Patent Application
20220363667
The present invention relates to cyclic amine compounds having amide bonds, and to a T-type calcium channel blocker containing these as active ingredients.
T-type calcium channels are expressed at the dorsal root ganglia and the spinal cord dorsal horns of primary afferent nerve fibers (Non Patent Literature 1). It has been reported that in knockout mice deficient in T-type calcium channels (Cav3.2 channels), pain-related behaviors in acute pain, inflammatory pain, and visceral pain are reduced (Non Patent Literature 2), and therefore, Cav3.2 channels are closely involved in the transmission of pain. Furthermore, it has been reported that at the dorsal root ganglia of pathological animal models associated with pain such as neuropathic pain (Non Patent Literature 3), painful diabetic neuropathy (Non Patent Literatures 4 and 5), and irritable bowel syndrome (Non Patent Literatures 6), the current density of T-type calcium channel increases, and T-type calcium channels become overactive. Thus, T-type calcium channels can serve as a target for a pain treatment drug of a new mechanism. Since T-type calcium channel blockers have an action mechanism different from that of opioid receptor agonists and α2δ ligands, it is expected that T-type calcium channel blockers may also be effective against chronic pain that is resistant to existing drugs.
Incidentally, regarding the cyclic amine compounds having amide bonds,
a compound represented by the following formula is known in Patent Literature 1:
a compound represented by the following formula is known in Patent Literature 2:
a compound represented by the following formula is known in Patent Literature 3:
and a compound represented by the following formula is known in Patent Literature 4:
However, in the above-described Patent Literatures 1 to 4, there is no description to the effect that these compounds have T-type calcium channel blocking action.
On the other hand, regarding compounds having voltage-dependent T-type calcium channel blocking action,
a compound represented by the following general formula is described in Patent Literature 5:
and a compound represented by the following general formula is described in Patent Literature 6:
Furthermore, a compound (RQ-00311651) represented by the following formula is described in Patent Literature 7:
a compound represented by the following formula is described in Patent Literature 8:
and a compound represented by the following general formula is described in Patent Literature 9:
Also, the inventors of the present invention have filed a patent application (Patent Literature 10) related to a compound represented by the following general formula:
Meanwhile, in the above-described Patent Literature 9, pain is mentioned as a target disease for the compound having T-type calcium channel blocking action, chronic pain is mentioned as a limited target disease, and neuropathic pain is mentioned as a further limited target disease.
Then, in this patent literature, it is described that “pain is classified into chronic and acute pains including neuropathic, inflammatory, cancerous, and visceral pains, and causative diseases thereof include diabetic neuropathy, traumatic neuropathy, nerve compression, strangulation, spinal cord injury, stroke, fibromyalgia, carpal tunnel syndrome, arthrosis deformans, rheumatoid arthritis and multiple sclerosis, herpes zoster, herpes simplex, syphilis, cancer chemotherapy, neuropathy induced by HIV and HIV treatment, chronic arthralgia, postherpetic neuralgia, neuroma pain, trigeminal neuralgia, phantom limb pain, postoperative pain, stump pain, toothache, nerve plexus neuropathy, glossopharyngeal neuralgia, laryngeal neuralgia, migraine, cancerous neuropathy, polyneuropathy, causalgia, low back pain, complex regional pain syndrome (CRPS), and thalamic pain”. Furthermore, it is also described to the effect that pains originating from causes other than the causes listed above are included in the target diseases of the active ingredient described in the above-described patent literature. Also,
it is described to the effect that “the diseases other than pain include diseases associated with disorders in the central nervous system (CNS), diseases associated with disorders in the bladder function, stroke, pruritus, atopic dermatitis, hypertension, hyperaldosteronemia, edema, ischemic heart disease, age-related macular degeneration, cancer, diabetes mellitus, infertility and sexual dysfunction, arrhythmia, and kidney diseases; the diseases associated with disorders in the central nervous system (CNS) include epilepsy, essential tremor, schizophrenia, Parkinson's disease, manic depression, bipolar disorder, depression, anxiety, cognitive impairment, drug dependence, Huntington's disease, and sleep disorders; and the diseases associated with disorders in the bladder function include overactive bladder, and the like”.
It is an object of the present invention to provide cyclic amine compounds having amide bonds, the cyclic amine compounds having T-type calcium channel blocking action, and to provide a T-type calcium channel blocker containing these as active ingredients.
The present inventors conducted an investigation on T-type calcium channel blockers, and as a result, the inventors found that cyclic amine compounds having amide bonds and having structures different from the structures of the compounds described in the above-described Patent Literatures 1 to 10, have excellent T-type calcium channel blocking action, thus completing the present invention.
That is, the present invention relates to a compound represented by the following General Formula (I), a tautomer or a stereoisomer of the compound, a pharmaceutically acceptable salt of the compound, or a solvate of the compound, the tautomer, the stereoisomer, or the salt.
wherein A represents a phenyl which may have a substituent, a 4- to 6-membered heteroaryl ring composed of one to three identical or different heteroatoms selected from an oxygen atom, a sulfur atom, and a nitrogen atom and carbon atoms as ring-constituting atoms, or a heterocondensed ring composed of the heteroaryl ring and either a benzene ring or a 6-membered heteroaryl ring composed of one to two nitrogen atoms and carbon atoms, while herein, the heteroaryl ring or the heterocondensed ring may have a substituent and is bonded to a nitrogen atom of the adjacent cyclic amine by means of a carbon atom constituting these rings;
B represents a phenyl which may have a substituent, a 5- or 6-membered heteroaryl ring composed of one to three identical or different heteroatoms selected from an oxygen atom, a sulfur atom, and a nitrogen atom and carbon atoms as ring-constituting atoms, or a heterocondensed ring composed of the heteroaryl ring and either a benzene ring or a 6-membered heteroaryl ring composed of one to two nitrogen atoms and carbon atoms, while herein, the heteroaryl ring or the heterocondensed ring may have a substituent and is bonded to the adjacent cyclopropane ring by means of a carbon atom constituting these rings;
R1 and R2, which may be identical or different, each represent a hydrogen atom, a halogen atom, a hydroxy group, a C1-8 alkyl group, or a C1-8 alkyl group substituted with one to three halogen atoms;
or R1, R2, and the carbon atom to which R1 and R2 are bonded may be joined together and form a 3- to 5-membered cycloalkyl group;
R3 represents a hydrogen atom, a halogen atom, a carboxyl group, a cyano group, a carbamoyl group, a C1-8 alkyl group, a C1-8 alkoxycarbonyl group, a C1-8 alkyl group substituted with a C1-8 alkoxy group, a C1-8 alkyl group substituted with a hydroxy group, a C1-8 alkyl group substituted with one to three halogen atoms, or a C1-8 alkyl group substituted with an acyloxy group;
or R2 and R3 may be joined together and form methylene or ethylene;
n and m, which may be identical or different, each represent 0 or 1; and p represents 1 or 2;
further, the substituent that may be carried by the phenyl of A, the heteroaryl ring of A, and the heterocondensed ring of A is selected from a C1-8 alkyl group, a C1-8 alkoxy group, a C1-8 alkyl group substituted with one to three halogen atoms, a C1-8 alkoxy group substituted with one to three halogen atoms, a C1-8 alkyl group substituted with a hydroxy group, a C1-8 alkoxy group substituted with a hydroxy group, a hydroxy group, a halogen atom, a cyano group, a C1-8 alkylsulfonyl group, and a C1-8 alkoxy group substituted with a C1-8 alkoxycarbonyl group;
the substituent that may be carried by the phenyl of B, the heteroaryl ring of B, and the heterocondensed ring of B is selected from a C1-8 alkyl group, a C1-8 alkoxy group, a C1-8 alkyl group substituted with one to three halogen atoms, a C1-8 alkoxy group substituted with one to three halogen atoms, a C1-8 alkyl group substituted with a hydroxy group, a C1-8 alkoxy group substituted with a hydroxy group, a hydroxy group, a halogen atom, a cyano group, a nitro group, an amino group, a C1-8 alkylamino group, a C2-12 dialkylamino group, a (C1-8 alkyl) (C1-8 alkoxy-substituted C1-8 alkyl)amino group, a tri (C1-8 alkyl)silyl group, an acylamino group, an (N-acyl)(N—C1-8 alkyl)amino group, a 3- to 6-membered cyclic ether, a cyclic amino group, or a 4- to 6-membered heteroaryl ring composed of one to three identical or different heteroatoms selected from an oxygen atom, a sulfur atom, and a nitrogen atom and carbon atoms as ring-constituting atoms, which may be substituted with a substituent selected from a halogen atom, a C1-8 alkyl group, a C1-8 alkoxy group, a C1-8 alkyl group substituted with one to three halogen atoms, and a C1-8 alkoxy group substituted with one to three halogen atoms, as a substituent; and
here, the cyclic amino group of the substituent that may be carried by the phenyl of B, the heteroaryl ring of B, and the heterocondensed ring of B is selected from pyrrolidino, piperidino, piperazino, 2- or 3-oxopyrrolidino, 2-, 3-, or 4-oxopiperidino, morpholino, 1,1-dioxide thiomorpholino, 1,4-dioxa-8-azaspiro[4.5]decan-8-yl, 2-oxa-6-azaspiro[3.3]heptan-6-yl, 3-oxa-8-azabicyclo[3.2.1]octan-8-yl, 2-oxa-5-azabicyclo[2.2.2]octan-5-yl, and 2-oxa-5-azabicyclo[2.2.1]heptan-5-yl, while such a cyclic amino group may be further substituted with a C1-8 alkyl group, a halogen atom, or an acyl group.
Furthermore, the present invention relates to a compound represented by the following General Formula (II), a tautomer or a stereoisomer of the compound, a pharmaceutically acceptable salt of the compound, or a solvate of the compound, the tautomer, the stereoisomer, or the salt.
wherein A1 represents a phenyl which may have a substituent, a 4- to 6-membered heteroaryl ring composed of one to three identical or different heteroatoms selected from an oxygen atom, a sulfur atom, and a nitrogen atom and carbon atoms as ring-constituting atoms, or a heterocondensed ring composed of the heteroaryl ring and either a benzene ring or a 6-membered heteroaryl ring composed of one to two nitrogen atoms and carbon atoms, while here, the heteroaryl ring or the heterocondensed ring may have a substituent and is bonded to a nitrogen atom of the adjacent pyrrolidine by means of a carbon atom constituting these rings; and
further, the substituent that may be carried by the phenyl of A1, the heteroaryl ring of A1, and the heterocondensed ring of A1 is selected from a C1-8 alkyl group, a C1-8 alkoxy group, a C1-8 alkyl group substituted with one to three halogen atoms, a C1-8 alkoxy group substituted with one to three halogen atoms, a C1-8 alkyl group substituted with a hydroxy group, a C1-8 alkoxy group substituted with a hydroxy group, a hydroxy group, a halogen atom, a cyano group, a C1-8 alkylsulfonyl group, and a C1-8 alkoxy group substituted with a C1-8 alkoxycarbonyl group;
the substituent that may be carried by the phenyl of B1, the heteroaryl ring of B1, and the heterocondensed ring of B1 is selected from a C1-8 alkyl group, a C1-8 alkoxy group, a C1-8 alkyl group substituted with one to three halogen atoms, a C1-8 alkoxy group substituted with one to three halogen atoms, a C1-8 alkyl group substituted with a hydroxy group, a C1-8 alkoxy group substituted with a hydroxy group, a hydroxy group, a halogen atom, a cyano group, a nitro group, an amino group, a C1-8 alkylamino group, a 02-12 dialkylamino group, a (C1-8 alkyl) (C1-8 alkoxy-substituted C1-8 alkyl)amino group, a tri (C1-8 alkyl)silyl group, an acylamino group, an (N-acyl)(N—C1-8 alkyl)amino group, a 3- to 6-membered cyclic ether, a cyclic amino group, or a 4- to 6-membered heteroaryl ring composed of one to three identical or different heteroatoms selected from an oxygen atom, a sulfur atom, and a nitrogen atom and carbon atoms as ring-constituting atoms, which may be substituted with a substituent selected from a halogen atom, a C1-8 alkyl group, a C1-8 alkoxy group, a C1-8 alkyl group substituted with one to three halogen atoms, and a C1-8 alkoxy group substituted with one to three halogen atoms, as a substituent; and
here, the cyclic amino group of the substituent that may be carried by the phenyl of B1, the heteroaryl ring of B1, and the heterocondensed ring of B1 is selected from pyrrolidino, piperidino, piperazino, 2- or 3-oxopyrrolidino, 2-, 3-, or 4-oxopiperidino, morpholino, 1,1-dioxide thiomorpholino, 1,4-dioxa-8-azaspiro[4.5]decan-8-yl, 2-oxa-6-azaspiro[3.3]heptan-6-yl, 3-oxa-8-azabicyclo[3.2.1]octan-8-yl, 2-oxa-5-azabicyclo[2.2.2]octan-5-yl, and 2-oxa-5-azabicyclo[2.2.1]heptan-5-yl, while such a cyclic amino group may be further substituted with a C1-8 alkyl group, a halogen atom, or an acyl group.
Furthermore, the present invention relates to a compound represented by the following General Formula (III), a tautomer or a stereoisomer of the compound, a pharmaceutically acceptable salt of the compound, or a solvate of the compound, the tautomer, the stereoisomer, or the salt.
wherein D, E, F, G, and J are such that any two of them each represent N while the others represent CRs which may be identical or different, or any one of them represents N while the others represent CRs which may be identical or different, or all of them are CRs which may be identical or different;
here, R represents a hydrogen atom, a C1-8 alkyl group, a C1-8 alkoxy group, a C1-8 alkyl group substituted with one to three halogen atoms, a C1-8 alkoxy group which may be substituted with one to three halogen atoms, a C1-8 alkyl group substituted with a hydroxy group, a C1-8 alkoxy group substituted with a hydroxy group, a hydroxy group, a halogen atom, a cyano group, a C1-8 alkylsulfonyl group, or a C1-8 alkoxy group substituted with a C1-8 alkoxycarbonyl group;
Ra1, Ra2, Rb1, and Rb2, which may be identical or different, each represent a hydrogen atom, a halogen atom, a hydroxy group, a C1-8 alkyl group, or a C1-8 alkyl group substituted with one to three halogen atoms;
or Ra1, Ra2, and the carbon atom to which Ra1 and Ra2 are bonded may be joined together and form a 3- to 5-membered cycloalkyl group, or Rb1, Rb2, and the carbon atom to which Rb1 and Rb2 are bonded may be joined together and form a 3- to 5-membered cycloalkyl group; s represents 0, 1, or 2; t represents 1 or 2;
Ba represents a phenyl which may have a substituent, a 5- or 6-membered heteroaryl ring composed of one to three identical or different heteroatoms selected from an oxygen atom, a sulfur atom, and a nitrogen atom and carbon atoms as ring-constituting atoms, or a heterocondensed ring composed of the heteroaryl ring and either a benzene ring or a 6-membered heteroaryl ring composed of one to two nitrogen atoms and carbon atoms, while here, the heteroaryl ring or the heterocondensed ring may have a substituent and is bonded to adjacent X by mean of a carbon atom constituting these rings;
X represents:
here, — represents a linking bond;
R4 and R5, which may be identical or different, each represent a hydrogen atom, deuterium, a hydroxy group, a C1-8 alkyl group, a C1-8 alkyl group substituted with one to three halogen atoms, an amino group, a C1-8 alkylamino group, or a C2-12 dialkylamino group;
or R4, R5, and the carbon atom to which R4 and R5 are bonded may be joined together and form a 3- to 5-membered cycloalkyl group;
further, the substituent that may be carried by the phenyl of Ba, the heteroaryl ring of Ba, and the heterocondensed ring of Ba is selected from a C1-8 alkyl group, a C1-8 alkoxy group, a C1-8 alkyl group substituted with one to three halogen atoms, a C1-8 alkoxy group substituted with one to three halogen atoms, a C1-8 alkyl group substituted with a hydroxy group, a C1-8 alkoxy group substituted with a hydroxy group, a hydroxy group, a halogen atom, a cyano group, a nitro group, an amino group, a C1-8 alkylamino group, a C2-12 dialkylamino group, a (C1-8 alkyl) (C1-8 alkoxy-substituted C1-8 alkyl)amino group, a tri(C1-8 alkyl)silyl group, an acylamino group, an (N-acyl) (N—C1-8 alkyl)amino group, a 3- to 6-membered cyclic ether, a cyclic amino group, or a 4- to 6-membered heteroaryl ring composed of one to three identical or different heteroatoms selected from an oxygen atom, a sulfur atom, and a nitrogen atom and carbon atoms as ring-constituting atoms, which may be substituted with a substituent selected from a halogen atom, a C1-8 alkyl group, a C1-8 alkoxy group, a C1-8 alkyl group substituted with one to three halogen atoms, and a C1-8 alkoxy group substituted with one to three halogen atoms, as a substituent; and
here, the cyclic amino group of the substituent that may be carried by the phenyl of Ba, the heteroaryl ring of Bar and the heterocondensed ring of Ba is selected from pyrrolidino, piperidino, piperazino, 2- or 3-oxopyrrolidino, 2-, 3-, or 4-oxopiperidino, morpholino, 1,1-dioxide thiomorpholino, 1,4-dioxa-8-azaspiro[4.5]decan-8-yl, 2-oxa-6-azaspiro[3.3]heptan-6-yl, 3-oxa-8-azabicyclo[3.2.1]octan-8-yl, 2-oxa-5-azabicyclo[2.2.2]octan-5-yl, and 2-oxa-5-azabicyclo[2.2.1]heptan-5-yl, while such a cyclic amino group may be further substituted with a C1-8 alkyl group, a halogen atom, or an acyl group;
provided that when a 6-membered ring composed of D to J may be a phenyl which may have a substituent, or a pyridazine which may have a substituent, and X represents the following:
Ba represents a heterocondensed ring which may have the above-mentioned substituent.
Furthermore, the present invention relates to a compound represented by the following General Formula (IV), a tautomer or a stereoisomer of the compound, a pharmaceutically acceptable salt of the compound, or a solvate of the compound, the tautomer, the stereoisomer, or the salt.
wherein A2 represents a phenyl which may have a substituent, a 4- to 6-membered heteroaryl ring composed of one to three identical or different heteroatoms selected from an oxygen atom, a sulfur atom, and a nitrogen atom and carbon atoms as ring-constituting atoms, or a heterocondensed ring composed of the heteroaryl ring and either a benzene ring or a 6-membered heteroaryl ring composed of one to two nitrogen atoms and carbon atoms, while herein, the heteroaryl ring or the heterocondensed ring may have a substituent and is bonded to a nitrogen atom of the adjacent cyclic amine by means of a carbon atom constituting these rings;
R01 and R02, which may be identical or different, each represent a hydrogen atom, a halogen atom, a hydroxy group, a C1-8 alkyl group, or a C1-8 alkyl group substituted with one to three halogen atoms;
or R01, R02, and the carbon atom to which Rn and R02 are bonded may be joined together and form a 3- to 5-membered cycloalkyl group;
R03 represents a hydrogen atom, a halogen atom, a carboxyl group, a cyano group, a carbamoyl group, a C1-8 alkyl group, a C1-8 alkoxycarbonyl group, a C1-8 alkyl group substituted with a C1-8 alkoxy group, a C1-8 alkyl group substituted with a hydroxy group, a C1-8 alkyl group substituted with one to three halogen atoms, or a C1-8 alkyl group substituted with an acyloxy group;
or R02 and R03 may be joined together and form methylene or ethylene;
R04 and R05, which may be identical or different, each represent a hydrogen atom, deuterium, a hydroxy group, a C1-8 alkyl group, a C1-8 alkyl group substituted with one to three halogen atoms, an amino group, a C1-8 alkylamino group, or a 02-12 dialkylamino group;
or R04, R05, and the carbon atom to which R04 and R05 are bonded may be joined together and form a 3- to 5-membered cycloalkyl group;
no and mo, which may be identical or different, each represent 0 or 1; and po represents 1 or 2;
further, the substituent that may be carried by the phenyl of A2, the heteroaryl ring of A2, and the heterocondensed ring of A2 is selected from a C1-8 alkyl group, a C1-8 alkoxy group, a C1-8 alkyl group substituted with one to three halogen atoms, a C1-8 alkoxy group substituted with one to three halogen atoms, a C1-8 alkyl group substituted with a hydroxy group, a C1-8 alkoxy group substituted with a hydroxy group, a hydroxy group, a halogen atom, a cyano group, a C1-8 alkylsulfonyl group, and a C1-8 alkoxy group substituted with a C1-8 alkoxycarbonyl group;
the substituent that may be carried by the phenyl of B2, the heteroaryl ring of B2, and the heterocondensed ring of B2 is selected from a C1-8 alkyl group, a C1-8 alkoxy group, a C1-8 alkyl group substituted with one to three halogen atoms, a C1-8 alkoxy group substituted with one to three halogen atoms, a C1-8 alkyl group substituted with a hydroxy group, a C1-8 alkoxy group substituted with a hydroxy group, a hydroxy group, a halogen atom, a cyano group, a nitro group, an amino group, a C1-8 alkylamino group, a 02-12 dialkylamino group, a (C1-8 alkyl)(C1-8 alkoxy-substituted C1-8 alkyl)amino group, a tri (C1-8 alkyl)silyl group, an acylamino group, an (N-acyl)(N—C1-8 alkyl)amino group, a 3- to 6-membered cyclic ether, a cyclic amino group, or a 4- to 6-membered heteroaryl ring composed of one to three identical or different heteroatoms selected from an oxygen atom, a sulfur atom, and a nitrogen atom and carbon atoms as ring-constituting atoms, which may be substituted with a substituent selected from a halogen atom, a C1-8 alkyl group, a C1-8 alkoxy group, a C1-8 alkyl group substituted with one to three halogen atoms, and a 01-8 alkoxy group substituted with one to three halogen atoms, as a substituent; and
here, the cyclic amino group of the substituent that may be carried by the phenyl of B2, the heteroaryl ring of B2, and the heterocondensed ring of B2 is selected from pyrrolidino, piperidino, piperazino, 2- or 3-oxopyrrolidino, 2-, 3-, or 4-oxopiperidino, morpholino, 1,1-dioxide thiomorpholino, 1,4-dioxa-8-azaspiro[4.5]decan-8-yl, 2-oxa-6-azaspiro[3.3]heptan-6-yl, 3-oxa-8-azabicyclo[3.2.1]octan-8-yl, 2-oxa-5-azabicyclo[2.2.2]octan-5-yl, and 2-oxa-5-azabicyclo[2.2.1]heptan-5-yl, while such a cyclic amino group may be further substituted with a C1-8 alkyl group, a halogen atom, or an acyl group;
provided that when A2 represents a phenyl which may have a substituent, a pyridazine which may have a substituent, and a quinazoline which may have a substituent, B2 represents a heterocondensed ring which may have the above-mentioned substituent.
Furthermore, the present invention relates to a compound represented by the following General Formula (V), a tautomer or a stereoisomer of the compound, a pharmaceutically acceptable salt of the compound, or a solvate of the compound, the tautomer, the stereoisomer, or the salt.
wherein A3 represents a phenyl which may have a substituent, a 4- to 6-membered heteroaryl ring composed of one to three identical or different heteroatoms selected from an oxygen atom, a sulfur atom, and a nitrogen atom and carbon atoms as ring-constituting atoms, or a heterocondensed ring composed of the heteroaryl ring and either a benzene ring or a 6-membered heteroaryl ring composed of one to two nitrogen atoms and carbon atoms, while here, the heteroaryl ring or the heterocondensed ring may have a substituent and is bonded to a nitrogen atom of the adjacent pyrrolidine by means of a carbon atom constituting these rings; and
R34 and R35, which may be identical or different, each represent a hydrogen atom, deuterium, a hydroxy group, a C1-8 alkyl group, a C1-8 alkyl group substituted with one to three halogen atoms, an amino group, a C1-8 alkylamino group, or a 02-12 dialkylamino group;
or R34, R35, and the carbon atom to which R34 and R35 are bonded may be joined together and form a 3- to 5-membered cycloalkyl group;
further, the substituent that may be carried by the phenyl of A3, the heteroaryl ring of A3, and the heterocondensed ring of A3 is selected from a C1-8 alkyl group, a C1-8 alkoxy group, a C1-8 alkyl group substituted with one to three halogen atoms, a C1-8 alkoxy group substituted with one to three halogen atoms, a C1-8 alkyl group substituted with a hydroxy group, a C1-8 alkoxy group substituted with a hydroxy group, a hydroxy group, a halogen atom, a cyano group, a C1-8 alkylsulfonyl group, and a C1-8 alkoxy group substituted with a C1-8 alkoxycarbonyl group;
the substituent that may be carried by the phenyl of B3, the heteroaryl ring of B3, and the heterocondensed ring of B3 is selected from a C1-8 alkyl group, a C1-8 alkoxy group, a C1-8 alkyl group substituted with one to three halogen atoms, a C1-8 alkoxy group substituted with one to three halogen atoms, a C1-8 alkyl group substituted with a hydroxy group, a C1-8 alkoxy group substituted with a hydroxy group, a hydroxy group, a halogen atom, a cyano group, a nitro group, an amino group, a C1-8 alkylamino group, a 02-12 dialkylamino group, a (C1-8 alkyl) (C1-8 alkoxy-substituted C1-8 alkyl)amino group, a tri (C1-8 alkyl)silyl group, an acylamino group, an (N-acyl)(N—C1-8 alkyl)amino group, a 3- to 6-membered cyclic ether, a cyclic amino group, or a 4- to 6-membered heteroaryl ring composed of one to three identical or different heteroatoms selected from an oxygen atom, a sulfur atom, and a nitrogen atom and carbon atoms as ring-constituting atoms, which may be substituted with a substituent selected from a halogen atom, a C1-8 alkyl group, a C1-8 alkoxy group, a C1-8 alkyl group substituted with one to three halogen atoms, and a C1-8 alkoxy group substituted with one to three halogen atoms, as a substituent; and
here, the cyclic amino group of the substituent that may be carried by the phenyl of B3, the heteroaryl ring of B3, and the heterocondensed ring of B3 is selected from pyrrolidino, piperidino, piperazino, 2- or 3-oxopyrrolidino, 2-, 3-, or 4-oxopiperidino, morpholino, 1,1-dioxide thiomorpholino, 1,4-dioxa-8-azaspiro[4.5]decan-8-yl, 2-oxa-6-azaspiro[3.3]heptan-6-yl, 3-oxa-8-azabicyclo[3.2.1]octan-8-yl, 2-oxa-5-azabicyclo[2.2.2]octan-5-yl, and 2-oxa-5-azabicyclo[2.2.1]heptan-5-yl, while such a cyclic amino group may be further substituted with a C1-8 alkyl group, a halogen atom, or an acyl group;
provided that when A3 represents a phenyl which may have a substituent, a pyridazine which may have a substituent, and a quinazoline which may have a substituent, B3 represents a heterocondensed ring which may have the above-mentioned substituent.
Furthermore, the present invention relates to a compound represented by the following General Formula (VI), a tautomer or a stereoisomer of the compound, a pharmaceutically acceptable salt of the compound, or a solvate of the compound, the tautomer, the stereoisomer, or the salt.
wherein Rd1, Rd2, and Rd3, which are identical or different, each represent a hydrogen atom, a halogen atom, a C1-8 alkyl group, a C1-8 alkyl group substituted with one to three halogen atoms, a C1-8 alkoxy group, a C1-8 alkoxy group substituted with one to three halogen atoms, a hydroxy group, or a C1-8 alkoxy group substituted with a C1-8 alkoxycarbonyl group;
Rd4 represents a C1-8 alkyl substituted with one to three halogen atoms, a tert-butyl, or a cyclopropyl;
and r represents 0, 1, or 2.
Furthermore, the present invention relates to a pharmaceutical composition containing a compound represented by any of the above-described General Formulae (I) to (VI), a tautomer or a stereoisomer of the compound, a pharmaceutically acceptable salt of the compound, or a solvate of the compound, the tautomer, the stereoisomer, or the salt, as an active ingredient.
Furthermore, the present invention relates to a T-type calcium channel blocker containing a compound represented by any of the above-described General Formulae (I) to (VI), a tautomer or a stereoisomer of the compound, a pharmaceutically acceptable salt of the compound, or a solvate of the compound, the tautomer, the stereoisomer, or the salt, as an active ingredient.
Furthermore, the present invention relates to a therapeutic or prophylactic agent for stroke, atopic dermatitis, hypertension, hyperaldosteronemia, edema, ischemic heart disease, age-related macular degeneration, cancer, diabetes mellitus, infertility, sexual dysfunction, arrhythmia, kidney diseases, epilepsy, essential tremor, schizophrenia, Parkinson's disease, manic depression, bipolar disorder, depression, anxiety, cognitive impairment, drug dependence, Huntington's disease, sleep disorders, or overactive bladder, the therapeutic or prophylactic agent containing a compound represented by any of the above-described General Formulae (I) to (VI), a tautomer or a stereoisomer of the compound, a pharmaceutically acceptable salt of the compound, or a solvate of the compound, the tautomer, the stereoisomer, or the salt, as an active ingredient.
Furthermore, the present invention relates to a therapeutic or prophylactic agent for a disease related to T-type calcium channels, the therapeutic or prophylactic agent containing a compound represented by any of the above-described General Formulae (I) to (VI), a tautomer or a stereoisomer of the compound, a pharmaceutically acceptable salt of the compound, or a solvate of the compound, the tautomer, the stereoisomer, or the salt, as an active ingredient.
Furthermore, the present invention relates to a prophylactic or therapeutic agent for acute pain, chronic pain, or neuropathic pain, the therapeutic or prophylactic agent containing a compound represented by any of the above-described General Formulae (I) to (VI), a tautomer or a stereoisomer of the compound, a pharmaceutically acceptable salt of the compound, or a solvate of the compound, the tautomer, the stereoisomer, or the salt, as an active ingredient.
Furthermore, the present invention relates to the use of a compound represented by any of the above-described General Formulae (I) to (VI), a tautomer or a stereoisomer of the compound, a pharmaceutically acceptable salt of the compound, or a solvate of the compound, the tautomer, the stereoisomer, or the salt, for the prevention or treatment of stroke, atopic dermatitis, hypertension, hyperaldosteronemia, edema, ischemic heart disease, age-related macular degeneration, cancer, diabetes mellitus, infertility, sexual dysfunction, arrhythmia, kidney diseases, epilepsy, essential tremor, schizophrenia, Parkinson's disease, manic depression, bipolar disorder, depression, anxiety, cognitive impairment, drug dependence, Huntington's disease, sleep disorders, or overactive bladder.
Furthermore, the present invention relates to the use of a compound represented by any of the above-described General Formulae (I) to (VI), a tautomer or a stereoisomer of the compound, a pharmaceutically acceptable salt of the compound, or a solvate of the compound, the tautomer, the stereoisomer, or the salt, for the prevention or treatment of acute pain, chronic pain, or neuropathic pain.
Moreover, the present invention relates to a method for treating acute pain, chronic pain, or neuropathic pain in a human being, the method including a step of administering an effective amount of a compound represented by any of the above-described General Formulae (I) to (VI), a tautomer or a stereoisomer of the compound, a pharmaceutically acceptable salt of the compound, or a solvate of the compound, the tautomer, the stereoisomer, or the salt, to a human being.
Furthermore, the present invention relates to the use of a compound represented by any of the above-described General Formulae (I) to (VI), a tautomer or a stereoisomer of the compound, a pharmaceutically acceptable salt of the compound, or a solvate of the compound, the tautomer, the stereoisomer, or the salt, for the production of a T-type calcium channel blocker.
Furthermore, the present invention relates to the use of a compound represented by any of the above-described General Formulae (I) to (VI), a tautomer or a stereoisomer of the compound, a pharmaceutically acceptable salt of the compound, or a solvate of the compound, the tautomer, the stereoisomer, or the salt, for the production of a prophylactic agent or a therapeutic agent for stroke, atopic dermatitis, hypertension, hyperaldosteronemia, edema, ischemic heart disease, age-related macular degeneration, cancer, diabetes mellitus, infertility, sexual dysfunction, arrhythmia, kidney diseases, epilepsy, essential tremor, schizophrenia, Parkinson's disease, manic depression, bipolar disorder, depression, anxiety, cognitive impairment, drug dependence, Huntington's disease, sleep disorders, or overactive bladder.
Furthermore, the present invention relates to the use of a compound represented by any of the above-described General Formulae (I) to (VI), a tautomer or a stereoisomer of the compound, a pharmaceutically acceptable salt of the compound, or a solvate of the compound, the tautomer, the stereoisomer, or the salt, for the production of a prophylactic agent or a therapeutic agent for acute pain, chronic pain, or neuropathic pain.
The compound of the present invention has excellent T-type calcium channel blocking action.
Next, the present invention will be described in more detail.
According to the present specification, the C1-8, alkyl group may be a linear, branched, or cyclic alkyl group such as a methyl group, an ethyl group, a propyl group, an isopropyl group, a butyl group, a cyclopropyl group, a cyclopentyl group, a cyclohexyl group, an isobutyl group, a tert-butyl group, a pentyl group, or a hexyl group.
The C1-8 alkyl group substituted with one to three halogen atoms may be a methyl group, an ethyl group, a propyl group, an isopropyl group, a butyl group, a tert-butyl group, or the like, each group being substituted with one to three of a halogen atom such as a fluorine atom, a chlorine atom, or a bromine atom, and preferred examples include a trifluoromethyl group, a chloromethyl group, a 2-chloroethyl group, a 2-bromoethyl group, a 2-fluoroethyl group, and the like.
The C1-8 alkoxy group may be a methoxy group, an ethoxy group, a propoxy group, an isopropoxy group, a butoxy group, an isobutoxy group, a tert-butoxy group, a pentyloxy group, a hexyloxy group, or the like.
The C1-8 alkoxy group substituted with one to three halogen atoms may be a methoxy group, an ethoxy group, a propoxy group, an isopropoxy group, a butoxy group, a tert-butoxy group, or the like, each group being substituted with one to three of a halogen atom such as a fluorine atom, a chlorine atom, or a bromine atom, and preferred examples include a trifluoromethoxy group, a chloromethoxy group, a 2-chloroethoxy group, a 2-bromoethoxy group, a 2-fluoroethoxy group, a 2,2,2-trifluoroethoxy group, and the like.
The halogen atom may be a fluorine atom, a chlorine atom, a bromine atom, or the like.
The C1-8 alkoxycarbonyl group may be a methoxycarbonyl group, an ethoxycarbonyl group, a butoxycarbonyl group, a tert-butoxycarbonyl group, or the like.
The acyl group may be preferably an acyl group having 1 to 7 carbon atoms, and more preferred examples include an acetyl group, a propionyl group, a benzoyl group, and the like.
The C1-8 alkyl group substituted with a hydroxy group may be a hydroxymethyl group, a 2-hydroxypropan-2-yl, or the like.
The C1-8 alkyl group substituted with an acyloxy group may be an acetyloxymethyl group, or the like.
The C1-8 alkoxy group substituted with a hydroxy group may be a 2-hydroxyethoxy group, or the like.
The C1-8 alkylsulfonyl group may be a methanesulfonyl group or the like.
The (C1-8 alkoxy-substituted C1-8 alkyl)amino group may be a (2-methoxyethyl)amino group, or the like.
The 3-membered to 5-membered cycloalkyl group may be a cyclopropyl group, a cyclobutyl group, or the like.
The C1-8 alkylamino group may be an ethylamino group, or the like.
The C2-12 dialkylamino group may be a dimethylamino group, a diethylamino group, or the like.
The (C1-8 alkyl) (C1-8 alkoxy-substituted C1-8 alkyl)amino group may be an N-ethyl-N-(2-methoxyethyl)amino group, or the like.
The tri(C1-8 alkyl)silyl group may be a trimethylsilyl group, a triethylsilyl group, or the like.
The acylamino group may be an acetylamino group, or the like.
The (N-acyl) (N—C1-8 alkyl)amino group may be an (N-acetyl) (N-ethyl)amino group, or the like.
The 3-membered to 6-membered cyclic ether may be THF, oxetane, or the like.
The C1-8 alkyl group substituted with a C1-8 alkoxy group may be a linear, branched, or cyclic alkyl group such as a methyl group, an ethyl group, a propyl group, an isopropyl group, a butyl group, a cyclopropyl group, a cyclopentyl group, a cyclohexyl group, an isobutyl group, a tert-butyl group, a pentyl group, or a hexyl group, each group being substituted with an alkoxy group having 1 to 6 carbon atoms, such as a methoxy group, an ethoxy group, a propoxy group, an isopropoxy group, a butoxy group, an isobutoxy group, a tert-butoxy group, a pentyloxy group, or a hexyloxy group.
The C1-8 alkoxy group substituted with a C1-8 alkoxycarbonyl group may be an isopropyloxy group substituted with ethoxycarbonyl, or the like.
The 4-membered to 6-membered heteroaryl ring composed of one to three identical or different heteroatoms selected from an oxygen atom, a sulfur atom, and a nitrogen atom and carbon atoms as ring-constituting atoms for A of General Formula (I), A1 of General Formula (II), A2 of General Formula (IV), and A3 of General Formula (V), may be pyridine, pyrazine, pyrimidine, pyridazine, oxazole, thiazole, pyrimidine, furan, thiophene, or the like.
The heterocondensed ring composed of a 4-membered to 6-membered heteroaryl ring composed of one to three identical or different heteroatoms selected from an oxygen atom, a sulfur atom, and a nitrogen atom and carbon atoms as ring-constituting atoms and a benzene ring or a 6-membered heteroaryl ring composed of one to two nitrogen atoms and carbon atoms, for A of General Formula (I), A1 of General Formula (II), A2 of General Formula (IV), and A3 of General Formula (V), may be quinoline, isoquinoline, benzimidazole, benzothiazole, pyridopyrazine, purine, imidazo[1,2-a]pyridine, or the like.
The 5-membered or 6-membered heteroaryl ring composed of one to three identical or different heteroatoms selected from an oxygen atom, a sulfur atom, and a nitrogen atom and carbon atoms as ring-constituting atoms for B of General Formula (I), B1 of General Formula (II), Ba of General Formula (III), B2 of General Formula (IV), and B3 of General Formula (V), may be pyridine, pyrazole, pyrrole, oxazole, or the like.
The heterocondensed ring composed of a 5-membered or 6-membered heteroaryl ring composed of one to three identical or different heteroatoms selected from an oxygen atom, a sulfur atom, and a nitrogen atom and carbon atoms as ring-constituting atoms and either a benzene ring or a 6-membered heteroaryl ring composed of one to two nitrogen atoms and carbon atoms, for B of General Formula (I), B1 of General Formula (II), Ba of General Formula (III), B2 of General Formula (IV), and B3 of General Formula (V), may be benzimidazole, benzoxazole, indazole, indole, pyridopyrazine, quinoline, quinazoline, benzothiazole, benzo[1,2,3]triazole, or the like.
The 4-membered to 6-membered heteroaryl ring composed of one to three identical or different heteroatoms selected from an oxygen atom, a sulfur atom, and a nitrogen atom and carbon atoms as ring-constituting atoms, which may have a substituent, the heteroaryl ring being a substituent that may be carried by the phenyl of B, the heteroaryl ring of B, and the heterocondensed ring of B in General Formula (I), may be oxazole, pyrazole, pyrazine, or the like.
Examples of the 4-membered to 6-membered heteroaryl ring composed of one to three identical or different heteroatoms selected from an oxygen atom, a sulfur atom, and a nitrogen atom and carbon atoms as ring-constituting atoms, which may have a substituent, in B1 of General Formula (II), Ba of General Formula (III), B2 of General Formula (IV), and B3 of General Formula (V), also include similar ones.
Furthermore, the number of substituents that may be carried by the phenyl, the 4-membered to 6-membered heteroaryl ring composed of one to three identical or different heteroatoms selected from an oxygen atom, a sulfur atom, and a nitrogen atom and carbon atoms as ring-constituting atoms, or the heterocondensed ring composed of the heteroaryl ring and either a benzene ring or a 6-membered heteroaryl ring composed of one to two nitrogen atoms and carbon atoms for A in General Formula (I), is preferably 1 to 5. Similarly, the rings for A′ of General Formula (II), A2 of General Formula (IV), or A3 of General Formula (V) may also have a similar number of substituents.
Furthermore, the number of substituents that may be carried by the phenyl, the 5-membered or 6-membered heteroaryl ring composed of one to three identical or different heteroatoms selected from an oxygen atom, a sulfur atom, and a nitrogen atom and carbon atoms as ring-constituting atoms, or the heterocondensed ring composed of the heteroaryl ring and either a benzene ring or a 6-membered heteroaryl ring composed of one to two nitrogen atoms and carbon atoms for B in General Formula (I), is preferably 1 to 5. Similarly, the rings for B1 of General Formula (II), Ba of General Formula (III), B2 of General Formula (IV), or B3 of General Formula (V) may also have a similar number of substituents.
(1) Among the above-described compound represented by General Formula (I), a tautomer or a stereoisomer of the compound, a pharmaceutically acceptable salt of the compound, or a solvate of the compound, the tautomer, the stereoisomer, or the salt, preferred examples include the following compounds.
(2)
The compound represented by General Formula (I), a tautomer or a stereoisomer of the compound, a pharmaceutically acceptable salt of the compound, or a solvate of the compound, the tautomer, the stereoisomer, or the salt, wherein A represents a phenyl which may have a substituent.
(3)
The compound represented by General Formula (I), a tautomer or a stereoisomer of the compound, a pharmaceutically acceptable salt of the compound, or a solvate of the compound, the tautomer, the stereoisomer, or the salt, wherein A represents a 4-membered to 6-membered heteroaryl ring composed of one to three identical or different heteroatoms selected from an oxygen atom, a sulfur atom, and a nitrogen atom and carbon atoms as ring-constituting atoms, which may have a substituent.
(4)
The compound described in the above item (3), a tautomer or a stereoisomer of the compound, a pharmaceutically acceptable salt of the compound, or a solvate of the compound, the tautomer, the stereoisomer, or the salt, wherein the heteroaryl ring of A is thiophene, oxazole, thiazole, pyridine, pyrazine, pyrimidine, or pyridazine.
(5)
The compound represented by General Formula (I), a tautomer or a stereoisomer of the compound, a pharmaceutically acceptable salt of the compound, or a solvate of the compound, the tautomer, the stereoisomer, or the salt, wherein A represents an optionally substituted heterocondensed ring of a 4-membered to 6-membered heteroaryl ring composed of one to three identical or different heteroatoms selected from an oxygen atom, a sulfur atom, and a nitrogen atom and carbon atoms as ring-constituting atoms, and a benzene ring.
(6)
The compound described in the above item (5), a tautomer or a stereoisomer of the compound, a pharmaceutically acceptable salt of the compound, or a solvate of the compound, the tautomer, the stereoisomer, or the salt, wherein the heterocondensed ring of A is quinoline or benzo[d]thiazole.
(7)
The compound represented by General Formula (I) or the compound described in any one of the above items (2) to (6), a tautomer or a stereoisomer of the compound, a pharmaceutically acceptable salt of the compound, or a solvate of the compound, the tautomer, the stereoisomer, or the salt, wherein B represents a phenyl which may have a substituent.
(8)
The compound represented by General Formula (I) or the compound described in any one of the above items (2) to (6), a tautomer or a stereoisomer of the compound, a pharmaceutically acceptable salt of the compound, or a solvate of the compound, the tautomer, the stereoisomer, or the salt, wherein B represents a 5-membered or 6-membered heteroaryl ring composed of one to three identical or different heteroatoms selected from an oxygen atom, a sulfur atom, and a nitrogen atom and carbon atoms as ring-constituting atoms, which may have a substituent.
(9)
The compound described in the above item (8), a tautomer or a stereoisomer of the compound, a pharmaceutically acceptable salt of the compound, or a solvate of the compound, the tautomer, the stereoisomer, or the salt, wherein the heteroaryl ring of B is pyridine.
(10)
The compound represented by General Formula (I) or the compound described in any one of the above items (2) to (6), a tautomer or a stereoisomer of the compound, a pharmaceutically acceptable salt of the compound, or a solvate of the compound, the tautomer, the stereoisomer, or the salt, wherein B represents an optionally substituted heterocondensed ring of a 5-membered or 6-membered heteroaryl ring composed of one to three identical or different heteroatoms selected from an oxygen atom, a sulfur atom, and a nitrogen atom and carbon atoms as ring-constituting atoms, and a benzene ring.
(11)
The compound described in the above item (10), a tautomer or a stereoisomer of the compound, a pharmaceutically acceptable salt of the compound, or a solvate of the compound, the tautomer, the stereoisomer, or the salt, wherein the heterocondensed ring of B is indole, benzimidazole, indazole, benzoxazole, benzothiazole, benzo[d][1,2,3]triazole, or quinoline.
(12)
The compound represented by General Formula (I) or the compound described in any one of the above items (2) to (11), a tautomer or a stereoisomer of the compound, a pharmaceutically acceptable salt of the compound, or a solvate of the compound, the tautomer, the stereoisomer, or the salt, wherein n is 1, and m is 0.
(13)
The compound represented by General Formula (I) or the compound described in any one of the above items (2) to (12), a tautomer or a stereoisomer of the compound, a pharmaceutically acceptable salt of the compound, or a solvate of the compound, the tautomer, the stereoisomer, or the salt, wherein p is 1.
(14)
The compound represented by General Formula (I) or the compound described in any one of the above items (2) to (13), a tautomer or a stereoisomer of the compound, a pharmaceutically acceptable salt of the compound, or a solvate of the compound, the tautomer, the stereoisomer, or the salt, wherein R1 and R2 each represent a hydrogen atom.
(15)
The compound represented by General Formula (I) or the compound described in any one of the above items (2) to (14), a tautomer or a stereoisomer of the compound, a pharmaceutically acceptable salt of the compound, or a solvate of the compound, the tautomer, the stereoisomer, or the salt, wherein R3 represents a hydrogen atom.
(16) Among the above-described compound represented by General Formula (II), a tautomer or a stereoisomer of the compound, a pharmaceutically acceptable salt of the compound, or a solvate of the compound, the tautomer, the stereoisomer, or the salt, preferred examples include the following compounds.
(17)
The compound represented by General Formula (II), a tautomer or a stereoisomer of the compound, a pharmaceutically acceptable salt of the compound, or a solvate of the compound, the tautomer, the stereoisomer, or the salt, wherein A1 represents a phenyl which may have a substituent.
(18)
The compound represented by General Formula (II), a tautomer or a stereoisomer of the compound, a pharmaceutically acceptable salt of the compound, or a solvate of the compound, the tautomer, the stereoisomer, or the salt, wherein A1 represents a 4-membered to 6-membered heteroaryl ring composed of one to three identical or different heteroatoms selected from an oxygen atom, a sulfur atom, and a nitrogen atom and carbon atoms as ring-constituting atoms, which may have a substituent.
(19)
The compound described in the above item (18), a tautomer or a stereoisomer of the compound, a pharmaceutically acceptable salt of the compound, or a solvate of the compound, the tautomer, the stereoisomer, or the salt, wherein the heteroaryl ring of A1 is thiophene, oxazole, thiazole, pyridine, pyrazine, pyrimidine, or pyridazine.
(20)
The compound described in the above item (18), a tautomer or a stereoisomer of the compound, a pharmaceutically acceptable salt of the compound, or a solvate of the compound, the tautomer, the stereoisomer, or the salt, wherein the heteroaryl ring of A1 is pyridine.
(21)
The compound represented by General Formula (II), a tautomer or a stereoisomer of the compound, a pharmaceutically acceptable salt of the compound, or a solvate of the compound, the tautomer, the stereoisomer, or the salt, wherein A1 represents an optionally substituted heterocondensed ring of a 4-membered to 6-membered heteroaryl ring composed of one to three identical or different heteroatoms selected from an oxygen atom, a sulfur atom, and a nitrogen atom and carbon atoms as ring-constituting atoms, and a benzene ring.
(22)
The compound described in the above item (21), a tautomer or a stereoisomer of the compound, a pharmaceutically acceptable salt of the compound, or a solvate of the compound, the tautomer, the stereoisomer, or the salt, wherein the heterocondensed ring of A1 is quinoline or benzo[d]thiazole.
(23)
The compound represented by General Formula (II) or the compound described in any one of the above items (17) to (22), a tautomer or a stereoisomer of the compound, a pharmaceutically acceptable salt of the compound, or a solvate of the compound, the tautomer, the stereoisomer, or the salt, wherein BI represents a phenyl which may have a substituent.
(24)
The compound represented by General Formula (II) or the compound described in any one of the above items (17) to (22), a tautomer or a stereoisomer of the compound, a pharmaceutically acceptable salt of the compound, or a solvate of the compound, the tautomer, the stereoisomer, or the salt, wherein B1 represents a 5-membered or 6-membered heteroaryl ring composed of one to three identical or different heteroatoms selected from an oxygen atom, a sulfur atom, and a nitrogen atom and carbon atoms as ring-constituting atoms, which may have a substituent.
(25)
The compound described in the above item (24), a tautomer or a stereoisomer of the compound, a pharmaceutically acceptable salt of the compound, or a solvate of the compound, the tautomer, the stereoisomer, or the salt, wherein the heteroaryl ring of B1 is pyridine.
(26)
The compound represented by General Formula (II) or the compound described in any one of the above items (17) to (22), a tautomer or a stereoisomer of the compound, a pharmaceutically acceptable salt of the compound, or a solvate of the compound, the tautomer, the stereoisomer, or the salt, wherein B1 represents an optionally substituted heterocondensed ring of a 5-membered or 6-membered heteroaryl ring composed of one to three identical or different heteroatoms selected from an oxygen atom, a sulfur atom, and a nitrogen atom and carbon atoms as ring-constituting atoms, and a benzene ring.
(27)
The compound described in the above item (26), a tautomer or a stereoisomer of the compound, a pharmaceutically acceptable salt of the compound, or a solvate of the compound, the tautomer, the stereoisomer, or the salt, wherein the heterocondensed ring of B1 is indole, benzimidazole, indazole, benzoxazole, benzothiazole, benzo[d][1,2,3]triazole, or quinoline.
(28)
The compound described in the above item (26), a tautomer or a stereoisomer of the compound, a pharmaceutically acceptable salt of the compound, or a solvate of the compound, the tautomer, the stereoisomer, or the salt, wherein the heterocondensed ring of B1 is benzo[d]oxazole.
(29) Among the above-described compound represented by General Formula (III), a tautomer or a stereoisomer of the compound, a pharmaceutically acceptable salt of the compound, or a solvate of the compound, the tautomer, the stereoisomer, or the salt, preferred examples include the following compounds.
(30)
The compound represented by General Formula (III), a tautomer or a stereoisomer of the compound, a pharmaceutically acceptable salt of the compound, or a solvate of the compound, the tautomer, the stereoisomer, or the salt, wherein D and J both represent CH.
(31)
The compound represented by General Formula (III), a tautomer or a stereoisomer of the compound, a pharmaceutically acceptable salt of the compound, or a solvate of the compound, the tautomer, the stereoisomer, or the salt, wherein any one of D, E, F, G, and J represents N, and the others each represent CR.
(32)
The compound represented by General Formula (III), a tautomer or a stereoisomer of the compound, a pharmaceutically acceptable salt of the compound, or a solvate of the compound, the tautomer, the stereoisomer, or the salt, wherein D, E, F, and J, which may be identical or different, each represent CR, and G represents N.
(33)
The compound represented by General Formula (III) or the compound described in any one of the above items (30) to (32), a tautomer or a stereoisomer of the compound, a pharmaceutically acceptable salt of the compound, or a solvate of the compound, the tautomer, the stereoisomer, or the salt, wherein Ba represents a phenyl which may have a substituent.
(34)
The compound represented by General Formula (III) or the compound described in any one of the above items (30) to (32), a tautomer or a stereoisomer of the compound, a pharmaceutically acceptable salt of the compound, or a solvate of the compound, the tautomer, the stereoisomer, or the salt, wherein Ba represents a 5-membered or 6-membered heteroaryl ring composed of one to three identical or different heteroatoms selected from an oxygen atom, a sulfur atom, and a nitrogen atom and carbon atoms as ring-constituting atoms, which may have a substituent.
(35)
The compound described in the above item (34), a tautomer or a stereoisomer of the compound, a pharmaceutically acceptable salt of the compound, or a solvate of the compound, the tautomer, the stereoisomer, or the salt, wherein the heteroaryl ring of Ba is pyridine.
(36)
The compound represented by General Formula (III) or the compound described in any one of the above items (30) to (32), a tautomer or a stereoisomer of the compound, a pharmaceutically acceptable salt of the compound, or a solvate of the compound, the tautomer, the stereoisomer, or the salt, wherein Ba represents an optionally substituted heterocondensed ring of a 5-membered or 6-membered heteroaryl ring composed of one to three identical or different heteroatoms selected from an oxygen atom, a sulfur atom, and a nitrogen atom and carbon atoms as ring-constituting atoms, and a benzene ring.
(37)
The compound described in the above item (36), a tautomer or a stereoisomer of the compound, a pharmaceutically acceptable salt of the compound, or a solvate of the compound, the tautomer, the stereoisomer, or the salt, wherein the heterocondensed ring of Ba is indole, benzimidazole, indazole, benzoxazole, benzothiazole, benzo[d][1,2,3]triazole, or quinoline.
(38)
The compound described in the above item (36), a tautomer or a stereoisomer of the compound, a pharmaceutically acceptable salt of the compound, or a solvate of the compound, the tautomer, the stereoisomer, or the salt, wherein the heterocondensed ring of Ba is benzoxazole.
(39)
The compound represented by General Formula (III) or the compound described in any one of the above items (30) to (38), a tautomer or a stereoisomer of the compound, a pharmaceutically acceptable salt of the compound, or a solvate of the compound, the tautomer, the stereoisomer, or the salt, wherein s is 1.
(40)
The compound represented by General Formula (III) or the compound described in any one of the above items (30) to (39), a tautomer or a stereoisomer of the compound, a pharmaceutically acceptable salt of the compound, or a solvate of the compound, the tautomer, the stereoisomer, or the salt, wherein t is 1.
(41)
The compound represented by General Formula (III) or the compound described in any one of the above items (30) to (40), a tautomer or a stereoisomer of the compound, a pharmaceutically acceptable salt of the compound, or a solvate of the compound, the tautomer, the stereoisomer, or the salt, wherein Ra1, Ra2, Rb1, and Rb2 each represent a hydrogen atom.
(42)
The compound represented by General Formula (III) or the compound described in any one of the above items (30) to (41), a tautomer or a stereoisomer of the compound, a pharmaceutically acceptable salt of the compound, or a solvate of the compound, the tautomer, the stereoisomer, or the salt, wherein X represents the following:
(43)
The compound represented by General Formula (III) or the compound described in any one of the above items (30) to (41), a tautomer or a stereoisomer of the compound, a pharmaceutically acceptable salt of the compound, or a solvate of the compound, the tautomer, the stereoisomer, or the salt, wherein X represents the following:
(44)
The compound described in the above item (43), a tautomer or a stereoisomer of the compound, a pharmaceutically acceptable salt of the compound, or a solvate of the compound, the tautomer, the stereoisomer, or the salt, wherein the R4 and R5 each represent a hydrogen atom.
(45) Among the above-described compound represented by General Formula (IV), a tautomer or a stereoisomer of the compound, a pharmaceutically acceptable salt of the compound, or a solvate of the compound, the tautomer, the stereoisomer, or the salt, preferred examples include the following compounds.
(46)
The compound represented by General Formula (IV), a tautomer or a stereoisomer of the compound, a pharmaceutically acceptable salt of the compound, or a solvate of the compound, the tautomer, the stereoisomer, or the salt, wherein A2 represents a phenyl which may have a substituent.
(47)
The compound represented by General Formula (IV), a tautomer or a stereoisomer of the compound, a pharmaceutically acceptable salt of the compound, or a solvate of the compound, the tautomer, the stereoisomer, or the salt, wherein A2 represents a 4-membered to 6-membered heteroaryl ring composed of one to three identical or different heteroatoms selected from an oxygen atom, a sulfur atom, and a nitrogen atom and carbon atoms as ring-constituting atoms, which may have a substituent.
(48)
The compound described in the above item (47), a tautomer or a stereoisomer of the compound, a pharmaceutically acceptable salt of the compound, or a solvate of the compound, the tautomer, the stereoisomer, or the salt, wherein the heteroaryl ring of A2 is thiophene, oxazole, thiazole, pyridine, pyrazine, pyrimidine, or pyridazine.
(49)
The compound represented by General Formula (IV), a tautomer or a stereoisomer of the compound, a pharmaceutically acceptable salt of the compound, or a solvate of the compound, the tautomer, the stereoisomer, or the salt, wherein A2 represents an optionally substituted heterocondensed ring of a 4-membered to 6-membered heteroaryl ring composed of one to three identical or different heteroatoms selected from an oxygen atom, a sulfur atom, and a nitrogen atom and carbon atoms as ring-constituting atoms, and a benzene ring.
(50)
The compound described in the above item (49), a tautomer or a stereoisomer of the compound, a pharmaceutically acceptable salt of the compound, or a solvate of the compound, the tautomer, the stereoisomer, or the salt, wherein the heterocondensed ring of A2 is quinoline or benzo[d]thiazole.
(51)
The compound represented by General Formula (IV) or the compound described in any one of the above items (46) to (50), a tautomer or a stereoisomer of the compound, a pharmaceutically acceptable salt of the compound, or a solvate of the compound, the tautomer, the stereoisomer, or the salt, wherein B2 represents a phenyl which may have a substituent.
(52)
The compound represented by General Formula (IV) or the compound described in any one of the above items (46) to (50), a tautomer or a stereoisomer of the compound, a pharmaceutically acceptable salt of the compound, or a solvate of the compound, the tautomer, the stereoisomer, or the salt, wherein B2 represents a 5-membered or 6-membered heteroaryl ring composed of one to three identical or different heteroatoms selected from an oxygen atom, a sulfur atom, and a nitrogen atom and carbon atoms as ring-constituting atoms, which may have a substituent.
(53)
The compound described in the above item (52), a tautomer or a stereoisomer of the compound, a pharmaceutically acceptable salt of the compound, or a solvate of the compound, the tautomer, the stereoisomer, or the salt, wherein the heteroaryl ring of B2 is pyridine.
(54)
The compound represented by General Formula (IV) or the compound described in any one of the above items (46) to (50), a tautomer or a stereoisomer of the compound, a pharmaceutically acceptable salt of the compound, or a solvate of the compound, the tautomer, the stereoisomer, or the salt, wherein B2 represents an optionally substituted heterocondensed ring of a 5-membered or 6-membered heteroaryl ring composed of one to three identical or different heteroatoms selected from an oxygen atom, a sulfur atom, and a nitrogen atom and carbon atoms as ring-constituting atoms, and a benzene ring.
(55)
The compound described in the above item (54), a tautomer or a stereoisomer of the compound, a pharmaceutically acceptable salt of the compound, or a solvate of the compound, the tautomer, the stereoisomer, or the salt, wherein the heterocondensed ring of B2 is indole, benzimidazole, indazole, benzoxazole, benzothiazole, benzo[d][1,2,3]triazole, or quinoline.
(56)
The compound represented by General Formula (IV) or the compound described in any one of the above items (46) to (55), a tautomer or a stereoisomer of the compound, a pharmaceutically acceptable salt of the compound, or a solvate of the compound, the tautomer, the stereoisomer, or the salt, wherein no is 1, and mo is 0.
(57)
The compound represented by General Formula (IV) or the compound described in any one of the above items (46) to (56), a tautomer or a stereoisomer of the compound, a pharmaceutically acceptable salt of the compound, or a solvate of the compound, the tautomer, the stereoisomer, or the salt, wherein po is 1.
(58)
The compound represented by General Formula (IV) or the compound described in any one of the above items (46) to (57), a tautomer or a stereoisomer of the compound, a pharmaceutically acceptable salt of the compound, or a solvate of the compound, the tautomer, the stereoisomer, or the salt, wherein R0′ and R02 each represent a hydrogen atom.
(59)
The compound represented by General Formula (IV) or the compound described in any one of the above items (46) to (58), a tautomer or a stereoisomer of the compound, a pharmaceutically acceptable salt of the compound, or a solvate of the compound, the tautomer, the stereoisomer, or the salt, wherein R03 represents a hydrogen atom.
(60)
The compound represented by General Formula (IV) or the compound described in any one of the above items (46) to (59), a tautomer or a stereoisomer of the compound, a pharmaceutically acceptable salt of the compound, or a solvate of the compound, the tautomer, the stereoisomer, or the salt, wherein R04 and R05 each represent a hydrogen atom.
(61) Among the above-described compound represented by General Formula (V), a tautomer or a stereoisomer of the compound, a pharmaceutically acceptable salt of the compound, or a solvate of the compound, the tautomer, the stereoisomer, or the salt, preferred examples include the following compounds.
(62)
The compound represented by General Formula (V), a tautomer or a stereoisomer of the compound, a pharmaceutically acceptable salt of the compound, or a solvate of the compound, the tautomer, the stereoisomer, or the salt, wherein A3 represents a phenyl which may have a substituent.
(63)
The compound represented by General Formula (V), a tautomer or a stereoisomer of the compound, a pharmaceutically acceptable salt of the compound, or a solvate of the compound, the tautomer, the stereoisomer, or the salt, wherein A3 represents a 4-membered to 6-membered heteroaryl ring composed of one to three identical or different heteroatoms selected from an oxygen atom, a sulfur atom, and a nitrogen atom and carbon atoms as ring-constituting atoms, which may have a substituent.
(64)
The compound described in the above item (63), a tautomer or a stereoisomer of the compound, a pharmaceutically acceptable salt of the compound, or a solvate of the compound, the tautomer, the stereoisomer, or the salt, wherein the heteroaryl ring of A3 is thiophene, oxazole, thiazole, pyridine, pyrazine, pyrimidine, or pyridazine.
(65)
The compound described in the above item (63), a tautomer or a stereoisomer of the compound, a pharmaceutically acceptable salt of the compound, or a solvate of the compound, the tautomer, the stereoisomer, or the salt, wherein the heteroaryl ring of A3 is pyridine.
(66)
The compound represented by General Formula (V), a tautomer or a stereoisomer of the compound, a pharmaceutically acceptable salt of the compound, or a solvate of the compound, the tautomer, the stereoisomer, or the salt, wherein A3 represents an optionally substituted heterocondensed ring of a 4-membered to 6-membered heteroaryl ring composed of one to three identical or different heteroatoms selected from an oxygen atom, a sulfur atom, and a nitrogen atom and carbon atoms as ring-constituting atoms, and a benzene ring.
(67)
The compound described in the above item (66), a tautomer or a stereoisomer of the compound, a pharmaceutically acceptable salt of the compound, or a solvate of the compound, the tautomer, the stereoisomer, or the salt, wherein the heterocondensed ring of A3 is quinoline or benzo[d]thiazole.
(68)
The compound represented by General Formula (V) or the compound described in any one of the above items (62) to (67), a tautomer or a stereoisomer of the compound, a pharmaceutically acceptable salt of the compound, or a solvate of the compound, the tautomer, the stereoisomer, or the salt, wherein B3 represents a phenyl which may have a substituent.
(69)
The compound represented by General Formula (V) or the compound described in any one of the above items (62) to (67), a tautomer or a stereoisomer of the compound, a pharmaceutically acceptable salt of the compound, or a solvate of the compound, the tautomer, the stereoisomer, or the salt, wherein B3 represents a 5-membered or 6-membered heteroaryl ring composed of one to three identical or different heteroatoms selected from an oxygen atom, a sulfur atom, and a nitrogen atom and carbon atoms as ring-constituting atoms, which may have a substituent.
(70)
The compound described in the above item (69), a tautomer or a stereoisomer of the compound, a pharmaceutically acceptable salt of the compound, or a solvate of the compound, the tautomer, the stereoisomer, or the salt, wherein the heteroaryl ring of B3 is pyridine.
(71)
The compound represented by General Formula (V) or the compound described in any one of the above items (62) to (67), a tautomer or a stereoisomer of the compound, a pharmaceutically acceptable salt of the compound, or a solvate of the compound, the tautomer, the stereoisomer, or the salt, wherein B3 represents an optionally substituted heterocondensed ring of a 5-membered or 6-membered heteroaryl ring composed of one to three identical or different heteroatoms selected from an oxygen atom, a sulfur atom, and a nitrogen atom and carbon atoms as ring-constituting atoms, and a benzene ring.
(72)
The compound described in the above item (71), a tautomer or a stereoisomer of the compound, a pharmaceutically acceptable salt of the compound, or a solvate of the compound, the tautomer, the stereoisomer, or the salt, wherein the heterocondensed ring of B3 is indole, benzimidazole, indazole, benzoxazole, benzothiazole, benzo[d][1,2,3]triazole, or quinoline.
(73)
The compound represented by General Formula (V) or the compound described in any one of the above items (62) to (72), a tautomer or a stereoisomer of the compound, a pharmaceutically acceptable salt of the compound, or a solvate of the compound, the tautomer, the stereoisomer, or the salt, wherein R34 and R35 both represent a hydrogen atom.
(74) Among the above-described compound represented by General Formula (VI), a tautomer or a stereoisomer of the compound, a pharmaceutically acceptable salt of the compound, or a solvate of the compound, the tautomer, the stereoisomer, or the salt, preferred examples include the following compounds.
(75)
The compound represented by General Formula (VI), a tautomer or a stereoisomer of the compound, a pharmaceutically acceptable salt of the compound, or a solvate of the compound, the tautomer, the stereoisomer, or the salt, wherein Rd1, Rd2, and Rd3 each differently represent a hydrogen atom, a halogen atom, a C1-8 alkyl group, a C1-8 alkyl group substituted with one to three halogen atoms, or a C1-8 alkoxy group.
(76)
The compound represented by General Formula (VI) or the compound described in the above item (75), a tautomer or a stereoisomer of the compound, a pharmaceutically acceptable salt of the compound, or a solvate of the compound, the tautomer, the stereoisomer, or the salt, wherein Rd4 represents trifluoromethyl or cyclopropyl.
(77)
The compound represented by General Formula (VI) or the compound described in the above item (75) or (76), a tautomer or a stereoisomer of the compound, a pharmaceutically acceptable salt of the compound, or a solvate of the compound, the tautomer, the stereoisomer, or the salt, wherein r is 1.
(78) Moreover, the compound of the present invention is preferably any of the following compounds, a tautomer or a stereoisomer of the compound, a pharmaceutically acceptable salt of the compound, or a solvate of the compound, the tautomer, the stereoisomer, or the salt.
A compound selected from the following:
a tautomer or a stereoisomer of the compound, a pharmaceutically acceptable salt of the compound, or a solvate of the compound, the tautomer, the stereoisomer, or the salt.
Examples of pharmacologically acceptable salts of the compounds represented by the above-described General Formulae (I) to (VI) include acid addition salts with mineral acids such as hydrochloric acid, sulfuric acid, and phosphoric acid; acid addition salts with organic acids such as formic acid, acetic acid, citric acid, tartaric acid, and methanesulfonic acid; salts with inorganic bases, such as sodium salts, potassium salts, lithium salts, and calcium salts; and addition salts with organic bases such as arginine and piperazine.
Furthermore, the compounds of the present invention may have cis/trans isomers, optically active substances, and stereoisomers such as racemates; however, all of them are included in the present invention, and mixtures of enantiomers or diastereomers are also included in the present invention.
Furthermore, the compounds of the present invention also include stable isotopes.
Furthermore, the compounds of the present invention also include a compound in which the pyridine in Example 134 that will be described below is pyridine 1-oxide, a compound in which the pyridine is pyrrolidine 1-oxide or piperidine 1-oxide, and the like.
Moreover, the compounds of the present invention may also be tautomers, hydrates, solvates with an organic solvent such as an alcohol, derivatives substituted with a stable isotope such as deuterium, or prodrugs.
General Synthesis Method
The compounds of the present invention can be each produced using commercially available compounds as raw materials and using any known method or the method described below. Examples of the known method include the methods described in Lectures on Experimental Chemistry, 5th Edition (Maruzen Publishing Co., Ltd.), New Edition Heterocyclic Compounds (KODANSHA LTD.), Protective Groups in Organic Synthesis (Wiley), and the like.
Depending on the compounds produced using the present production method, protection or deprotection and conversion or introduction of functional groups may be effective in the various stages of production. In such a case, the operation or procedure is not limited to the operation or procedure of the described production method, and any appropriate operation or procedure can be applied using known methods.
A prodrug of a compound of the present invention can be produced by applying any known method such as amidation, esterification, or alkylation in the various stages of production.
Depending on the compound produced using the present production method, various salts, hydrates, and crystal polymorphisms may be included. Furthermore, in a case in which an optical isomer, a geometric isomer, or a tautomer may exist, unless particularly limited, a mixture at any ratio may be included. A mixture of these isomers can be separated by any known method.
A method for producing the compounds of the present invention will be described below; however, the method for producing the compound of the present invention is not limited to the following method.
In the present specification, the following abbreviations may be used.
M: molar concentration, N: normal, MS: mass spectrum, [M+H]+: protonated molecular ion peak, [M+Na]+: sodium adduct molecular ion peak, [M−H]−: deprotonated molecular ion peak, CDCl3: deuterated chloroform, DMSO-d6: deuterated dimethyl sulfoxide, CD3OD: deuterated methanol, 1H NMR: proton nuclear magnetic resonance, br s: broad singlet, Me: methyl group, Et: ethyl group, t-Bu: tert-butyl group, CN: cyano group, CF3: trifluoromethyl group, Ts: p-toluenesulfonyl group, Boc: tert-butoxycarbonyl group, DMF: N,N-dimethylformamide, THF: tetrahydrofuran, DME: 1,2-dimethoxyethane, HATU: 0-(7-azabenzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium hexafluorophosphate, HOBT: 1-hydroxybenzotriazole, WSC: 1-ethyl-3-(dimethylaminopropyl)carbodiimide, DMT-MM: 4-(4,6-dimethoxy-1,3,5-triazin-2-yl)-4-methylmorpholinium chloride, DMAP: N,N-dimethyl-4-aminopyridine, DIBAL-H: diisobutylaluminum hydride, L-selectride: tri(sec-butyl)boron lithium hydride, DIPEA: N,N-diisopropylethylamine, BINAP: 2,2′-bis(diphenylphosphino)-1,1′-binaphthyl, DMSO: dimethyl sulfoxide, FBS: fetal bovine serum, DMEM: Dulbecco's modified Eagle medium, 002: carbon dioxide, NaCl: sodium chloride, KCl: potassium chloride, MgCl2: magnesium chloride, CaCl2: calcium chloride, CsCl: cesium chloride, CsF: cesium fluoride, HEPES: 4-(2-hydroxyethyl)-1-piperazine ethanesulfonic acid, EGTA: glycol ether diamine 4 tetraacetic acid, CYP: cytochrome P450, NADP or NADP+: nicotinamide adenine dinucleotide phosphate, G-6-P: glucose-6-phosphate, G-6-P DH(Y): glucose-6-phosphate dehydrogenase (yeast-derived), PSNL: partial sciatic nerve ligation
A production method for General Formula (Z) will be described below.
In the general formula, Az represents A in the compound represented by General Formula (I) and a 6-membered ring including D to J in the compound represented by General Formula (III),
represents the following in the compound represented by General Formula (I):
or the following in the compound represented by the above-described General Formula (III):
X represents the following in the compound represented by General Formula (I) or the compound represented by General Formula (III):
or the following in the compound represented by General Formula (III):
and Bz represents B in the compound represented by General Formula (I) or Ba in the compound represented by General Formula (III):
Compounds represented by General Formula (II), General Formula (IV), General Formula (V), and General Formula (VI) can also be similarly produced.
Method for producing compound (Z)
The above-described compound (Z) can be produced by, for example, the method shown below.
(Production Method 1)
wherein the reference symbols have the same meanings as described above.
Compound (Z) can be produced by causing compound (Z-A) to react with compound (Z-B) in an appropriate solvent such as DMF in the presence of a condensing agent such as HATU or WSC, and if necessary, in the presence of an additive such as HOBT or DMAP and if necessary, a base such as triethylamine or DIPEA, at 0° C. to 100° C.
Furthermore, the compound can be produced by causing compound (Z-A) to react with a carboxylic acid chloride or carboxylic acid anhydride corresponding to compound (Z-B) in an appropriate solvent such as tetrahydrofuran, and if necessary, in the presence of a base such as triethylamine, DIPEA, or pyridine, at 0° C. to 100° C.
In addition to that, the compound can be produced from compound (Z-A) and compound (Z-B), or compounds respectively equivalent thereto, using the condensation reaction described in Christian A. G. N. Montalbetti, et al, Tetrahedron, 61(46), 2005, 10827-10852, or a condensation reaction equivalent thereto.
Compound (Z-A) can be produced by, for example, the method described below.
wherein Prg means a protective group and represents an arbitrary functional group that can be converted to hydrogen by a deprotection reaction;
and the other reference symbols have the same meanings as described above.
Compound (Z-A) can be produced by causing compound (Z-C) to react with an acid such as hydrogen chloride or trifluoroacetic acid at −10° C. to 100° C. in an appropriate solvent such as methanol, or without solvent.
Furthermore, compound (Z-A) can be produced by subjecting compound (Z-C) to a hydrogenation reaction using a catalyst such as palladium-carbon or palladium hydroxide at 0° C. to 100° C. in an appropriate solvent such as methanol.
In addition to that, compound (Z-A) can be produced from compound (Z-C) or a compound equivalent thereto using a deprotection reaction for a protective group, which is described in Protective Groups in Organic Synthesis (Wiley) or the like, or a deprotection reaction equivalent thereto.
Compound (Z-C) can be produced by, for example, the method described below.
wherein Prg means a protective group and
represents any arbitrary functional group that can be converted to hydrogen by a deprotection reaction; Lv represents a leaving group; and the other reference symbols have the same meanings as described above.
Compound (Z-C) can be produced by causing compound (Z-D) to react with compound (Z-E) in an appropriate solvent such as DMF in the presence of a metal catalyst such as tris(dibenzylidene acetone)dipalladium or copper iodide, and if necessary, in the presence of a ligand such as BINAP or ethylenediamine, and if necessary, a base such as triethylamine or DIPEA, at 0° C. to 200° C. Regarding the leaving group, an appropriate functional group such as a halogen or a tosyl group is used.
In addition to that, compound (Z-C) can be produced by causing compound (Z-D) to react with compound (Z-E) in an appropriate solvent such as DMF, in the presence of a base such as sodium hydride or cesium carbonate, at 0° C. to 200° C.
Furthermore, the compound can be produced from compound (Z-D) and compound (Z-E), or compounds respectively equivalent thereto, using reactions equivalent to these reactions.
Compound (Z-D) can be a commercially available product or can be produced from a commercially available product according to a known method. For example, the compound can be produced from appropriate starting raw materials by combining known methods according to the synthesis methods described in known patent literatures such as WO 2014/159969, WO 2012/154274, WO 2017/190609, and WO 2016/027195, or according to synthesis methods equivalent to those.
Compound (Z-E) can be a commercially available product or can be produced from a commercially available product according to a known method. For example, the compound can be produced from appropriate starting raw materials by combining known methods according to the synthesis methods described in a known academic literature, Cottet Fabrice, et al, Eur. J. Org. Chem. (2), 2002, 327-330, or known patent literatures such as WO 2013/088404 and WO 2010/064707, or according to synthesis methods equivalent to those.
Compound (Z-B) can be produced by, for example, the method described below.
wherein Prg means a protective group and
represents any arbitrary functional group that can be converted to hydrogen by a deprotection reaction; the other reference symbols have the same meanings as described above.
Compound (Z-B) can be produced from compound (Z-F) by causing the compound to react with a base such as lithium hydroxide or sodium hydroxide in an appropriate solvent such as a mixed solvent of water and methanol or tetrahydrofuran, at 0° C. to 100° C.
In addition to that, the compound can be produced from compound (Z-F) or a compound equivalent thereto using a deprotection reaction for a protective group, which is described in Protective Groups in Organic Synthesis (Wiley) or the like, or a deprotection reaction equivalent thereto.
Compound (Z-F) can be a commercially available product or can be produced from a commercially available product according to a known method. For example, the compound can be produced from appropriate starting raw materials by combining known methods according to the synthesis methods described in known patent literatures such as WO 2017/122754, WO 2013/026914, and WO 2015/073528 and academic literatures such as Radoslaw Laufer, Bioorg. Med. Chem, 22(17), 2014, 4968-4997, or according to synthesis methods equivalent to those.
Furthermore, compound (Z-B) can be a commercially available product or can be produced from a commercially available product according to a known method. For example, the compound can be produced from appropriate starting raw materials by combining known methods according to the synthesis methods described in known patent literatures such as WO 2013/144295, WO 2014/010748, and WO 2008/125337, or according to synthesis methods equivalent to those.
(Production Method 2)
wherein Lv represents a leaving group; and the other reference symbols have the same meanings as described above.
Compound (Z) of the present invention can be produced by causing compound (Z-E) to react with compound (Z-G) in an appropriate solvent such as DMF in the presence of a metal catalyst such as tris(dibenzylidene acetone)dipalladium or copper iodide, and if necessary, in the presence of a ligand such as BINAP or ethylenediamine, and if necessary, a base such as triethylamine or DIPEA, at 0° C. to 200° C. Regarding the leaving group, an appropriate functional group such as a halogen or a tosyl group is used.
In addition to that, compound (Z) can be produced by causing compound (Z-E) to react with compound (Z-G) in an appropriate solvent such as DMF in the presence of a base such as sodium hydride or cesium carbonate at 0° C. to 200° C.
Furthermore, the compound can be produced from compound (Z-E) and compound (G-G), or compounds respectively equivalent thereto, using reactions equivalent to these reactions.
Compound (Z-G) can be produced by, for example, the method described below.
wherein Prg means a protective group and
represents any arbitrary functional group that can be converted to hydrogen by a deprotection reaction; the other reference symbols have the same meanings as described above.
Compound (Z-G) can be produced by causing compound (Z-H) to react with an acid such as hydrochloric acid or trifluoroacetic acid at −10° C. to 100° C. in an appropriate solvent such as methanol or chloroform, or without solvent.
Furthermore, compound (Z-G) can be produced by subjecting compound (Z-H) to a hydrogenation reaction using a catalyst such as palladium-carbon or palladium hydroxide at 0° C. to 100° C. in an appropriate solvent such as methanol or THF.
In addition to that, the compound can be produced from compound (Z-H) or a compound equivalent thereto using a deprotection reaction for a protective group, which is described in Protective Groups in Organic Synthesis (Wiley) or the like, or a deprotection reaction equivalent thereto.
Compound (Z-H) can be produced by, for example, the method described below.
wherein Prg means a protective group and
represents any arbitrary functional group that can be converted to hydrogen by a deprotection reaction; the other reference symbols have the same meanings as described above.
Compound (Z-H) can be produced by causing compound (Z-B) to react with compound (Z-I) in an appropriate solvent such as DMF in the presence of a condensing agent such as HATU or WSC, and if necessary, in the presence of an additive such as HOBT or DMAP and if necessary, a base such as triethylamine or DIPEA, at 0° C. to 100° C.
Furthermore, the compound can be produced by causing compound (Z-I) to react with a carboxylic acid chloride or carboxylic acid anhydride corresponding to compound (Z-B) in an appropriate solvent such as tetrahydrofuran, and if necessary, in the presence of a base such as triethylamine, DIPEA, or pyridine, at 0° C. to 100° C.
In addition to that, the compound can be produced from compound (Z-B) and compound (Z-I), or compounds respectively equivalent thereto, using the condensation reaction described in Christian A. G. N. Montalbetti, et al, Tetrahedron, 61(46), 2005, 10827-10852, or a condensation reaction equivalent thereto.
Compound (Z-I) can be a commercially available product or can be produced from a commercially available product according to a known method. For example, the compound can be produced from appropriate starting raw materials by combining known methods according to the synthesis methods described in known patent literatures such as WO 2016/100154, WO 2012/125893, and WO 2008/013130 and academic literatures such as Kyoji Tomita, J. Med. Chem, 45(25), 2002, 5564-5575, or according to synthesis methods equivalent to those.
Next, the pharmacological action of the compounds of the present invention will be described.
In Example 188 that will be described below, the results for a pharmacological experiment on the T-type calcium blocking action of the compounds of the present invention obtained by using cells that steadily express human Cav3.2 channels and measuring the intracellular calcium concentration are described.
As is obvious from Tables 1 to 4, it has been made clear that the compounds of the present invention have excellent T-type calcium blocking action.
Meanwhile, it is known that calcium channels have a property referred to as state-dependence.
That is, calcium channels adopt three states, namely, a stationary (closed) state, an activated (activated, open) state, and an inactivated (inactivated) state, depending on the difference in the membrane potential.
The compounds of the present invention also include compounds having superior voltage-dependent T-type calcium channel blocking action in an inactivated state compared to a stationary state or a closed state, and these are expected to have selective voltage-dependent T-type calcium channel blocking action.
Furthermore, the occasion of neuropathic pain is in a state in which depolarization is repeated; however, the compounds of the present invention also include compounds having a property in which antagonistic action is enhanced in such a state (frequency-dependence).
Furthermore, in Example 189 that will be described below, a formalin pain test using SD rats was performed, and as a result, the compounds of the present invention exhibited excellent pain behavioral suppression.
Moreover, in Example 190 that will be described below, in a pharmacological experiment for mechanical allodynia in a mouse partial sciatic nerve ligation (PSNL) model, as is obvious from
Therefore, the compounds of the present invention have excellent T-type calcium channel blocking action, and the compounds are highly safe T-type calcium channel blockers without causing serious side effects such as cardiotoxicity (hERG) and can be used for diseases such as neuropathic pain.
That is, the target diseases of the compounds of the present invention include pain as described in Patent Literature 9, limited target diseases include chronic pain, and more limited target diseases include neuropathic pain.
Furthermore, as described in the above-mentioned patent literatures, “pain is classified into chronic and acute pains including neuropathic, inflammatory, cancerous, and visceral pains, and causative diseases thereof include diabetic neuropathy, traumatic neuropathy, nerve compression, strangulation, spinal cord injury, stroke, fibromyalgia, carpal tunnel syndrome, arthrosis deformans, rheumatoid arthritis and multiple sclerosis, herpes zoster, herpes simplex, syphilis, cancer chemotherapy, neuropathy induced by HIV and HIV treatment, chronic arthralgia, postherpetic neuralgia, neuroma pain, trigeminal neuralgia, phantom limb pain, postoperative pain, stump pain, toothache, nerve plexus neuropathy, glossopharyngeal neuralgia, laryngeal neuralgia, migraine, cancerous neuropathy, polyneuropathy, causalgia, low back pain, complex regional pain syndrome (CRPS), and thalamic pain.” Furthermore, pains originating from causes other than the causes listed above are also included in the target diseases of the present invention. Further, as described in the literatures, examples of the target diseases other than pain include “diseases associated with disorders in the central nervous system (CNS), diseases associated with disorders in the bladder function, stroke, pruritus, atopic dermatitis, hypertension, hyperaldosteronemia, edema, ischemic heart disease, age-related macular degeneration, cancer, diabetes mellitus, infertility and sexual dysfunction, arrhythmia, and kidney diseases; the diseases associated with disorders in the central nervous system (CNS) include epilepsy, essential tremor, schizophrenia, Parkinson's disease, manic depression, bipolar disorder, depression, anxiety, cognitive impairment, drug dependence, Huntington's disease, and sleep disorders; and the diseases associated with disorders in the bladder function include overactive bladder,” and the like.
Furthermore, the compounds of the present invention can also be used in combination with known therapeutic agents for pain.
The compounds of the present invention can be administered by any suitable administration method such as oral administration or parenteral administration; and oral administration is preferred.
In order to formulate the compounds, formulations such as a tablet, granules, a powder, a capsule, a suspension, an injectable preparation, and a suppository can be produced by conventional methods in the technical field of preparation.
For the preparation of these, for example, in the case of a tablet, conventional excipients, disintegrants, binders, lubricating agents, colorants, and the like are used. Here, examples of the excipients include lactose, D-mannitol, crystalline cellulose, glucose, and the like; examples of the disintegrants include starch, carboxymethyl cellulose calcium (CMC-Ca), and the like; examples of the lubricating agents include magnesium stearate, talc, and the like; and examples of the binders include hydroxypropyl cellulose (HPC), gelatin, polyvinylpyrrolidone (PVP), and the like. For the preparation of an injectable preparation, a solvent, a stabilizer, a dissolution aid, a suspending agent, an emulsifier, a soothing agent, a buffering agent, a preservative, and the like are used.
The amount of administration is such that usually for an adult, each of the compounds of the present invention as an active ingredient for an injectable preparation is administered in an amount of about 0.01 mg to 100 mg per day, and in an amount of 1 mg to 2,000 mg per day by oral administration; however, the amount of administration can be increased or decreased according to the age, symptoms, and the like.
Next, the present invention will be described in more detail by way of Reference Examples and Examples; however, the present invention is not intended to be limited to these.
Regarding the column, PLC, and TLC used in Reference Examples and Examples, unless particularly stated otherwise, either silica gel or NH silica gel, or both of them were used. For an analysis of a synthesized compound, 1H-NMR (400 MHz), atmospheric pressure ionization high-resolution time-of-flight mass spectrometry (ESI), and other appropriate analysis methods were used.
Regarding the compound names of Reference Examples and Examples, a compound was denominated based on the name obtained by converting the structural formula drawn using any one of ChemDraw ver. 13, 14, or 15 manufactured by CambridgeSoft Corporation, by means of the denomination algorithm installed in the same software program.
3-Bromo-5-(trifluoromethyl)pyridine (230 mg, 1.02 mmol), tert-butyl (R)-pyrrolidin-3-ylcarbamate (190 mg, 1.02 mmol), tris(dibenzylidene acetone)dipalladium(0) (93 mg, 0.10 mmol), BINAP (67 mg, 0.22 mmol), and sodium tert-butoxide (196 mg, 2.04 mmol) were suspended in toluene (4.0 mL), and the suspension was stirred for 3 hours at 85° C. under a nitrogen gas stream. To the reaction liquid that had been left to cool to room temperature, water was added, the mixture was stirred for a while, and then the mixture was extracted with ethyl acetate. An organic layer thus separated was dried over anhydrous sodium sulfate, insoluble materials were filtered, and then the solvent was distilled off under reduced pressure. A residue thus obtained was purified by silica gel column chromatography (heptane:ethyl acetate) (concentration gradient: 0 to 100%), and thus the title compound (white amorphous, 116 mg, 34%) was obtained.
1H NMR (CDCl3, 400 MHz): δ=1.46 (s, 9H), 1.9-2.1 (m, 1H), 2.2-2.4 (m, 1H), 3.23 (dd, 1H, J=4.10 Hz), 3.3-3.6 (m, 2H), 3.65 (dd, 1H, J=6.10 Hz), 4.40 (br s, 1H), 4.69 (br s, 1H), 6.9-7.0 (m, 1H), 8.12 (d, 1H, J=3 Hz), 8.21 (s, 1H).
To tert-butyl (R)-(1-(5-(trifluoromethyl)pyridin-3-yl)pyrrolidin-3-yl)carbamate (116 mg, 0.35 mmol) synthesized in Reference Example 1-1, trifluoroacetic acid (2.0 mL) was added under ice cooling, and the mixture was stirred for 1 hour at room temperature. Under ice cooling, a saturated aqueous solution of sodium hydrogen carbonate and ethyl acetate were added to the reaction liquid, the mixture was stirred for a while, subsequently the organic layer was dried over anhydrous sodium sulfate, insoluble materials were filtered, subsequently the solvent was distilled off under reduced pressure, and thus the title compound (brown oily material, 60 mg, 74%) was obtained.
1H NMR (CDCl3, 400 MHz): δ=1.8-1.9 (m, 1H), 2.2-2.3 (m, 1H), 3.08 (dd, 1H, J=4.10 Hz), 3.3-3.5 (m, 1H), 3.5-3.6 (m, 2H), 3.7-3.9 (m, 1H), 6.92 (dd, 1H, J=2.2 Hz), 8.11 (d, 1H, J=3 Hz), 8.17 (s, 1H).
The 2H content is not observable.
According to a technique similar to Reference Example 1-1, the title compound (white powder, 41 mg, 3.0%) was obtained using 5-bromo-2-(trifluoromethyl)pyrimidine (940 mg, 4.14 mmol) and tert-butyl (R)-pyrrolidin-3-ylcarbamate (950 mg, 5.10 mmol).
1H NMR (CDCl3, 400 MHz): δ=1.46 (s, 9H), 2.0-2.1 (m, 1H), 2.3-2.5 (m, 1H), 3.28 (dd, 1H, J=4.10 Hz), 3.4-3.6 (m, 2H), 3.70 (dd, 1H, J=6.10 Hz), 4.3-4.5 (m, 1H), 4.68 (br s, 1H), 8.10 (s, 2H).
3-Bromo-5-(trifluoromethyl)pyridine (134 mg, 0.59 mmol), tert-butyl ((3S,4S)-4-hydroxypyrrolidin-3-yl)carbamate (100 mg, 0.49 mmol), tris(dibenzylidene acetone)dipalladium(0) (45 mg, 0.05 mmol), XantPhos (57 mg, 0.10 mmol), and potassium carbonate (137 mg, 0.99 mmol) were suspended in toluene (5.0 mL), and the suspension was stirred for 16 hours at 85° C. under a nitrogen gas stream. To the reaction liquid that had been left to cool to room temperature, ethyl acetate was added, insoluble materials were filtered through Celite, and the solvent was distilled off under reduced pressure. A residue thus obtained was purified by silica gel column chromatography, and the title compound (white crystals, 106 mg, 62%) was obtained.
1H
3-Bromo-5-(trifluoromethyl)pyridine (383 mg, 1.70 mmol), tert-butyl (R)-(5-azaspiro[2.4]heptan-7-yl)carbamate (300 mg, 1.41 mmol), tris(dibenzylidene acetone)dipalladium(0) (93 mg, 0.10 mmol), XantPhos (164 mg, 0.28 mmol), and sodium tert-butoxide (272 mg, 2.83 mmol) were suspended in toluene (14 mL), and the suspension was stirred for 16 hours at 85° C. under a nitrogen gas stream. To the reaction liquid that had been left to cool to room temperature, ethyl acetate was added, insoluble materials were filtered through Celite, and the solvent was distilled off under reduced pressure. A residue thus obtained was purified by silica gel column chromatography (heptane:ethyl acetate) (concentration gradient: 0 to 100%), and the title compound (yellow crystals, 336 mg, 67%) was obtained.
1H NMR (CDCl3, 400 MHz): δ=0.7-0.8 (m, 2H), 0.8-1.0 (m, 2H), 1.44 (s, 9H), 3.10 (d, 1H, J=10 Hz), 3.5-3.6 (m, 1H), 3.63 (d, 1H, J=9 Hz), 3.7-3.8 (m, 1H), 3.8-3.9 (m, 1H), 4.78 (br s, 1H), 6.9-7.0 (m, 1H), 8.09 (d, 1H, J=3 Hz), 8.21 (s, 1H).
According to a technique similar to Reference Example 4, the title compound (yellow crystals, 271 mg, 80%) was obtained using tert-butyl (R)-(5-azaspiro[2.4]heptan-7-yl)carbamate (200 mg, 0.94 mmol) and 5-bromo-2-(trifluoromethyl)pyridine (255 mg, 1.13 mmol).
1H NMR (CDCl3, 400 MHz): δ=0.7-0.8 (m, 2H), 0.8-1.0 (m, 2H), 1.44 (s, 9H), 3.11 (d, 1H, J=10 Hz), 3.5-3.6 (m, 1H), 3.63 (d, 1H, J=9 Hz), 3.7-3.8 (m, 1H), 3.8-3.9 (m, 1H), 4.76 (br s, 1H), 6.80 (dd, 1H, J=3.9 Hz), 7.49 (d, 1H, J=9 Hz), 7.98 (d, 1H, J=3 Hz).
According to a technique similar to Reference Example 4, the title compound (yellow crystals, 192 mg, 56%) was obtained using tert-butyl (R)-(5-azaspiro[2.4]heptan-7-yl)carbamate (200 mg, 0.94 mmol) and 2-bromo-4-(trifluoromethyl)thiazole (255 mg, 1.10 mmol).
1H NMR (CDCl3, 400 MHz): δ=0.6-0.8 (m, 2H), 0.8-1.0 (m, 2H), 1.44 (s, 9H), 3.32 (d, 1H, J=10 Hz), 3.57 (d, 1H, J=8 Hz), 3.74 (d, 1H, J=11 Hz), 3.8-3.9 (m, 2H), 4.77 (br s, 1H), 6.93 (d, 1H, J=0.8 Hz).
Tert-butyl (2S,4R)-4-amino-2-methylpyrrolidine-1-carboxylate (250 mg, 1.25 mmol) and 2-(4-cyclopropylphenyl)acetic acid (264 mg, 1.50 mmol) synthesized in Reference Example 33-2 were dissolved in DMF (13 mL), subsequently DIPEA (691 μL, 4.01 mmol) and HATU (570 mg, 1.50 mmol) were added thereto, and the mixture was stirred overnight at room temperature. Water was added to the reaction liquid, the mixture was stirred for a while, and then the mixture was extracted with ethyl acetate. An organic layer thus separated was dried over anhydrous sodium sulfate, insoluble materials were filtered, and then the solvent was distilled off under reduced pressure. A residue thus obtained was purified by silica gel column chromatography (heptane:ethyl acetate) (concentration gradient: 0 to 100%), and the title compound (colorless oily material, 365 mg, 82%) was obtained.
1H NMR (CDCl3, 400 MHz): δ=0.6-0.7 (m, 2H), 0.9-1.0 (m, 2H), 1.1-1.2 (m, 3H), 1.43 (s, 9H), 1.7-1.9 (m, 3H), 3.0-3.1 (m, 1H), 3.51 (s, 2H), 3.5-3.7 (m, 1H), 3.7-4.0 (m, 1H), 4.4-4.6 (m, 1H), 5.31 (d, 1H, J=7 Hz), 7.04 (d, 2H, J=8 Hz), 7.10 (d, 2H, J=8 Hz
A 2 N hydrochloric acid-methanol solution (15 mL) was added to tert-butyl (2S,4R)-4-(2-(4-cyclopropylphenyl)acetamido)-2-methylpyrrolidine-1-carboxylate (365 mg, 1.02 mmol) synthesized in Reference Example 7-1 under ice cooling, the mixture was stirred for 2 hours at room temperature, and then the solvent was distilled off under reduced pressure. A residue thus obtained was purified by silica gel column chromatography (ethyl acetate:methanol) (concentration gradient: 0 to 40%), and the title compound (white crystals, 270 mg, 103%) was obtained.
1H NMR (CDCl3, 400 MHz): δ=0.6-0.7 (m, 2H), 0.9-1.0 (m, 2H), 1.13 (d, 3H, J=6 Hz), 1.5-1.7 (m, 3H), 1.8-1.9 (m, 1H), 2.51 (dd, 1H, J=5.12 Hz), 3.1-3.2 (m, 1H), 3.38 (dd, 1H, J=7.12 Hz), 3.50 (s, 2H), 4.3-4.5 (m, 1H), 5.50 (br s, 1H), 7.05 (d, 2H, J=8 Hz), 7.12 (d, 2H, J=8 Hz).
According to a technique similar to Reference Example 4, the title compound (colorless oily material, 103 mg, 23%) was obtained using tert-butyl (3-azabicyclo[3.1.0]hexan-1-yl)carbamate (250 mg, 1.26 mmol) and 3-bromo-5-(trifluoromethyl)pyridine (342 mg, 1.51 mmol).
1H NMR (CDCl3, 400 MHz): δ=1.1-1.2 (m, 1H), 1.2-1.3 (m, 1H), 1.46 (s, 9H), 1.8-2.0 (m, 1H), 3.4-3.7 (m, 3H), 3.75 (d, 1H, J=8 Hz), 5.13 (br s, 1H), 6.93 (dd, 1H, J=2.2 Hz), 8.09 (d, 1H, J=2 Hz), 8.20 (s, 1H).
Tert-butyl (R)-pyrrolidin-3-ylcarbamate (250 mg, 1.34 mmol) was dissolved in DMF (13 mL), subsequently 2-chloro-6-(trifluoromethyl)pyrazine (294 mg, 1.61 mmol) and potassium carbonate (371 mg, 2.68 mmol) were added thereto, and the mixture was stirred for 20 hours at 120° C. To the reaction liquid that had been left to cool to room temperature, water was added, the mixture was stirred for a while, and then the mixture was extracted with a mixed liquid of chloroform and methanol. An organic layer thus separated was dried over anhydrous sodium sulfate, insoluble materials were filtered, and then the solvent was distilled off under reduced pressure. A residue thus obtained was purified by silica gel column chromatography (heptane:ethyl acetate) (concentration gradient: 0 to 100%), and the title compound (white crystals, 292 mg, 65%) was obtained.
1H NMR (CDCl3, 400 MHz): δ=1.46 (s, 9H), 1.9-2.1 (m, 1H), 2.2-2.4 (m, 1H), 3.43 (dd, 1H, J=4.11 Hz), 3.5-3.7 (m, 2H), 3.82 (dd, 1H, J=6.11 Hz), 4.39 (br s, 1H), 4.74 (d, 1H, J=7 Hz), 8.03 (s, 1H), 8.14 (s, 1H).
According to a technique similar to Reference Example 4, the title compound (yellow oily material, 139 mg, 30%) was obtained using tert-butyl (R)-pyrrolidin-3-ylcarbamate (200 mg, 1.07 mmol) and 5-bromo-3-(trifluoromethyl)picolinonitrile (323 mg, 1.29 mmol).
1H NMR (CDCl3, 400 MHz): δ=1.46 (s, 9H), 2.0-2.2 (m, 1H), 2.3-2.5 (m, 1H), 3.33 (dd, 1H, J=5.10 Hz), 3.4-3.6 (m, 2H), 3.7-3.8 (m, 1H), 4.3-4.5 (m, 1H), 4.84 (br s, 1H), 6.95 (d, 1H, J=3 Hz), 8.07 (d, 1H, J=3 Hz).
According to a technique similar to Reference Example 7-1, the title compound (white crystals, 362 mg, 86%) was obtained using methyl 3-(azanyl)-1-benzylpyrrolidine-3-carboxylate (250 mg, 1.07 mmol) and 2-(4-cyclopropylphenyl)acetic acid (226 mg, 1.28 mmol) synthesized in Reference Example 33-2.
1H NMR (CDCl3, 400 MHz): δ=0.6-0.8 (m, 2H), 0.9-1.0 (m, 2H), 1.8-2.0 (m, 2H), 2.4-2.5 (m, 1H), 2.5-2.7 (m, 1H), 2.75 (d, 1H, J=10 Hz), 2.79 (d, 1H, J=10 Hz), 2.8-2.9 (m, 1H), 3.50 (s, 2H), 3.54 (d, 1H, J=13 Hz), 3.62 (d, 1H, J=13 Hz), 3. 70 (s, 3H), 6.03 (br s, 1H), 7.0-7.1 (m, 2H), 7.1-7.2 (m, 2H), 7.2-7.3 (m, 5H).
Methyl 1-benzyl-3-(2-(4-cyclopropylphenyl)acetamido)pyrrolidine-3-carboxylate (362 mg, 0.92 mmol) synthesized in Reference Example 11-1 was dissolved in methanol (20 mL), palladium-carbon (36 mg) was added thereto, and the mixture was stirred for 4 hours at room temperature under a hydrogen gas stream. Insoluble materials were filtered, subsequently the solvent was distilled off under reduced pressure, a residue thus obtained was purified by silica gel column chromatography (ethyl acetate:methanol) (concentration gradient: 0 to 40%), and the title compound (94 mg, 34%) was obtained.
1H NMR (CDCl3, 400 MHz): δ=0.6-0.7 (m, 2H), 0.9-1.0 (m, 2H), 1.8-1.9 (m, 1H), 2.0-2.2 (m, 2H), 2.2-2.3 (m, 1H), 2.9-3.0 (m, 1H), 3.10 (d, 1H, J=12 Hz), 3.1-3.2 (m, 1H), 3.33 (d, 1H, J=12 Hz), 3.51 (s, 2H), 3.73 (s, 3H), 6.35 (br s, 1H), 7.0-7.1 (m, 2H), 7.1-7.2 (m, 2H).
According to a technique similar to Reference Example 9, the title compound (white crystals, 706 mg, 90%) was obtained using 2-bromo-4-(trifluoromethyl)thiazole (540 mg, 2.33 mmol) and tert-butyl (R)-pyrrolidin-3-ylcarbamate (520 mg, 2.79 mmol).
1H NMR (CDCl3, 400 MHz): δ=1.45 (s, 9H), 1.9-2.1 (m, 1H), 2.2-2.4 (m, 1H), 3.35 (dd, 1H, J=4.10 Hz), 3.5-3.7 (m, 2H), 3.75 (dd, 1H, J=6.10 Hz), 4.38 (br s, 1H), 4.68 (br s, 1H), 6.92 (d, 1H, J=0.7 Hz).
According to a technique similar to Reference Example 7-2, the title compound (white crystals, 480 mg, 97%) was obtained using tert-butyl (R)-(1-(4-(trifluoromethyl)thiazol-2-yl)pyrrolidin-3-yl)carbamate (706 mg, 2.09 mmol) synthesized in Reference Example 12-1.
1H NMR (CDCl3, 400 MHz): δ=1.34 (br s, 2H), 1.8-1.9 (m, 1H), 2.2-2.3 (m, 1H), 3.23 (dd, 1H, J=4.10 Hz), 3.5-3.6 (m, 1H), 3.6-3.7 (m, 2H), 3.7-3.9 (m, 1H), 6.90 (br s, 1H).
According to a technique similar to Reference Example 4, the title compound (white crystals, 22 mg, 4.9%) was obtained using 5-bromo-2-methyl-3-(trifluoromethyl)pyridine (310 mg, 1.29 mmol) and tert-butyl (R)-pyrrolidin-3-ylcarbamate (289 mg, 1.55 mmol).
1H NMR (CDCl3, 400 MHz): δ=1.46 (s, 9H), 1.9-2.1 (m, 1H), 2.2-2.4 (m, 1H), 2.5-2.6 (m, 3H), 3.20 (dd, 1H, J=4.10 Hz), 3.3-3.4 (m, 1H), 3.4-3.5 (m, 1H), 3.61 (dd, 1H, J=6.10 Hz), 4.40 (br s, 1H), 4.70 (br s, 1H), 7.00 (d, 1H, J=3 Hz), 7.98 (d, 1H, J=3 Hz).
According to a technique similar to Reference Example 3, the title compound (brown amorphous, 187 mg, 60%) was obtained using 2-(5-bromopyridin-3-yl)propan-2-ol (210 mg, 0.97 mmol) and tert-butyl (R)-pyrrolidin-3-ylcarbamate (217 mg, 1.17 mmol).
1H NMR (CDCl3, 400 MHz): δ=1.46 (s, 9H), 1.58 (s, 6H), 1.9-2.0 (m, 1H), 2.2-2.4 (m, 1H), 2.80 (br s, 1H), 3.17 (dd, 1H, J=4.10 Hz), 3.3-3.4 (m, 1H), 3.4-3.5 (m, 1H), 3.56 (dd, 1H, J=6.10 Hz), 4.36 (br s, 1H), 4.96 (br s, 1H), 6.99 (dd, 1H, J=2.2 Hz), 7.78 (d, 1H, J=3 Hz), 8.01 (d, 1H, J=2 Hz).
According to a technique similar to Reference Example 7-2, the title compound (brown oily material, 114 mg, 88%) was obtained using tert-butyl (R)-(1-(5-(2-hydroxypropan-2-yl)pyridin-3-yl)pyrrolidin-3-yl)-carbamate (187 mg, 0.58 mmol) synthesized in Reference Example 14-1.
1H NMR (CDCl3, 400 MHz): δ=1.59 (s, 6H), 1.7-1.9 (m, 1H), 2.1-2.3 (m, 1H), 3.03 (dd, 1H, J=4.10 Hz), 3.3-3.4 (m, 1H), 3.4-3.6 (m, 4H), 3.7-3.8 (m, 1H), 6.99 (dd, 1H, J=2.2 Hz), 7.80 (d, 1H, J=3 Hz), 8.00 (d, 1H, J=2 Hz). The 1H content is not observable.
According to a technique similar to Reference Example 4, the title compound (brown oily material, 90 mg, 26%) was obtained using 6-bromo-8-(trifluoromethyl)imidazo[1,2-a]pyridine (250 mg, 0.94 mmol) and tert-butyl (R)-pyrrolidin-3-ylcarbamate (211 mg, 1.13 mmol).
1H NMR (CDCl3, 400 MHz): δ=1.46 (s, 9H), 1.9-2.1 (m, 1H), 2.3-2.4 (m, 1H), 3.17 (dd, 1H, J=4.9 Hz), 3.2-3.4 (m, 1H), 3.4-3.5 (m, 1H), 3.5-3.6 (m, 1H), 4.40 (br s, 1H), 4.79 (br s, 1H), 7.19 (d, 1H, J=0.8 Hz), 7.40 (d, 1H, J=1 Hz), 7.56 (d, 1H, J=0.8 Hz), 7.64 (d, 1H, J=1 Hz).
According to a technique similar to Reference Example 3, the title compound (pale yellow oily material, 30 mg, 8.2%) was obtained using ethyl 2-(4-bromophenyl)acetate (300 mg, 1.23 mmol) and 1,1-dioxide thiomorpholine (334 mg, 2.47 mmol).
1H NMR (CDCl3, 400 MHz): δ=1.26 (t, 3H, J=7 Hz), 3.0-3.1 (m, 4H), 3.54 (s, 2H), 3.8-3.9 (m, 4H), 4.12 (q, 2H, J=7 Hz), 6.8-6.9 (m, 2H), 7.2-7.3 (m, 2H).
In a nitrogen atmosphere, a small amount of iodine was introduced into a round-bottom flask containing magnesium (168 mg, 6.98 mmol) and THF (1.0 mL), subsequently ethyl 2-(4-bromophenyl)acetate (500 mg, 2.06 mmol) dissolved in THF (3.4 mL) was added thereto, and the mixture was heated to reflux for 30 minutes. The reaction liquid was left to cool to room temperature, chlorotrimethylsilane (520 μL, 4.11 mmol) was added thereto, and the mixture was heated to reflux for 2 hours. To the reaction liquid that had been left to cool to room temperature, a saturated aqueous solution of ammonium chloride was added, the mixture was stirred for a while, and then the mixture was extracted with ethyl acetate. An organic layer thus separated was dried over anhydrous sodium sulfate, insoluble materials were filtered, and then the solvent was distilled off under reduced pressure. A residue thus obtained was purified by silica gel column chromatography (heptane:ethyl acetate) (concentration gradient: 0 to 100%), and the title compound (colorless oily material, 30 mg, 6.2%) was obtained.
1H
According to a technique similar to Reference Example 7-1, the title compound (yellow powder, 369 mg, 83%) was obtained using tert-butyl (3S,4S)-3-amino-4-fluoropyrrolidine-1-carboxylate (250 mg, 1.22 mmol) and 2-(4-cyclopropylphenyl)acetic acid (259 mg, 1.47 mmol) synthesized in Reference Example 33-2.
1H NMR (CDCl3, 400 MHz): δ=0.6-0.7 (m, 2H), 0.9-1.0 (m, 2H), 1.45 (s, 9H), 1.8-1.9 (m, 1H), 3.1-3.7 (m, 6H), 4.43 (br s, 1H), 4.8-5.1 (m, 1H), 5.32 (br s, 1H), 7.0-7.1 (m, 2H), 7.1-7.2 (m, 2H).
According to a technique similar to Reference Example 7-1, the title compound (yellow oily material, 454 mg, 86%) was obtained using tert-butyl 3-amino-3-cyanopyrrolidine-1-carboxylate (300 mg, 1.42 mmol) and 2-(4-cyclopropylphenyl)acetic acid (300 mg, 1.70 mmol) synthesized in Reference Example 33-2.
1H NMR (CDCl3, 400 MHz): δ=0.6-0.7 (m, 2H), 0.9-1.0 (m, 2H), 1.44 (s, 9H), 1.8-1.9 (m, 1H), 2.2-2.6 (m, 2H), 3.3-3.4 (m, 1H), 3.4-3.6 (m, 4H), 3.9-4.0 (m, 1H), 6.3-6.4 (m, 1H), 7.04 (d, 2H, J=8 Hz), 7.10 (d, 2H, J=8 Hz).
Methyl 3-amino-1-benzylpyrrolidine-3-carboxylate (500 mg, 2.13 mmol), DIPEA (788 μL, 4.57 mmol), and Boc anhydride (931 mg, 4.27 mmol) were dissolved in chloroform (21 mL), and the solution was stirred for 16 hours at room temperature. Water was added to the reaction liquid, the mixture was stirred for a while, and then the mixture was extracted with chloroform. An organic layer thus separated was dried over anhydrous sodium sulfate, insoluble materials were filtered, and then the solvent was distilled off under reduced pressure. A residue thus obtained was purified by silica gel column chromatography (heptane:ethyl acetate) (concentration gradient: 0 to 100%), and the title compound (colorless oily material, 522 mg, 73%) was obtained.
1H NMR (CDCl3, 400 MHz): δ=1.42 (s, 9H), 1.9-2.0 (m, 1H), 2.5-2.7 (m, 2H), 2.7-3.0 (m, 3H), 3.61 (d, 1H, J=13 Hz), 3.68 (d, 1H, J=13 Hz), 3.74 (s, 3H), 5.12 (br s, 1H), 7.2-7.4 (m, 5H).
According to a technique similar to Reference Example 11-2, a crude form of methyl 3-((tert-butoxycarbonyl)amino)pyrrolidine-3-carboxylate (colorless oily material, 402 mg) was obtained using methyl 1-benzyl-3-((tert-butoxycarbonyl)amino)pyrrolidine-3-carboxylate (522 mg, 1.56 mmol) synthesized in Example 20-1. According to a technique similar to Reference Example 4, the title compound (34 mg, 5.8%) was obtained using the crude form of methyl 3-((tert-butoxycarbonyl)amino)pyrrolidine-3-carboxylate (402 mg) thus obtained and (3-bromo-5-(trifluoromethyl)pyridine (423 mg, 1.87 mmol).
1H NMR (CDCl3, 400 MHz): δ=1.45 (s, 9H), 2.3-2.5 (m, 1H), 2.5-2.6 (m, 1H), 3.5-3.6 (m, 2H), 3.6-3.7 (m, 1H), 3.79 (s, 3H), 4.01 (d, 1H, J=10 Hz), 5.17 (br s, 1H), 6.9-7.0 (m, 1H), 8.11 (d, 1H, J=3 Hz), 8.22 (s, 1H).
According to a technique similar to Reference Example 7-1, the title compound (white powder, 352 mg, 62%) was obtained using tert-butyl 3-amino-3-cyanopyrrolidine-1-carboxylate (300 mg, 1.42 mmol) and 2-(4-(trifluoromethyl)phenyl)acetic acid (348 mg, 1.70 mmol).
1H NMR (CDCl3, 400 MHz): δ=1.45 (s, 9H), 2.2-2.6 (m, 2H), 3.3-3.7 (m, 3H), 3.68 (s, 2H), 3.9-4.1 (m, 1H), 5.7-5.8 (m, 1H), 7.40 (d, 2H, J=8 Hz), 7.64 (d, 2H, J=8 Hz).
According to a technique similar to Reference Example 7-2, the title compound (white powder, 213 mg, 73%) was obtained using tert-butyl 3-cyano-3-(2-(4-(trifluoromethyl)phenyl)acetamido)pyrrolidine-1-carboxylate (352 mg, 0.89 mmol) synthesized in Reference Example 21-1.
1H NMR (CDCl3, 400 MHz): δ=2.0-2.1 (m, 1H), 2.2-2.4 (m, 2H), 3.0-3.1 (m, 1H), 3.14 (d, 1H, J=12 Hz), 3.1-3.2 (m, 1H), 3.35 (d, 1H, J=12 Hz), 3.61 (s, 2H), 3.75 (s, 3H), 6.52 (br s, 1H), 7.40 (d, 2H, J=8 Hz), 7.61 (d, 2H, J=8 Hz).
(1S,2S)-cyclopropane-1,2-dicarboxylic acid (2.0 g, 15.4 mmol) was dissolved in methanol (30 mL), thionyl chloride (2.79 mL, 38.4 mmol) and a small amount of DMF were added thereto, the mixture was stirred for 4 hours at room temperature, and then the solvent was distilled off under reduced pressure. Water and ethyl acetate were added to a residue thus obtained, the mixture was stirred for a while, subsequently an organic layer thus separated was washed with a saturated aqueous solution of sodium hydrogen carbonate, and the organic layer was dried over anhydrous sodium sulfate. Insoluble materials were filtered, subsequently the solvent was distilled off under reduced pressure, and the title compound (brown oily material, 2.09 g, 86%) was obtained.
1H NMR (CDCl3, 400 MHz): δ=1.4-1.5 (m, 2H), 2.1-2.2 (m, 2H), 3.71 (s, 6H).
Dimethyl (1S,2S)-cyclopropane-1,2-dicarboxylate (2.09 g, 13.2 mmol) synthesized in Reference Example 22-1 was dissolved in methanol (13 mL) and water (2.0 mL), a 2 N aqueous solution of sodium hydroxide (6.28 mL) was added thereto, the mixture was stirred for 16 hours at room temperature, and then the solvent was distilled off under reduced pressure. Water was added to a residue thus obtained, the mixture was washed with chloroform, a 2 N aqueous solution of hydrochloric acid was added thereto to adjust the pH of the aqueous layer to 2 to 3, and then the aqueous layer was extracted with a mixed liquid of chloroform and methanol. An organic layer thus separated was dried over anhydrous sodium sulfate, insoluble materials were filtered, subsequently the solvent was distilled off under reduced pressure, and thereby the title compound (brown oily material, 1.45 g, 76%) was obtained.
1H NMR (CDCl3, 400 MHz): δ=1.4-1.6 (m, 2H), 2.1-2.2 (m, 1H), 2.2-2.3 (m, 1H), 3.72 (s, 3H). The 1H content is not observable.
According to a technique similar to Reference Example 7-1, the title compound (515 mg, 65%) was obtained using (1S,2S)-2-(methoxycarbonyl)cyclopropane-1-carboxylic acid (363 mg, 2.52 mmol) synthesized in Reference Example 22-2 and 2-bromo-4-fluoroaniline (574 mg, 3.02 mmol).
1H NMR (CDCl3, 400 MHz): δ=1.4-1.5 (m, 1H), 1.5-1.6 (m, 1H), 2.1-2.2 (m, 1H), 2.2-2.3 (m, 1H), 3.75 (s, 3H), 7.05 (ddd, 1H, J=6, 8.9 Hz), 7.31 (dd, 1H, J=3.8 Hz), 7.76 (br s, 1H), 8.28 (dd, 1H, J=6.9 Hz).
Methyl (1S,2S)-2-((2-bromo-4-fluorophenyl)carbamoyl)cyclopropane-1-carboxylate (515 mg, 1.63 mmol) synthesized in Reference Example 22-3, copper(I) iodide (31 mg, 0.16 mmol), 1,10-phenanthroline (59 mg, 0.33 mmol), and cesium carbonate (796 mg, 2.44 mmol) were suspended in DME (5.0 mL), and the suspension was heated to reflux for 16 hours under a nitrogen gas stream. The reaction liquid that had been left to cool to room temperature was filtered through Celite, and the solvent was distilled off under reduced pressure. A residue thus obtained was purified by silica gel column chromatography (heptane:ethyl acetate) (concentration gradient: 0 to 100%), and the title compound (pale yellow crystals, 226 mg, 59%) was obtained.
1H NMR (CDCl3, 400 MHz): δ=1.7-1.8 (m, 2H), 2.4-2.5 (m, 1H), 2.7-2.8 (m, 1H), 3.75 (s, 3H), 7.0-7.1 (m, 1H), 7.19 (dd, 1H, J=2.8 Hz), 7.55 (dd, 1H, J=5.9 Hz).
Ethyl 2-(4-bromophenyl)acetate (1.28 g, 5.27 mmol), morpholine (917 μL, 10.5 mmol), palladium acetate (118 mg, 0.53 mmol), tert-butyl XPhos (447 mg, 1.05 mmol), and cesium carbonate (3.43 g, 10.5 mmol) were suspended in toluene (25 mL), and the suspension was stirred for 16 hours at 110° C. under a nitrogen gas stream. The reaction liquid that had been left to cool to room temperature was filtered through Celite, and the solvent was distilled off under reduced pressure. A residue thus obtained was purified by silica gel column chromatography (heptane:ethyl acetate) (concentration gradient: 0 to 100%), and the title compound (yellow crystals, 760 mg, 58%) was obtained.
1H NMR (CDCl3, 400 MHz): δ=1.25 (t, 3H, J=7 Hz), 3.1-3.2 (m, 4H), 3.53 (s, 2H), 3.8-3.9 (m, 4H), 4.14 (q, 2H, J=7 Hz), 6.8-6.9 (m, 2H), 7.1-7.2 (m, 2H).
Ethyl 2-(4-morpholinophenyl)acetate (760 mg, 3.05 mmol) synthesized in Reference Example 23-1 was dissolved in methanol (5.0 mL), a 2 N aqueous solution of sodium hydroxide (4.6 mL) was added thereto, the mixture was stirred for 16 hours at room temperature, and the solvent was distilled off under reduced pressure. Water was added to a residue thus obtained, the mixture was washed with chloroform, a 2 N aqueous solution of hydrochloric acid was added thereto to neutralize the mixture, and then the solvent was distilled off under reduced pressure. A mixed liquid of chloroform and methanol was added to a residue thus obtained, the mixture was stirred for a while, insoluble materials were filtered, subsequently the solvent was distilled off under reduced pressure, and a crude form of the title compound (white powder, 733 mg) was obtained.
1H NMR (CD3OD, 400 MHz): δ=3.0-3.1 (m, 4H), 3.38 (s, 2H), 3.8-3.9 (m, 4H), 6.8-6.9 (m, 2H), 7.2-7.3 (m, 2H). The 1H content is not observable.
According to a technique similar to Reference Example 7-1, the title compound (white crystals, 782 mg, 90%) was obtained using tert-butyl 3-amino-3-ethylpyrrolidine-1-carboxylate (500 mg, 2.33 mmol) and 2-(4-cyclopropylphenyl)acetic acid (493 mg, 2.80 mmol) synthesized in Reference Example 33-2.
1H NMR (CDCl3, 400 MHz): δ=0.6-0.7 (m, 2H), 0.7-0.8 (m, 3H), 0.9-1.0 (m, 2H), 1.44 (s, 9H), 1.5-2.5 (m, 5H), 3.1-3.6 (m, 6H), 5.14 (d, 1H, J=14 Hz), 7.0-7.1 (m, 2H), 7.1-7.2 (m, 2H).
According to a technique similar to Reference Example 22-1, a crude form of dimethyl (1S,2S)-cyclopropane-1,2-dicarboxylate (brown oily material, 695 mg) was obtained using (1S,2S)-cyclopropane-1,2-dicarboxylic acid (500 mg, 3.84 mmol). According to a technique similar to Reference Example 22-2, (1S,2S)-2-(methoxycarbonyl) cyclopropane-1-carboxylic acid (427 mg, 77%) was obtained using the crude form of dimethyl (1S,2S)-cyclopropane-1,2-dicarboxylate (695 mg). According to a technique similar to Reference Example 7-1, the title compound (yellow powder, 397 mg, 45%) was obtained using (1S,2S)-2-(methoxycarbonyl) cyclopropane-1-carboxylic acid (427 mg, 2.96 mmol) thus obtained and 2-bromoaniline (612 mg, 3.56 mmol).
1H NMR (CDCl3, 400 MHz): δ=1.4-1.5 (m, 1H), 1.5-1.6 (m, 1H), 2.1-2.2 (m, 1H), 2.2-2.3 (m, 1H), 3.74 (s, 3H), 6.9-7.0 (m, 1H), 7.2-7.3 (m, 1H), 7.54 (dd, 1H, J=1, 8 Hz), 7.93 (br s, 1H), 8.30 (d, 1H, J=8 Hz).
According to a technique similar to Reference Example 22-4, the title compound (95 mg, 33%) was obtained using methyl (1S,2S)-2-((2-bromophenyl)carbamoyl)cyclopropane-1-carboxylate (397 mg, 1.33 mmol) synthesized in Reference Example 25-1.
1H NMR (CDCl3, 400 MHz): δ=1.7-1.8 (m, 2H), 2.4-2.5 (m, 1H), 2.7-2.8 (m, 1H), 3.75 (s, 3H), 7.2-7.3 (m, 2H), 7.4-7.5 (m, 1H), 7.6-7.7 (m, 1H).
According to a technique similar to Reference Example 7-1, the title compound (313 mg, 39%) was obtained using (1S,2S)-2-(methoxycarbonyl)cyclopropane-1-carboxylic acid (344 mg, 2.39 mmol) synthesized in Reference Example 22-2 and 2-bromo-4,5-difluoroaniline (596 mg, 2.87 mmol).
1H NMR (CDCl3, 400 MHz): δ=1.4-1.6 (m, 2H), 2.1-2.2 (m, 1H), 2.3-2.4 (m, 1H), 3.75 (s, 3H), 7.3-7.4 (m, 1H), 7.79 (br s, 1H), 8.3-8.4 (m, 1H).
According to a technique similar to Reference Example 22-4, the title compound (pale yellow oily material, 68 mg, 29%) was obtained using methyl (1S,2S)-2-((2-bromo-4,5-difluorophenyl)carbamoyl)cyclopropane-1-carboxylate (313 mg, 0.94 mmol) synthesized in Reference Example 26-1.
1H NMR (CDCl3, 400 MHz): δ=1.7-1.8 (m, 2H), 2.4-2.5 (m, 1H), 2.7-2.8 (m, 1H), 3.75 (s, 3H), 7.3-7.4 (m, 1H), 7.4-7.5 (m, 1H).
Ethyl 2-(4-bromophenyl)acetate (1.0 g, 4.11 mmol), 2-oxa-6-azaspiro[3.3]heptane (816 mg, 8.23 mmol), palladium acetate (92 mg, 0.41 mmol), XPhos (270 mg, 0.57 mmol), and cesium carbonate (2.68 g, 8.23 mmol) were suspended in toluene (30 mL), and the suspension was stirred for 16 hours at 110° C. under a nitrogen gas stream. The suspension was left to cool to room temperature, insoluble materials were filtered through Celite, and the solvent was distilled off under reduced pressure. A residue thus obtained was purified by silica gel column chromatography (heptane:ethyl acetate) (concentration gradient: 0 to 100%), and the title compound (colorless oily material, 1.26 g, 117%) was obtained.
1H
(1S,2S)-2-(methoxycarbonyl)cyclopropane-1-carboxylic acid (294 mg, 2.04 mmol) synthesized in Reference Example 22-2 and 2-bromo-5-fluoroaniline (465 mg, 2.45 mmol) were dissolved in DMF (15 mL), subsequently DIPEA (1.13 mL, 6.56 mmol) and HATU (931 mg, 2.45 mmol) were added thereto, and the mixture was stirred for 16 hours at 50° C. To the reaction liquid that had been left to cool to room temperature, water was added, the mixture was stirred for a while, and then the mixture was extracted with ethyl acetate. An organic layer thus separated was dried over anhydrous sodium sulfate, insoluble materials were filtered, and then the solvent was distilled off under reduced pressure. A residue thus obtained was purified by silica gel column chromatography (heptane:ethyl acetate) (concentration gradient: 0 to 100%), and the title compound (ivory-colored powder, 210 mg, 33%) was obtained.
1H NMR (CDCl3, 400 MHz): δ=1.4-1.5 (m, 1H), 1.5-1.6 (m, 1H), 2.1-2.2 (m, 1H), 2.3-2.4 (m, 1H), 3.74 (s, 3H), 6.73 (ddd, 1H, J=3, 8.9 Hz), 7.49 (dd, 1H, J=6, 9 Hz), 7.95 (br s, 1H), 8.21 (dd, 1H, J=2.11 Hz).
According to a technique similar to Reference Example 22-4, the title compound (ivory-colored powder, 47 mg, 30%) was obtained using methyl (1S,2S)-2-((2-bromo-5-fluorophenyl)carbamoyl)cyclopropane-1-carboxylate (210 mg, 0.66 mmol) synthesized in Reference Example 28-1.
1H NMR (CDCl3, 400 MHz): δ=1.7-1.8 (m, 2H), 2.4-2.5 (m, 1H), 2.7-2.8 (m, 1H), 3.75 (s, 3H), 7.0-7.1 (m, 1H), 7.31 (dd, 1H, J=2.8 Hz), 7.38 (dd, 1H, J=4.9 Hz).
According to a technique similar to Reference Example 22-2, the title compound (white crystals, 5.91 g, 95%) was obtained using diethyl trans-cyclopropane-1,2-dicarboxylate (7.3 g, 39.2 mmol).
1H NMR (CDCl3, 400 MHz): δ=1.28 (t, 3H, J=7 Hz), 1.4-1.6 (m, 2H), 2.1-2.3 (m, 2H), 4.16 (q, 2H, J=7 Hz). The 1H content is not observable.
According to a technique similar to Reference Example 28-1, the title compound (white powder, 3.42 g, 87%) was obtained using trans-2-(ethoxycarbonyl)cyclopropane-1-carboxylic acid (2.0 g, 12.6 mmol) synthesized in Reference Example 29-1 and 2-bromoaniline (2.61 g, 15.2 mmol).
1H NMR (CDCl3, 400 MHz): δ=1.30 (t, 3H, J=7 Hz), 1.4-1.5 (m, 1H), 1.5-1.6 (m, 1H), 2.1-2.2 (m, 1H), 2.2-2.3 (m, 1H), 4.19 (q, 2H, J=7 Hz), 6.9-7.0 (m, 1H), 7.2-7.3 (m, 1H), 7.55 (dd, 1H, J=1.8 Hz), 7.90 (br s, 1H), 8.33 (d, 1H, J=8 Hz).
According to a technique similar to Reference Example 22-4, the title compound (pale yellow oily material, 1.22 g, 48%) was obtained using ethyl trans-2-((2-bromophenyl)carbamoyl)cyclopropane-1-carboxylate (3.42 g, 11.0 mmol) synthesized in Reference Example 29-2.
1H NMR (CDCl3, 400 MHz): δ=1.29 (t, 3H, J=7 Hz), 1.7-1.8 (m, 2H), 2.4-2.5 (m, 1H), 2.7-2.8 (m, 1H), 4.20 (q, 2H, J=7 Hz), 7.2-7.3 (m, 2H), 7.4-7.5 (m, 1H), 7.6-7.7 (m, 1H).
(1S,2S)-cyclopropane-1,2-dicarboxylic acid (2.5 g, 19.2 mmol) was dissolved in ethanol (38 mL), thionyl chloride (3.48 mL, 48.0 mmol) and a small amount of DMF were added thereto, the mixture was stirred for 4 hours at room temperature, and then the solvent was distilled off under reduced pressure. Water and ethyl acetate were added to a residue thus obtained, the mixture was stirred for a while, subsequently an organic layer thus separated was washed with a saturated aqueous solution of sodium hydrogen carbonate, and the organic layer was dried over anhydrous sodium sulfate. Insoluble materials were filtered, subsequently the solvent was distilled off under reduced pressure, and thereby a crude form of (1S,2S)-2-(ethoxycarbonyl)cyclopropane-1-carboxylic acid (pale ivory-colored oily material, 3.66 g) was obtained.
According to a technique similar to Reference Example 22-2, the title compound (yellow oily material, 2.31 g, 76%) was obtained using the crude form of (1S,2S)-2-(ethoxycarbonyl)cyclopropane-1-carboxylic acid (3.66 g) thus obtained.
1H NMR (CDCl3, 400 MHz): δ=1.28 (t, 3H, J=7 Hz), 1.4-1.6 (m, 2H), 2.1-2.3 (m, 2H), 4.16 (q, 2H, J=7 Hz). The 1H content is not observable.
According to a technique similar to Reference Example 28-1, the title compound (ivory-colored powder, 530 g, 51%) was obtained using (1S,2S)-2-(ethoxycarbonyl)cyclopropane-1-carboxylic acid (500 mg, 3.16 mmol) synthesized in Reference Example 30-1 and 2-bromoaniline (721 mg, 3.79 mmol).
1H NMR (CDCl3, 400 MHz): δ=1.2-1.3 (m, 3H), 1.4-1.5 (m, 1H), 1.5-1.6 (m, 1H), 2.1-2.2 (m, 1H), 2.2-2.3 (m, 1H), 4.19 (q, 2H, J=7 Hz), 6.7-6.8 (m, 1H), 7.49 (dd, 1H, J=6.8 Hz), 7.93 (br s, 1H), 8.23 (dd, 1H, J=3.11 Hz).
According to a technique similar to Reference Example 22-4, the title compound (brown oily material, 141 mg, 35%) was obtained using ethyl (1S,2S)-2-((2-bromo-5-fluorophenyl)carbamoyl)cyclopropane-1-carboxylate (530 mg, 1.61 mmol) synthesized in Reference Example 30-2.
1H NMR (CDCl3, 400 MHz): δ=1.29 (t, 3H, J=7 Hz), 1.7-1.8 (m, 2H), 2.4-2.5 (m, 1H), 2.7-2.8 (m, 1H), 4.20 (q, 2H, J=7 Hz), 7.02 (ddd, 1H, J=2, 9.9 Hz), 7.31 (dd, 1H, J=3.8 Hz), 7.38 (dd, 1H, J=4.9 Hz).
2-Chloro-5-(trifluoromethyl)pyridine (5.00 g, 27.5 mmol), dimethyl malonate (5.46 g, 41.3 mmol), and cesium carbonate (18.0 g, 55.1 mmol) were dissolved in dimethyl sulfoxide (10.0 mL), and the solution was stirred overnight at 110° C. under a nitrogen gas stream. To the reaction liquid that had been left to cool to room temperature, water was added, the mixture was stirred for a while, and then the mixture was extracted with ethyl acetate. An organic layer thus separated was washed with saturated brine and dried over anhydrous sodium sulfate, insoluble materials were filtered, and then the solvent was distilled off under reduced pressure. A residue thus obtained was purified by silica gel column chromatography (heptane:ethyl acetate) (concentration gradient: 25 to 75%), and the title compound (yellow oily material, 2.46 g, 32%) was obtained.
1H
Dimethyl 2-(5-(trifluoromethyl)pyridin-2-yl)malonate (790 mg, 2.85 mmol) synthesized in Reference Example 31-1 was dissolved in methanol (18 mL), a 2 N aqueous solution of sodium hydroxide (3.6 mL) was added thereto, and then the mixture was stirred overnight at 50° C. To the reaction liquid that had been left to cool to room temperature, a 2 N aqueous solution of hydrochloric acid (3.5 mL) was added to adjust the pH of the aqueous layer to 6 to 7, subsequently the solvent was distilled off under reduced pressure, and thereby the title compound (pale yellow crystals, 864 mg) including sodium chloride was obtained.
1H NMR (DMSO-d6, 400 MHz): δ=3.85 (s, 2H), 7.60 (d, 1H, J=8 Hz), 8.15 (dd, 1H, J=2.8 Hz), 8.86 (s, 1H). The 1H content is not observable.
According to a technique similar to Reference Example 4, the title compound (pale yellow amorphous, 2.20 g, 89%) was obtained using 5-bromo-2-(trifluoromethyl)pyridine (2.55 g, 11.3 mmol) and tert-butyl (R)-pyrrolidin-3-ylcarbamate (1.50 g, 7.49 mmol).
1H NMR (CDCl3, 400 MHz): δ=1.46 (s, 9H), 1.9-2.0 (m, 1H), 2.2-2.4 (m, 1H), 3.2-3.3 (m, 1H), 3.3-3.6 (m, 2H), 3.6-3.7 (m, 1H), 4.3-4.5 (m, 1H), 4.6-4.8 (m, 1H), 6.82 (dd, 1H, J=3.9 Hz), 7.48 (d, 1H, J=9 Hz), 8.01 (d, 1H, J=3 Hz).
According to a technique similar to Reference Example 1-2, the title compound (pale yellow crystals, 1.50 g, 97%) was obtained using tert-butyl (R)-(1-(6-(trifluoromethyl)pyridin-3-yl)pyrrolidin-3-yl)carbamate (2.20 g, 6.64 mmol) synthesized in Reference Example 32-1.
1H NMR (CDCl3, 400 MHz): δ=1.40 (br s, 2H), 1.8-2.0 (m, 1H), 2.2-2.3 (m, 1H), 3.0-3.1 (m, 1H), 3.3-3.5 (m, 1H), 3.5-3.6 (m, 2H), 3.7-3.9 (m, 1H), 6.80 (dd, 1H, J=3.9 Hz), 7.47 (d, 1H, J=9 Hz), 8.00 (d, 1H, J=3 Hz).
Ethyl 4-bromophenylacetate (6.0 g, 24.7 mmol), cyclopropylboronic acid (2.76 g, 32.1 mmol), palladium acetate (276 mg, 1.23 mmol), tricyclohexylphosphine (0.6 M toluene solution, 4.2 mL, 2.46 mmol), and potassium phosphate monohydrate (19.9 g, 86.4 mmol) were suspended in toluene (60.0 mL) and water (3.0 mL), and the suspension was stirred for 16 hours at 100° C. under a nitrogen gas stream. The reaction liquid that had been left to cool to room temperature was filtered through a Celite pad, and then the solvent of the filtrate was distilled off under reduced pressure. A residue thus obtained was diluted with ethyl acetate, an organic layer was washed with an aqueous solution of sodium hydrogen carbonate, water, and saturated brine and then was dried over anhydrous sodium sulfate, insoluble materials were filtered, and then the solvent was distilled off under reduced pressure. A residue thus obtained was purified by silica gel column chromatography (heptane:ethyl acetate) (concentration gradient: 0 to 30%), and the title compound (yellow oily material, 4.90 g, 97%) was obtained.
1H NMR (CDCl3, 400 MHz): δ=0.6-0.7 (m, 2H), 0.9-1.0 (m, 2H), 1.24 (t, 3H, J=8 Hz), 1.8-1.9 (m, 1H), 3.52 (s, 2H), 4.12 (q, 2H, J=8 Hz), 7.01 (d, 2H, J=8 Hz), 7.15 (d, 2H, J=8 Hz).
According to a technique similar to Reference Example 22-2, the title compound (white crystals, 3.80 g, 90%) was obtained using ethyl 2-(4-cyclopropylphenyl)acetate (4.90 g, 24.0 mmol) synthesized in Reference Example 33-1.
1H NMR (CDCl3, 400 MHz): δ=0.6-0.7 (m, 2H), 0.9-1.0 (m, 2H), 1.8-2.0 (m, 1H), 3.60 (s, 2H), 7.03 (d, 2H, J=8 Hz), 7.16 (d, 2H, J=8 Hz).
The 1H content is not observable.
According to a technique similar to Reference Example 1-1, the title compound (pale yellow syrup, 273 mg, 77%) was obtained using 1-bromo-4-(trifluoromethyl)benzene (260 mg, 1.61 mmol) and tert-butyl (R)-pyrrolidin-3-ylcarbamate (200 mg, 1.07 mmol).
1H NMR (CDCl3, 400 MHz): δ=1.45 (s, 9H), 1.9-2.1 (m, 1H), 2.2-2.4 (m, 1H), 3.20 (dd, 1H, J=3.10 Hz), 3.3-3.5 (m, 2H), 3.62 (dd, 1H, J=6.10 Hz), 4.38 (br s, 1H), 4.69 (br s, 1H), 6.55 (d, 2H, J=9 Hz), 7.45 (d, 2H, J=9 Hz).
According to a technique similar to Reference Example 1-1, the title compound (pale yellow solid, 236 mg, 67%) was obtained using 1-bromo-4-(trifluoromethyl)benzene (260 mg, 1.61 mmol) and tert-butyl (S)-pyrrolidin-3-ylcarbamate (200 mg, 1.07 mmol).
1H NMR (CDCl3, 400 MHz): δ=1.46 (s, 9H), 1.9-2.1 (m, 1H), 2.2-2.4 (m, 1H), 3.20 (dd, 1H, J=3.10 Hz), 3.3-3.5 (m, 2H), 3.62 (dd, 1H, J=6.10 Hz), 4.37 (br s, 1H), 4.69 (br s, 1H), 6.55 (d, 2H, J=9 Hz), 7.45 (d, 2H, J=9 Hz).
According to a technique similar to Reference Example 1-1, the title compound (pale yellow solid, 53 mg, 59%) was obtained using 5-bromo-2-(trifluoromethyl)pyridine (67 mg, 0.29 mmol) and tert-butyl (R)-pyrrolidin-3-ylcarbamate (50 mg, 0.27 mmol).
1H NMR (CDCl3, 400 MHz): δ=1.45 (s, 9H), 1.9-2.1 (m, 1H), 2.2-2.4 (m, 1H), 3.23 (dd, 1H, J=4.10 Hz), 3.3-3.6 (m, 2H), 3.65 (dd, 1H, J=6.10 Hz), 4.40 (br s, 1H), 4.81 (br s, 1H), 6.82 (dd, 1H, J=3.9 Hz), 7.47 (d, 1H, J=9 Hz), 7.99 (d, 1H, J=3 Hz)
According to a technique similar to Reference Example 1-1, the title compound (pale yellow solid, 59 mg, 66%) was obtained using 5-bromo-2-(trifluoromethyl)pyridine (67 mg, 0.29 mmol) and tert-butyl (S)-pyrrolidin-3-ylcarbamate (50 mg, 0.27 mmol).
1H NMR (CDCl3, 400 MHz): δ=1.45 (s, 9H), 1.9-2.1 (m, 1H), 2.2-2.4 (m, 1H), 3.24 (dd, 1H, J=4.10 Hz), 3.3-3.6 (m, 2H), 3.65 (dd, 1H, J=6.10 Hz), 4.40 (br s, 1H), 4.89 (br s, 1H), 6.82 (dd, 1H, J=3.9 Hz), 7.47 (d, 1H, J=9 Hz), 7.99 (d, 1H, J=3 Hz).
According to a technique similar to Reference Example 9, the title compound (white solid, 86 mg, 97%) was obtained using 2-chloro-5-(trifluoromethyl)pyrimidine (49 mg, 0.27 mmol) and tert-butyl (R)-pyrrolidin-3-ylcarbamate (50 mg, 0.27 mmol).
1H NMR (CDCl3, 400 MHz): δ=1.45 (s, 9H), 1.9-2.1 (m, 1H), 2.2-2.4 (m, 1H), 3.50 (dd, 1H, J=5.12 Hz), 3.6-3.8 (m, 2H), 3.88 (dd, 1H, J=6.12 Hz), 4.36 (br s, 1H), 4.73 (d, 1H, J=7 Hz), 8.50 (s, 2H).
According to a technique similar to Reference Example 1-2, the title compound (white solid, 45 mg, 75%) was obtained using tert-butyl (R)-(1-(5-(trifluoromethyl)pyrimidin-2-yl)pyrrolidin-3-yl)carbamate (86 mg, 0.26 mmol) synthesized in Reference Example 38-1.
1H NMR (CDCl3, 400 MHz): δ=1.8-1.9 (m, 1H), 2.1-2.3 (m, 1H), 3.3-3.4 (m, 1H), 3.6-3.9 (m, 4H), 8.50 (s, 2H). The 2H content is not observable.
According to a technique similar to Reference Example 1-1, the title compound (pale yellow solid, 112 mg, 60%) was obtained using 4-bromo-1-fluoro-2-(trifluoromethyl)benzene (144 mg, 0.59 mmol) and tert-butyl (R)-pyrrolidin-3-ylcarbamate (100 mg, 0.54 mmol).
1H NMR (CDCl3, 400 MHz): δ=1.45 (s, 9H), 1.9-2.1 (m, 1H), 2.2-2.4 (m, 1H), 3.15 (dd, 1H, J=4.9 Hz), 3.2-3.5 (m, 2H), 3.55 (dd, 1H, J=6.10 Hz), 4.37 (br s, 1H), 4.79 (d, 1H, J=7 Hz), 6.5-6.6 (m, 2H), 7.04 (t, 1H, J=10 Hz).
According to a technique similar to Reference Example 28-1, a crude form of the title compound was obtained using (1S,2S)-2-((((1R,2S,5R)-2-isopropyl-5-methylcyclohexyl)oxy)carbonyl)cyclopropane-1-carboxylic acid (1.17 g, 4.35 mmol) and 2-aminobenzaldehyde (988 mg, 8.12 mmol).
The crude form of (1R,2S,5R)-2-isopropyl-5-methylcyclohexyl (1S,2S)-2-((2-formylphenyl)carbamoyl)cyclopropane-1-carboxylate synthesized in Reference Example 40-1 and ammonium acetate were heated to reflux for 10 hours at 120° C. in toluene. The reaction liquid was left to cool to room temperature, sodium hydrogen carbonate was added to the reaction liquid, the mixture was stirred for a while, and then the mixture was extracted with ethyl acetate. An organic layer thus separated was dried over anhydrous sodium sulfate, insoluble materials were filtered, and then the solvent was distilled off under reduced pressure. A residue thus obtained was purified by silica gel column chromatography (heptane:ethyl acetate) (concentration gradient: 10 to 50%), and the title compound (277 mg, 18%) was obtained.
1H
NMR (CDCl3, 400 MHz): δ=0.76 (d, 3H, J=7 Hz), 0.80 (d, 3H, J=7 Hz), 0.8-2.1 (m, 12H), 2.1-2.3 (m, 2H), 2.4-2.5 (m, 1H), 2.9-3.0 (m, 1H), 4.6-4.8 (m, 1H), 7.58 (ddd, 1H, J=1, 7.7 Hz), 7.8-8.0 (m, 3H), 9.27 (s, 1H).
(1R,2S,5R)-2-isopropyl-5-methylcyclohexyl (1S,2S)-2-(quinazolin-2-yl)cyclopropane-1-carboxylate (277 mg, 0.79 mmol) synthesized in Reference Example 40-2 was dissolved in isopropanol (2.1 mL) and water (170 μL), sodium hydroxide (63 mg, 1.57 mmol) was added thereto, the mixture was stirred for 25 hours at 80° C., and then the solvent was distilled off under reduced pressure. 3 N hydrochloric acid and water were added to a residue thus obtained, and the mixture was extracted with ethyl acetate. An organic layer thus separated was dried over anhydrous sodium sulfate, a solid precipitated using ethyl acetate and hexane was collected by filtration, and the title compound (pale yellow solid, 73 mg, 43%) was obtained.
1H NMR (CDCl3, 400 MHz): δ=1.6-1.7 (m, 1H), 1.7-1.9 (m, 1H), 2.3-2.4 (m, 1H), 2.8-2.9 (m, 1H), 7.67 (ddd, 1H, J=1, 7.7 Hz), 7.91 (d, 1H, J=7 Hz), 7.97 (ddd, 1H, J=1, 7.7 Hz), 8.03 (dd, 1H, J=1.7 Hz), 9.39 (s, 1H). The 1H content is not observable.
According to a technique similar to Reference Example 1-1, the title compound (pale yellow oil, 57 mg, 62%) was obtained using 1-bromo-3-(methylsulfonyl)benzene (63 mg, 0.27 mmol) and tert-butyl (R)-pyrrolidin-3-ylcarbamate (50 mg, 0.27 mmol).
1H NMR (CDCl3, 400 MHz): δ=1.46 (s, 9H), 1.9-2.1 (m, 1H), 2.2-2.4 (m, 1H), 3.04 (s, 3H), 3.21 (dd, 1H, J=4.10 Hz), 3.3-3.5 (m, 2H), 3.63 (dd, 1H, J=6.10 Hz), 4.34 (br s, 1H), 4.78 (br s, 1H), 6.75 (dd, 1H, J=2.8 Hz), 7.02 (t, 1H, J=2 Hz), 7.20 (d, 1H, J=8 Hz), 7.38 (t, 1H, J=8 Hz).
According to a technique similar to Reference Example 1-2, the title compound (pale yellow oil, 12 mg, 30%) was obtained using tert-butyl (R)-(1-(3-(methylsulfonyl)phenyl)pyrrolidin-3-yl)carbamate (57 mg, 0.17 mmol) synthesized in Reference Example 41-1.
1H NMR (CDCl3, 400 MHz): δ=1.8-1.9 (m, 1H), 2.2-2.3 (m, 1H), 3.04 (s, 3H), 3.78 (dd, 1H, J=6.10 Hz), 3.3-3.6 (m, 3H), 3.77 (quin, 1H, J=6 Hz), 6.74 (dd, 1H, J=2.8 Hz), 7.02 (t, 1H, J=2 Hz), 7.17 (d, 1H, J=8 Hz), 7.37 (t, 1H, J=8 Hz). The 2H content is not observable.
According to a technique similar to Reference Example 1-1, the title compound (pale yellow amorphous, 57 mg, 74%) was obtained using 3-bromobenzonitrile (54 mg, 0.30 mmol) and tert-butyl (R)-pyrrolidin-3-ylcarbamate (50 mg, 0.27 mmol).
1H NMR (CDCl3, 400 MHz): δ=1.46 (s, 9H), 1.9-2.1 (m, 1H), 2.2-2.4 (m, 1H), 3.16 (dd, 1H, J=4.10 Hz), 3.3-3.5 (m, 2H), 3.57 (dd, 1H, J=6.10 Hz), 4.37 (br s, 1H), 4.76 (d, 1H, J=6 Hz), 6.7-6.8 (m, 2H), 6.94 (d, 1H, J=7 Hz), 7.2-7.3 (m, 1H).
According to a technique similar to Reference Example 1-2, the title compound (pale yellow oil, 32 mg, 85%) was obtained using tert-butyl (R)-(1-(3-cyanophenyl)pyrrolidin-3-yl)carbamate (57 mg, 0.20 mmol) synthesized in Reference Example 42-1.
1H NMR (CDCl3, 400 MHz): δ=1.8-1.9 (m, 1H), 2.2-2.3 (m, 1H), 3.11 (dd, 1H, J=5.9 Hz), 3.2-3.6 (m, 3H), 3.76 (quin, 1H, J=6 Hz), 6.6-6.8 (m, 2H), 6.91 (d, 1H, J=7 Hz), 7.2-7.3 (m, 1H). The 2H content is not observable.
According to a technique similar to Reference Example 7-1, a crude form of the title compound was obtained using trans-2-(ethoxycarbonyl)cyclopropane-1-carboxylic acid (100 mg, 0.63 mmol) and 3,4-diaminobenzonitrile (101 mg, 0.76 mmol).
1H NMR (CDCl3, 400 MHz): δ=1.27 (t, 3H, J=7 Hz), 1.3-1.6 (m, 2H), 2.1-2.4 (m, 2H), 4.15 (q, 2H, J=7 Hz), 4.75 (br s, 2H), 6.72 (d, 1H, J=8 Hz), 6.72 (d, 1H, J=8 Hz), 7.22 (dd, 1H, J=2.8 Hz), 7.57 (d, 1H, J=2 Hz).
The crude form of ethyl trans-2-((2-amino-5-cyanophenyl)carbamoyl)cyclopropane-1-carboxylate synthesized in Reference Example 43-1 was heated for 5 hours at 85° C. in acetic acid and then was left to cool to room temperature, and the solvent was distilled off under reduced pressure. An aqueous solution of sodium hydrogen carbonate was added thereto, the mixture was stirred for a while, and then the mixture was extracted with ethyl acetate. An organic layer thus separated was dried over anhydrous sodium sulfate, insoluble materials were filtered, and then the solvent was distilled off under reduced pressure. A residue thus obtained was purified by silica gel column chromatography (hexane:ethyl acetate) (concentration gradient: 40 to 80%), and thus the title compound (light brown amorphous, 142 mg, 88%) was obtained.
1H NMR (CDCl3, 400 MHz): δ=1.27 (t, 3H, J=7 Hz), 1.7-1.9 (m, 2H), 2.4-2.6 (m, 1H), 2.7-2.8 (m, 1H), 4.15 (q, 2H, J=7 Hz), 7.4-8.0 (m, 2H), 7.49 (d, 1H, J=7 Hz), 11.58 (br s, 1H).
Ethyl trans-2-(5-cyano-1H-benzo[d]imidazol-2-yl)cyclopropane-1-carboxylate (142 mg, 0.56 mmol) synthesized in Reference Example 43-2 was dissolved in methanol (6 mL) and water (1 mL), lithium hydroxide monohydrate (47 mg, 1.11 mmol) was added thereto, the mixture was stirred at room temperature, and then the solvent was distilled off under reduced pressure. 3 N hydrochloric acid was added to a residue thus obtained, and the solvent was distilled off under reduced pressure. A solid precipitated using ethyl acetate and hexane was collected by filtration, and the title compound (85 mg, 67%) was obtained.
1H NMR (DMSO-d6, 400 MHz): δ=1.6-1.8 (m, 2H), 2.2-2.4 (m, 1H), 2.6-2.8 (m, 1H), 7.52 (dd, 1H, J=1.8 Hz), 7.61 (d, 1H, J=8 Hz), 7.87 (s, 1H).
The 2H content is not observable.
According to a technique similar to Reference Example 9, the title compound (white amorphous) was obtained using 4-chloro-2-(trifluoromethyl)pyridine (49 mg, 0.27 mmol) and tert-butyl (R)-pyrrolidin-3-ylcarbamate (50 mg, 0.27 mmol).
1H NMR (CDCl3, 400 MHz): δ=1.46 (s, 9H), 1.9-2.1 (m, 1H), 2.2-2.4 (m, 1H), 3.24 (dd, 1H, J=4.10 Hz), 3.4-3.6 (m, 2H), 3.66 (dd, 1H, J=6.10 Hz), 4.38 (br s, 1H), 4.8-5.1 (m, 1H), 6.46 (dd, 1H, J=2.6 Hz), 6.72 (d, 1H, J=2 Hz), 8.28 (d, 1H, J=6 Hz).
According to a technique similar to Reference Example 1-1, the title compound (light brown solid, 72 mg, 84%) was obtained using 5-bromo-2-(trifluoromethyl)pyridine (62 mg, 0.27 mmol) and tert-butyl (R)-piperidin-3-ylcarbamate (50 mg, 0.25 mmol).
1H NMR (CDCl3, 400 MHz): δ=1.4-2.0 (m, 4H), 1.46 (s, 9H), 2.9-4.0 (m, 5H), 4.5-4.9 (m, 1H), 7.33 (s, 1H), 8.31 (s, 1H), 8.46 (d, 1H, J=3 Hz).
According to a technique similar to Reference Example 1-2, the title compound (light brown syrup, 50 mg, 97%) was obtained using tert-butyl (R)-(1-(6-(trifluoromethyl)pyridin-3-yl)piperidin-3-yl)carbamate (72 mg, 0.21 mmol) synthesized in Reference Example 45-1.
1H NMR (CDCl3, 400 MHz): δ=1.2-1.4 (m, 1H), 1.6-1.8 (m, 1H), 1.8-2.1 (m, 2H), 2.68 (dd, 1H, J=9.12 Hz), 2.8-3.1 (m, 2H), 3.5-3.6 (m, 1H), 3.6-3.7 (m, 1H), 7.32 (s, 1H), 8.28 (d, 1H, J=1 Hz), 8.45 (d, 1H, J=3 Hz).
The 2H content is not observable.
4-(Trifluoromethyl)thiazol-2-amine (100 mg, 0.60 mmol) and copper(II) chloride (96 mg, 0.71 mmol) were suspended in acetonitrile (8 mL), tert-butyl nitrite (92 mg, 0.89 mmol) was added thereto, and the mixture was stirred for one hour at room temperature. The reaction liquid was added to 1 N hydrochloric acid that had been ice-cooled, and the reaction liquid was extracted with diethyl ether. An organic layer thus separated was dried over anhydrous sodium sulfate, insoluble materials were filtered, subsequently the solvent was distilled off at 30° C. under reduced pressure (700 mbar), and thereby a crude form of the title compound was obtained.
1H NMR (CDCl3, 400 MHz): δ=7.69 (s, 1H).
Tert-butyl (R)-pyrrolidin-3-ylcarbamate (111 mg, 0.60 mmol), the crude form of 2-chloro-4-(trifluoromethyl)thiazole synthesized in Reference Example 46-1, and potassium carbonate (99 mg, 0.72 mmol) were dissolved in acetonitrile (8 mL), and then the mixture was stirred for 17 hours at 60° C. To the reaction liquid that had been left to cool to room temperature, water was added, the mixture was stirred for a while, and then the mixture was extracted with ethyl acetate. An organic layer thus separated was dried over anhydrous sodium sulfate, insoluble materials were filtered, and then the solvent was distilled off under reduced pressure. A residue thus obtained was purified by silica gel column chromatography (hexane:ethyl acetate) (concentration gradient: 10 to 60%), and the title compound (pale yellow solid, 147 mg, 73%) was obtained.
1H NMR (CDCl3, 400 MHz): δ=1.45 (s, 9H), 1.9-2.1 (m, 1H), 2.2-2.4 (m, 1H), 3.35 (dd, 1H, J=4.10 Hz), 3.5-3.7 (m, 2H), 3.75 (dd, 1H, J=6.10 Hz), 4.38 (br s, 1H), 4.82 (br s, 1H), 6.92 (s, 1H).
According to a technique similar to Reference Example 1-2, the title compound (pale yellow syrup, 94 mg, 91%) was obtained using tert-butyl (R)-(1-(4-(trifluoromethyl)thiazol-2-yl)pyrrolidin-3-yl)carbamate (147 mg, 0.44 mmol) synthesized in Reference Example 46-2.
1H NMR (CDCl3, 400 MHz): δ=1.8-2.0 (m, 1H), 2.2-2.3 (m, 1H), 3.23 (dd, 1H, J=4.10 Hz), 3.4-3.6 (m, 1H), 3.6-3.7 (m, 2H), 3.7-3.9 (m, 1H), 6.90 (d, 1H, J=1 Hz). The 2H content is not observable.
According to a technique similar to Reference Example 1-1, the title compound (pale yellow solid, 59 mg, 68%) was obtained using 1-bromo-4-(trifluoromethyl)benzene (62 mg, 0.27 mmol) and tert-butyl (R)-piperidin-3-ylcarbamate (50 mg, 0.25 mmol).
1H NMR (CDCl3, 400 MHz): δ=1.4-1.9 (m, 13H), 2.8-3.9 (m, 5H), 4.4-4.9 (m, 1H), 6.94 (d, 2H, J=9 Hz), 7.46 (d, 2H, J=9 Hz).
According to a technique similar to Reference Example 1-2, the title compound (light brown syrup, 42 mg, 100%) was obtained using tert-butyl (R)-(1-(4-(trifluoromethyl)phenyl)piperidin-3-yl)carbamate (59 mg, 0.17 mmol) synthesized in Reference Example 47-1.
1H NMR (CDCl3, 400 MHz): δ=1.2-1.4 (m, 1H), 1.6-1.9 (m, 2H), 1.9-2.1 (m, 1H), 2.67 (dd, 1H, J=9.12 Hz), 2.8-3.0 (m, 2H), 3.54 (dt, 1H, J=4.12 Hz), 3.6-3.7 (m, 1H), 6.92 (d, 2H, J=9 Hz), 7.45 (d, 2H, J=9 Hz). The 2H content is not observable.
According to a technique similar to Reference Example 1-1, the title compound (pale yellow solid, 26 mg, 13%) was obtained using 5-bromo-2-methoxy-3-(trifluoromethyl)pyridine (151 mg, 0.59 mmol) and tert-butyl (R)-pyrrolidin-3-ylcarbamate (100 mg, 0.54 mmol).
1H NMR (CDCl3, 400 MHz): δ=1.46 (s, 9H), 1.9-2.0 (m, 1H), 2.2-2.4 (m, 1H), 3.15 (dd, 1H, J=4.9 Hz), 3.29 (dt, 1H, J=6.9 Hz), 3.3-3.5 (m, 1H), 3.53 (dd, 1H, J=6.10 Hz), 3.96 (s, 3H), 4.38 (br s, 1H), 4.75 (d, 1H, J=7 Hz), 7.12 (d, 1H, J=3 Hz), 7.62 (d, 1H, J=3 Hz).
According to a technique similar to Reference Example 1-2, the title compound (pale yellow syrup, 18 mg, 100%) was obtained using tert-butyl (R)-(1-(6-methoxy-5-(trifluoromethyl)pyridin-3-yl)pyrrolidin-3-yl)carbamate (26 mg, 0.07 mmol) synthesized in Reference Example 48-1.
1H NMR (CDCl3, 400 MHz): δ=1.7-1.9 (m, 1H), 2.2-2.3 (m, 1H), 3.01 (dd, 1H, J=5.9 Hz), 3.30 (dt, 1H, J=6.8 Hz), 3.4-3.5 (m, 2H), 3.76 (quin, 1H, J=6 Hz), 3.96 (s, 3H), 7.11 (d, 1H, J=3 Hz), 7.62 (d, 1H, J=3 Hz). The 2H content is not observable.
According to a technique similar to Reference Example 9, the title compound (colorless oil, 103 mg, 70%) was obtained using 2-bromo-4-(tert-butyl)thiazole (100 mg, 0.45 mmol) and tert-butyl (R)-pyrrolidin-3-ylcarbamate (127 mg, 0.68 mmol).
1H NMR (CDCl3, 400 MHz): δ=1.27 (s, 9H), 1.45 (s, 9H), 1.9-2.0 (m, 1H), 2.2-2.4 (m, 1H), 3.31 (dd, 1H, J=4.10 Hz), 3.4-3.6 (m, 2H)), 3.71 (dd, 1H, J=6.11 Hz), 4.35 (br s, 1H), 4.74 (br s, 1H), 6.06 (s, 1H).
According to a technique similar to Reference Example 1-2, the title compound (colorless oil, 65 mg, 91%) was obtained using tert-butyl (R)-(1-(4-(tert-butyl)thiazol-2-yl)pyrrolidin-3-yl)carbamate (103 mg, 0.32 mmol) synthesized in Reference Example 49-1.
1H NMR (CDCl3, 400 MHz): δ=1.27 (s, 9H), 1.7-1.9 (m, 1H), 2.1-2.3 (m, 1H), 3.17 (dd, 1H, J=4.10 Hz)(3.4-3.8 (m, 4H), 6.04 (s, 1H).
The 2H content is not observable.
According to a technique similar to Reference Example 9, the title compound (white powder, 90 mg, 84%) was obtained using 3-chloro-6-(trifluoromethyl)pyridazine (60 mg, 0.322 mmol) and tert-butyl (R)-pyrrolidin-3-ylcarbamate (59 mg, 0.322 mmol).
1H NMR (CDCl3, 400 MHz): δ=1.46 (s, 9H), 2.0-2.1 (m, 1H), 2.3-2.4 (m, 1H), 3.4-4.0 (m, 4H), 4.41 (br s, 1H), 4.71 (br s, 1H), 6.67 (d, 1H, J=10 Hz), 7.48 (d, 1H, J=10 Hz).
According to a technique similar to Reference Example 1-1, the title compound (yellow powder, 129 mg, 72%) was obtained using 5-bromo-2-(trifluoromethyl)pyrimidine (134 mg, 0.591 mmol) and tert-butyl (R)-pyrrolidin-3-ylcarbamate (100 mg, 0.537 mmol).
1H NMR (CDCl3, 400 MHz): δ=1.46 (s, 9H), 2.0-2.1 (m, 1H), 2.3-2.5 (m, 1H), 3.28 (dd, 1H, J=4.10 Hz), 3.4-3.6 (m, 2H), 3.70 (dd, 1H, J=6.10 Hz), 4.42 (br s, 1H), 4.69 (br s, 1H), 8.10 (s, 2H).
Tert-butyl (R)-pyrrolidin-3-ylcarbamate (50 mg, 0.268 mmol) and 2-chloro-6-fluorobenzothiazole (58 mg, 0.309 mmol) were dissolved in DMF (1 mL), subsequently cesium carbonate (101 mg, 0.309 mmol) was added thereto, and the mixture was stirred for 2 hours at 100° C. To the reaction liquid that had been left to cool to room temperature, water was added, the mixture was stirred for a while, and then the mixture was extracted with ethyl acetate. An organic layer thus separated was dried over anhydrous sodium sulfate, insoluble materials were filtered, and then the solvent was distilled off under reduced pressure. A residue thus obtained was purified by silica gel column chromatography (heptane:ethyl acetate) (concentration gradient: 25 to 40%), and the title compound (pale yellow powder, 85 mg, 94%) was obtained.
1H NMR (CDCl3, 400 MHz): δ=1.46 (s, 9H), 2.0-2.1 (m, 1H), 2.3-2.4 (m, 1H), 3.44 (dd, 1H, J=4.10 Hz), 3.6-3.8 (m, 2H), 3.83 (dd, 1H, J=6.10 Hz), 4.41 (br s, 1H), 4.70 (br s, 1H), 7.02 (dd, 1H, J=3.9 Hz), 7.32 (dd, 1H, J=3.8 Hz), 7.50 (dd, 1H, J=5.9 Hz).
Tert-butyl (R)-pyrrolidin-3-ylcarbamate (50 mg, 0.268 mmol) and 2-chloro-6-fluoroquinoline (54 mg, 0.295 mmol) were dissolved in toluene (1.5 mL) and water (150 μL), subsequently potassium carbonate (44 mg, 0.322 mmol) were added thereto, and the mixture was heated to reflux overnight in a nitrogen atmosphere. To the reaction liquid that had been left to cool to room temperature, water was added, the mixture was stirred for a while, and then the mixture was extracted with ethyl acetate. An organic layer thus separated was dried over anhydrous sodium sulfate, insoluble materials were filtered, and then the solvent was distilled off under reduced pressure. A residue thus obtained was purified by silica gel column chromatography (heptane:ethyl acetate) (concentration gradient: 20 to 32%), and the title compound (white powder, 39 mg, 44%) was obtained.
1H NMR (CDCl3, 400 MHz): δ=1.46 (s, 9H), 1.9-2.1 (m, 1H), 2.2-2.4 (m, 1H), 3.51 (dd, 1H, J=4.10 Hz), 3.6-3.8 (m, 2H), 3.87 (dd, 1H, J=6.10 Hz), 4.39 (br s, 1H), 4.73 (br s, 1H), 6.75 (d, 1H, J=9 Hz), 7.2-7.4 (m, 2H), 7.67 (dd, 1H, J=6.9 Hz), 7.82 (d, 1H, J=9 Hz).
(1R,2S,5R)-2-isopropyl-5-methylcyclohexyl (1S,2S)-2-(1H-benzo[d]imidazol-2-yl)cyclopropane-1-carboxylate (408 mg, 1.1 mmol), cyclopropylboronic acid (184 mg, 2.1 mmol), and sodium carbonate (227 mg, 2.1 mmol) were dissolved in toluene (4 mL), subsequently copper(II) acetate monohydrate (214 mg, 1.1 mmol) and 2,2′-bipyridyl (167 mg, 1.1 mmol) suspended in toluene (7 mL) were added thereto, and the mixture was stirred overnight at 70° C. A saturated aqueous solution of ammonium chloride and water were added to the reaction liquid, and the mixture was extracted with ethyl acetate. An organic layer thus separated was washed with saturated brine and dried over anhydrous sodium sulfate, insoluble materials were filtered, and then the solvent was distilled off under reduced pressure. A residue thus obtained was purified by silica gel column chromatography (hexane:ethyl acetate) (concentration gradient: 10% to 25%), and the title compound (colorless oily material, 270 mg, 66%) was obtained.
1H NMR (CDCl3, 400 MHz): δ=0.80 (d, 3H, J=7 Hz), 0.9-1.5 (m, 15H), 1.6-2.1 (m, 6H), 2.32 (ddd, 1H, J=4, 6.9 Hz), 2.87 (ddd, 1H, J=4, 6.9 Hz), 3.30 (ddd, 1H, J=4, 7.11 Hz), 4.73 (td, 1H, J=4.11 Hz), 7.2-7.3 (m, 2H), 7.4-7.7 (m, 2H).
(1R,2S,5R)-2-isopropyl-5-methylcyclohexyl (1S,2S)-2-(1-cyclopropyl-1H-benzo[d]imidazol-2-yl)cyclopropane-1-carboxylate (270 mg, 0.709 mmol) synthesized in Reference Example 54-1 was suspended in isopropanol (2 mL) and water (150 HL), subsequently sodium hydroxide (57 mg, 1.42 mmol) was added thereto, and the mixture was stirred for 5 hours at 80° C. The solvent was distilled off under reduced pressure, subsequently a 0.2 Normal aqueous solution of sodium hydroxide (20 mL) was added to a residue thus obtained, and the mixture was washed twice with diethyl ether. 1 Normal hydrochloric acid (15 mL) was added to the aqueous layer to made the aqueous layer acidic, subsequently to a residue obtained by distilling off the solvent, toluene and water were added, and the mixture was suspended. A solid thus obtained was collected by filtration and dried under reduced pressure at room temperature, and the title compound (white powder, 48 mg, 28%) was obtained.
1H NMR (DMSO-d6, 400 MHz): δ=1.1-1.4 (m, 4H), 1.71 (quin, 1H, J=5 Hz), 1.8-1.9 (m, 1H), 2.3-2.5 (m, 1H), 2.93 (ddd, 1H, J=4, 6.9 Hz), 3.5-3.7 (m, 1H), 7.44 (quin, 2H, J=8 Hz), 7.67 (d, 1H, J=8 Hz), 7.77 (d, 1H, J=8 Hz). The 1H content is not observable.
According to a technique similar to Reference Example 1-1, the title compound (white powder, 71 mg, 83%) was obtained using 3,5-dibromopyridine (178 mg, 0.751 mmol) and tert-butyl (R)-pyrrolidin-3-ylcarbamate (47 mg, 0.252 mmol).
1H NMR (CDCl3, 400 MHz): δ=1.46 (s, 9H), 1.9-2.1 (m, 1H), 2.2-2.4 (m, 1H), 3.17 (dd, 1H, J=4.10 Hz), 3.3-3.5 (m, 2H), 3.59 (dd, 1H, J=6.10 Hz), 4.38 (br s, 1H), 4.68 (br s, 1H), 6.95 (t, 1H, J=2 Hz), 7.78 (d, 1H, J=3 Hz), 8.80 (d, 1H, J=2 Hz).
4-(Trifluoromethyl)phenylacetic acid (50 mg, 0.245 mmol) was dissolved in deuterated water (1 mL), subsequently a 40% solution of sodium deuteroxide (0.5 mL, 7.00 mmol) was added thereto, and the mixture was heated to reflux overnight in a nitrogen atmosphere. Deuterated water was added to the reaction liquid that had been left to cool to room temperature, the mixture was washed with diethyl ether, subsequently 3 N hydrochloric acid was added to the aqueous layer to make the aqueous layer acidic, and the aqueous layer was extracted with diethyl ether. An organic layer thus separated was dried over anhydrous sodium sulfate, insoluble materials were filtered, and then the solvent was distilled off under reduced pressure. A residue thus obtained was suspended in chloroform, insoluble materials were filtered, subsequently the solvent was distilled off under reduced pressure, and the title compound (white powder, 30 mg, 59%) was obtained.
1H NMR (DMSO-d6, 400 MHz): δ=7.43 (d, 2H, J=8 Hz), 7.59 (d, 2H, J=8 Hz). The 1H content is not observable.
According to a technique similar to Reference Example 7-1, the title compound (pale yellow powder, 88 mg, 95%) was obtained using (R)-l-(6-(trifluoromethyl)pyridin-3-yl)pyrrolidin-3-amine (50 mg, 0.216 mmol) synthesized in Reference Example 32-2 and 4-bromophenylacetic acid (56 mg, 0.259 mmol).
1H NMR (CDCl3, 400 MHz): δ=1.9-2.0 (m, 1H), 2.3-2.4 (m, 1H), 3.16 (dd, 1H, J=4.10 Hz), 3.3-3.5 (m, 2H), 3.53 (s, 2H), 3.68 (dd, 1H, J=6.10 Hz), 4.5-4.7 (m, 1H), 5.52 (br s, 1H), 6.80 (dd, 1H, J=3.9 Hz), 7.14 (d, 2H, J=9 Hz), 7.4-7.5 (m, 3H), 7.98 (d, 1H, J=3 Hz).
According to a technique similar to Reference Example 4, the title compound (pale yellow powder, 112 mg, 25%) was obtained using 3-bromo-5-(trifluoromethyl)pyridine (390 mg, 1.73 mmol) and tert-butyl azetidin-3-ylcarbamate hydrochloride (300 mg, 1.44 mmol).
1H
According to a technique similar to Reference Example 1-2, the title compound (white powder, 60 mg, 79%) was obtained using tert-butyl (1-(5-(trifluoromethyl)pyridin-3-yl)azetidin-3-yl)carbamate (112 mg, 0.353 mmol) synthesized in Reference Example 58-1.
1H NMR (CDCl3, 400 MHz): δ=3.59 (dd, 2H, J=6.8 Hz), 4.0-4.1 (m, 1H), 4.27 (t, 2H, J=7 Hz), 6.85 (t, 1H, J=2 Hz), 7.99 (d, 1H, J=3 Hz), 8.24 (s, 1H). The 2H content is not observable.
According to a technique similar to Reference Example 7-1, the title compound (yellow powder, 176 mg, 90%) was obtained using (R)-1-(5-(trifluoromethyl)pyridin-3-yl)pyrrolidin-3-amine (80 mg, 0.346 mmol) synthesized in Reference Example 1-2 and 2-(4-(4-((benzyloxy)carbonyl)piperazin-1-yl)phenyl)acetic acid (135 mg, 0.381 mmol).
1H NMR (CDCl3, 400 MHz): δ=1.8-2.0 (m, 1H), 2.2-2.4 (m, 1H), 3.0-3.2 (m, 5H), 3.37 (t, 2H, J=7 Hz), 3.51 (s, 2H), 3.6-3.7 (m, 5H), 4.5-4.7 (m, 1H), 5.16 (s, 2H), 5.53 (d, 1H, J=7 Hz), 6.8-6.9 (m, 3H), 7.14 (d, 2H, J=9 Hz), 7.3-7.4 (m, 5H), 8.07 (d, 1H, J=3 Hz), 8.20 (s, 1H).
According to a technique similar to Reference Example 23-1, the title compound (yellow oily material, 16 mg, 4%) was obtained using ethyl 2-(4-bromophenyl)acetate (300 mg, 1.23 mmol) and 4-piperidone ethylene ketal (317 HL, 2.46 mmol).
1H
According to a technique similar to Reference Example 1-1, the title compound (white powder, 106 mg, 51%) was obtained using 3-bromo-5-(trifluoromethyl)pyridine (162 mg, 0.717 mmol) and benzyl N-(3-(hydroxymethyl)pyrrolidin-3-yl)carbamate (189 mg, 0.753 mmol).
1H NMR (CDCl3, 400 MHz): δ=2.2-2.5 (m, 2H), 3.4-3.6 (m, 4H), 4.41 (d, 1H, J=9 Hz), 4.45 (d, 1H, J=9 Hz), 5.57 (s, 1H), 6.97 (t, 1H, J=2 Hz), 8.14 (d, 1H, J=3 Hz), 8.29 (s, 1H).
7-(5-(Trifluoromethyl)pyridin-3-yl)-3-oxa-1,7-diazaspiro[4.4]nonan-2-one (95 mg, 0.331 mmol) synthesized in Reference Example 61-1 was dissolved in ethanol (4 mL) and water (1 mL), lithium hydroxide monohydrate (278 mg, 6.61 mmol) was added thereto, and the mixture was heated to reflux overnight in a nitrogen atmosphere. To the reaction liquid that had been left to cool to room temperature, water was added, the mixture was stirred for a while, and then the mixture was extracted with ethyl acetate. An organic layer thus separated was washed with saturated brine and dried over anhydrous sodium sulfate, insoluble materials were filtered, subsequently the solvent was distilled off under reduced pressure, and the title compound (yellow powder, 86 mg, 100%) was obtained.
1H NMR (CDCl3, 400 MHz): δ=1.8-2.0 (m, 1H), 2.1-2.2 (m, 1H), 3.19 (d, 1H, J=10 Hz), 3.4-3.7 (m, 5H), 6.93 (t, 1H, J=2 Hz), 8.11 (d, 1H, J=3 Hz), 8.20 (s, 1H).
The 3H content is not observable.
4-Amino-1-tert-butoxycarbonylpiperidine (1.00 g, 4.54 mmol) and 2-(4-isopropylphenyl)acetic acid (0.971 g, 5.45 mmol) were dissolved in DMF (13 mL), subsequently DIPEA (2.3 mL, 13.6 mmol) and HATU (2.42 g, 6.36 mmol) were added thereto, and the mixture was stirred overnight at room temperature. Water was added to the reaction liquid, the mixture was stirred for a while, and then the mixture was extracted with ethyl acetate. An organic layer thus separated was washed with saturated brine and dried over anhydrous sodium sulfate, insoluble materials were filtered, subsequently the solvent was distilled off under reduced pressure, and a crude form of tert-butyl 4-(2-(4-isopropylphenyl)acetamido)piperidine-1-carboxylate (dark brown oily material, 2.45 g) was obtained. According to a technique similar to Reference Example 1-2, the title compound (ocher-colored crystals, 0.911 g, 77%) was obtained using the crude form of tert-butyl 4-(2-(4-isopropylphenyl)acetamido)piperidine-1-carboxylate (2.45 g) thus obtained.
1H NMR (CDCl3, 400 MHz): δ=1.1-1.3 (m, 9H), 1.8-1.9 (m, 2H), 2.65 (td, 2H, J=3.12 Hz), 2.8-3.0 (m, 3H), 3.52 (s, 2H), 3.8-4.0 (m, 1H), 5.24 (d, 1H, J=6 Hz), 7.1-7.3 (m, 4H).
According to a technique similar to Reference Example 62, a crude form of tert-butyl (R)-3-(2-(4-isopropylphenyl)acetamido)pyrrolidine-1-carboxylate (4.25 g) was synthesized using (3R)-(+)-1-(tert-butoxycarbonyl)-3-aminopyrrolidine (2.00 g, 10.7 mmol) and 2-(4-isopropylphenyl)acetic acid (2.30 g, 12.9 mmol), and then the title compound (pale peach-colored crystals, 2.22 g, 84%) was obtained.
1H NMR (CDCl3, 400 MHz): δ=1.25 (d, 6H, J=7 Hz), 1.4-1.5 (m, 1H), 2.0-2.2 (m, 1H), 2.65 (dd, 1H, J=4.11 Hz), 2.8-3.0 (m, 3H), 3.11 (dd, 1H, J=7.11 Hz), 3.51 (s, 2H), 4.3-4.4 (m, 1H), 5.55 (br s, 1H), 7.16 (d, 2H, J=8 Hz), 7.21 (d, 2H, J=8 Hz).
The 1H content is not observable.
According to a technique similar to Reference Example 4, the title compound (pale yellow crystals, 185 mg, 20%) was obtained using tert-butyl (S)-pyrrolidin-3-ylcarbamate (500 mg, 2.68 mmol) and 5-bromo-2-(trifluoromethyl)pyridine (728 mg, 3.22 mmol).
1H NMR (CDCl3, 400 MHz): δ=1.46 (s, 9H), 1.9-2.1 (m, 1H), 2.3-2.4 (m, 1H), 3.23 (dd, 1H, J=4.10 Hz), 3.3-3.6 (m, 2H), 3.65 (dd, 1H, J=6.10 Hz), 4.40 (br s, 1H), 4.71 (br s, 1H), 6.94 (s, 1H), 8.12 (d, 1H, J=3 Hz), 8.21 (s, 1H).
According to a technique similar to Reference Example 1-2, the title compound (pale yellow crystals, 100 mg, 77%) was obtained using tert-butyl (S)-(1-(5-(trifluoromethyl)pyridin-3-yl)pyrrolidin-3-yl)carbamate (184 mg, 0.555 mmol) synthesized in Reference Example 64-1.
1H NMR (CDCl3, 400 MHz): δ=1.8-2.0 (m, 1H), 2.2-2.4 (m, 1H), 3.08 (dd, 1H, J=5.10 Hz), 3.3-3.6 (m, 3H), 3.81 (quin, 1H, J=6 Hz) 6.92 (s, 1H), 8.11 (d, 1H, J=3 Hz), 8. 17 (s, 1H). The 2H content is not observable.
According to a technique similar to Reference Example 7-1, the title compound (pale yellow amorphous, 964 mg, 100%) was obtained using tert-butyl 3-aminoazetidine-1-carboxylate (500 mg, 2.90 mmol) and 2-(4-isopropylphenyl)acetic acid (624 mg, 3.50 mmol).
1H NMR (CDCl3, 400 MHz): δ=1.26 (d, 6H, J=7 Hz), 2.8-3.0 (m, 1H), 3.54 (s, 2H), 3.5-3.7 (m, 2H), 4.2-4.4 (m, 2H), 4.5-4.7 (m, 1H), 6.6-6.8 (m, 1H), 7.15 (d, 2H, J=8 Hz), 7.23 (d, 2H, J=8 Hz).
According to a technique similar to Reference Example 4, the title compound (yellow amorphous, 100 mg, 20%) was obtained using 3-bromo-5-(trifluoromethyl)pyridine (407 mg, 1.80 mmol) and (R)-3-(tert-butoxycarbonylamino)piperidine (300 mg, 1.50 mmol).
1H NMR (CDCl3, 400 MHz): δ=1.46 (s, 9H), 1.6-1.8 (m, 1H), 1.8-2.0 (m, 2H), 2.9-3.2 (m, 2H), 3.2-3.4 (m, 1H), 3.5-3.6 (m, 1H), 3.8-3.9 (m, 1H), 4.7-4.8 (m, 1H), 7.33 (s, 1H), 8.32 (s, 1H), 8.46 (d, 1H, J=2 Hz). The 1H content is not observable.
According to a technique similar to Reference Example 7-1, the title compounds (diastereomer A: Rf value in TLC (ethyl acetate:heptane=1:1)=0.2, yellow amorphous, 15 mg, 5%; diastereomer B: Rf value in TLC (ethyl acetate:heptane=1:1)=0.18, yellow amorphous, 15 mg, 5%, diastereomer mixture: 290 mg, 88%) were respectively obtained using (R)-1-(5-(trifluoromethyl)pyridin-3-yl)pyrrolidin-3-amine (150 mg, 0.65 mmol) and 2-((tert-butoxycarbonyl)amino)-2-(4-cyclopropylphenyl)acetic acid (189 mg, 0.65 mmol).
Diastereomer A
1H NMR (CDCl3, 400 MHz): δ=0.6-0.7 (m, 2H), 0.9-1.0 (m, 2H), 1.39 (s, 9H), 1.8-1.9 (m, 1H), 2.0-2.1 (m, 1H), 2.3-2.4 (m, 1H), 3.0-3.1 (m, 1H), 3.3-3.5 (m, 2H), 3.5-3.6 (m, 1H), 4.5-4.7 (m, 1H), 5.0-5.1 (m, 1H), 5.5-5.7 (m, 1H), 6.2-6.3 (m, 1H), 6.83 (s, 1H), 7.00 (d, 2H, J=8 Hz), 7.19 (d, 2H, J=8 Hz), 8.00 (d, 1H, J=3 Hz), 8.14 (s, 1H).
Diastereomer B
1H NMR (CDCl3, 400 MHz): δ=0.6-0.8 (m, 2H), 0.9-1.0 (m, 2H), 1.40 (s, 9H) 1.8-2.0 (m, 2H), 2.2-2.3 (m, 1H), 3.2-3.4 (m, 3H), 3.6-3.7 (m, 1H), 4.6-4.7 (m, 1H), 5.0-5.1 (m, 1H), 5.5-5.7 (m, 1H), 6.2-6.3 (m, 1H), 6.85 (s, 1H), 7.04 (d, 2H, J=8 Hz), 7.22 (d, 2H, J=8 Hz), 8.01 (d, 1H, J=3 Hz), 8.12 (s, 1H).
According to a technique similar to Reference Example 4, the title compound (yellow amorphous, 50 mg, 63%) was obtained using 3-bromo-5-(trifluoromethyl)pyridine (79 mg, 0.23 mmol) and tert-butyl (R)-(3-methylpyrrolidin-3-yl)carbamate (47 mg, 0.23 mmol).
1H NMR (CDCl3, 400 MHz): δ=1.45 (s, 9H), 1.54 (s, 3H), 1.9-2.1 (m, 1H), 2.3-2.5 (m, 1H), 3.3-3.5 (m, 3H), 3.5-3.6 (m, 1H), 4.66 (br s, 1H), 6.92 (s, 1H), 8.10 (d, 1H, J=3 Hz), 8.19 (s, 1H).
According to a technique similar to Reference Example 27, the title compound (pale yellow amorphous, 87 mg, 70%) was obtained using ethyl 4-bromophenylacetate (109 mg, 0.45 mmol) and 3-oxa-8-azabicyclo[3.2.1]octane hydrochloride (100 mg, 0.67 mmol).
1H NMR (CDCl3, 400 MHz): δ=1.25 (t, 3H, J=7 Hz), 1.9-2.1 (m, 4H), 3.51 (s, 2H), 3.4-3.6 (m, 2H), 3.91 (d, 2H, J=10 Hz), 4.0-4.1 (m, 2H), 4.14 (q, 2H, J=7 Hz), 6.74 (d, 2H, J=8 Hz), 7.15 (d, 2H, J=8 Hz
According to a technique similar to Reference Example 27, the title compound (pale yellow amorphous, 109 mg, 88%) was obtained using ethyl 4-bromophenylacetate (109 mg, 0.45 mmol) and (1S,4S)-2-oxa-5-azabicyclo[2.2.2]octane oxalate (106 mg, 0.67 mmol).
1H NMR (CDCl3, 400 MHz): δ=1.25 (t, 3H, J=7 Hz), 1.6-1.8 (m, 1H), 1.8-2.0 (m, 1H), 2.0-2.3 (m, 2H), 3.3-3.4 (m, 1H), 3.51 (s, 2H), 3.7-3.9 (m, 2H), 4.0-4.1 (m, 2H), 4.1-4.2 (m, 1H), 4.13 (q, 2H, J=7 Hz), 6.59 (d, 2H, J=8 Hz), 7.16 (d, 2H, J=8 Hz
According to a technique similar to Reference Example 4, the title compound (yellow amorphous, 145 mg, 62%) was obtained using 3-bromo-5-(trifluoromethyl)pyridine (160 mg, 0.23 mmol) and tert-butyl 3-(trifluoromethyl)pyrrolidin-3-ylcarbamate (150 mg, 0.59 mmol).
1H NMR (CDCl3, 400 MHz): δ=1.45 (s, 9H), 2.5-2.8 (m, 2H), 3.5-3.7 (m, 2H), 3.8-3.9 (m, 1H), 3.9-4.0 (m, 1H), 4.85 (br s, 1H), 6.98 (s, 1H), 8.14 (d, 1H, J=3 Hz), 8.26 (s, 1H).
According to a technique similar to Reference Example 4, the title compound (yellow crystals, 400 mg, 77%) was obtained using 5-bromo-2-(trifluoromethyl)pyridine (407 mg, 1.80 mmol) and (R)-3-(tert-butoxycarbonylamino)piperidine (300 mg, 1.50 mmol).
1H NMR (CDCl3, 400 MHz): δ=1.45 (s, 9H), 1.6-2.0 (m, 4H), 2.9-3.1 (m, 1H), 3.1-3.2 (m, 1H), 3.3-3.5 (m, 1H), 3.6-3.7 (m, 1H), 3.7-3.8 (m, 1H), 4.65 (br s, 1H), 7.17 (d, 1H, J=7 Hz), 7.49 (d, 1H, J=7 Hz), 8.33 (s, 1H).
According to a technique similar to Reference Example 7-1, the title compound (white solid, 1.96 g, 88%) was obtained using tert-butyl (R)-aminopyrrolidine-1-carbamate (1.11 g, 6.0 mmol) and 2-(4-(trifluoromethyl)phenyl)acetic acid (1.35 g, 6.6 mmol).
1H NMR (CDCl3, 400 MHz): δ=1.45 (s, 9H), 1.6-1.9 (m, 1H), 2.0-2.2 (m, 1H), 3.0-3.5 (m, 3H), 3.5-3.7 (m, 1H), 3.60 (s, 2H), 4.3-4.5 (m, 1H), 5.53 (br s, 1H), 7.39 (d, 2H, J=8 Hz), 7.61 (d, 2H, J=8 Hz).
According to a technique similar to Reference Example 1-2, the title compound (white solid, 650 mg, 80%) was obtained using tert-butyl (R)-3-(2-(4-(trifluoromethyl)phenyl)acetamido)pyrrolidine-1-carboxylate (1.12 g, 3.0 mmol) synthesized in Reference Example 73-1.
1H NMR (CDCl3, 400 MHz): δ=1.4-1.6 (m, 1H), 2.0-2.2 (m, 1H), 2.71 (dd, 1H, J=4.11 Hz), 2.8-3.1 (m, 2H), 3.10 (dd, 1H, J=7.12 Hz), 3.57 (s, 2H), 4.3-4.4 (m, 1H), 5.69 (br s, 1H), 7.39 (d, 2H, J=8 Hz), 7.60 (d, 2H, J=8 Hz).
The 1H content is not observable.
According to a technique similar to Reference Example 7-1, the title compound (yellow crystals, 2.0 g, 70%) was obtained using tert-butyl 3-aminopyrrolidine-1-carboxylate (1.5 mL, 8.29 mmol) and 2-(4-cyclopropylphenyl)acetic acid (1.8 g, 9.95 mmol) synthesized in Reference Example 33-2.
1H NMR (CDCl3, 400 MHz): δ=0.6-0.7 (m, 2H), 0.9-1.0 (m, 2H), 1.43 (s, 9H), 1.5-1.7 (m, 1H), 1.8-1.9 (m, 1H), 2.0-2.1 (m, 1H), 2.9-3.1 (m, 1H), 3.2-3.5 (m, 2H), 3.51 (s, 2H), 3.5-3.6 (m, 1H), 4.3-4.5 (m, 1H), 5.3-5.5 (m, 1H), 7.04 (d, 2H, J=8 Hz), 7.10 (d, 2H, J=8 Hz).
According to a technique similar to Reference Example 1-2, the title compound (pale yellow crystals, 1.1 g, 77%) was obtained using tert-butyl (R)-3-(2-(4-cyclopropylphenyl)acetamido)pyrrolidine-1-carboxylate (2.0 g, 5.81 mmol) synthesized in Reference Example 74-1.
1H NMR (CDCl3, 400 MHz): δ=0.6-0.7 (m, 2H), 0.9-1.0 (m, 2H), 1.4-1.5 (m, 1H), 1.8-1.9 (m, 2H), 2.0-2.2 (m, 1H), 2.6-2.7 (m, 1H), 2.8-3.0 (m, 2H), 3.0-3.1 (m, 1H), 3.48 (s, 2H), 4.2-4.4 (br s, 1H), 5.62 (br s, 1H), 7.03 (d, 2H, J=8 Hz), 7.11 (d, 2H, J=8 Hz).
According to a technique similar to Reference Example 7-1, the title compound (white solid, 434 mg, 82%) was obtained using tert-butyl 3-aminoazetidine-1-carbamate (276 mg, 1.6 mmol) and 2-(4-cyclopropylphenyl)acetic acid (352 mg, 2.0 mmol) synthesized in Reference Example 33-2.
1H NMR (CDCl3, 400 MHz): δ=0.6-0.8 (m, 2H), 0.9-1.1 (m, 2H), 1.41 (s, 9H), 1.8-2.0 (m, 1H), 3.53 (s, 2H), 3.58 (dd, 2H, J=5.10 Hz), 4.28 (t, 2H, J=9 Hz), 4.5-4.7 (m, 1H), 5.71 (d, 1H, J=7 Hz), 7.07 (d, 2H, J=8 Hz), 7.12 (d, 2H, J=8 Hz).
According to a technique similar to Reference Example 1-2, the title compound (white solid, 83 mg, 28%) was obtained using tert-butyl 3-(2-(4-cyclopropylphenyl)acetamido)azetidine-1-carbamate (431 mg, 1.3 mmol) synthesized in Reference Example 75-1.
1H NMR (CDCl3, 400 MHz): δ=0.6-0.8 (m, 2H), 0.9-1.1 (m, 2H), 1.8-2.0 (m, 1H), 3.3-3.6 (m, 2H), 3.51 (s, 2H), 3.8-3.9 (m, 2H), 4.6-4.8 (m, 1H), 5.71 (d, 1H, J=7 Hz), 7.06 (d, 2H, J=8 Hz), 7.13 (d, 2H, J=8 Hz
The 1H content is not observable.
According to a technique similar to Reference Example 52, the title compound (white amorphous, 149 mg, 86%) was obtained using 3-bromophenol (173 mg, 1.0 mmol) and ethyl 2-bromo-2-methylpropanoate (195 mg, 1.0 mmol).
1H
According to a technique similar to Reference Example 1-1, the title compound (yellow powder, 105 mg, 59%) was obtained using 3-bromobenzotrifluoride (89 μL, 0.644 mmol) and tert-butyl (R)-pyrrolidin-3-ylcarbamate (100 mg, 0.537 mmol).
1H NMR (CDCl3, 400 MHz): δ=1.46 (s, 9H), 1.9-2.1 (m, 1H), 2.2-2.4 (m, 1H), 3.19 (dd, 1H, J=4.10 Hz), 3.3-3.5 (m, 2H), 3.60 (dd, 1H, J=6.10 Hz), 4.38 (br s, 1H), 4.69 (br s, 1H), 6.68 (dd, 1H, J=2.8 Hz), 6.73 (s, 1H), 6.93 (d, 1H, J=8 Hz), 7.31 (t, 1H, J=8 Hz).
(R)-1-(5-(trifluoromethyl)pyridin-3-yl)pyrrolidin-3-amine (20 mg, 0.09 mmol) synthesized in Reference Example 1-2 and 2-(4-cyclopropylphenyl)acetic acid (30 mg, 0.09 mmol) synthesized in Reference Example 33-2 were dissolved in DMF (2.0 mL), subsequently DIPEA (29 μL, 0.17 mmol) and HATU (33 mg, 0.09 mmol) were added thereto, and the mixture was stirred overnight at room temperature. Water was added to the reaction liquid, the mixture was stirred for a while, and then the mixture was extracted with ethyl acetate. An organic layer thus separated was dried over anhydrous sodium sulfate, insoluble materials were filtered, and then the solvent was distilled off under reduced pressure. A residue thus obtained was purified by silica gel column chromatography (heptane:ethyl acetate) (concentration gradient: 0 to 100%), and the title compound (white powder, 18 mg, 53%) was obtained.
1H NMR (CDCl3, 400 MHz): δ=0.6-0.7 (m, 2H), 0.9-1.0 (m, 2H), 1.8-2.0 (m, 2H), 2.2-2.4 (m, 1H), 3.11 (dd, 1H, J=4.10 Hz), 3.3-3.4 (m, 2H), 3.54 (s, 2H), 3.64 (dd, 1H, J=6.10 Hz), 4.6-4.7 (m, 1H), 5.60 (d, 1H, J=6 Hz), 6.8-6.9 (m, 1H), 7.04 (d, 2H, J=8 Hz), 7.12 (d, 2H, J=8 Hz), 8.06 (d, 1H, J=2 Hz), 8.19 (s, 1H).
MS:390.20[M+H]+
According to a technique similar to Example 1, the title compound (white crystals, 11 mg, 31%) was obtained using (R)-1-(5-(trifluoromethyl)pyridin-3-yl)pyrrolidin-3-amine (20 mg, 0.09 mmol) synthesized in Reference Example 1-2 and the crude form of 2-(5-(trifluoromethyl)pyridin-2-yl)acetic acid (26 mg) synthesized in Reference Example 31-2.
1H NMR (CDCl3, 400 MHz): δ=2.0-2.1 (m, 2H), 2.3-2.4 (m, 1H), 3.25 (dd, 1H, J=4.10 Hz), 3.4-3.6 (m, 2H), 3.68 (dd, 1H, J=6.10 Hz), 3.81 (s, 2H), 4.6-4.7 (m, 1H), 6.9-7.0 (m, 1H), 7.4-7.5 (m, 2H), 8.12 (br s, 1H), 8.22 (br s, 1H), 8.77 (s, 1H).
MS:419.15[M+H]+
To tert-butyl (R)-(1-(2-(trifluoromethyl)pyrimidin-5-yl)pyrrolidin-3-yl)carbamate (41 mg, 0.12 mmol) synthesized in Reference Example 2, trifluoroacetic acid (2.0 mL) was added under ice cooling, and the mixture was stirred for 3 hours at room temperature. Under ice cooling, a saturated aqueous solution of sodium hydrogen carbonate and ethyl acetate were added to the reaction liquid, the mixture was stirred for a while, subsequently the organic layer was dried over anhydrous sodium sulfate, insoluble materials were filtered, subsequently the solvent was distilled off under reduced pressure, and thus the a crude form of (R)-1-(2-(trifluoromethyl)pyrimidin-5-yl)pyrrolidin-3-amine (pale yellow oily material, 18 mg) was obtained. According to a technique similar to Example 1, the title compound (ivory-colored powder, 14 mg, 29%) was obtained using the crude form of (R)-1-(2-(trifluoromethyl)pyrimidin-5-yl)pyrrolidin-3-amine (18 mg) thus obtained and 2-(4-isopropylphenyl)acetic acid (26 mg, 0.15 mmol).
1H NMR (CDCl3, 400 MHz): δ=1.23 (d, 6H, J=7 Hz), 1.9-2.0 (m, 1H), 2.3-2.4 (m, 1H), 2.8-2.9 (m, 1H), 3.17 (dd, 1H, J=5.10 Hz), 3.4-3.5 (m, 2H), 3.56 (s, 2H), 3.71 (dd, 1H, J=6.10 Hz), 4.6-4.7 (m, 1H), 5.50 (d, 1H, J=6 Hz), 7.15 (d, 2H, J=8 Hz), 7.21 (d, 2H, J=8 Hz), 8.06 (s, 2H).
MS:391.26[M−H]−
According to a technique similar to Example 3, a crude form of (R)-1-(5-(trifluoromethyl)pyridin-3-yl)pyrrolidin-3-amine (100 mg) was synthesized from tert-butyl (R)-1-(5-(trifluoromethyl)pyridin-3-yl)pyrrolidin-3-yl)carbamate (130 mg, 0.39 mmol) synthesized in Reference Example 1-1, and the title compound (white amorphous, 90 mg, 58%) was obtained using 2-(4-isopropylphenyl)acetic acid (85 mg, 0.48 mmol).
1H NMR (CDCl3, 400 MHz): δ=1.22 (d, 6H, J=7 Hz), 1.9-2.0 (m, 1H), 2.3-2.4 (m, 1H), 2.8-2.9 (m, 1H), 3.12 (dd, 1H, J=4.9 Hz), 3.3-3.4 (m, 2H), 3.55 (s, 2H), 3.6-3.7 (m, 1H), 4.6-4.7 (m, 1H), 5.7-5.8 (m, 1H), 6.87 (s, 1H), 7.1-7.3 (m, 4H), 8.04 (s, 1H), 8.17 (s, 1H).
MS:391.19[M−H]−
According to a technique similar to Example 3, (3S,4S)-4-amino-1-(5-(trifluoromethyl)pyridin-3-yl)pyrrolidin-3-ol (white crystals) was synthesized from tert-butyl ((3S,4S)-4-hydroxy-1-(5-(trifluoromethyl)pyridin-3-yl)pyrrolidin-3-yl)carbamate (106 mg, 0.31 mmol) synthesized in Reference Example 3, and the title compound (white crystals, 15 mg, 12%) was obtained using 2-(4-cyclopropylphenyl)acetic acid (54 mg, 0.31 mmol) synthesized in Reference Example 33-2.
1H NMR (CDCl3, 400 MHz): δ=0.6-0.7 (m, 2H), 0.9-1.0 (m, 2H), 1.8-1.9 (m, 1H), 3.11 (dd, 1H, J=5.10 Hz), 3.27 (dd, 1H, J=4.10 Hz), 3.56 (s, 2H), 3.61 (dd, 1H, J=6.10 Hz), 3.76 (dd, 1H, J=6.10 Hz), 4.09 (br s, 1H), 4.3-4.4 (m, 2H), 5.97 (d, 1H, J=6 Hz), 6.8-6.9 (m, 1H), 7.0-7.1 (m, 2H), 7.1-7.2 (m, 2H), 8.02 (d, 1H, J=2 Hz), 8.17 (s, 1H).
MS:406.14[M+H]+
According to a technique similar to Example 3, (R)-5-(5-(trifluoromethyl)pyridin-3-yl)-5-azaspiro[2.4]heptan-7-amine (white crystals) was synthesized from tert-butyl (R)-(5-(5-(trifluoromethyl)pyridin-3-yl)-5-azaspiro[2.4]heptan-7-yl)carbamate (130 mg, 0.36 mmol) synthesized in Reference Example 4, and the title compound (white crystals, 30 mg, 20%) was obtained using 2-(4-cyclopropylphenyl)acetic acid (64 mg, 0.36 mmol) synthesized in Reference Example 33-2.
1H NMR (CDCl3, 400 MHz): δ=0.5-0.6 (m, 1H), 0.6-0.7 (m, 4H), 0.8-0.9 (m, 1H), 0.9-1.0 (m, 2H), 1.8-1.9 (m, 1H), 3.09 (d, 1H, J=9 Hz), 3.39 (dd, 1H, J=2.10 Hz), 3.45 (d, 1H, J=10 Hz), 3.52 (d, 2H, J=3 Hz), 3.74 (dd, 1H, J=6.10 Hz), 4.1-4.2 (m, 1H), 5.62 (d, 1H, J=8 Hz), 6.8-6.9 (m, 1H), 7.0-7.1 (m, 2H), 7.1-7.2 (m, 2H), 8.04 (d, 1H, J=3 Hz), 8.20 (s, 1H).
MS:416.18[M+H]+
To tert-butyl (R)-(5-(6-(trifluoromethyl)pyridin-3-yl)-5-azaspiro[2.4]heptan-7-yl)carbamate (271 mg, 0.76 mmol) synthesized in Reference Example 5, a 2 N hydrochloric acid-methanol solution (15 mL) was added under ice cooling, the mixture was stirred for 2 hours at room temperature, subsequently the solvent was distilled off under reduced pressure, and thereby (R)-5-(6-(trifluoromethyl)pyridin-3-yl)-5-azaspiro[2.4]heptan-7-amine (187 mg) was obtained. According to a technique similar to Example 1, the title compound (white crystals, 280 mg, 89%) was obtained using (R)-5-(6-(trifluoromethyl)pyridin-3-yl)-5-azaspiro[2.4]heptan-7-amine (187 mg) thus obtained and 2-(4-cyclopropylphenyl)acetic acid (154 mg, 0.87 mmol) synthesized in Reference Example 33-2.
1H NMR (CDCl3, 400 MHz): δ=0.5-0.7 (m, 5H), 0.8-0.9 (m, 1H), 0.9-1.0 (m, 2H), 1.8-1.9 (m, 1H), 3.11 (d, 1H, J=10 Hz), 3.40 (dd, 1H, J=3.10 Hz), 3.45 (d, 1H, J=10 Hz), 3.53 (d, 2H, J=3 Hz), 3.75 (dd, 1H, J=6.10 Hz), 4.1-4.2 (m, 1H), 5.56 (d, 1H, J=7 Hz), 6.77 (dd, 1H, J=3.8 Hz), 7.0-7.1 (m, 2H), 7.1-7.2 (m, 2H), 7.48 (d, 1H, J=9 Hz), 7.93 (d, 1H, J=3 Hz).
MS:415.19[M+H]+
According to a technique similar to Example 7, (R)-5-(4-(trifluoromethyl)thiazol-2-yl)-5-azaspiro[2.4]heptan-7-amine (white crystals) was synthesized from tert-butyl (R)-(5-(4-(trifluoromethyl)thiazol-2-yl)-5-azaspiro[2.4]heptan-7-yl)carbamate (192 mg, 0.53 mmol) synthesized in Reference Example 6, and the title compound (white crystals, 177 mg, 79%) was obtained using 2-(4-cyclopropylphenyl)acetic acid (112 mg, 0.64 mmol) synthesized in Reference Example 33-2.
1H NMR (CDCl3, 400 MHz): δ=0.5-0.6 (m, 1H), 0.6-0.7 (m, 4H), 0.7-0.8 (m, 1H), 0.9-1.0 (m, 2H), 1.8-1.9 (m, 1H), 3.32 (d, 1H, J=10 Hz), 3.44 (dd, 1H, J=2.10 Hz), 3.52 (d, 2H, J=2 Hz), 3.56 (d, 1H, J=10 Hz), 3.83 (dd, 1H, J=6.10 Hz), 4.1-4.2 (m, 1H), 5.53 (d, 1H, J=7 Hz), 6.93 (d, 1H, J=1 Hz), 7.0-7.1 (m, 2H), 7.1-7.2 (m, 2H).
MS:421.14[M+H]+
2-(4-Cyclopropylphenyl)-N-((3R,5S)-5-methylpyrrolidin-3-yl)acetamide (150 mg, 0.58 mmol) synthesized in Reference Example 7-2, 3-bromo-5-(trifluoromethyl)pyridine (157 mg, 0.70 mmol), tris(dibenzylidene acetone)dipalladium(0) (53 mg, 0.06 mmol), XantPhos (67 mg, 0.12 mmol), and sodium tert-butoxide (112 mg, 1.16 mmol) were suspended in toluene (5.8 mL), and the suspension was stirred for 16 hours at 85° C. under a nitrogen gas stream. To the reaction liquid that had been left to cool to room temperature, water was added, the mixture was stirred for a while, and then the mixture was extracted with ethyl acetate. An organic layer thus separated was dried over anhydrous sodium sulfate, insoluble materials were filtered, and then the solvent was distilled off under reduced pressure. A residue thus obtained was purified by silica gel column chromatography (heptane:ethyl acetate) (concentration gradient: 0 to 100%), and the title compound (white crystals, 45 mg, 19%) was obtained.
1H NMR (CDCl3, 400 MHz): δ=0.6-0.7 (m, 2H), 0.9-1.0 (m, 2H), 1.22 (d, 3H, J=6 Hz), 1.8-2.0 (m, 2H), 2.0-2.1 (m, 1H), 2.93 (dd, 1H, J=7.10 Hz), 3.54 (s, 2H), 3.80 (dd, 1H, J=8.10 Hz), 3.9-4.0 (m, 1H), 4.7-4.8 (m, 1H), 5.48 (d, 1H, J=8 Hz), 6.88 (dd, 1H, J=2.2 Hz), 7.0-7.1 (m, 2H), 7.1-7.2 (m, 2H), 8.07 (d, 1H, J=3 Hz), 8.17 (s, 1H).
MS:404.16[M+H]+
According to a technique similar to Example 7, 3-(5-(trifluoromethyl)pyridin-3-yl)-3-azabicyclo[3.1.0]hexan-1-amine (yellow oily material, 121 mg) was synthesized from tert-butyl (3-(5-(trifluoromethyl)pyridin-3-yl)-3-azabicyclo[3.1.0]hexan-1-yl)carbamate (103 mg, 0.30 mmol) synthesized in Reference Example 8, and the title compound (pale yellow amorphous, 73 mg, 61%) was obtained using 2-(4-cyclopropylphenyl)acetic acid (63 mg, 0.36 mmol) synthesized in Reference Example 33-2.
1H NMR (CDCl3, 400 MHz): δ=0.6-0.7 (m, 2H), 0.8-0.9 (m, 1H), 0.9-1.1 (m, 3H), 1.8-2.0 (m, 2H), 3.3-3.4 (m, 1H), 3.5-3.6 (m, 4H), 3.7-3.8 (m, 1H), 5.89 (s, 1H), 6.90 (s, 1H), 7.07 (d, 2H, J=8 Hz), 7.13 (d, 2H, J=8 Hz), 8.06 (d, 1H, J=2 Hz), 8.18 (s, 1H).
MS:402.16[M+H]+
According to a technique similar to Example 7, (R)-1-(6-(trifluoromethyl)pyrazin-2-yl)pyrrolidin-3-amine was synthesized from tert-butyl (R)-(1-(6-(trifluoromethyl)pyrazin-2-yl)pyrrolidin-3-yl)carbamate (159 mg, 0.48 mmol) synthesized in Reference Example 9, and the title compound (white powder, 187 mg, 94%) was obtained using 2-(4-(trifluoromethyl)phenyl)acetic acid (117 mg, 0.57 mmol).
1H NMR (CDCl3, 400 MHz): δ=1.9-2.0 (m, 1H), 2.3-2.4 (m, 1H), 3.38 (dd, 1H, J=4.11 Hz), 3.6-3.7 (m, 4H), 3.87 (dd, 1H, J=6.12 Hz), 4.6-4.7 (m, 1H), 5.53 (d, 1H, J=6 Hz), 7.40 (d, 2H, J=8 Hz), 7.61 (d, 2H, J=8 Hz), 8.03 (s, 1H), 8.17 (s, 1H).
MS:419.10[M+H]+
According to a technique similar to Example 3, (R)-1-(6-cyano-5-(trifluoromethyl)pyridin-3-yl)pyrrolidin-3-amine was synthesized from tert-butyl (R)-(1-(6-cyano-5-(trifluoromethyl)pyridin-3-yl)pyrrolidin-3-yl)carbamate (139 mg, 0.39 mmol) synthesized in Reference Example 10, and the title compound (white amorphous, 52 mg, 32%) was obtained using 2-(4-cyclopropylphenyl)acetic acid (82 mg, 0.47 mmol) synthesized in Reference Example 33-2.
1H NMR (CDCl3, 400 MHz): δ=0.6-0.7 (m, 2H), 0.9-1.0 (m, 2H), 1.8-1.9 (m, 1H), 1.9-2.0 (m, 1H), 2.3-2.4 (m, 1H), 3.23 (dd, 1H, J=8.10 Hz), 3.4-3.6 (m, 4H), 3.7-3.8 (m, 1H), 4.5-4.7 (m, 1H), 5.80 (d, 1H, J=6 Hz), 6.88 (d, 1H, J=3 Hz), 7.02 (d, 2H, J=8 Hz), 7.11 (d, 2H, J=8 Hz), 8.00 (d, 1H, J=2 Hz).
MS:413.15[M−H]−
According to a technique similar to Example 9, the title compound (white amorphous, 53 mg, 38%) was obtained using methyl 3-(2-(4-cyclopropylphenyl)acetamido)pyrrolidine-3-carboxylate (94 mg, 0.31 mmol) synthesized in Reference Example 11-2 and 3-bromo-5-(trifluoromethyl)pyridine (84 mg, 0.37 mmol).
1H NMR (CDCl3, 400 MHz): δ=0.6-0.7 (m, 2H), 0.9-1.0 (m, 2H), 1.8-1.9 (m, 1H), 2.3-2.4 (m, 1H), 2.5-2.6 (m, 1H), 3.4-3.5 (m, 2H), 3.55 (s, 2H), 3.5-3.6 (m, 1H), 3.75 (s, 3H), 3.98 (d, 1H, J=10 Hz), 6.17 (s, 1H), 6.8-6.9 (m, 1H), 7.0-7.1 (m, 2H), 7.1-7.2 (m, 2H), 8.05 (d, 1H, J=3 Hz), 8.20 (s, 1H).
MS:448.14[M+H]+
Methyl 3-(2-(4-cyclopropylphenyl)acetamido)-1-(5-(trifluoromethyl)pyridin-3-yl)pyrrolidine-3-carboxylate (50 mg, 0.11 mmol) synthesized in Example 13 was dissolved in THF (2.0 mL), a 2 N aqueous solution of sodium hydroxide (2.0 mL) was added thereto, and the mixture was stirred for 3 hours at room temperature. a 1 N aqueous solution of hydrochloric acid was added to the reaction liquid to neutralize the reaction liquid, and then the reaction liquid was extracted with a mixed liquid of chloroform and methanol. An organic layer thus separated was dried over anhydrous sodium sulfate, insoluble materials were filtered, and then the solvent was distilled off under reduced pressure. A residue thus obtained was purified by silica gel column chromatography (ethyl acetate:methanol) (concentration gradient: 0 to 90%), subsequently methanol and water were added to a powder thus obtained, and the mixture was stirred for a while. A precipitated powder was filtered and dried under reduced pressure for 3 hours at 100° C., and thereby the title compound (white powder, 38 mg, 79%) was obtained.
1H NMR (CD3OD, 400 MHz): δ=0.5-0.6 (m, 2H), 0.8-0.9 (m, 2H), 1.8-1.9 (m, 1H), 2.4-2.6 (m, 2H), 3.4-3.6 (m, 4H), 3.6-3.7 (m, 1H), 3.9-4.0 (m, 1H), 4.60 (br s, 1H), 6.9-7.0 (m, 2H), 7.0-7.2 (m, 3H), 8.0-8.1 (m, 2H). The 1H content is not observable.
MS:434.16[M+H]+
According to a technique similar to Example 1, the title compound (white powder, 82 mg, 74%) was obtained using (R)-1-(5-(trifluoromethyl)pyridin-3-yl)pyrrolidin-3-amine (66 mg, 0.28 mmol) synthesized in Reference Example 1-2 and 2-(1H-indazol-6-yl)acetic acid (50 mg, 0.28 mmol).
1H NMR (CDCl3, 400 MHz): δ=1.8-2.0 (m, 1H), 2.3-2.4 (m, 1H), 3.13 (dd, 1H, J=4.10 Hz), 3.3-3.4 (m, 2H), 3.63 (dd, 1H, J=6.10 Hz), 3.70 (s, 2H), 4.6-4.7 (m, 1H), 5.62 (d, 1H, J=7 Hz), 6.8-6.9 (m, 1H), 7.04 (dd, 1H, J=1.8 Hz), 7.39 (s, 1H), 7.72 (d, 1H, J=8 Hz), 8.0-8.1 (m, 2H), 8.18 (s, 1H), 10.1 (br s, 1H).
MS:388.15[M−H]−
According to a technique similar to Example 1, the title compound (yellow-green powder, 30 mg, 55%) was obtained using (R)-1-(4-(trifluoromethyl)thiazol-2-yl)pyrrolidin-3-amine (33 mg, 0.14 mmol) synthesized in Reference Example 12-2 and 2-(4-cyclopropylphenyl)acetic acid (29 mg, 0.17 mmol) synthesized in Reference Example 33-2.
1H NMR (CDCl3, 400 MHz): δ=0.6-0.7 (m, 2H), 0.9-1.0 (m, 2H), 1.8-2.0 (m, 2H), 2.2-2.4 (m, 1H), 3.23 (dd, 1H, J=4.10 Hz), 3.4-3.6 (m, 4H), 3.74 (dd, 1H, J=6.10 Hz), 4.5-4.7 (m, 1H), 5.47 (d, 1H, J=6 Hz), 6.92 (s, 1H), 7.04 (d, 2H, J=8 Hz), 7.10 (d, 2H, J=2 Hz).
MS:394.14[M−H]−
According to a technique similar to Example 1, the title compound (pale yellow amorphous, 50 mg, 79%) was obtained using (R)-1-(5-(trifluoromethyl)pyridin-3-yl)pyrrolidin-3-amine (35 mg, 0.15 mmol) synthesized in Reference Example 1-2 and 2-(4-isobutylphenyl)propanoic acid (37 mg, 0.18 mmol).
1H NMR (CDCl3, 400 MHz): δ=0.8-0.9 (m, 6H), 1.51 (d, 1.5H, J=8 Hz), 1.52 (d, 1.5H, J=8 Hz), 1.8-2.0 (m, 2H), 2.2-2.3 (m, 1H), 2.4-2.5 (m, 2H), 3.03 (dd, 0.5H, J=4.10 Hz), 3.12 (dd, 0.5H, J=4.10 Hz), 3.2-3.4 (m, 2H), 3.5-3.7 (m, 2H), 4.5-4.7 (m, 1H), 5.67 (d, 0.5H, J=7 Hz), 5.70 (d, 0.5H, J=7 Hz), 6.8-6.9 (m, 1H), 7.0-7.1 (m, 2H), 7.1-7.2 (m, 2H), 8.01 (dd, 1H, J=2.2 Hz), 8.15 (s, 1H).
MS:420.20 [M+H]+
According to a technique similar to Example 7, (R)-1-(6-methyl-5-(trifluoromethyl)pyridin-3-yl)pyrrolidin-3-amine (white powder, 22 mg) was synthesized from tert-butyl (R)-(1-(6-methyl-5-(trifluoromethyl)pyridin-3-yl)pyrrolidin-3-yl)carbamate (22 mg, 0.06 mmol) synthesized in Reference Example 13, and the title compound (white amorphous, 5.9 mg, 23%) was obtained using 2-(4-cyclopropylphenyl)acetic acid (13 mg, 0.07 mmol) synthesized in Reference Example 33-2.
1H NMR (CDCl3, 400 MHz): δ=0.6-0.7 (m, 2H), 0.9-1.0 (m, 2H), 1.8-1.9 (m, 2H), 2.2-2.4 (m, 1H), 2.57 (s, 3H), 3.08 (dd, 1H, J=4.10 Hz), 3.3-3.4 (m, 2H), 3.53 (s, 2H), 3.60 (dd, 1H, J=6.10 Hz), 4.5-4.7 (m, 1H), 5.50 (d, 1H, J=8 Hz), 6.95 (d, 1H, J=2 Hz), 7.04 (d, 2H, J=8 Hz), 7.11 (d, 2H, J=8 Hz), 7.93 (d, 1H, J=2 Hz).
MS:404.16[M+H]+
According to a technique similar to Example 1, the title compound (pale yellow amorphous, 81 mg, 86%) was obtained using (R)-2-(5-(3-aminopyrrolidin-1-yl)pyridin-3-yl)propan-2-ol (55 mg, 0.17 mmol) synthesized in Reference Example 14-2 and 2-(4-cyclopropylphenyl)acetic acid (36 mg, 0.20 mmol) synthesized in Reference Example 33-2.
1H NMR (CDCl3, 400 MHz): δ=0.6-0.7 (m, 2H), 0.9-1.0 (m, 2H), 1.59 (s, 6H), 1.7-1.8 (m, 1H), 1.8-1.9 (m, 2H), 2.2-2.4 (m, 1H), 3.0-3.1 (m, 1H), 3.3-3.4 (m, 2H), 3.53 (s, 2H), 3.60 (dd, 1H, J=4.10 Hz), 4.6-4.7 (m, 1H), 5.61 (d, 1H, J=7 Hz), 6.9-7.0 (m, 1H), 7.04 (d, 2H, J=8 Hz), 7.12 (d, 2H, J=8 Hz), 7.82 (br s, 1H), 8.04 (br s, 1H).
MS:380.20[M+H]+
According to a technique similar to Example 7, (R)-1-(8-(trifluoromethyl)imidazo[1,2-a]pyridin-6-yl)pyrrolidin-3-amine (56 mg) was synthesized from tert-butyl (R)-(1-(8-(trifluoromethyl)imidazo[1,2-a]pyridin-6-yl)pyrrolidin-3-yl)-carbamate (90 mg, 0.24 mmol) synthesized in Reference Example 15, and the title compound (yellow amorphous, 58 mg, 56%) was obtained using 2-(4-cyclopropylphenyl)acetic acid (44 mg, 0.25 mmol) synthesized in Reference Example 33-2.
1H NMR (CDCl3, 400 MHz): δ=0.6-0.7 (m, 2H), 0.9-1.0 (m, 2H), 1.8-2.0 (m, 2H), 2.3-2.4 (m, 1H), 3.0-3.1 (m, 1H), 3.2-3.3 (m, 1H), 3.3-3.4 (m, 1H), 3.5-3.6 (m, 1H), 3.56 (s, 2H), 4.6-4.7 (m, 1H), 6.70 (d, 1H, J=6 Hz), 7.04 (d, 2H, J=8 Hz), 7.08 (s, 1H), 7.15 (d, 2H, J=8 Hz), 7.52 (s, 1H), 7.60 (s, 1H). The 1H content is not observable.
MS:429.16[M+H]+
According to a technique similar to Example 1, the title compound (white powder, 11 mg, 73%) was obtained using 3-(2-(4-cyclopropylphenyl)acetamido)-1-(5-(trifluoromethyl)pyridin-3-yl)pyrrolidine-3-carboxylic acid (15 mg, 0.04 mmol) synthesized in Example 14 and ammonium acetate (5.3 mg, 0.07 mmol).
1H NMR (DMSO-d6, 400 MHz): δ=0.5-0.6 (m, 2H), 0.8-0.9 (m, 2H), 1.8-1.9 (m, 1H), 2.3-2.4 (m, 2H), 3.2-3.5 (m, 4H), 3.5-3.6 (m, 1H), 3.82 (d, 1H, J=10 Hz), 6.85 (d, 2H, J=8 Hz), 6.9-7.1 (m, 3H), 7.11 (s, 1H), 7.29 (br s, 1H), 8.1-8.2 (m, 2H), 8.54 (s, 1H).
MS:431.20[M−H]−
According to a technique similar to Example 1, the title compound (white amorphous, 292 mg, 92%) was obtained using (R)-1-(5-(trifluoromethyl)pyridin-3-yl)pyrrolidin-3-amine (200 mg, 0.86 mmol) synthesized in Example 1-2 and 2-(4-hydroxyphenyl)acetic acid (158 mg, 1.04 mmol).
1H NMR (CDCl3, 400 MHz): δ=1.8-2.0 (m, 1H), 2.3-2.4 (m, 1H), 3.12 (dd, 1H, J=5.10 Hz), 3.3-3.4 (m, 2H), 3.51 (s, 2H), 3.65 (dd, 1H, J=6.10 Hz), 5.18 (s, 1H), 5.50 (d, 1H, J=6 Hz), 6.8-6.9 (m, 2H), 6.9-7.0 (m, 1H), 7.1-7.2 (m, 2H), 8.07 (d, 2H, J=3 Hz), 8.21 (s, 1H).
MS:366.11[M+H]+
Ethyl 2-(4-(1,1-dioxide thiomorpholino)phenyl)acetate (30 mg, 0.10 mmol) synthesized in Reference Example 16 was dissolved in THF (2.0 mL), subsequently a 2 N aqueous solution of sodium hydroxide (2.0 mL) was added thereto, the mixture was stirred for 20 minutes at 50° C., and the solvent was distilled off under reduced pressure. Water and ethyl acetate were added to a residue thus obtained, the mixture was stirred for a while, subsequently a 1 N aqueous solution of hydrochloric acid was added to an aqueous layer thus separated to neutralize the aqueous layer, and the aqueous layer was extracted with a mixed liquid of chloroform and methanol. An organic layer thus separated was dried over anhydrous sodium sulfate, insoluble materials were filtered, subsequently the solvent was distilled off under reduced pressure, and thereby a crude form of 2-(4-(1,1-dioxide thiomorpholino)phenyl)acetic acid (pale yellow crystals) was obtained. According to a technique similar to Example 1, the title compound (white amorphous, 30 mg, 61%) was obtained using the crude form of 2-(4-(1,1-dioxide thiomorpholino)phenyl)acetic acid thus obtained and (R)-1-(5-(trifluoromethyl)pyridin-3-yl)pyrrolidin-3-amine (23 mg, 0.10 mmol) synthesized in Reference Example 1-2.
1H NMR (CDCl3, 400 MHz): δ=1.9-2.0 (m, 1H), 2.3-2.4 (m, 1H), 3.0-3.1 (m, 4H), 3.16 (dd, 1H, J=5.10 Hz), 3.3-3.5 (m, 2H), 3.51 (s, 2H), 3.67 (dd, 1H, J=6.10 Hz), 3.8-3.9 (m, 4H), 4.6-4.7 (m, 1H), 5.53 (d, 1H, J=7 Hz), 6.8-7.0 (m, 3H), 7.1-7.2 (m, 2H), 8.09 (d, 1H, J=2 Hz), 8.21 (s, 1H).
MS:481.18[M−H]−
According to a technique similar to Example 1, the title compound (white amorphous, 70 mg, 79%) was obtained using (R)-1-(5-(trifluoromethyl)pyridin-3-yl)pyrrolidin-3-amine (50 mg, 0.22 mmol) synthesized in Reference Example 1-2 and 1-(4-chlorophenyl)cyclopropane-1-carboxylic acid (51 mg, 0.26 mmol).
1H NMR (CDCl3, 400 MHz): δ=1.0-1.1 (m, 2H), 1.6-1.7 (m, 2H), 1.7-1.9 (m, 1H), 2.2-2.4 (m, 1H), 3.0-3.1 (m, 1H), 3.2-3.4 (m, 2H), 3.6-3.7 (m, 1H), 4.5-4.6 (m, 1H), 5.36 (d, 1H, J=5 Hz), 6.89 (s, 1H), 7.2-7.4 (m, 4H), 8.05 (s, 1H), 8.19 (s, 1H).
MS:410.07[M+H]+
According to a technique similar to Example 1, the title compound (white powder, 68 mg, 71%) was obtained using (R)-1-(5-(trifluoromethyl)pyridin-3-yl)pyrrolidin-3-amine (50 mg, 0.22 mmol) synthesized in Reference Example 1-2 and 2-(4-bromophenyl)-2-hydroxyacetic acid (60 mg, 0.26 mmol).
1H NMR (CDCl3, 400 MHz): δ=2.0-2.1 (m, 1H), 2.3-2.4 (m, 1H), 3.1-3.2 (m, 1H), 3.3-3.5 (m, 2H), 3.6-3.7 (m, 1H), 3.92 (s, 0.5H), 4.15 (s, 0.5H), 4.6-4.7 (m, 1H), 5.06 (s, 1H), 6.8-7.0 (m, 2H), 7.31 (d, 2H, J=8 Hz), 7.49 (d, 2H, J=8 Hz), 7.94 (d, 1H, J=8 Hz), 8.12 (d, 1H, J=4 Hz).
MS:444.00[M+H]+
Ethyl 2-(4-(trimethylsilyl)phenyl)acetate (30 mg, 0.13 mmol) synthesized in Reference Example 17 was dissolved in methanol (2.0 mL), a 2 N aqueous solution of sodium hydroxide (2.0 mL) was added thereto, the mixture was stirred for 4 hours at room temperature, and the solvent was distilled off under reduced pressure. Water was added thereto to obtain an aqueous solution, subsequently the aqueous solution was washed with ethyl acetate, a 1 N aqueous solution of hydrochloric acid was added thereto to neutralize the aqueous solution, and the aqueous layer was extracted with a mixed liquid of chloroform and methanol. An organic layer thus separated was dried over anhydrous sodium sulfate, insoluble materials were filtered, subsequently the solvent was distilled off under reduced pressure, and thereby a crude form of 2-(4-(trimethylsilyl)phenyl)acetic acid was obtained. According to a technique similar to Example 1, the title compound (colorless oily material, 6.8 mg, 13%) was obtained using the crude form of 2-(4-(trimethylsilyl)phenyl)acetic acid thus obtained and (R)-1-(5-(trifluoromethyl)pyridin-3-yl)pyrrolidin-3-amine (29 mg, 0.13 mmol) synthesized in Reference Example 1-2.
1H NMR (CDCl3, 400 MHz): δ=0.26 (s, 9H), 1.9-2.0 (m, 1H), 2.3-2.4 (m, 1H), 3.13 (dd, 1H, J=4.10 Hz), 3.3-3.4 (m, 2H), 3.58 (s, 2H), 3.66 (dd, 1H, J=6.10 Hz), 4.6-4.7 (m, 1H), 5.65 (d, 1H, J=7 Hz), 6.89 (dd, 1H, J=2.2 Hz), 7.2-7.3 (m, 2H), 7.4-7.5 (m, 2H), 8.07 (d, 1H, J=3 Hz), 8.19 (s, 1H).
MS:422.16[M+H]+
(R)-2-(4-hydroxyphenyl)-N-(1-(5-(trifluoromethyl)pyridin-3-yl)pyrrolidin-3-yl)acetamide (30 mg, 0.08 mmol) synthesized in Example 22 was dissolved in DMF (1.0 mL), subsequently 2,2-dimethyloxirane (22 μL, 0.25 mmol) and potassium carbonate (34 mg, 0.25 mmol) were added thereto, and the mixture was stirred for 16 hours at 110° C. To the reaction liquid that had been left to cool to room temperature, water was added, the mixture was stirred for a while, and then the mixture was extracted with a mixed liquid of chloroform and methanol. An organic layer thus separated was dried over anhydrous sodium sulfate, insoluble materials were filtered, and then the solvent was distilled off under reduced pressure. A residue thus obtained was purified by silica gel column chromatography (ethyl acetate:methanol) (concentration gradient: 0 to 40%), and the title compound (colorless oily material, 3.4 mg, 9.4%) was obtained.
1H NMR (CDCl3, 400 MHz): δ=1.35 (s, 6H), 1.8-1.9 (m, 1H), 2.25 (s, 1H), 2.3-2.4 (m, 1H), 3.12 (dd, 1H, J=5.10 Hz), 3.3-3.4 (m, 2H), 3.53 (s, 2H), 3.65 (dd, 1H, J=6.10 Hz), 3.78 (s, 2H), 4.6-4.7 (m, 1H), 5.48 (d, 1H, J=8 Hz), 6.8-6.9 (m, 3H), 7.1-7.2 (m, 2H), 8.07 (d, 1H, J=2 Hz), 8.21 (s, 1H).
MS:438.17[M+H]+
A 2 N hydrochloric acid-methanol solution (12 mL) was added to tert-butyl (35,45)-3-(2-(4-cyclopropylphenyl)acetamido)-4-fluoropyrrolidine-1-carboxylate (369 mg, 1.02 mmol) synthesized in Reference Example 18 under ice cooling, the mixture was stirred for 2 hours at room temperature, subsequently the solvent was distilled off under reduced pressure, and thereby a crude form of (2-(4-cyclopropylphenyl)-N-((3S,4S)-4-fluoropyrrolidin-3-ylacetamide (230 mg) was obtained. The crude form of 2-(4-Cyclopropylphenyl)-N-((3S,4S)-4-fluoropyrrolidin-3-ylacetamide (230 mg) thus obtained, 3-bromo-5-(trifluoromethyl)pyridine (230 mg, 1.02 mmol), tris(dibenzylidene acetone)dipalladium(0) (92 mg, 0.10 mmol), Xantphos (118 mg, 0.20 mmol), and potassium carbonate (281 mg, 2.04 mmol) were suspended in toluene (5.8 mL), and the suspension was stirred for 16 hours at 85° C. under a nitrogen gas stream. The reaction liquid that had been left to cool to room temperature was filtered through Celite, and the solvent was distilled off under reduced pressure. A residue thus obtained was purified by silica gel column chromatography (heptane:ethyl acetate) (concentration gradient: 0 to 100%), and the title compound (white amorphous, 28 mg, 6.7%) was obtained.
1H NMR (CDCl3, 400 MHz): δ=0.6-0.7 (m, 2H), 0.9-1.0 (m, 2H), 1.8-1.9 (m, 1H), 3.24 (d, 1H, J=11 Hz), 3.4-3.6 (m, 4H), 3.7-3.8 (m, 1H), 4.6-4.7 (m, 1H), 5.1-5.3 (m, 1H), 5.6-5.7 (m, 1H), 6.88 (dd, 1H, J=2.2 Hz), 7.0-7.1 (m, 4H), 8.04 (d, 1H, J=3 Hz), 8.21 (s, 1H).
MS:408.16[M+H]+
According to a technique similar to Example 1, the title compound (white amorphous, 40 mg, 51%) was obtained using (R)-1-(5-(trifluoromethyl)pyridin-3-yl)pyrrolidin-3-amine (46 mg, 0.20 mmol) synthesized in Reference Example 1-2 and 2-(4-(dimethylamino)phenyl)acetic acid (43 mg, 0.24 mmol).
1H NMR (CDCl3, 400 MHz): δ=1.8-1.9 (m, 1H), 2.3-2.4 (m, 1H), 2.94 (s, 6H), 3.09 (dd, 1H, J=5.10 Hz), 3.3-3.4 (m, 2H), 3.49 (s, 2H), 3.64 (dd, 1H, J=6.10 Hz), 4.6-4.7 (m, 1H), 5.63 (d, 1H, J=7 Hz), 6.6-6.7 (m, 2H), 6.88 (dd, 1H, J=2.2 Hz), 7.0-7.1 (m, 2H), 8.06 (d, 1H, J=3 Hz), 8.18 (s, 1H).
MS:393.16[M+H]+
According to a technique similar to Example 1, the title compound (pale yellow amorphous, 219 mg, 86%) was obtained using (R)-1-(5-(trifluoromethyl)pyridin-3-yl)pyrrolidin-3-amine (150 mg, 0.65 mmol) synthesized in Reference Example 1-2 and 2-(4-nitrophenyl)acetic acid (141 mg, 0.78 mmol).
1H NMR (CDCl3, 400 MHz): δ=2.0-2.1 (m, 1H), 2.3-2.4 (m, 1H), 3.20 (dd, 1H, J=3.10 Hz), 3.3-3.4 (m, 2H), 3.63 (dd, 1H, J=6.10 Hz), 3.67 (s, 2H), 4.6-4.7 (m, 1H), 6.59 (d, 1H, J=7 Hz), 6.8-6.9 (m, 1H), 7.4-7.5 (m, 2H), 7.97 (d, 1H, J=3 Hz), 8.11 (br s, 1H), 8.1-8.2 (m, 2H).
MS:395.09[M+H]+
According to a technique similar to Example 1, the title compound (white crystals, 22 mg, 81%) was obtained using (R)-1-(5-(trifluoromethyl)pyridin-3-yl)pyrrolidin-3-amine (15 mg, 0.06 mmol) synthesized in Reference Example 1-2 and (S)-2-(4-isobutylphenyl)propanoic acid (16 mg, 0.08 mmol).
1H NMR (CDCl3, 400 MHz): δ=0.8-0.9 (m, 6H), 1.51 (d, 3H, J=7 Hz), 1.8-1.9 (m, 2H), 2.2-2.3 (m, 1H), 2.45 (d, 2H, J=7 Hz), 3.13 (dd, 1H, J=4.10 Hz), 3.2-3.4 (m, 2H), 3.5-3.6 (m, 1H), 3.63 (dd, 1H, J=6.10 Hz), 4.5-4.7 (m, 1H), 5.59 (d, 1H, J=7 Hz), 6.86 (dd, 1H, J=2.2 Hz), 7.0-7.1 (m, 2H), 7.1-7.2 (m, 2H), 8.03 (d, 1H, J=3 Hz), 8.16 (s, 1H).
MS:418.25[M−H]−
According to a technique similar to Example 1, the title compound (white amorphous, 25 mg, 66%) was obtained using (R)-1-(5-(trifluoromethyl)pyridin-3-yl)pyrrolidin-3-amine (20 mg, 0.09 mmol) synthesized in Reference Example 1-2 and 2-(3-fluoro-4-(trifluoromethyl)phenyl)acetic acid (23 mg, 0.10 mmol).
1H NMR (CDCl3, 400 MHz): δ=2.0-2.1 (m, 1H), 2.3-2.4 (m, 1H), 3.20 (dd, 1H, J=4.10 Hz), 3.3-3.5 (m, 2H), 3.60 (s, 2H), 3.65 (dd, 1H, J=6.10 Hz), 4.6-4.7 (m, 1H), 6.27 (d, 1H, J=7 Hz), 6.86 (dd, 1H, J=2.2 Hz), 7.16 (s, 1H), 7.1-7.2 (m, 1H), 7.57 (t, 1H, J=7 Hz), 8.02 (d, 1H, J=3 Hz), 8.14 (s, 1H).
MS:436.08[M+H]+
(R)-2-(4-nitrophenyl)-N-(1-(5-(trifluoromethyl)pyridin-3-yl)pyrrolidin-3-yl)acetamide (215 mg, 0.55 mmol) synthesized in Example 30 was dissolved in methanol (20 mL), palladium-carbon (20 mg) was added thereto, and the mixture was stirred for 6 hours at room temperature under a hydrogen gas stream. Insoluble materials were filtered, subsequently the solvent was distilled off under reduced pressure, a residue thus obtained was purified by silica gel column chromatography (ethyl acetate:methanol) (concentration gradient: 0 to 30%), and the title compound (white amorphous, 195 mg, 98%) was obtained.
1H NMR (CDCl3, 400 MHz): δ=1.8-1.9 (m, 1H), 2.3-2.4 (m, 1H), 3.10 (dd, 1H, J=5.10 Hz), 3.3-3.4 (m, 2H), 3.48 (s, 2H), 3.64 (dd, 1H, J=6.10 Hz), 3.69 (br s, 2H), 4.6-4.7 (m, 1H), 5.59 (d, 1H, J=7 Hz), 6.6-6.7 (m, 2H), 6.8-6.9 (m, 1H), 7.0-7.1 (m, 2H), 8.06 (d, 1H, J=3 Hz), 8.19 (s, 1H).
MS:365.10[M+H]+
2-(4-(Trifluoromethyl)phenyl)acetonitrile (1.00 g, 5.40 mmol) was dissolved in THF (8.0 mL), subsequently the solution was stirred for a while at −50° C., a THF solution of lithium bis(trimethylsilyl)amide (1.3 M) (4.15 mL, 5.40 mmol) was added thereto, and then 1-bromo-2-chloroethane was added thereto. Subsequently, a THF solution of lithium bis(trimethylsilyl)amide (1.3 M) (4.15 mL, 5.40 mmol) was added thereto again, the mixture was stirred for 30 minutes, and then the mixture was stirred for 2 hours at room temperature. Water was added to the reaction liquid, the mixture was extracted with ethyl acetate, an organic layer thus separated was dried over anhydrous sodium sulfate, insoluble materials were filtered, subsequently the solvent was distilled off under reduced pressure, and thereby a crude form of 1-4-(trifluoromethyl)phenyl)cyclopropane-1-carbonitrile (pale yellow powder, 219 mg) was obtained. The crude form of 1-4-(trifluoromethyl)phenyl)cyclopropane-1-carbonitrile (219 mg) was dissolved in THF (3.0 mL), subsequently a 4 N aqueous solution of sodium hydroxide (3.0 mL) was added thereto, the mixture was stirred for 16 hours at 100° C., and the solvent was distilled off under reduced pressure. Water was added thereto to obtain an aqueous solution, subsequently the aqueous solution was washed with ethyl acetate, a 2 N aqueous solution of hydrochloric acid was added thereto to neutralize the aqueous solution, and the aqueous layer was extracted with a mixed liquid of chloroform and methanol. An organic layer thus separated was dried over anhydrous sodium sulfate, insoluble materials were filtered, subsequently the solvent was distilled off under reduced pressure, and thereby a crude form of 1-(4-(trifluoromethyl)phenyl)cyclopropane-1-carboxylic acid (yellow crystals, 42 mg) was obtained. According to a technique similar to Example 1, the title compound (white amorphous, 43 mg, 1.8%) was obtained using the crude form of 1-(4-(trifluoromethyl)phenyl)cyclopropane-1-carboxylic acid (42 mg) and (R)-1-(5-(trifluoromethyl)pyridin-3-yl)pyrrolidin-3-amine (42 mg, 0.18 mmol) synthesized in Reference Example 1-2.
1H NMR (CDCl3, 400 MHz): δ=1.0-1.2 (m, 2H), 1.6-1.7 (m, 2H), 1.7-1.8 (m, 1H), 2.3-2.4 (m, 1H), 3.05 (dd, 1H, J=5.10 Hz), 3.3-3.4 (m, 2H), 3.64 (dd, 1H, J=6.10 Hz), 4.5-4.6 (m, 1H), 5.26 (d, 1H, J=6 Hz), 6.8-6.9 (m, 1H), 7.53 (d, 2H, J=8 Hz), 7.64 (d, 2H, J=8 Hz), 8.0-8.1 (m, 1H), 8.20 (s, 1H).
MS:444.07[M+H]+
(R)-2-(4-aminophenyl)-N-(1-(5-(trifluoromethyl)pyridin-3-yl)pyrrolidin-3-yl)acetamide (30 mg, 0.08 mmol) synthesized in Example 33 was dissolved in chloroform (1.0 mL), subsequently acetyl chloride (5.9 μL, 0.08 mmol) and DIPEA (30 μL, 0.16 mmol) were added thereto, and the mixture was stirred for 60 hours at room temperature. Water was added to the reaction liquid, the mixture was stirred for a while, an organic layer thus separated was dried over anhydrous sodium sulfate, insoluble materials were filtered, and then the solvent was distilled off under reduced pressure. A residue thus obtained was purified by silica gel column chromatography (ethyl acetate:methanol) (concentration gradient: 0 to 40%), and the title compound (white amorphous, 6.0 mg, 18%) was obtained.
1H NMR (CDCl3, 400 MHz): δ=1.9-2.0 (m, 1H), 2.18 (s, 3H), 2.3-2.4 (m, 1H), 3.12 (dd, 1H, J=5.10 Hz), 3.3-3.4 (m, 2H), 3.54 (s, 2H), 3.64 (dd, 1H, J=6.10 Hz), 4.6-4.7 (m, 1H), 5.66 (d, 1H, J=7 Hz), 6.8-6.9 (m, 1H), 7.2-7.3 (m, 2H), 7.23 (br s, 1H), 7.4-7.5 (m, 2H), 8.05 (d, 1H, J=2 Hz), 8.19 (s, 1H)
MS:407.12[M+H]+
Trifluoroacetic acid (15 mL) was added to tert-butyl 3-cyano-3-(2-(4-cyclopropyiphenyl) acetamido) pyrrolidine-1-carboxylate (454 mg, 1.23 mmol) synthesized in Reference Example 19 under ice cooling, the mixture was stirred for 4 hours at room temperature, subsequently a residue obtained by distilling off the solvent under reduced pressure was purified by silica gel column chromatography (ethyl acetate:methanol) (concentration gradient: 0 to 80%), and N-(3-cyanopyrrolidin-3-yl)-2-(4-cyclopropylphenyl)acetamide (brown oily material, 367 mg) was obtained. According to a technique similar to Example 9, the title compound (yellow powder, 30 mg, 5.8%) was obtained using N-(3-cyanopyrrolidin-3-yl)-2-(4-cyclopropylphenyl)acetamide (367 mg) thus obtained and 3-bromo-5-(trifluoromethyl)pyridine (278 mg, 1.23 mmol).
1H NMR (CDCl3, 400 MHz): δ=0.6-0.7 (m, 2H), 0.9-1.0 (m, 2H), 1.8-1.9 (m, 1H), 2.1-2.2 (m, 1H), 2.4-2.5 (m, 1H), 3.49 (d, 1H, J=10 Hz), 3.67 (d, 1H, J=10 Hz), 3.6-3.8 (m, 4H), 6.9-7.0 (m, 1H), 7.0-7.1 (m, 2H), 7.1-7.2 (m, 2H), 8.00 (br s, 1H), 8.12 (d, 1H, J=3 Hz), 8.20 (s, 1H).
MS:415.13[M+H]+
According to a technique similar to Example 7, methyl 3-amino-1-(5-(trifluoromethyl)pyridin-3-yl)pyrrolidine-3-carboxylate was synthesized from methyl 3-((tert-butoxycarbonyl)amino)-1-(5-(trifluoromethyl)pyridin-3-yl)pyrrolidine-3-carboxylate (34 mg, 0.09 mmol) synthesized in Reference Example 20-2, and the title compound (white powder, 26 mg, 67%) was obtained using 2-(1H-indol-6-yl)acetic acid (15 mg, 0.09 mmol).
1H NMR (CDCl3, 400 MHz): δ=2.2-2.3 (m, 1H), 2.4-2.5 (m, 1H), 3.3-3.5 (m, 2H), 3.61 (d, 1H, J=10 Hz), 3.71 (s, 2H), 3.76 (s, 3H), 4.00 (d, 1H, J=10 Hz), 5.94 (s, 1H), 6.5-6.6 (m, 1H), 6.8-6.9 (m, 1H), 6.98 (dd, 1H, J=2.8 Hz), 7.2-7.3 (m, 2H), 7.62 (d, 1H, J=8 Hz), 8.06 (d, 1H, J=3 Hz), 8.16 (br s, 1H), 8.22 (s, 1H).
MS:447.10[M+H]+
Methyl 3-(2-(4-(trifluoromethyl)phenyl)acetamido)pyrrolidine-3-carboxylate (294 mg, 0.89 mmol) synthesized in Reference Example 21-2, 3-bromo-5-(trifluoromethyl)pyridine (302 mg, 1.34 mmol), palladium acetate (20 mg, 0.09 mmol), XPhos (85 mg, 0.18 mmol), and cesium carbonate (628 mg, 1.78 mmol) were suspended in toluene (9.0 mL), and the suspension was stirred for 6 hours at 85° C. under a nitrogen gas stream. The suspension was left to cool to room temperature, insoluble materials were filtered through Celite, and the solvent was distilled off under reduced pressure. A residue thus obtained was purified by silica gel column chromatography (heptane:ethyl acetate) (concentration gradient: 0 to 100%), and the title compound (white amorphous, 8.1 mg, 1.9%) was obtained.
1H NMR (CDCl3, 400 MHz): δ=2.4-2.5 (m, 1H), 2.5-2.6 (m, 1H), 3.4-3.5 (m, 2H), 3.6-3.7 (m, 3H), 3.76 (s, 3H), 3.98 (d, 1H, J=11 Hz), 6.24 (s, 1H), 6.9-7.0 (m, 1H), 7.40 (d, 2H, J=8 Hz), 7.61 (d, 2H, J=8 Hz), 8.06 (d, 1H, J=3 Hz), 8.21 (s, 1H).
MS:476.09[M+H]+
According to a technique similar to Example 26, (1S,2S)-2-(benzo[d]oxazol-2-yl)cyclopropane-1-carboxylic acid (white powder) was synthesized from methyl (1S,2S)-2-(benzo[d]oxazol-2-yl)cyclopropane-1-carboxylate (95 mg, 0.44 mmol) synthesized in Reference Example 25-2, and the title compound (white powder, 72 mg, 40%) was obtained using (R)-1-(5-(trifluoromethyl)pyridin-3-yl)pyrrolidin-3-amine (101 mg, 0.44 mmol) synthesized in Reference Example 1-2.
1H NMR (CDCl3, 400 MHz): δ=1.6-1.7 (m, 1H), 1.8-1.9 (m, 1H), 2.0-2.1 (m, 1H), 2.1-2.2 (m, 1H), 2.3-2.4 (m, 1H), 2.7-2.8 (m, 1H), 3.2-3.3 (m, 1H), 3.4-3.5 (m, 1H), 3.5-3.6 (m, 1H), 3.6-3.7 (m, 1H), 4.7-4.8 (m, 1H), 6.18 (d, 1H, J=6 Hz), 6.92 (s, 1H), 7.2-7.3 (m, 2H), 7.4-7.5 (m, 1H), 7.6-7.7 (m, 1H), 8.10 (d, 1H, J=2 Hz), 8.20 (s, 1H).
MS:417.11[M+H]+
According to a technique similar to Example 1, the title compound (white powder, 60 mg, 46%) was obtained using (R)-1-(4-(trifluoromethyl)thiazol-2-yl)pyrrolidin-3-amine (70 mg, 0.30 mmol) synthesized in Reference Example 12-2 and 2-(4-morpholinophenyl)acetic acid (98 mg, 0.44 mmol) synthesized in Reference Example 23-2.
1H NMR (CDCl3, 400 MHz): δ=1.8-1.9 (m, 1H), 2.3-2.4 (m, 1H), 3.1-3.2 (m, 4H), 3.23 (dd, 1H, J=4.10 Hz), 3.4-3.6 (m, 4H), 3.75 (dd, 1H, J=6.10 Hz), 3.8-3.9 (m, 4H), 4.5-4.7 (m, 1H), 5.48 (d, 1H, J=7 Hz), 6.88 (d, 2H, J=9 Hz), 6.92 (s, 1H), 7.12 (d, 2H, J=8 Hz).
MS:441.10[M+H]+
According to a technique similar to Example 7, methyl 3-amino-1-(5-(trifluoromethyl)pyridin-3-yl)pyrrolidine-3-carboxylate was synthesized from methyl 3-((tert-butoxycarbonyl)amino)-1-(5-(trifluoromethyl)pyridin-3-yl)pyrrolidine-3-carboxylate (39 mg, 0.10 mmol) synthesized in Reference Example 20-2, and the title compound (white powder, 21 mg, 43%) was obtained using 2-(4-morpholinophenyl)acetic acid (33 mg, 0.15 mmol) synthesized in Reference Example 23-2.
1H NMR (CDCl3, 400 MHz): δ=2.3-2.4 (m, 1H), 2.5-2.6 (m, 1H), 3.1-3.2 (m, 4H), 3.4-3.5 (m, 2H), 3.53 (s, 2H) 3.62 (d, 1H, J=10 Hz), 3.76 (s, 3H), 3.8-3.9 (m, 4H), 4.00 (d, 1H, J=10 Hz), 5.99 (s, 1H), 6.8-6.9 (m, 2H), 6.91 (dd, 1H, J=2.2 Hz), 7.1-7.2 (m, 2H), 8.07 (d, 1H, J=3 Hz), 8.22 (s, 1H).
MS:493.16[M+H]+
According to a technique similar to Example 1, the title compound (white powder, 59 mg, 45%) was obtained using (R)-1-(6-(trifluoromethyl)pyridin-3-yl)pyrrolidin-3-amine (70 mg, 0.30 mmol) synthesized in Reference Example 32-2 and 2-(4-morpholinophenyl)acetic acid (100 mg, 0.45 mmol) synthesized in Reference Example 23-2.
1H NMR (CDCl3, 400 MHz): δ=1.8-1.9 (m, 1H), 2.3-2.4 (m, 1H), 3.1-3.2 (m, 5H), 3.3-3.4 (m, 2H), 3.51 (s, 2H), 3.66 (dd, 1H, J=6.10 Hz), 3.8-3.9 (m, 4H), 4.6-4.7 (m, 1H), 5.50 (d, 1H, J=7 Hz), 6.79 (dd, 1H, J=3.9 Hz), 6.8-6.9 (m, 2H), 7.1-7.2 (m, 2H), 7.51 (d, 1H, J=9 Hz), 7.97 (d, 1H, J=9 Hz).
MS:435.15[M+H]+
According to a technique similar to Example 38, 2-(4-cyclopropylphenyl)-N-(3-ethylpyrrolidin-3-yl)acetamide (yellow amorphous, 578 mg) was synthesized from tert-butyl 3-(2-(4-cyclopropylphenyl) acetamido)-3-ethylpyrrolidine-1-carboxylate (782 mg, 2.10 mmol) synthesized in Reference Example 24, and the title compound (orange-colored amorphous, 400 mg, 46%) was obtained using 3-bromo-5-(trifluoromethyl)pyridine (575 mg, 2.54 mmol).
1H NMR (CDCl3, 400 MHz): δ=0.6-0.7 (m, 2H), 0.84 (t, 3H, J=8 Hz), 0.9-1.0 (m, 2H), 1.8-1.9 (m, 2H), 1.9-2.0 (m, 1H), 2.0-2.1 (m, 1H), 2.2-2.3 (m, 1H), 3.2-3.4 (m, 3H), 3.49 (s, 2H), 3.65 (d, 1H, J=10 Hz), 5.21 (s, 1H), 6.88 (dd, 1H, J=2.2 Hz), 6.9-7.0 (m, 2H), 7.0-7.1 (m, 2H), 8.05 (d, 1H, J=3 Hz), 8.19 (s, 1H).
MS:418.17[M+H]+
According to a technique similar to Example 26, (1S,2S)-2-(6-fluorobenzo[d]oxazol-2-yl)cyclopropane-1-carboxylic acid (white powder) was synthesized from methyl (1S,2S)-2-(6-fluorobenzo[d]oxazol-2-yl)cyclopropane-1-carboxylate (105 mg, 0.45 mmol) synthesized in Reference Example 22-4, and the title compound (white powder, 89 mg, 46%) was obtained using (R)-1-(5-(trifluoromethyl)pyridin-3-yl)pyrrolidin-3-amine (103 mg, 0.45 mmol) synthesized in Reference Example 1-2.
1H NMR (CDCl3, 400 MHz): δ=1.6-1.7 (m, 1H), 1.7-1.8 (m, 1H), 2.0-2.1 (m, 1H), 2.1-2.2 (m, 1H), 2.3-2.4 (m, 1H), 2.7-2.8 (m, 1H), 3.27 (dd, 1H, J=3.10 Hz), 3.3-3.5 (m, 2H), 3.65 (dd, 1H, J=6.10 Hz), 4.7-4.8 (m, 1H), 6.71 (d, 1H, J=7 Hz), 6.85 (dd, 1H, J=2.2 Hz), 7.0-7.1 (m, 1H), 7.16 (dd, 1H, J=2.8 Hz), 7.51 (dd, 1H, J=5.8 Hz), 8.04 (d, 1H, J=3 Hz), 8.15 (d, 1H, J=0.8 Hz).
MS:435.10[M+H]+
According to a technique similar to Example 26, (1S,2S)-2-(5,6-difluorobenzo[d]oxazol-2-yl)cyclopropane-1-carboxylic acid (white powder) was synthesized from methyl (1S,2S)-2-(5,6-difluorobenzo[d]oxazol-2-yl)cyclopropane-1-carboxylate (68 mg, 0.27 mmol) synthesized in Reference Example 26-2, and the title compound (white powder, 35 mg, 29%) was obtained using (R)-1-(5-(trifluoromethyl)pyridin-3-yl)pyrrolidin-3-amine (62 mg, 0.27 mmol) synthesized in Reference Example 1-2.
1H NMR (CDCl3, 400 MHz): δ=1.6-1.7 (m, 1H), 1.7-1.8 (m, 1H), 2.0-2.1 (m, 1H), 2.1-2.2 (m, 1H), 2.3-2.4 (m, 1H), 2.7-2.8 (m, 1H), 3.29 (dd, 1H, J=4.10 Hz), 3.4-3.5 (m, 1H), 3.5-3.6 (m, 1H), 3.67 (dd, 1H, J=6.10 Hz), 4.7-4.8 (m, 1H), 6.25 (d, 1H, J=7 Hz), 6.91 (dd, 1H, J=2.2 Hz), 7.30 (dd, 1H, J=7.9 Hz), 7.39 (dd, 1H, J=8.10 Hz), 8.10 (d, 1H, J=3 Hz), 8.19 (d, 1H, J=0.8 Hz).
MS:453.09[M+H]+
According to a technique similar to Example 26, 2-(4-(2-oxa-6-azaspiro[3.3]heptan-6-yl)phenyl)acetic acid (white powder, 1.02 g) was synthesized from ethyl 2-(4-(2-oxa-6-azaspiro[3.3]heptan-6-yl)phenyl)acetate (1.26 g, 4.82 mmol) synthesized in Reference Example 27, and the title compound (ivory-colored powder, 106 mg, 91%) was obtained using (R)-1-(5-(trifluoromethyl)pyridin-3-yl)pyrrolidin-3-amine (60 mg, 0.26 mmol) synthesized in Reference Example 1-2.
1H NMR (CDCl3, 400 MHz): δ=1.8-1.9 (m, 1H), 2.3-2.4 (m, 1H), 3.09 (dd, 1H, J=5.10 Hz), 3.3-3.4 (m, 2H), 3.47 (s, 2H), 3.62 (dd, 1H, J=6.10 Hz), 4.00 (s, 4H), 4.6-4.7 (m, 1H), 4.83 (s, 4H), 5.73 (d, 1H, J=7 Hz), 6.4-6.5 (m, 2H), 6.86 (dd, 1H, J=3.9 Hz), 7.0-7.1 (m, 2H), 8.04 (d, 1H, J=3 Hz), 8.17 (d, 1H, J=0.8 Hz).
MS:447.19[M+H]+
According to a technique similar to Example 26, (1S,2S)-2-(benzo[d]oxazol-2-yl)cyclopropane-1-carboxylic acid was synthesized from methyl (1S,2S)-2-(benzo[d]oxazol-2-yl)cyclopropane-1-carboxylate (110 mg, 0.51 mmol) synthesized in Reference Example 25-2, and the title compound (white powder, 90 mg, 42%) was obtained using (R)-1-(4-(trifluoromethyl)thiazol-2-yl)pyrrolidin-3-amine (120 mg, 0.51 mmol) synthesized in Reference Example 25-2.
1H NMR (CDCl3, 400 MHz): δ=1.6-1.7 (m, 1H), 1.7-1.8 (m, 1H), 2.0-2.1 (m, 1H), 2.1-2.2 (m, 1H), 2.3-2.4 (m, 1H), 2.7-2.8 (m, 1H), 3.44 (dd, 1H, J=4.10 Hz), 3.5-3.7 (m, 2H), 3.80 (dd, 1H, J=6.10 Hz), 4.6-4.7 (m, 1H), 5.95 (d, 1H, J=7 Hz), 6.95 (d, 1H, J=0.8 Hz), 7.2-7.3 (m, 2H), 7.4-7.5 (m, 1H), 7.6-7.7 (m, 1H).
MS:423.07[M+H]+
According to a technique similar to Example 26, (1S,2S)-2-(6-fluorobenzo[d]oxazol-2-yl)cyclopropane-1-carboxylic acid (ivory-colored powder) was synthesized from methyl (1S,2S)-2-(6-fluorobenzo[d]oxazol-2-yl)cyclopropane-1-carboxylate (121 mg, 0.51 mmol) synthesized in Reference Example 22-4, and the title compound (white powder, 118 mg, 53%) was obtained using (R)-1-(6-(trifluoromethyl)pyridin-3-yl)pyrrolidin-3-amine (119 mg, 0.51 mmol) synthesized in Reference Example 22-2.
1H NMR (CDCl3, 400 MHz): δ=1.6-1.7 (m, 1H), 1.7-1.8 (m, 1H), 2.1-2.2 (m, 1H), 2.2-2.3 (m, 1H), 2.3-2.4 (m, 1H), 2.7-2.8 (m, 1H), 3.2-3.3 (m, 1H), 3.3-3.4 (m, 1H), 3.4-3.5 (m, 1H), 3.6-3.7 (m, 1H), 4.7-4.8 (m, 1H), 6.7-6.8 (m, 2H), 7.0-7.1 (m, 1H), 7.1-7.2 (m, 1H), 7.39 (d, 1H, J=8 Hz), 7.50 (dd, 1H, J=5.8 Hz), 7.90 (s, 1H).
MS:435.10[M+H]+
According to a technique similar to Example 26, (1S,2S)-2-(5-fluorobenzo[d]oxazol-2-yl)cyclopropane-1-carboxylic acid (ivory-colored powder) was synthesized from methyl (1S,2S)-2-(5-fluorobenzo[d]oxazol-2-yl)cyclopropane-1-carboxylate (47 mg, 0.20 mmol) synthesized in Reference Example 28-2, and the title compound (white powder, 51 mg, 59%) was obtained using (R)-1-(5-(trifluoromethyl)pyridin-3-yl)pyrrolidin-3-amine (66 mg, 0.29 mmol) synthesized in Reference Example 1-2.
1H NMR (CDCl3, 400 MHz): δ=1.6-1.7 (m, 1H), 1.7-1.8 (m, 1H), 2.0-2.1 (m, 1H), 2.1-2.2 (m, 1H), 2.3-2.4 (m, 1H), 2.7-2.8 (m, 1H), 3.29 (dd, 1H, J=4.10 Hz), 3.4-3.5 (m, 1H), 3.5-3.6 (m, 1H), 3.69 (dd, 1H, J=6.10 Hz), 4.7-4.8 (m, 1H), 6.07 (d, 1H, J=7 Hz), 6.9-7.0 (m, 1H), 7.0-7.1 (m, 1H), 7.29 (dd, 1H, J=2.8 Hz), 7.37 (dd, 1H, J=4.9 Hz), 8.12 (d, 1H, J=3 Hz), 8.22 (s, 1H).
MS:435.10[M+H]+
According to a technique similar to Example 26, trans-2-(benzo[d]oxazol-2-yl)cyclopropane-1-carboxylic acid (ivory-colored powder) was synthesized from ethyl trans-2-(benzo[d]oxazol-2-yl)cyclopropane-1-carboxylate (200 mg, 0.86 mmol) synthesized in Reference Example 29-3, and the title compound (white amorphous, 7.3 mg, 2.0%) was obtained using (R)-1-(5-(trifluoromethyl)pyridin-3-yl)pyrrolidin-3-amine (200 mg, 0.86 mmol) synthesized in Reference Example 1-2.
1H NMR (CDCl3, 400 MHz): δ=1.6-1.7 (m, 1H), 1.7-1.8 (m, 1H), 2.0-2.1 (m, 1H), 2.1-2.2 (m, 1H), 2.3-2.4 (m, 1H), 2.7-2.8 (m, 1H), 3.27 (dd, 1H, J=4.10 Hz), 3.4-3.5 (m, 1H), 3.5-3.6 (m, 1H), 3.67 (dd, 1H, J=6.10 Hz), 4.7-4.8 (m, 1H), 6.07 (d, 1H, J=8 Hz), 6.9-7.0 (m, 1H), 7.2-7.3 (m, 2H), 7.4-7.5 (m, 1H), 7.6-7.7 (m, 1H), 8.10 (d, 1H, J=2 Hz), 8.20 (s, 1H).
MS:417.09[M+H]+
According to a technique similar to Example 26, (1S,2S)-2-(5-fluorobenzo[d]oxazol-2-yl)cyclopropane-1-carboxylic acid (ivory-colored powder) was synthesized from ethyl (1S,2S)-2-(5-fluorobenzo[d]oxazol-2-yl)cyclopropane-1-carboxylate (141 mg, 0.57 mmol) synthesized in Reference Example 30-3, and the title compound (white amorphous, 60 mg, 24%) was obtained using (R)-1-(6-(trifluoromethyl)pyridin-3-yl)pyrrolidin-3-amine (131 mg, 0.57 mmol) synthesized in Reference Example 32-2.
1H NMR (CDCl3, 400 MHz): δ=1.6-1.7 (m, 1H), 1.7-1.8 (m, 1H), 2.0-2.1 (m, 1H), 2.1-2.2 (m, 1H), 2.3-2.4 (m, 1H), 2.7-2.8 (m, 1H), 3.30 (dd, 1H, J=4.10 Hz), 3.4-3.5 (m, 1H), 3.5-3.6 (m, 1H), 3.69 (dd, 1H, J=6.10 Hz), 4.7-4.8 (m, 1H), 6.20 (d, 1H, J=7 Hz), 6.80 (dd, 1H, J=2.8 Hz), 7.0-7.1 (m, 1H), 7.2-7.3 (m, 1H), 7.36 (dd, 1H, J=4.8 Hz), 7.46 (d, 1H, J=8 Hz), 7.98 (d, 1H, J=2 Hz).
MS:435.10[M+H]+
According to a technique similar to Example 3, a crude form of (R)-1-(4-(trifluoromethyl)phenyl)pyrrolidin-3-amine (317 mg) was synthesized from tert-butyl (R)-(1-(4-(trifluoromethyl)phenyl)pyrrolidin-3-yl)carbamate (273 mg, 0.83 mmol) synthesized in Reference Example 34, and diastereomer A of the title compound (Rf value in TLC (ethyl acetate)=0.4, pale yellow amorphous, 16 mg, 19%) was obtained using trans-2-(1H-benzo[d]imidazol-2-yl)cyclopropane-1-carboxylic acid (40 mg, 0.20 mmol).
Diastereomer A
1H NMR (DMSO-d6, 400 MHz): δ=1.4-1.5 (m, 2H), 1.8-2.0 (m, 1H), 2.1-2.3 (m, 2H), 2.4-2.5 (m, 1H), 3.15 (dd, 1H, J=4.10 Hz), 3.3-3.5 (m, 2H), 3.55 (dd, 1H, J=6.10 Hz), 4.3-4.5 (m, 1H), 6.63 (d, 2H, J=9 Hz), 7.0-7.2 (m, 2H), 7.3-7.5 (m, 2H), 7.46 (d, 2H, J=9 Hz), 8.64 (d, 1H, J=6 Hz), 12.38 (s, 1H).
MS:415.16[M+H]+
According to a technique similar to Example 3, a crude form of (S)-1-(4-(trifluoromethyl)phenyl)pyrrolidin-3-amine (170 mg) was synthesized from tert-butyl (S)-(1-(4-(trifluoromethyl)phenyl)pyrrolidin-3-yl)carbamate (236 mg, 0.72 mmol) synthesized in Reference Example 35, and diastereomer A of the title compound (Rf value in TLC (ethyl acetate)=0.5, white powder, 14 mg, 17%) was obtained using trans-2-(1H-benzo[d]imidazol-2-yl)cyclopropane-1-carboxylic acid (40 mg, 0.20 mmol).
Diastereomer A
1H NMR (DMSO-d6, 400 MHz): δ=1.4-1.5 (m, 2H), 1.8-2.0 (m, 1H), 2.1-2.3 (m, 2H), 2.4-2.5 (m, 1H), 3.15 (dd, 1H, J=4.10 Hz), 3.3-3.6 (m, 3H), 4.3-4.5 (m, 1H), 6.63 (d, 2H, J=9 Hz), 7.0-7.2 (m, 2H), 7.3-7.5 (m, 2H), 7.46 (d, 2H, J=9 Hz), 8.64 (d, 1H, J=7 Hz), 12.39 (s, 1H).
MS:415.18[M+H]+
According to a technique similar to Example 3, a crude form of (R)-1-(6-(trifluoromethyl)pyridin-3-yl)pyrrolidin-3-amine (300 mg) was synthesized from tert-butyl (R)-(1-(6-(trifluoromethyl)pyridin-3-yl)pyrrolidin-3-yl)carbamate (429 mg, 1.30 mmol) synthesized in Reference Example 36, and the title compound (white powder, 32 mg, 48%) was obtained using (1S,2S)-2-(1H-benzo[d]imidazol-2-yl)cyclopropane-1-carboxylic acid (32 mg, 0.16 mmol).
1H NMR (DMSO-d6, 400 MHz): δ=1.4-1.5 (m, 2H), 1.9-2.0 (m, 1H), 2.1-2.3 (m, 2H), 2.4-2.5 (m, 1H), 3.21 (dd, 1H, J=4.10 Hz), 3.3-3.5 (m, 2H), 3.60 (dd, 1H, J=6.10 Hz), 4.4-4.5 (m, 1H), 7.01 (d, 1H, J=3.9 Hz), 7.0-7.2 (m, 2H), 7.3-7.5 (m, 2H), 7.59 (d, 1H, J=9 Hz), 8.04 (d, 1H, J=3 Hz), 8.65 (d, 1H, J=7 Hz), 12.41 (s, 1H).
MS:416.18[M+H]+
According to a technique similar to Example 3, a crude form of (S)-1-(6-(trifluoromethyl)pyridin-3-yl)pyrrolidin-3-amine (37 mg) was synthesized from tert-butyl (S)-(1-(6-(trifluoromethyl)pyridin-3-yl)pyrrolidin-3-yl)carbamate (59 mg, 0.18 mmol) synthesized in Reference Example 37, and the title compound (white powder, 48 mg, 73%) was obtained using (1S,2S)-2-(1H-benzo[d]imidazol-2-yl)cyclopropane-1-carboxylic acid (32 mg, 0.16 mmol).
1H NMR (DMSO-d6, 400 MHz): δ=1.4-1.5 (m, 2H), 1.9-2.0 (m, 1H), 2.1-2.3 (m, 2H), 2.4-2.5 (m, 1H), 3.18 (dd, 1H, J=4.10 Hz), 3.3-3.6 (m, 2H), 3.60 (dd, 1H, J=6.10 Hz), 4.4-4.6 (m, 1H), 7.00 (d, 1H, J=3.9 Hz), 7.0-7.2 (m, 2H), 7.3-7.5 (m, 2H), 7.58 (d, 1H, J=9 Hz), 8.02 (d, 1H, J=3 Hz), 8.64 (d, 1H, J=7 Hz), 12.34 (s, 1H).
MS:416.18[M+H]+
According to a technique similar to Example 1, the title compound (white powder, 28 mg, 68%) was obtained using (R)-1-(5-(trifluoromethyl)pyrimidin-2-yl)pyrrolidin-3-amine (45 mg, 0.20 mmol) synthesized in Reference Example 38-2 and (1S,2S)-2-(1H-benzo[d]imidazol-2-yl)cyclopropane-1-carboxylic acid (20 mg, 0.10 mmol).
1H NMR (DMSO-d6, 400 MHz): δ=1.4-1.5 (m, 2H), 1.8-2.0 (m, 1H), 2.1-2.3 (m, 2H), 2.4-2.5 (m, 1H), 3.49 (dd, 1H, J=4.8 Hz), 3.6-3.7 (m, 2H), 3.75 (dd, 1H, J=6.12 Hz), 4.3-4.5 (m, 1H), 7.0-7.2 (m, 2H), 7.3-7.5 (m, 2H), 8.64 (d, 1H, J=6 Hz), 8.71 (s, 2H), 12.39 (s, 1H).
MS:417.20[M+H]+
According to a technique similar to Example 3, a crude form of (R)-1-(4-fluoro-3-(trifluoromethyl)phenyl)pyrrolidin-3-amine (80 mg) was synthesized from tert-butyl (R)-(1-(4-fluoro-3-(trifluoromethyl)phenyl)pyrrolidin-3-yl)carbamate (112 mg, 0.32 mmol) synthesized in Reference Example 39, and the title compound (white powder, 35 mg, 77%) was obtained using (1S,2S)-2-(1H-benzo[d]imidazol-2-yl)cyclopropane-1-carboxylic acid (21 mg, 0.11 mmol).
1H NMR (CDCl3, 400 MHz): δ=1.6-1.8 (m, 2H), 1.9-2.1 (m, 1H), 2.2-2.4 (m, 2H), 2.6-2.7 (m, 1H), 3.23 (dd, 1H, J=4.10 Hz), 3.30 (dt, 1H, J=5.9 Hz), 3.4-3.5 (m, 1H), 3.59 (dd, 1H, J=6.10 Hz), 4.6-4.7 (m, 1H), 6.51 (d, 1H, J=7 Hz), 6.6-6.7 (m, 2H), 7.05 (t, 1H, J=9 Hz), 7.2-7.3 (m, 2H), 7.4-7.5 (m, 2H).
The 1H content is not observable.
MS:433.18[M+H]+
According to a technique similar to Example 3, a crude form of (R)-1-(4-fluoro-3-(trifluoromethyl)phenyl)pyrrolidin-3-amine (80 mg) was synthesized from tert-butyl (R)-(1-(4-fluoro-3-(trifluoromethyl)phenyl)pyrrolidin-3-yl)carbamate (112 mg, 0.32 mmol) synthesized in Reference Example 39, and the title compound (white powder, 23 mg, 56%) was obtained using (1S,2S)-2-(quinazolin-2-yl)cyclopropane-1-carboxylic acid (20 mg, 0.09 mmol) synthesized in Reference Example 40-3.
1H NMR (CDCl3, 400 MHz): δ=1.69 (ddd, 1H, J=4, 6.8 Hz), 1.7-1.8 (m, 1H), 1.9-2.1 (m, 1H), 2.1-2.4 (m, 2H), 2.9-3.0 (m, 1H), 3.22 (dd, 1H, J=4.10 Hz), 3.31 (dt, 1H, J=5.9 Hz), 3.4-3.5 (m, 1H), 3.59 (dd, 1H, J=6.10 Hz), 4.6-4.8 (m, 1H), 5.88 (d, 1H, J=7 Hz), 6.6-6.7 (m, 2H), 7.06 (t, 1H, J=9 Hz), 7.5-7.6 (m, 1H), 7.8-8.0 (m, 3H), 9.25 (s, 1H).
MS:445.19[M+H]+
According to a technique similar to Example 1, the title compound (pale yellow powder, 7 mg, 65%) was obtained using (R)-1-(3-(methylsulfonyl)phenyl)pyrrolidin-3-amine (6 mg, 0.02 mmol) synthesized in Reference Example 41-2 and (1S,2S)-2-(1H-benzo[d]imidazol-2-yl)cyclopropane-1-carboxylic acid (5 mg, 0.02 mmol).
1H NMR (CDCl3, 400 MHz): δ=1.5-1.8 (m, 2H), 2.0-2.1 (m, 1H), 2.2-2.4 (m, 2H), 2.6-2.7 (m, 1H), 3.04 (s, 3H), 3.27 (dd, 1H, J=4.10 Hz), 3.3-3.5 (m, 2H), 3.62 (dd, 1H, J=6.10 Hz), 4.5-4.7 (m, 1H), 6.53 (d, 1H, J=7 Hz), 6.72 (dd, 1H, J=2.8 Hz), 7.00 (t, 1H, J=2 Hz), 7.1-7.3 (m, 3H), 7.36 (t, 1H, J=8 Hz), 7.4-7.6 (m, 2H). The 1H content is not observable.
MS:425.19[M+H]+
According to a technique similar to Example 1, the title compound (pale yellow powder, 9 mg, 96%) was obtained using (R)-3-(3-aminopyrrolidin-1-yl)benzonitrile (5 mg, 0.02 mmol) synthesized in Reference Example 42-2 and (1S,2S)-2-(1H-benzo[d]imidazol-2-yl)cyclopropane-1-carboxylic acid (5 mg, 0.02 mmol).
1H NMR (CDCl3, 400 MHz): δ=1.6-1.8 (m, 2H), 1.9-2.1 (m, 1H), 2.2-2.4 (m, 2H), 2.6-2.8 (m, 1H), 3.2-3.5 (m, 2H), 3.22 (dd, 1H, J=4.10 Hz), 3.60 (dd, 1H, J=6.10 Hz), 4.5-4.7 (m, 1H), 6.61 (d, 1H, J=7 Hz), 6.7-6.8 (m, 2H), 6.96 (d, 1H, J=7 Hz), 7.1-7.3 (m, 3H), 7.4-7.6 (m, 2H).
The 1H content is not observable.
MS:372.21[M+H]+
According to a technique similar to Example 1, diastereomer A of the title compound (upper spot in TLC (methanol/ethyl acetate=1/9), white powder, 22 mg, 37%) and diastereomer B of the title compound (lower spot in TLC (methanol/ethyl acetate=1/9), white powder, 19 mg, 32%) were obtained using (R)-1-(6-(trifluoromethyl)pyridin-3-yl)pyrrolidin-3-amine (31 mg, 0.14 mmol) synthesized in Reference Example 1-2 and trans-2-(5-cyano-1H-benzo[d]imidazol-2-yl)cyclopropane-1-carboxylic acid (31 mg, 0.14 mmol) synthesized in Reference Example 43-3.
Diastereomer A
1H NMR (CDCl3, 400 MHz): δ=1.6-1.8 (m, 2H), 2.0-2.1 (m, 1H), 2.3-2.5 (m, 2H), 2.6-2.7 (m, 1H), 3.31 (dd, 1H, J=4.10 Hz), 3.4-3.6 (m, 2H), 3.72 (dd, 1H, J=6.10 Hz), 4.6-4.8 (m, 1H), 6.16 (d, 1H, J=7 Hz), 6.85 (dd, 1H, J=3.9 Hz), 7.4-7.6 (m, 3H), 7.8-7.9 (m, 1H), 8.03 (d, 1H, J=3 Hz), 9.78 (br s, 1H).
MS:439.28[M−H]−
Diastereomer B
1H NMR (CDCl3, 400 MHz): δ=1.7-1.9 (m, 2H), 2.0-2.5 (m, 3H), 2.6-2.7 (m, 1H), 3.23 (dd, 1H, J=4.10 Hz), 3.3-3.6 (m, 2H), 3.58 (dd, 1H, J=6.10 Hz), 4.6-4.7 (m, 1H), 6.35 (d, 1H, J=7 Hz), 6.77 (dd, 1H, J=3.9 Hz), 7.4-8.0 (m, 4H), 7.94 (d, 1H, J=3 Hz), 10.05 (br s, 1H).
MS:439.28[M−H]−
According to a technique similar to Example 3, a crude form of (R)-1-(2-(trifluoromethyl)pyridin-4-yl)pyrrolidin-3-amine (30 mg) was synthesized from tert-butyl (R)-(1-(2-(trifluoromethyl)pyridin-4-yl)pyrrolidin-3-yl)carbamate synthesized in Reference Example 44, and the title compound (white powder, 31 mg, 76%) was obtained using (1S,2S)-2-(1H-benzo[d]imidazol-2-yl)cyclopropane-1-carboxylic acid (20 mg, 0.10 mmol).
1H NMR (CDCl3, 400 MHz): δ=1.6-1.8 (m, 2H), 2.0-2.2 (m, 1H), 2.2-2.5 (m, 2H), 2.5-2.7 (m, 1H), 3.30 (dd, 1H, J=4.10 Hz), 3.4-3.6 (m, 2H), 3.73 (dd, 1H, J=6.11 Hz), 4.6-4.7 (m, 1H), 6.19 (d, 1H, J=7 Hz), 6.49 (dd, 1H, J=2.9 Hz), 6.74 (d, 1H, J=2 Hz), 7.2-7.3 (m, 2H), 7.4-7.5 (m, 2H), 8.31 (d, 1H, J=6 Hz). The 1H is not observable.
MS:416.17[M+H]+
According to a technique similar to Example 1, diastereomer A of the title compound (upper spot in TLC (ethyl acetate), white powder, 14 mg, 16%) and diastereomer B of the title compound (lower spot in TLC (ethyl acetate), white powder, 5 mg, 6%) were obtained using (R)-1-(6-(trifluoromethyl)pyridin-3-yl)piperidin-3-amine (50 mg, 0.20 mmol) synthesized in Reference Example 45-2 and trans-2-(1H-benzo[d]imidazol-2-yl)cyclopropane-1-carboxylic acid (41 mg, 0.20 mmol).
Diastereomer A
1H NMR (CDCl3, 400 MHz): δ=1.6-2.0 (m, 6H), 2.2-2.4 (m, 1H), 2.5-2.7 (m, 1H), 3.08 (dd, 1H, J=7.12 Hz), 3.1-3.4 (m, 2H), 3.55 (dd, 1H, J=3.12 Hz), 4.1-4.3 (m, 1H), 6.14 (d, 1H, J=8 Hz), 7.2-7.3 (m, 2H), 7.3-7.4 (m, 1H), 7.4-7.6 (m, 2H), 8.35 (s, 1H), 8.49 (d, 1H, J=3 Hz). The 1H content is not observable.
MS:430.17 [M+H]+
Diastereomer B
1H NMR (CDCl3, 400 MHz): δ=1.6-2.0 (m, 6H), 2.2-2.3 (m, 1H), 2.6-2.7 (m, 1H), 3.1-3.3 (m, 4H), 4.1-4.3 (m, 1H), 6.46 (d, 1H, J=7 Hz), 7.1-7.3 (m, 3H), 7.4-7.6 (m, 2H), 8.23 (s, 1H), 8.28 (d, 1H, J=3 Hz). The 1H content is not observable.
MS:430.18 [M+H]+
According to a technique similar to Example 1, the title compound (white powder, 20 mg, 47%) was obtained using (R)-1-(4-(trifluoromethyl)thiazol-2-yl)pyrrolidin-3-amine (24 mg, 0.10 mmol) synthesized in Reference Example 46-3 and (1S,2S)-2-(1H-benzo[d]imidazol-2-yl)cyclopropane-1-carboxylic acid (20 mg, 0.10 mmol).
1H NMR (CDCl3, 400 MHz): δ=1.5-1.8 (m, 2H), 2.0-2.1 (m, 1H), 2.2-2.4 (m, 2H), 2.5-2.7 (m, 1H), 3.43 (dd, 1H, J=4.10 Hz), 3.5-3.7 (m, 2H), 3.80 (dd, 1H, J=6.11 Hz), 4.6-4.7 (m, 1H), 6.29 (d, 1H, J=7 Hz), 6.94 (5,1H), 7.2-7.3 (m, 2H), 7.4-7.6 (m, 2H). The 1H content is not observable.
MS:422.13[M+H]+
According to a technique similar to Example 1, the title compound (white powder, 30 mg, 70%) was obtained using (R)-1-(4-(trifluoromethyl)phenyl)piperidin-3-amine (22 mg, 0.10 mmol) synthesized in Reference Example 47-2 and (1S,2S)-2-(1H-benzo[d]imidazol-2-yl)cyclopropane-1-carboxylic acid (20 mg, 0.10 mmol).
1H NMR (CDCl3, 400 MHz): δ=1.6-1.9 (m, 6H), 2.2-2.4 (m, 1H), 2.6-2.7 (m, 1H), 3.1-3.4 (m, 2H), 3.10 (dd, 1H, J=7.12 Hz), 3.57 (dd, 1H, J=3.12 Hz), 4.1-4.3 (m, 1H), 6.16 (d, 1H, J=8 Hz), 6.97 (d, 2H, J=9 Hz), 7.1-7.3 (m, 2H), 7.4-7.6 (m, 2H), 7.49 (d, 2H, J=9 Hz), 9.60 (br s, 1H).
MS:429.19[M+H]+
According to a technique similar to Example 3, diastereomer A of the title compound (Rf value in TLC (ethyl acetate)=0.9, pale yellow powder, 6 mg, 19%) was obtained using (R)-1-(6-(trifluoromethyl)pyridin-3-yl)pyrrolidin-3-amine (17 mg, 0.07 mmol) synthesized in Reference Example 1-2 and trans-2-(1H-indol-3-yl)cyclopropane-1-carboxylic acid (15 mg, 0.07 mmol).
Diastereomer A
1H NMR (CDCl3, 400 MHz): δ=1.3-1.4 (m, 1H), 1.5-1.7 (m, 2H), 2.0-2.2 (m, 1H), 2.3-2.5 (m, 1H), 2.6-2.7 (m, 1H), 3.28 (dd, 1H, J=4.10 Hz), 3.4-3.6 (m, 2H), 3.72 (dd, 1H, J=6.10 Hz), 4.7-4.8 (m, 1H), 5.85 (d, 1H, J=7 Hz), 6.84 (dd, 1H, J=3.9 Hz), 6.94 (dd, 1H, J=1.2 Hz), 7.14 (dt, 1H, J=1.7 Hz), 7.22 (dt, 1H, J=1.7 Hz), 7.36 (d, 1H, J=8 Hz), 7.49 (d, 1H, J=9 Hz), 7.65 (d, 1H, J=8 Hz), 7.97 (br s, 1H), 8.02 (d, 1H, J=3 Hz).
MS:415.18[M+H]+
According to a technique similar to Example 1, the title compound (white powder, 21 mg, 65%) was obtained using (R)-1-(6-methoxy-5-(trifluoromethyl)pyridin-3-yl)pyrrolidin-3-amine (18 mg, 0.07 mmol) synthesized in Reference Example 48-2 and (1S,2S)-2-(1H-benzo[d]imidazol-2-yl)cyclopropane-1-carboxylic acid (14 mg, 0.07 mmol).
1H NMR (CDCl3, 400 MHz): δ=1.6-1.8 (m, 2H), 1.9-2.1 (m, 1H), 2.2-2.4 (m, 2H), 2.6-2.7 (m, 1H), 3.2-3.5 (m, 3H), 3.57 (dd, 1H, J=6.10 Hz), 3.96 (s, 3H), 4.6-4.8 (m, 1H), 6.1-6.3 (m, 1H), 7.14 (d, 1H, J=3 Hz), 7.2-7.3 (m, 2H), 7.3-7.7 (m, 2H), 7.65 (d, 1H, J=3 Hz), 9.39 (br s, 1H).
MS:444.17[M−H]−
According to a technique similar to Example 1, the title compound (white powder, 23 mg, 57%) was obtained using (R)-1-(4-(tert-butyl)thiazol-2-yl)pyrrolidin-3-amine (22 mg, 0.10 mmol) synthesized in Reference Example 49-2 and (1S,2S)-2-(1H-benzo[d]imidazol-2-yl)cyclopropane-1-carboxylic acid (20 mg, 0.10 mmol).
1H NMR (CDCl3, 400 MHz): δ=1.27 (s, 9H), 1.6-1.8 (m, 2H), 2.0-2.2 (m, 1H), 2.2-2.5 (m, 2H), 2.5-2.7 (m, 1H), 3.4-3.6 (m, 2H), 3.41 (dd, 1H, J=4.10 Hz), 3.77 (dd, 1H, J=6.11 Hz), 4.5-4.7 (m, 1H), 6.09 (s, 1H), 6.1-6.3 (m, 1H), 7.1-7.3 (m, 2H), 7.3-7.7 (m, 2H), 9.68 (br s, 1H).
MS:410.21[M+H]+
According to a technique similar to Example 3, a crude form of (R)-1-(6-(trifluoromethyl)pyridazin-3-yl)pyrrolidin-3-amine (91 mg) was synthesized from tert-butyl (R)-(1-(6-(trifluoromethyl)pyridazin-3-yl)pyrrolidin-3-yl)carbamate (90 mg, 0.271 mmol) synthesized in Reference Example 50, and the title compound (white powder, 67 mg, 60%) was obtained using (1S,2S)-2-(1H-benzo[d]imidazol-2-yl)cyclopropane-1-carboxylic acid (110 mg, 0.542 mmol).
1H NMR (DMSO-d6,400 MHz): δ=1.4-1.5 (m, 2H), 1.9-2.0 (m, 1H), 2.1-2.3 (m, 2H), 2.4-2.5 (m, 1H), 3.3-3.4 (m, 2H), 3.5-3.8 (m, 2H), 4.4-4.5 (m, 1H), 7.04 (d, 1H, J=10 Hz), 7.10 (dd, 2H, J=2.6 Hz), 7.44 (br s, 2H), 7.77 (d, 1H, J=10 Hz), 8.66 (d, 1H, J=7 Hz), 12.4 (br s, 1H).
MS:417.20[M+H]+
According to a technique similar to Example 3, a crude form of (R)-1-(2-(trifluoromethyl)pyrimidin-5-yl)pyrrolidin-3-amine (101 mg) was synthesized from tert-butyl (R)-(1-(2-(trifluoromethyl)pyrimidin-5-yl)pyrrolidin-3-yl)carbamate (129 mg, 0.388 mmol) synthesized in Reference Example 51, and the title compound (white powder, 145 mg, 90%) was obtained using (1S,2S)-2-(1H-benzo[d]imidazol-2-yl)cyclopropane-1-carboxylic acid (157 mg, 0.776 mmol).
1H NMR (DMSO-d6, 400 MHz): δ=1.4-1.5 (m, 2H), 1.9-2.0 (m, 1H), 2.1-2.3 (m, 2H), 2.4-2.5 (m, 1H), 3.26 (dd, 1H, J=4.11 Hz), 3.3-3.5 (m, 2H), 3.64 (dd, 1H, J=6.11 Hz), 4.4-4.5 (m, 1H), 7.0-7.2 (m, 2H), 7.3-7.5 (m, 2H), 8.25 (s, 2H), 8.64 (d, 1H, J=7 Hz), 12.4 (br s, 1H).
MS:415.27[M−H]−
According to a technique similar to Example 3, a crude form of (R)-1-(5-(trifluoromethyl)pyridin-3-yl)pyrrolidin-3-amine (79 mg) was synthesized from tert-butyl (R)-(1-(5-(trifluoromethyl)pyridin-3-yl)pyrrolidin-3-yl)carbamate (102 mg, 0.308 mmol) synthesized in Reference Example 1-1, and the title compound (white powder, 73 mg, 57%) was obtained using (1S,2S)-2-(1H-benzo[d]imidazol-2-yl)cyclopropane-1-carboxylic acid (125 mg, 0.616 mmol).
1H NMR (CDCl3, 400 MHz): δ=1.5-1.8 (m, 3H), 2.0-2.1 (m, 1H), 2.3-2.4 (m, 2H), 2.6-2.7 (m, 1H), 3.28 (dd, 1H, J=4.10 Hz), 3.3-3.6 (m, 2H), 3.67 (dd, 1H, J=6.10 Hz), 4.6-4.8 (m, 1H), 6.66 (d, 1H, J=7 Hz), 6.92 (s, 1H), 7.1-7.3 (m, 2H), 7.49 (br s, 2H), 8.09 (d, 1H, J=3 Hz), 8.20 (s, 1H).
MS:416.18[M+H]+
According to a technique similar to Example 3, a crude form of (R)-1-(6-fluorobenzo[d]thiazol-2-yl)pyrrolidin-3-amine (93 mg) was synthesized from tert-butyl (R)-(1-(6-fluorobenzo[d]thiazol-2-yl)pyrrolidin-3-yl)carbamate (85 mg, 0.253 mmol) synthesized in Reference Example 52, and the title compound (white powder, 50 mg, 47%) was obtained using (1S,2S)-2-(1H-benzo[d]imidazol-2-yl)cyclopropane-1-carboxylic acid (90 mg, 0.380 mmol).
1H NMR (DMSO-d6, 400 MHz): δ=1.4-1.5 (m, 2H), 1.9-2.0 (m, 1H), 2.2-2.3 (m, 2H), 2.4-2.5 (m, 1H), 3.3-3.4 (m, 1H), 3.5-3.7 (m, 2H), 3.73 (dd, 1H, J=6.11 Hz), 4.4-4.5 (m, 1H), 7.0-7.2 (m, 3H), 7.3-7.5 (m, 3H), 7.71 (dd, 1H, J=3.9 Hz), 8.70 (d, 1H, J=6 Hz), 12.4 (br s, 1H).
MS:422.14[M+H]+
According to a technique similar to Example 1, the title compound (white powder, 15 mg, 35%) was obtained using (R)-1-(6-(trifluoromethyl)pyridin-3-yl)pyrrolidin-3-amine (21 mg, 0.090 mmol) synthesized in Reference Example 32-2 and (1S,2S)-2-(1-cyclopropyl-1H-benzo[d]imidazol-2-yl)cyclopropane-1-carboxylic acid (33 mg, 0.135 mmol) synthesized in Reference Example 54-2.
1H NMR (CD3OD, 400 MHz): δ=1.0-1.2 (m, 2H), 1.2-1.4 (m, 2H), 1.6-1.7 (m, 2H), 2.0-2.3 (m, 2H), 2.3-2.5 (m, 1H), 2.8-3.0 (m, 1H), 3.3-3.6 (m, 4H), 3.71 (dd, 1H, J=6.11 Hz), 4.5-4.7 (m, 1H), 7.07 (dd, 1H, J=3.9 Hz), 7.1-7.3 (m, 2H), 7.50 (d, 1H, J=7 Hz), 7.5-7.6 (m, 2H), 7.98 (d, 1H, J=3 Hz).
The 1H content is not observable.
MS:456.20[M+H]+
According to a technique similar to Example 3, a crude form of (R)-1-(6-fluoroquinolin-2-yl)pyrrolidin-3-amine (81 mg) was synthesized from tert-butyl (R)-(1-(6-fluoroquinolin-2-yl)pyrrolidin-3-yl)carbamate (39 mg, 0.118 mmol) synthesized in Reference Example 53, and the title compound (pale yellow powder, 10 mg, 21%) was obtained using (1S,2S)-2-(1H-benzo[d]imidazol-2-yl)cyclopropane-1-carboxylic acid (42 mg, 0.177 mmol).
1H NMR (DMSO-d6, 400 MHz): δ=1.4-1.5 (m, 2H), 1.8-2.0 (m, 1H), 2.1-2.5 (m, 3H), 3.4-3.5 (m, 1H), 3.5-3.7 (m, 2H), 3.76 (dd, 1H, J=6.11 Hz), 4.3-4.5 (m, 1H), 6.95 (d, 1H, J=9 Hz), 7.0-7.2 (m, 2H), 7.3-7.6 (m, 5H), 8.01 (d, 1H, J=9 Hz), 8.64 (d, 1H, J=7 Hz), 12.4 (br s, 1H).
MS:416.18[M+H]+
According to a technique similar to Example 3, a crude form of (R)-1-(3-(trifluoromethyl)phenyl)pyrrolidin-3-amine (99 mg) was synthesized from tert-butyl (R)-(1-(3-(trifluoromethyl)phenyl)pyrrolidin-3-yl)carbamate (105 mg, 0.319 mmol) synthesized in Reference Example 77, and the title compound (white powder, 27 mg, 28%) was obtained using (1S,2S)-2-(1-cyclopropyl-1H-benzo[d]imidazol-2-yl)cyclopropane-1-carboxylic acid (52 mg, 0.213 mmol) synthesized in Reference Example 54-2.
1H NMR (DMSO-d6, 400 MHz): δ=0.9-1.3 (m, 4H), 1.4-1.6 (m, 2H), 1.9-2.0 (m, 1H), 2.1-2.3 (m, 2H), 2.6-2.8 (m, 1H), 3.1-3.2 (m, 1H), 3.3-3.5 (m, 3H), 3.56 (dd, 1H, J=6.10 Hz), 4.4-4.5 (m, 1H), 6.72 (s, 1H), 6.80 (dd, 1H, J=2.8 Hz), 6.89 (d, 1H, J=8 Hz), 7.1-7.3 (m, 2H), 7.36 (t, 1H, J=8 Hz), 7.47 (d, 1H, J=7 Hz), 7.52 (d, 1H, J=7 Hz), 8.62 (d, 1H, 7 Hz).
MS:455.20[M+H]+
According to a technique similar to Example 3, a crude form of (R)-1-(5-bromopyridin-3-yl)pyrrolidin-3-amine (138 mg) was synthesized from tert-butyl (R)-(1-(5-bromopyridin-3-yl)pyrrolidin-3-yl)carbamate (71 mg, 0.209 mmol) synthesized in Reference Example 55, and the title compound (white powder, 56 mg, 62%) was obtained using (1S,2S)-2-(1H-benzo[d]imidazol-2-yl)cyclopropane-1-carboxylic acid (63 mg, 0.314 mmol).
1H NMR (DMSO-d6, 400 MHz): δ=1.4-1.5 (m, 2H), 1.8-2.0 (m, 1H), 2.1-2.5 (m, 3H), 3.14 (dd, 1H, J=4.10 Hz), 3.3-3.5 (m, 2H), 3.53 (dd, 1H, J=6.10 Hz), 4.3-4.5 (m, 1H), 7.0-7.2 (m, 3H), 7.3-7.5 (m, 2H), 7.89 (d, 1H, J=2 Hz), 7.91 (d, 1H, J=2 Hz), 8.60 (d, 1H, J=7 Hz), 12.4 (br s, 1H).
MS:426.09[M+H]+
According to a technique similar to Example 1, the title compound (pale yellow amorphous, 88 mg, 100%) was obtained using (R)-1-(5-(trifluoromethyl)pyridin-3-yl)pyrrolidin-3-amine (50 mg, 0.216 mmol) synthesized in Reference Example 1-2 and 6-quinolineacetic acid (49 mg, 0.259 mmol).
1H NMR (CDCl3, 400 MHz): δ=1.9-2.1 (m, 1H), 2.2-2.4 (m, 1H), 3.14 (dd, 1H, J=4.10 Hz), 3.2-3.4 (m, 2H), 3.57 (dd, 1H, J=6.10 Hz), 3.78 (s, 2H), 4.6-4.7 (m, 1H), 6.73 (s, 1H), 6.81 (d, 1H, J=7 Hz), 7.38 (dd, 1H, J=4.8 Hz), 7.60 (dd, 1H, J=2.8 Hz), 7.69 (s, 1H), 7.85 (br s, 1H), 8.0-8.1 (m, 3H), 8.86 (d, 1H, J=3 Hz).
MS:401.19[M+H]+
According to a technique similar to Example 1, the title compound (white amorphous, 87 mg, 100%) was obtained using (R)-1-(5-(trifluoromethyl)pyridin-3-yl)pyrrolidin-3-amine (50 mg, 0.216 mmol) synthesized in Reference Example 1-2 and 3-indoleacetic acid (45 mg, 0.259 mmol).
1H NMR (CDCl3, 400 MHz): δ=1.7-1.9 (m, 1H), 2.2-2.4 (m, 1H), 3.07 (dd, 1H, J=4.10 Hz), 3.1-3.4 (m, 2H), 3.59 (dd, 1H, J=6.10 Hz), 3.76 (s, 2H), 4.5-4.7 (m, 1H), 5.79 (d, 1H, J=6 Hz), 6.82 (s, 1H), 7.0-7.3 (m, 3H), 7.39 (d, 1H, J=8 Hz), 7.49 (d, 1H, J=7 Hz), 8.00 (d, 1H, J=3 Hz), 8.18 (s, 2H).
MS:389.19[M+H]+
According to a technique similar to Example 1, (R)-2-(quinolin-7-yl)-N-(1-(5-(trifluoromethyl)pyridin-3-yl)pyrrolidin-3-yl)acetamide (colorless oily material, 56 mg) was obtained using (R)-1-(5-(trifluoromethyl)pyridin-3-yl)pyrrolidin-3-amine (99 mg, 0.427 mmol) synthesized in Reference Example 1-2 and 7-quinolineacetic acid (80 mg, 0.427 mmol). (R)-2-(quinolin-7-yl)-N-(1-(5-(trifluoromethyl)pyridin-3-yl)pyrrolidin-3-yl)acetamide (56 mg) thus obtained was dissolved in ethyl acetate (2 mL), a 2 M solution (2 mL) of hydrogen chloride in ethyl acetate was added thereto, the mixture was stirred for a while, subsequently the solvent was distilled off under reduced pressure, and the title compound (yellow powder, 52 mg, 28%) was obtained.
1H NMR (DMSO-d6, 400 MHz): δ=1.9-2.1 (m, 1H), 2.1-2.3 (m, 1H), 3.2-3.9 (m, 6H), 4.4-4.5 (m, 1H), 7.2-7.3 (m, 1H), 7.84 (d, 1H, J=8 Hz), 7.9-8.1 (m, 1H), 8.1-8.3 (m, 4H), 8.7-8.8 (m, 1H), 9.0-9.1 (m, 1H), 9.24 (d, 1H, J=4 Hz). The 1H content is not observable.
MS:401.16[M+H]+
According to a technique similar to Example 27, the title compound (white powder, 61 mg, 92%) was obtained using 2-(4-cyclopropylphenyl)acetic acid (43 mg, 0.176 mmol) synthesized in Reference Example 33-2 and 2-bromo-4-(trifluoromethyl)-1,3-oxazole (38 mg, 0.176 mmol).
1H NMR (CDCl3, 400 MHz): δ=0.6-0.8 (m, 2H), 0.9-1.0 (m, 2H), 1.8-2.0 (m, 2H), 2.2-2.3 (m, 1H), 3.28 (dd, 1H, J=5.11 Hz), 3.4-3.6 (m, 4H), 3.77 (dd, 1H, J=6.11 Hz), 4.5-4.6 (m, 1H), 5.44 (d, 1H, J=7 Hz), 7.0-7.2 (m, 4H), 7.49 (dd, 1H, J=1.3 Hz).
MS:402.12[M+Na]+
According to a technique similar to Example 1, the title compound (white powder, 62 mg, 98%) was obtained using (R)-1-(5-(trifluoromethyl)pyridin-3-yl)pyrrolidin-3-amine (35 mg, 0.151 mmol) synthesized in Reference Example 1-2 and 2-(1-methyl-5-(trifluoromethyl)-1H-pyrazol-3-yl)acetic acid (33 mg, 0.159 mmol).
1H NMR (CDCl3, 400 MHz): δ=2.0-2.1 (m, 1H), 2.3-2.5 (m, 1H), 3.23 (dd, 1H, J=4.10 Hz), 3.3-3.6 (m, 4H), 3.68 (dd, 1H, J=6.10 Hz), 3.91 (s, 3H), 4.6-4.7 (m, 1H), 6.54 (s, 1H), 6.68 (d, 1H, J=6 Hz), 6.94 (t, 1H, J=2 Hz), 8.12 (d, 1H, J=3 Hz), 8.21 (d, 1H, J=1 Hz).
MS:444.09[M+Na]+
According to a technique similar to Example 1, the title compound (white powder, 27 mg, 74%) was obtained using (R)-1-(5-(trifluoromethyl)pyridin-3-yl)pyrrolidin-3-amine (20 mg, 0.0865 mmol) synthesized in Reference Example 1-2 and 2-(6-(trifluoromethyl)pyridin-3-yl)acetic acid (20 mg, 0.0952 mmol).
1H NMR (CDCl3, 400 MHz): δ=2.0-2.1 (m, 1H), 2.3-2.5 (m, 1H), 3.24 (dd, 1H, J=4.10 Hz), 3.3-3.6 (m, 2H), 3.62 (s, 2H), 3.67 (dd, 1H, J=6.10 Hz), 4.6-4.7 (m, 1H), 6.02 (d, 1H, J=7 Hz), 6.92 (s, 1H), 7.68 (d, 1H, J=8 Hz), 7.90 (dd, 1H, J=1.8 Hz), 8.08 (d, 1H, 3 Hz), 8.20 (s, 1H), 8.62 (d, 1H, J=2 Hz).
MS:419.09[M+H]+
According to a technique similar to Example 1, the title compound (white crystals, 34 mg, 57%) was obtained using (R)-1-(5-(trifluoromethyl)pyridin-3-yl)pyrrolidin-3-amine (34 mg, 0.145 mmol) synthesized in Reference Example 1-2 and 2-(4-(trifluoromethyl)phenyl)acetic acid-2,2-d2 (30 mg, 0.145 mmol) synthesized in Reference Example 56.
1H NMR (CDCl3, 400 MHz): δ=1.9-2.1 (m, 1H), 2.3-2.5 (m, 1H), 3.19 (dd, 1H, J=5.10 Hz), 3.3-3.5 (m, 2H), 3.67 (dd, 1H, J=6.10 Hz), 4.6-4.7 (m, 1H), 5.62 (d, 1H, J=6 Hz), 6.9-7.0 (m, 1H), 7.40 (d, 2H, J=8 Hz), 7.61 (d, 2H, J=8 Hz), 8.10 (d, 1H, J=3 Hz), 8.21 (s, 1H).
MS:420.10[M+H]+
According to a technique similar to Example 9, the title compound (pale yellow powder, 22 mg, 24%) was obtained using (R)-2-(4-bromophenyl)-N-(1-(6-(trifluoromethyl)pyridin-3-yl)pyrrolidin-3-yl)acetamide (88 mg, 0.205 mmol) synthesized in Reference Example 57 and 3,3-difluoropyrrolidine hydrochloride (35 mg, 0.247 mmol).
1H NMR (CDCl3, 400 MHz): δ=1.8-2.0 (m, 1H), 2.2-2.6 (m, 3H), 3.11 (dd, 1H, J=5.10 Hz), 3.38 (t, 2H, J=7 Hz), 3.4-3.6 (m, 4H), 3.6-3.7 (m, 3H), 4.5-4.7 (m, 1H), 5.49 (d, 1H, J=7 Hz), 6.4-6.6 (m, 2H), 6.79 (dd, 1H, J=3.8 Hz), 7.0-7.2 (m, 2H), 7.47 (d, 1H, J=9 Hz), 7.97 (d, 1H, J=3 Hz).
MS:477.12[M+Na]+
According to a technique similar to Example 1, the title compound (pale yellow amorphous, 35 mg, 84%) was obtained using (R)-1-(6-(trifluoromethyl)pyridin-3-yl)pyrrolidin-3-amine (25 mg, 0.108 mmol) synthesized in Reference Example 32-2 and 2-(1H-indol-6-yl)acetic acid (23 mg, 0.130 mmol).
1H NMR (CDCl3, 400 MHz): δ=1.8-1.9 (m, 1H), 2.2-2.4 (m, 1H), 3.10 (dd, 1H, J=5.10 Hz), 3.2-3.4 (m, 2H), 3.65 (dd, 1H, J=6.10 Hz), 3.70 (s, 2H), 4.5-4.7 (m, 1H), 5.45 (d, 1H, J=7 Hz), 6.5-6.6 (m, 1H), 6.75 (dd, 1H, J=3.8 Hz), 6.96 (dd, 1H, J=1.8 Hz), 7.2-7.3 (m, 2H), 7.45 (d, 1H, J=9 Hz), 7.62 (d, 1H, J=8 Hz), 7.94 (d, 1H, J=3 Hz), 8.17 (br s, 1H).
MS:389.12[M+H]+
According to a technique similar to Example 9, the title compound (white powder, 12 mg, 22%) was obtained using (R)-2-(4-bromophenyl)-N-(1-(5-(trifluoromethyl)pyridin-3-yl)pyrrolidin-3-yl)acetamide (50 mg, 0.117 mmol) synthesized in Example 171 and cis-2,6-dimethylmorpholine (16 mg, 0.140 mmol).
1H NMR (CDCl3, 400 MHz): δ=1.26 (d, 6H, J=6 Hz), 1.8-2.0 (m, 1H), 2.2-2.5 (m, 3H), 3.11 (dd, 1H, J=5.10 Hz), 3.37 (t, 2H, J=7 Hz), 3.4-3.5 (m, 2H), 3.51 (s, 2H), 3.65 (dd, 1H, J=6.10 Hz), 3.7-3.9 (m, 2H), 4.5-4.7 (m, 1H), 5.52 (d, 1H, J=7 Hz), 6.8-7.0 (m, 3H), 7.12 (d, 2H, J=9 Hz), 8.07 (d, 1H, J=3 Hz), 8.20 (s, 1H).
MS:463.18[M+H]+
According to a technique similar to Example 9, the title compound (white crystals, 8 mg, 16%) was obtained using (R)-2-(4-bromophenyl)-N-(1-(5-(trifluoromethyl)pyridin-3-yl)pyrrolidin-3-yl)acetamide (50 mg, 0.117 mmol) synthesized in Example 171 and pyrrolidine (12 μL, 0.140 mmol).
1H NMR (CDCl3, 400 MHz): δ=1.8-2.1 (m, 5H), 2.2-2.4 (m, 1H), 3.08 (dd, 1H, J=5.10 Hz), 3.2-3.3 (m, 4H), 3.35 (t, 2H, J=7 Hz), 3.49 (s, 2H), 3.64 (dd, 1H, J=6.10 Hz), 4.5-4.7 (m, 1H), 5.55 (d, 1H, J=7 Hz), 6.52 (d, 2H, J=9 Hz), 6.8-6.9 (m, 1H), 7.05 (d, 2H, J=9 Hz), 8.06 (d, 1H, J=3 Hz), 8.19 (s, 1H).
MS:419.17[M+H]+
According to a technique similar to Example 9, the title compound (white amorphous, 2.5 mg, 5%) was obtained using (R)-2-(4-bromophenyl)-N-(1-(5-(trifluoromethyl)pyridin-3-yl)pyrrolidin-3-yl)acetamide (50 mg, 0.117 mmol) synthesized in Example 171 and N-(2-methoxyethyl)methylamine (15 μL, 0.140 mmol).
1H NMR (CDCl3, 400 MHz): δ=1.8-2.0 (m, 1H), 2.2-2.4 (m, 1H), 2.97 (s, 3H), 3.10 (dd, 1H, J=5.10 Hz), 3.3-3.4 (m, 5H), 3.4-3.6 (m, 6H), 3.65 (dd, 1H, J=6.10 Hz), 4.5-4.7 (m, 1H), 5.54 (d, 1H, J=7 Hz), 6.69 (d, 2H, J=9 Hz), 6.8-7.0 (m, 1H), 7.06 (d, 2H, J=9 Hz), 8.07 (d, 1H, J=2 Hz), 8.20 (s, 1H).
MS:437.17[M+H]+
According to a technique similar to Example 1, the title compound (white crystals, 22 mg, 80%) was obtained using 1-(5-(trifluoromethyl)pyridin-3-yl)azetidin-3-amine (15 mg, 0.06691 mmol) synthesized in Reference Example 58-2 and 4-(trifluoromethyl)phenylacetic acid (17 mg, 0.0829 mmol).
1H NMR (DMSO-d6, 400 MHz): δ=3.56 (s, 2H), 3.77 (dd, 2H, J=5.8 Hz), 4.26 (t, 2H, J=8 Hz), 4.5-4.7 (m, 1H), 7.1-7.2 (m, 1H), 7.49 (d, 2H, J=8 Hz), 7.67 (d, 2H, J=8 Hz), 8.11 (t, 1H, J=2 Hz), 8.23 (s, 1H), 8.89 (d, 1H, J=7 Hz).
MS:404.06[M+H]+
According to a technique similar to Example 1, the title compound (white crystals, 20 mg, 75%) was obtained using 1-(5-(trifluoromethyl)pyridin-3-yl)azetidin-3-amine (15 mg, 0.0691 mmol) synthesized in Reference Example 58-2 and 2-(1H-indol-6-yl)acetic acid (15 mg, 0.0829 mmol).
1H NMR (DMSO-d6, 400 MHz): δ=3.48 (s, 2H), 3.76 (dd, 2H, J=6.8 Hz), 4.25 (t, 2H, J=8 Hz), 4.5-4.7 (m, 1H), 6.37 (t, 1H, J=2 Hz), 6.90 (dd, 1H, J=1.8 Hz), 7.13 (t, 1H, J=2 Hz), 7.2-7.3 (m, 2H), 7.44 (t, 1H, J=8 Hz), 8.10 (d, 1H, J=3 Hz), 8.23 (s, 1H), 8.72 (d, 1H, J=7 Hz), 11.0 (s, 1H).
MS:375.09[M+H]+
According to a technique similar to Example 1, the title compound (white crystals, 14 mg, 63%) was obtained using (R)-1-(5-(trifluoromethyl)pyridin-3-yl)pyrrolidin-3-amine (12 mg, 0.0529 mmol) synthesized in Reference Example 1-2 and 2-(1-methyl-1H-indol-6-yl)acetic acid (10 mg, 0.0529 mmol).
1H NMR (CDCl3, 400 MHz): δ=1.8-1.9 (m, 1H), 2.2-2.4 (m, 1H), 3.08 (dd, 1H, J=5.10 Hz), 3.2-3.4 (m, 2H), 3.64 (dd, 1H, J=6.10 Hz), 3.73 (s, 2H), 3.77 (s, 3H), 4.5-4.7 (m, 1H), 5.57 (d, 1H, J=7 Hz), 6.48 (d, 1H, J=2 Hz), 6.8-6.9 (m, 1H), 6.95 (dd, 1H, J=1.8 Hz), 7.07 (d, 1H, J=3 Hz), 7.19 (s, 1H), 7.60 (d, 1H, J=8 Hz), 8.05 (d, 1H, J=3 Hz), 8.19 (s, 1H).
MS:403.11[M+H]+
According to a technique similar to Example 1, the title compound (white crystals, 9 mg, 41%) was obtained using (R)-1-(6-(trifluoromethyl)pyridin-3-yl)pyrrolidin-3-amine (12 mg, 0.0529 mmol) synthesized in Reference Example 32-2 and 2-(1-methyl-1H-indol-6-yl)acetic acid (10 mg, 0.0529 mmol).
1H NMR (CDCl3, 400 MHz): δ=1.8-1.9 (m, 1H), 2.2-2.4 (m, 1H), 3.09 (dd, 1H, J=5.10 Hz), 3.2-3.4 (m, 2H), 3.65 (dd, 1H, J=6.10 Hz), 3.73 (s, 2H), 3.76 (s, 3H), 4.5-4.7 (m, 1H), 5.56 (d, 1H, J=7 Hz), 6.48 (d, 1H, J=3 Hz), 6.75 (dd, 1H, J=3, 9 Hz), 6.94 (dd, 1H, J=1.8 Hz), 7.07 (d, 1H, J=3 Hz), 7.19 (s, 1H), 7.45 (d, 1H, J=9 Hz), 7.59 (d, 1H, J=8 Hz), 7.93 (d, 1H, J=3 Hz).
MS:403.11[M+H]+
Ethyl 2-(4-(4-methylpiperazin-1-yl)phenyl)acetate (95 mg, 0.362 mmol) was dissolved in methanol (2 mL) and water (2 mL), lithium hydroxide monohydrate (46 mg, 1.09 mmol) was added thereto, and the mixture was stirred overnight at room temperature. Water was added to the reaction liquid, the mixture was washed with ethyl acetate, 6 M hydrochloric acid (190 μL) was added to an aqueous layer, and the aqueous layer was washed again with ethyl acetate. The aqueous layer was distilled off under reduced pressure, and a crude form of 2-(4-(4-methylpiperidin-1-yl)phenyl)acetic acid (colorless oily material, 192 mg) was obtained. The crude form of 2-(4-(4-methylpiperidin-1-yl)phenyl)acetic acid (96 mg) thus obtained and (R)-1-(5-(trifluoromethyl)pyridin-3-yl)pyrrolidin-3-amine (38 mg, 0.163 mmol) synthesized in Reference Example 1-2 were dissolved in methanol (1.5 mL), subsequently DMT-MM (90 mg, 0.326 mmol) and DIPEA (166 μL, 0.978 mmol) were added thereto, and the mixture was stirred overnight at room temperature. Water was added to the reaction liquid, the mixture was stirred for a while, and then the mixture was extracted with ethyl acetate. An organic layer thus separated was dried over anhydrous sodium sulfate, insoluble materials were filtered, and then the solvent was distilled off under reduced pressure. A residue thus obtained was purified by NH silica gel column chromatography (heptane:ethyl acetate) (concentration gradient: 50 to 100%), and the title compound (white powder, 51 mg, 69%) was obtained.
1H NMR (CDCl3, 400 MHz): δ=1.8-2.0 (m, 1H), 2.2-2.4 (m, 4H), 2.58 (t, 4H, J=5 Hz), 3.11 (dd, 1H, J=5.10 Hz), 3.21 (t, 4H, J=5 Hz), 3.37 (t, 2H, J=7 Hz), 3.51 (s, 2H), 3.65 (dd, 1H, J=6.10 Hz), 4.5-4.7 (m, 1H), 5.52 (d, 1H, J=7 Hz), 6.8-7.0 (m, 3H), 7.1-7.2 (m, 2H), 8.07 (d, 1H, J=3 Hz), 8.20 (s, 1H).
MS:448.17[M+H]+
According to a technique similar to Example 33, the title compound (white powder, 122 mg, 91%) was obtained using benzyl (R)-4-(4-(2-oxo-2-((1-(5-(trifluoromethyl)pyridin-3-yl)pyrrolidin-3-yl)amino)ethyl)phenyl)piperazine-1-carboxylate (176 mg, 0.310 mmol) synthesized in Reference Example 59.
1H NMR (CDCl3, 400 MHz): δ=1.8-2.0 (m, 1H), 2.2-2.4 (m, 1H), 3.0-3.2 (m, 9H), 3.37 (t, 2H, J=7 Hz), 3.51 (s, 2H), 3.65 (dd, 1H, J=6.10 Hz), 4.5-4.7 (m, 1H), 5.51 (d, 1H, J=7 Hz), 6.8-7.0 (m, 3H), 7.1-7.2 (m, 2H), 8.08 (d, 1H, J=3 Hz), 8.20 (s, 1H). The 1H content is not observable.
MS:434.15[M+Na]+
(R)-2-(4-(piperazin-1-yl)phenyl)-N-(1-(5-(trifluoromethyl)pyridin-3-yl)pyrrolidin-3-yl)acetamide (45 mg, 0.104 mmol) synthesized in Example 94 and triethylamine (36 μL, 0.104 mmol) were dissolved in chloroform (2 mL), subsequently acetic anhydride (12 μL, 0.125 mmol) was added thereto under ice cooling, and the mixture was stirred at room temperature. After 18 hours, the solvent was distilled off under reduced pressure, a residue thus obtained was purified by NH silica gel column chromatography (heptane:ethyl acetate) (concentration gradient: 90 to 100%), and the title compound (white powder, 43 mg, 86%) was obtained.
1H NMR (CDCl3, 400 MHz): δ=1.8-2.0 (m, 1H), 2.15 (s, 3H), 2.2-2.4 (m, 1H), 3.0-3.2 (m, 5H), 3.38 (t, 2H, J=7 Hz), 3.51 (s, 2H), 3.6-3.7 (m, 3H), 3.77 (t, 2H, J=5 Hz), 4.5-4.7 (m, 1H), 5.52 (d, 1H, J=7 Hz), 6.8-7.0 (m, 3H), 7.1-7.2 (m, 2H), 8.08 (d, 1H, J=3 Hz), 8.20 (s, 1H).
MS:498.14[M+Na]+
According to a technique similar to Example 1, the title compound (white powder, 45 mg, 47%) was obtained using (R)-1-(5-(trifluoromethyl)pyridin-3-yl)pyrrolidin-3-amine (50 mg, 0.215 mmol) synthesized in Reference Example 1-2 and 2-(4-(2-oxopiperidin-1-yl)phenyl)acetic acid (55 mg, 0.236 mmol).
1H NMR (CDCl3, 400 MHz): δ=1.8-2.1 (m, 5H), 2.2-2.4 (m, 1H), 2.53 (t, 2H, J=6 Hz), 3.18 (dd, 1H, J=5.10 Hz), 3.3-3.7 (m, 7H), 4.5-4.7 (m, 1H), 5.88 (d, 1H, J=7 Hz), 6.8-7.0 (m, 1H), 7.2-7.3 (m, 4H), 8.08 (d, 1H, J=3 Hz), 8.20 (s, 1H).
MS:469.11[M+H]+
According to a technique similar to Example 1, the title compound (yellow powder, 57 mg, 71%) was obtained using (R)-1-(5-(trifluoromethyl)pyridin-3-yl)pyrrolidin-3-amine (44 mg, 0.189 mmol) synthesized in Reference Example 1-2 and 2-(6-chloro-1,3-benzoxazol-2-yl)acetic acid (40 mg, 0.189 mmol).
1H NMR (CDCl3, 400 MHz): δ=2.1-2.2 (m, 1H), 2.3-2.5 (m, 1H), 3.33 (dd, 1H, J=4.10 Hz), 3.4-3.6 (m, 2H), 3.73 (dd, 1H, J=6.10 Hz), 3.69 (s, 2H), 4.6-4.8 (m, 1H), 6.9-7.0 (m, 1H), 7.34 (dd, 1H, J=2.9 Hz), 7.45 (d, 1H, J=9 Hz), 7.65 (d, 1H, J=2 Hz), 7.99 (d, 1H, J=6 Hz), 8.13 (d, 1H, J=3 Hz), 8.22 (s, 1H).
MS:425.06[M+H]+
According to a technique similar to Example 1, the title compound (yellow powder, 51 mg, 76%) was obtained using (R)-1-(5-(trifluoromethyl)pyridin-3-yl)pyrrolidin-3-amine (40 mg, 0.173 mmol) synthesized in Reference Example 1-2 and sodium 2-(benzo[d]oxazol-2-yl)acetate monohydrate (41 mg, 0.190 mmol).
1H NMR (CDCl3, 400 MHz): δ=2.1-2.2 (m, 1H), 2.3-2.5 (m, 1H), 3.34 (dd, 1H, J=4.10 Hz), 3.4-3.6 (m, 2H), 3.73 (dd, 1H, J=6.10 Hz), 3.97 (s, 2H), 4.6-4.8 (m, 1H), 6.9-7.0 (m, 1H), 7.3-7.4 (m, 2H), 7.5-7.6 (m, 1H), 7.6-7.7 (m, 1H), 8.13 (d, 1H, J=3 Hz), 8.21 (s, 2H).
MS:391.10[M+H]+
According to a technique similar to Example 1, diastereomer A (upper spot in TLC (ethyl acetate), white powder, 25 mg, 42%) and diastereomer B (lower spot in TLC (ethyl acetate), white powder, 19 mg, 32%) of the title compound were obtained using (R)-1-(5-(trifluoromethyl)pyridin-3-yl)pyrrolidin-3-amine (30 mg, 0.130 mmol) synthesized in Reference Example 1-2 and trans-2-(3,5-dichlorophenyl)cyclopropane-1-carboxylic acid (33 mg, 0.143 mmol).
Diastereomer A
1H NMR (CDCl3, 400 MHz): δ=1.2-1.3 (m, 1H), 1.5-1.7 (m, 2H), 2.0-2.2 (m, 1H), 2.3-2.6 (m, 2H), 3.28 (dd, 1H, J=4.10 Hz), 3.4-3.6 (m, 2H), 3.69 (dd, 1H, J=6.10 Hz), 4.6-4.8 (m, 1H), 5.87 (d, 1H, J=7 Hz), 6.9-7.0 (m, 3H), 7.19 (t, 1H, J=2 Hz), 8.13 (d, 1H, J=3 Hz), 8.22 (s, 1H).
MS:444.02[M+H]+
Diastereomer B
1H NMR (CDCl3, 400 MHz): δ=1.2-1.3 (m, 1H), 1.5-1.7 (m, 2H), 2.0-2.2 (m, 1H), 2.3-2.5 (m, 2H), 3.27 (dd, 1H, J=4.10 Hz), 3.4-3.6 (m, 2H), 3.68 (dd, 1H, J=6.10 Hz), 4.6-4.8 (m, 1H), 5.88 (d, 1H, J=7 Hz), 6.9-7.0 (m, 3H), 7.18 (t, 1H, J=2 Hz), 8.12 (d, 1H, J=3 Hz), 8.21 (s, 1H).
MS:444.01[M+H]+
According to a technique similar to Example 1, diastereomer A (upper spot in TLC (ethyl acetate), white powder, 26 mg, 43%) and diastereomer B (lower spot in TLC (ethyl acetate), white powder, 23 mg, 39%) of the title compound were obtained using (R)-1-(5-(trifluoromethyl)pyridin-3-yl)pyrrolidin-3-amine (30 mg, 0.130 mmol) synthesized in Reference Example 1-2 and trans-2-(4-bromophenyl)cyclopropane-1-carboxylic acid (34 mg, 0.143 mmol).
Diastereomer A
1H NMR (CDCl3, 400 MHz): δ=1.2-1.3 (m, 1H), 1.5-1.7 (m, 2H), 2.0-2.2 (m, 1H), 2.3-2.6 (m, 2H), 3.27 (dd, 1H, J=5.10 Hz), 3.4-3.6 (m, 2H), 3.69 (dd, 1H, J=6.10 Hz), 4.6-4.8 (m, 1H), 5.80 (d, 1H, J=7 Hz), 6.9-7.0 (m, 3H), 7.3-7.5 (m, 2H), 8.13 (d, 1H, J=3 Hz), 8.22 (s, 1H).
MS:454.00 [M+H]+
Diastereomer B
1H NMR (CDCl3, 400 MHz): δ=1.2-1.3 (m, 1H), 1.5-1.7 (m, 2H), 2.0-2.2 (m, 1H), 2.3-2.6 (m, 2H), 3.26 (dd, 1H, J=4.10 Hz), 3.4-3.6 (m, 2H), 3.68 (dd, 1H, J=6.10 Hz), 4.6-4.8 (m, 1H), 5.84 (d, 1H, J=7 Hz), 6.9-7.0 (m, 3H), 7.3-7.4 (m, 2H), 8.12 (d, 1H, J=3 Hz), 8.21 (s, 1H).
MS:454.01 [M+H]+
Ethyl 2-(4-(1,4-dioxa-8-azaspiro[4.5]decan-8-yl)phenyl)acetate (16 mg, 0.0524 mmol) synthesized in Reference Example 60 was dissolved in methanol (1 mL) and water (1 mL), lithium hydroxide monohydrate (7 mg, 0.176 mmol) was added thereto, and the mixture was stirred overnight at room temperature. Water was added to the reaction liquid, the mixture was washed with ethyl acetate, 2 M hydrochloric acid (88 μL) was added to an aqueous layer to neutralize the aqueous layer, and the aqueous layer was extracted with a mixed liquid of chloroform and methanol. An organic layer thus separated was dried over anhydrous sodium sulfate, insoluble materials were filtered, subsequently the solvent was distilled off under reduced pressure, and a crude form of 2-(4-(1,4-dioxa-8-azaspiro[4.5]decan-8-yl)phenyl)acetic acid (white powder, 28 mg) was obtained. According to a technique similar to Example 1, the title compound (white powder, 18 mg, 70%) was obtained using the crude form of 2-(4-(1,4-dioxa-8-azaspiro[4.5]decan-8-yl)phenyl)acetic acid (28 mg) thus obtained and (R)-1-(5-(trifluoromethyl)pyridin-3-yl)pyrrolidin-3-amine (28 mg, 0.0524 mmol) synthesized in Reference Example 1-2.
1H NMR (CDCl3, 400 MHz): δ=1.8-2.0 (m, 5H), 2.2-2.4 (m, 1H), 3.11 (dd, 1H, J=5.10 Hz), 3.3-3.4 (m, 6H), 3.50 (s, 2H), 3.65 (dd, 1H, J=6.10 Hz), 4.00 (s, 4H), 4.5-4.7 (m, 1H), 5.50 (d, 1H, J=7 Hz), 6.8-7.0 (m, 3H), 7.0-7.2 (m, 2H), 8.08 (d, 1H, J=3 Hz), 8.20 (s, 1H).
MS:491.18[M+H]+
(R)-2-(4-(1,4-dioxa-8-azaspiro[4.5]decan-8-yl)phenyl)-N-(1-(5-(trifluoromethyl)pyridin-3-yl)pyrrolidin-3-yl)acetamide (17 mg, 0.032 mmol) synthesized in Example 101 was dissolved in ethanol (1.0 mL), 2 N hydrochloric acid (1.0 mL) was added thereto, and the mixture was heated to reflux overnight in a nitrogen atmosphere. To the reaction liquid that had been left to cool to room temperature, a saturated aqueous solution of sodium hydrogen carbonate was added to neutralize the reaction liquid, and then the mixture was extracted with ethyl acetate. An organic layer thus separated was dried over anhydrous sodium sulfate, insoluble materials were filtered, and then the solvent was distilled off under reduced pressure. A residue thus obtained was purified by silica gel column chromatography (ethyl acetate:methanol) (concentration gradient: 0 to 5%), and the title compound (white powder, 2 mg, 14%) was obtained.
1H NMR (CDCl3, 400 MHz): δ=1.8-2.0 (m, 1H), 2.3-2.4 (m, 1H), 2.56 (t, 4H, 6 Hz), 3.14 (dd, 1H, J=5.10 Hz), 3.3-3.5 (m, 2H), 3.52 (s, 2H), 3.60 (t, 4H, J=6 Hz), 3.66 (dd, 1H, J=6.10 Hz), 4.5-4.7 (m, 1H), 5.52 (d, 1H, J=6 Hz), 6.8-7.0 (m, 3H), 7.16 (d, 2H, J=9 Hz), 8.09 (d, 1H, J=3 Hz), 8.21 (s, 1H).
MS:469.13[M+Na]+
(3-Amino-1-(5-(trifluoromethyl)pyridin-3-yl)pyrrolidin-3-yl)methanol (51 mg, 0.195 mmol) synthesized in Reference Example 61-2 and 2-(4-cyclopropylphenyl)acetic acid (34 mg, 0.195 mmol) synthesized in Reference Example 33-2 were dissolved in ethanol (3 mL), subsequently DMT-MM (81 mg, 0.293 mmol) was added thereto, and the mixture was stirred overnight at room temperature. Water was added to the reaction liquid, the mixture was stirred for a while, and then the mixture was extracted with ethyl acetate. An organic layer thus separated was dried over anhydrous sodium sulfate, insoluble materials were filtered, and then the solvent was distilled off under reduced pressure. A residue thus obtained was purified by silica gel column chromatography (ethyl acetate:methanol) (concentration gradient: 0 to 5%), and the title compound (white powder, 50 mg, 61%) was obtained.
1H NMR (CDCl3, 400 MHz): δ=0.6-0.7 (m, 2H), 0.9-1.0 (m, 2H), 1.8-1.9 (m, 1H), 2.1-2.3 (m, 2H), 3.2-3.5 (m, 3H), 3.54 (s, 2H), 3.59 (d, 1H, J=11 Hz), 3.82 (d, 2H, J=6 Hz), 4.03 (t, 1H, J=6 Hz), 5.62 (s, 1H), 6.8-7.1 (m, 5H), 8.06 (d, 1H, J=3 Hz), 8.22 (s, 1H).
MS:420.14[M+H]+
According to a technique similar to Example 95, the title compound (colorless oily material, 10 mg, 91%) was obtained using 2-(4-cyclopropylphenyl)-N-(3-(hydroxymethyl)-1-(5-(trifluoromethyl)pyridin-3-yl)pyrrolidin-3-yl)acetamide (10 mg, 0.0238 mmol) synthesized in Example 103.
1H NMR (CDCl3, 400 MHz): δ=0.6-0.7 (m, 2H), 0.9-1.0 (m, 2H), 1.8-1.9 (m, 1H), 2.02 (s, 3H), 2.1-2.4 (m, 2H), 3.3-3.5 (m, 2H), 3.51 (s, 2H), 3.55 (d, 1H, J=11 Hz), 3.63 (d, 1H, J=11 Hz), 4.35 (dd, 2H, J=12.16 Hz), 5.49 (s, 1H), 6.8-7.2 (m, 5H), 8.08 (d, 1H, J=2 Hz), 8.22 (s, 1H).
MS:484.14[M+Na]+
2-(4-Cyclopropylphenyl)-N-(3-(hydroxymethyl)-1-(5-(trifluoromethyl)pyridin-3-yl)pyrrolidin-3-yl)acetamide (37 mg, 0.0882 mmol) synthesized in Example 103 was dissolved in THF (1 mL), subsequently 60% sodium hydride (4 mg, 0.0926 mmol) and iodomethane (6 μL, 0.0926 mmol) were added thereto under ice cooling, and the mixture was stirred overnight at room temperature. A saturated aqueous solution of sodium hydrogen carbonate was added to the reaction liquid, the mixture was stirred for a while, and then the mixture was extracted with ethyl acetate. An organic layer thus separated was dried over anhydrous sodium sulfate, insoluble materials were filtered, and then the solvent was distilled off under reduced pressure. A residue thus obtained was purified by silica gel column chromatography (heptane:ethyl acetate) (concentration gradient: 60 to 80%), and the title compound (white powder, 16 mg, 42%) was obtained.
1H NMR (CDCl3, 400 MHz): δ=0.6-0.7 (m, 2H), 0.9-1.0 (m, 2H), 1.8-1.9 (m, 1H), 2.1-2.5 (m, 2H), 3.33 (s, 3H), 3.39 (t, 2H, J=7 Hz), 3.4-3.7 (m, 6H), 5.58 (s, 1H), 6.8-7.0 (m, 1H), 7.03 (d, 2H, J=8 Hz), 7.11 (d, 2H, J=8 Hz), 8.08 (d, 1H, J=3 Hz), 8.20 (s, 1H).
MS:434.15[M+Na]+
According to a technique similar to Example 1, diastereomer A (upper spot in TLC (ethyl acetate), white powder, 37 mg, 33%) and diastereomer B (lower spot in TLC (ethyl acetate), white powder, 35 mg, 31%) of the title compound were obtained using (R)-1-(5-(trifluoromethyl)pyridin-3-yl)pyrrolidin-3-amine (62 mg, 0.218 mmol) synthesized in Reference Example 1-2 and trans-2-(4-cyclopropylphenyl)cyclopropane-1-carboxylic acid (59 mg, 0.294 mmol).
Diastereomer A
1H NMR (CDCl3, 400 MHz): δ=0.6-0.7 (m, 2H), 0.9-1.0 (m, 2H), 1.2-1.3 (m, 1H), 1.5-1.7 (m, 2H), 1.8-1.9 (m, 1H), 2.0-2.1 (m, 1H), 2.3-2.5 (m, 2H), 3.26 (dd, 1H, J=4.10 Hz), 3.3-3.6 (m, 2H), 3.68 (dd, 1H, J=6.10 Hz), 4.6-4.8 (m, 1H), 5.78 (d, 1H, J=7 Hz), 6.9-7.0 (m, 5H), 8.13 (d, 1H, J=3 Hz), 8.21 (s, 1H).
MS:416.14[M+H]+
Diastereomer B
0.218 mmol) synthesized in Reference Example 1-2 and trans-2-(3,4-difluorophenyl)cyclopropane-1-carboxylic acid (58 mg, 0.294 mmol).
Diastereomer A
1H NMR (CDCl3, 400 MHz): δ=1.1-1.3 (m, 1H), 1.5-1.7 (m, 2H), 2.0-2.2 (m, 1H), 2.3-2.6 (m, 2H), 3.27 (dd, 1H, J=4.10 Hz), 3.4-3.6 (m, 2H), 3.69 (dd, 1H, J=6.10 Hz), 4.6-4.8 (m, 1H), 5.90 (d, 1H, J=7 Hz), 6.8-7.1 (m, 4H), 8.12 (d, 1H, J=3 Hz), 8.21 (s, 1H).
MS:412.10 [M+H]+
Diastereomer B
1H NMR (CDCl3, 400 MHz): δ=1.1-1.3 (m, 1H), 1.5-1.7 (m, 2H), 2.0-2.2 (m, 1H), 2.3-2.6 (m, 2H), 3.27 (dd, 1H, J=4.10 Hz), 3.4-3.6 (m, 2H), 3.68 (dd, 1H, J=6.10 Hz), 4.6-4.8 (m, 1H), 5.87 (d, 1H, J=7 Hz), 6.7-7.1 (m, 4H), 8.12 (d, 1H, J=2 Hz), 8.21 (s, 1H).
MS:412.10 [M+H]+
According to a technique similar to Example 1, diastereomer A (upper spot in TLC (ethyl acetate), white powder, 39 mg, 35%) and diastereomer B (lower spot in TLC (ethyl acetate), white powder, 33 mg, 30%) of the title compound were obtained using (R)-1-(5-(trifluoromethyl)pyridin-3-yl)pyrrolidin-3-amine (62 mg, 0.218 mmol) synthesized in Reference Example 1-2 and trans-2-(4-chlorophenyl)cyclopropane-1-carboxylic acid (58 mg, 0.294 mmol).
Diastereomer A
1H NMR (CDCl3, 400 MHz): δ=1.2-1.3 (m, 1H), 1.5-1.7 (m, 2H), 2.0-2.1 (m, 1H), 2.3-2.6 (m, 2H), 3.27 (dd, 1H, J=4.10 Hz), 3.3-3.6 (m, 2H), 3.68 (dd, 1H, J=6.10 Hz), 4.6-4.8 (m, 1H), 5.90 (d, 1H, J=7 Hz), 6.9-7.1 (m, 3H), 7.2-7.3 (m, 2H), 8.12 (d, 1H, J=3 Hz), 8.21 (s, 1H).
MS:410.07[M+H]+
Diastereomer B
1H NMR (CDCl3, 400 MHz): δ=1.2-1.3 (m, 1H), 1.5-1.7 (m, 2H), 2.0-2.2 (m, 1H), 2.3-2.6 (m, 2H), 3.26 (dd, 1H, J=4.10 Hz), 3.3-3.6 (m, 2H), 3.68 (dd, 1H, J=6.10 Hz), 4.6-4.8 (m, 1H), 5.87 (d, 1H, J=7 Hz), 6.9-7.1 (m, 3H), 7.2-7.3 (m, 2H), 8.11 (d, 1H, J=3 Hz), 8.21 (s, 1H).
MS:410.07[M+H]+
According to a technique similar to Example 9, the title compound (pale yellow crystals, 62 mg, 39%) was obtained using 2-(4-isopropylphenyl)-N-(piperidin-4-yl)acetamide (100 mg, 0.384 mmol) synthesized in Reference Example 62 and 3-bromo-5-(trifluoromethyl)pyridine (104 mg, 0.461 mmol).
1H NMR (CDCl3, 400 MHz): δ=1.1-1.5 (m, 8H), 2.02 (d, 2H, J=11 Hz), 2.8-3.1 (m, 3H), 3.5-3.7 (m, 4H), 3.9-4.1 (m, 1H), 5.32 (d, 1H, J=6 Hz), 7.1-7.3 (m, 5H), 8.29 (s, 1H), 8.41 (s, 1H).
MS:404.25[M−H]−
According to a technique similar to Example 9, the title compound (pale yellow crystals, 292 mg, 57%) was obtained using (R)-2-(4-isopropylphenyl)-N-(pyrrolidin-3-yl)acetamide (296 mg, 1.20 mmol) synthesized in Reference Example 63 and 5-bromo-2-methoxy-3-(trifluoromethyl)pyridine (369 mg, 1.44 mmol).
1H NMR (CDCl3, 400 MHz): δ=1.23 (d, 6H, J=7 Hz), 1.8-1.9 (m, 1H), 2.2-2.4 (m, 1H), 2.8-3.0 (m, 1H), 3.06 (dd, 1H, J=5.10 Hz), 3.2-3.4 (m, 2H), 3.5-3.6 (m, 3H), 3.95 (s, 3H), 4.5-4.7 (m, 1H), 5.53 (d, 1H, J=7 Hz), 7.09 (d, 1H, J=3 Hz), 7.16 (d, 2H, J=8 Hz), 7.20 (d, 2H, J=8 Hz), 7.59 (d, 1H, J=3 Hz).
MS:420.26[M−H]−
According to a technique similar to Example 27, the title compound (white crystals, 125 mg, 82%) was obtained using (R)-2-(4-isopropylphenyl)-N-(pyrrolidin-3-yl)acetamide (95 mg, 0.386 mmol) synthesized in Reference Example 63 and 2-chloro-5-(trifluoromethyl)pyrimidine (77 mg, 0.424 mmol).
1H NMR (CDCl3, 400 MHz): δ=1.23 (d, 6H, J=7 Hz), 1.8-2.0 (m, 1H), 2.2-2.4 (m, 1H), 2.8-3.0 (m, 1H), 3.36 (dd, 1H, J=5.12 Hz), 3.55 (s, 2H), 3.63 (t, 2H, J=7 Hz), 3.88 (dd, 1H, J=6.12 Hz), 4.5-4.7 (m, 1H), 5.50 (d, 1H, J=6 Hz), 7.15 (d, 2H, J=8 Hz), 7.19 (d, 2H, J=8 Hz), 8.48 (s, 2H).
MS:391.23[M−H]−
According to a technique similar to Example 9, the title compound (pale yellow crystals, 77 mg, 47%) was obtained using (R)-2-(4-isopropylphenyl)-N-(pyrrolidin-3-yl)acetamide (100 mg, 0.406 mmol) synthesized in Reference Example 63 and 2-bromo-4-(trifluoromethyl)thiazole (113 mg, 0.487 mmol).
1H NMR (CDCl3, 400 MHz): δ=1.24 (d, 6H, J=7 Hz), 1.8-2.0 (m, 1H), 2.2-2.4 (m, 1H), 2.8-3.0 (m, 1H), 3.24 (dd, 1H, J=5.11 Hz), 3.4-3.6 (m, 4H), 3.75 (dd, 1H, J=6.11 Hz), 4.5-4.7 (m, 1H), 5.52 (d, 1H, J=6 Hz), 6.92 (s, 1H), 7.14 (d, 2H, J=8 Hz), 7.21 (d, 2H, J=8 Hz).
MS:396.19[M−H]−
According to a technique similar to Example 9, the title compound (white crystals, 93 mg, 58%) was obtained using (R)-2-(4-isopropylphenyl)-N-(pyrrolidin-3-yl)acetamide (100 mg, 0.406 mmol) synthesized in Reference Example 63 and 5-bromo-2-(trifluoromethyl)pyridine (110 mg, 0.487 mmol).
1H NMR (CDCl3, 400 MHz): δ=1.23 (d, 6H, J=7 Hz), 1.8-2.0 (m, 1H), 2.2-2.4 (m, 1H), 2.8-3.0 (m, 1H), 3.13 (dd, 1H, J=5.10 Hz), 3.38 (t, 2H, J=7 Hz), 3.55 (s, 2H), 3.66 (dd, 1H, J=6.10 Hz), 4.5-4.7 (m, 1H), 5.57 (d, 1H, J=6 Hz), 6.78 (dd, 1H, J=2.9 Hz), 7.16 (d, 2H, J=8 Hz), 7.20 (d, 2H, J=8 Hz), 7.46 (d, 1H, J=9 Hz), 7.95 (d, 1H, J=2 Hz).
MS:390.23[M−H]−
According to a technique similar to Example 1, the title compound (white crystals, 144 mg, 86%) was obtained using (S)-1-(5-(trifluoromethyl)pyridin-3-yl)pyrrolidin-3-amine (99 mg, 0.428 mmol) synthesized in Reference Example 64-2 and 2-(4-isopropylphenyl)acetic acid (92 mg, 0.514 mmol).
1H NMR (CDCl3, 400 MHz): δ=1.23 (d, 6H, J=7 Hz), 1.8-2.0 (m, 1H), 2.2-2.4 (m, 1H), 2.8-3.0 (m, 1H), 3.12 (dd, 1H, J=5.10 Hz), 3.36 (t, 2H, J=7 Hz), 3.55 (s, 2H), 3.65 (dd, 1H, J=6.10 Hz), 4.5-4.7 (m, 1H), 5.61 (d, 1H, J=6 Hz), 6.89 (s, 1H), 7.16 (d, 2H, J=8 Hz), 7.20 (d, 2H, J=8 Hz), 8.06 (d, 1H, J=3 Hz), 8.19 (s, 1H).
MS:390.19[M−H]−
According to a technique similar to Example 1, the title compound (white crystals, 9 mg, 46%) was obtained using (R)-1-(5-(trifluoromethyl)pyridin-3-yl)pyrrolidin-3-amine (10 mg, 0.0432 mmol) synthesized in Reference Example 1-2 and 2-(4-(trifluoromethoxy)phenyl)acetic acid (11 mg, 0.0519 mmol).
1H NMR (CDCl3, 400 MHz): δ=1.9-2.1 (m, 1H), 2.3-2.4 (m, 1H), 3.18 (dd, 1H, J=4.10 Hz), 3.3-3.5 (m, 2H), 3.57 (s, 2H), 3.67 (dd, 1H, J=7.10 Hz), 4.6-4.7 (m, 1H), 5.65 (d, 1H, J=5 Hz), 6.91 (s, 1H), 7.1-7.4 (m, 4H), 8.09 (s, 1H), 8.21 (s, 1H).
MS:432.14[M−H]−
According to a technique similar to Example 1, the title compound (white crystals, 21 mg, 99%) was obtained using (R)-1-(5-(trifluoromethyl)pyridin-3-yl)pyrrolidin-3-amine (10 mg, 0.0432 mmol) synthesized in Reference Example 1-2 and 2-(4-(2,2,2-trifluoroethoxy)phenyl)acetic acid (12 mg, 0.0519 mmol).
1H NMR (CDCl3, 400 MHz): δ=1.8-2.0 (m, 1H), 2.2-2.4 (m, 1H), 3.14 (dd, 1H, J=5.10 Hz), 3.3-3.5 (m, 2H), 3.54 (s, 2H), 3.65 (dd, 1H, J=6.10 Hz), 4.34 (q, 2H, J=8 Hz), 4.5-4.7 (m, 1H), 5.59 (d, 1H, J=6 Hz), 6.8-7.0 (m, 3H), 7.21 (d, 2H, J=9 Hz), 8.07 (d, 1H, J=2 Hz), 8.20 (s, 1H).
MS:446.14[M−H]−
According to a technique similar to Example 36, a crude form of N-(azetidin-3-yl)-2-(4-isopropylphenyl)acetamide (600 mg) was synthesized from tert-butyl 3-(2-(4-isopropylphenyl)acetamido)azetidine-1-carboxylate (964 mg, 2.90 mmol) synthesized in Reference Example 65, and the title compound (white crystals, 57 mg, 43%) was obtained using a portion of the crude form thus obtained (100 mg) and 3-bromo-5-(trifluoromethyl)pyridine (118 mg, 0.52 mmol).
1H NMR (DMSO-d6, 400 MHz): δ=1.18 (d, 6H, J=7 Hz), 2.7-2.9 (m, 1H), 3.38 (s, 2H), 3.7-3.8 (m, 2H), 4.2-4.3 (m, 2H), 4.5-4.7 (m, 1H), 7.1-7.2 (m, 5H), 8.10 (d, 1H, J=2 Hz), 8.23 (s, 1H), 8.7-8.8 (m, 1H).
MS:378.21[M+H]+
According to a technique similar to Example 36, the title compound (white crystals, 55 mg, 34%) was obtained using the crude form of N-(azetidin-3-yl)-2-(4-isopropylphenyl)acetamide (100 mg) synthesized from tert-butyl 3-(2-(4-isopropylphenyl)acetamido)azetidine-1-carboxylate in Example 117, and 5-bromo-2-(trifluoromethyl)pyridine (118 mg, 0.52 mmol).
1H NMR (DMSO-d6,400 MHz): δ=1.17 (d, 6H, J=7 Hz), 2.7-2.9 (m, 1H), 3.38 (s, 2H), 3.7-3.9 (m, 2H), 4.2-4.3 (m, 2H), 4.5-4.7 (m, 1H), 6.95 (dd, 1H, J=3.8 Hz), 7.17 (s, 4H), 7.61 (d, 1H, J=8 Hz), 7.93 (d, 1H, J=3 Hz), 8.7-8.8 (m, 1H).
MS:378.21[M+H]+
According to a technique similar to Example 1, the title compound (white crystals, 83 mg, 76%) was obtained using (R)-1-(5-(trifluoromethyl)pyridin-3-yl)pyrrolidin-3-amine (60 mg, 0.26 mmol) synthesized in Reference Example 1-2 and 2-(3,5-dichlorophenyl)acetic acid (64 mg, 0.31 mmol).
1H NMR (DMSO-d6,400 MHz): δ=1.8-2.0 (m, 1H), 2.1-2.3 (m, 1H), 3.1-3.7 (m, 4H), 3.46 (s, 2H), 4.3-4.5 (m, 1H), 7.11 (s, 1H), 7.30 (d, 2H, J=2 Hz), 7.47 (t, 1H, J=2 Hz), 8.14 (s, 1H), 8.20 (d, 1H, J=2 Hz), 8.4-8.5 (m, 1H).
MS:416.13[M−H]−
According to a technique similar to Example 1, the title compound (white crystals, 70 mg, 67%) was obtained using (R)-1-(5-(trifluoromethyl)pyridin-3-yl)pyrrolidin-3-amine (60 mg, 0.26 mmol) synthesized in Reference Example 1-2 and 2-(3-chloro-5-fluorophenyl)acetic acid (58 mg, 0.31 mmol).
1H NMR (DMSO-d6,400 MHz): δ=1.8-2.0 (m, 1H), 2.1-2.3 (m, 1H), 3.1-3.2 (m, 1H), 3.2-3.6 (m, 3H), 3.45 (s, 2H), 4.3-4.5 (m, 1H), 7.0-7.1 (m, 2H), 7.17 (s, 1H), 7.28 (dt, 1H, J=3.8 Hz), 8.13 (s, 1H), 8.19 (d, 1H, J=3 Hz), 8.4-8.5 (m, 1H).
MS:400.16[M−H]−
According to a technique similar to Example 1, the title compound (white crystals, 89 mg, 100%) was obtained using (R)-l-(6-(trifluoromethyl)pyridin-3-yl)pyrrolidin-3-amine (60 mg, 0.18 mmol) synthesized in Reference Example 32-2 and 2-(4-cyclopropylphenyl)acetic acid (51 mg, 0.29 mmol) synthesized in Reference Example 33-2.
1H NMR (CDCl3, 400 MHz): δ=0.6-0.7 (m, 2H), 0.9-1.0 (m, 2H), 1.8-2.0 (m, 2H), 2.2-2.4 (m, 1H), 3.0-3.2 (m, 1H), 3.3-3.4 (m, 2H), 3.53 (s, 2H), 3.6-3.7 (m, 1H), 4.5-4.7 (m, 1H), 5.5-5.7 (m, 1H), 6.77 (dd, 1H, J=3.8 Hz), 7.03 (d, 2H, J=8 Hz), 7.11 (d, 2H, J=8 Hz), 7.46 (d, 1H, J=8 Hz), 7.94 (d, 1H, J=3 Hz).
MS:388.22[M−H]−
According to a technique similar to Example 9, the title compound (white crystals, 49 mg, 30%) was obtained using (R)-2-(4-isopropylphenyl)-N-(pyrrolidin-3-yl)acetamide (100 mg, 0.41 mmol) synthesized in Reference Example 63 and 2-bromo-5-(trifluoromethyl)thiophene (114 mg, 0.49 mmol).
1H NMR (CDCl3, 400 MHz): δ=1.23 (d, 6H, J=7 Hz), 1.8-2.0 (m, 1H), 2.2-2.4 (m, 1H), 2.8-3.0 (m, 1H), 3.0-3.1 (m, 1H), 3.2-3.4 (m, 2H), 3.54 (s, 2H), 3.5-3.6 (m, 1H), 4.5-4.7 (m, 1H), 5.4-5.6 (m, 1H), 5.63 (d, 1H, J=4 Hz), 7.0-7.2 (m, 1H), 7.14 (d, 2H, J=8 Hz), 7.20 (d, 2H, J=8 Hz).
MS:395.21[M−H]−
According to a technique similar to Example 1, the title compound (white crystals, 85 mg, 92%) was obtained using (R)-1-(5-(trifluoromethyl)pyridin-3-yl)pyrrolidin-3-amine (50 mg, 0.22 mmol) synthesized in Reference Example 1-2 and 2-(4-(trifluoromethyl)phenyl)acetic acid (53 mg, 0.26 mmol).
1H NMR (CDCl3, 400 MHz): δ=1.9-2.1 (m, 1H), 2.2-2.4 (m, 1H), 3.1-3.3 (m, 1H), 3.3-3.4 (m, 2H), 3.5-3.7 (m, 1H), 3.63 (s, 2H), 4.6-4.7 (m, 1H), 6.4-6.6 (m, 1H), 6.81 (s, 1H), 7.40 (d, 2H, J=8 Hz), 7.59 (d, 2H, J=8 Hz), 7.95 (d, 1H, J=2 Hz), 8.09 (s, 1H).
MS:416.19[M−H]−
According to a technique similar to Example 1, the title compound (white crystals, 89 mg, 100%) was obtained using (R)-1-(5-(trifluoromethyl)pyridin-3-yl)pyrrolidin-3-amine (50 mg, 0.22 mmol) synthesized in Reference Example 1-2 and 2-(1H-indol-6-yl)acetic acid (53 mg, 0.26 mmol).
1H NMR (CDCl3, 400 MHz): δ=0.6-0.7 (m, 2H), 0.9-1.0 (m, 2H), 1.7-2.0 (m, 2H), 2.2-2.4 (m, 1H), 2.9-3.1 (m, 1H), 3.1-3.4 (m, 2H), 3.4-3.6 (m, 1H), 3.52 (s, 2H), 4.5-4.7 (m, 1H), 4.67 (q, 2H, J=9 Hz), 5.5-5.6 (m, 1H), 6.75 (d, 1H, J=9 Hz), 6.92 (dd. 1H, J=3.9 Hz), 7.03 (d, 2H, J=8 Hz), 7.11 (d, 2H, J=8 Hz), 7.39 (d, 1H, J=3 Hz).
MS:387.22[M−H]−
According to a technique similar to Example 9, the title compound (yellow amorphous, 40 mg, 45%) was obtained using (R)-2-(4-cyclopropylphenyl)-N-(pyrrolidin-3-yl)acetamide (50 mg, 0.20 mmol) synthesized in Reference Example 74-2 and 5-bromo-2-(2,2,2-trifluoroethoxy)pyridine (61 mg, 0.24 mmol).
1H NMR (CDCl3, 400 MHz): δ=δ=0.6-0.7 (m, 2H), 0.9-1.0 (m, 2H), 1.7-2.0 (m, 2H), 2.2-2.4 (m, 1H), 2.9-3.1 (m, 1H), 3.1-3.4 (m, 2H), 3.4-3.6 (m, 1H), 3.52 (s, 2H), 4.5-4.7 (m, 1H), 4.67 (q, 2H, J=9 Hz), 5.5-5.6 (m, 1H), 6.75 (d, 1H, J=9 Hz), 6.92 (dd, 1H, J=3.9 Hz), 7.03 (d, 2H, J=8 Hz), 7.11 (d, 2H, J=8 Hz), 7.39 (d, 1H, J=3 Hz).
MS:420.16[M+H]+
According to a technique similar to Example 9, the title compound (yellow crystals, 36 mg, 40%) was obtained using (R)-2-(4-cyclopropylphenyl)-N-(pyrrolidin-3-yl)acetamide (50 mg, 0.20 mmol) synthesized in Reference Example 74-2 and 3-bromo-5-(2,2,2-trifluoroethoxy)pyridine (61 mg, 0.24 mmol).
1H NMRR (CDCl3, 400 MHz): δ=0.6-0.7 (m, 2H), 0.9-1.0 (m, 2H), 1.8-2.0 (m, 2H), 2.2-2.4 (m, 1H), 3.0-3.1 (m, 1H), 3.31 (t, 2H, J=7 Hz), 3.53 (s, 2H), 3.5-3.7 (m, 1H), 4.37 (q, 2H, J=8 Hz), 4.5-4.7 (m, 1H), 5.5-5.7 (m, 1H), 6.33 (t, 1H, J=2 Hz), 7.03 (d, 2H, J=8 Hz), 7.11 (d, 2H, J=8 Hz), 7.6-7.7 (m, 2H).
MS:420.16[M+H]+
According to a technique similar to Example 27, the title compound (yellow amorphous, 7 mg, 6%) was obtained using (R)-2-(4-cyclopropylphenyl)-N-(pyrrolidin-3-yl)acetamide (50 mg, 0.20 mmol) synthesized in Reference Example 74-2 and 2-chloro-4-(2,2,2-trifluoroethoxy)pyridine (51 mg, 0.24 mmol).
1H NMR (CDCl3, 400 MHz): δ=0.6-0.7 (m, 2H), 0.9-1.0 (m, 2H), 1.8-1.9 (m, 2H), 2.2-2.3 (m, 1H), 3.1-3.3 (m, 1H), 3.4-3.5 (m, 2H), 3.52 (s, 2H), 3.6-3.8 (m, 1H), 4.35 (q, 2H, J=8 Hz), 4.5-4.6 (m, 1H), 5.4-5.6 (m, 1H), 5.79 (d, 1H, J=2 Hz), 6.20 (dd, 1H, J=2.6 Hz), 7.03 (d, 2H, J=8 Hz), 7.10 (d, 2H, J=8 Hz), 8.02 (d, 1H, J=6 Hz).
MS:420.16[M+H]+
According to a technique similar to Example 9, the title compound (white crystals, 46 mg, 27%) was obtained using (R)-2-(4-cyclopropylphenyl)-N-(pyrrolidin-3-yl) acetamide (100 mg, 0.40 mmol) synthesized in Reference Example 74-2 and 3-bromo-2-methoxy-5-(trifluoromethyl) pyridine (123 mg, 0.48 mmol).
1H NMR (CDCl3, 400 MHz): δ=0.6-0.7 (m, 2H), 0.9-1.0 (m, 2H), 1.7-2.0 (m, 2H), 2.2-2.3 (m, 1H), 3.2-3.3 (m, 2H), 3.4-3.5 (m, 1H), 3.52 (s, 2H), 3.5-3.6 (m, 1H), 3.96 (s, 3H), 4.4-4.6 (m, 1H), 5.5-5.6 (m, 1H), 6.81 (d, 1H, J=2 Hz), 7.03 (d, 2H, J=8 Hz), 7.11 (d, 2H, J=8 Hz), 7.86 (d, 1H, J=2 Hz).
MS:420.16 [M+H]+
According to a technique similar to Example 3, a crude form of (R)-1-(5-(trifluoromethyl)pyridin-3-yl)piperidin-3-amine (70 mg) was synthesized from tert-butyl (R)-(1-(5-(trifluoromethyl)pyridin-3-yl)piperidin-3-yl)carbamate (100 mg, 0.29 mmol) synthesized in Reference Example 66, and the title compound (white crystals, 80 mg, 58%) was obtained using the crude form of (R)-1-(5-(trifluoromethyl)pyridin-3-yl)piperidin-3-amine thus obtained (70 mg) and 2-(4-cyclopropylphenyl)acetic acid (78 mg, 0.44 mmol) synthesized in Reference Example 33-2.
1H NMR (DMSO-d6, 400 MHz): δ=0.5-0.7 (m, 2H), 0.8-1.0 (m, 2H), 1.4-1.6 (m, 2H), 1.7-2.0 (m, 3H), 2.7-2.9 (m, 1H), 2.9-3.1 (m, 1H), 3.2-3.5 (m, 2H), 3.6-3.8 (m, 3H), 6.97 (d, 2H, J=8 Hz), 7.12 (d, 2H, J=8 Hz), 7.52 (s, 1H), 8.0-8.2 (m, 1H), 8.24 (s, 1H), 8.54 (d, 1H, J=3 Hz).
MS:404.17[M+H]+
According to a technique similar to Example 3, a crude form of (R)-1-(6-(trifluoromethyl)pyridin-3-yl)piperidin-3-amine (280 mg) was synthesized from tert-butyl (R)-(1-(6-(trifluoromethyl)pyridin-3-yl)piperidin-3-yl)carbamate (400 mg, 1.16 mmol) synthesized in Reference Example 72, and the title compound (pale yellow crystals, 65 mg, 54%) was obtained using a portion of the crude form of (R)-1-(6-(trifluoromethyl)pyridin-3-yl)piperidin-3-amine (70 mg) thus obtained and 2-(4-cyclopropylphenyl)acetic acid (78 mg, 0.44 mmol) synthesized in Reference Example 33-2.
1H NMR (DMSO-d6, 400 MHz): δ=0.5-0.7 (m, 2H), 0.8-1.0 (m, 2H), 1.4-1.6 (m, 2H), 1.7-1.9 (m, 3H), 2.8-3.0 (m, 1H), 3.0-3.1 (m, 1H), 3.2-3.5 (m, 2H), 3.6-3.8 (m, 3H), 6.97 (d, 2H, J=8 Hz), 7.11 (d, 2H, J=8 Hz), 7.37 (dd, 1H, J=3, 7 Hz), 7.58 (d, 1H, J=8 Hz), 8.0-8.2 (m, 1H), 8.37 (d, 1H, J=3 Hz).
MS:404.17[M+H]+
(R)-1-(5-(trifluoromethyl)pyridin-3-yl)pyrrolidin-3-amine (39 mg, 0.20 mmol) synthesized in Reference Example 76-2, 2-(4-(2-hydroxypropan-2-yl)phenyl)acetic acid (27 mg, 0.24 mmol), and DMT-MM (46 mg, 0.19 mmol) were dissolved in isopropanol (0.80 mL), and then the solution was stirred overnight at room temperature. Water was added to the reaction liquid, the mixture was stirred for a while, and then the mixture was extracted with ethyl acetate. An organic layer thus separated was dried over anhydrous sodium sulfate, insoluble materials were filtered, and then the solvent was distilled off under reduced pressure. A residue thus obtained was purified by silica gel column chromatography (chloroform:methanol) (concentration gradient: 0 to 40%), and the title compound (white amorphous, 57 mg, 99%) was obtained.
1H NMR (CDCl3, 400 MHz): δ=1.58 (s, 3H), 1.59 (s, 3H), 1.7-1.9 (br s, 1H), 1.9-2.0 (m, 1H), 2.3-2.4 (m, 1H), 3.1-3.2 (m, 2H), 3.3-3.5 (m, 2H), 3.58 (s, 2H), 3.6-3.7 (m, 1H), 4.6-4.7 (m, 1H), 5.5-5.6 (m, 1H), 6.92 (s, 1H), 7.26 (d, 1H, J=8 Hz), 7.47 (d, 2H, J=8 Hz), 8.0-8.1 (m, 1H), 8.21 (s, 1H).
MS:430.14[M+Na]+
According to a technique similar to Example 1, the title compound (white crystals, 14 mg, 62%) was obtained using (R)-1-(5-(trifluoromethyl)pyridin-3-yl)pyrrolidin-3-amine (10 mg, 0.048 mmol) synthesized in Reference Example 1-2 and 2-(4-(3-methylpyrazin-2-yl)phenyl)acetic acid (10 mg, 0.044 mmol).
1H NMR (CDCl3, 400 MHz): δ=1.9-2.1 (m, 1H), 2.3-2.4 (m, 1H), 2.63 (s, 3H), 3.1-3.2 (m, 1H), 3.3-3.5 (m, 2H), 3.6-3.7 (m, 1H), 3.66 (s, 2H), 4.6-4.7 (m, 1H), 5.7-5.9 (m, 1H), 6.90 (s, 1H), 7.39 (d, 2H, J=8H), 7.59 (d, 2H, J=8 Hz), 8.07 (d, 1H, J=3 Hz), 8.19 (s, 1H), 8.46 (d, 1H, J=2 Hz), 8.48 (d, 1H, J=2 Hz).
MS:442.15[M+H]+
According to a technique similar to Example 1, the title compound (white crystals, 8.6 mg, 100%) was obtained using (R)-1-(5-(trifluoromethyl)pyridin-3-yl)pyrrolidin-3-amine (6 mg, 0.024 mmol) synthesized in Reference Example 1-2 and 2-(4-(4-methyloxazol-5-yl)phenyl)acetic acid (4 mg, 0.020 mmol).
1H NMR (CDCl3, 400 MHz): δ=1.9-2.0 (m, 1H), 2.3-2.4 (m, 1H), 2.44 (s, 3H), 3.1-3.2 (m, 1H), 3.3-3.5 (m, 2H), 3.61 (s, 2H), 3.6-3.7 (m, 1H), 4.6-4.7 (m, 1H), 5.4-5.6 (m, 1H), 6.91 (s, 1H), 7.34 (d, 2H, J=8 Hz) 7.59 (d, 2H, J=8 Hz), 7.83 (s, 1H), 8.08 (s, 1H), 8.20 (s, 1H).
MS:429.17[M−H]−
(R)-2-(4-cyclopropylphenyl)-N-(1-(5-(trifluoromethyl)pyridin-3-yl)pyrrolidin-3-yl)acetamide (85 mg, 0.22 mmol) synthesized in Example 1 was dissolved in dichloromethane (3.0 mL), m-CPBA (purity 65%, 58 mg, 0.22 mmol) was added thereto, and the mixture was stirred overnight at room temperature. The reaction liquid was washed with a saturated aqueous solution of sodium hydrogen carbonate, an organic layer thus separated was dried over anhydrous sodium sulfate, insoluble materials were filtered, and then the solvent was distilled off under reduced pressure. A residue thus obtained was purified by silica gel column chromatography (chloroform:methanol) (concentration gradient: 0 to 20%), and (R)-3-(3-(2-(4-cyclopropylphenyl)acetamido)pyrrolidin-1-yl)-5-(trifluoromethyl)pyridine 1-oxide (Rf value in TLC (dichloromethane:methanol=10:1)=0.4, pale yellow amorphous, 12 mg, 13%) and (3R)-3-(2-(4-cyclopropylphenyl)acetamido)-1-(5-(trifluoromethyl)pyridin-3-yl)pyrrolidine 1-oxide (Rf value in TLC (dichloromethane:methanol=10:1)=0.2, white amorphous, 42 mg, 47%) were obtained.
1H NMR (CDCl3, 400 MHz): δ=0.6-0.7 (m, 2H), 0.9-1.0 (m, 2H), 1.8-2.0 (m, 2H), 2.2-2.4 (m, 1H), 3.0-3.1 (m, 1H), 3.31 (t, 2H, J=7 Hz), 3.54 (s, 2H), 3.5-3.7 (m, 1H), 4.5-4.7 (m, 1H), 5.7-5.9 (m, 1H), 6.54 (s, 1H), 7.04 (d, 2H, J=8 Hz), 7.12 (d, 2H, J=8 Hz), 7.63 (s, 1H), 7.81 (s, 1H).
MS:406.14[M+H]+
1H NMR (CDCl3, 400 MHz): δ=0.6-0.7 (m, 2H), 0.9-1.0 (m, 2H), 1.8-1.9 (m, 1H), 2.4-2.6 (m, 1H), 2.7-2.9 (m, 1H), 3.50 (s, 2H), 3.5-3.7 (m, 1H), 3.8-4.0 (m, 2H), 4.0-4.1 (m, 1H), 5.1-5.3 (m, 1H), 7.03 (d, 2H, J=8 Hz), 7.18 (d, 2H, J=8 Hz), 7.7-7.8 (m, 1H), 8.82 (s, 1H), 8.95 (s, 1H), 9.15 (s, 1H).
MS:406.14[M+H]+
According to a technique similar to Example 1, the title compound (white amorphous, 45 mg, 94%) was obtained using (R)-1-(5-(trifluoromethyl)pyridin-3-yl)pyrrolidin-3-amine (25 mg, 0.11 mmol) synthesized in Reference Example 1-2 and 2-(4-cyclopropylphenyl)-2-methylpropanoic acid (23 mg, 0.11 mmol).
1H NMR (CDCl3, 400 MHz): δ=0.6-0.7 (m, 2H), 0.9-1.0 (m, 2H), 1.54 (s, 3H), 1.55 (s, 3H), 1.7-1.9 (m, 2H), 2.2-2.4 (m, 1H), 3.0-3.1 (m, 1H), 3.2-3.4 (m, 2H), 3.6-3.7 (m, 1H), 4.5-4.6 (m, 1H), 5.2-5.3 (m, 1H), 6.88 (s, 1H), 7.02 (d, 2H, J=8 Hz), 7.21 (d, 2H, J=8 Hz), 8.05 (s, 1H), 8.19 (s, 1H).
MS:416.21 [M−H]−
According to a technique similar to Example 9, the title compound (pale yellow amorphous, 34 mg, 49%) was obtained using (R)-2-(4-cyclopropylphenyl)-N-(pyrrolidin-3-yl) acetamide (42 mg, 0.17 mmol) synthesized in Reference Example 74-2 and 1-fluoro-3-iodo-5-(trifluoromethyl) benzene (50 mg, 0.17 mmol).
1H NMR (CDCl3, 400 MHz): δ=0.6-0.7 (m, 2H), 0.9-1.0 (m, 2H), 1.8-2.0 (m, 2H), 2.2-2.4 (m, 1H), 3.0-3.1 (m, 1H), 3.2-3.4 (m, 2H), 3.53 (s, 2H), 3.5-3.7 (m, 1H), 4.5-4.7 (m, 1H), 5.4-5.6 (m, 1H), 6.2-6.4 (m, 1H), 6.47 (s, 1H), 6.5-6.7 (m, 1H), 7.04 (d, 2H, J=8 Hz), 7.11 (d, 2H, J=8 Hz).
MS:407.15 [M+H]+
To diastereomer A of tert-butyl (1-(4-cyclopropylphenyl)-2-oxo-2-(((R)-1-(5-(trifluoromethyl)pyridin-3-yl)pyrrolidin-3-yl)amino)ethyl)carbamate (15 mg, 0.030 mmol) synthesized in Reference Example 67, trifluoroacetic acid (0.50 mL) was added under ice cooling, and the mixture was stirred for 1 hour at room temperature. The solvent of the reaction liquid was distilled off under reduced pressure, a residue thus obtained was purified by silica gel column chromatography (chloroform:methanol) (concentration gradient: 0 to 20%), and diastereomer A of 2-amino-2-(4-cyclopropylphenyl)-N—((R)-1-(5-(trifluoromethyl)pyridin-3-yl)pyrrolidin-3-yl)acetamide (pale yellow amorphous, 3.8 mg, 9%) was obtained. According to a technique similar to that described above, diastereomer B of 2-amino-2-(4-cyclopropylphenyl)-N((R)-1-(5-(trifluoromethyl)pyridin-3-yl)pyrrolidin-3-yl)acetamide (pale yellow amorphous, 3.4 mg, 8%) was obtained using diastereomer B of tert-butyl (1-(4-cyclopropylphenyl)-2-oxo-2-(((R)-1-(5-(trifluoromethyl)pyridin-3-yl)pyrrolidin-3-yl)amino)ethyl)carbamate (15 mg, 0.030 mmol) synthesized in Reference Example 67.
Diastereomer A
1H NMR (CDCl3, 400 MHz): δ=0.6-0.8 (m, 2H), 0.9-1.0 (m, 2H), 1.2-1.3 (br s, 2H), 1.8-2.0 (m, 1H), 2.0-2.1 (m, 1H), 2.3-2.5 (m, 1H), 3.1-3.3 (m, 1H), 3.3-3.6 (m, 2H), 3.6-3.7 (m, 1H), 4.49 (s, 1H), 4.5-4.7 (m, 1H), 6.94 (s, 1H) 7.01 (d, 2H, J=8 Hz), 7.21 (d, 2H, J=8 Hz), 7.4-7.5 (m, 1H), 8.11 (d, 1H, J=3 Hz), 8.22 (s, 1H).
MS:405.14[M+H]+
Diastereomer B
1H NMR (CDCl3, 400 MHz): δ=0.6-0.7 (m, 2H), 0.9-1.0 (m, 2H), 1.2-1.3 (m, 2H), 1.8-1.9 (m, 1H), 2.0-2.1 (m, 1H), 2.3-2.4 (m, 1H), 3.2-3.3 (m, 1H), 3.3-3.6 (m, 2H), 3.6-3.7 (m, 1H), 4.50 (s, 1H), 4.6-4.7 (m, 1H), 6.95 (s, 1H), 7.05 (d, 2H, J=8 Hz), 7.25 (d, 2H, J=8 Hz), 7.4-7.5 (m, 1H), 8.13 (d, 1H, J=3 Hz), 8.22 (s, 1H).
MS:405.14[M+H]+
According to a technique similar to Example 137, a crude form of 2-amino-2-(4-cyclopropylphenyl)-N—((R)-1-(5-(trifluoromethyl)pyridin-3-yl)pyrrolidin-3-yl)acetamide (200 mg) was obtained using tert-butyl (1-(4-cyclopropylphenyl)-2-oxo-2-(((R)-1-(5-(trifluoromethyl)pyridin-3-yl)amino)ethyl)carbamate (290 mg, 0.57 mmol) synthesized in Reference Example 67. A portion of the crude form of 2-amino-2-(4-cyclopropylphenyl)-N—((R)-1-(5-(trifluoromethyl)pyridin-3-yl)pyrrolidin-3-yl)acetamide (50 mg) thus obtained was dissolved in dichloromethane (1.0 mL), paraformaldehyde (11 mg, 0.36 mmol), acetic acid (14 μL, 0.24 mmol), and triacetoxyborohydride (127 mg, 0.6 mmol) were added thereto, and the mixture was stirred overnight at room temperature. The reaction liquid was diluted with ethyl acetate, an organic layer was washed with a saturated aqueous solution of sodium hydrogen carbonate, water, and saturated brine, subsequently the separated organic layer was dried over anhydrous sodium sulfate, insoluble materials were filtered, and then the solvent was distilled off under reduced pressure. A residue thus obtained was purified by silica gel column chromatography (heptane:ethyl acetate) (concentration gradient: 10 to 70%), and 2-(4-cyclopropylphenyl)-2-(dimethylamino)-N—((R)-1-(5-(trifluoromethyl)pyridin-3-yl)pyrrolidin-3-yl)acetamide was obtained. 2-(4-Cyclopropylphenyl)-2-(dimethylamino)-N—((R)-1-(5-(trifluoromethyl)pyridin-3-yl)pyrrolidin-3-yl)acetamide thus obtained was dissolved in methanol (0.5 mL), subsequently a 1 N aqueous solution of hydrochloric acid (0.5 mL) was added thereto, and the solvent was distilled off under reduced pressure. Distilled water (0.1 mL) was added to a residue thus obtained, the residue was freeze-dried, and the title compound (yellow crystals, 10 mg, 19%) was obtained.
1H NMR (DMSO-d6, 400 MHz): δ=0.6-0.8 (m, 2H), 0.9-1.1 (m, 2H), 1.7-2.3 (m, 3H), 2.50 (s, 3H), 2.87 (s, 3H), 3.0-3.8 (m, 4H), 4.3-4.5 (m, 1H), 4.8-5.0 (m, 1H), 7.12 (d, 1H, J=8 Hz), 7.18 (d, 1H, J=8 Hz), 7.2-7.4 (m, 1H), 7.4-7.5 (m, 2H), 8.1-8.3 (m, 2H), 9.3-9.6 (m, 1H), 10.3-10.5 (m, 1H).
MS:433.18[M+H]+
According to a technique similar to Example 1, the title compound (white crystals, 6 mg, 26%) was obtained using (R)-1-(5-(trifluoromethyl)pyridin-3-yl)pyrrolidin-3-amine (13 mg, 0.058 mmol) synthesized in Reference Example 1-2 and 2-(1-methyl-1H-indol-5-yl)acetic acid (10 mg, 0.053 mmol).
1H NMR (CDCl3, 400 MHz): δ=1.7-1.9 (m, 1H), 2.2-2.4 (m, 1H), 3.0-3.1 (m, 1H), 3.2-3.4 (m, 2H), 3.6-3.7 (m, 1H), 3.70 (s, 2H), 3.80 (s, 3H), 4.5-4.7 (m, 1H), 5.5-5.6 (m, 1H), 6.44 (d, 1H, J=6 Hz), 6.86 (s, 1H), 7.0-7.1 (m, 2H), 7.29 (d, 1H, J-9 Hz), 7.46 (d, 1H, J=1 Hz), 8.03 (d, 1H, J=3 Hz), 8.17 (s, 1H).
MS:403.13[M+H]+
According to a technique similar to Example 1, the title compound (white crystals, 56 mg, 89%) was obtained using (R)-1-(5-(trifluoromethyl)pyridin-3-yl)pyrrolidin-3-amine (30 mg, 0.13 mmol) synthesized in Reference Example 1-2 and 2-(2,4-bis(trifluoromethyl)phenyl)acetic acid (44 mg, 0.16 mmol).
1H NMR (CDCl3, 400 MHz): δ=2.0-2.2 (m, 1H), 2.2-2.4 (m, 1H), 3.1-3.3 (m, 1H), 3.3-3.5 (m, 2H), 3.6-3.7 (m, 1H), 3.79 (s, 2H), 4.6-4.8 (m, 1H), 6.5-6.6 (m, 1H), 6.83 (s, 1H), 7.68 (d, 1H, J=8 Hz), 7.82 (d, 1H, J=8 Hz), 7.91 (s, 1H), 8.00 (d, 1H, J=2 Hz), 8.12 (s, 1H).
MS:484.11[M−H]−
According to a technique similar to Example 1, the title compound (white crystals, 59 mg, 100%) was obtained using (R)-1-(5-(trifluoromethyl)pyridin-3-yl)pyrrolidin-3-amine (30 mg, 0.13 mmol) synthesized in Reference Example 1-2 and 2-(2-fluoro-4-(trifluoromethyl)phenyl)acetic acid (36 mg, 0.16 mmol).
1H NMR (CDCl3, 400 MHz): δ=2.0-2.1 (m, 1H), 2.2-2.4 (m, 1H), 3.1-3.3 (m, 1H), 3.3-3.5 (m, 2H), 3.6-3.7 (m, 1H), 3.64 (s, 2H), 4.6-4.8 (m, 1H), 6.6-6.8 (m, 1H), 6.82 (s, 1H), 7.33 (d, 1H, J=10 Hz), 7.41 (d, 1H, J=8 Hz), 7.49 (t, 1H, J=8 Hz), 7.99 (d, 1H, J=8 Hz), 8.12 (s, 1H).
MS:434.12[M−H]−
According to a technique similar to Example 1, the title compound (white crystals, 36 mg, 56%) was obtained using (R)-1-(5-(trifluoromethyl)pyridin-3-yl)pyrrolidin-3-amine (30 mg, 0.13 mmol) synthesized in Reference Example 1-2 and 2-(1-methyl-1H-indazol-5-yl)acetic acid (32 mg, 0.16 mmol).
1H NMR (CDCl3, 400 MHz): δ=1.8-2.0 (m, 1H), 2.2-2.4 (m, 1H), 3.0-3.2 (m, 1H), 3.35 (t, 2H, J=7 Hz), 3.6-3.7 (m, 1H), 3.69 (s, 2H), 4.08 (s, 3H), 4.6-4.7 (m, 1H), 5.5-5.6 (m, 1H), 6.87 (s, 1H), 7.2-7.3 (m, 1H), 7.38 (d, 1H, J=9 Hz), 7.59 (s, 1H), 7.94 (s, 1H), 8.04 (d, 1H, J=2 Hz), 8.18 (s, 1H).
MS:404.10[M+H]+
According to a technique similar to Example 1, the title compound (white crystals, 35 mg, 66%) was obtained using (R)-1-(4-(trifluoromethyl)thiazol-2-yl)pyrrolidin-3-amine (31 mg, 0.13 mmol) synthesized in Reference Example 12-2 and 2-(1-methyl-1H-indazol-5-yl)acetic acid (32 mg, 0.16 mmol).
1H NMR (CDCl3, 400 MHz): δ=1.8-2.0 (m, 1H), 2.2-2.4 (m, 1H), 3.1-3.3 (m, 1H), 3.4-3.6 (m, 2H), 3.68 (s, 2H), 3.7-3.8 (m, 1H), 4.09 (s, 3H), 4.5-4.7 (m, 1H), 5.4-5.6 (m, 1H), 6.91 (s, 1H), 7.2-7.3 (m, 1H), 7.38 (d, 1H, J=8 Hz), 7.58 (s, 1H), 7.95 (s, 1H).
MS:410.06[M+H]+
According to a technique similar to Example 1, the title compound (white crystals, 35 mg, 67%) was obtained using (R)-l-(6-(trifluoromethyl)pyridin-3-yl)pyrrolidin-3-amine (30 mg, 0.13 mmol) synthesized in Reference Example 32-2 and 2-(1-methyl-1H-indazol-5-yl)acetic acid (32 mg, 0.16 mmol).
1H NMR (CDCl3, 400 MHz): δ=1.8-2.0 (m, 1H), 2.2-2.4 (m, 1H), 3.0-3.2 (m, 1H), 3.36 (t, 2H, J=7 Hz), 3.6-3.7 (m, 1H), 3.69 (s, 2H), 4.08 (s, 3H), 4.5-4.7 (m, 1H), 5.4-5.6 (m, 1H), 6.76 (dd, 1H, J=3.9 Hz), 7.2-7.3 (m, 1H), 7.37 (d, 1H, J=9 Hz), 7.45 (d, 1H, J=8 Hz), 7.59 (s, 1H), 7.9-8.0 (m, 2H).
MS:404.10[M+H]+
According to a technique similar to Example 9, the title compound (yellow amorphous, 2.1 mg, 5%) was obtained using (R)-2-(4-bromophenyl)-N-(1-(5-(trifluoromethyl)pyridin-3-yl)pyrrolidin-3-yl)acetamide (40 mg, 0.093 mmol) synthesized in Example 171 and 2,2-dimethylmorpholine (21 mg, 0.19 mmol).
1H NMR (CDCl3, 400 MHz): δ=1.32 (s, 6H), 1.8-2.0 (m, 1H), 2.3-2.4 (m, 1H), 2.94 (s, 2H), 3.0-3.2 (m, 3H), 3.3-3.4 (m, 2H), 3.51 (s, 2H), 3.6-3.7 (m, 1H) 3.8-3.9 (m, 2H), 4.5-4.7 (m, 1H), 5.4-5.6 (m, 1H), 6.85 (d, 2H, J=8 Hz), 6.94 (s, 1H), 7.12 (d, 2H, J=8 Hz), 8.0-8.4 (m, 2H).
MS:463.15[M+H]+
(R)-2-(4-bromophenyl)-N-(1-(5-(trifluoromethyl)pyridin-3-yl)pyrrolidin-3-yl)acetamide (40 mg, 0.093 mmol) synthesized in Example 171, pyrazole (13 mg, 0.19 mmol), copper(I) iodide (2 mg, 9.3 μmmol), N,N′-dimethylethylenediamine (2 μL, 18.6 μmmol), and cesium carbonate (91 mg, 0.30 mmol) were suspended in DMF (1.0 mL), and the suspension was stirred for 2 hours at 200° C. (microwaved). Ethyl acetate was added to the reaction liquid that had been left to cool to room temperature, and then the organic layer was washed with water and saturated brine. An organic layer thus separated was dried over anhydrous sodium sulfate, insoluble materials were filtered, and then the solvent was distilled off under reduced pressure. A residue thus obtained was purified by silica gel column chromatography (hexane:ethyl acetate) (concentration gradient: 0 to 100%), and the title compound (white crystals, 22 mg, 57%) was obtained.
1H NMR (CDCl3, 400 MHz): δ=1.9-2.0 (m, 1H), 2.3-2.4 (m, 1H), 3.1-3.2 (m, 1H), 3.3-3.5 (m, 2H), 3.62 (s, 2H), 3.6-3.7 (m, 1H), 4.6-4.7 (m, 1H), 5.5-5.6 (m, 1H), 6.4-6.5 (m, 1H), 6.9-7.0 (m, 1H), 7.35 (d, 2H, J=9 Hz), 7.69 (d, 2H, J=9 Hz), 7.73 (d, 1H, J=1 Hz), 7.92 (d, 1H, J=1 Hz), 8.0-8.1 (m, 1H), 8.20 (s, 1H).
MS:416.11[M+H]+
According to a technique similar to Example 3, a crude form of (R)-3-methyl-1-(5-(trifluoromethyl)pyridin-3-yl)pyrrolidin-3-amine (50 mg) was synthesized from tert-butyl (R)-(3-methyl-1-(5-(trifluoromethyl)pyridin-3-yl)pyrrolidin-3-yl)carbamate (47 mg, 0.23 mmol) synthesized in Reference Example 68, and the title compound (white crystals, 22 mg, 61%) was obtained using a portion of the crude form of (R)-3-methyl-1-(5-(trifluoromethyl)pyridin-3-yl)pyrrolidin-3-amine (20 mg) thus obtained and 2-(4-morpholinophenyl)acetic acid (30 mg, 0.12 mmol) synthesized in Reference Example 23-2.
1H NMR (CDCl3, 400 MHz): δ=1.53 (s, 3H), 1.9-2.1 (m, 1H), 2.2-2.4 (m, 1H), 3.13 (t, 4H, J=4 Hz), 3.2-3.4 (m, 3H), 3.46 (s, 2H), 3.6-3.7 (m, 1H), 3.86 (t, 4H, J=4 Hz), 5.37 (br s, 1H), 6.84 (d, 2H, J=8 Hz), 6.89 (s, 1H), 7.09 (d, 2H, J=8 Hz), 8.06 (s, 1H), 8.19 (s, 1H).
MS:449.15[M+H]+
According to a technique similar to Example 3, a crude form of (R)-3-methyl-1-(5-(trifluoromethyl)pyridin-3-yl)pyrrolidin-3-amine (20 mg) was synthesized from tert-butyl (R)-(3-methyl-1-(5-(trifluoromethyl)pyridin-3-yl)pyrrolidin-3-yl)carbamate (47 mg, 0.23 mmol) synthesized in Reference Example 68, and the title compound (white amorphous, 12 mg, 100%) was obtained using a portion of the crude form of (R)-3-methyl-1-(5-(trifluoromethyl)pyridin-3-yl)pyrrolidin-3-amine (7 mg) thus obtained and 2-(4-cyclopropylphenyl)acetic acid (8 mg, 0.044 mmol) synthesized in Reference Example 33-2.
1H NMR (CDCl3, 400 MHz): δ=0.6-0.7 (m, 2H), 0.9-1.0 (m, 2H), 1.53 (s, 3H), 1.8-1.9 (m, 1H), 1.9-2.1 (m, 1H), 2.2-2.4 (m, 1H), 3.2-3.4 (m, 3H), 3.48 (s, 2H), 3.62 (d, 1H, J=10 Hz), 5.36 (br s, 1H), 6.88 (s, 1H), 7.00 (d, 2H, J=8 Hz), 7.07 (d, 2H, J=8 Hz), 8.05 (d, 1H, J=2 Hz), 8.19 (s, 1H).
MS:404.12[M+H]+
Ethyl 2-(4-(3-oxa-8-azabicyclo[3.2.1]octan-8-yl)phenyl)acetate (87 mg, 0.32 mmol) synthesized in Reference Example 69 was dissolved in ethanol (1.6 mL), an 8 N aqueous solution of sodium hydroxide (0.20 mL, 1.6 mmol) was added thereto, and the mixture was stirred for 2 hours at room temperature. A 1 N aqueous solution of hydrochloric acid (1.6 mL, 1.6 mmol) was added to the reaction liquid in an ice bath, and then the mixture was distilled off under reduced pressure. A mixed liquid (5 mL) of chloroform:methanol=10:1 was added to a residue thus obtained, insoluble materials were filtered, subsequently the solvent was distilled off under reduced pressure, and a crude form of 2-(4-(3-oxa-8-azabicyclo[3.2.1]octan-8-yl)phenyl)acetic acid (white crystals) was obtained. Subsequently, according to a technique similar to Example 1, the title compound (pale yellow crystals, 50 mg, 71%) was obtained using (R)-1-(5-(trifluoromethyl)pyridin-3-yl)pyrrolidin-3-amine (35 mg, 0.15 mmol) synthesized in Reference Example 1-2 and a half of the crude form of 2-(4-(3-oxa-8-azabicyclo[3.2.1]octan-8-yl)phenyl)acetic acid synthesized as described above.
1H NMR (CDCl3, 400 MHz): δ=1.8-2.2 (m, 5H), 2.2-2.4 (m, 1H), 3.0-3.2 (m, 1H), 3.37 (t, 2H, J=7 Hz), 3.4-3.6 (m, 2H), 3.49 (s, 2H), 3.6-3.7 (m, 1H), 3.8-3.9 (m, 2H), 4.0-4.1 (m, 2H), 4.5-4.7 (m, 1H), 5.5-5.6 (m, 1H), 6.76 (d, 2H, J=9 Hz), 6.90 (s, 1H), 7.10 (d, 2H, J=9 Hz) 8.08 (d, 1H, J=3 Hz), 8.20 (s, 1H).
MS:461.17[M+H]+
According to a technique similar to Example 149, a crude form of 2-(4-(3-oxa-8-azabicyclo[3.2.1]octan-8-yl)phenyl)acetic acid (white crystals) was obtained from ethyl 2-(4-(3-oxa-8-azabicyclo[3.2.1]octan-8-yl)phenyl)acetate (87 mg, 0.32 mmol) synthesized in Reference Example 69. The title compound (pale yellow crystals, 51 mg, 73%) was obtained using (R)-1-(6-(trifluoromethyl)pyridin-3-yl)pyrrolidin-3-amine (35 mg, 0.15 mmol) synthesized in Reference Example 32-2 and a half of the crude form of 2-(4-(3-oxa-8-azabicyclo[3.2.1]octan-8-yl)phenyl)acetic acid synthesized as described above.
1H NMR (CDCl3, 400 MHz): δ=1.8-2.2 (m, 5H), 2.2-2.4 (m, 1H), 3.0-3.2 (m, 1H), 3.3-3.4 (m, 2H), 3.4-3.6 (m, 2H), 3.49 (s, 2H), 3.6-3.8 (m, 1H), 3.8-3.9 (m, 2H), 4.0-4.1 (m, 2H), 4.5-4.7 (m, 1H), 5.5-5.6 (m, 1H), 6.7-6.8 (m, 3H), 7.08 (d, 2H, J=8 Hz), 7.46 (d, 1H, J=8 Hz), 7.96 (d, 1H, J=3 Hz).
MS:461.17[M+H]+
According to a technique similar to Example 1, the title compound (white crystals, 26 mg, 52%) was obtained using (R)-1-(6-(trifluoromethyl)pyridin-3-yl)pyrrolidin-3-amine (30 mg, 0.13 mmol) synthesized in Reference Example 32-2 and 2-(benzo[d]oxazol-5-yl)acetic acid (35 mg, 0.16 mmol).
1H NMR (CDCl3, 400 MHz): δ=1.8-2.0 (m, 1H), 2.2-2.4 (m, 1H), 3.1-3.3 (m, 1H), 3.3-3.5 (m, 2H), 3.6-3.7 (m, 1H), 3.70 (s, 2H), 3.6-3.7 (m, 1H), 5.5-5.7 (m, 1H), 6.76 (dd, 1H, J=3.9 Hz) 7.30 (dd, 1H, J=1.8 Hz), 7.45 (d, 1H, J=9 Hz), 7.56 (d, 1H, J=8 Hz), 7.67 (d, 1H, J=1 Hz), 7.94 (d, 1H, J=3 Hz), 8.11 (s, 1H).
MS:391.10[M+H]+
According to a technique similar to Example 1, the title compound (pale yellow crystals, 33 mg, 65%) was obtained using (R)-1-(5-(trifluoromethyl)pyridin-3-yl)pyrrolidin-3-amine (30 mg, 0.13 mmol) synthesized in Reference Example 1-2 and 2-(benzo[d]oxazol-5-yl)acetic acid (35 mg, 0.16 mmol).
1H NMR (CDCl3, 400 MHz): δ=1.8-2.0 (m, 1H), 2.2-2.4 (m, 1H), 3.0-3.2 (m, 1H), 3.3-3.5 (m, 2H), 3.6-3.7 (m, 1H), 3.71 (s, 2H), 3.6-3.7 (m, 1H), 5.6-5.8 (m, 1H) 6.88 (s, 1H), 7.31 (dd, 1H, J=2.8 Hz), 7.57 (d, 1H, J=8 Hz), 7. 68 (d, 1H, J=2 Hz), 8.0-8.3 (m, 2H), 8.12 (s, 1H).
MS:391.10[M+H]+
According to a technique similar to Example 1, the title compound (pale yellow crystals, 48 mg, 89%) was obtained using (R)-1-(5-(trifluoromethyl)pyridin-3-yl)pyrrolidin-3-amine (30 mg, 0.13 mmol) synthesized in Reference Example 1-2 and 2-(2-methylbenzo[d]oxazol-5-yl)acetic acid (35 mg, 0.16 mmol) synthesized as described above.
1H NMR (CDCl3, 400 MHz): δ=1.8-2.0 (m, 1H), 2.2-2.4 (m, 1H), 2.65 (s, 3H), 3.0-3.2 (m, 1H), 3.36 (t, 2H, J=7 Hz), 3.6-3.7 (m, 1H), 3.89 (s, 2H), 4.6-4.7 (m, 1H), 5.5-5.7 (m, 1H), 6.88 (s, 1H), 7.19 (dd, 1H, J=2.8 Hz), 7.44 (d, 1H, J=8 Hz), 7.52 (d, 1H, J=2 Hz), 8.05 (d, 1H, J=2 Hz), 8.19 (s, 1H).
MS:405.12[M+H]+
According to a technique similar to Example 1, the title compound (white crystals, 53 mg, 100%) was obtained using (R)-1-(6-(trifluoromethyl)pyridin-3-yl)pyrrolidin-3-amine (30 mg, 0.13 mmol) synthesized in Reference Example 32-2 and 2-(2-methylbenzo[d]oxazol-5-yl)acetic acid (31 mg, 0.16 mmol).
1H NMR (CDCl3, 400 MHz): δ=1.8-2.0 (m, 1H), 2.2-2.4 (m, 1H), 2.64 (s, 3H), 3.0-3.2 (m, 1H), 3.37 (t, 2H, J=7 Hz), 3.6-3.7 (m, 1H), 3.68 (s, 2H), 4.6-4.7 (m, 1H), 5.6-5.8 (m, 1H), 6.75 (dd, 1H, J=3.9 Hz), 7.19 (dd, 1H, J=2.8 Hz), 7.43 (d, 1H, J=8 Hz), 7.45 (d, 1H, J=9 Hz), 7.51 (d, 1H, J=2 Hz), 7.91 (d, 1H, J=3 Hz).
MS:405.11[M+H]+
Ethyl 2-(4-((1S,4S)-2-oxa-5-azabicyclo[2.2.2]octan-5-yl)phenyl)acetate (112 mg, 0.41 mmol) synthesized in Reference Example 70 was dissolved in ethanol (2.0 mL), an 8 N aqueous solution of sodium hydroxide (0.30 mL, 2.4 mmol) was added thereto, and the mixture was stirred for 2 hours at room temperature. A 1 N aqueous solution of hydrochloric acid (2.4 mL, 2.4 mmol) was added to the reaction liquid in an ice bath, and then the mixture was distilled off under reduced pressure. A mixed liquid (5 mL) of chloroform:methanol=10:1 was added to a residue thus obtained, insoluble materials were filtered, subsequently the solvent was distilled off under reduced pressure, and a crude form of 2-(4-((1S,4S)-2-oxa-5-azabicyclo[2.2.2]octan-5-yl)phenyl)acetic acid (white crystals, 84 mg) was obtained. Subsequently, according to a technique similar to Example 131, the title compound (pale yellow crystals, 40 mg, 47%) was obtained using (R)-1-(5-(trifluoromethyl)pyridin-3-yl)pyrrolidin-3-amine (42 mg, 0.18 mmol) synthesized in Reference Example 1-2 and a portion of the crude form of 2-(4-((1S,4S)-2-oxa-5-azabicyclo[2.2.2]octan-5-yl)phenyl)acetic acid (41 mg) synthesized as described above.
1H NMR (CDCl3, 400 MHz): δ=1.6-1.8 (m, 1H), 1.8-2.0 (m, 2H), 2.0-2.3 (m, 2H), 2.3-2.4 (m, 1H), 3.0-3.2 (m, 1H), 3.2-3.4 (m, 3H), 3.49 (s, 2H), 3.6-3.7 (m, 1H), 3.7-3.9 (m, 2H), 4.0-4.1 (m, 2H), 4.1-4.2 (m, 1H), 4.5-4.7 (m, 1H), 5.5-5.6 (m, 1H), 6.60 (d, 2H, J=8 Hz), 6.91 (s, 1H), 7.09 (d, 2H, J=8 Hz), 8.08 (s, 1H), 8.20 (s, 1H).
MS:461.17[M+H]+
According to a technique similar to Example 155, a crude form of 2-(4-((1S,4S)-2-oxa-5-azabicyclo[2.2.2]octan-5-yl)phenyl)acetic acid (white crystals, 84 mg) was obtained from the crude form of ethyl 2-(4-((1S,4S)-2-oxa-5-azabicyclo[2.2.2]octan-5-yl)phenyl)acetate (112 mg, 0.41 mmol) synthesized in Reference Example 70. Subsequently, the title compound (white crystals, 16 mg, 18%) was obtained using (R)-1-(6-(trifluoromethyl)pyridin-3-yl)pyrrolidin-3-amine (42 mg, 0.18 mmol) synthesized in Reference Example 32-2 and a portion of the crude form of 2-(4-((1S,4S)-2-oxa-5-azabicyclo[2.2.2]octan-5-yl)phenyl)acetic acid (41 mg) synthesized as described above.
1H NMR (CDCl3, 400 MHz): δ=1.6-1.8 (m, 1H), 1.8-2.0 (m, 2H), 2.0-2.3 (m, 2H), 2.3-2.4 (m, 1H), 3.0-3.2 (m, 1H), 3.3-3.5 (m, 3H), 3.49 (s, 2H), 3.6-3.7 (m, 1H), 3.7-3.9 (m, 2H), 4.0-4.1 (m, 2H), 4.1-4.2 (m, 1H), 4.5-4.7 (m, 1H), 5.5-5.6 (m, 1H), 6.59 (d, 2H, J=8 Hz), 6.78 (dd, 1H, J=3.9 Hz), 7.08 (d, 2H, J=8 Hz), 7.47 (d, 1H, J=9 Hz), 7.99 (s, 1H).
MS:461.17[M+H]+
According to a technique similar to Example 1, the title compound (pale yellow amorphous, 33 mg, 61%) was obtained using (R)-1-(5-(trifluoromethyl)pyridin-3-yl)pyrrolidin-3-amine (30 mg, 0.13 mmol) synthesized in Reference Example 1-2 and 2-(benzo[d]thiazol-6-yl)acetic acid (31 mg, 0.16 mmol).
1H NMR (CDCl3, 400 MHz): δ=1.9-2.0 (m, 1H), 2.3-2.4 (m, 1H), 3.1-3.2 (m, 1H), 3.3-3.5 (m, 2H), 3.6-3.7 (m, 1H), 3.74 (s, 2H), 4.6-4.7 (m, 1H), 5.6-5.8 (m, 1H), 6.90 (s, 1H), 7.41 (dd, 1H, J=2.8 Hz), 7.89 (d, 1H, J=2 Hz), 8.0-8.1 (m, 1H), 8.11 (d, 1H, J=8 Hz), 8.19 (s, 1H), 9.00 (s, 1H).
MS:407.08[M+H]+
According to a technique similar to Example 1, the title compound (white crystals, 20 mg, 36%) was obtained using (R)-l-(6-(trifluoromethyl)pyridin-3-yl)pyrrolidin-3-amine (30 mg, 0.13 mmol) synthesized in Reference Example 32-2 and 2-(benzo[d]thiazol-6-yl)acetic acid (31 mg, 0.16 mmol).
1H NMR (CDCl3, 400 MHz): δ=1.9-2.0 (m, 1H), 2.3-2.4 (m, 1H), 3.1-3.2 (m, 1H), 3.3-3.5 (m, 2H), 3.6-3.7 (m, 1H), 3.73 (s, 2H), 4.6-4.7 (m, 1H), 5.7-5.8 (m, 1H), 6.76 (dd, 1H, J=2.8 Hz), 7.40 (d, 1H, J=2 Hz), 7.45 (d, 1H, J=8 Hz), 7.88 (s, 1H), 7.91 (d, 1H, J=3 Hz), 8.10 (d, 1H, J=8 Hz), 9.00 (s, 1H
MS:429.05[M+Na]+
According to a technique similar to Example 1, the title compound (white crystals, 59 mg, 57%) was obtained using (R)-1-(5-(trifluoromethyl)pyridin-3-yl)pyrrolidin-3-amine (60 mg, 0.26 mmol) synthesized in Reference Example 1-2 and 2-(1H-indazol-5-yl)acetic acid (56 mg, 0.32 mmol).
1H NMR (DMSO-d6,400 MHz): δ=1.8-2.0 (m, 1H), 2.1-2.3 (m, 1H), 3.1-3.3 (m, 1H), 3.3-3.7 (m, 4H), 3.49 (s, 2H), 4.39 (br s, 1H), 7.11 (s, 1H), 7.25 (d, 1H, J=8 Hz), 7.45 (d, 1H, J=8 Hz), 7.59 (s, 1H), 8.00 (s, 1H), 8.15 (s, 1H), 8.21 (s, 1H), 8.3-8.5 (m, 1H).
MS:390.12[M+H]+
According to a technique similar to Example 1, the title compound (white crystals, 55 mg, 53%) was obtained using (R)-1-(6-(trifluoromethyl)pyridin-3-yl)pyrrolidin-3-amine (60 mg, 0.26 mmol) synthesized in Reference Example 32-2 and 2-(1H-indazol-5-yl)acetic acid (56 mg, 0.32 mmol).
1H NMR (DMSO-d6, 400 MHz): δ=1.8-2.0 (m, 1H), 2.1-2.3 (m, 1H), 3.1-3.5 (m, 3H), 3.49 (s, 2H), 3.5-3.7 (m, 1H), 4.3-4.5 (m, 1H), 7.01 (dd, 1H, J=3.8 Hz), 7.24 (d, 1H, J=8 Hz), 7.45 (d, 1H, J=8 Hz), 7.5-7.7 (m, 2H), 7.99 (s, 1H), 8.04 (d, 2H, J=3 Hz), 8.3-8.5 (m, 1H).
MS:390.12[M+H]+
According to a technique similar to Example 3, a crude form of 3-(trifluoromethyl)-1-(5-(trifluoromethyl)pyridin-3-yl)pyrrolidin-3-amine (58 mg) was synthesized from tert-butyl (3-(trifluoromethyl)-1-(5-(trifluoromethyl)pyridin-3-yl)pyrrolidin-3-yl)carbamate (145 mg, 0.36 mmol) synthesized in Reference Example 71, and the title compound (white amorphous, 11 mg, 25%) was obtained using a portion of the crude form of 3-(trifluoromethyl)-1-(5-(trifluoromethyl)pyridin-3-yl)pyrrolidin-3-amine (29 mg) thus obtained and 2-(4-cyclopropylphenyl)acetic acid (26 mg, 0.15 mmol) synthesized in Reference Example 33-2.
1H NMR (CDCl3, 400 MHz): δ=0.6-0.7 (m, 2H), 0.9-1.0 (m, 2H), 1.8-1.9 (m, 1H), 2.5-2.6 (m, 2H), 3.4-3.6 (m, 2H), 3.56 (s, 2H), 3.86 (d, 1H, J=11 Hz), 3.96 (d, 1H, J=11 Hz), 5.45 (br s, 1H), 6.94 (s, 1H), 7.40 (d, 2H, J=8 Hz), 7.90 (d, 2H, J=8 Hz), 8.0-8.2 (m, 1H), 8.2-8.3 (m, 1H).
MS:458.13[M+H]+
According to a technique similar to Example 3, a crude form of 3-(trifluoromethyl)-1-(5-(trifluoromethyl)pyridin-3-yl)pyrrolidin-3-amine (58 mg) was synthesized from tert-butyl (3-(trifluoromethyl)-1-(5-(trifluoromethyl)pyridin-3-yl)pyrrolidin-3-yl)carbamate (145 mg, 0.36 mmol) synthesized in Reference Example 71, and the title compound (white amorphous, 25 mg, 51%) was obtained using a portion of the crude form of 3-(trifluoromethyl)-1-(5-(trifluoromethyl)pyridin-3-yl)pyrrolidin-3-amine (29 mg) thus obtained and 2-(4-(trifluoromethyl)phenyl)acetic acid (30 mg, 0.15 mmol).
1H NMR (CDCl3, 400 MHz): δ=2.5-2.7 (m, 2H), 3.4-3.6 (t, 2H, J=7 Hz), 3.66 (s, 2H), 3.91 (d, 1H, J=11 Hz), 3.95 (d, 1H, J=11 Hz), 5.52 (br s, 1H), 6.96 (s, 1H), 7.37 (d, 2H, J=8 Hz), 7.62 (d, 2H, J=8 Hz), 8.1-8.2 (m, 1H), 8.2-8.3 (m, 1H).
MS:486.09[M+H]+
According to a technique similar to Example 1, the title compound (white crystals, 30 mg, 57%) was obtained using (R)-1-(5-(trifluoromethyl)pyridin-3-yl)pyrrolidin-3-amine (30 mg, 0.13 mmol) synthesized in Reference Example 1-2 and 2-(1H-benzo[d][1,2,3]triazol-5-yl)acetic acid (28 mg, 0.16 mmol).
1H NMR (CD3OD, 400 MHz): δ=2.0-2.1 (m, 1H), 2.2-2.4 (m, 1H), 3.2-3.3 (m, 1H), 3.3-3.5 (m, 2H), 3.6-3.7 (m, 1H), 3.66 (s, 2H), 4.4-4.6 (m, 1H), 7.11 (s, 1H), 7.38 (d, 1H, J=9 Hz), 7.7-7.8 (m, 2H), 8.04 (s, 1H), 8.07 (d, 1H, J=3 Hz). The 2H content is not observable.
MS:391.11[M+H]+
According to a technique similar to Example 1, the title compound (white crystals, 20 mg, 37%) was obtained using (R)-1-(6-(trifluoromethyl)pyridin-3-yl)pyrrolidin-3-amine (30 mg, 0.13 mmol) synthesized in Reference Example 32-2 and 2-(1H-benzo[d][1,2,3]triazol-5-yl)acetic acid (28 mg, 0.16 mmol).
1H NMR (CD3OD, 400 MHz): δ=2.0-2.1 (m, 1H), 2.2-2.4 (m, 1H), 3.2-3.3 (m, 1H), 3.4-3.6 (m, 2H), 3.6-3.7 (m, 1H), 3.66 (s, 2H), 4.4-4.6 (m, 1H), 7.01 (dd, 1H, J=3.9 Hz), 7.38 (d, 1H, J=8 Hz), 7.52 (d, 1H, J=9 Hz), 7.7-7.8 (m, 2H), 7.93 (d, 1H, J=3 Hz). The 2H content is not observable.
MS:391.11[M+H]+
According to a technique similar to Example 38, a crude form of ethyl 2-(4-(2-oxa-5-azabicyclo[2.2.1]heptan-5-yl)phenyl)acetate (106 mg) was synthesized using ethyl 4-bromophenylacetate (109 mg, 0.45 mmol) and 2-oxa-5-azabicyclo[2.2.1]heptane hydrochloride (91 mg, 0.67 mmol), and subsequently, according to a technique similar to Example 155, a crude form of 2-(4-(2-oxa-5-azabicyclo[2.2.1]heptan-5-yl)phenyl)acetic acid (white crystals, 88 mg) was obtained from the crude form of ethyl 2-(4-(2-oxa-5-azabicyclo[2.2.1]heptan-5-yl)phenyl)acetate (106 mg) obtained as described above. Subsequently, diastereomer A of the title compound (pale yellow amorphous, 41 mg, 47%) was obtained using (R)-1-(5-(trifluoromethyl)pyridin-3-yl)pyrrolidin-3-amine (44 mg, 0.19 mmol) synthesized in Reference Example 1-2 and a portion of the crude form of 2-(4-(2-oxa-5-azabicyclo[2.2.1]heptan-5-yl)phenyl)acetic acid (44 mg) synthesized as described above.
1H NMR (CDCl3, 400 MHz): δ=1.8-2.1 (m, 3H), 2.2-2.4 (m, 1H), 3.0-3.2 (m, 2H), 3.36 (t, 2H, J=7 Hz), 3.49 (s, 2H), 3.54 (d, 1H, J=9 Hz), 3.6-3.7 (m, 1H), 3.8-3.9 (m, 2H), 4.38 (s, 1H), 4.5-4.7 (m, 1H), 4.65 (s, 1H), 5.5-5.7 (m, 1H), 6.54 (d, 2H, J=8 Hz), 6.90 (s, 1H), 7.07 (d, 2H, J=8 Hz), 8.07 (s, 1H), 8.19 (s, 1H).
MS:447.17[M+H]+
According to a technique similar to Example 165, diastereomer A of the title compound (pale yellow crystals, 41 mg, 47%) was obtained using (R)-1-(6-(trifluoromethyl)pyridin-3-yl)pyrrolidin-3-amine (44 mg, 0.19 mmol) synthesized in Reference Example 32-2 and a portion of the crude form of 2-(4-(2-oxa-5-azabicyclo[2.2.1]heptan-5-yl)phenyl)acetic acid (44 mg) synthesized in Example 165.
1H NMR (CDCl3, 400 MHz): δ=1.8-2.1 (m, 3H), 2.2-2.4 (m, 1H), 3.1-3.2 (m, 2H), 3.38 (t, 2H, J=7 Hz), 3.49 (s, 2H), 3.55 (d, 1H, J=9 Hz), 3.6-3.7 (m, 1H), 3.8-3.9 (m, 2H), 4.38 (s, 1H), 4.5-4.7 (m, 1H), 4.65 (s, 1H), 5.5-5.7 (m, 1H), 6.54 (d, 2H, J=8 Hz), 6.7-6.9 (m, 1H), 7.07 (d, 2H, J=8 Hz), 7.47 (d, 1H, J=8 Hz), 7.9-8.0 (m, 1H).
MS:447.15[M+H]+
According to a technique similar to Example 1, the title compound (yellow amorphous, 39 mg, 64%) was obtained using (R)-1-(5-(trifluoromethyl)pyridin-3-yl)pyrrolidin-3-amine (35 mg, 0.15 mmol) synthesized in Reference Example 1-2 and 2-(1-methyl-1H-benzo[d][1,2,3]triazol-5-yl)acetic acid (30 mg, 0.16 mmol).
1H NMR (CDCl3, 400 MHz): δ=1.9-2.1 (m, 1H), 2.2-2.4 (m, 1H), 3.1-3.2 (m, 1H), 3.2-3.4 (m, 2H), 3.5-3.7 (m, 1H), 3.37 (s, 2H), 4.27 (s, 3H), 4.6-4.7 (m, 1H), 6.48 (br s, 1H), 6.78 (s, 1H), 7.47 (d, 1H, J=9 Hz), 7.50 (d, 1H, J=9 Hz), 7.88 (s, 1H), 7.96 (d, 1H, J=3 Hz), 8.10 (s, 1H).
MS:405.12[M+H]+
According to a technique similar to Example 1, the title compound (white crystals, 8 mg, 13%) was obtained using (R)-1-(6-(trifluoromethyl)pyridin-3-yl)pyrrolidin-3-amine (35 mg, 0.15 mmol) synthesized in Reference Example 32-2 and 2-(1-methyl-1H-benzo[d][1,2,3]triazol-5-yl)acetic acid (30 mg, 0.16 mmol).
1H NMR (CD3OD, 400 MHz): δ=2.0-2.2 (m, 1H), 2.2-2.4 (m, 1H), 3.2-3.4 (m, 1H), 3.4-3.6 (m, 2H), 3.6-3.7 (m, 1H), 3.70 (s, 2H), 4.32 (s, 3H), 4.4-4.6 (m, 1H), 7.04 (dd, 1H, J=3.9 Hz), 7.52 (dd, 1H, J=1.8 Hz), 7.56 (d, 1H, J=8 Hz), 7.69 (d, 1H, J=8 Hz), 7.88 (s, 1H), 7.96 (d, 1H, J=3 Hz). The 1H content is not observable.
MS:405.12[M+H]+
According to a technique similar to Example 9, the title compound (pale yellow solid, 33 mg, 50%) was obtained using N-(azetidin-3-yl)-2-(4-cyclopropylphenyl)acetamide (40 mg, 0.17 mmol) synthesized in Reference Example 75-2 and 1-bromo-4-(trifluoromethyl)benzene (29 μL, 0.21 mmol).
1H NMR (CDCl3, 400 MHz): δ=0.6-0.8 (m, 2H), 0.9-1.1 (m, 2H), 1.8-2.0 (m, 1H), 3.5-3.7 (m, 4H), 4.23 (t, 2H, J=8 Hz), 4.7-4.9 (m, 1H), 5.78 (d, 1H, J=7 Hz), 6.39 (d, 2H, J=8 Hz), 7.06 (d, 2H, J=8 Hz), 7.13 (d, 2H, J=8 Hz), 7.42 (d, 2H, J=8 Hz).
MS:397.12[M+Na]+
According to a technique similar to Example 9, the title compound (pale yellow solid, 27 mg, 38%) was obtained using N-(azetidin-3-yl)-2-(4-cyclopropylphenyl)acetamide (40 mg, 0.17 mmol) synthesized in Reference Example 75-2 and 4-bromo-1-fluoro-2-(trifluoromethyl)benzene (29 μL, 0.21 mmol).
1H NMR (CDCl3, 400 MHz): δ=0.6-0.8 (m, 2H), 0.9-1.1 (m, 2H), 1.8-2.0 (m, 1H), 3.4-3.7 (m, 4H), 4.16 (t, 2H, J=8 Hz), 4.7-4.9 (m, 1H), 5.78 (d, 1H, J=6 Hz), 6.3-6.6 (m, 2H), 6.9-7.2 (m, 5H).
MS:415.11[M+Na]+
According to a technique similar to Example 1, the title compound (white solid, 100 mg, 100%) was obtained using (R)-1-(5-(trifluoromethyl)pyridin-3-yl)pyrrolidin-3-amine (52 mg, 0.22 mmol) synthesized in Reference Example 1-2 and 2-(4-bromophenyl)acetic acid (60 mg, 0.28 mmol).
1H NMR (CDCl3, 400 MHz): δ=1.9-2.1 (m, 1H), 2.2-2.4 (m, 1H), 3.14 (dd, 1H, J=4.10 Hz), 3.36 (t, 2H, J=7 Hz), 3.52 (s, 2H), 3.62 (dd, 1H, J=6.10 Hz), 4.6-4.7 (m, 1H), 6.22 (d, 1H, J=7 Hz), 6.8-6.9 (m, 1H), 7.14 (d, 2H, J=8 Hz), 7.46 (d, 2H, J=8 Hz), 7.98 (d, 1H, J=3 Hz), 8.13 (s, 1H).
MS:428.02[M+H]+
(R)-2-(4-cyclopropylphenyl)-N-(pyrrolidin-3-yl)acetamide (49 mg, 0.20 mmol) synthesized in Reference Example 74-2 was dissolved in DMF (1.0 mL), subsequently 2-chloro-6-fluorobenzo[d]thiazole (45 mg, 0.24 mmol) and cesium carbonate (78 mg, 0.24 mmol) were added thereto, and the mixture was stirred for 2 hours at 100° C. Saturated sodium hydrogen carbonate was added to the reaction liquid that had been left to cool to room temperature, and then the mixture was extracted with chloroform. An organic layer thus separated was dried over anhydrous sodium sulfate, insoluble materials were filtered, and then the solvent was distilled off under reduced pressure. A residue thus obtained was purified by silica gel column chromatography (heptane:ethyl acetate) (concentration gradient: 50 to 100%), and the title compound (white solid, 60 mg, 71%) was obtained.
1H NMR (CDCl3, 400 MHz): δ=0.6-0.7 (m, 2H), 0.9-1.0 (m, 2H), 1.8-2.0 (m, 2H), 2.2-2.4 (m, 1H), 3.31 (dd, 1H, J=5.11 Hz), 3.5-3.7 (m, 2H), 3.53 (s, 2H), 3.82 (dd, 1H, J=7.11 Hz), 4.5-4.7 (m, 1H), 5.48 (d, 1H, J=7 Hz), 6.9-7.1 (m, 3H), 7.11 (d, 2H, J=8 Hz), 7.31 (dd, 1H, J=3.8 Hz), 7.48 (dd, 1H, J=5.9 Hz).
MS:396.13[M+H]+
According to a technique similar to Example 172, the title compound (pale yellow solid, 26 mg, 32%) was obtained using (R)-2-(4-isopropylphenyl)-N-(pyrrolidin-3-yl)acetamide (49 mg, 0.20 mmol) synthesized in Reference Example 74-2 and 2,5-dibromothiazole (58 mg, 0.24 mmol).
1H NMR (CDCl3, 400 MHz): δ=0.6-0.8 (m, 2H), 0.9-1.0 (m, 2H), 1.8-2.0 (m, 2H), 2.2-2.4 (m, 1H), 3.16 (dd, 1H, J=5.11 Hz), 3.3-3.5 (m, 2H), 3.52 (s, 2H), 3.67 (dd, 1H, J=6.10 Hz), 4.5-4.7 (m, 1H), 5.46 (d, 1H, J=7 Hz), 7.0-7.1 (m, 3H), 7.11 (d, 2H, J=8 Hz).
MS:428.02[M+Na]+
According to a technique similar to Example 9, the title compound (white solid, 102 mg, 84%) was obtained using (R)-2-(4-cyclopropylphenyl)-N-(pyrrolidin-3-yl)acetamide (73 mg, 0.30 mmol) synthesized in Reference Example 74-2 and 4-bromo-1-fluoro-2-(trifluoromethyl)benzene (51 μL, 0.36 mmol).
1H NMR (CDCl3, 400 MHz): δ=0.6-0.8 (m, 2H), 0.9-1.1 (m, 2H), 1.8-2.0 (m, 2H), 2.2-2.4 (m, 1H), 3.04 (dd, 1H, J=4.9 Hz), 3.2-3.4 (m, 2H), 3.4-3.6 (m, 1H), 3.52 (s, 2H), 4.5-4.7 (m, 1H), 5.50 (d, 1H, J=7 Hz), 6.5-6.7 (m, 2H), 6.9-7.2 (m, 5H).
MS:407.16[M+H]+
According to a technique similar to Example 9, the title compound (white solid, 203 mg, 58%) was obtained using (R)-2-(4-cyclopropylphenyl)-N-(pyrrolidin-3-yl)acetamide (244 mg, 1.0 mmol) synthesized in Reference Example 74-2 and 1-bromo-3-methoxybenzene (152 μL, 1.2 mmol).
1H NMR (CDCl3, 400 MHz): δ=0.6-0.7 (m, 2H), 0.9-1.0 (m, 2H), 1.7-1.9 (m, 2H), 2.1-2.3 (m, 1H), 3.05 (dd, 1H, J=4.10 Hz), 3.2-3.4 (m, 2H), 3.5-3.6 (m, 3H), 3.51 (s, 3H), 4.5-4.7 (m, 1H), 5.53 (d, 1H, J=7 Hz), 6.07 (t, 1H, J=2 Hz), 6.15 (dd, 1H, J=1, 8 Hz), 6.28 (dd, 1H, J=2.8 Hz), 7.03 (d, 2H, J=8 Hz), 7.0-7.2 (m, 3H).
MS:351.19[M+H]+
According to a technique similar to Example 9, the title compound (white solid, 11 mg, 24%) was obtained using (R)-2-(4-bromophenyl)-N-(1-(5-(trifluoromethyl)pyridin-3-yl)pyrrolidin-3-yl)acetamide (43 mg, 0.10 mmol) synthesized in Example 171 and 3,3-difluoropyrrolidine hydrochloride (17 mg, 0.12 mmol).
1H NMR (CDCl3, 400 MHz): δ=1.8-2.0 (m, 1H), 2.2-2.4 (m, 1H), 2.4-2.6 (m, 2H), 3.10 (dd, 1H, J=5.10 Hz), 3.36 (t, 2H, J=7 Hz), 3.4-3.6 (m, 4H), 3.6-3.8 (m, 3H), 4.5-4.7 (m, 1H), 5.52 (d, 1H, J=7 Hz), 6.52 (d, 2H, J=9 Hz), 6.90 (s, 1H), 7.11 (d, 2H, J=8 Hz), 8.07 (s, 1H), 8.20 (s, 1H).
MS:455.15[M+H]+
According to a technique similar to Example 9, the title compound (white solid, 43 mg, 24%) was obtained using (R)-2-(4-cyclopropylphenyl)-N-(pyrrolidin-3-yl)acetamide (98 mg, 0.40 mmol) synthesized in Reference Example 74-2 and ethyl 2-(3-bromophenoxy)-2-methylpropanoate (138 mg, 0.48 mmol) synthesized in Reference Example 76.
1H NMR (CDCl3, 400 MHz): δ=0.6-0.8 (m, 2H), 0.9-1.0 (m, 2H), 1.25 (t, 3H, J=7 Hz), 1.59 (s, 6H), 1.7-2.0 (m, 2H), 2.1-2.3 (m, 1H), 3.01 (dd, 1H, J=4.10 Hz), 3.1-3.4 (m, 2H), 3.4-3.6 (m, 3H), 4.22 (dd, 2H, J=7.15 Hz), 4.5-4.7 (m, 1H), 5.55 (d, 1H, J=7 Hz), 6.0-6.1 (m, 1H), 6.1-6.2 (m, 2H), 7.0-7.1 (m, 3H), 7.11 (d, 2H, J=8 Hz).
MS:451.22[M+H]+
Pyridine hydrochloride (500 mg) was added to (R)-2-(4-cyclopropylphenyl)-N-(1-(3-methoxyphenyl)pyrrolidin-3-yl)acetamide (35 mg, 0.10 mmol) synthesized in Example 175, and the mixture was heated for 3 hours at 150° C. Saturated sodium hydrogen carbonate was added to the reaction liquid that had been left to cool to room temperature, and then the mixture was extracted with ethyl acetate. An organic layer thus separated was washed with saturated brine and dried over anhydrous sodium sulfate, insoluble materials were filtered, and then the solvent was distilled off under reduced pressure. A residue thus obtained was purified by NH silica gel column chromatography (heptane:ethyl acetate) (concentration gradient: 50 to 100%), and the title compound (white solid, 26 mg, 77%) was obtained.
1H NMR (CDCl3, 400 MHz): δ=1.5-2.0 (m, 5H), 2.1-2.3 (m, 1H), 3.04 (dd, 1H, J=4.10 Hz), 3.1-3.4 (m, 2H), 3.4-3.6 (m, 3H), 4.5-4.7 (m, 1H), 4.8-5.0 (m, 1H), 5.54 (d, 1H, J=7 Hz), 6.0-6.4 (m, 4H), 7.0-7.2 (m, 3H), 7.29 (d, 2H, J=8 Hz).
MS:337.17[M+H]+
According to a technique similar to Example 172, the title compound (pale yellow solid, 21 mg, 26%) was obtained using (R)-2-(4-cyclopropylphenyl)-N-(pyrrolidin-3-yl)acetamide (49 mg, 0.20 mmol) synthesized in Reference Example 74-2 and 2-chloro-6-(trifluoromethyl)pyridine (44 mg, 0.24 mmol).
1H NMR (CDCl3, 400 MHz): δ=0.6-0.7 (m, 2H), 0.9-1.0 (m, 2H), 1.8-2.0 (m, 2H), 2.2-2.4 (m, 1H), 3.24 (dd, 1H, J=5.11 Hz), 3.4-3.6 (m, 4H), 3.76 (dd, 1H, J=6.11 Hz), 4.5-4.7 (m, 1H), 5.60 (d, 1H, J=7 Hz), 6.45 (d, 1H, J=8 Hz), 6.90 (d, 1H, J=7 Hz), 7.02 (d, 2H, J=8 Hz), 7.10 (d, 2H, J=8 Hz), 7.53 (t, 1H, J=8 Hz).
MS:412.13[M+Na]+
According to a technique similar to Example 172, the title compound (white solid, 56 mg, 73%) was obtained using (R)-2-(4-cyclopropylphenyl)-N-(pyrrolidin-3-yl)acetamide (49 mg, 0.20 mmol) synthesized in Reference Example 74-2 and 2-chloro-4,6-dimethoxypyridine (44 mg, 0.24 mmol).
1H NMR (CDCl3, 400 MHz): δ=0.6-0.8 (m, 2H), 0.9-1.1 (m, 2H), 1.7-2.0 (m, 2H), 2.1-2.3 (m, 1H), 3.2-3.4 (m, 1H), 3.5-3.7 (m, 4H), 3.7-3.9 (m, 1H), 3.84 (s, 6H), 4.4-4.6 (m, 1H), 5.37 (s, 1H), 5.51 (d, 1H, J=5 Hz), 7.03 (d, 2H, J=8 Hz), 7.11 (d, 2H, J=7 Hz).
MS:405.16[M+Na]+
According to a technique similar to Example 9, the title compound (white solid, 12 mg, 13%) was obtained using (R)-2-(4-bromophenyl)-N-(1-(5-(trifluoromethyl)pyridin-3-yl)pyrrolidin-3-yl)acetamide (86 mg, 0.20 mmol) synthesized in Example 171 and morpholine (35 μL, 0.40 mmol).
1H NMR (CDCl3, 400 MHz): δ=1.8-2.0 (m, 1H), 2.2-2.4 (m, 1H), 3.0-3.2 (m, 5H), 3.37 (t, 2H, J=7 Hz).3.51 (s, 2H), 3.65 (dd, 1H, J=7.10 Hz), 3.8-3.9 (m, 4H), 4.5-4.7 (m, 1H), 5.4-5.6 (m, 1H), 6.8-7.0 (m, 3H), 7.14 (d, 2H, J=8 Hz), 8.07 (d, 1H, J=2 Hz), 8.20 (s, 1H).
MS:435.17[M+H]+
According to a technique similar to Example 172, the title compound (white solid, 40 mg, 51%) was obtained using (R)-2-(4-cyclopropylphenyl)-N-(pyrrolidin-3-yl)acetamide (49 mg, 0.20 mmol) synthesized in Reference Example 74-2 and 2-chloro-4-(trifluoromethyl)pyridine (44 mg, 0.24 mmol).
1H NMR (CDCl3, 400 MHz): δ=0.6-0.7 (m, 2H), 0.9-1.0 (m, 2H), 1.8-2.0 (m, 2H), 2.2-2.4 (m, 1H), 3.23 (dd, 1H, J=5.11 Hz), 3.4-3.6 (m, 4H), 3.76 (dd, 1H, J=6.10 Hz), 4.5-4.7 (m, 1H), 5.49 (d, 1H, J=6 Hz), 6.48 (s, 1H), 6.73 (d, 1H, J=5 Hz), 7.03 (d, 2H, J=8 Hz), 7.11 (d, 2H, J=8 Hz), 8.25 (d, 1H, J=5 Hz).
MS:390.14[M+H]+
According to a technique similar to Example 9, the title compound (pale yellow solid, 24 mg, 29%) was obtained using (R)—N-(pyrrolidin-3-yl)-2-(4-(trifluoromethyl)phenyl)acetamide (55 mg, 0.20 mmol) synthesized in Reference Example 73-2 and 5-bromo-2-(trifluoromethyl)pyridine (54 mg, 0.24 mmol).
1H NMR (CDCl3, 400 MHz): δ=1.9-2.1 (m, 1H), 2.3-2.5 (m, 1H), 3.19 (dd, 1H, J=4.11 Hz), 3.3-3.5 (m, 2H), 3.62 (s, 2H), 3.67 (dd, 1H, J=6.8 Hz), 4.6-4.7 (m, 1H), 5.70 (d, 1H, J=6 Hz), 6.79 (dd, 1H, J=3.9 Hz), 7.40 (d, 2H, J=8 Hz), 7.47 (d, 1H, J=9 Hz), 7.61 (d, 2H, J=8 Hz), 7.95 (d, 1H, J=2 Hz).
MS:418.11[M+H]+
According to a technique similar to Example 9, the title compound (pale yellow solid, 22 mg, 25%) was obtained using (R)—N-(pyrrolidin-3-yl)-2-(4-(trifluoromethyl)phenyl)acetamide (55 mg, 0.20 mmol) synthesized in Reference Example 73-2 and 4-bromo-1-fluoro-2-(trifluoromethyl)benzene (58 mg, 0.24 mmol).
1H NMR (CDCl3, 400 MHz): δ=1.8-2.0 (m, 1H), 2.2-2.4 (m, 1H), 3.11 (dd, 1H, J=4.10 Hz), 3.2-3.5 (m, 2H), 3.57 (dd, 1H, J=6.10 Hz), 3.61 (s, 2H), 4.5-4.7 (m, 1H), 5.56 (d, 1H, J=6 Hz), 6.5-6.7 (m, 2H), 7.05 (t, 1H, J=9 Hz), 7.39 (d, 2H, J=8 Hz), 7.61 (d, 2H, J=8 Hz
MS:435.11[M+H]+
Tert-butyl (R)-3-(2-(4-(trifluoromethyl) phenyl) acetamido) pyrrolidine-1-carbamate (149 mg, 0.40 mmol) synthesized in Reference Example 73-1 was dissolved in DMF (2 mL), sodium hydride (60% oil, 24 mg, 0.60 mmol) and methyl iodide (37 μL, 0.60 mmol) were added thereto, and the mixture was stirred for one hour at room temperature. Saturated sodium hydrogen carbonate was added to a residue thus obtained under ice cooling, and then the mixture was extracted with chloroform. An organic layer thus separated was dried over anhydrous sodium sulfate, insoluble materials were filtered, subsequently the solvent was distilled off under reduced pressure, and thereby a crude form of tert-butyl (3R)-3-(2-(4-trifluoromethyl)phenyl)propanamido)pyrrolidine-1-carbamate was obtained. Subsequently, according to a technique similar to Example 36, the title compound (white solid, 25 mg, 15% in three stages) was obtained using the crude form of tert-butyl (3R)3-(2-(4-trifluoromethyl)phenyl)propanamido)pyrrolidine-1-carbamate thus obtained and 5-bromo-2-(trifluoromethyl)pyridine (92 mg, 0.41 mmol).
1H NMR (CDCl3, 400 MHz): δ=1.53 (d, 3H, J=7 Hz), 1.9-2.1 (m, 1H), 2.3-2.5 (m, 1H), 3.07 (dd, 1H, J=4.10 Hz), 3.3-3.5 (m, 2H), 3.5-3.7 (m, 2H), 4.5-4.7 (m, 1H), 5.69 (d, 1H, J=6 Hz), 6.75 (dd, 1H, J=3.7 Hz), 7.3-7.5 (m, 3H), 7.57 (d, 2H, J=8 Hz), 7.89 (d, 1H, J=3 Hz).
MS:454.09[M+Na]+
According to a technique similar to Example 3, a crude form of (R)-1-(5-(trifluoromethyl)pyridin-3-yl)piperidin-3-amine (166 mg) was synthesized from tert-butyl (R)-(1-(5-(trifluoromethyl)pyridin-3-yl)piperidin-3-yl)carbamate (76 mg, 0.219 mmol) synthesized in Reference Example 66, and the title compound (white powder, 70 mg, 74%) was obtained using (1S,2S)-2-(1H-benzo[d]imidazol-2-yl)cyclopropane-1-carboxylic acid (66 mg, 0.329 mmol).
1H NMR (DMSO-d6, 400 MHz): δ=1.4-1.6 (m, 4H), 1.7-1.9 (m, 2H), 2.2-2.5 (m, 2H), 2.88 (dd, 1H, J=9.12 Hz), 2.9-3.1 (m, 1H), 3.6-3.9 (m, 3H), 7.0-7.2 (m, 2H), 7.3-7.6 (m, 3H), 8.24 (s, 1H), 8.37 (d, 1H, J=7 Hz), 8.56 (d, 1H, J=3 Hz), 12.4 (br s, 1H).
MS:430.18[M+H]+
According to a technique similar to Example 1, the title compound (pale yellow powder, 36 mg, 58%) was obtained using (R)-1-(4-(trifluoromethyl)thiazol-2-yl)pyrrolidin-3-amine (38 mg, 0.160 mmol) synthesized in Reference Example 12-2 and 2-(1H-indol-6-yl)acetic acid (34 mg, 0.192 mmol).
1H NMR (CDCl3, 400 MHz): δ=1.7-1.9 (m, 1H), 2.2-2.4 (m, 1H), 3.19 (dd, 1H, J=5.11 Hz), 3.3-3.6 (m, 2H), 3.69 (s, 2H), 3.72 (dd, 1H, J=6.11 Hz), 4.5-4.7 (m, 1H), 5.59 (d, 1H, J=6 Hz), 6.5-6.6 (m, 1H), 6.89 (d, 1H, J=1 Hz), 6.95 (dd, 1H, J=1.8 Hz) 7.2-7.3 (m, 2H), 7.61 (d, 1H, J=8 Hz), 8.25 (br s, 1H).
MS:417.07[M+Na]+
Pharmacological Test 1
T-Type Calcium Blocking Action
(Testing Method)
(1) Construction of Cells Steadily Expressing Human Cav3.2 Channels
A sequence obtained by adding HindIII site and a kozak sequence (GCCACC) to the 5′-side of human Cav3.2 channel ORF (Open Reading Frame) gene and adding a KpnI site to the 3′-side of the gene, was incorporated into pcDNA3.1 (+) (Thermo Fisher Scientific, #V790-20), and the plasmid was introduced into HEK293 cells (ATCC No. CRL-1573) according to the protocol of FuGENE (registered trademark) HD Transfection Reagent (Promega, #E2311).
(2) Method for Measuring Intracellular Calcium Concentration
The cell strain steadily expressing human Cav3.2 channels as produced by the testing method (1) was seeded on a 96-well plate using DMEM including 10% FBS, and the cells were cultured for 48 hours under the conditions of 37° C. and 5% CO2. Subsequently, the medium was removed, and each of the wells were washed with buffer A and treated with 80 μL of a fluorescent dye solution including a mixed liquid of 22 μg of a fluorescent calcium indicator, Fluo-4 AM (Dojindo Molecular Technologies, Inc., #F311), 20 μL of dimethyl sulfoxide (DMSO), 1 μL of 10% Pluronic F-127 (Thermo Fisher Scientific, #P6866), and 4 mL of buffer A. After the cells were left to stand for 45 minutes at room temperature under light-shielded conditions, and then the cells were washed with buffer B. DMSO as a negative control and various test compound solutions each obtained by dissolving a test compound dissolved in DMSO, in buffer B so as to obtain a 10-fold concentration of the evaluation concentration, were introduced into respective wells. The final concentration of DMSO was adjusted to 0.1%. The cells were left to stand for another 15 minutes at room temperature under light-shielded conditions, and measurement was made using a microplate reader, EnVision (PerkinElmer Inc.) using the following method. First, the background fluorescence of each well was measured, subsequently an ionophore was introduced into each well, and the baseline fluorescence was measured. Subsequently, buffer B having 83.8 mM KCl added thereto was introduced, and an increase in fluorescence caused by calcium influx generated by the stimulus was measured for 10 seconds. The percentage inhibition was calculated from the maximum fluorescence increase value from the baseline, the logarithmic value of the test compound concentration and the inhibitory activity are plotted, and thereby the IC50 value was calculated. The measurement was carried out by observing the fluorescence at 510 nm that was emitted when the cells were irradiated with excitation light at 485 nm.
(Buffer Composition)
Buffer A: 140 mM NaCl, 5 mM KCl, 1 mM MgCl2, 0.5 mM CaCl2, 10 mM Glucose, 10 mM HEPES, pH 7.3
Buffer B: 137.9 mM Choline-Cl, 4.1 mM KCl, 1 mM MgCl2, 0.5 mM CaCl2, 10 mM Glucose, 10 mM HEPES, pH 7.3, equilibrium potential of potassium: −92 mV
(Test Results)
The test results are presented in Tables 1 to 4.
Pharmacological Test 2
Rat Formalin Test
(Testing Method)
30 mg/kg of a vehicle or a test substance was orally administrated to SD rats once, and according to the method described in McNamara C. R., Mandel-Brehm J., Bautista D. M., Siemens J., Deranian K. L., Zhao M., Hayward N. J., Chong J. A., Julius D., Moran M. M., Fanger C. M.: TRPA1 mediates formalin-induced pain. Proc. Natl. Acad. Sci. U.S.A. 104, 2007, 13525-13530, 50 μL of a 2.0% formalin solution as a pain-inducing substance was subcutaneously administered under the skin of the plantar plate of the right hind limb of each rat.
Regarding the analysis, pain behavior of the rats such as licking or biting of the site of formalin administration exhibited for 45 minutes after the formalin administration was cumulatively measured in seconds at an interval of 5 minutes, and the pain behavior time was calculated. Regarding the evaluation, the pain behavior inhibition ratio was determined from the pain behavior time of each test substance-administered group with respect to the pain behavior time of the vehicle-administered group for 15 minutes measured from 15 minutes to 30 minutes after the administration.
(Test Results)
The test results are presented in Table 5.
Pharmacological Test 3
Mechanical Allodynia in Mouse Partial Sciatic Nerve Ligation (PSNL) Model
(Testing Method)
The production of a mouse PSNL model was achieved according to the method of Seltzer et al. A mouse was subjected to inhalation anesthesia with isoflurane. The femoral region of the mouse was shaved and disinfected with isodine. The skin on a thighbone of the mouse was incised, the fascia directly under the skin was cut, and the muscle heads of the musculus biceps femoris were split. The sciatic nerve directly under the fascia was checked, and then the sciatic nerve was detached so as not to damage the nerve. The needle of a needle with 8-0 silk thread was passed through the sciatic nerve to penetrate therethrough, and the sciatic nerve was ligated for about ½ to ⅓ of the whole nerve. The skin was sutured, and the mouse was raised for about 7 days. For the surgical operation of a Sham control moue, only the checking of the sciatic nerve was carried out, and the skin was sutured.
The measurement of the pain threshold was carried out after transferring the mice into a cage for measurement and waiting for the exploratory behavior to disappear. Regarding the pain threshold (paw withdrawal filament ((g)), the plantar plates of the mice were stimulated with von Frey filaments (Sttoelting Co.: TOUCH-TEST SENSORY EVLUATOR) having different stimulus intensities, and the presence or absence of an escape response was observed. The 50% threshold was calculated by an up-down method with reference to the method of Chaplan et al. (Quantitative assessment of tactile allodynia in the rat paw. J neurosci Methods, 53, 1994, 55-63).
Regarding the efficacy evaluation, the compound described in Example 4 or Example 144 was orally administered to PSNL, and the effect on pain threshold was observed through a von Frey filament test.
(Test Results)
The results are presented in
As is obvious from
The compounds of the present invention can be used as pain treatment drugs.
| Number | Date | Country | Kind |
|---|---|---|---|
| 2018-134402 | Jul 2018 | JP | national |
| Filing Document | Filing Date | Country | Kind |
|---|---|---|---|
| PCT/JP2019/028168 | 7/17/2019 | WO |
