Classifications

• • 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
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07D—HETEROCYCLIC COMPOUNDS
  • C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
  • C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
  • C07D471/04—Ortho-condensed systems
• • 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
  • A61P19/02—Drugs for skeletal disorders for joint disorders, e.g. arthritis, arthrosis
• • 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
  • A61P19/08—Drugs for skeletal disorders for bone diseases, e.g. rachitism, Paget's disease
• • 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
  • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P35/00—Antineoplastic agents
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P35/00—Antineoplastic agents
  • A61P35/02—Antineoplastic agents specific for leukemia
• • 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
• • 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
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07D—HETEROCYCLIC COMPOUNDS
  • C07D487/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00
  • C07D487/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains two hetero rings
  • C07D487/04—Ortho-condensed systems

Definitions

• the invention relates to heterocyclic compounds or their pharmaceutically acceptable salts thereof, suitable for regulating or inhibiting activities of Bruton tyrosine kinase (BTK) and its C481 mutant.
• BTK Bruton tyrosine kinase
• the present invention also relates to methods for preparing the compounds or their pharmaceutically acceptable salts thereof.
• the present invention further relates to the uses and methods of use of the compounds or their pharmaceutically acceptable salts thereof in the treatment and/or prevention of cancer and autoimmune diseases.
• BTK is an important non-receptor tyrosine kinase that mediates cell signal transduction, which exists in plasma cells including B-cells.
• B-cells are activated through B-cell receptor (BCR) and BTK plays an important role in the BCR-mediated signaling pathway.
• BCR B-cell receptor
• BTK plays an important role in the BCR-mediated signaling pathway.
• PLC phospholipase C
• PLC phospholipase C
• This signaling pathway can promote cell proliferation, adhesion and survival, and plays an important role in the development of B-cell lymphoma.
• BTK inhibitors inhibit the proliferation of B lymphoma cells by inhibiting the activity of BTK, destroy adhesion of tumor cells, and promote tumor cell apoptosis, making BTK a compelling drug target for B-cell related cancers, such as non-Hodgkin's lymphoma (NHL), chronic lymphocytic leukemia (CLL)/small lymphocytic lymphoma (SLL), mantle cell lymphoma (MCL), Waldenstrom's macroglobulinemia (WM), marginal zone Lymphoma (MZL), central nervous system leukemia (CNSL), etc.
• NHL non-Hodgkin's lymphoma
• CLL chronic lymphocytic leukemia
• SLL small lymphocytic lymphoma
• MCL mantle cell lymphoma
• W Waldenstrom's macroglobulinemia
• MZL marginal zone Lymphoma
• CNSL central nervous system leukemia
• BTK inhibitors are currently on the market, including Abbvie/JNJ's ibrutinib, AZ's acalabrutinib, Beigene's zanubrutinib and Gilead/Ono's tirabrutinib, and more BTK inhibitors are in clinical research.
• BTK inhibitors can also inhibit the production of B-cell autoantibodies and cytokines.
• B-cells present their own antigens, promote T-cell activation, secrete inflammatory factors that cause tissue damage, and at the same time activate B-cells to produce a large number of antibodies to trigger an autoimmune response.
• T- and B-cells interact to each other to form a positive feedback regulatory chain which leads to uncontrolled autoimmune responses and aggravates tissue pathological damage.
• IL-10 interleukin 10
• TGF- ⁇ 1 transforming growth factor ⁇ 1
• BTK can be a drug target for autoimmune diseases, such as rheumatoid arthritis (RA), multiple sclerosis (MS), systemic lupus erythematosus (SLE), pemphigus, etc.
• RA rheumatoid arthritis
• MS multiple sclerosis
• SLE systemic lupus erythematosus
• pemphigus etc.
• BTK inhibitors are still in clinical research.
• Sanofi's rilzabrutinib and Merck Serono's evobrutinib have achieved effective results in the treatment of pemphigus and multiple sclerosis, respectively.
• BTK inhibitors on the market and under research are irreversible inhibitors which inhibit the activity of BTK by covalently binding to the cysteine residue located at 481 of the BTK protein.
• BTK's C481 mutation such as C481S
• C481S makes ibrutinib lose its covalent binding point with the protein, resulting in a decrease in the activity of ibrutinib, thereby making patients resistant to the ibrutinib treatment.
• BTK inhibitors which effectively inhibit the activities of BTK and its C481 mutant, thereby overcoming the drug resistance caused by the C481 mutation associated with irreversible BTK inhibitors.
• CSF/plasma ratio refers to the ratio of a compound concentration in cerebrospinal fluid (CSF) vs. in plasma.
• BBB blood-brain barrier
• C x-y refers to a range of the number of carbon atoms, where x and y are both integers, for example, C 3-8 cycloalkyl stands for cycloalkyl having 3 to 8 carbon atoms.
• Alkyl refers to a saturated straight-chain or branched-chain hydrocarbyl substituent containing 1 to 20 carbon atoms, for example, 1 to 8 carbon atoms, 1 to 6 carbon atoms, or 1 to 4 carbon atoms.
• alkyl examples include but are not limited to methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, sec-butyl, n-pentyl, 1,1-dimethylpropyl, 1,2-dimethylpropyl, 2,2-dimethylpropyl, 1-ethylpropyl, 2-methylbutyl, 3-methylbutyl, n-hexyl, 1-ethyl-2-methylpropyl, 1,1,2-trimethylpropyl, 1,1-dimethylbutyl, 1,2-dimethylbutyl, 2,2-dimethylbutyl, 1,3-dimethylbutyl and 2-ethylbutyl.
• Cycloalkyl refers to a saturated cyclic hydrocarbyl substituent containing 3 to 14 annular carbon atoms. Cycloalkyl may be a mono carbon ring substituent, typically containing 3 to 8, 3 to 7, or 3 to 6 carbon atoms. Unrestricted examples of monocyclic cycloalkyl include but are not limited to cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl and cycloheptyl. Cycloalkyl may also be a substituent with two or three mono rings that are fused together, such as decahydronaphthyl, bicyclo[2.2.2]octane and spiro[3.3]heptane.
• Heterocyclyl or heterocycle refers to a saturated or partially unsaturated monocyclic or polycyclic group containing 3 to 20 annular atoms, for example, 3 to 14, 3 to 12, 3 to 10, 3 to 8, 3 to 6, or 5 to 6 annular atoms in which one or more of the annular atoms are selected from N, O and S(O) m (where m is an integer from 0 to 2).
• it may have 3 to 12 annular atoms, more preferably 3 to 10 ring atoms, more preferably 4 to 7 ring atoms, more preferably 4 to 6 ring atoms, most preferably 5 or 6 ring atoms, wherein 1 to 4 are heteroatoms, 1 to 3 are heteroatoms, or 1 to 2 are heteroatoms.
• monocyclic heterocyclyl examples include but are not limited to pyrrolidinyl, oxetanyl, piperidyl, piperazinyl, tetrahydrofuranyl, tetrahydropyranyl, tetrahydrothiopyranyl, morpholinyl, thiomorpholinyl, homopiperazinyl and azetidinyl.
• Polycyclic heterocyclyl includes fused, bridged or spiro polycyclic heterocycle, such as octahydrocyclopenta[c]pyrrole, octahydropyrrole[1,2-a]pyrazine, 3,8-diazabicyclo[3.2.1]octane, 5-azaspiro[2.4]heptane and 2-oxa-7-azaspiro[3.5]nonane.
• Aryl or aryl ring refers to an aromatic monocyclic or fused polycyclic group containing 6 to 14 carbon atoms, preferably 6- to 10-membered, such as phenyl and naphthyl, most preferably phenyl.
• the aryl ring may be fused with a heteroaryl, heterocyclic or cycloalkyl ring. Unrestricted examples include but are not limited to:
• Heteroaryl or heteroaryl ring refers to a heteroaromatic system containing 5 to 14 annular atoms, of which 1 to 4 annular atoms are selected from heteroatoms including O, S and N.
• Heteroaryl preferably is 5- to 10-membered, and more preferably 5- or 6-membered, such as furyl, thienyl, pyridyl, pyrrolyl, pyrimidyl, pyrazinyl, pyrazolyl, imidazolyl, tetrazolyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, quinolinyl, isoquinolinyl, indolyl and isoindolyl.
• the heteroaryl ring may be fused with an aryl, heterocyclyl or cycloalkyl ring. Unrestricted examples include but are not limited to:
• Halogen refers to F, Cl, Br, or I.
• Cyano refers to —CN.
• heterocyclic optionally substituted by an alkyl group includes the case where the heterocyclic is substituted by an alkyl group and the case where the heterocyclic is not substituted by an alkyl group.
• substitution refers to one or more hydrogen atoms in a group, for example, 1 to 3 hydrogen atoms that are independently substituted by a corresponding number of substituents.
• the substituents are located only in their possible chemical positions understood by those skilled in the art.
• the substituents include but are not limited to halogen, hydroxyl, cyano, nitro, oxo, —SFS, C 1-4 alkyl, C 1-4 alkoxyl, etc.
• “Isomers” refer to compounds that have the same molecular formula, but their atomic binding position or spatial arrangement is different. Isomers with different arrangement of their atoms in space are called “stereoisomers”. Stereoisomers include optical isomers, geometric isomers, and conformational isomers.
• Optical isomers include enantiomers and diastereomers.
• An enantiomer is one of two stereoisomers that are mirror images of each other and are non-superposable.
• a racemic mixture or racemate is one that has equal amounts of left- and right-handed enantiomers of a chiral molecule.
• Diastereomers are stereoisomers that are not mirror images of one another and are non-superimposable on one another.
• Compounds of the present invention may also have geometric isomers resulting from the distribution of substituents around carbon-carbon double bonds, carbon-nitrogen double bonds, cycloalkyl or heterocyclyl groups.
• the substituents around the carbon-carbon double bond or carbon-nitrogen bond are designated to be in a Z or E configuration, and the substituents around the cycloalkyl or heterocycle are designated to be in a cis or trans configuration.
• Compounds of the present invention may also show tautomerism, such as keto-enol tautomerism.
• the present invention includes any tautomeric or stereoisomeric forms and mixtures thereof and is not limited to any tautomeric or stereoisomeric forms used in the compound nomenclature or chemical structural formulae.
• isotopes include all stable isotopes of the atoms appearing in the compounds of the present invention. Isotopes include those atoms with the same atomic number but in different masses. Examples of isotopes suitable for incorporation into the compounds of the present invention are isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorus, fluorine and chlorine, for example but not limited to 2 H (D), 3 H, 13 C, 14 C, 15 N, 18 O, 17 O, 31 P, 32 P, 35 S, 18 F and 36 Cl.
• the isotopically labeled compounds of the present invention can generally be prepared by conventional techniques known to those skilled in the art or by methods similar to those described in the embodiments using appropriate isotopically labeled reagents instead of non-isotopically labeled reagents. Such compounds have various potential uses, for example, as standards and reagents in the determination of biological activities. In the case of stable isotopes, such compounds have the potential to beneficially alter biological, pharmacological, or pharmacokinetic properties.
• Deuterium 2 H (D) is a preferable isotope of the present invention. For example, hydrogen in methyl, methylene or methine can be replaced by deuterium.
• Prodrugs refer to derivatives that are converted into biologically active compounds under the physiological condition in vivo, for example, by oxidation, reduction, and hydrolysis (each of which occurs with or without the participation of enzymes).
• Examples of a prodrug are a compound of the present invention in which an amino is acylated, alkylated or phoshorylated, for example eicosanoyl amino, alanyl amino and pivaloyloxymethyl amino; a hydroxyl is acylated, alkylated or phoshorylated or converted into borate, for example acetoxy, palmitoyloxy, pivaloyloxy, succinyloxy, fumaroyloxy and alanyloxy; a carbonyl is esterified or amidated; and a thiol forms a disulfide bridge with a carrier molecule that selectively delivers the drug to the target and/or to the cytosol of cells, such as peptide.
• Prodrugs may be prepared from the compounds of the present invention according to well-known methods.
• “Pharmaceutically acceptable salts” refer to the salts made from compounds of the present invention with pharmaceutically acceptable bases or acids, including inorganic alkalis or acids and organic bases or acids, under the condition that the compounds contain one or more acidic or basic groups.
• Compounds of the present invention that contain acidic groups can exist in form of salts, for example, as alkali metal salts, alkaline earth metal salts, or ammonium salts.
• such salts include sodium salts, potassium salts, calcium salts, magnesium salts or ammonia or organic amine salts such as salts of ethylamine, ethanolamine, triethanolamine or amino acids.
• Compounds of the present invention that contain basic groups can exist in form of salts as inorganic or organic acid salts.
• acids examples include hydrochloric acid, hydrobromic acid, phosphoric acid, sulfuric acid, nitric acid, methanesulfonic acid, p-toluenesulfonic acid, naphthalene disulfonic acid, oxalic acid, acetic acid, tartaric acid, lactic acid, salicylic acid, benzoic acid, formic acid, propanoic acid, pivalic acid, malonic acid, succinic acid, pimelic acid, fumaric acid, maleic acid, malic acid, sulfamic acid, phenylpropionic acid, gluconic acid, ascorbic acid, isonicotinic acid, citric acid, adipic acid and other acids known to those skilled in the art.
• the present invention further includes internal salts in addition to the mentioned salt forms.
• Each salt can be obtained by conventional methods known to those skilled in the art, for example by mixing a compound of the present invention with an organic or inorganic acid or base in a solvent or dispersant, or by anion exchange or cation exchange with another salt.
• “Pharmaceutical composition” refers to a composition containing one or more of compounds of the present invention or their pharmaceutically acceptable salts, stable isotope derivatives, isomers, prodrugs, and mixtures thereof, and other components such as pharmaceutically acceptable carrier and excipients.
• “Cancer or lymphoma or leukemia” includes but is not limited to B-cell malignancies, B-cell lymphoma, diffuse large B-cell lymphoma, chronic lymphocytic leukemia, small lymphocytic lymphoma, non-Hodgkin Lymphoma (such as ABC-DLBCL), mantle cell lymphoma, follicular lymphoma, Waldenstrom's macroglobulinemia, marginal zone lymphoma, central nervous system lymphoma, chronic lymphocytic lymphoma, B-cell prelymphocytic leukemia, plasma cell lymphoma, multiple myeloma, various solid tumors (such as melanoma, bone cancer, brain cancer, colon cancer, liver cancer, skin cancer, kidney cancer, lung cancer, muscle cancer, bladder cancer, digestive tract/stomach Intestinal cancer, breast cancer, ovarian cancer, head and neck cancer, prostate cancer), etc.
• B-cell malignancies B-cell lymphoma, diffuse large
• “Autoimmune or inflammatory disease” includes but is not limited to arthritis, multiple sclerosis, osteoporosis, inflammatory bowel disease, colitis, Crohn's disease, lupus, rheumatoid Arthritis, psoriatic arthritis, lupus nephritis, Sjogren's syndrome, IgG4-related diseases, idiopathic thrombocytopenic purpura, immune thrombocytopenia, Wright's syndrome, psoriasis, Behcet's disease, asthma, Pemphigus, diabetes, myasthenia gravis, Guillain-Barre syndrome, Graves' disease, Hashimoto's thyroiditis, vasculitis, autoimmune vasculitis, granuloma with multiple vasculitis, autoimmune hepatitis, etc.
• “Therapeutically effective amount” refers to an amount of compounds of the present invention that can effectively inhibit activities of BTK and its C481 mutant, and/or treat or prevent the diseases mediated by BTK and its C481 mutant.
• “Patients” refer to mammals, preferably humans.
• the present invention are directed to compounds with a structure as shown in Formula (I) as reversible BTK inhibitors, which effectively inhibit the activities of BTK and its C481 mutant, thereby overcoming the drug resistance caused by the C481 mutation associated with irreversible BTK inhibitors.
• the present invention provides heterocyclic compounds as shown in Formula (I) or their pharmaceutically acceptable salts, stable isotope derivatives, isomers, and prodrugs thereof,
• ⁇ indicates that A is connected to the benzene ring and indicates that A is connected to E;
• Ring K is phenyl or pyridyl, where the phenyl and pyridyl are optionally substituted by one or more substituents selected from halogen, cyano, C 1-6 alkyl or —OR a ;
• E is C 1-6 alkyl, C 3-10 cycloalkyl, 3-10 membered heterocyclyl, C 6-10 aryl or 5-10 membered heteroaryl, where the alkyl, cycloalkyl, heterocyclyl, aryl and heteroaryl are optionally substituted by one or more substituents selected from D, halogen, cyano, —OR b , —NR b R c , —COOR b , —C(O)R b , —C(O)NR b R c or R e ;
• R e is C 1-6 alkyl, C 3-10 cycloalkyl or 3-10 membered heterocyclyl, where one or more hydrogens of the alkyl, cycloalkyl and heterocyclyl are optionally substituted by halogen, cyano, —OR b , —NR b R c , —COOR b , —C(O)R b or —C(O)NR b R c ;
• R 1 is H, halogen, —OR a or C 1-6 alkyl
• R a is C 1-6 alkyl, where one or more hydrogens of the alkyl are optionally substituted by D or fluorine;
• R b and R c are each independently selected from H, C 1-6 alkyl, C 3-6 cycloalkyl or 4-6 membered heterocyclyl.
• A is N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-phenyl
• A is N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-phenyl
• A is N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-phenyl
• A is N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-phenyl
• A is N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-phenyl
• E is C 1-6 alkyl, wherein one or more hydrogens of the alkyl are optionally substituted by D or fluorine, for example —CH(CH 3 )(CF 3 ).
• E is C 3-7 monocyclic cycloalkyl or 4-8 membered monocyclic heterocyclyl containing N and/or O.
• E is
• E is C 5-10 polycyclic cycloalkyl or 5-10 membered polycyclic heterocyclyl containing O.
• E is
• the monocyclic cycloalkyl, polycyclic cycloalkyl, monocyclic heterocyclyl, and polycyclic heterocyclyl are independently and optionally substituted by one or more substituents selected from D, halogen, —OR b , —NR b R c , —COOR b , —C(O)R b , —C(O)NR b R c or C 1-6 alkyl, where one or more hydrogens of the alkyl are further optionally substituted by halogen, —OR b or —NR b R c ; R b and R c are each independently selected from H, C 1-6 alkyl, C 3-6 cycloalkyl or 4-6 containing N and/or O containing heterocyclic group (e.g., morpholinyl).
• substituents selected from D, halogen, —OR b , —NR b R c , —COOR b , —C(O
• E is
• G is H, fluorine, —OR b , —NR b R c , —COOR b , —C(O)R b , —C(O)NR b R c or C 1-2 alkyl, where one or more hydrogens of the alkyl group are optionally substituted by fluorine, —OH or —NH 2 ;
• R b and R c are each independently selected from H, C 1-2 alkyl, C 3-6 cycloalkyl or N and/or O containing 4-6 membered heterocyclyl (for example, morpholinyl).
• ring K is phenyl, where the phenyl is optionally substituted by one or two substituents selected from halogen or —OR a ; R a is C 1-2 alkyl, where one or more hydrogens of the alkyl is optionally substituted by D.
• ring K is
• R a is a C 1-2 alkyl group, where one or more hydrogens of the alkyl are optionally substituted by D.
• R 1 is H.
• R 1 is halogen
• the present invention relates to compounds that are have a substantial brain penetration and have a blood-brain barrier permeability.
• the present invention relates to CNS penetrant compounds that have CSF/plasma concentration ratio Kp, CSF ⁇ 0.15.
• the present invention further relates to the following Compounds 1-29, and 31-54, or their pharmaceutically acceptable salts, prodrugs, stable isotope derivatives, isomers and mixtures thereof.
• N-(4-(4-amino-7-(1,1,1-trifluoropropan-2-yl)imidazo[5,1-f][1,2,4]triazin- 5-yl)benzyl)-5-fluoro-2-methoxybenzamide 27.
• Compounds of the present invention effectively inhibit the activities of BTK and its C481 mutant, preferably having an IC 50 of less than 100 nM, and more preferably less than 10 nM.
• the present invention also relates to pharmaceutical compositions comprising compounds of Formula (I) or their pharmaceutically acceptable salts, stable isotope derivatives, isomers and prodrugs thereof, and one or more pharmaceutically acceptable carriers or excipients.
• the present invention further relates to a pharmaceutical composition
• a pharmaceutical composition comprising a compound of Formula (I) or its pharmaceutically acceptable salt, stable isotope derivative, isomer, prodrug and a mixture thereof, and at least one additional therapeutic agent, wherein the agent may be a small molecule chemotherapeutic drug (such as anti-inflammatory steroid drug, kinase targeting drug, apoptosis inhibitor, inflammation modulator, cytotoxic drug, DNA damage related drug) or a macromolecular immune and/or inflammation modulator (such as CD-20 antibody, CD19 antibody, PD-1 antibody).
• chemotherapeutic drug such as anti-inflammatory steroid drug, kinase targeting drug, apoptosis inhibitor, inflammation modulator, cytotoxic drug, DNA damage related drug
• a macromolecular immune and/or inflammation modulator such as CD-20 antibody, CD19 antibody, PD-1 antibody.
• Compounds of Formula (I) and another therapeutic agent may be present in the same pharmaceutical composition or in different pharmaceutical compositions.
• Compounds of Formula (I) and another agent may be administered simultaneously or sequentially in the same or different forms.
• the present invention provides a method for treating or preventing diseases mediated by BTK or its C481 mutant.
• the method comprises administering to a patient in need a therapeutically effective amount of compounds of Formula (I) or their pharmaceutically acceptable salts, stable isotope derivatives, isomers, prodrugs and mixtures thereof, or pharmaceutical compositions containing compounds of Formula (I).
• the diseases include but are not limited to cancer, lymphoma, leukemia, autoimmune or inflammation diseases, such as B-cell malignancies, B-cell lymphoma, diffuse large B-cell lymphoma, chronic lymphocytic leukemia, small lymphocytic lymphoma, non-Hodgkin's lymphoma (such as ABC-DLBCL), mantle cell lymphoma, follicular lymphoma, Waldenstrom's macroglobulinemia, marginal zone lymphoma, central nervous system lymphoma, chronic lymphocytic lymphoma, B-cell prelymphocytic leukemia, plasma cell lymphoma, multiple myeloma, various solid tumors (such as lung cancer, prostate cancer, head and neck cancer, breast cancer, ovarian cancer, uterine cancer, pancreatic cancer, colon cancer, rectal cancer, stomach cancer, esophageal cancer, brain cancer, liver cancer, kidney cancer, skin cancer, muscle cancer, epithelial cancer, bladder cancer
• the pharmaceutical composition may be in any dosage form, including but not limited to tablets, capsules, solutions, freeze-dried preparations and injectable.
• the pharmaceutical formulation of the present invention may be administered in form of a dosage unit containing a predetermined amount of active ingredient.
• a dosage unit may contain 1 mg to 1 g, preferably 5 mg to 700 mg, particularly preferably 10 mg to 500 mg of a compound of the present invention, depending on the disease being treated, the method of administration, as well as age, weight, and condition of the patients.
• the pharmaceutical formulation may be prepared using methods well-known in the pharmaceutical field, for example, by formulating the active ingredient with one or more excipients or one or more adjuvants.
• the pharmaceutical formulation of the present invention is suitable for administration by any appropriate method, such as by oral (including oral or sublingual) or parenteral (including subcutaneous, intramuscular, intravenous, or intradermal).
• the present invention also provides methods for preparing compounds.
• the preparation of compounds of the present invention may be accomplished by the following exemplary methods and examples, but these methods and examples should not be considered as limitation of the scope of the present invention in any way.
• Compounds of the present invention may also be synthesized by synthetic techniques known to those skilled in the art or by combinations of methods known in the art and of the present invention.
• the products obtained at each step of reaction are isolated by separation techniques known in the art, including but not limited to extraction, filtration, distillation, crystallization, and chromatographic separation.
• the starting materials and chemical reagents used for syntheses may be conventionally made based on literature (for example, SciFinder) or purchased.
• Heterocyclic compounds shown in Formula (I) of the present invention can be synthesized according to the route shown below: 1) bromination of A1 with NBS to give A2; 2) substitution of A2 by a protected amine (for example, 2,4-dimethoxybenzylamine) to give A3; 3) Mitsunobu reaction between A3 and E-OH to provide A4; 4) Suzuki coupling of A4 with a phenylboronic acid to give A5; 5) deprotection of A5 to give A6.
• a functional group of E can be further derivatized to afford various target compounds.
• an ester in E can be hydrolyzed by alkali (such as LiOH) to form an acid and E containing protected amine or alcohol can be deprotected to give amine or alcohol, and the amine can be further amidated to afford amides, etc.
• alkali such as LiOH
• Heterocyclic compounds shown in Formula (I) of the present invention may also be synthesized according to the route shown below: 1) amide formation between B1 and E-COOH to give B2; 2) cyclization of B2 in phosphine oxychloride under heated to give B3; 3) bromination of B3 with NBS to give B4; 4) substitution of B4 by a protected amine (for example, 2,4-dimethoxybenzylamine) under base catalysis to give B5; 5) Suzuki coupling of B5 with a phenylboronic acid to give B6; 6) deprotection of B6 to give B7.
• a functional group of B7 can be further derivatized to afford various target compounds.
• Heterocyclic compounds shown in Formula (I) of the present invention may also be synthesized according to the route shown below: 1) amide formation of C1 with E-COOH to give C2; 2) cyclization of C2 in phosphine oxychloride under heat to give C3; 3) iodination of C3 with NIS to give C4; 4) amination of C4 to give C5; 5) Suzuki coupling of C5 a phenylboronic acid to give C6. Similarly, a functional group of C6 can be further derivatized to afford various target compounds.
• Heterocyclic compounds shown in Formula (I) of the present invention may also be synthesized according to the route shown below: 1) substitution of D1 (A is N or CH) by E-NH 2 under base catalysis to give D2; 2) further substitution of D2 by a protected amine (such as dibenzylamine) to give D3; 3) reduction of D3 to give D4 (for example, with a reducing agent Zn/NH 4 Cl); 4) cyclization of D4 with carbonyl diimidazole or triphosgene in the present of a base (such as NEt 3 ) to give D5; 5) deprotection of D5 to give D6; 6) Chan-Lam coupling of D6 with a phenylboronic acid to give D7. Similarly, a functional group of D7 can be further derivatized to afford various target compounds.
• the starting materials in the present invention were synthesized according to methods known in the art or purchased from ABCR GmbH & Co. KG, Acros Organics, Aldrich Chemical Company, Accela ChemBio Inc., Beijing Ouhe, etc.
• the structure of a compound was determined by nuclear magnetic resonance (NMR) or mass spectrometry (MS).
• NMR determination used a Bruker ASCEND-400 NMR spectrometer.
• the solvent for the determination was deuterated dimethyl sulfoxide (DMSO-d 6 ), deuterated chloroform (CDCl 3 ) or deuterated methanol (CD 3 OD).
• the internal standard was tetramethylsilane (TMS) and the chemical shift was given in a unit of 10 ⁇ 6 (ppm).
• MS determination used an Agilent SQD (ESI) mass spectrometer (Agilent 6120).
• HPLC determination used Agilent 1260 DAD high pressure liquid chromatograph (column: Poroshell 120 EC-C18, 50 ⁇ 3.0 mm, 2.7 ⁇ m) or Waters Arc high pressure liquid chromatograph (column: Sunfire C18, 150 ⁇ 4.6 mm, 5 ⁇ m).
• Thin layer chromatography used GF254 silica gel plates from Qingdao Haiyang Chemical Co., Ltd. with a thickness of 0.15 to 0.2 mm, and the separation/purification of products by thin layer chromatography used silica plates with a thickness 0.4 to 0.5 mm.
• reactions were run in room temperature (20-30° C.) and under an atmosphere of argon or nitrogen using a balloon with a volume of about 1 L.
• Hydrogenation was carried out under an atmosphere of hydrogen using a balloon with a volume of about 1 L that was attached to the reaction vessel after being vacuumed and filled with hydrogen repeatedly for 3 times.
• the microwave reaction used a CEM Discover-SP microwave reactor.
• the reaction was monitored using Agilent LCMS (1260/6120) or thin layer chromatography.
• the solvent eluting systems for column chromatography and TLC included a) dichloromethane/methanol, b) petroleum ether/ethyl acetate, or other systems as indicated.
• the ratio of the solvents was adjusted according to the polarity of the compound, and further adjusted by addition of a small amount of TEA, or an acidic or alkaline reagent as needed.
• the compound purification was alternatively done using Waters' MS-guided automated preparation system (abbreviated as prep-HPLC) with a MS detector (SQD2), eluting at a flow rate of 20 mL/min in an appropriate acetonitrile/water (containing 0.1% TFA or formic acid) or acetonitrile/water (containing 0.05% of 25-28% ammonium hydroxide) gradient (XBridge-C18, 19 ⁇ 150 mm, 5 ⁇ m).
• Some compounds were prepared as HCl salts after prep-HPLC purification by addition of 1 N HCl to the collected fractions, followed by drying under reduced pressure.
• DMF refers to N,N-dimethylformamide
• DIPEA N,N-diisopropylethylamine
• DBU refers to 1,8-diazabicycloundec-7-ene.
• NBS N-bromosuccinimide
• NIS refers to N-iodosuccinimide.
• Pd(dppf)Cl 2 refers to [1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium.
• HATU refers to 2-(7-azabenzotriazole)-N,N,N′,N′-tetramethylurea hexafluorophosphate.
• the abbreviation LDA refers to lithium diisopropylamide.
• Trifluoroacetic acid (5 mL) was added to a solution of 1g (80 mg, 0.13 mmol) in dichloromethane (2 mL) and the resulting mixture was heated to 40° C. and stirred for 2 hours. After cooling to room temperature, the solvent was removed under reduced pressure and the residue was purified by prep-HPLC to give the title compound 1 (21 mg, solid, 34%).
• Step 4 N-(4-(4-amino-1-((1s,4s)-4-hydroxycyclohexyl)-1H-pyrazolo[4,3-c]pyridin-3-yl)benzyl)-5-fluoro-2-methoxybenzamide (Compound 3) and N-(4-(4-amino-1-((1r,4r)-4-hydroxycyclohexyl)-1H-pyrazolo[4,3-c]pyridin-3-yl)benzyl)-5-fluoro-2-methoxybenzamide (Compound 4)
• the intermediate as shown below was synthesized according to the procedures for the first to fourth steps in Example 4, except that tetrahydro-2H-pyran-3-carboxylic acid was used instead of (1r,4r)-4-(methoxycarbonyl)cyclohexane-1-carboxylic acid in the first step.
• the intermediate as shown below was synthesized according to the procedures for the first to the fifth steps in Example 5, except that methyl 4-methylpiperidine-4-carboxylate was used instead of methyl piperidine-4-carboxylate in the first step.
• Compound 44 was synthesized according to the procedure in Example 5 (without the sixth step), except that morpholine was used instead of methyl piperidine-4-carboxylate in the first step.
• Step 8 (5-(8-amino-1-bromoimidazo[1,5-a]pyrazin-3-yl)tetrahydro-2H-pyran-2-yl)methyl acetate (8i)
• the intermediate as shown below was synthesized according to the procedures for the sixth to ninth step in Example 11, except that (1r,4r)-4-(methoxycarbonyl)cyclohexane-1-carboxylic acid was used instead of cyclopentanecarboxylic acid in the sixth step.
• Lithium aluminum hydride (8 mg, 0.19 mmol) was added to a solution of 18f (50 mg, 0.093 mmol) in THE (3 mL) at 0° C. The mixture was gradually warmed to room temperature and stirred for 3 hours. It was quenched with water (0.1 mL) and filtered. The filtrate was removed from the solvent under reduced pressure and the residue was purified by prep-HPLC to give the title compound 18 (15.4 mg, solid, 33%).
• Step 3 methyl (1r,4r)-4-(((3-chloropyrazin-2-yl)methyl)carbamoyl)-1,4-dimethylcyclohexane-1-carboxylate (32d) and methyl (1s,4s)-4-(((3-chloropyrazin-2-yl)methyl)carbamoyl)-1,4-dimethylcyclohexane-1-carboxylate (32e)
• Step 4 through Step 7. methyl (1r,4r)-4-(8-((2,4-dimethoxybenzyl)amino)-1-(4-((5-fluoro-2-methoxybenzamido)methyl)phenyl)imidazo[1,5-a]pyrazin-3-yl)-1,4-dimethylcyclohexane-1-carboxylate (32j)
• 32j was synthesized according to the procedures for step 2 to 5 in Example 4, except that 32d was used instead of 5b.
• Step 8 methyl (1r,4r)-4-(8-amino-1-(4-((5-fluoro-2-methoxybenzamido)methyl)phenyl)imidazo[1,5-a]pyrazin-3-yl)-1,4-dimethylcyclohexane-1-carboxylate (32k)
• Compound 39 was synthesized according to the procedures for the fourth to eighth step in Example 23, except that 32e was used instead of 32d in the fourth step.
• Step 1 methyl 4-(((3-chloropyrazin-2-yl)methyl)carbamoyl)bicyclo[2.2.2]octane-1-carboxylate (33b)
• Step 4 methyl 4-(8-((2,4-dimethoxybenzyl)amino)-1-iodoimidazo[1,5-a]pyrazin-3-yl)bicyclo[2.2.2]octane-1-carboxylate (33e)
• Step 5 methyl 4-(8-((2,4-dimethoxybenzyl)amino)-1-(4-((5-fluoro-2-methoxybenzamido)methyl)phenyl)imidazo[1,5-a]pyrazin-3-yl)bicyclo[2.2.2]octane-1-carboxylate (33f)
• Step 6 methyl 4-(8-amino-1-(4-((5-fluoro-2-methoxybenzamido)methyl)phenyl)imidazo[1,5-a]pyrazin-3-yl)bicyclo[2.2.2]octane-1-carboxylate (33)
• Step 1 dimethyl (1s,4s)-1,4-dimethylcyclohexane-1,4-dicarboxylate (46a) and dimethyl (1r,4r)-1,4-dimethylcyclohexane-1,4-dicarboxylate (46b)
• 46i was synthesized according to the procedures for the first to sixth step in Example 18, except that 46c was used instead of (R)-1-((benzyloxy)carbonyl)pyrrolidine-3-carboxylic acid 22a in the third step.
• 46 was synthesized according to the procedures for the first to the sixth step in Example 26, except that 46i was used instead of 33 in the third step.
• Compound 47 as shown below was synthesized according to the procedures for the second to the ninth step in Example 30, except that 46b was used instead of 46a in the second step.
• Compound 49 can be synthesized according to the procedures in Example 32.
• the enzymatic activity of BTK is determined by detecting the phosphorylation level of the substrate in the kinase reaction.
• the reaction buffer contains the enzyme reaction buffer (1 ⁇ ) from the kit, 5 mM MgCl 2 , 1 mM DTT, 10 nM SEB and 0.01% Tween-20; the kinase reaction solution contains human-derived recombinant BTK protein (Carna Biosciences, Catalog No.
• the substrate reaction solution contains biotin-labeled tyrosine kinase substrate diluted to 0.5 ⁇ M with the reaction buffer and 40 ⁇ M ATP;
• the detection buffer contains Eu 3+ -labeled cage antibody diluted to 0.05 ng/ ⁇ L and streptavidin-labeled XL665 antibody diluted to 31.25 nM with the reaction buffer;
• the test compound is dissolved and diluted to 100 ⁇ M with DMSO, followed by a 4-fold serial dilution with DMSO to the lowest concentration of 6.1 nM and finally 40-time dilution with the reaction buffer for each concentration point. If the IC 50 value of the compound is very low, the initial concentration of the compound is reduced.
• the group without BTK is the negative control (100% inhibition) and the group with BTK but no compound is the positive control (0% inhibition).
• the inhibition curve is plotted and the corresponding IC 50 value of the test compound is calculated using XLfit software (ID Business Solutions Ltd., UK).
• HTRF time-resolved fluorescence
• the reaction buffer contains the enzyme reaction buffer (1 ⁇ ) from the kit, 5 mM MgCl 2 , 1 mM DTT, 10 nM SEB, and 0.01% Tween-20;
• the kinase reaction solution contains human recombinant BTK C481S protein (purified in-house) diluted to 1.5 ng/ ⁇ L with the reaction buffer;
• the substrate reaction solution contains biotin-labeled tyrosine kinase substrate diluted to 0.5 ⁇ M with the reaction buffer and 35 ⁇ M ATP;
• the detection buffer contains Eu 3+ -labeled cage antibody diluted to 0.05 ng/ ⁇ L and streptavidin-labeled XL665 antibody diluted to 31.25 nM with the reaction buffer;
• the test compound is dissolved and diluted to 100 ⁇ M with DMSO, followed by a 4-fold serial dilution with DMSO to the lowest concentration of 6.1 nM and finally 40-time dilution with the reaction buffer for
• the group without BTK is the negative control (100% inhibition) and the group with BTK C481 S but no compound is the positive control (0% inhibition).
• the inhibition curve is plotted and the corresponding IC 50 value of the test compound is calculated using XLfit software (TD Business Solutions Ltd., UK).
• BTK IC 50 (nM)
• BTK C481S IC 50 (nM) 1. 17 3.5 2. 1.7 2.5 3. 3.2 4.6 4. 2.3 3.0 5. 4.6 2.6 6. 4.6 3.3 7. 3.4 1.7 8. 1.2 0.8 9. 718 498 10. 14 3.6 11. 20 3.9 12. 3.0 13. 1.4 0.8 14. 3.2 2.9 15. 1.4 1.1 16. 1.8 1.1 17. 6.3 2.4 18. 0.7 0.8 19. 212 201 21. 1.7 1.8 22. 155 36 23. 1.0 3.0 24. 3.9 2.5 25. 1.1 1.5 26. 3.8 11 27. 2.7 1.3 28. 1.0 2.2 29. 1.2 2.1 31. 0.6 3.0 32. 2.4 6.3 33. 0.8 1.8 34.

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