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WO2019013562A1 - Nouveau dérivé de 1h-pyrazolopyridine et composition pharmaceutique le contenant - Google Patents

Nouveau dérivé de 1h-pyrazolopyridine et composition pharmaceutique le contenant Download PDF

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Publication number
WO2019013562A1
WO2019013562A1 PCT/KR2018/007885 KR2018007885W WO2019013562A1 WO 2019013562 A1 WO2019013562 A1 WO 2019013562A1 KR 2018007885 W KR2018007885 W KR 2018007885W WO 2019013562 A1 WO2019013562 A1 WO 2019013562A1
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WO
WIPO (PCT)
Prior art keywords
pyridin
amino
pyrazolo
acryloylpiperidin
benzamide
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Ceased
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PCT/KR2018/007885
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English (en)
Korean (ko)
Inventor
방극찬
엄덕기
박준석
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Daewoong Pharmaceutical Co Ltd
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Daewoong Pharmaceutical Co Ltd
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Priority claimed from KR1020180079611A external-priority patent/KR102384924B1/ko
Application filed by Daewoong Pharmaceutical Co Ltd filed Critical Daewoong Pharmaceutical Co Ltd
Priority to CN201880046671.8A priority Critical patent/CN110914266A/zh
Priority to JP2020501212A priority patent/JP7061663B2/ja
Priority to ES18832639T priority patent/ES3046239T3/es
Priority to EP18832639.1A priority patent/EP3653626B1/fr
Priority to US16/629,392 priority patent/US11180496B2/en
Publication of WO2019013562A1 publication Critical patent/WO2019013562A1/fr
Anticipated expiration legal-status Critical
Ceased legal-status Critical Current

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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
    • A61K31/4353—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 ortho- or peri-condensed with heterocyclic ring systems
    • A61K31/437—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 ortho- or peri-condensed with heterocyclic ring systems the heterocyclic ring system containing a five-membered ring having nitrogen as a ring hetero atom, e.g. indolizine, beta-carboline
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
    • C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
    • C07D471/04—Ortho-condensed systems

Definitions

  • the present invention relates to a novel 1H-pyrazolopyridine derivative useful as a BTK (Bruton's tyrosine kinase) inhibitor and a pharmaceutical composition containing the same.
  • BTK Brunauer's tyrosine kinase
  • BTK Brady's Tyrosine Kinase
  • ITK Inter leukin-2 Tyros ine
  • Kinase is a type of tyrosine kinase that does not have a TEC family of receptors in combination with Tec (tyrosine kinase expressed in hepatocellular carcinoma), RLK (Resting Lymphocyte Kinase) and BMX (Bone Marrow tyrosine kinase gene on chromosome X) It acts on the immune response.
  • BTK functions as a modulator of mature B-cell activation, signal transduction and survival as well as early B-cell development.
  • the B-cell is signaled by a B cell receptor (BCR) that recognizes an antigen attached to the surface of an antigen presenting cell and is activated as a mature antibody-producing cell .
  • BCR B cell receptor
  • abnormal signal transduction by BCR can lead to abnormal B-cell proliferation and the formation of pathologic autoantibodies, leading to cancer, autoimmune and / or inflammatory diseases.
  • the BCI ⁇ l 'signal transmission by may be blocked if the BTK-deficient.
  • BTK can block the process of B-cell mediated disease, and the use of BTK inhibitors may be useful for the treatment of B-cell mediated diseases It can be a useful approach.
  • BTK can also be expressed by other cells that may be associated with disease besides B-cells.
  • BTK is an essential component of Fc-gamma signaling in bone marrow cells and is expressed by mast cells.
  • BTK-deficient bone marrow-derived mast cells exhibit damaged antigen-induced degranulation, and inhibition of BTK activity is known to be useful for treating pathological mast cell responses such as allergy and asthma (Iwaki et al. J. Biol Chem. 2005 280: 40261).
  • monocytes of patients with XKL without BTK activity are able to inhibit TNF alpha mediated inflammation by inhibiting BTF inhibitors by reducing TNF alpha production following stimulation (Horwood et al., J. Exp. Med. 197: 1603, 2003).
  • ITK is expressed in T cells as well as in NK cells and mast cells, and the production of important cytokines such as IL-2, IL-4, IL-5, IL-10, IL-13 and IL- (Schaeffer et al., 2001, 2, 1183; Fowell et al., 1999, 11, 399).
  • T cells are activated by TCR signaling and activated T cells activate inflammatory cytokine production, B cells and macrophages, leading to autoimmune diseases such as RA (Sahu N. et al. Curr Top Med Chem. 2009 , 9, 690).
  • Thl7 / Treg As well as Thl cells act as a pathogenesis of RA (J Lei J. et al., Arthritis Rheum. 2010, 62, 2876).
  • ITK has been developed as an immunotherapeutic drug target for asthma and has not been developed as a treatment for RA (Lo H. Y Expert Opin Ther Pat. 2010, 20, 459).
  • Thl7 and Treg cells are regulated by ITK - / - mice and it is possible to stratify into RA therapy target (Gomez-Rodriguez J. et al. J. Exp. Med.
  • W02015 / 061247 discloses hetero-compounds such as pyridine, pyrimidine, pyrazine and pyridazine compounds, and W02014 / 055934 discloses pyrimidinylphenylacrylamide derivatives.
  • ITK inhibitors W02005 / 066335 discloses aminobenzimidazole
  • W02005 / 056785 discloses pyridone
  • WO2002 / 0500 discloses aminothiazole derivatives.
  • W02014 / 036016 discloses benzimidazole derivatives.
  • the inventors of the present invention have studied the novel compounds and found that compounds having different chemical structures from those of BTK and ITK inhibitors reported to date have excellent BTK and ITK dual activity inhibitory effects and completed the present invention.
  • the compounds belonging to the present invention mainly have BTK and ITK inhibitory activity, but they do not exclude the possibility that they are absorbed into the body and then exhibit a pharmacological action by a specific body environment or products of metabolic processes as agonists.
  • the present invention provides a 1H-pyrazolopyridine derivative useful as a BTK inhibitor and a pharmaceutical composition containing the same.
  • the present invention provides a compound represented by the following formula (1), or a pharmaceutically acceptable salt thereof:
  • Y is a bond, 0, NH, COO, C0NH , or C0NC0 (C 2 - 4 alkenyl), and
  • 3 ⁇ 4 is a d- 4-alkyl, C 2 is substituted by hydrogen, halogen, d- 4-alkyl, hydroxy-and 4-alkenyl, cyano, or L-R ',
  • L is a bond, NH, d-4 alkylene, or C 2 - 4 alkenylene; R '
  • R ' is unsubstituted or substituted, or halogen, C M-alkyl, d- 4 haloalkyl, Tetrahydropyranyl, piperazinyl substituted with d- a 4 alkyl piperidinyl, - (d- 4 alkylene) -N (d- 4-alkyl) 2, - (Ci-4 alkylene) - avoid piperidinyl, or alkyl Lt; / RTI > phenylene,
  • 3 ⁇ 4 is halogen, d- 4-alkyl, C 6 - 10 aryl, or N and C comprising one or two heteroatoms selected from the group consisting of 0, 4 - 10 heteroaryl, eu
  • 3 ⁇ 4 is unsubstituted or substituted, or halogen, or C 3 - 6 cycloalkyl which is substituted by alkyl,
  • R4 is C 2 - 4 alkenyl, or C 2 - 4 is alkynyl.
  • the group is hydrogen, bromo, chloro, iodo, methyl, ethyl, hydroxymethyl, vinyl, cyano or -LR '
  • R ' is phenyl unsubstituted or substituted with fluoro; Unsubstituted thiophenyl; Thiazolyl substituted with methyl; Which is unsubstituted or substituted by methyl, difluoromethyl, tetrahydropyranyl, methylpiperidinyl, dimethylaminoethyl, pyridinylethyl, or morpholinoethyl.
  • R 2 is selected from the group consisting of bromo, tert-butyl, unsubstituted phenyl, cyclopropyl substituted pyrazolyl, unsubstituted benzoxazolyl, halogen substituted benzoxazolyl, unsubstituted dihydrobenzo di ≪ / RTI > pyridinyl, pyridinyl, pyrimidinyl, pyrimidinyl, pyrimidinyl, pyrimidinyl, pyrimidinyl, pyrimidinyl, pyrimidinyl, pyrimidinyl, pyrimidinyl, pyrimidinyl, Preferably, the group is hydrogen, fluoro, chloro, or methoxy.
  • 3 ⁇ 4 is -CH ⁇ C3 ⁇ 4, -C (CH 3 ) ⁇ C3 ⁇ 4, -C ⁇ CH, or -C ⁇ CC3 ⁇ 4.
  • the compounds of the present invention may exist in the form of a salt, particularly a pharmaceutically acceptable salt. Salts include, without limitation, salts commonly used in the art, such as acid addition salts formed by pharmaceutically acceptable free acids.
  • " pharmaceutically acceptable salt " of the present invention means a compound having a relatively nontoxic and innocuous effective action in a patient, wherein the adverse effect due to the salt does not degrade the beneficial effects of the compound represented by formula
  • the inorganic acid hydrochloric acid, phosphoric acid, sulfuric acid, nitric acid, tartaric acid and the like can be used.
  • organic acid examples include methanesulfonic acid, P- (Meth) acrylic acid, propionic acid, citric acid, lactic acid, maleic acid, maleic acid, succinic acid, oxalic acid, benzoic acid, tartaric acid, fumaric acid, mandelic acid, lactic acid, glycol ic acid, gluconic acid, galacturonic acid, glutamic acid, glutaric acid, glucuronic acid, but are not limited to, glucuronic acid, aspartic acid, ascorbic acid, carbonic acid, vanillic acid, hydroiodic acid, etc.
  • the salt may be a hydrochloride salt.
  • a pharmaceutically acceptable metal salt preferably sodium salt, potassium salt or hematite salt as the metal salt.
  • a pharmaceutically acceptable metal salt preferably sodium salt, potassium salt or hematite salt as the metal salt.
  • the salts or solvates can be used as intermediates in the preparation of compounds of formula (I), their pharmaceutically acceptable salts, or solvates.
  • the compounds represented by Formula 1 according to the present invention include, without limitation, pharmaceutically acceptable salts thereof, as well as solvates such as possible hydrates, which can be prepared therefrom, and all possible stereoisomers.
  • the solvates and stereoisomers of the compounds represented by the formula (1) can be prepared from the compounds represented by the formula (1) using methods known in the art.
  • the compound represented by Formula 1 according to the present invention may be prepared in the form of a colonic or amorphous form, and may be optionally hydrated or solvated when it is prepared in crystalline form.
  • compounds containing various amounts of water as well as stoichiometric hydrates of the compound represented by the formula (1) may be included.
  • Solvates of the compounds of formula (I) according to the present invention include both stoichiometric solvates and non-stoichiometric solvates.
  • Representative examples of the compound represented by the formula (1), or a pharmaceutically acceptable salt thereof are as follows:
  • Step 1-1 is a step of counteracting the compound represented by Formula 1-1 with N-bromosuccinimide to prepare a compound represented by Formula 1-2.
  • Step 1-2 is a step of counteracting the compound represented by Formula 1-2 and the compound represented by A '-OH to prepare the compound represented by Formula 1-3.
  • Step 1-3 is a step of counteracting the compound represented by Formula 1-3 with 2,4-dimeroxybenzylamine to prepare the compound represented by Formula 1-4.
  • the above Step 1-4 is a step of reacting the compound represented by Chemical Formula 1-4 with the compound represented by Chemical Formula 1-5 to prepare the compound represented by Formula 1-6.
  • Step 1-5 is a step of preparing the compound represented by the above formula 1-7 by reacting with the compound represented by the above formula 1-6 with an organic triethylsilane.
  • Step 1-6 is a step of reacting the compound represented by Formula 1-7 with a compound of R '-C0C1 to prepare a compound represented by Formula 1.
  • the manufacturing method of each of the above-described steps can be further specified in the following embodiments.
  • the present invention provides, for example, a compound represented by the above formula (1) through the following reaction formula (2).
  • the rest is as defined above.
  • Step 2-3 is carried out in Step 1-4 of Scheme 1, and the compound represented by Formula 2-3 is reacted with the compound represented by Formula 2-4 to obtain the compound represented by Formula 2-5 .
  • Step 2-4 is carried out in Step 1-2 of Van Gogh Formula 1.
  • the compound represented by Formula 1-5 is reacted with the compound represented by Formula A-OH to yield a compound represented by Formula 2-6, .
  • Steps 2-5 and 2-6 are the same as steps 1-5 and 1-6, respectively.
  • the manufacturing method of each of the above-described steps can be further specified in the following embodiments. Further, in the present invention, for example, when 3 ⁇ 4 is not hydrogen,
  • Step 3-5 is a step of preparing the compound represented by Formula 3-7 by counteracting the compound represented by Formula 3-6 with N-iodosuccinimide.
  • Step 3-6 is a step for preparing the compound represented by Formula 3-8 by counteracting the compound represented by Formula 3-7 and the compound capable of substituting 3 ⁇ 4.
  • a compound capable of replacing the 3 ⁇ 4 is, - ZnBr, Ri-B ( 0H) 2) or - ( ⁇ 0 2 (: 6 ⁇ 12).
  • the cancer is cancer of the blood, nodular extra-marginal B-cell lymphoma, glioblastoma, lymphoplasmacytic lymphoma, acute myelogenous leukemia,.
  • " prevention " of the present invention means any action that inhibits or delays the development, spread and recurrence of the disease upon administration of the composition of the present invention.
  • &Quot; Treatment 1 " Means any act that improves or alters the symptoms of
  • the pharmaceutical compositions of the present invention may be formulated into oral or parenteral administration forms according to standard pharmaceutical practice. These formulations may contain, in addition to the active ingredient, additives such as pharmaceutically acceptable carriers, adjuvants or chelating agents. Suitable carriers include, for example, physiological saline, polyethylene glycol, ethane, vegetable oils and isopropyl myristate.
  • diluents include lactose, dextrose, sucrose, mannitol, Cellulose, and / or glycine, but are not limited thereto.
  • the compounds of the present invention may be dissolved in oils, propylene glycol or other solvents commonly used in the preparation of injection solutions.
  • the compounds of the invention may also be formulated in ointments or creams for topical application.
  • the preferred dosage of the compound of the present invention varies depending on the condition and the weight of the patient, the degree of the disease, the form of the drug, the administration route and the period of time, but can be appropriately selected by those skilled in the art.
  • the compound is preferably administered at a daily dose of 0.0001 to 100 mg / kg (body weight), preferably 0.001 to 100 mg / kg (body weight). Administration may be by oral or parenteral route, once or divided once a day. Depending on the administration method, the pharmaceutical composition may contain 0.001 to 99% by weight, preferably 0.01 to 60% by weight, of the compound of the present invention.
  • the pharmaceutical composition according to the present invention can be administered to mammals including rats, mice, livestock and humans in various routes. All modes of administration may be expected, for example, by oral, rectal or intravenous, intramuscular, subcutaneous, intrauterine, or intracerebroventricular injection. ⁇ Effects of the Invention ⁇
  • the compound represented by the general formula (1) of the present invention can be usefully used for the prevention or treatment of diseases in which kinase inhibitory action is beneficial.
  • Step 1-1 Preparation of 3-bromo-4-chloro-lH-pyrazolo [4,3-c] pyridine
  • Step 1-2 Preparation of tert-butyl 3- (3-bromo-4-chloro-lH-pyrazolo [4,3-c] pyr- l-yl) piperidine-
  • Step 1-3 tert-Butyl 3- (3-bromo-4 - ((2,4-dimethoxybenzyl) amino) -1 H- pyrazolo [4,3- c] pyridin- Di-1-carboxylate < / RTI >
  • Step 1-4 Preparation of tert-butyl 3- (4 - ((2,4-dimethoxybenzyl) amino) -3- (4- phenoxyphenyl) -1H- pyrazolo [4,3- c] Yl) piperidine-1-carboxylate < / RTI >
  • Step 1-5 Preparation of 3- (4-phenoxyphenyl) -1- (piperidin-3-yl) -1H-pyrazolo [4,3-c]
  • Step 1-6 1- (3- (4-Amino-3- (4-phenoxyphenyl) -lH-pyrazolo [ c] pyr-l-yl) piperidin-1-yl) prop-2-en-
  • Step 3-1 Preparation of 3-bromo-N- (2,4-dimethicylbenzyl) -1H-pyrazolo [4,3-c] pyridin-
  • Step 3-2 Preparation of N- (2,4-dimethicylbenzyl) -3- (4-phenoxyphenyl) -1H-pyrazolo [4,3-c]
  • Step 3-3 tert-Butyl 4- (4 - ((2,4-dimethoxybenzyl) amino) -3- (4- phenoxyphenyl) -1H- pyrazolo [4,3- c] -Yl) piperidine-1-carboxylate < / RTI >
  • Step 3-4 3- (4-phenoxyphenyl) -1- (piperidin-4-yl) -1H- pyrazolo [ c] pyridin-4-ylamine
  • Step 3-5 1- (4- (4-Amino-3- (4- phenoxyphenyl) -lH-pyrazolo [4,3- c] pyridin- l-yl) piperidin- Prop-2-en-1-one
  • Example 5 1- (3- (4-Amino-7-iodo-3- (4-phenoxyphenyl) -lH-pyrazolo [4,3-c ] Pyridin- 1-yl) piperidin-1-yl) prop-2-en-1-one
  • Step 5-1 Synthesis of tert-butyl 3- (4 - ((2,4-dimethoxybenzyl) amino) -glyiodo-3- (4- phenoxyphenyl) -1H- pyrazolo [4,3-c ] Pyridin-1-yl) piperidine-1-carboxylate
  • Step 6-1 tert-Butyl 3- (7-benzyl-4 - ((2,4-dimethoxybenzyl) amino) -3- (4- phenoxyphenyl) -1H- pyrazolo [ ] Pyridin-1-yl) piperidine-1-carboxylate Produce
  • Step 6-2 Preparation of 7-benzyl-3- (4-phenoxyphenyl) -1- (piperidin-3-yl) -1H-pyrazolo [4,3-c] pyridin-
  • Step 6-1 tert- butyl obtained in Step 6-1 (7-benzyl-4 _ ((2, 4-dimethoxy hydroxybenzyl) amino) -3- (4-phenoxyphenyl) -1H- pyrazolo [4, 3 (1.7 mL) and triethylsilane (35.1 ⁇ L, 2.0 eq) were treated in the same manner as in Steps 3 and 4 of Example 3 with 3-fluorobenzaldehyde Following the same procedure to give the title compound which was used without purification in the next reaction.
  • Step 6-3 Preparation of 1- (3- (4-amino-7- benzyl-3- (4-phenoxyphenyl) -lH-l-yl) prop-
  • Phenoxy) phenyl] -1- (piperidin-3-yl) -lH-pyrazolo [4,3- c] pyridin-4-amine 1 (9.2 mg, 1.0 eq) and acryloyl chloride (8.9 uL, 1.0 eq) were treated in the same manner as in step 3 - 5 of Example 3 to give the title compound 15.0 mg (Yield 25.7 %). 2H), 7.33-7.27 (m, 2H), 7.23-7.18 (m, 1H), 7.17-7.07 (m, 2H), 7.57-7.
  • Example 7 l- (3- (4-Amino-7- (1-methyl-1H-pyrazol-4-yl) -3- (4-phenoxyphenyl) ) -IH-pyrazolo [4,3-c] pyridin- 1 -yl) piperidin-1-yl) prop-
  • Step 7-1 tert-Butyl 3- (4 - ((2,4-dimethoxybenzyl) amino) -7- Phenyl) -1H-pyrazolo [4,3-c] pyridin-l-yl)
  • Step 7-3 1- (3- (4-Amino-7- 4-yl) piperidin-1-yl) prop-2-en-1-ene Produce
  • Step 8-1 tert-Butyl 6- (3-bromo-4 - ((2,4-dimethoxybenzyl) amino) -1H-pyrazolo [4,3- c] pyridin- - azabicyclo [2.2.1] heptane-2- Carlsbad
  • Step 8-3 tert-Butyl 6- (4- - dimethoxybenzyl) amino) -7-iodo-3- (4-phenoxyphenyl) -1 H- pyrazolo [4,3- c] pyridin- l- yl) -2-azabicyclo [2.2.1 ] Heptane-2-carboxylate
  • Step 8-4 tert-Butyl 6- (4 - ((2,4-dimethoxybenzyl) amino) -7- (l- methyl- lH- pyrazol- Phenyl) -1H-pyrazolo [4,3-c] pyridin- 1-yl) -2-azabicyclo [2.2.1] heptane- 2-carboxylate
  • Step 8-5 1- (2-Azabicyclo [2.2.1] hept-2-yl) 6-yl) -7- (l-methyl-lH-) lH-pyrazolo [4,3- c] pyridin-
  • Step 8-6 1- (6- (4-Amino-7- (1- methyl-1H-pyrazol-4-yl) -3- (4- phenoxyphenyl) -1H- pyrazolo [ - c] pyridin-l-yl) -2-azabicyclo [
  • Step 9-1 tert-Butyl 3- (7-chloro-4 - ((2,4-dimethoxybenzyl) amino) -3- (4- phenoxyphenyl) -1H- pyrazolo [ ] Pyridin-l-yl) piperidin-l-
  • Example 10 l- (3- (4-Amino-7-bromo-3- (4-phenoxyphenyl) lH-pyrazolo [4,3- c] Pyridin-l-yl) piperidin-l-yl) prop-2-en-1-
  • Step 10-1 tert-Butyl 3- (7-bromo-4 - ((2,4-dimethoxybenzyl) amino) -3- (4-phenoxyphenyl) -1H-pyrazolo [4,3-c] pyridin-l-yl) piperidine-
  • Step 10-3 l- (3- (4-Amino-7-bromo-3- (4- phenoxyphenyl) -lH- pyrazol4,4- clpyridin- l- yl) piperidine -1-yl) prop-2-en-1-ene
  • Example 11 l- (3- (4-Amino-3- (4-phenoxyphenyl) -7-phenyl-1H- Step 1: Preparation of tert-butyl 3- (4 - ((2, 3-dihydro-pyrazolor4,3-clpyridin- , 4-dimethoxybenzyl) amino) -3- (4-phenoxyphenyl) -7-phenyl-lH- pyrazolo [4,3- c] pyridin- 1- yl) piperidin-
  • Step 11-2 Preparation of 3- (4-phenoxyphenyl) -7-phenyl-1- (piperidin-3-yl) -1H-pyrazolo [4,3-c] pyridin-
  • Step 11-3 Preparation of 1- (3- (4-amino-3- (4-phenoxyphenyl) -7-phenyl-1H-yl)
  • Step 12-1 Preparation of tert-butyl 4- (3-bromo-4-chloro-1H-pyrazolo [4,3-c] pyr- l-yl) piperidine-
  • Step 12-2 tert-Butyl 4- (3-bromo-4 - ((2,4-dimethoxybenzyl) amino) - lH-pyrazolo [4,3- c] pyridin- Di-1-carboxylate < / RTI >
  • Step 12-3 tert-Butyl 4- (4 - ((2,4-dimethoxybenzyl) amino) -3- (4- phenoxyphenyl) -1 H- pyrazolo [4,3- c] -Yl) piperidine-1-carboxylate < / RTI >
  • Step 12-4 tert-Butyl 4- (4 - ((2,4-dimethoxybenzyl) amino) -7-iodo-3- (4- phenoxyphenyl) -1H- pyrazolo [ c] pyridin-1-yl) piperidine-1-carboxylate
  • Step 12-5 Preparation of 7-iodo-3- (4-phenoxyphenyl) -1- (piperidin-4-yl) -lH- pyrazolo [4,3- c] pyridin-
  • Step 12-6 l- (4- (4-Amino-7-iodo-3- (4- phenoxyphenyl) -lH-pyrazol4,4- clpyridin- l- yl) piperidine -1-yl) prop-2-en-1-ene
  • Step 14-1 tert-Butyl (E) -3- (4 - ((2,4-dimethoxybenzyl) amino) -7- (4- fluorostyryl) -3- (4- -1H-pyrazolo [4,3-c] pyridin-l-yl) piperidine
  • Step 14-2 (E) -7- (4-Fluorostyryl) -3- (4-phenoxyphenyl) -1- (Piperid-c] pyridin-4-amine
  • Step 14-3 (E) -1- (3- (4-Amino-7- (4-fluorostyryl) -3- (4-chlorophenyl) -1H-pyrazolo [4,3-c ] Pyridin- 1-yl) piperidin-1-yl) prop-2-en-1-
  • Step 16-1 tert-Butyl (R) -3- (3-bromo-4-chloro-lH- pyrazolo [4,3- c] pyridin- l-yl) piperidine- Manufacturing
  • Step 16-2 tert-Butyl (R) -3- (3-bromo-4 - ((2,4- dimethoxybenzyl) amino) -1 H- pyrazolo [4,3- c] Yl) piperidine-l-carboxamide < / RTI >
  • Step 16-3 tert-Butyl (R) -3- (4 - ((2,4-dimethoxybenzyl) amino) -3- (4- phenoxyphenyl) -1 H- pyrazolo [ ] Pyridin-1-yl) piperidine-1-carboxylate
  • Step 16-4 tert-Butyl (R) -3- (4 - ((2,4-dimecicylbenzyl) amino) -7-iodo-3- (4- phenoxyphenyl) [4,3-c] pyridin-1-yl) piperidine-1-carboxylate
  • Step 16-6 (R) -3- (4 - ((2,4-dimeroxybenzyl) amino) -7-iodo-3- (4- phenoxyphenyl) -1H-pyrazole obtained in Step 16-4 (280.0 mg, 1.0 eq), trifluoroacetic acid (2.0 mL) and triethylsilane (117.1 uL, 2.0 eq) in tetrahydrofuran was carried out in the same manner as in step 7-2 of Example 7 to give 203.0 mg (yield 100.0%).
  • Step 16-6 (R) -1- (3- (4-Amino-7-isopropyl-pyridin- ) Piperidin-1-yl) prop-2-en-1-one
  • Example 17 (E) -1- (3- (4-Amino-3- (4-phenoxyphenyl) -7- (3-phenylprop- ) -1H-pyrazolo [4,3-c] pyridin- 1 -yl) piperidin-1-yl) prop-
  • Step 18-2 (R) -4- (4-Amino-1- (piperidin-3-yl) -1 H- pyrazolo [4,3- c] pyridin- -2-yl) benzamide
  • Step 18-3 (R) -4- (l- (l-Acryloylpiperidin-3-yl) -4-amino-1H-pyrazolo [4,3- c] pyridin- Preparation of N- (pyridin-2-yl) benzamide
  • Step 20-2 (R) -4- (4-Amino-7-bromo-1- (piperidin- -N- (pyridin-2-yl) benzamide
  • Step 20-3 Preparation of (R) -4- (1- (1-acryloylpiperidin-3-yl) -4-amino-7-bromo- -Yl) benzamide < / RTI >
  • Step 21-1 Synthesis of tert-butyl (R) -3- (4 - ((2,4-dimethicylbenzyl) amino) -7-iodo-3- (pyridin-2ylcarbamoyl) Pyrazolo [4,3-c] pyridin-l-yl) piperazine
  • Step 21-2 (R) -4- (4-Amino-7-iodo-1- (piperidin- - N- (pyridin-2-yl) benzamide
  • Step 21-3 Preparation of (R) -4- (l- (l-acryloylpiperidin-3-yl) -4-amino-7-iodo-lH-pyrazolo [4,3- c] pyridine- 3-yl) -N- (pyridin-2-yl) benzamide
  • Step 22-1 tert-Butyl (R) -3- (4 - ((2,4-dimethoxybenzyl) amino) -3-
  • Step 22-2 (R) -4- (4-Amino-1- (piperidin-3-yl) -1 H- pyrazolo [4,3- c] pyridin- Preparation of amide
  • Step 23-1 tert-Butyl (R) -3- (7-chloro-4 - ((2,4- dimecicylbenzyl) amino) -3- (4- (phenylcarbamoyl) Pyrazolo [4,3-c] pyridin-l-yl) piperidine
  • Step 23-3 (R) -4- (l- (l-Acryloylpiperidin-3-yl) -4-amino-7-chloro-lH- pyrazolo [4,3- c] -Yl) -N-phenylbenzamide < / RTI >
  • Step 24-1 tert-Butyl (R) -3- (7-bromo-4 - ((2,4- dimethoxybenzyl) amino) -3- (4- (phenylcarbamoyl) Pyrazolo [4,3-c] pyridin-l-yl) piperidine-1-carboxylate
  • Step 24-2 (R) -4- (4-Amino-7-bromo-1- (piperidin- -N-phenylbenzamide < / RTI >
  • Step 25-3 Preparation of (R) -4- (1- (1-acryloylpiperidin-3-yl) -4-amino-7-iodo-1H-pyrazolo [ -Yl) -N-phenylbenzamide < / RTI >
  • Step 26-1 tert-Butyl (R) -3- (4 - ((2,4-dimethoxybenzyl) amino) Preparation of 4- (phenylcarbamoyl) phenyl) -1H-pyrazolo [4,3-c] pyr- l-yl) piperidine-
  • Step 26-3 Preparation of (R) -4- (1- (1-acryloylpiperidin-3-yl) Methyl-1H-pyrazol-4-yl) -1H-pyrazolo [4,3- c] pyridin-3-yl) -N-phenylbenzamide
  • Step 27-2 Preparation of tert-butyl (R) -3- (4 - ((2,4- dimethoxybenzyl) amino) -7- (hydroxymethyl) -3- (4- (phenylcarbamoyl) Pyrazolo [4,3-c] pyridin-l-yl) piperidine-1-carboxylate
  • Step 27-3 Preparation of (R) -4- (4-amino-7- (hydoxymethyl) -1- (piperidin-3-yl) -lH-pyrazolo-N-phenylbenzamide
  • Example 28 (9.2%) was obtained in the same manner as in Example 28, by carrying out the same operations as in Example 28 to give the title compound (6.2 mg, 0.1 eq) and potassium carbonate (35.0 mg, 3.0 eq) ≪ / RTI >
  • Example 28 (5.1%) in the same manner as in Example 28, by carrying out the same operations as in Example 28 to give the title compound (6.2 mg, 0.1 eq) and potassium carbonate (35.0 mg, 3.0 eq) ≪ / RTI >
  • Step 39-1 tert-Butyl (S) -3- (3-bromo-4 - ((2,4-dimethoxybenzyl) amino) -1H-pyrazolo [ Yl) piperidine-1-carbox
  • Step 39-2 Synthesis of tert-butyl (S) -3- (4- (2,4-dimethoxybenzyl) amino) -3- (4- (pyridin-2ylcarbamoyl) phenyl) [4,3-c] pyridin-1-yl) piperidine-1-carboxylate
  • Step 40-3 (R) -4- (l- (l-Acryloylpiperidin-3-yl) -4-amino-lH- pyrazolo [4,3- c] pyridin- Preparation of 3-fluoro-N- (pyridin-2-yl) benzamide
  • Step 41-3 tert-Butyl (R) -3- (4-Amino-3- (4- (4-fluoropyridin-2- ylcarbamoyl) phenyl) -1H- pyrazolo [ -c] pyridin-1-yl) piperidine-1-carboxylate
  • Step 41-5 (R) -4- (l- (l-Acryloylpiperidin-3-yl) -4-amino-1H-pyrazolo [4,3- c] pyridin- Preparation of N- (4-fluoropyridin-2-yl) benzamide
  • Step 43-1 Synthesis of (R) -4- (4-amino-7-iodo-1- (pyridin- Preparation of N- (pyridin-2-yl) benzamide
  • Step 43-2 Synthesis of tert-butyl (R) -3- (4-amino-7-iodo-3- (4- (pyridine- 2- ylcarbamoyl) ] Pyridin-1-yl) piperidine-1-carboxylate
  • Step 43-3 tert-Butyl (R) -3- (4-amino-7- (phenylamino) -3- (4- (pyridin-2ylcarbamoyl) phenyl) -1H-pyrazolo [ -c] pyridin-1-yl) piperidine-1-carboxylate
  • Step 43-5 Preparation of (R) -4- (l- (1-acryloylpiperidin-3-yl) -4-amino- 7- (phenylamino) -1 H- pyrazolo [ Pyridin-3-yl) -N- (pyridin-2-yl) benzamide
  • Step 44-1 tert-Butyl (R) -3- (4 - ((2,4-dimethoxybenzyl) amino) -7- Gt; [4, 3-c] pyridin-l-yl) piperidine-
  • Step 44-2 Preparation of (R) -4- (4-amino-7-methyl-1- (piperidin- Preparation of N-phenylbenzamide
  • Step 44-1 (4 - ((2,4-dimethoxybenzyl) amino) -grimethyl-3- (4- (phenylcarbamoyl) phenyl) -1H-pyrazole obtained in Step 44-1 (41.0 mg, 1.0 eq), trifluoroacetic acid (1.0 mL) and triethylsilane (19.4 uL, 2.0 eq) were added to a solution of 4- Was carried out in the same manner as in the step 18-2 of Example 18 to give the title compound which was used without purification in the next reaction.
  • Step 44-3 Preparation of (R) -4- (1- (1-acryloylpiperidin-3-yl) -4-amino-
  • Step 45-1 Synthesis of tert-butyl (R) -3- (4 - ((2,4-dimethoxybenzyl) amino) Pyrazolo [4,3-c] pyridin-1-yl) piperidine-1-carboxylate
  • Step 45-2 (R) -4- (4-Amino-7-methyl-1- (piperidin- Preparation of N- (pyridin-2-yl) benzamide
  • Butyl (R) -3 - (4-amino-methyl-3- (4- (21.4 mg, 1.0 eq), sodium hydrogencarbonate (8.4 mg, 1.0 eq), and triethylamine mg, 2.0 eq) and acryloyl chloride (4.9 uL, 1.2 eq) were carried out in the same manner as in step 18-3 of Example 18 to give 18.2 mg (yield 63.0%) of the title compound.
  • Step 46-1 tert-Butyl (S) -3- (3-bromo-4 - ((2,6- dimethoxybenzyl) amino) -1 H- pyrazolo [4,3- c] Yl) pyridin-l-carboxylate
  • Step 46-3 tert-Butyl (S) -3- (4 - ((2,6-dimethoxybenzyl) amino) -7-iodo-3- (4- (phenylcarbamoyl) Pyrazolo [4,3-c] pyridin-l-yl)
  • Step 46-4 tert-Butyl (S) -3- (7- (l- (difluoromethyl) -1H-pyrazol- Pyrazolo [4,3-c] pyridin-l-yl) pyrrolidine-1-carboxylate
  • Step 46-5 (S) -4- (4-Amino-7- (1- (difluoromethyl) -1H-pyrazol- Pyrazolo [4,3-c] pyridin-3-yl) -N-phenylbenzamide
  • Step 46-6 (S) -4- (1- (1-acryloylpyridin-3-yl) -4-amino-7- (1- (difluoromethyl) -1H-pyrazolo -Yl) -1H-pyrazolo [4,3-c] pyridin-3-yl) -N-phenylbenzamide
  • Step 47-1 (S) -4- (4-Amino-1- (pyridin-3-yl) -1 H-pyrazolo [4,3- c] pyridin- Preparation of amide
  • Step 49-1 Synthesis of tert-butyl (R) -3- (4-amino-3- (2- fluoro-4- (pyridine- 2- ylcarbamoyl) phenyl) -1H-pyrazolo [ ] Pyridin-1-yl) piperidine-1-carbox
  • Step 49-2 tert-Butyl (R) -3- (4-amino-7-chloro-3- (2-fluoro-4- (pyridin-2ylcarbamoyl) , 3-c] pyridin-l-yl) piperidine-l-carboxylate
  • Step 50-1 tert-Butyl (R) -3- (4-Amino-3- (2- fluoro-4- (pyridine- 2- ylcarbamoyl) phenyl) -7-iodo-1H-pyrazolo [ 4,3-c] pyridin-l-yl) piperidine-l-carboxylate
  • Step 50-3 (R) -4- (l- (l-Acrylylpiperidin-3-yl) -4-amino-7-iodo-lH- pyrazolo [4,3- c] 3-yl) -3-fluoro-N- (pyridin-2-yl) benzamide
  • Example 51 4- (l- ((6R) -2-Acrylyl-2-azabicyclo [2.2.1] heptan-6-yl) -4- Pyrazolo [4,3-c] pyridin-3-yl) -3-fluoro-N- (pyridin-
  • Step 51-1 tert-Butyl (6R) -6- (4-amino-3-bromo-1H-pyrazolo [4,3-c] pyridin- l-yl) -2-azabicyclo [2.2. 1] heptane-2-carboxylate
  • Step 51-2 tert-Butyl (6R) -6- (4-Amino-3- (2- fluoro-4- (phenylcarbamoyl) phenyl) -lH- pyrazolo [4,3- c] 1-yl) -2-azabicyclo 2-carboxylate
  • Step 51-3 4- (l- ((6R) -2-Acrylyl-2-azabicyclo [2.2.1] heptan- [4,3-c] pyrid-3-yl) -3-fluoro-N- (pyridin-2-yl) benzamide
  • Step 52-1 Preparation of tert-butyl 3- (3-bromo-4 - ((2,4-dimethoxybenzyl) amino) -1H-phthalazetidine-1-carboxylate
  • tert-Butyl 3-hydroxyazetidine-1-carboxylate (500.0 mg eq) was dissolved in tetrahydrofuran (20.0 mL), then triphenylphosphine (541.6 mg, 1.5 eq) was added at room temperature and diisopropyl azodicarboxylate (406.6 uL, 1.5 eq) was added at 0 ° C Respectively.
  • the reaction mixture was stirred at room temperature for 10 minutes, and then 3-bromo-N- (2,4-dimethoxybenzyl) -1H-pyrazolo [4,3-c ] Pyridin-4-amine (363.3 mg, 1.0 eq) was added.
  • Step 52-2 tert -Butyl 3- (4 - ((2,4-dimethoxybenzyl) amino) -3- (2- fluoro-4- (pyridin- 2- ylcarbamoyl) Pyrazolo [4,3-c] pyridin-l-yl) azela
  • Step 53-1 tert-Butyl (R) -3- (4-amino-7-cyano-3- (2- (Pyridin-2-ylcarbamoyl) phenyl) -IH-pyrazolo [4,3- c] pyridin- 1 -yl) piperidine-
  • Step 53-2 (R) -4- (4-Amino-7-cyano-1- (piperidin- -3-fluoro-N- (pyridin-2-yl) benzamide hydrochloride
  • Example 54 (R) -4- (4-Amino-1- (1-methacryloylpiperidin-3-yl) -1H-pyrazolo [4,3 (R) -4- (4-amino-1- (piperidin-4-ylmethoxy) -phenyl] 3-yl) -3H-pyrazolo [4,3-c] pyrid-3-yl) -3-fluoro-N- (pyridin-2-yl) benzamide hydrochloride
  • Step 56- 2 (R) -4- (4-Amino-1- (piperidin-3-yl) -1 H- pyrazolo [4,3- Pyridin-2-yl) benzamide hydrochloride
  • Step 56-3 (R) -4- (1- (1-Acryloylpiperidin-3-yl) -4-amino-1H-pyrazole [ Preparation of 3-chloro-N- (pyridin-2-yl) benzamide
  • Step 57-2 (R) -4- (4-Amino-1- (piperidin-3-yl) -lH- pyrazolo [4,3- c] pyridin- -N- (pyridin-2-yl) benzamide hydrochloride
  • Step 58-1 tert-Butyl (R) -3- (4-amino-7-chloro-3- (2-
  • Step 58-2 ((R) -4- (4-Amino-7-chloro-1- (piperidin- -3-chloro-N- (pyridin-2-yl) -benzamide hydrochloride
  • Step 58-3 Preparation of (R) -4- (l- (l-acryloylpiperidin-3-yl) -4-amino-7-chloro-lH-pyrazolo [ -Yl) -3-chloro-N- (pyridin-2-yl) benzamide
  • Step 59-1 Preparation of tert-butyl (R) -3- (4-amino-7-chloro-3- (2- methoxy- 4- (pyridin- 2- ylcarbamoyl) 4,3-c] pyridin-1-yl) piperidine-1-carboxylate
  • Step 59-3 Preparation of (R) -4- (l- (l-acryloylpiperidin-3-yl) -4-amino-7-chloro-lH- pyrazolo [4,3- c] Yl) -3-methoxy-N- (pyridin-2-yl) benz
  • Step 60-1 tert-Butyl 3- (7-chloro-4 - ((2,4-dimethoxybenzyl) amino) -3- ) -1H-pyrazolo [4,3-c] pyridin-l-yl)
  • Step 60-2 4- (4-Amino-1- (azetidin-3-yl) -7-chloro-lH- pyrazolo [4,3- c] pyridin- Preparation of N- (pyridin-2-yl) benzamide
  • Step 60-3 4- (l- (1-Acrylyl azetidin-3-yl) -4-amino-7-chloro-lH- pyrazolo [4,3- c] pyridin- Preparation of 3-fluoro-N- (pyridin-2-yl) benzamide
  • Step 61-1 tert-Butyl (R) -3- (3 - ((l-cyclopropyl-lH-pyrazol- Pyrazolo [4,3-c] pyridin-l-yl) piperazine was prepared in accordance with the general method of example 1, step (b)
  • Step 61-2 Preparation of (R) -N- (l-cyclopropyl-lH-pyrazol-4-yl) Produce
  • Step 61-3 Preparation of (R) -1- (3- (4-Amino-3- (1- cyclopropyl-1H-pyrazol-4-ylamino) Yl) piperidin-1-yl) prop-2-en-1-
  • Step 62-1 Preparation of (R) -3-bromo-1- (piperidin-3-yl) -1H-pyrazolo [4,3-c] pyridin-
  • Step 63-2 4- (4-Amino-1- (azetidin-3-yl) -lH- pyrazolo [4,3- c] pyridin- 2-yl) benzamide
  • Step 63-3 4- (1- (1-acryloyl azetidin-3-yl) -4-amino-1H-pyrazole [ Preparation of N- (pyridin-2-yl) benzamide
  • Step 64-1 Preparation of tert-butyl 3- (7-chloro-3- (2-chloro-4- (pyridin- 2- ylcarbamoyl) - pyrazolo [4,3-c] pyridin-l-yl)
  • Step 64-2 4- (4-Amino-1- (azetidin-3-yl) -7- Pyrazole [4,3-c] pyridin-3-yl) -3-chloro-N- (pyridin-2-yl) benzamide
  • Step 64-3 Preparation of 4- (1- (1-acryloyl azetidin-3-yl) -4-amino-7-chloro-lH- pyrazolo [ 3-Chloro-N- (pyridin-2-yl) benzamide
  • Step 65-1 Synthesis of tert-butyl (R) -3- (4-amino-3- (2-chloro-4- (pyridin- 2- ylcarbamoyl) phenyl) -7-iodo-1H-pyrazolo [ 4,3-c] pyridin-l-yl) piperidin-l-
  • Step 65-3 Preparation of (R) -4- (l- (l-acryloylpiperidin-3-yl) -4-amino-7-iodo-lH-pyrazolo [4,3- c] pyridine- 3-yl) -3-chloro-N- (pyridin-2-yl) benz
  • Step 66-1 Synthesis of tert-butyl (R) -3- (4-amino-3- (2-chloro-4- (pyridin- 2- ylcarbamoyl) phenyl) -7- cyano- 4, 3-c] pyridin-l-yl) piperidine-l-
  • Step 67-1 Synthesis of tert-butyl (R) -3- (4-amino-3- (2-chloro-4- (pyridin- 2- ylcarbamoyl) Yl) -1H-pyrazolo [4,3-c] pyridin-l-yl) piperidine-1-carboxylate
  • Step 67-2 (R) -4- (4-Amino-7- (l -methyl-lH-pyrazol- 4, 3-c] pyridin-3-yl) -3-chloro-N- (pyridin-
  • Step 67-3 Preparation of (R) -4- (1- (1-acryloylpiperidin-3-yl) -Pyrazolo [4,3-c] pyridin-3-yl) -3-chloro-N- (pyridin-
  • Step 68-1 Synthesis of tert-butyl (R) -3- (4-amino-3- (2-chloro-4- (pyridin- 2- ylcarbamoyl) phenyl) -7-vinyl-1H-pyrazolo [4 , 3-c] pyridin-l-yl) piperidine-l-carboxylate
  • Step 68-2 tert-Butyl (R) -3- Carbamoyl) phenyl) -7-ethyl-lH-pyrazolo [4,3- c] pyridin- 1- yl) piperidine-
  • Step 69-1 (R) -4- (4-Amino-1- (piperidin-3-yl) Preparation of 3-chloro-N- (pyridin-2-yl) benzamide
  • Step 69-2 Synthesis of (R) -4- (1- 4-amino-7-vinyl-1H-pyrazolo [4,3-c] pyridin-3- yl) -3-chloro-N- (pyridin- Produce
  • Step 70-1 Preparation of (R) -4- (1- (1-acryloylpiperidin-3-yl) -4-amino-7-H-pyrazol- , 3-c] pyridin-3-yl) -3-chloro-N- (pyridin-2-yl) benzamide
  • Step 71-1 Methyl (R) -4-amino-1- (1- (tert-butyloxycarbonyl) piperidin- Yl) -1H-indine-3-carboxylate
  • Step 71-2 Preparation of (R) -4-amino-1- (1- (tert-butyloxycarbonyl) piperidin-3-yl)
  • Step 71-5 (R) -1- (1-acryloylpiperidin- Preparation of 4-amino-N- (5-chlorobenzo [d] oxazol-2-yl) -1H-pyrazolo [4,3-c] pyridine-
  • Example 72 Synthesis of (R) -tert-butyl 1- (1-acryloylpiperidin-3-yl) -4-amino-1H-pyrazolo [4,3 -c] pyridine-3-carboxylate < / RTI >
  • Step 72-1 tert-Butyl (R) -4-amino-1- (1- (tert-butylcycarbonyl) piperidin- -3-carboxylate
  • Step 73-1 tert-Butyl (R) -3- (4-amino-3 - ((6-bromobenzo [d] oxazol- -c] pyridin-1-yl) piperidine-1-carboxylate
  • Step 73-3 Preparation of (R) -1- (1-acryloylpiperidin-3-yl) -4-amino-N- (6-bromobenzo [d] oxazol- Pyrazolo [4,3-c] pyridine-3-carboxamide
  • Step 74-1 Preparation of methyl (R) -4-amino-1- (1- (tert-butylcycarbonyl) piperidin-3-yl) -7-chloro-1H-pyrazolo [ ] Pyridine-3-carboxylate
  • Step 74-2 3-c] pyridine-3-carboxylic acid.
  • the title compound was prepared in analogy to the procedure described for the preparation of
  • Step 74-3 tert-Butyl (R) -3- (4-amino-7-chloro-3- (5- chlorobenzo [d] oxazol- 2- yl) carbamoyl) -1H- pyrazolo [ 4, 3-c] pyridin-1-yl) piperidine-1-carboxylate
  • Step 74-4 (R) 4-Amino-7-chloro-N- (5-chlorobenzo [d] oxazol-2-yl) -lH- pyrazolo [4,3- c] pyridin- - Preparation of carboxamide
  • Step 75-1 Synthesis of 1-butyl (1- 3- (4-amino-3- (benzo [(1xoxazol-2-ylcarbamoyl) -7-chloro-1H-pyrazolo [ ] Pyridin-1-yl) piperidine-1-carboxylate
  • Step 76-1 Synthesis of tert-butyl (R) -3- (4-amino-7-chloro-3- ((5-fluorobenzo [d] oxazol- [4,3-c] pyridin-1-yl) piperidine-1-carboxylate
  • Step 77-1 Preparation of tert-butyl (R) -3- (4-amino-3- (benzo [d] oxazol- 2- ylcarbamoyl) -1H- pyrazolo [4,3- c] Yl) piperidine-1-carboxylate < / RTI >
  • Step 7 To a solution of (R) -4-amino-N- (benzo [d] oxazol-2-yl) -1- (piperidin- -c] pyridine-3-carboxamide (9.5 mg, 1.0 eq) was dissolved in dichloromethane (5.0 mL) and then triethylamine (12.8 uL 3.0 eq) was added at room temperature and quenched for 30 minutes. Acryloyl chloride (1.9 U L, 1.0 eq) was added to the reaction at room temperature. The reaction was stirred at room temperature for 30 minutes, then methanol was added thereto, followed by extraction with water and ethyl acetate.
  • Step 78-1 Synthesis of tert-butyl (R) -3- (4-amino-7-chloro-3- (phenylcarbamoyl) -lH-pyra- l-yl) piperidine- 1 -carboxylate Produce
  • Step 78-2 Preparation of (R) -4-amino-7-chloro-N-phenyl-1- (piperidin-3-yl) -1H-3-carboxamide
  • Step 79-1 tert-Butyl (R) -3- (4-amino-7-chloro-3 - ((2,3- dihydrobenzo [b] [1,4] dioxin- Yl) piperazin-1-yl) piperazine-1-carboxylate
  • Step 79-2 (R) 4-yl] -1- (piperidin-3-yl) -1H-pyrazolo [4,3-c] Pyridine-3-carboxamide < / RTI >
  • Step 79-3 ( R) -1- (1-acryloylpiperidin-3-yl) -4-amino-7-chloro-N- (2,3- dihydrobenzo [b] [1,4] dioxin- Yl) -1H-pyrazolo [4,3-c] pyridine-3-carboxamide
  • the inhibitory activity of ITK was evaluated using Promega's 'ADP_Glo TM + ITK Kinase enzyme system' kit. If Whi fa te 96-well plate a final concentration of 0.4 ng / uL ITK enzyme prepared such that 10 uL with one single concentration evaluated in the case to have a final concentration of 1 uM, one IC50 evaluation 1000, 300, 100, 30, 10, 3, 1, 0.3, 0.1, and 0.03 nM, were added to each well and incubated at room temperature for 15 minutes. 5 uL of substrate and 5 uL of ATP prepared to final concentration of 25 uM were added to the plate, and reacted at 30 ° C for 1 hour.
  • Example 1 BTK IC 50 (nM) ITK IC 50 (nM) ITK IC 50 (nM)
  • Example 1 1.4 37.7
  • Example 41 1.5 10.1 Example 2 3.5 15.7
  • Example 42 66.3 240.8
  • Example 3 2.7> 1000
  • Example 43 2.5 146.3
  • Example 4 5.5 276.7
  • Example 5 6.7 19.5
  • Example 45 11.2 66.8
  • Example 6 29.9 287.6
  • Example 46 >400> 1000
  • Example 7 3.0 36.4
  • Example 8 7.3> 500
  • Example 9 1.5 11.3
  • Example 49 1.2 3.3
  • Example 10 2.
  • Example 11 11.4 223.6
  • Example 51 0.5 30.8
  • Example 12 7.7> 1000
  • Example 52 1.6 51.6
  • Example 13 5.
  • Example 53 0.5 4.3 Example 14 4.1 4.4 38.4 Example 54 77.5> 1000 Example 15 3.7 > 500 Example 55 6.4 124. 1 Example 16 1.0 2.7 Example 56. 0.4 0.6 Example 17 14.0 13.4 Example 57 0.5 11.4 Example 18 1.0 26.4 Example 58 8.8 9.3 Example 19 1.7 7.8 Conduct Example 59 3.7 26.0 Example 20 15.2> 1000 Example 60 0.4 263.0 Example 21 10.7> 1000 Example 61 187. 1> 1000 Example 22 2.5 130.6 Example 62 6.3 8. 1 Example 23 1.2 48.0 Example 63 3 1 30 1 Example 24 1.2 36.8 Example 64 1.
  • Example 27 8.0> 500 Example 67 2 2.7 Example 28 4.4 180.8 Example 68 0.9 1.7 Example 29 3. 1 555.7 Example 69 2 2.9 Example 30 3.0 490.2 Example 70 2 5.2 Example 31 15.9 375.6 Example 71 3.4 4.1 Example 32 6.2 199.5 Example 72 88.9 68.2 Example 33 10.2 306.8 Example 73 32 140.8 Example 34 2.3 293.4 Example 74 3.3 6.4 Example 35 1.9 61 Example 75 2.2 2.4 Example 36 1.5 89 Example 76 1.5 2. 1 Example 37 3.0 91.3 Example 77 5 13. 1 Example 38 2.6 186.4 Example 78 22. 1 27 Example 39 3.5> 1000 Example 79 100.1 54.9 Example 40 2.7 6.4

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Abstract

La présente invention concerne un nouveau dérivé de 1H-pyrazolopyridine et une composition pharmaceutique le contenant. Le dérivé de 1H-pyrazolopyridine et la composition pharmaceutique le contenant peuvent être utilisés de manière efficace pour la prévention ou le traitement d'une maladie auto-immune ou d'un cancer.
PCT/KR2018/007885 2017-07-12 2018-07-12 Nouveau dérivé de 1h-pyrazolopyridine et composition pharmaceutique le contenant Ceased WO2019013562A1 (fr)

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JP2020501212A JP7061663B2 (ja) 2017-07-12 2018-07-12 新規な１ｈ－ピラゾロピリジン誘導体およびこれを含む薬学組成物
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US11091447B2 (en) 2020-01-03 2021-08-17 Berg Llc UBE2K modulators and methods for their use
WO2021164697A1 (fr) * 2020-02-18 2021-08-26 深圳市塔吉瑞生物医药有限公司 Dérivé d'amide substitué et composition de celui-ci et son utilisation

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