Replacement amino-pyrimidine

Abstract

The present invention relates to a compound represented by general formula (I) TIFF2023529637000067.tif30169 (In the formula, R 1 , R 2 , and R 3 The present invention provides novel compounds having the formula (I) (wherein R is as defined herein), compositions comprising the compounds, and methods of using the compounds.

Description

Technical Field

[0001] The present invention relates to organic compounds useful for the treatment or prevention in mammals, particularly 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 of their corresponding enantiomers and / or optical isomers.

[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 with 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 through signaling to several G protein-coupled receptors (GPCRs), initially called Edg (endothelial cell differentiation gene) receptors or ventricular zone gene 1 (vzg-1), but now called LPA receptors. Currently, 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 purine 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 diabetes. Therefore, an increase in the activity of ATX and / or an increase in the level of LPA, 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 symptoms associated with 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 a disease, disorder or condition 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 signaling. The autotaxin inhibitors described herein are useful as agents for the treatment or prevention of diseases or conditions in which ATX activity and / or LPA signaling is involved, is associated with the etiology or pathology of the disease, or otherwise is associated with at least one symptom of the disease. The ATX-LPA axis is associated with, 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, etc.), symptoms such as cholestasis or other forms of chronic pruritus, and acute and chronic organ transplant rejection.

[0007] The object of the present invention is a compound of formula I, as well as their aforementioned salts and esters, and their use as therapeutic active substances, a method for the manufacture of a medicament comprising said compound, intermediate, pharmaceutical composition, a medicament comprising said compound, their pharmaceutically acceptable salts or esters, the treatment or prevention of disorders or symptoms associated with the activity of ATX and / or the biological activity of lysophosphatidic acid (LPA), in particular 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, the use of said compound, salt or ester in the treatment or prevention thereof, and the use of said compound, salt or ester for the manufacture of a medicament 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, and acute and chronic organ transplant rejection. More specifically, a compound of formula I, as well as their aforementioned salts and esters, and their use as therapeutic active substances, a method for the manufacture of said compound, intermediate, pharmaceutical composition, a medicament comprising said compound, their pharmaceutically acceptable salts or esters, eye symptoms, more specifically the use of said compound, salt or ester for the treatment or prevention of glaucoma.

[0008] The term "C1-6-alkyl" means a monovalent straight-chain or branched-chain saturated hydrocarbon group of 1 to 6 carbon atoms. In some embodiments, unless otherwise specified, alkyl is 1 to 6 carbon atoms (C1- 6-contains (alkyl) or 1 to 4 carbon atoms (C1-C4 alkyl). Examples of C1-C6 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 may 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.

[0009] The term "cyano" means a -C≡N group.

[0010] The terms "halogen", "halide", and "halo" are used interchangeably herein and mean fluoro, chloro, bromo, or iodo. A specific halogen is chloro.

[0011] The term "halo-C1-C6 alkyl" means a C1-C6 alkyl group in which at least one hydrogen atom of the C1-C6 alkyl group is replaced by the same or different halogen atoms. Specific examples are difluoromethyl, trifluoromethyl, difluoroethyl, and trifluoroethyl. A more specific example is trifluoromethyl.

[0012] The term "heteroaryl", alone or in combination, means a monocyclic or polycyclic group containing at least one aromatic ring, and the aromatic ring contains at least one ring heteroatom. In some embodiments, the heteroatom is independently selected from the group consisting of N, O, and S. Unless otherwise specified, a heteroaryl group may contain 5, 6, 7, 8, 9, 10, 11, or 12 ring atoms containing 1, 2, 3, or 4 heteroatoms selected from N, O, and S, and the ring atoms refer to the total of carbon and heteroatoms within one or more rings (e.g., 5-membered, 6-membered, 7-membered, 8-membered, 9-membered, 10-membered, 11-membered, or 12-membered heteroaryl). Examples of heteroaryl groups include pyrrolyl, furanyl, oxazolyl, pyrazinyl, pyridazinyl, oxadiazolyl, isoxazole, pyrazole, triazolyl, and pyrimidinyl.

[0013] In the case of substituted heteroaryl, examples include 3-methyl-1,2,4-oxadiazol-5-yl, 3-methyl-1,2,4-triazol-1-yl, 3-methylisoxazol-5-yl, 3-methylpyrazol-1-yl, 4-methyloxazol-2-yl, 4-methylpyrazol-1-yl, 4-methyltriazol-2-yl, 5,5-dimethyl-4H-isoxazol-3-yl, 5-methyl-1,3,4-oxadiazol-2-yl, 5-methyloxazol-2-yl, 5-methylpyrazin-2-yl, and 5-methylpyrimidin-2-yl.

[0014] The term "heterocycloalkyl", alone or in combination, means a 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, with the remaining ring atoms being carbon. Bicyclic means consisting of two rings having at least 1 ring atom in common. The heterocycloalkyl group may be saturated or unsaturated, and may contain 5, 6, 7, 8, or 9 ring atoms, unless otherwise specified, where the ring atoms refer to the total of carbon atoms and heteroatoms within one or more rings (e.g., 5-membered, 6-membered, 7-membered, 8-membered, or 9-membered heterocycloalkyl). 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 rings. In some embodiments, heterocycloalkyl containing multiple rings includes a spiro ring system where one or more rings contain one or more heteroatoms. Examples are 4,5-dihydro-oxazolyl, oxetanyl, azetidinyl, pyrrolidinyl, 2-oxo-pyrrolidin-3-yl, tetrahydrofuranyl, tetrahydro-thienyl, pyrazolidinyl, imidazolidinyl, oxazolidinyl, isoxazolidinyl, thiazolidinyl, piperidinyl, tetrahydropyranyl, tetrahydrothiopyranyl, piperazinyl, morpholinyl, thiomorpholinyl, 1,1-dioxothiomorpholin-4-yl, azepanyl, diazepanyl, homopiperazinyl, oxazepanyl, dihydrofuryl, imidazolinyl, dihydro-oxazolyl, tetrahydro-pyridinyl, isoxazolyl, or dihydropyranyl.

[0015] In the case of substituted heterocycloalkyl, examples include methylisoxazolyl.

[0016] The term "pharmaceutically acceptable" refers to salts which retain the biological effectiveness and properties of the free bases or free acids and which are not biologically or otherwise undesirable. Such 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 inorganic or organic bases to the free acids. Salts derived from inorganic bases include, but are not limited to, sodium, potassium, lithium, ammonium, calcium and magnesium salts. 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 and the like. Particularly pharmaceutically acceptable salts of the compounds of formula I are the hydrochloride, methanesulfonate and citrate salts.

[0017] "Pharmaceutically acceptable ester" means that a derivative obtained by derivatizing a compound of general formula I with a functional group can provide a derivative that can be converted back to the parent compound in vivo. Examples of such compounds include physiologically acceptable and metabolically unstable ester derivatives such as methoxymethyl ester, methylthiomethyl ester, and pivaloyloxymethyl ester. Further, any physiologically acceptable equivalents of the compounds of general formula I that are similar to metabolically unstable esters that can be produced in vivo from the parent compound of general formula I are also within the scope of the present invention.

[0018] The abbreviation uM means micromole and corresponds to the symbol μM.

[0019] The abbreviation "uL" means microliter and corresponds to the symbol μL.

[0020] The abbreviation "ug" means microgram and corresponds to the symbol μg.

[0021] The compounds of formula I can contain several chiral centers and can exist in the form of optically pure enantiomers, mixtures of enantiomers such as racemates, optically pure diastereoisomers, mixtures of diastereoisomers, racemates of diastereoisomers or mixtures of racemates of diastereoisomers.

[0022] According to the Cahn-Ingold-Prelog rules, chiral carbon atoms can have the "R" or "S" configuration.

[0023] Also, embodiments of the present invention provide a compound according to formula I described herein and a pharmaceutically acceptable salt or ester thereof, in particular a compound according to formula I described herein and a pharmaceutically acceptable salt thereof, more specifically, a compound according to formula I described herein.

[0024] Also, certain embodiments of the present invention provide a compound according to formula I described herein (wherein R 1 is i) a 5- or 6-membered heteroaryl ii) a 5- or 6-membered substituted heteroaryl iii) a 5- or 6-membered heterocycloalkyl iv) a 5- or 6-membered substituted heterocycloalkyl selected from the group consisting of the substituted heteroaryl or substituted heterocycloalkyl is substituted with one or more alkyl substituents, R 2 is i) H, ii) cyano, iii) halogen, iv) C 1~6 alkyl, v) halo-C 1~6 alkyl (selected from the group consisting of) R 3 is i) H, ii) halogen, iii) C 1~6 alkyl, iv) halo-C 1~6 alkyl (selected from the group consisting of) or a pharmaceutically acceptable salt thereof is provided.

[0025] A particular embodiment of the present invention provides a compound of formula I as described herein, wherein R 3 is halogen.

[0026] A further particular embodiment of the present invention provides a compound of formula I as described herein, wherein R 3 is Cl.

[0027] A particular embodiment of the present invention provides a compound of formula I as described herein, wherein R 2 is i) H, ii) cyano (selected from the group consisting of).

[0028] A particular embodiment of the present invention provides a compound of formula I as described herein, wherein R 1 is i) a 5- or 6-membered heteroaryl ii) a 5- or 6-membered substituted heteroaryl iii) a 5- or 6-membered substituted heterocycloalkyl (selected from the group consisting of), and the substituted heteroaryl or substituted heterocycloalkyl is substituted with one or more alkyl substituents.

[0029] A particular embodiment of the present invention provides a compound of formula I as described herein, wherein R 1is selected from 3-methyl-1,2,4-oxadiazol-5-yl, 3-methyl-1,2,4-triazol-1-yl, 3-methylisoxazol-5-yl, 3-methylpyrazol-1-yl, 4-methyloxazol-2-yl, 4-methylpyrazol-1-yl, 4-methyltriazol-2-yl, 5,5-dimethyl-4H-isoxazol-3-yl, 5-methyl-1,3,4-oxadiazol-2-yl, 5-methyloxazol-2-yl, 5-methylpyrazin-2-yl, 5-methylpyrimidin-2-yl, oxazol-2-yl, pyrazin-2-yl, and pyridazin-3-yl, and provides a compound according to formula I described herein.

[0030] Certain embodiments of the present invention are compounds according to formula I described herein, wherein R 1 is i) a 5- or 6-membered heteroaryl ii) a 5- or 6-membered substituted heteroaryl iii) a 5- or 6-membered substituted heterocycloalkyl selected from the group consisting of, the substituted heteroaryl or substituted heterocycloalkyl is substituted with one or more alkyl substituents, R 2 is i) H ii) cyano selected from the group consisting of, R 3 is halogen), or a pharmaceutically acceptable salt.

[0031] More detailed embodiments of the present invention are compounds according to formula I described herein, wherein R 1 is i) a 5- or 6-membered heteroaryl ii) a 5- or 6-membered substituted heteroaryl iii) a 5- or 6-membered substituted heterocycloalkyl selected from the group consisting of, The substituted heteroaryl or substituted heterocycloalkyl is substituted with one or more alkyl substituents, R 2 is i) H ii) cyano selected from the group consisting of, R 3 is Cl) is provided.

[0032] The most detailed embodiment of the present invention is a compound according to formula I described herein, wherein R 1 is selected from 3 - methyl - 1,2,4 - oxadiazol - 5 - yl, 3 - methyl - 1,2,4 - triazol - 1 - yl, 3 - methylisoxazol - 5 - yl, 3 - methylpyrazol - 1 - yl, 4 - methyloxazol - 2 - yl, 4 - methylpyrazol - 1 - yl, 4 - methyltriazol - 2 - yl, 5,5 - dimethyl - 4H - isoxazol - 3 - yl, 5 - methyl - 1,3,4 - oxadiazol - 2 - yl, 5 - methyloxazol - 2 - yl, 5 - methylpyrazin - 2 - yl, 5 - methylpyrimidin - 2 - yl, oxazol - 2 - yl, pyrazin - 2 - yl, and pyridazin - 3 - yl,

[0033] R 2 is i) H ii) cyano selected from the group consisting of, R 3 is Cl) is provided.

[0034] Specific examples of the compounds of formula I described herein are selected from the following: N-(5 - chloro - 2,3 - dihydro - 1H - inden - 2 - yl)-5-(3 - methyl - 1,2,4 - oxadiazol - 5 - yl)pyrimidin - 2 - amine; N-(5 - chloro - 2,3 - dihydro - 1H - inden - 2 - yl)-5-(5 - methyl - 1,3,4 - oxadiazol - 2 - yl)pyrimidin - 2 - amine; N-(5-Chloro-2,3-dihydro-1H-inden-2-yl)-5-(4-methyloxazol-2-yl)pyrimidin-2-amine; N-(5-Chloro-2,3-dihydro-1H-inden-2-yl)-5-(3-methylisoxazol-5-yl)pyrimidin-2-amine; N-(5-Chloro-2,3-dihydro-1H-inden-2-yl)-5-(4-methyl-1H-pyrazol-1-yl)pyrimidin-2-amine; N-(5-Chloro-2,3-dihydro-1H-inden-2-yl)-5-(3-methyl-1H-pyrazol-1-yl)pyrimidin-2-amine; N-(5-Chloro-2,3-dihydro-1H-inden-2-yl)-5-(4-methyl-1,2,4-triazol-2-yl)pyrimidin-2-amine; N-(5-Chloro-2,3-dihydro-1H-inden-2-yl)-5-(5-methyloxazol-2-yl)pyrimidin-2-amine; (S or R)-N-(5-Chloro-2,3-dihydro-1H-inden-2-yl)-5-(3-methyl-1,2,4-oxadiazol-5-yl)pyrimidin-2-amine; (R or S)-N-(5-Chloro-2,3-dihydro-1H-inden-2-yl)-5-(3-methyl-1,2,4-oxadiazol-5-yl)pyrimidin-2-amine; N-(5-Chloro-2,3-dihydro-1H-inden-2-yl)-5-(5,5-dimethyl-4,5-dihydroisoxazol-3-yl)pyrimidin-2-amine; (S)-6-Chloro-2-((5-(3-methyl-1,2,4-oxadiazol-5-yl)pyrimidin-2-yl)amino)-2,3-dihydro-1H-inden-4-carbonitrile; (S)-6-Chloro-2-((5-(3-methylisoxazol-5-yl)pyrimidin-2-yl)amino)-2,3-dihydro-1H-inden-4-carbonitrile; (S)-6-Chloro-2-((5-(4-methyloxazol-2-yl)pyrimidin-2-yl)amino)-2,3-dihydro-1H-inden-4-carbonitrile; (S)-6-Chloro-2-((5-(5-methyloxazol-2-yl)pyrimidin-2-yl)amino)-2,3-dihydro-1H-inden-4-carbonitrile; (S)-6-Chloro-2-((5-(5-methylpyrazin-2-yl)pyrimidin-2-yl)amino)-2,3-dihydro-1H-inden-4-carbonitrile; (S)-6-Chloro-2-((5-methyl-[2,5’’-bipyrimidin]-2’’-yl)amino)-2,3-dihydro-1H-inden-4-carbonitrile; (S)-6-Chloro-2-[[5-(3-methyl-1,2,4-triazol-1-yl)pyrimidin-2-yl]amino]-2,3-dihydro-1H-inden-4-carbonitrile; and pharmaceutically acceptable salts thereof.

[0035] A method for producing the compound of formula I described herein is an object of the present invention.

[0036] The present compound of formula I and pharmaceutically acceptable salts thereof can be prepared by methods known in the art, for example, by the processes described below, which processes a) A compound of the formula

Chemical formula

Chemical formula

Chemical formula

Chemical formula

Chemical formula

Chemical formula

Chemical formula

Chemical formula

Chemical formula

Chemical formula

[0037] The compounds of formula I can be prepared according to the variations of the above process and Schemes 1 - 3 below. The starting materials are either commercially available or can be prepared according to known methods. [Chemical formula]

[0038] Compounds of general formula I can be prepared by reacting a thiomethyl derivative II with an oxidizing agent such as 3-chloroperbenzoic acid to convert II to its corresponding methyl sulfone derivative, followed by reaction with an amine derivative III. The thiomethyl derivative of formula II can be prepared by reacting a boronate ester X with a halogenated derivative IV in the presence of a catalyst such as [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium(II) and a base such as potassium carbonate. Alternatively, II can be prepared by reacting a halogenated thiomethyl derivative XI with an organometallic reagent VIII in the presence of a catalyst such as [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium(II) and a base such as potassium or cesium carbonate when M is B(OR)2, or in the presence of a catalyst such as bis(triphenylphosphine)palladium(II) chloride when M is -Sn(nBu)3. II can also be prepared by the reaction of XI with VI in the presence of a catalyst such as copper(I) iodide, a chelating agent such as 8-hydroxyquinoline, and a base such as potassium carbonate. [ka]

[0039] The compound of general formula I can be prepared by reacting the halogenated derivative VII with R1-H (VI) in the presence of a catalyst such as copper(I) iodide, a chelating agent such as 8-hydroxyquinoline, and a base such as potassium carbonate, or when M is -B(OR)2, in the presence of a catalyst such as [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium(II) and a base such as potassium or cesium carbonate, or when M is -Sn(nBu)3, by reacting VII with an organometallic reagent VIII in the presence of a catalyst such as bis(triphenylphosphine)palladium(II) chloride. Alternatively, I can be prepared by reacting the boronic acid ester V with the halogenated derivative IV in the presence of a catalyst such as [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium(II) and a base such as potassium carbonate. V can be prepared from the halogenated derivative VII in the presence of a catalyst such as bis(pinacolato)diboron, [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium(II), and a base such as potassium acetate. VII can be prepared by reacting the halogenated derivative XII with an amine III in the presence of a base such as N,N-diisopropylethylamine.

Chem.

[0040] The compound of general formula I can be prepared from acid IX by methods known in the art. IX can be prepared by reacting a halogenating reagent XIII with an amine derivative III in the presence of a base such as N,N-diisopropylethylamine.

[0041] Also, an object of the present invention is a compound according to formula I described herein for use as a therapeutic active substance.

[0042] Similarly, an object of the present invention is a pharmaceutical composition comprising a compound according to formula I described herein and a therapeutically inert carrier.

[0043] 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 pruritus, and acute and chronic organ transplant rejection.

[0044] 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, these conditions include reduced creatinine clearance and reduced glomerular filtration rate, microalbuminuria, albuminuria, and proteinuria, glomerulosclerosis with expansion of the plexiform mesangial matrix with or without pleocytosis (particularly diabetic nephropathy and amyloidosis), focal thrombosis of glomerular capillaries (particularly thrombotic microangiopathy), global fibrinoid necrosis, ischemic lesions, malignant nephrosclerosis (such as ischemic regression, reduced renal blood flow, and renal arteriopathy), swelling and proliferation of intracapillary (endothelial and mesangial) and / or extracapillary cells (crescents), such as glomerulonephritis, focal segmental glomerulosclerosis, IgA nephropathy, vasculitis / systemic disease, and acute and chronic kidney transplant rejection.

[0045] 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.

[0046] 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).

[0047] Additional respiratory manifestations include, but are not limited to, iatrogenic drug-induced fibrosis, occupational and / or environmental induced fibrosis, systemic diseases and other diffuse parenchymal lung diseases of different etiologies, including vasculitis, granulomatous diseases (sarcoidosis, hypersensitivity pneumonitis), collagen vascular diseases, pulmonary alveolar proteinosis, Langerhans cell granulomatosis, lymphangioleiomyomatosis (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).

[0048] Neurological conditions include, but are not limited to, neuropathic pain, schizophrenia, neuroinflammation (eg, astrogliosis), peripheral and / or autonomic (diabetic) neuropathy, and the like.

[0049] Vascular conditions include, but are not limited to, atherosclerosis, thrombotic vascular disease, and thrombotic microangiopathy, proliferative arteriopathy (such as swelling and nodular thickening of myointimal cells surrounded by a mucous extracellular matrix), atherosclerosis, decreased vascular pressure (such as stiffening, decreased ventricular compliance, decreased vascular compliance), endothelial dysfunction, and the like.

[0050] Cardiovascular conditions 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.

[0051] Fibrotic diseases include, but are not limited to, myocardial and vascular fibrosis, renal fibrosis, liver fibrosis, pulmonary fibrosis, skin fibrosis, scleroderma, and encapsulating peritonitis.

[0052] Cancer and cancer metastasis include, but are not limited to, breast cancer, ovarian cancer, lung cancer, prostate cancer, mesothelioma, glioma, hepatocellular carcinoma, gastrointestinal cancer and their progression and metastatic aggressiveness.

[0053] Eye symptoms include, but are not limited to, proliferative and non - proliferative (diabetic) retinopathy, atrophic and exudative age - related macular degeneration (AMD), macular edema, central artery / vein occlusion, traumatic injury, glaucoma, etc. In particular, the eye symptom is glaucoma.

[0054] Metabolic symptoms include, but are not limited to, obesity and diabetes.

[0055] The present invention also relates to the use of the compounds of 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.

[0056] The present invention also relates to the use of the compounds of formula I described herein for the treatment or prevention of kidney symptoms, liver symptoms and fibrotic diseases.

[0057] A particular embodiment of the present invention is a compound of 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] A particular embodiment of the present invention is a compound of formula I described herein for the treatment or prevention of kidney symptoms, liver symptoms and fibrotic diseases.

[0059] The present invention also relates to the use of the compounds of formula I described herein for the preparation of a medicament for the treatment or prevention of kidney symptoms, liver symptoms, inflammatory symptoms, nervous system symptoms, fibrotic diseases, and acute and chronic organ transplant rejection.

[0060] The present invention also relates to the use of the compounds of formula I described herein for the preparation of a medicament for the treatment or prevention of kidney symptoms, liver symptoms and fibrotic diseases.

[0061] Also an object of the present invention is a method for the treatment or prevention of renal conditions, liver conditions, inflammatory conditions, neurological conditions, fibrotic diseases, and acute and chronic organ transplant rejection, comprising administering an effective amount of a compound described according to formula I as described herein.

[0062] 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 described according to formula I as described herein.

[0063] Also, one embodiment of the present invention provides a compound of formula I as described herein when prepared according to any one of the processes described.

[0064] Assay procedure Production of full-length human ATX with or without a tag Autotaxin (ATX-ENPP2) cloning: cDNA Commercially available human hematopoietic cell total RNA was prepared and used as a template in overlapping PCR to generate the 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 clones was used to transfect Hek293 cells for protein expression verification. The sequence of the encoded ENPP2 conforms to Swissprot entry Q13822, with or without the additional C-terminal 6xHis tag.

[0065] 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, 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 suspended and cultured in FreeStyle 293 medium (Invitrogen) and transfected at approximately 1 - 1.5×10E6 cells / mL with the above plasmid DNA using X-tremeGENE Ro-1539 (commercial product, Roche Diagnostics) as the complexing agent. The cells were supplied 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. ATX Purification: 20 liters of culture supernatant was adjusted 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 prefiltered through a 0.2 pm 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). Before IMAC chromatography, NiSO4 was added to a final concentration of 1 mM. The clarified supernatant was then applied to a column equilibrated with 50 mM Na2HPO4 pH 7.0, 0.5 M NaCl, 10% glycerol,

[0066] and applied to a column equilibrated with 50 mM Na2HPO4 pH 7.0, 0.5 M NaCl, 10% glycerol,

[0067] It was applied to a HisTrap column (GE Healthcare) pre-equilibrated in 0.3% CHAPS and 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 fractions containing ATX 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 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 the purified protein was 5 - 10 mg of ATX per liter of culture supernatant. The protein was stored at -80 °C.

[0068] 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 the substrate and recombinant enzyme. ATX activity was assayed via a coupled enzyme format in which choline generated from LPC hydrolysis is converted to hydrogen peroxide by choline oxidase (CO). The hydrogen peroxide is then used as a co-substrate by horseradish peroxidase (HRP) to oxidize Amplex Red® and generate resorufin, a red fluorescent product.

[0069] Materials / Reagents 500 mM Tris-HCl pH 8.0 in H₂O; 1 M NaCl; 250 mM CaCl₂; 250 mM KCl; 250 mM MgCl₂; 10% Triton X-100.

[0070] 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, sterilized by filtration and stored at 4°C.

[0071] 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.

[0072] 100 mM 18:1 LPC dissolved in reagent dilution buffer.

[0073] 500 U / ml choline oxidase in reagent dilution buffer.

[0074] 2540 U / ml horseradish peroxidase (10.95 mg / ml) in reagent dilution buffer.

[0075] 20 mM Amplex Red (10-acetyl-3,7-dihydroxy-phenoxazine) in DMSO.

[0076] Reaction Plate Black, 384-well plate, black, untreated surface with a transparent bottom.

[0077] Test compounds are received pre-diluted in DMSO as an 11-point concentration-response (highest concentration 0.5 mM; 1 in 3.162 dilution). Test compounds are pre-diluted 1:1 (10 μL compound + 10 μL assay buffer) in a 96-well conical bottom plate prior to use.

[0078] 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 (solutions are 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 at room temperature for 10 minutes. Then add 15 μL of choline oxidase / horseradish peroxidase. To initiate the reaction, add 15 μL of LPC 18:1 / 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.

[0079] Final assay conditions: 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 endpoint data at 90 minutes and normalize to the positive control. Calculate the IC 50 value.

[0080] Provide the results of the enzyme ATX inhibition assay for the compound of Formula I.

Table 1

[0081] The compounds of Formula I described herein and their pharmaceutically acceptable salts or esters have an IC 50 value of 0.004 μM to 0.251 μM. These results were obtained by using the enzyme assay described above.

[0082] The compounds of formula I and their pharmaceutically 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 orally (e.g., in the form of tablets, coated tablets, dragees, hard / soft gelatin capsules, solutions, emulsions, or suspensions), nasally (e.g., in the form of nasal drops), 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 polymer inserts). However, administration can also be carried out parenterally (e.g., in the form of sterile injectable solutions), such as intramuscularly, intravenously, or intraocularly.

[0083] The compound of formula I and its pharmaceutically acceptable salts can be processed with pharmaceutically inert, inorganic or organic adjuvants for the preparation of tablets, coated tablets, dorazol, hard gelatin capsules, injections or external preparations. Lactose, corn starch or its derivatives, talc, stearic acid or its salts, etc. can be used as such adjuvants for tablets, dorazol and hard gelatin capsules.

[0084] Suitable adjuvants for soft gelatin capsules include, by way of example, vegetable oils, waxes, fats, semisolids, liquid polyols, etc.

[0085] Suitable adjuvants for the production of solutions and syrups are, for example, water, polyols, saccharose, invert sugar, glucose etc.

[0086] Suitable adjuvants for injection solutions are, for example, water, alcohols, polyols, glycerol, vegetable oils, etc.

[0087] Suitable adjuvants for suppositories are, for example, natural or hardened oils, waxes, fats, semi-solid or liquid polyols etc.

[0088] Suitable adjuvants for topical ophthalmic formulations are, for example, cyclodextrin, mannitol, or many other carriers and additives known in the art.

[0089] Furthermore, the pharmaceutical preparation can include preservatives, solubilizers, viscosity increasing substances, stabilizers, wetting agents, emulsifiers, sweeteners, coloring agents, flavoring agents, salts for changing osmotic pressure, buffering agents, masking agents, or antioxidants. The pharmaceutical preparation of the present invention can further include other therapeutically useful substances.

[0090] The dosage can be varied widely and will, of course, be adapted to the individual requirements in each particular case. Generally, in the case of oral administration, about 0.1 mg to 20 mg per kg of body weight, preferably about 0.5 mg to 4 mg per kg of body weight (for example, about 300 mg per person) as a daily dose, is preferably administered individually in 1 to 3 divided doses, which, if appropriate, can be constituted, for example, by the same amount. In the case of topical administration, the preparation can contain 0.001% to 15% by weight of the medicament, and the required amount can be between 0.1 and 25 mg, and can be a single administration per day, a single administration per week, multiple administrations per day (2 to 4 times), or multiple administrations per week. However, it is obvious that there may be cases where the upper or lower limits described herein are exceeded.

[0091] Hereinafter, the present invention will be described by way of examples, but the present invention is not limited thereto.

[0092] When the preparation example 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

[0093] Unless otherwise specified, all examples and intermediates were prepared under an argon atmosphere.

[0094] Intermediate A Intermediate A1: 5-Chloro-2,3-dihydro-1H-inden-2-amine hydrochloride

Chemical formula

[0095] Intermediate A2: (S)-6-chloro-4-cyano-2,3-dihydro-1H-inden-2-aminium chloride

Chem.

Chem.

[0096] Step 2: tert-Butyl (6-chloro-4-hydroxy-2,3-dihydro-1H-inden-2-yl)carbamate [Chemical formula] 4-(4,4,5,5-Tetramethyl-1,3,2-dioxaborolan-2-yl)-2,3-dihydro-1H-inden-2-yl)carbamate (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 mixture was stirred at room temperature for 18 hours. The solvent was evaporated, the residue was dissolved in water, and extracted with EtOAc. The layers were separated, and the aqueous layer was extracted with EtOAc two more times. 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 an off-white solid (220 mg, 42% yield). MS (ESI): m / z = 282.2 [M-H] +

[0097] Step 3: 2-((tert-Butoxycarbonyl)amino)-6-chloro-2,3-dihydro-1H-inden-4-yl trifluoromethanesulfonate [Chemical formula] 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, 1,1,1-trifluoro-N-phenyl-N-((trifluoromethyl)sulfonyl)methanesulfonamide (69.2 mg, 194 μmol) was added. The reaction mixture 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 [M-H] +

[0098] Step 4: tert-Butyl (6-chloro-4-cyano-2,3-dihydro-1H-inden-2-yl) carbamate

Chemical formula

[0099] Step 5: (S)-tert-Butyl (6-chloro-4-cyano-2,3-dihydro-1H-inden-2-yl)carbamate

Chem.

[0100] Step 6: (S)-6-Chloro-4-cyano-2,3-dihydro-1H-inden-2-aminium chloride

Chem.

[0101] Intermediate B Intermediate B1: 2-((5-Chloro-2,3-dihydro-1H-inden-2-yl)amino)pyrimidine-5-carboxylic acid

Chem.

[0102] Intermediate B2: 5-Bromo-N-(5-chloro-2,3-dihydro-1H-inden-2-yl)pyrimidin-2-amine

Chemical Structure

[0103] Intermediate B3: N-(5-chloro-2,3-dihydro-1H-inden-2-yl)-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyrimidin-2-amine [ka] A mixture of 5-bromo-N-(5-chloro-2,3-dihydro-1H-inden-2-yl)pyrimidin-2-amine (200 mg, 616 μmol, Intermediate B2), bis(pinacolato)diboron (319 mg, 1.23 mmol), potassium acetate (67.2 mg, 678 μmol), and 1,1′-bis(diphenylphosphino)ferrocene-palladium(II) dichloride dichloromethane complex (25.2 mg, 30.8 μmol) in dioxane (4 mL) was heated to 90° C. and stirred for 15 hours. 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 (0-100%) to give the title compound as an orange solid (175 mg, 76% yield). MS (ESI): m / z = 372.2 [M+H] +

[0104] Intermediate B4: 3-(2-chloropyrimidin-5-yl)-5,5-dimethyl-4,5-dihydroisoxazole [ka] Step 1: (Z)-2-chloro-N-hydroxypyrimidine-5-carbimidoyl chloride [ka] A solution of (E)-2-chloropyrimidine-5-carbaldehyde oxime (500 mg, 3.17 mmol, CAS: 1280538-48-8) in DMF (5 ml) was cooled to 0 °C. N-Chlorosuccinimide (432 mg, 3.17 mmol) was added portionwise. The reaction mixture was stirred and warmed to room temperature and stirred for 5 h. The resulting suspension was concentrated in vacuo. The residue was triturated with dichloromethane, filtered through sintered glass, washed with diethyl ether and dried in vacuo to give the title compound as an off-white solid (214 mg, 35% yield). MS (ESI): m / z = 192.0 [M+H] +

[0105] Step 2: 3-(2-Chloropyrimidin-5-yl)-5,5-dimethyl-4,5-dihydroisoxazole

Chem.

[0106] Intermediate B5: 3-Methyl-5-(2-(methylthio)pyrimidin-5-yl)-1,2,4-oxadiazole

Chem.

[0107] Intermediate B6: 3-methyl-5-(2-(methylthio)pyrimidin-5-yl)isoxazole [ka] Under nitrogen, to a yellow solution of 5-bromo-2-(methylthio)pyrimidine (150 mg, 731 μmol) in 1,4-dioxane (1.5 ml) and water (750 μl), 3-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)isoxazole (322 mg, 1.46 mmol) and cesium carbonate (715 mg, 2.19 mmol) were added. The mixture was degassed for 15 minutes. Then, 1,1-bis(diphenylphosphino)ferrocenedichloropalladium(II) (59.7 mg, 73.1 μmol) was added. The reaction mixture was stirred in a microwave at 80 °C for 45 minutes (15 minutes). The reaction mixture was quenched with water. Ethyl acetate and brine were 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 brown semi-solid (292 mg) was purified by silica gel flash column chromatography using a gradient of ethyl acetate / heptane 0 - 20% to give the title compound as a light brown solid (45 mg, yield 30%). MS(ESI): m / z = 208.1 [M+H] +

[0108] Intermediate B7: 4-Methyl-2-(2-(methylthio)pyrimidin-5-yl)isoxazole [Chemical formula] To a solution of 5-bromo-2-(methylthio)pyrimidine (150 mg, 731 μmol) in acetonitrile (5 ml) at room temperature under nitrogen, 4-methyl-2-(tributylstannyl)isoxazole (991 mg, 2.66 mmol) and bis(triphenylphosphine)palladium(II) chloride (69.3 mg, 98.7 μmol) were added. The reaction mixture was stirred at 80 °C for 18 hours. The resulting dark mixture was cooled to room temperature and evaporated in vacuo. The crude dark residue was purified by silica gel flash column chromatography using a gradient of ethyl acetate / heptane 0 - 30% to give the title compound as a light brown solid (73 mg, yield 48%). MS(ESI): m / z = 208.1 [M+H] +

[0109] Intermediate B8: 5-methyl-2-(2-(methylthio)pyrimidin-5-yl)oxazole [ka] To a solution of 2-(methylthio)-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyrimidine (1 g, 3.89 mmol, CAS: 940284-18-4) in dioxane (10 ml) and water (1 ml) at room temperature under nitrogen, 2-bromo-5-methyloxazole (994 mg, 5.83 mmol) and anhydrous potassium carbonate (1.07 g, 7.77 mmol) were added. Argon was bubbled through the reaction mixture for 10 minutes. Then, [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium(II) (284 mg, 389 μmol) was added. The reaction mixture was stirred at 110 °C for 4 to 5 hours. The mixture was cooled to room temperature. Water and ethyl acetate were 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 brown semi-solid (2.49 g) was purified by flash column chromatography on silica gel using a gradient of ethyl acetate / heptane 0-40% to give the title compound as a light brown solid (422 mg, 52% yield). MS (ESI): m / z = 208.1 [M+H] +

[0110] Intermediate B9: 5-(5-methylpyrazin-2-yl)-2-(methylthio)pyrimidine [ka] The title compound was prepared from 2-(methylthio)-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyrimidine (CAS: 940284-18-4) and 2-bromo-5-methylpyrazine as an off-white solid, similar to Intermediate B8. MS (ESI): m / z = 219.1 [M+H] + Intermediate B10: 5-Methyl-2'-(methylthio)-2,5'-bipyrimidine [Chemical formula] The title compound was prepared as an off-white solid from 2-(methylthio)-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyrimidine, CAS: 940284-18-4) and 2-chloro-5-methylpyrimidine in the same manner as Intermediate B8. MS(ESI): m / z = 219.1 [M+H] + Intermediate B11: 5-(3-Methyl-1H-1,2,4-triazol-1-yl)-2-(methylthio)pyrimidine [Chemical formula] To a mixture of 5-bromo-2-(methylthio)pyrimidine (500 mg, 2.44 mmol) in DMSO (9 ml) were added 3-methyl-1H-1,2,4-triazole (427 mg, 4.88 mmol), copper(I) iodide (92.9 mg, 488 μmol), 8-hydroxyquinoline (142 mg, 975 μmol) and potassium carbonate (674 mg, 4.88 mmol). After stirring at 130 °C in a microwave oven for 15 minutes, it was stirred at 150 °C in a microwave oven for 45 minutes. The mixture was quenched with NH4Cl solution (20%), then ethyl acetate was added, and the resulting suspension was filtered, and both layers of the filtrate were separated. The aqueous layer was extracted twice with ethyl acetate. The combined organic layers were dried over sodium sulfate and concentrated. The crude material (1.45 g) was purified by flash chromatography on silica gel using a gradient of ethyl acetate / heptane 0 - 60% to give the title compound as a yellow solid (56 mg, yield 10%). MS(ESI): m / z = 208.1 [M+H] +

[0111] Example Example 1: N-(5-Chloro-2,3-dihydro-1H-inden-2-yl)-5-(3-methyl-1,2,4-oxadiazol-5-yl)pyrimidin-2-amine [ka] To a suspension of 2-((5-chloro-2,3-dihydro-1H-inden-2-yl)amino)pyrimidine-5-carboxylic acid (60 mg, 207 μmol, Intermediate B1) in dry N,N-dimethylformamide (800 μl) at room temperature under nitrogen was added 1,1′-carbonyldiimidazole (38.1 mg, 228 μmol). The reaction mixture was stirred at room temperature for 30 minutes. Then, (E)-N′-hydroxyacetimidamide (17.8 mg, 228 μmol) was added. The reaction mixture was heated to 115° C. for 19 hours. The reaction mixture was cooled to room temperature, and the solvent was removed in vacuo. The crude solid was purified by flash column chromatography on silica gel using a gradient of 0-40% ethyl acetate / heptane to give the title compound as a white solid (26 mg, 38% yield). MS (ESI): m / z=328.2 [M+H] +

[0112] Example 2: N-(5-chloro-2,3-dihydro-1H-inden-2-yl)-5-(5-methyl-1,3,4 oxadiazol-2-yl)pyrimidin-2-amine [ka] Step 1: N'-acetyl-2-((5-chloro-2,3-dihydro-1H-inden-2-yl)amino)pyrimidine-5-carbohydrazide [ka] In a sealed tube, to a solution of 2-((5-chloro-2,3-dihydro-1H-inden-2-yl)amino)pyrimidine-5-carboxylic acid (100 mg, 345 μmol, Intermediate B1) in dichloromethane (3.8 ml) at room temperature under nitrogen, HOBt (74.9 mg, 554 μmol, 1.61 eq), EDCI HCl (108 mg, 554 μmol), triethylamine (87.3 mg, 120 μl, 863 μmol, 2.5 eq) were added, and finally N,N-dimethylformamide (633 μl) was added. Argon was bubbled through the mixture for 10 minutes. Then, acetohydrazide (25.6 mg, 345 μmol, 1 eq) was added. The reaction mixture was stirred at room temperature for 3 hours. The mixture was quenched with water. The resulting solid was filtered, washed with water, and dried to obtain the title compound (80 mg, yield 67%) as a light brown solid. MS (ESI): m / z = 346.2 [M+H] +

[0113] Step 2: N-(5-chloro-2,3-dihydro-1H-inden-2-yl)-5-(5-methyl-1,3,4-oxadiazol-2-yl)pyrimidin-2-amine

Chemical Structure

[0114] Example 3: N-(5-Chloro-2,3-dihydro-1H-inden-2-yl)-5-(4-methyloxazol-2-yl)pyrimidin-2-amine

Chemical formula

Chemical formula

[0115]

Chemical formula

[0116] Step 3: N-(5-chloro-2,3-dihydro-1H-inden-2-yl)-5-(4-methyloxazol-2-yl)pyrimidin-2-amine

Chemical Structure

[0117] Example 4: N-(5-chloro-2,3-dihydro-1H-inden-2-yl)-5-(3-methylisoxazol-5-yl)pyrimidin-2-amine [Chemical formula] The title compound was prepared as a white solid in the same manner as Intermediate B6 from 5-bromo-N-(5-chloro-2,3-dihydro-1H-inden-2-yl)pyrimidin-2-amine (Intermediate B2) and 3-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)isoxazole. MS(ESI): m / z = 327.2 [M+H] +

[0118] Example 5: N-(5-chloro-2,3-dihydro-1H-inden-2-yl)-5-(oxazol-2-yl)pyrimidin-2-amine [Chemical formula] The title compound was prepared as a white solid in the same manner as Intermediate B7 from 5-bromo-N-(5-chloro-2,3-dihydro-1H-inden-2-yl)pyrimidin-2-amine (Intermediate B2) and 2-(tributylstannyl)oxazole. MS(ESI): m / z = 313.2 [M+H] +

[0119] Example 6: N-(5-chloro-2,3-dihydro-1H-inden-2-yl)-5-(pyrazin-2-yl)pyrimidin-2-amine [Chemical formula] The title compound was prepared as an off-white solid in the same manner as Intermediate B7 from 5-bromo-N-(5-chloro-2,3-dihydro-1H-inden-2-yl)pyrimidin-2-amine (Intermediate B2) and 2-(tributylstannyl)pyrazine. MS(ESI): m / z = 324.2 [M+H] +

[0120] Example 7: N-(5-Chloro-2,3-dihydro-1H-inden-2-yl)-5-(4-methyl-1H-pyrazol-1-yl)pyrimidin-2-amine

Chemical formula

[0121] Example 8: N-(5-Chloro-2,3-dihydro-1H-inden-2-yl)-5-(3-methyl-1H-pyrazol-1-yl)pyrimidin-2-amine

Chemical formula

[0122] Example 9: N-(5-Chloro-2,3-dihydro-1H-inden-2-yl)-5-(4-methyl-1,2,3-triazol-2-yl)pyrimidin-2-amine

Chemical formula

[0123] Example 10: N-(5-chloro-2,3-dihydro-1H-inden-2-yl)-5-(5-methyloxazol-2-yl)pyrimidin-2-amine

Chemical formula

[0124] Example 11: N-(5-chloro-2,3-dihydro-1H-inden-2-yl)-5-(pyridazin-3-yl)pyrimidin-2-amine

Chemical formula

Chemical formula

[0125] Example 14: N-(5-chloro-2,3-dihydro-1H-inden-2-yl)-5-(5,5-dimethyl-4,5-dihydroisoxazol-3-yl)pyrimidin-2-amine [Chemistry] The title compound was prepared as an off-white solid in the same manner as Intermediate B2 from 3-(2-chloropyrimidin-5-yl)-5,5-dimethyl-4,5-dihydroisoxazole (Intermediate B4) and 5-chloro-2,3-dihydro-1H-inden-2-amine hydrochloride (Intermediate A1). MS(ESI): m / z = 343.3 [M+H] +

[0126] Example 15: (S)-6-chloro-2-((5-(3-methyl-1,2,4-oxadiazol-5-yl)pyrimidin-2-yl)amino)-2,3-dihydro-1H-indene-4-carbonitrile

Chem.

Chem.

[0127] Step 2: (S)-6-chloro-2-((5-(3-methyl-1,2,4-oxadiazol-5-yl)pyrimidin-2-yl)amino)-2,3-dihydro-1H-indene-4-carbonitrile

Chem.

[0128] Examples 16 - 21 below were prepared in two steps from Intermediate A2 and the indicated thiomethyl intermediates B6 - 11 in the same manner as Example 15. [Table 2]

[0129] Example A The compound of formula I can be used as an active ingredient in a manner known per se to produce tablets of the following composition.

[0130] Per tablet Active ingredient 200 mg Microcrystalline cellulose 155 mg Corn starch 25 mg Talc 25 mg Hydroxypropylmethylcellulose 20 mg 425 mg Example B: The compound of formula I can be used as an active ingredient in a manner known per se to produce 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 1】 wherein R １ is i) a 5- or 6-membered heteroaryl,[ ii) a 5- or 6-membered substituted heteroaryl,[ iii) a 5- or 6-membered heterocycloalkyl,[ iv) a 5- or 6-membered substituted heterocycloalkyl is selected from the group consisting of,[ the substituted heteroaryl or substituted heterocycloalkyl is substituted with one or more alkyl substituents,[ R ２ is i) H,[ ii) cyano,[ iii) halogen iv) C １～６ alkyl, v) Halo-C １～６ Alkyl is selected from the group consisting of,[ R ３ is i) H,[ ii) halogen iii) C １～６ alkyl, iv) Halo-C １～６ Alkyl is selected from the group consisting of) and is a compound of formula I, or a pharmaceutically acceptable salt thereof, excluding the following compounds 【Chemical 2】

2.

3. R ３ The compound according to claim 1 or a pharmaceutically acceptable salt thereof, wherein R is a halogen.

4. R ３ The compound according to claim 1 or 2, or a pharmaceutically acceptable salt thereof, wherein R is Cl.

5. R ２ is i) H,[ ii) cyano is selected from the group consisting of, the compound according to any one of Claims 1 to 3, or a pharmaceutically acceptable salt thereof.

6. R １ is i) a 5- or 6-membered heteroaryl ii) a 5- or 6-membered substituted heteroaryl iii) a 5- or 6-membered substituted heterocycloalkyl is selected from the group consisting of,[ the substituted heteroaryl or substituted heterocycloalkyl is substituted with one or more alkyl substituents,[ R ２ is i) H,[ ii) cyano is selected from the group consisting of,[ R ３ wherein R is a halogen the compound according to any one of Claims 1 to 4, or a pharmaceutically acceptable salt thereof.

7. R １ is i) a 5- or 6-membered heteroaryl,[ ii) a 5- or 6-membered substituted heteroaryl,[ iii) a 5- or 6-membered substituted heterocycloalkyl is selected from the group consisting of,[ the substituted heteroaryl or substituted heterocycloalkyl is substituted with one or more alkyl substituents,[ R ２ is i) H,[ ii) cyano is selected from the group consisting of,[ R ３ wherein R is Cl the compound according to any one of Claims 1 to 5, or a pharmaceutically acceptable salt thereof.

8. R １ is 3-methyl-1,2,4-oxadiazol-5-yl, 3-methyl-1,2,4-triazol-1-yl, 3-methylisoxazol-5-yl, 3-methylpyrazol-1-yl, 4-methyloxazol-2-yl, 4-methylpyrazol-1-yl, 4-methyltriazol-2-yl, 5,5-dimethyl-4H-isoxazol-3-yl, 5-methyl-1,3,4-oxadiazol-2-yl, 5-methyloxazol-2-yl, 5-methylpyrazin-2-yl, 5-methylpyrimidin-2-yl, oxazol-2-yl, pyrazin-2-yl, and pyridazin-3-yl, the compound according to any one of claims 1 to 6 or a pharmaceutically acceptable salt thereof.

9. R １ is selected from 3-methyl-1,2,4-oxadiazol-5-yl, 3-methyl-1,2,4-triazol-1-yl, 3-methylisoxazol-5-yl, 3-methylpyrazol-1-yl, 4-methyloxazol-2-yl, 4-methylpyrazol-1-yl, 4-methyltriazol-2-yl, 5,5-dimethyl-4H-isoxazol-3-yl, 5-methyl-1,3,4-oxadiazol-2-yl, 5-methyloxazol-2-yl, 5-methylpyrazin-2-yl, 5-methylpyrimidin-2-yl, oxazol-2-yl, pyrazin-2-yl, and pyridazin-3-yl, the substituted heteroaryl is substituted with one or more alkyl substituents,[ R ２ is i) H,[ ii) cyano is selected from the group consisting of,[ R ３ wherein R is Cl the compound according to any one of Claims 1 to 7, or a pharmaceutically acceptable salt thereof.

9. N-(5-chloro-2,3-dihydro-1H-inden-2-yl)-5-(3-methyl-1,2,4-oxadiazol-5-yl)pyrimidin-2-amine; N-(5-chloro-2,3-dihydro-1H-inden-2-yl)-5-(5-methyl-1,3,4-oxadiazol-2-yl)pyrimidin-2-amine; N-(5-chloro-2,3-dihydro-1H-inden-2-yl)-5-(4-methyloxazol-2-yl)pyrimidin-2-amine; N-(5-Chloro-2,3-dihydro-1H-inden-2-yl)-5-(3-methylisoxazol-5-yl)pyrimidin-2-amine; N-(5-Chloro-2,3-dihydro-1H-inden-2-yl)-5-(4-methyl-1H-pyrazol-1-yl)pyrimidin-2-amine; N-(5-Chloro-2,3-dihydro-1H-inden-2-yl)-5-(3-methyl-1H-pyrazol-1-yl)pyrimidin-2-amine; N-(5-Chloro-2,3-dihydro-1H-inden-2-yl)-5-(4-methyl-1,2,4-triazol-2-yl)pyrimidin-2-amine; N-(5-Chloro-2,3-dihydro-1H-inden-2-yl)-5-(5-methyloxazol-2-yl)pyrimidin-2-amine; (S or R)-N-(5-Chloro-2,3-dihydro-1H-inden-2-yl)-5-(3-methyl-1,2,4-oxadiazol-5-yl)pyrimidin-2-amine; (R or S)-N-(5-Chloro-2,3-dihydro-1H-inden-2-yl)-5-(3-methyl-1,2,4-oxadiazol-5-yl)pyrimidin-2-amine; N-(5-Chloro-2,3-dihydro-1H-inden-2-yl)-5-(5,5-dimethyl-4,5-dihydroisoxazol-3-yl)pyrimidin-2-amine; (S)-6-Chloro-2-((5-(3-methyl-1,2,4-oxadiazol-5-yl)pyrimidin-2-yl)amino)-2,3-dihydro-1H-inden-4-carbonitrile; (S)-6-Chloro-2-((5-(3-methylisoxazol-5-yl)pyrimidin-2-yl)amino)-2,3-dihydro-1H-inden-4-carbonitrile; (S)-6-Chloro-2-((5-(4-methyloxazol-2-yl)pyrimidin-2-yl)amino)-2,3-dihydro-1H-inden-4-carbonitrile; (S)-6-Chloro-2-((5-(5-methyloxazol-2-yl)pyrimidin-2-yl)amino)-2,3-dihydro-1H-inden-4-carbonitrile; (S)-6-Chloro-2-((5-(5-methylpyrazin-2-yl)pyrimidin-2-yl)amino)-2,3-dihydro-1H-inden-4-carbonitrile; (S)-6-Chloro-2-((5-methyl-[2,5''-bipyrimidin]-2''-yl)amino)-2,3-dihydro-1H-inden-4-carbonitrile; or (S)-6-Chloro-2-[[5-(3-methyl-1,2,4-triazol-1-yl)pyrimidin-2-yl]amino]-2,3-dihydro-1H-inden-4-carbonitrile The compound according to any one of claims 1 to 8, or a pharmaceutically acceptable salt thereof, selected from the above. **Claim 10** A method for preparing the compound according to any one of claims 1 to 9 or a pharmaceutically acceptable salt thereof, which comprises reacting a compound of formula II with a compound of formula III to prepare a compound of formula I. [Chemical Formula 3] (wherein R １ , R ２ and R ３ are as defined in any one of claims 1 to 9, and X is a halogen or a thiomethyl group). **Claim 11** The compound according to any one of claims 1 to 9 or a pharmaceutically acceptable salt thereof for use as a therapeutic active substance. **Claim 12** A pharmaceutical composition comprising the compound according to any one of claims 1 to 9 or a pharmaceutically acceptable salt thereof. **Claim 13** The pharmaceutical composition according to claim 12 for the treatment or prevention of at least one selected from kidney conditions, liver conditions, inflammatory conditions, nervous system conditions, respiratory system conditions, vascular and cardiovascular conditions, fibrotic diseases, cancer, eye conditions, metabolic conditions, cholestasis and other forms of chronic pruritus, and acute and chronic organ transplant rejection. **Claim 14** The compound according to any one of claims 1 to 9 or a pharmaceutically acceptable salt thereof for the treatment or prevention of at least one selected from kidney conditions, liver conditions, inflammatory conditions, nervous system conditions, fibrotic diseases, and acute and chronic organ transplant rejection. **Claim 15** Use of the compound according to any one of claims 1 to 9 or a pharmaceutically acceptable salt thereof for the preparation of a medicament for the treatment or prevention of at least one selected from kidney conditions, liver conditions, inflammatory conditions, nervous system conditions, fibrotic diseases, and acute and chronic organ transplant rejection. **Claim 16** The pharmaceutical composition according to claim 12 for the treatment or prevention of at least one selected from kidney conditions, liver conditions, inflammatory conditions, nervous system conditions, fibrotic diseases, and acute and chronic organ transplant rejection.

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