73 mg (0.550 mmol) of tert. Butylhydrazinecarboxylate 160 mg (93% of theory) of the title compound.

Ή-NMR (400 MHz, DMSO-de, δ / ppm): 10.86 (br.s, 1H), 8.29 (s, 1H), 4.13-3.98 (m, 2H), 2.64- 2.56 (m, 2H), 2.44 (s, 3H), 2.01-1.87 (m, 1H), 1.70-1.56 (m, 1H), 1.45 (s, 9H), 1.08-0.95 (m, 2H), 0.76-0.60 (m, 2H).

LC / MS (Method 2, ES Ineg): R _t = 1.05 min, m / z = 467 [MH] -. Example 405A tert. Butyl 2- ({3-cyclopropyl-l - [(2,2-difluorocyclobutyl) methyl] -5-methyl-2,4-dioxo-1,2,3,4-tetrahydrothieno [2,3- d] pyrimidin-6-yl} methylene) hydrazinecarboxylate {enantiomer 2)

Analogously to the process described under Example 156A, from 116 mg (0.327 mmol) of the compound from Ex. 327A and 65 mg (0.491 mmol) of tert. Butylhydrazinecarboxylate 144 mg (93% of theory) of the title compound. 'H-NMR (400 MHz, DMSO-de, δ / ρρηι): 10.85 (br.s, 1H), 8.28 (s, 1H), 4.12-3.97 (m, 2H), 2.65- 2.56 (m, 1H) , 2.43 (s, 3H), 2.02-1.88 (m, 1H), 1.71-1.56 (m, 1H), 1.45 (s, 9H), 1.07-0.95 (m, 2H), 0.76-0.61 (m, 2H) ,

LC / MS (Method 2, ES Ineg): R _t = 1.05 min, m / z = 467 [MH] -. Example 406A tert. -Butyl 2- ({3-cyclopropyl-1 - [(3,3-difluorocyclobutyl) methyl] -5-methyl-2,4-dioxo-1,2,3,4-tetrahydrothieno [2,3- d] pyrimidin-6-yl} methylene) hydrazinecarboxylate

A solution of 240 mg (0.677 mmol) of the compound from Example 328A in 7 ml of ethanol was initially tert with 134 mg (1.02 mmol). Butyl hydrazinecarboxylate and then with 3 drops of conc. Hydrochloric acid added. After the reaction mixture had been stirred for about 18 h at RT, most of the ethanol was removed on a rotary evaporator. The remaining residue was diluted with 150 ml of water and neutralized by the addition of saturated aqueous sodium bicarbonate solution. The precipitated solid was filtered off with suction, washed with a little water and dried under high vacuum. There were obtained 310 mg (97% of theory) of the title compound.

'H-NMR (400 MHz, DMSO-de, δ / ppm): 10.85 (br.s, 1H), 8.28 (s, 1H), 4.06 (br.d, 2H), 2.75-2.56 (m, 4H) , 2.43 (s, 3H), 1.45 (s, 9H), 1.07-0.94 (m, 2H), 0.73-0.62 (m, 2H).

LC / MS (Method 1, ES Ineg): R _t = 2.04 min, m / z = 467.16 [MH]. Example 407A tert. Butyl 2- ({3-cyclopropyl-l - [(2,2-difluorocyclopentyl) methyl] -5-methyl-2,4-dioxo-l, 2,3,4-tetrahydrothieno [2,3- d] pyrimidin-6-yl} methylene) hydrazinecarboxylate (enantiomer 1)

Analogously to the process described under Example 156A, from 120 mg (0.326 mmol) of the compound from Ex. 330A and 65 mg (0.489 mmol) of tert. -Butyl-hydrazinecarboxylate 147 mg (93% of theory) of the title compound. Ή-NMR (400 MHz, DMSO-d ₆ , δ / ppm): 10.85 (br.s, 1H), 8.29 (s, 1H), 4.08-3.91 (m, 2H), 2.83- 2.56 (m, 2H) , 2.44 (s, 3H), 2.25-2.03 (m, 2H), 1.98-1.87 (m, 1H), 1.83-1.52 (m, 3H), 1.45 (s, 9H), 1.07-0.96 (m, 2H) , 0.75-0.61 (m, 2H).

LC / MS (Method 1, ES Ineg): R _t = 2.12 min, m / z = 481.17 [MH]. Example 408A tert-Butyl 2- ({3-cyclopropyl-1 - [(2,2-difluorocyclopentyl) methyl] -5-methyl-2,4-dioxo-1,2,3,4-tetrahydrothieno [ 2,3-d] pyrimidin-6-yl} methylene) hydrazinecarboxylate (enantiomer 2)

A solution of 115 mg (0.312 mmol) of the compound from Ex. 331A in 4 ml of ethanol was first tert with 62 mg (0.468 mmol). Butyl hydrazinecarboxylate and then with 3 drops of conc. Hydrochloric acid. After the reaction mixture had been stirred for about 18 h at RT, most of the ethanol was removed on a rotary evaporator. The remaining residue was diluted with 150 ml of water and neutralized by the addition of saturated aqueous sodium bicarbonate solution. The precipitated solid was filtered off, washed with a little water and dried under high vacuum. 145 mg (96% of theory) of the title compound were obtained. 'H-NMR (400 MHz, DMSO-de, δ / ρρηι): 10.85 (br.s, 1H), 8.28 (s, 1H), 4.05-3.89 (m, 2H), 2.82- 2.68 (m, 1H) , 2.64-2.56 (m, 1H), 2.44 (s, 3H), 2.23-2.04 (m, 2H), 1.93 (qd, 1H), 1.81-1.52 (m, 3H), 1.45 (s, 9H), 1.06 -0.95 (m, 2H), 0.74-0.61 (m, 2H).

LC / MS (Method 1, ES Ineg): R _t = 2.12 min, m / z = 481.17 [MH] ^~ . Example 409A tert. Butyl 2- ({3-cyclopropyl-l - [(3,3-difluorocyclopentyl) methyl] -5-methyl-2,4-dioxo-1,2,3,4-tetrahydrothieno [2,3- d] pyrimidin-6-yl} methylene) hydrazinecarboxylate (racemate)

Analogously to the process described under Example 156A, from 290 mg (0.787 mmol) of the compound from Ex. 332A and 156 mg (1.18 mmol) of tert. Butylhydrazinecarboxylate 350 mg (92% of theory) of the title compound.

Ή-NMR (400 MHz, DMSO-de, δ / ppm): 10.85 (br.s, 1H), 8.28 (s, 1H), 4.03-3.84 (m, 2H), 2.69- 2.56 (m, 2H), 2.44 (s, 3H), 2.35-2.10 (m, 2H), 2.10-1.84 (m, 3H), 1.60 (dq, 1H), 1.45 (s, 9H), 1.06-0.95 (m, 2H), 0.74- 0.63 (m, 2H). LC / MS (Method 1, ES Ineg): R _t = 2.09 min, m / z = 481.17 [MH] -.

Example 410A tert. Butyl 2- {[1- (3-cyanopropyl) -3-cyclopropyl-5-methyl-2,4-dioxo-1,2,3,4-tetrahydrothieno [2,3-d] pyrimidine-6- yl] methylene} hydrazinecarboxylate

Analogously to the process described under Example 156A, from 141 mg (0.444 mmol) of the compound from Ex. 333A and 88 mg (0.666 mmol) of tert. Butylhydrazinecarboxylate 184 mg (95% of theory) of the title compound.

'H-NMR (400 MHz, DMSO-de, δ / ppm): 10.83 (br.s, 1H), 8.29 (s, 1H), 3.97 (t, 2H), 2.63 (t, 2H), 2.61-2.56 (m, 1H), 2.44 (s, 3H), 2.06-1.91 (m, 2H), 1.45 (s, 9H), 1.04-0.95 (m, 2H), 0.73-0.65 (m, 2H).

LC / MS (Method 1, ES Ineg): R _t = 1.72 min, m / z = 430.16 [MH]. Example 411A tert. Butyl-2 - [(3-cyclopropyl-5-methyl-2,4-dioxo-1 - {2 - [(trifluoromethyl) sulfanyl] ethyl} -1, 2,3,4-tetrahydrothieno [2,3-d ] pyrimidine-6-yl) methylene] hydrazinecarboxylate

Analogously to the process described under Example 156A, from 170 mg (0.440 mmol, 98% purity) of the compound from Ex. 334A and 87 mg (0.660 mmol) of tert. Butylhydrazinecarboxylate 211 mg (97% of theory) of the title compound. Ή-NMR (400 MHz, DMSO-d ₆ , δ / ppm): 10.84 (br.s, 1H), 8.29 (s, 1H), 4.15 (t, 2H), 3.34 (t, 2H), 2.60 (t , 1H), 2.44 (s, 3H), 1.45 (s, 9H), 1.07-0.97 (m, 2H), 0.72-0.64 (m, 2H).

LC / MS (Method 1, ES Ineg): R _t = 2.13 min, m / z = 491.10 [MH] -.

Example 412A tert. Butyl 2- ({5-methyl-3- (2-methylcyclopropyl) -2,4-dioxo-1- [2- (trifluoromethoxy) ethyl] -1,3,3,4-tetrahydrothieno [2,3- d] pyrimidin-6-yl} methylene) hydrazinecarboxylate (iran-y-racemate)

A solution of 350 mg (0.930 mmol) of the compound from Example 351A in 10 ml of ethanol was first tert with 184 mg (1.40 mmol). Butyl hydrazinecarboxylate and then with 2 drops of conc. Hydrochloric acid added. After the reaction mixture had been stirred for about 18 h at RT, most of the ethanol was removed on a rotary evaporator. The remaining residue was diluted with 150 ml of water and neutralized by the addition of saturated aqueous sodium bicarbonate solution. The precipitated solid was filtered off, washed with a little water and dried under high vacuum. 446 mg (97% of theory) of the title compound were obtained. Ή-NMR (400 MHz, DMSO-d ₆ , δ / ppm): 10.85 (br.s, 1H), 8.28 (s, 1H), 4.39 (t, 2H), 4.27-4.13 (m, 2H), 2.44 (s, 3H), 2.26 (dt, 1H), 1.45 (s, 9H), 1.15 (d, 3H), 1.06-0.93 (m, 1H), 0.89-0.79 (m, 2H).

LC / MS (Method 1, ES Ineg): R _t = 2.13 min, m / z = 489.14 [MH].

Example 413A tert. Butyl 2- ({1- (2-methoxyethyl) -5-methyl-2,4-dioxo-3- [2- (trifluoromethyl) cyclopropyl] -1,3,3,4-tetrahydrothieno [2,3- d] pyrimidin-6-yl} methylene) hydrazinecarboxylate (trans-Raccmat)

A solution of 300 mg (0.797 mmol) of the compound from Ex. 357A in 8 ml of ethanol was first tert with 158 mg (1.20 mmol). Butyl hydrazinecarboxylate and then with 3 drops of conc. Hydrochloric acid added. After the reaction mixture was stirred for about 18 h at RT, it was diluted with 150 ml of water and neutralized by the addition of saturated aqueous sodium bicarbonate solution. It was extracted three times with about 50 ml of ethyl acetate. The organic extract was washed successively with water and saturated aqueous sodium chloride solution. rule. After drying over anhydrous magnesium sulfate, it was filtered and evaporated. After drying under high vacuum, 381 mg (97% of theory) of the title compound were obtained.

'H-NMR (400 MHz, DMSO-de, δ / ppm): 10.85 (br.s, 1H), 8.28 (s, 1H), 4.12-3.93 (m, 2H), 3.64 (t, 2H), 3.26 (s, 3H), 3.03-2.92 (m, 1H), 2.43 (s, 3H), 2.25 (dtd, 1H), 1.50 (q, 1H), 1.45 (s, 9H), 1.38-1.27 (m, lH ).

LC / MS (Method 1, ES Ineg): R _t = 2.00 min, m / z = 489.14 [MH].

Example 414A tert. Butyl-2- {[3- (2-ethylcyclopropyl) -1- (2-methoxyethyl) -5-methyl-2,4-dioxo-1,2,3,4-tetrahydrothieno [2,3-d ] pyrimidin-6-yl] methylene} hydrazinecarboxylate (trans-racemate)

Analogously to the process described under Ex. 413A, from 275 mg (0.817 mmol) of the compound from Ex. 358A and 162 mg (1.23 mmol) of tert. -Butyl-hydrazinecarboxylate 402 mg (quant.) Of the title compound.

Ή-NMR (400 MHz, DMSO-de, δ / ppm): 10.83 (broad, 1H), 8.27 (s, 1H), 4.08-3.97 (m, 2H), 3.63 (t, 2H), 3.25 (s, 3H), 2.43 (s, 3H), 2.31 (dt, 1H), 1.69-1.54 (m, 1H), 1.45 (s, 9H), 1.31-1.16 (m, 1H), 1.08-0.94 (m, 1H) , 1.00 (t, 3H), 0.89-0.74 (m, 2H).

LC / MS (Method 2, ES Ineg): R _t = 1.09 min, m / z = 449 [MH] -.

Example 415A tert. Butyl-2- {[3- (2-methoxycyclopropyl) -1- (2-methoxyethyl) -5-methyl-2,4-dioxo-1,2,3,4-tetrahydrothieno [2,3-d ] pyrimidin-6-yl] methylene} hydrazinecarboxylate (trans-race at)

Analogously to the process described under Example 413A, from 350 mg (1.03 mmol) of the compound from Ex. 359A and 205 mg (1.55 mmol) of tert. -Butyl-hydrazinecarboxylate 438 mg (93% of theory) of the title compound. Ή-NMR (400 MHz, DMSO-d ₆ , δ / ppm): 10.84 (br, s, 1H), 8.28 (s, 1H), 4.14-3.96 (m, 2H), 3.67- 3.59 (m, 2H) , 3.47-3.38 (m, 1H), 3.24 (s, 3H), 3.23 (s, 3H), 2.61 (dt, 1H), 2.43 (s, 3H), 1.45 (s, 9H), 1.31 (td, 1H ), 0.91 (ddd, 1H).

LC / MS (Method 1, ESIpos): R _t = 1.66 min, m / z = 453.18 [M + H] ⁺ . Example 416A tert. Butyl 2 - [(3-cyclopropyl-1-ethyl-5-methyl-2,4-dioxo-1,2,3,4-tetrahydrothieno [2,3-d] pyrimidin-6-yl) methyl] hydrazinecarboxylate

Analogously to the process described under Example 200A, 155 mg (87% of theory) of the title compound were prepared from 177 mg (0.451 mmol) of the compound from Ex. 397A and a total of 213 mg (3.38 mmol) of sodium cyanoborohydride.

Ή-NMR (400 MHz, DMSO-de, δ / ppm): 8.24 (br.s, 1H), 4.99 (br.d, 1H), 3.96 (br.d, 2H), 3.87 (q, 2H), 2.63-2.56 (m, 1H), 2.31 (s, 3H), 1.38 (s, 9H), 1.24 (t, 3H), 1.05-0.95 (m, 2H), 0.72-0.62 (m, 2H).

LC / MS (Method 1, ES Ineg): R _t = 1.69 min, m / z = 439.17 [M-H + HCOOH] - Example 417A tert-Butyl 2 - [(3-cyclopropyl-5-methyl-2,4-dioxo-1-propyl-1,2,3,4-tetrahydrothieno [2,3-d] pyrimidin-6 -yl) methyl] hydrazinecarboxylate

Analogously to the process described under Example 200A, from 178 mg (0.438 mmol) of the compound from Ex. 398A and a total of 206 mg (3.28 mmol) of sodium cyanoborohydride 146 mg (77% of theory, 95% purity) of the title compound were prepared.

'H-NMR (500 MHz, DMSO-de, δ / ppm): 8.24 (br, s, 1H), 4.99 (br, d, 1H), 3.96 (br, d, 2H), 3.84- 3.74 (m, 2H), 2.62-2.56 (m, 1H), 2.31 (s, 3H), 1.70 (sec, 2H), 1.38 (s, 9H), 1.04-0.96 (m, 2H), 0.91 (t, 3H), 0.71 -0.61 (m, 2H).

LC / MS (Method 1, ES Ineg): R _t = 1.83 min, m / z = 453.18 [M-H + HCOOH] -.

Example 418A tert-Butyl 2 - {[3-cyclopropyl-1- (2-fluoroethyl) -5-methyl-2,4-dioxo-1,2,3,4-tetrahydrothieno [2,3-d] - pyrimidin-6-yl] methyl} hydrazinecarboxylate

200 mg (0.248 mmol) of the compound from Ex. 399A and a total of 117 mg (1.86 mmol) of sodium cyanoborohydride, 88 mg (85% of theory) of the title compound, were prepared analogously to the process described under Example 200A.

'H-NMR (400 MHz, DMSO-de, δ / ppm): 8.24 (br.s, 1H), 5.02-4.91 (m, 1H), 4.72 (dt, 2H), 4.15 (dt, 2H), 3.96 (br d, 2H), 2.65-2.57 (m, 1H), 2.31 (s, 3H), 1.38 (s, 9H), 1.06-0.95 (m, 2H), 0.73-0.63 (m, 2H). LC / MS (Method 1, ES Ineg): R _t = 1.62 min, m / z = 457.16 [M-H + HCOOH]. Example 419A tert. Butyl 2- {[3-cyclopropyl-1 - (3-fluoropropyl) -5-methyl-2,4-dioxo-1,2,3,4-tetrahydrothieno [2,3-d] pyrimidine-6 yl] methyl} hydrazinecarboxylate

Analogously to the procedure described in Example 200A, 166 mg (0.398 mmol) of the compound of Ex. 400A and a total of 188 mg (2.99 mmol) of sodium cyanoborohydride were used to produce 176 mg (88% of theory, 85% purity) of the title compound.

Ή-NMR (400 MHz, DMSO-de, δ / ppm): 8.24 (br.s, 1H), 4.99 (br.d, 1H), 4.65-4.42 (m, 2H), 4.01-3.90 (m, 4H ), 2.63-2.56 (m, 1H), 2.31 (s, 3H), 2.14-1.99 (m, 2H), 1.38 (s, 9H), 1.04-0.96 (m, 2H), 0.72-0.62 (m, 2H ).

LC / MS (Method 1, ES Ineg): R _t = 1.70 min, m / z = 471.17 [M-H + HCOOH] -. Example 420A tert. Butyl 2- {[3-cyclopropyl-1 - (4-fluorobutyl) -5-methyl-2,4-dioxo-1,2,3,4-tetrahydrothieno [2,3-d] pyrimidine-6 yl] methyl} hydrazinecarboxylate

Analogously to the process described in Example 200A, from 182 mg (0.403 mmol, 97% purity) of the compound from Ex. 401A and a total of 190 mg (3.02 mmol) of sodium cyanoborohydride 143 mg (72%) of theory. Th., 90%> purity) of the title compound. 'H-NMR (400 MHz, DMSO-de, δ / ρρηι): 8.24 (br.s, 1H), 4.99 (br.d, 1H), 4.47 (dt, 2H), 3.96 (br.d, 2H) , 3.88 (br t, 2H), 2.64-2.56 (m, 1H), 2.31 (s, 3H), 1.83-1.61 (m, 4H), 1.38 (s, 9H), 1.05-0.95 (m, 2H) , 0.71-0.61 (m, 2H).

LC / MS (method 1, ESIneg): R _t = 1.80 min, m / z = 485.19 [M-H + HCOOH] -. Example 421A tert. Butyl 2- {[3-cyclopropyl-1 - (2,2-difluoroethyl) -5-methyl-2,4-dioxo-1,2,3,4-tetrahydrothieno [2,3-d] pyrimidine 6-yl] methyl} hydrazinecarboxylate

Analogously to the process described under Example 200A, from 210 mg (0.480 mmol, 98% purity) of the compound from Example 402A and a total of 226 mg (3.60 mmol) of sodium cyanoborohydride, 130 mg (50% of theory, 81%) were obtained. Purity) of the title compound.

'H-NMR (400 MHz, DMSO-de, δ / ppm): 8.24 (br.s, 1H), 6.33 (tt, 1H), 4.99 (br.d, 1H), 4.27 (td, 2H), 3.97 (br d, 2H), 2.62 (tt, 1H), 2.31 (s, 3H), 1.38 (s, 9H), 1.06-0.96 (m, 2H), 0.75-0.64 (m, 2H). LC / MS (Method 2, ES Ineg): R _t = 0.91 min, m / z = 475 [M-H + HCOOH] -. Example 422A tert. Butyl 2- {[3-cyclopropyl-5-methyl-2,4-dioxo-1 - (4,4,4-trifluorobutyl)-1,2,3,4-tetrahydrothieno [2,3-d] pyrimidin-6-yl] methyl} hydrazinecarboxylate

Analogously to the process described under Example 200A, from 210 mg (0.434 mmol, 98% purity) of the compound from Example 403 A and a total of 204 mg (3.25 mmol) of sodium cyanoborohydride were added 188 mg (77% of theory, 85 % Purity) of the title compound.

'H-NMR (400 MHz, DMSO-de, δ / ppm): 8.23 (br.s, 1H), 4.99 (br.d, 1H), 3.97 (br.d, 2H), 3.92 (t, 2H) , 2.62-2.56 (m, 1H), 2.45-2.33 (m, 2H), 2.31 (s, 3H), 1.96-1.82 (m, 2H), 1.38 (s, 9H), 1.04-0.95 (m, 2H) , 0.72-0.62 (m, 2H).

LC / MS (Method 2, ES Ineg): R _t = 1.02 min, m / z = 521 [M-H + HCOOH] -. Example 423A tert. Butyl 2- ({3-cyclopropyl-l - [(2,2-difluorocyclobutyl) methyl] -5-methyl-2,4-dioxo-1,2,3,4-tetrahydrothieno [2,3- d] pyrimidin-6-yl} methyl) hydrazinecarboxylate {enantiomer 1)

Analogously to the procedure described under Ex. 200A, from 158 mg (0.337 mmol) of the compound from Ex. 404A and a total of 159 mg (2.53 mmol) of sodium cyanoborohydride were added 143 mg (58%) of theory. Th., 65%) purity) of the title compound. LC / MS (Method 1, ES Ineg): R _t = 1.93 min, m / z = 515.18 [M-H + HCOOH] -.

Example 424A tert. Butyl 2- ({3-cyclopropyl-l - [(2,2-difluorocyclobutyl) methyl] -5-methyl-2,4-dioxo-1,2,3,4-tetrahydrothieno [2,3- d] pyrimidin-6-yl} methyl) hydrazinecarboxylate {enantiomer 2)

Analogously to the process described under Example 200A, from 140 mg (0.299 mmol) of the compound of Ex. 405A and a total of 141 mg (2.24 mmol) of sodium cyanoborohydride, 103 mg (55% of theory, 76% purity) of the title compound were prepared.

LC / MS (Method 1, ES Ineg): R _t = 1.93 min, m / z = 515.18 [M-H + HCOOH] -. Example 425A tert. -Butyl 2- ({3-cyclopropyl-1 - [(3,3-difluorocyclobutyl) methyl] -5-methyl-2,4-dioxo-1,2,3,4-tetrahydrothieno [2,3- d] pyrimidin-6-yl} methyl) hydrazinecarboxylate

To a solution of 305 mg (0.651 mmol) of the compound of Ex. 406A in 12 ml of methanol was added 205 mg (3.26 mmol) of sodium cyanoborohydride and a little bromocresol green. Subsequently, enough titrated with acetic acid that the indicator color just turned from blue to yellow. Then the reaction mixture was heated to 65 ° C. After 1 h, an additional 102 mg (1.63 mmol) of sodium cyanoborohydride was added. During the entire reaction time, the pH value was adjusted again and again by adding further acetic acid, so that the indicator dye remained just yellow. After a total of 3 h, the volatile constituents of the reaction mixture were largely removed on a rotary evaporator. The remaining residue was taken up in ethyl acetate and washed successively with saturated aqueous sodium bicarbonate solution, water and saturated aqueous sodium chloride solution. After drying over anhydrous magnesium sulfate, it was filtered and concentrated to dryness. The crude product was purified by MPLC (Biotage Isolera One, cartridge SNAP Ultra, 25 g silica gel, eluent cyclohexane / ethyl acetate 2: 1). The product fractions were combined and evaporated. After drying under high vacuum, 236 mg (73% of theory, 95% purity) of the title compound were obtained.

'H-NMR (400 MHz, DMSO-de, δ / ppm): 8.24 (br, s, 1H), 5.02 (br, d, 1H), 4.02 (br, d, 2H), 3.96 (br, d, 2H), 2.75-2.56 (m, 5H), 2.30 (s, 3H), 1.38 (s, 9H), 1.09-0.92 (m, 2H), 0.74-0.58 (m, 2H).

LC / MS (method 1, ESIneg): R _t = 1.89 min, m / z = 515.18 [M-H + HCOOH] - Example 426A feri. Butyl-2- ({3-cyclopropyl-l - [(2,2-difluoro-c

hydrothieno [2,3-d] pyrimidin-6-yl} methyl) hydrazinecarboxylate {enantiomer 1)

Analogously to the process described under Example 200A, 122 mg (72% of theory, 87% purity) of the title compound were prepared from 145 mg (0.300 mmol) of the compound from Example 407A and a total of 142 mg (2.25 mmol) of sodium cyanoborohydride.

Ή-NMR (400 MHz, DMSO-de, δ / ppm): 8.24 (br.s, 1H), 5.00 (br.d, 1H), 4.07-3.85 (m, 4H), 2.82-2.67 (m, 1H ), 2.63-2.56 (m, 1H), 2.31 (s, 3H), 2.23-2.04 (m, 2H), 1.94-1.84 (m, 1H), 1.83-1.51 (m, 3H), 1.38 (s, 9H ), 1.06-0.94 (m, 2H), 0.72-0.59 (m, 2H).

LC / MS (Method 1, ES Ineg): R _t = 1.98 min, m / z = 529.19 [M-H + HCOOH] -.

Example 427A tert-Butyl 2- ({3-cyclopropyl-1 - [(2,2-difluorocyclopentyl) methyl] -5-methyl-2,4-dioxo-1,2,3,4-tetrahydrothieno [ 2,3-d] pyrimidin-6-yl} methyl) hydrazinecarboxylate {enantiomer 2)

To a solution of 142 mg (0.294 mmol) of the compound from Ex. 408A in 6 ml of methanol was added 92 mg (1.47 mmol) of sodium cyanoborohydride and some bromocresol green. Subsequently, enough titrated with acetic acid that the indicator color just turned from blue to yellow. Then the reaction mixture was heated to 65 ° C. After 1 h, an additional 46 mg (0.736 mmol) of sodium cyanoborohydride was added. Throughout the reaction time was through Addition of further acetic acid, the pH value repeatedly regulated so that the indicator color remained just yellow. After a total of 3 h, the volatile constituents of the reaction mixture were largely removed on a rotary evaporator. The remaining residue was taken up in ethyl acetate and washed successively with saturated aqueous sodium bicarbonate solution, water and saturated aqueous sodium chloride solution. After drying over anhydrous magnesium sulfate, it was filtered and concentrated to dryness. The crude product was purified by MPLC (Biotage Isolera One, cartridge SNAP Ultra, 25 g silica gel, eluent cyclohexane / ethyl acetate 1: 1). The product fractions were combined and evaporated. After drying under high vacuum, 130 mg (80% of theory, 88% purity) of the title compound were obtained.

'H-NMR (400 MHz, DMSO-de, δ / ppm): 8.24 (br.s, 1H), 5.00 (br.d, 1H), 4.08-3.84 (m, 4H), 2.82- 2.68 (m, 1H), 2.64-2.56 (m, 1H), 2.31 (s, 3H), 2.23-2.05 (m, 2H), 1.95-1.84 (m, 1H), 1.82-1.52 (m, 3H), 1.38 (s, 9H), 1.07-0.93 (m, 2H), 0.73-0.59 (m, 2H).

LC / MS (Method 1, ES Ineg): R _t = 1.98 min, m / z = 529.19 [M-H + HCOOH] -. Example 428A tert. Butyl 2- ({3-cyclopropyl-l - [(3,3-difluorocyclopentyl) methyl] -5-methyl-2,4-dioxo-1,2,3,4-tetrahydrothieno [2,3- d] pyrimidin-6-yl} methyl) hydrazinecarboxylate (racemate)

Analogously to the process described under Example 200A, from 340 mg (0.705 mmol) of the compound from Ex. 409A and a total of 332 mg (5.28 mmol) of sodium cyanoborohydride 241 mg (67% of theory, 95% purity) of the title compound were prepared ,

Ή-NMR (400 MHz, DMSO-de, δ / ppm): 8.24 (br.s, 1H), 5.00 (br.d, 1H), 3.96 (br.d, 2H), 3.90 (t, 2H), 2.70-2.56 (m, 2H), 2.39-2.11 (m, 2H), 2.31 (s, 3H), 2.10-1.81 (m, 3H), 1.68-1.52 (m, 1H), 1.38 (s, 9H), 1.07-0.93 (m, 2H), 0.74-0.59 (m, 2H). LC / MS (Method 1, ESIneg): R _t = 1.98 min, m / z = 529.19 [M-H + HCOOH] - Example 429A tert. Butyl 2- {[1- (3-cyanopropyl) -3-cyclopropyl-5-methyl-2,4-dioxo-1,2,3,4-tetrahydrothieno [2,3-d] pyrimidine-6- yl] methyl} hydrazinecarboxylate

Analogously to the process described in Example 200A, 125 mg (67% of theory) of the title compound were prepared from 184 mg (0.426 mmol) of the compound from Ex. 410A and a total of 201 mg (3.20 mmol) of sodium cyanoborohydride.

'H-NMR (400 MHz, DMSO-de, δ / ppm): 8.25 (br.s, 1H), 5.01 (br.d, 1H), 4.00-3.90 (m, 4H), 2.66-2.55 (m, 3H), 2.31 (s, 3H), 2.04-1.91 (m, 2H), 1.38 (s, 9H), 1.06-0.94 (m, 2H), 0.74-0.63 (m, 2H). LC / MS (Method 1, ES Ineg): R _t = 1.57 min, m / z = 478.18 [M-H + HCOOH].

Example 430A tert. Butyl-2 - [(3-cyclopropyl-5-methyl-2,4-dioxo-1 - {2 - [(trifluoromethyl) sulfanyl] ethyl} -1, 2,3,4-tetrahydrothieno [2,3-d ] pyrimidine-6-yl) methyl] hydrazinecarboxylate

Analogously to the process described under Example 200A, from 210 mg (0.418 mmol, 98% purity) of the compound from Example 411A and a total of 197 mg (3.13 mmol) of sodium cyanoborohydride were added 181 mg (78% of theory, 90%) Purity) of the title compound.

Ή-NMR (500 MHz, DMSO-de, δ / ppm): 8.23 (br, s, 1H), 5.00 (br, d, 1H), 4.11 (t, 2H), 3.97 (br, d, 2H), 3.34 (t, 2H), 2.62-2.56 (m, 1H), 2.31 (s, 3H), 1.38 (s, 9H), 1.06-0.96 (m, 2H), 0.72-0.63 (m, 2H). LC / MS (Method 6, ES Ineg): R _t = 1.38 min, m / z = 539 [M-H + HCOOH] -. Example 431A tert. Butyl 2- ({5-methyl-3- (2-methylcyclopropyl) -2,4-dioxo-1- [2- (trifluoromethoxy) ethyl] -1,3,3,4-tetrahydrothieno [2,3- d] pyrimidin-6-yl} methyl) hydrazinecarboxylate (trans-racemate)

A solution of 444 mg (0.905 mmol) of the compound from Ex. 412A in 18 ml of methanol was admixed with 284 mg (4.53 mmol) of sodium cyanoborohydride and a little bromocresol green. Subsequently, enough titrated with acetic acid that the indicator color just turned from blue to yellow. Then the reaction mixture was heated to 65 ° C. After 1 h, an additional 142 mg (2.26 mmol) of sodium cyanoborohydride were added. During the entire reaction time, the pH value was adjusted again and again by adding further acetic acid, so that the indicator color remained just yellow. After a total of 3 h, the volatile constituents of the reaction mixture were largely removed on a rotary evaporator. The remaining residue was taken up in ethyl acetate and washed successively with saturated aqueous sodium bicarbonate solution, water and saturated aqueous sodium chloride solution. After drying over anhydrous magnesium sulfate, it was filtered and concentrated to dryness. The crude product was purified by MPLC (Biotage Isolera One, cartridge SNAP Ultra, 25 g silica gel, eluent cyclohexane / ethyl acetate 1: 1). The product fractions were combined and evaporated. After drying under high vacuum, 375 mg (79% of theory, 95% purity) of the title compound were obtained.

Ή-NMR (400 MHz, DMSO-de, δ / ppm): 8.23 (br.s, 1H), 4.98 (br.d, 1H), 4.43-4.31 (m, 2H), 4.22 4.07 (m, 2H) , 3.96 (br d, 2H), 2.31 (s, 3H), 2.28-2.21 (m, 1H), 1.38 (s, 9H), 1.15 (d, 3H), 1.04 0.91 (m, 1H), 0.88- 0.76 (m, 2H).

LC / MS (Method 2, ES Ineg): R _t = 1.07 min, m / z = 537 [M-H + HCOOH] -.

Example 432A tert. Butyl 2- ({1- (2-methoxyethyl) -5-methyl-2,4-dioxo-3- [2- (trifluoromethyl) cyclopropyl] -1,3,3,4-tetrahydrothieno [2,3- d] pyrimidin-6-yl} methyl) hydrazinecarboxylate (iran-y-racemate)

381 mg (0.777 mmol) of the compound from Example 413A and 249 mg (3.88 mmol) of sodium cyanoborohydride were used to prepare 311 mg (79% of theory, 97% of purity) of the title compound analogously to the process described under Example 200A. By way of derogation, no further addition of sodium cyanoborohydride occurred here after 1 h and the reaction time was 4 h.

Ή-NMR (400 MHz, DMSO-de, δ / ppm): 8.24 (br.s, 1H), 4.98 (br.d, 1H), 4.08-3.88 (m, 4H), 3.63 (t, 2H), 3.25 (s, 3H), 3.02-2.94 (m, 1H), 2.31 (s, 3H), 2.24 (dtd, 1H), 1.55-1.44 (m, 1H), 1.41-1.29 (m, 1H), 1.39 ( s, 9H).

LC / MS (Method 1, ES Ineg): R _t = 1.90 min, m / z = 491.16 [M-H + HCOOH] -. Example 433A tert. Butyl-2- {[3- (2-ethylcyclopropyl) -1- (2-methoxyethyl) -5-methyl-2,4-dioxo-1,2,3,4-tetrahydrothieno [2,3-d ] pyrimidin-6-yl] methyl} hydrazinecarboxylate (trans-Raccmat)

401 mg (0.890 mmol) of the compound from Ex. 414A and 285 mg (4.45 mmol) sodium cyanoborohydride were used to prepare 357 mg (84% of theory, 95% purity) of the title compound analogously to the process described under Example 200A. By way of derogation, no further addition of sodium cyanoborohydride occurred here after 1 h and the reaction time was 4 h.

'H-NMR (400 MHz, DMSO-de, δ / ppm): 8.34-8.14 (m, 1H), 4.96 (brd, 1H), 4.05-3.89 (m, 4H), 3.62 (t, 2H) , 3.25 (s, 3H), 2.35-2.24 (m, 1H), 2.30 (s, 3H), 1.69-1.56 (m, 1H), 1.38 (s, 9H), 1.22 (dt, 1H), 1.04-0.96 (m, 1H), 0.99 (t, 3H), 0.88-0.72 (m, 2H). LC / MS (Method 2, ES Ineg): R _t = 1.03 min, m / z = 497 [M-H + HCOOH] -. Example 434A tert. Butyl-2- {[3- (2-methoxycyclopropyl) -1- (2-methoxyethyl) -5-methyl-2,4-dioxo-1,2,3,4-tetrahydrothieno [2,3-d ] pyrimidin-6-yl] methyl} hydrazinecarboxylate (trans-racemate)

Analogously to the process described under Example 200A, from 438 mg (0.958 mmol) of the compound from Example 415A and 307 mg (4.79 mmol) of sodium cyanoborohydride were prepared 305 mg (70% of theory) of the title compound. By way of derogation, no further addition of sodium cyanoborohydride occurred here after 1 h and the reaction time was 4 h. Ή-NMR (400 MHz, DMSO-d ₆ , δ / ppm): 8.26 (broad, 1H), 4.98 (br.d, 1H), 4.10-3.89 (m, 4H), 3.66- 3.59 (m, 2H) , 3.45-3.37 (m, 1H), 3.24 (s, 3H), 3.23 (s, 3H), 2.61 (dt, 1H), 2.30 (s, 3H), 1.39 (s, 9H), 1.30 (td, 1H ), 0.90 (ddd, 1H).

LC / MS (Method 1, ES Ineg): R _t = 1.53 min, m / z = 499.19 [M-H + HCOOH] -. Example 435A tert. Butyl 2-carbamoyl -2- [(3-cyclopropyl-1-ethyl-5-methyl-2,4-dioxo-1,2,3,4-tetrahydrothieno [2,3-d] pyrimidine-6- yl) methyl] hydrazinecarboxylate

Analogously to the process described under Example 244A, 170 mg (71% of theory, 72% purity) of the title compound were prepared from 155 mg (0.393 mmol) of the compound from Example 416A and 105 μM (0.786 mmol) of trimethylsilyl isocyanate. The reaction time was approx. 16 h.

LC / MS (Method 1, ES Ineg): R _t = 1.38 min, m / z = 436.17 [MH]. Example 436A tert -Butyl 2-carbamoyl-2 - [(3-cyclopropyl-5-methyl-2,4-dioxo-1-propyl-1,2,3,4-tetrahydrothieno [2,3-d] pyrimidin-6-yl) methyl] hydrazinecarboxylate

Analogously to the process described under Ex. 244A, from 145 mg (0.337 mmol, 95% purity) of the compound from Example 417A and 90 μΐ (0.674 mmol) of trimethylsilyl isocyanate 108 mg (67%) of theory. Th., 95% purity) of the title compound. The reaction time was about 40 hours.

'H-NMR (400 MHz, DMSO-de, δ / ppm): 8.90 (br.s, 1H), 6.18 (br.s, 2H), 3.79 (br.t, 2H), 2.64- 2.57 (m, 1H), 2.32 (s, 3H), 1.68 (sec, 2H), 1.38 (br, s, 9H), 1.06-0.97 (m, 2H), 0.90 (t, 3H), 0.66-0.61 (m, 2H) , LC / MS (Method 1, ESIneg): R _t = 1:50 min, m / z = 450.18 [MH] ^~.

Example 437A tert. Butyl 2-carbamoyl-2- {[3-cyclopropyl-1- (2-fluoroethyl) -5-methyl-2,4-dioxo-1,2,3,4-tetrahydrothieno [2,3-d ] pyrimidine-6-yl] methyl} hydrazinecarboxylate

Analogously to the process described under Example 244A, 71 mg (64% of theory, 88% purity) of the title compound were prepared from 88 mg (0.337 mmol) of the compound from Example 418A and 57 μM (0.427 mmol) of trimethylsilyl isocyanate. The reaction time was approx. 16 h. 'H-NMR (400 MHz, DMSO-d _6, δ / ppm): 8.91, 6.17 (s, 2H), 4.71 (dt, 2H), 4:56 (broad, 2H), 4.16 ((br s, 1H). dt, 2H), 2.62 (tt, 1H), 2.32 (s, 3H), 1.38 (br, s, 9H), 1.08-0.96 (m, 2H), 0.73-0.60 (m,

2H).

LC / MS (Method 1, ES Ineg): R _t = 1.35 min, m / z = 454.16 [MH]. Example 438A tert -Butyl 2-carbamoyl-2- {[3-cyclopropyl-1- (3-fluoropropyl) -5-methyl-2,4-dioxo-1,2,3,4-tetrahydrothieno [2 , 3-d] pyrimidin-6-yl] methyl} hydrazinecarboxylate

Analogously to the process described under Ex. 244A, from 176 mg (0.351 mmol, 85% purity) of the compound from Ex. 419A and 94 μΐ (0.702 mmol) of trimethylsilyl isocyanate 144 mg (87%) of theory. Th.) Of the title compound. Notwithstanding the method described above, in each case an additional 47 μΐ (0.351 mmol) of trimethylsilyl isocyanate was added after 16 h and after a reaction time of 40 h. 'H-NMR (500 MHz, DMSO-de, δ / ρρηι): 8.90 (br.s, 1H), 6.17 (br.s, 2H), 4.70 (broad, 2H), 4.53 (dt, 2H), 3.95 (br, t, 2H), 2.64-2.56 (m, 1H), 2.32 (s, 3H), 2.11-1.99 (m, 2H), 1.38 (br, s, 9H), 1.06-0.96 (m, 2H) , 0.71-0.58 (m, 2H).

LC / MS (Method 6, ES Ineg): R _t = 1.04 min, m / z = 468 [MH] -. Example 439A tert. Butyl 2-carbamoyl-2- {[3-cyclopropyl-1- (4-fluorobutyl) -5-methyl-2,4-dioxo-1,2,3,4-tetrahydrothieno [2,3-d ] pyrimidine-6-yl] methyl} hydrazinecarboxylate

Analogously to the process described under Ex. 244A, 143 mg (0.292 mmol, 90% purity) of the compound of Example 420A and 78 μΐ (0.584 mmol) of trimethylsilyl isocyanate were 135 mg (86% of theory, 91%) of purity ) of the title compound. The reaction time was approx. 16 h.

'H-NMR (400 MHz, DMSO-de, δ / ppm): 8.90 (br.s, 1H), 6.18 (br.s, 2H), 4.56 (broad, 2H) 4.46 (dt, 2H), 3.87 ( t, 2H), 2.61 (tt, 1H), 2.32 (s, 3H), 1.84-1.61 (m, 4H), 1.38 (br, s, 9H), 1.08-0.95 (m, 2H), 0.67- 0.61 (m, 2H). LC / MS (Method 1, ES Ineg): R _t = 1.50 min, m / z = 482.19 [MH].

Example 440A tert. Butyl 2-carbamoyl-2- {[3-cyclopropyl-1- (2,2-difluoroethyl) -5-methyl-2,4-dioxo-1,2,3,4-tetrahydrothieno [2,3 -d] pyrimidin-6-yl] methyl} hydrazinecarboxylate

Analogously to the process described under Ex. 244A, 130 mg (0.245 mmol, 81% purity) of the compound from Ex. 421A and 66 μΐ (0.489 mmol) of trimethylsilyl isocyanate were admixed with 103 mg (80%) of theory. Th., 90%) purity) of the title compound. The reaction time was about 40 hours. 'H-NMR (400 MHz, DMSO-d _6, δ / ppm): 8.93 (br s, 1H.), 6.40 (dt, 1H), 6.18 (br s., 2H), 4:56 (broad, 2H); 4.28 (td, 2H), 2.66-2.58 (m, 1H), 2.32 (s, 3H), 1.38 (br, s, 9H), 1.08-0.96 (m, 2H), 0.74-0.60 (m, 2H).

LC / MS (Method 1, ES Ineg): R _t = 1.42 min, m / z = 472.15 [MH] ^~ . Example 441A tert. Butyl 2-carbamoyl-2- {[3-cyclopropyl-5-methyl-2,4-dioxo-l- (4,4,4-trifluorobutyl) -1,3,3,4-tetrahydrothieno [2 , 3-d] pyrimidin-6-yl] methyl} hydrazinecarboxylate

Analogously to the process described under Ex. 244A, from 176 mg (0.314 mmol, 85% purity) of the compound from Ex. 422A and 84 μΐ (0.628 mmol) of trimethylsilyl isocyanate 159 mg (92% of theory, 95% of purity ) of the title compound. The reaction time was approx. 16 h.

'H-NMR (400 MHz, DMSO-de, δ / ppm): 8.89 (br, s, 1H), 6.18 (br, s, 2H), 4.57 (broad, 2H), 3.92 (br, t, 2H) , 2.64-2.56 (m, 1H), 2.46-2.35 (m, 2H), 2.32 (s, 3H), 1.88 (quin, 2H), 1.38 (br, s, 9H), 1.07-0.94 (m, 2H) , 0.72-0.59 (m, 2H). LC / MS (Method 1, ES Ineg): R _t = 1.66 min, m / z = 518.17 [MH]. Example 442A tert. Butyl 2-carbamoyl-2- ({3-cyclopropyl-1 - [(2,2-difluorocyclobutyl) methyl] -5-methyl-2,4-dioxo l, 2,3,4-tetrahydrothieno [2, 3-d] pyrimidin-6-yl} methyl) hydrazinecarboxylate {enantiomer 1)

143 mg (0.304 mmol) of the compound of Ex. 423A and 82 μΐ (0.608 mmol) of trimethylsilyl isocyanate were converted into 143 mg (66% of theory, 73% purity) of the title compound analogously to the process described under Example 244A. In contrast to the method described above, the purification of the product by means of MPLC was omitted here. LC / MS (Method 1, ES Ineg): R _t = 1.62 min, m / z = 512.18 [MH] ^~ .

Example 443A tert. Butyl 2-carbamoyl-2- ({3-cyclopropyl-1 - [(2,2-difluorocyclobutyl) methyl] -5-methyl-2,4-dioxo l, 2,3,4-tetrahydrothieno [2, 3-d] pyrimidin-6-yl} methyl) hydrazinecarboxylate {enantiomer 2)

Analogously to the process described under Ex. 244A, 100 mg (0.213 mmol) of the compound from Ex. 424A and 57 μΐ (0.425 mmol) of trimethylsilyl isocyanate were used to produce 128 mg (93% of theory, 80% purity) of the title compound. In contrast to the method described above, the purification of the product by means of MPLC was omitted here. LC / MS (method 1, ESIneg): R _t = 1.62 min, m / z = 512.18 [MH]. Example 444A tert -Butyl 2-carbamoyl-2 - ({3-cyclopropyl-l - [(3,3-difluorocyclobutyl) methyl] -5-methyl-2,4-dioxo-l, 2,3,4- tetrahydrothieno [2,3-d] pyrimidin-6-yl} methyl) hydrazinecarboxylate

A solution of 232 mg (0.468 mmol, 95% purity) of the compound from Ex. 425A in 15 ml of isopropanol was treated with 126 .mu.l (0.937 mmol) of trimethylsilyl isocyanate and stirred at RT for 2.5 days. Since the conversion was not complete, an additional 63 μΐ (468 mmol) of trimethylsilyl isocyanate was added and stirring continued at RT for 24 h. Thereafter, the reaction mixture was concentrated to dryness. The remaining residue was taken up in ethyl acetate and washed successively with saturated sodium bicarbonate solution and saturated sodium chloride solution. After drying over anhydrous magnesium sulfate, it was filtered and evaporated. The residue was purified by MPLC (Biotage Isolera One, cartridge SNAP Ultra, 25 g silica gel, eluent cyclohexane / ethyl acetate 1: 1). After evaporation of the product fractions and drying in a high vacuum, 232 mg (96% of theory) of the title compound were obtained.

'H-NMR (400 MHz, DMSO-de, δ / ppm): 8.90 (br, s, 1H), 6.18 (br, s, 2H), 4.57 (broad, 2H), 4.09- 3.96 (m, 2H) , 2.74-2.56 (m, 4H), 2.32 (s, 3H), 1.38 (br, s, 9H), 1.08-0.96 (m, 2H), 0.69-0.57 (m, 2H).

LC / MS (Method 1, ES Ineg): R _t = 1.61 min, m / z = 512.18 [MH].

Example 445A tert. Butyl 2-carbamoyl-2- ({3-cyclopropyl-1 - [(2,2-difluorocyclopentyl) methyl] -5-methyl-2,4-dioxo-l, 2,3,4-tetrahydrothieno [2, 3-d] pyrimidin-6-yl} methyl) hydrazinecarboxylate (enantiomer 1) H 3C CH 3

Analogously to the process described under Example 244A, from 120 mg (0.248 mmol) of the compound from Example 426A and 66 μΐ (0.495 mmol) of trimethylsilyl isocyanate, 130 mg (80% of theory, 80% purity) of the title compound were prepared. The reaction time was approx. 16 h. LC / MS (method 1, ESIneg): R _t = 1.70 min, m / z = 526.19 [MH].

Example 446A tert. Butyl 2-carbamoyl-2- ({3-cyclopropyl-1 - [(2,2-difluorocyclopentyl) methyl] -5-methyl-2,4-dioxo-l, 2,3,4-tetrahydrothieno [2, 3-d] pyrimidin-6-yl} methyl) hydrazinecarboxylate (enantiomer 2)

A solution of 127 mg (0.262 mmol) of the compound from Ex. 427A in 9 ml of isopropanol was treated with 70 .mu.l (0.524 mmol) of trimethylsilyl isocyanate and stirred at RT for 16 h. Thereafter, the reaction mixture was concentrated to dryness. The remaining residue was taken up in ethyl acetate and washed successively with saturated sodium bicarbonate solution and saturated sodium chloride solution. After drying over anhydrous magnesium sulfate, it was filtered and evaporated. The residue was purified by MPLC (Biotage Isolera One, cartridge SNAP Ultra, 25 g silica gel, eluent cyclohexane / ethyl acetate 1: 1). Evaporation of the product fractions and drying under high vacuum gave 138 mg (85% of theory, 85% purity) of the title compound.

LC / MS (method 1, ESIneg): R _t = 1.70 min, m / z = 526.19 [MH], Example 447A tert-Butyl 2-carbamoyl-2 - ({3-cyclopropyl-1 - [(3,3-difluorocyclopentyl) methyl] -5-methyl-2,4-dioxo-l, 2,3,4- tetrahydrothieno [2,3-d] pyrimidin-6-yl} methyl) hydrazinecarboxylate (racemate)

Analogously to the process described under Example 244A, from 238 mg (0.467 mmol, 95% purity) of the compound from Example 428A and 125 μM (0.933 mmol) of trimethylsilyl isocyanate, 216 mg (78% of theory, 90%) of purity ) of the title compound. The reaction time was 6 days.

'H-NMR (400 MHz, DMSO-de, δ / ppm): 8.90 (br.s, 1H), 6.18 (br.s, 2H), 4.57 (broad, 2H), 3.97-3.83 (m, 2H) , 2.69-2.56 (m, 2H), 2.32 (s, 3H), 2.28-2.11 (m, 2H), 2.10-1.91 (m, 2H), 1.91-1.80 (m, 1H), 1.60 (dq, 1H) , 1.38 (brs s, 9H), 1.08-0.93 (m, 2H), 0.67-0.60 (m, 2H).

LC / MS (Method 1, ES Ineg): R _t = 1.68 min, m / z = 526.19 [MH].

Example 448A tert-Butyl 2-carbamoyl-2- {[1- (3-cyanopropyl) -3-cyclopropyl-5-methyl-2,4-dioxo-1,2,3,4-tetrahydrothieno [2 , 3-d] pyrimidin-6-yl] methyl} hydrazinecarboxylate

Analogously to the process described under Example 244A, from 125 mg (0.288 mmol) of the compound from Example 429A and 77 μΐ (0.577 mmol) of trimethylsilyl isocyanate, 140 mg (96% of theory, 95% purity) of the title compound were prepared. The reaction time was approx. 16 h. 'H-NMR (400 MHz, DMSO-de, δ / ρρηι): 8.91 (br, s, 1H), 6.18 (br, s, 2H), 4.57 (broad, 2H), 3.94 (br, t, 2H) , 2.65-2.56 (m, 3H), 2.32 (s, 3H), 2.02-1.90 (m, 2H), 1.38 (br, s, 9H), 1.06-0.95 (m, 2H), 0.73-0.59 (m, 2H).

LC / MS (Method 1, ES Ineg): R _t = 1.30 min, m / z = 475.18 [MH]. Example 449A tert-Butyl 2-carbamoyl-2 - [(3-cyclopropyl-5-methyl-2,4-dioxo-1- {2 - [(trifluoromethyl) sulfanyl] ethyl} -1,3,3, 4-tetrahydrothieno [2,3-d] pyrimidin-6-yl) methyl] hydrazinecarboxylate

Analogously to the process described under Example 244A, from 181 mg (0.337 mmol, 92% purity) of the compound from Ex. 430A and 90 μΐ (0.859 mmol) of trimethylsilyl isocyanate, 154 mg (63% of theory, 75% of purity) ) of the title compound. The reaction time was about 40 hours.

LC / MS (method 1, ESIneg): R _t = 1.70 min, m / z = 536.12 [MH].

Example 450A tert. Butyl 2-carbamoyl-2 - ({5-methyl-3- (2-methylcyclopropyl) -2,4-dioxo-1- (2- (trifluoromethoxy) ethyl] -1,3,3,4-tetrahydrothieno [2,3-d] pyrimidin-6-yl} methyl) hydrazinecarboxylate (iran-y-racemate)

A solution of 324 mg (0.625 mmol, 95% purity) of the compound from Example 431A in 20 ml of isopropanol was treated with 168 μΐ (1.25 mmol) of trimethylsilyl isocyanate and stirred at RT for 16 h. Thereafter, the reaction mixture was concentrated to dryness and the remaining residue was purified by MPLC (Biotage Isolera One, cartridge SNAP Ultra, 25 g of silica gel, mobile phase cyclohexane / ethyl acetate gradient). Evaporation of the product fractions and drying under high vacuum gave 278 mg (77% of theory, 92% purity) of the title compound. 'H-NMR (400 MHz, DMSO-d _6, δ / ppm): 8.90, 6.17, 4:56 (broad, 2H), 4:38 (t, 2H), (br s, 1H). (Br s, 2H). 4.23-4.09 (m, 2H), 2.32 (s, 3H), 2.27 (dt, 1H), 1.37 (br s, 9H), 1.15 (d, 3H), 1.01-0.90 (m, 1H), 0.89- 0.74 (m, 2H).

LC / MS (Method 1, ES Ineg): R _t = 1.75 min, m / z = 534.16 [MH]. Example 451A tert. Butyl 2-carbamoyl-2- ({1- (2-methoxyethyl) -5-methyl-2,4-dioxo-3- [2- (trifluoromethyl) cyclopropyl] -1,3,3,4- tetrahydrothieno [2,3-d] pyrimidin-6-yl} methyl) hydrazinecarboxylate (iran-y-racemate)

A solution of 310 mg (0.617 mmol, 98%> purity) of the compound from Example 432A in 17 ml of isopropanol was admixed with 165 μl (1.23 mmol) of trimethylsilyl isocyanate and initially stirred at RT for 40 h. Then the reaction mixture was stirred for 24 h at 50 ° C and then allowed to stand for 2 days at RT. After addition of a further 124 .mu.l (0.926 mmol) of trimethylsilyl isocyanate, the reaction mixture was heated again to 50.degree. C. for 24 h. Then the reaction mixture was concentrated on a rotary evaporator to about half of the original volume. The product failed. It was filtered off, washed with diethyl ether and dried under high vacuum. 286 mg (81% of theory, 94% purity) of the title compound were obtained.

'H-NMR (400 MHz, DMSO-de, δ / ppm): 8.94 (br, s, 1H), 6.18 (br, s, 2H), 4.56 (broad, 2H), 4.08- 3.91 (m, 2H) , 3.62 (t, 2H), 3.25 (s, 3H), 3.05-2.96 (m, 1H), 2.32 (s, 3H), 2.23 (dtd, 1H), 1.51 (q, 1H), 1.39 (see also p , 9H), 1.35-1.28 (m, 1H).

LC / MS (Method 2, ESIneg): R _t = 0.91 min, m / z = 534 [MH] ^" Example 452A tert-Butyl 2-carbamoyl-2- {[3- (2-ethylcyclopropyl) -1- (2-methoxyethyl) -5-methyl-2,4-dioxo-1,2,3,4-tetrahydrothieno [2,3-d] pyrimidin-6-yl] methyl} hydrazinecarboxylate (trans-racemate)

A solution of 354 mg (0.767 mmol, 98% purity) of the compound from Ex. 433A in 16 ml of isopropanol was admixed with 206 μl (1.53 mmol) of trimethylsilyl isocyanate and stirred at RT for about 18 h. Thereafter, the reaction mixture was concentrated by about half. The product which was precipitated was filtered off with suction, washed with a little diethyl ether and dried under high vacuum. There was obtained 340 mg (85% of theory, 95% purity) of the title compound. 'H-NMR (400 MHz, DMSO-d _6, δ / ppm): (br. S, 1H) (br. S, 2H) 8.91, 6.17, 4.77-4.31 (broad, 2H), 4.08-3.88 (m , 2H), 3.61 (t, 2H), 3.24 (s, 3H), 2.39-2.24 (m, 1H), 2.31 (s, 3H), 1.63 (dquin, 1H), 1.38 (s, 9H), 1.28- 1.17 (m, 1H), 1.03-0.94 (m, 1H), 0.99 (t, 3H), 0.84 (q, 1H), 0.80-0.70 (m, 1H).

LC / MS (Method 6, ES Ineg): R _t = 1.19 min, m / z = 494 [MH] -.

Example 453A tert-Butyl 2-carbamoyl-2- {[3- (2-methoxycyclopropyl) -1- (2-methoxyethyl) -5-methyl-2,4-dioxo-1,2,3,4-tetrahydrothieno [2,3-d] pyrimidin-6-yl] methyl} hydrazinecarboxylate (trans-racemate)

Analogously to the process described under Example 452A, 277 mg (84% of theory) of the title compound were obtained from 297 mg (0.653 mmol) of the compound from Example 434A and 175 μΐ (1.31 mmol) of trimethylsilyl isocyanate.

'H-NMR (500 MHz, DMSO-de, δ / ppm): 8.95 (br, s, 1H), 6.17 (br, s, 2H), 5.05-4.15 (m, 2H), 4.09- 3.91 (m, 2H), 3.62 (t, 2H), 3.44-3.39 (m, 1H), 3.24 (s, 3H), 3.23 (s, 3H), 2.61 (dt, 1H), 2.31 (s, 3H), 1.39 (s , 9H), 1.31 (td, 1H), 0.92-0.85 (m, 1H).

LC / MS (Method 1, ES Ineg): R _t = 1.27 min, m / z = 496.19 [MH].

Example 454A tert. Butyl 2- {[3-cyclopropyl-5-methyl-2,4-dioxo-l - (3,3,3-trifluoropropyl) -l, 2,3,4-tetrahydrothieno [2,3-d] pyrimidin-6-yl] methyl} -2- [3-ethoxyprop-2-enoyl] hydrazinecarboxylate

A solution of 300 mg (0.649 mmol) of the compound of Ex. 202A in 7 ml of dichloromethane was treated at 0 ° C with 147 μM (0.843 mmol) of N, N-diisopropylethylamine and 123 mg (0.778 mmol, 85% purity) of 3-ethoxyacroyl chloride added. After the reaction mixture was stirred for about 16 h at RT, it was diluted with more dichloromethane and washed with water. The organic phase was dried over anhydrous magnesium sulfate, filtered and evaporated. The remaining residue was purified by preparative HPLC (Method 1 1). The product fractions were combined and evaporated. After drying under high vacuum, 213 mg (52% of theory, 90%) of the title compound were obtained. LC / MS (Method 1, ES Ineg): R _t = 1.99 min, m / z = 559.18 [MH].

Example 455A tert. Butyl 2- [3-ethoxyprop-2-enoyl] -2- {[5-methyl-3- (1-methylcyclopropyl) -2,4-dioxo-1 - (3,3,3-trifluoropropyl) -l, 2,3,4-tetrahydrothieno [2,3-d] pyrimidin-6-yl] methyl} hydrazinecarboxylate

Analogously to the process described under Example 454A, from 300 mg (0.630 mmol) of the compound from Ex. 215A and 120 mg (0.755 mmol, 85% purity) of 3-ethoxyacroyl chloride, 315 mg (85% of theory, 98% purity ) of the title compound. LC / MS (Method 2, ES Ineg): R _t = 1.10 min, m / z = 573 [MH] -.

Example 456A tert. Butyl 2- [3-ethoxyprop-2-enoyl] -2- ({5-methyl-3- (2-methylcyclopropyl) -2,4-dioxo-l - [2- (trifluoromethoxy) ethyl] - l, 2,3,4-tetrahydrothieno [2,3-d] pyrimidin-6-yl} methyl) hydrazinecarboxylate (trans -Race at)

Analogously to the process described under Example 454A, from 370 mg (0.751 mmol) of the compound from Example 431A and 143 mg (0.901 mmol, 85% purity) of 3-ethoxyacroyl chloride, 302 mg (65% of theory, 96% purity ) of the title compound.

LC / MS (method 2, ESIneg): R _t = 1.13 min, m / z = 589 [MH] -. Example 457A tert. Butyl 2- {[3 -cyclobutyl-5-methyl-2,4-dioxo-1 - (3, 3, 3-trifluoropropyl) -1,3,3,4-tetrahydrothieno [2,3-d] pyrimidin-6-yl] methyl} -2- [3-ethoxyprop-2-enoyl] hydrazinecarboxylate H ₃ CO

H ₃ C ^ (

Analogously to the process described under Example 454A, 250 mg (0.525 mmol) of the compound from Ex. 228A and 100 mg (0.630 mmol, 85% purity) of 3-ethoxyacroyl chloride gave 225 mg (37% of theory, 50% purity ) of the title compound. LC / MS (Method 1, ES Ineg): R _t = 2.31 min, m / z = 573.20 [MH].

Example 458A tert -Butyl 2 - {[3- (3,3-difluorocyclobutyl) -5-methyl-2,4-dioxo-l- (3,3,3-trifluoropropyl) -l, 2,3,4- tetrahydrothieno [2,3-d] pyrimidin-6-yl] methyl} -2- [3-ethoxyprop-2-enoyl] hydrazinecarboxylate

Analogously to the process described under Example 454A, 300 mg (0.585 mmol) of the compound from Ex. 230A and 111 mg (0.702 mmol, 85% purity) of 3-ethoxyacroyl chloride were admixed with 320 mg (89%) of theory. Th.) Of the title compound.

LC / MS (method 2, ESIneg): R _t = 1.16 min, m / z = 609 [MH] -. Example 459A tert -butyl 2 - {[3- (3,3-dimethylcyclobutyl) -5-methyl-2,4-dioxo-1- (3,3,3-trifluoropropyl) -l, 2,3,4 - tetrahydrothieno [2,3-d] pyrimidin-6-yl] methyl} -2- [3-ethoxyprop-2-enoyl] hydrazinecarboxylate

Analogously to the process described under Example 454A, from 280 mg (0.555 mmol) of the compound from Example 238A and 105 mg (0.666 mmol, 85% purity) of 3-ethoxyacroyl chloride, 275 mg (82% of theory) of the title compound were obtained , LC / MS (Method 1, ES Ineg): R _t = 2.50 min, m / z = 601.23 [MH].

Example 460A

Diethyl-5-amino-3-ethylthiophene-2,4-dicarboxylate

5.0 g (34.7 mmol) of ethyl 3-oxopentanoate and 3.92 g (34.7 mmol) of ethyl cyanoacetate were dissolved in 8 ml of ethanol and admixed with 1.22 g (38.1 mmol) of sulfur. The mixture was heated to 45 ° C and treated dropwise at this temperature with 4.2 ml (39.9 mmol) of diethylamine. After completion of the addition, the reaction mixture was stirred at 60 ° C for 16 h. It was then concentrated to dryness on a rotary evaporator. The remaining residue was taken up in 2.5 liters of water / ethyl acetate (1: 1). After phase separation, the aqueous phase was extracted twice more with 200 ml of ethyl acetate. The combined organic extracts were washed with saturated aqueous sodium chloride solution, dried over anhydrous magnesium sulfate, filtered and concentrated. The crude product thus obtained was crude by suction filtration over 300 g of silica gel with cyclohexane / ethyl acetate 10: 1 -> 5: 1 as the eluent in the desired title compound and the isomeric product ethyl 2-amino-4- (2-ethoxy-2-oxoethyl ) -5-methylthiophene-3-carboxylate prepurified. From the fraction containing the title compound, the title compound was isolated in sufficiently pure form by means of MPLC (Biotage Isolera, cartridge SNAP Ultra, 100 g of silica gel, cyclohexane / ethyl acetate 5: 1). Yield: 1.80 g (18%> D. Th., 96%> purity). Ή-ΝΜΡν (400 MHz, DMSO-d ₆ , δ / ρρηι): 7.93 (s, 2H), 4.23 (q, 2H), 4.17 (q, 2H), 3.17 (q, 2H), 1.28 (t, 3H ), 1.24 (t, 3H), 1.07 (t, 3H).

LC / MS (Method 1, ESIpos): R _t = 2.04 min, m / z = 272.10 [M + H] ⁺ . Example 461A Diethyl 3-ethyl-5- {[(1-methylcyclopropyl) carbamoyl] amino} thiophene-2,4-dicarboxylate

Analogously to the process described under Example 2A, from 1.75 g (6.45 mmol) of the compound from Ex. 460A, 2.09 g (12.9 mmol) of 1,1'-carbonyldiimidazole (CDI) and 1.46 g (12.9 mmol) of 1-methylcyclopropanamine Hydrochloride 2.09 g (87% of theory) of the title compound. The reaction time after addition of the 1-methylcyclopropanamine hydrochloride was 5 h and the product was finally purified by means of MPLC (Biotage Isolera, cartridge SNAP KP-Sil, 100 g of silica gel, cyclohexane / ethyl acetate 5: 1).

'H-NMR (400 MHz, DMSO-de, δ / ppm): 10.47 (br, s, 1H), 8.34 (br, s, 1H), 4.33 (q, 2H), 4.23 (q, 2H), 3.22 (q, 2H), 1.33 (s, 3H and t, 3H), 1.28 (t, 3H), 1.10 (t, 3H), 0.91 -0.38 (m, 4H). LC / MS (Method 2, ESIpos): R _t = 1.18 min, m / z = 369 [M + H] ⁺ .

Example 462A

Ethyl 5-ethyl-3- (1-methylcyclopropyl) -2,4-dioxo-1,2,3,4-tetrahydrothieno [2,3-d] pyrimidine-6-carboxylate

Analogously to the process described under Example 18A, 1.68 g (92% of theory) of the title compound were prepared from 2.08 g (5.64 mmol) of the compound from Example 461 A. 'H-NMR (400 MHz, DMSO-de, δ / ρρηι): 12.26 (s, 1H), 4.26 (q, 2H), 3.28 (q, 2H), 1.33 (s, 3H), 1.28 (t, 3H ), 1.11 (t, 3H), 0.96-0.78 (m, 4H).

LC / MS (Method 1, ESIpos): R _t = 1.83 min, m / z = 323.11 [M + H] ⁺ . Example 463A Ethyl 5-ethyl-3- (1-methylcyclopropyl) -2,4-dioxo-1- (3,3,3-trifluoropropyl) -l, 2,3,4-tetrahydrothieno [2,3-d ] pyrimidine-6-carboxylate

Analogously to the process described in Example 45A, from 870 mg (2.70 mmol) of the compound from Example 462A and 1.81 g (8.10 mmol) of 1,1'-trifluoro-3-iodopropane were added 1.10 g (87% of theory, 90% purity) of the title compound. The reaction did not take place here at RT but at 50.degree.

'H-NMR (400 MHz, DMSO-de, δ / ppm): 4.29 (q, 2H), 4.23-3.96 (m, 2H), 3.38-3.23 (m, 2H, partially covered by the water signal), 2.86 -2.70 (m, 2H), 1.35 (s, 3H), 1.30 (t, 3H), 1.14 (t, 3H), 0.99-0.77 (m, 4H). LC / MS (Method 2, ESIpos): R _t = 1.22 min, m / z = 419 [M + H] ⁺ .

Example 464A

Ethyl 5-ethyl-1- (2-methoxyethyl) -3- (1-methylcyclopropyl) -2,4-dioxo-1,2,3,4-tetrahydrothieno [2,3-d] pyrimidine-6-carboxylate

Analogously to the process described under Example 45A, 975 mg (94% of theory) of the title compound were prepared from 870 mg (2.70 mmol) of the compound from Example 462A and 750 mg (5.40 mmol) (2-bromoethyl) methyl ether , The reaction did not take place here at RT but at 50.degree.

'H-NMR (400 MHz, DMSO-de, δ / ppm): 4.28 (q, 2H), 4.20-3.84 (m, 2H), 3.64 (br t, 2H), 3.25 (s, 3H), 1.35 (s, 3H), 1.29 (t, 3H), 1.13 (t, 3H), 1.00-0.75 (m, 4H).

LC / MS (Method 2, ESIpos): R _t = 1.12 min, m / z = 381 [M + H] ⁺ .

Example 465A

5-Ethyl-6- (hydroxymethyl) -3- (1-methylcyclopropyl) -1- (3,3,3-trifluoropropyl) thieno [2,3-d] pyrimidine-2,4 (1H, 3H) -dione

1.04 g (2.49 mmol) of the compound from Ex. 463A were dissolved in 25 ml of anhydrous THF and treated dropwise at -78 ° C with 2.5 ml (2.49 mmol) of a 1 M solution of lithium aluminum hydride in THF. After 60 minutes, the reaction mixture was warmed to about -20 ° C and stirring continued at this temperature. After 1 h, the mixture was cautiously admixed with saturated aqueous ammonium chloride solution and then extracted with ethyl acetate. The organic extract was dried over anhydrous magnesium sulfate, filtered and concentrated. The remaining solid was purified by MPLC (Biotage Isolera, cartridge SNAP Ultra, 50 g silica gel, cyclohexane / ethyl acetate 2: 1). Evaporation of the product fractions and drying under high vacuum gave 875 mg (84% of theory, 90% purity) of the title compound. 'H-NMR (400 MHz, DMSO-d _6, δ / ppm): 5.61 (t, 1H), 4:59 (d, 2H), 4.21 -3.94 (m, 2H), 2.87-2.65 (m, 4H), 1.34 (s, 3H), 1.07 (t, 3H), 0.97-0.75 (m, 4H).

LC / MS (Method 2, ESIpos): R _t = 0.91 min, m / z = 377 [M + H] ⁺ .

Example 466A

5-Ethyl-6- (hydroxymethyl) -1- (2-methoxyethyl) -3- (1-methylcyclopropyl) thieno [2,3-d] pyrimidine-2,4 (1H, 3H) -dione

Analogously to the process described under Example 465A, from 965 mg (2.54 mmol) of the compound from Example 464A and 2.5 ml (2.54 mmol) of a 1 M solution of lithium aluminum hydride in THF, 713 mg (83% of theory) of the title compound were obtained receive. Ή-NMR (400 MHz, DMSO-d ₆ , δ / ppm): 5.55 (t, 1H), 4.57 (d, 2H), 4.16-3.83 (m, 2H), 3.62 (t, 2H), 3.25 (s , 3H), 2.88-2.68 (m, 2H), 1.34 (s, 3H), 1.07 (t, 3H), 0.97-0.75 (m, 4H).

LC / MS (Method 1, ESIpos): R _t = 1.49 min, m / z = 339.14 [M + H] ⁺ .

Example 467A

5-Ethyl-3- (1-methylcyclopropyl) -2,4-dioxo-1- (3,3,3-trifluoropropyl) -l, 2,3,4-tetrahydrothieno [2,3-d] pyrimidine-6 carbaldehyde

702 mg (1.86 mmol) of the compound from Example 465A were dissolved in 20 ml of anhydrous DMSO and treated with a little 4A molecular sieves and 2.6 ml (18.6 mmol) of triethylamine. Then three portions of each 297 mg (1.86 mmol) of sulfur trioxide-pyridine complex were added every 10 minutes. After 1.5 h and after a further 20 h in each case once again 297 mg (1.86 mmol) sulfur trioxide-pyridine complex was added. After a further 30 minutes, the reaction mixture was diluted with ethyl acetate and washed successively with water and saturated aqueous sodium chloride solution. It was dried over anhydrous magnesium sulfate, filtered and concentrated. The remaining residue was taken up three times with a little toluene and concentrated again. Then the solid was purified by MPLC (Biotage Isolera, cartridge SNAP Ultra, 25 g silica gel, cyclohexane / ethyl acetate 2: 1). After evaporation of the and high-vacuum drying, 121 mg (11% of theory, 66% purity) of the title compound were obtained.

LC / MS (Method 1, ESIpos): R _t = 2.01 min, m / z = 375.10 [M + H] ⁺ . Example 468A 5-Ethyl-1- (2-methoxyethyl) -3- (1-methylcyclopropyl) -2,4-dioxo-1,2,3,4-tetrahydrothieno [2,3-d] pyrimidine-6-carbaldehyde

At -60 ° C, a solution of 142 μΐ (2.00 mmol) of anhydrous DMSO in 1 ml of dichloromethane was added dropwise to a solution of 128 μΐ (1.46 mmol) of oxalyl chloride in 1 ml of dichloromethane. Subsequently, at the same temperature and over a period of 30 min, a solution of 450 mg (1.33 mmol) of the compound of Ex. 466A in 3.5 ml of dichloromethane was added dropwise. The reaction mixture was then stirred at -60 ° C for 1.5 h. Then, at the same temperature, a solution of 927 μΐ (6.65 mmol) of triethylamine in 1 ml of dichloromethane was added. The reaction mixture was warmed to 0 ° C and stirred for 20 min at this temperature. Then it was diluted at RT with 50 ml of dichloromethane and washed successively with water and saturated aqueous sodium chloride solution. The organic phase was dried over anhydrous magnesium sulfate, filtered and evaporated. The remaining solid was purified by MPLC (Biotage Isolera, cartridge SNAP Ultra, 25 g silica gel, cyclohexane / ethyl acetate 2: 1). Evaporation of the product fractions and drying under high vacuum gave 57 mg (10% of theory, 84% purity) of the title compound.

LC / MS (Method 1, ESIpos): R _t = 1.77 min, m / z = 337.12 [M + H] ⁺ . Example 469A

6 - {[(2-aminoethyl) amino] methyl} -5-ethyl-3- (1-methylcyclopropyl) -1- (3,3,3-trifluoropropyl) thieno [2,3-d] pyrimidine-2, 4 (lH, 3H) -dione

Analogously to the process described in Example 103A, 120 mg (0.321 mmol) of the compound from Example 467A, 129 μΐ (1.92 mmol) of 1,2-diaminoethane and 81 mg (1.28 mmol) of sodium cyanoborohydride were admixed with 160 mg (78% of theory). Th., 66% purity) of the title compound. LC / MS (Method 1, ESIpos): R _t = 0.88 min, m / z = 419.17 [M + H] ⁺ .

Example 470A

6 - {[(2-aminoethyl) amino] methyl} -5-ethyl-1- (2-methoxyethyl) -3- (1-methylcyclopropyl) thieno [2,3-d] pyrimidine-2,4 (1H, 3H) -dione

Analogously to the process described in Example 103A, 55 mg (0.166 mmol) of the compound from Example 468A, 67 μΐ (0.997 mmol) of 1,2-diaminoethane and 42 mg (0.665 mmol) of sodium cyanoborohydride were admixed with 59 mg (61%> d Th., 66%> purity) of the title compound. Notwithstanding the method described above, the same amounts of 1, 2-diaminoethane, acetic acid and sodium cyanoborohydride were here after 16 h reaction time again added and the reaction mixture stirred for a further 20 h at 60 ° C.

LC / MS (Method 1, ESIpos): R _t = 0.68 min, m / z = 321.13 [M + HC ₂ H ₈ N ₂ ] ⁺ . Example 471A tert. Butyl 2- ({1,5-dimethyl-3 - [(S, 2S) -2-methylcyclopropyl] -2,4-dioxo-1,2,3,4-tetrahydrothieno [2,3-d] pyrimidin-6-yl} methylene) hydrazinecarboxylate

A solution of 313 mg (1.13 mmol) of the compound from Ex. 362A in 11 ml of ethanol was treated with 223 mg (1.69 mmol) of tert. Butylhydrazinecarboxylate and 3 drops of conc. Hydrochloric acid added. After the reaction mixture was stirred for about 16 h at RT, it was mixed with 150 ml of cold water and neutralized with saturated sodium bicarbonate solution. The product failed. It was filtered off, washed with a little water and dried under high vacuum. 399 mg (90% of theory) of the title compound were obtained.

'H-NMR (500 MHz, DMSO-de, δ / ppm): 10.83 (br.s, 1H), 8.28 (br.s, 1H), 3.41 (s, 3H), 2.44 (s, 3H), 2.27 -2.19 (m, 1H), 1.45 (s, 9H), 1.15 (d, 3H), 1.04-0.94 (m, 1H), 0.88-0.78 (m, 2H). LC / MS (Method 2, ES Ineg): R _t = 1.00 min, m / z = 391 [MH] -.

Example 472A tert-Butyl-2- ({1,5-dimethyl-3 - [(S, 2S) -2-methylcyclopropyl] -2,4-dioxo-1,2,3,4-tetrahydrothieno [2, 3-d] pyrimidin-6-yl} methyl) hydrazinecarboxylate

A solution of 399 mg (1.02 mmol) of the compound from Ex. 471A in 13 ml of methanol was treated with 326 mg (5.08 mmol) of sodium cyanoborohydride and a little bromocresol green. Subsequently, enough titrated with acetic acid that the indicator color just turned from blue to yellow. Then the reaction mixture was heated to 65 ° C. During the entire reaction time, the pH value was adjusted again and again by addition of further acetic acid in such a way that the indicator color remained just yellow. After a reaction time of 4 hours, the volatile constituents of the reaction mixture were largely removed on a rotary evaporator. The remaining residue was taken up in ethyl acetate and washed in succession with saturated aqueous sodium bicarbonate. carbonate solution, water and saturated aqueous sodium chloride solution. After drying over anhydrous magnesium sulfate, it was filtered and concentrated to dryness. The crude product was purified by MPLC (Biotage Isolera One, cartridge SNAP Ultra, 10 g silica gel, eluent cyclohexane / ethyl acetate 1: 1). The product fractions were combined and evaporated. Drying of the residue under high vacuum gave 329 mg (75% of theory, 92% purity) of the title compound.

'H-NMR (500 MHz, DMSO-de, δ / ppm): 8.23 (br, s, 1H), 5.05-4.88 (br, m, 1H), 3.96 (br, d, 2H), 3.38 (s, 3H), 2.31 (s, 3H), 2.23 (td, 1H), 1.38 (s, 9H), 1.15 (d, 3H), 1.02-0.92 (m, 1H), 0.82 (dd, 2H). LC / MS (Method 1, ESIpos): R _t = 1.71 min, m / z = 263.08 [M + HC ₅ Hi ₂ N ₂ O ₂ ] ⁺ . Example 473A tert. Butyl 2-carbamoyl-2- ({1, 5-dimethyl-3 - [(S, 2S) -2-methylcyclopropyl] -2,4-dioxo-1,2,3,4-tetrahydrothieno [2 , 3-d] pyrimidin-6-yl} methyl) hydrazinecarboxylate

A solution of 329 mg (0.767 mmol, 92% purity) of the compound from Ex. 472A in 15 ml of isopropanol was admixed with 206 μl (1.54 mmol) of trimethylsilyl isocyanate and stirred at RT for about 18 h. Thereafter, the reaction mixture was concentrated to about half the original volume. The product failed. It was filtered off with suction and washed with a little diethyl ether. After drying under high vacuum, 273 mg (66% of theory, 82% purity) of the title compound were obtained.

LC / MS (Method 1, ESIpos): R _t = 1.46 min, m / z = 438.18 [M + H] ⁺ . Example 474A 1-Ethyl-5-methyl-3 - [(7S, 2S) -2-methylcyclopropyl] -2,4-dioxo-1,2,3,4-tetrahydrothieno [2,3-d] pyrimidine-6 carbaldehyde

Analogously to the process described under Example 362A, 346 mg (99% of theory, 95% purity) of the title compound were prepared from 300 mg (1.14 mmol) of the compound from Example 303A and 272 μΐ (3.41 mmol) of ethyl iodide. Ή-NMR (500 MHz, DMSO-d _6, δ / ppm): 8.10 (s, 1H), 3.98-3.88 (m, 2H), 2.77 (s, 3H), 2:29 to 2:23 (m, 1H), 1.24 (t, 3H), 1.15 (d, 3H), 1.07-0.97 (m, 1H), 0.90-0.80 (m, 2H).

LC / MS (Method 1, ESIpos): R _t = 1.69 min, m / z = 293.09 [M + H] ⁺ .

Example 475A

5-Methyl-3 - [(7S, 2S) -2-methylcyclopropyl] -2,4-dioxo-1-propyl-1,2,3,4-tetrahydrothieno [2,3-d] pyrimidine-6-carbaldehyde

Analogously to the process described under Example 362A, from 300 mg (1.14 mmol) of the compound from Example 303A and 332 μΐ (3.41 mmol) of propyl iodide, 321 mg (92% of theory) of the title compound were prepared. The reaction was carried out here at 100 ° C in a microwave oven (Biotage initiator with dynamic control of the irradiation power).

Ή-NMR (500 MHz, DMSO-de, δ / ppm): 10.07 (s, 1H), 3.91 -3.79 (m, 2H), 2.77 (s, 3H), 2.29-2.23 (m, 1H), 1.70 ( sext, 2H), 1.15 (d, 3H), 1.07-0.96 (m, 1H), 0.92 (t, 3H), 0.88-0.81 (m, 2H).

LC / MS (Method 1, ESIpos): R _t = 1.87 min, m / z = 307.11 [M + H] ⁺ .

Example 476A 1- (2-Fluoroethyl) -5-methyl-3 - [(7S, 2S) -2-methylcyclopropyl] thieno [2,3-d] pyrimidine-2,4 (1H, 3H) -dione H

300 mg (1.27 mmol) of the compound from Ex. 302A were dissolved in 5 ml of anhydrous DMF, mixed with 620 mg (1.90 mmol) of cesium carbonate and stirred at RT for 15 min. Then, 316 μΐ (3.81 mmol) of 1-fluoro-2-iodoethane was added. After the reaction mixture was stirred for 3 hours at 100 ° C in a microwave oven (Biotage Initiator with dynamic control of the irradiation power), it was poured onto water. The product failed. After 1 h stirring at RT was filtered off with suction, washed with a little water and dried under high vacuum. There were obtained 326 mg (90% of theory) of the title compound.

'H-NMR (500 MHz, DMSO-de, δ / ppm): 6.78 (d, 1H), 4.73 (dt, 2H), 4.16 (dq, 2H), 2.36 (d, 3H), 2.25 (dt, 1H ), 1.15 (d, 3H), 1.02 (tq, 1H), 0.90-0.79 (m, 2H).

LC / MS (Method 3, ESIpos): R _t = 2.47 min, m / z = 283 [M + H] ⁺ .

Example 477A 1- (2-fluoroethyl) -5-methyl-3 - [(S, 2S) -2-methylcyclopropyl] -2,4-dioxo-1,2,3,4-tetrahydrothieno [2,3-d ] pyrimidine-6-carbaldehyde

A solution of 320 mg (1.13 mmol) of the compound from Ex. 476A in 0.9 ml (11.3 mmol) of DMF was cautiously admixed with 1.3 ml (13.6 mmol) of phosphorus oxychloride. After the strongly exothermic reaction had subsided, the mixture was stirred for a further 15 min. Thereafter, the reaction mixture was carefully stirred into 30 ml of water. After about 1 h stirring at RT, the precipitated product was filtered off with suction, washed neutral with water and dried under high vacuum. There were obtained 322 mg (88% of theory, 96% purity) of the title compound. 'H-NMR (500 MHz, DMSO-de, δ / ρρηι): 10.08 (s, 1H), 4.74 (dt, 2H), 4.23 (dm, 2H), 2.77 (s, 3H), 2.27 (dt, 1H ), 1.15 (d, 3H), 1.09-0.99 (m, 1H), 0.92-0.80 (m, 2H).

LC / MS (Method 2, ESIpos): R _t = 0.87 min, m / z = 311 [M + H] ⁺ .

Example 478A 1- (2,2-Difluoroethyl) -5-methyl-3 - [(/ S, 2S) -2-methyl]

dion

Analogously to the process described under Example 476A, 300 mg (1.27 mmol) of the compound from Example 302A and 348 μΐ (3.81 mmol) of 1,1-dichloro-2-iodoethane were admixed with 346 mg (86% of theory, 95% of theory). Purity) of the title compound.

'H-NMR (500 MHz, DMSO-de, δ / ppm): 6.82 (d, 1H), 6.33 (tt, 1H), 4.37-4.20 (m, 2H), 2.37 (d, 3H), 2.26 (Eng , 1H), 1.15 (d, 3H), 1.07-0.97 (m, 1H), 0.90-0.80 (m, 2H).

LC / MS (Method 1, ESIpos): R _t = 1.81 min, m / z = 301.08 [M + H] ⁺ .

Example 479A 1- (2,2-Difluoroethyl) -5-methyl-3 - [(7S, 2S) -2-methylcyclopropyl] -2,4-dioxo-1,2,3,4-tetrahydrothieno [2,3 d] pyrimidine-6-carbaldehyde

Analogously to the process described under Example 477A, from 340 mg (1.08 mmol, 95% purity) of the compound from Example 478A, 0.9 ml (11.3 mmol) of DMF and 1.3 ml (13.6 mmol) of phosphorus oxychloride 335 mg (89 %> d. Th., 94%> purity) of the title compound. 'H-NMR (500 MHz, DMSO-de, δ / ρρηι): 10.09 (s, 1H), 6.34 (tt, 1H), 4.47-4.29 (m, 2H), 3H), 2.28 (dt, 1H), 1.15 (d, 3H), 1.10-0.99 (m, 1H), 0.92-0.81 (m, 2H).

LC / MS (Method 2, ESIpos): R _t = 0.92 min, m / z = 329 [M + H] ⁺ . Example 480A

5-Methyl-3 - [(7S, 2S) -2-methylcyclopropyl] -1- (2,2,2-trifluoroethyl) thieno [2,3-d] pyrimidine-2,4 (1H, 3H) -dione

300 mg (1.27 mmol) of the compound from Ex. 302A were dissolved in 5 ml of anhydrous DMF, combined with 620 mg (1.90 mmol) of cesium carbonate and stirred at RT for 10 min. Then, 375 μΐ (3.81 mmol) of 1,1'-trifluoro-2-iodoethane was added. After the reaction mixture was stirred for 4 hours at 100 ° C in a microwave oven (Biotage Initiator with dynamic control of the irradiation power), it was diluted with ethyl acetate and washed successively with water and saturated sodium chloride solution. After drying over anhydrous magnesium sulfate, it was filtered and evaporated. The crude product thus obtained was purified by preparative HPLC (Method 11). The product fraction was evaporated and dried under high vacuum. 195 mg (48% of theory) of the title compound were obtained.

Ή-NMR (500 MHz, DMSO-de, δ / ppm): 6.86 (d, 1H), 4.88-4.71 (m, 2H), 2.38 (d, 3H), 2.32-2.27 (m, 1H), 1.16 ( d, 3H), 1.07-0.97 (m, 1H), 0.89-0.82 (m, 2H).

LC / MS (Method 1, ESIpos): R _t = 1.96 min, m / z = 319.07 [M + H] ⁺ . Example 481A

5-methyl-3 - [(7S, 2S) -2-methylcyclopropyl] -2,4-dioxo-1- (2,2,2-trifluoroethyl) -1,2,3,4-tetrahydrothieno [2, 3-d] pyrimidine-6-carbaldehyde

Analogously to the process described under Example 477A, from 190 mg (0.597 mmol) of the compound from Example 480A, 0.5 ml (5.97 mmol) of DMF and 0.7 ml (7.16 mmol) of phosphorus oxychloride were added 183 mg (84% of theory, TL, 95%). Purity) of the title compound. Ή-NMR (500 MHz, DMSO-d ₆ , δ / ppm): 10.10 (s, 1H), 4.99-4.81 (m, 2H), 2.78 (s, 3H), 2.34-2.27 (m, 1H), 1.16 (d, 3H), 1.08-0.98 (m, 1H), 0.91-0.81 (m, 2H).

LC / MS (Method 2, ESIpos): R _t = 1.00 min, m / z = 347 [M + H] ⁺ .

Example 482A 1- (3-fluoropropyl) -5-methyl-3 - [(S, 2S) -2-methylcyclopropyl] -2,4-dioxo-1,2,3,4-tetrahydrothieno [2,3-d ] pyrimidine-6-carbaldehyde

300 mg (1.14 mmol) of the compound from Ex. 303A were dissolved in 2.9 ml of anhydrous DMF, mixed with 555 mg (1.70 mmol) of cesium carbonate and stirred at RT for 10 min. Then 348 μΐ (3.41 mmol) of 1-fluoro-3-iodopropane was added. After the reaction mixture was stirred for 4 hours at 100 ° C in a microwave oven (Biotage Initiator with dynamic control of the Einstrahlleistung), it was poured into water and acidified by the addition of 1 M hydrochloric acid. The product failed. After 1 h stirring at RT was filtered off with suction, washed with a little water and dried under high vacuum. 364 mg (98% of theory) of the title compound were obtained. 'H-NMR (500 MHz, DMSO-d _6, δ / ppm): 8.10 (s, 1H), 4:54 (dt, 2H), 4.08-3.94 (m, 2H), 2.77 (s, 3H), 2.29- 2.22 (m, 1H), 2.15-1.99 (m, 2H), 1.15 (d, 3H), 1.08-0.95 (m, 1H), 0.91-0.80 (m, 2H). LC / MS (Method 1, ESIpos): R _t = min, m / z = 325.10 [M + H]

Example 483A

5-methyl-3 - [(7S, 2S) -2-methylcyclopropyl] -2,4-dioxo-1- (3,3,3-trifluoropropyl) -1,3,3,4-tetrahydrothieno [2, 3-d] pyrimidine-6-carbaldehyde

Analogously to the process described under Ex. 482A, 300 mg (1.14 mmol) of the compound from Ex. 303A and 399 μΐ (3.41 mmol) of 1,1'-trifluoro-3-iodopropane gave 300 mg (73% of theory) of the mixture. ) of the title compound. The product was purified by preparative HPLC (Method 11). 'H-NMR (500 MHz, DMSO-d _6, δ / ppm): 10.09 (s, 1H), 4.13 (tq, 2H), 2.85-2.69 (m, 2H), 2.78 (s, 3H), 2.31- 2.23 (m, 1H), 1.16 (d, 3H), 1.08-0.96 (m, 1H), 0.90-0.81 (m, 2H).

LC / MS (Method 2, ESIpos): R _t = 1.02 min, m / z = 361 [M + H] ⁺ .

Example 484A

5-methyl-3 - [(7S, 2S) -2-methylcyclopropyl] -2,4-dioxo-1- (4,4,4-trifluorobutyl) -1,2,3,4-tetrahydrothieno [2, 3-d] pyrimidine-6-carbaldehyde

A solution of 300 mg (1.14 mmol) of the compound from Ex. 303A in 5 ml of anhydrous DMF was admixed with 392 mg (2.84 mmol) of potassium carbonate and stirred at RT for 15 min. Then, 810 mg (3.41 mmol) of 1,1,1-trifluoro-4-iodobutane was added, and the reaction mixture was stirred at 50 ° C for about 16 hours. After cooling to RT, it was diluted with 200 ml of ethyl acetate and washed successively with water and saturated sodium chloride solution. After drying over anhydrous magnesium sulfate, it was filtered and evaporated. The remaining residue was purified by MPLC (Biotage Isolera One, cartridge SNAP Ultra, 25 g silica gel, cyclohexane / ethyl acetate gradient). After evaporation of the product fraction and drying in a high vacuum, 402 mg (91% of theory, 96% purity) of the title compound were obtained.

'H-NMR (500 MHz, DMSO-de, δ / ppm): 10.08 (s, 1H), 4.04-3.91 (m, 2H), 2.77 (s, 3H), 2.48-2.37 (m, 2H), 2.25 (dt, 1H), 1.89 (quin, 2H), 1.15 (d, 3H), 1.07-0.97 (m, 1H), 0.90-0.80 (m, 2H).

LC / MS (Method 1, ESIpos): R _t = 1.96 min, m / z = 375.10 [M + H] ⁺ .

Example 485A l - [(3,3-Difluorocyclobutyl) methyl] -5-methyl-3 - [(7S, 2S) -2-methylcyclopropyl] -2,4-dioxo-1,2,3,4-tetrahydrothieno [2 , 3-d] pyrimidine-6-carbaldehyde

Analogously to the process described under Ex. 484A, 300 mg (1.14 mmol) of the compound from Example 303A and 941 mg (3.41 mmol) of the compound from Example 316A were used, 305 mg (68% of theory, 93% of theory) Purity) of the title compound.

Ή-NMR (500 MHz, DMSO-de, δ / ppm): 10.08 (s, 1H), 4.16-4.01 (m, 2H), 2.77 (s, 3H), 2.73-2.57 (m, 3H), 2.56- 2.46 (m, 2H, partially covered by the DMSO signal), 2.30-2.22 (m, 1H), 1.15 (d, 3H), 1.06-0.96 (m, 1H), 0.89-0.80 (m, 2H).

LC / MS (Method 1, ESIpos): R _t = 1.92 min, m / z = 369.11 [M + H] ⁺ . Example 486A

5-Methyl-3 - [(7S, 2S) -2-methylcyclopropyl] -2,4-dioxo-l - [(2R) -tetrahydrofuran-2-ylmethyl] -1,3,3,4-tetrahydrothieno [2, 3-d] pyrimidine-6-carbaldehyde

A solution of 300 mg (1.14 mmol) of the compound from Ex. 303A in 6 ml of anhydrous DMF was admixed with 392 mg (2.84 mmol) of potassium carbonate and stirred at RT for 15 min. Then, 375 mg (2.27 mmol) of (2R) -2- (bromomethyl) tetrahydrofuran was added, and the reaction mixture was stirred at 50 ° C. After 3 days, an additional 157 mg (1.13 mmol) of potassium carbonate and 187 mg (1.13 mmol) of (2R) -2- (bromomethyl) tetrahydrofuran were added and stirring continued at 50 ° C. After a further 3 days, the reaction mixture was diluted at RT with about 200 ml of ethyl acetate and washed successively with water and saturated sodium chloride solution. After drying over anhydrous magnesium sulfate, it was filtered and evaporated. The remaining residue was purified by preparative HPLC (Method 11). Evaporation of the product fraction and drying under high vacuum gave 172 mg (43% of theory) of the title compound.

'H-NMR (500 MHz, DMSO-de, δ / ppm): 10.07 (s, 1H), 4.25-4.17 (m, 1H), 4.12 (dd, 1H), 3.79-3.67 (m, 2H), 3.62 (td, 1H), 2.76 (s, 3H), 2.30-2.24 (m, 1H), 2.04-1.96 (m, 1H), 1.95-1.86 (m, 1H), 1.86-1.75 (m, 1H), 1.71 -1.61 (m, 1H), 1.15 (d, 3H), 1.06-0.97 (m, 1H), 0.91-0.80 (m, 2H).

LC / MS (Method 1, ESIpos): R _t = 1.76 min, m / z = 349.12 [M + H] ⁺ .

Example 487A tert. Butyl-2- ({1-ethyl-5-methyl-3 - [(7S, 2S) -2-methylcyclopropyl] -2,4-dioxo-1,2,3,4-tetrahydrothieno [2,3 -d] pyrimidin-6-yl} methylene) hydrazinecarboxylate

Analogously to the process described under Ex. 471A, from 346 mg (1.18 mmol, 95% purity) of the compound from Example 474A and 235 mg (1.78 mmol) of tert. Butylhydrazinecarboxylate 452 mg (95% of theory, 97% purity) of the title compound.

'H-NMR (500 MHz, DMSO-de, δ / ppm): 10.84 (br.s, 1H), 8.28 (s, 1H), 3.96-3.85 (m, 2H), 2.43 (s, 3H), 2.23 (dt, 1H), 1.45 (s, 9H), 1.24 (t, 3H), 1.15 (d, 3H), 1.05-0.94 (m, 1H), 0.88-0.79 (m, 2H).

LC / MS (method 2, ESIneg): R _t = 1.07 min, m / z = 405 [MH] -.

Example 488A tert-butyl 2- ({5-methyl-3 - [(S, 2S) -2-methylcyclopropyl] -2,4-dioxo-1-propyl-1,2,3,4-tetrahydrothieno [2,3-d] pyrimidin-6-yl} methylene) hydrazinecarboxylate

Analogously to the process described under Example 471 A, from 321 mg (1.05 mmol) of the compound from Ex. 475A and 208 mg (1.57 mmol) of tert. -Butyl-hydrazinecarboxylate 396 mg (88% of theory) of the title compound.

Ή-NMR (500 MHz, DMSO-de, δ / ppm): 10.84 (br.s, 1H), 8.28 (s, 1H), 3.89-3.76 (m, 2H), 2.43 (s, 3H), 2.26- 2.21 (m, 1H), 1.70 (sec, 2H), 1.45 (s, 9H), 1.15 (d, 3H), 1.04-0.95 (m, 1H), 0.92 (t, 3H), 0.87-0.79 (m, 2H).

LC / MS (Method 2, ESIpos): R _t = 1.14 min, m / z = 421 [M + H] ⁺ . Example 489A tert. Butyl-2- ({1-butyl-5-methyl-3 - [(7S, 2S) -2-methylcyclopropyl] -2,4-dioxo-1,2,3,4-tetrahydrothieno [2,3 -d] pyrimidin-6-yl} methylene) hydrazinecarboxylate

Analogously to the process described under Example 471 A, from 345 mg (1.08 mmol) of the compound from Ex. 339A and 213 mg (1.62 mmol) of tert. Butylhydrazinecarboxylate 442 mg (89% of theory, 94% purity) of the title compound. Ή-NMR (500 MHz, DMSO-d ₆ , δ / ppm): 10.85 (br.s, 1H), 8.28 (s, 1H), 3.92-3.79 (m, 2H), 2.44 (s, 3H), 2.27 -2.21 (m, 1H), 1.66 (quin, 2H), 1.46 (s, 9H), 1.40-1.31 (m, 2H), 1.15 (d, 3H), 1.04-0.96 (m, 1H), 0.93 (t , 3H), 0.88-0.79 (m, 2H).

LC / MS (Method 1, ESIpos): R _t = 2.29 min, m / z = 435.21 [M + H] ⁺ . Example 490A tert. Butyl-2- ({1- (2-fluoroethyl) -5-methyl-3 - [(7S, 2S) -2-methylcyclopropyl] -2,4-dioxo-1,2,3,4-tetrahydrothieno [2,3-d] pyrimidin-6-yl} methylene) hydrazinecarboxylate

Analogously to the process described under Example 471A, from 320 mg (0.990 mmol, 96%> purity) of the compound from Ex. 477A and 204 mg (1.55 mmol) of tert. Butylhydrazinecarboxylate 420 mg (95% of theory, 96% purity) of the title compound.

Ή-NMR (500 MHz, DMSO-de, δ / ppm): 10.84 (br.s, 1H), 8.27 (s, 1H), 4.73 (dt, 2H), 4.20 (dm, 2H), 2.43 (s, 3H), 2.25 (dt, 1H), 1.45 (s, 9H), 1.15 (d, 3H), 1.02 (tq, 1H), 0.91 -0.79 (m, 2H).

LC / MS (Method 1, ES Ineg): R _t = 1.07 min, m / z = 423.15 [MH], Example 491A tert. Butyl 2- ({1- (2,2-difluoroethyl) -5-methyl-3 - [(7S, 2S) -2-methylcyclopropyl] -2,4-dioxo-1,2,3,4-tetrahydrothieno [2,3-d] pyrimidin-6-yl} methylene) hydrazinecarboxylate

Analogously to the process described under Example 471A, from 330 mg (0.945 mmol, 94% purity) of the compound from Ex. 479A and 199 mg (1.51 mmol) of tert. Butylhydrazinecarboxylate 412 mg (78% of Tl, 80% purity) of the title compound.

LC / MS (Method 1, ES Ineg): R _t = 2.01 min, m / z = 441.14 [MH] ^~ .

Example 492A tert -Butyl 2- ({5-methyl-3 - [(7S, 2S) -2-methylcyclopropyl] -2,4-dioxo-1- (2,2,2-trifluoroethyl) -1, 2 , 3,4-tetrahydrothieno [2,3-d] pyrimidin-6-yl} methylene) hydrazinecarboxylate

Analogously to the process described under Example 471 A, from 180 mg (0.494 mmol, 95% purity) of the compound from Ex. 481A and 103 mg (0.780 mmol) of tert. Butylhydrazinecarboxylate 220 mg (82% of T, 85% purity) of the title compound.

'H-NMR (500 MHz, DMSO-de, δ / ppm): 10.88 (br.s, 1H), 8.28 (s, 1H), 4.95-4.76 (m, 2H), 2.44 (s, 3H), 2.32 -2.25 (m, 1H), 1.45 (s, 9H), 1.15 (d, 3H), 1.05-0.96 (m, 1H), 0.90-0.80 (m, 2H).

LC / MS (Method 1, ES Ineg): R _t = 2.13 min, m / z = 459.13 [MH], Example 493A tert -Butyl 2- ({1- (3-fluoropropyl) -5-methyl-3 - [(7S, 2S) -2-methylcyclopropyl] -2,4-dioxo-l, 2,3 , 4-tetrahydrothieno [2,3-d] pyrimidin-6-yl} methylene) hydrazinecarboxylate

Analogously to the process described under Example 471 A, from 345 mg (1.06 mmol) of the compound from Example 482A and 211 mg (1.60 mmol) of tert. Butylhydrazinecarboxylate 449 mg (92% of theory, 96% purity) of the title compound.

Ή-NMR (500 MHz, DMSO-de, δ / ppm): 10.84 (br.s, 1H), 8.28 (s, 1H), 4.55 (dt, 2H), 4.04-3.92 (m, 2H), 2.44 ( s, 3H), 2.26-2.21 (m, 1H), 2.14-2.01 (m, 2H), 1.46 (s, 9H), 1.15 (d, 3H), 1.05-0.95 (m, 1H), 0.90-0.78 ( m, 2H).

LC / MS (method 1, ESIneg): R _t = 2.01 min, m / z = 437.17 [MH] -.

Example 494A tert. Butyl 2- ({5-methyl-3 - [(/ S, 2S) -2-methylcyclopropyl] -2,4-dioxo-l - (3,3,3-trifluoropropyl) -1,3,3, 4-tetrahydrothieno [2,3-d] pyrimidin-6-yl} methylene) hydrazinecarboxylate

Analogously to the process described under Ex. 471A, from 300 mg (0.833 mmol) of the compound from Ex. 483A and 165 mg (1.25 mmol) of tert. Butylhydrazinecarboxylate 378 mg (90% of theory, 95% purity) of the title compound. 'H-NMR (500 MHz, DMSO-de, δ / ppm): 10.87 (br.s, 1H), 8.29 (s, 1H), 4.11 (tq, 2H), 2.77 (qt, 2H), 2.45 (s , 3H), 2.28-2.21 (m, 1H), 1.46 (s, 9H), 1.16 (d, 3H), 1.06-0.95 (m, 1H), 0.89-0.80 (m,

2H).

LC / MS (Method 1, ES Ineg): R _t = 2.15 min, m / z = 473.15 [MH] ^~ . Example 495A tert. Butyl 2- ({5-methyl-3 - [(7S, 2S) -2-methylcyclopropyl] -2,4-dioxo-1- (4,4,4-trifluorobutyl) -1,3,3,4 - tetrahydrothieno [2,3-d] pyrimidin-6-yl} methylene) hydrazinecarboxylate

395 mg (1.06 mmol) of the compound from Ex. 484A and 209 mg (1.58 mmol) of tert. Butylhydrazinecarboxylate 484 mg (88% of theory, 94% purity) of the title compound.

'H-NMR (500 MHz, DMSO-de, δ / ppm): 10.85 (br.s, 1H), 8.29 (s, 1H), 4.03-3.89 (m, 2H), 2.49- 2.37 (m, 2H) , 2.44 (s, 3H), 2.23 (dt, 1H), 1.90 (quin, 2H), 1.46 (s, 9H), 1.15 (d, 3H), 1.05-0.96 (m, 1H), 0.90-0.79 (m , 2H). LC / MS (Method 1, ES Ineg): R _t = 2.22 min, m / z = 487.16 [MH] ^~ .

Example 496A tert. Butyl 2- ({1- (2-methoxyethyl) -5-methyl-3 - [(7S, 2S) -2-methylcyclopropyl] -2,4-dioxo-1,2,3,4-tetrahydrothieno [2 , 3-d] pyrimidin-6-yl} methylene) hydrazinecarboxylate

Analogously to the process described under Example 471 A, from 325 mg (1.01 mmol) of the compound from Ex. 350A and 200 mg (1.51 mmol) of tert. Butylhydrazinecarboxylate 391 mg (85% of theory, 96% purity) of the title compound.

'H-NMR (500 MHz, DMSO-de, δ / ppm): 10.84 (br.s, 1H), 8.27 (s, 1H), 4.09-3.97 (m, 2H), 3.63 (t, 2H), 3.25 (s, 3H), 2.43 (s, 3H), 2.28-2.21 (m, 1H), 1.46 (s, 9H), 1.15 (d, 3H), 1.01 (tq, 1H), 0.89-0.79 (m, 2H ).

LC / MS (Method 1, ESIpos): R _t = 1.94 min, m / z = 437.18 [M + H] ^+. Example 497A tert-Butyl 2- ({1 - [(2,2-difluorocyclopropyl) methyl] -5-methyl-3 - [(S, 2S) -2-methylcyclopropyl] -2,4-dioxo-1 2,3,4-tetrahydrothieno [2,3-d] pyrimidin-6-yl} methylene) hydrazinecarboxylate

(Diastereoisomeric mixture)

Analogously to the process described under Example 471A, 325 mg (0.917 mmol) of the compound from Ex. 346A and 182 mg (1.38 mmol) of tert. Butylhydrazinecarboxylate 400 mg (93%> D. Th.) Of the title compound.

'H-NMR (500 MHz, DMSO-de, δ / ppm): 10.84 (br.s, 1H), 8.29 (br.s, 1H), 4.19-4.06 (m, 1H), 4.00-3.88 (m, 1H), 2.44 (s, 3H), 2.29-2.15 (m, 2H), 1.76-1.64 (m, 1H), 1.60-1.30 (m, 1H), 1.45 (s, 9H), 1.15 (d, 3H) , 1.06-0.96 (m, 1H), 0.89-0.78 (m, 2H).

LC / MS (Method 1, ESIpos): R _t = 2.11 min, m / z = 469.17 [M + H] ⁺ . Example 498A tert. Butyl-2- ({1 - (cyclobutylmethyl) -5-methyl-3 - [(7S, 2S) -2-methylcyclopropyl] -2,4-dioxo-1,2,3,4-tetrahydrothieno [2,3 -d] pyrimidin-6-yl} methylene) hydrazinecarboxylate

Analogously to the process described under Ex. 471A, 325 mg (0.978 mmol) of the compound from Ex. 345A and 194 mg (1.47 mmol) of tert. Butylhydrazinecarboxylate 389 mg (89% of theory) of the title compound. 'H-NMR (500 MHz, DMSO-d _6, δ / ppm): 10.85, 28.08 (s, 1H), 3.93 (tt, 2H), 2.84-2.71 (m, 1H), (br s, 1H). 2.43 (s, 3H), 2.24 (td, 1H), 2.05-1.92 (m, 2H), 1.89-1.75 (m, 4H), 1.46 (s, 9H), 1.15 (d, 3H), 1.04-0.91 ( m, 1H), 0.83 (dd, 2H).

LC / MS (Method 1, ESIpos): R _t = 2:34 min, m / z = 447.20 [M + H] ^+. Example 499A tert -Butyl 2- ({1 - [(3,3-difluorocyclobutyl) methyl] -5-methyl-3 - [(7S, 2S) -2-methylcyclopropyl] -2,4-dioxo-1, 2,3,4-tetrahydrothieno [2,3-d] pyrimidin-6-yl} methylene) hydrazinecarboxylate

300 mg (0.757 mmol, 93% purity) of the compound from Example 485A and 161 mg (1.22 mmol) of tert-butyl acetate were prepared analogously to the process described under Example 471A. Butylhydrazinecarboxylate 342 mg (86% of theory, 92% purity) of the title compound.

Ή-NMR (500 MHz, DMSO-de, δ / ppm): 10.85 (m, 1H), 8.28 (s, 1H), 4.13-3.99 (m, 2H), 2.76-2.58 (m, 3H), 2.56- 2.47 (m, 2H, partially masked by the DMSO signal), 2.44 (s, 3H), 2.28-2.20 (m, 1H), 1.46 (s, 9H), 1.15 (d, 3H), 1.06-0.94 (m, 1H), 0.88-0.80 (m, 2H).

LC / MS (Method 1, ESIneg): R _t = 2.20 min, m / z = 481.17 [MH], Example 500A ferric butyl 2- ({5-methyl-3 - [(/ S, 2S) -2-methylcyclo]

methyl] -l, 2,3,4-tetrahydrothieno [2,3-d] pyrimidin-6-yl} methylene) hydrazinecarboxylate

A solution of 170 mg (0.488 mmol) of the compound from Ex. 486A in 5 ml of ethanol was treated with 97 mg (0.732 mmol) of tert. Butylhydrazinecarboxylate and 3 drops of conc. Hydrochloric acid added. After the reaction mixture had been stirred for about 16 h at RT, it was evaporated to almost dryness, then treated with 150 ml of cold water and then neutralized with saturated sodium bicarbonate solution. The product failed. It was filtered off, washed with a little water and dried under high vacuum. 180 mg (71% of theory, 90% purity) of the title compound were obtained.

'H-NMR (500 MHz, DMSO-de, δ / ppm): 10.84 (br.s, 1H), 8.28 (br.s, 1H), 4.26-4.15 (m, 1H), 4.14-4.01 (m, 1H), 3.82-3.57 (m, 3H), 2.43 (s, 3H), 2.30-2.19 (m, 1H), 2.05-1.76 (m, 3H), 1.71- 1.60 (m, 1H), 1.46 (s, 9H), 1.15 (br d, 3H), 1.00 (br d, 1H), 0.85 (br d, 2H). LC / MS (Method 1 ESIneg): R _t = 2.04 min, m / z = 461.19 [MH] ^~ .

Example 501A tert. Butyl-2- ({1-ethyl-5-methyl-3 - [(7S, 2S) -2-methylcyclopropyl] -2,4-dioxo-1,2,3,4-tetrahydrothieno [2,3 -d] pyrimidin-6-yl} methyl) hydrazinecarboxylate

Analogously to the process described under Example 472A, from 452 mg (1.08 mmol, 97%> purity) of the compound from Example 487A and 346 mg (5.39 mmol) of sodium cyanoborohydride 339 mg (70% of theory, 91%) purity) of the title compound. The MPLC purification was carried out here via a cartridge with 25 g of silica gel and cyclohexane / ethyl acetate 2: 1 as the eluent.

'H-NMR (500 MHz, DMSO-de, δ / ppm): 8.24 (br, s, 1H), 4.99 (br, s, 1H), 3.97 (br, d, 2H), 3.92- 3.82 (m, 2H), 2.31 (s, 3H), 2.26-2.21 (m, 1H), 1.39 (s, 9H), 1.24 (t, 3H), 1.16 (d, 3H), 1.03-0.92 (m, 1H), 0.87 -0.79 (m, 2H).

LC / MS (Method 1, ESIpos): R _t = 1.88 min, m / z = 277.10 [M + HC ₅ Hi ₂ N ₂ O ₂ ] ⁺ .

Example 502A tert -Butyl 2- ({5-methyl-3 - [(S, 2S) -2-methylcyclopropyl] -2,4-dioxo-1-propyl-1,2,3,4-tetrahydrothieno [2,3-d] pyrimidin-6-yl} methyl) hydrazinecarboxylate

Analogously to the process described under Example 472A, 395 mg (0.923 mmol) of the compound of Ex. 488A and 296 mg (4.61 mmol) of sodium cyanoborohydride were used to prepare 345 mg (77% of theory, 88% purity) of the title compound , The MPLC purification was carried out here via a cartridge with 25 g of silica gel and cyclohexane / ethyl acetate 2: 1 as the eluent. 'H-NMR (500 MHz, DMSO-d _6, δ / ppm): (br. S, 1H) (br. D, 1 H) (br. D, 2H) 8.24, 4.99, 3.96, 3.86- 3.73 (m , 2H), 2.31 (s, 3H), 2.27-2.20 (m, 1H), 1.70 (sec, 2H), 1.39 (s, 9H), 1.15 (d, 3H), 0.97 (dtd, 1H), 0.91 ( t, 3H), 0.86-0.78 (m, 2H).

LC / MS (Method 1, ESIpos): R _t = 2.03 min, m / z = 291.12 [M + HC ₅ Hi ₂ N ₂ O ₂ ] ⁺ .

Example 503A tert -Butyl 2- ({1-butyl-5-methyl-3 - [(7S, 2S) -2-methylcyclopropyl] -2,4-dioxo-1,2,3,4-tetrahydrothieno [2,3-d] pyrimidin-6-yl} methyl) hydrazinecarboxylate

Analogously to the process described under Example 472A, from 440 mg (0.962 mmol, 94% purity) of the compound from Ex. 489A and 308 mg (4.81 mmol) sodium cyanoborohydride, 366 mg (78% of theory, 90%) were obtained ) of the title compound. The MPLC purification was carried out here via a cartridge with 25 g of silica gel and cyclohexane / ethyl acetate 2: 1 as the eluent.

Ή-NMR (500 MHz, DMSO-de, δ / ppm): 8.23 (br.s, 1H), 4.98 (br.d, 1H), 3.96 (br.d, 2H), 3.89- 3.75 (m, 2H ), 2.31 (s, 3H), 2.26-2.20 (m, 1H), 1.65 (quin, 2H), 1.38 (s, 9H), 1.38-1.30 (m, 2H), 1.15 (d, 3H), 1.00- 0.94 (m, 1H), 0.92 (t, 3H), 0.85-0.78 (m, 2H).

LC / MS (Method 1, ESIpos): R _t = 2.18 min, m / z = 305.13 [M + HC ₅ Hi ₂ N ₂ O ₂ ] ⁺ . Example 504A tert. Butyl-2- ({1- (2-fluoroethyl) -5-methyl-3 - [(7S, 2S) -2-methylcyclopropyl] -2,4-dioxo-1,2,3,4-tetrahydrothieno [2,3-d] pyrimidin-6-yl} methyl) hydrazinecarboxylate

To a solution of 415 mg (0.939 mmol, 96%> purity) of the compound from Ex. 490A in 20 ml of methanol was added 307 mg (4.89 mmol) of sodium cyanoborohydride and a little bromocresol green. Subsequently, enough titrated with acetic acid that the indicator color just turned from blue to yellow. Then the reaction mixture was heated to 65 ° C. After 1 h, an additional 154 mg (2.44 mmol) of sodium cyanoborohydride was added. During the entire reaction time, the pH value was adjusted again and again by adding further acetic acid, so that the indicator color remained just yellow. After a total reaction time of 3 hours, the volatile constituents of the reaction mixture were largely removed on a rotary evaporator. The remaining residue was taken up in ethyl acetate and washed in succession with saturated aqueous sodium hydroxide. hydrogen carbonate solution, water and saturated aqueous sodium chloride solution. After drying over anhydrous magnesium sulfate, it was filtered and concentrated to dryness. The crude product was purified by MPLC (Biotage Isolera One, cartridge SNAP Ultra, 25 g silica gel, eluent cyclohexane / ethyl acetate 2: 1). The product fractions were combined and evaporated. After drying in a high vacuum, 380 mg (85% of theory, 90% purity) of the title compound were obtained.

LC / MS (Method 1, ESIpos): R _t = 1.77 min, m / z = 295.09 [M + HC ₅ Hi ₂ N ₂ O ₂ ] ⁺ . Example 505A tert. Butyl 2- ({1- (2,2-difluoroethyl) -5-methyl-3 - [(7S, 2S) -2-methylcyclopropyl] -2,4-dioxo-1,2,3,4-tetrahydrothieno [2,3-d] pyrimidin-6-yl} methyl) hydrazinecarboxylate

Analogously to the process described under Example 504A, from 400 mg (0.723 mmol, 80% purity) of the compound from Example 491A and a total of 341 mg (5.42 mmol) of sodium cyanoborohydride, 205 mg (63% of theory, 72%) were obtained. Purity) of the title compound. LC / MS (Method 1, ESIpos): R _t = 1.88 min, m / z = 313.08 [M + HC ₅ Hi ₂ N ₂ O ₂ ] ⁺ .

Example 506A tert. Butyl-2- ({5-methyl-3 - [(7S, 2S) -2-methylcyclopropyl] -2,4-dioxo-1- (2,2,2-trifluoroethyl) -1,3,3,4 - tetrahydrothieno [2,3-d] pyrimidin-6-yl} methyl) hydrazinecarboxylate

Analogously to the process described under Example 504A, from 218 mg (0.402 mmol, 85% purity) of the compound from Example 492A and a total of 223 mg (3.55 mmol) of sodium cyanoborohydride, 170 mg (79% of theory, 87%) were obtained. Purity) of the title compound.

LC / MS (Method 1, ESIpos): R _t = 2.00 min, m / z = 331.07 [M + HC ₅ Hi ₂ N ₂ O ₂ ] ⁺ . Example 507A tert. Butyl 2- ({1- (3-fluoropropyl) -5-methyl-3 - [(7S, 2S) -2-methylcyclopropyl] -2,4-dioxo-1,2,3,4-tetrahydrothieno [2 , 3-d] pyrimidin-6-yl} methyl) hydrazinecarboxylate

Analogously to the process described under Ex. 472A, from 444 mg (0.972 mmol, 96% purity) of the compound from Ex. 493A and 312 mg (4.86 mmol) sodium cyanoborohydride 356 mg (73%) d. Th., 88%) purity) of the title compound. The MPLC purification was carried out here via a cartridge with 25 g of silica gel and cyclohexane / ethyl acetate 2: 1 as the eluent.

Ή-NMR (500 MHz, DMSO-de, δ / ppm): 8.24 (br.s, 1H), 4.99 (br.d, 1H), 4.54 (dt, 2H), 4.01 -3.86 (m, 4H), 2.31 (s, 3H), 2.26-2.20 (m, 1H), 2.13-2.00 (m, 2H), 1.38 (s, 9H), 1.15 (d, 3H), 1.04-0.92 (m, 1H), 0.82 ( dd, 2H).

LC / MS (Method 1, ESIpos): R _t = 1.89 min, m / z = 309.11 [M + HC ₅ Hi ₂ N ₂ O ₂ ] ⁺ .

Example 508A tert. Butyl-2- ({5-methyl-3 - [(S, 2S) -2-methylcyclopropyl] -2,4-dioxo-l - (3,3,3-trifluoropropyl) -1,3,3,4 -tetrahydrothieno [2,3-d] pyrimidin-6-yl} methyl) hydrazinecarboxylate

Analogously to the process described under Ex. 472A, 373 mg (0.745 mmol, 95% purity) of the compound from Example 494A and 239 mg (3.72 mmol) sodium cyanoborohydride were 323 mg (79% of theory, 87% of purity ) of the title compound. The MPLC purification was carried out here via a cartridge with 25 g of silica gel and cyclohexane / ethyl acetate 2: 1 as the eluent.

Ή-NMR (500 MHz, DMSO-de, δ / ppm): 8.24 (br.s, 1H), 5.04 (br.d, 1H), 4.14-4.00 (m, 2H), 3.97 (br. D, 2H ), 2.82-2.67 (m, 2H), 2.31 (s, 3H), 2.27-2.20 (m, 1H), 1.38 (s, 9H), 1.15 (d, 3H), 0.98 (qdd, 1H), 0.89- 0.78 (m, 2H).

LC / MS (Method 1, ESIpos): R _t = 2.06 min, m / z = 345.09 [M + HC ₅ Hi ₂ N ₂ O ₂ ] ⁺ . Example 509A tert. Butyl 2- ({5-methyl-3 - [(7S, 2S) -2-methylcyclopropyl] -2,4-dioxo-1- (4,4,4-trifluorobutyl) -1,3,3,4 - tetrahydrothieno [2,3-d] pyrimidin-6-yl} methyl) hydrazinecarboxylate

Analogously to the process described under Example 472A, from 484 mg (0.931 mmol, 94% purity) of the compound from Example 495A and 299 mg (4.66 mmol) sodium cyanoborohydride, 380 mg (66% of theory, 80% purity) ) of the title compound. The MPLC purification was carried out here via a cartridge with 25 g of silica gel and cyclohexane / ethyl acetate 2: 1 as the eluent.

LC / MS (Method 1, ESIpos): R _t = 2.11 min, m / z = 359.10 [M + HC ₅ Hi ₂ N ₂ O ₂ ] ⁺ . Example 510A tert -Butyl 2- ({1- (2-methoxyethyl) -5-methyl-3 - [^^

tetrahydrothieno [2,3-d] pyrimidin-6-yl} methyl) hydrazinecarboxylate

To a solution of 390 mg (0.893 mmol) of the compound of Ex. 496A in 20 ml of methanol was added 281 mg (4.47 mmol) of sodium cyanoborohydride and a little bromocresol green. Subsequently, enough titrated with acetic acid that the indicator color just turned from blue to yellow. Then the reaction mixture was heated to 65 ° C. After 1 h, a further 140 mg (2.23 mmol) of sodium cyanoborohydride were added and after a further hour, a further 281 mg (4.47 mmol). During the entire reaction time, the pH value was adjusted again and again by adding further acetic acid, so that the indicator color remained just yellow. After a total reaction time of 4 h, the volatile constituents of the reaction mixture were largely removed on a rotary evaporator. The remaining residue was taken up in ethyl acetate and washed successively with saturated aqueous sodium bicarbonate solution, water and saturated aqueous sodium chloride solution. After drying over anhydrous magnesium sulfate, it was filtered and concentrated to dryness. The crude product was purified by MPLC (Biotage Isolera One, cartridge SNAP Ultra, 10 g silica gel, mobile phase cyclohexane / ethyl acetate 2: 1). The product fractions were combined and evaporated. After drying under high vacuum, 308 mg (77% of theory, 98% purity) of the title compound were obtained. Ή-NMR (500 MHz, DMSO-d ₆ , δ / ppm): 8.23 (br.s, 1H), 4.95 (br.d, 1H), 4.06-3.90 (m, 4H), 3.62 (t, 2H) , 3.25 (s, 3H), 2.30 (s, 3H), 2.26-2.21 (m, 1H), 1.39 (s, 9H), 1.15 (d, 3H), 1.03-0.93 (m, 1H), 0.86-0.78 (m, 2H).

LC / MS (Method 1, ESIpos): R _t = 1.81 min, m / z = 307.11 [M + HC ₅ Hi ₂ N ₂ O ₂ ] ⁺ .

Example 511A tert -Butyl 2- ({1- [(2,2-difluorocyclopropyl) methyl] -5-methyl-3 - [(7S, 2S) -2-methylcyclopropyl] -2,4-dioxo-1, 2,3,4-tetrahydrothieno [2,3-d] pyrimidin-6-yl} methyl) hydrazinecarboxylate

(Mixture of diastereomers)

Analogously to the process described under Example 504A, 398 mg (0.843 mmol) of the compound from Example 497A and a total of 397 mg (6.32 mmol) sodium cyanoborohydride were used to produce 348 mg (76% of theory, 87% purity) of the title compound , 'H-NMR (500 MHz, DMSO-d _6, δ / ppm): 8.24, 5.01 4.09-3.88 (m, 4H), 2.31 (s, 3H (br s, 1H). (Br s, 1H). ), 2.28-2.13 (m, 2H), 1.74-1.63 (m, 1H), 1.52-1.43 (m, 1H), 1.38 (s, 9H), 1.15 (d, 3H), 1.04-0.93 (m, 1H ), 0.83 (dd, 2H).

LC / MS (Method 1, ESIpos): R _t = 2.04 min, m / z = 339.10 [M + HC ₅ Hi ₂ N ₂ O ₂ ] ⁺ . Example 512A tert. Butyl-2- ({1 - (cyclobutylmethyl) -5-methyl-3 - [(7S, 2S) -2-methylcyclopropyl] -2,4-dioxo-1,2,3,4-tetrahydrothieno [2,3 -d] pyrimidin-6-yl} methyl) hydrazinecarboxylate

Analogously to the process described under Example 472A, from 389 mg (0.871 mmol) of the compound from Example 498A and 279 mg (4.36 mmol) sodium cyanoborohydride, 270 mg (60% of theory, 87% purity) of the title compound were prepared , The MPLC purification was carried out here via a cartridge with 25 g of silica gel and cyclohexane / ethyl acetate 2: 1 as the eluent.

LC / MS (Method 1, ESIpos): R _t = 2.23 min, m / z = 317.13 [M + HC ₅ Hi ₂ N ₂ O ₂ ] ⁺ .

Example 513A tert. Butyl 2- ({1 - [(3,3-difluorocyclobutyl) methyl] -5-methyl-3 - [(7S, 2S) -2-methylcyclopropyl] -2,4-dioxo-1, 2,3, 4-tetrahydrothieno [2,3-d] pyrimidin-6-yl} methyl) hydrazinecarboxylate

430 mg (0.649 mmol, 92% purity) of the compound of Example 499A and a total of 553 mg (8.81 mmol) of sodium cyanoborohydride were converted into 325 mg (90% of theory, 87% by analogy with the process described under Example 510A). Purity) of the title compound. Ή-NMR (500 MHz, DMSO-d ₆ , δ / ppm): 8.24 (br.s, 1H), 5.01 (br.d, 1H), 4.09-3.91 (m, 4H), 2.73- 2.59 (m, 3H), 2.56-2.47 (m, 2H), 2.30 (s, 3H), 2.27-2.20 (m, 1H), 1.38 (s, 9H), 1.15 (d, 3H), 0.97 (dtt, 1H), 0.86 -0.78 (m, 2H).

LC / MS (Method 1, ESIpos): R _t = 2.09 min, m / z = 353.11 [M + HC ₅ Hi ₂ N ₂ O ₂ ] ⁺ . Example 514A tert. Butyl-2- ({5-methyl-3 - [(7S, 2S) -2-methylcyclopropyl] -2,4-dioxo-l - [(2R) -tetrahydrofuran-2-yl-methyl] -l, 2 , 3,4-tetrahydrothieno [2,3-d] pyrimidin-6-yl} methyl) hydrazinecarboxylate

Analogously to the process described under Example 504A, from 178 mg (0.347 mmol, 90% purity) of the compound from Example 500A and a total of 181 mg (2.89 mmol) of sodium cyanoborohydride 110 mg (47% of theory, 70%). Purity) of the title compound.

LC / MS (Method 1, ESIpos): R _t = 1.88 min, m / z = 333.13 [M + HC ₅ Hi ₂ N ₂ O ₂ ] ⁺ .

Example 515A tert. Butyl 2-carbamoyl-2- ({1-ethyl-5-methyl-3 - [(S, 2S) -2-methylcyclopropyl] -2,4-dioxo-1,2,3,4-tetrahydrothieno [2 , 3-d] pyrimidin-6-yl} methyl) hydrazinecarboxylate H

A solution of 339 mg (0.788 mmol, 95% purity) of the compound from Example 501A in 20 ml of isopropanol was admixed with 211 μΐ (1.58 mmol) of trimethylsilyl isocyanate and stirred at RT for about 18 h. Thereafter, the reaction mixture was evaporated. The remaining residue was purified by MPLC (Biotage Isolera One, cartridge SNAP Ultra, 25 g silica gel, cyclohexane / ethyl acetate 1: 1-> dichloromethane / methanol 10: 1). Evaporation of the product fraction and drying under high vacuum gave 288 mg (71% of theory, 88% purity) of the title compound.

'H-NMR (500 MHz, DMSO-de, δ / ppm): 8.90 (br, s, 1H), 6.17 (br, s, 2H), 4.94-4.25 (br, m, 2H), 3.92-3.81 ( m, 2H), 2.32 (s, 3H), 2.25 (dt, 1H), 1.38 (br s, 9H), 1.22 (t, 3H), 1.15 (d, 3H), 1.00-0.91 (m, 1H) , 0.87-0.77 (m, 2H).

LC / MS (Method 1, ESIpos): R _t = 1.57 min, m / z = 452.20 [M + H] ⁺ .

Example 516A tert. Butyl 2-carbamoyl-2 - ({5-methyl-3 - [(S, 2S) -2-methylcyclopropyl] -2,4-dioxo-1-propyl-1,2,3,4-tetrahydrothieno [2 , 3-d] pyrimidin-6-yl} methyl) hydrazinecarboxylate

Analogously to the process described under Example 473A, from 345 mg (0.735 mmol, 90% purity) of the compound from Ex. 502A and 197 μΐ (1.47 mmol) of trimethylsilyl isocyanate 323 mg (85%) of theory. Th., 91%) purity) of the title compound. 'H-NMR (500 MHz, DMSO-de, δ / ρρηι): 8.90 (br.s, 1H), 6.17 (br.s, 2H), 4.97-4.22 (m, 2H), 3.85- 3.73 (m, 2H), 2.32 (s, 3H), 2.27-2.22 (m, 1H), 1.68 (sec, 2H), 1.38 (br, s, 9H), 1.15 (d, 3H), 0.99-0.91 (m, 1H) , 0.90 (t, 3H), 0.86-0.76 (m, 2H).

LC / MS (Method 1, ESIpos): R _t = 1.69 min, m / z = 466.21 [M + H] ⁺ . Example 517A tert. Butyl-2- ({1-butyl-5-methyl-3 - [(7S, 2S) -2-methylcyclopropyl] -2,4-dioxo-1,2,3,4-tetrahydrothieno [2,3 -d] pyrimidin-6-yl} methyl) -2-carbamoylhydrazinecarboxylate

Analogously to the process described in Example 515A, from 364 mg (0.792 mmol, 95% purity) of the compound of Ex. 503A and 212 μΐ (1.58 mmol) of trimethylsilyl isocyanate, 286 mg (95% of theory, 94% purity) of the title compound were obtained produced.

'H-NMR (500 MHz, DMSO-de, δ / ppm): 8.90 (br.s, 1H), 6.18 (br.s, 2H), 4.99-4.14 (m, 2H), 3.88- 3.75 (m, 2H), 2.32 (s, 3H), 2.25 (dt, 1H), 1.64 (quin, 2H), 1.40 (s, 9H), 1.37-1.30 (m, 2H), 1.15 (d, 3H), 0.98-0.92 (m, 1H), 0.91 (t, 3H), 0.87-0.76 (m, 2H). LC / MS (Method 1, ESIpos): R _t = 1.79 min, m / z = 480.23 [M + H] ⁺ .

Example 518A tert. Butyl 2-carbamoyl-2- ({1- (2-fluoroethyl) -5-methyl-3 - [(S, 2S) -2-methylcyclopropyl] -2,4-dioxo l, 2,3,4 -tetrahydrothieno [2,3-d] pyrimidin-6-yl} methyl) hydrazinecarboxylate

A solution of 375 mg (0.791 mmol, 90% purity) of the compound from Ex. 504A in 25 ml of isopropanol was admixed with 236 μl (1.76 mmol) of trimethylsilyl isocyanate and stirred at RT for 2 days. Thereafter, the reaction mixture was evaporated. The remaining residue was taken up in ethyl acetate and washed successively with saturated solutions of sodium bicarbonate and sodium chloride. After drying over anhydrous magnesium sulfate was filtered and evaporated and the residue dried under high vacuum. There was obtained 465 mg (100% of theory, 80% purity) of the title compound.

LC / MS (Method 1, ESIpos): R _t = 1.51 min, m / z = 470.19 [M + H] ⁺ . Example 519A tert. Butyl 2-carbamoyl-2- ({1- (2,2-difluoroethyl) -5-methyl-3 - [(7S, 2S) -2-methylcyclopropyl] -2,4-dioxo-1, 2,3 , 4-tetrahydrothieno [2,3-d] pyrimidin-6-yl} methyl) hydrazinecarboxylate

Analogously to the process described under Example 518A, from 200 mg (0.324 mmol, 72% purity) of the compound from Ex. 505A and 121 μΐ (0.90 mmol) of trimethylsilyl isocyanate 275 mg (quant., 65%> purity) of the title compound were obtained.

LC / MS (Method 1, ES Ineg): R _t = 1.60 min, m / z = 486.16 [MH]. Example 520A tert-Butyl 2-carbamoyl-2 - ({5-methyl-3 - [(S, 2S) -2-methylcyclopropyl] -2,4-dioxo-l- (2,2,2-trifluoro-) ethyl) -l, 2,3,4-tetrahydrothieno [2,3-d] pyrimidin-6-yl} methyl) hydrazinecarboxylate

Analogously to the process described under Example 518A, from 165 mg (0.311 mmol, 87% purity) of the compound from Ex. 506A and 96 μΐ (0.714 mmol) of trimethylsilyl isocyanate, 250 mg (quant., 71% purity) of the title compound were obtained. The reaction time was approx. 16 h.

LC / MS (Method 1, ES Ineg): R _t = 1.73 min, m / z = 504.15 [MH].

Example 521A tert. Butyl 2-carbamoyl-2- ({1- (3-fluoropropyl) -5-methyl-3 - [(S, 2S) -2-methylcyclopropyl] -2,4-dioxo-1,2,3 , 4-tetrahydrothieno [2,3-d] pyrimidin-6-yl} methyl) hydrazinecarboxylate

A solution of 354 mg (0.699 mmol, 87% purity) of the compound from Ex. 507A in 22 ml of isopropanol was admixed with 188 μl (1.40 mmol) of trimethylsilyl isocyanate and stirred at RT for about 18 h. Thereafter, the reaction mixture was concentrated to about half the original volume. A part of the product precipitated out, which was filtered off with suction, washed with a little pentane and dried in vacuo. The mother liquor was completely evaporated and further product was isolated therefrom by preparative HPLC (Method 13). The product fraction was evaporated and dried in a high vacuum. After combining with the previously isolated solid, 285 mg (84% of theory) of the title compound were obtained.

'H-NMR (500 MHz, DMSO-de, δ / ppm): 8.90 (br.s, 1H), 6.17 (br.s, 2H), 5.04-4.08 (m, 2H), 4.53 (dt, 2H) , 4.02-3.87 (m, 2H), 2.32 (s, 3H), 2.25 (dt, 1H), 2.12-1.97 (m, 2H), 1.38 (br, s, 9H), 1.15 (d, 3H), 1.01 -0.91 (m, 1H), 0.88-0.75 (m, 2H).

LC / MS (Method 1, ESIpos): R _t = 1.57 min, m / z = 484.20 [M + H] ⁺ .

Example 522A tert -Butyl 2-carbamoyl-2 - ({5-methyl-3 - [(S, 2S) -2-methylcyclopropyl] -2,4-dioxo-1- (3,3,3-trifluoro-) propyl) -l, 2,3,4-tetrahydrothieno [2,3-d] pyrimidin-6-yl} methyl) hydrazinecarboxylate

Analogously to the process described under Example 473A, from 321 mg (0.586 mmol, 87% purity) of the compound from Example 508A and 118 μΐ (0.879 mmol) of trimethylsilyl isocyanate, 316 mg (98% of theory, 95% purity) of Title compound prepared.

'H-NMR (500 MHz, DMSO-de, δ / ppm): 8.91 (br, s, 1H), 6.19 (br, s, 2H), 5.01-4.17 (m, 2H), 4.14- 4.02 (m, 2H), 2.79-2.66 (m, 2H), 2.32 (s, 3H), 2.26 (dt, 1H), 1.38 (br, s, 9H), 1.15 (d, 3H), 1.01-0.91 (m, 1H) , 0.88-0.76 (m, 2H).

LC / MS (Method 1, ES Ineg): R _t = 1.76 min, m / z = 518.17 [MH]. Example 523A tert. Butyl 2-carbamoyl-2 - ({5-methyl-3 - [(S, 2S) -2-methylcyclopropyl] -2,4-dioxo-1- (4,4,4-trifluoro-butyl) -1 , 2,3,4-tetrahydrothieno [2,3-d] pyrimidin-6-yl} methyl) hydrazinecarboxylate

A solution of 380 mg (0.713 mmol, 92% purity) of the compound from Ex. 509A in 14 ml of isopropanol was admixed with 191 μΐ (1.43 mmol) of trimethylsilyl isocyanate and stirred at RT for about 18 h. Thereafter, the reaction mixture was treated with 100 ml of water and extracted twice with ethyl acetate. The organic extract was washed with saturated sodium chloride solution, dried over anhydrous magnesium sulfate, filtered and evaporated. The crude product thus obtained was purified by means of MPLC (Biotage Isolera One, cartridge SNAP Ultra, 10 g of silica gel, cyclohexane / ethyl acetate gradient). Evaporation of the product fraction and drying under high vacuum gave 325 mg (74% of theory, 87% purity) of the title compound. 'H-NMR (500 MHz, DMSO-d _6, δ / ppm): (br. S, 1H) (br. S, 2H) 8.89, 6.18, 5:05 to 4:14 (m, 2H), 3.99- 3.84 (m , 2H), 2.46-2.35 (m, 2H), 2.32 (s, 3H), 2.28-2.21 (m, 1H), 1.88 (quin, 2H), 1.38 (br, s, 9H), 1.15 (d, 3H ), 1.01-0.91 (m, 1H), 0.88-0.75 (m, 2H).

LC / MS (Method 1, ESIpos): R _t = 1.80 min, m / z = 534.20 [M + H] ⁺ .

Example 524A tert. Butyl 2-carbamoyl-2- ({1- (2-methoxyethyl) -5-methyl-3 - [(S, 2S) -2-methylcyclopropyl] -2,4-dioxo-1,2,3 , 4-tetrahydrothieno [2,3-d] pyrimidin-6-yl} methyl) hydrazinecarboxylate

Analogously to the process described under Example 521A, from 308 mg (0.688 mmol, 98% purity) of the compound from Example 510A and 323 μΐ (2.41 mmol) of trimethylsilyl isocyanate, 243 mg (71% of theory, 97% of purity) the title compound.

'H-NMR (500 MHz, DMSO-de, δ / ppm): 8.91 (br.s, 1H), 6.17 (br.s, 2H), 5.06-4.14 (m, 2H), 4.06- 3.91 (m, 2H), 3.61 (t, 2H), 3.24 (s, 3H), 2.31 (s, 3H), 2.25 (dt, 1H), 1.38 (br, s, 9H), 1.15 (d, 3H), 1.01-0.90 (m, 1H), 0.88-0.76 (m, 2H).

LC / MS (Method 1, ESIpos): R _t = 1.50 min, m / z = 482.21 [M + H] ⁺ . Example 525A tert. Butyl 2-carbamoyl-2- ({1 - [(2,2-difluorocyclopropyl) methyl] -5-methyl-3 - [(S, 2S) -2-methylcyclopropyl] -2,4-dioxo l, 2,3,4-tetrahydrothieno [2,3-d] pyrimidin-6-yl} methyl) hydrazinecarboxylate

(Mixture of diastereomers)

Analogously to the process described under Example 518A, 395 mg (quant., 84% purity) of the title compound were prepared from 345 mg (0.638 mmol, 87% purity) of the compound from Ex. 511A and 171 μΐ (1.28 mmol) of trimethylsilyl isocyanate.

LC / MS (Method 1, ESIpos): R _t = 1.71 min, m / z = 514.19 [M + H] ⁺ .

Example 526A tert. Butyl 2-carbamoyl-2- ({1 - (cyclobutylmethyl) -5-methyl-3 - [(S, 2S) -2-methylcyclopropyl] -2,4-dioxo-1,2,3,4-tetrahydrothieno [2,3-d] pyrimidin-6-yl} methyl) hydrazinecarboxylate

Analogously to the process described in Example 523A, from 270 mg (0.554 mmol, 92% purity) of the compound from Example 512A and 149 μΐ (1.11 mmol) of trimethylsilyl isocyanate were added 281 mg (92% of theory, 89% purity) of the title compound produced. 'H-NMR (500 MHz, DMSO-d _6, δ / ppm): (br. S, 1H) (br. S, 2H) 8.90, 6.17, 4.97-4.19 (m, 2H), 3.96- 3.83 (m , 2H), 2.82-2.69 (m, 1H), 2.31 (s, 3H), 2.25 (dt, 1H), 2.02-1.90 (m, 2H), 1.87-1.74 (m, 4H), 1.38 (see also p , 9H), 1.15 (d, 3H), 0.98-0.88 (m, 1H), 0.87-0.73 (m, 2H).

LC / MS (Method 1, ESIpos): R _t = 1.84 min, m / z = 492.23 [M + H] ⁺ .

Example 527A tert. Butyl 2-carbamoyl-2- ({1 - [(3,3-difluorocyclobutyl) methyl] -5-methyl-3 - [(7S, 2S) -2-methylcyclopropyl] -2,4-dioxo 1, 2,3, 4-tetrahydrothieno [2,3-d] pyrimidin-6-yl} methyl) hydrazinecarboxylate

Analogously to the process described under Example 521A, from 325 mg (0.590 mmol, 87% purity) of the compound from Example 513A and 277 μM (2.07 mmol) of trimethylsilyl isocyanate, 289 mg (92% of theory) of the title compound were prepared ,

'H-NMR (500 MHz, DMSO-de, δ / ppm): 8.90 (br, s, 1H), 6.18 (br, s, 2H), 4.95-4.21 (m, 2H), 4.09- 3.96 (m, 2H), 2.72-2.57 (m, 3H), 2.56-2.45 (m, 2H, partially covered by the DMSO signal), 2.31 (s, 3H), 2.25 (dt, 1H), 1.38 (brs s, 9H) , 1.15 (d, 3H), 1.00-0.90 (m, 1H), 0.87-0.74 (m, 2H). LC / MS (Method 1, ESIpos): R _t = 1.77 min, m / z = 528.21 [M + H] ⁺ . Example 528A tert -Butyl 2-carbamoyl-2 - ({5-methyl-3 - [(S, 2S) -2-methylcyclopropyl] -2,4-dioxo-l - [(2R) -tetrahydrofuran 2-ylmethyl] -l, 2,3,4-tetrahydrothieno [2,3-d] pyrimidin-6-yl} methyl) hydrazinecarboxylate

Analogously to the process described under Example 518A, from 105 mg (0.158 mmol, 70% purity) of the compound from Ex. 514A and 61 μΐ (0.452 mmol) of trimethylsilyl isocyanate 172 mg (quant., 65% purity) of the title compound were obtained.

LC / MS (Method 1, ESIneg): R _t = 1.61 min, m / z = 506.21 [MH] -

EXAMPLES

example 1

3-Cyclopropyl-l, 5-dimethyl-6 - [(2-oxoimidazolidin-1-yl) methyl] thieno [2,3-d] pyrimidine-2,4 (1H, 3H) -dione

A solution of 290 mg (0.752 mmol, 80% purity) of the compound from Example 100A and 157 μΐ (1.13 mmol) of triethylamine in 8 ml of THF was admixed with 146 mg (0.903 mmol) of NN'-carbonyldiimidazole (CDI) and ca. Stirred at RT for 16 h. It was then concentrated to dryness. The remaining residue was taken up in ethyl acetate and washed successively with 1 M hydrochloric acid, water, saturated sodium bicarbonate solution and saturated sodium chloride solution. After drying over anhydrous magnesium sulfate, it was filtered and concentrated. The solid residue was prepurified by preparative HPLC (Method 11). Evaporation of the product fractions was followed by a second normal phase chromatography (MPLC, Biotage Isolera One, cartridge SNAP KP-Sil, 10 g silica gel, eluent ethyl acetate). The product fractions were combined, concentrated and dried under high vacuum. There were 37 mg (14%) d. Th.) Of the title compound.

Ή-NMR (400 MHz, DMSO-de, δ / ppm): 6.51 (s, 1H), 4.34 (s, 2H), 3.37 (s, 3H), 3.27-3.16 (m, 4H), 2.58 (tt, 1H), 2.38 (s, 3H), 1.05-0.95 (m, 2H), 0.71-0.63 (m, 2H).

LC / MS (Method 1, ESIpos): R _t = 1.05 min, m / z = 335.12 [M + H] ⁺ . Example 2

3-Cyclopropyl-l, 5-dimethyl-6 - [(5-oxo-4,5-dihydro-1H-l, 2,4-triazol-1-yl) methyl] thieno [2,3-d] pyrimidine -2,4 (lH, 3H) -dione

130 mg (0.307 mmol) of the compound from Ex. 244A were dissolved in a mixture of 10 ml each of methanol and trimethyl orthoformate and treated at RT with 767 .mu.l (3.07 mmol) of a 4 M solution of hydrogen chloride in dioxane. After 2 days, the reaction mixture was evaporated and the residue taken up in ethyl acetate. It was washed successively with water and saturated sodium chloride solution. After drying over anhydrous magnesium sulfate, it was filtered and concentrated again. The remaining residue was purified by preparative HPLC (Method 11). Evaporation of the product fractions and drying under high vacuum gave 50 mg (48% of theory) of the title compound.

'H-NMR (400 MHz, DMSO-de, δ / ppm): 11.58 (br.s, 1H), 7.83 (s, 1H), 4.93 (s, 2H), 3.36 (s, 3H), 2.61-2.55 (m, 1H), 2.44 (s, 3H), 1.09-0.89 (m, 2H), 0.74-0.58 (m, 2H).

LC / MS (Method 1, ESIpos): R _t = 0.95 min, m / z = 334.10 [M + H] ⁺ .

Example 3 1-Butyl-3-cyclopropyl-5-methyl-6 - [(2-oxoimidazolidin-1-yl) methyl] thieno [2,3-d] pyrimidine-2,4 (1H, 3H) -dione

A solution of 250 mg (0.642 mmol, 90%> purity) of the compound from Example 101A and 134 μM (0.963 mmol) of triethylamine in 7 ml of THF was treated with 125 mg (0.770 mmol) of CDI and stirred at RT for about 16 h , It was then concentrated to dryness. The remaining residue was taken up in ethyl acetate and washed successively with 1 M hydrochloric acid, water, saturated sodium bicarbonate solution and saturated sodium chloride solution. After drying over anhydrous magnesium sulfate, it was filtered and concentrated. The solid residue was purified by preparative HPLC (Method 11). Evaporation of the product fractions and drying under high vacuum gave 132 mg (54% of theory) of the title compound.

Ή-NMR (400 MHz, DMSO-de, δ / ppm): 6.51 (s, 1H), 4.34 (s, 2H), 3.81 (t, 2H), 3.27-3.16 (m, 4H), 2.63-2.55 ( m, 1H), 2.38 (s, 3H), 1.63 (quin, 2H), 1.33 (sec, 2H), 1.05-0.96 (m, 2H), 0.91 (t, 3H), 0.72-0.62 (m, 2H) , LC / MS (Method 1, ESIpos): R _t = 1.46 min, m / z = 377.16 [M + H] ⁺ . Example 4 1-Butyl-3-cyclopropyl-5-methyl-6 - [(5-oxo-4,5-dihydro-1H-1,2,4-triazol-1-yl) methyl] thieno [2,3- d] - pyrimidine-2,4 (1H, 3H) -dione

Analogously to the process described under Example 2, 177 mg (68% of theory) of the title compound were prepared from 375 mg (0.685 mmol, 85% purity) of the compound from Example 245A.

Ή-NMR (400 MHz, DMSO-de, δ / ppm): 11.58 (br.s, 1H), 7.83 (s, 1H), 4.92 (s, 2H), 3.80 (br.t, 2H), 2.62- 2.56 (m, 1H), 2.43 (s, 3H), 1.62 (quin, 2H), 1.32 (sec, 2H), 1.05-0.94 (m, 2H), 0.90 (t, 3H), 0.71-0.61 (m, 2H).

LC / MS (Method 1, ESIpos): R _t = 1.37 min, m / z = 376.14 [M + H] ⁺ .

Example 5

3-Cyclopropyl-1- (3-fluoro-propyl) -5-methyl-6 - [(2-oxo-imidazolidin-1-yl) methyl] thieno [2,3-d] pyrimidine-2,4 (1H, 3H) - dion

225 mg (0.451 mmol) of the compound from Ex. 102A were dissolved in 20 ml of dioxane and admixed with 113 mg (0.676 mmol) of CDI. The mixture was stirred at RT for 19 h. The reaction solution was then concentrated on a rotary evaporator. The residue was dissolved in 3 ml of DMSO and this solution was purified by preparative HPLC (Method 14). After combining the product fractions and freeze-drying, 102 mg (58% of theory) of the title compound were obtained. 'H-NMR (400 MHz, DMSO-de, δ / ρρηι): 6.54 (s, 1H), 4.58 (t, 1H), 4.46 (t, 1H), 4.34 (s, 2H), 3.93 (t, 2H ), 3.27-3.16 (m, 4H), 2.62-2.54 (m, 1H), 2.38 (s, 3H), 2.11-1.96 (m, 2H), 1.03-0.96 (m, 2H), 0.70-0.63 (m , 2H).

LC / MS (Method 4, ESIpos): R _t = 0.84 min, m / z = 381 [M + H] ⁺ . Example 6

3-Cyclopropyl-1- (3-fluoropropyl) -5-methyl-6 - [(2-thioxoimidazolidin-1-yl) methyl] thieno [2,3-d] pyrimidine-2,4 (1H, 3H) - dion

120 mg (0.24 mmol) of the compound from Ex. 102A were dissolved in 15 ml of dioxane and treated with 68 mg (0.361 mmol) of Ι, Γ-thiocarbonyldiimidazole. The mixture was stirred at RT for 19 h. The reaction solution was concentrated on a rotary evaporator. The residue was dissolved in 3 ml of DMSO and this solution was purified by preparative HPLC (Method 14). After combining the product fractions and freeze-drying, 40 mg (40% of theory) of the title compound were obtained.

Ή-NMR (400 MHz, DMSO-de, δ / ppm): 8.35 (s, 1H), 4.82 (s, 2H), 4.58 (t, 1H), 4.46 (t, 1H), 3.93 (t, 2H) , 3.56-3.48 (m, 2H), 3.43-3.36 (m, 2H), 2.62-2.55 (m, 1H), 2.42 (s, 3H), 2.11 -1.96 (m, 2H), 1.03-0.96 (m, 2H), 0.70-0.63 (m, 2H).

LC / MS (Method 4, ESIpos): R _t = 0.94 min, m / z = 397 [M + H]

Example 7

[1- {[3-Cyclopropyl-1- (3-fluoropropyl) -5-methyl-2,4-dioxo-1,2,3,4-tetrahydrothieno [2,3-d] pyrimidin-6-yl] methyl} imidazolidine-2-ylidene] cyanamide

120 mg (0.24 mmol) of the compound from Ex. 102A were dissolved in 5 ml of DMF, and 56 mg (0.361 mmol) of dimethyl N-cyanodithioiminocarbonate and 67 mg (0.481 mmol) of potassium carbonate were added. The mixture was stirred at 80 ° C for 19 h. Subsequently, 30 ml of ethyl acetate were added. It was washed with saturated aqueous sodium bicarbonate solution and water. The organic phase was dried over anhydrous sodium sulfate, filtered and concentrated. The residue was dissolved in 3 ml of DMSO and this solution was purified by preparative HPLC (Method 14). After combining the product fractions and freeze-drying, 40 mg (40% of theory) of the title compound were obtained. Ή-NMR (400 MHz, DMSO-d ₆ , δ / ppm): 8.08 (s, 1H), 4.58 (t, 1H), 4.50-4.44 (m, 3H), 3.94 (t, 2H), 3.48-3.37 (m, 4H), 2.62-2.55 (m, 1H), 2.39 (s, 3H), 2.12-1.97 (m, 2H), 1.03-0.96 (m, 2H), 0.70-0.63 (m, 2H).

LC / MS (Method 4, ESIpos): R _t = 0.90 min, m / z = 405 [M + H]

Example 8

3-Cyclopropyl-6- [(2,3-dioxopiperazin-1-yl) methyl] -1- (3-fluoropropyl) -5-methylthieno

pyrimidine-2,4 (lH, 3H) -dione

120 mg (0.24 mmol) of the compound from Ex. 102A were dissolved in 5 ml of ethanol and admixed with 335 mg (2.4 mmol) of diethyl oxalate. The mixture was stirred at 80 ° C for 19 h. Thereafter, the reaction solution was concentrated on a rotary evaporator and the residue was dissolved in 30 ml of dichloromethane. It was washed with water and saturated sodium bicarbonate solution. The organic phase was dried over sodium sulfate, filtered and concentrated. Of the The residue obtained was dissolved in 3 ml of DMSO and this solution was purified by preparative HPLC (Method 14). After combining the product fractions and freeze-drying, 5 mg (5% of theory) of the title compound were obtained.

'H-NMR (400 MHz, DMSO-de, δ / ppm): 8.64 (br.s, 1H), 4.68 (s, 2H), 4.58 (t, 1H), 4.46 (t, 1H), 3.93 (t , 2H), 3.50-3.44 (m, 2H), 3.32-3.27 (m, 2H), 2.62-2.54 (m, 1H), 2.42 (s, 3H), 2.12-1.95 (m, 2H), 1.04-0.96 (m, 2H), 0.70-0.63 (m, 2H).

LC / MS (Method 4, ES Ineg): R _t = 0.76 min, m / z = 453 [M-H + HCO 2 H] ^" .

Example 9

3-Cyclopropyl-5-methyl-6- [(2-oxoimidazolidin-1-yl) methyl] -1- (3,3,3-trifluoropropyl) thieno-pyrimidine-2,4 (1H, 3H) -dione

Analogously to Ex. 5, 205 mg (0.42 mmol) of the compound from Ex. 103A in 20 ml of dioxane were reacted with 105 mg (0.63 mmol) of CDI. 116 mg (65% of theory) of the title compound were obtained. Ή-NMR (400 MHz, DMSO-d ₆ , δ / ppm): 6.55 (s, 1H), 4.35 (s, 2H), 4.05 (t, 2H), 3.28-3.16 (m, 4H), 2.80-2.68 (m, 2H), 2.59 (t, 1H), 2.38 (s, 3H), 1.05-0.96 (m, 2H), 0.70-0.63 (m, 2H).

LC / MS (Method 4, ESIpos): R _t = 0.95 min, m / z = 417 [M + H] ⁺ .

Example 10

3-Cyclopropyl-5-methyl-6- [(2-thioxoimidazolidin-1-yl) methyl] -1- (3,3,3-trifluoropropyl) thieno [2,3-d] pyrimidine-2,4 ( lH, 3H) -dione

Analogously to Ex. 6, 130 mg (0.266 mmol) of the compound from Ex. 103A in 15 ml of dioxane were reacted with 75 mg (0.4 mmol) of Ι, Γ-thiocarbonyldiimidazole. 56 mg (48% of theory) of the title compound were obtained. Ή-NMR (400 MHz, DMSO-d _6, δ / ppm): 8:36 (s, 1H), 4.83 (s, 2H), 4:05 (t, 2H), 3:57 to 3:47 (m, 2H), 3:45 to 3:36 (m, 2H), 2.82-2.68 (m, 2H), 2.64-2.56 (m, 1H), 2.42 (s, 3H), 1.05-0.96 (m, 2H), 0.71-0.63 (m, 2H).

LC / MS (Method 4, ESIpos): R _t = 1.05 min, m / z = 433 [M + H] ⁺ .

Example 11 [1- {[3-Cyclopropyl-5-methyl-2,4-dioxo-l- (3,3,3-trifluoropropyl) -l, 2,3,4-tetrahydrothieno [2,3-d] - pyrimidin-6-yl] methyl} imidazolidine-2-ylidene] cyanamide

130 mg (0.266 mmol) of the compound from Ex. 103A were dissolved in 5 ml of DMF, and 62 mg (0.4 mmol) of dimethyl N-cyanodithioiminocarbonate and 74 mg (0.649 mmol) of potassium carbonate were added. The mixture was stirred at 80 ° C for 19 h. Subsequently, 30 ml of ethyl acetate were added. It was washed with saturated aqueous sodium bicarbonate solution and water. The organic phase was dried over anhydrous sodium sulfate, filtered and concentrated. The residue was dissolved in 3 ml of DMSO and this solution was purified by preparative HPLC (Method 14). After combining the product fractions and freeze-drying, 46 mg (38% of theory) of the title compound were obtained. 'H-NMR (400 MHz, DMSO-de, δ / ρρηι): 8.10 (s, 1H), 4.48 (s, 2H), 4.06 (t, 2H), 3.49-3.37 (m, 4H), 2.81-2.69 (m, 2H), 2.59 (t, 1H), 2.39 (s, 3H), 1.05-0.97 (m, 2H), 0.70-0.63 (m, 2H).

LC / MS (Method 4, ESIpos): R _t = 1.0 min, m / z = 441 [M + H] ⁺ . Example 12 Methyl [1- {[3-cyclopropyl-5-methyl-2,4-dioxo-l- (3,3,3-trifluoropropyl) -l, 2,3,4-tetrahydrothieno [2,3- d] pyrimidin-6-yl] methyl} imidazolidine-2-ylidene] carbamate

310 mg (0.556 mmol, 70% purity) of the compound of Ex. 103A and 155 μΐ (1.11 mmol) of triethylamine were dissolved in 10 ml of dichloromethane and treated dropwise with a solution of 173 mg (1.11 mmol) of methyl (dichloromethylene) carbamate in 5 ml of dichloromethane. After the reaction mixture was stirred at RT for about 18 h, it was concentrated to dryness. The residue was stirred with a little acetonitrile at RT. The solid was filtered off with suction and discarded. The filtrate was evaporated and the residue was prepurified by preparative HPLC (Method 11). The product fraction obtained was subsequently purified a second time by preparative HPLC (column: Kinetex C18, 5 μm, 100 mm × 30 mm, eluent A: water + 0.07% formic acid, eluent B: acetonitrile, gradient: 0.0-2.0 min 10% B, 2.2 min 20% B, 7.0 min 60% B, 7.5-9.0 min 92% B, flow: 70 ml / min, temperature: 25 ° C, detection: 210 nm). Concentration of the product fraction and drying of the residue in a high vacuum gave 46 mg (17% of theory) of the title compound. Ή-NMR (400 MHz, DMSO-d _6, δ / ppm): 8:02 (s, 1H), 4:56 (s, 2H), 4:04 (t, 2H), 3:53 (s, 3H), 3.49- 3:41 (m , 2H), 3.36-3.28 (m, 2H, partially covered by the water signal), 2.81-2.65 (m, 2H), 2.63- 2.56 (m, 1H), 2.41 (s, 3H), 1.05-0.96 (m, 2H ), 0.74-0.61 (m, 2H).

LC / MS (Method 1, ESIpos): R _t = 1.39 min, m / z = 474.14 [M + H] ⁺ . Example 13

3-Cyclopropyl-6- [(2,3-dioxopiperazin-1-yl) methyl] -5-methyl-1- (3,3,3-trifluoropropyl) thieno-pyrimidine-2,4 (1H, 3H) -dione

130 mg (0.266 mmol) of the compound from Ex. 103A were dissolved in 5 ml of ethanol and admixed with 393 mg (2.66 mmol) of diethyl oxalate. The mixture was stirred at 80 ° C for 19 h. Thereafter, the reaction solution was concentrated on a rotary evaporator and the residue was dissolved in 30 ml of dichloromethane. It was washed with water and saturated sodium bicarbonate solution. The organic phase was dried over sodium sulfate, filtered and concentrated. The residue obtained was dissolved in 3 ml of DMSO and this solution was purified by preparative HPLC (Method 14). After combining the product fractions and freeze-drying, 34 mg (27% of theory) of the title compound were obtained.

Ή-NMR (400 MHz, DMSO-de, δ / ppm): 8.64 (br.s, 1H), 4.69 (s, 2H), 4.05 (t, 2H), 3.51 -3.45 (m, 2H), 3.32- 3.27 (m, 2H), 2.81-2.68 (m, 2H), 2.63-2.55 (m, 1H), 2.42 (s, 3H), 1.05-0.97 (m, 2H), 0.70-0.63 (m, 2H).

LC / MS (Method 4, ES Ineg): R _t = 0.86 min, m / z = 489 [M-H + HCO 2 H] ^" .

Example 14

3-Cyclopropyl-5-methyl-6- [(2-oxo-2,3-dihydro-1H-imidazol-1-yl) methyl] -1- (3,3,3-trifluoropropyl) thieno [2,3 -d] pyrimidine-2,4 (lH, 3H) -dione

A solution of 629 mg (0.93 mmol, 71% purity) of the compound from Ex. 153A in a mixture of 1.9 ml of water and 10 ml of methanol was admixed with 1.9 ml (0.92 mmol) of 0.5 M hydrochloric acid. After the reaction mixture had been stirred at RT for 40 h, it was fractionated directly into its components by preparative HPLC (Method 13). Evaporation and drying of the product fraction under high vacuum gave 167 mg (43% of theory) of the title compound.

'H-NMR (400 MHz, DMSO-de, δ / ppm): 9.99 (s, 1H), 6.43 (dd, 1H), 6.34 (dd, 1H), 4.79 (s, 2H), 4.03 (dd, 2H ), 2.78-2.65 (m, 2H), 2.61-2.58 (m, 1H), 2.45 (s, 3H), 1.03-0.98 (m, 2H), 0.68-0.64 (m, 2H).

LC / MS (Method 1, ES Ineg): R _t = 1.31 min, m / z = 413 [MH] ^" . Example 15

3-cyclopropyl-5-methyl-6 - [(5-oxo-4,5-dihydro-lH-l, 2,4-triazol-l-yl) methyl] -l- (3,3,3-trifluoro propyl) thieno [2,3-d] pyrimidine-2,4 (lH, 3H) -dione

181 mg (0.301 mmol, 84% purity) of the compound from Ex. 246A were dissolved in a mixture of 7.5 ml each of methanol and trimethyl orthoformate and treated at RT with 752 .mu.l (3.01 mmol) of a 4 M solution of hydrogen chloride in dioxane. After 2 days, another 371 μΐ (1.50 mmol) of the 4 M solution of hydrogen chloride in dioxane was added. After another day, the reaction mixture was added with water and extracted with ethyl acetate. The organic extract was concentrated and the residue obtained was purified by preparative HPLC (Method 11). After evaporation of the product fractions and drying in a high vacuum, 99 mg (79%) d. Th.) Of the title compound.

Ή-NMR (500 MHz, DMSO-de, δ / ppm): 11.59 (br.s, 1H), 7.83 (s, 1H), 4.94 (s, 2H), 4.04 (t, 2H), 2.79-2.66 ( m, 2H), 2.64-2.55 (m, 1H), 2.44 (s, 3H), 1.09-0.92 (m, 2H), 0.78-0.58 (m, 2H).

LC / MS (Method 1, ESIpos): R _t = 1.29 min, m / z = 416.10 [M + H] Example 16

3-Cyclopropyl-5-methyl-6- [(2-oxoimidazolidin-1-yl) dideuteromethyl] -1- (3,3,3-trifluoropropyl) thieno [2,3-d] pyrimidine-2,4 ( lH, 3H) -dione

A solution of 286 mg (3.32 mmol) of imidazolidin-2-o in 8 ml of DMF was treated with 133 mg (3.32 mmol) of sodium hydride (60% suspension in mineral oil), then heated to 60 ° C for 5 min and then cooled again to RT ("Solution 1"). In another reaction vessel, a solution of 291 mg (0.831 mmol) of the compound from Ex. 292A in 6 ml of dichloromethane at 0 ° C. with 289 μΐ (1.66 mmol) of N, N-diisopropylethylamine and 64 μΐ (0.872 mmol) of thionyl chloride was added. puts. After 20 min at 0 ° C, the solution 1 was added portionwise. The reaction mixture was then stirred for 2.5 days at RT. Thereafter, it was mixed with water and extracted with ethyl acetate. The organic extract was washed with water and saturated sodium chloride solution. After drying over anhydrous magnesium sulfate, it was filtered and concentrated. The remaining residue was first prepurified by means of MPLC (Instrument Biotage Isolera One, cartridge SNAP KP-Sil, 25 g of silica gel, mobile phase cyclohexane / ethyl acetate 1: 1 ^→ dichloromethane / methanol 10: 1). The still contaminated product fraction was subsequently purified by preparative HPLC (Method 11). Evaporation of the product fractions and drying under high vacuum gave 164 mg (47% of theory) of the title compound.

Ή NMR (400 MHz, DMSO-de, δ / ppm): 6.52 (s, 1H), 4.05 (t, 2H), 3.28-3.16 (m, 4H), 2.81-2.66 (m, 2H), 2.60 ( t, 1H), 2.38 (s, 3H), 1.08-0.93 (m, 2H), 0.74-0.60 (m, 2H).

LC / MS (Method 1, ESIpos): R _t = 1.38 min, m / z = 419.13 [M + H] ⁺ .

Example 17 1- (Cyclobutylmethyl) -3-cyclopropyl-5-methyl-6 - [(2-oxoimidazolidin-1-yl) methyl] thieno [2,3-d] pyrimidine-2,4 (1H, 3H) - dion

A solution of 240 mg (0.616 mmol, 93% purity) of the compound of Ex. 104A and 129 μM (0.924 mmol) of triethylamine in 7 ml of THF was admixed with 120 mg (0.739 mmol) of CDI and stirred at RT for about 16 h. It was then concentrated to dryness. The remaining residue was taken up in ethyl acetate and washed successively with water and saturated sodium chloride solution. After drying over anhydrous magnesium sulfate, it was filtered and concentrated. The solid residue was purified by preparative HPLC (Method 11). The product fractions were combined, evaporated and dried under high vacuum. There were 147 mg (61) d. Th.) Of the title compound. 'H-NMR (400 MHz, DMSO-d _6, δ / ppm): 6:51 (s, 1H), 4:33 (s, 2H), 3.88 (d, 2H), 3:28 to 3:14 (m, 4H), 2.81 - 2.67 (m, 1H), 2.63-2.55 (m, 1H), 2.37 (s, 3H), 2.05-1.89 (m, 2H), 1.87-1.72 (m, 4H), 1.08-0.92 (m, 2H), 0.75-0.59 (m, 2H).

LC / MS (Method 1, ESIpos): R _t = 1.50 min, m / z = 389.16 [M + H] ⁺ . Example 18 1- (Cyclobutylmethyl) -3-cyclopropyl-5-methyl-6 - [(5-oxo-4,5-dihydro-1H-1,2,4-triazol-1-yl) methyl] thieno [2 , 3-d] pyrimidine-2,4 (lH, 3H) -dione

Analogously to the process described under Example 2, 373 mg (64% of theory) of the title compound were prepared from 370 mg (0.775 mmol) of the compound from Example 247A.

'H-NMR (400 MHz, DMSO-de, δ / ppm): 11.58 (s, 1H), 7.83 (s, 1H), 4.91 (s, 2H), 3.87 (d, 2H), 2.80-2.65 (m , 1H), 2.63-2.55 (m, 1H), 2.43 (s, 3H), 2.04-1.88 (m, 2H), 1.87-1.71 (m, 4H), 1.09-0.89 (m, 2H), 0.75-0.56 (m, 2H). LC / MS (Method 1, ESIpos): R _t = 1.42 min, m / z = 388.14 [M + H] ⁺ . Example 19

3-Cyclopropyl-l - [(2,2-difluorocyclopropyl) methyl] -5-methyl-6 - [(2-oxoimidazolidin-1-yl) methyl] thieno [2,3-d] pyrimidine-2,4 ( 1H, 3H) -dione {racemate)

Analogously to the process described in Example 3, 495 mg (1.19 mmol, 92% purity) of the compound from Ex. 105A and 230 mg (1.42 mmol) of CDI were used to produce 254 mg (52% of theory) of the title compound.

'H-NMR (400 MHz, DMSO-de, δ / ppm): 6.52 (s, 1H), 4.35 (s, 2H), 4.13-4.00 (m, 1H), 3.90 (dd, 1H), 3.28-3.16 (m, 4H), 2.60 (t, 1H), 2.38 (s, 3H), 2.26-2.10 (m, 1H), 1.75-1.62 (m, 1H), 1.51-1.38 (m, 1H), 1.05-0.96 (m, 2H), 0.73-0.64 (m, 2H).

LC / MS (Method 1, ESIpos): R _t = 1.36 min, m / z = 411.13 [M + H] ⁺ .

Example 20

3-Cyclopropyl-l - [(2,2-difluorocyclopropyl) methyl] -5-methyl-6 - [(5-oxo-4,5-dihydro-1H-l, 2,4-triazol-1-yl) methyl ] thieno [2,3-d] pyrimidine-2,4 (1H, 3H) -dione (racemate)

Analogously to the process described in Example 2, 655 mg (1.22 mmol, 93% purity) of the compound from Ex. 248A were used to produce 380 mg (76% of theory) of the title compound. 'H-NMR (400 MHz, DMSO-de, δ / ρρηι): 11.59 (s, 1H), 7.83 (s, 1H), 4.93 (s, 2H), 4.13-4.02 (m, 1H), 3.87 (dd , 1H), 2.64-2.56 (m, 1H), 2.44 (s, 3H), 2.24-2.08 (m, 1H), 1.77-1.59 (m, 1H), 1.52- 1.36 (m, 1H), 1.07-0.92 (m, 2H), 0.74-0.60 (m, 2H).

LC / MS (Method 2, ESIpos): R _t = 0.70 min, m / z = 410 [M + H] ⁺ . Example 21

3-Cyclopropyl-l - [(2,2-difluorocyclopropyl) methyl] -5-methyl-6 - [(5-oxo-4,5-dihydro-1H-l, 2,4-triazol-1-yl) methyl ] thieno [2,3-d] pyrimidine-2,4 (1H, 3H) -dione {enantiomer 1)

372 mg of the racemic compound from Example 20 were dissolved in a mixture of 5 ml of ethanol and 5 ml of dioxane and separated in 20 portions by preparative HPLC on a chiral phase into the enantiomers [column: Daicel Chiralcel, 5 μm, 250 mm × 20 mm; Eluent: n-heptane / ethanol 1: 1; Flow: 15 ml / min; Temperature: 25 ° C; Detection: 210 nm]. Evaporation of the product fractions and drying of the solid in a high vacuum gave 171 mg (91% of theory) of enantiomer 1 (98.6% ee, chiral analytical HPLC). Ή-ΝΜΡ (400 MHz, DMSO-d ₆ , δ / ppm): 11.58 (brs s, 1H), 7.82 (s, 1H), 4.93 (s, 2H), 4.13-4.01 (m, 1H), 3.87 (dd, 1H), 2.60 (t, 1H), 2.44 (s, 3H), 2.24-2.08 (m, 1H), 1.75-1.60 (m, 1H), 1.52-1.37 (m, 1H), 1.07-0.94 (m, 2H), 0.72-0.61 (m, 2H).

Chiral analytical HPLC [column: Phenomenex cellulose, 3 μm, 50 mm × 4.6 mm; Mobile phase: isohexane / ethanol 1: 1; Flow: 1 ml / min; Temperature: 25 ° C; Detection: 220 nm]: R _t = 1.33 min. Example 22

3-Cyclopropyl-l - [(2,2-difluorocyclopropyl) methyl] -5-methyl-6 - [(5-oxo-4,5-dihydro-1H-l, 2,4-triazol-1-yl) methyl ] thieno [2,3-d] pyrimidine-2,4 (1H, 3H) -dione {enantiomer 2)

372 mg of the racemic compound from Example 20 were dissolved in a mixture of 5 ml of ethanol and 5 ml of dioxane and separated in 20 portions by preparative HPLC on a chiral phase into the enantiomers [column: Daicel Chiralcel, 5 μm, 250 mm × 20 mm; Eluent: n-heptane / ethanol 1: 1; Flow: 15 ml / min; Temperature: 25 ° C; Detection: 210 nm]. Evaporation of the product fractions and drying of the solid in a high vacuum gave 166 mg (89% of theory) of enantiomer 2 (99.1% ee, chiral analytical HPLC).

Ή-ΝΜΡ (400 MHz, DMSO-d ₆ , δ / ppm): 11.59 (br.s, 1H), 7.82 (s, 1H), 4.93 (s, 2H), 4.15-4.00 (m, 1H), 3.87 (dd, 1H), 2.64-2.56 (m, 1H), 2.44 (s, 3H), 2.23-2.08 (m, 1H), 1.75-1.61 (m, 1H), 1.51-1.38 (m, 1H), 1.05 -0.94 (m, 2H), 0.72-0.63 (m, 2H).

Chiral analytical HPLC [column: Phenomenex cellulose, 3 μm, 50 mm × 4.6 mm; Mobile phase: isohexane / ethanol 1: 1; Flow: 1 ml / min; Temperature: 25 ° C; Detection: 220 nm]: R _t = 1.85 min.

Example 23

{3-Cyclopropyl-5-methyl-2,4-dioxo-6 - [(5-oxo-4,5-dihydro-lH-l, 2,4-triazol-l-yl) methyl] -3,4- dihydrothieno [2,3-d] pyrimidin-l (2H) -yl} acetonitrile

Analogously to the process described under Example 2, 230 mg (0.487 mmol, 95% purity) of the compound from Ex. 249A were used to prepare 110 mg (63% of theory) of the title compound.

'H-NMR (400 MHz, DMSO-de, δ / ppm): 11.61 (br.s, 1H), 7.84 (s, 1H), 5.07 (s, 2H), 4.97 (s, 2H), 2.66-2.57 (m, 1H), 2.45 (s, 3H), 1.10-0.92 (m, 2H), 0.77-0.62 (m, 2H).

LC / MS (Method 1, ESIpos): R _t = 0.98 min, m / z = 359.09 [M + H] ⁺ . Example 24

3-Cyclopropyl-1- (2-methoxyethyl) -5-methyl-6 - [(2-oxoimidazolidin-1-yl) methyl] thieno-pyrimidine-2,4 (1H, 3H) -dione

138 mg (0.223 mmol) of the compound from Example 106A were dissolved in 15 ml of dioxane and admixed with 56 mg (0.335 mmol) of CDI. The mixture was stirred at RT for 15 h. The reaction solution was then concentrated on a rotary evaporator. The residue was dissolved in 3 ml of DMSO and this solution was purified by preparative HPLC (Method 14). After combining the product fractions and freeze-drying, 53 mg (62% of theory) of the title compound were obtained. Ή-NMR (400 MHz, DMSO-d ₆ , δ / ppm): 6.53 (s, 1H), 4.33 (s, 2H), 3.97 (t, 2H), 3.60 (t, 2H), 3.27- 3.15 (m , 7H), 2.59 (t, 1H), 2.36 (s, 3H), 1.03-0.96 (m, 2H), 0.70-0.63 (m, 2H).

LC / MS (Method 4, ESIpos): R _t = 0.80 min, m / z = 379 [M + H] ⁺ .

Example 25

[1- {[3-Cyclopropyl-1- (2-methoxyethyl) -5-methyl-2,4-dioxo-1,2,3,4-tetrahydrothieno [2,3-d] pyrimidin-6-yl] methyl} imidazolidine-2-ylidene] cyanamide

145 mg (0.267 mmol) of the compound from Example 106A were dissolved in 5 ml of DMF, and 62 mg (0.4 mmol) of dimethyl N-cyanodithioiminocarbonate and 73.9 mg (0.534 mmol) of potassium carbonate were added. The mixture was stirred at 80 ° C for 19 h. Subsequently, 30 ml of ethyl acetate were added. It was washed with saturated aqueous sodium bicarbonate solution and water. The organic phase was dried over anhydrous sodium sulfate, filtered and concentrated. geengt. The residue was dissolved in 3 ml of DMSO and this solution was purified by preparative HPLC (Method 14). After combining the product fractions and freeze-drying, 79 mg (70% of theory) of the title compound were obtained.

'H-NMR (400 MHz, DMSO-de, δ / ppm): 8.08 (s, 1H), 4.46 (s, 2H), 3.98 (t, 2H), 3.61 (t, 2H), 3.48-3.36 (m , 4H), 3.23 (s, 3H), 2.63-2.55 (m, 1H), 2.38 (s, 3H), 1.04-0.96 (m, 2H), 0.71-0.63 (m, 2H).

LC / MS (Method 4, ESIpos): R _t = 0.86 min, m / z = 403 [M + H] ⁺ .

Example 26

Methyl [1- {[3-cyclopropyl-1- (2-methoxyethyl) -5-methyl-2,4-dioxo-1,2,3,4-tetrahydrothieno [2,3-d] pyrimidine-6- yl] methyl} imidazolidine-2-ylidene] carbamate

400 mg (0.908 mmol, 80% purity) of the compound from Example 106A and 253 μΐ (1.82 mmol) of triethylamine were dissolved in 15 ml of dichloromethane and treated dropwise with a solution of 283 mg (1.82 mmol) of methyl (dichloromethylene) carbamate in 5 ml of dichloromethane. After the reaction mixture was stirred at RT for about 18 h, it was concentrated to dryness. The residue was prepurified by preparative HPLC (Method 11). Since the product fraction was still contaminated, a second chromatography followed by MPLC (Biotage Isolera One, cartridge SNAP KP-Sil, 50 g of silica gel, eluent ethyl acetate-> dichloromethane / methanol 10: 1). Concentration of the product fraction and drying of the residue in a high vacuum gave, after stirring with acetonitrile, 92 mg (23% of theory) of the title compound. Ή NMR (400 MHz, DMSO-d ₆ , δ / ppm): 8.01 (s, 1H), 4.54 (s, 2H), 3.96 (br t, 2H), 3.60 (br t, 2H), 3.53 (s, 3H), 3.49-3.40 (m, 2H), 3.35-3.28 (m, 2H, largely masked by the water signal), 3.22 (s, 3H), 2.62-2.56 (m, 1H), 2.40 (s, 3H ), 1.03-0.97 (m, 2H), 0.70-0.65 (m, 2H).

LC / MS (Method 1, ESIpos): R _t = 1.05 min, m / z = 436.16 [M + H] Example 27

3-Cyclopropyl-6 - [(2,3-dioxopiperazin-1-yl) methyl] -1- (2-methoxyethyl) -5-methylthieno-pyrimidine-2,4 (1H, 3H) -dione

Analogously to Ex. 8, 145 mg (0.267 mmol) of the compound from Example 106A in 5 ml of ethanol were reacted with 395 mg (2.67 mmol) of diethyl oxalate. There were obtained 28 mg (25% of theory) of the title compound.

Ή-NMR (400 MHz, DMSO-de, δ / ppm): 8.63 (br.s, 1H), 4.67 (s, 2H), 3.97 (t, 2H), 3.60 (t, 2H), 3.50-3.43 ( m, 2H), 3.31-3.26 (m, 2H), 3.23 (s, 3H), 2.59 (t, 1H), 2.40 (s, 3H), 1.04-0.96 (m, 2H), 0.70-0.63 (m, 2H).

LC / MS (Method 4, ESIpos): R _t = 0.72 min, m / z = 405 [M + H] ⁺ .

Example 28

3-Cyclopropyl-1- (2-methoxyethyl) -5-methyl-6 - [(2-oxo-2,3-dihydro-1H-imidazol-1-yl) methyl] thieno [2,3-d] pyrimidine -2,4 (lH, 3H) -dione

A solution of 1.06 g (1.59 mmol, 66%> purity) of the compound from Ex. 154A in a mixture of 3.2 ml of water and 11.6 ml of methanol was treated with 3.2 ml (1.58 mmol) of 0.5 M hydrochloric acid. After the reaction mixture had been stirred at RT for 16 h, it was fractionated directly into its components by preparative HPLC (Method 13). Evaporation and drying of the product fraction under high vacuum gave 392 mg (63% of theory) of the title compound. 'H-NMR (400 MHz, DMSO-de, δ / ρρηι): 9.98 (s, 1H), 6.41 (dd, 1H), 6.33 (dd, 1H), 4.77 (s, 2H), 3.96 (dd, 2H ), 3.59 (dd, 2H), 3.17 (s, 3H), 2.62-2.56 (m, 1H), 2.43 (s, 3H), 1.02-0.97 (m, 2H), 0.69-0.64 (m, 2H).

LC / MS (Method 1, ES Ineg): R _t = 1.04 min, m / z = 375 [MH] ^" . Example 29

3-Cyclopropyl-1- (2-methoxyethyl) -5-methyl-6 - [(5-oxo-4,5-dihydro-1H-1,2,4-triazol-1-yl) methyl] thieno [2 , 3-d] pyrimidine-2,4 (lH, 3H) -dione

120 mg (0.236 mmol, 92% purity) of the compound from Ex. 250A were dissolved in a mixture of 5.6 ml each of methanol and trimethyl orthoformate and treated at RT with 590 μΐ (2.36 mmol) of a 4 M solution of hydrogen chloride in dioxane. After 1 h and after 2 h each additional 295 μΐ (1.18 mmol) of 4 M solution of hydrogen chloride in dioxane were added. After a total of 16 h, the reaction mixture was diluted with water and extracted with ethyl acetate. The organic extract was concentrated and the residue was purified by preparative HPLC (Method 11). After evaporation of the product fractions, the residue was dissolved in ethyl acetate and washed with saturated sodium bicarbonate solution. After renewed concentration and drying in a high vacuum, 42 mg (47% of theory) of the title compound were obtained.

Ή-NMR (400 MHz, DMSO-de, δ / ppm): 11.58 (br.s, 1H), 7.83 (s, 1H), 4.91 (s, 2H), 3.96 (t, 2H), 3.60 (t, 2H), 3.22 (s, 3H), 2.63-2.56 (m, 1H), 2.43 (s, 3H), 1.07-0.91 (m, 2H), 0.75-0.60 (m, 2H).

LC / MS (Method 1, ESIpos): R _t = 1.00 min, m / z = 378.12 [M + H] ⁺ .

Example 30

3-Cyclopropyl-1- (2-methoxyethyl) -5-methyl-6 - [(2-oxoimidazolidin-1-yl) dideuteromethyl] thieno [2,3-d] pyrimidine-2,4 (1H, 3H) - dion

Analogously to the process described in Example 16, from 570 mg (1.83 mmol) of the compound from Ex. 293A and 628 mg (7.30 mmol) of imidazolidin-2-one 203 mg (28% of theory, purity 97%) of the title compound produced. The reaction time was in this case about 16 h. Ή-NMR (400 MHz, DMSO-d _6, δ / ppm): 6.50 (s, 1H), 3.97 (t, 2H), 3.61 (t, 2H), 3:27 to 3:16 (m, 4H), 3.23 (s , 3H), 2.64-2.55 (m, 1H), 2.37 (s, 3H), 1.06-0.95 (m, 2H), 0.72-0.62 (m, 2H).

LC / MS (Method 1, ESIpos): R _t = 1.08 min, m / z = 381.15 [M + H] ⁺ .

Example 31

3-Cyclopropyl-1- (2-ethoxyethyl) -5-methyl-6 - [(2-oxoimidazolidin-1-yl) methyl] thieno [2,3-d] pyrimidine-2,4 (1H, 3H) - dion

A solution of 280 mg (0.611 mmol, 80%> purity) of the compound from Example 107A and 128 μM (0.917 mmol) of triethylamine in 7 ml of THF was admixed with 119 mg (0.733 mmol) of CDI and stirred at RT for about 16 h , It was then concentrated to dryness. The remaining residue was taken up in ethyl acetate and washed successively with saturated sodium bicarbonate solution and saturated sodium chloride solution. After drying over anhydrous magnesium sulfate, it was filtered and concentrated. The solid residue was stirred with a little acetonitrile at RT. The solid was filtered off with suction and dried under high vacuum. The filtrate was purified by preparative HPLC (Method 11). The product fraction was evaporated, dried under high vacuum and combined with the previously obtained solid. A total of 102 mg (42% of theory) of the title compound were obtained. 'H-NMR (400 MHz, DMSO-d _6, δ / ρρηι): 6:51 (s, 1H), 4:33 (s, 2H), 3.97 (t, 2H), 3.63 (t, 2H), 3:43 (q, 2H), 3.27-3.14 (m, 4H), 2.63-2.56 (m, 1H), 2.37 (s, 3H), 1.08-0.94 (m, 2H), 1.04 (t, 3H), 0.72-0.63 (m, 2H).

LC / MS (Method 1, ESIpos): R _t = 1.24 min, m / z = 393.16 [M + H] ⁺ . Example 32

3-Cyclopropyl-1- (2-ethoxyethyl) -5-methyl-6 - [(5-oxo-4,5-dihydro-1H-1,2,4-triazol-1-yl) methyl] thieno [2 , 3-d] pyrimidine-2,4 (lH, 3H) -dione

Analogously to the process described under Example 2, from 260 mg (0.513 mmol, 95% purity) of the compound from Ex. 251A, 123 mg (61% of theory) of the title compound were prepared.

'H-NMR (400 MHz, DMSO-d _6, δ / ppm): 11:58 (br s, 1H.), 7.82 (s, 1H), 4.91 (s, 2H), 3.95, (br t, 2H). 3.62 (t, 2H), 3.42 (q, 2H), 2.64-2.56 (m, 1H), 2.43 (s, 3H), 1.08-0.91 (m, 2H), 1.02 (t, 3H), 0.74-0.58 ( m, 2H).

LC / MS (Method 1, ESIpos): R _t = 1.12 min, m / z = 392.14 [M + H] ⁺ . Example 33

3-Cyclopropyl-1- (2-isopropoxyethyl) -5-methyl-6 - [(2-oxoimidazolidin-1-yl) methyl] thieno-pyrimidine-2,4 (1H, 3H) -dione

H ₃ Analogously to the process described under Example 3, from 242 mg (0.541 mmol, 85% purity) of the compound from Example 108A and 105 mg (0.649 mmol) of CDI, 157 mg (71% of theory) of the title compound were prepared.

'H-NMR (400 MHz, DMSO-de, δ / ppm): 6.51 (s, 1H), 4.33 (s, 2H), 4.01-3.87 (m, 2H), 3.62 (t, 2H), 3.54 (eng , 1H), 3.26-3.14 (m, 4H), 2.63-2.56 (m, 1H), 2.37 (s, 3H), 1.03-0.98 (m, 2H), 1.01 (d, 6H), 0.74-0.60 (m , 2H).

LC / MS (Method 1, ESIpos): R _t = 1.34 min, m / z = 407.17 [M + H]

Example 34

3-Cyclopropyl-1- (2-isopropoxyethyl) -5-methyl-6 - [(5-oxo-4,5-dihydro-1H-1,2,4-triazol-1-yl) -methyl] thieno [2 , 3-d] pyrimidine-2,4 (lH, 3H) -dione

Analogously to the process described under Ex. 2, 145 mg (43% of theory) of the title compound were prepared from 405 mg (0.817 mmol) of the compound from Ex. 252A.

Ή-NMR (400 MHz, DMSO-de, δ / ppm): 11.57 (br.s, 1H), 7.82 (s, 1H), 4.91 (s, 2H), 3.92 (br.t, 2H), 3.61 ( t, 2H), 3.57-3.47 (m, 1H), 2.59 (dquin, 1H), 2.43 (s, 3H), 1.03-0.96 (m, 2H), 0.99 (d, 6H), 0.72-0.56 (m, 2H).

LC / MS (Method 1, ESIpos): R _t = 1.23 min, m / z = 406.15 [M + H]

Example 35

3-Cyclopropyl-5-methyl-6 - [(2-oxoimidazolidin-1-yl) methyl] -1- [2- (trifluoromethoxy) ethyl] thieno [2,3-d] pyrimidine-2,4 (1H, 3H) -dione

A solution of 330 mg (0.650 mmol, 80% purity) of the compound of Ex. 109A and 136 μΐ (0.974 mmol) of triethylamine in 7 ml of THF was combined with 126 mg (0.779 mmol) of CDI and stirred at RT for about 16 h. It was then concentrated to dryness. The remaining residue was taken up in ethyl acetate and washed successively with 1 M hydrochloric acid, water, saturated sodium bicarbonate solution and saturated sodium chloride solution. After drying over anhydrous magnesium sulfate, it was filtered and concentrated. The solid residue was purified by preparative HPLC (Method 11). After evaporation of the product fractions and drying in a high vacuum, 105 mg (37% of theory) of the title compound were obtained. Ή-NMR (400 MHz, DMSO-d ₆ , δ / ppm): 6.52 (s, 1H), 4.37 (t, 2H), 4.34 (s, 2H), 4.15 (t, 2H), 3.27- 3.14 (m , 4H), 2.61 (tt, 1H), 2.38 (s, 3H), 1.09-0.94 (m, 2H), 0.76-0.60 (m, 2H).

LC / MS (Method 1, ESIpos): R _t = 1.43 min, m / z = 433.11 [M + H]

Example 36

3-Cyclopropyl-5-methyl-6 - [(5-oxo-4,5-dihydro-1H-l, 2,4-triazol-1-yl) methyl] -1- [2- (trifluoromethoxy) ethyl ] thieno [2,3-d] pyrimidine-2,4 (lH, 3H) -dione

360 mg (0.656 mmol, 95% purity) of the compound from Ex. 253A were dissolved in a mixture of 20.5 ml of methanol and trimethyl orthoformate and treated at RT with 1.6 ml (6.56 mmol) of a 4 M solution of hydrogen chloride in dioxane. After 2 days, the reaction mixture was concentrated and the residue taken up in ethyl acetate. It was successively washed with water and saturated sodium chloride solution. After drying over anhydrous magnesium sulfate, it was filtered and concentrated again. The remaining residue was purified by preparative HPLC (Method 11). After evaporation of the product fractions and drying in a high vacuum, 144 mg (50% of theory) of the title compound were obtained. Ή-ΝΜΡ (400 MHz, DMSO-d ₆ , δ / ppm): 11.59 (brs s, 1H), 7.83 (s, 1H), 4.93 (s, 2H), 4.36 (t, 2H), 4.13 (t , 2H), 2.60 (t, 1H), 2.44 (s, 3H), 1.09-0.92 (m, 2H), 0.74-0.60 (m, 2H).

LC / MS (Method 1, ESIpos): R _t = 1.33 min, m / z = 432.09 [M + H] ⁺ .

Crystallization: 20.7 g of the title compound resulting from a larger scale synthesis were refluxed in a mixture of 490 ml of water and 325 ml of ethanol, with the solid just completely dissolving. The heating bath was then ramped down to 70 ° C until the product began to crystallize. Thereafter, the heating bath was again raised to 75 ° C, and the suspension was stirred at this temperature for about 16 h. Subsequently, the temperature of the heating bath was gradually reduced, and it was stirred for the following periods at the indicated temperatures: 5 h 65 ° C-> 16 h 50 ° C-> 2 h 40 ° C-> 2 h 30 ° C-> 90 min RT. Thereafter, the product was filtered off, washed with 200 ml of water / ethanol (3: 2) and washed first at 10 mbar and 40 ° C for 1 h and then at RT under high vacuum. 17.7 g (85% of theory) of the title compound were obtained in crystalline form.

'H-NMR (400 MHz, DMSO-de, δ / ppm): 11.59 (br.s, 1H), 7.83 (s, 1H), 4.93 (s, 2H), 4.36 (t, 2H), 4.13 (t , 2H), 2.60 (tt, 1H), 2.44 (s, 3H), 1.09-0.93 (m, 2H), 0.74-0.59 (m, 2H). LC / MS (Method 1, ESIpos): R _t = 1.33 min, m / z = 432.09 [M + H] ⁺ .

Melting point: 199 ° C.

Example 37

3-Cyclopropyl-5-methyl-6- [(2-oxoimidazolidin-1-yl) methyl] -1- (tetrahydrofuran-2-ylmethyl) thieno [2,3-d] pyrimidine-2,4 (1H, 3H) -dione (racemate)

Analogously to Ex. 5, 300 mg (0.674 mmol) of the compound from Ex. 110A in 30 ml of dioxane were reacted with 169 mg (1.01 mmol) of CDI. 101 mg (36% of theory) of the title compound were obtained.

'H-NMR (400 MHz, DMSO-de, δ / ppm): 6.53 (s, 1H), 4.32 (s, 2H), 4.23-4.15 (m, 1H), 3.99 (dd, 1H), 3.78-3.69 (m, 1H), 3.69-3.56 (m, 2H), 3.27-3.15 (m, 4H), 2.59 (t, 1H), 2.37 (s, 3H), 2.02-1.91 (m, 1H), 1.91-1.74 (m, 2H), 1.69-1.59 (m, 1H), 1.04-0.96 (m, 2H), 0.70-0.63 (m, 2H).

LC / MS (Method 4, ESIpos): R _t = 0.85 min, m / z = 405 [M + H] ⁺ .

Example 38

3-Cyclopropyl-5-methyl-6 - [(2-oxoimidazolidin-1-yl) methyl] -1 - [(2R) -tetrahydrofuran-2-ylmethyl] thieno [2,3-d] pyrimidine-2,4 (lH, 3H) -dione

Analogously to the process described under Example 3, 170 mg (0.404 mmol, 90% purity) of the compound from Example 111A and 79 mg (0.485 mmol) of CDI 79 mg (48% of theory) of the title compound were prepared. 'H-NMR (400 MHz, DMSO-d _6, δ / ppm): 6:51 (s, 1H), 4:33 (s, 2H), 4:25 to 4:15 (m, 1H), 3.99 (dd, 1H), 3.78- 3.70 (m, 1H), 3.70-3.56 (m, 2H), 3.27-3.15 (m, 4H), 2.64-2.56 (m, 1H), 2.37 (s, 3H), 2.03-1.73 (m, 3H), 1.71-1.57 (m, 1H), 1.07-0.94 (m, 2H), 0.72-0.61 (m, 2H).

LC / MS (Method 1, ESIpos): R _t = 1.21 min, m / z = 405.16 [M + H] ⁺ .

Specific optical rotation: [a] _D ²⁰ = -26.8 ° -ml-dm- ¹ -g- ¹ (DMSO). Example 39

3-Cyclopropyl-5-methyl-6 - [(2-oxoimidazolidin-1-yl) methyl] -1 - [(2S) -tetrahydrofuran-2-ylmethyl] thieno [2,3-d] pyrimidine-2,4 (lH, 3H) -dione

Analogously to the process described under Example 3, 150 mg (0.357 mmol, 90% purity) of the compound from Example 112A and 69 mg (0.428 mmol) of CDI 58 mg (40% of theory) of the title compound were prepared. 'H-NMR (400 MHz, DMSO-d _6, δ / ppm): 6:51 (s, 1H), 4:33 (s, 2H), 4:25 to 4:14 (m, 1H), 3.99 (dd, 1H), 3.79- 3.70 (m, 1H), 3.70-3.55 (m, 2H), 3.27-3.16 (m, 4H), 2.64-2.56 (m, 1H), 2.37 (s, 3H), 2.03-1.74 (m, 3H), 1.70-1.58 (m, 1H), 1.07-0.92 (m, 2H), 0.72-0.60 (m, 2H).

LC / MS (Method 1, ESIpos): R _t = 1.21 min, m / z = 405.16 [M + H] ⁺ .

Specific optical rotation: [a] _D ²⁰ = +25.5 ⁰ -ml-dm ¹ -g ¹ (DMSO). Example 40

3-Cyclopropyl-5-methyl-1- (tetrahydrofuran-2-ylmethyl) -6 - [(2-thioxoimidazolidin-1-yl) methyl] thieno [2,3-d] pyrimidine-2,4 (1H, 3H ) -dione (racemate)

Analogously to Ex. 6, 100 mg (0.225 mmol) of the compound from Ex. 110A in 15 ml of dioxane were reacted with 63 mg (0.337 mmol) of 1,1'-thiocarbonyldiimidazole. Thirty mg (31% of theory) of the title compound were obtained.

'H-NMR (400 MHz, DMSO-de, δ / ppm): 8.34 (s, 1H), 4.80 (s, 2H), 4.23-4.15 (m, 1H), 3.99 (dd, 1H), 3.78-3.70 (m, 1H), 3.69-3.56 (m, 2H), 3.55-3.47 (m, 2H), 3.43-3.36 (m, 2H), 2.63-2.56 (m, 1H), 2.41 (s, 3H), 2.02 -1.91 (m, 1H), 1.91-1.74 (m, 2H), 1.69-1.59 (m, 1H), 1.04-0.96 (m, 2H), 0.69-0.63 (m, 2H).

LC / MS (Method 4, ESIpos): R _t = 0.95 min, m / z = 421 [M + H] ⁺ . Example 41

[1 - {[3-Cyclopropyl-5-methyl-2,4-dioxo-1 - (tetrahydrofuran-2-ylmethyl)-1,2,3,4-tetrahydrothieno [2,3-d] pyrimidine-6- yl] methyl} imidazolidin-2-ylidene] cyanamide (racemate)

570 mg (1.21 mmol, 80% purity) of the compound from Ex. 110A were dissolved in 16 ml of DMF and admixed with 264 mg (1.81 mmol) of dimethyl N-cyanodithioiminocarbonate and 333 mg (2.41 mmol) of potassium carbonate. The mixture was stirred for 4 h at 80 ° C in a microwave oven (Biotage initiator with dynamic control of the irradiation power). Thereafter, the reaction mixture was diluted with ethyl acetate and washed successively with saturated sodium carbonate solution and saturated sodium chloride solution. After drying over anhydrous magnesium sulfate, it was filtered and concentrated. The crude product was purified by preparative HPLC (Method 11). The product fractions were combined, evaporated and dried under high vacuum. 215 mg (40% of theory, 97% purity) of the title compound were obtained.

'H-NMR (500 MHz, DMSO-de, δ / ppm): 8.06 (s, 1H), 4.46 (s, 2H), 4.23-4.17 (m, 1H), 4.01 (br dd, 1H), 3.75 (q, 1H), 3.70-3.57 (m, 2H), 3.48-3.36 (m, 4H), 2.65-2.56 (m, 1H), 2.38 (s, 3H), 2.03-1.75 (m, 3H), 1.72 -1.59 (m, 1H), 1.03-0.97 (m, 2H), 0.69-0.64 (m, 2H).

LC / MS (Method 6, ESIpos): R _t = 0.99 min, m / z = 429 [M + H] ⁺ .

Example 42

Methyl [1 - {[3-cyclopropyl-5-methyl-2,4-dioxo-1 - (tetrahydrofuran-2-ylmethyl) -1,2,3,4-tetrahydrothieno [2,3-d] pyrimidine -6-yl] methyl} imidazolidin-2-ylidene] carbamate (racemate)

510 mg (1.08 mmol, 80% purity) of the compound from Example 110A and 300 μΐ (2.16 mmol) of triethylamine were dissolved in 20 ml of dichloromethane and treated dropwise with a solution of 336 mg (2.16 mmol) of methyl (dichloromethylene) carbamate in 5 ml of dichloromethane. After the reaction mixture was stirred at RT for about 16 h, it was concentrated to dryness. The residue was prepurified by preparative HPLC (Method 11). Since the product fraction was still contaminated, a second chromatography by MPLC followed (Biotage Isolera One, cartridge SNAP KP-Sil, 50 g of silica gel, eluent ethyl acetate). Concentration of the product fraction and drying of the residue under high vacuum gave 166 mg (31% of theory, 95% purity) of the title compound. 'H-NMR (400 MHz, DMSO-d _6, δ / ppm): 8:01 (s, 1H), 4:53 (s, 2H), 4:25 to 4:15 (m, 1H), 4.00 (dd, 1H), 3.77- 3.68 (m, 1H), 3.66-3.55 (m, 2H), 3.53 (s, 3H), 3.49-3.41 (m, 2H), 3.35-3.28 (m, 2H, largely covered by the water signal), 2.64-2.56 ( m, 1H), 2.40 (s, 3H), 2.02-1.74 (m, 3H), 1.70-1.59 (m, 1H), 1.04-0.95 (m, 2H), 0.71-0.62 (m, 2H).

LC / MS (Method 1, ESIpos): R _t = 1.16 min, m / z = 462.18 [M + H] ⁺ . Example 43

Methyl [1 - {[3-cyclopropyl-5-methyl-2,4-dioxo-1 - (tetrahydrofuran-2-ylmethyl) -1,2,3,4-tetrahydrothieno [2,3-d] pyrimidine -6-yl] methyl} imidazolidin-2-ylidene] carbamate {enantiomer 1)

161 mg of the racemic compound from Ex. 42 were dissolved in a mixture of 4 ml of ethanol and 2 ml of acetonitrile and separated in 20 portions by preparative HPLC on a chiral phase into the enantiomers [column: YMC Chiralart SC, 5 μm, 250 mm x 20 mm; Eluent: ethanol; Flow: 15 ml / min; Temperature: 55 ° C; Detection: 220 um]. Evaporation of the product fractions and drying of the solid in a high vacuum gave 66 mg (81% of theory) of enantiomer 1 (> 99.0% ee, chiral analytical HPLC).

'H-NMR (400 MHz, DMSO-de, δ / ppm): 8.01 (s, 1H), 4.53 (s, 2H), 4.25-4.15 (m, 1H), 4.00 (dd, 1H), 3.77-3.68 (m, 1H), 3.66-3.56 (m, 2H), 3.53 (s, 3H), 3.48-3.41 (m, 2H), 3.35-3.28 (m, 2H, largely masked by the water signal), 2.60 (tt, 1H), 2.40 (s, 3H), 2.02-1.74 (m, 3H), 1.71-1.59 (m, 1H), 1.05-0.96 (m, 2H), 0.71-0.61 (m, 2H).

Chiral analytical HPLC [column: Daicel Chiralpak IC, 5 μm, 250 mm × 4.6 mm; Eluent: ethanol; Flow: 1 ml / min; Temperature: 55 ° C; Detection: 220 μm]: R _t = 13.93 min. Example 44

Methyl [1 - {[3-cyclopropyl-5-methyl-2,4-dioxo-1 - (tetrahydrofuran-2-ylmethyl) -1,2,3,4-tetrahydrothieno [2,3-d] pyrimidine -6-yl] methyl} imidazolidin-2-ylidene] carbamate {enantiomer 2)

161 mg of the racemic compound from Ex. 42 were dissolved in a mixture of 4 ml of ethanol and 2 ml of acetonitrile and separated in 20 portions by preparative HPLC on a chiral phase into the enantiomers [column: YMC Chiralart SC, 5 μm, 250 mm x 20 mm; Eluent: ethanol; Flow: 15 ml / min; Temperature: 55 ° C; Detection: 220 um]. Evaporation of the product fractions and drying of the solid in a high vacuum gave 59 mg (73% of theory) of enantiomer 2 (> 99.0% ee, chiral analytical HPLC). Ή-ΝΜΡ (400 MHz, DMSO-d ₆ , δ / ppm): 8.01 (s, 1H), 4.53 (s, 2H), 4.25-4.14 (m, 1H), 4.00 (dd, 1H), 3.77-3.68 (m, 1H), 3.66-3.56 (m, 2H), 3.53 (s, 3H), 3.49-3.41 (m, 2H), 3.35-3.28 (m, 2H), 2.63-2.56 (m, 1H), 2.40 (s, 3H), 2.02-1.74 (m, 3H), 1.70-1.59 (m, 1H), 1.07-0.92 (m, 2H), 0.72-0.60 (m, 2H).

Chiral analytical HPLC [column: Daicel Chiralpak IC, 5 μm, 250 mm × 4.6 mm; Eluent: ethanol; Flow: 1 ml / min; Temperature: 55 ° C; Detection: 220 μm]: R _t = 15.76 min.

Example 45

3-Cyclopropyl-6 - [(2,3-dioxopiperazin-1-yl) methyl] -5-methyl-1- (tetrahydrofuran-2-ylmethyl) -thieno [2,3-d] pyrimidine-2,4 (1H , 3H) -dione (racemate)

Analogously to Ex. 8, 100 mg (0.225 mmol) of the compound from Ex. 110A in 5 ml of ethanol were reacted with 331 mg (2.246 mmol) of diethyl oxalate. 27 mg (27% of theory) of the title compound were obtained. 'H-NMR (400 MHz, DMSO-d _6, δ / ppm): 8.63 (br s, 1H.), 4.67 (s, 2H), 4:24 to 4:15 (m, 1H), 4.00 (dd, 1H), 3.77-3.70 (m, 1H), 3.69-3.56 (m, 2H), 3.50-3.43 (m, 2H), 3.31 (brd, 2H), 2.60 (tt, 1H), 2.40 (s, 3H), 2.02-1.91 (m, 1H), 1.91-1.75 (m, 2H), 1.69-1.59 (m, 1H), 1.04-0.97 (m, 2H), 0.69-0.63 (m, 2H).

LC / MS (Method 4, ES Ineg): R _t = 0.77 min, m / z = 477 [M-H + HCO 2 H]. ^" Example 46

3-Cyclopropyl-5-methyl-6- [(2-oxo-2,3-dihydro-1H-imidazol-1-yl) methyl] -1- (tetrahydrofuran-2-ylmethyl) thieno [2,3- d] pyrimidine-2,4 (1H, 3H) -dione (racemate)

A solution of 1.1 g (1.38 mmol, 60% purity) of the compound from Ex. 155A in a mixture of 2.8 ml of water and 10 ml of methanol was admixed with 2.7 ml (1.36 mmol) of 0.5 M hydrochloric acid. After the reaction mixture had been stirred at RT for 40 h, it was fractionated directly into its components by preparative HPLC (Method 13). Evaporation and drying of the product fraction under high vacuum gave 151 mg (26% of theory) of the title compound.

'H-NMR (400 MHz, DMSO-de, δ / ppm): 9.98 (s, 1H), 6.41 (dd, 1H), 6.33 (dd, 1H), 4.77 (s, 2H), 4.21-4.15 (m , 1H), 3.99 (dd, 1H), 3.75-3.70 (m, 1H), 3.66-3.57 (m, 2H), 2.62-2.58 (m, 1H), 2.44 (s, 3H), 1.98-1.75 (m , 3H), 1.68-1.59 (m, 1H), 1.03-0.97 (m, 2H), 0.68-0.64 (m, 2H). LC / MS (Method 1, ES Ineg): R _t = 1.11 min, m / z = 401 [MH] -. Example 47

3-Cyclopropyl-5-methyl-6- [(2-oxo-2,3-dihydro-1H-imidazol-1-yl) methyl] -1- (tetrahydrofuran-2-ylmethyl) thieno [2,3- d] pyrimidine-2,4 (1H, 3H) -dione (enantiomer 1)

151 mg of the racemic compound from Example 46 were dissolved in 3 ml of a methanol / TBME / dichloromethane mixture (3: 2: 1) and fractionated by preparative HPLC on a chiral phase into the enantiomers [column: Daicel Chiralpak ID, 5 μιη, 250 mm x 20 mm; Eluent: TB ME / methanol 1: 1; Flow: 15 ml / min; Temperature: 30 ° C; Detection: 220 um]. The product fractions were concentrated on a rotary evaporator, washed with tert. Butanol added and freeze-dried. There were 50 mg (66% of theory) of the title compound (enantiomer 1) and 53 mg (70%) d. Th.) Of enantiomer 2 (see Ex. 48).

'H-NMR (400 MHz, DMSO-de, δ / ppm): 9.98 (s, 1H), 6.41 (dd, 1H), 6.33 (dd, 1H), 4.77 (s, 2H), 4.21-4.15 (m , 1H), 3.99 (dd, 1H), 3.75-3.70 (m, 1H), 3.66-3.57 (m, 2H), 2.62-2.58 (m, 1H), 2.44 (s, 3H), 1.98-1.75 (m , 3H), 1.68-1.59 (m, 1H), 1.03-0.97 (m, 2H), 0.68-0.64 (m, 2H).

LC / MS (Method 1, ES Ineg): R _t = 1.13 min, m / z = 401 [MH] ^" .

Chiral analytical HPLC [column: Daicel Chiralpak ID, 5 μm, 100 mm × 4.6 mm; Eluent: methanol + 0.2% acetic acid / TBME 15:85; Flow: 1.0 ml / min; Temperature: 30 ° C; Injection: 5 μΐ; DAD: 235 um]: R _t = 5.90 min. Example 48

3-Cyclopropyl-5-methyl-6- [(2-oxo-2,3-dihydro-1H-imidazol-1-yl) methyl] -1- (tetrahydrofuran-2-ylmethyl) thieno [2,3- d] pyrimidine-2,4 (1H, 3H) -dione {enantiomer 2)

The title compound (53 mg) was obtained as a second enantiomer in the preparative HPLC separation of Example 46 racemate described in Ex. 47.

LC / MS (Method 1, ES Ineg): R _t = 1.11 min, m / z = 401 [MH] ^" .

Chiral analytical HPLC [column: Daicel Chiralpak ID, 5 μm, 100 mm × 4.6 mm; Eluent: methanol + 0.2% acetic acid / TBME 15:85; Flow: 1.0 ml / min; Temperature: 30 ° C; Injection: 5 μΐ; DAD: 235 nm]: R _t = 6.69 min.

Example 49

3-Cyclopropyl-5-methyl-6 - [(5-oxo-4,5-dihydro-1H-l, 2,4-triazol-1-yl) methyl] -1- (tetrahydrofuran-2-ylmethyl) thieno [ 2,3-d] pyrimidine-2,4 (1H, 3H) -dione (racemate)

358 mg (0.689 mmol, 95% purity) of the compound from Ex. 254A were dissolved in a mixture of 15 ml each of methanol and trimethyl orthoformate and treated at RT with 1.7 ml (6.89 mmol) of a 4 M solution of hydrogen chloride in dioxane. After 1 h and after 2 h each additional 0.85 ml (3.45 mmol) of 4 M solution of hydrogen chloride in dioxane were added. After a total of 16 h, the reaction mixture was diluted with water and extracted with ethyl acetate. The organic extract was concentrated and the residue was then stirred with a little acetonitrile at RT. The solid was separated and dried under high vacuum. The filtrate was evaporated and the residue purified by preparative HPLC (Method 11). To Evaporation of the product fraction and drying under high vacuum, the residue was combined with the previously obtained solid. A total of 195 mg (70% of theory) of the title compound were obtained.

'H-NMR (400 MHz, DMSO-de, δ / ppm): 11.59 (broad, 1H), 7.82 (s, 1H), 4.91 (s, 2H), 4.24-4.13 (m, 1H), 3.99 (d , 1H), 3.77-3.69 (m, 1H), 3.68-3.55 (m, 2H), 2.60 (t, 1H), 2.43 (s, 3H), 2.03-1.74 (m, 3H), 1.71-1.58 (m , 1H), 1.06-0.93 (m, 2H), 0.74-0.60 (m, 2H).

LC / MS (Method 1, ESIpos): R _t = 1.06 min, m / z = 404.14 [M + H] ⁺ .

Example 50

3-Cyclopropyl-5-methyl-6 - [(5-oxo-4,5-dihydro-1H-l, 2,4-triazol-1-yl) methyl] -1 - [(2R) -tetrahydrofuran 2-ylmethyl] thieno [2,3-d] pyrimidine-2,4 (lH, 3H) -dione

255 mg (0.465 mmol, 90%> purity) of the compound from Ex. 255A were dissolved in a mixture of 10 ml each of methanol and trimethyl orthoformate and treated at RT with 1.2 ml (4.65 mmol) of a 4 M solution of hydrogen chloride in dioxane. After about 16 h, the reaction mixture was concentrated and the residue was taken up in ethyl acetate. It was washed successively with water and saturated sodium chloride solution. After drying over anhydrous magnesium sulfate, it was filtered and concentrated again. The remaining residue was purified by preparative HPLC (Method 11). Evaporation of the product fractions and drying under high vacuum gave 121 mg (64% of theory) of the title compound.

'H-NMR (400 MHz, DMSO-de, δ / ppm): 11.58 (br.s, 1H), 7.83 (s, 1H), 4.91 (s, 2H), 4.22-4.14 (m, 1H), 3.99 (brd dd, 1H), 3.73 (q, 1H), 3.68-3.55 (m, 2H), 2.63-2.56 (m, 1H), 2.43 (s, 3H), 2.03-1.74 (m, 3H), 1.71 -1.57 (m, 1H), 1.03-0.97 (m, 2H), 0.69-0.63 (m, 2H).

LC / MS (Method 1, ESIpos): R _t = 1.10 min, m / z = 404.14 [M + H] ⁺ .

Specific optical rotation: [a] _D ²⁰ = ^^ - ml-dm ¹ - ^ ¹ (DMSO). Example 51

3-Cyclopropyl-5-methyl-6 - [(5-oxo-4,5-dihydro-1H-1,2,4-triazol-1-yl) methyl] -1 - [(2S) -tetrahydrofuran 2-ylmethyl] thieno [2,3-d] pyrimidine-2,4 (lH, 3H) -dione

Analogously to the process described under Example 50, from 210 mg (0.383 mmol, 90% purity) of the compound from Ex. 256A, 107 mg (69% of theory) of the title compound were prepared.

'H-NMR (400 MHz, DMSO-de, δ / ppm): 11.58 (br.s, 1H), 7.82 (s, 1H), 4.91 (s, 2H), 4.22-4.14 (m, 1H), 3.99 (dd, 1H), 3.73 (q, 1H), 3.68-3.55 (m, 2H), 2.63-2.56 (m, 1H), 2.43 (s, 3H), 2.04-1.75 (m, 3H), 1.70-1.57 (m, 1H), 1.06-0.93 (m, 2H), 0.68-0.63 (m, 2H). LC / MS (Method 2, ESIpos): R _t = 0.63 min, m / z = 404 [M + H] ⁺ .

Specific optical rotation: [a] _D ²⁰ = + 30.0 ^o -ml-dm ¹ -g ¹ (DMSO).

Example 52 1, 5-Dimethyl-3- (1-methylcyclopropyl) -6 - [(2-oxoimidazolidin-1-yl) methyl] thieno [2,3-d] pyrimidine-2,4 (1H, 3H) -dione

Analogously to the process described under Example 3, from 247 mg (0.689 mmol, 90%> purity) of the compound from Ex. 113A and 134 mg (0.827 mmol) of CDI, 164 mg (68% of theory) of the title compound were prepared.

Ή-NMR (400 MHz, DMSO-de, δ / ppm): 6.51 (s, 1H), 4.34 (s, 2H), 3.31 (s, 3H), 3.27-3.14 (m, 4H), 2.39 (s, 3H), 1.33 (s, 3H), 0.95-0.77 (m, 4H).

LC / MS (Method 2, ESIpos): R _t = 0.66 min, m / z = 349 [M + H] Example 53 1, 5-Dimethyl-3- (1-methylcyclopropyl) -6 - [(5-oxo-4,5-dihydro-1H-1,2,4-triazol-1-yl) methyl] thieno [2 , 3-d] pyrimidine-2,4 (lH, 3H) -dione

Analogously to the process described under Example 50, from 275 mg (0.597 mmol, 95% purity) of the compound from Ex. 257A, 153 mg (73% of theory) of the title compound were prepared.

Ή-NMR (400 MHz, DMSO-de, δ / ppm): 11.58 (br, s, 1H), 7.83 (s, 1H), 4.93 (s, 2H), 3.36 (s, 3H), 2.45 (s, 3H), 1.32 (s, 3H), 0.98-0.73 (m, 4H).

LC / MS (Method 1, ESIpos): R _t = 1.08 min, m / z = 348.11 [M + H] ⁺ . Example 54

1-Butyl-5-methyl-3- (1-methylcyclopropyl) -6 - [(2-oxoimidazolidin-1-yl) methyl] thieno

pyrimidine-2,4 (lH, 3H) -dione

A solution of 295 mg (0.728 mmol, 90% purity) of the compound from Example 114A and 152 μΐ (1.09 mmol) of triethylamine in 8 ml of THF was combined with 142 mg (0.874 mmol) of CDI and stirred at RT for about 16 h. It was then concentrated to dryness. The remaining residue was taken up in ethyl acetate and washed successively with 1 M hydrochloric acid, water, saturated sodium bicarbonate solution and saturated sodium chloride solution. After drying over anhydrous magnesium sulfate, it was filtered and concentrated. The solid residue was purified by preparative HPLC (Method 11). Evaporation of the product fractions and drying under high vacuum gave 179 mg (63% of theory) of the title compound. 'H-NMR (400 MHz, DMSO-de, δ / ρρηι): 6.51 (s, 1H), 4.34 (s, 2H), 3.99-3.65 (m, 2H), 3.28-3.15 (m, 4H), 2.38 (s, 3H), 1.63 (quin, 2H), 1.42-1.26 (m, 2H), 1.33 (s, 3H), 0.91 (t, 3H), 0.89-0.78 (m,

4Η).

LC / MS (Method 2, ESIpos): R _t = 0.86 min, m / z = 391 [M + H] ⁺ . Example 55 1-Butyl-5-methyl-3- (1-methylcyclopropyl) -6 - [(5-oxo-4,5-dihydro-1H-1,2,4-triazol-1-yl) methyl] -thieno [2,3-d] pyrimidine-2,4 (lH, 3H) -dione

Analogously to the process described under Example 2, from 320 mg (0.594 mmol, 89% purity) of the compound from Ex. 258A, 174 mg (75% of theory) of the title compound were prepared.

Ή-NMR (400 MHz, DMSO-de, δ / ppm): 11.59 (br.s, 1H), 7.83 (s, 1H), 4.92 (s, 2H), 3.98-3.63 (m, 2H), 2.44 ( s, 3H), 1.62 (quin, 2H), 1.41-1.25 (m, 2H), 1.32 (s, 3H), 0.97-0.70 (m, 4H), 0.90 (t, 3H).

LC / MS (Method 1, ESIpos): R _t = 1.51 min, m / z = 390.16 [M + H] ⁺ .

Example 56 5-Methyl-3- (1-methylcyclopropyl) -6 - [(2-oxoimidazolidin-1-yl) methyl] -1- (3,3,3-trifluoropropyl) thieno [2,3-d] pyrimidine -2,4 (lH, 3H) -dione

320 mg (0.68 mmol, 86% purity) of the compound from Ex. 115A were dissolved in 5.6 ml of THF and admixed with 132 mg (0.81 mmol) of CDI and 0.14 ml (1.02 mmol) of triethylamine. The mixture was stirred at RT for 16 h. The reaction solution was then concentrated on a rotary evaporator. The residue was taken up in ethyl acetate and washed successively with 1 M hydrochloric acid, saturated aqueous sodium bicarbonate solution and saturated sodium chloride solution. Subsequently, the organic phase was dried over anhydrous magnesium sulfate, filtered and concentrated. The residue obtained was purified by preparative HPLC (Method 13). Evaporation of the product fractions and drying under high vacuum gave 195 mg (67% of theory) of the title compound.

'H-NMR (400 MHz, DMSO-de, δ / ppm): 6.52 (br.s, 1H), 4.35 (s, 2H), 4.14-3.97 (m, 2H), 3.30- 3.18 (m, 4H) , 2.80-2.66 (m, 2H), 2.39 (s, 3H), 1.35 (s, 3H), 1.00-0.50 (m, 4H).

LC / MS (Method 2, ESIpos): R _t = 0.83 min, m / z = 431 [M + H] ⁺ . Example 57

[1- {[5-Methyl-3- (1-methylcyclopropyl) -2,4-dioxo-1- (3,3,3-trifluoropropyl) -1,3,3,4-tetrahydrothieno [2,3 -d] pyrimidin-6-yl] methyl} imidazolidine-2-ylidene] cyanamide

451 mg (0.96 mmol, 86% purity) of the compound from Ex. 115A were dissolved in 38 ml of DMF and admixed with 264 mg (1.91 mmol) of potassium carbonate. The mixture was stirred at RT for 15 min, then 210 mg (1.43 mmol) of dimethyl N -cyanodithioiminocarbonate were added and the reaction mixture was stirred for 3 h at 80 ° C in a microwave oven (Biotage Initiator with dynamic control of the irradiation power). Thereafter, the reaction mixture was taken up in ethyl acetate and washed successively with saturated aqueous sodium hydrogencarbonate solution, water and saturated sodium chloride solution. Subsequently, the organic phase was dried over anhydrous magnesium sulfate, filtered and concentrated. The residue obtained was purified by preparative HPLC (Method 13). Evaporation of the product fractions and drying under high vacuum gave 129 mg (30% of theory) of the title compound.

'H-NMR (400 MHz, CD ₃ OD, δ / ppm): 4.55 (s, 2H), 4:22 to 4:13 (m, 2H), 3:53 (s, 4H), 2.75-2.65 (i 2H), 2:47 ( s, 3H), 1.41 (s, 3H), 1.02-0.96 (m, 1H), 0.95-0.87 (m, 3H).

LC / MS (Method 2, ESIpos): R _t = 0.88 min, m / z = 455 [M + H] ⁺ . Example 58

Methyl [1- {[5-methyl-3- (1-methylcyclopropyl) -2,4-dioxo-1- (3,3,3-trifluoropropyl) -1,3,3,4-tetrahydrothieno [2, 3-d] pyrimidin-6-yl] methyl} imidazolidine-2-ylidene] carbamate

250 mg (0.53 mmol, 86% purity) of the compound of Ex. 115A and 147 μΐ (1.06 mmol) of triethylamine were dissolved in 24 ml of dichloromethane and treated with 82 mg (0.53 mmol) of methyl (dichloromethylene) carbamate. After the reaction mixture was stirred for about 16 h at RT, it was diluted with ethyl acetate and washed successively with saturated sodium bicarbonate solution, water and saturated sodium chloride solution. After drying over anhydrous magnesium sulfate, it was filtered and concentrated. The remaining residue was purified by preparative HPLC (Method 13). Concentration of the product fraction and drying of the residue under high vacuum gave 210 mg (82% of theory) of the title compound.

Ή-NMR (400 MHz, CD ₃ OD, δ / ppm): 4.83 (s, 2H), 4:26 to 4:16 (m, 2H), 3.95 (s, 3H), 3.83 (t, 2H), 3.68 (t, 2H), 2.78-2.70 (m, 2H), 2.52 (s, 3H), 1.44 (s, 3H), 1.05-1.01 (m, 1H), 0.98-0.92 (m, 3H). LC / MS (Method 2, ESIpos): R _t = 0.79 min, m / z = 488 [M + H] ⁺ . Example 59

6 - [(2,3-dioxopiperazin-1-yl) methyl] -5-methyl-3- (1-methylcyclopropyl) -1- (3,3,3-trifluoropropyl) thieno [2,3-d] pyrimidine -2,4 (lH, 3H) -dione

230 mg (0.49 mmol, 86% purity) of the compound from Ex. 115A were dissolved in 19 ml of ethanol and admixed with 133 mg (0.90 mmol) of diethyl oxalate. The mixture was stirred at 80 ° C for 3 days. Thereafter, the reaction solution was concentrated on a rotary evaporator. The residue obtained was purified by preparative HPLC (Method 13). Evaporation of the product fractions and drying under high vacuum gave 89 mg (40% of theory) of the title compound.

'H-NMR (400 MHz, CD ₃ OD, δ / ppm): 4.80 (s, 2H), 4:22 to 4:12 (m, 2H), 3.60 (m, 2H), 3:46 (m, 2H), 2.74-2.66 (m, 2H), 2.51 (s, 3H), 1.42 (s, 3H), 1.03-0.97 (m, 1H), 0.95-0.88 (m, 3H).

LC / MS (Method 2, ESIpos): R _t = 0.75 min, m / z = 459 [M + H] ⁺ .

Example 60 5-Methyl-3- (1-methylcyclopropyl) -6 - [(5-oxo-4,5-dihydro-1H-1,2,4-triazol-1-yl) methyl] -1- (3, 3,3-trifluoropropyl) thieno [2,3-d] pyrimidine-2,4 (1H, 3H) -dione

500 mg (0.71 mmol, 74% purity) of the compound from Ex. 259A were initially charged in 17.5 ml of trimethyl orthoformate and 17.5 ml of methanol, and 1.8 ml (7.14 mmol) of a 4 M solution of hydrogen chloride in dioxane were added. Since the reaction was still incomplete after stirring for 18 h at RT, a further 0.9 ml of 4 M hydrogen chloride in dioxane were added and the mixture was stirred for a further 2.5 h. Thereafter, another 0.9 ml of 4 M hydrogen chloride in dioxane was added and stirred for a further 2.5 h. The reaction mixture was then added with water and extracted with ethyl acetate. The organic phase was concentrated and the residue was purified by preparative HPLC (Method 13). The product fractions were combined and concentrated and the residue was dried under high vacuum. 185 mg (61% of theory) of the title compound were obtained.

Ή-NMR (400 MHz, CD3OD, δ / ppm): 7.72 (s, 1H), 5.07 (s, 2H), 4.20-4.15 (m, 2H), 3.33-3.32 (i4H), 2.75-2.70 (m , 2H), 2.56 (s, 3H), 1.43 (s, 3H), 1.04-0.98 (m, 1H), 0.96-0.90 (m, 3H).

LC / MS (Method 2, ESIpos): R _t = 0.78 min, m / z = 430 [M + H] ⁺ . Example 61

1 - (cyclobutylmethyl) -5-methyl-3- (1-methylcyclopropyl) -6 - [(2-oxoimidazolidin-1-yl) -methyl] -thieno [2,3-d] pyrimidine-2,4 (1H, 3H) -dione

A solution of 240 mg (0.542 mmol, 85% purity) of the compound from Example 116A and 113 μΐ (0.813 mmol) of triethylamine in 6 ml of THF was admixed with 105 mg (0.650 mmol) of CDI and stirred at RT for 5 days. It was then concentrated to dryness. The remaining residue was taken up in ethyl acetate and washed successively with 1 M hydrochloric acid, water, saturated sodium bicarbonate solution and saturated sodium chloride solution. After drying over water-free magnesium sulfate, it was filtered and concentrated. The solid residue was purified by preparative HPLC (Method 11). After evaporation of the product fractions and drying in a high vacuum, 30 mg (13% of theory) of the title compound were obtained.

'H-NMR (400 MHz, DMSO-de, δ / ppm): 6.51 (s, 1H), 4.33 (s, 2H), 4.07-3.72 (m, 2H), 3.21 (br, s, 3H), 2.80 -2.64 (m, 1H), 2.37 (s, 3H), 2.00-1.93 (m, 2H), 1.87-1.73 (m, 4H), 1.32 (s, 3H), 0.98-0.67 (m, 4Η).

LC / MS (Method 1, ESIpos): R _t = 1.67 min, m / z = 403.18 [M + H] ⁺ . Example 62 1- (Cyclobutylmethyl) -5-methyl-3- (1-methylcyclopropyl) -6 - [(5-oxo-4,5-dihydro-1H-1,2,4-triazol-1-yl) methyl] thieno [2,3-d] pyrimidine-2,4 (lH, 3H) -dione

Analogously to the process described in Example 2, from 250 mg (0.458 mmol, 90% purity) of the compound from Ex. 260A, 65 mg (35% of theory) of the title compound were prepared. The reaction time in this case was 6 days.

'H-NMR (400 MHz, DMSO-de, δ / ppm): 11.58 (br.s, 1H), 7.83 (s, 1H), 4.91 (s, 2H), 4.06-3.69 (m, 2H), 2.80 -2.64 (m, 1H), 2.43 (s, 3H), 2.00-1.90 (m, 2H), 1.87-1.71 (m, 4H), 1.32 (s, 3H), 0.97-0.67 (m, 4H).

LC / MS (Method 1, ESIpos): R _t = 1.55 min, m / z = 402.16 [M + H] ⁺ . Example 63 1 - [(2,2-Difluorocyclopropyl) methyl] -5-methyl-3- (1-methylcyclopropyl) -6 - [(2-oxoimidazolidin-1-yl) methyl] thieno [2,3-d] pyrimidine -2,4 (1H, 3H) -dione (racemate)

A solution of 567 mg (1.27 mmol, 89% purity) of the compound from Example 117A and 265 μΐ (1.90 mmol) of triethylamine in 13 ml of THF was treated with 246 mg (1.52 mmol) of CDI and stirred at RT for about 16 h. It was then concentrated to dryness. The remaining residue was taken up in ethyl acetate and washed successively with 1 M hydrochloric acid, water, saturated sodium bicarbonate solution and saturated sodium chloride solution. After drying over anhydrous magnesium sulfate, it was filtered and concentrated. The solid residue was purified by preparative HPLC (Method 11). Evaporation of the product fractions and drying under high vacuum gave 410 mg (76% of theory) of the title compound.

'H-NMR (400 MHz, DMSO-de, δ / ppm): 6.52 (s, 1H), 4.35 (s, 2H), 4.22-3.75 (m, 2H), 3.28-3.16 (m, 4H), 2.39 (s, 3H), 2.27-2.11 (m, 1H), 1.78-1.62 (m, 1H), 1.50-1.39 (m, 1H), 1.34 (s, 3H), 0.98-0.75 (m, 4H).

LC / MS (Method 2, ESIpos): R _t = 0.82 min, m / z = 425 [M + H] ⁺ . Example 64 l - [(2,2-Difluorocyclopropyl) methyl] -5-methyl-3- (1-methylcyclopropyl) -6 - [(2-oxoimidazolidin-1-yl) methyl] thieno [2,3-d] pyrimidine -2,4 (1H, 3H) -dione (enantiomer 1)

398 mg of the racemic compound from Ex. 63 were dissolved in 40 ml of methanol and separated into 66 portions by preparative SFC-HPLC on a chiral phase into the enantiomers [column: Daicel Chiralpak OD-H, 5 μm, 250 mm × 20 mm ; Eluent: carbon dioxide / methanol 70:30; Flow: 150 ml / min; Temperature: 40 ° C; Detection: 210 nm]. Evaporation of the product fractions and drying of the solid in a high vacuum gave 192 mg (96% of theory) of enantiomer 1 (> 99% ee, chiral analytical HPLC).

Ή-ΝΜΡ (400 MHz, DMSO-d ₆ , δ / ppm): 6.52 (s, 1H), 4.35 (s, 2H), 4.21-3.76 (m, 2H), 3.28-3.17 (m, 4H), 2.39 (s, 3H), 2.26-2.10 (m, 1H), 1.78-1.62 (m, 1H), 1.50-1.40 (m, 1H), 1.34 (s, 3H), 0.98-0.75 (m, 4H).

Chiral analytical HPLC [column: Daicel Chiralpak OD-3, 3 μm, 50 mm × 4.6 mm; Mobile phase: carbon dioxide / methanol 95: 5 → 40:60 → 95: 5; Flow: 3 ml / min; Temperature: 40 ° C; detection:

Example 65 l - [(2,2-Difluorocyclopropyl) methyl] -5-methyl-3- (1-methylcyclopropyl) -6 - [(2-oxoimidazolidin-1-yl) methyl] thieno [2,3-d] pyrimidine -2,4 (1H, 3H) -dione {enantiomer 2)

398 mg of the racemic compound from Ex. 63 were dissolved in 40 ml of methanol and separated into 66 portions by preparative SFC-HPLC on a chiral phase into the enantiomers [column: Daicel Chiralpak OD-H, 5 μm, 250 mm × 20 mm ; Eluent: carbon dioxide / methanol 70:30; Flow: 150 ml / min; Temperature: 40 ° C; Detection: 210 nm]. Evaporation of the product fractions and drying of the solid in a high vacuum gave 156 mg (78% of theory) of enantiomer 2 (99% ee, chiral analytical HPLC).

Ή-ΝΜΡ (400 MHz, DMSO-d ₆ , δ / ppm): 6.52 (s, 1H), 4.35 (s, 2H), 4.22-3.75 (m, 2H), 3.28-3.16 (m, 4H), 2.39 (s, 3H), 2.27-2.08 (m, 1H), 1.78-1.61 (m, 1H), 1.50-1.40 (m, 1H), 1.34 (s, 3H), 0.97-0.74 (m, 4H). Chiral analytical HPLC [column: Daicel Chiralpak OD-3, 3 μm, 50 mm × 4.6 mm; Mobile phase: carbon dioxide / methanol 95: 5 → 40:60 → 95: 5; Flow: 3 ml / min; Temperature: 40 ° C; Detection: 220 nm]: R _t = 3.31 min.

Example 66 1 - [(2,2-Difluorocyclopropyl) methyl] -5-methyl-3- (1-methylcyclopropyl) -6 - [(5-oxo-4,5-dihydro-1H-1,2,4-triazole -l-yl) methyl] thieno [2,3-d] pyrimidine-2,4 (1H, 3H) -dione (racemate)

Analogously to the process described in Example 2, from 668 mg (1.20 mmol, 92% purity) of the compound from Example 261A, 357 mg (70% of theory) of the title compound were prepared.

'H-NMR (400 MHz, DMSO-de, δ / ppm): 11.59 (br.s, 1H), 7.83 (s, 1H), 4.93 (s, 2H), 4.22-3.74 (m, 2H), 2.45 (s, 3H), 2.24-2.08 (m, 1H), 1.77-1.60 (m, 1H), 1.49-1.39 (m, 1H), 1.33 (s, 3H), 0.98-0.73 (m, 4H).

LC / MS (Method 1, ESIpos): R _t = 1.42 min, m / z = 424.12 [M + H] ⁺ . Example 67 1 - [(2,2-Difluorocyclopropyl) methyl] -5-methyl-3- (1-methylcyclopropyl) -6 - [(5-oxo-4,5-dihydro-1H-1,2,4-triazole -l-yl) methyl] thieno [2,3-d] pyrimidine-2,4 (1H, 3H) -dione (enantiomer 1)

669 mg of the racemic compound from Ex. 66 were dissolved in 27 ml of methanol and separated into 33 portions by preparative SFC-HPLC on a chiral phase into the enantiomers [column: Daicel Chiralpak OD-H, 5 μm, 250 mm × 20 mm; Eluent: carbon dioxide / methanol 72:28; Flow: 70 ml / min; Temperature: 40 ° C; Detection: 210 nm]. Evaporation of the product fractions and drying of the solid in a high vacuum gave 151 mg (86% of theory) of enantiomer 1 (> 99% ee, chiral analytical HPLC).

Ή-ΝΜΡ (400 MHz, DMSO-d ₆ , δ / ppm): 11.58 (brs s, 1H), 7.83 (s, 1H), 4.93 (s, 2H), 4.23-3.73 (m, 2H), 2.45 (s, 3H), 2.24-2.06 (m, 1H), 1.77-1.61 (m, 1H), 1.49-1.38 (m, 1H), 1.33 (s, 3H), 0.99-0.68 (m, 4H).

Chiral analytical HPLC [column: Daicel Chiralpak OD-3, 3 μm, 50 mm × 4.6 mm; Eluent: carbon dioxide / methanol 70:30; Flow: 3 ml / min; Temperature: 40 ° C; Detection: 210 nm]: R _t = 0.97 min.

Example 68 l - [(2,2-Difluorocyclopropyl) methyl] -5-methyl-3- (1-methylcyclopropyl) -6 - [(5-oxo-4,5-dihydro-1H-1,2,4-triazole -l-yl) methyl] thieno [2,3-d] pyrimidine-2,4 (1H, 3H) -dione (enantiomer 2)

669 mg of the racemic compound from Ex. 66 were dissolved in 27 ml of methanol and separated into 33 portions by preparative SFC-HPLC on a chiral phase into the enantiomers [column: Daicel Chiralpak OD-H, 5 μm, 250 mm × 20 mm; Eluent: carbon dioxide / methanol 72:28; Flow: 70 ml / min; Temperature: 40 ° C; Detection: 210 nm]. After evaporation of the product fractions and Drying of the solid in a high vacuum gave 140 mg (80% of theory) of enantiomer 2 (> 99% ee, chiral analytical HPLC).

Ή-ΝΜΡ (400 MHz, DMSO-d ₆ , δ / ppm): 1 1.58 (br.s, 1H), 7.83 (s, 1H), 4.93 (s, 2H), 4.23-3.73 (m, 2H), 2.45 (s, 3H), 2.23-2.08 (m, 1H), 1.76-1.62 (m, 1H), 1.49-1.39 (m, 1H), 1.33 (s, 3H), 0.99-0.73 (m, 4H).

Chiral analytical HPLC [column: Daicel Chiralpak OD-3, 3 μm, 50 mm × 4.6 mm; Eluent: carbon dioxide / methanol 70:30; Flow: 3 ml / min; Temperature: 40 ° C; Detection: 210 nm]: R _t = 1.03 min.

Example 69 [5-Methyl-3- (1-methylcyclopropyl) -2,4-dioxo-6 - [(5-oxo-4,5-dihydro-1H-1,2,4-triazol-1-yl) - methyl] -3,4-dihydrothieno [2,3-d] pyrimidin-1 (2H) -yl] acetonitrile

Analogously to the process described under Example 2, from 123 mg (0.245 mmol, 92%> purity) of the compound from Example 262A, 56 mg (62% of theory) of the title compound were prepared. 'H-NMR (400 MHz, DMSO-d _6, δ / ppm): 1 1.61, 7.84 (s, 1H), 5.07 4.96 (s, 2H), (br s, 1H). (Br d, 2H). , 2.46 (s, 3H), 1.34 (s, 3H), 0.97-0.79 (m, 4H).

LC / MS (Method 1, ESIpos): R _t = 1.14 min, m / z = 373.1 1 [M + H] ⁺ .

Example 70 1- (2-Methoxyethyl) -5-methyl-3- (1-methylcyclopropyl) -6 - [(2-oxoimidazolidin-1-yl) methyl] thieno [2,3-d] pyrimidine-2,4 (lH, 3H) -dione

A solution of 19.1 g (42.2 mmol, 81% purity) of the compound from Example 118A and 8.8 ml (63.3 mmol) of triethylamine in 420 ml of THF was admixed with 8.21 g (50.7 mmol) of CDI and stirred at RT for about 16 h. It was then concentrated to dryness. The remaining residue was taken up in ethyl acetate and washed successively with 1 M hydrochloric acid, water, saturated sodium bicarbonate solution and saturated sodium chloride solution. After drying over anhydrous magnesium sulfate, it was filtered and concentrated. The solid residue was stirred first at RT in diethyl ether / ethyl acetate (10: 1) and then in hot ethyl acetate. After cooling, the solid was filtered off with suction and dried under high vacuum. There were obtained 7.18 g (43% of theory) of the title compound.

Ή-NMR (400 MHz, DMSO-de, δ / ppm): 6.51 (s, 1H), 4.33 (s, 2H), 4.12-3.83 (m, 2H), 3.61 (t, 2H), 3.27-3.15 ( m, 4H), 3.24 (s, 3H), 2.37 (s, 3H), 1.33 (s, 3H), 0.99-0.73 (m, 4H).

LC / MS (Method 1, ESIpos): R _t = 1.22 min, m / z = 393.16 [M + H] ⁺ .

Example 71 [1 - {[1- (2-Methoxyethyl) -5-methyl-3 - (1-methylcyclopropyl) -2,4-dioxo-1,2,3,4-tetrahydrothieno [2,3-d] pyrimidin-6-yl] methyl} imidazolidine-2-ylidene] cyanamide

310 mg (0.38 mmol, 44% purity) of the compound from Ex. 118A were dissolved in 14 ml of DMF and admixed with 103 mg (0.76 mmol) of potassium carbonate. The mixture was stirred at rt for 15 min, then 82 mg (0.57 mmol) of dimethyl N -cyanodithioiminocarbonate was added and the reaction mixture was stirred for 1.5 h at 80 ° C in a microwave oven (biotage initiator with dynamic control of the irradiation power). Thereafter, the reaction mixture was dissolved in ethyl acetate. taken and washed successively with saturated aqueous sodium bicarbonate solution, water and saturated sodium chloride solution. Subsequently, the organic phase was dried over anhydrous magnesium sulfate, filtered and concentrated. The residue obtained was purified by preparative HPLC (Method 13). Evaporation of the product fractions and drying under high vacuum gave 22 mg (14% of theory) of the title compound.

'H-NMR (400 MHz, CD ₃ OD, δ / ppm): 4.53 (s, 2H), 4:21 to 4:12 (m, 1H), 4.09-3.99 (m, 1H), 3.71 (t, 2H), 3:53 (s, 4H), 3.33 (s, 3H), 2.48 (s, 3H), 1.41 (s, 3H), 1.02-0.95 (m, 1H), 0.95-0.88 (m, 3H).

LC / MS (Method 2, ESIpos): R _t = 0.76 min, m / z = 417 [M + H] ⁺ . Example 72 Methyl [1- {[1- (2-methoxyethyl) -5-methyl-3- (1-methylcyclopropyl) -2,4-dioxo-1,2,3,4-tetrahydrothieno [2,3 -d] pyrimidin-6-yl] methyl} imidazolidine-2-ylidene] carbamate

250 mg (0.30 mmol, 44% purity) of the compound of Ex. 118A and 84 μΐ (0.61 mmol) of triethylamine were dissolved in 14 ml of dichloromethane and admixed with 47 mg (0.30 mmol) of methyl (dichloromethylene) carbamate. After the reaction mixture was stirred for about 16 h at RT, it was diluted with ethyl acetate and washed successively with saturated sodium bicarbonate solution, water and saturated sodium chloride solution. After drying over anhydrous magnesium sulfate, it was filtered and concentrated. The remaining residue was purified by preparative HPLC (Method 13). Concentration of the product fraction and drying of the residue under high vacuum gave 59 mg (42% of theory) of the title compound.

Ή NMR (400 MHz, CD3OD, δ / ppm): 4.78 (s, 2H), 4.23-4.15 (m, 1H), 4.10-3.98 (m, 1H), 3.91 (s, 3H), 3.79 (t, 2H), 3.74-3.68 (m, 2H), 3.65 (t, 2H), 3.31 (s, 3H), 2.47 (s, 3H), 1.41 (s, 3H), 1.03-0.87 (m, 4H).

LC / MS (Method 2, ESIpos): R _t = 0.65 min, m / z = 450 [M + H] ⁺ . Example 73

6 - [(2,3-dioxopiperazin-1-yl) methyl] -1- (2-methoxyethyl) -5-methyl-3- (1-methylcyclopropyl) thieno [2,3-d] pyrimidine-2,4 (lH, 3H) -dione

300 mg (0.36 mmol, 44% purity) of the compound from Ex. 118A were dissolved in 15 ml of ethanol and admixed with 99 mg (0.67 mmol) of diethyl oxalate. The mixture was stirred at 80 ° C overnight. Thereafter, the reaction solution was concentrated on a rotary evaporator. The residue obtained was purified by preparative HPLC (Method 13). Evaporation of the product fractions and drying under high vacuum gave 61 mg (39% of theory) of the title compound. Ή-NMR (400 MHz, CD ₃ OD, δ / ppm): 4.80 (s, 2H), 4:20 to 4:10 (m, 1H), 4.05-3.98 (m, 1H), 3.70 (dd, 2H), 3:58 ( dd, 2H), 3.45 (dd, 2H), 3.31 (br, s, 2H), 2.49 (s, 3H), 1.41 (s, 3H), 1.03-0.97 (m, 1H), 0.95-0.70 (m, 3H).

LC / MS (Method 2, ESIpos): R _t = 0.63 min, m / z = 421 [M + H] ⁺ . Example 74 1- (2-Methoxyethyl) -5-methyl-3- (1-methylcyclopropyl) -6 - [(5-oxo-4,5-dihydro-1H-1,2,4-triazol-1-yl) methyl] thieno [2,3-d] pyrimidine-2,4 (lH, 3H) -dione

500 mg (0.87 mmol, 83% purity) of the compound from Ex. 263A were initially charged in 21.3 ml of trimethyl orthoformate and 21.3 ml of methanol, and 2.2 ml (8.68 mmol) of a 4 M solution of hydrogen chloride in dioxane were added. Since the conversion was still incomplete after stirring for 18 h at RT, a further 1.1 ml of 4 M hydrogen chloride in dioxane were added and the Mixture continued to stir for 2.5 h. Thereafter, another 1.1 ml of 4 M hydrogen chloride in dioxane was added and stirred for a further 2.5 h. The reaction mixture was then added with water and extracted with ethyl acetate. The organic phase was concentrated and the residue was purified by preparative HPLC (Method 13). The product fractions were combined and concentrated and the residue was dried under high vacuum. 125 mg (36% of theory) of the title compound were obtained.

'H-NMR (400 MHz, CD ₃ OD, δ / ppm): 7.72 (s, 1H), 5:07 (s, 2H), 4:25 to 4:10 (m, 2H), 2.75-2.67 (m, 2H), 2:56 (s, 3H), 1.43 (s, 3H), 1.03-0.90 (m, 4H).

LC / MS (Method 2, ESIpos): R _t = 0.65 min, m / z = 392 [M + H] ⁺ . Example 75

5-methyl-3- (1-methylcyclopropyl) -6 - [(2-oxoimidazolidin-1-yl) methyl] -1- [2- (trifluoromethoxy) ethyl] thieno [2,3-d] pyrimidine-2, 4 (lH, 3H) -dione

A solution of 355 mg (0.785 mmol, 93% purity) of the compound from Example 119A and 164 μΐ (1.18 mmol) of triethylamine in 8 ml of THF was admixed with 153 mg (0.942 mmol) of CDI and stirred at RT for about 16 h. It was then concentrated to dryness. The remaining residue was taken up in ethyl acetate and washed successively with 1 M hydrochloric acid, water, saturated sodium bicarbonate solution and saturated sodium chloride solution. After drying over anhydrous magnesium sulfate, it was filtered and concentrated. The solid residue was purified by preparative HPLC (Method 11). Evaporation of the product fractions and drying under high vacuum gave 223 mg (63% of theory) of the title compound.

Ή NMR (400 MHz, DMSO-de, δ / ppm): 6.52 (s, 1H), 4.38 (br t, 2H), 4.34 (s, 2H), 4.27-4.00 (m, 2H), 3.26- 3.15 (m, 4H), 2.38 (s, 3H), 1.33 (s, 3H), 1.00-0.73 (m, 4H).

LC / MS (Method 1, ESIpos): R _t = 1.57 min, m / z = 447.13 [M + H] ⁺ . Example 76

5-Methyl-3- (l-methylcyclopropyl) -6 - [(5-o ^

fluoromethoxy) ethyl] thieno [2,3-d] pyrimidine-2,4 (lH, 3H) -dione

234 mg (0.411 mmol, 94% purity) of the compound from Ex. 264A were dissolved in a mixture of 14 ml of methanol and trimethyl orthoformate and treated at RT with 1 ml (4.11 mmol) of a 4 M solution of hydrogen chloride in dioxane. After 2 days, the reaction mixture was concentrated and the residue taken up in ethyl acetate. It was washed successively with water and saturated sodium chloride solution. After drying over anhydrous magnesium sulfate, it was filtered and concentrated again. The remaining residue was purified by preparative HPLC (Method 1 1). After evaporation of the product fractions and drying in a high vacuum, 125 mg (68% of theory) of the title compound were obtained.

Ή-NMR (400 MHz, DMSO-de, δ / ppm): 11.58 (br.s, 1H), 7.82 (s, 1H), 4.92 (s, 2H), 4.37 (br.t, 2H), 4.28- 3.99 (m, 2H), 2.44 (s, 3H), 1.33 (s, 3H), 0.97-0.72 (m, 4H). LC / MS (Method 1, ESIpos): R _t = 1.46 min, m / z = 446.11 [M + H] ⁺ .

Example 77

1- (2-ethoxyethyl) -5-methyl-3- (1-methylcyclopropyl) -6 - [(2-oxoimidazolidin-1-yl) methyl] thieno [2,3-d] pyrimidine-2,4 ( lH, 3H) -dione

Analogously to the process described under Example 3, 240 mg (0.536 mmol, 85% purity) of the compound of Ex. 120A and 104 mg (0.643 mmol) of CDI 122 mg (55% of theory) of the title compound were prepared.

'H-NMR (400 MHz, DMSO-de, δ / ppm): 6.51 (s, 1H), 4.33 (s, 2H), 4.12-3.82 (m, 2H), 3.64 (t, 2H), 3.43 (q , 2H), 3.26-3.15 (m, 4H), 2.38 (s, 3H), 1.33 (s, 3H), 1.04 (t, 3H), 0.96-0.74 (m, 4H).

LC / MS (Method 1, ESIpos): R _t = 1.38 min, m / z = 407.17 [M + H] ⁺ .

Example 78 1- (2-Ethoxyethyl) -5-methyl-3- (1-methylcyclopropyl) -6 - [(5-oxo-4,5-dihydro-1H-1,2,4-triazol-1-yl) - methyl] thieno [2,3-d] pyrimidine-2,4 (1H, 3H) -dione

Analogously to the process described under Example 2, 73 mg (57% of theory) of the title compound were prepared from 155 mg (0.313 mmol) of the compound from Example 265A. The product was then stirred after isolation by preparative HPLC still with acetonitrile at RT.

'H-NMR (400 MHz, DMSO-de, δ / ppm): 11.58 (br.s, 1H), 7.82 (s, 1H), 4.91 (s, 2H), 4.11 -3.80 (m, 2H), 3.62 (br t, 2H), 3.42 (q, 2H), 2.44 (s, 3H), 1.33 (s, 3H), 1.02 (t, 3H), 0.95-0.74 (m, 4H).

LC / MS (Method 1, ESIpos): R _t = 1.27 min, m / z = 406.15 [M + H] ⁺ .

Example 79

1 - (2-Isopropoxyethyl) -5-methyl-3- (1-methylcyclopropyl) -6 - [(2-oxoimidazolidin-1-yl) -yl] -thieno [2,3-d] pyrimidine-2,4 ( lH, 3H) -dione

Analogously to the process described under Example 3, 250 mg (0.570 mmol, 90% purity) of the compound of Ex. 121A and 111 mg (0.684 mmol) of CDI 153 mg (63% of theory) of the title compound were prepared. Ή NMR (400 MHz, DMSO-d ₆ , δ / ppm): 6.51 (s, 1H), 4.33 (s, 2H), 4.06-3.80 (m, 2H), 3.63 (t, 2H), 3.54 (sept , 1H), 3.26-3.15 (m, 4H), 2.37 (s, 3H), 1.33 (s, 3H), 1.00 (d, 6H), 0.96-0.74 (m, 4H).

LC / MS (Method 1, ESIpos): R _t = 1.50 min, m / z = 421.19 [M + H] ⁺ .

Example 80- (2-Isopropoxyethyl) -5-methyl-3- (1-methylcyclopropyl) -6 - [(5-oxo-4,5-dihydro-1H-1,2,4-triazol-1-yl) methyl] thieno [2,3-d] pyrimidine-2,4 (lH, 3H) -dione

255 mg (0.500 mmol) of the compound from Ex. 266A were dissolved in a mixture of 16 ml each of methanol and trimethyl orthoformate, and 1.3 ml (5.00 mmol) of a 4 M solution of hydrogen chloride in dioxane were added at RT. After 2 days, the reaction mixture was concentrated and the residue taken up in ethyl acetate. It was washed successively with water and saturated sodium chloride solution. After drying over anhydrous magnesium sulfate, it was filtered and concentrated again. The remaining residue was stirred with a little acetonitrile at RT. The solid was filtered off with suction and dried under high vacuum. The filtrate was concentrated and the residue was purified by preparative HPLC (Method 11). After one- Evaporation of the product fractions, drying under high vacuum and combining with the previously isolated solid, a total of 138 mg (65% of theory) of the title compound were obtained.

Ή-ΝΜΡ (400 MHz, DMSO-d ₆ , δ / ppm): 11.57 (br.s, 1H), 7.82 (s, 1H), 4.91 (s, 2H), 4.08-3.78 (m, 2H), 3.62 (t, 2H), 3.53 (sept, 1H), 2.44 (s, 3H), 1.33 (s, 3H), 0.99 (d, 6H), 0.95-0.72 (m, 4H). LC / MS (Method 1, ESIpos): R _t = 1.39 min, m / z = 420.17 [M + H] ⁺ .

Example 81

5-Methyl-3- (1-methylcyclopropyl) -6 - [(2-oxoimidazolidin-1-yl) methyl] -1 - [(2R) -tetrahydrofuran-2-ylmethyl] thieno [2,3-d] pyrimidine 2,4 (lH, 3H) -dione

A solution of 220 mg (0.532 mmol, 95% purity) of the compound from Example 122A and 111 μΐ (0.799 mmol) of triethylamine in 6 ml of THF was admixed with 104 mg (0.639 mmol) of CDI and stirred at RT for about 16 h. It was then concentrated to dryness. The remaining residue was taken up in ethyl acetate and washed successively with 1 M hydrochloric acid, water, saturated sodium bicarbonate solution and saturated sodium chloride solution. After drying over anhydrous magnesium sulfate, it was filtered and concentrated. The solid residue was purified by preparative HPLC (Method 11). Evaporation of the product fractions and drying under high vacuum gave 125 mg (56% of theory) of the title compound.

'H-NMR (400 MHz, DMSO-de, δ / ppm): 6.50 (s, 1H), 4.33 (s, 2H), 4.25-4.14 (m, 1H), 4.13-3.85 (m, 1H), 3.82 -3.48 (m, 3H), 3.27-3.15 (m, 4H), 2.37 (s, 3H), 2.03-1.74 (m, 3H), 1.70-1.58 (m, 1H), 1.33 (s, 3H), 0.98 -0.72 (m, 4H).

LC / MS (Method 1, ESIpos): R _t = 1.36 min, m / z = 419.17 [M + H] ⁺ .

Example 82

5-Methyl-3- (1-methylcyclopropyl) -6 - [(2-oxoimidazolidin-1-yl) methyl] -1 - [(2S) -tetrahydrofuran-2-ylmethyl] thieno [2,3-d] pyrimidine 2,4 (lH, 3H) -dione

Analogously to the process described in Example 3, from 308 mg (0.706 mmol, 90% purity) of the compound from Ex. 123A, 188 mg (63% of theory) of the title compound were prepared.

'H-NMR (400 MHz, DMSO-de, δ / ppm): 6.50 (s, 1H), 4.33 (s, 2H), 4.25-4.14 (m, 1H), 4.13-3.86 (m, 1H), 3.81 -3.50 (m, 3H), 3.26-3.15 (m, 4H), 2.38 (s, 3H), 2.03-1.75 (m, 3H), 1.71-1.58 (m, 1H), 1.33 (s, 3H), 0.99 -0.72 (m, 4H).

LC / MS (Method 1, ESIpos): R _t = 1.36 min, m / z = 419.17 [M + H] ⁺ .

Example 83

5-Methyl-3- (l-methylcyclopropyl) -6 - [(5-oxo-4,5-dihydro-lH-l, 2,4-triazol-l-yl) methyl] -l - [(2R) - -dione tetrahydrofuran-2-ylmethyl] thieno [2,3-d] pyrimidine-2,4 (lH, 3H)

Analogously to the process described under Example 2, 155 mg (0.266 mmol, 87% purity) of the compound from Example 267A were used to produce 40 mg (35% of theory) of the title compound. The reaction time was approx. 16 h. 'H-NMR (400 MHz, DMSO-d _6, δ / ppm): 11:58 (br s, 1H.), 7.82 (s, 1H), 4.91 (s, 2H), 4.26-3.84 (m, 2H), 3.80-3.46 (m, 3H), 2.43 (s, 3H), 2.02-1.74 (m, 3H), 1.71-1.56 (m, 1H), 1.33 (s, 3H), 0.98-0.70 (m, 4H).

LC / MS (Method 2, ESIpos): R _t = 0.69 min, m / z = 418 [M + H] Example 84

5-Methyl-3- (l-methylcyclopropyl) -6 - [(5-oxo-4,5-dihydro-lH-l, 2,4-triazol-l-yl) methyl] -l - [(2S) - -dione tetrahydrofuran-2-ylmethyl] thieno [2,3-d] pyrimidine-2,4 (lH, 3H)

Analogously to the process described under Example 2, 295 mg (0.581 mmol) of the compound from Example 268A were used to produce 90 mg (37% of theory) of the title compound. The reaction time was approx. 16 h.

'H-NMR (400 MHz, DMSO-de, δ / ppm): 11.57 (s, 1H), 7.83 (s, 1H), 4.91 (s, 2H), 4.28-3.86 (m, 2H), 3.80-3.46 (m, 3H), 2.43 (s, 3H), 2.03-1.75 (m, 3H), 1.70-1.53 (m, 1H), 1.33 (s, 3H), 0.99-0.70 (m, 4H).

LC / MS (Method 1, ESIpos): R _t = 1.25 min, m / z = 418.15 [M + H] ⁺ . Example 85 1- (2-Methoxyethyl) -5-methyl-6 - [(2-oxoimidazolidin-1-yl) methyl] -3- [1- (trifluoromethyl) cyclopropyl] thieno [2,3-d] pyrimidine -2,4 (lH, 3H) -dione

Analogously to the process described under Example 31, 320 mg (0.723 mmol, 95% purity) of the compound from Ex. 124A and 141 mg (0.868 mmol) of CDI 171 mg (52% of theory) of the title compound were prepared.

Ή-NMR (400 MHz, DMSO-de, δ / ppm): 6.53 (s, 1H), 4.34 (s, 2H), 4.11-3.90 (m, 2H), 3.61 (t, 2H), 3.28-3.16 ( m, 4H), 3.24 (s, 3H), 2.37 (s, 3H), 1.66-1.49 (m, 2H), 1.39-1.30 (m, 2H). LC / MS (Method 1, ESIpos): R _t = 1.43 min, m / z = 447.13 [M + H] ⁺ . Example 86

[1 - ({1- (2-methoxyethyl) -5-methyl-2,4-dioxo-3- [1- (trifluoromethyl) cyclopropyl] -1,2,3,4-tetrahydrothieno [2,3- d] pyrimidin-6-yl} methyl) imidazolidine-2-ylidene] cyanamide

41 mg (33% of theory) of 320 mg (0.723 mmol, 95% purity) of the compound from Example 124A and 159 mg (1.09 mmol) of dimethyl N-cyanodithioimino carbonate were prepared analogously to the process described under Example 41. ) of the title compound.

Ή-NMR (400 MHz, DMSO-de, δ / ppm): 8.08 (s, 1H), 4.47 (s, 2H), 4.09-3.93 (m, 2H), 3.62 (t, 2H), 3.51-3.36 ( m, 4H), 3.24 (s, 3H), 2.39 (s, 3H), 1.67-1.50 (m, 2H), 1.41-1.28 (m, 2H).

LC / MS (Method 1, ESIpos): R _t = 1.54 min, m / z = 471.14 [M + H] ⁺ .

Example 87

Methyl [1- ({1- (2-methoxyethyl) -5-methyl-2,4-dioxo-3- [1- (trifluoromethyl) cyclopropyl] -1, 2,3,4-tetrahydrothieno [2,3- d] pyrimidin-6-yl} methyl) imidazolidine-2-ylidene] carbamate

320 mg (0.723 mmol, 95% purity) of the compound from Ex. 124A and 202 μΐ (1.45 mmol) of triethylamine were dissolved in 10 ml of dichloromethane and treated dropwise with a solution of 226 mg (1.45 mmol) of methyl (dichloromethylene) carbamate in 5 ml of dichloromethane. After the reaction mixture was stirred at RT for about 18 h, it was diluted with water and extracted with ethyl acetate. The organic extract was washed with saturated sodium chloride solution. dried over anhydrous magnesium sulfate, filtered and concentrated. 115 mg (30% of theory) of the title compound were isolated from the residue by preparative HPLC (Method 11).

'H-NMR (400 MHz, DMSO-de, δ / ppm): 8.02 (s, 1H), 4.55 (s, 2H), 4.08-3.91 (m, 2H), 3.61 (t, 2H), 3.53 (s , 3H), 3.49-3.42 (m, 2H), 3.39-3.30 (m, 2H, partially covered by the water signal), 3.23 (s, 3H), 2.40 (s, 3H), 1.66-1.51 (m, 2H), 1.41-1.27 (m, 2H).

LC / MS (Method 1, ESIpos): R _t = 1.35 min, m / z = 504.15 [M + H] ⁺ .

Example 88

6 - [(2,3-dioxopiperazin-1-yl) methyl] -1- (2-methoxyethyl) -5-methyl-3- [1- (trifluoromethyl) cyclopropyl] thieno [2,3-d] pyrimidine -2,4 (lH, 3H) -dione

A solution of 320 mg (0.723 mmol, 95% purity) of the compound from Example 124A in 15 ml of ethanol was mixed with 185 μΐ (1.34 mmol) of diethyl oxalate and stirred at 80 ° C for about 16 h. Thereafter, the reaction mixture was concentrated and the residue was taken up in ethyl acetate. The organic phase was washed successively with saturated sodium bicarbonate solution, water and saturated sodium chloride solution. After drying over anhydrous magnesium sulfate, it was filtered and concentrated. From the remaining residue, 133 mg (37% of theory) of the title compound were isolated by preparative HPLC (Method 11).

Ή NMR (400 MHz, DMSO-de, δ / ppm): 8.62 (br.s, 1H), 4.69 (d, 2H), 4.09-3.93 (m, 2H), 3.61 (t, 2H), 3.54- 3.42 (m, 2H), 3.34-3.28 (m, 2H, almost completely covered by the water signal), 3.24 (s, 3H), 2.41 (s, 3H), 1.66-1.51 (m, 2H), 1.40-1.28 (m , 2H).

LC / MS (method 1, ESIneg): R _t = 1.28 min, m / z = 519.12 [MH] -.

Example 89 1- (2-Methoxyethyl) -5-methyl-6 - [(5-oxo-4,5-dihydro-1H-1,2,4-triazol-1-yl) methyl] -3- (trifluoromethyl) cyclopropyl] thieno [2,3-d] pyrimidine-2,4 (1H, 3H) -dione

Analogously to the process described under Example 50, from 490 mg (0.796 mmol, 87% purity) of the compound from Example 269A, 75 mg (21% of theory) of the title compound were prepared.

Ή-NMR (400 MHz, DMSO-de, δ / ppm): 11.59 (br.s, 1H), 7.83 (s, 1H), 4.93 (s, 2H), 4.08-3.89 (m, 2H), 3.60 ( t, 2H), 3.23 (s, 3H), 2.43 (s, 3H), 1.66-1.48 (m, 2H), 1.40-1.26 (m, 2H).

LC / MS (Method 1, ESIpos): R _t = 1.33 min, m / z = 446.11 [M + H] ⁺ .

Example 90 1- (3-Fluoropropyl) -5-methyl-3- (2-methylcyclopropyl) -6 - [(2-oxoimidazolidin-1-yl) methyl] thieno [2,3-d] pyrimidine-2,4 (1H, 3H) -dione (trans-racemate)

510 mg (0.941 mmol) of the compound from Ex. 125A were dissolved in 40 ml dioxane and admixed with 236 mg (1.412 mmol) CDI. The mixture was stirred at RT for 19 h. The reaction solution was then concentrated on a rotary evaporator. The residue was dissolved in 12 ml of DMSO and this solution was purified by preparative HPLC (Method 14). After combining the product fractions and freeze-drying, 228 mg (71% of theory) of the title compound were obtained.

'H-NMR (400 MHz, DMSO-de, δ / ppm): 6.53 (s, 1H), 4.58 (t, 1H), 4.46 (t, 1H), 4.34 (s, 2H), 3.99- 3.86 (m , 2H), 3.27-3.16 (m, 4H), 2.37 (s, 3H), 2.25-2.19 (m, 1H), 2.12-2.03 (m, 1H), 2.03-1.95 (m, 1H), 1.14 (i.e. , 3H), 1.04-0.92 (m, 1H), 0.86-0.78 (m, 2H).

LC / MS (Method 4, ESIpos): R _t = 0.96 min, m / z = 395 [M + H] ⁺ . Example 91 1- (3-Fluoro-phenyl) -5-methyl-3- (2-methylcyclopropyl) -6 - [(2-oxo-imidazolidin-1-yl) -methyl] thieno [2,3-d] pyrimidine-2 , 4 (1H, 3H) -dione {trans-enantiomer 1)

228 mg of the racemic compound from Ex. 90 were dissolved in 8 ml of an ethanol / methanol mixture (1: 1) and separated by preparative HPLC on a chiral phase into the enantiomers [column: Daicel Chiralpak AD-H, 5 μm, 250 mm x 30 mm; Eluent A: methanol + 0.1% diethylamine (99%), eluent B: ethanol + 0.1% diethylamine (99%), isocratic 50% A + 50% B; Flow: 60 ml / min; Detection: 254 um]. The product fractions were concentrated on a rotary evaporator, washed with tert. Butanol added and freeze-dried. There were obtained 88 mg (77% of theory) of the title compound (enantiomer 1) and 83 mg (72% of theory) of enantiomer 2 (see example 92).

Ή-NMR (400 MHz, DMSO-d ₆ , δ / ppm): 6.53 (s, 1H), 4.58 (t, 1H), 4.46 (t, 1H), 4.34 (s, 2H), 4.00- 3.86 (m , 2H), 3.27-3.16 (m, 4H), 2.37 (s, 3H), 2.26-2.19 (m, 1H), 2.12-2.03 (m, 1H), 2.03-1.95 (m, 1H), 1.14 (i.e. , 3H), 1.04-0.92 (m, 1H), 0.86-0.78 (m, 2H).

Chiral analytical HPLC [column: Daicel Chiralpak AD-H, 3 μm, 100 mm × 4.6 mm; Eluent A: methanol + 0.1% diethylamine (99%), eluent B: ethanol, isocratic 50% A + 50% B; Flow: 1.4 ml / min; Temperature: 25 ° C; Detection: 254 nm]: R _t = 2.43 min.

Example 92 1- (3-Fluoropropyl) -5-methyl-3- (2-methylcyclopropyl) -6 - [(2-oxoimidazolidin-1-yl) methyl] thieno [2,3-d] pyrimidine-2,4 (1H, 3H) -dione {trans-enantiomer 2)

The title compound (83 mg) was obtained as the second enantiomer in the preparative HPLC separation of the racemate from Ex. 90 (see Ex. 91).

'H-NMR (400 MHz, DMSO-de, δ / ppm): 6.53 (s, 1H), 4.58 (t, 1H), 4.46 (t, 1H), 4.34 (s, 2H), 4.00- 3.86 (m , 2H), 3.27-3.15 (m, 4H), 2.37 (s, 3H), 2.26-2.18 (m, 1H), 2.11-2.03 (m, 1H), 2.03-1.96 (m, 1H), 1.14 (i.e. , 3H), 1.04-0.92 (m, 1H), 0.86-0.78 (m, 2H).

Chiral analytical HPLC [column: Daicel Chiralpak AD-H, 3 μm, 100 mm × 4.6 mm; Eluent A: methanol + 0.1% diethylamine (99%), eluent B: ethanol, isocratic 50% A + 50% B; Flow: 1.4 ml / min; Temperature: 25 ° C; Detection: 254 nm]: R _t = 3.05 min.

Example 93 5-Methyl-3- (2-methylcyclopropyl) -6 - [(2-oxoimidazolidin-1-yl) methyl] -1- (3,3,3-trifluoropropyl) thieno [2,3-d] pyrimidine -2,4 (1H, 3H) -dione {trans-racemate)

610 mg (1.237 mmol) of the compound from Ex. 126A were dissolved in 50 ml of dioxane and admixed with 310 mg (1855 mmol) of CDI. The mixture was stirred at RT for 19 h. The reaction solution was then concentrated on a rotary evaporator. The residue was dissolved in 12 ml of DMSO and this solution was purified by preparative HPLC (Method 14). After combining the product fractions and freeze-drying, 380 mg (70% of theory) of the title compound were obtained.

Ή-NMR (400 MHz, DMSO-de, δ / ppm): 6.54 (s, 1H), 4.35 (s, 2H), 4.04 (dsext, 2H), 3.28-3.16 (m, 4H), 2.80-2.67 ( m, 2H), 2.38 (s, 3H), 2.26-2.20 (m, 1H), 1.15 (d, 3H), 1.04-0.93 (m, 1H), 0.87-0.79 (m, 2H).

LC / MS (Method 4, ESIpos): R _t = 1.06 min, m / z = 431 [M + H] ⁺ . Example 94 1- (2-Methoxyethyl) -5-methyl-3- (2-methylcyclopropyl) -6 - [(2-oxoimidazolidin-1-yl) methyl] thieno [2,3-d] pyrimidine-2,4 (1H, 3H) -dione (trans-racemate)

504 mg (1,114 mmol) of the compound from Example 127A were dissolved in 45 ml of dioxane and treated with 279 mg (1.671 mmol) of CDI. The mixture was stirred at RT for 20 h. The reaction solution was then concentrated on a rotary evaporator. The residue was dissolved in 12 ml of DMSO and this solution was purified by preparative HPLC (Method 14). After combining the product fractions and freeze-drying, 224 mg (58% of theory) of the title compound were obtained.

Ή-NMR (400 MHz, DMSO-de, δ / ppm): 6.53 (s, 1H), 4.33 (s, 2H), 3.97 (br, d, 2H), 3.63-3.57 (m, 2H), 3.27- 3.16 (m, 7H), 2.36 (s, 3H), 2.26-2.20 (m, 1H), 1.14 (d, 3H), 1.03-0.93 (m, 1H), 0.86-0.79 (m, 2H). LC / MS (Method 4, ESIpos): R _t = 0.92 min, m / z = 393 [M + H] ⁺ .

Example 95 1- (2-Methoxyethyl) -5-methyl-3- (2-methylcyclopropyl) -6 - [(2-oxoimidazolidin-1-yl) methyl] thieno [2,3-d] pyrimidine-2,4 (1H, 3H) -dione (trans-enantiomer 1)

224 mg of the racemic compound from Ex. 94 were dissolved in 13 ml of an ethanol / methanol mixture (1: 1) and separated by preparative HPLC on a chiral phase into the enantiomers [column: Daicel Chiralpak AD-H, 5 μm, 250 mm x 30 mm; Eluent A: methanol + 0.1% diethylamine (99%), eluent B: ethanol + 0.1% diethylamine (99%), isocratic 50% A + 50% B; Flow: 30 ml / min; Detection: 254 um]. The product fractions were concentrated on a rotary evaporator, tert. Butanol added and freeze-dried. 105 mg (93% of theory) of the title compound (enantiomer 1) and 106 mg (94% of theory) of the enantiomer 2 (see Example 96) were obtained. Ή-ΝΜΡν (400 MHz, DMSO-d ₆ , δ / ρρηι): 6.53 (s, 1H), 4.33 (s, 2H), 4.03-3.91 (m, 2H), 3.60 (t, 2H), 3.27-3.16 (m, 7H), 2.36 (s, 3H), 2.23 (dt, 1H), 1.14 (d, 3H), 1.04-0.93 (m, 1H), 0.86-0.79 (m, 2H).

Chiral analytical HPLC [column: Daicel Chiralpak AD-H, 3 μm, 100 mm × 4.6 mm; Eluent A: methanol + 0.1% diethylamine (99%), eluent B: ethanol, isocratic 50% A + 50% B; Flow: 1.4 ml / min; Temperature: 25 ° C; Detection: 254 nm]: R _t = 2.68 min.

Example 96 1- (2-Methoxyethyl) -5-methyl-3- (2-methylcyclopropyl) -6 - [(2-oxoimidazolidin-1-yl) methyl] thieno [2,3-d] pyrimidine-2,4 (lH, 3H) -dione (trans-enantiomer 2)

The title compound (106 mg) was obtained as a second enantiomer in the preparative HPLC separation of the racemate from Ex. 94 (see Ex. 95).

Ή-NMR (400 MHz, DMSO-de, δ / ppm): 6.53 (s, 1H), 4.33 (s, 2H), 4.03-3.91 (m, 2H), 3.60 (t, 2H), 3.27-3.16 ( m, 7H), 2.36 (s, 3H), 2.23 (dt, 1H), 1.14 (d, 4H), 1.03-0.92 (m, 1H), 0.82 (dd, 2H).

Chiral analytical HPLC [column: Daicel Chiralpak AD-H, 3 μm, 100 mm × 4.6 mm; Eluent A: methanol + 0.1% diethylamine (99%), eluent B: ethanol, isocratic 50% A + 50% B; Flow: 1.4 ml / min; Temperature: 25 ° C; Detection: 254 nm]: R _t = 3.60 min.

Example 97

3- (2,2-Dimethylcyclopropyl) -1- (3-fluoropropyl) -5-methyl-6 - [(2-oxoimidazolidin-1-yl) methyl] thieno [2,3-d] pyrimidine-2,4 (1H, 3H) -dione (racemate)

Analogously to Ex. 90, 869 mg (1.13 mmol, 49% purity) of the compound from Ex. 128A in 50 ml of dioxane were reacted with 279 mg (1.67 mmol) of CDI. 121 mg (26% of theory) of the title compound were obtained.

'H-NMR (400 MHz, DMSO-de, δ / ppm): 6.53 (s, 1H), 4.58 (t, 1H), 4.46 (t, 1H), 4.34 (s, 2H), 4.04- 3.86 (m , 2H), 3.29-3.16 (m, 4H), 2.41-2.34 (m, 4H), 2.12-2.04 (m, 1H), 2.04-1.96 (m, 1H), 1.16 (s, 3H), 1.03 (dd , 1H), 0.85 (s, 3H), 0.72 (dd, 1H).

LC / MS (Method 4, ESIpos): R _t = 1.03 min, m / z = 409 [M + H] ⁺ .

Example 98

3- (2,2-Dimethylcyclopropyl) -1- (3-fluoropropyl) -5-methyl-6 - [(2-oxoimidazolidin-1-yl) methyl] thieno [2,3-d] pyrimidine-2,4 (lH, 3H) -dione (enantiomer 1)

118 mg of the racemic compound from Example 97 were separated into the enantiomers by preparative HPLC on a chiral phase [column: Daicel Chiralpak IC, 5 μm, 250 mm × 30 mm; Eluent A: acetonitrile + 0.1% diethylamine (99%), eluent B: ethanol, isocratic 90% A + 10% B; Flow: 50 ml / min; Detection: 254 nm]. The product fractions were concentrated on a rotary evaporator, washed with tert. Butanol added and freeze-dried. 48 mg (81% of theory) of the title compound (enantiomer 1) and 50 mg (84% of theory) of the enantiomer 2 (see Example 99) were obtained.

Ή-NMR (400 MHz, DMSO-de, δ / ppm): 6.53 (s, 1H), 4.58 (t, 1H), 4.46 (t, 1H), 4.34 (s, 2H), 4.04- 3.86 (m, 2H), 3.29-3.17 (m, 4H), 2.41-2.34 (m, 4H), 2.12-2.04 (m, 1H), 2.04-1.96 (m, 1H), 1.19- 1.14 (m, 3H), 1.03 ( dd, 1H), 0.85 (s, 3H), 0.75-0.69 (m, 1H).

Chiral analytical HPLC [column: Daicel Chiralpak IC, 3 μm, 100 mm × 4.6 mm; Eluent A: acetonitrile + 0.1% diethylamine (99%), eluent B: ethanol, isocratic 90% A + 10% B; Flow: 1.4 ml / min; Temperature: 25 ° C; Detection: 254 nm]: R _t = 3.08 min. Example 99

3- (2,2-Dimethylcyclopropyl) -1- (3-fluorophenyl) -5-methyl-6 - [(2-oxoimidazolidin-1-yl) methyl] thieno [2,3-d] pyrimidine-2 , 4 (1H, 3H) -dione (enantiomer 2)

The title compound (50 mg) was obtained as the second enantiomer in the preparative HPLC separation of the racemate from Ex. 97 (see Ex. 98).

Ή-NMR (400 MHz, DMSO-de, δ / ppm): 6.53 (s, 1H), 4.58 (t, 1H), 4.46 (t, 1H), 4.34 (s, 2H), 4.04- 3.86 (m, 2H), 3.29-3.17 (m, 4H), 2.40-2.36 (m, 4H), 2.12-2.04 (m, 1H), 2.04-1.96 (m, 1H), 1.16 (s, 3H), 1.06-1.00 ( m, 1H), 0.85 (s, 3H), 0.75-0.69 (m, 1H). Chiral analytical HPLC [column: Daicel Chiralpak IC, 3 μm, 100 mm × 4.6 mm; Eluent A: acetonitrile + 0.1% diethylamine (99%), eluent B: ethanol, isocratic 90% A + 10% B; Flow: 1.4 ml / min; Temperature: 25 ° C; Detection: 254 nm]: R _t = 3.85 min.

Example 100

3 - (2,2-Dimethylcyclopropyl) -5-methyl-6- [(2-oxoimidazolidin-1-yl) methyl] -1- (3,3,3-trifluoropropyl) thieno [2,3-d] pyrimidine-2,4 (1H, 3H) -dione (racemate)

Analogously to Ex. 90, 699 mg (1.40 mmol, 84% purity) of the compound from Ex. 129A in 50 ml of dioxane were reacted with 352 mg (2.105 mmol) of CDI. There were obtained 348 mg (64% of theory) of the title compound. Ή-ΝΜΡν (400 MHz, DMSO-d ₆ , δ / ρρηι): 6.55 (s, 1H), 4.35 (s, 2H), 4.07 (td, 2H), 3.29-3.17 (m, 4H), 2.81-2.69 (m, 2H), 2.42-2.36 (m, 4H), 1.17 (s, 3H), 1.04 (dd, 1H), 0.85 (s, 3H), 0.72 (dd, 1H).

LC / MS (Method 4, ESIpos): R _t = 1.14 min, m / z = 445 [M + H] ⁺ . Example 101 3- (2,2-Dimethylcyclopropyl) -5-methyl-6 - [(2-oxoimidazolidin-1-yl) methyl] -1- (3,3,3-trifluoropropyl) thieno [2,3- d] pyrimidine-2,4 (1H, 3H) -dione (enantiomer 1)

348 mg of the racemic compound from Example 100 were fractionated by preparative HPLC on a chiral phase into the enantiomers [column: Daicel Chiralpak IC, 5 μm, 250 mm × 30 mm; Eluent A: acetonitrile + 0.1% diethylamine (99%), eluent B: MTBE + 0.1% diethylamine (99%), isocratically 50%) A + 50%) B; Flow: 50 ml / min; Detection: 254 nm]. The product fractions were concentrated on a rotary evaporator, washed with tert. Butanol added and freeze-dried. This gave 149 mg (85% of theory) of the title compound (enantiomer 1) and 151 mg (86% of theory) of the enantiomer 2 (see Example 102). 'H-NMR (400 MHz, DMSO-d _6, δ / ppm): (br. S, 1H) (br. S, 2H) 6:55, 4:35 (s, 2H), 4:07, 3:27 to 3:18 (m, 4H ), 2.82-2.69 (m, 2H), 2.41-2.36 (m, 4H), 1.16 (s, 3H), 1.04 (br t, 1H), 0.85 (s, 3H), 0.72 (t, 1H).

Chiral analytical HPLC [column: Daicel Chiralpak IC, 3 μm, 100 mm × 4.6 mm; Eluent A: acetonitrile + 0.1% diethylamine (99%), eluent B: MTBE + 0.1% diethylamine (99%), isocratic: 50% A + 50% B; Flow: 1.4 ml / min; Temperature: 25 ° C; Detection: 254 nm]: R _t = 3.63 min.

Example 102

3 - (2,2-Dimethylcyclopropyl) -5-methyl-6- [(2-oxoimidazolidin-1-yl) methyl] -1- (3,3,3-trifluoropropyl) thieno [2,3-d] pyrimidine-2,4 (1H, 3H) -dione {enantiomer 2)

The title compound (151 mg) was obtained as the second enantiomer in the preparative HPLC separation of the racemate from Ex. 100 (see Ex. 101).

'H-NMR (400 MHz, DMSO-de, δ / ppm): 6.55 (br.s, 1H), 4.35 (s, 2H), 4.07 (td, 2H), 3.29-3.17 (m, 4H), 2.81 -2.68 (m, 2H), 2.42-2.36 (m, 4H), 1.16 (s, 3H), 1.04 (dd, 1H), 0.85 (s, 3H), 0.72 (dd, 1H).

Chiral analytical HPLC [column: Daicel Chiralpak IC, 3 μm, 100 mm × 4.6 mm; Eluent A: acetonitrile + 0.1% diethylamine (99%), eluent B: MTBE + 0.1% diethylamine (99%), isocratic: 50% A + 50% B; Flow: 1.4 ml / min; Temperature: 25 ° C; Detection: 254 μm]: R _t = 4.42 min.

Example 103 3- (2,2-Dimethylcyclopropyl) -1- (2-methoxyethyl) -5-methyl-6 - [(2-oxoimidazolidin-1-yl) methyl] thieno [2,3-d] pyrimidine-2 , 4 (1H, 3H) -dione (racemate)

Analogously to Ex. 90, 465 mg (1.1 mmol, 90%> purity) of the compound from Ex. 130A in 45 ml of dioxane were reacted with 276 mg (1.65 mmol) of CDI. 310 mg (68% of theory) of the title compound were obtained.

Ή-NMR (400 MHz, DMSO-de, δ / ppm): 6.53 (s, 1H), 4.33 (s, 2H), 4.10-3.99 (m, 1H), 3.98-3.87 (m, 1H), 3.66- 3.5 (m, 2H), 3.29-3.16 (m, 6H), 2.42-2.34 (m, 4H), 1.16 (s, 3H), 1.03 (dd, 1H), 0.85 (s, 3H), 0.72 (dd, 1H).

LC / MS (Method 4, ESIpos): R _t = 0.99 min, m / z = 407 [M + H] ⁺ . Example 104

3- (2,2-Dimethylcyclopropyl) -1- (2-methoxyethyl) -5-methyl-6 - [(2-oxoimidazolidin-1-yl) methyl] thieno [2,3-d] pyrimidine-2,4 (lH, 3H) -dione (enantiomer 1)

264 mg of the racemic compound from Ex. 103 were separated into the enantiomers by preparative SFC-HPLC on a chiral phase [column: Daicel Chiralpak IC, 5 μm, 250 mm × 30 mm; Eluent A: carbon dioxide, eluent B: ethanol, isocratic 51% A + 49%>B; Flow: 100 ml / min; Temperature: 40 ° C; BPR: 150 bar; MWD: 254 nm]. The product fractions were concentrated on a rotary evaporator, washed with tert. Butanol added and freeze-dried. 114 mg (86% of theory) of the title compound (enantiomer 1) and 116 mg (87% of theory) of the enantiomer 2 (see Example 105) were obtained.

Ή-NMR (400 MHz, DMSO-de, δ / ppm): 6.53 (s, 1H), 4.33 (s, 2H), 4.10-3.99 (m, 1H), 3.97-3.87 (m, 1H), 3.65- 3.56 (m, 2H), 3.28-3.16 (m, 6H), 2.41-2.34 (m, 4H), 1.16 (s, 3H), 1.03 (dd, 1H), 0.85 (s, 3H), 0.72 (dd, 1H). Chiral analytical SFC-HPLC [column: Daicel Chiralpak IC, 5 μm, 100 mm × 4.6 mm; Eluent A: carbon dioxide, eluent B: ethanol, isocratic 51%> A + 49%>B; Flow: 4.0 ml / min; Temperature: 37.5 ° C; BPR: 100 bar; MWD: 254 nm]: R _t = 2.74 min.

Example 105

3- (2,2-Dimethylcyclopropyl) -1- (2-methoxyethyl) -5-methyl-6 - [(2-oxoimidazolidin-1-yl) methyl] thieno [2,3-d] pyrimidine-2,4 (1H, 3H) -dione {enantiomer 2)

The title compound (116 mg) was obtained as the second enantiomer in the preparative HPLC separation of the racemate from Ex. 103 (see Example 104).

'H-NMR (400 MHz, DMSO-de, δ / ppm): 6.53 (s, 1H), 4.33 (s, 2H), 4.10-3.99 (m, 1H), 3.98-3.87 (m, 1H), 3.66 -3.55 (m, 2H), 3.29-3.17 (m, 6H), 2.42-2.34 (m, 4H), 1.16 (s, 3H), 1.03 (dd, 1H), 0.85 (s, 3H), 0.72 (dd , 1H).

Chiral analytical SFC-HPLC [column: Daicel Chiralpak IC, 5 μm, 100 mm × 4.6 mm; Eluent A: carbon dioxide, eluent B: ethanol, isocratic 51% A + 49%>B; Flow: 4.0 ml / min; Temperature: 37.5 ° C; BPR: 100 bar; MWD: 254 μm]: R _t = 3.42 min.

Example 106 3 - (1-Ethylcyclopropyl) -5-methyl-6- [(2-oxoimidazolidin-1-yl) -methyl] -1- (3,3,3-trifluoropropyl) thieno [2,3-d] pyrimidine-2,4 (lH, 3H) -dione

Analogously to the process described under Example 3, from 159 mg (0.342 mmol, 90%> purity) of the compound from Example 131A and 67 mg (0.410 mmol) of CDI 82 mg (53% of theory) of the title compound produced.

Ή-NMR (400 MHz, DMSO-de, δ / ppm): 6.52 (s, 1H), 4.35 (s, 2H), 4.14-3.96 (m, 2H), 3.28-3.17 (m, 4H), 2.82- 2.65 (m, 2H), 2.38 (s, 3H), 1.69 (q, 2H), 1.01-0.87 (m, 2H), 0.86-0.77 (m, 2H), 0.81 (t, 3H).

LC / MS (Method 1, ESIpos): R _t = 1.69 min, m / z = 445.15 [M + H] ⁺ . Example 107

3- (l-ethylcyclopropyl) -5-methyl-6 - [(5-oxo-4,5-dihydro-lH-l, 2,4-triazol-l-yl) methyl] -l- (3,3, 3-trifluoropropyl) thieno [2,3-d] pyrimidine-2,4 (1H, 3H) -dione

Analogously to the process described under Example 2, from 116 mg (0.217 mmol) of the compound from Example 270A, 66 mg (68% of theory) of the title compound were prepared.

Ή-NMR (400 MHz, DMSO-de, δ / ppm): 11.59 (br.s, 1H), 7.83 (s, 1H), 4.94 (s, 2H), 4.12-3.96 (m, 2H), 2.80- 2.65 (m, 2H), 2.45 (s, 3H), 1.69 (q, 2H), 1.00-0.86 (m, 2H), 0.86-0.74 (m, 2H), 0.81 (t, 3H).

LC / MS (Method 1, ESIpos): R _t = 1.61 min, m / z = 444.13 [M + H] ⁺ .

Example 108

3- (1-Ethylcyclopropyl) -1- (2-methoxyethyl) -5-methyl-6 - [(2-oxoimidazolidin-1-yl) methyl] thieno [2,3-d] pyrimidine-2,4 (1H , 3H) -dione

Analogously to the process described in Example 3, 247 mg (0.584 mmol, 90% purity) of the compound of Ex. 132A and 114 mg (0.701 mmol) of CDI 104 mg (43% of theory) of the title compound were prepared. 'H-NMR (400 MHz, DMSO-d _6, δ / ppm): 6:51 (s, 1H), 4:33 (s, 2H), 4.07-3.87 (m, 2H), 3.60 (t, 2H), 3.28- 3.15 (m, 4H), 3.23 (s, 3H), 2.37 (s, 3H), 1.76-1.62 (m, 2H), 0.99-0.87 (m, 2H), 0.86-0.75 (m, 2H), 0.81 ( t, 3H).

LC / MS (Method 1, ESIpos): R _t = 1.44 min, m / z = 407.17 [M + H] ⁺ . Example 109

3- (1-Ethylcyclopropyl) -1- (2-methoxyethyl) -5-methyl-6 - [(5-oxo-4,5-dihydro-1H-1,2,4-triazol-1-yl) -methyl ] thieno [2,3-d] pyrimidine-2,4 (lH, 3H) -dione

Analogously to the process described under Example 50, 169 mg (0.324 mmol, 95% purity) of the compound from Example 271A were used to produce 62 mg (47% of theory) of the title compound.

Ή-NMR (400 MHz, DMSO-de, δ / ppm): 11.58 (br.s, 1H), 7.83 (s, 1H), 4.91 (s, 2H), 4.06-3.86 (m, 2H), 3.59 ( t, 2H), 3.22 (s, 3H), 2.43 (s, 3H), 1.69 (q, 2H), 0.99-0.86 (m, 2H), 0.86-0.74 (m, 2H), 0.81 (t, 3H) , LC / MS (Method 1, ESIpos): R _t = 1.33 min, m / z = 406.15 [M + H] ⁺ . Example 110

3-Cyclobutyl-5-methyl-6 - [(2-oxoimidazolidin-1-yl) methyl] -1- (3,3,3-trifluoropropyl) thieno-pyrimidine-2,4 (1H, 3H) -dione

Analogously to the process described under Example 3, from 500 mg (0.989 mmol, 80% purity) of the compound from Ex. 133A and 192 mg (1.19 mmol) of CDI 138 mg (32% of theory) of the title compound were prepared.

'H-NMR (400 MHz, DMSO-de, δ / ppm): 6.53 (s, 1H), 5.21 (quin, 1H), 4.36 (s, 2H), 4.06 (t, 2H), 3.29-3.17 (m , 4H), 2.92-2.66 (m, 4H), 2.39 (s, 3H), 2.16 (qt, 2H), 1.89-1.63 (m, 2H). LC / MS (Method 1, ESIpos): R _t = 1.77 min, m / z = 431.14 [M + H] ⁺ . Example 111

[1- {[3-Cyclobutyl-5-methyl-2,4-dioxo-l- (3,3,3-trifluoropropyl) -l, 2,3,4-tetrahydrothieno [2,3-d] pyrimidine 6-yl] methyl} imidazolidine-2-ylidene] cyanamide

500 mg (0.989 mmol, 80% purity) of the compound from Ex. 133A were dissolved in 10 ml of DMF and combined with 217 mg (1.48 mmol) of dimethyl N-cyanodithioiminocarbonate and 273 mg (1.98 mmol) of potassium carbonate. The mixture was stirred for 4 h at 80 ° C in a microwave oven (Biotage initiator with dynamic control of the irradiation power). Thereafter, the reaction mixture was concentrated to dryness and then purified by preparative HPLC (Method 11). The product fractions were combined, evaporated and dried under high vacuum. 224 mg (49% of theory) of the title compound were obtained.

'H-NMR (400 MHz, DMSO-de, δ / ppm): 8.08 (s, 1H), 5.21 (quin, 1H), 4.49 (s, 2H), 4.08 (t, 2H), 3.52-3.36 (m , 4H), 2.91-2.68 (m, 4H), 2.40 (s, 3H), 2.16 (qt, 2H), 1.88-1.65 (m, 2H). LC / MS (Method 2, ESIpos): R _t = 0.98 min, m / z = 455 [M + H] ⁺ .

Example 112

Methyl [1 - {[3 -cyclobutyl-5-methyl-2,4-dioxo-1 - (3,3,3-trifluoropropyl) -1,2,3,4-tetrahydrothieno [2,3-d] pyrimidin-6-yl] methyl} imidazolidine-2-ylidene] carbamate

Analogously to the process described under Ex. 26, from 500 mg (0.989 mmol, 80% purity) of the compound from Ex. 133A and 308 mg (1.98 mmol) of methyl (dichloromethylene) carbamate 204 mg (42% of theory) of th. ) of the title compound.

'H-NMR (400 MHz, DMSO-de, δ / ppm): 8.02 (s, 1H), 5.21 (quin, 1H), 4.57 (s, 2H), 4.05 (t, 2H), 3.53 (s, 3H ), 3.50-3.41 (m, 2H), 3.38-3.29 (m, 2H, partially covered by the water signal), 2.91 - 2.67 (m, 4H), 2.41 (s, 3H), 2.16 (qt, 2H), 1.88- 1.63 (m, 2H).

LC / MS (Method 1, ESIpos): R _t = 1.79 min, m / z = 488.16 [M + H] ⁺ .

Example 113

3-Cyclobutyl-6 - [(2,3-dioxopiperazin-1-yl) methyl] -5-methyl-1 - (3, 3, 3-trifluoropropyl) thieno-pyrimidine-2,4 (1H, 3H) -dione

A solution of 500 mg (0.989 mmol, 80% purity) of the compound from Ex. 133A in 40 ml of ethanol was mixed with 252 .mu.l (1.83 mmol) of diethyl oxalate and stirred at 80.degree. C. for about 16 h. Thereafter, the reaction mixture was concentrated and then purified by preparative HPLC (Method 11). Evaporation of the product fraction and drying under high vacuum gave 118 mg (26% of theory) of the title compound.

Ή-NMR (400 MHz, DMSO-de, δ / ppm): 8.62 (br.s, 1H), 5.20 (quin, 1H), 4.70 (s, 2H), 4.07 (t, 2H), 3.53-3.43 ( m, 2H), 3.34-3.28 (m, 2H, almost completely obscured by the water signal), 2.91 -2.68 (m, 4H), 2.42 (s, 3H), 2.23-2.10 (m, 2H), 1.88-1.63 (m , 2H).

LC / MS (method 2, ESIneg): R _t = 0.85 min, m / z = 503 [M-H + HCOOH] -

Example 114

3-cyclobutyl-5-methyl-6 - [(5-oxo-4,5-dihydro-lH-l, 2,4-triazol-l-yl) methyl] -l- (3,3,3-trifluoro propyl) thieno [2,3-d] pyrimidine-2,4 (lH, 3H) -dione

121 mg (0.233 mmol) of the compound from Ex. 272A were dissolved in a mixture of 5.6 ml each of methanol and trimethyl orthoformate, and 582 μl (2.33 mmol) of a 4 M solution of hydrogen chloride in dioxane were added at RT. After 1 h and after 2 h each additional 291 μΐ (1.17 mmol) of 4 M solution of hydrogen chloride in dioxane were added. After a total of 16 h, the reaction mixture was diluted with water and extracted with ethyl acetate. The organic extract was evaporated and the residue was purified by preparative HPLC (Method 11). After evaporation of the product fractions and drying in a high vacuum, 41 mg (41% of theory) of the title compound were obtained. Ή-NMR (400 MHz, DMSO-d ₆ , δ / ppm): 11.60 (br.s, 1H), 7.84 (s, 1H), 5.20 (quin, 1H), 4.94 (s, 2H), 4.05 (t , 2H), 2.90-2.64 (m, 4H), 2.45 (s, 3H), 2.23-2.10 (m, 2H), 1.88-1.63 (m, 2H).

LC / MS (Method 1, ESIpos): R _t = 1.64 min, m / z = 430.12 [M + H] ⁺ .

Example 115

3-cyclobutyl-1- (2-methoxyethyl) -5-methyl-6- [(2-oxoimidazolidin-1-yl) methyl] thieno [2,3-d] pyrimidine-2,4 (1H, 3H) -dione

A solution of 650 mg (1.42 mmol, 80% purity) of the compound from Ex. 134A and 297 μM (2.13 mmol) of triethylamine in 15 ml of THF was admixed with 276 mg (1.70 mmol) of CDI and stirred at RT for about 16 h , It was then concentrated to dryness. The remaining residue was taken up in ethyl acetate and washed successively with 1 M hydrochloric acid, water, saturated sodium bicarbonate solution and saturated sodium chloride solution. After drying over what- magnesium sulfate was filtered and concentrated. The solid residue was stirred in a little acetonitrile at RT, then filtered off with suction and dried under high vacuum. 170 mg (30% of theory) of the title compound were obtained.

'H-NMR (400 MHz, DMSO-de, δ / ppm): 6.52 (s, 1H), 5.22 (quin, 1H), 4.33 (s, 2H), 3.99 (t, 2H), 3.62 (t, 2H ), 3.28-3.16 (m, 4H), 3.24 (s, 3H), 2.92-2.77 (m, 2H), 2.37 (s, 3H), 2.22-2.09 (m, 2H), 1.87-1.64 (m, 2H ).

LC / MS (Method 2, ESIpos): R _t = 0.81 min, m / z = 393 [M + H] ⁺ . Example 116

[1- {[3-Cyclobutyl-1- (2-methoxyethyl) -5-methyl-2,4-dioxo-1,2,3,4-tetrahydrothieno [2,3-d] pyrimidin-6-yl] methyl} imidazolidine-2-ylidene] cyanamide

600 mg (1.31 mmol, 80% purity) of the compound from Ex. 134A were dissolved in 12 ml of DMF and admixed with 287 mg (1.97 mmol) of dimethyl N-cyanodithioiminocarbonate and 362 mg (2.62 mmol) of potassium carbonate. The mixture was stirred for 4 h at 80 ° C in a microwave oven (Biotage initiator with dynamic control of the irradiation power). Thereafter, the reaction mixture was concentrated to dryness and then purified by preparative HPLC (Method 11). The product fractions were combined, evaporated and dried under high vacuum. There were obtained 335 mg (61% of theory) of the title compound.

Ή-NMR (400 MHz, DMSO-de, δ / ppm): 8.07 (s, 1H), 5.21 (quin, 1H), 4.46 (s, 2H), 4.00 (t, 2H), 3.63 (t, 2H) , 3.50-3.37 (m, 4H), 3.24 (s, 3H), 2.91-2.77 (m, 2H), 2.39 (s, 3H), 2.16 (qt, 2H), 1.88- 1.64 (m, 2H).

LC / MS (Method 2, ESIpos): R _t = 0.87 min, m / z = 417 [M + H] ⁺ . Example 117

Methyl [1 - {[3 -cyclobutyl-1- (2-methoxyethyl) -5-methyl-2,4-dioxo-1,2,3,4-tetrahydrothieno [2,3-d] pyrimidine-6- yl] methyl} imidazolidine-2-ylidene] carbamate

Analogously to the process described under Example 26, from 650 mg (1.42 mmol, 80% purity) of the compound from Example 134A and 442 mg (2.84 mmol) of methyl (dichloromethylene) carbamate 336 mg (52% of theory) the title compound. In contrast to the previously described purification process, preparative HPLC according to MPLC was carried out here.

Ή NMR (400 MHz, DMSO-de, δ / ppm): 8.06 (br s, 1H), 5.22 (quin, 1H), 4.56 (s, 2H), 3.98 (t, 2H), 3.62 (t, 2H), 3.54 (s, 3H), 3.50-3.42 (m, 2H), 3.36-3.29 (m, 2H, partially obscured by the water signal), 3.23 (s, 3H), 2.91 -2.77 (m, 2H), 2.40 (s, 3H), 2.16 (qt, 2H), 1.88-1.64 (m, 2H).

LC / MS (Method 2, ESIpos): R _t = 0.82 min, m / z = 450 [M + H] ⁺ . Example 118

3-Cyclobutyl-6 - [(2,3-dioxopiperazin-1-yl) methyl] -1- (2-methoxyethyl) -5-methylthieno [2,3-d] pyrimidine-2,4 (1H, 3H) -dione

A solution of 480 mg (1.05 mmol, 80% purity) of the compound from Ex. 134A in 35 ml of ethanol was mixed with 267 μΐ (1.94 mmol) of diethyl oxalate and stirred at 80 ° C for about 16 h. Thereafter, the reaction mixture was concentrated and then prepurified by preparative HPLC (Method 11). After evaporation of the product fraction, the resulting solid was stirred in a little acetonitrile at RT. After aspirating and drying in a high vacuum, 74 mg (16%) d. Th.) Of the title compound. 'H-NMR (400 MHz, DMSO-de, δ / ρρηι): 8.61 (br.s, 1H), 5.21 (quin, 1H), 4.68 (s, 2H), 3.99 (t, 2H), 3.62 (t , 2H), 3.52-3.43 (m, 2H), 3.34-3.28 (m, 2H, almost completely obscured by the water signal), 3.24 (s, 3H), 2.92-2.76 (m, 2H), 2.41 (s, 3H) , 2.22-2.09 (m, 2H), 1.89-1.63 (m, 2H).

LC / MS (Method 2, ESIneg): R _t = 0.73 min, m / z = 465 [M-H + HCOOH] -. Example 119

3-Cyclobutyl-1- (2-methoxyethyl) -5-methyl-6 - [(5-oxo-4,5-dihydro-1H-1,2,4-triazol-1-yl) methyl] thieno [2 , 3-d] pyrimidine-2,4 (lH, 3H) -dione

110 mg (0.228 mmol) of the compound from Ex. 273A were dissolved in a mixture of 5.5 ml each of methanol and trimethyl orthoformate, and 571 μl (2.28 mmol) of a 4 M solution of hydrogen chloride in dioxane were added at RT. After 3 h and after 15 h each additional 285 μΐ (1.14 mmol) of 4 M solution of hydrogen chloride in dioxane were added. After a total of 40 hours, the reaction mixture was diluted with water and extracted with ethyl acetate. The organic extract was concentrated and the residue obtained was stirred in a mixture of acetonitrile, methanol and water. The solid was filtered off with suction and dried under high vacuum. The filtrate was purified by preparative HPLC (Method 11). Concentration of the product fractions, drying under high vacuum and combining with the previously isolated solid gave 70 mg (78% of theory) of the title compound.

Ή-NMR (400 MHz, DMSO-de, δ / ppm): 11.59 (br.s, 1H), 7.83 (s, 1H), 5.21 (quin, 1H), 4.92 (s, 2H), 3.97 (t, 2H), 3.61 (t, 2H), 3.23 (s, 3H), 2.90-2.76 (m, 2H), 2.43 (s, 3H), 2.21-2.10 (m, 2H), 1.87-1.63 (m, 2H) ,

LC / MS (Method 1, ESIpos): R _t = 1.39 min, m / z = 392.14 [M + H] ⁺ . Example 120

3- (3,3-Difluorocyclobutyl) -5-methyl-6 - [(2-oxoimidazolidin-1-yl) methyl] -1- (3,3,3-trifluoropropyl) thieno [2,3-d] pyrimidine -2,4 (lH, 3H) -dione

200 mg (0.39 mmol, 87% purity) of the compound from Ex. 135A were dissolved in 3 ml of THF and treated with 77 mg (0.47 mmol) of CDI. The mixture was stirred at RT for 16 h. The reaction solution was then concentrated on a rotary evaporator. The residue was taken up in ethyl acetate and washed successively with 1 M hydrochloric acid, saturated aqueous sodium bicarbonate solution and saturated sodium chloride solution. Subsequently, the organic phase was dried over anhydrous magnesium sulfate, filtered and concentrated. The residue obtained was purified by preparative HPLC (Method 13). Evaporation of the product fractions and drying under high vacuum yielded 29 mg (16%> th. 'H-NMR (400 MHz, DMSO-d _6, δ / ppm): 6:54 (s, 1H), 5.15 (td, 1H), 4:37 (s, 2H), 4:07 (t, 2H), 3:54 to 3:39 ( m, 2H), 3.28-3.18 (m, 4H), 2.91-2.67 (m, 4H), 2.39 (s, 3H).

LC / MS (Method 2, ESIpos): R _t = 0.95 min, m / z = 467 [M + H] ⁺ .

Example 121

[l- {[3- (3,3-difluorocyclobutyl) -5-methyl-2,4-dioxo-l- (3,3,3-trifluoropropyl) -1,3,3,4-tetrahydrothieno [2 , 3-d] pyrimidin-6-yl] methyl} imidazolidine-2-ylidene] cyanamide

200 mg (0.40 mmol, 87% purity) of the compound from Ex. 135A were dissolved in 16 ml of DMF and admixed with 109 mg (0.79 mmol) of potassium carbonate and 87 mg (0.593 mmol) of dimethyl N-cyanodithio-iminocarbonate. The mixture was stirred for 3 hours at 80 ° C in a microwave oven (biotage initiator with dynamic control of the irradiation power). Thereafter, the reaction taken up in ethyl acetate and washed successively with saturated aqueous sodium bicarbonate solution, water and saturated sodium chloride solution. Subsequently, the organic phase was dried over anhydrous magnesium sulfate, filtered and concentrated. The residue was purified by preparative HPLC (Method 13). Evaporation of the product fractions and drying under high vacuum gave 15 mg (8% of theory) of the title compound.

'H-NMR (400 MHz, DMSO-de, δ / ppm): 8.09 (s, 1H), 5.17-5.12 (m, 1H), 4.50 (s, 2H), 4.09 (t, 2H), 3.53-3.39 (m, 6H), 2.90-2.71 (m, 4H), 2.41 (s, 3H).

LC / MS (Method 2, ESIpos): R _t = 1.32 min, m / z = 491 [M + H] ⁺ .

Example 122 Methyl [1- {[3- (3,3-difluorocyclobutyl) -5-methyl-2,4-dioxo-1- (3,3,3-trifluoropropyl) -l, 2,3,4-tetra - hydrothieno [2,3-d] pyrimidin-6-yl] methyl} imidazolidin-2-ylidene] carbamate

250 mg (0.50 mmol, 87% purity) of the compound of Ex. 135A and 138 μM (0.99 mmol) of triethylamine were dissolved in 23 ml of dichloromethane and admixed with 77 mg (0.49 mmol) of methyl (dichloromethylene) carbamate. After the reaction mixture was stirred for about 16 h at RT, it was diluted with ethyl acetate and washed successively with saturated sodium bicarbonate solution, water and saturated sodium chloride solution. After drying over anhydrous magnesium sulfate, it was filtered and concentrated. The remaining residue was purified by preparative HPLC (Method 13). Concentration of the product fraction and drying of the residue under high vacuum gave 177 mg (68% of theory) of the title compound.

'H-NMR (400 MHz, DMSO-de, δ / ppm): 5.27-5.19 (m, 1H), 4.80 (s, 2H), 4.17 (dd, 2H), 3.91 (s, 3H), 3.79 (dd , 2H), 3.65 (dd, 2H), 3.57-3.47 (m, 2H), 2.87-2.79 (m, 2H), 2.77-2.67 (m, 2H), 2.48 (s, 3H).

LC / MS (Method 2, ESIpos): R _t = 0.93 min, m / z = 524 [M + H] Example 123

3- (3,3-difluorocyclobutyl) -6 - [(2,3-dioxopiperazin-l-yl ^

thieno [2,3-d] pyrimidine-2,4 (lH, 3H) -dione

200 mg (0.40 mmol, 87% purity) of the compound from Ex. 135A were dissolved in 16 ml of ethanol and admixed with 108 mg (0.73 mmol) of diethyl oxalate. The mixture was stirred at 80 ° C for 3 days. Thereafter, the reaction solution was concentrated on a rotary evaporator. The residue obtained was purified by preparative HPLC (Method 13). Evaporation of the product fractions and drying under high vacuum gave 96 mg (49% of theory) of the title compound. 'H-NMR (400 MHz, DMSO-d _6, δ / ppm): 8.63, 5:19 to 5:08 (m, 1H), 4.71 (s, 2H), 4:08 (t, 2H), (br s, 1H). 3.52-3.38 (m, 4H), 2.92-2.71 (m, 4H), 2.43 (s, 3H).

LC / MS (Method 2, ESIpos): R _t = 0.88 min, m / z = 495 [M + H] ⁺ . Example 124

3- (3,3-difluorocyclobutyl) -5-methyl-6 - [(5-oxo-4,5-dihydro-lH-l, 2,4-triazol-l-yl) methyl] -l- (3, 3,3-trifluoropropyl) thieno [2,3-d] pyrimidine-2,4 (1H, 3H) -dione

756 mg (1.07 mmol, 79% purity) of the compound from Ex. 274A were initially charged in 26.3 ml of trimethyl orthoformate and 26.3 ml of methanol, and 2.7 ml (10.7 mmol) of a 4 M solution of hydrogen chloride in dioxane were added. Since the turnover after 18 h stirring at RT still was incomplete, an additional 1.3 ml of 4 M hydrogen chloride in dioxane was added and the mixture was further stirred for 4 h. Thereafter, 1.3 ml of 4 M hydrogen chloride in dioxane were added again and stirred for a further 2.5 h. The reaction mixture was then added with water and extracted with ethyl acetate. The organic phase was concentrated and the residue was purified by preparative HPLC (Method 13). The product fractions were combined and concentrated and the residue was dried under high vacuum. There were obtained 267 mg (54% of theory) of the title compound.

'H-NMR (400 MHz, DMSO-de, δ / ppm): 11.60 (br.s, 1H), 7.84 (s, 1H), 5.18-5.09 (m, 1H), 4.95 (s, 2H), 4.06 (t, 2H), 3.52-3.41 (m, 2H), 2.90-2.67 (m, 4H), 2.45 (s, 3H). LC / MS (Method 2, ESIpos): R _t = 0.88 min, m / z = 466 [M + H] ⁺ .

Example 125

3- (3,3-Difluorocyclobutyl) -1- (2-methoxyethyl) -5-methyl-6 - [(2-oxoimidazolidin-1-yl) methyl] thieno [2,3-d] pyrimidine-2,4 (lH, 3H) -dione

300 mg (0.51 mmol, 69% purity) of the compound from Ex. 136A were dissolved in 4 ml of THF and combined with 99 mg (0.62 mmol) of CDI and 107 μM (0.77 mmol) of triethylamine. The mixture was stirred at RT for 16 h. The reaction solution was then concentrated on a rotary evaporator. The residue was taken up in ethyl acetate and washed successively with 1 M hydrochloric acid, saturated sodium bicarbonate solution and saturated sodium chloride solution. Subsequently, the organic phase was dried over anhydrous magnesium sulfate, filtered and concentrated. The residue obtained was purified by preparative HPLC (Method 13). Evaporation of the product fractions and drying under high vacuum gave 73 mg (33% of theory) of the title compound.

Ή-NMR (400 MHz, DMSO-de, δ / ppm): 6.53 (br.s, 1H), 5.20-5.11 (m, 1H), 4.35 (s, 2H), 4.00 (t, 2H), 3.62 ( t, 2H), 3.54-3.40 (m, 2H), 3.25-3.18 (m, 7H), 2.89-2.79 (m, 2H), 2.38 (s, 3H).

LC / MS (Method 2, ESIpos): R _t = 0.85 min, m / z = 429 [M + H] Example 126

[1 - {[3- (3,3-difluorocyclobutyl) -1- (2-methoxyethyl) -5-methyl-2,4-dioxo-1,2,3,4-tetrahydrothieno [2,3-d] pyrimidin-6-yl] methyl} imidazolidine-2-ylidene] cyanamide

377 mg (0.64 mmol, 69% purity) of the compound from Ex. 136A were dissolved in 25 ml of DMF and admixed with 178 mg (1.29 mmol) of potassium carbonate. The mixture was stirred at RT for 15 min, then 141 mg (0.97 mmol) of dimethyl N-cyanodithioiminocarbonate were added. The reaction mixture was stirred for 3 h at 80 ° C in a microwave oven (Biotage initiator with dynamic control of the irradiation power). Thereafter, the reaction mixture was taken up in ethyl acetate and washed successively with saturated sodium bicarbonate solution, water and saturated sodium chloride solution. Subsequently, the organic phase was dried over anhydrous magnesium sulfate, filtered and concentrated. The residue obtained was purified by preparative HPLC (Method 13). Evaporation of the product fractions and drying under high vacuum gave 52 mg (17% of theory) of the title compound. 'H-NMR (400 MHz, DMSO-d _6, δ / ppm): 8:09 (s, 1H), 5:20 to 5:12 (m, 1H), 4:48 (s, 2H), 4.01, (t, 2H), 3.63 ( t, 2H), 3.50-3.30 (m, 6H), 3.26 (s, 3H), 2.88-2.80 (m, 2H), 2.39 (s, 3H).

LC / MS (Method 2, ESIpos): R _t = 0.89 min, m / z = 453 [M + H] ⁺ .

Example 127

Methyl [1 - {[3- (3,3-difluorocyclobutyl) -1- (2-methoxyethyl) -5-methyl-2,4-dioxo-1,2,3,4-tetrahydrothieno [2,3 -d] pyrimidin-6-yl] methyl} imidazolidine-2-ylidene] carbamate

250 mg (0.54 mmol, 69% purity) of the compound of Ex. 136A and 151 μΐ (1.08 mmol) of triethylamine were dissolved in 25 ml of dichloromethane and admixed with 84 mg (0.54 mmol) of methyl (dichloromethylene) carbamate. After the reaction mixture was stirred for about 16 h at RT, it was diluted with ethyl acetate and washed successively with saturated sodium bicarbonate solution, water and saturated sodium chloride solution. After drying over anhydrous magnesium sulfate, it was filtered and concentrated. The remaining residue was purified by preparative HPLC (Method 13). Concentration of the product fraction and drying of the residue under high vacuum gave 104 mg (40% of theory) of the title compound. Ή-NMR (400 MHz, DMSO-d ₆ , δ / ppm): 5.20-5.12 (m, 1H), 4.72 (br, s, 2H), 4.01 (t, 2H), 3.72 (br, s, 3H) , 3.63 (t, 2H), 3.58 (d, 2H), 3.57-3.46 (m, 3H), 2.90-2.80 (m, 2H), 2.41 (s, 3H).

LC / MS (Method 1, ESIpos): R _t = 0.84 min, m / z = 486 [M + H] ⁺ .

Example 128

3- (3,3-Difluorocyclobutyl) -6 - [(2,3-dioxopiperazin-1-yl) methyl] -1- (2-methoxyethyl) -5-methylthieno [2,3-d] pyrimidine-2, 4 (lH, 3H) -dione

250 mg (0.43 mmol, 69%> purity) of the compound from Ex. 136A were dissolved in 17 ml of ethanol and admixed with 116 mg (0.79 mmol) of diethyl oxalate. The mixture was stirred at 80 ° C for 2 days. Thereafter, the reaction solution was concentrated on a rotary evaporator. The residue obtained was purified by preparative HPLC (Method 13). Evaporation of the product fractions and drying under high vacuum gave 85 mg (43% of theory) of the title compound. 'H-NMR (400 MHz, DMSO-de, δ / ρρηι): 8.62 (br.s, 1H), 5.19-5.08 (m, 1H), 4.69 (s, 2H), 4.00 (t, 2H), 3.62 (t, 2H), 3.54-4.40 (m, 4H), 3.33-3.29 (m, 2H), 3.24 (s, 3H), 2.90-2.79 (m, 2H), 2.42 (s,

3H).

LC / MS (Method 2, ESIpos): R _t = 0.80 min, m / z = 457 [M + H] ⁺ . Example 129

3- (3,3-Difluorocyclobutyl) -1- (2-methoxyethyl) -5-methyl-6 - [(5-oxo-4,5-dihydro-1H-1,2,4-triazol-1-yl) methyl] thieno [2,3-d] pyrimidine-2,4 (lH, 3H) -dione

232 mg (0.39 mmol, 86% purity) of the compound from Ex. 275A were initially charged in 9.5 ml of trimethyl orthoformate and 9.5 ml of methanol, and 1 ml (3.9 mmol) of a 4 M solution of hydrogen chloride in dioxane was added. Since the reaction was still incomplete after stirring at RT for 18 h, a further 0.5 ml of 4 M hydrogen chloride in dioxane were added and the mixture was stirred for a further 4 h. Thereafter, another 0.5 ml of 4 M hydrogen chloride in dioxane was added and stirred for a further 2.5 h. The reaction mixture was then treated with water and extracted with ethyl acetate. The organic phase was concentrated and the residue was purified by preparative HPLC (Method 13). The product fractions were combined and concentrated and the residue was dried under high vacuum. 90 mg (55% of theory) of the title compound were obtained.

Ή-NMR (400 MHz, DMSO-de, δ / ppm): 11.60 (br.s, 1H), 7.83 (s, 1H), 5.20-5.09 (m, 1H), 4.93 (s 2H), 3.99 (t , 2H), 3.61 (t, 2H), 3.52-3.39 (m, 2H), 3.23 (s, 3H), 2.90-2.80 (m, 2H), 2.44 (s, 3H).

LC / MS (Method 2, ESIpos): R _t = 0.77 min, m / z = 428 [M + H] ⁺ .

Example 130

5-Methyl-3- (oxetan-3-yl) -6- [(2-oxo-imidazolidin-1-yl) -methyl] -1- (3,3,3-trifluoropropyl) -thieno-pyrimidine-2,4 (1H, 3H ) -dione

Analogously to the process described under Example 3, 135 mg (0.266 mmol, 80% purity) of the compound of Ex. 137A and 52 mg (0.319 mmol) of CDI 49 mg (41% of theory) of the title compound were prepared. Ή-NMR (400 MHz, DMSO-d ₆ , δ / ppm): 6.54 (s, 1H), 5.02 (quin, 1H), 4.76-4.65 (m, 4H), 4.37 (s, 2H), 4.06 (t , 2H), 3.28-3.18 (m, 4H), 2.81-2.68 (m, 2H), 2.36 (s, 3H).

LC / MS (Method 1, ESIpos): R _t = 1.24 min, m / z = 433.11 [M + H] ⁺ .

Example 131

[1- {[5-Methyl-3- (oxetan-3-yl) -2,4-dioxo-1- (3,3,3-trifluoropropyl) -l, 2,3,4-tetrahydrothieno [2,3 -d] pyrimidin-6-yl] methyl} imidazolidin-2-ylidene] cyanamide

41 mg (0.266 mmol, 80% purity) of the compound of Ex. 137A and 58 mg (0.399 mmol) of dimethyl N-cyanodithioimino carbonate, 14 mg (11% of theory), were prepared analogously to the process described under Example 41. ) of the title compound. Ή-NMR (400 MHz, DMSO-d _6, δ / ppm): 8:09 (s, 1H), 5:02 (quin, 1H), 4.73-4.67 (m, 4H), and 4.50 (s, 2H), 4:07 (t , 2H), 3.55-3.37 (m, 4H), 2.84-2.67 (m, 2H), 2.38 (s, 3H).

LC / MS (Method 1, ESIpos): R _t = 1.35 min, m / z = 457.12 [M + H] ⁺ . Example 132

Methyl- [l - {[5-methyl-3- (oxetan-3-yl) -2,4-dioxo-l- (3,3,3-tr

[2,3-d] pyrimidin-6-yl] methyl} imidazolidine-2-ylidene] carbamate

Analogously to the process described under Example 87, 135 mg (0.266 mmol, 80% purity) of the compound from Ex. 137A and 83 mg (0.531 mmol) of methyl (dichloromethylene) carbamate were admixed with 7 mg (5% of theory). ) of the title compound.

Ή-NMR (400 MHz, DMSO-de, δ / ppm): 8.03 (s, 1H), 5.02 (quin, 1H), 4.75-4.65 (m, 4H), 4.58 (s, 2H), 4.05 (t, 2H), 3.53 (s, 3H), 3.50-3.43 (m, 2H), 3.38-3.32 (m, 2H), 2.82-2.64 (m, 2H), 2.39 (s, 3H).

LC / MS (Method 3, ESIpos): R _t = 1.82 min, m / z = 490 [M + H] ⁺ . Example 133

6 - [(2,3-dioxopiperazin-1-yl) methyl] -5-methyl-3- (oxetan-3-yl) -1- (3,3,3-trifluoropropyl) thieno [2,3-d ] pyrimidine-2,4 (lH, 3H) -dione

Analogously to the process described under Ex. 88, from 135 mg (0.266 mmol, 80% purity) of the compound of Ex. 137A and 73 mg (0.492 mmol) of diethyl oxalate 15 mg (12%) of theory. Th.) Of the title compound. 'H-NMR (400 MHz, DMSO-de, δ / ppm): 8.63 (br.s, 1H), 5.02 (quin, 1H), 4.75-4.65 (m, 4H), 4.71 (s, 2H), 4.06 (t, 2H), 3.53-3.45 (m, 2H), 2.83-2.67 (m, 2H), 2.40 (s, 3H).

LC / MS (Method 1, ESIpos): R _t = 1.08 min, m / z = 461.11 [M + H] ⁺ . Example 134 5-Methyl-3- (1-methylcyclobutyl) -6- [(2-oxoimidazolidin-1-yl) -methyl] -1- (3,3,3-trifluoropropyl) thieno [2,3-d] pyrimidine-2,4 (lH, 3H) -dione

Analogously to the process described in Example 3, 340 mg (0.650 mmol, 80% purity) of the compound of Ex. 138A and 126 mg (0.780 mmol) of CDI 174 mg (60% of theory) of the title compound were prepared.

Ή-NMR (400 MHz, DMSO-de, δ / ppm): 6.53 (s, 1H), 4.35 (s, 2H), 4.03 (t, 2H), 3.29-3.16 (m, 4H), 2.82-2.64 ( m, 2H), 2.36 (s, 3H), 2.34-2.21 (m, 4H), 1.82-1.56 (m, 2H), 1.51 (s, 3H).

LC / MS (Method 1, ESIpos): R _t = 1.80 min, m / z = 445.15 [M + H] ⁺ .

Example 135 [1- {[5-Methyl-3- (1-methylcyclobutyl) -2,4-dioxo-1- (3,3,3-trifluoropropyl) -l, 2,3,4-tetrahydrothieno- [2, 3-d] pyrimidin-6-yl] methyl} imidazolidine-2-ylidene] cyanamide

Analogously to the process described under Example 41, 340 mg (0.650 mmol, 80% purity) of the compound of Ex. 138A and 143 mg (0.975 mmol) of dimethyl N-cyanodithio-iminocarbonate 140 mg (45% of theory) were used. ) of the title compound. After preparative HPLC, a second purification step was carried out here by means of MPLC (Biotage Isolera One, cartridge SNAP KP-Sil, 50 g of silica gel, mobile phase cyclohexane / ethyl acetate 1: 2 → 0: 1).

'H-NMR (400 MHz, DMSO-de, δ / ppm): 8.07 (s, 1H), 4.48 (s, 2H), 4.05 (t, 2H), 3.52-3.37 (m, 4H), 2.83-2.65 (m, 2H), 2.38 (s, 3H), 2.33-2.24 (m, 4H), 1.81-1.56 (m, 2H), 1.51 (s, 3H).

LC / MS (Method 1, ESIpos): R _t = 1.89 min, m / z = 469.16 [M + H] ⁺ .

Example 136 Methyl [1- {[5-methyl-3- (1-methylcyclobutyl) -2,4-dioxo-1- (3,3,3-trifluoropropyl) -l, 2,3,4-tetrahydrothieno [2,3-d] pyrimidin-6-yl] methyl} imidazolidine-2-ylidene] carbamate

340 mg (0.650 mmol, 80% purity) of the compound of Ex. 138A and 181 μΐ (1.30 mmol) of triethylamine were dissolved in 15 ml of dichloromethane and treated dropwise with a solution of 203 mg (1.30 mmol) of methyl (dichloromethylene) carbamate in 10 ml of dichloromethane. After the reaction mixture had been stirred at RT for about 18 h, it was evaporated to dryness and the residue was purified by preparative HPLC (method 11). The product fractions were combined and evaporated and the residue was finally stirred with pentane. 84 mg (25% of theory) of the title compound were isolated. Ή-NMR (400 MHz, DMSO-d ₆ , δ / ppm): 8.02 (s, 1H), 4.56 (s, 2H), 4.03 (br.t, 2H), 3.53 (s, 3H), 3.49-3.42 (m, 2H), 3.37-3.31 (m, 2H, partially covered by the water signal), 2.80-2.63 (m, 2H), 2.39 (s, 3H), 2.33-2.25 (m, 4H), 1.82-1.56 (m , 2H), 1.51 (s, 3H).

LC / MS (Method 2, ESIpos): R _t = 0.93 min, m / z = 502 [M + H] ⁺ . Example 137

6 - [(2,3-dioxopiperazin-1-yl) methyl] -5-methyl-3- (1-methylcyclobutyl) -1- (3,3,3-trifluorophenyl) thieno [2,3-d] pyrimidine-2,4 (lH, 3H) -dione

Analogously to the process described under Ex. 88, 138 mg (44% of theory) of the title compound were prepared from 340 mg (0.650 mmol, 80% purity) of the compound of Example 138A and 178 mg (1.20 mmol) of diethyl oxalate. Before final purification by means of preparative HPLC, purification by MPLC was carried out here (Biotage Isolera One, cartridge SNAP KP-Sil, 50 g of silica gel, mobile phase cyclohexane / ethyl acetate 2: 1 → dichloromethane / methanol 10: 1 ).

Ή-NMR (400 MHz, DMSO-de, δ / ppm): 8.62 (br.s, 1H), 4.69 (s, 2H), 4.04 (t, 2H), 3.54-3.43 (m, 2H), 3.38- 3.26 (m, 2H, partially covered by the water signal), 2.82-2.65 (m, 2H), 2.40 (s, 3H), 2.33-2.23 (m, 4H), 1.83-1.56 (m, 2H), 1.51 (s, 3H).

LC / MS (Method 1, ES Ineg): R _t = 1.61 min, m / z = 517.14 [M-H + HCOOH] -. Example 138

5-Methyl-3- (l-methylcyclobutyl) -6 - [(5-oxo-4,5-dihydro-lH-l, 2,4-triazol-l-yl) methyl] -l- (3,3, 3-trifluoropropyl) thieno [2,3-d] pyrimidine-2,4 (1H, 3H) -dione

Analogously to the process described under Example 50, 117 mg (40% of theory) of the title compound were prepared from 408 mg (0.650 mmol, 85% purity) of the compound from Example 276A. The Purification of the product was in this case not by preparative HPLC, but by MPLC (Biotage Isolera One, cartridge SNAP KP-Sil, 100 g silica gel, eluent cyclohexane / ethyl acetate 1: 2 -> 0: 1).

Ή-ΝΜΡ (400 MHz, DMSO-d ₆ , δ / ppm): 11.59 (s, 1H), 7.84 (s, 1H), 4.94 (s, 2H), 4.08-3.95 (m, 2H), 2.80-2.64 (m, 2H), 2.42 (s, 3H), 2.34-2.22 (m, 4H), 1.82-1.56 (m, 2H), 1.51 (s, 3H).

LC / MS (Method 2, ESIpos): R _t = 0.92 min, m / z = 444 [M + H] ⁺ .

Example 139 1- (2-Methoxyethyl) -5-methyl-3- (1-methylcyclobutyl) -6 - [(2-oxoimidazolidin-1-yl) methyl] thieno [2,3-d] pyrimidine-2,4 (lH, 3H) -dione

Analogously to the process described in Example 1, from 315 mg (0.662 mmol, 80% purity) of the compound from Ex. 139A and 129 mg (0.795 mmol) of CDI 208 mg (77% of theory) of the title compound were prepared.

Ή-NMR (400 MHz, DMSO-de, δ / ppm): 6.51 (s, 1H), 4.33 (s, 2H), 3.95 (t, 2H), 3.60 (t, 2H), 3.28- 3.15 (m, 4H), 3.24 (s, 3H), 2.35 (s, 3H), 2.33-2.23 (m, 4H), 1.85-1.56 (m, 2H), 1.51 (s, 3H).

LC / MS (Method 2, ESIpos): R _t = 0.85 min, m / z = 407 [M + H] ⁺ .

Example 140

[1- {[1- (2-methoxyethyl) -5-methyl-3- (1-methylcyclobutyl) -2,4-dioxo-1,2,3,4-tetrahydrothieno [2,3-d] pyrimidine 6-yl] methyl} imidazolidine-2-ylidene] cyanamide

Analogously to the process described under Example 41, from 315 mg (0.662 mmol, 80% purity) of the compound from Example 139A and 145 mg (0.993 mmol) of dimethyl N-cyanodithio-iminocarbonate, 132 mg (46% of theory) were obtained. ) of the title compound. After preparative HPLC, a second purification step was carried out here by means of MPLC (Biotage Isolera One, cartridge SNAP KP-Sil, 50 g of silica gel, mobile phase cyclohexane / ethyl acetate 1: 2 → 0: 1).

Ή-NMR (400 MHz, DMSO-de, δ / ppm): 8.06 (s, 1H), 4.46 (s, 2H), 3.97 (br.t, 2H), 3.60 (t, 2H), 3.50-3.36 ( m, 4H), 3.25 (s, 3H), 2.36 (s, 3H), 2.33-2.24 (m, 4H), 1.80-1.57 (m, 2H), 1.51 (s, 3H).

LC / MS (Method 1, ESIpos): R _t = 1.66 min, m / z = 431.19 [M + H] ⁺ . Example 141

Methyl [1 - {[1- (2-methoxyethyl) -5-methyl-3- (1-methylcyclobutyl) -2,4-dioxo-1,2,3,4-tetrahydrothieno [2,3-d ] pyrimidine-6-yl] methyl} imidazolidine-2-ylidene] carbamate

315 mg (0.662 mmol, 80% purity) of the compound of Ex. 139A and 185 μΐ (1.33 mmol) of triethylamine were dissolved in 10 ml of dichloromethane and treated dropwise with a solution of 207 mg (1.33 mmol) of methyl (dichloromethylene) carbamate in 5 ml of dichloromethane. After the reaction mixture was stirred for about 18 h at RT, it was concentrated to dryness and the residue taken up in ethyl acetate. The organic phase was washed successively with water and saturated sodium chloride solution, dried over anhydrous magnesium sulfate, filtered and concentrated. The crude product was purified by double preparative HPLC (each Method 11). The product fractions were combined, evaporated and dried under high vacuum. 72 mg (23% of theory) of the title compound were isolated.

Ή-ΝΜΡ (400 MHz, DMSO-d ₆ , δ / ppm): 8.02 (s, 1H), 4.54 (s, 2H), 3.94 (t, 2H), 3.59 (t, 2H), 3.53 (s, 3H ), 3.49-3.42 (m, 2H), 3.35-3.30 (m, 2H, largely covered by the water signal), 3.23 (s, 3H), 2.37 (s, 3H), 2.34-2.22 (m, 4H), 1.83- 1.56 (m, 2H), 1.51 (s, 3H).

LC / MS (Method 1, ESIpos): R _t = 1.51 min, m / z = 464.20 [M + H] ⁺ .

Example 142

6 - [(2,3-dioxopiperazin-1-yl) methyl] -1- (2-methoxyethyl) -5-methyl-3- (1-methylcyclobutyl) thieno [2,3-d] pyrimidine-2,4 (lH, 3H) -dione

Analogous to the process described under Ex. 88, from 315 mg (0.662 mmol, 80% purity) of the compound from Ex. 139A and 181 mg (1.20 mmol) of diethyl oxalate 178 mg (60%) of theory. Th.) Of the title compound. Before final purification by means of preparative HPLC, purification by MPLC was carried out here (Biotage Isolera One, cartridge SNAP KP-Sil, 50 g of silica gel, mobile phase cyclohexane / ethyl acetate 2: 1 → dichloromethane / methanol 10: 1 ).

Ή NMR (400 MHz, DMSO-de, δ / ppm): 8.61 (br.s, 1H), 4.67 (s, 2H), 3.96 (t, 2H), 3.60 (t, 2H), 3.52-3.42 ( m, 2H), 3.33-3.28 (m, 2H, almost completely obscured by the water signal), 3.24 (s, 3H), 2.38 (s, 3H), 2.35-2.22 (m, 4H), 1.81-1.57 (m, 2H ), 1.51 (s, 3H). LC / MS (Method 2, ES Ineg): R _t = 0.76 min, m / z = 479 [M-H + HCOOH] -.

Example 143

1- (2-methoxyethyl) -5-methyl-3- (1-methylcyclobutyl) -6 - [(5-oxo-4,5-dihydro-1H-1,2,4-triazol-1-yl) -methyl ] thieno [2,3-d] pyrimidine-2,4 (lH, 3H) -dione

Analogously to the process described under Ex. 50, 377 mg (0.624 mmol, 82% purity) of the compound from Example 277A were used to prepare 45 mg (17% of theory) of the title compound. Before the final purification by means of preparative HPLC, purification by means of MPLC was carried out here (Biotage Isolera One, cartridge SNAP KP-Sil, 100 g of silica gel, mobile phase cyclohexane / ethyl acetate 1: 2).

Ή NMR (400 MHz, DMSO-de, δ / ppm): 11.58 (br, s, 1H), 7.83 (s, 1H), 4.91 (s, 2H), 3.94 (br, t, 2H), 3.59 ( t, 2H), 3.23 (s, 3H), 2.40 (s, 3H), 2.34-2.18 (m, 4H), 1.84-1.55 (m, 2H), 1.51 (s, 3H).

LC / MS (Method 2, ESIpos): R _t = 0.79 min, m / z = 406 [M + H] ⁺ . Example 144

3 - (trans-3-methoxycyclobutyl) -5-methyl-6 - [(2-oxoimidazolidin-1-yl) methyl] -1- (3,3,3-trifluoropropyl) thieno [2,3-d ] pyrimidine-2,4 (lH, 3H) -dione

400 mg (0.56 mmol, 61%> purity) of the compound from Ex. 140A were dissolved in 5 ml of THF and admixed with 109 mg (0.67 mmol) of CDI and 118 μM (0.84 mmol) of triethylamine. The mixture was stirred at RT for 16 h. The reaction solution was then concentrated on a rotary evaporator. The residue was taken up in ethyl acetate and washed successively with 1 M hydrochloric acid, saturated sodium bicarbonate solution and saturated sodium chloride solution. The organic phase was then dried over anhydrous magnesium sulfate, filtered and concentrated. The residue was purified by preparative HPLC (Method 13). Evaporate the Product fractions and drying under high vacuum gave 160 mg (62% of theory) of the title compound.

Ή-ΝΜΡ (400 MHz, CD3OD, δ / ppm): 5.63-5.56 (m, 1H), 4.46 (s, 2H), 4.24-4.21 (m, 2H), 4.16 (dd, 2H), 3.39-3.35 ( m, 4H), 3.27 (s, 3H), 3.07-3.01 (m, 2H), 2.74-2.65 (m, 2H), 2.45 (s, 3H), 2.35-2.30 (m, 2H).

LC / MS (Method 2, ESIpos): R _t = 0.84 min, m / z = 461 [M + H] ⁺ .

Example 145

[1- {[3- (1-i'-3-methoxycyclobutyl) -5-methyl-2,4-dioxo-1- (3,3,3-trifluoropropyl) -l, 2,3,4-tetra- hydrothieno [2,3-d] pyrimidin-6-yl] methyl} imidazolidine-2-ylidene] cyanamide

507 mg (0.72 mmol, 61% purity) of the compound from Ex. 140A were dissolved in 19 ml of DMF and admixed with 156 mg (1.07 mmol) of dimethyl N-cyanodithioiminocarbonate and 197 mg (1.42 mmol) of potassium carbonate. The mixture was stirred first for 15 min at RT and then for 3 h at 80 ° C. in a microwave oven (biotage initiator with dynamic control of the irradiation power). Thereafter, the reaction mixture was taken up in ethyl acetate and washed successively with saturated sodium bicarbonate solution, water and saturated sodium chloride solution. Subsequently, the organic phase was dried over anhydrous magnesium sulfate, filtered and concentrated. The residue obtained was purified by preparative HPLC (Method 13). Evaporation of the product fractions and drying under high vacuum gave 94 mg (27% of theory) of the title compound.

'H-NMR (400 MHz, DMSO-de, δ / ppm): 5.63-5.56 (m, 1H), 4.55 (s, 2H), 4.26-4.21 (m, 1H), 4.17 (dd, 2H), 3.54 (s, 4H), 3.11 (s, 3H), 3.07-3.01 (m, 2H), 2.75-2.66 (m, 2H), 2.46 (s, 3H), 2.35-2.30 (m, 2H).

LC / MS (Method 1, ESIpos): R _t = 0.91 min, m / z = 485 [M + H] ⁺ . Example 146

Methyl [1- {[3- (Irara-3-methoxycyclobutyl) -5-methyl-2,4-dioxo-1- (3,3,3-trifluoropropyl) -l, 2,3,4-tetrahydrothieno [2 , 3-d] pyrimidin-6-yl] methyl} imidazolidine-2-ylidene] carbamate

400 mg (0.56 mmol, 61% purity) of the compound of Ex. 140A and 156 μΐ (1.12 mmol) of triethylamine were dissolved in 25 ml of dichloromethane and treated with 67 .mu.l (0.56 mmol) of methyl (dichloromethylene) carbamate. After the reaction mixture was stirred for about 16 h at RT, it was diluted with ethyl acetate and washed successively with saturated sodium bicarbonate solution, water and saturated sodium chloride solution. After drying over anhydrous magnesium sulfate, it was filtered and concentrated. The remaining residue was purified by preparative HPLC (Method 13). Concentration of the product fraction and drying of the residue under high vacuum gave 156 mg (54% of theory) of the title compound.

Ή-NMR (400 MHz, CD ₃ OD, δ / ppm): 5.64-5.55 (m, 1H), 4.80 (s, 2H), 4:23 to 4:16 (m, 1H), 4.17 (dd, 2H), 3.92 ( s, 3H), 3.80 (dd, 2H), 3.66 (dd, 2H), 3.27 (s, 3H), 3.07-3-01 (m, 2H), 2.76-2.37 (m, 2H), 2.48 (s, 3H), 2.36-2.30 (m, 2H).

LC / MS (Method 2, ESIpos): R _t = 0.84 min, m / z = 518 [M + H] ⁺ .

Example 147

6 - [(2,3-dioxopiperazin-1-yl) methyl] -3- (trans-3-methoxycyclobutyl) -5-methyl-1 - (3,3,3-trifluoropropyl) thieno [2,3- d] pyrimidine-2,4 (lH, 3H) -dione

400 mg (0.56 mmol, 61% purity) of the compound from Ex. 140A were dissolved in 22 ml of ethanol and admixed with 153 mg (1.04 mmol) of diethyl oxalate. The mixture was stirred at 80 ° C for 2 days. Thereafter, the reaction solution was concentrated on a rotary evaporator. The residue obtained was purified by preparative HPLC (Method 13). Evaporation of the product fractions and drying under high vacuum gave 182 mg (66% of theory) of the title compound.

'H-NMR (400 MHz, CD ₃ OD, δ / ppm): 5.63-5.56 (m, 1H), 4.78 (s, 2H), 4:24 to 4:21 (m, 1H), 4.16 (dd, 2H), 3:59 (dd, 2H), 3.46 (dd, 2H), 3.27 (s, 3H), 3.06-3.01 (m, 2H), 2.74-2.65 (m, 2H), 2.49 (s, 3H), 2.36-2.30 (m , 2H).

LC / MS (Method 1, ES Ineg): R _t = 1.38 min, m / z = 534 [M-H + HCOOH] -. Example 148

3- (1α'-3-methoxycyclobutyl) -5-methyl-6 - [(5-oxo-4,5-dihydro-1H-1,2,4-triazol-1-yl) methyl] -1- (3,3,3-trifluoropropyl) thieno [2,3-d] pyrimidine-2,4 (lH, 3H) -dione

500 mg (0.57 mmol, 62% purity) of the compound from Ex. 278A were initially charged in 14 ml of trimethyl orthoformate and 14 ml of methanol, and 1.4 ml (5.63 mmol) of a 4 M solution of hydrogen chloride in dioxane were added. After stirring at RT for 18 h, a further 0.7 ml of 4 M hydrogen chloride in dioxane were added and stirring was continued at RT for 3 h. The reaction mixture was then added with water and extracted with ethyl acetate. Subsequently, the organic phase was dried over anhydrous magnesium sulfate, filtered and concentrated. The resulting residue was purified by preparative HPLC (Method 15). Evaporation of the product fractions and drying under high vacuum gave 75 mg (29% of theory) of the title compound.

Ή-NMR (400 MHz, DMSO-de, δ / ppm): 11.57 (br.s, 1H), 7.82 (s, 1H), 5.56-5.47 (m, 1H), 4.93 (s, 2H), 4.62 ( d, 2H), 4.09-4.05 (m, 1H), 3.17 (s, 3H), 2.95-2.88 (m, 4H), 2.47 (s, 3H), 2.32-2.28 (m, 2H). Example 149

3- (4-methoxycyclobutyl) -1- (2-methoxyethyl) -5-methyl-6 - [(2-oxoimidazolidin-1-yl) methyl] thieno [2,3-d] pyrimidine-2, 4 (lH, 3H) -dione

380 mg (0.61 mmol, 63% purity) of the compound from Ex. 141A were dissolved in 5 ml of THF and combined with 119 mg (0.73 mmol) of CDI and 128 μM (0.92 mmol) of triethylamine. The mixture was stirred at RT for 16 h. The reaction solution was then concentrated on a rotary evaporator. The residue was taken up in ethyl acetate and washed successively with 1 M hydrochloric acid, saturated sodium bicarbonate solution and saturated sodium chloride solution. Subsequently, the organic phase was dried over anhydrous magnesium sulfate, filtered and concentrated. The residue obtained was purified by preparative HPLC (Method 13). Evaporation of the product fractions and drying under high vacuum gave 127 mg (49% of theory) of the title compound.

Ή-NMR (400 MHz, CD ₃ OD, δ / ppm): 5.64-5.57 (m, 1H), 4:44 (s, 2H), 4:24 to 4:21 (m, 1H), 4:09 (dd, 2H), 3.70 ( dd, 2H), 3.40-3.36 (m, 4H), 3.32 (s, 3H), 3.27 (s, 3H), 3.07-3.01 (m, 2H), 2.44 (s, 3H), 2.35-2.30 (m, 2H).

LC / MS (Method 2, ESIpos): R _t = 0.71 min, m / z = 423 [M + H] ⁺ . Example 150

[l- {[3- (1α-i-3-methoxycyclobutyl) -1- (2-methoxyethyl) -5-methyl-2,4-dioxo-1,2,3,4-tetrahydrothieno [2, 3-d] pyrimidin-6-yl] methyl} imidazolidine-2-ylidene] cyanamide

475 mg (0.76 mmol, 64% purity) of the compound from Ex. 141A were dissolved in 19 ml of DMF and admixed with 168 mg (1.15 mmol) of dimethyl N-cyanodithioiminocarbonate and 211 mg (1.53 mmol) of potassium carbonate. The mixture was stirred first at RT for 15 minutes and then at 80 ° C. for 3 hours in a microwave oven (biotage initiator with dynamic control of the irradiation power). Thereafter, the reaction mixture was taken up in ethyl acetate and washed successively with saturated aqueous sodium bicarbonate solution, water and saturated sodium chloride solution. Subsequently, the organic phase was dried over anhydrous magnesium sulfate, filtered and concentrated. The resulting residue was purified by preparative HPLC (Method 15). Evaporation of the product fractions and drying under high vacuum gave 13 mg (4% of theory) of the title compound.

Ή-NMR (400 MHz, DMSO-de, δ / ppm): 8.06 (s, 1H), 5.52-5.43 (m, 1H), 4.47 (s, 2H), 4.16-4.11 (m, 1H), 4.00 ( d, 2H), 3.63 (dd, 2H), 3.46-3.39 (m, 4H), 3.24 (s, 3H), 2.96-2.88 (m, 2H), 2.54 (s, 3H), 2.39 (s, 3H) , 2.28-2.19 (m, 2H). LC / MS (Method 6, ESIpos): R _t = 1.11 min, m / z = 447 [M + H] ⁺ .

Example 151

Methyl [1 - {[3 - (1-methoxy-3-methoxycyclobutyl) -1- (2-methoxyethyl) -5-methyl-2,4-dioxo-1,2,3,4-tetrahydrothieno [2 , 3-d] pyrimidin-6-yl] methyl} imidazolidine-2-ylidene] carbamate

380 mg (0.61 mmol, 64% purity) of the compound of Example 141A and 170 μΐ (1.22 mmol) of triethylamine were dissolved in 28 ml of dichloromethane and treated with 95 mg (0.61 mmol) of methyl (dichloromethane). methylene) carbamate. After the reaction mixture was stirred for about 16 h at RT, it was diluted with ethyl acetate and washed successively with saturated sodium bicarbonate solution, water and saturated sodium chloride solution. After drying over anhydrous magnesium sulfate, it was filtered and concentrated. The remaining residue was purified by preparative HPLC (Method 13). Concentration of the product fraction and drying of the residue under high vacuum gave 248 mg (85% of theory) of the title compound.

'H-NMR (400 MHz, CD ₃ OD, δ / ppm): 5.64-5.57 (m, 1H), 4.79 (s, 2H), 4:24 to 4:21 (m, 1H), 4.10 (dd, 2H), 3.92 (s, 3H), 3.80 (dd, 2H), 3.72 (dd, 2H), 3.66 (dd, 2H), 3.32 (s, 3H), 3.27 (s, 3H), 3.07-3.01 (m, 2H), 2.47 (s, 3H), 2.36-2.30 (m, 2H). LC / MS (Method 2, ESIpos): R _t = 0.70 min, m / z = 481 [M + H] ⁺ .

Example 152

6 - [(2,3-dioxopiperazin-1-yl) methyl] -3- (irani'-3-methoxycyclobutyl) -1- (2-methoxyethyl) -5-methylthieno [2,3-d] pyrimidine 2,4 (lH, 3H) -dione

380 mg (0.61 mmol, 63% purity) of the compound from Ex. 141A were dissolved in 25 ml of ethanol and admixed with 167 mg (1.31 mmol) of diethyl oxalate. The mixture was stirred at 80 ° C for 2 days. Thereafter, the reaction solution was concentrated on a rotary evaporator. The residue obtained was purified by preparative HPLC (Method 13). Evaporation of the product fractions and drying under high vacuum gave 165 mg (57% of theory) of the title compound. Ή NMR (400 MHz, CD3OD, δ / ppm): 5.63-5.56 (m, 1H), 4.78 (s, 2H), 4.24-4.21 (m, 1H), 4.09 (dd, 2H), 3.70 (dd, 2H), 3.59 (dd, 2H), 3.46 (dd, 2H), 3.32 (s, 3H), 3.27 (s, 3H), 3.07-3.01 (m, 2H), 2.48 (s, 3H), 2.35-2.30 (m, 2H).

LC / MS (Method 1, ES Ineg): R _t = 0.88 min, m / z = 465 [M-H + HCOOH] -. Example 153

3- (Irara-3-methoxycyclobutyl) -1- (2-methoxyethyl) -5-methyl-6 - [(5-oxo-4,5-dihydro-1H-1,2,4-triazol-1-yl) methyl] thieno [2,3-d] pyrimidine-2,4 (lH, 3H) -dione

500 mg (0.52 mmol, 54% purity) of the compound from Ex. 279A were initially charged in 13 ml of trimethyl orthoformate and 13 ml of methanol, and 1.3 ml (5.20 mmol) of a 4 M solution of hydrogen chloride in dioxane were added. After stirring at RT for 18 h, a further 0.65 ml of 4 M hydrogen chloride in dioxane were added and stirring was continued at RT for 3 h. The reaction mixture was then added with water and extracted with ethyl acetate. Subsequently, the organic phase was dried over anhydrous magnesium sulfate, filtered and concentrated. The residue obtained was purified by preparative HPLC (Method 13). Evaporation of the product fractions and drying under high vacuum gave 9 mg (4% of theory) of the title compound.

Ή-NMR (400 MHz, DMSO-de, δ / ppm): 11.60 (s, 1H), 7.84 (s, 1H), 5.51-5.42 (m, 1H), 4.92 (s, 2H), 4.16-4.10 ( m, 1H), 3.98 (dd, 2H), 3.61 (dd, 2H), 3.23 (s, 3H), 3.16 (s, 3H), 2.96-2.88 (m, 2H), 2.43 (s, 2H), 2.26 -2.18 (m, 2H).

LC / MS (Method 2, ESIpos): R _t = 0.67 min, m / z = 422 [M + H] ⁺ .

Example 154

3 - (cis -3-methoxycyclobutyl) -5-methyl-6- [(2-oxoimidazolidin-1-yl) methyl] -1- (3,3,3-trifluoropropyl) thieno [2,3-d ] pyrimidine-2,4 (lH, 3H) -dione

299 mg (0.56 mmol, 81% purity) of the compound from Ex. 142A were dissolved in 4.6 ml of THF and treated with 108 mg (0.67 mmol) of CDI and 116 μΐ (0.84 mmol) of triethylamine. The mixture was stirred at RT for 16 h. The reaction solution was then concentrated on a rotary evaporator. The residue was taken up in ethyl acetate and washed successively with 1 M hydrochloric acid, saturated sodium bicarbonate solution and saturated sodium chloride solution. Subsequently, the organic phase was dried over anhydrous magnesium sulfate, filtered and concentrated. The resulting residue was purified by preparative HPLC (Method 15). Evaporation of the product fractions and drying under high vacuum gave 55 mg (21% of theory) of the title compound. 'H-NMR (400 MHz, DMSO-d _6, δ / ppm): 6:53 (s, 1H), 4.71 -4.62 (m, 1H), 4:36 (s, 2H), 4:05 (dd, 2H), 3.68- 3.31 (m, 1H), 3.28-3.19 (m, 4H), 3.15 (s, 3H), 2.81 -2.67 (m, 4H), 2.38 (s, 3H).

LC / MS (Method 2, ESIpos): R _t = 0.82 min, m / z = 461 [M + H] ⁺ .

Example 155

[1 - {[3 - (cis -methoxycyclobutyl) -5-methyl-2,4-dioxo-1 - (3,3,3-trifluoropropyl) -1,2,3,4-tetrahydrothieno] [2, 3-d] pyrimidin-6-yl] methyl} imidazolidine-2-ylidene] cyanamide

250 mg (0.47 mmol, 81% purity) of the compound from Ex. 142A were dissolved in 12 ml of DMF, and 102 mg (0.70 mmol) of dimethyl N-cyanodithioiminocarbonate and 129 mg (0.93 mmol) of potassium carbonate were added. The mixture was stirred first at RT for 15 minutes and then at 80 ° C. for 3 hours in a microwave oven (biotage initiator with dynamic control of the irradiation power). Thereafter, the reaction mixture was taken up in ethyl acetate and washed successively with saturated aqueous sodium bicarbonate solution, water and saturated sodium chloride solution. Subsequently, the organic phase was dried over anhydrous magnesium sulfate, filtered and concentrated. The resulting residue was purified by preparative HPLC (Method 15). Evaporation of the product fractions and drying under high vacuum gave 38 mg (17% of theory) of the title compound. 'H-NMR (400 MHz, DMSO-de, δ / ρρηι): 8.08 (s, 1H), 4.69-4.64 (m, 1H), 4.49 (s, 2H), 4.07 (dd, 2H), 3.68-3.61 (m, 1H), 3.47-3.40 (m, 4H), 3.15 (s, 3H), 2.79-2.69 (m, 4H), 2.39 (s, 3H).

LC / MS (Method 2, ESIpos): R _t = 0.87 min, m / z = 485 [M + H] ⁺ .

Example 156 Methyl [1- {[3- (di-3-methoxycyclobutyl) -5-methyl-2,4-dioxo-1- (3,3,3-trifluoropropyl) -l, 2,3,4- tetrahydrothieno [2,3-d] pyrimidin-6-yl] methyl} imidazolidin-2-ylidene] carbamate

229 mg (0.43 mmol, 81% purity) of the compound of Ex. 142A and 119 μΐ (0.85 mmol) of triethylamine were dissolved in 20 ml of dichloromethane and admixed with 67 mg (0.43 mmol) of methyl (dichloromethylene) carbamate. After the reaction mixture was stirred for about 16 h at RT, it was diluted with ethyl acetate and washed successively with saturated sodium bicarbonate solution, water and saturated sodium chloride solution. After drying over anhydrous magnesium sulfate, it was filtered and concentrated. The residue obtained was purified by preparative HPLC (Method 15). Evaporation of the product fractions and drying under high vacuum gave 60 mg (28% of theory) of the title compound.

Ή-NMR (400 MHz, DMSO-de, δ / ppm): 8.03 (s, 1H), 4.71 -4.62 (m, 1H), 4.57 (s, 2H), 4.04 (dd, 2H), 3.71 -3.61 ( m, 1H), 3.53 (s, 3H), 3.46 (dd, 2H), 3.34 (dd, 2H), 3.15 (s, 3H), 2.80-2.67 (m, 4H), 2.41 (s, 3H).

LC / MS (Method 2, ESIpos): R _t = 0.79 min, m / z = 518 [M + H] ⁺ . Example 157

6 - [(2,3-dioxopiperazin-1-yl) methyl] -3- (cis-3-methoxycyclobutyl) -5-methyl-1 - (3,3,3-trifluoropropyl) thieno [2,3- d] pyrimidine-2,4 (lH, 3H) -dione

249 mg (0.46 mmol, 81% purity) of the compound from Ex. 142A were dissolved in 19 ml of ethanol and admixed with 127 mg (0.86 mmol) of diethyl oxalate. The mixture was stirred at 80 ° C for 40 hours. Thereafter, the reaction solution was concentrated on a rotary evaporator. The residue obtained was purified by preparative HPLC (Method 15). Evaporation of the product fractions and drying under high vacuum gave 44 mg (19% of theory) of the title compound.

Ή-NMR (400 MHz, DMSO-de, δ / ppm): 8.62 (br.s, 1H), 4.70 (s, 2H), 4.68-4.62 (m, 1H), 4.06 (dd, 2H), 3.68- 3.31 (m, 1H), 3.48 (dd, 2H), 3.15 (s, 3H), 2.81 -2.67 (m, 4H), 2.42 (s, 3H).

LC / MS (Method 2, ESIpos): R _t = 0.75 min, m / z = 489 [M + H] ⁺ . Example 158

3- (di'-3-methoxycyclobutyl) -5-methyl-6 - [(5-oxo-4,5-dihydro-1H-1,2,4-triazol-1-yl) methyl] -1- (3 , 3,3-trifluoropropyl) thieno [2,3-d] pyrimidine-2,4 (lH, 3H) -dione

620 mg (0.60 mmol) of the compound from Ex. 280A were initially charged in 15 ml of trimethyl orthoformate and 15 ml of methanol, and 1.5 ml (6.05 mmol) of a 4 M solution of hydrogen chloride in dioxane were added. Since the reaction was still incomplete after stirring at RT for 18 h, a further 0.75 ml of 4 M hydrogen chloride in dioxane were added and the mixture was stirred for a further 3 h. The reaction mixture was then added with water and extracted with ethyl acetate. The organic phase was concentrated and the residue was purified by preparative HPLC (Method 13). The product fractions were combined and concentrated and the residue was dried under high vacuum. 29 mg (11% of theory) of the title compound were obtained. 'H-NMR (400 MHz, DMSO-de, δ / ρρηι): 11.60 (s, 1H), 7.84 (s, 1H), 4.94 (s, 2H), 4.69-4.60 (m, 1H), 4.04 (dd , 2H), 3.68-3.60 (m, 1H), 3.15 (s, 3H), 2.79-2.67 (m, 4H), 2.44 (s, 3H).

LC / MS (Method 2, ESIpos): R _t = 0.78 min, m / z = 460 [M + H] ⁺ . Example 159 3- (cw-3-Methoxycyclobutyl) -1- (2-methoxyethyl) -5-methyl-6 - [(2-oxoimidazolidin-1-yl) methyl] thieno [2,3-d] pyrimidine-2 , 4 (lH, 3H) -dione

250 mg (0.38 mmol, 69% purity) of the compound from Ex. 143A were dissolved in 3 ml of THF, and 74 mg (0.45 mmol) of CDI and 79 .mu.l (0.57 mmol) of triethylamine were added. The mixture was stirred at RT for 16 h. The reaction solution was then concentrated on a rotary evaporator. The residue was taken up in ethyl acetate and washed successively with 1 M hydrochloric acid, saturated aqueous sodium bicarbonate solution and saturated sodium chloride solution. Subsequently, the organic phase was dried over anhydrous magnesium sulfate, filtered and concentrated. The resulting residue was purified by preparative HPLC (Method 15). Evaporation of the product fractions and drying under high vacuum gave 16 mg (10% of theory) of the title compound.

Ή-NMR (400 MHz, DMSO-de, δ / ppm): 6.52 (s, 1H), 4.73-4.64 (m, 1H), 4.33 (s, 2H), 3.98 (dd, 2H), 3.68-3.60 ( m, 3H), 3.24-3.21 (m, 3H), 3.15 (s, 3H), 2.77-2.67 (m, 2H), 2.37 (s, 3H).

LC / MS (Method 2, ESIpos): R _t = 0.70 min, m / z = 423 [M + H] ⁺ . Example 160

[1- {[3- (cw-3-methoxycyclobutyl) -1- (2-methoxyethyl) -5-methyl-2,4-dioxo-1,2,3,4-tetrahydrothieno [2,3-d ] pyrimidine-6-yl] methyl} imidazolidine-2-ylidene] cyanamide

250 mg (0.38 mmol, 69% purity) of the compound from Ex. 143A were dissolved in 10 ml of DMF and admixed with 83 mg (0.57 mmol) of dimethyl N-cyanodithioiminocarbonate and 104 mg (0.76 mmol) of potassium carbonate. The mixture was stirred first at RT for 30 minutes and then at 80 ° C. for 2 hours in a microwave oven (biotage initiator with dynamic control of the irradiation power). Thereafter, the reaction mixture was taken up in ethyl acetate and washed successively with saturated aqueous sodium bicarbonate solution, water and saturated sodium chloride solution. Subsequently, the organic phase was dried over anhydrous magnesium sulfate, filtered and concentrated. The resulting residue was purified by preparative HPLC (Method 15). Evaporation of the product fractions and drying under high vacuum gave 21 mg (13% of theory) of the title compound.

Ή-NMR (400 MHz, DMSO-de, δ / ppm): 8.07 (s, 1H), 4.72-4.64 (m, 1H), 4.46 (s, 2H), 3.39 (dd, 2H), 3.66-3.61 ( m, 3H), 3.48-3.38 (m, 4H), 3.11 (s, 3H), 3.15 (s, 3H), 2.76-2.69 (m, 2H), 2.38 (s, 3H). LC / MS (Method 2, ESIpos): R _t = 0.76 min, m / z = 447 [M + H] ⁺ . Example 161

Methyl [1- {[3- (di-3-methoxycyclobutyl) -1- (2-methoxyethyl) -5-methyl-2,4-dioxo-1,2,3,4-tetrahydrothieno [2, 3-d] pyrimidin-6-yl] methyl} imidazolidine-2-ylidene] carbamate

250 mg (0.43 mmol, 69% purity) of the compound from Ex. 143A and 121 μΐ (0.87 mmol) of triethylamine were dissolved in 20 ml of dichloromethane and treated with 67 mg (0.43 mmol) of methyl (dichloromethane). methylene) carbamate. After the reaction mixture was stirred for about 16 h at RT, it was diluted with ethyl acetate and washed successively with saturated sodium bicarbonate solution, water and saturated sodium chloride solution. After drying over anhydrous magnesium sulfate, it was filtered and concentrated. The residue obtained was purified by preparative HPLC (Method 15). Evaporation of the product fractions and drying under high vacuum gave 29 mg (14% of theory) of the title compound.

'H-NMR (400 MHz, DMSO-de, δ / ppm): 8.02 (s, 1H), 4.73-4.64 (m, 1H), 4.55 (s, 2H), 3.97 (dd, 2H), 3.96-3.60 (m, 3H), 3.53 (s, 3H), 3.46 (dd, 2H), 3.33 (dd, 2H), 3.23 (s, 3H), 3.15 (s, 3H), 2.76- 2.65 (m, 2H), 2.39 (s, 3H). LC / MS (Method 2, ESIpos): R _t = 0.65 min, m / z = 480 [M + H] ⁺ .

Example 162

6 - [(2,3-dioxopiperazin-1-yl) methyl] -3- (cz, y-3-methoxycyclobutyl) -1- (2-methoxyethyl) -5-methylthieno [2,3-d] pyrimidine -2,4 (lH, 3H) -dione

250 mg (0.43 mmol, 69% purity) of the compound from Ex. 143A were dissolved in 17 ml of ethanol and admixed with 119 mg (0.81 mmol) of diethyl oxalate. The mixture was stirred at 80 ° C for 40 hours. Thereafter, the reaction solution was concentrated on a rotary evaporator. The resulting residue was purified by preparative HPLC (Method 15). Evaporation of the product fractions and drying under high vacuum gave 70 mg (36% of theory) of the title compound. Ή-NMR (400 MHz, DMSO-d _6, δ / ppm): 8.61 (s, 1H), 4.72-4.64 (m, 3H), 3.98 (dd, 2H), 3.68-3.60 (m, 3H), 3:47 (dd, 2H), 3.23 (s, 3H), 3.15 (s, 3H), 2.76-2.67 (m, 2H), 2.40 (s, 3H).

LC / MS (Method 2, ESIpos): R _t = 0.63 min, m / z = 451 [M + H] ⁺ .

Example 163

3- (di'-3-methoxycyclobutyl) -1- (2-methoxyethyl) -5-methyl-6 - [(5-oxo-4,5-dihydro-1H-1,2,4-triazol-1-yl ) methyl] thieno [2,3-d] pyrimidine-2,4 (lH, 3H) -dione

574 mg (0.58 mmol, 59% purity) of the compound from Ex. 281A were initially charged in 14.3 ml of trimethyl orthoformate and 14.3 ml of methanol, and 1.5 ml (5.83 mmol) of a 4 M solution of hydrogen chloride in dioxane were added. After stirring at RT for 48 h, water was added to the reaction mixture. The resulting solid was filtered off, washed with acetonitrile and dried under high vacuum. There was obtained 23 mg (10% of theory) of the title compound.

Ή-NMR (400 MHz, DMSO-de, δ / ppm): 11.59 (s, 1H), 7.84 (s, 1H), 4.92 (s, 2H), 4.71-4.63 (m, 1H), 3.97 (dd, 2H), 3.67-3.59 (m, 3H), 3.23 (s, 3H), 3.15 (s, 3H), 2.75-2.67 (m, 2H), 2.42 (s, 3H). LC / MS (Method 2, ESIpos): R _t = 0.63 min, m / z = 451 [M + H] ⁺ .

Example 164

3- (3,3-Dimethylcyclobutyl) -5-methyl-6 - [(2-oxoimidazolidin-1-yl) methyl] -1- (3,3,3-trifluoropropyl) thieno [2,3-d] pyrimidine -2,4 (lH, 3H) -dione

265 mg (0.56 mmol, 92% purity) of the compound from Ex. 144A were dissolved in 4.6 ml of THF and admixed with 109 mg (0.68 mmol) of CDI and 120 μM (0.84 mmol) of triethylamine. The mixture was stirred at RT for 16 h. The reaction solution was then concentrated on a rotary evaporator. The residue was taken up in ethyl acetate and washed successively with 1 M hydrochloric acid, saturated aqueous sodium bicarbonate solution and saturated sodium chloride solution. Subsequently, the organic phase was dried over anhydrous magnesium sulfate, filtered and concentrated. The residue obtained was purified by preparative HPLC (Method 15) cleaned. Evaporation of the product fractions and drying under high vacuum gave 85 mg (33% of theory) of the title compound.

Ή-ΝΜΡ (500 MHz, CD ₃ OD, δ / ppm): 5.30 (quin, 1H), 4:46 (s, 2H), 4:20 to 4:10 (m, 2H), 3:41 to 3:34 (m, 4H), 2.79- 2.64 (m, 4H), 2.45 (s, 3H), 2.03-1.99 (m, 2H), 1.22 (2s, 6H). LC / MS (Method 2, ESIpos): R _t = 1.08 min, m / z = 459 [M + H] ⁺ .

Example 165

[l- {[3- (3,3-Dimethylcyclobutyl) -5-methyl-2,4-dioxo-l- (3,3,3-trifluoropropyl) -1,3,3,4-tetrahydrothieno [2 , 3-d] pyrimidin-6-yl] methyl} imidazolidine-2-ylidene] cyanamide

265 mg (0.56 mmol, 92%> purity) of the compound from Ex. 144A were dissolved in 14 ml of DMF and admixed with 124 mg (0.84 mmol) of dimethyl N-cyanodithioiminocarbonate and 156 mg (1.13 mmol) of potassium carbonate. The mixture was stirred for 3 hours at 80 ° C in a microwave oven (biotage initiator with dynamic control of the irradiation power). Thereafter, the reaction mixture was taken up in ethyl acetate and washed successively with saturated sodium bicarbonate solution, water and saturated sodium chloride solution. Subsequently, the organic phase was dried over anhydrous magnesium sulfate, filtered and concentrated. The resulting residue was purified by preparative HPLC (Method 15). Evaporation of the product fractions and drying under high vacuum gave 71 mg (25% of theory) of the title compound.

LC / MS (Method 2, ESIpos): R _t = 1.12 min, m / z = 483 [M + H] ⁺ . Example 166

Methyl [1- {[3- (3,3-dimethylcyclobutyl) -5-methyl-2,4-dioxo-1- (3,3,3-trifluoropropyl) -l, 2,3,4-tetrahydrothieno] [2,3-d] pyrimidin-6-yl] methyl} imidazolidine-2-ylidene] carbamate

265 mg (0.56 mmol, 92% purity) of the compound of Ex. 144A and 160 μΐ (1.23 mmol) of triethylamine were dissolved in 26 ml of dichloromethane and admixed with 88 mg (0.56 mmol) of methyl (dichloromethylene) carbamate. After the reaction mixture was stirred for about 16 h at RT, it was diluted with ethyl acetate and washed successively with saturated sodium bicarbonate solution, water and saturated sodium chloride solution. After drying over anhydrous magnesium sulfate, it was filtered and concentrated. The remaining residue was purified by preparative HPLC (Method 15). Concentration of the product fraction and drying of the residue under high vacuum gave 70 mg (24% of theory) of the title compound. 'H-NMR (400 MHz, CD ₃ OD, δ / ppm): 5:33 to 5:26 (m, 1H), 4.63 (s, 2H), 4.14 (dd, 2H), 3.68 (s, 3H), 3:58 (dd , 2H), 3.42 (dd, 2H), 2.78-2.64 (m, 4H), 2.46 (s, 3H), 2.03-1.99 (m, 2H), 1.22 (2s, 6H).

LC / MS (Method 2, ESIpos): R _t = 1.06 min, m / z = 516 [M + H] ⁺ .

Example 167

3- (3,3-Dimethylcyclobutyl) -6 - [(2,3-dioxopiperazin-1-yl) methyl] -5-methyl-1- (3,3,3-trifluoropropyl) thieno [2,3-d ] pyrimidine-2,4 (lH, 3H) -dione

266 mg (0.56 mmol, 92% purity) of the compound from Ex. 144A were dissolved in 23 ml of ethanol and admixed with 154 mg (0.79 mmol) of diethyl oxalate. The mixture was stirred at 80 ° C for 3 days. Thereafter, the reaction solution was concentrated on a rotary evaporator. The obtained The residue was purified by preparative HPLC (Method 15). Evaporation of the product fractions and drying under high vacuum gave 64 mg (23% of theory) of the title compound.

'H-NMR (400 MHz, CD ₃ OD, δ / ppm): 5:33 to 5:25 (m, 1H), 4.79 (s, 2H), 4.15 (dd, 2H), 3:59 (dd, 2H), 3:46 (dd , 2H), 2.78-2.64 (m, 4H), 2.49 (s, 3H), 2.03-1.99 (m, 2H), 1.22 (2s, 6H). LC / MS (Method 2, ESIpos): R _t = 0.99 min, m / z = 487 [M + H] ⁺ .

Example 168

3- (3,3-Dimethylcyclobutyl) -5-methyl-6 - [(5-oxo-4,5-dihydro-1H-1,2,4-triazol-1-yl) methyl] -1- (3, 3,3-trifluoropropyl) thieno [2,3-d] pyrimidine-2,4 (lH, 3H) -dione

449 mg (0.70 mmol, 85% purity) of the compound from Ex. 282A were initially charged in 17 ml of trimethyl orthoformate and 17 ml of methanol, and 1.7 ml (6.96 mmol) of a 4 M solution of hydrogen chloride in dioxane were added. After stirring at RT for 48 h, a further 0.8 ml of 4 M hydrogen chloride in dioxane were added and stirring was continued at RT for 5 h. The reaction mixture was then added with water and extracted with ethyl acetate. Subsequently, the organic phase was dried over anhydrous magnesium sulfate, filtered and concentrated. The resulting residue was treated with acetonitrile and the precipitated solid was filtered off, washed with a little acetonitrile, dried in vacuo and finally purified by preparative HPLC (Method 13). Evaporation of the product fractions and drying under high vacuum gave 107 mg (34% of theory) of the title compound. H-NMR (400 MHz, DMSO-d _6, δ / ppm): 11:59 (s, 1H), 7.64 (s, 1H), 5:25 to 5:16 (m, 1H), 4.94 (s, 2H), 4:05 ( d, 2H), 2.77-2.64 (m, 4H), 2.45 (s, 3H), 1.96 (dd, 2H), 1.18 (s, 6H).

LC / MS (Method 2, ESIpos): R _t = 1.02 min, m / z = 458 [M + H] Example 169

3 - (3,3-dimethylcyclobutyl) -1- (2-methoxyethyl) -5-methyl-6- [(2-oxoimidazolidin-1-yl) -yl) -methyl] thieno [2,3-d] pyrimidine-2, 4 (lH, 3H) -dione

421 mg (0.52 mmol, 48% purity) of the compound from Ex. 145A were dissolved in 4.3 ml of THF and treated with 101 mg (0.62 mmol) of CDI and 110 .mu.l (0.78 mmol) of triethylamine. The mixture was stirred at RT for 16 h. The reaction solution was then concentrated on a rotary evaporator. The residue was taken up in ethyl acetate and washed successively with 1 M hydrochloric acid, saturated sodium bicarbonate solution and saturated sodium chloride solution. Subsequently, the organic phase was dried over anhydrous magnesium sulfate, filtered and concentrated. The resulting residue was purified by preparative HPLC (Method 15). Evaporation of the product fractions and drying under high vacuum gave 10 mg (5% of theory) of the title compound.

Ή-NMR (400 MHz, CD ₃ OD, δ / ppm): 5:32 to 5:24 (m, 1H), 4:42 (s, 2H), 4:06 (dd, 2H), 3.68 (dd, 2H), 3:36 to 3:34 ( m, 4H), 3.30 (s, 3H), 2.77-2.73 (m, 2H), 2.41 (s, 3H), 2.00-1.96 (m, 2H), 1.19 (2s, 6H).

LC / MS (Method 2, ESIpos): R _t = 0.97 min, m / z = 421 [M + H] ⁺ .

Example 170

[1 - {[3- (3,3-dimethylcyclobutyl) -1- (2-methoxyethyl) -5-methyl-2,4-dioxo-1,2,3,4-tetrahydrothieno [2,3-d] pyrimidin-6-yl] methyl} imidazolidine-2-ylidene] cyanamide

444 mg (0.55 mmol, 49% purity) of the compound from Ex. 145A were dissolved in 14 ml of DMF, and 120 mg (0.82 mmol) of dimethyl N-cyanodithioiminocarbonate and 151 mg (1.09 mmol) of potassium carbonate were added. The mixture was stirred for 3.5 h at 80 ° C in a microwave oven (Biotage initiator with dynamic control of the irradiation power). Thereafter, the reaction mixture was taken up in ethyl acetate and washed successively with saturated sodium bicarbonate solution, water and saturated sodium chloride solution. Subsequently, the organic phase was dried over anhydrous magnesium sulfate, filtered and concentrated. The resulting residue was purified by preparative HPLC (Method 15). Evaporation of the product fractions and drying under high vacuum gave 34 mg (14% of theory) of the title compound.

'H-NMR (400 MHz, DMSO-de, δ / ppm): 8.07 (s, 1H), 5.27-5.18 (m, 1H), 4.46 (s, 2H), 4.00 (t, 2H), 3.62 (t , 2H), 3.46-3.38 (m, 4H), 3.24 (s, 3H), 2.72-2.66 (m, 2H), 2.38 (s, 3H), 1.97-1.92 (m, 2H), 1.18 (2s, 6H ).

LC / MS (Method 2, ESIpos): R _t = 1.02 min, m / z = 445 [M + H] ⁺ . Example 171

Methyl [1 - {[3- (3,3-dimethylcyclobutyl) -1- (2-methoxyethyl) -5-methyl-2,4-dioxo-1,2,3,4-tetrahydrothieno [2,3 -d] pyrimidin-6-yl] methyl} imidazolidine-2-ylidene] carbamate

421 mg (0.52 mmol, 48% purity) of the compound of Ex. 145A and 140 μΐ (1.04 mmol) of triethylamine were dissolved in 24 ml of dichloromethane and treated with 81 mg (0.52 mmol) of methyl (dichloro) ethane. methylene) carbamate. After the reaction mixture was stirred for about 16 h at RT, it was diluted with ethyl acetate and washed successively with saturated sodium bicarbonate solution, water and saturated sodium chloride solution. After drying over anhydrous magnesium sulfate, it was filtered and concentrated. The remaining residue was purified by preparative HPLC (Method 15). Concentration of the product fraction and drying of the residue under high vacuum gave 41 mg (17% of theory) of the title compound.

'H-NMR (400 MHz, CD ₃ OD, δ / ppm): 5:33 to 5:26 (m, 1H), 4.77 (s, 2H), 4:08 (t, 2H), 3.91 (s, 3H), 3.79 (dd , 2H), 3.70 (t, 2H), 3.67 (dd, 2H), 3.30 (s, 3H), 2.77-2.73 (m, 2H), 2.45 (s, 3H), 2.01 -1.97 (m, 2H), 1.22 (2s, 6H). LC / MS (Method 2, ESIpos): R _t = 0.93 min, m / z = 478 [M + H] ⁺ .

Example 172

3- (3,3-Dimethylcyclobutyl) -6 - [(2,3-dioxopiperazin-1-yl) methyl] -1- (2-methoxyethyl) -5-methylthieno [2,3-d] pyrimidine-2 , 4 (lH, 3H) -dione

444 mg (0.55 mmol, 48% purity) of the compound from Ex. 145A were dissolved in 22 ml of ethanol and admixed with 149 mg (1.01 mmol) of diethyl oxalate. The mixture was stirred at 80 ° C for 2.5 days. Thereafter, the reaction solution was concentrated on a rotary evaporator. The resulting residue was purified by preparative HPLC (Method 15). Evaporation of the product fractions and drying under high vacuum gave 56 mg (23% of theory) of the title compound.

Ή-NMR (400 MHz, DMSO-de, δ / ppm): 8.61 (br.s, 1H), 5.27-5.18 (m, 1H), 4.68 (s, 2H), 3.99 (dd, 2H), 3.62 ( d, 2H), 3.48-3.45 (m, 2H), 3.23 (s, 3H), 2.71-2.66 (dd, 2H), 2.41 (s, 3H), 1.97-1.92 (m, 2H), 1.18 (2s, 6H).

LC / MS (Method 2, ESIpos): R _t = 0.87 min, m / z = 449 [M + H] ⁺ . Example 173

3- (3,3-Dimethylcyclobutyl) -1- (2-methoxyethyl) -5-methyl-6 - [(5-oxo-4,5-dihydro-1H-1,2,4-triazol-1-yl) methyl] thieno [2,3-d] pyrimidine-2,4 (lH, 3H) -dione

720 mg (0.834 mmol, 59% purity) of the compound from Ex. 283A were initially charged in 20 ml of trimethyl orthoformate and 20 ml of methanol, and 2.1 ml (8.34 mmol) of a 4 M solution of hydrogen chloride in dioxane were added. After stirring at RT for 48 h, a further 1 ml of 4 M hydrogen chloride in dioxane was added and stirring was continued at RT for 5 h. The reaction mixture was then added with water and extracted with ethyl acetate. Subsequently, the organic phase was dried over anhydrous magnesium sulfate, filtered and concentrated. The resulting residue was treated with acetonitrile and the precipitated solid was filtered off, washed with a little acetonitrile, dried in vacuo and then purified by preparative HPLC (Method 13). Evaporation of the product fractions and drying under high vacuum gave 15 mg (4% of theory) of the title compound. Ή-NMR (400 MHz, DMSO-d _6, δ / ppm): 11:59 (s, 1H), 7.84 (s, 1H), 5:27 to 5:17 (m, 1H), 4.92 (s, 2H), 3.97 (dd , 2H), 3.61 (dd, 2H), 3.23 (s, 3H), 2.68 (dd, 2H), 2.43 (s, 3H), 1.95 (dd, 2H), 1.18 (2s, 6H).

LC / MS (Method 2, ESIpos): R _t = 0.90 min, m / z = 420 [M + H] ⁺ . Example 174 5-Methyl-6 - [(2-oxoimidazolidin-1-yl) methyl] -3- (spiro [3.3] hept-2-yl) -1- (3,3,3-trifluoropropyl) thieno [2 , 3-d] pyrimidine-2,4 (lH, 3H) -dione

Analogously to the process described under Example 31, 365 mg (0.673 mmol, 82% purity) of the compound of Example 146A and 131 mg (0.808 mmol) of CDI 185 mg (58% of theory) of the title compound were prepared. 'H-NMR (400 MHz, DMSO-d _6, δ / ppm): 6:53 (s, 1H), 5.11 -4.98 (m, 1H), 4:35 (s, 2H), 4:04 (t, 2H), 3.28- 3.16 (m, 4H), 2.87-2.79 (m, 2H), 2.79-2.69 (m, 2H), 2.37 (s, 3H), 2.23 (td, 2H), 2.10-2.03 (m, 2H), 2.02- 1.93 (m, 2H), 1.88-1.75 (m, 2H).

LC / MS (Method 1, ESIpos): R _t = 2.12 min, m / z = 471.17 [M + H]

Example 175 [1- {[5-Methyl-2,4-dioxo-3- (spiro [3.3] hept-2-yl) -1- (3,3,3-trifluoropropyl) -l, 2,3,4 tetrahydrothieno [2,3-d] pyrimidin-6-yl] methyl} imidazolidin-2-ylidene] cyanamide

365 mg (0.673 mmol, 82%> purity) of the compound from Ex. 146A were dissolved in 7 ml of DMF and admixed with 148 mg (1.01 mmol) of dimethyl N-cyanodithioiminocarbonate and 186 mg (1.35 mmol) of potassium carbonate. The mixture was stirred for 4 h at 80 ° C in a microwave oven (Biotage initiator with dynamic control of the irradiation power). Thereafter, the reaction mixture was concentrated to dryness. After stirring the residue with a little acetonitrile at RT, filtering off with suction and drying in a high vacuum, 130 mg (39% of theory) of the title compound were obtained. 'H-NMR (400 MHz, DMSO-de, δ / ρρηι): 8.07 (s, 1H), 5.04 (quin, 1H), 4.48 (s, 2H), 4.06 (br.t, 2H), 3.50-3.36 (m, 4H), 2.87-2.69 (m, 4H), 2.39 (s, 3H), 2.24 (td, 2H), 2.11 -2.03 (m, 2H), 2.01- 1.94 (m, 2H), 1.87-1.75 (m, 2H).

LC / MS (Method 1, ESIpos): R _t = 2.18 min, m / z = 495.18 [M + H] ⁺ . Example 176

Methyl- [l - {[5-methyl-2,4-dioxo-3- (spiro [3.3] hept-2-yl) -l- (3,3,3-trifluoropropyl) -l, 2,3,4 tetrahydro thieno [2,3-d] pyrimidin-6-yl] methyl} imidazolidin-2-ylidene] carbamate

365 mg (0.673 mmol, 82% purity) of the compound of Ex. 146A and 188 μΐ (1.35 mmol) of triethylamine were dissolved in 10 ml of dichloromethane and treated dropwise with a solution of 210 mg (1.35 mmol) of methyl (dichloromethylene) carbamate in 5 ml of dichloromethane. After the reaction mixture was stirred for about 18 h at RT, it was concentrated to dryness and the residue taken up in ethyl acetate. The organic phase was washed successively with water and saturated sodium chloride solution, dried over anhydrous magnesium sulfate, filtered and concentrated. The crude product was purified by preparative HPLC (Method 11). The product fractions were combined and evaporated. The residue was stirred with a little acetonitrile at RT, filtered off with suction and dried under high vacuum. 110 mg (30% of theory) of the title compound were isolated.

'H-NMR (400 MHz, DMSO-de, δ / ppm): 8.02 (s, 1H), 5.04 (quin, 1H), 4.56 (s, 2H), 4.04 (br.t, 2H), 3.53 (s , 3H), 3.49-3.40 (m, 2H), 3.37-3.30 (m, 2H, partially covered by the water signal), 2.88-2.79 (m, 2H), 2.73 (dt, 2H), 2.40 (s, 3H), 2.30-2.18 (m, 2H), 2.11-2.02 (m, 2H), 2.01-1.93 (m, 2H), 1.87-1.75 (m, 2H).

LC / MS (Method 2, ESIpos): R _t = 1.09 min, m / z = 528 [M + H] ⁺ . Example 177

6 - [(2,3-dioxopiperazin-1-yl) methyl] -5-methyl-3- (spiro [3.3] hept-2-yl) -1- (3,3,3-trifluoropropyl) thieno [2 , 3-d] pyrimidine-2,4 (lH, 3H) -dione

88 mg (0.673 mmol, 82% purity) of the compound of Example 146A and 184 mg (1.25 mmol) of diethyl oxalate were used to prepare 184 mg (54% of theory) of the title compound analogously to the process described under Example 88.

'H-NMR (400 MHz, DMSO-de, δ / ppm): 8.64 (br.s, 1H), 5.04 (quin, 1H), 4.70 (s, 2H), 4.05 (t, 2H), 3.53-3.42 (m, 2H), 2.87-2.69 (m, 4H), 2.41 (s, 3H), 2.24 (td, 2H), 2.10-2.03 (m, 2H), 2.01- 1.93 (m, 2H), 1.87-1.75 (m, 2H).

LC / MS (method 1, ESIneg): R _t = 1.93 min, m / z = 543.15 [MH] ^"

Example 178

5-methyl-6 - [(5-oxo-4,5-dihydro-lH-l, 2,4-triazol-l-yl) methyl] -3- (spiro [3.3] hept-2-yl) -l - (3,3,3-trifluoropropyl) thieno [2,3-d] pyrimidine-2,4 (1H, 3H) -dione

455 mg (0.813 mmol) of the compound from Ex. 284A were dissolved in a mixture of 25 ml each of methanol and trimethyl orthoformate, and 2 ml (8.13 mmol) of a 4 M solution of hydrogen chloride in dioxane were added at RT. After about 16 h, the reaction mixture was evaporated and the residue taken up in ethyl acetate. It was successively with water and washed saturated sodium chloride solution. After drying over anhydrous magnesium sulfate, it was filtered and concentrated again. The remaining residue was stirred with a little acetonitrile at RT. The solid was filtered off with suction, dried under high vacuum, giving 153 mg (40% of theory) of the title compound. 'H-NMR (400 MHz, DMSO-d _6, δ / ppm): 11:59, 7.84 (s, 1H), 5:03 (quin, 1H), 4.94 (s, 2H), 4:03 ((br s, 1H). t, 2H), 2.86-2.78 (m, 2H), 2.78-2.68 (m, 2H), 2.44 (s, 3H), 2.28-2.19 (m, 2H), 2.11-2.02 (m, 2H), 2.02- 1.93 (m, 2H), 1.86-1.75 (m, 2H).

LC / MS (Method 1, ESIpos): R _t = 1.98 min, m / z = 470.15 [M + H]

Example 179 1- (2-Methoxyethyl) -5-methyl-6 - [(2-oxoimidazolidin-1-yl) methyl] -3- (spiro [3.3] hept-2-yl) thieno [2,3-d ] pyrimidine-2,4 (lH, 3H) -dione

Analogously to the process described under Example 31, 345 mg (0.687 mmol, 81% purity) of the compound of Example 147A and 134 mg (0.825 mmol) of CDI were used to produce 190 mg (63% of theory) of the title compound.

'H-NMR (400 MHz, DMSO-de, δ / ppm): 6.51 (s, 1H), 5.06 (quin, 1H), 4.33 (s, 2H), 3.97 (t, 2H), 3.61 (t, 2H ), 3.28-3.15 (m, 4H), 3.23 (s, 3H), 2.91-2.78 (m, 2H), 2.36 (s, 3H), 2.23 (td, 2H), 2.12- 2.03 (m, 2H), 2.02-1.93 (m, 2H), 1.87-1.74 (m, 2H).

LC / MS (Method 1, ESIpos): R _t = 1.90 min, m / z = 433.19 [M + H] ⁺ . Example 180

[1- {[1- (2-methoxyethyl) -5-methyl-2,4-dioxo-3- (spiro [3.3] hept-2-yl) -l, 2,3,4-tetrahydrothieno- [2, 3-d] pyrimidin-6-yl] methyl} imidazolidine-2-ylidene] cyanamide

345 mg (0.687 mmol, 81% purity) of the compound from Example 147A were dissolved in 7 ml of DMF and admixed with 151 mg (1.03 mmol) of dimethyl N-cyanodithioiminocarbonate and 190 mg (1.37 mmol) of potassium carbonate. The mixture was stirred for 4 h at 80 ° C in a microwave oven (Biotage initiator with dynamic control of the irradiation power). Thereafter, the reaction mixture was diluted with ethyl acetate and washed successively with saturated sodium carbonate solution, water and saturated sodium chloride solution. After drying over anhydrous magnesium sulfate, it was filtered and concentrated. The crude product was stirred with a little acetonitrile at RT. After suctioning off the solid and drying in a high vacuum, 115 mg (36% of theory) of the title compound were obtained.

'H-NMR (500 MHz, DMSO-de, δ / ppm): 8.06 (s, 1H), 5.19-4.94 (m, 1H), 4.46 (s, 2H), 3.98 (t, 2H), 3.61 (t , 2H), 3.51-3.35 (m, 4H), 3.24 (s, 3H), 2.95-2.77 (m, 2H), 2.37 (s, 3H), 2.23 (td, 2H), 2.13- 2.02 (m, 2H ), 2.01-1.92 (m, 2H), 1.89-1.73 (m, 2H).

LC / MS (Method 2, ESIpos): R _t = 1.05 min, m / z = 457 [M + H] ⁺ . Example 181

Methyl [1- {[1- (2-methoxyethyl) -5-methyl-2,4-dioxo-3- (spiro [3.3] hept-2-yl) -1,3,3,4-tetrahydrothieno [2,3-d] pyrimidin-6-yl] methyl} imidazolidine-2-ylidene] carbamate

Analogously to the process described under Ex. 176, from 345 mg (0.687 mmol, 81% purity) of the compound from Ex. 147A and 214 mg (1.37 mmol) of methyl (dichloromethylene) carbamate 166 mg (49% of theory) were obtained. ) of the title compound. 'H-NMR (400 MHz, DMSO-de, δ / ρρηι): 8.02 (s, 1H), 5.14-4.99 (m, 1H), 4.54 (s, 2H), 3.96 (t, 2H), 3.60 (t , 2H), 3.53 (s, 3H), 3.49-3.41 (m, 2H), 3.35-3.29 (m, 2H, partially covered by the water signal), 3.22 (s, 3H), 2.91 -2.78 (m, 2H), 2.39 (s, 3H), 2.28-2.17 (m, 2H), 2.10-2.02 (m, 2H), 2.01- 1.94 (m, 2H), 1.88-1.75 (m, 2H). LC / MS (Method 1, ESIpos): R _t = 1.88 min, m / z = 490.21 [M + H] ⁺ .

Example 182

6 - [(2,3-dioxopiperazin-1-yl) methyl] -1- (2-methoxyethyl) -5-methyl-3- (spiro [3.3] hept-2-yl) thieno [2,3-d ] pyrimidine-2,4 (lH, 3H) -dione

Analogously to the process described under Ex. 88, 162 mg (51% of theory) of the title compound were prepared from 345 mg (0.687 mmol, 81% purity) of the compound of Example 147A and 188 mg (1.27 mmol) of diethyl oxalate.

'H-NMR (400 MHz, DMSO-de, δ / ppm): 8.61 (br.s, 1H), 5.14-4.96 (m, 1H), 4.67 (s, 2H), 3.98 (t, 2H), 3.61 (t, 2H), 3.51-3.43 (m, 2H), 3.23 (s, 3H), 2.90-2.78 (m, 2H), 2.40 (s, 3H), 2.29-2.18 (m, 2H), 2.10-2.03 (m, 2H), 2.02-1.94 (m, 2H), 1.87-1.75 (m, 2H).

LC / MS (Method 1, ESIneg): R _t = 1.70 min, m / z = 505.18 [MH] ^"

Example 183 1- (2-Methoxyethyl) -5-methyl-6 - [(5-oxo-4,5-dihydro-1H-1,2,4-triazol-1-yl) methyl] -3- (spiro [ 3.3] - hept-2-yl) thieno [2,3-d] pyrimidine-2,4 (1H, 3H) -dione

375 mg (0.719 mmol) of the compound from Ex. 285A were dissolved in a mixture of 22 ml of methanol and trimethyl orthoformate and treated at RT with 1.8 ml (7.19 mmol) of a 4 M solution of hydrogen chloride in dioxane. After about 16 h, the reaction mixture was evaporated and the residue taken up in ethyl acetate. It was washed successively with water and saturated sodium chloride solution. After drying over anhydrous magnesium sulfate, it was filtered and concentrated again. The remaining residue was stirred with a little acetonitrile at RT. The solid was filtered off with suction, then redissolved in ethyl acetate, and the solution was shaken thoroughly with water. The organic phase was dried over anhydrous magnesium sulfate, filtered and concentrated. After drying the residue in a high vacuum, 170 mg (54% of theory) of the title compound were obtained.

'H-NMR (400 MHz, DMSO-de, δ / ppm): 11.58 (br.s, 1H), 7.83 (s, 1H), 5.05 (quin, 1H), 4.91 (s, 2H), 3.96 (br t, 2H), 3.60 (t, 2H), 3.22 (s, 3H), 2.90-2.75 (m, 2H), 2.42 (s, 3H), 2.23 (td, 2H), 2.10- 2.02 (m, 2H ), 2.01-1.93 (m, 2H), 1.87-1.74 (m, 2H). LC / MS (Method 1, ESIpos): R _t = 1.76 min, m / z = 432.17 [M + H] ⁺ .

Example 184

3-Cyclopentyl-5-methyl-6- [(2-oxoimidazolidin-1-yl) methyl] -1- (3,3,3-trifluoropropyl) thieno-pyrimidine-2,4 (1H, 3H) -dione

A solution of 240 mg (0.344 mmol, 60%> purity) of the compound of Example 148A and 72 μM (0.516 mmol) of triethylamine in 10 ml of THF was admixed with 67 mg (0.413 mmol) of CDI and Stirred at RT for 16 h. It was then concentrated to dryness. The remaining residue was taken up in ethyl acetate and washed successively with 1 M hydrochloric acid, water, saturated sodium bicarbonate solution and saturated sodium chloride solution. After drying over anhydrous magnesium sulfate, it was filtered and concentrated. The remaining residue was purified by preparative HPLC (Method 11). Evaporation of the product fractions and drying under high vacuum gave 42 mg (27% of theory) of the title compound.

'H-NMR (500 MHz, DMSO-de, δ / ppm): 6.53 (s, 1H), 5.30 (quin, 1H), 4.36 (s, 2H), 4.07 (t, 2H), 3.28-3.16 (m , 4H), 2.83-2.67 (m, 2H), 2.39 (s, 3H), 2.10-1.96 (m, 2H), 1.94-1.83 (m, 2H), 1.78- 1.68 (m, 2H), 1.60-1.48 (m, 2H).

LC / MS (Method 2, ESIpos): R _t = 1.01 min, m / z = 445 [M + H] ⁺ .

Example 185

[1- {[3-Cyclopentyl-5-methyl-2,4-dioxo-l- (3,3,3-trifluoropropyl) -l, 2,3,4-tetrahydrothieno [2,3-d] pyrimidine 6-yl] methyl} imidazolidine-2-ylidene] cyanamide

249 mg (0.357 mmol, 60%> purity) of the compound from Ex. 148A were dissolved in 5 ml of DMF and admixed with 78 mg (0.536 mmol) of dimethyl N-cyanodithioiminocarbonate and 99 mg (0.714 mmol) of potassium carbonate. The mixture was stirred for 5 hours at 80 ° C in a microwave oven (biotage initiator with dynamic control of the irradiation power). Thereafter, the reaction mixture was diluted with ethyl acetate and washed successively with water and saturated sodium chloride solution. After drying over anhydrous magnesium sulfate, it was filtered and concentrated. The crude product was purified by preparative HPLC (Method 11). The product fractions were combined, evaporated and dried under high vacuum. There were obtained 34 mg (20% of theory) of the title compound.

'H-NMR (500 MHz, DMSO-de, δ / ppm): 8.07 (s, 1H), 5.29 (quin, 1H), 4.49 (s, 2H), 4.08 (t, 2H), 3.52-3.36 (m , 4H), 2.84-2.68 (m, 2H), 2.41 (s, 3H), 2.09-1.96 (m, 2H), 1.93-1.84 (m, 2H), 1.81- 1.67 (m, 2H), 1.62-1.48 (m, 2H). LC / MS (Method 2, ESIpos): R _t = 1.06 min, m / z = 469 [M + H] ⁺ . Example 186

Methyl [1- {[3-cyclopentyl-5-methyl-2,4-dioxo-l- (3,3,3-trifluoropropyl) -l, 2,3,4-tetrahydrothieno [2,3-d] pyrimidin-6-yl] methyl} imidazolidine-2-ylidene] carbamate

248 mg (0.356 mmol, 60% purity) of the compound of Ex. 148A and 99 μΐ (0.711 mmol) of triethylamine were dissolved in 10 ml of dichloromethane and treated dropwise with a solution of 111 mg (0.711 mmol) of methyl (dichloromethylene) carbamate in 2 ml of dichloromethane. After the reaction mixture was stirred for about 16 h at RT, it was concentrated to dryness and the residue taken up in ethyl acetate. The organic phase was washed successively with saturated sodium carbonate solution and saturated sodium chloride solution, dried over anhydrous magnesium sulfate, filtered and concentrated again. The crude product was purified by preparative HPLC (Method 11). The product fractions were combined, evaporated and dried under high vacuum. 44 mg (24% of theory) of the title compound were isolated. Ή-NMR (500 MHz, DMSO-d _6, δ / ppm): 8:02 (s, 1H), 5.29 (quin, 1H), 4:57 (s, 2H), 4:06 (t, 2H), 3:53 (s, 3H ), 3.49-3.42 (m, 2H), 3.37-3.31 (m, 2H, partially covered by the water signal), 2.81 - 2.69 (m, 2H), 2.42 (s, 3H), 2.07-1.97 (m, 2H), 1.94-1.83 (m, 2H), 1.79-1.68 (m, 2H), 1.60-1.48 (m, 2H).

LC / MS (Method 1, ESIpos): R _t = 1.92 min, m / z = 502.17 [M + H] ⁺ . Example 187

3-cyclopentyl-6- [(2,3-dioxopiperazin-1-yl) methyl] -5-methyl-1- (3,3,3-trifluoropropyl) thieno [2,3-d] pyrimidine-2,4 (lH, 3H) -dione

A solution of 250 mg (0.358 mmol, 60% purity) of the compound from Ex. 148A in 10 ml of ethanol was mixed with 91 .mu.l (0.663 mmol) of diethyl oxalate and stirred at 80.degree. C. for about 19 h. Then, the reaction mixture was evaporated and the residue was taken up in ethyl acetate. The organic phase was washed with saturated sodium chloride solution. After drying over anhydrous magnesium sulfate, it was filtered and concentrated. From the remaining residue, a crude product was obtained by preparative HPLC (Method 11), which was redissolved in ethyl acetate and washed thoroughly with saturated sodium bicarbonate solution. After renewed drying over anhydrous magnesium sulfate, filtration and evaporation, 54 mg (31% of theory) of the title compound were obtained.

Ή-NMR (400 MHz, DMSO-de, δ / ppm): 8.62 (br.s, 1H), 5.29 (quin, 1H), 4.70 (s, 2H), 4.07 (t, 2H), 3.52-3.44 ( m, 2H), 3.34-3.29 (m, 2H, almost completely masked by the water signal), 2.83-2.69 (m, 2H), 2.43 (s, 3H), 2.08-1.96 (m, 2H), 1.95-1.82 (m , 2H), 1.80-1.68 (m, 2H), 1.62-1.49 (m, 2H).

LC / MS (Method 1, ES Ineg): R _t = 1.70 min, m / z = 517.14 [MH] -. Example 188

3-cyclopentyl-5-methyl-6 - [(5-oxo-4,5-dihydro-lH-l, 2,4-triazol-l-yl) methyl] -l- (3,3,3-trifluoro propyl) thieno [2,3-d] pyrimidine-2,4 (lH, 3H) -dione

280 mg (0.525 mmol) of the compound from Ex. 286A were dissolved in a mixture of 15 ml each of methanol and trimethyl orthoformate, and 1.3 ml (5.25 mmol) of a 4 M solution of hydrogen chloride in dioxane were added at RT. After approx. 16 h, an additional 656 μΐ (5.25 mmol) of the 4M solution of hydrogen chloride in dioxane. After a further 2 h, the reaction mixture was evaporated and the residue taken up in ethyl acetate. It was washed successively with water and saturated sodium chloride solution. After drying over anhydrous magnesium sulfate, it was filtered and concentrated again. The remaining residue was purified by preparative HPLC (Method 1 1). Evaporation of the product fractions and drying under high vacuum gave 1 16 mg (50% of theory) of the title compound.

'H-NMR (400 MHz, DMSO-de, δ / ppm): 1 1.60 (br.s, 1H), 7.84 (s, 1H), 5.29 (quin, 1H), 4.95 (s, 2H), 4.06 ( t, 2H), 2.82-2.67 (m, 2H), 2.46 (s, 3H), 2.07-1.96 (m, 2H), 1.95-1.82 (m, 2H), 1.79-1.67 (m, 2H), 1.61 - 1.47 (m, 2H). LC / MS (Method 2, ESIpos): R _t = 0.94 min, m / z = 444 [M + H] ⁺ .

Example 189

3-Cyclopentyl-1- (2-methoxyethyl) -5-methyl-6 - [(2-oxoimidazolidin-1-yl) methyl] thieno

pyrimidine-2,4 (lH, 3H) -dione

A solution of 479 mg (1.03 mmol, 82%> purity) of the compound of Ex. 149A and 216 μΐ (1.55 mmol) of triethylamine in 20 ml of THF was combined with 201 mg (1.24 mmol) of CDI and stirred at RT for about 16 h , It was then concentrated to dryness. The remaining residue was taken up in ethyl acetate and washed successively with 1 M hydrochloric acid, water, saturated sodium bicarbonate solution and saturated sodium chloride solution. After drying over water-free magnesium sulfate, it was filtered and concentrated. The solid residue was stirred with a little diisopropyl ether at RT, filtered off with suction and then purified by preparative HPLC (Method 1 1). After evaporation of the product fractions and drying in a high vacuum, 231 mg (55% of theory) of the title compound were obtained.

Ή-NMR (400 MHz, DMSO-de, δ / ppm): 6.52 (s, 1H), 5.30 (quin, 1H), 4.34 (s, 2H), 3.99 (t, 2H), 3.62 (t, 2H) , 3.28-3.15 (m, 4H), 3.24 (s, 3H), 2.38 (s, 3H), 2.09-1.96 (m, 2H), 1.95-1.81 (m, 2H), 1.81 -1.66 (m, 2H) , 1.62-1.48 (m, 2H). LC / MS (Method 1, ESIpos): R _t = min, m / z = 407.17 [M + H]

Example 190

[1- {[3-Cyclopentyl-1- (2-methoxyethyl) -5-methyl-2,4-dioxo-1,2,3,4-tetrahydrothieno [2,3-d] pyrimidin-6-yl] methyl} imidazolidine-2-ylidene] cyanamide

421 mg (0.907 mmol, 82% purity) of the compound from Ex. 149A were dissolved in 13 ml of DMF and admixed with 199 mg (1.36 mmol) of dimethyl N-cyanodithioiminocarbonate and 251 mg (1.81 mmol) of potassium carbonate. The mixture was stirred for 5 hours at 80 ° C in a microwave oven (biotage initiator with dynamic control of the irradiation power). Thereafter, the reaction mixture was diluted with ethyl acetate and washed successively with water and saturated sodium chloride solution. After drying over anhydrous magnesium sulfate, it was filtered and concentrated. The crude product was stirred with a little ethyl acetate at RT, filtered off with suction and then purified by preparative HPLC (Method 11). The product fractions were combined and concentrated and finally stirred at RT with a mixture of 15 ml of pentane and 0.5 ml of dichloromethane. After renewed suction and drying in a high vacuum, 143 mg (36% of theory) of the title compound were obtained.

'H-NMR (400 MHz, DMSO-de, δ / ppm): 8.06 (s, 1H), 5.30 (quin, 1H), 4.47 (s, 2H), 4.00 (t, 2H), 3.63 (t, 2H ), 3.50-3.36 (m, 4H), 3.24 (s, 3H), 2.39 (s, 3H), 2.09-1.96 (m, 2H), 1.95-1.82 (m, 2H), 1.80-1.68 (m, 2H ), 1.61-1.48 (m, 2H). LC / MS (Method 1, ESIpos): R _t = 1.76 min, m / z = 431.19 [M + H] ⁺ .

Example 191

Methyl [1 - {[3-cyclopentyl-1- (2-methoxyethyl) -5-methyl-2,4-dioxo-1,2,3,4-tetrahydrothieno [2,3-d] pyrimidine-6 yl] methyl} imidazolidine-2-ylidene] carbamate

Analogously to the process described under Example 87, from 453 mg (0.976 mmol, 82% purity) of the compound from Ex. 149A and 305 mg (1.95 mmol) of methyl (dichloromethylene) carbamate 142 mg (31% of theory) of th .) Of the title compound. The product was still stirred in a small volume of DMSO at room temperature after preparative HPLC purification.

Ή-NMR (400 MHz, DMSO-de, δ / ppm): 8.02 (s, 1H), 5.29 (quin, 1H), 4.55 (s, 2H), 3.98 (t, 2H), 3.61 (t, 2H) , 3.53 (s, 3H), 3.49-3.41 (m, 2H), 3.36-3.29 (m, 2H, partially covered by the water signal), 2.41 (s, 3H), 2.09-1.96 (m, 2H), 1.95-1.81 (m, 2H), 1.80-1.66 (m, 2H), 1.62-1.47 (m, 2H).

LC / MS (Method 2, ESIpos): R _t = 0.84 min, m / z = 464 [M + H] ⁺ . Example 192

3-Cyclopentyl-6 - [(2,3-dioxopiperazin-1-yl) methyl] -1- (2-methoxyethyl) -5-methylthieno-pyrimidine-2,4 (1H, 3H) -dione

Analogous to the procedure described under Ex. 88 were from 448 mg (0.965 mmol, 82% purity) of the compound from Ex. 149A and 264 mg (1.79 mmol) of diethyl oxalate 148 mg (35%) d. Th.) Of the title compound. Before purification by (here twice) preparative HPLC, a first purification step was carried out by MPLC (Biotage Isolera One, cartridge SNAP KP-Sil, 25 g silica gel, eluent cyclohexane / ethyl acetate 1: 1 - ^{> ■} dichloromethane / methanol 10: 1). 'H-NMR (400 MHz, DMSO-de, δ / ρρηι): 8.61 (br.s, 1H), 5.30 (quin, 1H), 4.68 (s, 2H), 4.00 (t, 2H), 3.62 (t , 2H), 3.52-3.43 (m, 2H), 3.36-3.27 (m, 2H, partially covered by the water signal), 2.42 (s, 3H), 2.09-1.96 (m, 2H), 1.95-1.82 (m, 2H ), 1.81-1.68 (m, 2H), 1.62-1.48 (m, 2H).

LC / MS (Method 2, ES Ineg): R _t = 0.79 min, m / z = 479 [M-H + HCOOH] -. Example 193

3-Cyclopentyl-1- (2-methoxyethyl) -5-methyl-6 - [(5-oxo-4,5-dihydro-1H-1,2,4-triazol-1-yl) methyl] thieno [2 , 3-d] pyrimidine-2,4 (lH, 3H) -dione

Analogously to the process described under Example 188, from 460 mg (0.845 mmol, 91% purity) of the compound from Ex. 287A, 108 mg (31% of theory) of the title compound were prepared.

Ή-NMR (400 MHz, DMSO-de, δ / ppm): 11.59 (br.s, 1H), 7.84 (s, 1H), 5.29 (quin, 1H), 4.92 (s, 2H), 3.98 (t, 2H), 3.61 (t, 2H), 3.23 (s, 3H), 2.44 (s, 3H), 2.07-1.96 (m, 2H), 1.94-1.82 (m, 2H), 1.80-1.67 (m, 2H) , 1.62-1.48 (m, 2H).

LC / MS (Method 1, ESIpos): R _t = 1.51 min, m / z = 406.15 [M + H] ⁺ . Example 194

3-cyclopropyl-l-ethyl-5-methyl-6 - [(5-oxo-4,5-dihydro-lH-l, 2,4-triazol-l-yl) methyl] thieno [2,3-d] - pyrimidine-2,4 (1H, 3H) -dione

170 mg (0.276 mmol, 71% purity) of the compound from Ex. 435A were dissolved in a mixture of in each case 7 ml of methanol and trimethyl orthoformate and treated at RT with 690 μΐ (2.76 mmol) of a 4 M solution of hydrogen chloride in dioxane. After 2 days, the reaction evaporated tion mixture and the remaining residue by means of two preparative preparative HPLC (first method 11, then method 13). After evaporation of the product fractions and drying in a high vacuum, 40 mg (41% of theory) of the title compound were obtained. 'H-NMR (400 MHz, DMSO-d _6, δ / ppm): 11:59, 7.83 (s, 1H), 4.93 (s, 2H), 3.84 (q, 2H), 2.62- (br s, 1H). 2.55 (m, 1H), 2.44 (s, 3H), 1.20 (t, 3H), 1.06-0.93 (m, 2H), 0.71-0.61 (m, 2H).

LC / MS (Method 1, ESIpos): R _t = 1.05 min, m / z = 348.11 [M + H] ⁺ . Example 195

3-Cyclopropyl-5-methyl-6 - [(5-oxo-4,5-dihydro-1H-1,2,4-triazol-1-yl) methyl] -1-propylthieno [2,3-d] pyrimidine-2,4 (lH, 3H) -dione

108 mg (0.227 mmol, 95% purity) of the compound from Ex. 436A were dissolved in a mixture of 5.6 ml each of methanol and trimethyl orthoformate and admixed at RT with 568 μl (2.27 mmol) of a 4 M solution of hydrogen chloride in dioxane. After 2 days, the reaction mixture was evaporated and the remaining residue was purified by preparative HPLC (Method 13). After evaporation of the product fractions and drying in a high vacuum, 55 mg (66% of theory) of the title compound were obtained.

'H-NMR (400 MHz, DMSO-de, δ / ppm): 11.57 (br.s, 1H), 7.83 (s, 1H), 4.92 (s, 2H), 3.82-3.72 (m, 2H), 2.59 (tt, 1H), 2.44 (s, 3H), 1.66 (sext, 2H), 1.04-0.95 (m, 2H), 0.89 (t, 3H), 0.71-0.62 (m, 2H). LC / MS (Method 1, ESIpos): R _t = 1.19 min, m / z = 362.13 [M + H] ⁺ .

Example 196

3-Cyclopropyl-1- (2-fluoroethyl) -5-methyl-6 - [(5-oxo-4,5-dihydro-1H-1,2,4-triazol-1-yl) methyl] thieno [2 , 3-d] pyrimidine-2,4 (lH, 3H) -dione

Analogously to the process described under Ex. 195, 71 mg (0.137 mmol, 88% purity) of the compound from Example 437A were used to prepare 30 mg (59% of theory) of the title compound.

Ή-NMR (400 MHz, DMSO-de, δ / ppm): 11.58 (br.s, 1H), 7.82 (s, 1H), 4.92 (s, 2H), 4.70 (dt, 2H), 4.13 (dt, 2H), 2.63-2.56 (m, 1H), 2.43 (s, 3H), 1.04-0.95 (m, 2H), 0.75-0.61 (m, 2H).

LC / MS (Method 2, ESIpos): R _t = 0.58 min, m / z = 366 [M + H] ⁺ .

Example 197

3-Cyclopropyl-1- (3-fluoropropyl) -5-methyl-6 - [(5-oxo-4,5-dihydro-1H-1,2,4-triazol-1-yl) -methyl] -thieno [2 , 3-d] pyrimidine-2,4 (lH, 3H) -dione

Analogously to the process described under Example 195, from 144 mg (0.307 mmol) of the compound from Example 438A, 74 mg (63% of theory) of the title compound were prepared.

Ή-NMR (400 MHz, DMSO-de, δ / ppm): 11.59 (br.s, 1H), 7.82 (s, 1H), 4.92 (s, 2H), 4.52 (dt, 2H), 3.92 (t, 2H), 2.62-2.55 (m, 1H), 2.44 (s, 3H), 2.12-1.94 (m, 2H), 1.04-0.95 (m, 2H), 0.70-0.61 (m, 2H).

LC / MS (Method 1, ESIpos): R _t = 1.09 min, m / z = 380.12 [M + H] ⁺ .

Example 198

3-Cyclopropyl-1- (4-fluorobutyl) -5-methyl-6 - [(5-oxo-4,5-dihydro-1H-1,2,4-triazol-1-yl) methyl] thieno [2 , 3-d] pyrimidine-2,4 (lH, 3H) -dione

Analogously to the process described in Example 2, from 134 mg (0.252 mmol, 91% purity) of the compound from Example 439A, 60 mg (60% of theory) of the title compound were prepared.

'H-NMR (400 MHz, DMSO-de, δ / ppm): 11.58 (br.s, 1H), 7.83 (s, 1H), 4.92 (s, 2H), 4.58-4.32 (m, 2H), 3.85 (br t, 2H), 2.62-2.55 (m, 1H), 2.44 (s, 3H), 1.80-1.58 (m, 4H), 1.04-0.94 (m, 2H), 0.71-0.62 (m, 2H) ,

LC / MS (Method 6, ESIpos): R _t = 0.93 min, m / z = 394 [M + H] ⁺ . Example 199

3-Cyclopropyl-1- (2,2-difluoroethyl) -5-methyl-6 - [(5-oxo-4,5-dihydro-1H-1,2,4-triazol-1-yl) methyl] thieno [2,3-d] pyrimidine-2,4 (lH, 3H) -dione

Analogously to the process described under Example 195, from 102 mg (0.194 mmol, 90%> purity) of the compound from Example 440A, 50 mg (67% of theory) of the title compound were prepared.

Ή-NMR (400 MHz, DMSO-de, δ / ppm): 11.59 (br.s, 1H), 7.83 (s, 1H), 6.30 (tt, 1H), 4.93 (s, 2H), 4.26 (td, 2H), 2.65-2.56 (m, 1H), 2.44 (s, 3H), 1.08-0.92 (m, 2H), 0.76-0.61 (m, 2H).

LC / MS (Method 1, ESIpos): R _t = 1.11 min, m / z = 384.09 [M + H] ⁺ .

Example 200

3-Cyclopropyl-5-methyl-6 - [(5-oxo-2,5-dihydro-1H-pyrazol-1-yl) methyl] -1- (3,3,3-trifluoropropyl) thieno [2,3 -d] pyrimidine-2,4 (lH, 3H) -dione

210 mg (0.337 mmol, 90% purity) of the compound from Ex. 454A were dissolved in 5 ml of dichloromethane and treated with a drop of concentrated sulfuric acid. After the reaction mixture was stirred for 30 min at RT, it was treated with ice-water. Subsequently, the organic phase was separated and washed with saturated aqueous sodium chloride solution, dried over anhydrous magnesium sulfate, filtered and concentrated. The remaining residue was purified by preparative HPLC (Method 11). Evaporation of the product fractions and drying under high vacuum gave 87 mg (62% of theory) of the title compound. Ή-NMR (400 MHz, DMSO-d ₆ , δ / ppm): 11.29 (broad, 1H), 7.15 (s, 1H), 5.30 (d, 1H), 5.14 (s, 2H), 4.02 (t, 2H ), 2.78-2.63 (m, 2H), 2.62-2.56 (m, 1H), 2.46 (s, 3H), 1.06-0.94 (m, 2H), 0.71-0.59 (m, 2H).

LC / MS (Method 1, ES Ineg): R _t = 1.36 min, m / z = 413.09 [MH] -. Example 201 3-Cyclopropyl-5-methyl-6 - [(5-oxo-4,5-dihydro-1H-l, 2,4-triazol-1-yl) methyl] -1- (4,4,4- trifluorobutyl) thieno [2,3-d] pyrimidine-2,4 (1H, 3H) -dione

1959 (0.291 mmol, 95% purity) of the compound from Ex. 441A, 78 mg (62% of theory) of the title compound were prepared analogously to the process described under Ex. 'H-NMR (400 MHz, DMSO-de, δ / ρρηι): 11.59 (br.s, 1H), 7.82 (s, 1H), 4.93 (s, 2H), 3.90 (t, 2H), 2.62-2.55 (m, 1H), 2.47-2.30 (m, 2H), 2.44 (s, 3H), 1.86 (quin, 2H), 1.05-0.93 (m, 2H), 0.73-0.61 (m, 2H).

LC / MS (Method 1, ESIpos): R _t = 1.38 min, m / z = 430.11 [M + H] ⁺ . Example 202

3-Cyclopropyl-l - [(2,2-difluorocyclobutyl) methyl] -5-methyl-6 - [(5-oxo-4,5-dihydro-1H-l, 2,4-triazol-1-yl) methyl ] thieno [2,3-d] pyrimidine-2,4 (1H, 3H) -dione (enantiomer 1)

Analogously to the process described in Example 2, from 143 mg (0.278 mmol) of the compound from Example 442A, 28 mg (23% of theory) of the title compound were prepared. The reaction time was 4 days.

Ή-NMR (400 MHz, DMSO-de, δ / ppm): 11.52 (br, s, 1H), 7.83 (br, s, 1H), 4.93 (br, s, 2H), 4.13- 3.87 (m, 2H ), 2.44 (brs s, 3H), 2.04-1.80 (m, 1H), 1.73-1.48 (m, 1H), 1.12-0.87 (m, 2H), 0.72-0.59 (m, 2H). LC / MS (Method 2, ESIpos): R _t = 0.74 min, m / z = 424 [M + H] ⁺ . Example 203

3-Cyclopropyl-l - [(2,2-difluorocyclobutyl) methyl] -5-methyl-6 - [(5-oxo-4,5-dihydro-1H-l, 2,4-triazol-1-yl) methyl ] thieno [2,3-d] pyrimidine-2,4 (1H, 3H) -dione {enantiomer 2)

Analogously to the process described in Example 2, from 128 mg (0.199 mmol, 80% purity) of the compound from Ex. 443A, 31 mg (36% of theory) of the title compound were prepared. The reaction time was 4 days.

'H-NMR (400 MHz, DMSO-de, δ / ppm): 11.59 (br.s, 1H), 7.83 (s, 1H), 4.93 (s, 2H), 4.10-3.88 (m, 2H), 3.34 -3.17 (m, 2H, partially covered by the water signal), 2.63-2.55 (m, 1H), 2.47-2.40 (m, 1H), 2.44 (s, 3H), 1.98-1.83 (m, 1H), 1.68 -1.53 (m, 1H), 1.08-0.93 (m, 2H), 0.73-0.58 (m, 2H).

LC / MS (Method 2, ESIpos): R _t = 0.74 min, m / z = 424 [M + H] ⁺ .

Example 204

3-Cyclopropyl-1 - [(3,3-difluorocyclobutyl) methyl] -5-methyl-6- [(2-oxoimidazolidin-1-yl) -yl) -thieno [2,3-d] pyrimidine-2,4 (lH, 3H) -dione

A solution of 185 mg (0.395 mmol, 85% purity) of the compound of Example 361 A and 83 μΐ (0.592 mmol) of triethylamine in 5 ml of THF was treated with 77 mg (0.474 mmol) of CDI and stirred at RT for about 16 h , It was then concentrated to dryness. The remaining residue was taken up in ethyl acetate and washed successively with water and saturated sodium chloride solution. After drying over anhydrous magnesium sulfate, it was filtered and concentrated. The solid residue was purified by preparative HPLC (Method 11). Evaporation of the product fractions and drying under high vacuum gave 86 mg (51% of theory) of the title compound. 'H-NMR (400 MHz, DMSO-d _6, δ / ppm): 6:52 (s, 1H), 4:34 (s, 2H), 4.01, (d, 2H), 3:27 to 3:16 (m, 4H), 2.76- 2.41 (m, 6H, partially covered by the DMSO signal), 2.37 (s, 3H), 1.05-0.96 (m, 2H), 0.72-0.61 (m, 2H).

LC / MS (Method 1, ESIpos): R _t = 1.46 min, m / z = 425.14 [M + H] Example 205

3-Cyclopropyl-1 - [(3,3-difluorocyclobutyl) methyl] -5-methyl-6- [(2-oxo-2,3-dihydro-1H-imidazol-1-yl) methyl] thieno [2,3 -d] pyrimidine-2,4 (lH, 3H) -dione

220 mg (0.375 mmol, 83% purity) of the compound from Ex. 392A were dissolved in 4 ml of methanol and admixed with 0.75 ml of water and 0.75 ml of 1 M hydrochloric acid. After the reaction mixture was stirred for 2 days at RT, it was diluted with water and extracted with ethyl acetate. The organic extract was washed successively with water and saturated sodium chloride solution. After drying over anhydrous magnesium sulfate, it was filtered and concentrated. The solid residue was purified by preparative HPLC (Method 11). After evaporation of the product fractions and drying in a high vacuum, 71 mg (44% of theory) of the title compound were obtained.

'H-NMR (400 MHz, DMSO-de, δ / ppm): 9.98 (br.s, 1H), 6.42 (dd, 1H), 6.34 (t, 1H), 4.78 (s, 2H), 4.00 (i.e. , 2H), 2.74-2.56 (m, 4H), 2.44 (s, 3H), 1.05-0.94 (m, 2H), 0.69-0.61 (m, 2H). LC / MS (Method 1, ESIpos): R _t = 1.36 min, m / z = 423.13 [M + H] ⁺ .

Example 206

3-Cyclopropyl-l - [(3,3-difluorocyclobutyl) methyl] -5-methyl-6 - [(5-oxo-4,5-dihydro-1H-l, 2,4-triazol-1-yl) methyl ] thieno [2,3-d] pyrimidine-2,4 (lH, 3H) -dione

230 mg (0.448 mmol) of the compound from Ex. 444A were dissolved in a mixture of 15 ml each of methanol and trimethyl orthoformate, and 1.1 ml (4.48 mmol) of a 4 M solution of hydrogen chloride in dioxane were added at RT. After 5 days, the reaction mixture was first evaporated and then taken up in ethyl acetate. It was washed successively with water and saturated sodium chloride solution. After drying over anhydrous magnesium sulfate, it was filtered and concentrated again. The remaining residue was purified by preparative HPLC (Method 11). After evaporation of the product fractions and drying in a high vacuum, 103 mg (54% of theory) of the title compound were obtained.

'H-NMR (400 MHz, DMSO-de, δ / ppm): 11.59 (br.s, 1H), 7.83 (s, 1H), 4.92 (s, 2H), 4.00 (d, 2H), 2.75-2.55 (m, 4H), 2.44 (s, 3H), 1.06-0.92 (m, 2H), 0.72-0.59 (m, 2H).

LC / MS (Method 2, ESIpos): R _t = 0.73 min, m / z = 424 [M + H] ⁺ .

Example 207

3-Cyclopropyl-l - [(2,2-difluorocyclopentyl) methyl] -5-methyl-6 - [(5-oxo-4,5-dihydro-1H-l, 2,4-triazol-1-yl) methyl ] thieno [2,3-d] pyrimidine-2,4 (1H, 3H) -dione {enantiomer 1)

Analogously to the process described in Example 2, from 128 mg (0.243 mmol) of the compound from Example 445A, 33 mg (31% of theory) of the title compound were prepared.

Ή-NMR (400 MHz, DMSO-de, δ / ppm): 11.57 (br.s, 1H), 7.83 (s, 1H), 4.93 (s, 2H), 4.05-3.82 (m, 2H), 2.79- 2.63 (m, 1H), 2.59 (t, 1H), 2.44 (s, 3H), 2.25-1.99 (m, 2H), 1.96-1.83 (m, 1H), 1.82-1.49 (m, 3H), 1.07- 0.93 (m, 2H), 0.75-0.56 (m, 2H).

LC / MS (Method 1, ESIpos): R _t = 1.40 min, m / z = 438.14 [M + H] ⁺ .

Example 208

3-Cyclopropyl-l - [(2,2-difluorocyclopentyl) methyl] -5-methyl-6 - [(5-oxo-4,5-dihydro-1H-l, 2,4-triazol-1-yl) methyl ] thieno [2,3-d] pyrimidine-2,4 (1H, 3H) -dione {enantiomer 2)

135 mg (0.256 mmol) of the compound from Ex. 446A were dissolved in a mixture of 8 ml of methanol and trimethyl orthoformate and treated at RT with 640 .mu.l (2.56 mmol) of a 4 M solution of hydrogen chloride in dioxane. After 2 days, the reaction mixture was first evaporated and then taken up in ethyl acetate. It was washed successively with water and saturated sodium chloride solution. After drying over anhydrous magnesium sulfate, it was filtered and concentrated again. The remaining residue was purified by preparative HPLC (Method 11). Evaporation of the product fractions and drying under high vacuum gave 35 mg (31% of theory) of the title compound. Ή-NMR (400 MHz, DMSO-d ₆ , δ / ppm): 11.59 (br.s, 1H), 7.83 (s, 1H), 4.93 (s, 2H), 4.05-3.82 (m, 2H), 2.80 -2.63 (m, 1H), 2.59 (t, 1H), 2.44 (s, 3H), 2.25-2.00 (m, 2H), 1.97-1.84 (m, 1H), 1.81-1.48 (m, 3H), 1.08 -0.92 (m, 2H), 0.76-0.54 (m, 2H).

LC / MS (Method 1, ESIpos): R _t = 1.40 min, m / z = 438.14 [M + H] ⁺ .

Example 209 3-Cyclopropyl-l - [(3,3-difluorocyclopentyl) methyl] -5-methyl-6 - [(5-oxo-4,5-dihydro-1H-l, 2,4-triazol-1-yl ) methyl] thieno [2,3-d] pyrimidine-2,4 (1H, 3H) -dione (racemate)

Analogously to the process described in Example 2, 212 mg (0.402 mmol) of the compound from Ex. 447A were used to prepare 95 mg (54% of theory) of the title compound. 'H-NMR (400 MHz, DMSO-de, δ / ρρηι): 11.58 (m, 1H), 7.83 (s, 1H), 4.92 (s, 2H), 3.99-3.75 (m, 2H), 2.64-2.55 (m, 2H), 2.44 (s, 3H), 2.31-1.79 (m, 5H), 1.57 (dq, 1H), 1.06-0.91 (m, 2H), 0.72-0.60 (m, 2H).

LC / MS (Method 1, ESIpos): R _t = 1.42 min, m / z = 438.14 [M + H] ⁺ . Example 210

3-Cyclopropyl-l - [(3,3-difluorocyclopentyl) methyl] -5-methyl-6 - [(5-oxo-4,5-dihydro-1H-l, 2,4-triazol-1-yl) methyl ] thieno [2,3-d] pyrimidine-2,4 (1H, 3H) -dione {enantiomer 1)

90 mg of the racemic compound from Ex. 209 were dissolved in 10 ml of a mixture of ethanol, heptane and dichloromethane and separated into 20 portions by preparative HPLC on a chiral phase into the enantiomers [column: Daicel Chiralpak OD-H, 5 μm, 250 mm x 20 mm; Eluent: n-heptane / ethanol 1: 1; Flow: 25 ml / min; Temperature: 40 ° C; Detection: 220 nm]. Evaporation of the product fractions and drying of the solid in a high vacuum gave 24 mg (53% of theory) of enantiomer 1 (99% ee, chiral analytical HPLC). Ή-NMR (400 MHz, DMSO-d ₆ , δ / ppm): 11.57 (br.s, 1H), 7.82 (s, 1H), 4.92 (s, 2H), 3.96-3.77 (m, 2H), 2.64 -2.55 (m, 2H), 2.44 (s, 3H), 2.32-1.80 (m, 5H), 1.57 (dq, 1H), 1.03-0.93 (m, 2H), 0.73-0.57 (m, 2H).

Chiral analytical HPLC [column: Daicel Chiraltek OD-3, 3 μm, 50 mm × 4.6 mm; Eluent: isohexane / ethanol 1: 1; Flow: 3 ml / min; Temperature: 40 ° C; Detection: 220 nm]: R _t = 2.93 min. LC / MS (Method 2, ESIpos): R _t = 0.77 min, m / z = 438 [M + H] ⁺ .

Example 211

3-Cyclopropyl-l - [(3,3-difluorocyclopentyl) methyl] -5-methyl-6 - [(5-oxo-4,5-dihydro-1H-l, 2,4-triazol-1-yl) methyl ] thieno [2,3-d] pyrimidine-2,4 (1H, 3H) -dione {enantiomer 2)

From the chiral phase HPLC separation described in Example 210, 27 mg (60% of theory) of enantiomer 2 were obtained (92.6% ee, chiral analytical HPLC).

Ή-NMR (400 MHz, DMSO-d ₆ , δ / ppm): 1 1.58 (br.s, 1H), 7.82 (s, 1H), 4.92 (s, 2H), 3.98-3.77 (m, 2H), 2.64-2.55 (m, 2H), 2.44 (s, 3H), 2.32-1.80 (m, 5H), 1.57 (dq, 1H), 1.07-0.91 (m, 2H), 0.74-0.57 (m, 2H).

Chiral analytical HPLC [column: Daicel Chiraltek OD-3, 3 μm, 50 mm × 4.6 mm; Eluent: isohexane / ethanol 1: 1; Flow: 3 ml / min; Temperature: 40 ° C; Detection: 220 nm]: R _t = 4.00 min.

LC / MS (Method 2, ESIpos): R _t = 0.77 min, m / z = 438 [M + H] ⁺ . Example 212

4- {3-Cyclopropyl-5-methyl-2,4-dioxo-6 - [(5-oxo-4,5-dihydro-1H-1,2,4-triazol-1-yl) methyl] -3, 4-dihydrothieno [2,3-d] pyrimidin-1 (2H) -yl} butanenitrile

195 mg (63% of theory) of the title compound were prepared from 140 mg (0.279 mmol, 95% purity) of the compound from Example 448A analogously to the process described under Example 195.

Ή NMR (400 MHz, DMSO-de, δ / ppm): 1 1.58 (br.s, 1H), 7.83 (s, 1H), 4.93 (s, 2H), 3.91 (t, 2H), 2.64-2.55 (m, 3H), 2.44 (s, 3H), 1.94 (quin, 2H), 1.06-0.92 (m, 2H), 0.75-0.61 (m, 2H).

LC / MS (Method 6, ESIpos): R _t = 0.81 min, m / z = 387 [M + H] ⁺ . Example 213

3-Cyclopropyl-5-methyl-6 - [(5-oxo-4,5-dihydro-1H-1,2,4-triazol-1-yl) methyl] -1- {2 - [(trifluoromethyl) sulfanyl] ethyl} thieno [2,3-d] pyrimidine-2,4 (lH, 3H) -dione

195 mg (0.215 mmol, 75% purity) of the compound from Ex. 449A, 75 mg (78% of theory) of the title compound, were prepared analogously to the process described under Example 195.

Ή-NMR (400 MHz, DMSO-de, δ / ppm): 11.52 (br.s, 1H), 7.83 (s, 1H), 4.93 (s, 2H), 4.08 (t, 2H), 3.27 (t, 2H, largely masked by the water signal), 2.63-2.55 (m, 1H), 2.44 (s, 3H), 1.08-0.93 (m, 2H), 0.73-0.59 (m, 2H). LC / MS (Method 1, ESIpos): R _t = 1.44 min, m / z = 448.07 [M + H] ⁺ .

Example 214

5-Methyl-3- (1-methylcyclopropyl) -6 - [(2-oxo-2,3-dihydro-1H-imidazol-1-yl) methyl] -1- (3,3,3-trifluoropropyl) thieno [2,3-d] pyrimidine-2,4 (lH, 3H) -dione

306 mg (0.621 mmol) of the compound from Ex. 393A were dissolved in 6 ml of methanol and combined with 1.2 ml of water and 1.2 ml of 1 M hydrochloric acid. Since no conversion was detectable after stirring at RT overnight, 1 ml of concentrated hydrochloric acid was added and stirring continued at RT. After 2 days, it was diluted with water and extracted with ethyl acetate. The organic extract was washed successively with water and saturated sodium chloride solution. After drying over anhydrous magnesium sulfate, it was filtered and concentrated. The fixed return was purified by preparative HPLC (Method 11). Evaporation of the product fractions and drying under high vacuum gave 178 mg (67% of theory) of the title compound.

Ή-ΝΜΡ (400 MHz, DMSO-d ₆ , δ / ppm): 9.99 (br, s, 1H), 6.42 (t, 1H), 6.34 (t, 1H), 4.79 (s, 2H), 4.22-3.84 (m, 2H), 2.81-2.63 (m, 2H), 2.46 (s, 3H), 1.33 (s, 3H), 1.01-0.72 (m, 4H).

LC / MS (Method 1, ESIpos): R _t = 1.44 min, m / z = 429.12 [M + H] ⁺ .

Example 215

5-Methyl-3- (1-methylcyclopropyl) -6 - [(5-oxo-2,5-dihydro-1H-pyrazol-1-yl) methyl] -1- (3,3,3-trifluoropropyl) thieno [2,3-d] pyrimidine-2,4 (lH, 3H) -dione

200 mg (0.539 mmol) of the compound from Ex. 455A 117 mg (50% of theory) of the title compound were prepared analogously to the process described under Ex.

Ή-NMR (400 MHz, DMSO-d ₆ , δ / ppm): 11.23 (br.s, 1H), 7.15 (s, 1H), 5.30 (d, 1H), 5.14 (s, 2H), 4.18-3.88 (m, 2H), 2.80-2.63 (m, 2H), 2.46 (s, 3H), 1.32 (s, 3H), 1.01-0.68 (m, 4H). LC / MS (method 1, ESIneg): R _t = 1.47 min, m / z = 427.11 [MH].

Example 216 1 - [(3,3-Difluorocyclobutyl) methyl] -5-methyl-3- (1-methylcyclopropyl) -6 - [(2-oxo-2,3-dihydro-1H-imidazol-1-yl) methyl ] thieno [2,3-d] pyrimidine-2,4 (lH, 3H) -dione

350 mg (0.699 mmol) of the compound from Ex. 394A were dissolved in 7 ml of methanol and mixed with 1.4 ml of water and 1.4 ml of 1 M hydrochloric acid. After the reaction mixture was stirred for 2 days at RT, it was diluted with water and extracted with ethyl acetate. The organic extract was washed successively with water and saturated sodium chloride solution. After drying over anhydrous magnesium sulfate, it was filtered and concentrated. The solid residue was purified by preparative HPLC (Method 11). After evaporation of the product fractions and drying in a high vacuum, 125 mg (40% of theory) of the title compound were obtained.

'H-NMR (400 MHz, DMSO-de, δ / ppm): 9.98 (br.s, 1H), 6.41 (t, 1H), 6.34 (t, 1H), 4.78 (s, 2H), 4.18-3.81 (m, 2H), 2.75-2.61 (m, 2H), 2.45 (s, 3H), 1.32 (s, 3H), 1.02-0.67 (m, 4H).

LC / MS (Method 1, ESIpos): R _t = 1.50 min, m / z = 437.14 [M + H] ⁺ .

Example 217 1- (2-Methoxyethyl) -5-methyl-3- (1-methylcyclopropyl) -6 - [(2-oxo-2,3-dihydro-1H-imidazol-1-yl) -methyl] -thieno [2 , 3-d] pyrimidine-2,4 (lH, 3H) -dione

Analogously to the process described in Example 214, from 305 mg (0.671 mmol) of the compound from Ex. 395A, 70 mg (26% of theory) of the title compound were prepared.

'H-NMR (400 MHz, DMSO-de, δ / ppm): 9.98 (br.s, 1H), 6.41 (t, 1H), 6.33 (t, 1H), 4.77 (s, 2H), 4.09-3.83 (m, 2H), 3.65-3.53 (m, 2H), 3.22 (s, 3H), 2.44 (s, 3H), 1.33 (s, 3H), 1.01-0.68 (m, 4H). LC / MS (Method 1, ES Ineg): R _t = 1.17 min, m / z = 389.13 [MH], Example 218

5-Ethyl-3 - (1-methylcyclopropyl) -6- [(2-oxoimidazolidin-1-yl) methyl] -1- (3,3,3-trifluoropropyl) thieno [2,3-d] pyrimidine 2,4 (lH, 3H) -dione

Analogously to the process described in Example 17, from 150 mg (0.323 mmol, 90% purity) of the compound from Example 469A, 49 mg (34% of theory) of the title compound were prepared.

'H-NMR (400 MHz, DMSO-de, δ / ppm): 6.54 (s, 1H), 4.36 (s, 2H), 4.18-3.92 (m, 2H), 3.29-3.16 (m, 4H), 2.94 -2.69 (m, 4H), 1.34 (s, 3H), 1.08 (t, 3H), 0.97-0.77 (m, 4H).

LC / MS (Method 1, ESIpos): R _t = 1.66 min, m / z = 445.15 [M + H] ⁺ . Example 219

5-Ethyl-1- (2-methoxyethyl) -3- (1-methylcyclopropyl) -6 - [(2-oxoimidazolidin-1-yl) methyl] thieno [2,3-d] pyrimidine-2,4 (1H , 3H) -dione

Analogously to the process described under Example 17, 58 mg (0.107 mmol, 70% pure) of the compound from Ex. 470A were used to prepare 18 mg (42% of theory) of the title compound. The reaction time was 2.5 days.

Ή-NMR (400 MHz, DMSO-de, δ / ppm): 6.52 (s, 1H), 4.34 (s, 2H), 4.14-3.81 (m, 2H), 3.67-3.56 (m, 2H), 3.24 ( s, 3H), 2.94-2.75 (m, 2H), 1.34 (s, 3H), 1.08 (t, 3H), 0.97-0.77 (m, 4H).

LC / MS (Method 6, ESIpos): R _t = 1.05 min, m / z = 407 [M + H] ⁺ . Example 220 1, 5-Dimethyl-3 - [(7S, 2S) -2-methylcyclopropyl] -6 - [(5-oxo-4,5-dihydro-1H-l, 2,4-triazol-1-yl) - methyl] thieno [2,3-d] pyrimidine-2,4 (1H, 3H) -dione

273 mg (0.499 mmol, 80% purity) of the compound from Ex. 473A were dissolved in a mixture of 11.5 ml of methanol and trimethyl orthoformate and treated at RT with 1.9 ml (7.49 mmol) of a 4 M solution of hydrogen chloride in dioxane. After the reaction mixture had been stirred at RT for about 16 h, it was concentrated to dryness and the residue was subsequently purified by preparative HPLC (Method 13). Evaporation of the product fraction and drying under high vacuum gave 122 mg (70% of theory) of the title compound.

Ή-NMR (500 MHz, DMSO-de, δ / ppm): 11.59 (br.s, 1H), 7.82 (s, 1H), 4.92 (s, 2H), 3.35 (s, 3H), 2.44 (s, 3H), 2.25-2.18 (m, 1H), 1.14 (d, 3H), 1.03-0.92 (m, 1H), 0.86-0.77 (m, 2H).

LC / MS (Method 1, ESIpos): R _t = 1.12 min, m / z = 348.11 [M + H] ⁺ .

Example 221 l, 5-Dimethyl-3- (2-methylcyclopropyl) -6 - [(2-oxoimidazolidin-1-yl) methyl] thieno [2,3-d] pyrimidine-2,4 (1H, 3H) -dione (trans-racemate)

A solution of 170 mg of the crude product from Example 363A (0.53 mmol, calculated with theoretical purity of 100%) and 110 μΐ (0.79 mmol) of triethylamine in 3.4 ml of THF was mixed with 103 mg (0.63 mmol) of 1,1-carbonyldiimidazole ( CDI) and heated in a microwave apparatus (Biotage Initiator) at 80 ° C for 10 min. The reaction mixture was then separated directly into its components by preparative HPLC (Method 17). After evaporation of the product fractions and drying in a high vacuum, 52 mg (28% of theory) of the title compound were obtained. 'H-NMR (400 MHz, DMSO-de, δ / ρρηι): 6.51 (s, 1H), 4.34 (s, 2H), 3.36 (s, 3H), 3.22 (m, 4H), 2.38 (s, 3H ), 2.22 (m, 1H), 1.15 (d, 3H), 1.02-0.93 (m, 1H), 0.86-0.79 (m, 2H).

LC / MS (Method 1, ESIpos): R _t = 1.26 min, m / z = 349.1 [M + H] ⁺ . Example 222 1, 5-Dimethyl-3- (2-methylcyclopropyl) -6 - [(2-oxoimidazolidin-1-yl) methyl] thieno [2,3-d] pyrimidine-2,4 (1H, 3H) -dione (iran-y-enantiomer 1)

46 mg of the racemic compound from Ex. 221 were dissolved in 3 ml of ethanol and 1 ml of acetonitrile and separated by preparative HPLC on a chiral phase into the enantiomers [column: Daicel Chiracel OJ-H, 5 μm, 250 mm × 20 mm; Eluent: n-heptane / ethanol 1: 1; Flow: 20 ml / min; Temperature: 40 ° C; Detection: 220 nm]. Evaporation of the product fractions and drying of the solid in a high vacuum gave 19 mg (41% of theory) of enantiomer 1 (> 99.0%> ee, chiral analytical HPLC).

Ή-NMR (400 MHz, DMSO-d ₆ , δ / ppm): 6.51 (s, 1H), 4.34 (s, 2H), 3.37 (s, 3H), 3.22 (m, 4H), 2.38 (s, 3H ), 2.22 (m, 1H), 1.15 (d, 3H), 1.02-0.93 (m, 1H), 0.86-0.79 (m, 2H).

Chiral analytical HPLC [column: Daicel IC-3, 3 μm, 50 mm × 4.6 mm; Eluent: ethanol; Flow: 1 ml / min; Detection: 220 nm]: R _t = 2.34 min.

Example 223 1, 5-Dimethyl-3- (2-methylcyclopropyl) -6 - [(2-oxoimidazolidin-1-yl) methyl] thieno [2,3-d] pyrimidine-2,4 (1H, 3H) -dione (iran-y-enantiomer 2)

46 mg of the racemic compound from Ex. 221 were dissolved in 3 ml of ethanol and 1 ml of acetonitrile and separated by preparative HPLC on a chiral phase into the enantiomers [column: Daicel Chiracel OJ-H, 5 μm, 250 mm × 20 mm; Eluent: n-heptane / ethanol 1: 1; Flow: 20 ml / min; Temperature: 40 ° C; Detection: 220 nm]. Evaporation of the product fractions and drying of the solid in a high vacuum gave 21 mg (46% of theory) of enantiomer 2 (> 99.0% ee, chiral analytical HPLC).

Ή-ΝΜΡ (400 MHz, DMSO-d ₆ , δ / ppm): 6.51 (s, 1H), 4.34 (s, 2H), 3.37 (s, 3H), 3.22 (m, 4H), 2.38 (s, 3H ), 2.22 (m, 1H), 1.15 (d, 3H), 1.02-0.93 (m, 1H), 0.86-0.79 (m, 2H).

Chiral analytical HPLC [column: Daicel IC-3, 3 μm, 50 mm × 4.6 mm; Eluent: ethanol; Flow: 1 ml / min; Detection: 220 nm]: R _t = 3.34 min.

Example 224 1-Ethyl-5-methyl-3- (2-methylcyclopropyl) -6 - [(2-oxoimidazolidin-1-yl) methyl] thieno [2,3-d] pyrimidine-2,4 (1H, 3H ) -dione (trans-racemate)

A solution of 238 mg of the crude product from Example 364A (0.71 mmol, calculated with theoretical purity of 100%) and a yield of 100%) and 148 μΐ (1.06 mmol) of triethylamine in 1.9 ml of THF was mixed with 138 mg (0.85 mmol). Ι, Γ-carbonyldiimidazole (CDI) and heated for 5 min in a microwave apparatus (Biotage Initiator) at 80 ° C. The reaction mixture was then separated directly into its components by preparative HPLC (Method 18). After evaporation of the product fractions and drying under high vacuum, 68 mg (27% of theory) of the title compound were obtained.

Ή-NMR (400 MHz, DMSO-de, δ / ppm): 6.51 (s, 1H), 4.34 (s, 2H), 3.85 (q, 2H), 3.23 (m, 4H), 2.38 (s, 3H) , 2.23 (m, 1H), 1.22 (t, 3H), 1.15 (d, 3H), 1.02-0.93 (m, 1H), 0.86-0.79 (m, 2H).

LC / MS (Method 1, ESIpos): R _t = 1.34 min, m / z = 363.1 [M + H] ⁺ . Example 225 1-Ethyl-5-methyl-3- (2-methylcyclopropyl) -6 - [(2-oxoimidazolidin-1-yl) methyl] thi

pyrimidine-2,4 (1H, 3H) -dione (iran-y-enantiomer 1)

60 mg of the racemic compound from Ex. 224 were dissolved in 2 ml of ethanol and 1 ml of acetonitrile and separated by preparative HPLC on a chiral phase into the enantiomers [column: Daicel Chiracel OX-H, 5 μm, 250 mm × 20 mm; Eluent: ethanol; Flow: 15 ml / min; Temperature: 50 ° C; Detection: 220 nm]. Evaporation of the product fractions and drying of the solid in a high vacuum gave 24 mg (41% of theory) of enantiomer 1 (> 99.0% ee, chiral analytical HPLC).

Ή NMR (400 MHz, DMSO-d ₆ , δ / ppm): 6.51 (s, 1H), 4.34 (s, 2H), 3.85 (q, 2H), 3.23 (m, 4H), 2.38 (s, 3H ), 2.23 (m, 1H), 1.22 (t, 3H), 1.15 (d, 3H), 1.02-0.93 (m, 1H), 0.86-0.79 (m, 2H).

Chiral analytical HPLC [column: Daicel Chiralcel OX-3, 3 μm, 50 mm × 4.6 mm; Eluent: ethanol; Flow: 1 ml / min; Temperature: 50 ° C; Detection: 220 nm]: R _t = 3.05 min. Example 226 1-Ethyl-5-methyl-3- (2-methylcyclopropyl) -6 - [(2-oxoimidazolidin-1-yl) methyl] thieno [2,3-d] pyrimidine-2,4 (1H, 3H ) -dione (iran-y-enantiomer 2)

60 mg of the racemic compound from Ex. 224 were dissolved in 2 ml of ethanol and 1 ml of acetonitrile and separated by preparative HPLC on a chiral phase into the enantiomers [column: Daicel Chiracel OX-H, 5 μm, 250 mm × 20 mm; Eluent: ethanol; Flow: 15 ml / min; Temperature: 50 ° C; Detection: 220 nm]. After evaporation of the product fractions and drying of the solid in High vacuum gave 26 mg (43% of theory) of enantiomer 2 (> 99.0% ee, chiral analytical HPLC).

'H-NMR (400 MHz, DMSO-de, δ / ppm): 6.51 (s, 1H), 4.34 (s, 2H), 3.85 (q, 2H), 3.23 (m, 4H), 2.38 (s, 3H ), 2.23 (m, 1H), 1.22 (t, 3H), 1.15 (d, 3H), 1.02-0.93 (m, 1H), 0.86-0.79 (m, 2H). Chiral analytical HPLC [column: Daicel Chiralcel OX-3, 3 μm, 50 mm × 4.6 mm; Eluent: ethanol; Flow: 1 ml / min; Temperature: 50 ° C; Detection: 220 nm]: R _t = 3.82 min.

Example 227

5-Methyl-3- (2-methylcyclopropyl) -6 - [(2-oxoimidazolidin-1-yl) methyl] -1-propylthieno [2,3-d] pyrimidine-2,4 (1H, 3H) -dione (iroro racemate)

A solution of 230 mg of the crude product from Example 365A (0.66 mmol, calculated with theoretical purity of 100%) and a yield of 100%) and 137 μΐ (0.98 mmol) of triethylamine in 4.2 ml of THF was reacted with 128 mg (0.78 mmol). 1, 1 'carbonyldiimidazole (CDI) and heated for 5 min in a microwave apparatus (Biotage initiator) at 80 ° C. The reaction mixture was then purified directly by preparative HPLC (Method 16). After evaporation of the product fractions and drying in a high vacuum, 154 mg (62% of theory) of the title compound were obtained.

'H-NMR (400 MHz, DMSO-de, δ / ppm): 6.51 (broad, 1H), 4.34 (s, 2H), 3.78 (m, 2H), 3.22 (m, 4H), 2.37 (s, 3H ), 2.23 (m, 1H), 1.67 (m, 2H), 1.15 (d, 3H), 1.02-0.93 (m, 1H), 0.90 (t, 3H), 0.86-0.79

(m, 2H).

LC / MS (Method 1, ESIpos): R _t = 1.52 min, m / z = 377.1 [M + H]

Example 228

5-methyl-3- (2-methylcyclopropyl) -6 - [(2-oxoimidazolidin-l-yl) methyl] -l-propylthi

pyrimidine-2,4 (1H, 3H) -dione (iran-y-enantiomer 1)

150 mg of the racemic compound from Ex. 227 were dissolved in 5 ml of ethanol / acetonitrile (1: 1) and separated by preparative HPLC on a chiral phase into the enantiomers [column: Daicel Chiralpak OX-H, 5 μm, 250 mm × 20 mm ; Eluent: n-heptane / ethanol 1: 1; Flow: 40 ml / min; Temperature: RT; Detection: 220 nm]. Evaporation of the product fractions and drying of the solid in a high vacuum gave 53 mg (35% of theory) of enantiomer 1 (> 99.0% ee, chiral analytical HPLC).

Ή-NMR (400 MHz, DMSO-de, δ / ppm): 6.51 (s, 1H), 4.34 (s, 2H), 3.78 (m, 2H), 3.22 (m, 4H), 2.37 (s, 3H) , 2.23 (m, 1H), 1.67 (m, 2H), 1.15 (d, 3H), 1.02-0.93 (m, 1H), 0.90 (t, 3H), 0.86-0.79 (m, 2H).

Chiral analytical HPLC [column: Daicel OX-3, 3 μm, 50 mm × 4.6 mm; Eluent: ethanol; Flow: 1 ml / min; Detection: 220 nm]: R _t = 2.94 min.

Example 229

5-Methyl-3- (2-methylcyclopropyl) -6 - [(2-oxoimidazolidin-1-yl) methyl] -1-propylthieno [2,3-d] pyrimidine-2,4 (1H, 3H) -dione (iran-y-enantiomer 2)

150 mg of the racemic compound from Ex. 227 were dissolved in 5 ml of ethanol / acetonitrile (1: 1) and separated by preparative HPLC on a chiral phase into the enantiomers [column: Daicel Chiralpak OX-H, 5 μm, 250 mm × 20 mm ; Eluent: n-heptane / ethanol 1: 1; Flow: 40 ml / min; Temperature: RT; Detection: 220 nm]. Evaporation of the product fractions and drying of the solid in a high vacuum gave 53 mg (35% of theory) of enantiomer 2 (> 99.0% ee, chiral analytical HPLC). 'H-NMR (400 MHz, DMSO-de, δ / ρρηι): 6.51 (s, 1H), 4.34 (s, 2H), 3.78 (m, 2H), 3.22 (m, 4H), 2.37 (s, 3H ), 2.23 (m, 1H), 1.67 (m, 2H), 1.15 (d, 3H), 1.02-0.93 (m, 1H), 0.90 (t, 3H), 0.86-0.79 (m, 2H).

Chiral analytical HPLC [column: Daicel OX-3, 3 μm, 50 mm × 4.6 mm; Eluent: ethanol; Flow: 1 ml / min; Detection: 220 μm]: R _t = 4.51 min.

Example 230 1-Butyl-5-methyl-3 - [(S, 2S) -2-methylcyclopropyl] -6 - [(2-oxoimidazolidin-1-yl) methyl] thieno [2,3-d] pyrimidine-2 , 4 (lH, 3H) -dione

A solution of 95 mg of the crude product of Example 366A (0.26 mmol, calculated with theoretical purity of 100%) and 54 μΐ (0.39 mmol) of triethylamine in 1.5 ml of THF was mixed with 51 mg (0.31 mmol) Ι, Γ-carbonyldiimidazole (CDI ) and heated in a microwave apparatus (Biotage Initiator) at 80 ° C for 5 min. The reaction mixture was then purified directly by preparative HPLC (Method 16). After evaporation of the product fractions and drying under high vacuum, 51 mg (50% of theory) of the title compound were obtained.

Ή-NMR (400 MHz, DMSO-de, δ / ppm): 6.52 (broad, 1H), 4.34 (s, 2H), 3.81 (m, 2H), 3.22 (m, 4H), 2.37 (s, 3H) , 2.23 (m, 1H), 1.62 (m, 2H), 1.33 (m, 2H), 1.15 (d, 3H), 1.02-0.93 (m, 1H), 0.91 (t, 3H), 0.86-0.79 (m , 2H).

LC / MS (Method 1, ESIpos): R _t = 1.63 min, m / z = 391.1 [M + H] ⁺ .

Example 231 1- (2-Fluoroethyl) -5-methyl-3- (2-methylcyclopropyl) -6 - [(2-oxoimidazolidin-1-yl) methyl] thieno [2,3-d] pyrimidine-2,4 (1H, 3H) -dione (trans-racemate)

A solution of 242 mg of the crude product from Example 367A (0.68 mmol, calculated with theoretical purity of 100% and a yield of 100%) and 143 μΐ (1.02 mmol) of triethylamine in 2 ml of THF was treated with 133 mg (0.82 mmol) of 1 , 1 '-Carbonyldiimidazole (CDI) and heated for 5 min in a microwave apparatus (Biotage Initiator) at 80 ° C. The reaction mixture was then separated directly into its components by preparative HPLC (Method 16). Evaporation of the product fractions and drying under high vacuum gave 78 mg (30% of theory) of the title compound.

'H-NMR (400 MHz, DMSO-de, δ / ppm): 6.51 (s, 1H), 4.70 (dt, 2H), 4.14 (dm, 2H), 3.22 (m, 4H), 2.37 (s, 3H ), 2.24 (m, 1H), 1.15 (d, 3H), 1.05-0.94 (m, 1H), 0.88-0.80 (m, 2H).

LC / MS (Method 1, ESIpos): R _t = 1.33 min, m / z = 381.1 [M + H] ⁺ .

Example 232 1- (2-Fluoroethyl) -5-methyl-3- (2-methylcyclopropyl) -6 - [(2-oxoimidazolidin-1-yl) methyl] thieno [2,3-d] pyrimidine-2,4 (lH, 3H) -dione (iroro-enantiomer 1)

72 mg of the racemic compound from Ex. 231 were dissolved in a mixture of 2 ml of isopropanol, 1 ml of dichloromethane, 1 ml of acetonitrile and 2 ml of n-heptane and separated into the enantiomers by preparative HPLC on a chiral phase [column: Daicel Chiralpak ID, 5 μm, 250 mm × 20 mm; Eluent: n-heptane / isopropanol 1: 1; Flow: 15 ml / min; Temperature: 40 ° C; Detection: 220 nm]. Evaporation of the product fractions and drying of the solid in a high vacuum gave 33 mg (45% of theory) of enantiomer 1 (> 99.0% ee, chiral analytical HPLC). 'H-NMR (400 MHz, DMSO-de, δ / ρρηι): 6.51 (s, 1H), 4.70 (dt, 2H), 4.14 (dm, 2H), 3.22 (m, 4H), 2.37 (s, 3H ), 2.24 (m, 1H), 1.15 (d, 3H), 1.05-0.94 (m, 1H), 0.88-0.80 (m, 2H).

Chiral analytical HPLC [column: Daicel ID-3, 3 μm, 50 mm × 4.6 mm; Eluent: isopropanol; Flow: 1 ml / min; Detection: 220 μm]: R _t = 3.55 min. Example 233 1- (2-Fluoroethyl) -5-methyl-3- (2-methylcyclopropyl) -6 - [(2-oxoimidazolidin-1-yl) methyl] thieno [2,3-d] pyrimidine-2,4 (lH, 3H) -dione (iroro-enantiomer 2)

72 mg of the racemic compound from Ex. 231 were dissolved in a mixture of 2 ml of isopropanol, 1 ml of dichloromethane, 1 ml of acetonitrile and 2 ml of n-heptane and separated into the enantiomers by preparative HPLC on a chiral phase [column: Daicel Chiralpak ID, 5 μm, 250 mm × 20 mm; Eluent: n-heptane / isopropanol 1: 1; Flow: 15 ml / min; Temperature: 40 ° C; Detection: 220 nm]. Evaporation of the product fractions and drying of the solid in a high vacuum gave 28 mg (40% of theory) of enantiomer 2 (> 99.0% ee, chiral analytical HPLC). Ή-ΝΜΡ (400 MHz, DMSO-d ₆ , δ / ppm): 6.51 (s, 1H), 4.70 (dt, 2H), 4.14 (dm, 2H), 3.22 (m, 4H), 2.37 (s, 3H ), 2.24 (m, 1H), 1.15 (d, 3H), 1.05-0.94 (m, 1H), 0.88-0.80 (m, 2H).

Chiral analytical HPLC [column: Daicel ID-3, 3 μm, 50 mm × 4.6 mm; Eluent: isopropanol; Flow: 1 ml / min; Detection: 220 nm]: R _t = 5.07 min.

Example 234 1- (2,2-Difluoroethyl) -5-methyl-3- (2-methylcyclopropyl) -6 - [(2-oxoimidazolidin-1-yl) methyl] thieno [2,3-d] pyrimidine-2 , 4 (1H, 3H) -dione (trans-racemate)

A solution of 189 mg of the crude product from Example 368A (0.51 mmol, calculated with theoretical purity of 100% and a yield of 100%) and 106 μΐ (0.76 mmol) of triethylamine in 2 ml of THF was treated with 107 mg (0.66 mmol) of 1 , 1 '-Carbonyldiimidazole (CDI) and heated for 5 min in a microwave apparatus (Biotage Initiator) at 80 ° C. The reaction mixture was then purified directly by preparative HPLC (Method 16). Evaporation of the product fractions and drying under high vacuum gave 125 mg (59% of theory) of the title compound.

'H-NMR (400 MHz, DMSO-de, δ / ppm): 6.52 (s, 1H), 6.31 (tt, 1H), 4.34 (s, 2H), 4.26 (tt, 2H), 3.22 (m, 4H ), 2.38 (s, 3H), 2.25 (m, 1H), 1.15 (d, 3H), 1.06-0.97 (m, 1H), 0.88-0.80 (m, 2H). LC / MS (Method 1, ESIpos): R _t = 1.40 min, m / z = 399.1 [M + H] ⁺ .

Example 235 1- (2,2-Difluoroethyl) -5-methyl-3- (2-methylcyclopropyl) -6 - [(2-oxoimidazolidin-1-yl) methyl] thieno [2,3-d] pyrimidine-2 , 4 (1H, 3H) -dione (iroro-enantiomer 1)

115 mg of the racemic compound from Ex. 234 were dissolved in 5 ml of ethanol / acetonitrile (1: 1) and separated by preparative HPLC on a chiral phase into the enantiomers [column: Daicel Chiralpak OX-H, 5 μm, 250 mm × 20 mm ; Eluent: n-heptane / ethanol 60:40; Flow: 40 ml / min; Temperature: 28 ° C; Detection: 220 nm]. Evaporation of the product fractions and drying of the solid in a high vacuum gave 31 mg (27% of theory) of enantiomer 1 (> 99.0% ee, chiral analytical HPLC).

'H-NMR (400 MHz, DMSO-de, δ / ppm): 6.52 (s, 1H), 6.31 (tt, 1H), 4.34 (s, 2H), 4.26 (tt, 2H), 3.22 (m, 4H ), 2.38 (s, 3H), 2.25 (m, 1H), 1.15 (d, 3H), 1.06-0.97 (m, 1H), 0.88-0.80 (m, 2H). Chiral analytical HPLC [column: Daicel OX-3, 3 μm, 50 mm × 4.6 mm; Eluent: ethanol; Flow: 1 ml / min; Detection: 220 nm]: R _t = 3.25 min.

Example 236 1- (2,2-Difluoroethyl) -5-methyl-3- (2-methylcyclopropyl) -6 - [(2-oxoimidazolidin-1-yl) methyl] thieno [2,3-d] pyrimidine-2 , 4 (1H, 3H) -dione (iran-y-enantiomer 2)

115 mg of the racemic compound from Ex. 234 were dissolved in 5 ml of ethanol / acetonitrile (1: 1) and separated by preparative HPLC on a chiral phase into the enantiomers [column: Daicel Chiralpak OX-H, 5 μm, 250 mm × 20 mm ; Eluent: n-heptane / ethanol 60:40; Flow: 40 ml / min; Temperature: 28 ° C; Detection: 220 nm]. Evaporation of the product fractions and drying of the solid in a high vacuum gave 32 mg (28% of theory) of enantiomer 2 (> 99.0% ee, chiral analytical HPLC).

'H-NMR (400 MHz, DMSO-de, δ / ppm): 6.52 (s, 1H), 6.31 (tt, 1H), 4.34 (s, 2H), 4.26 (tt, 2H), 3.22 (m, 4H ), 2.38 (s, 3H), 2.25 (m, 1H), 1.15 (d, 3H), 1.06-0.97 (m, 1H), 0.88-0.80 (m, 2H). Chiral analytical HPLC [column: Daicel OX-3, 3 μm, 50 mm × 4.6 mm; Eluent: ethanol; Flow: 1 ml / min; Detection: 220 nm]: R _t = 4.28 min.

Example 237

5-Methyl-3- (2-methylcyclopropyl) -6 - [(2-oxoimidazolidin-1-yl) methyl] -1- (2,2,2-trifluoroethyl) thieno [2,3-d] pyrimidine-2 , 4 (1H, 3H) -dione (trans-racemate)

A solution of 109 mg of the crude product from Example 369A (0.28 mmol, calculated with theoretical purity of 100% and a yield of 100%) and 58 μΐ (0.42 mmol) of triethylamine in 0.75 ml of THF was mixed with 54 mg (0.33 mmol) Ι , Γ-carbonyldiimidazole (CDI) and heated for 5 min in a microwave apparatus (Biotage Initiator) at 80 ° C. The reaction mixture was separated into its components by means of then preparative HPLC (Method 16). Evaporation of the product fractions and drying under high vacuum gave 39 mg (34% of theory) of the title compound.

'H-NMR (400 MHz, DMSO-de, δ / ppm): 6.54 (broad, 1H), 4.77 (m, 2H), 4.35 (s, 2H), 3.22 (m, 4H), 2.38 (s, 3H ), 2.27 (m, 1H), 1.15 (d, 3H), 1.04-0.97 (m, 1H), 0.87-0.81 (m, 2H). LC / MS (Method 1, ESIpos): R _t = 1.58 min, m / z = 417.1 [M + H] ⁺ .

Example 238

5-Methyl-3- (2-methylcyclopropyl) -6 - [(2-oxoimidazolidin-1-yl) methyl] -1- (2,2,2-trifluoroethyl) thieno [2,3-d] pyrimidine-2 , 4 (1H, 3H) -dione (iroro-enantiomer 1)

33 mg of the racemic compound from Ex. 237 were dissolved in 3 ml of isopropanol / acetonitrile (40:60) and separated by preparative HPLC on a chiral phase into the enantiomers [column: Daicel Chiralcel OX-H, 5 μm, 250 mm × 20 mm ; Eluent: n-heptane / isopropanol 30:70; Flow: 35 ml / min; Temperature: 28 ° C; Detection: 220 nm]. Evaporation of the product fractions and drying of the solid in a high vacuum gave 11 mg (32% of theory) of enantiomer 1 (> 99.0% ee, chiral analytical HPLC).

'H-NMR (400 MHz, DMSO-de, δ / ppm): 6.53 (s, 1H), 4.77 (m, 2H), 4.35 (s, 2H), 3.22 (m, 4H), 2.38 (s, 3H ), 2.27 (m, 1H), 1.15 (d, 3H), 1.04-0.97 (m, 1H), 0.87-0.81 (m, 2H).

Chiral analytical HPLC [column: Daicel Chiralpak OX-3, 3 μm, 50 mm × 4.6 mm; Eluent: n-heptane / isopropanol 1: 1; Flow: 1 ml / min; Detection: 220 nm]: R _t = 2.59 min. Example 239

5-Methyl-3- (2-methylcyclopropyl) -6 - [(2-oxoimidazolidin-1-yl) methyl] -1- (2,2,2-trifluoroethyl) thieno [2,3-d] pyrimidine-2 , 4 (1H, 3H) -dione (iroro-enantiomer 2)

33 mg of the racemic compound from Ex. 237 were dissolved in 3 ml of isopropanol / acetonitrile (40:60) and separated by preparative HPLC on a chiral phase into the enantiomers [column: Daicel Chiralcel OX-H, 5 μm, 250 mm × 20 mm ; Eluent: n-heptane / isopropanol 30:70; Flow: 35 ml / min; Temperature: 28 ° C; Detection: 220 nm]. Evaporation of the product fractions and drying of the solid in a high vacuum gave 11 mg (32% of theory) of enantiomer 2 (> 99.0% ee, chiral analytical HPLC).

Ή-ΝΜΡ (400 MHz, DMSO-d ₆ , δ / ppm): 6.53 (s, 1H), 4.77 (m, 2H), 4.35 (s, 2H), 3.22 (m, 4H), 2.38 (s, 3H ), 2.27 (m, 1H), 1.15 (d, 3H), 1.04-0.97 (m, 1H), 0.87-0.81 (m, 2H).

Chiral analytical HPLC [column: Daicel Chiralpak OX-3, 3 μm, 50 mm × 4.6 mm; Eluent: n-heptane / isopropanol 1: 1; Flow: 1 ml / min; Detection: 220 nm]: R _t = 4.61 min. Example 240

5-Methyl-3- (2-methylcyclopropyl) -6 - [(2-oxoimidazolidin-1-yl) methyl] -1- (3,3,3-trifluoropropyl) thieno [2,3-d] pyrimidine-2 , 4 (1H, 3H) -dione (iroro-enantiomer 1)

225 mg of the racemic compound from Example 93 were separated into the enantiomers by preparative SFC-HPLC on a chiral phase [instrument: Sepiatec Prep SFC100; Column: Reprosil chiral NR, 8 μm, 250 mm × 30 mm; Eluent A: carbon dioxide, eluent B: ethanol, isocratic with 29% B; Flow: 100 ml / min; Temperature: 40 ° C; BPR: 150 bar; Detection: MWD 220 nm]. The respective product fractions were concentrated on a rotary evaporator, treated with acetonitrile / water (1: 1) and freeze-dried. 110 mg (44% of theory) of the title compound (enantiomer 1) and 110 mg (44% of theory) of the enantiomer 2 (see Example 241) were obtained. 'H-NMR (400 MHz, DMSO-d _6, δ / ppm): 6:55 (s, 1H), 4:35 (s, 2H), 4:04 (q, 2H), 3:17 to 3:28 (m, 4H), 2.66- 2.80 (m, 2H), 2.38 (s, 3H), 2.20-2.26 (m, 1H), 1.15 (d, 3H), 0.94-1.04 (m, 1H), 0.79-0.86 (m, 2H).

Chiral analytical SFC-HPLC [instrument: Agilent 1260, Aurora SFC module; Column: Reprosil chiral NR, 5 μm, 100 mm × 4.6 mm; Eluent A: carbon dioxide, eluent B: ethanol, isocratic with 29% B; Flow: 4 ml / min; Temperature: 37.5 ° C; BPR: 100 bar; Detection: MWD 220 nm]: R _t = 3.07 min.

Example 241

5-Methyl-3- (2-methylcyclopropyl) -6 - [(2-oxoimidazolidin-1-yl) methyl] -1- (3,3,3-trifluoropropyl) thieno [2,3-d] pyrimidine-2 , 4 (1H, 3H) -dione (iroro-enantiomer 2)

The title compound (110 mg) was obtained as a second enantiomer from the preparative HPLC separation (see Ex. 240) of the racemate from Ex. 93.

'H-NMR (400 MHz, DMSO-de, δ / ppm): 6.55 (s, 1H), 4.35 (s, 2H), 3.97-4.12 (m, 2H), 3.17-3.27 (m, 4H), 2.66 -2.79 (m, 2H), 2.38 (s, 3H), 2.21-2.26 (m, 1H), 1.15 (d, 3H), 0.93-1.03 (m, 1H), 0.79-0.87 (m, 2H).

Chiral analytical SFC-HPLC [instrument: Agilent 1260, Aurora SFC module; Column: Reprosil chiral NR, 5 μm, 100 mm × 4.6 mm; Eluent A: carbon dioxide, eluent B: ethanol, isocratic with 29% B; Flow: 4 ml / min; Temperature: 37.5 ° C; BPR: 100 bar; Detection: MWD 220 nm]: R _t = 4.24 mm. Example 242

5-methyl-3- (2-methylcyclopropyl) -6 - [(2-oxoimidazolidm ^

thieno [2,3-d] pyrimidine-2,4 (1H, 3H) -dione (trans-racemate)

A solution of 257 mg of the crude product from Example 370A (0.61 mmol, calculated with theoretical purity of 100% and a yield of 100%) and 128 μΐ (0.92 mmol) of triethylamine in 1.9 ml of THF was mixed with 119 mg (0.74 mmol) 1 , 1 '-Carbonyldiimidazole (CDI) and heated for 5 min in a microwave apparatus (Biotage Initiator) at 80 ° C. The reaction mixture was then purified directly by preparative HPLC (Method 16). Evaporation of the product fractions and drying under high vacuum gave 167 mg (58% of theory) of the title compound.

'H-NMR (400 MHz, DMSO-de, δ / ppm): 6.51 (s, 1H), 4.34 (s, 2H), 3.91 (m, 2H), 3.22 (m, 4H), 2.41 (m, 2H ), 2.38 (s, 3H), 2.22 (m, 1H), 1.87 (m, 2H), 1.15 (d, 3H), 1.04-0.97 (m, 1H), 0.87-0.78

(m, 2Η).

LC / MS (Method 1, ESIpos): R _t = 1.65 min, m / z = 445.1 [M + H] ⁺ . Example 243

5-Methyl-3- (2-methylcyclopropyl) -6 - [(2-oxoimidazolidin-1-yl) methyl] -1- (4,4,4-trifluorobutyl) thieno [2,3-d] pyrimidine-2 , 4 (1H, 3H) -dione (iroro-enantiomer 1)

150 mg of the racemic compound from Ex. 242 were separated into the enantiomers by preparative HPLC on a chiral phase [column: Daicel Chiralcel OX-H, 5 μm, 250 mm × 20 mm; Eluent: n-heptane / ethanol 35:65; Flow: 15 ml / min; Temperature: 25 ° C; Detection: 220 nm]. To Evaporation of the product fractions and drying of the solid in a high vacuum gave 58 mg (39% of theory) of enantiomer 1 (> 99.0% ee, chiral analytical HPLC).

Ή-ΝΜΡ (400 MHz, DMSO-d ₆ , δ / ppm): 6.51 (s, 1H), 4.34 (s, 2H), 3.91 (m, 2H), 3.22 (m, 4H), 2.41 (m, 2H ), 2.38 (s, 3H), 2.22 (m, 1H), 1.87 (m, 2H), 1.15 (d, 3H), 1.04-0.97 (m, 1H), 0.87-0.78 (m, 2H).

Chiral analytical HPLC [column: Daicel Chiralpak OX-3, 3 μm, 50 mm × 4.6 mm; Eluent: ethanol; Flow: 1 ml / min; Detection: 220 nm]: R _t = 2.12 min.

Example 244

5-Methyl-3- (2-methylcyclopropyl) -6 - [(2-oxoimidazolidin-1-yl) methyl] -1- (4,4,4-trifluorobutyl) thieno [2,3-d] pyrimidine-2 , 4 (1H, 3H) -dione (iran-y-enantiomer 2)

150 mg of the racemic compound from Ex. 242 were separated into the enantiomers by preparative HPLC on a chiral phase [column: Daicel Chiralcel OX-H, 5 μm, 250 mm × 20 mm; Eluent: n-heptane / ethanol 35:65; Flow: 15 ml / min; Temperature: 25 ° C; Detection: 220 nm]. Evaporation of the product fractions and drying of the solid in a high vacuum gave 60 mg (40% of theory) of enantiomer 2 (> 99.0% ee, chiral analytical HPLC).

Ή-ΝΜΡ (400 MHz, DMSO-d ₆ , δ / ppm): 6.51 (s, 1H), 4.34 (s, 2H), 3.91 (m, 2H), 3.22 (m, 4H), 2.41 (m, 2H ), 2.38 (s, 3H), 2.22 (m, 1H), 1.87 (m, 2H), 1.15 (d, 3H), 1.04-0.97 (m, 1H), 0.87-0.78 (m, 2H). Chiral analytical HPLC [column: Daicel Chiralpak OX-3, 3 μm, 50 mm × 4.6 mm; Eluent: ethanol; Flow: 1 ml / min; Detection: 220 nm]: R _t = 2.88 min.

Example 245

5-Methyl-3- (2-methylcyclopropyl) -6 - [(2-oxoimidazolidin-1-yl) methyl] -1- (3,3,4,4-tetrafluorobutyl) thieno [2,3-d] pyrimidine -2,4 (1H, 3H) -dione (trans-racemate)

A solution of 245 mg (0.48 mmol, 86% purity) of the crude product from Example 371A and 100 μΐ (0.72 mmol) of triethylamine in 2.8 ml of THF was admixed with 93 mg (0.57 mmol) of 1,1-carbonyldiimidazole (CDI) and Heated to 80 ° C in a microwave apparatus (Biotage Initiator) for 5 min. The reaction mixture was then separated directly into its components by preparative HPLC (Method 16). Evaporation of the product fractions and drying under high vacuum gave 127 mg (57% of theory) of the title compound.

Ή-NMR (400 MHz, DMSO-de, δ / ppm): 6.54 (tt, 1H), 6.52 (s, 1H), 4.35 (s, 2H), 4.04 (m, 2H), 3.22 (m, 4H) , 2.38 (s, 3H), 2.24 (m, 1H), 1.15 (d, 3H), 1.03-0.94 (m, 1H), 0.86-0.79 (m, 2H). LC / MS (Method 2, ESIpos): R _t = 0.87 min, m / z = 463.0 [M + H] ⁺ .

Example 246

5-Methyl-3- (2-methylcyclopropyl) -6 - [(2-oxoimidazolidin-1-yl) methyl] -1- (3,3,4,4-tetrafluorobutyl) thieno [2,3-d] pyrimidine -2,4 (1H, 3H) -dione (iroro-enantiomer 1)

120 mg of the racemic compound from Ex. 245 were dissolved in about 20 ml of ethanol / acetonitrile (9: 1) and separated by preparative HPLC on a chiral phase into the enantiomers [column: Daicel Chiralpak OX-H, 5 μm, 250 mm × 30 mm; Eluent: n-heptane / ethanol 60:40; Flow: 60 ml / min; Temperature: 25 ° C; Detection: 220 nm]. Evaporation of the product fractions and drying of the solid in a high vacuum gave 46 mg (39% of theory) of enantiomer 1 (> 99.0% ee, chiral analytical HPLC). Ή-ΝΜΡν (400 MHz, DMSO-d ₆ , δ / ρρηι): 6.54 (tt, 1H), 6.52 (s, 1H), 4.35 (s, 2H), 4.05 (m, 2H), 3.22 (m, 4H ), 2.38 (s, 3H), 2.22 (m, 1H), 1.15 (d, 3H), 1.03-0.94 (m, 1H), 0.87-0.80 (m, 2H).

Chiral analytical HPLC [column: Daicel Chiralpak OX-3, 3 μm, 50 mm × 4.6 mm; Eluent: ethanol; Flow: 1 ml / min; Detection: 220 nm]: R _t = 2.27 min. Example 247

5-Methyl-3- (2-methylcyclopropyl) -6 - [(2-oxoimidazolidin-1-yl) methyl] -1- (3,3,4,4-tetrafluorobutyl) thieno [2,3-d] pyrimidine -2,4 (1H, 3H) -dione (iroro-enantiomer 2)

120 mg of the racemic compound from Ex. 245 were dissolved in about 20 ml of ethanol / acetonitrile (9: 1) and separated by preparative HPLC on a chiral phase into the enantiomers [column: Daicel Chiralpak OX-H, 5 μm, 250 mm × 30 mm; Eluent: n-heptane / ethanol 60:40; Flow: 60 ml / min; Temperature: 25 ° C; Detection: 220 nm]. Evaporation of the product fractions and drying of the solid in a high vacuum gave 43 mg (36% of theory) of enantiomer 2 (94.4% ee, chiral analytical HPLC). Ή-ΝΜΡ (400 MHz, DMSO-d ₆ , δ / ppm): 6.54 (tt, 1H), 6.52 (s, 1H), 4.35 (s, 2H), 4.05 (m, 2H), 3.22 (m, 4H ), 2.38 (s, 3H), 2.22 (m, 1H), 1.15 (d, 3H), 1.03-0.94 (m, 1H), 0.87-0.80 (m, 2H).

Chiral analytical HPLC [column: Daicel Chiralpak OX-3, 3 μm, 50 mm × 4.6 mm; Eluent: ethanol; Flow: 1 ml / min; Detection: 220 nm]: R _t = 3.32 min.

Example 248 1- (Cyclobutylmethyl) -5-methyl-3 - [(S, 2S) -2-methylcyclopropyl] -6 - [(2-oxoimidazolidin-1-yl) methyl] thieno [2,3-d] pyrimidine -2,4 (lH, 3H) -dione

A solution of 120 mg of the crude product from Example 372A (0.32 mmol, calculated with theoretical purity of 100% and a yield of 100%) and 67 μΐ (0.48 mmol) of triethylamine in 2 ml of THF was treated with 62 mg (0.38 mmol) Ι , Γ-carbonyldiimidazole (CDI) and heated for 5 min in a microwave apparatus (Biotage Initiator) at 80 ° C. The reaction mixture was then separated directly into its components by preparative HPLC (Method 16). After evaporation of the product fractions and drying in a high vacuum, 65 mg (50% of theory) of the title compound were obtained.

'H-NMR (400 MHz, DMSO-de, δ / ppm): 6.51 (s, 1H), 4.33 (s, 2H), 3.21 (m, 4H), 2.74 (m, 1H), 2.37 (s, 3H ), 2.22 (m, 1H), 1.97 (m, 2H), 1.91 (m, 4H), 1.15 (d, 3H), 1.01-0.92 (m, 1H), 0.85-0.78 (m, 2H).

LC / MS (Method 1, ESIpos): R _t = 1.72 min, m / z = 403.1 [M + H] ⁺ . Example 249 l - [(2,2-Difluorocyclopropyl) methyl] -5-methyl-3 - [(S, 2S) -2-methylcyclopropyl] -6 - [(2-oxo-imidazolidin-1-yl) methyl] thieno [2,3-d] pyrimidine-2,4 (1H, 3H) -dione (mixture of diastereomers)

A solution of 120 mg of the crude product from Example 373A (0.30 mmol, calculated with theoretical purity of 100%) and a yield of 100%) and 63 μΐ (0.45 mmol) of triethylamine in 1.9 ml of THF was mixed with 59 mg (0.36 mmol). Ι, Γ-carbonyldiimidazole (CDI) and heated for 5 min in a microwave apparatus (Biotage Initiator) at 80 ° C. The reaction mixture was then separated directly into its components by preparative HPLC (Method 16). After one- Evaporation of the product fractions and drying under high vacuum gave 64 mg (50% of theory) of the title compound.

Ή-ΝΜΡ (400 MHz, DMSO-d ₆ , δ / ppm): 6.52 (s, 1H), 4.35 (s, 2H), 4.06 (m, 1H), 3.90 (m, 1H), 3.22 (m, 4H ), 2.38 (s, 3H), 2.24 (m, 1H), 2.18 (m, 1H), 1.69 (m, 1H), 1.44 (m, 1H), 1.15 (d, 3H), 1.03-0.97 (m, 1H), 0.87-0.80 (m, 2H).

LC / MS (Method 2, ESIpos): R _t = 1.58 min, m / z = 425.1 [M + H] ⁺ .

Example 250 l - [(2,2-Difluorocyclopropyl) methyl] -5-methyl-3 - [(S, 2S) -2-methylcyclopropyl] -6 - [(2-oxo-imidazolidin-1-yl) methyl] thieno [2,3-d] pyrimidine-2,4 (1H, 3H) -dione {diastereomer 1)

58 mg of the diastereomer mixture from Example 249 were dissolved in 5 ml of ethanol / acetonitrile (6: 4) and separated by preparative HPLC on a chiral phase into the enantiomerically pure diastereomers [column: Daicel Chiralpak OJ-H, 5 μm, 250 mm × 20 mm ; Eluent: n-heptane / ethanol 80:20; Flow: 35 ml / min; Temperature: 28 ° C; Detection: 220 um]. Evaporation of the product fractions and drying of the solid in a high vacuum gave 25 mg (44% of theory) of diastereomer 1 (> 99.0% de, chiral analytical HPLC).

Ή-ΝΜΡ (400 MHz, DMSO-d ₆ , δ / ppm): 6.52 (s, 1H), 4.35 (s, 2H), 4.06 (m, 1H), 3.91 (m, 1H), 3.22 (m, 4H ), 2.38 (s, 3H), 2.24 (m, 1H), 2.18 (m, 1H), 1.69 (m, 1H), 1.44 (m, 1H), 1.15 (d, 3H), 1.03-0.97 (m, 1H), 0.87-0.80 (m, 2H). Chiral analytical HPLC [column: Daicel Chiralpak IA-3, 3 μm, 50 mm × 4.6 mm; Eluent: isohexane / ethanol 1: 1; Flow: 1 ml / min; Detection: 220 μm]: R _t = 1.41 min.

Example 251 l - [(2,2-Difluorocyclopropyl) methyl] -5-methyl-3 - [(S, 2S) -2-methylcyclopropyl] -6 - [(2-oxo-imidazolidin-1-yl) methyl] thieno [2,3-d] pyrimidine-2,4 (1H, 3H) -dione {diastereomer 2)

58 mg of the diastereomer mixture from Example 249 were dissolved in 5 ml of ethanol / acetonitrile (6: 4) and separated by preparative HPLC on a chiral phase into the enantiomerically pure diastereomers [column: Daicel Chiralpak OJ-H, 5 μm, 250 mm × 20 mm ; Eluent: n-heptane / ethanol 80:20; Flow: 35 ml / min; Temperature: 28 ° C; Detection: 220 um]. After evaporation of the product fractions and drying of the solid in a high vacuum, 25 mg (44% of theory) of diastereomer 2 were obtained (> 99.0% de, chiral analytical HPLC).

Ή-ΝΜΡ (400 MHz, DMSO-d ₆ , δ / ppm): 6.52 (s, 1H), 4.35 (s, 2H), 4.06 (m, 1H), 3.91 (m, 1H), 3.22 (m, 4H ), 2.38 (s, 3H), 2.24 (m, 1H), 2.18 (m, 1H), 1.69 (m, 1H), 1.44 (m, 1H), 1.15 (d, 3H), 1.03-0.97 (m, 1H), 0.87-0.80 (m, 2H).

Chiral analytical HPLC [column: Daicel Chiralpak IA-3, 3 μm, 50 mm × 4.6 mm; Eluent: isohexane / ethanol 1: 1; Flow: 1 ml / min; Detection: 220 μm]: R _t = 1.53 min.

Example 252 l - [(3,3-Difluorocyclobutyl) methyl] -5-methyl-3- (2-methylcyclopropyl) -6 - [(2-oxoimidazolidin-1-yl) methyl] thieno [2,3-d] pyrimidine-2,4 (1H, 3H) -dione (trans-racemate)

A solution of 190 mg of the crude product from Example 374A (0.46 mmol, calculated with theoretical purity of 100%) and a yield of 100%) and 96 μΐ (0.69 mmol) of triethylamine in 1.4 ml of THF was mixed with 89 mg (0.55 mmol). Ι, Γ-carbonyldiimidazole (CDI) and heated for 5 min in a microwave apparatus (Biotage Initiator) at 80 ° C. The reaction mixture was then separated directly into its components by preparative HPLC (Method 16). After one- Evaporation of the product fractions and drying under high vacuum gave 74 mg (37% of theory) of the title compound.

Ή-ΝΜΡ (400 MHz, DMSO-d ₆ , δ / ppm): 6.52 (s, 1H), 4.34 (s, 2H), 4.01 (m, 2H), 3.22 (m, 4H), 2.73-2.43 (m , 5H), 2.37 (s, 3H), 2.23 (m, 1H), 1.15 (d, 3H), 1.02-0.95 (m, 1H), 0.85-0.78 (m, 2H). LC / MS (Method 1, ESIpos): R _t = 1.65 min, m / z = 439.1 [M + H] ⁺ .

Example 253 l - [(3,3-Difluorocyclobutyl) methyl] -5-methyl-3- (2-methylcyclopropyl) -6 - [(2-oxo-imidazolidin-1-yl) -methyl] thieno [2,3-d] pyrimidine-2,4 (1H, 3H) -dione (iran-y-enantiomer 1)

70 mg of the racemic compound from Ex. 252 were dissolved in 4 ml of ethanol / acetonitrile (1: 1) and separated by preparative HPLC on a chiral phase into the enantiomers [column: Daicel Chiralpak OJ-H, 5 μm, 250 mm × 20 mm ; Eluent: n-heptane / ethanol 70:30; Flow: 20 ml / min; Temperature: 28 ° C; Detection: 220 nm]. Evaporation of the product fractions and drying of the solid in a high vacuum gave 29 mg (41% of theory) of enantiomer 1 (>99.0%> ee, chiral analytical HPLC).

Ή-NMR (400 MHz, DMSO-d ₆ , δ / ppm): 6.52 (s, 1H), 4.34 (s, 2H), 4.01 (m, 2H), 3.22 (m, 4H), 2.73-2.43 (m , 5H), 2.37 (s, 3H), 2.23 (m, 1H), 1.15 (d, 3H), 1.02-0.95 (m, 1H), 0.85-0.78 (m, 2H).

Chiral analytical HPLC [column: Daicel Chiralpak IC-3, 3 μm, 50 mm × 4.6 mm; Eluent: ethanol; Flow: 1 ml / min; Detection: 220 nm]: R _t = 1.55 min. Example 254 l - [(3,3-Difluorocyclobutyl) methyl] -5-methyl-3- (2-methylcyclopropyl) -6 - [(2-oxo-imidazolidin-1-yl) -methyl] thieno [2,3-d] pyrimidine-2,4 (1H, 3H) -dione (iran-y-enantiomer 2)

70 mg of the racemic compound from Ex. 252 were dissolved in 4 ml of ethanol / acetonitrile (1: 1) and separated by preparative HPLC on a chiral phase into the enantiomers [column: Daicel Chiralpak OJ-H, 5 μm, 250 mm × 20 mm ; Eluent: n-heptane / ethanol 70:30; Flow: 20 ml / min; Temperature: 28 ° C; Detection: 220 nm]. Evaporation of the product fractions and drying of the solid in a high vacuum gave 28 mg (39% of theory) of enantiomer 2 (97.3% ee, chiral analytical HPLC).

Ή-NMR (400 MHz, DMSO-d ₆ , δ / ppm): 6.52 (s, 1H), 4.34 (s, 2H), 4.01 (m, 2H), 3.22 (m, 4H), 2.73-2.43 (m , 5H), 2.37 (s, 3H), 2.23 (m, 1H), 1.15 (d, 3H), 1.02-0.95 (m, 1H), 0.85-0.78 (m, 2H). Chiral analytical HPLC [column: Daicel Chiralpak IC-3, 3 μm, 50 mm × 4.6 mm; Eluent: ethanol; Flow: 1 ml / min; Detection: 220 nm]: R _t = 1.93 min.

Example 255 l - [(3,3-Difluorocyclopentyl) methyl] -5-methyl-3 - [(S, 2S) -2-methylcyclopropyl] -6 - [(2-oxo-imidazolidin-1-yl) methyl] thieno [2,3-d] pyrimidine-2,4 (1H, 3H) -dione (mixture of diastereomers)

A solution of 102 mg of the crude product from Example 375A (0.24 mmol, calculated with theoretical purity of 100%) and a yield of 100%) and 50 μΐ (0.34 mmol) of triethylamine in 2 ml of THF was reacted with 47 mg (0.28 mmol). Ι, Γ-carbonyldiimidazole (CDI) and heated for 5 min in a microwave apparatus (Biotage Initiator) at 80 ° C. The reaction mixture was then separated directly into its components by preparative HPLC (Method 16). After one- Evaporation of the product fractions and drying under high vacuum gave 35 mg (32% of theory) of the title compound.

Ή-ΝΜΡ (400 MHz, DMSO-d ₆ , δ / ppm): 6.51 (s, 1H), 4.34 (s, 2H), 3.88 (m, 2H), 3.22 (m, 4H), 2.61 (m, 1H ), 2.38 (s, 3H), 2.34-1.82 (m, 6H), 1.58 (m, 1H), 1.15 (d, 3H), 1.03-0.94 (m, 1H), 0.86-0.79 (m, 2H).

LC / MS (Method 1, ESIpos): R _t = 1.67 min, m / z = 453.1 [M + H] ⁺ .

Example 256 1 - [(3,3-Difluorocyclopentyl) methyl] -5-methyl-3 - [(S, 2S) -2-methylcyclopropyl] -6 - [(2-oxo-imidazolidin-1-yl) methyl] thieno [2,3-d] pyrimidine-2,4 (1H, 3H) -dione {diastereomer 1)

255 mg of the diastereomer mixture from Example 255 were dissolved in 4 ml of ethanol / acetonitrile (1: 1) and separated by preparative HPLC on a chiral phase into the enantiomerically pure diastereomers [column: Daicel Chiralcel OX-H, 5 μm, 250 mm × 20 mm ; Eluent: n-heptane / ethanol 60:40; Flow: 20 ml / min; Temperature: 35 ° C; Detection: 220 um]. Evaporation of the product fractions and drying of the solid in a high vacuum gave 16 mg (49% of theory) of diastereomer 1 (> 99%> de, chiral analytical HPLC).

Ή-NMR (400 MHz, DMSO-d ₆ , δ / ppm): 6.51 (s, 1H), 4.34 (s, 2H), 3.88 (m, 2H), 3.22 (m, 4H), 2.61 (m, 1H ), 2.38 (s, 3H), 2.34-1.82 (m, 6H), 1.58 (m, 1H), 1.15 (d, 3H), 1.03-0.94 (m, 1H), 0.86-0.79 (m, 2H). Chiral analytical HPLC [column: Daicel Chiralpak OX-3, 3 μm, 50 mm × 4.6 mm; Eluent: ethanol; Flow: 1 ml / min; Detection: 220 μm]: R _t = 3.59 min.

Example 257 l - [(3,3-Difluorocyclopentyl) methyl] -5-methyl-3 - [(S, 2S) -2-methylcyclopropyl] -6 - [(2-oxo-imidazolidin-1-yl) methyl] thieno [2,3-d] pyrimidine-2,4 (1H, 3H) -dione {diastereomer 2)

255 mg of the diastereomer mixture from Example 255 were dissolved in 4 ml of ethanol / acetonitrile (1: 1) and separated by preparative HPLC on a chiral phase into the enantiomerically pure diastereomers [column: Daicel Chiralcel OX-H, 5 μm, 250 mm × 20 mm ; Eluent: n-heptane / ethanol 60:40; Flow: 20 ml / min; Temperature: 35 ° C; Detection: 220 um]. Evaporation of the product fractions and drying of the solid in a high vacuum gave 17 mg (50% of theory) of diastereomer 2 (94.7% by volume, chiral analytical HPLC).

Ή-NMR (400 MHz, DMSO-d ₆ , δ / ppm): 6.51 (s, 1H), 4.34 (s, 2H), 3.88 (m, 2H), 3.22 (m, 4H), 2.61 (m, 1H ), 2.38 (s, 3H), 2.34-1.82 (m, 6H), 1.58 (m, 1H), 1.15 (d, 3H), 1.03-0.94 (m, 1H), 0.86-0.79 (m, 2H).

Chiral analytical HPLC [column: Daicel Chiralpak OX-3, 3 μm, 50 mm × 4.6 mm; Eluent: ethanol; Flow: 1 ml / min; Detection: 220 μm]: R _t = 4.33 min.

Example 258 1- (2-Methoxyethyl) -5-methyl-3- (2-methylcyclopropyl) -6 - [(2-oxoimidazolidin-1-yl) methyl] thieno [2,3-d] pyrimidine-2,4 (lH, 3H) -dione (d-racemate)

600 mg (1.47 mmol, 90%> purity) of the compound from Ex. 376A were dissolved in 25 ml of THF and treated with 308 μΐ (2.21 mmol) of triethylamine and 287 mg (1.77 mmol) of CDI. The mixture was stirred at RT for about 16 h. It was then concentrated to dryness on a rotary evaporator. The remaining residue was purified by preparative HPLC (Method 11). After combining the product fractions and freeze-drying, 373 mg (64% of theory) of the title compound were obtained.

Ή-ΝΜΡ (400 MHz, DMSO-d ₆ , δ / ppm): 6.51 (s, 1H), 4.33 (s, 2H), 4.13-3.85 (m, 2H), 3.67-3.55 (m, 2H), 3.29 -3.16 (m, 4H), 3.22 (s, 3H), 2.62 (td, 1H), 2.37 (s, 3H), 1.27-1.18 (m, 2H), 0.84 (d, 3H), 0.60-0.45 (m , 1H).

LC / MS (Method 1, ESIpos): R _t = 1.23 min, m / z = 393.16 [M + H] ⁺ .

Example 259 1- (2-Methoxyethyl) -5-methyl-3- (2-methylcyclopropyl) -6 - [(2-oxoimidazolidin-1-yl) methyl] thieno [2,3-d] pyrimidine-2,4 (lH, 3H) -dione (d -enantiomer 1)

360 mg of the racemic compound from Ex. 258 were dissolved in 25 ml of methanol / ethanol / acetonitrile (2: 2: 1) and separated into the enantiomers in 26 portions by preparative SFC-HPLC on a chiral phase [column: Daicel Chiralpak OJ -H, 5 μιη, 250 mm x 20 mm; Eluent: carbon dioxide / methanol 86:14; Flow: 85 ml / min; Temperature: 40 ° C; Detection: 210 nm]. Evaporation of the product fractions and drying of the solid in a high vacuum gave 146 mg (81% of theory) of enantiomer 1 (> 99% ee, chiral analytical HPLC).

Ή-NMR (400 MHz, DMSO-d _6, δ / ppm): 6:51 (s, 1H), 4:33 (s, 2H), 4.12-3.86 (m, 2H), 3.67-3.55 (m, 2H), 3.29 -3.16 (m, 4H), 3.23 (s, 3H), 2.62 (td, 1H), 2.37 (s, 3H), 1.28-1.17 (m, 2H), 0.84 (d, 3H), 0.57-0.47 (m , 1H). Chiral analytical SFC-HPLC [column: Daicel Chiralpak OJ-H, 5 μm, 50 mm × 4.6 mm; Eluent: carbon dioxide / methanol 90:10; Flow: 3 ml / min; Temperature: 40 ° C; Detection: 210 nm]: R _t = 2.24 min.

Example 260 1- (2-Methoxyethyl) -5-methyl-3- (2-methylcyclopropyl) -6 - [(2-oxoimidazolidin-1-yl) methyl] thieno [2,3-d] pyrimidine-2,4 (lH, 3H) -dione (d -enantiomer 2)

From the preparative HPLC separation on chiral phase described under Example 259, 75 mg (41% of theory) of enantiomer 2 were obtained (> 99% ee, chiral analytical HPLC).

Ή NMR (400 MHz, DMSO-d ₆ , δ / ppm): 6.51 (s, 1H), 4.33 (s, 2H), 4.13-3.86 (m, 2H), 3.67-3.55 (m, 2H), 3.29 -3.17 (m, 4H), 3.22 (s, 3H), 2.62 (td, 1H), 2.37 (s, 3H), 1.29-1.16 (m, 2H), 0.84 (d, 3H), 0.58-0.47 (m , 1H).

Chiral analytical SFC-HPLC [column: Daicel Chiralpak OJ-H, 5 μm, 50 mm × 4.6 mm; Eluent: carbon dioxide / methanol 90:10; Flow: 3 ml / min; Temperature: 40 ° C; Detection: 210 nm]: R _t = 2.87 min. Example 261

5-methyl-3- (2-methylcyclopropyl) -6 - [(2-oxoimidazolidin-1-yl) methyl] -1- [2- (trifluoromethoxy) ethyl] thieno [2,3-d] pyrimidine-2, 4 (1H, 3H) -dione (iroro-racemate)

193 mg (0.438 mmol, 95% purity) of the compound from Ex. 378A were dissolved in 5 ml of THF and treated with 92 .mu.l (0.657 mmol) of triethylamine and 85 mg (0.525 mmol) of CDI. The mixture was stirred at RT for about 16 h. It was then concentrated to dryness on a rotary evaporator. The remaining residue was purified by preparative HPLC (Method 1 1). After combining the product fractions and freeze-drying, 125 mg (63% of theory) of the title compound were obtained. 'H-NMR (400 MHz, DMSO-de, δ / ρρηι): 6.52 (s, 1H), 4.37 (t, 2H), 4.34 (s, 2H), 4.21-4.08 (m, 2H), 3.27-3.15 (m, 4H), 2.38 (s, 3H), 2.28-2.22 (m, 1H), 1.15 (d, 3H), 1.04-0.93 (m, 1H), 0.87-0.78 (m, 2H).

LC / MS (Method 1, ESIpos): R _t = 1.59 min, m / z = 447.13 [M + H] ⁺ . Example 262

5-methyl-3- (2-methylcyclopropyl) -6 - [(2-oxoimidazolidin-1-yl) methyl] -1- [2- (trifluoromethoxy) ethyl] thieno [2,3-d] pyrimidine-2, 4 (lH, 3H) -dione (iroro-enantiomer 1)

120 mg of the racemic compound from Ex. 261 were dissolved in a mixture of 4 ml of ethanol and 2 ml of acetonitrile and separated in 12 portions by preparative HPLC on a chiral phase into the enantiomers [column: Daicel Chiralcel OX-H, 5 μιη, 250 mm x 20 mm; Eluent: isohexane / ethanol 60:40; Flow: 20 ml / min; Temperature: 50 ° C; Detection: 220 um]. Evaporation of the product fractions and drying of the solid in a high vacuum gave 53 mg (88% of theory) of enantiomer 1 (> 99% ee, chiral analytical HPLC). Ή-ΝΜΡ (400 MHz, DMSO-d ₆ , δ / ppm): 6.52 (s, 1H), 4.37 (t, 2H), 4.34 (s, 2H), 4.21 -4.07 (m, 2H), 3.27-3.15 (m, 4H), 2.38 (s, 3H), 2.25 (td, 1H), 1.15 (d, 3H), 1.05-0.92 (m, 1H), 0.86-0.79 (m, 2H).

Chiral analytical HPLC [column: Daicel Chiralpak OX-3, 3 μm, 50 mm × 4.6 mm; Eluent: isohexane / ethanol 1: 1; Flow: 1 ml / min; Temperature: 40 ° C; Detection: 220 nm]: R _t = 2.42 min.

Example 263 5-Methyl-3- (2-methylcyclopropyl) -6 - [(2-oxoimidazolidin-1-yl) methyl] -1- [2- (trifluoromethoxy) ethyl] thieno [2,3-d] pyrimidine 2,4 (1H, 3H) -dione (iroro-enantiomer 2)

From the preparative HPLC separation on chiral phase described under Ex. 262, 65 mg of enantiomer 2 were obtained (> 99% ee, chiral analytical HPLC).

Ή-ΝΜΡ (400 MHz, DMSO-d ₆ , δ / ppm): 6.52 (s, 1H), 4.37 (t, 2H), 4.34 (s, 2H), 4.21 -4.07 (m, 2H), 3.26-3.16 (m, 4H), 2.38 (s, 3H), 2.25 (td, 1H), 1.15 (d, 3H), 1.04-0.92 (m, 1H), 0.87-0.79 (m, 2H).

Chiral analytical HPLC [column: Daicel Chiralpak OX-3, 3 μm, 50 mm × 4.6 mm; Eluent: isohexane / ethanol 1: 1; Flow: 1 ml / min; Temperature: 40 ° C; Detection: 220 nm]: R _t = 3.84 min.

Example 264

[l - ({5-Methyl-3- (2-methylcyclopropyl) -2,4-dioxo-1- (2- (trifluoromethoxy) ethyl] -1,3,3,4-tetrahydrothieno [2,3- d] pyrimidin-6-yl} methyl) imidazolidin-2-ylidene] cyanamide (trans-racemate)

390 mg (0.881 mmol, 95% purity) of the compound from Ex. 378A were dissolved in 10 ml of DMF and admixed with 193 mg (1.32 mmol) of dimethyl N-cyanodithioiminocarbonate and 244 mg (1.76 mmol) of potassium carbonate. The mixture was stirred for 4 h at 80 ° C in a microwave oven (Biotage initiator with dynamic control of the irradiation power). Thereafter, the reaction mixture was treated with water and tert. -Butyl methyl ether extracted. The organic extract was washed with saturated sodium chloride solution, dried over anhydrous magnesium sulfate, filtered and evaporated. The crude product was purified by preparative HPLC (Method 11). The product fractions were combined, evaporated and dried in a high vacuum. 114 mg (26% of theory, 96%> purity) of the title compound were obtained. 'H-NMR (400 MHz, DMSO-de, δ / ρρηι): 8.06 (s, 1H), 4.47 (s, 2H), 4.37 (t, 2H), 4.22-4.09 (m, 2H), 3.48-3.36 (m, 4H), 2.39 (s, 3H), 2.29-2.21 (m, 1H), 1.15 (d, 3H), 1.04-0.92 (m, 1H), 0.88-0.77 (m, 2H).

LC / MS (Method 1, ESIpos): R _t = 1.68 min, m / z = 471.14 [M + H] ⁺ . Example 265

[l - ({5-Methyl-3- (2-methylcyclopropyl) -2,4-dioxo-l - [2- (trifluoromethoxy) ethyl] -1,3,3,4-tetrahydrothieno [2,3- d] pyrimidin-6-yl} methyl) imidazolidin-2-ylidene] cyanamide (iran-y-enantiomer 1)

1 1 1 mg of the racemic compound from Example 264 were dissolved in a mixture of 3 ml of dichloromethane and 2 ml of ethanol and separated into 16 portions via preparative HPLC on a chiral phase into the enantiomers [column: Daicel Chiralcel OX-H, 5 μιη, 250 mm x 20 mm; Eluent: ethanol; Flow: 15 ml / min; Temperature: 25 ° C; Detection: 210 nm]. Evaporation of the product fractions and drying of the solid in a high vacuum gave 44 mg (79% of theory) of enantiomer 1 (> 99% ee, chiral analytical HPLC). Ή-NMR (400 MHz, DMSO-d _6, δ / ppm): 8:06 (s, 1H), 4:47 (s, 2H), 4:37 (t, 2H), 4:22 to 4:09 (m, 2H), 3:48 to 3:35 (m, 4H), 2.39 (s, 3H), 2.29-2.21 (m, 1H), 1.15 (d, 3H), 1.04-0.92 (m, 1H), 0.88-0.78 (m, 2H).

Chiral analytical HPLC [column: Daicel Chiralpak OX-3, 3 μm, 50 mm × 4.6 mm; Eluent: ethanol; Flow: 1 ml / min; Temperature: 25 ° C; Detection: 220 nm]: R _t = 1.37 min. Example 266

[l - ({5-Methyl-3- (2-methylcyclopropyl) -2,4-dioxo-l - [2- (trifluoromethoxy) ethyl] -1,3,3,4-tetrahydrothieno [2,3- d] pyrimidin-6-yl} methyl) imidazolidin-2-ylidene] cyanamide (iran-y-enantiomer 2)

From the preparative HPLC separation on chiral phase described under Ex. 265, 43 mg (75% of theory, 98% purity) of enantiomer 2 were obtained (99% ee, chiral analytical HPLC).

Ή NMR (400 MHz, DMSO-de, δ / ppm): 8.06 (s, 1H), 4.47 (s, 2H), 4.37 (t, 2H), 4.22-4.09 (m, 2H), 3.48-3.36 ( m, 4H), 2.39 (s, 3H), 2.29-2.21 (m, 1H), 1.15 (d, 3H), 1.04-0.92 (m, 1H), 0.88-0.77 (m, 2H).

Chiral analytical HPLC [column: Daicel Chiralpak OX-3, 3 μm, 50 mm × 4.6 mm; Eluent: ethanol; Flow: 1 ml / min; Temperature: 25 ° C; Detection: 220 μm]: R _t = 2.25 min.

Example 267 Methyl [1- ({5-methyl-3- (2-methylcyclopropyl) -2,4-dioxo-1- [2- (trifluoromethoxy) ethyl] -1,3,3,4-tetrahydrothieno [2, 3-d] pyrimidin-6-yl} methyl) imidazolidin-2-ylidene] carbamate (trans-racemate)

260 mg (0.557 mmol, 90% purity) of the compound of Ex. 378A and 155 μΐ (1.11 mmol) of triethylamine were dissolved in 10 ml of dichloromethane and treated dropwise with a solution of 174 mg (1.11 mmol) of methyl (dichloromethylene) carbamate in 5 ml of dichloromethane. After the reaction mixture was stirred at RT for 3 h, it was concentrated to dryness. The remaining residue was purified by preparative HPLC (Method 11). Concentration of the product fraction and drying of the residue under high vacuum gave 205 mg (73% of theory) of the title compound.

'H-NMR (400 MHz, DMSO-de, δ / ppm): 8.29 (broad, 1H), 4.62 (s, 2H), 4.37 (t, 2H), 4.21 -4.06 (m, 2H), 3.60 (s , 3H), 3.54-3.45 (m, 2H), 3.41 -3.33 (m, 2H, partially covered by the water signal), 2.40 (s, 3H), 2.29-2.21 (m, 1H), 1.15 (d, 3H), 1.05-0.91 (m, 1H), 0.88-0.78 (m, 2H). LC / MS (Method 1, ESIpos): R _t = 1.62 min, m / z = 504.15 [M + H] ⁺ .

Example 268

Methyl [1- ({5-methyl-3- (2-methylcyclopropyl) -2,4-dioxo-1- [2- (trifluoromethoxy) ethyl] -1,3,3,4-tetrahydrothieno [2,3- d] pyrimidin-6-yl} methyl) imidazolidine-2-ylidene] carbamate

(iran-y-enantiomer 1)

195 mg of the racemic compound from Ex. 267 were dissolved in 20 ml of a methanol / acetonitrile mixture and separated in 7 portions by preparative SFC-HPLC on a chiral phase into the enantiomers [column: Daicel Chiralcel OX-H, 5 μιη, 250 mm x 20 mm; Eluent: carbon dioxide / ethanol 3: 1; Flow: 80 ml / min; Temperature: 40 ° C; Detection: 210 um]. Evaporation of the product fractions and drying of the solid in a high vacuum gave 66 mg (67% of theory) of enantiomer 1 (> 99% ee, chiral analytical HPLC).

Ή-ΝΜΡ (400 MHz, DMSO-d ₆ , δ / ppm): 8.02 (s, 1H), 4.56 (s, 2H), 4.36 (t, 2H), 4.19-4.06 (m, 2H), 3.53 (s , 3H), 3.48-3.40 (m, 2H), 3.35-3.29 (m, 2H, largely masked by the water signal), 2.40 (s, 3H), 2.29-2.21 (m, 1H), 1.15 (d, 3H ), 1.04-0.92 (m, 1H), 0.87-0.78 (m, 2H).

Chiral analytical SFC-HPLC [column: Daicel Chiralpak OX-H, 5 μm, 50 mm × 4.6 mm; Eluent: carbon dioxide / ethanol 60:40; Flow: 3 ml / min; Temperature: 40 ° C; Detection: 210 μm]: R _t = 1.67 min.

Example 269 Methyl [1- ({5-methyl-3- (2-methylcyclopropyl) -2,4-dioxo-1- [2- (trifluoromethoxy) ethyl] -1,3,3,4-tetrahydrothieno [2, 3-d] pyrimidin-6-yl} methyl) imidazolidine-2-ylidene] carbamate

(iran-y-enantiomer 2)

From the preparative HPLC separation on chiral phase described under Example 268, 48 mg (49% of theory) of enantiomer 2 were obtained (> 99% ee, chiral analytical HPLC).

Ή-ΝΜΡ (400 MHz, DMSO-d ₆ , δ / ppm): 8.08 (1H), 4.57 (2H), 4.36 (2H), 4.13 (2H), 3.54 (3H), 3.46 (2H), 2.40 (3H ), 2.25 (1H), 1.15 (3H), 0.98 (1H), 0.83 (2H).

Chiral analytical SFC-HPLC [column: Daicel Chiralpak OX-H, 5 μm, 50 mm × 4.6 mm; Eluent: carbon dioxide / ethanol 60:40; Flow: 3 ml / min; Temperature: 40 ° C; Detection: 210 nm]: R _t = 4.10 mm.

Example 270 5-Methyl-3- (2-methylcyclopropyl) -6 - [(2-oxo-2,3-dihydro-1H-imidazol-1-yl) methyl] -1- [2- (trifluoromethoxy) ethyl ] thieno [2,3-d] pyrimidine-2,4 (1H, 3H) -dione (trans-racemate)

540 mg (0.881 mmol, 83% purity) of the compound from Ex. 396A were dissolved in 10 ml of methanol and admixed with 1.8 ml of water and 1.8 ml of 1 M hydrochloric acid. After the reaction mixture was stirred for 2.5 days at RT, it was diluted with water and extracted with ethyl acetate. The organic extract was washed successively with water and saturated sodium chloride solution. After drying over anhydrous magnesium sulfate, it was filtered and concentrated. The solid residue was purified by preparative HPLC (Method 11). After evaporation of the product fractions and drying in a high vacuum, 242 mg (61% of theory) of the title compound were obtained. 'H-NMR (400 MHz, DMSO-de, δ / ρρηι): 9.98 (br.s, 1H), 6.40 (t, 1H), 6.33 (t, 1H), 4.78 (s, 2H), 4.36 (t , 2H), 4.19-4.05 (m, 2H), 2.44 (s, 3H), 2.28-2.21 (m, 1H), 1.15 (d, 3H), 1.03-0.91 (m, 1H), 0.87-0.77 (m , 2H).

LC / MS (Method 1, ESIpos): R _t = 1.51 min, m / z = 445.11 [M + H] ⁺ . Example 271

5-methyl-3- (2-methylcyclopropyl) -6 - [(2-oxo-2,3-dihydro-1H-imidazol-1-yl) methyl] -1- [2- (trifluoromethoxy) ethyl] thieno [2,3-d] pyrimidine-2,4 (1H, 3H) -dione (iran-y-enantiomer 1)

233 mg of the racemic compound from Ex. 270 were dissolved in 5 ml of acetonitrile / ethanol (1: 1) and separated into the enantiomers in 62 portions by preparative HPLC on a chiral phase [column: Daicel Chiralcel OX-H, 5 μm, 250 mm x 20 mm; Eluent: n-heptane / ethanol 1: 1; Flow: 40 ml / min; Temperature: 28 ° C; Detection: 220 um]. Evaporation of the product fractions and drying of the solid in a high vacuum gave 93 mg (79% of theory) of enantiomer 1 (99% ee, chiral analytical HPLC). Ή-ΝΜΡ (400 MHz, DMSO-d ₆ , δ / ppm): 9.98 (br.s, 1H), 6.40 (dd, 1H), 6.33 (t, 1H), 4.78 (s, 2H), 4.39-4.32 (m, 2H), 4.19-4.05 (m, 2H), 2.44 (s, 3H), 2.28-2.21 (m, 1H), 1.15 (d, 3H), 0.98 (tq, 1H), 0.87-0.77 (m , 2H).

Chiral analytical HPLC [column: Daicel Chiralpak OX-3, 3 μm, 50 mm × 4.6 mm; Eluent: n-heptane / ethanol 1: 1; Flow: 1 ml / min; Temperature: 25 ° C; Detection: 220 μm]: R _t = 1.64 min. Example 272

5-methyl-3- (2-methylcyclopropyl) -6 - [(2-oxo-2,3-dihydro-1H-imidazol-1-yl) methyl] -1- [2- (trifluoromethoxy) ethyl] thieno [2,3-d] pyrimidine-2,4 (1H, 3H) -dione (iran-y-enantiomer 2)

95 g (81% of theory) of enantiomer 2 were obtained from the preparative HPLC separation on chiral phase described under Example 271 (99% ee, chiral analytical HPLC).

Ή-ΝΜΡ (400 MHz, DMSO-d ₆ , δ / ppm): 9.98 (br s, 1H), 6.45-6.37 (m, 1H), 6.33 (t, 1H), 4.78 (s, 2H), 4.36 (t, 2H), 4.20-4.04 (m, 2H), 2.44 (s, 3H), 2.28-2.21 (m, 1H), 1.15 (d, 3H), 1.03-0.91 (m, 1H), 0.87-0.78 (m, 2H).

Chiral analytical HPLC [column: Daicel Chiralpak OX-3, 3 μm, 50 mm × 4.6 mm; Eluent: n-heptane / ethanol 1: 1; Flow: 1 ml / min; Temperature: 25 ° C; Detection: 220 μm]: R _t = 2.23 min.

Example 273 5-Methyl-3- (2-methylcyclopropyl) -6 - [(5-oxo-2,5-dihydro-1H-pyrazol-1-yl) methyl] -1- [2- (trifluoromethoxy) ethyl ] thieno [2,3-d] pyrimidine-2,4 (1H, 3H) -dione (trans-racemate)

200 mg (0.508 mmol) of the compound from Ex. 456A were used to prepare 158 mg (70% of theory) of the title compound analogously to the process described under Example 200. Ή-NMR (400 MHz, DMSO-d _6, δ / ppm): 12.11 (br s, 1H.), 7.14 (br s, 1H.), 5.30 (s, 1H), 5.13 (s, 2H), 4:34 (t, 2H), 4.19-4.04 (m, 2H), 2.45 (s, 3H), 2.28-2.20 (m, 1H), 1.14 (d, 3H), 1.03-0.91 (m, 1H), 0.87-0.77 (m, 2H).

LC / MS (Method 1, ES Ineg): R _t = 1.57 min, m / z = 443.10 [MH] -. Example 274

5-methyl-3- (2-methylcyclopropyl) -6 - [(5-oxo-2,5-dihydro-1H-pyrazol-1-yl) methyl] -1- [2- (trifluoromethoxy) ethyl] thieno [2,3-d] pyrimidine-2,4 (1H, 3H) -dione (trans enantiomer 1)

149 mg of the racemic compound from Ex. 273 were dissolved in a mixture of 6 ml of ethanol and 2 ml of acetonitrile and separated into the enantiomers in 16 portions by preparative HPLC on a chiral phase [column: Daicel Chiralcel OX-H, 5 μιη, 250 mm x 20 mm; Eluent: n-heptane / ethanol 1: 1; Flow: 20 ml / min; Temperature: 40 ° C; Detection: 220 um]. Evaporation of the product fractions and drying of the solid in a high vacuum gave 72 mg (96% of theory) of enantiomer 1 (99% ee, chiral analytical HPLC).

Ή-ΝΜΡ (400 MHz, DMSO-d ₆ , δ / ppm): 11.14 (br, s, 1H), 7.14 (br, s, 1H), 5.30 (d, 1H), 5.13 (s, 2H), 4.34 (t, 2H), 4.18-4.04 (m, 2H), 2.45 (s, 3H), 2.27-2.21 (m, 1H), 1.14 (d, 3H), 1.03-0.91 (m, 1H), 0.86-0.77 (m, 2H).

Chiral analytical HPLC [column: Daicel Chiralpak OX-3, 3 μm, 50 mm × 4.6 mm; Eluent: n-heptane / ethanol 1: 1; Flow: 1 ml / min; Temperature: 25 ° C; Detection: 220 μm]: R _t = 1.18 min.

Example 275

5-methyl-3- (2-methylcyclopropyl) -6 - [(5-oxo-2,5-dihydro-1H-pyrazol-1-yl) methyl] -1- [2- (trifluoromethoxy) ethyl] thieno [2,3-d] pyrimidine-2,4 (1H, 3H) -dione (iran-y-enantiomer 2)

From the preparative HPLC separation on chiral phase described under Example 274, 65 mg (87% of theory) of enantiomer 2 were obtained (99% ee, chiral analytical HPLC). 'H-NMR (400 MHz, DMSO-de, δ / ρρηι): 11.13 (br.s, 1H), 7.14 (br.s, 1H), 5.30 (s, 1H), 5.13 (s, 2H), 4.34 (t, 2H), 4.18-4.04 (m, 2H), 2.45 (s, 3H), 2.27-2.21 (m, 1H), 1.14 (d, 3H), 1.03-0.91 (m, 1H), 0.87-0.76 (m, 2H).

Chiral analytical HPLC [column: Daicel Chiralpak OX-3, 3 μm, 50 mm × 4.6 mm; Eluent: n-heptane / ethanol 1: 1; Flow: 1 ml / min; Temperature: 25 ° C; Detection: 220 μm]: R _t = 1.60 min.

Example 276

5-methyl-3- (2-methylcyclopropyl) -6 - [(5-oxo-4,5-dihydro-lH-l, 2,4-triazol-l-yl) methyl] -l- [2- (tri - fluoromethoxy) ethyl] thieno [2,3-d] pyrimidine-2,4 (1H, 3H) -dione (iroro-racemate)

270 mg (0.504 mmol) of the compound from Ex. 450A were dissolved in a mixture of 16.5 ml of methanol and trimethyl orthoformate and treated at RT with 1.3 ml (5.04 mmol) of a 4 M solution of hydrogen chloride in dioxane. After 4 days, the reaction mixture was evaporated and the remaining residue was purified by preparative HPLC (Method 11). After evaporation of the product fractions and drying in a high vacuum, 136 mg (60% of theory) of the title compound were obtained.

Ή-NMR (400 MHz, DMSO-de, δ / ppm): 11.59 (br.s, 1H), 7.82 (s, 1H), 4.92 (s, 2H), 4.36 (t, 2H), 4.21-4.05 ( m, 2H), 2.44 (s, 3H), 2.29-2.20 (m, 1H), 1.15 (d, 3H), 1.04-0.92 (m, 1H), 0.87-0.77 (m, 2H).

LC / MS (Method 1, ESIpos): R _t = 1.48 min, m / z = 446.11 [M + H] ⁺ .

Example 277

5-methyl-3- (2-methylcyclopropyl) -6 - [(5-oxo-4,5-dihydro-lH-l, 2,4-triazol-l-yl) methyl] -l- [2- (tri - fluoromethoxy) ethyl] thieno [2,3-d] pyrimidine-2,4 (1H, 3H) -dione (iran-y-enantiomer 1)

132 mg of the racemic compound from Ex. 276 were dissolved in 20 ml of a methanol / acetonitrile mixture and separated in 10 portions by preparative SFC-HPLC on a chiral phase into the enantiomers [column: Daicel Chiralcel OX-H, 5 μιη, 250 mm x 20 mm; Eluent: carbon dioxide / ethanol 83:17; Flow: 80 ml / min; Temperature: 40 ° C; Detection: 210 um]. Evaporation of the product fractions and drying of the solid in a high vacuum gave 46 mg (69% of theory) of enantiomer 1 (> 99% ee, chiral analytical HPLC).

Ή-ΝΜΡ (400 MHz, DMSO-d ₆ , δ / ppm): 1 1.58 (brs s, 1H), 7.82 (s, 1H), 4.92 (s, 2H), 4.36 (t, 2H), 4.21 - 4.05 (m, 2H), 2.44 (s, 3H), 2.28-2.21 (m, 1H), 1.15 (d, 3H), 1.04-0.92 (m, 1H), 0.87-0.78 (m, 2H).

Chiral analytical SFC-HPLC [column: Daicel Chiralpak OX-H, 5 μm, 50 mm × 4.6 mm; Eluent: carbon dioxide / ethanol 80:20; Flow: 3 ml / min; Temperature: 40 ° C; Detection: 210 μm]: R _t = 1.81 min.

Example 278 5-Methyl-3- (2-methylcyclopropyl) -6 - [(5-oxo-4,5-dihydro-1H-l, 2,4-triazol-1-yl) methyl] -1 - [2- (trifluoromethoxy) ethyl] thieno [2,3-d] pyrimidine-2,4 (1H, 3H) -dione (iran-y-enantiomer 2)

From the preparative HPLC separation on chiral phase described under Example 277, 43 mg (65% of theory) of enantiomer 2 were obtained (>99%> ee, chiral analytical HPLC). Ή-ΝΜΡ (400 MHz, DMSO-d ₆ , δ / ppm): 1 1.58 (br.s, 1H), 7.83 (s, 1H), 4.92 (s, 2H), 4.36 (t, 2H), 4.20- 4.06 (m, 2H), 2.44 (s, 3H), 2.29-2.21 (m, 1H), 1.15 (d, 3H), 1.04-0.92 (m, 1H), 0.87-0.77 (m, 2H). Chiral analytical SFC-HPLC [column: Daicel Chiralpak OX-H, 5 μm, 50 mm × 4.6 mm; Eluent: carbon dioxide / ethanol 80:20; Flow: 3 ml / min; Temperature: 40 ° C; Detection: 210 μm]: R _t = 3.79 min.

Example 279 5-Methyl-3- (2-methylcyclopropyl) -6 - [(2-oxoimidazolidin-1-yl) methyl] -1- {2 - [(trifluoromethyl) sulfanyl] ethyl} thieno [2,3-d ] pyrimidine-2,4 (1H, 3H) -dione (trans-racemate)

A solution of 294 mg of the crude product from Example 379A (0.67 mmol, calculated with theoretical purity of 100% and a yield of 100%) and 141 μΐ (1.01 mmol) of triethylamine in 2 ml of THF was mixed with 131 mg (0.81 mmol) of 1 , 1 '-Carbonyldiimidazole (CDI) and heated for 5 min in a microwave apparatus (Biotage Initiator) at 80 ° C. The reaction mixture was then stirred into water and extracted three times with 5 ml of ethyl acetate. The combined organic phases were washed with saturated aqueous sodium chloride solution, dried over sodium sulfate, filtered and concentrated on a rotary evaporator. The residue was purified by preparative HPLC (Method 16). Evaporation of the product fractions and drying under high vacuum gave 70 mg (23% of theory) of the title compound.

Ή-NMR (400 MHz, DMSO-de, δ / ppm): 6.52 (s, 1H), 4.35 (s, 2H), 4.10 (m, 2H), 3.32 (t, 2H), 3.22 (m, 4H) , 2.38 (s, 3H), 2.23 (m, 1H), 1.15 (d, 3H), 1.02-0.95 (m, 1H), 0.87-0.80 (m, 2H).

LC / MS (Method 1, ESIpos): R _t = 1.74 min, m / z = 463.1 [M + H] ⁺ .

Example 280

5-Methyl-3- (2-methylcyclopropyl) -6 - [(2-oxoimidazolidin-1-yl) methyl] -1- {2 - [(trifluoromethyl) sulfanyl] ethyl} thieno [2,3-d] pyrimidine -2,4 (1H, 3H) -dione (iroro-enantiomer 1)

65 mg of the racemic compound from Ex. 279 were dissolved in a mixture of 1 ml of ethanol and 3 ml of acetonitrile and separated by preparative HPLC on a chiral phase into the enantiomers [column: Daicel Chiralcel OX-H, 5 μm, 250 mm × 20 mm ; Eluent: n-heptane / ethanol 30:70; Flow: 15 ml / min; Temperature: 25 ° C; Detection: 220 um]. Evaporation of the product fractions and drying of the solid in a high vacuum gave 27 mg (42% of theory) of enantiomer 1 (> 99% ee, chiral analytical HPLC).

Ή-ΝΜΡ (400 MHz, DMSO-d ₆ , δ / ppm): 6.52 (s, 1H), 4.35 (s, 2H), 4.10 (m, 2H), 3.32 (t, 2H), 3.22 (m, 4H ), 2.38 (s, 3H), 2.23 (m, 1H), 1.15 (d, 3H), 1.02-0.95 (m, 1H), 0.87-0.80 (m, 2H). Chiral analytical HPLC [column: Daicel Chiralpak OX-3, 3 μm, 50 mm × 4.6 mm; Eluent: n-heptane / ethanol 1: 1; Flow: 1 ml / min; Detection: 220 nm]: R _t = 2.02 min.

Example 281

5-Methyl-3- (2-methylcyclopropyl) -6 - [(2-oxoimidazolidin-1-yl) methyl] -1- {2 - [(trifluoromethyl) sulfanyl] ethyl} thieno [2,3-d] pyrimidine -2,4 (1H, 3H) -dione (iroro-enantiomer 2)

65 mg of the racemic compound from Ex. 279 were dissolved in a mixture of 1 ml of ethanol and 3 ml of acetonitrile and separated by preparative HPLC on a chiral phase into the enantiomers [column: Daicel Chiralcel OX-H, 5 μm, 250 mm × 20 mm ; Eluent: n-heptane / ethanol 30:70; Flow: 15 ml / min; Temperature: 25 ° C; Detection: 220 nm]. Evaporation of the product fractions and drying of the solid in a high vacuum gave 28 mg (43% of theory) of enantiomer 2 (> 99% ee, chiral analytical HPLC). 'H-NMR (400 MHz, DMSO-de, δ / ρρηι): 6.52 (s, 1H), 4.35 (s, 2H), 4.10 (m, 2H), 3.32 (t, 2H), 3.22 (m, 4H ), 2.38 (s, 3H), 2.23 (m, 1H), 1.15 (d, 3H), 1.02-0.95 (m, 1H), 0.87-0.80 (m, 2H).

Chiral analytical HPLC [column: Daicel Chiralpak OX-3, 3 μm, 50 mm × 4.6 mm; Eluent: n-heptane / ethanol 1: 1; Flow: 1 ml / min; Detection: 220 nm]: R _t = 2.97 min. Example 282

5-Methyl-3 - [(S, 2S) -2-methylcyclopropyl] -1- (oxetan-2-ylmethyl) -6 - [(2-oxoimidazolidin-1-yl) methyl] thieno [2,3-d ] pyrimidine-2,4 (1H, 3H) -dione {diastereomer mixture)

A solution of 460 mg of the crude product of Example 380A (1.22 mmol, calculated with theoretical purity of 100%) and 254 μΐ (1.82 mmol) of triethylamine in 10 ml of THF was mixed with 236 mg (1.46 mmol) Ι, Γ-carbonyldiimidazole (CDI ) and heated in a microwave apparatus (Biotage Initiator) at 80 ° C for 5 min. The reaction mixture was then separated directly into its components by preparative HPLC (Method 16). After evaporation of the product fractions and drying in a high vacuum, 161 mg (32% of theory) of the title compound were obtained. 'H-NMR (400 MHz, DMSO-d _6, δ / ppm): 6:51 (broad, 1H), 4.98 (m, 1H), 4:47 (m, 1H), 4:41 (m, 1H), 4:33 (s, 2H), 4.09 (m, 2H), 3.21 (m, 4H), 2.67 (m, 1H), 2.37 (s, 3H), 2.23 (m, 1H), 1.15 (d, 3H), 1.03-0.95 (m , 1H), 0.86-0.78 (m, 2H).

LC / MS (Method 1, ESIpos): R _t = 1.25 min, m / z = 405.1 [M + H] ⁺ . Example 283 5-Methyl-3 - [(S, 2S) -2-methylcyclopropyl] -1- (oxetan-2-ylmethyl) -6 - [(2-oxoimidazolidin-1-yl) methyl] thieno [2,3 -d] pyrimidine-2,4 (1H, 3H) -dione {diastereomer 1)

161 mg of the diastereomer mixture from Ex. 282 were dissolved in about 4 ml of methanol / acetonitrile / dichloromethane (3: 3: 2) and separated by preparative HPLC on a chiral phase into the enantiomeric diastereomers [column: Daicel Chiralpak IC, 5 μmol , 250 mm x 20 mm; Eluent: acetonitrile / methanol 1: 1; Flow: 20 ml / min; Detection: 220 nm]. Evaporation of the product fractions and drying of the solid in a high vacuum gave 68 mg (42% of theory) of diastereomer 1 (> 99% de, chiral analytical HPLC).

Ή-ΝΜΡ (400 MHz, DMSO-d ₆ , δ / ppm): 6.50 (s, 1H), 4.98 (m, 1H), 4.47 (m, 1H), 4.41 (m, 1H), 4.33 (s, 2H ), 4.09 (d, 2H), 3.21 (m, 4H), 2.67 (m, 1H), 2.37 (s, 3H), 2.24 (m, 1H), 1.15 (d, 3H), 1.03-0.95 (m, 1H), 0.85-0.79 (m, 2H).

Chiral analytical HPLC [column: Daicel Chiralpak IC, 5 μm, 250 mm × 4.6 mm; Eluent: acetonitrile / methanol 1: 1; Flow: 1 ml / min; Detection: 220 nm]: R _t = 9.30 min.

Example 284

5-Methyl-3 - [(S, 2S) -2-methylcyclopropyl] -1- (oxetan-2-ylmethyl) -6 - [(2-oxoimidazolidin-1-yl) methyl] thieno [2,3-d ] pyrimidine-2,4 (1H, 3H) -dione {diastereomer 2)

161 mg of the diastereomer mixture from Example 282 were dissolved in about 4 ml of methanol / acetonitrile / dichloromethane (3: 3: 2) and separated by preparative HPLC on a chiral phase into the enantiomeric diastereomers [column: Daicel Chiralpak IC, 5 μmol , 250 mm x 20 mm; Eluent: acetonitrile / methanol 1: 1; Flow: 20 ml / min; Detection: 220 nm]. Evaporation of the product fractions and drying of the solid in a high vacuum gave 6.2 mg (4% of theory) of diastereomer 2 (99% de, chiral analytical HPLC). 'H-NMR (400 MHz, DMSO-de, δ / ρρηι): 6.51 (s, 1H), 4.98 (m, 1H), 4.47 (m, 1H), 4.41 (m, 1H), 4.33 (s, 2H ), 4.09 (dq, 2H), 3.22 (m, 4H), 2.67 (m, 1H), 2.37 (s, 3H), 2.24 (m, 1H), 1.15 (d, 3H), 1.02-0.95 (m, 1H), 0.86-0.79 (m, 2H).

Chiral analytical HPLC [column: Daicel Chiralpak IC, 5 μm, 250 mm × 4.6 mm; Eluent: acetonitrile / methanol 1: 1; Flow: 1 ml / min; Detection: 220 μm]: R _t = 11.54 min.

Example 285

5-Methyl-3 - [(S, 2S) -2-methylcyclopropyl] -1- (oxetan-3-ylmethyl) -6 - [(2-oxoimidazolidin-1-yl) methyl] thieno [2,3-d ] pyrimidine-2,4 (lH, 3H) -dione

A solution of 113 mg of the crude product from Example 381A (0.30 mmol, calculated with theoretical purity of 100% and a yield of 100%) and 62 μΐ (0.45 mmol) of triethylamine in 1.7 ml of THF was treated with 58 mg (0.36 mmol) of 1 , 1 '-Carbonyldiimidazole (CDI) and heated for 10 min in a microwave apparatus (Biotage Initiator) at 80 ° C. The reaction mixture was then separated directly into its components by preparative HPLC (Method 16). After evaporation of the product fractions and drying in a high vacuum, the material thus obtained was further purified by further preparative HPLC (Method 17). 5 mg (4% of theory) of the title compound were obtained.

'H-NMR (400 MHz, DMSO-de, δ / ppm): 6.52 (s, 1H), 4.61 (dd, 2H), 4.42 (t, 2H), 4.34 (s, 2H), 4.15 (m, 2H ), 3.39 (m, 1H), 3.22 (m, 4H), 2.37 (s, 3H), 2.22 (m, 1H), 1.15 (d, 3H), 1.02-0.92 (m, 1H), 0.85-0.78 ( m, 2H).

LC / MS (Method 1, ESIpos): R _t = 1.20 min, m / z = 405.1 [M + H] ⁺ .

Example 286

5-Methyl-3- (2-methylcyclopropyl) -6 - [(2-oxoimidazolidin-1-yl) methyl] -1 - [(2R) -tetrahydrofuran-2-ylmethyl] thieno [2,3-d] pyrimidine 2,4 (1H, 3H) -dione (iran-y-diastereomer mixture)

A solution of 230 mg of the crude product from Example 382A (0.58 mmol, calculated with theoretical purity of 100% and a yield of 100%) and 123 μΐ (0.88 mmol) of triethylamine in 3.8 ml of THF was treated with 114 mg (0.70 mmol) 1 , 1 '-Carbonyldiimidazole (CDI) and heated for 5 min in a microwave apparatus (Biotage Initiator) at 80 ° C. The reaction mixture was then separated directly into its components by preparative HPLC (Method 16). Evaporation of the product fractions and drying under high vacuum gave 100 mg (41% of theory) of the title compound.

Ή NMR (400 MHz, DMSO-de, δ / ppm): 6.51 (broad, 1H), 4.33 (s, 2H), 4.20 (broad, 1H), 4.00 (m, 1H), 3.77-3.58 (m, 3H), 3.21 (m, 4H), 2.37 (s, 3H), 2.24 (m, 1H), 2.01-1.75 (m, 3H), 1.64 (m, 1H), 1.15 (d, 3H), 1.02-0.92 (m, 1H), 0.85-0.79 (m, 2H).

LC / MS (Method 1, ESIpos): R _t = 1.42 min, m / z = 419.1 [M + H] ⁺ .

Example 287

5-Methyl-3- (2-methylcyclopropyl) -6 - [(2-oxoimidazolidin-1-yl) methyl] -1 - [(2R) -tetrahydrofuran-2-ylmethyl] thieno [2,3-d] pyrimidine 2,4 (1H, 3H) -dione (iroro-diastereomer 1)

94 mg of the diastereomer mixture from Example 286 were dissolved in 4 ml of ethanol and 1 ml of acetonitrile and separated by preparative HPLC on a chiral phase into the enantiomerically pure diastereomers [column: Daicel Chiralcel OJ-H, 5 μm, 250 mm × 20 mm; Eluent: n-heptane / ethanol 1: 1; Flow: 20 ml / min; Temperature: 40 ° C; Detection: 220 um]. After evaporation of the product fractions and drying of the solid in a high vacuum, 30 mg (32% of theory) of diastereomer 1 were obtained (>99%> de, chiral analytical HPLC). 'H-NMR (400 MHz, DMSO-de, δ / ρρηι): 6.50 (s, 1H), 4.33 (s, 2H), 4.20 (broad, 1H), 4.01 (dd, 1H), 3.75 (q, 1H ), 3.66-3.58 (m, 2H), 3.21 (m, 4H), 2.37 (s, 3H), 2.24 (m, 1H), 2.01-1.77 (m, 3H), 1.64 (m, 1H), 1.15 ( d, 3H), 1.02-0.92 (m, 1H), 0.85-0.79 (m, 2H).

Chiral analytical HPLC [column: Daicel OJ-3, 3 μm, 50 mm × 4.6 mm; Eluent: ethanol; Flow: 1 ml / min; Detection: 220 μm]: R _t = 1.56 min.

Example 288

5-Methyl-3- (2-methylcyclopropyl) -6 - [(2-oxoimidazolidin-1-yl) methyl] -1 - [(2R) -tetrahydrofuran-2-ylmethyl] thieno [2,3-d] pyrimidine 2,4 (1H, 3H) -dione (iroro-diastereomer 2)

94 mg of the diastereomer mixture from Example 286 were dissolved in 4 ml of ethanol and 1 ml of acetonitrile and separated by preparative HPLC on a chiral phase into the enantiomerically pure diastereomers [column: Daicel Chiralcel OJ-H, 5 μm, 250 mm × 20 mm; Eluent: n-heptane / ethanol 1: 1; Flow: 20 ml / min; Temperature: 40 ° C; Detection: 220 um]. After evaporation of the product fractions and drying of the solid in a high vacuum, 40 mg (43% of theory) of diastereomer 2 were obtained (98.6% by chiral analytical HPLC).

Ή-ΝΜΡ (400 MHz, DMSO-d ₆ , δ / ppm): 6.50 (s, 1H), 4.33 (s, 2H), 4.20 (broad, 1H), 3.99 (dd, 1H), 3.77-3.58 (m , 3H), 3.21 (m, 4H), 2.37 (s, 3H), 2.24 (m, 1H), 2.01 -1.77 (m, 3H), 1.64 (m, 1H), 1.15 (d, 3H), 1.02- 0.92 (m, 1H), 0.85-0.79 (m, 2H).

Chiral analytical HPLC [column: Daicel OJ-3, 3 μm, 50 mm × 4.6 mm; Eluent: ethanol; Flow: 1 ml / min; Detection: 220 μm]: R _t = 2.17 min.

Example 289

5-methyl-3- (2-methylcyclopropyl) -6 - [(2-oxoimidazolidin-1-yl) methyl] -1- (tetrahydrofuran-3-ylmethyl) thieno [2,3-d] pyrimidine-2, 4 (1H, 3H) -dione (mixture of all iroro stereoisomers)

Analogously to the process described under Ex. 286, 107 mg (32% of theory) of the title compound were obtained from 297 mg of the crude product from Example 383A (0.76 mmol, calculated with a theoretical purity of 100% and a yield of 100%) , Ή-NMR (400 MHz, DMSO-d ₆ , δ / ppm): 6.52 (s, 1H), 4.34 (s, 2H), 3.88-3.77 (m, 3H), 3.63 (m, 2H), 3.50 (m , 1H), 3.10 (q, 2H), 2.71 (m, 1H), 2.38 (s, 3H), 2.24 (m, 1H), 1.94 (m, 1H), 1.65 (m, 1H), 1.15 (d, 3H), 1.02-0.94 (m, 1H), 0.85-0.80 (m, 2H).

LC / MS (Method 1, ESIpos): R _t = 1.31 min, m / z = 419.1 [M + H] ⁺ .

Example 290 5-Methyl-3- (2-methylcyclopropyl) -6 - [(2-oxoimidazolidin-1-yl) methyl] -1- (tetrahydrofuran-3-ylmethyl) thieno [2,3-d] pyrimidine 2,4 (1H, 3H) -dione (iroro stereoisomer 1)

100 mg (0.24 mmol) of the diastereomer mixture from Ex. 289 were dissolved in 6 ml of ethanol and first separated by preparative HPLC on a chiral phase into 2 diastereomer pairs [column: YMC Chiralart Cellulose SC, 5 μm, 250 mm × 20 mm; Eluent: ethanol; Flow: 15 ml / min; Temperature: 60 ° C; Detection: 220 nm]. After evaporation of the corresponding product fractions, the pairs of diastereomers were then separated by further preparative HPLC on a chiral phase into the individual diastereomers [column: Daicel Chiralcel OX-H, 5 μm, 250 mm × 20 mm; Eluent: isopropanol; Flow: 15 ml / min; Temperature: 70 ° C; Detection: 220 nm]. Evaporation of the product fractions and drying of the solid in a high vacuum gave 16 mg (16% of theory) of diastereomer 1 (> 99% de, chiral analytical HPLC). 'H-NMR (400 MHz, DMSO-de, δ / ρρηι): 6.52 (s, 1H), 4.34 (s, 2H), 3.88-3.77 (m, 3H), 3.63 (m, 2H), 3.50 (m , 1H), 3.22 (m, 4H), 2.71 (m, 1H), 2.38 (s, 3H), 2.24 (m, 1H), 1.94 (m, 1H), 1.63 (m, 1H), 1.15 (d, 3H), 1.03-0.94 (m, 1H), 0.86-0.80 (m, 2H).

Chiral analytical HPLC [column: Daicel Chiralcel OX-H, 5 μm, 250 mm × 4.6 mm; Eluent: isopropanol; Flow: 1 ml / min; Detection: 220 μm]: R _t = 8.16 min.

Example 291

5-methyl-3- (2-methylcyclopropyl) -6 - [(2-oxoimidazolidin-1-yl) methyl] -1- (tetrahydrofuran-3-ylmethyl) thieno [2,3-d] pyrimidine-2, 4 (1H, 3H) -dione (iroro stereoisomer 2)

From the two-fold HPLC separation described under Example 290, 16 mg (16% of theory) of diastereomer 2 were obtained (> 99% de, chiral analytical HPLC).

Ή-NMR (400 MHz, DMSO-d ₆ , δ / ppm): 6.51 (s, 1H), 4.34 (s, 2H), 3.90-3.77 (m, 3H), 3.63 (m, 2H), 3.50 (m , 1H), 3.22 (m, 4H), 2.71 (m, 1H), 2.38 (s, 3H), 2.23 (m, 1H), 1.94 (m, 1H), 1.64 (m, 1H), 1.15 (d, 3H), 1.03-0.94 (m, 1H), 0.86-0.80 (m, 2H). Chiral analytical HPLC [column: Daicel Chiralcel OX-H, 5 μm, 250 mm × 4.6 mm; Eluent: isopropanol; Flow: 1 ml / min; Detection: 220 μm]: R _t = 9.45 min.

Example 292

5-methyl-3- (2-methylcyclopropyl) -6 - [(2-oxoimidazolidin-1-yl) methyl] -1- (tetrahydrofuran-3-ylmethyl) thieno [2,3-d] pyrimidine-2, 4 (1H, 3H) -dione (iroro stereoisomer 3)

From the two-fold HPLC separation described under Example 290, 17 mg (17% of theory) of diastereomer 3 were obtained (> 99% de, chiral analytical HPLC).

Ή-ΝΜΡ (400 MHz, DMSO-d ₆ , δ / ppm): 6.51 (s, 1H), 4.34 (s, 2H), 3.90-3.77 (m, 3H), 3.63 (m, 2H), 3.50 (m , 1H), 3.22 (m, 4H), 2.71 (m, 1H), 2.38 (s, 3H), 2.23 (m, 1H), 1.95 (m, 1H), 1.65 (m, 1H), 1.15 (d, 3H), 1.03-0.94 (m, 1H), 0.86-0.80 (m, 2H).

Chiral analytical HPLC [column: Daicel Chiralcel OX-H, 5 μm, 250 mm × 4.6 mm; Eluent: isopropanol; Flow: 1 ml / min; Detection: 220 μm]: R _t = 10.50 min.

Example 293

5-methyl-3- (2-methylcyclopropyl) -6 - [(2-oxoimidazolidin-1-yl) methyl] -1- (tetrahydrofuran-3-ylmethyl) thieno [2,3-d] pyrimidine-2, 4 (1H, 3H) -dione (iroro stereoisomer 4)

From the two-fold HPLC separation described under Example 290, 17 mg (17% of theory) of diastereomer 4 were obtained (> 99% de, chiral analytical HPLC).

Ή-NMR (400 MHz, DMSO-d ₆ , δ / ppm): 6.51 (s, 1H), 4.34 (s, 2H), 3.85-3.77 (m, 3H), 3.63 (m, 2H), 3.50 (m , 1H), 3.22 (m, 4H), 2.71 (m, 1H), 2.38 (s, 3H), 2.23 (m, 1H), 1.95 (m, 1H), 1.65 (m, 1H), 1.15 (d, 3H), 1.03-0.94 (m, 1H), 0.86-0.80 (m, 2H).

Chiral analytical HPLC [column: Daicel Chiralcel OX-H, 5 μm, 250 mm × 4.6 mm; Eluent: isopropanol; Flow: 1 ml / min; Detection: 220 μm]: R _t = 12.15 min.

Example 294 1- (2-Methoxyethyl) -5-methyl-6 - [(2-oxoimidazolidin-1-yl) methyl] -3- [2- (trifluoromethyl) cyclopropyl] thieno [2,3-d] pyrimidine -2,4 (1H, 3H) -dione (trans-racemate)

A solution of 411 mg (0.860 mmol, 88% purity) of the compound from Example 384A and 180 μΐ (1.29 mmol) of triethylamine in 12 ml of THF was admixed with 167 mg (1.03 mmol) of CDI and stirred at RT for about 16 h. It was then concentrated to dryness. The remaining residue was taken up in ethyl acetate and washed successively with water and saturated sodium chloride solution. After drying over anhydrous magnesium sulfate, it was filtered and the solution concentrated to about half the original volume. A part of the product precipitated, which was filtered off. The filtrate was then concentrated to dryness and the remaining residue purified by preparative HPLC (Method 11). After evaporation of the product fractions, this was combined with the previously isolated precipitate and dried under high vacuum. This gave 197 mg (51% of theory) of the title compound.

Ή-NMR (400 MHz, DMSO-de, δ / ppm): 6.52 (s, 1H), 4.34 (s, 2H), 4.07-3.90 (m, 2H), 3.61 (t, 2H), 3.28-3.16 ( m, 4H), 3.24 (s, 3H), 3.02-2.94 (m, 1H), 2.37 (s, 3H), 2.30-2.16 (m, 1H), 1.49 (q, 1H), 1.37-1.27 (m, 1H).

LC / MS (Method 1, ESIpos): R _t = 1.47 min, m / z = 447.13 [M + H] ⁺ . Example 295 1- (2-Methoxyethyl) -5-methyl-6 - [(2-oxoimidazolidin-1-yl) methyl] -3- [2- (trifluoromethyl) cyclopropyl] thieno [2,3-d] pyrimidine -2,4 (1H, 3H) -dione (iroro-enantiomer 1)

192 mg of the racemic compound from Ex. 294 were dissolved in 20 ml of acetonitrile and separated into the enantiomers in 8 portions by preparative SFC-HPLC on a chiral phase [column: Daicel Chiralcel OX-H, 5 μm, 250 mm × 20 mm ; Eluent: carbon dioxide / ethanol 70:30; Flow: 80 ml / min; Temperature: 40 ° C; Detection: 210 nm]. Evaporation of the product fractions and drying of the solid in a high vacuum gave 66 mg (68% of theory) of enantiomer 1 (> 99% ee, chiral analytical HPLC).

Ή-ΝΜΡ (400 MHz, DMSO-d ₆ , δ / ppm): 6.52 (s, 1H), 4.34 (s, 2H), 4.07-3.90 (m, 2H), 3.61 (t, 2H), 3.28-3.16 (m, 4H), 3.24 (s, 3H), 3.02-2.93 (m, 1H), 2.37 (s, 3H), 2.30-2.17 (m, 1H), 1.49 (q, 1H), 1.38-1.27 (m , 1H).

Chiral analytical SFC-HPLC [column: Daicel Chiralpak OX-H, 5 μm, 50 mm × 4.6 mm; Eluent: carbon dioxide / ethanol 70:30; Flow: 3 ml / min; Temperature: 40 ° C; Detection: 210 nm]: R _t = 2.47 min. Example 296 1- (2-Methoxyethyl) -5-methyl-6 - [(2-oxoimidazolidin-1-yl) methyl] -3- [2- (trifluoromethyl) cyclopropyl] thieno [2,3-d] pyrimidine -2,4 (1H, 3H) -dione (iran-y-enantiomer 2)

From the preparative HPLC separation on chiral phase described under Example 295, 64 mg (66% of theory) of enantiomer 2 were obtained (> 99%> ee, chiral analytical HPLC).

Ή NMR (400 MHz, DMSO-d ₆ , δ / ppm): 6.52 (s, 1H), 4.34 (s, 2H), 4.07-3.90 (m, 2H), 3.61 (t, 2H), 3.27-3.16 (m, 4H), 3.24 (s, 3H), 2.97 (ddd, 1H), 2.37 (s, 3H), 2.24 (dtd, 1H), 1.55-1.44 (m, 1H), 1.38-1.28 (m, 1H ).

Chiral analytical SFC-HPLC [column: Daicel Chiralpak OX-H, 5 μm, 50 mm × 4.6 mm; Eluent: carbon dioxide / ethanol 70:30; Flow: 3 ml / min; Temperature: 40 ° C; Detection: 210 nm]: R _t = 5.13 min.

Example 297 1- (2-Methoxyethyl) -5-methyl-6 - [(5-oxo-4,5-dihydro-1H-1,2,4-triazol-1-yl) methyl] -3- [2- (trifluoromethyl) cyclopropyl] thieno [2,3-d] pyrimidine-2,4 (1H, 3H) -dione (trans-racemate)

Analogously to the process described under Example 195, 171 mg (76% of theory) of the title compound were prepared from 284 mg (0.504 mmol, 95% purity) of the compound from Example 451A. The reaction time was 7 days. Ή-NMR (400 MHz, DMSO-d ₆ , δ / ppm): 11.59 (s, 1H), 7.83 (s, 1H), 4.92 (s, 2H), 4.06-3.89 (m, 2H), 3.60 (t , 2H), 3.23 (s, 3H), 2.97 (ddd, 1H), 2.43 (s, 3H), 2.23 (dtd, 1H), 1.55-1.43 (m, 1H), 1.36-1.27 (m, 1H).

LC / MS (Method 1, ESIpos): R _t = 1.37 min, m / z = 446.11 [M + H] ⁺ .

Example 298 1- (2-Methoxyethyl) -5-methyl-6 - [(5-oxo-4,5-dihydro-1H-1,2,4-triazol-1-yl) methyl] -3- [2- (trifluoromethyl) cyclopropyl] thieno [2,3-d] pyrimidine-2,4 (1H, 3H) -dione (iroro-enantiomer 1)

165 mg of the racemic compound from Ex. 297 were dissolved in 40 ml of an acetonitrile / methanol mixture and separated into the enantiomers in 10 portions by preparative SFC-HPLC on a chiral phase [column: Daicel Chiralcel OX-H, 5 μιη, 250 mm x 20 mm; Eluent: carbon dioxide / ethanol 3: 1; Flow: 90 ml / min; Temperature: 40 ° C; Detection: 210 nm]. Evaporation of the product fractions and drying of the solid in a high vacuum gave 71 mg (86% of theory) of enantiomer 1 (> 99% ee, chiral analytical HPLC).

'H-NMR (400 MHz, DMSO-de, δ / ppm): 11.58 (br.s, 1H), 7.83 (s, 1H), 4.92 (s, 2H), 4.06-3.89 (m, 2H), 3.60 (t, 2H), 3.23 (s, 3H), 3.02-2.92 (m, 1H), 2.43 (s, 3H), 2.28-2.16 (m, 1H), 1.49 (q, 1H), 1.32 (dt, 1H ). Chiral analytical SFC-HPLC [column: Daicel Chiralpak OX-H, 5 μm, 50 mm × 4.6 mm; Eluent: carbon dioxide / ethanol 70:30; Flow: 3 ml / min; Temperature: 40 ° C; Detection: 210 μm]: R _t = 1.26 min.

Example 299 1- (2-Methoxyethyl) -5-methyl-6 - [(5-oxo-4,5-dihydro-1H-1,2,4-triazol-1-yl) methyl] -3- [2- (trifluoromethyl) cyclopropyl] thieno [2,3-d] pyrimidine-2,4 (1H, 3H) -dione (iroro-enantiomer 2)

From the preparative HPLC separation on chiral phase described under Example 298, 83 mg (100% of theory) of enantiomer 2 were obtained (> 99% ee, chiral analytical HPLC). Ή NMR (400 MHz, DMSO-d ₆ , δ / ppm): 11.59 (br.s, 1H), 7.83 (s, 1H), 4.92 (s, 2H), 4.06-3.89 (m, 2H), 3.60 (t, 2H), 3.23 (s, 3H), 3.02-2.92 (m, 1H), 2.43 (s, 3H), 2.28-2.17 (m, 1H), 1.49 (q, 1H), 1.37-1.27 (m , 1H).

Chiral analytical SFC-HPLC [column: Daicel Chiralpak OX-H, 5 μm, 50 mm × 4.6 mm; Eluent: carbon dioxide / ethanol 70:30; Flow: 3 ml / min; Temperature: 40 ° C; Detection: 210 μm]: R _t = 1.95 min.

Example 300

3- (2-Ethylcyclopropyl) -1- (2-methoxyethyl) -5-methyl-6 - [(2-oxoimidazolidin-1-yl) methyl] thieno [2,3-d] pyrimidine-2,4 (1H , 3H) -dione (trans-racemate)

Analogously to the process described under Ex. 294, from 323 mg (0.696 mmol, 82% purity) of the compound from Example 385A and 135 mg (0.835 mmol) of CDI 93 mg (32% of theory) of the title compound were prepared.

'H-NMR (400 MHz, DMSO-de, δ / ppm): 6.51 (s, 1H), 4.33 (s, 2H), 4.04-3.89 (m, 2H), 3.60 (t, 2H), 3.27-3.14 (m, 4H), 3.23 (s, 3H), 2.37 (s, 3H), 2.30 (dt, 1H), 1.69-1.55 (m, 1H), 1.30-1.16 (m, 1H), 1.07-0.92 (m , 1H), 0.99 (t, 3H), 0.89-0.71 (m, 2H).

LC / MS (Method 1, ESIpos): R _t = 1.49 min, m / z = 407.17 [M + H] ⁺ .

Example 301

3- (2-Ethylcyclopropyl) -1- (2-methoxyethyl) -5-methyl-6 - [(2-oxoimidazolidin-1-yl) methyl] thieno [2,3-d] pyrimidine-2,4 (1H , 3H) -dione (iran enantiomer 1)

90 mg of the racemic compound from Ex. 300 were dissolved in a mixture of 3 ml of acetonitrile and 2 ml of ethanol and separated in 13 portions by preparative HPLC on a chiral phase into the enantiomers [column: Daicel Chiralcel OX-H, 5 μm, 250 mm x 20 mm; Eluent: n-heptane / ethanol 90:10; Flow: 15 ml / min; Temperature: 40 ° C; Detection: 210 nm]. Evaporation of the product fractions and drying of the solid in a high vacuum gave 39 mg (86% of theory) of enantiomer 1 (> 99% ee, chiral analytical HPLC).

Ή-NMR (400 MHz, DMSO-de, δ / ppm): 6.51 (s, 1H), 4.33 (s, 2H), 3.97 (td, 2H), 3.60 (t, 2H), 3.27-3.16 (m, 4H), 3.23 (s, 3H), 2.37 (s, 3H), 2.30 (dt, 1H), 1.70-1.55 (m, 1H), 1.29-1.15 (m, 1H), 1.06-0.94 (m, 1H) , 0.99 (t, 3H), 0.88-0.73 (m, 2H).

Chiral analytical HPLC [column: Daicel Chiralpak OX-3, 3 μm, 50 mm × 4.6 mm; Eluent: ethanol; Flow: 1 ml / min; Temperature: 50 ° C; Detection: 220 nm]: R _t = 1.65 min.

Example 302

3- (2-Ethylcyclopropyl) -1- (2-methoxyethyl) -5-methyl-6 - [(2-oxoimidazolidin-1-yl) methyl] thieno [2,3-d] pyrimidine-2,4 (1H , 3H) -dione (iroro-enantiomer 2)

From the preparative HPLC separation on chiral phase described under Example 301, 40 mg (88% of theory) of enantiomer 2 were obtained (> 99% ee, chiral analytical HPLC).

Ή-NMR (400 MHz, DMSO-d _6, δ / ppm): 6:51 (s, 1H), 4:33 (s, 2H), 3.97 (td, 2H), 3.60 (t, 2H), 3:27 to 3:15 (m , 4H), 3.23 (s, 3H), 2.37 (s, 3H), 2.34-2.27 (m, 1H), 1.68-1.55 (m, 1H), 1.29-1.16 (m, 1H), 1.07-0.94 (m , 1H), 0.99 (t, 3H), 0.88-0.74 (m, 2H).

Chiral analytical HPLC [column: Daicel Chiralpak OX-3, 3 μm, 50 mm × 4.6 mm; Eluent: ethanol; Flow: 1 ml / min; Temperature: 50 ° C; Detection: 220 μm]: R _t = 3.02 min.

Example 303 3- (2-Ethylcyclopropyl) -1- (2-methoxyethyl) -5-methyl-6 - [(5-oxo-4,5-dihydro-1H-1,2,4-triazol-1-yl) - methyl] thieno [2,3-d] pyrimidine-2,4 (1H, 3H) -dione (trans-racemate)

340 mg (0.652 mmol, 95% purity) of the compound from Example 452A were dissolved in a mixture of 15 ml each of methanol and trimethyl orthoformate, and 2.4 ml (9.78 mmol) of a 4 M solution of hydrogen chloride in dioxane were added at RT. After about 16 h, the reaction mixture was concentrated to half the original volume, whereupon a solid parted. The precipitate was completed by the addition of 15 ml of diethyl ether. After stirring for 10 min at RT, the solid was filtered off with suction and dried in vacuo. It was then stirred in a mixture of 5 ml of DMSO and 10 ml of water at 60 ° C. for 30 min. After renewed suction and drying in a high vacuum, 175 mg (66% of theory) of the title compound were obtained. 'H-NMR (500 MHz, DMSO-de, δ / ρρηι): 11.58 (broad, 1H), 7.82 (s, 1H), 4.91 (s, 2H), 4.03-3.89 (m, 2H), 3.59 (br t, 2H), 3.22 (s, 3H), 2.43 (s, 3H), 2.30 (dt, 1H), 1.62 (dquin, 1H), 1.22 (dquin, 1H), 0.99 (br, t, 4H), 0.88-0.72 (m, 2H).

LC / MS (Method 2, ESIpos): R _t = 0.76 min, m / z = 406 [M + H] ⁺ . Example 304

3- (2-Ethylcyclopropyl) -1- (2-methoxyethyl) -5-methyl-6 - [(5-oxo-4,5-dihydro-1H-1,2,4-triazol-1-yl) -methyl ] thieno [2,3-d] pyrimidine-2,4 (1H, 3H) -dione (iran-y-enantiomer 1)

168 mg of the racemic compound from Ex. 303 were dissolved in a mixture of 8 ml of dichloromethane and 2 ml of ethanol and separated into 20 portions by preparative HPLC on a chiral phase into the enantiomers [column: Daicel Chiralcel OX-H, 5 μιη, 250 mm x 20 mm; Eluent: n-heptane / ethanol 60:40; Flow: 15 ml / min; Temperature: 40 ° C; Detection: 210 nm]. Evaporation of the product fractions and drying of the solid in a high vacuum gave 73 mg (86% of theory) of enantiomer 1 (> 99% ee, chiral analytical HPLC). Ή-NMR (500 MHz, DMSO-d ₆ , δ / ppm): 11.58 (br.s, 1H), 7.83 (s, 1H), 4.91 (s, 2H), 4.02-3.90 (m, 2H), 3.59 (t, 2H), 3.22 (s, 3H), 2.43 (s, 3H), 2.30 (dt, 1H), 1.68-1.55 (m, 1H), 1.22 (dquin, 1H), 1.04-0.94 (m, 1H ), 0.99 (t, 3H), 0.87-0.73 (m, 2H).

Chiral analytical HPLC [column: Daicel Chiralpak OX-3, 3 μm, 50 mm × 4.6 mm; Eluent: ethanol; Flow: 1 ml / min; Temperature: 50 ° C; Detection: 220 nm]: R _t = 2.69 min. Example 305

3- (2-Ethylcyclopropyl) -1- (2-methoxyethyl) -5-methyl-6 - [(5-oxo-4,5-dihydro-1H-1,2,4-triazol-1-yl) -methyl ] thieno [2,3-d] pyrimidine-2,4 (1H, 3H) -dione (iran-y-enantiomer 2)

From the preparative HPLC separation on chiral phase described in Example 304, 74 mg (88% of theory) of enantiomer 2 were obtained (> 99% ee, chiral analytical HPLC).

Ή-NMR (500 MHz, DMSO-d ₆ , δ / ppm): 11.58 (br.s, 1H), 7.83 (s, 1H), 4.91 (s, 2H), 4.02-3.89 (m, 2H), 3.59 (t, 2H), 3.22 (s, 3H), 2.43 (s, 3H), 2.30 (dt, 1H), 1.69-1.55 (m, 1H), 1.22 (dquin, 1H), 1.04-0.93 (m, 1H ), 0.99 (t, 3H), 0.86-0.73 (m, 2H).

Chiral analytical HPLC [column: Daicel Chiralpak OX-3, 3 μm, 50 mm × 4.6 mm; Eluent: ethanol; Flow: 1 ml / min; Temperature: 50 ° C; Detection: 220 μm]: R _t = 4.71 min.

Example 306 3- (2-Methoxycyclopropyl) -1- (2-methoxyethyl) -5-methyl-6 - [(2-oxoimidazolidin-1-yl) methyl] thieno [2,3-d] pyrimidine-2,4 (1H, 3H) -dione (trans-racemate)

Analogously to the process described under Example 3, from 509 mg (0.932 mmol, 70% purity) of the compound from Ex. 386A and 196 mg (1.21 mmol) of CDI, 196 mg (51% of theory) of the title compound were prepared ,

'H-NMR (500 MHz, DMSO-de, δ / ppm): 6.51 (s, 1H), 4.34 (s, 2H), 4.08-3.90 (m, 2H), 3.66-3.55 (m, 2H), 3.41 (ddd, 1H), 3.30-3.16 (m, 10H), 2.60 (dt, 1H), 2.37 (s, 3H), 1.31 (td, 1H), 0.91 (ddd, 1H).

LC / MS (Method 2, ESIpos): R _t = 0.59 min, m / z = 409 [M + H] ⁺ . Example 307

3- (2-Methoxycyclopropyl) -1- (2-methoxyethyl) -5-methyl-6 - [(2-oxoimidazolidin-1-yl) methyl] thieno [2,3-d] pyrimidine-2,4 (1H , 3H) -dione (iroro-enantiomer 1)

191 mg of the racemic compound from Ex. 306 were dissolved in a mixture of 6 ml of acetonitrile and 2 ml of ethanol and separated into 32 portions by preparative HPLC on a chiral phase into the enantiomers [column: Daicel Chiralcel OD-H, 5 μιη, 250 mm x 20 mm; Eluent: n-heptane / ethanol 20:80; Flow: 15 ml / min; Temperature: 40 ° C; Detection: 210 nm]. Evaporation of the product fractions and drying of the solid in a high vacuum gave 84 mg (87% of theory) of enantiomer 1 (> 99% ee, chiral analytical HPLC).

Ή-NMR (500 MHz, DMSO-d _6, δ / ppm): 6:51 (s, 1H), 4:34 (s, 2H), 4.08-3.90 (m, 2H), 3.66-3.55 (m, 2H), 3:41 (ddd, 1H), 3.28-3.17 (m, 10H), 2.60 (dt, 1H), 2.37 (s, 3H), 1.31 (td, 1H), 0.90 (ddd, 1H).

Chiral analytical HPLC [column: Phenomenex cellulose 2, 3 μm, 50 mm × 4.6 mm; Eluent: isohexane / ethanol 1: 1; Flow: 1 ml / min; Temperature: 50 ° C; Detection: 220 nm]: R _t = 1.95 min.

Example 308

3- (2-Methoxycyclopropyl) -1- (2-methoxyethyl) -5-methyl-6 - [(2-oxoimidazolidin-1-yl) methyl] thieno [2,3-d] pyrimidine-2,4 (1H , 3H) -dione (iroro-enantiomer 2)

From the preparative HPLC separation on chiral phase described under Example 307, 83 mg (86% of theory) of enantiomer 2 were obtained (>99%> ee, chiral analytical HPLC). Ή-ΝΜΡν (600 MHz, DMSO-d ₆ , δ / ρρηι): 6.49 (s, 1H), 4.33 (s, 2H), 4.07-3.90 (m, 2H), 3.65-3.57 (m, 2H), 3.44 -3.38 (m, 1H), 3.28-3.18 (m, 10H), 2.60 (dt, 1H), 2.37 (s, 3H), 1.35-1.26 (m, 1H), 0.91 (ddd, 1H).

Chiral analytical HPLC [column: Phenomenex cellulose 2, 3 μm, 50 mm × 4.6 mm; Eluent: isohexane / ethanol 1: 1; Flow: 1 ml / min; Temperature: 50 ° C; Detection: 220 nm]: R _t = 3.26 min.

Example 309

3- (2-Methoxycyclopropyl) -1- (2-methoxyethyl) -5-methyl-6 - [(5-oxo-4,5-dihydro-1H-1,2,4-triazol-1-yl) methyl] thieno [2,3-d] pyrimidine-2,4 (1H, 3H) -dione (trans-racemate)

Analogously to the process described under Example 195, from 275 mg (0.553 mmol) of the compound from Ex. 453A, 180 mg (79% of theory) of the title compound were obtained.

Ή NMR (600 MHz, DMSO-d ₆ , δ / ppm): 8.91 (broad, 1H), 7.83 (s, 1H), 4.92 (s, 2H), 4.07-3.89 (m, 2H), 3.65-3.55 (m, 2H), 3.41 (td, 1H), 3.22 (2 s, 6H), 2.61 (dt, 1H), 2.42 (s, 3H), 1.30 (td, 1H), 0.90 (ddd, 1H). LC / MS (Method 1, ESIpos): R _t = 0.95 min, m / z = 408.13 [M + H] ⁺ . Example 310

3- (2-Methoxycyclopropyl) -1- (2-methoxyethyl) -5-methyl-6 - [(5-oxo-4,5-dihydro-1H-1,2,4-triazol-1-yl) methyl] thieno [2,3-d] pyrimidine-2,4 (1H, 3H) -dione (iran-y-enantiomer 1)

170 mg of the racemic compound from Ex. 309 were dissolved in 7.5 ml of acetonitrile / ethanol (1: 1) and separated in 75 portions by preparative HPLC on a chiral phase into the enantiomers [column: Daicel Chiralcel OX-H, 5 μm, 250 mm x 20 mm; Eluent: n-heptane / ethanol 30:70; Flow: 15 ml / min; Temperature: 40 ° C; Detection: 210 um]. Evaporation of the product fractions and drying of the solid in a high vacuum gave 60 mg (70% of theory) of enantiomer 1 (>99%> ee, chiral analytical HPLC).

Ή-ΝΜΡ (500 MHz, DMSO-d ₆ , δ / ppm): 11.56 (broad, 1H), 7.83 (s, 1H), 4.92 (s, 2H), 4.07-3.89 (m, 2H), 3.64-3.56 (m, 2H), 3.41 (ddd, 1H), 3.22 (2 s, 6H), 2.61 (dt, 1H), 2.42 (s, 3H), 1.30 (td, 1H), 0.90 (ddd, 1H). Chiral analytical HPLC [column: Daicel Chiralpak OX-3, 3 μm, 50 mm × 4.6 mm; Eluent: isohexane / ethanol 1: 1; Flow: 1 ml / min; Temperature: 50 ° C; Detection: 220 nm]: R _t = 4.55 min.

Example 311

3- (2-Methoxycyclopropyl) -1- (2-methoxyethyl) -5-methyl-6 - [(5-oxo-4,5-dihydro-1H-1,2,4-triazol-1-yl) methyl] thieno [2,3-d] pyrimidine-2,4 (1H, 3H) -dione (iran-y-enantiomer 2)

From the preparative HPLC separation on chiral phase described in Example 310, 48 mg (56% of theory) of enantiomer 2 were obtained (> 99%> ee, chiral analytical HPLC). The product was still present as a methanolic solution after HPLC chromatography on a hydrogen carbonate cartridge, then evaporated and dried in vacuo.

Ή-NMR (500 MHz, DMSO-d _6, δ / ppm): 7.81 (s, 1H), 4.91 (s, 2H), 4.07-3.89 (m, 2H), 3.65-3.56 (m, 2H), 3:44 -3.39 (m, 1H, partially covered by the water signal), 3.22 (2 s, 6H), 2.61 (dt, 1H), 2.42 (s, 3H), 1.30 (td, 1H), 0.90 (ddd, 1H) ,

Chiral analytical HPLC [column: Daicel Chiralpak OX-3, 3 μm, 50 mm × 4.6 mm; Eluent: isohexane / ethanol 1: 1; Flow: 1 ml / min; Temperature: 50 ° C; Detection: 220 nm]: R _t = 6.92 min. Example 312

3-Cyclobutyl-5-methyl-6 - [(5-oxo-2,5-dihydro-1H-pyrazol-1-yl) methyl] -1- (3,3,3-trifluoropropyl) thieno [2,3 -d] pyrimidine-2,4 (lH, 3H) -dione

200 mg (0.193 mmol, 50% purity) of the compound from Example 457A, 68 mg (82% of theory) of the title compound, were prepared analogously to the process described under Example 200.

Ή-NMR (400 MHz, DMSO-de, δ / ppm): 11.34 (broad, 1H), 7.15 (s, 1H), 5.30 (s, 1H), 5.20 (quin, 1H), 5.14 (s, 2H) , 4.03 (t, 2H), 2.89-2.64 (m, 4H), 2.46 (s, 3H), 2.22-2.08 (m, 2H), 1.88-1.62 (m, 2H). LC / MS (method 2, ESIneg): R _t = 0.91 min, m / z = 427 [MH] -. Example 313

3- (3,3-difluorocyclobutyl) -5-methyl-6 - [(5-oxo-2,5-dihydro-lH-pyrazol-l-yl) methyl] -l- (3,3,3-tri- fluoropropyl) thieno [2,3-d] pyrimidine-2,4 (lH, 3H) -dione

200 mg (66% of theory) of the title compound were prepared from 316 mg (0.518 mmol) of the compound from Example 458A analogously to the process described under Example 200. 'H-NMR (400 MHz, DMSO-de, δ / ρρηι): 11.29 (broad, 1H), 7.15 (s, 1H), 5.30 (s, 1H), 5.20-5.06 (m, 1H), 5.15 (s , 2H), 4.04 (t, 2H), 3.53-3.37 (m, 2H), 2.93-2.78 (m, 2H), 2.78-2.65 (m, 2H), 2.47 (s, 3H).

LC / MS (Method 1, ESIneg): R _t = 1.68 min, m / z = 463.09 [MH]. Example 314

3- (3,3-dimethylcyclobutyl) -5-methyl-6 - [(5-oxo-2,5-dihydro-lH-pyrazol-l-yl) methyl] -l- (3,3,3-tri- fluoropropyl) thieno [2,3-d] pyrimidine-2,4 (lH, 3H) -dione

Analogously to the process described under Example 200, from 270 mg (0.448 mmol) of the compound from Ex. 459A 123 mg (60% of theory) of the title compound were prepared. The reaction time was in this case only 5 min.

'H-NMR (400 MHz, DMSO-de, δ / ppm): 11.16 (br.s, 1H), 7.15 (br.s, 1H), 5.31 (d, 1H), 5.20 (quin, 1H), 5.15 (s, 2H), 4.03 (t, 2H), 2.80-2.61 (m, 4H), 2.46 (s, 3H), 2.01-1.89 (m, 2H), 1.18 (s, 6H). LC / MS (Method 2, ES Ineg): R _t = 1.03 min, m / z = 455 [MH] -. Example 315 1- (2-Methoxyethyl) -5-methyl-3 - [(S, 2S) -2-methylcyclopropyl] -6 - [(2-oxoimidazolidin-1-yl) methyl] thieno [2,3-d ] pyrimidine-2,4 (lH, 3H) -dione

A suspension of 273 g (621 mmol) of the compound from Ex. 377A in 5.7 liters of THF was admixed with 303 ml (2.17 mol) of triethylamine and 151 g (932 mmol) of CDI. The reaction mixture was stirred at RT for 55 h. Then the volatiles were removed on a rotary evaporator. The remaining residue was taken up in 12 liters of ethyl acetate and washed twice with 4 liters of 2 M hydrochloric acid. The combined aqueous phases were extracted twice with 4 liters of ethyl acetate each time. All ethyl acetate phases were combined and washed successively with 4 liters each of aqueous sodium chloride solution (10%) and aqueous sodium bicarbonate solution (10%). It was dried over anhydrous sodium sulfate, filtered and evaporated. The remaining solid was tert with a little. Added butyl-methyl ether and stirred for 1 h at RT. Then the solid was filtered off with suction and dried in vacuo at 50 ° C. There were obtained 167 g (68% of theory) of the title compound which is identical to the compound from Ex.

'H-NMR (400 MHz, DMSO-de, δ / ppm): 6.51 (s, 1H), 4.33 (s, 2H), 4.05-3.90 (m, 2H), 3.60 (t, 2H), 3.28-3.15 (m, 4H), 3.23 (s, 3H), 2.37 (s, 3H), 2.27-2.20 (m, 1H), 1.15 (d, 3H), 1.05-0.92 (m, 1H), 0.87-0.78 (m , 2H). LC / MS (Method 6, ESIpos): R _t = 0.99 min, m / z = 393 [M + H] ⁺ .

Crystallization: 6.75 g of the title compound were heated to reflux in a mixture of 135 ml of water and 15 ml of ethanol, with the solid just completely dissolving. It was hot filtered through a pleated filter. The filtrate was reheated to reflux for 30 minutes. Then, the heating bath was controlled down to 80 ° C, and it was stirred for 3 h at this temperature. During this time, part of the product slowly crystallized. Then, the heating bath was again raised to 90 ° C, and the suspension was stirred for 1 h at this temperature. Subsequently, the temperature of the heating bath was gradually reduced, and it was stirred for the following periods at the indicated temperatures: 15 h 80 ° C-> 75 min 70 ° C -> 75 min 60 ° C -> 75 min 50 ° C -> 75 min 40 ° C -> 60 min 30 ° C -> 60 min RT. Thereafter, the product was filtered off, washed with 15 ml of water / ethanol (9: 1) and dried under high vacuum at RT. There were obtained 5.83 g (86% of theory) of the title compound in crystalline form.

'H-NMR (400 MHz, DMSO-de, δ / ppm): 6.51 (s, 1H), 4.33 (s, 2H), 4.05-3.89 (m, 2H), 3.60 (t, 2H), 3.28-3.15 (m, 4H), 3.23 (s, 3H), 2.37 (s, 3H), 2.27-2.20 (m, 1H), 1.15 (d, 3H), 1.05-0.93 (m, 1H), 0.87-0.78 (m , 2H).

LC / MS (Method 2, ESIpos): R _t = 0.73 min, m / z = 393 [M + H] ⁺ . Chiral analytical HPLC [column: Daicel Chiralpak AY-3, 3 μm, 50 mm × 4.6 mm; Eluent: isohexane / ethanol 1: 1; Flow: 1 ml / min; Temperature: RT; Detection: 220 μm]: R _t = 2.13 min, ee = 99.5%.

Specific optical rotation: [O,] D ²⁰ = + 46.7 ° -ml-dm ^{~ 1} -g ^{~ 1} (chloroform). Melting point: 167 ° C. Example 316 1-Ethyl-5-methyl-3 - [(7S, 2S) -2-methylcyclopropyl] -6 - [(5-oxo-4,5-dihydro-1H-1, 2,4-triazole-1-one yl) - methyl] thieno [2,3-d] pyrimidine-2,4 (1H, 3H) -dione

Analogously to the process described under Ex. 220, from 287 mg (0.553 mmol, 87% purity) of the compound from Ex. 515A and 10 ml of trimethyl orthoformate were added 141 mg (70%) d. Th.) Of the title compound.

Ή-NMR (500 MHz, DMSO-de, δ / ppm): 11.59 (br.s, 1H), 7.83 (s, 1H), 4.92 (s, 2H), 3.91-3.78 (m, 2H), 2.44 ( s, 3H), 2.26-2.19 (m, 1H), 1.20 (t, 3H), 1.14 (d, 3H), 1.03-0.92 (m, 1H), 0.87-0.77 (m, 2H).

LC / MS (Method 1, ESIpos): R _t = 1.23 min, m / z = 362.13 [M + H] ⁺ . Example 317

5-Methyl-3 - [(7S, 2S) -2-methylcyclopropyl] -6 - [(5-oxo-4,5-dihydro-1H-l, 2,4-triazol-1-yl) methyl] -1 -propylthieno [2,3-d] pyrimidine-2,4 (lH, 3H) -dione

Analogously to the process described under Ex. 220, 190 mg (82% of theory) of the title compound were prepared from 323 mg (0.611 mmol, 88% purity) of the compound from Example 516A and 14 ml of trimethyl orthoformate 190 mg (82% of theory).

'H-NMR (500 MHz, DMSO-de, δ / ppm): 11.59 (br.s, 1H), 7.82 (s, 1H), 4.92 (s, 2H), 3.84-3.69 (m, 2H), 2.44 (s, 3H), 2.26-2.19 (m, 1H), 1.66 (sec, 2H), 1.14 (d, 3H), 1.02-0.93 (m, 1H), 0.89 (t, 3H), 0.84-0.78 (m , 2H).

LC / MS (Method 1, ESIpos): R _t = 1.38 min, m / z = 376.14 [M + H] ⁺ .

Example 318 1-Butyl-5-methyl-3 - [(7S, 2S) -2-methylcyclopropyl] -6 - [(5-oxo-4,5-dihydro-1H-1, 2,4-triazole-1-one yl) - methyl] thieno [2,3-d] pyrimidine-2,4 (1H, 3H) -dione

Analogously to the process described under Ex. 220, 199 mg (67% of theory) of the title compound were prepared from 386 mg (0.757 mmol, 94% purity) of the compound from Ex. 517A and 15 ml of trimethyl orthoformate 199 mg (67% of theory). Ή-NMR (500 MHz, DMSO-d ₆ , δ / ppm): 11.58 (br.s, 1H), 7.83 (s, 1H), 4.92 (s, 2H), 3.87-3.74 (m, 2H), 2.43 (s, 3H), 2.26-2.19 (m, 1H), 1.61 (quin, 2H), 1.32 (sec, 2H), 1.14 (d, 3H), 1.02-0.93 (m, 1H), 0.90 (t, 3H ), 0.81 (dd, 2H).

LC / MS (Method 2, ESIpos): R _t = 0.85 min, m / z = 390 [M + H]

Example 319 1- (2-Fluoroethyl) -5-methyl-3 - [(7S, 2S) -2-methylcyclopropyl] -6 - [(5-oxo-4,5-dihydro-1H-1, 2,4 -dione triazol-l-yl) methyl] thieno [2,3-d] pyrimidine-2,4 (lH, 3H)

Analogously to the process described under Ex. 220, from 465 mg (0.792 mmol, 80% purity) of the compound from Ex. 518A and 20 ml of trimethyl orthoformate 137 mg (45% of theory) of the title compound were prepared. The product was additionally purified here by preparative HPLC by stirring in acetonitrile.

'H-NMR (500 MHz, DMSO-de, δ / ppm): 11.61 (br.s, 1H), 7.83 (s, 1H), 4.92 (s, 2H), 4.70 (dt, 2H), 4.22-4.04 (m, 2H), 2.44 (s, 3H), 2.24 (dt, 1H), 1.15 (d, 3H), 1.05-0.95 (m, 1H), 0.89-0.79 (m, 2H).

LC / MS (Method 1, ESIpos): R _t = 1.21 min, m / z = 380.12 [M + H] ⁺ .

Example 320 1- (2,2-Difluoroethyl) -5-methyl-3 - [(7S, 2S) -2-methylcyclopropyl] -6 - [(5-oxo-4,5-dihydro-1H-1, 2, 4-triazol-1-yl) methyl] thieno [2,3-d] pyrimidine-2,4 (1H, 3H) -dione

Analogously to the process described under Ex. 220, from 275 mg (0.367 mmol, 65% purity) of the compound from Ex. 519A and 10 ml of trimethyl orthoformate 76 mg (52% of theory) of the title compound were prepared.

'H-NMR (500 MHz, DMSO-de, δ / ppm): 11.60 (br.s, 1H), 7.83 (s, 1H), 6.31 (tt, 1H), 4.93 (s, 2H), 4.36-4.16 (m, 2H), 2.44 (s, 3H), 2.29-2.22 (m, 1H), 1.15 (d, 3H), 1.06-0.95 (m, 1H), 0.90-0.79 (m, 2H).

LC / MS (Method 1, ESIpos): R _t = 1.31 min, m / z = 398.11 [M + H] Example 321

5-Methyl-3 - [(/ S, 2S) -2-methylcycloprop

l- (2,2,2-trifluoroethyl) thieno [2,3-d] pyrimidine-2,4 (lH, 3H) -dione

Analogously to the process described under Ex. 220, 55 mg (38% of theory) of the title compound were prepared from 250 mg (0.347 mmol, 70% purity) of the compound of Ex. 520A and 10 ml of trimethyl orthoformate 55 mg (38% of theory).

Ή-NMR (500 MHz, DMSO-de, δ / ppm): 11.61 (br.s, 1H), 7.84 (s, 1H), 4.95 (s, 2H), 4.85-4.68 (m, 2H), 2.45 ( s, 3H), 2.31-2.25 (m, 1H), 1.15 (d, 3H), 1.04-0.95 (m, 1H), 0.88-0.80 (m, 2H). LC / MS (Method 1, ESIpos): R _t = 1.44 min, m / z = 416.10 [M + H] ⁺ .

Example 322 1- (3-Fluoropropyl) -5-methyl-3 - [(7S, 2S) -2-methylcyclopropyl] -6 - [(5-oxo-4,5-dihydro-1H-1, 2,4 -dione triazol-l-yl) methyl] thieno [2,3-d] pyrimidine-2,4 (lH, 3H)

Analogously to the process described under Ex. 220, 182 mg (78% of theory) of the title compound were prepared from 285 mg (0.589 mmol) of the compound from Example 521 A and 12 ml of trimethyl orthoformate 182 mg.

'H-NMR (500 MHz, DMSO-de, δ / ppm): 11.60 (br.s, 1H), 7.83 (s, 1H), 4.93 (s, 2H), 4.52 (dt, 2H), 4.01-3.85 (m, 2H), 2.44 (s, 3H), 2.27-2.19 (m, 1H), 2.11-1.94 (m, 2H), 1.15 (d, 3H), 1.04-0.93 (m, 1H), 0.87-0.77 (m, 2H). LC / MS (Method 1, ESIpos): R _t = 1.31 min, m / z = 394.13 [M + H] ⁺ . Example 323

5-Methyl-3 - [(7S, 2S) -2-methylcyclopropyl] -6 - [(5-oxo-4,5-dihydro-1H-l, 2,4-triazol-1-yl) methyl] -1 - (3,3,3-trifluoropropyl) thieno [2,3-d] pyrimidine-2,4 (lH, 3H) -dione

Analogously to the process described under Ex. 220, from 172 mg (70% of theory) of the title compound were prepared from 316 mg (0.572 mmol, 94% purity) of the compound of Example 522A and 12 ml of trimethyl orthoformate.

'H-NMR (500 MHz, DMSO-de, δ / ppm): 11.59 (br.s, 1H), 7.83 (s, 1H), 4.94 (s, 2H), 4.13-3.94 (m, 2H), 2.72 (qt, 2H), 2.44 (s, 3H), 2.27-2.20 (m, 1H), 1.15 (d, 3H), 1.03-0.93 (m, 1H), 0.87-0.77 (m, 2H).

LC / MS (Method 2, ESIpos): R _t = 0.82 min, m / z = 430 [M + H] ⁺ . Example 324

5-Methyl-3 - [(7S, 2S) -2-methylcyclopropyl] -6 - [(5-oxo-4,5-dihydro-1H-l, 2,4-triazol-1-yl) methyl] -1 - (4,4,4-trifluorobutyl) thieno [2,3-d] pyrimidine-2,4 (lH, 3H) -dione

Analogously to the process described under Ex. 220, 196 mg (84% of theory) of the title compound were prepared from 310 mg (0.523 mmol, 90% purity) of the compound from Example 523 A and 13 ml of trimethyl orthoformate. 'H-NMR (500 MHz, DMSO-de, δ / ρρηι): 11.58 (s, 1H), 7.83 (d, 1H), 4.93 (s, 2H), 3.97-3.82 (m, 2H), 2.47-2.33 (m, 2H), 2.44 (s, 3H), 2.25-2.18 (m, 1H), 1.86 (quin, 2H), 1.14 (d, 3H), 1.03-0.93 (m, 1H), 0.87-0.76 (m , 2H).

LC / MS (Method 1, ESIpos): R _t = 1.58 min, m / z = 444.13 [M + H] ⁺ . Example 325 1- (2-Methoxyethyl) -5-methyl-3 - [(7S, 2S) -2-methylcyclopropyl] -6 - [(5-oxo-4,5-dihydro-1H-1, 2,4- -dione triazol-l-yl) methyl] thieno [2,3-d] pyrimidine-2,4 (lH, 3H)

Analogously to the process described under Ex. 220, 157 mg (81% of theory) of the title compound were prepared from 243 mg (0.492 mmol, 97% purity) of the compound from Example 524A and 12 ml of trimethyl orthoformate 157 mg.

Ή-NMR (500 MHz, DMSO-de, δ / ppm): 11.58 (br.s, 1H), 7.83 (s, 1H), 4.91 (s, 2H), 4.02-3.89 (m, 2H), 3.59 ( t, 2H), 3.22 (s, 3H), 2.43 (s, 3H), 2.23 (dt, 1H), 1.14 (d, 3H), 1.04-0.92 (m, 1H), 0.86-0.78 (m, 2H) , LC / MS (Method 1, ESIpos): R _t = 1.20 min, m / z = 392.14 [M + H] ⁺ . Example 326 l - [(2,2-Difluorocyclopropyl) methyl] -5-methyl-3 - [(S, 2S) -2-methylcyclopropyl] -6 - [(5-oxo-4,5-dihydro-1H -l, 2,4-triazol-l-yl) methyl] thieno [2,3-d] pyrimidine-2,4 (lH, 3H) -dione

(Mixture of diastereomers)

Analogously to the process described under Ex. 220, 188 mg (70% of theory) of the title compound were prepared from 385 mg (0.630 mmol, 84% purity) of the compound of Ex. 525A and 15 ml of trimethyl orthoformate 188 mg.

'H-NMR (500 MHz, DMSO-de, δ / ppm): 11.59 (br.s, 1H), 7.83 (s, 1H), 4.93 (s, 2H), 4.07 (tdd, 1H), 3.94-3.80 (m, 1H), 2.44 (s, 3H), 2.27-2.21 (m, 1H), 2.21-2.09 (m, 1H), 1.74-1.62 (m, 1H), 1.49-1.38 (m, 1H), 1.15 (d, 3H), 1.04-0.94 (m, 1H), 0.88-0.77 (m, 2H).

LC / MS (Method 1, ESIpos): R _t = 1.45 min, m / z = 424.12 [M + H]

Example 327 1- (Cyclobutylmethyl) -5-methyl-3 - [(7S, 2S) -2-methylcyclopropyl] -6 - [(5-oxo-4,5-dihydro-1H-l, 2,4-triazole) l-yl) methyl] thieno [2,3-d] pyrimidine-2,4 (lH, 3H) -dione

Analogously to the process described in Example 220, from 270 mg (0.494 mmol, 90%> purity) of the compound from Example 526A and 12 ml of trimethyl orthoformate 152 mg (76% of theory) of the title compound were prepared. 'H-NMR (500 MHz, DMSO-d _6, δ / ppm): 11:59 (s, 1H), 7.83 (d, 1H), 4.91 (s, 2H), 3.95-3.79 (m, 2H), 2.78- 2.67 (m, 1H), 2.43 (s, 3H), 2.27-2.19 (m, 1H), 2.03-1.88 (m, 2H), 1.86-1.73 (m, 4H), 1.14 (d, 3H), 1.01- 0.91 (m, 1H), 0.86-0.75 (m, 2H).

LC / MS (Method 1, ESIpos): R _t = 1.61 min, m / z = 402.16 [M + H] ⁺ .

Example 328 l - [(3,3-Difluorocyclobutyl) methyl] -5-methyl-3 - [(7S, 2S) -2-methylcyclopropyl] -6 - [(5-oxo-4,5-dihydro-1H -l, 2,4-triazol-l-yl) methyl] thieno [2,3-d] pyrimidine-2,4 (lH, 3H) -dione

285 mg (0.540 mmol) of the compound from Ex. 527A were dissolved in a mixture of 12.5 ml of methanol and trimethyl orthoformate and 2 ml (8.10 mmol) of a 4 M solution of hydrogen chloride in dioxane were added at RT. After the reaction mixture had been stirred at RT for about 16 h, it was concentrated to dryness and then purified by preparative HPLC (Method 13). Evaporation of the product fraction and drying under high vacuum gave 172 mg (73% of theory) of the title compound.

Ή-NMR (500 MHz, DMSO-de, δ / ppm): 11.59 (br.s, 1H), 7.83 (s, 1H), 4.92 (s, 2H), 4.08-3.90 (m, 2H), 2.73- 2.62 (m, 2H), 2.61 -2.54 (m, 1H), 2.53-2.45 (m, 2H, partially covered by the DMSO signal), 2.43 (s, 3H), 2.26-2.19 (m, 1H), 1.14 ( d, 3H), 1.02-0.92 (m, 1H), 0.85-0.77 (m, 2H).

LC / MS (Method 1, ESIpos): R _t = 1.52 min, m / z = 438.14 [M + H] ⁺ .

Example 329

5-Methyl-3 - [(7S, 2S) -2-methylcyclopropyl] -6 - [(5-oxo-4,5-dihydro-1H-l, 2,4-triazol-1-yl) methyl] -1 - [(2R) -tetrahydrofuran-2-ylmethyl] thieno [2,3-d] pyrimidine-2,4 (lH, 3H) -dione

Analogously to the process described under Ex. 220, 36 mg (39% of theory) of the title compound were prepared from 172 mg (0.220 mmol, 65% purity) of the compound of Example 528A and 10 ml of trimethyl orthoformate.

'H-NMR (500 MHz, DMSO-de, δ / ppm): 11.59 (br.s, 1H), 7.83 (s, 1H), 4.91 (s, 2H), 4.23-4.12 (m, 1H), 4.02 (dd, 1H), 3.78-3.69 (m, 1H), 3.67-3.56 (m, 2H), 2.43 (s, 3H), 2.28-2.20 (m, 1H), 2.02- 1.92 (m, 1H), 1.92-1.75 (m, 2H), 1.64 (ddt, 1H), 1.15 (d, 3H), 1.04-0.92 (m, 1H), 0.87-0.78 (m, 2H).

LC / MS (Method 1, ESIpos): R _t = 1.29 min, m / z = 418.15 [M + H] ⁺ . Example 330 l - [(2,2-Difluorocyclopropyl) methyl] -5-methyl-3 - [(S, 2S) -2-methylcyclopropyl] -6 - [(5-oxo-4,5-dihydro-1H -l, 2,4-triazol-1-yl) methyl] thieno [2,3-d] pyrimidine-2,4 (1H, 3H) -dione {diastereomer 1)

179 mg of the diastereomer mixture from Example 326 were dissolved in a mixture of 5 ml of acetonitrile and 2 ml of ethanol and separated in 47 portions via preparative HPLC on a chiral phase into the diastereomers [column: Daicel Chiralpak AS-H, 5 μm, 250 mm x 20 mm; Eluent: n-heptane / ethanol 20:80; Flow: 15 ml / min; Temperature: 50 ° C; Detection: 210 um]. After evaporation of the product fractions and drying of the solid in a high vacuum, 88 mg (98% of theory) of diastereomer 1 were obtained (> 99%> de, chiral analytical HPLC).

Ή-ΝΜΡ (500 MHz, DMSO-d ₆ , δ / ppm): 11.58 (br s, 1H), 7.83 (s, 1H), 4.93 (s, 2H), 4.06 (ddd, 1H), 3.88 (dd , 1H), 2.44 (s, 3H), 2.28-2.22 (m, 1H), 2.21-2.10 (m, 1H), 1.74-1.63 (m, 1H), 1.49- 1.38 (m, 1H), 1.15 (i.e. , 3H), 1.03-0.94 (m, 1H), 0.88-0.77 (m, 2H).

Chiral analytical HPLC [column: Daicel Chiralpak AS-3, 3 μm, 50 mm × 4.6 mm; Eluent: ethanol; Flow: 1 ml / min; Temperature: 50 ° C; Detection: 220 μm]: R _t = 1.12 min.

Example 331 l - [(2,2-Difluorocyclopropyl) methyl] -5-methyl-3 - [(7S, 2S) -2-methylcyclopropyl] -6 - [(5-oxo-4,5-dihydro-1H -l, 2,4-triazol-1-yl) methyl] thieno [2,3-d] pyrimidine-2,4 (1H, 3H) -dione {diastereomer 2)

From the diastereomer separation described in Example 330, 83 mg (92% of theory) of diastereomer 2 were obtained (99% de, chiral analytical HPLC).

Ή-ΝΜΡ (500 MHz, DMSO-d ₆ , δ / ppm): 11.56 (brs s, 1H), 7.83 (s, 1H), 4.93 (s, 2H), 4.09 (ddd, 1H), 3.86 (dd , 1H), 2.44 (s, 3H), 2.27-2.22 (m, 1H), 2.21-2.10 (m, 1H), 1.73-1.62 (m, 1H), 1.49- 1.39 (m, 1H), 1.15 (i.e. , 3H), 1.04-0.94 (m, 1H), 0.87-0.78 (m, 2H).

Chiral analytical HPLC [column: Daicel Chiralpak AS-3, 3 μm, 50 mm × 4.6 mm; Eluent: ethanol; Flow: 1 ml / min; Temperature: 50 ° C; Detection: 220 μm]: R _t = 2.70 min.

B. Evaluation of Pharmacological Activity

The pharmacological activity of the compounds of the invention can be demonstrated by in vitro and in vz ^'vo studies, as they are known in the art. The following application examples describe the biological activity of the compounds according to the invention without restricting the invention to these examples.

B-l. Cellular in vitro tests for the determination of A2b receptor activity and adenosine receptor selectivity

The identification of selective antagonists of the human adenosine A2b receptor and the quantification of the activity and selectivity of the compounds according to the invention was carried out with the aid of recombinant cell lines for the human adenosine receptors AI, A2a, A2b and A3. These cell lines are originally derived from a hamster ovary epithelial cell (Chinese Hamster Ovary, CHO-Kl, American Type Culture Collection, Manassas, VA 20108, USA). The cell lines for testing the activity at the AI, A2a and A2b receptors contain, in addition to the respective recombinantly expressed adenosine receptor, a reporter gene construct in which the expression of the firefly (Photinus pyralis) luciferase is under the control of a promoter, which can be activated via intracellular signaling cascades by stimulation of the receptors with the (not subtype-selective) adenosine receptor agonist NECA (5'-N-ethylcarboxamidoadenosine) [SJ Hill, J.G. Baker, S. Rhees, Curr. Opin. Pharmacol. \, 526-532 (2001)].

In the case of the A2a and A2b cell lines, it is a minimal promoter with several cAMP-responsive elements (CRE). Stimulation of the G _s -coupled A2b or A2a receptors by NECA ultimately leads, via the formation of cAMP, to CRE-dependent induction of luciferase expression, which is detected 3 hours after starting incubation with NECA with a detection solution in a suitable Luminometer is detected. To test the antagonists, the first step in a preliminary experiment is to determine the concentration of NECA which leads to the half-maximal stimulation of luciferase expression on the respective test day (ECso concentration). By co-incubation of this ECso concentration of NECA with the substances to be tested then their antagonistic effect can be determined.

The cell line for testing the Gi-linked AI receptor contains another reporter gene construct in which the expression of the firefly luciferase is under the control of a NF (nuclear factor of activated T cells) promoter. In addition to the AI receptor and the NFAT reporter gene, this cell line was also labeled with another gene coding for the promiscuous Goti6 protein [TT Amatruda, DA Steele, VZ Slepak, MI Simon, Proc. Natl. Acad. Be. USA 88, 5587-5591 (1991)], either independently or stably transfected as a fusion gene. The resulting test cells respond to stimulation of the normally Gi-linked Al receptor with an increase in intracellular calcium concentration, which then results in NFAT-dependent luciferase expression. The experimental procedure for testing the antagonists on the AI receptor corresponds to the procedure for testing with the A2a and A2b cell lines.

In the generation of the A3 receptor cell line, a co-transfection of A3 receptor and the promiscuous Gai6 protein was also performed, so that here too the stimulation of the receptor leads to an increase in the intracellular calcium concentration. This calcium increase is in the A3 receptor test but directly through the calcium-sensitive photoprotein Photina ^® [S. Bovolenta, M. Foti, S. Lohmer, S. Corazza, J. Biomol. Screen. 12, 694-704 (2007)]. After determining the ECso concentration of NECA, the substance effects are measured after 5-10 minutes of pre-incubation with substance by adding this ECso concentration in the measuring position in a suitable dispensable luminometer.

The following Table 1 lists the IC50 values from the A2b receptor assay for individual embodiments (in part as averages of several independent determinations and rounded to two significant digits, using different independent preparations of each embodiment come):

Table 1

Example No. A2b Receptor Example No. A2b Receptor

IC ₅₀ [nmol / L] IC ₅₀ [nmol / L]

1 20 12 4.2

2 81 13 4.0

3 6.9 14 3.7

4 34 15 14

5 12 16 3.0

6 12 17 4.1

7 18 18 25

8 44 19 19

9 1.5 20 130

10 1.5 21 53

11 3.3 22 280 Example No. A2b Receptor Example No. A2b Receptor IC ₅₀ [nmol / L] IC ₅₀ [nmol / L]

23 130 52 19

24 29 53 120

25 12 54 7.5

26 8.3 55 49

27 40 56 3.6

28 19 57 4.4

29 57 58 10

30 9.3 59 9.3

31 67 60 15

32 430 61 5.4

33 100 62 65

34 500 63 12

35 1.8 64 13

36 4.4 65 36

37 35 66 140

38 33 67 54

39 240 68 160

40 15 69 120

41 16 70 15

42 10 71 12

43 12 72 15

44 16 73 29

45 110 74 86

46 39 75 3.3

47 140 76 8.5

48 56 77 77

49 110 78 560

50 140 79 110

51 320 80 740 Example No. A2b Receptor Example No. A2b Receptor IC ₅₀ [nmol / L] IC ₅₀ [nmol / L]

81 39 110 0.59

82 77 111 1.7

83 130 112 1.2

84 460 113 2.0

85 310 114 1.9

86 270 115 4.3

87 140 116 4.0

88 690 117 1.3

89 1200 118 14

90 5.3 119 12

91 20 120 3.2

92 2.8 121 15

93 1.8 122 4.2

94 7.2 123 10

95 26 124 26

96 3.8 125 33

97 26 126 14

98 140 127 10

99 28 128 36

100 12 129 280

101 32 130 14

102 7.3 131 68

103 21 132 11

104 35 133 430

105 92 134 34

106 41 135 48

107 290 136 19

108 110 137 77

109 640 138 260 Example No. A2b Receptor Example No. A2b Receptor IC ₅₀ [nmol / L] IC ₅₀ [nmol / L]

139 310 168 16

140 230 169 14

141 110 170 8.6

142 460 171 17

143 880 172 36

144 10 173 83

145 23 174 2.8

146 6.2 175 18

147 48 176 4.0

148 66 177 17

149 82 178 26

150 120 179 10

151 45 180 13

152 340 181 6.7

153 220 182 27

154 23 183 70

155 56 184 6.9

156 18 185 16

157 63 186 7.9

158 180 187 19

159 200 188 100

160 200 189 40

161 130 190 28

162 730 191 18

163 1200 192 140

164 4.6 193 230

165 14 194 180

166 4.7 195 120

167 5.3 196 210 Example No. A2b Receptor Example No. A2b Receptor IC ₅₀ [nmol / L] IC ₅₀ [nmol / L]

197 120 226 1.9

198 190 227 2.9

199 130 228 5.8

200 55 229 1.2

201 53 230 1.3

202 140 231 2.3

203 160 232 0.86

204 1.8 233 11

205 7.0 234 1.9

206 6.2 235 18

207 910 236 1.2

208 10 237 4.4

209 200 238 24

210 200 239 4.7

211 1300 240 2.4

212 240 241 7.1

213 40 242 2.1

214 10 243 8.4

215 73 244 3.3

216 3.2 245 6.7

217 38 246 22

218 54 247 3.5

219 400 248 1.2

220 33 249 1.9

221 3.3 250 1.1

222 1.6 251 6.3

223 19 252 1.4

224 11 253 2.7

225 26 254 7.2 Example No. A2b Receptor Example No. A2b Receptor IC ₅₀ [nmol / L] IC ₅₀ [nmol / L]

255 6.7 284 8.6

256 5.5 285 4.1

257 6.8 286 17

258 6.4 287 2.8

259 4.1 288 47

260 82 289 35

261 15 290 270

262 1.2 291 19

263 1.1 292 150

264 16 293 12

265 1.3 294 20

266 0.96 295 120

267 2.4 296 16

268 1.5 297 120

269 2.0 298 1800

270 1.5 299 220

271 1.4 300 13

272 1.0 301 64

273 67 302 10

274 86 303 71

275 63 304 350

276 2.0 305 120

277 3.9 306 16

278 1.6 307 8.1

279 1.6 308 870

280 3.4 309 110

281 2.1 310 3900

282 4.1 311 44

283 25 312 15 Example No. A2b Receptor Example No. A2b Receptor

IC ₅₀ [nmol / L] IC ₅₀ [nmol / L]

313 93 322 14

314 49 323 3.1

315 3.8 324 5.5

316 25 325 43

317 19 326 17

318 12 327 8.5

320 13 328 4.9

321 17

B-2. Adenosine receptor binding assays

The binding properties of the test compounds to adenosine receptors were determined in binding studies with radioligands. For this purpose, membrane preparations of the human adenosine receptor subtypes were prepared from cell lines with recombinant receptor expression (CHO cells for the AI receptor, HEK293 cells for the A2a, A2b and A3 receptors). The following radioligands were used in the experiments: [ ³ H] DPCPX for the AI receptor, [ ³ H] - CGS 21680 for the A2a receptor, [ ³ H] CPX for the A2b receptor, and [ ¹²⁵ I] AB-MECA for the A3 receptor. The test substances were each tested in 8 different concentrations and 2 replicate tests per concentration. Displacement of the particular radioligand by the test compound was expressed as the percent inhibition of specific binding of the controls.

The IC ₅ o values (concentration causing a half-maximal inhibition of specific binding of the controls) and the Hill coefficient (nH) were determined by non-linear regression analysis determined using the competition curves generated from the mean values of the repeat testing and Carrying out a curve fit according to the Hill equation:

Y = D + [A-D / 1 + (0/050) ^]

(Y = specific binding, A = left asymptote of the curve D = right asymptote of the curve C = substance concentration; C50 = IC ₅ 0; nH = slope factor).

The inhibition constant (Κ;) was calculated using the Cheng-Prusoff equation: Ki = IC ₅ o / (l + L / K _D )

(L = concentration of the radioligand in the assay; K _D = receptor affinity of the radioligand for the receptor, determined with a Scatchard plot).

[References: AI Receptor: Townsend-Nicholson, A. and Schofield, P.R., J. Biol. Chem. 269: 2373-2376 (1994); A2a receptor: Luthin, D.R. et al, Mol. Pharmacol. 47: 307-313 (1995); A2b receptor: Stehle, J.H. et al, Mol. Endocrinol. 6: 384-393 (1992) and Linden et al, Mol. Pharmacol. 56: 705-713 (1999); A3 receptor: Salvatore, C A. et al, Proc. Natl. Acad. Be. U.S.A. 90: 10365-10369 (1993) and Jacobson, K.A. et al., Neuropharmacology 36: 1157-1165 (1997)].

The Kj values determined from these binding assays for representative exemplary embodiments are listed in the following Table 2 (in part as averages of several independent individual determinations and rounded to two significant digits, whereby different independent preparations of the respective embodiment may also have been used ):

Table 2

B-3. Measurement of NECA-induced IL-6 release of LL29 fibroblasts

Stimulation of fibroblasts with adenosine or the adenosine analogue 5'-N-ethylcarboxamidoadenosine (NECA) results in the release of the pro-inflammatory and pro-fibrotic cytokine IL-6, which can be prevented by inhibition of the A2b receptor.

Therefore, confluent cells of the human fibroblast cell line LL29 are treated with the test substances and stimulated with NECA (10 μΜ). After an incubation period of 24 hours, the cell supernatant is removed and human IL6 by ELISA (Quantikine ^® IL6 ELISA, R & D Systems, Minneapolis, USA) in the cell supernatant.

The following Table 3 lists IC50 values obtained in this way for inhibiting IL-6 release for representative embodiments (in part as averages from several independent determinations and rounded to two significant digits; in this case also different independent preparations of the respective embodiment can be used):

Table 3

B-4. Animal model of monocrotaline-induced pulmonary hypertension

Rat monocrotaline-induced pulmonary hypertension is a widely used animal model of pulmonary hypertension. The pyrrolizidine alkaloid monocrotaline is metabolized to the toxic monocrotaline pyrrole after subcutaneous injection in the liver and leads to endothelial damage in the pulmonary circulation within a few days, followed by remodeling of the small pulmonary arteries (mediastrophy, de novo muscularization). A single subcutaneous injection is sufficient to induce severe pulmonary hypertension in rats within 4 weeks [Cowan et al., Nature Med. 6, 698-702 (2000)].

The model uses male Sprague-Dawley rats. On day 0 the animals receive a subcutaneous injection of 60 mg / kg monocrotaline. The treatment of the animals with the test substance (by gavage, by addition in the feed or drinking water, by osmotic minipump, by subcutaneous or intraperitoneal injection or by inhalation) begins at the earliest 14 days after the monocrotaline injection and extends over a period of at least 14 days. At the end of the study hemodynamic examinations of the animals are carried out. For hemodynamic measurement, the rats are initially anesthetized with pentobarbital (60 mg / kg). The animals are then tracheotomized and artificially ventilated (frequency: 60 breaths / min, inspiration to expiration ratio: 50:50, positive end-expiratory pressure: 1 cm H2O, tidal volume: 10 ml / kg body weight, FIO2: 0.5). The anesthesia is maintained by isoflurane inhalation anesthesia. Systemic blood pressure is measured in the left carotid artery using a Millar microtip catheter. A polyethylene catheter is inserted into the right ventricle via the right jugular vein. pushed to determine the right ventricular pressure. Following hemodynamics, the heart is harvested, the ratio of right to left ventricles, including the septum, is determined, and the tissue deep frozen for expression analysis. The lung is also removed, the left half of the lung is fixed in formalin for histopathological examination, and the right half of the lung is deep-frozen for expression analysis. Furthermore, plasma samples for the determination of biomarkers (for example, proBNP) and plasma substance levels are obtained.

B-fifth Animal model of SU5416 / hypoxia-induced pulmonary hypertension

Rat SU5416 / hypoxia-induced pulmonary hypertension is a widely used animal model of pulmonary hypertension. By injecting the VEGF receptor antagonist SU5416 in combination with hypoxia, the effect of reduced oxygen levels may be increased and lead to endothelial changes in the form of plexiform lesions. A single subcutaneous injection, usually of 20 mg / kg, is sufficient to induce severe pulmonary hypertension in combination with hypoxia, that is, increased vascular shear through vasoconstriction [Oka et al, Circ. Res. 100. 923-929 (2007)]. The model uses male Sprague-Dawley rats or Dahl salt rats. On day 0, the animals receive a subcutaneous injection of SU5416 and are maintained in a controlled hypoxic atmosphere (10% oxygen). Appropriate control rats receive an injection of vehicle and are kept under normoxic conditions. Chronic hypoxia of at least 14 days with subsequent normoxia of at least 28 days leads to the development of functionally and morphologically demonstrable pulmonary hypertension. The treatment of the animals with the test substance (by gavage, by addition in food or drinking water, by osmotic minipump, by subcutaneous or intraperitoneal injection or by inhalation) begins at the earliest 14 days after SU5416 injection and beginning of the posture in a controlled hypoxic atmosphere and extends over a period of at least 14-28 days. At the end of the study hemodynamic examinations of the animals are carried out. For hemodynamic measurement, the rats are first anesthetized with pentobarbital (60 mg / kg). The animals are then tracheotomized and artificially ventilated (frequency: 60 breaths / min, inspiration to expiration ratio: 50:50, positive end-expiratory pressure: 1 cm H ₂ O, tidal volume: 10 ml / kg body weight, FIO 2: 0.5). The anesthesia is maintained by isoflurane inhalation anesthesia. Systemic blood pressure is determined in the left carotid artery using a Millar microtip catheter. A polyethylene catheter is advanced through the right jugular vein into the right ventricle to determine right ventricular pressure. Following hemodynamics, the heart is harvested, the ratio of right to left ventricles, including the septum, is determined, and the tissue deep frozen for expression analysis. The lungs will too The left half of the lung is fixed in formalin for histopathological examination and the right half of the lung is deep-frozen for expression analysis. Furthermore, plasma samples for the determination of biomarkers (for example, proBNP) and plasma substance levels are obtained. B-sixth Animal model of bleomycin-induced pulmonary fibrosis

Bleomycin-induced lung fibrosis in the mouse or rat is a widely used animal model of pulmonary fibrosis. Bleomycin is a glycopeptide antibiotic used in oncology for the treatment of testicular tumors, Hodgkin's and non-Hodgkin's tumors. It is eliminated renally, has a half-life of about 3 hours and, as a cytostatic, influences different phases of the division cycle [Lazo et al, Cancer Chemother. Biol. Response Modif. 15, 44-50 (1994)]. Its anti-neoplastic effect is due to an oxidative damaging effect on DNA [Hay et al, Arch. Toxicol. 65, 81-94 (1991)]. The lung tissue is particularly endangered in comparison with bleomycin, since so-called cysteine hydrolases, which lead to inactivation of bleomycin in other tissues, are only present in small numbers. After administration of bleomycin, the animals develop an acute respiratory distress syndrome (ARDS) with subsequent development of pulmonary fibrosis.

Administration of bleomycin may be single or multiple intratracheal, inhalational, intravenous or intraperitoneal. The treatment of the animals with the test substance (by gavage, by addition in food or drinking water, by osmotic minipump, by subcutaneous or intraperitoneal injection or by inhalation) starts on the day of the first application of bleomycin or therapeutically 3-14 days later and extends over a period of 2-6 weeks. At the end of the study, pulmonary function measurements, bronchoalveolar lavage to determine cell content and pro-inflammatory and pro-fibrotic markers, and histological assessment of pulmonary fibrosis are performed. B. 7 Animal model of D012 Ouarz-induced pulmonary fibrosis

Mouse and rat DQ12 quartz induced lung fibrosis is a widely used animal model of pulmonary fibrosis [Shimbori et al., Exp. Lung Res. 36, 292-301 (2010)]. DQ12 quartz is a highly active quartz that breaks or grinds. Intratracheal or inhaled administration of DQ12-quartz leads to alveolar proteinosis in mice and rats followed by interstitial pulmonary fibrosis. The animals receive a single or multiple intratracheal or inhaled instillation of DQ12 quartz. The treatment of the animals with the test substance (by gavage, by addition in the feed or drinking water, by osmotic minipump, by subcutaneous or intraperitoneal injection or by inhalation) starts on the day of the first instillation of the silicone. kats or therapeutically 3-14 days later and extends over a period of 3-20 weeks. At the end of the study, pulmonary function measurements, bronchoalveolar lavage to determine cell content and proinflammatory and pro-fibrotic markers, and histological assessment of pulmonary fibrosis are performed. B-eighth Animal model of DQ12 quartz or FITC-induced pulmonary inflammation

Intratracheal administration of DQ12 quartz or fluoresceimine thiocyanate (FITC) in mouse and rat leads to lung inflammation [Shimbori et al, Exp. Lung Res. 36, 292-301 (2010)]. The animals are treated with the test substance on day of instillation of DQ12 quartz or FITC or one day later for a period of 24 h to 7 days (by gavage, by addition in feed or drinking water, by osmotic minipump, by subcutaneous or intraperitoneal Injection or via inhalation). At the end of the experiment a bronchioalveolar lavage is performed to determine the cell content and the pro-inflammatory and pro-fibrotic markers.

B. 9 Animal model of ovalbumin-induced allergic airway inflammation and hyper-reactivity

The animal model of ovalbumin-induced allergic airway inflammation and hyperreactivity is a widely used animal model of bronchial asthma [Rückert et al, J. Immunol. II, 5507-5515 (2005)]. Mice are sensitized on day 0, 14 and 21 by intraperitoneal injection with the allergen ovalbumin in combination with adjuvant, the negative control receives intraperitoneal injection of NaCl in combination with adjuvant. On days 28 and 29, the animals receive intratracheal instillation of ovalbumin.

On day 30, a hyperreactivity test in the form of an inhalative provocation with a gradually increasing concentration of a bronchoconstrictor, such as methacholine or adenosine monophosphate, is performed. First, the animals are anesthetized by injection anesthesia, then intubated orotracheal intubated or tracheotomized and connected by means of a tube with a pulmonary function. First, pulmonary function is measured by body plethysmography before provocation (including parameters such as tidal volume, respiratory rate, dynamic compliance and lung resistance). Subsequently, the lung function is measured during inhalative provocation with a gradually increasing concentration of the bronchoconstrictor. Thereafter, a broncho-alveolar lavage is performed to determine the cell content and the pro-inflammatory markers. B-tenth Animal model of elastase-induced pulmonary emphysema

Mouse, rat or hamster elastase-induced pulmonary emphysema is a widely used animal model of pulmonary emphysema [Sawada et al., Exp. Lung Res. 33, 277-288 (2007)]. The animals receive orotracheal instillation of porcine pancreatic elastase. The treatment of the animals begins on the day of the instillation of the porcine pancreatic elastase and extends over a period of 3 weeks. At the end of the study, alveolar armor morphometry is performed.

B-l l. Animal model of permanent coronary ligature on mouse and rat

Mice or rats are anesthetized with 5% isoflurane in the anesthesia cage, intubated, connected to a respiratory pump and ventilated with 2% isoflurane / TShO / C. The body temperature is maintained at 37-38 ° C by a heat mat. As a painkiller Temgesic ^{® is} given. The thorax is opened laterally between the third and fourth ribs and the heart is exposed. The coronary artery of the left ventricle (LAD) is punctured with a occlusal thread just below its origin (below the left atrium) and permanently ligated. The thorax is closed again and the muscle layers and the epidermis sewn up. The animals are treated with the test substance from the day of the operation or up to one week later for a period of 4-8 weeks (by gavage, by addition of the test substance in the feed or drinking water, by osmotic minipump, by subcutaneous or intraperitoneal injection or by Inhalation). As a further control, a "sham" group is included, in which only the surgical procedure, but not the LAD occlusion was performed. At the end of the experiment, the animals are anesthetized again [1.5% isoflurane (mouse), 2% isoflurane (rat) / N20 / air], and a pressure catheter is introduced into the left ventricle via the carotid artery. There are heart rate, left ventricular pressure (LVP), left ventricular end-diastolic pressure (LVEDP), contractility (dp / dt) and relaxation rate (tau) with the help of the Powerlab system (AD Instruments, ADI-PWLB-4SP) and the Chart5 software (SN 425-0586) was recorded and evaluated. Subsequently, a blood sample is taken to determine the substance plasma levels and plasma bioparks and the animals are killed. Heart (ventricles, left ventricle plus septum, right ventricle), liver, lung and kidney are removed and weighed.

B-12th Animal Model of Tumor Growth Syngenic tumor models in immunocompetent mice or xenogeneic tumor models in immunosuppressed mice are used for substance evaluation. For this purpose, tumor cells are cultured in vitro and implanted subcutaneously or orthotopically. The treatment of the animals is done by oral, subcutaneous, intraperitoneal or intravenous therapy after tumor establishment or starting on the day of tumor inoculation. The efficacy of test substances is analyzed in monotherapy and in combination therapy with other pharmacologically active substances. During the experiment, the state of health of the animals is checked daily and the treatments are carried out according to animal welfare regulations. The tumor area is measured with calipers (length L, width B = smaller extent). The tumor volume is calculated according to the formula (L x B ² ) / 2. The inhibition of tumor growth is determined at the end of the experiment as T / C ratio of tumor areas or tumor weights and as TGI value (tumor growth inhibition, calculated according to the formula [1- (T / C)] × 100) (T = Tumor size of the treated group; C = tumor size of the untreated control group).

B. 13 Animal model of the formation of metastases in the lung

Syngeneic tumor models in immunocompetent mice or xenogeneic tumor models in immunosuppressed mice are used for substance evaluation. For this purpose, tumor cells are cultured in vitro and injected intravenously into the tail vein of the test animals. The animals are treated by oral, subcutaneous, intraperitoneal or intravenous therapy. The efficacy of test substances is analyzed in monotherapy and in combination therapy with other pharmacologically active substances. During the experiment, the state of health of the animals is checked daily and the treatments are carried out according to animal welfare regulations. After completion of the experiment, the lungs of the experimental animals are examined microscopically with regard to the number of tumor colonies formed.

C. Embodiments of Pharmaceutical Compositions

The compounds according to the invention can be converted into pharmaceutical preparations as follows:

Tablet: composition:

100 mg of the compound according to the invention, 50 mg of lactose (monohydrate), 50 mg of corn starch (native), 10 mg of polyvinylpyrrolidone (PVP 25) (BASF, Ludwigshafen, Germany) and 2 mg of magnesium stearate.

Tablet weight 212 mg. Diameter 8 mm, radius of curvature 12 mm. production:

The mixture of compound of the invention, lactose and starch is granulated with a 5% solution (m / m) of the PVP in water. The granules are mixed after drying with the magnesium stearate for 5 minutes. This mixture is compressed with a conventional tablet press (for the tablet format see above). As a guideline for the compression, a pressing force of 15 kN is used.

Orally administrable suspension:

Composition:

1000 mg of the compound of the invention, 1000 mg of ethanol (96%), 400 mg of Rhodigel ^® (xanthan gum of the firm FMC, Pennsylvania, USA) and 99 g of water. A single dose of 100 mg of the compound of the invention corresponds to 10 ml of oral suspension.

production:

The rhodigel is suspended in ethanol, the compound according to the invention is added to the suspension. While stirring, the addition of water. Until the completion of the swelling of Rhodigels is stirred for about 6 h. Orally administrable solution:

Composition:

500 mg of the compound according to the invention, 2.5 g of polysorbate and 97 g of polyethylene glycol 400. A single dose of 100 mg of the compound according to the invention correspond to 20 g of oral solution. production:

The compound of the invention is suspended in the mixture of polyethylene glycol and polysorbate with stirring. The stirring is continued until complete dissolution of the compound according to the invention. iv Solution: The compound of the present invention is dissolved in a concentration below the saturation solubility in a physiologically acceptable solvent (e.g., isotonic saline, glucose solution 5% and / or PEG 400 solution 30%). The solution is sterile filtered and filled into sterile and pyrogen-free injection containers.

Claims

claims

1. Compound of formula (I)

in which the ring A is an aza-heterocycle of the formula

in which * the linkage to the adjacent C (R) (R) group is labeled, identical or different and independently of one another denote hydrogen or (C 1 -C 10) -alkyl,

Is hydrogen or (Ci-C i) -alkyl, and

XO, S or N (R ⁷ ) means in which

R ^{7 represents} cyano, methoxycarbonyl or ethoxycarbonyl, independently of one another represent hydrogen or deuterium, represents methyl or ethyl, R ^{3 is} cyclopropyl, cyclobutyl, cyclopentyl, spiro [3.3] hept-2-yl, 3-oxetanyl or 3-tetrahydrofuranyl, wherein cyclopropyl, cyclobutyl, cyclopentyl and spiro [3.3] hept-2-yl are up to twice, the same or may be substituted with a radical selected from fluorine, methyl, ethyl, trifluoromethyl and methoxy, and wherein 3-oxetanyl and 3-tetrahydrofuranyl may be substituted up to two times, identically or differently, by a radical selected from fluorine and methyl, and R ^{4 is} methyl, ethyl, 2-fluoroethyl, 2,2-difluoroethyl, 2,2,2-trifluoroethyl, n-propyl,

3- cyanopropyl, 3-fluoropropyl, 3,3-difluoropropyl, 3,3,3-trifluoropropyl, n-butyl,

4- fluorobutyl, 4,4,4-trifluorobutyl, 3,3,4,4-tetrafluorobutyl, n-pentyl, z is o-pentyl or n-hexyl, or R ^{4 is} a group of the formula -CH ₂ -R ⁸ stands in which

R ^{10 is} methyl or trifluoromethyl, and their solvates.

2. A compound of formula (I) according to claim 1, in which the ring A for an aza-heterocycle of the formula

wherein * denotes the linkage to the adjacent C (R ^1A ) (R ^1B ) group,

R ^5A and R ^{5B are} identical or different and independently of one another denote hydrogen or (C 1 -C 4) -alkyl,

R ^{6 is} hydrogen or (C 1 -C ₄ ) -alkyl, and

XO, S or N (R ⁷ ) means in which

R ^{7 is} cyano, methoxycarbonyl or ethoxycarbonyl, and R ^1B independently of one another are hydrogen or deuterium, is methyl or ethyl, cyclopropyl, cyclobutyl, cyclopentyl, spiro [3.3] hept-2-yl, 3-oxetanyl or 3-tetrahydrofuranyl wherein cyclopropyl, cyclobutyl, cyclopentyl and spiro [3.3] hept-2-yl may be substituted up to two times, identically or differently, by a radical selected from fluoro, methyl, ethyl, trifluoromethyl and methoxy, and wherein 3-oxetanyl and 3-tetrahydrofuranyl may be substituted up to two times, identically or differently, by a radical selected from fluorine and methyl, and

R ^{4 is} methyl, ethyl, n-propyl, 3-fluoropropyl, 3,3-difluoropropyl, 3,3,3-trifluoropropyl, n-butyl, n-pentyl, z o-pentyl or n-hexyl, or R ^{4 is} a group of formula -CH 2 -R ⁸ wherein

R ^{4 is} a group of formula -CH 2 -CH 2 -OR ⁹ wherein

R ^{9 is} methyl, trifluoromethyl, ethyl or z o-propyl, and their solvates. 3. A compound of the formula (I) according to claim 1, in which the ring A is an aza-heterocycle of the formula

wherein ^* denotes the linkage to the adjacent C (R ^1A ) (R ^1B ) group,

R ^5A and R ^{5B are} identical or different and independently of one another denote hydrogen or methyl, R ^{6 is} hydrogen or methyl, and

X is O or N (R ⁷ ), in which

R ^{7 is} cyano or methoxycarbonyl, R ^1A and R ^{1B are} both hydrogen or both are deuterium, R ^{2 is} methyl,

R ^{4 is} methyl, ethyl, 2-fluoroethyl, 2,2-difluoroethyl, 2,2,2-trifluoroethyl, n-propyl, 3-fluoropropyl, 3,3-difluoropropyl, 3,3,3-trifluoropropyl, n-butyl , 4,4,4-trifluorobutyl, n-pentyl or n-hexyl, or

R ^{4 is} a group of formula -CH 2 -R ⁸ wherein

R ^{8 is} cyclopropyl, cyclobutyl or 2-tetrahydrofuranyl, where cyclopropyl and cyclobutyl may be substituted up to two times by fluorine, or

R ^{4 is} a group of formula -CH 2 -CH 2 -OR ⁹ wherein

R ^{9 is} methyl or trifluoromethyl, and their solvates.

A compound of the formula (I) according to claim 1, 2 or 3, in which the ring A is an aza-heterocycle of the formula

wherein ^* denotes the linkage to the adjacent C (R ^1A ) (R ^1B ) group,

R ^5A and R ^{5B are} identical or different and independently of one another denote hydrogen or methyl,

R ^{6 is} hydrogen or methyl, and

X is O or N (R ⁷ ), in which

R ^{4 is} a group of formula -CH 2 -CH 2 -OR ⁹ wherein

R ^{9 is} methyl or trifluoromethyl, and their solvates. 5. A compound of the formula (I) according to claim 1 or 3, in which the ring A is an aza-heterocycle of the formula

HN ^stands '

wherein ^* denotes the linkage to the adjacent C (R ^1A ) (R ^1B ) group, R ^5A and R ^{5B are} each hydrogen,

R ^{6 is} hydrogen, and

X is O or N (R ⁷ ), in which

R ^{7 is} cyano or methoxycarbonyl, R ^1A and R ^{1B are} both hydrogen or both are deuterium,

R ^{2 is} methyl,

R ^{3 is} cyclopropyl, cyclobutyl or cyclopentyl, wherein cyclopropyl, cyclobutyl and cyclopentyl may be substituted up to two times, identically or differently, by a radical selected from fluoro and methyl, and R ^{4 is} methyl, ethyl, 2-fluoroethyl, 2,2-difluoroethyl, 2,2,2-trifluoroethyl, w-propyl, 3-fluoropropyl, 3,3,3-trifluoropropyl or n-butyl, or

R ^{4 is} a group of formula -CH 2 -R ⁸ wherein R ^{8 is} cyclopropyl or cyclobutyl, wherein cyclopropyl and cyclobutyl may be substituted up to two times by fluorine, or

6. A compound of formula (I) according to any one of claims 1 to 5, in which the ring A is an aza-heterocycle of the formula

stands, wherein * denotes the linkage to the adjacent C (R ^1A ) (R ^1B ) group,

R ^5A and R ^{5B are} each hydrogen, R ^{6 is} hydrogen, and

X is O or N (R ⁷ ), where R ^{7 is} cyano or methoxycarbonyl,

R ^1A and R ^{1B are} both hydrogen or both are deuterium, stands for methyl,

R ^{3 is} cyclopropyl, cyclobutyl or cyclopentyl, wherein cyclopropyl, cyclobutyl and cyclopentyl may be substituted up to two times, identically or differently, by a radical selected from fluoro and methyl, and

R ^{4 is} 3-fluoropropyl, 3,3,3-trifluoropropyl or n-butyl, or

R ^{4 is} a group of formula -CH 2 -CH 2 -OR ⁹ wherein

R ^{9 is} methyl or trifluoromethyl, and their solvates.

A compound as defined in any one of claims 1 to 6 for the treatment and / or prevention of diseases.

A compound as defined in any one of claims 1 to 6 for use in a method for the treatment and / or prevention of idiopathic pulmonary fibrosis, pulmonary hypertension, bronchiolitis obliterans syndrome, chronic obstructive pulmonary disease, asthma, cystic fibrosis, myocardial infarction, heart failure, sickle cell anemia and of cancers.

Use of a compound as defined in any one of claims 1 to 6 for the manufacture of a medicament for the treatment and / or prevention of idiopathic pulmonary fibrosis, pulmonary hypertension, bronchiolitis obliterans syndrome, chronic obstructive pulmonary disease, asthma, cystic fibrosis, myocardial infarction, heart failure, Sickle cell disease and cancer.

10. A pharmaceutical composition comprising a compound as defined in any one of claims 1 to 6, in combination with one or more inert, non-toxic, pharmaceutically suitable excipients.

11. A medicament comprising a compound as defined in any one of claims 1 to 6, in combination with one or more further active compounds selected from the group consisting of PDE 5 inhibitors, sGC activators, sGC stimulators, prostacyclin analogs, IP Receptor agonists, endothelin antagonists, antifibrotic agents, anti-inflammatory, immunomodulatory, immunosuppressive and / or cytotoxic agents, and signal transduction cascade inhibiting compounds. 12. Medicament according to claim 10 or 11 for the treatment and / or prevention of idiopathic pulmonary fibrosis, pulmonary hypertension, bronchiolitis obliterans syndrome, chronic obstructive pulmonary disease, asthma, cystic fibrosis, myocardial infarction, heart failure, sickle cell disease and cancer.

13. A method for the treatment and / or prevention of idiopathic pulmonary fibrosis, pulmonary hypertension, bronchiolitis obliterans syndrome, chronic obstructive pulmonary disease, asthma, cystic fibrosis, myocardial infarction, heart failure, sickle cell anemia and cancers in humans and animals by administration of an effective amount at least one compound as defined in any one of claims 1 to 6, or a pharmaceutical composition as defined in any one of claims 10 to 12.