WO2022012550A1 - 1h-imidazo[1, 2-b]pyrazole-3-carboxamide substitués utilisés en tant qu'inhibiteurs de la tyrosine kinase de bruton - Google Patents

1h-imidazo[1, 2-b]pyrazole-3-carboxamide substitués utilisés en tant qu'inhibiteurs de la tyrosine kinase de bruton Download PDF

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WO2022012550A1
WO2022012550A1 PCT/CN2021/106090 CN2021106090W WO2022012550A1 WO 2022012550 A1 WO2022012550 A1 WO 2022012550A1 CN 2021106090 W CN2021106090 W CN 2021106090W WO 2022012550 A1 WO2022012550 A1 WO 2022012550A1
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imidazo
carboxamide
pyrazole
phenyl
phenoxyphenyl
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PCT/CN2021/106090
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English (en)
Inventor
Yuqin JIANG
Dandan Zhang
Qingjie Ding
Chunhua MA
Guiqing Xu
Wei Li
Shouning YANG
Yang Li
Chenchen Zhang
Lu Zhao
Zongjing HAO
Xin Shi
Peipei SHI
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Henan Normal University
Henan Zhiwei Biomedicine Co., Ltd.
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Priority to CN202180048850.7A priority Critical patent/CN116018138A/zh
Publication of WO2022012550A1 publication Critical patent/WO2022012550A1/fr

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    • 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
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents

Definitions

  • the invention relates to a series of substituted 1H-imidazo [1, 2-b] pyrazole-3-carboxamide compounds of formula I as kinase inhibitors, in particular BTK (Bruton’s Tyrosine Kinase) inhibitors, and the methods of making and using the same for the treatment of autoimmune disease, inflammatory disease, cancer and potentially allergies.
  • BTK Birton’s Tyrosine Kinase
  • BTK Tyrosine Kinase
  • BTK is an essential kinase in the B cell receptor (BCR) signaling pathway and a driving force for CLL and other B cell malignancies (Treon SP et al, New England journal of Medicine, 2015, 373, 584-586; Treon SP et al, New England journal of Medicine, 2015, 372, 1430-1440; Cao Y et al, British Journal of Haematology, 2015, 170, 134-138; Carrie J Li et al, Molecular Cancer Therapeutics, 2018) . It is primarily expressed in hematopoietic cells such as B cell, mast cell and microphages and exists in tissues including bone marrow, lymph nodes and spleens.
  • BCR B cell receptor
  • the pleckstrin homology domain binds phosphatidylinositol (3, 4, 5) -triphosphate (PIP3) and induces BTK to phosphorylate phospholipase C gamma which then hydrolyzes phosphatidylinositol 4, 5-biphosphate (PIP2) into two secondary messengers, inositol triphosphate (IP3) and diacylglycerol (DAG) which in turn modulate downstream B cell signaling.
  • Dysfunctional BTK activation has been the culprit of autoimmune disease such as rheumatoid arthritis, osteoporosis, lupus and implicated in many cancers. Mutations of BTK gene are directly implicated in the immunodeficiency disease X-linked agammaglobulinemia (XLA) . Patients with this disease have premature B cells in their bone marrow but they never mature and enter into circulation.
  • XLA immunodeficiency disease
  • Ibrutinib (Structure A. Lee A. Honigberg et al, Proceedings of the National Academy of Sciences of the United States of America, 2010, 107, 13075-13080) , as the first-generation BTK inhibitor, has been in clinical use for the treatment of chronic lymphocytic leukemia (CLL) , mantle cell lymphoma, and Waldenstrom’s macroglobulinemia (Novero A et al, Experimental Hematology &Oncology, 2014, 3, 1-7; Treon SP et al, New England journal of Medicine, 2015, 372, 1430-40; Wang ML et al, New England journal of Medicine, 2013, 369, 507-16; Brown JR et al, Blood, 2015, 125, 2915-22) .
  • CLL chronic lymphocytic leukemia
  • Waldenstrom macroglobulinemia
  • ibrutinib has demonstrated some untoward side effects such as vomit, nausea, bleeding, rash, diarrhea and atrial fibrillation with some of them being serious. These adverse effects are partly due to its off-target effects on the epidermis growth factor receptor and Tec family proteins other than BTK (Schwartzberg PL et al, Nature Reviews Immunology, 2005, 5, 284-295; Byrd JC et al, New England journal of Medicine, 2013, 369, 32-42; Rai K, Journal of Hematology &Oncology, 2015, 8, 85; Treon SP et al, New England journal of Medicine, 2015, 372, 1430-1440; Brown JR et al, Blood, 2015, 125, 2915-2922; Wu JJ et al, Journal of Hematology &Oncology, 2016, 21, 2-4) . Based on the findings, more selective BTK inhibitors are being explored.
  • Acalabrutinib (ACP-196. Structure B. Barf et al, Journal of Pharmacology and Experimental Therapeutics, 2017, 363, 240-252; Robert B. Kargbo, ACS Medicinal Chemistry Letters, 2017, 8, 911-913) is a novel irreversible second-generation BTK inhibitor, which is more selective than ibrutinib (Covey T et al, Cancer Research, 2015, 75, 2596; Wu J et al, Journal of Hematology &Oncology, 2016, 9, 21) .
  • ONO/GS-4059 (Structure C) is another novel highly potent and selective BTK inhibitor. Its anti-tumor activities were studied in preclinical models (Yasuhiro T et al, Cancer Research, 2013, 73, 2452) and in the clinical trials for the treatment of B cell malignancies (Dyer M HC et al, Journal of Clinical Oncology, 2014, 32, 8553; Rule S SN et al, Blood, 2013, 122, 4397; Jones R et al, Blood, 2015, 126, 1749) .
  • Zanubrutinib (BGB-3111. Structure D, WO2014/173289 A1; WO2018/137681 A1; Guo YH et al, Journal of Medicinal Chemistry, 2019, 62, 7923-7940) is another reportedly more selective and investigational second generation irreversible BTK inhibitor with good oral bioavailability, lower off-target inhibitory activity, than ibrutinib (Tam C et al, Blood, 2015, 126, 832; Na L et al, Cancer Research, 2015, 75, 2597) .
  • the present invention describes compounds as protein kinase, particularly BTK inhibitors which may be used for the treatment of autoimmune disease, inflammatory disease, cancer and potentially allergies.
  • the invention provides the compound represented by Formula I, the pharmaceutically acceptable salt, active metabolite, tautomer, stereoisomer and prodrug thereof.
  • R 1 is selected from H, and C 1-6 alkyl, C 1-6 cycloalkyl
  • R 2 and R 3 are independently selected from hydrogen; halogen; cyano; CF 3 , aryl, aryl substituted independently with -NR 6 Y, hydrogen, cyano, C 1-6 alkoxy, C 1-6 alkyl substituted with F;heteroaryl, heteroaryl substituted independently with -NR 6 Y, halogen, cyano, C 1-6 alkoxy, C 1-6 alkyl substituted with F; Nitrogen containing C 4-7 heterocycloalkyl where the N atom is substituted with Y; C 1-6 alkyl; C 1-6 alkyl substituted with C 1-6 alkoxy, NR 6 Y; C 3-6 cycloalkyl, C 3- 6 cycloalkyl substituted with NR 6 Y; Or R 2 and R 3 can together form a 5-8 member saturated carbon cycle which may be substituted with NR 6 Y or in the ring contain a nitrogen atom that is substituted with Y; Or R 2 and R 3 together form an aryl
  • R 6 is selected from hydrogen, C 1-6 alkyl, C 1-6 alkyl substituted with groups selected from F, hydroxyl and C 1-6 alkoxy; C 3-6 cycloalkyl, C 3-6 cycloalkyl substituted with F;
  • Rx is selected from the group consisting of H, cyano, C 1-6 alkyl, C 1-6 alkoxy, C 3-6 cycloalkyl, phenyl, - (CH 2 ) m NR 10 R 11 , C 1-6 alkyl substituted with halogen, hydroxy;
  • n is an integer selected from 1, 2, 3;
  • R 7 is selected from hydrogen, halogen, cyano, C 1-6 alkyl, C 1-6 alkyl substituted with groups selected from F, hydroxyl and C 1-6 alkoxy; C 3-6 cycloalkyl, C 3-6 cycloalkyl substituted with F;
  • R 8 and R 9 are independently selected from hydrogen; halogen; cyano; CF 3 ; aryl; aryl independently substituted with hydrogen, halogen, cyano, C 1-6 alkoxy and CF 3 ; heteroaryl; heteroaryl independently substituted with hydrogen, halogen, cyano, C 1-6 alkoxy and CF 3 ; C 1-6 alkyl; C 1-6 alkyl substituted with C 1-6 alkoxy, NR 10 R 11 , halogen, hydroxyl, C 6 or C 10 aryl, and heteroaryl; C 3-6 cycloalkyl; C 3-6 cycloalkyl substituted with halogen; C 2-6 alkenyl; C 2-6 alkenyl substituted with C 1-6 alkoxy, NR 10 R 11 , halogen, hydroxyl, C 6 or C 10 aryl and heteroaryl;
  • R 10 and R 11 are each independently selected from hydrogen, C 1-6 alkyl, C 3-6 cycloalkyl; Or together with the nitrogen they substitute form a 4-6 membered heterocycloalkyl;
  • R 4 is selected from aryl, C 1-6 alkyl, (C 1-4 ) fluoroalkyls, C 3-6 cycloalkyls; aryl independently substituted with halogen, cyano, C 1-6 alkoxy, (C 1-4 ) fluoroalkyls;
  • R 5 can substitute any suitable position of the phenyl ring it attaches and is selected from groups of hydrogen, halogen, (C 1-4 ) fluoroalkyls, cyano, C 1-6 alkyl, C 3-6 cycloalkyls, C 1-6 alkoxy;
  • R 1 is H or methyl.
  • the rest of the groups are as defined above.
  • R 1 is H
  • R 2 is selected from the group consisting of:
  • R 12 is independently selected from H, F, C 1-6 alkyl, C 1-6 alkyl substituted with halogen, C 1-6 alkoxy, and NR 6 R 7 ; and R 12 may substitute more than one position; or in the heterocycle cases R 12 may form a double bond in the ring, or form a 3-6 membered ring fused or spiraled with the original ring;
  • R 3 is H
  • R 4 is C 1-6 alkyl, C 1-6 cycloalkyl and
  • R 13 , R 14 , R 15 , R 16 and R 17 are independently selected from the group consisting of H; halogen; CN; C 1-6 alkyl; C 1-6 alkoxy, C 1-6 alkyl substituted with halogen;
  • R 5 is H
  • R 6 is selected from hydrogen, C 1-6 alkyl, C 1-6 alkyl substituted with groups selected from F, hydroxyl and C 1-6 alkoxy; C 3-6 cycloalkyl, C 3-6 cycloalkyl substituted with F.
  • R 1 is H
  • R 2 is selected from the group consisting of:
  • R 3 is H
  • R4 is:
  • R 13 , R 14 , R 15 , R 16 and R 17 are independently selected from H, OCH 3 , F, Cl, Br, CF 3 and CN.
  • R 1 is H
  • R 2 is selected from
  • R 7 is selected from hydrogen, cyano, and CF 3 ;
  • R 8 and R 9 are independently selected from hydrogen, CF 3 , CH 3 , cyclopropyl and C 1-6 alkyl substituted with NR 10 R 11 .
  • Rx is selected from the group consisting of H, CH 3 , CF 3 and cyclopropyl, -(CH 2 ) m NR 10 R 11 wherein
  • n is an integer selected from 1, 2, 3;
  • R 3 is H and R 4 is phenyl
  • R 5 is H
  • R 1 is H
  • R 2 and R 3 together with the pyrazole ring they substitute form a nitrogen containing heterocycloalkyl where the N atom is substituted with Y (Formula II) or form a phenyl ring that is substituted at any position of the ring with NR 6 Y (Formula III) ;
  • n 1 and n 2 are integers that are independently selected from 0, 1, 2;
  • R 4 , R 6 and Y are as defined above.
  • R 1 is H
  • R 2 is selected from
  • R 7 is selected from hydrogen or cyano
  • R 8 and R 9 are independently selected from hydrogen, CF 3 , CH 3 and C 1-6 alkyl substituted with NR 10 R 11 ;
  • Rx is selected from the group consisting of H, CH 3 , CF 3 ;
  • R 3 is H and R 4 is phenyl
  • R 5 is H
  • R 1 is H
  • R 2 is selected from
  • Y is CN
  • R 3 is H and R 4 is phenyl
  • R 5 is H
  • R 1 is H
  • R 4 is phenyl
  • R 9 is selected from hydrogen, CF 3 , CH 3 and C 1-6 alkyl substituted with NR 10 R 11 ;
  • R 1 is H
  • R 4 is phenyl
  • R 9 is selected from hydrogen, CF 3 , CH 3 and C 1-6 alkyl substituted with NR 10 R 11 ;
  • R 6 is H or methyl;
  • R 1 is H
  • R 2 is selected from
  • Rx is selected from the group consisting of H, CH 3 ;
  • R 3 is H and R 4 is phenyl
  • R 5 is H
  • R 1 is H
  • R 9 is selected from hydrogen, CF 3 ;
  • Rx is selected from the group consisting of H, CH 3 ;
  • R 3 is H and R 4 is phenyl
  • R 5 is H
  • the present invention provides the following compounds.
  • the invention provides a pharmaceutical composition which includes an effective amount of a compound of the invention, or a pharmaceutically acceptable salt, active metabolite, tautomer, stereoisomer, or prodrug thereof, and a pharmaceutically acceptable carrier.
  • the pharmaceutical composition is in a form suitable for administration including but not limited to oral administration, parenteral administration, topical administration and rectal administration.
  • the pharmaceutical composition is in the form of a tablet, capsule, pill, powder, sustained release formulation, solution and suspension, for parenteral injection as a sterile solution, suspension or emulsion, for topical administration as an ointment or cream or for rectal administration as a suppository.
  • the pharmaceutical composition is in unit dosage forms suitable for single administration of precise dosages.
  • the amount of compound of formula I is in the range of about 0.001 to about 1000 mg/kg body weight/day.
  • the amount of compound of formula I is about 0.001 to about 7 g/day. In further or additional embodiments, dosage levels below the lower limit of the aforesaid range may be more than adequate. In further or additional embodiments, dosage levels above the upper limit of the aforesaid range may be required. In further or additional embodiments, the compound of formula I is administered in a single dose, once daily. In further or additional embodiments, the compound of formula I is administered in multiple doses, more than once per day. In further or additional embodiments, the pharmaceutical composition further comprises at least one therapeutic agent.
  • the invention provides a method for preventing or treating a subject suffering from or at risk of BTK mediated disease or condition, comprising administering to said subject an effective amount of a compound of this invention or a pharmaceutically acceptable salt, active metabolite, tautomer, stereoisomer, or prodrug thereof, or a pharmaceutical composition of this invention.
  • the invention provides a method for preventing or treating a subject suffering from or at risk of a disease or disorder selected from the group consisting of an autoimmune disease, inflammatory disease, cancer, allergy, diffused large B cell lymphoma, follicular lymphoma, chronic lymphocytic leukemia, mantel cell lymphoma, splenic marginal zone lymphoma, large B cell lymphoma, lupus erythematosus, rheumatoid arthritis, Crohn’s disease, psoriasis, multiple sclerosis, asthma etc., comprising administering to said subject an effective amount of a compound of this invention or a pharmaceutically acceptable salt, active metabolite, tautomer, stereoisomer, or prodrug thereof, or a pharmaceutical composition of this invention.
  • a disease or disorder selected from the group consisting of an autoimmune disease, inflammatory disease, cancer, allergy, diffused large B cell lymphoma, follicular lymphoma, chronic lymphocytic
  • the invention provides a use of a compound of the invention, or a pharmaceutically acceptable salt, active metabolite, tautomer, stereoisomer, or prodrug thereof, in the preparation of a medicament for inhibiting the activity of BTK.
  • the invention provides a use of a compound of the invention, or a pharmaceutically acceptable salt, active metabolite, tautomer, stereoisomer, or prodrug thereof, in the preparation of a medicament for treating a disease or disorder that may benefit from the inhibition of BTK.
  • the invention provides a use of a compound of the invention, or a pharmaceutically acceptable salt, active metabolite, tautomer, stereoisomer, or prodrug thereof, in the preparation of a medicament for treating a disease or disorder selected from the group consisting of an autoimmune disease, inflammatory disease, cancer, allergy, diffused large B cell lymphoma, follicular lymphoma, chronic lymphocytic leukemia, mantel cell lymphoma, splenic marginal zone lymphoma, large B cell lymphoma, lupus erythematosus, rheumatoid arthritis, Crohn’s disease, psoriasis, multiple sclerosis, asthma etc.
  • a disease or disorder selected from the group consisting of an autoimmune disease, inflammatory disease, cancer, allergy, diffused large B cell lymphoma, follicular lymphoma, chronic lymphocytic leukemia, mantel cell lymphoma, splenic marginal zone lymphoma, large
  • the invention provides a compound of the invention, or a pharmaceutically acceptable salt, active metabolite, tautomer, stereoisomer, or prodrug thereof, for inhibiting BTK.
  • the invention provides a compound of the invention, or a pharmaceutically acceptable salt, active metabolite, tautomer, stereoisomer, or prodrug thereof, for the treatment of a disease or disorder that may benefit from the inhibition of BTK.
  • the invention provides a compound of the invention, or a pharmaceutically acceptable salt, active metabolite, tautomer, stereoisomer, or prodrug thereof, for treating a disease or disorder selected from the group consisting of an autoimmune disease, inflammatory disease, cancer, allergy, diffused large B cell lymphoma, follicular lymphoma, chronic lymphocytic leukemia, mantel cell lymphoma, splenic marginal zone lymphoma, large B cell lymphoma, lupus erythematosus, rheumatoid arthritis, Crohn’s disease, psoriasis, multiple sclerosis, asthma etc.
  • a disease or disorder selected from the group consisting of an autoimmune disease, inflammatory disease, cancer, allergy, diffused large B cell lymphoma, follicular lymphoma, chronic lymphocytic leukemia, mantel cell lymphoma, splenic marginal zone lymphoma, large B cell lymphoma, lupus
  • the subject is a mammal, such as human.
  • the foregoing disease or condition includes but not limit to cancer, autoimmune disease, inflammatory disease and allergy.
  • diseases include but not limit to diffused large B cell lymphoma, follicular lymphoma, chronic lymphocytic leukemia, mantel cell lymphoma, splenic marginal zone lymphoma, large B cell lymphoma, lupus erythematosus, rheumatoid arthritis, Crohn’s disease, psoriasis, multiple sclerosis, asthma etc.
  • the present invention also intended to include isotopically labeled compounds.
  • the commonly seen isotopic atoms include but not limited to 2 H, 3 H, 13 C, 14 C, 17 O, 18 O, 15 N etc. These atoms are the same as their naturally richest atom but have a different mass number. Applications of isotopically labeling in drug discovery are reported (Elmore, Charles S, Annual Report of Medicinal Chemistry, 2009, 44, 515-534) .
  • Reactions and purification techniques can be performed, e.g., using kits of manufacturer's specifications or as commonly accomplished in the art or as described herein.
  • the foregoing techniques and procedures can be generally performed of conventional methods well known in the art and as described in various general and more specific references that are cited and discussed throughout the present specification.
  • substituent groups are specified by their conventional chemical formulas, written from left to right, they equally encompass the chemically identical substituents that would result from writing the structure from right to left.
  • CH 2 O is equivalent to OCH 2 .
  • alkyl as used herein, includes optionally substituted alkyl.
  • the compounds presented herein may possess one or more stereo centers and each center may exist in the R or S configuration, or combinations thereof. Likewise, the compounds presented herein may possess one or more double bonds and each may exist in the E (trans) or Z (cis) configuration, or combinations thereof. Presentation of one particular stereoisomer should be understood to include all possible stereoisomers, including regioisomers, diastereomers, enantiomers or epimers and mixtures thereof. Thus, the compounds presented herein include all separate configurational stereoisomeric, regioisomeric, diastereomeric, enantiomeric, and epimeric forms as well as the corresponding mixtures thereof.
  • a racemate (a mixture of S and R form) , diastereomers and single isomers of either S or R can exist. It is the intention of the invention that compounds claimed here could be a mixture of diastereomers, a racemate or a single isomer of either S or R.
  • C 1 -C 6 indicates that there are one to six carbon atoms in the moiety, i.e. groups containing 1 carbon atom, 2 carbon atoms, 3 carbon atoms, 4 carbon atoms, 5 carbon atoms, and 6 carbon atoms.
  • C 1 -C 6 alkyl indicates that there are one to six carbon atoms in the alkyl group, i.e.
  • the alkyl group is selected from among methyl, ethyl, propyl, iso-propyl, n-butyl, isobutyl, sec-butyl, and t-butyl, n-pentyl, isopentyl, neopentyl, n-hexyl and the isomers thereof.
  • cycle refers to any covalently closed structure, including alicyclic, heterocyclic, aromatic, heteroaromatic and polycyclic fused or non-fused ring systems as described herein. Rings can be optionally substituted. Rings can form part of a fused ring system.
  • membered is meant to denote the number of skeletal atoms that constitute the ring. Thus, by way of example only, cyclohexane, pyridine, pyran and pyrimidine are 6-membered rings.
  • fused refers to cyclic structures in which two or more rings share one or more bonds.
  • heterocyclyl refers collectively to heteroalicyclyl groups.
  • the number of carbon atoms in a heterocycle is indicated (e.g. C 3 -C 6 heterocycle) , at least one non-carbon atom (the heteroatom) must be present in the ring.
  • Designations such as “C 3 -C 6 heterocycle” refer only to the number of carbon atoms in the ring and do not refer to the total number of atoms in the ring.
  • Designations such as “4-8 membered heterocycle” refer to the total number of atoms that are contained in the ring (i.e.
  • heterocycles having two or more heteroatoms those two or more heteroatoms can be the same or different from one another.
  • Heterocycles can be optionally substituted. Bonding (i.e. attachment to a parent molecule or further substitution) to a heterocycle can be via a heteroatom or a carbon atom.
  • the "heterocycle" wherein the ring is saturated is called as heterocycloalkyl.
  • spiral heterocyclyl refers to a polycyclyl wherein two rings share a carbon atom and at least one ring atom is a heteroatom.
  • the spiral heterocyclyl may have two or more cycles, each of them may be 4-8 membered cycles.
  • Spiral heterocyclyl can be optionally substituted. Bonding (i.e. attachment to a parent molecule or further substitution) to a spiral heterocycle can be via a heteroatom or a carbon atom.
  • the "spiral heterocycle” includes heterocycloalkyl.
  • cycloalkyl refers to an optionally substituted, saturated, hydrocarbon monoradical ring which may include additional, non-ring carbon atoms as substituents (e.g. methylcyclopropyl) .
  • the cycloalkyl may have three to about ten, or three to about eight, or three to about six, or three to five ring atoms.
  • the examples include but not limited to cyclopropyl, cyclobutyl, cyclopentyl, and cyclohexyl.
  • aryl refers to an optionally substituted aromatic hydrocarbon radical of six to about twenty ring carbon atoms, and includes fused and non-fused aryl rings.
  • a fused aryl ring radical contains from two to four fused rings where the ring of attachment is an aryl ring, and the other individual rings may be alicyclic, heterocyclic, aromatic, heteroaromatic or any combination thereof.
  • aryl includes fused and non-fused rings.
  • aryl includes but not limited to monocycle, bicycle and tricycle or more cycles.
  • the aryl (for example monocyclic aryl) contains, for example, from six to about twelve, or six to about ten, or six to about eight ring carbon atoms.
  • a non-limiting example of a single ring aryl group includes phenyl; a fused ring aryl group includes naphthyl, phenanthrenyl, anthracenyl, azulenyl; and a non-fused bi-aryl group includes biphenyl.
  • alkyl refers to an optionally substituted straight-chain, or optionally substituted branched-chain saturated hydrocarbon monoradical having, for example, from one to about eighteen, or one to about ten carbon atoms, or one to six carbon atoms.
  • lower alkyl refers to an alkyl having relatively less carbon atoms, for example having one to about eight carbon atoms, preferably having one to about six, or one to about four carbon atoms.
  • alkyl examples include, but are not limited to methyl, ethyl, n-propyl, isopropyl, 2-methyl-l-propyl, 2-methyl-2-propyl, 2-methyl-l-butyl, 3-methyl-l-butyl, 2-methyl-3-butyl, 2, 2-dimethyl-l-propyl, 2-methyl-l-pentyl, 3-methyl-1-pentyl, 4-methyl-l-pentyl, 2-methyl-2-pentyl, 3-methyl-2-pentyl, 4-methyl-2-pentyl, 2, 2-dimethyl-l-butyl, 3, 3-dimethyl-1-butyl, 2-ethyl-l-butyl, n-butyl, isobutyl, sec-butyl, t-butyl, n-pentyl, isopentyl, neopentyl, tert-amyl and hexyl, and the like.
  • alkyl as used in combination includes but not limited to the “alkyl” included in “alkoxy” .
  • alkoxy refers to an alkyl ether radical, O-alkyl.
  • alkoxy radicals include methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, iso-butoxy, sec-butoxy, tertbutoxy and the like.
  • alkenyl refers to an optionally substituted straight-chain, or optionally substituted branched-chain hydrocarbon monoradical having one or more carbon-carbon double-bonds and having, for example, from two to about eighteen or two to about ten carbon atoms, or two to about six carbon atoms.
  • the group may be in either the cis or trans conformation about the double bonds, and should be understood to include both isomers.
  • isopropenyl [-C (CH 3 ) CH 2 ]
  • alkenyl alkenyl
  • halogen , "halo” or “halide” as used herein, alone or in combination refer to fluoro, chloro, bromo and iodo.
  • Hydroxy or hydroxyl refers to a group of -OH.
  • Cyano refers to a group of -CN.
  • a solid wedge means the bond is pointing to the top of the paper while a dotted wedge means the bond is pointing to the back of the paper.
  • a solid bond line usually means all possible isomers.
  • subject encompasses mammals and non-mammals.
  • mammals include, but are not limited to, any member of the Mammalian class: humans, non-human primates such as chimpanzees, and other apes and monkey species; farm animals such as cattle, horses, sheep, goats, swine; domestic animals such as rabbits, dogs, and cats; laboratory animals including rodents, such as rats, mice and guinea pigs, and the like.
  • non-mammals include, but are not limited to, birds, fish and the like.
  • the mammal is a human.
  • treat include alleviating, abating or ameliorating a disease or condition symptoms, preventing additional symptoms, ameliorating or preventing the underlying metabolic causes of symptoms, inhibiting the disease or condition, e.g., arresting the development of the disease or condition, relieving the disease or condition, causing regression of the disease or condition, relieving a condition caused by the disease or condition, or stopping the symptoms of the disease or condition, and are intended to include prophylaxis.
  • the terms further include achieving a therapeutic benefit and/or a prophylactic benefit. By therapeutic benefit is meant eradication or amelioration of the underlying disorder being treated.
  • compositions may be administered to a patient at risk of developing a particular disease, or to a patient reporting one or more of the physiological symptoms of a disease, even though a diagnosis of this disease may not have been made.
  • an “effective amount” refers to a sufficient amount of at least one agent or compound being administered which will relieve to some extent one or more of the symptoms of the disease or condition being treated. The result can be reduction and/or alleviation of the signs, symptoms, or causes of a disease, or any other desired alteration of a biological system.
  • an “effective amount” for therapeutic uses is the amount of the composition comprising a compound as disclosed herein required to provide a clinically significant decrease in a disease.
  • An appropriate “effective” amount in any individual case may be determined using techniques, such as a dose escalation study.
  • administer refers to the methods that may be used to enable delivery of compounds or compositions to the desired site of biological action. These methods include, but are not limited to oral routes, intraduodenal routes, parenteral injection (including intravenous, subcutaneous, intraperitoneal, intramuscular, intravascular or infusion) , topical and rectal administration. Those of skill in the art are familiar with administration techniques that can be employed with the compounds and methods described herein, e.g., as discussed in Goodman and Gilman, The Pharmacological Basis of Therapeutics, current edition; Pergamon; and Remington's , Pharmaceutical Sciences (current edition) , Mack Publishing Co., Easton, Pa. In preferred embodiments, the compounds and compositions described herein are administered orally.
  • pharmaceutically acceptable refers to a material, such as a carrier or diluent, which does not abrogate the biological activity or properties of the compounds described herein, and is relatively nontoxic, i.e., the material may be administered to an individual without causing undesirable biological effects or interacting in a deleterious manner with any of the components of the composition in which it is contained.
  • composition refers to a biologically active compound, optionally mixed with at least one pharmaceutically acceptable chemical component, such as, though not limited to carriers, stabilizers, diluents, dispersing agents, suspending agents, thickening agents, and/or excipients.
  • pharmaceutically acceptable chemical component such as, though not limited to carriers, stabilizers, diluents, dispersing agents, suspending agents, thickening agents, and/or excipients.
  • carrier refers to relatively nontoxic chemical compounds or agents that facilitate the incorporation of a compound into cells or tissues.
  • pharmaceutically acceptable salt refers to salts that retain the biological effectiveness of the free acids and bases of the specified compound and that are not biologically or otherwise undesirable.
  • Compounds described herein may possess acidic or basic groups and therefore may react with any of a number of inorganic or organic bases, and inorganic and organic acids, to form a pharmaceutically acceptable salt.
  • These salts can be prepared in situ during the final isolation and purification of the compounds of the invention, or by separately reacting a purified compound in its free base form with a suitable organic or inorganic acid, and isolating the salt thus formed.
  • pharmaceutically acceptable salts include those salts prepared by reaction of the compounds described herein with a mineral or organic acid or an inorganic or organic base.
  • tautomer refers to an isomer readily interconverted from a compound of this invention by e.g., migration of a hydrogen atom or proton.
  • prodrug refers to any pharmaceutically acceptable salt, ester, salt of an ester or other derivative of a compound of this invention, which, upon administration to a recipient, is capable of providing, either directly or indirectly, a compound of this invention or a pharmaceutically active metabolite or residue thereof.
  • Particularly favored derivatives or prodrugs are those that increase the bioavailability of the compounds of this invention when such compounds are administered to a patient (e.g. by allowing orally administered compound to be more readily absorbed into blood) or which enhance delivery of the parent compound to a biological compartment (e.g. the brain or lymphatic system) .
  • active metabolite refers to a biologically active derivative of a compound that is formed when the compound is metabolized.
  • metabolic refers to the sum of the processes (including, but not limited to, hydrolysis reactions and reactions catalyzed by enzymes) by which a particular substance is changed by an organism.
  • IC 50 means the concentration of a particular compound that inhibits 50 %of a specific measured activity.
  • the compounds of Formula I can generally be made by the chemistry route described in Schemes 1-3. Particular examples are provided in the following text.
  • n when m is 0, n can only choose the number 1. When m is 1, n is a number selected from 1, and 2.
  • compounds 9a and 9b could be prepared.
  • n is a number selected from 1, and 2.
  • Step A Preparation of methyl-3-oxo-3- (4-phenoxyphenyl) propanoate
  • step A of example 1 To a solution of the product of step A of example 1 (81 g, 0.30 mol) in 1, 4-dioxane (100 mL) was added 7 M NH 3 /1, 4-dioxane (100 mL) at room temperature in a 300 mL of sealed tube. The mixture was stirred at 95 °C for 12 hs, then it was cooled to room temperature. The mixture was concentrated under vacuum The residue was purified by chromatography with petroleum ether and ethyl acetate (1: 1) to give the desired product 3-oxo-3- (4- phenoxyphenyl) propanamide as a white solid (40 g, 53 %) .
  • Step D Preparation of tert-butyl 4- (cyanomethylene) piperidine-1-carboxylate
  • Step E Preparation of tert-butyl 4- (cyanomethyl) piperidine-1-carboxylate
  • step D of example 1 80 g, 0.36 mol
  • 10 %Pd/C 8 g, 10 %
  • the suspension was degassed under vacuum and purged with H 2 several times.
  • the mixture was stirred under H 2 balloon at room temperature for 5 hs.
  • the mixture was passed through celite, and the solid was washed with ethyl acetate.
  • the filtrate was concentrated under vacuum to give the desired product tert-butyl 4- (cyanomethyl) piperidine-1-carboxylate as a white solid (61 g, 74.4 %) .
  • Step F Preparation of tert-butyl 4- (1-cyano-2-oxoethyl) piperidine-1-carboxylate
  • Step G Preparation of tert-butyl 4- (5-amino-1H-pyrazol-4-yl) piperidine-1-carboxylate
  • step F of example 1 A solution of the product of step F of example 1 (118 g, 0.47 mol) and hydrazine hydrate (80 %, 300 mL) in ethanol (300 mL) was heated to 80 °C for 10 hs. The reaction was then cooled to room temperature and the solvent was removed under vacuum, the crude residue was purified by chromatography with petroleum ether and ethyl acetate (1: 5) to give the desired product tert-butyl 4- (5-amino-1H-pyrazol-4-yl) piperidine-1-carboxylate as a yellow solid (31 g, the yield of the two steps was 43 %) .
  • Step H Preparation of tert-butyl 4- (3-carbamoyl-2- (4-phenoxyphenyl) -1H-imidazo [1, 2- b] pyrazol-7-yl) piperidine-1-carboxylate
  • Step I Preparation of 2- (4-phenoxyphenyl) -7- (piperidin-4-yl) -1H-imidazo [1, 2-b] pyrazole-3- carboxamide
  • step H of example 1 To a solution of the product of step H of example 1 (10 g, 19.9 mmol) in ethanol (2 mL) was added 33 %HCl/EtOH (10 mL) at room temperature. The mixture was stirred for 3 hs, then the mixture was concentrated under vacuum to get 9.5 g crude 2- (4-phenoxyphenyl) -7-(piperidin-4-yl) -1H-imidazo [1, 2-b] pyrazole-3-carboxamide. The residue was used to next step directly. MS (ESI, m/z) : 402.6 [M+H] + .
  • Step J Preparation of 7- (1-acryloylpiperidin-4-yl) -2- (4-phenoxyphenyl) -1H-imidazo [1, 2- b] pyrazole-3-carboxamide
  • Example 8 7- (1-acryloylpiperidin-4-yl) -1-methyl-2- (4-phenoxyphenyl) -1H-imidazo [1, 2- b] pyrazole-3-carboxamide
  • Example 13 7- (1-acryloylpiperidin-4-yl) -2- (4- (4-fluorophenoxy) phenyl) -1H- imidazo [1, 2-b] pyrazole-3-carboxamide
  • Step A Preparation of methyl 3- (4- (4-fluorophenoxy) phenyl) -3-oxopropanoate
  • Step B Preparation of 3- (4- (4-fluorophenoxy) phenyl) -3-oxopropanamide
  • step A of example 13 To a solution of the product of step A of example 13 (83 g, 0.29 mol) in 1, 4-dioxane (100 mL) was added 7 M NH 3 /1, 4-dioxane (100 mL) at room temperature in a 300 mL of sealed tube. The mixture was stirred at 95 °C for 12 hs, then it was cooled to room temperature. The mixture was concentrated under vacuum to get crude. The residue was purified by chromatography with petroleum ether and ethyl acetate (1: 1) to give the desired product 3- (4- (4-fluorophenoxy) phenyl) -3-oxopropanamide as a light-yellow solid (50 g, 63.1 %) .
  • Step C Preparation of 2-bromo-3- (4- (4-fluorophenoxy) phenyl) -3-oxopropanamide
  • Step D Preparation of tert-butyl 4- (3-carbamoyl-2- (4- (4-fluorophenoxy) phenyl) -1H- imidazo [1, 2-b] pyrazol-7-yl) piperidine-1-carboxylate
  • Step E Preparation of 2- (4- (4-fluorophenoxy) phenyl) -7- (piperidin-4-yl) -1H-imidazo [1, 2- b] pyrazole-3-carboxamide
  • step D of example 13 To a solution of the product of step D of example 13 (2.5 g, 4.8 mmol) in EtOH (2 mL) was added 33 %HCl/EtOH (10 mL) at room temperature in reaction still. The mixture was stirred for 3 hs, then the mixture was concentrated under vacuum to get 2.4 g crude 2- (4- (4-fluorophenoxy) phenyl) -7- (piperidin-4-yl) -1H-imidazo [1, 2-b] pyrazole-3-carboxamide. The residue was used to next step directly.
  • Step F Preparation of 7- (1-acryloylpiperidin-4-yl) -2- (4- (4-fluorophenoxy) phenyl) -1H- imidazo [1, 2-b] pyrazole-3-carboxamide
  • Example 17 7- (1-acryloylpiperidin-4-yl) -2- (4- (2, 4-difluorophenoxy) phenyl) -1H- imidazo [1, 2-b] pyrazole-3-carboxamide
  • Step A Preparation of methyl 3- (4- (2, 4-difluorophenoxy) phenyl) -3-oxopropanoate
  • Step B Preparation of 3- (4- (2, 4-difluorophenoxy) phenyl) -3-oxopropanamide
  • step A of example 17 To a solution of the product of step A of example 17 (81 g, 0.26 mol) in 1, 4-dioxane (100 mL) was added 7 M NH 3 /1, 4-dioxane (100 mL) at room temperature in a 300 mL of sealed tube. The mixture was stirred at 95 °C for 12 hs, then it was cooled to room temperature. The mixture was concentrated under vacuum to get crude. The residue was purified by chromatography with petroleum ether and ethyl acetate (1: 1) to give the desired product 3- (4- (2, 4-difluorophenoxy) phenyl) -3-oxopropanamide as a light-yellow solid (48 g, 63.4 %) .
  • Step C Preparation of 2-bromo-3- (4- (2, 4-difluorophenoxy) phenyl) -3-oxopropanamide
  • Step D Preparation of tert-butyl 4- (3-carbamoyl-2- (4- (2, 4-difluorophenoxy) phenyl) -1H- imidazo [1, 2-b] pyrazol-7-yl) piperidine-1-carboxylate
  • Step E Preparation of 2- (4- (2, 4-difluorophenoxy) phenyl) -7- (piperidin-4-yl) -1H-imidazo [1, 2- b] pyrazole-3-carboxamide
  • step D of example 17 To a solution of the product of step D of example 17 (3.2 g, 5.9 mmol) in EtOH (2 mL) was added 33 %HCl/EtOH (10 mL) at room temperature in reaction still. The mixture was stirred for 3 hs, then the mixture was concentrated under vacuum to get 3.0 g crude 2- (4- (2, 4-difluorophenoxy) phenyl) -7- (piperidin-4-yl) -1H-imidazo [1, 2-b] pyrazole-3-carboxamide. The residue was used to next step directly.
  • Step F Preparation of 7- (1-acryloylpiperidin-4-yl) -2- (4- (2, 4-difluorophenoxy) phenyl) -1H- imidazo [1, 2-b] pyrazole-3-carboxamide
  • Step A Preparation of methyl 3- (4- (4-methoxyphenoxy) phenyl) -3-oxopropanoate
  • Step B Preparation of 3- (4- (4-methoxyphenoxy) phenyl) -3-oxopropanamide
  • step A of example 20 To a solution of the product of step A of example 20 (85 g, 0.28 mol) in 1, 4-dioxane (100 mL) was added 7 M NH 3 /1, 4-dioxane (100 mL) at room temperature in a 300 mL of sealed tube. The mixture was stirred at 95 °C for 12 hs, then it was cooled to room temperature. The mixture was concentrated under vacuum to get crude. The residue was purified by chromatography with petroleum ether and ethyl acetate (1: 1) to give the desired product 3- (4- (4-methoxyphenoxy) phenyl) -3-oxopropanamide as a light yellow solid (50 g, 61.9 %) .
  • Step C Preparation of 2-bromo-3- (4- (4-methoxyphenoxy) phenyl) -3-oxopropanamide
  • Step D Preparation of tert-butyl 4- (3-carbamoyl-2- (4- (4-methoxyphenoxy) phenyl) -1H- imidazo [1, 2-b] pyrazol-7-yl) piperidine-1-carboxylate
  • Step E Preparation of 2- (4- (4-methoxyphenoxy) phenyl) -7- (piperidin-4-yl) -1H-imidazo [1, 2- b] pyrazole-3-carboxamide
  • step D of example 20 To a solution of the product of step D of example 20 (2.8 g, 5.3 mmol) in EtOH (2 mL) was added 33 %HCl/EtOH (10 mL) at room temperature in reaction still. The mixture was stirred for 3 hs, then the mixture was concentrated under vacuum to get 2.6 g crude 2- (4- (4-methoxyphenoxy) phenyl) -7- (piperidin-4-yl) -1H-imidazo [1, 2-b] pyrazole-3-carboxamide. The residue was used to next step directly.
  • Step F Preparation of 7- (1-acryloylpiperidin-4-yl) -2- (4- (4-methoxyphenoxy) phenyl) -1H- imidazo [1, 2-b] pyrazole-3-carboxamide
  • Step A Preparation of methyl 3- (4- (2-methoxyphenoxy) phenyl) -3-oxopropanoate
  • Step B Preparation of 3- (4- (2-methoxyphenoxy) phenyl) -3-oxopropanamide
  • step A of example 23 To a solution of the product of step A of example 23 (85 g, 0.28 mol) in 1, 4-dioxane (100 mL) was added 7 M NH 3 /1, 4-dioxane (100 mL) at room temperature in a 300 mL of sealed tube. The mixture was stirred at 95 °C for 12 hs, then it was cooled to room temperature. The mixture was concentrated under vacuum to get crude. The residue was purified by chromatography with petroleum ether and ethyl acetate (1: 1) to give the desired product 3- (4- (2-methoxyphenoxy) phenyl) -3-oxopropanamide as a light-yellow solid (53 g, 66.3 %) .
  • Step C Preparation of 2-bromo-3- (4- (2-methoxyphenoxy) phenyl) -3-oxopropanamide
  • Step D Preparation of tert-butyl 4- (3-carbamoyl-2- (4- (2-methoxyphenoxy) phenyl) -1H- imidazo [1, 2-b] pyrazol-7-yl) piperidine-1-carboxylate
  • Step E Preparation of 2- (4- (2-methoxyphenoxy) phenyl) -7- (piperidin-4-yl) -1H-imidazo [1, 2- b] pyrazole-3-carboxamide
  • step D of example 23 To a solution of the product of step D of example 23 (3.3 g, 6.2 mmol) in EtOH (2 mL) was added 33 %HCl/EtOH (10 mL) at room temperature in reaction still. The mixture was stirred for 3 hs, then the mixture was concentrated under vacuum to get 3.0 g crude 2- (4- (2-methoxyphenoxy) phenyl) -7- (piperidin-4-yl) -1H-imidazo [1, 2-b] pyrazole-3-carboxamide. The residue was used to next step directly.
  • Step F Preparation of 7- (1-acryloylpiperidin-4-yl) -2- (4- (2-methoxyphenoxy) phenyl) -1H- imidazo [1, 2-b] pyrazole-3-carboxamide
  • Step A Preparation of methyl 3- (4- (2-fluorophenoxy) phenyl) -3-oxopropanoate
  • Step B Preparation of 3- (4- (2-fluorophenoxy) phenyl) -3-oxopropanamide
  • step A of example 26 To a solution of the product of step A of example 26 (81 g, 0.28 mol) in 1, 4-dioxane (100 mL) was added 7 M NH 3 /1, 4-dioxane (100 mL) at room temperature in a 300 mL of sealed tube. The mixture was stirred at 95 °C for 12 hs, then it was cooled to room temperature. The mixture was concentrated under vacuum to get crude. The residue was purified by chromatography with petroleum ether and ethyl acetate (1: 1) to give the desired product 3- (4- (2-fluorophenoxy) phenyl) -3-oxopropanamide as a light-yellow solid (46 g, 59.9 %) .
  • Step C Preparation of 2-bromo-3- (4- (2-fluorophenoxy) phenyl) -3-oxopropanamide
  • Step D Preparation of tert-butyl 4- (3-carbamoyl-2- (4- (2-fluorophenoxy) phenyl) -1H- imidazo [1, 2-b] pyrazol-7-yl) piperidine-1-carboxylate
  • Step E Preparation of 2- (4- (2-fluorophenoxy) phenyl) -7- (piperidin-4-yl) -1H-imidazo [1, 2- b] pyrazole-3-carboxamide
  • step D of example 26 To a solution of the product of step D of example 26 (3.3 g, 6.4 mmol) in EtOH (2 mL) was added 33 %HCl/EtOH (10 mL) at room temperature in reaction still. The mixture was stirred for 3 hs, then the mixture was concentrated under vacuum to get 2.4 g crude 2- (4- (2-fluorophenoxy) phenyl) -7- (piperidin-4-yl) -1H-imidazo [1, 2-b] pyrazole-3-carboxamide. The residue was used to next step directly.
  • Step F Preparation of 7- (1-acryloylpiperidin-4-yl) -2- (4- (2-fluorophenoxy) phenyl) -1H- imidazo [1, 2-b] pyrazole-3-carboxamide
  • Step A Preparation of methyl 3- (4- (4-chlorophenoxy) phenyl) -3-oxopropanoate
  • Step B Preparation of 3- (4- (4-chlorophenoxy) phenyl) -3-oxopropanamide
  • Step C Preparation of 2-bromo-3- (4- (4-chlorophenoxy) phenyl) -3-oxopropanamide
  • Step D Preparation of tert-butyl 4- (3-carbamoyl-2- (4- (4-chlorophenoxy) phenyl) -1H- imidazo [1, 2-b] pyrazol-7-yl) piperidine-1-carboxylate
  • Step E Preparation of 2- (4- (4-chlorophenoxy) phenyl) -7- (piperidin-4-yl) -1H-imidazo [1, 2- b] pyrazole-3-carboxamide
  • step D of example 29 To a solution of the product of step D of example 29 (3.0 g, 5.6 mmol) in EtOH (2 mL) was added 33 %HCl/EtOH (10 mL) at room temperature in reaction still. The mixture was stirred for 3 hs, then the mixture was concentrated under vacuum to get 2.5 g crude 2- (4- (4-chlorophenoxy) phenyl) -7- (piperidin-4-yl) -1H-imidazo [1, 2-b] pyrazole-3-carboxamide. The residue was used to next step directly.
  • Step F Preparation of 7- (1-acryloylpiperidin-4-yl) -2- (4- (4-chlorophenoxy) phenyl) -1H- imidazo [1, 2-b] pyrazole-3-carboxamide
  • Step A Preparation of methyl 3- (4- (4-bromophenoxy) phenyl) -3-oxopropanoate
  • Step B Preparation of 3- (4- (4-bromophenoxy) phenyl) -3-oxopropanamide
  • Step C Preparation of 2-bromo-3- (4- (4-bromophenoxy) phenyl) -3-oxopropanamide
  • Step D Preparation of tert-butyl 4- (2- (4- (4-bromophenoxy) phenyl) -3-carbamoyl-1H- imidazo [1, 2-b] pyrazol-7-yl) piperidine-1-carboxylate
  • Step E Preparation of 2- (4- (4-bromophenoxy) phenyl) -7- (piperidin-4-yl) -1H-imidazo [1, 2- b] pyrazole-3-carboxamide
  • step D of example 31 To a solution of the product of step D of example 31 (2.8 g, 4.8 mmol) in EtOH (2 mL) was added 33 %HCl/EtOH (10 mL) at room temperature in reaction still. The mixture was stirred for 3 hs, then the mixture was concentrated under vacuum to get 2.0 g crude 2- (4- (4-bromophenoxy) phenyl) -7- (piperidin-4-yl) -1H-imidazo [1, 2-b] pyrazole-3-carboxamide. The residue was used to next step directly.
  • Step F Preparation of 7- (1-acryloylpiperidin-4-yl) -2- (4- (4-bromophenoxy) phenyl) -1H- imidazo [1, 2-b] pyrazole-3-carboxamide
  • Step A Preparation of methyl 3-oxo-3- (4- (p-tolyloxy) phenyl) propanoate
  • Step B Preparation of 3-oxo-3- (4- (p-tolyloxy) phenyl) propanamide
  • Step C Preparation of 2-bromo-3-oxo-3- (4- (p-tolyloxy) phenyl) propanamide
  • Step D Preparation of tert-butyl 4- (3-carbamoyl-2- (4- (p-tolyloxy) phenyl) -1H-imidazo [1, 2- b] pyrazol-7-yl) piperidine-1-carboxylate
  • Step E Preparation of 7- (piperidin-4-yl) -2- (4- (p-tolyloxy) phenyl) -1H-imidazo [1, 2- b] pyrazole-3-carboxamide
  • step D of example 32 To a solution of the product of step D of example 32 (3.0 g, 5.8 mmol) in EtOH (2 mL) was added 33 %HCl/EtOH (10 mL) at room temperature in reaction still. The mixture was stirred for 3 hs, then the mixture was concentrated under vacuum to get 2.6 g crude 7- (piperidin-4-yl) -2- (4- (p-tolyloxy) phenyl) -1H-imidazo [1, 2-b] pyrazole-3-carboxamide. The residue was used to next step directly.
  • Step F Preparation of 7- (1-acryloylpiperidin-4-yl) -2- (4- (p-tolyloxy) phenyl) -1H-imidazo [1, 2- b] pyrazole-3-carboxamide
  • Step A Preparation of tert-butyl-3- (cyanomethylene) pyrrolidine-1-carboxylate
  • Step B Preparation of tert-butyl 3- (cyanomethyl) pyrrolidine-1-carboxylate
  • step A of example 33 To a solution of the product of step A of example 33 (180 g, 0.86 mol) in ethyl acetate (1500 mL) was added 10 %Pd/C (18 g, 10 %) under N 2 . The suspension was degassed under vacuum and purged with H 2 several times. The mixture was stirred under H 2 balloon at room temperature for 5 hs. The mixture was passed through celite, and the solid was washed with ethyl acetate, and filtrate was concentrated under vacuum to give the desired product tert-butyl 3- (cyanomethyl) pyrrolidine-1-carboxylate as a white solid (170 g, 94.0 %) .
  • Step C Preparation of tert-butyl 3- (1-cyano-2-oxoethyl) pyrrolidine-1-carboxylate
  • Step D Preparation of tert-butyl 3- (5-amino-1H-pyrazol-4-yl) pyrrolidine-1-carboxylate
  • Step E Preparation of tert-butyl 3- (3-carbamoyl-2- (4-phenoxyphenyl) -1H-imidazo [1, 2- b] pyrazol-7-yl) pyrrolidine-1-carboxylate
  • Step F Preparation of 2- (4-phenoxyphenyl) -7- (pyrrolidin-3-yl) -1H-imidazo [1, 2-b] pyrazole- 3-carboxamide
  • step E of example 33 To a solution of the product of step E of example 33 (2.6 g, 5.33 mmol) in EtOH (2 mL) was added 33 %HCl/EtOH (5 mL) at room temperature in reaction still. The mixture was stirred for 3 hs, then the mixture was concentrated under vacuum to get 2.4 g crude 2- (4-phenoxyphenyl) -7- (pyrrolidin-3-yl) -1H-imidazo [1, 2-b] pyrazole-3-carboxamide. The residue was used to next step directly.
  • Step G Preparation of 7- (1-acryloylpyrrolidin-3-yl) -2- (4-phenoxyphenyl) -1H-imidazo [1, 2- b] pyrazole-3-carboxamide
  • step F of example 33 The mixture of the product of step F of example 33 (180 mg, 0.46 mmol) in DMF (5 mL) was alkalified to pH 7-8 with N, N-diisopropylethylamine. After 5 min, propiolic acid (48 mg, 0.69 mmol) and HATU (192 mg, 0.51 mmol) were added. The reaction mixture was continued to stir at room temperature for 30 min. Dichloromethane and water were added. The layers were separated, and the aqueous phase was extracted with dichloromethane. The combined organic phases were washed three times (3 ⁇ 50 mL) with brine solution. The organic phase was dried over anhydrous Na 2 SO 4 , filtered and concentrated.
  • Example 36 7- (1-acryloylpyrrolidin-3-yl) -2- (4- (4-fluorophenoxy) phenyl) -1H- imidazo [1, 2-b] pyrazole-3-carboxamide
  • Step A Preparation of tert-butyl 3- (3-carbamoyl-2- (4- (4-fluorophenoxy) phenyl) -1H- imidazo [1, 2-b] pyrazol-7-yl) pyrrolidine-1-carboxylate
  • Step B Preparation of 2- (4- (4-fluorophenoxy) phenyl) -7- (pyrrolidin-3-yl) -1H-imidazo [1, 2- b] pyrazole-3-carboxamide
  • step A of example 36 To a solution of the product of step A of example 36 (3.1 g, 6.1 mmol) in EtOH (2 mL) was added 33 %HCl/EtOH (5 mL) at room temperature in reaction still. The mixture was stirred for 3 hs, then the mixture was concentrated under vacuum to get 2.8 g crude 2- (4- (4-fluorophenoxy) phenyl) -7- (pyrrolidin-3-yl) -1H-imidazo [1, 2-b] pyrazole-3-carboxamide. The residue was used to next step directly.
  • Step C Preparation of 7- (1-acryloylpyrrolidin-3-yl) -2- (4- (4-fluorophenoxy) phenyl) -1H- imidazo [1, 2-b] pyrazole-3-carboxamide
  • Step A Preparation of tert-butyl 3- (3-carbamoyl-2- (4- (2, 4-difluorophenoxy) phenyl) -1H- imidazo [1, 2-b] pyrazol-7-yl) pyrrolidine-1-carboxylate
  • Step B Preparation of 2- (4- (2, 4-difluorophenoxy) phenyl) -7- (pyrrolidin-3-yl) -1H- imidazo [1, 2-b] pyrazole-3-carboxamide
  • step A of example 39 To a solution of the product of step A of example 39 (3.5 g, 6.7 mmol) in EtOH (2 mL) was added 33 %HCl/EtOH (5 mL) at room temperature in reaction still. The mixture was stirred for 3 hs, then the mixture was concentrated under vacuum to get 3.0 g crude 2- (4- (2, 4-difluorophenoxy) phenyl) -7- (pyrrolidin-3-yl) -1H-imidazo [1, 2-b] pyrazole-3-carboxamide. The residue was used to next step directly.
  • Step C Preparation of 2- (4- (2, 4-difluorophenoxy) phenyl) -7- (1-propioloylpyrrolidin-3-yl) - 1H-imidazo [1, 2-b] pyrazole-3-carboxamide
  • Example 40 7- (1-acryloylpyrrolidin-3-yl) -2- (4- (4-methoxyphenoxy) phenyl) -1H- imidazo [1, 2-b] pyrazole-3-carboxamide
  • Step A Preparation of tert-butyl 3- (3-carbamoyl-2- (4- (4-methoxyphenoxy) phenyl) -1H- imidazo [1, 2-b] pyrazol-7-yl) pyrrolidine-1-carboxylate
  • Step B Preparation of 2- (4- (4-methoxyphenoxy) phenyl) -7- (pyrrolidin-3-yl) -1H-imidazo [1, 2- b] pyrazole-3-carboxamide
  • step A of example 40 To a solution of the product of step A of example 40 (3.0 g, 7.2 mmol) in EtOH (2 mL) was added 33 %HCl/EtOH (5 mL) at room temperature in reaction still. The mixture was stirred for 3 hs. Then the mixture was concentrated under vacuum to get 2.8 g crude 2- (4- (4-methoxyphenoxy) phenyl) -7- (pyrrolidin-3-yl) -1H-imidazo [1, 2-b] pyrazole-3-carboxamide. The residue was used to next step directly.
  • Step C Preparation of 7- (1-acryloylpyrrolidin-3-yl) -2- (4- (4-methoxyphenoxy) phenyl) -1H- imidazo [1, 2-b] pyrazole-3-carboxamide
  • Step A Preparation of tert-butyl 3- (3-carbamoyl-2- (4- (2-methoxyphenoxy) phenyl) -1H- imidazo [1, 2-b] pyrazol-7-yl) pyrrolidine-1-carboxylate
  • Step B Preparation of 2- (4- (2-methoxyphenoxy) phenyl) -7- (pyrrolidin-3-yl) -1H-imidazo [1, 2- b] pyrazole-3-carboxamide
  • step A of example 43 To a solution of the product of step A of example 43 (3.8 g, 7.3 mmol) in EtOH (2 mL) was added 33 %HCl/EtOH (5 mL) at room temperature in reaction still. The mixture was stirred for 3 hs. Then the mixture was concentrated under vacuum to get 3.4 g crude 2- (4- (2-methoxyphenoxy) phenyl) -7- (pyrrolidin-3-yl) -1H-imidazo [1, 2-b] pyrazole-3-carboxamide. The residue was used to next step directly.
  • Step C Preparation of 7- (1-acryloylpyrrolidin-3-yl) -2- (4- (2-methoxyphenoxy) phenyl) -1H- imidazo [1, 2-b] pyrazole-3-carboxamide
  • Step A Preparation of tert-butyl 3- (3-carbamoyl-2- (4- (2-fluorophenoxy) phenyl) -1H-imidazo [1, 2-b] pyrazol-7-yl) pyrrolidine-1-carboxylate
  • Step B Preparation of 2- (4- (2-fluorophenoxy) phenyl) -7- (pyrrolidin-3-yl) -1H-imidazo [1, 2- b] pyrazole-3-carboxamide
  • step A of example 46 To a solution of the product of step A of example 46 (3.2 g, 6.3 mmol) in EtOH (2 mL) was added 33 %HCl/EtOH (5 mL) at room temperature in reaction still. The mixture was stirred for 3 hs. Then the mixture was concentrated under vacuum to get 3.0 g crude 2- (4- (2-fluorophenoxy) phenyl) -7- (pyrrolidin-3-yl) -1H-imidazo [1, 2-b] pyrazole-3-carboxamide. The residue was used to next step directly.
  • Step C Preparation of 7- (1-acryloylpyrrolidin-3-yl) -2- (4- (2-fluorophenoxy) phenyl) -1H- imidazo [1, 2-b] pyrazole-3-carboxamide
  • Step A Preparation of tert-butyl 3- (3-carbamoyl-2- (4- (p-tolyloxy) phenyl) -1H-imidazo [1, 2- b] pyrazol-7-yl) pyrrolidine-1-carboxylate
  • Step B Preparation of 7- (pyrrolidin-3-yl) -2- (4- (p-tolyloxy) phenyl) -1H-imidazo [1, 2- b] pyrazole-3-carboxamide
  • step A of example 48 To a solution of the product of step A of example 48 (3.5 g, 7.0 mmol) in EtOH (2 mL) was added 33 %HCl/EtOH (5 mL) at room temperature in reaction still. The mixture was stirred for 3 hs. Then the mixture was concentrated under vacuum to get 3.0 g crude 7- (pyrrolidin-3-yl) -2- (4- (p-tolyloxy) phenyl) -1H-imidazo [1, 2-b] pyrazole-3-carboxamide. The residue was used to next step directly.
  • Step C Preparation of (E) -2- (4- (p-tolyloxy) phenyl) -7- (1- (4, 4, 4-trifluorobut-2- enoyl) pyrrolidin-3-yl) -1H-imidazo [1, 2-b] pyrazole-3-carboxamide
  • Step A Preparation of tert-butyl 3- (cyanomethylene) azetidine-1-carboxylate
  • Step B Preparation of tert-butyl 3- (cyanomethyl) azetidine-1-carboxylate
  • Step C Preparation of tert-butyl 3- (1-cyano-2-oxoethyl) azetidine-1-carboxylate
  • Step D Preparation of tert-butyl 3- (5-amino-1H-pyrazol-4-yl) azetidine-1-carboxylate
  • Step E Preparation of tert-butyl 3- (3-carbamoyl-2- (4-phenoxyphenyl) -1H-imidazo [1, 2- b] pyrazol-7-yl) azetidine-1-carboxylate
  • step D of example 49 (10 g, 42.0 mmol) and the product of step C of example 1 (11 g, 33.6 mmol) in ethanol (200 mL) was heated to reflux for overnight. The reaction was then cooled to room temperature and the solvent was removed under vacuum, the crude residue was purified by chromatography with petroleum ether and ethyl acetate (3: 2) to give the desired product tert-butyl 3- (3-carbamoyl-2- (4-phenoxyphenyl) -1H-imidazo [1, 2-b] pyrazol-7-yl) azetidine-1-carboxylate as a yellow solid (3.2 g, 16.1 %) .
  • Step F Preparation of 7- (azetidin-3-yl) -2- (4-phenoxyphenyl) -1H-imidazo [1, 2-b] pyrazole-3- carboxamide
  • step E of example 49 To a solution of the product of step E of example 49 (3.2 g, 6.76 mmol) in EtOH (2 mL) was added 33 %HCl/EtOH (5 mL) at room temperature in reaction still. The mixture was stirred for 3 hs, then the mixture was concentrated under vacuum to get 2.9 g crude 7- (azetidin-3-yl) -2- (4-phenoxyphenyl) -1H-imidazo [1, 2-b] pyrazole-3-carboxamide. The residue was used to next step directly.
  • Step G Preparation of 7- (1-acryloylazetidin-3-yl) -2- (4-phenoxyphenyl) -1H-imidazo [1, 2- b] pyrazole-3-carboxamide
  • Example 50 7- (1- (but-2-ynoyl) azetidin-3-yl) -2- (4-phenoxyphenyl) -1H-imidazo [1, 2- b] pyrazole-3-carboxamide
  • step F of example 49 The mixture of the product of step F of example 49 (180 mg, 0.48 mmol) in DMF (5 mL) was alkalified to pH 7-8 with N, N-diisopropylethylamine. After 5 min, propiolic acid (51 mg, 0.72 mmol) and HATU (201 mg, 0.53 mmol) were added. The reaction mixture was continued to stir at room temperature for 30 min. Dichloromethane and water were added. The layers were separated, and the aqueous phase was extracted with dichloromethane. The combined organic phases were washed three times (3 ⁇ 50 mL) with brine solution. The organic phase was dried over anhydrous Na 2 SO 4 , filtered and concentrated.
  • Step A Preparation of tert-butyl 3- (3-carbamoyl-2- (4- (4-fluorophenoxy) phenyl) -1H- imidazo [1, 2-b] pyrazol-7-yl) azetidine-1-carboxylate
  • step D of example 49 (10 g, 42.0 mmol) and the product of step C of example 13 (12 g, 33.6 mmol) in ethanol (200 mL) was heated to reflux for overnight.
  • the reaction was then cooled to room temperature and the solvent was removed under vacuum, the crude residue was purified by chromatography with petroleum ether and ethyl acetate (3: 2) to give the desired product tert-butyl 3- (3-carbamoyl-2- (4- (4-fluorophenoxy) phenyl) -1H-imidazo [1, 2-b] pyrazol-7-yl) azetidine-1-carboxylate as a yellow solid (3.7 g, 18.0 %) .
  • Step B Preparation of 7- (azetidin-3-yl) -2- (4- (4-fluorophenoxy) phenyl) -1H-imidazo [1, 2- b] pyrazole-3-carboxamide
  • step A of example 53 To a solution of the product of step A of example 53 (3.7 g, 7.5 mmol) in EtOH (2 mL) was added 33 %HCl/EtOH (10 mL) at room temperature in reaction still. The mixture was stirred for 3 hs, then the mixture was concentrated under vacuum to get 3.2 g crude 7- (azetidin-3-yl) -2- (4- (4-fluorophenoxy) phenyl) -1H-imidazo [1, 2-b] pyrazole-3-carboxamide. The residue was used to next step directly.
  • Step C Preparation of 7- (1-acryloylazetidin-3-yl) -2- (4- (4-fluorophenoxy) phenyl) -1H- imidazo [1, 2-b] pyrazole-3-carboxamide
  • Example 54 7- (1- (but-2-ynoyl) azetidin-3-yl) -2- (4- (4-fluorophenoxy) phenyl) -1H- imidazo [1, 2-b] pyrazole-3-carboxamide
  • Step A Preparation of tert-butyl 3- (3-carbamoyl-2- (4- (2-methoxyphenoxy) phenyl) -1H- imidazo [1, 2-b] pyrazol-7-yl) azetidine-1-carboxylate
  • step D of example 49 (10 g, 42.0 mmol) and the product of step C of example 23 (12 g, 33.6 mmol) in ethanol (200 mL) were heated to reflux for overnight.
  • the reaction was then cooled to room temperature and the solvent was removed under vacuum, the crude residue was purified by chromatography with petroleum ether and ethyl acetate (3: 2) to give the desired product tert-butyl 3- (3-carbamoyl-2- (4- (2-methoxyphenoxy) phenyl) -1H-imidazo [1, 2-b] pyrazol-7-yl) azetidine-1-carboxylate as a yellow solid (3.8 g, 18.0 %) .
  • Step B Preparation of 7- (azetidin-3-yl) -2- (4- (2-methoxyphenoxy) phenyl) -1H-imidazo [1, 2- b] pyrazole-3-carboxamide
  • step A of example 56 (3.8 g, 7.5 mmol) in EtOH (2 mL) was added 33 %HCl/EtOH (5 mL) at room temperature in reaction still. The mixture was stirred for 3 hs. Then the mixture was concentrated under vacuum to get 3.2 g crude 7- (azetidin-3-yl) -2- (4- (2-methoxyphenoxy) phenyl) -1H-imidazo [1, 2-b] pyrazole-3-carboxamide. The residue was used to next step directly.
  • Step C Preparation of 7- (1-acryloylazetidin-3-yl) -2- (4- (2-methoxyphenoxy) phenyl) -1H- imidazo [1, 2-b] pyrazole-3-carboxamide
  • Step B Preparation of 7- (4-nitrophenyl) -2- (4-phenoxyphenyl) -1H-imidazo [1, 2-b] pyrazole-3- carboxamide
  • Step C Preparation of 7- (4-aminophenyl) -2- (4-phenoxyphenyl) -1H-imidazo [1, 2-b] pyrazole- 3-carboxamide
  • Step D Preparation of 7- (4-acrylamidophenyl) -2- (4-phenoxyphenyl) -1H-imidazo [1, 2- b] pyrazole-3-carboxamide
  • Step B Preparation of 7- (3-nitrophenyl) -2- (4-phenoxyphenyl) -1H-imidazo [1, 2-b] pyrazole-3- carboxamide
  • step A of example 61 (16 g, 78.4 mmol) and the product of step C of example 1 (21 g, 62.7 mmol) in ethanol (200 mL) was heated to reflux for overnight. The reaction was then cooled to room temperature and the solvent was removed under vacuum, the crude residue was purified by chromatography with petroleum ether and ethyl acetate (3: 2) to give the desired product 7- (3-nitrophenyl) -2- (4-phenoxyphenyl) -1H-imidazo [1, 2-b] pyrazole-3-carboxamide as a yellow solid (8.3 g, 24.1 %) .
  • Step C Preparation of 7- (3-aminophenyl) -2- (4-phenoxyphenyl) -1H-imidazo [1, 2-b] pyrazole- 3-carboxamide
  • step B of example 61 To a solution of the product of step B of example 61 (8.3 g, 18.9 mmol) in MeOH (20 mL) was added 10 %Pd/C (0.8 g, 10 %) under N 2 . The suspension was degassed under vacuum and purged with H 2 several times. The mixture was stirred under H 2 balloon at room temperature for 5 hs. The mixture was passed through celite, and the solid was washed with methyl alcohol, and filtrate was concentrated under vacuum to give the desired product 7- (3-aminophenyl) -2-(4-phenoxyphenyl) -1H-imidazo [1, 2-b] pyrazole-3-carboxamide as a yellow solid (7.5 g, 96.9 %) . MS (ESI, m/z) : 410.4 [M+H] + .
  • Step D Preparation of 7- (3-acrylamidophenyl) -2- (4-phenoxyphenyl) -1H-imidazo [1, 2- b] pyrazole-3-carboxamide
  • Step A Preparation of tert-butyl 3-amino-2, 4, 6, 7-tetrahydro-5H-pyrazolo [4, 3-c] pyridine-5- carboxylate
  • Step B Preparation of tert-butyl 3-carbamoyl-2- (4-phenoxyphenyl) -1, 6, 7, 9-tetrahydro-8H- imidazo [1', 2': 1, 5] pyrazolo [4, 3-c] pyridine-8-carboxylate
  • Step C Preparation of 2- (4-phenoxyphenyl) -6, 7, 8, 9-tetrahydro-1H- imidazo [1', 2': 1, 5] pyrazolo [4, 3-c] pyridine-3-carboxamide
  • step B of example 62 To a solution of the product of step B of example 62 (3.2 g, 6.76 mmol) in EtOH (2 mL) was added 33 %HCl/EtOH (5 mL) at room temperature in reaction still. The mixture was stirred for 3 hs, then the mixture was concentrated under vacuum to get 2.9 g crude 2- (4-phenoxyphenyl) -6, 7, 8, 9-tetrahydro-1H-imidazo [1', 2': 1, 5] pyrazolo [4, 3-c] pyridine-3-carboxamide. The residue was used to next step directly.
  • Step D Preparation of 8-acryloyl-2- (4-phenoxyphenyl) -6, 7, 8, 9-tetrahydro-1H- imidazo [1', 2': 1, 5] pyrazolo [4, 3-c] pyridine-3-carboxamide
  • Example 64 9-acryloyl-2- (4-phenoxyphenyl) -1, 6, 7, 8, 9, 10- hexahydroimidazo [1', 2': 1, 5] pyrazolo [4, 3-c] azepine-3-carboxamide
  • Step A Preparation of tert-butyl 3-bromo-4-oxoazepane-1-carboxylate and tert-butyl 4- bromo-5-oxoazepane-1-carboxylate
  • Step B Preparation of tert-butyl 3-cyano-4-oxoazepane-1-carboxylate
  • Step C Preparation of tert-butyl 3-amino-2, 6, 7, 8-tetrahydropyrazolo [4, 3-c] azepine-5 (4H) - carboxylate
  • Step D Preparation of tert-butyl 3-carbamoyl-2- (4-phenoxyphenyl) -1, 7, 8, 10- tetrahydroimidazo [1', 2': 1, 5] pyrazolo [4, 3-c] azepine-9 (6H) -carboxylate
  • Step E Preparation of 2- (4-phenoxyphenyl) -1, 6, 7, 8, 9, 10- hexahydroimidazo [1', 2': 1, 5] pyrazolo [4, 3-c] azepine-3-carboxamide
  • step D of example 64 To a solution of the product of step D of example 64 (0.8 g, 1.64 mmol) in dichloromethane (2 mL) was added 33 %HCl/EtOH (5 mL) at room temperature in reaction still. The mixture was stirred for 3 hs, then the mixture was concentrated under vacuum to get 2- (4-phenoxyphenyl) -1, 6, 7, 8, 9, 10-hexahydroimidazo [1', 2': 1, 5] pyrazolo [4, 3-c] azepine-3-carboxamide (0.7 g) . The residue was used to next step directly.
  • Step F Preparation of 9-acryloyl-2- (4-phenoxyphenyl) -1, 6, 7, 8, 9, 10- hexahydroimidazo [1', 2': 1, 5] pyrazolo [4, 3-c] azepine-3-carboxamide
  • Example 65 8-acryloyl-2- (4-phenoxyphenyl) -1, 6, 7, 8, 9, 10- hexahydroimidazo [1', 2': 1, 5] pyrazolo [3, 4-d] azepine-3-carboxamide
  • Step A Preparation of tert-butyl 4-cyano-5-oxoazepane-1-carboxylate
  • Step B Preparation of tert-butyl 3-amino-4, 5, 7, 8-tetrahydropyrazolo [3, 4-d] azepine-6 (2H) - carboxylate
  • Step C Preparation of tert-butyl 3-carbamoyl-2- (4-phenoxyphenyl) -6, 7, 9, 10- tetrahydroimidazo [1', 2': 1, 5] pyrazolo [3, 4-d] azepine-8 (1H) -carboxylate
  • Step D Preparation of 2- (4-phenoxyphenyl) -1, 6, 7, 8, 9, 10- hexahydroimidazo [1', 2': 1, 5] pyrazolo [3, 4-d] azepine-3-carboxamide
  • step C of example 65 To a solution of the product of step C of example 65 (1.5 g, 3.08 mmol) in dichloromethane (5 mL) was added 33 %HCl/EtOH (10 mL) at room temperature in reaction still. The mixture was stirred for 3 hs, then the mixture was concentrated under vacuum to get 0.7 g crude 2- (4-phenoxyphenyl) -1, 6, 7, 8, 9, 10-hexahydroimidazo [1', 2': 1, 5] pyrazolo [3, 4-d] azepine-3-carboxamide. The residue was used to next step directly.
  • Step E Preparation of 8-acryloyl-2- (4-phenoxyphenyl) -1, 6, 7, 8, 9, 10- hexahydroimidazo [1', 2': 1, 5] pyrazolo [3, 4-d] azepine-3-carboxamide
  • the assay was conducted in house.
  • kinase inhibitory activities of compounds were evaluated using the enzyme-linked immunosorbent assay (ELISA) .
  • the kinase enzyme of BTK (EGFR, BMX, or ITK, etc) was purchased from Carna Bioscience (Kobe, Japan) .
  • a total of 10 ng/mL antiphosphotyrosine (PY713) antibody (abcam, Cambridge Science Park, UK) was precoated in 96-well ELISA plates.
  • Active kinases were incubated with indicated drugs in 1 ⁇ reaction buffer (50 mmol/L HEPES pH 7.4, 20 mmol/L MgCl 2 , 0.1 mmol/L MnCl 2 , 1 mmol/L DTT) containing 20 ⁇ mol/L substrate (NH 2 -ETVYSEVRK-biotin) at 25 °C for 1 h. Then, a total of 3 ⁇ mol/L ATP was added and the reaction was continued for 2 hs. The products of reaction were transfered into 96-well ELISA plates containing antibody and incubated at 25 °C for 30 min.
  • 1 ⁇ reaction buffer 50 mmol/L HEPES pH 7.4, 20 mmol/L MgCl 2 , 0.1 mmol/L MnCl 2 , 1 mmol/L DTT
  • substrate NH 2 -ETVYSEVRK-biotin

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Abstract

Cette invention concerne une série de composés 1H-imidazo[1, 2-b]pyrazole-3-carboxamide substitués représentés par la formule I utilisés en tant qu'inhibiteurs de kinase, en particulier des inhibiteurs BTK (tyrosine kinase de Bruton), et les procédés de fabrication et d'utilisation de ceux-ci pour le traitement d'une maladie auto-immune, d'une maladie inflammatoire, d'un cancer et potentiellement d'allergies.
PCT/CN2021/106090 2020-07-13 2021-07-13 1h-imidazo[1, 2-b]pyrazole-3-carboxamide substitués utilisés en tant qu'inhibiteurs de la tyrosine kinase de bruton WO2022012550A1 (fr)

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