HK1245763A1 - Pyrazolopyridinamines as mknk1 and mknk2 inhibitors - Google Patents

Description

Pyrazolopyridines as MKNK1 and MKNK2 inhibitors

Technical Field

The present invention relates to substituted pyrazolopyridinamine compounds of general formula (I) as described and defined herein, to methods of preparing said compounds, to intermediate compounds useful for preparing said compounds, to pharmaceutical compositions and combinations comprising said compounds and to the use of said compounds for manufacturing a pharmaceutical composition for the treatment or prophylaxis of a disease, in particular of a hyperproliferative, angiogenic disorder, inflammatory disease or disease associated with inflammatory pain, as a sole agent or in combination with other active ingredients.

Background

The present invention relates to chemical compounds that inhibit MKNK1 kinase (also known as MAP kinase interacting kinase, Mnk1) and/or MKNK2 kinase (also known as MAP kinase interacting kinase, Mnk 2). Human MKNKs comprise a set of four proteins encoded by two genes (gene symbols: MKNK1 and MKNK2) by alternative splicing. Type b lacks the C-terminal MAP kinase binding domain. The catalytic domains of MKNK1 and MKNK2 are very similar and contain a unique DFD (Asp-Phe-Asp) motif in subdomain VII, which is typically DFG (Asp-Phe-Gly) among other protein kinases and is believed to alter ATP binding [ Jauch et al, Structure 13, 1559-. MKNK1a binds to and is activated by ERK and p38 MAP kinases, but is not activated by JNK 1. MKNK2a binds to and is only activated by ERK. MKNK1b had low activity under all conditions, and MKNK2b had basal activity independent of ERK or p38 MAP kinase [ Buxade M et al, Frontiers in Bioscience 5359-5374, 1/5/2008 ].

MKNKs have been shown to phosphorylate eukaryotic initiation factor 4E (eIF4E), heterogeneous nuclear RNA-binding protein A1 (hnRNPA1), polypyrimidine sequence-binding protein-related splicing factor (PSF), cytoplasmic phospholipase A2 (cPLA2) and Sprouty 2(hSPRY2) [ Buxade M et al, Frontiers in Bioscience 5359-5374, 2008. 5.1.1.d ].

eIF4E is an oncogene that is amplified in many cancers and is phosphorylated only by mknkks proteins as shown in the KO-mouse study [ Konicek et al, Cell Cycle 7:16, 2466-2471, 2008; ueda et al Mol Cell Biol24, 6539-. eIF4E has a key role in achieving translation of cellular mRNAs. eIF4E binds to the 7-methylguanosine cap at the 5' end of cellular mRNAs and delivers them to the ribosome as part of an eIF4F complex that also contains eIF4G and eIF 4A. Although all capped mRNAs required eIF4E for translation, the pool of mRNAs depended abnormally on increased eIF4E activity for translation. These so-called "weak mRNAs" are generally translated less efficiently due to their long and complex 5' UTR region, and they encode proteins that play an important role in all aspects of malignancy, including VEGF, FGF-2, c-Myc, cyclin D1, survivin, BCL-2, MCL-1, MMP-9, heparanase, and the like. expression and function of eIF4E is elevated in a variety of human cancers and is directly associated with disease progression [ Konicek et al, Cell Cycle 7:16, 2466-2471, 2008 ].

MKNK1 and MKNK2 are the only kinases known to phosphorylate eIF4E at Ser 209. The overall translation rate was not affected by phosphorylation of eIF4E, but it was shown that eIF4E phosphorylation contributed to polysome formation (i.e., multiple ribosomes on a single mRNA) that ultimately enabled more efficient translation of "weak mRNAs" [ Buxade M et al, Frontiers in bioscience 5359-]. Alternatively, phosphorylation of eIF4E by MKNK protein may facilitate release of eIF4E from the 5' cap, allowing the 48S complex to move along the "weak mRNA" to locate the initiation codons [ Blagden SP and Willis AE, Nat Rev Clin Oncol.8 (5):280-91, 2011]. Accordingly, increased eIF4E phosphorylation predicts poor prognosis in non-small cell lung Cancer patients [ Yoshizawa et al, Clin Cancer Res. 16(1):240-8, 2010)]. Further data point to the functional role of MKNK1 in carcinogenesis, as overexpression of constitutively active MKNK1 (but not kinase-inactive MKNK1) accelerated tumor formation in mouse embryonic fibroblasts [ Chrestensen c. a. et al, Genes Cells 12, 1133-]. Furthermore, in breast cancer, increased phosphorylation and activity of MKNK protein is associated with overexpression of HER2 [ Chrestensen, c. a. et al, j. biol. chem. 282, 4243-4252, 2007]. In useEμ-MycIn a model of transgenic hematopoietic stem cells to generate tumors in mice, constitutively active (rather than kinase-inactive) MKNK1 also accelerated tumor growth. Comparable results were obtained when eIF4E carrying the S209D mutation was analyzed. The S209D mutation mimics phosphorylation at the MKNK1 phosphorylation site. In contrast, the non-phosphorylatable form of eIF4E attenuates tumor growth [ Wendel HG et al, Genes Dev. 21(24): 3232-one 7,2007]. Selective MKNK inhibitors that block phosphorylation of eIF4E induced apoptosis and inhibited proliferation of cancer cells and soft agar growth in vitro. Such a suppressorThe preparation also inhibited the outgrowth of experimental B16 melanoma lung metastases and the growth of subcutaneous HCT116 colon Cancer xenograft tumors without affecting body weight [ Konicek et al, Cancer Res. 71(5):1849-]. In summary, phosphorylation of eIF4E by MKNK protein activity can promote cell proliferation and survival and is critical for malignant transformation. Inhibition of MKNK activity may provide an easy to handle approach to cancer therapy.

Furthermore, MKNK1 has been found to be an acinar cell-specific kinase required for exocrine pancreatic secretion [ Cendrowski J, S. cnhez-Ar ivalo VJ, Sendler M, et al Gut first viewed online: 18 months 7 2014; doi: 10.1136/gutjnl-2013-.

The kinases MKNK1 and MKNK2 are important downstream targets of the Erk and p38 mitogen-activated protein kinase (MAPK) pathway, and their activities can also be regulated by MAPK-independent signals. MKNKs are directly involved in regulating mRNA translation and are therefore key mediators of oncogenic progression and cytokine signaling. In particular, MAPK pathways such as Erk and p38 have been shown to play important roles in modulating immune responses by: mediates the production of cytokines that control the initiation of innate immunity; activating adaptive immunity; and modulating cellular responses to cytokines involved in immune responses. Furthermore, Erk and p38 contribute to Pain sensitivity, and p38 kinase inhibitors have been shown to have preclinical and clinical efficacy on Pain [ Brown, Heitmeyer, et al, J infilam (Lond), 2008; Hill, Dabbagh, et al, J Pharmacol Exp TherJi,2008; Gereau, et al, Brain Res Rev, 2009; Cheng, Dauch, et al, Mol Pain, 2010; Anand, Shenoy, et al, European Journal of Pain, 2011; Daves, tchaiison, et al, American College of rhematology Annual Meeting, 2012; Lin, Wang, et al, CurrMed Chem, 2014]. Since MKNK kinases are effectors of the MAPK pathway, these observations suggest that they may play an important role in mediating cytokine production and inflammatory pain. Recent studies have supported the involvement of MKNK kinase in different inflammatory processes [ Rowlett, Christensen, et al, Am J Physiol Gastrointest Liver Physiol, 2008; Kjellreup, Kragbale, et al, Experimental Dermatology, 2008; Melemedjian, Asidu, et al, J Neurosci, 2010, Fortin, Mayer, et al, Journal of Leucocytebiol, 2013]. Due to the induction of MKNK kinase by different inflammatory stimuli (sterile inflammation and pathogens) and its ability to modulate the expression of different cytokines that mediate the pathogenesis of a variety of conditions such as autoimmune diseases, allergies, neurological conditions, sepsis, cardiovascular diseases, metabolic diseases, obesity and cancer. MKNKs represent central nodes that regulate inflammation. [JoshiWait for; World J Biol Chem2014 August 26, 5(3) 321-333, Joschi et al,Biomol Concepts. 2012 April ; 3(2): 127–139]。

article [2 ]American Journal of Reproductive Immunology68 (2012) 138–145]The imbalance of cytokines from the interleukin-1 family and their role in the pathogenesis of endometriosis as well as the possible pathophysiological role of mitogen-activated protein kinases (MAPKs) in endometriosis are reportedYoshinoWait for; AJRI 2004; 52:306–311]. More recently, proinflammatory cytokines have been described for use in evaluating the inflammatory state and its pathogenic mechanism in endometriosisTostiWait for; Reproductive Sciences2015,1-7; MalutanWait for, Centr Eur J Immunol 2015; 40 (1): 96-102; Soo Hyun AhnAnd the like,BioMed Research International, Vol. 2015, arrow ID 795976, page 12]Women with endometriosis have elevated levels of key proinflammatory cytokines, namely IL-1 β, IL-6 and TNF- α while IL-1 β and IL-6 can be used as predictors of endometriosis.

There is no disclosure in the prior art of substituted pyrazolopyridine amine compounds of general formula (I) for use in the treatment or prevention of different diseases.

Thus, the state of the art described above does not describe the specific substituted pyrazolopyridine amine compounds of general formula (I) of the present invention as defined herein, or stereoisomers, tautomers, N-oxides, hydrates, solvates or salts thereof, or mixtures thereof, or the pharmacological activity thereof, as described and defined herein and hereinafter referred to as "compounds of the present invention".

It has now been found that the compounds of the invention described have surprising and advantageous properties and this forms the basis of the invention.

In particular, the compounds of the invention have been found to be effective in inhibiting MKNK-1 kinase.

Furthermore, the compounds according to the invention were found to be effective in inhibiting MKNK2 kinase.

In contrast to other MKNK1 and/or MKNK2 kinase inhibitors, the pyrazolopyridine amines according to the invention are mainly active against sterile and pathogenic inflammatory reactions and do not directly interfere with cell viability.

Pyrazolopyridinamines according to the invention may be used for the treatment or prevention of diseases of uncontrolled cell growth, proliferation and/or survival, an inappropriate cellular immune response or an inappropriate cellular inflammatory response, or of diseases accompanied by uncontrolled cell growth, proliferation and/or survival, an inappropriate cellular immune response or an inappropriate cellular inflammatory response, in particular wherein said uncontrolled cell growth, proliferation and/or survival, inappropriate cellular immune response or inappropriate cellular inflammatory response is mediated by MKNK1 and/or MKNK2 kinase, such as hematological tumors, solid tumors and/or metastases thereof, such as leukemias and myelodysplastic syndromes, malignant lymphomas, head and neck tumors including brain tumors and brain metastases, breast tumors including non-small cell lung tumors and small cell lung tumors, brain tumors including non-small cell lung tumors, brain tumors, Gastrointestinal tumors, endocrine tumors, breast tumors and other gynecological tumors, urological tumors including kidney, bladder and prostate tumors, skin tumors and sarcomas, and/or metastases thereof.

The pyrazolopyridinamines according to the invention can be used for the treatment or prophylaxis of inflammatory and/or immunological diseases as described in the summary of the invention.

Furthermore, the compounds according to the invention can be used for the treatment or prevention of gynaecological disorders, preferably dysmenorrhea, dyspareunia or endometriosis, adenomyosis, endometriosis-related pain or other endometriosis-related symptoms, wherein the symptoms are in particular endometriosis-related proliferation, dysmenorrhea, dyspareunia, dysuria or constipation.

Summary of The Invention

The present invention encompasses compounds of general formula (I):

wherein:

R¹represents a hydrogen atom or a halogen atom or a group selected from:

hydroxy-, cyano-, C₁-C₆-alkyl-, C₂-C₆-alkenyl-, C₂-C₆-alkynyl-, C₁-C₆-alkoxy-, halo-C₁-C₆-alkoxy-, C₃-C₆-cycloalkyl-, C₄-C₈-cycloalkenyl-, C₃-C₆-cycloalkyloxy-, (3-to 10-membered heterocycloalkyl) -O-, C₅-C₈-cycloalkenyloxy-, (5-to 10-membered heterocycloalkenyl) -O-, -N (R)^5a)R^5b、-SR^5aand-SF₅；

Wherein said C₁-C₆-alkyl-, C₂-C₆-alkenyl-, C₂-C₆-alkynyl-, C₁-C₆-alkoxy-, C₃-C₆-cycloalkyl-, C₄-C₈-cycloalkenyl-, C₃-C₆-cycloalkyloxy-, (3-to 10-membered heterocycloalkyl) -O-, C₅-C₈-cycloalkenyloxy-, (5-to 10-membered heterocycloalkenyl) -and (5-to 10-membered heterocycloalkenyl) -O-groups optionally substituted with 1,2, 3,4 or 5R⁴The radicals are substituted identically or differently;

R²represents a hydrogen atom or a group selected from: c₁-C₆-alkyl-, C₂-C₆-alkenyl-, C₁-C₆-alkoxy-, halo-C₁-C₆-alkyl-and halo-C₁-C₆-alkoxy-;

wherein said C₁-C₆-alkyl-, C₂-C₆-alkenyl-and C₁-C₆-alkoxy-groups optionally substituted by 1,2 or 3R⁷The radicals are substituted identically or differently;

R³represents a hydrogen atom or a group selected from: c₁-C₆-alkyl-, C₃-C₆-cycloalkyl-, C₄-C₆-cycloalkenyl-, C₂-C₆-alkenyl-, C₂-C₆-alkynyl-, 3-to 10-membered heterocycloalkyl-, 4-to 10-membered heterocycloalkenyl-, aryl-, heteroaryl-, cyano-and- (CH)₂)_q-X-(CH₂)_p-R⁵；

Wherein said C₁-C₆-alkyl-, C₃-C₆-cycloalkyl-, C₄-C₆-cycloalkenyl-, C₂-C₆-alkenyl-, C₂-C₆-alkynyl-, 3-to 10-membered heterocycloalkyl-, 4-to 10-membered heterocycloalkenyl-, aryl-and heteroaryl-groups optionally substituted with 1,2, 3,4 or 5R⁴The radicals are substituted identically or differently;

x represents a bond or a divalent group selected from: -O-, -S (= O)₂-、-S(=O)-N(R^5a)-、-N(R^5a)-S(=O)-、-S(=O)₂-N(R^5a)-、-N(R^5a)-S(=O)₂-、-S(=O)(=NR^5a)-、-C(=O)-、-N(R^5a)-、-C(=O)-O-、-O-C(=O)-、-C(=S)-O-、-O-C(=S)-、-C(=O)-N(R^5a)-、-N(R^5a)-C(=O)-、-N(R^5a)-C(=O)-N(R^5b)-、-O-C(=O)-N(R^5a)-、-N(R^5a)-C(=O)-O-；

R⁴Represents halo-, hydroxy-, oxo- (O =), cyano-, nitro-, C₁-C₆-alkyl-, C₂-C₆-alkenyl-, C₂-C₆-alkynyl-, halo-C₁-C₆-alkyl-, C₁-C₆-alkoxy-, halo-C₁-C₆-alkoxy-, hydroxy-C₁-C₆-alkyl-, C₁-C₆-alkoxy-C₁-C₆-alkyl-, halo-C₁-C₆-alkoxy-C₁-C₆-alkyl-, R⁶-O-、-C(=O)-R⁶、-C(=O)-O-R⁶、-O-C(=O)-R⁶、-N(R^6a)-C(=O)-R^6b、-N(R^6a)-C(=O)-O-R^6b、-N(R^6a)-C(=O)-N(R^6b)R^6c、-N(R^6a)R^6b、-N(R^6a)R^6d、-C(=O)-N(R^6a)R^6b、R⁶-S-、R⁶-S(=O)-、R⁶-S(=O)₂-、-N(R^6a)-S(=O)-R^6b、-S(=O)-N(R^6a)R^6b、-N(R^6a)-S(=O)₂-R^6b、-S(=O)₂-N(R^6a)R^6b、-S(=O)=N(R^6a)R^6b、-N=S(=O)(R^6a)R^6bOr- (C)₁-C₆-alkyl) -N (R)^6a)R^6b；

R^5a、R^5bAre the same or different and are independently selected from R⁵；

R⁵Represents a hydrogen atom or a group selected from: c₁-C₆-alkyl-, C₃-C₆-cycloalkyl-, 3-to 10-membered heterocycloalkyl-, aryl-and heteroaryl-;

wherein said C₁-C₆-alkyl-, C₃-C₆-cycloalkyl-, 3-to 10-memberedHeterocycloalkyl-, aryl-and heteroaryl-groups are optionally substituted with 1,2, 3,4 or 5R⁴The radicals are substituted identically or differently;

or

N(R^5a)R⁵Together represent a 3-to 10-membered heterocycloalkyl-group, optionally substituted by 1,2, 3,4 or 5R⁴The radicals are substituted identically or differently;

R^6a、R^6b、R^6care the same or different and are independently selected from R⁶；

R⁶Represents a hydrogen atom, C₁-C₆-alkyl-or C₃-C₆-a cycloalkyl-group;

or

R^6aAnd R^6b，

Or R^6aAnd R^6c，

Or R^6bAnd R^6cMay together form C₂-C₆An alkylene radical in which one methylene group may optionally be replaced by-O-, -C (= O) -, -NH-or-N (C)₁-C₄-alkyl) -substitution;

R^6drepresents- (C)₁-C₆-alkyl) -N (R)^6a)R^6b；

R⁷Represents halo-, hydroxy-, oxo- (O =), cyano-, nitro-,

p represents an integer of 0, 1,2 or 3;

q represents an integer of 0, 1,2 or 3;

or a tautomer, an N-oxide, a hydrate, a solvate, or a salt thereof, or a mixture of same.

The invention further relates to processes for the preparation of the compounds of general formula (I), pharmaceutical compositions and combinations comprising said compounds, the use of said compounds for the manufacture of pharmaceutical compositions for the treatment or prophylaxis of diseases, and intermediate compounds useful in the preparation of said compounds.

Detailed Description

The terms as referred to herein preferably have the following meanings:

the term "halogen atom", "halo-" or "halo-" is understood to mean a fluorine, chlorine, bromine or iodine atom, preferably a fluorine, chlorine or bromine atom.

The term "C₁-C₁₀Alkyl "is understood as preferably meaning a straight-chain or branched, saturated monovalent hydrocarbon radical having 1,2, 3,4, 5,6,7,8, 9 or 10 carbon atoms, for example methyl, ethyl, propyl, butyl, pentyl, hexyl, isopropyl, isobutyl, sec-butyl, tert-butyl, isopentyl, 2-methylbutyl, 1-ethylpropyl, 1, 2-dimethylpropyl, neopentyl, 1-dimethylpropyl, 4-methylpentyl, 3-methylpentyl, 2-methylpentyl, 1-methylpentyl, 2-ethylbutyl, 1-ethylbutyl, 3-dimethylbutyl, 2-dimethylbutyl, 1-dimethylbutyl, 2, 3-dimethylbutyl, 1, 3-dimethylbutyl or 1, 2-dimethylbutyl group, or isomers thereof. In particular, the group has 1,2, 3,4, 5 or 6 carbon atoms ("C)₁-C₆-alkyl "), more particularly said group having 1,2, 3 or 4 carbon atoms (" C ")₁-C₄-alkyl "), such as methyl, ethyl, propyl, butyl, isopropyl, isobutyl, sec-butyl, tert-butyl groups; even more specifically having 1,2 or 3 carbon atoms ("C)₁-C₃-alkyl "), such as a methyl, ethyl, n-propyl or isopropyl group.

The term "C₁-C₁₀Alkylene is understood as meaning preferably a straight-chain or branched, saturated divalent hydrocarbon radical having 1,2, 3,4, 5,6,7,8, 9 or 10 carbon atoms, for example methylene, ethylene, n-propylene, n-butylene, n-pentylene, 2-methylbutylene, n-hexylene, 3-methylpentylene or isomers thereof. Utensil for cleaning buttockIn particular, the radicals are straight-chain and have 2,3,4 or 5 carbon atoms ("C)₂-C₅Alkylene), for example ethylene, n-propylene, n-butylene, n-pentylene, more particularly having 3 or 4 carbon atoms ("C)₃-C₄Alkylene "), for example n-propylene or n-butylene.

The term "halo-C₁-C₆Alkyl is understood as preferably meaning a straight-chain or branched saturated monovalent hydrocarbon radical, where the term "C" is₁-C₆-alkyl "is defined above and wherein one or more hydrogen atoms are replaced by halogen atoms, identically or differently (i.e. one halogen atom is independent of the other). Specifically, the halogen atom is F. Said halo-C₁-C₆The alkyl radical being, for example, -CF₃、-CHF₂、-CH₂F、-CF₂CF₃or-CH₂CF₃。

The term "C₁-C₆Alkoxy is understood as meaning preferably-O- (C)₁-C₆-alkyl) straight or branched chain saturated monovalent hydrocarbon radical, wherein the term "C₁-C₆-alkyl- "is defined above, for example methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, isobutoxy, tert-butoxy, sec-butoxy, pentoxy, isopentoxy or n-hexoxy, or isomers thereof.

The term "halo-C₁-C₆Alkoxy "is understood as preferably meaning a straight-chain or branched, saturated, monovalent C as defined above₁-C₆-alkoxy groups in which one or more hydrogen atoms are replaced, identically or differently, by halogen atoms. Specifically, the halogen atom is F. Said halo-C₁-C₆Alkoxy radicals are, for example, -OCF₃、-OCHF₂、-OCH₂F、-OCF₂CF₃or-OCH₂CF₃。

The term "C₁-C₆-alkoxy-C₁-C₆-alkyl group "should be taken to meanSolution to preferably means a linear or branched saturated monovalent C as defined above₁-C₆-an alkyl group in which one or more hydrogen atoms are replaced by C as defined above₁-C₆The alkoxy groups are replaced identically or differently, for example, the methoxyalkyl, ethoxyalkyl, propoxyalkyl, isopropoxyalkyl, butoxyalkyl, isobutoxyalkyl, tert-butoxyalkyl, sec-butoxyalkyl, pentoxyalkyl, isopentyloxyalkyl, hexyloxyalkyl groups, or isomers thereof.

The term "halo-C₁-C₆-alkoxy-C₁-C₆Alkyl "is understood as preferably meaning a straight-chain or branched, saturated, monovalent C as defined above₁-C₆-alkoxy-C₁-C₆-alkyl groups in which one or more hydrogen atoms are replaced, identically or differently, by halogen atoms. Specifically, the halogen atom is F. Said halo-C₁-C₆-alkoxy-C₁-C₆The alkyl radical being, for example, -CH₂CH₂OCF₃、-CH₂CH₂OCHF₂、-CH₂CH₂OCH₂F、-CH₂CH₂OCF₂CF₃or-CH₂CH₂OCH₂CF₃。

The term "C₂-C₁₀Alkenyl "is understood as meaning preferably a straight-chain or branched monovalent hydrocarbon radical which contains one or more double bonds and has 2,3,4, 5,6,7,8, 9 or 10 carbon atoms, in particular 2,3,4, 5 or 6 carbon atoms (" C)₂-C₆-alkenyl "), more particularly 2 or 3 carbon atoms (" C ")₂-C₃-alkenyl ") it is understood that in case the alkenyl group contains more than one double bond, then the double bonds may be separated from each other or conjugated. Said alkenyl is, for example, vinyl, allyl, (E) -2-methylethenyl group, ((iii))Z) -2-methylvinyl, homoallyl (homoallyl), (b), (c), (dE) -but-2-enyl, ((iii))Z) -but-2-enyl, ((iii))E) -but-1-enyl group, ((iii))Z) -but-1-enyl, pent-4-enyl, ((iii))E) Pent-3-enyl group, ((iii))Z) Pent-3-enyl group, ((iii))E) Pent-2-enyl group, ((iii))Z) Pent-2-enyl group, ((iii))E) Pent-1-enyl group, ((iii))Z) Pent-1-enyl, hex-5-enyl, ((iii))E) -hex-4-enyl, (Z) -hex-4-enyl, (E) -hex-3-enyl, (Z) -hex-3-enyl, (E) -hex-2-enyl, (Z) -hex-2-enyl, (E) -hex-1-enyl, (Z) -hex-1-enyl, isopropenyl, 2-methylprop-2-enyl, 1-methylprop-2-enyl, 2-methylprop-1-enyl, (iii)E) -1-methylprop-1-enyl group, (b) and (c)Z) -1-methylprop-1-enyl, 3-methylbut-3-enyl, 2-methylbut-3-enyl, 1-methylbut-3-enyl, 3-methylbut-2-enyl, (iii)E) -2-methylbut-2-enyl group, ((iii))Z) -2-methylbut-2-enyl group, ((iii))E) -1-methylbut-2-enyl group, ((iii))Z) -1-methylbut-2-enyl group, ((iii))E) -3-methylbut-1-enyl group, ((iii))Z) -3-methylbut-1-enyl group, ((iii))E) -2-methylbut-1-enyl group, ((iii))Z) -2-methylbut-1-enyl group, ((iii))E) -1-methylbut-1-enyl group, (b) and (c)Z) -1-methylbut-1-enyl, 1-dimethylprop-2-enyl, 1-ethylprop-1-enyl, 1-propylvinyl, 1-isopropylvinyl, 4-methylpent-4-enyl, 3-methylpent-4-enyl, 2-methylpent-4-enyl, 1-methylpent-4-enyl, 4-methylpent-3-enyl, (ii) a salt thereofE) -3-methylpent-3-enyl group, ((iii))Z) -3-methylpent-3-enyl group, ((iii))E) -2-methylpent-3-enyl group, ((iii))Z) -2-methylpent-3-enyl group, ((iii))E) -1-methylpent-3-enyl group, ((iii))Z) -1-methylpent-3-enyl group, ((iii))E) -4-methylpent-2-enyl group, (b) and (c)Z) -4-methylpent-2-enyl group, (b) and (c)E) -3-methylpent-2-enyl group, ((iii))Z) -3-methylpent-2-enyl group, ((iii))E) -2-methylpent-2-enyl group, ((ii))Z) -2-methylpent-2-enyl group, ((ii))E) -1-methylpent-2-enyl group, (b) and (c)Z) -1-methylpent-2-enyl group, (b) and (c)E) -4-methylpent-1-enyl group, (b) and (c)Z) -4-methylpent-1-enyl group, (b) and (c)E) -3-methylpent-1-enyl group, ((iii))Z) -3-methylpent-1-enyl group, ((iii))E) -2-methylpent-1-enyl group, (b) and (c)Z) -2-methylpent-1-enyl group, (b) and (c)E) -1-methylpent-1-enyl group, (b) and (c)Z) -1-methylpent-1-enyl, 3-ethylbut-3-enyl, 2-ethylbut-3-enyl, 1-ethylbut-3-enyl, (ii) methyl-but-1-enylE) -3-ethylbut-2-enyl group, ((iii))Z) -3-ethylbut-2-enyl、(E) -2-ethylbut-2-enyl group, ((iii))Z) -2-ethylbut-2-enyl group, ((iii))E) -1-ethylbut-2-enyl group, ((iii))Z) -1-ethylbut-2-enyl group, ((iii))E) -3-ethylbut-1-enyl group, ((iii))Z) -3-ethylbut-1-enyl, 2-ethylbut-1-enyl, (iii) andE) -1-ethylbut-1-enyl group, ((iii))Z) -1-ethylbut-1-enyl, 2-propylprop-2-enyl, 1-propylprop-2-enyl, 2-isopropylprop-2-enyl, 1-isopropylprop-2-enyl, (ii) a salt thereof, and (iii) a salt thereofE) -2-propylprop-1-enyl, ((iii))Z) -2-propylprop-1-enyl, ((iii))E) -1-propylprop-1-enyl, (iii)Z) -1-propylprop-1-enyl, (iii)E) -2-isopropylprop-1-enyl group, ((iii))Z) -2-isopropylprop-1-enyl group, ((iii))E) -1-isopropylprop-1-enyl group, ((iii))Z) -1-isopropylprop-1-enyl group, ((iii))E) -3, 3-dimethylprop-1-enyl group, ((iii))Z) -3, 3-dimethylprop-1-enyl, 1- (1, 1-dimethylethyl) vinyl, but-1, 3-dienyl, penta-1, 4-dienyl, hex-1, 5-dienyl or methylhexadienyl groups. In particular, the group is vinyl or allyl.

The term "C₂-C₁₀Alkynyl "is understood as meaning preferably a straight-chain or branched monovalent hydrocarbon radical which contains one or more triple bonds and contains 2,3,4, 5,6,7,8, 9 or 10 carbon atoms, in particular 2,3,4, 5 or 6 carbon atoms (" C)₂-C₆Alkynyl), more particularly 2 or 3 carbon atoms ("C₂-C₃-alkynyl "). Said C is₂-C₁₀Alkynyl radicals are, for example, ethynyl, prop-1-ynyl, prop-2-ynyl, but-1-ynyl, but-2-ynyl, but-3-ynyl, pent-1-ynyl, pent-2-ynyl, pent-3-ynyl, pent-4-ynyl, hex-1-ynyl, hex-2-ynyl, hex-3-ynyl, hex-4-ynyl, hex-5-ynyl, 1-methylprop-2-ynyl, 2-methylbut-3-ynyl, 1-methylbut-2-ynyl, 3-methylbut-1-ynyl, 1-ethylprop-2-ynyl, prop-2-ynyl, but-3-methylbut-1-ynyl, but-2-ynyl, 3-methylpent-4-ynyl, 2-methylpent-4-ynyl, 1-methylpent-4-ynyl, 2-methylpent-3-ynyl, 1-methylpent-3-ynyl, 4-methylpent-2-ynyl, 1-methylpent-2-ynyl, 4-methylpent-1-ynyl, 3-methylpent-1-ynyl, 2-ethylbut-3-ynyl, 1-ethylbut-2-ynyl, 1-propylbut-4-ynyl, 1-methylpent-1-ynyl, 1-methylpent-3-ynyl, 2-ethylbut-3-ynyl, 1-ethylbut-2-ynyl, 1-propylbut-1-ynylProp-2-ynyl, 1-isopropylprop-2-ynyl, 2-dimethylbut-3-ynyl, 1-dimethylbut-2-ynyl or 3, 3-dimethylbut-1-ynyl. In particular, the alkynyl group is vinyl, prop-1-ynyl or prop-2-ynyl.

The term "C₃-C₁₀-cycloalkyl "is understood to mean a saturated monovalent monocyclic or bicyclic hydrocarbon ring containing 3,4, 5,6,7,8, 9 or 10 carbon atoms (" C)₃-C₁₀-cycloalkyl "). Said C is₃-C₁₀Cycloalkyl radicals are, for example, monocyclic hydrocarbon rings, such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, cyclononyl or cyclodecyl, or bicyclic hydrocarbon rings, such as perhydropentalene or decahydronaphthalene rings. In particular, the ring contains 3,4, 5 or 6 carbon atoms ("C)₃-C₆-cycloalkyl ").

The term "C₃-C₆By a cycloalkyloxy radical is meant (C)₃-C₆-cycloalkyl) -O-group, wherein "C₃-C₆-cycloalkyl "is as defined herein. Examples include, but are not limited to, cyclopropoxy and cyclobutoxy.

The term "C₄-C₁₀Cycloalkenyl is understood as meaning preferably a nonaromatic, monovalent, monocyclic or bicyclic hydrocarbon ring which contains 4,5, 6,7,8, 9 or 10 carbon atoms and one, two, three or four conjugated or unconjugated double bonds, as far as the size of the cycloalkenyl ring allows. Said C is₄-C₁₀Cycloalkenyl groups are, for example, monocyclic hydrocarbon rings, such as cyclobutenyl, cyclopentenyl or cyclohexenyl, or bicyclic hydrocarbons, such as:

。

the term "C₅-C₈-Cycloalkenyloxy "means (C)₅-C₈-cycloalkenyl) -O-group, wherein "C₅-C₈-cycloalkenesThe radical "is as defined herein.

The term "3 to 10-membered heterocycloalkyl" is understood to mean a saturated monovalent monocyclic or bicyclic hydrocarbon ring containing 2,3,4, 5,6,7,8 or 9 carbon atoms and selected from the group consisting of-C (= O) -, -O-, -S (= O)₂-、-N(R^a) One or more heteroatom containing groups of (A) wherein R^aRepresents a hydrogen atom, or C₁-C₆-an alkyl-group; the heterocycloalkyl group may be attached to the rest of the molecule through any of the carbon atoms or the nitrogen atom (if present). Heterospirocycloalkyl, heterobicycloalkyl and bridged heterocycloalkyl groups as defined below are also included within the scope of this definition.

The term "heterospirocycloalkyl" is understood to mean a saturated monovalent bicyclic hydrocarbon radical, wherein the two rings share a common ring carbon atom, and wherein the bicyclic hydrocarbon radical contains 2,3,4, 5,6,7,8, or 9 carbon atoms and is selected from the group consisting of C (= O), O, S, S (= O), S (= O)₂、NR^aWherein R is^aRepresents a hydrogen atom, or C₁-C₆-alkyl-, or C₃-C₇-a cycloalkyl-group; the heterospirocycloalkyl-group may be attached to the rest of the molecule through any of the carbon atoms or nitrogen atom (if present). The hetero-spirocycloalkyl-group is, for example, azaspiro [2.3]Hexyl-, azaspiro [3.3]Heptyl-, oxaazaspiro [3.3]Heptyl-, thiaazaspiro [3.3]]Heptyl-, oxaspiro [3.3]]Heptyl-, oxaazaspiro [5.3]Nonyl-, oxaazaspiro [4.3 ]]Octyl-oxaazaspiro [5.5 ]]Undecyl-, diazaspiro [3.3]Heptyl-, thiaazaspiro [3.3]]Heptyl-, thiaazaspiro [4.3 ]]Octyl-or azaspiro [5.5]Decyl-.

The term "heterobicycloalkyl" is understood to mean a saturated monovalent bicyclic hydrocarbon radical, wherein the two rings share two immediately adjacent ring atoms, and wherein the bicyclic hydrocarbon radical contains 2,3,4, 5,6,7,8 or 9 carbon atoms and is selected from the group consisting of C (= O), O, S, S (= O), S (= O)₂、NR^aWherein R is^aRepresents a hydrogen atom, or C₁-C₆-alkyl-, or C₃-C₇-a cycloalkyl-group; the heterobicycloalkyl-group may be attached to the rest of the molecule through any one of the carbon atoms or the nitrogen atom (if present). The heterobicycloalkyl-group is, for example, azabicyclo [3.3.0]Octyl-azabicyclo [4.3.0]Nonyl-diazabicyclo [4.3.0]Nonyl-, oxaazabicyclo [4.3.0]Nonyl-, thiaazabicyclo [4.3.0]Nonyl-or azabicyclo [4.4.0]Decyl-.

The term "bridged heterocycloalkyl" is understood to mean a saturated monovalent bicyclic hydrocarbon radical, wherein the two rings share two common ring atoms which are not immediately adjacent, and wherein the bicyclic hydrocarbon radical contains 2,3,4, 5,6,7,8, or 9 carbon atoms and is selected from the group consisting of C (= O), O, S, S (= O), S (= O)₂、NR^aWherein R is^aRepresents a hydrogen atom, or C₁-C₆-alkyl-, or C₃-C₇-a cycloalkyl-group; the bridged heterocycloalkyl-group may be connected to the rest of the molecule through any of the carbon atoms or the nitrogen atom (if present). The bridged heterocycloalkyl-group is, for example, azabicyclo [2.2.1]Heptyl-, oxaazabicyclo [2.2.1]Heptyl-, thiaazabicyclo [2.2.1]Heptyl-, diazabicyclo [2.2.1]Heptyl-azabicyclo [2.2.2]Octyl-diazabicyclo [2.2.2]Octyl-oxaazabicyclo [2.2.2]Octyl-thiaazabicyclo [2.2.2 ]]Octyl-and azabicyclo [3.2.1]Octyl-diazabicyclo [3.2.1]Octyl-oxaazabicyclo [3.2.1]Octyl-thiaazabicyclo [3.2.1 ]]Octyl-and azabicyclo [3.3.1]Nonyl-, diazabicyclo [3.3.1]Nonyl-, oxaazabicyclo [3.3.1]Nonyl-, thiaazabicyclo [3.3.1]Nonyl-azabicyclo [4.2.1]Nonyl-, diazabicyclo [4.2.1]Nonyl-, oxaazabicyclo [4.2.1]Nonyl, thiaazabicyclo [4.2.1 ]]Nonyl-, azabicyclo [3.3.2]Decyl-, diazabicyclo [3.3.2]Decyl-, oxaazabicyclo [3.3.2]Decyl-, thiaazabicyclo [3.3.2]Decyl-or azabicyclo [ alpha ]4.2.2]Decyl-.

Specifically, the 3-to 10-membered heterocycloalkyl group can contain 2,3,4, or 5 carbon atoms and one or more of the aforementioned heteroatom-containing groups ("3-to 6-membered heterocycloalkyl"), more specifically, the 3-to 10-membered heterocycloalkyl group can contain 4 or 5 carbon atoms and one or more of the aforementioned heteroatom-containing groups ("5-to 6-membered heterocycloalkyl").

Specifically, without being limited thereto, the 3-to 10-membered heterocycloalkyl group may be, for example, a 4-membered ring such as azetidinyl, oxetanyl; or a 5-membered ring such as tetrahydrofuranyl, dioxolanyl, pyrrolidinyl, imidazolidinyl, pyrazolidinyl; or a 6-membered ring, such as tetrahydropyranyl, piperidinyl, morpholinyl, dithianyl, thiomorpholinyl, piperazinyl, or trithianyl; or a 7-membered ring, such as a diazepanyl (diazepanyl) ring.

The 3-to 10-membered heterocycloalkyl group can be bicyclic, such as, without limitation, a 5, 5-membered ring, such as a hexahydrocyclopenta [ c ] pyrrol-2 (1H) -yl ring, or a 5, 6-membered bicyclic ring, such as a hexahydropyrrolo [1,2a ] pyrazin-2 (1H) -yl ring.

The term "4 to 10-membered heterocycloalkenyl" is understood to mean a non-aromatic, unsaturated, monovalent monocyclic or bicyclic hydrocarbon ring which contains 3,4, 5,6,7,8 or 9 carbon atoms and is selected from the group consisting of-C (= O) -, -O-, -S (= O)₂-、-N(R^a) One or more heteroatom containing groups of (A) wherein R^aRepresents a hydrogen atom or C₁-C₆-an alkyl-group; the heterocycloalkenyl group may be attached to the rest of the molecule through any of the carbon atoms or the nitrogen atom (if present). Examples of said heterocycloalkenyl are, for example, 4H-pyranyl, 2H-pyranyl, 3H-diazirinyl, 2, 5-dihydro-1H-pyrrolyl, [1, 3]]Dioxolyl, 4H- [1,3,4 [ ]]Thiadiazinyl, 2, 5-dihydrofuryl, 2, 3-dihydrofuryl, 2, 5-dihydrothienyl (dihydrothiophenyl), 2, 3-dihydrothienyl, 4, 5-dihydrooxazolyl or 4H- [1,4 [ ]]A thiazinyl group.

The term "aryl" is understood to mean preferably a monovalent aromatic or partially aromatic monocyclic, bicyclic or tricyclic hydrocarbon ring having 6,7,8, 9, 10, 11, 12, 13 or 14 carbon atoms ("C)₆-C₁₄An aryl "group), in particular a ring having 6 carbon atoms (" C)₆An aryl "group), such as a phenyl group; or a biphenyl group, or a ring having 9 carbon atoms ("C)₉An aryl "group), such as an indanyl or indenyl group; or a ring having 10 carbon atoms ("C)₁₀An aryl "group), such as a tetrahydronaphthyl (tetralinyl), dihydronaphthyl or naphthyl group; or a ring having 13 carbon atoms ("C)₁₃An aryl "group), such as a fluorenyl group; or a ring having 14 carbon atoms ("C)₁₄An aryl "group), such as an anthracenyl group. Preferably, the aryl group is a phenyl group.

The term "heteroaryl" is understood as meaning preferably a monovalent monocyclic, bicyclic or tricyclic aromatic ring system which has 5,6,7,8, 9, 10, 11, 12, 13 or 14 ring atoms ("5-to 14-membered heteroaryl" group), in particular 5, or 6, or 9, or 10 atoms, and which contains at least one heteroatom, which may be identical or different, for example oxygen, nitrogen or sulfur, and which, in addition, may be benzo-condensed (benzo-condensed) in each case. Specifically, the heteroaryl group is selected from thienyl, furyl, pyrrolyl, oxazolyl, thiazolyl, imidazolyl, pyrazolyl, isoxazolyl, isothiazolyl, oxadiazolyl, triazolyl, thiadiazolyl, thia-4H-Pyrazolyl and the like, and benzo derivatives thereof such as benzofuranyl, benzothienyl, benzoxazolyl, benzisoxazolyl, benzimidazolyl, benzotriazolyl, indazolyl, indolyl, isoindolyl and the like; or pyridyl, pyridazinyl, pyrimidinyl, pyrazinyl, triazinyl, and the like, and benzo derivatives thereof, such as quinolyl, quinazolinyl, isoquinolyl, and the like; or azocinyl, indolizinyl, purinyl and the like, and benzo derivatives thereof; or cinnolinyl, phthalazinyl, quinazolinyl, quinoxalinyl, naphthyridinyl,Pteridinyl, carbazolyl, acridinyl, phenazinyl, phenothiazinyl, phenoxazinyl, xanthenyl or oxepinyl and the like.

Generally and unless otherwise indicated, a heteroaryl or heteroarylene radical includes all possible isomeric forms thereof, e.g., positional isomers thereof. Thus, for some illustrative, non-limiting examples, the term pyridyl or pyridinylene includes pyridin-2-yl, pyridin-2-ylidene, pyridin-3-yl, pyridin-3-ylidene, pyridin-4-yl, and pyridin-4-ylidene; alternatively, the term thienyl or thienylene includes thien-2-yl, thien-2-ylidene, thien-3-yl, and thien-3-ylidene.

As throughout this text, for example at "C₁-C₆-alkyl group "," C₁-C₆-haloalkyl "," C₁-C₆-alkoxy "or" C₁-C₆The term "C" as used in the context of the definition of-haloalkoxy₁-C₆"is understood to mean an alkyl group having a limited number of carbon atoms from 1 to 6, i.e. 1,2, 3,4, 5 or 6 carbon atoms. It is to be further understood that the term "C" refers to₁-C₆"should be interpreted as including any sub-range therein, such as C₁-C₆、C₂-C₅、C₃-C₄、C₁-C₂、C₁-C₃、C₁-C₄、C₁-C₅(ii) a In particular C₁-C₂、C₁-C₃、C₁-C₄、C₁-C₅、C₁-C₆(ii) a More particularly C₁-C₄(ii) a In "C₁-C₆-haloalkyl "or" C₁-C₆In the case of haloalkoxy ", still more particularly C₁-C₂。

Similarly, as used herein, as used throughout, for example at "C₂-C₆-alkenyl "and" C₂-C₆-alkynyl "is a term used in the context of the definition of"C₂-C₆"is to be understood as meaning alkenyl or alkynyl groups having a limited number of carbon atoms of from 2 to 6, i.e. 2,3,4, 5 or 6 carbon atoms. It is to be further understood that the term "C" refers to₂-C₆"should be interpreted as including any sub-range therein, such as C₂-C₆、C₃-C₅、C₃-C₄、C₂-C₃、C₂-C₄、C₂-C₅(ii) a In particular C₂-C₃。

Further, as used herein, as used throughout, for example at "C₃-C₆The term "C" as used in the context of the definition of-cycloalkyl₃-C₆"is understood to mean a cycloalkyl radical having a limited number of carbon atoms of from 3 to 6, i.e. 3,4, 5 or 6 carbon atoms. It is to be further understood that the term "C" refers to₃-C₆"should be interpreted as including any sub-range therein, such as C₃-C₆、C₄-C₅、C₃-C₅、C₃-C₄、C₄-C₆、C₅-C₆(ii) a In particular C₃-C₆。

The term "substituted" means that one or more hydrogens on the designated atom is replaced with a selection from the indicated group, provided that the normal valency of the designated atom in the current case is not exceeded, and that the substitution results in a stable compound. Combinations of substituents and/or variables are permissible only if such combinations result in stable compounds.

The term "optionally substituted" means that the designated group, radical, or moiety is optionally substituted.

As used herein, the term "one or more", for example in the definition of a substituent of a compound of the general formula of the invention, is to be understood as meaning "one, two, three, four or five, in particular one, two, three or four, more in particular one, two or three, still more in particular one or two".

As used herein, the term "leaving group" refers to an atom or group of atoms with which a bonding electron is replaced in a chemical reaction to a stable species. Preferably, the leaving group is selected from the group comprising: halogen (in particular chlorine, bromine or iodine), mesyloxy, p-toluenesulfonyloxy, trifluoromethanesulfonyloxy, nonafluorobutanesulfonyloxy, (4-bromo-benzene) sulfonyloxy, (4-nitro-benzene) sulfonyloxy, (2-nitro-benzene) -sulfonyloxy, (4-isopropyl-benzene) sulfonyloxy, (2,4, 6-triisopropyl-benzene) -sulfonyloxy, (2,4, 6-trimethyl-benzene) sulfonyloxy, (4-tert-butyl-benzene) sulfonyloxy, benzenesulfonyloxy and (4-methoxy-benzene) sulfonyloxy.

As used herein, the term "protecting group" is a protecting group attached to the nitrogen in an intermediate used to prepare the compound of formula (I). Such groups are introduced, for example, by chemical modification of the respective amino groups in order to obtain chemoselectivity in subsequent chemical reactions. Protecting groups for amino groups are described, for example, in t.w. Greene and p.g.m. Wuts,Protective Groups in Organic Synthesis3 rd edition, Wiley 1999; more specifically, the group may be selected from a substituted sulfonyl group, such as methanesulfonyl-, toluenesulfonyl-or phenylsulfonyl-, an acyl group, such as benzoyl, acetyl or tetrahydropyranoyl-, or a carbamate-based group, such as tert-butyloxycarbonyl (Boc), or may comprise silicon, as for example in 2- (trimethylsilyl) ethoxymethyl (SEM).

The present invention includes all suitable isotopic variations of the compounds of the present invention. Isotopic variations of the compounds of the present invention are defined as those in which at least one atom is replaced by an atom having the same atomic number but an atomic mass different from the atomic mass usually or predominantly found in nature. Examples of isotopes that can be incorporated into the compounds of the invention include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorus, sulfur, fluorine, chlorine, bromine and iodine, such as²H (deuterium),³H (tritium),¹¹C、¹³C、¹⁴C、¹⁵N、¹⁷O、¹⁸O、³²P、³³P、³³S、³⁴S、³⁵S、³⁶S、¹⁸F、³⁶Cl、⁸²Br、¹²³I、¹²⁴I、¹²⁹I and¹³¹I. certain isotopic variations of the compounds of the present invention, for example, wherein one or more radioactive isotopes are incorporated (e.g.³H or¹⁴C) Are useful in drug and/or substrate tissue distribution studies. Tritiated and carbon-14 (i.e., due to their ease of preparation and detectability)¹⁴C) Isotopes are particularly preferred. Further, substitution with isotopes such as deuterium may afford certain therapeutic advantages resulting from greater metabolic stability, for example increased in vivo half-life or reduced dosage requirements, and hence may be preferred in some circumstances. Isotopic variations of the compounds of the present invention can generally be prepared by conventional procedures known to those skilled in the art, for example by procedures described for illustration or by preparation of an appropriate isotopic variation using suitable reagents as described in the examples hereinafter.

When the plural forms of the words compound, salt, polymorph, hydrate, solvate and the like are used herein, this also means a single compound, salt, polymorph, isomer, hydrate, solvate and the like.

By "stable compound" or "stable structure" is meant a compound that is sufficiently robust to withstand isolation to a useful degree of purity from a reaction mixture and formulation into an effective therapeutic agent.

Depending on the location and nature of the various substituents desired, the compounds of the present invention may contain one or more asymmetric centers. The asymmetric carbon atom may be represented byR) Or (a)S) Configurations exist that produce racemic mixtures in the case of a single asymmetric center and diastereomeric mixtures in the case of multiple asymmetric centers. In some cases, due to limitations with respect to a given bond (e.g., a central bond adjacent to two substituted aromatic rings of a given compound)With constant rotation, asymmetry may also exist.

The compounds of the invention may contain an asymmetric sulfur atom, such as an asymmetric sulfoxide or aminosulfoxide group of the following structure:

for example, where indicates an atom that may be bonded to the remainder of the molecule.

The substituents on the ring may also be present in cis or trans form. All such configurations (including enantiomers and diastereomers) are intended to be included within the scope of the present invention.

Preferred compounds are those that produce a more desirable biological activity. Isolated, pure or partially purified isomers and stereoisomers or racemic or diastereomeric mixtures of the compounds of the invention are also included within the scope of the invention. Purification and isolation of such materials can be accomplished by standard techniques known in the art.

Pure stereoisomers may be obtained by resolution of the racemic mixture according to conventional methods, for example by formation of diastereomeric salts using optically active acids or bases, or by formation of covalent diastereomers. Examples of suitable acids are tartaric acid, diacetyltartaric acid, di (methylbenzoyl) tartaric acid and camphorsulfonic acid. Mixtures of diastereomers may be separated into their individual diastereomers by methods known in the art (e.g., by chromatography or fractional crystallization) based on their physical and/or chemical differences. The optically active base or acid is then released from the separated diastereomeric salt. Different methods for separating optical isomers include the use of chiral chromatography (e.g., a chiral HPLC column) with or without conventional derivatization, optionally selected to maximize separation of enantiomers. Suitable chiral HPLC columns are manufactured by Daicel, e.g. chiralcel OD and chiralcel OJ, among numerous chiral HPLC columns, which are both routinely selectable. Enzymatic separation with or without derivatization is also useful. The optically active compounds of the present invention can also be obtained by chiral synthesis using optically active starting materials.

To define different kinds of isomers between each other, reference is made to IUPAC Rules Section E (Pureappl Chem 45, 11-30, 1976).

The present invention includes as a single stereoisomer or as the stereoisomer (e.g.,) (R) Or (a)S) Isomer or (A)E) Or (a)Z) Isomers) of the compounds of the present invention in any mixture in any ratio. Separation of individual stereoisomers (e.g. individual enantiomers or individual diastereomers) of the compounds of the invention may be achieved by any suitable prior art method, such as chromatography, particularly, for example, chiral chromatography.

Further, the compounds of the present invention may exist as tautomers. For example, any compound of the invention containing a pyrazole moiety as heteroaryl group may be present, for example, as a 1H tautomer or a 2H tautomer, or even a mixture of any amount of both tautomers, or a triazole moiety may be present, for example, as a 1H tautomer, a 2H tautomer, or a 4H tautomer, or even a mixture of any amount of the 1H, 2H, and 4H tautomers, i.e.:

。

the present invention includes all possible tautomers of the compounds of the invention either as a single tautomer or as any mixture of any ratio of said tautomers.

Further, the compounds of the present invention may be present as N-oxides, which are defined as compounds of the present invention in which at least one nitrogen is oxidized. The present invention includes all such possible N-oxides.

The invention also relates to useful forms of the compounds as disclosed herein, such as metabolites, hydrates, solvates, prodrugs, salts, especially pharmaceutically acceptable salts, and co-precipitates.

The compounds of the invention may exist as hydrates or as solvates, wherein the compounds of the invention contain, for example, a polar solvent, in particular water, methanol or ethanol, as a structural element of the crystal lattice of the compound. The amount of polar solvent, particularly water, may be present in a stoichiometric ratio or a non-stoichiometric ratio. In the case of stoichiometric solvates, e.g. hydrates, there may be semi (hemi) solvates or hydrates, (hemi) solvates or hydrates), mono-solvates or hydrates, sesqui-solvates or hydrates, di-solvates or hydrates, tri-solvates or hydrates, tetra-solvates or hydrates, pentasolvates or hydrates, etc. respectively. The present invention includes all such hydrates or solvates.

Further, the compounds of the invention may be present in free form, e.g. as a free base, or as a free acid, or as a zwitterion, or may be present in the form of a salt. The salt may be any salt, which may be an organic or inorganic addition salt, in particular any pharmaceutically acceptable organic or inorganic addition salt commonly used in pharmacy.

The term "pharmaceutically acceptable salts" refers to addition salts of inorganic or organic acids that are relatively non-toxic to the compounds of the present invention. See, for example, S.M. Berge et al, "Pharmaceutical Salts," J.pharm. Sci. 1977, 66, 1-19.

Suitable pharmaceutically acceptable salts of the compounds of the invention may be, for example, sufficiently basic acid addition salts of the compounds of the invention with nitrogen atoms in the chain or in the ring, for example with inorganic acids such as hydrochloric acid, hydrobromic acid, hydroiodic acid, sulfuric acid, disulfuric acid (bisfuric acid), phosphoric acid or nitric acid; or acid addition salts with, for example, organic acids such as formic acid, acetic acid, acetoacetic acid, pyruvic acid, trifluoroacetic acid, propionic acid, butyric acid, caproic acid, heptanoic acid, undecanoic acid, lauric acid, benzoic acid, salicylic acid, 2- (4-hydroxybenzoyl) benzoic acid, camphoric acid, cinnamic acid, cyclopentanepropionic acid, digluconic acid (digluconic acid), 3-hydroxy-2-naphthoic acid, nicotinic acid, pamoic acid, pectinic acid, persulfuric acid, 3-phenylpropionic acid, picric acid, pivalic acid, 2-hydroxyethanesulfonic acid, itaconic acid, sulfamic acid, trifluoromethanesulfonic acid, dodecylsulfuric acid, ethanesulfonic acid, benzenesulfonic acid, p-toluenesulfonic acid, methanesulfonic acid, 2-naphthalenesulfonic acid, naphthalenedisulfonic acid, camphorsulfonic acid, citric acid, tartaric acid, stearic acid, lactic acid, oxalic acid, malonic acid, succinic acid, caproic acid, heptanoic acid, pimelic acid, malic acid, adipic acid, alginic acid, maleic acid, fumaric acid, D-gluconic acid, mandelic acid, ascorbic acid, glucoheptonic acid, glycerophosphoric acid, aspartic acid, sulfosalicylic acid, hemisulfuric acid (hemifuric acid), or thiocyanic acid.

Further, another suitable pharmaceutically acceptable salt of a compound of the invention which is sufficiently acidic is an alkali metal salt, such as a sodium or potassium salt; alkaline earth metal salts, such as calcium or magnesium salts; ammonium salts or salts with organic bases which provide physiologically acceptable cations, for example salts with: n-methylglucamine, dimethylglucamine, ethylglucamine, lysine, dicyclohexylamine, 1, 6-hexanediamine, ethanolamine, glucosamine, sarcosine, serinol, trihydroxymethylaminomethane, aminopropanediol, sovak-base, 1-amino-2, 3, 4-butanetriol, or quaternary ammonium salts, such as tetramethylammonium, tetraethylammonium, tetra (N-propyl) ammonium, tetra (N-butyl) ammonium orN-benzyl-N,N,N-trimethylammonium.

One skilled in the art will further recognize that acid addition salts of the claimed compounds can be prepared by any of a variety of known methods by reacting the compounds with the appropriate inorganic or organic acid. Alternatively, alkali metal salts and alkaline earth metal salts of the acidic compounds of the present invention can be prepared by reacting the compounds of the present invention with an appropriate base by various known methods.

The present invention includes all possible salts of the compounds of the present invention as a single salt or as any mixture of any ratio of the salts.

Further, the present invention includes all possible crystalline forms or polymorphs of the compounds of the present invention, either as single polymorphs or as mixtures of more than one polymorph in any ratio.

According to a first aspect, the invention encompasses compounds of general formula (I):

wherein:

R¹represents a hydrogen atom or a halogen atom or a group selected from:

hydroxy-, cyano-, C₁-C₆-alkyl-, C₂-C₆-alkenyl-, C₂-C₆-alkynyl-, C₁-C₆-alkoxy-, halo-C₁-C₆-alkoxy-, C₃-C₆-cycloalkyl-, C₄-C₈-cycloalkenyl-, C₃-C₆-cycloalkyloxy-, (3-to 10-membered heterocycloalkyl) -O-, C₅-C₈-cycloalkenyloxy-, (5-to 10-membered heterocycloalkenyl) -O-, -N (R)^5a)R^5b、-SR^5aand-SF₅；

Wherein said C₁-C₆-alkyl-, C₂-C₆-alkenyl-, C₂-C₆-alkynyl-, C₁-C₆-alkoxy-, C₃-C₆-cycloalkyl-, C₄-C₈-cycloalkenyl-, C₃-C₆-cycloalkyloxy-, (3-to 10-membered heterocycloalkyl) -O-、C₅-C₈-cycloalkenyloxy-, (5-to 10-membered heterocycloalkenyl) -and (5-to 10-membered heterocycloalkenyl) -O-groups optionally substituted with 1,2, 3,4 or 5R⁴The radicals are substituted identically or differently;

R²represents a hydrogen atom or a group selected from: c₁-C₆-alkyl-, C₂-C₆-alkenyl-, C₁-C₆-alkoxy-, halo-C₁-C₆-alkyl-and halo-C₁-C₆-alkoxy-;

wherein said C₁-C₆-alkyl-, C₂-C₆-alkenyl-and C₁-C₆-alkoxy-groups optionally substituted by 1,2 or 3R⁷The radicals are substituted identically or differently;

R³represents a hydrogen atom or a group selected from: c₁-C₆-alkyl-, C₃-C₆-cycloalkyl-, C₄-C₆-cycloalkenyl-, C₂-C₆-alkenyl-, C₂-C₆-alkynyl-, 3-to 10-membered heterocycloalkyl-, 4-to 10-membered heterocycloalkenyl-, aryl-, heteroaryl-, cyano-and- (CH)₂)_q-X-(CH₂)_p-R⁵；

Wherein said C₁-C₆-alkyl-, C₃-C₆-cycloalkyl-, C₄-C₆-cycloalkenyl-, C₂-C₆-alkenyl-, C₂-C₆-alkynyl-, 3-to 10-membered heterocycloalkyl-, 4-to 10-membered heterocycloalkenyl-, aryl-and heteroaryl-groups optionally substituted with 1,2, 3,4 or 5R⁴The radicals are substituted identically or differently;

x represents a bond or a divalent group selected from: -O-, -S (= O)₂-、-S(=O)-N(R^5a)-、-N(R^5a)-S(=O)-、-S(=O)₂-N(R^5a)-、-N(R^5a)-S(=O)₂-、-S(=O)(=NR^5a)-、-C(=O)-、-N(R^5a)-、-C(=O)-O-、-O-C(=O)-、-C(=S)-O-、-O-C(=S)-、-C(=O)-N(R^5a)-、-N(R^5a)-C(=O)-、-N(R^5a)-C(=O)-N(R^5b)-、-O-C(=O)-N(R^5a)-、-N(R^5a)-C(=O)-O-；

R⁴Represents halo-, hydroxy-, oxo- (O =), cyano-, nitro-, C₁-C₆-alkyl-, C₂-C₆-alkenyl-, C₂-C₆-alkynyl-, halo-C₁-C₆-alkyl-, C₁-C₆-alkoxy-, halo-C₁-C₆-alkoxy-, hydroxy-C₁-C₆-alkyl-, C₁-C₆-alkoxy-C₁-C₆-alkyl-, halo-C₁-C₆-alkoxy-C₁-C₆-alkyl-, R⁶-O-、-C(=O)-R⁶、-C(=O)-O-R⁶、-O-C(=O)-R⁶、-N(R^6a)-C(=O)-R^6b、-N(R^6a)-C(=O)-O-R^6b、-N(R^6a)-C(=O)-N(R^6b)R^6c、-N(R^6a)R^6b、-N(R^6a)R^6d、-C(=O)-N(R^6a)R^6b、R⁶-S-、R⁶-S(=O)-、R⁶-S(=O)₂-、-N(R^6a)-S(=O)-R^6b、-S(=O)-N(R^6a)R^6b、-N(R^6a)-S(=O)₂-R^6b、-S(=O)₂-N(R^6a)R^6b、-S(=O)=N(R^6a)R^6b、-N=S(=O)(R^6a)R^6bOr- (C)₁-C₆-alkyl) -N (R)^6a)R^6b；

R^5a、R^5bAre the same or different and are independently selected from R⁵；

R⁵Represents a hydrogen atom or a group selected from: c₁-C₆-alkyl-, C₃-C₆-cycloalkyl-, 3-to 10-membered heterocycloalkyl-, aryl-and heteroaryl-;

wherein said C₁-C₆-alkyl-, C₃-C₆-cycloalkanesThe radical-, 3-to 10-membered heterocycloalkyl-, aryl-and heteroaryl-groups are optionally substituted by 1,2, 3,4 or 5R⁴The radicals are substituted identically or differently;

or

N(R^5a)R⁵Together represent a 3-to 10-membered heterocycloalkyl-group, optionally substituted by 1,2, 3,4 or 5R⁴The radicals are substituted identically or differently;

R^6a、R^6b、R^6care the same or different and are independently selected from R⁶；

R⁶Represents a hydrogen atom, C₁-C₆-alkyl-or C₃-C₆-a cycloalkyl-group;

or

R^6aAnd R^6b，

Or R^6aAnd R^6c，

Or R^6bAnd R^6cMay together form C₂-C₆An alkylene radical in which one methylene group may optionally be replaced by-O-, -C (= O) -, -NH-or-N (C)₁-C₄-alkyl) -substitution;

R^6drepresents- (C)₁-C₆-alkyl) -N (R)^6a)R^6b；

R⁷Represents halo-, hydroxy-, oxo- (O =), cyano-, nitro-,

p represents an integer of 0, 1,2 or 3;

q represents an integer of 0, 1,2 or 3;

or a tautomer, an N-oxide, a hydrate, a solvate, or a salt thereof, or a mixture of same.

In a preferred embodiment, the present invention relates to compounds of formula (I) as described above, wherein R is¹Represents a hydrogen atom or a halogen atom or is selected fromThe following groups: hydroxy-, cyano-, C₁-C₆-alkyl-, C₂-C₆-alkenyl-, C₂-C₆-alkynyl-, C₁-C₆-alkoxy-, halo-C₁-C₆-alkyl-, halo-C₁-C₆-alkoxy-, hydroxy-C₁-C₆-alkyl-, C₁-C₃-alkoxy-C₁-C₃-alkyl-, -N (R)^5a)R^5b、-SR^5a、-SCF₃and-SF₅。

In another preferred embodiment, the present invention relates to compounds of formula (I) as described above, wherein R is¹Represents a hydrogen atom or a halogen atom or a group selected from: cyano-, C₁-C₆-alkyl-, C₁-C₆-alkoxy-, halo-C₁-C₆-alkyl-, halo-C₁-C₆-alkoxy-, hydroxy-C₁-C₆-alkyl-, C₁-C₃-alkoxy-C₁-C₃-alkyl-and-S- (C)₁-C₆-an alkyl group).

In another preferred embodiment, the present invention relates to compounds of formula (I) as described above, wherein R is¹Represents a hydrogen atom or a group selected from: cyano-, C₁-C₆-alkyl-, C₁-C₆-alkoxy-, halo-C₁-C₆-alkyl-, halo-C₁-C₆-alkoxy-, hydroxy-C₁-C₆-alkyl-, C₁-C₃-alkoxy-C₁-C₃-alkyl-and-S- (C)₁-C₆-an alkyl group).

In another preferred embodiment, the present invention relates to compounds of formula (I) as described above, wherein R is¹Represents a hydrogen atom or a group selected from: c₁-C₃-alkyl-, C₁-C₃-alkoxy-, halo-C₁-C₃-alkyl-, halo-C₁-C₃-alkoxy-, hydroxy-C₁-C₃-alkyl-, C₁-C₃-alkoxy-C₁-C₃-alkyl-and-S- (C)₁-C₃-an alkyl group).

In another preferred embodiment, the present invention relates to compounds of formula (I) as described above, wherein R is¹Represents a hydrogen atom or a group selected from: c₁-C₃-alkyl-, C₁-C₃-alkoxy-, halo-C₁-C₃-alkyl-and-S- (C)₁-C₃-an alkyl group).

In another preferred embodiment, the present invention relates to compounds of formula (I) as described above, wherein R is¹Represents a hydrogen atom or a group selected from: -O-CH₃、-S-CH₃。

In another preferred embodiment, the present invention relates to compounds of formula (I) as described above, wherein R is¹Represents a hydrogen atom or a chlorine atom or a group selected from: -O-CH₃、-N(CH₃)₂。

In another preferred embodiment, the present invention relates to compounds of formula (I) as described above, wherein R is¹Represents a hydrogen atom or-O-CH₃A group.

In another preferred embodiment, the present invention relates to compounds of formula (I) as described above, wherein R is¹Represents a hydrogen atom.

In another preferred embodiment, the present invention relates to compounds of formula (I) as described above, wherein R is¹represents-O-CH₃A group.

In another preferred embodiment, the present invention relates to compounds of formula (I) as described above, wherein R is²Represents a hydrogen atom.

In another preferred embodiment, the present invention relates to compounds of formula (I) as described above, wherein R is²Represents a chlorine atom.

In another preferred embodiment, the present invention relates to compounds of formula (I) as described above, wherein R is²represents-N (CH)₃)₂A group.

In another preferred embodiment, the present invention relates to compounds of formula (I) as described above, wherein R is¹Represents a hydrogen atom and R²Represents a hydrogen atom.

In another preferred embodiment, the present invention relates to compounds of formula (Ia):

wherein R is¹And R³As defined for the compounds of formula (I).

In another preferred embodiment, the present invention relates to compounds of formula (Ia) as described above, wherein R is¹Represents a hydrogen atom or-O-CH₃A group, and wherein R³As defined for the compounds of formula (I).

In another preferred embodiment, the present invention relates to compounds of formula (Ia) as described above, wherein R is¹Represents a hydrogen atom, and wherein R³As defined for the compounds of formula (I).

In another preferred embodiment, the present invention relates to compounds of formula (I) as described above, wherein R is³Represents a hydrogen atom or a group selected from: c₁-C₆-alkyl-, C₃-C₆-cycloalkyl-, 3-to 10-membered heterocycloalkyl-, cyano-, and- (CH)₂)_q-X-(CH₂)_p-R⁵；

Wherein said C₁-C₆-alkyl-, C₃-C₆-cycloalkyl-and 3-to 10-membered heterocycloalkyl-groups optionally substituted by 1,2, 3,4 or 5R⁴The radicals are substituted identically or differently.

In another preferred embodiment, the present invention relates to compounds of formula (I) as described above, wherein R is³Represents a hydrogen atom or a group selected from: c₁-C₆-alkyl-and- (CH)₂)_q-X-(CH₂)_p-R⁵；

Wherein said C₁-C₆-alkyl-group optionally substituted by 1,2, 3,4 or 5R⁴The radicals are substituted identically or differently.

In another preferred embodiment, the present invention relates to compounds of formula (I) as described above, wherein R is³Represents a hydrogen atom.

In another preferred embodiment, the present invention relates to compounds of formula (I) as described above, wherein R is³Represents- (CH)₂)_q-X-(CH₂)_p-R⁵。

In another preferred embodiment, the present invention relates to compounds of formula (I) as described above, wherein R is³represents-X-R⁵。

In another preferred embodiment, the present invention relates to compounds of formula (I) as described above, wherein R is³represents-C (= O) -O-R⁵。

In another preferred embodiment, the present invention relates to compounds of formula (I) as described above, wherein R is³represents-C (= O) -R⁵。

In another preferred embodiment, the present invention relates to compounds of formula (I) as described above, wherein R is³represents-C (= O) -N (R)^5a)R⁵。

In another preferred embodiment, the present invention relates to compounds of formula (I) as described above, wherein R is³represents-S (= O)₂-R⁵。

In another preferred embodiment, the present invention relates to compounds of formula (I) as described above, wherein R is³represents-C (= O) -N (R)^5a)R⁵(ii) a And wherein R¹Represents a hydrogen atom.

In another preferred embodiment, the present invention relates to compounds of formula (I) as described above, wherein R is³represents-C (= O) -N (R)^5a)R⁵(ii) a And wherein R¹Represents a hydrogen atom or-O-CH₃A group.

In another preferred embodiment, the present invention relates to compounds of formula (I) as described above, wherein R is³represents-C (= O) -N (R)^5a)R⁵(ii) a And wherein R¹represents-O-CH₃A group.

In another preferred embodiment, the present invention relates to compounds of formula (I) as described above, wherein R is³represents-C (= O) -N (R)^5a)R⁵(ii) a And wherein R²Represents a hydrogen atom.

In another preferred embodiment, the present invention relates to compounds of formula (I) as described above, wherein R is³represents-C (= O) -N (R)^5a)R⁵(ii) a Wherein R is¹Represents a hydrogen atom, and wherein R²Represents a hydrogen atom.

In another preferred embodiment, the present invention relates to compounds of formula (I) as described above, wherein R is³represents-C (= O) -N (R)^5a)R⁵(ii) a Wherein R is¹Represents a hydrogen atom or-O-CH₃A group, and wherein R²Represents a hydrogen atom.

In another preferred embodiment, the present invention relates to compounds of formula (I) as described above, wherein R is³represents-C (= O) -N (R)^5a)R⁵(ii) a Wherein R is¹represents-O-CH₃A group, and wherein R²Represents a hydrogen atom.

In another preferred embodiment, the present invention relates to a compound of formula (I) as described above, wherein X represents a bond or a divalent group selected from:

-O-、-S-、-S(=O)-、-S(=O)₂-、-S(=O)-N(R^5a)-、-N(R^5a)-S(=O)-、-S(=O)₂-N(R^5a)-、-N(R^5a)-S(=O)₂-、-S(=O)(=NR^5a)-、-C(=O)-、-N(R^5a)-、-C(=O)-O-、-O-C(=O)-、-C(=S)-O-、-O-C(=S)-、-C(=O)-N(R^5a) -and-N (R)^5a)-C(=O)-。

In another preferred embodiment, the present invention relates to compounds of formula (I) as described above, wherein X represents a bond or is selected fromThe following divalent groups: -S (= O)₂-、-C(=O)-、-N(R^5a) -, -C (= O) -O-and-C (= O) -N (R)^5a)-。

In another preferred embodiment, the present invention relates to a compound of formula (I) as described above, wherein X represents a divalent group selected from: -S (= O)₂-、-C(=O)-、-N(R^5a) -, -C (= O) -O-and-C (= O) -N (R)^5a)-。

In another preferred embodiment, the present invention relates to a compound of formula (I) as described above, wherein X represents-S (= O)₂-。

In another preferred embodiment, the present invention relates to a compound of formula (I) as described above, wherein X represents-C (= O) -.

In another preferred embodiment, the present invention relates to a compound of formula (I) as described above, wherein X represents-N (R)^5a)-。

In another preferred embodiment, the present invention relates to a compound of formula (I) as described above, wherein X represents-C (= O) -O-.

In another preferred embodiment, the present invention relates to compounds of formula (I) as described above, wherein X represents-C (= O) -N (R)^5a)-。

In another preferred embodiment, the present invention relates to compounds of formula (I) as described above, wherein X represents-C (= O) -or-C (= O) -N (R)^5a)-。

In another preferred embodiment, the present invention relates to compounds of formula (I) as described above, wherein X represents-C (= O) -N (R)^5a) -; and wherein R¹Represents a hydrogen atom.

In another preferred embodiment, the present invention relates to compounds of formula (I) as described above, wherein X represents-C (= O) -N (R)^5a) -; and wherein R¹Represents a hydrogen atom or-O-CH₃A group.

In another preferred embodiment, the present invention relates to compounds of formula (I) as described above, wherein X represents-C (= O) -N (R)^5a) -; and wherein R¹represents-O-CH₃A group.

In another preferred embodiment, the present invention relates to compounds of formula (I) as described above, wherein X represents-C (= O) -N (R)^5a) -; and wherein R²Represents a hydrogen atom.

In another preferred embodiment, the present invention relates to compounds of formula (I) as described above, wherein X represents-C (= O) -N (R)^5a) -; wherein R is¹Represents a hydrogen atom, and wherein R²Represents a hydrogen atom.

In another preferred embodiment, the present invention relates to compounds of formula (I) as described above, wherein X represents-C (= O) -N (R)^5a) -; wherein R is¹Represents a hydrogen atom or-O-CH₃A group, and wherein R²Represents a hydrogen atom.

In another preferred embodiment, the present invention relates to compounds of formula (I) as described above, wherein X represents-C (= O) -N (R)^5a) -; wherein R is¹represents-O-CH₃A group, and wherein R²Represents a hydrogen atom.

In another preferred embodiment, the present invention relates to compounds of formula (Ib):

wherein R is¹、R^5aAnd R⁵As defined for the compounds of formula (I).

In another preferred embodiment, the present invention relates to compounds of formula (Ib) as described above,

wherein R is¹Represents a hydrogen atom or-O-CH₃A group, and wherein R^5aAnd R⁵As defined for the compounds of formula (I).

In another preferred embodiment, the present invention relates to compounds of formula (Ib) as described above,

wherein R is¹Represents a hydrogen atom, and wherein R^5aAnd R⁵As defined for the compounds of formula (I).

In another preferred embodiment, the present invention relates to compounds of formula (I) as described above, wherein R is⁴Represents halo-, hydroxy-, cyano-, nitro-, C₁-C₆-alkyl-, halo-C₁-C₆-alkyl-, C₁-C₆-alkoxy-, halo-C₁-C₆-alkoxy-, hydroxy-C₁-C₆-alkyl-, C₁-C₆-alkoxy-C₁-C₆-alkyl-, halo-C₁-C₆-alkoxy-C₁-C₆-alkyl-, R⁶-O-、-C(=O)-R⁶、-C(=O)-O-R⁶、-O-C(=O)-R⁶、-N(R^6a)-C(=O)-R^6b、-N(R^6a)-C(=O)-N(R^6b)R^6c、-N(R^6a)R^6b、-C(=O)-N(R^6a)R^6b、R⁶-S-、R⁶-S(=O)-、R⁶-S(=O)₂-、-N(R^6a)-S(=O)-R^6b、-S(=O)-N(R^6a)R^6b、-N(R^6a)-S(=O)₂-R^6b、-S(=O)₂-N(R^6a)R^6b、-S(=O)=N(R^6a)R^6bor-N = S (= O) (R)^6a)R^6b。

In another preferred embodiment, the present invention relates to compounds of formula (I) as described above, wherein R is⁴Represents halo-, hydroxy-, cyano-, nitro-, C₁-C₃-alkyl-, halo-C₁-C₃-alkyl-, C₁-C₃-alkoxy-, halo-C₁-C₃-alkoxy-, hydroxy-C₁-C₃-alkyl-, C₁-C₃-alkoxy-C₁-C₃-alkyl-, halo-C₁-C₃-alkoxy-C₁-C₃-alkyl-, R⁶-O-、-C(=O)-R⁶、-C(=O)-O-R⁶、-O-C(=O)-R⁶、-N(R^6a)R^6b、-C(=O)-N(R^6a)R^6b、R⁶-S-、R⁶-S(=O)-、R⁶-S(=O)₂-、-N(R^6a)-S(=O)-R^6b、-S(=O)-N(R^6a)R^6b、-N(R^6a)-S(=O)₂-R^6bor-S (= O)₂-N(R^6a)R^6b。

In another preferred embodiment, the present invention relates to compounds of formula (I) as described above, wherein R is⁴Represents halo-, hydroxy-, cyano-, C₁-C₃-alkyl-, halo-C₁-C₃-alkyl-, C₁-C₃-alkoxy-, halo-C₁-C₃-alkoxy-, hydroxy-C₁-C₃-alkyl-, C₁-C₃-alkoxy-C₁-C₃-alkyl-or-N (R)^6a)R^6b。

In another preferred embodiment, the present invention relates to compounds of formula (I) as described above,

wherein R is⁴Represents halo-, hydroxy-, cyano-, C₁-C₆-alkyl-, C₁-C₆-alkoxy-, -N (R)^6a)-C(=O)-O-R^6b、-N(R^6a)R^6b、-N(R^6a)R^6d、-C(=O)-N(R^6a)R^6bOr- (C)₁-C₆-alkyl) -N (R)^6a)R^6b。

In another preferred embodiment, the present invention relates to compounds of formula (I) as described above,

wherein R is⁴Represents halo-, hydroxy-, cyano-, C₁-C₃-alkyl-, C₁-C₃-alkoxy-, -N (R)^6a)-C(=O)-O-R^6b、-N(R^6a)R^6b、-N(R^6a)R^6d、-C(=O)-N(R^6a)R^6bOr- (C)₁-C₆-alkyl) -N (R)^6a)R^6b。

In another preferred embodiment, the present invention relates to compounds of formula (I) as described above,

wherein R is⁴Represents hydroxyradical-C₁-C₃-alkyl-, -N (R)^6a)R^6bor-N (R)^6a)R^6d。

In another preferred embodiment, the present invention relates to compounds of formula (I) as described above,

wherein R is⁴Represents hydroxy-, C₁-C₃-alkyl-, -N (R)^6a)R^6bor-N (R)^6a)R^6dAnd wherein R is¹Represents a hydrogen atom.

In another preferred embodiment, the present invention relates to compounds of formula (I) as described above,

wherein R is⁴Represents hydroxy-, C₁-C₃-alkyl-, -N (R)^6a)R^6bor-N (R)^6a)R^6dAnd wherein R is²Represents a hydrogen atom.

In another preferred embodiment, the present invention relates to compounds of formula (I) as described above,

wherein R is⁴Represents hydroxy-, C₁-C₃-alkyl-, -N (R)^6a)R^6bor-N (R)^6a)R^6dAnd wherein R is¹Represents a hydrogen atom, and R²Represents a hydrogen atom.

In another preferred embodiment, the present invention relates to compounds of formula (I) as described above,

wherein R is⁴Represents fluorine-, hydroxyl-, cyano-, methyl-, methoxy-, -N (CH)₃)₂、-NH₂、-(C₁-C₃-alkyl) -N (CH)₃)₂、-C(=O)-N(CH₃)₂、-N(CH₃)-(C₁-C₃-alkyl) -N (CH)₃)₂or-N (H) -C (= O) -O- (C)₁-C₄-an alkyl group).

In another preferred embodiment, the present invention relates to compounds of formula (I) as described above,

wherein R is⁴Represents fluorine-Hydroxy-, cyano-, methyl-, methoxy-, -N (CH)₃)₂、-NH₂、-(C₁-C₃-alkyl) -N (CH)₃)₂、-C(=O)-N(CH₃)₂、-N(CH₃)-(C₁-C₃-alkyl) -N (CH)₃)₂or-N (H) -C (= O) -O- (C)₁-C₄-alkyl), and wherein R¹Represents a hydrogen atom.

In another preferred embodiment, the present invention relates to compounds of formula (I) as described above,

wherein R is⁴Represents fluorine-, hydroxyl-, cyano-, methyl-, methoxy-, -N (CH)₃)₂、-NH₂、-(C₁-C₃-alkyl) -N (CH)₃)₂、-C(=O)-N(CH₃)₂、-N(CH₃)-(C₁-C₃-alkyl) -N (CH)₃)₂or-N (H) -C (= O) -O- (C)₁-C₄-alkyl), and wherein R²Represents a hydrogen atom.

In another preferred embodiment, the present invention relates to compounds of formula (I) as described above,

wherein R is⁴Represents fluorine-, hydroxyl-, cyano-, methyl-, methoxy-, -N (CH)₃)₂、-NH₂、-(C₁-C₃-alkyl) -N (CH)₃)₂、-C(=O)-N(CH₃)₂、-N(CH₃)-(C₁-C₃-alkyl) -N (CH)₃)₂or-N (H) -C (= O) -O- (C)₁-C₄-alkyl), and wherein R¹Represents a hydrogen atom, and R²Represents a hydrogen atom.

In another preferred embodiment, the present invention relates to compounds of formula (I) as described above,

wherein R is⁴Represents hydroxy-, methyl-, -N (CH)₃)₂、-NH₂or-N (CH)₃)-(C₁-C₃-alkyl) -N (CH)₃)₂。

In another preferred embodiment, the present invention relates to compounds of formula (I) as described above,

wherein R is⁴Represents hydroxy-, methyl-, -N (CH)₃)₂、-NH₂or-N (CH)₃)-(CH₂)₂-N(CH₃)₂。

In another preferred embodiment, the present invention relates to compounds of formula (I) as described above, wherein R is⁴Represents halo-, hydroxy-, cyano-, C₁-C₃-alkyl-, C₁-C₃-alkoxy-, -N (R)^6a)-C(=O)-O-、-N(R^6a)R^6bor-C (= O) -N (R)^6a)R^6b。

In another preferred embodiment, the present invention relates to compounds of formula (I) as described above, wherein R is⁴Represents fluorine-, hydroxy-, cyano-, C₁-C₃-alkyl-, C₁-C₃-alkoxy-, -N (R)^6a)-C(=O)-O-、-N(R^6a)R^6bor-C (= O) -N (R)^6a)R^6b。

In another preferred embodiment, the present invention relates to compounds of formula (I) as described above, wherein R is⁴Represents halo-, hydroxy-, cyano-, C₁-C₃-alkyl-, C₁-C₃-alkoxy-or-N (R)^6a)R^6b。

In another preferred embodiment, the present invention relates to compounds of formula (I) as described above, wherein R is⁴Represents fluorine-, hydroxy-, cyano-, C₁-C₃-alkyl-, C₁-C₃-alkoxy-or-N (R)^6a)R^6b。

In another preferred embodiment, the present invention relates to compounds of formula (I) as described above, wherein R is^5aRepresents a hydrogen atom or C₁-C₃-an alkyl-group.

In another preferred embodiment, the present invention relates to compounds of formula (I) as described above, wherein R is^5aRepresents a hydrogen atom.

In another preferred embodiment, the present invention relates to compounds of formula (I) as described above, wherein R is^5aRepresents C₁-C₆-an alkyl-group; wherein said C₁-C₆-alkyl-group optionally substituted by 1,2, 3,4 or 5R⁴The radicals are substituted identically or differently.

In another preferred embodiment, the present invention relates to compounds of formula (I) as described above, wherein R is^5aRepresents C₁-C₃-an alkyl-group; wherein said C₁-C₃-alkyl-group optionally substituted by 1,2, 3,4 or 5R⁴The radicals are substituted identically or differently.

In another preferred embodiment, the present invention relates to compounds of formula (I) as described above, wherein R is^5aRepresents C₁-C₃-an alkyl-group.

In another preferred embodiment, the present invention relates to compounds of formula (I) as described above, wherein R is^5aRepresents a methyl-group.

In another preferred embodiment, the present invention relates to compounds of formula (I) as described above, wherein R is^5bRepresents a hydrogen atom or C₁-C₃-an alkyl-group.

In another preferred embodiment, the present invention relates to compounds of formula (I) as described above, wherein R is^5bRepresents a hydrogen atom.

In another preferred embodiment, the present invention relates to compounds of formula (I) as described above, wherein R is^5bRepresents C₁-C₆-an alkyl-group; wherein said C₁-C₆-alkyl-group optionally substituted by 1,2, 3,4 or 5R⁴The radicals are substituted identically or differently.

In another preferred embodiment, the present invention relates to compounds of formula (I) as described above, wherein R is^5bRepresents C₁-C₃-an alkyl-group; wherein said C₁-C₃-alkyl-group optionally substituted by 1,2, 3,4 or 5R⁴The radicals are substituted identically or differently.

In another preferred embodiment, the present invention relates to compounds of formula (I) as described above, wherein R is^5bRepresents C₁-C₃-an alkyl-group.

In another preferred embodiment, the present invention relates to compounds of formula (I) as described above, wherein R is^5bRepresents a methyl-group.

In another preferred embodiment, the present invention relates to compounds of formula (I) as described above,

wherein R is^5bRepresents a 3-to 10-membered heterocycloalkyl-group, wherein the 3-to 10-membered heterocycloalkyl-group is optionally substituted by 1,2, 3,4 or 5R⁴The radicals are substituted identically or differently.

In another preferred embodiment, the present invention relates to compounds of formula (I) as described above,

wherein R is^5bRepresents a 4-to 7-membered heterocycloalkyl-group, wherein the 4-to 7-membered heterocycloalkyl-group is optionally substituted by 1,2 or 3R⁴The radicals are substituted identically or differently.

In another preferred embodiment, the present invention relates to compounds of formula (I) as described above, wherein R is⁵Represents a hydrogen atom.

In another preferred embodiment, the present invention relates to compounds of formula (I) as described above, wherein R is⁵Represents C₁-C₆-an alkyl-group; wherein said C₁-C₆-alkyl-group optionally substituted by 1,2, 3,4 or 5R⁴The radicals are substituted identically or differently.

In another preferred embodiment, the present invention relates to compounds of formula (I) as described above, wherein R is⁵Represents C₁-C₃-an alkyl-group; wherein said C₁-C₃-alkyl-group optionally substituted by 1,2, 3,4 or 5R⁴The radicals are substituted identically or differently.

In anotherIn a preferred embodiment, the present invention relates to compounds of formula (I) as described above, wherein R is⁵Represents C₁-C₃-an alkyl-group; wherein said C₁-C₃-alkyl-group optionally substituted by 1 or 2R⁴The radicals are substituted identically or differently.

In another preferred embodiment, the present invention relates to compounds of formula (I) as described above, wherein R is⁵Represents C₁-C₃-alkyl-group, wherein said C₁-C₃-alkyl-group by-N (R)^6a)R^6bAnd (4) substituting the group.

In another preferred embodiment, the present invention relates to compounds of formula (I) as described above, wherein R is⁵Represents C₂-C₃-alkyl-group, wherein said C₂-C₃-alkyl-group by-N (CH)₃)₂or-NH₂And (4) substituting the group.

In another preferred embodiment, the present invention relates to compounds of formula (I) as described above, wherein R is⁵Represents- (CH)₂)₂-NH₂A group or- (CH)₂)₃-N(CH₃)₂A group.

In another preferred embodiment, the present invention relates to compounds of formula (I) as described above, wherein R is⁵Represents C₁-C₃-an alkyl-group.

In another preferred embodiment, the present invention relates to compounds of formula (I) as described above,

wherein R is⁵Represents a 3-to 10-membered heterocycloalkyl-group, wherein the 3-to 10-membered heterocycloalkyl-group is optionally substituted by 1,2, 3,4 or 5R⁴The radicals are substituted identically or differently.

In another preferred embodiment, the present invention relates to compounds of formula (I) as described above,

wherein R is⁵Represents a group selected from: c₁-C₄-alkyl-, 4-to 7-membered heterocycloalkyl-; wherein said C₁-C₄-alkyl-groups and 4-to 7-membered heterocycloalkyl-groups optionally substituted with 1 or 2R⁴The radicals are substituted identically or differently.

In another preferred embodiment, the present invention relates to compounds of formula (I) as described above,

wherein R is⁵Represents a group selected from: c₁-C₄-alkyl-, 4-to 7-membered heterocycloalkyl-; wherein the 4-to 7-membered heterocycloalkyl-group is selected from:

oxaazaspiro [3.3] heptyl, azabicyclo [3.1.0] hexyl, oxaazabicyclo [2.2.1] heptyl-, diazabicyclo [2.2.1] heptyl, pyrrolidinyl, piperidinyl, piperazinyl, azetidinyl, morpholinyl;

wherein said C₁-C₄-alkyl-groups and 4-to 7-membered heterocycloalkyl-groups optionally substituted with 1 or 2R⁴The radicals are substituted identically or differently.

In another preferred embodiment, the present invention relates to compounds of formula (I) as described above,

wherein R is⁵Represents a group selected from: c₁-C₄-alkyl-, 4-to 7-membered heterocycloalkyl-; wherein the 4-to 7-membered heterocycloalkyl-group is selected from:

oxaazaspiro [3.3] heptyl, azabicyclo [3.1.0] hexyl, oxaazabicyclo [2.2.1] heptyl-, diazabicyclo [2.2.1] heptyl, pyrrolidinyl, piperidinyl, piperazinyl, azetidinyl, morpholinyl;

wherein said C₁-C₄-alkyl-groups and 4-to 7-membered heterocycloalkyl-groups optionally substituted with 1 or 2R⁴The radicals being identically or differently substituted, and wherein the compounds R¹Represents a hydrogen atom.

In another preferred embodiment, the present invention relates to compounds of formula (I) as described above,

wherein R is⁵Represents a group selected from: c₁-C₄-alkyl-, 4-to 7-membered heterocycloalkyl-; wherein the 4-to 7-membered heterocycloalkyl-group is selected from:

oxaazaspiro [3.3] heptyl, azabicyclo [3.1.0] hexyl, oxaazabicyclo [2.2.1] heptyl-, diazabicyclo [2.2.1] heptyl, pyrrolidinyl, piperidinyl, piperazinyl, azetidinyl, morpholinyl;

wherein said C₁-C₄-alkyl-groups and 4-to 7-membered heterocycloalkyl-groups optionally substituted with 1 or 2R⁴The radicals being identically or differently substituted, and wherein the compounds R²Represents a hydrogen atom.

In another preferred embodiment, the present invention relates to compounds of formula (I) as described above,

wherein R is⁵Represents a group selected from: c₁-C₄-alkyl-, 4-to 7-membered heterocycloalkyl-; wherein the 4-to 7-membered heterocycloalkyl-group is selected from:

oxaazaspiro [3.3] heptyl, azabicyclo [3.1.0] hexyl, oxaazabicyclo [2.2.1] heptyl-, diazabicyclo [2.2.1] heptyl, pyrrolidinyl, piperidinyl, piperazinyl, azetidinyl, morpholinyl;

wherein said C₁-C₄-alkyl-groups and 4-to 7-membered heterocycloalkyl-groups optionally substituted with 1 or 2R⁴The radicals being identically or differently substituted, and wherein the compounds R¹Represents a hydrogen atom, and R²Represents a hydrogen atom.

In another preferred embodiment, the present invention relates to compounds of formula (I) as described above,

wherein R is⁵Represents a group selected from: c₂-C₃-alkyl-, 4-to 7-membered heterocycloalkyl-; wherein the 4-to 7-membered heterocycloalkyl-group is selected from:

diazabicyclo [2.2.1] heptyl, pyrrolidinyl, piperidinyl, azetidinyl;

wherein said C₂-C₃-alkyl-groups and 4-to 7-membered heterocycloalkyl-groups optionally substituted with 1 or 2R⁴The radicals are substituted identically or differently.

In another preferred embodiment, the present invention relates to compounds of formula (I) as described above, wherein N (R)^5a)R⁵Together represent a 3-to 10-membered heterocycloalkyl-group, optionally substituted by 1,2, 3,4 or 5R⁴The radicals are substituted identically or differently.

In another preferred embodiment, the present invention relates to compounds of formula (I) as described above, wherein N (R)^5a)R⁵Together represent a 4-to 7-membered heterocycloalkyl-group, optionally substituted by 1,2, 3,4 or 5R⁴The radicals are substituted identically or differently.

In another preferred embodiment, the present invention relates to compounds of formula (I) as described above, wherein N (R)^5a)R⁵Together represent a 4-to 7-membered heterocycloalkyl-group,

wherein the 4-to 7-membered heterocycloalkyl-group is selected from:

oxaazaspiro [3.3] heptyl, azabicyclo [3.1.0] hexyl, oxaazabicyclo [2.2.1] heptyl-, diazabicyclo [2.2.1] heptyl, pyrrolidinyl, piperidinyl, piperazinyl, azetidinyl, morpholinyl;

wherein said 4-to 7-membered heterocycloalkyl-group is optionally substituted by 1 or 2R⁴The radicals are substituted identically or differently.

In another preferred embodiment, the present invention relates to compounds of formula (I) as described above, wherein N (R)^5a)R⁵Together represent a 4-to 7-membered heterocycloalkyl-group,

wherein the 4-to 7-membered heterocycloalkyl-group is selected from:

oxaazaspiro [3.3] heptyl, azabicyclo [3.1.0] hexyl, oxaazabicyclo [2.2.1] heptyl-, diazabicyclo [2.2.1] heptyl, pyrrolidinyl, piperidinyl, piperazinyl, azetidinyl, morpholinyl;

wherein said 4-to 7-membered heterocycloalkyl-group is optionally substituted by 1 or 2R⁴The radicals being identically or differently substituted, and wherein the compounds R¹Represents a hydrogen atom.

In another preferred embodiment, the present invention relates to compounds of formula (I) as described above, wherein N (R)^5a)R⁵Together represent a 4-to 7-membered heterocycloalkyl-group,

wherein the 4-to 7-membered heterocycloalkyl-group is selected from:

oxaazaspiro [3.3] heptyl, azabicyclo [3.1.0] hexyl, oxaazabicyclo [2.2.1] heptyl-, diazabicyclo [2.2.1] heptyl, pyrrolidinyl, piperidinyl, piperazinyl, azetidinyl, morpholinyl;

wherein said 4-to 7-membered heterocycloalkyl-group is optionally substituted by 1 or 2R⁴The radicals being identically or differently substituted, and wherein the compounds R²Represents a hydrogen atom.

In another preferred embodiment, the present invention relates to compounds of formula (I) as described above, wherein N (R)^5a)R⁵Together represent a 4-to 7-membered heterocycloalkyl-group,

wherein the 4-to 7-membered heterocycloalkyl-group is selected from:

oxaazaspiro [3.3] heptyl, azabicyclo [3.1.0] hexyl, oxaazabicyclo [2.2.1] heptyl-, diazabicyclo [2.2.1] heptyl, pyrrolidinyl, piperidinyl, piperazinyl, azetidinyl, morpholinyl;

wherein said 4-to 7-membered heterocycloalkyl-group is optionally substituted by 1 or 2R⁴The radicals being identically or differently substituted, and wherein the compounds R¹Represents a hydrogen atom, and R²Represents a hydrogen atom.

In another preferred embodiment, the present invention relates to compounds of formula (I) as described above, wherein N (R)^5a)R⁵Together represent a 4-to 7-membered heterocycloalkyl-group,

wherein the 4-to 7-membered heterocycloalkyl-group is selected from:

diazabicyclo [2.2.1] heptyl, pyrrolidinyl, piperidinyl, azetidinyl;

wherein said 4-to 7-membered heterocycloalkyl-group is optionally substituted by 1 or 2R⁴The radicals are substituted identically or differently.

In another preferred embodiment, the present invention relates to compounds of formula (I) as described above,

wherein N (R)^5a)R⁵Together represent a group selected from:

wherein indicates the point of attachment of the group to the remainder of the molecule.

In another preferred embodiment, the present invention relates to compounds of formula (I) as described above,

wherein N (R)^5a)R⁵Together represent a group selected from:

wherein indicates the point of attachment of the group to the remainder of the molecule.

In another preferred embodiment, the present invention relates to compounds of formula (I) as described above,

wherein R is^6aRepresents a hydrogen atom or C₁-C₆-an alkyl-group.

In another preferred embodiment, the present invention relates to compounds of formula (I) as described above,

wherein R is^6aRepresents a hydrogen atom or C₁-C₃-an alkyl-group.

In another preferred embodiment, the present invention relates to compounds of formula (I) as described above,

wherein R is^6aRepresents C₁-C₃-an alkyl-group.

In another preferred embodiment, the present invention relates to compounds of formula (I) as described above,

wherein R is^6aRepresents a methyl-group.

In another preferred embodiment, the present invention relates to compounds of formula (I) as described above,

wherein R is^6aRepresents a methyl-group and wherein R^6bRepresents a methyl-group.

In another preferred embodiment, the present invention relates to compounds of formula (I) as described above,

wherein R is^6aRepresents a methyl group, wherein R^6bRepresents a methyl-group, and wherein R²Represents a hydrogen atom.

In another preferred embodiment, the present invention relates to compounds of formula (I) as described above,

wherein R is^6aRepresents a methyl group, wherein R^6bRepresents a methyl-group, and wherein R¹Represents a hydrogen atom.

In another preferred embodiment, the present invention relates to compounds of formula (I) as described above,

wherein R is^6aRepresents a methyl group, wherein R^6bRepresents a methyl-group, and wherein R¹Represents a hydrogen atom or-O-CH₃A group.

In another preferred embodiment, the present invention relates to compounds of formula (I) as described above,

wherein R is^6aRepresents a methyl group, wherein R^6bRepresents a methyl group, wherein R²Represents a hydrogen atom, and wherein R¹Represents a hydrogen atom or-O-CH₃A group.

In another preferred embodiment, the present invention relates to compounds of formula (I) as described above,

wherein R is^6bRepresents a hydrogen atom or C₁-C₆-an alkyl-group.

In another preferred embodiment, the present invention relates to compounds of formula (I) as described above,

wherein R is^6bRepresents a hydrogen atom or C₁-C₃-an alkyl-group.

In another preferred embodiment, the present invention relates to compounds of formula (I) as described above,

wherein R is^6bRepresents C₁-C₃-an alkyl-group.

In another preferred embodiment, the present invention relates to compounds of formula (I) as described above,

wherein R is^6bRepresents a methyl-group.

In another preferred embodiment, the present invention relates to compounds of formula (I) as described above,

wherein R is^6cRepresents a hydrogen atom or C₁-C₆-an alkyl-group.

In another preferred embodiment, the present invention relates to compounds of formula (I) as described above,

wherein R is^6cRepresents a hydrogen atom or C₁-C₃-an alkyl-group.

In another preferred embodiment, the present invention relates to compounds of formula (I) as described above,

wherein R is^6cRepresents C₁-C₃-an alkyl-group.

In another preferred embodiment, the present invention relates to compounds of formula (I) as described above,

wherein R is^6cRepresents a methyl-group.

In another preferred embodiment, the present invention relates to compounds of formula (I) as described above,

wherein R is^6dRepresents- (C)₁-C₃-alkyl) -N (R)^6a)R^6bA group.

In another preferred embodiment, the present invention relates to compounds of formula (I) as described above,

wherein R is^6dRepresents- (C)₁-C₃-alkyl) -N (CH)₃)₂A group.

In another preferred embodiment, the present invention relates to compounds of formula (I) as described above,

wherein R is⁶Represents a hydrogen atom or C₁-C₆-an alkyl-group.

In another preferred embodiment, the present invention relates to compounds of formula (I) as described above,

wherein R is⁶Represents a hydrogen atom or C₁-C₃-an alkyl-group.

In another preferred embodiment, the present invention relates to compounds of formula (I) as described above,

wherein R is⁶Represents C₁-C₃-an alkyl-group.

In another preferred embodiment, the present invention relates to compounds of formula (I) as described above,

wherein R is⁶Represents a methyl-group.

In another preferred embodiment, the present invention relates to compounds of formula (I) as described above,

wherein R is⁷Represents a halogen atom.

In another preferred embodiment, the present invention relates to compounds of formula (I) as described above,

wherein p represents 0 or 1.

In another preferred embodiment, the present invention relates to compounds of formula (I) as described above,

wherein q represents 0 or 1.

In another preferred embodiment, the present invention relates to compounds of formula (I) as described above,

wherein p represents 0.

In another preferred embodiment, the present invention relates to compounds of formula (I) as described above,

wherein q represents 0.

In another preferred embodiment, the present invention relates to compounds of formula (I) as described above,

wherein p represents 0 and q represents 0.

It is to be understood that the present invention also relates to any combination of the above preferred embodiments. Some examples of combinations are given below. However, the present invention is not limited to these combinations.

In a preferred embodiment, the present invention relates to compounds of formula (I) as described above,

wherein:

R¹represents a hydrogen atom or a halogen atom or a group selected from:

hydroxy-, cyano-, C₁-C₆-alkyl-, C₂-C₆-alkenyl-, C₂-C₆-alkynyl-, C₁-C₆-alkoxy-, halo-C₁-C₆-alkoxy-, C₃-C₆-cycloalkyl-, C₄-C₈-cycloalkenyl-, C₃-C₆-cycloalkyloxy-, (3-to 10-membered heterocycloalkyl) -O-, C₅-C₈-cycloalkenyloxy-, (5-to 10-membered heterocycloalkenyl) -, (5-to 10-membered heterocycle)Alkenyl) -O-, -N (R)^5a)R^5b、-SR^5aand-SF₅；

Wherein said C₁-C₆-alkyl-, C₂-C₆-alkenyl-, C₂-C₆-alkynyl-, C₁-C₆-alkoxy-, C₃-C₆-cycloalkyl-, C₄-C₈-cycloalkenyl-, C₃-C₆-cycloalkyloxy-, (3-to 10-membered heterocycloalkyl) -O-, C₅-C₈-cycloalkenyloxy-, (5-to 10-membered heterocycloalkenyl) -and (5-to 10-membered heterocycloalkenyl) -O-groups optionally substituted with 1,2, 3,4 or 5R⁴The radicals are substituted identically or differently;

R²represents a hydrogen atom or a group selected from: c₁-C₆-alkyl-, C₂-C₆-alkenyl-, C₁-C₆-alkoxy-, halo-C₁-C₆-alkyl-and halo-C₁-C₆-alkoxy-;

wherein said C₁-C₆-alkyl-, C₂-C₆-alkenyl-and C₁-C₆-alkoxy-groups optionally substituted by 1,2 or 3R⁷The radicals are substituted identically or differently;

R³represents a hydrogen atom or a group selected from: c₁-C₆-alkyl-, C₃-C₆-cycloalkyl-, C₄-C₆-cycloalkenyl-, C₂-C₆-alkenyl-, C₂-C₆-alkynyl-, 3-to 10-membered heterocycloalkyl-, 4-to 10-membered heterocycloalkenyl-, aryl-, heteroaryl-, cyano-and- (CH)₂)_q-X-(CH₂)_p-R⁵；

Wherein said C₁-C₆-alkyl-, C₃-C₆-cycloalkyl-, C₄-C₆-cycloalkenyl-, C₂-C₆-alkenyl-, C₂-C₆-alkynyl-, 3-to 10-membered heterocycloalkyl-, 4-to 10-membered heterocycleAlkenyl-, aryl-and heteroaryl-groups are optionally substituted by 1,2, 3,4 or 5R⁴The radicals are substituted identically or differently;

x represents a bond or a divalent group selected from: -O-, -S (= O)₂-、-S(=O)-N(R^5a)-、-N(R^5a)-S(=O)-、-S(=O)₂-N(R^5a)-、-N(R^5a)-S(=O)₂-、-S(=O)(=NR^5a)-、-C(=O)-、-N(R^5a)-、-C(=O)-O-、-O-C(=O)-、-C(=S)-O-、-O-C(=S)-、-C(=O)-N(R^5a)-、-N(R^5a)-C(=O)-、-N(R^5a)-C(=O)-N(R^5b)-、-O-C(=O)-N(R^5a)-、-N(R^5a)-C(=O)-O-；

R⁴Represents halo-, hydroxy-, oxo- (O =), cyano-, nitro-, C₁-C₆-alkyl-, C₂-C₆-alkenyl-, C₂-C₆-alkynyl-, halo-C₁-C₆-alkyl-, C₁-C₆-alkoxy-, halo-C₁-C₆-alkoxy-, hydroxy-C₁-C₆-alkyl-, C₁-C₆-alkoxy-C₁-C₆-alkyl-, halo-C₁-C₆-alkoxy-C₁-C₆-alkyl-, R⁶-O-、-C(=O)-R⁶、-C(=O)-O-R⁶、-O-C(=O)-R⁶、-N(R^6a)-C(=O)-R^6b、-N(R^6a)-C(=O)-N(R^6b)R^6c、-N(R^6a)R^6b、-C(=O)-N(R^6a)R^6b、R⁶-S-、R⁶-S(=O)-、R⁶-S(=O)₂-、-N(R^6a)-S(=O)-R^6b、-S(=O)-N(R^6a)R^6b、-N(R^6a)-S(=O)₂-R^6b、-S(=O)₂-N(R^6a)R^6b、-S(=O)=N(R^6a)R^6bor-N = S (= O) (R)^6a)R^6b；

R^5a、R^5bAre the same or different and are independently selected from R⁵；

R⁵Represents a hydrogen atom or a group selected from: c₁-C₆-alkyl-, C₃-C₆-cycloalkyl-, 3-to 10-membered heterocycloalkyl-, aryl-and heteroaryl-;

wherein said C₁-C₆-alkyl-, C₃-C₆-cycloalkyl-, 3-to 10-membered heterocycloalkyl-, aryl-and heteroaryl-groups optionally substituted with 1,2, 3,4 or 5R⁴The radicals are substituted identically or differently;

or

N(R^5a)R⁵Together represent a 3-to 10-membered heterocycloalkyl-group, optionally substituted by 1,2, 3,4 or 5R⁴The radicals are substituted identically or differently;

R^6a、R^6b、R^6care the same or different and are independently selected from R⁶；

R⁶Represents a hydrogen atom, C₁-C₆-alkyl-or C₃-C₆-a cycloalkyl-group;

or

R^6aAnd R^6b，

Or R^6aAnd R^6c，

Or R^6bAnd R^6cMay together form C₂-C₆An alkylene radical in which one methylene group may optionally be replaced by-O-, -C (= O) -, -NH-or-N (C)₁-C₄-alkyl) -substitution;

R⁷represents halo-, hydroxy-, oxo- (O =), cyano-, nitro-,

p represents an integer of 0, 1,2 or 3;

q represents an integer of 0, 1,2 or 3;

or a tautomer, an N-oxide, a hydrate, a solvate, or a salt thereof, or a mixture of same.

In another preferred embodiment, the present invention relates to compounds of formula (I) as described above,

wherein:

R¹represents a hydrogen atom or a group selected from: c₁-C₃-alkyl-, C₁-C₃-alkoxy-, halo-C₁-C₃-alkyl-and-S- (C)₁-C₃-an alkyl group);

R²represents a hydrogen atom;

R³represents a group selected from: c₁-C₆-alkyl-, C₃-C₆-cycloalkyl-, 3-to 10-membered heterocycloalkyl-, cyano-, and- (CH)₂)_q-X-(CH₂)_p-R⁵；

Wherein said C₁-C₆-alkyl-, C₃-C₆-cycloalkyl-and 3-to 10-membered heterocycloalkyl-groups optionally substituted by 1,2, 3,4 or 5R⁴The radicals are substituted identically or differently;

x represents a bond or a divalent group selected from:

-O-、-S-、-S(=O)-、-S(=O)₂-、-S(=O)-N(R^5a)-、-N(R^5a)-S(=O)-、-S(=O)₂-N(R^5a)-、-N(R^5a)-S(=O)₂-、-S(=O)(=NR^5a)-、-C(=O)-、-N(R^5a)-、-C(=O)-O-、-O-C(=O)-、-C(=S)-O-、-O-C(=S)-、-C(=O)-N(R^5a) -and-N (R)^5a)-C(=O)-；

R⁴Represents halo-, hydroxy-, cyano-, nitro-, C₁-C₃-alkyl-, halo-C₁-C₃-alkyl-, C₁-C₃-alkoxy-, halo-C₁-C₃-alkoxy-, hydroxy-C₁-C₃-alkyl-, C₁-C₃-alkoxy-C₁-C₃-alkyl-, halo-C₁-C₃-alkoxy-C₁-C₃-alkyl-, R⁶-O-、-C(=O)-R⁶、-C(=O)-O-R⁶、-O-C(=O)-R⁶、-N(R^6a)R^6b、-C(=O)-N(R^6a)R^6b、R⁶-S-、R⁶-S(=O)-、R⁶-S(=O)₂-、-N(R^6a)-S(=O)-R^6b、-S(=O)-N(R^6a)R^6b、-N(R^6a)-S(=O)₂-R^6bor-S (= O)₂-N(R^6a)R^6b；

R^5a、R^5bAre the same or different and are independently selected from R⁵；

R⁵Represents a hydrogen atom or a group selected from: c₁-C₆-alkyl-, C₃-C₆-cycloalkyl-, 3-to 10-membered heterocycloalkyl-, aryl-and heteroaryl-;

wherein said C₁-C₆-alkyl-, C₃-C₆-cycloalkyl-, 3-to 10-membered heterocycloalkyl-, aryl-and heteroaryl-groups optionally substituted with 1,2, 3,4 or 5R⁴The radicals are substituted identically or differently;

or

N(R^5a)R⁵Together represent a 3-to 10-membered heterocycloalkyl-group, optionally substituted by 1,2, 3,4 or 5R⁴The radicals are substituted identically or differently;

R^6a、R^6b、R^6care the same or different and are independently selected from R⁶；

R⁶Represents a hydrogen atom or C₁-C₆-an alkyl-group;

p represents an integer of 0 or 1;

q represents an integer of 0 or 1;

or a tautomer, an N-oxide, a hydrate, a solvate, or a salt thereof, or a mixture of same.

In another preferred embodiment, the present invention relates to compounds of formula (I) as described above,

wherein:

R¹represents a hydrogen atom or a group selected from: c₁-C₃-alkyl-, C₁-C₃-alkoxy-, halo-C₁-C₃-alkyl-and-S- (C)₁-C₃-an alkyl group);

R²represents a hydrogen atom;

R³represents a group selected from: c₁-C₆-alkyl-, C₃-C₆-cycloalkyl-, 3-to 10-membered heterocycloalkyl-, cyano-, and- (CH)₂)_q-X-(CH₂)_p-R⁵(ii) a Wherein said C₁-C₆-alkyl-, C₃-C₆-cycloalkyl-and 3-to 10-membered heterocycloalkyl-groups optionally substituted by 1,2, 3,4 or 5R⁴The radicals are substituted identically or differently;

x represents a divalent group selected from:

-C (= O) -, -C (= O) -O-, and-C (= O) -N (R)^5a)-；

R⁴Represents halo-, hydroxy-, cyano-, C₁-C₃-alkyl-, halo-C₁-C₃-alkyl-, C₁-C₃-alkoxy-, halo-C₁-C₃-alkoxy-, hydroxy-C₁-C₃-alkyl-, C₁-C₃-alkoxy-C₁-C₃-alkyl-, -NR^6aR^6b、-(C₁-C₆-alkyl) -N (R)^6a)R^6bor-N (R)^6a)R^6d；

R^5a、R^5bAre the same or different and are independently selected from R⁵；

R⁵Represents a hydrogen atom or C₁-C₃-an alkyl-group;

wherein said C₁-C₃-alkyl-group optionally substituted by 1,2, 3,4 or 5R⁴The radicals are substituted identically or differently;

or

N(R^5a)R⁵Together represent a 3-to 10-membered heterocycloalkyl-group, optionally substituted by 1 or 2R⁴The radicals are substituted identically or differently;

R^6a、R^6b、R^6care the same or different and are independently selected from R⁶；

R⁶Represents a hydrogen atom or C₁-C₆-an alkyl-group;

R^6drepresents- (C)₁-C₃-alkyl) -NR^6aR^6bA group;

p represents an integer of 0 or 1;

q represents an integer of 0 or 1;

or a tautomer, an N-oxide, a hydrate, a solvate, or a salt thereof, or a mixture of same.

In another preferred embodiment, the present invention relates to compounds of formula (I) as described above,

wherein:

R¹represents a hydrogen atom or a group selected from: c₁-C₃-alkyl-, C₁-C₃-alkoxy-, halo-C₁-C₃-alkyl-and-S- (C)₁-C₃-an alkyl group);

R²represents a hydrogen atom;

R³represents a group selected from: c₁-C₆-alkyl-, C₃-C₆-cycloalkyl-, 3-to 10-membered heterocycloalkyl-, cyano-, and- (CH)₂)_q-X-(CH₂)_p-R⁵(ii) a Wherein said C₁-C₆-alkyl-, C₃-C₆-cycloalkyl-and 3-to 10-membered heterocycloalkyl-groups optionally substituted by 1,2, 3,4 or 5R⁴The radicals are substituted identically or differently;

x represents a divalent group selected from:

-C (= O) -, -C (= O) -O-, and-C (= O) -N (R)^5a)-；

R⁴Represents halo-, hydroxy-, cyano-, C₁-C₃-alkyl-, halo-C₁-C₃-alkyl-, C₁-C₃-alkoxy-, halo-C₁-C₃-alkoxy-, hydroxy-C₁-C₃-alkyl-, C₁-C₃-alkoxy-C₁-C₃-alkyl-or-N (R)^6a)R^6b；

R^5a、R^5bAre the same or different and are independently selected from R⁵；

R⁵Represents a hydrogen atom or C₁-C₃-an alkyl-group;

wherein said C₁-C₃-alkyl-group optionally substituted by 1,2, 3,4 or 5R⁴The radicals are substituted identically or differently;

or

N(R^5a)R⁵Together represent a 3-to 10-membered heterocycloalkyl-group, optionally substituted by 1 or 2R⁴The radicals are substituted identically or differently;

R^6a、R^6b、R^6care the same or different and are independently selected from R⁶；

R⁶Represents a hydrogen atom or C₁-C₆-an alkyl-group;

p represents an integer of 0 or 1;

q represents an integer of 0 or 1;

or a tautomer, an N-oxide, a hydrate, a solvate, or a salt thereof, or a mixture of same.

In another preferred embodiment, the present invention relates to compounds of formula (I) as described above,

wherein:

R¹represents a hydrogen atom or a group selected from: -O-CH₃、-S-CH₃；

R²Represents a hydrogen atom;

R³represents- (CH)₂)_q-X-(CH₂)_p-R⁵；

X represents a divalent group selected from:

-C (= O) -, -C (= O) -O-, and-C (= O) -N (R)^5a)-；

R⁴Represents halo-, hydroxy-, cyano-, C₁-C₃-alkyl-, halo-C₁-C₃-alkyl-, C₁-C₃-alkoxy-, halo-C₁-C₃-alkoxy-, hydroxy-C₁-C₃-alkyl-, C₁-C₃-alkoxy-C₁-C₃-alkyl-or-N (R)^6a)R^6b；

R^5a、R^5bAre the same or different and are independently selected from R⁵；

R⁵Represents a hydrogen atom or C₁-C₃-an alkyl-group;

wherein said C₁-C₃-alkyl-group optionally substituted by 1 or 2R⁴The radicals are substituted identically or differently;

or

N(R^5a)R⁵Together represent a 3-to 10-membered heterocycloalkyl-group, orSaid group being optionally substituted by 1 or 2R⁴The radicals are substituted identically or differently;

R^6a、R^6b、R^6care the same or different and are independently selected from R⁶；

R⁶Represents a hydrogen atom or C₁-C₃-an alkyl-group;

p represents 0;

q represents 0;

or a tautomer, an N-oxide, a hydrate, a solvate, or a salt thereof, or a mixture of same.

In another preferred embodiment, the present invention relates to compounds of formula (I) as described above, wherein

R¹Represents a hydrogen atom;

R²represents a hydrogen atom;

R³represents- (CH)₂)_q-X-(CH₂)_p-R⁵A group;

x represents a divalent group selected from: -C (= O) -, -C (= O) -N (R)^5a)-；

R⁴Represents halo-, hydroxy-, cyano-, C₁-C₃-alkyl-, C₁-C₃-alkoxy-, -N (R)^6a)-C(=O)-O-R^6b、-N(R^6a)R^6b、-N(R^6a)R^6d、-C(=O)-N(R^6a)R^6bOr- (C)₁-C₃-alkyl) -N (R)^6a)R^6b；

R^5aRepresents C₁-C₃-an alkyl-group;

R⁵represents a group selected from: c₁-C₄-alkyl-, 4-to 7-membered heterocycloalkyl-;

wherein said C₁-C₄-alkyl-groups and 4-to 7-membered heterocycloalkyl-groups optionally substituted with 1 or 2R⁴The radicals are substituted identically or differently;

or

N(R^5a)R⁵Together represent a 4-to 7-membered heterocycloalkyl-group, optionally substituted by 1 or 2R⁴The radicals are substituted identically or differently;

R^6a、R^6bare the same or different and are independently selected from R⁶；

R⁶Represents a hydrogen atom or C₁-C₃-an alkyl-group;

R^6drepresents- (C)₁-C₃-alkyl) -N (R)^6a)R^6bA group;

p represents 0;

q represents 0;

or a tautomer, an N-oxide, a hydrate, a solvate, or a salt thereof, or a mixture of same.

In another preferred embodiment, the present invention relates to a compound of formula (I) or (Ib) as described above, wherein:

R¹represents a hydrogen atom;

R²represents a hydrogen atom;

R³represents- (CH)₂)_q-X-(CH₂)_p-R⁵A group;

x represents divalent-C (= O) -N (R)^5a) -a group;

R⁴represents halo-, hydroxy-, cyano-, C₁-C₃-alkyl-, C₁-C₃-alkoxy-, -N (R)^6a)-C(=O)-O-R^6b、-N(R^6a)R^6b、-N(R^6a)R^6d、-C(=O)-N(R^6a)R^6bOr- (C)₁-C₃-alkyl) -N (R)^6a)R^6b；

R^5aRepresents C₁-C₃-an alkyl-group;

R⁵represents a group selected from: c₁-C₄-alkyl-;

wherein said C₁-C₄-alkyl-group optionally substituted by 1 or 2R⁴The radicals are substituted identically or differently;

or

N(R^5a)R⁵Together represent a 4-to 7-membered heterocycloalkyl-group;

wherein the 4-to 7-membered heterocycloalkyl-group is selected from:

oxaazaspiro [3.3] heptyl, azabicyclo [3.1.0] hexyl, oxaazabicyclo [2.2.1] heptyl-, diazabicyclo [2.2.1] heptyl, pyrrolidinyl, piperidinyl, piperazinyl, azetidinyl, morpholinyl;

wherein said 4-to 7-membered heterocycloalkyl-group is optionally substituted by 1 or 2R⁴The radicals are substituted identically or differently;

R^6a、R^6bare the same or different and are independently selected from R⁶；

R⁶Represents a hydrogen atom or C₁-C₃-an alkyl-group;

R^6drepresents- (C)₁-C₃-alkyl) -N (R)^6a)R^6bA group;

p represents 0;

q represents 0;

or a tautomer, an N-oxide, a hydrate, a solvate, or a salt thereof, or a mixture of same.

In another preferred embodiment, the present invention relates to a compound of formula (I) or (Ib) as described above, wherein:

R¹represents a hydrogen atom;

R²represents a hydrogen atom;

R³represents- (CH)₂)_q-X-(CH₂)_p-R⁵A group;

x represents divalent-C (= O) -N (R)^5a) -a group;

R⁴represents hydroxy-, C₁-C₃-alkyl-, -N (R)^6a)R^6bor-N (R)^6a)R^6d；

R^5aRepresents a methyl-group;

R⁵represents a group selected from: c₁-C₃-alkyl-;

wherein said C₁-C₃-alkyl-group by-N (R)^6a)R^6bSubstituted by groups;

or

N(R^5a)R⁵Together represent a 4-to 7-membered heterocycloalkyl-group;

wherein the 4-to 7-membered heterocycloalkyl-group is selected from:

diazabicyclo [2.2.1] heptyl, pyrrolidinyl, piperidinyl, azetidinyl;

wherein said 4-to 7-membered heterocycloalkyl-group is optionally substituted by 1 or 2R⁴The radicals are substituted identically or differently;

R^6a、R^6bare the same or different and are independently selected from R⁶；

R⁶Represents a hydrogen atom or a methyl-group;

R^6drepresents- (C)₁-C₃-alkyl) -N (CH)₃)₂A group;

p represents 0;

q represents 0;

or a tautomer, an N-oxide, a hydrate, a solvate, or a salt thereof, or a mixture of same.

In another preferred embodiment, the present invention relates to compounds of formula (Ia):

wherein:

R¹represents a hydrogen atom or a chlorine atom or a group selected from:

methoxy group-, -N (CH)₃)₂；

R³represents-X-R⁵；

X represents-C (= O) -O-or-C (= O) -N (R)^5a)-；

R⁴Represents fluorine-, hydroxyl-, cyano-, methyl-, methoxy-, -N (R)^6a)-C(=O)-O-R^6b、-N(R^6a)R^6bor-C (= O) -N (R)^6a)R^6b；

R^5aRepresents a hydrogen atom or a methyl group;

R⁵represents C₁-C₆-an alkyl-group;

wherein said C₁-C₆-alkyl-group optionally substituted by 1,2 or 3R⁴The radicals are substituted identically or differently;

or

N(R^5a)R⁵Together represent a 4-to 7-membered heterocycloalkyl-group, optionally substituted by 1 or 2R⁴The radicals are substituted identically or differently;

R^6arepresents a hydrogen atom or a methyl-group;

R^6brepresents a hydrogen atom or a methyl-group;

or a tautomer, an N-oxide, a hydrate, a solvate, or a salt thereof, or a mixture of same.

It is to be understood that the present invention relates to any subcombination within any embodiment or aspect of the invention of a compound of formula (I) above.

Still more specifically, the present invention encompasses the compounds of formula (I) disclosed in the present example section hereinafter.

According to another aspect, the invention encompasses a method of making a compound of the invention, said method comprising the steps as described in the experimental section herein.

In a preferred embodiment, the present invention relates to a process for the preparation of the above-mentioned compounds of the general formula (I), in which an intermediate compound of the general formula (II) is reacted with an intermediate compound of the general formula (III):

wherein R is²And R³As defined for formula (I) above, and LG represents a leaving group, preferably a chlorine atom;

wherein R is¹As defined for the above general formula (I).

According to a further aspect, the present invention encompasses intermediate compounds useful in the preparation of the compounds of the invention of general formula (I), in particular in the methods described herein. In particular, the invention encompasses compounds of general formula (II):

wherein R is²And R³As defined for the compounds of general formula (I) above, and LG represents a leaving group, preferably a chlorine atom.

Synthesis of the Compounds of the general formula (I) according to the invention

Compounds of general formula (I) can be synthesized according to the general procedure depicted in scheme 1, wherein LG represents a leaving group.

Scheme 1

Scheme 1 illustrates the admission of R¹、R²And R³The major route of change in (c). A compound of formula (II) with pyrazolo [1,5-a ]]Coupling of pyridin-5-amine compounds (e.g., (III)) can be accomplished by reacting the two reactants in a suitable solvent, such as ethanol or formula C, optionally in the presence of an acid (e.g., hydrochloric acid)₁-C₄Relatively low aliphatic alcohols of alkyl-OH, or cyclic ethers, such as tetrahydrofuran or 1, 4-dioxane. The compounds of formula (III) can be used as free bases or corresponding salts with organic or inorganic acids. Alternatively, such amination reactions can be carried out using catalysis by metals (e.g., palladium) (see, e.g., j.y. Yoon et al, Synthesis2009,(5)815, and the references cited therein) to obtain a compound of formula (I) or (III).

Substituent R¹、R²And R³Modification of any of (a) can be effected before and/or after the exemplified transformation. However, other routes may also be used to synthesize the target compound, according to common general knowledge of those skilled in the art of organic synthesis.

The modification may be, for example, the introduction of a protecting group, cleavage of a protecting group, reduction or oxidation of a functional group, formation or cleavage of an ester or carboxamide, halogenation, metallation, substitution or other reactions known to those skilled in the art. These transformations include those that introduce functionality that allows further substituent interchange. Suitable protecting groups and their introduction and cleavage are well known to those skilled in the art (see, e.g., T.W. Greene and P.G.M. Wuts, in protective groups in Organic Synthesis, 3 rd edition, Wiley 1999). Further, two or more consecutive steps may be carried out without carrying out a post-treatment between said steps, such as a "one-pot" reaction, as it is well known to the person skilled in the art.

A compound of the general formula (II) (wherein R²And R³Having the meaning given for the general formula (I) and wherein LG represents a leaving group) can be synthesized as shown in scheme 2 by the so-called Gewald thiophene (for important publications, see e.g. k, Chem. Ber.1966,9499) are easily prepared starting from ketones of general formula (IV) to give the intermediate thiophene derivatives (V). Then using the appropriate C₁A synthon, such as formamide, cyclizes the intermediate to the thienopyrimidinone compound (VI). The resulting pyrimidinone compound (VI) is then transferred to the compound of formula (II) by suitable procedures known to the skilled person, e.g. treatment with a chlorinating agent. An instructive exemplary protocol for the sequence outlined in scheme 2 can be found in WO 2005/010008, example 14, steps 1 to 3.

If R in the compound of formula (II)³Comprising a carboxylic ester, such as an ethyl ester, it is possible to convert said ester to a carboxamide in the presence of LG (for example representing the chloride) by mild ester hydrolysis using, for example, lithium hydroxide, followed by carboxamide coupling by procedures well known to those skilled in the art.

Scheme 2

Various methods for separating pure enantiomers from mixtures of isomers, for example racemic mixtures of chiral compounds, are known to the person skilled in the art. The method comprises the following steps: preparative HPLC on chiral stationary phase; kinetic resolution of racemic mixtures (for some examples, see e.g., i. Shiina et al, cat. Sci technol. 2012,22200-&Development 2001,523-27, B.N. Roy et al, organic Process Research&Development 2009,13450, T, Storz and P, Dittmar, organic Process Research&Development 2003,7559); enantioselective protonation (see, for some examples, e.g., c. Fehr and g. Galindo, helv. chim. Acta 1995,78539-Asonic 552, S. H ü nig et al, chem. Ber. 1994,1271981-1988, S. H ü nig et al, chem. Ber. 1994,1271969); enzymatic resolution (see, for some examples, e.g., t. Miyazawa, Amino Acids 1999,16191-213) or, preferably and as outlined in more detail below, temporary derivatization with an enantiomerically pure chiral synthon, separation of The resulting diastereomers and removal of said chiral synthon, leading to separation of The pure enantiomers of The parent compound (for some examples see, for example, Asymmetric Synthesis-The essences, Mathias Christmann and stem Br ä se, editing WILEY-VCH Verlag GmbH&Co. KGaA, Weinheim)。

Scheme 3

Scheme 3 illustrates the conversion of a racemic pyrimidine synthon of formula (IIa-rac) to an activated form, for example an acid chloride of formula (VII-rac), wherein R^ERepresents C₁-C₆-an alkyl group, and wherein Y represents a leaving group LG or a hydroxyl group. Such as those skilled in the artIt is known to the skilled worker that it is possible to hydrolyze the ester group present in the synthon (IIa-rac) in the presence of Y, for example representing the group LG, for example representing chloride, by mild ester hydrolysis using, for example, lithium hydroxide, to give a carboxylic acid of the formula (IIb-rac). These can be readily converted to the acid chlorides of formula (VII-rac) by methods well known to those skilled in the art, for example by reaction with inorganic acid chlorides, such as thionyl chloride.

Subsequently, after deprotonation of the oxazolidinone of formula (VIII) using a suitable deprotonating agent, such as n-butyllithium or sodium hydride, at a temperature in the range from-78 ℃ to 0 ℃, preferably below-40 ℃, the acid chloride (VII-rac) is reacted with a chiral, enantiomerically pure synthon, such as the oxazolidinone of formula (VIII), to give the amide coupling product of formula (IX) as a mixture of two diastereomers, wherein R is^Ox1Represents a hydrogen atom or C₁-C₄-an alkyl group, preferably methyl, and wherein R^Ox2Represents aryl, aryl- (CH)₂)_n-or C₁-C₄-an alkyl-group, wherein n is an integer selected from 1,2 and 3, and wherein R is^Ox2Preferably represents phenyl. The mixture can then be separated into the pure stereoisomers of formulae (Xa) and (Xb) using methods known to those skilled in the art, such as fractional crystallization or column chromatography on silica gel.

Scheme 4

Scheme 4 illustrates the conversion of enantiomerically pure stereoisomers (Xa) or (Xb) to compounds of formula (IIa) or (IIa-ent), wherein R^ERepresents C₁-C₆-an alkyl group, and wherein Y represents a leaving group LG or a hydroxyl group, and wherein (IIa) and (ent-IIa) refer to both enantiomers of the indicated structure. Subsequently, the enantiomerically pure stereoisomer (IIa) or (IIa-ent) can be converted further into the instant text as outlined in scheme 1The compounds of the invention. The transformation can be accomplished by a variety of means known to those skilled in the art; preferably, the intermediate of formula (Xa) or (Xb) is subjected to a transesterification reaction using, for example, titanium (IV) tetraethoxide, preferably at elevated temperature, in ethanol. The resulting pyrimidine-based ester synthon, which is a pure stereoisomer of formula (IIa) or (IIa-ent), can then be subjected to mild hydrolysis as discussed above to give an enantiomerically pure carboxylic acid of formula (IIb) or (IIb-ent).

For example, a compound of formula (IIb) or (IIb-ent) is further processed to, for example, a compound of formula (IIc) or (IIc-ent) (wherein R is³represents-C (= O) NR⁵R⁴) Can be prepared by the formula HN (R)⁵)R⁴Amine (wherein R is⁴And R⁵Having the meaning as given for formula (I) and widely commercially available) with a suitable coupling agent, e.g. HATU, TBTU or 2,4, 6-tripropyl-1, 3,5,2,4, 6-trioxatriphosphane 2,4, 6-trioxide (also known as T3P), as outlined in scheme 4, to finally obtain enantiomerically pure amides of formula (I).

If desired, compounds of the formulae (IIa), (IIa-ent), (IIa-rac), (IIb-ent), (IIb-rac), (IIc-ent), (VII-rac), (IX), (Xa) and (Xb) in which Y represents a hydroxyl group can be converted by the methods described above into the respective compounds in which Y represents a leaving group LG, i.e. into the compounds of the formula (II) indicated in schemes 1 and 2.

Scheme 5

The compounds of formula (III) are commercially available or can be synthesized by adapting methods known to those skilled in the art (see e.g. j.d. Kendall et al,Bioorganic & Medicinal Chemistry Vol. 20(2012) 69–85; J. D. KendallCurrent Organic Chemistry, 2011, 15, 2481-2518)。

scheme 5 illustrates R as allowed starting from a commercially available 4-amino-pyridine compound of formula (XI)¹A route of change or modification. The amino group in (XI) may optionally be protected by a suitable Protecting Group (PG), such as a tert-butoxycarbonyl-or allyloxycarbonyl-group, to give a compound of formula (XII).

N-amination of the compound of formula (XIV) is achieved by reacting a compound of formula (XII) with a commercially available aminooxy-sulfonyl compound of formula (XIII) wherein Ar represents an optionally substituted aryl group, such as for example 2- [ (aminooxy) sulfonyl ] -1,3, 5-trimethylbenzene. This conversion can also be achieved by reacting a compound of formula (XII) with O- (2, 4-dinitrophenyl) hydroxylamine.

A compound of formula (XIV) and an propargylic ester compound of formula (XV) (wherein R is^ERepresents hydrogen or C₁-C₆-alkyl groups) optionally in the presence of an organic or inorganic base, to obtain a compound of formula (XVI). Cleavage of the ester (R)^E= hydrogen), decarboxylation and removal of the Protecting Group (PG) to give the compound of formula (III).

However, other routes may also be used to synthesize the target compound (III) according to common general knowledge of those skilled in the art of organic synthesis. Thus, the order of transformation exemplified in scheme 5 is not intended to be limiting. Further, as herein for R¹PG and R^EInterconversion of any substituents as defined may be achieved before and/or after exemplary transformations as described above.

In this context, in particular in the experimental section for the synthesis of intermediates and examples of the invention, when a compound is mentioned as a salt form with the corresponding base or acid, the exact stoichiometric composition of said salt form, as obtained by the respective preparation and/or purification method, is in most cases unknown.

Suffixes of chemical names or structural formulae such as "hydrochloride", "trifluoroacetate", "sodium salt" or "x HCl", "x CF", unless otherwise specified₃COOH”、“x Na⁺"for example is to be understood as meaning not a stoichiometric specification, but merely as a salt form.

This applies analogously to the case where synthetic intermediates or example compounds or salts thereof have been obtained by the described preparation and/or purification methods, as solvates, for example hydrates, having (if defined) an unknown stoichiometric composition.

The IUPAC names of the examples and intermediates were generated using program 'ACD/name batch version 12.01' from ACD LABS and adjusted if necessary.

Example 1

(RS) N, N-dimethyl-4- (pyrazolo [1,5-a ] pyridin-5-ylamino) -5,6,7, 8-tetrahydro [1] benzothieno [2,3-d ] pyrimidine-7-carboxamide

A mixture comprising 100 mg (338 μmol) (RS) -4-chloro-N, N-dimethyl-5, 6,7, 8-tetrahydro [1] benzothieno [2,3-d ] pyrimidine-7-carboxamide (prepared according to intermediate example 1 a), 45 mg pyrazolo [1,5-a ] pyridin-5-amine, 2 mL dimethyl sulfoxide, and 177 μ L N-ethyl-N-isopropylpropan-2-amine was heated at 100 ℃ for 16 hours. The crude product was purified by chromatography to yield 48.8 mg (37%) of the title compound.

Example 1a

(RS) -4-chloro-N, N-dimethyl-5, 6,7, 8-tetrahydro [1] benzothieno [2,3-d ] pyrimidine-7-carboxamide

A mixture comprising 4.54 g (16.90 mmol) of (RS) -4-chloro-5, 6,7, 8-tetrahydro [1] benzothieno [2,3-d ] pyrimidine-7-carboxylic acid (prepared according to WO 2013174744), 182 mL of N, N-dimethylformamide, 8.83 mL of N-ethyl-N-isopropylpropan-2-amine, 42.2 mL of N-methylmethanamine solution (2M in tetrahydrofuran) and 40.2 mL of 2,4, 6-tripropyl-1, 3,5,2,4, 6-trioxatriphospha-cyclohexane 2,4, 6-trioxide solution (50% in N, N-dimethylformamide) was stirred at 23 ℃ for 1 hour. The mixture was poured into water, ice was added, and the precipitate was washed with water and diethyl ether and dried to give 3.44 g (65%) of the title compound.

Example 2

(7S) -4- (pyrazolo [1,5-a ] pyridin-5-ylamino) -5,6,7, 8-tetrahydro [1] benzothieno [2,3-d ] pyrimidine-7-carboxylic acid

A mixture comprising 1.17 g (2.97 mmol) ethyl (7S) -4- (pyrazolo [1,5-a ] pyridin-5-ylamino) -5,6,7, 8-tetrahydro [1] benzothieno [2,3-d ] pyrimidine-7-carboxylate (prepared according to intermediate example 2 a), 51 mL tetrahydrofuran and 17.8 mL lithium hydroxide solution (1M in water) was stirred at 23 ℃ for 16 h. The mixture was acidified with hydrochloric acid, the precipitate was filtered off, washed with water and dried to yield 895 mg (54%) of the title compound.

Example 2a

(7S) -4- (pyrazolo [1,5-a ] pyridin-5-ylamino) -5,6,7, 8-tetrahydro [1] benzothieno [2,3-d ] pyrimidine-7-carboxylic acid ethyl ester

750 mg (2.53 mmol) of ethyl (7S) -4-chloro-5, 6,7, 8-tetrahydro [1] benzothieno [2,3-d ] pyrimidine-7-carboxylate (prepared according to intermediate example 2 b) are converted analogously to example 1 in order to yield 1.17 g (59%) of the title compound after workup and purification.

Example 2b

(7S) -4-chloro-5, 6,7, 8-tetrahydro [1] benzothieno [2,3-d ] pyrimidine-7-carboxylic acid ethyl ester

A mixture comprising 27.6 g (64.6 mmol) of (4S,5R) -3- { [ (7S) -4-chloro-5, 6,7, 8-tetrahydro [1] benzothieno [2,3-d ] pyrimidin-7-yl ] carbonyl } -4-methyl-5-phenyl-1, 3-oxazolidin-2-one (prepared according to intermediate example 2 c), 830 mL of ethanol and 24.4 mL of titanium tetraethoxide (4+) was refluxed for 20 hours. Ethyl acetate 1.4L and 18 mL of water were added and the mixture was stirred for 30 minutes. Silica gel was added and stirring was continued for 10 minutes. The mixture was filtered through celite, the solvent was removed, and the residue was purified by chromatography to give 18.8 g (93%) of the title compound.

Example 2c

(4S,5R) -3- { [ (7S) -4-chloro-5, 6,7, 8-tetrahydro [1] benzothieno [2,3-d ] pyrimidin-7-yl ] carbonyl } -4-methyl-5-phenyl-1, 3-oxazolidin-2-one (A) and (4S,5R) -3- { [ (7R) -4-chloro-5, 6,7, 8-tetrahydro [1] benzothieno [2,3-d ] pyrimidin-7-yl ] carbonyl } -4-methyl-5-phenyl-1, 3-oxazolidin-2-one (B)

To a solution of 26.8 g (4S,5R) -4-methyl-5-phenyl-1, 3-oxazolidin-2-one in 428 mL tetrahydrofuran at-78 deg.C was added 70 mL n-butyllithium (2.5M in hexanes) and the mixture was stirred at-60 deg.C for 1 h. A solution of 45.8 g (159 mmol) 4-chloro-5, 6,7, 8-tetrahydro [1] benzothieno [2,3-d ] pyrimidine-7 (RS) -carbonyl chloride (prepared according to intermediate example 2 d) in 428 mL tetrahydrofuran was added and stirring was continued for 1h at-70 ℃. The mixture was poured into water, the tetrahydrofuran was removed, the precipitate was filtered off, washed with water and dissolved in dichloromethane. The organic layer was dried over sodium sulfate, followed by addition of acetonitrile. The dichloromethane was removed and the precipitate was filtered and washed with acetonitrile and diethyl ether to give 27.6 g (38%) of the title compound a. A second precipitate was obtained from the mother liquor after standing overnight to yield 25.5 g (35%) of the title compound B.

Example 2d

4-chloro-5, 6,7, 8-tetrahydro [1] benzothieno [2,3-d ] pyrimidine-7 (RS) -carbonyl chloride

A mixture comprising 42.87 g (159 mmol) (RS) -4-chloro-5, 6,7, 8-tetrahydro [1] benzothieno [2,3-d ] pyrimidine-7-carboxylic acid (prepared according to WO 2013174744) and 349 mL thionyl chloride was heated at 100 ℃ for 3 hours. The reagents were removed to give the title compound, which was used without further purification.

Example 3

[ (3R) -3-methylmorpholin-4-yl ] [ (7S) -4- (pyrazolo [1,5-a ] pyridin-5-ylamino) -5,6,7, 8-tetrahydro [1] benzothieno [2,3-d ] pyrimidin-7-yl ] methanone

Comprising 150 mg (410 μmol) (7S) -4- (pyrazolo [1,5-a ] pyridin-5-ylamino) -5,6,7, 8-tetrahydro [1] benzothieno [2,3-d ] pyrimidine-7-carboxylic acid (prepared according to example 2), 6.13 mL dimethyl sulfoxide, a mixture of 215 μ L N-ethyl-N-isopropylpropan-2-amine, 280 μ L (3R) -3-methylmorpholine and 716 μ L2, 4, 6-tripropyl-1, 3,5,2,4, 6-trioxatriphosphabicyclohexane 2,4, 6-trioxide solution (50% in N, N-dimethylformamide) was stirred at 23 ℃ for 16 hours. The crude mixture was purified by chromatography to give 55.4 mg (30%) of the title compound.

Example 4

(7S) -N- [2- (dimethylamino) ethyl ] -N-methyl-4- (pyrazolo [1,5-a ] pyridin-5-ylamino) -5,6,7, 8-tetrahydro [1] benzothieno [2,3-d ] pyrimidine-7-carboxamide

150 mg (410 μmol) (7S) -4- (pyrazolo [1,5-a ] pyridin-5-ylamino) -5,6,7, 8-tetrahydro [1] benzothieno [2,3-d ] pyrimidine-7-carboxylic acid (prepared according to example 2) was converted in analogy to example 3 using N, N, N' -trimethylethane-1, 2-diamine to give 46.4 mg (25%) of the title compound after work-up and purification.

Example 5

[ (2R,6S) -2, 6-dimethylmorpholin-4-yl ] [ (7S) -4- (pyrazolo [1,5-a ] pyridin-5-ylamino) -5,6,7, 8-tetrahydro [1] benzothieno [2,3-d ] pyrimidin-7-yl ] methanone

150 mg (410 μmol) of (7S) -4- (pyrazolo [1,5-a ] pyridin-5-ylamino) -5,6,7, 8-tetrahydro [1] benzothieno [2,3-d ] pyrimidine-7-carboxylic acid (prepared according to example 2) was converted in analogy to example 3 using (2R,6S) -2, 6-dimethylmorpholine to give 7.1 mg (4%) of the title compound after work-up and purification.

Example 6

[ (3R) -3- (dimethylamino) pyrrolidin-1-yl ] [ (7S) -4- (pyrazolo [1,5-a ] pyridin-5-ylamino) -5,6,7, 8-tetrahydro [1] benzothieno [2,3-d ] pyrimidin-7-yl ] methanone

150 mg (410 μmol) (7S) -4- (pyrazolo [1,5-a ] pyridin-5-ylamino) -5,6,7, 8-tetrahydro [1] benzothieno [2,3-d ] pyrimidine-7-carboxylic acid (prepared according to example 2) was converted in analogy to example 3 using (3R) -N, N-dimethylpyrrolidin-3-amine to yield 35.2 mg (19%) of the title compound after work-up and purification.

Example 7

[ (3S) -3-methylmorpholin-4-yl ] [ (7S) -4- (pyrazolo [1,5-a ] pyridin-5-ylamino) -5,6,7, 8-tetrahydro [1] benzothieno [2,3-d ] pyrimidin-7-yl ] methanone

100 mg (274 μmol) of (7S) -4- (pyrazolo [1,5-a ] pyridin-5-ylamino) -5,6,7, 8-tetrahydro [1] benzothieno [2,3-d ] pyrimidine-7-carboxylic acid (prepared according to example 2) was converted in analogy to example 3 using (3S) -3-methylmorpholine to yield 24.7 mg (19%) of the title compound after work-up and purification.

Example 8

(7S) -N- (2-methoxyethyl) -N-methyl-4- (pyrazolo [1,5-a ] pyridin-5-ylamino) -5,6,7, 8-tetrahydro [1] benzothieno [2,3-d ] pyrimidine-7-carboxamide

100 mg (274 μmol) (7S) -4- (pyrazolo [1,5-a ] pyridin-5-ylamino) -5,6,7, 8-tetrahydro [1] benzothieno [2,3-d ] pyrimidine-7-carboxylic acid (prepared according to example 2) was converted in analogy to example 3 using 2-methoxy-N-methylethylamine to give 32.7 mg (27%) of the title compound after work-up and purification.

Example 9

[ (2S,6S) -2, 6-dimethylmorpholin-4-yl ] [ (7S) -4- (pyrazolo [1,5-a ] pyridin-5-ylamino) -5,6,7, 8-tetrahydro [1] benzothieno [2,3-d ] pyrimidin-7-yl ] methanone

100 mg (274 μmol) (7S) -4- (pyrazolo [1,5-a ] pyridin-5-ylamino) -5,6,7, 8-tetrahydro [1] benzothieno [2,3-d ] pyrimidine-7-carboxylic acid (prepared according to example 2) was converted in analogy to example 3 using (2S,6S) -2, 6-dimethylmorpholine to yield 30.3 mg (24%) of the title compound after work-up and purification.

Example 10

[ (2R,6R) -2, 6-dimethylmorpholin-4-yl ] [ (7S) -4- (pyrazolo [1,5-a ] pyridin-5-ylamino) -5,6,7, 8-tetrahydro [1] benzothieno [2,3-d ] pyrimidin-7-yl ] methanone

100 mg (274 μmol) (7S) -4- (pyrazolo [1,5-a ] pyridin-5-ylamino) -5,6,7, 8-tetrahydro [1] benzothieno [2,3-d ] pyrimidine-7-carboxylic acid (prepared according to example 2) was converted in analogy to example 3 using (2R,6R) -2, 6-dimethylmorpholine to yield 25.2 mg (19%) of the title compound after work-up and purification.

Example 11

Morpholin-4-yl [ (7S) -4- (pyrazolo [1,5-a ] pyridin-5-ylamino) -5,6,7, 8-tetrahydro [1] benzothieno [2,3-d ] pyrimidin-7-yl ] methanone

100 mg (274 μmol) (7S) -4- (pyrazolo [1,5-a ] pyridin-5-ylamino) -5,6,7, 8-tetrahydro [1] benzothieno [2,3-d ] pyrimidine-7-carboxylic acid (prepared according to example 2) was converted in analogy to example 3 using morpholine to obtain 24.0 mg (18%) of the title compound after work-up and purification.

Example 12

3-azabicyclo [3.1.0] hex-3-yl [ (7S) -4- (pyrazolo [1,5-a ] pyridin-5-ylamino) -5,6,7, 8-tetrahydro [1] benzothieno [2,3-d ] pyrimidin-7-yl ] methanone

100 mg (274 μmol) (7S) -4- (pyrazolo [1,5-a ] pyridin-5-ylamino) -5,6,7, 8-tetrahydro [1] benzothieno [2,3-d ] pyrimidine-7-carboxylic acid (prepared according to example 2) was converted in analogy to example 3 using 3-azabicyclo [3.1.0] hexane to give 5.0 mg (4%) of the title compound after work-up and purification.

Example 13

[ (3R,5S) -3, 5-Dimethylmorpholin-4-yl ] [ (7S) -4- (pyrazolo [1,5-a ] pyridin-5-ylamino) -5,6,7, 8-tetrahydro [1] benzothieno [2,3-d ] pyrimidin-7-yl ] methanone

80 mg (219 μmol) of (7S) -4- (pyrazolo [1,5-a ] pyridin-5-ylamino) -5,6,7, 8-tetrahydro [1] benzothieno [2,3-d ] pyrimidine-7-carboxylic acid (prepared according to example 2) was converted in analogy to example 3 using (3R,5S) -3, 5-dimethylmorpholine to yield 11.2 mg (11%) of the title compound after work-up and purification.

Example 14

[ (3R,5R) -3, 5-Dimethylmorpholin-4-yl ] [ (7S) -4- (pyrazolo [1,5-a ] pyridin-5-ylamino) -5,6,7, 8-tetrahydro [1] benzothieno [2,3-d ] pyrimidin-7-yl ] methanone

80 mg (219 μmol) of (7S) -4- (pyrazolo [1,5-a ] pyridin-5-ylamino) -5,6,7, 8-tetrahydro [1] benzothieno [2,3-d ] pyrimidine-7-carboxylic acid (prepared according to example 2) was converted in analogy to example 3 using (3R,5R) -3, 5-dimethylmorpholine to yield 15.4 mg (14%) of the title compound after work-up and purification.

Example 15

(7S) -4- [ (6-methoxypyrazolo [1,5-a ] pyridin-5-yl) amino ] -N, N-dimethyl-5, 6,7, 8-tetrahydro [1] benzothieno [2,3-d ] pyrimidine-7-carboxamide

A mixture comprising 52.2 mg (176 μmol) (7S) -4-chloro-N, N-dimethyl-5, 6,7, 8-tetrahydro [1] benzothieno [2,3-d ] pyrimidine-7-carboxamide (prepared according to intermediate example 15 a), 28.8 mg 6-methoxypyrazolo [1,5-a ] pyridin-5-amine (prepared according to intermediate example 15 c), 1 mL ethanol was heated at 120 ℃ for 16 hours. 300 μ L N, N-diethylethylamine were added, and the precipitate was filtered off and dried to give 3.8 mg (5%) of the title compound.

Example 15a

(7S) -4-chloro-N, N-dimethyl-5, 6,7, 8-tetrahydro [1] benzothieno [2,3-d ] pyrimidine-7-carboxamide

372 mg (1.38 mmol) of (7S) -4-chloro-5, 6,7, 8-tetrahydro [1] benzothieno [2,3-d ] pyrimidine-7-carboxylic acid (prepared according to intermediate example 15 b) are converted in analogy to intermediate example 1a so as to yield 308 mg (75%) of the title compound after workup and purification.

Example 15b

(7S) -4-chloro-5, 6,7, 8-tetrahydro [1] benzothieno [2,3-d ] pyrimidine-7-carboxylic acid

4.38 g (14.76 mmol) of ethyl (7S) -4-chloro-5, 6,7, 8-tetrahydro [1] benzothieno [2,3-d ] pyrimidine-7-carboxylate (prepared according to intermediate example 2 b) were converted analogously to example 2 in order to yield 3.87g (93%) of the title compound after workup and purification.

Example 15c

6-methoxy pyrazolo [1,5-a ] pyridin-5-amine

A mixture comprising 120 mg (358 μmol) ethyl 5- [ (tert-butoxycarbonyl) amino ] -6-methoxypyrazolo [1,5-a ] pyridine-3-carboxylate (prepared according to intermediate example 15 d) and 3.0 mL sulfuric acid (40%) was heated at reflux for 16 hours. Under cooling, the mixture was neutralized by addition of sodium hydroxide solution and extracted with dichloromethane. After removal of the solvent, 29.5 mg (51%) of the title compound are isolated.

Example 15d

5- [ (tert-Butoxycarbonyl) amino ] -6-methoxypyrazolo [1,5-a ] pyridine-3-carboxylic acid ethyl ester

A mixture containing 3.75 g (8.52 mmol) of 1-amino-4- [ (tert-butoxycarbonyl) amino ] -3-methoxypyridinium 2,4, 6-trimethylbenzenesulfonate (prepared according to intermediate example 15 e), 12 mL of N, N-dimethylformamide, 1.25 g of potassium carbonate and 459. mu.L of ethyl propiolate was stirred at 23 ℃ for 16 hours.

Example 15e

1-amino-4- [ (tert-butoxycarbonyl) amino ] -3-methoxypyridinium 2,4, 6-trimethylbenzenesulfonate

A solution of 2.33 g of 2- [ (aminooxy) sulfonyl ] -1,3, 5-trimethylbenzene (CAS-No:36015-40-7) in 100 mL of dichloromethane was cooled to 3 ℃. A solution of 1.99g (8.87 mmol) of tert-butyl (3-methoxypyridin-4-yl) carbamate (prepared according to intermediate example 15 f) in 30 mL of dichloromethane was added dropwise and the mixture was stirred at 23 ℃ for 16 h. The solvent was removed to give 3.74 g (96%) of the title compound, which was used without further purification.

Example 15f

(3-methoxypyridin-4-yl) carbamic acid tert-butyl ester

A mixture comprising 1.00 g (8.06 mmol) of 3-methoxypyridin-4-amine (CAS-No: 52334-90-4), 10 mL of tetrahydrofuran, 1.54 mL of N-ethyl-N-isopropylpropan-2-amine and 2.04 mL of di-tert-butyl dicarbonate was stirred at 23 ℃ for 16 hours. Saturated aqueous ammonium chloride solution was added and the mixture was extracted with ethyl acetate. The organic layer was washed with water, brine and dried. After removal of the solvent, 1.99g of the crude title compound was obtained, which was used without further purification.

Example 16

(7S) -N-isopropyl-N-methyl-4- (pyrazolo [1,5-a ] pyridin-5-ylamino) -5,6,7, 8-tetrahydro [1] benzothieno [2,3-d ] pyrimidine-7-carboxamide

A mixture comprising 100 mg (274 μmol) (7S) -4- (pyrazolo [1,5-a ] pyridin-5-ylamino) -5,6,7, 8-tetrahydro [1] benzothieno [2,3-d ] pyrimidine-7-carboxylic acid (prepared according to example 2), 5.0 mL N, N-dimethylacetamide, 286 μ L N-ethyl-N-isopropylpropan-2-amine, 143 μ L N-methylpropan-2-amine, and 489 μ L2, 4, 6-tripropyl-1, 3,5,2,4, 6-trioxatriphosphane 2,4, 6-trioxide solution (50% in ethyl acetate) was stirred at 50 ℃ for 16 hours. The crude mixture was purified by chromatography to give 68.5 mg (57%) of the title compound.

Example 17

(7S) -N, N-dimethyl-4- (pyrazolo [1,5-a ] pyridin-5-ylamino) -5,6,7, 8-tetrahydro [1] benzothieno [2,3-d ] pyrimidine-7-carboxamide

70 mg (192. mu. mol) (7S) -4- (pyrazolo [1,5-a ] pyridin-5-ylamino) -5,6,7, 8-tetrahydro [1] benzothieno [2,3-d ] pyrimidine-7-carboxylic acid (prepared according to example 2) was converted using N-methyl methylamine in analogy to example 16 to yield 47.9 mg (61%) of the title compound after work-up and purification.

Example 18

(7S) -N- (2, 2-difluoroethyl) -N-methyl-4- (pyrazolo [1,5-a ] pyridin-5-ylamino) -5,6,7, 8-tetrahydro [1] benzothieno [2,3-d ] pyrimidine-7-carboxamide

70 mg (192 μmol) (7S) -4- (pyrazolo [1,5-a ] pyridin-5-ylamino) -5,6,7, 8-tetrahydro [1] benzothieno [2,3-d ] pyrimidine-7-carboxylic acid (prepared according to example 2) was converted in analogy to example 16 using 2, 2-difluoro-N-methylethylamine to give 51.5 mg (58%) of the title compound after work-up and purification.

Example 19

(7S) -N- (2-hydroxy-2-methylpropyl) -N-methyl-4- (pyrazolo [1,5-a ] pyridin-5-ylamino) -5,6,7, 8-tetrahydro [1] benzothieno [2,3-d ] pyrimidine-7-carboxamide

75 mg (205 μmol) (7S) -4- (pyrazolo [1,5-a ] pyridin-5-ylamino) -5,6,7, 8-tetrahydro [1] benzothieno [2,3-d ] pyrimidine-7-carboxylic acid (prepared according to example 2) was converted in analogy to example 16 using 2-methyl-1- (methylamino) propan-2-ol to give 64.3 mg (66%) of the title compound after work-up and purification.

Example 20

Azetidin-1-yl [ (7S) -4- (pyrazolo [1,5-a ] pyridin-5-ylamino) -5,6,7, 8-tetrahydro [1] benzothieno [2,3-d ] pyrimidin-7-yl ] methanone

75 mg (205 μmol) (7S) -4- (pyrazolo [1,5-a ] pyridin-5-ylamino) -5,6,7, 8-tetrahydro [1] benzothieno [2,3-d ] pyrimidine-7-carboxylic acid (prepared according to example 2) was converted using azetidine in analogy to example 16 to yield 42.6 mg (49%) of the title compound after work-up and purification.

Example 21

(7S) -N-Ethyl-N- (2-hydroxyethyl) -4- (pyrazolo [1,5-a ] pyridin-5-ylamino) -5,6,7, 8-tetrahydro [1] benzothieno [2,3-d ] pyrimidine-7-carboxamide

75 mg (205 μmol) (7S) -4- (pyrazolo [1,5-a ] pyridin-5-ylamino) -5,6,7, 8-tetrahydro [1] benzothieno [2,3-d ] pyrimidine-7-carboxylic acid (prepared according to example 2) was converted in analogy to example 16 using 2- (ethylamino) ethanol to yield 23.2 mg (25%) of the title compound after work-up and purification.

Example 22

1- { [ (7S) -4- (pyrazolo [1,5-a ] pyridin-5-ylamino) -5,6,7, 8-tetrahydro [1] benzothieno [2,3-d ] pyrimidin-7-yl ] carbonyl } azetidine-3-carbonitrile

75 mg (205 μmol) (7S) -4- (pyrazolo [1,5-a ] pyridin-5-ylamino) -5,6,7, 8-tetrahydro [1] benzothieno [2,3-d ] pyrimidine-7-carboxylic acid (prepared according to example 2) was converted using azetidine-3-carbonitrile analogously to example 16 to yield 67.2 mg (69%) of the title compound after workup and purification.

Example 23

(3, 3-Difluoroazetidin-1-yl) [ (7S) -4- (pyrazolo [1,5-a ] pyridin-5-ylamino) -5,6,7, 8-tetrahydro [1] benzothieno [2,3-d ] pyrimidin-7-yl ] methanone

75 mg (205 μmol) (7S) -4- (pyrazolo [1,5-a ] pyridin-5-ylamino) -5,6,7, 8-tetrahydro [1] benzothieno [2,3-d ] pyrimidine-7-carboxylic acid (prepared according to example 2) was converted in analogy to example 16 using 3, 3-difluoroazetidine to give 59.7 mg (63%) of the title compound after work-up and purification.

Example 24

(3-hydroxyazetidin-1-yl) [ (7S) -4- (pyrazolo [1,5-a ] pyridin-5-ylamino) -5,6,7, 8-tetrahydro [1] benzothieno [2,3-d ] pyrimidin-7-yl ] methanone

75 mg (205 μmol) (7S) -4- (pyrazolo [1,5-a ] pyridin-5-ylamino) -5,6,7, 8-tetrahydro [1] benzothieno [2,3-d ] pyrimidine-7-carboxylic acid (prepared according to example 2) was converted using azetidin-3-ol analogously to example 16 to yield 45.1 mg (50%) of the title compound after work-up and purification.

Example 25

[ tert-butyl [2- (methyl { [ (7S) -4- (pyrazolo [1,5-a ] pyridin-5-ylamino) -5,6,7, 8-tetrahydro [1] benzothieno [2,3-d ] pyrimidin-7-yl ] carbonyl } amino) ethyl ] carbamate

200 mg (547 μmol) of (7S) -4- (pyrazolo [1,5-a ] pyridin-5-ylamino) -5,6,7, 8-tetrahydro [1] benzothieno [2,3-d ] pyrimidine-7-carboxylic acid (prepared according to example 2) was converted analogously to example 16 using tert-butyl [2- (methylamino) ethyl ] carbamate to yield 134 mg (45%) of the title compound after work-up and purification.

Example 26

(7S) -N- [2- (dimethylamino) -2-oxoethyl ] -N-methyl-4- (pyrazolo [1,5-a ] pyridin-5-ylamino) -5,6,7, 8-tetrahydro [1] benzothieno [2,3-d ] pyrimidine-7-carboxamide

75 mg (205. mu. mol) (7S) -4- (pyrazolo [1, 5-a)]Pyridin-5-ylamino) -5,6,7, 8-tetrahydro [1]Benzothieno [2,3-d ]]Pyrimidine-7-carboxylic acid (prepared according to example 2) N, N was used analogously to example 16²Conversion of trimethylglycinamide in order to obtain, after workup and purification, 55.4 mg (55%) of the title compound.

Example 27

(7S) -N- [3- (dimethylamino) propyl ] -N-methyl-4- (pyrazolo [1,5-a ] pyridin-5-ylamino) -5,6,7, 8-tetrahydro [1] benzothieno [2,3-d ] pyrimidine-7-carboxamide

75 mg (205 μmol) (7S) -4- (pyrazolo [1,5-a ] pyridin-5-ylamino) -5,6,7, 8-tetrahydro [1] benzothieno [2,3-d ] pyrimidine-7-carboxylic acid (prepared according to example 2) was converted in analogy to example 16 using N, N, N' -trimethylpropane-1, 3-diamine to give 55.1 mg (55%) of the title compound after work-up and purification.

Example 28

[3- (dimethylamino) azetidin-1-yl ] [ (7S) -4- (pyrazolo [1,5-a ] pyridin-5-ylamino) -5,6,7, 8-tetrahydro [1] benzothieno [2,3-d ] pyrimidin-7-yl ] methanone

75 mg (205 μmol) (7S) -4- (pyrazolo [1,5-a ] pyridin-5-ylamino) -5,6,7, 8-tetrahydro [1] benzothieno [2,3-d ] pyrimidine-7-carboxylic acid (prepared according to example 2) was converted in analogy to example 16 using N, N-dimethylazetidin-3-amine to yield 68.6 mg (71%) of the title compound after work-up and purification.

Example 29

(4-methylpiperazin-1-yl) [ (7S) -4- (pyrazolo [1,5-a ] pyridin-5-ylamino) -5,6,7, 8-tetrahydro [1] benzothieno [2,3-d ] pyrimidin-7-yl ] methanone

75 mg (205 μmol) (7S) -4- (pyrazolo [1,5-a ] pyridin-5-ylamino) -5,6,7, 8-tetrahydro [1] benzothieno [2,3-d ] pyrimidine-7-carboxylic acid (prepared according to example 2) was converted in analogy to example 16 using 1-methylpiperazine to yield 63.5 mg (66%) of the title compound after work-up and purification.

Example 30

(3-hydroxy-3-methylazetidin-1-yl) [ (7S) -4- (pyrazolo [1,5-a ] pyridin-5-ylamino) -5,6,7, 8-tetrahydro [1] benzothieno [2,3-d ] pyrimidin-7-yl ] methanone

75 mg (205 μmol) (7S) -4- (pyrazolo [1,5-a ] pyridin-5-ylamino) -5,6,7, 8-tetrahydro [1] benzothieno [2,3-d ] pyrimidine-7-carboxylic acid (prepared according to example 2) was converted in analogy to example 16 using 3-methylazetidin-3-ol to yield 49.5 mg (53%) of the title compound after work-up and purification.

Example 31

{4- [2- (dimethylamino) ethyl ] piperazin-1-yl } [ (7S) -4- (pyrazolo [1,5-a ] pyridin-5-ylamino) -5,6,7, 8-tetrahydro [1] benzothieno [2,3-d ] pyrimidin-7-yl ] methanone

75 mg (205 μmol) (7S) -4- (pyrazolo [1,5-a ] pyridin-5-ylamino) -5,6,7, 8-tetrahydro [1] benzothieno [2,3-d ] pyrimidine-7-carboxylic acid (prepared according to example 2) was converted in analogy to example 16 using N, N-dimethyl-2- (piperazin-1-yl) ethylamine to give 59.3 mg (54%) of the title compound after work-up and purification.

Example 32

[4- (dimethylamino) piperidin-1-yl ] [ (7S) -4- (pyrazolo [1,5-a ] pyridin-5-ylamino) -5,6,7, 8-tetrahydro [1] benzothieno [2,3-d ] pyrimidin-7-yl ] methanone

75 mg (205 μmol) (7S) -4- (pyrazolo [1,5-a ] pyridin-5-ylamino) -5,6,7, 8-tetrahydro [1] benzothieno [2,3-d ] pyrimidine-7-carboxylic acid (prepared according to example 2) was converted in analogy to example 16 using N, N-dimethylpiperidin-4-amine to give 54.9 mg (53%) of the title compound after work-up and purification.

Example 33

1- { [ (7S) -4- (pyrazolo [1,5-a ] pyridin-5-ylamino) -5,6,7, 8-tetrahydro [1] benzothieno [2,3-d ] pyrimidin-7-yl ] carbonyl } piperidin-4-one

75 mg (205 μmol) (7S) -4- (pyrazolo [1,5-a ] pyridin-5-ylamino) -5,6,7, 8-tetrahydro [1] benzothieno [2,3-d ] pyrimidine-7-carboxylic acid (prepared according to example 2) was converted in analogy to example 16 using piperidin-4-one to yield 46.5 mg (48%) of the title compound after work-up and purification.

Example 34

(3, 3-difluoropyrrolidin-1-yl) [ (7S) -4- (pyrazolo [1,5-a ] pyridin-5-ylamino) -5,6,7, 8-tetrahydro [1] benzothieno [2,3-d ] pyrimidin-7-yl ] methanone

75 mg (205 μmol) (7S) -4- (pyrazolo [1,5-a ] pyridin-5-ylamino) -5,6,7, 8-tetrahydro [1] benzothieno [2,3-d ] pyrimidine-7-carboxylic acid (prepared according to example 2) was converted in analogy to example 16 using 3, 3-difluoropyrrolidine to give 61.0 mg (62%) of the title compound after work-up and purification.

Example 35

2-oxa-6-azaspiro [3.3] hept-6-yl [ (7S) -4- (pyrazolo [1,5-a ] pyridin-5-ylamino) -5,6,7, 8-tetrahydro [1] benzothieno [2,3-d ] pyrimidin-7-yl ] methanone

75 mg (205 μmol) (7S) -4- (pyrazolo [1,5-a ] pyridin-5-ylamino) -5,6,7, 8-tetrahydro [1] benzothieno [2,3-d ] pyrimidine-7-carboxylic acid (prepared according to example 2) was converted in analogy to example 16 using 2-oxa-6-azaspiro [3.3] heptane to yield 37.2 mg (39%) of the title compound after work-up and purification.

Example 36

(1S,4S) -2-oxa-5-azabicyclo [2.2.1] hept-5-yl [ (7S) -4- (pyrazolo [1,5-a ] pyridin-5-ylamino) -5,6,7, 8-tetrahydro [1] benzothieno [2,3-d ] pyrimidin-7-yl ] methanone

75 mg (205 μmol) (7S) -4- (pyrazolo [1,5-a ] pyridin-5-ylamino) -5,6,7, 8-tetrahydro [1] benzothieno [2,3-d ] pyrimidine-7-carboxylic acid (prepared according to example 2) was converted in analogy to example 16 using (1S,4S) -2-oxa-5-azabicyclo [2.2.1] heptane to yield 71.9 mg (75%) of the title compound after work-up and purification.

Example 37

(1R,4R) -2-oxa-5-azabicyclo [2.2.1] hept-5-yl [ (7S) -4- (pyrazolo [1,5-a ] pyridin-5-ylamino) -5,6,7, 8-tetrahydro [1] benzothieno [2,3-d ] pyrimidin-7-yl ] methanone

75 mg (205 μmol) (7S) -4- (pyrazolo [1,5-a ] pyridin-5-ylamino) -5,6,7, 8-tetrahydro [1] benzothieno [2,3-d ] pyrimidine-7-carboxylic acid (prepared according to example 2) was converted in analogy to example 16 using (1R,4R) -2-oxa-5-azabicyclo [2.2.1] heptane to yield 59.7 mg (62%) of the title compound after work-up and purification.

Example 38

[ (1S,4S) -5-methyl-2, 5-diazabicyclo [2.2.1] hept-2-yl ] [ (7S) -4- (pyrazolo [1,5-a ] pyridin-5-ylamino) -5,6,7, 8-tetrahydro [1] benzothieno [2,3-d ] pyrimidin-7-yl ] methanone

75 mg (205 μmol) of (7S) -4- (pyrazolo [1,5-a ] pyridin-5-ylamino) -5,6,7, 8-tetrahydro [1] benzothieno [2,3-d ] pyrimidine-7-carboxylic acid (prepared according to example 2) was converted in analogy to example 16 using (1S,4S) -2-methyl-2, 5-diazabicyclo [2.2.1] heptane to yield 22.0 mg (22%) of the title compound after work-up and purification.

Example 39

(7S) -N- (2-aminoethyl) -N-methyl-4- (pyrazolo [1,5-a ] pyridin-5-ylamino) -5,6,7, 8-tetrahydro [1] benzothieno [2,3-d ] pyrimidine-7-carboxamide

A mixture comprising 50 mg (96 μmol) of tert-butyl [2- (methyl { [ (7S) -4- (pyrazolo [1,5-a ] pyridin-5-ylamino) -5,6,7, 8-tetrahydro [1] benzothieno [2,3-d ] pyrimidin-7-yl ] carbonyl } amino) ethyl ] carbamate (prepared according to example 25), 2.0 mL of dichloromethane, and 221 μ L of trifluoroacetic acid was stirred at 23 ℃ for 3 hours. 0.5 ml of N-diethylethylamine was added and the solvent was removed. The residue was purified by chromatography to give 26.1 mg (61%) of the title compound.

Example 40

(4- { [2- (dimethylamino) ethyl ] (methyl) amino } piperidin-1-yl) [ (7S) -4- (pyrazolo [1,5-a ] pyridin-5-ylamino) -5,6,7, 8-tetrahydro [1] benzothieno [2,3-d ] pyrimidin-7-yl ] methanone

75 mg (205 μmol) (7S) -4- (pyrazolo [1,5-a ] pyridin-5-ylamino) -5,6,7, 8-tetrahydro [1] benzothieno [2,3-d ] pyrimidine-7-carboxylic acid (prepared according to example 2) was converted in analogy to example 16 using N, N, N '-trimethyl-N' - (piperidin-4-yl) ethane-1, 2-diamine to yield 52.0 mg (45%) of the title compound after work-up and purification.

EXAMPLE 41

[ (3S) -3- (dimethylamino) pyrrolidin-1-yl ] [ (7S) -4- (pyrazolo [1,5-a ] pyridin-5-ylamino) -5,6,7, 8-tetrahydro [1] benzothieno [2,3-d ] pyrimidin-7-yl ] methanone

75 mg (205 μmol) (7S) -4- (pyrazolo [1,5-a ] pyridin-5-ylamino) -5,6,7, 8-tetrahydro [1] benzothieno [2,3-d ] pyrimidine-7-carboxylic acid (prepared according to example 2) was converted in analogy to example 16 using (3S) -N, N-dimethylpyrrolidin-3-amine to give 51.3 mg (51%) of the title compound after work-up and purification.

Example 42

[ (1R,4R) -5-methyl-2, 5-diazabicyclo [2.2.1] hept-2-yl ] [ (7S) -4- (pyrazolo [1,5-a ] pyridin-5-ylamino) -5,6,7, 8-tetrahydro [1] benzothieno [2,3-d ] pyrimidin-7-yl ] methanone

75 mg (205 μmol) of (7S) -4- (pyrazolo [1,5-a ] pyridin-5-ylamino) -5,6,7, 8-tetrahydro [1] benzothieno [2,3-d ] pyrimidine-7-carboxylic acid (prepared according to example 2) was converted in analogy to example 16 using (1R,4R) -2-methyl-2, 5-diazabicyclo [2.2.1] heptane to yield 74.8 mg (71%) of the title compound after work-up and purification.

Example 43

(7S) -4- [ (6-chloropyrazolo [1,5-a ] pyridin-5-yl) amino ] -N- (3,3, 3-trifluoropropyl) -5,6,7, 8-tetrahydro [1] benzothieno [2,3-d ] pyrimidine-7-carboxamide

Comprising 75 mg (188 μmol) (7S) -4- [ (6-chloropyrazolo [1,5-a ] pyridin-5-yl) amino ] -5,6,7, 8-tetrahydro [1] benzothieno [2,3-d ] pyrimidine-7-carboxylic acid (prepared according to example 43 a), 3.65 mL N, a mixture of N-dimethylacetamide, 294 μ g of L N-ethyl-N-isopropylpropan-2-amine, 140 mg of 3,3, 3-trifluoropropan-1-aminium chloride and 335 μ g of L2, 4, 6-tripropyl-1, 3,5,2,4, 6-trioxatriphosphane 2,4, 6-trioxide solution (50% in N, N-dimethylformamide) was stirred at 23 ℃ for 5 hours. The crude mixture was concentrated and the residue was crystallized from diethyl ether and ethanol to give 46.9 mg (48%) of the title compound.

Example 43a

(7S) -4- [ (6-chloropyrazolo [1,5-a ] pyridin-5-yl) amino ] -5,6,7, 8-tetrahydro [1] benzothieno [2,3-d ] pyrimidine-7-carboxylic acid

965 mg (2.26 mmol) of ethyl (7S) -4- [ (6-chloropyrazolo [1,5-a ] pyridin-5-yl) amino ] -4b,5,6,7,8,8 a-hexahydro [1] benzothieno [2,3-d ] pyrimidine-7-carboxylate (prepared according to intermediate example 43 b) were converted in analogy to example 2 to yield 857 mg (95%) of the title compound after work-up.

Example 43b

(7S) -4- [ (6-Chloropyrazolo [1,5-a ] pyridin-5-yl) amino ] -4b,5,6,7,8,8 a-hexahydro [1] benzothieno [2,3-d ] pyrimidine-7-carboxylic acid ethyl ester

To a solution of 2.00 g (6.7 mmol) of ethyl (7S) -4-chloro-5, 6,7, 8-tetrahydro [1] benzothieno [2,3-d ] pyrimidine-7-carboxylate (prepared according to intermediate example 2 b) were added 76 mg of palladium (II) acetate, 315 mg of 1,1 '-binaphthalene-2, 2' -diylbis (diphenylphosphine), 1.10 g of 6-chloropyrazolo [1,5-a ] pyridin-5-amine (prepared according to intermediate example 43 c) and 3.29 g of cesium carbonate. The mixture was stirred at 80 ℃ for 15 hours. Water was added, the mixture was extracted with DCM and the organic layer was washed with hydrochloric acid (2M), water, brine and dried over sodium sulfate. After filtration and concentration, the residue was crystallized from ethanol to yield 1.73 mg (57%) of the title compound.

Example 43c

6-chloropyrazolo [1,5-a ] pyridin-5-amines

2.60 g (10.9 mmol) of 5-amino-6-chloro-pyrazolo [1,5-a]Pyridine-3-carboxylic acid ethyl ester (prepared according to intermediate example 43 d) in 40 mL H₂SO₄The suspension in (40%) was stirred at 100 ℃ for 4 hours. The solution was cooled to 15 ℃ and then added to 150 mL of saturated aqueous potassium carbonate solution. The mixture was extracted with dichloromethane and the combined organic layers were dried over sodium sulfate, filtered and concentrated under reduced pressure. The residue was diluted with concentrated hydrochloric acid and the solvent was removed under reduced pressure to give the crude product, which was purified by chromatography to give 1.52g (84%) of the title compound.

Example 43d

5-amino-6-chloro-pyrazolo [1,5-a ] pyridine-3-carboxylic acid ethyl ester

A mixture of 16 g (44 mmol) of ethyl 5- (tert-butoxycarbonylamino) -6-chloro-pyrazolo [1,5-a ] pyridine-3-carboxylate and ethyl 5- (tert-butoxycarbonylamino) -4-chloro-pyrazolo [1,5-a ] pyridine-3-carboxylate (prepared according to intermediate example 43 e) in 50 mL of dichloromethane and 50 mL of trifluoroacetic acid is stirred at 10 ℃ for 2 hours. The residue was diluted with saturated aqueous potassium carbonate solution, extracted with dichloromethane and concentrated. The crude product was purified by column chromatography to give 2.6 g (24%) of the title compound.

Example 43e

5- (tert-Butoxycarbonylamino) -6-chloro-pyrazolo [1,5-a ] pyridine-3-carboxylic acid ethyl ester and 5- (tert-butoxycarbonylamino) -4-chloro-pyrazolo [1,5-a ] pyridine-3-carboxylic acid ethyl ester

To a solution of 25 g of crude 1-amino-4- ((tert-butoxycarbonyl) amino) -3-chloropyridin-1-ium 2, 4-dinitrophenol (phenolate) (prepared according to intermediate example 43 f) in 100 mL of DMF was added 24.2 g of potassium carbonate. The mixture was stirred at 20 ℃ for 1 hour, 5.73 g of ethyl propiolate were added, and the mixture was stirred at 20 ℃ for 18 hours. The mixture was diluted with water, extracted with ethyl acetate and concentrated. The residue was purified by chromatography to give 8.0 g (60%) of a mixture of the title compounds.

Example 43f

1-amino-4- ((tert-butoxycarbonyl) amino) -3-chloropyridin-1-ium 2, 4-dinitrophenol

A solution of 9.0 g (39.4 mmol) of tert-butyl N- (3-chloro-4-pyridinyl) carbamate (prepared according to WO 2008130021) and 15.7 g O- (2, 4-dinitrophenyl) hydroxylamine in 120 mL of acetonitrile is stirred at 50 ℃ for 40 hours. The mixture was evaporated under reduced pressure to give 25 g of crude product, which was used without further purification.

Example 44

(7S) -4- [ (6-chloropyrazolo [1,5-a ] pyridin-5-yl) amino ] -N- (prop-2-yl) -5,6,7, 8-tetrahydro [1] benzothieno [2,3-d ] pyrimidine-7-carboxamide

75 mg (188 μmol) of (7S) -4- [ (6-chloropyrazolo [1,5-a ] pyridin-5-yl) amino ] -5,6,7, 8-tetrahydro [1] benzothieno [2,3-d ] pyrimidine-7-carboxylic acid (prepared according to example 43 a) were converted in analogy to example 43 using propan-2-amine to yield 56.5 mg (65%) of the title compound after workup and purification.

Example 45

(7S) -4- [ (6-chloropyrazolo [1,5-a ] pyridin-5-yl) amino ] -N, N-dimethyl-5, 6,7, 8-tetrahydro [1] benzothieno [2,3-d ] pyrimidine-7-carboxamide

75 mg (188 μmol) of (7S) -4- [ (6-chloropyrazolo [1,5-a ] pyridin-5-yl) amino ] -5,6,7, 8-tetrahydro [1] benzothieno [2,3-d ] pyrimidine-7-carboxylic acid (prepared according to example 43 a) were converted in analogy to example 43 using N-methylmethylamine to yield 42.6 mg (51%) of the title compound after work-up and purification.

Example 46

(7S) -4- [ (6-chloropyrazolo [1,5-a ] pyridin-5-yl) amino ] -N-ethyl-N-methyl-5, 6,7, 8-tetrahydro [1] benzothieno [2,3-d ] pyrimidine-7-carboxamide

75 mg (188 μmol) of (7S) -4- [ (6-chloropyrazolo [1,5-a ] pyridin-5-yl) amino ] -5,6,7, 8-tetrahydro [1] benzothieno [2,3-d ] pyrimidine-7-carboxylic acid (prepared according to example 43 a) were converted in analogy to example 43 using N-methylethylamine to yield 66.1 mg (83%) of the title compound after work-up and purification.

Example 47

(7S) -4- [ (6-chloropyrazolo [1,5-a ] pyridin-5-yl) amino ] -N- (2, 2-difluoroethyl) -N-methyl-5, 6,7, 8-tetrahydro [1] benzothieno [2,3-d ] pyrimidine-7-carboxamide

75 mg (188 μmol) of (7S) -4- [ (6-chloropyrazolo [1,5-a ] pyridin-5-yl) amino ] -5,6,7, 8-tetrahydro [1] benzothieno [2,3-d ] pyrimidine-7-carboxylic acid (prepared according to example 43 a) were converted in analogy to example 43 using 2, 2-difluoro-N-methylethylamine to yield 67.1 mg (71%) of the title compound after work-up and purification.

Example 48

(7S) -4- [ (6-chloropyrazolo [1,5-a ] pyridin-5-yl) amino ] -N-methyl-N- (3,3, 3-trifluoropropyl) -5,6,7, 8-tetrahydro [1] benzothieno [2,3-d ] pyrimidine-7-carboxamide

75 mg (188 μmol) of (7S) -4- [ (6-chloropyrazolo [1,5-a ] pyridin-5-yl) amino ] -5,6,7, 8-tetrahydro [1] benzothieno [2,3-d ] pyrimidine-7-carboxylic acid (prepared according to example 43 a) were converted analogously to example 43 using 3,3, 3-trifluoro-N-methylpropane-1-ammonium chloride to yield 68.9 mg (69%) of the title compound after work-up and purification.

Example 49

(7S) -N-butyl-4- [ (6-chloropyrazolo [1,5-a ] pyridin-5-yl) amino ] -N-methyl-5, 6,7, 8-tetrahydro [1] benzothieno [2,3-d ] pyrimidine-7-carboxamide

75 mg (188 μmol) of (7S) -4- [ (6-chloropyrazolo [1,5-a ] pyridin-5-yl) amino ] -5,6,7, 8-tetrahydro [1] benzothieno [2,3-d ] pyrimidine-7-carboxylic acid (prepared according to example 43 a) were converted in analogy to example 43 using N-methylbutan-1-amine to yield 75.3 mg (81%) of the title compound after workup and purification.

Example 50

1- ((7S) -4- [ (6-chloropyrazolo [1,5-a ] pyridin-5-yl) amino ] -5,6,7, 8-tetrahydro [1] benzothieno [2,3-d ] pyrimidin-7-ylcarbonyl) azetidine-3-carbonitrile

75 mg (188. mu. mol) of (7S) -4- [ (6-chloropyrazolo [1,5-a ] pyridin-5-yl) amino ] -5,6,7, 8-tetrahydro [1] benzothieno [2,3-d ] pyrimidine-7-carboxylic acid (prepared according to example 43 a) were converted analogously to example 43 using 3-cyanoazetidinium chloride to yield 34.2 mg (46%) of the title compound after workup and purification.

Example 51

(7S) -4- [ (6-chloropyrazolo [1,5-a ] pyridin-5-yl) amino ] -N- [3- (dimethylamino) propyl ] -N-methyl-5, 6,7, 8-tetrahydro [1] benzothieno [2,3-d ] pyrimidine-7-carboxamide

75 mg (188. mu. mol) of (7S) -4- [ (6-chloropyrazolo [1,5-a ] pyridin-5-yl) amino ] -5,6,7, 8-tetrahydro [1] benzothieno [2,3-d ] pyrimidine-7-carboxylic acid (prepared according to example 43 a) were converted analogously to example 43 using N, N, N' -trimethylpropane-1, 3-diamine to yield 72.3 mg (74%) of the title compound after work-up and purification.

Example 52

(7S) -4- [ (6-chloropyrazolo [1,5-a ] pyridin-5-yl) amino ] -5,6,7, 8-tetrahydro [1] benzothieno [2,3-d ] pyrimidin-7-yl (3-hydroxy-3-methylazetidin-1-yl) methanone

40 mg (100. mu. mol) of (7S) -4- [ (6-chloropyrazolo [1,5-a ] pyridin-5-yl) amino ] -5,6,7, 8-tetrahydro [1] benzothieno [2,3-d ] pyrimidine-7-carboxylic acid (prepared according to example 43 a) were converted analogously to example 43 using 3-hydroxy-3-methylazetidinium chloride to yield 40.6 mg (82%) of the title compound after work-up and purification.

Example 53

(7S) -4- [ (6-chloropyrazolo [1,5-a ] pyridin-5-yl) amino ] -N- [2- (dimethylamino) ethyl ] -N-methyl-5, 6,7, 8-tetrahydro [1] benzothieno [2,3-d ] pyrimidine-7-carboxamide

75 mg (188. mu. mol) of (7S) -4- [ (6-chloropyrazolo [1,5-a ] pyridin-5-yl) amino ] -5,6,7, 8-tetrahydro [1] benzothieno [2,3-d ] pyrimidine-7-carboxylic acid (prepared according to example 43 a) were converted analogously to example 43 using N, N, N' -trimethylethane-1, 2-diamine to yield 71.1 mg (74%) of the title compound after work-up and purification.

Example 54

(7S) -4- [ (6-chloropyrazolo [1,5-a ] pyridin-5-yl) amino ] -5,6,7, 8-tetrahydro [1] benzothieno [2,3-d ] pyrimidin-7-yl [3- (dimethylamino) azetidin-1-yl ] methanone

40 mg (100 μmol) of (7S) -4- [ (6-chloropyrazolo [1,5-a ] pyridin-5-yl) amino ] -5,6,7, 8-tetrahydro [1] benzothieno [2,3-d ] pyrimidine-7-carboxylic acid (prepared according to example 43 a) were converted analogously to example 43 using 3- (dimethylammonio) azetidinium dichloride in order to yield 35.5 mg (70%) of the title compound after work-up and purification.

Example 55

(7S) -4- [ (6-chloropyrazolo [1,5-a ] pyridin-5-yl) amino ] -N- (2-hydroxyethyl) -N-methyl-5, 6,7, 8-tetrahydro [1] benzothieno [2,3-d ] pyrimidine-7-carboxamide

75 mg (188 μmol) of (7S) -4- [ (6-chloropyrazolo [1,5-a ] pyridin-5-yl) amino ] -5,6,7, 8-tetrahydro [1] benzothieno [2,3-d ] pyrimidine-7-carboxylic acid (prepared according to example 43 a) were converted analogously to example 43 using 2- (methylamino) ethanol to yield 30.3 mg (34%) of the title compound after work-up and purification.

Example 56

(7S) -4- [ (6-chloropyrazolo [1,5-a ] pyridin-5-yl) amino ] -N- (2-methoxyethyl) -N-methyl-5, 6,7, 8-tetrahydro [1] benzothieno [2,3-d ] pyrimidine-7-carboxamide

75 mg (188 μmol) of (7S) -4- [ (6-chloropyrazolo [1,5-a ] pyridin-5-yl) amino ] -5,6,7, 8-tetrahydro [1] benzothieno [2,3-d ] pyrimidine-7-carboxylic acid (prepared according to example 43 a) were converted in analogy to example 43 using 2-methoxy-N-methylethylamine to yield 78.1 mg (84%) of the title compound after workup and purification.

Example 57

(7S) -4- [ (6-chloropyrazolo [1,5-a ] pyridin-5-yl) amino ] -N-methyl-N- (prop-2-yl) -5,6,7, 8-tetrahydro [1] benzothieno [2,3-d ] pyrimidine-7-carboxamide

75 mg (188 μmol) of (7S) -4- [ (6-chloropyrazolo [1,5-a ] pyridin-5-yl) amino ] -5,6,7, 8-tetrahydro [1] benzothieno [2,3-d ] pyrimidine-7-carboxylic acid (prepared according to example 43 a) were converted in analogy to example 43 using N-methylpropan-2-amine to yield 65.5 mg (73%) of the title compound after workup and purification.

Example 58

(7S) -4- [ (6-chloropyrazolo [1,5-a ] pyridin-5-yl) amino ] -5,6,7, 8-tetrahydro [1] benzothieno [2,3-d ] pyrimidin-7-yl [ (3R) -3- (dimethylamino) pyrrolidin-1-yl ] methanone

40 mg (100 μmol) of (7S) -4- [ (6-chloropyrazolo [1,5-a ] pyridin-5-yl) amino ] -5,6,7, 8-tetrahydro [1] benzothieno [2,3-d ] pyrimidine-7-carboxylic acid (prepared according to example 43 a) were converted in analogy to example 43 using (3R) -N, N-dimethylpyrrolidin-3-amine, so as to obtain 41.3 mg (79%) of the title compound after work-up and purification.

Example 59

(7S) -4- [ (6-chloropyrazolo [1,5-a ] pyridin-5-yl) amino ] -5,6,7, 8-tetrahydro [1] benzothieno [2,3-d ] pyrimidin-7-yl [ (3S) -3- (dimethylamino) pyrrolidin-1-yl ] methanone

40 mg (100 μmol) of (7S) -4- [ (6-chloropyrazolo [1,5-a ] pyridin-5-yl) amino ] -5,6,7, 8-tetrahydro [1] benzothieno [2,3-d ] pyrimidine-7-carboxylic acid (prepared according to example 43 a) were converted in analogy to example 43 using (3S) -N, N-dimethylpyrrolidin-3-amine, so as to yield 39.4 mg (75%) of the title compound after work-up and purification.

Example 60

(7S) -4- [ (6-chloropyrazolo [1,5-a ] pyridin-5-yl) amino ] -5,6,7, 8-tetrahydro [1] benzothieno [2,3-d ] pyrimidin-7-yl [ (3S,4S) -3, 4-dihydroxypyrrolidin-1-yl ] methanone

40 mg (100 μmol) of (7S) -4- [ (6-chloropyrazolo [1,5-a ] pyridin-5-yl) amino ] -5,6,7, 8-tetrahydro [1] benzothieno [2,3-d ] pyrimidine-7-carboxylic acid (prepared according to example 43 a) were converted in analogy to example 43 using (3S,4S) -pyrrolidine-3, 4-diol to yield 74.8 mg (51%) of the title compound after work-up and purification.

Example 61

(7S) -4- [ (6-chloropyrazolo [1,5-a ] pyridin-5-yl) amino ] -5,6,7, 8-tetrahydro [1] benzothieno [2,3-d ] pyrimidin-7-yl [4- (dimethylamino) piperidin-1-yl ] methanone

40 mg (100 μmol) of (7S) -4- [ (6-chloropyrazolo [1,5-a ] pyridin-5-yl) amino ] -5,6,7, 8-tetrahydro [1] benzothieno [2,3-d ] pyrimidine-7-carboxylic acid (prepared according to example 43 a) were converted analogously to example 43 using N, N-dimethylpiperidin-4-amine to yield 40.1 mg (75%) of the title compound after work-up and purification.

Example 62

(7S) -4- [ (6-chloropyrazolo [1,5-a ] pyridin-5-yl) amino ] -5,6,7, 8-tetrahydro [1] benzothieno [2,3-d ] pyrimidin-7-yl (4- [2- (dimethylamino) ethyl ] (methyl) aminopiperidin-1-yl) methanone

40 mg (100 μmol) of (7S) -4- [ (6-chloropyrazolo [1,5-a ] pyridin-5-yl) amino ] -5,6,7, 8-tetrahydro [1] benzothieno [2,3-d ] pyrimidine-7-carboxylic acid (prepared according to example 43 a) were converted in analogy to example 43 using 4- { [2- (dimethylammonio) ethyl ] (methyl) ammonio } piperidinium trichloride to yield 32.7 mg (55%) of the title compound after workup and purification.

Example 63

(7S) -4- [ (6-chloropyrazolo [1,5-a ] pyridin-5-yl) amino ] -N- [3- (dimethylamino) propyl ] -N- (2-hydroxyethyl) -5,6,7, 8-tetrahydro [1] benzothieno [2,3-d ] pyrimidine-7-carboxamide

40 mg (100 μmol) of (7S) -4- [ (6-chloropyrazolo [1,5-a ] pyridin-5-yl) amino ] -5,6,7, 8-tetrahydro [1] benzothieno [2,3-d ] pyrimidine-7-carboxylic acid (prepared according to example 43 a) were converted analogously to example 43 using 2- { [3- (dimethylamino) propyl ] amino } ethanol to yield 74.8 mg (71%) of the title compound after work-up and purification.

Example 64

(7S) -4- [ (6-chloropyrazolo [1,5-a ] pyridin-5-yl) amino ] -5,6,7, 8-tetrahydro [1] benzothieno [2,3-d ] pyrimidin-7-yl [ (2R,6S) -2, 6-dimethylmorpholin-4-yl ] methanone

75 mg (188 μmol) of (7S) -4- [ (6-chloropyrazolo [1,5-a ] pyridin-5-yl) amino ] -5,6,7, 8-tetrahydro [1] benzothieno [2,3-d ] pyrimidine-7-carboxylic acid (prepared according to example 43 a) were converted in analogy to example 43 using (2R,6S) -2, 6-dimethylmorpholine to yield 44.0 mg (45%) of the title compound after work-up and purification.

Example 65

(7S) -4- [ (6-chloropyrazolo [1,5-a ] pyridin-5-yl) amino ] -5,6,7, 8-tetrahydro [1] benzothieno [2,3-d ] pyrimidin-7-yl (4-methylpiperazin-1-yl) methanone

40 mg (100 μmol) of (7S) -4- [ (6-chloropyrazolo [1,5-a ] pyridin-5-yl) amino ] -5,6,7, 8-tetrahydro [1] benzothieno [2,3-d ] pyrimidine-7-carboxylic acid (prepared according to example 43 a) were converted in analogy to example 43 using 1-methylpiperazine to yield 37.6 mg (74%) of the title compound after work-up and purification.

Example 66

(7S) -4- [ (6-chloropyrazolo [1,5-a ] pyridin-5-yl) amino ] -5,6,7, 8-tetrahydro [1] benzothieno [2,3-d ] pyrimidin-7-yl 4- [2- (dimethylamino) ethyl ] piperazin-1-yl methanone

40 mg (100 μmol) of (7S) -4- [ (6-chloropyrazolo [1,5-a ] pyridin-5-yl) amino ] -5,6,7, 8-tetrahydro [1] benzothieno [2,3-d ] pyrimidine-7-carboxylic acid (prepared according to example 43 a) were converted in analogy to example 43 using N, N-dimethyl-2- (piperazin-1-yl) ethylamine to yield 38.9 mg (69%) of the title compound after work-up and purification.

Example 67

(7S) -4- [ (6-chloropyrazolo [1,5-a ] pyridin-5-yl) amino ] -N- [2- (dimethylamino) ethyl ] -N-ethyl-5, 6,7, 8-tetrahydro [1] benzothieno [2,3-d ] pyrimidine-7-carboxamide

75 mg (188. mu. mol) of (7S) -4- [ (6-chloropyrazolo [1,5-a ] pyridin-5-yl) amino ] -5,6,7, 8-tetrahydro [1] benzothieno [2,3-d ] pyrimidine-7-carboxylic acid (prepared according to example 43 a) were converted analogously to example 43 using N' -ethyl-N, N-dimethylethane-1, 2-diamine to yield 61.7 mg (63%) of the title compound after work-up and purification.

Example 68

(7S) -4- [ (6-chloropyrazolo [1,5-a ] pyridin-5-yl) amino ] -5,6,7, 8-tetrahydro [1] benzothieno [2,3-d ] pyrimidin-7-yl (morpholin-4-yl) methanone

75 mg (188 μmol) of (7S) -4- [ (6-chloropyrazolo [1,5-a ] pyridin-5-yl) amino ] -5,6,7, 8-tetrahydro [1] benzothieno [2,3-d ] pyrimidine-7-carboxylic acid (prepared according to example 43 a) were converted in analogy to example 43 using morpholine to yield 61.7 mg (63%) of the title compound after work-up and purification.

Example 69

(7S) -4- [ (6-chloropyrazolo [1,5-a ] pyridin-5-yl) amino ] -N-ethyl-N- (2-hydroxyethyl) -5,6,7, 8-tetrahydro [1] benzothieno [2,3-d ] pyrimidine-7-carboxamide

75 mg (188 μmol) of (7S) -4- [ (6-chloropyrazolo [1,5-a ] pyridin-5-yl) amino ] -5,6,7, 8-tetrahydro [1] benzothieno [2,3-d ] pyrimidine-7-carboxylic acid (prepared according to example 43 a) were converted analogously to example 43 using 2- (ethylamino) ethanol to yield 67.4 mg (72%) of the title compound after work-up and purification.

Example 70

(7S) -4- [ (6-chloropyrazolo [1,5-a ] pyridin-5-yl) amino ] -N-ethyl-N- (2-methoxyethyl) -5,6,7, 8-tetrahydro [1] benzothieno [2,3-d ] pyrimidine-7-carboxamide

75 mg (188 μmol) of (7S) -4- [ (6-chloropyrazolo [1,5-a ] pyridin-5-yl) amino ] -5,6,7, 8-tetrahydro [1] benzothieno [2,3-d ] pyrimidine-7-carboxylic acid (prepared according to example 43 a) were converted in analogy to example 43 using N-ethyl-2-methoxyethylamine to yield 72.7 mg (76%) of the title compound after workup and purification.

Example 71

(7S) -4- [ (6-chloropyrazolo [1,5-a ] pyridin-5-yl) amino ] -N, N-bis (2-methoxyethyl) -5,6,7, 8-tetrahydro [1] benzothieno [2,3-d ] pyrimidine-7-carboxamide

75 mg (188 μmol) of (7S) -4- [ (6-chloropyrazolo [1,5-a ] pyridin-5-yl) amino ] -5,6,7, 8-tetrahydro [1] benzothieno [2,3-d ] pyrimidine-7-carboxylic acid (prepared according to example 43 a) were converted in analogy to example 43 using 2-methoxy-N- (2-methoxyethyl) ethylamine to yield 81.4 mg (80%) of the title compound after work-up and purification.

Example 72

(7S) -4- [ (6-chloropyrazolo [1,5-a ] pyridin-5-yl) amino ] -5,6,7, 8-tetrahydro [1] benzothieno [2,3-d ] pyrimidin-7-yl [ (1S,4S) -5-methyl-2, 5-diazabicyclo [2.2.1] hept-2-yl ] methanone

40 mg (100. mu. mol) of (7S) -4- [ (6-chloropyrazolo [1,5-a ] pyridin-5-yl) amino ] -5,6,7, 8-tetrahydro [1] benzothieno [2,3-d ] pyrimidine-7-carboxylic acid (prepared according to example 43 a) were converted in analogy to example 43 using (1S,4S) -2-methyl-2, 5-diazoniabicyclo [2.2.1] heptane dibromide to yield 33.7 mg (65%) of the title compound after workup and purification.

Example 73

(7S) -4- [ (6-chloropyrazolo [1,5-a ] pyridin-5-yl) amino ] -5,6,7, 8-tetrahydro [1] benzothieno [2,3-d ] pyrimidin-7-yl [ (1R,4R) -5-methyl-2, 5-diazabicyclo [2.2.1] hept-2-yl ] methanone

40 mg (100. mu. mol) of (7S) -4- [ (6-chloropyrazolo [1,5-a ] pyridin-5-yl) amino ] -5,6,7, 8-tetrahydro [1] benzothieno [2,3-d ] pyrimidine-7-carboxylic acid (prepared according to example 43 a) were converted in analogy to example 43 using (1R,4R) -2-methyl-2, 5-diazoniabicyclo [2.2.1] heptane dibromide to yield 38.6 mg (74%) of the title compound after workup and purification.

Example 74

(7S) -4- [ (6-chloropyrazolo [1,5-a ] pyridin-5-yl) amino ] -5,6,7, 8-tetrahydro [1] benzothieno [2,3-d ] pyrimidin-7-yl [ (1S,4S) -2-oxa-5-azabicyclo [2.2.1] hept-5-yl ] methanone

40 mg (100. mu. mol) of (7S) -4- [ (6-chloropyrazolo [1,5-a ] pyridin-5-yl) amino ] -5,6,7, 8-tetrahydro [1] benzothieno [2,3-d ] pyrimidine-7-carboxylic acid (prepared according to example 43 a) were converted analogously to example 43 using (1S,4S) -2-oxa-5-azoniabicyclo [2.2.1] heptanechloride to yield 35.3 mg (70%) of the title compound after work-up and purification.

Example 75

(7S) -4- [ (6-chloropyrazolo [1,5-a ] pyridin-5-yl) amino ] -5,6,7, 8-tetrahydro [1] benzothieno [2,3-d ] pyrimidin-7-yl [ (1R,4R) -2-oxa-5-azabicyclo [2.2.1] hept-5-yl ] methanone

40 mg (100. mu. mol) of (7S) -4- [ (6-chloropyrazolo [1,5-a ] pyridin-5-yl) amino ] -5,6,7, 8-tetrahydro [1] benzothieno [2,3-d ] pyrimidine-7-carboxylic acid (prepared according to example 43 a) were converted analogously to example 43 using (1R,4R) -2-oxa-5-azoniabicyclo [2.2.1] heptanechloride to yield 38.2 mg (75%) of the title compound after work-up and purification.

Example 76

(7S) -4- [ (6-chloropyrazolo [1,5-a ] pyridin-5-yl) amino ] -5,6,7, 8-tetrahydro [1] benzothieno [2,3-d ] pyrimidin-7-yl [ (3S) -3-methylmorpholin-4-yl ] methanone

40 mg (100 μmol) of (7S) -4- [ (6-chloropyrazolo [1,5-a ] pyridin-5-yl) amino ] -5,6,7, 8-tetrahydro [1] benzothieno [2,3-d ] pyrimidine-7-carboxylic acid (prepared according to example 43 a) were converted in analogy to example 43 using (3S) -3-methylmorpholine to yield 37.4 mg (74%) of the title compound after work-up and purification.

Example 77

(7S) -4- [ (6-chloropyrazolo [1,5-a ] pyridin-5-yl) amino ] -5,6,7, 8-tetrahydro [1] benzothieno [2,3-d ] pyrimidin-7-yl [ (3R) -3-methylmorpholin-4-yl ] methanone

40 mg (100 μmol) of (7S) -4- [ (6-chloropyrazolo [1,5-a ] pyridin-5-yl) amino ] -5,6,7, 8-tetrahydro [1] benzothieno [2,3-d ] pyrimidine-7-carboxylic acid (prepared according to example 43 a) were converted in analogy to example 43 using (3R) -3-methylmorpholine to yield 35.7 mg (70%) of the title compound after work-up and purification.

Example 78

(7S) -4- [ (6-methoxypyrazolo [1,5-a ] pyridin-5-yl) amino ] -N-methyl-5, 6,7, 8-tetrahydro [1] benzothieno [2,3-d ] pyrimidine-7-carboxamide

50 mg (126 μmol) of (7S) -4- [ (6-methoxypyrazolo [1,5-a ] pyridin-5-yl) amino ] -5,6,7, 8-tetrahydro [1] benzothieno [2,3-d ] pyrimidine-7-carboxylic acid (prepared according to example 78 a) was converted using methylamine in analogy to example 43 to yield 39.0 mg (72%) of the title compound after work-up and purification.

Example 78a

(7S) -4- [ (6-methoxypyrazolo [1,5-a ] pyridin-5-yl) amino ] -5,6,7, 8-tetrahydro [1] benzothieno [2,3-d ] pyrimidine-7-carboxylic acid

1.98 g (4.68 mmol) of ethyl (7S) -4- [ (6-methoxypyrazolo [1,5-a ] pyridin-5-yl) amino ] -5,6,7, 8-tetrahydro [1] benzothieno [2,3-d ] pyrimidine-7-carboxylate (prepared according to intermediate example 78 b) were converted in analogy to example 2 to yield 1.85 g (99%) of the title compound after work-up.

Example 78b

(7S) -4- [ (6-Methoxypyrazolo [1,5-a ] pyridin-5-yl) amino ] -5,6,7, 8-tetrahydro [1] benzothieno [2,3-d ] pyrimidine-7-carboxylic acid ethyl ester

2.20 g (7.41 mmol) of ethyl (7S) -4-chloro-5, 6,7, 8-tetrahydro [1] benzothieno [2,3-d ] pyrimidine-7-carboxylate (prepared according to intermediate example 2 b) were converted in analogy to example 43b using 6-methoxypyrazolo [1,5-a ] pyridin-5-amine (prepared according to intermediate example 78 c) so as to yield 1.98 g (63%) of the title compound after work-up.

Example 78c

6-methoxy pyrazolo [1,5-a ] pyridin-5-amine

2.10 g (6.26 mmol) of ethyl 5- [ (tert-butoxycarbonyl) amino ] -6-methoxypyrazolo [1,5-a ] pyridine-3-carboxylate (prepared according to intermediate example 78 d) were converted in analogy to intermediate example 43c to yield 220 mg (17%) of the title compound isolated as the HCl salt after work-up.

Example 78d

5- [ (tert-Butoxycarbonyl) amino ] -6-methoxypyrazolo [1,5-a ] pyridine-3-carboxylic acid ethyl ester

28 g of crude 1-amino-4- [ (tert-butoxycarbonyl) amino ] -3-methoxypyridinium 2, 4-dinitrophenol (phenolate), prepared according to intermediate example 78e, were converted analogously to intermediate example 43e to yield 2.10 g of the title compound after work-up.

Example 78e

1-amino-4- [ (tert-butoxycarbonyl) amino ] -3-methoxypyridinium 2, 4-dinitrophenol (phenolate)

10.0 g (44.6 mmol) of tert-butyl (3-methoxypyridin-4-yl) carbamate (prepared according to intermediate example 78 f) were converted in analogy to intermediate example 43f to yield 56 g of the crude title compound after work-up.

Example 78f

(3-methoxypyridin-4-yl) carbamic acid tert-butyl ester

To a suspension of 25.0 g of 3-methoxypyridin-4-amine (201.39 mmol) in 100 mL THF at 0 deg.C was added 402.8 mL lithium bis (trimethylsilyl) amide (1M in tetrahydrofuran). After stirring for 1 hour, 48.4 g of di-tert-butyl dicarbonate was added to the reaction mixture. The reaction mixture was stirred at 0 ℃ for 3 hours, poured into saturated ammonium chloride, and extracted with ethyl acetate. The combined organic layers were dried over magnesium sulfate, filtered and concentrated under reduced pressure. The residue was purified by column chromatography to give 37 g of crude product, which was triturated with petroleum ether to give 20 g of the title compound.

Example 79

(7S) -N- (2, 2-difluoroethyl) -4- [ (6-methoxypyrazolo [1,5-a ] pyridin-5-yl) amino ] -5,6,7, 8-tetrahydro [1] benzothieno [2,3-d ] pyrimidine-7-carboxamide

50 mg (126 μmol) of (7S) -4- [ (6-methoxypyrazolo [1,5-a ] pyridin-5-yl) amino ] -5,6,7, 8-tetrahydro [1] benzothieno [2,3-d ] pyrimidine-7-carboxylic acid (prepared according to example 78 a) was converted in analogy to example 43 using 2, 2-difluoroethylamine to give 46.3 mg (76%) of the title compound after work-up and purification.

Example 80

(7S) -4- [ (6-methoxypyrazolo [1,5-a ] pyridin-5-yl) amino ] -N- (3,3, 3-trifluoropropyl) -5,6,7, 8-tetrahydro [1] benzothieno [2,3-d ] pyrimidine-7-carboxamide

75 mg (190. mu. mol) of (7S) -4- [ (6-methoxypyrazolo [1,5-a ] pyridin-5-yl) amino ] -5,6,7, 8-tetrahydro [1] benzothieno [2,3-d ] pyrimidine-7-carboxylic acid (prepared according to example 78 a) were converted in analogy to example 43 using 3,3, 3-trifluoropropan-1-ammonium chloride to yield 47.5 mg (49%) of the title compound after workup and purification.

Example 81

(7S) -N- (2-hydroxy-2-methylpropyl) -4- [ (6-methoxypyrazolo [1,5-a ] pyridin-5-yl) amino ] -5,6,7, 8-tetrahydro [1] benzothieno [2,3-d ] pyrimidine-7-carboxamide

50 mg (126 μmol) of (7S) -4- [ (6-methoxypyrazolo [1,5-a ] pyridin-5-yl) amino ] -5,6,7, 8-tetrahydro [1] benzothieno [2,3-d ] pyrimidine-7-carboxylic acid (prepared according to example 78 a) were converted in analogy to example 43 using 1-amino-2-methylpropan-2-ol to yield 39.4 mg (63%) of the title compound after work-up and purification.

Example 82

(7S) -N- [2- (dimethylamino) ethyl ] -4- [ (6-methoxypyrazolo [1,5-a ] pyridin-5-yl) amino ] -5,6,7, 8-tetrahydro [1] benzothieno [2,3-d ] pyrimidine-7-carboxamide

50 mg (126 μmol) of (7S) -4- [ (6-methoxypyrazolo [1,5-a ] pyridin-5-yl) amino ] -5,6,7, 8-tetrahydro [1] benzothieno [2,3-d ] pyrimidine-7-carboxylic acid (prepared according to example 78 a) were converted in analogy to example 43 using N, N-dimethylethane-1, 2-diamine to yield 44.8 mg (72%) of the title compound after work-up and purification.

Example 83

(7S) -N- (2-hydroxyethyl) -4- [ (6-methoxypyrazolo [1,5-a ] pyridin-5-yl) amino ] -5,6,7, 8-tetrahydro [1] benzothieno [2,3-d ] pyrimidine-7-carboxamide

50 mg (126 μmol) of (7S) -4- [ (6-methoxypyrazolo [1,5-a ] pyridin-5-yl) amino ] -5,6,7, 8-tetrahydro [1] benzothieno [2,3-d ] pyrimidine-7-carboxylic acid (prepared according to example 78 a) were converted in analogy to example 43 using 2-aminoethanol to yield 15.8 mg (27%) of the title compound after work-up and purification.

Example 84

(7S) -N- (2-methoxyethyl) -4- [ (6-methoxypyrazolo [1,5-a ] pyridin-5-yl) amino ] -5,6,7, 8-tetrahydro [1] benzothieno [2,3-d ] pyrimidine-7-carboxamide

50 mg (126 μmol) of (7S) -4- [ (6-methoxypyrazolo [1,5-a ] pyridin-5-yl) amino ] -5,6,7, 8-tetrahydro [1] benzothieno [2,3-d ] pyrimidine-7-carboxylic acid (prepared according to example 78 a) were converted in analogy to example 43 using 2-methoxyethylamine to yield 40.2 mg (67%) of the title compound after work-up and purification.

Example 85

(7S) -4- [ (6-methoxypyrazolo [1,5-a ] pyridin-5-yl) amino ] -N- (prop-2-yl) -5,6,7, 8-tetrahydro [1] benzothieno [2,3-d ] pyrimidine-7-carboxamide

75 mg (190. mu. mol) of (7S) -4- [ (6-methoxypyrazolo [1,5-a ] pyridin-5-yl) amino ] -5,6,7, 8-tetrahydro [1] benzothieno [2,3-d ] pyrimidine-7-carboxylic acid (prepared according to example 78 a) were converted in analogy to example 43 using propan-2-amine to give 58.6 mg (67%) of the title compound after workup and purification.

Example 86

(7S) -N-tert-butyl-4- [ (6-methoxypyrazolo [1,5-a ] pyridin-5-yl) amino ] -5,6,7, 8-tetrahydro [1] benzothieno [2,3-d ] pyrimidine-7-carboxamide

50 mg (126 μmol) of (7S) -4- [ (6-methoxypyrazolo [1,5-a ] pyridin-5-yl) amino ] -5,6,7, 8-tetrahydro [1] benzothieno [2,3-d ] pyrimidine-7-carboxylic acid (prepared according to example 78 a) was converted in analogy to example 43 using 2-methylpropan-2-amine to yield 19.8 mg (33%) of the title compound after work-up and purification.

Example 87

(7S) -4- [ (6-methoxypyrazolo [1,5-a ] pyridin-5-yl) amino ] -N- (1-methylcyclobutyl) -5,6,7, 8-tetrahydro [1] benzothieno [2,3-d ] pyrimidine-7-carboxamide

50 mg (126 μmol) of (7S) -4- [ (6-methoxypyrazolo [1,5-a ] pyridin-5-yl) amino ] -5,6,7, 8-tetrahydro [1] benzothieno [2,3-d ] pyrimidine-7-carboxylic acid (prepared according to example 78 a) were converted in analogy to example 43 using 1-methylcyclobutylamine to yield 41.9 mg (68%) of the title compound after work-up and purification.

Example 88

(7S) -N- (4-fluorophenyl) -4- [ (6-methoxypyrazolo [1,5-a ] pyridin-5-yl) amino ] -5,6,7, 8-tetrahydro [1] benzothieno [2,3-d ] pyrimidine-7-carboxamide

40 mg (101 μmol) of (7S) -4- [ (6-methoxypyrazolo [1,5-a ] pyridin-5-yl) amino ] -5,6,7, 8-tetrahydro [1] benzothieno [2,3-d ] pyrimidine-7-carboxylic acid (prepared according to example 78 a) were converted in analogy to example 43 using 4-fluoroaniline to give 39.2 mg (75%) of the title compound after work-up and purification.

Example 89

(7S) -N- (3-chlorophenyl) -4- [ (6-methoxypyrazolo [1,5-a ] pyridin-5-yl) amino ] -5,6,7, 8-tetrahydro [1] benzothieno [2,3-d ] pyrimidine-7-carboxamide

40 mg (101 μmol) of (7S) -4- [ (6-methoxypyrazolo [1,5-a ] pyridin-5-yl) amino ] -5,6,7, 8-tetrahydro [1] benzothieno [2,3-d ] pyrimidine-7-carboxylic acid (prepared according to example 78 a) were converted in analogy to example 43 using 3-chloroaniline to give 29.9 mg (56%) of the title compound after work-up and purification.

Example 90

(7S) -N- (3, 4-dichlorophenyl) -4- [ (6-methoxypyrazolo [1,5-a ] pyridin-5-yl) amino ] -5,6,7, 8-tetrahydro [1] benzothieno [2,3-d ] pyrimidine-7-carboxamide

40 mg (101 μmol) of (7S) -4- [ (6-methoxypyrazolo [1,5-a ] pyridin-5-yl) amino ] -5,6,7, 8-tetrahydro [1] benzothieno [2,3-d ] pyrimidine-7-carboxylic acid (prepared according to example 78 a) were converted in analogy to example 43 using 3, 4-dichloroaniline to give 22.7 mg (40%) of the title compound after work-up and purification.

Example 91

(7S) -N- (3-chloro-4-fluorophenyl) -4- [ (6-methoxypyrazolo [1,5-a ] pyridin-5-yl) amino ] -5,6,7, 8-tetrahydro [1] benzothieno [2,3-d ] pyrimidine-7-carboxamide

40 mg (101 μmol) of (7S) -4- [ (6-methoxypyrazolo [1,5-a ] pyridin-5-yl) amino ] -5,6,7, 8-tetrahydro [1] benzothieno [2,3-d ] pyrimidine-7-carboxylic acid (prepared according to example 78 a) was converted in analogy to example 43 using 3-chloro-4-fluoroaniline to yield 24.9 mg (45%) of the title compound after work-up and purification.

Example 92

(7S) -N- (3-fluorophenyl) -4- [ (6-methoxypyrazolo [1,5-a ] pyridin-5-yl) amino ] -5,6,7, 8-tetrahydro [1] benzothieno [2,3-d ] pyrimidine-7-carboxamide

40 mg (101 μmol) of (7S) -4- [ (6-methoxypyrazolo [1,5-a ] pyridin-5-yl) amino ] -5,6,7, 8-tetrahydro [1] benzothieno [2,3-d ] pyrimidine-7-carboxylic acid (prepared according to example 78 a) were converted in analogy to example 43 using 3-fluoroaniline to yield 37.6 mg (72%) of the title compound after work-up and purification.

Example 93

(7S) -N- (1H-indol-5-yl) -4- [ (6-methoxypyrazolo [1,5-a ] pyridin-5-yl) amino ] -5,6,7, 8-tetrahydro [1] benzothieno [2,3-d ] pyrimidine-7-carboxamide

40 mg (101 μmol) of (7S) -4- [ (6-methoxypyrazolo [1,5-a ] pyridin-5-yl) amino ] -5,6,7, 8-tetrahydro [1] benzothieno [2,3-d ] pyrimidine-7-carboxylic acid (prepared according to example 78 a) were converted in analogy to example 43 using 1H-indol-5-amine to yield 19.6 mg (35%) of the title compound after work-up and purification.

Example 94

(7S) -N-ethyl-4- [ (6-methoxypyrazolo [1,5-a ] pyridin-5-yl) amino ] -N-methyl-5, 6,7, 8-tetrahydro [1] benzothieno [2,3-d ] pyrimidine-7-carboxamide

75 mg (190. mu. mol) of (7S) -4- [ (6-methoxypyrazolo [1,5-a ] pyridin-5-yl) amino ] -5,6,7, 8-tetrahydro [1] benzothieno [2,3-d ] pyrimidine-7-carboxylic acid (prepared according to example 78 a) were converted in analogy to example 43 using N-methylethylamine to yield 66.4 mg (76%) of the title compound after workup and purification.

Example 95

(7S) -N- (2, 2-difluoroethyl) -4- [ (6-methoxypyrazolo [1,5-a ] pyridin-5-yl) amino ] -N-methyl-5, 6,7, 8-tetrahydro [1] benzothieno [2,3-d ] pyrimidine-7-carboxamide

75 mg (190 μmol) of (7S) -4- [ (6-methoxypyrazolo [1,5-a ] pyridin-5-yl) amino ] -5,6,7, 8-tetrahydro [1] benzothieno [2,3-d ] pyrimidine-7-carboxylic acid (prepared according to example 78 a) were converted in analogy to example 43 using 2, 2-difluoro-N-methylethylamine to yield 77.7 mg (82%) of the title compound after work-up and purification.

Example 96

(7S) -4- [ (6-methoxypyrazolo [1,5-a ] pyridin-5-yl) amino ] -N-methyl-N- (3,3, 3-trifluoropropyl) -5,6,7, 8-tetrahydro [1] benzothieno [2,3-d ] pyrimidine-7-carboxamide

75 mg (190. mu. mol) of (7S) -4- [ (6-methoxypyrazolo [1,5-a ] pyridin-5-yl) amino ] -5,6,7, 8-tetrahydro [1] benzothieno [2,3-d ] pyrimidine-7-carboxylic acid (prepared according to example 78 a) were converted in analogy to example 43 using 3,3, 3-trifluoro-N-methylpropane-1-ammonium chloride to yield 81.4 mg (81%) of the title compound after work-up and purification.

Example 97

(7S) -N-butyl-4- [ (6-methoxypyrazolo [1,5-a ] pyridin-5-yl) amino ] -N-methyl-5, 6,7, 8-tetrahydro [1] benzothieno [2,3-d ] pyrimidine-7-carboxamide

75 mg (190. mu. mol) of (7S) -4- [ (6-methoxypyrazolo [1,5-a ] pyridin-5-yl) amino ] -5,6,7, 8-tetrahydro [1] benzothieno [2,3-d ] pyrimidine-7-carboxylic acid (prepared according to example 78 a) were converted in analogy to example 43 using N-methylbutan-1-amine to yield 76.0 mg (82%) of the title compound after workup and purification.

Example 98

1- ((7S) -4- [ (6-methoxypyrazolo [1,5-a ] pyridin-5-yl) amino ] -5,6,7, 8-tetrahydro [1] benzothieno [2,3-d ] pyrimidin-7-ylcarbonyl) azetidine-3-carbonitrile

75 mg (190. mu. mol) of (7S) -4- [ (6-methoxypyrazolo [1,5-a ] pyridin-5-yl) amino ] -5,6,7, 8-tetrahydro [1] benzothieno [2,3-d ] pyrimidine-7-carboxylic acid (prepared according to example 78 a) were converted in analogy to example 43 using 3-cyanoazetidinium chloride to give 79.4 mg (87%) of the title compound after workup and purification.

Example 99

(7S) -N- [3- (dimethylamino) propyl ] -4- [ (6-methoxypyrazolo [1,5-a ] pyridin-5-yl) amino ] -N-methyl-5, 6,7, 8-tetrahydro [1] benzothieno [2,3-d ] pyrimidine-7-carboxamide

75 mg (190. mu. mol) of (7S) -4- [ (6-methoxypyrazolo [1,5-a ] pyridin-5-yl) amino ] -5,6,7, 8-tetrahydro [1] benzothieno [2,3-d ] pyrimidine-7-carboxylic acid (prepared according to example 78 a) were converted in analogy to example 43 using N, N, N' -trimethylpropane-1, 3-diamine to yield 75.5 mg (77%) of the title compound after work-up and purification.

Example 100

(3-hydroxy-3-methylazetidin-1-yl) (7S) -4- [ (6-methoxypyrazolo [1,5-a ] pyridin-5-yl) amino ] -5,6,7, 8-tetrahydro [1] benzothieno [2,3-d ] pyrimidin-7-yl methanone

75 mg (190. mu. mol) of (7S) -4- [ (6-methoxypyrazolo [1,5-a ] pyridin-5-yl) amino ] -5,6,7, 8-tetrahydro [1] benzothieno [2,3-d ] pyrimidine-7-carboxylic acid (prepared according to example 78 a) were converted in analogy to example 43 using 3-hydroxy-3-methylazetidinium chloride to yield 81.5 mg (88%) of the title compound after work-up and purification.

Example 101

(7S) -N- [2- (dimethylamino) ethyl ] -4- [ (6-methoxypyrazolo [1,5-a ] pyridin-5-yl) amino ] -N-methyl-5, 6,7, 8-tetrahydro [1] benzothieno [2,3-d ] pyrimidine-7-carboxamide

75 mg (190. mu. mol) of (7S) -4- [ (6-methoxypyrazolo [1,5-a ] pyridin-5-yl) amino ] -5,6,7, 8-tetrahydro [1] benzothieno [2,3-d ] pyrimidine-7-carboxylic acid (prepared according to example 78 a) were converted in analogy to example 43 using N, N, N' -trimethylethane-1, 2-diamine to yield 64.4 mg (67%) of the title compound after work-up and purification.

Example 102

[3- (dimethylamino) azetidin-1-yl ] (7S) -4- [ (6-methoxypyrazolo [1,5-a ] pyridin-5-yl) amino ] -5,6,7, 8-tetrahydro [1] benzothieno [2,3-d ] pyrimidin-7-yl methanone

50 mg (126 μmol) of (7S) -4- [ (6-methoxypyrazolo [1,5-a ] pyridin-5-yl) amino ] -5,6,7, 8-tetrahydro [1] benzothieno [2,3-d ] pyrimidine-7-carboxylic acid (prepared according to example 78 a) were converted in analogy to example 43 using 3- (dimethylammonio) azetidinium dichloride in order to obtain 44.0 mg (69%) of the title compound after work-up and purification.

Example 103

(7S) -N- (2-hydroxyethyl) -4- [ (6-methoxypyrazolo [1,5-a ] pyridin-5-yl) amino ] -N-methyl-5, 6,7, 8-tetrahydro [1] benzothieno [2,3-d ] pyrimidine-7-carboxamide

75 mg (190. mu. mol) of (7S) -4- [ (6-methoxypyrazolo [1,5-a ] pyridin-5-yl) amino ] -5,6,7, 8-tetrahydro [1] benzothieno [2,3-d ] pyrimidine-7-carboxylic acid (prepared according to example 78 a) were converted in analogy to example 43 using 2- (methylamino) ethanol to yield 47.1 mg (52%) of the title compound after workup and purification.

Example 104

(7S) -N- (2-methoxyethyl) -4- [ (6-methoxypyrazolo [1,5-a ] pyridin-5-yl) amino ] -N-methyl-5, 6,7, 8-tetrahydro [1] benzothieno [2,3-d ] pyrimidine-7-carboxamide

75 mg (190 μmol) of (7S) -4- [ (6-methoxypyrazolo [1,5-a ] pyridin-5-yl) amino ] -5,6,7, 8-tetrahydro [1] benzothieno [2,3-d ] pyrimidine-7-carboxylic acid (prepared according to example 78 a) were converted in analogy to example 43 using 2-methoxy-N-methylethylamine to yield 73.1 mg (78%) of the title compound after workup and purification.

Example 105

(7S) -4- [ (6-methoxypyrazolo [1,5-a ] pyridin-5-yl) amino ] -N-methyl-N- (prop-2-yl) -5,6,7, 8-tetrahydro [1] benzothieno [2,3-d ] pyrimidine-7-carboxamide

75 mg (190. mu. mol) of (7S) -4- [ (6-methoxypyrazolo [1,5-a ] pyridin-5-yl) amino ] -5,6,7, 8-tetrahydro [1] benzothieno [2,3-d ] pyrimidine-7-carboxylic acid (prepared according to example 78 a) were converted in analogy to example 43 using N-methylpropan-2-amine to yield 61.6 mg (68%) of the title compound after work-up and purification.

Example 106

[ (3R) -3- (dimethylamino) pyrrolidin-1-yl ] (7S) -4- [ (6-methoxypyrazolo [1,5-a ] pyridin-5-yl) amino ] -5,6,7, 8-tetrahydro [1] benzothieno [2,3-d ] pyrimidin-7-yl-methanone

75 mg (190. mu. mol) of (7S) -4- [ (6-methoxypyrazolo [1,5-a ] pyridin-5-yl) amino ] -5,6,7, 8-tetrahydro [1] benzothieno [2,3-d ] pyrimidine-7-carboxylic acid (prepared according to example 78 a) were converted in analogy to example 43 using (3R) -N, N-dimethylpyrrolidin-3-amine, so as to yield 79.6 mg (81%) of the title compound after work-up and purification.

Example 107

[ (3S) -3- (dimethylamino) pyrrolidin-1-yl ] (7S) -4- [ (6-methoxypyrazolo [1,5-a ] pyridin-5-yl) amino ] -5,6,7, 8-tetrahydro [1] benzothieno [2,3-d ] pyrimidin-7-yl-methanone

75 mg (190. mu. mol) of (7S) -4- [ (6-methoxypyrazolo [1,5-a ] pyridin-5-yl) amino ] -5,6,7, 8-tetrahydro [1] benzothieno [2,3-d ] pyrimidine-7-carboxylic acid (prepared according to example 78 a) were converted in analogy to example 43 using (3S) -N, N-dimethylpyrrolidin-3-amine, so as to yield 81.0 mg (83%) of the title compound after work-up and purification.

Example 108

[ (3S,4S) -3, 4-dihydroxypyrrolidin-1-yl ] (7S) -4- [ (6-methoxypyrazolo [1,5-a ] pyridin-5-yl) amino ] -5,6,7, 8-tetrahydro [1] benzothieno [2,3-d ] pyrimidin-7-yl-methanone

50 mg (126 μmol) of (7S) -4- [ (6-methoxypyrazolo [1,5-a ] pyridin-5-yl) amino ] -5,6,7, 8-tetrahydro [1] benzothieno [2,3-d ] pyrimidine-7-carboxylic acid (prepared according to example 78 a) were converted in analogy to example 43 using (3S,4S) -pyrrolidine-3, 4-diol to yield 27.5 mg (43%) of the title compound after work-up and purification.

Example 109

[4- (dimethylamino) piperidin-1-yl ] (7S) -4- [ (6-methoxypyrazolo [1,5-a ] pyridin-5-yl) amino ] -5,6,7, 8-tetrahydro [1] benzothieno [2,3-d ] pyrimidin-7-yl methanone

50 mg (126 μmol) of (7S) -4- [ (6-methoxypyrazolo [1,5-a ] pyridin-5-yl) amino ] -5,6,7, 8-tetrahydro [1] benzothieno [2,3-d ] pyrimidine-7-carboxylic acid (prepared according to example 78 a) were converted in analogy to example 43 using N, N-dimethylpiperidin-4-amine to give 45.3 mg (67%) of the title compound after work-up and purification.

Example 110

(4- [2- (dimethylamino) ethyl ] (methyl) aminopiperidin-1-yl) (7S) -4- [ (6-methoxypyrazolo [1,5-a ] pyridin-5-yl) amino ] -5,6,7, 8-tetrahydro [1] benzothieno [2,3-d ] pyrimidin-7-yl methanone

40 mg (101 μmol) of (7S) -4- [ (6-methoxypyrazolo [1,5-a ] pyridin-5-yl) amino ] -5,6,7, 8-tetrahydro [1] benzothieno [2,3-d ] pyrimidine-7-carboxylic acid (prepared according to example 78 a) were converted in analogy to example 43 using 4- { [2- (dimethylammonio) ethyl ] (methyl) ammonio } piperidinium trichloride to yield 39.2 mg (65%) of the title compound after workup and purification.

Example 111

(7S) -N- [3- (dimethylamino) propyl ] -N- (2-hydroxyethyl) -4- [ (6-methoxypyrazolo [1,5-a ] pyridin-5-yl) amino ] -5,6,7, 8-tetrahydro [1] benzothieno [2,3-d ] pyrimidine-7-carboxamide

50 mg (126 μmol) of (7S) -4- [ (6-methoxypyrazolo [1,5-a ] pyridin-5-yl) amino ] -5,6,7, 8-tetrahydro [1] benzothieno [2,3-d ] pyrimidine-7-carboxylic acid (prepared according to example 78 a) were converted in analogy to example 43 using 2- { [3- (dimethylamino) propyl ] amino } ethanol to yield 54.4 mg (78%) of the title compound after work-up and purification.

Example 112

[ (2R,6S) -2, 6-dimethylmorpholin-4-yl ] (7S) -4- [ (6-methoxypyrazolo [1,5-a ] pyridin-5-yl) amino ] -5,6,7, 8-tetrahydro [1] benzothieno [2,3-d ] pyrimidin-7-yl-methanone

75 mg (190. mu. mol) of (7S) -4- [ (6-methoxypyrazolo [1,5-a ] pyridin-5-yl) amino ] -5,6,7, 8-tetrahydro [1] benzothieno [2,3-d ] pyrimidine-7-carboxylic acid (prepared according to example 78 a) were converted in analogy to example 43 using (2R,6S) -2, 6-dimethylmorpholine to yield 60.1 mg (61%) of the title compound after work-up and purification.

Example 113

(7S) -4- [ (6-methoxypyrazolo [1,5-a ] pyridin-5-yl) amino ] -5,6,7, 8-tetrahydro [1] benzothieno [2,3-d ] pyrimidin-7-yl (4-methylpiperazin-1-yl) methanone

50 mg (126 μmol) of (7S) -4- [ (6-methoxypyrazolo [1,5-a ] pyridin-5-yl) amino ] -5,6,7, 8-tetrahydro [1] benzothieno [2,3-d ] pyrimidine-7-carboxylic acid (prepared according to example 78 a) were converted in analogy to example 43 using 1-methylpiperazine to give 31.4 mg (49%) of the title compound after work-up and purification.

Example 114

4- [2- (dimethylamino) ethyl ] piperazin-1-yl (7S) -4- [ (6-methoxypyrazolo [1,5-a ] pyridin-5-yl) amino ] -5,6,7, 8-tetrahydro [1] benzothieno [2,3-d ] pyrimidin-7-yl methanone

40 mg (101 μmol) of (7S) -4- [ (6-methoxypyrazolo [1,5-a ] pyridin-5-yl) amino ] -5,6,7, 8-tetrahydro [1] benzothieno [2,3-d ] pyrimidine-7-carboxylic acid (prepared according to example 78 a) were converted in analogy to example 43 using N, N-dimethyl-2- (piperazin-1-yl) ethylamine to yield 38.4 mg (67%) of the title compound after work-up and purification.

Example 115

(7S) -N- [2- (dimethylamino) ethyl ] -N-ethyl-4- [ (6-methoxypyrazolo [1,5-a ] pyridin-5-yl) amino ] -5,6,7, 8-tetrahydro [1] benzothieno [2,3-d ] pyrimidine-7-carboxamide

75 mg (190. mu. mol) of (7S) -4- [ (6-methoxypyrazolo [1,5-a ] pyridin-5-yl) amino ] -5,6,7, 8-tetrahydro [1] benzothieno [2,3-d ] pyrimidine-7-carboxylic acid (prepared according to example 78 a) were converted in analogy to example 43 using N' -ethyl-N, N-dimethylethane-1, 2-diamine to yield 75.2 mg (76%) of the title compound after work-up and purification.

Example 116

(7S) -4- [ (6-methoxypyrazolo [1,5-a ] pyridin-5-yl) amino ] -5,6,7, 8-tetrahydro [1] benzothieno [2,3-d ] pyrimidin-7-yl (morpholin-4-yl) methanone

75 mg (190. mu. mol) of (7S) -4- [ (6-methoxypyrazolo [1,5-a ] pyridin-5-yl) amino ] -5,6,7, 8-tetrahydro [1] benzothieno [2,3-d ] pyrimidine-7-carboxylic acid (prepared according to example 78 a) were converted in analogy to example 43 using morpholine to yield 76.2 mg (82%) of the title compound after work-up and purification.

Example 117

(7S) -N-ethyl-N- (2-hydroxyethyl) -4- [ (6-methoxypyrazolo [1,5-a ] pyridin-5-yl) amino ] -5,6,7, 8-tetrahydro [1] benzothieno [2,3-d ] pyrimidine-7-carboxamide

75 mg (190. mu. mol) of (7S) -4- [ (6-methoxypyrazolo [1,5-a ] pyridin-5-yl) amino ] -5,6,7, 8-tetrahydro [1] benzothieno [2,3-d ] pyrimidine-7-carboxylic acid (prepared according to example 78 a) were converted in analogy to example 43 using 2- (methylamino) ethanol to yield 67.6 mg (73%) of the title compound after workup and purification.

Example 118

(7S) -N-ethyl-N- (2-methoxyethyl) -4- [ (6-methoxypyrazolo [1,5-a ] pyridin-5-yl) amino ] -5,6,7, 8-tetrahydro [1] benzothieno [2,3-d ] pyrimidine-7-carboxamide

75 mg (190. mu. mol) of (7S) -4- [ (6-methoxypyrazolo [1,5-a ] pyridin-5-yl) amino ] -5,6,7, 8-tetrahydro [1] benzothieno [2,3-d ] pyrimidine-7-carboxylic acid (prepared according to example 78 a) were converted in analogy to example 43 using N-ethyl-2-methoxyethylamine to yield 76.2 mg (79%) of the title compound after workup and purification.

Example 119

(7S) -N, N-bis (2-methoxyethyl) -4- [ (6-methoxypyrazolo [1,5-a ] pyridin-5-yl) amino ] -5,6,7, 8-tetrahydro [1] benzothieno [2,3-d ] pyrimidine-7-carboxamide

75 mg (190. mu. mol) of (7S) -4- [ (6-methoxypyrazolo [1,5-a ] pyridin-5-yl) amino ] -5,6,7, 8-tetrahydro [1] benzothieno [2,3-d ] pyrimidine-7-carboxylic acid (prepared according to example 78 a) were converted in analogy to example 43 using 2-methoxy-N- (2-methoxyethyl) ethylamine to yield 74.1 mg (73%) of the title compound after work-up and purification.

Example 120

(7S) -N-tert-butyl-4- [ (6-methoxypyrazolo [1,5-a ] pyridin-5-yl) amino ] -N-methyl-5, 6,7, 8-tetrahydro [1] benzothieno [2,3-d ] pyrimidine-7-carboxamide

75 mg (190. mu. mol) of (7S) -4- [ (6-methoxypyrazolo [1,5-a ] pyridin-5-yl) amino ] -5,6,7, 8-tetrahydro [1] benzothieno [2,3-d ] pyrimidine-7-carboxylic acid (prepared according to example 78 a) were converted in analogy to example 43 using N, 2-dimethylpropan-2-amine to yield 51.7 mg (56%) of the title compound after work-up and purification.

Example 121

(7S) -4- [ (6-methoxypyrazolo [1,5-a ] pyridin-5-yl) amino ] -5,6,7, 8-tetrahydro [1] benzothieno [2,3-d ] pyrimidin-7-yl [ (1S,4S) -5-methyl-2, 5-diazabicyclo [2.2.1] hept-2-yl ] methanone

40 mg (101 μmol) of (7S) -4- [ (6-methoxypyrazolo [1,5-a ] pyridin-5-yl) amino ] -5,6,7, 8-tetrahydro [1] benzothieno [2,3-d ] pyrimidine-7-carboxylic acid (prepared according to example 78 a) were converted in analogy to example 43 using (1S,4S) -2-methyl-2, 5-diazoniabicyclo [2.2.1] heptane dibromide to yield 40.4mg (78%) of the title compound after workup and purification.

Example 122

(7S) -4- [ (6-methoxypyrazolo [1,5-a ] pyridin-5-yl) amino ] -5,6,7, 8-tetrahydro [1] benzothieno [2,3-d ] pyrimidin-7-yl [ (1R,4R) -5-methyl-2, 5-diazabicyclo [2.2.1] hept-2-yl ] methanone

40 mg (101 μmol) of (7S) -4- [ (6-methoxypyrazolo [1,5-a ] pyridin-5-yl) amino ] -5,6,7, 8-tetrahydro [1] benzothieno [2,3-d ] pyrimidine-7-carboxylic acid (prepared according to example 78 a) were converted in analogy to example 43 using (1R,4R) -2-methyl-2, 5-diazoniabicyclo [2.2.1] heptane dibromide to yield 40.6mg (78%) of the title compound after work-up and purification.

Example 123

(7S) -4- [ (6-methoxypyrazolo [1,5-a ] pyridin-5-yl) amino ] -5,6,7, 8-tetrahydro [1] benzothieno [2,3-d ] pyrimidin-7-yl [ (1S,4S) -2-oxa-5-azabicyclo [2.2.1] hept-5-yl ] methanone

40 mg (101 μmol) of (7S) -4- [ (6-methoxypyrazolo [1,5-a ] pyridin-5-yl) amino ] -5,6,7, 8-tetrahydro [1] benzothieno [2,3-d ] pyrimidine-7-carboxylic acid (prepared according to example 78 a) were converted in analogy to example 43 using (1S,4S) -2-oxa-5-azoniabicyclo [2.2.1] heptanechloride to yield 37.6 mg (74%) of the title compound after work-up and purification.

Example 124

(7S) -4- [ (6-methoxypyrazolo [1,5-a ] pyridin-5-yl) amino ] -5,6,7, 8-tetrahydro [1] benzothieno [2,3-d ] pyrimidin-7-yl [ (1R,4R) -2-oxa-5-azabicyclo [2.2.1] hept-5-yl ] methanone

40 mg (101 μmol) of (7S) -4- [ (6-methoxypyrazolo [1,5-a ] pyridin-5-yl) amino ] -5,6,7, 8-tetrahydro [1] benzothieno [2,3-d ] pyrimidine-7-carboxylic acid (prepared according to example 78 a) were converted in analogy to example 43 using (1R,4R) -2-oxa-5-azoniabicyclo [2.2.1] heptanechloride to yield 40.5 mg (80%) of the title compound after work-up and purification.

Example 125

(7S) -4- [ (6-methoxypyrazolo [1,5-a ] pyridin-5-yl) amino ] -5,6,7, 8-tetrahydro [1] benzothieno [2,3-d ] pyrimidin-7-yl [ (3S) -3-methylmorpholin-4-yl ] methanone

50 mg (126 μmol) of (7S) -4- [ (6-methoxypyrazolo [1,5-a ] pyridin-5-yl) amino ] -5,6,7, 8-tetrahydro [1] benzothieno [2,3-d ] pyrimidine-7-carboxylic acid (prepared according to example 78 a) were converted in analogy to example 43 using (3S) -3-methylmorpholine to yield 52.7 mg (83%) of the title compound after work-up and purification.

Example 126

(7S) -4- [ (6-methoxypyrazolo [1,5-a ] pyridin-5-yl) amino ] -5,6,7, 8-tetrahydro [1] benzothieno [2,3-d ] pyrimidin-7-yl [ (3R) -3-methylmorpholin-4-yl ] methanone

50 mg (126 μmol) of (7S) -4- [ (6-methoxypyrazolo [1,5-a ] pyridin-5-yl) amino ] -5,6,7, 8-tetrahydro [1] benzothieno [2,3-d ] pyrimidine-7-carboxylic acid (prepared according to example 78 a) were converted in analogy to example 43 using (3R) -3-methylmorpholine to yield 50.0 mg (79%) of the title compound after work-up and purification.

The following example compounds were prepared analogously to the above method:

example 127

(7S) -N-methyl-4- (pyrazolo [1,5-a ] pyridin-5-ylamino) -N- (3,3, 3-trifluoropropyl) -5,6,7, 8-tetrahydro [1] benzothieno [2,3-d ] pyrimidine-7-carboxamide

。

Example 128

(2, 2-dimethylpyrrolidin-1-yl) [ (7S) -4- (pyrazolo [1,5-a ] pyridin-5-ylamino) -5,6,7, 8-tetrahydro [1] benzothieno [2,3-d ] pyrimidin-7-yl ] methanone

。

Example 129

(7S) -N- [ (2S) -1-methoxypropan-2-yl ] -N-methyl-4- (pyrazolo [1,5-a ] pyridin-5-ylamino) -5,6,7, 8-tetrahydro [1] benzothieno [2,3-d ] pyrimidine-7-carboxamide

。

Example 130

(7S) -N- [ (2R) -1-methoxypropan-2-yl ] -N-methyl-4- (pyrazolo [1,5-a ] pyridin-5-ylamino) -5,6,7, 8-tetrahydro [1] benzothieno [2,3-d ] pyrimidine-7-carboxamide

。

Example 131

(7S) -N- [ (2S) -2-methoxypropyl ] -N-methyl-4- (pyrazolo [1,5-a ] pyridin-5-ylamino) -5,6,7, 8-tetrahydro [1] benzothieno [2,3-d ] pyrimidine-7-carboxamide

。

Example 132

(7S) -N- [ (2R) -2-methoxypropyl ] -N-methyl-4- (pyrazolo [1,5-a ] pyridin-5-ylamino) -5,6,7, 8-tetrahydro [1] benzothieno [2,3-d ] pyrimidine-7-carboxamide

。

Example 133

(7S) -N- (1-methoxy-2-methylpropan-2-yl) -N-methyl-4- (pyrazolo [1,5-a ] pyridin-5-ylamino) -5,6,7, 8-tetrahydro [1] benzothieno [2,3-d ] pyrimidine-7-carboxamide

。

Example 134

(7S) -N- (2-hydroxy-2-methylpropyl) -4- [ (6-methoxypyrazolo [1,5-a ] pyridin-5-yl) amino ] -N-methyl-5, 6,7, 8-tetrahydro [1] benzothieno [2,3-d ] pyrimidine-7-carboxamide

。

Example 135

(7S) -N- (2-aminoethyl) -4- [ (6-methoxypyrazolo [1,5-a ] pyridin-5-yl) amino ] -N-methyl-5, 6,7, 8-tetrahydro [1] benzothieno [2,3-d ] pyrimidine-7-carboxamide

。

Example 136

(7S) -N- [2- (dimethylamino) -2-oxoethyl ] -4- [ (6-methoxypyrazolo [1,5-a ] pyridin-5-yl) amino ] -N-methyl-5, 6,7, 8-tetrahydro [1] benzothieno [2,3-d ] pyrimidine-7-carboxamide

。

Example 137

Azetidin-1-yl { (7S) -4- [ (6-methoxypyrazolo [1,5-a ] pyridin-5-yl) amino ] -5,6,7, 8-tetrahydro [1] benzothieno [2,3-d ] pyrimidin-7-yl } methanone

。

Example 138

(3, 3-Difluoroazetidin-1-yl) { (7S) -4- [ (6-methoxypyrazolo [1,5-a ] pyridin-5-yl) amino ] -5,6,7, 8-tetrahydro [1] benzothieno [2,3-d ] pyrimidin-7-yl } methanone

。

Example 139

(3-hydroxyazetidin-1-yl) { (7S) -4- [ (6-methoxypyrazolo [1,5-a ] pyridin-5-yl) amino ] -5,6,7, 8-tetrahydro [1] benzothieno [2,3-d ] pyrimidin-7-yl } methanone

。

Example 140

1- ({ (7S) -4- [ (6-methoxypyrazolo [1,5-a ] pyridin-5-yl) amino ] -5,6,7, 8-tetrahydro [1] benzothieno [2,3-d ] pyrimidin-7-yl } carbonyl) piperidin-4-one

。

Example 141

(3, 3-difluoropyrrolidin-1-yl) { (7S) -4- [ (6-methoxypyrazolo [1,5-a ] pyridin-5-yl) amino ] -5,6,7, 8-tetrahydro [1] benzothieno [2,3-d ] pyrimidin-7-yl } methanone

。

Example 142

(2, 2-dimethylpyrrolidin-1-yl) { (7S) -4- [ (6-methoxypyrazolo [1,5-a ] pyridin-5-yl) amino ] -5,6,7, 8-tetrahydro [1] benzothieno [2,3-d ] pyrimidin-7-yl } methanone

。

Example 143

{ (7S) -4- [ (6-methoxypyrazolo [1,5-a ] pyridin-5-yl) amino ] -5,6,7, 8-tetrahydro [1] benzothieno [2,3-d ] pyrimidin-7-yl } (2-oxa-6-azaspiro [3.3] hept-6-yl) methanone

。

Example 144

[ (2R,6R) -2, 6-dimethylmorpholin-4-yl ] { (7S) -4- [ (6-methoxypyrazolo [1,5-a ] pyridin-5-yl) amino ] -5,6,7, 8-tetrahydro [1] benzothieno [2,3-d ] pyrimidin-7-yl } methanone

。

Example 145

[ (2S,6S) -2, 6-dimethylmorpholin-4-yl ] { (7S) -4- [ (6-methoxypyrazolo [1,5-a ] pyridin-5-yl) amino ] -5,6,7, 8-tetrahydro [1] benzothieno [2,3-d ] pyrimidin-7-yl } methanone

。

Example 146

(7S) -N- [ (2S) -1-methoxypropan-2-yl ] -4- [ (6-methoxypyrazolo [1,5-a ] pyridin-5-yl) amino ] -N-methyl-5, 6,7, 8-tetrahydro [1] benzothieno [2,3-d ] pyrimidine-7-carboxamide

。

Example 147

(7S) -N- [ (2R) -1-methoxypropan-2-yl ] -4- [ (6-methoxypyrazolo [1,5-a ] pyridin-5-yl) amino ] -N-methyl-5, 6,7, 8-tetrahydro [1] benzothieno [2,3-d ] pyrimidine-7-carboxamide

。

Example 148

(7S) -N- [ (2S) -2-methoxypropyl ] -4- [ (6-methoxypyrazolo [1,5-a ] pyridin-5-yl) amino ] -N-methyl-5, 6,7, 8-tetrahydro [1] benzothieno [2,3-d ] pyrimidine-7-carboxamide

。

Example 149

(7S) -N- [ (2R) -2-methoxypropyl ] -4- [ (6-methoxypyrazolo [1,5-a ] pyridin-5-yl) amino ] -N-methyl-5, 6,7, 8-tetrahydro [1] benzothieno [2,3-d ] pyrimidine-7-carboxamide

。

Example 150

(7S) -N- (1-methoxy-2-methylpropan-2-yl) -4- [ (6-methoxypyrazolo [1,5-a ] pyridin-5-yl) amino ] -N-methyl-5, 6,7, 8-tetrahydro [1] benzothieno [2,3-d ] pyrimidine-7-carboxamide

。

Example 151

(7S) -4- [ (6-chloropyrazolo [1,5-a ] pyridin-5-yl) amino ] -N- (2-hydroxy-2-methylpropyl) -N-methyl-5, 6,7, 8-tetrahydro [1] benzothieno [2,3-d ] pyrimidine-7-carboxamide

。

Example 152

(7S) -N- (2-aminoethyl) -4- [ (6-chloropyrazolo [1,5-a ] pyridin-5-yl) amino ] -N-methyl-5, 6,7, 8-tetrahydro [1] benzothieno [2,3-d ] pyrimidine-7-carboxamide

。

Example 153

(7S) -4- [ (6-chloropyrazolo [1,5-a ] pyridin-5-yl) amino ] -N- [2- (dimethylamino) -2-oxoethyl ] -N-methyl-5, 6,7, 8-tetrahydro [1] benzothieno [2,3-d ] pyrimidine-7-carboxamide

。

Example 154

Azetidin-1-yl { (7S) -4- [ (6-chloropyrazolo [1,5-a ] pyridin-5-yl) amino ] -5,6,7, 8-tetrahydro [1] benzothieno [2,3-d ] pyrimidin-7-yl } methanone

。

Example 155

{ (7S) -4- [ (6-chloropyrazolo [1,5-a ] pyridin-5-yl) amino ] -5,6,7, 8-tetrahydro [1] benzothieno [2,3-d ] pyrimidin-7-yl } (3, 3-difluoroazetidin-1-yl) methanone

。

Example 156

{ (7S) -4- [ (6-chloropyrazolo [1,5-a ] pyridin-5-yl) amino ] -5,6,7, 8-tetrahydro [1] benzothieno [2,3-d ] pyrimidin-7-yl } (3-hydroxyazetidin-1-yl) methanone

。

Example 157

1- ({ (7S) -4- [ (6-chloropyrazolo [1,5-a ] pyridin-5-yl) amino ] -5,6,7, 8-tetrahydro [1] benzothieno [2,3-d ] pyrimidin-7-yl } carbonyl) piperidin-4-one

。

Example 158

{ (7S) -4- [ (6-chloropyrazolo [1,5-a ] pyridin-5-yl) amino ] -5,6,7, 8-tetrahydro [1] benzothieno [2,3-d ] pyrimidin-7-yl } (3, 3-difluoropyrrolidin-1-yl) methanone

。

Example 159

{ (7S) -4- [ (6-chloropyrazolo [1,5-a ] pyridin-5-yl) amino ] -5,6,7, 8-tetrahydro [1] benzothieno [2,3-d ] pyrimidin-7-yl } (2, 2-dimethylpyrrolidin-1-yl) methanone

。

Example 160

{ (7S) -4- [ (6-chloropyrazolo [1,5-a ] pyridin-5-yl) amino ] -5,6,7, 8-tetrahydro [1] benzothieno [2,3-d ] pyrimidin-7-yl } (2-oxa-6-azaspiro [3.3] hept-6-yl) methanone

。

Example 161

{ (7S) -4- [ (6-chloropyrazolo [1,5-a ] pyridin-5-yl) amino ] -5,6,7, 8-tetrahydro [1] benzothieno [2,3-d ] pyrimidin-7-yl } [ (2R,6R) -2, 6-dimethylmorpholin-4-yl ] methanone

。

Example 162

{ (7S) -4- [ (6-chloropyrazolo [1,5-a ] pyridin-5-yl) amino ] -5,6,7, 8-tetrahydro [1] benzothieno [2,3-d ] pyrimidin-7-yl } [ (2S,6S) -2, 6-dimethylmorpholin-4-yl ] methanone

。

Example 163

(7S) -4- [ (6-chloropyrazolo [1,5-a ] pyridin-5-yl) amino ] -N- [ (2S) -1-methoxypropan-2-yl ] -N-methyl-5, 6,7, 8-tetrahydro [1] benzothieno [2,3-d ] pyrimidine-7-carboxamide

。

Example 164

(7S) -4- [ (6-chloropyrazolo [1,5-a ] pyridin-5-yl) amino ] -N- [ (2R) -1-methoxypropan-2-yl ] -N-methyl-5, 6,7, 8-tetrahydro [1] benzothieno [2,3-d ] pyrimidine-7-carboxamide

。

Example 165

(7S) -4- [ (6-chloropyrazolo [1,5-a ] pyridin-5-yl) amino ] -N- [ (2S) -2-methoxypropyl ] -N-methyl-5, 6,7, 8-tetrahydro [1] benzothieno [2,3-d ] pyrimidine-7-carboxamide

。

Example 166

(7S) -4- [ (6-chloropyrazolo [1,5-a ] pyridin-5-yl) amino ] -N- [ (2R) -2-methoxypropyl ] -N-methyl-5, 6,7, 8-tetrahydro [1] benzothieno [2,3-d ] pyrimidine-7-carboxamide

。

Example 167

(7S) -4- [ (6-chloropyrazolo [1,5-a ] pyridin-5-yl) amino ] -N- [ 1-methoxy-2-methylpropan-2-yl ] -N-methyl-5, 6,7, 8-tetrahydro [1] benzothieno [2,3-d ] pyrimidine-7-carboxamide

。

Example 168

(7S) -4- [ (6- (dimethylamino) pyrazolo [1,5-a ] pyridin-5-yl) amino ] -N, N-dimethyl-5, 6,7, 8-tetrahydro [1] benzothieno [2,3-d ] pyrimidine-7-carboxamide

。

Example 169

(7S) -4- [ (6- (dimethylamino) pyrazolo [1,5-a ] pyridin-5-yl) amino ] -N-methyl-N- (3,3, 3-trifluoropropyl) -5,6,7, 8-tetrahydro [1] benzothieno [2,3-d ] pyrimidine-7-carboxamide

。

Example 170

(7S) -N- (2-hydroxy-2-methylpropyl) -4- [ (6- (dimethylamino) pyrazolo [1,5-a ] pyridin-5-yl) amino ] -N-methyl-5, 6,7, 8-tetrahydro [1] benzothieno [2,3-d ] pyrimidine-7-carboxamide

。

Example 171

(7S) -N- (2, 2-difluoroethyl) -4- [ (6- (dimethylamino) pyrazolo [1,5-a ] pyridin-5-yl) amino ] -N-methyl-5, 6,7, 8-tetrahydro [1] benzothieno [2,3-d ] pyrimidine-7-carboxamide

。

Example 172

(7S) -4- [ (6- (dimethylamino) pyrazolo [1,5-a ] pyridin-5-yl) amino ] -N-isopropyl-N-methyl-5, 6,7, 8-tetrahydro [1] benzothieno [2,3-d ] pyrimidine-7-carboxamide

。

Example 173

(7S) -4- [ (6- (dimethylamino) pyrazolo [1,5-a ] pyridin-5-yl) amino ] -N-ethyl-N- (2-hydroxyethyl) -5,6,7, 8-tetrahydro [1] benzothieno [2,3-d ] pyrimidine-7-carboxamide

。

Example 174

(7S) -4- [ (6- (dimethylamino) pyrazolo [1,5-a ] pyridin-5-yl) amino ] -N- (2-methoxyethyl) -N-methyl-5, 6,7, 8-tetrahydro [1] benzothieno [2,3-d ] pyrimidine-7-carboxamide

。

Example 175

(7S) -N- (2-aminoethyl) -4- [ (6- (dimethylamino) pyrazolo [1,5-a ] pyridin-5-yl) amino ] -N-methyl-5, 6,7, 8-tetrahydro [1] benzothieno [2,3-d ] pyrimidine-7-carboxamide

。

Example 176

(7S) -N- [2- (dimethylamino) ethyl ] -4- [ (6- (dimethylamino) pyrazolo [1,5-a ] pyridin-5-yl) amino ] -N-methyl-5, 6,7, 8-tetrahydro [1] benzothieno [2,3-d ] pyrimidine-7-carboxamide

。

Example 177

(7S) -N- [2- (dimethylamino) -2-oxoethyl ] -4- [ (6- (dimethylamino) pyrazolo [1,5-a ] pyridin-5-yl) amino ] -N-methyl-5, 6,7, 8-tetrahydro [1] benzothieno [2,3-d ] pyrimidine-7-carboxamide

。

Example 178

(7S) -N- [3- (dimethylamino) propyl ] -4- [ (6- (dimethylamino) pyrazolo [1,5-a ] pyridin-5-yl) amino ] -N-methyl-5, 6,7, 8-tetrahydro [1] benzothieno [2,3-d ] pyrimidine-7-carboxamide

。

Example 179

Azetidin-1-yl { (7S) -4- [ (6- (dimethylamino) pyrazolo [1,5-a ] pyridin-5-yl) amino ] -5,6,7, 8-tetrahydro [1] benzothieno [2,3-d ] pyrimidin-7-yl } methanone

。

Example 180

(3, 3-Difluoroazetidin-1-yl) { (7S) -4- [ (6- (dimethylamino) pyrazolo [1,5-a ] pyridin-5-yl) amino ] -5,6,7, 8-tetrahydro [1] benzothieno [2,3-d ] pyrimidin-7-yl } methanone

。

Example 181

{ (7S) -4- [ (6- (dimethylamino) pyrazolo [1,5-a ] pyridin-5-yl) amino ] -5,6,7, 8-tetrahydro [1] benzothieno [2,3-d ] pyrimidin-7-yl } (3-hydroxyazetidin-1-yl) methanone

。

Example 182

{ (7S) -4- [ (6- (dimethylamino) pyrazolo [1,5-a ] pyridin-5-yl) amino ] -5,6,7, 8-tetrahydro [1] benzothieno [2,3-d ] pyrimidin-7-yl } (3-hydroxy-3-methylazetidin-1-yl) methanone

。

Example 183

1- ({ (7S) -4- [ (6- (dimethylamino) pyrazolo [1,5-a ] pyridin-5-yl) amino ] -5,6,7, 8-tetrahydro [1] benzothieno [2,3-d ] pyrimidin-7-yl } carbonyl) azetidine-3-carbonitrile

。

Example 184

[3- (dimethylamino) azetidin-1-yl ] { (7S) -4- [ (6- (dimethylamino) pyrazolo [1,5-a ] pyridin-5-yl) amino ] -5,6,7, 8-tetrahydro [1] benzothieno [2,3-d ] pyrimidin-7-yl } methanone

。

Example 185

{ (7S) -4- [ (6- (dimethylamino) pyrazolo [1,5-a ] pyridin-5-yl) amino ] -5,6,7, 8-tetrahydro [1] benzothieno [2,3-d ] pyrimidin-7-yl } (4-methylpiperazin-1-yl) methanone

。

Example 186

{4- [2- (dimethylamino) ethyl ] piperazin-1-yl } { (7S) -4- [ (6- (dimethylamino) pyrazolo [1,5-a ] pyridin-5-yl) amino ] -5,6,7, 8-tetrahydro [1] benzothieno [2,3-d ] pyrimidin-7-yl } methanone

。

Example 187

(4- { [2- (dimethylamino) ethyl ] (methyl) amino } piperidin-1-yl) { (7S) -4- [ (6- (dimethylamino) pyrazolo [1,5-a ] pyridin-5-yl) amino ] -5,6,7, 8-tetrahydro [1] benzothieno [2,3-d ] pyrimidin-7-yl } methanone

。

Example 188

[4- (dimethylamino) piperidin-1-yl ] { (7S) -4- [ (6- (dimethylamino) pyrazolo [1,5-a ] pyridin-5-yl) amino ] -5,6,7, 8-tetrahydro [1] benzothieno [2,3-d ] pyrimidin-7-yl } methanone

。

Example 189

1- ({ (7S) -4- [ (6- (dimethylamino) pyrazolo [1,5-a ] pyridin-5-yl) amino ] -5,6,7, 8-tetrahydro [1] benzothieno [2,3-d ] pyrimidin-7-yl } carbonyl) piperidin-4-one

。

Example 190

(3, 3-difluoropyrrolidin-1-yl) { (7S) -4- [ (6- (dimethylamino) pyrazolo [1,5-a ] pyridin-5-yl) amino ] -5,6,7, 8-tetrahydro [1] benzothieno [2,3-d ] pyrimidin-7-yl } methanone

。

Example 191

{ (7S) -4- [ (6- (dimethylamino) pyrazolo [1,5-a ] pyridin-5-yl) amino ] -5,6,7, 8-tetrahydro [1] benzothieno [2,3-d ] pyrimidin-7-yl } (2, 2-dimethylpyrrolidin-1-yl) methanone

。

Example 192

{ (7S) -4- [ (6- (dimethylamino) pyrazolo [1,5-a ] pyridin-5-yl) amino ] -5,6,7, 8-tetrahydro [1] benzothieno [2,3-d ] pyrimidin-7-yl } (morpholin-4-yl) methanone

。

Example 193

{ (7S) -4- [ (6- (dimethylamino) pyrazolo [1,5-a ] pyridin-5-yl) amino ] -5,6,7, 8-tetrahydro [1] benzothieno [2,3-d ] pyrimidin-7-yl } (2-oxa-6-azaspiro [3.3] hept-6-yl) methanone

。

Example 194

{ (7S) -4- [ (6- (dimethylamino) pyrazolo [1,5-a ] pyridin-5-yl) amino ] -5,6,7, 8-tetrahydro [1] benzothieno [2,3-d ] pyrimidin-7-yl } [ (2R,6S) -2, 6-dimethylmorpholin-4-yl ] methanone

。

Example 195

{ (7S) -4- [ (6- (dimethylamino) pyrazolo [1,5-a ] pyridin-5-yl) amino ] -5,6,7, 8-tetrahydro [1] benzothieno [2,3-d ] pyrimidin-7-yl } [ (2R,6R) -2, 6-dimethylmorpholin-4-yl ] methanone

。

Example 196

{ (7S) -4- [ (6- (dimethylamino) pyrazolo [1,5-a ] pyridin-5-yl) amino ] -5,6,7, 8-tetrahydro [1] benzothieno [2,3-d ] pyrimidin-7-yl } [ (2S,6S) -2, 6-dimethylmorpholin-4-yl ] methanone

。

Example 197

{ (7S) -4- [ (6- (dimethylamino) pyrazolo [1,5-a ] pyridin-5-yl) amino ] -5,6,7, 8-tetrahydro [1] benzothieno [2,3-d ] pyrimidin-7-yl } [ (3S) -3-methylmorpholin-4-yl ] methanone

。

Example 198

{ (7S) -4- [ (6- (dimethylamino) pyrazolo [1,5-a ] pyridin-5-yl) amino ] -5,6,7, 8-tetrahydro [1] benzothieno [2,3-d ] pyrimidin-7-yl } [ (3R) -3-methylmorpholin-4-yl ] methanone

。

Example 199

{ (7S) -4- [ (6- (dimethylamino) pyrazolo [1,5-a ] pyridin-5-yl) amino ] -5,6,7, 8-tetrahydro [1] benzothieno [2,3-d ] pyrimidin-7-yl } [ (1S,4S) -2-oxa-5-azabicyclo [2.2.1] hept-5-yl ] methanone

。

Example 200

{ (7S) -4- [ (6- (dimethylamino) pyrazolo [1,5-a ] pyridin-5-yl) amino ] -5,6,7, 8-tetrahydro [1] benzothieno [2,3-d ] pyrimidin-7-yl } [ (1R,4R) -2-oxa-5-azabicyclo [2.2.1] hept-5-yl ] methanone

。

Example 201

{ (7S) -4- [ (6- (dimethylamino) pyrazolo [1,5-a ] pyridin-5-yl) amino ] -5,6,7, 8-tetrahydro [1] benzothieno [2,3-d ] pyrimidin-7-yl } [ (1S,4S) -5-methyl-2, 5-diazabicyclo [2.2.1] hept-2-yl ] methanone

。

Example 202

{ (7S) -4- [ (6- (dimethylamino) pyrazolo [1,5-a ] pyridin-5-yl) amino ] -5,6,7, 8-tetrahydro [1] benzothieno [2,3-d ] pyrimidin-7-yl } [ (1R,4R) -5-methyl-2, 5-diazabicyclo [2.2.1] hept-2-yl ] methanone

。

Example 203

(7S) -4- [ (6- (dimethylamino) pyrazolo [1,5-a ] pyridin-5-yl) amino ] -N- [ (2S) -1-methoxypropan-2-yl ] -N-methyl-5, 6,7, 8-tetrahydro [1] benzothieno [2,3-d ] pyrimidine-7-carboxamide

。

Example 204

(7S) -4- [ (6- (dimethylamino) pyrazolo [1,5-a ] pyridin-5-yl) amino ] -N- [ (2R) -1-methoxypropan-2-yl ] -N-methyl-5, 6,7, 8-tetrahydro [1] benzothieno [2,3-d ] pyrimidine-7-carboxamide

。

Example 205

(7S) -4- [ (6- (dimethylamino) pyrazolo [1,5-a ] pyridin-5-yl) amino ] -N- [ (2S) -2-methoxypropyl ] -N-methyl-5, 6,7, 8-tetrahydro [1] benzothieno [2,3-d ] pyrimidine-7-carboxamide

。

Example 206

(7S) -4- [ (6- (dimethylamino) pyrazolo [1,5-a ] pyridin-5-yl) amino ] -N- [ (2R) -2-methoxypropyl ] -N-methyl-5, 6,7, 8-tetrahydro [1] benzothieno [2,3-d ] pyrimidine-7-carboxamide

。

Example 207

(7S) -4- [ (6- (dimethylamino) pyrazolo [1,5-a ] pyridin-5-yl) amino ] -N- (1-methoxy-2-methylpropan-2-yl) -N-methyl-5, 6,7, 8-tetrahydro [1] benzothieno [2,3-d ] pyrimidine-7-carboxamide

。

Pharmaceutical compositions of the compounds of the invention

The invention also relates to pharmaceutical compositions comprising one or more compounds of the invention. These compositions can be utilized by administration to a patient in need thereof to achieve a desired pharmacological effect. For the purposes of the present invention, a patient is a mammal, including a human, in need of treatment for a particular condition or disease. Accordingly, the present invention includes pharmaceutical compositions comprising a pharmaceutically acceptable carrier and a pharmaceutically effective amount of a compound of the present invention or a salt thereof. The pharmaceutically acceptable carrier is preferably one that is relatively non-toxic and non-injurious to the patient at concentrations consistent with effective activity of the active ingredient, such that any side effects attributable to the carrier do not detract from the beneficial effects of the active ingredient. A pharmaceutically effective amount of a compound is preferably one that produces a result of, or exerts an effect on, the particular condition being treated. The compounds of the present invention may be administered in the following manner, together with pharmaceutically acceptable carriers well known in the art, using any effective conventional dosage unit form, including immediate release, sustained release and timed release formulations: oral, parenteral, topical, nasal, ocular (opthalmologicaly), ocular (opthalmally), sublingual, rectal, vaginal, and the like.

For oral administration, the compounds may be formulated into solid or liquid preparations such as capsules, pills, tablets, dragees (troche), lozenges (lozenes), fast-melts (melts), powders, solutions, suspensions or emulsions and may be prepared according to methods known in the art for the preparation of pharmaceutical compositions. The solid unit dosage form may be a capsule, which may be of the ordinary hard-or soft-shelled gelatin type containing, for example, surfactants, lubricants, and inert fillers (e.g., lactose, sucrose, calcium phosphate, and corn starch).

In another embodiment, the compounds of the present invention may be tableted with conventional tablet bases (e.g., lactose, sucrose, and corn starch) in combination with: binders (e.g., acacia, corn starch or gelatin), disintegrating agents to aid in the disintegration and dissolution of the tablet after administration (e.g., potato starch, alginic acid, corn starch and guar gum, tragacanth, acacia), lubricants (e.g., talc, stearic acid or magnesium stearate, calcium stearate or zinc stearate) to improve the flowability of the tablet granulation and to prevent tablet materials from adhering to the surfaces of the tablet die and punch, dyes, colorants, and flavoring agents (e.g., peppermint, wintergreen or cherry flavoring) to improve the sensory qualities of the tablets and make them more acceptable to the patient. Suitable excipients for use in oral liquid dosage forms include dicalcium phosphate and diluents such as water and alcohols (e.g., ethanol, benzyl alcohol and polyvinyl alcohols), with or without the addition of pharmaceutically acceptable surfactants, suspending or emulsifying agents. Various other materials may be present as coatings or to modify the physical form of the dosage unit. For example, tablets, pills, or capsules may be coated with shellac, sugar or both.

Dispersible powders and granules are suitable for use in the preparation of an aqueous suspension. They provide the active ingredient in admixture with a dispersing or wetting agent, suspending agent and one or more preservatives. Suitable dispersing or wetting agents and suspending agents are exemplified by those already mentioned above. Additional excipients, for example sweetening, flavoring and coloring agents such as those described above, may also be present.

The pharmaceutical compositions of the present invention may also be in the form of oil-in-water emulsions. The oily phase may be a vegetable oil, for example liquid paraffin or a mixture of vegetable oils. Suitable emulsifying agents may be (1) naturally-occurring gums, for example gum acacia and gum tragacanth, (2) naturally-occurring phosphatides, for example soy bean and lecithin, (3) esters or partial esters derived from fatty acids and hexitol anhydrides, for example sorbitan monooleate, (4) condensation products of the said partial esters with ethylene oxide, for example polyoxyethylene sorbitan monooleate. The emulsion may also contain sweetening and flavoring agents.

Oily suspensions may be formulated by suspending the active ingredient in a vegetable oil, for example arachis oil, olive oil, sesame oil or coconut oil, or in a mineral oil such as liquid paraffin. Oily suspensions may contain a thickening agent, for example beeswax, hard paraffin or cetyl alcohol. The suspension may also contain one or more preservatives, such as ethyl or n-propyl p-hydroxybenzoate; one or more colorants; one or more flavoring agents; and one or more sweetening agents, such as sucrose or saccharin.

Syrups and elixirs may be formulated with sweetening agents, for example glycerol, propylene glycol, sorbitol or sucrose. Such formulations may also contain a demulcent and a preservative (e.g. methyl and propyl parabens) as well as flavoring and coloring agents.

The compounds of the invention may also be administered parenterally, i.e. subcutaneously, intravenously, intraocularly, intrasynovially, intramuscularly or intraperitoneally, as injectable doses of the compounds in preferably physiologically acceptable diluents, with a pharmaceutical carrier, which may be a sterile liquid or a liquid mixture, e.g. water, saline, aqueous dextrose and related sugar solutions, with or without the addition of pharmaceutically acceptable surfactants (e.g. soaps or detergents), suspending agents (e.g. pectin, carbomer, methylcellulose, hydroxypropylmethylcellulose or carboxymethylcellulose), or emulsifying agents and other pharmaceutical adjuvants; alcohols, such as ethanol, isopropanol or hexadecanol; glycols, such as propylene glycol or polyethylene glycol; glycerol ketals, such as 2, 2-dimethyl-1, 1-dioxolane-4-methanol; ethers, such as poly (ethylene glycol) 400; an oil, a fatty acid ester, or a fatty acid glyceride, or an acetylated fatty acid glyceride.

Examples of oils which may be used in the parenteral formulations of the invention are those of petroleum, animal, vegetable or synthetic origin, for example peanut oil, soybean oil, sesame oil, cottonseed oil, corn oil, olive oil, petrolatum and mineral oil. Suitable fatty acids include oleic acid, stearic acid, isostearic acid and myristic acid. Suitable fatty acid esters are, for example, ethyl oleate and isopropyl myristate. Suitable soaps include fatty acid alkali metal, ammonium and triethanolamine salts, and suitable detergents include cationic detergents such as dimethyl dialkyl ammonium halides, alkyl pyridinium halides and alkylamine acetates; anionic detergents such as alkyl sulfonates, aryl sulfonates and olefin sulfonates, alkyl sulfates and alkyl sulfosuccinates, olefin sulfates and olefin sulfosuccinates, ether sulfates and ether sulfosuccinates, and monoglyceride sulfates and monoglycerides sulfosuccinates; nonionic detergents such as fatty amine oxides, fatty acid alkanolamides, and poly (oxyethylene-oxypropylene), or ethylene oxide or propylene oxide copolymers; and amphoteric detergents such as alkyl-beta-aminopropionates and 2-alkylimidazoline quats, and mixtures thereof.

The parenteral compositions of the invention will generally comprise from about 0.5% to about 25% by weight of the active ingredient in solution. Preservatives and buffers may also be advantageously employed. To minimize or eliminate irritation at the injection site, such compositions may comprise a nonionic surfactant having a hydrophilic-lipophilic balance (HLB) of preferably from about 12 to about 17. The amount of surfactant in such formulations is preferably from about 5% to about 15% by weight. The surfactant may be a single component having the above HLB, or a mixture of two or more components having the desired HLB.

Examples of surfactants used in parenteral formulations are polyethylene sorbitan fatty acid esters, such as sorbitan monooleate, and the high molecular weight adducts of ethylene oxide with a hydrophobic base formed by condensing propylene oxide and propylene glycol.

The pharmaceutical compositions may be in the form of a sterile injectable aqueous suspension. Such suspensions may be formulated according to known methods using the following: suitable dispersing or wetting agents and suspending agents, for example, sodium carboxymethylcellulose, methylcellulose, hydroxypropylmethylcellulose, sodium alginate, polyvinylpyrrolidone, gum tragacanth and gum acacia; dispersing or wetting agents which may be a naturally occurring phosphatide (for example lecithin), a condensation product of an alkylene oxide with a fatty acid (for example polyoxyethylene stearate), a condensation product of ethylene oxide with a long chain aliphatic alcohol (for example heptadecaethyleneoxycetanol), a condensation product of ethylene oxide with a partial ester derived from a fatty acid and a hexitol (for example polyoxyethylene sorbitol monooleate), or a condensation product of ethylene oxide with a partial ester derived from a fatty acid and a hexitol anhydride (for example polyoxyethylene sorbitan monooleate).

The sterile injectable preparation may also be a sterile injectable solution or suspension in a non-toxic parenterally-acceptable diluent or solvent. Diluents and solvents which may be used are, for example, water, ringer's solution, isotonic sodium chloride solution and isotonic glucose solution. In addition, sterile, fixed oils are conventionally employed as a solvent or suspending medium. For this purpose, any bland fixed oil may be employed including synthetic mono-or diglycerides. In addition, fatty acids, such as oleic acid, may be used in the preparation of injectables.

The compositions of the present invention may also be administered in the form of suppositories for rectal administration of the drug. These compositions may be prepared by mixing the drug with a suitable non-irritating excipient which is solid at ordinary temperatures but liquid at the rectal temperature and will therefore melt in the rectum to release the drug. Such materials are, for example, cocoa butter and polyethylene glycols.

Another formulation used in the methods of the invention utilizes a transdermal delivery device ("patch"). Such transdermal patches may be used to provide continuous or discontinuous infusions of the compounds of the present invention in controlled amounts. The construction and use of transdermal patches for delivering agents is well known in the art (see, e.g., U.S. Pat. No. 5,023,252 issued on 6/11 of 1991, which is incorporated herein by reference). Such patches may be configured for continuous, pulsed, or on-demand delivery of the agent.

Controlled release formulations for parenteral administration include liposome, polymeric microsphere and polymeric gel formulations known in the art.

It may be desirable or necessary to introduce a pharmaceutical composition into a patient via a mechanical delivery device. The construction and use of mechanical delivery devices for delivering pharmaceutical agents is well known in the art. Direct techniques for, for example, administering drugs directly to the brain typically involve placing a drug delivery catheter into the ventricular system of a patient to bypass the blood brain barrier. One such implantable delivery system for delivering agents to specific anatomical regions of the body is described in U.S. patent No. 5,011,472 issued 4/30 1991.

The compositions of the present invention may also contain other conventional pharmaceutically acceptable compounding ingredients, often referred to as carriers or diluents, as necessary or desired. Conventional procedures for preparing such compositions in appropriate dosage forms may be utilized.

Such ingredients and procedures include those described in the following references, each of which is incorporated herein by reference: powell, M.F. et al, "Complex of Excipients for particulate Formulations" PDA Journal of Pharmaceutical Science & Technology 1998, 52(5), 238-.

Common pharmaceutical ingredients that may be used where appropriate to formulate a composition for its intended route of administration include:

acidulants (examples include, but are not limited to, acetic acid, citric acid, fumaric acid, hydrochloric acid, nitric acid);

alkalizing agents (examples include, but are not limited to, ammonia solution, ammonium carbonate, diethanolamine, monoethanolamine, potassium hydroxide, sodium borate, sodium carbonate, sodium hydroxide, triethanolamine (triethanolamine), triethanolamine (trolamine));

adsorbents (examples include, but are not limited to, powdered cellulose and activated carbon);

aerosol propellants (examples include, but are not limited to, carbon dioxide, CCl₂F₂、F₂ClC-CClF₂And CClF₃)；

Air displacement agents (examples include, but are not limited to, nitrogen and argon);

antifungal preservatives (examples include, but are not limited to, benzoic acid, butyl paraben, ethyl paraben, methyl paraben, propyl paraben, sodium benzoate);

antimicrobial preservatives (examples include, but are not limited to, benzalkonium chloride, benzethonium chloride, benzyl alcohol, cetylpyridinium chloride, chlorobutanol, phenol, phenylethyl alcohol, phenylmercuric nitrate, and thimerosal);

antioxidants (examples include, but are not limited to, ascorbic acid, ascorbyl palmitate, butylated hydroxyanisole, butylated hydroxytoluene, hypophosphorous acid, monothioglycerol, propyl gallate, sodium ascorbate, sodium bisulfite, sodium formaldehyde sulfoxylate, sodium metabisulfite);

adhesive materials (examples include, but are not limited to, block polymers, natural and synthetic rubbers, polyacrylates, polyurethanes, silicones, polysiloxanes, and styrene-butadiene copolymers);

buffering agents (examples include, but are not limited to, potassium metaphosphate, dipotassium hydrogen phosphate, sodium acetate, anhydrous sodium citrate, and sodium citrate dihydrate);

carrier agents (examples include, but are not limited to, acacia syrup, aromatic elixir, cherry syrup, cocoa syrup, citrus syrup, corn oil, mineral oil, peanut oil, sesame oil, bacteriostatic sodium chloride injection, and bacteriostatic water for injection);

chelating agents (examples include, but are not limited to, edetate disodium and edetic acid);

coloring agents (examples include, but are not limited to, FD & C Red number 3, FD & C Red number 20, FD & C Yellow number 6, FD & C Blue number 2, D & C Green number 5, D & C Orange number 5, D & C Red number 8, caramel, and Red iron oxide);

clarifying agents (examples include, but are not limited to, bentonite);

emulsifying agents (examples include, but are not limited to, acacia, cetomacrogol, cetyl alcohol, glycerol monostearate, lecithin, sorbitan monooleate, polyoxyethylene 50 monostearate);

encapsulating agents (examples include, but are not limited to, gelatin and cellulose acetate phthalate);

flavors (examples include, but are not limited to, anise oil, cinnamon oil, cocoa, menthol, orange oil, peppermint oil, and vanillin);

humectants (examples include, but are not limited to, glycerin, propylene glycol, and sorbitol);

abrasives (examples include, but are not limited to, mineral oil and glycerin);

oils (examples include, but are not limited to, peanut oil (arachis oil), mineral oil, olive oil, peanut oil (peanout oil), sesame oil, and vegetable oils);

ointment bases (examples include, but are not limited to, lanolin, hydrophilic ointment, polyethylene glycol ointment, petrolatum, hydrophilic petrolatum, white ointment, yellow ointment, and rose water ointment);

penetration enhancers (transdermal delivery) (examples include, but are not limited to, monohydric or polyhydric alcohols, monovalent or polyvalent alcohols, saturated or unsaturated fatty esters, saturated or unsaturated dicarboxylic acids, essential oils, phosphatidyl derivatives, cephalins, terpenes, amides, ethers, ketones, and ureas);

plasticizers (examples include, but are not limited to, diethyl phthalate and glycerol);

solvents (examples include, but are not limited to, ethanol, corn oil, cottonseed oil, glycerol, isopropanol, mineral oil, oleic acid, peanut oil, purified water, water for injection, sterile water for injection, and sterile water for rinsing);

hardening agents (examples include, but are not limited to, cetyl alcohol, cetyl esters wax, microcrystalline wax, paraffin, stearyl alcohol, white wax, and yellow wax);

suppository bases (examples include, but are not limited to, cocoa butter and polyethylene glycol (mixtures));

surfactants (examples include, but are not limited to, benzalkonium chloride, nonylphenol polyether 10, octylphenol polyether (oxoynol) 9, polysorbate 80, sodium lauryl sulfate, and sorbitan monopalmitate);

suspending agents (examples include, but are not limited to, agar, bentonite, carbomer, sodium carboxymethylcellulose, hydroxyethylcellulose, hydroxypropylcellulose, hydroxypropylmethylcellulose, kaolin, methylcellulose, tragacanth and magnesium aluminum silicate (veegum));

sweeteners (examples include, but are not limited to, aspartame, dextrose, glycerin, mannitol, propylene glycol, sodium saccharin, sorbitol, and sucrose);

tablet antiadherents (examples include, but are not limited to, magnesium stearate and talc);

tablet binders (examples include, but are not limited to, acacia, alginic acid, sodium carboxymethylcellulose, compressible sugar, ethylcellulose, gelatin, liquid glucose, methylcellulose, non-crosslinked polyvinylpyrrolidone, and pregelatinized starch);

tablet and capsule diluents (examples include, but are not limited to, dibasic calcium phosphate, kaolin, lactose, mannitol, microcrystalline cellulose, powdered cellulose, precipitated calcium carbonate, sodium phosphate, sorbitol, and starch);

tablet coatings (examples include, but are not limited to, liquid glucose, hydroxyethyl cellulose, hydroxypropyl methylcellulose, ethylcellulose, cellulose acetate phthalate, and shellac);

tablet direct compression excipients (examples include, but are not limited to, dibasic calcium phosphate);

tablet disintegrating agents (examples include, but are not limited to, alginic acid, carboxymethylcellulose calcium, microcrystalline cellulose, polacrillin potassium, cross-linked polyvinylpyrrolidone, sodium alginate, sodium starch glycolate, and starch);

tablet glidants (examples include, but are not limited to, colloidal silicon dioxide, corn starch, and talc);

tablet lubricants (examples include, but are not limited to, calcium stearate, magnesium stearate, mineral oil, stearic acid, and zinc stearate);

tablet/capsule opacifiers (examples include but are not limited to titanium dioxide);

tablet polishes (examples include, but are not limited to, carnauba wax and white wax);

thickening agents (examples include, but are not limited to, beeswax, cetyl alcohol, and paraffin wax);

tonicity agents (examples include, but are not limited to, dextrose and sodium chloride);

viscosity increasing agents (examples include, but are not limited to, alginic acid, bentonite, carbomer, sodium carboxymethylcellulose, methylcellulose, polyvinylpyrrolidone, sodium alginate, and tragacanth); and

wetting agents (examples include, but are not limited to, heptadecaethyleneoxycetanol, lecithin, sorbitol monooleate, polyoxyethylene sorbitol monooleate, and polyoxyethylene stearate).

The pharmaceutical composition according to the invention may be exemplified as follows:

sterile intravenous solution: sterile injectable water can be used to prepare a5 mg/mL solution of the desired compound of the invention and, if necessary, to adjust the pH. The solution was diluted to 1-2 mg/mL with sterile 5% dextrose for administration and administered as an intravenous infusion over about 60 minutes.

Lyophilized powder for intravenous administration: sterile preparations can be prepared with (i)100-1000 mg of the desired compound of the invention as a lyophilized powder, (ii)32-327 mg/mL sodium citrate, and (iii)300-3000 mg dextran 40. The formulation is reconstituted with sterile injectable saline or 5% dextrose to a concentration of 10-20 mg/mL, then further diluted with saline or 5% dextrose to 0.2-0.4 mg/mL and administered as an intravenous bolus or by intravenous infusion over 15-60 minutes.

Intramuscular suspension: the following solutions or suspensions can be prepared for intramuscular injection:

50 mg/mL of the desired Water-insoluble Compound of the invention

5 mg/mL sodium carboxymethylcellulose

4 mg/mL TWEEN 80

9 mg/mL sodium chloride

9 mg/mL benzyl alcohol.

Hard shell capsule: a large number of unit capsules are prepared by filling standard two-piece hard galantine capsules with 100 mg of each of the powdered active ingredient, 150 mg of lactose, 50 mg of cellulose and 6mg of magnesium stearate.

Soft gelatin capsules: a mixture of the active ingredient in a digestible oil (such as soybean oil, cottonseed oil or olive oil) is prepared and injected by a positive displacement pump into molten gelatin to form soft gelatin capsules containing 100 mg of the active ingredient. The capsules are washed and dried. The active ingredient may be dissolved in a mixture of polyethylene glycol, glycerol and sorbitol to prepare a water-miscible drug mixture.

And (3) tablet preparation: a number of tablets were prepared by conventional procedures so that the dosage unit was 100 mg of active ingredient, 0.2 mg of colloidal silicon dioxide, 5 mg of magnesium stearate, 275 mg of microcrystalline cellulose, 11 mg of starch and 98.8 mg of lactose. Appropriate aqueous and non-aqueous coatings may be applied to increase palatability, improve aesthetics and stability, or delay absorption.

Immediate release tablets/capsules: these are solid oral dosage forms prepared by conventional and novel processes. For immediate dissolution and delivery of the drug, these units are therefore taken orally in a non-aqueous manner. The active ingredient is mixed in a liquid containing ingredients such as sugar, gelatin, pectin and sweeteners. These liquids are solidified into solid tablets or caplets by freeze-drying and solid-state extraction techniques. The pharmaceutical compound may be tableted with viscoelastic and thermoelastic sugars and polymers or effervescent components to produce a porous matrix intended for immediate release without the need for water.

Combination therapy

The term "combination" in the present invention is used in a manner known to the person skilled in the art and may exist as a fixed combination, an unfixed combination or a kit-of-parts.

The "fixed combination" in the present invention is used in a manner known to the skilled person and is defined as a combination wherein the first active ingredient and the second active ingredient are present together in one unit dose or single entity. An example of a "fixed combination" is a pharmaceutical composition, wherein the first active ingredient and the second active ingredient are present in a mixture for simultaneous administration, e.g. in a formulation. Another example of a "fixed combination" is a pharmaceutical combination, wherein the first active ingredient and the second active ingredient are present in one unit, but not in the form of a mixture.

The non-fixed combination or "kit-of-parts" in the present invention is used in a manner known to the person skilled in the art and is defined as a combination in which the first active ingredient and the second active ingredient are present in more than one unit. An example of an ambulatory combination or kit-of-parts is a combination in which the first active ingredient and the second active ingredient are present separately. The non-fixed combination or the components of the kit of parts may be administered separately, sequentially, simultaneously, concurrently or chronologically staggered.

The compounds of the present invention may be administered as a single agent or in combination with one or more other agents, wherein the combination does not cause unacceptable adverse effects. The invention also relates to such a combination. For example, the compounds of the present invention can be combined with known chemotherapeutic or anti-cancer agents (e.g., anti-hyperproliferative or other indications, etc.), as well as with mixtures and combinations thereof. Other indication agents include, but are not limited to, anti-angiogenic agents, mitotic inhibitors, alkylating agents, antimetabolites, DNA-intercalating antibiotics, growth factor inhibitors, cell cycle inhibitors, enzyme inhibitors, topoisomerase inhibitors, proteasome inhibitors, biological response modifiers, anti-hormones, or agents useful for treating inflammatory diseases or pain disorders.

The terms "chemotherapeutic agent" and "anti-cancer agent" include, but are not limited to, 131I-chTNT, abarelix, abiraterone, aclarubicin, aldesleukin, alemtuzumab, alitretinoin, altretamine, aminoglutethimide, amrubicin, amsacrine, anastrozole, parthenolide derivatives (arglabin), arsenic trioxide, asparaginase, azacitidine, basiliximab, BAY 80-6946, BAY 1000394, BAY 86-9766 (RDEA 119), belotecan, bendamustine, bevacizumab, bexarotene, bicalutamide, bisbiotine, bleomycin, bortezomib, buserelin, cabazitaxel, calcium folinate, calcium levofolinate, capecitabine, carboplatin, carmofur, carmustine, cetuximab, chlorambucil, chlormadecane, clotrimazole, and derivatives of parthenolide (argatroban), arsenic trioxide, and combinations thereof, Mechlorethamine, cisplatin, cladribine, clodronic acid, clofarabine, critase (crisantapase), cyclophosphamide, cyproterone, cytarabine, dacarbazine, actinomycin D, daltepid alpha, dasatinib, daunomycin, decitabine, defofolimus, degarelix, dinil interleukin 2, denosumab, deslorelin, desloratadine, docetaxel, doxifluridine, doxorubicin, adriamycin + estrone, eculizumab, edroloumab, eletriuminium, eltromape, endostatin, enocitabine, enzastalin, epirubicin, epitiazerol, erythropoietin alpha, erythropoietin beta, eptaplatin, eribulin, erlotinib, estradiol, estramustine, etoposide, everolimus, etamestane, favozole, filgrastim, fludarabine, flutamide, fluvastatin, Fotemustine, fulvestrant, gallium nitrate, ganirelix, gefitinib, gemcitabine, gemtuzumab, glutathione oxide (glutoxim), goserelin, histamine dihydrochloride, histrelin, hydroxyurea, I-125 seeds (I-125 seeds), ibandronic acid, ibritumomab, idarubicin, ifosfamide, imatinib, imiqimod, improsulfan, interferon alpha, interferon beta, interferon gamma, ipilimumab, irinotecan, ixabepilone, lanreotide, lapatinib, larotaxel, lenalidomide, leucistin, lentinan, letrozole, leuprolide, levamisole, lisuride, lobaplatin, lomustine, lonidamine, maxol, medroxyprogesterone, megestrol, melphalan, melam, mercaptopurine, androsterone, methothrexate, methoprene, mefenaminovalerate, methoprimate, mefenamate, and salts thereof, Mifamutide, miltefosine, miifolin, miilplatin, dibromomannitol, mitoguazone, dibromodulcitol, mitomycin, mitotane, mitoxantrone, nedaplatin, nelarabine, nilotinib, nilutamide, nimotuzumab, nimustine, nitrazine, novolimus, ofatumumab, omeprazole, omprex interleukin, oxaliplatin, p53 gene therapy, paclitaxel, palifermin, palladium-103seed (palladium-103seed), pamidronic acid, panitumumab, pazopanib, pemetrexed, PEG-erythropoietin beta (methoxy PEG-erythropoietin beta), PEG filgrastim, PEG interferon alpha-2 b, pemetrexed, pentazocine, stavudine, pellomycin, perphosphamide, pefloxacin, piscibacil, pirarubicin, prasufloxacin, plicamycin, tramadol, poliomycins, polidocromide, tramadol, pravastatin, pemphigomycin, poliomycins, estradiol polyphosphate, polysaccharide-k, porfimer sodium, pralatrexate, prednimustine, procarbazine, quinagolide, raloxifene, raltitrexed, ramosestine, rapamycin, razoxane, regorafenib, risedronic acid, rituximab, romidepsin, sarapirone, saretinib, sipuleucel-T, cilazan, sobuzosin, sodium glycineazole, sorafenib, streptozocin, sunitinib, talaporfin, tamibarotene, tamoxifen, solanosine, tesil, tegafur + gimeracilazameride + oteracil, temoporfin, temozolomide, temozolimus, teniposide, testosterone, tetrodotoxin, thalidomide, temazepridopril, thioprine, tiotropine, tiotropium, remoxibexate, timothorafenib, timothoramide, timothorazine, timothorax, valcepin, temoporfin, temozoloside, testosterone, temoporfin, temab, Trabetilidine, trametinib, trastuzumab, Triosulfan, tretinoin, triciribine, trilostane, triptorelin, trofosfamide, tryptophan, ubenix, valrubicin, Vatanib, vapreotide, Vemurafenib, vinblastine, vincristine, vindesine, vinflunine, vinorelbine, Vorinostat, vorozole, yttrium-90 glass microspheres, neat stastin esters, zoledronic acid, zorubicin, zotarolimus, ARRY-162, ARRY-300, ARRY-704, AS-703026, AZD-5363, AZD-8055, BEZ-235, BGT-226, BKM-120, BYL-719, CAL-101, CC-223, CH-5132799, E-6201, GDC-0032, GDC-0068, GDC-0063, GDC-06241, GDC-0973, GDC-0980, and the like, GSK-2110183, GSK-2126458, GSK-2141795, INK128, MK-2206, OSI-027, PF-04691502, PF-05212384, PX-866, RG-7167, RO-4987655, RO-5126766, TAK-733, UCN-01, WX-554, XL-147, XL-765, ZSTK-474.

The terms "chemotherapeutic agent" and "anti-cancer agent" also include protein therapeutics such AS interferon (e.g., interferon alpha, beta or gamma) hyperactivating monoclonal antibodies, Tuebingen, TRP-1 protein vaccines, Colostrinin, anti-FAP antibodies, YH-16, gemtuzumab, infliximab, cetuximab, trastuzumab, denileukin diftitox, rituximab, thymosin alpha 1, bevacizumab, mecalermin rinfabate, opulin, natalizumab, rhMBL, MFE-CP1 + ZD-2767-P, ABT-828, ErbB2 specific immunotoxin, SGN-35, MT-103, rinfabate, AS-1402, B43-genistein, L-19-based radioimmunotherapeutic, AC-9301, NY-O-1 vaccines, IMC-1C 57, HCC-10, CRP-322, CRP-2-gamma-gene-gamma-, MORAB-009, avicumine, MDX-1307, Her-2 vaccine, APC-8024, NGR-hTNF, rhH1.3, IGN-311, endostatin, volociximab, PRO-1762, lexamumab, SGN-40, pertuzumab, EMD-273063, L19-IL-2 fusion protein, PRX-321, CNTO-328, MDX-214, tigopotide, CAT-3888, labuuzumab, alpha-emitting radioisotope linked lintuzumab, EM-1421, HyperAcute vaccine, tucomuzumab cellilein, galiximab, HPV-16-E7, Javelin-prostate cancer, Javelin-melanoma, NY-ESO-1, monoclonal antibody, CYT-Melqbg-10, Gorgol 1, Orubu-84, Plumbum-250, Avkungumex-3580, albuzosin, albunx-250, Avicukumab, Avicumab, Avicu-b-interferon-gamma, Avicukx-interferon-gamma, gamma-interferon-3, gamma-interferon-3, gamma-interferon-3, gamma-interferon-, CTP-37, efletuzumab or 131I-chTNT-1/B.

The terms "chemotherapeutic agent" and "anti-cancer agent" also include monoclonal antibodies that can be used as protein therapeutics, such as, for example, molobumab-CD 3, abciximab, ibritumomab, daclizumab, gentuzumab, alemtuzumab, ibritumomab, cetuximab, bevacizumab, efuzumab, adalimumab, omalizumab, moruzumab-CD 3, rituximab, dallizumab, trastuzumab, palivizumab, basiliximab, and infliximab.

In general, the use of cytotoxic and/or cytostatic agents in combination with a compound or composition of the invention will serve the following functions:

(1) produces better efficacy in reducing tumor growth or even eliminating tumors than either agent administered alone,

(2) provides for administration of smaller amounts of the chemotherapeutic agent administered,

(3) providing a chemotherapeutic treatment that is well tolerated by patients with fewer harmful pharmacological complications than observed with single agent chemotherapy and certain other combination therapies,

(4) provides for the treatment of a broader spectrum of different cancer types in mammals, particularly humans,

(5) providing a higher response rate in the treated patient,

(6) providing a longer survival time in the treated patient compared to standard chemotherapy treatment,

(7) provide longer tumor progression time, and/or

(8) Results in efficacy and tolerability at least as good as the agents used alone, as compared to known cases where other cancer agents produce antagonistic effects in combination.

In addition to "chemotherapeutic agents" and "anti-cancer agents," the present invention may be combined with other "anti-inflammatory agents" and "anti-pain agents" including, but not limited to, abacavir or antibacterial agents (e.g., penicillin, vancomycin, ciprofloxacin), antiviral agents (e.g., acyclovir, oseltamivir), antifungal agents (e.g., naftifine, nystatin), azathioprine, belimumab, corticosteroids (e.g., prednisone, prednisolone, methylprednisolone, hydrocortisone, betamethasone), cyclophosphamide, IgE antibodies, immunoglobulins and gammaglobulin, IL-1 inhibitors (e.g., anakinra, canazumab, linacept), "immunomodulators and immunosuppressants" such as cyclosporine, mercaptopurine, Methotrexat; interferons include beta-interferon (IFN beta-1 a: Avonex and IFN beta-1 b: Betaferon), Jak/STAT inhibitors (e.g., Tofacitinib, Baricitinib, GLPG0634), leflunomide, mycophenolic acid, non-steroidal anti-inflammatory drugs (NSAIDS) (e.g., ibuprofen, naproxen, etodolac, celecoxib, colchicine), acetaminophen, phosphodiesterase inhibitors (e.g., Apremilast, roflumilast), rapamycin, rituximab, sulfasalazine, tacrolimus, and TNF antagonists (e.g., Humira @, etanercept, infliximab).

In addition, combinations include ACE (angiotensin converting enzyme) inhibitors (e.g., benazepril), acetylsalicylic acid, acetylcholinesterase inhibitors (e.g., donepezil, rivastigmine, galantamine, tacrine), anticholinergics (e.g., trihexyphenidyl, glycopyrrolate bromide), anticonvulsants (e.g., gabapentin), anti-diarrheals (e.g., loperamide or laxatives), anti-leukotrienes (e.g., montelukast), beta blockers (e.g., metoprolol), beta 2-adrenergic agonists (e.g., salbutamol), calcium channel blockers (e.g., nifedipine), chloroquine, COMT (catechol-O-methyltransferase) -inhibitors (e.g., entacapone), diuretics (e.g., hydrochlorothiazide), dopamine agonists (e.g., roprolone, pramipexole, bromocriptine), efamuzumab, amantidine, and combinations thereof, Fingolimod, glatiramer acetate, glyburide, insulin therapy, L-DOPA/carbidopa (L-3, 4-dihydroxyphenylalanine), MAO-B (monoamine oxidase B) inhibitors (e.g., selegiline), mesalamine, metformin, methylxanthine drugs (e.g., theophylline), mitoxantrone, natalizumab, NMDA (N-methyl-D-aspartate) receptor antagonists (e.g., amantadine, memantine), probiotics (e.g., mutaflor, VSL #3 @, Lactobacillus GG, Lactobacillus plantarum, Lactobacillus acidophilus, Lactobacillus casei, Bifidobacterium infantis 35624, enterococcus faecalis SF68, Bifidobacterium longum), statins (e.g., simvastatin), sulfonylureas (e.g., tolnutamide, glimepiride), urea, and vitamin-D analogs (e.g., calcipotriol, glitazide, or a combination thereof), or a combination thereof, Calcitriol, tacalcitol).

Mention should also be made of medicaments comprising at least one compound according to the invention and one or more other active ingredients, in particular EP4 inhibitors (prostaglandin E2 receptor 4 inhibitors), P2X3 inhibitors (P2X purine receptor 3), PTGES inhibitors (prostaglandin E synthase inhibitors) or AKR1C3 inhibitors (aldehyde-ketone reductase family 1 member C3 inhibitors), for the treatment and/or prevention of the above-mentioned diseases.

Method for sensitizing cells to irradiation

In a different embodiment of the invention, the compounds of the invention can be used to sensitize cells to radiation. That is, treatment of cells with a compound of the invention prior to radiation treatment of the cells makes the cells more susceptible to DNA damage and cell death than would be the case without any treatment with the compound of the invention. In one aspect, a cell is treated with at least one compound of the invention.

Accordingly, the present invention also provides a method of killing cells wherein one or more compounds of the present invention are administered to the cells in combination with conventional radiation therapy.

The invention also provides methods of making a cell more susceptible to cell death, wherein the cell is treated with one or more compounds of the invention prior to treating the cell to cause or induce cell death. In one aspect, after treating the cells with one or more compounds of the invention, the cells are treated with at least one compound, or at least one method, or a combination thereof, to cause DNA damage for the purpose of inhibiting the function of normal cells or killing cells.

In one embodiment, the cells are killed by treating the cells with at least one DNA damaging agent. That is, after treating a cell with one or more compounds of the invention to render the cell susceptible to cell death, the cell is treated with at least one DNA damaging agent to kill the cell. DNA damaging agents useful in the present invention include, but are not limited to, chemotherapeutic agents (e.g., cisplatin), ionizing radiation (X-rays, ultraviolet radiation), carcinogens, and mutagens.

In another embodiment, the cells are killed by treating the cells with at least one method to cause or induce DNA damage. Such methods include, but are not limited to: activating a cellular signaling pathway that results in DNA damage when the pathway is activated, inhibiting a cellular signaling pathway that results in DNA damage when the pathway is inhibited, and inducing a biochemical change in a cell, wherein the change results in DNA damage. By way of non-limiting example, DNA repair pathways in cells may be inhibited, thereby avoiding repair of DNA damage and resulting in abnormal accumulation of DNA damage in cells.

In one aspect of the invention, the compounds of the invention are administered to cells prior to irradiation or induction of DNA damage in other cells. In another aspect of the invention, the compounds of the invention are administered to cells concurrently with irradiation or other induction of DNA damage in the cells. In yet another aspect of the invention, the compounds of the invention are administered to the cells immediately after the initiation of irradiation or induction of DNA damage in other cells.

In another aspect, the cell is in vitro. In another embodiment, the cell is in vivo.

As mentioned above, it has been surprisingly found that the compounds of the present invention effectively inhibit MKNK1 and thus may be used for the treatment or prevention of diseases of or accompanied by uncontrolled cell growth, proliferation and/or survival, an inappropriate cellular immune response or an inappropriate cellular inflammatory response, in particular wherein said uncontrolled cell growth, proliferation and/or survival, inappropriate cellular immune response or inappropriate cellular inflammatory response is mediated by MKNK1, such as hematological tumors, solid tumors and/or metastases thereof, such as leukemias and myelodysplastic syndromes, malignant lymphomas, head and neck tumors including brain tumors and brain metastases, breast tumors including non-small cell lung tumors and small cell lung tumors, Gastrointestinal tumors, endocrine tumors, breast tumors and other gynecological tumors, urinary system tumors including kidney, bladder and prostate tumors, skin tumors and sarcomas, and/or metastases thereof, or pancreatitis.

Thus, according to another aspect, the present invention encompasses compounds of general formula (I) as described and defined herein, or stereoisomers, tautomers, N-oxides, hydrates, solvates or salts thereof, particularly pharmaceutically acceptable salts thereof, or mixtures thereof, for use in the treatment or prevention of a disease as mentioned above.

Thus, another particular aspect of the present invention is the use of a compound of general formula (I), or a stereoisomer, a tautomer, an N-oxide, a hydrate, a solvate, or a salt thereof, particularly a pharmaceutically acceptable salt thereof, or a mixture of same, as described above, for the prophylaxis or treatment of a disease.

Thus, another particular aspect of the invention is the use of a compound of general formula (I) as described above for the manufacture of a pharmaceutical composition for the treatment or prevention of a disease.

The diseases mentioned in the two preceding paragraphs are diseases of uncontrolled cell growth, proliferation and/or survival, inappropriate cellular immune response or inappropriate cellular inflammatory response, or diseases accompanied by uncontrolled cell growth, proliferation and/or survival, inappropriate cellular immune response or inappropriate cellular inflammatory response, in particular wherein the uncontrolled cell growth, proliferation and/or survival, inappropriate cellular immune response or inappropriate cellular inflammatory response is mediated by MKNK1, such as hematological tumors, solid tumors and/or metastases thereof, for example leukemia and myelodysplastic syndrome, malignant lymphomas, head and neck tumors including brain tumors and brain metastases, breast tumors including non-and small cell lung tumors, gastrointestinal tumors, endocrine tumors, breast tumors and other gynecological tumors, Urological tumours, skin tumours and sarcomas, including renal, bladder and prostate tumours, and/or metastases thereof.

In the context of the present invention, in particular in the context of "inappropriate cellular immune responses or inappropriate cellular inflammatory responses" as used herein, the term "inappropriate" is to be understood as preferably meaning a response which is weaker or stronger than normal and which is associated with, is the cause of or leads to the pathology of the disease.

Preferably, the use is for the treatment or prevention of a disease, wherein the disease is a hematological tumor, a solid tumor and/or metastases thereof.

Methods of treating hyperproliferative disorders

The present invention relates to methods of treating hyperproliferative disorders in mammals using the compounds of the present invention and their compositions. The compounds may be used to inhibit, block, reduce, etc., cell proliferation and/or cell division, and/or cause apoptosis. The method comprises administering to a mammal (including a human being) in need thereof an amount of a compound of the present invention, or a pharmaceutically acceptable salt, isomer, polymorph, metabolite, hydrate, solvate or ester thereof, and the like, effective for treating the condition. Hyperproliferative disorders include, but are not limited to, for example, psoriasis, keloids and other hyperplasia affecting the skin, Benign Prostatic Hyperplasia (BPH), solid tumors such as breast cancer, respiratory tract cancer, brain cancer, reproductive organ cancer, digestive tract cancer, urinary tract cancer, eye cancer, liver cancer, skin cancer, head and neck cancer, thyroid cancer, parathyroid cancer and their distant metastases. Such conditions also include lymphomas, sarcomas and leukemias.

Examples of breast cancer include, but are not limited to, invasive ductal carcinoma, invasive lobular carcinoma, ductal carcinoma in situ, and lobular carcinoma in situ.

Examples of cancers of the respiratory tract include, but are not limited to, small cell lung cancer and non-small cell lung cancer as well as bronchial adenomas and pleural pneumococcal tumors.

Examples of brain cancers include, but are not limited to, brainstem and hypothalamic gliomas, cerebellum and brain astrocytomas, medulloblastomas, ependymomas, and neuroectodermal and pineal tumors.

Tumors of the male reproductive organs include, but are not limited to, prostate cancer and testicular cancer. Tumors of female reproductive organs include, but are not limited to, endometrial, cervical, ovarian, vaginal, and vulvar cancers, as well as uterine sarcomas.

Tumors of the digestive tract include, but are not limited to, anal, colon, colorectal, esophageal, gallbladder, gastric, pancreatic, rectal, small intestine, and salivary gland cancers.

Urinary tract tumors include, but are not limited to, bladder cancer, penile cancer, kidney cancer, renal pelvis cancer, ureter cancer, urinary tract cancer, and human papillary renal cancer.

Eye cancers include, but are not limited to, intraocular melanoma and retinoblastoma.

Examples of liver cancer include, but are not limited to, hepatocellular carcinoma (hepatocellular carcinoma with or without the fibrolamellar variant), cholangiocarcinoma (intrahepatic cholangiocarcinoma), and mixed hepatocellular cholangiocarcinoma.

Skin cancers include, but are not limited to, squamous cell carcinoma, kaposi's sarcoma, malignant melanoma, merkel cell skin cancer, and non-melanoma skin cancer.

Head and neck cancers include, but are not limited to, laryngeal, hypopharyngeal, nasopharyngeal, oropharyngeal, lip, and oral cancers, as well as squamous epithelial cells. Lymphomas include, but are not limited to, AIDS-associated lymphoma, non-hodgkin's lymphoma, cutaneous T-cell lymphoma, burkitt's lymphoma, hodgkin's disease, and central nervous system lymphoma.

Sarcomas include, but are not limited to, soft tissue sarcomas, osteosarcomas, malignant fibrous histiocytomas, lymphosarcomas, and rhabdomyosarcomas.

Leukemias include, but are not limited to, acute myelogenous leukemia, acute lymphocytic leukemia, chronic myelogenous leukemia, and hairy cell leukemia.

These conditions have been well characterized in humans, but also exist in other mammals with similar etiologies, and can be treated by administering the pharmaceutical compositions of the present invention.

The terms "treating" or "treatment" as claimed throughout this document are used routinely, e.g. to manage or care for a subject with the purpose of resisting, alleviating, reducing, ameliorating, improving the condition of a disease or disorder, such as cancer, etc.

Methods of treating kinase disorders

The invention also provides methods for treating disorders associated with abnormal mitogen extracellular kinase activity including, but not limited to, stroke, heart failure, hepatomegaly, cardiac enlargement, diabetes, alzheimer's disease, cystic fibrosis, symptoms of xenograft rejection, septic shock, or asthma.

An effective amount of a compound of the invention may be used to treat such conditions, including those diseases mentioned in the background section above (e.g., cancer). Nevertheless, such cancers and other diseases may be treated with the compounds of the present invention regardless of the mechanism of action and/or the relationship between the kinase and the condition.

The phrase "abnormal kinase activity" or "abnormal serine threonine kinase activity" includes any abnormal expression or activity of the gene encoding the kinase or the polypeptide encoded thereby. Examples of such aberrant activity include, but are not limited to, overexpression of the gene or polypeptide; gene amplification; mutations that produce constitutively active or highly active kinase activity; gene mutation, deletion, substitution, addition, and the like.

The present invention also provides methods of inhibiting kinase activity, particularly mitogen extracellular kinase activity, comprising administering an effective amount of a compound of the present invention, including salts, polymorphs, metabolites, hydrates, solvates, prodrugs (e.g., esters) and diastereomeric forms thereof. Kinase activity can be inhibited in cells (e.g., in vitro) or in cells of a mammalian subject, particularly a human patient in need of treatment.

Methods of treating pain-related disorders and gynecological conditions.

The invention also provides methods for treating or preventing inflammation and pain-related disorders.

In a particular aspect of the invention as reported above, the compounds of formula (I), (Ia) or (Ib) are used for the treatment of pain syndromes including acute, chronic, inflammatory and neuropathic pain, preferably inflammatory pain, surgical pain, visceral pain, dental pain, premenstrual pain, gynaecological diseases, preferably dysmenorrhea, dyspareunia or endometriosis, adenomyosis, endometriosis-related pain or other endometriosis-related symptoms, in particular dysmenorrhea, dyspareunia, dysuria or constipation associated with endometriosis, pain associated with fibrotic diseases, central pain, pain due to burning, pain due to burns, pain due to migraine, cluster headache, pain due to nerve injury, pain due to neuritis, neuralgia, pain due to intoxication, pain associated with inflammatory diseases, pain due to burning syndrome, pain due to burning, pain due to cluster headache, pain due to nerve injury, pain due to neuritis, pain due to neurodynia, Pain due to ischemic injury, pain due to interstitial cystitis, cancer pain, pain due to viral, parasitic or bacterial infection, pain due to traumatic nerve injury, pain due to post-traumatic injury (including bone fractures and sports injuries), pain due to trigeminal neuralgia, pain associated with small fiber neuropathy, pain associated with diabetic neuropathy, chronic lower back pain, phantom limb pain, pelvic pain syndrome, chronic pelvic pain, neuroma pain, complex regional pain syndrome, pain associated with gastrointestinal tract distension, chronic arthritic pain and associated neuralgia and pain associated with cancer, pain associated with chemotherapy, HIV and HIV treatment-induced neuropathy; and pain associated with a disease or condition selected from hyperalgesia, allodynia, irritable bowel syndrome.

In addition, the invention relates to compositions and methods for treating and preventing inflammatory diseases, including inflammatory bowel disease (ulcerative colitis and crohn's disease), congestion, sepsis, metabolic disorders such as obesity, insulin resistance, diabetes; atherosclerosis, reperfusion injury, inflammatory bone resorption, pulmonary fibrosis, acute respiratory distress syndrome and intestinal polyposis, inflammatory skin diseases such as psoriasis, pemphigus vulgaris, fibrotic diseases such as idiopathic pulmonary fibrosis, skin fibrosis, systemic sclerosis, autism, liver diseases such as non-alcoholic fatty liver disease, liver fibrosis; lung diseases such as chronic obstructive pulmonary disease, asthma, pneumonia; neurodegenerative diseases such as Parkinson's disease, Alzheimer's disease; stroke, post-ischemic brain injury, cerebral ischemia, alopecia, acute coronary syndrome, myocardial infarction, autoimmune diseases such as autoimmune encephalomyelitis, multiple sclerosis; arthritis (e.g., osteoarthritis and rheumatoid arthritis); interstitial cystitis, hypertrophy, ischemia/reperfusion injury, allergic rhinitis, burns, osteoporosis.

Dosage and administration

Effective dosages of the compounds of the present invention can be readily determined for treatment of each desired indication based on standard laboratory techniques known to evaluate compounds useful for the treatment of hyperproliferative and angiogenic disorders, by standard toxicity tests and by standard pharmacological assays for determining treatment of the conditions in mammals indicated above, and by comparing these results to those of known drugs used to treat these conditions. The amount of active ingredient to be administered in the treatment of one of these conditions may vary widely depending on, for example, the following considerations: the particular compound and dosage unit employed, the mode of administration, the course of treatment, the age and sex of the patient being treated, and the nature and extent of the condition being treated.

The total amount of active ingredient to be administered will generally be between about 0.001 mg/kg to about 200 mg/kg body weight/day, and preferably about 0.01 mg/kg to about 20 mg/kg body weight/day. A clinically useful dosing regimen will be one to three times daily to once every four weeks. Furthermore, a "drug withdrawal period" in which no drug is administered to a patient for a certain period of time may be advantageous for the overall balance between pharmacological effects and tolerance. A unit dose may contain from about 0.5 mg to about 1500mg of the active ingredient and may be administered once or more times daily, or less than once daily. For administration by injection, including intravenous, intramuscular, subcutaneous and parenteral injection, and using infusion techniques, the average daily dose will preferably be from 0.01 to 200 mg/kg of total body weight. The average daily rectal dosage regimen will preferably be from 0.01 to 200 mg/kg of total body weight. The average daily vaginal dosage regimen will preferably be from 0.01 to 200 mg/kg total body weight. The average daily topical dosage regimen will preferably be administered from 0.1 to 200 mg once to four times daily. Transdermal concentrations will preferably be those required to maintain a daily dose of 0.01 to 200 mg/kg. The average daily inhaled dose regimen will preferably be from 0.01 to 100 mg/kg of total body weight.

Of course, the specific starting dose and sustained dose regimen will vary for each patient depending on the following factors: the nature and severity of the condition being determined by the attending diagnostician, the activity of the particular compound being used, the age and general condition of the patient, the time of administration, the route of administration, the rate of excretion of the drug, the drug combination, and the like. The desired therapeutic regimen and dosage amount of a compound of the invention or a pharmaceutically acceptable salt, or ester, or composition thereof, can be determined by one skilled in the art using routine therapeutic testing.

Preferably, the disease of the method is a hematological tumor, a solid tumor and/or metastases thereof.

The compounds of the invention may be used for the treatment and prevention (i.e. prevention) of tumor growth and metastasis, in particular in solid tumors of all indications and stages, in particular with or without pre-treatment of tumor growth.

Methods of testing for a particular pharmacological property or drug property are well known to those skilled in the art.

The example test experiments described herein are intended to illustrate the invention and the invention is not limited to the examples given.

Biological assay

The examples were tested one or more times in the selected bioassay. When tested more than once, data were reported as mean or median values, where:

the mean, also called arithmetic mean, represents the sum of the values obtained divided by the number of tests, and

the median value represents the median of the set of values when arranged in ascending or descending order. If the number of values in the data set is odd, the median value is the middle value. If the number of values in the data set is even, the median value is the arithmetic mean of the two intermediate values.

The examples were synthesized one or more times. When synthesized more than once, the data from the bioassay represents mean or median values calculated using data sets obtained from testing one or more synthetic batches.

MKNK1 kinase assay

The MKNK1 inhibitory activity of the compounds of the invention was quantified using the MKNK1 TR-FRET assay described in the following paragraphs.

Recombinant fusion proteins of glutathione-S-transferase (GST, N-terminus) and human full-length MKNK1 (amino acids 1-424 and T344D of accession BAA 19885.1) expressed in insect cells using a baculovirus expression system and purified by glutathione agarose affinity chromatography were purchased from Carna Biosciences (product No. 02-145) and used as enzymes. As substrate for the kinase reaction, the biotinylated peptide biotin-Ahx-IKKRKLTRRKSLKG (C-terminus in amide form) is used, which is available, for example, from Biosyntan (Berlin-Buch, Germany).

For the assay, 50 nL of a 100-fold concentrated solution of the test compound in DMSO was pipetted into a black low-volume 384-well microtiter plate (Greiner Bio-One, Frickenhausen, Germany), 2 μ L of MKNK1 was added in aqueous assay buffer [50 mM HEPES pH 7.5, 5 mM MgCl₂1.0 mM dithiothreitol, 0.005% (v/v) Nonidet-P40 (Sigma)]And incubating the mixture at 22 ℃ for 15min to allow pre-binding of the test compound to the enzyme before starting the kinase reaction. Then, by adding 3 μ L of adenosine triphosphate (ATP, 16.7 μ M =)>Final concentration in 5 μ L assay volume of 10 μ M) and substrate (0.1 μ M =>Final concentration of 0.06 μ M in a5 μ L assay volume) in assay buffer to initiate the kinase reaction, and the resulting mixture was incubated at 22 ℃ for a reaction time of 45 min. The concentration of MKNK1 was adjusted according to the activity of the enzyme batch and was chosen appropriately to bring the assay in a linear range, typical concentrations being in the range of 0.05 μ g/ml. By adding 5 μ L of TR-FRET detection reagent (5 nM streptavidin-XL 665[ Cisbio Bioassays, Codolet, France)]And 1 nM of anti-ribosomal protein S6 (pSer236) -antibody from Invitrogen [ # 44921G]And 1 nM LANCE EU-W1024-labeled protein G [ Perkin-Elmer, product number AD0071]) The reaction was stopped with a solution in aqueous EDTA (100 mM EDTA, 0.1% (w/v) bovine serum albumin, 50 mM HEPES pH 7.5).

The resulting mixture was incubated at 22 ℃ for 1h to allow the formation of a complex between the phosphorylated biotinylated peptide and the detection reagent. Subsequently, the amount of phosphorylated substrate is determined byThe amount was evaluated from the resonance energy transfer of the Eu-chelate to streptavidin-XL. Thus, the fluorescence emission at 620 nm and 665 nm after excitation at 350nm is measured in a TR-FRET reader, such as Rubystar (BMG Labtechnologies, Offenburg, Germany) or Viewlux (Perkin-Elmer). The ratio of the emissions at 665 nm and 622 nm was used as a measure of the amount of phosphorylated substrate. Data were normalized (enzyme reaction without inhibitor = 0% inhibition, all other assay components but no enzyme =100% inhibition). Typically, test compounds are tested on the same microtiter plate at 11 different concentrations with two values for each concentration, and the IC is calculated by 4-parameter fitting using internal software₅₀Values in the concentration range of 20 μ M to 0.1 nM (20 μ M, 5.9 μ M, 1.7 μ M, 0.51 μ M, 0.15 μ M, 44 nM, 13 nM, 3.8 nM, 1.1 nM, 0.33 nM and 0.1 nM, the dilution series being prepared separately by a 1:3.4 dilution series at a level of 100-fold concentrated solution in DMSO) prior to assay.

MKNK1 kinase high ATP assay

The MKNK1 inhibitory activity at high ATP of the compounds of the invention after their preincubation with MKNK1 was quantified using a TR-FRET based MKNK1 high ATP assay as described in the following paragraphs.

Recombinant fusion proteins of glutathione-S-transferase (GST, N-terminus) and human full-length MKNK1 (amino acids 1-424 and T344D of accession BAA 19885.1) expressed in insect cells using a baculovirus expression system and purified by glutathione agarose affinity chromatography were purchased from Carna Biosciences (product No. 02-145) and used as enzymes. As substrate for the kinase reaction, the biotinylated peptide biotin-Ahx-IKKRKLTRRKSLKG (C-terminus in amide form) is used, which is available, for example, from Biosyntan (Berlin-Buch, Germany).

For the assay, 50 nL of a 100-fold concentrated solution of the test compound in DMSO was pipetted into a black low-volume 384-well microtiter plate (Greiner Bio-One, Frickenhausen, Germany), 2 μ L of MKNK1 was added in aqueous assay buffer [50 mM HEPES pH 7.5, 5 mM MgCl₂1.0 mM twoThixoitol, 0.005% (v/v) Nonidet-P40 (Sigma)]And incubating the mixture at 22 ℃ for 15min to allow pre-binding of the test compound to the enzyme before starting the kinase reaction. Then, by adding 3 μ L of adenosine triphosphate (ATP, 3.3 mM = g)>Final concentration in 5 μ L assay volume of 2 mM) and substrate (0.1 μ M =>Final concentration of 0.06 μ M in a5 μ L assay volume) in assay buffer to initiate the kinase reaction, and the resulting mixture was incubated at 22 ℃ for a reaction time of 30 min. The concentration of MKNK1 was adjusted according to the activity of the enzyme batch and was chosen appropriately to bring the assay in a linear range, typical concentrations being in the range of 0.003 μ g/ml. By adding 5 μ L of TR-FRET detection reagent (5 nM streptavidin-XL 665[ Cisbio Bioassays, Codolet, France)]And 1 nM of anti-ribosomal protein S6 (pSer236) -antibody from Invitrogen [ # 44921G]And 1 nM LANCE EU-W1024-labeled protein G [ Perkin-Elmer, product number AD0071]) The reaction was stopped with a solution in aqueous EDTA (100 mM EDTA, 0.1% (w/v) bovine serum albumin, 50 mM HEPES pH 7.5).

The resulting mixture was incubated at 22 ℃ for 1h to allow the formation of a complex between the phosphorylated biotinylated peptide and the detection reagent. Subsequently, the amount of phosphorylated substrate is evaluated by measuring the resonance energy transfer from the Eu-chelate to streptavidin-XL. Thus, the fluorescence emission at 620 nm and 665 nm after excitation at 350nm is measured in a TR-FRET reader, such as Rubystar (BMG Labtechnologies, Offenburg, Germany) or Viewlux (Perkin-Elmer). The ratio of the emissions at 665 nm and 622 nm was used as a measure of the amount of phosphorylated substrate. Data were normalized (enzyme reaction without inhibitor = 0% inhibition, all other assay components but no enzyme =100% inhibition). Typically, test compounds are tested at 11 different concentrations on the same microtiter plate with two values for each concentration, and the IC is calculated₅₀Values in the concentration range of 20 μ M to 0.1 nM (e.g., 20 μ M, 5.9 μ M, 1.7 μ M, 0.51 μ M, 0.15 μ M, 44 nM, 13 nM, 3.8 nM, 1.1 nM, 0.33 nM and 0.1 nM) before measurement, respectively by serial dilution at a 100-fold level of concentrated solution in DMSOThe exact concentration may vary depending on the pipette used, in preparation for the dilution series). The data are shown in table 1.

nd: has not been determined.

MKNK2 kinase high ATP assay

The MKNK 2-inhibitory activity at high ATP of the compounds of the invention after their preincubation with MKNK2 was quantified using a TR-FRET based MKNK2 high ATP assay as described in the following paragraphs.

Recombinant fusion proteins of glutathione-S-transferase (GST, N-terminus) and human full-length MKNK2 (Genbank accession No. NP _ 060042.2) were purchased from Invitrogen (product No. PV5608) and used as enzymes, were expressed in insect cells using a baculovirus expression system, purified by glutathione agarose affinity chromatography, and activated in vitro with MAPK 12. As substrate for the kinase reaction, the biotinylated peptide biotin-Ahx-IKKRKLTRRKSLKG (C-terminus in amide form) is used, which is available, for example, from Biosyntan (Berlin-Buch, Germany).

For the assay, 50 nL of a 100-fold concentrated solution of the test compound in DMSO was pipetted into a black low-volume 384-well microtiter plate (Greiner Bio-One, Frickenhausen, Germany), and 2 μ L of MKNK2 was added in aqueous assay buffer [50 mM HEPES pH 7.5, 5 mM MgCl₂1.0 mM dithiothreitol, 0.005% (v/v) Nonidet-P40 (G-Biosciences, St. Louis, USA)]And incubating the mixture at 22 ℃ for 15min to allow test compoundsThe substance is pre-bound to the enzyme before the kinase reaction is initiated. Then, by adding 3 μ L of adenosine triphosphate (ATP, 3.3 mM = g)>Final concentration in 5 μ L assay volume of 2 mM) and substrate (0.1 μ M =>Final concentration of 0.06 μ M in a5 μ L assay volume) in assay buffer to initiate the kinase reaction, and the resulting mixture was incubated at 22 ℃ for a reaction time of 30 min. The concentration of MKNK2 was adjusted according to the activity of the enzyme batch and was chosen appropriately to bring the assay in a linear range, typical concentrations being in the range of 0.0045 μ g/ml. By adding 5 μ L of TR-FRET detection reagent (5 nM streptavidin-XL 665[ Cisbio Bioassays, Codolet, France)]And 1 nM of anti-ribosomal protein S6 (pSer236) -antibody from Invitrogen [ # 44921G]And 1 nM LANCEEU-W1024-labeled protein G [ Perkin-Elmer, product number AD0071]) The reaction was stopped with a solution in aqueous EDTA (100 mM EDTA, 0.1% (w/v) bovine serum albumin, 50 mM HEPES pH 7.5).

The resulting mixture was incubated at 22 ℃ for 1h to allow the formation of a complex between the phosphorylated biotinylated peptide and the detection reagent. Subsequently, the amount of phosphorylated substrate was evaluated by measuring the resonance energy transfer from the Eu-chelate to streptavidin-XL 665. Thus, the fluorescence emission at 620 nm and 665 nm after excitation at 350nm is measured in a TR-FRET reader, such as, for example, Pherastar (BMG Labtechnologies, Offenburg, Germany) or Viewlux (Perkin-Elmer). The ratio of the emissions at 665 nm and 622 nm was used as a measure of the amount of phosphorylated substrate. Data were normalized (enzyme reaction without inhibitor = 0% inhibition, all other assay components but no enzyme =100% inhibition). Typically, test compounds are tested at 11 different concentrations on the same microtiter plate with two values for each concentration, and the IC is calculated₅₀Values in the range of 20 μ M to 0.1 nM (e.g., 20 μ M, 5.9 μ M, 1.7 μ M, 0.51 μ M, 0.15 μ M, 44 nM, 13 nM, 3.8 nM, 1.1 nM, 0.33 nM and 0.1 nM), the dilution series being prepared separately by serial dilution at a level of 100-fold concentrated solution in DMSO before the assay, the exact concentration being variable depending on the pipettor used).

EGFR kinase assay

The EGFR inhibitory activity of the compounds of the invention is quantified using a TR-FRET based EGFR assay as described in the following paragraphs.

Epidermal Growth Factor Receptor (EGFR) (Sigma-Aldrich, # E3641) affinity purified from human cancer a431 cells was used as the kinase. As substrate for the kinase reaction, the biotinylated peptide biotin-Ahx-AEEEEYFELVAKKK (C-terminus in amide form) is used, which is available, for example, from Biosyntan GmbH (Berlin-Buch, Germany).

For the assay, 50 nL of a 100-fold concentrated solution of the test compound in DMSO was pipetted into a black low-volume 384-well microtiter plate (Greiner Bio-One, Frickenhausen, Germany), and 2 μ L of EGFR was added in an aqueous assay [50 mM Hepes/HCl pH 7.0, 1 mM MgCl pH 7.0)₂, 5 mM MnCl₂0.5 mM activated sodium orthovanadate, 0.005% (v/v) Tween-20]And incubating the mixture at 22 ℃ for 15min to allow pre-binding of the test compound to the enzyme before starting the kinase reaction. Then, by adding 3 μ L of adenosine triphosphate (ATP, 16.7 μ M =)>Final concentration in 5 μ L assay volume of 10 μ M) and substrate (1.67 μ M =>1 μ M final concentration in a5 μ L assay volume) in assay buffer to initiate the kinase reaction, and the resulting mixture was incubated at 22 ℃ for a reaction time of 30 min. The concentration of EGFR is adjusted according to the activity of the enzyme batch and is suitably chosen to bring the assay in the linear range, typical concentrations are in the range of 3U/ml. Detection of the reagent by addition of 5 μ L of HTRF (0.1 μ M streptavidin-XL 665[ Cis Biointernational ]]And 1 nM PT 66-Tb-chelate (terbium-chelate labeled anti-phospho-tyrosine-antibody from Cis biointerative) [ PT 66-Eu-chelate from Perkin Elmer can also be used instead of PT 66-Tb-chelate]) The reaction was stopped with a solution in aqueous EDTA (80 mM EDTA, 0.2% (w/v) bovine serum albumin, 50 mM HEPES pH 7.5).

The resulting mixture was incubated at 22 ℃ for 1h to allow the biotinylated phosphorylated peptide to bind to streptavidin-XL665 and PT 66-Eu-chelate. Subsequently, the amount of phosphorylated substrate was evaluated by measuring the resonance energy transfer from PT 66-Eu-chelate to streptavidin-XL 665. Thus, the fluorescence emission at 620 nm and 665 nm after excitation at 337 nm was measured in an HTRF reader, such as Pherastar (BMGLAbtechnologies, Offenburg, Germany) or Viewlux (Perkin-Elmer). The ratio of the emissions at 665 nm and 622 nm was used as a measure of the amount of phosphorylated substrate. Data were normalized (enzyme reaction without inhibitor = 0% inhibition, all other assay components but no enzyme =100% inhibition). Typically, test compounds are tested at 11 different concentrations on the same microtiter plate with two values for each concentration, and the IC is calculated₅₀Values in the range of 20 μ M to 0.1 nM (e.g., 20 μ M, 5.9 μ M, 1.7 μ M, 0.51 μ M, 0.15 μ M, 44 nM, 13 nM, 3.8 nM, 1.1 nM, 0.33 nM and 0.1 nM), the dilution series being prepared separately by serial dilution at a level of 100-fold concentrated solution in DMSO before the assay, the exact concentration being variable depending on the pipettor used).

CDK2/CycE kinase assay

The CDK2/CycE inhibitory activity of the compounds of the invention can be quantified using the CDK2/CycE TR-FRET assay as described in the following paragraphs.

Recombinant fusion proteins of GST and human CDK2 and GST and human CycE, expressed in insect cells (Sf9) and purified by glutathione-agarose affinity chromatography, are commercially available from ProQinase GmbH (Freiburg, Germany). As substrate for the kinase reaction, the biotinylated peptide biotin-Ttds-YISPLKSPYKISEG (C-terminus in amide form) is used, which is available, for example, from JERINI peptide technologies, Inc. (Berlin, Germany).

For the assay, 50 nL of a 100-fold concentrated solution of test compound in DMSO was pipetted into a black low-volume 384-well microtiter plate (Greiner Bio-One, Frickenhausen, Germany), and 2 μ L of CDK2/CycE was added in aqueous assay buffer [50 mM Tris/HCl pH 8.0, 10 mM MgCl₂1.0 mM dithiothreitol, 0.1 mM positiveSodium vanadate, 0.01% (v/v) Nonidet-P40 (Sigma)]And incubating the mixture at 22 ℃ for 15min to allow pre-binding of the test compound to the enzyme before starting the kinase reaction. Then, by adding 3 μ L of adenosine triphosphate (ATP, 16.7 μ M =)>Final concentration in 5 μ L assay volume of 10 μ M) and substrate (1.25 μ M =>Final concentration of 0.75 μ M in a5 μ L assay volume) in assay buffer to initiate the kinase reaction, and the resulting mixture was incubated at 22 ℃ for a reaction time of 25 min. The concentration of CDK2/CycE was adjusted according to the activity of the enzyme batch and was chosen appropriately to bring the assay in a linear range, with typical concentrations in the range of 130 ng/ml. By adding 5 μ L of TR-FRET detection reagent (0.2 μ M streptavidin-XL 665[ Cisbio Bioassays, Codolet, France)]And 1 nM of anti-ribosome (pSer807/pSer811) -antibody from BD Pharmingen [ # 558389]And 1.2 nMulNCE EU-W1024 labeled anti-mouse IgG antibody [ Perkin-Elmer, product number AD0077, alternatively, terbium-cryptate labeled anti-mouse IgG antibody from Cisbio Bioassays can be used]) The reaction was stopped with a solution in aqueous EDTA (100 mM EDTA, 0.2% (w/v) bovine serum albumin, 100 mM HEPES/NaOH pH 7.0).

The resulting mixture was incubated at 22 ℃ for 1h to allow the formation of a complex between the phosphorylated biotinylated peptide and the detection reagent. Subsequently, the amount of phosphorylated substrate is evaluated by measuring the resonance energy transfer from the Eu-chelate to streptavidin-XL. Thus, the fluorescence emission at 620 nm and 665 nm after excitation at 350nm is measured in a TR-FRET reader, such as Rubystar (BMG Labtechnologies, Offenburg, Germany) or Viewlux (Perkin-Elmer). The ratio of the emissions at 665 nm and 622 nm was used as a measure of the amount of phosphorylated substrate. Data were normalized (enzyme reaction without inhibitor = 0% inhibition, all other assay components but no enzyme =100% inhibition). Typically, test compounds are tested at 11 different concentrations on the same microtiter plate with two values for each concentration, and the IC is calculated₅₀Value, the concentration range is 20 [ mu ] M to 0.1 nM (20 [ mu ] M, 5.9 [ mu ] M, 1.7 [ mu ] M, 0.51 [ mu ] M, 0.15 [ mu ] M, 44 nM, 13 nM, 3 nM8 nM, 1.1 nM, 0.33 nM and 0.1 nM, the dilution series being prepared separately by a 1:3.4 serial dilution at the level of 100-fold concentrated solution in DMSO) before the assay.

PDGFR beta kinase assay

PDGFR β inhibitory activity of compounds of the invention was quantified using the PDGFR β HTRF assay as described in the following paragraphs.

As kinase, GST-His fusion protein containing a C-terminal fragment of human PDGFR β (amino acids 561-. As a substrate for the kinase reaction, biotinylated poly-Glu, Tyr (4:1) copolymer (# 61GT0BLA) from Cis biointerational (Marcoule, France) was used.

For the assay, 50 nL of a 100-fold concentrated solution of the test compound in DMSO was pipetted into a black low-volume 384-well microtiter plate (Greiner Bio-One, Frickenhausen, Germany), and 2 μ L of PDGFRCbeta was added in aqueous assay buffer [50 mM HEPES/NaOH pH 7.5, 10 mM MgCl. beta. ]₂2.5 mM dithiothreitol, 0.01% (v/v) Triton-X100 (Sigma)]And incubating the mixture at 22 ℃ for 15min to allow pre-binding of the test compound to the enzyme before starting the kinase reaction. Then, by adding 3 μ L of adenosine triphosphate (ATP, 16.7 μ M =)>Final concentration in 5 μ L assay volume of 10 μ M) and substrate (2.27 μ g/ml =>The final concentration in a5 μ L assay volume is 1.36 μ g/ml [ -30 nM]) The concentration of PDGFR β in the assay is adjusted according to the enzyme batch activity and is suitably selected to bring the assay in a linear range, with typical enzyme concentrations in the range of about 125 pg/μ L (final concentration in 5 μ L assay volume), detection by addition of 5 μ L of HTRF detection reagent (200 nM streptavidin-Xlout [ CisBioInternational ] with a reaction time of 25 min incubation of the resulting mixture at 22 ℃. PDGFR β concentration in the assay is adjusted according to the enzyme batch activity]And 1.4 nM PT 66-Eu-chelate (europium-chelate labeled anti-phospho-tyrosine antibody from Perkin Elmer) [ PT66-Tb-Cryptates instead of PT 66-Eu-chelates]The reaction was stopped with a solution in aqueous EDTA (100 mM EDTA, 0.2% (w/v) bovine serum albumin, 50 mM HEPES/NaOH pH 7.5).

The resulting mixture was incubated at 22 ℃ for 1h to allow binding of biotinylated phosphorylated peptides to streptavidin-XLent and PT 66-Eu-chelate. Subsequently, the amount of phosphorylated substrate was evaluated by measuring the resonance energy transfer from PT 66-Eu-chelate to streptavidin-XLent. Thus, the fluorescence emission at 620 nm and 665 nm after excitation at 350nm was measured in an HTRF reader, such as Rubystar (BMGLAbtechnologies, Offenburg, Germany) or Viewlux (Perkin-Elmer). The ratio of the emissions at 665 nm and 622 nm was used as a measure of the amount of phosphorylated substrate. Data were normalized (enzyme reaction without inhibitor = 0% inhibition, all other assay components but no enzyme =100% inhibition). Typically, test compounds are tested at 10 different concentrations on the same microtiter plate with two values for each concentration, and the IC is calculated₅₀Values in the concentration range of 20 μ M to 1 nM (20 μ M, 6.7 μ M, 2.2 μ M, 0.74 μ M, 0.25 μ M, 82 nM, 27 nM, 9.2 nM, 3.1 nM and 1 nM, the dilution series prepared by 1:3 serial dilutions at 100-fold level of concentrated stock solution prior to assay).

Fyn kinase assay

The C-terminal His 6-tagged human recombinant kinase domain of human T-Fyn was used as kinase, which was expressed in baculovirus-infected insect cells (purchased from Invitrogen, P3042). As substrate for the kinase reaction, the biotinylated peptide biotin-KVEKIGEGTYGVV (C-terminus in amide form) is used, which is available, for example, from Biosynthan GmbH (Berlin-Buch, Germany).

For the assay, 50 nL of a 100-fold concentrated solution of the test compound in DMSO was pipetted into a black low-volume 384-well microtiter plate (Greiner Bio-One, Frickenhausen, Germany), and 2 μ L of T-Fyn was added in aqueous assay buffer [25 mM Tris/HCl pH 7.2, 25 mM MgCl₂2mM dithiothreitol, 0.1% (w/v) bovine serum albumin, 0.03% (v-v) Nonidet-P40 (Sigma)]And incubating the mixture at 22 ℃ for 15min to allow pre-binding of the test compound to the enzyme before starting the kinase reaction. Then, by adding 3 μ L of adenosine triphosphate (ATP, 16.7 μ M =)>Final concentration in 5 μ L assay volume of 10 μ M) and substrate (2 μ M =>Final concentration of 1.2 μ M in 5 μ L assay volume) in assay buffer to initiate the kinase reaction and the resulting mixture was incubated at 22 ℃ for a reaction time of 60 min. The concentration of Fyn is adjusted according to the activity of the enzyme batch and is suitably chosen to bring the assay in the linear range, typical concentration is 0.13 nM. Detection of the reagent by addition of 5 μ L of HTRF (0.2 μ M streptavidin-XL [ Cisbio Bioassays, Codolet, France)]And 0.66 nM PT 66-Eu-chelate (europium-chelate labeled anti-phospho-tyrosine antibody from Perkin Elmer [ PT 66-Tb-cryptate from CisbioBioassays can also be used instead of PT 66-Eu-chelate]) The reaction was stopped with a solution in aqueous EDTA (125 mM EDTA, 0.2% (w/v) bovine serum albumin, 50 mM HEPES/NaOH pH 7.0).

The resulting mixture was incubated at 22 ℃ for 1h to allow the biotinylated phosphorylated peptides to bind to the streptavidin-XL and PT 66-Eu-chelate. Subsequently, the amount of phosphorylated substrate was evaluated by measuring the resonance energy transfer from PT 66-Eu-chelate to streptavidin-XL. Thus, the fluorescence emission at 620 nm and 665 nm after excitation at 350nm was measured in an HTRF reader, such as Rubystar (BMGLAbtechnologies, Offenburg, Germany) or Viewlux (Perkin-Elmer). The ratio of the emissions at 665 nm and 622 nm was used as a measure of the amount of phosphorylated substrate. Data were normalized (enzyme reaction without inhibitor = 0% inhibition, all other assay components but no enzyme =100% inhibition). Typically, test compounds are tested at 10 different concentrations on the same microtiter plate with two values for each concentration, and the IC is calculated₅₀Values in the concentration range of 20 μ M to 1 nM (20 μ M, 6.7 μ M, 2.2 μ M, 0.74 μ M, 0.25 μ M, 82 nM, 27 nM, 9.2 nM, 3.1 nM and 1 nM), the thin is prepared by 1:3 serial dilutions at a level of 100 times of the concentrated stock solution prior to measurementA release series).

Flt4 kinase assay

Flt4 inhibitory activity of compounds of the invention may be quantified using the Flt4 TR-FRET assay as described in the following paragraphs.

As kinase, GST-His fusion proteins containing the C-terminal fragment of human Flt4 (amino acids 799-1298) purchased from Proqinase [ Freiburg i.Brsg., Germany ], expressed in insect cells [ SF9] and purified by affinity chromatography were used. As substrate for the kinase reaction, the biotinylated peptide biotin-Ahx-GGEEEEYFELVKKKK (C-terminus in amide form, from Biosyntan, Berlin-Buch, Germany) was used.

For the assay, 50 nL of a 100-fold concentrated solution of test compound in DMSO was pipetted into a black low-volume 384-well microtiter plate (Greiner Bio-One, Frickenhausen, Germany), and 2 μ L of Flt4 was added in aqueous assay buffer [25 mM HEPES pH 7.5, 10 mM MgCl₂2mM dithiothreitol, 0.01% (v/v) Triton-X100 (Sigma), 0.5 mM EGTA and 5 mM β -Glycerol phosphate]And incubating the mixture at 22 ℃ for 15min to allow pre-binding of the test compound to the enzyme before starting the kinase reaction. Then, by adding 3 μ L of adenosine triphosphate (ATP, 16.7 μ M =)>Final concentration in 5 μ L assay volume of 10 μ M) and substrate (1.67 μ M =>1 μ M final concentration in a5 μ L assay volume) in assay buffer to initiate the kinase reaction, and the resulting mixture was incubated at 22 ℃ for a reaction time of 45 min. The concentration of Flt4 in the assay was adjusted according to the enzyme batch activity and was suitably selected to bring the assay in a linear range, with typical enzyme concentrations in the range of about 120 pg/μ L (final concentration in a5 μ L assay volume). Detection of the assay by addition of 5 μ L of HTRF (200 nM streptavidin-XL 665[ Cis Biointernational ]]And 1 nM of PT 66-Tb-cryptate (terbium-cryptate-labeled anti-phosphotyrosine antibody from Cisbio Bioassays (Codolet, France)) in aqueous EDTA (50 mM EDTA, 0.2% (w/v) bovine serum albumin, 50 mM HEPES pH 7.5).

The resulting mixture was incubated at 22 ℃ for 1h to allow the biotinylated phosphorylated peptides to bind to streptavidin-XL 665 and PT 66-Tb-cryptate. Subsequently, the amount of phosphorylated substrate was evaluated by measuring the resonance energy transfer from PT 66-Tb-cryptate to streptavidin-XL 665. Thus, the fluorescence emission at 620 nm and 665 nm after excitation at 350nm was measured in an HTRF reader, such as Rubystar (BMG Labtechnologies, Offenburg, Germany) or Viewlux (Perkin-Elmer). The ratio of the emissions at 665 nm and 622 nm was used as a measure of the amount of phosphorylated substrate. Data were normalized (enzyme reaction without inhibitor = 0% inhibition, all other assay components but no enzyme =100% inhibition). Typically, test compounds are tested at 10 different concentrations on the same microtiter plate with two values for each concentration, and the IC is calculated₅₀Values in the concentration range of 20 μ M to 1 nM (20 μ M, 6.7 μ M, 2.2 μ M, 0.74 μ M, 0.25 μ M, 82 nM, 27 nM, 9.2 nM, 3.1 nM and 1 nM, the dilution series prepared by 1:3 serial dilutions at 100-fold level of concentrated stock solution prior to assay).

TrkA kinase assay

The TrkA inhibitory activity of the compounds of the present invention may be quantified using the TrkA HTRF assay as described in the following paragraphs.

As kinase, GST-His fusion protein containing the C-terminal fragment of human TrkA (amino acid 443-796) purchased from Proqinase [ Freiburg i.Brsg., Germany ], which was expressed in insect cells [ SF9] and purified by affinity chromatography was used. As a substrate for the kinase reaction, biotinylated poly-Glu, Tyr (4:1) copolymer (# 61GT0BLA) from Cis biointerational (Marcoule, France) was used.

For the assay, 50 nL of a 100-fold concentrated solution of the test compound in DMSO was pipetted into a black low-volume 384-well microtiter plate (Greiner Bio-One, Frickenhausen, Germany), and 2 μ L of TrkA was added in aqueous assay buffer [8 mM MOPS/HCl pH 7.0, 10 mM MgCl, Germany)₂1 mM dithiothreitol, 0.01% (v/v) NP-40 (Sigma),0.2 mM EDTA]and incubating the mixture at 22 ℃ for 15min to allow pre-binding of the test compound to the enzyme before starting the kinase reaction. Then, by adding 3 μ L of adenosine triphosphate (ATP, 16.7 μ M =)>Final concentration in 5 μ L assay volume of 10 μ M) and substrate (2.27 μ g/ml =>The final concentration in a5 μ L assay volume is 1.36 μ g/ml [ -30 nM]) The kinase reaction was initiated by a solution in assay buffer and the resulting mixture was incubated at 22 ℃ for a reaction time of 60 min. The concentration of TrkA in the assay is adjusted according to enzyme batch activity and is suitably selected to bring the assay in a linear range, with typical enzyme concentrations in the range of about 20 pg/μ L (final concentration in a5 μ L assay volume). Detection of the assay by addition of 5 μ L of HTRF (30 nM streptavidin-XL 665[ CisBioInternational)]And 1.4 nM PT 66-Eu-chelate (europium-chelate labeled anti-phospho-tyrosine antibody from Perkin Elmer [ PT 66-Tb-cryptate from Cis biointenal can also be used instead of PT 66-Eu-chelate]) The reaction was stopped with a solution in aqueous EDTA (100 mM EDTA, 0.2% (w/v) bovine serum albumin, 50 mM HEPES/NaOH pH 7.5).

The resulting mixture was incubated at 22 ℃ for 1h to allow the biotinylated phosphorylated peptides to bind to streptavidin-XL 665 and PT 66-Eu-chelate. Subsequently, the amount of phosphorylated substrate was evaluated by measuring the resonance energy transfer from PT 66-Eu-chelate to streptavidin-XL 665. Thus, the fluorescence emission at 620 nm and 665 nm after excitation at 350nm was measured in an HTRF reader, such as Rubystar (BMGLAbtechnologies, Offenburg, Germany) or Viewlux (Perkin-Elmer). The ratio of the emissions at 665 nm and 622 nm was used as a measure of the amount of phosphorylated substrate. Data were normalized (enzyme reaction without inhibitor = 0% inhibition, all other assay components but no enzyme =100% inhibition). Typically, test compounds are tested at 10 different concentrations on the same microtiter plate with two values for each concentration, and the IC is calculated₅₀Values in the concentration range of 20 μ M to 1 nM (20 μ M, 6.7 μ M, 2.2 μ M, 0.74 μ M, 0.25 μ M, 82 nM, 27 nM, 9.2 nM, 3.1 nM and 1 nM, before measurement,the dilution series was prepared by 1:3 serial dilutions at 100-fold level of concentrated stock solution).

AlphaScreen Surefire eIF4E Ser209 phosphorylation assay

The AlphaScreen SureFire eIF4E Ser209 phosphorylation assay can be used to measure the phosphorylation of endogenous eIF4E in cell lysates. The AlphaScreen SureFire technology allows for the detection of phosphorylated proteins in cell lysates. In this assay, a sandwich antibody complex formed only in the presence of the analyte (p-eIF4E Ser209) is captured by the AlphaScreen donor and acceptor beads, such that they are in close proximity. Excitation of the donor beads causes the release of singlet oxygen molecules, which trigger an energy transfer cascade in the acceptor beads, producing light emission at 520-620 nm.

Surefire EIF4e Alphascreen stimulated with 20% FCS in A549 cells

For the determination, those from Perkin Elmer were usedAlphaScreen SureFire p-eIF4E Ser209 10K Assay kitAndAlphaScreen protein A kit (for 10K assay points)。

On the first day, 50.000 a549 cells were plated in growth medium (DMEM/Hams' F12 with stabilized glutamine, 10% FCS) at 100 μ L per well in 96-well plates and incubated at 37 ℃. After cell attachment, the medium was changed to starvation medium (DMEM, 0.1% FCS, no glucose, with glutamine, supplemented with 5 g/L maltose). On the next day, test compounds were serially diluted in 50 μ L starvation medium at a final DMSO concentration of 1% and added to a549 cells in the test plate at a final concentration range of 10 μ M up to 10 nM low, depending on the activity of the test compounds. The treated cells were incubated at 37 ℃ for 2 h. 37 μ L FCS was added to each well for 20 min (= final FCS concentration 20%). The medium was then removed and the cells were lysed by adding 50 μ L of cell lysis buffer. The plate was then shaken on a plate shaker for 10 min. After a lysis time of 10min, 4 μ L of lysate was transferred to 384 well plates (proxoplate, from Perkin Elmer) and 5 μ L of reaction buffer containing AlphaScreen receptor beads plus activation buffer mixture was added. Plates were sealed with TopSeal-A adhesive film and gently shaken on a plate shaker at room temperature for 2 h. Thereafter, 2 μ L of dilution buffer with AlphaScreen donor beads was added under soft light, and the plate was sealed again with TopSeal-a glue film and covered with foil. Incubations were performed for an additional 2h with gentle shaking at room temperature. The plates were then measured in an EnVision reader (Perkin Elmer) with AlphaScreen program. Each data point (compound dilution) was measured in triplicate.

Proliferation assay

The tumor cell proliferation assay useful for testing the compounds of the present invention involved the development of a test product of Promega @, called CellTiter-Glow^®A Luminescent Cell visual assessment reader (B.A. Cunningham, "advancing Issue: Cell promotion Assays, model kit access qualification of Cell growth",The Scientist2001, 15(13), 26; S.P. Crouch et al, "The use of ATP biolummesce as a measure of cell promotion and cytoxicity",Journal of Immunological Methods1993, 160, 81-88) which measures inhibition of cell proliferation. The generation of a luminescent signal corresponds to the amount of ATP present, which is directly proportional to the number of metabolically active (proliferating) cells.

In vitro tumor cell proliferation assay:

cultured tumor cells (MOLM-13 (human acute myeloid leukemia cells obtained from DSMZ # ACC554), JJN-3 (human plasma cell leukemia cells obtained from DSMZ # ACC541), Ramos (RA1) (human Burkitt lymphoma cells obtained from ATCC # CRL-159)) were plated in 100 μ L of their respective growth media supplemented with 10% fetal bovine serum in 96-well multi-titer (multititer) plates (Costar 3603 black/clear bottom) at a density of 2,500 cells/well (JJN-3), 3,000 cells/well (MOLM-13), 4,000 cells/well (Ramos (RA 1)). After 24 hours, the viability of the cells of one plate (zero plate) was measured. Therefore, 70 μ L/well CTG solution (Promega Cell Titer Glo solution (catalog # G755B and G756B)) was added to the zero point plate. The plates were mixed on an orbital shaker for two minutes to ensure cell lysis and incubated in the dark for 10 minutes at room temperature to stabilize the luminescence signal. The samples were read on a VICTOR 3 plate reader. In parallel, test compounds were serially diluted in growth medium and 50 μ L of 3x dilutions/well were aspirated into the test plate (final concentration: 0 μ M, and in the range of 0.001-30 μ M). The final concentration of the solvent dimethyl sulfoxide is 0.3-0.4%. Cells were incubated for 3 days in the presence of the test substance. A 105 µ L/well CTG solution (Promega Cell Titer Glo solution (catalog # G755B and G756B)) was added to the test wells. The plates were mixed on an orbital shaker for 2 minutes to ensure cell lysis and incubated at room temperature in the dark for 10 minutes to stabilize the luminescence signal. The samples were read on a VICTOR 3 plate reader. The change in the number of cells (in percent) was calculated by normalizing the measured values for the extinction values of the zero-point plate (= 0%) and the untreated (0 μm) cells (= 100%).

Overview of cell lines for proliferation assays

Cell lines	Origin of origin	Number of cells/well	Culture medium
				MOLM-13 (obtained from DSMZ # ACC554)	Acute myeloid leukemia in humans	3000	RPMI 1640 containing stabilized glutamine and 10% fetal bovine serum
JJN-3 (obtained from DSMZ # ACC541)	Human plasma cell leukemia	2500	45% Dulbecco's modified Eagle Medium containing stabilized Glutamine, 45% Iscove's modified Dulbecco's Medium containing stabilized Glutamine and 10% fetal bovine serum
				Ramos (RA1) (obtained from ATCC # CRL-159)	Human burkitt's lymphoma	4000	RPMI 1640 medium containing stable glutamine and 10% fetal bovine serum

Accordingly, the compounds of the present invention effectively inhibit one or more kinases and are therefore suitable for the treatment or prevention of diseases of uncontrolled cell growth, proliferation and/or survival, an inappropriate cellular immune response or an inappropriate cellular inflammatory response, in particular wherein said diseases of uncontrolled cell growth, proliferation and/or survival, an inappropriate cellular immune response or an inappropriate cellular inflammatory response are mediated by MKNK, more particularly wherein said diseases of uncontrolled cell growth, proliferation and/or survival, inappropriate cellular immune response or inappropriate cellular inflammatory response are hematological tumors, solid tumors and/or metastases thereof, such as leukemias and myelodysplastic syndromes, malignant lymphomas, head and neck tumors including brain tumors and brain metastases, breast tumors including non-small cell lung tumors and small cell lung tumors, breast tumors, lung tumors, brain tumors, gastrointestinal tumors, endocrine tumors, breast tumors and other gynecological tumors, urological tumors including kidney, bladder and prostate tumors, skin tumors and sarcomas, and/or metastases thereof.

IL-1 beta (interleukin-1 beta, IL-1b) -induced cytokine secretion in vitro by human PBMCs (peripheral blood mononuclear cells)

The effect of chemical compounds on the induced cytokine secretion of human PBMCs has been investigated. Here, cytokine secretion has been induced by IL-1 β, which binds to its receptor, resulting in activation of the MKNK signaling pathway.

Human PBMCs have been isolated from anticoagulated human whole blood donated from healthy volunteers by pre-filling the Leucosep tube with ficoll-paque (15 ml, Biochrom, order ID: L6115) and adding 20 ml of whole blood. After centrifugation of the blood at 800g for 15 minutes at Room Temperature (RT), the plasma including platelets was discarded. PBMCs were transferred to a fresh falcon tube, washed with PBS (phosphate buffered saline) at 250g for 10min at RT and resuspended in complete medium [ RPMI 1640, L-glutamine free (PAA, order ID: E15-039), 10% FCS; 50U/ml penicillin, 50. mu.g/ml streptomycin (PAA, order ID: P11-010) and 1% L-glutamine (Sigma, order ID. G7513)]. Assay at 2.5 × 10 in 96-well plates⁵Cell density of individual cells/well was performed in triplicate. Compounds were serially diluted in DMSO and individually at 3x10^-9M to 1x10^-5M range was added to PBMCs at a final concentration of 0.4% DMSO PBMCs treated with 0.4% DMSO were used as controls PBMCs were incubated for 30min with 20 ng/ml IL-1 β (R)&D, order ID:201-LB CF) 24 hours the cell viability was measured using the CellTiter-Glo luminescence assay (Promega, order ID: G7571) following the manufacturer's protocol the amount of secreted TNF- α (tumor necrosis factor- α) in the supernatant was determined using Human ProInflumate 9-Plex (MSD, order ID: K15007B) according to the manufacturer's instructions the inhibitory activity was determined in percent relative to control IC was calculated using a4 parameter logic model₅₀The value is obtained.

By way of illustration, the compound from example 41, which had no effect on cell viability but inhibited the secretion of TNF- α, is shown in FIG. 1₅₀The values are shown in table 3.

FIGS. 1 a-b: the compound of example 41 had no effect on cell viability (fig. 1a), but inhibited TNF- α secretion in a dose-dependent manner (fig. 1 b).

IC₅₀A compound of not less than 0.1 μ M: +

IC₅₀0.1-0.01 μ M of a compound: ++

IC₅₀0.01-0.001 μ M of a compound: +++.

CFA (complete Freund's adjuvant) -induced inflammatory pain in vivo in rats

A Complete Freund's Adjuvant (CFA) induced inflammatory pain model can be used to assess the effect of chemical compounds on pain.

On day 0, rats (Sprague-Dawley, 10 animals/group) received vehicle or chemical compound by daily treatment before injection of CFA until day 7. To inject 100 μ l of 100% CFA (Sigma, order ID: F5881) subcutaneously onto the plantar surface of the left hind paw, rats were anesthetized with 2.5-5% isoflurane/oxygen. Mechanical allodynia was assessed on day 7 using von Frey filaments according to the "Up-Down" method described by Chaplan et al (1994). Here, calibrated monofilaments (von Frey filaments) were applied to the plantar surface of the rat hind paw for a period of 4-6 seconds, or until paw withdrawal in a painful reaction occurred.

In vivo pharmacokinetics in rats

For in vivo pharmacokinetic experiments, test compounds formulated as solutions in well tolerated amounts using solubilizing agents such as PEG400 were administered intravenously to male Wistar rats at doses ranging from 0.3 to 1 mg/kg and gavaged at doses ranging from 0.5 to 10 mg/kg.

For pharmacokinetics after intravenous administration, the test compound is administered as an intravenous bolus and blood samples are taken at 2 min, 8 min, 15min, 30min, 45 min, 1h, 2h, 4 h, 6 h, 8 h, and 24 h post-administration. Additional samples were taken at later time points (e.g., 48 h, 72 h) depending on the expected half-life. For thePharmacokinetics after gavage, test compounds were gavage administered to fasted rats, and blood samples were taken 5min, 15min, 30min, 45 min, 1h, 2h, 4 h, 6 h, 8 h, and 24 h after administration. Additional samples were taken at later time points (e.g., 48 h, 72 h) depending on the expected half-life. Blood was collected into lithium-heparin (Monovitenten)^®Sarstedt) and centrifuged at 3000rpm for 15 min. From the supernatant (plasma) 100 u L aliquots were taken, and through the addition of 400 u L cold acetonitrile to precipitate and at-20 degrees C frozen overnight. The samples were then thawed and centrifuged at 3000rpm for 20 minutes at 4 ℃. An aliquot of the supernatant was taken for analytical testing using an Agilent 1200 HPLC-system with LCMS/MS detection. PK parameters were calculated by non-compartmental analysis using PK calculation software.

PK parameters derived from concentration-time curve after i.v.: CL plasma: total plasma clearance of test compound (in L/kg/h); CL blood: total blood clearance of test compounds: CL plasma^*Cp/Cb (in L/kg/h), where Cp/Cb is the ratio of the concentrations in plasma and blood. PK parameters calculated from concentration-time curves after i.g.: cmax, maximum plasma concentration (in mg/L); cmaxnor: cmax divided by the dose administered (in kg/L); tmax-time point (in h) at which Cmax was observed. Parameters calculated from i.v. and i.g. concentration-time curves: AUCnorm: area under the concentration-time curve from t =0h to infinity (extrapolated) divided by the dose administered (in kg x h/L); AUC (0-tlast) norm: the area under the concentration-time curve from t =0h to the last time point at which plasma concentrations could be measured divided by the dose administered (in kg x h/L); t 1/2: terminal half-life (in h); f: oral bioavailability: aucnom after gavage divided by aucnom after intravenous administration (%).

Sequence listing

<110>Bayer Pharma AG

<120> pyrazolopyridines as MKNK1 and MKNK2 inhibitors

<130>BHC143015

<160>5

<170>BiSSAP 1.3

<210>1

<211>14

<212>PRT

<213> unknown

<220>

<223> Biotin-Ahx-IKKRKLTRRKSLKG

<400>1

Ile Lys Lys Arg Lys Leu Thr Arg Arg Lys Ser Leu Lys Gly

1 5 10

<210>2

<211>14

<212>PRT

<213> unknown

<220>

<223> Biotin-Ahx-AEEEEYFELVAKKK

<400>2

Ala Glu Glu Glu Glu Tyr Phe Glu Leu Val Ala Lys Lys Lys

1 5 10

<210>3

<211>14

<212>PRT

<213> unknown

<220>

<223> Biotin-Ttds-YISPLKSPYKISEG

<400>3

Tyr Ile Ser Pro Leu Lys Ser Pro Tyr Lys Ile Ser Glu Gly

1 5 10

<210>4

<211>13

<212>PRT

<213> unknown

<220>

<223> Biotin-KVEKIGEGTYGVV

<400>4

Lys Val Glu Lys Ile Gly Glu Gly Thr Tyr Gly Val Val

1 5 10

<210>5

<211>15

<212>PRT

<213> unknown

<220>

<223> Biotin-Ahx-GGEEEEYFELVKKKK

<400>5

Gly Gly Glu Glu Glu Glu Tyr Phe Glu Leu Val Lys Lys Lys Lys

1 5 10 15

Claims (26)

1. A compound of the general formula (I):

wherein:

R¹represents a hydrogen atom or a halogen atom or a group selected from:

hydroxy-, cyano-, C₁-C₆-alkyl-, C₂-C₆-alkenyl-, C₂-C₆-alkynyl-, C₁-C₆-alkoxy-, halo-C₁-C₆-alkoxy-, C₃-C₆-cycloalkyl-, C₄-C₈-cycloalkenyl-, C₃-C₆-cycloalkyloxy-, (3-to 10-membered heterocycloalkyl) -O-, C₅-C₈-cycloalkenyloxy-, (5-to 10-membered heterocycloalkenyl) -O-, -N (R)^5a)R^5b、-SR^5aand-SF₅；

Wherein said C₁-C₆-alkyl-, C₂-C₆-alkenyl-, C₂-C₆-alkynyl-, C₁-C₆-alkoxy-, C₃-C₆-cycloalkyl-, C₄-C₈-cycloalkenyl-, C₃-C₆-cycloalkyloxy-, (3-to 10-membered heterocycloalkyl) -O-, C₅-C₈-cycloalkenyloxy-, (5-to 10-membered heterocycloalkenyl) -and (5-to 10-membered heterocycloalkenyl) -O-groups optionally substituted with 1,2, 3,4 or 5R⁴The radicals are substituted identically or differently;

R²represents a hydrogen atom or a group selected from: c₁-C₆-alkyl-, C₂-C₆-alkenyl-, C₁-C₆-alkoxy-, halo-C₁-C₆-alkyl-and halo-C₁-C₆-alkoxy-;

wherein said C₁-C₆-alkyl-, C₂-C₆-alkenyl-and C₁-C₆-alkoxy-groups optionally substituted by 1,2 or 3R⁷The radicals are substituted identically or differently;

R³represents a hydrogen atom or a group selected from: c₁-C₆-alkyl-, C₃-C₆-cycloalkyl-, C₄-C₆-cycloalkenyl-, C₂-C₆-alkenyl-, C₂-C₆-alkynyl-, 3-to 10-membered heterocycloalkyl-, 4-to 10-membered heterocycloalkenyl-, aryl-, heteroaryl-, cyano-and- (CH)₂)_q-X-(CH₂)_p-R⁵；

Wherein said C₁-C₆-alkyl-, C₃-C₆-cycloalkyl-, C₄-C₆-cycloalkenyl-, C₂-C₆-alkenyl-, C₂-C₆-alkynyl-, 3-to 10-membered heterocycloalkyl-, 4-to 10-membered heterocycloalkenyl-, aryl-and heteroaryl-groups optionally substituted with 1,2, 3,4 or 5R⁴The radicals are substituted identically or differently;

x represents a bond or a divalent group selected from: -O-, -S (= O)₂-、-S(=O)-N(R^5a)-、-N(R^5a)-S(=O)-、-S(=O)₂-N(R^5a)-、-N(R^5a)-S(=O)₂-、-S(=O)(=NR^5a)-、-C(=O)-、-N(R^5a)-、-C(=O)-O-、-O-C(=O)-、-C(=S)-O-、-O-C(=S)-、-C(=O)-N(R^5a)-、-N(R^5a)-C(=O)-、-N(R^5a)-C(=O)-N(R^5b)-、-O-C(=O)-N(R^5a)-、-N(R^5a)-C(=O)-O-；

R⁴Represents halogen-, hydroxy-, oxo- (O =), cyano-, nitro-, C₁-C₆-alkyl-, C₂-C₆-alkenyl-, C₂-C₆-alkynyl-, halo-C₁-C₆-alkyl-, C₁-C₆-alkoxy-, halo-C₁-C₆-alkoxy-, hydroxy-C₁-C₆-alkyl-, C₁-C₆-alkoxy-C₁-C₆-alkyl-, halo-C₁-C₆-alkoxy-C₁-C₆-alkyl-, R⁶-O-、-C(=O)-R⁶、-C(=O)-O-R⁶、-O-C(=O)-R⁶、-N(R^6a)-C(=O)-R^6b、-N(R^6a)-C(=O)-O-R^6b、-N(R^6a)-C(=O)-N(R^6b)R^6c、-N(R^6a)R^6b、-N(R^6a)R^6d、-C(=O)-N(R^6a)R^6b、R⁶-S-、R⁶-S(=O)-、R⁶-S(=O)₂-、-N(R^6a)-S(=O)-R^6b、-S(=O)-N(R^6a)R^6b、-N(R^6a)-S(=O)₂-R^6b、-S(=O)₂-N(R^6a)R^6b、-S(=O)=N(R^6a)R^6b、-N=S(=O)(R^6a)R^6bOr- (C)₁-C₆-alkyl) -N (R)^6a)R^6b；

R^5a、R^5bAre the same or different and are independently selected from R⁵；

R⁵Represents a hydrogen atom or a group selected from: c₁-C₆-alkyl-, C₃-C₆-cycloalkyl-, 3-to 10-membered heterocycloalkyl-, aryl-and heteroaryl-;

wherein said C₁-C₆-alkyl-, C₃-C₆-cycloalkyl-, 3-to 10-membered heterocycloalkyl-, aryl-and heteroaryl-groups optionally substituted with 1,2, 3,4 or 5R⁴The radicals are substituted identically or differently;

or

N(R^5a)R⁵Together represent a 3-to 10-membered heterocycloalkyl-group, optionally substituted by 1,2, 3,4 or 5R⁴The radicals are substituted identically or differently;

R^6a、R^6b、R^6care the same or different and are independently selected from R⁶；

R⁶Represents a hydrogen atom, C₁-C₆-alkyl-or C₃-C₆-a cycloalkyl-group;

or

R^6aAnd R^6b，

Or R^6aAnd R^6c，

Or R^6bAnd R^6cMay together form C₂-C₆An alkylene radical in which one methylene group may optionally be replaced by-O-, -C (= O) -, -NH-or-N (C)₁-C₄-alkyl) -substitution;

R^6drepresents- (C)₁-C₆-alkyl) -N (R)^6a)R^6b；

R⁷Represents halogen-, hydroxy-, oxo- (O =), cyano-, nitro-,

p represents an integer of 0, 1,2 or 3;

q represents an integer of 0, 1,2 or 3;

or a tautomer, an N-oxide, a hydrate, a solvate, or a salt thereof, or a mixture of same.

2. The compound of claim 1, wherein

R¹Represents a hydrogen atom or a halogen atom or a group selected from: c₁-C₃-alkyl-, C₁-C₃-alkoxy-, halo-C₁-C₃-alkyl-, -N (CH)₃)₂and-S- (C)₁-C₃-an alkyl group).

3. A compound according to claim 1 or 2, wherein

R¹Represents a hydrogen atom or-O-CH₃A group.

4. A compound according to any one of claims 1 to 3, wherein

R²Represents a hydrogen atom.

5. The compound according to any one of claims 1 to 4, wherein

R³Represents a group selected from: c₁-C₆-alkyl-and- (CH)₂)_q-X-(CH₂)_p-R⁵(ii) a Wherein said C₁-C₆-alkyl-group optionally substituted by 1,2, 3,4 or 5R⁴The radicals are substituted identically or differently.

6. The compound according to any one of claims 1 to 5, wherein

X represents a divalent group selected from: -C (= O) -, -C (= O) -O-, and-C (= O) -N (R)^5a)-。

7. The compound according to any one of claims 1 to 6, wherein

X represents divalent-C (= O) -N (R)^5a) -a group.

8. The compound according to any one of claims 1 to 7, wherein

R⁴Represents halogen-, hydroxy-, cyano-, C₁-C₃-alkyl-, C₁-C₃-alkoxy-, -N (R)^6a)-C(=O)-O-R^6b、-N(R^6a)R^6b、-N(R^6a)R^6d、-C(=O)-N(R^6a)R^6bOr- (C)₁-C₃-alkyl) -N (R)^6a)R^6b。

9. The compound according to any one of claims 1 to 8, wherein

R^5a、R^5bAre the same or different and are independently selected from R⁵；

R⁵Represents a hydrogen atom or C₁-C₃-an alkyl-group;

wherein said C₁-C₃-alkyl-group optionally substituted by 1,2 or 3R⁴The radicals are substituted identically or differently.

10. The compound according to any one of claims 1 to 8, wherein

N(R^5a)R⁵Together represent a 3-to 10-membered heterocycloalkyl-group, optionally substituted by 1 or 2R⁴The radicals are substituted identically or differently.

11. A compound according to any one of claims 1 to 10, wherein

R^6a、R^6b、R^6cAre the same or different and are independently selected from R⁶；

R⁶Represents a hydrogen atom or C₁-C₃-an alkyl-group; and is

R^6dRepresents- (C)₁-C₃-alkyl) -N (R)^6a)R^6bA group.

12. A compound according to any one of claims 1 to 11, wherein

p represents 0; and is

q represents 0.

13. The compound according to claim 1, selected from:

(RS) N, N-dimethyl-4- (pyrazolo [1,5-a ] pyridin-5-ylamino) -5,6,7, 8-tetrahydro [1] benzothieno [2,3-d ] pyrimidine-7-carboxamide,

(7S) -4- (pyrazolo [1,5-a ] pyridin-5-ylamino) -5,6,7, 8-tetrahydro [1] benzothieno [2,3-d ] pyrimidine-7-carboxylic acid,

[ (3R) -3-methylmorpholin-4-yl ] [ (7S) -4- (pyrazolo [1,5-a ] pyridin-5-ylamino) -5,6,7, 8-tetrahydro [1] benzothieno [2,3-d ] pyrimidin-7-yl ] methanone,

(7S) -N- [2- (dimethylamino) ethyl ] -N-methyl-4- (pyrazolo [1,5-a ] pyridin-5-ylamino) -5,6,7, 8-tetrahydro [1] benzothieno [2,3-d ] pyrimidine-7-carboxamide,

[ (2R,6S) -2, 6-dimethylmorpholin-4-yl ] [ (7S) -4- (pyrazolo [1,5-a ] pyridin-5-ylamino) -5,6,7, 8-tetrahydro [1] benzothieno [2,3-d ] pyrimidin-7-yl ] methanone,

[ (3R) -3- (dimethylamino) pyrrolidin-1-yl ] [ (7S) -4- (pyrazolo [1,5-a ] pyridin-5-ylamino) -5,6,7, 8-tetrahydro [1] benzothieno [2,3-d ] pyrimidin-7-yl ] methanone,

[ (3S) -3-methylmorpholin-4-yl ] [ (7S) -4- (pyrazolo [1,5-a ] pyridin-5-ylamino) -5,6,7, 8-tetrahydro [1] benzothieno [2,3-d ] pyrimidin-7-yl ] methanone,

(7S) -N- (2-methoxyethyl) -N-methyl-4- (pyrazolo [1,5-a ] pyridin-5-ylamino) -5,6,7, 8-tetrahydro [1] benzothieno [2,3-d ] pyrimidine-7-carboxamide,

[ (2S,6S) -2, 6-dimethylmorpholin-4-yl ] [ (7S) -4- (pyrazolo [1,5-a ] pyridin-5-ylamino) -5,6,7, 8-tetrahydro [1] benzothieno [2,3-d ] pyrimidin-7-yl ] methanone,

[ (2R,6R) -2, 6-dimethylmorpholin-4-yl ] [ (7S) -4- (pyrazolo [1,5-a ] pyridin-5-ylamino) -5,6,7, 8-tetrahydro [1] benzothieno [2,3-d ] pyrimidin-7-yl ] methanone,

morpholin-4-yl [ (7S) -4- (pyrazolo [1,5-a ] pyridin-5-ylamino) -5,6,7, 8-tetrahydro [1] benzothieno [2,3-d ] pyrimidin-7-yl ] methanone,

3-azabicyclo [3.1.0] hex-3-yl [ (7S) -4- (pyrazolo [1,5-a ] pyridin-5-ylamino) -5,6,7, 8-tetrahydro [1] benzothieno [2,3-d ] pyrimidin-7-yl ] methanone,

[ (3R,5S) -3, 5-dimethylmorpholin-4-yl ] [ (7S) -4- (pyrazolo [1,5-a ] pyridin-5-ylamino) -5,6,7, 8-tetrahydro [1] benzothieno [2,3-d ] pyrimidin-7-yl ] methanone,

[ (3R,5R) -3, 5-dimethylmorpholin-4-yl ] [ (7S) -4- (pyrazolo [1,5-a ] pyridin-5-ylamino) -5,6,7, 8-tetrahydro [1] benzothieno [2,3-d ] pyrimidin-7-yl ] methanone,

(7S) -4- [ (6-methoxypyrazolo [1,5-a ] pyridin-5-yl) amino ] -N, N-dimethyl-5, 6,7, 8-tetrahydro [1] benzothieno [2,3-d ] pyrimidine-7-carboxamide,

(7S) -N-isopropyl-N-methyl-4- (pyrazolo [1,5-a ] pyridin-5-ylamino) -5,6,7, 8-tetrahydro [1] benzothieno [2,3-d ] pyrimidine-7-carboxamide,

(7S) -N, N-dimethyl-4- (pyrazolo [1,5-a ] pyridin-5-ylamino) -5,6,7, 8-tetrahydro [1] benzothieno [2,3-d ] pyrimidine-7-carboxamide,

(7S) -N- (2, 2-difluoroethyl) -N-methyl-4- (pyrazolo [1,5-a ] pyridin-5-ylamino) -5,6,7, 8-tetrahydro [1] benzothieno [2,3-d ] pyrimidine-7-carboxamide,

(7S) -N- (2-hydroxy-2-methylpropyl) -N-methyl-4- (pyrazolo [1,5-a ] pyridin-5-ylamino) -5,6,7, 8-tetrahydro [1] benzothieno [2,3-d ] pyrimidine-7-carboxamide,

azetidin-1-yl [ (7S) -4- (pyrazolo [1,5-a ] pyridin-5-ylamino) -5,6,7, 8-tetrahydro [1] benzothieno [2,3-d ] pyrimidin-7-yl ] methanone,

(7S) -N-ethyl-N- (2-hydroxyethyl) -4- (pyrazolo [1,5-a ] pyridin-5-ylamino) -5,6,7, 8-tetrahydro [1] benzothieno [2,3-d ] pyrimidine-7-carboxamide,

1- { [ (7S) -4- (pyrazolo [1,5-a ] pyridin-5-ylamino) -5,6,7, 8-tetrahydro [1] benzothieno [2,3-d ] pyrimidin-7-yl ] carbonyl } azetidine-3-carbonitrile,

(3, 3-difluoroazetidin-1-yl) [ (7S) -4- (pyrazolo [1,5-a ] pyridin-5-ylamino) -5,6,7, 8-tetrahydro [1] benzothieno [2,3-d ] pyrimidin-7-yl ] methanone,

(3-hydroxyazetidin-1-yl) [ (7S) -4- (pyrazolo [1,5-a ] pyridin-5-ylamino) -5,6,7, 8-tetrahydro [1] benzothieno [2,3-d ] pyrimidin-7-yl ] methanone,

tert-butyl [2- (methyl { [ (7S) -4- (pyrazolo [1,5-a ] pyridin-5-ylamino) -5,6,7, 8-tetrahydro [1] benzothieno [2,3-d ] pyrimidin-7-yl ] carbonyl } amino) ethyl ] carbamate,

(7S) -N- [2- (dimethylamino) -2-oxoethyl ] -N-methyl-4- (pyrazolo [1,5-a ] pyridin-5-ylamino) -5,6,7, 8-tetrahydro [1] benzothieno [2,3-d ] pyrimidine-7-carboxamide,

(7S) -N- [3- (dimethylamino) propyl ] -N-methyl-4- (pyrazolo [1,5-a ] pyridin-5-ylamino) -5,6,7, 8-tetrahydro [1] benzothieno [2,3-d ] pyrimidine-7-carboxamide,

[3- (dimethylamino) azetidin-1-yl ] [ (7S) -4- (pyrazolo [1,5-a ] pyridin-5-ylamino) -5,6,7, 8-tetrahydro [1] benzothieno [2,3-d ] pyrimidin-7-yl ] methanone,

(4-methylpiperazin-1-yl) [ (7S) -4- (pyrazolo [1,5-a ] pyridin-5-ylamino) -5,6,7, 8-tetrahydro [1] benzothieno [2,3-d ] pyrimidin-7-yl ] methanone,

(3-hydroxy-3-methylazetidin-1-yl) [ (7S) -4- (pyrazolo [1,5-a ] pyridin-5-ylamino) -5,6,7, 8-tetrahydro [1] benzothieno [2,3-d ] pyrimidin-7-yl ] methanone,

{4- [2- (dimethylamino) ethyl ] piperazin-1-yl } [ (7S) -4- (pyrazolo [1,5-a ] pyridin-5-ylamino) -5,6,7, 8-tetrahydro [1] benzothieno [2,3-d ] pyrimidin-7-yl ] methanone,

[4- (dimethylamino) piperidin-1-yl ] [ (7S) -4- (pyrazolo [1,5-a ] pyridin-5-ylamino) -5,6,7, 8-tetrahydro [1] benzothieno [2,3-d ] pyrimidin-7-yl ] methanone,

1- { [ (7S) -4- (pyrazolo [1,5-a ] pyridin-5-ylamino) -5,6,7, 8-tetrahydro [1] benzothieno [2,3-d ] pyrimidin-7-yl ] carbonyl } piperidin-4-one,

(3, 3-difluoropyrrolidin-1-yl) [ (7S) -4- (pyrazolo [1,5-a ] pyridin-5-ylamino) -5,6,7, 8-tetrahydro [1] benzothieno [2,3-d ] pyrimidin-7-yl ] methanone,

2-oxa-6-azaspiro [3.3] hept-6-yl [ (7S) -4- (pyrazolo [1,5-a ] pyridin-5-ylamino) -5,6,7, 8-tetrahydro [1] benzothieno [2,3-d ] pyrimidin-7-yl ] methanone,

(1S,4S) -2-oxa-5-azabicyclo [2.2.1] hept-5-yl [ (7S) -4- (pyrazolo [1,5-a ] pyridin-5-ylamino) -5,6,7, 8-tetrahydro [1] benzothieno [2,3-d ] pyrimidin-7-yl ] methanone,

(1R,4R) -2-oxa-5-azabicyclo [2.2.1] hept-5-yl [ (7S) -4- (pyrazolo [1,5-a ] pyridin-5-ylamino) -5,6,7, 8-tetrahydro [1] benzothieno [2,3-d ] pyrimidin-7-yl ] methanone,

[ (1S,4S) -5-methyl-2, 5-diazabicyclo [2.2.1] hept-2-yl ] [ (7S) -4- (pyrazolo [1,5-a ] pyridin-5-ylamino) -5,6,7, 8-tetrahydro [1] benzothieno [2,3-d ] pyrimidin-7-yl ] methanone,

(7S) -N- (2-aminoethyl) -N-methyl-4- (pyrazolo [1,5-a ] pyridin-5-ylamino) -5,6,7, 8-tetrahydro [1] benzothieno [2,3-d ] pyrimidine-7-carboxamide,

(4- { [2- (dimethylamino) ethyl ] (methyl) amino } piperidin-1-yl) [ (7S) -4- (pyrazolo [1,5-a ] pyridin-5-ylamino) -5,6,7, 8-tetrahydro [1] benzothieno [2,3-d ] pyrimidin-7-yl ] methanone,

[ (3S) -3- (dimethylamino) pyrrolidin-1-yl ] [ (7S) -4- (pyrazolo [1,5-a ] pyridin-5-ylamino) -5,6,7, 8-tetrahydro [1] benzothieno [2,3-d ] pyrimidin-7-yl ] methanone,

[ (1R,4R) -5-methyl-2, 5-diazabicyclo [2.2.1] hept-2-yl ] [ (7S) -4- (pyrazolo [1,5-a ] pyridin-5-ylamino) -5,6,7, 8-tetrahydro [1] benzothieno [2,3-d ] pyrimidin-7-yl ] methanone,

(7S) -4- [ (6-chloropyrazolo [1,5-a ] pyridin-5-yl) amino ] -N- (3,3, 3-trifluoropropyl) -5,6,7, 8-tetrahydro [1] benzothieno [2,3-d ] pyrimidine-7-carboxamide,

(7S) -4- [ (6-chloropyrazolo [1,5-a ] pyridin-5-yl) amino ] -N- (prop-2-yl) -5,6,7, 8-tetrahydro [1] benzothieno [2,3-d ] pyrimidine-7-carboxamide,

(7S) -4- [ (6-chloropyrazolo [1,5-a ] pyridin-5-yl) amino ] -N, N-dimethyl-5, 6,7, 8-tetrahydro [1] benzothieno [2,3-d ] pyrimidine-7-carboxamide,

(7S) -4- [ (6-chloropyrazolo [1,5-a ] pyridin-5-yl) amino ] -N-ethyl-N-methyl-5, 6,7, 8-tetrahydro [1] benzothieno [2,3-d ] pyrimidine-7-carboxamide,

(7S) -4- [ (6-chloropyrazolo [1,5-a ] pyridin-5-yl) amino ] -N- (2, 2-difluoroethyl) -N-methyl-5, 6,7, 8-tetrahydro [1] benzothieno [2,3-d ] pyrimidine-7-carboxamide,

(7S) -4- [ (6-chloropyrazolo [1,5-a ] pyridin-5-yl) amino ] -N-methyl-N- (3,3, 3-trifluoropropyl) -5,6,7, 8-tetrahydro [1] benzothieno [2,3-d ] pyrimidine-7-carboxamide,

(7S) -N-butyl-4- [ (6-chloropyrazolo [1,5-a ] pyridin-5-yl) amino ] -N-methyl-5, 6,7, 8-tetrahydro [1] benzothieno [2,3-d ] pyrimidine-7-carboxamide,

1- ((7S) -4- [ (6-chloropyrazolo [1,5-a ] pyridin-5-yl) amino ] -5,6,7, 8-tetrahydro [1] benzothieno [2,3-d ] pyrimidin-7-ylcarbonyl) azetidine-3-carbonitrile,

(7S) -4- [ (6-chloropyrazolo [1,5-a ] pyridin-5-yl) amino ] -N- [3- (dimethylamino) propyl ] -N-methyl-5, 6,7, 8-tetrahydro [1] benzothieno [2,3-d ] pyrimidine-7-carboxamide,

(7S) -4- [ (6-chloropyrazolo [1,5-a ] pyridin-5-yl) amino ] -5,6,7, 8-tetrahydro [1] benzothieno [2,3-d ] pyrimidin-7-yl (3-hydroxy-3-methylazetidin-1-yl) methanone,

(7S) -4- [ (6-chloropyrazolo [1,5-a ] pyridin-5-yl) amino ] -N- [2- (dimethylamino) ethyl ] -N-methyl-5, 6,7, 8-tetrahydro [1] benzothieno [2,3-d ] pyrimidine-7-carboxamide,

(7S) -4- [ (6-chloropyrazolo [1,5-a ] pyridin-5-yl) amino ] -5,6,7, 8-tetrahydro [1] benzothieno [2,3-d ] pyrimidin-7-yl [3- (dimethylamino) azetidin-1-yl ] methanone,

(7S) -4- [ (6-chloropyrazolo [1,5-a ] pyridin-5-yl) amino ] -N- (2-hydroxyethyl) -N-methyl-5, 6,7, 8-tetrahydro [1] benzothieno [2,3-d ] pyrimidine-7-carboxamide,

(7S) -4- [ (6-chloropyrazolo [1,5-a ] pyridin-5-yl) amino ] -N- (2-methoxyethyl) -N-methyl-5, 6,7, 8-tetrahydro [1] benzothieno [2,3-d ] pyrimidine-7-carboxamide,

(7S) -4- [ (6-chloropyrazolo [1,5-a ] pyridin-5-yl) amino ] -N-methyl-N- (propan-2-yl) -5,6,7, 8-tetrahydro [1] benzothieno [2,3-d ] pyrimidine-7-carboxamide,

(7S) -4- [ (6-chloropyrazolo [1,5-a ] pyridin-5-yl) amino ] -5,6,7, 8-tetrahydro [1] benzothieno [2,3-d ] pyrimidin-7-yl [ (3R) -3- (dimethylamino) pyrrolidin-1-yl ] methanone,

(7S) -4- [ (6-chloropyrazolo [1,5-a ] pyridin-5-yl) amino ] -5,6,7, 8-tetrahydro [1] benzothieno [2,3-d ] pyrimidin-7-yl [ (3S) -3- (dimethylamino) pyrrolidin-1-yl ] methanone,

(7S) -4- [ (6-chloropyrazolo [1,5-a ] pyridin-5-yl) amino ] -5,6,7, 8-tetrahydro [1] benzothieno [2,3-d ] pyrimidin-7-yl [ (3S,4S) -3, 4-dihydroxypyrrolidin-1-yl ] methanone,

(7S) -4- [ (6-chloropyrazolo [1,5-a ] pyridin-5-yl) amino ] -5,6,7, 8-tetrahydro [1] benzothieno [2,3-d ] pyrimidin-7-yl [4- (dimethylamino) piperidin-1-yl ] methanone,

(7S) -4- [ (6-chloropyrazolo [1,5-a ] pyridin-5-yl) amino ] -5,6,7, 8-tetrahydro [1] benzothieno [2,3-d ] pyrimidin-7-yl (4- [2- (dimethylamino) ethyl ] (methyl) aminopiperidin-1-yl) methanone,

(7S) -4- [ (6-chloropyrazolo [1,5-a ] pyridin-5-yl) amino ] -N- [3- (dimethylamino) propyl ] -N- (2-hydroxyethyl) -5,6,7, 8-tetrahydro [1] benzothieno [2,3-d ] pyrimidine-7-carboxamide,

(7S) -4- [ (6-chloropyrazolo [1,5-a ] pyridin-5-yl) amino ] -5,6,7, 8-tetrahydro [1] benzothieno [2,3-d ] pyrimidin-7-yl [ (2R,6S) -2, 6-dimethylmorpholin-4-yl ] methanone,

(7S) -4- [ (6-chloropyrazolo [1,5-a ] pyridin-5-yl) amino ] -5,6,7, 8-tetrahydro [1] benzothieno [2,3-d ] pyrimidin-7-yl (4-methylpiperazin-1-yl) methanone,

(7S) -4- [ (6-chloropyrazolo [1,5-a ] pyridin-5-yl) amino ] -5,6,7, 8-tetrahydro [1] benzothieno [2,3-d ] pyrimidin-7-yl 4- [2- (dimethylamino) ethyl ] piperazin-1-yl-methanone,

(7S) -4- [ (6-chloropyrazolo [1,5-a ] pyridin-5-yl) amino ] -N- [2- (dimethylamino) ethyl ] -N-ethyl-5, 6,7, 8-tetrahydro [1] benzothieno [2,3-d ] pyrimidine-7-carboxamide,

(7S) -4- [ (6-chloropyrazolo [1,5-a ] pyridin-5-yl) amino ] -5,6,7, 8-tetrahydro [1] benzothieno [2,3-d ] pyrimidin-7-yl (morpholin-4-yl) methanone,

(7S) -4- [ (6-chloropyrazolo [1,5-a ] pyridin-5-yl) amino ] -N-ethyl-N- (2-hydroxyethyl) -5,6,7, 8-tetrahydro [1] benzothieno [2,3-d ] pyrimidine-7-carboxamide,

(7S) -4- [ (6-chloropyrazolo [1,5-a ] pyridin-5-yl) amino ] -N-ethyl-N- (2-methoxyethyl) -5,6,7, 8-tetrahydro [1] benzothieno [2,3-d ] pyrimidine-7-carboxamide,

(7S) -4- [ (6-chloropyrazolo [1,5-a ] pyridin-5-yl) amino ] -N, N-bis (2-methoxyethyl) -5,6,7, 8-tetrahydro [1] benzothieno [2,3-d ] pyrimidine-7-carboxamide,

(7S) -4- [ (6-chloropyrazolo [1,5-a ] pyridin-5-yl) amino ] -5,6,7, 8-tetrahydro [1] benzothieno [2,3-d ] pyrimidin-7-yl [ (1S,4S) -5-methyl-2, 5-diazabicyclo [2.2.1] hept-2-yl ] methanone,

(7S) -4- [ (6-chloropyrazolo [1,5-a ] pyridin-5-yl) amino ] -5,6,7, 8-tetrahydro [1] benzothieno [2,3-d ] pyrimidin-7-yl [ (1R,4R) -5-methyl-2, 5-diazabicyclo [2.2.1] hept-2-yl ] methanone,

(7S) -4- [ (6-chloropyrazolo [1,5-a ] pyridin-5-yl) amino ] -5,6,7, 8-tetrahydro [1] benzothieno [2,3-d ] pyrimidin-7-yl [ (1S,4S) -2-oxa-5-azabicyclo [2.2.1] hept-5-yl ] methanone,

(7S) -4- [ (6-chloropyrazolo [1,5-a ] pyridin-5-yl) amino ] -5,6,7, 8-tetrahydro [1] benzothieno [2,3-d ] pyrimidin-7-yl [ (1R,4R) -2-oxa-5-azabicyclo [2.2.1] hept-5-yl ] methanone,

(7S) -4- [ (6-chloropyrazolo [1,5-a ] pyridin-5-yl) amino ] -5,6,7, 8-tetrahydro [1] benzothieno [2,3-d ] pyrimidin-7-yl [ (3S) -3-methylmorpholin-4-yl ] methanone,

(7S) -4- [ (6-chloropyrazolo [1,5-a ] pyridin-5-yl) amino ] -5,6,7, 8-tetrahydro [1] benzothieno [2,3-d ] pyrimidin-7-yl [ (3R) -3-methylmorpholin-4-yl ] methanone,

(7S) -4- [ (6-methoxypyrazolo [1,5-a ] pyridin-5-yl) amino ] -N-methyl-5, 6,7, 8-tetrahydro [1] benzothieno [2,3-d ] pyrimidine-7-carboxamide,

(7S) -N- (2, 2-difluoroethyl) -4- [ (6-methoxypyrazolo [1,5-a ] pyridin-5-yl) amino ] -5,6,7, 8-tetrahydro [1] benzothieno [2,3-d ] pyrimidine-7-carboxamide,

(7S) -4- [ (6-methoxypyrazolo [1,5-a ] pyridin-5-yl) amino ] -N- (3,3, 3-trifluoropropyl) -5,6,7, 8-tetrahydro [1] benzothieno [2,3-d ] pyrimidine-7-carboxamide,

(7S) -N- (2-hydroxy-2-methylpropyl) -4- [ (6-methoxypyrazolo [1,5-a ] pyridin-5-yl) amino ] -5,6,7, 8-tetrahydro [1] benzothieno [2,3-d ] pyrimidine-7-carboxamide,

(7S) -N- [2- (dimethylamino) ethyl ] -4- [ (6-methoxypyrazolo [1,5-a ] pyridin-5-yl) amino ] -5,6,7, 8-tetrahydro [1] benzothieno [2,3-d ] pyrimidine-7-carboxamide,

(7S) -N- (2-hydroxyethyl) -4- [ (6-methoxypyrazolo [1,5-a ] pyridin-5-yl) amino ] -5,6,7, 8-tetrahydro [1] benzothieno [2,3-d ] pyrimidine-7-carboxamide,

(7S) -N- (2-methoxyethyl) -4- [ (6-methoxypyrazolo [1,5-a ] pyridin-5-yl) amino ] -5,6,7, 8-tetrahydro [1] benzothieno [2,3-d ] pyrimidine-7-carboxamide,

(7S) -4- [ (6-methoxypyrazolo [1,5-a ] pyridin-5-yl) amino ] -N- (prop-2-yl) -5,6,7, 8-tetrahydro [1] benzothieno [2,3-d ] pyrimidine-7-carboxamide,

(7S) -N-tert-butyl-4- [ (6-methoxypyrazolo [1,5-a ] pyridin-5-yl) amino ] -5,6,7, 8-tetrahydro [1] benzothieno [2,3-d ] pyrimidine-7-carboxamide,

(7S) -4- [ (6-methoxypyrazolo [1,5-a ] pyridin-5-yl) amino ] -N- (1-methylcyclobutyl) -5,6,7, 8-tetrahydro [1] benzothieno [2,3-d ] pyrimidine-7-carboxamide,

(7S) -N- (4-fluorophenyl) -4- [ (6-methoxypyrazolo [1,5-a ] pyridin-5-yl) amino ] -5,6,7, 8-tetrahydro [1] benzothieno [2,3-d ] pyrimidine-7-carboxamide,

(7S) -N- (3-chlorophenyl) -4- [ (6-methoxypyrazolo [1,5-a ] pyridin-5-yl) amino ] -5,6,7, 8-tetrahydro [1] benzothieno [2,3-d ] pyrimidine-7-carboxamide,

(7S) -N- (3, 4-dichlorophenyl) -4- [ (6-methoxypyrazolo [1,5-a ] pyridin-5-yl) amino ] -5,6,7, 8-tetrahydro [1] benzothieno [2,3-d ] pyrimidine-7-carboxamide,

(7S) -N- (3-chloro-4-fluorophenyl) -4- [ (6-methoxypyrazolo [1,5-a ] pyridin-5-yl) amino ] -5,6,7, 8-tetrahydro [1] benzothieno [2,3-d ] pyrimidine-7-carboxamide,

(7S) -N- (3-fluorophenyl) -4- [ (6-methoxypyrazolo [1,5-a ] pyridin-5-yl) amino ] -5,6,7, 8-tetrahydro [1] benzothieno [2,3-d ] pyrimidine-7-carboxamide,

(7S) -N- (1H-indol-5-yl) -4- [ (6-methoxypyrazolo [1,5-a ] pyridin-5-yl) amino ] -5,6,7, 8-tetrahydro [1] benzothieno [2,3-d ] pyrimidine-7-carboxamide,

(7S) -N-ethyl-4- [ (6-methoxypyrazolo [1,5-a ] pyridin-5-yl) amino ] -N-methyl-5, 6,7, 8-tetrahydro [1] benzothieno [2,3-d ] pyrimidine-7-carboxamide,

(7S) -N- (2, 2-difluoroethyl) -4- [ (6-methoxypyrazolo [1,5-a ] pyridin-5-yl) amino ] -N-methyl-5, 6,7, 8-tetrahydro [1] benzothieno [2,3-d ] pyrimidine-7-carboxamide,

(7S) -4- [ (6-methoxypyrazolo [1,5-a ] pyridin-5-yl) amino ] -N-methyl-N- (3,3, 3-trifluoropropyl) -5,6,7, 8-tetrahydro [1] benzothieno [2,3-d ] pyrimidine-7-carboxamide,

(7S) -N-butyl-4- [ (6-methoxypyrazolo [1,5-a ] pyridin-5-yl) amino ] -N-methyl-5, 6,7, 8-tetrahydro [1] benzothieno [2,3-d ] pyrimidine-7-carboxamide,

1- ((7S) -4- [ (6-methoxypyrazolo [1,5-a ] pyridin-5-yl) amino ] -5,6,7, 8-tetrahydro [1] benzothieno [2,3-d ] pyrimidin-7-ylcarbonyl) azetidine-3-carbonitrile,

(7S) -N- [3- (dimethylamino) propyl ] -4- [ (6-methoxypyrazolo [1,5-a ] pyridin-5-yl) amino ] -N-methyl-5, 6,7, 8-tetrahydro [1] benzothieno [2,3-d ] pyrimidine-7-carboxamide,

(3-hydroxy-3-methylazetidin-1-yl) (7S) -4- [ (6-methoxypyrazolo [1,5-a ] pyridin-5-yl) amino ] -5,6,7, 8-tetrahydro [1] benzothieno [2,3-d ] pyrimidin-7-yl-methanone,

(7S) -N- [2- (dimethylamino) ethyl ] -4- [ (6-methoxypyrazolo [1,5-a ] pyridin-5-yl) amino ] -N-methyl-5, 6,7, 8-tetrahydro [1] benzothieno [2,3-d ] pyrimidine-7-carboxamide,

[3- (dimethylamino) azetidin-1-yl ] (7S) -4- [ (6-methoxypyrazolo [1,5-a ] pyridin-5-yl) amino ] -5,6,7, 8-tetrahydro [1] benzothieno [2,3-d ] pyrimidin-7-yl methanone,

(7S) -N- (2-hydroxyethyl) -4- [ (6-methoxypyrazolo [1,5-a ] pyridin-5-yl) amino ] -N-methyl-5, 6,7, 8-tetrahydro [1] benzothieno [2,3-d ] pyrimidine-7-carboxamide,

(7S) -N- (2-methoxyethyl) -4- [ (6-methoxypyrazolo [1,5-a ] pyridin-5-yl) amino ] -N-methyl-5, 6,7, 8-tetrahydro [1] benzothieno [2,3-d ] pyrimidine-7-carboxamide,

(7S) -4- [ (6-methoxypyrazolo [1,5-a ] pyridin-5-yl) amino ] -N-methyl-N- (propan-2-yl) -5,6,7, 8-tetrahydro [1] benzothieno [2,3-d ] pyrimidine-7-carboxamide,

[ (3R) -3- (dimethylamino) pyrrolidin-1-yl ] (7S) -4- [ (6-methoxypyrazolo [1,5-a ] pyridin-5-yl) amino ] -5,6,7, 8-tetrahydro [1] benzothieno [2,3-d ] pyrimidin-7-yl-methanone,

[ (3S) -3- (dimethylamino) pyrrolidin-1-yl ] (7S) -4- [ (6-methoxypyrazolo [1,5-a ] pyridin-5-yl) amino ] -5,6,7, 8-tetrahydro [1] benzothieno [2,3-d ] pyrimidin-7-yl-methanone,

[ (3S,4S) -3, 4-dihydroxypyrrolidin-1-yl ] (7S) -4- [ (6-methoxypyrazolo [1,5-a ] pyridin-5-yl) amino ] -5,6,7, 8-tetrahydro [1] benzothieno [2,3-d ] pyrimidin-7-yl-methanone,

[4- (dimethylamino) piperidin-1-yl ] (7S) -4- [ (6-methoxypyrazolo [1,5-a ] pyridin-5-yl) amino ] -5,6,7, 8-tetrahydro [1] benzothieno [2,3-d ] pyrimidin-7-yl methanone,

(4- [2- (dimethylamino) ethyl ] (methyl) aminopiperidin-1-yl) (7S) -4- [ (6-methoxypyrazolo [1,5-a ] pyridin-5-yl) amino ] -5,6,7, 8-tetrahydro [1] benzothieno [2,3-d ] pyrimidin-7-yl methanone,

(7S) -N- [3- (dimethylamino) propyl ] -N- (2-hydroxyethyl) -4- [ (6-methoxypyrazolo [1,5-a ] pyridin-5-yl) amino ] -5,6,7, 8-tetrahydro [1] benzothieno [2,3-d ] pyrimidine-7-carboxamide,

[ (2R,6S) -2, 6-dimethylmorpholin-4-yl ] (7S) -4- [ (6-methoxypyrazolo [1,5-a ] pyridin-5-yl) amino ] -5,6,7, 8-tetrahydro [1] benzothieno [2,3-d ] pyrimidin-7-yl-methanone,

(7S) -4- [ (6-methoxypyrazolo [1,5-a ] pyridin-5-yl) amino ] -5,6,7, 8-tetrahydro [1] benzothieno [2,3-d ] pyrimidin-7-yl (4-methylpiperazin-1-yl) methanone,

4- [2- (dimethylamino) ethyl ] piperazin-1-yl (7S) -4- [ (6-methoxypyrazolo [1,5-a ] pyridin-5-yl) amino ] -5,6,7, 8-tetrahydro [1] benzothieno [2,3-d ] pyrimidin-7-yl-methanone,

(7S) -N- [2- (dimethylamino) ethyl ] -N-ethyl-4- [ (6-methoxypyrazolo [1,5-a ] pyridin-5-yl) amino ] -5,6,7, 8-tetrahydro [1] benzothieno [2,3-d ] pyrimidine-7-carboxamide,

(7S) -4- [ (6-methoxypyrazolo [1,5-a ] pyridin-5-yl) amino ] -5,6,7, 8-tetrahydro [1] benzothieno [2,3-d ] pyrimidin-7-yl (morpholin-4-yl) methanone,

(7S) -N-ethyl-N- (2-hydroxyethyl) -4- [ (6-methoxypyrazolo [1,5-a ] pyridin-5-yl) amino ] -5,6,7, 8-tetrahydro [1] benzothieno [2,3-d ] pyrimidine-7-carboxamide,

(7S) -N-ethyl-N- (2-methoxyethyl) -4- [ (6-methoxypyrazolo [1,5-a ] pyridin-5-yl) amino ] -5,6,7, 8-tetrahydro [1] benzothieno [2,3-d ] pyrimidine-7-carboxamide,

(7S) -N, N-bis (2-methoxyethyl) -4- [ (6-methoxypyrazolo [1,5-a ] pyridin-5-yl) amino ] -5,6,7, 8-tetrahydro [1] benzothieno [2,3-d ] pyrimidine-7-carboxamide,

(7S) -N-tert-butyl-4- [ (6-methoxypyrazolo [1,5-a ] pyridin-5-yl) amino ] -N-methyl-5, 6,7, 8-tetrahydro [1] benzothieno [2,3-d ] pyrimidine-7-carboxamide,

(7S) -4- [ (6-methoxypyrazolo [1,5-a ] pyridin-5-yl) amino ] -5,6,7, 8-tetrahydro [1] benzothieno [2,3-d ] pyrimidin-7-yl [ (1S,4S) -5-methyl-2, 5-diazabicyclo [2.2.1] hept-2-yl ] methanone,

(7S) -4- [ (6-methoxypyrazolo [1,5-a ] pyridin-5-yl) amino ] -5,6,7, 8-tetrahydro [1] benzothieno [2,3-d ] pyrimidin-7-yl [ (1R,4R) -5-methyl-2, 5-diazabicyclo [2.2.1] hept-2-yl ] methanone,

(7S) -4- [ (6-methoxypyrazolo [1,5-a ] pyridin-5-yl) amino ] -5,6,7, 8-tetrahydro [1] benzothieno [2,3-d ] pyrimidin-7-yl [ (1S,4S) -2-oxa-5-azabicyclo [2.2.1] hept-5-yl ] methanone,

(7S) -4- [ (6-methoxypyrazolo [1,5-a ] pyridin-5-yl) amino ] -5,6,7, 8-tetrahydro [1] benzothieno [2,3-d ] pyrimidin-7-yl [ (1R,4R) -2-oxa-5-azabicyclo [2.2.1] hept-5-yl ] methanone,

(7S) -4- [ (6-methoxypyrazolo [1,5-a ] pyridin-5-yl) amino ] -5,6,7, 8-tetrahydro [1] benzothieno [2,3-d ] pyrimidin-7-yl [ (3S) -3-methylmorpholin-4-yl ] methanone,

(7S) -4- [ (6-methoxypyrazolo [1,5-a ] pyridin-5-yl) amino ] -5,6,7, 8-tetrahydro [1] benzothieno [2,3-d ] pyrimidin-7-yl [ (3R) -3-methylmorpholin-4-yl ] methanone,

(7S) -N-methyl-4- (pyrazolo [1,5-a ] pyridin-5-ylamino) -N- (3,3, 3-trifluoropropyl) -5,6,7, 8-tetrahydro [1] benzothieno [2,3-d ] pyrimidine-7-carboxamide,

(2, 2-dimethylpyrrolidin-1-yl) [ (7S) -4- (pyrazolo [1,5-a ] pyridin-5-ylamino) -5,6,7, 8-tetrahydro [1] benzothieno [2,3-d ] pyrimidin-7-yl ] methanone,

(7S) -N- [ (2S) -1-methoxypropan-2-yl ] -N-methyl-4- (pyrazolo [1,5-a ] pyridin-5-ylamino) -5,6,7, 8-tetrahydro [1] benzothieno [2,3-d ] pyrimidine-7-carboxamide,

(7S) -N- [ (2R) -1-methoxypropan-2-yl ] -N-methyl-4- (pyrazolo [1,5-a ] pyridin-5-ylamino) -5,6,7, 8-tetrahydro [1] benzothieno [2,3-d ] pyrimidine-7-carboxamide,

(7S) -N- [ (2S) -2-methoxypropyl ] -N-methyl-4- (pyrazolo [1,5-a ] pyridin-5-ylamino) -5,6,7, 8-tetrahydro [1] benzothieno [2,3-d ] pyrimidine-7-carboxamide,

(7S) -N- [ (2R) -2-methoxypropyl ] -N-methyl-4- (pyrazolo [1,5-a ] pyridin-5-ylamino) -5,6,7, 8-tetrahydro [1] benzothieno [2,3-d ] pyrimidine-7-carboxamide,

(7S) -N- (1-methoxy-2-methylpropan-2-yl) -N-methyl-4- (pyrazolo [1,5-a ] pyridin-5-ylamino) -5,6,7, 8-tetrahydro [1] benzothieno [2,3-d ] pyrimidine-7-carboxamide,

(7S) -N- (2-hydroxy-2-methylpropyl) -4- [ (6-methoxypyrazolo [1,5-a ] pyridin-5-yl) amino ] -N-methyl-5, 6,7, 8-tetrahydro [1] benzothieno [2,3-d ] pyrimidine-7-carboxamide,

(7S) -N- (2-aminoethyl) -4- [ (6-methoxypyrazolo [1,5-a ] pyridin-5-yl) amino ] -N-methyl-5, 6,7, 8-tetrahydro [1] benzothieno [2,3-d ] pyrimidine-7-carboxamide,

(7S) -N- [2- (dimethylamino) -2-oxoethyl ] -4- [ (6-methoxypyrazolo [1,5-a ] pyridin-5-yl) amino ] -N-methyl-5, 6,7, 8-tetrahydro [1] benzothieno [2,3-d ] pyrimidine-7-carboxamide,

azetidin-1-yl { (7S) -4- [ (6-methoxypyrazolo [1,5-a ] pyridin-5-yl) amino ] -5,6,7, 8-tetrahydro [1] benzothieno [2,3-d ] pyrimidin-7-yl } methanone,

(3, 3-difluoroazetidin-1-yl) { (7S) -4- [ (6-methoxypyrazolo [1,5-a ] pyridin-5-yl) amino ] -5,6,7, 8-tetrahydro [1] benzothieno [2,3-d ] pyrimidin-7-yl } methanone,

(3-hydroxyazetidin-1-yl) { (7S) -4- [ (6-methoxypyrazolo [1,5-a ] pyridin-5-yl) amino ] -5,6,7, 8-tetrahydro [1] benzothieno [2,3-d ] pyrimidin-7-yl } methanone,

1- ({ (7S) -4- [ (6-methoxypyrazolo [1,5-a ] pyridin-5-yl) amino ] -5,6,7, 8-tetrahydro [1] benzothieno [2,3-d ] pyrimidin-7-yl } carbonyl) piperidin-4-one,

(3, 3-difluoropyrrolidin-1-yl) { (7S) -4- [ (6-methoxypyrazolo [1,5-a ] pyridin-5-yl) amino ] -5,6,7, 8-tetrahydro [1] benzothieno [2,3-d ] pyrimidin-7-yl } methanone,

(2, 2-dimethylpyrrolidin-1-yl) { (7S) -4- [ (6-methoxypyrazolo [1,5-a ] pyridin-5-yl) amino ] -5,6,7, 8-tetrahydro [1] benzothieno [2,3-d ] pyrimidin-7-yl } methanone,

{ (7S) -4- [ (6-methoxypyrazolo [1,5-a ] pyridin-5-yl) amino ] -5,6,7, 8-tetrahydro [1] benzothieno [2,3-d ] pyrimidin-7-yl } (2-oxa-6-azaspiro [3.3] hept-6-yl) methanone,

[ (2R,6R) -2, 6-dimethylmorpholin-4-yl ] { (7S) -4- [ (6-methoxypyrazolo [1,5-a ] pyridin-5-yl) amino ] -5,6,7, 8-tetrahydro [1] benzothieno [2,3-d ] pyrimidin-7-yl } methanone,

[ (2S,6S) -2, 6-dimethylmorpholin-4-yl ] { (7S) -4- [ (6-methoxypyrazolo [1,5-a ] pyridin-5-yl) amino ] -5,6,7, 8-tetrahydro [1] benzothieno [2,3-d ] pyrimidin-7-yl } methanone,

(7S) -N- [ (2S) -1-methoxypropan-2-yl ] -4- [ (6-methoxypyrazolo [1,5-a ] pyridin-5-yl) amino ] -N-methyl-5, 6,7, 8-tetrahydro [1] benzothieno [2,3-d ] pyrimidine-7-carboxamide,

(7S) -N- [ (2R) -1-methoxypropan-2-yl ] -4- [ (6-methoxypyrazolo [1,5-a ] pyridin-5-yl) amino ] -N-methyl-5, 6,7, 8-tetrahydro [1] benzothieno [2,3-d ] pyrimidine-7-carboxamide,

(7S) -N- [ (2S) -2-methoxypropyl ] -4- [ (6-methoxypyrazolo [1,5-a ] pyridin-5-yl) amino ] -N-methyl-5, 6,7, 8-tetrahydro [1] benzothieno [2,3-d ] pyrimidine-7-carboxamide,

(7S) -N- [ (2R) -2-methoxypropyl ] -4- [ (6-methoxypyrazolo [1,5-a ] pyridin-5-yl) amino ] -N-methyl-5, 6,7, 8-tetrahydro [1] benzothieno [2,3-d ] pyrimidine-7-carboxamide,

(7S) -N- (1-methoxy-2-methylpropan-2-yl) -4- [ (6-methoxypyrazolo [1,5-a ] pyridin-5-yl) amino ] -N-methyl-5, 6,7, 8-tetrahydro [1] benzothieno [2,3-d ] pyrimidine-7-carboxamide,

(7S) -4- [ (6-chloropyrazolo [1,5-a ] pyridin-5-yl) amino ] -N- (2-hydroxy-2-methylpropyl) -N-methyl-5, 6,7, 8-tetrahydro [1] benzothieno [2,3-d ] pyrimidine-7-carboxamide,

(7S) -N- (2-aminoethyl) -4- [ (6-chloropyrazolo [1,5-a ] pyridin-5-yl) amino ] -N-methyl-5, 6,7, 8-tetrahydro [1] benzothieno [2,3-d ] pyrimidine-7-carboxamide,

(7S) -4- [ (6-chloropyrazolo [1,5-a ] pyridin-5-yl) amino ] -N- [2- (dimethylamino) -2-oxoethyl ] -N-methyl-5, 6,7, 8-tetrahydro [1] benzothieno [2,3-d ] pyrimidine-7-carboxamide,

azetidin-1-yl { (7S) -4- [ (6-chloropyrazolo [1,5-a ] pyridin-5-yl) amino ] -5,6,7, 8-tetrahydro [1] benzothieno [2,3-d ] pyrimidin-7-yl } methanone,

{ (7S) -4- [ (6-chloropyrazolo [1,5-a ] pyridin-5-yl) amino ] -5,6,7, 8-tetrahydro [1] benzothieno [2,3-d ] pyrimidin-7-yl } (3, 3-difluoroazetidin-1-yl) methanone,

{ (7S) -4- [ (6-chloropyrazolo [1,5-a ] pyridin-5-yl) amino ] -5,6,7, 8-tetrahydro [1] benzothieno [2,3-d ] pyrimidin-7-yl } (3-hydroxyazetidin-1-yl) methanone,

1- ({ (7S) -4- [ (6-chloropyrazolo [1,5-a ] pyridin-5-yl) amino ] -5,6,7, 8-tetrahydro [1] benzothieno [2,3-d ] pyrimidin-7-yl } carbonyl) piperidin-4-one,

{ (7S) -4- [ (6-chloropyrazolo [1,5-a ] pyridin-5-yl) amino ] -5,6,7, 8-tetrahydro [1] benzothieno [2,3-d ] pyrimidin-7-yl } (3, 3-difluoropyrrolidin-1-yl) methanone,

{ (7S) -4- [ (6-chloropyrazolo [1,5-a ] pyridin-5-yl) amino ] -5,6,7, 8-tetrahydro [1] benzothieno [2,3-d ] pyrimidin-7-yl } (2, 2-dimethylpyrrolidin-1-yl) methanone,

{ (7S) -4- [ (6-chloropyrazolo [1,5-a ] pyridin-5-yl) amino ] -5,6,7, 8-tetrahydro [1] benzothieno [2,3-d ] pyrimidin-7-yl } (2-oxa-6-azaspiro [3.3] hept-6-yl) methanone,

{ (7S) -4- [ (6-chloropyrazolo [1,5-a ] pyridin-5-yl) amino ] -5,6,7, 8-tetrahydro [1] benzothieno [2,3-d ] pyrimidin-7-yl } [ (2R,6R) -2, 6-dimethylmorpholin-4-yl ] methanone,

{ (7S) -4- [ (6-chloropyrazolo [1,5-a ] pyridin-5-yl) amino ] -5,6,7, 8-tetrahydro [1] benzothieno [2,3-d ] pyrimidin-7-yl } [ (2S,6S) -2, 6-dimethylmorpholin-4-yl ] methanone,

(7S) -4- [ (6-chloropyrazolo [1,5-a ] pyridin-5-yl) amino ] -N- [ (2S) -1-methoxypropan-2-yl ] -N-methyl-5, 6,7, 8-tetrahydro [1] benzothieno [2,3-d ] pyrimidine-7-carboxamide,

(7S) -4- [ (6-chloropyrazolo [1,5-a ] pyridin-5-yl) amino ] -N- [ (2R) -1-methoxypropan-2-yl ] -N-methyl-5, 6,7, 8-tetrahydro [1] benzothieno [2,3-d ] pyrimidine-7-carboxamide,

(7S) -4- [ (6-chloropyrazolo [1,5-a ] pyridin-5-yl) amino ] -N- [ (2S) -2-methoxypropyl ] -N-methyl-5, 6,7, 8-tetrahydro [1] benzothieno [2,3-d ] pyrimidine-7-carboxamide,

(7S) -4- [ (6-chloropyrazolo [1,5-a ] pyridin-5-yl) amino ] -N- [ (2R) -2-methoxypropyl ] -N-methyl-5, 6,7, 8-tetrahydro [1] benzothieno [2,3-d ] pyrimidine-7-carboxamide,

(7S) -4- [ (6-chloropyrazolo [1,5-a ] pyridin-5-yl) amino ] -N- [ 1-methoxy-2-methylpropan-2-yl ] -N-methyl-5, 6,7, 8-tetrahydro [1] benzothieno [2,3-d ] pyrimidine-7-carboxamide,

(7S) -4- [ (6- (dimethylamino) pyrazolo [1,5-a ] pyridin-5-yl) amino ] -N, N-dimethyl-5, 6,7, 8-tetrahydro [1] benzothieno [2,3-d ] pyrimidine-7-carboxamide,

(7S) -4- [ (6- (dimethylamino) pyrazolo [1,5-a ] pyridin-5-yl) amino ] -N-methyl-N- (3,3, 3-trifluoropropyl) -5,6,7, 8-tetrahydro [1] benzothieno [2,3-d ] pyrimidine-7-carboxamide,

(7S) -N- (2-hydroxy-2-methylpropyl) -4- [ (6- (dimethylamino) pyrazolo [1,5-a ] pyridin-5-yl) amino ] -N-methyl-5, 6,7, 8-tetrahydro [1] benzothieno [2,3-d ] pyrimidine-7-carboxamide,

(7S) -N- (2, 2-difluoroethyl) -4- [ (6- (dimethylamino) pyrazolo [1,5-a ] pyridin-5-yl) amino ] -N-methyl-5, 6,7, 8-tetrahydro [1] benzothieno [2,3-d ] pyrimidine-7-carboxamide,

(7S) -4- [ (6- (dimethylamino) pyrazolo [1,5-a ] pyridin-5-yl) amino ] -N-isopropyl-N-methyl-5, 6,7, 8-tetrahydro [1] benzothieno [2,3-d ] pyrimidine-7-carboxamide,

(7S) -4- [ (6- (dimethylamino) pyrazolo [1,5-a ] pyridin-5-yl) amino ] -N-ethyl-N- (2-hydroxyethyl) -5,6,7, 8-tetrahydro [1] benzothieno [2,3-d ] pyrimidine-7-carboxamide,

(7S) -4- [ (6- (dimethylamino) pyrazolo [1,5-a ] pyridin-5-yl) amino ] -N- (2-methoxyethyl) -N-methyl-5, 6,7, 8-tetrahydro [1] benzothieno [2,3-d ] pyrimidine-7-carboxamide,

(7S) -N- (2-aminoethyl) -4- [ (6- (dimethylamino) pyrazolo [1,5-a ] pyridin-5-yl) amino ] -N-methyl-5, 6,7, 8-tetrahydro [1] benzothieno [2,3-d ] pyrimidine-7-carboxamide,

(7S) -N- [2- (dimethylamino) ethyl ] -4- [ (6- (dimethylamino) pyrazolo [1,5-a ] pyridin-5-yl) amino ] -N-methyl-5, 6,7, 8-tetrahydro [1] benzothieno [2,3-d ] pyrimidine-7-carboxamide,

(7S) -N- [2- (dimethylamino) -2-oxoethyl ] -4- [ (6- (dimethylamino) pyrazolo [1,5-a ] pyridin-5-yl) amino ] -N-methyl-5, 6,7, 8-tetrahydro [1] benzothieno [2,3-d ] pyrimidine-7-carboxamide,

(7S) -N- [3- (dimethylamino) propyl ] -4- [ (6- (dimethylamino) pyrazolo [1,5-a ] pyridin-5-yl) amino ] -N-methyl-5, 6,7, 8-tetrahydro [1] benzothieno [2,3-d ] pyrimidine-7-carboxamide,

azetidin-1-yl { (7S) -4- [ (6- (dimethylamino) pyrazolo [1,5-a ] pyridin-5-yl) amino ] -5,6,7, 8-tetrahydro [1] benzothieno [2,3-d ] pyrimidin-7-yl } methanone,

(3, 3-difluoroazetidin-1-yl) { (7S) -4- [ (6- (dimethylamino) pyrazolo [1,5-a ] pyridin-5-yl) amino ] -5,6,7, 8-tetrahydro [1] benzothieno [2,3-d ] pyrimidin-7-yl } methanone,

{ (7S) -4- [ (6- (dimethylamino) pyrazolo [1,5-a ] pyridin-5-yl) amino ] -5,6,7, 8-tetrahydro [1] benzothieno [2,3-d ] pyrimidin-7-yl } (3-hydroxyazetidin-1-yl) methanone,

{ (7S) -4- [ (6- (dimethylamino) pyrazolo [1,5-a ] pyridin-5-yl) amino ] -5,6,7, 8-tetrahydro [1] benzothieno [2,3-d ] pyrimidin-7-yl } (3-hydroxy-3-methylazetidin-1-yl) methanone,

1- ({ (7S) -4- [ (6- (dimethylamino) pyrazolo [1,5-a ] pyridin-5-yl) amino ] -5,6,7, 8-tetrahydro [1] benzothieno [2,3-d ] pyrimidin-7-yl } carbonyl) azetidine-3-carbonitrile,

[3- (dimethylamino) azetidin-1-yl ] { (7S) -4- [ (6- (dimethylamino) pyrazolo [1,5-a ] pyridin-5-yl) amino ] -5,6,7, 8-tetrahydro [1] benzothieno [2,3-d ] pyrimidin-7-yl } methanone,

{ (7S) -4- [ (6- (dimethylamino) pyrazolo [1,5-a ] pyridin-5-yl) amino ] -5,6,7, 8-tetrahydro [1] benzothieno [2,3-d ] pyrimidin-7-yl } (4-methylpiperazin-1-yl) methanone,

{4- [2- (dimethylamino) ethyl ] piperazin-1-yl } { (7S) -4- [ (6- (dimethylamino) pyrazolo [1,5-a ] pyridin-5-yl) amino ] -5,6,7, 8-tetrahydro [1] benzothieno [2,3-d ] pyrimidin-7-yl } methanone,

(4- { [2- (dimethylamino) ethyl ] (methyl) amino } piperidin-1-yl) { (7S) -4- [ (6- (dimethylamino) pyrazolo [1,5-a ] pyridin-5-yl) amino ] -5,6,7, 8-tetrahydro [1] benzothieno [2,3-d ] pyrimidin-7-yl } methanone,

[4- (dimethylamino) piperidin-1-yl ] { (7S) -4- [ (6- (dimethylamino) pyrazolo [1,5-a ] pyridin-5-yl) amino ] -5,6,7, 8-tetrahydro [1] benzothieno [2,3-d ] pyrimidin-7-yl } methanone,

1- ({ (7S) -4- [ (6- (dimethylamino) pyrazolo [1,5-a ] pyridin-5-yl) amino ] -5,6,7, 8-tetrahydro [1] benzothieno [2,3-d ] pyrimidin-7-yl } carbonyl) piperidin-4-one,

(3, 3-difluoropyrrolidin-1-yl) { (7S) -4- [ (6- (dimethylamino) pyrazolo [1,5-a ] pyridin-5-yl) amino ] -5,6,7, 8-tetrahydro [1] benzothieno [2,3-d ] pyrimidin-7-yl } methanone,

{ (7S) -4- [ (6- (dimethylamino) pyrazolo [1,5-a ] pyridin-5-yl) amino ] -5,6,7, 8-tetrahydro [1] benzothieno [2,3-d ] pyrimidin-7-yl } (2, 2-dimethylpyrrolidin-1-yl) methanone,

{ (7S) -4- [ (6- (dimethylamino) pyrazolo [1,5-a ] pyridin-5-yl) amino ] -5,6,7, 8-tetrahydro [1] benzothieno [2,3-d ] pyrimidin-7-yl } (morpholin-4-yl) methanone,

{ (7S) -4- [ (6- (dimethylamino) pyrazolo [1,5-a ] pyridin-5-yl) amino ] -5,6,7, 8-tetrahydro [1] benzothieno [2,3-d ] pyrimidin-7-yl } (2-oxa-6-azaspiro [3.3] hept-6-yl) methanone,

{ (7S) -4- [ (6- (dimethylamino) pyrazolo [1,5-a ] pyridin-5-yl) amino ] -5,6,7, 8-tetrahydro [1] benzothieno [2,3-d ] pyrimidin-7-yl } [ (2R,6S) -2, 6-dimethylmorpholin-4-yl ] methanone,

{ (7S) -4- [ (6- (dimethylamino) pyrazolo [1,5-a ] pyridin-5-yl) amino ] -5,6,7, 8-tetrahydro [1] benzothieno [2,3-d ] pyrimidin-7-yl } [ (2R,6R) -2, 6-dimethylmorpholin-4-yl ] methanone,

{ (7S) -4- [ (6- (dimethylamino) pyrazolo [1,5-a ] pyridin-5-yl) amino ] -5,6,7, 8-tetrahydro [1] benzothieno [2,3-d ] pyrimidin-7-yl } [ (2S,6S) -2, 6-dimethylmorpholin-4-yl ] methanone,

{ (7S) -4- [ (6- (dimethylamino) pyrazolo [1,5-a ] pyridin-5-yl) amino ] -5,6,7, 8-tetrahydro [1] benzothieno [2,3-d ] pyrimidin-7-yl } [ (3S) -3-methylmorpholin-4-yl ] methanone,

{ (7S) -4- [ (6- (dimethylamino) pyrazolo [1,5-a ] pyridin-5-yl) amino ] -5,6,7, 8-tetrahydro [1] benzothieno [2,3-d ] pyrimidin-7-yl } [ (3R) -3-methylmorpholin-4-yl ] methanone,

{ (7S) -4- [ (6- (dimethylamino) pyrazolo [1,5-a ] pyridin-5-yl) amino ] -5,6,7, 8-tetrahydro [1] benzothieno [2,3-d ] pyrimidin-7-yl } [ (1S,4S) -2-oxa-5-azabicyclo [2.2.1] hept-5-yl ] methanone,

{ (7S) -4- [ (6- (dimethylamino) pyrazolo [1,5-a ] pyridin-5-yl) amino ] -5,6,7, 8-tetrahydro [1] benzothieno [2,3-d ] pyrimidin-7-yl } [ (1R,4R) -2-oxa-5-azabicyclo [2.2.1] hept-5-yl ] methanone,

{ (7S) -4- [ (6- (dimethylamino) pyrazolo [1,5-a ] pyridin-5-yl) amino ] -5,6,7, 8-tetrahydro [1] benzothieno [2,3-d ] pyrimidin-7-yl } [ (1S,4S) -5-methyl-2, 5-diazabicyclo [2.2.1] hept-2-yl ] methanone,

{ (7S) -4- [ (6- (dimethylamino) pyrazolo [1,5-a ] pyridin-5-yl) amino ] -5,6,7, 8-tetrahydro [1] benzothieno [2,3-d ] pyrimidin-7-yl } [ (1R,4R) -5-methyl-2, 5-diazabicyclo [2.2.1] hept-2-yl ] methanone,

(7S) -4- [ (6- (dimethylamino) pyrazolo [1,5-a ] pyridin-5-yl) amino ] -N- [ (2S) -1-methoxypropan-2-yl ] -N-methyl-5, 6,7, 8-tetrahydro [1] benzothieno [2,3-d ] pyrimidine-7-carboxamide,

(7S) -4- [ (6- (dimethylamino) pyrazolo [1,5-a ] pyridin-5-yl) amino ] -N- [ (2R) -1-methoxypropan-2-yl ] -N-methyl-5, 6,7, 8-tetrahydro [1] benzothieno [2,3-d ] pyrimidine-7-carboxamide,

(7S) -4- [ (6- (dimethylamino) pyrazolo [1,5-a ] pyridin-5-yl) amino ] -N- [ (2S) -2-methoxypropyl ] -N-methyl-5, 6,7, 8-tetrahydro [1] benzothieno [2,3-d ] pyrimidine-7-carboxamide,

(7S) -4- [ (6- (dimethylamino) pyrazolo [1,5-a ] pyridin-5-yl) amino ] -N- [ (2R) -2-methoxypropyl ] -N-methyl-5, 6,7, 8-tetrahydro [1] benzothieno [2,3-d ] pyrimidine-7-carboxamide,

(7S) -4- [ (6- (dimethylamino) pyrazolo [1,5-a ] pyridin-5-yl) amino ] -N- (1-methoxy-2-methylpropan-2-yl) -N-methyl-5, 6,7, 8-tetrahydro [1] benzothieno [2,3-d ] pyrimidine-7-carboxamide,

or a tautomer, an N-oxide, a hydrate, a solvate, or a salt thereof, or a mixture of same.

14. A process for the preparation of a compound of general formula (I) according to any one of claims 1 to 13, in which process an intermediate compound of general formula (II) is reacted with an intermediate compound of general formula (III):

wherein R is²And R³As defined for general formula (I) in any one of claims 1 to 13, and LG represents a leaving group, preferably a chlorine atom;

wherein R is¹As defined in any one of claims 1 to 13 for the general formula (I)And (4) defining.

15. A compound of general formula (I), or a stereoisomer, a tautomer, an N-oxide, a hydrate, a solvate, or a salt thereof, particularly a pharmaceutically acceptable salt thereof, or a mixture of same, according to any one of claims 1 to 13, for use in the treatment or prophylaxis of a disease.

16. A pharmaceutical composition comprising a compound of general formula (I), or a stereoisomer, a tautomer, an N-oxide, a hydrate, a solvate, or a salt thereof, particularly a pharmaceutically acceptable salt thereof, or a mixture of same, according to any one of claims 1 to 13, and a pharmaceutically acceptable diluent or carrier.

17. A pharmaceutical combination comprising:

-one or more first active ingredients selected from compounds of general formula (I) according to any one of claims 1 to 13, and

-one or more second active ingredients selected from chemotherapeutic anti-cancer agents.

18. Use of a compound of general formula (I), or a stereoisomer, a tautomer, an N-oxide, a hydrate, a solvate, or a salt thereof, particularly a pharmaceutically acceptable salt thereof, or a mixture of same, according to any one of claims 1 to 13, for the prophylaxis or treatment of a disease.

19. Use of a compound of general formula (I), or a stereoisomer, a tautomer, an N-oxide, a hydrate, a solvate, or a salt thereof, particularly a pharmaceutically acceptable salt thereof, or a mixture of same, according to any one of claims 1 to 13, for the preparation of a medicament for the prophylaxis or treatment of a disease.

20. The use of claim 15, 18 or 19, wherein the disease is a disease of uncontrolled cell growth, proliferation and/or survival, an inappropriate cellular immune response or an inappropriate cellular inflammatory response, in particular wherein the uncontrolled cell growth, proliferation and/or survival, inappropriate cellular immune response or inappropriate cellular inflammatory response is mediated by the MKNK1 pathway, the MKNK2 pathway or the MKNK1 and MKNK2 pathways, more particularly wherein the disease of uncontrolled cell growth, proliferation and/or survival, inappropriate cellular immune response or inappropriate cellular inflammatory response is a hematologic tumor, a solid tumor and/or metastases thereof, such as leukemia and myelodysplastic syndrome, malignant lymphoma, head and neck tumors including brain tumors and brain metastases, chest tumors including non-small cell lung tumors and small cell lung tumors, Gastrointestinal tumors, endocrine tumors, breast tumors and other gynecological tumors, urinary system tumors including kidney, bladder and prostate tumors, skin tumors and sarcomas, and/or metastases thereof, or pancreatitis.

21. The use according to claim 15, 18 or 19, wherein the disease is one of the following inflammatory and/or pain related diseases.

22. Use according to claim 15, 18 or 19 for the treatment of pain syndromes including acute, chronic, inflammatory and neuropathic pain, preferably inflammatory pain, surgical pain, visceral pain, dental pain, premenstrual pain, endometriosis-related pain or other endometriosis-related symptoms, wherein said symptoms are in particular endometriosis-related dysmenorrhea, dyspareunia, dysuria or constipation, pain associated with fibrotic diseases, central pain, pain due to causalgia, pain due to burns, pain due to migraine, cluster headache, pain due to nerve injury, pain due to neuritis, neuralgia, pain due to poisoning, pain due to ischemic injury, pain due to interstitial cystitis, cancer pain, pain due to viruses, interstitial cystitis, pain, Pain due to parasitic or bacterial infection, pain due to traumatic nerve injury, pain due to post-traumatic injury (including fracture and sports injuries), pain due to trigeminal neuralgia, pain associated with small fiber neuropathy, pain associated with diabetic neuropathy, chronic lower back pain, phantom limb pain, pelvic pain syndrome, chronic pelvic pain, neuroma pain, complex regional pain syndrome, pain associated with gastrointestinal tract dilatation, chronic arthritic pain and associated neuropathic pain and pain associated with cancer, pain associated with chemotherapy, HIV and HIV treatment-induced neuropathy; and pain associated with a disease or condition selected from hyperalgesia, allodynia, irritable bowel syndrome.

23. Use according to claim 15, 18 or 19, wherein the disease is dysmenorrhea, dyspareunia, endometriosis, adenomyosis, endometriosis-related pain or other endometriosis-related symptoms, wherein the symptoms are in particular endometriosis-related proliferation, dysmenorrhea, dyspareunia, dysuria or constipation.

24. The use according to claim 15, 18 or 19 for the treatment of inflammatory bowel disease (ulcerative colitis and crohn's disease), congestion, sepsis, metabolic disorders such as obesity, diabetes; atherosclerosis, reperfusion injury, inflammatory bone resorption, pulmonary fibrosis, acute respiratory distress syndrome and intestinal polyposis, inflammatory skin diseases such as psoriasis, pemphigus vulgaris, fibrotic diseases such as idiopathic pulmonary fibrosis, skin fibrosis, systemic sclerosis, autism, liver diseases such as non-alcoholic fatty liver disease, liver fibrosis; lung diseases such as chronic obstructive pulmonary disease, asthma, pneumonia; neurodegenerative diseases such as Parkinson's disease, Alzheimer's disease; stroke, post-ischemic brain injury, cerebral ischemia, alopecia, acute coronary syndrome, myocardial infarction, autoimmune diseases such as autoimmune encephalomyelitis, multiple sclerosis; arthritis (e.g., osteoarthritis and rheumatoid arthritis); interstitial cystitis, hypertrophy, ischemia/reperfusion injury, allergic rhinitis, burns, osteoporosis.

25. A compound of the general formula (II):

wherein R is²And R³As defined in any one of claims 1 to 13, and LG represents a leaving group, preferably a chlorine atom.

26. Use of a compound of general formula (II) as defined in claim 25 for the preparation of a compound of formula (I) as defined in any one of claims 1 to 13.