WO2022100727A1 - 咪唑并噻唑类化合物、其药物组合物及其用途 - Google Patents
咪唑并噻唑类化合物、其药物组合物及其用途 Download PDFInfo
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- WO2022100727A1 WO2022100727A1 PCT/CN2021/130584 CN2021130584W WO2022100727A1 WO 2022100727 A1 WO2022100727 A1 WO 2022100727A1 CN 2021130584 W CN2021130584 W CN 2021130584W WO 2022100727 A1 WO2022100727 A1 WO 2022100727A1
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- Prior art keywords
- alkyl
- compound
- cycloalkyl
- thiazol
- ethyl
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- 125000004628 isothiazolidinyl group Chemical group S1N(CCC1)* 0.000 description 1
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- 125000003538 pentan-3-yl group Chemical group [H]C([H])([H])C([H])([H])C([H])(*)C([H])([H])C([H])([H])[H] 0.000 description 1
- VLTRZXGMWDSKGL-UHFFFAOYSA-M perchlorate Inorganic materials [O-]Cl(=O)(=O)=O VLTRZXGMWDSKGL-UHFFFAOYSA-M 0.000 description 1
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- JRKICGRDRMAZLK-UHFFFAOYSA-L peroxydisulfate Chemical compound [O-]S(=O)(=O)OOS([O-])(=O)=O JRKICGRDRMAZLK-UHFFFAOYSA-L 0.000 description 1
- 125000001484 phenothiazinyl group Chemical group C1(=CC=CC=2SC3=CC=CC=C3NC12)* 0.000 description 1
- 125000001644 phenoxazinyl group Chemical group C1(=CC=CC=2OC3=CC=CC=C3NC12)* 0.000 description 1
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 description 1
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- 239000003757 phosphotransferase inhibitor Substances 0.000 description 1
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- 229920001223 polyethylene glycol Polymers 0.000 description 1
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- RYYKJJJTJZKILX-UHFFFAOYSA-M sodium octadecanoate Chemical compound [Na+].CCCCCCCCCCCCCCCCCC([O-])=O RYYKJJJTJZKILX-UHFFFAOYSA-M 0.000 description 1
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- FAGLEPBREOXSAC-UHFFFAOYSA-N tert-butyl isocyanide Chemical compound CC(C)(C)[N+]#[C-] FAGLEPBREOXSAC-UHFFFAOYSA-N 0.000 description 1
- 150000003512 tertiary amines Chemical class 0.000 description 1
- 125000003039 tetrahydroisoquinolinyl group Chemical group C1(NCCC2=CC=CC=C12)* 0.000 description 1
- 125000000147 tetrahydroquinolinyl group Chemical group N1(CCCC2=CC=CC=C12)* 0.000 description 1
- 125000001984 thiazolidinyl group Chemical group 0.000 description 1
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- 125000000876 trifluoromethoxy group Chemical group FC(F)(F)O* 0.000 description 1
- GNMJFQWRASXXMS-UHFFFAOYSA-M trimethyl(phenyl)azanium;bromide Chemical compound [Br-].C[N+](C)(C)C1=CC=CC=C1 GNMJFQWRASXXMS-UHFFFAOYSA-M 0.000 description 1
- PRXNKYBFWAWBNZ-UHFFFAOYSA-N trimethylphenylammonium tribromide Chemical compound Br[Br-]Br.C[N+](C)(C)C1=CC=CC=C1 PRXNKYBFWAWBNZ-UHFFFAOYSA-N 0.000 description 1
- CSRZQMIRAZTJOY-UHFFFAOYSA-N trimethylsilyl iodide Chemical compound C[Si](C)(C)I CSRZQMIRAZTJOY-UHFFFAOYSA-N 0.000 description 1
- 208000029729 tumor suppressor gene on chromosome 11 Diseases 0.000 description 1
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- ZDPHROOEEOARMN-UHFFFAOYSA-N undecanoic acid Chemical compound CCCCCCCCCCC(O)=O ZDPHROOEEOARMN-UHFFFAOYSA-N 0.000 description 1
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Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D513/00—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for in groups C07D463/00, C07D477/00 or C07D499/00 - C07D507/00
- C07D513/02—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for in groups C07D463/00, C07D477/00 or C07D499/00 - C07D507/00 in which the condensed system contains two hetero rings
- C07D513/04—Ortho-condensed systems
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K45/00—Medicinal preparations containing active ingredients not provided for in groups A61K31/00 - A61K41/00
- A61K45/06—Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
- A61P1/16—Drugs for disorders of the alimentary tract or the digestive system for liver or gallbladder disorders, e.g. hepatoprotective agents, cholagogues, litholytics
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P11/00—Drugs for disorders of the respiratory system
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P19/00—Drugs for skeletal disorders
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P25/00—Drugs for disorders of the nervous system
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P3/00—Drugs for disorders of the metabolism
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P35/00—Antineoplastic agents
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P37/00—Drugs for immunological or allergic disorders
- A61P37/02—Immunomodulators
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P9/00—Drugs for disorders of the cardiovascular system
Definitions
- the present invention relates to the field of medicinal chemistry, in particular to a new class of imidazothiazole compounds as ATX (Autotaxin) inhibitors, a pharmaceutical composition comprising the compounds, and the use of the compounds or compositions in the treatment of ATX (Autotaxin) ) in diseases expressing increased pathological features.
- ATX Autotaxin
- ATX Autotaxin
- PDE phosphodiesterase
- ENPP extracellular pyrophosphatase/phosphodiesterase
- lysoPLD lysophospholipase D activity, which can catalyze the production of lysophosphatidic acid (LPA) with lysophosphatidylcholine (LPC) as a substrate.
- LPA is not only a precursor of phospholipid synthesis, but also can cause a wide range of biological effects through various signaling pathways.
- LPA1-6 cell surface-specific receptor proteins
- GPCRs G protein-coupled receptors
- LPA1-6 are named LPA1/Edg-2/VZG-1, LPA2/Edg-4, LPA3/Edg-7, LPA4/p2y9/GPR23, LPA5/GPR92, respectively, according to endothelial cell differentiation gene (Edg) and ventricular zone gene names and LPA6/p2Y5, each receptor is mediated by G ⁇ proteins (Gs, Gi, Gq, and G12/13), which in turn initiate a series of cellular signaling cascades.
- GPCRs G protein-coupled receptors
- the main pathways include hydrolysis of phosphatidylinositol diphosphate (PIP2), which in turn triggers intracellular calcium release and protein kinase C (PKC) activation; inhibition of adenylate cyclase (cAMP) signaling pathway; activation Ras-MAPK, MERK, ERK pathway regulates cell proliferation activity; activates phosphoinositide PI3K-AKT pathway, regulates cell survival and apoptosis; finally, activates Rho pathway to regulate cytoskeleton remodeling, shape change and cell migration activity.
- PIP2 phosphatidylinositol diphosphate
- PLC protein kinase C
- cAMP adenylate cyclase
- the concentration of LPA can be increased to 10 ⁇ mol/L, which is much higher than the normal level of 100 nmol/L.
- Excessive LPA will increase the production of vascular endothelial growth factor (VEGF) and promote angiogenesis; reduce the expression of tumor suppressor p53 and increase the survival and metastasis of tumor cells.
- VEGF vascular endothelial growth factor
- the ATX-LPA signaling pathway is involved in many physiological and pathological processes, and thus has an important connection with many serious diseases, including cardiovascular diseases, autoimmune diseases, cancer, fibrotic diseases, inflammation, nervous system diseases, pain, etc.
- LPA has multiple functions in tumorigenesis, promoting tumor cell growth, angiogenesis, metastasis and emergence of drug resistance. Therefore, reducing the concentration level of LPA is beneficial to the treatment and control of tumors.
- inhibiting the activity of AXT and blocking the production pathway of LPA is a research hotspot in the treatment of many serious diseases.
- Fibrotic diseases are mainly idiopathic pulmonary fibrosis (IPF) and liver fibrosis.
- IPF idiopathic pulmonary fibrosis
- IPF is a lethal disease characterized by diffuse alveolitis and alveolar structural disorder, leading to the progressive development of pulmonary interstitial fibrosis.
- the prognosis is poor, with an average survival time of 2 to 5 years.
- IPF is probably the disease most closely linked to the ATX-LPA pathway, because in lung tissue, ATX expression is most concentrated in bronchial epithelial cells and alveolar macrophages, which can juxtapose fibroblast foci.
- GLPG-1690 as an Autotaxin inhibitor, has entered the clinical phase II trial for the treatment of idiopathic pulmonary fibrosis; serum ATX concentration is closely related to liver fibrosis and liver stiffness value, which is the best predictor of liver cirrhosis.
- ATX is highly expressed in many tumor tissues, including melanoma, non-small cell lung cancer, liver cancer, kidney cancer, breast cancer, thyroid cancer, ovarian cancer, and Hodgkin lymphoma.
- LPA/ATX can promote cell invasion and metastasis during tumor cell growth. Therefore, ATX inhibitors, which block the signal transduction pathway, provide a new way for clinical treatment of cancer and fibrotic diseases.
- ATX inhibitors Compared with traditional kinase inhibitors, ATX inhibitors inhibit the activity of ATX and affect multiple signaling pathways related to cell proliferation, growth and apoptosis, and have a better inhibitory effect on some drug-resistant tumors.
- the fibrosis of organs is closely related and is an important target for the research and development of new drugs for fibrotic diseases.
- the present invention provides a new class of imidazothiazole compounds, which have good inhibitory activity on ATX, and are much better than Comparative Example 1 for in vitro enzymatic activity.
- the compounds of the present invention have higher exposure and bioavailability.
- the compounds of the present invention have excellent efficacy, pharmacokinetic properties and/or toxicological properties, and have good clinical application prospects.
- the present invention provides a new class of imidazothiazole compounds, which have very good inhibitory activity to ATX, and have high exposure and bioavailability in rats, and can be used to prepare and treat diseases with increased ATX expression.
- Diseases with physical characteristics such as cancer, fibrotic diseases (eg, pulmonary fibrosis or liver fibrosis), metabolic diseases, myelodysplastic syndromes, cardiovascular diseases, autoimmune diseases, inflammation, neurological diseases, or pain medications .
- the present invention also provides methods of preparing the compounds of the present invention, methods of using these compounds to treat the above-mentioned diseases in mammals, especially humans, and pharmaceutical compositions comprising these compounds.
- the present invention provides a new imidazothiazole compound, which has the structure shown in formula (I):
- Z is H, -CN, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 haloalkyl, C 1-6 hydroxyalkyl, C 1-6 cyanoalkane base, C 3-8 cycloalkyl, C 2-7 heterocyclyl, C 2-7 heterocyclyl, C 1-6 alkyl, C 3-8 cycloalkyl, C 1-6 alkyl, C 6-10 Aryl, or C 1-9 heteroaryl; wherein said Z is optionally substituted with one or more R 5 ;
- R 1b is H, C 1-4 alkyl, C 3-6 cycloalkyl, or C 3-6 cycloalkyl C 1-4 alkyl; wherein said R 1b is optionally replaced by 1, 2, 3 or 4 R 7 substitutions;
- R 2 is H, -CN, -NO 2 , -OH, -NH 2 , -N 3 , F, Cl, Br, I, C 1-4 alkyl, C 1-4 haloalkyl, or C 1-4 hydroxyalkyl;
- R 3 is H, -CN, -NO 2 , -OH, -NH 2 , -N 3 , F, Cl, Br, I, C 1-6 alkyl, C 1-6 alkenyl, C 1-6 alkyne group, C 1-6 haloalkyl, C 1-6 cyanoalkyl, or C 1-6 hydroxyalkyl;
- m1 is independently 1, 2, or 3;
- m2 is independently 0, 1, 2, or 3;
- m3 is independently 1, 2, or 3;
- n1 0, 1, 2, 3 or 4;
- t 0, 1, 2, 3, or 4;
- t1 and t2 are each independently 1, 2, 3 or 4.
- the present invention provides a pharmaceutical composition
- a pharmaceutical composition comprising the compound of the present invention or a pharmaceutically acceptable salt, hydrate, solvate, stereoisomer, tautomer thereof compounds, nitrogen oxides, metabolites, prodrugs, and pharmaceutically acceptable excipients, diluents or carriers.
- compositions described herein further comprise additional therapeutic agents.
- the present invention provides a use of the compound of the present invention or the pharmaceutical composition of the present invention in the preparation of a medicament for the prevention or treatment of a disease in a mammal having pathological characteristics of increased ATX expression .
- the disease characterized by the pathology of increased ATX expression comprises: cancer, fibrotic disease, metabolic disease, myelodysplastic syndrome, cardiovascular disease, autoimmune disease, inflammation, neurological disease, or pain.
- the disease pathologically characterized by increased ATX expression is pulmonary fibrosis or liver fibrosis.
- the articles “a”, “an” and “the” are intended to include “at least one” or “one or more” unless stated otherwise or otherwise clearly contradicted by context.
- these articles refer to one or more than one (ie, at least one) object of the article.
- a component refers to one or more components, ie, there may be more than one component contemplated for use or use in the implementation of the described embodiments.
- Stereoisomers refer to compounds that have the same chemical structure, but differ in the arrangement of atoms or groups in space. Stereoisomers include enantiomers, diastereomers, conformational isomers (rotamers), geometric isomers (cis/trans), atropisomers, etc. .
- substituted means that one or more hydrogen atoms in a given structure have been replaced with a specified substituent.
- a substituted group may have a substituent at each substitutable position of the group.
- the substituents can be substituted identically or differently at each position.
- C1-6 alkyl specifically refers to the independently disclosed methyl, ethyl, C3 alkyl, C4 alkyl, C5 alkyl and C6 alkyl groups .
- alkyl or “alkyl group” used in the present invention refers to a saturated linear or branched monovalent hydrocarbon group containing 1 to 20 carbon atoms, wherein the alkyl group may optionally be is substituted with one or more substituents described herein. Unless otherwise specified, alkyl groups contain 1-20 carbon atoms. In one embodiment, the alkyl group contains 1-12 carbon atoms; in another embodiment, the alkyl group contains 1-6 carbon atoms; in yet another embodiment, the alkyl group contains 1 -4 carbon atoms; in yet another embodiment, the alkyl group contains 1-3 carbon atoms. The alkyl group may be optionally substituted with one or more substituents described herein.
- alkyl groups include, but are not limited to, methyl (Me, -CH3 ), ethyl (Et, -CH2CH3), n - propyl (n - Pr, -CH2CH2CH3 ) ), isopropyl (i-Pr, -CH(CH 3 ) 2 ), n-butyl (n-Bu, -CH 2 CH 2 CH 2 CH 3 ), isobutyl (i-Bu, -CH 2 CH ) (CH 3 ) 2 ), sec-butyl (s-Bu, -CH(CH 3 )CH 2 CH 3 ), tert-butyl (t-Bu, -C(CH 3 ) 3 ), n-pentyl (-CH 2CH2CH2CH2CH3), 2 -pentyl (-CH( CH3 ) CH2CH2CH3 ) , 3 - pentyl (-CH( CH2CH3 ) 2 ) , 2 -methyl
- deuterated alkyl or “deuterated ethyl” refers to an alkyl group or ethyl group substituted with 1, 2, 3, 4, 5 or 6 D atoms, wherein the alkyl group is of the present invention said definition.
- deuterated alkyl or deuterated ethyl include, but are not limited to, -CD3 , -CH2D , -CHD2 , -CD2CD3 , -CH2CD3 , -CD2CH3 , and the like.
- alkoxy means that an alkyl group is attached to the remainder of the molecule through an oxygen atom, wherein the alkyl group has the definition as described herein. Unless otherwise specified, the alkoxy groups contain 1-12 carbon atoms. In one embodiment, the alkoxy group contains 1-6 carbon atoms; in another embodiment, the alkoxy group contains 1-4 carbon atoms; in yet another embodiment, the alkoxy group The group contains 1-3 carbon atoms. The alkoxy groups may be optionally substituted with one or more substituents described herein.
- alkoxy groups include, but are not limited to, methoxy (MeO, -OCH 3 ), ethoxy (EtO, -OCH 2 CH 3 ), 1-propoxy (n-PrO, n- Propoxy, -OCH 2 CH 2 CH 3 ), 2-propoxy (i-PrO, i-propoxy, -OCH(CH 3 ) 2 ), 1-butoxy (n-BuO, n- Butoxy, -OCH 2 CH 2 CH 2 CH 3 ), 2-methyl-l-propoxy (i-BuO, i-butoxy, -OCH 2 CH(CH 3 ) 2 ), 2-butanyl Oxy (s-BuO, s-butoxy, -OCH(CH 3 )CH 2 CH 3 ), 2-methyl-2-propoxy (t-BuO, t-butoxy, -OC(CH 3 ) 3 ), 1 -pentyloxy (n - pentyloxy, -OCH2CH2CH2CH2CH2
- haloalkyl or “haloalkoxy” means that an alkyl or alkoxy group is substituted with one or more halogen atoms (such as F, Cl, Br, or I), examples of which include, but are not limited to, Trifluoromethyl, trifluoroethyl, 2,2,3,3-tetrafluoropropyl, trifluoromethoxy and the like.
- halogen atoms such as F, Cl, Br, or I
- hydroxyalkyl or “hydroxyalkyl” as used herein means that an alkyl group is substituted with one or more hydroxy groups, wherein the alkyl group is as defined herein, such examples include , but not limited to hydroxyethyl, 2-hydroxypropyl, hydroxymethyl, etc.
- cycloalkyl refers to a monovalent saturated or partially unsaturated (but not aromatic) monocyclic or polycyclic hydrocarbon.
- the cycloalkyl groups can be bridged or unbridged, spirocyclic or non-spirocyclic, and/or fused or non-fused bicyclic groups.
- the cycloalkyl group includes 3-10 carbon atoms, ie, C3 to C10 cycloalkyl.
- the cycloalkyl group has 3-15 (C 3-15 ), 3-10 (C 3-10 ), or 3-7 (C 3-7 ) carbon atoms.
- the cycloalkyl group is monocyclic or bicyclic. In some embodiments, the cycloalkyl group is monocyclic. In some embodiments, the cycloalkyl group is bicyclic. In some embodiments, the cycloalkyl group is tricyclic. In some embodiments, the cycloalkyl group is fully saturated. In some embodiments, the cycloalkyl group is partially saturated.
- the cycloalkyl group is cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, bicyclo[2.1.1]hexyl, bicyclo[2.2.1]heptyl, deca Hydronaphthyl, or adamantyl.
- a cycloalkyl group When a cycloalkyl group is substituted, it may be independently substituted with one or more substituents described herein on any ring, ie, on any aromatic or non-aromatic ring contained by the cycloalkyl group.
- heterocyclyl and “heterocycle” are used interchangeably herein, unless otherwise specified, to refer to a monovalent monocyclic non-aromatic ring system and/or polycyclic ring system comprising at least one non-aromatic ring; wherein the One or more (in certain embodiments, 1, 2, 3, or 4) of the non-aromatic monocyclic atoms are heteroatoms independently selected from O, S(O) 0-2 , and N, and the The remaining ring atoms are all carbon atoms; and wherein one or more (in certain embodiments, 1, 2, 3, or 4) of the ring atoms of the polycyclic ring system are independently selected from O, S(O ) heteroatoms of 0-2 and N, and the remaining ring atoms are all carbon atoms.
- the heterocycle contains 1 or 2 heteroatoms, all of which are nitrogen atoms.
- the heterocyclyl group is polycyclic and contains one heteroatom in a non-aromatic ring, or one heteroatom in an aromatic ring, or two heteroatoms in an aromatic ring, or two One of the heteroatoms is in an aromatic ring and the other is in a non-aromatic ring.
- the heterocyclyl group has 3-20, 3-15, 3-10, 3-8, 4-7, or 5-6 ring atoms.
- the heterocyclyl group is a monocyclic, bicyclic, tricyclic, or tetracyclic ring system.
- the heterocyclyl group can be bridged or unbridged, spirocyclic or non-spirocyclic, and/or fused or non-fused bicyclic groups.
- One or more nitrogen and sulfur atoms may be optionally oxidized, one or more nitrogen atoms may be optionally quaternized, and one or more carbon atoms may be optionally replace.
- Some rings may be partially or fully saturated, or aromatic, provided that the heterocycle is not fully aromatic.
- the monocyclic and polycyclic heterocycles can be attached to the main structure at any heteroatom or carbon atom that results in a stable compound.
- the polycyclic heterocyclyl may be attached to the main structure through any of its rings, including any aromatic or non-aromatic ring, whether or not the ring contains a heteroatom.
- the heterocyclyl group is "heterocycloalkyl", which is 1) a saturated or partially unsaturated (but non-aromatic) monovalent monocyclic group as described herein containing at least one ring heteroatom , or 2) a saturated or partially unsaturated (but non-aromatic) monovalent bicyclic or tricyclic group wherein at least one ring contains at least one heteroatom as described herein.
- heterocyclyl and heterocycloalkyl When heterocyclyl and heterocycloalkyl are substituted, they may be substituted on either ring, ie, on any aromatic or non-aromatic ring contained by heterocyclyl and heterocycloalkyl.
- heterocyclyl groups include, but are not limited to, oxiranyl, azetidinyl, oxetanyl, thietanyl, pyrrolidinyl, 2-pyrrolinyl, 3-pyrrolinyl, pyrazolinyl, pyrazolidine, imidazolinyl, imidazolidinyl, tetrahydrofuranyl, dihydrofuranyl, tetrahydrothienyl, dihydrothienyl, 1,3-dioxolane base, dithiocyclopentyl, tetrahydropyranyl, dihydropyranyl, 2H-pyranyl, 4H-pyranyl, tetra
- oxidized sulfur atom in the heterocyclyl group include, but are not limited to, sulfolanyl, 1,1-dioxothiomorpholinyl.
- the heterocyclyl group may be optionally substituted with one or more substituents described herein.
- the heterocyclyl group is a heterocyclyl group consisting of 3-8 atoms, which refers to a saturated or partially unsaturated monocyclic ring containing 3-8 ring atoms, wherein at least one ring atom is selected from nitrogen, sulfur and oxygen atoms.
- Ring sulfur atoms can optionally be oxidized to S-oxides.
- the nitrogen atoms of the rings can be optionally oxidized to N-oxygen compounds.
- heterocyclyl groups of 3-8 atoms include, but are not limited to: azetidinyl, oxetanyl, thietanyl, pyrrolidinyl, 2-pyrrolinyl, 3-pyrroline base, pyrazolinyl, pyrazolidine, imidazolinyl, imidazolidinyl, tetrahydrofuranyl, dihydrofuranyl, tetrahydrothienyl, dihydrothienyl, 1,3-dioxocyclopentyl, disulfide Cyclopentyl, tetrahydropyranyl, dihydropyranyl, 2H-pyranyl, 4H-pyranyl, tetrahydrothiopyranyl, piperidinyl, morpholinyl, thiomorpholinyl, piperazine base, dioxanyl, dithianyl, thioxanyl, homopiperazinyl, homopiperidinyl
- oxidized sulfur atom in the heterocyclyl group include, but are not limited to, sulfolanyl, 1,1-dioxothiomorpholinyl.
- Said heterocyclyl group consisting of 3-8 atoms can be optionally substituted by one or more substituents described in the present invention.
- the heterocyclyl group is a heterocyclyl group consisting of 3-6 atoms, which refers to a saturated or partially unsaturated monocyclic ring containing 3-6 ring atoms, wherein at least one ring atom is selected from nitrogen, sulfur and oxygen atoms.
- Ring sulfur atoms can optionally be oxidized to S-oxides.
- the nitrogen atoms of the rings can be optionally oxidized to N-oxygen compounds.
- the 3-6 atom heterocyclyl group can be optionally substituted by one or more substituents described in the present invention.
- the heterocyclyl group is a heterocyclyl group consisting of 5-6 atoms, which refers to a saturated or partially unsaturated monocyclic ring containing 5-6 ring atoms, wherein at least one ring atom is selected from nitrogen, sulfur and oxygen atoms.
- Ring sulfur atoms can optionally be oxidized to S-oxides.
- the nitrogen atoms of the rings can be optionally oxidized to N-oxygen compounds.
- heterocyclic groups of 5-6 atoms include, but are not limited to: pyrrolidinyl, 2-pyrrolinyl, 3-pyrrolinyl, pyrazolinyl, pyrazolidinyl, imidazolinyl, imidazolidine base, tetrahydrofuranyl, dihydrofuranyl, tetrahydrothienyl, dihydrothienyl, 1,3-dioxocyclopentyl, dithiocyclopentyl, 2-oxopyrrolidinyl, oxo-1,3 -Thiazolidinyl, sulfolanyl, tetrahydropyranyl, dihydropyranyl, 2H-pyranyl, 4H-pyranyl, tetrahydrothiopyranyl, piperidinyl, morpholinyl, thiomorpholine base, piperazinyl, dioxanyl, dithianyl, thioxanyl,
- cycloalkylalkyl means that an alkyl group may be substituted by one or more cycloalkyl groups, wherein cycloalkyl and alkyl are as defined herein, examples of which include, but do not Limited to, cyclopropylmethyl, cyclopropylethyl, cyclopropylpropyl, cyclobutylmethyl, cyclobutylethyl, cyclopentylmethyl, cyclopentylethyl, cyclopentylpropyl, cyclohexyl Ethyl etc.
- heterocyclylalkyl includes a heterocyclyl-substituted alkyl group
- heterocyclylalkoxy includes a heterocyclyl-substituted alkoxy group in which the oxygen atom is attached to the remainder of the molecule
- heterocyclylalkoxy includes a heterocyclyl-substituted alkoxy group in which the oxygen atom is attached to the remainder of the molecule
- heterocyclylalkoxy “Alkylamino” includes heterocyclyl-substituted alkylamino groups in which the nitrogen atom is attached to the remainder of the molecule.
- heterocyclyl, alkyl, alkoxy and alkylamino are as defined herein, such examples include, but are not limited to, azetidin-1-ylmethyl, azetidine -1-ylethyl, azetidin-1-ylpropyl, pyrrol-1-ylmethyl, pyrrol-1-ylethyl, pyrrol-1-ylpropyl, morpholin-4-ylethyl group, morpholin-4-ylethoxy, piperazin-4-ylethoxy, piperidin-4-ylethylamino and the like.
- n typically describes the number of ring-forming atoms in a molecule where the number of ring-forming atoms is n.
- piperidinyl is a 6-atom heterocycloalkyl group
- 1,2,3,4-tetrahydronaphthalene is a 10-atom cycloalkyl group.
- heteroatom refers to O, S, N, P, and Si, including N, S, and P in any oxidation state; in the form of primary, secondary, tertiary amines, and quaternary ammonium salts; or on a nitrogen atom in a heterocyclic ring.
- Hydrogen substituted form for example, N (like N in 3,4-dihydro-2H-pyrrolidinyl), NH (like NH in pyrrolidinyl) or NR (like in N-substituted pyrrolidinyl) NR).
- cyano-substituted alkyl or “cyanoalkyl” includes a C1-10 straight or branched chain alkyl group substituted with one or more cyano groups.
- cyano-substituted alkyl is a C 1-6 "lower cyanoalkyl” substituted with one or more cyano groups
- cyano-substituted Alkyl is a C1-4 "lower cyanoalkyl" substituted with one or more cyano groups, examples of which include, but are not limited to, CNCH2- , CNCH2CH2- , CNCH 2 CH 2 CH 2 -, CNCH 2 CHCNCH 2 -, etc.
- the substituents draw a bond to the central ring to form a ring system (as shown in the figure below) to represent that the substituents can be substituted at any substitutable position on any ring.
- formula b represents any possible substituted position on ring A or ring B, such as formula c, d, e, f, g, h, i, j, k, l, m, n, o, p, q, etc.
- pharmaceutically acceptable salts refer to organic and inorganic salts of the compounds of the present invention.
- Pharmaceutically acceptable salts are well known in the art, as described in the literature: SM Berge et al., describe pharmaceutically acceptable salts in detail in J. Pharmaceutical Sciences, 1977, 66: 1-19.
- Pharmaceutically acceptable non-toxic acid-formed salts include, but are not limited to, inorganic acid salts such as hydrochloride, hydrobromide, phosphate, sulfate, perchlorate, And organic acid salts such as acetate, oxalate, maleate, tartrate, citrate, succinate, malonate, or obtained by other methods such as ion exchange method described in books and literature these salts.
- salts include adipate, alginate, ascorbate, aspartate, besylate, benzoate, bisulfate, borate, butyrate, camphoric acid Salt, camphorsulfonate, cyclopentylpropionate, digluconate, lauryl sulfate, ethanesulfonate, formate, fumarate, glucoheptonate, glycerophosphate Salt, Gluconate, Hemisulfate, Heptanoate, Caproate, Hydroiodide, 2-Hydroxy-ethanesulfonate, Lacturonate, Lactate, Laurate, Lauryl Sulfate, Malonate, Malonate, Mesylate, 2-Naphthalenesulfonate, Nicotinate, Nitrate, Oleate, Palmitate, Pamoate, Pectate, Persulfate, 3 - Phenylpropionate, picrate, pivalate, propionate,
- Salts obtained by reaction with suitable bases include alkali metal, alkaline earth metal, ammonium and N + ( C1 -C4alkyl )4 salts .
- the present invention also contemplates quaternary ammonium salts formed from any compound containing an N-group. Water- or oil-soluble or dispersible products can be obtained by quaternization.
- Alkali metal or alkaline earth metal salts include sodium, lithium, potassium, calcium, magnesium, and the like.
- Pharmaceutically acceptable salts further include appropriate, non-toxic ammonium, quaternary ammonium salts and amine cations that resist the formation of counterions, such as halides, hydroxides, carboxylates, sulfates, phosphates, nitrates, C1 -8 Sulfonates and aromatic sulfonates.
- counterions such as halides, hydroxides, carboxylates, sulfates, phosphates, nitrates, C1 -8 Sulfonates and aromatic sulfonates.
- a “solvate” of the present invention refers to an association of one or more solvent molecules with a compound of the present invention.
- Solvate-forming solvents include, but are not limited to, water, isopropanol, ethanol, methanol, dimethyl sulfoxide, ethyl acetate, acetic acid, and aminoethanol.
- hydrate refers to an association in which the solvent molecule is water.
- the term "hydrate" may be used.
- one molecule of a compound of the present invention may be associated with one molecule of water, such as a monohydrate; in other embodiments, a molecule of a compound of the present invention may be associated with more than one molecule of water, such as a dihydrate In yet other embodiments, one molecule of the compound of the present invention may be associated with less than one molecule of water, such as a hemihydrate. It should be noted that the hydrates of the present invention retain the bioavailability of the non-hydrated form of the compounds.
- the imidazothiazole compounds provided by the present invention can effectively inhibit the activity of ATX, and the in vitro enzyme activity is much better than that of Comparative Example 1, and has higher exposure and bioavailability in rats, and can be used for the preparation of therapeutic agents with ATX Diseases expressing increased pathological features, eg, cancer, fibrotic diseases (eg, pulmonary fibrosis or liver fibrosis), metabolic diseases, myelodysplastic syndromes, cardiovascular diseases, autoimmune diseases, inflammation, neurological diseases or pain medication.
- fibrotic diseases eg, pulmonary fibrosis or liver fibrosis
- metabolic diseases eg, myelodysplastic syndromes, cardiovascular diseases, autoimmune diseases, inflammation, neurological diseases or pain medication.
- the present invention provides a new imidazothiazole compound, which has the structure shown in formula (I):
- Z is H, -CN, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 haloalkyl, C 1-6 hydroxyalkyl, C 1-6 cyanoalkane base, C 3-8 cycloalkyl, C 2-7 heterocyclyl, C 2-7 heterocyclyl, C 1-6 alkyl, C 3-8 cycloalkyl, C 1-6 alkyl, C 6-10 Aryl, or C 1-9 heteroaryl; wherein said Z is optionally substituted with one or more R 5 ;
- R 1b is H, C 1-4 alkyl, C 3-6 cycloalkyl, or C 3-6 cycloalkyl C 1-4 alkyl; wherein said R 1b is optionally replaced by 1, 2, 3 or 4 R 7 substitutions;
- R 2 is H, -CN, -NO 2 , -OH, -NH 2 , -N 3 , F, Cl, Br, I, C 1-4 alkyl, C 1-4 haloalkyl, or C 1-4 hydroxyalkyl;
- R 3 is H, -CN, -NO 2 , -OH, -NH 2 , -N 3 , F, Cl, Br, I, C 1-6 alkyl, C 1-6 alkenyl, C 1-6 alkyne group, C 1-6 haloalkyl, C 1-6 cyanoalkyl, or C 1-6 hydroxyalkyl;
- m1 is independently 1, 2, or 3;
- m2 is independently 0, 1, 2, or 3;
- m3 is independently 1, 2, or 3;
- n1 0, 1, 2, 3 or 4;
- t 0, 1, 2, 3, or 4;
- t1 and t2 are each independently 1, 2, 3 or 4.
- the compounds of the present invention have the structure of formula (II):
- R 1a is H, ethyl, deuterated ethyl, isopropyl, trifluoroethyl, trifluoromethyl, hydroxyethyl, cyclopropyl, or cyclopropylmethyl.
- Cy is wherein X 3 is -NH-, or -(CH 2 ) 1-2 -; m3 is 1, 2, or 3; and n1 is 0, 1, 2, 3, or 4.
- R 1b is H, methyl, or ethyl.
- Z is C 1-6 alkyl, C 1-6 haloalkyl, C 1-6 hydroxyalkyl, C 1-6 cyanoalkyl, C 3-6 heterocyclyl C 1-4 Alkyl, or C 3-6 cycloalkyl C 1-4 alkyl, wherein said C 1-6 alkyl, C 1-6 haloalkyl, C 1-6 hydroxyalkyl, C 1-6 cyanoalkane group, C 3-6 heterocyclyl C 1-4 alkyl and C 3-6 cycloalkyl C 1-4 alkyl optionally substituted with one or more R 5 ; or Z is in
- X 4 is N, or -CH 2 -;
- X5 is -O-, -S-, -NH-, - ( CH2 ) m4 -NH-( CH2 ) m5- , -( CH2 ) m4 -O-( CH2 ) m5- , -(CH 2 ) m4 -S-(CH 2 ) m5 -, or -(CH 2 ) m6 -;
- each m4 is independently 1, 2, 3 or 4;
- each m5 is independently 0, 1, 2, 3 or 4;
- each m6 is independently 1, 2, 3 or 4;
- n2 is 0, 1, 2, 3 or 4.
- Z is -CH2CH2OH , -CH2C ( CH3 ) 2OH, -CH2C ( CH3 ) 2CH2OH , -CH2CH2CN , -CH2CHF 2 , -CH( CH3 )CH2OH, -C ( CH3 ) 2CH2OH , -CH2C ( CH3 ) 3 ,
- the compounds of the present invention are compounds having one of the following structures:
- the present invention provides a pharmaceutical composition
- a pharmaceutical composition comprising the compound of the present invention or a pharmaceutically acceptable salt, hydrate, solvate, stereoisomer, tautomer thereof compounds, nitrogen oxides, metabolites, prodrugs, and pharmaceutically acceptable excipients, diluents, or carriers.
- compositions described herein further comprise additional therapeutic agents.
- the additional therapeutic agent is associated with fibrotic diseases, proliferative diseases, inflammatory diseases, autoimmune diseases, respiratory diseases, cardiovascular diseases, neurodegenerative diseases, skin diseases
- a therapeutic agent for diseases associated with biological disorders and/or abnormal angiogenesis is associated with fibrotic diseases, proliferative diseases, inflammatory diseases, autoimmune diseases, respiratory diseases, cardiovascular diseases, neurodegenerative diseases, skin diseases.
- the pharmaceutical composition of the present invention wherein the additional therapeutic agent includes, but is not limited to, immunomodulatory agents, analgesics, non-steroidal anti-inflammatory drugs, steroids, synthetic DMARDS, drugs for the treatment of proliferative diseases Drugs, glucocorticoids, cytostatics, alkylating agents, antimetabolites, cytotoxic antibiotics, antibodies, etc.
- additional therapeutic agent includes, but is not limited to, immunomodulatory agents, analgesics, non-steroidal anti-inflammatory drugs, steroids, synthetic DMARDS, drugs for the treatment of proliferative diseases Drugs, glucocorticoids, cytostatics, alkylating agents, antimetabolites, cytotoxic antibiotics, antibodies, etc.
- the present invention provides a use of the compound of the present invention or the pharmaceutical composition of the present invention in the preparation of a medicament for the prevention or treatment of a disease in a mammal having pathological characteristics of increased ATX expression .
- the disease characterized by the pathology of increased ATX expression comprises: cancer, fibrotic disease, metabolic disease, myelodysplastic syndrome, cardiovascular disease, autoimmune disease, inflammation, neurological disease, or pain.
- the disease pathologically characterized by increased ATX expression is pulmonary fibrosis or liver fibrosis.
- a compound of the present invention or a pharmaceutical composition thereof may be administered in combination with an additional therapeutic agent.
- the uses of the present invention comprise administering to a mammal an amount of a compound or pharmaceutical composition of the present invention sufficient to effect the treatment or prevention.
- the compounds of the present invention are usually administered in the form of a pharmaceutical composition.
- the composition may be prepared in a manner well known in the pharmaceutical art and comprises at least one compound of the invention according to formula I, or II.
- the compounds of the present invention are administered in a pharmaceutically effective amount.
- the amount of the compound of the present invention actually administered will generally be determined by the physician in light of the circumstances, including the condition to be treated, the route of administration chosen, the actual compound of the present invention administered, the age, weight and response of the individual patient, the patient's symptoms severity, etc.
- compositions of the present invention can be administered by a variety of routes, including oral, rectal, transdermal, subcutaneous, intraarticular, intravenous, intramuscular, and intranasal.
- routes including oral, rectal, transdermal, subcutaneous, intraarticular, intravenous, intramuscular, and intranasal.
- the compounds of the present invention are preferably formulated as injectable or oral compositions or as ointments, as lotions or as patches (all for transdermal administration).
- compositions for oral administration pharmaceutically acceptable solutions, suspensions, emulsions, syrups and elixirs containing inert diluents such as water or liquid paraffin can be used.
- inert diluents such as water or liquid paraffin
- These compositions may also contain substances other than diluents, and in some embodiments, wetting agents, sweeteners, or flavoring preparations.
- compositions for parenteral administration may be emulsions or sterile solutions.
- propylene glycol, polyethylene glycol, vegetable oils, especially olive oil, or injectable organic esters can be used as a solvent or carrier, and in some embodiments, ethyl oleate can be used as a solvent or carrier.
- These compositions may also contain adjuvants, especially wetting agents, isotonic agents, emulsifying agents, dispersing agents and stabilizing agents.
- Sterilization can be performed in several ways, in certain embodiments, by use of bacteriological filters, by radiation or by heat. They can also be prepared in the form of sterile solid compositions which, at the time of use, can be dissolved in sterile water or any other sterile injectable medium.
- the composition may also be an aerosol.
- the compositions may be stable sterile solutions or solid compositions dissolved in sterile pyrogen-free water, saline or any other pharmaceutically acceptable carrier at the time of use.
- the active ingredient is finely divided and combined with a water-soluble solid diluent or carrier, in certain embodiments, dextran, mannitol or lactose.
- Typical pharmaceutical compositions and dosage forms contain one or more excipients.
- suitable excipients are well known to those skilled in the art of pharmacy, and in certain embodiments, suitable excipients include starch, glucose, lactose, sucrose, gelatin, malt, rice, flour, chalk, silica gel, sodium stearate, Glycerol monostearate, talc, sodium chloride, skimmed milk powder, glycerin, propylene, glycol, water, ethanol, etc.
- a particular adjuvant is suitable for incorporation into a pharmaceutical composition or dosage form depends on various factors well known in the art, including but not limited to the manner in which the dosage form is administered to a subject and the particular active ingredient in the dosage form.
- the composition or single unit dosage form may also contain minor amounts of wetting or emulsifying agents, or pH buffering agents.
- the present invention provides a compound of the present invention or a pharmaceutical composition comprising a compound of the present invention for use in medicine.
- the present invention provides compounds of the present invention or pharmaceutical compositions comprising the compounds of the present invention for use in the prevention and/or treatment of fibrotic diseases, proliferative diseases, inflammatory diseases, autoimmune diseases, respiratory diseases, Cardiovascular disease, neurodegenerative disease, dermatological disorders and/or disorders related to abnormal angiogenesis.
- the present invention provides a compound of the present invention or a pharmaceutical composition comprising a compound of the present invention for use in the manufacture of a compound for the prevention and/or treatment of fibrotic, proliferative, inflammatory, autoimmune, respiratory Drugs for diseases, cardiovascular diseases, neurodegenerative diseases, dermatological disorders and/or disorders related to abnormal angiogenesis.
- the present invention provides pharmaceutical compositions comprising a compound of the present invention and other therapeutic agents.
- the other therapeutic agent is a disease associated with fibrotic disease, proliferative disease, inflammatory disease, autoimmune disease, respiratory disease, cardiovascular disease, neurodegenerative disease, dermatological disorder and/or abnormal angiogenesis therapeutic agent.
- the present invention provides a compound of the present invention or a pharmaceutical composition comprising a compound of the present invention for use in the prevention and/or treatment of a fibrotic disease.
- the fibrotic disease is selected from the group consisting of idiopathic pulmonary fibrosis (IPF), cystic fibrosis, other diffuse parenchymal lung diseases of various etiologies (including iatrogenic drug-induced fibrosis, occupational and /or environment-induced fibrosis), granulomatous disease (sarcoidosis, hypersensitivity pneumonitis), collagen vascular disease, alveolar protein deposition, Langerhans cell granuloma, lymphangiopathy, genetic disease (Hermans Kipdrak syndrome, tuberous sclerosis, neurofibromatosis, metabolic accumulation disorder, familial interstitial lung disease), radiation-induced fibrosis, chronic obstructive pulmonary disease (COPD), scleroderma, blemishes Mycin-
- IPPF id
- the present invention provides a compound of the present invention or a pharmaceutical composition comprising a compound of the present invention for use in the manufacture of a medicament for the prevention and/or treatment of fibrotic diseases.
- the fibrotic disease is selected from the group consisting of idiopathic pulmonary fibrosis (IPF), cystic fibrosis, other diffuse parenchymal lung diseases of various etiologies (including iatrogenic drug-induced fibrosis, occupational and/or environment-induced fibrosis), granulomatous disease (sarcoidosis, hypersensitivity pneumonitis), collagen vascular disease, alveolar protein deposition, Langerhans cell granuloma, lymphangiopathy, genetic disease (Hermann Sky-Pudelac syndrome, tuberous sclerosis, neurofibromatosis, metabolic accumulation disorder, familial interstitial lung disease), radiation-induced fibrosis, chronic obstructive pulmonary disease (COPD), scleroderma, Bleomycin-induced
- PPF chronic o
- the present invention provides a method of preventing and/or treating a mammal suffering from a fibrotic disease, the method comprising administering an effective amount of one of the compounds or pharmaceutical compositions of the present invention or more for the treatment or prevention of the condition.
- the fibrotic disease is selected from the group consisting of idiopathic pulmonary fibrosis (IPF), cystic fibrosis, other diffuse parenchymal lung diseases of various etiologies (including iatrogenic drug-induced fibrosis, occupational and /or environment-induced fibrosis), granulomatous disease (sarcoidosis, hypersensitivity pneumonitis), collagen vascular disease, alveolar protein deposition, Langerhans cell granuloma, lymphangiopathy, genetic disease (Hermans Ki-Pudelak syndrome, tuberous sclerosis, neurofibromatosis, metabolic accumulation disorder, familial interstitial lung disease), radiation-induced fibrosis, chronic obstructive pulmonary disease (COPD), scleroderma, rheumatoid arthritis Leomycin-induced pulmonary fibrosis, chronic asthma, silicosis, asbestos-induced pulmonary fibrosis, acute respiratory distress syndrome (ARDS), renal fibrosis, tubul
- IPPF
- Particular aspects of the methods of the invention include administering to an individual suffering from a fibrotic disease an effective amount of a compound of the invention of Formula I, Ia, II, or IIa for a period of time sufficient to reduce the level of fibrosis in the individual, and preferably The process causing the fibrosis is terminated.
- Specific embodiments of the methods include administering to an individual patient suffering from developing idiopathic pulmonary fibrosis an effective amount of a compound of the invention of Formula I, Ia, II, or IIa for a period of time sufficient to reduce or prevent idiopathic pulmonary fibrosis in said patient, and preferably termination of the process causing said idiopathic pulmonary fibrosis.
- co-administration includes any means of delivering two or more therapeutic agents to a patient as part of the same treatment regimen.
- two or more active agents may be administered simultaneously in a single formulation (ie, as a single pharmaceutical composition), this is not required.
- the active agents may also be administered in different formulations and at different times.
- the compounds of the present invention can be prepared by the methods described in the present invention, and unless otherwise specified, the definitions of the substituents are as shown in formula I, or II.
- the following reaction schemes and examples serve to further illustrate the content of the present invention.
- Anhydrous tetrahydrofuran, dioxane, toluene and diethyl ether were obtained by refluxing and drying with metallic sodium.
- Anhydrous dichloromethane and chloroform were obtained by refluxing with calcium hydride.
- Ethyl acetate, petroleum ether, n-hexane, N,N-dimethylacetamide and N,N-dimethylformamide were dried over anhydrous sodium sulfate before use.
- reaction flasks are plugged with suitable rubber stoppers, and the substrate is injected through a syringe. Glassware is dry.
- the chromatographic column is a silica gel column.
- Silica gel 300-400 mesh was purchased from Qingdao Ocean Chemical Factory.
- 1 H NMR spectra were recorded using a Bruker 400 MHz or 600 MHz nuclear magnetic resonance spectrometer. 1H NMR spectra were performed with CDC13, DMSO - d6, CD3OD or acetone - d6 as solvent (in ppm) and TMS (0 ppm) or chloroform (7.26 ppm) as reference standards. When multiplets are present, the following abbreviations are used: s (singlet), d (doublet), t (triplet), m (multiplet), br (broadened) peak), dd (doublet of doublets, double doublet), dt (doublet of triplets, double triplet). Coupling constant, expressed in Hertz (Hz).
- the measurement conditions for low-resolution mass spectrometry (MS) data are: Agilent 6120 quadrupole HPLC-M (column model: Zorbax SB-C18, 2.1 x 30 mm, 3.5 microns, 6 min, flow rate 0.6 mL/min.
- Mobile phase 5 %-95% (( CH3CN with 0.1% formic acid) in ( H2O with 0.1% formic acid)) using electrospray ionization (ESI) at 210 nm/254 nm with UV detection.
- ESI electrospray ionization
- E 1 is selected from Cl, Br or I
- E 2 is selected from Cl, Br, I or B(OH) 2
- E 3 is selected from Cl, Br, I, OMs, OTs or OTf
- Pr 1 is selected from Boc, Cbz or PMB
- Pr 2 is selected from tert-butyl or 2,4,4-trimethylpent-2-yl
- R 1a , R 2 , R 3 , R 6 , Y, Z, Cy and t all have the present invention said definition.
- Intermediate 1-1 reacts with NBS or phenyltrimethylammonium bromide to obtain intermediate 1-2; intermediate 1-2 undergoes ring closure reaction with thiourea to obtain intermediate 1-3; intermediate 1-3 reacts with Pr 2 NC and aldehyde R 2 CHO are catalyzed by Lewis acid to generate intermediates 1-4 through three-component reactions; intermediates 1-4 are reacted with acetic acid under heating conditions, and the obtained intermediates are then reacted with Boc anhydride or CbzCl to obtain Intermediate 1-5; Intermediate 1-5 is first reacted with a strong base, then undergoes a nucleophilic substitution reaction with intermediate 1-6, and then reacts with a substituted alkyl R 1a E 2 to obtain intermediate 1-7; Intermediates 1-7 can be hydrogenated under acidic conditions or palladium catalyzed or reacted with trimethyliodosilane to remove the protecting group Pr 1 to obtain intermediates 1-8; intermediates 1-8 and 2-7 are in alkaline and under heating conditions,
- Step 2) Benzyl 4-(oxoethyl)piperidine-1-carboxylate
- Step 7) 4-(5-((5-cyano-4-(4-fluorophenyl)thiazol-2-yl)(ethyl)amino)-6-ethylimidazo[2,1-b] Thiazol-2-yl)piperidine-1-carboxylate tert-butyl ester
- tert-butyl 4-(5-acetamido-6-ethylimidazo[2,1-b]thiazol-2-yl)piperidine-1-carboxylate 150 mg, 0.38 mmol
- 60% NaH 46 mg, 1.14 mmol
- 2-chloro-4-(4-fluorophenyl)thiazole-5-carbonitrile 91 mg was slowly added dropwise , 0.38 mmol) in tetrahydrofuran (3 mL).
- the mixture was warmed to room temperature and reacted for 30 minutes, and the reaction was completed by TLC monitoring.
- Step 2) 2-(4-(5-((5-cyano-4-(4-fluorophenyl)thiazol-2-yl)(ethyl)amino)-6-ethylimidazo[2,1 -b]thiazol-2-yl)piperidin-1-yl)acetic acid
- Step 1) 4-(5-((5-cyano-4-(4-fluorophenyl)thiazol-2-yl)amino)-6-ethylimidazo[2,1-b]thiazole-2- yl)piperidine-1-carboxylate tert-butyl ester
- Step 2) 4-(5-((5-cyano-4-(4-fluorophenyl)thiazol-2-yl)(cyclopropyl)amino)-6-ethylimidazo[2,1-b ]Thiazol-2-yl)piperidine-1-carboxylate tert-butyl ester
- Step 1) 4-(5-((5-cyano-4-(4-fluorophenyl)thiazol-2-yl)(isopropyl)amino)-6-ethylimidazo[2,1-b ]Thiazol-2-yl)piperidine-1-carboxylate tert-butyl ester
- Step 2) 2-((6-ethyl-2-(piperidin-4-yl)imidazo[2,1-b]thiazol-5-yl)(isopropyl)amino)-4-(4- Fluorophenyl)thiazole-5-carbonitrile
- Comparative Example 1 can be synthesized with reference to compound 7 in Table III of PCT patent application WO 2014139882A1.
- the lysoPLD enzyme activity can hydrolyze the substrate lysophosphatidylcholine (LPC) to generate lysophosphatidic acid (LPA) and choline, and choline is oxidized to H 2 O 2 under the action of choline oxidase.
- LPC lysophosphatidylcholine
- LPA lysophosphatidic acid
- choline is oxidized to H 2 O 2 under the action of choline oxidase.
- HRP horseradish peroxidase
- Amplex Red reagent reacts with H 2 O 2 in a 1:1 stoichiometric ratio to form a strong fluorescent product for fluorescence quantitative detection.
- test compound of the present invention and Comparative Example 1 were respectively dissolved in DMSO into a 10 mM stock solution, and 3-fold gradient dilution was carried out with DMSO, the initial concentration was 10 mM, and there were 10 concentration points.
- a mixed solution 1 with a final concentration of 2ng/ ⁇ l ATX, 2U/ml HRP and 0.2U/ml choline oxidase was prepared with the reaction buffer solution.
- a mixed solution 2 with a final concentration of 60 mM LPC and 400 uM Amplex Red was prepared with the reaction buffer solution, and 20 ⁇ l of the mixed solution 2 was added to each well of the experimental plate. After adding the sample, the experimental plate was shaken for 30 s on a shock plate apparatus, and incubated at room temperature for 30 min. Excitation light 530nm, emission light 590nm fluorescence signal was read with Envision. Calculate the inhibition rate of the compound to the enzymatic reaction according to the fluorescence ratio, and use the software to analyze and calculate the IC 50 value of the compound, as shown in Table 1.
- Example 1 ++++ Example 2 ++++ Example 3 +++ Example 4 ++++ Example 5 ++++ Example 6 ++++ Example 7 ++++ Example 8 ++++ Example 9 ++++ Example 10 ++++ Example 11 ++++ Example 12 ++++ Example 13 +++ Example 14 ++++ Example 15 +++ Example 16 ++++ Example 17 +++ Example 18 +++ Example 19 ++++ Example 20 ++++ Example 21 ++++ Example 22 ++++ Example 23 ++++ Example 24 +++ Example 25 ++++ Example 26 ++++ Example 27 ++++ Comparative Example 1 +++++
- the clear solution of the test compound was injected into SD rats (ad libitum, 6-8 weeks old) via the foot vein, and the suspension solution of the test compound was administered by gavage to SD rats (ad libitum, 6-8 weeks old). ).
- the animals were all collected blood samples from the tail vein at 0.083, 0.25, 0.5, 1, 2, 4, 6, 8, 10 and 24 hours after administration, with a blood volume of 0.15 mL each time.
- In the centrifuge tube of EDTA-K2 invert the centrifuge tube upside down to fully mix the anticoagulant and blood, centrifuge at 4°C and 1500g for 10min within 30min to separate the plasma, transfer the plasma sample to a new centrifuge tube, and store it at -90 ⁇ -60°C conditions to analysis.
- Adopt LC-MS/MS to measure the blood concentration of the test compound of the present invention, adopt the non-compartmental model in Pharsight Phoenix 8.0 software to calculate the pharmacokinetic parameters, and calculate the absolute bioavailability
- the compounds of the present invention have higher exposure and bioavailability.
- the compounds of the present invention have good inhibitory activity against ATX, excellent in vitro and in vivo efficacy and pharmacokinetic properties, and have good clinical application prospects.
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Abstract
Description
受试化合物 | LPC-IC 50 | 受试化合物 | LPC-IC 50 |
实施例1 | ++++ | 实施例2 | ++++ |
实施例3 | +++ | 实施例4 | ++++ |
实施例5 | ++++ | 实施例6 | ++++ |
实施例7 | ++++ | 实施例8 | ++++ |
实施例9 | ++++ | 实施例10 | ++++ |
实施例11 | ++++ | 实施例12 | ++++ |
实施例13 | +++ | 实施例14 | ++++ |
实施例15 | +++ | 实施例16 | ++++ |
实施例17 | +++ | 实施例18 | +++ |
实施例19 | ++++ | 实施例20 | ++++ |
实施例21 | ++++ | 实施例22 | ++++ |
实施例23 | ++++ | 实施例24 | +++ |
实施例25 | ++++ | 实施例26 | ++++ |
实施例27 | ++++ | 对比例1 | +++ |
Claims (16)
- 化合物,其具有式(I)所示结构:或其药学上可接受的盐、水合物、溶剂化物、立体异构体、互变异构体、氮氧化物、代谢物、前药、或混合物;其中,Y是-C(=O)-、-N(R 1b)C(=O)-、-S(=O) 1-2-、-(CH 2) t1-、-C(=O)-(CH 2) t1-、-N(R 1b)C(=O)-(CH 2) t1-、-(CH 2) t2-N(R 1b)C(=O)-(CH 2) t1-、-C(=O)-CH 2-N(R 1b)-、或-NHC(=O)NH-;Z是H、-CN、C 1-6烷基、C 2-6烯基、C 2-6炔基、C 1-6卤代烷基、C 1-6羟基烷基、C 1-6氰基烷基、C 3-8环烷基、C 2-7杂环基、C 2-7杂环基C 1-6烷基、C 3-8环烷基C 1-6烷基、C 6-10芳基、或C 1-9杂芳基;其中所述Z任选地被一个或多个R 5取代;X 1、X 2和X 3各自独立地为-O-、-S-、-NH-、-(CH 2) m1-NH-(CH 2) m2-、-(CH 2) m1-O-(CH 2) m2-、-(CH 2) m1-S-(CH 2) m2-、-C(=O)-、-C(=O)NR 8-、-S(=O) 1-2-、或-(CH 2) m3-;R 1a是H、C 2-6烷基、C 1-6卤代烷基、C 1-6羟基烷基、C 3-6环烷基、或C 3-6环烷基C 1-6烷基;其中所述C 2-6烷基、C 1-6卤代烷基、C 1-6羟基烷基、C 3-6环烷基和C 3-6环烷基C 1-6烷基任选地被1、2、3、4或5个独立地选自H、D、氧代(C=O)、-CN、-NO 2、-OH、-NH 2、-N 3、F、Cl、Br和I的取代基取代;R 1b是H、C 1-4烷基、C 3-6环烷基、或C 3-6环烷基C 1-4烷基;其中所述R 1b任选地被1、2、3或4个R 7取代;R 1c是H、F、Cl、Br、I、-CN、-C(=O)NHR 8、-CF 2H、-CF 3、-C(=O)OR 8、-NO 2、-S(=O) 1-2OR 8、C 1-3烷基、C 1-3烯基、或C 1-3炔基;R 2为H、-CN、-NO 2、-OH、-NH 2、-N 3、F、Cl、Br、I、C 1-4烷基、C 1-4卤代烷基、或C 1-4羟基烷基;R 3为H、-CN、-NO 2、-OH、-NH 2、-N 3、F、Cl、Br、I、C 1-6烷基、C 1-6烯基、C 1-6炔基、C 1-6卤代烷基、C 1-6氰基烷基、或C 1-6羟基烷基;R 4、R 5、R 6、R 7和R 8,在每次出现时,各自独立地为H、D、氧代(C=O)、-CN、-NO 2、-OH、-NH 2、-N 3、F、Cl、Br、I、C 1-6烷基、C 1-6卤代烷基、C 1-6氰基烷基、C 1-6羟基烷基、C 1-6烷氧基、C 1-6卤代烷氧基、或C 1-6卤代烷氧基C 1-6烷基;m1在每次出现时,各自独立地为1、2、或3;m2在每次出现时,各自独立地为0、1、2、或3;m3在每次出现时,各自独立地为1、2、或3;n1是0、1、2、3或4;t为0、1、2、3或4;和t1和t2分别独立地为1、2、3或4。
- 根据权利要求1或2所述的化合物,其中R 1a是H、C 2-4烷基、C 1-4卤代烷基、C 1-4羟基烷基、C 3-6环烷基、或C 3-6环烷基C 1-4烷基;其中所述C 2-4烷基、C 1-4卤代烷基、C 1-4羟基烷基、C 3-6环烷基和C 3-6环烷基C 1-4烷基任选地被1、2、3、4或5个独立地选自H、D、氧代(C=O)、-CN、-NO 2、-OH、-NH 2、-N 3、F、Cl、Br和I的取代基取代。
- 根据权利要求1或2所述的化合物,其中R 1a是H、乙基、氘代乙基、异丙基、三氟甲基、三氟乙基、羟乙基、环丙基、或环丙基甲基。
- 根据权利要求1或2所述的化合物,其中R 1b是H、甲基、或乙基。
- 根据权利要求1或2所述的化合物,其中Z是C 1-6烷基、C 1-6卤代烷基、C 1-6羟基烷基、C 1-6氰基烷基、C 3-6杂环基C 1-4烷基、或C 3-6环烷基C 1-4烷基,其中所述C 1-6烷基、C 1-6卤代烷基、C 1-6羟基烷基、C 1-6氰 基烷基、C 3-6杂环基C 1-4烷基和C 3-6环烷基C 1-4烷基任选地被一个或多个R 5取代;或Z是 其中X 4是N、或-CH 2-;X 5是-O-、-S-、-NH-、-(CH 2) m4-NH-(CH 2) m5-、-(CH 2) m4-O-(CH 2) m5-、-(CH 2) m4-S-(CH 2) m5-、或-(CH 2) m6-;各m4分别独立地为1、2、3或4;各m5分别独立地为0、1、2、3或4;各m6分别独立地为1、2、3或4;和n2是0、1、2、3或4。
- 根据权利要求1或2所述的化合物,其中,R 4、R 5、R 6、R 7和R 8,在每次出现时,各自独立地为H、D、氧代(C=O)、-CN、-NO 2、-OH、-NH 2、F、Cl、Br、I、甲基、乙基、丙基、异丙基、叔丁基、甲氧基、乙氧基、-OCH 2CF 3、-OCH 2CH 2F、-CF 3、-CH 2F、-CH 2CF 3、-CH 2CH 2F、-CH 2CH 2CN、CHF 2-O-CH 2-、CF 3-O-CH 2-、-CH 2OH、或-CH 2CH 2OH。
- 药物组合物,所述药物组合物包含权利要求1-11中任一项所述的化合物或其药学上可接受的盐、水合物、溶剂化物、立体异构体、互变异构体、氮氧化物、代谢物、前药,以及药学上可以接受的辅料、稀释剂或载体。
- 根据权利要求12所述的药物组合物,其进一步包含附加治疗剂。
- 使用根据权利要求1-11任一项所述的化合物或权利要求12-13任一项所述的药物组合物在制备用于预防或治疗哺乳动物具有ATX表达增加的病理学特征的疾病的药物中的用途。
- 根据权利要求14所述的用途,其中,所述具有ATX表达增加的病理学特征的疾病包括:癌症、纤维化疾病、代谢疾病、骨髓增生异常综合征、心血管疾病、自身免疫性疾病、炎症、神经系统疾病或疼痛。
- 根据权利要求14所述的用途,其中,所述具有ATX表达增加的病理学特征的疾病为肺纤维化或肝纤维化。
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Citations (4)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
WO2014139882A1 (en) | 2013-03-14 | 2014-09-18 | Galapagos Nv | Compounds and pharmaceutical compositions thereof for the treatment of inflammatory disorders |
CN105339370A (zh) * | 2013-06-19 | 2016-02-17 | 加拉帕戈斯股份有限公司 | 用于治疗炎症性疾病的新化合物和及其药物组合物 |
CN105814065A (zh) * | 2013-12-09 | 2016-07-27 | Ucb生物制药私人有限公司 | 用作tnf活性调节剂的咪唑并噻唑衍生物 |
CN110526929A (zh) * | 2018-05-24 | 2019-12-03 | 广州市恒诺康医药科技有限公司 | 芳杂环化合物、其药物组合物及其应用 |
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WO2019029620A1 (zh) * | 2017-08-09 | 2019-02-14 | 广州市恒诺康医药科技有限公司 | Atx抑制剂及其制备方法和应用 |
WO2021088957A1 (zh) * | 2019-11-07 | 2021-05-14 | 广州市恒诺康医药科技有限公司 | 芳杂环化合物、其药物组合物及其应用 |
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Patent Citations (5)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
WO2014139882A1 (en) | 2013-03-14 | 2014-09-18 | Galapagos Nv | Compounds and pharmaceutical compositions thereof for the treatment of inflammatory disorders |
CN105143221A (zh) * | 2013-03-14 | 2015-12-09 | 加拉帕戈斯股份有限公司 | 用于治疗炎性障碍的化合物及其药物组合物 |
CN105339370A (zh) * | 2013-06-19 | 2016-02-17 | 加拉帕戈斯股份有限公司 | 用于治疗炎症性疾病的新化合物和及其药物组合物 |
CN105814065A (zh) * | 2013-12-09 | 2016-07-27 | Ucb生物制药私人有限公司 | 用作tnf活性调节剂的咪唑并噻唑衍生物 |
CN110526929A (zh) * | 2018-05-24 | 2019-12-03 | 广州市恒诺康医药科技有限公司 | 芳杂环化合物、其药物组合物及其应用 |
Non-Patent Citations (5)
Title |
---|
"Handbook of Chemistry and Physics", 1994 |
MICHAEL B. SMITHJERRY MARCH: "March's Advanced Organic Chemistry", 2007, JOHN WILEY & SONS |
S. M. BERGE ET AL., J. PHARMACEUTICAL SCIENCES, vol. 66, 1977, pages 1 - 19 |
See also references of EP4242211A4 |
THOMAS SORRELL: "Organic Chemistry", 1999 |
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US20240002401A1 (en) | 2024-01-04 |
CN114507244B (zh) | 2023-10-27 |
AU2021378438B2 (en) | 2024-02-29 |
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