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WO2025143152A1 - Composé thiazolyle-pyrazolo[1,5-a]pyridine et son utilisation en tant qu'inhibiteur de mylk4 - Google Patents

Composé thiazolyle-pyrazolo[1,5-a]pyridine et son utilisation en tant qu'inhibiteur de mylk4 Download PDF

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Publication number
WO2025143152A1
WO2025143152A1 PCT/JP2024/046238 JP2024046238W WO2025143152A1 WO 2025143152 A1 WO2025143152 A1 WO 2025143152A1 JP 2024046238 W JP2024046238 W JP 2024046238W WO 2025143152 A1 WO2025143152 A1 WO 2025143152A1
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Prior art keywords
compound
pyridin
pyrazolo
thiazol
thiazole
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Japanese (ja)
Inventor
賢一 斉藤
綾香 本城
哲夫 渡辺
邦吉 保田
翼 長崎
東 永華 山口
隆一郎 大下
康智 中島
祐真 村田
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Zenyaku Kogyo KK
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Zenyaku Kogyo KK
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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
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
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    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
    • A61K31/4427—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems
    • A61K31/444—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems containing a six-membered ring with nitrogen as a ring heteroatom, e.g. amrinone
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
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    • A61K31/47—Quinolines; Isoquinolines
    • A61K31/4709—Non-condensed quinolines and containing further heterocyclic rings
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    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
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    • 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
    • A61K31/47—Quinolines; Isoquinolines
    • A61K31/472—Non-condensed isoquinolines, e.g. papaverine
    • A61K31/4725—Non-condensed isoquinolines, e.g. papaverine containing further heterocyclic rings
    • 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
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/496—Non-condensed piperazines containing further heterocyclic rings, e.g. rifampin, thiothixene or sparfloxacin
    • 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
    • A61K31/535—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with at least one nitrogen and one oxygen as the ring hetero atoms, e.g. 1,2-oxazines
    • A61K31/5375—1,4-Oxazines, e.g. morpholine
    • A61K31/5377—1,4-Oxazines, e.g. morpholine not condensed and containing further heterocyclic rings, e.g. timolol
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
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    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/55—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having seven-membered rings, e.g. azelastine, pentylenetetrazole
    • A61K31/551—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having seven-membered rings, e.g. azelastine, pentylenetetrazole having two nitrogen atoms, e.g. dilazep
    • 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
    • A61K31/55—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having seven-membered rings, e.g. azelastine, pentylenetetrazole
    • A61K31/553—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having seven-membered rings, e.g. azelastine, pentylenetetrazole having at least one nitrogen and one oxygen as ring hetero atoms, e.g. loxapine, staurosporine
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    • A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
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    • A—HUMAN NECESSITIES
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    • A61P27/00—Drugs for disorders of the senses
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    • 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
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
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Definitions

  • myosin phosphatase is known as a protein that regulates the amount of phosphorylation of the regulatory light chain of myosin. MLCP dephosphorylates myosin light chain. MLCP activity is controlled by Rho-kinase, which reduces MLCP activity by phosphorylating MLCP. In other words, Rho-kinase prevents the dephosphorylation of myosin light chain by phosphorylating MLCP, and inhibition of Rho-kinase induces a decrease in phosphorylated myosin light chain.
  • a compound of formula (I) or a pharma- ceutically acceptable derivative thereof (In the formula, R 1 to R 5 are each independently hydrogen or a C 1-3 chain aliphatic hydrocarbon; R 6 is an optionally substituted 5- to 10-membered aromatic hydrocarbon, an optionally substituted 5- to 10-membered heterocycle having 1 to 5 heteroatoms independently selected from nitrogen, oxygen, and sulfur as ring-constituting atoms, or a fused ring of any of these with an optionally substituted 4- to 10-membered heterocyclyl having 1 to 3 heteroatoms independently selected from nitrogen, oxygen, and sulfur as ring-constituting atoms.
  • the 5- to 10-membered aromatic hydrocarbon, the 5- to 10-membered heterocycle, and the 4- to 10-membered heterocyclyl forming a condensed ring with these in R 6 are each independently unsubstituted or (1) halogen, nitro, cyano, hydroxy, difluoromethyl, trifluoromethyl, (2) -NR 31 2 , -N(R 31 )(CH 2 ) 1-5 NR 31 2 , -N(R 31 )S(O) 2 R 32 , -N(R 31 )C(O)R 31 , -N(R 31 )C(O)(CH 2 ) 0-3 NR 31 2 , -N(R 31 )C(O)(CH 2 ) 0-3 R 32 , (3) C 1-6 alkyl, -(CH 2 ) 1-5 OR 31 , -(CH 2 ) 1-5 O(CH 2 ) 1-5 OR 31 , -(CH 2 ) 1-5 R 32 ,
  • R6 is The compound according to [1] or a pharma- ceutically acceptable derivative thereof, selected from: [5] 3-(2-(pyrazolo[1,5-a]pyridin-3-yl)thiazol-4-yl)phenol (compound 3), 4-phenyl-2-(pyrazolo[1,5-a]pyridin-3-yl)thiazole (compound 71), 2-Methoxy-5-(2-(pyrazolo[1,5-a]pyridin-3-yl)thiazol-4-yl)phenol (compound 79), 4-(3-fluorophenyl)-2-(pyrazolo[1,5-a]pyridin-3-yl)thiazole (compound 112), 4-(2-fluorophenyl)-2-(pyrazolo[1,5-a]pyridin-3-yl)thiazole (compound 122), 4-(2-(pyrazolo[1,5-a]pyridin-3-yl)thiazol-4-yl
  • MYLK4 myosin light chain kinase 4
  • [13] The compound according to any one of [1] to [5] or a pharma- ceutically acceptable derivative thereof for use as a medicament.
  • [14] The compound according to [13] or a pharma- ceutically acceptable derivative thereof, which is used to inhibit myosin light chain kinase 4 (MYLK4) activity.
  • MYLK4 myosin light chain kinase 4
  • [15] The compound according to [13] or a pharma- ceutically acceptable derivative thereof, which is used for alleviating or treating a disease, disorder, or symptom involving myosin light chain kinase 4 (MYLK4).
  • [18] The compound according to [13] or a pharma- ceutically acceptable derivative thereof, which is used for alleviating or treating glaucoma, ocular hypertension, or aqueous humor outflow disorder.
  • [19] Use of the compound according to any one of [1] to [5] or a pharma- ceutically acceptable derivative thereof for preparing a medicament.
  • [20] The use according to [19] for preparing a medicament for inhibiting myosin light chain kinase 4 (MYLK4) activity.
  • MYLK4 myosin light chain kinase 4
  • MYLK4 myosin light chain kinase 4
  • arteriosclerosis inflammatory bowel disease
  • osteosarcoma ischemic heart disease
  • glaucoma ocular hypertension
  • aqueous humor outflow disorder dry eye
  • uveitis age-related macular degeneration
  • diabetic retinopathy or diabetic retinopathy.
  • [24] The use according to [19] for preparing a medicament for alleviating or treating glaucoma, ocular hypertension, or aqueous humor outflow disorder.
  • a method for inhibiting myosin light chain kinase 4 (MYLK4) activity comprising administering to a patient an amount of the compound according to any one of [1] to [5] or a pharma- ceutically acceptable derivative thereof effective for inhibiting MYLK4 activity.
  • a method for alleviating or treating a disease, disorder, or symptom associated with myosin light chain kinase 4 comprising administering to a patient a therapeutically effective amount of the compound according to any one of [1] to [5] or a pharma- ceutical acceptable derivative thereof.
  • the disease, disorder, or symptom involving myosin light chain kinase 4 is arteriosclerosis, inflammatory bowel disease, osteosarcoma, ischemic heart disease, glaucoma, ocular hypertension, aqueous humor outflow disorder, dry eye, uveitis, age-related macular degeneration, or diabetic retinopathy.
  • a method for alleviating or treating dry eye, uveitis, age-related macular degeneration, or diabetic retinopathy comprising administering to a patient a therapeutically effective amount of the compound according to any one of [1] to [5] or a pharma- ceutical acceptable derivative thereof.
  • a method for alleviating or treating glaucoma, ocular hypertension, or aqueous humor outflow disorder comprising administering to a patient a therapeutically effective amount of the compound according to any one of [1] to [5] or a pharma-ceutically acceptable derivative thereof.
  • halogen and halo mean fluorine, chlorine, bromine, or iodine and are used as a substituent by itself or as a part of a larger substituent or structure.
  • Halide and “halide” refer to a compound to which a halogen has been added, such as fluoride, chloride, bromide, and iodide.
  • hydroxy and “hydroxy group” refer to an --OH group and may be used to represent a substituent by itself or as a part of a larger substituent or structure.
  • cyano and “cyano group” refer to the radical --CN and are used either alone or as a part of a larger substituent or structure.
  • difluoromethyl and difluoromethyl group refer to the -CHF2 group and are used either as the sole substituent or as part of a larger substituent or structure.
  • trifluoromethyl and trifluoromethyl group refer to the -CF3 group and are used either as the sole substituent or as part of a larger substituent or structure.
  • acetyl and acetyl group refer to the group CH 3 --C(O)-- and are used as the sole substituent or as a part of a larger substituent or structure.
  • amino and amino group refer to the -NR2 group (where R is hydrogen or a substituent, including the case where the two R's form a ring structure together with the N) (a functional group excluding one H bonded to the N of ammonia or an amine), and are used as terms indicating a substituent alone or as a part of a larger substituent or structure.
  • amine refers to a compound having an "amino group”.
  • nitro and “nitro group” refer to the -NO2 radical and may be used alone to represent a substituent or as part of a larger substituent or structure.
  • nitro compound refers to a compound that contains a "nitro.”
  • aldehyde aldehyde group
  • formyl and “formyl group” refer to the -CHO group and are used as terms to represent a substituent alone or as a part of a larger substituent or structure.
  • aldehyde compound refers to a compound having an "aldehyde”.
  • carbonyl and “carbonyl group” refer to the divalent radical -C(O)- and are used as the sole substituent or as a part of a larger substituent or structure.
  • thiocarbonyl refers to the divalent radical -C(S)- and may be used as the sole substituent or as a part of a larger substituent or structure.
  • alkyl and alkyl group mean a straight or branched chain saturated hydrocarbon group (monovalent groups represented by the general formula: -C n H 2n+1 ) used alone as a substituent or as part of a larger substituent or structure.
  • alkyl and alkyl group mean a monovalent group when used alone as a substituent, but when used as a term indicating part of a larger substituent or structure, they can mean a divalent or higher valent group, in which case they have the same meaning as “alkylene”.
  • C x-y alkyl means an alkyl having x to y carbon atoms.
  • alkenyl and alkenyl group mean a straight or branched unsaturated hydrocarbon group having at least one double bond (monovalent groups are represented by the general formula: -C n H 2n-1 ) and are used either alone to represent a substituent or as part of a larger substituent or structure.
  • alkenyl and alkenyl group mean a monovalent group when used alone to represent a substituent, but when used as a term indicating a part of a larger substituent or structure, they can mean a divalent or higher valent group, in which case they have the same meaning as "alkenylene".
  • the solvent used varies depending on the starting materials and reagents, and is not particularly limited as long as it does not inhibit the reaction and dissolves the starting materials to some extent. Preferred examples include acetone, toluene, hexane, xylene, dioxane, THF, ethanol, methanol, DME, and DMF.
  • the reaction temperature is usually 80 to 120°C, and the reaction time is 0.5 to 6 hours, but is preferably 1 hour at 100°C.
  • the reduction reaction of the nitro group under neutral conditions is shown, but the reaction conditions are not limited to these conditions, and as an alternative method, the reduction reaction can be carried out using a metal such as zinc, iron, or tin under acidic conditions.
  • the solvent to be used varies depending on the starting material and reagents, and is not particularly limited as long as it does not inhibit the reaction and dissolves the starting material to some extent, but preferred examples include acetonitrile, acetone, toluene, hexane, xylene, dioxane, THF, ethanol, methanol, DME, and DMF.
  • Examples of the Boc-reacting agent include Boc 2 O and Boc-ON.
  • the reaction temperature is usually ⁇ 20 to 80° C., and the reaction time is usually 1 to 48 hours, but is preferably 24 hours at room temperature.
  • Step B a Boc group is used as a protecting group, but the protecting group is not limited thereto, and other protecting groups such as a benzoyl group can also be used without any problem.
  • Step C A carbamate compound in which the amino group is protected with a Boc group is added to a hydrochloric acid dioxane solution to remove the protecting group, and the hydrochloride of the amine can be synthesized. In this reaction, the carbamate compound can also be dissolved in a solvent and an acid can be added thereto.
  • the solvent used varies depending on the starting material and reagents, and is not particularly limited as long as it does not inhibit the reaction and dissolves the starting material to some extent.
  • Preferred solvents include acetonitrile, acetone, toluene, hexane, xylene, dioxane, dichloromethane, ethanol, methanol, DME, DMF, water, and the like.
  • the acid includes nitric acid, sulfuric acid, acetic acid, trifluoroacetic acid, and the like.
  • the reaction temperature is usually ⁇ 20 to 80° C., and the reaction time is 0.5 to 12 hours, but is preferably 1 hour at 0° C.
  • Step A In this reaction, an amine hydrochloride is suspended in dichloromethane, a halide is added thereto, and then a base such as triethylamine is added to synthesize a compound having a desired substituent (R ' ) introduced into an amino group.
  • the solvent used varies depending on the starting materials and reagents, and is not particularly limited as long as it does not inhibit the reaction and dissolves the starting materials to some extent. Preferred examples include acetonitrile, acetone, toluene, hexane, xylene, dioxane, THF, dichloromethane, DME, DMF, and other solvents or mixed solvents thereof.
  • acid scavengers include an equivalent to excess amount of triethylamine, sodium carbonate, potassium carbonate, sodium hydrogen carbonate, sodium hydride, sodium methoxide, sodium ethoxide, sodium hydroxide, potassium hydroxide, DBU, DBN, pyridine, and other bases.
  • the reaction temperature is usually -20 to 80°C, and the reaction time is 1 to 48 hours, but is preferably 0°C for 1 hour.
  • Step A In this condensation reaction, an amine hydrochloride, a carboxylic acid having a desired substituent (R ' ), and a condensing agent such as EDC.HCl are added to an anhydrous solvent such as dichloromethane, and an equivalent to excess amount of a base such as triethylamine is added as an acid scavenger to synthesize various amides.
  • the solvent to be used varies depending on the starting materials and reagents, and is not particularly limited as long as it does not inhibit the reaction and dissolves the starting materials to some extent.
  • the solvent include anhydrous solvents such as dichloromethane, acetonitrile, acetone, toluene, hexane, xylene, dioxane, THF, DME, and DMF.
  • Preferred examples of the acid scavenger include an equivalent to excess amount of triethylamine, sodium carbonate, potassium carbonate, sodium hydrogen carbonate, sodium hydride, sodium methoxide, sodium ethoxide, sodium hydroxide, potassium hydroxide, DBU, DBN, or pyridine.
  • the reaction temperature is -20 to 80°C
  • the reaction time is 1 to 48 hours, but is preferably 24 hours at room temperature. If necessary, a reaction catalyst such as DMAP can be used.
  • EDC was used as the condensation agent, but DCC and other agents can also be used.
  • HOBt and HOAt may be added to prevent epimerization.
  • BOP-based reagents can also be used as the condensation agent, and HATU, TATU, COMU, and other agents can also be used.
  • Step A This reaction is carried out under the same conditions as in Step B described above (reduction of the nitro group with a metal, and protection and deprotection
  • R and A are a bond or any structure (e.g., C 1-5 alkylene, -C(O)-, -(CH 2 ) 0-5 N(R 31 )C(O)(CH 2 ) 0-5 -, -C(R 31 ) 2 C(O)-, -(CH 2 ) 1-5 O(CH 2 ) 1-5 -, -O(CH 2 ) 1-5 -, -(OCH 2 ) 1-5 -, etc.).
  • Step A This reaction is carried out under the same conditions as step C described above (reduction of the nitro group with a metal, and protection and deprotection of the resulting amino group).
  • n is an integer of 0 or more (e.g., an integer from 0 to 3), and R is a hydrogen atom or an arbitrary substituent (e.g., a C1-3 alkyl group).
  • Step A In these reactions, the amine is added to a solvent such as acetonitrile, and a catalytic amount of a base such as DMAP or TEA is added as a catalyst together with an acetylating agent to synthesize an acetylated form.
  • a solvent such as acetonitrile
  • a catalytic amount of a base such as DMAP or TEA
  • an acetylating agent to synthesize an acetylated form.
  • the solvent used varies depending on the starting materials and reagents, and is not particularly limited as long as it does not inhibit the reaction and dissolves the starting materials to some extent.
  • Preferred examples include acetonitrile, acetone, toluene, hexane, xylene, dioxane, THF, dichloromethane, DME, and DMF.
  • examples of acid scavengers include bases such as TEA, DIPEA, sodium carbonate, potassium carbonate, sodium bicarbonate, sodium hydride, sodium methoxide, sodium ethoxide, sodium hydroxide, potassium hydroxide, DBU, DBN, and pyridine.
  • examples of acetylating agents include acetic anhydride and acetyl chloride.
  • the reaction temperature is usually -20 to 80°C, and the reaction time is 1 to 48 hours, but is preferably 24 hours at room temperature.
  • acetyl group Removal reaction of protecting group (acetyl group)
  • an additional reaction represented by the following exemplary reaction formula.
  • n is an integer of 0 or more (e.g., an integer from 0 to 3)
  • R is a hydrogen atom or an arbitrary substituent (e.g., a C1-3 alkyl group).
  • Step A In these reactions, a compound in which the amino group is protected with an acetyl group is suspended in a solvent and reacted under acidic or basic conditions by heating for a predetermined time to deprotect the acetyl group.
  • the solvent used varies depending on the starting materials and reagents, and is not particularly limited as long as it does not inhibit the reaction and dissolves the starting materials to some extent, but preferred examples include methanol, ethanol, dioxane, DME, DMF, water, etc.
  • acids include hydrochloric acid, nitric acid, sulfuric acid, trifluoroacetic acid, hydrobromic acid, etc.
  • bases include sodium hydroxide, potassium hydroxide, lithium hydroxide, etc.
  • the reaction temperature is usually 50 to 160°C, and the reaction time is 0.5 to 24 hours, but is preferably 1 hour at 100°C.
  • Step A In this reaction, a phthalimide derivative and hydrazine monohydrate are added to a solvent such as ethanol, and the mixture is heated for a predetermined time to react and deprotect the amine derivative.
  • the solvent used varies depending on the starting materials and reagents, and is not particularly limited as long as it does not inhibit the reaction and dissolves the starting materials to some extent.
  • Preferred examples include ethanol, methanol, water, dichloromethane, THF, DMF, toluene, chloroform, acetonitrile, diethyl ether, 1-butanol, isopropanol, acetic acid, acetone, benzene, tert-butanol, and DMSO.
  • alkylation reaction When a compound having an amino functional group, such as an acetamide group, is synthesized in the main reaction or in an additional reaction, an alkyl group can be introduced to the amino group by an additional reaction represented by the following reaction scheme: (wherein R ' is a bond or any structure (e.g., C 1-3 alkylene), R '' is any group (e.g., C 1-3 alkyl, C(O)C 1-3 alkyl), R ''' is an alkyl group (e.g., C 1-3 alkyl), etc.)
  • Step A In this reaction, a compound having an amino functional group such as an acetamide group is added to a suspension of sodium hydride in a solvent such as DMF, and an alkyl halide (Halo-R ''' ) is added dropwise to react with the mixture to obtain an N-alkylamide.
  • the solvent used varies depending on the starting materials and reagents, and is not particularly limited as long as it does not inhibit the reaction and dissolves the starting materials to some extent.
  • Preferred examples of the solvent include THF, DME, and DMF.
  • strong bases include bases such as sodium hydride, sodium methoxide, sodium ethoxide, sodium butoxide, sodium hydroxide, potassium hydroxide, DBU, and DBN.
  • the reaction temperature is usually -20 to 50°C, and the reaction time is 1 to 24 hours, but is preferably 1 hour at 0°C.
  • n is an integer of 0 or more (e.g., an integer of 0 to 3).
  • Step B A compound having an amide group can be reacted with a strong base in a dry DMF solution and then with an alkyl halide to synthesize an N-alkylamide.
  • reaction of Hydroxyl Group with Halide When a derivative having a hydroxyl group is synthesized in the main reaction or in an additional reaction, the derivative can be subjected to an additional reaction represented by the following reaction formula to introduce a desired substituent (R ' ) into the hydroxyl group, thereby synthesizing an ether (phenoxy ether) compound.
  • Step A In this reaction, the ester compound is added to a solvent such as a mixed solvent of aqueous sodium hydroxide and ethanol, and the mixture is heated and stirred for a predetermined time to react, followed by acid-base treatment to obtain a carboxylic acid.
  • the solvent used varies depending on the starting materials and reagents, and is not particularly limited as long as it does not inhibit the reaction and dissolves the starting materials to some extent, but preferred examples include methanol, ethanol, dioxane, DME, DMF, and water.
  • strong bases include sodium hydroxide, potassium hydroxide, sodium hydride, sodium methoxide, sodium ethoxide, sodium butoxide, DBU, and DBN.
  • the reaction temperature is usually 30 to 140°C, and the reaction time is 1 to 24 hours, but is preferably 1 hour at 100°C.
  • Halo is a halogen such as iodine, bromine, chlorine, or fluorine, and is preferably bromine.
  • Step A In this reaction, an amine derivative is reacted with phthalic anhydride to obtain a phthalimide derivative in which the amino group is protected.
  • the reaction is carried out in a solvent or without a solvent in the presence of an acid.
  • the solvent used varies depending on the starting material, reagents, etc., and is not particularly limited as long as it does not inhibit the reaction and dissolves the starting material to some extent, but examples of the solvent include ethanol, methanol, DMF, toluene, water, and dichloromethane.
  • the acid used varies depending on the starting material, solvent used, etc., and is not particularly limited as long as it does not inhibit the reaction, but preferably includes acetic acid, sulfuric acid, etc.
  • the reaction is carried out in a solvent or without a solvent and in the presence of an acid.
  • the solvent used varies depending on the starting material, reagents, etc., and is not particularly limited as long as it does not inhibit the reaction and dissolves the starting material to a certain extent, but preferably includes chloroform, dichloromethane, diethyl ether, dioxane, methanol, ethanol, DMF, THF, acetonitrile, etc.
  • the acid used varies depending on the starting material, solvent used, etc., and is not particularly limited as long as it does not inhibit the reaction, but preferably includes acetic acid, hydrobromic acid, p-toluenesulfonic acid, hydrochloric acid, sulfuric acid, etc.
  • the reaction temperature is 0 to 90° C.
  • the reaction time is 1 to 12 hours, but is preferably 70° C. and 1 hour.
  • Step B In this reaction, the compound represented by formula (X) is dissolved in a solvent such as toluene together with carbon tetrabromide and triphenylphosphine, and the mixture is heated for a predetermined time to react, whereby the Appel reaction proceeds to obtain the corresponding halide.
  • a solvent such as toluene together with carbon tetrabromide and triphenylphosphine
  • the solvent used varies depending on the reagents, etc., and is not particularly limited as long as it does not inhibit the reaction and dissolves the starting materials to some extent, but preferred examples include DME, acetone, toluene, hexane, xylene, acetonitrile, ethyl acetate, dioxane, THF, ethanol, methanol, dichloromethane, chloroform, dichloroethane, DMF, water, etc.
  • the reaction reagent in addition to carbon tetrabromide, carbon tetrachloride, etc. can be used.
  • the reaction temperature is 0 to 200°C
  • the reaction time is 1 to 24 hours, but preferably, it is 1 hour at 110°C.
  • the compound of formula (V) which is a starting material may be a commercially available product, but can be obtained, for example, by the reaction shown below.
  • R 1 to R 5 are as defined in formula (I) above, and Tf represents triflate.
  • Step A In this reaction, the compound represented by formula (X) is dissolved in a solvent such as dichloromethane together with N-phenylbis(trifluoromethanesulfonimide) and a base, and reacted to obtain the corresponding triflate compound.
  • the starting material may be a commercially available product, but can be obtained, for example, as shown in the following reaction scheme.
  • Step A In this reaction, the compound represented by formula (V) is dissolved in a solvent such as DME, acetone, toluene, hexane, xylene, acetonitrile, ethyl acetate, dioxane, THF, ethanol, methanol, dichloromethane, chloroform, dichloroethane, DMF, or water, and a diborane compound such as 4,4,4',4',5,5,5',5'-octamethyl-2,2'-bi(1,3,2-dioxaborolane) or 4,4,4',
  • a solvent such as DME, acetone, toluene, hexane, xylene, acetonitrile, ethyl acetate, dioxane, THF, ethanol, methanol, dichlorome
  • Thiazolyl-pyrazolo[1,5-a]pyridine derivatives may take the form of a hydrate, a solvate, or a pharma- ceutically acceptable salt (an acid addition salt or a base addition salt), a prodrug, etc.
  • Thiazolyl-pyrazolo[1,5-a]pyridine or a derivative thereof includes various isomers.
  • “Pharmaceutically acceptable salt” means a salt that is pharmaceutically acceptable and capable of exerting the desired pharmacological activity of the parent compound.
  • “Pharmaceutically acceptable salt” means a salt that is pharmaceutically acceptable and capable of exerting the desired pharmacological activity of the parent compound.
  • Examples of pharma- ceutically acceptable acid addition salts include those with inorganic acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, and phosphoric acid; as well as those with acetic acid, trifluoroacetic acid, propionic acid, hexanoic acid, cyclopentanepropionic acid, glycolic acid, pyruvic acid, lactic acid, oxalic acid, maleic acid, malonic acid, succinic acid, fumaric acid, malic acid, tartaric acid, citric acid, benzoic acid, cinnamic acid, 3-(4-hydroxybenzoyl)benzoic acid, mandelic acid, methanesulfonic acid, ethanesulfonic acid, 1,2-ethanedisulfonic acid, 2-hydroxybenzoylbenzoic acid, and 2-hydroxybenzoylbenzoic acid.
  • inorganic acids such as hydrochloric acid, hydrobromic acid, sulfuric acid,
  • salts include those formed by the addition of organic acids such as ethanesulfonic acid, benzenesulfonic acid, 4-chlorobenzenesulfonic acid, 2-naphthalenesulfonic acid, 4-toluenesulfonic acid, camphorsulfonic acid, glucoheptonic acid, 4,4'-methylenebis-(3-hydroxy-2-ene-1-carboxylic acid), 3-phenylpropionic acid, trimethylacetic acid, tert-butylacetic acid, lauryl sulfuric acid, gluconic acid, glutamic acid, hydroxynaphthoic acid, stearic acid, muconic acid, and salicylic acid.
  • organic acids such as ethanesulfonic acid, benzenesulfonic acid, 4-chlorobenzenesulfonic acid, 2-naphthalenesulfonic acid, 4-toluenesulfonic acid, camphorsulfonic acid, glu
  • Examples of pharma- ceutically acceptable base addition salts include salts in which an acidic proton present in the parent compound is replaced by a metal ion, such as, for example, sodium, potassium, lithium, ammonium, calcium, magnesium, iron, zinc, copper, manganese, and aluminum salts.
  • salts derived from organic bases such as, for example, primary, secondary, and tertiary amines, substituted amines, and cyclic amines, are also included.
  • organic bases include, for example, isopropylamine, trimethylamine, diethylamine, triethylamine, tripropylamine, ethanolamine, 2-dimethylaminoethanol, dicyclohexylamine, lysine, arginine, histidine, caffeine, procaine, hydrabamine, choline, betaine, ethylenediamine, glucosamine, methylglucamine, theobromine, purine, piperazine, piperidine, N-ethylpiperidine, tromethamine, N-methylglucamine, and polyamine resins.
  • Representative organic bases include, for example, isopropylamine, diethylamine, ethanolamine, trimethylamine, dicyclohexylamine, choline, and caffeine.
  • Solvates include hydrates as well as organic solvent solvates such as dimethylsulfoxide solvates, dimethylformamide solvates, or alcohol solvates such as ethanol solvates, methanol solvates, or n-propyl alcohol solvates.
  • the compound or its pharma- ceutically acceptable salt or solvate can exist in an amorphous form.
  • amorphous form can be produced by various methods well known in the art.
  • various crystalline forms, including amorphous forms can be produced by melting methods, extruders, etc.
  • the amorphous form can also be provided in the form of a solid dispersion containing excipients, etc. (However, even for the compounds, raw materials, and reagents described so far, it is essential to take measures against the following points. First, when using compounds that increase the risk of contamination with nitrosamines in pharmaceuticals, great care must be taken.
  • prodrug refers to a compound that is converted into the present compound (the compound of formula (I)) by a reaction such as oxidation, reduction, hydrolysis, etc. catalyzed by an enzyme or the like under physiological conditions in a living body.
  • prodrugs include: (1) A compound in which the amino of the present compound is acylated, alkylated or phosphorylated (for example, a compound in which the amino of compound (I) is eicosanoylated, alanylated, pentylaminocarbonylated, (5-methyl-2-oxo-1,3-dioxolen-4-yl)methoxycarbonylated, tetrahydrofuranylated, pyrrolidylmethylated, pivaloyloxymethylated, tert-butylated, ethoxycarbonylated, tert-butoxycarbonylated, acetylated or cyclopropylcarbonylated); (2) A compound in which the hydroxyl of the present compound is acylated, alkylated, phosphorylated or borated (e.g., a compound in which the hydroxyl of compound (I) is acetylated, palmitoylated, propanoyl
  • prodrugs are described in detail, for example, in T. Higuchi and V. Stella, "Pro-drugs as Novel Delivery Systems", Vol. 14 of the A.C.S. Symposium Series, Bioreversible Carriers in Drug Design, ed. Edward B. Roche, American Pharmaceutical Association and Pergamon Press, 1987, and Hirokawa Shoten, 1990, "Drug Development", Vol. 7, Molecular Design, pp. 163 to 198, the contents of which are incorporated herein by reference.
  • Thiazolyl-pyrazolo[1,5-a]pyridine or its derivatives can take various isomeric forms, such as geometric isomers, optical isomers, rotational isomers, stereoisomers, tautomers, etc. These isomers can be purified and isolated using conventional separation methods, such as recrystallization, the diastereomeric salt method, enzymatic resolution, and various types of chromatography (e.g., thin layer chromatography, column chromatography, gas chromatography, etc.).
  • the compound of formula (I) can inhibit myosin light chain kinase 4 (MYLK4) activity. Therefore, the compound of formula (I) or a pharma- ceutical acceptable derivative thereof, or a pharmaceutical composition containing the same, can be used to inhibit MYLK4 activity in a biological sample or in a living body. In addition, the compound of formula (I) or a pharma- ceutical acceptable derivative thereof, or a pharmaceutical composition containing the same, can be used to prevent, alleviate, or treat diseases, disorders, or symptoms associated with MYLK4 through its MYLK4 activity inhibitory action.
  • MYLK4 myosin light chain kinase 4
  • MYLK4 Diseases, disorders, or symptoms in which MYLK4 may be involved include, for example, arteriosclerosis, inflammatory bowel disease, osteosarcoma, ischemic heart disease, glaucoma, ocular hypertension, aqueous humor outflow disorder, dry eye, uveitis, age-related macular degeneration, or diabetic retinopathy. Therefore, the compound of formula (I) or its pharma- ceutical acceptable derivative, or a pharmaceutical composition containing the same, can be used to prevent, alleviate, and/or treat these diseases, disorders, or symptoms.
  • it is effective in preventing, alleviating, and/or treating arteriosclerosis, inflammatory bowel disease, osteosarcoma, ischemic heart disease, glaucoma, ocular hypertension, aqueous humor outflow disorder, dry eye, uveitis, age-related macular degeneration, or diabetic retinopathy, particularly glaucoma, ocular hypertension, or aqueous humor outflow disorder, and is particularly effective when used to reduce intraocular pressure in a subject.
  • compositions can be prepared by mixing an effective amount of the compound of formula (I) or a pharma- ceutically acceptable derivative thereof with a pharma- ceutically acceptable carrier and other auxiliary agents, if necessary. It is to be noted that the compound of formula (I) or a derivative thereof may be used as a medicine in its original form.
  • the pharmaceutical composition can be administered orally or parenterally.
  • the dosage form includes, for example, tablets, fine granules, coated tablets, powders, granules, pills, capsules (e.g., hard gelatin capsules, soft gelatin capsules), microcapsules, and syrups.
  • the dosage form includes, for example, injections (including lyophilized injections that are dissolved when used), eye drops, lotions, aerosols, ointments, patches, and suppositories. It can also be prepared as a liposome.
  • the compound of formula (I) or a pharma- ceutical acceptable derivative thereof can be pre-dispersed in a pharma-ceutical acceptable solvent to prepare a liquid, and in this case, for example, it can be a syrup for oral administration, an injection for parenteral administration (including lyophilized injections that are dissolved when used), or eye drops.
  • compositions may also be administered, for example, as solutions, suspensions, emulsions, microemulsions, multiple emulsions, foams, salves, pastes, plasters, ointments, coated tablets, rinses, rectal capsules, drops, gels, sprays, powders, aerosols, inhalants, eye drops, eye ointments, eye rinses, infusions, or implants.
  • the pharmaceutical composition can be in various dosage forms, and can be prepared by blending various carriers (excipients) and, if necessary, various auxiliary agents, depending on the dosage form, administration method, etc.
  • auxiliary agent include coloring agents, sweetening agents, flavoring agents, binders, adsorbents, lubricants, disintegrating agents, softeners, suspending agents, emulsifying agents, preservatives, antioxidants, surfactants, stabilizers, pH adjusters, dispersing agents, isotonic agents, wetting agents, solubilizers, solubilization aids, and/or absorption enhancers.
  • carriers include crystalline cellulose, sugars (glucose, sucrose, lactose, D-mannitol, D-sorbitol, etc.), starches (corn starch, potato starch, wheat starch, rice starch, etc.), magnesium silicate, sodium hydrogen phosphate, calcium hydrogen phosphate, sodium citrate, talc, etc.
  • Disintegrants include, for example, sodium carbonate, calcium carbonate, gum arabic, starches (corn starch, potato starch, wheat starch, tapioca starch, rice starch, etc.), agar, alginic acid, silicate complexes, tragacanth, crystalline cellulose, low-substituted hydroxypropyl cellulose, croscarmellose sodium, carmellose calcium, carmellose sodium, and sodium carboxymethyl starch.
  • Binders include, for example, cellulose derivatives, starch, alginates, gelatin, polyvinylpyrrolidone, sucrose, and gum acacia.
  • Wetting agents include, for example, glycerol, cetyl alcohol, and glycerol monostearate, magnesium stearate, talc, calcium stearate, solid polyethylene glycols, sodium lauryl sulfate, and the like.
  • absorption enhancers include quaternary ammonium compounds.
  • Adsorbents include, for example, kaolin and bentonite.
  • lubricants examples include carnauba wax, hardened oil, magnesium stearate, calcium stearate, sodium hydrogen phosphate, calcium hydrogen phosphate, and white beeswax.
  • preservatives include paraben, chlorobutanol, phenol, sorbic acid, and benzalkonium chloride.
  • compositions in liquid dosage forms for oral administration include pharma- ceutical acceptable emulsions, solutions, suspensions, syrups, and elixirs.
  • Pharmaceutical compositions in such dosage forms are generally prepared by dissolving or dispersing the ingredients in a carrier, such as, for example, distilled water, saline, aqueous dextrose, glycerol, ethanol, isopropyl alcohol, ethyl carbonate, ethyl acetate, benzyl alcohol, benzyl benzoate, propylene glycol, 1,3-butylene glycol, dimethylformamide, and other solubilizers and emulsifiers; oils, such as cottonseed oil, peanut oil, corn germ oil, olive oil, castor oil, and sesame oil, glycerol, tetrahydrofurfuryl alcohol, polyethylene glycols, and sorbitan fatty acid ester oils; or mixtures of these substances, to form a solution or suspension.
  • Liquid dosage forms of pharmaceutical compositions may contain suspending agents, solubilizing agents, or solubilizing agents as necessary.
  • suspending agents include ethoxylated isostearyl alcohols, polyoxyethylene sorbitol and sorbitan esters, microcrystalline cellulose, aluminum metahydroxide, bentonite, agar, and tragacanth.
  • solubilizing agents include ethanol, dilute hydrochloric acid, sodium hydroxide, sodium bicarbonate, olive oil, squalene, squalane, physiological saline, water for injection, rapeseed oil, glucose, propylene glycol, polysorbate, and macrogol.
  • solubilizing agents include L-arginine, ⁇ -cyclodextrin, ⁇ -cyclodextrin, D-sorbitol, soybean oil, urea, white sugar, hydroxypropyl cellulose, hypromellose, povidone, and D-mannitol.
  • compositions suitable for injection may be in the form of physiologically acceptable aqueous or non-aqueous sterile solutions, dispersions, suspensions or emulsions, or sterile powders to be reconstituted into sterile injectable solutions and/or dispersions when used.
  • suitable aqueous or non-aqueous carriers, diluents, solvents or vehicles include, for example, distilled water, ethanol, polyols (propylene glycol, polyethylene glycol, glycerol, etc.), suitable mixtures thereof, vegetable oils (e.g. olive oil, etc.), or injectable organic esters such as ethyl oleate.
  • aqueous or non-aqueous carriers, diluents, solvents or vehicles may further contain suitable salts, pH adjusters, etc., such as physiological saline. Also, suspending agents, solubilizers, or solubilizing agents may be included as necessary. In addition, agents for delaying the absorption of injectable drugs, such as aluminum monostearate and gelatin, may be used.
  • pH adjusters, buffers, stabilizers, preservatives, etc. are added as necessary, and the injections or eye drops are prepared in a usual manner as subcutaneous, intramuscular, or intravenous injections.
  • the solution may be placed in a container, and then freeze-dried or otherwise made into a solid preparation, which can be prepared just before use. A single dose may be placed in a container, or multiple doses may be placed in the same container.
  • compositions suitable for rectal administration are usually prepared, for example as suppositories, using non-irritating excipients that are solid at room temperature but melt at body temperature to release the active ingredient in the appropriate body cavity, such as cocoa butter, polyethylene glycol, or certain waxes.
  • compositions in dosage forms for topical application include ointments, powders, sprays, and inhalants.
  • the pharmaceutical composition is usually prepared by mixing the ingredients under sterile conditions with a pharma- ceutical acceptable carrier and, if necessary, any preservatives, buffers, or propellants.
  • Ophthalmic preparations, ointments, powders, and solutions are typical examples of topical applications, and suitable carriers (excipients) and adjuvants will be apparent to those skilled in the art.
  • any dosage form suitable for the desired delivery route may be used, for example, orally, transdermally, intradermally, intrabronchially, intranasally, intraarterially, intravenously, intramuscularly, subcutaneously, intraperitoneally, vaginally, rectally, sublingually, intracranially, epidurally, intratracheally, intraocularly or at other localized sites.
  • a mammal e.g., mouse, rat, hamster, rabbit, cat, dog, cow, sheep, monkey, human
  • any dosage form suitable for the desired delivery route may be used, for example, orally, transdermally, intradermally, intrabronchially, intranasally, intraarterially, intravenously, intramuscularly, subcutaneously, intraperitoneally, vaginally, rectally, sublingually, intracranially, epidurally, intratracheally, intraocularly or at other localized sites.
  • the compounds of the present invention can be produced, for example, by the methods described in the following examples, and the effects of the compounds can be confirmed by the methods described in the following examples.
  • sica gel in “silica gel column chromatography” described in this example refers to Wakogel C-200 (particle size 75-150 ⁇ m) manufactured by Fujifilm Wako Pure Chemical Industries, Ltd., or Cartridge (Universal Column Premium, particle size 30 ⁇ m) manufactured by Yamazen Corporation.
  • TLC in the "preparative TLC” described in this example means Merck TLC glass plate silica gel 60F254 (0.5 mm, 1 mm, 2 mm) unless otherwise specified.
  • Reduced pressure refers to a state of reduced pressure of approximately 1 to 50 mmHg using a vacuum pump or similar.
  • Root temperature refers to the range of approximately 10°C to 30°C. Percentages are by weight unless otherwise specified.
  • the filtrate was concentrated under reduced pressure to about 50 mL, and an excess of anhydrous dibutoxycarbonyl solution (8 mL) was added under ice cooling, and the mixture was stirred at room temperature for 16 hours.
  • the solvent was distilled off from the reaction solution under reduced pressure, and the residue was purified by silica gel column chromatography to obtain the title compound (1-2) (1.31 g, 3.37 mmol, yield 41.1%) from the n-hexane:ethyl acetate (1:1) fraction.
  • compound (65) was synthesized from compound (10), compound (81) from compound (74), and compound (80) was synthesized from compound (72-1).
  • reaction solution was poured into ice water (100 mL) and dissolved.
  • the insoluble matter was filtered off to obtain the sodium salt of the title compound (73) (27.4 mg, 0.20 mmol, yield 64.9%).
  • the aqueous layer was made weakly acidic by adding 2N hydrochloric acid, and the precipitated solid was stirred for a while, then filtered, washed thoroughly with water, and dried to obtain the title compound (73) (27.4 mg, 0.067 mmol, yield 49.6%).
  • Potassium carbonate (0.1 g, 0.72 mmol) was added to a solution of pyrazolo[1,5-a]pyridine-3-carbothioamide (75 mg, 0.4 mmol) and 1-(2-amino-4-methylthiazol-5-yl)-2-bromoethan-1-one (100 mg, 0.4 mmol) in acetone (3 mL), and the mixture was stirred at room temperature for 12 hours. Water (20 mL) was added, and the resulting precipitate was filtered by suction, washed with methanol and diethyl ether in this order, and dried to obtain a crude compound.
  • the reaction solution was heated at 180° C. for 20 minutes using a microwave heating device. Water (3 mL) was added to the reaction solution, and the resulting precipitate was collected by suction filtration to obtain a crude product.
  • the crude product was purified by preparative TLC (preparative thin layer chromatography), and the title compound (165) (6.40 mg, 0.0240 mmol, yield 40.1%) was obtained from the dichloromethane:methanol (30:1) fraction.
  • reaction solution was neutralized with a saturated aqueous solution of sodium bicarbonate, and then extracted with dichloromethane.
  • the organic layer was washed with saturated saline, dried over sodium sulfate, and then filtered, and the solvent was distilled off under reduced pressure.
  • the residue was purified by silica gel column chromatography, and the title compound (177) (13.0 mg, 0.0401 mmol, yield 53.1%) was obtained from the dichloromethane:methanol fraction (5:1).
  • reaction solution was neutralized with a saturated aqueous solution of sodium bicarbonate, and then extracted with dichloromethane.
  • the organic layer was dried over sodium sulfate, filtered, and the solvent was removed under reduced pressure.
  • the residue was purified by column chromatography (amino silica gel), and the title compound (182) (29.2 mg, 0.0868 mmol, yield 68.2%) was obtained from the dichloromethane:methanol (20:1) fraction.
  • the reaction solution was heated at 170° C. for 1.5 hours using a microwave heating device. Water (5 mL) was added to the reaction solution, and the resulting precipitate was collected by suction filtration. The residue was purified by silica gel column chromatography, and the title compound (193-1) (117 mg, 0.345 mmol, yield 28.4%) was obtained from the dichloromethane:methanol (20:1) fraction.
  • the reaction solution was heated at 180° C. for 1.5 hours using a microwave heating device. Water (15 mL) was added to the reaction solution, and the resulting precipitate was collected by suction filtration. The residue was purified by silica gel column chromatography, and the title compound (194-1) (131 mg, 0.450 mmol, yield 25.2%) was obtained from the dichloromethane:methanol (20:1) fraction.
  • reaction solution was warmed to room temperature and stirred for 5 hours.
  • Water (15 mL) was added to the reaction solution, and the mixture was extracted with dichloromethane.
  • the organic layer was dried over sodium sulfate, and then insoluble matter was filtered off.
  • the organic layer was distilled off under reduced pressure.
  • the residue was purified by preparative thin-layer chromatography (TLC), and the title compound (194-2) (16.5 mg, 0.0416 mmol, yield 15.6%) was obtained from the dichloromethane:methanol (30:1) fraction.
  • reaction solution was diluted with ethyl acetate, and then washed with a saturated aqueous ammonium chloride solution and saturated saline.
  • organic layer was dried over anhydrous sodium sulfate, filtered, and the solvent was distilled off under reduced pressure.
  • the residue was purified by silica gel column chromatography, and the title compound (195) (25.2 mg, 0.0709 mmol, yield 45.5%) was obtained from the dichloromethane:methanol (10:1) fraction.
  • the reaction solution was neutralized with a saturated aqueous solution of sodium bicarbonate and extracted twice with dichloromethane.
  • the organic layer was dried over anhydrous sodium sulfate, filtered, and the solvent was distilled off under reduced pressure.
  • the residue was purified by silica gel column chromatography to obtain a crude product from the dichloromethane:methanol (10:1) fraction.
  • the crude product was subjected to preparative TLC (preparative thin layer chromatography) to obtain the title compound (197) (3.10 mg, 0.00999 mmol, yield 10.5%) from the dichloromethane:methanol (10:1) fraction.
  • 2-Bromopyrimidine (35.6 mg, 0.224 mmol), potassium carbonate (42.2 mg, 0.306 mmol), and Pd(PPh 3 ) 4 (23.5 mg, 0.0203 mmol) were added to a solution of 2-(pyrazolo[1,5-a]pyridin-3-yl)-4-(4,4,5,5-tetraethyl-1,3,2-dioxaborolan-2-yl)thiazole (compound 181-1) (78.1 mg, 0.204 mmol) in DME ( 2 mL), and the mixture was heated at 160° C. for 10 minutes using a microwave synthesis apparatus. After cooling, water was added and the mixture was extracted with dichloromethane.
  • reaction solution was neutralized with a saturated aqueous solution of sodium bicarbonate, and then extracted with dichloromethane.
  • the organic layer was dried over sodium sulfate, filtered, and the solvent was distilled off under reduced pressure.
  • the residue was purified by column chromatography (amino silica gel), and the title compound (204) (10.3 mg, 0.0303 mmol, yield 64.8%) was obtained from the dichloromethane:methanol (20:1) fraction.
  • reaction solution was neutralized with a saturated aqueous solution of sodium bicarbonate, and then extracted with dichloromethane.
  • the organic layer was dried over sodium sulfate, filtered, and the solvent was distilled off under reduced pressure.
  • the residue was purified by column chromatography (amino silica gel), and the title compound (205) (10.7 mg, 0.0315 mol, yield 48.2%) was obtained from the dichloromethane:methanol (20:1) fraction.
  • reaction solution was neutralized with a saturated aqueous solution of sodium bicarbonate, and then extracted with dichloromethane.
  • the organic layer was dried over sodium sulfate, filtered, and the solvent was distilled off under reduced pressure.
  • the residue was purified by preparative TLC (preparative thin layer chromatography), and the title compound (206) (27.9 mg, 0.0865 mmol, yield 53.3%) was obtained from the dichloromethane:methanol (20:1) fraction.
  • reaction solution was concentrated under reduced pressure, and the resulting residue was dissolved in DMF (3 mL), and water (0.5 mL), 5-methylpyrazolo[1,5-a]pyridine-3-carbothioamide (67.7 mg, 0.354 mmol), and cesium carbonate (231 mg, 0.708 mmol) were added, followed by stirring at 70° C. for 1 hour. After cooling, water was added, and the precipitated solid was collected by suction filtration. The obtained solid was suspended in diethyl ether, filtered, and dried to obtain the title compound (213) (16.3 mg, 0.0448 mmol, yield 12.7%).
  • MYLK4 inhibitory activity (kinase assay) (Abbreviations) The meanings of the abbreviated symbols in the following tests are as follows: ATP: Adenosine triphosphate ADP: Adenosine diphosphate BSA: bovine serum albumin DMSO: dimethyl sulfoxide DTT: dithiothreitol EDTA: ethylenediaminetetraacetic acid EGTA: glycol ether diaminetetraacetic acid IOP: intraocular pressure MOPS: 3-morpholinopropanesulfonic acid MYLK: myosin light chain kinase ROCK: Rho kinase
  • MLC peptide is a peptide based on a partial sequence of LC20 recombinant protein, and has the same phosphorylation site.
  • a 96-well half-area microplate (Greiner) was used, and 12.5 ⁇ L of assay buffer (5 mM MOPS (pH 7.2), 2.5 mM ⁇ -glycerol phosphate, 5 mM MgCl 2 , 1 mM EGTA, 0.4 mM EDTA, 0.05 mM DTT, 200 ⁇ g/mL BSA) was used to measure the activity of the test substance (final concentration 1 nM to 10 ⁇ M), MYLK4 recombinant protein (SignalChem, final concentration 8 ⁇ g/mL), LC20 recombinant protein (SignalChem, final concentration 20 ⁇ g/mL), or MLC Peptide (SignalChem, final concentration 40 ⁇ g/mL) and ATP (Promega, final concentration 50 ⁇ M) were mixed and the kinase reaction was carried out at 30 ° C.
  • assay buffer 5 mM MOPS (pH 7.2), 2.5 m
  • test substance was diluted in DMSO to a concentration 1000 times the final concentration, and serially diluted with assay buffer.
  • Kinase activity was measured using ADP-Glo (registered trademark) Kinase Assay (Promega), and the operation was performed according to the procedure manual.
  • the amount of luminescence obtained from the reaction in each well was measured using SpectraMax (registered trademark) iD3 (MOLECULAR DEVICES). The amount of luminescence when a solvent was added instead of the test compound was 100%, and the amount of luminescence when MYLK4 was not added and the kinase reaction did not proceed was 0%, and the luminescence rate in the presence of the test substance was calculated.
  • the luminescence rate was plotted against the concentration of the test substance added, and the concentration of the test substance required to inhibit 50% of the kinase activity of MYLK4 ( IC50 value) was calculated from the obtained regression curve (dosersplgst).
  • Test Results The IC50 value of each compound for the enzyme activity of MYLK4 is shown in the table below. The results when LC20 recombinant protein was used as the substrate are shown in Tables 1-1 and 1-2, and the results when MLC peptide was used are shown in Table 2.
  • Animals and administration method Normal intraocular pressure rabbits (Kbl: NZW, male, 11-12 weeks old) were used in the experiment. Blank was instilled into the left eye, and 50 ⁇ L of the test compound solution was instilled into the right eye. The same test compound solution was instilled into the same animal at increasing concentrations, with one week between each instillation.
  • Intraocular pressure (IOP) measurement method After topical anesthesia with instillation of 0.4% Benoxil ophthalmic solution (Santen Pharmaceutical Co., Ltd.), intraocular pressure was measured using a pneumatic plane tonometer (Model 30 Classic, Reichert). The intraocular pressure was measured before administration of a blank or test compound solution (0 hour) and 0.5, 1, 2, 4, 8, and 24 hours after administration.
  • IOP Intraocular pressure
  • test compound solutions at concentrations of 1 mg/mL and 4 mg/mL exhibited a maximum decrease in intraocular pressure 2 hours after administration.
  • test compound A 1 mg/mL solution of the test compound was observed to reduce intraocular pressure to a maximum level 4 hours after administration.
  • intraocular pressure was measured using a pneumatic plane tonometer (Model 30 Classic, Reichert). The intraocular pressure was measured before (0 hour) and 0.5, 1, 2, 4, 8, and 24 hours after administration of a blank or test compound solution.

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Abstract

La présente invention concerne un nouveau composé qui inhibe l'activité de MYLK4, et son utilisation pharmaceutique.　L'invention concerne un composé de formule (I) (dans laquelle R1 à R5 sont chacun indépendamment hydrogène ou un hydrocarbure aliphatique à chaîne en C1-3, et R6 est un hydrocarbure aromatique de 5 à 10 chaînons éventuellement substitué, un hétérocycle de 5 à 10 chaînons éventuellement substitué ayant de 1 à 5 hétéroatomes choisis chacun indépendamment parmi l'azote, l'oxygène et le soufre en tant qu'atome(s) cyclique(s), ou un cycle fusionné dans lequel l'un quelconque de l'hydrocarbure aromatique et de l'hétérocycle est fusionné avec un hétérocyclyle de 4 à 10 chaînons éventuellement substitué ayant de 1 à 3 hétéroatomes sélectionnés chacun indépendamment parmi l'azote, l'oxygène et le soufre en tant qu'atome(s) cyclique(s)) ou un dérivé pharmaceutiquement acceptable de celui-ci, et une utilisation pharmaceutique du composé ou du dérivé.
PCT/JP2024/046238 2023-12-27 2024-12-26 Composé thiazolyle-pyrazolo[1,5-a]pyridine et son utilisation en tant qu'inhibiteur de mylk4 Pending WO2025143152A1 (fr)

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Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JP2012516329A (ja) * 2009-01-30 2012-07-19 ミレニアム ファーマシューティカルズ， インコーポレイテッド Ｐｉ３ｋ阻害剤としてのヘテロアリールおよびその使用
CN113336751A (zh) * 2021-05-31 2021-09-03 南京谷睿生物科技有限公司 一种高效盐诱导激酶抑制剂及其制备方法
JP2022504988A (ja) * 2018-10-16 2022-01-13 ダナ－ファーバー キャンサー インスティテュート，インコーポレイテッド Ｌｒｒｋ２の野生型および変異型のアザインドール阻害剤
US20220144823A1 (en) * 2019-02-25 2022-05-12 Galapagos Nv Pyrazolopyridine derivatives as inhibitors of pask

Patent Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JP2012516329A (ja) * 2009-01-30 2012-07-19 ミレニアム ファーマシューティカルズ， インコーポレイテッド Ｐｉ３ｋ阻害剤としてのヘテロアリールおよびその使用
JP2022504988A (ja) * 2018-10-16 2022-01-13 ダナ－ファーバー キャンサー インスティテュート，インコーポレイテッド Ｌｒｒｋ２の野生型および変異型のアザインドール阻害剤
US20220144823A1 (en) * 2019-02-25 2022-05-12 Galapagos Nv Pyrazolopyridine derivatives as inhibitors of pask
CN113336751A (zh) * 2021-05-31 2021-09-03 南京谷睿生物科技有限公司 一种高效盐诱导激酶抑制剂及其制备方法

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Title
DATABASE Registry 6 April 2021 (2021-04-06), ANONYMOUS: "Pyrazolo[1,5-a]pyridine, 3-[4-(4-fluorophenyl)-2-thiazolyl]- (CA INDEX NAME) OTHER CA INDEX NAMES: 3-[4-(4-Fluorophenyl)-2-thiazolyl]pyrazolo[1,5-a]pyridine", XP093330163, Database accession no. 2627115-17-5 *

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