Patent Application
20240294522
The present invention relates to certain 3-substituted 1H-pyrrolo[2,3-b]pyridine compounds of the formula (I) and pharmaceutically acceptable salts thereof. These compounds are useful in the treatment or prevention of a disease or medical condition mediated through GRK5 selected from heart disease, inflammatory and immunological disease, metabolic disease and cancer.
G protein-coupled receptor kinases (GRKs) constitute a family of seven mammalian serine/threonine protein kinases that based on sequence homology can be divided into the three subfamilies “GRK1” (composed of GRK1 and GRK7), “GRK2” (composed of GRK2 and GRK3) and “GRK4” (composed of GRK4, GRK5, and GRK6). Whereas GRK1, GRK4, and GRK7 are expressed in limited tissues such as retina (GRK1 and GRK7) and testis (GRK4), GRK2, GRK3, GRK5, and GRK6 are expressed ubiquitously throughout the body.
GRKs were originally identified by their ability to phosphorylate and desensitize agonist-bound G protein-coupled receptors (GPCRs). GPCRs represent the largest superfamily of transmembrane receptor proteins and facilitate cell sensitivity to a diverse array of external stimuli. As a consequence, GPCR dysregulation is a critical contributor to many diseases such as neurodegeneration, cancer and autoimmune diseases (Hauser et al., Nat Rev Drug Discov. 2017 Dec., 16(12):829-842). Upon ligand binding, GPCRs become activated resulting in downstream intracellular signaling via heterotrimeric G proteins. The phosphorylation of agonist-bound GPCR by GRKs leads to the translocation and binding of β-arrestins to the receptors, inhibiting further G protein activation by blocking receptor-G protein coupling and promoting the internalization of agonist-bound GPCR. Thus, GRK-catalyzed phosphorylation and binding of β-arrestin to the receptors are believed to be the common mechanism to turn off activated GPCRs as an important mechanism for maintaining homeostasis (Wang et al., Trends Pharmacol Sci. 2018 April; 39(4):367-386).
In addition to their canonical role in GPCR desensitization, recent studies have demonstrated a much broader, non-canonical function for this kinase family including phosphorylation of cytosolic substrates involved in cell signaling pathways stimulated by both GPCRs and non-GPCRs. Moreover, GRKs modulate signaling via phosphorylation-independent functions (Lieu and Koch, Expert Opin Ther Targets. 2019 March; 23(3):201-214.). Since GRKs possess multiple biologic functions and have been shown to affect critical physiological and pathophysiological processes, they are considered as drug targets in diseases such as as cardiac hypertrophy and heart failure, obesity and diabetes, atherosclerosis, inflammation and fibrosis, neurodegeneration, opioid tolerance and addiction, and cancer (Hullmann et al., Pharmacol Res. 2016 August; 110:52-64; Gold et al., Circ Res. 2012 Sep. 28; 111(8):1048-53; Li et al., Diabetes. 2013 January; 62(1):291-8.; Lutz et al., Sci Rep. 2018 May 17; 8(1):7745.; Xia et al., PLoS One. 2014 Mar. 3; 9(3):e90597; Packiriswamy and Parameswaran, Genes Immun. 2015 September; 16(6):367-77; Murga et al., Front Pharmacol. 2019 Feb. 19; 10:112; Pham et al., Oncotarget. 2020 Apr. 21; 11(16):1448-1461; Jiang et al, Cell Death Dis. 2018 Feb. 20; 9(3):295; Sommer et al., Sci Rep. 2019 Oct. 29; 9(1):15548; Hendrickx et al., Front Pharmacol. 2018 Dec. 17; 9:1484; Marzano et al., Int J Mol Sci. 2021 Feb. 15; 22(4):1920; Patial et al., J Cell Physiol. 2011 May; 226(5):1323-33; De Lucia et al., Cardiovasc Res. 2021 Feb. 9:cvab044; Eguchi et al., Proc Natl Acad Sci USA. 2021 Feb. 2; 118(5):e2012854118, Kliewer et al., Nat Commun. 2019 Jan. 21; 10(1):367).
Among the cardiovascular diseases that involve the heart is a pathologic condition termed concentric ventricular hypertrophy (VH). VH can affect both the right ventricular (RVH) as well as the left ventricular (LVH) with the latter being the more common form. In contrast to eccentric VH which is regarded as a physiologic, adaptive process resulting from intense aerobic exercise training or in pregnancy in response to increased blood volume, concentric VH is considered as a maladaptive cardiac remodeling of the heart that is commonly observed in conditions of increased hemodynamic or metabolic stress from various stressors including hypertension, congenital heart defects, valvular defects (aortic coarction or stenosis) and primary defects of the myocardium which directly cause VH (hypertrophic cardiomyopathy). The underlying commonality in these disease states is an increase in pressures that the ventricles try to compensate by undergoing thickening. VH as a result of increased ventricular pressure or volume load is problematic and actually poses a serious health risk which can even lead to heart failure (Nakamura and Sadoshima, Nat Rev Cardiol. 2018 July; 15(7):387-407; Shimizu and Minamino, J Mol Cell Cardiol. 2016 August; 97:245-62).
In the treatment of LVH, sarcolemmal receptors of the renin-angiotensin-aldosterone (RAAS) system remain the most important targets for the therapeutic treatment of cardiac hypertrophy. However, several trials have shown that a combination of RAAS inhibitors, despite synergistic, may increase the risk of unwanted side effects in some patients (Weir et al., Eur J Heart Fail. 2008 February; 10(2):157-63). A variety of intracellular targets have been identified in maladaptive signaling cascades, but the lack of target- and organ-specific small molecules delays clinical translation (Bisping et al., J Cardiovasc Pharmacol. 2014 October; 64(4):293-305).
GRK2 and GRK5 are the predominant GRKs in the heart and have been intensively studied for their potential role in cardiac hypertrophy (Gold et al., Circ Res. 2012 Sep. 28; 111(8):1048-53). It has been observed that GRK5 expression is increased after cardiac injury resulting in worsen disease prognosis and mortality which is clinically associated with maladaptive cardiac remodelling (Dzimiri et al., Eur J Pharmacol. 2004 Apr. 12; 489(3):167-77). In contrast, depletion GRK5 in knock-out (KO) mice delays maladaptive cardiac hypertrophy after ventricular pressure-overload (TAC) surgery (Traynham et al., Circ Res. 2015 Dec. 4; 117(12):1001-12). The development of TAC-induced hypertrophy seems to be dependent on the presence of GRK5 in the nucleus as deletion of its nuclear location sequence (NLS) significantly ameliorates maladaptive cardiac remodeling after TAC (Johnson et al., Mol Cell Biol. 2004 December; 24(23):10169-79). This points to a non-canonical function of GRK5 in cardiac hypertrophy which is believed to be triggered by the nuclear translocation of GRK5 upon hypertrophic stress. Subsequent phosphorylation of HDAC5 by GRK5 in the nucleus leads to derepression of MEF2 resulting in activation of MEF2-dependent hypertrophic genes. In addition, nuclear GRK5 interacts and enhances the activity of pro-hypertrophic transcription factors NFkB and NFAT in a kinase-independent manner.
Little has been reported regarding GRK5 inhibitors in clinical development. The anti-inflammatory, antiallergic immunomodulator Amlexanox is the only marketed drug that is known to moderately inhibit GRK5 (with an IC50 value of ca. 10 μM) which could contribute to its mechanism of action which, on the other hand, is not well-determined (Homan et al., Molecules. 2014 Oct. 22; 19(10):16937-49, Lee et al., Biomol Ther (Seoul). 2020 Sep. 1; 28(5):482-489).
Compared to GRK5, the role of GRK2 in cardiac hypertrophy is less clear. Although in vitro overexpression of GRK2 is enough to elict hypertrophic response via NFkB and NFAT activation, cardiac-specific transgenic GRK2 mice stressed with TAC undergo maladaptive hypertrophy not significantly different from non-transgenic controls but have increased mortality and decreased cardiac function. Thus, as GRK2 obviously has a role in other maladaptive pathways, dual inhibition of GRK2 and GRK5 could be a therapeutic strategy for pathological hypertrophy and overall cardiovascular health (Huang et al., Antioxid Redox Signal. 2014 Nov. 10; 21(14):2032-43; Pfleger et al., Nat Rev Cardiol. 2019 October; 16(10):612-622).
It is object to the present invention to provide novel compounds as mono-specific GRK5 or dual-specific GRK2/5 inhibitors and/or pharmaceutically acceptable salts thereof, which can be used as pharmaceutically active agents, and use thereof especially for prophylaxis and/or treatment of selected from heart disease, inflammatory and immunological disease, metabolic disease and cancer as well as compositions comprising at least one of those compounds and/or pharmaceutically acceptable salts thereof as pharmaceutically active ingredients. The objective of the present invention is solved by the teaching of the independent claims. Further advantageous features, aspects and details of the invention are evident from the dependent claims, the description, and the examples of the present application.
The following two compounds are known as such from Chemical Abstracts without the disclosure of the chemical synthesis or any use of such compounds are both compounds are excluded from the scope of the present application:
The present invention relates to a compound of the general formula (I)
cyclo-C3H5, cyclo-C4H7, cyclo-C5H9, cyclo-C6H11, cyclo-C7H13, —H, —OH, —OCH3, —OC2H5, —OC3H7, —O-cyclo-C3H5, —OCH(CH3)2, —OC(CH3)3, —OC4H9, —OPh, —OCH2-Ph, —OCPh3, —CH2—OCH3, —C2H4—OCH3, —C3H6—OCH3, —CH2—OC2H5, —C2H4—OC2H5, —C3H6—OC2H5, —CH2—OC3H7, —C2H4—OC3H7, —C3H6—OC3H7, —CH2—O-cyclo-C3H5, —C2H4—O-cyclo-C3H5, —C3H6—O-cyclo-C3H5, —CH2—OCH(CH3)2, —C2H4—OCH(CH3)2, —C3H6—OCH(CH3)2, —CH2—OC(CH3)3, —C2H4—OC(CH3)3, —C3H6—OC(CH3)3, —CH2—OC4H9, —C2H4—OC4H9, —C3H6—OC4H9, —CH2—OPh, —C2H4—OPh, —C3H6—OPh, —CH2—OCH2-Ph, —C2H4—OCH2-Ph, —C3H6—OCH2-Ph, —SH, —SCH3, —SC2H5, —SC3H7, —S-cyclo-C3H5, —SCH(CH3)2, —SC(CH3)3, —F, —Cl, —Br, —I, —CN, —COCH3, —COC2H5, —COC3H7, —CO-cyclo-C3H5, —COCH(CH3)2, —COC(CH3)3, —COOH, —COOCH3, —COOC2H5, —COOC3H7, —COO-cyclo-C3H5, —COOCH(CH3)2, —COOC(CH3)3, —OOC—CH3, —OOC≡C2H5, —OOC≡C3H7, —OOC-cyclo-C3H5, —OOC—CH(CH3)2, —OOC—C(CH3)3, —CONH2, —CONHCH3, —CONHC2H5, —CONHC3H7, —CONH-cyclo-C3H5, —CONH[CH(CH3)2], —CONH[C(CH3)3], —CON(CH3)2, —CON(C2H5)2, —CON(C3H7)2, —CON(cyclo-C3H5)2, —CON[CH(CH3)2]2, —CON[C(CH3)3]2, —NHCOCH3, —NHCOC2H5, —NHCOC3H7, —NHCO-cyclo-C3H5, —NHCO—CH(CH3)2, —NHCO—C(CH3)3, —NHCO—OCH3, —NHCO—OC2H5, —NHCO—OC3H7, —NHCO—O-cyclo-C3H5, —NHCO—OCH(CH3)2, —NHCO—OC(CH3)3, —NH2, —NHCH3, —NHC2H5, —NHC3H7, —NH-cyclo-C3H5, —NHCH(CH3)2, —NHC(CH3)3, —N(CH3)2, —N(C2H5)2, —N(C3H7)2, —N(cyclo-C3H5)2, —N[CH(CH3)2]2, —N[C(CH3)3]2, —SOCH3, —SOC2H5, —SOC3H7, —SO-cyclo-C3H5, —SOCH(CH3)2, —SOC(CH3)3, —SO2CH3, —SO2C2H5, —SO2C3H7, —SO2-cyclo-C3H5, —SO2CH(CH3)2, —SO2C(CH3)3, —SO3H, —SO3CH3, —SO3C2H5, —SO3C3H7, —SO3-cyclo-C3H5, —SO3CH(CH3)2, —SO3C(CH3)3, —SO2NH2, —SO2NHCH3, —SO2NHC2H5, —SO2NHC3H7, —SO2NH-cyclo-C3H5, —SO2NHCH(CH3)2, —SO2NHC(CH3)3, —SO2N(CH3)2, —SO2N(C2H5)2, —SO2N(C3H7)2, —SO2N(cyclo-C3H5)2, —SO2N[CH(CH3)2]2, —SO2N[C(CH3)3]2, —CH2—SO2NH2, —CH2—SO2NHCH3, —CH2—SO2NHC2H5, —CH2—SO2NHC3H7, —CH2—SO2NH-cyclo-C3H5, —CH2—SO2NHCH(CH3)2, —CH2—SO2NHC(CH3)3, —CH2—SO2N(CH3)2, —CH2—SO2N(C2H5)2, —CH2—SO2N(C3H7)2, —CH2—SO2N(cyclo-C3H5)2, —CH2—SO2N[CH(CH3)2]2, —CH2—SO2N[C(CH3)3]2, —O—S(═O)CH3, —O—S(═O)C2H5, —O—S(═O)C3H7, —O—S(═O)-cyclo-C3H5, —O—S(═O)CH(CH3)2, —O—S(═O)C(CH3)3, —S(═O)(═NH)CH3, —S(═O)(═NH)C2H5, —S(═O)(═NH)C3H7, —S(═O)(═NH)-cyclo-C3H5, —S(═O)(═NH)CH(CH3)2, —S(═O)(═NH)C(CH3)3, —NH—SO2—CH3, —NH—SO2—C2H5, —NH—SO2—C3H7, —NH—SO2-cyclo-C3H5, —NH—SO2—CH(CH3)2, —NH—SO2—C(CH3)3, —O—SO2—CH3, —O—SO2—C2H5, —O—SO2—C3H7, —O—SO2-cyclo-C3H5, —O—SO2—CH(CH3)2, —O—SO2—C(CH3)3, —OCH2F, —OCHF2—OCF3, —CH2—OCF3, —C2H4—OCF3, —C3H6—OCF3, —OC2F5, —CH2—OC2F5, —C2H4—OC2F5, —C3H6—OC2F5, —O—COOCH3, —O—COOC2H5, —O—COOC3H7, —O—COO-cyclo-C3H5, —O—COOCH(CH3)2, —O—COOC(CH3)3, —NH—CO—NH2, —NH—CO—NHCH3, —NH—CO—NHC2H5, —NH—CO—NHC3H7, —NH—C(═NH)—NH2, —NH—CO—N(C3H7)2, —NH—CO—NH[CH(CH3)2], —NH—CO—NH[C(CH3)3], —NH—CO—N(CH3)2, —NH—CO—N(C2H5)2, —NH—CO—NH-cyclo-C3H5, —NH—CO—N(cyclo-C3H5)2, —NH—CO—N[CH(CH3)2]2, —NH—C(═NH)—NHCH3, —NH—C(═NH)—NHC2H5, —NH—C(═NH)—NHC3H7, —O—CO—NH-cyclo-C3H5, —NH—C(═NH)—NH-cyclo-C3H5, —NH—C(═NH)—NH[CH(CH3)2], —O—CO—NH[CH(CH3)2], —NH—C(═NH)—NH[C(CH3)3], —NH—C(═NH)—N(CH3)2, —NH—C(═NH)—N(C2H5)2, —NH—C(═NH)—N(C3H7)2, —NH—C(═NH)—N(cyclo-C3H5)2, —O—CO—NHC3H7, —NH—C(═NH)—N[CH(CH3)2]2, —NH—C(═NH)—N[C(CH3)3]2, —O—CO—NH2, —O—CO—NHCH3, —O—CO—NHC2H5, —O—CO—NH[C(CH3)3], —O—CO—N(CH3)2, —O—CO—N(C2H5)2, —O—CO—N(C3H7)2, —O—CO—N(cyclo-C3H5)2, —O—CO—N[CH(CH3)2]2, —O—CO—N[C(CH3)3]2, —O—CO—OCH3, —O—CO—OC2H5, —O—CO—OC3H7, —O—CO—O-cyclo-C3H5, —O—CO—OCH(CH3)2, —O—CO—OC(CH3)3, —CH2F, —CHF2, —CF3, —CH2—CH2F, —CH2—CHF2, —CH2—CF3, cyclo-CBH15, -Ph, —CH2-Ph, —CH2—CH2-Ph, —CH═CH-Ph, —CPh3, —CH3, —C2H5, —C3H7, —CH(CH3)2, —C4H9, —CH2—CH(CH3)2, —CH(CH3)—C2H5, —C(CH3)3, —C5H11, —CH(CH3)—C3H7, —CH2—CH(CH3)—C2H5, —CH(CH3)—CH(CH3)2, —C(CH3)2—C2H5, —CH2—C(CH3)3, —CH(C2H5)2, —C2H4—CH(CH3)2, —C6H13, —C7H15, —C8H17, —C3H6—CH(CH3)2, —C2H4—CH(CH3)—C2H5, —CH(CH3)—C4H9, —CH2—CH(CH3)—C3H7, —CH(CH3)—CH2—CH(CH3)2, —CH(CH3)—CH(CH3)—C2H5, —CH2—CH(CH3)—CH(CH3)2, —CH2—C(CH3)2—C2H5, —C(CH3)2—C3H7, —C(CH3)2—CH(CH3)2, —C2H4—C(CH3)3, —CH(CH3)—C(CH3)3, —CH═CH2, —CH2—CH═CH2, —C(CH3)═CH2, —CH═CH—CH3, —C2H4—CH═CH2, —CH2—CH═CH—CH3, —CH═CH—C2H5, —CH2—C(CH3)═CH2, —CH(CH3)—CH═CH, —CH═C(CH3)2, —C(CH3)═CH—CH3, —CH═CH—CH═CH2, —C3H6—CH═CH2, —C2H4—CH═CH—CH3, —CH2—CH═CH—C2H5, —CH═CH—C3H7, —CH═CH—CH═CH—CH3, —C2H4—C(CH3)═CH2, —CH2—CH(CH3)—CH═CH2, —CH(CH3)—CH2—CH═CH2, —CH2—CH═C(CH3)2, —CH2—C(CH3)═CH—CH3, —CH(CH3)—CH═CH—CH3, —CH═CH—CH(CH3)2, —CH═C(CH3)—C2H5, —C(CH3)═CH—C2H5, —C(CH3)═C(CH3)2, —C(CH3)2—CH═CH2, —CH(CH3)—C(CH3)═CH2, —C4H8—CH═CH2, —C3H6—CH═CH—CH3, —C2H4—CH═CH—C2H5, —CH2—CH═CH—C3H7, —CH═CH—C4H9, —C3H6—C(CH3)═CH2, —C2H4—CH(CH3)—CH═CH2, —CH2—CH(CH3)—CH2—CH═CH2, —C2H4—CH═C(CH3)2, —CH(CH3)—C2H4—CH═CH2, —C2H4—C(CH3)═CH—CH3, —CH2—CH(CH3)—CH═CH—CH3, —CH(CH3)—CH2—CH═CH—CH3, —CH2—CH═CH—CH(CH3)2, —CH2—CH═C(CH3)—C2H5, —CH2—C(CH3)═CH—C2H5, —CH(CH3)—CH═CH—C2H5, —CH═CH—CH2—CH(CH3)2, —CH═CH—CH(CH3)—C2H5, —CH═C(CH3)—C3H7, —C(CH3)═CH—C3H7, —CH2—CH(CH3)—C(CH3)═CH2, —C[C(CH3)3]═CH2, —CH(CH3)—CH2—C(CH3)═CH2, —CH(CH3)—CH(CH3)—CH═CH2, —CH═CH—C2H4—CH═CH2, —C(CH3)2—CH2—CH═CH2, —CH2—C(CH3)═C(CH3)2, —CH(CH3)—CH═C(CH3)2, —C(CH3)2—CH═CH—CH3, —CH═CH—CH2—CH═CH—CH3, —CH(CH3)—C(CH3)═CH—CH3, —CH═C(CH3)—CH(CH3)2, —C(CH3)═CH—CH(CH3)2, —C(CH3)═C(CH3)—C2H5, —CH═CH—C(CH3)3, —C(CH3)2—C(CH3)═CH2, —CH(C2H5)—C(CH3)═CH2, —C(CH3)(C2H5)—CH═CH2, —CH(CH3)—C(C2H5)═CH2, —CH2—C(C3H7)═CH2, —CH2—C(C2H5)═CH—CH3, —CH(C2H5)—CH═CH—CH3, —C(C4H9)═CH2, —C(C3H7)═CH—CH3, —C(C2H5)═CH—C2H5, —C(C2H5)═C(CH3)2, —C[CH(CH3)(C2H5)]═CH2, —C[CH2—CH(CH3)2]═CH2, —C2H4—CH═CH—CH═CH2, —CH2—CH═CH—CH2—CH═CH2, —C3H6—C═C—CH3, —CH2—CH═CH—CH═CH—CH3, —CH═CH—CH═CH—C2H5, —CH(CH3)—CH2—C═CH, —CH(CH3)—C═C—CH3, —C2H4—CH(CH3)—C═CH, —CH═CH—CH═C(CH3)2, —CH2—CH(CH3)—CH2—C═CH, —CH═CH—C(CH3)═CH—CH3, —CH═C(CH3)—CH═CH—CH3, —CH2—CH(CH3)—C═CH, —C(CH3)═CH—CH═CH—CH3, —C═CH, —C═C—CH3, —CH2—C═CH, —C2H4—C═CH, —CH2—C═C—CH3, —C═C≡C2H5, —C3H6—C═CH, —C2H4—C═C—CH3, —CH2—C═C—C2H5, —C═C≡C3H7, —CH(CH3)—C═CH, —C4H8—C═CH, —C2H4—C═C—C2H5, —CH2—C═C—C3H7, —C═C≡C4H9, —C═C—CH2—CH(CH3)2, —CH(CH3)—C2H4—C═CH, —CH2—CH(CH3)—C═C—CH3, —C(CH3)(C2H5)—C═CH, —CH(CH3)—CH2—C═C—CH3, —CH(CH3)—C═C—C2H5, —CH2—C═C—CH(CH3)2, —C═C—CH(CH3)—C2H5, —CH2—C═C≡C═C—CH3, —CH(C2H5)—C═C—CH3, —C(CH3)2—C═C—CH3, —CH(C2H5)—CH2—C═CH, —CH2—CH(C2H5)—C═CH, —C(CH3)2—CH2—C═CH, —CH2—C(CH3)2—C═CH, —CH(CH3)—CH(CH3)—C═CH, —CH(C3H7)—C═CH, —CH2—CH(C═CH)2, —C═C≡C═CH, —CH2—C═C≡C═CH, —C═C≡C═C—CH3, —CH(C═CH)2, —C2H4—C═C≡C═CH, —CH2—C═C—CH2—C═CH, —C═C≡C2H4—C═CH, —C═C—C(CH3)3, —C═C—CH2—C═C—CH3, or —C═C≡C═C≡C2H5, or
or an enantiomer, a stereoisomeric form, a mixture of enantiomers, a diastereomer, a mixture of diastereomers, a hydrate, a solvate, an acid salt form, a tautomer, or a racemate of the above mentioned compound, or a pharmaceutically acceptable salt thereof.
Preferred are compounds wherein R4 is different from hydrogen (—H). In case R4 is hydrogen one or at least one of the substituents R1-R3 and R5-R7 is not hydrogen and preferably two or three or more than three substituents R1-R3 and R5-R7 are not hydrogen. Even more preferred are the compounds wherein one or at least one of the substituents R4-R7 is not hydrogen. Still more preferred are the compounds wherein one or at least one of the substituents R1-R4 is not hydrogen. Most preferred are the compounds wherein one or at least one of the substituents R1-R3 is not hydrogen and wherein one or at least one of the substituents R5-R7 is not hydrogen.
Preferably, the compounds of general formula (I) as defined herein are under the proviso that when X is —H at least one of R1-R3 is not —H and under the second proviso that R5, R6 and R7 are not —H at the same time or preferably under the further proviso that at least one of R1-R3 is not —H, when R5 and R6 or R6 and R7 form together
more preferably under the further proviso that when X is —CN or when R4 is —H or —C2H5 or —CH2OH or —C2H4OH, at least one of R5, R6 and R7 is different from —H or still more preferably under the second proviso that in case X is —CN and R4 is —H or —C2H5 or —CH2OH or —C2H4OH, at least one of R5, R6 and R7 is different from —H.
Preferably, a compound of the general formula (Ia)
cyclo-C3H5, cyclo-C4H7, cyclo-C5H8, cyclo-C6H11, cyclo-C7H13, —H, —OH, —OCH3, —OC2H5, —OC3H7, —O-cyclo-C3H5, —OCH(CH3)2, —OC(CH3)3, —OC4H9, —OPh, —OCH2-Ph, —OCPh3, —CH2—OCH3, —C2H4—OCH3, —C3H6—OCH3, —CH2—OC2H5, —C2H4—OC2H5, —C3H6—OC2H5, —CH2—OC3H7, —C2H4—OC3H7, —C3H6—OC3H7, —CH2—O-cyclo-C3H5, —C2H4—O-cyclo-C3H5, —C3H6—O-cyclo-C3H5, —CH2—OCH(CH3)2, —C2H4—OCH(CH3)2, —C3H6—OCH(CH3)2, —CH2—OC(CH3)3, —C2H4—OC(CH3)3, —C3H6—OC(CH3)3, —CH2—OC4H9, —C2H4—OC4H9, —C3H6—OC4H9, —CH2—OPh, —C2H4—OPh, —C3H6—OPh, —CH2—OCH2-Ph, —C2H4—OCH2-Ph, —C3H6—OCH2-Ph, —SH, —SCH3, —SC2H5, —SC3H7, —S-cyclo-C3H5, —SCH(CH3)2, —SC(CH3)3, —F, —Cl, —Br, —I, —CN, —COCH3, —COC2H5, —COC3H7, —CO-cyclo-C3H5, —COCH(CH3)2, —COC(CH3)3, —COGH, —COOCH3, —COOC2H5, —COOC3H7, —COO-cyclo-C3H5, —COOCH(CH3)2, —COOC(CH3)3, —OOC—CH3, —OOC≡C2H5, —OOC≡C3H7, —OOC-cyclo-C3H5, —OOC—CH(CH3)2, —OOC—C(CH3)3, —CONH2, —CONHCH3, —CONHC2H5, —CONHC3H7, —CONH-cyclo-C3H5, —CONH[CH(CH3)2], —CONH[C(CH3)3], —CON(CH3)2, —CON(C2H5)2, —CON(C3H7)2, —CON(cyclo-C3H5)2, —CON[CH(CH3)2]2, —CON[C(CH3)3]2, —NHCOCH3, —NHCOC2H5, —NHCOC3H7, —NHCO-cyclo-C3H5, —NHCO—CH(CH3)2, —NHCO—C(CH3)3, —NHCO—OCH3, —NHCO—OC2H5, —NHCO—OC3H7, —NHCO—O-cyclo-C3H5, —NHCO—OCH(CH3)2, —NHCO—OC(CH3)3, —NH2, —NHCH3, —NHC2H5, —NHC3H7, —NH-cyclo-C3H5, —NHCH(CH3)2, —NHC(CH3)3, —N(CH3)2, —N(C2H5)2, —N(C3H7)2, —N(cyclo-C3H5)2, —N[CH(CH3)2]2, —N[C(CH3)3]2, —SOCH3, —SOC2H5, —SOC3H7, —SO-cyclo-C3H5, —SOCH(CH3)2, —SOC(CH3)3, —SO2CH3, —SO2C2H5, —SO2C3H7, —SO2-cyclo-C3H5, —SO2CH(CH3)2, —SO2C(CH3)3, —SO3H, —SO3CH3, —SO3C2H5, —SO3C3H7, —SO3-cyclo-C3H5, —SO3CH(CH3)2, —SO3C(CH3)3, —SO2NH2, —SO2NHCH3, —SO2NHC2H5, —SO2NHC3H7, —SO2NH-cyclo-C3H5, —SO2NHCH(CH3)2, —SO2NHC(CH3)3, —SO2N(CH3)2, —SO2N(C2H5)2, —SO2N(C3H7)2, —SO2N(cyclo-C3H5)2, —SO2N[CH(CH3)2]2, —SO2N[C(CH3)3]2, —CH2—SO2NH2, —CH2—SO2NHCH3, —CH2—SO2NHC2H5, —CH2—SO2NHC3H7, —CH2—SO2NH-cyclo-C3H5, —CH2—SO2NHCH(CH3)2, —CH2—SO2NHC(CH3)3, —CH2—SO2N(CH3)2, —CH2—SO2N(C2H5)2, —CH2—SO2N(C3H7)2, —CH2—SO2N(cyclo-C3H5)2, —CH2—SO2N[CH(CH3)2]2, —CH2—SO2N[C(CH3)3]2, —O—S(═O)CH3, —O—S(═O)C2H5, —O—S(═O)C3H7, —O—S(═O)-cyclo-C3H5, —O—S(═O)CH(CH3)2, —O—S(═O)C(CH3)3, —S(═O)(═NH)CH3, —S(═O)(═NH)C2H5, —S(═O)(═NH)C3H7, —S(═O)(═NH)-cyclo-C3H5, —S(═O)(═NH)CH(CH3)2, —S(═O)(═NH)C(CH3)3, —NH—SO2—CH3, —NH—SO2—C2H5, —NH—SO2—C3H7, —NH—SO2-cyclo-C3H5, —NH—SO2—CH(CH3)2, —NH—SO2—C(CH3)3, —O—SO2—CH3, —O—SO2—C2H5, —O—SO2—C3H7, —O—SO2-cyclo-C3H5, —O—SO2—CH(CH3)2, —O—SO2—C(CH3)3, —OCH2F, —OCHF2—OCF3, —CH2—OCF3, —C2H4—OCF3, —C3H6—OCF3, —OC2F5, —CH2—OC2F5, —C2H4—OC2F5, —C3H6—OC2F5, —O—COOCH3, —O—COOC2H5, —O—COOC3H7, —O—COO-cyclo-C3H5, —O—COOCH(CH3)2, —O—COOC(CH3)3, —NH—CO—NH2, —NH—CO—NHCH3, —NH—CO—NHC2H5, —NH—CO—NHC3H7, —NH—C(═NH)—NH2, —NH—CO—N(C3H7)2, —NH—CO—NH[CH(CH3)2], —NH—CO—NH[C(CH3)3], —NH—CO—N(CH3)2, —NH—CO—N(C2H5)2, —NH—CO—NH-cyclo-C3H5, —NH—CO—N(cyclo-C3H5)2, —NH—CO—N[CH(CH3)2]2, —NH—C(═NH)—NHCH3, —NH—C(═NH)—NHC2H5, —NH—C(═NH)—NHC3H7, —O—CO—NH-cyclo-C3H5, —NH—C(═NH)—NH-cyclo-C3H5, —NH—C(═NH)—NH[CH(CH3)2], —O—CO—NH[CH(CH3)2], —NH—C(═NH)—NH[C(CH3)3], —NH—C(═NH)—N(CH3)2, —NH—C(═NH)—N(C2H5)2, —NH—C(═NH)—N(C3H7)2, —NH—C(═NH)—N(cyclo-C3H5)2, —O—CO—NHC3H7, —NH—C(═NH)—N[CH(CH3)2]2, —NH—C(═NH)—N[C(CH3)3]2, —O—CO—NH2, —O—CO—NHCH3, —O—CO—NHC2H5, —O—CO—NH[C(CH3)3], —O—CO—N(CH3)2, —O—CO—N(C2H5)2, —O—CO—N(C3H7)2, —O—CO—N(cyclo-C3H5)2, —O—CO—N[CH(CH3)2]2, —O—CO—N[C(CH3)3]2, —O—CO—OCH3, —O—CO—OC2H5, —O—CO—OC3H7, —O—CO—O-cyclo-C3H5, —O—CO—OCH(CH3)2, —O—CO—OC(CH3)3, —CH2F, —CHF2, —CF3, —CH2—CH2F, —CH2—CHF2, —CH2—CF3, cyclo-C5H15, -Ph, —CH2-Ph, —CH2—CH2-Ph, —CH═CH-Ph, —CPh3, —CH3, —C2H5, —C3H7, —CH(CH3)2, —C4H9, —CH2—CH(CH3)2, —CH(CH3)—C2H5, —C(CH3)3, —C5H1l, —CH(CH3)—C3H7, —CH2—CH(CH3)—C2H5, —CH(CH3)—CH(CH3)2, —C(CH3)2—C2H5, —CH2—C(CH3)3, —CH(C2H5)2, —C2H4—CH(CH3)2, —C6H13, —C7H15, —C8H17, —C3H6—CH(CH3)2, —C2H4—CH(CH3)—C2H5, —CH(CH3)—C4H9, —CH2—CH(CH3)—C3H7, —CH(CH3)—CH2—CH(CH3)2, —CH(CH3)—CH(CH3)—C2H5, —CH2—CH(CH3)—CH(CH3)2, —CH2—C(CH3)2—C2H5, —C(CH3)2—C3H7, —C(CH3)2—CH(CH3)2, —C2H4—C(CH3)3, —CH(CH3)—C(CH3)3, —CH═CH2, —CH2—CH═CH2, —C(CH3)═CH2, —CH═CH—CH3, —C2H4—CH═CH2, —CH2—CH═CH—CH3, —CH═CH—C2H5, —CH2—C(CH3)═CH2, —CH(CH3)—CH═CH, —CH═C(CH3)2, —C(CH3)═CH—CH3, —CH═CH—CH═CH2, —C3H6—CH═CH2, —C2H4—CH═CH—CH3, —CH2—CH═CH—C2H5, —CH═CH—C3H7, —CH═CH—CH═CH—CH3, —C2H4—C(CH3)═CH2, —CH2—CH(CH3)—CH═CH2, —CH(CH3)—CH2—CH═CH2, —CH2—CH═C(CH3)2, —CH2—C(CH3)═CH—CH3, —CH(CH3)—CH═CH—CH3, —CH═CH—CH(CH3)2, —CH═C(CH3)—C2H5, —C(CH3)═CH—C2H5, —C(CH3)═C(CH3)2, —C(CH3)2—CH═CH2, —CH(CH3)—C(CH3)═CH2, —C4H8—CH═CH2, —C3H6—CH═CH—CH3, —C2H4—CH═CH—C2H5, —CH2—CH═CH—C3H7, —CH═CH—C4H9, —C3H6—C(CH3)═CH2, —C2H4—CH(CH3)—CH═CH2, —CH2—CH(CH3)—CH2—CH═CH2, —C2H4—CH═C(CH3)2, —CH(CH3)—C2H4—CH═CH2, —C2H4—C(CH3)═CH—CH3, —CH2—CH(CH3)—CH═CH—CH3, —CH(CH3)—CH2—CH═CH—CH3, —CH2—CH═CH—CH(CH3)2, —CH2—CH═C(CH3)—C2H5, —CH2—C(CH3)═CH—C2H5, —CH(CH3)—CH═CH—C2H5, —CH═CH—CH2—CH(CH3)2, —CH═CH—CH(CH3)—C2H5, —CH═C(CH3)—C3H7, —C(CH3)═CH—C3H7, —CH2—CH(CH3)—C(CH3)═CH2, —C[C(CH3)3]═CH2, —CH(CH3)—CH2—C(CH3)═CH2, —CH(CH3)—CH(CH3)—CH═CH2, —CH═CH—C2H4—CH═CH2, —C(CH3)2—CH2—CH═CH2, —CH2—C(CH3)═C(CH3)2, —CH(CH3)—CH═C(CH3)2, —C(CH3)2—CH═CH—CH3, —CH═CH—CH2—CH═CH—CH3, —CH(CH3)—C(CH3)═CH—CH3, —CH═C(CH3)—CH(CH3)2, —C(CH3)═CH—CH(CH3)2, —C(CH3)═C(CH3)—C2H5, —CH═CH—C(CH3)3, —C(CH3)2—C(CH3)═CH2, —CH(C2H5)—C(CH3)═CH2, —C(CH3)(C2H5)—CH═CH2, —CH(CH3)—C(C2H5)═CH2, —CH2—C(C3H7)═CH2, —CH2—C(C2H5)═CH—CH3, —CH(C2H5)—CH═CH—CH3, —C(C4H9)═CH2, —C(C3H7)═CH—CH3, —C(C2H5)═CH—C2H5, —C(C2H5)═C(CH3)2, —C[CH(CH3)(C2H5)]═CH2, —C[CH2—CH(CH3)2]═CH2, —C2H4—CH═CH—CH═CH2, —CH2—CH═CH—CH2—CH═CH2, —C3H6—C═C—CH3, —CH2—CH═CH—CH═CH—CH3, —CH═CH—CH═CH—C2H5, —CH(CH3)—CH2—C═CH, —CH(CH3)—C═C—CH3, —C2H4—CH(CH3)—C═CH, —CH═CH—CH═C(CH3)2, —CH2—CH(CH3)—CH2—C═CH, —CH═CH—C(CH3)═CH—CH3, —CH═C(CH3)—CH═CH—CH3, —CH2—CH(CH3)—C═CH, —C(CH3)═CH—CH═CH—CH3, —C═CH, —C═C—CH3, —CH2—C═CH, —C2H4—C═CH, —CH2—C═C—CH3, —C═C≡C2H5, —C3H6—C═CH, —C2H4—C═C—CH3, —CH2—C═C—C2H5, —C═C≡C3H7, —CH(CH3)—C═CH, —C4H$—C═CH, —C2H4—C═C—C2H5, —CH2—C═C—C3H7, —C═C≡C4H9, —C═C—CH2—CH(CH3)2, —CH(CH3)—C2H4—C═CH, —CH2—CH(CH3)—C═C—CH3, —C(CH3)(C2H5)—C═CH, —CH(CH3)—CH2—C═C—CH3, —CH(CH3)—C═C—C2H5, —CH2—C═C—CH(CH3)2, —C═C—CH(CH3)—C2H5, —CH2—C═C≡C═C—CH3, —CH(C2H5)—C═C—CH3, —C(CH3)2—C═C—CH3, —CH(C2H5)—CH2—C═CH, —CH2—CH(C2H5)—C═CH, —C(CH3)2—CH2—C═CH, —CH2—C(CH3)2—C═CH, —CH(CH3)—CH(CH3)—C═CH, —CH(C3H7)—C═CH, —CH2—CH(C═CH)2, —C═C≡C═CH, —CH2—C═C≡C═CH, —C═C≡C═C—CH3, —CH(C═CH)2, —C2H4—C═C≡C═CH, —CH2—C═C—CH2—C═CH, —C═C≡C2H4—C═CH, —C═C—C(CH3)3, —C═C—CH2—C═C—CH3, or —C═C≡C═C≡C2H5, or
or an enantiomer, a stereoisomeric form, a mixture of enantiomers, a diastereomer, a mixture of diastereomers, a hydrate, a solvate, an acid salt form, a tautomer, or a racemate of the above mentioned compound, or a pharmaceutically acceptable salt thereof.
Preferred are compounds wherein R4 is different from hydrogen (—H). In case R4 is hydrogen one or at least one of the substituents R1-R3 and R5-R7 is not hydrogen and preferably two or three or more than three substituents R1-R3 and R5-R7 are not hydrogen. Even more preferred are the compounds wherein one or at least one of the substituents R4-R7 is not hydrogen. Still more preferred are the compounds wherein one or at least one of the substituents R1-R4 is not hydrogen. Most preferred are the compounds wherein one or at least one of the substituents R1-R3 is not hydrogen and wherein one or at least one of the substituents R5-R7 is not hydrogen.
Preferably, the present invention relates to a compound of the general formula (Ia)
cyclo-C3H5, cyclo-C4H7, cyclo-C5H8, cyclo-C6H11, cyclo-C7H13, —H, —OH, —OH—, —OC2H5, —OC3H7, —O-cyclo-C3H5, —OCH(CH3)2, —OC(CH3)3, —OC4H9, —OPh, —OCH2-Ph, —OCPh3, —CH2—OCH3, —C2H4—OCH3, —C3H6—OCH3, —CH2—OC2H5, —C2H4—OC2H5, —C3H6—OC2H5, —CH2—OC3H7, —C2H4—OC3H7, —C3H6—OC3H7, —CH2—O-cyclo-C3H5, —C2H4—O-cyclo-C3H5, —C3H6—O-cyclo-C3H5, —CH2—OCH(CH3)2, —C2H4—OCH(CH3)2, —C3H6—OCH(CH3)2, —CH2—OC(CH3)3, —C2H4—OC(CH3)3, —C3H6—OC(CH3)3, —CH2—OC4H9, —C2H4—OC4H9, —C3H6—OC4H9, —CH2—OPh, —C2H4—OPh, —C3H6—OPh, —CH2—OCH2-Ph, —C2H4—OCH2-Ph, —C3H6—OCH2-Ph, —SH, —SCH3, —SC2H5, —SC3H7, —S-cyclo-C3H5, —SCH(CH3)2, —SC(CH3)3, —F, —Cl, —Br, —I, —CN, —COCH3, —COC2H5, —COC3H7, —CO-cyclo-C3H5, —COCH(CH3)2, —COC(CH3)3, —COOH, —COOCH3, —COOC2H5, —COOC3H7, —COO-cyclo-C3H5, —COOCH(CH3)2, —COOC(CH3)3, —OOC—CH3, —OOC≡C2H5, —OOC≡C3H7, —OOC-cyclo-C3H5, —OOC—CH(CH3)2, —OOC—C(CH3)3, —CONH2, —CONHCH3, —CONHC2H5, —CONHC3H7, —CONH-cyclo-C3H5, —CONH[CH(CH3)2], —CONH[C(CH3)3], —CON(CH3)2, —CON(C2H5)2, —CON(C3H7)2, —CON(cyclo-C3H5)2, —CON[CH(CH3)2]2, —CON[C(CH3)3]2, —NHCOCH3, —NHCOC2H5, —NHCOC3H7, —NHCO-cyclo-C3H5, —NHCO—CH(CH3)2, —NHCO—C(CH3)3, —NHCO—OCH3, —NHCO—OC2H5, —NHCO—OC3H7, —NHCO—O-cyclo-C3H5, —NHCO—OCH(CH3)2, —NHCO—OC(CH3)3, —NH2, —NHCH3, —NHC2H5, —NHC3H7, —NH-cyclo-C3H5, —NHCH(CH3)2, —NHC(CH3)3, —N(CH3)2, —N(C2H5)2, —N(C3H7)2, —N(cyclo-C3H5)2, —N[CH(CH3)2]2, —N[C(CH3)3]2, —SOCH3, —SOC2H5, —SOC3H7, —SO-cyclo-C3H5, —SOCH(CH3)2, —SOC(CH3)3, —SO2CH3, —SO2C2H5, —SO2C3H7, —SO2-cyclo-C3H5, —SO2CH(CH3)2, —SO2c(cH3)3, —SO3H, —SO3CH3, —SO3C2H5, —SO3C3H7, —SO3-cyclo-C3H5, —SO3CH(CH3)2, —SO3C(CH3)3, —SO2NH2, —SO2NHCH3, —SO2NHC2H5, —SO2NHC3H7, —SO2NH-cyclo-C3H5, —SO2NHCH(CH3)2, —SO2NHC(CH3)3, —SO2N(CH3)2, —SO2N(C2H5)2, —SO2N(C3H7)2, —SO2N(cyclo-C3H5)2, —SO2N[CH(CH3)2]2, —SO2N[C(CH3)3]2, —CH2—SO2NH2, —CH2—SO2NHCH3, —CH2—SO2NHC2H5, —CH2—SO2NHC3H7, —CH2—SO2NH-cyclo-C3H5, —CH2—SO2NHCH(CH3)2, —CH2—SO2NHC(CH3)3, —CH2—SO2N(CH3)2, —CH2—SO2N(C2H5)2, —CH2—SO2N(C3H7)2, —CH2—SO2N(cyclo-C3H5)2, —CH2—SO2N[CH(CH3)2]2, —CH2—SO2N[C(CH3)3]2, —O—S(═O)CH3, —O—S(═O)C2H5, —O—S(═O)C3H7, —O—S(═O)-cyclo-C3H5, —O—S(═O)CH(CH3)2, —O—S(═O)C(CH3)3, —S(═O)(═NH)CH3, —S(═O)(═NH)C2H5, —S(═O)(═NH)C3H7, —S(═O)(═NH)-cyclo-C3H5, —S(═O)(═NH)CH(CH3)2, —S(═O)(═NH)C(CH3)3, —NH—SO2—CH3, —NH—SO2—C2H5, —NH—SO2—C3H7, —NH—SO2-cyclo-C3H5, —NH—SO2—CH(CH3)2, —NH—SO2—C(CH3)3, —O—SO2—CH3, —O—SO2—C2H5, —O—SO2—C3H7, —O—SO2-cyclo-C3H5, —O—SO2—CH(CH3)2, —O—SO2—C(CH3)3, —OCH2F, —OCHF2—OCF3, —CH2—OCF3, —C2H4—OCF3, —C3H6—OCF3, —OC2F5, —CH2—OC2F5, —C2H4—OC2F5, —C3H6—OC2F5, —O—COOCH3, —O—COOC2H5, —O—COOC3H7, —O—COO-cyclo-C3H5, —O—COOCH(CH3)2, —O—COOC(CH3)3, —NH—CO—NH2, —NH—CO—NHCH3, —NH—CO—NHC2H5, —NH—CO—NHC3H7, —NH—C(═NH)—NH2, —NH—CO—N(C3H7)2, —NH—CO—NH[CH(CH3)2], —NH—CO—NH[C(CH3)3], —NH—CO—N(CH3)2, —NH—CO—N(C2H5)2, —NH—CO—NH-cyclo-C3H5, —NH—CO—N(cyclo-C3H5)2, —NH—CO—N[CH(CH3)2]2, —NH—C(═NH)—NHCH3, —NH—C(═NH)—NHC2H5, —NH—C(═NH)—NHC3H7, —O—CO—NH-cyclo-C3H5, —NH—C(═NH)—NH-cyclo-C3H5, —NH—C(═NH)—NH[CH(CH3)2], —O—CO—NH[CH(CH3)2], —NH—C(═NH)—NH[C(CH3)3], —NH—C(═NH)—N(CH3)2, —NH—C(═NH)—N(C2H5)2, —NH—C(═NH)—N(C3H7)2, —NH—C(═NH)—N(cyclo-C3H5)2, —O—CO—NHC3H7, —NH—C(═NH)—N[CH(CH3)2]2, —NH—C(═NH)—N[C(CH3)3]2, —O—CO—NH2, —O—CO—NHCH3, —O—CO—NHC2H5, —O—CO—NH[C(CH3)3], —O—CO—N(CH3)2, —O—CO—N(C2H5)2, —O—CO—N(C3H7)2, —O—CO—N(cyclo-C3H5)2, —O—CO—N[CH(CH3)2]2, —O—CO—N[C(CH3)3]2, —O—CO—OCH3, —O—CO—OC2H5, —O—CO—OC3H7, —O—CO—O-cyclo-C3H5, —O—CO—OCH(CH3)2, —O—CO—OC(CH3)3, —CH2F, —CHF2, —CF3, —CH2—CH2F, —CH2—CHF2, —CH2—CF3, cyclo-C3H15, -Ph, —CH2-Ph, —CH2—CH2-Ph, —CH═CH-Ph, —CPh3, —CH3, —C2H5, —C3H7, —CH(CH3)2, —C4H9, —CH2—CH(CH3)2, —CH(CH3)—C2H5, —C(CH3)3, —C5H11, —CH(CH3)—C3H7, —CH2—CH(CH3)—C2H5, —CH(CH3)—CH(CH3)2, —C(CH3)2—C2H5, —CH2—C(CH3)3, —CH(C2H5)2, —C2H4—CH(CH3)2, —C6H13, —C7H15, —C8H17, —C3H6—CH(CH3)2, —C2H4—CH(CH3)—C2H5, —CH(CH3)—C4H9, —CH2—CH(CH3)—C3H7, —CH(CH3)—CH2—CH(CH3)2, —CH(CH3)—CH(CH3)—C2H5, —CH2—CH(CH3)—CH(CH3)2, —CH2—C(CH3)2—C2H5, —C(CH3)2—C3H7, —C(CH3)2—CH(CH3)2, —C2H4—C(CH3)3, —CH(CH3)—C(CH3)3, —CH═CH2, —CH2—CH═CH2, —C(CH3)═CH2, —CH═CH—CH3, —C2H4—CH═CH2, —CH2—CH═CH—CH3, —CH═CH—C2H5, —CH2—C(CH3)═CH2, —CH(CH3)—CH═CH, —CH═C(CH3)2, —C(CH3)═CH—CH3, —CH═CH—CH═CH2, —C3H6—CH═CH2, —C2H4—CH═CH—CH3, —CH2—CH═CH—C2H5, —CH═CH—C3H7, —CH═CH—CH═CH—CH3, —C2H4—C(CH3)═CH2, —CH2—CH(CH3)—CH═CH2, —CH(CH3)—CH2—CH═CH2, —CH2—CH═C(CH3)2, —CH2—C(CH3)═CH—CH3, —CH(CH3)—CH═CH—CH3, —CH═CH—CH(CH3)2, —CH═C(CH3)—C2H5, —C(CH3)═CH—C2H5, —C(CH3)═C(CH3)2, —C(CH3)2—CH═CH2, —CH(CH3)—C(CH3)═CH2, —C4H8—CH═CH2, —C3H6—CH═CH—CH3, —C2H4—CH═CH—C2H5, —CH2—CH═CH—C3H7, —CH═CH—C4H9, —C3H6—C(CH3)═CH2, —C2H4—CH(CH3)—CH═CH2, —CH2—CH(CH3)—CH2—CH═CH2, —C2H4—CH═C(CH3)2, —CH(CH3)—C2H4—CH═CH2, —C2H4—C(CH3)═CH—CH3, —CH2—CH(CH3)—CH═CH—CH3, —CH(CH3)—CH2—CH═CH—CH3, —CH2—CH═CH—CH(CH3)2, —CH2—CH═C(CH3)—C2H5, —CH2—C(CH3)═CH—C2H5, —CH(CH3)—CH═CH—C2H5, —CH═CH—CH2—CH(CH3)2, —CH═CH—CH(CH3)—C2H5, —CH═C(CH3)—C3H7, —C(CH3)═CH—C3H7, —CH2—CH(CH3)—C(CH3)═CH2, —C[C(CH3)3]═CH2, —CH(CH3)—CH2—C(CH3)═CH2, —CH(CH3)—CH(CH3)—CH═CH2, —CH═CH—C2H4—CH═CH2, —C(CH3)2—CH2—CH═CH2, —CH2—C(CH3)═C(CH3)2, —CH(CH3)—CH═C(CH3)2, —C(CH3)2—CH═CH—CH3, —CH═CH—CH2—CH═CH—CH3, —CH(CH3)—C(CH3)═CH—CH3, —CH═C(CH3)—CH(CH3)2, —C(CH3)═CH—CH(CH3)2, —C(CH3)═C(CH3)—C2H5, —CH═CH—C(CH3)3, —C(CH3)2—C(CH3)═CH2, —CH(C2H5)—C(CH3)═CH2, —C(CH3)(C2H5)—CH═CH2, —CH(CH3)—C(C2H5)═CH2, —CH2—C(C3H7)═CH2, —CH2—C(C2H5)═CH—CH3, —CH(C2H5)—CH═CH—CH3, —C(C4H9)═CH2, —C(C3H7)═CH—CH3, —C(C2H5)═CH—C2H5, —C(C2H5)═C(CH3)2, —C[CH(CH3)(C2H5)]═CH2, —C[CH2—CH(CH3)2]═CH2, —C2H4—CH═CH—CH═CH2, —CH2—CH═CH—CH2—CH═CH2, —C3H6—C═C—CH3, —CH2—CH═CH—CH═CH—CH3, —CH═CH—CH═CH—C2H5, —CH(CH3)—CH2—C═CH, —CH(CH3)—C═C—CH3, —C2H4—CH(CH3)—C═CH, —CH═CH—CH═C(CH3)2, —CH2—CH(CH3)—CH2—C═CH, —CH═CH—C(CH3)═CH—CH3, —CH═C(CH3)—CH═CH—CH3, —CH2—CH(CH3)—C═CH, —C(CH3)═CH—CH═CH—CH3, —C═CH, —C═C—CH3, —CH2—C═CH, —C2H4—C═CH, —CH2—C═C—CH3, —C═C≡C2H5, —C3H6—C═CH, —C2H4—C═C—CH3, —CH2—C═C—C2H5, —C═C≡C3H7, —CH(CH3)—C═CH, —C4H8—C═CH, —C2H4—C═C—C2H5, —CH2—C═C—C3H7, —C═C≡C4H9, —C═C—CH2—CH(CH3)2, —CH(CH3)—C2H4—C═CH, —CH2—CH(CH3)—C═C—CH3, —C(CH3)(C2H5)—C═CH, —CH(CH3)—CH2—C═C—CH3, —CH(CH3)—C═C—C2H5, —CH2—C═C—CH(CH3)2, —C═C—CH(CH3)—C2H5, —CH2—C═C≡C═C—CH3, —CH(C2H5)—C═C—CH3, —C(CH3)2—C═C—CH3, —CH(C2H5)—CH2—C═CH, —CH2—CH(C2H5)—C═CH, —C(CH3)2—CH2—C═CH, —CH2—C(CH3)2—C═CH, —CH(CH3)—CH(CH3)—C═CH, —CH(C3H7)—C═CH, —CH2—CH(C═CH)2, —C═C≡C═CH, —CH2—C═C≡C═CH, —C═C≡C═C—CH3, —CH(C═CH)2, —C2H4—C═C≡C═CH, —CH2—C═C—CH2—C═CH, —C═C≡C2H4—C═CH, —C═C—C(CH3)3, —C═C—CH2—C═C—CH3, or —C═C≡C═C≡C2H5, or
or an enantiomer, a stereoisomeric form, a mixture of enantiomers, a diastereomer, a mixture of diastereomers, a hydrate, a solvate, an acid salt form, a tautomer, or a racemate of the above mentioned compound, or a pharmaceutically acceptable salt thereof.
Preferred are compounds wherein R4 is different from hydrogen (—H). In case R4 is hydrogen one or at least one of the substituents R1-R3 and R5-R7 is not hydrogen and preferably two or three or more than three substituents R1-R3 and R5-R7 are not hydrogen. Even more preferred are the compounds wherein one or at least one of the substituents R4-R7 is not hydrogen. Still more preferred are the compounds wherein one or at least one of the substituents R1-R4 is not hydrogen. Most preferred are the compounds wherein one or at least one of the substituents R1-R3 is not hydrogen and wherein one or at least one of the substituents R5-R7 is not hydrogen.
Preferably, the compounds of general formula (Ia) as defined herein are under the proviso that when X is —H at least one of R1-R3 is not —H and under the second proviso that R5, R6 and R7 are not —H at the same time or preferably under the further proviso that at
least one of R1-R3 is not —H, when R5 and R6 or R6 and R7 form together
more preferably under the further proviso that when X is —CN or when R4 is —H or —C2H5 or —CH2OH or —C2H4OH, at least one of R5, R6 and R7 is different from —H or still more preferably under the second proviso that in case X is —CN and R4 is —H or —C2H5 or —CH2OH or —C2H4OH, at least one of R5, R6 and R7 is different from —H.
Also preferred are the following general formulae (Ia-1), (Ia-2), (Ia-3), and (Ia-4)
wherein the substituents R1-R7 and X have the meanings or the preferred meanings as disclosed herein, but the substituents R1 and R2 are different from hydrogen (—H).
In general formula (I) and all other general formulae disclosed herein, the substituents R5 and R6 or R6 and R7 form together preferably one of the following five-membered ring systems
more preferably one of the following five-membered ring systems
still more preferably one of the following five-membered ring systems
In some embodiments, the present invention refers to the compound of the formula (I), or (Ia), wherein
wherein R9, R10, R11, R12, RN2, Z3, Z4 have the meanings as defined in the formula (I).
In some embodiments, the present invention refers to the compound of the formula (I), wherein
R10 is —CH(CH3)2, —CH2—CH(CH3)2, —CH(CH3)—C2H5, —(CH2)n—N(CH3)2,
wherein n, p, R11, R12, RN2, Z3, Z4 have the meanings as defined in the formula (I).
Preferred, is the compound of the formula (I):
R8 represents
preferably
Preferably, R11 and R12 represent independently of each other —H, —CH3, —C2H5, —C3H7, —CH(CH3)2, —CF3, —(CH2)m—N(CH3)2, —(CH2)m—N(C2H5)2, —OCH3, —OC2H5, —OC3H7, —O-cyclo-C3H5, —OCH(CH3)2, —F, —Cl, —Br, —CN, —(CH2)m—SO2CH3, —(CH2)m-SO2cyclo-C3H5, —O—(CH2)m—N(CH3)2, —O—(CH2)m—N(C2H5)2, —NHCOCH3, —(CH2)m—NHCOCH3, —(CH2)m—NHCOC2H5, —(CH2)m—NHCO-cyclo-C3H5, —(CH2)m—NHCO—CH(CH3)2, —(CH2)m—NHCO—CH═CH2, —SO2NH2, —SO2NHCH3, —SO2NHC2H5, —SO2NHC3H7, —SO2NH-cyclo-C3H5, —SO2NHCH(CH3)2, —SO2N(CH3)2, —SO2N(C2H5)2, —SO2N(C3H7)2, —SO2N(cyclo-C3H5)2, —SO2N[CH(CH3)2]2, —NH—SO2—CH3, —NH—SO2—C2H5, —NH—SO2—C3H7, —NH—SO2-cyclo-C3H5, —NH—SO2—CH(CH3)2, —CONH2, —SOCH3, —SOC2H5, —SOC3H7, —SO-cyclo-C3H5, —SOCH(CH3)2, —SCH3, —SOCF3, —SO2CF3, or —SO(NH)CH3;
More preferably, R11 and R12 represent independently of each other —H, —CH3, —C2H5, —CF3, —(CH2)m—N(CH3)2, —OCH3, —OC2H5, —F, —Cl, —Br, —CN, —(CH2)m—SO2CH3, —(CH2)m—SO-cyclo-C3H5, —O—(CH2)m—N(CH3)2, —NHCOCH3, —(CH2)m—NHCOCH3, —(CH2)m—NHCO—CH═CH2, —SO2NH2, —SO2NHCH3, —SO2N(CH3)2, —SO2N(C2H5)2, —SO2N(C3H7)2, —NH—SO2—CH3, —NH—SO2—C2H5, —NH—SO2—C3H7, —NH—SO2-cyclo-C3H5, —NH—SO2—CH(CH3)2, —CONH2, —SOCH3, —SOC2H5, —SOC3H7, —SO-cyclo-C3H5, —SOCH(CH3)2, —SCH3, —SOCF3, —SO2CF3, or —SO(NH)CH3;
RN1 and RN2 represents independently of each other —H, —CH3, —C2H5, —C3H7, —CH(CH3)2, cyclo-C3H5, cyclo-C4H7, —CH2—CH(CH3)2, -Ph, —CH2-Ph, —COCH3, —COC2H5, —COC3H7, —CO-cyclo-C3H5, —COCH(CH3)2, —COOCH3, —COOC2H5, —COOC3H7, —COO-cyclo-C3H5, —COOCH(CH3)2, —COOC(CH3)3, —CH2CH(OH)—CH3, (CH2)q—NH2, —(CH2)q—NHCH3, —(CH2)q—NHC2H5, —(CH2)q—NHC3H7, —(CH2)q—N(CH3)2, —(CH2)q—N(C2H5)2, —(CH2)q—N(C3H7)2,
Also preferred, is the compound of the formula (Ia):
more preferred, R5 and R6, or R6 and R7 form
preferably
Preferably, R11 and R12 represent independently of each other —H, —CH3, —C2H5, —C3H7, —CH(CH3)2, —CF3, —(CH2)m—N(CH3)2, —(CH2)m—N(C2H5)2, —OCH3, —OC2H5, —OC3H7, —O-cyclo-C3H5, —OCH(CH3)2, —F, —Cl, —Br, —CN, —(CH2)m—SO2CH3, —(CH2)m—SO2-cyclo-C3H5, —O—(CH2)m—N(CH3)2, —O—(CH2)m—N(C2H5)2, —NHCOCH3, —(CH2)m—NHCOCH3, —(CH2)m—NHCOC2H5, —(CH2)m—NHCO-cyclo-C3H5, —(CH2)m—NHCO—CH(CH3)2, —(CH2)m—NHCO—CH═CH2, —SO2NH2, —SO2NHCH3, —SO2NHC2H5, —SO2NHC3H7, —SO2NH-cyclo-C3H5, —SO2NHCH(CH3)2, —SO2N(CH3)2, —SO2N(C2H5)2, —SO2N(C3H7)2, —SO2N(cyclo-C3H5)2, —SO2N[CH(CH3)2]2, —NH—SO2—CH3, —NH—SO2—C2H5, —NH—SO2—C3H7, —NH—SO2-cyclo-C3H5, —NH—SO2—CH(CH3)2, —CONH2, —SOCH3, —SOC2H5, —SOC3H7, —SO-cyclo-C3H5, —SOCH(CH3)2, —SCH3, —SOCF3, —SO2CF3, or —SO(NH)CH3;
More preferably, R11 and R12 represent independently of each other —H, —CH3, —C2H5, —CF3, —(CH2)m—N(CH3)2, —OCH3, —OC2H5, —F, —Cl, —Br, —CN, —(CH2)m—SO2CH3, (CH2)m—SO2-cyclo-C3H5, —O—(CH2)m—N(CH3)2, —NHCOCH3, —(CH2)m—NHCOCH3, —(CH2)m—NHCO—CH═CH2, —SO2NH2, —SO2NHCH3, —SO2N(CH3)2, —SO2N(C2H5)2, —SO2N(C3H7)2, —NH—SO2—CH3, —NH—SO2—C2H5, —NH—SO2—C3H7, —NH—SO2-cyclo-C3H5, —NH—SO2—CH(CH3)2, —CONH2, —SOCH3, —SOC2H5, —SOC3H7, —SO-cyclo-C3H5, —SOCH(CH3)2, —SCH3, —SOCF3, —SO2CF3, or —SO(NH)CH3;
RN1 and RN2 represents independently of each other —H, —CH3, —C2H5, —C3H7, —CH(CH3)2, cyclo-C3H5, cyclo-C4H7, —CH2—CH(CH3)2, -Ph, —CH2-Ph, —COCH3, —COC2H5, —COC3H7, —CO-cyclo-C3H5, —COCH(CH3)2, —COOCH3, —COOC2H5, —COOC3H7, —COO-cyclo-C3H5, —COOCH(CH3)2, —COOC(CH3)3, —CH2—CH(OH)—CH3, —(CH2)q—NH2, —(CH2)q—NHCH3, —(CH2)q—NHC2H5, —(CH2)q—NHC3H7, —(CH2)q—N(CH3)2, —(CH2)q—N(C2H5)2, —(CH2)q—N(C3H7)2,
More preferred, is the compound of the formula (I)
with the proviso that when X is —H at least one of R1-R3 is not —H; when R4 is —H, at least one of R1-R3 and R5-R7 is not —H; and (E)-N-benzyl-2-cyano-3-(1H-pyrrolo[2,3-b]pyridin-3-yl)acrylamide and (E)-N-(1,3-benzodioxol-5-yl-methyl)-2-cyano-3-(1H-pyrrolo[2,3-b]pyridin-3-yl)acrylamide are excluded;
More preferred, is the compound of the formula (Ia)
Still more preferred, is the compound of the formula (Ia)
or R5 and R6, or R6 and R7 form
In some embodiments, the present invention relates to the compound having any one of the formulae (Ia), (Ib). (II-1)-(II-5):
In formulae (I1-1) and (11-5) R1 is preferably not —H.
In formulae (II-2) and (11-6) R2 is preferably not —H.
In formulae (II-3) and (11-4) when X is —H at least one of R1-R3 is not —H and preferably at least one of R5, Re and R7 is not —H; or more preferably in case X is —CN at least one of R5, R6 and R7 is not —H.
Preferably, is the compound of any one of the formulae (II-1) to (II-6), wherein
preferably
Preferably, R11 and R12 represent independently of each other —H, —CH3, —C2H5, —C3H7, —CH(CH3)2, —CF3, —(CH2)m—N(CH3)2, —(CH2)m—N(C2H5)2, —OCH3, —OC2H5, —OC3H7, —O-cyclo-C3H5, —OCH(CH3)2, —F, —Cl, —Br, —CN, —(CH2)m—SO2CH3, —(CH2)m—SO2-cyclo-C3H5, —O—(CH2)m—N(CH3)2, —O—(CH2)m—N(C2H5)2, —NHCOCH3, —(CH2)m—NHCOCH3, —(CH2)m—NHCOC2H5, —(CH2)m—NHCO-cyclo-C3H5, —(CH2)m—NHCO—CH(CH3)2, —(CH2)m—NHCO—CH═CH2, —SO2NH2, —SO2NHCH3, —SO2NHC2H5, —SO2NHC3H7, —SO2NH-cyclo-C3H5, —SO2NHCH(CH3)2, —SO2N(CH3)2, —SO2N(C2H5)2, —SO2N(C3H7)2, —SO2N(cyclo-C3H5)2, —SO2N[CH(CH3)2]2, —NH—SO2—CH3, —NH—SO2—C2H5, —NH—SO2—C3H7, —NH—SO2-cyclo-C3H5, —NH—SO2—CH(CH3)2, —CONH2, —SOCH3, —SOC2H5, —SOC3H7, —SO-cyclo-C3H5, —SOCH(CH3)2, —SCH3, —SOCF3, —SO2CF3, or —SO(NH)CH3;
More preferably, R11 and R12 represent independently of each other —H, —CH3, —C2H5, —CF3, —(CH2)m—N(CH3)2, —OCH3, —OC2H5, —F, —Cl, —Br, —CN, —(CH2)m—SO2CH3, —(CH2)m—SO2-cyclo-C3H5, —O—(CH2)m—N(CH3)2, —NHCOCH3, —(CH2)m—NHCOCH3, —(CH2)m—NHCO—CH═CH2, —SO2NH2, —SO2NHCH3, —SO2N(CH3)2, —SO2N(C2H5)2, —SO2N(C3H7)2, —NH—SO2—CH3, —NH—SO2—C2H5, —NH—SO2—C3H7, —NH—SO2-cyclo-C3H5, —NH—SO2—CH(CH3)2, —CONH2, —SOCH3, —SOC2H5, —SOC3H7, —SO-cyclo-C3H5, —SOCH(CH3)2, —SCH3, —SOCF3, —SO2CF3, or —SO(NH)CH3; RN1 and RN2 represents independently of each other —H, —CH3, —C2H5, —C3H7, —CH(CH3)2, cyclo-C3H5, cyclo-C4H7, —CH2—CH(CH3)2, -Ph, —CH2-Ph, —COCH3, —COC2H5, —COC3H7, —CO-cyclo-C3H5, —COCH(CH3)2, —COOCH3, —COOC2H5, —COOC3H7, —COO-cyclo-C3H5, —COOCH(CH3)2, —COOC(CH3)3, —CH2—CH(OH)—CH3, —(CH2)q—NH2, —(CH2)q—NHCH3, —(CH2)q—NHC2H5, —(CH2)q—NHC3H7, —(CH2)q—N(CH3)2, —(CH2)q—N(C2H5)2, —(CH2)q—N(C3H7)2,
More preferably, is the compound of any one of the formulae (II-1) to (II-6), wherein X represents —H or —CN;
with the proviso that when X is —H, at least one of R1-R3 is not —H; when R4 is —H, at least one of R1-R3 and R5-R7 is not —H; and (E)-N-benzyl-2-cyano-3-(1H-pyrrolo[2,3-b]pyridin-3-yl)acrylamide and (E)-N-(1,3-benzodioxol-5-yl-methyl)-2-cyano-3-(1H-pyrrolo[2,3-b]pyridin-3-yl)acrylamide are excluded;
Still more preferably, is the compound of any one of the formulae (II-1) to (II-6), wherein
In formulae (III-4), (III-5) and (III-6) R2 is preferably not —H.
In formulae (III-2) and (III-3) when X is —H at least one of R1-R3 is not —H and preferably at least one of R6 and R7 is not —H; or more preferably in case X is —CN at least one of R6 and R7 is not —H.
In formula (III-1) when X is —H at least one of R1-R3 is not —H and preferably at least one of R6 and R7 is not —H; or more preferably in case X is —CN or R4 is —H or —C2H5 or —CH2OH or —C2H4OH, at least one of R6 and R7 is not —H; or still more preferably in case X is —CN and R4 is —H or —C2H5 or —CH2OH or —C2H4OH, at least one of R6 and R7 is not —H.
Preferably, is the compound of any one of the formulae (III-1) to (III-6), wherein X represents —H or —CN,
preferably
Preferably, R11 and R12 represent independently of each other —H, —CH3, —C2H5, —C3H7, —CH(CH3)2, —CF3, —(CH2)m—N(CH3)2, —(CH2)m—N(C2H5)2, —OCH3, —OC2H5, —OC3H7, —O-cyclo-C3H5, —OCH(CH3)2, —F, —Cl, —Br, —CN, —(CH2)m—SO2CH3, —(CH2)mSO2-cyclo-C3H5, —O—(CH2)m—N(CH3)2, —O—(CH2)m—N(C2H5)2, —NHCOCH3, —(CH2)m—NHCOCH3, —(CH2)m—NHCOC2H5, (CH2)m—NHCO-cyclo-C3H5, (CH2)m—NHCO—CH(CH3)2, (CH2)m—NHCO—CH═CH2, —SO2NH2, —SO2NHCH3, —SO2NHC2H5, —SO2NHC3H7, —SO2NH-cyclo-C3H5, —SO2NHCH(CH3)2, —SO2N(CH3)2, —SO2N(C2H5)2, —SO2N(C3H7)2, —SO2N(cyclo-C3H5)2, —SO2N[CH(CH3)2]2, —NH—SO2—CH3, —NH—SO2—C2H5, —NH—SO2—C3H7, —NH—SO2-cyclo-C3H5, —NH—SO2—CH(CH3)2, —CONH2, —SOCH3, —SOC2H5, —SOC3H7, —SO-cyclo-C3H5, —SOCH(CH3)2, —SCH3, —SOCF3, —SO2CF3, or —SO(NH)CH3;
More preferably, R11 and R12 represent independently of each other —H, —CH3, —C2H5, —CF3, —(CH2)m—N(CH3)2, —OCH3, —OC2H5, —F, —Cl, —Br, —CN, —(CH2)m—SO2CH3, —(CH2)m—SO2-cyclo-C3H5, —O—(CH2)m—N(CH3)2, —NHCOCH3, —(CH2)m—NHCOCH3, —(CH2)m—NHCO—CH═CH2, —SO2NH2, —SO2NHCH3, —SO2N(CH3)2, —SO2N(C2H5)2, —SO2N(C3H7)2, —NH—SO2—CH3, —NH—SO2—C2H5, —NH—SO2—C3H7, —NH—SO2-cyclo-C3H5, —NH—SO2—CH(CH3)2, —CONH2, —SOCH3, —SOC2H5, —SOC3H7, —SO-cyclo-C3H5, —SOCH(CH3)2, —SCH3, —SOCF3, —SO2CF3, or —SO(NH)CH3;
More preferably, is the compound of any one of the formulae (III-1) to (III-6), wherein X represents —H or —CN;
Still more preferably, is the compound of any one of the formulae (III-1) to (III-6), wherein
In some embodiments, the present invention relates to the compound having any one of the formulae (IV-1)-(IV-6) and (V-1)-(V-6):
In formulae (IV-4), (IV-5) and (IV-6) R2 is preferably not —H.
In formula (V-1) one of R6 and R7 is preferably not —H.
Preferably, is the compound of any one of the formulae (IV-1) to (IV-6),
Preferably, R11 and R12 represent independently of each other —H, —CH3, —C2H5, —C3H7, —CH(CH3)2, —CF3, —(CH2)m—N(CH3)2, —(CH2)m—N(C2H5)2, —OCH3, —OC2H5, —OC3H7, —O-cyclo-C3H5, —OCH(CH3)2, —F, —Cl, —Br, —CN, —(CH2)m—SO2CH3, —(CH2)m—SO2-cyclo-C3H5, —O—(CH2)m—N(CH3)2, —O—(CH2)m—N(C2H5)2, —NHCOCH3, —(CH2)m—NHCOCH3, —(CH2)m—NHCOC2H5, —(CH2)m—NHCO-cyclo-C3H5, —(CH2)m—NHCO—CH(CH3)2, —(CH2)m—NHCO—CH═CH2, —SO2NH2, —SO2NHCH3, —SO2NHC2H5, —SO2NHC3H7, —SO2NH-cyclo-C3H5, —SO2NHCH(CH3)2, —SO2N(CH3)2, —SO2N(C2H5)2, —SO2N(C3H7)2, —SO2N(cyclo-C3H5)2, —SO2N[CH(CH3)2]2, —NH—SO2—CH3, —NH—SO2—C2H5, —NH—SO2—C3H7, —NH—SO2-cyclo-C3H5, —NH—SO2—CH(CH3)2, —CONH2, —SOCH3, —SOC2H5, —SOC3H7, —SO-cyclo-C3H5, —SOCH(CH3)2, —SCH3, —SOCF3, —SO2CF3, or —SO(NH)CH3;
More preferably, R11 and R12 represent independently of each other —H, —CH3, —C2H5, —CF3, —(CH2)m—N(CH3)2, —OCH3, —OC2H5, —F, —Cl, —Br, —CN, —(CH2)m—SO2CH3, —(CH2)m—SO2-cyclo-C3H5, —O—(CH2)m—N(CH3)2, —NHCOCH3, —(CH2)m—NHCOCH3, —(CH2)m—NHCO—CH═CH2, —SO2NH2, —SO2NHCH3, —SO2N(CH3)2, —SO2N(C2H5)2, —SO2N(C3H7)2, —NH—SO2—CH3, —NH—SO2—C2H5, —NH—SO2—C3H7, —NH—SO2-cyclo-C3H5, —NH—SO2—CH(CH3)2, —CONH2, —SOCH3, —SOC2H5, —SOC3H7, —SO-cyclo-C3H5, —SOCH(CH3)2, —SCH3, —SOCF3, —SO2CF3, or —SO(NH)CH3, RN2 represents —H, —CH3, —C2H5, —C3H7, —CH(CH3)2, cyclo-C3H5, cyclo-C4H7, —CH2—CH(CH3)2, -Ph, —CH2-Ph, —COCH3, —COC2H5, —COC3H7, —CO-cyclo-C3H5, —COCH(CH3)2, —COOCH3, —COOC2H5, —COOC3H7, —COO-cyclo-C3H5, —COOCH(CH3)2, —COOC(CH3)3, —CH2—CH(OH)—CH3, —(CH2)q—NH2, —(CH2)q—NHCH3, —(CH2)q—NHC2H5, —(CH2)q—NHC3H7, —(CH2)q—N(CH3)2, —(CH2)q—N(C2H5)2, —(CH2)q—N(C3H7)2,
More preferably, is the compound of any one of the formulae (IV-1) to (IV-6), wherein X represents —H or —CN;
Still more preferably, is the compound of any one of the formulae (IV-1) to (IV-6), wherein
Preferred, is the compound of any one of the formulae (V-1) to (V-6):
Preferably, R11 and R12 represent independently of each other —H, —CH3, —C2H5, —C3H7, —CH(CH3)2, —CF3, —(CH2)m—N(CH3)2, —(CH2)m—N(C2H5)2, —OCH3, —OC2H5, —OC3H7, —O-cyclo-C3H5, —OCH(CH3)2, —F, —Cl, —Br, —CN, —(CH2)m—SO2CH3, —(CH2)m—SO2-cyclo-C3H5, —O—(CH2)m—N(CH3)2, —O—(CH2)m—N(C2H5)2, —NHCOCH3, —(CH2)m—NHCOCH3, —(CH2)m—NHCOC2H5, —(CH2)m—NHCO-cyclo-C3H5, —(CH2)m—NHCO—CH(CH3)2, —(CH2)m—NHCO—CH═CH2, —SO2NH2, —SO2NHCH3, —SO2NHC2H5, —SO2NHC3H7, —SO2NH-cyclo-C3H5, —SO2NHCH(CH3)2, —SO2N(CH3)2, —SO2N(C2H5)2, —SO2N(C3H7)2, —SO2N(cyclo-C3H5)2, —SO2N[CH(CH3)2]2, —NH—SO2—CH3, —NH—SO2—C2H5, —NH—SO2—C3H7, —NH—SO2-cyclo-C3H5, —NH—SO2—CH(CH3)2, —CONH2, —SOCH3, —SOC2H5, —SOC3H7, —SO-cyclo-C3H5, —SOCH(CH3)2, —SCH3, —SOCF3, —SO2CF3, or —SO(NH)CH3;
More preferred, is the compound of any one of the formulae (V-1) to (V-6):
R10 represents —CH(CH3)2, —CH2—CH(CH3)2, —CH(CH3)—C2H5, —(CH2)n—N(CH3)2,
Preferably, the present invention relates to the compound having any one of the formulae (VI-1)-(VI-6):
Especially preferred compounds according to the present invention include compounds presented by Table 1.
The compound of formula (I) is prepared by reference to the methods illustrated in the following schemes 1-4. The compound of formula (I) is produced by Schemes 1-4 by the suitable selection of reagents with appropriate substitutions. Solvents, temperatures, pressures, and other reaction conditions may readily be selected by one of ordinary skill in the art. Starting materials are commercially available or readily prepared by one of ordinary skill in the art.
As shown in Scheme 1, in some embodiments, the present invention is directed to a method for producing the compound of the formula (I) comprising:
In each of the steps 2, and 2a condensation reaction is performed in the present of an amine such as pyridine, piperidine and a mixture thereof. The molar ratio of compound 2* and compound 3* is 1:1 to 1:3, preferred 1:1 to 1:2, more preferred, 1:1 to 1:1.5, most preferred 1:1.2 to 1:1.5. The molar ratio of compound 2* and maleic acid or cyanoacetic acid is 1:1 to 1:5, preferred 1:1 to 1:4, more preferred, 1:2 to 1:4, most preferred 1:2 to 1:3. The reaction temperature is in a range of 70° C. to 150° C., preferred 80° C. to 130° C., more preferred 90° C. to 120° C., and most preferred 100° C. to 120° C.
In each of the steps 3, the amide coupling reaction is performed in the presence of a coupling reagent and a base in an aprotic solvent. The coupling reagent activates a carboxyl acid of compound (4*) and promote the coupling reaction with an amino group of the compound (5*). Any of the following coupling reagent can be used to activate the carboxylic group: BOP, PyBOP, AOP, PyAOP, TBTU, EEDQ, Polyphosphoric Acid (PPA), DPPA, HATU, HOBt, HOAt, DCC, EDCI, BOP-CI, TFFH, Brop, PyBrop, and CIP, preferred HATU and HOBt. The base may be a tertiary amine such as Et3N, and DIPEA, DABCO, DBU, pyrrolidine or piperidine. The molar ratio of the compound (4*) and compound 5* is in a range of 1:1 to 1:2, preferred 1:1 to 1.5, and the molar ratio of the comopund (4*) and the coupling reagent is in a range of 1:1 to 1:2, preferred 1:1 to 1:1.5. The molar ratio of the comopund (4*) and the base is in a range of 1:1 to 1:5, preferred 1:2 to 1:4. The aprotic solvent is DMF, acetonirile, dichloromethane, chlorform, THF, dioxane, or a mixture thereof. The reaction temperature is in a range of −20° C. to 30° C., preferred −10° C. to 30° C., more preffered −10° C. to 20° C., and most preferred −10° C. to 10° C.
An alternative synthetic route to obtain the product compound Ia is shown in Scheme 2.
Step4A: Performing a Mitsunobu reaction of compound 6* with alcohol compound 6 to obtain the product compound (Ia) using standard Mitsunobu-conditions.
In the Step 4A, the molar ratio of compound 6* and compound 7* is in a range of 1:1 to 1:2, preferred 1:1 to 1:1.5, more preferred 1:1 to 1:1.3. The molar ratio of compound 6* and tripehnylphosphine (TTP) is in a range of 1:1 to 1:5, preferred 1:1 to 1:3, more preferred 1:1 to 1:2. The molar ratio of compound 6* and diisopropyl azodicarboxylate (DIAD) is in a range of 1:1 to 1:3, preferred, 1:1 to 1:2, more preferred 1:1 to 1:1.5. The reaction is pefomred in an aprotic solvent such as dichloromethane, and chlorform. The reaction temperature is in a range of −20° C. to 30° C., preferred −10° C. to 30° C., more preffered −10° C. to 30° C., and most preferred 0° C. to 25° C.
Another method for producing a compound of the formula (Ia) is shown in Scheme 3. Step 4B: Performing a cross-coupling reaction of the compound 8* with compound 9* in the presence of a palladium catalyst and base to obtain the final compound (Ia).
In the step 4B, coupling compound is performed in the present of the palladium catalyst, and the base. The palladium catalyst for C-C coupling reaction (Suzuki reaction) is Pd(0) or Pd(II) catalyst, preferred PdCl2, Pd(PPh3)4, Pd(acac)2, PdCl2(CH3CN)2, PdCl2(PCy3)2, PdCl2(PPh3)2, Pd(dppf)Cl2, [(Π-ally)PdCl]2, (SIPr)PdCl2(TEA). Optionally, further phosphine ligand may be used together with the palladium catalyst.
A ratio of the palladium catalyst to the starting material is in the range of 0.01 to 20 mol-%, preferred 0.01-10 mol-%, more preferred 0.01-5 mol-%, most preferred 0.01-1 mol-%.
The Pd(0) catalyst may be tetrakis(triphenylphosphine)palladium(0) [Pd(PPh3)4], tris(dibenzylideneacetone)di-palladium(0) [Pd2(dba)3]. Pd(II) catalyst may be dichlorobis(triphenylphosphine)-palladium(II) [Pd(PPh3)2Cl2], palladium(II) acetate and triphenylphosphine or [1,1′-bis(diphenylphosphino)ferrocene]palladium dichloride. The reaction is preferably carried out in a mixture of a solvent like dioxane, DMF, DME, THF, or isopropanol with water and in the presence of a base.
The base may be an organic base or inorganic bases. The organic base may be tertiary amine such as Et3N, and DIPEA, DABCO, DBU, pyrrolidine or piperidine. The inorganic base may be Na2CO3, K2CO3, Cs2CO3 or K3PO4. A ratio of the first base to the starting material is in the range of 1.0 to 5.0 equivalents, preferred 1.0 to 3.0 equivalents, more preferred 1.0 to 3.0 equivalents, most preferred 1.0 to 2.0 equivalents.
Preferred, the boronic acid derivative 9* may be a boronic acid (R′=—H) or an ester of the boronic acid, e.g. its isopropyl ester (R′=—CH(CH3)2), an ester derived from pinacol (R′-R′=—C(CH3)2—C(CH3)2—).
Preferred, this reaction is performed in a polar aprotic solvent such as DMF or DMSO under N2 atmosphere at a temperature in a range of 80° C. to 200° C., preferred 100° C. to 180° C., more preferred 100° C. to 150° C., and most preferred 120° C. to 150° C. Optionally, this reaction is carried out in the microwave.
The intermediates for compound of formula (I) are prepared by reference to the methods illustrated in the following schemes4-5. The intermediates are produced by Schemes 5-7 by the suitable selection of reagents with appropriate substitution. Solvents, temperatures, pressures, and other reaction conditions may readily be selected by one of ordinary skill in the art. Starting materials are commercially available or readily prepared by one of ordinary skill in the art.
As shown in Scheme 4, optionally the method for producing the compound of the formula (I) further comprises the following steps before the Step 1:
Step1b: performing a formylation reaction of 1H-pyrrolo[2,3-b]pyridine compound (1*) to obtain 1H-pyrrolo[2,3-b]pyridine-3-aldehyde compound (2*);
The synthetic route for the intermediate (6*) used for a late stage Mitsunobu reaction (Scheme 2) is described in Scheme 5.
In a further aspect of the present invention, the novel compounds according to the general formula (I) are used as pharmaceutically active agent.
Surprisingly it was found that the above-mentioned compounds of general formula (I), as well as the pharmaceutical compositions thereof are acting as G protein-coupled receptor kinases (GRKs) inhibitors and more specifically as inhibitor of GRK2/5 kinases.
In the present application, the Lance Kinase Activity Assay was performed to determine IC50 values of compounds of general formula (I) against GRK5 and GRK2. Table 4 shows activity data (indicated as IC50 values) in the biochemical Lance assay. It is proven that the inventive compounds inhibits GRK5 and GRK2 very effectively
The pharmaceutical compositions according to the present invention comprise at least one compound according to the present invention as an active ingredient together with at least one pharmaceutically acceptable (i.e. non-toxic) carrier, excipient and/or diluent.
As used herein, G protein-coupled receptor kinases (GRKs) “inhibitor” refers to any compound capable of downregulating, decreasing, suppressing or otherwise regulating the amount and/or activity of a kinase. Inhibition of these GRKs can be achieved by any of a variety of mechanisms known in the art, including, but not limited to binding directly to said kinase polypeptide, denaturing or otherwise inactivating said kinase, or inhibiting the expression of the gene (e.g., transcription to mRNA, translation to a nascent polypeptide, and/or final polypeptide modifications to a mature protein), which encodes said kinase.
As used herein the term “inhibiting” or “inhibition” refers to the ability of a compound to downregulate, decrease, reduce, suppress, inactivate, or inhibit at least partially the activity of an enzyme, or the expression of an enzyme or protein.
Further aspects of the present invention relate to the compound of the general formula (I), or the above-mentioned pharmaceutical composition, for use in prophylaxis and/or treatment of diseases caused by or associated with G protein-coupled receptor kinases (GRK5) selected from heart disease, inflammatory and immunological disease, metabolic disease and cancer.
Preferred, the diseases caused by or associated with G protein-coupled receptor kinases 5 (GRK5) are heart diseases, in particular cardiovascular diseases.
Further aspects of the present invention relate to the use of the compounds of general formula (I) for the preparation of a pharmaceutical composition useful for prophylaxis and/or treatment of diseases caused by or associated with G protein-coupled receptor kinases 5 (GRK5) selected from heart disease, inflammatory and immunological disease, metabolic disease and cancer, preferred cardiovascular diseases.
In a further aspect of the present invention, methods for preventing and/or treating diseases caused by or associated with G protein-coupled receptor kinases 5 (GRK5) in a mammal, especially in a human, are provided, which methods comprise administering to the mammal an amount of at least one compound according to the general formula (I) and/or pharmaceutically acceptable salts thereof, effective to prevent and/or treat the diseases caused by or associated with G protein-coupled receptor kinases 5 (GRK5) selected from heart disease, inflammatory and immunological disease, metabolic disease and cancer, preferred cardiovascular diseases.
The term “effective amount” means an amount of compound that, when administered to a patient in need of such treatment, is sufficient to
The amount of a compound of general formula (I) that will correspond to such an amount will vary depending upon factors such as the particular compound, disease condition and its severity, the identity (e.g., weight) of the patient in need of treatment, but can nevertheless be routinely determined by one skilled in the art.
The inventive compounds, or the pharmaceutical composition thereof are useful for prophylaxis and/or treatment of cardiovascular diseases such as cardiac hypertrophy, adult congenital heart disease, aneurysm, stable angina, unstable angina, angina pectoris, angioneurotic edema, aortic valve stenosis, aortic aneurysm, arrhythmia, arrhythmogenic right ventricular dysplasia, arteriosclerosis, arteriovenous malformations, atrial fibrillation, Behcet syndrome, bradycardia, cardiac tamponade, cardiomegaly, congestive cardiomyopathy, hypertrophic cardiomyopathy, restrictive cardiomyopathy, cardiovascular disease prevention, carotid stenosis, cerebral hemorrhage, Churg-Strauss syndrome, diabetes, Ebstein's Anomaly, Eisenmenger complex, cholesterol embolism, bacterial endocarditis, fibromuscular dysplasia, congenital heart defects, heart diseases, congestive heart failure, heart valve diseases, heart attack, epidural hematoma, hematoma, subdural, Hippel-Lindau disease, hyperemia, hypertension, pulmonary hypertension, hypertrophic growth, left ventricular hypertrophy, right ventricular hypertrophy, hypoplastic left heart syndrome, hypotension, intermittent claudication, ischemic heart disease, Klippel-Trenaunay-Weber syndrome, lateral medullary syndrome, long QT syndrome mitral valve prolapse, moyamoya disease, mucocutaneous lymph node syndrome, myocardial infarction, myocardial ischemia, myocarditis, pericarditis, peripheral vascular diseases, phlebitis, polyarteritis nodosa, pulmonary atresia, Raynaud disease, restenosis, Sneddon syndrome, stenosis, superior vena cava syndrome, syndrome X, tachycardia, Takayasu's arteritis, hereditary hemorrhagic telangiectasia, telangiectasis, temporal arteritis, tetralogy of fallot, thromboangiitis obliterans, thrombosis, thromboembolism, tricuspid atresia, varicose veins, vascular diseases, vasculitis, vasospasm, ventricular fibrillation, Williams syndrome, peripheral vascular disease, varicose veins and leg ulcers, deep vein thrombosis, Wolff-Parkinson-White syndrome.
Preferred are cardiac hypertrophy, adult congenital heart disease, aneurysms, angina, angina pectoris, arrhythmias, cardiovascular disease prevention, cardiomyopathies, congestive heart failure, myocardial infarction, pulmonary hypertension, hypertrophic growth, restenosis, stenosis, thrombosis and arteriosclerosis.
Nuclear factor κ-B (NFκB) signaling pathway is intricately tied with many inflammatory processes and thus, regulatory molecules in NFκB signaling pathway are potential therapeutic targets in a number of inflammatory diseases. GRKs, in particular GRK2 and GRK5 have been reported to modulate NFκB signaling pathway in immune and non-immune cells (Packiriswamy and Parameswaran, Genes Immun. 2015 September; 16(6):367-77).
Therefore, the inventive compounds, or the pharmaceutical composition thereof are useful for prophylaxis and/or treatment of an inflammatory and/or an immunological disease, wherein the inflammatory and/or the immunological disease includes inflammatory disease associated with an autoimmune disease, a central nervous system (CNS) inflammatory disease, a joint inflammation disease, an inflammatory digestive tract disease, and inflammatory skin. Among them, Inflammatory Bowel Disease, Rheumatoid Arthritis and Multiple Sclerosis are of particular interest.
As GRK5 modulates the insulin release in a significant manner (WO 2012/028335 A1), it became a preferred target for the therapy of metabolic diseases, preferably for the therapy of diabetes, obesity and impaired adipogenesis. Thus in a preferred embodiment of this invention, the compounds of general formula (I), pharmaceutical acceptable salts thereof, or the pharmaceutical composition thereof are useful for the treatment and/or prophylaxis of the metabolic disease selected from diabetes, obesity and impaired adipogenesis.
Furthermore, it was found that the inhibition of GRK5 is correlated to a significant increase in insulin release. Consequently, GRK5 represents a preferable target for the therapy of diabetes mellitus type 2. Thus, another aspect of the present invention is directed to the use of compound of general formula (I) and/or pharmaceutically acceptable salts thereof for the treatment or prophylaxis of diabetes mellitus type 2.
Moreover the compounds of the present application influence the glucose dependent regulation of insulin production and/or release and/or the increase of glucose uptake. Therefore, another aspect of the present invention is directed to the use of compounds of general formula (I) for glucose dependent regulation of insulin production and/or release of insulin, as well as for increasing glucose uptake.
Furthermore, the compounds of the present application or the pharmaceutical composition thereof are useful for the treatment and/or prophylaxis of cancer, wherein the cancer is selected from the group consisting of: adenocarcinoma, choroidal melanoma, acute leukemia, acoustic neurinoma, ampullary carcinoma, anal carcinoma, astrocytoma, basal cell carcinoma, pancreatic cancer, desmoid tumour, bladder cancer, bronchial carcinoma, non-small cell lung cancer (NSCLC), breast cancer, Burkitt's lymphoma, corpus cancer, CUP-syndrome (carcinoma of unknown primary), colorectal cancer, small intestine cancer, small intestinal tumours, ovarian cancer, endometrial carcinoma, ependymoma, epithelial cancer types, Ewing's tumours, gastrointestinal tumours, gastric cancer, gallbladder cancer, gall bladder carcinomas, uterine cancer, cervical cancer, glioblastomas, gynecologic tumours, ear, nose and throat tumours, hematologic neoplasias, hairy cell leukemia, urethral cancer, skin cancer, skin testis cancer, brain tumours (gliomas), brain metastases, testicle cancer, hypophysis tumour, carcinoids, Kaposi's sarcoma, laryngeal cancer, germ cell tumour, bone cancer, colorectal carcinoma, head and neck tumours (tumours of the ear, nose and throat area), colon carcinoma, craniopharyngiomas, oral cancer (cancer in the mouth area and on lips), cancer of the central nervous system, liver cancer, liver metastases, leukemia, eyelid tumor, lung cancer, lymph node cancer (Hodgkin's/Non-Hodgkin's), lymphomas, stomach cancer, malignant melanoma, malignant neoplasia, malignant tumours gastrointestinal tract, breast carcinoma, rectal cancer, medulloblastomas, melanoma, meningiomas, Hodgkin's disease, mycosis fungoides, nasal cancer, neurinoma, neuroblastoma, kidney cancer, renal cell carcinomas, non-Hodgkin's lymphomas, oligodendroglioma, esophageal carcinoma, osteolytic carcinomas and osteoplastic carcinomas, osteosarcomas, ovarial carcinoma, pancreatic carcinoma, penile cancer, plasmocytoma, squamous cell carcinoma of the head and neck (SCCHN), prostate cancer, pharyngeal cancer, rectal carcinoma, retinoblastoma, vaginal cancer, thyroid carcinoma, Schneeberger disease, esophageal cancer, spinalioms, T-cell lymphoma (mycosis fungoides), thymoma, tube carcinoma, eye tumours, urethral cancer, urologic tumours, urothelial carcinoma, vulva cancer, wart appearance, soft tissue tumours, soft tissue sarcoma, Wilm's tumour, cervical carcinoma, tongue cancer, astrocytomas, bronchial cancer, laryngeal cancer, malignant melanoma, oesophageal cancer, and renal cell cancer.
Particularly suitable for treatment are, for example, astrocytomas, glioblastomas, pancreatic cancer, bronchial cancer, breast cancer, colorectal cancer, ovarian cancer, gastric cancer, laryngeal cancer, malignant melanoma, oesophageal cancer, cervical cancer, liver cancer, bladder cancer, and renal cell cancer.
The compounds enlisted explicitly in Table 1 are preferred to be used within the methods or indications disclosed herein.
The pharmaceutical compositions of the present invention can be prepared in a conventional solid or liquid carrier or diluent and a conventional pharmaceutically-made adjuvant at suitable dosage level in a known way. The preferred preparations are adapted for oral application. These administration forms include, for example, pills, tablets, film tablets, coated tablets, capsules, powders and deposits.
Furthermore, the present invention also includes pharmaceutical preparations for parenteral application, including dermal, intradermal, intragastral, intracutan, intravasal, intravenous, intramuscular, intraperitoneal, intranasal, intravaginal, intrabuccal, percutan, rectal, subcutaneous, sublingual, topical, or transdermal application, which preparations in addition to typical vehicles and/or diluents contain at least one compound according to the present invention and/or a pharmaceutical acceptable salt thereof as active ingredient.
The pharmaceutical compositions according to the present invention containing at least one compound according to the present invention and/or a pharmaceutical acceptable salt thereof as active ingredient will typically be administered together with suitable carrier materials selected with respect to the intended form of administration, i.e. for oral administration in the form of tablets, capsules (either solid filled, semi-solid filled or liquid filled), powders for constitution, gels, elixirs, dispersable granules, syrups, suspensions, and the like, and consistent with conventional pharmaceutical practices. For example, for oral administration in the form of tablets or capsules, the active drug component may be combined with any oral non-toxic pharmaceutically acceptable carrier, preferably with an inert carrier like lactose, starch, sucrose, cellulose, magnesium stearate, dicalcium phosphate, calcium sulfate, talc, mannitol, ethyl alcohol (liquid filled capsules) and the like. Moreover, suitable binders, lubricants, disintegrating agents and coloring agents may also be incorporated into the tablet or capsule. Powders and tablets may contain about 5 to about 95-weight % of the 3-substituted 1H-pyrrolo[2,3-b]pyridine compounds of the formula (I) or the respective pharmaceutically active salt as active ingredient.
Suitable binders include starch, gelatin, natural sugars, corn sweeteners, natural and synthetic gums such as acacia, sodium alginate, carboxymethylcellulose, polyethylene glycol and waxes. Among suitable lubricants there may be mentioned boric acid, sodium benzoate, sodium acetate, sodium chloride, and the like. Suitable disintegrants include starch, methylcellulose, guar gum, and the like. Sweetening and flavoring agents as well as preservatives may also be included, where appropriate. The disintegrants, diluents, lubricants, binders etc. are discussed in more detail below.
Moreover, the pharmaceutical compositions of the present invention may be formulated in sustained release form to provide the rate controlled release of any one or more of the components or active ingredients to optimise the therapeutic effect(s), e.g. antihistaminic activity and the like. Suitable dosage forms for sustained release include tablets having layers of varying disintegration rates or controlled release polymeric matrices impregnated with the active components and shaped in tablet form or capsules containing such impregnated or encapsulated porous polymeric matrices.
Liquid form preparations include solutions, suspensions, and emulsions. As an example, there may be mentioned water or water/propylene glycol solutions for parenteral injections or addition of sweeteners and opacifiers for oral solutions, suspensions, and emulsions. Liquid form preparations may also include solutions for intranasal administration.
Aerosol preparations suitable for inhalation may include solutions and solids in powder form, which may be present in combination with a pharmaceutically acceptable carrier such as an inert, compressed gas, e.g. nitrogen.
For preparing suppositories, a low melting wax, such as a mixture of fatty acid glycerides like cocoa butter is melted first, and the active ingredient is then dispersed homogeneously therein e.g. by stirring. The molten, homogeneous mixture is then poured into conveniently sized moulds, allowed to cool, and thereby solidified. Also included are solid form preparations, which are intended to be converted, shortly before use, to liquid form preparations for either oral or parenteral administration. Such liquid forms include solutions, suspensions, and emulsions.
The compounds according to the present invention may also be delivered transdermally. The transdermal compositions may have the form of a cream, a lotion, an aerosol and/or an emulsion and may be included in a transdermal patch of the matrix or reservoir type as is known in the art for this purpose.
The term capsule as recited herein refers to a specific container or enclosure made e.g. of methylcellulose, polyvinyl alcohols, or denatured gelatins or starch for holding or containing compositions comprising the active ingredient(s). Capsules with hard shells are typically made of blended of relatively high gel strength gelatins from bones or pork skin. The capsule itself may contain small amounts of dyes, opaquing agents, plasticisers and/or preservatives.
Under tablet a compressed or moulded solid dosage form is understood which comprises the active ingredients with suitable diluents. The tablet may be prepared by compression of mixtures or granulations obtained by wet granulation, dry granulation, or by compaction well known to a person of ordinary skill in the art.
Oral gels refer to the active ingredients dispersed or solubilised in a hydrophilic semi-solid matrix.
Powders for constitution refers to powder blends containing the active ingredients and suitable diluents which can be suspended e.g. in water or in juice.
Suitable diluents are substances that usually make up the major portion of the composition or dosage form. Suitable diluents include sugars such as lactose, sucrose, mannitol, and sorbitol, starches derived from wheat, corn rice, and potato, and celluloses such as microcrystalline cellulose. The amount of diluent in the composition can range from about 5 to about 95% by weight of the total composition, preferably from about 25 to about 75 weight %, and more preferably from about 30 to about 60 weight %.
The term disintegrants refers to materials added to the composition to support break apart (disintegrate) and release the pharmaceutically active ingredients of a medicament. Suitable disintegrants include starches, “cold water soluble” modified starches such as sodium carboxymethyl starch, natural and synthetic gums such as locust bean, karaya, guar, tragacanth and agar, cellulose derivatives such as methylcellulose and sodium carboxymethylcellulose, microcrystalline celluloses, and cross-linked microcrystalline celluloses such as sodium croscaramellose, alginates such as alginic acid and sodium alginate, clays such as bentonites, and effervescent mixtures. The amount of disintegrant in the composition may range from about 2 to about 20 weight % of the composition, more preferably from about 5 to ca. 10 weight %.
Binders are substances which bind or “glue” together powder particles and make them cohesive by forming granules, thus serving as the “adhesive” in the formulation. Binders add cohesive strength already available in the diluent or bulking agent. Suitable binders include sugars such as sucrose, starches derived from wheat corn rice and potato, natural gums such as acacia, gelatin and tragacanth, derivatives of seaweed such as alginic acid, sodium alginate and ammonium calcium alginate, cellulose materials such as methylcellulose, sodium carboxymethylcellulose and hydroxypropylmethylcellulose, polyvinylpyrrolidone, and inorganic compounds such as magnesium aluminum silicate. The amount of binder in the composition may range from about 2 to about 20 weight % of the composition, preferably from about 3 to about 10 weight %, and more preferably from about 3 to about 6 weight %.
Lubricants refer to a class of substances which are added to the dosage form to enable the tablet granules etc. after being compressed to release from the mould or die by reducing friction or wear. Suitable lubricants include metallic stearates such as magnesium stearate, calcium stearate, or potassium stearate, stearic acid, high melting point waxes, and other water soluble lubricants such as sodium chloride, sodium benzoate, sodium acetate, sodium oleate, polyethylene glycols and D,L-leucine. Lubricants are usually added at the very last step before compression, since they must be present at the surface of the granules. The amount of lubricant in the composition may range from about 0.2 to about 5 weight % of the composition, preferably from about 0.5 to about 2 weight %, and more preferably from about 0.3 to about 1.5 weight % of the composition.
Glidents are materials that prevent caking of the components of the pharmaceutical composition and improve the flow characteristics of granulate so that flow is smooth and uniform. Suitable glidents include silicon dioxide and talc. The amount of glident in the composition may range from about 0.1 to about 5 weight % of the final composition, preferably from about 0.5 to about 2 weight %.
Coloring agents are excipients that provide coloration to the composition or the dosage form. Such excipients can include food grade dyes adsorbed onto a suitable adsorbent such as clay or aluminum oxide. The amount of the coloring agent may vary from about 0.1 to about 5 weight % of the composition, preferably from about 0.1 to about 1 weight %.
The following examples are included to demonstrate preferred embodiments of the invention. It should be appreciated by those of skill in the art that the techniques disclosed in the examples which follow represent techniques discovered by the inventor to function well in the practice of the invention, and thus can be considered to constitute preferred modes for its practice. However, those of skill in the art should, in light of the present disclosure, appreciate that many changes can be made in the specific embodiments which are disclosed and still obtain a like or similar result without departing from the spirit and scope of the invention.
Further modifications and alternative embodiments of various aspects of the invention will be apparent to those skilled in the art in view of this description. Accordingly, this description is to be construed as illustrative only and is for the purpose of teaching those skilled in the art the general manner of carrying out the invention. It is to be understood that the forms of the invention shown and described herein are to be taken as examples of embodiments. Elements and materials may be substituted for those illustrated and described herein, parts and processes may be reversed, and certain features of the invention may be utilized independently, all as would be apparent to one skilled in the art after having the benefit of this description of the invention. Changes may be made in the elements described herein without departing from the spirit and scope of the invention as described in the following claims.
All reactions involving air- or moisture-sensitive reagents or intermediates were carried out in flame-dried glassware under an argon atmosphere. Dry solvents (THF, toluene, MeOH, DMF, DCM) were used as commercially available. 1H-NMR and 13C-NMR were recorded on a Bruker DRX400 (400 MHz). Multiplicities are indicated as: br s (broadened singlet), s (singlet), d (doublet), t (triplet), q (quartet), quin (quintet), m (multiplet); and coupling constants (J) are given in Hertz (Hz). HPLC—electrospray mass spectra (HPLC ES-MS) were obtained using Waters Acquity Performance Liquid Chromatography (UPLC) equipped SQ 3100 Mass detector spectrometer. Column: Acquity UPLC BEH C18 1.7 um, 2.1×50 mm. Flow: 0.5 ml/min. Eluents: A: H2O with 0.05% formic acid and B: ACN with 0.05% TFA. All chemicals and solvents were purchased from commercial sources like Sigma-Aldrich, Fluka, TCI, Acros Organics, ABCR, Alfa Aesar, Enamine, VWR, Combi-Blocks, Apollo Scientific, Aquilla Pharmatech, Ark Pharm, D-L Chiral Chemicals, ChemBridge, Renno Tech, Accela, KeyOrganics, Pharmablock and Chem Impex. Unless otherwise noted, all commercially available compounds were used as received without further purifications.
ACN or MeCN (acetonitrile); br (broad); BOC (tet-butyloxycarbonyl), CDCl3 (deuterated chloroform); cHex (cyclohexane); DCM (dichloromethane); DIAD (diisopropyl azodicarboxylate); DIPEA (di-iso-propylethylamine); DMF (dimethylformamide); DMSO (dimethyl sulfoxide); eq. (equivalent); ES (electrospray); EDTA (ethylenediaminetetraacetic acid), EtOAc (ethyl acetate); EtOH (ethanol); HATU (O-(7-azabenzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium hexafluorophosphate); HBTU (3-[Bis(dimethylamino)methyliumyl]-3H-benzotriazol-1-oxide hexafluorophosphate); HCl (hydrochloric acid); AcOH (acetic acid); H2O (water); K2CO3 (potassium carbonate); KOH (potassium hydroxide); MecOH (methanol); MS (mass spectrometry); Mwt (molecular weight); NaHCO3 (sodium hydrogencarbonate); NH4Cl (ammonium chloride); NIS (N-lodosuccinimide); NMP (N-methyl-2-pyrrolidon); NMR (nuclear magnetic resonance); iPrOH (iso-propanol; RP (reversed-phase); RT (room temperature); sat. aq. (saturated aqueous); SiO2 (silica gel); TFA (trifluoroacetic acid); THE (tetrahydrofurane).
To a solution of HBTU (201 mg, 0.53 mmol, 1.5 eq.) in DMF (4 mL) at 0° C. was added (E)-2-cyano-3-(1H-pyrrolo[2,3-b]pyridin-3-yl)acrylic acid (75 mg, 0.35 mmol, 1.0 eq.) and DIPEA (135 mg, 1.1 mmol, 3.0 eq.). The mixture was stirred for 15 min. Then (R)-2-cyano-N-(1-(3-fluorophenyl)ethyl)acetamide (73 mg, 0.53 mmol, 1.5 eq.) was added and the mixture was stirred for 4 h at 0° C. Afterwards, the solvents were evaporated in vacuo. The crude was purified by reverse phase RP-HPLC (column: C18), using H2O (0.1% TFA) and ACN (0.1% TFA) as eluents. The desired fractions were lyophilized to yield the title compound A1 (14 mg, 0.04 mmol, 12%) as a yellow solid.
1H NMR (400 MHz, d6-DMSO, 300K) δ 12.87 (s, 1H), 8.68 (d, J=7.8 Hz, 1H). 8.52-8.48 (m, 1H), 8.45 (s, 1H), 8.43-8.36 (m, 2H), 7.43-7.35 (m, 1H), 7.34-7.29 (m, 1H), 7.27-7-21 (m, 2H), 5.14-5.04 (m, 1H), 1.49 (d, J=7.1 Hz, 3H). MS (ES) C19H15FN4O requires: 334, found: 335 (M+H)+.
The examples in the following table 1A were prepared according to the procedure described for A1 (Example 1
7-Azaindole-3-carboxaldehyde (73 mg, 0.5 mmol, 1.0 eq.) was dissolved in dry pyridine (3 mL). 2—Cyano-N-(4-fluorobenzyl)acetamide (125 mg, 0.65 mmol, 1.3 eq.) was added to the solution. The reaction mixture was stirred for 48 h at 110° C. The solvents were removed in vacuo. EtOH was added and the resulting precipitate was filtered and led to the desired product B1 (141 mg, 0.44 mmol, 88%) as a beige solid.
1H NMR (400 MHz, d6-DMSO, 300K) δ 12.87 (s, 1H), 8.84 (t, J=6.0 Hz, 1H), 8.49 (d, J=10.2 Hz, 2H), 8.43-8.36 (m, 2H), 7.41-7.33 (m, 2H), 7.32-7.27 (m, 1H), 7.20-7.12 (m, 2H), 4.42 (d, J=5.9 Hz, 2H). MS (ES) C18H13FN4O requires: 320, found: 321 (M+H)+.
The examples in the following table were prepared according to the procedure described for B1 (Example 57).
In order to obtain example 89, a subsequent standard acidic BOC-deprotection was performed.
To a suspension of (R,E)-2-cyano-N-(1-(3,4-dimethoxyphenyl)ethyl)-3-(5-hydroxy-1H-pyrrolo[2,3-b]pyridin-3-yl)acrylamide (17 mg, 0.043 mmol, 1.0 eq.) (R)-(−)-2-Butanol (4 mg, 0.054 mmol, 1.25 eq.) and triphenylphosphine (22.7 mg, 0.087 mmol, 2 eq.) in dry DCM (5 mL), a solution of diisopropyl azodicarboxylate (13 mg, 0.065 mmol 1.5 eq.) in DCM (1 mL) was added dropwise at 0° C. After 15 min, the reaction mixture was allowed to warm to room temperature and stirred for another 1 h. The reaction was quenched by the addition of H2O and the resulting mixture was purified by reverse phase RP-HPLC (column: C18), using H2O (0.1% TFA) and ACN (0.1% TFA) as eluents. The desired fractions were lyophilized to yield the title compound C1 (2.1 mg, 0.0047 mmol, 11%) as a white solid.
1H NMR (400 MHz, d6-DMSO, 300K) δ 12.79-12.34 (m, 1H), 9.06-7.91 (m, 5H), 7.10-6-81 (m, 3H), 5.10-4.97 (m, 1H), 4.55-4.36 (m, 1H), 3.77-3-73 (m, 3H), 3.73-3-69 (m, 3H), 1.77-1.56 (m, 2H), 1.50.1.38 (m, 3H), 1.29-1.24 (m, 3H), 0.96 (t, J=7.4 Hz, 3H). MS (ES) C25H28N4O4 requires: 448, found: 449 (M+H)+.
The examples in the following table were prepared according to the procedure described for C1 (Example 109).
(R,E)-3-(5-bromo-1H-pyrrolo[2,3-b]pyridin-3-yl)-2-cyano-N-(1-(3,4-dimethoxyphenyl)ethyl)acrylamide (60 mg, 0.13 mmol, 1.0 eq.), (4-(4-methylpiperazin-1-yl)phenyl)boronic acid (57 mg, 0.26 mmol, 2.0 eq.), potassium carbonate (36 mg, 0.26 mmol, 2.0 eq.) was suspended in DMF/H2O (10:1) (4 mL). The reaction mixture was degassed with a stream of N2 for 5 min, tetrakis(triphenylphosphine)palladium(0) (15 mg, 0.01, 0.1 eq.) was added and the reaction mixture was heated to 130° C. for 2 h in the microwave. The crude solution was directly purified by reverse phase RP-HPLC (column: C18), using H2O (0.1% TFA) and ACN (0.1% TFA) as eluents. The desired fractions were lyophilized to yield the title compound D1 (8.9 mg, 0.016 mmol, 12%) as a yellow solid (TFA salt). 1H NMR (400 MHz, d6-DMSO, 300K) δ 12.88 (s, 1H), 9.63 (s, 1H), 8.66 (d, J=2.1 Hz, 1H), 8.62 (d, J=2.0 Hz, 1H), 8.54-8.48 (m, 3H), 7.71 (d, J=8.6 Hz, 2H), 7.15 (d, J=8.7 Hz, 2H), 7.06 (s, 1H), 6.95-6.88 (m, 2H), 3.99-3.90 (m, 2H), 3.77 (s, 3H), 3.73 (s, 3H), 3.58-3-50 (m, 2H), 3.27-3.12 (m, 2H), 3.07-2.95 (m, 2H), 2.89 (s, 3H), 1.48 (d, J=6.9 Hz, 3H).
MS (ES) C32H34N6O3 requires: 550, found: 551 (M+H)+.
The examples in the following table 1D were prepared according to the procedure described for D1 (Example 112).
To a solution of (R,E)-3-(5-bromo-1H-pyrrolo[2,3-b]pyridin-3-yl)-N-(1-(3,4-dimethoxyphenyl)ethyl)acrylamide (500 mg, 1.16 mmol, 1.0 eq.) in dry THE (60 mL) at 0° C. was added DMAP (156 mg, 1.27 mmol, 1.1 eq.), followed by Boc2O (301 mg, 1.40 mmol, 1.2 eq.) in three portions. After 2 min the reaction mixture was warmed to RT and stirred for 1 h. The mixture was extracted with EtOAc. The organic layer was washed with sat. brine, dried over MgSO4 and the solvent was removed in vacuo. The crude product was purified by flash chromatography on silica gel (0-100% PE/EA) to yield the desired product 249a* (478 mg, 77.6%). LC-MS: 431.6 [MS-99]+.
To a solution of tert-butyl (R,E)-5-bromo-3-(3-((1-(3,4-dimethoxyphenyl)ethyl)amino)-3-oxoprop-1-en-1-yl)-1H-pyrrolo[2,3-b]pyridine-1-carboxylate (94 mg, 0.17 mmol, 1.0 eq.) in dry dioxane (1 mL) was added B2(Pin)2 (62.77 mg, 0.25 mmol, 1.5 eq.), AcOK (33.08 mg, 0.34 mmol, 2.0 eq.) and Pd(dppf)Cl2 (12.5 mg, 0.017 mmol, 0.1 eq.). The reaction mixture was recharged with Ar for three times and heat to 90° C. overnight. The mixture was filtered through celite and wash the cake was rinsed with EA. The filtrate was concentrated in vacuo and the crude residue was purified by flash chromatography on silical gel (PE/EA:0%-100%) to yield the product 249b* (37 mg, 36.2%). LC-MS: 578.3 [M+H]+.
To a solution of 1-bromo-3-fluoro-5-(methylsulfonyl)benzene (148 mg, 0.26 mmol, 1.5 eq.) in dioxane/H2O (3/1, 0.4 mL) were added tert-butyl (R,E)-3-(3-((1-(3,4-dimethoxyphenyl)ethyl)amino)-3-oxoprop-1-en-1-yl)-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrrolo[2,3-b]pyridine-1-carboxylate (43 mg, 0.17 mmol, 1.0 eq.), K2CO3 (46.92 mg, 0.34 mmol, 2.0 eq.), and Pd(PPh3)4(19.64 mg, 0.017 mmol, 0.1 eq.). The reaction mixture was recharged with Ar for 5 min and heated to 90° C. overnight. The mixture was purified by reversed-phase Pre-HPLC (column:C18), using aq. HCOOH and ACN as eluents. The desired fractions were collected and lyophilized to yield the final product 249 (10 mg, 7.5%). HPLC purity: 98.51%; 1H NMR (DMSO-D6, 400 MHz) δ 12.23 (s, 1H), 8.64 (d, J=2.1 Hz, 1H), 8.50 (d, J=2.2 Hz, 1H), 8.12 (d, J=8.2 Hz, 1H), 8.06 (t, J=1.6 Hz, 1H), 7.99 (dt, J2=10.0 Hz, J2=2.2 Hz, 1H), 7.93 (d, J=1.7 Hz, 1H), 7.74-7.70 (m, 1H), 7.56 (d, J=15.9 Hz, 1H), 6.90 (d, J=2.0 Hz, 1H), 6.84 (d, J=8.3 Hz, 1H), 6.81 (dd, J2=8.3H7, J2=1.9 Hz, 1H), 6.70 (d, J=15.9 Hz, 1H), 4.99 (s, 1H), 3.69 (s, 3H), 3.65 (s, 3H), 3.32 (s, 3H), 1.35 (d, J=7.0 Hz, 3H); LC-MS: 524.1 [M+H]+.
4-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)tetrahydro-2H-thiopyran 1,1-dioxide (190 mg, 0.71 mmol, 1 eq.) was suspended in acetic acid/1H2O (1:3, 12 mL). Hexamethylentetramine (200 mg, 1.4 mmol, 2 eq.) was added and the reaction mixture was stirred for 12 h at 120° C. The solution was diluted with EtOAc and washed tree times with aq. sat. NaHCO3-solution. The organic layer was dried over MgSO4 and solvent was removed in vacuo. The crude product was purified by flash chromatography on silica gel (0-100% EtOAc/cHex, 0-100% MeOH/DCM) to yield the desired product E1 (90 mg, 0.31 mmol, 44%).
1H NMR (300 MHz, d6-DMSO, 300K) b 12.65 (s, 1H), 9.89 (s, 1H), 8.44 (s, 1H), 8.21 (d, J=2.7 Hz, 1H), 8.06 (d, J=2.8 Hz, 1H), 4.86-4.66 (m, 1H), 3.29-3.08 (m, 4H), 2.33-2.14 (in, 4H). MS (ES) C13H14N2O4S requires: 294, found: 295 (M+H)+.
The examples in the following table were prepared according to the procedure described
To a solution of 5-((1,1-dioxidotetrahydro-2H-thiopyran-4-yl)oxy)-1H-pyrrolo[2,3-b]pyridine-3-carbaldehyde (37 mg, 0.13 mmol, 1 eq.) in pyridine (4 mL), piperidine (0.2 mL) and malonic acid (37 mg, 0.35 mmol, 2.8 eq.) were added and the reaction mixture was stirred for 12 h at 120° C. The solution was diluted with EtOAc and washed tree times with aq. sat. NaHCO3-solution. The organic layer was dried over MgSO4 and solvent was removed in vacuo. The crude product was purified by flash chromatography on silica gel (0-100% EtOAc/cHex, 0-100% MeOH/DCM) to yield the desired product F1 (34 mg, 0.10 mmol, 77%). MS (ES) C15H16N2O5S requires: 336, found: 337 (M+H)+.
The examples in the following table were prepared according to the procedure described for F1 (I-B-1).
(R,E)-3-(5-(Allyloxy)-1H-pyrrolo[2,3-b]pyridin-3-yl)-2-cyano-N-(1-(3,4-dimethoxyphenyl)ethyl)acrylamide (57 mg, 0.132 mmol, 1.0 eq.) was dissolved in MeCOH (3 mL). Barbituric acid (34 mg, 0.264 mmol, 2.0 eq.) and tetrakis(triphenylphosphine) palladium(0) (15.2 mg, 0.013 mmol, 0.1 eq.) were added to the solution. The reaction mixture was stirred for 30 min at 45° C. After a complete reaction, the solvent was removed in vacuo and the crude was purified by flash chromatography on silica gel (0-100% EtOAc/cHex) to yield the desired product G4 (27 mg, 0.069 mmol, 52%) as a yellowish solid.
1H NMR (400 MHz, d6-DMSO, 300K) δ 12.62 (s, 1H), 9.61 (s, 1H), 8.50 (d, J=8.0 Hz, 1H), 8.39 (s, 1H), 8.31 (s, 1H), 7.99 (d, J=2.6 Hz, 1H), 7.68 (d, J=2.6 Hz, 1H), 7.02 (s, 1H), 6.91-6.90 (m, 2H), 5.08-4.98 (m, 1H), 3.77 (2, 3H), 3.73 (s, 3H), 1.47 (d, J=7.0 Hz, 3H). MS (ES) C21H20N4O4 requires: 392, found: 393 (M+H)+.
1H-Pyrrolo[2,3-b]pyridin-5-ol (5.8 g, 43 mmol, 1.0 eq.) was dissolved in dry THE (20 mL). Allyl alcohol (3 g, 52 mmol, 1.2 eq.) and triphenylphosphine (13.7 g, 52 mmol, 1.2 eq.) were added to the solution. DIAD (10.5 g, 52 mmol, 1.2 eq.) was added dropwise via syringe at 0° C. over 5 min. After 10 min the reaction mixture was allowed to warm to RT. The reaction was stirred for 1 h. The reaction was quenched with drops of H2O and the solvents were removed in vacuo. The crude product was purified by flash chromatography on silica gel (0-100% EtOAc/cHex) to yield the desired product G1.
MS (ES) C10H10N2O requires: 174, found: 175 (M+H)+.
G1 (50 mg, 0.29 mmol, 1 eq.) was suspended in acetic acid/H2O (1:3, 5 mL). Hexamethylentetramine (80 mg, 0.57 mmol, 2 eq.) was added and the reaction mixture was stirred for 12 h at 110° C. After a complete reaction, the solution was diluted with EtOAc and washed tree times with aq. sat. NaHCO3-solution. The organic layer was dried over MgSO4 and solvent was removed in vacuo. The crude product was purified by flash chromatography on silica gel (0-100% EtOAc/cHex) to yield the desired product G2 (35 mg, 0.17 mmol, 60%) as a white solid.
MS (ES) C11H10N2O2 requires: 202, found: 203 (M+H)+.
G2 (30 mg, 0.19 mmol, 1 eq.) and (R)-2-cyano-N-(1-(3,4-dimethoxyphenyl)ethyl)acetamide (41 mg, 0.2 mmol, 1.1 eq.) was dissolved in pyridine (2 mL). The reaction mixture was stirred for 48 h at 120° C. The solvent was removed in vacuo and the crude was purified by flash chromatography on silica gel (0-100% EtOAc/cHex) to yield the desired product G3 (57 mg, 0.13 mmol, 89%) as a yellowish solid. 1H NMR (400 MHz, d6-DMSO, 300K) δ 12.74 (s, 1H), 9.00-8.33 (ml, 3H), 8.16-7-86 (m, 2H), 7.02 (s, 1H), 6.97-6.79 (m, 2H), 6.15-5.99 (m, 1H), 5.42 (d, J=17.3H7, 1H), 5.27 (d, J=10.5 Hz, 1H), 5.08-4.96 (m, 1H), 4.69-4.59 (m, 2H), 3.75 (s, 1H), 3.71 (s, 1H), 1.49-1.34 (m, 3H). MS (ES) C24H24N4O4 requires: 432, found: 433 (M+H)+.
To a solution of 1-bromo-3-((trifluoromethyl)sulfinyl)benzene H1) (150 mg, 0.35 mmol, 1.0 eq.) in dioxane were added diboron pinacol ester (104.76 mg, 0.42 mmol, 1.2 eq.), potassium acetate (68.70 mg, 0.70 mmol, 2.0 eq.), and Pd(dppf)Cl2 (21.95 mg, 0.03 mmol, 0.1 eq.). The reaction mixture was recharged with Ar for three times, and heated to 100° C. with vigorous stirring for 12 h. The mixture was then cooled to room temperature, diluted with water (5 mL), and extracted with EtOAc (5 mL×3). The combined organic layers were washed with brine (10 mL), and dried over Na2SO4. The solvent was removed in vacuo and the crude residue was purified by flash chromatography (0-100% EtOAc/PE) to afford the product H2 (135.1 mg, 76.1%). LC-MS: 321.1 [M+H]+.
To a solution of (3-bromophenyl)(trifluoromethyl)sulfane (200 mg, 0.78 mmol, 1.0 eq.) in dry CH3CN (1 mL) was added m-CPBA (214.8 mg, 0.93 mmol, 1.2 eq.). The reaction mixture was heated to 40° C. for 12 h, then cooled to room temperature, diluted with aq. Na2SO3 (5 mL) and extracted with EtOAc (5 mL×3). The combined organic layers were washed with brine (10 mL) and dried over Na2SO4. The solvent was removed in vacuo and the residue was purified by flash chromatography (0-100% EtOAc/PE) to provide the product H1 (65.5 mg, 30.7%). LC-MS: 272.9 [M+H]+.
To a solution of (S)-N-(1-(5,6-dimethoxypyridin-3-yl)ethyl)-2-methylpropane-2-sulfinamide J2 (150 mg, 0.51 mmol, 1.0 eq.) in DCM (1 mL) was added 4 N HCl in 1,4-dioxane (0.7 mL, 2.61 mmol, 4 M, 5.0 eq.). The reaction was stirred at room temperature and monitored by LC-MS. The solvent was removed and the crude product J3 (HCl salt) was used directly in the next step. LC-MS: 183.0 [M+H]+.
A solution of 5,6-dimethoxynicotinaldehyde (500 mg, 3.0 mmol, 1.0 eq.), (S)-2-methylpropane-2-sulfinamide (440 mg, 3.6 mmol, 1.2 eq.) and Ti(OEt)4 (2.7 g, 9.0 mmol, 2.0 eq., containing 34% wt TiO2) in dry THF (10 mL) was stirred at room temperature overnight. Water and EtOAc were added, and the insoluble solid was filtered off. The filtrate was transferred to separatory funnel and the organic layer was separated, washed with sat. brine, and dried over Na2SO4. The solvent was removed in vacuo and the crude residue was purified by flash chromatography on silica gel (PE/EA: 0%-9%) to provide the product J1 (642 mg, 79.4%). 1H NMR (DMSO-D6, 400 MHz) δ 8.60 (s, 1H), 8.34 (d, J=1.8 Hz, 1H), 7.71 (d, J=1.8 Hz, 1H), 4.01 (s, 3H), 3.92 (s, 3H), 1.24 (s, 9H).
To a solution of (S,E)-N-((5,6-dimethoxypyridin-3-yl)methylene)-2-methylpropane-2-sulfinamide (642 mg, 2.4 mmol, 1.0 eq.) in dry THF (12 mL) at −50° C. under Ar atmosphere was added lithium methide (1.3 mL, 3.2 mmol, 2.7 M in DEM, 1.5 eq.) dropwise. The reaction mixture was stirred at −50° C. and monitored by LC-MS. After completion, saturated NH4Cl (aq.) was added slowly to quench the reaction. The mixture was extracted with EtOAc, and the organic layer was washed with sat. brine, dried over Na2SO4. The solvent was removed in vacuo to give the crude product J2 (648.3 mg, two diastereoisomers 1:1) which was used in the next step without further purification. 1H NMR (DMSO-D6, 400 MHz) δ 7.71 (dd, J1=14.5 Hz, J2=1.8 Hz, 1H), 7.36 (dd, J1=38.2 Hz, J2=1.9 Hz, 1H), 5.55 (dd, J1=91.4 Hz, J2=6.1 Hz, 1H), 4.31-4.48 (m, 1H), 3.90 (d, J=1.3H7, 3H), 3.83 (d, J=7.6 Hz, 3H), 1.50 (dd, J1=17.8 Hz, J2=6.8 Hz, 3H), 1.17 (d, J=4.7 Hz, 9H).
To a solution of K6 (1.50 g, 7.05 mmol, 1.0 eq.) in 1,4-dioxane (10 mL) at 0° C. was added 4 N HCl in 1,4-dioxane (10 mL). The mixture was stirred at 0° C. for 4 h. The solvent was removed in vacuo and the crude product K7 (HCl salt) was used in the next step without further purification. LC-MS: 160.0 [M-NH2]+
To a solution of 1-(5-bromo-2-hydroxyphenyl)ethan-1-one (10.0 g, 46.73 mmol, 1.0 eq.) in ethanol (60 mL) was added hydroxylamine hydrochloride (4.87 g, 70.10 mmol, 1.5 eq.). The reaction mixture was stirred at 80° C. for 16 h, then cooled to RT. The solvent was removed in vacuo and the crude product was purified by flash chromatography on silica gel (0-100% EtOAc/PE, 0-10% MeOH/DCM) to yield the product K1 (8.7 g, 82%).
LC-MS: 229.6 [M+H]+.
To a solution of 1-(5-bromo-2-hydroxyphenyl)ethan-1-one oxime (8.7 g, 38.00 mmol, 1.0 eq.) in DMA (60 mL) at 0° C. were added acetic anhydride (4.26 g, 41.8 mmol, 1.1 eq.) and K2CO3 (2.89 g, 20.9 mmol, 0.5 eq.). The reaction mixture was stirred at 100° C. for 5 h, cooled to RT, then water (60 mL) and DCM (60 mL) were added. The organic layer was separated and washed with sat. brine, dried over Na2SO4. The solvent was removed in vacuo and the crude product was purified by flash chromatography on silica gel (0-60% EtOAc/PE) to yield the product K2 (5.8 g, 72.4%). LC-MS: 211.6 [M+H]+.
A solution of 5-bromo-3-methylbenzo[d]isoxazole (5.8 g, 27.49 mmol, 1.0 eq.), tributyl(1-ethoxyvinyl)tin (5.46 g, 41.24 mmol, 1.5 eq.), and Pd(PPh3)4(1.59 g, 1.37 mmol, 0.05 eq) in 1,4-dioxane (80 mL) was recharged with Ar for three times and stirred at 100° C. overnight. The reaction mixture was cooled to room temperature and aq. sat. potassium fluoride (200 mL) was added. The mixture was filtered through celite, and sat. NH4Cl (aq.) and EtOAc were added. The organic layer was separated and washed with sat. brine, dried over Na2SO4. The solvent was removed in vacuo and the crude residue was purified by flash chromatography on silica gel (0-55% PE/EtOAc) to yield the product K3 (2.83 g, 50.7%). LC-MS: 203.6 [M+H]+.
To a solution of 5-(1-ethoxyvinyl)-3-methylbenzo[d]isoxazole (2.83 g, 13.93 mmol, 1.0 eq.) in 1,4-dioxane/water (10 mL/1 mL) was added HCl in 1,4-dioxane (2 mL) at 0° C. The mixture was stirred at 0° C. for 4 h. The solvent was removed in vacuo and the crude product K4 was used in the next step without further purification. LC-MS: 175.6 [M+H]+.
To a solution of 1-(3-methylbenzo[d]isoxazol-5-yl)ethan-1-one (1.80 g, 10.19 mmol, 1.0 eq.) and (R)-2-methylpropane-2-sulfinamide (1.85 g, 15.29 mmol, 1.5 eq.) in THE (60 mL) was added Ti(OEt)4 (8.8 g, 25.48 mmol, 2.5 eq., containing 34% wt TiO2). The mixture was recharged with N2 balloon for three times and stirred at 70° C. overnight. The mixture containing K5 was used directly in the next step. LC-MS: 279.1 [M+H]1.
The above solution containing K5 was cooled to −50° C., then NaBH4 (3.90 g, 102.5 mmol, 10.0 eq.) was added. The mixture was recharged with N2 balloon for three times and stirred at −50° C. for 12 h. Upon completion, sat. brine (100 mL) was added and the mixture was filtered through celite. Saturated NH4Cl (aq.) and EtOAc were added to the filtrate. The organic layer was separated and washed with sat. brine, dried over Na2SO4. The solvent was removed in vacuo and the crude residue was purified by flash chromatography on silica gel (0-55% EtOAc/PE) to yield the product K6 (1.30 g, 46.6%).
LC-MS: 281.1 [M+H]+.
To a solution of (S)-N-(1-(3-cyclopropyl-4-methoxyphenyl)ethyl)-2-methylpropane-2-sulfinamide (170 mg, 0.58 mmol, 1.0 eq.) in DCM (1.5 mL) was added 4 N HCl in 1,4-dioxane (0.72 mL, 2.88 mmol, 4 M, 5.0 eq.). The reaction was stirred at room temperature and monitored by LC-MS. After completion, the solvent was removed in vacuo and the crude product L4 (HCl salt) was used directly in the next step. LC-MS: 175.0 [M-NH2]+.
A solution of 3-bromo-4-methoxybenzaldehyde (1 g, 4.65 mmol, 1.0 eq.), (S)-2-methylpropane-2-sulfinamide (676.3 mg, 5.58 mmol, 1.2 eq.) and Ti(OEt)4 (4.82 g, 13.95 mmol, 3.0 eq., containing 34% wt TiO2) in dry THE (15 mL). was stirred at room temperature for 2.5 h. Water and EtOAc were added, and insoluble solid was filtered off through celite. The two layers of the obtained clear liquid was separated. The organic layer was washed with sat. brine, dried over Na2SO4. The solvent was removed in vacuo and the residue was purified by flash chromatography on silica gel (0-30% EtOAc/PE) to give the product I-L1 (1.19 g, 80.2%). LC-MS: 318.2 [M+H]+.
To a solution of (S,E)-N-(3-bromo-4-methoxybenzylidene)-2-methylpropane-2-sulfinamide (963.3 mg, 3.03 mmol, 1.0 eq.) in dry THE (15 mL) at −50° C. was added lithium methide (2.2 mL, 6.06 mmol, 2.7 M in DEM, 2.0 eq.) dropwise. The reaction mixture was kept at −50° C. and monitored by LC-MS. After completion of the reaction, sat. NH4Cl (aq.) was added slowly to quench the reaction. The mixture was extracted with EtOAc, and the organic layer was washed with sat. brine, dried over Na2SO4. The solvent was removed in vacuo to give the crude product L2 (1.09 g, two diastereoisomers 1:1) which was used in the next step without purification. LC-MS: 334.0 [M+H]+.
A suspension of (S)-N-(1-(3-bromo-4-methoxyphenyl)ethyl)-2-methylpropane-2-sulfinamide (360 mg, 1.08 mmol, 1.0 eq.), 2-cyclopropyl-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (272 mg, 1.62 mmol, 1.5 eq.), anhydrous Na2CO3 (228.3 mg, 2.15 mmol, 2.0 eq.) and Pd(dppf)Cl2 (79 mg, 0.11 mmol, 0.1 eq.) in 1,4-dioxane/water (4.2/1.4 mL) was heated at 90° C. overnight. The mixture was cooled to room temperature, and water and EtOAc were added. The organic phase was separated, washed with sat. brine, dried over Na2SO4. The solvent was removed in vacuo and the crude residue was purified by flash chromatography on silica gel (0-50% EtOAc/PE) to afford the product L3 (170 mg, 53.4%). LC-MS: 296.0 [M+H]+.
To a solution of tert-butyl (1-(3-methoxy-4-(methylsulfinyl)phenyl)ethyl)carbamate (M5) (310 mg, 0.99 mmol, 1.0 eq.) in DCM (4.5 mL) was added 4 N HCl in 1,4-dioxane (1.24 mL, 4.95 mmol, 4 M, 5.0 eq.). The reaction mixture was stirred at room temperature and monitored by LC-MS. The solvent was removed in vacuo to yield the crude product M6 (HCl salt), which was used directly in the next step. LC-MS: 214.0 [M+H]+.
A solution of 3-methoxy-4-(methylthio)benzaldehyde (0.5 g, 2.74 mmol, 1.0 eq.), (S)-2-methylpropane-2-sulfinamide (399 mg, 3.29 mmol, 1.2 eq.) and Ti(OEt)4 (1.9 g, 5.48 mmol, 2.0 eq., containing 34% wt TiO2) was stirred at room temperature for 2.5 h. Water and EtOAc were added, and the insoluble solid was filtered off through celite. The two layers of the obtained clear liquid was separated. The organic layer was washed with sat. brine, dried over Na2SO4. The solvent was removed in vacuo and the residue was purified by flash chromatography on silica gel (0-40% EtOAc/PE) to afford the product M1 (0.65 g, 83.1%). LC-MS: 286.1 [M+H]+.
To a solution of (S)-N-(3-methoxy-4-(methylthio)benzylidene)-2-methylpropane-2-sulfinamide (650 mg, 2.28 mmol, 1.0 eq.) in dry THF (12 mL) at −50° C. was added lithium methide (1.3 mL, 3.41 mmol, 2.7 M in DEM, 1.5 eq.) dropwise. The reaction was kept at −50° C. and monitored by LC-MS. Upon completion, saturated NH4Cl (aq.) was added slowly to quench the reaction. The mixture was extracted with EtOAc, and the organic layer was washed with sat. brine, dried over Na2SO4. The solvent was removed in vacuo to give the crude product M2 (0.67 g, two diastereoisomers 1:1) which was used in the next step without purification. LC-MS: 301.6 [M+H]+.
To a solution of (S)-N-(1-(3-methoxy-4-(methylthio)phenyl)ethyl)-2-methylpropane-2-sulfinamide (670 mg, 2.22 mmol, 1.0 eq.) in DCM (3 mL) was added 4 N HCl in 1,4-dioxane (2.8 mL, 11.11 mmol, 4 M, 5.0 eq.). The reaction was stirred at room temperature and monitored by LC-MS. The solvent was removed in vacuo to yield the crude product (M3) (HCl salt), which was used directly in the next step. LC-MS: 181.0 [M-NH2]+.
A suspension of 1-(3-methoxy-4-(methylthio)phenyl)ethan-1-amine (519 mg, 2.22 mmol, HCl salt, 1.0 eq.), (Boc)2O (533 mg, 2.44 mmol, 1.1 eq.), and triethylamine (0.87 mL, 6.22 mmol, 2.8 eq.) in DCM (14 mL) was stirred at 0° C. The reaction mixture was warmed up to room temperature and monitored by LC-MS. Upon completion, sat. NaHCO3 (aq.) and DCM were added, and the organic phase was separated, washed with sat. brine, dried over Na2SO4. The solvent was removed in vacuo to give the crude product M4 (600 mg, 91%). LC-MS: 298.0 [M+H]+.
To a solution of tert-butyl (1-(3-methoxy-4-(methylthio)phenyl)ethyl)carbamate (300 mg, 1.02 mmol, 1.0 eq.) in DCM (9 mL) at 0° C. was added m-CPBA (225 mg, 1.11 mmol, 1.1 eq.). The reaction was slowly warmed up to room temperature and monitored by LC-MS. Upon completion, sat. NaHCO3 (aq.) was added to adjust the aq. solution pH˜8-9. The reaction mixture was extracted with EtOAc and the organic layer was separated, washed with sat. brine, dried over Na2SO4. The solvent was removed in vacuo to give the crude product M5 (310 mg). LC-MS: 313.8 [M+H]+.
To a solution of (R)-N-((R)-1-(1,3-dimethyl-1H-indazol-5-yl)ethyl)-2-methylpropane-2-sulfinamide N6 (1.30 g, 4.43 mmol, 1.0 eq.) in 1,4-dioxane (10 mL) was added 4 N HCl in 1,4-dioxane (10 mL, 40 mmol, 4 M, 9.0 eq.). The reaction mixture was stirred at room temperature and monitored by LC-MS. The solvent was removed in vacuo and the crude product N7 (HCl salt) was used directly in the next step. LC-MS: 189.8 [M+H]+.
To a solution of 1-(2-amino-5-bromophenyl)ethan-1-one (10.0 g, 46.53 mmol, 1.0 eq.) in ethanol (60 mL) was added hydroxylamine hydrochloride (4.89 g, 70.43 mmol, 1.5 eq.). The reaction mixture was stirred at 80° C. for 16 h, and then cooled to rt. The solvent was removed and the resulting residue was purified by flash chromatography on silica gel (0-100% EtOAc/PE, 0-10% MeOH/DCM) to yield the product N1 (8.10 g, 76.4%).
LC-MS: 228.6 [M+H]+.
To a solution of 1-(2-amino-5-bromophenyl)ethan-1-one oxime N1 (8.10 g, 34.53 mmol, 1.0 eq.) in DCM (60 mL) at 0° C. were added trifluoroacetic anhydride (7.51 g, 37.30 mmol, 1.08 eq.) and DIPEA (15.45 g, 119.7 mmol, 3.0 eq.) dropwise. The reaction mixture was stirred at 0° C. for 8 h, then water (60 mL) and DCM (60 mL) were added. The organic layer was separated and washed with sat. brine, dried over Na2SO4. The solvent was removed in vacuo and the residue was purified by flash chromatography on silica gel (0-60% PE/EtOAc) to yield the product N2 (6.36 g, 87.8%). LC-MS: 210.6 [M+H]+.
To a solution of 5-bromo-3-methyl-1H-indazole N2 (6.36 g, 30.30 mmol, 1.0 eq.) in DMF (40 mL) was added NaH (1.45 g, 36.36 mmol, 60% wt in paraffin, 1.2 eq,) at 0° C., then methyl iodide (6.45 g, 45.45 mmol, 1.5 eq.) was added dropwise. The reaction mixture was stirred at 0° C. for 2 h, then sat. NH4Cl (aq.) (60 mL) and DCM (60 mL) were added. The organic layer was separated, washed with sat. brine, and dried over Na2SO4. The solvent was removed in vacuo and the crude residue was purified by flash chromatography on silica gel (0-60% EtOAc/PE) to yield the product N3 (3.10 g, 45.6%).
1H NMR (CDCl3, 400 MHz) b 7.78 (d, J=2.0 Hz, 1H), 7.43 (dd, J2=8.9 Hz, J2=1.8 Hz, 1H), 7.20 (d, J=8.9 Hz, 1H), 3.98 (s, 3H), 2.53 (s, 3H). LC-MS: 224.6 [M+H]+.
To a solution of 5-bromo-1,3-dimethyl-1H-indazole N3 (3.10 g, 13.84 mmol, 1.0 eq.) and tributyl(1-ethoxyvinyl)tin (7.52 g, 20.76 mmol, 1.5 eq.) in 1,4-dioxane (50 mL) was added Pd(PPh3)4(1.59 g, 1.38 mmol, 0.1 eq.). The mixture was recharged with N2 balloon for three times and stirred at 100° C. overnight. Then the reaction mixture was cooled to room temperature and sat. potassium fluoride (aq.) (200 mL) was added. The resulting mixture was filtered through celite, and sat. NH4Cl (aq.) and EtOAc were added. The organic layer was separated and washed with sat. brine, dried over Na2SO4. The solvent was removed in vacuo and the crude residue was purified by flash chromatography on silica gel (0-70% PE/EtOAc) to yield the product N4 (2.16 g, 72.3%). LC-MS: 216.6 [M+H]+.
To a solution of 5-(1-ethoxyvinyl)-1,3-dimethyl-1H-indazole N4 (2.16 g, 10.0 mmol, 1.0 eq.) in 1,4-dioxane (10 mL) was added 2 M HCl (aq.) (2 mL) at 0° C. The mixture was stirred at 0° C. for 4 h. The solvent was removed in vacuo and the crude product N5 (1.80 g, 95.8%) was used in the next step without further purification. LC-MS: 188.6 [M+H]+.
To a solution of 1-(1,3-dimethyl-1H-indazol-5-yl)ethan-1-one N5 (1.80 g, 9.58 mmol, 1.0 eq.) and (R)-2-methylpropane-2-sulfinamide (1.73 g, 14.25 mmol, 1.5 eq.) in THE (60 mL) was added Ti(OEt)4 (15.93 g, 23.75 mmol, 2.5 eq, containing 34% wt TiO2). The mixture was recharged with N2 balloon for three times and stirred at 70° C. overnight. The mixture was then cooled to −48° C. and NaBH4 (3.64 g, 95.80 mmol, 10.0 eq.) was added. Upon completion, sat. brine (100 mL) was added and the mixture was filtered through celite. Sat. NH4Cl (aq.) and EtOAc were added to the filtrate. The organic layer was separated and washed with sat. brine, dried over Na2SO4. The solvent was removed in vacuo and the crude residue was purified by flash chromatography on silica gel (0-60% EtOAc/PE) to yield the product N6 (1.30 g, 46.2%). LC-MS: 293.8 [M+H]+.
To a solution of (R)-N-((R)-1-(1,3-dimethyl-1H-indazol-6-yl)ethyl)-2-methylpropane-2-sulfinamide O7 (1.35 g, 4.61 mmol, 1.0 eq.) in 1,4-dioxane (10 mL) was added 4 N HCl in 1,4-dioxane (10 mL, 40 mmol, 4 M, 8.7 eq.). The reaction mixture was stirred at room temperature and monitored by LC-MS. The solvent was removed in vacuo and the crude product O8 (HCl salt) was used directly in the next step. LC-MS: 189.6 [M+H]+.
To a solution of 1-(2-amino-4-bromophenyl)ethan-1-one (10.0 g, 46.53 mmol, 1.0 eq.) in ethanol (60 mL) was added hydroxylamine hydrochloride (4.89 g, 70.43 mmol, 1.5 eq.). The reaction mixture was stirred at 80° C. for 16 h, and then cooled to rt. The solvent was removed in vacuo, and the resulting residue was purified by flash chromatography on silica gel (0-100% EtOAc/PE, 0-10% MeOH/DCM) to yield the product O1 (9.10 g, 85.8%). LC-MS: 228.6 [M+H]+.
To a solution of 1-(2-amino-4-bromophenyl)ethan-1-one oxime O1 (9.10 g, 39.91 mmol, 1.0 eq.) in DCM (60 mL) were added dropwise trifluoroacetic anhydride (8.61 g, 43.05 mmol, 1.08 eq.) and DIPEA (15.45 g, 119.70 mmol, 3.0 eq.) at 0° C. The reaction mixture was stirred at 0° C. for 8 h. Water (60 mL) and DCM (60 mL) were added, and the organic layer was separated, washed with sat. brine, dried over Na2SO4. The solvent was removed in vacuo and the residue was purified by flash chromatography on silica gel (0-60% EtOAc/PE) to yield the product O2 (7.80 g, 93.0%). 1H NMR (DMSO-D6, 400 MHz) δ 12.76 (s, 1H), 7.65-7.70 (m, 2H), 7.20 (dd, J2=8.6 Hz, J2=1.5 Hz, 1H), 2.48 (s, 3H). LC-MS: 210.6 [M+H]+.
To a solution of 6-bromo-3-methyl-1H-indazole O2 (7.80 g, 37.15 mmol, 1.0 eq.) in DMF (40 mL) at 0° C. was added NaH (1.78 g, 44.58 mmol, 60% wt in paraffin, 1.2 eq.), followed by methyl iodide (7.91 g, 55.73 mmol, 1.5 eq.) dropwise. The reaction mixture was stirred for 2 h at 0° C. Upon completion, sat. NH4Cl (aq.) (60 mL) and DCM (60 mL) were added. The organic layer was separated, washed with sat. brine, dried over Na2SO4. The solvent was removed in vacuo and the crude residue was purified by flash chromatography on silica gel (0-60% EtOAc/PE) to yield the product O3 (3.10 g, 37.3%).
1H NMR (DMSO-D6, 400 MHz) δ 7.88 (d, J=1.5 Hz, 1H), 7.65 (d, J=8.5 Hz, 1H), 7.20 (dd, J2=8.6 Hz, J2=1.5 Hz, 1H), 3.93 (s, 3H), 2.45 (s, 3H). LC-MS: 224.6 [M+H]+.
To a solution of 6-bromo-1,3-dimethyl-1H-indazole O3 (3.10 g, 13.84 mmol, 1.0 eq.) and tributyl(1-ethoxyvinyl)tin (7.52 g, 20.76 mmol, 1.5 eq.) in 1,4-dioxane (50 mL) was added Pd(PPh3)4(1.59 g, 1.38 mmol, 0.1 eq.). The mixture was recharged with N2 balloon for three times and stirred at 100° C. overnight. The reaction mixture was cooled to room temperature and sat. potassium fluoride (aq.) (200 mL) was added. The resulting mixture was filtered through celite and sat. NH4Cl (aq.) and EtOAc were added. The organic layer was separated, washed with sat. brine, and dried over Na2SO4. The solvent was removed in vacuo and the crude residue was purified by flash chromatography on silica gel (0-55% EtOAc/PE) to yield the product O4 (2.03 g, 68.0%).
LC-MS: 216.6 [M+H]+.
To a solution of 6-(1-ethoxyvinyl)-1,3-dimethyl-1H-indazole O4 (2.03 g, 9.40 mmol, 1.0 eq.) in 1,4-dioxane/water (10 mL/1 mL) at 0° C. was added 2 M HCl (aq.) (4 mL). The mixture was stirred at 0° C. for 4 h. The solvent was removed in vacuo and the crude product O5 (1.68 g, 95%) was used in the next step without further purification. LC-MS: 188.6 [M+H]+.
To a solution of 1-(1,3-dimethyl-1H-indazol-6-yl)ethan-1-one 05 (1.68 g, 8.93 mmol, 1.0 eq.) and (R)-2-methylpropane-2-sulfinamide (1.62 g, 13.40 mmol, 1.5 eq.) in THE (60 mL) was added Ti(OEt)4 (14.97 g, 22.33 mmol, containing 34% wt TiO2, 2.5 eq.). The reaction mixture was recharged with N2 balloon for three times and then refluxed overnight. The mixture containing 06 was cooled to rt and used directly in the next step.
LC-MS: 291.6 [M+H]+.
The above solution containing (R)-N-(1-(1,3-dimethyl-1H-indazol-6-yl)ethylidene)-2-methylpropane-2-sulfinamide 06_was cooled to −50° C., then NaBH4 (4.41 g, 116.09 mmol, 13.0 eq.) was added. The mixture was recharged with N2 balloon for three times and stirred at −50° C. for 12 h. After complete consumption by LC-MS detection, sat. brine (100 mL) was added. The mixture was filtered through celite, then sat. NH4Cl (aq.) and EtOAc were added. The organic layer was separated and washed with sat. brine, dried over Na2SO4. The solvent was removed in vacuo and the crude residue was purified by flash chromatography on silica gel (0-55% PE/EtOAc) to yield the product O7 (1.35 g, 51.6%). LC-MS: 293.8 [M+H]+.
The exemplified compounds described herein were tested for activity and were found to have an IC50 value less than 10 μM in the following assay:
This protocol describes how the Lance Kinase Activity Assay was performed to determine IC50 values of compounds of general formula (I) against GRK5 and GRK2.
The principle behind this enzymatic assay is based upon the phosphorylation of the Ulight-peptide substrate. It is detected by using a specific EU-labeled anti-phospho peptide antibody. The binding of the Eu labeled anti-phospho peptide antibody to the phosphorylated ULight labeled peptide gives rise to a FRET-signal. Binding of an inhibitor to the kinase prevents phosphorylation of the Ulight-substrate, resulting in a loss of FRET. In tables 2 and 3 the relevant information for these two LANCE assays is summarized.
For every sample, 2 μl of assay buffer (50 mM HEPES pH 7,5, 10 mM MgCL2, 1 mM EGTA 0,01% Tween 20, 1% DMSO, 2 mM DTT) were transferred into a suitable assay plate (e.g. Corning #3673). Compounds were added in a concentration range from 10 μM to 0.0025 μM using an acoustic dispenser (Echo520 from Labcycte, San Jose, USA) equipped with Echo Dose Response software. After that 6 μl of kinase-substrate mix was added. Reaction was started by addition of 2 μl ATP working solution and mixed using a Bioshake 5000 microplate shaker (Q Instruments, Jena, Germany).
After 1 h incubation at room temperature the reaction was stopped with 10 μl detection mix containing the Eu-labeled phosphospecific antibody and 10 mM EDTA. After a second incubation period of 1 h at room temperature the FRET signal was measured at 340 nm excitation, 665 nm and 615 nm emission (for the ULight-substrate and Eu-AB, respectively) with an Envision microplate reader (Perkin Elmer, Waltham, MA, USA) with 50 μs delay and 300 μs integration time. IC50 values were determined from the sigmoidal dose response curves with the software Quattro Workflow (Quattro GmbH, Munich, Germany).
Table 4 shows activity data in the biochemical Lance assay. Inhibition is indicated as IC50 [nM] (“−”=not measured). Compounds having an activity designated as “A” provided an IC50≤50 nM; compounds having an activity designated as “B” provided an 50 nM<IC50≤100 nM; compounds having an activity designated as “C” provided an 100 nM<IC50≤500 nM; compounds having an activity designated as “D” provided an 500 nM<IC50≤1000 nM; compounds having an activity designated as “E” provided an 1000 nM<IC50≤10000 nM; and compounds having an activity designated as “F” provided an IC50>10000 nM.
5-6 days old Wistar rats were sacrificed by decapitation and neonatal rat ventricular cardiac myocytes (NRVCMs) were prepared using the Neonatal heart dissociation kit (Miltenyi Biotec) according to the manufacturer's instructions. The cardiac single cell suspension was resuspended in DMEM low glucose medium supplemented with 2% fetal bovine serum (FBS) and 50 μg/ml penicillin/streptomycin. 1500 cells/well were seeded on 0.1% gelatin-coated 384-well plates and incubated in medium at 37° C. and 5% CO2 for 24 h prior to the addition of test compounds to the cells at titrated concentrations. Cellular hypertrophy was then stimulated by adding phenylephrine and leukemia inhibitory factor at final concentrations of 20 μM and 50 ng/ml, respectively, and the cells were incubated for another 96 h. For immunocytochemistry, cells were fixed with 4% formaldehyde on day 5 of compound treatment and cardiomyocytes were stained with antibodies against a-actinin while cell nuclei were stained with DAPI. Image acquisition and phenotypic analysis was performed using an Image-Xpress Micro XL automated microscope (Molecular Devices).
Table 5 shows activity data measured in the in vitro cardiomyocyte hypertrophy assay. Inhibition of cellular hypertrophy is indicated as IC50 [nM]. Compounds having an activity designated as “A” provided an IC50≤500 nM; compounds having an activity designated as “B” provided an 500 nM<IC50≤1000 nM; compounds having an activity designated as “C” provided an IC50>1000 nM.
| Number | Date | Country | Kind |
|---|---|---|---|
| 21179666.9 | Jun 2021 | EP | regional |
| Filing Document | Filing Date | Country | Kind |
|---|---|---|---|
| PCT/EP2022/066372 | 6/15/2022 | WO |
