TW201529585A - Substituted pyrazolopyridines - Google Patents

Abstract

The present invention relates to substituted pyrazolopyridine 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 and/or angiogenesis disorder, as a sole agent or in combination with other active ingredients.

Description

Substituted pyrazolopyridine

The present invention relates to a substituted pyrazolopyridine compound of the formula I as described and defined herein, a process for the preparation of the compounds, an intermediate compound suitable for the preparation of the compounds, a pharmaceutical composition comprising the compounds, and Combinations and the use of such compounds for the manufacture of a pharmaceutical composition for use as a sole agent or in combination with other active ingredients for the treatment or prevention of a disease, in particular a hyperproliferative disorder and/or an angiogenic disorder.

The present invention relates to compounds which inhibit MKNK1 kinase (also known as MAP kinase interacting kinase Mnk1) and/or MKNK2 kinase (also known as MAP kinase interacting kinase Mnk2).

Human MKNK contains a set of four proteins encoded by two genes (gene symbols: MKNK1 and MKNK2) by alternative splicing. The b-form lacks the MAP kinase binding domain at the C-terminus. MKNK1 is very similar to the catalytic domain of MKNK2 and contains a unique DFD (Asp-Phe-Asp) motif in subdomain VII, and DFG (Asp-Phe-Gly) in other protein kinases and proposes to alter ATP. In combination [Jauch et al, Structure 13, 1559-1568, 2005 and Jauch et al, EMBO J25, 4020-4032, 2006]. MKNK1a binds to and is activated by ERK and p38 MAP kinase but not by JNK1. MKNK2a binds to ERK and is only activated by it. MKNK1b has low activity under all conditions and MKNK2b has a basic activity independent of ERK or p38 MAP kinase [Buxade M et al, Frontiers in Bioscience 5359-5374, May 1, 2008].

MKNK has been shown to enable eukaryotic initiation factor 4E (eIF4E), heterogeneous nuclear ribonucleic acid Binding protein A1 (hnRNP A1), polypyrimidine-binding protein-associated splicing factor (PSF), cytosolic phospholipase A2 (cPLA2), and Sprouty 2 (hSPRY2) phosphorylation [Buxade M et al., Frontiers in Bioscience 5359-5374, 2008 May 1st].

eIF4E is an oncogene that is amplified in many cancers and exclusively phosphorylated by MKNK protein as shown in the KO mouse study [Konicek et al, Cell Cycle 7: 16, 2466-2471, 2008; Ueda et al, Mol Cell Biol 24, 6539-6549, 2004]. eIF4E plays a key role in enabling translation of cellular mRNA. eIF4E binds to the 7-methylguanosine end of the 5' end of cellular mRNA and delivers it to the ribosome as part of the eIF4F complex, which also contains eIF4G and eIF4A. Although eIF4E is required for translation of all capped mRNAs, translation of one pool of mRNA is particularly dependent on elevated eIF4E activity. These so-called "weak mRNAs" are generally less efficient for translation due to their long and complex 5' UTR region, and encode proteins that play a significant role in all malignant disease states, including VEGF, FGF-2, c. - Myc, cyclin D1, survivin, BCL-2, MCL-1, MMP-9, heparinase, and the like. The antagonism and function of eIF4E is elevated in a variety of human cancers and is directly related to disease progression [Konicek et al, Cell Cycle 7: 16, 2466-2471, 2008].

MKNK1 and MKNK2 are the only kinases known to phosphorylate eIF4E in Ser209. Although the overall translation rate is not affected by eIF4E phosphorylation, it has been suggested that eIF4E phosphorylation promotes polyribosome formation (ie, multiple ribosomes on a single mRNA), which ultimately enables more efficient translation of "weak mRNA" [Buxade M] Etc. Frontiers in Bioscience 5359-5374, May 1, 2008]. Alternatively, phosphorylation of eIF4E by MKNK protein may contribute to the release of eIF4E from the 5' end, allowing the 48S complex to move along the "weak mRNA" to locate the initiation codon [Blagden SP and Willis AE, Nat Rev Clin Oncol .8(5): 280-91, 2011]. Therefore, increased eIF4E phosphorylation in patients with non-small cell lung cancer predicts poor prognosis [Yoshizawa et al, Clin Cancer Res. 16(1): 240-8, 2010]. Further information indicates that the functional role of MKNK1 in carcinogenesis accelerates tumor formation in mouse embryonic fibroblasts due to overexpression of constitutively active MKNK1 but not kinase MKNK1 [Chrestensen CA et al., Genes Cells 12, 1133-1140, 2007]. Furthermore, increased phosphorylation and activity of MKNK proteins is associated with overexpression of HER2 in breast cancer [Chrestensen, CA et al, J. Biol. Chem. 282, 4243-4252, 2007]. Constitutive activity rather than kinase failure MKNK1 also accelerates tumor growth in a mouse model of tumor production using Eμ-Myc transgenic hematopoietic stem cells. Comparable results were achieved when analyzing eIF4E with the S209D mutation. The S209D mutation mimics the phosphorylation of the MKNK1 phosphorylation site. In contrast, the non-phosphorylated form of eIF4E slows tumor growth [Wendel HG, et al, Genes Dev. 21 (24): 3232-7, 2007]. Selective MKNK inhibitors that block eIF4E phosphorylation cause apoptosis and inhibit proliferation and soft agar growth in vitro in cancer cells. This inhibitor also inhibits the growth of experimental B16 melanoma lung cancer metastasis and the growth of subcutaneous HCT116 colon cancer xenograft tumors without affecting body weight [Konicek et al., Cancer Res. 71(5): 1849-57, 2011] . Screening for pancreatic ductal adenocarcinoma patient populations by immunohistochemistry showed that eIF4E phosphorylation was associated with disease grade, early onset of disease, and worse prognosis. In addition, based on preclinical in vitro findings, the MNK/eIF4E pathway is proposed to represent the escape route of pancreatic ductal adenocarcinoma cells to resist chemotherapy (eg, gemcitabine) [Adesso L et al., Oncogene. July 16, 2012 ]. Furthermore, Rapamycin was activated to activate MKNK1 kinase activity in a multiple myeloma cell line and the major specimen was activated by a MKNK-dependent mechanism. Pharmacological inhibition of MKNK activity or gene silencing of MKNK1 prevents up-regulation of rapamycin-induced c-myc IRES activity. Although rapamycin used alone has little effect on myc protein, when combined with MKNK inhibitors, myc protein expression is abolished. Such data provide the rationale for therapeutically targeting MKNK kinase in combination with mTOR inhibitors [Shi Y et al., Oncogene. February 27, 2012]. In summary, phosphorylation of eIF4E via MKNK protein activity promotes cell proliferation and survival and is critical for malignant transformation. Inhibition of MKNK activity provides an easy to treat cancer treatment.

WO2006/136402 (A1) and WO2007/059905 (A2) (Develogen AG) disclose thienopyrimidine-4-amine and its use for preventing and/or treating diseases which are affected by inhibition of Mnk1 and/or Mnk2 kinase activity . The 4-amino- group is substituted with a substituted phenyl group. The WO publication does not disclose any biological data.

WO2010/023181 (A1), WO2011/104334 (A1), WO2011/104337 (A1), WO2011/104338 (A1) and WO2011/104340 (A1) (Boehringer Ingelheim) are related to thienopyrimidine-4-amine, For preventing and/or treating diseases which may be affected by inhibition of Mnk1 and/or Mnk2 kinase activity.

WO 2014/001973 (A1) discloses 4-(substituted-amino)-7H-pyrrolo[2,3-d]pyrimidines as LRRK2 inhibitors.

The specific substituted pyrazolopyridines of the formula I of the invention as defined herein and as hereinafter referred to as "compounds of the invention" have not been disclosed, or the stereoisomers thereof as described and defined herein , tautomers, N-oxides, hydrates, solvates or salts, or mixtures of such substances, or pharmacological activities thereof.

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

In particular, it has been surprisingly discovered that such compounds of the invention are effective for inhibiting MKNK kinase and are therefore useful for treating or preventing diseases of uncontrolled cell growth, proliferation and/or survival, inappropriate cellular immune responses or inappropriate cellular inflammatory responses; Or a disease accompanied by uncontrolled cell growth, proliferation and/or survival, inappropriate cellular immune response, or inappropriate cellular inflammatory response; particularly where uncontrolled cell growth, proliferation and/or survival, inappropriate cellular immune response, or inappropriate cellular inflammatory response A disease mediated by MKNK kinase, such as hematological tumors, solid tumors and/or metastases (such as leukemia and myelodysplastic syndromes), malignant lymphomas, head and neck tumors (including brain tumors and brain metastases), and chest tumors (including Non-small cell lung tumors and small cell lung tumors), gastrointestinal tumors, endocrine tumors, breast and other gynecological tumors, urinary tumors (including kidney tumors, bladder tumors and prostate tumors), skin tumors and meat Tumor and/or its metastasis.

The invention encompasses compounds of formula I :

Wherein: QV represents a group selected from the group consisting of C(R ^1a )-N, NC(R ^1a ); and A represents a group selected from the group consisting of: Wherein * indicates the point of attachment of the rest of the molecule such group; R ^1a represents a hydrogen atom or a halogen atom or a group selected from the group of: hydroxy - cyano -, C ₁ -C ₆ alkyl -, C ₂ - C ₆ alkenyl-, C ₂ -C ₆ alkynyl-, C ₁ -C ₆ alkoxy-, halo-C ₁ -C ₆ alkyl-, halo-C ₁ -C ₆ alkoxy-, Hydroxy-C ₁ -C ₆ alkyl-, C ₁ -C ₃ alkoxy-C ₁ -C ₃ alkyl-, -N(R ^5b )R ^5c , -SCF ₃ , -SF ₅ ; R ^1b represents hydrogen An atom or a halogen atom or a group selected from the group consisting of hydroxy-, cyano-, C ₁ -C ₆ alkyl-, C ₂ -C ₆ alkenyl-, C ₂ -C ₆ alkynyl-, C ₁ -C ₆ alkoxy-, halo-C ₁ -C ₆ alkyl-, halo-C ₁ -C ₆ alkoxy-, hydroxy-C ₁ -C ₆ alkyl-, C ₁ -C ₃ alkoxy -C ₁ -C ₃ alkyl-, -N(R ^5b )R ^5c , -SCF ₃ , -SF ₅ ; R ^1c represents a hydrogen atom or a halogen atom or a group selected from the group consisting of hydroxy-, cyano-, C ₁ -C ₆ alkyl-, C ₂ -C ₆ alkenyl-, C ₂ -C ₆ alkynyl-, C ₁ -C ₆ alkoxy-, halo-C ₁ -C ₆ alkyl-, halo -C ₁ -C ₆ alkoxy-, hydroxy-C ₁ -C ₆ alkyl-, C ₁ -C ₃ alkoxy-C ₁ -C ₃ alkyl-, -N(R ^5b )R ^5c , -SCF _3, -SF _5; R ^2a represents a hydrogen atom A halogen atom or a group selected from the group: C ₁ -C ₆ alkyl -, C ₃ -C ₆ cycloalkyl -, heterocycloalkyl 3-10 - 4-10 heterocycloalkenyl -, aryl Base-, heteroaryl-, cyano-, -(CH ₂ ) _q -U-(CH ₂ ) _p -R ^3a ; wherein the C ₁ -C ₆ alkyl-, C ₃ -C ₆ cycloalkyl- 3 to 10 membered heterocycloalkyl-, 4 to 10 membered heterocycloalkenyl-, aryl- or heteroaryl-, as the case may be, 1, 2, 3, 4 or 5 R ⁴ groups identically or differently Substituted; R ^2b represents a hydrogen atom or a halogen atom or a group selected from the group consisting of C ₁ -C ₆ alkyl-, C ₃ -C ₆ cycloalkyl-, 3 to 10 membered heterocycloalkyl-, 4 to 10 a heterocycloalkenyl-, aryl-, heteroaryl-, cyano-, -(CH ₂ ) _q -U-(CH ₂ ) _p -R ^3a ; wherein the C ₁ -C ₆ alkyl-, C _3- C ₆ cycloalkyl-, 3 to 10 membered heterocycloalkyl-, 4 to 10 membered heterocycloalkenyl-, aryl- or heteroaryl-, as the case may be the same or different, 1, 2, 3, 4 or 5 R ⁴ groups substituted; or R ^2a and R ^2b together

Represents -(CH ₂ ) _r -T-(CH ₂ ) _s -; T represents a group selected from the group consisting of U, -C[R ^6a ][(C(R ^6b )(R ^6c )) _t -UR ^3a U- represents a single bond or a divalent group selected from the group consisting of -O-, -S-, -S(=O)-, -S(=O) ₂ -, -S(=O) -N(R ^3b )-, -N(R ^3c )-S(=O)-, -S(=O) ₂ -N(R ^3b )-, -N(R ^3c )-S(=O) ₂ -, -C(=O)-, -N(R ^3b )-, -C(=O)-O-, -OC(=O)-, -C(=S)-O-, -OC(= S)-, -C(=O)-N(R ^3b )-, -N(R ^3c )-C(=O)-, -N(R ^3c )-C(=O)-N(R ^3b ) -, -OC(=O)-N(R ^3b )-, -N(R ^3c )-C(=O)-O-; R ^3a represents a hydrogen atom or a group selected from the group consisting of C ₁ -C ₆ Alkyl-, C ₃ -C ₆ cycloalkyl-, 3 to 10 membered heterocycloalkyl-, 4 to 10 membered heterocycloalkenyl-, aryl-, heteroaryl-; wherein C ₁ -C ₆ Alkyl-, C ₃ -C ₆ cycloalkyl-, 3 to 10 membered heterocycloalkyl-, 4 to 10 membered heterocycloalkenyl-, aryl- or heteroaryl-, as the case may be the same or different , 2, 3, 4 or 5 R ⁴ groups are substituted; R ^3b represents a hydrogen atom or a group selected from the group consisting of C ₁ -C ₆ alkyl-, C ₃ -C ₆ cycloalkyl-, 3 to 10 Heterocycloalkyl-, 4 to 10 membered heterocycloalkenyl-, aryl-, heteroaryl-; wherein the C ₁ -C ₆ alkyl-, C ₃ -C ₆ naphthenic Base, 3 to 10 membered heterocycloalkyl-, 4 to 10 membered heterocycloalkenyl-, aryl- or heteroaryl-, as the case may be, 1, 2, 3, 4 or 5 R ⁴ a group substituted; R ^3c represents a hydrogen atom or a group selected from the group consisting of C ₁ -C ₆ alkyl-, C ₃ -C ₆ cycloalkyl-, 3 to 10 membered heterocycloalkyl-, 4 to 10 members Heterocyclenyl-, aryl-, heteroaryl-, wherein the C ₁ -C ₆ alkyl-, C ₃ -C ₆ cycloalkyl-, 3 to 10 membered heterocycloalkyl-, 4 to 10 members Heterocyclenyl-, aryl- or heteroaryl-, as the case may be, identically or differently substituted by 1, 2, 3, 4 or 5 R ⁴ groups; or N(R ^3b )R ^3a together

Forming a 3 to 10 membered heterocycloalkyl group or a 4 to 10 membered heterocycloalkenyl group, wherein the 3 to 10 membered heterocycloalkyl group or 4 to 10 membered heterocycloalkenyl group - as the case may be the same or different , 2, 3, 4 or 5 R ⁴ groups are substituted; R ⁴ represents halo-, hydroxy-, pendant oxy-(O=), cyano-, nitro-, C ₁ -C ₆ alkyl- , C ₂ -C ₆ alkenyl-, C ₂ -C ₆ alkynyl-, halo-C ₁ -C ₆ alkyl-, C ₁ -C ₆ alkoxy-, halo-C ₁ -C ₆ alkane Oxy-, hydroxy-C ₁ -C ₆ alkyl-, C ₁ -C ₆ alkoxy-C ₁ -C ₆ alkyl-, halo-C ₁ -C ₆ alkoxy-C ₁ -C ₆ Alkyl-, R ^5c -O-, -C(=O)-R ^5c , -C(=O)-OR ^5c , -OC(=O)-R ^5c , -N(R ^5b )-C(= O)-R ^5c , -N(R ^5c )-C(=O)-N(R ^5a )R ^5b , -N(R ^5a )R ^5b , -C(=O)-N(R ^5a )R ^5b , R ^5c -S-, R ^5c -S(=O)-, R ^5c -S(=O) ₂ -, -N(R ^5c )-S(=O)-R ^5b , -S(=O) -N(R ^5a )R ^5b , -N(R ^5c )-S(=O) ₂ -R ^5b , -S(=O) ₂ -N(R ^5a )R ^5b , -S(=O)=N (R ^5c ) R ^5b , -S(=O)=N(R ^5c )R ^5b or -N=S(=O)(R ^5c )R ^5b ; R ^5a represents a hydrogen atom, C ₁ -C ₆ alkyl a C ₃ -C ₆ cycloalkyl-, phenyl- or 3 to 10 membered heterocycloalkyl- group; wherein the C ₁ -C ₆ alkyl group - optionally substituted once by phenyl group; ^5b represents a hydrogen atom, a C ₁ -C ₆ alkyl-, a C ₃ -C ₆ cycloalkyl- or a 3 to 10 membered heterocycloalkyl group; R ^5c represents a hydrogen atom, a C ₁ -C ₆ alkyl group, C _3- C ₆ cycloalkyl- or 3 to 10 membered heterocycloalkyl-; or N(R ^5a )R ^5b

3 to 7 membered heterocycloalkyl-formed together; R ^6a represents a hydrogen atom or a group selected from the group consisting of C ₁ -C ₆ alkyl-, C ₂ -C ₆ alkenyl-, C ₂ -C ₆ alkynyl Wherein the C ₁ -C ₆ alkyl-, C ₂ -C ₆ alkenyl- or C ₂ -C ₆ alkynyl group is optionally substituted with 1, 2 or 3 R ⁴ groups, as the case may be; R ^6b represents a hydrogen atom or a C ₁ -C ₃ alkyl group; R ^6c represents a hydrogen atom or a C ₁ -C ₃ alkyl group; p represents an integer of 0, 1, 2 or 3; q represents 0, 1, 2 or 3 An integer; r represents an integer of 1, 2 or 3; s represents an integer of 1, 2 or 3; and t represents an integer of 0 or 1; or a tautomer thereof, an N-oxide, a hydrate or a solvate thereof Or a salt, or a mixture of such substances.

The invention further relates to a process for the preparation of a compound of the formula I , to pharmaceutical compositions and combinations comprising the compounds, to the use of such compounds for the manufacture of a pharmaceutical composition for the treatment or prophylaxis of diseases, and to the preparation of such compounds Intermediate compound.

The term as referred to in the text of the present invention preferably has the following meaning: the terms "halogen atom", "halo-" or "halo-" are understood to mean a fluorine, chlorine, bromine or iodine atom, preferably fluorine. , chlorine or bromine atoms.

The term "C ₁ -C ₁₀ alkyl" is understood to preferably mean a saturated monovalent hydrocarbon radical having a straight or branched chain of 1, 2, 3, 4, 5, 6, 7, 8, 9 or 10 carbon atoms. , for example, methyl, ethyl, propyl, butyl, pentyl, hexyl, isopropyl, isobutyl, second butyl, tert-butyl, isopentyl, 2-methylbutyl, 1- Methyl butyl, 1-ethylpropyl, 1,2-dimethylpropyl, neopentyl, 1,1-dimethylpropyl, 4-methylpentyl, 3-methylpentyl, 2-methylpentyl, 1-methylpentyl, 2-ethylbutyl, 1-ethylbutyl, 3,3-dimethylbutyl, 2,2-dimethylbutyl, 1, 1-dimethylbutyl, 2,3-dimethylbutyl, 1,3-dimethylbutyl or 1,2-dimethylbutyl or an isomer thereof. In particular, the group has 1, 2, 3, 4, 5 or 6 carbon atoms ("C ₁ -C ₆ alkyl"), more specifically, the group has 1, 2, 3 or 4 Carbon atoms ("C ₁ -C ₄ alkyl"), such as methyl, ethyl, propyl, butyl, isopropyl, isobutyl, t-butyl, t-butyl; even more specific 1, 1, 2 or 3 carbon atoms ("C ₁ -C ₃ alkyl"), such as methyl, ethyl, n-propyl- or isopropyl.

The term "C ₁ -C ₁₀ alkylene" is understood to mean preferably a saturated or branched chain having 1, 2, 3, 4, 5, 6, 7, 8, 9 or 10 carbon atoms. A valent hydrocarbon group such as methylene, ethyl, n-propyl, n-butyl, n-pentyl, 2-methyl-butyl, n-hexyl, 3-methyl-amyl or an isomer thereof. In particular, the group is straight-chain and has 2, 3, 4 or 5 carbon atoms ("C ₂ -C ₅ alkyl"), such as ethyl, n-propyl, n-butyl, and n-butyl. More specifically, 3 or 4 carbon atoms ("C ₃ -C ₄ alkyl"), such as propyl or n-butyl.

The term "halo-C ₁ -C ₆ alkyl" is understood to mean a saturated monovalent hydrocarbon radical, preferably a straight or branched chain, wherein the term "C ₁ -C ₆ alkyl" is defined above and one of A plurality of hydrogen atoms are replaced by a halogen atom identically or differently, that is, one halogen atom is independent of the other halogen atom. Specifically, the halogen atom is F. The halo-C ₁ -C ₆ alkyl group is, for example, -CF ₃ , -CHF ₂ , -CH ₂ F, -CF ₂ CF ₃ or -CH ₂ CF ₃ .

The term "C ₁ -C ₆ alkoxy" is understood to mean a saturated or monovalent hydrocarbon radical of the straight-chain or branched chain of the formula -O-(C ₁ -C ₆ alkyl), wherein the term "C ₁ -C ₆ Alkyl" is defined above, for example methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, isobutoxy, tert-butoxy, second butoxy, pentyl Oxyl, isopentyloxy or n-hexyloxy or an isomer thereof.

The term "halo-C ₁ -C ₆ alkoxy" is understood to preferably mean a straight-chain or branched-chain saturated monovalent C ₁ -C ₆ alkoxy group as defined above, wherein one or more hydrogen atoms Replacement by halogen atom identically or differently. Specifically, the halogen atom is F. The halo-C ₁ -C ₆ alkoxy group is, for example, -OCF ₃ , -OCHF ₂ , -OCH ₂ F, -OCF ₂ CF ₃ or -OCH ₂ CF ₃ .

The term "C ₁ -C ₆ alkoxy-C ₁ -C ₆ alkyl" is understood to preferably mean a saturated monovalent C ₁ -C ₆ alkyl group of a straight or branched chain as defined above, wherein one or The plurality of hydrogen atoms are the same or differently substituted by a C ₁ -C ₆ alkoxy group as defined above, such as methoxyalkyl, ethoxyalkyl, propoxyalkyl, isopropoxyalkyl, Butoxyalkyl, isobutoxyalkyl, tert-butoxyalkyl, second butoxyalkyl, pentoxyalkyl, isopentyloxyalkyl, hexyloxyalkyl or the like Structure.

The term "halo-C ₁ -C ₆ alkoxy-C ₁ -C ₆ alkyl" is understood to mean a saturated monovalent C ₁ -C ₆ alkoxy group, preferably as defined above, a straight or branched chain. a -C ₁ -C ₆ alkyl group in which one or more hydrogen atoms are replaced by a halogen atom identically or differently. Specifically, the halogen atom is F. The halo-C ₁ -C ₆ alkoxy-C ₁ -C ₆ alkyl group is, for example, -CH ₂ CH ₂ OCF ₃ , -CH ₂ CH ₂ OCHF ₂ , -CH ₂ CH ₂ OCH ₂ F, -CH ₂ CH ₂ OCF ₂ CF ₃ or -CH ₂ CH ₂ OCH ₂ CF ₃ .

The term "C ₂ -C ₁₀ alkenyl" is understood to preferably mean one or more double bonds and have 2, 3, 4, 5, 6, 7, 8, 9 or 10 carbon atoms, in particular 2. a linear or branched monovalent hydrocarbon group of 3, 4, 5 or 6 carbon atoms ("C ₂ -C ₆ alkenyl"), more particularly 2 or 3 carbon atoms ("C ₂ -C ₃ alkenyl") It should be understood that where the alkenyl group contains more than one double bond, the double bonds may be separated or conjugated to each other. The alkenyl group is, for example, a vinyl group, an allyl group, ( E )-2-methylvinyl group, ( Z )-2-methylvinyl group, homoallyl group, ( E )-but-2-enyl group, ( Z )-but-2-enyl, ( E )-but-1-enyl, ( Z )-but-1-enyl, pent-4-enyl, ( E )-pent-3-enyl ( Z )-pent-3-enyl, ( E )-pent-2-enyl, ( Z )-pent-2-enyl, ( E )-pent-1-enyl, ( Z )-pentyl -1-alkenyl, hex-5-alkenyl, ( 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, ( E )-1-methylpropan-1- Alkenyl, ( Z )-1-methylprop-1-enyl, 3-methylbut-3-enyl, 2-methylbut-3-enyl, 1-methylbut-3-enyl , 3-methylbut-2-enyl, ( E )-2-methylbut-2-enyl, ( Z )-2-methylbut-2-enyl, ( E )-1-methyl But-2-enyl, ( Z )-1-methylbut-2-enyl, ( E )-3-methylbut-1-enyl, ( Z )-3-methylbut-1-ene group, (E) -2- methylbut-1-enyl, (Z) -2- methylbut-1-enyl, (E) -1- methyl 1-enyl, (the Z) -1- methylbut-1-enyl, 1,1-dimethyl-2-enyl, 1-ethyl-1-enyl, 1-propyl Vinyl, 1-isopropylvinyl, 4-methylpent-4-enyl, 3-methylpent-4-enyl, 2-methylpent-4-enyl, 1-methylpentane- 4-alkenyl, 4-methylpent-3-enyl, ( E )-3-methylpent-3-enyl, ( Z )-3-methylpent-3-enyl, ( E )- 2-methylpent-3-enyl, ( Z )-2-methylpent-3-enyl, ( E )-1-methylpent-3-enyl, ( Z )-1-methylpentyl 3-alkenyl, ( E )-4-methylpent-2-enyl, ( Z )-4-methylpent-2-enyl, ( E )-3-methylpent-2-enyl ( Z )-3-methylpent-2-enyl, ( E )-2-methylpent-2-enyl, ( Z )-2-methylpent-2-enyl, ( E )- 1-methylpent-2-enyl, ( Z )-1-methylpent-2-enyl, ( E )-4-methylpent-1-enyl, ( Z )-4-methylpentyl 1-enyl, ( E )-3-methylpent-1-enyl, ( Z )-3-methylpent-1-enyl, ( E )-2-methylpent-1-enyl ( Z )-2-methylpent-1-enyl, ( E )-1-methylpent-1-enyl, ( Z )-1-methylpent-1-enyl, 3-ethyl But-3-enyl, 2-ethylbut-3-enyl, 1-ethylbut-3-enyl, ( E )-3-ethylbut-2-enyl, ( Z )-3- B But-2-enyl, (E) -2- ethyl-2-enyl, (Z) -2- ethyl-2-enyl, (E) -1- ethyl-2-ene , ( Z )-1-ethylbut-2-enyl, ( E )-3-ethylbut-1-enyl, ( Z )-3-ethylbut-1-enyl, 2-B Butyl-1-alkenyl, ( E )-1-ethylbut-1-enyl, ( Z )-1-ethylbut-1-enyl, 2-propylprop-2-enyl, 1 -propylprop-2-enyl, 2-isopropylprop-2-enyl, 1-isopropylprop-2-enyl, ( E )-2-propylprop-1-enyl, ( Z )-2-propylprop-1-enyl, ( E )-1-propylprop-1-enyl, ( Z )-1-propylprop-1-enyl, ( E )-2- Isopropyl prop-1-enyl, ( Z )-2-isopropylprop-1-enyl, ( E )-1-isopropylprop-1-enyl, ( Z )-1-isopropyl Propi-1-enyl, ( E )-3,3-dimethylprop-1-enyl, ( Z )-3,3-dimethylprop-1-enyl, 1-(1,1 - dimethylethyl)vinyl, butadiene-1,3-dienyl, pent-1,4-dienyl, hex-1,5-dienyl or methylhexadienyl. In particular, the group is a vinyl or allyl group.

The term "C ₂ -C ₁₀ alkynyl" is understood to preferably mean one or more reference bonds and contain 2, 3, 4, 5, 6, 7, 8, 9 or 10 carbon atoms, in particular 2. a linear or branched monovalent hydrocarbon group of 3, 4, 5 or 6 carbon atoms ("C ₂ -C ₆ alkynyl"), more particularly 2 or 3 carbon atoms ("C ₂ -C ₃ alkynyl") . The C ₂ -C ₁₀ alkynyl group is, for example, ethynyl, prop-1-ynyl, prop-2-ynyl, but-1-ynyl, but-2-ynyl, but-3-ynyl, pentane- 1-alkynyl, pent-2-ynyl, pent-3-ynyl, pent-4-ynyl, hex-1-ynyl, hex-2-ynyl, hex-3-ynyl, hex-4 - alkynyl, hex-5-alkynyl, 1-methylprop-2-ynyl, 2-methylbut-3-ynyl, 1-methylbut-3-ynyl, 1-methylbutyl- 2-Alkynyl, 3-methylbut-1-ynyl, 1-ethylprop-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-methylpentan-2 - alkynyl, 4-methylpent-1-ynyl, 3-methylpent-1-ynyl, 2-ethylbut-3-ynyl, 1-ethylbut-3-ynyl, 1- Ethylbut-2-ynyl, 1-propylprop-2-ynyl, 1-isopropylprop-2-ynyl, 2,2-dimethylbut-3-ynyl, 1,1- Dimethylbut-3-ynyl, 1,1-dimethylbut-2-ynyl or 3,3-dimethylbut-1-ynyl. In particular, the alkynyl group is ethynyl, prop-1-ynyl or prop-2-ynyl.

The term "C ₃ -C ₁₀ 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 -C" ₁₀ cycloalkyl"). The C ₃ -C ₁₀ cycloalkyl group is, for example, a monocyclic hydrocarbon ring such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, cyclodecyl or cyclodecyl, or A bicyclic hydrocarbon ring such as a perhydrocyclodecadiene or a decahydronaphthalene ring. Specifically, the ring contains 3, 4, 5 or 6 carbon atoms ("C ₃ -C ₆ cycloalkyl").

The term "C ₃ -C ₆ cycloalkyloxy" refers to a (C ₃ -C ₆ cycloalkyl)-O- group, wherein "C ₃ -C ₆ cycloalkyl" is as defined herein. Examples include, but are not limited to, cyclopropoxy and cyclobutoxy.

The term "C ₄ -C ₁₀ cycloalkenyl" is understood to preferably mean a non-aromatic monovalent monocyclic or bicyclic hydrocarbon ring containing 4, 5, 6, 7, 8, 9 or 10 carbon atoms and The size of the cycloalkenyl ring allows for the next, two, three or four conjugated or non-conjugated double bonds. The C ₄ -C ₁₀ cycloalkenyl group is, for example, a monocyclic hydrocarbon ring such as a cyclobutenyl group, a cyclopentenyl group or a cyclohexenyl group; or a bicyclic hydrocarbon group, for example:

The term "C ₅ -C ₈ cycloalkenyloxy" refers to a (C ₅ -C ₈ cycloalkenyl)-O- group, wherein "C ₅ -C ₈ cycloalkenyl" is as defined herein.

The term "3 to 10 membered heterocycloalkyl" is understood to mean 2, 3, 4, 5, 6, 7, 8 or 9 carbon atoms and one or more selected from -C(=O)-, a saturated monovalent monocyclic or bicyclic hydrocarbon ring of a hetero atom-containing group of -O-, -S-, -S(=O)-, -S(=O) ₂ -, -N(R ^a )-, wherein R ^a represents a hydrogen atom or a C ₁ -C ₆ alkyl group; the heterocycloalkyl group may be attached to the remainder of the molecule via any one of a carbon atom or a nitrogen atom, if present. Heterospirocycloalkyl, heterobicycloalkyl and bridged heterocycloalkyl as defined below are also included within the scope of this definition.

The term "heterospirocycloalkyl" is understood to mean a saturated monovalent bicyclic hydrocarbon group in which two rings share a common ring carbon atom and wherein the bicyclic hydrocarbon group contains 2, 3, 4, 5, 6, 7, 8 or 9 a carbon atom and one or more hetero atom-containing groups selected from the group consisting of C(=O), O, S, S(=O), S(=O) ₂ , NR ^a , wherein R ^a represents a hydrogen atom or C ₁ -C ₆ alkyl- or C ₃ -C ₇ cycloalkyl-; the heterospirocycloalkyl group can be attached to the remainder of the molecule via any of a carbon atom or a nitrogen atom, if any. The heterospirocycloalkyl- is, for example, azaspiro[2.3]hexyl-, azaspiro[3.3]heptyl-, oxazaspiro[3.3]heptyl-, thiazaspiro[3.3]heptyl-, Oxanspiro[3.3]heptyl-, oxazaspiro[5.3]mercapto-, oxazaspiro[4.3]octyl-, oxazaspiro[5.5]undecyl-, diazaspiro[ 3.3] Heptyl-, thiazaspiro[3.3]heptyl-, thiazepine[4.3]octyl- or azaspiro[5.5]dodecyl-.

The term "heterobicycloalkyl" is understood to mean a saturated monovalent bicyclic hydrocarbon group in which two rings share two immediately adjacent ring carbon atoms and wherein the bicyclic hydrocarbon group contains 2, 3, 4, 5, 6, 7, 8 or 9 carbon atoms and one or more hetero atom-containing groups selected from C(=O), O, S, S(=O), S(=O) ₂ , NR ^a , wherein R ^a represents a hydrogen atom Or C ₁ -C ₆ alkyl- or C ₃ -C ₇ -cycloalkyl-; the heterobicycloalkyl group can be attached to the remainder of the molecule via any of a carbon atom or a nitrogen atom, if present. The heterobicycloalkyl- is, for example, azabicyclo[3.3.0]octyl-, azabicyclo[4.3.0]nonyl-, diazabicyclo[4.3.0]decyl-, oxygen Azabicyclo[4.3.0]nonyl-, thiazabicyclo[4.3.0]decyl- or azabicyclo[4.4.0]dodecyl-.

The term "bridged heterocycloalkyl" is understood to mean a saturated monovalent bicyclic hydrocarbon group in which two rings share two carbon atoms which are not immediately adjacent to the ring and wherein the bicyclic hydrocarbon group contains 2, 3, 4, 5, 6, 7, 8 Or a carbon atom and one or more hetero atom-containing groups selected from the group consisting of C(=O), O, S, S(=O), S(=O) ₂ , NR ^a , wherein R ^a represents hydrogen Atom or C ₁ -C ₆ alkyl- or C ₃ -C ₇ -cycloalkyl-; the bridged heterocycloalkyl group can be attached to the remainder of the molecule via any of a carbon atom or a nitrogen atom, if present. The bridged heterocycloalkyl- is, for example, azabicyclo[2.2.1]heptyl-, oxazabicyclo[2.2.1]heptyl-, thiazabicyclo[2.2.1]heptyl-, Diazabicyclo[2.2.1]heptyl-,azabicyclo[2.2.2]octyl-, diazabicyclo[2.2.2]octyl-, oxazabicyclo[2.2.2 ] octyl-, thiazabicyclo[2.2.2]octyl-, azabicyclo[3.2.1]octyl-, diazabicyclo[3.2.1]octyl-, oxazepine Ring [3.2.1]octyl-, thiazabicyclo[3.2.1]octyl-, azabicyclo[3.3.1]nonyl-, diazabicyclo[3.3.1]fluorenyl- , oxazabicyclo[3.3.1]fluorenyl-, thiazabicyclo[3.3.1]fluorenyl-, azabicyclo[4.2.1]decyl-, diazabicyclo[4.2. 1] fluorenyl-, oxazabicyclo[4.2.1]fluorenyl, thiazabicyclo[4.2.1]decyl-, azabicyclo[3.3.2]dodecyl-, dinitrogen Heterobicyclo[3.3.2]dodecyl-, oxazabicyclo[3.3.2]dodecyl-, thiazabicyclo[3.3.2]dodecyl- or azabicyclo [4.2.2] Dodecyl-.

In particular, the 3 to 10 membered heterocycloalkyl group may contain 2, 3, 4 or 5 carbon atoms and one or more of the above mentioned hetero atom-containing groups ("3 to 6 membered heterocycloalkyl" "), more specific words The 3- to 10-membered heterocycloalkyl group may contain 4 or 5 carbon atoms and one or more of the above-mentioned hetero atom-containing groups ("5 to 6 membered heterocycloalkyl").

Specifically, but not limited thereto, the 3 to 10 membered heterocycloalkyl group may be a 4-membered ring such as azetidinyl or oxetane; or a 5-membered ring such as tetrahydrofuranyl or dioxane. Heterocyclopentyl, pyrrolidinyl, imidazolidinyl, pyrazolidinyl; or 6-membered ring, such as tetrahydropyranyl, piperidinyl, morpholinyl, dithiaalkyl, thiomorpholinyl, Piperazinyl or trithiaalkyl; or a 7-membered ring, such as a diazepanyl ring.

The 3 to 10 membered heterocycloalkyl group can be bicyclic, such as, but not limited to, a 5,5 membered ring, such as a hexahydrocyclopenta[c]pyrrole-2(1H)-yl ring; or 5,6 A bicyclic ring such as a hexahydropyrrolo[1,2-a]pyrazine-2(1H)-yl ring.

The term "4 to 10 membered heterocycloalkenyl" is understood to mean 3, 4, 5, 6, 7, 8 or 9 carbon atoms and one or more selected from -C(=O)-, -O. Non-aromatic unsaturated monovalent monocyclic or bicyclic hydrocarbons of -, -S-, -S(=O)-, -S(=O) ₂ -, -N(R ^a )-heteroatom-containing groups Ring, wherein R ^a represents a hydrogen atom or a C ₁ -C ₆ alkyl group; the heterocycloalkenyl group can be attached to the remainder of the molecule via any of a carbon atom or a nitrogen atom, if present. Examples of the heterocycloalkenyl group are, for example, 4H-piperidyl, 2H-piperidyl, 3H-diazacyclopropenyl, 2,5-dihydro-1H-pyrrolyl, [1,3]dioxan Cyclopentenyl, 4H-[1,3,4]thiadiazinyl, 2,5-dihydrofuranyl, 2,3-dihydrofuranyl, 2,5-dihydrothienyl, 2,3- Dihydrothienyl, 4,5-dihydrooxazolyl or 4H-[1,4]thiazinyl.

The term "aryl" is understood to mean preferably a monovalent, bicyclic or tricyclic hydrocarbon having a monovalent aromatic or partially aromatic radical of 6, 7, 8, 9, 10, 11, 12, 13 or 14 carbon atoms. a ring ("C ₆ -C ₁₄ aryl"), especially a ring having 6 carbon atoms ("C ₆ aryl"), such as phenyl; or a biphenyl group; or a ring having 9 carbon atoms (" C ₉ aryl"), such as indanyl or fluorenyl; or a ring having 10 carbon atoms ("C ₁₀ aryl"), such as a naphthyl, dihydronaphthyl or naphthyl group; or having 13 A ring of carbon atoms ("C ₁₃ aryl"), such as a fluorenyl group; or a ring having 14 carbon atoms ("C ₁₄ aryl"), such as a fluorenyl group. The aryl group is preferably a phenyl group.

The term "heteroaryl" is understood to preferably mean a monovalent monocyclic, bicyclic or tricyclic aromatic ring system having 5, 6, 7, 8, 9, 10, 11, 12, 13 or 14 ring atoms ( "5 to 14 membered heteroaryl"), especially 5 or 6 or 9 or 10 atoms, and which contains at least one hetero atom which may be the same or different, such as oxygen, nitrogen or sulfur, and additionally In the case of benzo condensation. In particular, the heteroaryl is selected from the group consisting of 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, oxazolyl, fluorenyl, isodecyl, etc.; or pyridyl, pyridazinyl, pyrimidinyl, pyrazinyl, triazinyl, etc. and benzo derivatives thereof, such as quinoline a group, a quinazolinyl group, an isoquinolyl group or the like; or an indomethacin group, a pyridazinyl group, a fluorenyl group or the like and a benzo derivative thereof; Lolinyl, pyridazinyl, quinazolinyl, quinoxalinyl, naphthylpyridyl, acridinyl, oxazolyl, acridinyl, cyanozinyl, phenothiazine, phenoxazinyl, dibenzo Piperyl or oxonyl and the like.

In general and unless otherwise mentioned, a heteroaryl or heteroaryl group includes all possible isomeric forms thereof, such as positional isomers thereof. Thus, for some illustrative, non-limiting examples, the term pyridyl or extended pyridyl includes pyridin-2-yl, pyridin-2-yl, pyridin-3-yl, pyridin-3-yl, pyridine-4 And a pyridyl-4-yl group; or the term thienyl or thienyl includes thiophen-2-yl, thiophen-2-exyl, thiophen-3-yl and thiophen-3- exo.

As used herein, for example, "C ₁ -C ₆ alkyl", "C ₁ -C ₆ haloalkyl", "C ₁ -C ₆ alkoxy" or "C ₁ -C ₆ haloalkoxy" In the case of the definition, the term "C ₁ -C ₆ " is understood to mean an alkyl group having from 1 to 6 finite number of carbon atoms, that is, 1, 2, 3, 4, 5 or 6 carbon atoms. It should be further understood that the term "C ₁ -C ₆ " is interpreted to mean any subrange contained therein, such as C ₁ -C ₆ , C ₂ -C ₅ , C ₃ -C ₄ , C ₁ -C ₂ , C ₁ - C ₃ , C ₁ -C ₄ , C ₁ -C ₅ ; especially C ₁ -C ₂ , C ₁ -C ₃ , C ₁ -C ₄ , C ₁ -C ₅ , C ₁ -C ₆ ; more especially C ₁ -C ₄ ; in the case of "C ₁ -C ₆ haloalkyl" or "C ₁ -C ₆ haloalkoxy", even C ₁ -C ₂ especially.

Similarly, as used herein, the term "C ₂ -C ₆ ", as used throughout the definition of "C ₂ -C ₆ alkenyl" and "C ₂ -C ₆ alkynyl", as used herein. It is understood to mean an alkenyl or alkynyl group having a finite number of carbon atoms of 2 to 6, ie 2, 3, 4, 5 or 6 carbon atoms. It should also be understood that the term "C ₂ -C ₆ " should be interpreted as any subrange contained therein, such as C ₂ -C ₆ , C ₃ -C ₅ , C ₃ -C ₄ , C ₂ -C ₃ , C ₂ -C ₄ , C ₂ -C ₅ ; especially C ₂ -C ₃ .

Further, as used herein, as used herein, for example, in the context of the definition of "C ₃ -C ₆ cycloalkyl", the term "C ₃ -C ₆ " is understood to mean 3 to 6 That is, a cycloalkyl group having a finite number of carbon atoms of 3, 4, 5 or 6 carbon atoms. It should be understood that the term "C ₃ -C ₆ " should be interpreted as any subrange contained therein, such as C ₃ -C ₆ , C ₄ -C ₅ , C ₃ -C ₅ , C ₃ -C ₄ , C ₄ -C ₆ , C ₅ -C ₆ ; especially C ₃ -C ₆ .

The term "substituted" means that one or more hydrogens on a given atom are replaced by a selected group selected from the indicated group, with the proviso that in the prior case not exceeding the normal valence of the specified atom, and the substitution can be stabilized. Compound. Such combinations are only permitted if a combination of substituents and/or variables results in a stable compound.

The term "optionally substituted" means substituted with a particular group, radical or moiety, as appropriate.

As used herein, for example, in the definition of a substituent of a compound of the formula of the present invention, the term "one or more" is understood to mean "one, two, three, four or five, especially one, Two, three or four, more especially one, two or three, even more especially one or two."

As used herein, the term "leaving group" refers to an atom or group of atoms that, in a chemical reaction, is replaced with a bonding electron to a stabilizing substance. The leaving group is preferably selected from the group consisting of halo groups, especially chloro, bromo or iodo, methanesulfonyloxy, p-toluenesulfonyloxy, trifluoromethanesulfonyloxy , nonafluorobutanesulfonyloxy, (4-bromo-phenyl)sulfonyloxy, (4-nitro-phenyl)sulfonyloxy, (2-nitro-phenyl)-sulfonyl Oxyl, (4-isopropyl) Benzene sulfonyloxy, (2,4,6-triisopropyl-benzene)-sulfonyloxy, (2,4,6-trimethyl-benzene)sulfonyloxy, (4 -T-butyl-benzene)sulfonyloxy, phenylsulfonyloxy and (4-methoxy-benzene)sulfonyloxy.

As used herein, the term "protecting group" is a protecting group attached to nitrogen in the intermediate used to prepare a compound of formula I. Such groups are introduced, for example, by chemical modification of the respective amine groups to achieve chemoselectivity in subsequent chemical reactions. Amino protecting groups are described, for example, in TW Greene and PGM Wuts, Protective Groups in Organic Synthesis , 3rd edition, Wiley 1999; more specifically, the groups may be selected from substituted sulfonyl groups such as methylsulfonyl- , toluenesulfonyl- or phenylsulfonyl-; fluorenyl, such as benzamidine, ethenyl or tetrahydropyranyl-; or urethane-based groups, such as third butoxide The carbonyl group (Boc), or may include hydrazine, such as, for example, 2-(trimethyldecyl)ethoxymethyl (SEM).

The invention includes all suitable isotopic variations of the compounds of the invention. An isotopic variation of a compound of the invention is defined as a variant of an atom having at least one atom that has the same atomic number but differs in atomic weight from the atomic mass normally or predominantly found in nature. Examples of isotopes which may be incorporated into the compounds of the invention include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorus, sulfur, fluorine, chlorine, bromine and iodine, such as ² H (氘), ³ H (氚), ¹¹ C, respectively. , ¹³ C, ¹⁴ C, ¹⁵ N, ¹⁷ O, ¹⁸ O, ³² P, ³³ P, ³³ S, ³⁴ S, ³⁵ S, ³⁶ S, ¹⁸ F, ³⁶ Cl, ⁸² Br, ¹²³ I, ¹²⁴ I, ¹²⁹ I and ¹³¹ I. Certain isotopic variations of the compounds of the invention, for example, isotopic variations of one or more radioisotopes (such as ³ H or ¹⁴ C), are useful for drug and/or matrix tissue distribution studies. Deuterated and carbon 14 (i.e., ¹⁴ C) isotopes are particularly preferred due to their ease of preparation and detectability. In addition, certain isotopic substitutions such as hydrazine may provide certain therapeutic advantages resulting from greater metabolic stability, such as increased in vivo half-life or reduced dosage requirements, and thus may be preferred in some circumstances. Isotopic variations of the compounds of the invention can generally be prepared by conventional procedures known to those skilled in the art, such as by descriptive methods or by the preparation of suitable isotopic variations using suitable reagents as described in the Examples below.

When the plural forms of the word compounds, salts, polymorphs, hydrates, solvates, and the like are used herein, they also mean a single compound, a salt, a polymorph, an isomer, a hydrate, a solvate or an analog thereof.

By "stable compound" or "stable structure" is meant a sufficiently robust compound that can be isolated from the reaction mixture to a useful degree of purity and formulated into an effective therapeutic agent.

Depending on the location and nature of the various substituents desired, the compounds of the invention may contain one or more asymmetric centers. Asymmetric carbon atoms may be present in the ( R ) or ( S ) configuration, producing a racemic mixture in the case of a single asymmetric center, and producing a mixture of diastereomers in the case of multiple asymmetric centers. In some cases, asymmetry may also be present by limited rotation about a specified bond (eg, a central bond connecting two substituted aromatic rings of a particular compound).

The compounds of the present invention may contain an asymmetric sulfur atom such as an asymmetric anthracene or sulfonium imine group having, for example, the following structure:

Where * indicates the atom to which the remainder of the molecule can bind.

Substituents on the ring may also exist in cis or trans form. All such configurations, including enantiomers and diastereomers, are contemplated as being within the scope of the invention.

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

Pure stereoisomers can be resolved by conventional methods to resolve racemic mixtures, for example by the use of optically active acids or bases to form diastereomeric salts, or to form covalent diastereoisomers. Get it. Examples of suitable acids are tartaric acid, dimercapto tartaric acid, xylylmercapto tartaric acid and camphorsulfonic acid. Mixtures of diastereomers can be separated into their individual diastereomers on the basis of their physical and/or chemical differences by methods known in the art, such as chromatography or fractional crystallization. The optically active base or acid is then released from the separated diastereomeric salt. Different methods for separating optical isomers involve the use of palm chromatography, which is optimally selected to maximize separation of enantiomers, with or without conventional derivatization (eg, for palm chromatography HPLC columns) ). Suitable for palmar HPLC column lines are manufactured by Diacel, such as, in particular, Chiracel OD and Chiracel OJ, all of which can be selected conventionally. Enzymatic separation with or without derivatization is also applicable. The optically active compounds of the present invention can also be obtained by palm-forming synthesis using optically active starting materials.

To limit the different types of isomers to each other, refer to IUPAC Guidelines Part E (Pure Appl Chem 45, 11-30, 1976).

The present invention includes all possible stereoisomers of the compounds of the invention, either in the form of a single stereoisomer or in any mixture of such stereoisomers, such as any ratio of ( R ) or ( S ) isomers. Or ( E ) or ( Z ) isomers. Separation of a single stereoisomer (e.g., a single enantiomer or a single diastereomer) of a compound of the invention may utilize any suitable current state of the art method (such as chromatography, especially for example, for the palm layer) Analytical method) to achieve.

Additionally, the compounds of the invention may exist in the form of tautomers. For example, any compound of the invention containing a pyrazole moiety as a heteroaryl group can exist, for example, as a 1H tautomer, or a 2H tautomer, or even a mixture of two tautomers in any amount, or Any of the compounds of the invention containing a triazole moiety as a heteroaryl group may, for example, be a 1H tautomer, a 2H tautomer or a 4H tautomer or even a mixture of the 1H, 2H and 4H tautomers in any amount. The form exists, namely:

The invention includes all possible tautomers of the compounds of the invention in the form of a single tautomeric form or in any mixture of any of these tautomers.

Additionally, the compounds of the invention may exist in the form of N-oxides which are defined as oxidation of at least one nitrogen of the compounds of the invention. The invention includes all such possible N-oxides.

The invention also relates to suitable forms of the compounds as disclosed herein, such as metabolites, hydrates, solvates, prodrugs, salts (especially pharmaceutically acceptable salts) and coprecipitates.

The compounds of the invention may exist in the form of hydrates or solvates wherein the compounds of the invention contain a polar solvent, especially such as water, methanol or ethanol as the structural element of the compound crystal lattice. The amount of polar solvent, especially water, can be present in stoichiometric or non-stoichiometric ratios. In the case of stoichiometric solvates (e.g., hydrates), hemi-/semi-, mono-, sesqui-, di-, tri-, tetra-, penta-, etc. solvates or hydrates are possible. The invention includes all such hydrates or solvates.

Additionally, the compounds of the invention may exist in free form (for example in the form of the free base, or in the free acid or zwitterionic form) or may be in the form of a salt. The salt may be any salt, may be an organic or inorganic addition salt, and in particular may be any pharmaceutically acceptable organic or inorganic addition salt conventionally used in pharmacy.

The term "pharmaceutically acceptable salt" refers to a relatively non-toxic, inorganic or organic acid addition salt of a compound of the invention. See, for example, SM 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, acid addition salts of the compounds of the invention which are sufficiently basic in the chain or carrying a nitrogen atom in the ring, such as An acid addition salt formed with an inorganic acid such as hydrochloric acid, hydrobromic acid, hydroiodic acid, sulfuric acid, disulfuric acid, phosphoric acid or nitric acid; or an acid addition salt formed with an organic acid, such 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-hydroxybenzene) Mercapto)-benzoic acid, camphoric acid, cinnamic acid, cyclopentanepropionic acid, digluconic acid, 3-hydroxy-2-naphthoic acid, nicotinic acid, pamoic acid, pectinic acid , persulfate, 3-phenylpropionic acid, picric acid, pivalic acid, 2-hydroxyethanesulfonic acid, itaconic acid, aminesulfonic acid, trifluoromethanesulfonic acid, dodecyl sulfate, ethanesulfonic acid , benzenesulfonic acid, p-toluenesulfonic acid, methanesulfonic acid, 2-naphthalenesulfonic acid, naphthalene disulfonic acid, camphorsulfonic acid, citric acid, tartaric acid, stearic acid, lactic acid, oxalic acid, malonic acid, dibutyl Acid, malic acid, adipic acid, alginic acid, maleic acid, fumaric acid, D-gluconic acid, almond acid, ascorbic acid, glucose heptanoic acid, glycerophosphoric acid, aspartic acid Acid, sulfosalicylic acid, sulfuric acid, or semi-thiocyanate.

Further, another suitable pharmaceutically acceptable salt of the compound of the present invention which is sufficiently acidic is an alkali metal salt such as a sodium salt or a potassium salt; an alkaline earth metal salt such as a calcium salt or a magnesium salt; an ammonium salt; or an organic base a salt formed to give a physiologically acceptable cation, for example with N-methyl-reduced glucosamine, dimethyl-reduced glucosamine, ethyl-reduced glucosamine, lysine, dicyclohexylamine 1,6-hexanediamine, ethanolamine, glucosamine, sarcosine, silkamine, cis-hydroxy-methyl-aminomethane, alanine propylene glycol, sowak-base, 1- a salt formed from amino-2,3,4-butanetriol; or a quaternary ammonium such as tetramethylammonium, tetraethylammonium, tetra(n-propyl)ammonium, tetra(n-butyl)ammonium or N -benzoic acid Base - N , N , N - trimethylammonium.

It will be further appreciated by those skilled in the art that the acid addition salts of the claimed compounds can be prepared by reacting the compounds with a suitable mineral or organic acid via any of a variety of known methods. Further, the alkali metal and alkaline earth metal salts of the acidic compound of the present invention can be produced by reacting the compound of the present invention with a suitable base by various known methods.

The invention includes all possible salts of the compounds of the invention in the form of a single salt or in any mixture of any of the salts.

As used herein, the term "in vivo hydrolyzable ester" is understood to mean an in vivo hydrolysable ester of a compound of the invention containing a carboxy or hydroxy group, for example, pharmaceutically effective in the hydrolysis of a parent or a parent alcohol in a human or animal body. An acceptable ester. Suitable pharmaceutically acceptable esters of carboxy include, for example, alkyl esters, cycloalkyl esters and optionally substituted phenylalkyl esters, especially benzyl esters; C ₁ -C ₆ alkoxymethyl esters, such as methoxymethyl An ester; a C ₁ -C ₆ alkyl decyloxymethyl ester, such as a pentyl methoxymethyl ester, an oxime ester; a C ₃ -C ₈ cycloalkoxy-carbonyloxy-C ₁ -C ₆ alkyl ester, For example, 1-cyclohexylcarbonyloxyethyl ester; 1,3-dioxol-2-indenylmethyl ester, such as 5-methyl-1,3-dioxol-2-yl Methyl ester; and C ₁ -C ₆ alkoxycarbonyloxyethyl ester, such as 1-methoxycarbonyloxyethyl ester, and may be formed at any of the carboxyl groups in the compounds of the present invention.

In vivo hydrolysable esters of the compounds of the invention containing a hydroxy group include inorganic esters (such as phosphate esters) and [α]-nonyloxyalkyl ethers and esters which are hydrolytically degraded in vivo to release the parent hydroxyl group. Examples of the [α]-nonyloxyalkyl ether include an ethenyloxymethoxy group and a 2,2-dimethylpropoxycarbonyl group. The selection of the hydrolyzable ester which forms a hydroxyl group in vivo includes an alkyl fluorenyl group, a benzamidine group, a phenyl ethane group, a substituted benzyl fluorenyl group, a phenyl ethane group, an alkoxycarbonyl group (to produce an alkyl group). Carbonate), dialkylamine methyl sulfhydryl and N- (dialkylaminoethyl)-N-alkylaminecarbamyl (to produce urethane), dialkylaminoethyl fluorenyl And carboxyethyl thiol. The present invention covers all such esters.

Furthermore, the invention includes all possible crystalline forms or polymorphs of the compounds of the invention in the form of a single polymorph or in the form of a mixture of any ratio of more than one polymorph.

According to a first aspect, the invention encompasses a compound of formula I :

Wherein: QV represents a group selected from the group consisting of C(R ^1a )-N, NC(R ^1a ); and A represents a group selected from the group consisting of: Wherein * indicates the point of attachment of the rest of the molecule such group; R ^1a represents a hydrogen atom or a halogen atom or a group selected from the group of: hydroxy - cyano -, C ₁ -C ₆ alkyl -, C ₂ - C ₆ alkenyl-, C ₂ -C ₆ alkynyl-, C ₁ -C ₆ alkoxy-, halo-C ₁ -C ₆ alkyl-, halo-C ₁ -C ₆ alkoxy-, Hydroxy-C ₁ -C ₆ alkyl-, C ₁ -C ₃ alkoxy-C ₁ -C ₃ alkyl-, -N(R ^5b )R ^5c , -SCF ₃ , -SF ₅ ; R ^1b represents hydrogen An atom or a halogen atom or a group selected from the group consisting of hydroxy-, cyano-, C ₁ -C ₆ alkyl-, C ₂ -C ₆ alkenyl-, C ₂ -C ₆ alkynyl-, C ₁ -C ₆ alkoxy-, halo-C ₁ -C ₆ alkyl-, halo-C ₁ -C ₆ alkoxy-, hydroxy-C ₁ -C ₆ alkyl-, C ₁ -C ₃ alkoxy -C ₁ -C ₃ alkyl-, -N(R ^5b )R ^5c , -SCF ₃ , -SF ₅ ; R ^1c represents a hydrogen atom or a halogen atom or a group selected from the group consisting of hydroxy-, cyano-, C ₁ -C ₆ alkyl-, C ₂ -C ₆ alkenyl-, C ₂ -C ₆ alkynyl-, C ₁ -C ₆ alkoxy-, halo-C ₁ -C ₆ alkyl-, halo -C ₁ -C ₆ alkoxy-, hydroxy-C ₁ -C ₆ alkyl-, C ₁ -C ₃ alkoxy-C ₁ -C ₃ alkyl-, -N(R ^5b )R ^5c , -SCF _3, -SF _5; R ^2a represents a hydrogen atom A halogen atom or a group selected from the group: C ₁ -C ₆ alkyl -, C ₃ - C ₆ cycloalkyl -, heterocycloalkyl 3-10 - 4-10 heterocycloalkenyl -, aryl Base-, heteroaryl-, cyano-, -(CH ₂ ) _q -U-(CH ₂ ) _p -R ^3a ; wherein the C ₁ -C ₆ alkyl-, C ₃ -C ₆ cycloalkyl- 3 to 10 membered heterocycloalkyl-, 4 to 10 membered heterocycloalkenyl-, aryl- or heteroaryl-, as the case may be, 1, 2, 3, 4 or 5 R ⁴ groups identically or differently Substituted; R ^2b represents a hydrogen atom or a halogen atom or a group selected from the group consisting of C ₁ -C ₆ alkyl-, C ₃ -C ₆ cycloalkyl-, 3 to 10 membered heterocycloalkyl-, 4 to 10 a heterocycloalkenyl-, aryl-, heteroaryl-, cyano-, -(CH ₂ ) _q -U-(CH ₂ ) _p -R ^3a ; wherein the C ₁ -C ₆ alkyl-, C _3- C ₆ cycloalkyl-, 3 to 10 membered heterocycloalkyl-, 4 to 10 membered heterocycloalkenyl-, aryl- or heteroaryl-, as the case may be the same or different, 1, 2, 3, 4 or 5 R ⁴ groups substituted; or R ^2a and R ^2b together

Represents -(CH ₂ ) _r -T-(CH ₂ ) _s -; T represents a group selected from the group consisting of U, -C[R ^6a ][(C(R ^6b )(R ^6c )) _t -UR ^3a U- represents a single bond or a divalent group selected from the group consisting of -O-, -S-, -S(=O)-, -S(=O) ₂ -, -S(=O) -N(R ^3b )-, -N(R ^3c )-S(=O)-, -S(=O) ₂ -N(R ^3b )-, -N(R ^3c )-S(=O) ₂ -, -C(=O)-, -N(R ^3b )-, -C(=O)-O-, -OC(=O)-, -C(=S)-O-, -OC(= S)-, -C(=O)-N(R ^3b )-, -N(R ^3c )-C(=O)-, -N(R ^3c )-C(=O)-N(R ^3b ) -, -OC(=O)-N(R ^3b )-, -N(R ^3c )-C(=O)-O-; R ^3a represents a hydrogen atom or a group selected from the group consisting of C ₁ -C ₆ Alkyl-, C ₃ -C ₆ cycloalkyl-, 3 to 10 membered heterocycloalkyl-, 4 to 10 membered heterocycloalkenyl-, aryl-, heteroaryl-; wherein C ₁ -C ₆ Alkyl-, C ₃ -C ₆ cycloalkyl-, 3 to 10 membered heterocycloalkyl-, 4 to 10 membered heterocycloalkenyl-, aryl- or heteroaryl-, as the case may be the same or different , 2, 3, 4 or 5 R ⁴ groups are substituted; R ^3b represents a hydrogen atom or a group selected from the group consisting of C ₁ -C ₆ alkyl-, C ₃ -C ₆ cycloalkyl-, 3 to 10 membered heterocycloalkyl -, 4-10 heterocycloalkenyl -, aryl -, heteroaryl -; wherein the C ₁ -C ₆ alkyl -, C ₃ -C ₆ cycloalkyl -, heterocycloalkyl 3-10 - 4-10 heterocycloalkenyl -, aryl - aryl or heteroaryl group - are the same or different optionally substituted with 4 or 5 R ⁴ groups a group substituted; R ^3c represents a hydrogen atom or a group selected from the group consisting of C ₁ -C ₆ alkyl-, C ₃ -C ₆ cycloalkyl-, 3 to 10 membered heterocycloalkyl-, 4 to 10 member hetero Cycloalkenyl-, aryl-, heteroaryl-, wherein the C ₁ -C ₆ alkyl-, C ₃ -C ₆ cycloalkyl-, 3 to 10 membered heterocycloalkyl-, 4 to 10 member Cycloalkenyl-, aryl- or heteroaryl-substituted as the same or differently by 1, 2, 3, 4 or 5 R ⁴ groups; or N(R ^3b )R ^3a together

Forming a 3 to 10 membered heterocycloalkyl- or 4 to 10 membered heterocycloalkenyl-; wherein the 3 to 10 membered heterocycloalkyl- or 4 to 10 membered heterocycloalkenyl-, as the case may be the same or different , 2, 3, 4 or 5 R ⁴ groups are substituted; R ⁴ represents halo-, hydroxy-, pendant oxy-(O=), cyano-, nitro-, C ₁ -C ₆ alkyl- , C ₂ -C ₆ alkenyl-, C ₂ -C ₆ alkynyl-, halo-C ₁ -C ₆ alkyl-, C ₁ -C ₆ alkoxy-, halo-C ₁ -C ₆ alkane Oxy-, hydroxy-C ₁ -C ₆ alkyl-, C ₁ -C ₆ alkoxy-C ₁ -C ₆ alkyl-, halo-C ₁ -C ₆ alkoxy-C ₁ -C ₆ Alkyl-, R ^5c -O-, -C(=O)-R ^5c , -C(=O)-OR ^5c , -OC(=O)-R ^5c , -N(R ^5b )-C(= O)-R ^5c , -N(R ^5c )-C(=O)-N(R ^5a )R ^5b , -N(R ^5a )R ^5b , -C(=O)-N(R ^5a )R ^5b , R ^5c -S-, R ^5c -S(=O)-, R ^5c -S(=O) ₂ -, -N(R ^5c )-S(=O)-R ^5b , -S(=O) -N(R ^5a )R ^5b , -N(R ^5c )-S(=O) ₂ -R ^5b , -S(=O) ₂ -N(R ^5a )R ^5b , -S(=O)=N (R ^5c ) R ^5b , -S(=O)=N(R ^5c )R ^5b or -N=S(=O)(R ^5c )R ^5b ; R ^5a represents a hydrogen atom, C ₁ -C ₆ alkyl a C ₃ -C ₆ cycloalkyl-, phenyl- or 3 to 10 membered heterocycloalkyl- group; wherein the C ₁ -C ₆ alkyl group - optionally substituted by phenyl group; R ^5b represents a hydrogen atom, a C ₁ -C ₆ alkyl-, a C ₃ -C ₆ cycloalkyl- or a 3 to 10 membered heterocycloalkyl group; R ^5c represents a hydrogen atom, a C ₁ -C ₆ alkyl group, C _3- C ₆ cycloalkyl- or 3 to 10 membered heterocycloalkyl-; or N(R ^5a )R ^5b

3 to 7 membered heterocycloalkyl-formed together; R ^6a represents a hydrogen atom or a group selected from the group consisting of C ₁ -C ₆ alkyl-, C ₂ -C ₆ alkenyl-, C ₂ -C ₆ alkynyl Wherein the C ₁ -C ₆ alkyl-, C ₂ -C ₆ alkenyl- or C ₂ -C ₆ alkynyl group is optionally substituted with 1, 2 or 3 R ⁴ groups, as the case may be; R ^6b represents a hydrogen atom or a C ₁ -C ₃ alkyl group; R ^6c represents a hydrogen atom or a C ₁ -C ₃ alkyl group; p represents an integer of 0, 1, 2 or 3; q represents 0, 1, 2 or 3 An integer; r represents an integer of 1, 2 or 3; s represents an integer of 1, 2 or 3; and t represents an integer of 0 or 1; or a tautomer thereof, an N-oxide, a hydrate or a solvate thereof Or a salt, or a mixture of such substances.

In a preferred embodiment, the invention is directed to a compound of formula I above, wherein QV represents NC(R ^1a ).

In another preferred embodiment, the invention is directed to a compound of formula I above, wherein QV represents C(R ^1a )-N.

In another preferred embodiment, the invention relates to a compound of formula I above, wherein A represents a group selected from the group consisting of: Where * indicates the point of attachment of the groups to the rest of the molecule.

In another preferred embodiment, the invention is directed to a compound of formula I above, wherein A represents: Where * indicates the point of attachment of the group to the rest of the molecule.

In another preferred embodiment, the invention is directed to a compound of formula I above, wherein A represents: Wherein * indicates the point of attachment of the group to the rest of the molecule, and wherein R ^2a and R ^2b together represent -(CH ₂ ) _r -T-(CH ₂ ) _s -.

In another preferred embodiment, the invention relates to a compound of formula I above, wherein A represents Where * indicates the point of attachment of the group to the rest of the molecule.

In another preferred embodiment, the invention relates to a compound of formula I above, wherein R ^1a represents a hydrogen atom or a halogen atom or a group selected from the group consisting of cyano-, C ₁ -C ₆ alkyl-, C ₁ -C ₆ alkoxy-, halo-C ₁ -C ₆ alkyl-, halo-C ₁ -C ₆ alkoxy-, hydroxy-C ₁ -C ₆ alkyl-, C ₁ -C ₃ alkane Oxy-C ₁ -C ₃ alkyl-.

In another preferred embodiment, the invention relates to a compound of formula I above, wherein R ^1a represents a hydrogen atom or a group selected from the group consisting of cyano-, C ₁ -C ₆ alkyl-, C ₁ -C ₆ Alkoxy-, halo-C ₁ -C ₆ alkyl-, halo-C ₁ -C ₆ alkoxy-, hydroxy-C ₁ -C ₆ alkyl-, C ₁ -C ₃ alkoxy- C ₁ -C ₃ alkyl-.

In another preferred embodiment, the invention relates to a compound of formula I above, wherein R ^1a represents a hydrogen atom or a group selected from the group consisting of C ₁ -C ₃ alkyl-, C ₁ -C ₃ alkoxy- , halo-C ₁ -C ₃ alkyl-, halo-C ₁ -C ₃ alkoxy-, hydroxy-C ₁ -C ₃ alkyl-, C ₁ -C ₃ alkoxy-C ₁ -C ₃ alkyl-.

In another preferred embodiment, the invention relates to a compound of formula I above, wherein R ^1a represents a hydrogen atom or a group selected from the group consisting of C ₁ -C ₃ alkyl-, C ₁ -C ₃ alkoxy- , halo-C ₁ -C ₃ alkyl-.

In another preferred embodiment, the invention relates to a compound of formula I above, wherein R ^1a represents a hydrogen atom or a C ₁ -C ₃ alkyl-.

In another preferred embodiment, the invention relates to a compound of formula I above, wherein R ^1a represents a hydrogen atom or a hydroxy- or C ₁ -C ₃ alkoxy group.

In another preferred embodiment, the invention relates to a compound of formula I above, wherein R ^1a represents a hydrogen atom or a hydroxy- or methoxy- group.

In another preferred embodiment, the invention relates to a compound of formula I above, wherein R ^1a represents hydroxy-.

In another preferred embodiment, the invention relates to a compound of formula I above, wherein R ^1a represents methoxy-.

In another preferred embodiment, the invention is directed to a compound of formula I above, wherein R ^1a represents a hydrogen atom.

In another preferred embodiment, the invention relates to a compound of formula (I) above, wherein QV represents NC(R ^1a ) and R ^1a represents a C ₁ -C ₃ alkyl-, C ₁ -C ₃ alkoxy group a group of a radical - a halo group.

In another preferred embodiment, the invention relates to a compound of formula (I) above, wherein QV represents NC(R ^1a ) and R ^1a represents a group selected from C ₁ -C ₃ alkoxy-, halo- .

In another preferred embodiment, the invention relates to a compound of formula (I) above, wherein QV represents NC(R ^1a ) and R ^1a represents C ₁ -C ₃ alkoxy-, preferably methoxy-.

In another preferred embodiment, the invention relates to a compound of formula (I) above, wherein QV represents C(R ^1a )-N and R ^1a represents a hydrogen atom.

In another preferred embodiment, the invention relates to a compound of formula I above, wherein R ^1b represents a hydrogen atom or a halogen atom or a group selected from the group consisting of cyano-, C ₁ -C ₆ alkyl-, C ₁ -C ₆ alkoxy-, halo-C ₁ -C ₆ alkyl-, halo-C ₁ -C ₆ alkoxy-, hydroxy-C ₁ -C ₆ alkyl-, C ₁ -C ₃ alkane Oxy-C ₁ -C ₃ alkyl-.

In another preferred embodiment, the invention relates to a compound of formula I above, wherein R ^1b represents a hydrogen atom or a group selected from the group consisting of cyano-, C ₁ -C ₆ alkyl-, C ₁ -C ₆ Alkoxy-, halo-C ₁ -C ₆ alkyl-, halo-C ₁ -C ₆ alkoxy-, hydroxy-C ₁ -C ₆ alkyl-, C ₁ -C ₃ alkoxy- C ₁ -C ₃ alkyl-.

In another preferred embodiment, the invention relates to a compound of formula I above, wherein R ^1b represents a hydrogen atom or a group selected from the group consisting of C ₁ -C ₃ alkyl-, C ₁ -C ₃ alkoxy- , halo-C ₁ -C ₃ alkyl-, halo-C ₁ -C ₃ alkoxy-, hydroxy-C ₁ -C ₃ alkyl-, C ₁ -C ₃ alkoxy-C ₁ -C ₃ alkyl-.

In another preferred embodiment, the invention relates to a compound of formula I above, wherein R ^1b represents a hydrogen atom or a group selected from the group consisting of C ₁ -C ₃ alkyl-, C ₁ -C ₃ alkoxy- , halo-C ₁ -C ₃ alkyl-.

In another preferred embodiment, the invention relates to a compound of formula I above, wherein R ^1b represents a hydrogen atom or a C ₁ -C ₃ alkyl-.

In another preferred embodiment, the invention relates to a compound of formula I above, wherein R ^1b represents a hydrogen atom.

In another preferred embodiment, the invention relates to a compound of formula I above, wherein R ^1c represents a hydrogen atom or a halogen atom or a group selected from the group consisting of cyano-, C ₁ -C ₆ alkyl-, C ₁ -C ₆ alkoxy-, halo-C ₁ -C ₆ alkyl-, halo-C ₁ -C ₆ alkoxy-, hydroxy-C ₁ -C ₆ alkyl-, C ₁ -C ₃ alkane Oxy-C ₁ -C ₃ alkyl-.

In another preferred embodiment, the invention relates to a compound of formula I above, wherein R ^1c represents a hydrogen atom or a group selected from the group consisting of cyano-, C ₁ -C ₆ alkyl-, C ₁ -C ₆ Alkoxy-, halo-C ₁ -C ₆ alkyl-, halo-C ₁ -C ₆ alkoxy-, hydroxy-C ₁ -C ₆ alkyl-, C ₁ -C ₃ alkoxy- C ₁ -C ₃ alkyl-.

In another preferred embodiment, the invention relates to a compound of formula I above, wherein R ^1c represents a hydrogen atom or a group selected from the group consisting of C ₁ -C ₃ alkyl-, C ₁ -C ₃ alkoxy- , halo-C ₁ -C ₃ alkyl-, halo-C ₁ -C ₃ alkoxy-, hydroxy-C ₁ -C ₃ alkyl-, C ₁ -C ₃ alkoxy-C ₁ -C ₃ alkyl-.

In another preferred embodiment, the invention relates to a compound of formula I above, wherein R ^1c represents a hydrogen atom or a group selected from the group consisting of C ₁ -C ₃ alkyl-, C ₁ -C ₃ alkoxy- , halo-C ₁ -C ₃ alkyl-.

In another preferred embodiment, the invention relates to a compound of formula I above, wherein R ^1c represents a hydrogen atom or a C ₁ -C ₃ alkyl-.

In another preferred embodiment, the invention is directed to a compound of formula I above, wherein R ^1c represents a hydrogen atom.

In another preferred embodiment, the invention relates to a compound of formula I above, wherein each of R ^1a , R ^1b and R ^1c represents a hydrogen atom.

In another preferred embodiment, the invention relates to a compound of formula I above, wherein each of R ^1b and R ^1c represents a hydrogen atom, and wherein R ^1a represents methoxy-.

In another preferred embodiment, the invention relates to a compound of formula I above, wherein R ^2a represents a hydrogen atom or a halogen atom or a group selected from the group consisting of C ₁ -C ₆ alkyl-, C ₃ -C ₆ rings Alkyl-, 3 to 10 membered heterocycloalkyl-, halo-C ₁ -C ₃ alkyl-, cyano-, -(CH ₂ ) _q -U-(CH ₂ ) _p -R ^3a ; C ₁ -C ₆ alkyl-, C ₃ -C ₆ cycloalkyl-, 3 to 10 membered heterocycloalkyl- or 4 to 10 membered heterocycloalkenyl - as the case may be the same or different, 1, 2 or 3 The R ⁴ group is substituted with the proviso that the halo-C ₁ -C ₃ alkyl group - does not contain more than 5 halogen atoms.

In another preferred embodiment, the invention relates to a compound of formula I above, wherein R ^2a represents a hydrogen atom or a halogen atom or a group selected from the group consisting of C ₁ -C ₆ alkyl-, cyano-, -( CH ₂ ) _q -U-(CH ₂ ) _p -R ^3a ; wherein the C ₁ -C ₆ alkyl group - as the case may be the same or different, is substituted by 1, 2 or 3 R ⁴ groups.

In another preferred embodiment, the invention relates to a compound of formula I above, wherein R ^2a represents a hydrogen atom or a halogen atom or a group selected from the group consisting of C ₁ -C ₆ alkyl-, halo-C ₁ - C ₃ alkyl-, cyano-, -(CH ₂ ) _q -U-(CH ₂ ) _p -R ^3a ; wherein the C ₁ -C ₆ alkyl group - as the case may be substituted by one R ⁴ group, The limitation is that the halo-C ₁ -C ₃ alkyl group - does not contain more than 5 halogen atoms.

In another preferred embodiment, the invention relates to a compound of formula I above, wherein R ^2a represents a hydrogen atom or a group selected from the group consisting of C ₁ -C ₆ alkyl-, -(CH ₂ ) _q -U- (CH ₂ ) _p -R ^3a ; wherein the C ₁ -C ₆ alkyl group - optionally substituted with 1 R ⁴ group.

In another preferred embodiment, the invention relates to a compound of formula I above, wherein R ^2a represents a hydrogen atom or a group selected from the group consisting of C ₁ -C ₆ alkyl-, -(CH ₂ ) _q -U- (CH ₂ ) _p -R ^3a .

In another preferred embodiment, the invention relates to a compound of formula I above, wherein R ^2a represents a hydrogen atom or a C ₁ -C ₆ alkyl-.

In another preferred embodiment, the invention relates to a compound of formula I above, wherein R ^2a represents a hydrogen atom or a C ₁ -C ₃ alkyl-.

In another preferred embodiment, the invention relates to a compound of formula I above, wherein R ^2a represents a hydrogen atom.

In another preferred embodiment, the invention relates to a compound of formula I above, wherein R ^2a represents -(CH ₂ ) _q -U-(CH ₂ ) _p -R ^3a .

In another preferred embodiment, the invention relates to a compound of formula I above, wherein R ^2b represents a hydrogen atom or a halogen atom or a group selected from the group consisting of C ₁ -C ₆ alkyl-, halo-C ₁ - C ₃ alkyl-, cyano-, -(CH ₂ ) _q -U-(CH ₂ ) _p -R ^3a ; wherein the C ₁ -C ₆ alkyl group - as the case may be the same or different, 1, 2 or 3 The R ⁴ group is substituted with the proviso that the halo-C ₁ -C ₃ alkyl group - does not contain more than 5 halogen atoms.

In another preferred embodiment, the invention relates to a compound of formula I above, wherein R ^2b represents a hydrogen atom or a halogen atom or a group selected from the group consisting of C ₁ -C ₆ alkyl-, halo-C ₁ - C ₃ alkyl-, -(CH ₂ ) _q -U-(CH ₂ ) _p -R ^3a ; wherein the C ₁ -C ₆ alkyl group - optionally substituted with 1 R ⁴ group, is limited thereto Halo-C ₁ -C ₃ alkyl-free of more than 5 halogen atoms.

In another preferred embodiment, the invention relates to a compound of formula I above, wherein R ^2b represents a hydrogen atom or a halogen atom or a group selected from the group consisting of C ₁ -C ₃ alkyl-, halo-C ₁ - C ₃ alkyl-; wherein the C ₁ -C ₃ alkyl group - optionally substituted with 1 R ⁴ group, with the proviso that the halo-C ₁ -C ₃ alkyl group - does not contain more than 5 halogen atoms .

In another preferred embodiment, the invention is directed to a compound of formula I above, wherein R ^2b represents -(CH ₂ ) _q -U-(CH ₂ ) _p -R ^3a .

In another preferred embodiment, the invention relates to a compound of formula I above, wherein R ^2b represents a hydrogen atom or a C ₁ -C ₃ alkyl-.

In another preferred embodiment, the invention is directed to a compound of formula I above, wherein R ^2b represents a hydrogen atom.

In another preferred embodiment, the invention relates to a compound of formula I above, wherein one of R ^2a and R ^2b represents -(CH ₂ ) _q -U-(CH ₂ ) _p -R ^3a and the other represents A hydrogen atom or a C ₁ -C ₃ alkyl group.

In another preferred embodiment, the invention relates to a compound of formula I above, wherein R ^2a and R ^2b together represent -(CH ₂ ) _r -T-(CH ₂ ) _s -.

In another preferred embodiment, the invention relates to compounds of formula I above, wherein R ^2a and R ^2b together represent -(CH ₂ ) ₂ -T-CH ₂ -.

In another preferred embodiment, the invention relates to compounds of formula I above, wherein R ^2a and R ^2b together represent -CH ₂ -T-(CH ₂ ) ₂ -.

In another preferred embodiment, the invention relates to a compound of formula I above, wherein T represents -C[R ^6a ][(C(R ^6b )(R ^6c )) _t -UR ^3a ]-.

In another preferred embodiment, the invention relates to a compound of formula I above, wherein T represents -C[H][(CH ₂ ) _t -UR ^3a ]-.

In another preferred embodiment, the invention relates to a compound of formula I above, wherein T represents -C(R ^6a )(UR ^3a )-.

In another preferred embodiment, the invention relates to a compound of formula I above, wherein T represents -C(H)(UR ^3a )-.

In another preferred embodiment, the invention is directed to a compound of formula I above, wherein U represents a single bond.

In another preferred embodiment, the invention relates to a compound of formula I above, wherein U represents a divalent group selected from the group consisting of -O-, -S-, -S(=O)-, -S (=O) ₂ -, -S(=O)-N(R ^3b )-, -N(R ^3c )-S(=O)-, -S(=O) ₂ -N(R ^3b )-, -N(R ^3c )-S(=O) ₂ -, -C(=O)-, -N(R ^3b )-, -C(=O)-O-, -OC(=O)-,- C(=S)-O-, -OC(=S)-, -C(=O)-N(R ^3b )-, -N(R ^3c )-C(=O)-, -N(R ^3c )-C(=O)-N(R ^3b )-, -OC(=O)-N(R ^3b )-, -N(R ^3c )-C(=O)-O-.

In another preferred embodiment, the invention relates to a compound of formula I above, wherein U represents a single bond or a divalent group selected from the group consisting of -O-, -C(=O)-, -N( R ^3b )-, -C(=O)-O-, -OC(=O)-, -C(=S)-O-, -C(=O)-N(R ^3b )-, -N( R ^3c )-C(=O)-, -N(R ^3c )-C(=O)-N(R ^3b )-, -OC(=O)-N(R ^3b )-, -N(R ^3c )-C(=O)-O-.

In another preferred embodiment, the invention relates to a compound of formula I above, wherein U represents a divalent group selected from the group consisting of -C(=O)-, -N( ^R3b )-, -C (=O)-O-, -OC(=O)-, -C(=O)-N(R ^3b )-, -N(R ^3c )-C(=O)-.

In another preferred embodiment, the invention relates to a compound of formula I above, wherein U represents a divalent group selected from the group consisting of -C(=O)-O-, -C(=O)-N (R ^3b )-.

In another preferred embodiment, the invention is directed to a compound of formula I above, wherein U represents -C(=O)-O-.

In another preferred embodiment, the invention is directed to a compound of formula I above, wherein U represents -C(=O)-N( ^R3b )-.

In another preferred embodiment, the invention relates to a compound of formula I above, wherein U represents -S(=O) ₂ -N(R ^3b )- or -N(R ^3c )-S(=O) ₂ - .

In another preferred embodiment, the invention relates to a compound of formula I above, wherein R ^3a represents a hydrogen atom or a group selected from the group consisting of C ₁ -C ₆ alkyl-, C ₃ -C ₆ cycloalkyl- a 3 to 10 membered heterocycloalkyl- group; wherein the C ₁ -C ₆ alkyl-, C ₃ -C ₆ cycloalkyl- or 3 to 10 membered heterocycloalkyl-, as the case may be the same or different 2 or 3 R ⁴ groups are substituted.

In another preferred embodiment, the invention relates to a compound of formula I above, wherein R ^3a represents a hydrogen atom or a C ₁ -C ₆ alkyl-; wherein the C ₁ -C ₆ alkyl- is the same or different, as the case may be Substituted by 1, 2 or 3 R ⁴ groups.

In another preferred embodiment, the invention relates to a compound of formula I above, wherein R ^3a represents a hydrogen atom or a C ₁ -C ₃ alkyl-; wherein the C ₁ -C ₃ alkyl group - as the case may be 1 R ⁴ group substitution.

In another preferred embodiment, the invention relates to a compound of formula I above, wherein R ^3a represents C ₃ -C ₆ cycloalkyl-; wherein the C ₃ -C ₆ cycloalkyl- is the same or different, as the case may be 1, 2 or 3 R ⁴ groups are substituted.

In another preferred embodiment, the invention relates to a compound of formula I above, wherein R ^3a represents 3 to 10 membered heterocycloalkyl-; wherein the 3 to 10 membered heterocycloalkyl - as the case may be the same or different 1, 2 or 3 R ⁴ groups are substituted.

In another preferred embodiment, the invention relates to a compound of formula I above, wherein R ^3b represents a hydrogen atom or a C ₁ -C ₃ alkyl-; wherein the C ₁ -C ₃ alkyl group - as the case may be 1 R ⁴ group substitution.

In another preferred embodiment, the invention relates to a compound of formula I above, wherein R ^3b represents a hydrogen atom or a C ₁ -C ₃ alkyl-.

In another preferred embodiment, the invention relates to a compound of formula I above, wherein R ^3c represents a hydrogen atom or a C ₁ -C ₃ alkyl-; wherein the C ₁ -C ₃ alkyl group - as the case may be 1 R ⁴ group substitution.

In another preferred embodiment, the invention relates to a compound of formula I above, wherein R ^3c represents a hydrogen atom or a C ₁ -C ₃ alkyl-.

In another preferred embodiment, the invention relates to a compound of formula I above, wherein N(R ^3b )R ^3a together form a 3 to 10 membered heterocycloalkyl- or 4 to 10 membered heterocycloalkenyl-; 3 to 10 membered heterocycloalkyl- or 4 to 10 membered heterocycloalkenyl-substituted as the same or differently by 1, 2 or 3 R ⁴ groups.

In another preferred embodiment, the invention relates to a compound of formula I above, wherein N(R ^3b )R ^3a together form a 3 to 10 membered heterocycloalkyl- group, wherein the 3 to 10 membered heterocycloalkyl- The same or different substitutions are made with 1, 2 or 3 R ⁴ groups.

In another preferred embodiment, the invention relates to a compound of formula I above, wherein N(R ^3b )R ^3a together form a 3 to 10 membered heterocycloalkyl- group, wherein the 3 to 10 membered heterocycloalkyl- The situation is replaced by one R ⁴ group.

In another preferred embodiment, the present invention relates to a compound of the above formula I, wherein R ⁴ represents halo -, hydroxy -, cyano -, nitro -, C ₁ -C ₃ alkyl -, halo -C _1- C ₃ alkyl-, C ₁ -C ₃ alkoxy-, halo-C ₁ -C ₃ alkoxy-, hydroxy-C ₁ -C ₃ alkyl-, C ₁ -C ₃ alkoxy -C ₁ -C ₃ alkyl-, halo-C ₁ -C ₃ alkoxy-C ₁ -C ₃ alkyl-, R ^5c -O-, -C(=O)-R ^5c , -C( =O)-OR ^5c , -OC(=O)-R ^5c , -N(R ^5b )-C(=O)-R ^5c , -N(R ^5c )-C(=O)-N(R ^5a R ^5b , -N(R ^5a )R ^5b , -C(=O)-N(R ^5a )R ^5b , R ^5c -S-, R ^5c -S(=O)-, R ^5c -S(= O) ₂ -, -N(R ^5c )-S(=O)-R ^5b , -S(=O)-N(R ^5a )R ^5b , -N(R ^5c )-S(=O) ₂ - R ^5b or -S(=O) ₂ -N(R ^5a )R ^5b .

In another preferred embodiment, the present invention relates to a compound of the above formula I, wherein R ⁴ represents halo -, hydroxy -, cyano -, C ₁ -C ₃ alkyl -, halo -C ₁ -C ₃ Alkyl-, C ₁ -C ₃ alkoxy-, halo-C ₁ -C ₃ alkoxy-, hydroxy-C ₁ -C ₃ alkyl-, C ₁ -C ₃ alkoxy-C ₁ - C ₃ alkyl-, R ^5c -O-, -C(=O)-R ^5c , -C(=O)-OR ^5c , -OC(=O)-R ^5c , -N(R ^5b )-C (=O)-R ^5c , -N(R ^5c )-C(=O)-N(R ^5a )R ^5b , -N(R ^5a )R ^5b , -C(=O)-N(R ^5a ) R ^5b or R ^5c -S(=O) ₂ -.

In another preferred embodiment, the present invention relates to a compound of the above formula I, wherein R ⁴ represents halo -, hydroxy -, or -N (R ^5a) R ^5b.

In another preferred embodiment, the invention relates to a compound of formula I above, wherein R ^5a represents a hydrogen atom or a C ₁ -C ₆ alkyl- or benzyl-.

In another preferred embodiment, the invention relates to a compound of formula I above, wherein R ^5a represents a hydrogen atom or a C ₁ -C ₆ alkyl-.

In another preferred embodiment, the invention relates to compounds of formula I above, wherein R ^5a represents C ₁ -C ₆ alkyl-.

In another preferred embodiment, the invention relates to a compound of formula I above, wherein R ^5a represents a hydrogen atom.

In another preferred embodiment, the invention relates to a compound of formula I above, wherein R ^5b represents a hydrogen atom or a C ₁ -C ₆ alkyl-.

In another preferred embodiment, the invention relates to a compound of formula I above, wherein R ^5b represents C ₁ -C ₆ alkyl-.

In another preferred embodiment, the invention relates to a compound of formula I above, wherein R ^5b represents a hydrogen atom.

In another preferred embodiment, the invention relates to a compound of formula I above, wherein R ^5c represents a hydrogen atom or a C ₁ -C ₆ alkyl-.

In another preferred embodiment, the invention relates to a compound of formula I above, wherein R ^5c represents C ₁ -C ₆ alkyl-.

In another preferred embodiment, the invention relates to a compound of formula I above, wherein R ^5c represents a hydrogen atom.

In another preferred embodiment, the invention relates to a compound of formula I above, wherein N(R ^5a )R ^5b together form a 3 to 7 membered heterocycloalkyl- group.

In another preferred embodiment, the invention relates to a compound of formula I above, wherein R ^6a represents a hydrogen atom or a C ₁ -C ₆ alkyl-; wherein the C ₁ -C ₆ alkyl- is the same or different, as the case may be Substituted by 1, 2 or 3 R ⁴ groups.

In another preferred embodiment, the invention relates to a compound of formula I above, wherein R ^6a represents C ₂ -C ₆ alkenyl- or C ₂ -C ₆ alkynyl-; wherein the C ₂ -C ₆ alkenyl- Or C ₂ -C ₆ alkynyl - as the case may be substituted by 1, 2 or 3 R ⁴ groups identically or differently.

In another preferred embodiment, the invention relates to a compound of formula I above, wherein R ^6a represents a hydrogen atom or a C ₁ -C ₆ alkyl-, C ₂ -C ₆ alkenyl- or C ₂ -C ₆ alkynyl group -.

In another preferred embodiment, the invention relates to a compound of formula I above, wherein R ^6a represents a hydrogen atom or a C ₁ -C ₆ alkyl-.

In another preferred embodiment, the invention relates to a compound of formula I above, wherein R ^6a represents C ₂ -C ₆ alkenyl- or C ₂ -C ₆ alkynyl-.

In another preferred embodiment, the invention relates to a compound of formula I above, wherein R ^6a represents C ₁ -C ₆ alkyl-.

In another preferred embodiment, the invention relates to a compound of formula I above, wherein R ^6a represents C ₁ -C ₃ alkyl-.

In another preferred embodiment, the invention is directed to a compound of formula I above, wherein R ^6a represents a hydrogen atom.

In another preferred embodiment, the invention is directed to a compound of formula I above, wherein R ^6a represents C ₁ -C ₃ alkyl-, and wherein t represents 0.

In another preferred embodiment, the invention relates to a compound of formula I above, wherein R ^6a represents a hydrogen atom, and wherein t represents 0.

In another preferred embodiment, the invention relates to a compound of formula I above, wherein R ^6b represents a hydrogen atom or a C ₁ -C ₃ alkyl-.

In another preferred embodiment, the invention is directed to a compound of formula I above, wherein R ^6b represents C ₁ -C ₃ alkyl-.

In another preferred embodiment, the invention is directed to a compound of formula I above, wherein R ^6b represents a hydrogen atom.

In another preferred embodiment, the invention relates to a compound of formula I above, wherein R ^6c represents a hydrogen atom or a C ₁ -C ₃ alkyl-.

In another preferred embodiment, the invention relates to a compound of formula I above, wherein R ^6c represents C ₁ -C ₃ alkyl-.

In another preferred embodiment, the invention relates to a compound of formula I above, wherein R ^6c represents a hydrogen atom.

In another preferred embodiment, the invention relates to a compound of formula I above, wherein p represents 0 or 1.

In another preferred embodiment, the invention is directed to a compound of formula I above, wherein p represents zero.

In another preferred embodiment, the invention is directed to a compound of formula I above, wherein q represents 0 or 1.

In another preferred embodiment, the invention is directed to a compound of formula I above, wherein q represents zero.

In another preferred embodiment, the invention is directed to a compound of formula I above, wherein r represents 1 or 2.

In another preferred embodiment, the invention is directed to a compound of formula I above, wherein r represents 1.

In another preferred embodiment, the invention is directed to a compound of formula I above, wherein r represents 2.

In another preferred embodiment, the invention is directed to a compound of formula I above, wherein s represents 1 or 2.

In another preferred embodiment, the invention is directed to a compound of formula I above, wherein s represents 1.

In another preferred embodiment, the invention is directed to a compound of formula I above, wherein s represents 2.

In another preferred embodiment, the invention is directed to a compound of formula I above, wherein s represents 1 and r represents 2.

In another preferred embodiment, the invention is directed to a compound of formula I above, wherein s represents 2 and r represents 1.

In another preferred embodiment, the invention is directed to a compound of formula I above, wherein t represents zero.

It should be understood that the present invention is also directed to any combination of the above-described preferred embodiments.

Some examples of combinations are given below. However, the invention is not limited to such combinations.

In a preferred embodiment, the invention relates to a compound of formula I above, wherein: QV represents a group selected from the group consisting of C(R ^1a )-N, NC(R ^1a ); A represents a group selected from the group consisting of : Wherein * indicates the point of attachment of the rest of the molecule such group; R ^1a represents a hydrogen atom or a halogen atom or a group selected from the group of: hydroxy - cyano -, C ₁ -C ₆ alkyl -, C ₂ - C ₆ alkenyl-, C ₂ -C ₆ alkynyl-, C ₁ -C ₆ alkoxy-, halo-C ₁ -C ₆ alkyl-, halo-C ₁ -C ₆ alkoxy-, Hydroxy-C ₁ -C ₆ alkyl-, C ₁ -C ₃ alkoxy-C ₁ -C ₃ alkyl-, -N(R ^5b )R ^5c , -SCF ₃ , -SF ₅ ; R ^1b represents hydrogen An atom or a halogen atom or a group selected from the group consisting of hydroxy-, cyano-, C ₁ -C ₆ alkyl-, C ₂ -C ₆ alkenyl-, C ₂ -C ₆ alkynyl-, C ₁ -C ₆ alkoxy-, halo-C ₁ -C ₆ alkyl-, halo-C ₁ -C ₆ alkoxy-, hydroxy-C ₁ -C ₆ alkyl-, C ₁ -C ₃ alkoxy -C ₁ -C ₃ alkyl-, -N(R ^5b )R ^5c , -SCF ₃ , -SF ₅ ; R ^1c represents a hydrogen atom or a halogen atom or a group selected from the group consisting of hydroxy-, cyano-, C ₁ -C ₆ alkyl-, C ₂ -C ₆ alkenyl-, C ₂ -C ₆ alkynyl-, C ₁ -C ₆ alkoxy-, halo-C ₁ -C ₆ alkyl-, halo -C ₁ -C ₆ alkoxy-, hydroxy-C ₁ -C ₆ alkyl-, C ₁ -C ₃ alkoxy-C ₁ -C ₃ alkyl-, -N(R ^5b )R ^5c , -SCF _3, -SF _5; R ^2a represents a hydrogen atom A halogen atom or a group selected from the group: C ₁ -C ₆ alkyl -, C ₃ -C ₆ cycloalkyl -, heterocycloalkyl 3-10 - 4-10 heterocycloalkenyl -, aryl , -heteroaryl-, cyano-, -(CH ₂ ) _q -U-(CH ₂ ) _p -R ^3a ; wherein the C ₁ -C ₆ alkyl-, C ₃ -C ₆ cycloalkyl- 3 to 10 membered heterocycloalkyl-, 4 to 10 membered heterocycloalkenyl-, aryl- or heteroaryl-, as the case may be, 1, 2, 3, 4 or 5 R ⁴ groups identically or differently Substituted; R ^2b represents a hydrogen atom or a halogen atom or a group selected from the group consisting of C ₁ -C ₆ alkyl-, C ₃ -C ₆ cycloalkyl-, 3 to 10 membered heterocycloalkyl-, 4 to 10 a heterocycloalkenyl-, aryl-, heteroaryl-, cyano-, -(CH ₂ ) _q -U-(CH ₂ ) _p -R ^3a ; wherein the C ₁ -C ₆ alkyl-, C _3- C ₆ cycloalkyl-, 3 to 10 membered heterocycloalkyl-, 4 to 10 membered heterocycloalkenyl-, aryl- or heteroaryl-, as the case may be the same or different, 1, 2, 3, 4 or 5 R ⁴ groups substituted; or R ^2a and R ^2b together

Represents -(CH ₂ ) _r -T-(CH ₂ ) _s -; T represents a group selected from the group consisting of U, -C[H][(CH ₂ ) _t -UR ^3a ]-; U represents a single bond or a divalent group selected from the group consisting of -O-, -S-, -S(=O)-, -S(=O) ₂ -, -S(=O)-N(R ^3b )-, -N(R ^3c )-S(=O)-, -C(=O)-, -N(R ^3b )-, -C(=O)-O-, -OC(=O)-, -C (=S)-O-, -OC(=S)-, -C(=O)-N(R ^3b )-, -N(R ^3c )-C(=O)-, -N(R ^3c ) -C(=O)-N(R ^3b )-, -OC(=O)-N(R ^3b )-, -N(R ^3c )-C(=O)-O-; R ^3a represents a hydrogen atom or a group selected from the group consisting of C ₁ -C ₆ alkyl-, C ₃ -C ₆ cycloalkyl-, 3 to 10 membered heterocycloalkyl-, 4 to 10 membered heterocycloalkenyl-, aryl-, Heteroaryl-; wherein the C ₁ -C ₆ alkyl-, C ₃ -C ₆ cycloalkyl-, 3 to 10 membered heterocycloalkyl-, 4 to 10 membered heterocycloalkenyl-, aryl- or Heteroaryl - optionally, differently substituted with 1, 2, 3, 4 or 5 R ⁴ groups; R ^3b represents a hydrogen atom or a group selected from C ₁ -C ₆ alkyl-, C _3- C ₆ cycloalkyl-, 3 to 10 membered heterocycloalkyl-, 4 to 10 membered heterocycloalkenyl-, aryl-, heteroaryl-; wherein the C ₁ -C ₆ alkyl-, C ₃ -C ₆ cycloalkyl -, heterocycloalkyl 3-10 - 4-10 heterocycloalkenyl -, Group - aryl or heteroaryl group - are the same or different optionally substituted 3, 4 or 5 R ⁴ groups; R ^3c represents a hydrogen atom or a group selected from the group: C ₁ -C ₆ alkyl -, C ₃ -C ₆ cycloalkyl-, 3 to 10 membered heterocycloalkyl-, 4 to 10 membered heterocycloalkenyl-, aryl-, heteroaryl-; wherein the C ₁ -C ₆ alkyl group -, C ₃ -C ₆ cycloalkyl-, 3 to 10 membered heterocycloalkyl-, 4 to 10 membered heterocycloalkenyl-, aryl- or heteroaryl-, as the case may be the same or different, 1, 2 , 3, 4 or 5 R ⁴ groups substituted; or N(R ^3b )R ^3a together

Forming a 3 to 10 membered heterocycloalkyl- or 4 to 10 membered heterocycloalkenyl-; wherein the 3 to 10 membered heterocycloalkyl- or 4 to 10 membered heterocycloalkenyl-, as the case may be the same or different , 2, 3, 4 or 5 R ⁴ groups are substituted; R ⁴ represents halo-, hydroxy-, pendant oxy-(O=), cyano-, nitro-, C ₁ -C ₆ alkyl- , C ₂ -C ₆ alkenyl-, C ₂ -C ₆ alkynyl-, halo-C ₁ -C ₆ alkyl-, C ₁ -C ₆ alkoxy-, halo-C ₁ -C ₆ alkane Oxy-, hydroxy-C ₁ -C ₆ alkyl-, C ₁ -C ₆ alkoxy-C ₁ -C ₆ alkyl-halo-C ₁ -C ₆ alkoxy-C ₁ -C ₆ alkane ^Base- , R ^5c -O-, -C(=O)-R ^5c , -C(=O)-OR ^5c , -OC(=O)-R ^5c , -N(R ^5b )-C(=O )-R ^5c , -N(R ^5c )-C(=O)-N(R ^5a )R ^5b , -N(R ^5a )R ^5b , -C(=O)-N(R ^5a )R ^5b , R ^5c -S-, R ^5c -S(=O)-, R ^5c -S(=O) ₂ -, -N(R ^5c )-S(=O)-R ^5b , -S(=O)- N(R ^5a )R ^5b , -N(R ^5c )-S(=O) ₂ -R ^5b , -S(=O) ₂ -N(R ^5a )R ^5b , -S(=O)=N( R ^5c )R ^5b , -S(=O)=N(R ^5c )R ^5b or -N=S(=O)(R ^5c )R ^5b ; R ^5a represents a hydrogen atom, C ₁ -C ₆ alkyl- , C ₃ -C ₆ cycloalkyl- or 3 to 10 membered heterocycloalkyl-; R ^5b represents a hydrogen atom, C ₁ -C ₆ alkyl-, C ₃ -C ₆ cycloalkyl- or 3 to 10 members miscellaneous Cycloalkyl-; R ^5c represents a hydrogen atom, a C ₁ -C ₆ alkyl-, a C ₃ -C ₆ cycloalkyl- or a 3 to 10 membered heterocycloalkyl group; or N(R ^5a )R ^5b

Form 3 to 7 membered heterocycloalkyl- together; p represents an integer of 0, 1, 2 or 3; q represents an integer of 0, 1, 2 or 3; r represents an integer of 1, 2 or 3; An integer of 2 or 3; and t represents an integer of 0 or 1; or a tautomer, N-oxide, hydrate, solvate or salt thereof, or a mixture of such substances.

In another preferred embodiment, the invention relates to a compound of formula I above, wherein: QV represents a group selected from the group consisting of C(R ^1a )-N, NC(R ^1a ); A represents a group selected from the group consisting of group: Wherein * indicates the point of attachment of the group to the rest of the molecule; R ^1a represents a hydrogen atom or a group selected from the group consisting of cyano-, C ₁ -C ₆ alkyl-, C ₁ -C ₆ alkoxy- , halo-C ₁ -C ₆ alkyl-, halo-C ₁ -C ₆ alkoxy-, hydroxy-C ₁ -C ₆ alkyl-, C ₁ -C ₃ alkoxy-C ₁ -C ₃ alkyl-; R ^1b represents a hydrogen atom or a group selected from the group consisting of cyano-, C ₁ -C ₆ alkyl-, C ₁ -C ₆ alkoxy-, halo-C ₁ -C ₆ alkane Base-, halo-C ₁ -C ₆ alkoxy-, hydroxy-C ₁ -C ₆ alkyl-, C ₁ -C ₃ alkoxy-C ₁ -C ₃ alkyl-; R ^1c represents a hydrogen atom Or a group selected from the group consisting of cyano-, C ₁ -C ₆ alkyl-, C ₁ -C ₆ alkoxy-, halo-C ₁ -C ₆ alkyl-, halo-C ₁ -C ₆ alkoxy-, hydroxy-C ₁ -C ₆ alkyl-, C ₁ -C ₃ alkoxy-C ₁ -C ₃ alkyl-; R ^2a represents a hydrogen atom or a halogen atom or a group selected from the group consisting of :C ₁ -C ₆ alkyl-, C ₃ -C ₆ cycloalkyl-, 3 to 10 membered heterocycloalkyl-, halo-C ₁ -C ₃ alkyl-, cyano-, -(CH _{2 q} -U-(CH ₂ ) _p -R ^3a ; wherein the C ₁ -C ₆ alkyl-, C ₃ -C ₆ cycloalkyl-, 3 to 10 membered heterocycloalkyl- or 4 to 10 membered Cycloalkenyl - the same or not as the case By 1, 2 or 3 R ⁴ groups, with the proviso halo -C ₁ -C ₃ alkyl that - does not contain more than 5 halogen atoms; R ^2b represents a hydrogen atom or a halogen atom or is selected from a group: C ₁ -C ₆ alkyl-, halo-C ₁ -C ₃ alkyl-, cyano-, -(CH ₂ ) _q -U-(CH ₂ ) _p -R ^3a ; wherein the C _1- C ₆ alkyl-substituted as the same or differently by 1, 2 or 3 R ⁴ groups, with the proviso that the halo-C ₁ -C ₃ alkyl group - does not contain more than 5 halogen atoms; Or R ^2a and R ^2b together

Represents -(CH ₂ ) _r -T-(CH ₂ ) _s -; T represents -C[R ^6a ][(C(R ^6b )(R ^6c )) _t -UR ^3a ]-; U represents a single bond or Divalent groups from the following groups: -O-, -S-, -S(=O)-, -S(=O) ₂ -, -S(=O)-N(R ^3b )-, - N(R ^3c )-S(=O)-, -C(=O)-, -N(R ^3b )-, -C(=O)-O-, -OC(=O)-, -C( =S)-O-, -OC(=S)-, -C(=O)-N(R ^3b )-, -N(R ^3c )-C(=O)-, -N(R ^3c )- C(=O)-N(R ^3b )-, -OC(=O)-N(R ^3b )-, -N(R ^3c )-C(=O)-O-; R ^3a represents a hydrogen atom or From the following groups: C ₁ -C ₆ alkyl-, C ₃ -C ₆ cycloalkyl-, 3 to 10 membered heterocycloalkyl-, 4 to 10 membered heterocycloalkenyl-, aryl-, hetero Aryl-, halo-C ₁ -C ₃ alkyl-; wherein the C ₁ -C ₆ alkyl-, C ₃ -C ₆ cycloalkyl-, 3 to 10 membered heterocycloalkyl-, aryl- , heteroaryl- or halo-C ₁ -C ₃ alkyl-, as the case may be, identically or differently substituted by 1, 2, 3, 4 or 5 R ⁴ groups, with the proviso that the halo-C ₁ -C ₃ alkyl - together with the R ⁴ group optionally attached thereto, does not contain more than 5 halogen atoms; R ^3b represents a hydrogen atom or a group selected from C ₁ -C ₆ alkyl-, C ₃ -C ₆ cycloalkyl-, 3 to 10 membered heterocycloalkyl-, 4 to 10 membered heterocycloalkyl Base-, aryl-, heteroaryl-, halo-C ₁ -C ₃ alkyl-; wherein the C ₁ -C ₆ alkyl-, C ₃ -C ₆ cycloalkyl-, 3 to 10 member Cycloalkyl-, aryl-, heteroaryl- or halo-C ₁ -C ₃ alkyl-substituted as the same or differently by 1, 2, 3, 4 or 5 R ⁴ groups, the limitation Provided that the halo-C ₁ -C ₃ alkyl group, together with the R ⁴ group to which it is optionally attached, does not contain more than 5 halogen atoms; R ^3c represents a hydrogen atom or a group selected from: C ₁ - C ₆ alkyl-, C ₃ -C ₆ cycloalkyl-, 3 to 10 membered heterocycloalkyl-, 4 to 10 membered heterocycloalkenyl-, aryl-, heteroaryl-, halo-C ₁ -C ₃ alkyl-; wherein the C ₁ -C ₆ alkyl-, C ₃ -C ₆ cycloalkyl-, 3 to 10 membered heterocycloalkyl-, aryl-, heteroaryl- or halo- C ₁ -C ₃ alkyl-substituted as the same or differently by 1, 2, 3, 4 or 5 R ⁴ groups, with the proviso that the halo-C ₁ -C ₃ alkyl group - together with the case The R ⁴ groups attached thereto do not contain more than 5 halogen atoms together; or N(R ^3b )R ^3a

Forming together a 3 to 10 membered heterocycloalkyl group or a 4 to 10 membered heterocycloalkenyl group; wherein the 3 to 10 membered heterocycloalkyl group or 4 to 10 membered heterocycloalkenyl group - as the case may be the same or different 1, 2, 3, 4 or 5 R ⁴ groups are substituted; R ⁴ represents halo-, hydroxy-, pendant oxy-(O=), cyano-, nitro-, C ₁ -C ₆ alkyl -, C ₂ -C ₆ alkenyl-, C ₂ -C ₆ alkynyl-, halo-C ₁ -C ₆ alkyl-, C ₁ -C ₆ alkoxy-, halo-C ₁ -C ₆ Alkoxy-, hydroxy-C ₁ -C ₆ alkyl-, C ₁ -C ₆ alkoxy-C ₁ -C ₆ alkyl-, halo-C ₁ -C ₆ alkoxy-C ₁ -C ₆ alkyl-, R ^5c -O-, -C(=O)-R ^5c , -C(=O)-OR ^5c , -OC(=O)-R ^5c , -N(R ^5b )-C( =O)-R ^5c , -N(R ^5c )-C(=O)-N(R ^5a )R ^5b , -N(R ^5a )R ^5b , -C(=O)-N(R ^5a )R ^5b , R ^5c -S-, R ^5c -S(=O)-, R ^5c -S(=O) ₂ -, -N(R ^5c )-S(=O)-R ^5b , -S(=O )-N(R ^5a )R ^5b , -N(R ^5c )-S(=O) ₂ -R ^5b , -S(=O) ₂ -N(R ^5a )R ^5b , -S(=O)= N(R ^5c )R ^5b , -S(=O)=N(R ^5c )R ^5b or -N=S(=O)(R ^5c )R ^5b ; R ^5a represents a hydrogen atom, C ₁ -C ₆ alkane group -, C ₃ -C ₆ cycloalkyl - or 3-10 heterocycloalkyl -; R ^5b represents a hydrogen atom, C ₁ -C ₆ alkyl -, C ₃ -C ₆ cycloalkyl, - 3 or Heterocycloalkyl 10 -; R ^5c represents a hydrogen atom, C ₁ -C ₆ alkyl -, C ₃ -C ₆ cycloalkyl - or heterocycloalkyl 3-10 -; or N (R ^5a) R ^5b together form a 3 to 7 membered heterocycloalkyl-; R ^6a represents a hydrogen atom or a group selected from the group consisting of C ₁ -C ₆ alkyl-, C ₂ -C ₆ alkenyl-, C ₂ -C ₆ alkyne a group wherein the C ₁ -C ₆ alkyl-, C ₂ -C ₆ alkenyl- or C ₂ -C ₆ alkynyl group is optionally substituted with 1, 2 or 3 R ⁴ groups; R ^6b represents a hydrogen atom or a C ₁ -C ₃ alkyl group; R ^6c represents a hydrogen atom or a C ₁ -C ₃ alkyl group; p represents an integer of 0, 1, 2 or 3; q represents 0, 1, 2 or An integer of 3; r represents an integer of 1, 2 or 3; s represents an integer of 1, 2 or 3; and t represents an integer of 0 or 1; or a tautomer thereof, an N-oxide, a hydrate, a solvent Or a salt, or a mixture of such substances.

In another preferred embodiment, the invention relates to a compound of formula I above, wherein: QV represents a group selected from the group consisting of C(R ^1a )-N, NC(R ^1a ); A represents a group selected from the group consisting of group: Wherein * indicates the point of attachment of the group is the rest of the molecule; R ^1a represents a hydrogen atom or a halogen atom or a group selected from the group of: hydroxy - cyano -, C ₁ -C ₆ alkyl -, C ₂ -C ₆ alkenyl-, C ₂ -C ₆ alkynyl-, C ₁ -C ₆ alkoxy-, halo-C ₁ -C ₆ alkoxy-, -N(R ^5b )R ^5c , -SCF ₃ , -SF ₅ ; R ^1b represents a hydrogen atom or a halogen atom or a group selected from the group consisting of hydroxy-, cyano-, C ₁ -C ₆ alkyl-, C ₂ -C ₆ alkenyl-, C ₂ -C ₆ Alkynyl-, C ₁ -C ₆ alkoxy-, halo-C ₁ -C ₆ alkoxy-, -N(R ^5b )R ^5c , -SCF ₃ , -SF ₅ ; R ^1c represents a hydrogen atom or a halogen atom or a group selected from the group consisting of hydroxy-, cyano-, C ₁ -C ₆ alkyl-, C ₂ -C ₆ alkenyl-, C ₂ -C ₆ alkynyl-, C ₁ -C ₆ alkane Oxy-, halo-C ₁ -C ₆ alkoxy-, -N(R ^5b )R ^5c , -SCF ₃ , -SF ₅ ; R ^2a represents a hydrogen atom or a halogen atom or a group selected from the group consisting of: C ₁ -C ₆ alkyl-, C ₃ -C ₆ cycloalkyl-, 3 to 10 membered heterocycloalkyl-, 4 to 10 membered heterocycloalkenyl-, aryl-, heteroaryl-, halo -C ₁ -C ₃ alkyl-, cyano-, -(CH ₂ ) _q -U-(CH ₂ ) _p -R ^3a ; wherein the C ₁ -C ₆ alkyl-, C ₃ -C ₆ naphthenes Base, 3 to 10 membered heterocycloalkyl-, 4 to 10 membered heterocycloalkenyl-, aryl- or heteroaryl-, as the case may be, 1, 2, 3, 4 or 5 R ⁴ Substituent substitution, the limitation is that the halo-C ₁ -C ₃ alkyl group - does not contain more than 5 halogen atoms; R ^2b represents a hydrogen atom or a halogen atom or a group selected from C ₁ -C ₆ alkane Base-, C ₃ -C ₆ cycloalkyl-, 3 to 10 membered heterocycloalkyl-, 4 to 10 membered heterocycloalkenyl-, aryl-, heteroaryl-, halo-C ₁ -C ₃ Alkyl-, cyano-, -(CH ₂ ) _q -U-(CH ₂ ) _p -R ^3a ; wherein the C ₁ -C ₆ alkyl-, C ₃ -C ₆ cycloalkyl-, 3 to 10 Heterocycloalkyl-, 4 to 10 membered heterocycloalkenyl-, aryl- or heteroaryl-substituted as the same or differently by 1, 2, 3, 4 or 5 R ⁴ groups, the limitation Provided that the halo-C ₁ -C ₃ alkyl group - does not contain more than 5 halogen atoms; or R ^2a and R ^2b together

Represents -(CH ₂ ) _r -T-(CH ₂ ) _s -; T represents a group selected from the group consisting of U, -C[R ^6a ][(C(R ^6b )(R ^6c )) _t -UR ^3a U- represents a single bond or a divalent group selected from the group consisting of -O-, -S-, -S(=O)-, -S(=O) ₂ -, -S(=O) -N(R ^3b )-, -N(R ^3c )-S(=O)-, -C(=O)-, -N(R ^3b )-, -C(=O)-O-, -OC (=O)-, -C(=S)-O-, -OC(=S)-, -C(=O)-N(R ^3b )-, -N(R ^3c )-C(=O) -, -N(R ^3c )-C(=O)-N(R ^3b )-, -OC(=O)-N(R ^3b )-, -N(R ^3c )-C(=O)-O R ^3a represents a hydrogen atom or a group selected from the group consisting of C ₁ -C ₆ alkyl-, C ₃ -C ₆ cycloalkyl-, 3 to 10 membered heterocycloalkyl-; wherein the C ₁ -C ₆ alkyl-, C ₃ -C ₆ cycloalkyl- or 3 to 10 membered heterocycloalkyl-substituted as the same or differently by 1, 2 or 3 R ⁴ groups; R ^3b represents a hydrogen atom or C ₁ -C ₃ alkyl-; wherein the C ₁ -C ₃ alkyl group - optionally substituted with 1 R ⁴ group; R ^3c represents a hydrogen atom or a C ₁ -C ₃ alkyl group; or N(R ^3b ) R ^3a together

Forming a 3 to 10 membered heterocycloalkyl- or 4 to 10 membered heterocycloalkenyl-; wherein the 3 to 10 membered heterocycloalkyl- or 4 to 10 membered heterocycloalkenyl-, as the case may be the same or different , 2 or 3 R ⁴ groups are substituted; R ⁴ represents halo-, hydroxy-, pendant oxy-(O=), cyano-, nitro-, C ₁ -C ₃ alkyl-, halo- C ₁ -C ₃ alkyl-, C ₁ -C ₃ alkoxy-, halo-C ₁ -C ₃ alkoxy-, hydroxy-C ₁ -C ₃ alkyl-, C ₁ -C ₃ alkoxy -C ₁ -C ₃ alkyl-, halo-C ₁ -C ₃ alkoxy-C ₁ -C ₃ alkyl-, R ^5c -O-, -C(=O)-R ^5c , -C (=O)-OR ^5c , -OC(=O)-R ^5c , -N(R ^5b )-C(=O)-R ^5c , -N(R ^5c )-C(=O)-N(R ^5a ) R ^5b , -N(R ^5a )R ^5b , -C(=O)-N(R ^5a )R ^5b , R ^5c -S-, R ^5c -S(=O)-, R ^5c -S( =O) ₂ -, -N(R ^5c )-S(=O)-R ^5b , -S(=O)-N(R ^5a )R ^5b , -N(R ^5c )-S(=O) ₂ -R ^5b or -S(=O) ₂ -N(R ^5a )R ^5b ; R ^5a represents a hydrogen atom or a C ₁ -C ₃ alkyl group; R ^5b represents a hydrogen atom or a C ₁ -C ₃ alkyl group; R ^5c represents a hydrogen atom or a C ₁ -C ₃ alkyl group; R ^6a represents a hydrogen atom or a group selected from the group consisting of C ₁ -C ₆ alkyl-, C ₂ -C ₆ alkenyl-, C ₂ -C ₆ alkynyl-; wherein the C ₁ -C ₆ alkyl-, C ₂ -C ₆ alkenyl- or C ₂ -C ₆ alkynyl - as the case may be substituted with 1, 2 or 3 R ⁴ groups; R ^6b represents a hydrogen atom or a C ₁ -C ₃ alkyl group; R ^6c represents a hydrogen atom or C ₁ -C ₃ alkyl-; or N(R ^5a )R ^5b

Form 3 to 7 membered heterocycloalkyl- together; p represents an integer of 0, 1, 2 or 3; q represents an integer of 0, 1, 2 or 3; r represents an integer of 1, 2 or 3; An integer of 2 or 3; and t represents an integer of 0 or 1; or a tautomer, N-oxide, hydrate, solvate or salt thereof, or a mixture of such substances.

In another preferred embodiment, the invention relates to a compound of formula I above, wherein: QV represents a group selected from the group consisting of C(R ^1a )-N, NC(R ^1a ); A represents a group selected from the group consisting of group: Wherein * indicates the point of attachment of the group to the rest of the molecule; R ^1a represents a hydrogen atom or a halogen atom or a group selected from the group consisting of hydroxy-, C ₁ -C ₃ alkyl-C ₁ -C ₃ alkoxy -, halo-C ₁ -C ₃ alkoxy-; R ^1b represents a hydrogen atom; R ^1c represents a hydrogen atom; R ^2a represents a hydrogen atom or a halogen atom or a group selected from C ₁ -C ₆ alkyl -, C ₃ -C ₆ cycloalkyl-, 3 to 10 membered heterocycloalkyl-, 4 to 10 membered heterocycloalkenyl-, aryl-, heteroaryl-, halo-C ₁ -C ₃ alkane -Cyano-, -(CH ₂ ) _q -U-(CH ₂ ) _p -R ^3a ; wherein the C ₁ -C ₆ alkyl-, C ₃ -C ₆ cycloalkyl-, 3 to 10 members Heterocycloalkyl-, 4 to 10 membered heterocycloalkenyl-, aryl- or heteroaryl-substituted as the same or differently by 1, 2, 3, 4 or 5 R ⁴ groups, the restrictions Is a halo-C ₁ -C ₃ alkyl group-containing no more than 5 halogen atoms; R ^2b represents a hydrogen atom or a halogen atom or a group selected from the group consisting of C ₁ -C ₆ alkyl-, C ₃ -C ₆ cycloalkyl-, 3 to 10 membered heterocycloalkyl-, 4 to 10 membered heterocycloalkenyl-, aryl-, heteroaryl-, halo-C ₁ -C ₃ alkyl-, cyano- , -(CH ₂ ) _q -U-(CH ₂ ) _p -R ^3a ; wherein the C ₁ -C ₆ Alkyl-, C ₃ -C ₆ cycloalkyl-, 3 to 10 membered heterocycloalkyl-, 4 to 10 membered heterocycloalkenyl-, aryl- or heteroaryl-, as the case may be the same or different , 2, 3, 4 or 5 R ⁴ groups substituted with the limitation that the halo-C ₁ -C ₃ alkyl group - does not contain more than 5 halogen atoms; or R ^2a and R ^2b together

Represents -(CH ₂ ) _r -T-(CH ₂ ) _s -; T represents a group selected from the group consisting of U, -C[R ^6a ][(C(R ^6b )(R ^6c )) _t -UR ^3a U- represents a single bond or a divalent group selected from the group consisting of -O-, -S-, -S(=O)-, -S(=O) ₂ -, -S(=O) -N(R ^3b )-, -N(R ^3c )-S(=O)-, -C(=O)-, -N(R ^3b )-, -C(=O)-O-, -OC (=O)-, -C(=S)-O-, -OC(=S)-, -C(=O)-N(R ^3b )-, -N(R ^3c )-C(=O) -, -N(R ^3c )-C(=O)-N(R ^3b )-, -OC(=O)-N(R ^3b )-, -N(R ^3c )-C(=O)-O R ^3a represents a hydrogen atom or a group selected from the group consisting of C ₁ -C ₆ alkyl-, C ₃ -C ₆ cycloalkyl-, 3 to 10 membered heterocycloalkyl-; wherein the C ₁ -C ₆ alkyl-, C ₃ -C ₆ cycloalkyl- or 3 to 10 membered heterocycloalkyl-substituted as the same or differently by 1, 2 or 3 R ⁴ groups; R ^3b represents a hydrogen atom or C ₁ -C ₃ alkyl-; wherein the C ₁ -C ₃ alkyl group - optionally substituted with 1 R ⁴ group; R ^3c represents a hydrogen atom or a C ₁ -C ₃ alkyl group; or N(R ^3b ) R ^3a together

Forming a 3 to 10 membered heterocycloalkyl- or 4 to 10 membered heterocycloalkenyl-; wherein the 3 to 10 membered heterocycloalkyl- or 4 to 10 membered heterocycloalkenyl-, as the case may be the same or different , 2 or 3 R ⁴ groups are substituted; R ⁴ represents halo-, hydroxy-, pendant oxy-(O=), cyano-, nitro-, C ₁ -C ₃ alkyl-, halo- C ₁ -C ₃ alkyl-, C ₁ -C ₃ alkoxy-, halo-C ₁ -C ₃ alkoxy-, hydroxy-C ₁ -C ₃ alkyl-, C ₁ -C ₃ alkoxy -C ₁ -C ₃ alkyl-, halo-C ₁ -C ₃ alkoxy-C ₁ -C ₃ alkyl-, R ^5c -O-, -C(=O)-R ^5c , -C (=O)-OR ^5c , -OC(=O)-R ^5c , -N(R ^5b )-C(=O)-R ^5c , -N(R ^5c )-C(=O)-N(R ^5a ) R ^5b , -N(R ^5a )R ^5b , -C(=O)-N(R ^5a )R ^5b , R ^5c -S-, R ^5c -S(=O)-, R ^5c -S( =O) ₂ -, -N(R ^5c )-S(=O)-R ^5b , -S(=O)-N(R ^5a )R ^5b , -N(R ^5c )-S(=O) ₂ -R ^5b or -S(=O) ₂ -N(R ^5a )R ^5b ; R ^5a represents a hydrogen atom or a C ₁ -C ₃ alkyl group; R ^5b represents a hydrogen atom or a C ₁ -C ₃ alkyl group; R ^5c represents a hydrogen atom or a C ₁ -C ₃ alkyl-; or N(R ^5a )R ^5b

Forming a 3- to 7-membered heterocycloalkyl- together; R ^6a represents a hydrogen atom or a C ₁ -C ₆ alkyl-; wherein the C ₁ -C ₆ alkyl group is the same or different, 1, 2 or 3 as the case may be R ⁴ groups are substituted; R ^6b represents a hydrogen atom or C ₁ -C ₃ alkyl-; R ^6c represents a hydrogen atom or C ₁ -C ₃ alkyl-; p represents an integer of 0, 1, 2 or 3; An integer representing 0, 1, 2 or 3; r represents an integer of 1, 2 or 3; s represents an integer of 1, 2 or 3; and t represents an integer of 0 or 1; or a tautomer thereof, N-oxidation A hydrate, solvate or salt, or a mixture of such materials.

In another preferred embodiment, the invention relates to a compound of formula I above, wherein: QV represents a group selected from the group consisting of C(R ^1a )-N, NC(R ^1a ); A represents a group selected from the group consisting of group: Wherein * indicates the point of attachment of the group to the rest of the molecule; R ^1a represents a hydrogen atom or a halogen atom or a group selected from the group consisting of C ₁ -C ₃ alkyl-C ₁ -C ₃ alkoxy-, halo a group -C ₁ -C ₃ alkoxy-; R ^1b represents a hydrogen atom; R ^1c represents a hydrogen atom; R ^2a represents a hydrogen atom or a halogen atom or a group selected from the group consisting of C ₁ -C ₆ alkyl-, C _3- C ₆ cycloalkyl-, 3 to 10 membered heterocycloalkyl-, -(CH ₂ ) _q -U-(CH ₂ ) _p -R ^3a ; wherein the C ₁ -C ₆ alkyl-, C ₃ -C ₆ cycloalkyl- or 3 to 10 membered heterocycloalkyl - as the case may be substituted with 1, 2, 3, 4 or 5 R ⁴ groups; R ^2b represents a hydrogen atom or a halogen atom or From the following groups: C ₁ -C ₆ alkyl-, C ₃ -C ₆ cycloalkyl-, 3 to 10 membered heterocycloalkyl-, halo-C ₁ -C ₃ alkyl-, -(CH ₂ ) _q -U-(CH ₂ ) _p - R ^3a ; wherein the C ₁ -C ₆ alkyl-, C ₃ -C ₆ cycloalkyl- or 3 to 10 membered heterocycloalkyl - as the case may be the same or different Substituted by 1, 2, 3, 4 or 5 R ⁴ groups, with the proviso that the halo-C ₁ -C ₃ alkyl group - does not contain more than 5 halogen atoms; or R ^2a and R ^2b together

Represents -(CH ₂ ) _r -T-(CH ₂ ) _s -; T represents a group selected from the group consisting of U, -C[R ^6a ][(C(R ^6b )(R ^6c )) _t -UR ^3a U- represents a single bond or a divalent group selected from the group consisting of -O-, -C(=O)-, -N(R ^3b )-, -C(=O)-O-, - OC(=O)-, -C(=S)-O-, -C(=O)-N(R ^3b )-, -N(R ^3c )-C(=O)-, -N(R ^3c )-C(=O)-N(R ^3b )-, -OC(=O)-N(R ^3b )-, -N(R ^3c )-C(=O)-O-; R ^3a represents a hydrogen atom Or a group selected from the group consisting of C ₁ -C ₆ alkyl-, C ₃ -C ₆ cycloalkyl-, 3 to 10 membered heterocycloalkyl-; wherein the C ₁ -C ₆ alkyl-, C ₃ -C ₆ cycloalkyl- or 3 to 10 membered heterocycloalkyl - as the case may be substituted with 1, 2 or 3 R ⁴ groups; R ^3b represents a hydrogen atom or a C ₁ -C ₃ alkyl group - Wherein the C ₁ -C ₃ alkyl group - optionally substituted with 1 R ⁴ group; R ^3c represents a hydrogen atom or a C ₁ -C ₃ alkyl group; or N(R ^3b )R ^3a together

Forming a 3 to 10 membered heterocycloalkyl- or 4 to 10 membered heterocycloalkenyl-; wherein the 3 to 10 membered heterocycloalkyl- or 4 to 10 membered heterocycloalkenyl-, as the case may be the same or different , 2 or 3 R ⁴ groups are substituted; R ⁴ represents halo-, hydroxy-, cyano-, nitro-, C ₁ -C ₃ alkyl-, halo-C ₁ -C ₃ alkyl-, C ₁ -C ₃ alkoxy-, halo-C ₁ -C ₃ alkoxy-, hydroxy-C ₁ -C ₃ alkyl-, C ₁ -C ₃ alkoxy-C ₁ -C ₃ alkyl -, halo-C ₁ -C ₃ alkoxy-C ₁ -C ₃ alkyl-, R ^5c -O-, -C(=O)-R ^5c , -C(=O)-OR ^5c ,- OC(=O)-R ^5c , -N(R ^5b )-C(=O)-R ^5c , -N(R ^5c )-C(=O)-N(R ^5a )R ^5b , -N(R ^5a ) R ^5b , -C(=O)-N(R ^5a )R ^5b , R ^5c -S(=O) ₂ -, -N(R ^5c )-S(=O)-R ^5b , -S( =O)-N(R ^5a )R ^5b , -N(R ^5c )-S(=O) ₂ -R ^5b or -S(=O) ₂ -N(R ^5a )R ^5b ; R ^5a represents a hydrogen atom Or C ₁ -C ₃ alkyl-; R ^5b represents a hydrogen atom or a C ₁ -C ₃ alkyl-; R ^5c represents a hydrogen atom or a C ₁ -C ₃ alkyl-; or N(R ^5a )R ^5b

3 to 7 membered heterocycloalkyl-formed together; R ^6a represents a hydrogen atom or a group selected from the group consisting of C ₁ -C ₆ alkyl-, C ₂ -C ₆ alkenyl-, C ₂ -C ₆ alkynyl Wherein the C ₁ -C ₆ alkyl-, C ₂ -C ₆ alkenyl- or C ₂ -C ₆ alkynyl group is optionally substituted with 1, 2 or 3 R ⁴ groups, as the case may be; R ^6b represents a hydrogen atom or a C ₁ -C ₃ alkyl group; R ^6c represents a hydrogen atom or a C ₁ -C ₃ alkyl group; p represents 0; q represents 0; r represents 1 or 2; s represents 1 or 2; t represents 0; or a tautomer, N-oxide, hydrate, solvate or salt thereof, or a mixture of such materials.

In another preferred embodiment, the invention relates to a compound of formula I above, wherein: A represents a group selected from the group consisting of: Wherein * indicates the point of attachment of the group to the rest of the molecule; QV represents C(R ^1a )-N, and R ^1a represents a hydrogen atom; or QV represents NC(R ^1a ), and R ^1a represents a hydrogen atom or a halogen atom Or a group selected from the group consisting of: hydroxy-, C ₁ -C ₃ alkyl-C ₁ -C ₃ alkoxy-, halo-C ₁ -C ₃ alkoxy-; R ^1b represents a hydrogen atom; R ^1c Represents a hydrogen atom; R ^2a represents a hydrogen atom or a halogen atom or a group selected from the group consisting of C ₁ -C ₆ alkyl-, C ₃ -C ₆ cycloalkyl-, 3 to 10 membered heterocycloalkyl-, 4 To 10 membered heterocycloalkenyl-, aryl-, heteroaryl-, halo-C ₁ -C ₃ alkyl-, cyano-, -(CH ₂ ) _q -U-(CH ₂ ) _p -R ^3a ; wherein the C ₁ -C ₆ alkyl-, C ₃ -C ₆ cycloalkyl-, 3 to 10 membered heterocycloalkyl-, 4 to 10 membered heterocycloalkenyl-, aryl- or heteroaryl - substituted 1, 2, 3, 4 or 5 R ⁴ groups, if the same or different, with the proviso that the halo-C ₁ -C ₃ alkyl group - does not contain more than 5 halogen atoms; R ^2b a hydrogen atom or a halogen atom or a group selected from the group consisting of C ₁ -C ₆ alkyl-, C ₃ -C ₆ cycloalkyl-, 3 to 10 membered heterocycloalkyl-, 4 to 10 membered heterocycloalkyl Base-, aryl-, heteroaryl-, halo-C ₁ -C ₃ alkyl-, cyano-, -(CH ₂ ) _q -U-(CH ₂ ) _p -R ^3a ; wherein the C ₁ -C ₆ alkyl-, C ₃ -C ₆ cycloalkyl-, 3 to 10 membered heterocycloalkyl-, 4 to 10 membered heterocycloalkenyl-, aryl- or heteroaryl-substituted as the same or differently by 1, 2, 3, 4 or 5 R ⁴ groups, The limitation is that the halo-C ₁ -C ₃ alkyl group - does not contain more than 5 halogen atoms; or R ^2a and R ^2b together

Represents -(CH ₂ ) _r -T-(CH ₂ ) _s -; T represents -C[R ^6a ][(C(R ^6b )(R ^6c )) _t -UR ^3a ]-; U represents a single bond or Divalent groups from the following groups: -O-, -C(=O)-, -N(R ^3b )-, -C(=O)-O-, -OC(=O)-, -C (=O)-N(R ^3b )-, -N(R ^3c )-C(=O)-, -N(R ^3c )-C(=O)-N(R ^3b )-, -OC(= O)-N(R ^3b )-, -N(R ^3c )-C(=O)-O-; R ^3a represents a hydrogen atom or a group selected from the group consisting of C ₁ -C ₆ alkyl-, C ₃ -C ₆ cycloalkyl-, 3 to 10 membered heterocycloalkyl-; wherein the C ₁ -C ₆ alkyl-, C ₃ -C ₆ cycloalkyl- or 3 to 10 membered heterocycloalkyl - as appropriate Substituted or substituted by 1, 2 or 3 R ⁴ groups; R ^3b represents a hydrogen atom or a C ₁ -C ₃ alkyl group; wherein the C ₁ -C ₃ alkyl group - as the case may be 1 R ⁴ group a group substituted; R ^3c represents a hydrogen atom or a C ₁ -C ₃ alkyl group; or N(R ^3b )R ^3a together

Forming a 3 to 10 membered heterocycloalkyl- or 4 to 10 membered heterocycloalkenyl-; wherein the 3 to 10 membered heterocycloalkyl- or 4 to 10 membered heterocycloalkenyl-, as the case may be the same or different , 2 or 3 R ⁴ groups are substituted; R ⁴ represents halo-, hydroxy-, pendant oxy-(O=), cyano-, nitro-, C ₁ -C ₃ alkyl-, halo- C ₁ -C ₃ alkyl-, C ₁ -C ₃ alkoxy-, halo-C ₁ -C ₃ alkoxy-, hydroxy-C ₁ -C ₃ alkyl-, C ₁ -C ₃ alkoxy -C ₁ -C ₃ alkyl-, halo-C ₁ -C ₃ alkoxy-C ₁ -C ₃ alkyl-, R ^5c -O-, -C(=O)-R ^5c , -C (=O)-OR ^5c , -OC(=O)-R ^5c , -N(R ^5b )-C(=O)-R ^5c , -N(R ^5c )-C(=O)-N(R ^5a ) R ^5b , -N(R ^5a )R ^5b , -C(=O)-N(R ^5a )R ^5b , R ^5c -S-, R ^5c -S(=O)-, R ^5c -S( =O) ₂ -, -N(R ^5c )-S(=O)-R ^5b , -S(=O)-N(R ^5a )R ^5b , -N(R ^5c )-S(=O) ₂ -R ^5b or -S(=O) ₂ -N(R ^5a )R ^5b ; R ^5a represents a hydrogen atom or a C ₁ -C ₃ alkyl group; R ^5b represents a hydrogen atom or a C ₁ -C ₃ alkyl group; R ^5c represents a hydrogen atom or a C ₁ -C ₃ alkyl-; or N(R ^5a )R ^5b

3 to 7 membered heterocycloalkyl-formed together; R ^6a represents a hydrogen atom or a group selected from the group consisting of C ₁ -C ₆ alkyl-, C ₂ -C ₆ alkenyl-, C ₂ -C ₆ alkynyl Wherein the C ₁ -C ₆ alkyl-, C ₂ -C ₆ alkenyl- or C ₂ -C ₆ alkynyl group is optionally substituted with 1, 2 or 3 R ⁴ groups, as the case may be; R ^6b represents a hydrogen atom or a C ₁ -C ₃ alkyl group; R ^6c represents a hydrogen atom or a C ₁ -C ₃ alkyl group; p represents an integer of 0, 1, 2 or 3; q represents 0, 1, 2 or 3 An integer; r represents an integer of 1, 2 or 3; s represents an integer of 1, 2 or 3; and t represents an integer of 0 or 1; or a tautomer thereof, an N-oxide, a hydrate or a solvate thereof Or a salt, or a mixture of such substances.

In another preferred embodiment, the invention relates to a compound of formula I above, wherein: A represents a group selected from the group consisting of: Wherein * indicates the point of attachment of the group to the rest of the molecule; QV represents C(R ^1a )-N, and R ^1a represents a hydrogen atom; or QV represents NC(R ^1a ), and R ^1a represents a hydrogen atom or a halogen atom Or a group selected from the group consisting of: hydroxy-, C ₁ -C ₃ alkyl-C ₁ -C ₃ alkoxy-, halo-C ₁ -C ₃ alkoxy-; R ^1b represents a hydrogen atom; R ^1c Represents a hydrogen atom; R ^2a represents a hydrogen atom or a halogen atom or a group selected from the group consisting of C ₁ -C ₆ alkyl-, C ₃ -C ₆ cycloalkyl-, 3 to 10 membered heterocycloalkyl-, 4 To 10 membered heterocycloalkenyl-, aryl-, heteroaryl-, halo-C ₁ -C ₃ alkyl-, cyano-, -(CH ₂ ) _q -U-(CH ₂ ) _p -R ^3a ; wherein the C ₁ -C ₆ alkyl-, C ₃ -C ₆ cycloalkyl-, 3 to 10 membered heterocycloalkyl-, 4 to 10 membered heterocycloalkenyl-, aryl- or heteroaryl - substituted 1, 2, 3, 4 or 5 R ⁴ groups, if the same or different, with the proviso that the halo-C ₁ -C ₃ alkyl group - does not contain more than 5 halogen atoms; R ^2b a hydrogen atom or a halogen atom or a group selected from the group consisting of C ₁ -C ₆ alkyl-, C ₃ -C ₆ cycloalkyl-, 3 to 10 membered heterocycloalkyl-, 4 to 10 membered heterocycloalkyl Base-, aryl-, heteroaryl-, halo-C ₁ -C ₃ alkyl-, cyano-, -(CH ₂ ) _q -U-(CH ₂ ) _p -R ^3a ; wherein the C ₁ -C ₆ alkyl-, C ₃ -C ₆ cycloalkyl-, 3 to 10 membered heterocycloalkyl-, 4 to 10 membered heterocycloalkenyl-, aryl- or heteroaryl-substituted as the same or differently by 1, 2, 3, 4 or 5 R ⁴ groups, The limitation is that the halo-C ₁ -C ₃ alkyl group - does not contain more than 5 halogen atoms; or R ^2a and R ^2b together

Represents -(CH ₂ ) _r -T-(CH ₂ ) _s -; T represents -C[R ^6a ][(C(R ^6b )(R ^6c )) _t -UR ^3a ]-; U represents a single bond or Divalent groups from the following groups: -O-, -C(=O)-, -N(R ^3b )-, -C(=O)-O-, -OC(=O)-, -C (=O)-N(R ^3b )-, -N(R ^3c )-C(=O)-, -N(R ^3c )-C(=O)-N(R ^3b )-, -OC(= O)-N(R ^3b )-, -N(R ^3c )-C(=O)-O-; R ^3a represents a hydrogen atom or a group selected from the group consisting of C ₁ -C ₆ alkyl-, C ₃ -C ₆ cycloalkyl-, 3 to 10 membered heterocycloalkyl-; wherein the C ₁ -C ₆ alkyl-, C ₃ -C ₆ cycloalkyl- or 3 to 10 membered heterocycloalkyl - as appropriate Substituted or substituted by 1, 2 or 3 R ⁴ groups; R ^3b represents a hydrogen atom or a C ₁ -C ₃ alkyl group; wherein the C ₁ -C ₃ alkyl group - as the case may be 1 R ⁴ group a group substituted; R ^3c represents a hydrogen atom or a C ₁ -C ₃ alkyl group; or N(R ^3b )R ^3a together

Forming a 3 to 10 membered heterocycloalkyl- group; wherein the 3 to 10 membered heterocycloalkyl- group is optionally substituted with 1, 2 or 3 R ⁴ groups; R ⁴ represents halo-, Hydroxy-, pendant oxy-(O=), cyano-, nitro-, C ₁ -C ₃ alkyl-, halo-C ₁ -C ₃ alkyl-, C ₁ -C ₃ alkoxy- , halo-C ₁ -C ₃ alkoxy-, hydroxy-C ₁ -C ₃ alkyl-, C ₁ -C ₃ alkoxy-C ₁ -C ₃ alkyl-, halo-C ₁ -C ₃ alkoxy-C ₁ -C ₃ alkyl-, R ^5c -O-, -C(=O)-R ^5c , -C(=O)-OR ^5c , -OC(=O)-R ^5c , -N(R ^5b )-C(=O)-R ^5c , -N(R ^5c )-C(=O)-N(R ^5a )R ^5b , -N(R ^5a )R ^5b , -C(= O)-N(R ^5a )R ^5b , R ^5c -S-, R ^5c -S(=O)-, R ^5c -S(=O) ₂ -, -N(R ^5c )-S(=O) -R ^5b , -S(=O)-N(R ^5a )R ^5b , -N(R ^5c )-S(=O) ₂ -R ^5b or -S(=O) ₂ -N(R ^5a )R ^5b ; R ^5a represents a hydrogen atom or a C ₁ -C ₃ alkyl group; R ^5b represents a hydrogen atom or a C ₁ -C ₃ alkyl group; R ^5c represents a hydrogen atom or a C ₁ -C ₃ alkyl group; R ^6a represents a hydrogen atom or a group selected from the group consisting of C ₁ -C ₆ alkyl-, C ₂ -C ₆ alkenyl-, C ₂ -C ₆ alkynyl-; wherein the C ₁ -C ₆ alkyl-, C ₂ -C ₆ alkenyl - or C ₂ -C ₆ alkynyl group - optionally substituted with the same or different 1 2 or 3 substituents R ⁴ groups; R ^6b represents a hydrogen atom or a C ₁ -C ₃ alkyl -; R ^6c represents a hydrogen atom or a C ₁ -C ₃ alkyl -; p represents 0; q represents 0; r represents 1 or 2; s represents 1 or 2; and t represents 0; or a tautomer, N-oxide, hydrate, solvate or salt thereof, or a mixture of such substances.

In another preferred embodiment, the invention relates to a compound of formula I above, wherein: QV represents a group selected from the group consisting of C(R ^1a )-N, NC(R ^1a ); A represents a group selected from the group consisting of group: Wherein * indicates the point of attachment of the rest of the molecule such group; R ^1a represents a hydrogen atom or a halogen atom or a group selected from the group of: hydroxy - cyano -, C ₁ -C ₆ alkyl -, C ₂ - C ₆ alkenyl-, C ₂ -C ₆ alkynyl-, C ₁ -C ₆ alkoxy-, halo-C ₁ -C ₆ alkoxy-, -N(R ^5b )R ^5c , -SCF ₃ , -SF ₅ ; R ^1b represents a hydrogen atom; R ^1c represents a hydrogen atom; one of R ^2a and R ^2b represents -(CH ₂ ) _q -U-(CH ₂ ) _p -R ^3a , and R ^2a and R ^2b The other one represents a hydrogen atom or a C ₁ -C ₃ alkyl group; or R ^2a and R ^2b together

Represents -(CH ₂ ) _r -T-(CH ₂ ) _s -; T represents a group selected from the group consisting of U, -C[R ^6a ][(C(R ^6b )(R ^6c )) _t -UR ^3a U- represents a single bond or a divalent group selected from the group consisting of -C(=O)-, -N(R ^3b )-, -C(=O)-O-, -OC(=O) -, -C(=O)-N(R ^3b )-, -N(R ^3c )-C(=O)-; R ^3a represents a hydrogen atom or a group selected from the group consisting of C ₁ -C ₆ alkane Base-, C ₃ -C ₆ cycloalkyl-, 3 to 10 membered heterocycloalkyl-, 4 to 10 membered heterocycloalkenyl-, aryl-, heteroaryl-, halo-C ₁ -C ₃ Alkyl-; wherein the C ₁ -C ₆ alkyl-, C ₃ -C ₆ cycloalkyl-, 3 to 10 membered heterocycloalkyl-, aryl-, heteroaryl- or halo-C ₁ - C ₃ alkyl - as the case may be, the same or different, substituted by 1, 2, 3, 4 or 5 R ⁴ groups, with the proviso that the halo-C ₁ -C ₃ alkyl group - together with the case optionally attached thereto The R ⁴ groups together contain no more than 5 halogen atoms; R ^3b represents a hydrogen atom or a group selected from the group consisting of C ₁ -C ₆ alkyl-, C ₃ -C ₆ cycloalkyl-, 3 to 10 members Heterocycloalkyl-, 4 to 10 membered heterocycloalkenyl-, aryl-, heteroaryl-, halo-C ₁ -C ₃ alkyl-; wherein the C ₁ -C ₆ alkyl-, C ₃ -C ₆ cycloalkyl -, 3-10 heterocycloalkyl -, aryl - Heteroaryl - or halo -C ₁ -C ₃ alkyl - the same or different optionally substituted by 4 or 5 R ⁴ groups, with the proviso that halo -C ₁ - C ₃ alkyl- together with the R ⁴ group optionally attached thereto does not contain more than 5 halogen atoms; R ^3c represents a hydrogen atom or a group selected from C ₁ -C ₆ alkyl-, C ₃ - C ₆ cycloalkyl-, 3 to 10 membered heterocycloalkyl-, 4 to 10 membered heterocycloalkenyl-, aryl-, heteroaryl-, halo-C ₁ -C ₃ alkyl-; C ₁ -C ₆ alkyl-, C ₃ -C ₆ cycloalkyl-, 3 to 10 membered heterocycloalkyl-, aryl-, heteroaryl- or halo-C ₁ -C ₃ alkyl- Substituting the same or differently with 1, 2, 3, 4 or 5 R ⁴ groups, with the proviso that the halo-C ₁ -C ₃ alkyl group, together with the R ⁴ group optionally attached thereto Contains no more than 5 halogen atoms; or N(R ^3b )R ^3a together

Forming a 3 to 10 membered heterocycloalkyl group or a 4 to 10 membered heterocycloalkenyl group, wherein the 3 to 10 membered heterocycloalkyl group or 4 to 10 membered heterocycloalkenyl group - as the case may be the same or different , 2, 3, 4 or 5 R ⁴ groups are substituted; R ⁴ represents halo-, hydroxy-, pendant oxy-(O=), cyano-, nitro-, C ₁ -C ₆ alkyl- , C ₂ -C ₆ alkenyl-, C ₂ -C ₆ alkynyl-, halo-C ₁ -C ₆ alkyl-, C ₁ -C ₆ alkoxy-, halo-C ₁ -C ₆ alkane Oxy-, hydroxy-C ₁ -C ₆ alkyl-, C ₁ -C ₆ alkoxy-C ₁ -C ₆ alkyl-, halo-C ₁ -C ₆ alkoxy-C ₁ -C ₆ Alkyl-, R ^5c -O-, -C(=O)-R ^5c , -C(=O)-OR ^5c , -OC(=O)-R ^5c , -N(R ^5b )-C(= O)-R ^5c , -N(R ^5c )-C(=O)-N(R ^5a )R ^5b , -N(R ^5a )R ^5b , -C(=O)-N(R ^5a )R ^5b , R ^5c -S-, R ^5c -S(=O)-, R ^5c -S(=O) ₂ -, -N(R ^5c )-S(=O)-R ^5b , -S(=O) -N(R ^5a )R ^5b , -N(R ^5c )-S(=O) ₂ -R ^5b , -S(=O) ₂ -N(R ^5a )R ^5b , -S(=O)=N (R ^5c ) R ^5b , -S(=O)=N(R ^5c )R ^5b or -N=S(=O)(R ^5c )R ^5b ; R ^5a represents a hydrogen atom, C ₁ -C ₆ alkyl -, C ₃ -C ₆ cycloalkyl- or 3 to 10 membered heterocycloalkyl-; R ^5b represents a hydrogen atom, a C ₁ -C ₆ alkyl-, a C ₃ -C ₆ cycloalkyl group or a 3 to 10 member Heterocycloalkyl-; R ^5c represents a hydrogen atom, a C ₁ -C ₆ alkyl-, a C ₃ -C ₆ cycloalkyl- or a 3 to 10 membered heterocycloalkyl group; or N(R ^5a )R ^5b

3 to 7 membered heterocycloalkyl-formed together; R ^6a represents a hydrogen atom or a group selected from the group consisting of C ₁ -C ₆ alkyl-, C ₂ -C ₆ alkenyl-, C ₂ -C ₆ alkynyl Wherein the C ₁ -C ₆ alkyl-, C ₂ -C ₆ alkenyl- or C ₂ -C ₆ alkynyl group is optionally substituted with 1, 2 or 3 R ⁴ groups, as the case may be; R ^6b represents a hydrogen atom or a C ₁ -C ₃ alkyl group; R ^6c represents a hydrogen atom or a C ₁ -C ₃ alkyl group; p represents 0 or 1; q represents 0 or 1; r represents 1 and s represents 2; s represents 1 and r represents 2; and t represents an integer of 0 or 1; or a tautomer, N-oxide, hydrate, solvate or salt thereof, or a mixture of such substances.

In another preferred embodiment, the invention relates to a compound of formula I above, wherein: QV represents a group selected from the group consisting of C(R ^1a )-N, NC(R ^1a ); A represents a group selected from the group consisting of group: Wherein * indicates the point of attachment of the group to the rest of the molecule; R ^1a represents a hydrogen atom; R ^1b represents a hydrogen atom; R ^1c represents a hydrogen atom; and one of R ^2a and R ^2b represents -(CH ₂ ) _q -U -(CH ₂ ) _p -R ^3a , and the other of R ^2a and R ^2b represents a hydrogen atom or a C ₁ -C ₃ alkyl group; or R ^2a and R ^2b together

Represents -(CH ₂ ) _r -T-(CH ₂ ) _s -; T represents a group selected from the group consisting of U, -C[R ^6a ][(C(R ^6b )(R ^6c )) _t -UR ^3a U- represents a single bond or a divalent group selected from the group consisting of -C(=O)-, -N(R ^3b )-, -C(=O)-O-, -OC(=O) -, -C(=O)-N(R ^3b )-, -N(R ^3c )-C(=O)-; R ^3a represents a hydrogen atom or a group selected from the group consisting of C ₁ -C ₆ alkane Base-, C ₃ -C ₆ cycloalkyl-, 3 to 10 membered heterocycloalkyl-, 4 to 10 membered heterocycloalkenyl-, aryl-, heteroaryl-, halo-C ₁ -C ₃ Alkyl-; wherein the C ₁ -C ₆ alkyl-, C ₃ -C ₆ cycloalkyl-, 3 to 10 membered heterocycloalkyl-, aryl-, heteroaryl- or halo-C ₁ - C ₃ alkyl - as the case may be, the same or different, substituted by 1, 2, 3, 4 or 5 R ⁴ groups, with the proviso that the halo-C ₁ -C ₃ alkyl group - together with the case optionally attached thereto The R ⁴ groups together contain no more than 5 halogen atoms; R ^3b represents a hydrogen atom or a group selected from the group consisting of C ₁ -C ₆ alkyl-, C ₃ -C ₆ cycloalkyl-, 3 to 10 members Heterocycloalkyl-, 4 to 10 membered heterocycloalkenyl-, aryl-, heteroaryl-, halo-C ₁ -C ₃ alkyl-; wherein the C ₁ -C ₆ alkyl-, C ₃ -C ₆ cycloalkyl -, 3-10 heterocycloalkyl -, aryl - Heteroaryl - or halo -C ₁ -C ₃ alkyl - the same or different optionally substituted by 4 or 5 R ⁴ groups, with the proviso that halo -C ₁ - C ₃ alkyl- together with the R ⁴ group optionally attached thereto does not contain more than 5 halogen atoms; R ^3c represents a hydrogen atom or a group selected from C ₁ -C ₆ alkyl-, C ₃ - C ₆ cycloalkyl-, 3 to 10 membered heterocycloalkyl-, 4 to 10 membered heterocycloalkenyl-, aryl-, heteroaryl-, halo-C ₁ -C ₃ alkyl-; C ₁ -C ₆ alkyl-, C ₃ -C ₆ cycloalkyl-, 3 to 10 membered heterocycloalkyl-, aryl-, heteroaryl- or halo-C ₁ -C ₃ alkyl- Substituting the same or differently with 1, 2, 3, 4 or 5 R ⁴ groups, with the proviso that the halo-C ₁ -C ₃ alkyl group, together with the R ⁴ group optionally attached thereto Contains no more than 5 halogen atoms; or N(R ^3b )R ^3a together

Forming a 3 to 10 membered heterocycloalkyl- or 4 to 10 membered heterocycloalkenyl-; wherein the 3 to 10 membered heterocycloalkyl- or 4 to 10 membered heterocycloalkenyl-, as the case may be the same or different , 2, 3, 4 or 5 R ⁴ groups are substituted; R ⁴ represents halo-, hydroxy-, pendant oxy-(O=), cyano-, nitro-, C ₁ -C ₆ alkyl- , C ₂ -C ₆ alkenyl-, C ₂ -C ₆ alkynyl-, halo-C ₁ -C ₆ alkyl-, C ₁ -C ₆ alkoxy-, halo-C ₁ -C ₆ alkane Oxy-, hydroxy-C ₁ -C ₆ alkyl-, C ₁ -C ₆ alkoxy-C ₁ -C ₆ alkyl-, halo-C ₁ -C ₆ alkoxy-C ₁ -C ₆ Alkyl-, R ^5c -O-, -C(=O)-R ^5c , -C(=O)-OR ^5c , -OC(=O)-R ^5c , -N(R ^5b )-C(= O)-R ^5c , -N(R ^5c )-C(=O)-N(R ^5a )R ^5b , -N(R ^5a )R ^5b , -C(=O)-N(R ^5a )R ^5b , R ^5c -S-, R ^5c -S(=O)-, R ^5c -S(=O) ₂ -, -N(R ^5c )-S(=O)-R ^5b , -S(=O) -N(R ^5a )R ^5b , -N(R ^5c )-S(=O) ₂ -R ^5b , -S(=O) ₂ -N(R ^5a )R ^5b , -S(=O)=N (R ^5c )R ^5b , -S(=O)=N(R ^5c )R ^5b or -N=S(=O)(R ^5c )R ^5b ; R ^5a represents a hydrogen atom, a C ₁ -C ₆ alkyl group -, C ₃ -C ₆ cycloalkyl - or 3-10 membered heterocycloalkyl -; R ^5b represents a hydrogen atom, C ₁ -C ₆ alkyl -, C ₃ -C ₆ cycloalkyl, - 3 to 10 or Heterocycloalkyl -; R ^5c represents a hydrogen atom, C ₁ -C ₆ alkyl -, C ₃ -C ₆ cycloalkyl - or heterocycloalkyl 3-10 -; or N (R ^5a) R ^5b

Forming a 3 to 7 membered heterocycloalkyl group together; R ^6a represents a hydrogen atom or a C ₁ -C ₆ alkyl group; wherein the C ₁ -C ₆ alkyl group - as the case may be the same or different, 1, 2 or 3 R ⁴ group substituted; R ^6b represents a hydrogen atom or C ₁ -C ₃ alkyl-; R ^6c represents a hydrogen atom or C ₁ -C ₃ alkyl-; p represents 0 or 1; q represents 0 or 1; r represents 1 and s represents 2; or s represents 1 and r represents 2; and t represents an integer of 0 or 1; or a tautomer, N-oxide, hydrate, solvate or salt thereof, or the like mixture.

It will be understood that the present invention is directed to any subcombination of any of the embodiments or aspects of the invention of the above formula I.

More specifically, the invention encompasses compounds of formula I as disclosed herein below in the Examples section.

According to another aspect, the invention encompasses methods of preparing the compounds of the invention, which comprise the steps as described in the experimental section herein.

In a preferred embodiment, the invention relates to a process for the preparation of a compound of formula I above, in which an intermediate compound of formula IV is employed:

Wherein QV, R ^1b and R ^1c are as defined above for formula I , and PG represents a protecting group or a hydrogen atom; reacting with an intermediate compound of formula II :

Wherein A is as defined above for Formula I , and LG represents a leaving group.

In another aspect, the invention relates to intermediate compounds suitable for use in the preparation of compounds of formula I above.

In particular, the invention relates to intermediate compounds of formula IV :

Wherein QV, R ^1b and R ^1c are as defined above for formula I , and PG represents a protecting group or a hydrogen atom.

Synthesis of the compound of formula I of the present invention

Compounds of formula I , I' , II , III and IV can be synthesized according to the procedure depicted in Scheme 1, wherein R ^1b , R ^1c , QV and A have the meanings given above for formula I , LG represents Deprotected and PG represents a protecting group or a hydrogen atom.

Process 1

Scheme 1 illustrates a pathway for the alteration and upgrading of A, R ^1b and R ^1c at different stages of synthesis. However, other approaches can also be used to synthesize target compounds based on common knowledge of those skilled in the art of organic synthesis. Therefore, the order of transitions exemplified in the process is not intended to be limiting. Furthermore, the interconversion of any substituent as defined herein with respect to A, R ^1b and R ^1c is achieved before and/or after the exemplified transition.

Such modifications may be, for example, protection group (PG) introduction, protecting group cleavage, functional group reduction or oxidation, halogenation, metallation, substitution or other reactions known to those skilled in the art.

Such transformations include the introduction of a transition that allows the substituents to further convert to each other. Suitable protecting groups, as well as their introduction and cleavage, are well known to those skilled in the art (see, for example, T. W. Greene and P. G. M. Wuts, Protective Groups in Organic Synthesis, 3rd edition, Wiley 1999). Specific examples are described in subsequent paragraphs. Additionally, as is well known to those skilled in the art, two or more consecutive steps can be performed without treatment between such steps, such as a "one pot" reaction.

Compounds of formula II , III or IV are commercially available or can be synthesized according to procedures known to those skilled in the art.

LG denotes a compound of formula II which is a leaving group such as, for example, a halogen atom such as a chlorine or bromine atom, which is commercially available or can be obtained from a compound of formula III by reacting an alcohol with a halogenating agent such as, for example, phosphorus trichloride or tribromination. Phosphorus) is obtained by reaction at a temperature ranging, for example, from room temperature to the boiling point of the solvent, with or without an additional inert solvent such as, for example, toluene.

Wherein LG represents a leaving group (such as, for example, an alkyl sulfonate group (such as, for example, a methanesulfonate or trifluoromethanesulfonate group or 1,1,2,2,3,3,4,4,4- compound II from a compound of formula III nonafluorobutane-l-sulfonate group) or aryl sulfonate group (e.g. tosylate group such as methyl tosylate or 4)) of the formula, by The alcohol and the suitable alkyl sulfonium halide (such as, for example, methanesulfonium chloride or trifluoromethanesulfonium chloride or 1,1,2,2,3,3,4,4,4-nonafluorobutane-1-sulfonate醯 Fluorine) reaction or by reacting an alcohol with a suitable arylsulfonium halide such as, for example, benzenesulfonium chloride or 4-methylbenzenesulfonium chloride, in an inert solvent such as, for example, tetrahydrofuran or toluene or dichloromethane It is obtained by reacting in the presence of a base such as, for example, triethylamine or pyridine or N,N-dimethylpyridin-4-amine, at a temperature ranging, for example, from -40 ° C to the boiling point of the solvent.

Compounds of formula I' can be synthesized by reacting a compound of formula II with a compound of formula IV to provide a compound of formula I wherein R ^1b , R ^1c , V, Q and A are as defined above. The amine group present in IV replaces the LG of the compound of formula II to form an amine of formula I' or I.

The compound of the formula II may be in the presence of an amine of the formula IV in which PG represents a protecting group or a hydrogen atom, optionally in the presence of an acid such as, for example, hydrochloric acid, in an inert solvent such as, for example, ethanol or 1,4-dioxane. The reaction is carried out at a temperature within the range of the boiling point of the solvent to give a compound of the formula I' or I.

The compound of the formula I' or I can also be used in a suitable catalyst (such as a copper-based catalyst such as copper (II) acetate or copper (I)) by a Ullmann-type coupling reaction. In the presence of a suitable base (such as, for example, cesium carbonate), the compound of formula IV is used as a starting material. Suitable ligands such as N,N-dimethylglycine or pyrrolidine-2-ylphosphonate may optionally be added. The reaction can be carried out, for example, at a temperature ranging from -40 ° C to the boiling point of the solvent. Similarly, palladium catalyzed amination can be employed to form compounds of formula I' or I from compounds of formula IV and II ; for a contemporary review of such aminations, see, for example, David S. Surry and Stephen L Buchwald, Chem. Sci. 2011 , 2, 27 and the literature cited therein.

A compound of the formula I , I' , II , III and IV wherein R ^1a , R ^1b , R ^1c , R ^2a and/or R ^2b represents a halogen atom such as a chlorine, bromine or iodine atom may be via a coupling reaction, such as The coupling reaction of Ullmann, Negishi, Suzuki or Sonogashira is further modified.

Such coupling reactions are suitable catalysts (such as copper or palladium based catalysts such as, for example, copper (II) diacetate, copper (I) chloride, palladium (II) acetate, tetrakis(triphenylphosphine) palladium (0), chlorine. In the presence of bis(triphenylphosphine)palladium(II) or (1,1,-bis(diphenylphosphino)ferrocene-dichloropalladium(II)) and optionally in suitable additives (such as phosphines, such as For example, in the presence of P(oTol) ₃ or triphenylphosphine, and in a suitable solvent (such as potassium carbonate, sodium 2-methylpropan-2-ol, tetrabutylammonium fluoride or tripotassium phosphate) It is carried out in (such as tetrahydrofuran).

Examples of such coupling reactions can be found in the title "Metal-Catalyzed Cross-Coupling Reactions", Armin de Meijere (ed.), François Diederich (ed.) September 2004, Wiley Interscience ISBN: 978-3-527-30518-6 In the textbook.

Compounds of the formulae I , I' , II , III and IV in which R ^1a , R ^1b , R ^1c , R ^2a and/or R ^2b represent a halogen atom such as a fluorine, chlorine, bromine or iodine atom may also be substituted The reaction was further modified. The halogen atoms in R ^1a , R ^1b , R ^1c , R ^2a and/or R ^2b may be substituted by a nucleophile such as a primary or secondary amine, an alkoxide, a thiolate or a group carrying a carbon anion. To add a secondary or tertiary amine, ether, thioether or carbon linking group. The reaction is carried out in an inert solvent such as tetrahydrofuran.

Furthermore, the groups of the compounds of formula I , I' , II , III and IV may optionally be modified using conditions such as oxidation, reduction, substitution or elimination reactions and conditions well known to those skilled in the art of organic synthesis. For example, the thioether can be oxidized in an inert solvent such as dichloromethane or acetone, respectively, using an oxidizing agent such as 3-chloroperoxybenzoic acid, potassium hydrogenpersulfate or dimethyldioxirane. Depending on the stoichiometric ratio of the oxidizing agent to the above-mentioned compounds, the hydrazine or hydrazine or a mixture thereof will be obtained.

Additionally, the compounds of formula I of the present invention can be converted to any of the salts described herein using any method known to those skilled in the art. Similarly, any salt of a compound of formula I of the present invention can be converted to the free compound by any method known to those skilled in the art.

Compounds and intermediates produced according to the methods of the invention may require purification. Purification of organic compounds is well known to those skilled in the art and there may be several ways to purify the same compound. In some cases, purification may not be necessary. In some cases, the compound can be purified by crystallization. In some cases, impurities can be removed by agitation using a suitable solvent. In some cases, the compound may be by chromatography, particularly flash chromatography, using for example prepacked silica gel cartridge (e.g. from Separtis, such as Isolute ^® Flash silica gel or Isolute ^® Flash NH ₂ silica gel) chromatography with a suitable system ( Purification is carried out in combination, such as the Isolera system (Biotage) and a dissolving agent such as a gradient of hexane/ethyl acetate or dichloromethane/methanol. In some cases, a preparative HPLC can be used, for example, with a Waters automated purifier equipped with a diode array detector and/or an on-line electrospray ionization mass spectrometer with a suitable pre-filled reverse phase column and eliminator ( A gradient such as water and acetonitrile, which may contain additives such as trifluoroacetic acid, formic acid or aqueous ammonia, is used to purify the compound.

Instance

Chemical naming of the examples and intermediates was performed using ACD/LABS (Name Batch 12.01.) using ACD software.

Example 1 N-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazolo[3,4-b]pyridine-5-amine

Will contain 57.2 mg (373 μmol) of 4-chloro-7H-pyrrolo[2,3-d]pyrimidine (CAS-No. 3680-69-1), 100 mg of 1H-pyrazolo[3,4-b]pyridine- A mixture of 5-amine (CAS-No. 942185-01-5), 23.3 μL hydrochloric acid (4M) and 1.5 mL of ethanol was heated under reflux for 6 hours. The solvent was removed to give 95.0 mg (100%).

¹ H-NMR (DMSO-d6): δ=6.95 (1H), 7.46 (1H), 8.23 (1H), 8.30 (1H), 8.48 (1H), 8.68 (1H), 11.39 (1H), 12.74 (1H) ), 13.86 (1H) ppm.

Example 2 N-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazolo[3,4-c]pyridine-5-amine

Will contain 114.5 mg (745 μmol) of 4-chloro-7H-pyrrolo[2,3-d]pyrimidine (CAS-No. 3680-69-1), 100 mg of 1H-pyrazolo[3,4-c]pyridine- A mixture of 5-amine (CAS-No. 1049672-75-4), 93 μL of hydrochloric acid (4M) and 5 mL of ethanol was heated at 120 ° C for 2 hours under microwave irradiation. The solvent was removed and the residue was purified mpjjjjjj

¹ H-NMR (DMSO-d6): δ=7.01 (1H), 7.20 (1H), 8.20 (1H), 8.34 (1H), 8.81-8.84 (2H), 9.86 (1H), 11.72 (1H), 13.43 (1H) ppm.

Example 3 N-(5-methyl-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazolo[3,4-b]pyridine-5-amine

124.9 mg (745 μmol) of 4-chloro-5-methyl-7H-pyrrolo[2,3-d]pyrimidine (CAS-No. 1618-36-6) was similar to the conversion of Example 1 to give 198 mg (100%) of title Compound.

¹ H-NMR (DMSO-d6): δ=2.52 (3H), 7.28 (1H), 8.17 (1H), 8.24 (1H), 8.42 (1H), 8.63 (1H), 9.75 (1H), 12.47 (1H) ), 13.87 (1H) ppm.

Example 4 N-(5-methyl-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazolo[3,4-c]pyridine-5-amine

124.9 mg (745 μmol) of 4-chloro-5-methyl-7H-pyrrolo[2,3-d]pyrimidine (CAS-No. 1618-36-6) was similar to the conversion of Example 2, and after treatment and purification, 26.0 mg was obtained. (13%) title compound.

¹ H-NMR (DMSO-d6): δ=2.53 (3H), 7.04 (1H), 8.12 (1H), 8.21 (1H), 8.33 (1H), 8.77 (1H), 8.81 (1H), 11.54 (1H) ), 13.45 (1H) ppm.

Example 5 N-(5-ethyl-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazolo[3,4-b]pyridine-5-amine

47 mg (259 μmol) of 4-chloro-5-ethyl-7H-pyrrolo[2,3-d]pyrimidine (CAS-No. 1004992-44-2) was similar to the conversion of Example 1, after treatment and purification to give 45 mg (62 %)title Compound.

¹ H-NMR (DMSO-d6): δ = 1.28 (3H), 2.99 (2H), 7.27 (1H), 8.18 (1H), 8.24 (1H), 8.41 (1H), 8.62 (1H), 9.62 (1H) ), 12.51 (1H), 13.83 (1H) ppm.

Example 6 N-(5-ethyl-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazolo[3,4-c]pyridine-5-amine

Will contain 43 mg (237 μmol) of 4-chloro-5-ethyl-7H-pyrrolo[2,3-d]pyrimidine (CAS-No. 1004992-44-2), 34.9 mg of 1H-pyrazole [3,4 A mixture of -c]pyridine-5-amine (CAS-No. 1049672-75-4), 17 μL of hydrochloric acid (solution of 4 M dioxane) and 1.0 mL of ethanol was heated at 120 ° C for 16 hours in a sealed tube. The solvent was removed and the residue was purified mpqqqqqq

¹ H-NMR (DMSO-d6): δ=1.32 (3H), 2.96 (2H), 7.05 (1H), 8.01 (1H), 8.22 (1H), 8.35 (1H), 8.80 (1H), 8.82 (1H) ), 11.62 (1H), 13.48 (1H) ppm.

Example 7 N-(6-ethyl-5-methyl-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazolo[3,4-b]pyridine-5-amine

Will contain 50 mg (256 μmol) of 4-chloro-6-ethyl-5-methyl-7H-pyrrolo[2,3-d]pyrimidine (prepared according to Intermediate Example 7a), 34.3 mg of 1H-pyrazolo[3 ,4-b]pyridine-5-amine A mixture of (CAS-No. 942185-01-5), 15.9 μL of hydrochloric acid (4 M dioxane solution) and 0.8 mL of ethanol was irradiated under microwave irradiation at 150 ° C for 5 hours. Methanol was added, the precipitate was filtered, washed with EtOAc EtOAc EtOAc

¹ H-NMR (DMSO-d6): δ = 1.20 (3H), 2.45 (3H), 2.71 (2H), 8.12 (1H), 8.22 (1H), 8.40 (1H), 8.62 (1H), 9.53 (1H) ), 12.39 (1H), 13.83 (1H) ppm.

Example 7a 4-chloro-6-ethyl-5-methyl-7H-pyrrolo[2,3-d]pyrimidine

Will contain 1.18 g (6.64 mmol) of 6-ethyl-5-methyl-7H-pyrrolo[2,3-d]pyrimidin-4-ol (prepared according to intermediate example 7b) and 37.1 mL of phosphorus oxychloride The mixture was heated at 100 ° C for 1 hour. The reagent was removed and the residue was purified by chromatography. The product was further purified by digested with diethyl ether to afford EtOAc (EtOAc)

Example 7b 6-ethyl-5-methyl-7H-pyrrolo[2,3-d]pyrimidin-4-ol

Will contain 735 mg (3.78 mmol) of 6-[2-(pentane-3-ylidene)indolyl-4-pyrimidin-4-ol (prepared according to intermediate example 7c) and 20 mL of 2-[2-(2-third A mixture of oxyethoxy)ethoxy]-2-methylpropane was heated at 250 ° C for 2.5 hours. The solid was filtered and washed with diethyl ether to afford 437 g,

Example 7c 6-[2-(pentane-3-ylidene)indolyl-4-pyrimidin-4-ol

Will contain 5.0 g (39.6 mmol) of 6-mercaptopyrimidin-4-ol/6-mercaptopyrimidine-4(1H)-one (CAS-No: 29939-37-5), 5.12 g of pentan-3-one and A mixture of 80.8 mL of ethanol was heated under reflux for 2 hours. After cooling to 3 ° C, the precipitated solid was filtered and washed with diethyl ether.

Example 8 N-(6-ethyl-5-methyl-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazolo[3,4-c]pyridine-5-amine

50 mg (256 μmol) (256 μmol) of 4-chloro-6-ethyl-5-methyl-7H-pyrrolo[2,3-d]pyrimidine (prepared according to Intermediate Example 7a) was similar to Example 7, using 1H-pyridin Conversion of the oxazolo[3,4-c]pyridine-5-amine (CAS-No. 1049672-75-4), after treatment and purification afforded 15.4 mg (20%) of the title compound.

¹ H-NMR (DMSO-d6): δ=1.19 (3H), 2.45 (3H), 2.66 (2H), 8.07 (1H), 8.20 (1H), 8.28 (1H), 8.75 (1H), 8.80 (1H) ), 11.51 (1H), 13.42 (1H) ppm.

Example 9 4-(1H-pyrazolo[3,4-b]pyridin-5-ylamino)-7H-pyrrolo[2,3-d]pyrimidine-6-carboxylic acid ethyl ester

168 mg (745 μmol) of ethyl 4-chloro-7H-pyrrolo[2,3-d]pyrimidine-6-carboxylate (CAS-No. 187725-00-4) was similar to the conversion of Example 1, after treatment and purification to give 204 mg ( 85%) of the title compound.

¹ H-NMR (DMSO-d6): δ=1.34 (3H), 4.33 (2H), 7.58 (1H), 8.14 (1H), 8.36 (1H), 8.77 (2H), 9.86 (1H), 12.62 (1H) ), 13.59 (1H) ppm.

Example 10 4-(1H-pyrazolo[3,4-c]pyridin-5-ylamino)-7H-pyrrolo[2,3-d]pyrimidine-6-carboxylic acid ethyl ester

168 mg (745 μmol) of ethyl 4-chloro-7H-pyrrolo[2,3-d]pyrimidine-6-carboxylate (CAS-No. 187725-00-4) was similar to the conversion of Example 2, after treatment and purification to give 220 mg ( 91%) title compound.

¹ H-NMR (DMSO-d6): δ = 1.35 (3H), 4.36 (2H), 8.11 (1H), 8.31 (1H), 8.37 (1H), 8.62 (1H), 8.99 (1H), 12.31 (1H) ), 13.47 (1H), 13.84 (1H) ppm.

Example 11 4-(1H-pyrazolo[3,4-c]pyridin-5-ylamino)-7H-pyrrolo[2,3-d]pyrimidine-6-carboxylic acid

Will contain 1.00 g (3.09 mmol) of ethyl 4-(1H-pyrazolo[3,4-c]pyridin-5-ylamino)-7H-pyrrolo[2,3-d]pyrimidine-6-carboxylate A mixture (prepared according to Example 10), 30 mL of dioxane, 10 mL of ethanol and 37.1 mL of lithium hydroxide solution (1M aqueous solution) was stirred overnight at 23 °C. The mixture was acidified with EtOAc (EtOAc)EtOAc.

¹ H-NMR (DMSO-d6): δ = 8.23 (1H), 8.36 (2H), 8.64 (1H), 9.1 (1H), 12.92 (1H), 13.42 (1H), 13.92 (1H) ppm.

Example 12 Ethyl 5-bromo-4-(1H-pyrazolo[3,4-b]pyridin-5-ylamino)-7H-pyrrolo[2,3-d]pyrimidine-6-carboxylate

52 mg (171 μmol) of ethyl 5-bromo-4-chloro-7H-pyrrolo[2,3-d]pyrimidine-6-carboxylate (prepared according to Intermediate Example 12a) was similar to Example 6 using 1H-pyrazole [ Conversion of 3,4-b]pyridine-5-amine (CAS-No. 942185-01-5), after treatment and purification afforded 17.0 mg (25%) of title compound.

¹ H-NMR (DMSO-d6): δ = 1.35 (3H), 4.35 (2H), 8.15 (1H), 8.31 (1H), 8.55 (1H), 8.68 (1H), 8.73 (1H), 12.99 (1H) ), 13.63 (1H) ppm.

Example 12a Ethyl 5-bromo-4-chloro-7H-pyrrolo[2,3-d]pyrimidine-6-carboxylate

Contains 1.01 g (4.45 mmol) of 4-chloro-7H-pyrrolo[2,3-d]pyrimidine-6-carboxylic acid ethyl ester (CAS-No. 187725-00-4), 10 mL N,N-dimethyl A mixture of decylamine and 832 mg of N-bromosuccinimide was stirred at 23 ° C for 16 hours. The mixture was poured into ice water, the precipitate was filtered and dried to give 1.

Example 13 Ethyl 5-bromo-4-(1H-pyrazolo[3,4-c]pyridin-5-ylamino)-7H-pyrrolo[2,3-d]pyrimidine-6-carboxylate

49 mg (161 μmol) of 5-bromo-4-chloro-7H-pyrrolo[2,3-d]pyrimidine-6-carboxylic acid ethyl ester (prepared according to Intermediate Example 12a) was similar to Example 6 transformation, obtained and purified to afford 31.0. Mg (65%) of the title compound.

¹ H-NMR (DMSO-d6): δ=1.35 (3H), 4.36 (2H), 8.28 (1H), 8.55 (1H), 8.86 (1H), 8.90 (1H), 9.08 (1H), 13.14 (1H) ), 13.59 (1H) ppm.

Example 14 5-bromo-4-(1H-pyrazolo[3,4-c]pyridin-5-ylamino)-7H-pyrrolo[2,3-d]pyrimidine-6-carboxylic acid

26 mg (65 μmol) of 5-bromo-4-(1H-pyrazolo[3,4-c]pyridin-5-ylamino)-7H-pyridyl Ethyl bromide [2,3-d]pyrimidine-6-carboxylate (prepared according to Example 13) was similar to the compound from Example 11 to afford 9.0 mg (37%) of title compound.

¹ H-NMR (DMSO-d6): δ = 8.28 (1H), 8.53 (1H), 8.86 (1H), 8.87 (1H), 9.15 (1H), 13.03 (1H), 13.57 (1H) ppm.

Example 15 N-[5-(Trifluoromethyl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl]-1H-pyrazolo[3,4-b]pyridine-5-amine

50 mg (226 μmol) of 4-chloro-5-(trifluoromethyl)-7H-pyrrolo[2,3-d]pyrimidine (prepared according to Intermediate Example 15a) was similar to Example 2, using 1H-pyrazole[3] , 4-b]pyridine-5-amine (CAS-No. 942185-01-5) was converted, treated and purified to give 55 mg (76%).

¹ H-NMR (DMSO-d6): δ=7.38 (1H), 8.16 (1H), 8.39 (1H), 8.69 (1H), 8.74 (1H), 10.12 (1H), 13.20 (1H), 13.63 (1H) )ppm.

Example 15a 4-chloro-5-(trifluoromethyl)-7H-pyrrolo[2,3-d]pyrimidine

Containing 940 mg (6.12 mmol) of 4-chloro-7H-pyrrolo[2,3-d]pyrimidine (CAS-No. 3680-69-1), 2.87 g of sodium trifluoromethylsulfinate, at 0 ° C, 4.37 mL of dibutyl hydroperoxide was slowly added to a mixture of 26 mL of dichloromethane and 10 mL of water. The mixture was stirred at 23 ° C for 3 days, dichloromethane and saturated sodium bicarbonate solution were added, and the aqueous layer was extracted with dichloromethane. The combined organic layers were dried over sodium sulfate. After filtration and removal of solvent, EtOAcqqqqqq

Example 16 N-[5-(Trifluoromethyl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl]-1H-pyrazolo[3,4-c]pyridine-5-amine

50 mg (226 μmol) of 4-chloro-5-(trifluoromethyl)-7H-pyrrolo[2,3-d]pyrimidine (prepared according to intermediate example 15a) was similar to the conversion of Example 2, after treatment and purification to give 55.0 mg. (69%) of the title compound.

¹ H-NMR (DMSO-d6): δ=7.96 (1H), 8.34 (1H), 8.37 (1H), 8.65 (1H), 8.99 (1H), 12.24 (1H), 13.77 (1H), 13.90 (1H) )ppm.

Example 17 [4-(1H-pyrazolo[3,4-b]pyridin-5-ylamino)-7H-pyrrolo[2,3-d]pyrimidin-5-yl]methanol

50 mg (272 μmol) (4-chloro-7H-pyrrolo[2,3-d]pyrimidin-5-yl)methanol (available from FCH Group Company, Ukraine) similar to Example 2, using 1H-pyrazolo[3, 4-b]pyridine-5-amine (CAS-No. 942185-01-5) was converted, treated and purified to give 24.0 mg (28%)

¹ H-NMR (DMSO-d6): δ=4.78 (2H), 6.42 (1H), 7.18 (1H), 8.12 (1H), 8.29 (1H), 8.58 (1H), 8.83 (1H), 10.09 (1H) ), 11.63 (1H), 13.52 (1H) ppm.

Example 18 N,N-Dimethyl-4-(1H-pyrazolo[3,4-c]pyridin-5-ylamino)-7H-pyrrolo[2,3-d]pyrimidin-6-carboxamide

Will contain 50 mg (169 μmol) of 4-(1H-pyrazolo[3,4-c]pyridin-5-ylamino)-7H-pyrrolo[2,3-d]pyrimidine-6-carboxylic acid (according to Example 11 Preparation), 2 mL of dimethyl hydrazine, 88 μL of N-ethyl-N-isopropylpropan-2-amine, 51 μL of N-methylmethylamine and 302 μL of 2,4,6-tripropyl-1,3,5 A mixture of 2,4,6-trioxatriphosphorane 2,4,6-trioxide solution (50% in ethyl acetate) was stirred at 23 ° C overnight. The solvent was removed and the residue was purified mpqqqqq

¹ H-NMR (DMSO-d6): δ=3.34 (6H), 7.56 (1H), 8.23 (1H), 8.41 (1H), 8.82-8.89 (2H), 10.18 (1H), 12.16 (1H), 13.47 (1H) ppm.

Example 19 [4-(1H-pyrazolo[3,4-c]pyridin-5-ylamino)-7H-pyrrolo[2,3-d]pyrimidin-6-yl](pyrrolidin-1-yl) Ketone

50 mg (169 μmol) of 4-(1H-pyrazolo[3,4-c]pyridin-5-ylamino)-7H-pyrrolo[2,3-d]pyrimidine-6-carboxylic acid (prepared according to Example 11) Similar to Example 18, a pyrrolidine conversion, treatment and purification afforded 4.2 mg (7%) of the title compound.

¹ H-NMR (DMSO-d6): δ = 1.89 (2H), 2.00 (2H), 3.54 (2H), 3.81 (2H), 7.72 (1H), 8.22 (1H), 8.42 (1H), 8.85 (1H) ), 8.87 (1H), 10.20 (1H), 12.12 (1H), 13.48 (1H) ppm.

Example 20 Piperidin-1-yl[4-(1H-pyrazolo[3,4-c]pyridin-5-ylamino)-7H-pyrrolo[2,3-d]pyrimidin-6-yl]methanone

50 mg (169 μmol) of 4-(1H-pyrazolo[3,4-c]pyridin-5-ylamino)-7H-pyrrolo[2,3-d]pyrimidine-6-carboxylic acid (prepared according to Example 11) Similar to Example 18, after piperidine conversion, workup and purification afforded 6.4 mg (10%) of the title compound.

¹ H-NMR (DMSO-d6): δ=1.55-1.64 (4H), 1.68 (2H), 3.68 (4H), 7.39 (1H), 8.22 (1H), 8.40 (1H), 8.83-8.86 (2H) , 10.16 (1H), 12.15 (1H), 13.47 (1H) ppm.

Example 21 Morpholin-4-yl[4-(1H-pyrazolo[3,4-c]pyridin-5-ylamino)-7H-pyrrolo[2,3-d]pyrimidin-6-yl]methanone

50 mg (169 μmol) of 4-(1H-pyrazolo[3,4-c]pyridin-5-ylamino)-7H-pyrrolo[2,3-d]pyrimidine-6-carboxylic acid (prepared according to Example 11) Similar to Example 18, using morpholine conversion, workup and purification afforded 11.0 mg (18%) of the title compound.

¹ H-NMR (DMSO-d6): δ = 3.62-3.80 (8H), 7.46 (1H), 8.22 (1H), 8.42 (1H), 8.85 (2H), 10.15 (1H), 12.23 (1H), 13.46 (1H) ppm.

Example 22 N-[2-(Dimethylamino)ethyl]-4-(1H-pyrazolo[3,4-c]pyridin-5-ylamino)-7H-pyrrolo[2,3-d Pyrimidine-6-formamide

50 mg (169 μmol) of 4-(1H-pyrazolo[3,4-c]pyridin-5-ylamino)-7H-pyrrolo[2,3-d]pyrimidine-6-carboxylic acid (prepared according to Example 11) Analogously to Example 18, using N,N-dimethylethyl-1,2-diamine to afford, afforded 10.0 mg (16%) of the title compound.

¹ H-NMR (DMSO-d6): δ=2.19 (6H), 2.41 (2H), 3.37 (2H), 7.49 (1H), 8.07 (1H), 8.22 (1H), 8.40 (1H), 8.73 (1H) ), 8.85 (1H), 10.13 (1H), 12.16 (1H), 13.48 (1H) ppm.

Example 23 (RS)-N-(propan-2-yl)-4-(1H-pyrazolo[3,4-b]pyridin-5-ylamino)-5,6,7,8-tetrahydro[1 Benzothieno[2,3-d]pyrimidine-7-carboxamide

100 mg (323 μmol) of (RS)-4-chloro-N-isopropyl-5,6,7,8-tetrahydro[1]benzothieno[2,3-d]pyrimidin-7-carboxamide ( Prepared according to Example 23), similar to Example 6, using 1H-pyrazolo[3,4-b]pyridine-5-amine (CAS-No. 942185-01-5), after treatment and purification, 23.5 mg (17) %) Title compound.

¹ H-NMR (DMSO-d6): δ=1.00-1.11 (6H), 1.79 (1H), 2.05 (1H), 2.59 (1H), 2.90 (2H), 3.08 (1H), 3.26 (1H), 3.41 (1H), 3.85 (1H), 7.81 (1H), 8.11 (1H), 8.27 (1H), 8.33 (1H), 8.58 (1H), 13.58 (1H) ppm.

Example 23a (RS)-4-chloro-N-isopropyl-5,6,7,8-tetrahydro[1]benzothieno[2,3-d]pyrimidin-7-carboxamide

13.2 g (49.0 mmol) (RS)-4-chloro-5,6,7,8-tetrahydro[1]benzothieno[2,3-d]pyrimidine-7-carboxylic acid (prepared according to Intermediate Example 23b) Similar to Example 18, using propan-2-amine conversion, after workup and purification afforded 11.4 g (71%) of the title compound.

Example 23b (RS)-4-chloro-5,6,7,8-tetrahydro[1]benzothieno[2,3-d]pyrimidin-7-carboxylic acid

20.0 g (37.4 mmol) of (RS)-4-chloro-5,6,7,8-tetrahydro[1]benzothieno[2,3-d]pyrimidin-7-carboxylic acid ethyl ester (according to an intermediate example) Preparation of 23c) Similar to the conversion of Example 11 to afforded 17.2 g (95%) of the title compound.

Example 23c (RS)-4-chloro-5,6,7,8-tetrahydro[1]benzothieno[2,3-d]pyrimidin-7-carboxylic acid ethyl ester

Will contain 195g (700.6mmol) of (RS)-4-hydroxy-5,6,7,8-tetrahydro[1]benzothieno[2,3-d]pyrimidin-7-carboxylic acid ethyl ester (according to WO2005/ A mixture of 1.008 L of toluene, 1.9 mL of N-ethyl-N-isopropylpropan-2-amine and 78.4 mL of phosphorus oxychloride was heated overnight at 80 °C. The mixture was poured into a sodium bicarbonate solution and extracted with ethyl acetate. The organic layer was washed with brine and dried over sodium sulfate. After filtering and removing the solvent, the residue is from diisopropyl The ether crystallized to give 120 g (yiel.

Example 24 (RS)-N-(propan-2-yl)-4-(1H-pyrazolo[3,4-c]pyridin-5-ylamino)-5,6,7,8-tetrahydro[1 Benzothieno[2,3-d]pyrimidine-7-carboxamide

100 mg (323 μmol) of (RS)-4-chloro-N-isopropyl-5,6,7,8-tetrahydro[1]benzothieno[2,3-d]pyrimidin-7-carboxamide ( Prepared according to Example 23).

¹ H-NMR (DMSO-d6): δ=1.01-1.10 (6H), 1.80 (1H), 2.07 (1H), 2.58 (1H), 2.90 (2H), 3.05-3.45 (2H), 3.84 (1H) , 7.84 (1H), 8.21 (1H), 8.36 (1H), 8.50 (1H), 8.63 (1H), 8.82 (1H), 13.54 (1H) ppm.

Example 25 (RS)-(4-methylpiperazin-1-yl)[4-(1H-pyrazolo[3,4-b]pyridin-5-ylamino)-5,6,7,8-tetra Hydrogen [1] benzothieno[2,3-d]pyrimidin-7-yl]methanone

70 mg (200 μmol) (RS)-(4-chloro-5,6,7,8-tetrahydro[1]benzothieno[2,3-d]pyrimidin-7-yl)(4-methylpiperazine) The -1-yl)methanone (prepared according to the intermediate Example 25a) was similar to the compound of Example 7 to afford 38.0 mg (38%) of the title compound.

¹ H-NMR (DMSO-d6): δ=1.81 (1H), 2.04 (1H), 2.21 (3H), 2.30 (2H), 2.37 (2H), 2.84-3.06 (2H), 3.13-3.29 (3H) , 3.50 (2H), 3.57 (2H), 8.13 (1H), 8.30 (1H), 8.36 (2H), 8.60 (1H), 13.61 (1H) ppm.

Example 25a (RS)-(4-chloro-5,6,7,8-tetrahydro[1]benzothieno[2,3-d]pyrimidin-7-yl)(4-methylpiperazin-1-yl) Ketone

500 mg (1.861 mmol) of (RS)-4-chloro-5,6,7,8-tetrahydro[1]benzothieno[2,3-d]pyrimidine-7-carboxylic acid (prepared according to Intermediate Example 23b) Analogously to Example 18, 1-methylpiperazine was used for the title compound.

Example 26 (RS)-(4-methylpiperazin-1-yl)[4-(1H-pyrazolo[3,4-c]pyridin-5-ylamino)-5,6,7,8-tetra Hydrogen [1] benzothieno[2,3-d]pyrimidin-7-yl]methanone

70 mg (200 μmol) (RS)-(4-chloro-5,6,7,8-tetrahydro[1]benzothieno[2,3-d]pyrimidin-7-yl)(4-methylpiperazine) 1-yl)methanone (prepared according to intermediate example 25a) was similar to Example 7, using 1H-pyrazolo[3,4-c]pyridine-5-amine conversion, after treatment and purification to give 14.6 mg (16%) ) title compound.

¹ H-NMR (DMSO-d6): δ=1.81 (1H), 2.10 (1H), 2.19 (3H), 2.25-2.38 (4H), 2.86-3.04 (2H), 3.16 (1H), 3.27 (2H) , 3.50 (2H), 3.56 (2H), 8.24 (1H), 8.33 (1H), 8.53 (1H), 8.68 (1H), 8.84 (1H), 13.55 (1H) ppm.

Example 27 (RS)-N,N-Dimethyl-4-(1H-pyrazolo[3,4-b]pyridin-5-ylamino)-5,6,7,8-tetrahydro[1]benzene Thieno[2,3-d]pyrimidin-7-carboxamide

60 mg (203 μmol) (RS)-4-chloro-N,N-dimethyl-5,6,7,8-tetrahydro[1]benzothieno[2,3-d]pyrimidin-7-formamidine Amine (prepared according to Intermediate Example 27a) was similar to Example 6 using 1H-pyrazolo[3,4-b]pyridin-5-amine to afford to afford 10.6 mg (13%) of the title compound.

¹ H-NMR (DMSO-d6): δ = 1.76 (1H), 2.05 (1H), 2.85 (3H), 2.87-2.98 (2H), 3.07 (3H), 3.10-3.23 (2H), 3.31 (1H) , 8.11 (1H), 8.27 (1H), 8.34 (2H), 8.58 (1H), 13.58 (1H) ppm.

Example 27a (RS)-4-chloro-N,N-dimethyl-5,6,7,8-tetrahydro[1]benzothieno[2,3-d]pyrimidin-7-carboxamide

500 mg (1.861 mmol) of (RS)-4-chloro-5,6,7,8-tetrahydro[1]benzothieno[2,3-d]pyrimidine-7-carboxylic acid (prepared according to Intermediate Example 23b) Similar to Example 18, using N-methylmethylamine to afford, afforded 350 mg (64%) of title compound.

Example 28 (RS)-N,N-dimethyl-4-(1H-pyrazolo[3,4-c]pyridin-5-ylamino)-5,6,7,8-tetrahydro[1]benzene Thieno[2,3-d]pyrimidin-7-carboxamide

60 mg (203 μmol) (RS)-4-chloro-N,N-dimethyl-5,6,7,8-tetrahydro[1]benzothieno[2,3-d]pyrimidin-7-formamidine The amine (prepared according to Intermediate Example 27a) was similar to the one obtained in Example 6 to afford 24.7 mg (29%) of title compound.

¹ H-NMR (DMSO-d6): δ = 1.76 (1H), 2.10 (1H), 2.85 (3H), 2.86-2.97 (2H), 3.07 (3H), 3.11 (1H), 3.24 (2H), 8.21. (1H), 8.32 (1H), 8.51 (1H), 8.66 (1H), 8.81 (1H), 13.53 (1H) ppm.

Example 29 (RS)-N-(propan-2-yl)-4-(1H-pyrazolo[3,4-b]pyridin-5-ylamino)-6,7,8,9-tetrahydro-5H -pyrimido[4,5-b]indole-6-carboxamide

60 mg (205 μmol) of (RS)-4-chloro-N-isopropyl-6,7,8,9-tetrahydro-5H-pyrimido[4,5-b]indole-6-carboxamide (according to Intermediate Example 29a was prepared) analogous to Example 6 using 1H-pyrazolo[3,4-b]pyridin-5-amine to afford, afforded 58.7 mg (70%) of the title compound.

¹ H-NMR (DMSO-d6): δ=1.04 (6H), 1.77 (1H), 1.95 (1H), 2.51 (1H), 2.68 (1H), 2.94 (1H), 3.09 (1H), 3.36 (1H) ), 3.84 (1H), 7.75 (1H), 8.03 (1H), 8.06 (1H), 8.20 (1H), 8.33 (1H), 8.60 (1H), 11.42 (1H), 13.50 (1H) ppm.

Example 29a (RS)-4-chloro-N-isopropyl-6,7,8,9-tetrahydro-5H-pyrimido[4,5-b]indole-6-carboxamide

550 mg (2.19 mmol) of (RS)-4-chloro-6,7,8,9-tetrahydro-5H-pyrimido[4,5-b]indole-6-carboxylic acid (prepared according to Intermediate Example 29b) In Example 18, a propan-2-amine conversion, workup and purification afforded 526.7 mg (82%).

Example 29b (RS)-4-chloro-6,7,8,9-tetrahydro-5H-pyrimido[4,5-b]indole-6-carboxylic acid

4.56 g (16.3 mmol) of (RS)-4-chloro-6,7,8,9-tetrahydro-5H-pyrimido[4,5-b]indole-6-carboxylic acid ethyl ester (according to intermediate example 29c Preparation) Similar to the conversion of Example 11, after workup and purification, 3.57 g (83%) of title compound.

Example 29c (RS)-4-chloro-6,7,8,9-tetrahydro-5H-pyrimido[4,5-b]indole-6-carboxylic acid ethyl ester

Will contain 412 mg (1.58 mmol) of (RS)-4-hydroxy-6,7,8,9-tetrahydro-5H-pyrimido[4,5-b]indole-6-carboxylic acid ethyl ester (according to intermediate examples) A mixture of 29d) and 8.82 mL of phosphorus oxychloride was heated at 100 ° C for 1 hour. The reagent was removed and the residue was purified mpqqqqq

Example 29d (RS)-4-hydroxy-6,7,8,9-tetrahydro-5H-pyrimido[4,5-b]indole-6-carboxylic acid ethyl ester

A mixture containing 3.17 g (11.37 mmol) of 4-[(6-hydroxypyrimidin-4-yl)indenyl]cyclohexanecarboxylate (prepared according to Intermediate Example 29e) and 20 mL of xylene under microwave irradiation Heat at 250 ° C for 5 hours. The solid was filtered and washed with diethyl ether afforded title:

Example 29e 4-[(6-Hydroxypyrimidin-4-yl)indenyl]cyclohexanecarboxylic acid ethyl ester

Will contain 4.29g (34.0mmol) of 6-mercaptopyrimidin-4-ol/6-mercaptopyrimidine-4(1H)-one (CAS-No: 29939-37-5), 8.69g 4-sided oxy ring A mixture of ethyl hexanecarboxylate and 69 mL of ethanol was heated under reflux for 1.5 hours. After cooling to 3 ° C, the precipitated solid was filtered and washed with diethyl ether.

Example 30 (RS)-N,N-Dimethyl-4-(1H-pyrazolo[3,4-b]pyridin-5-ylamino)-6,7,8,9-tetrahydro-5H-pyrimidine And [4,5-b]吲哚-6-carbamamine

80 mg (287 μmol) of (RS)-4-chloro-N,N-dimethyl-6,7,8,9-tetrahydro-5H-pyrimidine [4,5-b]Indole-6-carbamimid (prepared according to Intermediate Example 27a) was similar to Example 7 <EMI ID=9.1>

¹ H-NMR (DMSO-d6): δ=1.79 (1H), 1.99 (1H), 2.74-2.95 (3H), 2.85 (3H), 3.01-3.19 (2H), 3.09 (3H), 8.15 (1H) , 8.23 (1H), 8.36 (1H), 8.59 (1H), 9.75 (1H), 12.56 (1H), 13.84 (1H) ppm.

Example 31 (RS)-N,N-Dimethyl-4-(1H-pyrazolo[3,4-c]pyridin-5-ylamino)-6,7,8,9-tetrahydro-5H-pyrimidine And [4,5-b]吲哚-6-carbamamine

80 mg (287 μmol) (RS)-4-chloro-N,N-dimethyl-6,7,8,9-tetrahydro-5H-pyrimido[4,5-b]indole-6-carboxamide (Prepared according to Intermediate Example 27a) was similar to Example 7 using 1H-pyrazolo[3,4-c]pyridin-5-amine as the title compound.

¹ H-NMR (DMSO-d6): δ = 1.77 (1H), 1.98 (1H), 2.67-2.84 (2H), 2.89 (3H), 2.95-3.14 (3H), 3.10 (3H), 7.95 (1H) , 8.19 (1H), 8.28 (1H), 8.72 (1H), 8.78 (1H), 11.54 (1H), 13.42 (1H) ppm.

Example 32

(RS)-(4-methylpiperazin-1-yl)[4-(1H-pyrazolo[3,4-b]pyridin-5-ylamino)-6,7,8,9-tetra Hydrogen-5H-pyrimido[4,5-b]indol-6-yl]methanone

60 mg (180 μmol) (RS)-(4-chloro-6,7,8,9-tetrahydro-5H-pyrimido[4,5-b]indole- The 6-yl)(4-methylpiperazin-l-yl)methanone (prepared according to the intermediate Example 32a) was obtained from the title compound.

¹ H-NMR (DMSO-d6): δ = 1.81 (1H), 1.95 (1H), 2.25 (3H), 2.29-2.46 (3H), 2.67-2.85 (2H), 2.92-3.13 (3H), 3.33 3.38 (1H), 3.39-3.69 (4H), 8.07 (1H), 8.09 (1H), 8.20 (1H), 8.39 (1H), 8.64 (1H), 11.44 (1H), 13.50 (1H) ppm.

Example 32a (RS)-(4-chloro-6,7,8,9-tetrahydro-5H-pyrimido[4,5-b]indol-6-yl)(4-methylpiperazin-1-yl) Ketone

500 mg (1.99 mmol) of (RS)-4-chloro-6,7,8,9-tetrahydro-5H-pyrimido[4,5-b]indole-6-carboxylic acid (prepared according to Intermediate Example 29b) In Example 18, 1-methylpiperazine conversion, treatment and purification afforded 411 mg (62%)

Example 33 (RS)-(4-methylpiperazin-1-yl)[4-(1H-pyrazolo[3,4-c]pyridin-5-ylamino)-6,7,8,9-tetra Hydrogen-5H-pyrimido[4,5-b]indol-6-yl]methanone

60 mg (180 μmol) (RS)-(4-chloro-6,7,8,9-tetrahydro-5H-pyrimido[4,5-b]indol-6-yl) (4-methylpiperazine- 1-yl)methanone (prepared according to intermediate example 32a) was similar to Example 7, using 1H-pyrazolo[3,4-c]pyridine-5-amine conversion, after treatment and purification to give 4.0 mg (5%) Title compound.

¹ H-NMR (DMSO-d6): δ=1.78 (1H), 1.96 (1H), 2.20 (3H), 2.24-2.39 (4H), 2.65-2.86 (2H), 2.99-3.17 (3H), 3.46- 3.63 (4H), 7.98 (1H), 8.20 (1H), 8.28 (1H), 8.70 (1H), 8.79 (1H), 11.56 (1H), 13.45 (1H) ppm.

Example 34 {(7S)-4-[(6-Methoxy-1H-pyrazolo[3,4-b]pyridin-5-yl)amino]-5,6,7,8-tetrahydro[1] Benzothieno[2,3-d]pyrimidin-7-yl}(morpholin-4-yl)methanone

100 mg (252 μmol) of (7S)-4-[(6-methoxy-1H-pyrazolo[3,4-b]pyridin-5-yl)amino]-5,6,7,8-tetrahydro [1] Benzothieno[2,3-d]pyrimidine-7-carboxylic acid (prepared according to Intermediate Example 34a) was similar to Example 18, using morpholine conversion, after workup and purification to give 43.5 mg (35%) of title compound .

¹ H-NMR (DMSO-d6): δ=1.86 (1H), 2.12 (1H), 2.86-3.05 (2H), 3.12-3.29 (3H), 3.45-3.66 (8H), 4.02 (3H), 8.01 ( 1H), 8.09 (1H), 8.41 (1H), 8.82 (1H), 13.37 (1H) ppm.

Example 34a (7S)-4-[(6-methoxy-1H-pyrazolo[3,4-b]pyridin-5-yl)amino]-5,6,7,8-tetrahydro[1]benzene Thio[2,3-d]pyrimidine-7-carboxylic acid

2.60 g (6.13 mmol) of (7S)-4-[(6-methoxy-1H-pyrazolo[3,4-b]pyridin-5-yl)amino]-5,6,7,8- Ethyl tetrahydro[1]benzothieno[2,3-d]pyrimidin-7-carboxylate (prepared according to Intermediate Example 34b) was similar to the compound of Example 11 and afforded 2.36 g (97%). Title compound.

Example 34b (7S)-4-[(6-methoxy-1H-pyrazolo[3,4-b]pyridin-5-yl)amino]-5,6,7,8-tetrahydro[1]benzene Thieno[2,3-d]pyrimidine-7-formate

Will contain 2.38g (8.01mmol) of (7S)-4-chloro-5,6,7,8-tetrahydro[1]benzothieno[2,3-d]pyrimidin-7-carboxylic acid ethyl ester (according to the middle A mixture of 1.32 g of 6-methoxy-1H-pyrazolo[3,4-b]pyridine-5-amine (prepared according to intermediate Example 34f) and 25 mL of ethanol was heated under reflux overnight. 1.2 mL of triethylamine was added and the precipitate was purified by recrystallization from ethanol to give 2.60 g (76%) of the title compound.

Example 34c (7S)-4-chloro-5,6,7,8-tetrahydro[1]benzothieno[2,3-d]pyrimidin-7-carboxylic acid ethyl ester

Containing 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 34d), 830 mL of ethanol and 24.4 mL of titanium tetraethoxide (4+ The mixture was refluxed for 20 hours. 1.4 L of ethyl acetate and 18 mL of water were added and the mixture was stirred for 30 minutes. Add the silicone and continue to stir for 10 minutes. The mixture was filtered through EtOAc (EtOAc)EtOAc.

Example 34d (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-oxazolidine-2-one (B)

To a solution of 26.8 g of (4S,5R)-4-methyl-5-phenyl-1,3-oxazolidin-2-one in 428 mL of tetrahydrofuran was added 70 mL of n-butyllithium (2.5) at -78 °C. M hexane solution) and the mixture was stirred at -60 ° C for 1 hour. 45.8 g (159 mmol) of 4-chloro-5,6,7,8-tetrahydro[1]benzothieno[2,3-d]pyrimidin-7(RS)-carbonyl chloride (prepared according to intermediate example 34e) The solution in 428 mL of tetrahydrofuran was stirred at -70 °C for an additional 1 hour. The mixture was poured into water, the tetrahydrofuran was removed, and the precipitate was filtered, washed with water and then dissolved in dichloromethane. The organic layer was dried over sodium sulfate and then acetonitrile was added. The dichloromethane was removed, and the precipitate was filtered, washed with EtOAc EtOAc From the mother liquor, a second precipitate was obtained after standing overnight to give 25.5 g (35%) of title compound B.

Example 34e 4-chloro-5,6,7,8-tetrahydro[1]benzothieno[2,3-d]pyrimidin-7(RS)-carbonyl chloride

Will contain 42.87g (159mmol) of 4-chloro-5,6,7,8-tetrahydro[1]benzothieno[2,3-d]pyrimidine-7-carboxylic acid (prepared according to intermediate example 23b) and 349mL The mixture of sulfoxide chloride was heated at 100 ° C for 3 hours. The reagent was removed to give the title compound which was used without further purification.

Example 34f 6-methoxy-1H-pyrazolo[3,4-b]pyridine-5-amine

It will contain 4.00 g (20.6 mmol) of 6-methoxy-5-nitro-1H-pyrazolo[3,4-b]pyridine (prepared according to intermediate example 34g), 120 mL of ethanol, 120 mL of tetrahydrofuran and 1.10 g of palladium. The mixture of charcoal (10%) was stirred overnight at 23 ° C under a hydrogen atmosphere. The catalyst and solvent were removed to give 3.26 g (96%) of title compound.

Example 34g 6-methoxy-5-nitro-1H-pyrazolo[3,4-b]pyridine

2.2 mL of fuming nitric acid was carefully added to 6.8 mL of acetic anhydride at 0 °C. 1.00 g (mmol) of 6-methoxy-1H-pyrazolo[3,4-b]pyridine (CAS-No. 1260664-24-1) was added in portions, and the mixture was stirred at 10 ° C for 22 hours and poured over On the ice. Sodium bicarbonate was carefully added until a pH between 2 and 3, and the mixture was extracted with dichloromethane. The organic layer was washed with brine and dried over sodium sulfate. After filtration and removal of the solvent, EtOAc m.

Example 35 Azetidin-1-yl {(7S)-4-[(6-methoxy-1H-pyrazolo[3,4-b]pyridin-5-yl)amino]-5,6, 7,8-tetrahydro[1]benzothieno[2,3-d]pyrimidin-7-yl}methanone

100 mg (252 μmol) of (7S)-4-[(6-methoxy-1H-pyrazolo[3,4-b]pyridin-5-yl)amino]-5,6,7,8-tetrahydro [1] Benzothieno[2,3-d]pyrimidine-7-carboxylic acid (prepared according to Intermediate Example 34a) was similar to Example 18, using azetidine conversion, treatment and purification. 44.8 mg (39%) of the title compound.

¹ H-NMR (DMSO-d6): δ = 1.80 (1H), 2.11 (1H), 2.17-2.27 (2H), 2.76 (1H), 2.90 (2H), 3.13 (1H), 3.24 (1H), 3.88 (2H), 4.02 (3H), 4.24 (2H), 8.01 (1H), 8.09 (1H), 8.41 (1H), 8.83 (1H), 13.35 (1H) ppm.

Example 36 [(2R,6S)-2,6-Dimethylmorpholin-4-yl]{(7S)-4-[(6-methoxy-1H-pyrazolo[3,4-b]pyridine- 5-yl)amino]-5,6,7,8-tetrahydro[1]benzothieno[2,3-d]pyrimidin-7-yl}methanone

100 mg (252 μmol) of (7S)-4-[(6-methoxy-1H-pyrazolo[3,4-b]pyridin-5-yl)amino]-5,6,7,8-tetrahydro [1] benzothieno[2,3-d]pyrimidine-7-carboxylic acid (prepared according to intermediate example 34a) analogous to Example 18, using (2R,6S)-2,6-dimethylmorpholine, After treatment and purification, 27.6 mg (21%) of title compound.

¹ H-NMR (DMSO-d6): δ=1.07-1.15 (6H), 1.85 (1H), 2.09 (1H), 2.27 (1H), 2.77 (1H), 2.87-3.06 (2H), 3.23 (3H) , 3.44 (1H), 3.52 (1H), 3.99 (1H), 4.01 (3H), 4.31 (1H), 8.01 (1H), 8.08 (1H), 8.40 (1H), 8.81 (1H), 13.36 (1H) Ppm.

Example 37 (7S)-4-[(6-Methoxy-1H-pyrazolo[3,4-b]pyridin-5-yl)amino]-N-methyl-N-(propan-2-yl) -5,6,7,8-tetrahydro[1]benzothieno[2,3-d]pyrimidin-7-carboxamide

100 mg (252 μmol) of (7S)-4-[(6-methoxy-1H-pyrazolo[3,4-b]pyridine-5- Amino]-5,6,7,8-tetrahydro[1]benzothieno[2,3-d]pyrimidine-7-carboxylic acid (prepared according to Intermediate Example 34a) is similar to Example 18, using N -Methylpropan-2-amine conversion, treatment and purification afforded 57.8 mg (48%)

¹ H-NMR (DMSO-d6): δ=1.05+1.18 (6H), 1.84 (1H), 2.10 (1H), 2.71+2.91 (3H), 2.85-3.06 (2H), 3.07-3.25 (3H), 4.02 (3H), 4.29 + 4.72 (1H), 8.02 (1H), 8.08 (1H), 8.40-8.42 (1H), 8.82+8.86 (1H), 13.33 (1H) ppm.

Example 38 (7S)-4-[(6-methoxy-1H-pyrazolo[3,4-b]pyridin-5-yl)amino]-N-methyl-N-propyl-5,6, 7,8-tetrahydro[1]benzothieno[2,3-d]pyrimidin-7-carboxamide

100 mg (252 μmol) of (7S)-4-[(6-methoxy-1H-pyrazolo[3,4-b]pyridin-5-yl)amino]-5,6,7,8-tetrahydro [1] Benzothieno[2,3-d]pyrimidine-7-carboxylic acid (prepared according to Intermediate Example 34a) was similar to Example 18, using N-methylpropan-1-amine to be converted, treated and purified to give 66.0. Mg (55%) of the title compound.

¹ H-NMR (DMSO-d6): δ = 0.83 + 0.87 (3H), 1.49 + 1.57 (2H), 1.84 (1H), 2.10 (1H), 2.85 + 3.08 (3H), 2.88-3.03 (2H), 3.12-3.43 (5H), 4.02 (3H), 8.01 (1H), 8.08 (1H), 8.41 (1H), 8.82+8.86 (1H), 13.35 (1H) ppm.

Example 39 (7S)-N-ethyl-4-[(6-methoxy-1H-pyrazolo[3,4-b]pyridin-5-yl)amino]-N-methyl-5,6, 7,8-tetrahydro[1]benzothieno[2,3-d]pyrimidin-7-carboxamide

100 mg (252 μmol) of (7S)-4-[(6-methoxy-1H-pyrazolo[3,4-b]pyridin-5-yl)amino]-5,6,7,8-tetrahydro [1] Benzothieno[2,3-d]pyrimidine-7-carboxylic acid (prepared according to Intermediate Example 34a) was similar to Example 18, using N-methylethylamine to afford, affording 51.3mg %) Title compound.

¹ H-NMR (DMSO-d6): δ=1.03+1.15 (3H), 1.84 (1H), 2.10 (1H), 2.85+3.07 (3H), 2.86-3.02 (2H), 3.10-3.52 (5H), 4.02 (3H), 8.01 (1H), 8.08 (1H), 8.41 (1H), 8.83 + 8.85 (1H), 13.35 (1H) ppm.

Example 40 {(7S)-4-[(6-Methoxy-1H-pyrazolo[3,4-b]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

100 mg (252 μmol) of (7S)-4-[(6-methoxy-1H-pyrazolo[3,4-b]pyridin-5-yl)amino]-5,6,7,8-tetrahydro [1] Benzothieno[2,3-d]pyrimidine-7-carboxylic acid (prepared according to Intermediate Example 34a) is similar to Example 18, using (1S,4S)-2-oxa-5-azabicyclo ring [2.2.1] Heptane conversion, treatment and purification afforded 53.7 mg (42%)

¹ H-NMR (DMSO-d6): δ=1.75-1.92 (3H), 2.12 (1H), 2.80-3.03 (3H), 3.08-3.25 (3H), 3.53+3.65 (1H), 3.58+3.72 (1H) ), 3.76 (1H), 4.01 (3H), 4.61 + 4.66 (1H), 4.77 + 4.87 (1H), 8.01 (1H), 8.07 (1H), 8.40 + 8.41 (1H), 8.80 + 8.85 (1H), 13.35 (1H) ppm.

Example 41 {(7S)-4-[(6-Methoxy-1H-pyrazolo[3,4-b]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

100 mg (252 μmol) of (7S)-4-[(6-methoxy-1H-pyrazolo[3,4-b]pyridin-5-yl)amino]-5,6,7,8-tetrahydro [1] Benzothieno[2,3-d]pyrimidine-7-carboxylic acid (prepared according to Intermediate Example 34a) is similar to Example 18, using (1R,4R)-2-oxa-5-azabicyclo ring [2.2.1] Heptane conversion, treatment and purification afforded 38.1 mg (30%) of the title compound.

¹ H-NMR (DMSO-d6): δ=1.75-1.96 (3H), 2.16 (1H), 2.77-3.25 (5H), 3.51+3.65 (1H), 3.60+3.73 (1H), 3.74 (2H), 4.01 (3H), 4.61 + 4.67 (1H), 4.78 + 4.86 (1H), 8.01 (1H), 8.09 (1H), 8.42 (1H), 8.86 + 8.88 (1H), 13.35 (1H) ppm.

Example 42 {(7S)-4-[(6-Methoxy-1H-pyrazolo[3,4-b]pyridin-5-yl)amino]-5,6,7,8-tetrahydro[1] Benzothieno[2,3-d]pyrimidin-7-yl}(4-methylpiperazin-1-yl)methanone

100 mg (252 μmol) of (7S)-4-[(6-methoxy-1H-pyrazolo[3,4-b]pyridin-5-yl)amino]-5,6,7,8-tetrahydro [1] Benzothieno[2,3-d]pyrimidine-7-carboxylic acid (prepared according to Intermediate Example 34a) was similar to Example 18, using 1-methylpiperazine conversion, treatment and purification. 80.2 mg (63%) of the title compound.

¹ H-NMR (DMSO-d6): δ = 1.85 (1H), 2.10 (1H), 2.19 (3H), 2.25-2.38 (4H), 2.85-3.01 (2H), 3.14-3.25 (3H), 3.50 ( 2H), 3.58 (2H), 4.02 (3H), 8.01 (1H), 8.08 (1H), 8.41 (1H), 8.83 (1H), 13.35 (1H) ppm.

Example 43 [4-(Dimethylamino)piperidin-1-yl]{(7S)-4-[(6-methoxy-1H-pyrazolo[3,4-b]pyridin-5-yl) Amino]-5,6,7,8-tetrahydro[1]benzothieno[2,3-d]pyrimidin-7-yl}methanone

100 mg (252 μmol) of (7S)-4-[(6-methoxy-1H-pyrazolo[3,4-b]pyridin-5-yl)amino]-5,6,7,8-tetrahydro [1] benzothieno[2,3-d]pyrimidine-7-carboxylic acid (prepared according to intermediate example 34a) analogous to Example 18, using N,N-dimethylpiperidin-4-amine conversion, treatment and After purification, 65.0 mg (48%) of title compound.

¹ H-NMR (DMSO-d6): δ = 1.21 (1H), 1.35 (1H), 1.73-1.90 (3H), 2.10 (1H), 2.20 (6H), 2.36 (1H), 2.61 (1H), 2.84 - 3.24 (6H), 4.02 (3H), 4.06 (1H), 4.41 (1H), 8.02 (1H), 8.08 (1H), 8.41 (1H), 8.83 (1H), 13.34 (1H) ppm.

Example 44 {(7S)-4-[(6-Methoxy-1H-pyrazolo[3,4-b]pyridin-5-yl)amino]-5,6,7,8-tetrahydro[1] Benzothieno[2,3-d]pyrimidin-7-yl}[(3R)-3-methylmorpholin-4-yl]methanone

100 mg (252 μmol) of (7S)-4-[(6-methoxy-1H-pyrazolo[3,4-b]pyridin-5-yl)amino]-5,6,7,8-tetrahydro [1] Benzothieno[2,3-d]pyrimidine-7-carboxylic acid (prepared according to Intermediate Example 34a) was similar to Example 18, using (3R)-3-methylmorpholine, after treatment and purification. 51.1 mg (40%) of the title compound.

¹ H-NMR (DMSO-d6): δ=1.15+1.31 (3H), 1.90 (1H), 2.09 (1H), 2.85-3.89 (11H), 4.02 (3H), 4.14+4.42 (1H), 8.01 ( 1H), 8.08 (1H), 8.41 (1H), 8.82 (1H), 13.35 (1H) ppm.

Example 45 {(7S)-4-[(6-Methoxy-1H-pyrazolo[3,4-b]pyridin-5-yl)amino]-5,6,7,8-tetrahydro[1] Benzothieno[2,3-d]pyrimidin-7-yl}[(3S)-3-methylmorpholin-4-yl]methanone

100 mg (252 μmol) of (7S)-4-[(6-methoxy-1H-pyrazolo[3,4-b]pyridin-5-yl)amino]-5,6,7,8-tetrahydro [1] Benzothieno[2,3-d]pyrimidine-7-carboxylic acid (prepared according to Intermediate Example 34a) was similar to Example 18, using (3S)-3-methylmorpholine, after treatment and purification. 83.0 mg (65%) of the title compound.

¹ H-NMR (DMSO-d6): δ=1.16+1.29 (3H), 1.83 (1H), 2.10 (1H), 2.84-3.90 (11H), 4.02 (3H), 4.13+4.43 (1H), 8.02 ( 1H), 8.08 (1H), 8.42 (1H), 8.85 (1H), 13.35 (1H) ppm.

Example 46 (7S)-N-ethyl-N-(propan-2-yl)-4-(1H-pyrazolo[3,4-c]pyridin-5-ylamino)-5,6,7,8 -tetrahydro[1]benzothieno[2,3-d]pyrimidin-7-carboxamide

100 mg (273 μmol) of (7S)-4-(1H-pyrazolo[3,4-c]pyridin-5-ylamino)-5,6,7,8-tetrahydro[1]benzothieno[ 2,3-d]pyrimidine-7-carboxylic acid (prepared according to intermediate Example 46a) was similar to Example 18, using N-ethylpropan-2-amine to afford to afford 18.6 mg (15%) of the title compound.

¹ H-NMR (DMSO-d6): δ=1.04-1.23 (9H), 1.84 (1H), 2.07 (1H), 2.85-36 (7H), 4.24+4.55 (1H), 8.24 (1H), 8.33 ( 1H), 8.54 (1H), 8.69 (1H), 8.84 (1H), 13.54 (1H) ppm.

Example 46a (7S)-4-(1H-pyrazolo[3,4-c]pyridin-5-ylamino)-5,6,7,8-tetrahydro[1]benzothieno[2,3- d]pyrimidine-7-formic acid

1.79 g (4.53 mmol) of (7S)-4-(1H-pyrazolo[3,4-c]pyridin-5-ylamino)-5,6,7,8-tetrahydro[1]benzothiophene And [2,3-d]pyrimidin-7-carboxylic acid ethyl ester (prepared according to Intermediate Example 46b) was obtained from EtOAc (m.

Example 46b (7S)-4-(1H-pyrazolo[3,4-c]pyridin-5-ylamino)-5,6,7,8-tetrahydro[1]benzothieno[2,3- d]pyrimidine-7-carboxylic acid ethyl ester

Will contain 1.20 g (4.04 mmol) of (7S)-4-chloro-5,6,7,8-tetrahydro[1]benzothieno[2,3-d]pyrimidin-7-carboxylic acid ethyl ester (according to the middle A mixture of 515 mg of 1H-pyrazolo[3,4-c]pyridine-5-amine (CAS-No. 10496671-75-4) and 36 mL of ethanol was heated at 150 ° C under microwave irradiation. The precipitate was washed with ethanol and diethyl ether to give 618mg (39%

Example 47 (7S)-N-(2-hydroxy-2-methylpropyl)-N-methyl-4-(1H-pyrazolo[3,4-c]pyridin-5-ylamino)-5, 6,7,8-tetrahydro[1]benzothieno[2,3-d]pyrimidin-7-carboxamide

100 mg (273 μmol) of (7S)-4-(1H-pyrazolo[3,4-c]pyridin-5-ylamino)-5,6,7,8-tetrahydro[1]benzothieno[ 2,3-d]pyrimidine-7-carboxylic acid (prepared according to intermediate example 46a) analogous to Example 18, using 2-methyl-1-(methylamino)propan-2-ol to afford, workup and purification 38.9 mg (30%) of the title compound.

¹ H-NMR (DMSO-d6): δ=1.05-1.15 (6H), 1.81 (1H), 2.08+2.16 (1H), 2.84-3.01 (2H), 2.95+3.20 (3H), 3.14-3.44 (5H ), 4.49 + 4.56 (1H), 8.24 (1H), 8.34 (1H), 8.53 (1H), 8.68 (1H), 8.84 (1H), 13.53 (1H) ppm.

Example 48 (7S)-N-methyl-4-(1H-pyrazolo[3,4-c]pyridin-5-ylamino)-N-(3,3,3-trifluoropropyl)-5, 6,7,8-tetrahydro[1]benzothieno[2,3-d]pyrimidin-7-carboxamide

100 mg (273 μmol) of (7S)-4-(1H-pyrazolo[3,4-c]pyridin-5-ylamino)-5,6,7,8-tetrahydro[1]benzothieno[ 2,3-d]pyrimidine-7-carboxylic acid (prepared according to intermediate example 46a) analogous to Example 18, using 3,3,3-trifluoro-N-methylpropan-1-amine, 37.6 mg (28%) of the title compound.

¹ H-NMR (DMSO-d6): δ=1.80 (1H), 2.12 (1H), 2.53 (2H), 2.87+3.12 (3H), 2.93 (2H), 3.05-3.72 (5H), 8.24 (1H) , 8.34 (1H), 8.54 (1H), 8.68 (1H), 8.84 (1H), 13.54 (1H) ppm.

Example 49 (7S)-N-(2-methoxyethyl)-4-[(6-methoxy-1H-pyrazolo[3,4-b]pyridin-5-yl)amino]-N- Propyl-5,6,7,8-tetrahydro[1]benzothieno[2,3-d]pyrimidin-7-carboxamide

50 mg (136 μmol) of (7S)-4-[(6-methoxy-1H-pyrazolo[3,4-b]pyridin-5-yl)amino]-5,6,7,8-tetrahydro [1] Benzothieno[2,3-d]pyrimidine-7-carboxylic acid (prepared according to Intermediate Example 34a) was similar to Example 18, using N-(2-methoxyethyl)propan-1-amine. After treatment and purification, 6.9 mg (9%) of the title compound was obtained.

¹ H-NMR (DMSO-d6): δ = 0.80-0.89 (3H), 1.41-1.62 (2H), 1.85 (1H), 2.09 (1H), 2.85-3.03 (2H), 3.07-3.66 (12H), 4.02 (3H), 8.02 (1H), 8.10 (1H), 8.41 (1H), 8.84 (1H), 13.36 (1H) ppm.

Example 50 (7S)-4-[(6-Hydroxy-1H-pyrazolo[3,4-b]pyridin-5-yl)amino]-N-(2-methoxyethyl)- N-propyl-5,6,7,8-tetrahydro[1]benzothieno[2,3-d]pyrimidin-7-carboxamide

Will contain 31.1 mg (63 μmol) of (7S)-N-(2-methoxyethyl)-4-[(6-methoxy-1H-pyrazolo[3,4-b]pyridin-5-yl Amino]-N-propyl-5,6,7,8-tetrahydro[1]benzothieno[2,3-d]pyrimidin-7-carboxamide (prepared according to Example 49), 0.7 mL A mixture of ethanol and 15.7 μL of hydrochloric acid (4 M solution of dioxane) was heated at 140 ° C for two hours under microwave irradiation. 100 μL of triethylamine was added and the mixture was purified by chromatography to give 15.1 mg (47%) of the title compound.

¹ H-NMR (DMSO-d6): δ = 0.80-0.88 (3H), 1.44-1.61 (2H), 1.86 (1H), 2.07 (1H), 2.84-3.04 (2H), 3.07-3.66 (12H), 8.09 (1H), 8.55 (1H), 8.88 (1H), 8.96 (1H), 12.40 (1H), 13.05 (1H) ppm.

Example 51 (7S)-N-butyl-4-[(6-methoxy-1H-pyrazolo[3,4-b]pyridin-5-yl)amino]-N-methyl-5,6, 7,8-tetrahydro[1]benzothieno[2,3-d]pyrimidin-7-carboxamide

50 mg (148 μmol) of (7S)-4-[(6-methoxy-1H-pyrazolo[3,4-b]pyridin-5-yl)amino]-5,6,7,8-tetrahydro [1] Benzothieno[2,3-d]pyrimidin-7-carboxylic acid (prepared according to Intermediate Example 34a) was similar to Example 18, using N-methylbutan-1-amine to be converted, treated and purified to give 17.1. Mg (24%) of the title compound.

¹ H-NMR (DMSO-d6): δ = 0.86-0.95 (3H), 1.27 (2H), 1.40-1.59 (2H), 1.83 (1H), 2.09 (1H), 2.85+3.07 (3H), 2.93 ( 2H), 3.03-3.45 (5H), 4.02 (3H), 8.02 (1H), 8.10 (1H), 8.41 (1H), 8.81 + 8.85 (1H), 13.38 (1H) ppm.

Example 52 (7S)-N-butyl-4-[(6-hydroxy-1H-pyrazolo[3,4-b]pyridin-5-yl)amino]-N-methyl-5,6,7, 8-tetrahydro[1]benzothieno[2,3-d]pyrimidin-7-carboxamide

42.5 mg (91 μmol) of (7S)-N-butyl-4-[(6-methoxy-1H-pyrazolo[3,4-b]pyridin-5-yl)amino]-N-methyl -5,6,7,8-Tetrahydro[1]benzothieno[2,3-d]pyrimidine-7-carboxamide (prepared according to Example 51) was similar to Example 50. Mg (16%) of the title compound.

¹ H-NMR (DMSO-d6): δ = 0.89 (3H), 1.26 (2H), 1.40-1.59 (2H), 1.85 (1H), 2.10 (1H), 2.85+3.07 (3H), 2.86-3.45 ( 7H), 8.08 (1H), 8.55 (1H), 8.89 (1H), 8.96 (1H), 12.46 (1H), 13.04 (1H) ppm.

Example 53 (7S)-4-[(6-Methoxy-1H-pyrazolo[3,4-b]pyridin-5-yl)amino]-N,N-dimethyl-5,6,7, 8-tetrahydro[1]benzothieno[2,3-d]pyrimidin-7-carboxamide

50 mg (169 μmol) of (7S)-4-[(6-methoxy-1H-pyrazolo[3,4-b]pyridin-5-yl)amino]-5,6,7,8-tetrahydro [1] Benzothieno[2,3-d]pyrimidine-7-carboxylic acid (prepared according to Intermediate Example 34a) was similar to Example 18, using N-methylmethylamine to be converted, treated and purified. 32.7 mg (43%) of the title compound.

¹ H-NMR (DMSO-d6): δ=1.82 (1H), 2.12 (1H), 2.87 (3H), 2.93 (2H), 3.10 (3H), 3.13-3.28 (3H), 4.01 (3H), 8.02 (1H), 8.10 (1H), 8.41 (1H), 8.83 (1H), 13.38 (1H) ppm.

Example 54 (7S)-4-[(6-Hydroxy-1H-pyrazolo[3,4-b]pyridin-5-yl)amino]-N,N-dimethyl-5,6,7,8- Tetrahydro[1]benzothieno[2,3-d]pyrimidin-7-carboxamide

31 mg (73 μmol) of (7S)-4-[(6-methoxy-1H-pyrazolo[3,4-b]pyridin-5-yl)amino]-N,N-dimethyl-5, 6,7,8-Tetrahydro[1]benzothieno[2,3-d]pyrimidine-7-carboxamide (prepared according to Example 53) was similar to Example 50. %) Title compound.

¹ H-NMR (DMSO-d6): δ=1.82 (1H), 2.12 (1H), 2.87 (3H), 2.90-3.02 (2H), 3.10 (3H), 3.16-3.26 (3H), 8.07 (1H) , 8.55 (1H), 8.90 (1H), 8.95 (1H), 12.47 (1H), 13.03 (1H) ppm.

Example 55 Azetidine-1-yl[(7S)-4-(1H-pyrazolo[3,4-c]pyridin-5-ylamino)-5,6,7,8-tetrahydro[1] Benzothieno[2,3-d]pyrimidin-7-yl]methanone

78 mg (213 μmol) of (7S)-4-(1H-pyrazolo[3,4-c]pyridin-5-ylamino)-5,6,7,8-tetrahydro[1]benzothieno[ 2,3-d]pyrimidine-7-carboxylic acid (according to Intermediate Example 46a) Prepared analogously to Example 18, using aziridine to afford, afforded 63.1 mg (69%) of the title compound.

¹ H-NMR (DMSO-d6): δ=1.78 (1H), 2.10 (1H), 2.21 (2H), 2.72 (1H), 2.80-2.98 (2H), 3.14-3.28 (2H), 3.88 (2H) , 4.24 (2H), 8.24 (1H), 8.34 (1H), 8.53 (1H), 8.68 (1H), 8.84 (1H), 13.50 (1H) ppm.

Example 56 (7S)-N,N-bis(2-methoxyethyl)-4-(1H-pyrazolo[3,4-c]pyridin-5-ylamino)-5,6,7,8 -tetrahydro[1]benzothieno[2,3-d]pyrimidin-7-carboxamide

100 mg (273 μmol) of (7S)-4-(1H-pyrazolo[3,4-c]pyridin-5-ylamino)-5,6,7,8-tetrahydro[1]benzothieno[ 2,3-d]pyrimidine-7-carboxylic acid (prepared according to intermediate example 46a) analogous to Example 18, using 2-methoxy-N-(2-methoxyethyl)ethylamine for conversion, treatment and purification 42.6 mg (11%) of the title compound are obtained.

¹ H-NMR (DMSO-d6): δ = 1.81 (1H), 2.07 (1H), 2.92 (2H), 3.11-3.67 (11H), 3.25 (3H), 3.26 (3H), 8.24 (1H), 8.35 (1H), 8.53 (1H), 8.68 (1H), 8.84 (1H), 13.55 (1H) ppm.

Example 57 (7S)-N-(2-methoxyethyl)-N-methyl-4-(1H-pyrazolo[3,4-c]pyridin-5-ylamino)-5,6,7 , 8-tetrahydro[1]benzothieno[2,3-d]pyrimidin-7-carboxamide

100 mg (273 μmol) of (7S)-4-(1H-pyrazolo[3,4-c]pyridin-5-ylamino)-5,6,7,8-tetrahydro[1]benzothieno[ 2,3-d]pyrimidine-7-carboxylic acid (prepared according to intermediate example 46a) was similar to Example 18, using 2-methoxy-N-methylethylamine to afford, affording 25.3mg (21%) Title compound.

¹ H-NMR (DMSO-d6): δ=1.80 (1H), 2.11 (1H), 2.87+3.12 (3H), 2.93 (2H), 3.08-3.64 (7H), 3.25+3.27 (3H), 8.24 ( 1H), 8.35 (1H), 8.54 (1H), 8.69 (1H), 8.84 (1H), 13.55 (1H) ppm.

Example 58 (7S)-N-ethyl-N-methyl-4-(1H-pyrazolo[3,4-c]pyridin-5-ylamino)-5,6,7,8-tetrahydro[1 Benzothieno[2,3-d]pyrimidine-7-carboxamide

100 mg (273 μmol) of (7S)-4-(1H-pyrazolo[3,4-c]pyridin-5-ylamino)-5,6,7,8-tetrahydro[1]benzothieno[ 2,3-d]pyrimidine-7-carboxylic acid (prepared according to intermediate Example 46a) was obtained from EtOAc (m.

¹ H-NMR (DMSO-d6): δ=1.03+1.15 (3H), 1.80 (1H), 1.78 (1H), 2.10 (1H), 2.84+3.06 (3H), 2.93 (2H), 3.08 (1H) , 3.22-3.49 (3H), 8.24 (1H), 8.35 (1H), 8.54 (1H), 8.69 (1H), 8.84 (1H), 13.55 (1H) ppm.

Example 59 (7S)-N,N-Dimethyl-4-(1H-pyrazolo[3,4-b]pyridin-5-ylamino)-5,6,7,8-tetrahydro[1]benzene Thieno[2,3-d]pyrimidin-7-carboxamide

50 mg (169 μmol) of (7S)-4-(1H-pyrazolo[3,4-b]pyridin-5-ylamino)-5,6,7,8-tetrahydro[1]benzothieno[ 2,3-d]pyrimidine-7-carboxylic acid (prepared according to intermediate Example 59a) was similar to Example 18, using N-methylmethylamine to afford to afford 30.0 mg (43%) of title compound.

¹ H-NMR (DMSO-d6): δ=1.78 (1H), 2.08 (1H), 2.87 (3H), 2.93 (2H), 3.09 (3H), 3.13-3.36 (3H), 8.13 (1H), 8.30 (1H), 8.36 (2H), 8.61 (1H), 13.60 (1H) ppm.

Example 59a (7S)-4-(1H-pyrazolo[3,4-b]pyridin-5-ylamino)-5,6,7,8-tetrahydro[1]benzothieno[2,3- d]pyrimidine-7-formic acid

5.13g (13.0mmol)(7S)-4-(1H-pyrazolo[3,4-b]pyridin-5-ylamino)-5,6,7,8-tetrahydro[1]benzothiophene And [2,3-d]pyrimidin-7-carboxylic acid ethyl ester (prepared according to Intermediate Example 59b) was obtained from EtOAc (m.).

Example 59b (7S)-4-(1H-pyrazolo[3,4-b]pyridin-5-ylamino)-5,6,7,8-tetrahydro[1]benzothieno[2,3- d]pyrimidine-7-carboxylic acid ethyl ester

5.00 g (16.8 mmol) of (7S)-4-chloro-5,6,7,8-tetrahydro[1]benzothieno[2,3-d]pyrimidin-7-carboxylic acid ethyl ester (according to an intermediate example) Preparation of 34c) Similar to Intermediate Example 34b, using 1H-pyrazolo[3,4-b]pyridine-5-amine (CAS-No. 942185-01-5), after treatment and purification, 5.05 g (72) %) Title compound.

Example 60 (7S)-N,N-Dimethyl-4-(1H-pyrazolo[3,4-c]pyridin-5-ylamino)-5,6,7,8-tetrahydro[1]benzene Thieno[2,3-d]pyrimidin-7-carboxamide

89 mg (301 μmol) (7S)-4-chloro-N,N-dimethyl-5,6,7,8-tetrahydro[1]benzothieno[2,3-d]pyrimidin-7-formamidine The amine (prepared according to intermediate example 60a) was similar to intermediate intermediate 46b, which afforded 46.4 mg (37%) of title compound.

¹ H-NMR (DMSO-d6): δ = 1.79 (1H), 2.12 (1H), 2.87 (3H), 2.93 (2H), 3.09 (3H), 3.15 (1H), 3.27 (2H), 8.24 (1H) ), 8.34 (1H), 8.54 (1H), 8.69 (1H), 8.84 (1H), 13.53 (1H) ppm.

Example 60a (7S)-4-chloro-N,N-dimethyl-5,6,7,8-tetrahydro[1]benzothieno[2,3-d]pyrimidin-7-carboxamide

2.64 g (9.82 mmol) of (7S)-4-chloro-5,6,7,8-tetrahydro[1]benzothieno[2,3-d]pyrimidine-7-carboxylic acid (prepared according to Intermediate Example 60b) Analogously to Example 18, N-methylmethylamine was used for conversion, and after workup and purification, 2.74 g (94%) of title compound.

Example 60b (7S)-4-chloro-5,6,7,8-tetrahydro[1]benzothieno[2,3-d]pyrimidin-7-carboxylic acid

5.00 g (16.8 mmol) of (7S)-4-chloro-5,6,7,8-tetrahydro[1]benzothieno[2,3-d]pyrimidin-7-carboxylic acid ethyl ester (according to an intermediate example) Preparation of 34c) Similar to the conversion of Example 11 afforded 4.35 g (96%) of title compound.

Example 61 [5-Bromo-4-(1H-pyrazolo[3,4-b]pyridin-5-ylamino)-7H-pyrrolo[2,3-d]pyrimidin-6-yl](piperidine- 1-yl)methanone

100 mg (267 μmol) of 5-bromo-4-(1H-pyrazolo[3,4-b]pyridin-5-ylamino)-7H-pyrrolo[2,3-d]pyrimidine-6-carboxylic acid (according to Intermediate Example 61a was prepared to give 20.0 mg (16%) of the title compound.

¹ H-NMR (DMSO-d6): δ=1.56 (4H), 1.63 (2H), 3.61 (4H), 8.13 (1H), 8.25 (1H), 8.46 (1H), 8.51 (1H), 8.66 (1H) ), 12.69 (1H), 13.59 (1H) ppm.

Example 61a 5-bromo-4-(1H-pyrazolo[3,4-b]pyridin-5-ylamino)-7H-pyrrolo[2,3-d]pyrimidine-6-carboxylic acid

1.71 g (4.26 mmol) of 5-bromo-4-(1H-pyrazolo[3,4-b]pyridin-5-ylamino)-7H-pyrrolo[2,3-d]pyrimidine-6-carboxylic acid Ethyl ester (prepared according to Example 12) was similar to Example 11 <EMI ID=9.1>>

Example 62 5-bromo-N-[2-(dimethylamino)ethyl]-4-[(6-methoxy-1H-pyrazolo[3,4-b]pyridin-5-yl)amino ]-N-methyl-7H-pyrrolo[2,3-d]pyrimidine-6-carboxamide

200 mg (495 μmol) contains 5-bromo-4-[(6-methoxy-1H-pyrazolo[3,4-b]pyridin-5-yl)amino]-7H-pyrrolo[2,3- d]pyrimidine-6-carboxylic acid and 5-bromo-4-[(6-hydroxy-1H-pyrazolo[3,4-b]pyridin-5-yl)amino]-7H-pyrrolo[2,3 a mixture of -d]pyrimidine-6-carboxylic acid (prepared according to intermediate example 62a) analogous to Example 18, using N,N,N'-trimethylethyl-1,2-diamine conversion, treated and purified to give 31.7 Mg (12%) of the title compound.

¹ H-NMR (DMSO-d6): δ=2.10-2.25 (6H), 3.03 (3H), 3.35-3.63 (4H), 4.12 (3H), 7.97-8.07 (1H), 8.44 (1H), 8.65- 8.75 (1H), 9.28 (1H), 13.05-13.56 (1H) ppm.

Example 62a 5-bromo-4-[(6-methoxy-1H-pyrazolo[3,4-b]pyridin-5-yl)amino]-7H-pyrrolo[2,3-d]pyrimidine-6 -formic acid (A) and 5-bromo-4-[(6-hydroxy-1H-pyrazolo[3,4-b]pyridin-5-yl)amino]-7H-pyrrolo[2,3-d Pyrimidine-6-formic acid (B)

1.65 g (3.81 mmol) contains 5-bromo-4-[(6-methoxy-1H-pyrazolo[3,4-b]pyridin-5-yl)amino]-7H-pyrrolo[2, 3-d]pyrimidine-6-carboxylic acid ethyl ester and 5-bromo-4-[(6-hydroxy-1H-pyrazolo[3,4-b]pyridin-5-yl)amino]-7H-pyrrole A mixture of [2,3-d]pyrimidin-6-carboxylic acid ethyl ester (prepared according to Intermediate Example 62b) was obtained in the same manner as in Example 11 to give 1.52 g (50%) of a mixture of title compound A and B. No separation was made.

Example 62b 5-bromo-4-[(6-methoxy-1H-pyrazolo[3,4-b]pyridin-5-yl)amino]-7H-pyrrolo[2,3-d]pyrimidine-6 -ethyl formate (A) and 5-bromo-4-[(6-hydroxy-1H-pyrazolo[3,4-b]pyridin-5-yl)amino]-7H-pyrrolo[2,3 -d]pyrimidine-6-carboxylic acid ethyl ester (B)

1.94 g (6.36 mmol) of 5-bromo-4-chloro-7H-pyrrolo[2,3-d]pyrimidine-6-carboxylic acid ethyl ester (prepared according to Intermediate Example 61c) was similar to Example 6 using 6-methoxy Conversion of yl-1H-pyrazolo[3,4-b]pyridine-5-amine (prepared according to intermediate Example 34f), after workup and purification afforded 1.65 g (60%) of a mixture of title compound A and B. Separate.

Example 63 5-bromo-N-[2-(dimethylamino)ethyl]-4-[(6-hydroxy-1H-pyrazolo[3,4-b]pyridin-5-yl)amino]- N-methyl-7H-pyrrolo[2,3-d]pyrimidin-6-carboxamide

200 mg (495 μmol) contains 5-bromo-4-[(6-methoxy-1H-pyrazolo[3,4-b]pyridin-5-yl)amino]-7H-pyrrolo[2,3- d]pyrimidine-6-carboxylic acid and 5-bromo-4-[(6-hydroxy-1H-pyrazolo[3,4-b]pyridin-5-yl)amino]-7H-pyrrolo[2,3 a mixture of -d]pyrimidine-6-carboxylic acid (prepared according to intermediate example 62a) analogous to Example 18, using N,N,N'-trimethylethyl-1,2-diamine conversion, treated and purified to give 68.6 Mg (28%) of the title compound.

¹ H-NMR (DMSO-d6): δ=2.10 (3H), 2.26 (3H), 3.02 (3H), 3.34, 3.70 (4H), 8.09 (1H), 8.16 (1H), 8.47 (1H), 9.04 (1H), 9.26-9.40 (1H), 11.78-12.63 (1H), 12.70-13.24 (1H) ppm.

Example 64 {5-Bromo-4-[(6-methoxy-1H-pyrazolo[3,4-b]pyridin-5-yl)amino]-7H-pyrrolo[2,3-d]pyrimidine- 6-yl}[4-(dimethylamino)piperidin-1-yl]methanone

200 mg (495 μmol) contains 5-bromo-4-[(6-methoxy-1H-pyrazolo[3,4-b]pyridin-5-yl)amino]-7H-pyrrolo[2,3- d]pyrimidine-6-carboxylic acid and 5-bromo-4-[(6-hydroxy-1H-pyrazolo[3,4-b]pyridin-5-yl)amino]-7H-pyrrolo[2,3 a mixture of -d]pyrimidine-6-carboxylic acid (prepared according to intermediate example 62a) analogous to Example 18, using N,N-dimethylpiperidin-4-amine to afford, afforded 32.2 mg (12%). Title compound.

¹ H-NMR (DMSO-d6): δ = 1.39 (2H), 1.79 (2H), 2.17 (6H), 2.37 (1H), 2.82-3.31 (4H), 4.10 (3H), 8.03 (1H), 8.39 (1H), 8.64 (1H), 9.28 (1H), 13.33 (1H) ppm.

Example 65 {5-Bromo-4-[(6-hydroxy-1H-pyrazolo[3,4-b]pyridin-5-yl)amino]-7H-pyrrolo[2,3-d]pyrimidine-6- }[4-(dimethylamino)piperidin-1-yl]methanone

200 mg (495 μmol) contains 5-bromo-4-[(6-methoxy-1H-pyrazolo[3,4-b]pyridin-5-yl)amino]-7H-pyrrolo[2,3- d]pyrimidine-6-carboxylic acid and 5-bromo-4-[(6-hydroxy-1H-pyrazolo[3,4-b]pyridin-5-yl)amino]-7H-pyrrolo[2,3 a mixture of -d]pyrimidine-6-carboxylic acid (prepared according to intermediate example 62a) analogous to Example 18, using N,N-dimethylpiperidin-4-amine to afford, afforded 32.2 mg (12%). Title compound.

¹ H-NMR (DMSO-d6): δ=1.39 (2H), 1.79 (2H), 2.18 (6H), 2.39 (1H), 2.83-3.69 (4H), 8.08 (1H), 8.46 (1H), 9.02 (1H), 9.30 (1H), 12.26 (1H), 13.05 (1H) ppm.

Example 66 {5-Bromo-4-[(6-methoxy-1H-pyrazolo[3,4-b]pyridin-5-yl)amino]-7H-pyrrolo[2,3-d]pyrimidine- 6-yl}[(3R)-3-methylmorpholin-4-yl]methanone

200 mg (495 μmol) contains 5-bromo-4-[(6-methoxy-1H-pyrazolo[3,4-b]pyridin-5-yl)amino]-7H-pyrrolo[2,3- d]pyrimidine-6-carboxylic acid and 5-bromo-4-[(6-hydroxy-1H-pyrazolo[3,4-b]pyridin-5-yl)amino]-7H-pyrrolo[2,3 A mixture of -d-pyrimidin-6-carboxylic acid (prepared according to Intermediate Example 62a) was similar to Example 18, using (3R)-3-methylmorpholine to afford 9.6 mg (4%) of title compound.

¹ H-NMR (DMSO-d6): δ=1.28 (3H), 3.19-3.73 (6H), 3.88 (1H), 4.11 (3H), 8.03 (1H), 8.44 (1H), 8.66 (1H), 9.26 (1H), 12.73 (1H), 13.33 (1H) ppm.

Example 67 {5-Bromo-4-[(6-methoxy-1H-pyrazolo[3,4-b]pyridin-5-yl)amino]-7H-pyrrolo[2,3-d]pyrimidine- 6-yl}(morpholin-4-yl)methanone

200 mg (495 μmol) contains 5-bromo-4-[(6-methoxy-1H-pyrazolo[3,4-b]pyridin-5-yl)amino]-7H-pyrrolo[2,3- d]pyrimidine-6-carboxylic acid and 5-bromo-4-[(6-hydroxy-1H-pyrazolo[3,4-b]pyridin-5-yl)amino]-7H-pyrrolo[2,3 A mixture of -d]pyrimidine-6-carboxylic acid (prepared according to Intermediate Example 62a) was similar to Example 18, using (3R)-3-methylmorpholine to afford to afford 28.0 mg (12%) of the title compound.

¹ H-NMR (DMSO-d6): δ=3.40-3.76 (8H), 4.11 (3H), 8.03 (1H), 8.44 (1H), 8.67 (1H), 9.25 (1H), 12.74 (1H), 13.34 (1H) ppm.

Example 68 {5-Bromo-4-[(6-hydroxy-1H-pyrazolo[3,4-b]pyridin-5-yl)amino]-7H-pyrrolo[2,3-d]pyrimidine-6- (morpholin-4-yl)methanone

200 mg (495 μmol) contains 5-bromo-4-[(6-methoxy-1H-pyrazolo[3,4-b]pyridin-5-yl)amino]-7H-pyrrolo[2,3- d]pyrimidine-6-carboxylic acid and 5-bromo-4-[(6-hydroxy-1H-pyrazolo[3,4-b]pyridin-5-yl)amino]-7H-pyrrolo[2,3 a mixture of -d]pyrimidine-6-carboxylic acid (prepared according to intermediate example 62a) analogous to Example 18, using (3R)-3-methylmorpholine conversion, treatment and After purification, 59.0 mg (26%) of title compound.

^{1 H-NMR (DMSO-d6} ): δ = 3.41-3.72 (8H), 8.08 (1H), 8.47 (1H), 9.03 (1H), 9.32 (1H), 12.41 (1H), 13.04 (1H) ppm.

Example 69 [5-Bromo-4-(1H-pyrazolo[3,4-c]pyridin-5-ylamino)-7H-pyrrolo[2,3-d]pyrimidin-6-yl][4-( Dimethylamino)piperidin-1-yl]methanone

100 mg (267 μmol) of 5-bromo-4-(1H-pyrazolo[3,4-c]pyridin-5-ylamino)-7H-pyrrolo[2,3-d]pyrimidine-6-carboxylic acid (according to Example 14 was prepared in a similar manner to Example 18, using N,N-dimethylpiperidine-4-amine as the title compound.

¹ H-NMR (DMSO-d6): δ = 1.40 (2H), 1.80 (2H), 2.19 (6H), 2.26 (1H), 2.40 (1H), 2.85-3.72 (3H), 8.26 (1H), 8.49 (1H), 8.72 (1H), 8.85 (1H), 8.87 (1H), 12.74 (1H), 13.55 (1H) ppm.

Example 70 [5-Bromo-4-(1H-pyrazolo[3,4-c]pyridin-5-ylamino)-7H-pyrrolo[2,3-d]pyrimidin-6-yl][(3R) -3-methylmorpholin-4-yl]methanone

100 mg (267 μmol) of 5-bromo-4-(1H-pyrazolo[3,4-c]pyridin-5-ylamino)-7H-pyrrolo[2,3-d]pyrimidine-6-carboxylic acid (according to Intermediate Example 14 was prepared) similar to Example 18, Conversion with (3R)-3-methylmorpholine afforded 17.1 mg (13%) of title compound.

¹ H-NMR (DMSO-d6): δ=1.29 (3H), 3.42 (2H), 3.64 (2H), 3.87 (1H), 8.28 (1H), 8.50 (1H), 8.78 (1H), 8.88 (2H) ), 12.98 (1H) ppm.

Example 71 [5-Bromo-4-(1H-pyrazolo[3,4-c]pyridin-5-ylamino)-7H-pyrrolo[2,3-d]pyrimidin-6-yl](morpholine- 4-yl)methanone

100 mg (267 μmol) of 5-bromo-4-(1H-pyrazolo[3,4-c]pyridin-5-ylamino)-7H-pyrrolo[2,3-d]pyrimidine-6-carboxylic acid (according to Intermediate Example 14 was prepared) analogous to Example 18, using morpholine, afforded to afford 27.8 mg (23%) of title compound.

¹ H-NMR (DMSO-d6): δ=3.30-3.75 (8H), 8.26 (1H), 8.50 (1H), 8.74 (1H), 8.85 (1H), 8.87 (1H), 12.85 (1H), 13.56 (1H) ppm.

Example 72 [5-Bromo-4-(1H-pyrazolo[3,4-c]pyridin-5-ylamino)-7H-pyrrolo[2,3-d]pyrimidin-6-yl](piperidine- 1-yl)methanone

100 mg (267 μmol) of 5-bromo-4-(1H-pyrazolo[3,4-c]pyridin-5-ylamino)-7H-pyrrolo[2,3-d]pyrimidine-6-carboxylic acid (according to Intermediate Example 14 was prepared to give 21.0 mg (17%) of the title compound.

¹ H-NMR (DMSO-d6): δ=1.56 (4H), 1.63 (2H), 3.37 (2H), 3.61 (2H), 8.29 (1H), 8.50 (1H), 8.75 (1H), 8.89 (1H) ), 8.93 (1H), 12.96 (1H) ppm.

Example 73 [5-Bromo-4-(1H-pyrazolo[3,4-b]pyridin-5-ylamino)-7H-pyrrolo[2,3-d]pyrimidin-6-yl][(3R) -3-methylmorpholin-4-yl]methanone

100 mg (267 μmol) of 5-bromo-4-(1H-pyrazolo[3,4-b]pyridin-5-ylamino)-7H-pyrrolo[2,3-d]pyrimidine-6-carboxylic acid (according to Intermediate Example 61a was prepared in a similar manner to Example 18, using (3R)-3-methylmorpholine, affording 23.1 mg (17%) of title compound.

¹ H-NMR (DMSO-d6): δ=1.28 (3H), 3.21-3.49 (4H), 3.53-3.75 (2H), 3.87 (1H), 8.13 (1H), 8.26 (1H), 8.47 (1H) , 8.51 (1H), 8.66 (1H), 12.74 (1H), 13.60 (1H) ppm.

Example 74 [5-Bromo-4-(1H-pyrazolo[3,4-b]pyridin-5-ylamino)-7H-pyrrolo[2,3-d]pyrimidin-6-yl](morpholine- 4-yl)methanone

100 mg (267 μmol) of 5-bromo-4-(1H-pyrazolo[3,4-b]pyridin-5-ylamino)-7H-pyrrolo[2,3-d]pyrimidine-6-carboxylic acid (according to Intermediate Example 61a was prepared) similar to Example 18, Using morpholine conversion, treatment and purification gave 33.2 mg (26%) of the title compound.

¹ H-NMR (DMSO-d6): δ=3.24-3.70 (8H), 8.13 (1H), 8.26 (1H), 8.49 (1H), 8.51 (1H), 8.66 (1H), 12.73 (1H), 13.60 (1H) ppm.

Example 75 [5-Bromo-4-(1H-pyrazolo[3,4-b]pyridin-5-ylamino)-7H-pyrrolo[2,3-d]pyrimidin-6-yl][(3S) -3-methylmorpholin-4-yl]methanone

100 mg (267 μmol) of 5-bromo-4-(1H-pyrazolo[3,4-b]pyridin-5-ylamino)-7H-pyrrolo[2,3-d]pyrimidine-6-carboxylic acid (according to Intermediate Example 61a was prepared in a similar manner to Example 18, using (3S)-3-methyl morpholine, afforded to afford 21.9 mg (17%) of the title compound.

¹ H-NMR (DMSO-d6): δ=1.28 (3H), 3.20-3.48 (4H), 3.55-3.74 (2H), 3.87 (1H), 8.13 (1H), 8.26 (1H), 8.47 (1H) , 8.51 (1H), 8.66 (1H), 12.75 (1H), 13.60 (1H) ppm.

Example 76 N-[2-(Dimethylamino)-2-oxoethyl]-4-(1H-pyrazolo[3,4-c]pyridin-5-ylamino)-7H-pyrrole [2,3-d]pyrimidine-6-carboxamide

100 mg (339 μmol) of 4-(1H-pyrazolo[3,4-c]pyridin-5-ylamino)-7H-pyrrolo[2,3-d]pyrimidine-6-carboxylic acid (prepared according to Example 11) Similar to Example 18, using N,N-dimethyl The glucosamine amide was converted, treated and purified to give 5.0 mg (4%) of the title compound.

¹ H-NMR (DMSO-d6): δ=2.87 (3H), 3.01 (3H), 3.10 (1H), 4.15 (2H), 7.59 (1H), 8.19 (1H), 8.22 (1H), 8.41 (1H) ), 8.75 (1H), 8.86 (1H), 10.22 (1H), 13.46 (1H) ppm.

Example 77 N-[2-(Dimethylamino)ethyl]-N-methyl-4-(1H-pyrazolo[3,4-c]pyridin-5-ylamino)-7H-pyrrolo[ 2,3-d]pyrimidine-6-formamide

100 mg (339 μmol) of 4-(1H-pyrazolo[3,4-c]pyridin-5-ylamino)-7H-pyrrolo[2,3-d]pyrimidine-6-carboxylic acid (prepared according to Example 11) Analogously to Example 18, N,N,N'-trimethylethyl-1,2-diamine was used for the title compound.

¹ H-NMR (DMSO-d6): δ=2.18 (6H), 2.93-3.39 (2H), 3.30 (3H), 3.62 (2H), 7.53 (1H), 8.22 (1H), 8.41 (1H), 8.84 (2H), 10.14 (1H), 12.15 (1H), 13.47 (1H) ppm.

Example 78 N-{2-[benzyl(methyl)amino]ethyl}-N-methyl-4-(1H-pyrazolo[3,4-c]pyridin-5-ylamino)-7H -pyrrolo[2,3-d]pyrimidine-6-carboxamide

50 mg (169 μmol) of 4-(1H-pyrazolo[3,4-c]pyridin-5-ylamino)-7H-pyrrolo[2,3-d]pyrimidine-6-carboxylic acid (prepared according to Example 11) Similar to Example 18, using N-benzyl- Conversion of N,N'-dimethylethyl-1,2-diamine, treatment and purification afforded 5.0 mg (6%) of title compound.

¹ H-NMR (DMSO-d6): δ = 2.17 (3H), 2.60 (2H), 3.30 (3H), 3.52 (2H), 3.68 (2H), 7.16-7.34 (5H), 7.60 (1H), 8.23 (1H), 8.41 (1H), 8.85 (2H), 10.19 (1H), 12.17 (1H), 13.49 (1H) ppm.

Example 79 2-(2-Phenylethyl)-N-(1H-pyrazolo[3,4-c]pyridin-5-yl)[1,3]thiazolo[5,4-d]pyrimidine-7- amine

40 mg (145 μmol) of 7-chloro-2-(2-phenylethyl)[1,3]thiazolo[5,4-d]pyrimidine (prepared according to Intermediate Example 79a) was similar to Intermediate Example 46b Conversion, Treatment After purification, 9.4 mg (16%) of title compound.

¹ H-NMR (DMSO-d6): δ=3.18 (2H), 3.49 (2H), 7.17-7.36 (5H), 8.26 (1H), 8.60 (1H), 8.62 (1H), 8.89 (1H), 9.26 (1H), 13.60 (1H) ppm.

Example 79a 7-Chloro-2-(2-phenylethyl)[1,3]thiazolo[5,4-d]pyrimidine

485 mg (1.89 mmol) of 2-(2-phenylethyl)[1,3]thiazolo[5,4-d]pyrimidin-7-ol (prepared according to Intermediate Example 79b) was similar to Intermediate Example 7a. After treatment and purification, 226 mg (43%)

Example 79b 2-(2-phenylethyl)[1,3]thiazolo[5,4-d]pyrimidin-7-ol

Will contain 789 mg (2.66 mmol) of N-(4,6-dichloropyrimidin-5-yl)-3-phenylpropanamide (prepared according to Intermediate Example 79c), 7.5 mL of ethanol, 203 mg of thiourea, and 35.7 μL of formic acid. The mixture was heated at 90 ° C for 12 hours. The resulting precipitate was washed with EtOAc (EtOAc) elute

Example 79c N-(4,6-dichloropyrimidin-5-yl)-3-phenylpropanamide

A mixture comprising 1.00 g (6.10 mmol) of 4,6-dichloropyrimidine-5-amine (CAS-No. 5413-85-4), 4 mL of tetrahydrofuran and 1.82 mL of 3-phenylpropionyl chloride was heated at 70 ° C. Overnight. Dichloromethane and methanol were added, the solvent was removed and the residue was purifiedjjjjjjjj

Example 80 (7S)-N-(propan-2-yl)-4-(1H-pyrazolo[3,4-c]pyridin-5-ylamino)-5,6,7,8-tetrahydro[1 Benzothieno[2,3-d]pyrimidine-7-carboxamide

100 mg (273 μmol) of (7S)-4-(1H-pyrazolo[3,4-c]pyridin-5-ylamino)-5,6,7,8-tetrahydro[1]benzothieno[ 2,3-d]pyrimidine-7-carboxylic acid (prepared according to intermediate Example 46a) was similar to Example 18, using </ RTI> </ RTI> </ RTI> <RTIgt;

¹ H-NMR (DMSO-d6): δ = 1.07 (6H), 1.83 (1H), 2.11 (1H), 2.61 (1H), 2.93 (2H), 3.15 (1H), 3.25 (1H), 3.87 (1H) ), 7.84 (1H), 8.24 (1H), 8.39 (1H), 8.53 (1H), 8.66 (1H), 8.85 (1H), 13.55 (1H) ppm.

Example 81 (7S)-N-methyl-N-propyl-4-(1H-pyrazolo[3,4-c]pyridin-5-ylamino)-5,6,7,8-tetrahydro[1 Benzothieno[2,3-d]pyrimidine-7-carboxamide

100 mg (273 μmol) of (7S)-4-(1H-pyrazolo[3,4-c]pyridin-5-ylamino)-5,6,7,8-tetrahydro[1]benzothieno[ 2,3-d]pyrimidine-7-carboxylic acid (prepared according to Intermediate Example 46a) was obtained from the title compound (m.

¹ H-NMR (DMSO-d6): δ = 0.83 + 0.87 (3H), 1.44-1.62 (2H), 1.81 (1H), 2.10 (1H), 2.85 + 3.07 (3H), 2.86-3.01 (2H), 3.09-3.41 (5H), 8.24 (1H), 8.34 (1H), 8.53 (1H), 8.68 (1H), 8.83 (1H), 13.56 (1H) ppm.

Example 82 1-{[(7S)-4-(1H-pyrazolo[3,4-c]pyridin-5-ylamino)-5,6,7,8-tetrahydro[1]benzothieno[ 2,3-d]pyrimidin-7-yl]carbonyl}azetidin-3-carbonitrile

70 mg (191 μmol) of (7S)-4-(1H-pyrazolo[3,4-c]pyridin-5-ylamino)- 5,6,7,8-Tetrahydro[1]benzothieno[2,3-d]pyrimidine-7-carboxylic acid (prepared according to Intermediate Example 46a) was similar to Example 18 using azetidine-3 - carbonitrile conversion, treatment and purification afforded 70.2 mg (81%) of the title compound.

¹ H-NMR (DMSO-d6): δ = 1.77 (1H), 2.12 (1H), 2.68-3.02 (3H), 3.12-3.42 (2H), 3.81 (1H), 4.05 (1H), 4.18 (1H) , 4.51 (2H), 8.24 (1H), 8.36 (1H), 8.53 (1H), 8.67 (1H), 8.84 (1H), 13.58 (1H) ppm.

Example 83 2-oxa-6-azaspiro[3.3]hept-6-yl[(7S)-4-(1H-pyrazolo[3,4-c]pyridin-5-ylamino)-5,6 ,7,8-tetrahydro[1]benzothieno[2,3-d]pyrimidin-7-yl]methanone

75 mg (205 μmol) of (7S)-4-(1H-pyrazolo[3,4-c]pyridin-5-ylamino)-5,6,7,8-tetrahydro[1]benzothieno[ 2,3-d]pyrimidine-7-carboxylic acid (prepared according to Intermediate Example 46a) was similar to Example 18, using 2-oxa-6- azaspiro[3.3]heptane to afford, afforded, 4%) title compound.

¹ H-NMR (DMSO-d6): δ = 1.76 (1H), 2.10 (1H), 2.71 (1H), 2.82-2.95 (2H), 3.15-3.29 (2H), 4.05 (2H), 4.41 (2H) , 4.68 (4H), 8.24 (1H), 8.36 (1H), 8.53 (1H), 8.67 (1H), 8.84 (1H), 13.53 (1H) ppm.

Example 84 [(3R)-3-(Dimethylamino)pyrrolidin-1-yl][(7S)-4-(1H-pyrazolo[3,4-c]pyridin-5-ylamino)- 5,6,7,8-tetrahydro[1]benzothieno[2,3-d]pyrimidin-7-yl]methanone

100 mg (273 μmol) of (7S)-4-(1H-pyrazolo[3,4-c]pyridin-5-ylamino)-5,6,7,8-tetrahydro[1]benzothieno[ 2,3-d]pyrimidine-7-carboxylic acid (prepared according to intermediate example 46a) was similar to Example 18, using (3R)-N,N-dimethylpyrrolidine-3-amines. Mg (72%) of the title compound.

¹ H-NMR (DMSO-d6): δ=1.60-1.84 (2H), 1.99-2.20 (9H), 2.59-2.74 (1H), 2.92-3.05 (3H), 3.17-3.65 (4H), 3.77+3.86 (1H), 8.24 (1H), 8.34 (1H), 8.53 (1H), 8.69 (1H), 8.84 (1H), 13.49 (1H) ppm.

Example 85 [(3S)-3-(Dimethylamino)pyrrolidin-1-yl][(7S)-4-(1H-pyrazolo[3,4-c]pyridin-5-ylamino)- 5,6,7,8-tetrahydro[1]benzothieno[2,3-d]pyrimidin-7-yl]methanone

100 mg (273 μmol) of (7S)-4-(1H-pyrazolo[3,4-c]pyridin-5-ylamino)-5,6,7,8-tetrahydro[1]benzothieno[ 2,3-d]pyrimidine-7-carboxylic acid (prepared according to intermediate example 46a) was similar to Example 18, using (3S)-N,N-dimethylpyrrolidine-3-amines. (78%) of the title compound.

¹ H-NMR (DMSO-d6): δ=1.58-1.83 (2H), 1.98-2.21 (9H), 2.61+2.72 (1H), 2.89-3.04 (3H), 3.18-3.46 (4H), 3.73+3.81 (1H), 8.24 (1H), 8.34 (1H), 8.54 (1H), 8.69 (1H), 8.83 (1H), 13.48 (1H) ppm.

Example 86 Morpholin-4-yl[(7S)-4-(1H-pyrazolo[3,4-c]pyridin-5-ylamino)-5,6,7,8-tetrahydro[1]benzo Thieno[2,3-d]pyrimidin-7-yl]methanone

100 mg (273 μmol) of (7S)-4-(1H-pyrazolo[3,4-c]pyridin-5-ylamino)-5,6,7,8-tetrahydro[1]benzothieno[ 2,3-d]pyrimidine-7-carboxylic acid (prepared according to intermediate Example 46a) was similar to Example 18, using morpholine, afforded to afford 67.8mg (54%) of the title compound.

¹ H-NMR (DMSO-d6): δ=1.81 (1H), 2.11 (1H), 2.87-3.04 (2H), 3.10-3.41 (3H), 3.45-3.66 (8H), 8.24 (1H), 8.34 ( 1H), 8.54 (1H), 8.69 (1H), 8.83 (1H), 13.55 (1H) ppm.

Example 87 [(3S)-3-methylmorpholin-4-yl][(7S)-4-(1H-pyrazolo[3,4-c]pyridin-5-ylamino)-5,6,7 , 8-tetrahydro[1]benzothieno[2,3-d]pyrimidin-7-yl]methanone

100 mg (273 μmol) of (7S)-4-(1H-pyrazolo[3,4-c]pyridin-5-ylamino)-5,6,7,8-tetrahydro[1]benzothieno[ 2,3-d]pyrimidine-7-carboxylic acid (prepared according to Intermediate Example 46a) was similar to Example 18, using (3S)-3-methylmorpholine, afforded to afford 24.1 mg (19%) of title compound. .

¹ H-NMR (DMSO-d6): δ=1.16+1.29 (3H), 1.79 (1H), 2.10 (1H), 2.82-4.46 (12H), 8.24 (1H), 8.32 (1H), 8.53 (1H) , 8.68 (1H), 8.83 (1H), 13.58 (1H) ppm.

Example 88 [(3R)-3-methylmorpholin-4-yl][(7S)-4-(1H-pyrazolo[3,4-c]pyridin-5-ylamino)-5,6,7 , 8-tetrahydro[1]benzothieno[2,3-d]pyrimidin-7-yl]methanone

100 mg (273 μmol) of (7S)-4-(1H-pyrazolo[3,4-c]pyridin-5-ylamino)-5,6,7,8-tetrahydro[1]benzothieno[ 2,3-d]pyrimidine-7-carboxylic acid (prepared according to intermediate example 46a) was similar to Example 18, using (3R)-3-methylmorpholine to give 27.4 mg (21%) of title compound. .

¹ H-NMR (DMSO-d6): δ=1.15+1.31 (3H), 1.87 (1H), 2.10 (1H), 2.86-4.45 (12H), 8.24 (1H), 8.34 (1H), 8.54 (1H) , 8.69 (1H), 8.83 (1H), 13.53 (1H) ppm.

Example 89 [(2R,6S)-2,6-Dimethylmorpholin-4-yl][(7S)-4-(1H-pyrazolo[3,4-c]pyridin-5-ylamino)- 5,6,7,8-tetrahydro[1]benzothieno[2,3-d]pyrimidin-7-yl]methanone

100 mg (273 μmol) of (7S)-4-(1H-pyrazolo[3,4-c]pyridin-5-ylamino)-5,6,7,8-tetrahydro[1]benzothieno[ 2,3-d]pyrimidine-7-carboxylic acid (prepared according to intermediate example 46a) was similar to Example 18, using (2R, 6S)-2,6-dimethylmorpholine, after treatment and purification afforded 13.1 mg ( 10%) title compound.

¹ H-NMR (DMSO-d6): δ = 1.10 (6H), 1.81 (1H), 2.10 (1H), 2.26 (1H), 2.76 (1H), 2.87-3.03 (2H), 3.11-3.60 (5H) , 3.95 (1H), 4.31 (1H), 8.24 (1H), 8.34 (1H), 8.54 (1H), 8.69 (1H), 8.84 (1H), 13.54 (1H) ppm.

Example 90 (4-methylpiperazin-1-yl)[(7S)-4-(1H-pyrazolo[3,4-c]pyridin-5-ylamino)-5,6,7,8-tetra Hydrogen [1] benzothieno[2,3-d]pyrimidin-7-yl]methanone

100 mg (273 μmol) of (7S)-4-(1H-pyrazolo[3,4-c]pyridin-5-ylamino)-5,6,7,8-tetrahydro[1]benzothieno[ 2,3-d]pyrimidine-7-carboxylic acid (prepared according to intermediate Example 46a) was similar to Example 18, using 1-methylpiperazine to afford, to afford 66.5 mg (52%) of the title compound.

¹ H-NMR (DMSO-d6): δ = 1.80 (1H), 2.10 (1H), 2.19 (3H), 2.27 (2H), 2.34 (2H), 2.82-3.03 (2H), 3.10-3.40 (3H) , 3.50 (2H), 3.56 (2H), 8.24 (1H), 8.33 (1H), 8.53 (1H), 8.68 (1H), 8.84 (1H), 13.55 (1H) ppm.

Example 91 [4-(Dimethylamino)piperidin-1-yl][(7S)-4-(1H-pyrazolo[3,4-c]pyridin-5-ylamino)-5,6, 7,8-tetrahydro[1]benzothieno[2,3-d]pyrimidin-7-yl]methanone

100 mg (273 μmol) of (7S)-4-(1H-pyrazolo[3,4-c]pyridin-5-ylamino)-5,6,7,8-tetrahydro[1]benzothieno[ 2,3-d]pyrimidine-7-carboxylic acid (prepared according to intermediate example 46a) was similar to Example 18, using N,N-dimethylpiperidin-4-amine to afford, 39.5 mg (29%). ) title compound.

¹ H-NMR (DMSO-d6): δ = 1.20 (1H), 1.35 (1H), 1.71-1.87 (3H), 2.10 (1H), 2.17 (6H), 2.32 (1H), 2.61 (1H), 2.84 -3.37 (6H), 4.03 (1H), 4.40 (1H), 8.24 (1H), 8.33 (1H), 8.53 (1H), 8.69 (1H), 8.84 (1H), 13.56 (1H) ppm.

Example 92 (7S)-N-ethyl-N-methyl-4-(1H-pyrazolo[3,4-b]pyridin-5-ylamino)-5,6,7,8-tetrahydro[1 Benzothieno[2,3-d]pyrimidine-7-carboxamide

80 mg (218 μmol) of (7S)-4-(1H-pyrazolo[3,4-b]pyridin-5-ylamino)-5,6,7,8-tetrahydro[1]benzothieno[ 2,3-d]pyrimidine-7-carboxylic acid (prepared according to intermediate Example 59a) was obtained from the title compound (m.

¹ H-NMR (DMSO-d6): δ=1.03+1.15 (3H), 1.81 (1H), 2.05 (1H), 2.84+3.06 (3H), 2.86-3.02 (2H), 3.08-3.39 (4H), 3.44 (1H), 8.13 (1H), 8.30 (1H), 8.34 (1H), 8.36 (1H), 8.61 (1H), 13.59 (1H) ppm.

Example 93 (7S)-N-methyl-N-propyl-4-(1H-pyrazolo[3,4-b]pyridin-5-ylamino)-5,6,7,8-tetrahydro[1 Benzothieno[2,3-d]pyrimidine-7-carboxamide

80 mg (218 μmol) of (7S)-4-(1H-pyrazolo[3,4-b]pyridin-5-ylamino)-5,6,7,8-tetrahydro[1]benzothieno[ 2,3-d]pyrimidine-7-carboxylic acid (prepared according to intermediate Example 59a) was similar to Example 18, using N-methylpropan-1-amine to afford to afford 71.6 mg (74%) of the title compound.

¹ H-NMR (DMSO-d6): δ = 0.83 + 0.87 (3H), 1.44-1.62 (2H), 1.81 (1H), 2.05 (1H), 2.85 + 3.07 (3H), 2.87-3.02 (2H), 3.08-3.40 (5H), 8.13 (1H), 8.30 (1H), 8.34 (1H), 8.36 (1H), 8.61 (1H), 13.60 (1H) ppm.

Example 94 (7S)-N-methyl-4-(1H-pyrazolo[3,4-b]pyridin-5-ylamino)-N-(3,3,3-trifluoropropyl)-5, 6,7,8-tetrahydro[1]benzothieno[2,3-d]pyrimidin-7-carboxamide

70 mg (191 μmol) of (7S)-4-(1H-pyrazolo[3,4-b]pyridin-5-ylamino)-5,6,7,8-tetrahydro[1]benzothieno[ 2,3-d]pyrimidine-7-carboxylic acid (prepared according to intermediate Example 59a) was similar to Example 18, using 3,3,3-trifluoro-N-methylpropan-1-amines as a conversion, treatment and purification. 57.1 mg (91%) of the title compound.

¹ H-NMR (DMSO-d6): δ=1.79 (1H), 2.06 (1H), 2.43-2.60 (2H), 2.87+3.12 (3H), 2.93 (2H), 3.13-3.70 (5H), 8.13 ( 1H), 8.24-8.47 (3H), 8.60 (1H), 13.59 (1H) ppm.

Example 95 (7S)-N-methyl-N-(propan-2-yl)-4-(1H-pyrazolo[3,4-b]pyridin-5-ylamino)-5,6,7,8 -tetrahydro[1]benzothieno[2,3-d]pyrimidin-7-carboxamide

80 mg (218 μmol) of (7S)-4-(1H-pyrazolo[3,4-b]pyridin-5-ylamino)-5,6,7,8-tetrahydro[1]benzothieno[ 2,3-d]pyrimidine-7-carboxylic acid (prepared according to intermediate Example 59a) was similar to Example 18, using N-methylpropan-2-amine to afford to afford 55.6 mg (57%) of the title compound.

¹ H-NMR (DMSO-d6): δ=1.05+1.18 (6H), 1.81 (1H), 2.04 (1H), 2.71+2.90 (3H), 2.84-3.35 (5H), 4.26+4.72 (1H), 8.13 (1H), 8.24-8.45 (1H), 8.30 (1H), 8.36 (1H), 8.61 (1H), 13.60 (1H) ppm.

Example 96 (7S)-N-(2-methoxyethyl)-N-methyl-4-(1H-pyrazolo[3,4-b]pyridin-5-ylamino)-5,6,7 , 8-tetrahydro[1]benzothieno[2,3-d]pyrimidin-7-carboxamide

300 mg (819 μmol) of (7S)-4-(1H-pyrazolo[3,4-b]pyridin-5-ylamino)-5,6,7,8-tetrahydro[1]benzothieno[ 2,3-d]pyrimidine-7-carboxylic acid (prepared according to intermediate Example 59a) was similar to Example 18, using 2-methoxy-N-methylethylamine to afford 241 mg (64%). Compound.

¹ H-NMR (DMSO-d6): δ=1.80 (1H), 2.06 (1H), 2.87+3.12 (3H), 2.93 (2H), 3.14-3.34 (3H), 3.25+3.28 (3H), 3.41 3.53 (3H), 3.59 (1H), 8.13 (1H), 8.22-8.42 (1H), 8.30 (1H), 8.36 (1H), 8.61 (1H), 13.60 (1H) ppm.

Example 97 Azetidin-1-yl[(7S)-4-(1H-pyrazolo[3,4-b]pyridin-5-ylamino)-5,6,7,8-tetrahydro[1] Benzothieno[2,3-d]pyrimidin-7-yl]methanone

80 mg (218 μmol) of (7S)-4-(1H-pyrazolo[3,4-b]pyridin-5-ylamino)-5,6,7,8-tetrahydro[1]benzothieno[ 2,3-d]pyrimidine-7-carboxylic acid (prepared according to intermediate Example 59a) was similar to Example 18, using az.

¹ H-NMR (DMSO-d6): δ = 1.77 (1H), 2.06 (1H), 2.22 (2H), 2.74 (1H), 2.90 (2H), 3.17 (1H), 3.32 (1H), 3.88 (2H) ), 4.17-4.32 (2H), 8.13 (1H), 8.30 (1H), 8.34 (1H), 8.36 (1H), 8.61 (1H), 13.60 (1H) ppm.

Example 98 2-oxa-6-azaspiro[3.3]hept-6-yl[(7S)-4-(1H-pyrazolo[3,4-b]pyridin-5-ylamino)-5,6 ,7,8-tetrahydro[1]benzothieno[2,3-d]pyrimidin-7-yl]methanone

75 mg (205 μmol) of (7S)-4-(1H-pyrazolo[3,4-b]pyridin-5-ylamino)-5,6,7,8-tetrahydro[1]benzothieno[ 2,3-d]pyrimidine-7-carboxylic acid (according to Intermediate Example 59a) Prepared analogously to Example 18, using 2-oxo-6- azaspiro[3.3]heptane to afford to afford 17.2 mg (18%) of the title compound.

¹ H-NMR (DMSO-d6): δ = 1.75 (1H), 2.05 (1H), 2.73 (1H), 2.89 (2H), 3.15 (1H), 3.29 (1H), 4.05 (2H), 4.38 (1H) ), 4.44 (1H), 4.67 (4H), 8.13 (1H), 8.30 (1H), 8.33 (1H), 8.36 (1H), 8.60 (1H), 13.59 (1H) ppm.

Example 99 1-{[(7S)-4-(1H-pyrazolo[3,4-b]pyridin-5-ylamino)-5,6,7,8-tetrahydro[1]benzothieno[ 2,3-d]pyrimidin-7-yl]carbonyl}azetidin-3-carbonitrile

70 mg (191 μmol) of (7S)-4-(1H-pyrazolo[3,4-b]pyridin-5-ylamino)-5,6,7,8-tetrahydro[1]benzothieno[ 2,3-d]pyrimidine-7-carboxylic acid (prepared according to intermediate Example 59a) was similar to Example 18, using azetidine-3-carbonitrile to give the title compound, 45. .

¹ H-NMR (DMSO-d6): δ=1.76 (1H), 2.08 (1H), 2.70-2.99 (3H), 3.15 (1H), 3.28 (1H), 3.81 (1H), 4.04 (1H), 4.18 (1H), 4.41-4.61 (2H), 8.13 (1H), 8.30 (1H), 8.36 (2H), 8.60 (1H), 13.61 (1H) ppm.

Example 100 [(3S)-3-(Dimethylamino)pyrrolidin-1-yl][(7S)-4-(1H-pyrazolo[3,4-b]pyridin-5-ylamino)- 5,6,7,8-tetrahydro[1]benzothieno[2,3-d]pyrimidin-7-yl]methanone

70 mg (191 μmol) of (7S)-4-(1H-pyrazolo[3,4-b]piperazin-5-ylamino)-5,6,7,8-tetrahydro[1]benzothiophene [2,3-d]pyrimidine-7-carboxylic acid (prepared according to Intermediate Example 59a) was similar to Example 18, using (3S)-N,N-dimethylpyrrolidine-3-amine, 60.2 mg (65%) of the title compound.

¹ H-NMR (DMSO-d6): δ=1.55-1.88 (2H), 1.96-2.13 (2H), 2.16 (6H), 2.54-2.76 (1H), 2.86-3.04 (4H), 3.11-3.28 (2H ), 3.51-3.82 (3H), 8.13 (1H), 8.30 (1H), 8.36 (2H), 8.60 (1H), 13.62 (1H) ppm.

Example 101 [(3R)-3-(Dimethylamino)pyrrolidin-1-yl][(7S)-4-(1H-pyrazolo[3,4-b]pyridin-5-ylamino)- 5,6,7,8-tetrahydro[1]benzothieno[2,3-d]pyrimidin-7-yl]methanone

75 mg (205 μmol) of (7S)-4-(1H-pyrazolo[3,4-b]pyridin-5-ylamino)-5,6,7,8-tetrahydro[1]benzothieno[ 2,3-d]pyrimidine-7-carboxylic acid (prepared according to Intermediate Example 59a) was similar to Example 18, using (3R)-N,N-dimethylpyrrolidine-3-amines. Mg (29%) of the title compound.

¹ H-NMR (DMSO-d6): δ=1.59-1.84 (2H), 1.97-2.14 (2H), 2.16 (6H), 2.59-2.75 (1H), 2.91-3.06 (3H), 3.12-3.64 (5H ), 3.79 + 3.89 (1H), 8.13 (1H), 8.29 (1H), 8.33 (1H), 8.36 (1H), 8.60 (1H), 13.60 (1H) ppm.

Example 102 Morpholin-4-yl[(7S)-4-(1H-pyrazolo[3,4-b]pyridin-5-ylamino)-5,6,7,8-tetrahydro[1]benzo Thieno[2,3-d]pyrimidin-7-yl]methanone

80 mg (218 μmol) of (7S)-4-(1H-pyrazolo[3,4-b]pyridin-5-ylamino)-5,6,7,8-tetrahydro[1]benzothieno[ 2,3-d]pyrimidine-7-carboxylic acid (prepared according to the intermediate Example 59a) was obtained from the title compound.

¹ H-NMR (DMSO-d6): δ = 1.82 (1H), 2.06 (1H), 2.87-3.03 (2H), 3.19 (2H), 3.32 (1H), 3.44 - 3.66 (8H), 8.13 (1H) , 8.30 (1H), 8.34 (1H), 8.36 (1H), 8.61 (1H), 13.60 (1H) ppm.

Example 103 [(3R)-3-methylmorpholin-4-yl][(7S)-4-(1H-pyrazolo[3,4-b]pyridin-5-ylamino)-5,6,7 , 8-tetrahydro[1]benzothieno[2,3-d]pyrimidin-7-yl]methanone

80 mg (218 μmol) of (7S)-4-(1H-pyrazolo[3,4-b]pyridin-5-ylamino)-5,6,7,8-tetrahydro[1]benzothieno[ 2,3-d]pyrimidine-7-carboxylic acid (prepared according to intermediate Example 59a) was similar to Example 18, using (3R)-3-methylmorpholine to afford 64.2 mg (62%) of title compound. .

¹ H-NMR (DMSO-d6): δ=1.16+1.31 (3H), 1.87 (1H), 2.03 (1H), 2.84-4.47 (12H), 8.13 (1H), 8.30 (1H), 8.33 (1H) , 8.36 (1H), 8.60 (1H), 13.60 (1H) ppm.

Example 104 [(3S)-3-methylmorpholin-4-yl][(7S)-4-(1H-pyrazolo[3,4-b]pyridin-5-ylamino)-5,6,7 , 8-tetrahydro[1]benzothieno[2,3-d]pyrimidin-7-yl]methanone

80 mg (218 μmol) of (7S)-4-(1H-pyrazolo[3,4-b]pyridin-5-ylamino)-5,6,7,8-tetrahydro[1]benzothieno[ 2,3-d]pyrimidine-7-carboxylic acid (prepared according to intermediate Example 59a) was similar to Example 18, using (3S)-3-methylmorpholine to give 75.3 mg (73%) of title compound. .

¹ H-NMR (DMSO-d6): δ=1.15+1.29 (3H), 1.79 (1H), 2.03 (1H), 2.84-4.47 (12H), 8.13 (1H), 8.30 (1H), 8.33 (1H) , 8.36 (1H), 8.60 (1H), 13.61 (1H) ppm.

Example 105 [(2R,6S)-2,6-Dimethylmorpholin-4-yl][(7S)-4-(1H-pyrazolo[3,4-b]pyridin-5-ylamino)- 5,6,7,8-tetrahydro[1]benzothieno[2,3-d]pyrimidin-7-yl]methanone

80 mg (218 μmol) of (7S)-4-(1H-pyrazolo[3,4-b]pyridin-5-ylamino)-5,6,7,8-tetrahydro[1]benzothieno[ 2,3-d]pyrimidine-7-carboxylic acid (prepared according to intermediate Example 59a) was similar to Example 18, using (2R,6S)-2,6-dimethylmorpholine, after treatment and purification afforded 74.0 mg ( 69%) title compound.

¹ H-NMR (DMSO-d6): δ = 1.10 (6H), 1.81 (1H), 2.05 (1H), 2.27 (1H), 2.77 (1H), 2.83-3.05 (2H), 3.14-3.58 (5H) , 3.95 (1H), 4.31 (1H), 8.13 (1H), 8.30 (1H), 8.36 (2H), 8.60 (1H), 13.62 (1H) ppm.

Example 106 (4-methylpiperazin-1-yl)[(7S)-4-(1H-pyrazolo[3,4-b]pyridin-5-ylamino)-5,6,7,8-tetra Hydrogen [1] benzothieno[2,3-d]pyrimidin-7-yl]methanone

80 mg (218 μmol) of (7S)-4-(1H-pyrazolo[3,4-b]pyridin-5-ylamino)-5,6,7,8-tetrahydro[1]benzothieno[ 2,3-d]pyrimidine-7-carboxylic acid (prepared according to intermediate Example 59a) was similar to Example 18, using 1-methylpiperazine to afford, affording 58.0 mg (56%) of the title compound.

¹ H-NMR (DMSO-d6): δ=1.82 (1H), 2.04 (1H), 2.19 (3H), 2.27 (2H), 2.34 (2H), 2.84-3.02 (2H), 3.12-3.43 (3H) , 3.45-3.61 (4H), 8.13 (1H), 8.23-8.46 (3H), 8.60 (1H), 13.61 (1H) ppm.

Example 107 [4-(Dimethylamino)piperidin-1-yl][(7S)-4-(1H-pyrazolo[3,4-b]pyridin-5-ylamino)-5,6, 7,8-tetrahydro[1]benzothieno[2,3-d]pyrimidin-7-yl]methanone

80 mg (218 μmol) of (7S)-4-(1H-pyrazolo[3,4-b]pyridin-5-ylamino)-5,6,7,8-tetrahydro[1]benzothieno[ 2,3-d]pyrimidine-7-carboxylic acid (prepared according to intermediate example 59a) analogous to Example 18, using N,N-dimethylpiperidin-4-amine to be converted, treated and purified To 36.4 mg (33%) of the title compound.

¹ H-NMR (DMSO-d6): δ = 1.20 (1H), 1.34 (1H), 1.70-1.89 (3H), 2.04 (1H), 2.17 (6H), 2.24-2.40 (2H), 2.61 (1H) , 2.85-3.12(3H), 3.21(2H), 4.02(1H), 4.40(1H), 8.13(1H), 8.30(1H), 8.34(1H), 8.36(1H), 8.61(1H), 13.61( 1H) ppm.

Example 108 1-({(7S)-4-[(6-methoxy-1H-pyrazolo[3,4-b]pyridin-5-yl)amino]-5,6,7,8-tetrahydro) [1] benzothieno[2,3-d]pyrimidin-7-yl}carbonyl)azetidin-3-carbonitrile

100 mg (252 μmol) of (7S)-4-[(6-methoxy-1H-pyrazolo[3,4-b]pyridin-5-yl)amino]-5,6,7,8-tetrahydro [1] Benzothieno[2,3-d]pyrimidine-7-carboxylic acid (prepared according to Intermediate Example 34a) was similar to Example 18, using azetidine-3-carbonitrile to be converted, treated and purified. 99.3 mg (81%) of the title compound.

¹ H-NMR (DMSO-d6): δ = 1.80 (1H), 2.14 (1H), 2.77 (1H), 2.83-3.01 (2H), 3.13 (1H), 3.25 (1H), 3.81 (1H), 4.01 (3H), 4.04 (1H), 4.18 (1H), 4.44 - 4.60 (2H), 8.00 (1H), 8.09 (1H), 8.41 (1H), 8.82 (1H), 13.35 (1H) ppm.

Example 109 {(7S)-4-[(6-Methoxy-1H-pyrazolo[3,4-b]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

50 mg (126 μmol) of (7S)-4-[(6-methoxy-1H-pyrazolo[3,4-b]pyridin-5-yl)amino]-5,6,7,8-tetrahydro [1] benzothieno[2,3-d]pyrimidine-7-carboxylic acid (prepared according to intermediate example 34a) analogous to Example 18, using 2-oxa-6-azaspiro[3.3]heptane, After treatment and purification, 4.5 mg (7%) of the title compound was obtained.

¹ H-NMR (DMSO-d6): δ=1.78 (1H), 2.10 (1H), 2.74 (1H), 2.82-2.96 (2H), 3.11 (1H), 3.24 (1H), 4.02 (3H), 4.06 (2H), 4.41 (2H), 4.64 - 4.73 (4H), 8.01 (1H), 8.07 (1H), 8.41 (1H), 8.83 (1H), 13.35 (1H) ppm.

Example 110 [(3R)-3-(Dimethylamino)pyrrolidin-1-yl]{(7S)-4-[(6-methoxy-1H-pyrazolo[3,4-b]pyridine- 5-yl)amino]-5,6,7,8-tetrahydro[1]benzothieno[2,3-d]pyrimidin-7-yl}methanone

100 mg (252 μmol) of (7S)-4-[(6-methoxy-1H-pyrazolo[3,4-b]pyridin-5-yl)amino]-5,6,7,8-tetrahydro [1] Benzothieno[2,3-d]pyrimidine-7-carboxylic acid (prepared according to Intermediate Example 34a) was similar to Example 18 using (3R)-N,N-dimethylpyrrolidine-3-amine After conversion, workup and purification, 70.4 mg (54%)

¹ H-NMR (DMSO-d6): δ=1.58-1.89 (2H), 1.97-2.22 (2H), 2.16 (6H), 2.55-3.67 (9H), 3.78+3.88 (1H), 4.01 (3H), 8.02 (1H), 8.10 (1H), 8.40 (1H), 8.81 + 8.83 (1H), 13.37 (1H) ppm.

Example 111 [(3S)-3-(Dimethylamino)pyrrolidin-1-yl]{(7S)-4-[(6-methoxy-1H-pyrazolo[3,4-b]pyridine- 5-yl)amino]-5,6,7,8-tetrahydro[1]benzothieno[2,3-d]pyrimidin-7-yl}methanone

100 mg (252 μmol) of (7S)-4-[(6-methoxy-1H-pyrazolo[3,4-b]pyridin-5-yl)amino]-5,6,7,8-tetrahydro [1] Benzothieno[2,3-d]pyrimidine-7-carboxylic acid (prepared according to Intermediate Example 34a) was similar to Example 18 using (3S)-N,N-dimethylpyrrolidine-3-amine After conversion, workup and purification, 94.9 mg (73%)

¹ H-NMR (DMSO-d6): δ=1.56-1.88 (2H), 1.97-2.23 (2H), 2.17 (6H), 2.53-3.86 (10H), 4.01 (3H), 8.01 (1H), 8.08 ( 1H), 8.40 (1H), 8.83 + 8.85 (1H), 13.34 (1H) ppm.

Example 112 (7S)-N-ethyl-4-[(6-hydroxy-1H-pyrazolo[3,4-b]pyridin-5-yl)amino]-N-methyl-5,6,7, 8-tetrahydro[1]benzothieno[2,3-d]pyrimidin-7-carboxamide

18.5 mg (42 μmol) of (7S)-N-ethyl-4-[(6-methoxy-1H-pyrazolo[3,4-b]pyridin-5-yl)amino]-N-methyl -5,6,7,8-tetrahydro[1]benzothieno[2,3-d]pyrimidin-7-carboxamide (prepared according to Example 39) is similar to intermediate Example 50 conversion, treatment and purification This gave 6.8 mg (36%) of the title compound.

¹ H-NMR (DMSO-d6): δ=1.02+1.14 (3H), 1.85 (1H), 2.09 (1H), 2.84+3.07 (3H), 2.86-3.03 (2H), 3.09-3.53 (5H), 8.07 (1H), 8.33 (2H), 8.55 (1H), 8.86 (1H), 8.95 (1H) ppm.

Example 113 (7S)-4-[(6-Hydroxy-1H-pyrazolo[3,4-b]pyridin-5-yl)amino]-N-methyl-N-propyl-5,6,7, 8-tetrahydro[1]benzothieno[2,3-d]pyrimidin-7-carboxamide

18.6 mg (41 μmol) (7S)-4-[(6-methoxy-1H-pyrazolo[3,4-b]pyridin-5-yl)amino]-N-methyl-N-propyl -5,6,7,8-tetrahydro[1]benzothieno[2,3-d]pyrimidin-7-carboxamide (prepared according to Example 38) is similar to intermediate Example 50 conversion, treatment and purification 5.7 mg (30%) of the title compound are obtained.

¹ H-NMR (DMSO-d6): δ=0.82+0.87 (3H), 1.42-1.64 (2H), 1.85 (1H), 2.09 (1H), 2.85+3.07 (3H), 2.86-3.04 (2H), 3.11-3.44 (5H), 8.09 (1H), 8.55 (1H), 8.88 (1H), 8.96 (1H), 12.49 (1H), 13.06 (1H) ppm.

Example 114 (7S)-4-[(6-Hydroxy-1H-pyrazolo[3,4-b]pyridin-5-yl)amino]-N-methyl-N-(propan-2-yl)-5 ,6,7,8-tetrahydro[1]benzothieno[2,3-d]pyrimidin-7-carboxamide

19.2 mg (43 μmol) of (7S)-4-[(6-methoxy-1H-pyrazolo[3,4-b]pyridin-5-yl)amino]-N-methyl-N-(propane 2-yl)-5,6,7,8-tetrahydro[1]benzothieno[2,3-d]pyrimidin-7-carboxamide (prepared according to Example 37) is similar to Intermediate Example 50 Transformation After treatment and purification, 5.1 mg (26%) of title compound was obtained.

¹ H-NMR (DMSO-d6): δ=1.01-1.22 (6H), 1.84 (1H), 2.09 (1H), 2.70+2.91 (3H), 2.83-3.23 (5H), 4.29+4.71 (1H), 8.09 (1H), 8.55 (1H), 8.88 (1H), 8.96 (1H), 12.48 (1H), 13.07 (1H) ppm.

Example 115 {(7S)-4-[(6-Hydroxy-1H-pyrazolo[3,4-b]pyridin-5-yl)amino]-5,6,7,8-tetrahydro[1]benzo Thieno[2,3-d]pyrimidin-7-yl}[(1S,4S)-2-oxa-5-azabicyclo[2.2.1]hept-5-yl]methanone

18.4 mg (39 μmol) {(7S)-4-[(6-methoxy-1H-pyrazolo[3,4-b]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 The ketone (prepared according to Example 40) was similar to Intermediate Example 50.

¹ H-NMR (DMSO-d6): δ=1.73-1.91 (3H), 2.12 (1H), 2.82-3.80 (9H), 4.60+4.85 (1H), 4.76+4.88 (1H), 8.08 (1H), 8.55 (1H), 8.86 + 8.87 (1H), 8.95 (1H), 12.45 (1H), 13.06 (1H) ppm.

Example 116 {(7S)-4-[(6-Hydroxy-1H-pyrazolo[3,4-b]pyridin-5-yl)amino]-5,6,7,8-tetrahydro[1]benzo Thieno[2,3-d]pyrimidin-7-yl}(4-methylpiperazin-1-yl)methanone

19.4 mg (41 μmol) {(7S)-4-[(6-methoxy-1H-pyrazolo[3,4-b]pyridin-5-yl)amino]-5,6,7,8- Tetrahydro[1]benzothieno[2,3-d]pyrimidin-7-yl}(4-methylpiperazin-1- Methyl ketone (prepared according to Example 42) was similar to Intermediate Example 50.

¹ H-NMR (DMSO-d6): δ = 1.83 (1H), 2.10 (1H), 2.19 (3H), 2.24 - 2.38 (4H), 2.88 (1H), 3.00 (1H), 3.12-3.29 (3H) , 3.50 (2H), 3.58 (2H), 8.08 (1H), 8.55 (1H), 8.86 (1H), 8.95 (1H), 12.40 (1H), 13.07 (1H) ppm.

Example 117 [4-(Dimethylamino)piperidin-1-yl]{(7S)-4-[(6-hydroxy-1H-pyrazolo[3,4-b]pyridin-5-yl)amino ]-5,6,7,8-tetrahydro[1]benzothieno[2,3-d]pyrimidin-7-yl}methanone

19.7 mg (39 μmol) [4-(dimethylamino)piperidin-1-yl]{(7S)-4-[(6-methoxy-1H-pyrazolo[3,4-b]pyridine -5-yl)amino]-5,6,7,8-tetrahydro[1]benzothieno[2,3-d]pyrimidin-7-yl}methanone (prepared according to Example 43) is similar to the middle The title compound 50 was converted, treated and purified to give 5.5 mg (27%).

¹ H-NMR (DMSO-d6): δ=1.22 (1H), 1.37 (1H), 1.74-1.90 (3H), 2.09 (1H), 2.22 (6H), 2.41 (1H), 2.61 (1H), 2.82 - 3.28 (6H), 4.07 (1H), 4.42 (1H), 8.09 (1H), 8.55 (1H), 8.86 (1H), 8.96 (1H), 12.43 (1H), 13.04 (1H) ppm.

Example 118 5-bromo-N-[3-(dimethylamino)propyl]-4-(1H-pyrazolo[3,4-c]pyridin-5-ylamino)-7H-pyrrolo[2 , 3-d] pyrimidine-6-formamide

Will contain 100 mg (267 μmol) of 5-bromo-4-(1H-pyrazolo[3,4-c]pyridin-5-ylamino)-7H-pyrrolo[2,3-d]pyrimidine-6-carboxylic acid (Prepared according to Example 14), 1.85 mL of dimethyl hydrazine, 67 μL of N,N-dimethylpropane-1,3-diamine, 140 μL of N-ethyl-N-isopropylpropan-2-amine and 209 mg of six A mixture of fluorophosphoric acid (1H-benzotriazol-1-yloxy)(tripyrrolidin-1-yl)anthracene was heated overnight at 50 °C. The crude mixture was purified by chromatography to give 20.5 mg (16%

¹ H-NMR (DMSO-d6): δ = 1.68 (2H), 2.16 (6H), 2.32 (2H), 3.32 (2H), 8.22 (1H), 8.26 (1H), 8.49 (1H), 8.85 (1H) ), 8.89 (1H), 8.96 (1H), 13.56 (1H) ppm.

Example 119 5-bromo-N-[3-(dimethylamino)propyl]-N-methyl-4-(1H-pyrazolo[3,4-c]pyridin-5-ylamino)-7H -pyrrolo[2,3-d]pyrimidine-6-carboxamide

100 mg (267 μmol) of 5-bromo-4-(1H-pyrazolo[3,4-c]pyridin-5-ylamino)-7H-pyrrolo[2,3-d]pyrimidine-6-carboxylic acid (according to Example 14 was prepared in a similar manner to Example 118, using N--ethyl-N,N-dimethylethyl-1,2-diamine to afford 27.0 mg (21%) of the title compound.

¹ H-NMR (DMSO-d6): δ = 1.71-1.88 (2H), 2.19 (2H), 2.31 (6H), 2.97 (3H), 3.40-3.54 (2H), 8.25 (1H), 8.48 (1H) , 8.82 (1H), 8.84 (1H), 8.90 (1H), 13.54 (1H) ppm.

Example 120 5-bromo-N-[2-(dimethylamino)ethyl]-4-(1H-pyrazolo[3,4-c]pyridin-5-ylamino)-7H-pyrrolo[2 , 3-d] pyrimidine-6-formamide

100 mg (267 μmol) of 5-bromo-4-(1H-pyrazolo[3,4-c]pyridin-5-ylamino)-7H-pyrrolo[2,3-d]pyrimidine-6-carboxylic acid (according to Example 14 was prepared in a similar manner to Example 118 using N,N-dimethylethyl-1,2-diamine to afford to afford 5.0 mg (4%) of the title compound.

¹ H-NMR (DMSO-d6): δ=2.21 (6H), 2.44 (2H), 3.40 (2H), 8.03 (1H), 8.26 (1H), 8.50 (1H), 8.85 (1H), 8.89 (1H) ), 8.97 (1H), 13.59 (1H) ppm.

Example 121 [5-Bromo-4-(1H-pyrazolo[3,4-c]pyridin-5-ylamino)-7H-pyrrolo[2,3-d]pyrimidin-6-yl][(3S) -3-methylmorpholin-4-yl]methanone

100 mg (267 μmol) of 5-bromo-4-(1H-pyrazolo[3,4-c]pyridin-5-ylamino)-7H-pyrrolo[2,3-d]pyrimidine-6-carboxylic acid (according to Example 14 was prepared in a similar manner to Example 18, using (3S)-3-methylmorpholine, affording 12.6 mg (10%) of the title compound.

^{1 H-NMR (DMSO-d6} ): δ = 1.28 (3H), 3.34-3.91 (7H), 8.26 (2H), 8.49 (1H), 8.71 (1H), 8.85 (1H), 8.87 (1H) ppm.

Example 122 N-[2-(Dimethylamino)-2-yloxyethyl]-N-methyl-7-(1H-pyrazolo[3,4-c]pyridin-5-ylamino) [1,3]thiazolo[5,4-d]pyrimidine-2-carboxamide

Will contain 100 mg (280 μmol) of N-[2-(dimethylamino)-2-oxoethyl]-N-methyl-7-(methylsulfonyl)[1,3]thiazolo[ a solution of 5,4-d]pyrimidine-2-carboxamide in dimethyl hydrazine (prepared according to intermediate example 122a) and a mixture of 37.5 mg of 1H-pyrazolo[3,4-c]pyridine-5-amine at It was heated at 140 ° C for 4 hours under microwave irradiation. The solvent was removed and the residue was purified mpqqqqqq

¹ H-NMR (DMSO-d6): δ=2.86+2.88 (3H), 3.00+3.09 (3H), 3.13+3.58 (3H), 4.39+5.02 (2H), 8.27+8.29 (1H), 8.55+8.71 (1H), 8.67+8.72 (1H), 8.91+8.92 (1H), 9.37+10.13 (1H), 13.64 (1H) ppm.

Example 122a N-[2-(Dimethylamino)-2-oxoethyl]-N-methyl-7-(methylsulfonyl)[1,3]thiazolo[5,4-d] Pyrimidine-2-carboxamide

Will contain 800 mg (2.46 mmol) of N-[2-(dimethylamino)-2-oxoethyl]-N-methyl-7-(methylthio)[1,3]thiazolo[ A mixture of 5,4-d]pyrimidine-2-carboxamide (prepared according to intermediate example 122b), 35 mL of dichloromethane and 1.41 g of 3-chloroperoxybenzoic acid (75%) was stirred at 23 ° C for 2 hours. Add 22 mL of dimethyl hydrazine and remove the dichloromethane to obtain the standard The 0.1M solution of the compound in dimethyl hydrazine.

Example 122b N-[2-(Dimethylamino)-2-oxoethyl]-N-methyl-7-(methylthio)[1,3]thiazolo[5,4-d]pyrimidine 2-carbamamine

1.00 g (4.40 mmol) of 7-(methylthio)[1,3]thiazolo[5,4-d]pyrimidine-2-carboxylic acid (prepared according to Intermediate Example 122c) was similar to Example 18 using N,N Conversion of N ² -trimethylglycine decylamine afforded 1.03 g (72%) of title compound.

Example 122c 7-(Methylthio)[1,3]thiazolo[5,4-d]pyrimidine-2-carboxylic acid

Will contain 35.2 g (146 mmol) of ethyl 7-thio[1,3]thiazolo[5,4-d]pyrimidine-2-carboxylate (prepared according to intermediate example 122d), 750 mL of aqueous sodium hydroxide (2M) and A mixture of 9.08 mL of methyl iodide was stirred overnight at 23 °C. The precipitate was collected and washed with ethanol and diethyl ether. 400 mL of water was added and the pH was adjusted to 2 by the addition of hydrochloric acid (4M). The precipitate was collected, washed with ethyl acetate and ethyl ether and evaporated

Example 122d Ethyl 7-thio[1,3]thiazolo[5,4-d]pyrimidine-2-carboxylate

To a solution of 26.4 g (135 mmol) of 5-aminopyrimidine-4,6-dithiol (prepared according to intermediate example 122e) in 720 mL of pyridine was slowly added 20.5 mL of chloro(s). Ethyl acetate and the mixture was stirred at 23 ° C for 4 hours. Remove the solvent and add water. The precipitate was collected, crystallized from EtOAc (EtOAc) elute

Example 122e 5-aminopyrimidine-4,6-dithiol

A mixture comprising 25 g (152 mmol) of 4,6-dichloropyrimidine-5-amine (CAS-No: 5413-85-4), 45.2 g of sodium thioate hydrate (1:1) and 600 mL of water was heated under reflux 3 hours. 16.9 g of sodium thiolate hydrate (1:1) was added and heating was continued for 3 hours. The mixture was neutralized and concentrated by adding concentrated hydrochloric acid under cooling. After the pH was adjusted to between 2 and 3 by the addition of hydrochloric acid (2M) under cooling, the precipitate was collected, washed with cold water and dried to give 26.4 g (88%)

Example 123 N,N-Dimethyl-7-(1H-pyrazolo[3,4-b]pyridin-5-ylamino)[1,3]thiazolo[5,4-d]pyrimidine-2-methyl Guanamine

100 mg (349 μmol) of N,N-dimethyl-7-(methylsulfonyl)[1,3]thiazolo[5,4-d]pyrimidin-2-carboxamide (prepared according to Intermediate Example 123a) Analogously to Example 122, 1H-pyrazolo[3,4-b]pyridin-5-amine was used for the title compound.

¹ H-NMR (DMSO-d6): δ=3.09 (3H), 3.56 (3H), 8.17 (1H), 8.54 (1H), 8.55 (1H), 8.76 (1H), 10.29 (1H), 13.67 (1H) )ppm.

Example 123a N,N-Dimethyl-7-(methylsulfonyl)[1,3]thiazolo[5,4-d]pyrimidine-2-carboxamide

635 mg (2.50 mmol) of N,N-dimethyl-7-(methylthio)[1,3]thiazolo[5,4-d]pyrimidin-2-carboxamide (prepared according to Intermediate Example 123b) Similar to the intermediate example 122a conversion, a 0.1 M solution of the title compound in dimethylhydrazine was obtained.

Example 123b N,N-Dimethyl-7-(methylthio)[1,3]thiazolo[5,4-d]pyrimidine-2-carboxamide

1.00 g (4.40 mmol) of 7-(methylthio)[1,3]thiazolo[5,4-d]pyrimidine-2-carboxylic acid (prepared according to Intermediate Example 122c) was similar to Example 18, using N-A The methylamine was converted, treated and purified to give 907 mg (81%) of the title compound.

Example 124 5-bromo-N-[2-(dimethylamino)ethyl]-4-(1H-pyrazolo[3,4-b]pyridin-5-ylamino)-7H-pyrrolo[2 , 3-d] pyrimidine-6-formamide

100 mg (267 μmol) of 5-bromo-4-(1H-pyrazolo[3,4-b]pyridin-5-ylamino)-7H-pyrrolo[2,3-d]pyrimidine-6-carboxylic acid (according to Intermediate Example 61a was prepared in a similar manner to Example 118, using N,N-dimethylethyl-1,2-diamine to afford to afford to afford 1.8 mg (1%) of the title compound.

¹ H-NMR (DMSO-d6): δ=2.21 (6H), 2.45 (2H), 3.40 (2H), 7.97 (1H), 8.14 (1H), 8.28 (1H), 8.56 (1H), 8.61 (1H) ), 8.67 (1H), 13.61 (1H) ppm.

Example 125 5-bromo-N-[3-(dimethylamino)propyl]-4-(1H-pyrazolo[3,4-b]pyridin-5-ylamino)-7H-pyrrolo[2 , 3-d] pyrimidine-6-formamide

100 mg (267 μmol) of 5-bromo-4-(1H-pyrazolo[3,4-b]pyridin-5-ylamino)-7H-pyrrolo[2,3-d]pyrimidine-6-carboxylic acid (according to Intermediate Example 61a was prepared in a similar manner to Example 118, which afforded 18.8 mg (14%) of title compound.

¹ H-NMR (DMSO-d6): δ = 1.68 (2H), 2.16 (6H), 2.33 (2H), 3.34 (2H), 8.14 (1H), 8.17 (1H), 8.28 (1H), 8.57 (1H) ), 8.60 (1H), 8.68 (1H), 13.61 (1H) ppm.

Example 126 Piperidin-1-yl[7-(1H-pyrazolo[3,4-b]pyridin-5-ylamino)[1,3]thiazolo[5,4-d]pyrimidin-2-yl] Ketone

100 mg (306 μmol) of [7-(methylsulfonyl)[1,3]thiazolo[5,4-d]pyrimidin-2-yl](piperidin-1-yl)methanone (according to intermediate example 126a) Preparation) Analogous to Example 122 conversion, after workup and purification afforded 32.7 mg (27%) of title compound.

¹ H-NMR (DMSO-d6): δ = 1.44-1.75 (6H), 3.65 (2H), 4.15 (2H), 8.16 (1H), 8.53 (2H), 8.74 (1H), 10.28 (1H), 13.68 (1H) ppm.

Example 126a [7-(Methylsulfonyl)[1,3]thiazolo[5,4-d]pyrimidin-2-yl](piperidin-1-yl)methanone

100 mg (306 μmol) of [7-(methylthio)[1,3]thiazolo[5,4-d]pyrimidin-2-yl](piperidin-1-yl)methanone (prepared according to Intermediate Example 126b) Similar to the intermediate instance 122a conversion, a 0.1 M solution of the title compound in dimethyl hydrazine was obtained.

Example 126b [7-(Methylthio)[1,3]thiazolo[5,4-d]pyrimidin-2-yl](piperidin-1-yl)methanone

1.00 g (4.40 mmol) of 7-(methylthio)[1,3]thiazolo[5,4-d]pyrimidine-2-carboxylic acid (prepared according to intermediate example 122c) analogous to Example 18 using a piperidine transition After treatment and purification, 998 mg (77%) of title compound.

Example 127 [5-Bromo-4-(1H-pyrazolo[3,4-b]pyridin-5-ylamino)-7H-pyrrolo[2,3-d]pyrimidin-6-yl][4-( Dimethylamino)piperidin-1-yl]methanone

100 mg (267 μmol) of 5-bromo-4-(1H-pyrazolo[3,4-b]pyridin-5-ylamino)-7H- Pyrrolo[2,3-d]pyrimidine-6-carboxylic acid (prepared according to intermediate example 61a) was similar to Example 18, using N,N-dimethylpiperidin-4-amine to be converted, treated and purified to give 21.0 mg. (15%) of the title compound.

¹ H-NMR (DMSO-d6): δ = 1.39 (2H), 1.80 (2H), 2.18 (6H), 2.38 (2H), 2.82-3.17 (2H), 3.62 (1H), 4.40 (1H), 8.13 (1H), 8.25 (1H), 8.46 (1H), 8.52 (1H), 8.66 (1H), 13.60 (1H) ppm.

Example 128 N-[2-(Dimethylamino)-2-yloxyethyl]-N-methyl-7-(1H-pyrazolo[3,4-b]pyridin-5-ylamino) [1,3]thiazolo[5,4-d]pyrimidine-2-carboxamide

100 mg (280 μmol) of N-[2-(dimethylamino)-2-oxoethyl]-N-methyl-7-(methylsulfonyl)[1,3]thiazolo[5, 4-d]pyrimidine-2-carboxamide (prepared according to intermediate example 122a).

¹ H-NMR (DMSO-d6): δ=2.75+2.86 (3H), 3.00+3.01 (3H), 3.04+3.56 (3H), 4.40+5.21 (2H), 8.17 (1H), 8.55+8.62 (2H) ), 8.78 (1H), 10.20 + 10.31 (1H), 13.66 (1H) ppm.

Example 129 N-[3-(Dimethylamino)-3-oxopropyl]-N-methyl-7-(1H-pyrazolo[3,4-b]pyridin-5-ylamino) [1,3]thiazolo[5,4-d]pyrimidine-2-carboxamide

95 mg (256 μmol) of N-[3-(dimethylamino)-3-oxopropyl]-N-methyl-7-(methylsulfonyl)[1,3]thiazolo[5, 4-d]pyrimidine-2-carboxamide (prepared according to intermediate example 129a) was similar to the compound of Example 122, which afforded 73.5 mg (64%) of title compound.

¹ H-NMR (DMSO-d6): δ=2.69+2.88 (2H), 2.79+2.83 (3H), 2.98+3.01 (3H), 3.12+3.58 (3H), 3.69+4.25 (2H), 8.17 (1H) ), 8.54 + 8.61 (1H), 8.55 + 8.80 (1H), 8.76 + 8.95 (1H), 10.29 + 10.35 (1H), 13.66 (1H) ppm.

Example 129a N-[3-(Dimethylamino)-3-oxopropyl]-N-methyl-7-(methylsulfonyl)[1,3]thiazolo[5,4-d] Pyrimidine-2-carboxamide

700 mg (2.06 mmol) of N-[3-(dimethylamino)-3-oxopropyl]]-N-methyl-7-(methylthio)[1,3]thiazolo[5, 4-d]pyrimidine-2-carboxamide (prepared according to intermediate example 129b) was similar to intermediate <RTIgt;

Example 129b N-[3-(Dimethylamino)-3-oxopropyl]-N-methyl-7-(methylthio)[1,3]thiazole [5,4-d]pyrimidine-2-carboxamide

1.00 g (4.40 mmol) of 7-(methylthio)[1,3]thiazolo[5,4-d]pyrimidine-2-carboxylic acid (prepared according to Intermediate Example 122c) was similar to Example 18 using N,N Conversion of N ³ -trimethyl-β-alanamine, 756 mg (51%) of the title compound.

Example 130 N-[2-(Dimethylamino)-2-oxoethyl]-7-[(6-methoxy-1H-pyrazolo[3,4-b]pyridin-5-yl) Amino]-N-methyl[1,3]thiazolo[5,4-d]pyrimidine-2-carboxamide

100 mg (280 μmol) of N-[2-(dimethylamino)-2-oxoethyl]-N-methyl-7-(methylsulfonyl)[1,3]thiazolo[5, 4-d]pyrimidine-2-carboxamide (prepared according to intermediate example 122a) analogous to Example 122, using 6-methoxy-1H-pyrazolo[3,4-b]pyridine-5-amine, After treatment and purification, 53.7 mg (41%) of title compound.

¹ H-NMR (DMSO-d6): δ=2.78+2.85 (3H), 2.98+3.01 (3H), 3.04+3.48 (3H), 3.92+3.96 (3H), 4.37+5.13 (2H), 8.02+8.04 (1H), 8.36+8.49 (1H), 8.51+8.53 (1H), 9.30+9.69 (1H), 13.46 (1H) ppm.

Example 131 5-bromo-N-[3-(dimethylamino)propyl]-4-[(6-methoxy-1H-pyrazolo[3,4-b]pyridin-5-yl)amino ]-N-methyl-7H-pyrrolo[2,3-d]pyrimidine-6-carboxamide

175 mg (433 μmol) contains 5-bromo-4-[(6-methoxy-1H-pyrazolo[3,4-b]pyridin-5-yl)amino]-7H-pyrrolo[2,3- d]pyrimidine-6-carboxylic acid and 5-bromo-4-[(6-hydroxy-1H-pyrazolo[3,4-b]pyridin-5-yl)amino]-7H-pyrrolo[2,3 a mixture of -d]pyrimidine-6-carboxylic acid (prepared according to intermediate example 62a) analogous to Example 118, using N'-ethyl-N,N-dimethylethyl-1,2-diamine conversion, treatment and purification After that 5.8 mg (2%) of the title compound was obtained.

¹ H-NMR (DMSO-d6): δ=1.82 (2H), 2.19-2.41 (8H), 2.97 (3H), 3.44 (2H), 4.10 (3H), 8.03 (1H), 8.18 (1H), 8.43 (1H), 8.67+8.73 (1H), 9.30 (1H), 13.28 (1H) ppm.

¹ H-NMR (DMSO-d6): δ = 1.68 (2H), 2.16 (6H), 2.33 (2H), 3.34 (2H), 8.14 (1H), 8.17 (1H), 8.28 (1H), 8.57 (1H) ), 8.60 (1H), 8.68 (1H), 13.61 (1H) ppm.

Example 132 5-bromo-N-[3-(dimethylamino)propyl]-4-[(6-hydroxy-1H-pyrazolo[3,4-b]pyridin-5-yl)amino]- N-methyl-7H-pyrrolo[2,3-d]pyrimidin-6-carboxamide

175 mg (433 μmol) contains 5-bromo-4-[(6-methoxy-1H-pyrazolo[3,4-b]pyridin-5-yl)amino]-7H-pyrrolo[2,3- d]pyrimidine-6-carboxylic acid and 5-bromo-4-[(6-hydroxy-1H-pyrazolo[3,4-b]pyridin-5-yl)amino]-7H-pyrrolo[2,3 a mixture of -d]pyrimidine-6-carboxylic acid (prepared according to intermediate example 62a) analogous to Example 118, using N'-ethyl-N,N-dimethylethyl-1,2-diamine conversion, treatment and purification This gave 19 mg (8%) of the title compound.

¹ H-NMR (DMSO-d6): δ = 1.80 (2H), 2.27 (6H), 2.43 (2H), 2.97 (3H), 3.42 (2H), 8.08 (1H), 8.45 (1H), 9.04 (1H) ), 9.35 (1H), 12.38 (1H), 13.02 (1H) ppm.

Example 133 {7-[(6-Methoxy-1H-pyrazolo[3,4-b]pyridin-5-yl)amino][1,3]thiazolo[5,4-d]pyrimidin-2- (piperidin-1-yl)methanone

100 mg (306 μmol) of [7-(methylsulfonyl)[1,3]thiazolo[5,4-d]pyrimidin-2-yl](piperidin-1-yl)methanone (according to intermediate example 126a) Preparation) Analogous to Example 122, using 6-methoxy-1H-pyrazolo[3,4-b]pyridin-5-amine to afford, afforded 51.9 mg (39%) of the title compound.

¹ H-NMR (DMSO-d6): δ=1.46-1.73 (6H), 3.61 (2H), 3.80-4.24 (2H), 3.90 (3H), 8.01 (1H), 8.37 (1H), 8.49 (1H) , 9.65 (1H), 13.45 (1H) ppm.

Example 134 {5-Bromo-4-[(6-hydroxy-1H-pyrazolo[3,4-b]pyridin-5-yl)amino]-7H-pyrrolo[2,3-d]pyrimidine-6- (piperidin-1-yl)methanone

200 mg (495 μmol) contains 5-bromo-4-[(6-methoxy-1H-pyrazolo[3,4-b]pyridin-5-yl)amino]-7H-pyrrolo[2,3- d]pyrimidine-6-carboxylic acid and 5-bromo-4-[(6-hydroxy-1H-pyrazolo[3,4-b]pyridin-5-yl)amino]-7H-pyrrolo[2,3 -d]pyrimidine-6-carboxylic acid mixture (according to Intermediate Example 62a was prepared to give 9.1 mg (4%) of the title compound.

¹ H-NMR (DMSO-d6): δ=1.47-1.69 (6H), 3.36-3.71 (4H), 8.09 (1H), 8.46 (1H), 9.02 (1H), 9.30 (1H), 12.39 (1H) , 12.75 (1H), 13.03 (1H) ppm.

Example 135 {5-Bromo-4-[(6-methoxy-1H-pyrazolo[3,4-b]pyridin-5-yl)amino]-7H-pyrrolo[2,3-d]pyrimidine- 6-yl}[(3S)-3-methylmorpholin-4-yl]methanone

200 mg (495 μmol) contains 5-bromo-4-[(6-methoxy-1H-pyrazolo[3,4-b]pyridin-5-yl)amino]-7H-pyrrolo[2,3- d]pyrimidine-6-carboxylic acid and 5-bromo-4-[(6-hydroxy-1H-pyrazolo[3,4-b]pyridin-5-yl)amino]-7H-pyrrolo[2,3 A mixture of -d]pyrimidine-6-carboxylic acid (prepared according to intermediate Example 62a) was obtained from the titled compound (yield: EtOAc).

¹ H-NMR (DMSO-d6): δ=1.28 (3H), 3.28-3.93 (7H), 4.10 (3H), 8.04 (1H), 8.44 (1H), 8.66 (1H), 9.26 (1H), 12.60 (1H), 13.30 (1H) ppm.

Example 136 (7S)-4-[(6-methoxy-1H-pyrazolo[3,4-b]pyridin-5-yl)amino]-N-methyl-N-(3,3,3- Trifluoropropyl)-5,6,7,8-tetrahydro[1]benzothieno[2,3-d]pyrimidin-7-carboxamide

100 mg (252 μmol) of (7S)-4-[(6-methoxy-1H-pyrazolo[3,4-b]pyridin-5-yl)amino]-5,6,7,8-tetrahydro [1] Benzothieno[2,3-d]pyrimidine-7-carboxylic acid (prepared according to Intermediate Example 34a) was similar to Example 18 using 3,3,3-trifluoro-N-methylpropan-1- Amine conversion, treatment and purification gave 94.0 mg (yiel.

¹ H-NMR (DMSO-d6): δ=1.82 (1H), 2.12 (1H), 2.41-2.66 (2H), 2.87+3.13 (3H), 2.92 (2H), 3.09-3.71 (5H), 4.02 ( 3H), 8.01 (1H), 8.08 (1H), 8.41 (1H), 8.81 + 8.84 (1H), 13.37 (1H) ppm.

Example 137 N-[3-(Dimethylamino)-3-oxopropyl]]-N-methyl-7-(1H-pyrazolo[3,4-c]pyridin-5-ylamino) [1,3]thiazolo[5,4-d]pyrimidine-2-carboxamide

95 mg (256 μmol) of N-[3-(dimethylamino)-3-oxopropyl]-N-methyl-7-(methylsulfonyl)[1,3]thiazolo[5, 4-d]pyrimidine-2-carboxamide (prepared according to intermediate example 129a) was similar to the Example 122 transformation using 1H-pyrazolo[3,4-c]pyridine-5-amine. Mg (3%) of the title compound.

¹ H-NMR (DMSO-d6): δ=2.74+3.00 (2H), 2.84 (3H), 2.94+3.00 (3H), 3.13+3.70 (3H), 3.73+4.19 (2H), 6.06 (2H), 6.80 + 6.83 (1H), 8.29 + 8.56 (1H), 9.12 + 9.13 (1H), 9.56 + 9.69 (1H) ppm.

Example 138 N-[3-(Dimethylamino)-3-oxopropyl]-7-[(6-methoxy-1H-pyrazolo[3,4-b]pyridin-5-yl) Amino]-N-methyl[1,3]thiazolo[5,4-d]pyrimidine-2-carboxamide

95 mg (256 μmol) of N-[3-(dimethylamino)-3-oxopropyl]-N-methyl-7-(methylsulfonyl)[1,3]thiazolo[5, 4-d]pyrimidine-2-carboxamide (prepared according to intermediate example 129a) analogous to Example 122, using 6-methoxy-1H-pyrazolo[3,4-b]pyridine-5-amine, After treatment and purification, 49.7 mg (41%) of title compound.

¹ H-NMR (DMSO-d6): δ=2.66+2.76 (2H), 2.72+2.82 (3H), 2.95+2.97 (3H), 3.08+3.31 (3H), 3.66+4.23 (2H), 3.92+3.95 (3H), 8.01+8.02 (1H), 8.38+8.52 (1H), 8.48+8.52 (1H), 9.40+9.62 (1H), 13.43 (1H) ppm.

Example 139 (7S)-4-[(6-Hydroxy-1H-pyrazolo[3,4-b]pyridin-5-yl)amino]-N-methyl-N-(3,3,3-trifluoro Propyl)-5,6,7,8-tetrahydro[1]benzothieno[2,3-d]pyrimidin-7-carboxamide

10 mg (20 μmol) of (7S)-4-[(6-methoxy-1H-pyrazolo[3,4-b]pyridin-5-yl)amino]-N-methyl-N-(3, 3,3-Trifluoropropyl)-5,6,7,8-tetrahydro[1]benzothieno[2,3-d]pyrimidin-7-carboxamide (prepared according to Example 136) is analogous to the example 50 conversion, treatment and purification To 9.0 mg (93%) of the title compound.

¹ H-NMR (DMSO-d6): δ=1.81 (1H), 2.11 (1H), 2.39-2.62 (2H), 2.87+3.13 (3H), 2.92 (2H), 3.09-3.72 (5H), 7.49 ( 1H), 8.43 (1H), 8.63 (1H), 9.77 (1H), 11.68 (1H) ppm.

Example 140 [3-(Dimethylamino)azetidin-1-yl][(7S)-4-(1H-pyrazolo[3,4-c]pyridin-5-ylamino)-5 ,6,7,8-tetrahydro[1]benzothieno[2,3-d]pyrimidin-7-yl]methanone

50 mg (136 μmol) of (7S)-4-(1H-pyrazolo[3,4-c]pyridin-5-ylamino)-5,6,7,8-tetrahydro[1]benzothieno[ 2,3-d]pyrimidine-7-carboxylic acid (prepared according to intermediate example 46a) was similar to Example 18, using N,N-dimethylazetidin-3-amine to afford, afforded 44.6 mg after treatment and purification. 69%) title compound.

¹ H-NMR (DMSO-d6): δ = 1.77 (1H), 2.09 (6H), 2.11 (1H), 2.76 (1H), 2.91 (2H), 3.05 (1H), 3.15-3.30 (2H), 3.66 (1H), 3.88 (1H), 4.04 (1H), 4.24 (1H), 8.24 (1H), 8.35 (1H), 8.53 (1H), 8.68 (1H), 8.84 (1H), 13.51 (1H) ppm.

Example 141 [3-(Dimethylamino)azetidin-1-yl]{(7S)-4-[(6-methoxy-1H-pyrazolo[3,4-b]pyridine-5 -amino)amino]-5,6,7,8-tetrahydro[1]benzothieno[2,3-d]pyrimidin-7-yl}methanone

50 mg (126 μmol) of (7S)-4-[(6-methoxy-1H-pyrazolo[3,4-b]pyridin-5-yl)amino]-5,6,7,8-tetrahydro [1] benzothieno[2,3-d]pyrimidine-7-carboxylic acid (prepared according to intermediate example 34a) analogous to Example 18, using N,N-dimethylazetidin-3-amine, After treatment and purification, 17.4 mg (27%) of title compound was obtained.

¹ H-NMR (DMSO-d6): δ = 1.80 (1H), 2.10 (6H), 2.12 (1H), 2.79 (1H), 2.90 (2H), 2.97-3.30 (3H), 3.67 (1H), 3.88 (1H), 4.02 (3H), 4.05 (1H), 4.25 (1H), 8.01 (1H), 8.08 (1H), 8.41 (1H), 8.84 (1H), 13.34 (1H) ppm.

Example 142 [3-(Dimethylamino)azetidin-1-yl][(7S)-4-(1H-pyrazolo[3,4-b]pyridin-5-ylamino)-5 ,6,7,8-tetrahydro[1]benzothieno[2,3-d]pyrimidin-7-yl]methanone

50 mg (136 μmol) of (7S)-4-(1H-pyrazolo[3,4-b]pyridin-5-ylamino)-5,6,7,8-tetrahydro[1]benzothieno[ 2,3-d]pyrimidine-7-carboxylic acid (prepared according to intermediate Example 59a) was similar to Example 18, using N,N-dimethylazetidin-3-amine to be converted, treated and purified to afford 47.5 mg ( 74%) title compound.

¹ H-NMR (DMSO-d6): δ = 1.78 (1H), 2.05 (1H), 2.08 (6H), 2.78 (1H), 2.91 (2H), 3.05 (1H), 3.16 (1H), 3.30 (1H) ), 3.66 (1H), 3.88 (1H), 4.02 (1H), 4.24 (1H), 8.13 (1H), 8.30 (1H), 8.34 (1H), 8.36 (1H), 8.61 (1H), 13.59 (1H) )ppm.

Example 143 {(7S)-4-[(6-Methoxy-1H-pyrazolo[3,4-b]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

50 mg (126 μmol) of (7S)-4-[(6-methoxy-1H-pyrazolo[3,4-b]pyridin-5-yl)amino]-5,6,7,8-tetrahydro [1] benzothieno[2,3-d]pyrimidine-7-carboxylic acid (prepared according to intermediate example 34a) analogous to Example 18, using 2-oxa-6-azaspiro[3.3]heptane, After treatment and purification, 4.5 mg (7%) of the title compound was obtained.

¹ H-NMR (DMSO-d6): δ = 1.78 (1H), 2.11 (1H), 2.73 (1H), 2.88 (2H), 3.11 (1H), 3.24 (1H), 4.02 (3H), 4.06 (2H) ), 4.42 (2H), 4.68 (4H), 8.01 (1H), 8.07 (1H), 8.41 (1H), 8.83 (1H), 13.35 (1H) ppm.

Additionally, the compounds of formula I of the present invention can be converted to any of the salts described herein using any method known to those skilled in the art. Similarly, any salt of a compound of formula I of the present invention can be converted to the free compound by any method known to those skilled in the art.

Pharmaceutical composition of the compound of the present invention

The invention also relates to pharmaceutical compositions containing one or more compounds of the invention. Such compositions can be used to achieve the desired pharmacological effect by administering to a patient in need thereof. A patient for achieving the object of the present invention is a mammal, including a human, in need of treatment for a particular condition or disease. Accordingly, the invention includes a pharmaceutical composition comprising a pharmaceutically acceptable carrier and a pharmaceutically effective amount of a compound of the invention or a salt thereof. The pharmaceutically acceptable carrier is preferably relatively non-toxic and non-toxic to the patient at concentrations effective to the active ingredient, such that A carrier that is not detrimental to the beneficial effects of the active ingredient due to any side effects of the carrier. The pharmaceutically effective amount of the compound is preferably an amount that produces an effect or exerts an effect on the particular condition being treated. The compounds of the present invention can be used in any effective conventional unit dosage form including immediate release, sustained release and time release formulations, together with pharmaceutically acceptable carriers well known in the art, orally, parenterally, Topical, nasal, ophthalmically, optic, sublingual, rectal, transvaginal, and the like.

For oral administration, the compound can be formulated into a solid or liquid preparation, such as a capsule, a pill, a lozenge, a dragee, a buccal, a flux, a powder, a solution, a suspension or an emulsion, and can be used according to the art. It is known to prepare a method for producing a pharmaceutical composition. The solid unit dosage form can be a capsule which can be a conventional hard or soft shell gelatin type capsule containing, for example, a surfactant, a lubricant, and an inert filler such as lactose, sucrose, calcium phosphate, and corn starch.

In another embodiment, a compound of the invention may be formulated with a conventional lozenge base (such as lactose, sucrose, and corn starch) in combination with the following: a binder, such as gum arabic, corn starch or gelatin. a disintegrant intended to assist in the decomposition and dissolution of the tablet after administration, such as potato starch, alginic acid, corn starch, and guar gum, tragacanth, gum arabic; Lubricant that prevents fluidity of the tablet material from sticking to the tablet mold and the surface of the punch, such as talc, stearic acid or magnesium stearate, calcium stearate or zinc stearate; A dye that is more versatile and acceptable to the patient, a coloring agent, and a flavoring such as peppermint, wintergreen oil or cherry flavoring. Excipients suitable for oral liquid dosage forms include dicalcium phosphate, and diluents such as water and alcohols such as ethanol, benzyl alcohol and polyvinyl alcohol with or without the addition of pharmaceutically acceptable surfactants, suspending agents Or an emulsifier. Various other materials may be present in the form of a coating or otherwise alter the physical form of the dosage unit. For example, a lozenge, pill or capsule may be coated with shellac, sugar or both.

Dispersible powders and granules are suitable for the preparation of aqueous suspensions. It provides active ingredients and points A powder or humectant, a suspending agent, and a mixture of one or more preservatives. Suitable dispersing or wetting agents and suspending agents are exemplified by the above-mentioned reagents. Other excipients, such as the above-described sweeteners, flavoring agents, and coloring agents, may also be present.

The pharmaceutical compositions of the invention may also be in the form of an oil-in-water emulsion. The oil phase can be a vegetable oil (such as liquid paraffin) or a mixture of vegetable oils. Suitable emulsifiers can be (1) naturally occurring gums such as acacia and tragacanth; (2) naturally occurring phospholipids such as soy and lecithin; (3) esters derived from fatty acids and hexitol anhydrides or Partial esters, such as sorbitan monooleate; (4) condensation products of such partial esters with ethylene oxide, such as polyoxyethylene sorbitan monooleate. The lotion may also contain sweeteners and flavoring agents.

An oily suspension can be formulated by suspending the active ingredient in a vegetable oil such as groundnut oil, olive oil, sesame oil or coconut oil or mineral oil such as liquid paraffin. The oily suspensions may contain a thickening agent, such as beeswax, hard paraffin or cetyl alcohol. The suspension may also contain one or more preservatives, for example ethyl p-hydroxybenzoate or n-propyl p-hydroxybenzoate; one or more coloring agents; one or more flavoring agents; and one or more sweeteners such as sucrose or saccharin.

Syrups and elixirs may be formulated with sweetening agents such as glycerol, propylene glycol, sorbitol or sucrose. These formulations may also contain a demulcent and preservative (such as methylparaben and propylparaben) as well as flavoring and coloring agents.

The compound of the present invention may also be administered parenterally in a preferred physiologically acceptable diluent and a pharmaceutical carrier, that is, subcutaneously, intravenously, intraocularly, intrasynovally, intramuscularly or intraperitoneally. (interperitoneally) administration, diluent and carrier may be a sterile liquid or liquid mixture such as water, saline, aqueous dextrose and related sugar solutions, alcohols (such as ethanol, isopropanol or cetyl alcohol), glycols ( Such as propylene glycol or polyethylene glycol), glycerol ketal (such as 2,2-dimethyl-1,1-dioxolan-4-methanol), ether (such as poly(ethylene glycol) 400), oil, Fatty acid, fatty acid ester or fatty acid glyceride or acetylated fatty acid glyceride with or without the addition of a pharmaceutically acceptable surfactant (such as soap or Detergents, suspending agents (such as gums, carbomers, methylcellulose, hydroxypropylmethylcellulose or carboxymethylcellulose) or emulsifiers and other pharmaceutical adjuvants.

Exemplary oils useful in parenteral formulations of the invention are oils of petroleum, animal, vegetable or synthetic origin, such as peanut oil, soybean oil, sesame oil, cottonseed oil, corn oil, olive oil, paraffin oil, 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 alkali metal salts, ammonium salts and triethanolamine salts of fatty acids, and suitable cleaning agents include cationic detergents such as dimethyldialkylammonium halides, alkylpyridyl halides and alkylamine acetates; anionic cleaning Agents such as alkyl, aryl and olefin sulfonates, alkyl, olefin, ether and monoglyceride sulfates and sulfosuccinates; nonionic detergents such as fatty amine oxides, fatty acid alkanols Amines and poly(oxyethylidene-oxypropyl) or ethylene oxide or propylene oxide copolymers; and amphoteric detergents such as alkyl-β-aminopropionates and 2-alkylimidazolines Grade ammonium salts and mixtures.

The parenteral compositions of the present invention typically comprise from about 0.5% to about 25% by weight of active ingredient in solution. Preservatives and buffers should also be used. To minimize or eliminate irritation to the injection site, such compositions may contain a nonionic surfactant having a hydrophilic-lipophilic balance (HLB) of preferably from about 12 to about 17. The amount of surfactant in the formulation is preferably in the range of from about 5% by weight 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.

Exemplary surfactants for use in parenteral formulations are polyethylene sorbitan fatty acid esters (eg, sorbitan monooleate) and ethylene oxide formed by condensation of propylene oxide with propylene glycol. A high molecular weight adduct of a hydrophobic matrix.

The pharmaceutical compositions may be in the form of a sterile injectable aqueous suspension. These suspensions may be formulated according to known methods using suitable dispersing or wetting agents and suspending agents such as sodium carboxymethylcellulose, methylcellulose, hydroxypropylmethylcellulose, sodium alginate , polyvinylpyrrolidone, tragacanth and acacia; dispersants or humectants may be naturally occurring a phospholipid (such as lecithin), a condensation product of an alkylene oxide with a fatty acid (such as polyoxyethylene stearate), a condensation product of ethylene oxide with a long-chain aliphatic alcohol (eg, hepta-ethyloxy ten) Hexaol), a condensation product of ethylene oxide with a partial ester derived from a fatty acid and a hexitol (such as polyoxyethylene sorbitan monooleate) or ethylene oxide and a derivative derived from a fatty acid and a hexitol anhydride. A condensation product of a partial ester (eg, 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 can 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 suspension medium. For this purpose, any bland fixed oil including synthetic mono- or diglycerides can be used. In addition, fatty acids such as oleic acid find use in the preparation of injectables.

The compositions of the invention may also be administered in the form of a suppository for rectal administration of the drug. These compositions can 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 thus melts in the rectum to release the drug. Such materials are, for example, cocoa butter and polyethylene glycol.

Another formulation used in the method of the invention employs a transdermal delivery device ("patch"). These transdermal patches can be used to continuously or discontinuously infuse a controlled amount of a compound of the invention. The construction and use of a transdermal patch for the delivery of a medicament is well known in the art (see, for example, U.S. Patent No. 5,023,252, issued toJ.S. The patches can be configured for continuous, pulsed or on-demand delivery of the medicament.

Controlled release formulations for parenteral administration include lipid polymerized microspheres and polymeric gel formulations known in the art.

It may be necessary 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 medicaments are well known in the art. For example, direct techniques for the direct administration of drugs to the brain usually involve the delivery of drugs. The tube is placed in the ventricular system of the patient to bypass the blood-brain barrier. One such implantable delivery system for delivering a medicament to a particular anatomical region of the body is described in U.S. Patent No. 5,011,472 (issued Apr. 30, 1991).

The compositions of the present invention may also contain other conventional pharmaceutically acceptable compounding ingredients (commonly referred to as carriers or diluents) as needed or desired. Conventional procedures for preparing such compositions into suitable dosage forms can be utilized. Such components and procedures include those components and procedures described in the following documents, each of which is incorporated herein by reference: Powell, MF et al., "Compendium of Excipients for Parenteral Formulations", PDA Journal of Pharmaceutical Science & Technology 1998 , 52(5), 238-311; Strickley, RG, "Parenteral Formulations of Small Molecule Therapeutics Marketed in the United States (1999)-Part-1", PDA Journal of Pharmaceutical Science & Technology 1999 , 53 ( 6), 324-349; and Nema, S. et al., "Excipients and Their Use in Injectable Products", PDA Journal of Pharmaceutical Science & Technology 1997 , 51(4), 166-171.

Common pharmaceutical ingredients that may be used to formulate compositions suitable for the intended route of administration, as appropriate, 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, trilamine, and adsorbents (examples) Including (but not limited to) powdered cellulose and activated carbon); aerosol propellants (examples include (but not limited to) carbon dioxide, CCl ₂ F ₂ , F ₂ ClC-CClF ₂ and CClF ₃ ) venting agents (examples include But not limited to) nitrogen and argon; antifungal preservatives (examples include, but are not limited to, benzoic acid, butyl paraben, ethyl p-hydroxybenzoate, methyl p-hydroxybenzoate, p-hydroxybenzoic acid Propyl ester, sodium benzoate); antimicrobial preservatives (examples include, but are not limited to, benzalkonium chloride, benzethonium chloride, benzyl alcohol, cetylpyridinium chloride , chlorobutanol, phenol, phenylethyl alcohol, nitric acid Mercury and thimerosal); antioxidants (examples include (but are not limited to) ascorbic acid, ascorbyl palmitate, butylated hydroxy methoxybenzyl, butylated hydroxytoluene, hypophosphorous acid, monothioglycerol, gallic Acid propyl ester, sodium ascorbate, sodium hydrogen sulfite, sodium formaldehyde sulfoxylate, sodium metabisulfite); bonding materials (examples include (but not limited to) block polymers, natural and synthetic rubbers, polyacrylates, Polyurethane, polyoxyl, polyoxyalkylene and styrene-butadiene copolymers; buffers (examples include, but are not limited to, potassium metaphosphate, dipotassium hydrogen phosphate, sodium acetate, anhydrous lemon Sodium citrate and sodium citrate dihydrate); carrier (examples include (but are not limited to) gum arabic syrup, aromatic syrup, aromatic elixirs, cherry syrup, cocoa syrup, orange syrup, syrup, corn oil, mineral oil, peanut oil , sesame oil, bacteriostatic sodium chloride injection and bacteriostatic water for injection); chelating agents (examples include (but not limited to) disodium edetate and ethylenediaminetetraacetic acid); colorants (examples include (but Not limited to) FD&C Red No. 3, FD&C Red No. 20, FD&C Yellow 6 No., FD&C Blue No. 2, D&C Green No. 5, D&C Orange No. 5, D&C Red No. 8, Caramel and Iron Oxide Red); clarifying agent (examples include (but not limited to) bentonite); emulsifiers (examples include But not limited to) gum arabic, cetomacrogol, cetyl alcohol, glyceryl monostearate, lecithin, sorbitan monooleate, polyoxyethylene 50 monostearate; Encapsulating agents (examples include, but are not limited to, gelatin and cellulose acetate phthalate); flavoring agents (examples include, but are not limited to, anise oil, cinnamon oil, cocoa beans, menthol, orange oil, peppermint oil) And vanilla extracts; humectants (examples include, but are not limited to, glycerin, propylene glycol, and sorbitol); water-grinding agents (examples include, but are not limited to, mineral oil and glycerin); oils (examples include (but are not limited to) groundnuts Oil, mineral oil, olive oil, peanut oil, sesame oil and vegetable oil); ointment base (examples include (but not limited to) lanolin, hydrophilic ointment, polyethylene glycol ointment, paraffin oil, hydrophilic paraffin oil, white ointment, yellow ointments and rose water ointment); penetration enhancers (transdermal delivery) (examples include (but Limited to monohydric or polyhydric alcohols, monovalent or polyvalent alcohols, saturated or unsaturated fatty alcohols, saturated or unsaturated fatty esters, saturated or unsaturated dicarboxylic acids, essential oils, phospholipid derivatives, cephalins, quinones , guanamine, ether, ketone and urea); plasticizers (examples include (but not limited to) diethyl phthalate and glycerol); solvents (examples include, but are not limited to) ethanol, corn oil, cottonseed oil, Glycerin, isopropanol, mineral oil, oleic acid, peanut oil, purified water, water for injection, sterile water for injection, and sterile water for perfusion); hardeners (examples include, but are not limited to, cetyl alcohol, cetyl alcohol wax, Microcrystalline wax, paraffin wax, stearyl alcohol, white wax and yellow wax); suppository base (examples include but not limited to cocoa butter and polyethylene glycol (mixture)); surfactants (examples include, but are not limited to, chlorination) Benzammonium chloride, nonoxynol ether 10, octetoxynol 9 (polyoxylol 80), polysorbate 80, sodium lauryl sulfate and sorbitan monopalmitate; suspension agents (examples include But not limited to) agar, bentonite, carbomer, sodium carboxymethyl cellulose, hydroxyethyl cellulose, hydroxypropyl Cellulose, hydroxypropyl methylcellulose, kaolin, methylcellulose, tragacanth, and veegum; sweeteners (examples include, but are not limited to, aspartame, Dextrose, glycerin, mannitol, propylene glycol, sodium saccharin, sorbitol and sucrose); lozenge anti-adhesives (examples include (but not limited to) magnesium stearate and talc); tablet adhesives (examples include (but not limited to) gum arabic, alginic acid, sodium carboxymethylcellulose, compressible sugar, ethyl cellulose, gelatin, liquid glucose, methylcellulose, non-crosslinked polyvinylpyrrolidone and pregelatinization Starch); tablets and capsule diluents (examples include, but are not limited to) calcium hydrogen phosphate, kaolin, lactose, mannitol, microcrystalline cellulose, powdered cellulose, precipitated calcium carbonate, sodium carbonate, sodium phosphate, sorbus Sugar alcohol and starch); tablet coating agent (examples include, but are not limited to) liquid glucose, hydroxyethyl cellulose, hydroxypropyl cellulose, hydroxypropyl methyl cellulose, methyl cellulose, ethyl fiber Su, shellac and cellulose acetate phthalate); lozenges direct compression excipients (examples package (But not limited to) calcium hydrogen phosphate); lozenges disintegrants (examples include (but are not limited to) alginic acid, carboxymethylcellulose calcium, microcrystalline cellulose, potassium mooring pull succinylcholine (polacrillin potassium), crosslinked Polyvinylpyrrolidone, sodium alginate, sodium starch glycolate and starch); lozenge slippers (examples include (but not limited to) colloidal ceria, corn starch and talc); lozenge lubricants (examples include But not limited to) calcium stearate, magnesium stearate, mineral oil, stearic acid and zinc stearate); lozenge/capsule opacifiers (examples include (but not limited to) titanium dioxide); tablet polishes (examples) Including, but not limited to, carnauba wax and white wax; thickeners (examples include, but not limited to, beeswax, cetyl alcohol, and paraffin); tonicity agents (examples include, but are not limited to, dextrose and chlorination) Sodium); tackifiers (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) ethyl seventeen extending oxycetanol, lecithin, sorbitol monooleate, polyoxyethylene Sorbitan monooleate, and polyoxyethylene stearate).

The pharmaceutical composition according to the present invention can be exemplified as follows: Sterile intravenous solution: A 5 mg/mL solution of the desired compound of the present invention can be prepared using sterile injectable water, and if necessary, the pH is adjusted. The solution was diluted to 1-2 mg/mL with sterile 5% dextrose for administration and administered by intravenous infusion over about 60 minutes.

Lyophilized powder for intravenous administration: a sterile preparation may be used (i) 100-1000 mg of the compound of the invention in the form of a lyophilized powder, (ii) 32-327 mg/mL sodium citrate, and (iii) 300-3000 mg of polydextrose 40. preparation. The formulation was reconstituted to a concentration of 10 to 20 mg/mL with 5% sterile injectable saline or dextrose, further diluted to 0.2-0.4 mg/mL with 5% saline or dextrose, and injected or rapidly intravenously. It is administered by intravenous infusion for 15-60 minutes.

Intramuscular suspension: The following solutions or suspensions can be prepared for intramuscular injection: 50 mg/mL of the water-insoluble compound required by the present invention

5mg/mL sodium carboxymethylcellulose

4mg/mL TWEEN 80

9mg/mL sodium chloride

9mg/mL benzyl alcohol

Hard shell capsules: A large number of unit capsules were prepared by filling standard two-part hard gelatin capsules with 100 mg of powdered active ingredient, 150 mg of lactose, 50 mg of cellulose and 6 mg of magnesium stearate.

Soft Gelatin Capsules: A mixture of the active ingredients in a digestible oil such as soybean oil, cottonseed oil or olive oil is prepared and injected into molten gelatin by means of a positive displacement pump to form a soft gelatin capsule containing 100 mg of the active ingredient. The capsules are washed and dried. Active ingredient Dissolved in a mixture of polyethylene glycol, glycerin and sorbitol to prepare a water-miscible pharmaceutical mixture.

Lozenges: A large amount of tablet is prepared by conventional procedures such that the dosage unit is 100 mg active ingredient, 0.2 mg colloidal ceria, 5 mg magnesium stearate, 275 mg microcrystalline cellulose, 11 mg starch, and 98.8 mg lactose. Appropriate aqueous and non-aqueous coatings can be applied to increase palatability, improve aesthetics and stability, or delay absorption.

Immediate Release Lozenges/Capsules: These dosage forms are solid oral dosage forms prepared by conventional and novel methods. These units can be administered orally in the absence of water for rapid dissolution and delivery of the drug. The active ingredient is incorporated into 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 can be compressed with a viscoelastic and thermoelastic sugar and a polymeric or sudsing component to produce a porous matrix intended for immediate release without the need for water.

Combination therapy

The term "combination" as used in the present invention is used as known to those skilled in the art and may exist in the form of a fixed combination, a non-fixed combination or a portion of a dispensing portion.

A "fixed combination" in the present invention is used as known to those skilled in the art and is defined as a combination wherein the first active ingredient is present in the unit dosage or single entity together with the second active ingredient. An example of a "fixed combination" is a pharmaceutical combination in which the first active ingredient and the second active ingredient are present in a contaminant (such as a formulation) for simultaneous administration. Another example of a "fixed combination" is a pharmaceutical combination in which the first active ingredient and the second active ingredient are present in one unit without being mixed.

The non-fixed combination or "package portion" of the present invention is used as known to those skilled in the art and is defined as wherein the first active ingredient and the second active ingredient are present in more than one The combination in the unit. An example of a set of non-fixed combinations or dispensing portions is one in which the first active ingredient and the second active ingredient are separately present. The components of the non-fixed combination or sub-assembly can be individually, sequentially, simultaneously, in parallel or in time. They are staggered in between.

The compounds of the invention may be administered as the sole 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 combinations. For example, the compounds of the invention may be combined with known chemotherapeutic or anticancer agents, such as anti-hyperproliferative or other indication agents and their analogs, as well as mixtures and combinations thereof. Other indications include, but are not limited to, anti-angiogenic agents, mitotic inhibitors, alkylating agents, antimetabolites, DNA-embedded antibiotics, growth factor inhibitors, cell cycle inhibitors, enzyme inhibitors, topoisomerase inhibition Agent, proteasome inhibitor, biological response modifier or anti-hormone.

The terms "chemotherapeutic agent" and "anticancer agent" include, but are not limited to, 131I-chTNT, abarelix, abiraterone, aclarubicin, and adiponectin. (aldesleukin), alemtuzumab, alitretinoin, altretamine, aminoglutethimide, amrubicin, amsacrine ), anastrozole, arglabin, arsenic trioxide, asparaginase, azacitidine, basiliximab, BAY 80-6946, BAY 1000394, BAY 86-9766 (RDEA 119), belonotecan, bendamustine, bevacizumab, bexarotene, bicalutamide ), bisantrene, bleomycin, bortezomib, buserelin, busulfan, cabazitaxel, calcium leucovorin, Calcium levofolinate, capecitabine, carboplatin, carmofur (carmofur) Carmustine, cartomaximab, celecoxib, celmoleukin, cetuximab, chlorambucil ), chlormadinone, chlormethine, cisplatin, cladribine (cladribine), clodronic acid, clofarabine, crisantaspase, cyclophosphamide, cyproterone, cytarabine , dacarbazine, dactinomycin, darbepoetin alfa, dasatinib, daunorubicin, decitabine, Deforolimus, degarelix, denileukin diftitox, denosumab, deslorelin, dibromochloride Dibrospidium chloride, docetaxel, doxifluridine, doxorubicin, cranberry + estrone, eculizumab, elixir Edrecolomab, elliptinium acetate, eltrombopag, endostatin, enocitabine, enzastaurin, soft Epirubicin, epitiostol, ebertin alfa, ebertin beta, ibine (ept Aplatin), eribulin, erlotinib, estradiol, estramustine, etoposide, everolimus, yixi Exemestane, fadrozole, filgrastim, fludarabine, fluorouracil, flutamide, formestane, formo Fotemustine, fulvestrant, gallium nitrate, ganirelix, gefitinib, gemcitabine, gemtuzumab, oxidized glutathione Glutoxim), goserelin, histamine dihydrochloride, histrelin, hydroxycarbamide, I-125 seed, ibandronic acid, Ibritumomab tiuxetan, idarubicin, ifosfamide, imatinib, imiquimod, improsulfan, Interferon alpha, interferon beta, interferon gamma, ipilimumab, irinotecan (irinotecan), ixabepilone, lanreotide, lapatinib, larotaxel, lenalidomide, lenograstim , lentinan, letrozole, leuprorelin, levamisole, lisuride, lobaplatin, lomustine, Lonidamine, masoprocol, medroxyprogesterone, megestrol, melphalan, mepitiostane, mercaptopurine, Methotrexate, methoxsalen, Methyl aminolevulinate, methyltestosterone, mifamurtide, miltefosine, Miriplatin, mitobronitol, mitoguazone, mitolactol, mitomycin, mitotan, mitoxantrone Mitoxantrone), nedaplatin, nelarabine, nilotinib Nilutamide, nimotuzumab, nimustine, nitracrine, novolimus, umvazumab (ofatumumab), Austria Meprazole, oprelvekin, oxaliplatin, p53 gene therapy, paclitaxel, palifermin, palladium-103 seed, pamidronate Acid (pamidronic acid), panitumumab, pazopanib, pegaspargase, PEG-Ebertin beta (methoxy PEG-Ebertin beta), Paifei Pegfilgrastim, peginterferon alpha-2b (peginterferon alfa-2b), pemetrexed, pentazocine, pentostatin, and pilomycin (peplomycin), perfosfamide, perifosine, picibanil, pirarubicin, plerixafor, procamycin ), poliglusam, polyestradiol phosphate, and more Sugar-K, porfimer sodium, pralatrexate, prednimustine, procarbazine, quinagolide, raloxifene, Raltitrexed, ranimustine, rapamycin, razoxane, regorafenib, risedronic acid, rituximab ( Rituximab), romidepsin, romiplostim, sagopilone, sargramostim, selumetinib, xipuliangsai-T ( sipuleucel-T), sizofiran, sobuzuxane, sodium glycididazole, sorafenib, streptozocin, sunitinib (sunitinib), talaporfin (talaporfin), tamibarrotene, tamoxifen, tasonermin, teceleukin, tegafur (tegafur) , flupiridine + gimeracil + oteracil, temoporfin, temozolomide, temsirolimus Temsirolimus), teniposide, testosterone, tetrofosmin, thalidomide, thiotepa, thymalfasin, thioguanine ), tocilizumab, topotecan, toremifene, tositumomab, trabectedin, trametinib , trastuzumab, treosulfan, tretinoin, triciribine, trilostane, triptorelin, kojen Amine (trofosfamide), tryptophan, ubenimex, valrubicin, vandetanib, vapreotide, vemurafenib, vinblastine (vinblastine), vincristine, vindesine, vinflunine, vinorelbine, vorinostat, vorozole, 钇-90 Glass microspheres, zinostatin, zinostatin stimalamer, zoledron 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-0623, GDC-0941, GDC-0973, GDC- 0980, 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 "anticancer agent" also include protein therapeutics, such as interferon (eg, interferon alpha, interferon beta or interferon gamma) super-promoting monoclonal antibodies, Tuebingen, TRP-1. Protein vaccine, colostrin, anti-FAP antibody, YH-16, gemtuzumab, infliximab, cetuximab, trastuzumab, and dinisin Tos, rituximab, thymosin alpha 1, bevacizumab, mecasermin, mecasermin rinfabate, oprisminin, that Natalizumab, rhMBL, MFE-CP1+ZD-2767-P, ABT-828, ErbB2-specific immunotoxin, SGN-35, MT-103, rinfabate, AS-1402, B43 - genistein (B43-genistein), radioimmunotherapy agent based on L-19, AC-9301, NY-ESO-1 vaccine, IMC-1C11, CT-322, rhCC10, r(m)CRP, MORAb-009 , aviscurin (aviscumine), MDX-1307, Her-2 vaccine, APC-8024, NGR-hTNF, rhH1.3, IGN-311, endostatin, volociximab, PRO-1762, come to sand single Anti- (lexatumumab), SGN-40, pertuzumab, EMD-273063, L19-IL-2 fusion protein, PRX-321, CNTO-328, MDX-214, tigapotide, CAT-3888, labetuzumab, alpha-particle-emitting radioisotope-linked lintuzumab, EM-1421, super HyperAcute vaccine, tukotuzumab celmoleukin, galiximab, HPV-16-E7, Javelin-prostate cancer, melanin Javelin-melanoma, NY-ESO-1 vaccine, EGF vaccine, CYT-004-MelQbG10, WT1 peptide, orgoviromab, ofatumumab, zarum Anti-zalutumumab, cintredekin besudotox, WX-G250, albumin, affercept, denosumab, vaccine, CTP -37, efungumab or 131I-chTNT-1/B.

The terms "chemotherapeutic agent" and "anticancer agent" also include monoclonal antibodies suitable for use as protein therapeutics, such as morozumab-CD3 (muromonab-CD3), abciximab, and ecitazumab. (edrecolomab), daclizumab, gentuzumab, alemtuzumab, ibritumomab, cetuximab, bevacizumab ), efalizumab, adalimumab, omalizumab, muramomab-CD3, rituximab, daclizumab , trastuzumab, palivizumab, basiliximab, and infliximab.

In general, the combination of a cytotoxic agent and/or a cytostatic agent in combination with a compound or composition of the invention can be used to: (1) produce a reduction in tumor growth or even tumor elimination as compared to administration of only any agent Good efficacy; (2) administration of a smaller amount of chemotherapeutic agent; (3) providing harmful pharmacological complications less than complications observed with single-agent chemotherapy and some other combination therapies, thereby providing good patient Tolerant chemotherapeutic treatment; (4) to provide a wider range of different types of cancer to mammals, especially humans (5) providing a higher response rate in the patient being treated; (6) providing a longer survival period than the standard chemotherapy treatment in the patient being treated; (7) providing longer tumor progression; and / Or (8) producing at least as good efficacy and tolerability results as those of the other agents alone, in combination with other cancer agents that produce an antagonistic effect.

Method of making cells sensitive to radiation

In a unique embodiment of the invention, the compounds of the invention are useful for sensitizing cells to radiation. That is, treatment of cells with a compound of the invention prior to irradiation treatment of the cells renders the cells more susceptible to DNA damage and cell death than if the cells were not treated with any of the compounds of the invention. In one aspect, the cells are 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 invention are administered to a cell in combination with conventional radiation therapy.

The invention also provides a method of making cells more susceptible to cell death, wherein the cells are treated with one or more compounds of the invention prior to treatment of the cells 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, thereby achieving inhibition of normal cell function or killing of cells. .

In one embodiment, the cells are killed by treating the cells with at least one DNA damaging agent. That is, after treating the cells with one or more compounds of the invention such that the cells are sensitive to cell death, the cells are treated with at least one DNA damaging agent to kill the cells. DNA damaging agents suitable for use 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 cell signaling pathways Pathway, which causes DNA damage when activated; inhibits cell signaling pathways that cause DNA damage when the pathway is inhibited; and induces biochemical changes in cells that cause DNA damage. By way of non-limiting example, DNA repair pathways in cells can be inhibited, thereby preventing repair of DNA damage and resulting in abnormal accumulation of DNA damage in the cells.

In one aspect of the invention, a compound of the invention is administered to a cell prior to inducing DNA damage in the cell by radiation or otherwise. In another aspect of the invention, the compounds of the invention are administered to cells while inducing DNA damage in the cells by radiation or other means. In yet another aspect of the invention, the compounds of the invention are administered to cells immediately after initiation of radiation or otherwise induced DNA damage in the cells.

In another aspect, the cells are in vitro. In another embodiment, the cells are in vivo.

As mentioned above, it has surprisingly been found that the compounds of the present invention are effective in inhibiting MKNK1 and are therefore useful for treating or preventing diseases of uncontrolled cell growth, proliferation and/or survival, inappropriate cellular immune responses or inappropriate cellular inflammatory responses; Diseases that control cell growth, proliferation and/or survival, inappropriate cellular immune responses, or inappropriate cellular inflammatory responses, particularly uncontrolled cell growth, proliferation and/or survival, inappropriate cellular immune responses, or inappropriate cellular inflammatory responses mediated by MKNK1 Diseases, such as hematological tumors, solid tumors and/or their metastases, such as leukemia and myelodysplastic syndromes, malignant lymphomas, head and neck tumors (including brain tumors and brain metastases), chest tumors (including non-small cell lung tumors and small cells) Lung neoplasms), gastrointestinal tumors, endocrine tumors, breast and other gynecological tumors, urinary tumors (including kidney tumors, bladder tumors and prostate tumors), skin tumors and sarcomas and/or their metastases.

Thus, according to another aspect, the invention encompasses a compound of formula I , or a stereoisomer, tautomer, N-oxide, hydrate, solvate or salt thereof, as described and defined herein, especially A pharmaceutically acceptable salt thereof or a mixture of such substances for use in the treatment or prevention of a disease as mentioned above.

Thus, another particular aspect of the invention is a compound of the above formula I , or a stereoisomer, tautomer, N-oxide, hydrate, solvate or salt thereof, especially pharmaceutically acceptable The use of a salt or a mixture of such substances for the prevention or treatment of a disease.

Accordingly, another particular aspect of the invention is the use of a compound of formula I above for the manufacture of a pharmaceutical composition for the treatment or prevention of a disease.

The diseases mentioned in the first two paragraphs are diseases of uncontrolled cell growth, proliferation and/or survival, inappropriate cellular immune responses or inappropriate cell inflammatory responses, or accompanied by uncontrolled cell growth, proliferation and/or survival, inappropriate cells. Immune response or disease of inappropriate cell inflammatory response, especially uncontrolled cell growth, proliferation and/or survival, inappropriate cellular immune response or inappropriate cell inflammatory response by MKNK1 mediated diseases such as hematological tumors, solid tumors and/or metastases thereof Such as leukemia and myelodysplastic syndromes, 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 and other Gynecological tumors, urinary tumors (including kidney tumors, bladder tumors, and prostate tumors), skin tumors and sarcomas and/or their metastases.

In the context of the present invention, particularly in the context of "inappropriate cellular immune response or inappropriate cellular inflammatory response", the term "inappropriate" as used herein is understood to mean preferably that the response is less than or exceeds the normal response and is associated with such diseases. The pathology is associated with, causing or causing the pathology of such diseases.

A preferred use is in the treatment or prevention of a disease wherein the disease is a hematological tumor, a solid tumor and/or its metastasis.

Method for treating hyperproliferative disorders

The present invention relates to a method of treating a hyperproliferative disorder in a mammal using the compounds of the invention and compositions thereof. The compounds are useful for inhibiting, blocking, reducing, reducing, etc., and/or producing apoptosis of cell proliferation and/or cell division. The method comprises, in an amount effective to treat the condition, a compound of the invention or a pharmaceutically acceptable salt thereof, isomerized The body, polymorph, metabolite, hydrate, solvate or ester is administered to a mammal in need thereof, including humans. Hyperproliferative disorders include, but are not limited to, for example, psoriasis, keloids and other hyperproliferation affecting the skin; benign prostatic hyperplasia (BPH); solid tumors such as breast cancer, respiratory cancer, brain cancer, genital cancer, digestive tract cancer, urinary Cancer, eye cancer, liver cancer, skin cancer, head and neck cancer, thyroid cancer, parathyroid cancer and their distant metastasis. These conditions also include lymphoma, sarcoma and leukemia. These conditions also include lymphoma, sarcoma and leukemia.

Examples of breast cancer include, but are not limited to, invasive breast ductal carcinoma, invasive lobular carcinoma, ductal carcinoma in situ, and lobular carcinoma in situ.

Examples of respiratory cancer include, but are not limited to, small cell lung cancer and non-small cell lung cancer, as well as bronchial adenomas and pleural pulmonary blastomas.

Examples of brain cancer include, but are not limited to, brainstem and hypothalamic gliomas, cerebellum and cerebral astrocytoma, chorioblastoma, ependymoma, and neuroectoderm and pineal tumors.

Male reproductive organ tumors include, but are not limited to, prostate cancer and testicular cancer. Tumors of the female reproductive organs include, but are not limited to, endometrial cancer, cervical cancer, ovarian cancer, vaginal cancer, and genital cancer, as well as uterine sarcoma.

Gastrointestinal tumors include, but are not limited to, anal cancer, colon cancer, colorectal cancer, esophageal cancer, gallbladder cancer, gastric cancer, pancreatic cancer, rectal cancer, small intestine cancer, and salivary gland cancer.

Urinary tract tumors include, but are not limited to, bladder cancer, penile cancer, kidney cancer, renal pelvic cancer, ureteral cancer, urethral cancer, and human papillary renal cancer.

Eye cancer includes, but is not limited to, intraocular melanoma and retinoblastoma.

Examples of liver cancer include, but are not limited to, hepatocellular carcinoma (hepatocellular carcinoma with or without fibrolamellar variation), cholangiocarcinoma (intrahepatic cholangiocarcinoma), and mixed hepatocyte cholangiocarcinoma.

Skin cancer includes, but is not limited to, squamous cell carcinoma, Kaposi's sarcoma, malignant melanoma, Merkel cell skin cancer, and non- Melanoma skin cancer.

Head and neck cancer includes, but is not limited to, laryngeal cancer, hypopharyngeal cancer, nasopharyngeal cancer, oropharyngeal cancer, lip and oral cancer, and squamous cell carcinoma. Lymphomas include, but are not limited to, AIDS-associated lymphoma, non-Hodgkin's lymphoma, cutaneous T-cell lymphoma, Burkitt lymphoma, Hodgkin's disease ( Hodgkin's disease) and central nervous system lymphoma.

Sarcomas include, but are not limited to, soft tissue sarcoma, osteosarcoma, malignant fibrous histiocytoma, lymphosarcoma, and rhabdomyosarcoma.

Leukemias include, but are not limited to, acute myeloid leukemia, acute lymphoblastic leukemia, chronic lymphocytic leukemia, chronic myelogenous leukemia, and hairy cell leukemia.

Such conditions have been well characterized in humans and are also present in similar sources in other mammals and can be treated by administration of the pharmaceutical compositions of the invention.

The term "treatment" as used throughout the text is used in the conventional sense, for example, to treat or care for an individual for the purpose of combating, alleviating, reducing, alleviating, ameliorating a disease or condition, such as a cancerous tumor, and the like.

Method of treating a kinase disorder

The invention also provides methods of treating disorders associated with aberrant mitogen-extracellular kinase activity, including but not limited to stroke, heart failure, hepatomegaly, cardiac hypertrophy, diabetes, Alzheimer's disease, cysts Sexual fibrosis, symptoms of xenograft rejection, septic shock or asthma.

An effective amount of a compound of the invention can be used to treat such conditions, including those diseases (e.g., cancer) as mentioned in the [Prior Art] section above. Nonetheless, regardless of the mechanism of action and/or the relationship between the kinase and the condition, such cancers and other diseases can be treated with the compounds of the invention.

The phrase "abnormal kinase activity" or "abnormal serine sulphate kinase activity" includes any abnormal expression or activity of a gene encoding a kinase or a polypeptide encoded by the gene. The exception Examples of activities include, but are not limited to, overexpression of a gene or polypeptide; gene amplification; mutations that produce constitutive or hyperactive kinase activity; gene mutations, deletions, substitutions, additions, and the like.

The invention also provides a method of inhibiting kinase activity, particularly mitogen extracellular kinase activity, comprising administering an effective amount of a compound of the invention, including salts, polymorphs, metabolites, hydrates, solvates thereof, Drugs such as esters and their diastereomeric forms. It is possible to inhibit kinase activity in cells (e.g., in vitro) or in a mammalian subject in need of treatment, particularly in a human patient.

Dosage and administration

Based on standard laboratory techniques known for assessing compounds useful in the treatment of hyperproliferative disorders and angiogenic disorders, by standard toxicity testing and standard pharmacological analysis for the treatment of conditions identified above in mammals, And, as a result of comparing the results with known agents for treating such conditions, an effective dosage of a compound of the invention for treating various desired indications can be readily determined. The amount of active ingredient administered to treat such a condition can vary greatly depending on factors such as 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 condition being treated Nature and extent.

The total amount of active ingredient to be administered is generally in the range of from about 0.001 mg to about 200 mg per kg of body weight per day and preferably from about 0.01 mg to about 20 mg per kg of body weight per day. Clinically useful dosing schedules range from one to three times a day to once every four weeks. In addition, the "drug holiday" (which does not give the patient's medication for a certain period of time) may be beneficial to the overall balance between pharmacological effects and tolerance. A unit dose may contain from about 0.5 mg to about 1500 mg of active ingredient and may be administered one or more times a day or less than once a day. The average daily dose administered by injection (including intravenous, intramuscular, subcutaneous and parenteral injection) and by infusion techniques is preferably from 0.01 to 200 mg per kg of total body weight. The average daily rectal dosage regimen is preferably from 0.01 to 200 mg per kg of total body weight. The average daily vaginal dose regimen is preferred It is 0.01 to 200 mg in weight per kg. The average daily topical dosage regimen is preferably from 0.1 to 200 mg, and the number of administrations per day is between one and four times. The transdermal concentration is preferably a concentration required to maintain a daily dose of 0.01 to 200 mg/kg. The average daily inhalation dosage regimen is preferably from 0.01 to 100 mg per kg of total body weight.

Of course, the specific initial and continuous dosing regimen for each patient will be based on the nature and severity of the condition as determined by the attending physician, the activity of the particular compound employed, the age and overall condition of the patient, the time of administration, the route of administration, the rate of drug excretion, The drug combination and its similar factors vary. The number of doses of the desired mode of treatment and the compound of the invention or a pharmaceutically acceptable salt or ester or composition thereof can be determined by those skilled in the art using conventional therapeutic tests.

The disease of the method is preferably a blood tumor, a solid tumor and/or a metastasis thereof.

The compounds of the invention are especially useful for the treatment and prevention (i.e., prevention) of tumor growth and metastasis, particularly in solid tumors of all indications and stages with or without tumor growth pretreatment.

Methods of testing specific pharmacological or pharmaceutical properties are well known to those skilled in the art.

The example test experiments described herein are illustrative of the invention and the invention is not limited to the examples obtained.

Biological analysis

Test the example one or more times in the selected bioanalytical. When more than one test is performed, the data is reported as an average or median, where 平均值 also known as the mean of the arithmetic mean represents the sum of the values obtained divided by the number of tests, and ̇ the median is expressed in increasing or decreasing order. The middle number of the value group when arranging. If the number of values in the data set is odd, the median is the intermediate value. If the number of values in the data set is even, the median is the arithmetic mean of the two intermediate values.

The instance will be synthesized one or more times. When more than one synthesis is performed, the data from the bioanalyze represents the average or median calculated using the data set obtained by 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 as described in the following paragraphs.

Glutathione-S-transferase (GST, N-terminal) and human full-length MKNK1 (registered number BAA) expressed in baculovirus expression system and purified by glutathione sepharose affinity chromatography in insect cells The recombinant fusion protein line of amino acid 1-424 and T344D) of 19885.1 was purchased from Carna Biosciences (Product No. 02-145) and used as an enzyme. The biotin-labeled peptide biotin-Ahx-IKKRKLTRRKSLKG (C-terminal in the guanamine form) was used as a substrate for the kinase reaction, which is commercially available, for example, from Biosyntan (Berlin-Buch, Germany).

For the analysis, 50 nL of the test compound was taken up in a 100-fold concentrated solution in DMSO to a black low-capacity 384-well microtiter plate (Greiner Bio-One, Frickenhausen, Germany), and MKNK1 was added to the aqueous assay buffer [50 mM HEPES pH 7.5, ₂ μL of solution in 5 mM MgCl ₂ , 1.0 mM dithiothreitol, 0.005% (v/v) Nonidet-P40 (Sigma) and the mixture was incubated at 22 ° C for 15 minutes to allow testing of compound pre-binding before the start of the kinase reaction To the enzyme. This was followed by the addition of adenosine triphosphate (ATP, 16.7 μM = >5 μL final concentration in the assay volume of 10 μM) and the substrate (0.1 μM = >5 μL final concentration in the assay volume of 0.06 μM) in a 3 μL solution in assay buffer. The kinase reaction was started and the resulting mixture was incubated at 22 ° C for a reaction time of 45 minutes. The concentration of MKNK1 is adjusted depending on the activity of the enzyme batch and is selected to allow the analysis to be in the linear range, typically in the range of 0.05 μg/ml. By adding TR-FRET detection reagent (5nM streptavidin-XL665 [Cisbio Bioassays, Codolet, France] and 1nM anti-ribosomal protein S6 (pSer236) antibody (from Invitrogen) [# 44921G] and 1nM LANCE EU- The W1024-labeled protein G [Perkin-Elmer, product number AD0071] was stopped in 5 μL of a solution of EDTA in water (100 mM EDTA, 0.1% (w/v) bovine serum albumin in 50 mM HEPES pH 7.5).

The resulting mixture was incubated at 22 ° C for 1 hour to form a complex between the phosphorylated biotin-labeled peptide and the detection reagent. Subsequently, the amount of phosphorylated host was assessed by measuring the resonance energy transfer of the Eu chelating agent to streptavidin-XL. Therefore, the amount of fluorescence emission at 620 nm and 665 nm after excitation at 350 nm was measured with a TR-FRET reader, such as Rubystar (BMG Labtechnologies, Offenburg, Germany) or Viewlux (Perkin-Elmer). The ratio of the amount of emission at 665 nm to 622 nm is considered a measure of the amount of phosphorylated host. Corrected data (enzyme reaction without inhibitor = 0% inhibition, all other analysis components except enzyme = 100% inhibition). Typically, 11 different concentrations (20 μM, 5.9 μM, 1.7 μM, 0.51 μM, 0.15 μM, 44 nM, 13 nM, 3.8 nM, 1.1 nM, 0.33 nM, and 0.1 nM) in the range of 20 μM to 0.1 nM on the same microtiter plate. Test compounds were tested by serial dilution of each of the serial dilutions prepared in 1: DMSO at a level of 100 times concentrated solution in DMSO (two values were obtained for each concentration), and by 4 Parameter fitting, using homemade software to calculate IC ₅₀ values.

High ATP analysis of MKNK1 kinase

MKNK1 inhibitory activity at high ATP after pre-incubation of a compound of the invention with MKNK1 was quantified using a TR-FRET based MKNK1 high ATP assay as described in the following paragraphs.

Glutathione-S-transferase (GST, N-terminal) and human full-length MKNK1 (registered number BAA) expressed in baculovirus expression system and purified by glutathione sepharose affinity chromatography in insect cells The recombinant fusion protein line of amino acid 1-424 and T344D) of 19885.1 was purchased from Carna Biosciences (Product No. 02-145) and used as an enzyme. The biotin-labeled peptide biotin-Ahx-IKKRKLTRRKSLKG (C-terminal in the guanamine form) was used as a substrate for the kinase reaction, which is commercially available, for example, from Biosyntan (Berlin-Buch, Germany).

For the analysis, 50 nL of the test compound was taken up in a 100-fold concentrated solution in DMSO to a black low-capacity 384-well microtiter plate (Greiner Bio-One, Frickenhausen, Germany), and MKNK1 was added to the aqueous assay buffer [50 mM HEPES pH 7.5, ₂ μL of solution in 5 mM MgCl ₂ , 1.0 mM dithiothreitol, 0.005% (v/v) Nonidet-P40 (Sigma) and the mixture was incubated at 22 ° C for 15 minutes to allow testing of compound pre-binding before the start of the kinase reaction To the enzyme. This was followed by the addition of adenosine triphosphate (ATP, 3.3 mM = > 5 μL final concentration in the assay volume of 2 mM) and the substrate (0.1 μM = > 5 μL final concentration in the assay volume of 0.06 μM) in a 3 μL solution in assay buffer. The kinase reaction was started and the resulting mixture was incubated at 22 ° C for a reaction time of 30 minutes. The concentration of MKNK1 is adjusted depending on the activity of the enzyme lot and is selected to allow the analysis to be in the linear range, typically in the range of 0.003 μg/mL. By adding TR-FRET detection reagent (5nM streptavidin-XL665 [Cisbio Bioassays, Codolet, France] and 1nM anti-ribosomal protein S6 (pSer236) antibody (from Invitrogen) [# 44921G] and 1nM LANCE EU- The W1024-labeled protein G [Perkin-Elmer, product number AD0071] was stopped in 5 μL of a solution of EDTA in water (100 mM EDTA, 0.1% (w/v) bovine serum albumin in 50 mM HEPES pH 7.5).

The resulting mixture was incubated at 22 ° C for 1 hour to form a complex between the phosphorylated biotin-labeled peptide and the detection reagent. Subsequently, the amount of phosphorylated host was assessed by measuring the resonance energy transfer of the Eu chelating agent to streptavidin-XL. Therefore, the amount of fluorescence emission at 620 nm and 665 nm after excitation at 350 nm was measured with a TR-FRET reader, such as Rubystar (BMG Labtechnologies, Offenburg, Germany) or Viewlux (Perkin-Elmer). The ratio of the amount of emission at 665 nm to 622 nm is considered a measure of the amount of phosphorylated host. Corrected data (enzyme reaction without inhibitor = 0% inhibition, all other analysis components except enzyme = 100% inhibition). Typically, 11 different concentrations in the range of 20 μM to 0.1 nM on the same microtiter plate (eg 20 μM, 5.9 μM, 1.7 μM, 0.51 μM, 0.15 μM, 44 nM, 13 nM, 3.8 nM, 1.1 nM, 0.33 nM and 0.1) nM, test compound was tested by serial dilution of each successive serial dilution in DMSO at a level of 100 times concentrated solution in DMSO (according to the pipette used) Values) and calculate the IC ₅₀ value. The data is presented in Table 1.

MKNK 2 Kinase High ATP Analysis

MKNK2 inhibitory activity at high ATP after pre-incubation of a compound of the invention with MKNK2 was quantified using a TR-FRET based MKNK2 high ATP assay as described in the following paragraphs.

Use of baculovirus expression system expression in insect cells, glutathione-S-transfer purified via glutathione agarose gel affinity chromatography and activated in vitro with MAPK12 The recombinant fusion protein of the enzyme (GST, N-terminus) and human full-length MKNK2 (Genbank Accession No. NP_060042.2) was purchased from Invitrogen (Product No. PV5608) and used as an enzyme. The biotin-labeled peptide biotin-Ahx-IKKRKLTRRKSLKG (C-terminal in the guanamine form) was used as a substrate for the kinase reaction, which is commercially available, for example, from Biosyntan (Berlin-Buch, Germany).

For analysis, 50 nl of the test compound in 100-fold concentrated solution in DMSO was pipetted into a black low volume 384-well microtiter plate (Greiner Bio-One, Frickenhausen, Germany), and MKNK 2 was added to the aqueous assay buffer [50 mM HEPES pH 7.5 ₂ μL of solution in 5 mM MgCl ₂ , 1.0 mM dithiothreitol, 0.005% (v/v) Nonidet-P40 (G-Biosciences, St. Louis, USA) and the mixture was incubated at 22 ° C for 15 minutes to allow The test compound is pre-bound to the enzyme prior to the start of the kinase reaction. This was followed by the addition of adenosine triphosphate (ATP, 3.3 mM = > 5 μl final concentration in the assay volume of 2 mM) and the substrate (0.1 μM = > 5 μl final concentration in the assay volume of 0.06 μM) in a 3 μl solution in assay buffer. The kinase reaction was started and the resulting mixture was incubated at 22 ° C for a reaction time of 30 minutes. The concentration of MKNK 2 is adjusted depending on the activity of the enzyme batch and is selected to allow the analysis to be in the linear range, typically in the range of 0.0045 μg/ml. By adding TR-FRET detection reagent (5nM streptavidin-XL665 [Cisbio Bioassays, Codolet, France] and 1nM anti-ribosomal protein S6 (pSer236) antibody (from Invitrogen) [# 44921G] and 1nM LANCE EU- The W1024-labeled protein G [Perkin-Elmer, product number AD0071] was stopped in 5 μL of a solution of EDTA in water (100 mM EDTA, 0.1% (w/v) bovine serum albumin in 50 mM HEPES pH 7.5).

The resulting mixture was incubated at 22 ° C for 1 hour to form a complex between the phosphorylated biotin-labeled peptide and the detection reagent. The amount of phosphorylated host was then assessed by measuring the resonance energy transfer of the Eu chelating agent to streptavidin-XL665. Therefore, the amount of fluorescence emission at 620 nm and 665 nm after excitation at 350 nm was measured with a TR-FRET reader, such as Pherastar (BMG Labtechnologies, Offenburg, Germany) or Viewlux (Perkin-Elmer). The ratio of the amount of emission at 665 nm to 622 nm is considered a measure of the amount of phosphorylated host. Corrected data (enzyme reaction without inhibitor = 0% inhibition, all other analysis components except enzyme = 100% inhibition). Typically, 11 different concentrations in the range of 20 μM to 0.1 nM on the same microtiter plate (eg 20 μM, 5.9 μM, 1.7 μM, 0.51 μM, 0.15 μM, 44 nM, 13 nM, 3.8 nM, 1.1 nM, 0.33 nM and 0.1) nM, test compound was tested by serial dilution of each successive serial dilution in DMSO at a level of 100 times concentrated solution in DMSO (according to the pipette used) Values) and calculate the IC ₅₀ value.

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) affinity-purified from human carcinoma A431 cells (Sigma-Aldrich, #E3641) was used as a kinase. The biotin-labeled peptide biotin-Ahx-AEEEEYFELVAKKK (C-terminal in the guanamine form) was used as a substrate for the kinase reaction, which is commercially available, for example, from Biosynthan GmbH (Berlin-Buch, Germany).

For the analysis, 50 nL of the test compound was taken up in a 100-fold concentrated solution in DMSO to a black low-capacity 384-well microtiter plate (Greiner Bio-One, Frickenhausen, Germany), and EGFR was added to the aqueous solution [50 mM Hepes/HCl pH 7.0, ₂ μL of 1 mM MgCl ₂ , 5 mM MnCl ₂ , 0.5 mM activated sodium orthovanadate, 0.005% (v/v) Tween-20] and the mixture was incubated at 22 ° C for 15 minutes to allow testing of the compound before the start of the kinase reaction. Bind to the enzyme. This was followed by the addition of adenosine triphosphate (ATP, 16.7 μM = >5 μL final concentration in the assay volume of 10 μM) and the substrate (1.67 μM = >5 μL final concentration in the assay volume of 1 μM) in a 3 μL solution in assay buffer. The kinase reaction was started and the resulting mixture was incubated at 22 ° C for a reaction time of 30 minutes. The concentration of EGFR is adjusted depending on the activity of the enzyme lot and is selected to allow the analysis to be in the linear range, typically in the range of 3 U/ml. By adding HTRF detection reagent (0.1 μM streptavidin-XL665 [Cis Biointernational] and 1 nM PT66-Tb chelating agent (a chelating agent-labeled anti-phosphotyrosinate antibody (from Cis Biointernational)) [also PT66-Eu-crypts from Perkin Elmer can be used instead of PT66-Tb chelating agent] 5 μl in EDTA aqueous solution (80 mM EDTA, 0.2% (w/v) bovine serum albumin in 50 mM HEPES pH 7.5) The solution stops the reaction.

The resulting mixture was incubated at 22 ° C for 1 hour to allow the biotin-labeled phosphorylated peptide to bind to the streptavidin-XL665 and PT66-Eu chelating agents. The amount of phosphorylated host was then assessed by measuring the resonance energy transfer of the PT66-Eu chelating agent to streptavidin-XL665. Thus, the amount of fluorescence emission at 620 nm and 665 nm after excitation at 337 nm was measured with an HTRF reader, such as Pherastar (BMG Labtechnologies, Offenburg, Germany) or Viewlux (Perkin-Elmer). The ratio of the amount of emission at 665 nm to 622 nm is considered a measure of the amount of phosphorylated host. Corrected data (enzyme reaction without inhibitor = 0% inhibition, all other analysis components except enzyme = 100% inhibition). Typically, 11 different concentrations in the range of 20 μM to 0.1 nM on the same microtiter plate (eg 20 μM, 5.9 μM, 1.7 μM, 0.51 μM, 0.15 μM, 44 nM, 13 nM, 3.8 nM, 1.1 nM, 0.33 nM and 0.1) nM, test compound was tested by serial dilution of each successive serial dilution in DMSO at a level of 100 times concentrated solution in DMSO (according to the pipette used) Values) and calculate the IC ₅₀ value.

CDK2/CycE kinase analysis

The CDK2/CycE inhibitory activity of the compounds of the invention is quantified using a CDK2/CycE TR-FRET assay as described in the following paragraphs.

GST expressed in insect cells (Sf9) and purified by glutathione agarose gel affinity chromatography and recombinant fusion proteins of human CDK2 with GST and human CycE were purchased from ProQinase GmbH (Freiburg, Germany). Biotin-labeled peptide biotin - Ttds-YISPLKSPYKISEG (C-terminal in the guanamine form) serves as a substrate for the kinase reaction, which is commercially available, for example, from JERINI peptide Technologies (Berlin, Germany).

For analysis, 50 nL of the test compound was pipetted into a black low volume 384-well microtiter plate (Greiner Bio-One, Frickenhausen, Germany) in a black low volume 384-well microtiter plate (Greiner Bio-One, Frickenhausen, Germany), and added with CDK2/CycE in aqueous assay buffer [50 mM Tris/ ₂ μL of solution in HCl pH 8.0, 10 mM MgCl ₂ , 1.0 mM dithiothreitol, 0.1 mM sodium orthovanadate, 0.01% (v/v) Nonidet-P40 (Sigma) and the mixture was incubated at 22 ° C for 15 minutes. To allow for the pre-binding of the compound to the enzyme prior to the start of the kinase reaction. This was followed by the addition of adenosine triphosphate (ATP, 16.7 μM = >5 μL final concentration in the assay volume of 10 μM) and the substrate (1.25 μM = >5 μL final concentration in the assay volume of 0.75 μM) in a 3 μL solution in assay buffer. The kinase reaction was started and the resulting mixture was incubated at 22 ° C for a reaction time of 25 minutes. The concentration of CDK2/CycE is adjusted depending on the activity of the enzyme lot and is selected to allow the analysis to be in the linear range, typically in the range of 130 ng/ml. By adding TR-FRET detection reagent (0.2 μM streptavidin-XL665 [Cisbio Bioassays, Codolet, France] and 1 nM anti-RB (pSer807/pSer811) antibody (from BD Pharmingen) [# 558389] and 1.2 nM LANCE EU-W1024 labeled anti-mouse IgG antibody [Perkin-Elmer, product number AD0077, as an alternative to the use of cesium-labeled anti-mouse IgG antibody from Cisbio Bioassays]) in aqueous EDTA (100 mM EDTA, 0.2% ( The reaction was stopped by a 5 μL solution of w/v) bovine serum albumin in 100 mM HEPES/NaOH pH 7.0).

The resulting mixture was incubated at 22 ° C for 1 hour to form a complex between the phosphorylated biotin-labeled peptide and the detection reagent. The amount of phosphorylated host was then assessed by measuring the resonance energy transfer of the Eu chelating agent to streptavidin-XL. Therefore, the amount of fluorescence emission at 620 nm and 665 nm after excitation at 350 nm was measured with a TR-FRET reader, such as Rubystar (BMG Labtechnologies, Offenburg, Germany) or Viewlux (Perkin-Elmer). The ratio of the amount of emission at 665 nm to 622 nm is considered a measure of the amount of phosphorylated host. Corrected data (enzyme reaction without inhibitor = 0% inhibition, all other analysis components except enzyme = 100% inhibition). Typically, 11 different concentrations (20 μM, 5.9 μM, 1.7 μM, 0.51 μM, 0.15 μM, 44 nM, 13 nM, 3.8 nM, 1.1 nM, 0.33 nM, and 0.1 nM) in the range of 20 μM to 0.1 nM on the same microtiter plate. Test compounds were tested by serial dilution of each of the serial dilutions prepared in 1: DMSO at a level of 100 times concentrated solution in DMSO (two values were obtained for each concentration) and the IC _{50 was} calculated. value.

PDGFRß kinase analysis

The PDGFRß inhibitory activity of the compounds of the invention can be quantified using the PDGFRß HTRF assay as described in the following paragraphs.

GST-His containing the C-terminal fragment of human PDGFRß (amino acid 561-1106), which was obtained from Proqinase [Freiburg i. Brsg., Germany] and expressed in insect cells [SF9] and purified by affinity chromatography. The fusion protein acts as a kinase. A biotin-labeled poly Glu, Tyr (4:1) copolymer (#61GT0BLA) from Cis Biointernational (Marcoule, France) was used as a substrate for the kinase reaction.

For analysis, 50 nL of the test compound was pipetted into a black low volume 384-well microtiter plate (Greiner Bio-One, Frickenhausen, Germany) with a 100-fold concentrated solution in DMSO, and added with PDGFRß in aqueous assay buffer [50 mM HEPES/NaOH pH 7.5, 2 μL of 10 mM MgCl ₂ , 2.5 mM dithiothreitol, 0.01% (v/v) Triton-X100 (Sigma)] and the mixture was incubated at 22 ° C for 15 minutes to allow testing of the compound before the start of the kinase reaction Pre-bonded to the enzyme. Subsequently, by adding adenosine triphosphate (ATP, 16.7 μM => 5 μL of the final concentration in the assay volume of 10 μM) and the substrate (2.27 μg / ml => 5 μL of the final concentration in the assay volume of 1.36 μg / ml [about 30 nM]) 3 μL of the solution in the buffer was analyzed to start the kinase reaction, and the resulting mixture was incubated at 22 ° C for a reaction time of 25 minutes. The concentration of PDGFRß in the assay was adjusted depending on the activity of the enzyme lot and was chosen to allow the assay to be in the linear range, with typical enzyme concentrations ranging from about 125 pg/μL (the final concentration in the 5 μL assay volume). By adding HTRF detection reagent (200nM streptavidin-XLent [Cis Biointernational] and 1.4nM PT66-Eu chelating agent (an anti-phosphotyrosinate antibody from Perkin Elmer chelating agent) [replacing PT66- Eu chelating agent, can also use PT66-Tb cryptate from Cis Biointernational]) 5 μL in EDTA aqueous solution (100 mM EDTA, 0.2% (w/v) bovine serum albumin in 50 mM HEPES/NaOH pH 7.5) The solution is used to stop the reaction.

The resulting mixture was incubated at 22 ° C for 1 hour to allow the biotin-labeled phosphorylated peptide to bind to the streptavidin-XLent and PT66-Eu chelating agents. The amount of phosphorylated host was then assessed by measuring the resonance energy transfer of the PT66-Eu chelating agent to streptavidin-XLent. Therefore, the amount of fluorescence emission at 620 nm and 665 nm after excitation at 350 nm was measured with an HTRF reader, such as Rubystar (BMG Labtechnologies, Offenburg, Germany) or Viewlux (Perkin-Elmer). The ratio of the amount of emission at 665 nm to 622 nm is considered a measure of the amount of phosphorylated host. Corrected data (enzyme reaction without inhibitor = 0% inhibition, all other analysis components except enzyme = 100% inhibition). Typically, 10 different concentrations (20 μM, 6.7 μM, 2.2 μM, 0.74 μM, 0.25 μM, 82 nM, 27 nM, 9.2 nM, 3.1 nM and 1 nM) in the range of 20 μM to 1 nM on the same microtiter plate, before analysis the level of 100-fold concentrated stock solutions by 1: preparation of serial dilutions of 3 serial dilutions) of the test compounds were tested (two values acquired for each concentration), and ₅₀ values _were calculated IC.

Fyn kinase analysis

The C-terminal His6-tagged human recombinant kinase domain (purchased from Invitrogen, P3042) of human T-Fyn expressed in baculovirus-infected insect cells was used as a kinase. The biotin-labeled peptide biotin-KVEKIGEGTYGVV (C-terminal in the guanamine form) was used as a substrate for the kinase reaction, which is commercially available, for example, from Biosynthan GmbH (Berlin-Buch, Germany).

For the analysis, 50 nL of the test compound was pipetted into a black low-capacity 384-well microtiter plate (Greiner Bio-One, Frickenhausen, Germany) in a black low-capacity 384-well microtiter plate (Greiner Bio-One, Frickenhausen, Germany), and T-Fyn was added to the aqueous assay buffer [25 mM Tris/ ₂ μL of HCl pH 7.2, 25 mM MgCl ₂ , 2 mM dithiothreitol, 0.1% (w/v) bovine serum albumin, 0.03% (v/v) Nonidet-P40 (Sigma) and mixture at 22 ° C Incubate for 15 minutes to allow for pre-binding of the test compound to the enzyme prior to the start of the kinase reaction. This was followed by the addition of adenosine triphosphate (ATP, 16.7 μM = >5 μL final concentration in the assay volume of 10 μM) and the substrate (2 μM = >5 μL final concentration in the assay volume of 1.2 μM) in a 3 μL solution in assay buffer. The kinase reaction was started and the resulting mixture was incubated at 22 ° C for a reaction time of 60 minutes. The concentration of Fyn is adjusted depending on the activity of the enzyme batch and is selected to allow the analysis to be in the linear range, typically at a concentration of 0.13 nM. Labeling anti-phosphotyrosinate antibody by addition of HTRF detection reagent (0.2 μM streptavidin-XL [Cisbio Bioassays, Codolet, France] and 0.66 nM PT66-Eu chelating agent (a chelating agent from Perkin Elmer) [Alternative to PT66-Eu chelating agent, PT66-Tb cryptate from Cisbio Bioassays] can also be used in aqueous EDTA (125 mM EDTA, 0.2% (w/v) bovine serum albumin at 50 mM HEPES/NaOH pH 7.0) 5 μL of the solution in the middle) to stop the reaction.

The resulting mixture was incubated at 22 ° C for 1 hour to allow the biotin-labeled phosphorylated peptide to bind to the streptavidin-XL and PT66-Eu chelating agents. The amount of phosphorylated host was then assessed by measuring the resonance energy transfer of PT66-Eu chelating agent to streptavidin-XL. Therefore, the amount of fluorescence emission at 620 nm and 665 nm after excitation at 350 nm was measured with an HTRF reader, such as Rubystar (BMG Labtechnologies, Offenburg, Germany) or Viewlux (Perkin-Elmer). The ratio of the amount of emission at 665 nm to 622 nm is considered a measure of the amount of phosphorylated host. Corrected data (enzyme reaction without inhibitor = 0% inhibition, all other analysis components except enzyme = 100% inhibition). Typically, 10 different concentrations (20 μM, 6.7 μM, 2.2 μM, 0.74 μM, 0.25 μM, 82 nM, 27 nM, 9.2 nM, 3.1 nM and 1 nM) in the range of 20 μM to 1 nM on the same microtiter plate, before analysis the level of 100-fold concentrated stock solutions by 1: preparation of serial dilutions of 3 serial dilutions) of the test compounds were tested (two values acquired for each concentration), and ₅₀ values _were calculated IC.

Flt4 kinase analysis

The Flt4 inhibitory activity of the compounds of the invention is quantified using the Flt4 TR-FRET assay as described in the following paragraphs.

GST-His containing a human Clt fragment of Flt4 (amino acid 799-1298), which was obtained from Proqinase [Freiburg i. Brsg., Germany] and expressed in insect cells [SF9] and purified by affinity chromatography. The fusion protein acts as a kinase. The biotin-labeled peptide biotin-Ahx-GGEEEEYFELVKKKK (C-terminal of the guanamine form, purchased from Biosyntan, Berlin-Buch, Germany) was used as a substrate for the kinase reaction.

For the analysis, 50 nL of the test compound was pipetted into a black low volume 384 well microtiter plate (Greiner Bio-One, Frickenhausen, Germany) in a black low volume 384 well microtiter plate (Greiner Bio-One, Frickenhausen, Germany), and Flt4 was added to the aqueous assay buffer [25 mM HEPES pH 7.5, ₂ μL of 10 mM MgCl ₂ , 2 mM dithiothreitol, 0.1% (w/v) Triton X100 (Sigma), 0.5 mM EGTA and 5 mM ß-phosphonium-glycerol] and the mixture was incubated at 22 ° C for 15 minutes. To allow for the pre-binding of the compound to the enzyme prior to the start of the kinase reaction. This was followed by the addition of adenosine triphosphate (ATP, 16.7 μM = >5 μL final concentration in the assay volume of 10 μM) and the substrate (1.67 μM = >5 μL final concentration in the assay volume of 1 μM) in a 3 μL solution in assay buffer. The kinase reaction was started and the resulting mixture was incubated at 22 ° C for a reaction time of 45 minutes. The concentration of Flt4 in the assay is adjusted depending on the activity of the enzyme batch and is selected to be such that the assay is in the linear range, with typical enzyme concentrations ranging from about 120 pg/μL (the final concentration in the 5 μL assay volume). Labeling anti-phosphorylated cheese by adding HTRF detection reagent (200 nM streptavidin-XL665 [Cis Biointernational] and 1 nM PT66-Tb acupoint (a cryptate from Cisbio Bioassays (Codolet, France) Amino acid antibody)) The reaction was stopped in 5 μL of a solution of EDTA in water (50 mM EDTA, 0.2% (w/v) bovine serum albumin in 50 mM HEPES pH 7.5).

The resulting mixture was incubated at 22 °C for 1 hour to allow the biotin-labeled phosphorylated peptide to bind to streptavidin-XL665 and PT66-Tb cryptate. The amount of phosphorylated host was then assessed by measuring the resonance energy transfer of PT66-Tb cryptate to streptavidin-XL665. Therefore, the amount of fluorescence emission at 620 nm and 665 nm after excitation at 350 nm was measured with an HTRF reader, such as Rubystar (BMG Labtechnologies, Offenburg, Germany) or Viewlux (Perkin-Elmer). The ratio of the amount of emission at 665 nm to 622 nm is considered a measure of the amount of phosphorylated host. Corrected data (enzyme reaction without inhibitor = 0% inhibition, all other analysis components except enzyme = 100% inhibition). Typically, 10 different concentrations (20 μM, 6.7 μM, 2.2 μM, 0.74 μM, 0.25 μM, 82 nM, 27 nM, 9.2 nM, 3.1 nM and 1 nM) in the range of 20 μM to 1 nM on the same microtiter plate, before analysis the level of 100-fold concentrated stock solutions by 1: preparation of serial dilutions of 3 serial dilutions) of the test compounds were tested (two values acquired for each concentration), and ₅₀ values _were calculated IC.

TrkA kinase assay

The TrkA inhibitory activity of the compounds of the invention was quantified using the TrkA HTRF assay as described in the following paragraphs.

GST-His containing the C-terminal fragment of human TrkA (amino acid 443-796), which was obtained from Proqinase [Freiburg i. Brsg., Germany] and expressed in insect cells [SF9] and purified by affinity chromatography. The fusion protein acts as a kinase. As a substrate for the kinase reaction, a biotin-labeled poly Glu, Tyr (4:1) copolymer (#61GT0BLA) from Cis Biointernational (Marcoule, France) was used.

For analysis, 50 nL of the test compound was pipetted into a black low volume 384 well microtiter plate (Greiner Bio-One, Frickenhausen, Germany) in a black low volume 384 well microtiter plate (Greiner Bio-One, Frickenhausen, Germany), and TrkA in aqueous assay buffer [8 mM MOPS/HCl pH] was added. A 2 μL solution of 7.0, 10 mM MgCl ₂ , 1 mM dithiothreitol, 0.01% (v/v) NP-40 (Sigma), 0.2 mM EDTA] and the mixture was incubated at 22 ° C for 15 minutes to allow the start of the kinase reaction. The test compound was previously pre-bound to the enzyme. Subsequently, by adding adenosine triphosphate (ATP, 16.7 μM => 5 μL of the final concentration in the assay volume of 10 μM) and the substrate (2.27 μg / ml => 5 μL of the final concentration in the assay volume of 1.36 μg / ml [about 30 nM]) 3 μL of the solution in the buffer was analyzed to start the kinase reaction, and the resulting mixture was incubated at 22 ° C for a reaction time of 60 minutes. The concentration of TrkA in the assay is adjusted depending on the activity of the enzyme lot and is selected to be such that the assay is in the linear range, with typical enzyme concentrations ranging from about 20 pg/μL (the final concentration in the 5 μL assay volume). By adding HTRF detection reagent (30nM streptavidin-XL665 [Cis Biointernational] and 1.4nM PT66-Eu chelating agent (a labeled anti-phosphotyrosinate antibody from Perkin Elmer) [replacing PT66- Eu chelating agent, can also use PT66-Tb cryptate from Cis Biointernational]) 5 μL in EDTA aqueous solution (100 mM EDTA, 0.2% (w/v) bovine serum albumin in 50 mM HEPES/NaOH pH 7.5) The solution is used to stop the reaction.

The resulting mixture was incubated at 22 ° C for 1 hour to allow the biotin-labeled phosphorylated peptide to bind to the streptavidin-XL665 and PT66-Eu chelating agents. The amount of phosphorylated host was then assessed by measuring the resonance energy transfer of the PT66-Eu chelating agent to streptavidin-XL665. Therefore, the amount of fluorescence emission at 620 nm and 665 nm after excitation at 350 nm was measured with an HTRF reader, such as Rubystar (BMG Labtechnologies, Offenburg, Germany) or Viewlux (Perkin-Elmer). The ratio of the amount of emission at 665 nm to 622 nm is considered a measure of the amount of phosphorylated host. Corrected data (enzyme reaction without inhibitor = 0% inhibition, all other analysis components except enzyme = 100% inhibition). Typically, 10 different concentrations (20 μM, 6.7 μM, 2.2 μM, 0.74 μM, 0.25 μM, 82 nM, 27 nM, 9.2 nM, 3.1 nM and 1 nM) in the range of 20 μM to 1 nM on the same microtiter plate, before analysis the level of 100-fold concentrated stock solutions by 1: preparation of serial dilutions of 3 serial dilutions) of the test compounds were tested (two values acquired for each concentration), and ₅₀ values _were calculated IC.

AlphaScreen SureFire eIF4E Ser209 Phosphorylation Analysis

AlphaScreen SureFire eIF4E Ser209 Phosphorylation assay can be used to measure cell lysis Phosphorylation of endogenous eIF4E in the product. AlphaScreen SureFire technology allows the detection of phosphorylated proteins in cell lysates. In this assay, the sandwich antibody complex formed only in the presence of the analyte (p-eIF4E Ser209) was captured by the AlphaScreen donor and acceptor beads, bringing them in close proximity. Excitation of the donor beads causes the release of unimodal oxygen molecules that trigger a cascade of energy transfer in the acceptor beads, resulting in light emission at 520-620 nm.

Surefire EIF4e Alphascreen stimulated by 20% FCS in A549 cells

For analysis, the AlphaScreen SureFire p-eIF4E Ser209 10K assay kit and the AlphaScreen ProteinA kit (for 10K analysis points) were used from Perkin Elmer.

On the first day, 50.000 A549 cells were plated in a 96-well plate in a growth medium (DMEM/Hams' F12 with stable bran acid, 10% FCS) at 100 μL per well, and incubated at 37 °C. After the cells were attached, the medium was changed to starvation medium (DMEM, 0.1% FCS, no glucose, glutamic acid, supplemented with 5 g/L maltose). On the next day, the test compound was serially diluted in 50 μL of starvation medium to a final DMSO concentration of 1%, and added to the test plate at a final concentration ranging from 10 μM to as low as 10 nM depending on the activity of the test compound. In A549 cells. The treated cells were incubated for 2 hours at 37 °C. 37 μl of FCS was added to the wells (= final FCS concentration of 20%) for 20 minutes. The medium was then removed and the cells were lysed by the addition of 50 [mu]L of lysis buffer. The tray was then agitated on a disc shaker for 10 minutes. After a 10 minute dissolution time, 4 μL of the lysate was transferred to a 384-well plate (Proxiplate from Perkin Elmer), and 5 μL of reaction buffer containing AlphaScreen acceptor beads plus activation buffer mixture was added. The disc was sealed with a TopSeal-A adhesive film and gently agitated on a disc shaker for 2 hours at room temperature. Subsequently, 2 μL of a dilution buffer with AlphaScreen donor beads was added under soft light, and the disk was again sealed with a TopSeal-A adhesive film and covered with a foil. Incubation was carried out for 2 hours at room temperature with gentle agitation. Then at the EnVision reader (Perkin Elmer) uses the AlphaScreen program to measure the disk. Each data point (compound dilution) was measured in triplicate.

Hyperplasia analysis

The tumor cell proliferation assay that can be used to test the compounds of the invention comprises a reader called Cell Titer-Glow® luminescence cell viability assay developed by Promega® (BACunningham, "A Growing Issue: Cell Proliferation Assays, Modern kits ease quantification of cell Growth, The Scientist 2001 , 15(13), 26; SPCrouch et al, "The use of ATP bioluminescence as a measure of cell proliferation and cytotoxicity", Journal of Immunological Methods 1993 , 160, 81-88), its measurement Inhibition of cell proliferation. The generation of the luminescent signal corresponds to the amount of ATP present, and the amount of ATP present is proportional to the number of metabolically active (proliferating) cells.

In vitro tumor cell proliferation analysis:

Cultured tumor cells (MOLM-13 (human acute myeloid leukemia cells obtained from DSMZ # ACC 554), JJN-3 (human plasma cell leukemia cells obtained from DSMZ # ACC 541), Ramos (RA1) (obtained from ATCC) # CRL-159 Human Burkitt Lymphoma Cells)) 2,500 cells/well (JJN-3), 3,000 cells/well (MOLM-13) in 100 μL of their respective growth medium supplemented with 10% fetal bovine serum The density of 4,000 cells/well (Ramos (RA1)) was spread in a 96-well porous titration plate (Costar 3603 black/clear bottom). After 24 hours, the viability of cells in one plate (zero plate) was measured. Therefore, a 70 microliter/well CTG solution (Promega Cell Titer Glo solution (catalog numbers G755B and G756B)) was added to the zero point plate. The plates were mixed on a rotary shaker for two minutes to ensure cell lysis and incubation in the dark for 10 minutes at room temperature to stabilize the luminescence signal. Samples were read on a VICTOR 3 disc reader. At the same time, test compounds were serially diluted in growth medium and 50 [mu]L of 3x dilutions/well was pipetted into the assay wells (final concentration: 0 [mu]M, and in the range of 0.001-30 [mu]M). The final concentration of the solvent dimethyl hydrazine is from 0.3% to 0.4%. cell Incubate for 3 days in the presence of the test substance. A 105 microwell/well CTG solution (Promega Cell Titer Glo solution (catalog numbers G755B and G756B)) was added to the test wells. The plates were mixed on a rotary shaker for 2 minutes to ensure cell lysis and incubation in the dark for 10 minutes at room temperature to stabilize the luminescence signal. Samples were read on a VICTOR 3 disc reader. The change (%) in the number of cells was calculated by correcting the measured value with respect to the extinction value (=0%) of the zero dot disk and the extinction degree (=100%) of the untreated (0 μm) cell.

Overview of cell lines for proliferative analysis

Thus, the compounds of the invention are effective for inhibiting one or more kinases and are therefore suitable for treating or preventing diseases of uncontrolled cell growth, proliferation and/or survival, inappropriate cellular immune responses or inappropriate cellular inflammatory responses, particularly where uncontrolled cell growth , hyperplasia and/or survival, inappropriate cellular immune response or inappropriate cell inflammatory response mediated by MKNK, more particularly diseases in which uncontrolled cell growth, proliferation and/or survival, inappropriate cellular immune response or inappropriate cellular inflammatory response are hematological tumors , solid tumors and / or its metastasis, such as leukemia and myelodysplastic syndromes, 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 tumors (including kidney tumors, bladder tumors and prostate tumors), skin tumors and sarcomas and/or their metastases.

Claims (19)

a compound of formula I , Wherein: QV represents a group selected from the group consisting of C(R ^1a )-N, NC(R ^1a ); and A represents a group selected from the group consisting of: Wherein * indicates the point of attachment of the rest of the molecule such group; R ^1a represents a hydrogen atom or a halogen atom or a group selected from the group of: hydroxy - cyano -, C ₁ -C ₆ alkyl -, C ₂ - C ₆ alkenyl-, C ₂ -C ₆ alkynyl-, C ₁ -C ₆ alkoxy-, halo-C ₁ -C ₆ alkyl-, halo-C ₁ -C ₆ alkoxy-, Hydroxy-C ₁ -C ₆ alkyl-, C ₁ -C ₃ alkoxy-C ₁ -C ₃ alkyl-, -N(R ^5b )R ^5c , -SCF ₃ , -SF ₅ ; R ^1b represents hydrogen An atom or a halogen atom or a group selected from the group consisting of hydroxy-, cyano-, C ₁ -C ₆ alkyl-, C ₂ -C ₆ alkenyl-, C ₂ -C ₆ alkynyl-, C ₁ -C ₆ alkoxy-, halo-C ₁ -C ₆ alkyl-, halo-C ₁ -C ₆ alkoxy-, hydroxy-C ₁ -C ₆ alkyl-, C ₁ -C ₃ alkoxy -C ₁ -C ₃ alkyl-, -N(R ^5b )R ^5c , -SCF ₃ , -SF ₅ ; R ^1c represents a hydrogen atom or a halogen atom or a group selected from the group consisting of hydroxy-, cyano-, C ₁ -C ₆ alkyl-, C ₂ -C ₆ alkenyl-, C ₂ -C ₆ alkynyl-, C ₁ -C ₆ alkoxy-, halo-C ₁ -C ₆ alkyl-, halo -C ₁ -C ₆ alkoxy-, hydroxy-C ₁ -C ₆ alkyl-, C ₁ -C ₃ alkoxy-C ₁ -C ₃ alkyl-, -N(R ^5b )R ^5c , -SCF _3, -SF _5; R ^2a represents a hydrogen atom A halogen atom or a group selected from the group: C ₁ -C ₆ alkyl -, C ₃ -C ₆ cycloalkyl -, heterocycloalkyl 3-10 - 4-10 heterocycloalkenyl -, aryl Base-, heteroaryl-, cyano-, -(CH ₂ ) _q -U-(CH ₂ ) _p -R ^3a ; wherein the C ₁ -C ₆ alkyl-, C ₃ -C ₆ cycloalkyl- 3 to 10 membered heterocycloalkyl-, 4 to 10 membered heterocycloalkenyl-, aryl- or heteroaryl-, as the case may be, 1, 2, 3, 4 or 5 R ⁴ groups identically or differently Substituted; R ^2b represents a hydrogen atom or a halogen atom or a group selected from the group consisting of C ₁ -C ₆ alkyl-, C ₃ -C ₆ cycloalkyl-, 3 to 10 membered heterocycloalkyl-, 4 to 10 a heterocycloalkenyl-, aryl-, heteroaryl-, cyano-, -(CH ₂ ) _q -U-(CH ₂ ) _p -R ^3a ; wherein the C ₁ -C ₆ alkyl-, C _3- C ₆ cycloalkyl-, 3 to 10 membered heterocycloalkyl-, 4 to 10 membered heterocycloalkenyl-, aryl- or heteroaryl-, as the case may be the same or different, 1, 2, 3, 4 or 5 R ⁴ groups are substituted; or R ^2a and R ^2b together represent -(CH ₂ ) _r -T-(CH ₂ ) _s -; T represents a group selected from the group consisting of U, -C[R ^6a ][(C(R ^6b )(R ^6c )) _t -UR ^3a ]-; U represents a single bond or a divalent group selected from the group consisting of -O-, -S-, -S(=O) -, - S (= O) 2 - -S (= O) -N (R 3b) -, - N (R 3c) -S (= O) -, - S (= O) 2 -N (R 3b) -, - N (R 3c) - S(=O) ₂ -, -C(=O)-, -N(R ^3b )-, -C(=O)-O-, -OC(=O)-, -C(=S)-O -, -OC(=S)-, -C(=O)-N(R ^3b )-, -N(R ^3c )-C(=O)-, -N(R ^3c )-C(=O) -N(R ^3b )-, -OC(=O)-N(R ^3b )-, -N(R ^3c )-C(=O)-O-; R ^3a represents a hydrogen atom or a group selected from the group consisting of : C ₁ -C ₆ alkyl-, C ₃ -C ₆ cycloalkyl-, 3 to 10 membered heterocycloalkyl-, 4 to 10 membered heterocycloalkenyl-, aryl-, heteroaryl-; The C ₁ -C ₆ alkyl-, C ₃ -C ₆ cycloalkyl-, 3 to 10 membered heterocycloalkyl-, 4 to 10 membered heterocycloalkenyl-, aryl- or heteroaryl--as appropriate Substituted or substituted by 1, 2, 3, 4 or 5 R ⁴ groups; R ^3b represents a hydrogen atom or a group selected from the group consisting of C ₁ -C ₆ alkyl-, C ₃ -C ₆ naphthenes Base-, 3 to 10 membered heterocycloalkyl-, 4 to 10 membered heterocycloalkenyl-, aryl-, heteroaryl-; wherein the C ₁ -C ₆ alkyl-, C ₃ -C ₆ naphthenic Base, 3 to 10 membered heterocycloalkyl-, 4 to 10 membered heterocycloalkenyl-, aryl- or heteroaryl-, as the case may be, 1, 2, 3, 4 or 5 R ⁴ a group substituted; R ^3c represents a hydrogen atom or a group selected from the group consisting of C ₁ - C ₆ alkyl-, C ₃ -C ₆ cycloalkyl-, 3 to 10 membered heterocycloalkyl-, 4 to 10 membered heterocycloalkenyl-, aryl-, heteroaryl-, wherein the C ₁ - C ₆ alkyl-, C ₃ -C ₆ cycloalkyl-, 3 to 10 membered heterocycloalkyl-, 4 to 10 membered heterocycloalkenyl-, aryl- or heteroaryl - the same or different, as the case may be Substituted by 1, 2, 3, 4 or 5 R ⁴ groups; or N(R ^3b )R ^3a together form 3 to 10 membered heterocycloalkyl- or 4 to 10 membered heterocycloalkenyl-, wherein 3 Up to 10 membered heterocycloalkyl- or 4 to 10 membered heterocycloalkenyl - as the case may be substituted with 1, 2, 3, 4 or 5 R ⁴ groups; R ⁴ represents halo-, hydroxy- , pendant oxy-(O=), cyano-, nitro-, C ₁ -C ₆ alkyl-, C ₂ -C ₆ alkenyl-, C ₂ -C ₆ alkynyl-, halo-C ₁ -C ₆ alkyl-, C ₁ -C ₆ alkoxy-, halo-C ₁ -C ₆ alkoxy-, hydroxy-C ₁ -C ₆ alkyl-, C ₁ -C ₆ alkoxy- C ₁ -C ₆ alkyl-, halo-C ₁ -C ₆ alkoxy-C ₁ -C ₆ alkyl-, R ^5c -O-, -C(=O)-R ^5c , -C(= O)-OR ^5c , -OC(=O)-R ^5c , -N(R ^5b )-C(=O)-R ^5c , -N(R ^5c )-C(=O)-N(R ^5a ) R ^5b , -N(R ^5a )R ^5b , -C(=O)-N(R ^5a )R ^5b , R ^5c -S-, R ^5c -S(=O)-, R ^5c -S(=O ) ₂ -, -N(R ^5c )- S(=O)-R ^5b , -S(=O)-N(R ^5a )R ^5b , -N(R ^5c )- S(=O) ₂ -R ^5b , -S(=O) ₂ -N (R ^5a )R ^5b , -S(=O)=N(R ^5c )R ^5b , -S(=O)=N(R ^5c )R ^5b or -N=S(=O)(R ^5c )R ^5b ; R ^5a represents a hydrogen atom or a C ₁ -C ₆ alkyl-, C ₃ -C ₆ cycloalkyl-, phenyl- or 3 to 10 membered heterocycloalkyl group; wherein the C ₁ -C ₆ alkyl group - optionally substituted once by phenyl group; R ^5b represents a hydrogen atom, a C ₁ -C ₆ alkyl group, a C ₃ -C ₆ cycloalkyl group or a 3 to 10 membered heterocycloalkyl group; and R ^5c represents a hydrogen atom , C ₁ -C ₆ alkyl-, C ₃ -C ₆ cycloalkyl- or 3 to 10 membered heterocycloalkyl-; or N(R ^5a )R ^5b together form a 3 to 7 membered heterocycloalkyl-; R ^6a represents a hydrogen atom or a group selected from the group consisting of C ₁ -C ₆ alkyl-, C ₂ -C ₆ alkenyl-, C ₂ -C ₆ alkynyl-; wherein the C ₁ -C ₆ alkyl- , C ₂ -C ₆ alkenyl- or C ₂ -C ₆ alkynyl-, as the case may be, the same or different, substituted by 1, 2 or 3 R ⁴ groups; R ^6b represents a hydrogen atom or a C ₁ -C ₃ alkyl group - R ^6c represents a hydrogen atom or a C ₁ -C ₃ alkyl group; p represents an integer of 0, 1, 2 or 3; q represents an integer of 0, 1, 2 or 3; r represents an integer of 1, 2 or 3. ;s represents an integer of 1, 2 or 3; and t represents an integer of 0 or 1; or its mutual variation Body, N- oxide, hydrate, a salt or solvate or a mixture of such substances. The compound of claim 1, wherein: A represents a group selected from the group consisting of: Wherein * indicates the point of attachment of the group to the rest of the molecule; or a tautomer, N-oxide, hydrate, solvate or salt thereof, or a mixture of such materials. The compound according to any one of claims 1 to 2, wherein: QV represents C(R ^1a )-N and R ^1a represents a hydrogen atom; or QV represents NC(R ^1a ) and R ^1a represents a hydrogen atom or a halogen atom or is selected From the following groups: hydroxy-, cyano-, C ₁ -C ₃ alkyl-, C ₁ -C ₃ alkoxy-, halo-C ₁ -C ₃ alkyl-, halo-C ₁ - C ₃ alkoxy-, hydroxy-C ₁ -C ₃ alkyl-, C ₁ -C ₃ alkoxy-C ₁ -C ₃ alkyl-, -N(R ^5b )R ^5c ; R ^1b represents a hydrogen atom And R ^1c represents a hydrogen atom; or a tautomer, an N-oxide, a hydrate, a solvate or a salt thereof, or a mixture of such substances. The compound according to any one of claims 1 to 3, wherein: R ^2a represents a hydrogen atom or a halogen atom or a group selected from the group consisting of C ₁ -C ₆ alkyl-, -CH ₂ ) _q -U-(CH ₂ ) _p -R ^3a ; wherein the C ₁ -C ₆ alkyl group - as the case may be the same or differently substituted by 1, 2 or 3 R ⁴ groups; R ^2b represents a hydrogen atom or a halogen atom or a group selected from the group consisting of a group: C ₁ -C ₆ alkyl-, halo-C ₁ -C ₃ alkyl-, -(CH ₂ ) _q -U-(CH ₂ ) _p -R ^3a ; wherein the C ₁ -C ₆ alkyl group Substituting the same or differently with 1, 2 or 3 R ⁴ groups, with the proviso that the halo-C ₁ -C ₃ alkyl group - does not contain more than 5 halogen atoms; or R ^2a and R ^2b Together, -(CH ₂ ) ₂ -T-CH ₂ -; or R ^2a and R ^2b together represent -CH ₂ -T-(CH ₂ ) ₂ -; or its tautomer, N-oxide, hydrate , a solvate or a salt, or a mixture of such materials. The compound of any one of claims 1 to 4, wherein: T represents -C(H)(UR ^3a )-; U represents a single bond or a divalent group selected from the group consisting of -C(=O) -, -N(R ^3b )-, -C(=O)-O-, -OC(=O)-, -C(=O)-N(R ^3b )-, -N(R ^3c )-C (=O)-; or a tautomer, N-oxide, hydrate, solvate or salt thereof, or a mixture of such substances. The compound according to any one of claims 1 to 5, wherein: R ^3a represents a hydrogen atom or a group selected from the group consisting of C ₁ -C ₆ alkyl-, C ₃ -C ₆ cycloalkyl-, 3 to 10 Heterocycloalkyl-; wherein the C ₁ -C ₆ alkyl-, C ₃ -C ₆ cycloalkyl-, 3 to 10 membered heterocycloalkyl-, as the case may be the same or different, 1, 2 or 3 R ⁴ group substituted; R ^3b represents a hydrogen atom or C ₁ -C ₆ alkyl-; or N(R ^3b )R ^3a together form a 3 to 10 membered heterocycloalkyl group, wherein the 3 to 10 membered heterocycloalkane Substituting the same or differently with one R ⁴ group; and R ^3c represents a hydrogen atom or a C ₁ -C ₆ alkyl group; or a tautomer thereof, an N-oxide, a hydrate, a solvent Or a salt, or a mixture of such substances. The compound according to 6 as the requested item, wherein: R ⁴ represents halo -, hydroxy -, cyano -, nitro -, C ₁ -C ₃ alkyl -, halo -C ₁ -C ₃ Alkyl-, C ₁ -C ₃ alkoxy-, halo-C ₁ -C ₃ alkoxy-, hydroxy-C ₁ -C ₃ alkyl-, C ₁ -C ₃ alkoxy-C ₁ - C ₃ alkyl-, R ^5c -O-, -C(=O)-R ^5c , -C(=O)-OR ^5c , -OC(=O)-R ^5c , -N(R ^5a )R ^5b , -C(=O)-N(R ^5a )R ^5b , R ^5c -S(=O) ₂ -, -N(R ^5c )-S(=O) ₂ R ^5b or -S(=O) ₂ -N(R ^5a )R ^5b ; or a tautomer, N-oxide, hydrate, solvate or salt thereof, or a mixture of such materials. The compound according to any one of claims 1 to 7, wherein: R ^5a represents a hydrogen atom or a C ₁ -C ₆ alkyl- or benzyl-; R ^5b represents a hydrogen atom or a C ₁ -C ₆ alkyl-; R ^5c represents a hydrogen atom or a C ₁ -C ₆ alkyl-; or a tautomer, an N-oxide, a hydrate, a solvate or a salt thereof, or a mixture of such substances. The compound of any one of claims 1 to 8, wherein: p represents an integer of 0 or 1, q represents an integer of 0 or 1, r represents an integer of 1 or 2; s represents an integer of 1 or 2; and t represents An integer of 0 or 1; or a tautomer, N-oxide, hydrate, solvate or salt thereof, or a mixture of such materials. The compound of claim 1, which is selected from the group consisting of N-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazolo[3,4-b Pyridine-5-amine; N-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazolo[3,4-c]pyridine-5-amine; N-(5-methyl-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazolo[3,4-b]pyridine-5-amine; N-(5-A -7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazolo[3,4-c]pyridine-5-amine; N-(5-ethyl-7H-pyrrole [2,3-d]pyrimidin-4-yl)-1H-pyrazolo[3,4-b]pyridine-5-amine; N-(5-ethyl-7H-pyrrolo[2,3-d Pyrimidin-4-yl)-1H-pyrazolo[3,4-c]pyridine-5-amine; N-(6-ethyl-5-methyl-7H-pyrrolo[2,3-d] Pyrimidin-4-yl)-1H-pyrazolo[3,4-b]pyridine-5-amine; N-(6-ethyl-5-methyl-7H-pyrrolo[2,3-d]pyrimidine 4-yl)-1H-pyrazolo[3,4-c]pyridine-5-amine; 4-(1H-pyrazolo[3,4-b]pyridin-5-ylamino)-7H- Pyrrolo[2,3-d]pyrimidine-6-carboxylic acid ethyl ester; 4-(1H-pyrazolo[3,4-c]pyridin-5-ylamino)-7H-pyrrolo[2,3- d]pyrimidine-6-carboxylic acid ethyl ester; 4-(1H-pyrazolo[3,4-c]pyridin-5-ylamino)-7H-pyrrolo[2,3-d]pyrimidine-6-carboxylic acid ; 5-bromo-4-(1H-pyrazolo[3,4-b]pyridin-5-ylamino)-7H-pyrrolo[2,3-d]pyrimidine-6-carboxylic acid ethyl ester; 5- Bromo-4-(1H-pyrazolo[3,4-c]pyridin-5-ylamino)-7H-pyrrolo[2,3-d]pyrimidine-6-carboxylic acid ethyl ester; 5-bromo-4 -(1H-pyrazolo[3,4-c]pyridin-5-ylamino)-7H-pyrrolo[2,3-d]pyrimidine-6- Acid; N- [5- (trifluoromethyl) -7H- pyrrolo [2,3-d] pyrimidin-4-yl] -1H- pyrazolo [3,4-b] pyridin-5-amine; N-[5-(Trifluoromethyl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl]-1H-pyrazolo[3,4-c]pyridine-5-amine; [4 -(1H-pyrazolo[3,4-b]pyridin-5-ylamino)-7H-pyrrolo[2,3-d]pyrimidin-5-yl]methanol; N,N-dimethyl- 4-(1H-pyrazolo[3,4-c]pyridin-5-ylamino)-7H-pyrrolo[2,3-d]pyrimidine-6-carboxamide; [4-(1H-pyridyl) Zoxao[3,4-c]pyridin-5-ylamino)-7H-pyrrolo[2,3-d]pyrimidin-6-yl](pyrrolidin-1-yl)methanone; piperidine-1 -yl [4-(1H-pyrazolo[3,4-c]pyridin-5-ylamino)-7H-pyrrolo[2,3-d]pyrimidin-6-yl]methanone; morpholine- 4-yl[4-(1H-pyrazolo[3,4-c]pyridin-5-ylamino)-7H-pyrrolo[2,3-d]pyrimidin-6-yl]methanone; N- [2-(Dimethylamino)ethyl]-4-(1H-pyrazolo[3,4-c]pyridin-5-ylamino)-7H-pyrrolo[2,3-d]pyrimidine -6-carbamamine; (RS)-N-(propan-2-yl)-4-(1H-pyrazolo[3,4-b]pyridin-5-ylamino)-5,6,7 , 8-tetrahydro[1]benzothieno[2,3-d]pyrimidin-7-carboxamide; (RS)-N-(propan-2-yl)-4-(1H-pyrazolo[ 3,4-c]pyridin-5-ylamino)-5,6,7,8-tetrahydro[1]benzothieno[2,3-d]pyrimidin-7-carboxamide; (RS) -(4-methylpiperazin-1-yl)[4-(1H-pyrazolo[3,4-b]pyridin-5-ylamino)-5,6,7,8- Hydrogen [1] benzothieno[2,3-d]pyrimidin-7-yl]methanone; (RS)-(4-methylpiperazin-1-yl)[4-(1H-pyrazole[ 3,4-c]pyridin-5-ylamino)-5,6,7,8-tetrahydro[1]benzothieno[2,3-d]pyrimidin-7-yl]methanone; (RS )-N,N-Dimethyl-4-(1H-pyrazolo[3,4-b]pyridin-5-ylamino)-5,6,7,8-tetrahydro[1]benzothiophene And [2,3-d]pyrimidine-7-formamide; (RS)-N,N-dimethyl-4-(1H-pyrazolo[3,4-c]pyridin-5-ylamino -5,6,7,8-tetrahydro[1]benzothieno[2,3-d]pyrimidin-7-carboxamide; (RS)-N-(propan-2-yl)-4-(1H-pyrazolo[3,4-b]pyridin-5-ylamino)-6,7,8,9-tetrahydro-5H -pyrimido[4,5-b]indole-6-formamide; (RS)-N,N-dimethyl-4-(1H-pyrazolo[3,4-b]pyridine-5- Amino)-6,7,8,9-tetrahydro-5H-pyrimido[4,5-b]indole-6-carboxamide; (RS)-N,N-dimethyl-4- (1H-pyrazolo[3,4-c]pyridin-5-ylamino)-6,7,8,9-tetrahydro-5H-pyrimido[4,5-b]indole-6- Indoleamine; (RS)-(4-methylpiperazin-1-yl)[4-(1H-pyrazolo[3,4-b]pyridin-5-ylamino)-6,7,8, 9-tetrahydro-5H-pyrimido[4,5-b]fluoren-6-yl]methanone; (RS)-(4-methylpiperazin-1-yl)[4-(1H-pyrazole) And [3,4-c]pyridin-5-ylamino)-6,7,8,9-tetrahydro-5H-pyrimido[4,5-b]indol-6-yl]methanone; 7S)-4-[(6-methoxy-1H-pyrazolo[3,4-b]pyridin-5-yl)amino]-N-methyl-N-(3,3,3-tri Fluoropropyl)-5,6,7,8-tetrahydro[1]benzothieno[2,3-d]pyrimidin-7-carboxamide; N-[3-(dimethylamino)- 3-Phenoxypropyl]-N-methyl-7-(1H-pyrazolo[3,4-c]pyridin-5-ylamino)[1,3]thiazolo[5,4-d Pyrimidine-2-carbamide; N-[3-(dimethylamino)-3-oxopropyl]-7-[(6-methoxy-1H-pyrazolo[3,4] -b]pyridine-5-yl)amino]-N-methyl [1,3 Thiazolo[5,4-d]pyrimidine-2-carboxamide; (7S)-4-[(6-hydroxy-1H-pyrazolo[3,4-b]pyridin-5-yl)amino ]-N-methyl-N-(3,3,3-trifluoropropyl)-5,6,7,8-tetrahydro[1]benzothieno[2,3-d]pyrimidin-7- Methionamine; [3-(dimethylamino)azetidin-1-yl][(7S)-4-(1H-pyrazolo[3,4-c]pyridin-5-ylamine -5,6,7,8-tetrahydro[1]benzothieno[2,3-d]pyrimidin-7-yl]methanone; [3-(dimethylamino)azetidine Alken-1-yl]{(7S)-4-[(6-methoxy-1H-pyrazolo[3,4-b]pyridin-5-yl)amino]-5,6,7,8 - tetrahydro[1]benzothieno[2,3-d]pyrimidin-7-yl}methanone; [3-(Dimethylamino)azetidin-1-yl][(7S)-4-(1H-pyrazolo[3,4-b]pyridin-5-ylamino)-5 ,6,7,8-tetrahydro[1]benzothieno[2,3-d]pyrimidin-7-yl]methanone; {(7S)-4-[(6-methoxy-1H-pyridyl) Zoxao[3,4-b]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-methoxy-1H-pyrazolo[3,4-b]pyridine -5-yl)amino]-5,6,7,8-tetrahydro[1]benzothieno[2,3-d]pyrimidin-7-yl}(morpholin-4-yl)methanone; Azetidin-1-yl {(7S)-4-[(6-methoxy-1H-pyrazolo[3,4-b]pyridin-5-yl)amino]-5,6, 7,8-tetrahydro[1]benzothieno[2,3-d]pyrimidin-7-yl}methanone; [(2R,6S)-2,6-dimethylmorpholin-4-yl] {(7S)-4-[(6-Methoxy-1H-pyrazolo[3,4-b]pyridin-5-yl)amino]-5,6,7,8-tetrahydro[1] Benzothieno[2,3-d]pyrimidin-7-yl}methanone; (7S)-4-[(6-methoxy-1H-pyrazolo[3,4-b]pyridine-5- Amino]-N-methyl-N-(propan-2-yl)-5,6,7,8-tetrahydro[1]benzothieno[2,3-d]pyrimidin-7- Indoleamine; (7S)-4-[(6-methoxy-1H-pyrazolo[3,4-b]pyridin-5-yl)amino]-N-methyl-N-propyl-5 , 6,7,8-tetrahydro[1]benzo Benzo[2,3-d]pyrimidine-7-carboxamide; (7S)-N-ethyl-4-[(6-methoxy-1H-pyrazolo[3,4-b]pyridine- 5-yl)amino]-N-methyl-5,6,7,8-tetrahydro[1]benzothieno[2,3-d]pyrimidin-7-carboxamide; {(7S)- 4-[(6-methoxy-1H-pyrazolo[3,4-b]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-methoxy-1H-pyrazolo[3,4-b]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-Methoxy-1H-pyrazolo[3,4-b]pyridin-5-yl)amino]-5,6,7,8-tetrahydro[1]benzothieno[2, 3-d]pyrimidin-7-yl}(4-methylpiperazin-1-yl)methanone; [4-(Dimethylamino)piperidin-1-yl]{(7S)-4-[(6-methoxy-1H-pyrazolo[3,4-b]pyridin-5-yl) Amino]-5,6,7,8-tetrahydro[1]benzothieno[2,3-d]pyrimidin-7-yl}methanone; {(7S)-4-[(6-methoxy) -1H-pyrazolo[3,4-b]pyridin-5-yl)amino]-5,6,7,8-tetrahydro[1]benzothieno[2,3-d]pyrimidine- 7-yl}[(3R)-3-methylmorpholin-4-yl]methanone; {(7S)-4-[(6-methoxy-1H-pyrazolo[3,4-b] Pyridin-5-yl)amino]-5,6,7,8-tetrahydro[1]benzothieno[2,3-d]pyrimidin-7-yl}[(3S)-3-methyl? (7S)-N-ethyl-N-(propan-2-yl)-4-(1H-pyrazolo[3,4-c]pyridin-5-ylamino -5,6,7,8-tetrahydro[1]benzothieno[2,3-d]pyrimidin-7-carboxamide; (7S)-N-(2-hydroxy-2-methylpropane -N-methyl-4-(1H-pyrazolo[3,4-c]pyridin-5-ylamino)-5,6,7,8-tetrahydro[1]benzothieno[ 2,3-d]pyrimidine-7-formamide; (7S)-N-methyl-4-(1H-pyrazolo[3,4-c]pyridin-5-ylamino)-N-( 3,3,3-trifluoropropyl)-5,6,7,8-tetrahydro[1]benzothieno[2,3-d]pyrimidin-7-carboxamide; (7S)-N- (2-methoxyethyl)-4-[(6-methoxy-1H-pyrazolo[3,4-b]pyridin-5-yl)amino]-N-propyl-5,6 ,7,8-tetrahydro[1]benzothieno[2,3 -d]pyrimidin-7-formamide; (7S)-4-[(6-hydroxy-1H-pyrazolo[3,4-b]pyridin-5-yl)amino]-N-(2- Methoxyethyl)-N-propyl-5,6,7,8-tetrahydro[1]benzothieno[2,3-d]pyrimidin-7-carboxamide; (7S)-N- Butyl-4-[(6-methoxy-1H-pyrazolo[3,4-b]pyridin-5-yl)amino]-N-methyl-5,6,7,8-tetrahydro [1] benzothieno[2,3-d]pyrimidin-7-carboxamide; (7S)-N-butyl-4-[(6-hydroxy-1H-pyrazolo[3,4-b Pyridyl-5-yl)amino]-N-methyl-5,6,7,8-tetrahydro[1]benzothieno[2,3-d]pyrimidin-7-carboxamide; (7S )-4-[(6-methoxy-1H-pyrazolo[3,4-b]pyridin-5-yl)amino]-N,N-dimethyl-5,6,7,8- Tetrahydro[1]benzothieno[2,3-d]pyrimidin-7-carboxamide; (7S)-4-[(6-Hydroxy-1H-pyrazolo[3,4-b]pyridin-5-yl)amino]-N,N-dimethyl-5,6,7,8- Tetrahydro[1]benzothieno[2,3-d]pyrimidin-7-carboxamide; azetidin-1-yl[(7S)-4-(1H-pyrazolo[3,4 -c]pyridin-5-ylamino)-5,6,7,8-tetrahydro[1]benzothieno[2,3-d]pyrimidin-7-yl]methanone; (7S)-N ,N-bis(2-methoxyethyl)-4-(1H-pyrazolo[3,4-c]pyridin-5-ylamino)-5,6,7,8-tetrahydro[1 Benzothieno[2,3-d]pyrimidin-7-carboxamide; (7S)-N-(2-methoxyethyl)-N-methyl-4-(1H-pyrazolo[ 3,4-c]pyridin-5-ylamino)-5,6,7,8-tetrahydro[1]benzothieno[2,3-d]pyrimidin-7-carboxamide; (7S) -N-ethyl-N-methyl-4-(1H-pyrazolo[3,4-c]pyridin-5-ylamino)-5,6,7,8-tetrahydro[1]benzo Thieno[2,3-d]pyrimidin-7-carboxamide; (7S)-N,N-dimethyl-4-(1H-pyrazolo[3,4-b]pyridin-5-ylamine -5,6,7,8-tetrahydro[1]benzothieno[2,3-d]pyrimidin-7-carboxamide; (7S)-N,N-dimethyl-4-( 1H-pyrazolo[3,4-c]pyridin-5-ylamino)-5,6,7,8-tetrahydro[1]benzothieno[2,3-d]pyrimidin-7-A Indoleamine; [5-bromo-4-(1H-pyrazolo[3,4-b]pyridin-5-ylamino)-7H-pyrrolo[2,3-d]pyrimidin-6-yl]( Piperidin-1-yl) ; 5-bromo-N-[2-(dimethylamino)ethyl]-4-[(6-methoxy-1H-pyrazolo[3,4-b]pyridin-5-yl)amine -N-methyl-7H-pyrrolo[2,3-d]pyrimidine-6-carboxamide; 5-bromo-N-[2-(dimethylamino)ethyl]-4-[ (6-Hydroxy-1H-pyrazolo[3,4-b]pyridin-5-yl)amino]-N-methyl-7H-pyrrolo[2,3-d]pyrimidin-6-carboxamide ;{5-Bromo-4-[(6-methoxy-1H-pyrazolo[3,4-b]pyridin-5-yl)amino]-7H-pyrrolo[2,3-d]pyrimidine -6-yl}[4-(dimethylamino)piperidin-1-yl]methanone; {5-bromo-4-[(6-hydroxy-1H-pyrazolo[3,4-b] Pyridyl-5-yl)amino]-7H-pyrrolo[2,3-d]pyrimidin-6-yl}[4-(dimethylamino)piperidin-1-yl]methanone; {5- Bromo-4-[(6-methoxy-1H-pyrazolo[3,4-b]pyridin-5-yl)amino]-7H-pyrrolo[2,3-d]pyrimidin-6-yl }[(3R)-3-methylmorpholin-4-yl]methanone; {5-Bromo-4-[(6-methoxy-1H-pyrazolo[3,4-b]pyridin-5-yl)amino]-7H-pyrrolo[2,3-d]pyrimidine- 6-yl}(morpholin-4-yl)methanone; {5-bromo-4-[(6-hydroxy-1H-pyrazolo[3,4-b]pyridin-5-yl)amino]- 7H-pyrrolo[2,3-d]pyrimidin-6-yl}(morpholin-4-yl)methanone; [5-bromo-4-(1H-pyrazolo[3,4-c]pyridine- 5-ylamino)-7H-pyrrolo[2,3-d]pyrimidin-6-yl][4-(dimethylamino)piperidin-1-yl]methanone; [5-bromo-4 -(1H-pyrazolo[3,4-c]pyridin-5-ylamino)-7H-pyrrolo[2,3-d]pyrimidin-6-yl][(3R)-3-methyl? [4-bromo-4-(1H-pyrazolo[3,4-c]pyridin-5-ylamino)-7H-pyrrolo[2,3-d]pyrimidine -6-yl](morpholin-4-yl)methanone; [5-bromo-4-(1H-pyrazolo[3,4-c]pyridin-5-ylamino)-7H-pyrrolo[ 2,3-d]pyrimidin-6-yl](piperidin-1-yl)methanone; [5-bromo-4-(1H-pyrazolo[3,4-b]pyridin-5-ylamino -7H-pyrrolo[2,3-d]pyrimidin-6-yl][(3R)-3-methylmorpholin-4-yl]methanone; [5-bromo-4-(1H-pyrazole) And [3,4-b]pyridin-5-ylamino)-7H-pyrrolo[2,3-d]pyrimidin-6-yl](morpholin-4-yl)methanone; [5-bromo- 4-(1H-pyrazolo[3,4-b]pyridin-5-ylamino)-7H-pyrrolo[2,3-d]pyrimidin-6-yl][(3S)-3-methyl What? Phenyl-4-yl]methanone; N-[2-(dimethylamino)-2-oxoethyl]-4-(1H-pyrazolo[3,4-c]pyridine-5- Amino)-7H-pyrrolo[2,3-d]pyrimidine-6-carboxamide; N-[2-(dimethylamino)ethyl]-N-methyl-4-(1H- Pyrazolo[3,4-c]pyridin-5-ylamino)-7H-pyrrolo[2,3-d]pyrimidine-6-carboxamide; N-{2-[benzyl (methyl) Amino]ethyl}-N-methyl-4-(1H-pyrazolo[3,4-c]pyridin-5-ylamino)-7H-pyrrolo[2,3-d]pyrimidine- 6-carbamide; 2-(2-phenylethyl)-N-(1H-pyrazolo[3,4-c]pyridin-5-yl)[1,3]thiazolo[5,4- d] pyrimidine-7-amine; (7S)-N-(propan-2-yl)-4-(1H-pyrazolo[3,4-c]pyridin-5-ylamino)-5,6,7,8-tetrahydro[1 Benzothieno[2,3-d]pyrimidin-7-carboxamide; (7S)-N-methyl-N-propyl-4-(1H-pyrazolo[3,4-c]pyridine -5-ylamino)-5,6,7,8-tetrahydro[1]benzothieno[2,3-d]pyrimidin-7-carboxamide; 1-{[(7S)-4- (1H-pyrazolo[3,4-c]pyridin-5-ylamino)-5,6,7,8-tetrahydro[1]benzothieno[2,3-d]pyrimidin-7- Alkyl}carbonyl azetidine-3-carbonitrile; 2-oxa-6-azaspiro[3.3]hept-6-yl[(7S)-4-(1H-pyrazolo[3,4 -c]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-(1H-pyrazolo[3,4-c]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-(1H-pyrazolo[3,4-c]pyridin-5-ylamino)-5,6,7,8-tetrahydro[1]benzothieno[2,3- d]pyrimidin-7-yl]methanone;morpholin-4-yl[(7S)-4-(1H-pyrazolo[3,4-c]pyridin-5-ylamino)-5,6, 7,8-tetrahydro[1]benzothieno[2,3-d]pyrimidin-7-yl]methanone; [(3S)-3-methylmorpholin-4-yl][(7S)- 4-(1H-pyrazolo[3 , 4-c]pyridin-5-ylamino)-5,6,7,8-tetrahydro[1]benzothieno[2,3-d]pyrimidin-7-yl]methanone; [(3R )-3-methylmorpholin-4-yl][(7S)-4-(1H-pyrazolo[3,4-c]pyridin-5-ylamino)-5,6,7,8- Tetrahydro[1]benzothieno[2,3-d]pyrimidin-7-yl]methanone; [(2R,6S)-2,6-dimethylmorpholin-4-yl][(7S) 4-(1H-pyrazolo[3,4-c]pyridin-5-ylamino)-5,6,7,8-tetrahydro[1]benzothieno[2,3-d]pyrimidine -7-yl]methanone; (4-methylpiperazin-1-yl)[(7S)-4-(1H-pyrazolo[3,4-c]pyridin-5-ylamino)-5 ,6,7,8-tetrahydro[1]benzothieno[2,3-d]pyrimidin-7-yl]methanone; [4-(dimethylamino)piperidin-1-yl][ (7S)-4-(1H-pyrazolo[3,4-c]pyridin-5-ylamino)-5,6,7,8-tetrahydro[1]benzothieno[2,3- d]pyrimidin-7-yl]methanone; (7S)-N-ethyl-N-methyl-4-(1H-pyrazolo[3,4-b]pyridin-5-ylamino)-5 , 6,7,8-tetrahydro[1]benzothieno[2,3-d]pyrimidin-7-carboxamide; (7S)-N-methyl-N-propyl-4-(1H-pyrazolo[3,4-b]pyridin-5-ylamino)-5,6,7,8-tetrahydro[1 Benzothieno[2,3-d]pyrimidin-7-carboxamide; (7S)-N-methyl-4-(1H-pyrazolo[3,4-b]pyridin-5-ylamine -N-(3,3,3-trifluoropropyl)-5,6,7,8-tetrahydro[1]benzothieno[2,3-d]pyrimidin-7-carboxamide; (7S)-N-methyl-N-(propan-2-yl)-4-(1H-pyrazolo[3,4-b]pyridin-5-ylamino)-5,6,7,8 -tetrahydro[1]benzothieno[2,3-d]pyrimidin-7-carboxamide; (7S)-N-(2-methoxyethyl)-N-methyl-4-(1H -pyrazolo[3,4-b]pyridin-5-ylamino)-5,6,7,8-tetrahydro[1]benzothieno[2,3-d]pyrimidin-7-formamidine Amine; azetidin-1-yl[(7S)-4-(1H-pyrazolo[3,4-b]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-(1H -pyrazolo[3,4-b]pyridin-5-ylamino)-5,6,7,8-tetrahydro[1]benzothieno[2,3-d]pyrimidin-7-yl] Methyl ketone; 1-{[(7S)-4-(1H-pyrazolo[3,4-b]pyridin-5-ylamino)-5,6,7,8-tetrahydro[1]benzo Thieno[2,3-d]pyrimidin-7-yl]carbonyl}azetidin-3-carbonitrile; [(3S)-3-(dimethylamino)pyrrolidin-1-yl][ (7S)-4-(1H- Zoxao[3,4-b]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-(1H-pyrazolo[3,4-b]pyridin-5-ylamino) -5,6,7,8-tetrahydro[1]benzothieno[2,3-d]pyrimidin-7-yl]methanone;morpholin-4-yl[(7S)-4-(1H- Pyrazolo[3,4-b]pyridin-5-ylamino)-5,6,7,8-tetrahydro[1]benzothieno[2,3-d]pyrimidin-7-yl]- Ketone; [(3R)-3-methylmorpholin-4-yl][(7S)-4-(1H-pyrazolo[3,4-b]pyridin-5-ylamino)-5,6 ,7,8-tetrahydro[1]benzothieno[2,3-d]pyrimidin-7-yl]methanone; [(3S)-3-methylmorpholin-4-yl][(7S) -4-(1H-pyrazolo[3,4-b]pyridin-5-ylamino)-5,6,7,8-tetrahydro[1]benzothieno[2,3-d]pyrimidine -7-yl]methanone; [(2R,6S)-2,6-dimethylmorpholin-4-yl][(7S)-4-(1H-pyrazolo[3,4-b]pyridine -5-ylamino)-5,6,7,8-tetrahydro[1]benzothieno[2,3-d]pyrimidin-7-yl]methanone; (4-methylpiperazin-1-yl)[(7S)-4-(1H-pyrazolo[3,4-b]pyridin-5-ylamino)-5,6,7,8-tetra Hydrogen [1] benzothieno[2,3-d]pyrimidin-7-yl]methanone; [4-(dimethylamino)piperidin-1-yl][(7S)-4-(1H -pyrazolo[3,4-b]pyridin-5-ylamino)-5,6,7,8-tetrahydro[1]benzothieno[2,3-d]pyrimidin-7-yl] Methyl ketone; 1-({(7S)-4-[(6-methoxy-1H-pyrazolo[3,4-b]pyridin-5-yl)amino]-5,6,7,8 -tetrahydro[1]benzothieno[2,3-d]pyrimidin-7-yl}carbonyl)azetidin-3-carbonitrile; {(7S)-4-[(6-methoxy) -1H-pyrazolo[3,4-b]pyridin-5-yl)amino]-5,6,7,8-tetrahydro[1]benzothieno[2,3-d]pyrimidine-7 -yl}(2-oxa-6-azaspiro[3.3]hept-6-yl)methanone; [(3R)-3-(dimethylamino)pyrrolidin-1-yl]{(7S --4-[(6-Methoxy-1H-pyrazolo[3,4-b]pyridin-5-yl)amino]-5,6,7,8-tetrahydro[1]benzothiophene And [2,3-d]pyrimidin-7-yl}methanone; [(3S)-3-(dimethylamino)pyrrolidin-1-yl]{(7S)-4-[(6-A) oxy-1H-pyrazolo[3,4-b]pyridin-5-yl)amino]-5,6,7,8-tetrahydro[1]benzothieno[2,3-d]pyrimidine -7-yl}methanone; (7S)-N-ethyl-4-[(6-hydroxy-1H-pyrazolo[3,4-b]pyridin-5-yl)amino]-N- Base-5,6,7,8-four [1] benzothieno[2,3-d]pyrimidin-7-carboxamide; (7S)-4-[(6-hydroxy-1H-pyrazolo[3,4-b]pyridine-5- Amino]-N-methyl-N-propyl-5,6,7,8-tetrahydro[1]benzothieno[2,3-d]pyrimidin-7-carboxamide; (7S )-4-[(6-Hydroxy-1H-pyrazolo[3,4-b]pyridin-5-yl)amino]-N-methyl-N-(propan-2-yl)-5,6 , 7,8-tetrahydro[1]benzothieno[2,3-d]pyrimidin-7-carboxamide; {(7S)-4-[(6-hydroxy-1H-pyrazolo[3, 4-b]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-hydroxy-1H-pyrazolo[3,4-b Pyridine-5-yl)amino]-5,6,7,8-four Hydrogen [1] benzothieno[2,3-d]pyrimidin-7-yl}(4-methylpiperazin-1-yl)methanone; [4-(dimethylamino)piperidine-1 -yl]{(7S)-4-[(6-hydroxy-1H-pyrazolo[3,4-b]pyridin-5-yl)amino]-5,6,7,8-tetrahydro[1 Benzothieno[2,3-d]pyrimidin-7-yl}methanone; 5-bromo-N-[3-(dimethylamino)propyl]-4-(1H-pyrazole[ 3,4-c]pyridin-5-ylamino)-7H-pyrrolo[2,3-d]pyrimidin-6-carboxamide; 5-bromo-N-[3-(dimethylamino) Propyl]-N-methyl-4-(1H-pyrazolo[3,4-c]pyridin-5-ylamino)-7H-pyrrolo[2,3-d]pyrimidin-6-carboxamidine Amine; 5-bromo-N-[2-(dimethylamino)ethyl]-4-(1H-pyrazolo[3,4-c]pyridin-5-ylamino)-7H-pyrrole [2,3-d]pyrimidine-6-formamide; [5-bromo-4-(1H-pyrazolo[3,4-c]pyridin-5-ylamino)-7H-pyrrolo[2 ,3-d]pyrimidin-6-yl][(3S)-3-methylmorpholin-4-yl]methanone; N-[2-(dimethylamino)-2-oxoethyl ]-N-methyl-7-(1H-pyrazolo[3,4-c]pyridin-5-ylamino)[1,3]thiazolo[5,4-d]pyrimidin-2-carboxamidine Amine; N,N-dimethyl-7-(1H-pyrazolo[3,4-b]pyridin-5-ylamino)[1,3]thiazolo[5,4-d]pyrimidine-2 -Procarbamide; 5-bromo-N-[2-(dimethylamino)ethyl]-4-(1H-pyrazolo[3,4-b]pyridine -5-ylamino)-7H-pyrrolo[2,3-d]pyrimidine-6-carboxamide; 5-bromo-N-[3-(dimethylamino)propyl]-4-( 1H-pyrazolo[3,4-b]pyridin-5-ylamino)-7H-pyrrolo[2,3-d]pyrimidine-6-carboxamide; piperidin-1-yl [7-( 1H-pyrazolo[3,4-b]pyridin-5-ylamino)[1,3]thiazolo[5,4-d]pyrimidin-2-yl]methanone; [5-bromo-4- (1H-pyrazolo[3,4-b]pyridin-5-ylamino)-7H-pyrrolo[2,3-d]pyrimidin-6-yl][4-(dimethylamino)per Acridine-1-yl]methanone; N-[2-(dimethylamino)-2-oxoethyl]-N-methyl-7-(1H-pyrazolo[3,4-b Pyridine-5-ylamino)[1,3]thiazolo[5,4-d]pyrimidin-2-carboxamide; N-[3-(Dimethylamino)-3-oxopropyl]-N-methyl-7-(1H-pyrazolo[3,4-b]pyridin-5-ylamino) [1,3]thiazolo[5,4-d]pyrimidine-2-carboxamide; N-[2-(dimethylamino)-2-oxoethyl]-7-[(6- Methoxy-1H-pyrazolo[3,4-b]pyridin-5-yl)amino]-N-methyl[1,3]thiazolo[5,4-d]pyrimidin-2-carboxamidine Amine; 5-bromo-N-[3-(dimethylamino)propyl]-4-[(6-methoxy-1H-pyrazolo[3,4-b]pyridin-5-yl) Amino]-N-methyl-7H-pyrrolo[2,3-d]pyrimidine-6-carboxamide; 5-bromo-N-[3-(dimethylamino)propyl]-4- [(6-Hydroxy-1H-pyrazolo[3,4-b]pyridin-5-yl)amino]-N-methyl-7H-pyrrolo[2,3-d]pyrimidin-6-carboxamidine Amine; {7-[(6-methoxy-1H-pyrazolo[3,4-b]pyridin-5-yl)amino][1,3]thiazolo[5,4-d]pyrimidine- 2-yl}(piperidin-1-yl)methanone; {5-bromo-4-[(6-hydroxy-1H-pyrazolo[3,4-b]pyridin-5-yl)amino]- 7H-pyrrolo[2,3-d]pyrimidin-6-yl}(piperidin-1-yl)methanone; {5-bromo-4-[(6-methoxy-1H-pyrazolo[3] ,4-b]pyridin-5-yl)amino]-7H-pyrrolo[2,3-d]pyrimidin-6-yl}[(3S)-3-methylmorpholin-4-yl]methanone Or its tautomers, N-oxides, hydrates, solvates or salts, or such a mixture of substances. A process for the preparation of a compound of the formula I according to any one of claims 1 to 10, in which an intermediate compound of the formula II is obtained: Wherein A is as defined in any one of claims 1 to 10, and LG represents a leaving group; reacting with an intermediate compound of formula IV : Wherein R ^1b , R ^1c and QV are as defined in any one of claims 1 to 10, and PG represents a protecting group or a hydrogen atom; thus providing a compound of the formula I' or I : Wherein R ^1b , R ^1c , QV and A are as defined in any one of claims 1 to 10, and PG represents a protecting group or a hydrogen atom. A compound of the formula I , or a stereoisomer, tautomer, N-oxide, hydrate, solvate or salt thereof, according to any one of claims 1 to 10, especially pharmaceutically acceptable A salt, or a mixture of such substances, for use in treating or preventing a disease. The compound of claim 12, wherein the disease is a disease of uncontrolled cell growth, proliferation and/or survival, inappropriate cellular immune response, or inappropriate cellular inflammatory response, particularly wherein the uncontrolled cell growth, proliferation and/or survival, Improper cellular immune response or inappropriate cell inflammatory response is mediated by the MKNK1 pathway, more particularly the disease in which uncontrolled cell growth, proliferation and/or survival, inappropriate cellular immune response, or inappropriate cellular inflammatory response are hematological tumors, solid tumors and/or Or metastasis, such as leukemia and myelodysplastic syndromes, 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 tumors (including kidney tumors, bladder tumors, and prostate tumors), skin tumors, and sarcomas, and/or Transfer. A pharmaceutical composition comprising a compound of the formula I according to any one of claims 1 to 10, or a stereoisomer, tautomer, N-oxide, hydrate, solvate or salt thereof, especially A pharmaceutically acceptable salt thereof, or a mixture of such materials, and a pharmaceutically acceptable diluent or carrier. A pharmaceutical combination comprising: one or more first active ingredients selected from the group consisting of the compounds of formula I according to any one of claims 1 to 10; and one or more second active ingredients selected from the group consisting of chemotherapeutic anticancer agents. A compound of the formula I , or a stereoisomer, tautomer, N-oxide, hydrate, solvate or salt thereof, according to any one of claims 1 to 10, especially pharmaceutically acceptable The use of a salt or a mixture of such substances for the preparation of a medicament for the prevention or treatment of a disease. The use of claim 16, wherein the disease is a disease of uncontrolled cell growth, proliferation and/or survival, inappropriate cellular immune response, or inappropriate cellular inflammatory response, particularly wherein the uncontrolled cell grows, proliferates, and/or survives, Improper cellular immune response or inappropriate cell inflammatory response is mediated by the MKNK1 pathway, more particularly the disease in which uncontrolled cell growth, proliferation and/or survival, inappropriate cellular immune response, or inappropriate cellular inflammatory response are hematological tumors, solid tumors and/or Or metastasis, such as leukemia and myelodysplastic syndromes, 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 tumors (including kidney tumors, bladder tumors, and prostate tumors), skin tumors, and sarcomas, and/or their metastases. An intermediate compound of formula IV , Wherein R ^1b , R ^1c and QV are as defined in any one of claims 1 to 10, and PG represents a protecting group or a hydrogen atom. Use of a compound of formula II or IV as defined in claim 11 for the preparation of a compound of formula I according to any one of claims 1 to 10.