Classifications

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  • A61K31/5375—1,4-Oxazines, e.g. morpholine
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  • A61K31/5375—1,4-Oxazines, e.g. morpholine
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Definitions

• the present invention provides a compound that activates autophagy function and is useful as a pharmaceutical, and is useful, for example, in the pharmaceutical field.
• Autophagy is an intracellular degradation mechanism in which a portion of the cytoplasm is surrounded by an isolation membrane to form a membrane structure called an autophagosome, which then fuses with a lysosome to form an autolysosome, thereby breaking down waste products, unnecessary proteins, and the like.
• Autophagy plays an important role in physiological and pathological functions in living organisms, and numerous diseases and symptoms have been reported in recent years, including those caused in part by a decrease in autophagy, and those in which the pathology is suppressed or improved by the enhancement of autophagy.
• Such diseases and symptoms include neurodegenerative diseases, infectious diseases, inflammatory diseases, immune diseases, kidney diseases, respiratory diseases, eye diseases, muscle diseases, mitochondrial diseases, lifestyle-related diseases, skin aging, and various other diseases or symptoms (Patent Document 1). Therefore, various pharmaceuticals and foods containing active ingredients that activate autophagy have been investigated to prevent or treat diseases and symptoms caused in part by impaired autophagy, or diseases and symptoms whose pathology can be suppressed or improved by enhancing autophagy (Patent Documents 1 to 3). However, medical practice demands drugs that activate a wider variety of autophagy functions, and for this reason, the creation of compounds that activate autophagy with structures that are different from conventional compounds has been awaited.
• One of the embodiments of the present invention is to provide a compound that activates autophagy and is useful as a preventive or therapeutic agent for diseases caused by decreased autophagy or diseases whose pathology can be suppressed or ameliorated by enhancing autophagy.
• Rx and Ry each independently represent an oxo group, an optionally substituted aryloxy group, or an optionally substituted C 1-6 alkyl group, and two Rx and two Ry each independently may be joined together to form a heterocycloalkane or a cycloalkane together with the carbon atom to which they are attached;
• Rz represents a hydrogen atom or an optionally substituted C 1-6 alkyl group;
• n1 and n2 each independently represent an integer of 0 to 3.
• R 1 and R 2 each independently represent an optionally substituted C 1-6 alkyl group
• f R3s each independently represent a C 1-6 alkyl group, a C 2-6 alkenyl group, —COR g (R g is a C 1-6 alkyl group), a hydrocarbon ring group, an aromatic heterocyclic group, —NR a1 R b1 (R a1 and R b1 are as defined below), —OR c1 (R c1 is as defined below), or a halogen atom;
• f represents an integer of 0 to 3;
• R 3a represents a hydrogen atom, a C 1-6 alkyl group, a C 2-6 alkenyl group, —COR g (R g is a C 1-6 alkyl group), a hydrocarbon ring group, an aromatic heterocyclic group, —NR a1 R b1 (R a1 and R b1 are as defined below), —OR c1 (R c
• M 1 represents an optionally substituted C 1-4 alkylene group
• M 2 represents —(CH 2 ) j1 —, —(CH 2 ) j2 —O—(CH 2 ) j3 —, —CONR a4 —, —NR a5 CO—, —(CH 2 ) j4 —CO—(CH 2 ) j5 —, —(CH 2 ) j6 —CH(R)—(CH 2 ) j7 —, —(CH 2 ) j8 —S—(CH 2 ) j9 —, or —NR a6 — (wherein R a4 to R a6 are as defined below, and j1 to j9 each independently represent an integer of 0 to 4); R represents a hydroxyl group or an aryl group; R a1 to R a6 and R b1 to R b3 each independently represent a hydrogen atom, an optionally substituted C
• Rx and Ry each independently represent an oxo group, an optionally substituted C 6-14 aryloxy group, or an optionally substituted C 1-6 alkyl group, and two Rx and two Ry each independently may be joined together with the carbon atom to which they are attached to form a 3- to 8-membered heterocycloalkane or a C 3-8 cycloalkane;
• Rz is a hydrogen atom or an optionally substituted C 1-6 alkyl group;
• n1 and n2 each independently represent an integer of 0 to 3.
• R 1 and R 2 are each independently an optionally substituted C 1-6 alkyl group
• f R3s each independently represent a C 1-6 alkyl group, a C 2-6 alkenyl group, —COR g (R g is a C 1-6 alkyl group), a C 6-14 aryl group, a 5- to 8-membered aromatic heterocyclic group, —NR a1 R b1 (R a1 and R b1 are as defined below), —OR c1 (R c1 is as defined below), or a halogen atom;
• f represents an integer of 0 to 3;
• R 3a represents a hydrogen atom or a C 1-6 alkyl group;
• A is an optionally substituted divalent C 3-14 hydrocarbon ring group, a divalent 8- to 14-membered fused aromatic heterocyclic group, or an optionally substituted 3- to 8-membered heterocycloalkylene group;
• Q is a C 1-6 alky
• R a1 to R a3 and R b1 to R b3 are each independently a hydrogen atom, an optionally substituted C 1-6 alkyl group, an optionally substituted C 2-8 alkynyl group, an optionally substituted C 3-14 hydrocarbon ring group, an optionally substituted 3- to 8-membered heterocycloalkyl group, or —COR f (R f is a C 1-6 alkyl group, an optionally substituted C 3-8 hydrocarbon ring group, or a C 3-8 heterocycloalkyl group); R c1 to R c3 are each independently a hydrogen atom, an optionally substituted C 1-6 alkyl group, —COR h (R h is a C 1-6 alkyl group), or an optionally substituted C 6-14 aryl group;
• Rx and Ry each independently represent an oxo group, a C 6-14 aryloxy group, or a C 1-6 alkyl group optionally substituted with a hydroxyl group, and two Rx and two Ry each independently may combine with the carbon atom to which they are attached to form a 3- to 8-membered heterocycloalkane or a C 3-8 cycloalkane;
• Rz is a hydrogen atom or a C 1-6 alkyl group;
• n1 and n2 each independently represent an integer of 0 to 3; (wherein n1 is preferably an integer of 0 to 2, more preferably 0, and n2 is preferably 0 or 1.) or R 1 and R 2 each independently represent a C 1-6 alkyl group optionally substituted by a C 1-6 alkoxy group;
• f R3s each independently represent a C1-6 alkyl group, a C2-6 alkenyl group, -CORg ( Rg is a C1-6 alkyl group), a
• [4] (1) 1) g represents 1; 2) (i) M 1 represents an optionally substituted C 2-4 alkylene group; (ii) M 1 is —(CH 2 )—, and A represents an optionally substituted divalent non-aromatic hydrocarbon ring group, a divalent fused aromatic heterocyclic group, or an optionally substituted heterocycloalkylene group; or (iii) M1 is —(CH 2 )—; A represents an optionally substituted divalent aromatic hydrocarbon ring group, and Q represents a C 1-6 alkyl group, a hydrocarbon ring group, or a heterocycloalkyl group, each of which may be the same or different and may be substituted with 1 to 3 R 4 (wherein R 4 is as defined in [1] above); or (2) 1) g is 0; 2) (i) M 1 represents an optionally substituted C 2-4 alkylene group; (ii) M 1 is —(CH 2 )—, and Q is a C 1-6 alkyl group, a non
• Rx and Ry each independently represent an oxo group, an optionally substituted aryloxy group, or an optionally substituted C 1-6 alkyl group, and two Rx and two Ry each independently may be joined together to form a heterocycloalkane or a cycloalkane together with the carbon atom to which they are attached;
• Rz represents a hydrogen atom or an optionally substituted C 1-6 alkyl group;
• n1 and n2 each independently represent an integer of 0 to 3; (wherein n1 is preferably an integer of 0 to 2, more preferably 0, and n2 is preferably 0 or 1) or
• R 1 and R 2 each independently represent an optionally substituted C 1-6 alkyl group;
• f R3s each independently represent a C 1-6 alkyl group, a C 2-6 alkenyl group, —COR g (R g is a C 1-6 alkyl group), a hydrocarbon ring group, an aromatic heterocyclic group, —NR a
• Rx is a C 1-6 alkyl group optionally substituted with a hydroxyl group, and two Rx may be joined together with the carbon atom to which they are attached to form a 3- to 8-membered heterocycloalkane or a C 3-8 cycloalkane;
• n1 represents an integer of 0 to 3; (wherein n1 is preferably an integer of 0 to 2, more preferably 0).
• (1) g represents 1; (2) (i) M 1 represents an optionally substituted C 2-4 alkylene group; (ii) M 1 is —(CH 2 )—, and A represents an optionally substituted divalent non-aromatic hydrocarbon ring group, a divalent fused aromatic heterocyclic group, or an optionally substituted heterocycloalkylene group; or (iii) M1 is —(CH 2 )—; A represents an optionally substituted divalent aromatic hydrocarbon ring group, and Q represents a C 1-6 alkyl group, a hydrocarbon ring group, or a heterocycloalkyl group, each of which may be the same or different and which is selected from the group consisting of 1 to 3 R 4 (wherein R 4 is as defined in [1] above) may be substituted; The compound according to any one of the above [1], [4], [4A] or [5], or a pharmaceutically acceptable salt thereof.
• g is 1; f R 3s each independently represent -OR c1 (wherein R c1 is as defined below); f represents an integer of 0 to 3; R 3a represents a hydrogen atom or a C 1-6 alkyl group; A is a C 3-8 cycloalkylene group, a C 3-8 cycloalkenylene group, a C 6-14 arylene group, a divalent 8- to 14-membered fused aromatic heterocyclic group, or a 3- to 8-membered heterocycloalkylene group; Q is a C 3-8 cycloalkyl group or a C 6-14 aryl group, each of which may be the same or different and which is selected from 1 to 3 R 4 (wherein each R 4 independently represents a C 1-6 alkoxy group, a C 6-14 aryl-C 1-6 alkoxy group, a hydroxyl group, or a C 1-6 alkyl group optionally substituted with a halogen atom; a nitro
• n1 represents 0
• n1 represents 0
• g 0
• M 1 represents an optionally substituted C 2-4 alkylene group
• M 1 is —(CH 2 )—
• Q is a C 1-6 alkyl group, a non-aromatic hydrocarbon ring group, a heterocycloalkyl group, or an aromatic heterocyclic group, each of which may be substituted with 1 to 3 R 4 s , which may be the same or different, where R 4 s are as defined in [1] above
• M1 is —(CH 2 )—
• Q represents an aromatic hydrocarbon ring group, which may be substituted with 1 to 3 R 4 s , which may be the same or different, each independently represent an optionally substituted C 1-6 alkyl group, a nitro group, —NR a2 R b2 ( R
• g is 0; f R 3 's are -OR c1 (R c1 is as defined below); f is an integer from 0 to 3; Q is a C 1-6 alkyl group, a C 3-14 cycloalkyl group, a C 6-14 aryl group, or a 5- to 14-membered spirocyclic group, each of which may be the same or different and which is selected from 1 to 3 R 4 (wherein each R 4 is independently optionally substituted with a C 1-6 alkyl group, —OR c2 (R c2 is as defined below), a halogen atom, a cyano group, —CO 2 R c3 (R c3 is as defined below), —CONR a3 R b3 (R a3 and R b3 are as defined below, and R a3 and R b3 may be joined together with the nitrogen atom to which they are attached to form a 3- to 8-membered heterocycloalkyl
• n1 represents 0
• g is 1; f R 3 's are -OR c1 (R c1 is a hydrogen atom or -COR h (R h is a C 1-6 alkyl group)); f is 0 or 1; R 3a is a hydrogen atom or a C 1-6 alkyl group; A is a C 3-8 cycloalkylene group; Q is a C 6-14 aryl group, each of which may be the same or different and which is selected from 1 to 3 R 4 (wherein each R4 is independently a C 1-6 alkoxy group, a C 6-14 aryl-C 1-6 alkoxy group, a hydroxyl group, or a C 1-6 alkyl group optionally substituted with a halogen atom; -NR a2 R b2 (R a2 and R b2
• M 1 is —(CH 2 ) i — (wherein i is 1 to 4); M 2 is —(CH 2 ) j1 —, —(CH 2 ) j2 —O—(CH 2 ) j3 — (wherein j1 to j3 each independently represent an integer of 0 to 4).
• M 1 is —(CH 2 ) i — (wherein i is 1 to 4); M 2 is —(CH 2 ) j1 —, —(CH 2 ) j2 —O—(CH 2 ) j3 — (wherein j1 to j3 each independently represent an integer of 0 to 4).
• g is 0; f R3 's are hydroxyl groups; f is an integer of 0 or 1; R 3a is a hydrogen atom; Q is a C 3-14 cycloalkyl group, a C 6-14 aryl group, or a 5- to 14-membered spirocyclic group; M 1 is a C 1-4 alkylene group optionally substituted by a C 1-6 alkyl group; M 2 is —(CH 2 ) j1 — (wherein j1 represents 0) The compound according to the above-mentioned [11] or a pharmaceutically acceptable salt thereof. [14] The compound represented by formula (I) is one or more compounds selected from the group of compounds represented by the following structural formulas: The compound according to any one of the above [1] to [13] or a pharmaceutically acceptable salt thereof.
• M 1 is —(CH 2 ) i — (wherein i is 1 to 4); M 2 is —(CH 2 ) j1 — or —(CH 2 ) j2 —O—(CH 2 ) j3 — (wherein j1 to j3 each independently represent an integer of 0 to 4).
• M 1 is —(CH 2 ) i — (wherein i is 1 to 4); M 2 is —(CH 2 ) j1 — or —(CH 2 ) j2 —O—(CH 2 ) j3 — (wherein j1 to j3 each independently represent an integer of 0 to 4).
• a medicine comprising the compound according to any one of the above [1] to [16] or a pharmaceutically acceptable salt thereof as an active ingredient.
• the pharmaceutical agent according to the above-mentioned [17] which is an autophagy function activator.
• the pharmaceutical agent according to the above-mentioned [17] which is an agent for preventing or treating neurodegenerative diseases; cardiovascular diseases; musculoskeletal diseases; skeletal diseases; lung diseases; kidney diseases; metabolic syndromes; liver lesions; immune, inflammatory and immune-related diseases; eye diseases; reproductive system dysfunction; congenital multisystem disorders; and/or cancer.
• a method for activating autophagy in a mammal comprising administering to the mammal an effective amount of the compound according to any one of the above-mentioned [1] to [16] or a pharmaceutically acceptable salt thereof.
• a method for preventing or treating a disease caused by a decrease in autophagy function in a mammal in need thereof, or a disease whose pathology can be suppressed or ameliorated by enhancement of autophagy function comprising administering to the mammal an effective amount of the compound according to any of the above-mentioned [1] to [16] or a pharmaceutically acceptable salt thereof.
• the present invention provides a compound that activates autophagy and is useful as a preventive or therapeutic agent for diseases caused by decreased autophagy or diseases whose pathology can be suppressed or ameliorated by enhancing autophagy.
• each group used in this specification are described in detail below. Unless otherwise specified, each group has the following definition.
• C a-b e.g., C 1-6
• C a -C b e.g., C 1 -C 6
• halogen atom includes, for example, fluorine, chlorine, bromine, and iodine.
• C 1-6 alkyl (group) examples include methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, pentyl, isopentyl, neopentyl, 1-ethylpropyl, hexyl, isohexyl, 1,1-dimethylbutyl, 2,2-dimethylbutyl, 3,3-dimethylbutyl, 2-ethylbutyl and the like.
• examples of the "C alkenyl (group)" include ethenyl, 1-propenyl, 2-propenyl, 2-methyl-1-propenyl, 1-butenyl, 2-butenyl, 3-butenyl, 3-methyl-2-butenyl, 1-pentenyl, 2-pentenyl, 3-pentenyl, 4-pentenyl, 4-methyl-3-pentenyl, 1-hexenyl, 3-hexenyl, 5-hexenyl and the like.
• C alkynyl (group) examples include ethynyl, 1-propynyl, 2-propynyl, 1-butynyl, 2-butynyl, 3-butynyl, 1-pentynyl, 2-pentynyl, 3-pentynyl, 4-pentynyl, 1-hexynyl, 2-hexynyl, 3-hexynyl, 4-hexynyl, 5-hexynyl, 4-methyl-2-pentynyl, 6-heptynyl, 7-octynyl and the like.
• C 1-6 alkoxy (group) examples include methoxy, ethoxy, propoxy, isopropoxy, butoxy, isobutoxy, sec-butoxy, tert-butoxy, pentyloxy, hexyloxy and the like.
• hydrocarbon ring includes aromatic and non-aromatic rings formed with carbon atoms as ring-constituting atoms, such as aromatic hydrocarbon rings and non-aromatic hydrocarbon rings (cycloalkanes, cycloalkenes).
• non-aromatic encompasses both non-aromatic and anti-aromatic rings according to Hückel's rule.
• aromatic hydrocarbon ring examples include benzene, naphthalene, etc., and preferably C 6-14 aromatic hydrocarbon rings.
• examples of the "cycloalkane” include cyclopropane, cyclobutane, cyclopentane, cyclohexane, cycloheptane, cyclooctane and the like, preferably a C 3-14 cycloalkane, more preferably a C 3-8 cycloalkane.
• examples of the "cycloalkene” include cyclopropene, cyclobutene, cyclopentene, cyclohexene, cycloheptene, cyclooctene and the like, preferably C 3-14 cycloalkene, more preferably C 3-8 cycloalkene.
• hydrocarbon ring includes bicyclic rings formed by a spiro bond between the same or different hydrocarbon rings ("spiro rings").
• spiro rings may contain, in addition to carbon atoms, 1 to 4 heteroatoms selected from nitrogen, sulfur, and oxygen atoms as ring-constituting atoms.
• Examples include 5- to 14-membered spiro rings such as spiro[3.3]heptane, spiro[5.5]undecane, 3-oxaspiro[5.5]undecane, 2-azaspiro[3.3]heptane, 6-azaspiro[2.5]octane, 2-azaspiro[3.5]nonane, 7-azaspiro[3.5]nonane, and 3-azaspiro[5.5]undecane.
• 5- to 14-membered spiro rings such as spiro[3.3]heptane, spiro[5.5]undecane, 3-oxaspiro[5.5]undecane, 2-azaspiro[3.3]heptane, 6-azaspiro[2.5]octane, 2-azaspiro[3.5]nonane, 7-azaspiro[3.5]nonane, and 3-azaspiro[5.5]undecane.
• these include 5- to 14-membered spirohydrocarbon rings, or 5- to 14-membered spirohydrocarbon rings containing 1 to 4 heteroatoms selected from nitrogen, sulfur, and oxygen atoms (preferably 7- to 12-membered spirohydrocarbon rings or 7- to 12-membered spirohydrocarbon rings containing 1 to 3 oxygen atoms).
• hydrocarbon ring group refers to a monovalent group having one bond derived from the above-mentioned "hydrocarbon ring”, and a C3-14 hydrocarbon ring group is preferred.
• specific examples include non-aromatic hydrocarbon ring groups such as cycloalkyl (groups), cycloalkenyl (groups), and spiro ring groups derived from the above-mentioned spiro rings, and aromatic hydrocarbon ring groups such as aryl (groups).
• cycloalkyl (group) is preferably a "C cycloalkyl (group)", and examples thereof include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, bicyclo[2.2.1]heptyl, bicyclo[2.2.2]octyl, bicyclo[3.2.1]octyl, adamantyl and the like.
• cycloalkenyl (group) is preferably a "C 3-14 cycloalkenyl (group)", and examples thereof include cyclopropenyl, cyclobutenyl, cyclopentenyl, cyclohexenyl, cycloheptenyl, cyclooctenyl and the like.
• aryl (group) is preferably a "C 6-14 aryl (group)", and examples thereof include phenyl, 1-naphthyl, 2-naphthyl, 1-anthryl, 2-anthryl, 9-anthryl, etc. More preferably, it is a C 6-14 aryl (group), and even more preferably, it is a C 6-10 aryl (group).
• divalent hydrocarbon ring group refers to a divalent group having two bonds derived from the above-mentioned "hydrocarbon ring”.
• divalent non-aromatic hydrocarbon ring groups such as cycloalkylene (group) and cycloalkenylene (group)
• divalent aromatic hydrocarbon ring groups such as arylene (group).
• cycloalkylene (group) is preferably a "C cycloalkylene (group)", and examples thereof include cyclopropylene, cyclobutylene, cyclopentylene, cyclohexylene, cycloheptylene, cyclooctylene, bicyclo[2.2.1]heptylene, bicyclo[2.2.2]octylene, bicyclo[3.2.1]octylene, adamantylene, and the like.
• the "cycloalkenylene (group)” is preferably a "C 3-14 cycloalkenylene (group)", and examples thereof include cyclopropenylene, cyclobutenylene, cyclopentenylene, cyclohexenylene, cycloheptenylene, cyclooctenylene and the like.
• the "arylene (group)” is preferably a "C 6-14 arylene (group)", and examples thereof include phenylene, 1-naphthylene, 2-naphthylene, 1-anthrylene, 2-anthrylene, 9-anthrylene, etc. More preferably, a C 6-10 arylene (group) is used.
• heterocycle includes, for example, aromatic heterocycles and non-aromatic heterocycles each containing, in addition to carbon atoms, one to four heteroatoms selected from nitrogen atoms, sulfur atoms, and oxygen atoms as ring-constituting atoms.
• non-aromatic encompasses both non-aromatic and anti-aromatic rings according to Hückel's rule.
• examples of the "aromatic heterocycle” include 5- to 14-membered (preferably 5- to 10-membered, more preferably 5- to 8-membered) aromatic heterocycles containing, as ring-constituting atoms other than carbon atoms, 1 to 4 heteroatoms selected from a nitrogen atom, a sulfur atom and an oxygen atom.
• aromatic heterocycle examples include 5- or 6-membered monocyclic aromatic heterocycles such as thiophene, furan, pyrrole, imidazole, pyrazole, thiazole, isothiazole, oxazole, isoxazole, pyridine, pyrazine, pyrimidine, pyridazine, 1,2,4-oxadiazole, 1,3,4-oxadiazole, 1,2,4-thiadiazole, 1,3,4-thiadiazole, triazole, tetrazole, and triazine; Benzothiophene, benzofuran, benzimidazole, benzoxazole, benzisoxazole, benzothiazole, benzisothiazole, benzotriazole, imidazopyridine, thienopyridine, furopyridine, pyrrolopyridine, pyrazolopyridine, oxazolopyridine, thiazolo
• non-aromatic heterocycle examples include 3- to 14-membered (preferably 3- to 10-membered, more preferably 3- to 8-membered) non-aromatic heterocycles containing, as ring-constituting atoms other than carbon atoms, 1 to 4 heteroatoms selected from a nitrogen atom, a sulfur atom and an oxygen atom.
• non-aromatic heterocycle examples include 3- to 8-membered monocyclic non-aromatic heterocycles such as aziridine, oxirane, thiirane, azetidine, oxetane, thietane, tetrahydrothiophene, tetrahydrofuran, pyrroline, pyrrolidine, imidazoline, imidazolidine, oxazoline, oxazolidine, pyrazoline, pyrazolidine, thiazoline, thiazolidine, tetrahydroisothiazole, tetrahydrooxazole, tetrahydroisoxazole, piperidine, piperazine, tetrahydropyridine, dihydropyridine, dihydrothiopyran, tetrahydropyrimidine, tetrahydropyridazine, dihydropyran, tetrahydropyran, tetrahydropyran,
• heterocycloalkane refers to a saturated ring among the above-mentioned monocyclic non-aromatic heterocycles, and preferably includes those having 3 to 8 members.
• nitrogen-containing heterocycle includes, among “heterocycles", those containing at least one nitrogen atom as a ring-constituting atom.
• heterocyclic groups include (i) aromatic heterocyclic groups, (ii) non-aromatic heterocyclic groups, and (iii) 6- to 10-membered bridged heterocyclic groups, each of which contains, in addition to carbon atoms, 1 to 4 heteroatoms selected from nitrogen atoms, sulfur atoms, and oxygen atoms as ring-constituting atoms.
• examples of the "aromatic heterocyclic group” include 5- to 14-membered (preferably 5- to 10-membered, more preferably 5- to 8-membered) aromatic heterocyclic groups containing, as ring-constituting atoms other than carbon atoms, 1 to 4 heteroatoms selected from a nitrogen atom, a sulfur atom and an oxygen atom.
• aromatic heterocyclic group examples include 5- or 6-membered monocyclic aromatic heterocyclic groups such as thienyl, furyl, pyrrolyl, imidazolyl, pyrazolyl, thiazolyl, isothiazolyl, oxazolyl, isoxazolyl, pyridyl, pyrazinyl, pyrimidinyl, pyridazinyl, 1,2,4-oxadiazolyl, 1,3,4-oxadiazolyl, 1,2,4-thiadiazolyl, 1,3,4-thiadiazolyl, triazolyl, tetrazolyl, triazinyl, etc.; benzothiophenyl, benzofuranyl, benzimidazolyl, benzoxazolyl, benzisoxazolyl, benzothiazolyl, benzisothiazolyl, benzotriazolyl, imidazopyridinyl, thienopyr
• non-aromatic heterocyclic group examples include a 3- to 14-membered (preferably 4- to 10-membered) non-aromatic heterocyclic group containing, as ring-constituting atoms other than carbon atoms, 1 to 4 heteroatoms selected from a nitrogen atom, a sulfur atom and an oxygen atom.
• non-aromatic heterocyclic group examples include aziridinyl, oxiranyl, thiiranyl, azetidinyl, oxetanyl, thietanyl, tetrahydrothienyl, tetrahydrofuranyl, pyrrolinyl, pyrrolidinyl, imidazolinyl, imidazolidinyl, oxazolinyl, oxazolidinyl, pyrazolinyl, pyrazolidinyl, thiazolinyl, thiazolidinyl, tetrahydroisothiazolyl, tetrahydrooxazolyl, tetrahydroisoisothiazolyl, tetrahydroiso ...
• 3- to 8-membered monocyclic non-aromatic heterocyclic groups such as xazolyl, piperidinyl, piperazinyl, tetrahydropyridinyl, dihydropyridinyl, dihydrothiopyranyl, tetrahydropyrimidinyl, tetrahydropyridazinyl, dihydropyranyl, tetrahydropyranyl, tetrahydrothiopyranyl, morpholinyl, thiomorpholinyl, azepanyl, diazepanyl, azepinyl, oxepanyl, azocanyl, diazocanyl, oxazepanyl, and the like; Dihydrobenzofuranyl, dihydrobenzimidazolyl, dihydrobenzoxazolyl, dihydrobenzothiazolyl, dihydrobenzisothiazolyl, dihydronaphtho[2,3-
• a "divalent aromatic heterocyclic group” refers to a divalent group having two bonds derived from the above-mentioned "aromatic heterocycle.” Suitable examples include divalent groups having two bonds derived from a fused polycyclic (preferably bicyclic or tricyclic) aromatic heterocycle, and preferably divalent groups having two bonds derived from an 8- to 14-membered nitrogen-containing fused aromatic heterocycle (e.g., indole-diyl).
• heterocycloalkyl refers to a saturated group among the monocyclic non-aromatic heterocyclic groups listed above, preferably 3- to 8-membered groups.
• heterobridged ring group includes “6- to 10-membered heterobridged ring groups,” and suitable examples thereof include quinuclidinyl, 7-azabicyclo[2.2.1]heptanyl, 3-azabicyclo[3.1.0]hexanyl, 6-oxa-3-azabicyclo[3.1.0]hexanyl, 3-azabicyclo[3.1.1]heptanyl, 6-oxa-3-azabicyclo[3.1.1]heptanyl, Examples include 2-azabicyclo[3.1.1]heptanyl, 2-azabicyclo[2.2.1]heptanyl, 2-oxa-5-azabicyclo[2.2.1]heptanyl, 3-azabicyclo[3.2.1]octanyl, 8-oxa-3-azabicyclo[3.2.1]octanyl, 8-azabicyclo[3.2.1]octanyl, and 3-oxa-8-azabicyclo[3.2.1]octanyl.
• nitrogen-containing heterocyclic group refers to a “heterocyclic group” that contains at least one nitrogen atom as a ring-constituting atom.
• heterocycloalkylene refers to a divalent group having two bonds derived from a saturated “heterocycloalkane” group among the monocyclic non-aromatic heterocyclic groups described above.
• heterocycloalkane a saturated “heterocycloalkane” group among the monocyclic non-aromatic heterocyclic groups described above.
• 3- to 8-membered groups are used.
• nitrogen-containing groups such as piperidine-diyl and piperazine-diyl.
• examples of the "substituent" in the “optionally substituted group or ring” in the definitions of the compound represented by formula (I) include substituents selected from the following [Substituent group A].
• the “substituents” can be present in 1 to 5 (preferably 1 to 3) substitutable positions, and when the number of substituents is 2 or more, the respective substituents may be the same or different.
• substituents selected from the following [Substituent group A].
• [Substituent group A] (1) a halogen atom, (2) a nitro group, (3) a cyano group, (4) an oxo group, (5) a hydroxy group, (6) optionally halogenated C 1 -C 6 alkoxy groups (e.g., methoxy, chloromethoxy, trifluoroethoxy); (7) C 6 -C 14 aryloxy groups (e.g., phenoxy, naphthoxy), (8) C 7 -C 16 aralkyloxy group (e.g., benzyloxy), (9) C 1 -C 6 alkyl-carbonyloxy groups (e.g., acetoxy, propanoyloxy), (10) C 6 -C 14 aryl-carbonyloxy groups (e.g., benzoyloxy, 1-naphthoyloxy, 2-naphthoyloxy), (11) C 1 -C 6 alkoxy-carbonyloxy groups (e.g.
• R1 and R2 are as defined above, but (1)
• the aryl group is represented by the following formulas (IIa) to (IIe) together with the nitrogen atom to which they are attached:
• Rx and Ry each independently represent an oxo group, an optionally substituted C 6-14 aryloxy group, or an optionally substituted C 1-6 alkyl group, and two Rx and two Ry each independently may be joined together with the carbon atom to which they are attached to form a 3- to 8-membered heterocycloalkane or a C 3-8 cycloalkane;
• Rz is a hydrogen atom or an optionally substituted C 1-6 alkyl group;
• n1 and n2 each independently represent an integer of 0 to 3.
• Rx is an optionally substituted C 1-6 alkyl group, and two Rx may be joined together with the carbon atom to which they are attached to form a 3- to 8-membered heterocycloalkane or a C 3-8 cycloalkane
• Ry is an oxo group or an optionally substituted C 6-14 aryloxy group
• Rz is a hydrogen atom or an optionally substituted C 1-6 alkyl group
• n1 and n2 each independently represent an integer of 0 to 3.
• Rx is a C 1-6 alkyl group optionally substituted with a hydroxyl group, and two Rx may be joined together with the carbon atom to which they are attached to form a 3- to 8-membered heterocycloalkane or a C 3-8 cycloalkane;
• n1 represents an integer of 0 to 3.
• n1 is preferably an integer of 0 to 2, more preferably 0).
• Another preferred embodiment is An embodiment in which R 1 and R 2 are each independently a C 1-6 alkyl group optionally substituted with a C 1-6 alkoxy group is given.
• f R3 's are as defined above, In a preferred embodiment, each independently represents a C 1-6 alkyl group, a C 2-6 alkenyl group, —COR g (R g is a C 1-6 alkyl group), a C 6-14 aryl group, a 5- to 8-membered aromatic heterocyclic group, —OR c1 (R c1 is a hydrogen atom, a C 1-6 alkyl group, or —COR h (R h is a C 1-6 alkyl group)), or a halogen atom; A more preferred embodiment is —OR c1 (R c1 is a hydrogen atom, a C 1-6 alkyl group, or —COR h (R h is a C 1-6 alkyl group)).
• f is as defined above, In a preferred embodiment, f is 0 or 1.
• R 3a is as defined above, but In a preferred embodiment, it is a hydrogen atom.
• A is as defined above, but In a preferred embodiment, an optionally substituted divalent C 3-14 hydrocarbon ring group, a divalent 8- to 14-membered fused aromatic heterocyclic group, or an optionally substituted 3- to 8-membered heterocycloalkylene group; In a more preferred embodiment, a divalent C 3-14 hydrocarbon ring group, a divalent 8- to 14-membered fused aromatic heterocyclic group, or a 3- to 8-membered heterocycloalkylene group optionally substituted with a hydroxyl group; In a more preferred embodiment, Examples of embodiments include a C 3-8 cycloalkylene group, a C 3-8 cycloalkenylene group, a C 6-14 arylene group, a divalent 8- to 14-membered fused aromatic heterocyclic group (more preferably a divalent 8- to 14-membered nitrogen-containing fused aromatic heterocyclic group), or a 3- to 8-membered heterocycloalkylene group.
• g is as defined above.
• R 4 is independently an optionally substituted C 1-6 alkyl group; an optionally substituted 5- to 8-membered aromatic heterocyclic group; nitro group; -NR a2 R b2 (R a2 and R b2 each independently represent a hydrogen atom, an optionally substituted C 1-6 alkyl group, an optionally substituted C 3-8 cycloalkyl group, an optionally substituted 3- to 8-membered heterocycloalkyl group, or -COR f (R f represents a C 1-6 alkyl group, a C 2-8 alkynyl group, an optionally substituted C 3-8 hydrocarbon ring group, or a C 3-8 heterocycloal
• M1 is as defined above, but In one preferred embodiment, An embodiment in which it is a C 1-4 alkylene group optionally substituted with a C 1-6 alkyl group or a C 6-14 aryl group is exemplified.
• M2 is as defined above, but In one preferred embodiment, -(CH 2 ) j1 -, -(CH 2 ) j2 -O-(CH 2 ) j3 -, -CONR a4 -, -NR a5 CO-, -(CH 2 ) j4 -CO-(CH 2 ) j5 - (wherein R a4 to R a5 each represent a hydrogen atom, and j1 to j5 each independently represent an integer of 0 to 4).
• Rx and Ry each independently represent an oxo group, an optionally substituted C 6-14 aryloxy group, or an optionally substituted C 1-6 alkyl group, and two Rx and two Ry each independently may be joined together with the carbon atom to which they are attached to form a 3- to 8-membered heterocycloalkane or a C 3-8 cycloalkane;
• Rz is a hydrogen atom or an optionally substituted C 1-6 alkyl group;
• n1 and n2 each independently represent an integer of 0 to 3.
• R 1 and R 2 are each independently an optionally substituted C 1-6 alkyl group
• f R3s each independently represent a C 1-6 alkyl group, a C 2-6 alkenyl group, —COR g (R g is a C 1-6 alkyl group), a C 6-14 aryl group, a 5- to 8-membered aromatic heterocyclic group, —NR a1 R b1 (R a1 and R b1 are as defined below), —OR c1 (R c1 is as defined below), or a halogen atom;
• f represents an integer of 0 to 3;
• R 3a represents a hydrogen atom or a C 1-6 alkyl group;
• A is an optionally substituted divalent C 3-14 hydrocarbon ring group, a divalent 8- to 14-membered fused aromatic heterocyclic group, or an optionally substituted 3- to 8-membered heterocycloalkylene group;
• Q is a C 1-6 alky
• R a1 to R a3 and R b1 to R b3 are each independently a hydrogen atom, an optionally substituted C 1-6 alkyl group, an optionally substituted C 2-8 alkynyl group, an optionally substituted C 3-8 hydrocarbon ring group, an optionally substituted 3- to 8-membered heterocycloalkyl group, or —COR f
• R f is a C 1-6 alkyl group, an optionally substituted C 3-8 hydrocarbon ring group, or a C 3-8 heterocycloalkyl group
• R c1 to R c3 are each independently a hydrogen atom, an optionally substituted C 1-6 alkyl group, —COR h (R h is a C 1-6 alkyl group), or an optionally substituted C 6-14 aryl group.
• Rx and Ry each independently represent an oxo group, a C 6-14 aryloxy group, or a C 1-6 alkyl group optionally substituted with a hydroxyl group, and two Rx and two Ry each independently may combine with the carbon atom to which they are attached to form a 3- to 8-membered heterocycloalkane or a C 3-8 cycloalkane;
• Rz is a hydrogen atom or a C 1-6 alkyl group;
• n1 and n2 each independently represent an integer of 0 to 3.
• R 1 and R 2 each independently represent a C 1-6 alkyl group optionally substituted by a C 1-6 alkoxy group
• f R3s each independently represent a C1-6 alkyl group, a C2-6 alkenyl group, -CORg ( Rg is a C1-6 alkyl group), a C6-14 aryl group, a 5- to 8-membered aromatic heterocyclic group, -ORc1 ( Rc1 is as defined below), or a halogen atom
• f represents an integer of 0 to 3
• R 3a represents a hydrogen atom or a C 1-6 alkyl group
• A is a divalent C 3-14 hydrocarbon ring group optionally substituted with a hydroxyl group, a divalent 8- to 14-membered fused aromatic heterocyclic group, or a 3- to 8-membered heterocycloalkylene group
• Q is
• Rx and Ry each independently represent an oxo group, an optionally substituted aryloxy group, or an optionally substituted C 1-6 alkyl group, and two Rx and two Ry each independently may be joined together to form a heterocycloalkane or a cycloalkane together with the carbon atom to which they are attached;
• Rz represents a hydrogen atom or an optionally substituted C 1-6 alkyl group;
• n1 and n2 each independently represent an integer of 0 to 3.
• R 1 and R 2 each independently represent an optionally substituted C 1-6 alkyl group
• f R3s each independently represent a C 1-6 alkyl group, a C 2-6 alkenyl group, —COR g (R g is a C 1-6 alkyl group), a hydrocarbon ring group, an aromatic heterocyclic group, —NR a1 R b1 (R a1 and R b1 are as defined below), —OR c1 (R c1 is as defined below), or a halogen atom;
• f represents an integer of 0 to 3;
• R 3a represents a hydrogen atom, a C 1-6 alkyl group, a C 2-6 alkenyl group, —COR g (R g is a C 1-6 alkyl group), a hydrocarbon ring group, an aromatic heterocyclic group, —NR a1 R b
• g is 1; f R 3s each independently represent -OR c1 (wherein R c1 is as defined below); f represents an integer of 0 to 3; R 3a represents a hydrogen atom or a C 1-6 alkyl group; A is a C 3-8 cycloalkylene group, a C 3-8 cycloalkenylene group, a C 6-14 arylene group, a divalent 8- to 14-membered fused aromatic heterocyclic group, or a 3- to 8-membered heterocycloalkylene group; Q is a C 3-8 cycloalkyl group or a C 6-14 aryl group, each of which may be the same or different and which is selected from 1 to 3 R 4 (wherein each R 4 independently represents a C 1-6 alkoxy group, a C 6-14 aryl-C 1-6 alkoxy group, a hydroxyl group, or a C 1-6 alkyl group optionally substituted with a hal
• [Compound A-8] (1) g is 0; (2) (i) M 1 represents an optionally substituted C 2-4 alkylene group; (ii) M 1 is —(CH 2 )—, and Q is a C 1-6 alkyl group, a non-aromatic hydrocarbon ring group, a heterocycloalkyl group, or an aromatic heterocyclic group, each of which may be substituted with 1 to 3 R 4 s , which may be the same or different, where R 4 s are as defined in [1] above; or (iii) M 1 is —(CH 2 )—; Q represents an aromatic hydrocarbon ring group, which may be substituted with 1 to 3 R 4 s , which may be the same or different, each independently represent an optionally substituted C 1-6 alkyl group, a nitro group, —NR a2 R b2 ( R a2 and R b2 are as defined below), —OR c2 (R c2 is as defined below), a halogen atom,
• g is 0; f R 3 's are -OR c1 (R c1 is as defined below); f is an integer from 0 to 3; Q is a C 1-6 alkyl group, a C 3-14 cycloalkyl group, a C 6-14 aryl group, or a 5- to 14-membered spirocyclic group, each of which may be the same or different and which is selected from 1 to 3 R 4 (wherein each R 4 is independently optionally substituted with a C 1-6 alkyl group, —OR c2 (R c2 is as defined below), a halogen atom, a cyano group, —CO 2 R c3 (R c3 is as defined below), —CONR a3 R b3 (R a3 and R b3 are as defined below, and R a3 and R b3 may be joined together with the nitrogen atom to which they are attached to form a 3- to 8-membered heterocyclo
• g is 1; f R 3 's are -OR c1 (R c1 is a hydrogen atom or -COR h (R h is a C 1-6 alkyl group)); f is 0 or 1; R 3a is a hydrogen atom or a C 1-6 alkyl group; A is a C 3-8 cycloalkylene group; Q is a C 6-14 aryl group, each of which may be the same or different and which is selected from 1 to 3 R 4 (wherein each R4 is independently a C 1-6 alkoxy group, a C 6-14 aryl-C 1-6 alkoxy group, a hydroxyl group, or a C 1-6 alkyl group optionally substituted with a halogen atom; -NR a2 R b2 (R a2 and R b2 are each independently a hydrogen atom, a C 1-6 alkyl group, or -COR f (R f is a C 1-6 alkyl group, or
• M 1 is —(CH 2 ) i — (wherein i is 1 to 4); M 2 is —(CH 2 ) j1 —, —(CH 2 ) j2 —O—(CH 2 ) j3 — (wherein j1 to j3 each independently represent an integer of 0 to 4).
• M 2 is —(CH 2 ) j1 —, —(CH 2 ) j2 —O—(CH 2 ) j3 — (wherein j1 to j3 each independently represent an integer of 0 to 4).
• [Compound A-11] g is 0; f R3 's are hydroxyl groups; f is an integer of 0 or 1; R 3a is a hydrogen atom; Q is a C 3-14 cycloalkyl group, a C 6-14 aryl group, or a 5- to 14-membered spirocyclic group; M 1 is a C 1-4 alkylene group optionally substituted by a C 1-6 alkyl group; M 2 is —(CH 2 ) j1 — (wherein j1 represents 0)
• the compound represented by formula (I) is one or more compounds selected from the group of compounds represented by the following structural formulas: The compound according to any one of the above [Compound A-1] to [Compound A-11] or a pharmaceutically acceptable salt thereof.
• compound (I) can be used in either the free form or the form of a pharmaceutically acceptable salt thereof.
• pharmaceutically acceptable salts include salts with inorganic acids such as hydrochloride, hydrobromide, sulfate, and phosphate; salts with organic acids such as acetate, fumarate, oxalate, citrate, methanesulfonate, benzenesulfonate, tosylate, and maleate; salts with bases such as alkali metal salts such as sodium salt and potassium salt, and alkaline earth metal salts such as calcium salt; and salts with amino acids such as glycine salt, lysine salt, arginine salt, ornithine salt, glutamate, and aspartate.
• Rx and Ry each independently represent an oxo group, an optionally substituted aryloxy group, or an optionally substituted C 1-6 alkyl group, and two Rx and two Ry each independently may be joined together to form a heterocycloalkane or a cycloalkane together with the carbon atom to which they are attached;
• Rz represents a hydrogen atom or an optionally substituted C 1-6 alkyl group;
• n1 and n2 each independently represent an integer of 0 to 3.
• R 1 and R 2 each independently represent an optionally substituted C 1-6 alkyl group
• f R3s each independently represent -NR a1 R b1 (R a1 and R b1 are as defined below), -OR c1 (R c1 is as defined below), or a halogen atom
• f represents an integer of 0 to 3
• R 3a represents a hydrogen atom
• A represents an optionally substituted divalent hydrocarbon ring group or an optionally substituted heterocycloalkylene group
• g represents 0 or 1
• Q represents a C 1-6 alkyl group, a hydrocarbon ring group, a heterocycloalkyl group, or an aromatic heterocyclic group, each of which is optionally substituted with the same or different 1 to 3 R 4 (wherein each R 4 is independently an optionally substituted C 1-6 alkyl group, an optionally substituted aromatic heterocyclic group, a nitro group, —NR a2 R b2 (R a2 and R
• M 1 is —(CH 2 )—, g is 0, M 2 is —(CH 2 ) j1 —, j1 is 0, and Q is benzene, R4 is not a pyrazolyl group substituted with a methyl group.
• M 1 is —(CH 2 )—, g is 1, A is benzene, M 2 is —(CH 2 ) j1 —, j1 is 0, and Q is pyrazole, R4 is not a methyl group; or a pharmaceutically acceptable salt thereof.
• Rx and Ry each independently represent an oxo group, an optionally substituted C 6-14 aryloxy group, or an optionally substituted C 1-6 alkyl group, and two Rx and two Ry each independently may be joined together with the carbon atom to which they are attached to form a 3- to 8-membered heterocycloalkane or a C 3-8 cycloalkane;
• Rz is a hydrogen atom or an optionally substituted C 1-6 alkyl group;
• n1 and n2 each independently represent an integer of 0 to 3.
• R 1 and R 2 are each independently an optionally substituted C 1-6 alkyl group;
• A is an optionally substituted divalent C 3-14 hydrocarbon ring group or an optionally substituted 3- to 8-membered heterocycloalkylene group;
• Q is a C 1-6 alkyl group, a C 3-14 hydrocarbon ring group, a 3- to 8-membered heterocycloalkyl group, or a 5- to 8-membered aromatic heterocyclic group, each of which may be the same or different and is selected from 1 to 3 R 4 (wherein each R 4 is independently an optionally substituted C 1-6 alkyl group, an optionally substituted 5- to 8-membered aromatic heterocyclic group, a nitro group, —NR a2 R b2 (R a2 and R b2 are as defined below), —OR c2 (R c2 is as defined below), a halogen atom, a cyano group, —CO 2 R c3 (R c3 is as defined
• Rx and Ry each independently represent an oxo group, a C 6-14 aryloxy group, or a C 1-6 alkyl group optionally substituted with a hydroxyl group, and two Rx and two Ry each independently may join together to form a 3- to 8-membered heterocycloalkane or a C 3-8 cycloalkane together with the carbon atom to which they are attached;
• Rz is a hydrogen atom or a C 1-6 alkyl group;
• n1 and n2 each independently represent an integer of 0 to 3.
• R 1 and R 2 each independently represent a C 1-6 alkyl group optionally substituted by a C 1-6 alkoxy group
• A is a divalent C 3-14 hydrocarbon ring group optionally substituted with a hydroxyl group or a 3- to 8-membered heterocycloalkylene group
• Q is a C 1-6 alkyl group, a C 3-14 hydrocarbon ring group, a 3- to 8-membered heterocycloalkyl group, or a 5- to 8-membered aromatic heterocyclic group, each of which may be the same or different and which is selected from 1 to 3 R 4 (wherein each R 4 independently represents a C 1-6 alkyl group optionally substituted with a group selected from a hydroxyl group and a halogen atom, a 5- to 8-membered aromatic heterocyclic group optionally substituted with a C 1-6 alkyl group, a nitro group, —NR a2 R b2 (R a2 and R b2 are as defined below),
• R a1 to R a6 and R b1 to R b3 are each independently a hydrogen atom, a C 3-14 cycloalkyl group, a 3- to 8-membered heterocycloalkyl group, or —COR f (R f is a C 3-8 hydrocarbon ring group); R c1 to R c3 each independently represent a hydrogen atom, a C 1-6 alkyl group, or a C 6-14 aryl group;
• [Compound B-4] (1) 1) g represents 1; 2) (i) M 1 represents —(CH 2 ) i — (wherein i represents 2 to 4); (ii) M 1 is —(CH 2 )—, and A represents an optionally substituted divalent non-aromatic hydrocarbon ring group or an optionally substituted heterocycloalkylene group; or (iii) M1 is —(CH 2 )—; A represents an optionally substituted divalent aromatic hydrocarbon ring group, and Q represents a C 1-6 alkyl group, hydrocarbon ring group, or heterocycloalkyl group, each of which may be the same or different and may be substituted with 1 to 3 R 4 (wherein R 4 is as defined in [Compound B-1] above); or (2) 1) g is 0; 2) (i) M 1 represents —(CH 2 ) i — (wherein i represents 2 to 4); (ii) M 1 is —(CH 2 )—, and Q is a C 1-6 alkyl
• Rx and Ry each independently represent an oxo group, an optionally substituted aryloxy group, or an optionally substituted C 1-6 alkyl group, and two Rx and two Ry each independently may be joined together to form a heterocycloalkane or a cycloalkane together with the carbon atom to which they are attached;
• Rz represents a hydrogen atom or an optionally substituted C 1-6 alkyl group;
• n1 and n2 each independently represent an integer of 0 to 3.
• R 1 and R 2 each independently represent an optionally substituted C 1-6 alkyl group
• f R3s each independently represent -NR a1 R b1 (R a1 and R b1 are as defined below), -OR c1 (R c1 is as defined below), or a halogen atom
• f represents an integer of 0 to 3
• R 3a represents a hydrogen atom
• (1) 1) g represents 1, 2)
• M 1 represents —(CH 2 ) i — (wherein i represents 2 to 4);
• M 2 is —(CH 2 ) j1 —, —(CH 2 ) j2 —O—(CH 2 ) j3 —, —CONR a4 —, —NR a5 CO—, —(CH 2 ) j4 —CO—(CH 2 ) j5 —, —(CH 2 ) j6 —CH(OH)—(CH 2 ) j7 —, or
• Rx is a C 1-6 alkyl group optionally substituted with a hydroxyl group, and two Rx may be joined together with the carbon atom to which they are attached to form a 3- to 8-membered heterocycloalkane or a C 3-8 cycloalkane; n1 represents an integer of 0 to 3.
• [Compound B-6] (1) g represents 1; (2) (i) M 1 represents —(CH 2 ) i — (wherein i represents 2 to 4); (ii) M 1 is —(CH 2 )—, and A represents an optionally substituted divalent non-aromatic hydrocarbon ring group or an optionally substituted heterocycloalkylene group; or (iii) M1 is —(CH 2 )—; A represents an optionally substituted divalent aromatic hydrocarbon ring group, and Q represents a C 1-6 alkyl group, a hydrocarbon ring group, or a heterocycloalkyl group, each of which may be the same or different and may be substituted with 1 to 3 R 4 (wherein R 4 is as defined in [Compound B-1] above); The compound according to any one of the above [Compound B-1], [Compound B-4], [Compound B-4A] and [Compound B-5], or a pharmaceutically acceptable salt thereof.
• g is 1; f R 3s each independently represent -OR c1 (wherein R c1 is as defined below); f represents an integer of 0 to 3; A is a C 3-8 cycloalkylene group, a C 3-8 cycloalkenylene group, a C 6-14 arylene group, or a 3- to 8-membered heterocycloalkylene group; Q is a C 3-8 cycloalkyl group or a C 6-14 aryl group, each of which is optionally substituted with the same or different 1 to 3 R 4 (wherein R 4 is each independently a C 1-6 alkyl group optionally substituted with a halogen atom, a nitro group, —NR a2 R b2 (R a2 and R b2 are as defined below), —OR c2 (R c2 is as defined below), —CONR a3 R b3 (R a3 and R b3 are as defined below, and where R
• g is 0; f R 3 's are -OR c1 (R c1 is as defined below); f is an integer from 0 to 3; Q is a C 1-6 alkyl group, a C 3-8 cycloalkyl group, or a C 6-14 aryl group, each of which is optionally substituted with the same or different 1 to 3 R 4 (wherein R 4 is each independently a C 1-6 alkyl group, —OR c2 (R c2 is as defined below), a halogen atom, a cyano group, —CO 2 R c3 (R c3 is as defined below), —CONR a3 R b3 (R a3 and R b3 are as defined below, and where R a3 and R b3 may be joined together with the nitrogen atom to which they are attached to form a 3- to 8-membered heterocycloalkyl group), or —COR e (R e is a C 1-6
• Method for producing compound (I) or a pharmaceutically acceptable salt thereof Representative embodiments of the method for producing compound (I) or a pharmaceutically acceptable salt thereof are given below. However, the method for producing compound (I) or a pharmaceutically acceptable salt thereof is not limited to these, and a person skilled in the art can produce compound (I) or a pharmaceutically acceptable salt thereof by appropriately selecting and carrying out a synthesis scheme depending on the target compound.
• R 1 , R 2 , R 3 , R 3a , A, Q, M 1 , M 2 , f and g are each defined as in the compound represented by formula (I), and L represents a leaving group.
• Compound (I) or a pharmaceutically acceptable salt thereof can be prepared by reacting compound (III) or a salt thereof with compound (IV) or a salt thereof.
• the leaving group represented by L include a halogen atom and a sulfonyloxy group (for example, a C 1-6 alkylsulfonyloxy group (eg, a methanesulfonyloxy group)).
• salts of compounds (III) and (IV) include those exemplified for compound (I).
• the conditions for the substitution reaction are not particularly limited, and those skilled in the art can select the solvent, temperature, and other conditions appropriately depending on the raw material compounds to be subjected to the reaction.
• any solvent that does not adversely affect the reaction can be used, and a suitable example of the solvent is N,N-dimethylformamide.
• the reaction can be carried out in the presence of a suitable base, such as sodium hydride, sodium tert-butoxide, or potassium carbonate.
• a suitable base such as sodium hydride, sodium tert-butoxide, or potassium carbonate.
• the reaction can be carried out within a temperature range, for example, at room temperature, warmed, or heated.
• Compound (I) or a pharmaceutically acceptable salt thereof can be prepared by reacting compound (V) or a salt thereof with compound (VI) or a salt thereof.
• salts of compounds (V) and (VI) include those exemplified for compound (I).
• the conditions for the condensation reaction are not particularly limited, and a person skilled in the art can appropriately select the solvent, temperature, and other conditions depending on the raw material compounds to be subjected to the reaction. Any solvent that does not adversely affect the reaction can be used, and a suitable example of the solvent is N,N-dimethylformamide.
• the reaction can be carried out in the presence of a suitable base, such as N,N-diisopropylethylamine.
• the reaction can be carried out in the presence of a suitable condensing agent, such as 1-(bis(dimethylamino)methylene)-1H-1,2,3-triazolo[4,5-b]pyridinium 3-oxide hexafluorophosphate.
• a suitable condensing agent such as 1-(bis(dimethylamino)methylene)-1H-1,2,3-triazolo[4,5-b]pyridinium 3-oxide hexafluorophosphate.
• the reaction can be carried out within a temperature range, for example, at room temperature or at elevated temperatures.
• compound (I) has the effect of activating autophagy function. Therefore, through this activating effect, compound (I) or a pharmaceutically acceptable salt thereof and a prodrug described below (hereinafter also referred to as "compound (I) of the present application") normalize, maintain, and/or activate autophagy function, and are useful for the prevention or treatment of diseases caused by decreased autophagy function or diseases whose pathology is suppressed or ameliorated by increased autophagy function.
• Such diseases include neurodegenerative diseases (e.g., Alzheimer's disease, Parkinson's disease, Huntington's disease, amyotrophic lateral sclerosis, ischemic brain injury, focal cortical dysplasia, frontotemporal dementia, neuronal ceroid lipofuscinosis, dementia with Lewy bodies, spinocerebellar degeneration, cortical atrophy, epilepsy, childhood-onset, beta-propeller protein-associated neurodegeneration, spastic quadriplegia, primary microcephaly, Hereditary spastic paraplegia, ataxia with spasticity, Rett syndrome, Joubert syndrome, leukoencephalopathy, dystonia, Cednik syndrome, Pelizaeus-Merzbacher disease, West syndrome, sensory autonomic neuropathy type IF, sensory autonomic neuropathy type II, distal hereditary motor neuropathy, Charcot-Marie-Tooth disease, El-Hattab-Alkuraya syndrome, autosomal recessive spinocere
• compound (I) of the present application when compound (I) of the present application is used as a pharmaceutical for the prevention or treatment of a disease caused by a decrease in autophagy function or a disease whose pathology is suppressed or improved by an increase in autophagy function, compound (I) of the present application can be used either alone or in the form of a pharmaceutical composition containing compound (I) of the present application as an active ingredient together with a pharmaceutically acceptable carrier.
• prevention includes preventing the onset of a disease (including symptoms of the disease) (the entire pathology or one or more pathologies) and delaying the onset of the disease.
• a “prophylactically effective amount” refers to a dose of compound (I) of the present application sufficient to achieve such a purpose.
• treatment includes curing a disease (including symptoms of the disease) (the entire pathology or one or more pathologies), ameliorating the disease, and inhibiting the progression of the severity of the disease.
• a “therapeutically effective amount” refers to a dose of compound (I) of the present application sufficient to achieve such a purpose.
• Such pharmaceutical compositions include, for example, tablets (including sugar-coated tablets, film-coated tablets, sublingual tablets, orally disintegrating tablets, buccal tablets, etc.), pills, powders, granules, capsules (including soft capsules and microcapsules), syrups, liquids, emulsions, suspensions, controlled-release preparations (e.g., immediate-release preparations, sustained-release preparations, sustained-release microcapsules), aerosols, films (e.g., orally disintegrating films, oral mucosal patch films), injections (e.g., subcutaneous injections, intravenous injections (e.g., bolus), intramuscular injections, intraperitoneal injections), drip infusions, transdermal preparations, ointments, lotions, patches, suppositories (e.g., rectal suppositories, vaginal suppositories), pellets, nasal preparations, pulmonary preparations (inhalants), eye drops, etc.
• tablets
• pharmaceutically acceptable carriers refer to various carriers commonly used in the field of pharmaceutical formulation technology.
• pharmaceutically acceptable carriers include excipients (e.g., lactose, sucrose, D-mannitol, starch, corn starch, crystalline cellulose, light anhydrous silicic acid, etc.), lubricants (e.g., magnesium stearate, talc, colloidal silica, etc.), binders (e.g., crystalline cellulose, sucrose, D-mannitol, dextrin, hydroxypropyl cellulose, hydroxypropylmethylcellulose, polyvinylpyrrolidone, starch, sucrose, gelatin, methylcellulose, sodium carboxymethylcellulose, etc.), and disintegrants (e.g., starch, carboxymethylcellulose, calcium carboxymethylcellulose, sodium carboxymethylstarch, L-hydroxypropylcellulose, etc.).
• excipients e.g., lactose, sucrose, D-mannitol, starch, corn starch, crystalline cellulose, light anhydrous silicic acid, etc.
• Liquid formulations may contain solvents (e.g., water for injection, isotonic saline, alcohol, propylene glycol, macrogol, sesame oil, etc.), solubilizing agents (e.g., polyethylene glycol, propylene glycol, D-mannitol, benzyl benzoate, ethanol, triethanolamine, sodium carbonate, sodium citrate, etc.), suspending agents (e.g., surfactants such as stearyltriethanolamine, sodium lauryl sulfate, laurylaminopropionic acid, lecithin, benzalkonium chloride, glycerin monostearate, etc.; hydrophilic polymers such as polyvinyl alcohol, polyvinylpyrrolidone, sodium carboxymethylcellulose, methylcellulose, hydroxymethylcellulose, hydroxypropylcellulose, etc.), isotonic agents (e.g., glucose, D-sorbitol, sodium chloride, glycerin, D-mannito
• formulation additives such as preservatives (e.g., parahydroxybenzoic acid esters, chlorobutanol, benzyl alcohol, sorbic acid, etc.), antioxidants (e.g., sulfites, ascorbic acid, ⁇ -tocopherol, etc.), colorants, sweeteners, etc. may also be added.
• preservatives e.g., parahydroxybenzoic acid esters, chlorobutanol, benzyl alcohol, sorbic acid, etc.
• antioxidants e.g., sulfites, ascorbic acid, ⁇ -tocopherol, etc.
• colorants e.g., ascorbic acid, ⁇ -tocopherol, etc.
• the above pharmaceutical compositions can be manufactured by adding the compound of the present invention in a proportion of typically 0.01 to 99% (w/w), preferably 0.1 to 85% (w/w), based on the total amount of the formulation, although this will vary depending on the dosage form, administration method, carrier, etc.
• the pharmaceutical composition can be manufactured using conventional methods in the field of formulation technology, depending on its form.
• the pharmaceutical composition may also be formed into a sustained-release formulation containing the active ingredient.
• Compound (I) of the present invention is expected to have low toxicity and few side effects, and has excellent properties as a pharmaceutical. Therefore, Compound (I) of the present invention can be safely administered to mammals (e.g., humans, dogs, or cats, particularly humans).
• mammals e.g., humans, dogs, or cats, particularly humans.
• Compound (I) of the present application can be administered alone or as a pharmaceutical composition orally or parenterally (e.g., intravenously, intramuscularly, subcutaneously, intraorganly, intranasally, intradermally, by ophthalmic administration, intracerebrally, intrarectally, intravaginally, intraperitoneally, and into a lesion).
• parenterally e.g., intravenously, intramuscularly, subcutaneously, intraorganly, intranasally, intradermally, by ophthalmic administration, intracerebrally, intrarectally, intravaginally, intraperitoneally, and into a lesion.
• the dose of Compound (I) of the present invention varies depending on the subject, route of administration, and age and symptoms of the subject, but is not particularly limited.
• the dose is 1 to 250 mg of Compound (I) per administration when administered orally, and 0.1 to 1000 mg when administered parenterally.
• a prodrug of compound (I) refers to a compound that is converted to compound (I) by a reaction with an enzyme, gastric acid, or the like under physiological conditions in a living body, i.e., a compound that is converted to compound (I) by enzymatic oxidation, reduction, hydrolysis, or the like, or a compound that is converted to compound (I) by hydrolysis, etc., with gastric acid, or the like.
• Prodrugs of compound (I) include compounds in which the amino group of compound (I) is acylated, alkylated or phosphorylated [for example, compounds in which the amino group of compound (I) is eicosanoylated, alanylated, pentylaminocarbonylated, (5-methyl-2-oxo-1,3-dioxolen-4-yl)methoxycarbonylated, tetrahydrofuranylated, pyrrolidylmethylated, pivaloyloxymethylated or tert-butylated, etc.]; compounds in which the hydroxyl group of compound (I) is acylated, alkylated, phosphorylated or borated (for example, compounds in which the hydroxyl group of compound (I) is acetylated, palmitoylated, propanoylated, pivaloylated or succinylated, etc.].
• compounds in which the carboxyl group of compound (I) is esterified or amidated for example, compounds in which the carboxyl group of compound (I) is ethyl-esterified, phenyl-esterified, carboxymethyl-esterified, dimethylaminomethyl-esterified, pivaloyloxymethyl-esterified, ethoxycarbonyloxyethyl-esterified, phthalidyl-esterified, (5-methyl-2-oxo-1,3-dioxolen-4-yl)methyl-esterified, cyclohexyloxycarbonylethyl-esterified, or methylamidized); and the like.
• These compounds can be produced from compound (I) by methods known per se.
• the prodrug of compound (I) may be one that is converted into compound (I) under physiological conditions, as described in "Drug Development,” Hirokawa Publishing, 1990, Vol. 7, Molecular Design, pp. 163 to 198.
• the prodrug of compound (I) may be in the form of a salt. Suitable salts include the pharmaceutically acceptable salts exemplified for compound (I).
• Compound (I) may be any of a hydrate, a non-hydrate, a solvate, and a non-solvate.
• Compound (I) may also be a compound labeled or substituted with an isotope (e.g., 2H , 3H , 11C , 14C , 18F , 35S , 125I , etc.), and the isotope-labeled or substituted compound can be used, for example, as a tracer (PET tracer) used in positron emission tomography (PET), and may be useful in fields such as medical diagnosis.
• Compounds (I) also include deuterium conversion products in which 1 H is converted to 2 H (D).
• Compound (I) also encompasses tautomers.
• Compound (I) may be a pharmaceutically acceptable cocrystal or cocrystal salt.
• a cocrystal or cocrystal salt refers to a crystalline substance composed of two or more distinct solids at room temperature, each having different physical properties (e.g., structure, melting point, heat of fusion, hygroscopicity, solubility, stability, etc.).
• a cocrystal or cocrystal salt can be produced by a cocrystallization method known per se.
• the compound (I) of the present invention may be used in combination with other active ingredients (hereinafter abbreviated as concomitant drugs).
• concomitant drugs a compound or a salt thereof that can have a preventive and/or therapeutic effect can be appropriately combined depending on the disease to be prevented or treated.
• a concomitant drug By combining the compound (I) of the present application with a concomitant drug, (1) The dose of the compound (I) of the present application or a concomitant drug can be reduced compared to when the compound (I) or a concomitant drug is administered alone.
• Drugs to be used in combination with Compound (I) of the present invention can be selected depending on the symptoms of the patient (mild, severe, etc.).
• the combined use of the compound (I) of the present invention and a concomitant drug will be referred to as the "concomitant drug of the present invention.”
• the administration timing of the compound (I) of the present application and the concomitant drug is not limited, and the compound (I) of the present application or a pharmaceutical composition thereof and the concomitant drug or a pharmaceutical composition thereof may be administered to the subject simultaneously or at staggered times.
• the dose of the concomitant drug may be in accordance with the dose used clinically and may be appropriately selected depending on the subject, administration route, disease, combination, etc.
• the administration form of the present combination drug is not particularly limited, as long as compound (I) of the present application and the concomitant drug are combined at the time of administration.
• administration forms include (1) administration of a single preparation obtained by simultaneously formulating compound (I) of the present application and the concomitant drug, (2) simultaneous administration of two preparations obtained by separately formulating compound (I) and the concomitant drug via the same administration route, (3) administration of two preparations obtained by separately formulating compound (I) and the concomitant drug via the same administration route with a time lag, (4) simultaneous administration of two preparations obtained by separately formulating compound (I) and the concomitant drug via different administration routes, and (5) administration of two preparations obtained by separately formulating compound (I) and the concomitant drug via different administration routes with a time lag (e.g., administration of compound (I) of the present application followed by the concomitant drug, or administration in the reverse order).
• a time lag e.g., administration of compound (I) of the present application followed
• the mixing ratio of the compound (I) of the present invention to the concomitant drug in the present combination agent can be appropriately selected depending on the subject of administration, the administration route, the disease, etc.
• the content of Compound (I) of the present invention in the present combination drug varies depending on the form of the formulation, but is usually about 0.01 to 100% by weight, preferably about 0.1 to 50% by weight, and more preferably about 0.5 to 20% by weight, based on the total weight of the formulation.
• the content of the concomitant drug in the present combination agent varies depending on the form of the preparation, but is usually about 0.01 to 100% by weight, preferably about 0.1 to 50% by weight, more preferably about 0.5 to 20% by weight of the total preparation.
• the content of additives such as carriers in the present combination drug varies depending on the form of the formulation, but is usually about 1 to 99.99% by weight, preferably about 10 to 90% by weight, of the total formulation. Furthermore, when the compound (I) of the present invention and the concomitant drug are separately formulated, the contents may be similar.
• Example 1 Morpholino(1-(4-phenylbutyl)-1H-pyrrolo[3,2-b]pyridin-3-yl)methanone (1) To a solution of 0.2 g of 4-azaindole-3-carboxylic acid in 3 mL of dichloromethane, 0.127 mL of oxalyl chloride and 1 drop of N,N-dimethylformamide were added at 0°C under a nitrogen atmosphere, and the mixture was stirred at 0°C for 1 hour.
• the resulting organic layer was separated, washed with saturated brine, dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure to obtain the crude product.
• Example 2 Methyl 3-(4-(3-(morpholine-4-carbonyl)-1H-pyrrolo[3,2-b]pyridin-1-yl)butyl)benzoate (1) To 1.50 g of 3-butyn-1-ol, 0.122 g of copper(I) iodide, and 0.124 g of tetrakis(triphenylphosphine)palladium(0) were added 1.5 mL of triethylamine and 5.31 g of 3-(methoxycarbonyl)-1-iodobenzene at room temperature under a nitrogen atmosphere, and the mixture was stirred at 50°C for 24 hours.
• the mixture was then filtered through Celite, neutralized with saturated aqueous ammonium chloride, and separated with ethyl acetate.
• the resulting organic layer was separated, washed with saturated brine, dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure to obtain a crude product.
• Example 3 To a solution of 0.030 g of (1-(5-methylhexyl)-1H-pyrrolo[3,2-b]pyridin-3-yl)(morpholino)methanone (morpholin-4-yl)(1H-pyrrolo[3,2-b]pyridin-3-yl)methanone in 3 mL of N,N-dimethylformamide, 0.008 g of sodium hydride (60%, dispersed in liquid paraffin) was added under a nitrogen atmosphere at room temperature, and the mixture was stirred at room temperature for 30 minutes. 0.093 g of 1-bromo-5-methylhexane was then added, and the mixture was stirred at room temperature for 72 hours.
• sodium hydride 60%, dispersed in liquid paraffin
• Example 4 To a solution of 0.020 g of (1-(4-cyclopropylbutyl)-1H-pyrrolo[3,2-b]pyridin-3-yl)(morpholino)methanone (morpholin-4-yl)(1H-pyrrolo[3,2-b]pyridin-3-yl)methanone in 5 mL of N,N-dimethylformamide, 0.010 g of sodium hydride (60%, dispersed in liquid paraffin) was added under a nitrogen atmosphere at room temperature, and the mixture was stirred at room temperature for 30 minutes. 0.061 g of (4-bromobutyl)cyclopropane was then added, and the mixture was stirred at room temperature for 72 hours.
• Example 5 (Morpholin-4-yl)(1-((3-phenylcyclobutyl)methyl)-1H-pyrrolo[3,2-b]pyridin-3-yl)methanone (1) To a solution of 0.05 g of 3-phenylcyclobutanecarboxylic acid in 1 mL of tetrahydrofuran, 0.035 mL of dimethylsulfide borane was added at 0°C under a nitrogen atmosphere, and the mixture was stirred at 0°C for 2 hours. The reaction mixture was then added dropwise to ice-cooled methanol, and the solvent was evaporated under reduced pressure. Water was then added, and the mixture was separated using ethyl acetate.
• Example 6 3-(4-(3-(morpholine-4-carbonyl)-1H-pyrrolo[3,2-b]pyridin-1-yl)butyl)benzonitrile
• 0.980 g of 3-iodobenzonitrile, 0.068 g of copper(I) iodide, and 0.206 g of tetrakis(triphenylphosphine)palladium(0) were added to 7 mL of triethylamine and 0.250 g of 3-butyn-1-ol at room temperature under a nitrogen atmosphere, and the mixture was stirred at 70°C for 5 hours. The mixture was then filtered through Celite, neutralized with saturated aqueous ammonium chloride, and separated with ethyl acetate.
• the mixture was separated using a 1:1 mixture of ethyl acetate and ethyl acetate.
• the resulting organic layer was separated, washed with saturated brine, dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure to obtain a crude product.
• Example 7 (Morpholin-4-yl)(1-((2-phenylcyclopropyl)methyl)-1H-pyrrolo[3,2-b]pyridin-3-yl)methanone (1) To a solution of 0.361 mL of diiodomethane in 25 mL of dichloromethane, 2.795 mL of diethylzinc (1 mol/L toluene solution) was added at 0°C under a nitrogen atmosphere.
• the resulting organic layer was separated, washed with saturated brine, dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure to obtain a crude product.
• Example 8 (Morpholin-4-yl)(1-((3-phenylcyclopentyl)methyl)-1H-pyrrolo[3,2-b]pyridin-3-yl)methanone (1) To a solution of 0.6 g of 4-phenylcyclohexan-1-one in 8 mL of dichloromethane, 0.697 g of sulfuryl chloride was added at room temperature under a nitrogen atmosphere, and the mixture was stirred at room temperature for 3 hours. Saturated aqueous sodium bicarbonate was then added, and the mixture was separated using ethyl acetate.
• Example 9 (1-(4-(2-chlorophenyl)butyl)-1H-pyrrolo[3,2-b]pyridin-3-yl)(morpholino)methanone (1) 3-butyn-1-ol (0.600 g), copper(I) iodide (0.049 g), and tetrakis(triphenylphosphine)palladium(0) (0.148 g) were added to 20 mL of triethylamine and 2.12 g of 1-chloro-2-iodobenzene at room temperature under a nitrogen atmosphere, and the mixture was stirred at 50°C for 6 hours.
• the mixture was then filtered through Celite, neutralized with saturated aqueous ammonium chloride, and separated with ethyl acetate.
• the resulting organic layer was separated, washed with saturated brine, dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure to obtain a crude product.
• Example 10 (1-(4-(2-fluorophenyl)butyl)-1H-pyrrolo[3,2-b]pyridin-3-yl)(morpholino)methanone (1) 3-butyn-1-ol (1.20 g), copper(I) iodide (0.098 g), tetrakis(triphenylphosphine)palladium(0) (0.297 g) were added to triethylamine (30 mL) and 1-fluoro-2-iodobenzene (3.80 g) under a nitrogen atmosphere at room temperature, and the mixture was stirred at 50 ° C. for 24 hours.
• the mixture was then filtered through Celite, neutralized with saturated aqueous ammonium chloride, and separated with ethyl acetate.
• the resulting organic layer was separated, washed with saturated brine, dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure to obtain a crude product.
• Example 11 (1-(4-(3-fluorophenyl)butyl)-1H-pyrrolo[3,2-b]pyridin-3-yl)(morpholino)methanone (1) 3-butyn-1-ol (1.00 g), copper(I) iodide (0.082 g), tetrakis(triphenylphosphine)palladium(0) (0.247 g) were added to 30 mL of triethylamine and 3.17 g of 1-fluoro-3-iodobenzene under a nitrogen atmosphere at room temperature, and the mixture was stirred at 50 ° C for 3 hours.
• the mixture was then filtered through Celite, neutralized with saturated aqueous ammonium chloride, and separated with ethyl acetate.
• the resulting organic layer was separated, washed with saturated brine, dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure to obtain a crude product.
• Example 12 (1-(6-Methylheptyl)-1H-pyrrolo[3,2-b]pyridin-3-yl)(morpholin-4-yl)methanone (1) To a solution of 0.24 g of 6-methylheptanoic acid in 4 mL of toluene, 0.925 mL of sodium bis(2-methoxyethoxy)aluminum hydride (70% toluene solution, approximately 3.6 mol/L) was added under a nitrogen atmosphere at 0°C and stirred at room temperature for 1.5 hours. Saturated aqueous potassium sodium tartrate was then added, and the mixture was separated using ethyl acetate.
• sodium bis(2-methoxyethoxy)aluminum hydride 70% toluene solution, approximately 3.6 mol/L
• Example 13 Morpholino(1-((trans-4-phenylcyclohexyl)methyl)-1H-pyrrolo[3,2-b]pyridin-3-yl)methanone (1)
• 0.272 mL of sodium bis(2-methoxyethoxy)aluminum hydride 70% toluene solution, approximately 3.6 mol/L
• a saturated aqueous solution of potassium sodium tartrate was then added, and the mixture was separated using ethyl acetate.
• the resulting organic layer was separated, washed with saturated brine, dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure to obtain the crude product.
• Example 14 To a solution of 0.07 g of (morpholin-4-yl)(1H-pyrrolo[3,2-b]pyridin-3-yl) methanone in 2 mL of N,N-dimethylformamide, 0.03 g of sodium hydride (60%, dispersed in liquid paraffin) was added under a nitrogen atmosphere at room temperature, and the mixture was stirred at room temperature for 30 minutes. 0.06 g of 1-bromo-4-methylpentane was then added, and the mixture was stirred at room temperature for 19 hours. Water was then added, and the mixture was separated using a 1:1 mixture of hexane and ethyl acetate.
• Example 15 (1-(4-(4-fluorophenyl)butyl)-1H-pyrrolo[3,2-b]pyridin-3-yl)(morpholino)methanone (1) 3-butyn-1-ol (1.00 g), copper(I) iodide (0.082 g), tetrakis(triphenylphosphine)palladium(0) (0.247 g) were added to triethylamine (30 mL) and 1-fluoro-4-iodobenzene (3.17 g) under a nitrogen atmosphere at room temperature, and the mixture was stirred at 50 ° C for 27 hours.
• the mixture was then filtered through Celite, neutralized with saturated aqueous ammonium chloride, and separated with ethyl acetate.
• the resulting organic layer was separated, washed with saturated brine, dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure to obtain a crude product.
• Example 16 (1-(4-(3-chlorophenyl)butyl)-1H-pyrrolo[3,2-b]pyridin-3-yl)(morpholino)methanone (1) 0.250 g of 3-butyn-1-ol, 0.034 g of copper(I) iodide, and 0.206 g of tetrakis(triphenylphosphine)palladium(0) were added to 20 mL of triethylamine and 0.851 g of 1-chloro-3-iodobenzene at room temperature under a nitrogen atmosphere, and the mixture was stirred at 50°C for 24 hours.
• the mixture was then filtered through Celite, neutralized with saturated aqueous ammonium chloride, and separated with ethyl acetate.
• the resulting organic layer was separated, washed with saturated brine, dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure to obtain a crude product.
• Example 17 (1-(4-(2-Methoxyphenyl)butyl)-1H-pyrrolo[3,2-b]pyridin-3-yl)(morpholino)methanone (1) 0.400 g of 3-butyn-1-ol, 0.033 g of copper(I) iodide, and 0.099 g of tetrakis(triphenylphosphine)palladium(0) were added to 20 mL of triethylamine and 1.34 g of 2-iodoanisole at room temperature under a nitrogen atmosphere, and the mixture was stirred at 50°C for 24 hours. The mixture was then filtered through Celite, neutralized with saturated aqueous ammonium chloride, and separated with ethyl acetate.
• the resulting organic layer was separated, washed with saturated brine, dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure to obtain a crude product.
• (2) 0.795 g of palladium-fibroin was added to 0.500 g of 4-(2-methoxyphenyl)-3-butyn-1-ol under a nitrogen atmosphere, followed by the addition of 10 mL of methanol and stirring for 24 hours at room temperature under a hydrogen atmosphere.
• Example 18 (1-(4-(3-Methoxyphenyl)butyl)-1H-pyrrolo[3,2-b]pyridin-3-yl)(morpholino)methanone (1) 0.400 g of 3-butyn-1-ol, 0.054 g of copper(I) iodide, and 0.200 g of dichlorobis(triphenylphosphine)palladium(II) were added to 20 mL of triethylamine and 1.34 g of 3-iodoanisole at room temperature under a nitrogen atmosphere, and the mixture was stirred at 50°C for 24 hours. The mixture was then filtered through Celite, neutralized with saturated aqueous ammonium chloride, and separated with ethyl acetate.
• the resulting organic layer was separated, washed with saturated brine, dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure to obtain a crude product.
• (2) 0.625 g of 4-(3-methoxyphenyl)-3-butyn-1-ol was added with 0.993 g of palladium-fibroin under a nitrogen atmosphere, followed by the addition of 10 mL of methanol and stirring at room temperature for 48 hours under a hydrogen atmosphere.
• Example 19 (1-(4-(4-Methoxyphenyl)butyl)-1H-pyrrolo[3,2-b]pyridin-3-yl)(morpholino)methanone (1) 0.400 g of 3-butyn-1-ol, 0.054 g of copper(I) iodide, and 0.200 g of dichlorobis(triphenylphosphine)palladium(II) were added to 20 mL of triethylamine and 1.34 g of 4-iodoanisole at room temperature under a nitrogen atmosphere, and the mixture was stirred at 50°C for 24 hours. The mixture was then filtered through Celite, neutralized with saturated aqueous ammonium chloride, and separated with ethyl acetate.
• Example 20 (Morpholin-4-yl)(1-(3-phenoxypropyl)-1H-pyrrolo[3,2-b]pyridin-3-yl)methanone (1) To a solution of 0.1 g of phenol in 3 mL of N,N-dimethylformamide, 0.051 g of sodium hydride (60%, dispersed in liquid paraffin) was added under a nitrogen atmosphere at room temperature and stirred for 30 minutes. 0.323 g of (3-bromopropoxy)(tert-butyl)dimethylsilane was added and stirred at room temperature for 1 hour. Water was then added, and the mixture was separated using a 1:1 mixture of hexane and ethyl acetate.
• the resulting organic layer was separated, washed with saturated brine, dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure to obtain a crude product.
• Example 21 To 0.758 g of (1-(4-(2,3-dimethoxyphenyl)butyl)-1H-pyrrolo[3,2-b]pyridin-3-yl)(morpholino)methanone (1) magnesium, 1 grain of iodine, 9 mL of tetrahydrofuran, and 0.758 g of benzyl 3-bromopropyl ether were added under a nitrogen atmosphere at 0°C, and the mixture was stirred at room temperature for 6 hours to prepare a Grignard reagent.
• the Grignard reagent was added to a solution of 0.5 g of 2,3-dimethoxybenzaldehyde in 9 mL of tetrahydrofuran under a nitrogen atmosphere at 0°C, and the mixture was stirred at room temperature for 16 hours. Saturated aqueous ammonium chloride was then added, and the mixture was separated with ethyl acetate. The resulting organic layer was separated, washed with saturated brine, dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure to obtain a crude product.
• Example 22 To 0.758 g of (1-(4-(2,5-dimethoxyphenyl)butyl)-1H-pyrrolo[3,2-b]pyridin-3-yl)(morpholino)methanone (1) magnesium, 1 grain of iodine, 9 mL of tetrahydrofuran, and 0.758 g of benzyl 3-bromopropyl ether were added under a nitrogen atmosphere at 0°C, and the mixture was stirred at room temperature for 6 hours to prepare a Grignard reagent.
• the Grignard reagent was added to a solution of 0.5 g of 2,5-dimethoxybenzaldehyde in 9 mL of tetrahydrofuran under a nitrogen atmosphere at 0°C, and the mixture was stirred at room temperature for 16 hours. Saturated aqueous ammonium chloride was then added, and the mixture was separated with ethyl acetate. The resulting organic layer was separated, washed with saturated brine, dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure to obtain a crude product.
• Example 23 (1-(4-Cyclohexylbutyl)-1H-pyrrolo[3,2-b]pyridin-3-yl)(morpholino)methanone (1) To a solution of 0.125 g of 4-cyclohexylbutan-1-ol in 5 mL of dichloromethane, 0.167 g of methanesulfonic anhydride, 0.277 mL of triethylamine, and 0.010 g of 4-dimethylaminopyridine were added under a nitrogen atmosphere at 0°C, and the mixture was stirred at room temperature for 26 hours. Water was then added, and the mixture was separated using dichloromethane.
• Example 24 1-(4-(4-(3-(morpholine-4-carbonyl)-1H-pyrrolo[3,2-b]pyridin-1-yl)butyl)phenyl)ethanone (1) 0.500 g of 3-butyn-1-ol, 0.102 g of copper(I) iodide, and 0.376 g of dichlorobis(triphenylphosphine)palladium(II) were added to 20 mL of triethylamine and 2.63 g of 4-iodoacetophenone at room temperature under a nitrogen atmosphere, and the mixture was stirred at 50°C for 19 hours.
• the mixture was then filtered through Celite, neutralized with saturated aqueous ammonium chloride, and separated with ethyl acetate. The resulting organic layer was separated, washed with saturated brine, and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure to obtain a crude product.
• Example 25 1-(3-(4-(3-(morpholine-4-carbonyl)-1H-pyrrolo[3,2-b]pyridin-1-yl)butyl)phenyl)ethanone (1) 0.500 g of 3-butyn-1-ol, 0.102 g of copper(I) iodide, and 0.376 g of dichlorobis(triphenylphosphine)palladium(II) were added to 30 mL of triethylamine and 2.63 g of 3-iodoacetophenone at room temperature under a nitrogen atmosphere, and the mixture was stirred at 50°C for 19 hours.
• the mixture was then filtered through Celite, neutralized with saturated aqueous ammonium chloride, and separated with ethyl acetate.
• the resulting organic layer was separated, washed with saturated brine, and dried over anhydrous sodium sulfate.
• the solvent was evaporated under reduced pressure to obtain a crude product.
• Example 26 Methyl 2-(4-(3-(morpholine-4-carbonyl)-1H-pyrrolo[3,2-b]pyridin-1-yl)butyl)benzoate (1) To 1.50 g of 3-butyn-1-ol, 0.122 g of copper(I) iodide, and 40.1 g of tetrakis(triphenylphosphine)palladium(0) were added 20 mL of triethylamine and 5.31 g of 2-(methoxycarbonyl)-1-iodobenzene at room temperature under a nitrogen atmosphere, and the mixture was stirred at 50°C for 17 hours.
• the mixture was then filtered through Celite, neutralized with saturated aqueous ammonium chloride, and separated with ethyl acetate.
• the resulting organic layer was separated, washed with saturated brine, and dried over anhydrous sodium sulfate.
• the solvent was evaporated under reduced pressure to obtain a crude product.
• the resulting organic layer was separated, washed with saturated brine, dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure to obtain the crude product.
• Example 27 Methyl 4-(4-(3-(morpholine-4-carbonyl)-1H-pyrrolo[3,2-b]pyridin-1-yl)butyl)benzoate (1) To 1.00 g of 3-butyn-1-ol, 0.082 g of copper(I) iodide, and 0.247 g of tetrakis(triphenylphosphine)palladium(0) were added 30 mL of triethylamine and 3.54 g of 4-(methoxycarbonyl)-1-iodobenzene at room temperature under a nitrogen atmosphere, and the mixture was stirred at 50°C for 18 hours.
• the mixture was then filtered through Celite, neutralized with saturated aqueous ammonium chloride, and separated with ethyl acetate.
• the resulting organic layer was separated, washed with saturated brine, and dried over anhydrous sodium sulfate.
• the solvent was evaporated under reduced pressure to obtain a crude product.
• Example 28 (Morpholin-4-yl)(1-(2-(2-phenylcyclopropyl)ethyl)-1H-pyrrolo[3,2-b]pyridin-3-yl)methanone (1).
• Example 29 To a solution of 0.068 g of 1-(3-(morpholin-4-yl)-1H-pyrrolo[3,2-b]pyridin-1-yl)-4-phenylbutan-2-one (morpholin-4-yl)(1H-pyrrolo[3,2-b]pyridin-3-yl)methanone in 3 mL of N,N-dimethylformamide, 0.014 g of sodium hydride (60%, dispersed in liquid paraffin) was added under a nitrogen atmosphere at room temperature, and the mixture was stirred at room temperature for 30 minutes. 0.073 g of 1-bromo-4-phenylbutan-2-one was then added, and the mixture was stirred at room temperature for 18.5 hours.
• Example 30 (Morpholin-4-yl)(1-((3-phenoxycyclobutyl)methyl)-1H-pyrrolo[3,2-b]pyridin-3-yl)methanone (1) To a solution of 0.25 g of 3-((benzyloxy)methyl)cyclobutan-1-one in 3 mL of ethanol, 0.06 g of sodium borohydride was added under a nitrogen atmosphere at 0°C and stirred at room temperature for 30 minutes. Saturated aqueous ammonium chloride solution was then added, and the mixture was separated using ethyl acetate.
• the resulting organic layer was separated, washed with saturated brine, dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure to obtain a crude product.
• Example 31 (4-(4-(3-(morpholine-4-carbonyl)-1H-pyrrolo[3,2-b]pyridin-1-yl)butyl)phenyl)(piperidin-1-yl)methanone (1) To a solution of 0.320 g of methyl 4-(4-(3-(morpholine-4-carbonyl)-1H-pyrrolo[3,2-b]pyridin-1-yl)butyl)benzoate in 3 mL of tetrahydrofuran and 3 mL of water, 0.055 g of lithium hydroxide was added under a nitrogen atmosphere at room temperature, and the mixture was stirred at room temperature for 24 hours.
• Example 32 N-cyclohexyl-4-(4-(3-(morpholine-4-carbonyl)-1H-pyrrolo[3,2-b]pyridin-1-yl)butyl)benzamide.
• 4-(4-(3-(morpholine-4-carbonyl)-1H-pyrrolo[3,2-b]pyridin-1-yl)butyl)benzoic acid in 1 mL of N,N-dimethylformamide was added 0.024 g of cyclohexylamine hydrochloride, 0.041 mL of N,N-diisopropylethylamine, and 0.067 g of 1-(bis(dimethylamino)methylene)-1H-1,2,3-triazolo[4,5-b]pyridinium 3-oxide hexafluorophosphate under a nitrogen atmosphere at room temperature, and the mixture was stirred at room temperature for 24 hours.
• Example 33 N-cyclohexyl-3-(3-(3-(morpholine-4-carbonyl)-1H-pyrrolo[3,2-b]pyridin-1-yl)propyl)benzamide (1) To 0.900 g of 2-propyn-1-ol, 0.031 g of copper(I) iodide, and 0.186 g of tetrakis(triphenylphosphine)palladium(0), 30 mL of triethylamine and 4.21 g of 3-(methoxycarbonyl)-1-iodobenzene were added under a nitrogen atmosphere at room temperature, and the mixture was stirred at 50°C for 6 hours.
• the mixture was then filtered through Celite, neutralized with saturated aqueous ammonium chloride, and separated with ethyl acetate.
• the resulting organic layer was separated, washed with saturated brine, dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure to obtain a crude product.
• Example 34 Morpholino(1-(5-phenylpentyl)-1H-pyrrolo[3,2-b]pyridin-3-yl)methanone (1) To a solution of 0.2 g of 5-phenyl-1-pentanol in 5 mL of dichloromethane, 0.348 g of p-toluenesulfonyl chloride and 0.338 mL of triethylamine were added under a nitrogen atmosphere at 0°C, and the mixture was stirred at room temperature for 18 hours. Water was then added, and the mixture was separated using dichloromethane.
• the resulting organic layer was separated, washed with saturated brine, dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure to obtain a crude product.
• the resulting organic layer was separated, washed with saturated brine, dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure to obtain the crude product.
• Example 35 (1-(4-(4-(1-hydroxyethyl)phenyl)butyl)-1H-pyrrolo[3,2-b]pyridin-3-yl)(morpholino)methanone.
• 0.009 g of sodium borohydride was added at 0°C under a nitrogen atmosphere, and the mixture was stirred at room temperature for 17 hours.
• Example 36 (1-(4-(3-(1-hydroxyethyl)phenyl)butyl)-1H-pyrrolo[3,2-b]pyridin-3-yl)(morpholino)methanone.
• 0.011 g of sodium borohydride was added at 0°C under a nitrogen atmosphere, and the mixture was stirred at room temperature for 17 hours.
• Example 37 (3-(4-(3-(morpholine-4-carbonyl)-1H-pyrrolo[3,2-b]pyridin-1-yl)butyl)phenyl)(morpholino)methanone (1) To a solution of 0.442 g of methyl 3-(4-(3-(morpholine-4-carbonyl)-1H-pyrrolo[3,2-b]pyridin-1-yl)butyl)benzoate in 3 mL of tetrahydrofuran and 3 mL of water, 0.075 g of lithium hydroxide was added under a nitrogen atmosphere at room temperature, and the mixture was stirred at room temperature for 1 hour.
• Example 38 (3-(4-(3-(morpholine-4-carbonyl)-1H-pyrrolo[3,2-b]pyridin-1-yl)butyl)phenyl)(piperidin-1-yl)methanone.
• Example 39 N-cyclohexyl-3-(4-(3-(morpholine-4-carbonyl)-1H-pyrrolo[3,2-b]pyridin-1-yl)butyl)benzamide.
• Example 40 N-Cyclohexyl-trans-4-((3-(morpholine-4-carbonyl)-1H-pyrrolo[3,2-b]pyridin-1-yl)methyl)cyclohexanecarboxamide (1) To a solution of 0.5 g of methyl trans-4-(hydroxymethyl)cyclohexanecarboxylate in 1 mL of dichloromethane, 1.155 g of carbon tetrabromide and 0.99 g of triphenylphosphine were added under a nitrogen atmosphere at 0°C, and the mixture was stirred at room temperature for 16 hours.
• Example 41 (trans-4-((3-(morpholine-4-carbonyl)-1H-pyrrolo[3,2-b]pyridin-1-yl)methyl)cyclohexyl)(piperidin-1-yl)methanone.
• trans-4-((3-(morpholine-4-carbonyl)-1H-pyrrolo[3,2-b]pyridin-1-yl)methyl)cyclohexanecarboxylic acid in 1 mL of N,N-dimethylformamide 0.007 g of piperidine, 0.018 mL of N,N-diisopropylethylamine, and 0.029 g of 1-(bis(dimethylamino)methylene)-1H-1,2,3-triazolo[4,5-b]pyridinium 3-oxide hexafluorophosphate were added under a nitrogen atmosphere at room temperature, and the mixture was stirred at room temperature for 17 hours.
• Example 42 (morpholin-4-yl)(1-(4-(oxan-4-yl)butyl)-1H-pyrrolo[3,2-b]pyridin-3-yl)methanone (1) To a solution of 1 g of benzyl 3-bromopropyl ether in 9 mL of acetonitrile, 1.145 g of triphenylphosphine was added at room temperature under a nitrogen atmosphere, and the mixture was stirred under reflux for 16 hours. After that, the solvent was distilled off under reduced pressure, and the residue was purified by recrystallization (hexane-diethyl ether).
• Example 43 (4-(3-(3-(morpholine-4-carbonyl)-1H-pyrrolo[3,2-b]pyridin-1-yl)propyl)phenyl)(piperidin-1-yl)methanone (1) To 1.14 g of 2-propyn-1-ol, 0.039 g of copper(I) iodide, and 0.234 g of tetrakis(triphenylphosphine)palladium(0), 30 mL of triethylamine and 5.31 g of 4-(methoxycarbonyl)-1-iodobenzene were added at room temperature under a nitrogen atmosphere, and the mixture was stirred at 50°C for 4 hours.
• Example 44 N-cyclohexyl-4-(3-(3-(morpholine-4-carbonyl)-1H-pyrrolo[3,2-b]pyridin-1-yl)propyl)benzamide.
• 4-(3-(3-(morpholine-4-carbonyl)-1H-pyrrolo[3,2-b]pyridin-1-yl)propyl)benzoic acid in 1 mL of N,N-dimethylformamide was added 0.019 g of cyclohexylamine hydrochloride, 0.033 mL of N,N-diisopropylethylamine, and 0.053 g of 1-(bis(dimethylamino)methylene)-1H-1,2,3-triazolo[4,5-b]pyridinium 3-oxide hexafluorophosphate at room temperature under a nitrogen atmosphere, and the mixture was stirred at room temperature for 24 hours.
• Example 45 (1-(4-(3-(5-methyl-1,3,4-oxadiazol-2-yl)phenyl)butyl)-1H-pyrrolo[3,2-b]pyridin-3-yl)(morpholino)methanone (1)
• 0.371 g of triethyl orthoacetate and 0.061 g of ammonium chloride were added under a nitrogen atmosphere at 0°C, and the mixture was stirred under reflux for 6 hours. Water was then added, and the mixture was separated using ethyl acetate.
• Example 46 Morpholino(1-((cis-4-phenoxycyclohexyl)methyl)-1H-pyrrolo[3,2-b]pyridin-3-yl)methanone (1) To 0.5 g of trans-4-hydroxycyclohexane-1-carboxylic acid, 5.2 mL of an ethanol-concentrated sulfuric acid mixture was added at room temperature under a nitrogen atmosphere, and the mixture was stirred under reflux for 19 hours. Saturated aqueous sodium bicarbonate was then added, and the mixture was separated using ethyl acetate. The resulting organic layer was separated, washed with saturated brine, and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure to obtain a crude product.
• Example 47 Morpholino(1-((trans-4-phenoxycyclohexyl)methyl)-1H-pyrrolo[3,2-b]pyridin-3-yl)methanone (1) To a solution of 0.2 g of ethyl cis-4-hydroxycyclohexane-1-carboxylate in 3 mL of toluene, 0.131 g of phenol, 0.366 g of triphenylphosphine, and 0.326 g of bis(2-methoxyethyl)azodicarboxylate were added under a nitrogen atmosphere at 0°C, and the mixture was stirred at room temperature for 22 hours. Water was then added, and the mixture was separated using ethyl acetate.
• Example 48 (1-((4-Hydroxy-4-phenylcyclohexyl)methyl)-1H-pyrrolo[3,2-b]pyridin-3-yl)(morpholino)methanone (1) To a solution of 0.5 g of 4-(hydroxymethyl)cyclohexanone in 5 mL of pyridine, 0.892 g of p-toluenesulfonyl chloride was added at 0°C under a nitrogen atmosphere, and the mixture was stirred at room temperature for 26 hours. Water was then added, and the mixture was separated using ethyl acetate. The resulting organic layer was separated, washed with saturated brine, and dried over anhydrous sodium sulfate.
• Example 49 (1-((trans-4-Benzoylcyclohexyl)methyl)-1H-pyrrolo[3,2-b]pyridin-3-yl)(morpholino)methanone (1) To a solution of 1 g of methyl trans-4-(hydroxymethyl)cyclohexanecarboxylate in 3 mL of N,N-dimethylformamide was added 0.791 g of imidazole at room temperature under a nitrogen atmosphere and stirred at room temperature for 30 minutes. 0.963 g of tert-butyldimethylchlorosilane was added and stirred at room temperature for 20 hours. Water was then added, and the mixture was separated using a 1:1 mixture of hexane and ethyl acetate.
• Example 50 (1-((4-(hydroxy(phenyl)methyl)cyclohexyl)methyl)-1H-pyrrolo[3,2-b]pyridin-3-yl)(morpholino)methanone.
• 0.173 g of (1-((trans-4-benzoylcyclohexyl)methyl)-1H-pyrrolo[3,2-b]pyridin-3-yl)(morpholino)methanone in 2 mL of tetrahydrofuran and 1 mL of water 0.023 g of sodium borohydride was added under a nitrogen atmosphere at room temperature, and the mixture was stirred at room temperature for 17 hours. Water was then added, and the mixture was separated with ethyl acetate.
• Example 51 N-(trans-4-((3-(morpholine-4-carbonyl)-1H-pyrrolo[3,2-b]pyridin-1-yl)methyl)cyclohexyl)benzamide
• 8.583 mL of triethylamine, 8.446 g of di-tert-butyl dicarbonate, and 0.095 g of 4-dimethylaminopyridine were added under a nitrogen atmosphere at room temperature, and the mixture was stirred at room temperature for 5 hours. Water was then added, and the mixture was separated using dichloromethane.
• Example 52 To a solution of 0.03 g of N-(trans-4-((3-(morpholine-4-carbonyl)-1H-pyrrolo[3,2-b]pyridin-1-yl)methyl)cyclohexyl)cyclohexanecarboxamide (1-((trans-4-aminocyclohexyl)methyl)-1H-pyrrolo[3,2-b]pyridin-3-yl)(morpholino)methanone hydrochloride in 1 mL of N,N-dimethylformamide, 0.111 mL of triethylamine and 0.022 mL of cyclohexanecarbonyl chloride were added at room temperature under a nitrogen atmosphere, and the mixture was stirred at room temperature for 17 hours.
• Example 53 (1-((1,1'-Bi(cyclohexane))-4-ylmethyl)-1H-pyrrolo[3,2-b]pyridin-3-yl)(morpholino)methanone (1) To a solution of 2 g of 4-cyclohexylcyclohexanol in 10 mL of dichloromethane was added 4.886 g of Dess-Martin periodinane at 0°C under a nitrogen atmosphere, and the mixture was stirred at room temperature for 5 hours. Saturated aqueous sodium thiosulfate was then added, and the mixture was separated using dichloromethane. The resulting organic layer was separated, washed with saturated brine, and dried over anhydrous sodium sulfate.
• the solvent was evaporated under reduced pressure to obtain a crude product.
• Example 55 Morpholino(6-bromo-1-(4-phenylbutyl)-1H-pyrrolo[3,2-b]pyridin-3-yl)methanone (1) To a solution of 0.700 g of 6-bromo-1H-pyrrolo[3,2-b]pyridine-3-carboxaldehyde in 10 mL of N,N-dimethylformamide was added 0.149 g of sodium hydride (60%, dispersed in liquid paraffin) under a nitrogen atmosphere at 0°C and stirred at room temperature for 40 minutes.
• Example 56 A mixture of 0.049 g of morpholino(6-amino-1-(4-phenylbutyl)-1H-pyrrolo[3,2-b]pyridin-3-yl)methanone tris(dibenzylideneacetone)dipalladium(0), 0.066 g of ( ⁇ )-2,2'-bis(diphenylphosphino)-1,1'-binaphthyl, 0.071 g of sodium tert-butoxide, 0.235 g of morpholino(6-bromo-1-(4-phenylbutyl)-1H-pyrrolo[3,2-b]pyridin-3-yl)methanone, 0.153 g of benzophenone imine, and 3 mL of toluene was stirred at 90°C for 19 hours under a nitrogen atmosphere.
• Example 57 Morpholino(6-hydroxy-1-(4-phenylbutyl)-1H-pyrrolo[3,2-b]pyridin-3-yl)methanone (1) 0.002 g of palladium(II) acetate, 0.071 g of potassium acetate, 0.107 g of morpholino(6-bromo-1-(4-phenylbutyl)-1H-pyrrolo[3,2-b]pyridin-3-yl)methanone, 0.074 g of bis(pinacolato)diboron, and 3 mL of N,N-dimethylformamide were added sequentially and stirred at 85°C for 19 hours under a nitrogen atmosphere.
• Example 58 (1-(4-Cyclohexylbenzyl)-1H-pyrrolo[3,2-b]pyridin-3-yl)(morpholino)methanone (1) To a solution of 0.200 g of 4-cyclohexylbenzoic acid in 3 mL of tetrahydrofuran, 0.21 mL of dimethylsulfide borane was added at room temperature under a nitrogen atmosphere, and the mixture was stirred at room temperature for 1 hour. The reaction solution was then added dropwise to ice-cooled methanol, and the solvent was evaporated under reduced pressure. Water was then added, and the mixture was separated using ethyl acetate.
• the resulting organic layer was separated, washed with saturated brine, dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure to obtain a crude product.
• Example 59 (1-((4-benzylcyclohexyl)methyl)-1H-pyrrolo[3,2-b]pyridin-3-yl)(morpholino)methanone: 0.03 g of (1-((4-(hydroxy(phenyl)methyl)cyclohexyl)methyl)-1H-pyrrolo[3,2-b]pyridin-3-yl)(morpholino)methanone was added with 0.5 mL of trifluoroacetic anhydride under a nitrogen atmosphere and stirred at room temperature for 30 minutes. After that, the mixture was concentrated under reduced pressure, and 0.007 g of palladium-carbon was added, followed by the addition of 1 mL of methanol.
• Example 60 To a solution of 8.44 g of morpholino(1-((cis-4-phenylcyclohexyl)methyl)-1H-pyrrolo[3,2-b]pyridin-3-yl)methanone (1) (methoxymethyl)triphenylphosphonium chloride in 60 mL of tetrahydrofuran, 15.388 mL of n-butyllithium (1.6 mol/L hexane solution) was added under a nitrogen atmosphere at ⁇ 78°C, and the mixture was stirred at ⁇ 78°C for 30 minutes. 3.9 g of 4-phenylcyclohexanone was then added, and the mixture was stirred for 21 hours while warming from 0°C to room temperature.
• Example 61 (1-((4-(4-Fluorophenyl)cyclohexyl)methyl)-1H-pyrrolo[3,2-b]pyridin-3-yl)(morpholino)methanone (1) 0.250 g of 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)cyclohex-3-ene-1-carboxylic acid ethyl ester, 0.312 g of tetrakis(triphenylphosphine)palladium(0), 0.300 g of 1-fluoro-4-iodobenzene, and 0.373 g of potassium carbonate were added to 3 mL of 1,4-dioxane and 1 mL of water under a nitrogen atmosphere at room temperature, and the mixture was stirred at 90°C for 24 hours.
• Example 62 (6-Hydroxy-1-((trans-4-phenylcyclohexyl)methyl)-1H-pyrrolo[3,2-b]pyridin-3-yl)(morpholino)methanone (1) To a solution of 0.8 g of (trans-4-phenylcyclohexyl)methanol in 8 mL of dichloromethane, 1.673 g of carbon tetrabromide and 1.434 g of triphenylphosphine were added under a nitrogen atmosphere at 0°C, and the mixture was stirred at room temperature for 4 hours.
• the resulting organic layer was separated and dried over anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure to obtain the crude product.
• Example 63 (1-((4-benzylbicyclo[2.2.1]heptan-1-yl)methyl)-1H-pyrrolo[3,2-b]pyridin-3-yl)(morpholino)methanone (1) To a solution of 0.25 g of dimethylbicyclo[2.2.1]heptane-1,4-dicarboxylate in 3 mL of toluene, 1.309 mL of sodium bis(2-methoxyethoxy)aluminum hydride (70% toluene solution, approximately 3.6 mol/L) was added at 0°C under a nitrogen atmosphere, and the mixture was stirred at room temperature for 3 hours.
• (5) 0.5 mL of trifluoroacetic anhydride was added to 0.064 g of (4-((benzyloxy)methyl)bicyclo[2.2.1]heptan-1-yl)(phenyl)methanol under a nitrogen atmosphere, and the mixture was stirred at room temperature for 1 hour. The mixture was then azeotroped three times with dichloromethane.
• Example 64 (1-((4-(3-fluorophenyl)cyclohexyl)methyl)-1H-pyrrolo[3,2-b]pyridin-3-yl)(morpholino)methanone (1) 0.198 g of 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)cyclohex-3-ene-1-carboxylic acid ethyl ester, 0.245 g of tetrakis(triphenylphosphine)palladium(0), 0.235 g of 1-fluoro-3-iodobenzene, and 0.292 g of potassium carbonate were added to 3 mL of 1,4-dioxane and 1.5 mL of water under a nitrogen atmosphere at room temperature, and the mixture was stirred at 90°C for 24 hours.
• Example 65 (1-((4-(2-fluorophenyl)cyclohexyl)methyl)-1H-pyrrolo[3,2-b]pyridin-3-yl)(morpholino)methanone (1) 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)cyclohex-3-ene-1-carboxylic acid ethyl ester 0.255 g, tetrakis(triphenylphosphine)palladium(0) 0.315 g, 1-fluoro-2-iodobenzene 0.303 g, potassium carbonate 0.377 g, 1,4-dioxane 3 mL, water 1.5 mL were added under a nitrogen atmosphere at room temperature, and the mixture was stirred at 90 ° C.
• Example 66 Morpholino(1-((4-(4-(trifluoromethyl)phenyl)cyclohexyl)methyl)-1H-pyrrolo[3,2-b]pyridin-3-yl)methanone (1) To 0.202 g of 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)cyclohex-3-ene-1-carboxylic acid ethyl ester, 0.250 g of tetrakis(triphenylphosphine)palladium(0), 0.294 g of 4-iodobenzotrifluoride, and 0.299 g of potassium carbonate were added 3 mL of 1,4-dioxane and 1.5 mL of water under a nitrogen atmosphere at room temperature, and the mixture was stirred at 90°C for 24 hours.
• Example 67 Morpholino(1-((4-(3-(trifluoromethyl)phenyl)cyclohexyl)methyl)-1H-pyrrolo[3,2-b]pyridin-3-yl)methanone (1) To 0.200 g of 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)cyclohex-3-ene-1-carboxylic acid ethyl ester, 0.253 g of tetrakis(triphenylphosphine)palladium(0), 0.298 g of 3-iodobenzotrifluoride, and 0.303 g of potassium carbonate, 3 mL of 1,4-dioxane and 1.5 mL of water were added under a nitrogen atmosphere at room temperature, and the mixture was stirred at 90°C for 24 hours.
• Example 68 Morpholino(1-((4-(m-tolyl)cyclohexyl)methyl)-1H-pyrrolo[3,2-b]pyridin-3-yl)methanone (1) tetrakis(triphenylphosphine)palladium(0) 0.309 g, 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)cyclohex-3-ene-1-carboxylic acid ethyl ester 0.25 g, 3-iodotoluene 0.292 g, and potassium carbonate 0.37 g were added to 1,4-dioxane 3 mL and water 1.5 mL at room temperature under a nitrogen atmosphere, and the mixture was stirred at 90°C for 14 hours.
• the mixture was then filtered through Celite, neutralized with saturated aqueous ammonium chloride, and separated with ethyl acetate.
• the resulting organic layer was separated, washed with saturated brine, dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure to obtain a crude product.
• Example 69 Morpholino(1-((4-(p-tolyl)cyclohexyl)methyl)-1H-pyrrolo[3,2-b]pyridin-3-yl)methanone (1) tetrakis(triphenylphosphine)palladium(0) 0.309 g, 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)cyclohex-3-ene-1-carboxylic acid ethyl ester 0.25 g, 4-iodotoluene 0.292 g, and potassium carbonate 0.37 g were added to 1,4-dioxane 3 mL and water 1.5 mL at room temperature under a nitrogen atmosphere, and the mixture was stirred at 90°C for 14 hours.
• the mixture was then filtered through Celite, neutralized with saturated aqueous ammonium chloride, and separated with ethyl acetate.
• the resulting organic layer was separated, washed with saturated brine, dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure to obtain a crude product.
• Example 70 To a solution of 3 g of (1-((benzylbicyclo[2.2.2]octan-1-yl)methyl)-1H-pyrrolo[3,2-b]pyridin-3-yl)(morpholino)methanone (1) bicyclo[2.2.2]octane-1,4-dimethyl ester in 40 mL of toluene, 7.366 mL of sodium bis(2-methoxyethoxy)aluminum hydride (70% toluene solution, approximately 3.6 mol/L) was added under a nitrogen atmosphere at 0°C, and the mixture was stirred at room temperature for 3.5 hours.
• Example 72 (1-((4-(4-Methoxyphenyl)cyclohexyl)methyl)-1H-pyrrolo[3,2-b]pyridin-3-yl)(morpholino)methanone (1) tetrakis(triphenylphosphine)palladium(0) 0.062 g, 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)cyclohex-3-ene-1-carboxylic acid ethyl ester 0.15 g, 4-iodoanisole 0.188 g, and potassium carbonate 0.222 g were added to 1,4-dioxane 3 mL and water 1.5 mL at room temperature under a nitrogen atmosphere, and the mixture was stirred at 90°C for 24 hours.
• the mixture was then filtered through Celite, neutralized with saturated aqueous ammonium chloride, and separated with ethyl acetate.
• the resulting organic layer was separated, washed with saturated brine, dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure to obtain a crude product.
• Example 73 (1-((4-(3-Methoxyphenyl)cyclohexyl)methyl)-1H-pyrrolo[3,2-b]pyridin-3-yl)(morpholino)methanone (1) tetrakis(triphenylphosphine)palladium(0) 0.062 g, 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)cyclohex-3-ene-1-carboxylic acid ethyl ester 0.15 g, 3-iodoanisole 0.188 g, and potassium carbonate 0.222 g were added to 1,4-dioxane 3 mL and water 1.5 mL at room temperature under a nitrogen atmosphere, and the mixture was stirred at 90 °C for 24 hours.
• the mixture was then filtered through Celite, neutralized with saturated aqueous ammonium chloride, and separated with ethyl acetate.
• the resulting organic layer was separated, washed with saturated brine, dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure to obtain a crude product.
• Example 74 (1-((4-(benzyloxy)cyclohexyl)methyl)-1H-pyrrolo[3,2-b]pyridin-3-yl)(morpholino)methanone (1) To 0.15 g of ethyl 4-hydroxycyclohexanecarboxylate, 1.5 mL of N,N-diisopropylethylamine and 0.194 g of benzyl bromide were added under a nitrogen atmosphere at room temperature, and the mixture was stirred at 120°C for 4 hours. Water was then added, and the mixture was separated using ethyl acetate. The resulting organic layer was separated, washed with saturated brine, and dried over anhydrous sodium sulfate.
• Example 75 Morpholino(1-(4-phenylbutyl)-1H-pyrrolo[3,2-b]pyridin-3-yl)methanone hydrochloride: To a solution of 0.158 g of morpholino(1-(4-phenylbutyl)-1H-pyrrolo[3,2-b]pyridin-3-yl)methanone in 3 mL of ethyl acetate, 0.227 mL of hydrogen chloride/ethyl acetate solution (approximately 4 mol/L) was added at 0° C. under a nitrogen atmosphere, and the mixture was stirred for 10 minutes at 0° C.
• the resulting organic layer was separated, washed with saturated brine, dried over anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure to obtain a crude product.
• Example 77 To a solution of 0.1 g of morpholino(1-((1-phenylpiperidin-4-yl)methyl)-1H-pyrrolo[3,2-b]pyridin-3-yl)methanone (1-phenylpiperidin-4-yl)methanol in 1 mL of dichloromethane, 0.109 g of methanesulfonic anhydride and 0.181 mL of triethylamine were added under a nitrogen atmosphere at 0°C, and the mixture was stirred at room temperature for 30 minutes. Water was then added, and the mixture was separated using dichloromethane.
• Example 78 (6-Hydroxy-1-((trans-4-phenoxycyclohexyl)methyl)-1H-pyrrolo[3,2-b]pyridin-3-yl)(morpholino)methanone (1) To a solution of 0.528 g of (trans-4-phenoxycyclohexyl)methanol in 5 mL of dichloromethane was added 0.535 g of methanesulfonic anhydride, 0.886 mL of triethylamine, and 0.031 g of 4-dimethylaminopyridine under a nitrogen atmosphere at 0°C, and the mixture was stirred at room temperature for 2 hours. Water was then added, and the mixture was separated using dichloromethane.
• the resulting organic layer was separated and dried over anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure to obtain the crude product.
• Example 79 (1-((4-(3-aminophenyl)cyclohexyl)methyl)-1H-pyrrolo[3,2-b]pyridin-3-yl)(morpholino)methanone.
• morpholino(1-((3'-nitro-2,3,4,5-tetrahydro-(1,1'-biphenyl)-4-yl)methyl)-1H-pyrrolo[3,2-b]pyridin-3-yl)methanone 0.041 g of palladium-carbon was added under a nitrogen atmosphere, followed by addition of 2 mL of ethanol, and the mixture was stirred at room temperature for 24 hours under a hydrogen atmosphere.
• Example 80 Morpholino(1-(2-(4-phenylpiperazin-1-yl)ethyl)-1H-pyrrolo[3,2-b]pyridin-3-yl)methanone (1).
• Example 81 To a solution of 0.567 g of morpholino(1-(spiro[5.5]undecan-3-ylmethyl)-1H-pyrrolo[3,2-b]pyridin-3-yl)methanone (1) (methoxymethyl)triphenylphosphonium chloride in 5 mL of tetrahydrofuran, 1.034 mL of n-butyllithium (1.6 mol/L hexane solution) was added under a nitrogen atmosphere at ⁇ 78°C, and the mixture was stirred at ⁇ 78°C for 30 minutes. 0.25 g of spiro[5.5]undecan-3-one was then added, and the mixture was stirred at 0°C for 18 hours.
• morpholino(1-(spiro[5.5]undecan-3-ylmethyl)-1H-pyrrolo[3,2-b]pyridin-3-yl)methanone (1) (methoxymethyl)triphenylphosphonium chloride in 5 mL of
• Example 82 (1-((4-(2,4-Dimethoxyphenyl)cyclohexyl)methyl)-1H-pyrrolo[3,2-b]pyridin-3-yl)(morpholino)methanone (1) To 0.062 g of tetrakis(triphenylphosphine)palladium(0), 0.15 g of 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)cyclohex-3-ene-1-carboxylic acid ethyl ester, 0.156 g of 2,4-dimethoxyiodobenzene, and 0.222 g of potassium carbonate, 3 mL of 1,4-dioxane and 1.5 mL of water were added under a nitrogen atmosphere at room temperature and stirred at 90°C for 24 hours.
• the mixture was then filtered through Celite, neutralized with saturated aqueous ammonium chloride, and separated with ethyl acetate.
• the resulting organic layer was separated, washed with saturated brine, dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure to obtain a crude product.
• Example 83 Morpholino(1-((4-(3,4,5-trimethoxyphenyl)cyclohexyl)methyl)-1H-pyrrolo[3,2-b]pyridin-3-yl)methanone (1) tetrakis(triphenylphosphine)palladium(0) 0.062 g, 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)cyclohex-3-ene-1-carboxylic acid ethyl ester 0.15 g, 5-iodo-1,2,3-trimethoxybenzene 0.236 g, and potassium carbonate 0.222 g were added to 1,4-dioxane 3 mL and water 1.5 mL under a nitrogen atmosphere at room temperature, and the mixture was stirred at 90°C for 24 hours.
• the mixture was then filtered through Celite, neutralized with saturated aqueous ammonium chloride, and separated with ethyl acetate.
• the resulting organic layer was separated, washed with saturated brine, dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure to obtain a crude product.
• Example 84 Morpholino(1-((trans-4-(phenoxymethyl)cyclohexyl)methyl)-1H-pyrrolo[3,2-b]pyridin-3-yl)methanone (1) To a solution of 0.15 g of ethyl trans-4-(hydroxymethyl)cyclohexanecarboxylate in 2 mL of toluene, 0.091 g of phenol, 0.253 g of triphenylphosphine, and 0.226 g of bis(2-methoxyethyl)azodicarboxylate were added under a nitrogen atmosphere at 0°C, and the mixture was stirred at room temperature for 18 hours. Water was then added, and the mixture was separated using ethyl acetate.
• the resulting organic layer was separated, washed with saturated brine, dried over anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure to obtain the crude product.
• Example 85 (3-Methylmorpholino)(1-((trans-4-phenylcyclohexyl)methyl)-1H-pyrrolo[3,2-b]pyridin-3-yl)methanone (1) To a solution of 1.007 g of trans-4-phenylcyclohexane-1-carboxaldehyde in 2 mL of ethanol was added 0.304 g of sodium borohydride under a nitrogen atmosphere at 0°C, and the mixture was stirred at room temperature for 12 hours. Water was then added, and the mixture was separated using ethyl acetate. The resulting organic layer was separated, washed with saturated brine, and dried over anhydrous sodium sulfate.
• Example 86 (2-Methylmorpholino)(1-((trans-4-phenylcyclohexyl)methyl)-1H-pyrrolo[3,2-b]pyridin-3-yl)methanone.
• Example 87 (1R,4R)-2-oxa-5-azabicyclo[2.2.1]hept-5-yl(1-((trans-4-phenylcyclohexyl)methyl)-1H-pyrrolo[3,2-b]pyridin-3-yl)methanone 0.015 g of 1-((trans-4-phenylcyclohexyl)methyl)-1H-pyrrolo[3,2-b]pyridine-3-carboxylic acid in 1 mL of N,N-dimethylformamide To the solution, 0.018 g of (1R,4R)-2-oxa-5-azabicyclo[2.2.1]heptane hydrochloride, 0.032 mL of N,N-diisopropylethylamine, and 0.02 g of 1-(bis(dimethylamino)methylene)-1H-1,2,3-triazolo[4,5-b]pyridinium 3-oxide hexafluorophosphate were added under a nitrogen atmosphere at
• Example 88 (1-((trans-4-phenylcyclohexyl)methyl)-1H-pyrrolo[3,2-b]pyridin-3-yl)(thiomorpholino)methanone.
• Example 89 (1-((trans-4-phenylcyclohexyl)methyl)-1H-pyrrolo[3,2-b]pyridin-3-yl)(piperidin-1-yl)methanone.
• Example 90 To a solution of 0.015 g of 1-(1-((trans-4-phenylcyclohexyl)methyl)-1H-pyrrolo[3,2-b]pyridine-3-carbonyl)piperidin-4-one ( 1-((trans-4-phenylcyclohexyl)methyl)-1H-pyrrolo[3,2-b]pyridine-3-carboxylic acid) in 1 mL of N,N-dimethylformamide, 0.018 g of 4-oxopiperidine hydrochloride, 0.032 mL of N,N-diisopropylethylamine, and 0.02 g of 1-(bis(dimethylamino)methylene)-1H-1,2,3-triazolo[4,5-b]pyridinium 3-oxide hexafluorophosphate were added under a nitrogen atmosphere at room temperature, and the mixture was stirred at room temperature for 16 hours.
• Example 91 (4-Methylpiperazin-1-yl)(1-((trans-4-phenylcyclohexyl)methyl)-1H-pyrrolo[3,2-b]pyridin-3-yl)methanone: To a solution of 0.015 g of 1-((trans-4-phenylcyclohexyl)methyl)-1H-pyrrolo[3,2-b]pyridine-3-carboxylic acid in 1 mL of N,N-dimethylformamide, 0.013 g of N-methylpiperazine, 0.013 mL of N,N-diisopropylethylamine, and 0.02 g of 1-(bis(dimethylamino)methylene)-1H-1,2,3-triazolo[4,5-b]pyridinium 3-oxide hexafluorophosphate were added under a nitrogen atmosphere at room temperature, and the mixture was stirred at room temperature for 16 hours.
• Example 92 To a solution of 0.015 g of N,N-dimethyl-1-((trans-4-phenylcyclohexyl)methyl)-1H-pyrrolo[3,2-b]pyridine-3-carboxyamide 1-((trans-4-phenylcyclohexyl)methyl)-1H-pyrrolo[3,2-b]pyridine-3-carboxylic acid in 1 mL of N,N-dimethylformamide, 0.011 g of dimethylamine hydrochloride, 0.013 mL of N,N-diisopropylethylamine, and 0.02 g of 1-(bis(dimethylamino)methylene)-1H-1,2,3-triazolo[4,5-b]pyridinium 3-oxide hexafluorophosphate were added under a nitrogen atmosphere at room temperature, and the mixture was stirred at room temperature for 16 hours.
• Example 93 To a solution of 0.015 g of N,N-diethyl-1-((trans-4-phenylcyclohexyl)methyl)-1H-pyrrolo[3,2-b]pyridine-3-carboxyamide 1-((trans-4-phenylcyclohexyl)methyl)-1H-pyrrolo[3,2-b]pyridine-3-carboxylic acid in 1 mL of N,N-dimethylformamide, 0.015 g of diethylamine hydrochloride, 0.013 mL of N,N-diisopropylethylamine, and 0.02 g of 1-(bis(dimethylamino)methylene)-1H-1,2,3-triazolo[4,5-b]pyridinium 3-oxide hexafluorophosphate were added under a nitrogen atmosphere at room temperature, and the mixture was stirred at room temperature for 16 hours.
• Example 94 To a solution of 0.015 g of N-(2-methoxyethyl)-N-methyl-1-((trans-4-phenylcyclohexyl)methyl)-1H-pyrrolo[3,2-b]pyridine-3-carboxyamide (1-((trans-4-phenylcyclohexyl)methyl)-1H-pyrrolo[3,2-b]pyridine-3-carboxylic acid) in 1 mL of N,N-dimethylformamide, 0.012 g of N-(2-methoxyethyl)methylamine, 0.013 mL of N,N-diisopropylethylamine, and 0.02 g of 1-(bis(dimethylamino)methylene)-1H-1,2,3-triazolo[4,5-b]pyridinium 3-oxide hexafluorophosphate were added under a nitrogen atmosphere at room temperature, and the mixture was stirred at room temperature for 16 hours.
• Example 96 To a solution of 0.015 g of 1-((trans-4-phenylcyclohexyl)methyl)-1H-pyrrolo[3,2-b]pyridin-3-yl)methanone ( 3-hydroxymethylmorpholino)(1-((trans-4-phenylcyclohexyl)methyl)-1H-pyrrolo[3,2-b]pyridine-3-carboxylic acid in 1 mL of N,N-dimethylformamide, 0.016 g of 3-hydroxymethylmorpholine, 0.013 mL of N,N-diisopropylethylamine, and 0.02 g of 1-(bis(dimethylamino)methylene)-1H-1,2,3-triazolo[4,5-b]pyridinium 3-oxide hexafluorophosphate were added under a nitrogen atmosphere at room temperature, and the mixture was stirred at room temperature for 68 hours.
• Example 97 To a solution of 0.015 g of 1-((trans-4-phenylcyclohexyl)methyl)-1H-pyrrolo[3,2-b]pyridin-3-yl)methanone (2-(hydroxymethyl)morpholino )(1-((trans-4-phenylcyclohexyl)methyl)-1H-pyrrolo[3,2-b]pyridine-3-carboxylic acid) in 1 mL of N,N-dimethylformamide, 0.016 g of morpholin-2-ylmethanol, 0.013 mL of N,N-diisopropylethylamine, and 0.02 g of 1-(bis(dimethylamino)methylene)-1H-1,2,3-triazolo[4,5-b]pyridinium 3-oxide hexafluorophosphate were added under a nitrogen atmosphere at room temperature, and the mixture was stirred at room temperature for 68 hours.
• Example 98 (4-Phenoxypiperidin-1-yl)(1-((trans-4-phenylcyclohexyl)methyl)-1H-pyrrolo[3,2-b]pyridin-3-yl)methanone: To a solution of 0.015 g of 1-((trans-4-phenylcyclohexyl)methyl)-1H-pyrrolo[3,2-b]pyridine-3-carboxylic acid in 1 mL of N,N-dimethylformamide, 0.024 g of 4-phenoxypiperidine, 0.013 mL of N,N-diisopropylethylamine, and 0.02 g of 1-(bis(dimethylamino)methylene)-1H-1,2,3-triazolo[4,5-b]pyridinium 3-oxide hexafluorophosphate were added under a nitrogen atmosphere at room temperature, and the mixture was stirred at room temperature for 68 hours.
• Example 100 (1-((trans-4-(4-chlorophenyl)cyclohexyl)methyl)-1H-pyrrolo[3,2-b]pyridin-3-yl)(morpholino)methanone (1) To a solution of 1 g of trans-4-(4-chlorophenyl)cyclohexane-1-carboxylic acid in 5 mL of tetrahydrofuran was added 0.517 mL of dimethyl sulfide borane at room temperature under a nitrogen atmosphere, and the mixture was stirred at room temperature for 23 hours. The reaction mixture was then added dropwise to ice-cooled methanol, and the solvent was evaporated under reduced pressure.
• Example 101 (4-(4-((3-(morpholine-4-carbonyl)-1H-pyrrolo[3,2-b]pyridin-1-yl)methyl)cyclohexyl)phenyl)(morpholino)methanone (1)
• 4-iodobenzoic acid in 2 mL of N,N-dimethylformamide, 0.13 g of morpholine, 0.35 mL of N,N-diisopropylethylamine, and 0.568 g of 1-(bis(dimethylamino)methylene)-1H-1,2,3-triazolo[4,5-b]pyridinium 3-oxide hexafluorophosphate were added under a nitrogen atmosphere at room temperature, and the mixture was stirred for 24 hours at room temperature.
• the mixture was then filtered through Celite, neutralized with saturated aqueous ammonium chloride, and separated with ethyl acetate.
• the resulting organic layer was separated, washed with saturated brine, dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure to obtain a crude product.
• Example 102 (3-(4-((3-(morpholine-4-carbonyl)-1H-pyrrolo[3,2-b]pyridin-1-yl)methyl)cyclohexyl)phenyl)(morpholino)methanone (1)
• 3-iodobenzoic acid in 2 mL of N,N-dimethylformamide, 0.13 g of morpholine, 0.348 mL of N,N-diisopropylethylamine, and 0.565 g of 1-(bis(dimethylamino)methylene)-1H-1,2,3-triazolo[4,5-b]pyridinium 3-oxide hexafluorophosphate were added under a nitrogen atmosphere at room temperature, and the mixture was stirred for 24 hours at room temperature.
• the mixture was then filtered through Celite, neutralized with saturated aqueous ammonium chloride, and separated with ethyl acetate.
• the resulting organic layer was separated, washed with saturated brine, dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure to obtain a crude product.
• Example 103 Morpholino(1-((1-phenylpyrrolidin-3-yl)methyl)-1H-pyrrolo[3,2-b]pyridin-3-yl)methanone (1) To a solution of 0.026 g of (1-phenylpyrrolidin-3-yl)methanol in 3 mL of dichloromethane, 0.03 g of methanesulfonic anhydride, 0.05 mL of triethylamine, and 0.002 g of 4-dimethylaminopyridine were added under a nitrogen atmosphere at 0°C, and the mixture was stirred at room temperature for 30 minutes.
• Example 104 Morpholino(1-((3-phenoxycyclohexyl)methyl)-1H-pyrrolo[3,2-b]pyridin-3-yl)methanone (1) To a solution of 0.3 g of ethyl 3-hydroxycyclohexanecarboxylate in 3 mL of toluene, 0.197 g of phenol, 0.548 g of triphenylphosphine, and 0.49 g of bis(2-methoxyethyl)azodicarboxylate were added under a nitrogen atmosphere at 0°C, and the mixture was stirred at room temperature for 24 hours. Water was then added, and the mixture was separated using ethyl acetate.
• the resulting organic layer was separated, washed with saturated brine, and dried over anhydrous sodium sulfate.
• the solvent was evaporated under reduced pressure to obtain a crude product.
• Example 105 To a solution of 0.075 g of morpholino(1-(4-(pyridin-4-yl)butyl)-1H-pyrrolo[3,2-b]pyridin-3-yl)methanone (morpholin-4-yl)(1H-pyrrolo[3,2-b]pyridin-3-yl)methanone in 3 mL of N,N-dimethylformamide, 0.078 g of sodium tert-butoxide was added at room temperature under a nitrogen atmosphere, and the mixture was stirred at room temperature for 30 minutes.
• Example 106 Morpholino(1-((1-phenylazetidin-3-yl)methyl)-1H-pyrrolo[3,2-b]pyridin-3-yl)methanone (1) To a solution of 0.089 g of (morpholin-4-yl)(1H-pyrrolo[3,2-b]pyridin-3-yl)methanone in 3 mL of N,N-dimethylformamide, 0.074 g of sodium tert-butoxide was added at room temperature under a nitrogen atmosphere, and the mixture was stirred at room temperature for 30 minutes.
• the mixture was then filtered through Celite, neutralized with saturated aqueous ammonium chloride, and separated with ethyl acetate.
• the resulting organic layer was separated, washed with saturated brine, dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure to obtain a crude product.
• Example 107 4-((trans-4-((3-(morpholine-4-carbonyl)-1H-pyrrolo[3,2-b]pyridin-1-yl)methyl)cyclohexyl)oxy)benzonitrile (1) To a solution of 0.21 g of cis-ethyl-4-hydroxycyclohexanecarboxylate in 1 mL of toluene, 0.174 g of 4-cyanophenol, 0.384 g of triphenylphosphine, and 0.343 g of bis(2-methoxyethyl)azodicarboxylate were added under a nitrogen atmosphere at 0°C, and the mixture was stirred at room temperature for 24 hours.
• Example 108 3-((trans-4-((3-(morpholine-4-carbonyl)-1H-pyrrolo[3,2-b]pyridin-1-yl)methyl)cyclohexyl)oxy)benzonitrile (1) To a solution of 0.198 g of cis-ethyl-4-hydroxycyclohexanecarboxylate in 1 mL of toluene, 0.164 g of 3-cyanophenol, 0.362 g of triphenylphosphine, and 0.323 g of bis(2-methoxyethyl)azodicarboxylate were added under a nitrogen atmosphere at 0°C, and the mixture was stirred at room temperature for 24 hours.
• Example 109 (4-(4-((3-(morpholine-4-carbonyl)-1H-pyrrolo[3,2-b]pyridin-1-yl)methyl)cyclohexyl)phenyl) (piperidin-1-yl)methanone (1)
• 4-iodobenzoic acid in 2 mL of N,N-dimethylformamide, 0.128 g of piperidine, 0.351 mL of N,N-diisopropylethylamine, and 0.569 g of 1-(bis(dimethylamino)methylene)-1H-1,2,3-triazolo[4,5-b]pyridinium 3-oxide hexafluorophosphate were added under a nitrogen atmosphere at room temperature, and the mixture was stirred for 24 hours at room temperature.
• the mixture was then filtered through Celite, neutralized with saturated aqueous ammonium chloride, and separated with ethyl acetate.
• the resulting organic layer was separated, washed with saturated brine, dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure to obtain a crude product.
• Example 110 (3-(4-((3-(morpholine-4-carbonyl)-1H-pyrrolo[3,2-b]pyridin-1-yl)methyl)cyclohexyl)phenyl)(piperidin-1-yl)methanone (1)
• 4-iodobenzoic acid in 2 mL of N,N-dimethylformamide, 0.125 g of piperidine, 0.344 mL of N,N-diisopropylethylamine, and 0.559 g of 1-(bis(dimethylamino)methylene)-1H-1,2,3-triazolo[4,5-b]pyridinium 3-oxide hexafluorophosphate were added under a nitrogen atmosphere at room temperature, and the mixture was stirred at room temperature for 24 hours.
• the mixture was then filtered through Celite, neutralized with saturated aqueous ammonium chloride, and separated with ethyl acetate.
• the resulting organic layer was separated, washed with saturated brine, dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure to obtain a crude product.
• Example 111 (1-(2-Hydroxy-4-phenylbutyl)-1H-pyrrolo[3,2-b]pyridin-3-yl)(morpholino)methanone: To a solution of 0.012 g of 1-(3-(morpholine-4-carbonyl)-1H-pyrrolo[3,2-b]pyridin-1-yl)-4-phenylbutan-2-one in 1 mL of methanol and 0.5 mL of tetrahydrofuran, 0.001 g of sodium borohydride was added under a nitrogen atmosphere at 0°C, and the mixture was stirred at room temperature for 1 hour.
• Example 112 (4-(4-(3-(morpholine-4-carbonyl)-1H-pyrrolo[3,2-b]pyridin-1-yl)butyl)phenyl)(morpholino)methanone.
• Example 113 To a solution of 0.025 g of trans-4-((3-(morpholine-4-carbonyl)-1H-pyrrolo[3,2-b]pyridin-1-yl)methyl)cyclohexanecarboxylic acid in 1 mL of N,N-dimethylformamide , 0.007 g of aniline, 0.019 mL of N,N-diisopropylethylamine, and 0.031 g of 1-(bis(dimethylamino)methylene)-1H-1,2,3-triazolo[4,5-b]pyridinium 3-oxide hexafluorophosphate were added under a nitrogen atmosphere at room temperature, and the mixture was stirred at room temperature for 24 hours.
• Example 114 N-Cyclohexyl-4-(4-((3-(morpholine-4-carbonyl)-1H-pyrrolo[3,2-b]pyridin-1-yl)methyl)cyclohexyl)benzamide
• 4-iodobenzoic acid in 2 mL of N,N-dimethylformamide, 0.144 g of cyclohexylamine, 0.34 mL of N,N-diisopropylethylamine, and 0.552 g of 1-(bis(dimethylamino)methylene)-1H-1,2,3-triazolo[4,5-b]pyridinium 3-oxide hexafluorophosphate were added under a nitrogen atmosphere at room temperature, and the mixture was stirred for 24 hours at room temperature.
• the mixture was then filtered through Celite, neutralized with saturated aqueous ammonium chloride, and separated with ethyl acetate.
• the resulting organic layer was separated, washed with saturated brine, dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure to obtain a crude product.

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