Amino-pyrimidine amides

Abstract

The present invention relates to novel compounds having the general formula (I): TIFF2023529406000075.tif27165 In the formula, R 1 , R 2 , R 3 , R 4 and R 5 provides compositions comprising and methods of using the compounds, wherein the compounds are as described herein.

Description

[Technical field]

[0001] The present invention relates to organic compounds useful for the treatment or prevention in mammals, in particular autotaxin (ATX) inhibitors that are inhibitors of lysophosphatidic acid (LPA) production and thus modulators of LPA levels and associated signaling, for the treatment or prevention of renal conditions, hepatic conditions, inflammatory conditions, neurological conditions, respiratory conditions, vascular and cardiovascular conditions, fibrotic diseases, cancer, ocular conditions, metabolic conditions, cholestatic and other forms of chronic pruritus, and acute and chronic organ transplant rejection. [Background technology]

[0002] The present invention relates to novel compounds of formula (I) [ka] During the ceremony, R 1 , R 2 and R 3 is, independently, i) H, ii) C 1-6 -alkyl, iii) C 2-6 -alkynyl, iv) halogens, v) Halo-C 1-6 -alkyl, vi) Halo-C 1-6 -Alkoxy vii) cyano, viii) Cyano-C 1-6 -Alkyl is selected from the group consisting of R 1 and R 3 at least one of is other than H; R 4 and R 5 is, independently, i) H, ii) C 1-6 -Alkyl or selected from the group consisting of Or R4 and R 5 taken together with the carbon atom to which they are attached, form a heterocycloalkyl or substituted C 3-8 -Cycloalkyl, substituted C 3-8 Cycloalkyl is R 6 and R 7 is replaced by R 6 and R 7 is independently selected from the group consisting of halogen, hydroxy or alkyl; The compound, or a pharma- ceutically acceptable salt, is provided.

[0003] Autotaxin (ATX), also called ectonucleotide pyrophosphatase / phosphodiesterase 2 or lysophospholipase D, is a secreted enzyme that is important for converting lysophosphatidylcholine (LPC) to the bioactive signaling molecule lysophosphatidic acid (LPA). Plasma LPA levels have been shown to correlate well with ATX activity, and ATX is therefore considered to be an important source of extracellular LPA. Early experiments with prototype ATX inhibitors have shown that such compounds can inhibit LPA synthesis 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, and more. LPA mediates its effects through signal transduction to several G protein-coupled receptors (GPCRs). Initially meaning Edg (endothelial cell differentiation gene) receptor or ventricular zone gene 1 (vzg-1), it is now called the LPA receptor. 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, have been described that are more closely related to nucleotide-selective purinergic receptors than the prototype LPA1-3 receptor. The ATX-LPA signaling axis is involved in a wide range of physiological and pathophysiological functions, including, for example, nervous system function, vascular development, cardiovascular physiology, reproduction, immune system function, chronic inflammation, tumor metastasis and progression, organ fibrosis, and other metabolic diseases such as obesity and / or diabetes mellitus. Thus, increased activity of ATX and / or increased levels of LPA, changes in LPA receptor expression and changes in response to LPA may contribute to the initiation, progression and / or outcome of several different pathophysiological conditions associated with the ATX / LPA axis.

[0004] According to the present invention, the compounds of formula (I) or their pharma- ceutically acceptable salts and esters can be used to treat or prevent diseases, disorders or conditions associated with the activity of autotaxin and / or the biological activity of lysophosphatidic acid (LPA).

[0005] The compounds of formula (I) herein or their pharma- ceutically acceptable salts and esters inhibit autotaxin activity, thus inhibiting LPA production and regulating LPA levels and associated signal transduction.The autotaxin inhibitors described herein are useful as drugs for the treatment or prevention of diseases or conditions in which ATX activity and / or LPA signal transduction is involved, is involved in the pathogenesis or pathology of a disease, or is otherwise associated with at least one symptom of a disease.The ATX-LPA axis is involved in, for example, angiogenesis, chronic inflammation, autoimmune diseases, fibrotic diseases, cancer and tumor metastasis and progression, ophthalmic conditions, metabolic conditions such as obesity and / or diabetes mellitus, conditions such as cholestatic or other forms of chronic pruritus, and acute and chronic organ transplant rejection.

[0006] The object of the present invention is the compounds of formula (I) and the aforementioned salts and esters thereof and their use as therapeutically active substances, processes for the preparation of said compounds, intermediates, pharmaceutical compositions, medicinal products containing said compounds, their pharma- ceutically acceptable salts or esters, the use of said compounds, salts or esters for the treatment or prevention of disorders or conditions related to the activity of ATX and / or the biological activity of lysophosphatidic acid (LPA), in particular in the treatment or prevention of renal conditions, hepatic conditions, inflammatory conditions, neurological conditions, respiratory conditions, vascular and cardiovascular conditions, fibrotic diseases, cancer, ocular conditions, metabolic conditions, cholestatic and other forms of chronic pruritus and acute and chronic organ transplant rejection, and the use of said compounds, salts or esters for the preparation of medicinal products for the treatment or prevention of renal conditions, hepatic conditions, inflammatory conditions, neurological conditions, respiratory conditions, vascular and cardiovascular conditions, fibrotic diseases, cancer, ocular conditions, metabolic conditions, cholestatic and other forms of chronic pruritus and acute and chronic organ transplant rejection. More particularly, the compounds of formula (I) and the aforementioned salts and esters thereof and their use as therapeutically active substances, processes for the preparation of said compounds, intermediates, pharmaceutical compositions, medicaments containing said compounds, pharma-ceutically acceptable salts or esters thereof, and the use of said compounds, salts or esters for the treatment or prevention of ophthalmic conditions, more particularly glaucoma.

[0007] As used herein, the terms "including," "containing," and "comprising" are used in their open-ended sense.

[0008] As used in this disclosure, the articles "a" and "an" can refer to one or to more than one (e.g., to at least one) of the grammatical object of the article. For example, "an element" can mean one element or to more than one element.

[0009] "C 1-6 The term "-alkoxy" refers to a compound in which R' is C 1-6 - means a group of the formula -O-R' which is an alkyl group. 1-6 Examples of -alkoxy groups include methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, isobutoxy, tert-butoxy. Particular examples are methoxy and isopropoxy.

[0010] "C 1 - 6 The term "alkyl" refers to a monovalent linear or branched saturated hydrocarbon group having 1 to 6 carbon atoms. In some embodiments, unless otherwise specified, alkyl refers to a group having 1 to 6 carbon atoms (C 1 - 6 -alkyl) or 1 to 4 carbon atoms (C 1 - 4 -alkyl). 1 - 6 Examples of -alkyl include methyl, ethyl, propyl, isopropyl, n-butyl, iso-butyl, sec-butyl, tert-butyl, and pentyl. Particular 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, isobutyl, and t-butyl, and "propyl" can include n-propyl and isopropyl.

[0011] "C 2 - 6 The term "alkynyl" refers to an unsaturated unbranched or branched monovalent hydrocarbon chain having at least one site of acetylenic unsaturation (i.e., of formula C≡C). In some embodiments, unless otherwise specified, alkynyl is an alkyl group having 2 to 6 carbon atoms (C 2 - 6 -alkynyl) or 2 to 4 carbon atoms (C 2 - 4 -alkynyl). Examples of alkynyl groups include, but are not limited to, ethynyl (or acetylenyl), prop-1-ynyl, prop-2-ynyl (or propargyl), but-1-ynyl, but-2-ynyl, and but-3-ynyl.

[0012] The term "cyano" refers to the group -C≡N.

[0013] "Cyano-C 1-6 The term "C-alkyl" refers to 1-6 -C where one of the hydrogen atoms of the alkyl group is replaced by a cyano group 1-6 represents an alkyl group. Particular examples are cyanomethyl, cyanoethyl, cyanopropyl and cyanobutyl. Particular example is cyanopropyl.

[0014] "C 3-8 The term "cycloalkyl" refers to a monocyclic or polycyclic, saturated or partially unsaturated non-aromatic hydrocarbon. In some embodiments, unless otherwise specified, cycloalkyl refers to a cycloalkyl group having 3 to 8 carbon atoms (C 3-8 -cycloalkyl), 3 to 6 carbon atoms (C 3-6 -cycloalkyl) or 3 to 5 carbon atoms (C 3-5-cycloalkyl). In some embodiments, the cycloalkyl is a saturated monocyclic or polycyclic hydrocarbon. In other embodiments, the cycloalkyl contains one or more double bonds (e.g., a cycloalkyl fused to an aryl or heteroaryl ring, or a non-aromatic monocyclic hydrocarbon containing one or two double bonds). Polycyclic cycloalkyl groups may contain spiro, fused, or bridged polycyclic moieties, where each ring is a saturated or partially unsaturated non-aromatic hydrocarbon. Examples of cycloalkyl groups include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, octahydropentalenyl, spiro[3.3]heptanyl, and the like. Bicyclic means a ring system consisting of two saturated carbocyclic rings having two carbon atoms in common. Examples of monocyclic cycloalkyl are cyclopropyl, cyclobutanyl, cyclopentyl, cyclohexyl, or cycloheptyl.

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

[0016] "Haro-C 1 - 6 The term "C-alkoxy" refers to 1 - 6 At least one hydrogen atom of the alkoxy group is substituted with the same or different halogen atom. 1 - 6 -alkoxy group. Particular examples are difluoromethoxy, trifluoromethoxy, difluoroethoxy and trifluoroethoxy. A more particular example is trifluoromethoxy.

[0017] "Haro-C 1 - 6 The term "C-alkyl" refers to 1 - 6 At least one hydrogen atom of the alkyl group is replaced by the same or different halogen atom. 1 - 6-alkyl group. Particular examples are difluoromethyl, trifluoromethyl, difluoroethyl and trifluoroethyl. A more particular example is trifluoromethyl.

[0018] The term "heterocycloalkyl", alone or in combination, refers to a monovalent saturated or partially unsaturated monocyclic or bicyclic ring system of 4 to 9 ring atoms containing 1, 2, or 3 ring heteroatoms selected from N, O, and S, with the remaining ring atoms being carbon. Bicyclic means consisting of two rings that have at least one ring atom in common. Heterocycloalkyl groups may be saturated or unsaturated and, unless otherwise specified, may contain 5, 6, 7, 8, or 9 ring atoms, where the ring atoms refer to the total of the carbon atoms and heteroatoms in the ring or rings (e.g., 5-, 6-, 7-, 8-, or 9-membered heterocycloalkyl). Heterocycloalkyls may contain 1 to 5 ring heteroatoms, 1 to 4 heteroatoms, 1 to 3 ring heteroatoms, 1 or 2 ring heteroatoms, or groups containing 1 ring heteroatom. In some embodiments, heterocycloalkyls contain 1 ring, 2 rings, 3 rings, or 4 rings, e.g., as polycyclic fused systems. In some embodiments, heterocycloalkyls containing multiple rings include spiro ring systems in which one or more rings contain one or more heteroatoms. Examples of heterocycloalkyls are dihydrofuryl, imidazolinyl, dihydro-oxazolyl, tetrahydro-pyridinyl, or dihydropyranyl. A particular example is tetrahydropyranyl.

[0019] The term "hydroxy" refers to an --OH group.

[0020] The term "pharmaceutically acceptable salt" refers to a salt that retains the biological effectiveness and properties of the free base or free acid, without being biologically or otherwise undesirable. Salts are formed with inorganic acids, such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, and the like, 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, and the like. These salts may also be prepared by adding an inorganic or 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, and the like. Salts derived from organic bases include, but are not limited to, 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. Particular pharma-ceutically acceptable salts of the compounds of formula (I) include hydrochloride, methanesulfonate, citrate, and the like.

[0021] By "pharmaceutical acceptable ester" is meant that the compounds of general formula (I) can be derivatized at functional groups to provide derivatives 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. Furthermore, any physiologically acceptable equivalent of the compounds of general formula (I) that resembles the metabolically labile esters that the parent compounds of general formula (I) can produce in vivo is also within the scope of the present invention.

[0022] The abbreviation uM means micromolar and is equivalent to the symbol μM.

[0023] The abbreviation uL means microliter and is equivalent to the symbol μL.

[0024] The abbreviation ug stands for microgram and is equivalent to the symbol μg.

[0025] The compounds of formula (I) may contain several asymmetric centers and may exist as optically pure enantiomers, mixtures of enantiomers, e.g. racemates, optically pure diastereoisomers, mixtures of diastereoisomers, diastereomeric racemates or mixtures of diastereomeric racemates.

[0026] According to the Cahn-Ingold-Prelog rules, the asymmetric carbon atom can be of the "R" or "S" configuration.

[0027] Embodiments of the present invention also provide compounds according to formula (I) as described herein and pharma- ceutically acceptable salts or esters thereof, particularly compounds according to formula (I) as described herein and pharma- ceutically acceptable salts thereof, particularly compounds according to formula (I) as described herein.

[0028] Certain embodiments of the present invention are compounds according to formula (I) as described herein, R 1 , R 2 and R 3 is, independently, i) H, ii) C 1-6 -alkyl, iii) C 2-6 -alkynyl, iv) halogens, v) Halo-C 1-6 -alkyl, vi) Halo-C 1-6 -alkoxy, vii) cyano, viii) Cyano-C 1-6 -Alkyl is selected from the group consisting of R 1 and R 3 at least one of is other than H; R 4 and R 5 is, independently, i) H, ii) C 1-6 -Alkyl or selected from the group consisting of Or R 4 and R 5 taken together with the carbon atom to which they are attached, form a heterocycloalkyl or substituted C 3-8 -cycloalkyl, and the substituted cycloalkyl is R 6 and R 7 is replaced by R 6 and R 7 is independently selected from the group consisting of halogen, hydroxy or alkyl; The compound, or a pharma- ceutically acceptable salt, is provided.

[0029] Certain embodiments of the present invention are compounds according to formula (I) as described herein, R 1 , R 2 and R 3 is, independently, i) H, ii) C 1-6 -alkyl, iii) C 2-6 -alkynyl, iv) halogens, v) Halo-C 1-6 -alkyl, vi) Halo-C 1-6 -alkoxy, vii) Cyano is selected from the group consisting of R 1 and R 3 is other than H.

[0030] Another further particular embodiment of the present invention is a compound according to formula (I) as described herein, wherein R 4 and R 5 is, independently, i) H, ii) C1-6 -Alkyl or selected from the group consisting of Or R 4 and R 5 taken together with the carbon atom to which they are attached, are 4-membered heterocycloalkyl or substituted C 4 -cycloalkyl, and the substituted cycloalkyl is R 6 and R 7 The compound is provided in which the compound is substituted with

[0031] Another further particular embodiment of the present invention is a compound according to formula (I) as described herein, wherein R4 and R 5 is, independently, i) H, ii) Methyl or selected from the group consisting of Or R 4 and R 5 together with the carbon atom to which they are attached form an oxetane ring or a substituted C 4 -cycloalkyl, and the substituted cycloalkyl is R 6 and R 7 The compound is provided in which the compound is substituted with

[0032] Another further particular embodiment of the present invention is a compound according to formula (I) as described herein, R 6 and R 7 are both halogens, or R 6 is hydroxy and R 7 is alkyl.

[0033] Another further particular embodiment of the present invention is a compound according to formula (I) as described herein, R 6 and R 7 are both fluorine, or R 6 is hydroxy and R 7 is methyl.

[0034] In some embodiments, R 4 and R 5 taken together with the carbons to which they are attached, form a heterocycloalkyl ring. In certain embodiments, a heterocycloalkyl contains 1 to 3 ring heteroatoms independently selected from the group consisting of O, N, and S. In certain embodiments, R 4 and R 5 taken together with the carbon atom to which they are attached form a 4-membered heterocycloalkyl with a single oxygen. In certain embodiments, R 4 and R 5 together with the carbon atoms to which they are attached form an oxetane ring.

[0035] In some embodiments, R 4 and R 5 together with the carbon to which they are attached form the substitution C 3-8 -cycloalkyl, and the substituted cycloalkyl is R 6 and R 7 In certain embodiments, R 4 and R 5 together with the carbon atom to which they are attached form the substitution C 4 -cycloalkyl, and the substituted cycloalkyl is R 6 and R 7 has been replaced with.

[0036] In some embodiments, R 4 and R 5 are both methyl.

[0037] In some embodiments, R 6 and R 7 are both halogen. In certain embodiments, R 6 and R 7 are both fluorine atoms.

[0038] In some embodiments, R 6 is hydroxy and R 7 is methyl.

[0039] Certain embodiments of the present invention are compounds according to formula I(a) as described herein, R 1 , R 2 and R 3 is, independently, i) H, ii) C 1-6 -alkyl, iii) C 2-6 -alkynyl, iv) halogens, v) Halo-C 1-6 -alkyl, vi) Halo-C 1-6 -alkoxy, vii) Cyano is selected from the group consisting of R 1 and R 3 at least one of is other than H; R 4 and R 5 is, independently, i) H, ii) C 1-6 -Alkyl or selected from the group consisting of Or R 4 and R 5 together with the carbon atom to which they are attached form an oxetane ring or a substituted C 4 -cycloalkyl, and the substituted cycloalkyl is R 6 and R 7 is replaced by R 6 and R 7 are both halogens, or R 6 is hydroxy and R 7 is alkyl, The compound, or a pharma- ceutically acceptable salt, is provided.

[0040] Certain embodiments of the present invention are compounds according to formula I(a) as described herein, R 1 , R 2and R 3 is, independently, i) H, ii) C 1-6 -alkyl, iii) C 2-6 -alkynyl, iv) halogens, v) Halo-C 1-6 -alkyl, vi) Halo-C 1-6 -alkoxy, vii) Cyano is selected from the group consisting of R 1 and R 3 at least one of is other than H; R 4 and R 5 is, independently, i) H, ii) Methyl or selected from the group consisting of Or R 4 and R 5 together with the carbon atom to which they are attached form an oxetane ring or a substituted C 4 -cycloalkyl, and the substituted cycloalkyl is R 6 and R 7 is replaced by R 6 and R 7 are both fluorine, or R 6 is hydroxy and R 7 is methyl, The compound, or a pharma- ceutically acceptable salt, is provided.

[0041] Particular examples of compounds of formula (I) described herein are (2-((4-chloro-2,3-dihydro-1H-inden-2-yl)amino)pyrimidin-5-yl)(6-oxa-1-azaspiro[3.3]heptan-1-yl)methanone, (2-((4,6-dichloro-2,3-dihydro-1H-inden-2-yl)amino)pyrimidin-5-yl)(6-oxa-1-azaspiro[3.3]heptan-1-yl)methanone, (2-((6-chloro-4-methyl-2,3-dihydro-1H-inden-2-yl)amino)pyrimidin-5-yl)(6-oxa-1-azaspiro[3.3]heptan-1-yl)methanone, (2-((4,5-dichloro-2,3-dihydro-1H-inden-2-yl)amino)pyrimidin-5-yl)(6-oxa-1-azaspiro[3.3]heptan-1-yl)methanone, 2-((5-(6-oxa-1-azaspiro[3.3]heptane-1-carbonyl)pyrimidin-2-yl)amino)-6-chloro-2,3-dihydro-1H-indene-4-carbonitrile, (S)-2-((5-(6-oxa-1-azaspiro[3.3]heptane-1-carbonyl)pyrimidin-2-yl)amino)-6-chloro-2,3-dihydro-1H-indene-4-carbonitrile, (2-((6-chloro-4-(difluoromethoxy)-2,3-dihydro-1H-inden-2-yl)amino)pyrimidin-5-yl)(6-oxa-1-azaspiro[3.3]heptan-1-yl)methanone, (2-((5-chloro-4-methyl-2,3-dihydro-1H-inden-2-yl)amino)pyrimidin-5-yl)(6-oxa-1-azaspiro[3.3]heptan-1-yl)methanone, (2-((6-chloro-4-(prop-1-yn-1-yl)-2,3-dihydro-1H-inden-2-yl)amino)pyrimidin-5-yl)(6-oxa-1-azaspiro[3.3]heptan-1-yl)methanone, (2-((6-chloro-4-fluoro-2,3-dihydro-1H-inden-2-yl)amino)pyrimidin-5-yl)(6-oxa-1-azaspiro[3.3]heptan-1-yl)methanone, (2-((5-chloro-4-fluoro-2,3-dihydro-1H-inden-2-yl)amino)pyrimidin-5-yl)(6-oxa-1-azaspiro[3.3]heptan-1-yl)methanone, (S or R)-(2-((6-chloro-4-fluoro-2,3-dihydro-1H-inden-2-yl)amino)pyrimidin-5-yl)(6-oxa-1-azaspiro[3.3]heptan-1-yl)methanone, (2-((6-chloro-4-(trifluoromethyl)-2,3-dihydro-1H-inden-2-yl)amino)pyrimidin-5-yl)(6-oxa-1-azaspiro[3.3]heptan-1-yl)methanone, (S)-6-chloro-2-((5-(6,6-difluoro-1-azaspiro[3.3]heptane-1-carbonyl)pyrimidin-2-yl)amino)-2,3-dihydro-1H-indene-4-carbonitrile, (S)-6-chloro-2-((5-(2,2-dimethylazetidine-1-carbonyl)pyrimidin-2-yl)amino)-2,3-dihydro-1H-indene-4-carbonitrile, (cis)-6-chloro-2-(S)-((5-(6-hydroxy-6-methyl-1-azaspiro[3.3]heptane-1-carbonyl)pyrimidin-2-yl)amino)-2,3-dihydro-1H-indene-4-carbonitrile, and pharma- ceutically acceptable salts thereof.

[0042] Processes for the preparation of compounds of formula (I) as described herein are an object of the present invention.

[0043] The present compounds of formula I and their pharma- ceutically acceptable salts can be prepared by methods known in the art, for example by the methods described below, which methods comprise: a) Formula [ka] Compounds of formula [ka] in the presence of an activating agent such as HATU (1-[bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5-b]pyridinium 3-oxide hexafluorophosphate) to give a compound of the formula [ka] in which the substituents are as described above, or b) Formula [ka] Compounds of formula [ka] in the presence of a base such as diisopropylethylamine to give a compound of the formula [ka] wherein X is a halogen, such as Cl, and the other substituents are as described above, or, if desired, converting the resulting compound into a pharma- ceutically acceptable acid addition salt.

[0044] Compounds of formula I can be prepared according to process variant a) or b) and the following schemes 1-2. The starting materials are commercially available or can be prepared according to known methods.

[0045] Scheme 1 [ka]

[0046] Compounds of general formula I can be prepared by reacting an acid derivative of formula II with an amine of formula III in the presence of an activating agent such as HATU (1-[bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5-b]pyridinium 3-oxide hexafluorophosphate). Acids of formula II can be prepared by reacting an amine of formula IV with a halogenated ester of formula VI in the presence of a base such as diisopropylethylamine, followed by saponification in the presence of a base such as sodium hydroxide or lithium hydroxide.

[0047] Scheme 2 [ka]

[0048] Alternatively, compounds of general formula I can be prepared by reacting a halogenated derivative of formula V with an amine of formula IV in the presence of a base such as diisopropylethylamine. The halogenated derivative of formula V can be prepared by reacting an amine of formula III with an acid of formula VII in the presence of an activating agent such as 1-propanephosphonic anhydride.

[0049] Also an object of the present invention are the compounds according to formula (I) as described herein for use as therapeutically active substances.

[0050] Also 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.

[0051] An object of the present invention is the use of compounds according to formula (I) as described herein for the treatment or prevention of renal conditions, hepatic conditions, inflammatory conditions, neurological conditions, respiratory conditions, vascular and cardiovascular conditions, fibrotic diseases, cancer, ophthalmic conditions, metabolic conditions, cholestatic and other forms of chronic pruritis and acute and chronic organ transplant rejection.

[0052] Renal conditions include, but are not limited to, acute kidney injury and chronic kidney disease with or without proteinuria, including end-stage renal disease (ESRD). More specifically, they include swelling and proliferation of intracapillary (endothelial and mesangial) and / or extracapillary cells (crescents), such as reduced creatinine clearance and reduced glomerular filtration rate, microalbuminuria, albuminuria and proteinuria, glomerulosclerosis with expansion of plexiform mesangial matrix with or without significant hypercellularity (particularly diabetic nephropathy and amyloidosis), focal thrombosis of glomerular capillaries (particularly thrombotic microangiopathy), global fibrinoid necrosis, ischemic lesions, malignant nephrosclerosis (such as ischemic contraction, reduced renal blood flow and renal arteriopathy), glomerulonephritis entities, focal segmental glomerulosclerosis, IgA nephropathy, vasculitis / systemic disease and acute and chronic kidney transplant rejection.

[0053] Liver conditions include, but are not limited to, cirrhosis, liver congestion, cholestatic liver disease including pruritus, nonalcoholic steatohepatitis, and acute and chronic liver transplant rejection.

[0054] Inflammatory conditions include, but are not limited to, arthritis, osteoarthritis, multiple sclerosis, systemic lupus erythematosus, inflammatory bowel disease, abnormal bowel movements, and the like, as well as inflammatory airway diseases such as idiopathic pulmonary fibrosis (IPF), chronic obstructive pulmonary disease (COPD) or chronic bronchial asthma.

[0055] Further manifestations of the respiratory system include, but are not limited to, iatrogenic drug-induced fibrosis, occupational and / or environmentally induced fibrosis, systemic diseases and other diffuse parenchymal lung diseases of different etiology including vasculitis, granulomatous diseases (sarcoidosis, hypersensitivity pneumonitis), collagen 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).

[0056] Conditions of the nervous system include, but are not limited to, neuropathic pain, schizophrenia, neuroinflammation (eg, astrogliosis), peripheral and / or autonomic (diabetic) neuropathies, and the like.

[0057] Vascular conditions include, but are not limited to, atherosclerosis, thrombotic vascular disease, as well as thrombotic microangiopathy, proliferative arteriopathy (such as swollen myointimal cells surrounded by myxoid extracellular matrix and nodular thickening), atherosclerosis, decreased vascular compliance (stiffness, decreased ventricular compliance, and decreased vascular compliance), endothelial dysfunction, and the like.

[0058] Cardiovascular conditions include, but are not limited to, acute coronary syndromes, coronary heart disease, myocardial infarction, arterial and pulmonary hypertension, cardiac arrhythmias such as atrial fibrillation, stroke and other vascular injuries.

[0059] Fibrotic diseases include, but are not limited to, myocardial and vascular fibrosis, renal fibrosis, hepatic fibrosis, pulmonary fibrosis, skin fibrosis, scleroderma, and encapsulating peritonitis.

[0060] 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 their progression and metastatic aggressiveness.

[0061] Ophthalmic conditions include, but are not limited to, proliferative and non-proliferative (diabetic) retinopathy, dry and wet age-related macular degeneration (AMD), macular edema, central arterial / venous occlusion, traumatic injury, glaucoma, etc. In particular, the ophthalmic condition is glaucoma.

[0062] Metabolic conditions include, but are not limited to, obesity and diabetes.

[0063] The present invention also relates to the use of the compounds according to formula (I) as described herein for the treatment or prevention of renal conditions, hepatic conditions, inflammatory conditions, neurological conditions, fibrotic diseases and acute and chronic organ transplant rejection.

[0064] The present invention also relates to the use of the compounds according to formula (I) as described herein for the treatment or prevention of renal conditions, hepatic conditions and fibrotic diseases.

[0065] A particular embodiment of the present invention is a compound according to formula (I) as described herein for the treatment or prevention of renal conditions, hepatic conditions, inflammatory conditions, neurological conditions, fibrotic diseases and acute and chronic organ transplant rejection.

[0066] A particular embodiment of the present invention are compounds according to formula (I) as described herein for the treatment or prevention of renal conditions, hepatic conditions and fibrotic diseases.

[0067] The present invention also relates to the use of a compound according to formula (I) as described herein for the preparation of a medicament for the treatment or prevention of renal conditions, hepatic conditions, inflammatory conditions, neurological conditions, fibrotic diseases and acute and chronic organ transplant rejection.

[0068] The present invention also relates to the use of a compound according to formula (I) as described herein for the preparation of a medicament for the treatment or prevention of renal conditions, hepatic conditions and fibrotic diseases.

[0069] Also an object of the present invention is a method for the treatment or prevention of renal conditions, hepatic conditions, inflammatory conditions, neurological conditions, fibrotic diseases and acute and chronic organ transplant rejection, comprising administering an effective amount of a compound according to formula (I) as described herein.

[0070] Also an object of the present invention is a method for the treatment or prevention of renal conditions, hepatic conditions and fibrotic diseases comprising administering an effective amount of a compound according to formula (I) as described herein.

[0071] One embodiment of the present invention also provides a compound of formula (I) as described herein when prepared according to any one of the processes described.

[0072] Assay procedure Producing human full-length ATX with or without a tag

[0073] Autotaxin (ATX-ENPP2) cloning: cDNA was prepared from commercially available human hematopoietic cell total RNA and used as template in overlap PCR to generate full-length human ENPP2 ORF with or without the 3'-6xHis tag. These full-length inserts were cloned into the pcDNA3.1V5-His TOPO (Invitrogen) vector. The DNA sequence of several single clones was verified. DNA from the correct full-length clone was used to transfect Hek293 cells for verification of protein expression. The sequence of the encoded ENPP2 follows Swissprot entry Q13822, with or without the additional C-terminal 6xHis tag.

[0074] ATX fermentation: Recombinant proteins were produced by large-scale transient transfection in a 20 L controlled stirred tank bioreactor (Sartorius). During cell growth and transfection, 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) and transfected at approximately 30°C, approximately 1-1.5 x 10E6 cells / mL with the above plasmid DNA using X-tremeGENE Ro-1539 (commercially available, Roche Diagnostics) as a complexing agent. Cells were fed with 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 assays and / or analytical IMAC chromatography. After cooling the cell suspension to 4°C in a flow-through heat exchanger, cell separation and sterile filtration of the supernatant was performed by filtration through Zeta Plus 60M02 E16 (Cuno) and Sartopore 2 XLG (Sartorius) filter units. Supernatants were stored at 4°C prior to purification.

[0075] ATX purification: 20 liters of culture supernatant was adjusted by adding Brij 35 to a final concentration of 0.02% and adjusting the pH to 7.0 with 1M HCl. The supernatant was then microfiltered first with a 0.2 pm Ultratran-Pilot Open Channel PES filter (Whatman) and then concentrated to 1 liter with an Ultratran-Pilot Screen Channel PES filter with 30 kDa MWCO (Whatman). NiSO4 was added to a final concentration of 1 mM before IMAC chromatography. The clarified supernatant was then applied to a HisTrap column (GE Healthcare) pre-equilibrated in 50 mM Na2HPO4 pH 7.0, 0.5 M NaCl, 10% glycerol, 0.3% CHAPS, 0.02% NaN3.

[0076] The column was washed stepwise with the same buffer containing 20 mM, 40 mM and 50 mM imidazole, respectively. Protein was subsequently eluted using a linear gradient to 0.5 M imidazole over 15 column volumes. ATX-containing fractions were pooled and concentrated using an Amicon cell equipped with a 30 kDa PES filter membrane. Protein was further purified by size-exclusion chromatography on a 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 protein after purification was 5-10 mg ATX per liter of culture supernatant. Protein was stored at -80 °C.

[0077] Human ATX enzyme inhibition assay To identify inhibitors of the human autotaxin (ATX) enzyme, an in vitro biochemical profiling assay was developed using lysophosphatidylcholine (LPC) as a substrate and recombinant enzyme. ATX activity is assayed via a coupled enzyme format in which choline generated from LPC hydrolysis is converted to hydrogen peroxide by choline oxidase (CO). Hydrogen peroxide is then used as a co-substrate by horseradish peroxidase (HRP) to oxidize Amplex Red® and generate the red fluorescent product, resorufin.

[0078] Materials / Reagents 500mM Tris-HCl pH8.0; 1M NaCl; 250mM CaCl 2 ;250mM KCl;250mM MgCl 2 ;H 2 10% Triton X-100 in O.

[0079] Assay buffer 50mM Tris-HCl (pH 8.0); 120mM NaCl; 20mM CaCl 2 ;5mM KCl;1mM MgCl 2 0.01% Triton X-100, sterile filtered and stored at 4°C.

[0080] Reagent Dilution Buffer 50mM Tris-HCl (pH 8.0); 150mM NaCl Human autotaxin (hATX): 0.97 mg / ml (9.718 μM) molecular weight 99817. A working solution of 1.5 μM was used in this assay.

[0081] 100 mM 18:1 LPC was dissolved in reagent dilution buffer.

[0082] Choline oxidase at 500 U / ml in reagent dilution buffer.

[0083] Horseradish peroxidase at 2540 U / ml in reagent dilution buffer (10.95 mg / ml).

[0084] 20 mM Amplex Red (10-acetyl-3,7-dihydroxy-phenoxazine) in DMSO.

[0085] Reaction Plate Black, 384 well plate, black with clear bottom, untreated surface.

[0086] Test compounds are received prediluted in DMSO as an 11-point concentration-response (0.5 mM top concentration; 1 in 3.162 dilutions). Test compounds are prediluted 1:1 (10 μL compound + 10 μL assay buffer) in 96-well conical bottom plates prior to use.

[0087] procedure ATX is diluted to 2.2 nM in assay buffer. Choline oxidase and horseradish peroxidase are diluted to 7.3 U / ml and 14.7 U / ml, respectively. 18:1 LPC and Amplex Red® are diluted to 110 μM and 183.3 μM, respectively (solutions protected from light). 2.2 μL of compound pre-dilutions or 50% DMSO are added to the reaction plate, followed by 25 μL of ATX or assay buffer (negative control). The assay plate is mixed and incubated at room temperature for 10 minutes. Then 15 μL of choline oxidase / horseradish peroxidase are added. To start the reaction, 15 μL of LPC18:1 / Amplex Red is added. The assay plate is mixed and incubated at room temperature in the dark. Fluorescence is measured at 5 minutes (for background subtraction) and 90 minutes.

[0088] Final assay concentration: hATX:1nM 18:1 LPC: 30μM Choline oxidase: 2U / ml Horseradish peroxidase: 4U / ml Amplex Red®: 50 μM DMSO: 2% Fluorescence at 5 min is subtracted from the 90 min endpoint data and normalized to the positive control. IC 50 Calculate the value.

[0089] Results of the enzyme ATX inhibition assay are provided for compounds of formula (I). [Table 1]

[0090] The compounds of formula (I) and their pharma- ceutically acceptable salts or esters described herein have IC 50 These results were obtained by using the enzyme assay described above.

[0091] The compounds of formula (I) and their pharma- ceutically acceptable salts can be used as medicines (e.g., in the form of pharmaceutical preparations). The pharmaceutical preparations of the present invention can be administered internally, such as orally (e.g., in the form of tablets, coated tablets, dragees, hard or soft gelatin capsules, solutions, emulsions or suspensions), nasally (e.g., in the form of nasal sprays), rectally (e.g., in the form of suppositories), or topically to the eye (e.g., in the form of solutions, ointments, gels or water-soluble polymeric inserts). However, administration can also be carried out parenterally, such as intramuscularly, intravenously, intraocularly, etc. (e.g., in the form of sterile injection solutions).

[0092] The compounds of formula (I) and their pharma- ceutically acceptable salts can be processed with pharma- ceutically inert, inorganic or organic adjuvants for the preparation of tablets, coated tablets, dragees, hard gelatin capsules, injectable 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.

[0093] Suitable adjuvants for soft gelatin capsules include, by way of example, vegetable oils, waxes, fats, semisolids, liquid polyols, etc.

[0094] Suitable adjuvants for the production of solutions and syrups are, for example, water, polyols, saccharose, invert sugars, glucose etc.

[0095] Suitable adjuvants for injection solutions are, for example, water, alcohols, polyols, glycerol, vegetable oils, etc.

[0096] Suitable adjuvants for suppositories are, for example, natural or hardened oils, waxes, fats, semisolid or liquid polyols etc.

[0097] Suitable adjuvants for topical ophthalmic formulations are, for example, cyclodextrin, mannitol or many other carriers and excipients known in the art.

[0098] In addition, pharmaceutical preparations may contain preservatives, solubilizers, viscosity-increasing substances, stabilizers, wetting agents, emulsifiers, sweeteners, colorants, flavorings, salts for varying the osmotic pressure, buffers, masking agents, or antioxidants. They may also contain other therapeutically valuable substances.

[0099] The dosage can vary widely and will of course be adapted to the individual requirements in each particular case. In general, for oral administration, the daily dose is from about 0.1 mg to about 20 mg per kg of body weight, preferably from about 0.5 mg to about 4 mg per kg of body weight (e.g., about 300 mg per person), preferably administered separately in 1 to 3 separate doses, which, if appropriate, can be composed, for example, of equal amounts. For topical administration, the formulation can contain 0.001% to 15% by weight of the pharmaceutical agent, and the required amount, which can be between 0.1 and 25 mg, can be a single dose per day, a single dose per week, multiple doses per day (2 to 4 times), or multiple doses per week. However, it is clear that, where this is indicated, the upper or lower limits described herein may be exceeded.

[0100] The present invention will be described below with reference to examples, but the present invention is not limited to these.

[0101] Where a preparative example is obtained as a mixture of enantiomers, the pure enantiomers can be obtained by methods described herein or known to those skilled in the art, such as chiral chromatography or crystallization. EXAMPLES

[0102] Unless otherwise stated, all examples and intermediates were prepared under an argon atmosphere.

[0103] Intermediate A Intermediate A1: 4,6-dichloro-2,3-dihydro-1H-inden-2-aminium 2,2,2-trifluoroacetate [ka]

[0104] Step 1: 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-2,3-dihydro-1H-inden-2-yl)carbamate [ka]

[0105] 4,4,4',4',5,5,5',5'-Octamethyl-2,2'-bi(1,3,2 dioxaborolane) (2.42 g, 9.34 mmol), (1,5-cyclooctadiene)(methoxy)iridium(I) dimer (309 mg, 467 μmol), tert-butyl (5-chloro-2,3-dihydro-1H-inden-2-yl)carbamate (2.50 g, 9.34 mmol, CAS: 1934835-81-0) and 3,4,7,8-tetramethyl-1,10-phenanthroline (221 mg, 934 μmol) were combined in a microwave vial (dried using high vacuum and flushed with argon) and suspended in dry THF (10 ml). Upon mixing the reagents the suspension turned dark green. Argon was bubbled through the suspension for 10 min. The reaction mixture was heated to 80° C. and stirred for 15 hours (became dark purple). The reaction mixture was filtered through sintered glass and concentrated in vacuo. The crude material was purified by flash chromatography on silica gel using a gradient ethyl acetate / heptane 0-30% to give the title compound as an off-white solid (2.30 g, 63% yield). MS (ESI): m / z=294.2 [M-Boc+H] +

[0106] Step 2: tert-Butyl (4,6-dichloro-2,3-dihydro-1H-inden-2-yl)carbamate [ka]

[0107] 4-(4,4,5,5-Tetramethyl-1,3,2-dioxaborolan-2-yl)-2,3-dihydro-1H-inden-2-yl)carbamate (100 mg, 254 μmol) was dissolved in EtOH (2.54 ml) and added to a solution of copper(II) chloride (104 mg, 775 μmol) in distilled water (2.54 ml). The reaction was heated to 90° C. for 6 h, poured into water and extracted with EtOAc. The layers were separated and the aqueous layer was extracted two more times with EtOAc. The combined organic layers were washed with brine, dried over anhydrous sodium sulfate and evaporated to dryness. The crude product was purified by flash chromatography on silica gel using a gradient ethyl acetate / heptane 0-50% to give the title compound as a brown solid (20 mg, 26% yield). MS (ESI): m / z=246.1 [M-tBu]

[0108] Step 3: 4,6-Dichloro-2,3-dihydro-1H-inden-2-aminium 2,2,2-trifluoroacetate [ka]

[0109] tert-Butyl (4,6-dichloro-2,3-dihydro-1H-inden-2-yl)carbamate (17 mg, 56.3 μmol, equiv.: 1) was dissolved in TFA (811 μl) and stirred at room temperature for 1 h. The solvent was evaporated to give the title compound as a colorless oil (13 mg, 41.1 μmol, 73.1% yield). MS (ESI): m / z=202.1 M-TFA

[0110] Intermediate A2: 6-chloro-4-methyl-2,3-dihydro-1H-inden-2-aminium chloride [ka]

[0111] Step 1: tert-Butyl (6-chloro-4-hydroxy-2,3-dihydro-1H-inden-2-yl)carbamate [ka]

[0112] 4-(4,4,5,5-Tetramethyl-1,3,2-dioxaborolan-2-yl)-2,3-dihydro-1H-inden-2-yl)carbamate (Intermediate A1, Step 1) (850 mg, 1.84 mmol) was dissolved in THF (5.56 ml) and water (556 μl) and sodium perborate monohydrate (549 mg, 5.51 mmol) was added. The reaction was stirred at room temperature for 18 hours. The solvent was evaporated and the residue was dissolved in water and extracted with EtOAc. The layers were separated and the aqueous layer was extracted two more times with EtOAc. The combined organic layers were washed with brine, dried over anhydrous sodium sulfate and evaporated to dryness. The crude product was subjected to flash chromatography on silica gel using a gradient of 0-50% ethyl acetate / heptane to give the title compound as an off-white solid (220 mg, 42% yield). MS(ESI): m / z=282.2[MH] +

[0113] Step 2: 2-((tert-butoxycarbonyl)amino)-6-chloro-2,3-dihydro-1H-inden-4-yl trifluoromethanesulfonate [ka]

[0114] tert-Butyl (6-chloro-4-hydroxy-2,3-dihydro-1H-inden-2-yl)carbamate (50 mg, 176 μmol) was dissolved in dry DCM (705 μl) and triethylamine (19.6 mg, 27 μl, 194 μmol) was added. To this stirred solution was added 1,1,1-trifluoro-N-phenyl-N-((trifluoromethyl)sulfonyl)methanesulfonamide (69.2 mg, 194 μmol). The reaction was stirred at room temperature for 3 h, poured into water and extracted with EtOAc. The layers were separated and the aqueous layer was extracted twice with EtOAc. The combined organic layers were washed with brine, dried over anhydrous sodium sulfate and evaporated to dryness. The crude product was subjected to silica gel flash chromatography using a gradient of 0-50% ethyl acetate / heptane to give the title compound as a white solid (42 mg, 57% yield). MS(ESI): m / z=414.1[MH] +

[0115] Step 3: tert-Butyl (6-chloro-4-methyl-2,3-dihydro-1H-inden-2-yl)carbamate [ka]

[0116] Potassium trifluoro(methyl)borate (17.6 mg, 144 μmol) was suspended in THF (1.31 ml). Cesium carbonate (141 mg, 433 μmol), bis(diphenylphosphino)ferrocene]dichloropalladium(II) dichloromethane complex (11.8 mg, 14.4 μmol) and 2-((tert-butoxycarbonyl)amino)-6-chloro-2,3-dihydro-1H-inden-4-yl trifluoromethanesulfonate (60 mg, 144 μmol) were added followed by water (131 μl). Argon was bubbled through the reaction for 5 min and then the reaction was heated to 80° C. for 22 h. The reaction was poured into water and extracted with EtOAc. The layers were separated and the aqueous layer was extracted two more times with EtOAc. The combined organic layers were washed with brine, dried over anhydrous sodium sulfate and evaporated to dryness. The crude product was subjected to silica gel flash chromatography using a gradient of 0-50% ethyl acetate / heptane to give the title compound as a colorless oil (24 mg, 53% yield). MS (ESI): m / z=226.1 [M-tBu] +

[0117] Step 4: 6-chloro-4-methyl-2,3-dihydro-1H-indene-2-aminium chloride [ka]

[0118] tert-Butyl (6-chloro-4-methyl-2,3-dihydro-1H-inden-2-yl)carbamate (25 mg, 79.8 μmol) was dissolved in HCl 4M in dioxane (1.01 ml) and stirred at room temperature for 1 h. The solvent was evaporated to give the title compound as a white solid (17 mg, 97.6% yield). MS (ESI): m / z=182.1 [M+H] +

[0119] Intermediate A3: 4,5-dichloro-2,3-dihydro-1H-indene-2-aminium chloride [ka]

[0120] Step 1: tert-Butyl (5-amino-4-chloro-2,3-dihydro-1H-inden-2-yl)carbamate [ka]

[0121] A solution of tert-butyl (5-amino-2,3-dihydro-1H-inden-2-yl)carbamate (200 mg, 773 μmol, CAS: 246873-45-0) and N-chlorosuccinimide (105 mg, 773 μmol) in DMF (2 ml) was stirred at room temperature for 2 h. The reaction mixture was poured into water and extracted twice with EtOAc. The combined organic layers were washed once with brine and twice with water, dried over sodium sulfate and concentrated in vacuo. The crude material was purified by flash chromatography followed by SFC separation of the two resulting regioisomers to give the title compound as an off-white solid (10 mg, 5% yield). MS (ESI): m / z=227.1 [M-tBu] +

[0122] Step 2: tert-Butyl (4,5-dichloro-2,3-dihydro-1H-inden-2-yl)carbamate [ka]

[0123] CuCl in acetonitrile (1 ml) 2To a stirred suspension of (84.1 mg, 620 μmol) was added dropwise tert-butyl nitrite (88.7 mg, 774 μmol). The reaction mixture was cooled to 0° C. and a solution of tert-butyl (5-amino-4-chloro-2,3-dihydro-1H-inden-2-yl)carbamate (146 mg, 516 μmol) in acetonitrile (2 ml) was added dropwise over 5 min. The reaction mixture was warmed to room temperature and stirred for 2 h. The resulting dark mixture was poured into water and extracted twice with EtOAc. The combined organic layers were washed once with brine and twice with water, dried over sodium sulfate and concentrated in vacuo. The crude material was purified by flash chromatography on silica gel using a gradient ethyl acetate / heptane 0-50% to give the title compound as a white solid (102 mg, 65% yield). MS (ESI): m / z=246.1 [M-tBu] +

[0124] Step 3: 4,5-Dichloro-2,3-dihydro-1H-indene-2-aminium chloride [ka]

[0125] The title compound was prepared from tert-butyl (4,5-dichloro-2,3-dihydro-1H-inden-2-yl)carbamate according to the procedure described for Intermediate A2, step 4 (83% yield, white solid). MS (ESI): m / z=202.1 [M+H] +

[0126] Intermediate A4: 6-chloro-4-cyano-2,3-dihydro-1H-indene-2-aminium chloride [ka]

[0127] Step 1: tert-Butyl (6-chloro-4-cyano-2,3-dihydro-1H-inden-2-yl)carbamate [ka]

[0128] 2-((tert-butoxycarbonyl)amino)-6-chloro-2,3-dihydro-1H-inden-4-yl trifluoromethanesulfonate (60 mg, 144 μmol, Intermediate A2, Step 2), zinc cyanide (9.32 mg, 79.4 μmol) and tetrakis(triphenylphosphine)palladium(0) (16.7 mg, 14.4 μmol) were dissolved in dry DMF (721 μl) and argon was bubbled through the reaction for 5 minutes. The reaction was heated to 110° C. for 2 hours. The reaction was poured into LiCl 10% and extracted with EtOAc. The layers were separated and the aqueous layer was extracted two more times with EtOAc. The combined organic layers were washed with brine, dried over anhydrous sodium sulfate and evaporated to dryness. The crude product was subjected to silica gel flash chromatography using a gradient of 0-50% ethyl acetate / heptane to give the title compound as a white solid (24 mg, 57% yield). MS (ESI): m / z=237.1 [M-tBu] +

[0129] Step 2: 6-chloro-4-cyano-2,3-dihydro-1H-indene-2-aminium chloride [ka]

[0130] The title compound was prepared from tert-butyl (6-chloro-4-cyano-2,3-dihydro-1H-inden-2-yl)carbamate according to the procedure described for Intermediate A2, step 4 (100% yield, white solid). MS (ESI): m / z=193.1 [M+H] +

[0131] Intermediate A5: (S)-6-chloro-4-cyano-2,3-dihydro-1H-indene-2-aminium chloride [ka]

[0132] Step 1: (S)-tert-butyl (6-chloro-4-cyano-2,3-dihydro-1H-inden-2-yl)carbamate [ka]

[0133] Tert-butyl (6-chloro-4-cyano-2,3-dihydro-1H-inden-2-yl)carbamate (65 mg, 222 μmol, Intermediate A4, step 1) was separated on a chiral column (OZ-H, 12 nm, 5 μm, 250 × 4.6 mm) under SFC conditions to give the title compound as a white solid (32 mg, 49.2% yield, 96% ee, second eluting enantiomer, retention time: 6.6 min). MS (ESI) m / z: 237.1 [M-tBu] +

[0134] Step 2: (S)-6-Chloro-4-cyano-2,3-dihydro-1H-indene-2-aminium chloride [ka]

[0135] The title compound was prepared from (S)-tert-butyl (6-chloro-4-cyano-2,3-dihydro-1H-inden-2-yl)carbamate according to the procedure described for Intermediate A2, step 4 (100% yield, white solid). MS (ESI): m / z=193.1 [M+H] +

[0136] Intermediate A6: 6-chloro-4-(difluoromethoxy)-2,3-dihydro-1H-inden-2-aminium chloride [ka]

[0137] Step 1: tert-Butyl (6-chloro-4-(difluoromethoxy)-2,3-dihydro-1H-inden-2-yl)carbamate [ka]

[0138] tert-Butyl (6-chloro-4-hydroxy-2,3-dihydro-1H-inden-2-yl)carbamate (Intermediate A2, Step 1) (70 mg, 247 μmol) and potassium hydroxide (138 mg, 2.47 mmol) were dissolved in a mixture of MeCN (1.23 ml) and water (1.23 ml). The mixture was cooled to 0° C. and diethyl (bromodifluoromethyl)phosphonate (132 mg, 87.7 μl, 493 μmol) was added. The reaction was stirred at 0° C. for 1 h and then allowed to warm to room temperature. The reaction was stirred at room temperature for 18 h. After this time a second portion of diethyl (bromodifluoromethyl)phosphonate (132 mg, 87.7 μl, 493 μmol) was added. The solvent was evaporated and then dissolved in water and extracted with EtOAc. The layers were separated and the aqueous layer was extracted two more times with EtOAc. The combined organic layers were washed with brine, dried over anhydrous sodium sulfate and evaporated to dryness. The crude product was subjected to flash chromatography on silica gel using a gradient of ethyl acetate / heptane 0-100% to give the title compound as a colorless oil (42 mg, 47% yield). MS (ESI): m / z=378.3 [M+HCOO] +

[0139] Step 2: 6-chloro-4-(difluoromethoxy)-2,3-dihydro-1H-indene-2-aminium chloride [ka]

[0140] The title compound was prepared from tert-butyl (6-chloro-4-(difluoromethoxy)-2,3-dihydro-1H-inden-2-yl)carbamate according to the procedure described for Intermediate A2, step 4 (96% yield, white solid). MS (ESI): m / z=234.1 [M+H] +

[0141] Intermediate A7: 5-chloro-4-methyl-2,3-dihydro-1H-inden-2-aminium chloride [ka]

[0142] Step 1: tert-Butyl (5-amino-6-chloro-2,3-dihydro-1H-inden-2-yl)carbamate [ka]

[0143] A solution of tert-butyl (5-amino-2,3-dihydro-1H-inden-2-yl)carbamate (200 mg, 773 μmol, CAS: 246873-45-0) and N-chlorosuccinimide (105 mg, 773 μmol) in DMF (2 ml) was stirred at room temperature for 2 h. The reaction mixture was poured into water and extracted twice with EtOAc. The combined organic layers were washed once with brine and twice with water, dried over sodium sulfate and concentrated in vacuo. The crude material was purified by flash chromatography on silica gel using a gradient ethyl acetate / heptane 0-50% to give the title compound as a yellow gum (48 mg, 16% yield). MS (ESI): m / z=227.1 [M-tBu] +

[0144] Step 2: tert-Butyl (5-amino-6-chloro-4-iodo-2,3-dihydro-1H-inden-2-yl)carbamate [ka]

[0145] To a stirred solution of tert-butyl (5-amino-6-chloro-2,3-dihydro-1H-inden-2-yl)carbamate (47 mg, 123 μmol) in DMF (2 ml) was added N-iodo-succinimide (29.1 mg, 129 μmol). The resulting dark brown solution was stirred at room temperature for 20 h, 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 ethyl acetate / heptane 0-50% to give the title compound as a white solid (37 mg, 74% yield). MS (ESI): m / z=353.0 [M-tBu] +

[0146] Step 3: tert-Butyl (5-amino-6-chloro-4-methyl-2,3-dihydro-1H-inden-2-yl)carbamate [ka]

[0147] A mixture of tert-butyl (5-amino-6-chloro-4-iodo-2,3-dihydro-1H-inden-2-yl)carbamate (36 mg, 88.1 μmol), trimethylboroxine (15.6 mg, 17.4 μl, 123 μmol), potassium carbonate (18.3 mg, 132 μmol) and tetrakistriphenylphosphinepalladium(0) (5.14 mg, 4.4 μmol) in dioxane (750 μl) and water (250 μl) was heated to 110° C. and stirred for 15 h. 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 ethyl acetate / heptane 0-50% to give the title compound as a colorless gum (21 mg, 80% yield). MS(ESI): m / z=241.1[M-tBu] +

[0148] Step 4: tert-Butyl (5-amino-4-methyl-2,3-dihydro-1H-inden-2-yl)carbamate [ka]

[0149] tert-Butyl (5-amino-6-chloro-4-methyl-2,3-dihydro-1H-inden-2-yl)carbamate (152 mg, 512 μmol) was dissolved in methanol (5 ml), Pd / C (54.5 mg, 51.2 μmol) was added, and the reaction mixture was stirred at room temperature for 15 hours. The reaction mixture was filtered through Celite and concentrated in vacuo to give the title compound as a pale grey solid (130 mg, 97% yield). MS (ESI): m / z=207.2 [M-tBu] +

[0150] Step 5: 5-Chloro-4-methyl-2,3-dihydro-1H-indene-2-aminium chloride [ka]

[0151] The title compound was prepared from tert-butyl (5-amino-4-methyl-2,3-dihydro-1H-inden-2-yl)carbamate according to the procedure described for Intermediate A2, step 4 (80% yield, off-white solid). MS (ESI): m / z=182.1 [M+H] +

[0152] Intermediate A8: 6-chloro-4-(prop-1-yn-1-yl)-2,3-dihydro-1H-inden-2-aminium chloride [ka]

[0153] Step 1: tert-Butyl (6-chloro-4-cyano-2,3-dihydro-1H-inden-2-yl)carbamate [ka]

[0154] 2-((tert-butoxycarbonyl)amino)-6-chloro-2,3-dihydro-1H-inden-4-yl trifluoromethanesulfonate (80 mg, 192 μmol, intermediate A2, step 2), trimethyl(prop-1-yn-1-yl)silane (64.8 mg, 56.7 μl, 577 μmol), triethylamine (58.4 mg, 80.4 μl, 577 μmol), bis(diphenylphosphino)ferrocene]dichloropalladium(II) (42.2 mg, 57.7 μmol), potassium fluoride (33.5 mg, 577 μmol) and copper(I) iodide (5.5 mg, 28.9 μmol) were suspended in dry DMF (1.28 ml). Argon was bubbled through the solution for 5 min. The reaction was then heated to 80° C. for 4 h. The reaction was diluted with EtOAc and poured into 10% LiCl solution. The layers were separated and the aqueous layer was extracted two more times with EtOAc. The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, filtered through Celite, and evaporated to dryness. The crude product was subjected to flash chromatography on silica gel using a gradient ethyl acetate / heptane 0-100% to give the title compound as a yellow oil (57 mg, 97% yield). MS (ESI): m / z=250.1 [M-tBu] +

[0155] Step 2: 6-chloro-4-(prop-1-yn-1-yl)-2,3-dihydro-1H-indene-2-aminium chloride [ka]

[0156] The title compound was prepared from tert-butyl (6-chloro-4-cyano-2,3-dihydro-1H-inden-2-yl)carbamate according to the procedure described for Intermediate A2, step 4 (100% yield, light brown solid). MS (ESI): m / z=206.1 [M+H] +

[0157] Intermediate A9: 6-chloro-4-fluoro-2,3-dihydro-1H-indene-2-aminium chloride [ka]

[0158] Step 1: 1,2-bis(bromomethyl)-5-chloro-3-fluorobenzene [ka]

[0159] A mixture of 2-(bromomethyl)-5-chloro-1-fluoro-3-methylbenzene (620 mg, 2.61 mmol, CAS: 1807268-05-8), N-bromosuccinimide (516 mg, 2.87 mmol) and AIBN (8.75 mg, 52.2 μmol) in CCl 4 The suspension in (15 ml) was heated to 85° C. and stirred for 15 h. The reaction mixture was filtered through sintered glass and concentrated in vacuo. The residue was purified by flash chromatography on silica gel using a gradient ethyl acetate / heptane 0-20% to give the title compound as a colorless oil (698 mg, 67% yield).

[0160] Step 2: Dimethyl 6-chloro-4-fluoro-1,3-dihydro-2 H-indene-2,2-dicarboxylate [ka]

[0161] To a solution of dimethyl malonate (131 mg, 114 μl, 973 μmol) in THF (2 ml) was added NaH (38.9 mg, 973 μmol) at 0° C. After stirring for 15 min at 0° C., a solution of 1,2-bis(bromomethyl)-5-chloro-3-fluorobenzene (350 mg, 885 μmol) in THF (3 ml) was added dropwise at 0° C. After stirring for 15 min at 0° C., NaH (38.9 mg, 973 μmol) was added again. The reaction mixture was allowed to warm to room temperature and stirred for 15 h. The resulting suspension was poured into a saturated ammonium chloride solution 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 ethyl acetate / heptane 0-50% to give the title compound as a white solid (62 mg, 25% yield). MS(ESI): m / z=287.1[M+H] +

[0162] Step 3: 6-chloro-4-fluoro-2,3-dihydro-1H-indene-2-carboxylic acid [ka]

[0163] Dimethyl 6-chloro-4-fluoro-1,3-dihydro-2 H-indene-2,2-dicarboxylate (400 mg, 1.4 mmol) and concentrated HCl (25%) (6 ml) were heated to 120° C. and stirred for 6 h. 1 ml of concentrated HCl (25%) was added and stirring was continued at 120° C. for 1 h. The reaction mixture was extracted twice with EtOAc. The combined organic layers were dried over sodium sulfate and concentrated in vacuo. The crude material was purified by preparative HPLC to give the title compound as a white solid (137 mg, 46% yield). MS (ESI): m / z=213.1 [MH] +

[0164] Step 4: tert-Butyl (6-chloro-4-fluoro-2,3-dihydro-1H-inden-2-yl)carbamate [ka]

[0165] A solution of 6-chloro-4-fluoro-2,3-dihydro-1H-indene-2-carboxylic acid (136 mg, 634 μmol), triethylamine (128 mg, 177 μl, 1.27 mmol) and diphenylphosphoryl azide (187 mg, 146 μl, 665 μmol) in tert-butanol (4 ml) was heated to 50° C. and stirred for 15 h. 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 ethyl acetate / heptane 0-50% to give the title compound as an off-white solid (90 mg, 45% yield). MS (ESI): m / z=230.1 [M-tBu] +

[0166] Step 5: 6-Chloro-4-fluoro-2,3-dihydro-1H-indene-2-aminium chloride [ka]

[0167] The title compound was prepared from tert-butyl (6-chloro-4-fluoro-2,3-dihydro-1H-inden-2-yl)carbamate following the procedure described for Intermediate A2, step 4 (100% yield, off-white solid). MS (ESI): m / z=186.1 [M+H] +

[0168] Intermediate A10: 5-chloro-4-fluoro-2,3-dihydro-1H-inden-2-amine [ka]

[0169] Step 1: (Z)-5-chloro-4-fluoro-2-(hydroxyimino)-2,3-dihydro-1H-inden-1-one [ka]

[0170] 5-Chloro-4-fluoro-2,3-dihydro-1H-inden-1-one (344mg, 1.86mmol, CAS:1260013-11-3) was combined with diethyl ether (6ml) to obtain a white suspension. Then, 25% aqueous HCl (272mg, 226μl, 1.86mmol) was added, followed by tert-butyl nitrite (192mg, 222μl, 1.86mmol) at room temperature and stirring for 2 hours. The precipitate was filtered and purified. Flash chromatography on silica gel using a gradient of 0-60% ethyl acetate / heptane afforded the title compound as a white solid (250 mg, 63% yield). MS (ESI): m / z=214.1 [M+H] +

[0171] Step 2: 5-Chloro-4-fluoro-2,3-dihydro-1H-inden-2-amine [ka]

[0172] (Z)-5-Chloro-4-fluoro-2-(hydroxyimino)-2,3-dihydro-1H-inden-1-one (100 mg, 0.468 mmol) in acetic acid (2 ml) was hydrogenated in the presence of Pd / C 5% (11 mg) and sulfuric acid (100 ul) at 4 bar pressure for 16 hours at room temperature. The catalyst was filtered and washed with methanol and the filtrate was basified to pH 8-9 with a saturated solution of sodium carbonate and diluted with dichloromethane and water. The aqueous layer was extracted twice with dichloromethane. 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 0-20% dichloromethane / methanol to give the title compound as a colorless oil (50 mg, 42% yield). MS (ESI): m / z=186.1 [M+H] +

[0173] Intermediate A11: 6-chloro-4-(trifluoromethyl)-2,3-dihydro-1H-inden-2-aminium chloride [ka]

[0174] Step 1: tert-Butyl (6-chloro-4-(trifluoromethyl)-2,3-dihydro-1H-inden-2-yl)carbamate [ka]

[0175] 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-2,3-dihydro-1H-inden-2-yl)carbamate (Intermediate A1, Step 1) (150 mg, 381 μmol), potassium fluoride (22.1 mg, 381 μmol) and (1,10-phenanthroline)(trifluoromethyl)copper(I) (trifluoromethylating agent) (143 mg, 457 μmol) were dissolved in dry DMF (3.81 ml) and air was bubbled through the solution. The reaction was then heated to 50° C. for 4 hours. The reaction was diluted with EtOAc and poured into 10% LiCl solution. The layers were separated and the aqueous layer was extracted two more times with EtOAc. The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, filtered through Celite and evaporated to dryness. The crude product was subjected to flash chromatography on silica gel using a gradient ethyl acetate / heptane 0-100% to give the title compound as an orange solid (24 mg, 13% yield). MS (ESI): m / z=280.1 [M-tBu] +

[0176] Step 2: 6-chloro-4-(trifluoromethyl)-2,3-dihydro-1H-indene-2-aminium chloride [ka]

[0177] The title compound was prepared from tert-butyl (6-chloro-4-(trifluoromethyl)-2,3-dihydro-1H-inden-2-yl)carbamate according to the procedure described for Intermediate A2, step 4 (100% yield, off-white solid). MS (ESI): m / z=236.1 [M+H] +

[0178] Intermediate B1-3: Intermediates B1-2 are either commercially available or known and are listed in the table below. [Table 2]

[0179] Intermediate B4: cis-6-methyl-1-azaspiro[3.3]heptane-6-ol bis(2,2,2-trifluoroacetate) [ka]

[0180] Step 1: cis-tert-butyl-6-hydroxy-6-methyl-1-azaspiro[3.3]heptane-1-carboxylate [ka]

[0181] To a suspension of tert-butyl 6-oxo-1-azaspiro[3.3]heptane-1-carboxylate (500 mg, 2.37 mmol, CAS: 1363380-93-1) in diethyl ether (500 μl) at 0 °C under nitrogen, methylmagnesium bromide (3 M in diethyl ether) (2.37 ml, 7.1 mmol) was added. The reaction mixture was stirred at room temperature for 1.5 h. The mixture was cooled to 0 °C and carefully quenched with a saturated solution of ammonium chloride. Ethyl acetate was added. Both layers were separated and the aqueous layer was extracted twice with ethyl acetate. The combined organic layers were dried over sodium sulfate and evaporated. The crude yellow oil was purified by flash column chromatography on silica gel using a gradient ethyl acetate / heptane 0-80% to give the title compound as a colorless oil (320 mg, 60% yield). MS (ESI): m / z = 172.2 [M-tBu] +

[0182] Step 2: cis-6-methyl-1-azaspiro[3.3]heptane-6-ol bis(2,2,2-trifluoroacetate) [ka]

[0183] To a mixture of cis-tert-butyl-6-hydroxy-6-methyl-1-azaspiro[3.3]heptane-1-carboxylate (319 mg, 1.4 mmol) in dichloromethane (640 μl) at 0° C. under nitrogen was added trifluoroacetic acid (1.63 g, 1.1 ml, 14 mmol). The mixture was stirred at room temperature for 2-5 h. The reaction mixture was evaporated to dryness to give the title compound as a pale yellow oil (552 mg, 100% yield). MS (ESI): m / z=128.2 [M+H] +

[0184] Intermediate C1-3 Intermediate C1: 2-[(4-chloroindan-2-yl)amino]pyrimidine-5-carboxylic acid [ka]

[0185] Step 1: Methyl 2-[(4-chloroindan-2-yl)amino]pyrimidine-5-carboxylate [ka]

[0186] To a mixture of methyl 2-aminopyrimidine-5-carboxylate (250 mg, 1.63 mmol, CAS: 308348-93-8, commercially available) and 4-chloro-1,3-dihydro-2 H-inden-2-one (544 mg, 3.26 mmol, CAS: 74124-90-6) in MeCN (2.5 mL) was added TFA (667 μL, 8.65 mmol) and triethylsilane (1.36 mL, 8.49 mmol). The reaction mixture was stirred overnight at 70° C. in a sealed tube, then carefully poured into saturated sodium bicarbonate solution and extracted with ethyl acetate. The organic layer was washed with brine, dried over sodium sulfate, and concentrated. The crude material was purified by flash chromatography on silica gel using a 0-60% ethyl acetate / heptane gradient to give the title compound as a light brown solid (166 mg, 16% yield). MS(ESI): m / z=304.1[M+H] +

[0187] Step 2: 2-[(4-chloroindan-2-yl)amino]pyrimidine-5-carboxylic acid [ka]

[0188] To a mixture of methyl 2-((4-chloro-2,3-dihydro-1H-inden-2-yl)amino)pyrimidine-5-carboxylate (157 mg, 0.517 mmol) in MeOH (2.5 mL) was added 6M NaOH (103 μL, 0.620 mmol). The suspension was stirred at room temperature overnight, 6M NaOH (103 μL, 0.620 mmol) was added and the mixture was heated to 50° C. for 9 h. The reaction mixture was cooled to room temperature, acidified with Amberlite IR-120, filtered and washed well with DCM / MeOH. The filtrate was evaporated to dryness. The resin was dissolved in 1M HCl, MeOH was added and the mixture was stirred for 30 min and then filtered. The filtrate was evaporated to dryness to give the title compound (21 mg, 13% yield) which was used in the next step without purification.

[0189] Intermediate C2: (2-chloropyrimidin-5-yl)(6-oxa-1-azaspiro[3.3]heptan-1-yl)methanone [ka]

[0190] CH of 2-chloropyrimidine-5-carboxylic acid (600 mg, 3.78 mmol), N,N-diisopropylethylamine (3.96 ml, 22.7 mmol) and 6-oxa-1-azaspiro[3.3]heptane hemioxalate (Intermediate B1, 859 mg, 4.54 mmol). 2 Cl 2 To a stirred suspension in 1,2-dichlorophenyl ether (20 ml) was added 1-propanephosphonic anhydride (4.51 ml, 7.57 mmol) over 50 wt % in EtOAc. The reaction mixture was stirred at room temperature for 2 days, poured into water and diluted with CH 2 Cl 2 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 0-100% ethyl acetate / heptane gradient to give the title compound as a white solid (250 mg, 28% yield). MS (ESI): m / z=240.1 [M+H] +

[0191] Intermediate C3: (S)-2-((6-chloro-4-cyano-2,3-dihydro-1H-inden-2-yl)amino)pyrimidine-5-carboxylic acid [ka]

[0192] Step 1: Ethyl (S)-2-((6-chloro-4-cyano-2,3-dihydro-1H-inden-2yl)amino)pyrimidine-5-carboxylate [ka]

[0193] A suspension of ethyl 2-chloropyrimidine-5-carboxylate (74.8 mg, 393 μmol), (S)-6-chloro-4-cyano-2,3-dihydro-1H-indene-2-aminium chloride (Intermediate A5) (75 mg, 327 μmol) and N,N-diisopropylethylamine (130 mg, 171 μl, 982 μmol) in DMA (1.5 ml) was stirred at room temperature for 15 hours. The resulting solution 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 0-100% ethyl acetate / heptane gradient to give the title compound as a white solid (94 mg, 84%% yield). MS (ESI): m / z=343.2 [M+H] +

[0194] Step 2: (S)-2-((6-chloro-4-cyano-2,3-dihydro-1H-inden-2-yl)amino)pyrimidine-5-carboxylic acid [ka]

[0195] To a solution of ethyl (S)-2-((6-chloro-4-cyano-2,3-dihydro-1H-inden-2-yl)amino)pyrimidine-5-carboxylate (121 mg, 353 μmol) in THF (1.5 ml) / water (0.5 ml) was added lithium hydroxide monohydrate (37.4 mg, 882 μmol). The reaction mixture was stirred at room temperature for 15 h, poured into water and extracted twice with EtOAc. The aqueous layer was acidified with 1N citric acid and extracted twice with EtOAc. The combined organic layers were dried over sodium sulfate and concentrated in vacuo. The residue was triturated with ethyl ether, filtered through sintered glass and dried in vacuo to give the title compound as a white solid (99 mg, 89.1% yield). MS (ESI) m / z: 315.1 [M+H] +

[0196] Working Example Example 1: (2-((4-chloro-2,3-dihydro-1H-inden-2-yl)amino)pyrimidin-5-yl)(6-oxa-1-azaspiro[3.3]heptan-1-yl)methanone [ka]

[0197] 4,6-Dichloro-2,3-dihydro-1H-inden-2-aminium 2,2,2-trifluoroacetate (Intermediate A1) (50 mg, 158 μmol) was dissolved in DMA (1.58 ml) and diisopropylethylamine (81.8 mg, 110 μl, 633 μmol) was added followed by (2-chloropyrimidin-5-yl)(6-oxa-1-azaspiro[3.3]heptan-1-yl)methanone (Intermediate C2) (37.9 mg, 158 μmol). The reaction was stirred at room temperature for 20 hours, then poured into LiCl 10% and extracted with 2-Me-THF. The layers were separated and the aqueous layer was extracted twice with 2-Me-THF. The combined organic layers were washed with brine, dried over anhydrous sodium sulfate and evaporated to dryness. The crude product was subjected to flash chromatography on silica gel using a gradient ethyl acetate / heptane 0-100% to give the title compound as a white solid (24 mg, 36% yield). MS (ESI): m / z=405.2 [M+H] +

[0198] The following Examples 2-10 were prepared in a similar manner to Example 1 from the indicated building block A and (2-chloropyrimidin-5-yl)(6-oxa-1-azaspiro[3.3]heptan-1-yl)methanone (Intermediate C2). [Table 3] TIFF0007662671000067.tif65169

[0199] Example 11: (S)-2-((5-(6-oxa-1-azaspiro[3.3]heptane-1-carbonyl)pyrimidin-2-yl)amino)-6-chloro-2,3-dihydro-1H-indene-4-carbonitrile [ka]

[0200] To a suspension of (S)-2-((6-chloro-4-cyano-2,3-dihydro-1H-inden-2-yl)amino)pyrimidine-5-carboxylic acid (Intermediate C3) (50 mg, 159 μmol) and HATU (72.5 mg, 191 μmol) in DMF (500 μl) was added N,N-diisopropylethylamine (105 mg, 139 μl, 794 μmol). After stirring at room temperature for 10 min, 6-oxa-1-azaspiro[3.3]heptane hemioxalate (28.3 mg, 95.3 μmol, Intermediate B1) was added. The reaction mixture was stirred at room temperature for 15 h, poured into brine 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 ethyl acetate / heptane 0-100% to give the title compound as a white solid (24 mg, 36% yield). MS (ESI): m / z=396.2 [M+H] +

[0201] The following Examples 12-14 were prepared in a similar manner to Example 11 from the indicated building block B and (S)-2-((6-chloro-4-cyano-2,3-dihydro-1H-inden-2-yl)amino)pyrimidine-5-carboxylic acid (Intermediate C3). [Table 4]

[0202] Example 15: (2-((4-chloro-2,3-dihydro-1H-inden-2-yl)amino)pyrimidin-5-yl)(6-oxa-1-azaspiro[3.3]heptan-1-yl)methanone [ka]

[0203] The title compound was prepared from Building Block B 1 and 2-[(4-chloroindan-2-yl)amino]pyrimidine-5-carboxylic acid (Intermediate C1) in the same manner as in Example 11. MS (ESI): m / z=371.2 [M+H] + Example 16: (S or R)-(2-((6-chloro-4-fluoro-2,3-dihydro-1H-inden-2-yl)amino)pyrimidin-5-yl)(6-oxa-1-azaspiro[3.3]heptan-1-yl)methanone [ka]

[0204] Chiral HPLC separation of racemic Example 8 using SFC methodology (column: AY-H, 12 nm, 5 μm, 250×4.6 mm) gave the title compound (second eluting enantiomer, retention time: 5.53 min, 98% ee, off-white solid). MS (ESI) m / z: 389.3 [M+H] +

[0205] Example A The compounds of formula (I) can be used in a manner known per se as active ingredient to prepare tablets of the following composition:

[0206] Per tablet Active ingredient: 200mg Microcrystalline cellulose 155mg Cornstarch 25mg Talc 25mg Hydroxypropyl methylcellulose 20mg 425mg

[0207] Example B The compounds of formula (I) can be used in a manner known per se as active ingredient to prepare capsules of the following composition:

[0208] Per capsule Active ingredient 100.0mg Cornstarch 20.0mg Lactose 95.0mg Talc 4.5mg Magnesium stearate 0.5mg 220.0mg

Claims

1. A compound of formula (I) or a pharma- ceutically acceptable salt thereof 【Chemistry 1】 (In the formula, R １ , R ２ and R ３ is, independently, i) H; ii) C １－６ -alkyl, iii) C ２－６ -alkynyl, iv) halogens, v) Halo-C １－６ -alkyl, vi) Halo-C １－６ -alkoxy, vii) Cyano is selected from the group consisting of R １ and R ３ is other than H; R ４ and R ５ is, independently, i) H; ii) C １－６ -alkyl, iii) halogens, iv) halo-C １－６ -Alkyl with the proviso that at least one of R 4 and R 5 is other than H; Or, R ４ and R ５ taken together with the carbon atom to which they are attached, represent a heterocycloalkyl or substituted C ３－８ -cycloalkyl, and the substituted cycloalkyl is R ６ and R ７ is replaced by R ６ and R ７ is independently selected from the group consisting of halogen, hydroxy or alkyl.

2. R １ , R ２ and R ３ is, independently, i) H; ii) C １－６ -alkyl, iii) C ２－６ -alkynyl, iv) halogens, v) Halo-C １－６ -alkyl, vi) Halo-C １－６ -alkoxy, vii) Cyano is selected from the group consisting of R １ and R ３ is other than H.

3. R ４ and R ５ is, independently, i) H; ii) C １－６ -Alkyl with the proviso that at least one of R 4 and R 5 is other than H; Or, R ４ and R ５ together with the carbon atom to which they are attached, a 4-membered heterocycloalkyl or substituted C ４ -cycloalkyl, and the substituted cycloalkyl is R ６ and R ７ 3. The compound of claim 1 or 2, substituted with

4. R ４ and R ５ is, independently, i) H; ii) Methyl with the proviso that at least one of R 4 and R 5 is other than H; Or, R ４ and R ５ together with the carbon atom to which they are attached form an oxetane ring or a substituted C ４ -cycloalkyl, and the substituted cycloalkyl is R ６ and R ７ 3. The compound of claim 1 or 2, substituted with

5. R ６ and R ７ are both halogens, or R ６ is hydroxy, R ７ The compound according to any one of claims 1 to 4, wherein is alkyl.

6. R ６ and R ７ are both fluorine, or R ６ is hydroxy, R ７ The compound according to any one of claims 1 to 5, wherein is methyl.

7. R １ , R ２ and R ３ is, independently, i) H; ii) C １－６ -alkyl, iii) C ２－６ -alkynyl, iv) halogens, v) Halo-C １－６ -alkyl, vi) Halo-C １－６ -alkoxy, vii) Cyano is selected from the group consisting of R １ and R ３ is other than H; R ４ and R ５ is, independently, i) H; ii) Methyl with the proviso that at least one of R 4 and R 5 is other than H; Or, R ４ and R ５ together with the carbon atom to which they are attached form an oxetane ring or a substituted C ４ -cycloalkyl, and the substituted cycloalkyl is R ６ and R ７ is replaced by R ６ and R ７ are both fluorine, or R ６ is hydroxy, R ７ The compound according to any one of claims 1 to 6, or a pharma- ceutically acceptable salt thereof, wherein: is methyl.

8. (2-((4-chloro-2,3-dihydro-1H-inden-2-yl)amino)pyrimidin-5-yl)(6-oxa-1-azaspiro[3.3]heptan-1-yl)methanone, (2-((4,6-dichloro-2,3-dihydro-1H-inden-2-yl)amino)pyrimidin-5-yl)(6-oxa-1-azaspiro[3.3]heptan-1-yl)methanone, (2-((6-chloro-4-methyl-2,3-dihydro-1H-inden-2-yl)amino)pyrimidin-5-yl)(6-oxa-1-azaspiro[3.3]heptan-1-yl)methanone, (2-((4,5-dichloro-2,3-dihydro-1H-inden-2-yl)amino)pyrimidin-5-yl)(6-oxa-1-azaspiro[3.3]heptan-1-yl)methanone, 2-((5-(6-oxa-1-azaspiro[3.3]heptane-1-carbonyl)pyrimidin-2-yl)amino)-6-chloro-2,3-dihydro-1H-indene-4-carbonitrile, (S)-2-((5-(6-oxa-1-azaspiro[3.3]heptane-1-carbonyl)pyrimidin-2-yl)amino)-6-chloro-2,3-dihydro-1H-indene-4-carbonitrile, (2-((6-chloro-4-(difluoromethoxy)-2,3-dihydro-1H-inden-2-yl)amino)pyrimidin-5-yl)(6-oxa-1-azaspiro[3.3]heptan-1-yl)methanone, (2-((5-chloro-4-methyl-2,3-dihydro-1H-inden-2-yl)amino)pyrimidin-5-yl)(6-oxa-1-azaspiro[3.3]heptan-1-yl)methanone, (2-((6-chloro-4-(prop-1-yn-1-yl)-2,3-dihydro-1H-inden-2-yl)amino)pyrimidin-5-yl)(6-oxa-1-azaspiro[3.3]heptan-1-yl)methanone, (2-((6-chloro-4-fluoro-2,3-dihydro-1H-inden-2-yl)amino)pyrimidin-5-yl)(6-oxa-1-azaspiro[3.3]heptan-1-yl)methanone, (2-((5-chloro-4-fluoro-2,3-dihydro-1H-inden-2-yl)amino)pyrimidin-5-yl)(6-oxa-1-azaspiro[3.3]heptan-1-yl)methanone, (S or R)-(2-((6-chloro-4-fluoro-2,3-dihydro-1H-inden-2-yl)amino)pyrimidin-5-yl)(6-oxa-1-azaspiro[3.3]heptan-1-yl)methanone, (2-((6-chloro-4-(trifluoromethyl)-2,3-dihydro-1H-inden-2-yl)amino)pyrimidin-5-yl)(6-oxa-1-azaspiro[3.3]heptan-1-yl)methanone, (S)-6-chloro-2-((5-(6,6-difluoro-1-azaspiro[3.3]heptane-1-carbonyl)pyrimidin-2-yl)amino)-2,3-dihydro-1H-indene-4-carbonitrile, (S)-6-chloro-2-((5-(2,2-dimethylazetidine-1-carbonyl)pyrimidin-2-yl)amino)-2,3-dihydro-1H-indene-4-carbonitrile, (cis)-6-chloro-2-(S)-((5-(6-hydroxy-6-methyl-1-azaspiro[3.3]heptane-1-carbonyl)pyrimidin-2-yl)amino)-2,3-dihydro-1H-indene-4-carbonitrile, The compound according to any one of claims 1 to 7, and pharma- ceutically acceptable salts thereof, selected from:

9. Reaction of a compound of formula (II) in the presence of a compound of formula (III) 【Chemistry 2】 Including R １ , R ２ , R ３ , R ４ and R ５ The method for producing the compound according to any one of claims 1 to 8, wherein is as described above.

10. A compound according to any one of claims 1 to 8 for use as a therapeutically active substance.

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

12. 10. A pharmaceutical composition comprising a compound according to any one of claims 1 to 8 for the treatment or prevention of renal conditions, hepatic conditions, inflammatory conditions, neurological conditions, respiratory conditions, vascular and cardiovascular conditions, fibrotic diseases, cancer, ophthalmic conditions, metabolic conditions, cholestatic and other forms of chronic pruritus and acute and chronic organ transplant rejection.

13. A compound according to any one of claims 1 to 8 for the treatment or prevention of renal conditions, hepatic conditions, inflammatory conditions, neurological conditions, fibrotic diseases and acute and chronic organ transplant rejection.

14. 10. Use of a compound according to any one of claims 1 to 8 for the preparation of a medicament for the treatment or prevention of renal conditions, hepatic conditions, inflammatory conditions, neurological conditions, fibrotic diseases and acute and chronic organ transplant rejection.

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