WO2017162007A1 - Dérivé d'amide aromatique et procédé de préparation et application médicale correspondants - Google Patents

Dérivé d'amide aromatique et procédé de préparation et application médicale correspondants Download PDF

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Publication number
WO2017162007A1
WO2017162007A1 PCT/CN2017/075207 CN2017075207W WO2017162007A1 WO 2017162007 A1 WO2017162007 A1 WO 2017162007A1 CN 2017075207 W CN2017075207 W CN 2017075207W WO 2017162007 A1 WO2017162007 A1 WO 2017162007A1
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compound
alkyl
pharmaceutically acceptable
aryl
independently selected
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PCT/CN2017/075207
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English (en)
Chinese (zh)
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陈向阳
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北京天诚医药科技有限公司
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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
    • A61K31/4427—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems
    • A61K31/4439—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems containing a five-membered ring with nitrogen as a ring hetero atom, e.g. omeprazole
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
    • C07D401/04—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings directly linked by a ring-member-to-ring-member bond
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
    • A61K31/445—Non condensed piperidines, e.g. piperocaine
    • A61K31/4523—Non condensed piperidines, e.g. piperocaine containing further heterocyclic ring systems
    • A61K31/4545—Non condensed piperidines, e.g. piperocaine containing further heterocyclic ring systems containing a six-membered ring with nitrogen as a ring hetero atom, e.g. pipamperone, anabasine
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D213/00—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members
    • C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
    • C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D213/60—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D213/78—Carbon atoms having three bonds to hetero atoms, with at the most one bond to halogen, e.g. ester or nitrile radicals
    • C07D213/81—Amides; Imides
    • C07D213/82—Amides; Imides in position 3
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D231/00—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings
    • C07D231/02—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings not condensed with other rings
    • C07D231/10—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members
    • C07D231/14—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
    • C07D401/06—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings linked by a carbon chain containing only aliphatic carbon atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
    • C07D401/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings linked by a chain containing hetero atoms as chain links
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/14—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing three or more hetero rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
    • C07D403/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings
    • C07D403/04—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings directly linked by a ring-member-to-ring-member bond
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D417/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00
    • C07D417/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings
    • C07D417/04—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings directly linked by a ring-member-to-ring-member bond

Definitions

  • the present invention relates to a novel aromatic amide derivative, a pharmaceutically acceptable salt thereof, or a pharmaceutical composition containing the same, and a process for the preparation thereof.
  • the present invention also relates to the above-mentioned derivatives and pharmaceutically acceptable salts thereof or pharmaceutical compositions containing the same, in the preparation of therapeutic agents, Bruton tyrosine kinase inhibitors, and in the preparation of diseases for the treatment and/or prevention of diseases such as tumors and inflammation Use in medicine.
  • BTK Bruton tyrosine kinase
  • BCR B cell receptor
  • PLC phospholipase C
  • BTK mutants in the population demonstrates that BTK can be a drug target.
  • Affinity-free agammaglobulinemia (XLA) is a rare genetic disease found in 1/250,000 men. In this disease, the function of BTK is inhibited, resulting in the production or maturation of B cells. Men with XLA disease have almost no B cells in their bodies, and there are few circulating antibodies, which are prone to serious or even fatal infections. Thus, BTK plays an extremely important role in the growth and differentiation of B cells.
  • BTK inhibitors can inhibit the proliferation of B lymphoma cells, destroy the adhesion of tumor cells, promote the apoptosis of tumor cells, and make Btk a attractive drug target in B cell-associated cancers.
  • B-cell lymphomas and leukemias such as non-Hodgkin's lymphoma (NHL), chronic lymphocytic leukemia (CLL), and anti-recurrent or refractory mantle cell lymphoma ( Mantle cell lymphoma, MCL) and so on.
  • NDL non-Hodgkin's lymphoma
  • CLL chronic lymphocytic leukemia
  • MCL mantle cell lymphoma
  • the only drug on the market with specific inhibition of BTK is Ibrutinib from Pharmacyclics/JNJ.
  • Ibrutinib is a non-reversible small molecule BTK inhibitor, which has very obvious therapeutic effect on the treatment of MCL, CLL and WM, and is safe.
  • Other BTK inhibitors that enter clinical lymphomas include Celgene's CC-292, Acerta's ACP-196, ONO's ONO-4059, and Beigene's BGB-3111.
  • BTK inhibitors can also inhibit B cell autoantibodies and cytokine production.
  • B cells present autoantigens, promote T cell activation and secretion, cause inflammatory factors to cause tissue damage, and activate B cells to produce large amounts of antibodies, triggering autoimmune responses.
  • the interaction of T and B cells forms a positive feedback regulatory chain, leading to uncontrolled autoimmune response and aggravation of histopathological damage.
  • regulatory B cells exist in the body, which can negatively regulate immune responses and inhibit immune-mediated inflammatory responses by secreting interleukin-10 (IL-10) or transforming growth factor beta 1 (TGF- ⁇ 1) and other mechanisms. .
  • IL-10 interleukin-10
  • TGF- ⁇ 1 transforming growth factor beta 1
  • B cells can be used as autoimmune diseases, such as rheumatoid arthritis (RA), systemic lupus erythematosus (SLE), allergic diseases (such as esophagitis, eosoniphilic esophagitis).
  • RA rheumatoid arthritis
  • SLE systemic lupus erythematosus
  • allergic diseases such as esophagitis, eosoniphilic esophagitis
  • Target There are currently no specific BTK inhibitors for immune diseases on the market, but several are in clinical stages, such as CC-292 from Celgene, ACP-196 from Acerta, HM-71224 from Hanmi, and PRN- from Principia. 1008, a compound of Merck Serono's M-2951 and Pharmacyclics.
  • BTK inhibitors Due to the important role played by BTK in multiple signaling pathways, the development of BTK inhibitors has attracted the attention of many biopharmaceutical companies.
  • a series of patent applications for BTK inhibitors have been published, including WO2007087068, WO2010126960, WO2011019780, WO2011090760, WO2012135801, WO2012158764, WO2013060098, WO2013081016, WO2013010869, WO2013113097, CN103113375, WO2014068527, WO2014125410, WO2014173289, WO2013118986, WO2015017502 and WO2015048689, etc., but still need to develop new compounds with better pharmacodynamics.
  • the present invention has designed a compound having a structure represented by the general formula (I), and it has been found that a compound having such a structure exhibits an excellent effect and effect.
  • the object of the present invention is to provide a compound represented by the formula (I) or a tautomer, a mesogen, a racemate, an enantiomer, a diastereomer thereof, or a mixture thereof.
  • Rings A and B 1 are each independently selected from aryl or heteroaryl, wherein the aryl or heteroaryl is optionally substituted by one or more G 1 ;
  • B 2 is independently selected from H, C 3-8 cyclo, 3-8 membered heterocyclyl, aryl or heteroaryl, wherein the cyclo, heterocyclyl, aryl or heteroaryl is optionally Or replaced by multiple G 2 ;
  • L 1 is independently selected from -C 0-2 alkyl-, -CR 2 R 3 -, -C 1-2 alkyl (R 1 )(OH)-, -C(O)-, -CR 1 R 2 O-, -OCR 1 R 2 -, -SCR 1 R 2 -, -CR 1 R 2 S-, -NR 1 -, -NR 1 C(O)-, -C(O)NR 1 -, -NR 1 CONR 2 -, -CF 2 -, -O-, -S-, -S(O) m -, -NR 1 S(O) m - or -S(O) m NR 1 -;
  • L 2 is independently selected from -C 0-4 alkyl-, -C(O)-, -O-, -NR 3 -, -NR 3 C(O)- or -NR 3 S(O) m -;
  • X is independently selected from C 0-4 alkyl, C 3-8 cyclo, 3-8 membered heterocyclyl, aryl or heteroaryl, wherein the alkyl, cyclo, heterocyclyl, aryl or The heteroaryl group is optionally substituted with one or more G 3 ;
  • Y is independently selected from -C(O)-, -NR 4 C(O)-, -S(O) m - or -NR 4 S(O) m -;
  • R is independently selected from H, D, alkyl, cyclo, heterocyclyl, aryl or heteroaryl, wherein the alkyl, cyclo, heterocyclyl, aryl or heteroaryl is optionally taken by one or Replaced by multiple G 4 ;
  • R 1 , R 2 , R 3 and R 4 are each independently selected from H, D, C 1-8 alkyl, C 3-8 cyclic, 3-8 membered heterocyclyl, aryl or heteroaryl, wherein The alkyl, cyclo, heterocyclyl, aryl or heteroaryl group is optionally substituted by one or more G 5 ;
  • G 1 , G 2 , G 3 , G 4 and G 5 are each independently selected from H, D, halogen, cyano, alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, heteroaryl , -OR 5 , -OC(O)NR 5 R 6 , -C(O)OR 5 , -C(O)NR 5 R 6 , -C(O)R 5 , -NR 5 R 6 , -NR 5 C(O)R 6 , -NR 5 C(O)NR 6 R 7 , -S(O) m R 5 or -NR 5 S(O) m R 6 , wherein the alkyl, alkenyl, alkynyl group Or a cycloalkyl, heterocyclyl, aryl or heteroaryl group optionally selected from one or more selected from the group consisting of D, halogen, cyano, C 1-8 alkyl, C 3-8
  • R 5 , R 6 , R 7 , R 8 and R 9 are each independently selected from H, C 1-6 alkyl, C 1-6 heteroalkyl, C 3-8 cycloalkyl, 3-8 membered monocyclic hetero a cyclic group, a monocyclic heteroaryl group or a monocyclic aryl group;
  • n 1 or 2.
  • a compound of the formula (I) or a tautomer, a mesomer, a racemate, an enantiomer or a diastereomer thereof And a mixture thereof, and a pharmaceutically acceptable salt thereof which is a compound of the formula (II) or a tautomer thereof, a mesogen, a racemate, an enantiomer, a non-pair Isomers, mixtures thereof, and pharmaceutically acceptable salts thereof:
  • Z 1 and Z 2 are each independently selected from CH or N;
  • Z 3 is O or S
  • B 1 , B 2 , L 1 , L 2 , X, Y and R are as set forth in claim 1.
  • a compound of the formula (I) or a tautomer, a mesogen, a racemate, an enantiomer or a diastereomer thereof And a mixture thereof, and a pharmaceutically acceptable salt thereof which is a compound of the formula (III) or a tautomer thereof, a mesogen, a racemate, an enantiomer, a non- Enantiomers, mixtures thereof, and pharmaceutically acceptable salts thereof:
  • B 1 and B 2 are a benzene ring or a six-membered heteroaryl ring
  • Rings B, L 2 , X, Y, R, G 1 and G 2 are as defined in claims 1-2.
  • a compound of the formula (I) or a tautomer, a mesogen, a racemate, an enantiomer or a diastereomer thereof And mixtures thereof, and pharmaceutically acceptable salts thereof which are compounds of the formula (IV) or tautomers, meso, racemates, enantiomers, non- Enantiomers, mixtures thereof, and pharmaceutically acceptable salts thereof:
  • P 1 and P 2 are each independently selected from C(R a ) or N;
  • R a is H or an alkyl group
  • n and o are each independently selected from 0, 1 or 2;
  • Rings B, B 1 , B 2 , L 2 , Y and R are as defined in claims 1-3.
  • Typical compounds of the invention include, but are not limited to:
  • the invention further relates to a pharmaceutical composition
  • a pharmaceutical composition comprising a therapeutically effective amount of a compound of the formula (I) or a tautomer, a mesogen, a racemate, an enantiomer, a non- Enantiomers, mixtures thereof, and pharmaceutically acceptable salts thereof, and pharmaceutically acceptable carriers, diluents and excipients.
  • Another aspect of the invention relates to a compound of the formula (I) or a tautomer, a mesophil, a racemate, an enantiomer, a diastereomer, a mixture thereof And a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising the same, for use in the preparation of a Bruton tyrosine kinase inhibitor.
  • Another aspect of the invention relates to a compound of the formula (I) or a tautomer, a mesophil, a racemate, an enantiomer, a diastereomer, a mixture thereof And a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising the same, for use in the manufacture of a medicament for the treatment and/or prevention of diseases such as tumors and inflammation.
  • the present invention also relates to a method for treating and/or preventing a disease such as a tumor and inflammation, which comprises administering to a patient in need of treatment a therapeutically effective amount of a compound of the formula (I) or a tautomer thereof, internal elimination A rot, a racemate, an enantiomer, a diastereomer, a mixture thereof, a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising the same.
  • Another aspect of the invention relates to a compound of the formula (I) or a tautomer, a mesogen, a racemate, an enantiomer thereof, which is a medicament for the treatment and/or prevention of diseases such as tumors and inflammation.
  • C xy denotes a range of the number of carbon atoms, wherein x and y are both integers, for example, a C 3-8 cyclo group represents a cyclic group having 3 to 8 carbon atoms, -C 0-2
  • the alkyl group means an alkyl group having 0 to 2 carbon atoms, and the -C 0 alkyl group means a chemical single bond.
  • Alkyl means a saturated aliphatic hydrocarbon group, including straight chain and branched chain groups of 1 to 20 carbon atoms, for example It may be a linear or branched group of 1 to 18 carbon atoms, 1 to 12 carbon atoms, 1 to 8 carbon atoms, 1 to 6 carbon atoms or 1 to 4 carbon atoms.
  • alkyl can be a monovalent, divalent or trivalent group.
  • Non-limiting examples include 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, 2-ethylbutyl, and various branched isomers thereof.
  • Non-limiting examples also include methylene, methine, ethylene, sec-ethyl, propylene, propylene, butylene, butyl, and various branched isomers thereof.
  • the alkyl group can be optionally substituted or unsubstituted.
  • Cycloalkyl refers to a saturated or partially unsaturated monocyclic or polycyclic cyclic hydrocarbon substituent comprising from 3 to 12 ring atoms, for example from 3 to 12, from 3 to 10 or from 3 to 6 ring atoms, Or it can be a 3, 4, 5, or 6-membered ring.
  • monocyclic ring groups include cyclopropyl, cyclobutyl, cyclopentyl, cyclopentenyl, cyclohexyl, cyclohexenyl, cyclohexadienyl, cycloheptyl, cycloheptatriene Base, cyclooctyl and the like.
  • the cyclic group can be optionally substituted or unsubstituted.
  • Heterocyclyl means a saturated or partially unsaturated monocyclic or polycyclic cyclic hydrocarbon substituent comprising from 3 to 20 ring atoms, for example 3 to 16, 3 to 12, 3 to 10, 3 Up to 6 or 5 to 6 ring atoms, wherein one or more ring atoms are selected from nitrogen, oxygen or S(O) m (where m is an integer from 0 to 2), but excluding -OO-, - The ring portion of OS- or -SS-, the remaining ring atoms are carbon.
  • the heterocycloalkyl ring contains from 3 to 10 ring atoms, most preferably a 5- or 6-membered ring, of which 1 to 4 are hetero More preferably, one to three atoms are hetero atoms, and most preferably one or two are hetero atoms.
  • monocyclic heterocyclic groups include pyrrolidinyl, piperidinyl, piperazinyl, morpholinyl, thiomorpholinyl, homopiperazinyl, azetidinyl and the like.
  • Polycyclic heterocyclic groups include spiro, fused, and bridged heterocyclic groups.
  • “Spiroheterocyclyl” means a polycyclic heterocyclic group of 5 to 20 members in which one atom (referred to as a spiro atom) is shared between monocyclic rings, wherein one or more ring atoms are selected from nitrogen, oxygen or S(O) m
  • the hetero atom (where m is an integer from 0 to 2) and the remaining ring atoms are carbon. These may contain one or more double bonds, but none of the rings have a fully conjugated pi-electron system. It is preferably 6 to 14 members, more preferably 7 to 10 members.
  • the spirocycloalkyl group is classified into a monospiroheterocyclic group, a dispiroheterocyclic group or a polyspirocyclic group according to the number of common spiro atoms between the ring and the ring, and is preferably a monospirocycloalkyl group and a bispirocycloalkyl group. More preferably, it is 4 yuan / 4 yuan, 4 yuan / 5 yuan, 4 yuan / 6 yuan, 5 yuan / 5 yuan or 5 yuan / 6-membered monospirocycloalkyl group.
  • Non-limiting examples of spirocycloalkyl groups include
  • “Fused heterocyclyl” refers to 5 to 20 members, each ring of the system sharing an adjacent pair of atoms of a polycyclic heterocyclic group with other rings in the system, and one or more rings may contain one or more a bond, but none of the rings have a fully conjugated ⁇ -electron system in which one or more ring atoms are selected from nitrogen, oxygen or S(O) m (where m is an integer from 0 to 2), and the remaining ring atoms are carbon. It is preferably 6 to 14 members, more preferably 7 to 10 members.
  • fused heterocyclic groups include
  • the heterocyclyl ring may be fused to an aryl, heteroaryl or cycloalkyl ring wherein the ring to which the parent structure is attached is a heterocyclic group, non-limiting examples comprising:
  • the heterocyclic group may be optionally substituted or unsubstituted.
  • Aryl means a 6 to 14 membered all-carbon monocyclic or fused polycyclic ring (ie, a ring that shares a pair of adjacent carbon atoms), a polycyclic ring having a conjugated ⁇ -electron system (ie, with adjacent pairs)
  • the ring group of a carbon atom is preferably 6 to 10 members, such as a phenyl group and a naphthyl group, and most preferably a phenyl group.
  • the aryl ring may be fused to a heteroaryl, heterocyclyl or cycloalkyl ring wherein the ring to which the parent structure is attached is an aryl ring, non-limiting examples comprising:
  • the aryl group can be substituted or unsubstituted.
  • Heteroaryl refers to a heteroaromatic system containing from 1 to 4 heteroatoms, from 5 to 14 ring atoms, wherein the heteroatoms include oxygen, sulfur and nitrogen. It is preferably 5 to 10 yuan. More preferably, the heteroaryl group is 5- or 6-membered, such as furyl, thienyl, pyridyl, pyrrolyl, N-alkylpyrrolyl, pyrimidinyl, pyrazinyl, imidazolyl, tetrazolyl, oxazolyl, Isoxazolyl, thiazolyl, isothiazolyl, etc., the heteroaryl ring may be fused to an aryl, heterocyclic or cycloalkyl ring, wherein the ring to which the parent structure is attached is a heteroaryl ring Non-limiting examples include:
  • the heteroaryl group can be optionally substituted or unsubstituted.
  • Halogen means fluoro, chloro, bromo or iodo.
  • heterocyclic group optionally substituted by an alkyl group means that an alkyl group may be, but not necessarily, present, and the description includes the case where the heterocyclic group is substituted with an alkyl group and the case where the heterocyclic group is not substituted with an alkyl group.
  • Substituted refers to one or more hydrogen atoms in the group, preferably up to 5, more preferably 1 to 3, hydrogen atoms, independently of each other, substituted by a corresponding number of substituents. It goes without saying that the substituents are only in their possible chemical positions, and those skilled in the art will be able to determine (by experiment or theory) substitutions that may or may not be possible without undue effort. For example, an amino group or a hydroxyl group having a free hydrogen may be unstable when combined with a carbon atom having an unsaturated (e.g., olefinic) bond.
  • “Pharmaceutical composition” means a mixture comprising one or more of the compounds described herein, or a physiologically/pharmaceutically acceptable salt or prodrug thereof, and other chemical components, as well as other components such as physiological/pharmaceutically acceptable carriers. And excipients.
  • the purpose of the pharmaceutical composition is to promote the administration of the organism, which facilitates the absorption of the active ingredient. Biological activity.
  • the structure of the compound is determined by nuclear magnetic resonance (NMR) or mass spectrometry (MS). NMR was measured using a Bruker AVANCE-400 or Varian Oxford-300 nuclear magnetic apparatus, and the solvent was deuterated dimethyl sulfoxide (DMSO-d6), deuterated chloroform (CDC1 3 ), deuterated methanol (CD 3 OD). The internal standard is tetramethylsilane (TMS) and the chemical shift is given in units of 10 -6 (ppm).
  • NMR nuclear magnetic resonance
  • MS mass spectrometry
  • the MS was measured using an Agilent SQD (ESI) mass spectrometer (manufacturer: Agilent, model: 6110) or a Shimadzu SQD (ESI) mass spectrometer (manufacturer: Shimadzu, model: 2020).
  • ESI Agilent SQD
  • ESI Shimadzu SQD
  • the HPLC was measured using an Agilent 1200 DAD high pressure liquid chromatograph (Sunfirc C18, 150 x 4.6 mm, 5 ⁇ m, column) and a Waters 2695-2996 high pressure liquid chromatograph (Gimini C18 150 x 4.6 mm, 5 ⁇ m column).
  • the thin-layer chromatography silica gel plate uses Qingdao Ocean GF254 silica gel plate, and the silica gel plate used for thin-layer chromatography (TLC) has a specification of 0.15 mm to 0.2 mm.
  • the specification for separation and purification of thin layer chromatography is 0.4 mm to 0.5 mm. silicone board.
  • the known starting materials of the present invention may be synthesized by or according to methods known in the art, or may be purchased from ABCR GmbH & Co. KG, Acros Organics, Aldrich Chemical Company, Accela ChemBio Inc, Beijing Coupling Companies such as chemicals.
  • An argon atmosphere or a nitrogen atmosphere means that the reaction flask is connected to an argon or nitrogen balloon having a volume of about 1 L.
  • the hydrogen atmosphere means that the reaction flask is connected to a hydrogen balloon of about 1 L volume.
  • the pressurized hydrogenation reaction was carried out using a GCD-500G high purity hydrogen generator and a BLT-2000 medium pressure hydrogenator from Beijing Jiawei Kechuang Technology Co., Ltd.
  • the hydrogenation reaction is usually evacuated, charged with hydrogen, and operated three times.
  • the microwave reaction used a CEM Discover-SP type microwave reactor.
  • the temperature of the reaction is room temperature, and the temperature range is from 20 ° C to 30 ° C.
  • reaction progress in the examples was monitored by thin layer chromatography (TLC), and the system used for the reaction was A: dichloromethane and methanol system; B: petroleum ether and ethyl acetate system, the volume ratio of the solvent was based on The polarity of the compound is adjusted to adjust.
  • TLC thin layer chromatography
  • the system for purifying the compound using the column chromatography eluent and the system for developing the thin layer chromatography include A: dichloromethane and methanol systems; B: petroleum ether and ethyl acetate system, the volume ratio of the solvent according to the compound The polarity is adjusted to adjust, and a small amount of triethylamine and an acidic or alkaline reagent may be added for adjustment.
  • the compound can be obtained according to the following classical amide coupling reaction, and the amine precursor can be obtained according to the synthesis method of the patent WO2015048662.
  • Example 2 was synthesized by referring to the procedure of Example 1, but in the sixth step, butynoic acid was substituted with propiolic acid.
  • Example 3 was synthesized by referring to the procedure of Example 1, but in the third step, tert-butyl 3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan- 2-(2-)2-dihydro-1H-pyrrole-1-carboxylate substituted (1-(tert-butoxycarbonyl)-1,2,3,6-tetrahydropyridin-4-yl)boronic acid .
  • Example 5 was synthesized by following the procedure of Example 4, but in the first step, tert-butyl piperazine-1-carboxylate was replaced with t-butylpyrrolidin-3-ylcarbamate.
  • Example 6 was synthesized by reference to the procedure of Example 4, except that tert-butyl 3-aminopyrrolidin-1-carboxylate was substituted for tert-butyl piperazine-1-carboxylate in the first step.
  • the compound tert-butyl 3-hydroxypyrrolidine-1-carboxylate 7a (561 mg, 3.0 mmol), methanesulfonyl chloride (410 mg, 3.6 mmol), triethylamine (606 mg, 6.0 mmol) and dichloromethane 50 mL) was mixed and stirred at room temperature for 4 hours. This mixture was diluted with 50 mL of dichloromethane and washed successively with a saturated aqueous solution of ammonium chloride (20 mL) and brine (20 mL ⁇ 2).
  • Example 8 was synthesized by following the procedure of Example 7, but in the first step, tert-butyl 3-hydroxypyrrolidine-1 was replaced with t-butyl 4-(hydroxymethyl)piperidine-1-carboxylate. - a carboxylic acid ester.
  • Example 9 was synthesized by following the procedure of Example 7, but in the first step, tert-butyl 3-hydroxypyrrolidine-1-carboxylate was substituted with tert-butyl 3-hydroxypyrrolidine-1-carboxylic acid. ester.
  • the in vitro activity of BTK was determined by detecting the level of ADP produced in the kinase reaction using Promega's ADP-Glo Kinase Assay Kit.
  • the kinase consumes ATP to phosphorylate the substrate while producing ADP.
  • the ADP-Glo reagent will stop the kinase reaction and completely consume the remaining ATP, and finally add the kinase detection reagent to convert the ADP to a new ATP.
  • the luciferase in the detection reagent can catalyze fluorescein with the participation of ATP and O 2 to produce oxidized fluorescein, AMP and generate photons, thereby converting the chemical signal into an optical signal (Luminecence).
  • the intensity of the light signal is positively correlated with the amount of ADP produced in the kinase reaction, thereby enabling quantitative detection of the activity of the kinase BTK.
  • the assay buffer included 40 mM Tris-HC (pH 7.5), 10 mM MgCl 2 (Sigma), 2 mM MnCl 2 (Sigma), 0.05 mM DTT (Sigma), and 0.01% BSA (Sigma); the kinase BTK was prepared using assay buffer as A kinase reaction solution having a concentration of 1.6 ng/uL; the substrate reaction solution includes 0.2 mg/mL of polypeptide substrate and 50 ⁇ m of ATP.
  • the compound IC 50 was calculated from the 10 concentration points by the following formula.
  • Compounds were first diluted in 100% DMSO to 1 mM, then serially diluted 3 fold with DMSO to a minimum concentration of 0.05 ⁇ m, and each concentration was diluted 40-fold with assay buffer.
  • the percent inhibition is calculated based on the following formula:
  • Inhibition % [1-(RLU compound -RLU min )/(RLU max -RLU min )]X100
  • RLU compounds are cold light readings at a given compound concentration
  • RLU min is a cold light reading without the addition of a kinase
  • RLU max is a cold light reading without the addition of a compound.
  • a ⁇ 100nM; B 100 to 500nM; C>500nM
  • the compounds of the present invention have a significant inhibitory effect on the activity of Bruton tyrosine kinase (BTK).

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Abstract

La présente invention concerne un dérivé d'amide aromatique et un procédé de préparation et une application médicale correspondants. Plus particulièrement, la présente invention concerne un nouveau dérivé représenté par la formule générale (I) et un sel pharmaceutiquement acceptable correspondant ou une composition pharmaceutique le comprenant et un procédé de préparation associé. La présente invention concerne en outre l'utilisation du dérivé et du sel pharmaceutiquement acceptable correspondant ou de la composition pharmaceutique le comprenant dans la préparation d'un agent thérapeutique, en particulier d'un inhibiteur de tyrosine kinase de Bruton, et dans la préparation d'un médicament pour le traitement et/ou la prévention d'une maladie telle qu'une tumeur ou une maladie liée au système immunitaire. Les substituants dans la formule générale (I) sont tels que définis dans la description.
PCT/CN2017/075207 2016-03-24 2017-02-28 Dérivé d'amide aromatique et procédé de préparation et application médicale correspondants WO2017162007A1 (fr)

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US10836769B2 (en) 2018-02-26 2020-11-17 Gilead Sciences, Inc. Substituted pyrrolizine compounds and uses thereof
US11034669B2 (en) 2018-11-30 2021-06-15 Nuvation Bio Inc. Pyrrole and pyrazole compounds and methods of use thereof
US11247987B2 (en) 2017-10-06 2022-02-15 Forma Therapeutics, Inc. Inhibiting ubiquitin specific peptidase 30
US11535618B2 (en) 2018-10-05 2022-12-27 Forma Therapeutics, Inc. Fused pyrrolines which act as ubiquitin-specific protease 30 (USP30) inhibitors

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AU2020276334B2 (en) * 2019-05-10 2022-12-22 Henan Zhiwei Biomedicine Co., Ltd. Substituted 1-amino-1H-imidazole-5-carboxamide as Bruton's Tyrosine Kinase inhibitors
CN113563305B (zh) * 2020-04-28 2022-07-01 新发药业有限公司 一种2-(4-苯氧基苯基)-6-(n-取代氧基羰基哌啶-4-)基烟酰胺的制备方法
CN113563306B (zh) * 2020-04-28 2022-07-01 新发药业有限公司 一种2-(4-苯氧基苯基)-6-(哌啶-4-)基烟酰胺的制备方法
CN114957242B (zh) * 2021-02-23 2023-08-22 药雅科技(上海)有限公司 吡啶并杂环类化合物作为激酶抑制剂的制备及其应用
CN114853752B (zh) * 2021-02-03 2023-08-22 药雅科技(上海)有限公司 Btk抑制剂吡啶并杂环类化合物的制备及其应用
CN114853723B (zh) * 2021-02-03 2023-11-24 药雅科技(上海)有限公司 吲哚类化合物btk抑制剂的制备及其应用
CA3223769A1 (fr) * 2021-07-01 2023-01-05 Xinglu ZHOU Tyrosine kinase de bruton et agent de degradation mutant, composition et utilisation associees

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US10874640B2 (en) 2016-08-26 2020-12-29 Gilead Sciences, Inc. Substituted pyrrolizine compounds and uses thereof
US11247987B2 (en) 2017-10-06 2022-02-15 Forma Therapeutics, Inc. Inhibiting ubiquitin specific peptidase 30
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US11420974B2 (en) 2018-02-26 2022-08-23 Gilead Sciences, Inc. Substituted pyrrolizine compounds and uses thereof
US11535618B2 (en) 2018-10-05 2022-12-27 Forma Therapeutics, Inc. Fused pyrrolines which act as ubiquitin-specific protease 30 (USP30) inhibitors
US11814386B2 (en) 2018-10-05 2023-11-14 Forma Therapeutics, Inc. Fused pyrrolines which act as ubiquitin-specific protease 30 (USP30) inhibitors
US11034669B2 (en) 2018-11-30 2021-06-15 Nuvation Bio Inc. Pyrrole and pyrazole compounds and methods of use thereof

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