Amino-pyrimidine cyclic amide

Abstract

The present invention relates to a compound represented by general formula (I) TIFF2023529638000040.tif30169 Novel compounds having the formula 1 , R 2 , R 3 and n is as defined herein), compositions comprising the compounds and methods of using the compounds are provided.

Description

Technical Field

[0001] The present invention relates to organic compounds useful for the treatment or prevention in mammals, in particular inhibitors of lysophosphatidic acid (LPA) production, and thus autotaxin (ATX) inhibitors which are modulators of LPA levels and related signal transduction, for the treatment or prevention of kidney symptoms, liver symptoms, inflammatory symptoms, nervous system symptoms, respiratory system symptoms, vascular and cardiovascular symptoms, fibrotic diseases, cancer, eye symptoms, metabolic symptoms, cholestasis and other forms of chronic pruritus as well as acute and chronic organ transplant rejection.

[0002] The present invention relates to novel compounds of formula (I),

Chemical Formula

[0003] Furthermore, the present invention includes all racemic mixtures, all their corresponding enantiomers and / or optical isomers.

Background Art

[0004] Autotaxin (ATX) is a secreted enzyme also known as ectonucleotide pyrophosphatase / phosphodiesterase 2 or lysophospholipase D, which is important for converting lysophosphatidylcholine (LPC) into the bioactive signaling molecule lysophosphatidic acid (LPA). Plasma LPA levels have been shown to be well correlated with ATX activity, and thus ATX is considered an important source of extracellular LPA. Initial experiments using prototype ATX inhibitors have shown that such compounds can inhibit LPA synthetic activity in mouse plasma. Studies conducted in the 1970s and early 1980s demonstrated that LPA can induce a wide range of cellular responses, including smooth muscle cell contraction, platelet activation, cell proliferation, chemotaxis, etc. LPA mediates its effects via signaling to several G protein-coupled receptors (GPCRs). Initially meaning Edg (endothelial cell differentiation gene) receptors or ventricular zone gene 1 (vzg-1), they are now called LPA receptors. At this time, the prototype group consists of LPA1 / Edg-2 / VZG-1, LPA2 / Edg-4, and LPA3 / Edg-7. Recently, three additional LPA receptors, LPA4 / p2y9 / GPR23, LPA5 / GPR92, and LPA6 / p2Y5, which are more closely related to nucleotide-selective purinergic receptors than the prototype LPA1-3 receptors, have been described. The ATX-LPA signaling axis is involved in a wide range of physiological and pathophysiological functions, including, for example, nervous system function, angiogenesis, cardiovascular physiology, reproduction, immune system function, chronic inflammation, tumor metastasis and progression, organ fibrosis, and other metabolic diseases such as obesity and / or type 2 diabetes. Therefore, an increase in ATX activity and / or an increase in LPA levels, changes in LPA receptor expression, and changes in the response to LPA can contribute to the initiation, progression, and / or outcome of several different pathophysiological conditions related to the ATX / LPA axis.

[0005] According to the present invention, the compound of formula (I) or a pharmaceutically acceptable salt and ester thereof can be used for treating or preventing diseases, disorders or symptoms associated with the activity of autotaxin and / or the biological activity of lysophosphatidic acid (LPA).

[0006] The compound of formula (I) or a pharmaceutically acceptable salt and ester thereof herein inhibits autotaxin activity, thus inhibiting LPA production and regulating LPA levels and related signal transduction. The autotaxin inhibitors described herein are useful as agents for treating or preventing diseases or symptoms in which ATX activity and / or LPA signaling is involved, is involved in the etiology or pathology of the disease, or is otherwise associated with at least one manifestation of the disease. The ATX-LPA axis is involved in, for example, angiogenesis, chronic inflammation, autoimmune diseases, fibrotic diseases, cancer and tumor metastasis and progression, ocular symptoms, metabolic symptoms such as obesity and / or type 2 diabetes, symptoms such as biliary stasis or other forms of chronic pruritus, and acute and chronic organ transplant rejection.

Summary of the Invention

[0007] The object of the present invention is a compound of formula (I) and its aforementioned salts and esters and their use as therapeutically active substances, a method for producing the above compound, an intermediate, a pharmaceutical composition, a pharmaceutical product containing the above compound, their pharmaceutically acceptable salts or esters, the activity of ATX and / or the biological activity of lysophosphatidic acid (LPA) related disorders or symptoms for treatment or prevention, particularly kidney symptoms, liver symptoms, inflammatory symptoms, nervous system symptoms, respiratory system symptoms, vascular and cardiovascular symptoms, fibrotic diseases, cancer, eye symptoms, metabolic symptoms, cholestasis and other forms of chronic pruritus and acute and chronic organ transplant rejection treatment or prevention of the above compounds, salts or esters, kidney symptoms, liver symptoms, inflammatory symptoms, nervous system symptoms, respiratory system symptoms, vascular and cardiovascular symptoms, fibrotic diseases, cancer, eye symptoms, metabolic symptoms, cholestasis and other forms of chronic pruritus and acute and chronic organ transplant rejection treatment or prevention of pharmaceutical products for the manufacture of the above compounds, salts or esters. More specifically, a compound of formula (I) and its aforementioned salts and esters and their use as therapeutically active substances, a method for producing the above compound, an intermediate, a pharmaceutical composition, a pharmaceutical product containing the above compound, their pharmaceutically acceptable salts or esters, eye symptoms, and more particularly glaucoma treatment or prevention of the above compounds, salts or esters.

Mode for carrying out the invention

[0008] The term "C1-6-alkoxy" means a group of the formula -O-R' where R' is a C1-6-alkyl group. Examples of C1-6-alkoxy groups include methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, isobutoxy, tert-butoxy.

[0009] 「C1-6-alkoxy-C 1-6The term "-alkyl" means a C1-6-alkyl group in which at least one hydrogen atom of the C1-6-alkyl group is replaced by a C1-6-alkoxy group. Specific examples are methoxymethyl, methoxyethyl, ethoxymethyl, ethoxyethyl, isopropoxymethyl and isopropoxyethyl.

[0010] The term "C1-6-alkyl" means a monovalent straight-chain or branched saturated hydrocarbon group having 1 to 6 carbon atoms. In some embodiments, unless otherwise specified, alkyl includes 1 to 6 carbon atoms (C1-6-alkyl) or 1 to 4 carbon atoms (C1-4-alkyl). Examples of C1-6-alkyl include methyl, ethyl, propyl, isopropyl, n-butyl, iso-butyl, sec-butyl, tert-butyl and pentyl. Specific alkyl groups include methyl, isopropyl and tert-butyl. When an alkyl residue having a specific number of carbons is named, all geometric isomers having that number of carbons can be included. Thus, for example, "butyl" can include n-butyl, sec-butyl, iso-butyl and t-butyl, and "propyl" can include n-propyl and isopropyl.

[0011] The term "carbonyl" means a -C(O)- group.

[0012] The term "cyano" means a -C≡N group.

[0013] The term "C3-8-cycloalkyl" means a monocyclic or polycyclic saturated or partially unsaturated non-aromatic hydrocarbon. In some embodiments, unless otherwise specified, cycloalkyl contains 3 to 8 carbon atoms (C3-8-cycloalkyl), 3 to 6 carbon atoms (C3-6-cycloalkyl) or 3 to 5 carbon atoms (C3-5-cycloalkyl). In some embodiments, cycloalkyl is a saturated monocyclic or polycyclic hydrocarbon. In other embodiments, cycloalkyl contains one or more double bonds (e.g., cycloalkyl fused to an aryl ring or heteroaryl ring, or a non-aromatic monocyclic hydrocarbon containing one or two double bonds). The polycyclic cycloalkyl group may contain a spiro, fused or bridged polycyclic moiety, and each ring is a saturated or partially unsaturated non-aromatic hydrocarbon. Examples of monocyclic cycloalkyl are cyclopropyl, cyclobutanil, cyclopentyl, cyclohexyl, hydroxycyclobutyl, difluorocyclobutyl, difluoro-methyl-cyclobutyl and methylcyclopropyl. An example of bicyclic cycloalkyl is difluorospiroheptanyl.

[0014] The term "cycloalkylalkyl" means an alkyl group in which at least one of the hydrogen atoms of the alkyl group is replaced by a cycloalkyl group. Examples of cycloalkylalkyl include cyclopropylmethyl, cyclopropylethyl, cyclopropylbutyl, cyclobutylpropyl, 2-cyclopropylbutyl, cyclopentylbutyl, cyclohexylmethyl, cyclohexylethyl and hydroxycyclopropylmethyl.

[0015] The terms "halogen", "halide" and "halo" are used interchangeably herein and mean fluoro, chloro, bromo or iodo. A particular halogen is chloro.

[0016] The term "halo-C1-6-alkoxy" means a C1-6-alkoxy group in which at least one of the hydrogen atoms of the C1-6-alkoxy group is replaced by the same or different halogen atoms. Specific examples are difluoromethoxy, trifluoromethoxy, difluoroethoxy and trifluoroethoxy.

[0017] The term "halo-C1-6-alkyl" means a C1-6-alkyl group in which at least one of the hydrogen atoms of the C1-6-alkyl group is replaced by the same or different halogen atoms. Specific examples are fluoroethyl, difluoromethyl, trifluoromethyl, difluoroethyl, trifluoroethyl and 2-fluoro-1-(fluoromethyl)ethyl.

[0018] The term "heterocycloalkyl" means a monovalent saturated or partially unsaturated monocyclic or bicyclic ring system consisting of 4 to 9 ring atoms, containing 1, 2, or 3 ring heteroatoms selected from N, O, and S alone or in combination, with the remaining ring atoms being carbon. Bicyclic means consisting of two rings having at least one ring atom in common. The heterocycloalkyl group may be saturated or unsaturated and, unless otherwise specified, may contain 5, 6, 7, 8, or 9 ring atoms, and the ring atoms refer to the total of carbon atoms and heteroatoms in one or more (e.g., 5-membered, 6-membered, 7-membered, 8-membered, or 9-membered heterocycloalkyl) rings. Heterocycloalkyl may include groups containing 1 to 5 ring heteroatoms, 1 to 4 heteroatoms, 1 to 3 ring heteroatoms, 1 or 2 ring heteroatoms, or 1 ring heteroatom. In some embodiments, heterocycloalkyl includes, for example, as a polycyclic fused system, 1 ring, 2 rings, 3 rings, 4 rings, or more than 4 rings. In some embodiments, heterocycloalkyl containing multiple rings includes a spiro ring system in which one or more rings contain one or more heteroatoms. Examples of monocyclic heterocycloalkyl are oxetanyl, methyloxetanyl, tetrahydropyranyl, acetylpiperidyl, tetrahydrofuranyl.

[0019] The term "heterocycloalkylalkyl" means an alkyl group in which at least one hydrogen atom of the alkyl group is replaced by a heterocycloalkyl group. Examples of heterocycloalkylalkyl include oxetanylmethyl and (methyloxetanyl)methyl.

[0020] The term "hydroxy" means an -OH group.

[0021] "Hydroxy-C 1-6 -alkyl" means a C 1-6 -alkyl group in which one hydrogen atom of the C 1-6 -alkyl group is replaced by a hydroxy group. Specific examples are hydroxymethyl, hydroxyethyl and hydroxymethylpropyl.

[0022] The term "pharmaceutically acceptable salt" refers to salts that retain the biological effectiveness and properties of the free base or free acid and are not biologically or otherwise undesirable. Salts are formed with inorganic acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, etc., especially hydrochloric acid, and organic acids such as acetic acid, propionic acid, glycolic acid, pyruvic acid, oxalic acid, maleic acid, malonic acid, succinic acid, fumaric acid, tartaric acid, citric acid, benzoic acid, cinnamic acid, mandelic acid, methanesulfonic acid, ethanesulfonic acid, p-toluenesulfonic acid, salicylic acid, N-acetylcysteine, etc. These salts may also be prepared by adding an inorganic base or an organic base to the free acid. Salts derived from inorganic bases include, but are not limited to, sodium, potassium, lithium, ammonium, calcium, and magnesium salts, etc. Salts derived from organic bases include salts of primary, secondary, and tertiary amines, substituted amines including naturally occurring substituted amines, cyclic amines, and basic ion exchange resins such as isopropylamine, trimethylamine, diethylamine, triethylamine, tripropylamine, ethanolamine, lysine, arginine, N-ethylpiperidine, piperidine, polyimine resins, etc., but are not limited to these. Particularly pharmaceutically acceptable salts of the compound of formula (I) include hydrochloride, methanesulfonate, citrate, etc.

[0023] "Pharmaceutically acceptable ester" means that a compound of general formula (I) is derivatized with a functional group to provide a derivative that can be converted back to the parent compound in vivo. Examples of such compounds include physiologically acceptable and metabolically soluble ester derivatives such as methoxymethyl ester, methylthiomethyl ester, pivaloyloxymethyl ester, etc. Further, any physiologically acceptable equivalents of the compound of general formula (I) that are similar to metabolically labile esters that can be produced in vivo from the parent compound of general formula (I) are also within the scope of the present invention.

[0024] The abbreviation uM means micromole and corresponds to the symbol μM.

[0025] The abbreviation "uL" means microliter and corresponds to the symbol μL.

[0026] The abbreviation "ug" means microgram and corresponds to the symbol μg.

[0027] The compounds of formula (I) may contain several chiral centers and can exist as optically pure enantiomers, mixtures of enantiomers such as racemates, optically pure diastereoisomers, mixtures of diastereoisomers, racemates of diastereoisomers or mixtures of racemates of diastereoisomers.

[0028] According to the Cahn-Ingold-Prelog rules, chiral carbon atoms can have the "R" or "S" configuration.

[0029] Also, embodiments of the present invention provide compounds of formula (I) described herein and pharmaceutically acceptable salts or esters thereof, in particular compounds of formula (I) described herein and pharmaceutically acceptable salts thereof, in particular compounds of formula (I) described herein.

[0030] Specific embodiments of the present invention are compounds of formula (I) described herein, wherein R 1 is i) H, ii) C 1-6 -alkyl, iii) C 3-8 -cycloalkyl, iv) C 3-8 -cycloalkylalkyl, v) C 1-6 -alkoxy, vi) C 1-6 -alkoxy-C 1-6 -alkyl, vii) heterocycloalkyl, viii) heterocycloalkylalkyl, ix) substituted C 3-8 -cycloalkyl, x) substituted C 3-8-Cycloalkylalkyl, xi) Substituted heterocycloalkyl, xii) Substituted heterocycloalkylalkyl, xiii) Halo-C 1-6 -alkyl, xiv) Hydroxy-C 1-6 -alkyl, selected from the group consisting of, Substituted C 3-8 -cycloalkyl or substituted heterocycloalkyl is substituted with one or more substituents selected from H, C 1-6 -alkyl, halogen, hydroxy, and C 1-6 -carbonyl, R 2 is, i) H, ii) halogen, iii) Halo-C 1-6 -alkyl, iv) C 1-6 -alkyl, v) cyano, selected from the group consisting of wherein R 1 and R 2 at least one of which is other than H, R 3 is, i) H, ii) halogen, selected from the group consisting of n is 0 or 1, A compound, or a pharmaceutically acceptable salt thereof, is provided.

[0031] A particular embodiment of the invention provides a compound according to formula (I) herein, wherein R 3 is halogen.

[0032] A further particular embodiment of the invention provides a compound according to formula (I) herein, wherein R 3 is Cl.

[0033] Another further particular embodiment of the invention provides a compound according to formula (I) herein, wherein R 2 is i) H, ii) Provide a compound of formula (I) as described herein, selected from the group consisting of cyano.

[0034] Certain embodiments of the invention have R 1 being i) H, ii) C 1-6 -alkyl, iii) C 3-8 -cycloalkyl, iv) C 3-8 -cycloalkylalkyl, v) C 1-6 -alkoxy, vi) C 1-6 -alkoxy-C 1-6 -alkyl, vii) heterocycloalkyl, viii) heterocycloalkylalkyl, ix) substituted C 3-8 -cycloalkyl, x) substituted C 3-8 -cycloalkylalkyl, xi) substituted heterocycloalkyl, xii) substituted heterocycloalkylalkyl, xiii) halo-C 1-6 -alkyl, xiv) hydroxy-C 1-6 -alkyl, and is selected from the group consisting of, substituted C 3-8 -cycloalkyl or substituted heterocycloalkyl is substituted with one or more substituents selected from H, C 1-6 -alkyl, halogen, hydroxy, and C 1-6 -carbonyl, and "heterocycloalkyl" is a 4- to 6-atom ring system containing one heteroatom selected from N and O, and provides a compound of formula (I) as described herein.

[0035] Certain embodiments of the invention have R 3 being Cl, R 2 being H or cyano, R 1 being i) H, ii) C 1-6 -alkyl, iii) C 3-8 -cycloalkyl, iv) C 3-8 -cycloalkylalkyl, v) C 1-6 -alkoxy, vi) C 1-6 -alkoxy-C 1-6 -alkyl, vii) heterocycloalkyl, viii) heterocycloalkylalkyl, ix) substituted C 3-8 -cycloalkyl, x) substituted C 3-8 -cycloalkylalkyl, xi) substituted heterocycloalkyl, xii) substituted heterocycloalkylalkyl, xiii) halo-C 1-6 -alkyl, xiv) hydroxy-C 1-6 -alkyl, and is selected from the group consisting of, substituted C 3-8 -cycloalkyl or substituted heterocycloalkyl is substituted with one or more substituents selected from H, C 1-6 -alkyl, halogen, hydroxy, and C 1-6 -carbonyl, "heterocycloalkyl" is a 4- to 6-membered ring system containing one heteroatom selected from N and O, wherein R 1 and R 2 at least one of is other than H, n is 0 or 1, There is provided a compound according to formula I described herein, or a pharmaceutically acceptable salt.

[0036] Specific examples of the compounds of formula (I) described herein are 2-((5-Chloro-2,3-dihydro-1H-inden-2-yl)amino)-6-(oxetan-3-yl)-6,7-dihydro-5H-pyrrolo[3,4-d]pyrimidin-5-one, 2-((5-Chloro-2,3-dihydro-1H-inden-2-yl)amino)-6-(3-methyloxetan-3-yl)-6,7-dihydro-5H-pyrrolo[3,4-d]pyrimidin-5-one, (S)-6-Chloro-2-((6-(3-methyloxetan-3-yl)-5-oxo-6,7-dihydro-5H-pyrrolo[3,4-d]pyrimidin-2-yl)amino)-2,3-dihydro-1H-inden-4-carbonitrile, 2-((5-Chloro-2,3-dihydro-1H-inden-2-yl)amino)-6-(6,6-difluorospiro[3.3]heptan-2-yl)-6,7-dihydro-5H-pyrrolo[3,4-d]pyrimidin-5-one, 2-((5-Chloro-2,3-dihydro-1H-inden-2-yl)amino)-6-(3,3-difluorocyclobutyl)-6,7-dihydro-5H-pyrrolo[3,4-d]pyrimidin-5-one, (S)-6-Chloro-2-((6-(3,3-difluoro-1-methylcyclobutyl)-5-oxo-6,7-dihydro-5H-pyrrolo[3,4-d]pyrimidin-2-yl)amino)-2,3-dihydro-1H-inden-4-carbonitrile, (S)-6-Chloro-2-((6-(6,6-difluorospiro[3.3]heptan-2-yl)-5-oxo-6,7-dihydro-5H-pyrrolo[3,4-d]pyrimidin-2-yl)amino)-2,3-dihydro-1H-inden-4-carbonitrile, (S)-6-Chloro-2-((6-(3,3-difluorocyclobutyl)-5-oxo-6,7-dihydro-5H-pyrrolo[3,4-d]pyrimidin-2-yl)amino)-2,3-dihydro-1H-inden-4-carbonitrile, (S)-6-Chloro-2-((5-oxo-6-(tetrahydro-2H-pyran-4-yl)-6,7-dihydro-5H-pyrrolo[3,4-d]pyrimidin-2-yl)amino)-2,3-dihydro-1H-inden-4-carbonitrile, (S)-6-Chloro-2-((5-oxo-6-(2,2,2-trifluoroethyl)-6,7-dihydro-5H-pyrrolo[3,4-d]pyrimidin-2-yl)amino)-2,3-dihydro-1H-inden-4-carbonitrile, (S,S) and (S,R)-6-Chloro-2-((5-oxo-6-(tetrahydrofuran-3-yl)-6,7-dihydro-5H-pyrrolo[3,4-d]pyrimidin-2-yl)amino)-2,3-dihydro-1H-inden-4-carbonitrile, (S)-6-Chloro-2-((6-isopropyl-5-oxo-6,7-dihydro-5H-pyrrolo[3,4-d]pyrimidin-2-yl)amino)-2,3-dihydro-1H-inden-4-carbonitrile, (S)-6-Chloro-2-((6-cyclopropyl-5-oxo-6,7-dihydro-5H-pyrrolo[3,4-d]pyrimidin-2-yl)amino)-2,3-dihydro-1H-inden-4-carbonitrile, (S)-6-Chloro-2-((6-(oxetan-3-ylmethyl)-5-oxo-6,7-dihydro-5H-pyrrolo[3,4-d]pyrimidin-2-yl)amino)-2,3-dihydro-1H-inden-4-carbonitrile, (S)-6-Chloro-2-((6-(1-methylcyclopropyl)-5-oxo-6,7-dihydro-5H-pyrrolo[3,4-d]pyrimidin-2-yl)amino)-2,3-dihydro-1H-inden-4-carbonitrile, (S)-6-Chloro-2-((6-(oxetan-3-yl)-5-oxo-6,7-dihydro-5H-pyrrolo[3,4-d]pyrimidin-2-yl)amino)-2,3-dihydro-1H-inden-4-carbonitrile, (S)-6-Chloro-2-((6-(oxetan-3-yl)-5-oxo-5,6,7,8-tetrahydropyrido[4,3-d]pyrimidin-2-yl)amino)-2,3-dihydro-1H-inden-4-carbonitrile, (S)-6-Chloro-2-((6-(cyclopropylmethyl)-5-oxo-6,7-dihydro-5H-pyrrolo[3,4-d]pyrimidin-2-yl)amino)-2,3-dihydro-1H-inden-4-carbonitrile, (S)-6-Chloro-2-((6-((1r,3S)-3-hydroxycyclobutyl)-5-oxo-6,7-dihydro-5H-pyrrolo[3,4-d]pyrimidin-2-yl)amino)-2,3-dihydro-1H-inden-4-carbonitrile, (S)-6-Chloro-2-((6-(2-methoxyethyl)-5-oxo-6,7-dihydro-5H-pyrrolo[3,4-d]pyrimidin-2-yl)amino)-2,3-dihydro-1H-inden-4-carbonitrile, (S)-6-Chloro-2-((6-(2-hydroxy-2-methylpropyl)-5-oxo-6,7-dihydro-5H-pyrrolo[3,4-d]pyrimidin-2-yl)amino)-2,3-dihydro-1H-inden-4-carbonitrile, (S)-6-Chloro-2-((6-(2-fluoroethyl)-5-oxo-6,7-dihydro-5H-pyrrolo[3,4-d]pyrimidin-2-yl)amino)-2,3-dihydro-1H-inden-4-carbonitrile, (S)-6-Chloro-2-((6-methyl-5-oxo-6,7-dihydro-5H-pyrrolo[3,4-d]pyrimidin-2-yl)amino)-2,3-dihydro-1H-inden-4-carbonitrile, (S)-6-Chloro-2-((6-((1-hydroxycyclopropyl)methyl)-5-oxo-6,7-dihydro-5H-pyrrolo[3,4-d]pyrimidin-2-yl)amino)-2,3-dihydro-1H-inden-4-carbonitrile, (S)-2-((6-(1-Acetylpiperidin-4-yl)-5-oxo-6,7-dihydro-5H-pyrrolo[3,4-d]pyrimidin-2-yl)amino)-6-chloro-2,3-dihydro-1H-inden-4-carbonitrile, (S)-6-Chloro-2-((6-(1,3-difluoropropan-2-yl)-5-oxo-6,7-dihydro-5H-pyrrolo[3,4-d]pyrimidin-2-yl)amino)-2,3-dihydro-1H-inden-4-carbonitrile, (S)-6-Chloro-2-((5-oxo-5,6,7,8-tetrahydropyrido[4,3-d]pyrimidin-2-yl)amino)-2,3-dihydro-1H-inden-4-carbonitrile, (S)-6-Chloro-2-((6-((3-methyloxetan-3-yl)methyl)-5-oxo-6,7-dihydro-5H-pyrrolo[3,4-d]pyrimidin-2-yl)amino)-2,3-dihydro-1H-inden-4-carbonitrile, (S)-6-Chloro-2-((5-oxo-6-(tetrahydro-2H-pyran-4-yl)-5,6,7,8-tetrahydropyrido[4,3-d]pyrimidin-2-yl)amino)-2,3-dihydro-1H-inden-4-carbonitrile, (S)-6-Chloro-2-((6-isopropyl-5-oxo-5,6,7,8-tetrahydropyrido[4,3-d]pyrimidin-2-yl)amino)-2,3-dihydro-1H-inden-4-carbonitrile, (S)-6-Chloro-2-((6-(cyclopropylmethyl)-5-oxo-5,6,7,8-tetrahydropyrido[4,3-d]pyrimidin-2-yl)amino)-2,3-dihydro-1H-inden-4-carbonitrile, (S,S) and (S,R)-6-Chloro-2-((5-oxo-6-(tetrahydrofuran-3-yl)-5,6,7,8-tetrahydropyrido[4,3-d]pyrimidin-2-yl)amino)-2,3-dihydro-1H-inden-4-carbonitrile, (S)-6-Chloro-2-((6-ethyl-5-oxo-6,7-dihydro-5H-pyrrolo[3,4-d]pyrimidin-2-yl)amino)-2,3-dihydro-1H-inden-4-carbonitrile, (S)-6-Chloro-2-((6-ethyl-5-oxo-5,6,7,8-tetrahydropyrido[4,3-d]pyrimidin-2-yl)amino)-2,3-dihydro-1H-inden-4-carbonitrile, (S)-6-Chloro-2-((5-oxo-6,7-dihydro-5H-pyrrolo[3,4-d]pyrimidin-2-yl)amino)-2,3-dihydro-1H-inden-4-carbonitrile, (S)-6-Chloro-2-((5-oxo-6-(2,2,2-trifluoroethyl)-5,6,7,8-tetrahydropyrido[4,3-d]pyrimidin-2-yl)amino)-2,3-dihydro-1H-inden-4-carbonitrile, and is selected from pharmaceutically acceptable salts thereof.

[0037] The method for producing the compound of formula (I) described herein is an object of the present invention.

[0038] The compounds of the present invention of formula I and their pharmaceutically acceptable salts can be prepared by methods known in the art, for example, by the methods described below. This method involves converting the compound of formula I

Chemical formula

Chemical formula

[0039] The compounds of formula I can be prepared according to the above process variations and Schemes 1 - 3 below. The starting materials are either commercially available or can be prepared according to known methods. Scheme 1 [Chemical formula]

[0040] Compounds of general formula I where n is 0 can be prepared by reacting the thiomethyl derivative II with an oxidizing agent such as 3-chloroperbenzoic acid to convert II to its corresponding methylsulfone derivative, and then reacting with the amine derivative III. The thiomethyl derivative of formula II can be prepared by reacting the amine V with a halomethyl derivative of formula IV, which itself can be prepared from VI, in the presence of a halogenating agent such as bromine. Scheme 2 [Chemical formula]

[0041] Compounds of general formula I where n is 1 can be prepared by reacting the thiomethyl derivative II with an oxidizing agent such as 3-chloroperbenzoic acid to convert II to its corresponding methylsulfone derivative, and then reacting with the amine derivative III. The thiomethyl derivative of formula II can be prepared by reductively aminating an aldehyde or ketone with the amine VII in the presence of a reducing agent such as sodium triacetoxyborohydride, followed by cyclization in situ. VII can be prepared from tert-butyl 2,4-dioxopiperidine-1-carboxylate VIII in the presence of 1,1-dimethoxy-N,N-dimethylmethanamine and 2-methylisothiourea in a solvent such as ethanol, and then treated with an acid such as HCl. Scheme 3 [Chemical formula]

[0042] Alternatively, a compound of general formula I where n is 1 can be prepared by reacting a thiomethyl derivative II with an oxidizing agent such as 3-chloroperbenzoic acid to convert II to its corresponding methylsulfone derivative, and then reacting it with an amine derivative III. The thiomethyl derivative of formula II can be prepared by alkylation of cyclic amide IX in the presence of an alkylating agent R1-X (where X is a halogen or a base such as alkyl-trifluoromethanesulfonate and diisopropylethylamine). IX can be prepared from tert-butyl 2,4-dioxopiperidine-1-carboxylate VIII in the presence of 1,1-dimethoxy-N,N-dimethylmethanamine and 2-methylisothiourea in a solvent such as ethanol, and subsequently treated with an acid such as HCl.

[0043] Also, an object of the present invention is a compound according to formula (I) described herein for use as a therapeutically active substance.

[0044] Similarly, an object of the present invention is a pharmaceutical composition comprising a compound according to formula (I) as described herein and a therapeutically inert carrier.

[0045] An object of the present invention is the use of a compound according to formula (I) described herein for the treatment or prevention of kidney symptoms, liver symptoms, inflammatory symptoms, nervous system symptoms, respiratory system symptoms, vascular and cardiovascular symptoms, fibrotic diseases, cancer, eye symptoms, metabolic symptoms, cholestasis and other forms of chronic pruritus, as well as acute and chronic organ transplant rejection.

[0046] Renal symptoms include, but are not limited to, chronic kidney diseases with or without proteinuria, including acute kidney injury and end-stage renal disease (ESRD). More specifically, this includes decreased creatinine clearance and decreased glomerular filtration rate, microalbuminuria, albuminuria and proteinuria, glomerulosclerosis (especially diabetic nephropathy and amyloidosis) with or without significant hypercellularity and with expansion of the reticular mesangial matrix, glomerular capillary thrombosis (especially thrombotic microangiopathy), overall fibrinoid necrosis, ischemic lesions, malignant nephrosclerosis (such as ischemic atrophy, decreased renal blood flow and renal artery disease), glomerulonephritis entities, focal segmental glomerulosclerosis, IgA nephropathy, vasculitis / systemic diseases and acute and chronic kidney transplant rejection, including swelling and proliferation of intravascular (endothelial and mesangial) and / or extravascular cells (crescents).

[0047] Liver symptoms include, but are not limited to, cirrhosis, hepatic congestion, cholestatic liver diseases including pruritus, non-alcoholic fatty hepatitis, and acute and chronic liver transplant rejection.

[0048] Inflammatory symptoms include, but are not limited to, arthritis, osteoarthritis, multiple sclerosis, systemic lupus erythematosus, inflammatory bowel disease, abnormal defecation disorders, etc., and inflammatory airway diseases such as idiopathic pulmonary fibrosis (IPF), chronic obstructive pulmonary disease (COPD) or chronic bronchial asthma.

[0049] Additional respiratory system symptoms include, but are not limited to, other diffuse parenchymal lung diseases of different etiologies including iatrogenic drug-induced fibrosis, occupational and / or environmental-induced fibrosis, systemic diseases and vasculitis, granulomatous diseases (sarcoidosis, hypersensitivity pneumonitis), collagenous vascular diseases, pulmonary alveolar proteinosis, Langerhans cell granulomatosis, lymphangioleiomyomatosis, genetic diseases (Hermansky-Pudlak syndrome, tuberous sclerosis, neurofibromatosis, metabolic storage disorders, familial interstitial lung disease), radiation-induced fibrosis, silicosis, asbestos-induced pulmonary fibrosis or acute respiratory distress syndrome (ARDS).

[0050] Nervous system symptoms include, but are not limited to, neuropathic pain, schizophrenia, neuroinflammation (e.g., astrogliosis), peripheral and / or autonomic (diabetic) neuropathy, and the like.

[0051] Vascular symptoms include, but are not limited to, atherosclerosis, thrombotic vascular diseases, as well as thrombotic microangiopathy, proliferative arteriopathy (such as swollen intimal cells surrounded by mucoid extracellular matrix and nodular thickening), atherosclerosis, decreased vascular compliance (rigidity, decreased ventricular compliance, and decreased vascular compliance), endothelial dysfunction, and the like.

[0052] Cardiovascular symptoms include, but are not limited to, acute coronary syndrome, coronary heart disease, myocardial infarction, arterial and pulmonary hypertension, cardiac arrhythmias such as atrial fibrillation, stroke, and other vascular injuries.

[0053] Fibrotic diseases include, but are not limited to, myocardial and vascular fibrosis, renal fibrosis, hepatic fibrosis, pulmonary fibrosis, dermal fibrosis, scleroderma, and encapsulating peritonitis.

[0054] Cancer and cancer metastasis include, but are not limited to, breast cancer, ovarian cancer, lung cancer, prostate cancer, mesothelioma, glioma, liver cancer, gastrointestinal cancer, and its progression and metastatic aggressiveness.

[0055] Eye symptoms include, but are not limited to, proliferative and non-proliferative (diabetic) retinopathy, dry and exudative age-related macular degeneration (AMD), macular edema, central artery / vein occlusion, traumatic injury, glaucoma, and the like. In particular, the eye symptom is glaucoma.

[0056] Metabolic symptoms include, but are not limited to, obesity and diabetes.

[0057] The present invention also relates to the use of the compounds according to formula (I) described herein for the treatment or prevention of kidney symptoms, liver symptoms, inflammatory symptoms, nervous system symptoms, fibrotic diseases, and acute and chronic organ transplant rejection.

[0058] The present invention also relates to the use of a compound of formula (I) described herein for the treatment or prevention of kidney disorders, liver disorders and fibrotic diseases.

[0059] A particular embodiment of the present invention is a compound of formula (I) described herein for the treatment or prevention of kidney disorders, liver disorders, inflammatory disorders, nervous system disorders, fibrotic diseases and acute and chronic organ transplant rejection.

[0060] A particular embodiment of the present invention is a compound of formula (I) described herein for the treatment or prevention of kidney disorders, liver disorders and fibrotic diseases.

[0061] The present invention also relates to the use of a compound of formula (I) described herein for the preparation of a medicament for the treatment or prevention of kidney disorders, liver disorders, inflammatory disorders, nervous system disorders, fibrotic diseases and acute and chronic organ transplant rejection.

[0062] The present invention also relates to the use of a compound of formula (I) described herein for the preparation of a medicament for the treatment or prevention of kidney disorders, liver disorders and fibrotic diseases.

[0063] Also, an object of the present invention is a method for the treatment or prevention of kidney disorders, liver disorders, inflammatory disorders, nervous system disorders, fibrotic diseases and acute and chronic organ transplant rejection, the method comprising administering an effective amount of a compound of formula (I) described herein.

[0064] Also, an object of the present invention is a method for the treatment or prevention of kidney disorders, liver disorders and fibrotic diseases, the method comprising administering an effective amount of a compound of formula (I) described herein.

[0065] Also, one embodiment of the present invention provides a compound of formula (I) described herein when manufactured according to any one of the processes described.

[0066] Assay procedure Produce human full-length ATX regardless of the presence or absence of tags Autotaxin (ATX-ENPP2) cloning: cDNA was prepared from total RNA of commercially available human hematopoietic cells and used as a template for overlapping PCR to generate full-length human ENPP2 ORF with or without a 3'-6xHis tag. These full-length inserts were cloned into the pcDNA3.1V5-His TOPO (Invitrogen) vector. The DNA sequences of several single clones were verified. DNA from the correct full-length clone was used to transfect Hek293 cells for protein expression verification. The sequence of the encoded ENPP2 follows the Swissprot entry Q13822 regardless of the presence or absence of an additional C-terminal 6xHis tag.

[0067] ATX fermentation: Recombinant protein was produced by large-scale transient transfection in a 20 L controlled stirred tank bioreactor (Sartorius). During cell growth and transfection, the temperature, stirring speed, pH, and dissolved oxygen concentration were maintained at 37°C, 120 rpm, 7.1, and 30% DO, respectively. FreeStyle 293-F cells (Invitrogen) were cultured in suspension in FreeStyle 293 medium (Invitrogen) at approximately 30°C and approximately 1 - 1.5×10E6 cells / mL and transfected with the above plasmid DNA using X-tremeGENE Ro-1539 (commercial product, Roche Diagnostics) as a complexing agent. The cells were fed with a concentrated nutrient solution (J Immunol Methods 194 (1996), 19, 1 - 199 (page 193)), induced with sodium butyrate (2 mM) 72 hours after transfection, and harvested 96 hours after transfection. Expression was analyzed by Western blot, enzyme assay, and / or analytical IMAC chromatography. After cooling the cell suspension to 4°C with a flow-through heat exchanger, cell separation and sterile filtration of the supernatant were performed by filtration through Zeta Plus 60M02 E16 (Cuno) and Sartopore 2 XLG (Sartorius) filter units. The supernatant was stored at 4°C before purification.

[0068] ATX Purification: 20 liters of culture supernatant was conditioned for ultrafiltration by adding Brij 35 to a final concentration of 0.02% and adjusting the pH to 7.0 with 1 M HCl. The supernatant was then first microfiltered through a 0.2 μm Ultran-Pilot Open Channel PES filter (Whatman) and then concentrated to 1 liter using an Ultran-Pilot Screen Channel PES filter with a 30 kDa MWCO (Whatman). Prior to IMAC chromatography, NiSO4 was added to a final concentration of 1 mM. The clarified supernatant was then applied to a HisTrap column (GE Healthcare) pre-equilibrated with 50 mM Na2HPO4 pH 7.0, 0.5 M NaCl, 10% glycerol, 0.3% CHAPS, 0.02% NaN3. The column was washed stepwise with the same buffer containing 20 mM, 40 mM, and 50 mM imidazole, respectively. Subsequently, the protein was eluted using a linear gradient to 0.5 M imidazole over 15 column volumes. The ATX-containing fractions were pooled and concentrated using an Amicon cell equipped with a 30 kDa PES filter membrane. The protein was further purified by size exclusion chromatography on Superdex S-200 prep grade (XK 26 / 100) (GE Healthcare) in 20 mM BICINE pH 8.5, 0.15 M NaCl, 10% glycerol, 0.3% CHAPS, 0.02% NaN3. The final yield of the purified protein was 5 - 10 mg of ATX per liter of culture supernatant. The protein was stored at -80 °C.

[0069] Human ATX Enzyme Inhibition Assay To identify inhibitors of human autotaxin (ATX) enzyme, an in vitro biochemical profiling assay was developed using lysophosphatidylcholine (LPC) as a substrate and recombinant enzyme. ATX activity was assayed via a coupled enzyme format in which choline generated from LPC hydrolysis was converted to hydrogen peroxide by choline oxidase (CO). Hydrogen peroxide was then used as a co-substrate by horseradish peroxidase (HRP) to oxidize Amplex Red® and generate resorufin, a red fluorescent product.

[0070] Materials / Reagents 500 mM Tris-HCl pH 8.0; 1 M NaCl; 250 mM CaCl2; 250 mM KCl; 250 mM MgCl2; 10% Triton X-100 in H2O. Assay Buffer 50 mM Tris-HCl (pH 8.0); 120 mM NaCl; 20 mM CaCl2; 5 mM KCl; 1 mM MgCl2; 0.01% Triton X-100, filtered through a sterile filter and stored at 4°C. Reagent Dilution Buffer 50 mM Tris-HCl (pH 8.0); 150 mM NaCl Human autotaxin (hATX): 0.97 mg / ml (9.718 μM) molecular weight 99817. A 1.5 μM working solution was used in this assay. 100 mM 18:1 LPC was dissolved in reagent dilution buffer. 500 U / ml choline oxidase in reagent dilution buffer. 2540 U / ml horseradish peroxidase in reagent dilution buffer (10.95 mg / ml). 20 mM Amplex Red (10-acetyl-3,7-dihydroxy-phenoxazine) in DMSO. Reaction Plate Black, 384-well plate, black, untreated surface with clear bottom.

[0071] Receive the test compound pre-diluted in DMSO as an 11-point concentration-response (highest concentration 0.5 mM; 3.162-fold dilution). Pre-dilute the test compound 1:1 (10 μL compound + 10 μL assay buffer) in a 96-well conical bottom plate before use.

[0072] Procedure Dilute ATX to 2.2 nM with assay buffer. Dilute choline oxidase and horseradish peroxidase to 7.3 U / ml and 14.7 U / ml, respectively. Dilute 18:1 LPC and Amplex Red® to 110 μM and 183.3 μM, respectively (solution protected from light). Add 2.2 μL of the pre-diluted compound or 50% DMSO to the reaction plate, followed by 25 μL of ATX or assay buffer (negative control). Mix the assay plate and incubate for 10 minutes at room temperature. Then add 15 μL of choline oxidase / horseradish peroxidase. To initiate the reaction, add 15 μL of LPC18:1 / Amplex Red. Mix the assay plate and incubate in the dark at room temperature. Measure fluorescence at 5 minutes (for background subtraction) and 90 minutes.

[0073] Final assay concentrations: hATX: 1 nM 18:1 LPC: 30 μM Choline oxidase: 2 U / ml Horseradish peroxidase: 4 U / ml Amplex Red®: 50 μM DMSO: 2% Subtract the fluorescence at 5 minutes from the end point data at 90 minutes and normalize to the positive control. Calculate the IC 50 value.

[0074] Provide the results of the enzyme ATX inhibition assay for the compounds of formula (I).

[0075] [Table 1]

[0076] The compounds of formula (I) described in this specification and their pharmaceutically acceptable salts or esters have an IC of 0.00001 μM to 1000 μM 50 value, and certain compounds have an IC of 0.0005 μM to 500 μM 50 value, and certain further compounds have an IC of 0.0005 μM to 50 μM 50 value, and certain further compounds have an IC of 0.0005 μM to 5 μM 50 value. These results were obtained by using the above enzyme assay.

[0077] The compounds of formula (I) and their pharmaceutically acceptable salts can be used as pharmaceuticals (for example, in the form of pharmaceutical preparations). The pharmaceutical preparations of the present invention can be administered orally (for example, in the form of tablets, coated tablets, dragees, hard and soft gelatin capsules, solutions, emulsions or suspensions), nasally (for example, in the form of nasal sprays), rectally (for example, in the form of suppositories), or topically to the eye (for example, in the form of solutions, ointments, gels or water-soluble polymer inserts). However, administration can also be carried out parenterally, such as intramuscularly, intravenously, intravitreally, etc. (for example, in the form of a sterile injection).

[0078] The compounds of formula (I) and their pharmaceutically acceptable salts can be processed with pharmaceutically inert, inorganic or organic adjuvants for the manufacture of tablets, coated tablets, dragees, hard gelatin capsules, injection solutions or topical preparations. Lactose, corn starch or its derivatives, talc, stearic acid or its salts, etc. can be used, for example, as such adjuvants for tablets, dragees and hard gelatin capsules.

[0079] Examples of adjuvants suitable for soft gelatin capsules include vegetable oils, waxes, fats and oils, semi-solids, liquid polyols, etc.

[0080] Adjuvants suitable for the production of solutions and syrups are, for example, water, polyols, sucrose, invert sugar, glucose, and the like.

[0081] Adjuvants suitable for injection solutions are, for example, water, alcohol, polyols, glycerol, vegetable oils, and the like.

[0082] Adjuvants suitable for suppositories are, for example, natural or hardened oils, waxes, fats, semi-solid or liquid polyols, and the like.

[0083] Adjuvants suitable for topical ophthalmic preparations are, for example, cyclodextrins, mannitol, or many other carriers and excipients known in the art.

[0084] Furthermore, pharmaceutical preparations can include preservatives, solubilizers, viscosity-increasing substances, stabilizers, wetting agents, emulsifiers, sweeteners, coloring agents, flavoring agents, salts for changing osmotic pressure, buffers, masking agents, or antioxidants. They can also contain further other therapeutically valuable substances.

[0085] The dosage can vary widely and, of course, be adapted to the individual requirements in each specific case. Generally, in the case of oral administration, about 0.1 mg to about 20 mg per kg of body weight, preferably about 0.5 mg to about 4 mg per kg of body weight (for example, about 300 mg per person) is used as the daily dose, preferably administered individually in 1 to 3 divided doses, which, if appropriate, can be composed of the same amount, for example. In the case of topical administration, the preparation can contain 0.001 wt% to 15 wt% of the pharmaceutical, and the required amount can be between 0.1 and 25 mg, and it can be administered once a day, once a week, multiple times a day (2 to 4 times), or multiple times a week. However, it is obvious that there may be cases where the upper or lower limits described here are exceeded.

[0086] Hereinafter, the present invention will be described by way of examples, but the present invention is not limited thereto.

[0087] When the aliquot is obtained as a mixture of enantiomers, the pure enantiomers can be obtained by the methods described herein or methods known to those skilled in the art, such as chiral chromatography or crystallization.

Examples

[0088] Unless otherwise specified, all examples and intermediates were prepared under an argon atmosphere.

[0089] Intermediate A Intermediate A1: 5-Chloro-2,3-dihydro-1H-inden-2-amine hydrochloride

Chemical formula

[0090] Intermediate A2: (S)-6-Chloro-4-cyano-2,3-dihydro-1H-inden-2-aminium chloride

Chemical formula

[0091] Step 1: 4-(4,4,5,5-Tetramethyl-1,3,2-dioxaborolan-2-yl)-2,3-dihydro-1H-inden-2-yl) carbamate

Chemical formula

[0092] Step 2: tert-Butyl (6-chloro-4-hydroxy-2,3-dihydro-1H-inden-2-yl)carbamate

Chemical formula

[0093] Step 3: 2-((tert-Butoxycarbonyl)amino)-6-chloro-2,3-dihydro-1H-inden-4-yl trifluoromethanesulfonate

Chemical Structure

[0094] Step 4: tert-Butyl (6-chloro-4-cyano-2,3-dihydro-1H-inden-2-yl)carbamate

Chem.

[0095] Step 5: (S)-tert-Butyl (6-chloro-4-cyano-2,3-dihydro-1H-inden-2-yl)carbamate

Chem.

[0096] Step 6: (S)-6-Chloro-4-cyano-2,3-dihydro-1H-inden-2-aminium chloride [Chemical formula] (S)-tert-Butyl (6-chloro-4-cyano-2,3-dihydro-1H-inden-2-yl)carbamate solution; (300 mg, 1.02 mmol,) and 4 M HCl in dioxane (3.84 ml, 15.4 mmol) (2 ml) were stirred at room temperature for 15 hours. The resulting suspension was concentrated in vacuo to give the title compound (237 mg, 100% yield) as a white solid. MS (ESI): m / z = 193.1 [M+H]+

[0097] Intermediate B Intermediate B1: Methyl 4-(bromomethyl)-2-(methylthio)pyrimidine-5-carboxylate [Chemical formula] Bromine (774 mg, 249 μl, 4.79 mmol) was added to a solution of methyl 4-methyl-2-(methylthio)pyrimidine-5-carboxylate (1.00 g, 4.79 mmol, CAS: 166392-24-1) in acetic acid (10 ml). The reaction mixture was heated to 60 °C and stirred for 1 hour. Bromine (232 mg, 74.6 μl, 1.44 mmol) was added again and stirring was continued at 60 °C for 1 hour. The reaction mixture was poured into water and extracted twice with EtOAc. The combined organic layers were dried over sodium sulfate and concentrated in vacuo. The crude material was purified by flash chromatography on silica gel using a gradient of ethyl acetate / heptane 0 - 50% to give the title compound as a pale yellow viscous oil (822 mg, 54% yield). MS (ESI): m / z = 277.0 [M+H] +

[0098] Intermediate B2: Ethyl 4-(2-aminoethyl)-2-(methylthio)pyrimidine-5-carboxylate hydrochloride [Chemical formula]

[0099] Step 1: Ethyl 4-(2-((tert-butoxycarbonyl)amino)ethyl)-2-(methylthio)pyrimidine-5-carboxylate

Chem.

[0100] Step 2: Ethyl 4-(2-aminoethyl)-2-(methylthio)pyrimidine-5-carboxylate hydrochloride

Chem.

[0101] Intermediate B3: tert-Butyl 2-(methylthio)-5-oxo-7,8-dihydropyrido[4,3-d]pyrimidine-6(5H)-carboxylate

Chem.

[0102] Intermediate C Intermediate C1: 2-(Methylthio)-6-(oxetan-3-yl)-6,7-dihydro-5H-pyrrolo[3,4-d]pyrimidin-5-one

Chem.

[0103] The following Intermediates C2 - 24 were prepared in the same manner as Intermediate C1 from the indicated commercially available amine components and methyl 4-(bromomethyl)-2-(methylthio)pyrimidine-5-carboxylate (Intermediate B1).

Table 2

[0104] Intermediate C25: 2-(methylthio)-6-(oxetan-3-yl)-7,8-dihydropyrido[4,3-d]pyrimidin-5(6H)-one

Chemical formula

[0105] The following Intermediates C26 - 30 were prepared in the same manner as Intermediate C25 from the indicated commercially available aldehyde or ketone components and ethyl 4-(2-aminoethyl)-2-(methylthio)pyrimidine-5-carboxylate hydrochloride (Intermediate B2).

Table 3

[0106] Intermediate C31: 2-(Methylthio)-7,8-dihydropyrido[4,3-d]pyrimidin-5(6H)-one

Chem.

[0107] Intermediate C32: 2-(methylthio)-6-(2,2,2-trifluoroethyl)-7,8-dihydropyrido[4,3-d]pyrimidin-5(6H)-one

Chemical Structure

[0108] [Examples] Example 12 - ((5 - chloro - 2,3 - dihydro - 1H - inden - 2 - yl)amino) - 6 - (oxetan - 3 - yl) - 6,7 - dihydro - 5H - pyrrolo[3,4 - d]pyrimidin - 5 - one

Chemical Structure

[0109] The following Examples 2 - 36 were prepared in the same manner as Example 1 from the indicated dihydro - 1H - inden - 2 - amine Intermediate A1 or A2 and thiomethyl Intermediates C2 - 32.

Table 4

[0110] Example A The compound of formula (I) can be used as an active ingredient in a manner known per se for producing tablets of the following composition.

[0111] Per tablet Active ingredient 200 mg Microcrystalline cellulose 155 mg Corn starch 25 mg Talc 25 mg Hydroxypropylmethylcellulose 20 mg 425 mg

[0112] Example B The compound of formula (I) can be used as an active ingredient in a manner known per se for producing capsules of the following composition. Per capsule Active ingredient 100.0 mg Corn starch 20.0 mg Lactose 95.0 mg Talc 4.5 mg Magnesium stearate 0.5 mg 220.0 mg

Claims

1. A compound of formula (I), 【Chemical Formula 25】 R １ is i) H, ii) C １－６ -alkyl, iii) C ３－８ -cycloalkyl, iv) C ３－８ -cycloalkylalkyl, v) C １－６ -alkoxy, vi) C １－６ -alkoxy-C １－６ -alkyl, vii) heterocycloalkyl, viii) heterocycloalkylalkyl, ix) Substituted C ３－８ -cycloalkyl, x) Replacement C ３－８ - cycloalkylalkyl, xi) substituted heterocycloalkyl, xii) substituted heterocycloalkylalkyl, xiii) halo-C １－６ -alkyl, xiv) hydroxy-C １－６ -alkyl, selected from the group consisting of, Replacement C ３－８ -Cycloalkyl or substituted heterocycloalkyl is substituted with one or more substituents selected from H, C １－６ -Alkyl, halogen, hydroxy, and C １－６ -Carbonyl, and is substituted with one or more substituents selected therefrom R ２ is i) H, ii) cyano, selected from the group consisting of, In the formula, R １ and R ２ at least one of which is other than H, R3 is halogen, and n is 0 or 1, a compound, or a pharmaceutically acceptable salt.

2. R ３ The compound according to claim 1, wherein R is Cl.

3. R １ is i) H, ii) C １－６ -alkyl, iii) C ３－８ -cycloalkyl, iv) C ３－８ -cycloalkylalkyl, v) C １－６ -alkoxy, vi) C １－６ -alkoxy-C １－６ -alkyl, vii) heterocycloalkyl, viii) heterocycloalkylalkyl, ix) Substituted C ３－８ - cycloalkyl, x) Replacement C ３－８ - cycloalkylalkyl, xi) substituted heterocycloalkyl, xii) substituted heterocycloalkylalkyl, xiii) halo-C １－６ -alkyl, xiv) hydroxy-C １－６ -alkyl, selected from the group consisting of, Replacement C ３－８ -Cycloalkyl or substituted heterocycloalkyl is substituted with one or more substituents selected from H, C １－６ -Alkyl, halogen, hydroxy, and C １－６ -Carbonyl, and the "heterocycloalkyl" is a 4- to 6-membered ring system containing one heteroatom selected from N and O, the compound according to claim 1 or 2.

4. R ３ is Cl, R １ is i) H, ii) C １－６ -alkyl, iii) C ３－８ -cycloalkyl, iv) C ３－８ -cycloalkylalkyl, v) C １－６ -alkoxy, vi) C １－６ -alkoxy-C １－６ -alkyl, vii) heterocycloalkyl, viii) heterocycloalkylalkyl, ix) Substituted C ３－８ -cycloalkyl, x) Substituted C ３－８ - cycloalkylalkyl, xi) substituted heterocycloalkyl, xii) substituted heterocycloalkylalkyl, xiii) halo-C １－６ -alkyl, xiv) hydroxy-C １－６ -alkyl, selected from the group consisting of, Replacement C ３－８ -Cycloalkyl or substituted heterocycloalkyl is substituted with one or more substituents selected from H, C １－６ -Alkyl, halogen, hydroxy, and C １－６ -Carbonyl, and "heterocycloalkyl" is a 4- to 6-membered ring system containing one heteroatom selected from N and O R １ and R ２ at least one of which is other than H, and n is 0 or 1, a compound according to any one of Claims 1 to 3, or a pharmaceutically acceptable salt.

5. 2 - ((5 - chloro - 2,3 - dihydro - 1H - inden - 2 - yl)amino) - 6 - (oxetan - 3 - yl) - 6,7 - dihydro - 5H - pyrrolo[3,4 - d]pyrimidin - 5 - one, 2 - ((5 - chloro - 2,3 - dihydro - 1H - inden - 2 - yl)amino) - 6 - (3 - methyloxetan - 3 - yl) - 6,7 - dihydro - 5H - pyrrolo[3,4 - d]pyrimidin - 5 - one, (S) - 6 - chloro - 2 - ((6 - (3 - methyloxetan - 3 - yl) - 5 - oxo - 6,7 - dihydro - 5H - pyrrolo[3,4 - d]pyrimidin - 2 - yl)amino) - 2,3 - dihydro - 1H - inden - 4 - carbonitrile, 2 - ((5 - chloro - 2,3 - dihydro - 1H - inden - 2 - yl)amino) - 6 - (6,6 - difluorospiro[3.3]heptan - 2 - yl) - 6,7 - dihydro - 5H - pyrrolo[3,4 - d]pyrimidin - 5 - one, 2 - ((5 - chloro - 2,3 - dihydro - 1H - inden - 2 - yl)amino) - 6 - (3,3 - difluorocyclobutyl) - 6,7 - dihydro - 5H - pyrrolo[3,4 - d]pyrimidin - 5 - one, (S) - 6 - chloro - 2 - ((6 - (3,3 - difluoro - 1 - methylcyclobutyl) - 5 - oxo - 6,7 - dihydro - 5H - pyrrolo[3,4 - d]pyrimidin - 2 - yl)amino) - 2,3 - dihydro - 1H - inden - 4 - carbonitrile, (S)-6-Chloro-2-((6-(6,6-difluorospiro[3.3]heptan-2-yl)-5-oxo-6,7-dihydro-5H-pyrrolo[3,4-d]pyrimidin-2-yl)amino)-2,3-dihydro-1H-inden-4-carbonitrile, (S)-6-Chloro-2-((6-(3,3-difluorocyclobutyl)-5-oxo-6,7-dihydro-5H-pyrrolo[3,4-d]pyrimidin-2-yl)amino)-2,3-dihydro-1H-inden-4-carbonitrile, (S)-6-Chloro-2-((5-oxo-6-(tetrahydro-2H-pyran-4-yl)-6,7-dihydro-5H-pyrrolo[3,4-d]pyrimidin-2-yl)amino)-2,3-dihydro-1H-inden-4-carbonitrile, (S)-6-Chloro-2-((5-oxo-6-(2,2,2-trifluoroethyl)-6,7-dihydro-5H-pyrrolo[3,4-d]pyrimidin-2-yl)amino)-2,3-dihydro-1H-inden-4-carbonitrile, (S,S) and (S,R)-6-Chloro-2-((5-oxo-6-(tetrahydrofuran-3-yl)-6,7-dihydro-5H-pyrrolo[3,4-d]pyrimidin-2-yl)amino)-2,3-dihydro-1H-inden-4-carbonitrile, (S)-6-Chloro-2-((6-isopropyl-5-oxo-6,7-dihydro-5H-pyrrolo[3,4-d]pyrimidin-2-yl)amino)-2,3-dihydro-1H-inden-4-carbonitrile, (S)-6-Chloro-2-((6-cyclopropyl-5-oxo-6,7-dihydro-5H-pyrrolo[3,4-d]pyrimidin-2-yl)amino)-2,3-dihydro-1H-inden-4-carbonitrile, (S)-6-Chloro-2-((6-(oxetan-3-ylmethyl)-5-oxo-6,7-dihydro-5H-pyrrolo[3,4-d]pyrimidin-2-yl)amino)-2,3-dihydro-1H-inden-4-carbonitrile, (S)-6-Chloro-2-((6-(1-methylcyclopropyl)-5-oxo-6,7-dihydro-5H-pyrrolo[3,4-d]pyrimidin-2-yl)amino)-2,3-dihydro-1H-inden-4-carbonitrile, (S)-6-Chloro-2-((6-(oxetan-3-yl)-5-oxo-6,7-dihydro-5H-pyrrolo[3,4-d]pyrimidin-2-yl)amino)-2,3-dihydro-1H-inden-4-carbonitrile, (S)-6-Chloro-2-((6-(oxetan-3-yl)-5-oxo-5,6,7,8-tetrahydropyrido[4,3-d]pyrimidin-2-yl)amino)-2,3-dihydro-1H-inden-4-carbonitrile, (S)-6-Chloro-2-((6-(cyclopropylmethyl)-5-oxo-6,7-dihydro-5H-pyrrolo[3,4-d]pyrimidin-2-yl)amino)-2,3-dihydro-1H-inden-4-carbonitrile, (S)-6-Chloro-2-((6-((1r,3S)-3-hydroxycyclobutyl)-5-oxo-6,7-dihydro-5H-pyrrolo[3,4-d]pyrimidin-2-yl)amino)-2,3-dihydro-1H-inden-4-carbonitrile, (S)-6-Chloro-2-((6-(2-methoxyethyl)-5-oxo-6,7-dihydro-5H-pyrrolo[3,4-d]pyrimidin-2-yl)amino)-2,3-dihydro-1H-inden-4-carbonitrile, (S)-6-Chloro-2-((6-(2-hydroxy-2-methylpropyl)-5-oxo-6,7-dihydro-5H-pyrrolo[3,4-d]pyrimidin-2-yl)amino)-2,3-dihydro-1H-inden-4-carbonitrile, (S)-6-Chloro-2-((6-(2-fluoroethyl)-5-oxo-6,7-dihydro-5H-pyrrolo[3,4-d]pyrimidin-2-yl)amino)-2,3-dihydro-1H-inden-4-carbonitrile, (S)-6-Chloro-2-((6-methyl-5-oxo-6,7-dihydro-5H-pyrrolo[3,4-d]pyrimidin-2-yl)amino)-2,3-dihydro-1H-inden-4-carbonitrile, (S)-6-Chloro-2-((6-((1-hydroxycyclopropyl)methyl)-5-oxo-6,7-dihydro-5H-pyrrolo[3,4-d]pyrimidin-2-yl)amino)-2,3-dihydro-1H-inden-4-carbonitrile, (S)-2-((6-(1-Acetylpiperidin-4-yl)-5-oxo-6,7-dihydro-5H-pyrrolo[3,4-d]pyrimidin-2-yl)amino)-6-chloro-2,3-dihydro-1H-inden-4-carbonitrile, (S)-6-Chloro-2-((6-(1,3-difluoropropan-2-yl)-5-oxo-6,7-dihydro-5H-pyrrolo[3,4-d]pyrimidin-2-yl)amino)-2,3-dihydro-1H-inden-4-carbonitrile, (S)-6-Chloro-2-((5-oxo-5,6,7,8-tetrahydropyrido[4,3-d]pyrimidin-2-yl)amino)-2,3-dihydro-1H-inden-4-carbonitrile, (S)-6-Chloro-2-((6-((3-methyloxetan-3-yl)methyl)-5-oxo-6,7-dihydro-5H-pyrrolo[3,4-d]pyrimidin-2-yl)amino)-2,3-dihydro-1H-inden-4-carbonitrile, (S)-6-Chloro-2-((5-oxo-6-(tetrahydro-2H-pyran-4-yl)-5,6,7,8-tetrahydropyrido[4,3-d]pyrimidin-2-yl)amino)-2,3-dihydro-1H-inden-4-carbonitrile, (S)-6-Chloro-2-((6-isopropyl-5-oxo-5,6,7,8-tetrahydropyrido[4,3-d]pyrimidin-2-yl)amino)-2,3-dihydro-1H-inden-4-carbonitrile, (S)-6-Chloro-2-((6-(cyclopropylmethyl)-5-oxo-5,6,7,8-tetrahydropyrido[4,3-d]pyrimidin-2-yl)amino)-2,3-dihydro-1H-inden-4-carbonitrile, (S,S) and (S,R)-6-Chloro-2-((5-oxo-6-(tetrahydrofuran-3-yl)-5,6,7,8-tetrahydropyrido[4,3-d]pyrimidin-2-yl)amino)-2,3-dihydro-1H-inden-4-carbonitrile, (S)-6-Chloro-2-((6-ethyl-5-oxo-6,7-dihydro-5H-pyrrolo[3,4-d]pyrimidin-2-yl)amino)-2,3-dihydro-1H-inden-4-carbonitrile, (S)-6-Chloro-2-((6-ethyl-5-oxo-5,6,7,8-tetrahydropyrido[4,3-d]pyrimidin-2-yl)amino)-2,3-dihydro-1H-inden-4-carbonitrile, (S)-6-Chloro-2-((5-oxo-6,7-dihydro-5H-pyrrolo[3,4-d]pyrimidin-2-yl)amino)-2,3-dihydro-1H-inden-4-carbonitrile, (S)-6-Chloro-2-((5-oxo-6-(2,2,2-trifluoroethyl)-5,6,7,8-tetrahydropyrido[4,3-d]pyrimidin-2-yl)amino)-2,3-dihydro-1H-inden-4-carbonitrile, The compound according to any one of claims 1 to 4, selected from the above, and a pharmaceutically acceptable salt thereof.

6. A method for preparing the compound according to any one of claims 1 to 5, comprising the reaction of the compound of formula (II) in the presence of the compound of formula (III). 【Chemical 26】

7. The compound according to any one of claims 1 to 5, for use as a therapeutically active substance.

8. A pharmaceutical composition comprising the compound according to any one of claims 1 to 5 and a therapeutically inert carrier.

9. For the treatment or prevention of kidney symptoms, liver symptoms, inflammatory symptoms, nervous system symptoms, respiratory system symptoms, vascular and cardiovascular symptoms, fibrotic diseases, cancer, eye symptoms, metabolic symptoms, cholestasis and other forms of chronic pruritus, as well as acute and chronic organ transplant rejection, a pharmaceutical composition comprising the compound according to any one of claims 1 to 5.

10. The compound according to any one of claims 1 to 5, for the treatment or prevention of kidney symptoms, liver symptoms, inflammatory symptoms, nervous system symptoms, fibrotic diseases, as well as acute and chronic organ transplant rejection.

11. Use of the compound according to any one of claims 1 to 5 for the preparation of a medicament for the treatment or prevention of kidney symptoms, liver symptoms, inflammatory symptoms, nervous system symptoms, fibrotic diseases, as well as acute and chronic organ transplant rejection.

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