5-Morpholin-4-yl-pyrazolo[4,3-b]pyridine derivatives

Abstract

Compounds of formula Ia and Ib, wherein R 1 , R 2 and R 3 have the meanings shown in claim 1, said compounds being inhibitors of ATR and being useful for the treatment of diseases such as cancer.

Description

Background Art

[0001] The object of the present invention is to discover new compounds having valuable properties, in particular those which can be used for the preparation of medicaments.

[0002] The present invention relates to 5-morpholin-4-yl-pyrazolo[4,3-b]pyridine derivatives which inhibit ATR (ataxia telangiectasia mutated and Rad3-related kinase). Thus, the compounds of the present invention can be used for treating diseases such as cancer.

[0003] The present invention also provides methods for preparing these compounds, pharmaceutical compositions comprising these compounds, and methods for treating diseases using the pharmaceutical compositions comprising these compounds.

[0004] The chemical entities of the present invention are inhibitors of ATR and have many therapeutic applications, especially in the treatment of cancer.

[0005] Cancer is the result of uncontrolled cell growth in a variety of different tissues. In many cases, the new cells penetrate into the existing tissues, or they metastasize to distant organs. Cancer occurs in a variety of organs and usually develops in a tissue-specific manner. Thus, the term "cancer" as a general term describes a large group of defined diseases of different organs, tissues and cell types.

[0006] In 2008, more than 12 million people worldwide were diagnosed with cancer. Approximately 7.5 million deaths in the same year were considered to be the result of these diseases (Globocan 2008 Report). In the United States alone, in 2012, it was predicted that there would be more than 1.6 million new cases and more than 500,000 deaths due to cancer. Most of these new cases involve colon cancer (~100,000), lung cancer (~230,000), breast cancer (~230,000) and prostate cancer (~240,000) (American Cancer Society, Cancer Facts and Figures 2012).

[0007] Many current cancer treatments, including chemotherapeutic agents and ionizing radiation, induce DNA damage and replication fork stalling, thereby activating the cell cycle checkpoint pathway and leading to cell cycle arrest. Multiple studies have shown that this response is an important mechanism for helping cancer cells survive during treatment. These findings have promoted the development of reagents that target the DNA damage response signaling pathway.

[0008] ATR is a member of the phosphatidylinositol kinase-related kinase (PIKK) protein family and is activated by a variety of DNA damage events. In particular, ATR is essential for coordinating the response to replication stress (RS), which represents the pathological accumulation of single-stranded DNA (ssDNA). The recombinogenic nature of ssDNA leads to chromosomal rearrangements, which are hallmarks of cancer. In response to RS, ATR triggers the arrest of the S and G2 / M phases of the cell cycle through the phosphorylation of CHK1.

[0009] ATR can prevent cancer development because the ATR checkpoint response may limit the expansion of pre-cancerous cells undergoing RS as a result of proto-oncogene activation. In addition, because the ATR-CHK1 checkpoint pathway is used to ensure cell survival after RS, a normal and robust ATR-CHK1 checkpoint can be a mechanism of chemoresistance and can allow cancer cells to survive at high levels of endogenous RS.

[0010] Inhibiting components of the ATR-CHK1 pathway may potentially enhance the efficacy of replication inhibitors. In addition, ATR inhibition may be particularly toxic to cells with high levels of RS, such as cells expressing proto-oncogenes or lacking tumor suppressors. In these cells, a strong limitation of ATR activity (e.g., by using an ATR inhibitor) will generate a lethal amount of RS, leading to cell death.

[0011] The potential advantage of sensitizing cells in this way is the ability to reduce the dose of replication inhibitors. If normal cells are not sensitized to the same extent, this will result in reduced toxicity to blood and gastrointestinal organ systems, etc. The fact that untransformed cells have more robust S and G2 checkpoints than tumor cells helps the specificity of replication inhibitors to cause cancer cell death. For example, many cancers have mutations in p53 or other components of the p53 pathway, leading to dependence on the S and G2 checkpoints to arrest the cell cycle and provide repair and survival. Then inhibiting the S and G2 checkpoints can preferentially kill these p53-deficient tumor cells.

[0012] The listing or discussion of apparently prior art documents in this specification should not necessarily be taken as an admission that such documents are part of the prior art or common general knowledge.

[0013] There is a lack of effective ATR inhibitors. Therefore, there is a need for chemical entities that selectively inhibit ATR for clinical applications or for further research on ATR responses.

[0014] It has been found that the compounds and salts according to the present invention have very valuable pharmacological properties while being well tolerated.

[0015] The subject or patient can belong to any mammalian species, such as a primate species, especially a human; a rodent, including a mouse, a rat, and a hamster; a rabbit; a horse, a cow, a dog, a cat, etc. Animal models are of interest for experimental research, which provide models for treating human diseases.

[0016] The sensitivity of a particular cell to treatment with a compound according to the invention can be determined by in vitro tests. Generally, a cell culture is combined with different concentrations of the compound according to the invention for a period of time sufficient for an active agent such as anti-IgM to induce a cellular response such as the expression of a surface marker, usually between about one hour and one week. The in vitro test can be carried out using cultured cells from blood or from a biopsy sample. The expression level of the surface marker is evaluated by flow cytometry using a specific antibody that recognizes the marker.

[0017] The dose varies depending on the specific compound used, the specific disease, the patient's condition, etc. The therapeutic dose is usually sufficient to significantly reduce the unwanted cell population in the target tissue while maintaining the viability of the patient. The treatment usually continues until a substantial reduction occurs, for example, the cell load is reduced by at least about 50%, and can continue until the unwanted cells are essentially no longer detected in the body.

[0018] Prior art

[0019] Other bicyclic heterocyclic compounds for treating cancer have been described in WO 2013 / 130660A1 and WO 2017 / 121684A1. Summary of the invention

[0020] The present invention relates to compounds of formula Ia and Ib

[0021]

[0022] wherein

[0023] R 1 represents H, Het, Ar, (CH2) n OH, 1-methanesulfonyl-cyclopropyl-1-yl, CONH2, CONHA, CONA2, Cyc, OA or CH(A)SO2A,

[0024] R 2 represents H, A, (CH2) n Ar, (CH2) n Cyc or (CH2) n Het,

[0025] R 3 represents H or A,

[0026] Het represents a mono- or bicyclic aromatic, unsaturated or saturated heterocycle having 1 to 4 N, O and / or S atoms, which may be unsubstituted or mono-, di- or trisubstituted by NH2, NHA, NA2, COOH, COOA, CONH2, CONHA, CONA2, CONHAr, CN, OH, (CH2) n Ar 1 、O(CH2) n Ar 1 、A, SOA, SO2A, Hal, =NH and / or =O,

[0027] Ar represents phenyl, naphthyl or biphenyl, each of which is unsubstituted or mono-, di- or trisubstituted by NH2, NHA, NA2, COOH, COOA, CONH2, CONHA, CONA2, NHCOA, CHO, COA, SO3H, SO2NH2, O(CH2) p NH2, (CH2) n Het 1 、O(CH2) n Het 1 、(CH2) n Ar 1 、O(CH2) n Ar 1 、O(CH2) p CONH2, O(CH2) p NHCOA, Hal, SOA, S(=O, =NH)A, SO2A, A, CN and / or (CH2) n OH,

[0028] Ar 1 represents phenyl which is unsubstituted or mono-, di- or trisubstituted by Hal, A, OH and / or OA,

[0029] Het 1 represents a mono- or bicyclic aromatic, unsaturated or saturated heterocycle having 1 to 4 N, O and / or S atoms, which may be unsubstituted or mono-, di- or trisubstituted by Hal, A, COOA, NH2, NHA and / or NA2,

[0030] A represents a straight-chain or branched alkyl having 1 to 6 C atoms, where 1 to 7 H atoms may be replaced by OH, F, Cl and / or Br, and / or where one or two non-adjacent CH2 groups may be replaced by O and / or NH groups,

[0031] Cyc represents a cycloalkyl having 3, 4, 5, 6 or 7 C atoms,

[0032] Hal represents F, Cl, Br or I,

[0033] n represents 0, 1, 2, 3 or 4,

[0034] p represents 1, 2, 3 or 4,

[0035] and their pharmaceutically acceptable salts, tautomers and stereoisomers, including mixtures thereof in all ratios.

[0036] The present invention also relates to the optically active forms (stereoisomers), enantiomers, racemates, diastereoisomers and hydrates and solvates of these compounds.

[0037] Furthermore, the present invention relates to pharmaceutically acceptable derivatives of the compounds of formulae Ia and Ib.

[0038] The term solvate of a compound refers to the adduct formed on the compound by inert solvent molecules due to their mutual attraction. Solvates are, for example, mono- or dihydrates or alcoholates.

[0039] It is to be understood that the present invention also relates to solvates of said salts.

[0040] The term pharmaceutically acceptable derivative refers to, for example, salts of the compounds according to the invention and so-called prodrug compounds.

[0041] Unless otherwise indicated, the term "prodrug" as used herein refers to a derivative of a compound of formula I which is hydrolysable, oxidisable or otherwise reactive under biological conditions (in vitro or in vivo) to provide the active compound, in particular a compound of formula I. Examples of prodrugs include, but are not limited to, derivatives and metabolites of compounds of formula I which include a biolysable moiety such as a biolysable amide, a biolysable ester, a biolysable carbamate, a biolysable carbonate, a biolysable acylurea and a biolysable phosphate ester analogue. In certain embodiments, the prodrug of a compound having a carboxyl functional group is a lower alkyl ester of the carboxylic acid. The carboxylic acid ester is conveniently formed by esterifying any carboxylic acid moiety present on the molecule. Prodrugs can generally be prepared using well-known methods, such as those described in Burger's Medicinical Chemistry and Drug Discovery, 6th Edition (Donald J. Abraham ed., 2001, Wiley) and Design and Application of Prodrugs (H. Bundgaard ed., 1985, Harwood Academic Publishers Gmfh).

[0042] The expression "effective amount" means the amount of a drug or pharmacologically active ingredient that elicits a biological or medical response, such as that sought or desired by a researcher or physician, in a tissue, system, animal or human.

[0043] Furthermore, the expression "therapeutically effective amount" means an amount that has the following results compared to a corresponding subject who has not received that amount:

[0044] Improving the treatment, cure, prevention or elimination of a disease, syndrome, condition, discomfort, disorder or side effect, or also reducing the progression of a disease, discomfort or disorder.

[0045] The expression "therapeutically effective amount" also includes an amount that effectively increases normal physiological functions.

[0046] The present invention also relates to the use of mixtures of compounds of formula Ia and Ib (for example, mixtures of two diastereomers), the ratio of the two diastereomers being, for example, 1:1, 1:2, 1:3, 1:4, 1:5, 1:10, 1:100 or 1:1000.

[0047] These are mixtures of stereoisomeric compounds that are particularly preferred.

[0048] "Tautomers" refer to isomeric forms of a compound that are in equilibrium with each other. The concentration of the isomeric forms will depend on the environment in which the compound is located and can vary, for example, depending on whether the compound is a solid or in an organic or aqueous solution.

[0049] Unless otherwise expressly stated, the groups R 1 、R 2 and R 3 have the meanings shown in formula I.

[0050] A represents an alkyl group which is unbranched (linear) or branched and has 1, 2, 3, 4, 5, 6, 7 or 8 C atoms. A preferably represents methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl or tert-butyl, and also represents pentyl, 1-, 2- or 3-methylbutyl, 1,1-, 1,2- or 2,2-dimethylpropyl, 1-ethylpropyl, hexyl, 1-, 2-, 3- or 4-methylpentyl, 1,1-, 1,2-, 1,3-, 2,2-, 2,3- or 3,3-dimethylbutyl, 1- or 2-ethylbutyl, 1-ethyl-1-methylpropyl, 1-ethyl-2-methylpropyl, 1,1,2- or 1,2,2-trimethylpropyl, and also preferably, for example, trifluoromethyl.

[0051] A very particularly preferably represents an alkyl group having 1, 2, 3, 4, 5 or 6 C atoms, preferably methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, pentyl, hexyl, trifluoromethyl, pentafluoroethyl or 1,1,1-trifluoroethyl.

[0052] Furthermore, A preferably represents CH2OCH3, CH2CH2OH or CH2CH2OCH3.

[0053] R 3 Preferably represents H or CH3, most preferably H.

[0054] Cyc represents cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl or cycloheptyl.

[0055] The heterocyclic substituent pyridyl = pyridyl.

[0056] Without considering further substitution, Het represents, for example, 2- or 3-furyl, 2- or 3-thienyl, 1-, 2- or 3-pyrrolyl, 1-, 2-, 4- or 5-imidazolyl, 1-, 3-, 4- or 5-pyrazolyl, 2-, 4- or 5-oxazolyl, 3-, 4- or 5-isoxazolyl, 2-, 4- or 5-thiazolyl, 3-, 4- or 5-isothiazolyl, 2-, 3- or 4-pyridyl, 2-, 4-, 5- or 6-pyrimidinyl, more preferably 1,2,3-triazol-1-, -4- or -5-yl, 1,2,4-triazol-1-, -3- or 5-yl, 1- or 5-tetrazolyl, 1,2,3-oxadiazol-4- or -5-yl, 1,2,4-oxadiazol-3- or -5-yl, 1,3,4-thiadiazol-2- or -5-yl, 1,2,4-thiadiazol-3- or -5-yl, 1,2,3-thiadiazol-4- or -5-yl, 3- or 4-pyridazinyl, pyrazinyl, 1-, 2-, 3-, 4-, 5-, 6- or 7-indolyl, 4- or 5-isoindolyl, indazolyl, 1-,2-,4- or 5-benzimidazolyl, 1-,3-,4-,5-,6- or 7-benzopyrazolyl, 2-,4-,5-,6- or 7-benzoxazolyl, 3-,4-,5-,6- or 7-benzisoxazolyl, 2-,4-,5-,6- or 7-benzothiazolyl, 2-,4-,5-,6- or 7-benzisothiazolyl, 4-,5-,6- or 7-benzo-2,1,3-oxadiazolyl, 2-,3-,4-,5-,6-,7- or 8-quinolyl, 1-,3-,4-,5-,6-,7- or 8-isoquinolyl, 3-,4-,5-,6-,7- or 8-cinnolinyl, 2-,4-,5-,6-,7- or 8-quinazolinyl, 5- or 6-quinoxalin, 2-,3-,5-,6-,7- or 8-2H-benzo-1,4-oxazinyl, pyrrolopyridyl, purinyl, more preferably 1,3-benzodioxol-5-yl, 1,4-benzodioxan-6-yl, 2,1,3-benzothiadiazol-4- or -5-yl, 2,1,3-benzoxadiazol-5-yl, azabicyclo[3.2.1]octyl or dibenzofuryl.

[0057] The heterocyclic group may also be partially or fully hydrogenated.

[0058] Without considering further substitution, Het may thus also represent, for example, 2,3-dihydro-2-, -3-, -4- or -5-furanyl, 2,5-dihydro-2-, -3-, -4- or -5-furanyl, tetrahydro-2- or -3-furanyl, 1,3-dioxolan-4-yl, tetrahydro-2- or -3-thienyl, 2,3-dihydro-1-, -2-, -3-, -4- or -5-pyrrolyl, 2,5-dihydro-1-, -2-, -3-, -4- or -5-pyrrolyl, 1-, 2- or 3-pyrrolidinyl, tetrahydro-1-, -2- or -4-imidazolyl, 2,3-dihydro-1-, -2-, -3-, -4- or -5-pyrazolyl, tetrahydro-1-, -3- or -4-pyrazolyl, 1,4-dihydro-1-, -2-, -3- or -4-pyridinyl, 1,2,3,4-tetrahydro-1-, -2-, -3-, -4-, -5- or -6-pyridinyl, 1-, 2-, 3- or 4-piperidinyl, 2-, 3- or 4-morpholinyl, tetrahydro-2-, -3- or -4-pyranyl, 1,4-dioxanyl, 1,3-dioxan-2-, -4- or -5-yl, hexahydro-1-, -3- or -4-pyridazinyl, hexahydro-1-, -2-, -4- or -5-pyrimidinyl, 1-, 2- or 3-piperazinyl, 1,2,3,4-tetrahydro-1-, -2-, -3-, -4-, -5-, -6-, -7- or -8-quinolinyl, 1,2,3,4-tetrahydro-1-, -2-, -3-, -4-, -5-, -6-, -7- or -8-isoquinolinyl, 2-, 3-, 5-, 6-, 7- or 8-3,4-dihydro-2H-benzo-1,4-oxazinyl, further preferably 2,3-methylenedioxyphenyl, 3,4-methylenedioxyphenyl, 2,3-ethylenedioxyphenyl, 3,4-ethylenedioxyphenyl, 3,4-(difluoromethylenedioxy)phenyl, 2,3-dihydrobenzofuran-5- or 6-yl, 2,3-(2-oxomethylenedioxy)phenyl, or also represents 3,4-dihydro-2H-1,5-benzodioxepin-6- or -7-yl, further preferably 2,3-dihydrobenzofuranyl, 2,3-dihydro-2-oxofuranyl, 3,4-dihydro-2-oxo-1H-quinazolinyl, 2,3-dihydrobenzoxazolyl, 2-oxo-2,3-dihydrobenzoxazolyl, 2,3-dihydrobenzimidazolyl, 1,3-dihydroindole, 2-oxo-1,3-dihydroindole or 2-oxo-2,3-dihydrobenzimidazolyl.

[0059] Without considering further substitution, Het 1represent, for example, 2- or 3-furyl, 2- or 3-thienyl, 1-, 2- or 3-pyrrolyl, 1-, 2-, 4- or 5-imidazolyl, 1-, 3-, 4- or 5-pyrazolyl, 2-, 4- or 5-oxazolyl, 3-, 4- or 5-isoxazolyl, 2-, 4- or 5-thiazolyl, 3-, 4- or 5-isothiazolyl, 2-, 3- or 4-pyridyl, 2-, 4-, 5- or 6-pyrimidinyl, more preferably 1,2,3-triazol-1-, -4- or -5-yl, 1,2,4-triazol-1-, -3- or 5-yl, 1- or 5-tetrazolyl, 1,2,3-oxadiazol-4- or -5-yl, 1,2,4-oxadiazol-3- or -5-yl, 1,3,4-thiadiazol-2- or -5-yl, 1,2,4-thiadiazol-3- or -5-yl, 1,2,3-thiadiazol-4- or -5-yl, 3- or 4-pyridazinyl, pyrazinyl, 1-, 2-, 3-, 4-, 5-, 6- or 7-indolyl, 4- or 5-isoindolyl, indazolyl, 1-,2-,4- or 5-benzimidazolyl, 1-,3-,4-,5-,6- or 7-benzopyrazolyl, 2-,4-,5-,6- or 7-benzoxazolyl, 3-,4-,5-,6- or 7-benzisoxazolyl, 2-,4-,5-,6- or 7-benzothiazolyl, 2-,4-,5-,6- or 7-benzisothiazolyl, 4-,5-,6- or 7-benzo-2,1,3-oxadiazolyl, 2-,3-,4-,5-,6-,7- or 8-quinolyl, 1-,3-,4-,5-,6-,7- or 8-isoquinolyl, 3-,4-,5-,6-,7- or 8-cinnolinyl, 2-,4-,5-,6-,7- or 8-quinazolinyl, 5- or 6-quinoxalinyl, 2-,3-,5-,6-,7- or 8-2H-benzo-1,4-oxazinyl, pyrrolopyridyl, purinyl, more preferably 1,3-benzodioxol-5-yl, 1,4-benzodioxan-6-yl, 2,1,3-benzothiadiazol-4- or -5-yl, 2,1,3-benzoxadiazol-5-yl, azabicyclo[3.2.1]octyl or dibenzofuranyl.

[0060] The heterocyclic group may also be partially or fully hydrogenated.

[0061] Without further substitution, Het 1Thus, it can also represent, for example, 2,3-dihydro-2-, -3-, -4- or -5-furanyl, 2,5-dihydro-2-, -3-, -4- or -5-furanyl, tetrahydro-2- or -3-furanyl, 1,3-dioxolan-4-yl, tetrahydro-2- or -3-thienyl, 2,3-dihydro-1-, -2-, -3-, -4- or -5-pyrrolyl, 2,5-dihydro-1-, -2-, -3-, -4- or -5-pyrrolyl, 1-, 2- or 3-pyrrolidinyl, tetrahydro-1-, -2- or -4-imidazolyl, 2,3-dihydro-1-, -2-, -3-, -4- or -5-pyrazolyl, tetrahydro-1-, -3- or -4-pyrazolyl, 1,4-dihydro-1-, -2-, -3- or -4-pyridinyl, 1,2,3,4-tetrahydro-1-, -2-, -3-, -4-, -5- or -6-pyridinyl, 1-, 2-, 3- or 4-piperidinyl, 2-, 3- or 4-morpholinyl, tetrahydro-2-, -3- or -4-pyranyl, 1,4-dioxanyl, 1,3-dioxan-2-, -4- or -5-yl, hexahydro-1-, -3- or -4-pyridazinyl, hexahydro-1-, -2-, -4- or -5-pyrimidinyl, 1-, 2- or 3-piperazinyl, 1,2,3,4-tetrahydro-1-, -2-, -3-, -4-, -5-, -6-, -7- or -8-quinolinyl, 1,2,3,4-tetrahydro-1-, -2-, -3-, -4-, -5-, -6-, -7- or -8-isoquinolinyl, 2-, 3-, 5-, 6-, 7- or 8-3,4-dihydro-2H-benzo-1,4-oxazinyl, more preferably 2,3-methylenedioxyphenyl, 3,4-methylenedioxyphenyl, 2,3-ethylenedioxyphenyl, 3,4-ethylenedioxyphenyl, 3,4-(difluoromethylenedioxy)phenyl, 2,3-dihydrobenzofuran-5- or 6-yl, 2,3-(2-oxomethylenedioxy)phenyl, or also represents 3,4-dihydro-2H-1,5-benzodioxepin-6- or -7-yl, more preferably 2,3-dihydrobenzofuranyl, 2,3-dihydro-2-oxofuranyl, 3,4-dihydro-2-oxo-1H-quinazolinyl, 2,3-dihydrobenzoxazolyl, 2-oxo-2,3-dihydrobenzoxazolyl, 2,3-dihydrobenzimidazolyl, 1,3-dihydroindole, 2-oxo-1,3-dihydroindole or 2-oxo-2,3-dihydrobenzimidazolyl.

[0062] Ar represents, for example, phenyl, o-, m- or p-tolyl, o-, m- or p-ethylphenyl, o-, m- or p-propylphenyl, o-, m- or p-isopropylphenyl, o-, m- or p-tert-butylphenyl, o-, m- or p-hydroxyphenyl, o-, m- or p-nitrophenyl, o-, m- or p-aminophenyl, o-, m- or p-(N-methylamino)phenyl, o-, m- or p-(N-methylaminocarbonyl)phenyl, o-, m- or p-acetamidophenyl, o-, m- or p-methoxyphenyl, o-, m- or p-ethoxyphenyl, o-, m- or p-ethoxycarbonylphenyl, o-, m- or p-(N,N-dimethylamino)phenyl, o-, m- or p-(N,N-dimethylaminocarbonyl)phenyl, o-, m- or p-(N-ethylamino)phenyl, o-, m- or p-(N,N-diethylamino)phenyl, o-, m- or p-fluorophenyl, o-, m- or p-bromophenyl, o-, m- or p-chlorophenyl, o-, m- or p-(methylsulfonamido)phenyl, o-, m- or p-(methylsulfonyl)phenyl, o-, m- or p-cyanophenyl, o-, m- or p-carboxyphenyl, o-, m- or p-methoxycarbonylphenyl, o-, m- or p-aminosulfonylphenyl, o-, m- or p-(benzylamino)phenyl, more preferably 2,3-, 2,4-, 2,5-, 2,6-, 3,4- or 3,5-difluorophenyl, 2,3-, 2,4-, 2,5-, 2,6-, 3,4- or 3,5-dichlorophenyl, 2,3-, 2,4-, 2,5-, 2,6-, 3,4- or 3,5-dibromophenyl, 2,4- or 2,5-dinitrophenyl, 2,5- or 3,4-dimethoxyphenyl, 3-nitro-4-chlorophenyl, 3-amino-4-chloro-, 2-amino-3-chloro-, 2-amino-4-chloro-, 2-amino-5-chloro- or 2-amino-6-chlorophenyl, 2-nitro-4-N,N-dimethylamino- or 3-nitro-4-N,N-dimethylaminophenyl, 2,3-diaminophenyl, 2,3,4-, 2,3,5-, 2,3,6-, 2,4,6- or 3,4,5-trichlorophenyl, 2,4,6-trimethoxyphenyl, 2-hydroxy-3,5-dichlorophenyl, p-iodophenyl, 3,6-dichloro-4-aminophenyl, 4-fluoro-3-chlorophenyl, 2-fluoro-4-bromophenyl, 2,5-difluoro-4-bromophenyl, 3-bromo-6-methoxyphenyl, 3-chloro-6-methoxyphenyl, 3-chloro-4-acetamidophenyl, 3-fluoro-4-methoxyphenyl, 3-amino-6-methylphenyl, 3-chloro-4-acetamidophenyl or 2,5-dimethyl-4-chlorophenyl.

[0063] Het preferably represents 1H-pyrrolo[2,3-b]pyridinyl, 1H-pyrrolo[2,3-c]pyridinyl, indolyl, benzimidazolyl, imidazolyl, 1,2,3,4-tetrahydroisoquinolinyl, pyridinyl, pyrimidinyl, triazolyl, pyrazolyl, quinolinyl, isoquinolinyl, quinazolinyl, furyl, tetrahydrofuryl, pyranyl, 3,6-dihydro-2H-pyranyl, tetrahydropyranyl, 3,6-dihydro-2H-thiopyranyl or hexahydro-thiopyranyl, each of which is unsubstituted or mono-, di- or trisubstituted by A, SOA, SO2A, Hal and / or ═O.

[0064] Ar preferably represents phenyl, which is unsubstituted or mono-, di- or trisubstituted by SOA, S(═O,═NH)A, SO2A, A, CN and / or (CH2) n OH.

[0065] Throughout the invention, all groups that occur more than once may be the same or different, i.e., independent of each other.

[0066] The compounds of formulae Ia and Ib may have one or more chiral centers and may thus exist in various stereoisomeric forms. Formulae Ia and Ib include all such forms.

[0067] Accordingly, the present invention particularly relates to compounds of formulae Ia and Ib, wherein at least one of said groups has one of the above preferred meanings. Some preferred groups of compounds may be represented by the following sub-formulae Iaa and Iba to Iad and Ibd, which conform to formulae Ia and Ib, and wherein the groups not more specifically specified have the meanings shown in formulae Ia and Ib, but wherein

[0068] in Iaa and Iba, Het represents 1H-pyrrolo[2,3-b]pyridinyl, 1H-pyrrolo[2,3-c]pyridinyl, indolyl, benzimidazolyl, imidazolyl, 1,2,3,4-tetrahydroisoquinolinyl, pyridinyl, pyrimidinyl, triazolyl, pyrazolyl, quinolinyl, isoquinolinyl, quinazolinyl, furyl, tetrahydrofuryl, pyranyl, 3,6-dihydro-2H-pyranyl, tetrahydropyranyl, 3,6-dihydro-2H-thiopyranyl or hexahydro-thiopyranyl, each of which is unsubstituted or mono-, di- or trisubstituted by A, SOA, SO2A, Hal and / or ═O;

[0069] in Iab and Ibb, Ar represents phenyl, which is unsubstituted or mono-, di- or trisubstituted by SOA, S(═O,═NH)A, SO2A, A, CN and / or (CH2) n OH;

[0070] in Iac and Ibc, R 3 represents H or methyl;

[0071] in Iad and Ibd, R1 represent H, Het, Ar, (CH2) n OH, 1 - mesyl - cyclopropyl - 1 - yl, CONH2, CONHA, CONA2, Cyc, OA or CH(A)SO2A;

[0072] R 2 represent H, A, (CH2) n Ar, (CH2) n Cyc or (CH2) n Het,

[0073] R 3 represent H or A,

[0074] Het represents 1H - pyrrolo[2,3 - b]pyridinyl, 1H - pyrrolo[2,3 - c]pyridinyl, indolyl, benzimidazolyl, imidazolyl, 1,2,3,4 - tetrahydroisoquinolinyl, pyridinyl, pyrimidinyl, triazolyl, pyrazolyl, quinolinyl, isoquinolinyl, quinazolinyl, furyl, tetrahydrofuryl, pyranyl, 3,6 - dihydro - 2H - pyranyl, tetrahydropyranyl, 3,6 - dihydro - 2H - thiopyranyl or hexahydro - thiopyranyl, each of which is unsubstituted or mono - , di - or tri - substituted by A, SOA, SO2A, Hal and / or =O,

[0075] Ar represents phenyl, which is unsubstituted or mono - , di - or tri - substituted by SOA, S(=O, =NH)A, SO2A, A, CN and / or (CH2) n OH,

[0076] A represents a non - branched or branched alkyl having 1 - 6 C atoms, where 1 - 7 H atoms can be replaced by OH, F, Cl and / or Br, and / or where one or two non - adjacent CH2 groups can be replaced by O and / or NH groups,

[0077] Cyc represents a cycloalkyl having 3, 4, 5, 6 or 7 C atoms,

[0078] Hal represents F, Cl, Br or I,

[0079] n represents 0, 1, 2, 3 or 4,

[0080] and its pharmaceutically acceptable salts, tautomers and stereoisomers, including mixtures thereof in all ratios.

[0081] The most preferred compounds according to the present invention are Examples 1, 26, 42 and 61.

[0082] In addition, the compounds of formulae Ia and Ib and the starting materials for their preparation are prepared by methods known per se, as described in the literature (for example in standard works such as Houben-Weyl, Methoden der organischen Chemie [Methods of Organic Chemistry], Georg-Thieme-Verlag, Stuttgart), more precisely under reaction conditions known and suitable for the said reactions. Variants known per se can also be used here, which are not mentioned in more detail herein.

[0083] Pharmaceutical salts and other forms

[0084] The compounds according to the invention can be used in their final non-salt form. On the other hand, the invention also encompasses the use of these compounds in the form of their pharmaceutically acceptable salts, which can be derived from various organic and inorganic acids and bases by procedures known in the art. The pharmaceutically acceptable salt forms of the compounds of formulae Ia and Ib are mostly prepared by conventional methods. If the compounds of formulae Ia and Ib contain a carboxyl group, one of their suitable salts can be formed by reacting the compound with a suitable base to obtain the corresponding base addition salt. Such bases are, for example, alkali metal hydroxides, including potassium hydroxide, sodium hydroxide and lithium hydroxide; alkaline earth metal hydroxides, such as barium hydroxide and calcium hydroxide; alkali metal alkoxides, such as potassium ethoxide and sodium propoxide; and various organic bases, such as piperidine, diethanolamine and N-methylglutamine. Aluminum salts of the compounds of formulae Ia and Ib are also included. In the case of certain compounds of formulae Ia and Ib, acid addition salts can be formed by treating these compounds with pharmaceutically acceptable organic and inorganic acids, such as hydrogen halides, such as hydrogen chloride, hydrogen bromide or hydrogen iodide, other inorganic acids and their corresponding salts, such as sulfates, nitrates or phosphates, etc., and alkyl- and monoarylsulfonates, such as ethanesulfonate, toluenesulfonate and benzenesulfonate, and other organic acids and their corresponding salts, such as acetate, trifluoroacetate, tartrate, maleate, succinate, citrate, benzoate, salicylate, ascorbate, etc. Accordingly, the pharmaceutically acceptable acid addition salts of the compounds of formulae Ia and Ib include the following: acetate, adipate, alginate, arginate, aspartate, benzoate, besylate, bisulfate, bisulfite, bromide, butyrate, camphorate, camphorsulfonate, caprylate, chloride, chlorobenzoate, citrate, cyclopentanepropionate, digluconate, dihydrogen phosphate, dinitrobenzoate, dodecyl sulfate, ethanesulfonate, fumarate, formate, galactonate (from mucic acid), galacturonate, glucoheptonate, gluconate, glutamate, glycerophosphate, hemisuccinate, hemisulfate, heptanoate, hexanoate, hippurate, hydrochloride, hydrobromide, hydroiodide, 2-hydroxyethanesulfonate, iodide, isethionate, isobutyrate, lactate, lactobionate, malate, maleate, malonate, mandelate, metaphosphate, methanesulfonate, benzoate, monohydrogen phosphate, 2-naphthalenesulfonate, nicotinate, nitrate, oxalate, oleate, palmitate, pectinate, persulfate, phenylacetate, 3-phenylpropionate, phosphate, phosphonate, phthalate, but this is not meant to be limiting.

[0085] In addition, the basic salts of the compounds according to the invention include aluminum, ammonium, calcium, copper, iron(III), iron(II), lithium, magnesium, manganese(III), manganese(II), potassium, sodium and zinc salts, but this is not restrictive. Among the above salts, ammonium is preferred; the alkali metal salts sodium and potassium, and the alkaline earth metal salts calcium and magnesium. The salts of the compounds of formula Ia and Ib derived from pharmaceutically acceptable organic non-toxic bases include primary, secondary and tertiary amines, substituted amines, and also include naturally occurring substituted amines, cyclic amines, and salts of basic ion exchange resins, such as arginine, betaine, caffeine, chloroprocaine, choline, N,N'-dibenzylethylenediamine (benzathine), dicyclohexylamine, diethanolamine, diethylamine, 2-diethylaminoethanol, 2-dimethylaminoethanol, ethanolamine, ethylenediamine, N-ethylmorpholine, N-ethylpiperidine, glucosamine, glucosamine, histidine, homatropine, isopropylamine, lidocaine, lysine, meglumine, N-methyl-D-glucosamine, morpholine, piperazine, piperidine, polyamine resin, procaine, purine, theobromine, triethanolamine, triethylamine, trimethylamine, tripropylamine and tris(hydroxymethyl)methylamine (tromethamine), but this is not restrictive.

[0086] The compounds of the invention containing a basic nitrogen-containing group can be quaternized using reagents such as (C1-C4) alkyl halides, such as chlorine, bromine and iodine of methyl, ethyl, isopropyl and tert-butyl; di(C1-C4) alkyl sulfates, such as sulfates of dimethyl, diethyl and dipentyl; (C 10 -C 18 ) alkyl halides, such as chlorides, bromides and iodides of decyl, dodecyl, lauryl, myristyl and stearyl; and aryl(C1-C4) alkyl halides, such as benzyl chloride and phenethyl bromide. Both water-soluble and oil-soluble compounds according to the invention can be prepared using such salts.

[0087] The above-mentioned preferred pharmaceutical salts include acetate, trifluoroacetate, benzenesulfonate, citrate, fumarate, gluconate, hemisuccinate, hippurate, hydrochloride, hydrobromide, hydroxyethanesulfonate, mandelate, meglumine, nitrate, oleate, phosphonate, pivalate, sodium phosphate, stearate, sulfate, sulfosalicylate, tartrate, thiomalate, toluenesulfonate and tromethamine, but this is not restrictive.

[0088] Particularly preferred are hydrochloride, dihydrochloride, hydrobromide, maleate, mesylate, phosphate, sulfate and succinate.

[0089] Acid addition salts of the basic compounds of formulae Ia and Ib are prepared by contacting the free base form with a sufficient amount of the desired acid to cause salt formation in a conventional manner. The free base can be regenerated by contacting the salt form with a base and separating the free base in a conventional manner. The free base form differs in certain respects from its corresponding salt form, in certain physical properties, such as solubility in polar solvents; however, for the purposes of the present invention, the salts correspond in other respects to their respective free base forms.

[0090] As described above, the pharmaceutically acceptable base addition salts of the compounds of formula I are formed with metals or amines, such as alkali metals and alkaline earth metals or organic amines. Preferred metals are sodium, potassium, magnesium and calcium. Preferred organic amines are N,N'-dibenzylethylenediamine, chloroprocaine, choline, diethanolamine, ethylenediamine, N-methyl-D-glucamine and procaine.

[0091] Base addition salts of the acidic compounds according to the invention are prepared by contacting the free acid form with a sufficient amount of the desired base to cause salt formation in a conventional manner. The free acid can be regenerated by contacting the salt form with an acid and separating the free acid in a conventional manner. The free acid form differs in certain respects from its corresponding salt form, in certain physical properties, such as solubility in polar solvents; however, for the purposes of the present invention, the salts correspond in other respects to their respective free acid forms.

[0092] If the compounds according to the invention contain more than one group capable of forming a pharmaceutically acceptable salt of this type, the present invention also includes multiple salts. Typical multiple salt forms include, for example, hydrogen tartrate, diacetate, hydrogen fumarate, diglucomine, diphosphate, disodium and trihydrochloride, but this is not limiting.

[0093] Regarding the above, it can be seen that the expression "pharmaceutically acceptable salt" herein refers to an active ingredient comprising a compound of formulae Ia and Ib in the form of one of its salts, especially if this salt form confers improved pharmacokinetic properties on the active ingredient compared to the free form of the active ingredient or any other salt form of the previously used active ingredient. The pharmaceutically acceptable salt form of the active ingredient can also for the first time provide the active ingredient with desired pharmacokinetic properties that it did not previously have, and can even have a positive impact on the pharmacodynamics of the active ingredient with respect to its therapeutic efficacy in the body.

[0094] Isotope

[0095] In addition, the compounds of formulae Ia and Ib include their isotopically labeled forms. The isotopically labeled forms of the compounds of formulae Ia and Ib are identical to the compounds, except that one or more atoms of the compounds are replaced by one or more atoms having an atomic mass or mass number different from the atomic mass or mass number usually found in nature. Examples of isotopes that are readily commercially available and can be incorporated into the compounds of formulae Ia and Ib by well-known methods include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorus, fluorine, and chlorine, such as 2 H, 3 H, 13 C, 14 C, 15 N, 18 O, 17 O, 31 P, 32 P, 35 S, 18 F, and 36 Cl, respectively. Compounds of formulae Ia and Ib or pharmaceutically acceptable salts thereof containing one or more of the above isotopes and / or other isotopes of other atoms are part of the present invention. The isotopically labeled compounds of formulae Ia and Ib can be used in many advantageous ways. For example, isotopically labeled compounds of formulae Ia and Ib in which a radioactive isotope such as 3 H or 14 C has been incorporated are suitable for drug and / or substrate tissue distribution assays. These radioactive isotopes, namely tritium ( 3 H) and carbon-14 ( 14 C), are particularly preferred because of their simple preparation and excellent detectability. Incorporating a heavier isotope, such as deuterium ( 2 H), into the compounds of formulae Ia and Ib has therapeutic advantages because of the higher metabolic stability of the isotopically labeled compounds. The higher metabolic stability directly translates into an increased in vivo half-life or a lower dose, which in most cases represents a preferred embodiment of the present invention. The isotopically labeled compounds of formulae Ia and Ib can generally be prepared by carrying out the procedures disclosed in the synthetic schemes and the relevant descriptions in the Examples and Preparation sections herein, and replacing the non-isotopically labeled reactants with readily available isotopically labeled reactants.

[0096] In order to control the oxidative metabolism of the compounds of formulae Ia and Ib by the primary kinetic isotope effect, deuterium ( 2H) Incorporated into the said compound. The primary kinetic isotope effect is the change in the rate of a chemical reaction caused by the exchange of isotopic nuclei, which in turn is caused by the change in the ground state energy required to form a covalent bond after such isotope exchange. The exchange of heavier isotopes generally results in a decrease in the ground state energy of the chemical bond and thus a decrease in the rate of rate-limiting bond cleavage. If the bond cleavage occurs in or near the saddle point region along the coordinate of a multi-product reaction, the product distribution ratio can be significantly altered. To explain: if deuterium is bonded to a carbon atom at a non-exchangeable position, the typical rate difference is k M / k D = 2 - 7. If such rate differences are successfully applied to compounds of formulae Ia and Ib that are sensitive to oxidation, the in vivo properties of the compound can be significantly altered and lead to improved pharmacokinetic properties.

[0097] When discovering and developing therapeutic agents, those skilled in the art attempt to optimize pharmacokinetic parameters while maintaining the desired in vitro properties. It is reasonable to assume that many compounds with poor pharmacokinetic properties are sensitive to oxidative metabolism. Currently available in vitro liver microsome assays provide valuable information about this type of oxidative metabolic process, which in turn allows for the rational design of deuterated compounds of formula I with improved stability through resistance to such oxidative metabolism. A significant improvement in the pharmacokinetic properties of the compounds of formula I is thereby obtained and can be quantitatively represented by an increase in the in vivo half-life (t1 / 2), the maximum therapeutic effect concentration (C max ), the area under the dose-response curve (AUC), and F; as well as a decrease in clearance rate, dose, and material cost.

[0098] The following is intended to illustrate the above: Compounds of formulae Ia and Ib having multiple potential sites for oxidative metabolic attack, such as benzylic hydrogen atoms and hydrogen atoms bonded to nitrogen atoms, are prepared as a series of analogues in which various combinations of hydrogen atoms are replaced by deuterium atoms such that some, most, or all of these hydrogen atoms are replaced by deuterium atoms. The determination of the half-life enables the advantageous and accurate determination of the degree of improvement in resistance to oxidative metabolism. In this way, it has been determined that the half-life of the parent compound can be extended by up to 100% due to this type of deuterium-hydrogen exchange.

[0099] Deuterium-hydrogen exchange in the compounds of formulae Ia and Ib can also be used to effect a favorable modification of the metabolite profile of the starting compound to reduce or eliminate unwanted toxic metabolites. For example, if a toxic metabolite is produced by oxidative carbon-hydrogen (C-H) bond cleavage, it is reasonable to assume that the deuterated analogue will greatly reduce or eliminate the production of the unwanted metabolite, even if the particular oxidation is not the rate-determining step. Further information on the state of the art regarding deuterium-hydrogen exchange can be found, for example, in Hanzlik et al., J. Org. Chem. 55, 3992-3997, 1990, Reider et al., J. Org. Chem. 52, 3326-3334, 1987, Foster, Adv. Drug Res. 14, 1-40, 1985, Gillette et al., Biochemistry 33(10) 2927-2937, 1994, and Jarman et al. Carcinogenesis 16(4), 683-688, 1993.

[0100] The invention also relates to a medicament comprising at least one compound of formulae Ia and Ib and / or a pharmaceutically acceptable salt, solvate and stereoisomer thereof, including mixtures thereof in all ratios, and optionally an excipient and / or an adjuvant.

[0101] The pharmaceutical preparation can be administered in unit dose form containing a predetermined amount of the active ingredient per dose unit. Such unit can contain, for example, from 0.5 mg to 1 g, preferably from 1 mg to 700 mg, particularly preferably from 5 mg to 100 mg of the compound of the invention, depending on the condition being treated, the method of administration and the age, weight and condition of the patient, or the pharmaceutical preparation can be administered in unit dose form containing a predetermined amount of the active ingredient per dose unit. Preferred unit dose preparations are those containing the active ingredient in a daily dose or a divided dose as described above or a corresponding fraction thereof. In addition, pharmaceutical preparations of this type can be prepared using methods commonly known in the pharmaceutical art.

[0102] The pharmaceutical preparation can be adapted for administration by any desired suitable method, such as orally (including buccal or sublingual), rectally, nasally, topically (including buccal, sublingual or transdermal), vaginally or parenterally (including subcutaneous, intramuscular, intravenous or intradermal) methods. All methods known in the pharmaceutical art can be used to prepare such preparations, for example, by combining the active ingredient with one or more excipients or one or more adjuvants.

[0103] A pharmaceutical preparation suitable for oral administration can be administered as a separate unit, such as a capsule or tablet; powder or granule; solution or suspension in an aqueous or non-aqueous liquid; edible foam or foam food; or water-in-oil liquid emulsion or oil-in-water liquid emulsion.

[0104] Thus, for example, in the case of oral administration in the form of tablets or capsules, the active ingredient component can be combined with oral, non-toxic and pharmaceutically acceptable inert excipients such as ethanol, glycerol, water, etc. Powders are prepared by comminuting the compound into a suitable small size and mixing it with a pharmaceutically excipient comminuted in a similar manner, such as an edible carbohydrate such as starch or mannitol. Flavoring agents, preservatives, dispersants and dyes can also be present.

[0105] Capsules are produced by preparing the powder mixture as described above and filling a shaped gelatin shell therewith. Glidants and lubricants, such as highly dispersed silicic acid, talc, magnesium stearate, calcium stearate or polyethylene glycol in solid form, can be added to the powder mixture before the filling operation. Disintegrants or solubilizers, such as agar, calcium carbonate or sodium carbonate, can also be added in order to improve the utilization of the drug after taking the capsule.

[0106] In addition, if desired or necessary, suitable binders, lubricants and disintegrants and dyes can also be incorporated into the mixture. Suitable binders include starch, gelatin, natural sugars such as glucose or β-lactose, sweeteners made from corn, natural and synthetic rubbers such as gum arabic, tragacanth or sodium alginate, carboxymethyl cellulose, polyethylene glycol, waxes, etc. Lubricants for these dosage forms include sodium oleate, sodium stearate, magnesium stearate, sodium benzoate, sodium acetate, sodium chloride, etc. Disintegrants include, but are not limited to, starch, methyl cellulose, agar, bentonite, xanthan gum, etc. Tablets are prepared by, for example, preparing a powder mixture, granulating or dry-pressing the mixture, adding lubricants and disintegrants, and pressing the whole mixture into tablets. A powder mixture is prepared by mixing the compound comminuted in a suitable manner with a diluent or base as described above, and optionally with a binder such as carboxymethyl cellulose, alginate, gelatin or polyvinylpyrrolidone, a dissolution retardant such as paraffin wax, an absorption promoter such as a quaternary salt, and / or an absorbent such as bentonite, kaolin or dicalcium phosphate. The powder mixture can be granulated by wetting it with a binder such as syrup, starch paste, acadia mucilage or a solution of a cellulose or polymeric material and passing it through a sieve. As an alternative to granulation, the powder mixture can be passed through a tableting machine to obtain lumps of uneven shape, which are broken to form granules. The granules can be lubricated by adding stearic acid, stearates, talc or mineral oil to prevent adhesion to the tablet mold. The lubricated mixture is then pressed to obtain tablets. The compounds of the present invention can also be mixed with a free-flowing inert excipient and then directly pressed into tablets without the granulation or dry-pressing step. A transparent or opaque protective layer consisting of a shellac sealing layer, a layer of sugar or polymeric material and a gloss layer of wax can be present. Dyes can be added to these coatings in order to be able to distinguish between different dosage units.

[0107] Oral liquids, such as solutions, syrups and elixirs, can be prepared in dosage unit form so that a given quantity contains a predetermined amount of the compound. Syrups can be prepared by dissolving the compound in an aqueous solution having a suitable flavor, while elixirs are prepared using a non-toxic alcoholic vehicle. Suspensions can be formulated by dispersing the compound in a non-toxic vehicle. Solubilizers and emulsifiers, such as ethoxylated isostearyl alcohol and polyoxyethylene sorbitan ethers, preservatives, flavoring agents, such as peppermint oil or natural sweeteners or saccharin, or other artificial sweeteners, etc. can also be added.

[0108] If desired, dosage unit formulations for oral administration can be encapsulated in microcapsules. The formulations can also be prepared in extended or delayed release form, for example by coating or embedding particulate materials in polymers, waxes, etc.

[0109] The compounds of formulae Ia and Ib and their pharmaceutically acceptable salts, tautomers and stereoisomers can also be administered in the form of lipid delivery systems, such as small unilamellar vesicles, large unilamellar vesicles and multilamellar vesicles. Liposomes can be formed from a variety of phospholipids, such as cholesterol, stearylamine or phosphatidylcholine.

[0110] The compounds of formulae Ia and Ib and their salts, tautomers and stereoisomers can also be delivered using monoclonal antibodies as separate carriers conjugated with the compound molecules. The compound can also be conjugated with a soluble polymer as a targeted drug carrier. Such polymers can include polyvinylpyrrolidone, pyran copolymer, poly(hydroxypropylmethacrylamide)phenyl, poly(hydroxyethylasparaginyl)phenyl or poly(ethylene oxide)-polylysine, which is substituted with palmitoyl groups. In addition, the compound can be conjugated with a class of biodegradable polymers suitable for achieving controlled release of the drug, such as polylactic acid, poly-ε-caprolactone, polyhydroxybutyric acid, polyorthoesters, polyacetals, poly(dihydroxypyran), polycyanoacrylates and crosslinked or amphiphilic block copolymers of hydrogels.

[0111] Drug formulations suitable for transdermal administration can be administered as self-adhesive plasters for extended, intimate contact with the epidermis of the recipient. Thus, for example, the active ingredient can be released from the plaster by iontophoresis, as generally described in Pharmaceutical Research, 3(6), 318 (1986).

[0112] Drug compounds suitable for topical administration can be formulated as ointments, creams, suspensions, lotions, powders, solutions, pastes, gels, sprays, aerosols or oils.

[0113] For the treatment of the eye or other external tissues such as the oral cavity and skin, the preparation is preferably administered as a topical ointment or cream. In the case of being formulated as an ointment, the active ingredient can be used together with a paraffin or water-miscible cream base. Alternatively, the active ingredient can be formulated into a cream having an oil-in-water cream base or a water-in-oil base.

[0114] Pharmaceutical preparations suitable for topical administration to the eye include eye drops, in which the active ingredient is dissolved or suspended in a suitable carrier, especially an aqueous solvent.

[0115] Pharmaceutical preparations suitable for topical administration in the oral cavity include lozenges, troches and mouthwashes.

[0116] Pharmaceutical preparations suitable for rectal administration can be administered in the form of suppositories or enemas.

[0117] Pharmaceutical preparations suitable for nasal administration, in which the carrier substance is solid, include coarse powders having a particle size in the range of, for example, 20 - 500 microns, which are administered by nasal inhalation, i.e., rapidly inhaled through the nasal cavity from a container containing the powder held near the nose. Preparations suitable for administration as a nasal spray or nasal drops together with a liquid as the carrier substance include aqueous or oily solutions of the active ingredient.

[0118] Pharmaceutical preparations suitable for administration by inhalation include fine particle powders or aerosols, which can be produced by various types of pressurized dispensers having an aerosol, nebulizer or insufflator.

[0119] Pharmaceutical preparations suitable for vaginal administration can be administered as vaginal suppositories, tampons, creams, gels, pastes, foams or sprays.

[0120] Pharmaceutical preparations suitable for parenteral administration include aqueous and non-aqueous sterile injection solutions, which contain antioxidants, buffers, bacteriostatic agents and solutes by which the preparation is made isotonic with the blood of the recipient to be treated; and aqueous and non-aqueous sterile suspensions, which can contain suspending media and thickening agents. The preparations can be administered in single-dose or multi-dose containers, such as sealed ampoules and vials, and stored in a freeze-dried (lyophilized) state so that only a sterile carrier liquid, such as water for injection purposes, needs to be added immediately before use. The injections and suspensions prepared according to the prescription can be prepared from sterile powders, granules and tablets.

[0121] It goes without saying that in addition to the components specifically mentioned above, the preparation can also contain other reagents that are common in the art for specific types of preparations; thus, for example, preparations suitable for oral administration can contain flavoring agents.

[0122] The therapeutically effective amount of the compounds of formula Ia and Ib depends on a number of factors, including for example the age and weight of the animal, the exact disorder to be treated and its severity, the nature of the formulation and the method of administration, and is ultimately determined by the treating physician or veterinarian. However, the effective amount of the compounds of the present invention is generally 0.1 - 100 mg / kg recipient (mammal) body weight per day, particularly typically 1 - 10 mg / kg body weight per day. Thus, for an adult mammal weighing 70 kg, the actual amount per day is generally 70 - 700 mg, where this amount can be administered as a single daily dose, or generally in a series of partial doses per day (e.g., two, three, four, five or six) such that the total daily dose is the same. The effective amount of its salt or solvate or physiologically functional derivative can be determined as a fraction of the effective amount of the compound of the present invention itself. It is assumed that similar doses are suitable for treating the other disorders mentioned above.

[0123] This type of combined treatment can be achieved by simultaneously, continuously or separately dispensing the individual components of the treatment. Such combined products use the compounds of the present invention.

[0124] The present invention also relates to a medicament comprising at least one compound of formula Ia and Ib and / or a pharmaceutically acceptable salt, tautomer and stereoisomer thereof, including mixtures thereof in all ratios, and at least one further pharmaceutically active ingredient.

[0125] The present invention also relates to a kit consisting of the following separate packages

[0126] (a) An effective amount of a compound of formula Ia and Ib and / or a pharmaceutically acceptable salt, tautomer and stereoisomer thereof, including mixtures thereof in all ratios,

[0127] and

[0128] (b) An effective amount of a further pharmaceutically active ingredient.

[0129] The kit includes suitable containers, such as boxes, individual bottles, bags or ampoules. The kit can for example contain individual ampoules, each containing an effective amount of a compound of formula I and / or a pharmaceutically acceptable salt, tautomer and stereoisomer thereof, including mixtures thereof in all ratios,

[0130] and an effective amount of the further pharmaceutically active ingredient in dissolved or lyophilized form.

[0131] As used herein, "treatment" means in a subject at risk of developing a disease or disorder, completely or partially alleviating the symptoms associated with the disease or disorder, or slowing or stopping the further progression or worsening of these symptoms, or preventing or precluding the disease or disorder.

[0132] The term "effective amount" in relation to the compounds of formulae Ia and Ib can refer to an amount capable of alleviating in whole or in part the symptoms associated with a disorder or disease, or slowing or halting the further progression or worsening of those symptoms, or preventing or providing prophylaxis against a disease or disorder, in a subject suffering from or at risk of developing a disease or disorder disclosed herein, such as an inflammatory disorder, an immunological disorder, cancer or a metabolic disorder.

[0133] In one embodiment, an effective amount of the compounds of formulae Ia and Ib is, for example, an amount that inhibits ATR in cells in vitro or in vivo. In some embodiments, the effective amount of the compound of formula (I) inhibits teloamerase in cells by 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90% or 99% compared to the activity of ATR in untreated cells. For example, in a pharmaceutical composition, an effective amount of the compounds of formulae Ia and Ib can be a level capable of producing the desired effect; for example, for oral and parenteral administration, from about 0.005 mg / kg of subject body weight to about 10 mg / kg of subject body weight per unit dose.

[0134] Use

[0135] The compounds of the present invention are suitable as pharmaceutically active ingredients for mammals, especially humans. For the treatment of cancer.

[0136] The present invention includes the use of the compounds of formulae Ia and Ib and / or their pharmaceutically acceptable salts, tautomers and stereoisomers in the preparation of a medicament for the treatment or prophylaxis of cancer.

[0137] Furthermore, the present invention includes the compounds of formulae Ia and Ib and / or their pharmaceutically acceptable salts, tautomers and stereoisomers for the treatment or prophylaxis of cancer,

[0138] Also included is the use of the compounds of formulae Ia and Ib and / or their pharmaceutically acceptable salts, tautomers and stereoisomers in the preparation of a medicament for the treatment or prophylaxis of ATR-induced diseases or ATR-induced conditions in mammals, wherein for this method a therapeutically effective amount of a compound according to the present invention is administered to an afflicted mammal in need of such treatment. The therapeutically effective amount varies according to the particular disease and can be determined by a person skilled in the art without undue effort.

[0139] The present invention specifically relates to the compounds of formulae Ia and Ib and their pharmaceutically acceptable salts, tautomers and stereoisomers, including mixtures thereof in all ratios, which are used for the treatment of diseases in which the inhibition, regulation and / or modulation of ATR plays a role.

[0140] The present invention specifically relates to compounds of formulae Ia and Ib for inhibiting ATR, and pharmaceutically acceptable salts, tautomers and stereoisomers thereof, including mixtures thereof in all ratios.

[0141] Representative cancers for which the compounds of formulae Ia and Ib can be used for treatment or prevention include, but are not limited to, cancers of the head, neck, eye, mouth, throat, esophagus, bronchus, larynx, pharynx, chest, bone, lung, colon, rectum, stomach, prostate, bladder, uterus, cervix, breast, ovary, testis or other reproductive organs, skin, thyroid, blood, lymph nodes, kidney, liver, pancreas, brain, central nervous system, solid tumors and hematogenous tumors.

[0142] Preferably, the present invention relates to methods wherein the disease is cancer.

[0143] Particularly preferably, the present invention relates to methods wherein the disease is cancer, wherein administration is simultaneous with, sequential to, or alternating with the administration of at least one other active agent.

[0144] The disclosed compounds of formulae Ia and Ib can be administered in combination with other known therapeutic agents, including anti-cancer agents. As used herein, the term "anti-cancer agent" refers to any agent administered to a cancer patient for the treatment of cancer.

[0145] The anti-cancer treatment as defined above can be applied as a single therapy, or in addition to the compound of formula I disclosed herein, can involve conventional surgery or radiotherapy or drug therapy. Such drug therapy, for example chemotherapy or targeted therapy, can include one or more, but preferably one, of the following anti-tumor agents:

[0146] Alkylating agents

[0147] Such as altretamine, bendamustine, busulfan, carmustine, chlorambucil, chlormethine, cyclophosphamide, dacarbazine, ifosfamide, improsulfan tosilate, lomustine, melphalan, dibromomannitol, dibromodulcitol, nimustine, ranimustine, temozolomide, thiotepa, treosulfan, mechloretamine, carboquone;

[0148] Aperazone, fotemustine, glufosfamide, paliomycin, pipobroman, trofosfamide, uramustine, TH-302 4 , VAL-083 4 ;

[0149] Platinum compounds

[0150] Such as carboplatin, cisplatin, iproplatin, miriplatine hydrate, oxaliplatin, lobaplatin, nedaplatin, picoplatin, satraplatin;

[0151] Lobaplatin, nedaplatin, picoplatin, satraplatin;

[0152] DNA altering agent

[0153] such as amrubicin, bisantrene, decitabine, mitoxantrone, procarbazine, trabectedin, clofarabine;

[0154] amsacrine, brotllicin, pixantrone, Laromustine 1,3 ;

[0155] Topoisomerase inhibitors

[0156] such as etoposide, irinotecan, razoxane, sobuzoxane, teniposide, topotecan;

[0157] anarfitide, belotecan, elcitonin, voreloxin;

[0158] Microtubule modifiers

[0159] such as cabazitaxel, docetaxel, eribulin, ixabepilone, paclitaxel, vinblastine, vincristine, vinorelbine, vindesine, vinflunine;

[0160] fosbretabulin, tesetaxel;

[0161] Antimetabolites

[0162] such as asparaginase 3 , azacitidine, calcium levofolinate, capecitabine,

[0163] cladribine, cytarabine, enocitabine, floxuridine, fludarabine, fluorouracil, gemcitabine, mercaptopurine, methotrexate, nelarabine, pemetrexed, pralatrexate, azathioprine, thioguanine, carmofur;

[0164] doxifluridine, cytarabine, raltitrexed, sapacitabine, tegafur 2,3 , trimetrexate;

[0165] Anticancer antibiotics

[0166] such as bleomycin, actinomycin D, doxorubicin, epirubicin, idarubicin, levamisole, miltefosine, mitomycin C, romidepsin, streptozocin, valrubicin, zilascorbicin, zorubicin, rubomycin, plicamycin;

[0167] aclacinomycin, peplomycin, pirarubicin;

[0168] Hormones / antagonists

[0169] For example, abarelix, abiraterone, bicalutamide, buserelin, carusone, chlorphenesin, degarelix, dexamethasone, estradiol, flucortolone

[0170] fluoxymesterone, flutamide, fulvestrant, goserelin, histrelin, leuprorelin, megestrol acetate, mitotane, nafarelin, nandrolone, nilutamide, octreotide, prednisolone, raloxifene, tamoxifen, thyrotropin alpha, toremifene, trilostane, triptorelin, diethylstilbestrol;

[0171] acobifene, danazol, deslorelin, epiandrosterol, orteronel, enzalutamide 1,3 ;

[0172] Aromatase inhibitors

[0173] For example, aminoglutethimide, anastrozole, exemestane, fadrozole, letrozole, testolactone;

[0174] formestane;

[0175] Small molecule kinase inhibitors

[0176] For example, crizotinib, dasatinib, erlotinib, imatinib, lapatinib, nilotinib, pazopanib, regorafenib, ruxolitinib, sorafenib, sunitinib, vandetanib, vemurafenib, bosutinib, gefitinib, axitinib;

[0177] afatinib, alitinib, dabrafenib, dacomitinib, dinaciclib, dovitinib, ensartinib, nintedanib, neratinib, linitinib, masitinib, midostaurin, motesanib, neratinib, orantinib, perifosine, ponatinib, radatinib, rigosertib, tepotinib, tipifarnib, tivatinib, tivozanib, trametinib, pimasertib, briganinate, shenib, apatinib 4, cabozantinib S-malate 1,3 , ibrutinib 1,3 , icotinib 4 , buparlisib 2 , ciprotilinib 4 , cobimetinib 1,3 , elitinib 1,3 , fedratinib 1 , XL-647 4 ;

[0178] Photosensitizers

[0179] For example, methoxsalen 3 ;

[0180] Porfimer sodium, talaporfin, temoporfin;

[0181] antibody

[0182] such as alemtuzumab, besilesomab, blinatumomab, cetuximab, denosumab, ipilimumab, ofatumumab, panitumumab, rituximab, tositumomab,

[0183] trastuzumab, bevacizumab, pertuzumab 2,3 ;

[0184] catumaxomab, elotuzumab, epratuzumab, farletuzumab, mogamulizumab, necitumumab, nimotuzumab, obinutuzumab, ocaratuzumab, oregovomab, ramucirumab, rilotumumab, siltuximab, tocilizumab, zalutumumab, zanolimumab, matuzumab, dalotuzumab 1,2,3 , onartuzumab 1,3 , racotumomab 1 ,

[0185] tabalumab 1,3 , EMD - 525797 4 , avelumab, nivolumab 1,3 ;

[0186] cytokine

[0187] such as aldesleukin, interferon α 2 , interferon α2a 3 , interferon α2b 2,3 ;

[0188] Celmoleukin, tasquinimod, Teceleukin, Oprelvekin 1,3 , recombinant interferon β - 1a 4 ;

[0189] drug conjugate

[0190] such as adenine interleukin detopside, iodine - 131 tositumomab, iobenguane I123, prednimustine, trastuzumab, estramustine phosphate, gemtuzumab, octreotide, aflibercept;

[0191] Cintrekin Besudotox, edotreotide, inotuzumab ozogamicin, naptumomab estafenatox, oportuzumab monatox, technetium (99mTc) arcitumomab 1,3 ,

[0192] vinflumine 1,3 ;

[0193] vaccines

[0194] such as sipuleucel 3 ; vitespen 3 , emepepimut-S 3 , oncoVAX 4 , rindopepimut 3 , troVax 4 , MGN-1601 4 , MGN-1703 4 ;

[0195] others

[0196] alitretinoin, bexarotene, bortezomib, everolimus, ibandronic acid, imiquimod, lenalidomide, lentinan, metelotrime, miltefosine, pamidronic acid, pegaspargase, pentostatin, sipuleucel 3 , sizopren, tamibarotene, temsirolimus, thalidomide, tretinoin, vismodegib, zoledronic acid, vorinostat;

[0197] celecoxib, cilengitide, enzastaurin, etanidazole, ganetespib, idronoxil, iniparib, ixazomib, lonidamine, nimorazole, panobinostat, peretinoin, plitidepsin, pomalidomide, procodazol, ridaforolimus, taskinimmod, telotristat, thymalfasin, tirapazamine, tozasertib, ubenimex, vaspad, gendicine 4 ,

[0198] lysin 4 , reolysin 4 , rebimamycin hydrochloride 1,3 , trabectedin 2,3 , virulizin 4 , carfilzomib 1,3 , endostatin 4 , immucothel 4 , belinostat3 , MGN-1703 4 ;

[0199] PARP inhibitor

[0200] Olaparib, Veliparib.

[0201] 1 Prop.INN (Proposed International Nonproprietary Name)

[0202] 2 Rec.INN (Recommended International Nonproprietary Name)

[0203] 3 USAN (United States Adopted Name)

[0204] 4 No INN.

[0205] The following abbreviations refer to the following definitions respectively:

[0206] aq (aqueous solution), h (hour), g (gram), L (liter), mg (milligram), MHz (megahertz), min. (minute), mm (millimeter), mmol (millimole), mM (millimole), m.p. (melting point), eq (equivalent), mL (milliliter), μL (microliter), ACN (acetonitrile), AcOH (acetic acid), CDCl3 (deuterochloroform), CD3OD (deuteromethanol), CH3CN (acetonitrile), c-hex (cyclohexane), DCC (dicyclohexylcarbodiimide), DCM (dichloromethane), DIC (diisopropylcarbodiimide), DIEA (diisopropylethylamine), DMF (dimethylformamide), DMSO (dimethyl sulfoxide), DMSO-d6 (deuterated dimethyl sulfoxide), EDC (1-(3-dimethylaminopropyl)-3-ethylcarbodiimide), ESI (electrospray ionization), EtOAc (ethyl acetate), Et2O (diethyl ether), EtOH (ethanol), HATU (dimethylamino-([1,2,3]triazolo[4,5-b]pyridin-3-yloxy)-methylene]-dimethyl-ammonium hexafluorophosphate), HPLC (high performance liquid chromatography), i-PrOH (2-propanol), K2CO3 (potassium carbonate), LC (liquid chromatography), MeOH (methanol), MgSO4 (magnesium sulfate), MS (mass spectrometry), MTBE (methyl tert-butyl ether), NaHCO3 (sodium bicarbonate), NaBH4 (sodium borohydride), NMM (N-methylmorpholine), NMR (nuclear magnetic resonance), PyBOP (benzotriazol-1-yloxy-tris-pyrrolidino-phosphonium hexafluorophosphate), RT (room temperature), Rt (retention time), SPE (solid phase extraction), TBTU (2-(1-H-benzotriazol-1-yl)-1,1,3,3-tetramethyluronium tetrafluoroborate), TEA (triethylamine), TFA (trifluoroacetic acid), THF (tetrahydrofuran), TLC (thin layer chromatography), UV (ultraviolet).

[0207] Above and below, all temperatures are expressed in °C. In the following examples, "conventional work-up" means: if necessary, adding water, if necessary, adjusting the pH to a value of 2 - 10 depending on the composition of the final product, extracting the mixture with ethyl acetate or dichloromethane, separating the phases, drying the organic phase over sodium sulfate and evaporating, and purifying the residue by chromatography on silica gel and / or crystallization. Rf value on silica gel; eluent: ethyl acetate / methanol 9:1.

[0208] 1 1H NMR was recorded on a Bruker DPX-300, DRX-400, AVII-400 or 500 MHz spectrometer, using the residual signal of the deuterated solvent as the internal standard. Chemical shifts (δ) are reported in ppm relative to the residual solvent signal (for 1HNMR, δ = 2.49 ppm). 1 The H NMR data are reported as follows: chemical shift (multiplicity, coupling constant, and number of hydrogens). The multiplicity abbreviations are as follows: s (singlet), d (doublet), t (triplet), q (quartet), m (multiplet), br (broad).

[0209] LC-MS

[0210] The LCMS data provided in the examples are given as retention time, purity, and / or mass (m / z). The results are obtained as follows: Mass spectrometry: LC / MS Waters ZMD (ESI) of HP 1100 series or Hewlett Packard system (ion source: electrospray (positive mode) or Waters Acquity H class SQD; scan: 100 - 1000 m / z; fragmentation voltage: 60 V; gas - temperature: 300 °C, DAD: 220 nm. Flow rate: 2.4 ml / Min. The used splitter reduces the flow rate after the DAD of the MS to 0.75 ml / Min; column: Chromolith Speed ROD RP - 18e 50 - 4.6; solvent: LiChrosolv - qualy from Merck KGaA or as mentioned in the method.

[0211] Method A: Shimadzu LCMS - 2020 column: Poroshell HPH - C18, 3.0 * 50 mm, 2.7 μm; mobile phase A: water / 5 mM NH4HCO3, mobile phase B: acetonitrile; flow rate: 1.2 mL / min; gradient: 10% B to 95% B in 2.1 min, hold for 0.6 min; 254 nm

[0212] Method B: Shimadzu LCMS - 2020 column: Shim - pack XR - ODS, 3.0 * 50 mm, 2.2 μm; mobile phase A: water / 0.05% TFA, mobile phase B: ACN / 0.05% TFA; flow rate: 1.2 mL / min; gradient: 5% B to 100% B in 3.8 min, hold for 1.0 min; 254 nm

[0213] Method C: Waters Acquity H - Class - SQD; column: BEH C - 18 2.1 - 50 1.7 μm; column temperature: 40 °C; detection: 220 nm; eluent A: water + 0.1% HCOOH; eluent B: acetonitrile + 0.08% HCOOH; flow: 0.9 ml / min; gradient: 4% B at 0 min, rise to 100% B in 1 min, hold 100% B until 1.3 min, until 1.4 min to 4% B, until 2 min 4% B

[0214] Method D: Shimadzu LCMS-2020 Column: Ascentis Express C18, 3.0*50mm, 2.7μm; Mobile phase A: water / 0.05% TFA, Mobile phase: ACN / 0.05% TFA; Flow rate: 1.5 mL / min; Gradient: 5% B to 100% B in 2.1 min, hold for 0.7 min; 254 nm

[0215] Method E: Shimadzu LCMS-2020 Column: Shim-pack XR-ODS, 3.0*50mm, 2.2μm; Mobile phase A: water / 0.05% TFA, Mobile phase B: ACN / 0.05% TFA; Flow rate: 1.2 mL / min; Gradient: 5% B to 100% B in 2.0 min, hold for 0.7 min; 254 nm

[0216] Method F: Agilent 1200-6120B; Chromolith Performance RP18e, 100 mm long, inner diameter 3 mm; Wavelength 220 nm; Gradient: 4.2 min; Flow: 2 ml / min 99:01 to 0:100; Water + 0.1% (v / v) TFA: Acetonitrile + 0.1% (v / v) TFA; 0.0 to 0.2 min: 99:01; 0.2 to 3.8 min: 99:01 to 0:100; 3.8 to 4.2 min: 0:100

[0217] Method G: Shimadzu LCMS-2020, LC20ADXR, Column: Kinetex EVO C18, 3.0*50mm, 2.6μm; Mobile phase A: water / 5 mM NH4HCO3, Mobile phase B: ACN; Flow rate: 1.3 mL / min; Gradient: 10% B to 95% B in 2.1 min, hold for 0.6 min; 254 nm

[0218] Method H: Shimadzu LCMS-2020 Column: Poroshell HPH-C18, 3.0*50mm, 2.7μm; Mobile phase A: water / 5 mM NH4HCO3, Mobile phase B: acetonitrile; Flow rate: 1.3 mL / min; Gradient: 10% B to 95% B in 2.1 min, hold for 0.6 min; 254 nm

[0219] Method I: Shimadzu LCMS-2020 Column: Poroshell HPH-C18, 3.0*50mm, 2.7μm; Mobile phase A: water / 5mM NH4HCO3, Mobile phase B: acetonitrile; Flow rate: 1.3mL / min; Gradient: 10% B to 95% B in 4.0min, hold for 0.8min; 254nm

[0220] Method J: Shimadzu LCMS-2020 Column: Shim-pack XR-ODS, 3.0*50mm, 2.2μm; Mobile phase A: water / 0.05% TFA, Mobile phase B: ACN / 0.05% TFA; Flow rate: 1.2mL / min; Gradient: 5% B to 100% B in 1.1min, hold for 0.6min; 254nm

[0221] Method K: Waters Acquity H-Class-SQD; Column: kinetex EVO C18 2.1-50 1.7μm; Column temperature: 40°C; Detection: 220nm; Eluent A: water + 0.1% HCOOH; Eluent B: acetonitrile + 0.08% HCOOH; Flow: 0.9ml / min; Gradient: 4% B at 0min, increase to 100% B in 1min, hold 100% B until 1.3min, decrease to 4% B until 1.4min, hold 4% B until 2min

[0222] Method L: Shimadzu LCMS-2020 Column: CORTECS C18+100A, 2.1*50mm, 2.7um; Mobile phase A: water / 0.1% FA, Mobile phase B: acetonitrile / 0.1% FA; Flow rate: 1.0mL / min; Gradient: 10% B to 100% B in 1.1min, hold for 0.5min; 254nm

[0223] Method M: Shimadzu LCMS-2020 Column: Ascentis Express C18, 3.0*50mm, 2.7μm; Mobile phase A: water / 0.05% TFA, Mobile phase: ACN / 0.05% TFA; Flow rate: 1.5mL / min; Gradient: 5% B to 100% B in 2.0min, hold for 0.7min; 254nm

[0224] Method N: Shimadzu LCMS-2020 Column: Shim-pack XR-ODS, 3.0*50mm, 2.2μm; Mobile phase A: water / 0.05% TFA, Mobile phase B: MeOH; Flow rate: 0.82mL / min; Gradient: 30% B to 100% B in 6.2min, hold for 1.1min; 254nm

[0225] Method O: Shimadzu LCMS-2020 Column: kinetex EVO C18 3.0 - 50 2.6μm; Mobile phase A: water / 5mM NH4HCO3, Mobile phase B: acetonitrile; Flow rate: 1.2 mL / min; Gradient: 10% B to 95% B in 2.1 min, hold for 0.6 min; 254 nm

[0226] Method P: Shimadzu LCMS-2020 Column: Ascentis Express C18, 3.0 * 50 mm, 2.7μm; Mobile phase A: water / 0.05% TFA, Mobile phase: ACN / 0.05% TFA; Flow rate: 1.5 mL / min; Gradient: 5% B to 100% B in 1.2 min, hold for 0.5 min; 254 nm

[0227] Method Q: Waters Acquity H-Class-SQD; Column: CORTECS C18 2.1 - 50 1.6μm; Column temperature: 30°C; Detection: 220 nm; Eluent A: water + 0.05% HCOOH; Eluent B: acetonitrile + 0.04% HCOOH; Flow: 0.9 ml / min; Gradient: 2% B to 100% B in 1.0 min, hold for 0.3 min

[0228] Method R: Waters Acquity H-Class-SQD; Column: kinetex EVO C18 2.1 - 50 1.7μm; Column temperature: 30°C; Detection: 220 nm; Eluent A: water + 0.05% HCOOH; Eluent B: acetonitrile + 0.04% HCOOH; Flow: 0.9 ml / min; Gradient: 1% B to 99% B in 1.0 min, hold for 0.3 min

[0229] Method S: Shimadzu LCMS-2020 Column: kinetex EVO C18 3.0 - 50 2.6μm; Mobile phase A: water / 0.04% NH4OH, Mobile phase B: acetonitrile; Flow rate: 1.2 mL / min; Gradient: 10% B to 95% B in 2.1 min, hold for 0.6 min; 254 nm

[0230] Method T: Shimadzu LCMS-2020 Column: kinetex EVO C18 3.0 - 50 2.6μm; Mobile phase A: water / 0.04% NH4OH, Mobile phase B: acetonitrile; Flow rate: 1.2 mL / min; Gradient: 10% B to 95% B in 1.2 min, hold for 0.5 min; 254 nm

[0231] Method U: Shimadzu LCMS - 2020 Column: Shim - pack XR - ODS, 3.0 * 50 mm, 2.2 μm; Mobile phase A: water / 0.05% TFA, Mobile phase B: ACN / 0.05% TFA; Flow rate: 1.2 mL / min; Gradient: 5% B to 100% B in 4.2 min, hold for 0.8 min; 254 nm

[0232] Method V: Agilent 1200 - 6120B; Column: waters sunfire C18, 3 * 100 mm, 5 μm; Gradient: 4.3 min; Flow: 1.3 ml / min 99:01 to 0:100; Water + 0.1% (v / v) TFA: Acetonitrile + 0.1% (v / v) TFA; 0.0 to 0.2 min: 99:01; 0.2 to 3.8 min: 99:01 to 0:100; 3.8 to 4.3 min: 0:100

[0233] Method W: Shimadzu LCMS - 2020 Column: CORTECS C18 + 100A, 2.1 * 50 mm, 2.7 um; Mobile phase A: water / 0.1% FA, Mobile phase B: acetonitrile / 0.1% FA; Flow rate: 1.0 mL / min; Gradient: 10% B to 100% B in 2.0 min, hold for 0.6 min; 254 nm

[0234] Method X: Shimadzu LCMS - 2020 Column: Ascentis Express C18, 3.0 * 50 mm, 2.7 μm; Mobile phase A: water / 0.05% TFA, Mobile phase: ACN / 0.05% TFA; Flow rate: 1.5 mL / min; Gradient: 5% B to 100% B in 3.0 min, hold for 1.5 min; 254 nm

[0235] Preparative column chromatography was carried out using a silica gel column with one of the following solvent systems on a Teledyne Isco Combi Flash Rf

[0236] Method A: Dichloromethane / methanol 10:1

[0237] Method B: Ethyl acetate / petroleum ether 2:3

[0238] Method C: (Ethyl acetate / petroleum ether 3:7)

[0239] Method D: (n - Heptane / EtOAc).

[0240] Method E: Ethyl acetate / petroleum ether 1:1

[0241] Method F: Ethyl acetate / PE 1:10

[0242] Method G: Ethyl acetate / petroleum ether 1:5

[0243] Method H: Dichloromethane / methanol 2:3

[0244] Method I: Ethyl acetate / PE 4:1

[0245] Method J: EA / PE 10:1

[0246] Method K: CH3CN / H2O 3:7

[0247] Method L: DCM-MeOH gradient

[0248] Method M: n-Heptane / EtOAc gradient

[0249] Method N: n-Heptane / EtOAc / MeOH gradient

[0250] Method O: DCM / MeOH gradient

[0251] Method P: Ethyl acetate / petroleum ether gradient

[0252] Preparative HPLC was performed on an Agilent 1200. Column: Chromolith prep RP 18e Merck KGaA. Mobile phase: 0.1% formic acid aqueous solution / 0.1% formic acid acetonitrile solution. Alternative methods are:

[0253] Method A: 1 min 99% A. From 99% A to 100% B within 2.5 min. Then 1.5 min 100% B and 1 min 99% A. Chromolith SpeedRod RP-18e column; 50 - 4.6 mm; detection at 220 nM (solvent A: H20 (0.1% TFA), solvent B: ACN (0.1% TFA)

[0254] Method B: 2#-AnalyseHPLC-SHIMADZU (HPLC-10)): Column, XBridge Shield RP 18 OBD column, 5um, 19*150 mm; Mobile phase, water (0.05% NH3H2O) and ACN (20% ACN, up to 39% within 8 min); Detector, UV254 nm

[0255] Method C: 2#-AnalyseHPLC-SHIMADZU (HPLC-10)): Column, XBridge Prep C18 OBD column, 19??150 mm 5um; Mobile phase, water (10MMOL / L NH4HCO3 + 0.1% NH3.H2O) and ACN (25.0% ACN, up to 46.0% in 8 min); Detector, UV 254 nm.

[0256] Method D: 2#-AnalyseHPLC-SHIMADZU (HPLC-10)): Column, XBridge Prep C18 OBD column, 19*150 mm 5um; Mobile phase, water (10MMOL / L NH4HCO3 + 0.1% NH3.H2O) and ACN (31% ACN, up to 53% in 8 min); Detector, UV 254 / 220 nm

[0257] Method E: 2#-AnalyseHPLC-SHIMADZU (HPLC-10)): Column, XBridge Shield RP 18OBD column, 5um, 19*150 mm; Mobile phase, water (10MMOL / L NH4HCO3 + 0.1% NH3.H2O) and ACN (22% ACN, up to 58% in 9 min); Detector, UV 254 nm

[0258] Method F: 2#-AnalyseHPLC-SHIMADZU (HPLC-10)): Column, XBridge Prep C18 OBD column, 19??150 mm 5um; Mobile phase, water (10MMOL / L NH4HCO3 + 0.1% NH3.H2O) and ACN (45.0% ACN, up to 65.0% in 8 min); Detector, UV 254 nm

[0259] Method G: 2#-AnalyseHPLC-SHIMADZU (HPLC-10)): Column, XBridge Shield RP 18OBD column, 5um, 19*150 mm; Mobile phase, water (10MMOL / L NH4HCO3 + 0.1% NH3.H2O) and ACN (20.0% ACN, up to 35.0% in 10 min); Detector, UV 254 nm

[0260] Method H: 2#-AnalyseHPLC-SHIMADZU (HPLC-10)): Column, XBridge Prep C18 OBD column, 19??150 mm 5um; Mobile phase, and (rising from 60% to 62% in 10 min); Detector, UV 254 nm.

[0261] Method I: Chiral-Prep-HPLC(): column, mobile phase, detector, to obtain 20 mg of product, with an α℃ of

[0262] Method J: 2# SHIMADZU (HPLC-01)): column, XBridge Shield RP 18 OBD column, 5um, 19*150mm; mobile phase, water (10 mmol / L NH4HCO3 + 0.1% NH3.H2O) and ACN (10% ACN, up to 33% in 7 min); detector, UV 254 nm

[0263] Method K: 2#-AnalyseHPLC-SHIMADZU (HPLC-10)): column, XBridge Shield RP 18 OBD column, 5um, 19*150mm; mobile phase, water (10 mmol / L NH4HCO3 + 0.1% NH3.H2O) and ACN (10% ACN, up to 35% in 8 min); detector, UV 254 nm

[0264] Method L: 2#-AnalyseHPLC-SHIMADZU (HPLC-10)): column, XBridge Shield RP 18 OBD column, 5um, 19*150mm; mobile phase, water (10 mmol / L NH4HCO3 + 0.1% NH3.H2O) and ACN (18.0% ACN, up to 53.0% in 8 min); detector, UV 254 nm

[0265] Method M: 2#-AnalyseHPLC-SHIMADZU (HPLC-10)): column, XBridge Shield RP 18 OBD column, 5um, 19*150mm; mobile phase, water (10 mmol / L NH4HCO3 + 0.1% NH3.H2O) and ACN (18.0% ACN, up to 60.0% in 9 min); detector, UV 254 nm.

[0266] Method N: 2#-AnalyseHPLC-SHIMADZU (HPLC-10)): column, XBridge Prep C18 OBD column, 19*150mm 5um; mobile phase, water (10 mmol / L NH4HCO3 + 0.1% NH3.H2O) and ACN (25% ACN, up to 41% in 8 min); detector, UV 254 nm.

[0267] Method O: 2#-Analyse HPLC-SHIMADZU (HPLC-10)): Column, XBridge Prep OBD C18 column, 19 * 250 mm, 5 μm; Mobile phase, water (10 mmol / L NH4HCO3 + 0.1% NH3.H2O) and ACN (18% ACN, up to 41% within 8 min); Detector, UV 254 nm.

[0268] Method P: (2#-Analyse HPLC-SHIMADZU (HPLC-10)): Column, XBridge Prep C18 OBD column, 19 * 150 mm 5 μm; Mobile phase, water (10 mmol / L NH4HCO3 + 0.1% NH3.H2O) and ACN (18% ACN, up to 38% within 8 min); Detector, UV 254 nm.

[0269] Method Q: 2#-Analyse HPLC-SHIMADZU (HPLC-10)): Column, XBridge Shield RP18 OBD column, 5 μm, 19 * 150 mm; Mobile phase, water (10 mmol / L NH4HCO3 + 0.1% NH3.H2O) and ACN (20% phase B, up to 60% within 9 min); Detector, UV 254 nm.

[0270] Method R: Waters Acquity H-Class-SQD; Column: BEH C-18 2, 1 - 50 1.7 μm; Column temperature: 40 °C; Detection: 220 nm; Eluent A: water + 0.1% HCOOH; Eluent B: acetonitrile + 0.08% HCOOH; Flow: 0.9 ml / min; Gradient: 0 min 4% B, increased to 100% B within 1 min, held at 100% B until 1.3 min, held at 100% B until 1.4 min, held at 4% B until 2 min.

[0271] Microwave chemistry was carried out on a single-mode microwave reactor EmrysTM Optimiser from Personal Chemistry.

[0272] ATR / ATRIP kinase assay - Measurement of ATR / ATRIP inhibition

[0273] IC 50The value is determined by an ATR / ATRIP enzyme assay. The assay comprises two steps: an enzymatic reaction and a detection step. First, a mixture of ATR / ATRIP protein (ataxia telangiectasia and Rad3-related protein / ATR interacting protein), different concentrations of the compound, p53 as a substrate protein, and adenosine triphosphate (ATP) is incubated in an assay buffer. ATR phosphorylates Ser15 and other residues of p53. Then, the amount of phosphorylated p53 is detected using a specific antibody and TR-FRET assay technology.

[0274] Specifically: The ATR / ATRIP enzyme assay is performed as a 384-well assay based on TR-FRET-(HTRFTM, Cisbio Bioassays). In the first step, purified human recombinant ATR / ATRIP (human ATR, full length, GenBank ID: NM_001184.3, and human ATRIP, full length, GenBank ID AF451323.1, co-expressed in a mammalian cell line) is incubated in an assay buffer at 22 °C for 15 minutes with different concentrations of the test compound or without the test compound (as a negative control). The assay buffer contains 25 mM HEPES pH 8.0, 10 mM Mg(CH3COO)2, 1 mM MnCl2, 0.1% BSA, 0.01% 35 and 5 mM dithiothreitol (DTT). Echo 555 (Labcyte) was used for the dispensing of the compound solutions. Then, in a second step, purified human recombinant cmyc-tagged p53 (human p53, full length, GenBank ID: BC003596, expressed in Sf21 insect cells) and ATP were added, and the reaction mixture was incubated at 22 °C for 25 - 35 minutes, typically 25 minutes. The volume for the pharmacologically relevant assay was 5 μl. During the incubation of the reaction mixture, the final concentrations in the assay were 0.3 - 0.5 nM, typically 0.3 nM, ATR / ATRIP, 50 nM p53 and 0.5 μM ATP. The enzymatic reaction was terminated by the addition of EDTA. The production of phosphorylated p53 as a result of the ATR-mediated reaction in the presence of ATP was detected by using a specific antibody capable of performing FRET [labeled with the fluorophore europium (Eu) as the donor and d2 as the acceptor (Cisbio Bioassays)]. For this purpose, 2 μl of an antibody-containing stop solution (12.5 mM HEPES pH 8.0, 125 mM EDTA, 30 mM sodium chloride, 300 mM potassium fluoride, 0.006% Tween-20, 0.005% Brijorni 35, 0.21 nM anti-phospho-p53(Ser15)-Eu antibody, 15 nM anti-cmyc-d2 antibody) was added to the reaction mixture. After 2 h of signal development, the plate was analyzed using laser excitation in the TRF mode in an EnVision (PerkinElmer) microplate reader. After excitation of the donor europium at 340 nm, the fluorescence emitted by the acceptor d2 at 665 nm and the fluorescence emitted by the donor Eu at 615 nm were measured. The amount of phosphorylated p53 was proportional to the ratio of the amount of light emitted, i.e., the ratio of the relative fluorescence units (rfu) at 665 nm and 615 nm. The data were processed using Genedata Screner software. In particular, the IC 50 values were determined in the usual way by fitting a dose-response curve to the data points using non-linear regression analysis.

[0275] IC 50 = half maximal inhibitory concentration

[0276] ATP = adenosine triphosphate

[0277] TR-FRET = time-resolved fluorescence resonance energy transfer

[0278] = homogeneous time-resolved fluorescence

[0279] HEPES = 2-(4-(2-hydroxyethyl)-1-piperazinyl)-ethanesulfonic acid

[0280] Mg(CH3COO)2 = magnesium acetate

[0281] MnCl2 = Manganese(II) chloride

[0282] BSA = Bovine serum albumin

[0283] EDTA = Ethylenediaminetetraacetate

[0284] TRF = Time-resolved fluorescence

[0285] pCHK1 cell assay

[0286] The Chk1 kinase functions downstream of ATR and has a key role in DNA damage checkpoint control. Activation of Chk1 involves phosphorylation of Ser317 and Ser 345 (which are considered to be preferred targets for phosphorylation / ATR activation), and occurs in response to blocked DNA replication and certain forms of genotoxic stress. Phosphorylation of Ser 345 serves to localize Chk1 to the nucleus following checkpoint activation.

[0287] The assay measures the reduction in Chk1 (Ser 345) phosphorylation in HT29 colon adenocarcinoma cells following treatment with a compound and hydroxyurea (which promotes fork stalling due to dNTP depletion), and following immunocytochemistry and high-content imaging.

[0288] For the assay, HT29 cells were plated in medium (DMEM high glucose (without phenol red), 2 mM Glutamax, 1 mM pyruvate, 10% FCS in Greiner 384-well plates, black, μClear #781090 (2500 cells / well / 30 μl)) and incubated at 37 °C for at least 20 h. A test compound (final concentration 1 nM - 30 μM) and hydroxyurea (final concentration 3 mM), diluted in 10% CO2 and 90% rH, were added simultaneously, and the cells were incubated at 37 °C for 4 h following fixation / elution with 100% H (-20 °C cold) and permeabilization with 0.2% Meoton X-100. A complete immunocytochemistry procedure was carried out using a specific anti-HK1 antibody (Cell Signaling, #2348BF) and a fluorescently labeled secondary antibody (Alexa or 488) goat anti-rabbit F(ab')2 fragment, Invitrogen A11070), along with parallel nuclear staining for cell counting.

[0289] The nuclear localization of the pChk1 signal was detected on an ImageXpress confocal high-content reader and reported as the percentage of positive cells (nuclei).

[0290] Kv11.1 (hERG) ion channel activity

[0291] In this assay, the potential in vitro effects of test compounds on Kv11.1 (hERG) ion channel currents, which mediate rapidly activating, delayed rectifier cardiac potassium currents (IKr), were investigated. The assay was performed at room temperature using a whole-cell patch-clamp technique on a human embryonic kidney cell line (HEK293) stably transfected with Kv11.1 (hERG).

[0292] The Kv11.1 (hERG) ion channel blocker quinidine was used as a reference compound. The effects of the test compounds and quinidine were normalized relative to the respective vehicle control. Whole-cell recordings were made using an automated patch-clamp device (PatchlinerTM, Nanion Technologies, Munich). Thus, patch-clamp measurements were performed on a silicate-coated chip with apertures of defined diameter. Solutions, cell suspensions, and compounds were applied through Teflon-laminated pipette needles via microfluidic silicate-laminated channels. Patch-clamp recordings were made using a commercially available patch-clamp amplifier (EPC10, HEKA Elektronik Dr. Schulze GmbH, Germany). HEK293 cells stably expressing the hERG gene were maintained at -80 mV. A pulse pattern with fixed amplitudes was used to measure the steady-state inhibition of Kv11.1 (hERG) potassium currents due to the application of test / reference compounds: 51 ms / -80 mV, 500 ms / -40 mV, 200 ms / -80 mV. The hERG-specific voltage protocol was repeated at 10 s intervals. Leakage currents were subtracted by P4 leakage subtraction. Cells were resuspended in the extracellular patch-clamp solution (EC) and applied to the chip. After cell collection, the EC was exchanged with a seal enhancer solution (SE) to improve the sealing procedure. When the whole-cell configuration was achieved, the seal enhancer was washed away by applying the EC. Recordings were started in the EC for 1.5 min. Then DMSO (vehicle control, 0.1% DMSO) was applied, and the control current was measured for 3 min. After the control steady-state current, the test compound was applied twice at the same concentration, and the tail current was measured for 3.5 min each time. To determine the concentration relationship, the test compound was applied as a cumulative concentration-response curve, and the current was measured for 5 min at each concentration. The reference compound quinidine was treated in the same way. The effect on Kv11.1 (hERG) ion channel activity was judged from the amplitude of the tail current monitored at -40 mV (current of interest, COI). Results were calculated from the last recorded current trace. Changes in Kv11.1 (hERG) ion channel activity between the control value defined as 100% Kv11.1 (hERG) ion channel activity, the application of the test compound, and the application of quinidine were reported as percentage changes in the COI control value. Aliquots of the test compound were collected during the recording for concentration verification. Samples were immediately measured by HPLC, and the final compound concentration in the assay was calculated according to the calibration curve.

[0293] Pharmacological data

[0294] Inhibition of ATR-ATRIP (IC 50 );

[0295] pCHK1 cell assay;

[0296] Kv11.1 (hERG) ion channel activity

[0297] Table 1

[0298]

[0299]

[0300]

[0301]

[0302]

[0303] pCHK1:

[0304] <10 nM = xxxx xxx: 10 - 100 nM xx: 100 - 1000 nM x: 1000 - 10000 nM

[0305] The compounds shown in Table 1 are particularly preferred compounds according to the present invention.

[0306] Description of synthetic schemes and compound examples:

[0307] In the following formula, "Abs" refers to the absolute stereochemistry as shown.

[0308] The azaindazole derivatives can be synthesized according to Scheme 1.

[0309] Scheme 1: Synthetic route of azaindazole 10

[0310]

[0311] The 1'-substituted nitropyrazole 1 can be reduced to the amine 2 using H2 / PdC or Fe or SnCl2. The formation of the imine 3 can be carried out by reacting acetylmorpholine with phosphoryl chloride. Cyclization to the azaindazole 4 is possible under basic conditions, such as LiHMDS. Then, the hydroxyl group can be converted to a leaving group, such as Tf or Cl, to give 5 (R4 = leaving group). A Suzuki-type reaction gives the azaindazole 6. Halogenation with NIS or NBS gives the compound 7. A Suzuki-type reaction with a protected pyrazole gives the 1'- or 2'-protected derivative 8 or 9. After deprotection, the azaindazole 10 can be isolated.

[0312] Unsubstituted azaindazole derivatives can be synthesized according to Scheme 2.

[0313]

[0314] Scheme 2: Synthetic route of unsubstituted azaindazole 13

[0315] Starting from 3 (R2 = H), a protecting group can be introduced into the azaindazole core to form 11. The following steps can remove the protecting group from 12 in the final step as described in Scheme 1 to obtain unsubstituted azaindazole 13.

[0316] An alternative route from pyridine derivatives to azaindazole derivatives is described in Scheme 3.

[0317]

[0318] Scheme 3: Alternative synthetic route of azaindazole 10

[0319] 2,6-Dichloro-3-nitropyridin-4-amine 14 can be brominated to 15 under Sandmeyer conditions. A Suzuki-type reaction gives 16. Methylmorpholine can be introduced under Buchwald conditions or by nucleophilic aromatic substitution under basic conditions to form 17. The nitro group can be reduced to amine 18 using H2 / PdC or Fe or SnCl2. Cyclization to 19 with sodium nitrite in acetic acid is possible. This compound can be halogenated to 20 using NBS, NIS, Br2, or I2 and alkylated to 7. Alternatively, 7 can be prepared by alkylating 19 to 21 and halogenating with NBS or NIS. The steps from 7 to 10 are as described in Scheme 1.

[0320] Azaindazole derivatives can also be synthesized according to Scheme 4.

[0321]

[0322] Scheme 4: Alternative Suzuki-type reaction to azaindazole 6 and then to 10.

[0323] Azaindazole 5 can be converted to boronic acid 22. A Suzuki-type reaction gives 6, which can react to 10 as described in Scheme 1.

[0324] At the R 1 position unsubstituted azaindazole derivatives (R 1 = H) can be synthesized according to Scheme 5.

[0325]

[0326] Scheme 5: Synthetic route of azaindazole 24

[0327] Starting from azaindazole 5 with PdCl2 and a phosphine ligand such as dppf, azaindazole 23 can be prepared. Alternatively, azaindazole 25 can react under Buchwald conditions to form azaindazole 23. The reaction steps to 24 are as described in Scheme 1 for the synthesis of azaindazole 10.

[0328] Another synthetic route for azaindazole 34 is described in Scheme 6.

[0329]

[0330] Scheme 6: Synthetic route for cyclopropyl azaindazole 35

[0331] Azaindazole 5 can be carbonylated to 26, which can be halogenated with NBS or NIS to 27. A Suzuki-type reaction gives azaindazole 28. Reduction of the ester with, for example, LiBH4 produces alcohol 29, which can be converted to a leaving group such as Tf or Cl to become 30 (R4 = leaving group). R4 can be exchanged with a sulfinate to a sulfone 31. The olefin 32 can be synthesized with (dimethylamino)methyldimethylamine. Reaction with methanesulfonyl iodide gives cyclopropyl sulfone 33. After deprotection of the pyrazole, azaindazole 34 can be isolated.

[0332] The cyclopropyl azaindazole derivative 34 can alternatively be synthesized as described in Scheme 7.

[0333]

[0334] Scheme 7: Alternative synthetic route for cyclopropyl azaindazole derivative

[0335] Azaindazole 27 can be reduced to alcohol 34 with, for example, LiBH4, which can be converted to a leaving group such as Tf or Cl to form 35 (R4 = leaving group). R4 can be exchanged with a sulfinate to a sulfone 36. Reaction with dibromoethane or dichloroethane gives cyclopropyl 37, which can be synthesized to azaindazole 34 as described in the above reaction scheme.

[0336] Structural unit

[0337] Methyl 4-amino-1-methyl-1H-pyrazole-5-carboxylate

[0338]

[0339] Methyl 1-methyl-4-nitro-1H-pyrazole-5-carboxylate (10 g, 51.31 mmol, 1 equiv) and palladium on carbon (11.50 g, 103 mmol, 2.00 equiv) were suspended in methanol (100 mL). The resulting solution was stirred at 25 °C for 16 h under a H2 atmosphere. The solid was filtered off. The resulting mixture was concentrated in vacuo. The residue was purified by column chromatography (Method A). Methyl 4-amino-1-methyl-1H-pyrazole-5-carboxylate was isolated as a pink solid (9 g, quantitative); LC / MS (Method J): Rt 0.641 min, [MH]+ 156.1 m / z.

[0340] 1-[(3R)-3-Methylmorpholin-4-yl]ethan-1-one

[0341]

[0342] (3R)-3-Methylmorpholine (12 g, 112.71 mmol) and potassium carbonate (86.08 g, 591.70 mmol, 5.25 equiv) were dissolved in dichloromethane (280 mL) and stirred at 0 °C for 30 min. Acetyl chloride (32.60 g, 395 mmol, 3.50 equiv) was added thereto. The resulting solution was stirred at 25 °C for 16 h. The solid was filtered off. The resulting mixture was concentrated in vacuo to give 1-[(3R)-3-methylmorpholin-4-yl]ethan-1-one as a yellow oil (15 g, 88%); LC / MS (Method J): Rt 1.151 min, [MH]+ 144.0 m / z.

[0343] Methyl 1-methyl-4-[(E)-{1-[(3R)-3-methylmorpholin-4-yl]ethylidene}amino]-1H-pyrazole-5-carboxylate

[0344]

[0345] Methyl 4-amino-1-methyl-1H-pyrazole-5-carboxylate (9 g, 52.21 mmol) and 1-[(3R)-3-methylmorpholin-4-yl]ethan-1-one (15 g, 94.28 mmol, 1.81 eq) were dissolved in DCE (200 mL, 2.40 mol). The solution was stirred at 0 °C for 0.5 h. Phosphorus oxychloride (40 g, 247.95 mmol, 4.75 eq) was added thereto. The resulting solution was stirred at 40 °C for 16 h. Then the reaction was quenched by adding 20 mL of NH4Cl. The resulting solution was extracted with ethyl acetate, and the organic layers were combined and concentrated in vacuo. The residue was purified by column chromatography (Method B). Methyl 1-methyl-4-[(E)-[1-[(3R)-3-methylmorpholin-4-yl]ethylidene]amino]-1H-pyrazole-5-carboxylate was isolated as a yellow solid (11 g, 68%); LC-MS (Method J) Rt: 0.664 min, [MH]+ 281.2.

[0346] 1-Methyl-5-[(3R)-3-methylmorpholin-4-yl]-1H-pyrazolo[4,3-b]pyridin-7-ol

[0347]

[0348] Methyl 1-methyl-4-[(E)-[1-[(3R)-3-methylmorpholin-4-yl]ethylidene]amino]-1H-pyrazole-5-carboxylate (11 g, 35.32 mmol, 1 eq) was dissolved in DMF (300 mL). The solution was stirred at 0 °C for 30 min. LiHMDS (100 mL, 6.19 mmol) was added thereto. The resulting solution was stirred at 0 °C in a water / ice bath for 1 h. Then the reaction was quenched by adding an aqueous solution of NH4Cl. The resulting solution was extracted with ethyl acetate, and the organic layers were combined, dried over anhydrous sodium sulfate, and concentrated in vacuo. The residue was purified by column chromatography (Method A) and recrystallized from ethyl acetate. 1-Methyl-5-[(3R)-3-methylmorpholin-4-yl]-1H-pyrazolo[4,3-b]pyridin-7-ol was obtained as a colorless solid (6 g, 68%); LC / MS (Method B): Rt 1.458 min, [MH]+ 249.2.

[0349] 1-Methyl-5-[(3R)-3-methylmorpholin-4-yl]-1H-pyrazolo[4,3-b]pyridin-7-yl trifluoromethanesulfonate

[0350]

[0351] 1-Methyl-5-[(3R)-3-methylmorpholin-4-yl]-1H-pyrazolo[4,3-b]pyridin-7-ol (6 g, 21.75 mmol, 1.00 equiv), DCM (700 mL), DIEA (20.26 g, 148.92 mmol, 3.16 equiv) and 1,1,1-trifluoro-N-phenyl-N-(trifluoromethyl)sulfonylmethanesulfonamide (37.39 g, 99.43 mmol, 2.11 equiv) were combined and stirred at room temperature for 16 h. The resulting mixture was concentrated in vacuo. The residue was purified by column chromatography (Method C). 1-Methyl-5-[(3R)-3-methylmorpholin-4-yl]-1H-pyrazolo[4,3-b]pyridin-7-yl trifluoromethanesulfonate was isolated as a yellow oil (18 g, 90%); LC / MS (Method L): Rt 0.978 min, [MH]+ 381.0.

[0352] 1-Isopropyl-5-((R)-3-methylmorpholin-4-yl)-1H-pyrazolo[4,3-b]pyridin-7-yl trifluoromethanesulfonate

[0353]

[0354] 1-Isopropyl-5-((R)-3-methylmorpholin-4-yl)-1H-pyrazolo[4,3-b]pyridin-7-yl trifluoromethanesulfonate was prepared in a similar manner to the above structural unit. 1-Isopropyl-5-((R)-3-methylmorpholin-4-yl)-1H-pyrazolo[4,3-b]pyridin-7-yl trifluoromethanesulfonate was isolated as a brown solid (105 mg, 86%); LC / MS (Method F): Rt 2.781 min; [MH]+ 409.1 m / z.

[0355] Methyl 4-amino-2H-pyrazole-3-carboxylate

[0356]

[0357] Methyl 4-nitro-2H-pyrazole-3-carboxylate (3 g, 0.017 mol) and 5% Pd-C (0.75 g) were suspended in methanol (30 ml) and stirred under hydrogen at room temperature for 14 h. The suspension was filtered and the solvent removed in vacuo. Methyl 4-amino-2H-pyrazole-3-carboxylate was isolated as a pale pink solid (2.4 g, quantitative); LC / MS (Method F) Rt 0.363 min; [MNa]+ 164.1 m / z.

[0358] Methyl 4-[1-((R)-3-methylmorpholin-4-yl)-(E)-ethylideneamino]-2H-pyrazole-3-carboxylate

[0359]

[0360] 1-((R)-3-Methylmorpholin-4-yl)ethanone (3.409 g; 23.808 mmol; 1.40 eq) was dissolved in 1,2-dichloroethane (24 ml), and phosphoryl chloride (4.684 ml; 51.018 mmol; 3 eq) was added dropwise. The brown solution was stirred at RT for 30 minutes, then methyl 4-amino-2H-pyrazole-3-carboxylate (2.400 g; 17.006 mmol; 1 eq) was added and the mixture was stirred at 80 °C for 2 hours. The reaction solution was evaporated to dryness. The residue was suspended in water (50 ml), the pH was adjusted to 12 with aqueous NaOH solution (32%), and the mixture was extracted with EtOAc. The combined organic phases were dried over sodium sulfate, filtered and evaporated to dryness. Methyl 4-[1-((R)-3-methylmorpholin-4-yl)-(E)-ethylideneamino]-2H-pyrazole-3-carboxylate was isolated as a yellow solid (5 g, quantitative); LC / MS (method F): Rt 0.968 min; [MH]+ 267 m / z.

[0361] Methyl 4-[1-((R)-3-methylmorpholin-4-yl)-(E)-ethylideneamino]-2-(2-trimethylsilylethoxymethyl)-2H-pyrazole-3-carboxylate

[0362]

[0363] Methyl 4-[1-((R)-3-methylmorpholin-4-yl)-(E)-ethylideneamino]-2H-pyrazole-3-carboxylate (1 g; 3.755 mmol) was suspended in THF (20 ml), triethylamine (781 μl; 5.633 mmol; 1.50 eq) and 2-(trimethylsilyl)ethoxymethyl chloride (731.084 μl; 4.131 mmol; 1.10 eq) were added and the mixture was stirred at RT for 1 hour. The solvent was removed in vacuo and the residue was extracted with EtOAc / water. The combined organic phases were dried over sodium sulfate and evaporated to dryness. The crude product was purified by column chromatography (method D). Methyl 4-[1-((R)-3-methylmorpholin-4-yl)-(E)-ethylideneamino]-2-(2-trimethylsilylethoxymethyl)-2H-pyrazole-3-carboxylate was isolated as a colorless solid (580 mg, 38%); LC / MS (method F): Rt 2.251 min, [MH]+ 397.2 m / z.

[0364] 5-((R)-3-Methylmorpholin-4-yl)-1-(2-trimethylsilylethoxymethyl)-1H-pyrazolo[4,3-b]pyridin-7-ol

[0365]

[0366] Methyl 4-[1-((R)-3-methylmorpholin-4-yl)-(E)-ethylideneamino]-2-(2-trimethylsilylethoxymethyl)-2H-pyrazole-3-carboxylate (200 mg; 0.494 mmol; 1 eq) was dissolved in THF (3 ml), and a THF solution of 1 M lithium bis(trimethylsilyl)amide (1.977 ml; 1.977 mmol; 4 eq) was added, and the mixture was stirred at RT for 2 h. Water (0.2 ml) was added to the reaction solution, and the solvent was removed in vacuo. The residue was suspended in water (2 ml), the pH was adjusted to 7 with 2 N HCl and saturated ammonium chloride solution, and the mixture was extracted with DCM. The combined organic phases were dried, filtered and evaporated. 5-((R)-3-Methylmorpholin-4-yl)-1-(2-trimethylsilylethoxymethyl)-1H-pyrazolo[4,3-b]pyridin-7-ol was isolated as a yellow solid (182 mg, 95%); LC / MS (method F): Rt 2.28 min; [MH]+ 365.2 m / z.

[0367] 5-((R)-3-Methylmorpholin-4-yl)-1-(2-trimethylsilylethoxymethyl)-1H-pyrazolo[4,3-b]pyridin-7-yl trifluoromethanesulfonate

[0368]

[0369] 5-((R)-3-Methylmorpholin-4-yl)-1-(2-trimethylsilylethoxymethyl)-1H-pyrazolo[4,3-b]pyridin-7-ol (50 mg; 0.137 mmol; 1.0 eq) was dissolved in DCM (1 ml), and triethylamine (34.226 μl; 0.247 mmol; 1.80 eq) was added. The reaction mixture was cooled to 5 °C, trifluoromethanesulfonic anhydride (41 μl; 0.247 mmol; 1.80 eq) was added, and the mixture was stirred for 1 h and warmed to room temperature. The reaction solution was extracted with DCM and water, the combined organic phases were washed with brine, dried over sodium sulfate, filtered and evaporated to dryness. 5-((R)-3-Methylmorpholin-4-yl)-1-(2-trimethylsilylethoxymethyl)-1H-pyrazolo[4,3-b]pyridin-7-yl trifluoromethanesulfonate was isolated as an orange-brown solid (61 mg, 90%). LC / MS (method F): Rt 3.006 min, [MH]+ 497.1 m / z. Example

[0370] Example 1: 1-Methyl-5-((R)-3-methylmorpholin-4-yl)-7-(6-methylpyridin-3-yl)-3-(1H-pyrazol-3-yl)-1H-pyrazolo[4,3-b]pyridine (1)

[0371]

[0372] Structural unit for the synthesis of Example 1: (3R)-3-methyl-4-[1-methyl-7-(6-methylpyridin-3-yl)-1H-pyrazolo[4,3-b]pyridin-5-yl]morpholine

[0373]

[0374] 1-Methyl-5-[(3R)-3-methylmorpholin-4-yl]-1H-pyrazolo[4,3-b]pyridin-7-yl trifluoromethanesulfonate (1 g, 2.37 mmol, 1.0 equiv), (6-methylpyridin-3-yl)boronic acid (680 mg, 4.72 mmol, 1.99 equiv), Pd(dppf)Cl2·CH2Cl2 (210 mg, 0.23 mmol, 0.10 equiv) and sodium carbonate (790 mg, 7.08 mmol, 2.99 equiv) were suspended in DMF (12 mL) and water (3 mL). The final reaction mixture was heated to 100 °C in a microwave for 1 h. The yellow solid (3R)-3-methyl-4-[1-methyl-7-(6-methylpyridin-3-yl)-1H-pyrazolo[4,3-b]pyridin-5-yl]morpholine (600 mg, 70%) was isolated.

[0375] Structural unit for the synthesis of Example 1: (3R)-4-[3-bromo-1-methyl-7-(6-methylpyridin-3-yl)-1H-pyrazolo[4,3-b]pyridin-5-yl]-3-methylmorpholine

[0376]

[0377] (3R)-3-Methyl-4-[1-methyl-7-(6-methylpyridin-3-yl)-1H-pyrazolo[4,3-b]pyridin-5-yl]morpholine (12 g, 33.40 mmol, 1 equiv) and NBS (9.39 g, 50.12 mmol, 1.50 equiv) were dissolved in MeCN (480 mL) and stirred at 25 °C for 1 h. The resulting mixture was concentrated in vacuo. The residue was purified by column chromatography (Method E). The yellow solid (3R)-4-[3-bromo-1-methyl-7-(6-methylpyridin-3-yl)-1H-pyrazolo[4,3-b]pyridin-5-yl]-3-methylmorpholine (15 g, 100%) was isolated.

[0378] Structural unit for the synthesis of Example 1: (3R)-3-methyl-4-[1-methyl-7-(6-methylpyridin-3-yl)-3-[1-(oxan-2-yl)-1H-pyrazol-3-yl]-1H-pyrazolo[4,3-b]pyridin-5-yl]morpholine

[0379]

[0380] Suspend (3R)-4-[3-bromo-1-methyl-7-(6-methylpyridin-3-yl)-1H-pyrazolo[4,3-b]pyridin-5-yl]-3-methylmorpholine (1.20 g, 2.68 mmol, 1.0 equiv), 1-(oxan-2-yl)-3-(tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (2.36 g, 8.06 mmol, 3 equiv), Pd(PPh3)4 (340 mg, 0.26 mmol, 0.10 equiv) and sodium carbonate (900 mg, 8.07 mmol, 3 equiv) in tetrahydrofuran (12 mL), water (3 mL, 158.20 mmol, 58.93 equiv). Stir the resulting solution at 90 °C for 1 h. Extract the resulting solution with ethyl acetate, combine the organic layers and concentrate in vacuo. Purify the residue by column chromatography (Method E). Isolate (3R)-3-methyl-4-[1-methyl-7-(6-methylpyridin-3-yl)-3-[1-(oxan-2-yl)-1H-pyrazol-3-yl]-1H-pyrazolo[4,3-b]pyridin-5-yl]morpholine as a yellow solid (700 mg, 50%).

[0381] Example 1: 1-Methyl-5-((R)-3-methyl-morpholin-4-yl)-7-(6-methyl-pyridin-3-yl)-3-(1H-pyrazol-3-yl)-1H-pyrazolo[4,3-b]pyridine (1)

[0382]

[0383] (3R)-3-Methyl-4-[1-methyl-7-(6-methylpyridin-3-yl)-3-[1-(oxan-2-yl)-1H-pyrazol-3-yl]-1H-pyrazolo[4,3-b]pyridin-5-yl]morpholine (10 g, 19.00 mmol, 1 equiv) was dissolved in HCl in methanol solution (200 mL). The resulting solution was stirred at 25 °C for 1 h. The resulting solution was extracted with ethyl acetate, and the organic layers were combined and concentrated in vacuo. The crude product was purified by preparative HPLC. 1-Methyl-5-((R)-3-methyl-morpholin-4-yl)-7-(6-methyl-pyridin-3-yl)-3-(1H-pyrazol-3-yl)-1H-pyrazolo[4,3-b]pyridine as a yellow solid was isolated (2 g, 28%); melting point: 118 - 120 °C;

[0384] 1 1H NMR (300 MHz, DMSO-d6): δ 12.81 (s, 1H), 8.63 (d, J = 2.4 Hz, 1H), 7.88 (dd, J = 7.9, 2.4 Hz, 1H), 7.62 (s, 1H), 7.41 (d, J = 8.1 Hz, 1H), 7.00 (s, 1H), 6.89 - 6.81 (m, 1H), 4.46 (s, 1H), 4.07 - 3.90 (m, 2H), 3.72 (s, 1H), 3.62 - 3.48 (m, 1H), 3.23 (td, J = 12.5, 11.7, 3.7 Hz, 1H), 3.01 (s, 1H), 2.58 (d, J = 2.8 Hz, 4H), 2.02 (d, J = 2.7 Hz, 0H), 1.21 (dd, J = 6.9, 2.6 Hz, 3H);

[0385] LC / MS (method A) Rt 1.338 min, [MH]+ 390.0.

[0386] Example 2: 5-((R)-3-Methyl-morpholin-4-yl)-7-(6-methyl-pyridin-3-yl)-3-(1H-pyrazol-3-yl)-1H-pyrazolo[4,3-b]pyridine (2)

[0387]

[0388] Structural unit for the synthesis of Example 2: 6-chloro-2-methyl-3-nitropyridin-4-amine

[0389]

[0390] Dissolve 2,6-dichloro-3-nitropyridin-4-amine (1 g, 4.33 mmol, 1 equiv), Pd(PPh3)4 (557 mg, 0.46 mmol, 0.11 equiv) and AlMe3 (2.64 mL, 23.94 mmol, 5.53 equiv) in DMF (15 mL), and stir at 70 °C for 3 h. Quench the reaction by adding 50 mL of ice / salt. Filter out the solid. Extract the resulting solution with ethyl acetate, combine the organic layers and concentrate in vacuo. Purify the residue by column chromatography (Method B). Isolate 6-chloro-2-methyl-3-nitropyridin-4-amine as a yellow solid (500 mg, 55%).

[0391] Structural unit for the synthesis of Example 2: 4-bromo-6-chloro-2-methyl-3-nitropyridine

[0392]

[0393] Dissolve 6-chloro-2-methyl-3-nitropyridin-4-amine (1 g, 4.80 mmol, 1 equiv), CuBr2 (1601.79 mg, 6.81 mmol, 1.42 equiv) and tBuONO (697.86 mg, 6.43 mmol, 1.34 equiv) in MeCN (20 mL), and stir at 65 °C for 2 h. Adjust the pH of the solution to 2 with hydrogen chloride. Extract the resulting solution with ethyl acetate, combine the organic layers and concentrate in vacuo. Purify the residue by column chromatography (Method F). Isolate 4-bromo-6-chloro-2-methyl-3-nitropyridine as a yellow solid (1 g, 75%).

[0394] Structural unit for the synthesis of Example 2: 6-chloro-2-methyl-4-(pyridin-3-yl)-3-nitropyridine

[0395]

[0396] Dissolve 4-bromo-6-chloro-2-methyl-3-nitropyridine (500 mg, 1.79 mmol, 1 equiv), (pyridin-3-yl)boronic acid (326.75 mg, 2.15 mmol, 1.20 equiv), Pd(PPh3)2Cl2 (130 mg, 0.18 mmol, 0.10 equiv) and sodium carbonate (604.65 mg, 5.42 mmol, 3.03 equiv) in dioxane (2 mL), water (0.4 mL), and stir at 80 °C for 3 h. Extract the resulting solution with ethyl acetate, combine the organic layers and concentrate in vacuo. Purify the residue by column chromatography (Method G). Isolate 6-chloro-2-methyl-4-(pyridin-3-yl)-3-nitropyridine as a yellow solid (400 mg, 76%).

[0397] Structural unit for the synthesis of Example 2: (3R)-3-methyl-4-[6-methyl-4-(6-methylpyridin-3-yl)-5-nitropyridin-2-yl]morpholine

[0398]

[0399] Dissolve 6-chloro-2-methyl-4-(6-methylpyridin-3-yl)-3-nitropyridine (500 mg, 1.71 mmol, 1 equiv), (3R)-3-methylmorpholine (230.16 mg, 2.05 mmol, 1.20 equiv), and DIPEA (696.53 mg, 5.12 mmol, 3 equiv) in DMA (25 mL), and stir at 110 °C for 16 h. The resulting solution was extracted with ethyl acetate, the organic layers were combined and concentrated in vacuo. The crude product (3R)-3-methyl-4-[6-methyl-4-(6-methylpyridin-3-yl)-5-nitropyridin-2-yl]morpholine was isolated and used in the next step without further purification.

[0400] Structural unit for the synthesis of Example 2: 2-methyl-6-[(3R)-3-methylmorpholin-4-yl]-4-(6-methylpyridin-3-yl)pyridin-3-amine

[0401]

[0402] Dissolve (3R)-3-methyl-4-[6-methyl-4-(6-methylpyridin-3-yl)-5-nitropyridin-2-yl]morpholine (200 mg, 0.55 mmol, 1 equiv), Fe (170 mg, 2.89 mmol, 5.28 equiv), and NH4Cl (170 mg, 3.02 mmol, 5.51 equiv) in water (10 mL) and isopropanol (10 mL), and stir at 70 °C for 5 h. Filter off the solid. The resulting solution was extracted with ethyl acetate, the organic layers were combined, dried over anhydrous sodium sulfate, and concentrated in vacuo. The residue was purified by column chromatography (Method H). 2-Methyl-6-[(3R)-3-methylmorpholin-4-yl]-4-(6-methylpyridin-3-yl)pyridin-3-amine was isolated as a yellow oil (70 mg, 38%).

[0403] Structural unit for the synthesis of Example 2: (3R)-3-methyl-4-[7-(6-methylpyridin-3-yl)-1H-pyrazolo[4,3-b]pyridin-5-yl]morpholine

[0404]

[0405] 2-Methyl-6-[(3R)-3-methylmorpholin-4-yl]-4-(6-methylpyridin-3-yl)pyridin-3-amine (480 mg, 1.45 mmol, 1 equiv) and NaNO2 (95.69 mg, 1.32 mmol, 0.91 equiv) were dissolved in AcOH (96 mL) and stirred at 25 °C for 2 h. The resulting solution was extracted with ethyl acetate, the organic layers were combined, dried over anhydrous sodium sulfate and concentrated in vacuo. The residue was purified by column chromatography (Method B). (3R)-3-Methyl-4-[7-(6-methylpyridin-3-yl)-1H-pyrazolo[4,3-b]pyridin-5-yl]morpholine as a yellow solid was isolated (100 mg, 20%).

[0406] Structural unit for the synthesis of Example 2: (3R)-4-[3-Iodo-7-(6-methylpyridin-3-yl)-1H-pyrazolo[4,3-b]pyridin-5-yl]-3-methylmorpholine

[0407]

[0408] (3R)-3-Methyl-4-[7-(6-methylpyridin-3-yl)-1H-pyrazolo[4,3-b]pyridin-5-yl]morpholine (100 mg, 0.29 mmol, 1 equiv), potassium hydroxide (59.96 mg, 1.02 mmol, 3.49 equiv) and I2 (150.01 mg, 0.56 mmol, 1.93 equiv) were dissolved in methanol (10 mL) and stirred at 25 °C for 16 h. The resulting solution was extracted with ethyl acetate, the organic layers were combined, dried over sodium sulfate and concentrated in vacuo. The residue was purified by column chromatography (Method I). (3R)-4-[3-Iodo-7-(6-methylpyridin-3-yl)-1H-pyrazolo[4,3-b]pyridin-5-yl]-3-methylmorpholine as a yellow solid was isolated (90 mg, 64%).

[0409] Structural unit for the synthesis of Example 2: (3R)-3-Methyl-4-[7-(6-methylpyridin-3-yl)-3-[1-(oxan-2-yl)-1H-pyrazol-3-yl]-1H-pyrazolo[4,3-b]pyridin-5-yl]morpholine

[0410]

[0411] (3R)-4-[3-Iodo-7-(6-methylpyridin-3-yl)-1H-pyrazolo[4,3-b]pyridin-5-yl]-3-methylmorpholine (90 mg, 0.19 mmol, 1.0 equiv), 1-(oxan-2-yl)-3-(tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (180 mg, 0.58 mmol, 3.13 equiv), Pd(PPh3)4 (27 mg, 0.02 mmol, 0.12 equiv), water (3 mL), tetrahydrofuran (12 mL), and sodium carbonate (65 mg, 0.58 mmol, 3.13 equiv) were combined, and the resulting solution was stirred at 80 °C for 1 h. The resulting solution was extracted with ethyl acetate, the organic layers were combined, dried over anhydrous sodium sulfate, and concentrated in vacuo. The residue was purified by column chromatography (Method B). (3R)-3-Methyl-4-[7-(6-methylpyridin-3-yl)-3-[1-(oxan-2-yl)-1H-pyrazol-3-yl]-1H-pyrazolo[4,3-b]pyridin-5-yl]morpholine as a yellow solid (75 mg, 77%) was isolated.

[0412] Example 2: 5-((R)-3-Methyl-morpholin-4-yl)-7-(6-methyl-pyridin-3-yl)-3-(1H-pyrazol-3-yl)-1H-pyrazolo[4,3-b]pyridine (2)

[0413]

[0414] (3R)-3-Methyl-4-[7-(6-methylpyridin-3-yl)-3-[1-(oxan-2-yl)-1H-pyrazol-3-yl]-1H-pyrazolo[4,3-b]pyridin-5-yl]morpholine (70 mg, 0.14 mmol, 1 equiv) was dissolved in a methanolic solution of hydrogen chloride (3 mL) and stirred at 25 °C for 1 h. The pH of the solution was adjusted to 9 with sodium bicarbonate (0.5 mL mol / L). The resulting mixture was concentrated in vacuo. The crude product was purified by preparative HPLC. 5-((R)-3-Methyl-morpholin-4-yl)-7-(6-methyl-pyridin-3-yl)-3-(1H-pyrazol-3-yl)-1H-pyrazolo[4,3-b]pyridine was isolated as a yellow solid (4 mg, 8%); melting point 180–182 °C;

[0415] 11H NMR (400 MHz, DMSO-d6): δ 13.31 (s, 1H), 8.89 (s, 1H), 8.12 (s, 1H), 7.65 (s, 1H), 7.46 (d, J = 8.2 Hz, 1H), 7.14 (s, 1H), 7.07 (s, 1H), 4.54 (s, 1H), 4.08 (d, J = 13.1 Hz, 1H), 3.99 (dd, J = 11.3, 3.4 Hz, 1H), 3.80 - 3.66 (m, 2H), 3.54 (m, 1H), 3.25 - 3.13 (m, 1H), 2.57 (s, 3H), 1.18 (d, J = 6.6 Hz, 3H);

[0416] LC / MS (Method B): Rt 1.544 min, [M+H]+ 376.0.

[0417] Example 3: (3R)-3-Methyl-4-[3-(3-methyl-1H-pyrazol-5-yl)-7-(6-methylpyridin-3-yl)-1H-pyrazolo[4,3-b]pyridin-5-yl]morpholine (3)

[0418] Absolute

[0419]

[0420] Structural unit for the synthesis of Example 3: 5-((R)-3-methyl-morpholin-4-yl)-7-(6-methyl-pyridin-3-yl)-3-[5-methyl-2-(tetrahydro-pyran-2-yl)-2H-pyrazol-3-yl]-1H-pyrazolo[4,3-b]pyridine

[0421]

[0422] (3R)-4-[3-Iodo-7-(6-methylpyridin-3-yl)-1H-pyrazolo[4,3-b]pyridin-5-yl]-3-methylmorpholine (56 mg; 0.114 mmol; 0.789 equiv) and (3R)-4-[3-iodo-7-(6-methylpyridin-3-yl)-1H-pyrazolo[4,3-b]pyridin-5-yl]-3-methylmorpholine (15 mg; 0.031 mmol; 0.211 equiv) were dissolved in tetrahydrofuran (1.42 ml) and water (142.00 μl). 1-BOC-3-methylpyrazole-5-boronic acid (49 mg; 0.217 mmol; 1.5 equiv), sodium carbonate (0.02 ml; 0.434 mmol; 3 equiv) and tetrakis(triphenylphosphine)palladium(0) (20 mg; 0.017 mmol; 0.120 equiv) were added. The reaction suspension was stirred at 80 °C for 1 h. 3-Methyl-1-(oxan-2-yl)-5-(tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (66.67 mg; 0.217 mmol; 1.5 equiv) and tetrakis(triphenylphosphine)palladium(0) (20.04 mg; 0.017 mmol; 0.120 equiv) were added and stirred at 80 °C for 1 h. The solid was filtered off and the filtrate was concentrated under reduced pressure. The product was purified by flash chromatography (n-heptane / EtOAc gradient) to give 35 mg (47.9%) of a brown solid; LC / MS (method C): Rt 0.946 min; [MH]+ 474.2.

[0423] Example 3: (3R)-3-Methyl-4-[3-(3-methyl-1H-pyrazol-5-yl)-7-(6-methylpyridin-3-yl)-1H-pyrazolo[4,3-b]pyridin-5-yl]morpholine (3)

[0424]

[0425] 5-((R)-3-Methyl-morpholin-4-yl)-7-(6-methyl-pyridin-3-yl)-3-[5-methyl-2-(tetrahydro-pyran-2-yl)-2H-pyrazol-3-yl]-1H-pyrazolo[4,3-b]pyridine (35 mg; 0.069 mmol; 1 equiv) was dissolved in a dioxane solution of hydrogen chloride (0.86 ml). The suspension was stirred at room temperature for 48 h. The reaction mixture was concentrated under reduced pressure and purified by flash chromatography (method O). (3R)-3-Methyl-4-[3-(3-methyl-1H-pyrazol-5-yl)-7-(6-methylpyridin-3-yl)-1H-pyrazolo[4,3-b]pyridin-5-yl]morpholine as a yellow solid was isolated (10 mg, 37%);

[0426] 11H NMR (400 MHz, DMSO-d6 / 90 °C) δ 9.09–9.04 (m, 1H), 8.37–8.32 (m, 1H), 7.53 (d, J = 8.1 Hz, 1H), 7.16 (s, 1H), 6.78 (s, 1H), 4.56–4.49 (m, 1H), 4.10–4.03 (m, 1H), 4.01–3.96 (m, 1H), 3.76–3.71 (m, 2H), 3.58 (td, J = 11.5, 3.1 Hz, 1H), 3.32–3.23 (m, 1H), 2.62 (s, 3H), 2.30 (s, 3H), 1.23 (d, J = 6.7 Hz, 3H);

[0427] LC / MS (Method C): Rt 0.821 min; [M+H]+ 390.2.

[0428] Example 4: 1-Methyl-5-((R)-3-methylmorpholin-4-yl)-7-(2-methylpyridin-3-yl)-3-(1H-pyrazol-3-yl)-1H-pyrazolo[4,3-b]pyridine (4)

[0429]

[0430] 1-Methyl-5-((R)-3-methylmorpholin-4-yl)-7-(2-methylpyridin-3-yl)-3-(1H-pyrazol-3-yl)-1H-pyrazolo[4,3-b]pyridine was prepared analogously to the above example and isolated as a yellow solid (160 mg, 36%), melting point 228 - 230 °C;

[0431] 1 1H NMR (300 MHz, DMSO-d6): δ 13.24 (s, 1H), 8.64 (dd, J = 4.9, 1.7 Hz, 1H), 7.83 (dt, J = 7.6, 2.1 Hz, 1H), 7.69 (s, 1H), 7.43 (dd, J = 7.6, 4.9 Hz, 1H), 7.09 (s, 1H), 6.97 (s, 1H), 4.46 (s, 1H), 4.13 - 3.94 (m, 2H), 3.82 - 3.62 (m, 2H), 3.62 - 3.49 (m, 1H), 3.46 (s, 3H), 3.18 (td, J = 12.7, 3.7 Hz, 1H), 2.33 (d, J = 1.4 Hz, 3H), 1.20 (dd, J = 6.7, 3.0 Hz, 3H);

[0432] LC / MS (Method D): Rt 0.782 min, [M+H]+ 390.2.

[0433] Example 5: 7-(4-Methylsulfinyl-phenyl)-1-methyl-5-((R)-3-methyl-morpholin-4-yl)-3-(1H-pyrazol-3-yl)-1H-pyrazolo[4,3-b]pyridine (5)

[0434]

[0435] 7-(4-Methylsulfinyl-phenyl)-1-methyl-5-((R)-3-methyl-morpholin-4-yl)-3-(1H-pyrazol-3-yl)-1H-pyrazolo[4,3-b]pyridine was prepared analogously to the above example, and a yellow solid (90 mg, 23%) was isolated; melting point 155 - 157 °C.

[0436] 1 H NMR (methanol-d4): δ 7.89 (d, J = 8.2 Hz, 2H), 7.78 (d, J = 8.0 Hz, 2H), 7.68 (s, 1H), 7.12 (s, 1H), 6.89 (s, 1H), 4.47 (t, J = 6.8 Hz, 1H), 4.04 (dd, J = 11.3, 3.2 Hz, 2H), 3.82 (d, J = 2.2 Hz, 2H), 3.73 - 3.62 (m, 4H), 3.38 - 3.32 (m, 1H), 2.65 (s, 1H), 1.29 (d, J = 6.7 Hz, 3H);

[0437] LC / MS (method B): Rt 1.993 min, [MH]+ 437.1.

[0438] Example 6: Imino(methyl)(4-{1-methyl-5-[(3R)-3-methylmorpholin-4-yl]-3-(1H-pyrazol-3-yl)-1H-pyrazolo[4,3-b]pyridin-7-yl}phenyl)-λ6-sulfanone (6)

[0439]

[0440] Structural unit for the synthesis of Example 6: 2,2,2-trifluoro-N-[methane(4-{1-methyl-5-[(3R)-3-methylmorpholin-4-yl]-3-[1-(oxan-2-yl)-1H-pyrazol-3-yl]-1H-pyrazolo[4,3-b]pyridin-7-yl}benzene)sulfinyl]acetamide

[0441]

[0442] (3R)-4-[7-(4-Methylsulfinylphenyl)-1-methyl-3-[1-(oxan-2-yl)-1H-pyrazol-3-yl]-1H-pyrazolo[4,3-b]pyridin-5-yl]-3-methylmorpholine (70 mg, 0.12 mmol, 1 equiv), MgO (25.67 mg, 0.61 mmol, 5 equiv), dichloromethane (5 mL), Rh2(OAc)4 (5.63 mg, 0.01 mmol, 0.10 equiv) and phenyliodonium diacetate (82.05 mg, 0.24 mmol, 2 equiv) were combined and the solution was stirred at 25 °C for 12 h. The resulting mixture was concentrated in vacuo. 2,2,2-Trifluoro-N-[methanediyl(4-[1-methyl-5-[(3R)-3-methylmorpholin-4-yl]-3-[1-(oxan-2-yl)-1H-pyrazol-3-yl]-1H-pyrazolo[4,3-b]pyridin-7-yl]benzene)sulfinimidoyl]acetamide was isolated as a yellow solid (70 mg, 74%) and used in the next step without further purification.

[0443] Structural unit for the synthesis of Example 6: (3R)-4-(7-{4-[imino(methanediyl)sulfinyl]phenyl}-1-methyl-3-[1-(oxan-2-yl)-1H-pyrazol-3-yl]-1H-pyrazolo[4,3-b]pyridin-5-yl)-3-methylmorpholine

[0444]

[0445] 2,2,2-Trifluoro-N-[methanediyl(4-[1-methyl-5-[(3R)-3-methylmorpholin-4-yl]-3-[1-(oxan-2-yl)-1H-pyrazol-3-yl]-1H-pyrazolo[4,3-b]pyridin-7-yl]benzene)sulfinimidoyl]acetamide (70 mg, 0.08 mmol, 1.0 equiv 70%) in methanol (5 mL) and potassium carbonate (33.86 mg, 0.23 mmol, 3 equiv) were combined and the solution was stirred at 25 °C for 1 h. The resulting mixture was concentrated in vacuo. (3R)-4-(7-[4-[imino(methanediyl)sulfinyl]phenyl]-1-methyl-3-[1-(oxan-2-yl)-1H-pyrazol-3-yl]-1H-pyrazolo[4,3-b]pyridin-5-yl)-3-methylmorpholine was isolated as a yellow solid (70 mg, quantitative) and used in the next step without further purification.

[0446] Example 6: Imino(methyl)(4-{1-methyl-5-[(3R)-3-methylmorpholin-4-yl]-3-(1H-pyrazol-3-yl)-1H-pyrazolo[4,3-b]pyridin-7-yl}phenyl)-λ6-sulfanone (6)

[0447]

[0448] (3R)-4-(7-[4-[Imino(methane)sulfinyl]phenyl]-1-methyl-3-[1-(oxan-2-yl)-1H-pyrazol-3-yl]-1H-pyrazolo[4,3-b]pyridin-5-yl)-3-methylmorpholine (70 mg, 0.09 mmol, 1.0 eq, 70%) was dissolved in hydrogen chloride in dioxane (5 mL) and stirred at 25 °C for 1 h. The resulting solution was extracted with ethyl acetate, the organic layers were combined, dried over sodium sulfate and concentrated in vacuo. The crude product was purified by preparative HPLC (Method B). Imino(methyl)(4-{1-methyl-5-[(3R)-3-methylmorpholin-4-yl]-3-(1H-pyrazol-3-yl)-1H-pyrazolo[4,3-b]pyridin-7-yl}phenyl)-λ6-sulfanone was isolated as a yellow solid (14 mg, 34%); mp 180 °C;

[0449] 1 H NMR (300 MHz, DMSO-d6) δ 13.17 (br, 1H) 8.10 (d, J = 8.4 Hz, 2H), 7.84 (d, J = 8.4 Hz, 2H), 7.67 (s, 1H), 7.07 (d, J = 1.9 Hz, 1H), 6.93 (s, 1H), 4.56 - 4.41 (m, 1H), 4.37 (s, 1H), 4.02 (ddd, J = 24.4, 11.9, 3.1 Hz, 2H), 3.80 - 3.64 (m, 2H), 3.61 (s, 3H), 3.58 - 3.44 (m, 1H), 3.34 - 3.16 (m, 4H), 1.18 (d, J = 6.5 Hz, 3H). LC / MS (Method B): Rt 1.857 min, [MH]+ 452.1.

[0450] Example 7: 7-(4-Methylsulfonyl-phenyl)-1-methyl-5-((R)-3-methyl-morpholin-4-yl)-3-(1H-pyrazol-3-yl)-1H-pyrazolo[4,3-b]pyridine (7)

[0451]

[0452] 7-(4-Methylsulfonyl-phenyl)-1-methyl-5-((R)-3-methyl-morpholin-4-yl)-3-(1H-pyrazol-3-yl)-1H-pyrazolo[4,3-b]pyridine was prepared analogously to the above example and isolated as a yellow solid (18 mg, 31%); mp > 300 °C;

[0453] 11H NMR (300 MHz, DMSO-d6) δ 13.09 (d, J = 90.7 Hz, 1H), 8.28 - 7.99 (m, 2H), 7.71 (d, J = 67.8 Hz, 1H), 7.04 (s, 1H), 6.96 (s, 1H), 4.46 (d, J = 11.2 Hz, 1H), 4.18 - 3.92 (m, 2H), 3.81 - 3.64 (m, 2H), 3.64 - 3.44 (m, 4H), 3.32 (s, 4H), 3.24 - 3.04 (m, 1H), 1.18 (d, J = 6.5 Hz, 3H);

[0454] LC / MS (Method F): Rt 1.298 min, [MH]+ 453.1.

[0455] Example 8: 7-(6-Methylsulfinyl-2-methyl-pyridin-3-yl)-1-methyl-5-((R)-3-methyl-morpholin-4-yl)-3-(1H-pyrazol-3-yl)-1H-pyrazolo[4,3-b]pyridine (8)

[0456]

[0457] Structural unit for the synthesis of Example 8: 3-Bromo-2-methyl-6-(methylthio)pyridine

[0458]

[0459] 3-Bromo-6-fluoro-2-methylpyridine (3 g, 15.00 mmol, 1.0 equiv), DMF (300 mL) and sodium (methylthio) (1.44 g, 19.52 mmol, 1.30 equiv) were combined and stirred at 0 °C for 4 h. The resulting solution was extracted with ethyl acetate, the organic layers were combined and concentrated in vacuo. 3-Bromo-2-methyl-6-(methylthio)pyridine as a yellow oil was isolated (2.5 g, 69%); LC / MS (Method J): Rt 1.324 min, [MH]+ 220.0.

[0460] Structural unit for the synthesis of Example 8: 3-Bromo-6-methylsulfinyl-2-methylpyridine

[0461]

[0462] 3-Bromo-2-methyl-6-(methylthio)pyridine (2.50 g, 10.32 mmol, 1.0 equiv), dichloromethane (200 mL), and m-CPBA (1.87 g, 10.29 mmol, 1.0 equiv) were combined and stirred at 25 °C for 2 h. The resulting solution was extracted with ethyl acetate, the organic layers were combined, dried over sodium sulfate, and concentrated in vacuo. The residue was purified by column chromatography (Method J). 3-Bromo-6-methylsulfinyl-2-methylpyridine as a yellow oil (1.8 g, 67%); LC / MS (Method J): Rt 0.937 min, [MH]+ 233.9.

[0463] Structural unit for the synthesis of Example 8: 6-Methylsulfinyl-2-methyl-3-(tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine

[0464]

[0465] 3-Bromo-6-methylsulfinyl-2-methylpyridine (1.80 g, 6.92 mmol, 1.0 equiv), 4,4,5,5-tetramethyl-2-(tetramethyl-1,3,2-dioxaborolan-2-yl)-1,3,2-dioxaborolane (7.77 g, 29.07 mmol, 4.20 equiv), dioxane (120 mL, 1.35 mol, 194.47 equiv), CH3COOK (3 g, 29.04 mmol, 4.19 equiv), and Pd(dppf)Cl2·CH2Cl2 (820 mg, 0.90 mmol, 0.13 equiv) were combined at 25 °C for 3 h. The resulting solution was extracted with ethyl acetate, the organic layers were combined, dried over sodium sulfate, and concentrated in vacuo. The residue was purified by column chromatography (Method J). 6-Methylsulfinyl-2-methyl-3-(tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine as a yellow oil (1.8 g 83%); LC / MS (Method J): Rt 1.131 min [MH]+ 282.1.

[0466] Example 8: 7-(6-Methylsulfinyl-2-methyl-pyridin-3-yl)-1-methyl-5-((R)-3-methyl-morpholin-4-yl)-3-(1H-pyrazol-3-yl)-1H-pyrazolo[4,3-b]pyridine (8)

[0467]

[0468] 7-(6-Methylsulfinyl-2-methyl-pyridin-3-yl)-1-methyl-5-((R)-3-methyl-morpholin-4-yl)-3-(1H-pyrazol-3-yl)-1H-pyrazolo[4,3-b]pyridine was prepared in a similar manner to the above example, and a yellow solid (150 mg, 41%) was isolated; melting point 174 - 176 °C;

[0469] 1 H NMR (300 MHz, CD3O D ): δ 8.05 (dd, J = 7.9, 1.8 Hz, 1H), 7.94 (dd, J = 7.9, 3.0 Hz, 1H), 7.64 (s, 1H), 7.08 (s, 1H), 6.90 (s, 1H), 4.44 (d, J = 7.0 Hz, 1H), 4.09 - 3.96 (m, 2H), 3.80 (d, J = 1.9 Hz, 2H), 3.64 (td, J = 11.8, 3.1 Hz, 1H), 3.51 (s, 3H), 3.38 - 3.30 (m, 0H), 2.93 (d, J = 6.0 Hz, 3H), 2.40 (d, J = 2.6 Hz, 3H), 1.27 (dd, J = 6.7, 4.4 Hz, 3H);

[0470] LC / MS (Method E): Rt 1.199 min, [MH]+ 452.0.

[0471] Example 9: (3R)-4-(7-{6-[(S)-Methylsulfinyl]-2-methylpyridin-3-yl}-1-methyl-3-(1H-pyrazol-3-yl)-1H-pyrazolo[4,3-b]pyridin-5-yl)-3-methylmorpholine (9)

[0472]

[0473] The diastereomers of (3R)-4-[7-(6-Methylsulfinyl-2-methylpyridin-3-yl)-1-methyl-3-(1H-pyrazol-3-yl)-1H-pyrazolo[4,3-b]pyridin-5-yl]-3-methylmorpholine were separated by chiral chromatography (ChiralPak AS-H, solvent system CO2:2-propanol + 0.5% DEA 60:40), and (3R)-4-(7-{6-[(S)-Methylsulfinyl]-2-methylpyridin-3-yl}-1-methyl-3-(1H-pyrazol-3-yl)-1H-pyrazolo[4,3-b]pyridin-5-yl)-3-methylmorpholine was isolated as a yellow solid (30 mg, 40%);

[0474] 11H NMR (500 MHz, DMSO-d6): δ 13.26 - 12.90 (m, 1H), 8.15 - 8.12 (m, 1H), 7.94 - 7.89 (m, 1H), 7.86 - 7.56 (m, 1H), 7.14 - 6.96 (m, 2H), 4.50 - 4.38 (m, 1H), 4.15 - 4.02 (m, 1H), 3.99 (dd, J = 11.4, 3.6 Hz, 1H), 3.77 - 3.72 (m, 1H), 3.71 - 3.67 (m, 1H), 3.54 (td, J = 11.8, 3.0 Hz, 1H), 3.49 - 3.44 (m, 3H), 3.21 - 3.14 (m, 1H), 2.90 - 2.86 (m, 3H), 2.39 - 2.36 (m, 3H), 1.21 - 1.16 (m, 3H), LC / MS (Method F): Rt 2.017 min; [M + H]+ 452.2.

[0475] Example 10: (3R)-4-(7-{6-[(R)-Methylsulfinyl]-2-methylpyridin-3-yl}-1-methyl-3-(1H-pyrazol-3-yl)-1H-pyrazolo[4,3-b]pyridin-5-yl)-3-methylmorpholine (10)

[0476]

[0477] The diastereomers of (3R)-4-[7-(6-Methylsulfinyl-2-methylpyridin-3-yl)-1-methyl-3-(1H-pyrazol-3-yl)-1H-pyrazolo[4,3-b]pyridin-5-yl]-3-methylmorpholine were separated by chiral chromatography (ChiralPak AS-H, solvent system CO2: 2-propanol + 0.5% DEA 60:40), and (3R)-4-(7-{6-[(R)-Methylsulfinyl]-2-methylpyridin-3-yl}-1-methyl-3-(1H-pyrazol-3-yl)-1H-pyrazolo[4,3-b]pyridin-5-yl)-3-methylmorpholine was isolated as a yellow solid (33 mg, 44%); 11H NMR (500 MHz, DMSO-d6): δ 13.25 - 12.90 (m, 1H), 8.16 - 8.11 (m, 1H), 7.93 - 7.89 (m, 1H), 7.86 - 7.55 (m, 1H), 7.14 - 6.97 (m, 2H), 4.51 - 4.38 (m, 1H), 4.13 - 4.02 (m, 1H), 3.98 (dd, J = 11.4, 3.5 Hz, 1H), 3.77 - 3.72 (m, 1H), 3.69 (dd, J = 11.3, 3.0 Hz, 1H), 3.54 (td, J = 11.7, 3.0 Hz, 1H), 3.49 - 3.43 (m, 3H), 3.22 - 3.13 (m, 1H), 2.90 - 2.86 (m, 3H), 2.39 - 2.36 (m, 3H), 1.21 - 1.16 (m, 3H);

[0478] LC / MS (Method F): Rt 2.024 min; [M + H]+ 452.

[0479] Example 11: (3R)-4-[7-(6-Methylsulfonyl-2-methylpyridin-3-yl)-1-methyl-3-(1H-pyrazol-3-yl)-1H-pyrazolo[4,3-b]pyridin-5-yl]-3-methylmorpholine (11)

[0480]

[0481] (3R)-4-[7-(6-Methylsulfinyl-2-methylpyridin-3-yl)-1-methyl-3-[1-(oxan-2-yl)-1H-pyrazol-3-yl]-1H-pyrazolo[4,3-b]pyridin-5-yl]-3-methylmorpholine (20 mg, 0.04 mmol, 1.0 equiv), methanol (0.1 mL), water (1.5 mL) and Oxone® (7.69 mg, 0.04 mmol, 1.23 equiv) were combined and stirred at 25 °C for 16 h. The resulting mixture was concentrated in vacuo. The crude product was purified by preparative HPLC (Method C). (3R)-4-[7-(6-Methylsulfonyl-2-methylpyridin-3-yl)-1-methyl-3-(1H-pyrazol-3-yl)-1H-pyrazolo[4,3-b]pyridin-5-yl]-3-methylmorpholine as a yellow solid (3 mg, 16%); mp 276 - 278 °C; 11H NMR (400 MHz, methanol-d4): δ 8.12 (d, J = 1.4 Hz, 2H), 7.71 (s, 1H), 7.16 (s, 1H), 6.95 (s, 1H), 4.49 (q, J = 6.8, 6.2 Hz, 1H), 4.08 (dq, J = 11.1, 3.9, 3.3 Hz, 2H), 3.90 - 3.82 (m, 2H), 3.69 (td, J = 11.7, 3.1 Hz, 1H), 3.56 (d, J = 1.2 Hz, 3H), 3.41 - 3.36 (m, 1H), 2.50 (d, J = 3.8 Hz, 3H), 1.31 (d, J = 4.9 Hz, 3H); LC / MS (Method G): Rt 1.213 min [MH]+ 468.2.

[0482] Example 12: 7-(6-Methylsulfonyl-2-methyl-pyridin-3-yl)-5-((R)-3-methyl-morpholin-4-yl)-3-(1H-pyrazol-3-yl)-1H-pyrazolo[4,3-b]pyridine (12)

[0483]

[0484] 7-(6-Methylsulfonyl-2-methyl-pyridin-3-yl)-5-((R)-3-methyl-morpholin-4-yl)-3-(1H-pyrazol-3-yl)-1H-pyrazolo[4,3-b]pyridine was prepared analogously to the above example and isolated as a light yellow solid (58 mg, 72%);

[0485] 1 1H NMR (400 MHz, DMSO-d6): δ 13.09 (s, 1H), 8.17 (d, J = 7.8 Hz, 1H), 8.05 (d, J = 7.9 Hz, 1H), 7.73 - 7.65 (m, 1H), 7.09 (d, J = 2.2 Hz, 2H), 4.46 (d, J = 7.3 Hz, 1H), 4.14 - 4.06 (m, 1H), 4.00 (dd, J = 11.3, 3.5 Hz, 1H), 3.81 - 3.66 (m, 2H), 3.56 (td, J = 11.7, 3.0 Hz, 1H), 3.32 (s, 3H), 3.20 (td, J = 12.8, 3.8 Hz, 1H), 2.49 (s, 3H), 1.21 (d, J = 6.6 Hz, 3H);

[0486] LC / MS (Method E): Rt 1.191; [MH]+ 454.0.

[0487] Example 13: (3R)-4-[7-(6-Methylsulfonyl-2-methylpyridin-3-yl)-3-(3-methyl-1H-pyrazol-5-yl)-1H-pyrazolo[4,3-b]pyridin-5-yl]-3-methylmorpholine (13)

[0488]

[0489] (3R)-4-[7-(6-Methylsulfonyl-2-methylpyridin-3-yl)-3-(3-methyl-1H-pyrazol-5-yl)-1H-pyrazolo[4,3-b]pyridin-5-yl]-3-methylmorpholine was prepared analogously to the above example, and a yellow solid was isolated (2 mg, 15%); LC / MS (Method F): Rt 2.049 min; [MH]+ 468.2.

[0490] Example 14: 2-Methyl-5-((R)-3-methyl-morpholin-4-yl)-7-(6-methyl-pyridin-3-yl)-3-(1H-pyrazol-3-yl)-2H-pyrazolo[4,3-b]pyridine (14)

[0491]

[0492] Structural unit for the synthesis of Example 14: (3R)-3-Methyl-4-[2-methyl-7-(6-methylpyridin-3-yl)-3-[1-(oxan-2-yl)-1H-pyrazol-3-yl]-2H-pyrazolo[4,3-b]pyridin-5-yl]morpholine

[0493]

[0494] (3R)-3-Methyl-4-[7-(6-Methylpyridin-3-yl)-3-[1-(oxan-2-yl)-1H-pyrazol-3-yl]-1H-pyrazolo[4,3-b]pyridin-5-yl]morpholine (75.000 mg, 0.15 mmol, 1 equiv), DMF (5 mL) and sodium hydride (8.812 mg, 0.22 mmol, 1.5 equiv) were combined, and the solution was stirred at 0 - 5 °C for 0.5 h. CH3I (32.919 mg, 0.22 mmol, 1.50 equiv) was added thereto. The resulting solution was stirred at 25 °C for 2 h. Then the reaction was quenched by adding an aqueous NH4Cl solution. The resulting mixture was concentrated in vacuo. The residue was purified by column chromatography (Method E). (3R)-3-Methyl-4-[2-Methyl-7-(6-methylpyridin-3-yl)-3-[1-(oxan-2-yl)-1H-pyrazol-3-yl]-2H-pyrazolo[4,3-b]pyridin-5-yl]morpholine as a yellow solid was isolated (20 mg, 25%).

[0495] Example 14: 2-Methyl-5-((R)-3-methylmorpholin-4-yl)-7-(6-methylpyridin-3-yl)-3-(1H-pyrazol-3-yl)-2H-pyrazolo[4,3-b]pyridine (14)

[0496]

[0497] (3R)-3-Methyl-4-[2-methyl-7-(6-methylpyridin-3-yl)-3-[1-(oxan-2-yl)-1H-pyrazol-3-yl]-2H-pyrazolo[4,3-b]pyridin-5-yl]morpholine (20 mg, 0.04 mmol, 1.0 eq) was dissolved in a methanol solution of HCl (5 mL) and stirred at 25 °C for 2 h. The resulting mixture was concentrated in vacuo. The crude product was purified by preparative HPLC (Method D). 2-Methyl-5-((R)-3-methylmorpholin-4-yl)-7-(6-methylpyridin-3-yl)-3-(1H-pyrazol-3-yl)-2H-pyrazolo[4,3-b]pyridine was isolated as a yellow solid (6 mg, 38%); melting point 140–142 °C;

[0498] 1 H NMR (400 MHz, DMSO-d6); δ 13.19 (s, 1H), 9.32 (d, J = 2.4 Hz, 1H), 8.51 (dd, J = 8.0, 2.5 Hz, 1H), 7.93 (s, 1H), 7.43 (d, J = 8.1 Hz, 1H), 7.35 (s, 1H), 7.32 (s, 1H), 4.57 (d, J = 7.6 Hz, 1H), 4.46 (s, 3H), 4.10 (d, J = 13.2 Hz, 1H), 4.00 (dd, J = 11.7, 3.6 Hz, 1H), 3.75 (q, J = 11.0 Hz, 2H), 3.56 (t, J = 10.9 Hz, 1H), 3.23 (dt, J = 14.5, 7.2 Hz, 1H), 2.57 (s, 3H), 1.21 (d, J = 6.6 Hz, 3H); LC / MS (Method G): Rt 1.303 min, [MH]+ 390.2.

[0499] Example 15: 1-Methyl-5-((R)-3-methylmorpholin-4-yl)-3-(1H-pyrazol-3-yl)-7-(1H-pyrrolo[2,3-b]pyridin-4-yl)-1H-pyrazolo[4,3-b]pyridine (15)

[0500]

[0501] Structural unit for the synthesis of Example 15: (3R)-3-methyl-4-(1-methyl-7-{1-[(4-methylphenyl)sulfonyl]-1H-pyrrolo[2,3-b]pyridin-4-yl}-3-(1H-pyrazol-3-yl)-1H-pyrazolo[4,3-b]pyridin-5-yl)morpholine

[0502]

[0503] (3R)-3-methyl-4-(1-methyl-7-[1-[(4-methylphenyl)sulfonyl]-1H-pyrrolo[2,3-b]pyridin-4-yl]-3-(1H-pyrazol-3-yl)-1H-pyrazolo[4,3-b]pyridin-5-yl)morpholine was prepared analogously to the above example and isolated as a yellow solid (100 mg, 83%).

[0504] Example 15: 1-methyl-5-((R)-3-methyl-morpholin-4-yl)-3-(1H-pyrazol-3-yl)-7-(1H-pyrrolo[2,3-b]pyridin-4-yl)-1H-pyrazolo[4,3-b]pyridine (15)

[0505]

[0506] (3R)-3-methyl-4-(1-methyl-7-[1-[(4-methylphenyl)sulfonyl]-1H-pyrrolo[2,3-b]pyridin-4-yl]-3-(1H-pyrazol-3-yl)-1H-pyrazolo[4,3-b]pyridin-5-yl)morpholine (50.000 mg, 0.08 mmol, 1.0 equiv) was dissolved in methanol (5 mL), and sodium hydroxide (9.995 mg, 0.24 mmol, 3.0 equiv) was added. The resulting solution was stirred at 25 °C for 6 hours. The resulting solution was extracted with ethyl acetate, the organic layers were combined, dried over anhydrous sodium sulfate, and concentrated in vacuo. The crude product was purified by preparative HPLC (Method E). 1-methyl-5-((R)-3-methyl-morpholin-4-yl)-3-(1H-pyrazol-3-yl)-7-(1H-pyrrolo[2,3-b]pyridin-4-yl)-1H-pyrazolo[4,3-b]pyridine as a yellow solid was isolated (4 mg, 12%); melting point 200 °C;

[0507] 11H NMR (300 MHz, DMSO-d6): δ 13.09 (d, J = 86.7 Hz, 1H), 11.97 (s, 1H), 8.39 (d, J = 4.8 Hz, 1H), 7.57 (t, J = 2.9 Hz, 2H), 7.25 (d, J = 4.8 Hz, 1H), 7.04 (d, J = 29.0 Hz, 2H), 6.18 (dd, J = 3.4, 1.6 Hz, 1H), 4.44 (d, J = 7.6 Hz, 1H), 4.21 - 3.86 (m, 2H), 3.85 - 3.63 (m, 2H), 3.54 (td, J = 11.7, 2.9 Hz, 1H), 3.42 (s, 3H), 3.18 (td, J = 12.7, 3.7 Hz, 1H), 1.19 (d, J = 6.5 Hz, 3H);

[0508] LC / MS (Method H): Rt 1.258 min [MH]+ 415.3.

[0509] Example 16: 2-Methyl-5-((R)-3-methyl-morpholin-4-yl)-3-(1H-pyrazol-3-yl)-7-(1H-pyrrolo[2,3-b]pyridin-4-yl)-2H-pyrazolo[4,3-b]pyridine (16)

[0510] Absolute

[0511]

[0512] 2-Methyl-5-((R)-3-methyl-morpholin-4-yl)-3-(1H-pyrazol-3-yl)-7-(1H-pyrrolo[2,3-b]pyridin-4-yl)-2H-pyrazolo[4,3-b]pyridine was prepared analogously to the above example and isolated as a yellow solid (74 mg, 99%); melting point 280 °C; 1 1H NMR (300 MHz, DMSO-d6): 13.16 (s, 1H), 11.83 (s, 1H), 8.33 (d, J = 4.9 Hz, 1H), 7.91 (s, 1H), 7.67 (d, J = 4.9 Hz, 1H), 7.58? 7.44 (m, 1H), 7.30 (d, J = 3.7 Hz, 2H), 6.55 (dd, J = 3.5, 1.7 Hz, 1H), 4.39 (s, 4H), 4.10 - 3.83 (m, 2H), 3.73 (t, J = 9.4 Hz, 2H), 3.54 (t, J = 11.2 Hz, 1H), 3.19 (d, J = 12.6 Hz, 1H), 1.21 (d, J = 6.5 Hz, 4H); LC / MS (Method I): 2.41 min, [MH]+ 415.3.

[0513] Example 17: 7-(6-Methylsulfonyl-4-methyl-pyridin-3-yl)-1-methyl-5-((R)-3-methyl-morpholin-4-yl)-3-(1H-pyrazol-3-yl)-1H-pyrazolo[4,3-b]pyridine (17)

[0514]

[0515] 7-(6-Methylsulfonyl-4-methyl-pyridin-3-yl)-1-methyl-5-((R)-3-methyl-morpholin-4-yl)-3-(1H-pyrazol-3-yl)-1H-pyrazolo[4,3-b]pyridine was prepared in a similar manner to the above example, and a yellow solid (30 mg, 22%) was isolated; melting point 189 - 190 °C;

[0516] 1 H NMR (300 MHz, DMSO-d6): δ 13.24 (m, 1H), 8.79 (s, 1H), 8.17 (s, 1H), 7.61 (m, 1H), 7.04 (d, J = 11.1 Hz, 2H), 4.44 (s, 1H), 4.08 - 3.99 (m, 2H), 3.81 - 3.63 (m, 2H), 3.62 - 3.51 (m, 1H), 3.47 (s, 3H), 3.36 (s, 3H), 3.18 (m, 1H), 2.29 (s, 3H), 1.19 (t, J = 6.4 Hz, 3H);

[0517] LC / MS (method G): Rt 1.212 min, [MH]+ 468.3.

[0518] Example 18: 7-(1-Isopropyl-1H-pyrazol-4-yl)-1-methyl-5-((R)-3-methyl-morpholin-4-yl)-3-(1H-pyrazol-3-yl)-1H-pyrazolo[4,3-b]pyridine (18)

[0519]

[0520] 7-(1-Isopropyl-1H-pyrazol-4-yl)-1-methyl-5-((R)-3-methyl-morpholin-4-yl)-3-(1H-pyrazol-3-yl)-1H-pyrazolo[4,3-b]pyridine was prepared in a similar manner to the above example, and a white solid (50 mg, 41%) was isolated; melting point 114 - 115 °C;

[0521] 11H NMR (300 MHz, DMSO-d6): δ 13.22 - 13.14 (m, 1H), 8.27 (s, 1H), 7.84 (s, 1H), 7.58 (s, 1H), 7.01 (s, 1H), 6.87 (d, J = 11.2 Hz, 1H), 4.70 - 4.56 (m, 1H), 4.56 - 4.44 (m, 1H), 4.09 - 3.93 (m, 2H), 3.80 - 3.65 (m, 2H), 3.88 (s, 3H), 3.53 (td, J = 11.6, 2.9 Hz, 1H), 3.17 (td, J = 12.7, 3.7 Hz, 1H), 1.50 (d, J = 6.6 Hz, 6H), 1.17 (d, J = 6.5 Hz, 3H); LC / MS (Method G): Rt 1.295 min [MH]+ 407.3.

[0522] Example 19: 7-(1,3-Dimethyl-1H-pyrazol-4-yl)-1-methyl-5-((R)-3-methyl-morpholin-4-yl)-3-(1H-pyrazol-3-yl)-1H-pyrazolo[4,3-b]pyridine (19)

[0523]

[0524] 7-(1,3-Dimethyl-1H-pyrazol-4-yl)-1-methyl-5-((R)-3-methyl-morpholin-4-yl)-3-(1H-pyrazol-3-yl)-1H-pyrazolo[4,3-b]pyridine was prepared analogously to the above example, and a colorless solid (35 mg, 28%) was isolated; melting point 139 - 140 °C;

[0525] 1 1H NMR (300 MHz, DMSO-d6): δ 13.17 - 12.90 (m, 1H), 7.95 (s, 1H), 7.79 - 7.61 (m, 1H), 7.02 (s, 1H), 6.80 (s, 1H), 4.42 (s, 1H), 4.09 - 3.95 (m, 2H), 3.89 (s, 3H), 3.77 - 3.70 (m, 5H), 3.54 (td, J = 11.7, 3.0 Hz, 1H), 3.14 (td, J = 12.7, 3.8 Hz, 1H), 2.12 (s, 3H), 1.16 (d, J = 6.5 Hz, 3H); LC / MS (Method G): Rt 1.158 min [MH]+ 393.3.

[0526] Example 20: 7-(3-Fluoro-pyridin-4-yl)-1-methyl-5-((R)-3-methyl-morpholin-4-yl)-3-(1H-pyrazol-3-yl)-1H-pyrazolo[4,3-b]pyridine (20)

[0527]

[0528] 7-(3-Fluoro-pyridin-4-yl)-1-methyl-5-((R)-3-methyl-morpholin-4-yl)-3-(1H-pyrazol-3-yl)-1H-pyrazolo[4,3-b]pyridine was prepared analogously to the above example, and a yellow solid (33 mg, 40%) was isolated; melting point 145 - 147 °C; 1 H NMR (300 MHz, DMSO-d6): δ 13.05 (s, 1H), 8.78 (d, J = 1.4 Hz, 1H), 8.62 (dd, J = 4.8, 1.2 Hz, 1H), 7.77 - 7.61 (m, 2H), 7.07 - 6.99 (m, 2H), 4.43 (q, J = 7.0 Hz, 1H), 4.07 - 3.89 (m, 2H), 3.78 - 3.42 (m, 6H), 3.15 (td, J = 12.7, 3.7 Hz, 1H), 1.15 (d, J = 6.5 Hz, 3H);

[0529] LC / MS (method E): Rt 1.285 min, [MH]+ 394.0.

[0530] Example 21: 7-(6-Methylsulfonyl-4-methyl-pyridin-3-yl)-2-methyl-5-((R)-3-methyl-morpholin-4-yl)-3-(1H-pyrazol-3-yl)-2H-pyrazolo[4,3-b]pyridine (21)

[0531]

[0532] 7-(6-Methylsulfonyl-4-methyl-pyridin-3-yl)-2-methyl-5-((R)-3-methyl-morpholin-4-yl)-3-(1H-pyrazol-3-yl)-2H-pyrazolo[4,3-b]pyridine was prepared analogously to the above example, and a yellow solid (2 mg, 4%) was isolated; melting point 188 - 190 °C;

[0533] 11H NMR (300 MHz, CDCl3): δ 8.67 (s, 1H), 8.06 (s, 1H), 7.72 (d, J = 2.0 Hz, 1H), 6.79 (d, J = 14.0 Hz, 2H), 4.32 (s, 3H), 4.15 - 3.94 (m, 2H), 3.84 (d, J = 2.2 Hz, 2H), 3.68 (td, J = 11.8, 3.0 Hz, 1H), 3.40 (td, J = 12.6, 3.7 Hz, 1H), 3.25 (s, 3H), 2.43 (s, 3H), 1.34 (d, J = 6.7 Hz, 3H), 1.23 (s, 1H);

[0534] LC / MS (Method G): Rt 1.265 min, [MH]+ 468.0.

[0535] Example 22: 7-(2,4-Dimethyl-pyridin-3-yl)-1-methyl-5-((R)-3-methyl-morpholin-4-yl)-3-(1H-pyrazol-3-yl)-1H-pyrazolo[4,3-b]pyridine (22)

[0536]

[0537] 7-(2,4-Dimethyl-pyridin-3-yl)-1-methyl-5-((R)-3-methyl-morpholin-4-yl)-3-(1H-pyrazol-3-yl)-1H-pyrazolo[4,3-b]pyridine was prepared analogously to the above example and isolated as a yellow solid (11 mg, 18%); melting point 128 - 130 °C; 1 1H NMR (300 MHz, DMSO-d6): δ 8.48 (d, J = 5.1 Hz, 1H), 7.69 (s, 1H), 7.32 (d, J = 5.1 Hz, 1H), 7.08 (s, 1H), 6.95 (s, 1H), 4.42 (d, J = 7.5 Hz, 1H), 4.16 - 3.95 (m, 2H), 3.73 (d, J = 4.6 Hz, 2H), 3.64 - 3.49 (m, 1H), 3.33 (s, 3H), 3.17 (td, J = 12.7, 3.7 Hz, 1H), 2.23 (d, J = 1.7 Hz, 3H), 2.06 (d, J = 2.1 Hz, 3H), 1.28 - 1.14 (m, 3H); LC / MS (Method B): Rt 2.095 min, [MH]+ 404.0.

[0538] Example 23: 1-Methyl-5-((R)-3-methyl-morpholin-4-yl)-7-(3-methyl-pyridin-4-yl)-3-(1H-pyrazol-3-yl)-1H-pyrazolo[4,3-b]pyridine (23)

[0539]

[0540] 1-Methyl-5-((R)-3-methylmorpholin-4-yl)-7-(3-methylpyridin-4-yl)-3-(1H-pyrazol-3-yl)-1H-pyrazolo[4,3-b]pyridine was prepared in a manner similar to the above-described example, and a yellow solid (32 mg, 44%) was isolated; melting point 145 °C; 1 H NMR (300 MHz, DMSO-d6) δ 13.15 (s, 1H), 8.64 (s, 1H), 8.57 (d, J = 4.9 Hz, 1H), 7.67 (s, 1H), 7.44 (dd, J = 5.0, 2.0 Hz, 1H), 7.06 (s, 1H), 6.90 (s, 1H), 4.55 - 4.33 (m, 1H), 4.02 (ddd, J = 23.6, 11.5, 4.7 Hz, 2H), 3.83 - 3.61 (m, 2H), 3.53 (td, J = 11.7, 3.0 Hz, 1H), 3.44 (d, J = 1.1 Hz, 3H), 3.16 (td, J = 12.6, 3.7 Hz, 1H), 2.11 (s, 3H), 1.17 (dd, J = 6.6, 4.0 Hz, 3H);

[0541] LC / MS (Method E): RT 1.021 min, [MH]+ 390.1.

[0542] Example 24: [1-Methyl-5-((R)-3-methylmorpholin-4-yl)-3-(1H-pyrazol-3-yl)-1H-pyrazolo[4,3-b]pyridin-7-yl]-methanol (24)

[0543]

[0544] Structural unit for the synthesis of Example 24: Methyl 1-methyl-5-[(3R)-3-methylmorpholin-4-yl]-1H-pyrazolo[4,3-b]pyridine-7-carboxylate

[0545]

[0546] 7-Chloro-1-methyl-5-((R)-3-methylmorpholin-4-yl)-1H-pyrazolo[4,3-b]pyridine (2.95 g, 11.06 mmol), Pd(dppf)Cl2·CH2Cl2 (271 mg, 0.332 mmol, 0.03 equiv), 1,1-bis-(diphenylphosphino)ferrocene (184 mg, 0.332 mmol), triethylamine (1.5 g, 14.4 mmol, 1.3 equiv), THF (30 mL) and methanol (30 mL) were combined and stirred under a CO atmosphere at 6.3 bar and stirred at 100 °C for 16 h. The resulting solution was concentrated in vacuo and purified by column chromatography. 1-Methyl-5-[(3R)-3-methylmorpholin-4-yl]-1H-pyrazolo[4,3-b]pyridine-7-carboxylate as a yellow solid was isolated (3.1 g, 96%); LC / MS (method K): RT 0.872 min, [MH]+ 291.1.

[0547] Structural unit for the synthesis of Example 24: Methyl 3-bromo-1-methyl-5-[(3R)-3-methylmorpholin-4-yl]-1H-pyrazolo[4,3-b]pyridine-7-carboxylate

[0548]

[0549] Methyl 1-methyl-5-[(3R)-3-methylmorpholin-4-yl]-1H-pyrazolo[4,3-b]pyridine-7-carboxylate (200 mg, 0.62 mmol, 1.0 equiv), NBS (147.13 mg, 0.74 mmol, 1.20 equiv) and MeCN (20 mL) were combined and stirred at 25 °C for 1 h. The resulting mixture was concentrated in vacuo. The residue was purified by column chromatography (method E). Methyl 3-bromo-1-methyl-5-[(3R)-3-methylmorpholin-4-yl]-1H-pyrazolo[4,3-b]pyridine-7-carboxylate was isolated as a yellow solid (120 mg, 43%). LC / MS (method J): RT 1.238 min, [MH]+ 369.0.

[0550] Structural unit for the synthesis of Example 24: Methyl 1-methyl-5-[(3R)-3-methylmorpholin-4-yl]-3-[1-(oxan-2-yl)-1H-pyrazol-3-yl]-1H-pyrazolo[4,3-b]pyridine-7-carboxylate

[0551]

[0552] Methyl 3-bromo-1-methyl-5-[(3R)-3-methylmorpholin-4-yl]-1H-pyrazolo[4,3-b]pyridine-7-carboxylate (110 mg, 0.27 mmol, 1.0 eq), 1-(oxan-2-yl)-3-(tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (235.53 mg, 0.80 mmol, 3 eq), Pd(PPh3)4 (34.43 mg, 0.03 mmol, 0.10 eq), sodium carbonate (89.75 mg, 0.80 mmol, 3.0 eq), tetrahydrofuran (17.60 mL) and water (4.40 mL) were combined and stirred in a microwave at 80 °C for 1 h. The resulting solution was extracted with ethyl acetate and concentrated in vacuo. The residue was purified by column chromatography (Method E). Methyl 1-methyl-5-[(3R)-3-methylmorpholin-4-yl]-3-[1-(oxan-2-yl)-1H-pyrazol-3-yl]-1H-pyrazolo[4,3-b]pyridine-7-carboxylate was isolated as a yellow solid (80 mg, 61%); LC / MS (Method J): RT 1.242 min, [MH]+ 441.0.

[0553] Structural unit for the synthesis of Example 24: {1-Methyl-5-[(3R)-3-methylmorpholin-4-yl]-3-[1-(oxan-2-yl)-1H-pyrazol-3-yl]-1H-pyrazolo[4,3-b]pyridin-7-yl}methanol

[0554] absolute

[0555]

[0556] At 0 °C and under a nitrogen atmosphere, LiBH4 (1117 mg, 48.71 mmol, 1.5 eq, 95%) was added dropwise to a stirred mixture of methyl 1-methyl-5-[(3R)-3-methylmorpholin-4-yl]-3-[1-(oxan-2-yl)-1H-pyrazol-3-yl]-1H-pyrazolo[4,3-b]pyridine-7-carboxylate (16 g, 32.69 mmol) in THF (400 mL). The resulting mixture was stirred at room temperature and under a nitrogen atmosphere for 2 h. The reaction was quenched with saturated NH4Cl (aqueous solution) at 0 °C. The resulting mixture was concentrated under reduced pressure. The aqueous layer was extracted with CH2Cl2. The resulting mixture was concentrated under reduced pressure. The residue was purified by column chromatography (Method O) to give [1-Methyl-5-[(3R)-3-methylmorpholin-4-yl]-3-[1-(oxan-2-yl)-1H-pyrazol-3-yl]-1H-pyrazolo[4,3-b]pyridin-7-yl]methanol (13 g, 87%) as a yellow solid.

[0557] Example 24: [1-Methyl-5-((R)-3-methyl-morpholin-4-yl)-3-(1H-pyrazol-3-yl)-1H-pyrazolo[4,3-b]pyridin-7-yl]-methanol

[0558]

[0559] Dissolve [1-Methyl-5-[(3R)-3-methylmorpholin-4-yl]-3-[1-(oxan-2-yl)-1H-pyrazol-3-yl]-1H-pyrazolo[4,3-b]pyridin-7-yl]methanol (50 mg, 0.11 mmol, 1 eq) in a methanol solution of HCl (3.000 mL). Stir the resulting solution at 25 °C for 1 h. Adjust the pH of the solution to 9 with sodium bicarbonate (0.5 mL). Extract the resulting solution with dichloromethane, combine the organic layers and concentrate in vacuo. Purify the crude product by preparative HPLC (Method F). Isolate [1-Methyl-5-[(3R)-3-methylmorpholin-4-yl]-3-(1H-pyrazol-3-yl)-1H-pyrazolo[4,3-b]pyridin-7-yl]methanol as a colorless solid (30 mg, 82%); melting point 195 - 197 °C;

[0560] 1 H NMR (300 MHz, DMSO-d6): δ 13.09 (s, 1H), 7.55 (s, 1H), 6.99 (d, J = 14.7 Hz, 2H), 5.59 (t, J = 5.5 Hz, 1H), 4.90 (d, J = 4.4 Hz, 2H), 4.36 (d, J = 10.8 Hz, 1H), 3.96 (dd, J = 11.1, 3.6 Hz, 2H), 3.79 - 3.60 (m, 2H), 3.50 (td, J = 11.7, 3.0 Hz, 1H), 3.28 (s, 2H), 3.12 (td, J = 12.8, 3.8 Hz, 1H), 1.12 (d, J = 6.6 Hz, 3H). LC / MS (Method E): RT 0.932 min, [MH]+ 329.1.

[0561] Example 25: 2-[1-Methyl-5-((R)-3-methyl-morpholin-4-yl)-3-(1H-pyrazol-3-yl)-1H-pyrazolo[4,3-b]pyridin-7-yl]-propan-2-ol (25)

[0562]

[0563] Structural unit for the synthesis of Example 25: 2-{1-methyl-5-[(3R)-3-methylmorpholin-4-yl]-3-[1-(oxan-2-yl)-1H-pyrazol-3-yl]-1H-pyrazolo[4,3-b]pyridin-7-yl}propan-2-ol

[0564]

[0565] A solution of methyl 1-methyl-5-[(3R)-3-methylmorpholin-4-yl]-3-[1-(oxan-2-yl)-1H-pyrazol-3-yl]-1H-pyrazolo[4,3-b]pyridine-7-carboxylate (700 mg, 1.43 mmol) and CH3MgBr (575.11 mg, 4.58 mmol, 3.0 equiv) in tetrahydrofuran (20 mL) was combined and stirred at 25 °C for 2 h. The reaction was quenched by the addition of NH4Cl. The resulting solution was extracted with ethyl acetate, and the organic layers were combined and concentrated in vacuo. 2-[1-Methyl-5-[(3R)-3-methylmorpholin-4-yl]-3-[1-(oxan-2-yl)-1H-pyrazol-3-yl]-1H-pyrazolo[4,3-b]pyridin-7-yl]propan-2-ol as a yellow solid was isolated (600 mg, 86%).

[0566] Example 25: 2-[1-Methyl-5-((R)-3-methyl-morpholin-4-yl)-3-(1H-pyrazol-3-yl)-1H-pyrazolo[4,3-b]pyridin-7-yl]-propan-2-ol

[0567]

[0568] 2-[1-Methyl-5-[(3R)-3-methylmorpholin-4-yl]-3-(1H-pyrazol-3-yl)-1H-pyrazolo[4,3-b]pyridin-7-yl]propan-2-ol was prepared analogously to the above example and isolated as a colorless solid (80 mg, 18%); mp 123-125 °C; 1 H NMR (300 MHz, DMSO-d6): δ 13.11 (s, 1H), 12.85 (s, 0H), 7.75 (s, 0H), 7.53 (s, 1H), 7.08 (s, 0H), 6.96 (s, 1H), 6.81 (s, 1H), 5.70 (s, 1H), 4.38 (s, 4H), 3.95 (dd, J = 11.1, 3.5 Hz, 2H), 3.79 - 3.60 (m, 2H), 3.50 (td, J = 11.7, 2.9 Hz, 1H), 3.12 (td, J = 12.6, 3.8 Hz, 1H), 2.04 (s, 0H), 1.62 (d, J = 3.5 Hz, 5H), 1.12 (d, J = 6.6 Hz, 3H);

[0569] LC / MS (Method D): Rt 0.867 min, [MH]+ 357.2.

[0570] Example 26: 7-(1-Methanesulfonyl-cyclopropyl)-1-methyl-5-((R)-3-methyl-morpholin-4-yl)-3-(1H-pyrazol-3-yl)-1H-pyrazolo[4,3-b]pyridine (26)

[0571]

[0572] Structural unit for the synthesis of Example 26: {1-Methyl-5-[(3R)-3-methylmorpholin-4-yl]-3-[1-(oxan-2-yl)-1H-pyrazol-3-yl]-1H-pyrazolo[4,3-b]pyridin-7-yl}methyl methanesulfonate

[0573]

[0574] Dissolve [1-Methyl-5-[(3R)-3-methylmorpholin-4-yl]-3-[1-(oxan-2-yl)-1H-pyrazol-3-yl]-1H-pyrazolo[4,3-b]pyridin-7-yl]methanol (700 mg, 1.53 mmol, 1.0 eq) in dichloromethane (34.48 mL), and stir at 0 °C for 0.5 h. Add triethylamine (700 mg, 6.57 mmol, 3 eq), MsCl (340 mg, 2.82 mmol, 1.30 eq) thereto. Stir the resulting solution at 25 °C for 1 h. Then quench the reaction by adding 2 mL of NH4Cl solution. Extract the resulting solution with dichloromethane, combine the organic layers and concentrate in vacuo. Purify the residue by column chromatography (Method E). Isolate {1-Methyl-5-[(3R)-3-methylmorpholin-4-yl]-3-[1-(oxan-2-yl)-1H-pyrazol-3-yl]-1H-pyrazolo[4,3-b]pyridin-7-yl}methyl methanesulfonate as a yellow solid (1 g, quantitative). LC / MS (Method J): RT 1.165 min, [MH]+ 491.0.

[0575] Structural unit for the synthesis of Example 26: (3R)-4-[7-(Methanesulfonylmethyl)-1-methyl-3-[1-(oxan-2-yl)-1H-pyrazol-3-yl]-1H-pyrazolo[4,3-b]pyridin-5-yl]-3-methylmorpholine

[0576]

[0577] Combine [1-methyl-5-[(3R)-3-methylmorpholin-4-yl]-3-[1-(oxan-2-yl)-1H-pyrazol-3-yl]-1H-pyrazolo[4,3-b]pyridin-7-yl]methyl methanesulfonate (900 mg, 1.65 mmol, 1 equiv), sodium methanesulfinate (230.66 mg, 2.15 mmol, 1.30 equiv), triethylamine (527.61 mg, 4.95 mmol, 3.0 equiv), CH3CN (90 mL) and DMF (9 mL), and stir at 120 °C for 16 h. Extract the resulting solution with ethyl acetate, combine the organic layers, and concentrate in vacuo. Purify the residue by column chromatography (Method E). Isolate (3R)-4-[7-(methanesulfonylmethyl)-1-methyl-3-[1-(oxan-2-yl)-1H-pyrazol-3-yl]-1H-pyrazolo[4,3-b]pyridin-5-yl]-3-methylmorpholine as a yellow solid (700 mg, 80%); LC / MS (Method L): RT 0.788 min, [MH]+ 413.1.

[0578] Structural unit for the synthesis of Example 26: (3R)-4-[7-(1-methanesulfonylethylene)-1-methyl-3-[1-(oxan-2-yl)-1H-pyrazol-3-yl]-1H-pyrazolo[4,3-b]pyridin-5-yl]-3-methylmorpholine

[0579]

[0580] Combine (3R)-4-[7-(methanesulfonylmethyl)-1-methyl-3-[1-(oxan-2-yl)-1H-pyrazol-3-yl]-1H-pyrazolo[4,3-b]pyridin-5-yl]-3-methylmorpholine (100 mg, 0.19 mmol, 1 equiv), [(dimethylamino)methyl]dimethylamine (44.87 mg, 0.42 mmol, 2.20 equiv), acetic anhydride (44.83 mg, 0.42 mmol, 2.20 equiv) and DMF (20 mL), and stir at 60 °C for 16 h. Extract the resulting solution with dichloromethane, combine the organic layers, and concentrate in vacuo. Purify the residue by column chromatography (Method E). Isolate (3R)-4-[7-(1-methanesulfonylethylene)-1-methyl-3-[1-(oxan-2-yl)-1H-pyrazol-3-yl]-1H-pyrazolo[4,3-b]pyridin-5-yl]-3-methylmorpholine as a yellow solid (60 mg, 58%); LC / MS (Method J): Rt 1.119 min [MH]+ 487.2.

[0581] Structural unit for the synthesis of Example 26: (3R)-4-[7-(1-Methanesulfonylcyclopropyl)-1-methyl-3-[1-(oxan-2-yl)-1H-pyrazol-3-yl]-1H-pyrazolo[4,3-b]pyridin-5-yl]-3-methylmorpholine

[0582]

[0583] Methanesulfonyl iodide (24.06 mg, 0.11 mmol, 1.20 eq) and DMSO (10 mL) were combined and stirred at 0 °C for 30 min. Sodium hydride (4.40 mg, 0.11 mmol, 1.19 eq, 60%) and (3R)-4-[7-(1-Methanesulfonylethyl)-1-methyl-3-[1-(oxan-2-yl)-1H-pyrazol-3-yl]-1H-pyrazolo[4,3-b]pyridin-5-yl]-3-methylmorpholine (50 mg, 0.09 mmol, 1.0 eq) were added thereto. The mixture was stirred in a microwave at 25 °C for 1 h. Then the reaction was quenched by adding NH4Cl. The resulting solution was extracted with ethyl acetate, the organic layers were combined and concentrated in vacuo. (3R)-4-[7-(1-Methanesulfonylcyclopropyl)-1-methyl-3-[1-(oxan-2-yl)-1H-pyrazol-3-yl]-1H-pyrazolo[4,3-b]pyridin-5-yl]-3-methylmorpholine as a yellow solid was isolated (40 mg, 80%); LC / MS (method L): RT: 0.887 min, [MH]+ 501.0.

[0584] Example 26: 7-(1-Methanesulfonyl-cyclopropyl)-1-methyl-5-((R)-3-methyl-morpholin-4-yl)-3-(1H-pyrazol-3-yl)-1H-pyrazolo[4,3-b]pyridine

[0585]

[0586] (3R)-4-[7-(1-Methanesulfonylcyclopropyl)-1-methyl-3-[1-(oxan-2-yl)-1H-pyrazol-3-yl]-1H-pyrazolo[4,3-b]pyridin-5-yl]-3-methylmorpholine (30 mg, 0.05 mmol, 1 eq) was dissolved in a methanol solution of hydrogen chloride (3 mL). The resulting solution was stirred at 25 °C for 1 h. The resulting solution was extracted with dichloromethane, the organic layers were combined and concentrated in vacuo. The crude product was purified by preparative HPLC (method G). (3R)-4-[7-(1-Methanesulfonylcyclopropyl)-1-methyl-3-(1H-pyrazol-3-yl)-1H-pyrazolo[4,3-b]pyridin-5-yl]-3-methylmorpholine as a light yellow solid was isolated (5 mg, 24%); melting point 180–182 °C;

[0587] 1 1H NMR (400 MHz, methanol-d4): δ 7.64 (s, 1H), 7.25 (s, 2H), 7.06 (s, 1H), 4.51 (d, J = 7.1 Hz, 2H), 4.38 (s, 5H), 4.07 (d, J = 12.5 Hz, 4H), 3.86 (s, 3H), 3.76 - 3.65 (m, 2H), 3.05 (s, 4H), 2.28 (dd, J = 10.7, 5.6 Hz, 2H), 1.82 (p, J = 5.1 Hz, 2H), 1.70 (q, J = 6.7, 5.9 Hz, 4H), 1.30 (t, J = 6.0 Hz, 7H); LC / MS (Method E): Rt 1.235 min [MH]+ 417.0.

[0588] Example 26 can be synthesized by an alternative synthetic route.

[0589] Structural unit of the alternative synthetic route of Example 26: 3-bromo-7-chloromethyl-1-methyl-5-((R)-3-methyl-morpholin-4-yl)-1H-pyrazolo[4,3-b]pyridine

[0590]

[0591] Combine [3-bromo-1-methyl-5-((R)-3-methyl-morpholin-4-yl)-1H-pyrazolo[4,3-b]pyridin-7-yl]-methanol (500 mg, 1.46 mmol), dichloromethane (3.72 ml) and thionyl chloride (0.32 ml, 4.37 mmol, 3 eq.), and stir at room temperature for 14 h. Concentrate the reaction mixture under reduced pressure, and extract with saturated NaHCO3 solution and DCM. Concentrate the combined organic layers under reduced pressure. Isolate 3-bromo-7-chloromethyl-1-methyl-5-((R)-3-methyl-morpholin-4-yl)-1H-pyrazolo[4,3-b]pyridine as a brown solid (519 mg, 99%); LC / MS (Method F): Rt 2.798 min; [MH]+ 359.0.

[0592] Structural unit of the alternative synthetic route of Example 26: 3-bromo-7-methylsulfonylmethyl-1-methyl-5-((R)-3-methyl-morpholin-4-yl)-1H-pyrazolo[4,3-b]pyridine

[0593]

[0594] 3-Bromo-7-chloromethyl-1-methyl-5-((R)-3-methyl-morpholin-4-yl)-1H-pyrazolo[4,3-b]pyridine (518.70 mg; 1.44 mmol; 1 equiv), 2-propanol (3.86 ml), and sodium methanesulfinate (250 mg; 2.45 mmol; 1.70 equiv) were combined and stirred at 80 °C for 14 h. The reaction suspension was concentrated under reduced pressure. The residue was treated with water, and the resulting precipitate was filtered, washed with water, and dried for 5 days. 3-Bromo-7-methylsulfonylmethyl-1-methyl-5-((R)-3-methyl-morpholin-4-yl)-1H-pyrazolo[4,3-b]pyridine as a yellow solid was isolated (484 mg, 83%); LC / MS (Method F): Rt 2.339 min; [MH]+ 403.1.

[0595] Structural unit of an alternative synthetic route of Example 26: 3-bromo-7-(1-methylsulfonyl-cyclopropyl)-1-methyl-5-((R)-3-methyl-morpholin-4-yl)-1H-pyrazolo[4,3-b]pyridine

[0596]

[0597] 3-Bromo-7-methylsulfonylmethyl-1-methyl-5-((R)-3-methyl-morpholin-4-yl)-1H-pyrazolo[4,3-b]pyridine (800 mg; 1.9 mmol; 1.0 equiv), cesium carbonate (12.63 g; 38.8 mmol; 20 equiv), and tetrabutylammonium bromide (126 mg; 0.39 mmol; 0.2 equiv) were mixed. Under a nitrogen atmosphere, dry dimethyl sulfoxide (20 ml) and 1,2-dimethyleneethane (506 μl; 5.8 mmol; 3.0 equiv) were added, and the reaction suspension was stirred at 60 °C for 2 days. The reaction mixture was poured into water, the solid was filtered off, washed with water, and dried under reduced pressure.

[0598] The aqueous layer was extracted with DCM, the combined organic layers were dried over MgSO4, filtered, and concentrated under reduced pressure. 3-Bromo-7-(1-methylsulfonyl-cyclopropyl)-1-methyl-5-((R)-3-methyl-morpholin-4-yl)-1H-pyrazolo[4,3-b]pyridine as a brown solid was isolated (311 mg, 37.4%); LC / MS (Method K), RT: 0.967 min [MH]+ 429.1.

[0599] Structural unit of an alternative synthetic route of Example 26: 7-(1-methylsulfonyl-cyclopropyl)-1-methyl-5-((R)-3-methyl-morpholin-4-yl)-3-[2-(2-trimethylsilyl-ethoxymethyl)-2H-pyrazol-3-yl]-1H-pyrazolo[4,3-b]pyridine

[0600]

[0601] 1-(2-(Trimethylsilylethoxy)methyl)-1H-pyrazole-5-boronic acid pinacol ester (421 mg; 1.2 mmol; 1.5 equiv), sodium carbonate (264 mg; 2.5 mmol; 3.0 equiv), and tetrakis(triphenylphosphine)palladium(0) (116 mg; 0.1 mmol; 0.1 equiv) were added. Then 3-bromo-7-(1-(methylsulfonyl)cyclopropyl)-1-methyl-5-((R)-3-methylmorpholin-4-yl)-1H-pyrazolo[4,3-b]pyridine (357 mg; 0.8 mmol; 1.0 equiv) in THF (7 ml) solution and water (0.65 ml) was added while flushing with nitrogen. The reaction suspension was stirred at 90 °C for 3 h. The reaction mixture was filtered and concentrated under reduced pressure. The residue was dissolved in DCM and purified by column chromatography (Method M). 7-(1-(Methylsulfonyl)cyclopropyl)-1-methyl-5-((R)-3-methylmorpholin-4-yl)-3-(2-(2-(trimethylsilyl)ethoxymethyl)-2H-pyrazol-3-yl)-1H-pyrazolo[4,3-b]pyridine was isolated as a yellow solid (364; 80.1%); LC / MS (Method K): Rt 1.176 min, [MH]+ 547.2.

[0602] Alternative synthetic route for Example 26: 1-(1-(Methylsulfonyl)cyclopropyl)-1-methyl-5-((R)-3-methylmorpholin-4-yl)-3-(1H-pyrazol-3-yl)-1H-pyrazolo[4,3-b]pyridine

[0603]

[0604] 7-(1-(Methylsulfonyl)cyclopropyl)-1-methyl-5-((R)-3-methylmorpholin-4-yl)-3-(2-(2-(trimethylsilyl)ethoxymethyl)-2H-pyrazol-3-yl)-1H-pyrazolo[4,3-b]pyridine (364 mg; 0.666 mmol; 1 equiv) was dissolved in a solution of HCl in MeOH (10.7 ml, 1.25 M). The solution was stirred at room temperature for 14 h. The reaction solution was concentrated under reduced pressure and diluted with 1 M NaOH. The resulting precipitate was filtered off, washed with water and dried under reduced pressure at 50 °C for 14 h. 7-(1-(Methylsulfonyl)cyclopropyl)-1-methyl-5-((R)-3-methylmorpholin-4-yl)-3-(1H-pyrazol-3-yl)-1H-pyrazolo[4,3-b]pyridine was isolated as a yellow solid (230 mg, 83%); LC / MS (Method K), RT: 0.843 min [MH]+ 417.2.

[0605] Example 27: 5-((R)-3-Methyl-morpholin-4-yl)-3-(1H-pyrazol-3-yl)-1H-pyrazolo[4,3-b]pyridine-7-carboxylic dimethylamide (27)

[0606]

[0607] Structural unit for the synthesis of Example 27: Methyl 5-[(3R)-3-methylmorpholin-4-yl]-1-{[2-(trimethylsilyl)ethoxy]methyl}-1H-pyrazolo[4,3-b]pyridine-7-carboxylate

[0608] Absolute

[0609]

[0610] 5-[(3R)-3-Methylmorpholin-4-yl]-1-[[2-(trimethylsilyl)ethoxy]methyl]-1H-pyrazolo[4,3-b]pyridin-7-yl trifluoromethanesulfonate (2 g, 3.6 mmol, 1.0 eq., 90%), Pd(dppf)Cl2·CH2Cl2 (165 mg, 0.18 mmol, 0.05 eq., 90%), methanol (20 ml) and triethylamine (1.5 g, 3.9 eq.) were combined, purged with nitrogen for 2 min, and then pressurized with carbon monoxide to 10 atm at 80 °C for 14 h. The resulting solution was extracted with ethyl acetate, the organic layers were combined, dried over sodium sulfate, and concentrated in vacuo. The residue was purified by column chromatography (Method P). Methyl 5-[(3R)-3-methylmorpholin-4-yl]-1-[[2-(trimethylsilyl)ethoxy]methyl]-1H-pyrazolo[4,3-b]pyridine-7-carboxylate was isolated as a yellow solid (1.5 g, 92%).

[0611] Structural unit for the synthesis of Example 27: Methyl 3-iodo-5-[(3R)-3-methylmorpholin-4-yl]-1H-pyrazolo[4,3-b]pyridine-7-carboxylate

[0612] Absolute

[0613]

[0614] Methyl 5-[(3R)-3-methylmorpholin-4-yl]-1H-pyrazolo[4,3-b]pyridine-7-carboxylate (350 mg, 1.14 mmol, 1.0 equiv), methanol (4 mL), potassium carbonate (261 mg, 1.8 mmol, 1.6 equiv) and I₂ (481 mg, 1.8 mmol, 1.6 equiv) were combined. The resulting solution was stirred at 25 °C for 1 h, extracted with ethyl acetate, the organic layers were combined, dried over anhydrous sodium sulfate and concentrated in vacuo. Methyl 3-iodo-5-[(3R)-3-methylmorpholin-4-yl]-1H-pyrazolo[4,3-b]pyridine-7-carboxylate was isolated as a yellow solid (130 mg, 26%).

[0615] Structural unit for the synthesis of Example 27: Methyl 3-iodo-5-[(3R)-3-methylmorpholin-4-yl]-1-{[2-(trimethylsilyl)ethoxy]methyl}-1H-pyrazolo[4,3-b]pyridine-7-carboxylate

[0616] Absolute

[0617]

[0618] Methyl 3-iodo-5-[(3R)-3-methylmorpholin-4-yl]-1H-pyrazolo[4,3-b]pyridine-7-carboxylate (75 mg, 0.17 mmol, 1.0 equiv), tetrahydrofuran (10 mL) and sodium hydride (8.06 mg, 0.20 mmol, 1.2 equiv, 60%) were combined and stirred at 0 - 5 °C for 0.5 h in a water / ice bath. SEMCl (32.37 mg, 0.20 mmol, 1.20 equiv) was added thereto. The resulting solution was stirred at 25 °C for 1 h. Then the reaction was quenched by adding an aqueous NH₄Cl solution. The resulting mixture was concentrated in vacuo, extracted with ethyl acetate, the organic layers were combined and concentrated in vacuo. Methyl 3-iodo-5-[(3R)-3-methylmorpholin-4-yl]-1-[[2-(trimethylsilyl)ethoxy]methyl]-1H-pyrazolo[4,3-b]pyridine-7-carboxylate was isolated as a yellow solid (90 mg, 91%).

[0619] Structural unit for the synthesis of Example 27: Methyl 5-[(3R)-3-methylmorpholin-4-yl]-3-[1-(oxan-2-yl)-1H-pyrazol-3-yl]-1-{[2-(trimethylsilyl)ethoxy]methyl}-1H-pyrazolo[4,3-b]pyridine-7-carboxylate

[0620] Absolute

[0621]

[0622] Methyl 3-iodo-5-[(3R)-3-methylmorpholin-4-yl]-1-[[2-(trimethylsilyl)ethoxy]methyl]-1H-pyrazolo[4,3-b]pyridine-7-carboxylate (90 mg, 0.15 mmol, 1.0 eq), 1-(oxan-2-yl)-3-(tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (67 mg, 0.23 mmol, 1.50 eq), Pd(PPh3)4 (18.50 mg, 0.02 mmol, 0.10 eq), sodium carbonate (50.92 mg, 0.46 mmol, 3 eq), tetrahydrofuran (18 mL) and water (4.50 mL) were combined and stirred at 80 °C for 2 h. The resulting mixture was concentrated in vacuo and the residue was purified by column chromatography (Method O). Methyl 5-[(3R)-3-methylmorpholin-4-yl]-3-[1-(oxan-2-yl)-1H-pyrazol-3-yl]-1-[[2-(trimethylsilyl)ethoxy]methyl]-1H-pyrazolo[4,3-b]pyridine-7-carboxylate was isolated as a yellow solid (90 mg, 96%).

[0623] Structural unit for the synthesis of Example 27: 5-[(3R)-3-methylmorpholin-4-yl]-3-[1-(oxan-2-yl)-1H-pyrazol-3-yl]-1-{[2-(trimethylsilyl)ethoxy]methyl}-1H-pyrazolo[4,3-b]pyridine-7-carboxylic acid

[0624] Absolute

[0625]

[0626] 5-[(3R)-3-methylmorpholin-4-yl]-3-[1-(oxan-2-yl)-1H-pyrazol-3-yl]-1-[[2-(trimethylsilyl)ethoxy]methyl]-1H-pyrazolo[4,3-b]pyridine-7-carboxylate (85 mg, 0.14 mmol), tetrahydrofuran (17 mL, 199 mmol), water (4.25 mL) and LiOH (17.3 mg, 0.69 mmol, 5.0 eq) were combined. The resulting solution was stirred at 25 °C for 14 h. The pH of the solution was adjusted to 5 with hydrogen chloride. The resulting solution was extracted with ethyl acetate, the organic layers were combined and concentrated in vacuo. 5-[(3R)-3-methylmorpholin-4-yl]-3-[1-(oxan-2-yl)-1H-pyrazol-3-yl]-1-[[2-(trimethylsilyl)ethoxy]methyl]-1H-pyrazolo[4,3-b]pyridine-7-carboxylic acid was isolated as a yellow solid (60 mg, 72%).

[0627] Structural unit for the synthesis of Example 27: N,N-dimethyl-5-[(3R)-3-methylmorpholin-4-yl]-3-[1-(oxan-2-yl)-1H-pyrazol-3-yl]-1-{[2-(trimethylsilyl)ethoxy]methyl}-1H-pyrazolo[4,3-b]pyridine-7-carboxamide

[0628] absolute

[0629]

[0630] Dissolve 5-[(3R)-3-methylmorpholin-4-yl]-3-[1-(oxan-2-yl)-1H-pyrazol-3-yl]-1-{[2-(trimethylsilyl)ethoxy]methyl}-1H-pyrazolo[4,3-b]pyridine-7-carboxylic acid (10 mg, 0.02 mmol, 1.0 eq) in dichloromethane (2 mL), add N,N-dimethylformamide (0.5 mL) and HATU (7.965 mg, 0.02 mmol, 1.2 eq), dimethylamine hydrochloride (2.847 mg, 0.03 mmol) and DIEA (6.768 mg, 0.05 mmol, 3.0 eq). Stir the resulting solution at 25 °C for 2 h. Concentrate the resulting mixture in vacuo to give N,N-dimethyl-5-[(3R)-3-methylmorpholin-4-yl]-3-[1-(oxan-2-yl)-1H-pyrazol-3-yl]-1-{[2-(trimethylsilyl)ethoxy]methyl}-1H-pyrazolo[4,3-b]pyridine-7-carboxamide as a yellow solid (5 mg, 48%).

[0631] Example 27: 5-((R)-3-methyl-morpholin-4-yl)-3-(1H-pyrazol-3-yl)-1H-pyrazolo[4,3-b]pyridine-7-carboxylic dimethylamide

[0632]

[0633] N,N-dimethyl-5-[(3R)-3-methylmorpholin-4-yl]-3-[1-(oxan-2-yl)-1H-pyrazol-3-yl]-1-[[2-(trimethylsilyl)ethoxy]methyl]-1H-pyrazolo[4,3-b]pyridine-7-carboxamide (50 mg, 0.08 mmol, 1 eq) was dissolved in a methanol solution of HCl (5 mL). The resulting solution was stirred at 25 °C for 5 h. The resulting mixture was concentrated in vacuo. The crude product was purified by preparative HPLC (method K) to give 5-((R)-3-methyl-morpholin-4-yl)-3-(1H-pyrazol-3-yl)-1H-pyrazolo[4,3-b]pyridine-7-carboxamide dimethylamine as a yellow solid (5 mg, 17%); melting point 168 - 170 °C. 1H NMR (400 MHz, methanol-d4): δ 7.70 (m, 1H), 7.06 (m, 2H), 4.46 (d, J = 7.2 Hz, 1H), 4.05 (dd, J = 11.8, 4.8 Hz, 2H), 3.83 (d, J = 2.3 Hz, 2H), 3.67 (td, J = 11.7, 3.1 Hz, 1H), 3.34 (dd, J = 12.8, 3.2 Hz, 1H), 3.01 (s, 3H), 1.28 (d, J = 6.6 Hz, 3H); LC / MS (method B): Rt 2.075 min, [MH]+ 356.0.

[0634] Example 28: 5-((R)-3-Methyl-morpholin-4-yl)-3-(1H-pyrazol-3-yl)-1H-pyrazolo[4,3-b]pyridine-7-carboxamide dimethylamine (28)

[0635]

[0636] 5-((R)-3-Methyl-morpholin-4-yl)-3-(1H-pyrazol-3-yl)-1H-pyrazolo[4,3-b]pyridine-7-carboxamide dimethylamine was prepared analogously to the above example and isolated as a light yellow solid (8 mg, 38%); melting point 186 - 188 °C;

[0637] 11H NMR (300 MHz, methanol-d4): δ 7.68 (d, J = 2.1 Hz, 1H), 7.39 (s, 1H), 7.09 (d, J = 2.1 Hz, 1H), 4.47 (d, J = 6.9 Hz, 1H), 4.03 (dd, J = 11.4, 3.3 Hz, 2H), 3.82 (d, J = 2.2 Hz, 2H), 3.66 (td, J = 11.4, 2.9 Hz, 1H), 3.36 (dd, J = 13.1, 3.8 Hz, 1H), 2.99 (s, 3H), 1.27 (d, J = 6.7 Hz, 3H); LC / MS (method M): Rt 0.824 min, [MH]+ 342.1.

[0638] Example 29: 5-((R)-3-Methyl-morpholin-4-yl)-3-(1H-pyrazol-3-yl)-1H-pyrazolo[4,3-b]pyridine-7-carboxamide (29)

[0639]

[0640] 5-((R)-3-Methyl-morpholin-4-yl)-3-(1H-pyrazol-3-yl)-1H-pyrazolo[4,3-b]pyridine-7-carboxamide was prepared analogously to the above example and isolated as a yellow solid (2 mg, 10%); melting point > 280 °C; 1 1H NMR (300 MHz, methanol-d4): δ 7.68 (s, 1H), 7.48 (s, 1H), 7.11 (s, 1H), 4.52 (d, J = 7.1 Hz, 1H), 4.14 - 3.99 (m, 2H), 3.85 (d, J = 2.2 Hz, 2H), 3.69 (t, J = 10.4 Hz, 1H), 3.44 - 3.35 (m, 1H), 1.30 (d, J = 6.7 Hz, 3H); LC / MS (method N) Rt 2.694 min, [MH]+ 327.9.

[0641] Example 30: 1-Methyl-5-((R)-3-methyl-morpholin-4-yl)-3-(1H-pyrazol-3-yl)-1H-pyrazolo[4,3-b]pyridine-7-carboxylic dimethylamide (30)

[0642]

[0643] 1-Methyl-5-((R)-3-methyl-morpholin-4-yl)-3-(1H-pyrazol-3-yl)-1H-pyrazolo[4,3-b]pyridine-7-carboxylic dimethylamide was prepared analogously to the above example and isolated as a yellow solid (10 mg, 29%); melting point 128 - 130 °C. 11H NMR (400 MHz, DMSO-d6): δ 13.23 (s, 1H), 7.58 (s, 1H), 7.14 - 6.88 (m, 2H), 4.44 (s, 1H), 4.12 - 3.94 (m, 2H), 3.88 (d, J = 9.3 Hz, 3H), 3.80 - 3.66 (m, 2H), 3.54 (td, J = 11.9, 3.0 Hz, 1H), 3.11 (m, 4H), 2.90 (d, J = 2.1 Hz, 3H), 1.16 (d, J = 6.5 Hz, 3H); LC / MS (Method O): Rt 1.045 min, [M+H]+ 370.3.

[0644] Example 31: 1-Methyl-5-((R)-3-methylmorpholin-4-yl)-3-(1H-pyrazol-3-yl)-1H-pyrazolo[4,3-b]pyridine-7-carboxymethylamide (31)

[0645]

[0646] 1-Methyl-5-((R)-3-methylmorpholin-4-yl)-3-(1H-pyrazol-3-yl)-1H-pyrazolo[4,3-b]pyridine-7-carboxymethylamide was prepared analogously to the above example and isolated as a yellow solid (10 mg, 31%); melting point 146 - 148 °C; 1 1H NMR (400 MHz, DMSO-d6): δ 13.22 (s, 1H), 8.82 (d, J = 5.8 Hz, 1H), 7.57 (s, 1H), 7.20 - 6.91 (m, 2H), 4.46 (s, 1H), 3.99 (d, J = 10.3 Hz, 5H), 3.82 - 3.64 (m, 2H), 3.53 (td, J = 11.9, 3.0 Hz, 1H), 3.18 (t, J = 11.6 Hz, 1H), 2.86 (d, J = 4.6 Hz, 3H), 1.18 (d, J = 6.6 Hz, 3H); LC / MS (Method O): Rt 0.983 min, [M+H]+ 356.3.

[0647] Example 32: 1-Methyl-5-((R)-3-methylmorpholin-4-yl)-3-(1H-pyrazol-3-yl)-1H-pyrazolo[4,3-b]pyridine-7-carboxamide (32)

[0648]

[0649] 1-Methyl-5-((R)-3-methyl-morpholin-4-yl)-3-(1H-pyrazol-3-yl)-1H-pyrazolo[4,3-b]pyridine-7-carboxamide was prepared analogously to the above example and isolated as a yellow solid (5 mg, 15%); melting point 228 - 230 °C; 1 H NMR (400 MHz, DMSO-d6): δ 13.23 (s, 1H), 8.34 (m, J = 10.1 Hz, 1H), 8.09 - 7.53 (m, 2H), 7.21 - 6.89 (m, 2H), 4.48 (d, J = 8.0 Hz, 1H), 4.15 - 3.92 (m, 4H), 3.84 - 3.66 (m, 2H), 3.54 (td, J = 11.7, 2.9 Hz, 1H), 3.26 - 3.12 (m, 1H), 1.19 (d, J = 6.6 Hz, 3H); LC / MS (method O): Rt 0.920 min, [MH]+ 342.3.

[0650] Example 33: 1-Methyl-5-((R)-3-methyl-morpholin-4-yl)-7-(6-methyl-pyridin-2-yl)-3-(1H-pyrazol-3-yl)-1H-pyrazolo[4,3-b]pyridine (33)

[0651]

[0652] 1-Methyl-5-((R)-3-methyl-morpholin-4-yl)-7-(6-methyl-pyridin-2-yl)-3-(1H-pyrazol-3-yl)-1H-pyrazolo[4,3-b]pyridine was prepared analogously to the above example and isolated as a yellow solid (14 mg, 33%); melting point 115 °C; 1 H NMR (400 MHz, DMSO-d6): δ 13.21 (s, 1H), 7.92 (t, J = 7.7 Hz, 1H), 7.66 (d, J = 7.7 Hz, 2H), 7.43 (d, J = 7.8 Hz, 1H), 7.06 (d, J = 11.8 Hz, 2H), 4.50 (s, 1H), 4.11 - 3.94 (m, 2H), 3.73 (s, 5H), 3.56 (td, J = 11.7, 3.0 Hz, 1H), 3.20 (td, J = 12.9, 3.7 Hz, 1H), 2.60 (s, 3H), 1.19 (d, J = 6.6 Hz, 3H); LC / MS (method E): RT 1.190 min, [MH]+ 390.1.

[0653] Example 34: 7-[1-(2-Fluoroethyl)-1H-pyrazol-3-yl]-1-methyl-5-((R)-3-methylmorpholin-4-yl)-3-(1H-pyrazol-3-yl)-1H-pyrazolo[4,3-b]pyridine (34)

[0654]

[0655] Structural unit for the synthesis of Example 34: (3R)-3-methyl-4-[1-methyl-7-(1H-pyrazol-5-yl)-1H-pyrazolo[4,3-b]pyridin-5-yl]morpholine

[0656]

[0657] Dissolve (3R)-3-methyl-4-[1-methyl-7-[1-(oxan-2-yl)-1H-pyrazol-5-yl]-1H-pyrazolo[4,3-b]pyridin-5-yl]morpholine (340 mg, 0.84 mmol, 1.0 equivalent 95%) in a methanol solution of hydrogen chloride (10 mL) and stir at room temperature for 2 hours. Concentrate the resulting mixture under vacuum. Adjust the pH of the solution to 7 - 8 with sodium bicarbonate. Extract the resulting solution with dichloromethane, combine the organic layers and concentrate under vacuum. Isolate (3R)-3-methyl-4-[1-methyl-7-(1H-pyrazol-5-yl)-1H-pyrazolo[4,3-b]pyridin-5-yl]morpholine as a yellow oil (250 mg, 96%); LC / MS (method P): Rt 0.566 min, [MH]+ 299.2.

[0658] Structural unit for the synthesis of Example 34: (3R)-4-{7-[1-(2-Fluoroethyl)-1H-pyrazol-3-yl]-1-methyl-1H-pyrazolo[4,3-b]pyridin-5-yl}-3-methylmorpholine

[0659]

[0660] (3R)-3-Methyl-4-[1-methyl-7-(1H-pyrazol-5-yl)-1H-pyrazolo[4,3-b]pyridin-5-yl]morpholine (150 mg, 0.48 mmol, 1.0 eq, 96%), DMF (5 mL), sodium hydride (80.3 mg, 2 mmol, 4.2 eq, 60%) and 1-fluoro-2-iodoethane (174.6 mg, 0.95 mmol, 1.98 eq) were combined and stirred at room temperature for 2 h. The reaction was then quenched by the addition of NH4Cl. The resulting solution was extracted with dichloromethane, the organic layers were combined, dried over anhydrous sodium sulfate and concentrated in vacuo. The residue was purified by column chromatography (Method K). (3R)-4-[7-[1-(2-Fluoroethyl)-1H-pyrazol-3-yl]-1-methyl-1H-pyrazolo[4,3-b]pyridin-5-yl]-3-methylmorpholine as a yellow oil (110 mg, 66%) was isolated; LC / MS (Method P): Rt 0.667 min, [MH]+ 345.3.

[0661] Example 34: 7-[1-(2-Fluoro-ethyl)-1H-pyrazol-3-yl]-1-methyl-5-((R)-3-methyl-morpholin-4-yl)-3-(1H-pyrazol-3-yl)-1H-pyrazolo[4,3-b]pyridine

[0662]

[0663] 7-[1-(2-Fluoro-ethyl)-1H-pyrazol-3-yl]-1-methyl-5-((R)-3-methyl-morpholin-4-yl)-3-(1H-pyrazol-3-yl)-1H-pyrazolo[4,3-b]pyridine was prepared analogously to the above example and isolated as a light yellow solid (8 mg, 21%); melting point 106-107 °C; light yellow solid;

[0664] 1 H NMR (300 MHz, methanol-d4): δ 7.86 (d, J = 2.4 Hz, 1H), 7.63 (s, 1H), 7.04 (s, 2H), 6.71 (d, J = 2.3 Hz, 1H), 4.91 (t, J = 4.7 Hz, 2H), 4.75 (t, J = 4.7 Hz, 1H), 4.62 (t, J = 4.7 Hz, 1H), 4.53 (t, J = 4.7 Hz, 1H), 4.04 (d, J = 11.9 Hz, 2H), 3.95 (s, 3H), 3.83 (d, J = 2.2 Hz, 2H), 3.68 (td, J = 11.7, 3.1 Hz, 1H), 1.29 (d, J = 6.7 Hz, 3H); LC / MS (Method E): Rt 1.238 min, [MH]+ 411.2.

[0665] Example 35: (3R)-3-Methyl-4-[7-(2-methylphenyl)-3-(1H-pyrazol-3-yl)-1H-pyrazolo[4,3-b]pyridin-5-yl]morpholine (35)

[0666]

[0667] (3R)-3-Methyl-4-[7-(2-methylphenyl)-3-(1H-pyrazol-3-yl)-1H-pyrazolo[4,3-b]pyridin-5-yl]morpholine was prepared analogously to the above example and isolated as a yellow solid (17 mg, 64%); 1 1H NMR (400 MHz, DMSO-d6): δd 7.74 (d, J = 1.9 Hz, 1H), 7.47–7.34 (m, 5H), 7.08 (d, J = 1.9 Hz, 1H), 6.91 (s, 1H), 4.49–4.42 (m, 1H), 4.10–4.04 (m, 1H), 4.02–3.96 (m, 1H), 3.77–3.73 (m, 1H), 3.70 (dd, J = 11.1, 2.9 Hz, 1H), 3.56 (td, J = 11.7, 3.0 Hz, 1H), 3.21 (td, J = 12.5, 3.6 Hz, 1H), 2.20 (s, 3H), 1.20 (d, J = 6.6 Hz, 3H); LC / MS (method F): Rt 2.102 min; [MH]+ 375.2.

[0668] Example 36: 7-[2-(2-Fluoroethyl)-2H-pyrazol-3-yl]-1-methyl-5-((R)-3-methylmorpholin-4-yl)-3-(1H-pyrazol-3-yl)-1H-pyrazolo[4,3-b]pyridine (36)

[0669]

[0670] Structural unit for the synthesis of Example 36: (3R)-4-{7-[1-(2-fluoroethyl)-1H-pyrazol-5-yl]-1-methyl-1H-pyrazolo[4,3-b]pyridin-5-yl}-3-methylmorpholine

[0671]

[0672] (3R)-3-Methyl-4-[1-methyl-7-(1H-pyrazol-5-yl)-1H-pyrazolo[4,3-b]pyridin-5-yl]morpholine (450 mg, 1.49 mmol, 1.0 eq., 99%), DMF (10 mL), sodium hydride (240.8 mg, 6.02 mmol, 4.03 eq., 60%) and 1-fluoro-2-iodoethane (523.7 mg, 2.86 mmol, 1.92 eq.) were combined and stirred at room temperature for 2 h. The reaction was then quenched by the addition of NH4Cl. The resulting solution was extracted with dichloromethane, the organic layers were combined, dried over anhydrous sodium sulfate and concentrated in vacuo. The crude product was purified by preparative HPLC (method H). (3R)-4-[7-[1-(2-Fluoroethyl)-1H-pyrazol-5-yl]-1-methyl-1H-pyrazolo[4,3-b]pyridin-5-yl]-3-methylmorpholine was isolated as a yellow oil (60 mg, 12%); LC / MS (method P): Rt 0.668 min, [MH]+ 345.3.

[0673] Example 36: 7-[2-(2-Fluoro-ethyl)-2H-pyrazol-3-yl]-1-methyl-5-((R)-3-methyl-morpholin-4-yl)-3-(1H-pyrazol-3-yl)-1H-pyrazolo[4,3-b]pyridine

[0674]

[0675] 7-[2-(2-Fluoro-ethyl)-2H-pyrazol-3-yl]-1-methyl-5-((R)-3-methyl-morpholin-4-yl)-3-(1H-pyrazol-3-yl)-1H-pyrazolo[4,3-b]pyridine was prepared analogously to the above example and isolated as a light yellow solid (15 mg, 30%); melting point 120 - 121 °C; 1 H NMR (300 MHz, DMSO-d6): δ 12.93 - 13.24 (m, 1H), 7.89 - 7.59 (m, 2H), 7.13 - 6.94 (m, 2H), 6.66 (s, 1H), 4.77 (s, 1H), 4.61 (s, 1H), 4.39 (dd, J = 27.7, 16.9 Hz, 3H), 4.04 (dd, J = 29.2, 12.1 Hz, 2H), 3.79 - 3.64 (m, 2H), 3.62 - 3.42 (m, 4H), 3.17 (t, J = 13.0 Hz, 1H), 1.18 (d, J = 6.5 Hz, 3H); LC / MS (method B): Rt 2.294 min, [MH]+ 411.2.

[0676] Example 37: 2-{3-[1-Methyl-5-((R)-3-methylmorpholin-4-yl)-3-(1H-pyrazol-3-yl)-1H-pyrazolo[4,3-b]pyridin-7-yl]-pyrazol-1-yl}-ethanol (37)

[0677]

[0678] 2-{3-[1-Methyl-5-((R)-3-methylmorpholin-4-yl)-3-(1H-pyrazol-3-yl)-1H-pyrazolo[4,3-b]pyridin-7-yl]-pyrazol-1-yl}-ethanol was prepared analogously to the above example and isolated as a light yellow solid (60 mg, 33%); melting point 110 - 111 °C; 1 H NMR (300 MHz, DMSO-d6): δ 13.18 (s, 1H), 7.91 (d, J = 2.3 Hz, 1H), 7.65 (s, 1H), 7.04 (d, J = 11.3 Hz, 2H), 6.78 (d, J = 2.3 Hz, 1H), 4.95 (t, J = 5.4 Hz, 1H), 4.54 - 4.41 (m, 1H), 4.28 (t, J = 5.6 Hz, 2H), 4.05 - 3.97 (m, 5H), 3.88 - 3.64 (m, 4H), 3.55 (td, J = 11.8, 3.0 Hz, 1H), 3.18 (td, J = 12.7, 3.7 Hz, 1H), 1.17 (d, J = 6.6 Hz, 3H); LC / MS (method E): Rt 1.073 min, [MH]+ 409.2.

[0679] Example 38: (3R)-3-Methyl-4-[3-(1H-pyrazol-3-yl)-7-(pyridin-2-yl)-1H-pyrazolo[4,3-b]pyridin-5-yl]morpholine (38)

[0680]

[0681] Structural unit for the synthesis of Example 38: [5-[(3R)-3-Methylmorpholin-4-yl]-1-(2-trimethylsilylethoxymethyl)pyrazolo[4,3-b]pyridin-7-yl]boronic acid

[0682]

[0683] 5-((R)-3-Methyl-morpholin-4-yl)-1-(2-trimethylsilyl-ethoxymethyl)-1H-pyrazolo[4,3-b]pyridin-7-yl ester (50 mg; 0.101 mmol; 1.0 eq) was dissolved in 1,4-dioxane (2 ml), potassium acetate (19.764 mg; 0.201 mmol; 2.0 eq), bis(pinacolato)diboron (38.353 mg; 0.151 mmol; 1.50 eq) and (1,1'-bis(diphenylphosphino)ferrocene)-dichloropalladium(II) (7.067 mg; 0.010 mmol; 0.10 eq) were added, and the mixture was stirred at 110 °C for 4 h. The reaction solution was used in the next reaction step without further purification.

[0684] Structural unit for the synthesis of Example 38: 5-((R)-3-Methyl-morpholin-4-yl)-7-pyridin-2-yl-1-(2-trimethylsilyl-ethoxymethyl)-1H-pyrazolo[4,3-b]pyridine

[0685]

[0686] To the reaction mixture of [5-[(3R)-3-methylmorpholin-4-yl]-1-(2-trimethylsilylethoxymethyl)pyrazolo[4,3-b]pyridin-7-yl]boronic acid, 2-bromopyridine (19.149 mg; 0.121 mmol; 1.20 eq), potassium carbonate (42.038 mg; 0.304 mmol; 3.01 eq), water (0.300 ml) and 1,1'-bis(diphenylphosphino)-ferrocenedichloropalladium-(II)*DCM (8.248 mg; 0.010 mmol; 0.10 eq) were added and the mixture was stirred at 100 °C for 2 h. The reaction mixture was concentrated and the crude product was purified by column chromatography (Method L). 5-((R)-3-Methyl-morpholin-4-yl)-7-pyridin-2-yl-1-(2-trimethylsilyl-ethoxymethyl)-1H-pyrazolo[4,3-b]pyridine was isolated as a brown resin (64 mg, 79%); LC / MS (Method F): Rt 2.464 min; [MH]+ 426.2.

[0687] Example 38: (3R)-3-Methyl-4-[3-(1H-pyrazol-3-yl)-7-(pyridin-2-yl)-1H-pyrazolo[4,3-b]pyridin-5-yl]morpholine

[0688]

[0689] (3R)-3-Methyl-4-[3-(1H-pyrazol-3-yl)-7-(pyridin-2-yl)-1H-pyrazolo[4,3-b]pyridin-5-yl]morpholine was prepared in a similar manner to the above example and isolated as a yellow solid (7 mg, 38%); 1 H NMR (400 MHz, DMSO-d6): δ 8.86–8.83 (m, 1H), 8.49–8.44 (m, 1H), 8.03 (td, J = 7.8, 1.9 Hz, 1H), 7.69 (d, J = 1.8 Hz, 1H), 7.66 (s, 1H), 7.55–7.51 (m, 1H), 7.09 (d, J = 1.9 Hz, 1H), 4.65–4.57 (m, 1H), 4.15–4.10 (m, 1H), 4.03 (dd, J = 11.3, 3.5 Hz, 1H), 3.83–3.78 (m, 1H), 3.75 (dd, J = 11.2, 3.0 Hz, 1H), 3.63–3.55 (m, 1H), 3.28–3.20 (m, 1H), 1.21 (d, J = 6.6 Hz, 3H); LC / MS (method F): Rt 2.026 min; [MH]+ 362.2.

[0690] Example 39: (3R)-3-Methyl-4-[7-(3-methylpyridin-2-yl)-3-(1H-pyrazol-3-yl)-1H-pyrazolo[4,3-b]pyridin-5-yl]morpholine (39)

[0691]

[0692] (3R)-3-Methyl-4-[7-(3-methylpyridin-2-yl)-3-(1H-pyrazol-3-yl)-1H-pyrazolo[4,3-b]pyridin-5-yl]morpholine was prepared in a similar manner to the above example and isolated as a yellow solid (11 mg, 50%); 11H NMR (400 MHz, DMSO-d6) δ 13.28 - 13.10 (m, 1H), 12.99 - 12.78 (m, 1H), 8.63 - 8.58 (m, 1H), 7.88 - 7.83 (m, 1H), 7.68 - 7.53 (m, 1H), 7.45 (dd, J = 7.7, 4.7 Hz, 1H), 7.11 - 7.03 (m, 2H), 4.48 - 4.42 (m, 1H), 4.11 - 4.03 (m, 1H), 4.00 (dd, J = 11.4, 3.5 Hz, 1H), 3.79 - 3.74 (m, 1H), 3.71 (dd, J = 11.4, 2.9 Hz, 1H), 3.57 (td, J = 11.7, 2.9 Hz, 1H), 3.19 (td, J = 12.7, 3.7 Hz, 1H), 2.34 (s, 3H), 1.19 (d, J = 6.6 Hz, 3H); LC / MS (Method F): Rt 1.836 min; [M+H]+ 376.

[0693] Example 40: (3R)-3-Methyl-4-[1-methyl-3-(1H-pyrazol-5-yl)-1H-pyrazolo[4,3-b]pyridin-5-yl]morpholine (40)

[0694]

[0695] Structural unit for the synthesis of Example 40: 1-Methyl-5-((R)-3-methyl-morpholin-4-yl)-1H-pyrazolo[4,3-b]pyridine

[0696]

[0697] 1-Methyl-5-((R)-3-methyl-morpholin-4-yl)-1H-pyrazolo[4,3-b]pyridine-7-yl trifluoromethanesulfonate (350 mg; 0.810 mmol; 1 equiv), dioxane (7.00 ml), triethylamine (354.48 μl; 2.429 mmol; 3 equiv), palladium(II) acetate (18.18 mg; 0.081 mmol; 0.1 equiv), 1,1'-bis-(diphenylphosphino)ferrocene (47.12 mg; 0.081 mmol; 0.1 equiv) and formic acid (61.10 μl; 1.620 mmol; 2 equiv) were combined and stirred at 80 °C for 45 min. The reaction mixture was evaporated to dryness and the crude product was purified by column chromatography (Method M). 1-Methyl-5-((R)-3-methyl-morpholin-4-yl)-1H-pyrazolo[4,3-b]pyridine as a yellow solid was isolated (104 mg, 55%); LC / MS (Method C): Rt 0.662 min; [M+H]+ 233.1.

[0698] Example 40: (3R)-3-Methyl-4-[1-methyl-3-(1H-pyrazol-5-yl)-1H-pyrazolo[4,3-b]pyridin-5-yl]morpholine

[0699]

[0700] (3R)-3-Methyl-4-[1-methyl-3-(1H-pyrazol-5-yl)-1H-pyrazolo[4,3-b]pyridin-5-yl]morpholine was prepared analogously to the above example and isolated as a yellow solid (52 mg, 82%); 1 1H NMR (700 MHz, DMSO-d6): δ 7.99 (d, J = 9.3 Hz, 1H), 7.66 (d, J = 1.9 Hz, 1H), 7.12 (d, J = 9.4 Hz, 1H), 7.01 (d, J = 1.9 Hz, 1H), 4.60–4.27 (m, 1H), 4.07–3.95 (m, 5H), 3.76 (d, J = 11.1 Hz, 1H), 3.70 (dd, J = 11.2, 3.1 Hz, 1H), 3.54 (td, J = 11.8, 3.1 Hz, 1H), 3.15 (td, J = 12.8, 3.9 Hz, 1H), 1.15 (d, J = 6.7 Hz, 3H); LC / MS (Method C): Rt 0.832 min; [MH]+ 299.1.

[0701] Example 41: (3R)-4-[7-(4-Methylsulfonylphenyl)-1-(propan-2-yl)-3-(1H-pyrazol-3-yl)-1H-pyrazolo[4,3-b]pyridin-5-yl]-3-methylmorpholine (41)

[0702]

[0703] (3R)-4-[7-(4-Methylsulfonylphenyl)-1-(propan-2-yl)-3-(1H-pyrazol-3-yl)-1H-pyrazolo[4,3-b]pyridin-5-yl]-3-methylmorpholine was prepared analogously to the above example and isolated as a yellow solid (21 mg, 34%); 1HNMR(400MHz, DMSO-d6): δ 8.13–8.09 (m, 2H), 7.91–7.86 (m, 2H), 7.70 (d, J = 1.9 Hz, 1H), 7.08 (d, J = 2.0 Hz, 1H), 6.87 (s, 1H), 4.50–4.43 (m, 1H), 4.12–4.01 (m, 2H), 3.98 (dd, J = 11.3, 3.5 Hz, 1H), 3.75 (d, J = 11.2 Hz, 1H), 3.68 (dd, J = 11.3, 3.1 Hz, 1H), 3.57–3.53 (m, 1H), 3.33 (s, 3H), 3.18 (td, J = 12.6, 3.6 Hz, 1H), 1.30–1.25 (m, 6H), 1.19 (d, J = 6.7 Hz, 3H); LC / MS (method F): Rt 2.273 min; [M+H]+ 481.2.

[0704] Example 42: 1-Methyl-7-(3-methyl-3H-imidazol-4-yl)-5-((R)-3-methylmorpholin-4-yl)-3-(1H-pyrazol-3-yl)-1H-pyrazolo[4,3-b]pyridine (42)

[0705]

[0706] Structural unit for the synthesis of Example 42: 1-Methyl-7-(3-methyl-3H-imidazol-4-yl)-5-((R)-3-methylmorpholin-4-yl)-3-[2-(2-trimethylsilylethoxymethyl)-2H-pyrazol-3-yl]-1H-pyrazolo[4,3-b]pyridine

[0707]

[0708] 3-Bromo-1-methyl-7-(3-methyl-3H-imidazol-4-yl)-5-((R)-3-methylmorpholin-4-yl)-1H-pyrazolo[4,3-b]pyridine (63 mg; 0.161 mmol; 0.694 eq), 1-(2-(trimethylsilyl)ethoxymethyl)-1H-pyrazole-5-boronic acid pinacol ester (158.45 mg; 0.464 mmol; 2 eq), sodium carbonate (73.80 mg; 0.696 mmol; 3 eq), and tetrakis(triphenylphosphine)palladium(0) (32.51 mg; 0.028 mmol; 0.120 eq) were combined, and THF (1.90 ml) and water (190.00 μl) were added. The mixture was stirred at 90 °C for 1.5 h. The reaction mixture was filtered and concentrated under reduced pressure. The crude product was purified by column chromatography (Method N). 1-Methyl-7-(3-methyl-3H-imidazol-4-yl)-5-((R)-3-methylmorpholin-4-yl)-3-[2-(2-(trimethylsilyl)ethoxymethyl)-2H-pyrazol-3-yl]-1H-pyrazolo[4,3-b]pyridine was isolated as a brown solid (61.50 mg; 52.1%); LC / MS (Method Q): Rt 0.946 min; [MH]+ 509.8.

[0709] Example 42: 1-Methyl-7-(3-methyl-3H-imidazol-4-yl)-5-((R)-3-methylmorpholin-4-yl)-3-(1H-pyrazol-3-yl)-1H-pyrazolo[4,3-b]pyridine

[0710]

[0711] 1-Methyl-7-(3-methyl-3H-imidazol-4-yl)-5-((R)-3-methylmorpholin-4-yl)-3-[2-(2-(trimethylsilyl)ethoxymethyl)-2H-pyrazol-3-yl]-1H-pyrazolo[4,3-b]pyridine (61.50 mg; 0.121 mmol; 1 eq) was added and dissolved in a solution of HCl in MeOH (1.93 ml). The mixture was stirred at room temperature for 21 h. The reaction solution was concentrated under reduced pressure. The crude product was purified by column chromatography (Method O). 1-Methyl-7-(3-methyl-3H-imidazol-4-yl)-5-((R)-3-methylmorpholin-4-yl)-3-(2H-pyrazol-3-yl)-1H-pyrazolo[4,3-b]pyridine was isolated as a yellow solid (35 mg; 75.0%); 11H NMR (500 MHz, DMSO-d6): δ 13.27–12.88 (m, 1H), 7.93–7.53 (m, 2H), 7.30–6.94 (m, 3H), 4.47 (s, 1H), 4.08 (d, J = 13.7 Hz, 1H), 3.99 (dd, J = 11.3, 3.6 Hz, 1H), 3.75 (d, J = 11.2 Hz, 1H), 3.69 (dd, J = 11.3, 3.1 Hz, 1H), 3.61 (s, 3H), 3.56–3.50 (m, 4H), 3.17 (td, J = 12.7, 3.8 Hz, 1H), 1.18 (d, J = 6.6 Hz, 3H); LC / MS (method R): Rt 0.399 min; [M+H]+ 379.2.

[0712] Example 43: 7-Cyclopropyl-1-methyl-5-((R)-3-methyl-morpholin-4-yl)-3-(2H-pyrazol-3-yl)-1H-pyrazolo[4,3-b]pyridine (43)

[0713]

[0714] 7-Cyclopropyl-1-methyl-5-((R)-3-methyl-morpholin-4-yl)-3-(2H-pyrazol-3-yl)-1H-pyrazolo[4,3-b]pyridine hydrochloride was prepared analogously to the above example and isolated as a yellow solid (5 mg, 26%); melting point 234 - 235 °C; 1 1H NMR (300 MHz, methanol-d4): δ 7.88 (d, J = 2.4 Hz, 1H), 6.95 - 6.84 (m, 2H), 4.46 (s, 4H), 4.12 (d, J = 9.3 Hz, 1H), 3.96 - 3.84 (m, 3H), 3.73 (q, J = 12.5, 12.0 Hz, 2H), 2.65 (p, J = 5.9, 4.8 Hz, 1H), 1.45 (d, J = 6.5 Hz, 3H), 1.40 - 1.31 (m, 2H), 1.19 (q, J = 4.5, 3.8 Hz, 2H); LC / MS (method S): Rt 1.340 min [M+H]+ 339.3.

[0715] Example 44: 7-Isopropoxy-1-methyl-5-((R)-3-methyl-morpholin-4-yl)-3-(2H-pyrazol-3-yl)-1H-pyrazolo[4,3-b]pyridine (44)

[0716]

[0717] Structural unit for the synthesis of Example 44: (3R)-3-methyl-4-[1-methyl-7-(propan-2-yloxy)-1H-pyrazolo[4,3-b]pyridin-5-yl]morpholine

[0718]

[0719] 1-Methyl-5-[(3R)-3-methylmorpholin-4-yl]-1H-pyrazolo[4,3-b]pyridin-7-ol (500 mg, 1.81 mmol, 1 equiv), DMF (50 mL), potassium carbonate (545.1 mg, 3.75 mmol, 2.07 equiv) and 2-iodopropane (450 mg, 2.51 mmol, 1.39 equiv) were combined and stirred at room temperature for 2 h. The reaction mixture was filtered and concentrated in vacuo. The crude product was purified by column chromatography (Method E). (3R)-3-Methyl-4-[1-methyl-7-(propan-2-yloxy)-1H-pyrazolo[4,3-b]pyridin-5-yl]morpholine was isolated as a yellow oil (500 mg (89%); LC / MS (Method T): Rt 0.997 min, [MH]+ 291.3).

[0720] Example 44: 7-Isopropoxy-1-methyl-5-((R)-3-methyl-morpholin-4-yl)-3-(2H-pyrazol-3-yl)-1H-pyrazolo[4,3-b]pyridine

[0721]

[0722] 7-Isopropoxy-1-methyl-5-((R)-3-methyl-morpholin-4-yl)-3-(2H-pyrazol-3-yl)-1H-pyrazolo[4,3-b]pyridine was prepared analogously to the above example and isolated as a white solid (10 mg, 31%); mp 134-135 °C;

[0723] 11H NMR (300 MHz, DMSO-d6): δ 12.72 (s, 1H), 7.54 (s, 1H), 6.90 (s, 1H), 6.41 (s, 1H), 4.96 (h, J = 6.0 Hz, 1H), 4.39 (d, J = 7.3 Hz, 1H), 4.12 (s, 3H), 3.97 (d, J = 3.4 Hz, 1H), 3.93 (d, J = 3.3 Hz, 1H), 3.71 (t, J = 2.2 Hz, 2H), 3.54 (td, J = 11.4, 3.0 Hz, 1H), 3.26 - 3.10 (m, 1H), 1.42 (d, J = 6.0 Hz, 6H), 1.18 (d, J = 6.6 Hz, 3H); LC / MS (Method E): Rt 1.219 min, [MH]+ 357.2.

[0724] Example 45: 1-Methyl-5-((R)-3-methyl-morpholin-4-yl)-3-(2H-pyrazol-3-yl)-1H-pyrazolo[4,3-b]pyridin-7-ol (45)

[0725]

[0726] Structural unit for the synthesis of Example 45: 1-Methyl-5-[(3R)-3-methylmorpholin-4-yl]-1H-pyrazolo[4,3-b]pyridin-7-yl acetate

[0727]

[0728] 1-Methyl-5-[(3R)-3-methylmorpholin-4-yl]-1H-pyrazolo[4,3-b]pyridin-7-ol (300 mg, 1.09 mmol, 1 equiv), dichloromethane (10 mL), NEt3 (366.8 mg, 3.44 mmol, 3.17 equiv) and acetyl chloride (189.7 mg, 2.30 mmol, 2.11 equiv) were combined and stirred at room temperature for 2 h. The resulting mixture was concentrated in vacuo. The pH of the solution was adjusted to 7 - 8 with sodium bicarbonate. The resulting solution was extracted with dichloromethane, the organic layers were combined, dried over anhydrous sodium sulfate and concentrated in vacuo. The residue was purified by column chromatography (Method E). 1-Methyl-5-[(3R)-3-methylmorpholin-4-yl]-1H-pyrazolo[4,3-b]pyridin-7-yl acetate was isolated as a yellow oil (310 mg, 88%); LC / MS (Method P): Rt 0.621 min, [MH]+ 291.3.

[0729] Example 45: 1-Methyl-5-((R)-3-methyl-morpholin-4-yl)-3-(2H-pyrazol-3-yl)-1H-pyrazolo[4,3-b]pyridin-7-ol

[0730]

[0731] 1-Methyl-5-((R)-3-methyl-morpholin-4-yl)-3-(2H-pyrazol-3-yl)-1H-pyrazolo[4,3-b]pyridin-7-ol was prepared in a similar manner to the above example, and a colorless solid (20 mg, 70%) was isolated; melting point 190-191 °C; 1 H NMR (300 MHz, DMSO-d6): δ 7.67-7.59 (m, 1H), 6.80 (s, 1H), 5.94 (s, 1H), 4.16 (m, 4H), 3.93 (d, J = 7.9 Hz, 1H), 3.70 (d, J = 2.4 Hz, 2H), 3.65-3.47 (m, 3H), 3.20 (m, 1H), 1.17 (d, J = 6.6 Hz, 3H); LC / MS (method E): Rt 1.035 min, [MH]+ 315.1.

[0732] Example 46: 1-(4-Methanesulfonyl-phenyl)-5-((R)-3-methyl-morpholin-4-yl)-3-(1H-pyrazol-3-yl)-1H-pyrazolo[4,3-b]pyridine (46)

[0733]

[0734] (3R)-4-[1-(4-Methanesulfonylphenyl)-3-[1-(oxan-2-yl)-1H-pyrazol-3-yl]-1H-pyrazolo[4,3-b]pyridin-5-yl]-3-methylmorpholine (200 mg, 0.34 mmol, 1 equivalent) was dissolved in a methanol solution of hydrogen chloride (10 mL) and stirred at 25 °C for 1 hour. The resulting solution was extracted with ethyl acetate, the organic layers were combined, dried over anhydrous sodium sulfate, and concentrated in vacuo. The crude product was purified by preparative HPLC (method I). 1-(4-Methanesulfonyl-phenyl)-5-((R)-3-methyl-morpholin-4-yl)-3-(1H-pyrazol-3-yl)-1H-pyrazolo[4,3-b]pyridine as a yellow solid was isolated (20 mg, 13%); melting point 155-157 °C; 11H NMR (300 MHz, DMSO-d6): δ 13.22 (s, 1H), 8.37 (d, J = 9.5 Hz, 1H), 8.22 - 8.07 (m, 4H), 7.80 (s, 1H), 7.29 - 7.19 (m, 2H), 4.54 - 4.43 (m, 1H), 4.15 - 3.97 (m, 2H), 3.86 - 3.66 (m, 2H), 3.57 (td, J = 11.8, 2.8 Hz, 1H), 3.37 - 3.12 (m, 3H), 1.21 (d, J = 6.6 Hz, 3H); LC / MS (Method E): Rt 1.396 min [MH]+ 439.1.

[0735] Example 47: 1-(3-Methylsulfonyl-phenyl)-5-((R)-3-methyl-morpholin-4-yl)-3-(1H-pyrazol-3-yl)-1H-pyrazolo[4,3-b]pyridine (47)

[0736]

[0737] 1-(3-Methylsulfonyl-phenyl)-5-((R)-3-methyl-morpholin-4-yl)-3-(1H-pyrazol-3-yl)-1H-pyrazolo[4,3-b]pyridine was prepared analogously to the above example, and a yellow solid was isolated (4 mg, 10%); melting point 133 - 135 °C; 1 1H NMR (300 MHz, CD3OD): δ 8.46 (s, 2H), 8.22 (t, J = 8.5 Hz, 4H), 8.00 - 7.80 (m, 4H), 7.71 (s, 1H), 7.37 (s, 1H), 7.28 (s, 1H), 7.18 (d, J = 9.5 Hz, 2H), 4.52 (d, J = 7.1 Hz, 2H), 4.09 (dd, J = 12.4, 6.1 Hz, 4H), 3.86 (d, J = 2.6 Hz, 3H), 3.70 (td, J = 11.8, 3.2 Hz, 2H), 3.38 (dd, J = 12.7, 3.9 Hz, 2H), 3.26 (s, 5H), 1.33 (d, J = 6.7 Hz, 7H); LC / MS (Method E): Rt 1.395 min [MH]+ 439.2.

[0738] Example 48: 3-{1-Methyl-5-[(3R)-3-methylmorpholin-4-yl]-3-(1H-pyrazol-3-yl)-1H-pyrazolo[4,3-b]pyridin-7-yl}benzonitrile (48)

[0739] Absolute

[0740]

[0741] 3-{1-Methyl-5-[(3R)-3-methylmorpholin-4-yl]-3-(1H-pyrazol-3-yl)-1H-pyrazolo[4,3-b]pyridin-7-yl}benzonitrile was prepared in a similar manner to the above example and isolated as a yellow solid (34 mg, 25%); 1 1H NMR (400 MHz, DMSO-d6): δ 8.16–8.14 (m, 1H), 8.03–8.00 (m, 1H), 7.98–7.94 (m, 1H), 7.79–7.73 (m, 1H), 7.68 (d, J = 1.9 Hz, 1H), 7.07 (d, J = 2.0 Hz, 1H), 6.96 (s, 1H), 4.53–4.46 (m, 1H), 4.09–4.03 (m, 1H), 4.01–3.96 (m, 1H), 3.78–3.74 (m, 1H), 3.68 (dd, J = 11.4, 3.0 Hz, 1H), 3.60 (s, 3H), 3.54 (td, J = 11.7, 3.0 Hz, 1H), 3.18 (td, J = 12.7, 3.7 Hz, 1H), 1.19 (d, J = 6.6 Hz, 3H); LC / MS (method F): Rt 2.226 min; [MH]+ 400.2.

[0742] Example 49: (3R)-3-Methyl-4-[1-methyl-7-(2-methylphenyl)-3-(1H-pyrazol-5-yl)-1H-pyrazolo[4,3-b]pyridin-5-yl]morpholine (49)

[0743]

[0744] (3R)-3-Methyl-4-[1-methyl-7-(2-methylphenyl)-3-(1H-pyrazol-5-yl)-1H-pyrazolo[4,3-b]pyridin-5-yl]morpholine was prepared in a similar manner to the above example and isolated as an off-white solid (27 mg, 18%); 11H NMR (500 MHz, DMSO-d6): δ 7.68 (d, J = 1.9 Hz, 1H), 7.48–7.32 (m, 4H), 7.06 (dd, J = 1.9, 0.9 Hz, 1H), 6.84 (s, 1H), 4.43 (t, J = 7.6 Hz, 1H), 4.12–3.94 (m, 2H), 3.77–3.66 (m, 2H), 3.54 (td, J = 11.8, 3.0 Hz, 1H), 3.40 (d, J = 0.8 Hz, 3H), 3.17 (td, J = 12.6, 3.8 Hz, 1H), 2.10 (s, 3H), 1.99 (s, 1H), 1.91 (s, 0H), 1.20 - 1.15 (m, 3H). LC / MS (Method C): Rt 1.116 min; [M+H]+ 389.2.

[0745] Example 50: (3R)-4-[7-(4-Methylsulfonyl-2-methylphenyl)-1-methyl-3-(1H-pyrazol-3-yl)-1H-pyrazolo[4,3-b]pyridin-5-yl]-3-methylmorpholine (50)

[0746]

[0747] (3R)-4-[7-(4-Methylsulfonyl-2-methylphenyl)-1-methyl-3-(1H-pyrazol-3-yl)-1H-pyrazolo[4,3-b]pyridin-5-yl]-3-methylmorpholine was prepared analogously to the above example and isolated as a yellow solid (41 mg, 31%); 1 1H NMR (400 MHz, DMSO-d6): δ 8.01 - 7.99 (m, 1H), 7.93 - 7.89 (m, 1H), 7.70 - 7.65 (m, 2H), 7.08 - 7.06 (m, 1H), 6.91 (s, 1H), 4.47 - 4.39 (m, 1H), 4.12 - 4.03 (m, 1H), 4.01 - 3.95 (m, 1H), 3.77 - 3.66 (m, 2H), 3.58 - 3.50 (m, 1H), 3.43 - 3.40 (m, 3H), 3.30 (s, 3H), 3.17 (td, J = 12.7, 3.8 Hz, 1H), 2.21 (s, 3H), 1.21 - 1.16 (m, 3H); LC / MS (Method F): Rt 2.136 min; [M+H]+ 467.1.

[0748] Example 51: (3R)-4-{7-[4-(Methoxymethyl)phenyl]-1-methyl-3-(1H-pyrazol-3-yl)-1H-pyrazolo[4,3-b]pyridin-5-yl}-3-methylmorpholine (51)

[0749]

[0750] (3R)-4-{7-[4-(Methoxymethyl)phenyl]-1-methyl-3-(1H-pyrazol-3-yl)-1H-pyrazolo[4,3-b]pyridin-5-yl}-3-methylmorpholine was prepared analogously to the above example and isolated as a yellow solid (104 mg, 74%);

[0751] 1 H NMR (500 MHz, DMSO-d6): δ 7.68 - 7.67 (m, 1H), 7.59 - 7.56 (m, 2H), 7.51 - 7.48 (m, 2H), 7.06 (d, J = 1.9 Hz, 1H), 6.87 (s, 1H), 4.53 (s, 2H), 4.50 - 4.44 (m, 1H), 4.07 - 4.02 (m, 1H), 3.98 (dd, J = 11.4, 3.6 Hz, 1H), 3.77 - 3.73 (m, 1H), 3.69 (dd, J = 11.3, 3.0 Hz, 1H), 3.60 (s, 3H), 3.54 (td, J = 11.7, 3.0 Hz, 1H), 3.36 (s, 3H), 3.18 (td, J = 12.7, 3.7 Hz, 1H), 1.19 (d, J = 6.6 Hz, 3H); LC / MS (method F): Rt 2.259 min; [MH]+ 419.2.

[0752] Example 52: (4-{1-Methyl-5-[(3R)-3-methylmorpholin-4-yl]-3-(1H-pyrazol-3-yl)-1H-pyrazolo[4,3-b]pyridin-7-yl}phenyl)methanol (52)

[0753]

[0754] (4-{1-Methyl-5-[(3R)-3-methylmorpholin-4-yl]-3-(1H-pyrazol-3-yl)-1H-pyrazolo[4,3-b]pyridin-7-yl}phenyl)methanol was prepared analogously to the above example and isolated as a yellow solid (112 mg, 65%);

[0755] 11H NMR (400 MHz, DMSO-d6): δ 7.69 (d, J = 1.9 Hz, 1H), 7.56 - 7.53 (m, 2H), 7.51 - 7.48 (m, 2H), 7.07 (d, J = 2.0 Hz, 1H), 6.85 (s, 1H), 4.61 (s, 2H), 4.51 - 4.43 (m, 1H), 4.07 - 4.01 (m, 1H), 4.01 - 3.95 (m, 1H), 3.78 - 3.66 (m, 2H), 3.61 (s, 3H), 3.54 (td, J = 11.8, 3.0 Hz, 1H), 3.19 (td, J = 12.6, 3.7 Hz, 1H), 1.19 - 1.18 (m, 3H); LC / MS (Method F): Rt 1.997 min; [M + H]+ 405.2.

[0756] Example 53: 3-[5-((3R)-3-Methyl-morpholin-4-yl)-3-(1H-pyrazol-3-yl)-1H-pyrazolo[4,3-b]pyridin-1-yl]-benzonitrile (53)

[0757]

[0758] 3-[5-((3R)-3-Methyl-morpholin-4-yl)-3-(1H-pyrazol-3-yl)-1H-pyrazolo[4,3-b]pyridin-1-yl]-benzonitrile was prepared analogously to the above example, and a yellow solid (8 mg, 26%) was isolated; melting point 115 - 117 °C;

[0759] 1 1H NMR (300 MHz, DMSO-d6): δ 13.50 (s, 1H), 13.15 (s, 1H), 8.37 (s, 4H), 8.24 (s, 3H), 7.84 (s, 5H), 7.68 (s, 1H), 7.22 (d, J = 16.2 Hz, 4H), 4.50 (s, 2H), 4.03 (d, J = 9.7 Hz, 3H), 3.86 - 3.67 (m, 4H), 3.65 - 3.50 (m, 2H), 3.29 - 3.14 (m, 2H), 1.21 (d, J = 6.5 Hz, 7H); LC / MS (Method U): Rt 2.952 min [M + H]+ 386.2.

[0760] Example 54: (3R)-4-[7-(3,6-Dihydro-2H-pyran-4-yl)-1-methyl-3-(1H-pyrazol-3-yl)-1H-pyrazolo[4,3-b]pyridin-5-yl]-3-methylmorpholine (54)

[0761]

[0762] (3R)-4-[7-(3,6-dihydro-2H-pyran-4-yl)-1-methyl-3-(1H-pyrazol-3-yl)-1H-pyrazolo[4,3-b]pyridin-5-yl]-3-methylmorpholine was prepared analogously to the above example and isolated as a yellow solid (35 mg, 65%);

[0763] 1 H NMR (500 MHz, DMSO-d6): δ 13.19 - 12.86 (m, 1H), 7.82 - 7.53 (m, 1H), 7.11 - 6.95 (m, 1H), 6.86 - 6.77 (m, 1H), 6.01 - 5.96 (m, 1H), 4.50 - 4.39 (m, 1H), 4.29 - 4.25 (m, 2H), 4.04 - 3.95 (m, 5H), 3.90 (t, J = 5.4 Hz, 2H), 3.75 (d, J = 11.2 Hz, 1H), 3.68 (dd, J = 11.2, 3.0 Hz, 1H), 3.52 (td, J = 11.7, 3.0 Hz, 1H), 3.14 (td, J = 12.7, 3.8 Hz, 1H), 2.50 - 2.45 (m, 2H), 1.16 (d, J = 6.6 Hz, 3H); LC / MS (method F): Rt 1.941 min; [MH]+ 381.2.

[0764] Example 55: 1-Methyl-5-((R)-3-methyl-morpholin-4-yl)-3-(2H-pyrazol-3-yl)-7-(tetrahydro-pyran-4-yl)-1H-pyrazolo[4,3-b]pyridine (55)

[0765]

[0766] Structural unit for the synthesis of Example 55: (3R)-3-methyl-4-[1-methyl-7-(oxan-4-yl)-1H-pyrazolo[4,3-b]pyridin-5-yl]morpholine

[0767]

[0768] (3R)-4-[7-(3,6-Dihydro-2H-pyran-4-yl)-1-methyl-1H-pyrazolo[4,3-b]pyridin-5-yl]-3-methylmorpholine (400 mg, 1.15 mmol, 1 equiv), methanol (30 mL) and Pd / C (2437.24 mg, 2.29 mmol, 2.0 equiv 10%) were combined and stirred at 25 °C for 5 h. The reaction mixture was filtered and concentrated in vacuo. (3R)-3-Methyl-4-[1-methyl-7-(oxan-4-yl)-1H-pyrazolo[4,3-b]pyridin-5-yl]morpholine as a yellow solid was isolated (300 mg 74%); LC / MS (method J): Rt 0.752 min, [MH]+ 317.2.

[0769] Example 55: 1-Methyl-5-((R)-3-methyl-morpholin-4-yl)-3-(2H-pyrazol-3-yl)-7-(tetrahydro-pyran-4-yl)-1H-pyrazolo[4,3-b]pyridine

[0770]

[0771] 1-Methyl-5-((R)-3-methyl-morpholin-4-yl)-3-(2H-pyrazol-3-yl)-7-(tetrahydro-pyran-4-yl)-1H-pyrazolo[4,3-b]pyridine was prepared analogously to the above example and isolated as a colorless solid (20 mg (27%); melting point 240 - 242 °C; 1 H NMR (300 MHz, methanol-d4): δ 7.62 (s, 1H), 7.01 (s, 1H), 6.84 (s, 1H), 4.43 (d, J = 7.3 Hz, 1H), 4.25 (s, 3H), 4.15 - 4.03 (m, 2H), 4.07 - 3.91 (m, 2H), 3.80 (d, J = 2.2 Hz, 2H), 3.64 (dtd, J = 14.3, 11.1, 6.6 Hz, 2H), 3.32 (d, J = 4.0 Hz, 0H), 3.23 (d, J = 3.7 Hz, 0H), 2.04 - 1.85 (m, 4H), 1.23 (d, J = 6.7 Hz, 3H); LC / MS (method E): Rt 1.150 min, [MH]+ 383.2.

[0772] Example 56: (3R)-3-Methyl-4-[3-(1H-pyrazol-3-yl)-1H-pyrazolo[4,3-b]pyridin-5-yl]morpholine (56)

[0773]

[0774] Structural unit for the synthesis of Example 56: 3-bromo-5-((R)-3-methyl-morpholin-4-yl)-1H-pyrazolo[4,3-b]pyridine

[0775]

[0776] Combine 3-bromo-5-chloro-1H-pyrazolo[4,3-b]pyridine (2 g, 8.6 mmol), (R)-3-methyl-morpholine (957 mg, 9.5 mmol), XPhos-Pd-G2 (339 mg, 0.43 mmol), bis-cy-xPhos (205 mg, 0.43 mmol), LHMDS (3 g, 17 mmol) and dioxane (20 ml), stir at 60 °C for 3 hours. Filter the reaction mixture and concentrate under reduced pressure. Purify the crude product by column chromatography (n-heptane / EtOAc gradient). Isolate 3-bromo-5-((R)-3-methyl-morpholin-4-yl)-1H-pyrazolo[4,3-b]pyridine as a yellow solid (280 mg, 6%); LC / MS (Method V): Rt 2.802 min; [MH]+ 297.

[0777] Structural unit for the synthesis of Example 56: 5-((R)-3-methyl-morpholin-4-yl)-3-[1-(tetrahydro-pyran-2-yl)-1H-pyrazol-3-yl]-1H-pyrazolo[4,3-b]pyridine

[0778] Absolute

[0779]

[0780] 3-Bromo-5-((R)-3-methyl-morpholin-4-yl)-1H-pyrazolo[4,3-b]pyridine (280 mg; 0.518 mmol; 1.0 eq) was dissolved in THF (8 ml) and water (0.800 ml). 1-(Tetrahydropyran-2-yl)-3-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-1H-pyrazole (294.194 mg; 1,037 mmol; 2.0 eq), sodium carbonate (164.786 mg; 1.555 mmol; 3.0 eq) and tetrakis(triphenylphosphine)palladium(0) (72.591 mg; 0.062 mmol; 0.12 eq) were combined and stirred at 90 °C for 3 h. 1-(Tetrahydropyran-2-yl)-3-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-1H-pyrazole (294.194 mg; 1.037 mmol; 2.0 eq) and tetrakis(triphenylphosphine)palladium(0) (72.591 mg; 0.062 mmol; 0.12 eq) were added and stirred at 90 °C for 14 h. The reaction mixture was concentrated under reduced pressure and the crude product was purified by column chromatography (n-heptane / EtOAc gradient). 5-((R)-3-Methyl-morpholin-4-yl)-3-[1-(tetrahydro-pyran-2-yl)-1H-pyrazol-3-yl]-1H-pyrazolo[4,3-b]pyridine was isolated as a yellow solid (131 mg, 61%); LC / MS (method F): Rt 1.903 min; [MH]+ 369.2.

[0781] Example 56: (3R)-3-Methyl-4-[3-(1H-pyrazol-3-yl)-1H-pyrazolo[4,3-b]pyridin-5-yl]morpholine

[0782]

[0783] 5-((R)-3-Methyl-morpholin-4-yl)-3-[1-(tetrahydro-pyran-2-yl)-1H-pyrazol-3-yl]-1H-pyrazolo[4,3-b]pyridine (131 mg; 0.316 mmol; 1.0 eq) was dissolved in methanol (3.500 ml) and a dioxane solution of hydrogen chloride (3.164 ml; 4.0 M). The reaction solution was stirred at room temperature for 2 h. The reaction mixture was concentrated under reduced pressure and the crude product was purified by column chromatography (DCM / MeOH gradient). (3R)-3-Methyl-4-[3-(1H-pyrazol-3-yl)-1H-pyrazolo[4,3-b]pyridin-5-yl]morpholine was isolated as a yellow solid (90 mg, 99%); 11H NMR (400 MHz, DMSO-d6): δ 13.21–12.76 (m, 2H), 7.89–7.53 (m, 2H), 7.11–6.96 (m, 2H), 4.45–4.36 (m, 1H), 4.06–3.93 (m, 2H), 3.76 (d, J = 11.2 Hz, 1H), 3.70 (dd, J = 11.3, 3.0 Hz, 1H), 3.54 (td, J = 11.7, 3.0 Hz, 1H), 3.15 (td, J = 12.7, 3.8 Hz, 1H), 1.16 (d, J = 6.6 Hz, 3H); LC / MS (Method F): Rt 1.586 min; [M+H]+ 285.1.

[0784] Example 57: (3R)-4-{1-[(3-Methylsulfonylphenyl)methyl]-3-(1H-pyrazol-3-yl)-1H-pyrazolo[4,3-b]pyridin-5-yl}-3-methylmorpholine (57)

[0785]

[0786] 5-((R)-3-Methyl-morpholin-4-yl)-3-(1H-pyrazol-3-yl)-1H-pyrazolo[4,3-b]pyridine (56 mg; 0.197 mmol; 1.0 equiv), acetonitrile (2.8 ml), potassium carbonate (42.981 mg; 0.295 mmol; 1.50 equiv) and 1-bromomethyl-3-methylsulfonyl-benzene (51.651 mg; 0.197 mmol; 1.0 equiv) were combined and stirred at 80 °C for 2 h. The reaction solution was extracted with EtOAc / water, the organic layer was dried over sodium sulfate, filtered and the solvent was removed in vacuo. The crude product was purified by preparative HPLC. (3R)-4-{1-[(3-Methylsulfonylphenyl)methyl]-3-(1H-pyrazol-3-yl)-1H-pyrazolo[4,3-b]pyridin-5-yl}-3-methylmorpholine as a yellow solid was isolated (27 mg, 28%); 11H NMR (700 MHz, DMSO-d6): δ 8.14 (d, J = 9.4 Hz, 1H), 7.90 - 7.88 (m, 1H), 7.87 - 7.84 (m, 1H), 7.81 (d, J = 1.9 Hz, 1H), 7.61 (t, J = 7.8 Hz, 1H), 7.53 - 7.50 (m, 1H), 7.18 (d, J = 9.5 Hz, 1H), 7.11 (d, J = 1.9 Hz, 1H), 5.80 (s, 2H), 4.44 - 4.40 (m, 1H), 4.04 - 4.01 (m, 1H), 3.99 (dd, J = 11.3, 3.7 Hz, 1H), 3.78 - 3.75 (m, 1H), 3.69 (dd, J = 11.2, 3.1 Hz, 1H), 3.53 (td, J = 11.7, 3.1 Hz, 1H), 3.20 (s, 3H), 3.19 - 3.15 (m, 1H), 1.16 (d, J = 6.6 Hz, 3H);

[0787] LC / MS (Method F): Rt 1.981 min; [M+H]+ 453.1.

[0788] Example 58: (3R)-3-Methyl-4-[1-methyl-3-(1H-pyrazol-3-yl)-7-(pyridin-2-yl)-1H-pyrazolo[4,3-b]pyridin-5-yl]morpholine (58)

[0789]

[0790] (3R)-3-Methyl-4-[1-methyl-3-(1H-pyrazol-3-yl)-7-(pyridin-2-yl)-1H-pyrazolo[4,3-b]pyridin-5-yl]morpholine was prepared analogously to the above example and isolated as an orange solid (40 mg, 72.9%); 1 1H NMR (400 MHz, DMSO-d6): δ 8.82–8.79 (m, 1H), 8.07 (td, J = 7.7, 1.8 Hz, 1H), 7.90–7.86 (m, 1H), 7.74 (d, J = 2.0 Hz, 1H), 7.62–7.57 (m, 1H), 7.09 (d, J = 1.9 Hz, 1H), 7.08 (s, 1H), 4.54–4.47 (m, 1H), 4.09–4.03 (m, 1H), 3.99 (dd, J = 11.2, 3.5 Hz, 1H), 3.77 (d, J = 11.3 Hz, 1H), 3.71 (s, 3H), 3.73–3.68 (m, 1H), 3.55 (td, J = 11.8, 3.0 Hz, 1H), 3.26–3.17 (m, 1H), 1.20 (d, J = 6.6 Hz, 3H);

[0791] LC / MS (Method C): Rt 0.947 min; [MH]+ 376.2.

[0792] Example 59: (3R)-4-[1-Benzyl-3-(1H-pyrazol-5-yl)-1H-pyrazolo[4,3-b]pyridin-5-yl]-3-methylmorpholine (59)

[0793]

[0794] (3R)-4-[1-Benzyl-3-(1H-pyrazol-5-yl)-1H-pyrazolo[4,3-b]pyridin-5-yl]-3-methylmorpholine hydrochloride was prepared analogously to the above example and isolated as a beige solid (120 mg; 52.3%); 1 H NMR (500 MHz, DMSO-d6): δ 8.04 (d, J = 9.4 Hz, 1H), 7.73 (d, J = 2.0 Hz, 1H), 7.34–7.30 (m, 2H), 7.28–7.22 (m, 3H), 7.12 (d, J = 9.5 Hz, 1H), 7.07 (d, J = 2.0 Hz, 1H), 5.65 (s, 2H), 4.44–4.38 (m, 1H), 4.03–3.97 (m, 2H), 3.76 (d, J = 11.2 Hz, 1H), 3.68 (dd, J = 11.2, 3.1 Hz, 1H), 3.54–3.50 (m, 1H), 3.16 (td, J = 12.8, 3.9 Hz, 1H), 1.16 (d, J = 6.6 Hz, 3H); LC / MS (Method C): Rt 1.075 min; [MH]+ 375.2.

[0795] Example 60: 4-[5-[(3R)-3-Methylmorpholin-4-yl]-3-(1H-pyrazol-3-yl)-1H-pyrazolo[4,3-b]pyridin-1-yl]benzonitrile (60)

[0796]

[0797] 4-[5-[(3R)-3-Methylmorpholin-4-yl]-3-(1H-pyrazol-3-yl)-1H-pyrazolo[4,3-b]pyridin-1-yl]benzonitrile was prepared analogously to the above example and isolated as a yellow solid (10 mg, 26%); melting point 140–142 °C; 11H NMR (300 MHz, DMSO-d6): δ 13.20 (s, 1H), 8.33 (d, J = 9.5 Hz, 1H), 8.05 (q, J = 8.9 Hz, 4H), 7.76 (s, 1H), 7.23 - 7.14 (m, 2H), 4.53 - 4.40 (m, 1H), 4.11 - 3.94 (m, 2H), 3.83 - 3.63 (m, 2H), 3.53 (td, J = 11.8, 2.9 Hz, 1H), 3.26 - 3.09 (m, 1H), 1.17 (d, J = 6.5 Hz, 3H); LC / MS (Method D): Rt 1.295 min [MH]+ 386.0.

[0798] Example 61: (3R)-3-Methyl-4-[1-methyl-7-(1-methyl-1H-pyrazol-5-yl)-3-(1H-pyrazol-3-yl)-1H-pyrazolo[4,3-b]pyridin-5-yl]morpholine (61)

[0799]

[0800] (3R)-3-Methyl-4-[1-methyl-7-(1-methyl-1H-pyrazol-5-yl)-3-(1H-pyrazol-3-yl)-1H-pyrazolo[4,3-b]pyridin-5-yl]morpholine was prepared analogously to the above example and isolated as a yellow solid (30 mg, 16%); 1 1H NMR (300 MHz, DMSO-d6): δ 13.11 (s, 1H), 7.85 - 7.51 (m, 2H), 7.06 (d, J = 1.7 Hz, 2H), 6.61 (d, J = 1.9 Hz, 1H), 4.47 (d, J = 7.4 Hz, 1H), 4.22 - 3.88 (m, 2H), 3.72 (d, J = 6.5 Hz, 5H), 3.32 (s, 4H), 3.25 - 3.01 (m, 1H), 1.18 (d, J = 6.6 Hz, 3H);

[0801] LC / MS (Method K): Rt 1.177 min [MH]+ 379.3.

[0802] Example 62: (3R)-3-Methyl-4-[1-methyl-7-(3-methylpyridin-2-yl)-3-(1H-pyrazol-3-yl)-1H-pyrazolo[4,3-b]pyridin-5-yl]morpholine (62)

[0803]

[0804] (3R)-3-methyl-4-[1-methyl-7-(3-methylpyridin-2-yl)-3-(1H-pyrazol-3-yl)-1H-pyrazolo[4,3-b]pyridin-5-yl]morpholine was prepared in a manner similar to the above-described embodiment and isolated as a yellow solid (15.70 mg, 18.2%); 1 HNMR (500 MHz, DMSO-d6): δ 13.24–12.88 (m, 1H), 8.59–8.57 (m, 1H), 7.89–7.86 (m, 1H), 7.84–7.56 (m, 1H), 7.49 (dd, J = 7.7, 4.8 Hz, 1H), 7.15–6.92 (m, 2H), 4.49–4.40 (m, 1H), 4.13–4.01 (m, 1H), 3.99 (dd, J = 11.4, 3.6 Hz, 1H), 3.76–3.72 (m, 1H), 3.70 (dd, J = 11.4, 3.0 Hz, 1H), 3.55 (td, J = 11.7, 3.0 Hz, 1H), 3.42–3.36 (m, 3H), 3.17 (td, J = 12.7, 3.8 Hz, 1H), 2.20 (s, 3H), 1.17 (d, J = 6.6 Hz, 3H); LC / MS (Method C): Rt 0.953 min; [MH]+ 390.2.

[0805] Example 63: (3R)-4-[1-(Cyclopropylmethyl)-3-(1H-pyrazol-3-yl)-1H-pyrazolo[4,3-b]pyridin-5-yl]-3-methylmorpholine (63)

[0806]

[0807] (3R)-4-[1-(Cyclopropylmethyl)-3-(1H-pyrazol-3-yl)-1H-pyrazolo[4,3-b]pyridin-5-yl]-3-methylmorpholine was prepared in a manner similar to the above-described embodiment and isolated as a colorless solid (20 mg, 43%); melting point 80 °C; 11H NMR (300 MHz, DMSO-d6): δ 13.07 (s, 1H), 8.05 (d, J = 9.3 Hz, 1H), 7.67 (s, 1H), 7.11 (d, J = 9.4 Hz, 1H), 7.04 (d, J = 1.9 Hz, 1H), 4.43 (d, J = 7.1 Hz, 1H), 4.29 (d, J = 6.9 Hz, 2H), 4.10 - 3.90 (m, 2H), 3.83 - 3.62 (m, 2H), 3.62 - 3.47 (m, 1H), 3.23 - 3.08 (m, 1H), 1.29 (q, J = 5.6 Hz, 1H), 1.17 (d, J = 6.6 Hz, 3H), 0.58 - 0.45 (m, 2H), 0.4 - 0.33 (m, 2H);

[0808] LC / MS (Method A): RT 1.475 min, [MH]+ 339.3.

[0809] Example 64: 5 - ((R)-3 - methyl - morpholin - 4 - yl)-1 - phenethyl - 3-(1H - pyrazol - 3 - yl)-1H - pyrazolo[4,3 - b]pyridine (64)

[0810]

[0811] (3R)-3 - methyl - 4 - [1-(2 - phenylethyl)-3-(1H - pyrazol - 3 - yl)-1H - pyrazolo[4,3 - b]pyridin - 5 - yl]morpholine was prepared analogously to the above example as a colorless solid (27 mg, 52%); melting point 83 °C; 1 1H NMR (300 MHz, DMSO-d6): δ 13.04 (d, J = 86.7 Hz, 1H), 7.95 - 7.45 (m, 2H), 7.38 - 6.82 (m, 7H), 4.60 (s, 2H), 4.36 (s, 1H), 3.96 (d, J = 10.0 Hz, 2H), 3.86 - 3.62 (m, 2H), 3.59 - 3.39 (m, 1H), 3.22 - 3.01 (m, 3H), 1.11 (d, J = 6.6 Hz, 3H);

[0812] LC / MS (Method J): RT 1.030 min, [MH]+ 389.1.

[0813] Example 65: (3R)-3 - methyl - 4 - [1 - methyl - 3-(1H - pyrazol - 3 - yl)-7 - [6-(trifluoromethyl)pyridin - 3 - yl]-1H - pyrazolo[4,3 - b]pyridin - 5 - yl]morpholine (65)

[0814]

[0815] (3R)-3-Methyl-4-[1-methyl-3-(1H-pyrazol-3-yl)-7-[6-(trifluoromethyl)pyridin-3-yl]-1H-pyrazolo[4,3-b]pyridin-5-yl]morpholine was prepared analogously to the above example and isolated as a yellow solid (26 mg, 93%);

[0816] 1 H NMR (500 MHz, DMSO-d6): δ 13.29 - 12.89 (m, 1H), 9.05 - 9.03 (m, 1H), 8.41 - 8.37 (m, 1H), 8.12 - 8.09 (m, 1H), 7.85 - 7.54 (m, 1H), 7.13 - 7.00 (m, 2H), 4.55 - 4.45 (m, 1H), 4.08 (q, J = 5.3 Hz, 1H), 3.99 (dd, J = 11.4, 3.6 Hz, 1H), 3.76 (d, J = 11.2 Hz, 1H), 3.69 (dd, J = 11.3, 3.0 Hz, 1H), 3.63 (s, 3H), 3.54 (td, J = 11.7, 3.1 Hz, 1H), 3.23 - 3.16 (m, 1H), 1.19 (d, J = 6.6 Hz, 3H); LC / MS (method F): Rt 2.351 min; [MH]+ 444.1.

[0817] Example 66: (3R)-3-Methyl-4-[1-methyl-3-(1H-pyrazol-3-yl)-7-[2-(trifluoromethyl)pyridin-3-yl]-1H-pyrazolo[4,3-b]pyridin-5-yl]morpholine (66)

[0818]

[0819] (3R)-3-Methyl-4-[1-methyl-3-(1H-pyrazol-3-yl)-7-[2-(trifluoromethyl)pyridin-3-yl]-1H-pyrazolo[4,3-b]pyridin-5-yl]morpholine hydrochloride was prepared analogously to the above example and isolated as an orange solid (90 mg, quantitative); 11H NMR (700 MHz, DMSO-d6): δ 8.95–8.93 (m, 1H), 8.24–8.21 (m, 1H), 7.93–7.91 (m, 1H), 7.71 (d, J = 1.5 Hz, 1H), 7.08–7.06 (m, 1H), 7.03 (d, J = 10.1 Hz, 1H), 4.41–4.35 (m, 1H), 4.08–4.03 (m, 1H), 4.01–3.96 (m, 1H), 3.75–3.66 (m, 2H), 3.54 (tt, J = 11.7, 2.8 Hz, 1H), 3.41–3.39 (m, 3H), 3.16 (td, J = 12.8, 3.9 Hz, 1H), 1.19–1.13 (m, 3H);

[0820] LC / MS (Method C): Rt 1.058 min; [M+H]+ 444.2.

[0821] Example 67: 1-Methyl-5-((R)-3-methylmorpholin-4-yl)-3-(2H-pyrazol-3-yl)-7-(tetrahydro-pyran-3-yl)-1H-pyrazolo[4,3-b]pyridine (67) (diastereomeric mixture)

[0822]

[0823] 1-Methyl-5-((R)-3-methylmorpholin-4-yl)-3-(2H-pyrazol-3-yl)-7-(tetrahydro-pyran-3-yl)-1H-pyrazolo[4,3-b]pyridine was prepared analogously to the above example and isolated as a colorless solid (30 mg, 41%); melting point 198 - 200 °C; 1 1H NMR (300 MHz, methanol-d4): δ 7.60 (s, 1H), 6.99 (s, 1H), 6.90 (d, J = 5.7 Hz, 1H), 4.42 (d, J = 7.6 Hz, 1H), 4.25 (s, 3H), 4.08 (dd, J = 10.1, 2.6 Hz, 1H), 4.07 - 3.90 (m, 3H), 3.80 (d, J = 2.2 Hz, 2H), 3.71 - 3.50 (m, 4H), 3.32 (s, 0H), 3.23 (d, J = 3.7 Hz, 0H), 2.16 (d, J = 12.2 Hz, 1H), 2.04 - 1.71 (m, 2H), 1.27 - 1.18 (m, 3H); LC / MS (Method W): Rt 0.970 min, [M+H]+ 383.1.

[0824] Example 68: 1-Methyl-5-((R)-3-methyl-morpholin-4-yl)-3-(2H-pyrazol-3-yl)-7-(R)-tetrahydro-pyran-3-yl-1H-pyrazolo[4,3-b]pyridine (68)

[0825]

[0826] The diastereomers of 1-Methyl-5-((R)-3-methyl-morpholin-4-yl)-3-(2H-pyrazol-3-yl)-7-(tetrahydro-pyran-3-yl)-1H-pyrazolo[4,3-b]pyridine were separated by chiral SFC (ChiralCel OJ-H; CO2: methanol + 0.5% DEA 88:12). Colorless solid 1-Methyl-5-((R)-3-methyl-morpholin-4-yl)-3-(2H-pyrazol-3-yl)-7-(R)-tetrahydro-pyran-3-yl-1H-pyrazolo[4,3-b]pyridine was isolated (14 mg; 41.5%); LC / MS (Method C): Rt 0.932 min; [MH]+ 383.3; eluted first from the column by Rt.

[0827] Example 69: 1-Methyl-5-((R)-3-methyl-morpholin-4-yl)-3-(2H-pyrazol-3-yl)-7-(S)-tetrahydro-pyran-3-yl-1H-pyrazolo[4,3-b]pyridine (69)

[0828]

[0829] The diastereomers of 1-Methyl-5-((R)-3-methyl-morpholin-4-yl)-3-(2H-pyrazol-3-yl)-7-(tetrahydro-pyran-3-yl)-1H-pyrazolo[4,3-b]pyridine were separated by chiral SFC (ChiralCel OJ-H; CO2: methanol + 0.5% DEA 88:12). Colorless solid 1-Methyl-5-((R)-3-methyl-morpholin-4-yl)-3-(2H-pyrazol-3-yl)-7-(S)-tetrahydro-pyran-3-yl-1H-pyrazolo[4,3-b]pyridine was isolated (17.80 mg; 52.7%); LC / MS (Method C): Rt 0.93 min; [MH]+ 383.3; eluted later from the column by Rt.

[0830] Example 70: 1-Methyl-5-((R)-3-methyl-morpholin-4-yl)-3-(2H-pyrazol-3-yl)-7-(tetrahydro-furan-3-yl)-1H-pyrazolo[4,3-b]pyridine (70) (diastereomeric mixture)

[0831]

[0832] 1-Methyl-5-((R)-3-methyl-morpholin-4-yl)-3-(2H-pyrazol-3-yl)-7-(tetrahydro-furan-3-yl)-1H-pyrazolo[4,3-b]pyridine was prepared analogously to the above example and isolated as a colorless solid (40 mg (53%); melting point 98 - 100 °C; 1 H NMR (300 MHz, methanol-d4): δ 7.59 (s, 1H), 7.14 (s, 0H), 6.98 (s, 1H), 6.87 (s, 1H), 4.25 (s, 3H), 4.24 - 3.88 (m, 7H), 3.79 (d, J = 2.2 Hz, 2H), 3.78 - 3.54 (m, 2H), 3.35 - 3.18 (m, 1H), 2.52 (ddd, J = 13.1, 8.1, 6.6 Hz, 1H), 2.19 - 2.05 (m, 1H), 1.52 (s, 0H), 1.22 (dd, J = 6.7, 1.3 Hz, 3H);

[0833] LC / MS (method W): Rt 0.870 min, [MH]+ 369.0.

[0834] Example 71: 1-Methyl-5-((R)-3-methyl-morpholin-4-yl)-3-(2H-pyrazol-3-yl)-7-(S)-tetrahydro-furan-3-yl-1H-pyrazolo[4,3-b]pyridine (71)

[0835]

[0836] The diastereomers of 1-Methyl-5-((R)-3-methyl-morpholin-4-yl)-3-(2H-pyrazol-3-yl)-7-(tetrahydro-furan-3-yl)-1H-pyrazolo[4,3-b]pyridine were separated by chiral SFC (ChiralCel OJ-H; CO2: methanol + 0.5% DEA 90:10). The colorless solid 1-Methyl-5-((R)-3-methyl-morpholin-4-yl)-3-(2H-pyrazol-3-yl)-7-(S)-tetrahydro-furan-3-yl-1H-pyrazolo[4,3-b]pyridine was isolated (7 mg; 41.2%); LC / MS (method C): Rt 0.867 min; [MH]+ 369.3; eluted first from the column Rt.

[0837] Example 72: 1-Methyl-5-((R)-3-methyl-morpholin-4-yl)-3-(2H-pyrazol-3-yl)-7-(R)-tetrahydro-furan-3-yl-1H-pyrazolo[4,3-b]pyridine (72)

[0838]

[0839] The diastereomers of 1-methyl-5-((R)-3-methyl-morpholin-4-yl)-3-(2H-pyrazol-3-yl)-7-(tetrahydro-furan-3-yl)-1H-pyrazolo[4,3-b]pyridine were separated by chiral SFC (ChiralCel OJ-H; CO2: methanol + 0.5% DEA 90:10). The colorless solid 1-methyl-5-((R)-3-methyl-morpholin-4-yl)-3-(2H-pyrazol-3-yl)-7-(R)-tetrahydro-furan-3-yl-1H-pyrazolo[4,3-b]pyridine (7 mg; 41.2%) was isolated; LC / MS (method C): Rt 0.867 min; [MH]+ 369.2;; Rt was eluted again from the column.

[0840] Example 73: (3R)-3-methyl-4-[1-(propan-2-yl)-3-(1H-pyrazol-3-yl)-1H-pyrazolo[4,3-b]pyridin-5-yl]morpholine (73)

[0841]

[0842] (3R)-3-methyl-4-[1-(propan-2-yl)-3-(1H-pyrazol-3-yl)-1H-pyrazolo[4,3-b]pyridin-5-yl]morpholine was prepared analogously to the above example as a colorless solid (18 mg, 28%); melting point 94 - 95 °C; 1 H NMR (400 MHz, DMSO-d6): δ 12.99 (d, J = 89.2 Hz, 1H), 8.05 (d, J = 9.1 Hz, 1H), 7.68 (d, J = 89.7 Hz, 1H), 7.03 (d, J = 49.1 Hz, 2H), 4.98 - 4.89 (m, 1H), 4.41 (s, 1H), 3.99 (dd, J = 11.2, 3.6 Hz, 2H), 3.76 (d, J = 11.2 Hz, 1H), 3.69 (dd, J = 11.2, 3.0 Hz, 1H), 3.54 (td, J = 11.7, 3.0 Hz, 1H), 3.14 (td, J = 12.7, 3.8 Hz, 1H), 1.51 (d, J = 6.5 Hz, 6H), 1.15 (d, J = 6.6 Hz, 3H); LC / MS (method E): RT 1.241 min, [MH]+ 327.4.

[0843] Example 74: (3R)-4-[7-(6-methylsulfonyl-2-methylpyridin-3-yl)-1-methyl-3-[3-(trifluoromethyl)-1H-pyrazol-5-yl]-1H-pyrazolo[4,3-b]pyridin-5-yl]-3-methylmorpholine (74)

[0844]

[0845] Prepare (3R)-4-[7-(6-methylsulfonyl-2-methylpyridin-3-yl)-1-methyl-3-[3-(trifluoromethyl)-1H-pyrazol-5-yl]-1H-pyrazolo[4,3-b]pyridin-5-yl]-3-methylmorpholine as in the above example and isolate as a yellow solid (19 mg; 64%); 1 H NMR (500 MHz, DMSO-d6): δ 14.14 (s, 1H), 8.22–8.19 (m, 1H), 8.07–8.04 (m, 1H), 7.33–7.31 (m, 1H), 7.12–7.10 (m, 1H), 4.48–4.39 (m, 1H), 4.15–4.07 (m, 1H), 4.00 (dd, J = 11.4, 3.6 Hz, 1H), 3.76 (dd, J = 11.3, 7.0 Hz, 1H), 3.69 (dd, J = 11.3, 3.1 Hz, 1H), 3.58–3.51 (m, 1H), 3.52–3.50 (m, 3H), 3.36 (s, 3H), 3.19 (td, J = 12.8, 3.8 Hz, 1H), 2.46–2.43 (m, 3H), 1.21–1.17 (m, 3H); LC / MS (method C): Rt 1.146 min; [MH]+ 536.2.

[0846] Example 75: (3R)-4-[7-(5-methylsulfonyl-2-methylphenyl)-1-methyl-3-(1H-pyrazol-5-yl)-1H-pyrazolo[4,3-b]pyridin-5-yl]-3-methylmorpholine (75)

[0847]

[0848] Prepare (3R)-4-[7-(5-methylsulfonyl-2-methylphenyl)-1-methyl-3-(1H-pyrazol-5-yl)-1H-pyrazolo[4,3-b]pyridin-5-yl]-3-methylmorpholine as in the above example and isolate as a yellow solid (144 mg; quantitative); 11H NMR (700 MHz, DMSO-d6): δ 8.00 - 7.97 (m, 1H), 7.92 - 7.90 (m, 1H), 7.76 - 7.74 (m, 1H), 7.72 - 7.70 (m, 1H), 7.11 - 7.09 (m, 1H), 6.98 - 6.96 (m, 1H), 4.48 - 4.44 (m, 1H), 4.09 - 4.04 (m, 1H), 4.00 - 3.96 (m, 1H), 3.77 - 3.73 (m, 1H), 3.72 - 3.65 (m, 1H), 3.54 (dd, J = 11.6, 3.1 Hz, 1H), 3.42 - 3.40 (m, 3H), 3.29 - 3.27 (m, 3H), 3.22 - 3.16 (m, 1H), 2.22 - 2.20 (m, 3H), 1.21 - 1.16 (m, 3H);

[0849] LC / MS (Method C): Rt 0.991 min; [M+H]+ 467.

[0850] Example 76: (3R)-4-[7-(3-Methylsulfonylphenyl)-1-methyl-3-(1H-pyrazol-5-yl)-1H-pyrazolo[4,3-b]pyridin-5-yl]-3-methylmorpholine (76)

[0851]

[0852] (3R)-4-[7-(3-Methylsulfonylphenyl)-1-methyl-3-(1H-pyrazol-5-yl)-1H-pyrazolo[4,3-b]pyridin-5-yl]-3-methylmorpholine was prepared analogously to the above example and isolated as a yellow solid (47 mg, 30%); 1 1H NMR (700 MHz, DMSO-d6): δ 8.15 - 8.13 (m, 1H), 8.10 - 8.08 (m, 1H), 8.00 - 7.98 (m, 1H), 7.84 (t, J = 7.7 Hz, 1H), 7.70 - 7.68 (m, 1H), 7.09 - 7.07 (m, 1H), 6.99 (s, 1H), 4.53 - 4.49 (m, 1H), 4.07 - 4.04 (m, 1H), 3.99 (dd, J = 11.2, 3.8 Hz, 1H), 3.78 - 3.75 (m, 1H), 3.69 (dd, J = 11.3, 3.1 Hz, 1H), 3.59 (s, 3H), 3.54 (td, J = 11.6, 3.1 Hz, 1H), 3.33 (s, 3H), 3.19 (td, J = 12.7, 3.8 Hz, 1H), 1.19 (d, J = 6.7 Hz, 3H); LC / MS (Method C): Rt 0.992 min; [M+H]+ 453.2.

[0853] Example 77: (3R)-3-Methyl-4-[3-(1H-pyrazol-3-yl)-1-[2-(pyridin-4-yl)ethyl]-1H-pyrazolo[4,3-b]pyridin-5-yl]morpholine (77)

[0854]

[0855] (3R)-3-Methyl-4-[3-(1H-pyrazol-3-yl)-1-[2-(pyridin-4-yl)ethyl]-1H-pyrazolo[4,3-b]pyridin-5-yl]morpholine was prepared analogously to the above example and isolated as a yellow solid (10 mg, 20%); melting point 180 - 181 °C; 1 H NMR (300 MHz, DMSO-d6): δ 13.18 (s, 1H), 8.41 - 8.32 (m, 2H), 7.84 (d, J = 9.4 Hz, 1H), 7.23 - 7.14 (m, 2H), 7.00 (d, J = 9.6 Hz, 2H), 4.65 (t, J = 7.0 Hz, 2H), 4.37 (s, 1H), 4.02 - 3.91 (m, 2H), 3.79 - 3.60 (m, 2H), 3.57 - 3.42 (m, 1H), 3.24 - 3.02 (m, 3H), 1.11 (d, J = 6.6 Hz, 3H); LC / MS (Method E): Rt 0.929 min, [MH]+ 390.0.

[0856] Example 78: (3R)-4-{7-[1-(Difluoromethyl)-1H-pyrazol-5-yl]-1-methyl-3-(1H-pyrazol-5-yl)-1H-pyrazolo[4,3-b]pyridin-5-yl}-3-methylmorpholine (78)

[0857]

[0858] (3R)-4-{7-[1-(Difluoromethyl)-1H-pyrazol-5-yl]-1-methyl-3-(1H-pyrazol-5-yl)-1H-pyrazolo[4,3-b]pyridin-5-yl}-3-methylmorpholine was prepared analogously to the above example and isolated as a yellow solid (49 mg; 94%); 11H NMR (400 MHz, DMSO-d6): δ 13.27–12.85 (m, 1H), 8.02 (d, J = 1.7 Hz, 1H), 7.90–7.57 (m, 1H), 7.16–6.98 (m, 2H), 6.94 (d, J = 1.8 Hz, 1H), 4.53–4.28 (m, 1H), 4.12–3.95 (m, 2H), 3.80–3.49 (m, 6H), 3.24–3.10 (m, 2H), 1.18 (dd, J = 6.8, 5.3 Hz, 3H); LC / MS (Method C): Rt 0.989 min; [M+H]+ 415.3.

[0859] Example 79: (3R)-4-[7-(3,6-Dihydro-2H-thiopyran-4-yl)-1-methyl-3-(1H-pyrazol-5-yl)-1H-pyrazolo[4,3-b]pyridin-5-yl]-3-methylmorpholine (79)

[0860]

[0861] (3R)-4-[7-(3,6-Dihydro-2H-thiopyran-4-yl)-1-methyl-3-(1H-pyrazol-5-yl)-1H-pyrazolo[4,3-b]pyridin-5-yl]-3-methylmorpholine was prepared analogously to the above example, and a yellow solid (10 mg, 18%) was isolated; melting point 215 - 216 °C; 1 1H NMR (400 MHz, DMSO-d6): δ 13.05 (d, J = 108.8 Hz, 1H), 7.60 (s, 1H), 7.02 (s, 1H), 6.79 (s, 1H), 6.05 (d, J = 4.9 Hz, 1H), 4.44 (s, 1H), 4.01 (d, J = 9.5 Hz, 5H), 3.75 (d, J = 11.2 Hz, 1H), 3.68 (dd, J = 11.3, 3.0 Hz, 1H), 3.52 (td, J = 11.6, 3.1 Hz, 1H), 3.36 (d, J = 3.7 Hz, 2H), 3.14 (td, J = 12.6, 3.8 Hz, 1H), 2.92 (t, J = 5.7 Hz, 2H), 2.61 (s, 2H), 1.16 (d, J = 6.6 Hz, 3H);

[0862] LC / MS (Method D) Rt 1.129 min, [M+H]+ 397.1.

[0863] Example 80: 4-[1-Methyl-5-[(3R)-3-methylmorpholin-4-yl]-3-(1H-pyrazol-5-yl)-1H-pyrazolo[4,3-b]pyridin-7-yl]-3,6-dihydro-2H-1λ4-thiopyran-1-one (80)

[0864]

[0865] Structural unit for the synthesis of Example 80: 4-{1-Methyl-5-[(3R)-3-methylmorpholin-4-yl]-3-[1-(oxan-2-yl)-1H-pyrazol-5-yl]-1H-pyrazolo[4,3-b]pyridin-7-yl}-3,6-dihydro-2H-1λ4-thiopyran-1-one

[0866]

[0867] 4-[3-Bromo-1-methyl-5-[(3R)-3-methylmorpholin-4-yl]-1H-pyrazolo[4,3-b]pyridin-7-yl]-3,6-dihydro-2H-1λ4-thiopyran-1-one (100 mg, 0.21 mmol, 1.0 equiv), 1-(oxan-2-yl)-5-(tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (123.91 mg, 0.42 mmol, 2.0 equiv), Pd(dppf)Cl2·CH2Cl2 (19.20 mg, 0.02 mmol, 0.10 equiv), K3PO4 (141.83 mg, 0.63 mmol, 3.0 equiv), dioxane (12 mL) and water (3 mL) were combined and stirred in a microwave at 100 °C for 1 h. The resulting mixture was concentrated under vacuum. The residue was purified by column chromatography (Method E). 4-[1-Methyl-5-[(3R)-3-methylmorpholin-4-yl]-3-[1-(oxan-2-yl)-1H-pyrazol-5-yl]-1H-pyrazolo[4,3-b]pyridin-7-yl]-3,6-dihydro-2H-1λ4-thiopyran-1-one as a yellow oil was isolated (70 mg, 60%); LC / MS (Method P): Rt 0.875 min, [MH]+ 425.2.

[0868] Example 80: 4-[1-Methyl-5-[(3R)-3-methylmorpholin-4-yl]-3-(1H-pyrazol-5-yl)-1H-pyrazolo[4,3-b]pyridin-7-yl]-3,6-dihydro-2H-1λ4-thiopyran-1-one

[0869]

[0870] 4-[1-Methyl-5-[(3R)-3-methylmorpholin-4-yl]-3-[1-(oxan-2-yl)-1H-pyrazol-5-yl]-1H-pyrazolo[4,3-b]pyridin-7-yl]-3,6-dihydro-2H-1λ4-thiopyran-1-one (60 mg, 0.11 mmol, 1.0 equiv), dichloromethane (5 mL), and trifluoroacetic acid (1 mL) were combined and stirred at room temperature for 5 h. The resulting mixture was concentrated in vacuo. The crude product was purified by preparative HPLC (method J). 20 mg of 4-[1-Methyl-5-[(3R)-3-methylmorpholin-4-yl]-3-(1H-pyrazol-5-yl)-1H-pyrazolo[4,3-b]pyridin-7-yl]-3,6-dihydro-2H-1λ4-thiopyran-1-one as a red oil was obtained (20 mg, 32%); 1 1H NMR (400 MHz, methanol-d4): δ 7.81 (s, 1H), 7.06 (d, J = 14.8 Hz, 2H), 5.95 (d, J = 4.6 Hz, 1H), 4.44 (d, J = 7.6 Hz, 1H), 4.11 (d, J = 26.7 Hz, 4H), 4.00 (d, J = 13.0 Hz, 1H), 3.92 - 3.80 (m, 2H), 3.77 - 3.66 (m, 2H), 3.62 (dd, J = 18.3, 5.1 Hz, 1H), 3.47 (td, J = 12.5, 3.7 Hz, 1H), 3.39 (d, J = 12.8 Hz, 1H), 3.19 - 2.97 (m, 2H), 2.79 - 2.65 (m, 1H), 1.37 (d, J = 6.7 Hz, 3H);

[0871] LC / MS (method X): Rt 0.953 min, [MH]+ 413.1.

[0872] Example 81: 4-[1-Methyl-5-[(3R)-3-methylmorpholin-4-yl]-3-(1H-pyrazol-5-yl)-1H-pyrazolo[4,3-b]pyridin-7-yl]-3,6-dihydro-2H-1λ6-thiopyran-1,1-dione (81)

[0873]

[0874] Structural unit for the synthesis of Example 81: 4-{1-Methyl-5-[(3R)-3-methylmorpholin-4-yl]-1H-pyrazolo[4,3-b]pyridin-7-yl}-3,6-dihydro-2H-1λ6-thiopyran-1,1-dione

[0875]

[0876] 4-[1-Methyl-5-[(3R)-3-methylmorpholin-4-yl]-1H-pyrazolo[4,3-b]pyridin-7-yl]-3,6-dihydro-2H-1λ4-thiopyran-1-one (500 mg, 1.30 mmol, 1.0 eq), methanol (20 mL) and an aqueous solution (5 mL) of potassium peroxymonosulfate preparation (484 mg, 2.73 mmol, 2.10 eq) were combined and stirred at room temperature for 2 h. The resulting mixture was concentrated in vacuo. The residue was purified by column chromatography (Method A). 4-[1-Methyl-5-[(3R)-3-methylmorpholin-4-yl]-1H-pyrazolo[4,3-b]pyridin-7-yl]-3,6-dihydro-2H-1λ6-thiopyran-1,1-dione was isolated as a yellow oil (500 mg, 96%); LC / MS (Method T): Rt 0.833 min, [MH]+ 363.2.

[0877] Example 81: 4-[1-Methyl-5-[(3R)-3-methylmorpholin-4-yl]-3-(1H-pyrazol-5-yl)-1H-pyrazolo[4,3-b]pyridin-7-yl]-3,6-dihydro-2H-1λ6-thiopyran-1,1-dione

[0878]

[0879] 4-[1-Methyl-5-[(3R)-3-methylmorpholin-4-yl]-3-(1H-pyrazol-5-yl)-1H-pyrazolo[4,3-b]pyridin-7-yl]-3,6-dihydro-2H-1λ6-thiopyran-1,1-dione was prepared analogously to the above example and isolated as a yellow solid (15 mg, 25%); melting point 167 - 168 °C; 1 1H NMR (400 MHz, methanol-d4): δ 7.87 (d, J = 2.4 Hz, 1H), 7.10 (s, 1H), 7.04 (d, J = 2.3 Hz, 1H), 6.00 - 5.92 (m, 1H), 4.43 (d, J = 7.3 Hz, 1H), 4.16 (s, 3H), 4.09 (dd, J = 11.6, 3.8 Hz, 1H), 3.98 (d, J = 10.2 Hz, 3H), 3.89 - 3.81 (m, 2H), 3.73 - 3.66 (m, 1H), 3.53 (dd, J = 12.6, 3.9 Hz, 1H), 3.45 (d, J = 6.3 Hz, 2H), 3.15 (s, 2H), 1.38 (d, J = 6.8 Hz, 3H); LC / MS (Method D): Rt 0.869 min, [MH]+ 429.1.

[0880] Example 82: 4-[1-Methyl-5-[(3R)-3-methylmorpholin-4-yl]-3-(1H-pyrazol-5-yl)-1H-pyrazolo[4,3-b]pyridin-7-yl]-2H-1λ6-thiopyran-1,1-dione (82)

[0881]

[0882] 4-[1-Methyl-5-[(3R)-3-methylmorpholin-4-yl]-3-(1H-pyrazol-5-yl)-1H-pyrazolo[4,3-b]pyridin-7-yl]-2H-1λ6-thiopyran-1,1-dione was prepared analogously to the above example and isolated as a yellow solid (10 mg, 16%); melting point 189 - 190 °C; 1 H NMR (400 MHz, methanol-d4): δ 7.83 (d, J = 2.3 Hz, 1H), 7.07 (s, 1H), 6.98 (d, J = 2.2 Hz, 1H), 4.45 (d, J = 7.3 Hz, 1H), 4.36 (s, 3H), 4.10 (dd, J = 11.7, 3.7 Hz, 1H), 3.97 (d, J = 12.4 Hz, 1H), 3.91 - 3.67 (m, 4H), 3.61 - 3.47 (m, 3H), 3.22 (d, J = 13.9 Hz, 2H), 2.52 - 2.38 (m, 4H), 1.39 (d, J = 6.8 Hz, 3H); LC / MS (method D): Rt 0.831 min, [MH]+ 431.1.

[0883] Example 83: (3R)-3-Methyl-4-[3-(1H-pyrazol-3-yl)-1-[(pyridin-3-yl)methyl]-1H-pyrazolo[4,3-b]pyridin-5-yl]morpholine (83)

[0884]

[0885] (3R)-3-Methyl-4-[3-(1H-pyrazol-3-yl)-1-[(pyridin-3-yl)methyl]-1H-pyrazolo[4,3-b]pyridin-5-yl]morpholine hydrochloride was prepared analogously to the above example and isolated as a yellow solid (6 mg; 75%); 11H NMR (700 MHz, DMSO-d6): δ 8.82 - 8.80 (m, 1H), 8.76 - 8.74 (m, 1H), 8.16 - 8.13 (m, 2H), 7.82 (dd, J = 8.1, 5.4 Hz, 1H), 7.72 (d, J = 2.0 Hz, 1H), 7.16 (d, J = 9.5 Hz, 1H), 7.07 (d, J = 2.0 Hz, 1H), 5.83 (s, 2H), 4.44 - 4.40 (m, 1H), 4.02 (dd, J = 13.4, 2.8 Hz, 1H), 3.99 (dd, J = 11.3, 3.7 Hz, 1H), 3.76 (d, J = 11.1 Hz, 1H), 3.68 (dd, J = 11.2, 3.1 Hz, 1H), 3.53 (td, J = 11.7, 3.1 Hz, 1H), 3.15 (td, J = 12.7, 3.8 Hz, 1H), 1.16 (d, J = 6.7 Hz, 3H);

[0886] LC / MS (Method R): Rt 0.483 min; [M + H]+ 376.2.

[0887] Example 84: (3R)-4-[7-(1,5-Dimethyl-1H-1,2,3-triazol-4-yl)-1-methyl-3-(1H-pyrazol-3-yl)-1H-pyrazolo[4,3-b]pyridin-5-yl]-3-methylmorpholine (84)

[0888]

[0889] (3R)-4-[7-(1,5-Dimethyl-1H-1,2,3-triazol-4-yl)-1-methyl-3-(1H-pyrazol-3-yl)-1H-pyrazolo[4,3-b]pyridin-5-yl]-3-methylmorpholine was prepared analogously to the above example and isolated as a yellow solid (34 mg; 85%); 11H NMR (500 MHz, DMSO-d6): δ 13.23 - 12.90 (m, 1H), 7.84 - 7.57 (m, 1H), 7.14 - 7.01 (m, 1H), 6.95 - 6.87 (m, 1H), 4.48 - 4.37 (m, 1H), 4.07 (s, 3H), 4.10 - 4.05 (m, 1H), 4.02 - 3.97 (m, 1H), 3.82 - 3.74 (m, 4H), 3.70 (dd, J = 11.3, 3.0 Hz, 1H), 3.55 (td, J = 11.7, 3.0 Hz, 1H), 3.21 - 3.13 (m, 1H), 2.40 - 2.37 (m, 3H), 1.18 (d, J = 6.6 Hz, 3H); LC / MS (Method C): Rt 0.877 min; [M + H]+ 394.3.

[0890] Example 85: 2-Methyl-1-{5-[(3R)-3-methylmorpholin-4-yl]-3-(1H-pyrazol-3-yl)-1H-pyrazolo[4,3-b]pyridin-1-yl}propan-2-ol (85)

[0891]

[0892] Structural unit for the synthesis of Example 85: Methyl 2-{3-iodo-5-[(3R)-3-methylmorpholin-4-yl]-1H-pyrazolo[4,3-b]pyridin-1-yl}acetate

[0893]

[0894] (3R)-4-[3-Iodo-1H-pyrazolo[4,3-b]pyridin-5-yl]-3-methylmorpholine (200 mg, 0.52 mmol, 1 equiv), DMF (2 mL), methyl 2-bromoacetate (126.33 mg, 0.78 mmol, 1.50 equiv) and Cs2CO3 (358.76 mg, 1.05 mmol, 2.0 equiv) were combined and stirred at 25 °C for 2 h. The resulting mixture was concentrated in vacuo. The residue was purified by column chromatography (Method P). Methyl 2-[3-iodo-5-[(3R)-3-methylmorpholin-4-yl]-1H-pyrazolo[4,3-b]pyridin-1-yl]acetate was isolated as a yellow solid.

[0895] Structural unit for the synthesis of Example 85: Methyl 2-{5-[(3R)-3-methylmorpholin-4-yl]-3-[1-(oxan-2-yl)-1H-pyrazol-3-yl]-1H-pyrazolo[4,3-b]pyridin-1-yl}acetate

[0896]

[0897] Methyl 2-[3-iodo-5-[(3R)-3-methylmorpholin-4-yl]-1H-pyrazolo[4,3-b]pyridin-1-yl]acetate (200 mg, 0.43 mmol, 1.0 equiv), tetrahydrofuran (2 mL), sodium carbonate (96.50 mg, 0.86 mmol, 2 equiv), water (0.2 mL), 1-(oxan-2-yl)-3-(tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (189.94 mg, 0.65 mmol, 1.50 equiv) and Pd(PPh3)4 (55.53 mg, 0.04 mmol, 0.10 equiv) were combined and stirred in a microwave at 80 °C for 1 h. The resulting mixture was concentrated under vacuum. The residue was purified by column chromatography (Method P). Methyl 2-[5-[(3R)-3-methylmorpholin-4-yl]-3-[1-(oxan-2-yl)-1H-pyrazol-3-yl]-1H-pyrazolo[4,3-b]pyridin-1-yl]acetate was isolated as a yellow solid (100 mg; 48%).

[0898] Structural unit for the synthesis of Example 85: 2-methyl-1-{5-[(3R)-3-methylmorpholin-4-yl]-3-[1-(oxan-2-yl)-1H-pyrazol-3-yl]-1H-pyrazolo[4,3-b]pyridin-1-yl}propan-2-ol

[0899]

[0900] Methyl 2-[5-[(3R)-3-methylmorpholin-4-yl]-3-[1-(oxan-2-yl)-1H-pyrazol-3-yl]-1H-pyrazolo[4,3-b]pyridin-1-yl]acetate (90 mg, 0.18 mmol, 1.0 equiv), tetrahydrofuran (1 mL) and bromo(methyl)magnesium (461.62 mg, 3.68 mmol, 20 equiv) were combined and stirred at 25 °C for 5 h. The reaction was then quenched by the addition of water. The resulting mixture was concentrated under vacuum. The residue was purified by column chromatography (Method P). 2-Methyl-1-[5-[(3R)-3-methylmorpholin-4-yl]-3-[1-(oxan-2-yl)-1H-pyrazol-3-yl]-1H-pyrazolo[4,3-b]pyridin-1-yl]propan-2-ol was isolated as a brown solid (60 mg; 68%).

[0901] Example 85: 2-Methyl-1-{5-[(3R)-3-methylmorpholin-4-yl]-3-(1H-pyrazol-3-yl)-1H-pyrazolo[4,3-b]pyridin-1-yl}propan-2-ol

[0902]

[0903] 2-Methyl-1-{5-[(3R)-3-methylmorpholin-4-yl]-3-(1H-pyrazol-3-yl)-1H-pyrazolo[4,3-b]pyridin-1-yl}propan-2-ol was prepared in a similar manner to the above example and isolated as a colorless solid (8 mg, 22%); melting point 235 - 236 °C; 1 1H NMR (400 MHz, methanol-d4): δ 7.93 (d, J = 9.4 Hz, 1H), 7.66 (s, 1H), 7.07 (d, J = 9.4 Hz, 2H), 4.46 (d, J = 7.0 Hz, 1H), 4.35 (s, 2H), 4.10 - 3.99 (m, 2H), 3.84 (d, J = 2.2 Hz, 2H), 3.68 (td, J = 11.7, 3.1 Hz, 1H), 3.29 (d, J = 3.7 Hz, 1H), 1.27 (d, J = 10.4 Hz, 9H);

[0904] LC / MS (method E): Rt 1.034 min, [MH]+ 357.2.

[0905] Example 86: 2-Methyl-2-{5-[(3R)-3-methylmorpholin-4-yl]-3-(1H-pyrazol-3-yl)-1H-pyrazolo[4,3-b]pyridin-1-yl}propan-1-ol (86)

[0906]

[0907] 2-Methyl-2-{5-[(3R)-3-methylmorpholin-4-yl]-3-(1H-pyrazol-3-yl)-1H-pyrazolo[4,3-b]pyridin-1-yl}propan-1-ol was prepared in a similar manner to the above example and isolated as a yellow solid (50 mg, 52%); melting point 210 - 212 °C; 1 1H NMR (400 MHz, methanol-d4): δ 8.11 (d, J = 9.5 Hz, 1H), 7.64 (s, 1H), 7.27 - 6.97 (m, 2H), 4.45 (d, J = 13.1 Hz, 1H), 4.09 - 3.97 (m, 4H), 3.84 (d, J = 2.2 Hz, 2H), 3.68 (td, J = 11.7, 3.0 Hz, 1H), 3.36 - 3.25 (m, 1H), 1.75 (s, 6H), 1.27 (d, J = 6.7 Hz, 3H); LC / MS (method E): Rt 1.102 min, [MH]+ 357.2.

[0908] Example 87: (3R)-3-Methyl-4-[1-methyl-7-(4-methylpyrimidin-5-yl)-3-(1H-pyrazol-3-yl)-1H-pyrazolo[4,3-b]pyridin-5-yl]morpholine (87)

[0909]

[0910] (3R)-3-Methyl-4-[1-methyl-7-(4-methylpyrimidin-5-yl)-3-(1H-pyrazol-3-yl)-1H-pyrazolo[4,3-b]pyridin-5-yl]morpholine was prepared analogously to the above example and isolated as a yellow solid (15 mg, 20%); melting point 140 - 142 °C; 1 1H NMR (300 MHz, DMSO-d6): δ 9.17 (s, 1H), 8.76 (s, 1H), 7.63 (s, 1H), 7.01 (s, 1H), 6.96 (s, 1H), 4.44 (s, 1H), 4.14 - 3.90 (m, 2H), 3.72 (s, 2H), 3.65 - 3.52 (m, 1H), 3.50 (s, 3H), 3.25 (d, J = 10.7 Hz, 1H), 2.35 (s, 3H), 1.22 (d, J = 6.6 Hz, 3H); LC / MS (Method A) Rt 1.146 min, [MH]+ 391.2.

[0911] Example 88: (3R)-3-Methyl-4-[3-(1H-pyrazol-3-yl)-1-[(pyridin-2-yl)methyl]-1H-pyrazolo[4,3-b]pyridin-5-yl]morpholine (88)

[0912]

[0913] (3R)-3-Methyl-4-[3-(1H-pyrazol-3-yl)-1-[(pyridin-2-yl)methyl]-1H-pyrazolo[4,3-b]pyridin-5-yl]morpholine hydrochloride was prepared analogously to the above example and isolated as a yellow solid (62 mg; 92%); 11H NMR (500 MHz, DMSO-d6): δ 8.60 - 8.57 (m, 1H), 8.06 (d, J = 9.4 Hz, 1H), 7.88 (td, J = 7.7, 1.8 Hz, 1H), 7.73 (d, J = 2.0 Hz, 1H), 7.44 - 7.40 (m, 1H), 7.17 - 7.13 (m, 2H), 7.08 (d, J = 2.0 Hz, 1H), 5.82 (s, 2H), 4.45 - 4.39 (m, 1H), 4.05 - 3.97 (m, 2H), 3.79 - 3.75 (m, 1H), 3.69 (dd, J = 11.3, 3.1 Hz, 1H), 3.54 (td, J = 11.4, 2.8 Hz, 1H), 3.17 (td, J = 12.9, 3.8 Hz, 1H), 1.17 (d, J = 6.6 Hz, 3H); LC / MS (Method C): Rt 0.875 min; [M+H]+ 376.2.

[0914] Example 89: (3R)-4-[7-(1-Methanesulfonylethyl)-1-methyl-3-(1H-pyrazol-3-yl)-1H-pyrazolo[4,3-b]pyridin-5-yl]-3-methylmorpholine (89)

[0915]

[0916] Structural unit for the synthesis of Example 89: 3-Bromo-7-(1-methanesulfonylethyl)-1-methyl-5-((R)-3-methylmorpholin-4-yl)-1H-pyrazolo[4,3-b]pyridine

[0917]

[0918] 3-Bromo-7-methanesulfonylmethyl-1-methyl-5-((R)-3-methylmorpholin-4-yl)-1H-pyrazolo[4,3-b]pyridine (100 mg; 0.25 mmol; 1 equiv), toluene (1523 μl), water (170 μl), sodium hydroxide (199 mg; 20.07 equiv), tetra-n-butylammonium iodide (8.24 mg; 0.02 mmol; 0.09 equiv), dichloromethane (170 μl) and iodomethane (30.99 μl; 0.50 mmol; 2 equiv) were combined and stirred at 80 °C for 3 h. The reaction mixture was extracted with water and DCM. The combined organic layers were concentrated under reduced pressure. 3-Bromo-7-(1-methanesulfonylethyl)-1-methyl-5-((R)-3-methylmorpholin-4-yl)-1H-pyrazolo[4,3-b]pyridine as a yellow solid was isolated (130 mg, 55%); LC / MS (Method F): Rt 2.433 min; [M+H]+ 417.1.

[0919] Example 89: (3R)-4-[7-(1-Methanesulfonylethyl)-1-methyl-3-(1H-pyrazol-3-yl)-1H-pyrazolo[4,3-b]pyridin-5-yl]-3-methylmorpholine

[0920]

[0921] (3R)-4-[7-(1-Methanesulfonylethyl)-1-methyl-3-(1H-pyrazol-3-yl)-1H-pyrazolo[4,3-b]pyridin-5-yl]-3-methylmorpholine was prepared analogously to the above example and isolated as a yellow solid (20 mg, 30%); 1 H NMR (500 MHz, DMSO-d6): δ 13.42–12.64 (m, 1H), 7.68–7.62 (m, 1H), 7.04 (d, J = 5.0 Hz, 1H), 7.02–6.99 (m, 1H), 5.29–5.22 (m, 1H), 4.45–4.38 (m, 1H), 4.28 (s, 3H), 4.04–3.97 (m, 2H), 3.79–3.75 (m, 1H), 3.73–3.69 (m, 1H), 3.59–3.52 (m, 1H), 3.20–3.12 (m, 1H), 3.13 (d, J = 9.9 Hz, 3H), 1.85 (d, J = 6.9 Hz, 3H), 1.18–1.13 (m, 3H); LC / MS (Method F): Rt 2.022 min; [MH]+ 405.2.

[0922] The following examples relate to medicaments:

[0923] Example A: Injection vial

[0924] The solution of 100 g of the active ingredient of formula I and 5 g of disodium hydrogen phosphate in 3 l of double-distilled water was adjusted to pH 6.5 with 2N hydrochloric acid, sterile filtered, transferred to injection vials, freeze-dried under sterile conditions and sealed under sterile conditions. Each injection vial contains 5 mg of the active ingredient.

[0925] Example B: Suppository

[0926] 20 g of the active ingredient of formula I was melted with a mixture of 100 g of soya lecithin and 1400 g of cocoa butter, poured into moulds and allowed to cool. Each suppository contains 20 mg of the active ingredient.

[0927] Example C: Solution

[0928] A solution is prepared from 1 g of the active ingredient of formula I, 9.38 g of NaH2PO4·2H2O, 28.48 g of Na2HPO4·12H2O and 0.1 g of benzalkonium chloride in 940 ml of double-distilled water. The pH is adjusted to 6.8, the solution is made up to 1 l and sterilized by irradiation. The solution can be used in the form of eye drops.

[0929] Example D: Ointment

[0930] 500 mg of the active ingredient of formula I is mixed with 99.5 g of petrolatum under aseptic conditions.

[0931] Example E: Tablets

[0932] A mixture of 1 kg of the active ingredient of formula I, 4 kg of lactose, 1.2 kg of potato starch, 0.2 kg of talc and 0.1 kg of magnesium stearate is compressed into tablets in a conventional manner such that each tablet contains 10 mg of the active ingredient.

[0933] Example F: Sugar-coated Pills

[0934] Tablets are compressed analogously to Example E and subsequently coated in a conventional manner with a coating material of sucrose, potato starch, talc, tragacanth and dye.

[0935] Example G: Capsules

[0936] 2 kg of the active ingredient of formula I is added to hard gelatin capsules in a conventional manner such that each capsule contains 20 mg of the active ingredient.

[0937] Example H: Ampoules

[0938] A solution of 1 kg of the active ingredient of formula I in 60 l of double-distilled water is aseptically filtered, transferred to ampoules, freeze-dried under aseptic conditions and sealed under aseptic conditions. Each ampoule contains 10 mg of the active ingredient.

Claims

1. Compounds of formula Ia or Ib wherein R 1 represents H, Het, Ar, (CH2) n OH, 1 - mesyl - cyclopropyl - 1 - yl, CONH2, CONHA, CONA2, Cyc, OA or CH(A)SO2A, R 2 represents H, A, (CH2) n Ar, (CH2) n Cyc or (CH2) n Het, R 3 represents H or A, Het represents 1H-pyrrolo[2,3-b]pyridinyl, 1H-pyrrolo[2,3-c]pyridinyl, indolyl, benzimidazolyl, imidazolyl, 1,2,3,4-tetrahydroisoquinolinyl, pyridinyl, pyrimidinyl, triazolyl, pyrazolyl, quinolinyl, isoquinolinyl, quinazolinyl, furanyl, tetrahydrofuranyl, pyranyl, 3,6-dihydro-2H-pyranyl, tetrahydropyranyl, 3,6-dihydro-2H-thiopyranyl or hexahydro-thiopyranyl, each of which is unsubstituted or mono-, di- or tri-substituted by A, SOA, SO2A, Hal and / or ═O, Ar represents phenyl, naphthyl or biphenyl, each of which is unsubstituted or substituted by NH2, NHA, NA2, COOH, COOA, CONH2, CONHA, CONA2, NHCOA, CHO, COA, SO3H, SO2NH2, O(CH2) p NH2, (CH2) n Het 1 , O(CH2) n Het 1 、(CH2) n Ar 1 、O(CH2) n Ar 1 、O(CH2) p CONH2、O(CH2) p NHCOA、Hal、SOA、S(=O,=NH)A、SO2A、A、CN and / or (CH2) n mono-, di- or tri-substituted by OH, Ar 1 represents phenyl which is unsubstituted or mono-, di- or tri-substituted by Hal, A, OH and / or OA, Without further substitution, Het 1 represents 2- or 3-furyl, 2- or 3-thienyl, 1-, 2- or 3-pyrrolyl, 1-, 2-, 4- or 5-imidazolyl, 1-, 3-, 4- or 5-pyrazolyl, 2-, 4- or 5-oxazolyl, 3-, 4- or 5-isoxazolyl, 2-, 4- or 5-thiazolyl, 3-, 4- or 5-isothiazolyl, 2-, 3- or 4-pyridyl, 2-, 4-, 5- or 6-pyrimidinyl, A represents a straight-chain or branched alkyl having 1-6 C atoms, where 1-7 H atoms may be replaced by OH, F, Cl and / or Br, and / or where one or two non-adjacent CH2 groups may be replaced by O and / or NH groups, Cyc represents a cycloalkyl having 3, 4, 5, 6 or 7 C atoms, Hal represents F, Cl, Br or I, n represents 0, 1, 2, 3 or 4, p represents 1, 2, 3 or 4, and their pharmaceutically acceptable salts.

2. The compound according to claim 1, wherein Ar represents phenyl, which is unsubstituted or mono-, di- or trisubstituted by SOA, S(=O,=NH)A, SO2A, A, CN and / or (CH2) n OH, and its pharmaceutically acceptable salts.

3. The compound according to claim 1 or 2, wherein R 1 represents H, Het, Ar, (CH2) n OH, 1 - mesyl - cycloprop - 1 - yl, CONH2, CONHA, CONA2, Cyc, OA or CH(A)SO2A, R 2 represents H, A, (CH2) n Ar, (CH2) n Cyc or (CH2) n Het, R 3 represents H or A, Ar represents phenyl, which is unsubstituted or mono-, di- or trisubstituted by SOA, S(=O,=NH)A, SO2A, A, CN and / or (CH2) n OH A represents a straight-chain or branched alkyl having 1-6 C atoms, where 1-7 H atoms may be replaced by OH, F, Cl and / or Br, and / or where one or two non-adjacent CH2 groups may be replaced by O and / or NH groups, Cyc represents a cycloalkyl having 3, 4, 5, 6 or 7 C atoms, Hal represents F, Cl, Br or I, n represents 0, 1, 2, 3 or 4, and their pharmaceutically acceptable salts.

4. The compound according to claim 1, which is selected from and its pharmaceutically acceptable salts.

5. The compound according to claim 1, wherein Het 1 represents 1,2,3-triazol-1-yl, -4-yl or -5-yl, 1,2,4-triazol-1-yl, -3-yl or -5-yl, 1-yl or 5-yl tetrazolyl, 1,2,3-oxadiazol-4-yl or -5-yl, 1,2,4-oxadiazol-3-yl or -5-yl, 1,3,4-thiadiazol-2-yl or -5-yl, 1,2,4-thiadiazol-3-yl or -5-yl, 1,2,3-thiadiazol-4-yl or -5-yl, 3-yl or 4-yl pyridazinyl, pyrazinyl, 1-yl, 2-yl, 3-yl, 4-yl, 5-yl, 6-yl or 7-yl indolyl, 4-yl or 5-yl isoindolyl, indazolyl, 1-yl, 2-yl, 4-yl or 5-yl benzimidazolyl, 1-yl, 3-yl, 4-yl, 5-yl, 6-yl or 7-yl benzopyrazolyl, 2-yl, 4-yl, 5-yl, 6-yl or 7-yl benzoxazolyl, 3-yl, 4-yl, 5-yl, 6-yl or 7-yl benzisoxazolyl, 2-yl, 4-yl, 5-yl, 6-yl or 7-yl benzothiazolyl, 2-yl, 4-yl, 5-yl, 6-yl or 7-yl benzisothiazolyl, 4-yl, 5-yl, 6-yl or 7-yl benzo-2,1,3-oxadiazolyl, 2-yl, 3-yl, 4-yl, 5-yl, 6-yl, 7-yl or 8-yl quinolinyl, 1-yl, 3-yl, 4-yl, 5-yl, 6-yl, 7-yl or 8-yl isoquinolinyl, 3-yl, 4-yl, 5-yl, 6-yl, 7-yl or 8-yl cinnolinyl, 2-yl, 4-yl, 5-yl, 6-yl, 7-yl or 8-yl quinazolinyl, 5-yl or 6-yl quinoxalinyl, 2-yl, 3-yl, 5-yl, 6-yl, 7-yl or 8-yl 2H-benzo-1,4-oxazinyl, pyrrolopyridinyl, purinyl.

6. The compound according to claim 1, wherein Het 1 represents 1,3-benzodioxol-5-yl, 1,4-benzodioxan-6-yl, 2,1,3-benzothiadiazol-4- or -5-yl, 2,1,3-benzoxadiazol-5-yl, azabicyclo[3.2.1]octyl or dibenzofuranyl.

7. A medicament, which comprises at least one compound of formula Ia or Ib according to claim 1 and / or its pharmaceutically acceptable salt, and optionally a pharmaceutically acceptable carrier, excipient or vehicle.

8. Use of a compound of formula Ia or Ib according to claim 1 and its pharmaceutically acceptable salt in the manufacture of a medicament for the treatment and / or prevention of cancer, age-related macular degeneration (AMD), choroidal neovascularization (CNV), diabetic retinopathy, diabetic macular edema (DME), progressive osseous heteroplasia, inflammation, angiogenesis-related disorders and bacterial infections.

9. The use according to claim 8, wherein the medicament is for the treatment and / or prevention of diseases selected from cancers, solid tumors and hematogenous tumors of the head, neck, eye, mouth, throat, esophagus, bronchus, larynx, pharynx, chest, bone, lung, colon, rectum, stomach, prostate, bladder, uterus, cervix, breast, ovary, testis or other reproductive organs, skin, thyroid, blood, lymph nodes, kidney, liver, pancreas, brain, central nervous system.

10. A medicament comprising at least one compound of formula Ia or Ib according to claim 1 and / or a pharmaceutically acceptable salt thereof, and at least one further pharmaceutically active ingredient.

11. A group consisting of the following individual packages: (a) An effective amount of a compound of formula Ia or Ib according to claim 1 and / or a pharmaceutically acceptable salt thereof, and (b) An effective amount of a further pharmaceutically active ingredient.

12. The group according to claim 11, wherein the group is a kit.

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