compound, medication, methods for activating a type 2 orexin receptor and for prophylaxis or treatme

专利摘要:
The present invention provides a heterocyclic compound with a type 2 orexin receptor agonist activity. A compound represented by formula (I): where each symbol is as described in the specification, or a salt thereof, is useful as an agent for prophylactic treatment of narcolepsy.
公开号:BR112020000823A2
申请号:R112020000823-0
申请日:2018-08-02
公开日:2020-07-21
发明作者:Keisuke Imamura；Yoshiteru Ito；Norihito Tokunaga；Takahiro Sugimoto；Tohru Miyazaki；Tsuneo Oda；Yasutaka Hoashi；Yasushi Hattori；Yuichi Kajita；Satoshi Mikami；Yuhei Miyanohana；Tatsuki Koike；Masaki Daini；Norio Oyabu；Masaki Ogino；Kohei Takeuchi
申请人:Takeda Pharmaceutical Company Limited；
IPC主号:

专利说明:

[001] [001] The present invention relates to a heterocyclic compound, particularly a heterocyclic compound with a type 2 orexin receptor agonist activity. (Background of the Invention)
[002] [002] Orexin is a neuropeptide produced specifically in specific neurons sparsely located in the lateral hypothalamus and its surrounding area, and consists of two subtypes, orexin A and orexin B. Both orexin A and orexin B are endogenous ligands of receptors for orexin, which are receptors coupled to protein G mainly present in the brain, and two types of subtypes, type 1 and type 2, are known as orexin receptors (non-patent document 1).
[003] [003] As orexin-producing neurons (orexin neurons) are located in close proximity to the feeding center, and intraventricular administration of the orexin peptide results in an increase in food intake, orexin initially attracted attention as a neuropeptide with behavioral regulation of food. Later, however, it was reported that the cause of canine narcolepsy is the genetic variation of the type 2 orexin receptor (non-patent document 2), and the role of orexin in controlling sleep and wakefulness was also attracted.
[004] [004] From the studies that used a transgenic mouse with denatured orexin neurons and a double transgenic mouse obtained by crossing that mouse with transgenic mouse with orexin overexpression, it was clarified that narcolepsy-like symptoms that appear due to degeneration of orexin neurons disappear due to prolonged orexin expression. Similarly,
[005] [005] Furthermore, it is suggested that a peptide agonist that acts selectively on the type 2 orexin receptor improves obesity due to the high fat load in the mice diet (non-patent document 7).
[006] [006] Furthermore, it is suggested that intraventricular administration of orexin peptide shortens the rat's systemic anesthetic time (non-patent document 8).
[007] [007] In addition, it is suggested that patients with sleep apnea syndrome have low levels of orexin A in plasma (non-patent document 9).
[008] [008] In addition, it is suggested that intraventricular administration of the orexin peptide improves memory retention in the senescence-accelerated model mouse (SAMP8) with cognitive dysfunction (non-patent document 10).
[009] [009] Furthermore, it is suggested that the type 2 orexin receptor agonist is a therapeutic drug for heart failure (patent document 1, non-patent document 11).
[0010] [0010] Furthermore, it is suggested that the daytime sleepiness of patients with Parkinson's disease is caused by precipitation of the orexin nerve (non-patent document 12).
[0011] [0011] Furthermore, it is suggested that orexin regulates bone formation and bone loss, and the type 2 orexin receptor agonist will be a therapeutic drug for diseases related to bone loss, such as osteoporosis, rheumatoid arthritis and the like (document of patent 2).
[0012] [0012] Furthermore, it is suggested that the orexin receptor agonist is useful for prophylaxis or treatment of sepsis, severe sepsis and septic shock, since mortality was significantly improved by the mere continuous administration of orexin from the periphery in model mice of septic shock (patent document 3).
[0013] [0013] Therefore, a compound with type 2 orexin receptor agonist activity is expected to be useful as a new therapeutic drug for narcolepsy, idiopathic hypersomnia, hypersomnia, sleep apnea syndrome, consciousness disorders, such as coma and the like, narcolepsy syndrome accompanied by symptoms similar to narcolepsy, hypersomnia syndrome accompanied by daytime hypersomnia (eg Parkinson's disease, Guillain-Barre syndrome and Kleine Levin syndrome), Alzheimer's, obesity, insulin resistance syndrome, heart failure, diseases related to bone loss, sepsis and the like, in addition to an anesthetic antagonist, a prophylactic or therapeutic drug for side effects.
[0014] [0014] As sulfonamide derivatives, a compound represented by the formula in which each symbol is as described in the document (Patent Document 4), a compound represented by the formula
[0015] [0015] Furthermore, as compounds with type 2 orexin receptor agonist activity, the following compounds have been reported.
[0016] [0016] A compound represented by the formula in which each symbol is as described in the document
[0017] [0017] A compound represented by the formula in which each symbol is as described in the document (Patent Document 6).
[0018] [0018] A compound represented by the formula in which each symbol is as described in the document (Patent Document 7).
[0019] [0019] A compound represented by the formula in which each symbol is as described in the document (Patent Document 8).
[0020] [0020] However, it is considered that these compounds are not satisfactory in terms of activity, pharmacokinetics or safety, and it is still desirable to develop a compound with type 2 orexin receptor agonist activity. List of documents Patent document
[0021] [0021] The present invention aims to provide a heterocyclic compound with type 2 orexin receptor agonist activity. Means for solving problems
[0022] [0022] The present inventors have found that a compound represented by the following formula (I) or a salt thereof (sometimes called compound (I) in this specification) has an orexin type 2 agonist activity. As a result of further studies, they completed the present invention.
[0023] [0023] Therefore, the present invention provides the following.
[1] [1] A compound represented by the formula:
[2] [2] The compound or salt of [1] mentioned above, where Ring B is a ring
[3] [3] The compound or salt of [1] mentioned above, where R1 is (1) a C1-6 alkyl group optionally substituted with 1 to 3 substituents selected from (a) a halogen atom, (b) a cyano group , (c) a hydroxy group, and (d) a C1-6 alkoxy group, (2) a C2-6 alkenyl group, (3) a C3-10 cycloalkyl group optionally substituted with 1 to 3 halogen atoms, (4 ) a mono- or di-C1-6 alkylamino group, or (5) a 3- to 14-membered non-aromatic heterocyclic group; R2 is a hydrogen atom; R3 is (1) a hydrogen atom, (2) an optionally substituted C1-6 alkoxycarbonyl group
[4] [4] The compound or salt of [1] mentioned above, where R1 is (1) a C1-6 alkyl group optionally substituted with 1 to 3 substituents selected from (a) a halogen atom, and (b) a group C1-6 alkoxy, (2) a C3-6 cycloalkyl group optionally substituted with 1 to 3 halogen atoms, or (3) a mono- or di-C1-6 alkylamino group; R2 is a hydrogen atom; R3 is (1) a C1-6 alkoxycarbonyl group, (2) a C1-6 alkylcarbonyl group optionally substituted with 1 to 3 hydroxy groups, (3) a mono- or di-C1-6 alkylcarbamoyl group , (4) an N-C1-6 alkyl-N-C1-6 alkoxy-carbamoyl group, (5) a C3-6 cycloalkyl-carbonyl group (the C3-6 cycloalkyl in the C3-6 cycloalkyl-carbonyl group can be a group of bridged rings) optionally substituted with 1 to 3 substituents selected from (a) a halogen atom, (b) a C1-6 alkyl group optionally substituted with 1 to 3 halogen atoms, (c) a hydroxy group, ( d) a C1-6 alkoxy group, and (e) a cyano group, (6) an oxetanylcarbonyl group,
[5] [5] The compound or salt of [1] mentioned above, where R1 is (1) a C1-6 alkyl group, (2) a C3-6 cycloalkyl group optionally substituted with 1 to 3 halogen atoms, or (3 ) a mono- or di-C 1-6 alkylamino group;
[6] [6] N - ((2S, 3S) -2 - (((2,3'-difluorobiphenyl-3-yl) methyl) -1- (2-hydroxy-2-methylpropanoyl) pyrrolidin-3-yl) ethanesulfonamide or a salt from it.
[7] [7] N - ((2S, 3S) -1- (2-hydroxy-2-methylpropanoyl) -2 - ((2,3 ', 5'-trifluorobiphenyl-3-yl) methyl) pyrrolidin-3-yl) methanesulfonamide or a salt thereof.
[8] [8] N - (((2S, 3S) -1- (2-hydroxy-2-methylpropanoyl) -2 - ((2,3 ', 5'-trifluorobiphenyl-3-yl) methyl) pyrrolidin-3-yl) ethanesulfonamide or a salt thereof.
[9] [9] A compound selected from (1) N - ((2S, 3S) -1- (azetidin-1-ylcarbonyl) -2 - ((2,3'-difluorobiphenyl-3-yl) methyl) pyrrolidin-3- yl) methanesulfonamide, (2) N - ((2S, 3S) -1- (azetidin-1-ylcarbonyl) -2 - ((3 ', 5'-difluorobiphenyl-3-yl) methyl) pyrrolidin-3-yl) ethanesulfonamide, (3) N - ((2S, 3S) -1- (azetidin-1-ylcarbonyl) -2- (biphenyl-3-
[10] [10] A medicine that comprises the compound or salt of
[1] [1] - [9] mentioned above.
[11] [11] The drug from [10] mentioned above, which is a type 2 orexin receptor agonist.
[12] [12] The drug from [10] mentioned above, which is a
[13] [13] The compound or salt of [1] - [9] mentioned above for use in the prophylaxis or treatment of narcolepsy.
[14] [14] A method for activating a type 2 orexin receptor in a mammal, which comprises administering an effective amount of the compound or salt of [1] - [9] mentioned above to the mammal.
[15] [15] A method for prophylaxis or treatment of narcolepsy in a mammal, comprising administering an effective amount of the compound or salt of [1] - [9] mentioned above to the mammal.
[16] [16] Use of the compound or salt of [1] - [9] mentioned above for the manufacture of an agent for the prophylaxis or treatment of narcolepsy. Effect of the invention
[0024] [0024] The compound of the present invention has an orexin type 2 receptor agonist activity and is useful as an agent for prophylaxis or treatment of narcolepsy. (Detailed Description of the Invention)
[0025] [0025] The definition of each substituent used in this specification is described in detail below. Unless otherwise specified, each substituent has the following definition.
[0026] [0026] In this specification, Examples of the “halogen atom” include fluorine, chlorine, bromine and iodine.
[0027] [0027] In this specification, Examples of the “C1-6 alkyl group” include methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, pentyl, isopentyl, neopentyl, 1-ethylpropyl, hexyl, isohexyl, 1,1-dimethylbutyl, 2,2-dimethylbutyl, 3,3-dimethylbutyl and 2-ethylbutyl.
[0028] [0028] In the present specification, Examples of the "optionally halogenated C1-6 alkyl group" include a C1-6 alkyl group with optionally 1 to 7, preferably 1 to 5 halogen atoms. Specific examples of the same include methyl, chloromethyl, difluoromethyl,
[0029] [0029] In this specification, Examples of the "C2-6 alkenyl group" include ethylene, 1-propenyl, 2-propenyl, 2-methyl-1-propenyl, 1-butenyl, 2-butenyl, 3-butenyl, 3- methyl-2-butenyl, 1-pentenyl, 2-pentenyl, 3-pentenyl, 4-pentenyl, 4-methyl-3-pentenyl, 1-hexenyl, 3-hexenyl and 5-hexenyl.
[0030] [0030] In this specification, Examples of the “C2-6 alkynyl group” include ethynyl, 1-propynyl, 2-propynyl, 1-butynyl, 2-butynyl, 3-butynyl, 1-pentynyl, 2-pentynyl, 3- pentynyl, 4-pentynyl, 1-hexynyl, 2-hexynyl, 3-hexynyl, 4-hexynyl, 5-hexynyl and 4-methyl-2-pentynyl.
[0031] [0031] In this specification, Examples of the “C3-10 cycloalkyl group” include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, bicycle [2.2.1] heptila, bicycle [2.2.2] octyl, bicycles [3.2.1] octyl and adamantyl.
[0032] [0032] In this specification, Examples of the "optionally halogenated C3-10 cycloalkyl group" include a C3-10 cycloalkyl group with optionally 1 to 7, preferably 1 to 5 halogen atoms. Specific examples thereof include cyclopropyl, 2,2-difluorocyclopropyl, 2,3-difluorocyclopropyl, cyclobutyl, difluorocyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl and cyclooctyl.
[0033] [0033] In this specification, Examples of the "C3-10 cycloalkenyl group" include cyclopropenyl, cyclobutenyl, cyclopentenyl, cyclohexenyl, cycloheptenyl and cyclooctenyl.
[0034] [0034] In this specification, Examples of the "C6-14 aryl group" include phenyl, 1-naphthyl, 2-naphthyl, 1-anthryl, 2-anthryl and 9-anthryl.
[0035] [0035] In this specification, Examples of the "C7-16 aralkyl group" include benzyl, phenethyl, naphthylmethyl and phenylpropyl.
[0036] [0036] In this specification, Examples of the "C1-6 alkoxy group" include methoxy, ethoxy, propoxy, isopropoxy, butoxy, isobutoxy, sec-butoxy, tert-butoxy, pentyloxy and hexyloxy.
[0037] [0037] In this specification, Examples of the "optionally halogenated C1-6 alkoxy group" include a C1-6 alkoxy group with optionally 1 to 7, preferably 1 to 5 halogen atoms. Specific examples of it include methoxy, difluoromethoxy, trifluoromethoxy, ethoxy, 2,2,2-trifluoroethoxy, propoxy, isopropoxy, butoxy, 4,4,4-trifluorobutoxy, isobutoxy, sec-butoxy, pentyloxy and hexyloxy.
[0038] [0038] In this specification, Examples of the "C3-10 cycloalkyloxy group" include cyclopropyloxy, cyclobutyloxy, cyclopentyloxy, cyclohexyloxy, cycloheptyloxy and cyclooctyloxy.
[0039] [0039] In this specification, Examples of the "C1-6 alkylthio group" include methylthio, ethylthio, propylthio, isopropylthio, butylthio, sec-butylthio, tert-butylthio, pentylthio and hexylthio.
[0040] [0040] In the present specification, Examples of the "optionally halogenated C1-6 alkylthio group" include a C1-6 alkylthio group with optionally 1 to 7, preferably 1 to 5 halogen atoms. Specific examples thereof include methylthio, difluoromethylthio, trifluoromethylthio, ethylthio, propylthio, isopropylthio, butylthio, 4,4,4-trifluorobutylthio, pentylthio and hexylthio.
[0041] [0041] In this specification, Examples of the "C1-6 alkylcarbonyl group" include acetyl, propanoyl, butanoyl, 2-methylpropanoyl, pentanoyl, 3-methylbutanoyl, 2-methylbutanoyl, 2,2-dimethylpropanoyl, hexanoyl and heptanoyl.
[0042] [0042] In this specification, Examples of the “optionally halogenated C1-6 alkylcarbonyl group” include a C1-6 alkyl-
[0043] [0043] In this specification, Examples of the "C1-6 alkoxycarbonyl group" include methoxycarbonyl, ethoxycarbonyl, propoxycarbonyl, isopropoxycarbonyl, butoxycarbonyl, isobutoxycarbonyl, sec-butoxycarbonyl, tert-butoxycarbonyl, pentyloxycarbonyl and hexyloxycarbonyl.
[0044] [0044] In this specification, Examples of the "C6-14 aryl-carbonyl group" include benzoyl, 1-naphthyl and 2-naphthyl.
[0045] [0045] In this specification, Examples of the "C7-16 aralkylcarbonyl group" include phenylacetyl and phenylpropionyl.
[0046] [0046] In the present specification, Examples of the "5- to 14-membered aromatic heterocyclylcarbonyl group" include nicotinoil, isonicotinoil, tenoyl and furoyl.
[0047] [0047] In this specification, Examples of the "3- to 14-membered non-aromatic heterocyclylcarbonyl group" include morpholinylcarbonyl, piperidinylcarbonyl and pyrrolidinylcarbonyl.
[0048] [0048] In this specification, Examples of the "mono- or di-C1-6 alkyl-carbamoyl group" include methylcarbamoyl, ethylcarbamoyl, dimethylcarbamoyl, diethylcarbamoyl and N-ethyl-N-methylcarbamoyl.
[0049] [0049] In this specification, Examples of the "mono- or di-C7-16 aralkyl-carbonyl group" include benzylcarbamoyl and phenethylcarbamoyl.
[0050] [0050] In this specification, Examples of the "C1-6 alkylsulfonyl group" include methylsulfonyl, ethylsulfonyl, propylsulfonyl, isopropylsulfonyl, butylsulfonyl, sec-butylsulfonyl and tert-butylsulfonyl.
[0051] [0051] In this specification, Examples of the "optionally halogenated C1-6 alkylsulfonyl group" include a C1-6 alkylsulfonyl group with optionally 1 to 7, preferably 1 to 5 halogen atoms. Specific examples of this include methylsulfonyl,
[0052] [0052] In this specification, Examples of the "C6-14 arylsulfonyl group" include phenylsulfonyl, 1-naphthylsulfonyl and 2-naphthylsulfonyl.
[0053] [0053] In this specification, Examples of the "substituent" include a halogen atom, a cyano group, a nitro group, an optionally substituted hydrocarbon group, an optionally substituted heterocyclic group, an acyl group, an optionally substituted amino group, an an optionally substituted carbamoyl group, an optionally substituted thiocarbamoyl group, an optionally substituted sulfamoyl group, an optionally substituted hydroxy group, an optionally substituted sulfanyl (SH) group and an optionally substituted silyl group.
[0054] [0054] In this specification, Examples of the "hydrocarbon group" (including "optionally substituted" hydrocarbon group ") include a C1-6 alkyl group, a C2-6 alkenyl group, a C2-6 alkynyl group, a C3-10 cycloalkyl group, a C3-10 cycloalkenyl group, a C6-14 aryl group and a C7-16 aralkyl group.
[0055] [0055] In this specification, Examples of the "optionally substituted hydrocarbon group" include a hydrocarbon group with optionally selected substituent (s) from the following group of substituents A. [Substituent group A] (1) a halogen atom , (2) a nitro group, (3) a cyano group, (4) an oxo group, (5) a hydroxy group, (6) an optionally halogenated C1-6 alkoxy group,
[0056] [0056] The number of the substituents mentioned above in the "optionally substituted hydrocarbon group" is, for example, 1 to 5, preferably 1 to 3. When the number of the substituents is two or more, the respective substituents can be the same or different.
[0057] [0057] In this specification, Examples of the "heterocyclic group" (including "optionally substituted heterocyclic group" heterocyclic group) include (i) an aromatic heterocyclic group, (ii) a non-aromatic heterocyclic group and (iii) a non-aromatic heterocyclic group 7 to 10-membered bridged heterocyclic group, each containing, as a ring constituent atom in addition to the carbon atom, 1 to 4 heteroatoms selected from a nitrogen atom, a sulfur atom and an oxygen atom.
[0058] [0058] In this specification, Examples of the "aromatic heterocyclic group" (including "5- to 14-membered aromatic heterocyclic group") include a 5- to 14-membered aromatic heterocyclic group (preferably 5 to 10 members) containing, as an atom constituent of the ring in addition to the carbon atom, 1 to 4 heteroatoms selected from a nitrogen atom, a sulfur atom and an oxygen atom.
[0059] [0059] Preferable examples of the "aromatic heterocyclic group" include 5- or 6-membered monocyclic aromatic heterocyclic groups such as thienyl, furyl, pyrrolyl, imidazolyl, pyrazolyl, thiazolyl, isothiazolyl,
[0060] [0060] In this specification, Examples of the "non-aromatic heterocyclic group" (including "3-14 membered non-aromatic heterocyclic group") include a 3-14 membered (preferably 4-10 membered) non-aromatic heterocyclic group containing, as a ring constituent atom in addition to the carbon atom, 1 to 4 heteroatoms selected from a nitrogen atom, a sulfur atom and an oxygen atom.
[0061] Preferred examples of the "non-aromatic heterocyclic group" include 3- to 8-membered monocyclic non-aromatic heterocyclic groups such as aziridinyl, oxiranyl, thyranyl, azetidinyl, oxetanyl, tietanyl, tetrahydrothienyl, tetrahydrofuranyl, pyrrolinyl, pyrrolinyl, pyrrolinyl, pyrrolinyl, pyrrolinyl, pyrrolinyl, pyrrolinyl, pyrrolinyl, pyrrolidinyl, pyrrolidinyl, pyrrolidinyl, pyrrolidinyl, pyrrolidinyl, pyrrolidinyl, pyrrolidinyl, pyrrolidinyl, pyrrolidinyl, pyrrolidinyl. , imidazolidinyl, oxazolinyl, oxazolidinyl, pyrazolinyl, pyrazolidinyl, thiazolinyl, thiazolidinyl, tetrahydroisothiazolyl, tetrahydro-oxazolyl, tetrahydroiso-oxazolyl, piperidinyl, piperazinyl, tetrahydropyridinyl, di
[0062] [0062] In this descriptive report, Preferable examples of the "7 to 10 membered heterocyclic bridging group" include quinuclidinyl and 7-azabicyclo [2.2.1] heptanyl.
[0063] [0063] In this specification, Examples of the "nitrogen-containing heterocyclic group" include a "heterocyclic group" containing at least one nitrogen atom as a ring constituent atom.
[0064] [0064] In this specification, Examples of the "optionally substituted heterocyclic group" include a heterocyclic group with optionally selected substituent (s) from the group of substituents A mentioned above.
[0065] [0065] The number of the substituents in the "optionally substituted heterocyclic group" is, for example, 1 to 3. When the number of the substituents is two or more, the respective substituents can be equal
[0066] [0066] In this specification, Examples of the "acyl group" include a formyl group, a carboxy group, a carbamoyl group, a thiocarbamoyl group, a sulfino group, a sulfo group, a sulfamoyl group and a phosphono group, each optionally with “1 or 2 substituents selected from a C1-6 alkyl group, a C2-6 alkenyl group, a C3-10 cycloalkyl group, a C3-10 cycloalkenyl group, a C6-14 aryl group, a C7-16 aralkyl group, a 5- to 14-membered aromatic heterocyclic group and a 3- to 14-membered non-aromatic heterocyclic group, each of which optionally has 1 to 3 substituents selected from a halogen atom, an optionally halogenated C1-6 alkoxy group, a hydroxy group , a nitro group, a cyano group, an amino group and a carbamoyl group ”.
[0067] [0067] Examples of the "acyl group" also include a hydrocarbon-sulfonyl group, a heterocyclylsulfonyl group, a hydrocarbon-sulfinyl group and a heterocyclylsulfinyl group.
[0068] [0068] Here, the hydrocarbon-sulfonyl group means a sulfonyl group attached to the hydrocarbon group, the heterocyclyl sulfonyl group means a sulfonyl group attached to the heterocyclic group, the hydrocarbon-sulfinyl group means a sulfinyl group attached to the hydrocarbon group and the heterocyclyl sulfinyl group means sulfinyl group attached to the heterocyclic group.
[0069] [0069] Preferable examples of the "acyl group" include a formyl group, a carboxy group, a C1-6 alkylcarbonyl group, a C2-6 alkenylcarbonyl group (for example, crotonoyl), a C3-10 cycloalkyl- carbonyl (for example, cyclobutanocarbonyl, cyclopentanocarbonyl, cyclohexanocarbonyl, cycloheptanocarbonyl), a C3-10 cycloalkenylcarbonyl group (eg, 2-cyclohexenocarbonyl), a C6-14 arylcarbonyl group, a C7- 16 aralkylcarbonyl, a heterocyclylcarbonyl group
[0070] [0070] In this specification, Examples of the "optionally substituted amino group" include an amino group with optionally "1 or 2 substituents selected from a C1-6 alkyl group, a C2-6 alkenyl group, a C3-10 cycloalkyl group, a C6-14 aryl group, a C7-16 aralkyl group, a C1-6 alkylcarbonyl group, a C6-14 arylcarbonyl group, a
[0071] Preferred examples of the optionally substituted amino group include an amino group, an optionally halogenated mono- or di- (C1-6 alkyl) amino group (e.g., methylamino, trifluoromethylamino, dimethylamino, ethylamino, diethylamino, propylamino, dibutylamino), a mono- or di-C2-6 alkenylamino group (for example, diallylamino), a mono- or di-C3-10 cycloalkylamino group (for example, cyclopropylamino, cyclohexylamino), a mono- or di-C6-14 group arylamino (for example, phenylamino), a mono- or di-C7-16 aralkylamino group (for example, benzylamino, dibenzylamino), a mono- or di- (C1-6 alkyl) - carbonylamino group optionally halogenated (for example, acetylamino , propionylamino), a mono- or di-C6-14 aryl-carbonylamino group (for example, benzoylamino), a mono- or di-C7-16 aralkyl-carbonylamino group (for example, benzylcarbonylamino), a mono- or di group - aromatic heterocyclylcarbonylamino of 5 to 14 members (for example, nicotinoylamino, isonicotinoylamino), a group m non-aromatic 3- to 14-membered ono- or di-heterocyclylcarbonylamino (for example, piperidinylcarbonylamino), a mono- or di-C1-6 alkoxycarbonylamino group (for example, tert-butoxycarbonylamino), an aromatic heterocyclyl group of 5 to 14 members (for example, pyridylamino), a carbamoylamino group, an (mono- or di-C1-6 alkyl-carbamoyl) amino group (for example, methylcarbamoylamino), a group (mono- or di-C7-16 aralkyl-
[0072] [0072] In this specification, Examples of the "optionally substituted carbamoyl group" include a carbamoyl group with optionally "1 or 2 substituents selected from a C1-6 alkyl group, a C2-6 alkenyl group, a C3-10 cycloalkyl group, a C6-14 aryl group, a C7-16 aralkyl group, a C1-6 alkylcarbonyl group, a C6-14 arylcarbonyl group, a C7-16 aralkylcarbonyl group, an aromatic heterocyclylcarbonyl group of 5 to 14 members , a 3- to 14-membered non-aromatic heterocyclylcarbonyl group, a 5- to 14-membered C1-6 alkoxycarbonyl group, a 5- to 14-membered aromatic heterocyclic group, a carbamoyl group, a mono- or di-C1-6 alkyl carbamoyl group and a mono- or di-C7-16 aralkyl carbamoyl group, each of which optionally has 1 to 3 substituents selected from the group of substituents A ”.
[0073] Preferable examples of the optionally substituted carbamoyl group include a carbamoyl group, a mono- or di-C1-6 alkyl-carbamoyl group, a mono- or di-C2-6 alkenyl-carbamoyl group (for example, diallyl-carbamoyl), a mono- or di-C3-10 cycloalkyl-carbamoyl group (for example, cyclopropylcarbamoyl, cyclohexylcarbamoyl), a mono- or di-C6-14 aryl-carbamoyl group (for example, phenylcarbamoyl), a mono- or di- C7-16 aralkyl-carbamoyl, a mono- or di-C1-6 alkyl-carbonyl-carbamoyl group (for example, acetylcarbamoyl, propionylcarbamoyl), a mono- or di-C6-14 aryl-carbonyl-carbamoyl group (for example, benzoylcarbamoyl) and a 5- to 14-membered aromatic heterocyclylcarbamoyl group (eg, pyridylcarbamoyl).
[0074] [0074] In this specification, Examples of the "optionally substituted thiocarbamoyl group" include a thiocarbamoyl group with optionally "1 or 2 substituents selected from a C1-6 alkyl group, a C2-6 alkenyl group, a C3-10 cycloalkyl group, a C6-14 aryl group, a C7-16 aralkyl group, a C1-6 alkylcarbonyl group, a C6-14 arylcarbonyl group, a C7-16 aralkylcarbonyl group, an aromatic heterocyclylcarbonyl group of 5 to 14 members , a 3- to 14-membered non-aromatic heterocyclylcarbonyl group, a 5- to 14-membered C1-6 alkoxycarbonyl group, a 5- to 14-membered aromatic heterocyclic group, a carbamoyl group, a mono- or di-C1-6 alkyl carbamoyl group and a mono- or di-C7-16 aralkyl carbamoyl group, each of which optionally has 1 to 3 substituents selected from the group of substituents A ”.
[0075] Preferred examples of the optionally substituted thiocarbamoyl group include a thiocarbamoyl group, a mono- or di-C1-6 alkyl-thiocarbamoyl group (e.g., methylthiocarbamoyl, ethylthiocarbamoyl, dimethylthiocarbamoyl, diethylthiocarbamoyl, N-ethylamyl-N-methyl-n-methyl-n-methyl-n-methyl-n-methyl-carbamyl, mono- or di-C2-6 alkenyl-thiocarbamoyl group (for example, diallylthiocarbamoyl), a mono- or di-C3-10 cycloalkyl-thiocarbamoyl group (for example, cyclopropylthiocarbamoyl, cyclohexylthiocarbamoyl), a mono- or di- C6-14 aryl-thiocarbamoyl (for example, phenylthiocarbamoyl), a mono- or di-C7-16 aralkyl-thiocarbamoyl group (for example, benzylthiocarbamoyl, phenethylthiocarbamoyl), a mono- or di-C1-6 alkyl-carbonyl-thiocarbamoyl group (for example, acetylthiocarbamoyl, propionylthiocarbamoyl), a mono- or di-C6-14 aryl-carbonyl-thiocarbamoyl group (for example, benzoylthiocarbamoyl) and an aromatic 5- to 14-membered heterocyclylthiocarbamoyl group (for example, pyridylthiocarbamoyl).
[0076] [0076] In this specification, Examples of the “optionally substituted sulfamoyl group” include a sulfamoyl group with
[0077] Preferred examples of the optionally substituted sulfamoyl group include a sulfamoyl group, a mono- or di-C1-6 alkylsulfamoyl group (e.g., methylsulfamoyl, ethylsulfamoyl, dimethylsulfamoyl, diethylsulfamoyl, N-ethyl-N-methylsulfamoyl), one mono- or di-C2-6 alkenyl sulfamoyl group (for example, diallylsulfamoyl), a mono- or di-C3-10 cycloalkyl sulfamoyl group (for example, cyclopropylsulfamoyl, cyclohexylsulfamoyl), a mono- or di- C6-14 aryl-sulfamoyl (for example, phenylsulfamoyl), a mono- or di-C7-16 aralkyl-sulfamoyl group (for example, benzylsulfamoyl, phenethylsulfamoyl), a mono- or di-C1-6 alkyl-carbonyl-sulfamoyl group (for example, acetylsulfamoyl, propionylsulfamoyl), a mono- or di-C6-14 aryl-carbonyl-sulfamoyl group (for example, benzoylsulfamoyl) and an aromatic heterocyclyl sulfamoyl group of 5 to 14 members (for example, pyridylsulfamoyl).
[0078] [0078] In this specification, Examples of the “optionally substituted hydroxy group” include a hydroxy group with optionally “a substituent selected from a C1-6 alkyl group, a C2-6 alkenyl group, a C3-10 cycloalkyl group, a group C6-14 aryl, a C7-16 aralkyl group, a C1-6 alkylcarbonyl group, a C6-14 arylcarbonyl group, a C7-16 aralkylcarbonyl group, an aromatic heterocyclylcarbonyl group of 5
[0079] Preferred examples of the optionally substituted hydroxy group include a hydroxy group, a C1-6 alkoxy group, a C2-6 alkenyloxy group (for example, allyloxy, 2-butenyloxy, 2-pentenyloxy, 3-hexenyloxy), a C3 group -10 cycloalkyloxy (eg, cyclohexyloxy), a C6-14 aryloxy group (eg, phenoxy, naphthyloxy), a C7-16 aralkyloxy group (eg, benzyloxy, phenethyloxy), a C1-6 alkylcarbonyloxy group (for example, acetyloxy, propionyloxy, butyryloxy, isobutyryloxy, pivaloyloxy), a C6-14 aryl-carbonyloxy group (for example, benzoyloxy), a C7-16 aralkyl-carbonyloxy group (for example, benzylcarbonyloxy), a heterocyclic carbonyloxycarbonyloxy group 5 to 14 members (for example, nicotinoyloxy), a 3- to 14-membered non-aromatic heterocyclylcarbonyloxy group (for example, piperidinylcarbonyloxy), a C1-6 alkoxycarbonyloxy group (for example, tert-butoxycarbonyloxy), an aromatic heterocyclyloxy group 5 to 14 members (eg, pyridyloxy), a carbam group oiloxy, a C1-6 alkyl-carbamoyloxy group (for example, methylcarbamoyloxy), a C7-16 aralkyl-carbamoyloxy group (for example, benzylcarbamoyloxy), a C1-6 alkylsulfonyloxy group (for example, methylsulfonyloxy, ethylsulfonyloxy) and a C6 group -14 arylsulfonyloxy (for example, phenylsulfonyloxy).
[0080] [0080] In this specification, Examples of the "optionally substituted sulfanyl group" include a sulfanyl group with optionally "a substituent selected from a C1-6 alkyl group, a C2-6 group
[0081] Preferred examples of the optionally substituted sulfanyl group include a sulfanyl group (-SH), a C1-6 alkylthio group, a C2-6 alkenyl thio group (for example, allyl, 2-butenylthio, 2-pentenylthio, 3-hexenylthio) , a C3-10 cycloalkylthio group (for example, cyclohexylthio), a C6-14 arylthio group (for example, phenylthio, naphthylthio), a C7-16 aralkylthio group (for example, benzylthio, phenethylthio), a C1- group 6 alkyl-carbonylthio (for example, acetylthio, propionylthio, butyrylthio, isobutyrylthio, pivaloylthio), a C6-14 aryl-carbonylthio group (for example, benzoylthio), an aromatic heterocyclyl group of 5 to 14 members (for example, pyridylthio) and a halogenated thio group (for example, pentafluorothio).
[0082] [0082] In this specification, Examples of the “optionally substituted silyl group” include a silyl group with optionally “1 to 3 substituents selected from a C1-6 alkyl group, a C2-6 alkenyl group, a C3-10 cycloalkyl group, a C6-14 aryl group and a C7-16 aralkyl group, each of which optionally has 1 to 3 substituents selected from the group of substituents A ”.
[0083] Preferable examples of the optionally substituted silyl group include a tri-C 1-6 alkylsilyl group (e.g., trimethylsilyl, tert-butyl (dimethyl) silyl).
[0084] [0084] In this specification, Examples of the “hydrocarbon ring” include a C6-14 aromatic hydrocarbon ring, C3-10 cycloalkane and C3-10 cycloalkene.
[0085] [0085] In this specification, Examples of the “C6-14 aromatic hydrocarbon ring” include benzene and naphthalene.
[0086] [0086] In this specification, Examples of the “C3-10 cycloalkane” include cyclopropane, cyclobutane, cyclopentane, cyclohexane, cycloheptane and cyclooctane.
[0087] [0087] In this specification, Examples of the "C3-10 cycloalkene" include cyclopropene, cyclobutene, cyclopentene, cyclohexene, cycloheptene and cyclooctene.
[0088] [0088] In this specification, Examples of the "heterocycle" include an aromatic heterocycle and a non-aromatic heterocycle, each containing, as a ring constituent atom in addition to the carbon atom, 1 to 4 hetero atoms selected from a nitrogen atom, a sulfur atom and an oxygen atom.
[0089] [0089] In the present specification, Examples of the "aromatic heterocycle" include an aromatic heterocycle of 5 to 14 members (preferably 5 to 10 members) containing, as an atom constituting the ring in addition to the carbon atom, 1 to 4 hetero atoms selected from a nitrogen atom, a sulfur atom and an oxygen atom. Preferable examples of the "aromatic heterocycle" include 5- or 6-membered monocyclic aromatic heterocycles such as thiophene, furan, pyrrole, imidazole, pyrazole, thiazole, isothiazole, oxazole, isoxazole, pyridine, pyrazine, pyrimidine, pyridazine, 1,2,4- oxadiazole, 1,3,4-oxadiazole, 1,2,4-thiadiazole, 1,3,4-thiadiazole, triazole, tetrazole, triazine and the like; and 8 to 14 membered fused polycyclic aromatic heterocycles (preferably bi or tricyclic) such as benzothiophene, benzofuran, benzimidazole, benzoxazole, benzisoxazole, benzothiazole, benzisothiazole, benzotriazole, imidazopyridine, thienopyridine, pyridine, pyridine, pyridine, pyridine, pyridine, pyridine imidazopyrimidine, thienopyrimidine, furopyrimidine, pyrrolpyrimidine, pyrazolpyrimidine, oxazolpyrimidine, thiazolpyrimidine, pyrazolpyrimidine, pyrazoltriazine, naphtho [2,3-b] thiophene, phenoxathine, indole, isoindol, 1-isoindole
[0090] [0090] In this specification, Examples of the "non-aromatic heterocycle" include a 3 to 14 membered (preferably 4 to 10 membered) non-aromatic heterocycle containing, as a ring constituent atom in addition to the carbon atom, 1 to 4 heteroatoms selected from a nitrogen atom, a sulfur atom and an oxygen atom. Preferable examples of the "non-aromatic heterocycle" include 3- to 8-membered monocyclic non-aromatic heterocycles such as aziridine, oxirane, thyrane, azetidine, oxetane, tiethane, tetrahydrothiophene, tetrahydrofuran, pyrroline, pyrrolidine, imidazoline, imidazolidine, oxazoline oxazolidine, pyrazoline, pyrazolidine, thiazoline, thiazolidine, tetrahydroisothiazole, tetrahydro-oxazole, tetrahydroisoxazole, piperidine, piperazine, tetrahydropyridine, dihydropyridine, dihydrothiopyran, tetrahydropyrimidine, tetrahydropyrimidine, tetrahydropyrimidine, hydropyran, tetrahydropyran, tetrahydrothiopyran, morpholine, thiomorpholine, azepane, diazepane, azepine, azocane, diazocane, oxepan and the like; and non-aromatic polycyclic heterocycles (preferably bi or tricyclic) fused from 9 to 14 members such as dihydrobenzofuran, dihydrobenzimidazole, dihydrobenzoxazol, dihydrobenzothiazole, dihydrobenzisothiazole, dihydronaphth [2,3-b] thiophene , tetrahydroisoquinoline, tetrahydroquinoline, 4H-quinolizine, indoline, isoindoline, tetrahydrothieno [2,3-c] pyridine, tetrahydrobenzazepine, tetrahydroxinoxaline, tetrahydrophenanthridine, hexahydrophenothiazine, hexahydrophenoxine - hydrophthalazine, tetrahydronaphthyridine, tetrahydroquinazoline, tetrahydrocinoline, tetrahydrocarbazole, tetrahydro-β-carboline, tetrahydroacridine, tetrahydrophenazine, tetrahydrotioxanthene, octahydroisoquinoline and the like.
[0091] [0091] In this specification, Examples of the “heterocycle
[0092] [0092] In this specification, Examples of the “4- to 7-membered saturated heterocyclic heterocycle include a 4- to 7-membered saturated heterocycle containing at least one nitrogen atom as a ring constituent atom, among the“ non-heterocycle aromatic monocyclic with 3 to 8 members ”.
[0093] [0093] In this specification, Examples of the "ring" include a "hydrocarbon ring" and a "heterocycle".
[0094] [0094] The definition of each symbol in formula (I) is explained in detail below. R1 is a substituent. R1 is preferably (1) an optionally substituted C1-6 alkyl group (for example, methyl, ethyl, propyl, isopropyl, butyl, isobutyl), (2) an optionally substituted C2-6 alkenyl group (for example, vinyl, ally) , (3) an optionally substituted C3-10 cycloalkyl group (for example, cyclopropyl), (4) an optionally substituted mono- or di-C1-6 alkylamino group (for example, dimethylamino), or (5) a non-heterocyclic group optionally substituted 3-14 membered aromatic (preferably a 3-8 membered non-aromatic monocyclic heterocyclic group (e.g., oxetanyl)).
[0095] [0095] Examples of the substituent of the "optionally substituted C1-6 alkyl group", "optionally substituted C2-6 alkenyl group", "optionally substituted C3-10 cycloalkyl group", "optionally substituted mono- or di-C1-6 alkylamino group" ”And“ optionally substituted 3- to 14-membered non-aromatic heterocyclic group ”include substituents selected from
[0096] [0096] R1 is more preferably (1) a C1-6 alkyl group (for example, methyl, ethyl, propyl, isopropyl, butyl, isobutyl) optionally substituted with 1 to 3 substituents selected from (a) a halogen atom (for Example, a fluorine atom, a chlorine atom), (b) a cyano group, (c) a hydroxy group, and (d) a C1-6 alkoxy group (for example, methoxy), (2) a C2 group -6 alkenyl (for example, vinyl, allyl), (3) a C3-10 cycloalkyl group (for example, cyclopropyl), (4) a mono- or di-C1-6 alkylamino group (for example, dimethylamino), or (5) a 3- to 14-membered non-aromatic heterocyclic group (preferably a 3- to 8-membered non-aromatic heterocyclic group (e.g., oxetanyl)).
[0097] [0097] R1 is even more preferably (1) a C1-6 alkyl group (e.g., methyl, ethyl, propyl, isopropyl, butyl, isobutyl) optionally substituted with 1 to 3 substituents selected from (a) a halogen atom ( for example, a fluorine atom, a chlorine atom), (b) a cyano group, (c) a hydroxy group, and (d) a C1-6 alkoxy group (for Example, methoxy), (2) a group C2-6 alkenyl (for example, vinyl, allyl),
[0098] [0098] R1 is even more preferably (1) a C1-6 alkyl group (for example, methyl, ethyl, propyl) optionally substituted with 1 to 3 substituents selected from (a) a halogen atom (for example, a fluorine, a chlorine atom), and (b) a C1-6 alkoxy group (for example, methoxy), (2) a C3-6 cycloalkyl group (for example, cyclopropyl), or (3) a mono- or di-C1-6 alkylamino (for example, dimethylamino).
[0099] [0099] R1 is particularly preferably (1) a C1-6 alkyl group (for example, methyl, ethyl) optionally substituted with 1 to 3 substituents selected from (a) a halogen atom (for example, a fluorine atom), and (b) a C1-6 alkoxy group (for example, methoxy), or (2) a C3-6 cycloalkyl group (for example, cyclopropyl).
[00100] [00100] As another embodiment, R1 is more preferably (1) a C1-6 alkyl group (for example, methyl, ethyl, propyl, isopropyl, butyl, isobutyl) optionally substituted with 1 to 3 substituents selected from (a) a halogen atom (for example, a fluorine atom, a chlorine atom), (b) a cyano group, (c) a hydroxy group, and (d) a C1-6 alkoxy group (for example, methoxy),
[00101] [00101] In this embodiment, R1 is even more preferably (1) a C1-6 alkyl group (for example, methyl, ethyl, propyl, isopropyl, butyl, isobutyl) optionally substituted with 1 to 3 substituents selected from (a) an atom halogen (for example, a fluorine atom, a chlorine atom), (b) a cyano group, (c) a hydroxy group, and (d) a C1-6 alkoxy group (for example, methoxy), (2 ) a C2-6 alkenyl group (for example, vinyl, allyl), (3) a C3-6 cycloalkyl group (for example, cyclopropyl) optionally substituted with 1 to 3 halogen atoms (for example, a fluorine atom), (4) a mono- or di-C 1-6 alkylamino group (for example, dimethylamino), or (5) an oxetanyl group.
[00102] [00102] In this embodiment, R1 is even more preferably (1) a C1-6 alkyl group (for example, methyl, ethyl, propyl) optionally substituted with 1 to 3 substituents selected from (a) a halogen atom (for example, a fluorine atom,
[00103] [00103] In this embodiment, R1 is even more preferably (1) a C1-6 alkyl group (for example, methyl, ethyl) optionally substituted with 1 to 3 substituents selected from (a) a halogen atom (for example, an atom fluorine), and (b) a C1-6 alkoxy group (for example, methoxy), (2) a C3-6 cycloalkyl group (for example, cyclopropyl) optionally substituted with 1 to 3 halogen atoms (for example, one fluorine atom), or (3) a mono- or di-C1-6 alkylamino group (for example, dimethylamino).
[00104] [00104] In this embodiment, R1 is particularly preferably (1) a C1-6 alkyl group (for example, methyl, ethyl), (2) a C3-6 cycloalkyl group (for example, cyclopropyl) optionally substituted with 1 to 3 atoms halogen (for example, a fluorine atom), or (3) a mono- or di-C1-6 alkylamino group (for example, dimethylamino).
[00105] [00105] Or, R1 is particularly preferably a C1-6 alkyl group (for example, methyl, ethyl).
[00106] [00106] R2, R3, R4 and R5 are each independently a hydrogen atom, or a substituent.
[00107] [00107] R2 is preferably a hydrogen atom.
[00108] [00108] R3 is preferably a hydrogen atom or an acyl group.
[00109] [00109] R3 is more preferably (1) a hydrogen atom, (2) an optionally substituted C1-6 alkoxycarbonyl group (e.g., methoxycarbonyl, ethoxycarbonyl, propoxycarbonyl, isopropoxycarbonyl, butoxycarbonyl, isobutoxycarbonyl, sec-butoxycarbonyl, tert- butoxycarbonyl, 1,2-dimethylpropoxycarbonyl), (3) an optionally substituted C1-6 alkylcarbonyl group (for example, acetyl, propanoyl, 2-methylpropanoyl, butanoyl, 2-methylbutanoyl, 3-methylbutanoyl, pivaloyl), (4) an optionally substituted mono- or di-C1-6 alkylcarbamoyl group (for example, dimethylcarbamoyl, ethylcarbamoyl, N-ethyl-N-methylcarbamoyl), (5) an optionally substituted C3-10 cycloalkylcarbonyl group (at C3-10 cycloalkyl in the C3-10 group cycloalkylcarbonyl can be a bridged ring group, for example, cyclopropylcarbonyl, cyclobutylcarbonyl, cyclopentylcarbonyl, bicyclo [1.1.1] pentylcarbonyl), (6) an optionally substituted C3-10 cycloalkoxycarbonyl group (for example lo, cyclopropoxycarbonyl, cyclobutyloxycarbonyl, cyclopentyloxycarbonyl, cyclohexyloxycarbonyl), (7) an optionally substituted 3 to 14 membered non-aromatic heterocyclylcarbonyl group (preferably a 3 to 8 membered non-aromatic monocyclic heterocyclylcarbonyl group in the heterocyclic non-aromatic heterocyclyl group in the heterocyclic non-aromatic heterocyclic group aromatic can be a spiro ring, for example, oxetanylcarbonyl, azetidinylcarbonyl, 5-azaspiro [2.3] hexylcarbonyl)), (8) a non-aromatic heterocyclyloxycarbonyl group from 3 to 14
[00110] [00110] Examples of the substituent of "optionally substituted C1-6 alkoxycarbonyl group", "optionally substituted C1-6 alkylcarbonyl group", "optionally substituted mono- or di-C1-6 alkylcarbamoyl group", "group Optionally substituted C3-10 cycloalkylcarbonyl group "," optionally substituted C3-10 cycloalkoxycarbonyl group "," optionally substituted 3 to 14 membered non-aromatic heterocyclylcarbonyl group "," optionally substituted 3 to 14 membered non-aromatic heterocyclylcarbonyl group ", "Optionally substituted C6-14 aryloxycarbonyl group" and "optionally substituted C7-16 aralkyloxycarbonyl group" mentioned above include the "substituent" mentioned above. The number of the substituents is preferably 1 to 3. When the number of the substituents is 2 or more, the respective substituents can be the same or different.
[00111] [00111] R3 is even more preferably (1) a hydrogen atom, (2) a C1-6 alkoxycarbonyl group (e.g., methoxycarbonyl, ethoxycarbonyl, propoxycarbonyl, isopropoxycarbonyl, butoxycarbonyl, isobutoxycarbonyl, sec-butoxycarbonyl, tert-butoxycarbonyl , 1,2-dimethylpropoxycarbonyl) optionally substituted with 1 to 3 substituents selected from (a) a halogen atom (for example, a fluorine atom),
[00112] [00112] R3 is even more preferably (1) a hydrogen atom, (2) a C1-6 alkoxycarbonyl group (e.g., methoxycarbonyl, ethoxycarbonyl, propoxycarbonyl, isopropoxycarbonyl, butoxycarbonyl, isobutoxycarbonyl, sec-butoxycarbonyl, tert-
[00113] [00113] R3 is even more preferably (1) a C1-6 alkoxycarbonyl group (for example, methoxycarbonyl, ethoxycarbonyl, isopropoxycarbonyl), (2) a C1-6 alkylcarbonyl group (for example, acetyl, 2-methylpropanoyl , pivaloyl), (3) a mono- or di-C1-6 alkyl-carbamoyl group (for example, dimethylcarbamoyl, ethylcarbamoyl), (4) a C3-6 cycloalkyl-carbonyl group (a C3-6 cycloalkyl in the
[00114] [00114] R3 is particularly preferably (1) a C1-6 alkoxycarbonyl group (for example, ethoxycarbonyl, isopropoxycarbonyl), (2) a C1-6 alkylcarbonyl group (for example, 2-methylpropanoyl, pivaloyl), ( 3) a C3-6 cycloalkyl-carbonyl group (the C3-6 cycloalkyl in the C3-6 cycloalkyl-carbonyl group can be a bridged ring group, for example, cyclopropylcarbonyl, cyclobutylcarbonyl, bicycles [1.1.1] pentylcarbonyl) optionally replaced with 1 to 3
[00115] [00115] As another embodiment, R3 is more preferably (1) a hydrogen atom, (2) an optionally substituted C1-6 alkoxycarbonyl group (for example, methoxycarbonyl, ethoxycarbonyl, propoxycarbonyl, isopropoxycarbonyl, butoxycarbonyl, isobutoxycarbonyl, sec -butoxycarbonyl, tert-butoxycarbonyl, 1,2-dimethylpropoxycarbonyl), (3) an optionally substituted C1-6 alkylcarbonyl group (for example, acetyl, propanoyl, 2-methylpropanoyl, butanoyl, 2-methylbutanoyl, 3-methylbutanoyl, pivaloyl ), (4) an optionally substituted mono- or di-C1-6 alkylcarbamoyl group (for example, dimethylcarbamoyl, ethylcarbamoyl, N-ethyl-N-methylcarbamoyl, N-isopropyl-N-methylcarbamoyl), (5) N-C1-6 alkyl-N-C1-6 alkoxycarbamoyl optionally substituted (for example, N-methoxy-N-methylcarbamoyl), (6) an optionally C3-10 cycloalkylcarbonyl group
[00116] [00116] Examples of the substituent of "optionally substituted C1-6 alkoxycarbonyl group", "optionally substituted C1-6 alkylcarbonyl group", "optionally substituted mono- or di-C1-6 alkylcarbonyl group", "group N-C1-6 alkyl-N-C1-6 optionally substituted alkoxycarbonyl group ”,“ optionally substituted C3-10 cycloalkylcarbonyl group ”,“ optionally substituted C3-10 cycloalkoxycarbonyl group ”,“ non-aromatic heterocyclyl carbonyl group of 3 optionally substituted to 14 members ”,“ non-aromatic heterocyclyloxycarbonyl group 3 to 14
[00117] [00117] In this embodiment, R3 is even more preferably (1) a hydrogen atom, (2) a C1-6 alkoxycarbonyl group (e.g., methoxycarbonyl, ethoxycarbonyl, propoxycarbonyl, isopropoxycarbonyl, butoxycarbonyl, isobutoxycarbonyl, sec-butoxycarbonyl, tert-butoxycarbonyl, 1,2-dimethylpropoxycarbonyl) optionally substituted with 1 to 3 substituents selected from (a) a halogen atom (for example, a fluorine atom), (b) a C1-6 alkoxy group (for example, methoxy ), (c) a C3-10 cycloalkyl group (eg, cyclopropyl, cyclobutyl, cyclopentyl) optionally substituted with 1 to 3 substituents selected from (i) a halogen atom (eg, a fluorine atom), and (ii ) a C1-6 alkyl group (for example, methyl), and (d) a 3- to 14-membered non-aromatic heterocyclic group (preferably a 3- to 8-membered non-aromatic monocyclic heterocyclic group (for example, oxetanyl, tetrahydrofuryl )), (3) a C1-6 alkylcarbonyl group (for example, acetyl la, propanoyl, 2-methylpropanoyl, butanoyl, 2-methylbutanoyl, 3-methylbutanoyl, pivaloyl) optionally substituted with 1 to 3 substituents selected from (a) a halogen atom (eg, a fluorine atom), (b) a C3-10 cycloalkyl group (eg cyclopropyl),
[00118] [00118] In this embodiment, R3 is even more preferably (1) a hydrogen atom, (2) a C1-6 alkoxycarbonyl group (e.g., methoxycarbonyl, ethoxycarbonyl, propoxycarbonyl, isopropoxycarbonyl, butoxycarbonyl, isobutoxycarbonyl, sec-butoxycarbonyl, tert-butoxycarbonyl, 1,2-dimethylpropoxycarbonyl) optionally substituted with 1 to 3 substituents selected from (a) a halogen atom (for example, a fluorine atom), (b) a C1-6 alkoxy group (for example, methoxy ), (c) a C3-6 cycloalkyl group (eg, cyclopropyl, cyclobutyl, cyclopentyl) optionally substituted with 1 to 3 substituents selected from (i) a halogen atom (eg, a fluorine atom), and (ii ) a C1-6 alkyl group (for example, methyl), (d) an oxetanyl group, and
[00119] [00119] In this embodiment, R3 is even more preferably (1) a C1-6 alkoxycarbonyl group (for example, methoxycarbonyl, ethoxycarbonyl, isopropoxycarbonyl), (2) a C1-6 alkyl-carbonyl group (for example, acetyl, 2-methylpropanoyl, pivaloyl) optionally substituted with 1 to 3 hydroxy groups, (3) a mono- or di-C1-6 alkyl-carbamoyl group (for example, dimethylcarbamoyl, ethylcarbamoyl), (4) a C3-6 cycloalkyl- group carbonyl (the C3-6 cycloalkyl in the C3-6 cycloalkyl-carbonyl group can be a bridged ring group, For example, cyclopropylcarbonyl, cyclobutylcarbonyl, bicyclo [1.1.1] pentylcarbonyl) optionally substituted with 1 to 3 substituents selected from ( a) a halogen atom (for example, a fluorine atom), (b) a C1-6 alkyl group (for example, methyl) optionally
[00120] [00120] In this embodiment, R3 is particularly preferably (1) a C1-6 alkoxycarbonyl group (for example, ethoxycarbonyl, isopropoxycarbonyl), (2) a C1-6 alkylcarbonyl group (for example, 2-methylpropanoyl, pivaloyl ) optionally substituted with 1 to 3 hydroxy groups, (3) a mono- or di-C1-6 alkyl-carbamoyl group (e.g., dimethylcarbamoyl), (4) a C3-6 cycloalkyl-carbonyl group (to C3-6 cycloalkyl in the C3-6 cycloalkylcarbonyl group it can be a bridged ring group, for example, cyclopropylcarbonyl, cyclobutylcarbonyl, bicyclo [1.1.1] pentylcarbonyl) optionally substituted with 1 to 3 substituents selected from (a) a halogen atom ( (for example, a fluorine atom), (b) a C1-6 alkyl group (for example, methyl) optionally
[00121] [00121] As another embodiment, R3 is more preferably (1) a hydrogen atom, (2) an optionally substituted C1-6 alkoxycarbonyl group (for example, methoxycarbonyl, ethoxycarbonyl, propoxycarbonyl, isopropoxycarbonyl, butoxycarbonyl, isobutoxycarbonyl, sec -butoxycarbonyl, tert-butoxycarbonyl, 1,2-dimethylpropoxycarbonyl), (3) an optionally substituted C1-6 alkylcarbonyl group (for example, acetyl, propanoyl, 2-methylpropanoyl, butanoyl, 2-methylbutanoyl, 3-methylbutanoyl, pivaloyl ), (4) an optionally substituted mono- or di-C1-6 alkylcarbamoyl group (for example, dimethylcarbamoyl, ethylcarbamoyl, N-ethyl-N-methylcarbamoyl, N-isopropyl-N-methylcarbamoyl), (5) N-C1-6 alkyl-N-C1-6 alkoxycarbamoyl optionally substituted (for example, N-methoxy-N-methylcarbamoyl), (6) an optionally substituted C3-10 cycloalkylcarbonyl group (a C3-10 cycloalkyl in C3-10 cycloalkylcarbonyl group may be a bridged ring group, for example plo, cyclopropylcarbonyl, cyclobutylcarbonyl, cyclopentylcarbonyl, bicycles [1.1.1] pentylcarbonyl),
[00122] [00122] Examples of the substituent of "optionally substituted C1-6 alkoxycarbonyl group", "optionally C1-6 alkylcarbonyl group
[00123] [00123] In this embodiment, R3 is even more preferably (1) a hydrogen atom, (2) a C1-6 alkoxycarbonyl group (e.g., methoxycarbonyl, ethoxycarbonyl, propoxycarbonyl, isopropoxycarbonyl, butoxycarbonyl, isobutoxycarbonyl, sec-butoxycarbonyl, tert-butoxycarbonyl, 1,2-dimethylpropoxycarbonyl) optionally substituted with 1 to 3 substituents selected from (a) a halogen atom (for example, a fluorine atom), (b) a C1-6 alkoxy group (for example, methoxy ), (c) a C3-10 cycloalkyl group (for example, cyclopropyl, cyclobutyl, cyclopentyl) optionally substituted with 1 to 3 substituents selected from (i) a halogen atom (for example, a fluorine atom), and
[00124] [00124] In this embodiment, R3 is even more preferably (1) a hydrogen atom, (2) a C1-6 alkoxycarbonyl group (e.g., methoxycarbonyl, ethoxycarbonyl, propoxycarbonyl, isopropoxycarbonyl, butoxycarbonyl, isobutoxycarbonyl, sec-butoxycarbonyl, tert-butoxycarbonyl, 1,2-dimethylpropoxycarbonyl) optionally substituted with 1 to 3 substituents selected from (a) a halogen atom (for example, a fluorine atom), (b) a C1-6 alkoxy group (for example, methoxy ), (c) a C3-6 cycloalkyl group (eg, cyclopropyl, cyclobutyl, cyclopentyl) optionally substituted with 1 to 3 substituents selected from (i) a halogen atom (eg, a fluorine atom), and (ii ) a C1-6 alkyl group (for example, methyl), (d) an oxetanyl group, and (e) a tetrahydrofuryl group, (3) a C1-6 alkylcarbonyl group (for example, acetyl,
[00125] [00125] In this modality, R3 is even more preferably
[00126] [00126] In this embodiment, R3 is even more preferably (1) a C1-6 alkoxycarbonyl group (for example, ethoxycarbonyl, isopropoxycarbonyl), (2) a C1-6 alkylcarbonyl group (for example, 2-methylpropanoyl, pivaloyl) optionally substituted with 1 to 3 hydroxy groups, (3) a mono- or di-C1-6 alkyl-carbamoyl group (e.g., dimethylcarbamoyl), (4) an N-C1-6 alkyl-N-C1- group 6 alkoxy-carbamoyl (for example, N-methoxy-N-methylcarbamoyl), (5) a C3-6 cycloalkyl-carbonyl group (the C3-6 cycloalkyl in the C3-6 cycloalkyl-carbonyl group can be a ring group attached at bridge, for example, cyclopropylcarbonyl, cyclobutylcarbonyl, bicyclo [1.1.1] pentylcarbonyl) optionally substituted with 1 to 3 substituents selected from (a) a halogen atom (eg, a fluorine atom), (b) a C1- group 6 alkyl (for example, methyl) optionally substituted with 1 to 3 halogen atoms (for example, a fluorine atom), (c) a hydroxy group, (d) a C1-6 alkoxy group (for Exe (methoxy), and (e) a cyano group, (6) an oxetanylcarbonyl group, (7) an azetidinylcarbonyl group optionally substituted with 1 to 3 substituents selected from (a) a halogen atom (for example, a fluorine atom ), and (b) a C1-6 alkyl group (for example, methyl), or (8) a 5-azaspiro [2.3] hexylcarbonyl group.
[00127] [00127] In this embodiment, R3 is particularly preferably (1) a C1-6 alkylcarbonyl group (e.g., 2-methylpropanoyl) optionally substituted with 1 to 3 hydroxy groups, (2) a mono- or di-C1- group 6 alkyl-carbamoyl (for example, dimethylcarbamoyl), (3) an N-C1-6 alkyl-N-C1-6 alkoxy-carbamoyl group (for example, N-methoxy-N-methylcarbamoyl), or (4) a group azetidinylcarbonyl.
[00128] [00128] Or, R3 is particularly preferably a C1-6 alkylcarbonyl group (for example, 2-methylpropanoyl) optionally substituted with 1 to 3 hydroxy groups.
[00129] [00129] R4 and R5 are preferably each independently a hydrogen atom or a halogen atom (for example, a fluorine atom).
[00130] [00130] R4 and R5 are particularly preferably both hydrogen atoms.
[00131] [00131] Ring A is a saturated monocyclic heterocycle containing 4 to 7 membered nitrogen optionally optionally substituted.
[00132] [00132] Ring A has optionally substituent (s), in addition to R3, - NR2SO2R1 and -CR4R5-Ring B in formula (I). Examples of the substituent include the "substituent" mentioned above. The number of the substituents is preferably 1 to 3. When the number of the substituents is 2 or more, the respective substituents can be the same or different.
[00133] [00133] Ring A is preferably (1) an optionally substituted pyrrolidine ring, (2) an optionally substituted piperidine ring, or (3) an optionally substituted azetidine ring
[00134] [00134] Ring A is most preferably (1) a pyrrolidine ring, (2) a piperidine ring, or (3) an azetidine ring.
[00135] [00135] Ring A is even more preferably (1) a pyrrolidine ring, or (2) a piperidine ring.
[00136] [00136] Ring B is an optionally additionally replaced ring.
[00137] [00137] Ring B has optionally substituent (s), in addition to -CR4R5- Ring A in formula (I). Examples of the substituent include the "substituent" mentioned above. The number of the substituents is preferably 1 to 3. When the number of the substituents is 2 or more, the respective substituents can be the same or different.
[00138] [00138] Ring B is preferably (1) an optionally substituted C6-14 aromatic hydrocarbon ring (for example, benzene, naphthalene), (2) an optionally substituted 5 to 14 membered aromatic heterocycle (preferably a monocyclic aromatic heterocycle 5- to 6-membered (for example, pyridine, pyrazole, thiazole, oxazole)) or (3) an optionally substituted 3- to 14-membered non-aromatic heterocycle (preferably a 3- to 8-membered monocyclic non-aromatic heterocycle (eg, pyrrolidine , piperidine), a non-aromatic polycyclic heterocycle (preferably bi- or tricyclic) fused from 9 to 14 members (for example, dibenzofuran)).
[00139] [00139] Ring B is more preferably (1) a C6-14 aromatic hydrocarbon ring (for example, benzene, naphthalene) optionally substituted with 1 to 3
[00140] [00140] Ring B is even more preferably (1) a benzene ring optionally substituted additionally with 1 to 3 substituents selected from (a) a halogen atom (for example, a fluorine atom, a chlorine atom, an atom of bromine, an iodine atom), (b) a C1-6 alkyl group (eg, methyl, isopropyl) optionally substituted with 1 to 3 halogen atoms (eg, a fluorine atom), (c) a C2 group -6 alkenyl (for example, vinyl, propen-2-yl), (d) a mono- or di-C1-6 alkylamino group (for example, dimethylamino), (e) a tri-C1-6 alkylsilyloxy group (for Example, triisopropylsilyloxy), (f) a C6-14 aryl group (for example, phenyl) optionally substituted with 1 to 4 substituents selected from (i) a halogen atom (for example, a fluorine atom, an atom of chlorine), (ii) a C1-6 alkyl group (for example, methyl) optionally substituted with 1 to 3 halogen atoms (for example, a fluorine atom), and (iii) a C1-6 alkoxy group (for example , methoxy), (g) a C6-14 aryloxy group (for example, phenoxy), (h) a C7-16 aralkyl group (for example, benzyl) optionally substituted with 1 to 3 C1-6 alkyl groups (for example, methyl ), (i) a C3-10 cycloalkyl group (for example, cyclopropyl, cyclobutyl), (j) a C3-10 cycloalkenyl group (for example, cyclopenten-1-
[00141] [00141] Ring B is even more preferably (1) a benzene ring optionally substituted additionally with 1 to 3 substituents selected from (a) a halogen atom (for example, a fluorine atom, a chlorine atom, an atom of bromine, an iodine atom), (b) a C1-6 alkyl group (eg, methyl, isopropyl) optionally substituted with 1 to 3 halogen atoms (eg, a fluorine atom), (c) a C2 group -6 alkenyl (for example, vinyl, propen-2-yl), (d) a mono- or di-C1-6 alkylamino group (for example, dimethylamino), (e) a tri-C1-6 alkylsilyloxy group (for Example, triisopropylsilyloxy), (f) a phenyl group optionally substituted with 1 to 4 substituents selected from (i) a halogen atom (for example, a fluorine atom, a chlorine atom), (ii) a C1 group -6 alkyl (eg methyl)
[00142] [00142] Ring B is even more preferably (1) a benzene ring further substituted with 1 or 2 substituents selected from (a) a halogen atom (e.g., a fluorine atom), (b) a C2-6 group alkenyl (for example, propen-2-yl), (c) a tri-C 1-6 alkylsilyloxy group (for example, triisopropylsilyloxy), (d) a phenyl group optionally substituted with 1 to 3 substituents selected from (i) a halogen atom (for example, a fluorine atom, a chlorine atom), and (ii) a C1-6 alkyl group (for example, methyl) optionally substituted with 1 to 3 halogen atoms (for example, an atom fluorine), (e) a phenoxy group,
[00143] [00143] Ring B is particularly preferably (1) a benzene ring further substituted with 1 or 2 substituents selected from (a) a halogen atom (for example, a fluorine atom), and (b) an optionally substituted phenyl group with 1 to 3 substituents selected from (i) a halogen atom (for example, a fluorine atom,
[00144] [00144] As in another embodiment, ring B is preferably (1) an optionally substituted C6-14 aromatic hydrocarbon ring (for example, benzene, naphthalene), (2) an optionally substituted 5 to 14 membered aromatic heterocycle (preferably a 5- to 6-membered monocyclic aromatic heterocycle (for example, pyridine, pyrazole, thiazole, oxazole), an 8 to 14-membered fused polycyclic (preferably bi- or tricyclic) heterocycle (for example, benzofuran)), or (3 ) an optionally substituted 3- to 14-membered non-aromatic heterocycle (preferably a 3- to 8-membered monocyclic non-aromatic heterocycle (e.g., pyrrolidine, piperidine), a 9 to 14 polycyclic (preferably bi- or tricyclic) non-aromatic heterocycle members (eg dibenzofuran)).
[00145] [00145] In this embodiment, ring B is more preferably (1) a C6-14 aromatic hydrocarbon ring (for example, benzene, naphthalene) optionally substituted additionally with 1 to 3 substituents selected from (a) a halogen atom (for example , a fluorine atom, a chlorine atom, a bromine atom, an iodine atom),
[00146] [00146] In this embodiment, ring B is even more preferably
[00147] [00147] In this embodiment, ring B is even more preferably (1) a benzene ring optionally substituted additionally with 1 to 3 substituents selected from (a) a halogen atom (e.g., a fluorine atom, a chlorine atom, a bromine atom, an iodine atom), (b) a C1-6 alkyl group (for example, methyl, isopropyl) optionally substituted with 1 to 3 halogen atoms (for example, a fluorine atom), (c) a C2-6 alkenyl group (for example, vinyl, propen-2-yl), (d) a mono- or di-C1-6 alkylamino group (for example, dimethylamino), (e) a tri-C1-6 group alkylsilyloxy (for example, triisopropylsilyloxy), (f) a phenyl group optionally substituted with 1 to 4 substituents selected from (i) a halogen atom (for example, a fluorine atom, a chlorine atom),
[00148] [00148] In this embodiment, ring B is even more preferably (1) a benzene ring additionally substituted with 1 or 2 substituents selected from (a) a halogen atom (eg, a fluorine atom), (b) a group C2-6 alkenyl (for example, propen-2-yl), (c) a tri-C1-6 alkylsilyloxy group (for example, triisopropylsilyloxy), (d) a phenyl group optionally substituted with 1 to 3 substituents selected from (i) a halogen atom (for example, a fluorine atom, a chlorine atom), and (ii) a C1-6 alkyl group (for example, methyl)
[00149] [00149] As in another embodiment, ring B is preferably a ring additionally substituted with (a) an optionally substituted C6-14 aryl group, (b) an optionally substituted C6-14 aryloxy group,
[00150] [00150] In this embodiment, ring B is more preferably (1) a C6-14 aromatic hydrocarbon ring (for example, benzene) additionally substituted with (a) an optionally substituted aryl group (for example, phenyl), ( b) an optionally substituted C6-14 aryloxy group (for example, phenoxy), (c) an optionally substituted C7-16 aralkyl group (for example, benzyl), (d) an optionally substituted C3-10 cycloalkyl group (for example, cyclopropyl, cyclobutyl), (e) an optionally substituted C3-10 cycloalkenyl group (for example, cyclopenten-1-yl, cyclohexen-1-yl), (f) an optionally substituted C3-10 cycloalkoxy group (for example, cyclohexyloxy), (g) an optionally substituted 5- to 14-membered aromatic heterocyclic group (preferably a 5- to 6-membered monocyclic aromatic heterocyclic group (e.g., pyridyl, thienyl, pyrazolyl, pyrimidinyl), a polycyclic aromatic heterocyclic group ( preferably
[00151] [00151] In this embodiment, ring B is even more preferably (1) a C6-14 aromatic hydrocarbon ring (for example, benzene) additionally substituted with (a) a C6-14 aryl group (for example, phenyl) optionally substituted with 1 to 4 substituents selected from (i) a halogen atom (for example, a fluorine atom, a chlorine atom),
[00152] [00152] In this embodiment, ring B is even more preferably (1) a benzene ring additionally substituted with (a) a C6-14 aryl group (for example, phenyl) optionally substituted with 1 to 4 substituents selected from (i) one halogen atom (for example, a fluorine atom, a chlorine atom), (ii) a C1-6 alkyl group (for example, methyl) optionally substituted with 1 to 3 halogen atoms (for example, a fluorine atom ), and (iii) a C1-6 alkoxy group (for example, methoxy), (b) a C6-14 aryloxy group (for example, phenoxy), (c) a C7-16 aralkyl group (for example, benzyl) optionally substituted with 1 to 3 C1-6 alkyl groups (for example,
[00153] [00153] In this embodiment, ring B is even more preferably (1) a benzene ring additionally substituted with (a) a phenyl group optionally substituted with 1 to 4 substituents selected from (i) a halogen atom (for example, an atom fluorine, a chlorine atom), (ii) a C1-6 alkyl group (for example, methyl) optionally substituted with 1 to 3 halogen atoms (for example, a fluorine atom), and (iii) a C1 group -6 alkoxy (for example, methoxy), (b) a phenoxy group, (c) a benzyl group optionally substituted with 1 to 3 C1-6 alkyl groups (for example, methyl), (d) a C3-6 cycloalkyl group (e.g. cyclopropyl, cyclobutyl),
[00154] [00154] In this embodiment, ring B is even more preferably (1) a benzene ring additionally substituted with (a) a phenyl group optionally substituted with 1 to 3 substituents selected from (i) a halogen atom (for example, an atom fluorine, a chlorine atom), and (ii) a C1-6 alkyl group (for example, methyl) optionally substituted with 1 to 3 halogen atoms (for example, a fluorine atom), (b) a phenoxy group , (c) a benzyl group optionally substituted with 1 to 3 C1-6 alkyl groups (for example, methyl), (d) a C3-6 cycloalkyl group (for example, cyclobutyl), (e) a C3-6 cycloalkoxy group (for example, cyclohexyloxy), (f) a thienyl group, (g) an indazolyl group optionally substituted with 1 to 3 C1-6 alkyl groups (for example, methyl), or (h) a pyrrolidinyl group, and optionally additionally substituted with a halogen atom (for example, a fluorine atom), (2) a pyridine ring additionally substituted with an optionally phenyl group substituted with 1 to 3 halogen atoms (for
[00155] [00155] In this embodiment, ring B is particularly preferably (1) a benzene ring additionally substituted with a phenyl group optionally substituted with 1 to 3 substituents selected from (i) a halogen atom (for example, a fluorine atom, a chlorine atom), and (ii) a C1-6 alkyl group (for example, methyl), and optionally substituted additionally with a halogen atom (for example, a fluorine atom), (2) a pyridine ring additionally substituted with a phenyl group optionally substituted with 1 to 3 halogen atoms (for example, a fluorine atom), (3) a thiazole ring additionally substituted with a phenyl group optionally substituted with 1 to 3 halogen atoms (for example, one atom of fluorine), or (4) a piperidine ring additionally substituted with a phenyl group.
[00156] [00156] In this embodiment, ring B is more preferably a benzene ring additionally substituted with a phenyl group optionally substituted with 1 to 3 halogen atoms (for example, a
[00157] [00157] With respect to Ring A of compound (I), the configuration based on the carbon atom to which -NR2SO2R1 is attached and the carbon atom to which -CR4R5-Ring B is attached (for example, when Ring A is a pyrrolidine ring or a piperidine ring, the configuration based on positions 2 and 3) is preferably the cis form. That is, the compound (I) is preferably represented by the formula (IA) or (IB):
[00158] Preferred examples of compound (I) include the following compounds. These compounds are preferably represented by the formula (IA) or (IB) above, more preferably represented by the formula (IA). [Compound A-1]
[00159] [00159] Compound (I) in which
[00160] [00160] Compound (I) in which R1 is (1) a C1-6 alkyl group (for example, methyl, ethyl, propyl, isopropyl, butyl, isobutyl) optionally substituted with 1 to 3 substituents selected from (a) an atom halogen (for example, a fluorine atom, a chlorine atom), (b) a cyano group, (c) a hydroxy group, and (d) a C1-6 alkoxy group (for example, methoxy), (2 ) a C2-6 alkenyl group (for example, vinyl, allyl), (3) a C3-10 cycloalkyl group (for example, cyclopropyl), (4) a mono- or di-C1-6 alkylamino group (for example, dimethylamino), or (5) a 3- to 14-membered non-aromatic heterocyclic group (preferably a 3- to 8-membered non-aromatic heterocyclic group (e.g., oxetanyl)); R2 is a hydrogen atom;
[00161] [00161] Compound B-1 mentioned above wherein ring B is (1) a benzene ring optionally substituted further with 1 to 3 substituents selected from (a) a halogen atom (e.g., a fluorine atom, an atom chlorine, a bromine atom, an iodine atom), (b) a C1-6 alkyl group (for example, methyl, isopropyl) optionally substituted with 1 to 3 halogen atoms (for example, a fluorine atom), (c) a C2-6 alkenyl group (for example, vinyl, propen-2-yl), (d) a mono- or di-C1-6 alkylamino group (for example, dimethylamino), (e) a triple group C1-6 alkylsilyloxy (for example, triisopropylsilyloxy), (f) a C6-14 aryl group (for example, phenyl) optionally
[00162] [00162] Compound (I) in which R1 is (1) a C1-6 alkyl group (eg, methyl, ethyl, propyl, isopropyl, butyl, isobutyl) optionally substituted with 1 to 3 substituents
[00163] [00163] Compound (I) in which R1 is (1) a C1-6 alkyl group (for example, methyl, ethyl, propyl) optionally substituted with 1 to 3 substituents selected from (a) a halogen atom (for example, a fluorine atom, a chlorine atom), and (b) a C1-6 alkoxy group (for example, methoxy), (2) a C3-6 cycloalkyl group (for example, cyclopropyl), or (3) a group mono- or di-C1-6 alkylamino (for example,
[00164] [00164] Compound (I) in which R1 is (1) a C1-6 alkyl group (for example, methyl, ethyl) optionally substituted with 1 to 3 substituents selected from (a) a halogen atom (for example, an atom fluorine), and (b) a C1-6 alkoxy group (for example, methoxy), or (2) a C3-6 cycloalkyl group (for example, cyclopropyl); R2 is a hydrogen atom; R3 is (1) a C1-6 alkoxycarbonyl group (for example, ethoxycarbonyl, isopropoxycarbonyl), (2) a C1-6 alkylcarbonyl group (for example, 2-methylpropanoyl, pivaloyl), (3) a C3 group -6 cycloalkyl-carbonyl (the C3-6 cycloalkyl in the C3-6 cycloalkyl-carbonyl group can be a bridged ring group,
[00165] [00165] Compound (I) wherein R1 is (1) an optionally substituted C1-6 alkyl group (for example, methyl, ethyl, propyl, isopropyl, butyl, isobutyl), (2) an optionally substituted C2-6 alkenyl group (for example, vinyl, ally), (3) an optionally substituted C3-10 cycloalkyl group (for example, cyclopropyl), (4) an optionally substituted mono- or di-C1-6 alkylamino group (for example, dimethylamino), or (5) an optionally substituted 3- to 14-membered non-aromatic heterocyclic group (preferably a 3- to 8-membered non-aromatic heterocyclic group (e.g., oxetanyl)); R2 is a hydrogen atom; R3 is (1) a hydrogen atom, (2) an optionally substituted C1-6 alkoxycarbonyl group (for example, methoxycarbonyl, ethoxycarbonyl, propoxycarbonyl, isopropoxycarbonyl, butoxycarbonyl, isobutoxycarbonyl, sec-butoxycarbonyl,
[00166] [00166] Compound (I) in which R1 is (1) a C1-6 alkyl group (for example, methyl, ethyl, propyl, isopropyl, butyl, isobutyl) optionally substituted with 1 to 3 substituents selected from
[00167] [00167] Compound B-2 mentioned above wherein ring B is (1) a benzene ring optionally substituted further with 1 to 3 substituents selected from (a) a halogen atom (e.g., a fluorine atom, an atom chlorine, a bromine atom, an iodine atom), (b) a C1-6 alkyl group (for example, methyl, isopropyl) optionally substituted with 1 to 3 halogen atoms (for example, a fluorine atom), (c) a C2-6 alkenyl group (for example, vinyl, propen-2-yl), (d) a mono- or di-C1-6 alkylamino group (for example, dimethylamino), (e) a triple group C1-6 alkylsilyloxy (for example, triisopropylsilyloxy), (f) a C6-14 aryl group (for example, phenyl) optionally substituted with 1 to 4 substituents selected from (i) a halogen atom (for example, a atom fluorine, a chlorine atom), (ii) a C1-6 alkyl group (for example, methyl) optionally substituted with 1 to 3 halogen atoms (for example, a fluorine atom), and (iii) a C1 group -6 alkoxy (p or Example, methoxy), (g) a C6-14 aryloxy group (for example, phenoxy), (h) a C7-16 aralkyl group (for example, benzyl) optionally substituted with 1 to 3 C1-6 alkyl groups (for Example, methyl), (i) a C3-10 cycloalkyl group (for example, cyclopropyl,
[00168] [00168] Compound (I) wherein R1 is (1) a C1-6 alkyl group (e.g., methyl, ethyl, propyl, isopropyl, butyl, isobutyl) optionally substituted with 1 to 3 substituents selected from (a) an atom halogen (for example, a fluorine atom, a chlorine atom), (b) a cyano group, (c) a hydroxy group, and (d) a C1-6 alkoxy group (for example, methoxy), (2 ) a C2-6 alkenyl group (for example, vinyl, allyl), (3) a C3-6 cycloalkyl group (for example, cyclopropyl), (4) a mono- or di-C1-6 alkylamino group (for example, dimethylamino), or (5) an oxetanyl group; R2 is a hydrogen atom;
[00169] [00169] Compound (I) in which R1 is (1) a C1-6 alkyl group (for example, methyl, ethyl, propyl) optionally substituted with 1 to 3 substituents selected from (a) a halogen atom (for example, a fluorine atom, a chlorine atom), and (b) a C1-6 alkoxy group (for example, methoxy), (2) a C3-6 cycloalkyl group (for example, cyclopropyl), or (3) a group mono- or di-C1-6 alkylamino (for example, dimethylamino). R2 is a hydrogen atom; R3 is (1) a C1-6 alkoxycarbonyl group (for example, methoxycarbonyl, ethoxycarbonyl, isopropoxycarbonyl), (2) a C1-6 alkylcarbonyl group (for example, acetyl, 2-methylpropanoyl, pivaloyl) optionally substituted with 1 to 3 hydroxy groups,
[00170] [00170] Compound (I) in which R1 is (1) a C1-6 alkyl group (for example, methyl, ethyl) optionally substituted with 1 to 3 substituents selected from (a) a halogen atom (for example, an atom fluorine), and (b) a C1-6 alkoxy group (for example, methoxy), or (2) a C3-6 cycloalkyl group (for example, cyclopropyl); R2 is a hydrogen atom; R3 is (1) a C1-6 alkoxycarbonyl group (for example, ethoxycarbonyl, isopropoxycarbonyl), (2) a C1-6 alkylcarbonyl group (for example, 2-methylpropanoyl, pivaloyl) optionally substituted with 1 to 3 groups hydroxy, (3) a mono- or di-C1-6 alkyl-carbamoyl group (e.g., dimethylcarbamoyl), (4) a C3-6 cycloalkyl-carbonyl group (to C3-6 cycloalkyl in the C3-6 cycloalkyl-carbonyl group may be a bridged ring group, for example, cyclopropylcarbonyl, cyclobutylcarbonyl, bicyclo [1.1.1] pentylcarbonyl) optionally substituted with 1 to 3 substituents selected from (a) a halogen atom (for example, a fluorine atom) ,
[00171] [00171] Compound (I) wherein R1 is (1) an optionally substituted C1-6 alkyl group (for example, methyl, ethyl, propyl, isopropyl, butyl, isobutyl), (2) an optionally substituted C2-6 alkenyl group (for example, vinyl, ally), (3) an optionally substituted C3-10 cycloalkyl group (for example, cyclopropyl), (4) an optionally substituted mono- or di-C1-6 alkylamino group (for example, dimethylamino), or (5) an optionally substituted 3- to 14-membered non-aromatic heterocyclic group (preferably a 3- to 8-membered non-aromatic heterocyclic group (e.g., oxetanyl)); R2 is a hydrogen atom; R3 is (1) a hydrogen atom, (2) an optionally substituted C1-6 alkoxycarbonyl group (for example, methoxycarbonyl, ethoxycarbonyl, propoxycarbonyl, isopropoxycarbonyl, butoxycarbonyl, isobutoxycarbonyl, sec-butoxycarbonyl, tert-butoxycarbonyl, 1,2 -dimethylpropoxycarbonyl), (3) an optionally substituted C1-6 alkylcarbonyl group (for example, acetyl, propanoyl, 2-methylpropanoyl, butanoyl, 2-methylbutanoyl, 3-methylbutanoyl, pivaloyl),
[00172] [00172] Compound A-3 mentioned above wherein ring B is (1) a C6-14 aromatic hydrocarbon ring (for example, benzene) further substituted with (a) an optionally substituted C6-14 aryl group (for example, phenyl), (b) an optionally substituted C6-14 aryloxy group (for example, phenoxy), (c) an optionally substituted C7-16 aralkyl group (for example, benzyl), (d) an optionally substituted C3-10 cycloalkyl group (for example, cyclopropyl, cyclobutyl), (e) an optionally substituted C3-10 cycloalkenyl group (for example, cyclopenten-1-yl, cyclohexen-1-yl), (f) an optionally substituted C3-10 cycloalkoxy group (for example, cyclohexyloxy), (g) an optionally substituted 5- to 14-membered aromatic heterocyclic group (preferably a 5- to 6-membered monocyclic aromatic heterocyclic group (for example, pyridyl, thienyl, pyrazolyl, pyrimidinyl), a group aromatic polycyclic heterocyclic (preferably bi- or tricyclic) fused 8 to 14 members (for example, indazolyl)), or (h) an optionally substituted 3- to 14-membered non-aromatic heterocyclic group (preferably a 3- to 8-membered non-aromatic heterocyclic group (for example, pyrrolidinyl), a heterocyclic group non-aromatic polycyclic (preferably bi- or tricyclic) fused from 9 to 14 members (eg dihydroindolyl), and optionally with additional substituent (s),
[00173] [00173] Compound (I) in which R1 is (1) a C1-6 alkyl group (eg, methyl, ethyl, propyl, isopropyl, butyl, isobutyl) optionally substituted with 1 to 3 substituents selected from (a) an atom halogen (for example, a fluorine atom, a chlorine atom), (b) a cyano group, (c) a hydroxy group, and (d) a C1-6 alkoxy group (for example, methoxy), (2 ) a C2-6 alkenyl group (for example, vinyl, ally), (3) a C3-10 cycloalkyl group (for example, cyclopropyl) optionally substituted with 1 to 3 halogen atoms (for example, a fluorine atom),
[00174] [00174] Compound B-3 mentioned above wherein ring B is (1) a C6-14 aromatic hydrocarbon ring (for example, benzene) further substituted with (a) a C6-14 aryl group (for example, phenyl) optionally substituted with 1 to 4 substituents selected from (i) a halogen atom (for example, a fluorine atom, a chlorine atom), (ii) a C1-6 alkyl group (for example, methyl) optionally substituted with 1 to 3 halogen atoms (for example, a fluorine atom), and (iii) a C1-6 alkoxy group (for example, methoxy), (b) a C6-14 aryloxy group (for example, phenoxy), (c ) a C7-16 aralkyl group (for example, benzyl)
[00175] [00175] Compound B-3 mentioned above wherein ring B is (1) a benzene ring optionally substituted additionally with 1 to 3 substituents selected from (a) a halogen atom (for example, a fluorine atom, an atom chlorine, a bromine atom, an iodine atom), (b) a C1-6 alkyl group (for example, methyl, isopropyl) optionally substituted with 1 to 3 halogen atoms (for example, a fluorine atom), (c) a C2-6 alkenyl group (for example, vinyl, propen-2-yl), (d) a mono- or di-C1-6 alkylamino group (for example, dimethylamino), (e) a triple group C1-6 alkylsilyloxy (for example, triisopropylsilyloxy), (f) a C6-14 aryl group (for example, phenyl) optionally substituted with 1 to 4 substituents selected from (i) a halogen atom (for example, a atom fluorine, a chlorine atom),
[00176] [00176] Compound B-3 mentioned above wherein ring B is (1) a benzene ring additionally substituted with (a) a C6-14 aryl group (for example, phenyl) optionally
[00177] [00177] Compound (I) in which R1 is (1) a C1-6 alkyl group (for example, methyl, ethyl, propyl, isopropyl, butyl, isobutyl) optionally substituted with 1 to 3 substituents selected from
[00178] [00178] Compound D-3 mentioned above wherein ring B is (1) a benzene ring additionally substituted with (a) a phenyl group optionally substituted with 1 to 4 substituents selected from (i) a halogen atom (for example , a fluorine atom, a chlorine atom), (ii) a C1-6 alkyl group (for example, methyl) optionally substituted with 1 to 3 halogen atoms (for example, a fluorine atom), and (iii) a C1-6 alkoxy group (for example, methoxy), (b) a phenoxy group, (c) a benzyl group optionally substituted with 1 to 3 C1-6 alkyl groups (for example, methyl),
[00179] [00179] Compound (I) in which R1 is (1) a C1-6 alkyl group (for example, methyl, ethyl, propyl) optionally substituted with 1 to 3 substituents selected from (a) a halogen atom (for example, a fluorine atom, a chlorine atom), and (b) a C1-6 alkoxy group (for example, methoxy), (2) a C3-6 cycloalkyl group (for example, cyclopropyl) optionally substituted with 1 to 3 atoms halogen (for example, a fluorine atom), or (3) a mono- or di-C1-6 alkylamino group (for example, dimethylamino). R2 is a hydrogen atom; R3 is (1) a C1-6 alkoxycarbonyl group (for example, methoxycarbonyl, ethoxycarbonyl, isopropoxycarbonyl), (2) a C1-6 alkylcarbonyl group (for example, acetyl, 2-methylpropanoyl, pivaloyl) optionally substituted with 1 to 3 hydroxy groups, (3) a mono- or di-C1-6 alkyl carbamoyl group (for example
[00180] [00180] Compound E-3 mentioned above wherein ring B is (1) a benzene ring additionally substituted with (a) a phenyl group optionally substituted with 1 to 3 substituents selected from (i) a halogen atom (for example , a fluorine atom, a chlorine atom), and (ii) a C1-6 alkyl group (for example, methyl) optionally substituted with 1 to 3 halogen atoms (for example, a fluorine atom), (b) a phenoxy group, (c) a benzyl group optionally substituted with 1 to 3 C1-6 alkyl groups (for example, methyl), (d) a C3-6 cycloalkyl group (for example, cyclobutyl), (e) a C3 group -6 cycloalkoxy (for example, cyclohexyloxy), (f) a thienyl group, (g) an indazolyl group optionally substituted with 1 to 3 C1-6 alkyl groups (for example, methyl), or (h) a pyrrolidinyl group , and optionally substituted additionally with a halogen atom (for example, a fluorine atom),
[00181] [00181] [Compound F-3]
[00182] [00182] Compound (I) in which R1 is (1) a C1-6 alkyl group (for example, methyl, ethyl) optionally substituted with 1 to 3 substituents selected from (a) a halogen atom (for example, an atom fluorine), and (b) a C1-6 alkoxy group (for example, methoxy), (2) a C3-6 cycloalkyl group (for example, cyclopropyl) optionally substituted with 1 to 3 halogen atoms (for example, one fluorine atom), or (3) a mono- or di-C1-6 alkylamino group (for example, dimethylamino). R2 is a hydrogen atom; R3 is (1) a C1-6 alkoxycarbonyl group (for example, ethoxycarbonyl, isopropoxycarbonyl), (2) a C1-6 alkylcarbonyl group (for example, 2-methylpropanoyl, pivaloyl) optionally substituted with 1 to 3 groups
[00183] [00183] Compound (I) wherein R1 is (1) a C1-6 alkyl group (for example, methyl, ethyl), (2) a C3-6 cycloalkyl group (for example, cyclopropyl) optionally substituted with 1 to 3 halogen atoms (for example, a fluorine atom), or (3) a mono- or di-C1-6 alkylamino group (for example, dimethylamino). R2 is a hydrogen atom; R3 is (1) a C1-6 alkylcarbonyl group (for example, 2-methylpropanoyl) optionally substituted with 1 to 3 hydroxy groups, (2) a mono- or di-C1-6 alkylcarbamoyl group (for example
[00184] [00184] Compound (I) wherein R1 is a C1-6 alkyl group (for example, methyl, ethyl); R2 is a hydrogen atom; R3 is a C1-6 alkylcarbonyl group (for example, 2-methylpropanoyl) optionally substituted with 1 to 3 hydroxy groups; R4 and R5 are both hydrogen atoms; ring A is a pyrrolidine ring; and ring B is a benzene ring additionally substituted with a phenyl group optionally substituted with 1 to 3 halogen atoms (for example, a fluorine atom), and optionally substituted additionally with a halogen atom (for example, a fluorine atom ). [Compound H]
[00185] [00185] N - ((2S, 3S) -2 - ((2,3'-difluorobiphenyl-3-yl) methyl) -1- (2-hydroxy-2-methylpropanoyl) pyrrolidin-3-yl) ethanesulfonamide or a salt from it.
[00186] [00186] N - (((2S, 3S) -1- (2-hydroxy-2-methylpropanoyl) -2 - ((2,3 ', 5'-trifluorobiphenyl-3-yl) methyl) pyrrolidin-3-yl) methanesulfonamide or a salt thereof. [Compound J]
[00187] [00187] N - (((2S, 3S) -1- (2-hydroxy-2-methylpropanoyl) -2 - ((2,3 ', 5'-trifluorobiphenyl-3-yl) methyl) pyrrolidin-3-yl) ethanesulfonamide or a salt thereof. [Compound K]
[00188] [00188] A compound selected from (1) N - ((2S, 3S) -1- (azetidin-1-ylcarbonyl) -2 - ((2,3'-difluorobiphenyl-3-yl) methyl) pyrrolidin-3- yl) methanesulfonamide, (2) N - ((2S, 3S) -1- (azetidin-1-ylcarbonyl) -2 - ((3 ', 5'-difluorobiphenyl-3-yl) methyl) pyrrolidin-3-yl) ethanesulfonamide, (3) N - ((2S, 3S) -1- (azetidin-1-ylcarbonyl) -2- (biphenyl-3-ylmethyl) pyrrolidin-3-yl) ethanesulfonamide, (4) N - ((2S, 3S) -1- (azetidin-1-ylcarbonyl) -2 - ((2,3'-difluorobiphenyl-3-yl) methyl) pyrrolidin-3-yl) ethanesulfonamide, (5) (2S, 3S) -2- ( (2,3'-difluorobiphenyl-3-yl) methyl) -3- ((ethylsulfonyl) amino)) - N, N-dimethylpyrrolidine-1-carboxamide, (6) (2S, 3S) -2 - ((2, 3'-difluorobiphenyl-3-yl) methyl) -3- ((dimethylsulfamoyl) amino) -N, N-dimethylpyrrolidine-1-carboxamide, (7) (2S, 3S) -3 - ((ethylsulfonyl) amino)) - N, N-dimethyl-2 - ((2,3 ', 5'-trifluorobiphenyl-3-yl) methyl) pyrrolidine-1-carboxamide, (8) (2S, 3S) -2- (biphenyl-3-ylmethyl) -3 - ((ethylsulfonyl) amino)) - N- methoxy-N-methylpyrrolidine-1-carboxamide, (9) N - [(2S, 3S) -2 - [(2,3'-difluoro [1,1 ' -biphenyl] -3-yl) methyl] -1- (2-hydroxy-2-me tilpropanoyl) pyrrolidin-3-yl] -1-fluorocyclopropane-1-sulfonamide, (10) N - {(2S, 3S) -1- (azetidine-1-carbonyl) -2 - [(2-fluoro [1,1 '-
[00189] [00189] A compound selected from (1) (2S, 3S) -2 - ((2,3'-difluorobiphenyl-3-yl) methyl) -3- ((ethylsulfonyl) amino)) - N, N-dimethylpyrrolidine- 1-carboxamide, (2) (2S, 3S) -3 - ((ethylsulfonyl) amino)) - N, N-dimethyl-2 - ((2,3 ', 5'-trifluorobiphenyl-3-yl) methyl) pyrrolidine -1-carboxamide, (3) N - [(2S, 3S) -2 - [(2,3'-difluoro [1,1'-biphenyl] -3-yl) methyl] -1- (2-hydroxy- 2-methylpropanoyl) pyrrolidin-3-yl] -1-fluorocyclopropane-1-sulfonamide, (4) N - {(2S, 3S) -1- (azetidine-1-carbonyl) -2 - [(2-fluoro [1 , 1'- biphenyl] -3-yl) methyl] pyrrolidin-3-yl} ethanesulfonamide, (5) (2S, 3S) -3 - [(ethanesulfonyl) amino] -2 - [(3'-fluoro [1, 1'- biphenyl] -3-yl) methyl] -N-methoxy-N-methylpyrrolidine-1-carboxamide, and (6) (2S, 3S) -3 - [(dimethylsulfamoyl) amino] -2 - [(2- fluoro [1,1'-biphenyl] -3-yl) methyl] -N, N-dimethylpyrrolidine-1-carboxamide or a salt thereof.
[00190] [00190] Specific examples of compound (I) include the compounds of Examples 1 to 488 mentioned below.
[00191] [00191] As a salt of a compound represented by formula (I), a pharmacologically acceptable salt is preferred, and Examples of that salt
[00192] Preferred examples of inorganic based salt include alkali metal salts such as sodium salt, potassium salt and the like, alkaline earth metal salts such as calcium salt, magnesium salt and the like, aluminum salt, ammonium salt and the like.
[00193] [00193] Preferable examples of the organic based salt include salts with trimethylamine, triethylamine, pyridine, picoline, ethanolamine, diethanolamine, triethanolamine, tromethamine [tris (hydroxymethyl) methylamine], tert-butylamine, cyclohexylamine, benzylamine, dicyclohexylamine, N, N'-dibenzylethylenediamine and the like.
[00194] Preferred examples of the salt with inorganic acid include salts with hydrochloric acid, hydrobromic acid, nitric acid, sulfuric acid, phosphoric acid and the like.
[00195] [00195] Preferable examples of the salt with organic acid include salts with formic acid, acetic acid, trifluoroacetic acid, phthalic acid, oxalic acid, tartaric acid, maleic acid, citric acid, succinic acid, malic acid, methanesulfonic acid, benzenesulfonic acid, p-toluenesulfonic acid and the like.
[00196] Preferred examples of the basic amino acid salt include salts with arginine, lysine, ornithine and the like.
[00197] Preferred examples of the salt with acidic amino acid include salts with aspartic acid, glutamic acid and the like.
[00198] [00198] The method of producing the compound of the present invention is explained below.
[00199] [00199] The raw material compound and reagent used and the compound obtained at each stage in the following production method can each be in the form of a salt and Examples of that salt include those similar
[00200] [00200] When the compound obtained in each step is a free form, it can be converted into the objective salt according to a method known per se. When the compound obtained in each step is a salt, it can be converted to the objective free form or to the other salt according to a method known per se.
[00201] [00201] The compound obtained in each step can be used directly as the reaction mixture or as a crude product for the next reaction. Alternatively, the compound obtained at each stage can be isolated and purified from a reaction mixture according to a method known per se, for example, a separation medium such as concentration, crystallization, recrystallization, distillation, solvent extraction, distillation fractionated, column chromatography and the like.
[00202] [00202] When the raw material compound and the reagent used in each step are commercially available, the commercially available product can also be used directly.
[00203] [00203] In the reaction in each step, although the reaction time varies according to the type of reagent and solvent to be used, it is generally 1 min to 48 h, preferably 10 min to 8 h, unless otherwise specified .
[00204] [00204] In the reaction in each step, although the reaction temperature varies according to the type of reagent and solvent to be used, it is generally - 78 ° C to 300 ° C, preferably -78 ° C to 150 ° C, at unless otherwise specified.
[00205] [00205] In the reaction in each step, although the pressure varies according to the type of reagent and solvent to be used, it is generally 1 atm to 20 atm, preferably 1 atm to 3 atm, unless otherwise specified.
[00206] [00206] The microwave synthesizer, like the initiator manufactured by Biotage and the like, can be used for the reaction in each step. While the reaction temperature varies according to the type of reagent and solvent to be
[00207] [00207] In the reaction in each step, the reagent is used in an amount of 0.5 equivalent to 20 equivalents, preferably 0.8 equivalent to 5 equivalents, in relation to the substrate, unless otherwise specified. When the reagent is used as a catalyst, the reagent is used in an amount of 0.001 equivalent to 1 equivalent, preferably 0.01 equivalent to 0.2 equivalent with respect to the substrate. When the reagent is used as a reaction solvent, the reagent is used in an amount of solvent.
[00208] [00208] Unless otherwise specified, the reaction in each step is carried out without solvent, or by dissolving or suspending the raw material compound in a suitable solvent. Examples of the solvent include those described in the Examples and the following solvents. alcohols: methanol, ethanol, tert-butyl alcohol, 2-methoxyethanol and the like; ethers: diethyl ether, diphenyl ether, tetrahydrofuran, 1,2-dimethoxyethane and the like; aromatic hydrocarbons: chlorobenzene, toluene, xylene and the like; saturated hydrocarbons: cyclohexane, hexane and the like; amides: N, N-dimethylformamide, N-methylpyrrolidone and the like; halogenated hydrocarbons: dichloromethane, carbon tetrachloride and the like; nitriles: acetonitrile and the like;
[00209] [00209] The solvent mentioned above can be used in a mixture of two or more of these types in a suitable ratio.
[00210] [00210] When a base is used for the reaction in each step, their Examples include those described in the Examples and the following bases. inorganic bases: sodium hydroxide, magnesium hydroxide, sodium carbonate, calcium carbonate, sodium hydrogen carbonate and the like; organic bases: triethylamine, diethylamine, pyridine, 4-dimethylaminopyridine, N, N-dimethylaniline, 1,4-diazabicyclo [2.2.2] octane, 1,8-diazabicyclo [5.4.0] -7-undecene, imidazole, piperidine and similar; metal alkoxides: sodium ethoxide, potassium tert-butoxide and the like; alkali metal hydrides: sodium hydride and the like; metal amides: sodium amide, lithium diisopropylamide, lithium hexamethyldisilazide and the like; organic lithiums: n-butyl lithium and the like.
[00211] [00211] When an acid or an acid catalyst is used for the reaction in each step, their Examples include those described in
[00212] [00212] Unless otherwise specified, the reaction in each step is carried out according to a method known per se, for example, the method described in Jikken Kagaku Kouza, 5th Edition, vol.13-19 (the Chemical Society of Japan ed.); Shin Jikken Kagaku Kouza, vol.14-15 (the Chemical Society of Japan ed.); Fine Organic Chemistry, Revised 2nd Edition (L. F. Tietze, Th. Eicher, Nankodo); Organic Name Reactions, the Reaction Mechanism and Essence, Revised Edition (Hideo Togo, Kodansha); ORGANIC SYNTHESES Collective Volume I-VII (John Wiley & Sons Inc.); Modern Organic Synthesis in the Laboratory A Collection of Standard Experimental Procedures (Jie Jack Li, OXFORD UNIVERSITY); Comprehensive Heterocyclic Chemistry III, Vol.1 -Vol.14 (Elsevier Japan); Strategic Applications of Named Reactions in Organic Synthesis (translated by Kiyoshi Tomioka, Kagakudojin); Comprehensive Organic Transformations (VCH Publishers Inc.), 1989, or the like, or the method described in the Examples.
[00213] [00213] At each stage, the protection or deprotection reaction of a functional group is carried out according to a method known per se, for example, the method described in “Protective Groups in Organic Synthesis, 4th Ed”, Wiley-Interscience, Inc., 2007 (Theodora W. Greene, Peter GM Wuts); “Protecting Groups 3rd Ed.” Tieme, 2004 (P.J. Kocienski), or the like, or the method described in the Examples.
[00214] [00214] Examples of the protecting group for a hydroxy group of an alcohol and the like and a phenolic hydroxy group include ether-protecting groups such as methoxymethyl ether, benzyl ether, tert-butyldimethylsilyl ether, tetrahydropyranyl ether and the like; carboxylate ester-protecting groups such as acetate ester and the like; sulfonate ester-protecting groups such as methanesulfonate ester and the like; carbonate ester-type protecting groups such as tert-butylcarbonate and the like, and the like.
[00215] [00215] Examples of the protecting group for an aldehyde carbonyl group include protecting groups of the acetal type such as dimethylacetal and the like; protecting groups of cyclic acetal type such as 1,3-dioxane and the like, and the like.
[00216] [00216] Examples of the protecting group for a carbonyl group of a ketone include protecting groups of the ketal type such as dimethyl ketal and the like; protecting groups of cyclic ketal type such as 1,3-dioxane and the like; oxime-type protecting groups such as O-methyloxime and the like; hydrazone-type protecting groups such as N, N-dimethylhydrazone and the like, and the like.
[00217] [00217] Examples of the protecting group for a carboxyl group include ester-protecting groups such as methyl ester and the like; amide-type protecting groups such as N, N-dimethylamide and the like, and the like.
[00218] [00218] Examples of the protecting group for a thiol include ether-protecting groups such as benzyl thioether and the like; ester-type protecting groups such as thioacetate ester, thiocarbonate, thiocarbamate and the like, and the like.
[00219] [00219] Examples of the protecting group for an amino group and an aromatic heterocycle such as imidazole, pyrrole, indole and the like include carbamate-protecting groups such as benzyl carbamate and the like; amide-type protecting groups such as acetamide and the like;
[00220] [00220] Protecting groups can be removed according to a method known per se, for example, using a method using acid, base, ultraviolet rays, hydrazine, phenylhydrazine, sodium N-methyldithiocarbamate, tetrabutylammonium fluoride, acetate palladium, trialkylsilyl halide (e.g., trimethylsilyl iodide, trimethylsilyl bromide) and the like, a reduction method and the like.
[00221] [00221] When the reduction reaction is carried out in each step, Examples of the reducing agent to be used include metal hydrides such as aluminum and lithium hydride, sodium triacetoxyborohydride, sodium cyanoborohydride, diisobutylaluminum hydride (DIBAL-H) , sodium borohydride, tetramethylammonium triacetoxyborohydride and the like; boranes such as tetrahydrofuran borane complex and the like; Raney nickel; Raney cobalt; hydrogen; formic acid; triethylsilane and the like. When the carbon-carbon double bond or triple bond is reduced, a method using a catalyst such as palladium-carbon, Lindlar's catalyst and the like can be used.
[00222] [00222] When the oxidation reaction is carried out at each step, Examples of the oxidizing agent to be used include peroxides such as m-chloroperbenzoic acid (mCPBA), hydrogen peroxide, tert-butyl hydroperoxide and the like; perchlorates such as tetrabutylammonium perchlorate and the like; chlorides such as sodium chlorate and the like; chlorites such as sodium chlorite and the like; periodates such as sodium periodate and the like; hypervalent iodine reagents such as iodosylbenzene and the like; reagents containing manganese such as manganese dioxide, potassium permanganate and the like; lead such as lead tetraacetate and the like; chromium-containing reagents such as chlorochromate
[00223] [00223] When the radical cyclization reaction is carried out at each stage, Examples of the radical initiator to be used include azo compounds such as azobisisobutyronitrile (AIBN) and the like; water-soluble radical initiators such as 4-4'-azobis-4-cyanopentanoic acid (ACPA) and the like; triethylboro in the presence of air or oxygen; benzoyl peroxide and the like. Examples of the radical reagent to be used include tributilstanane, tristrimethylsilylsilane, 1,1,2,2-tetrafenyldisilane, diphenylsilane, samarium iodide and the like.
[00224] [00224] When the Wittig reaction is carried out at each step, Examples of the Wittig reagent to be used include alkylidenephosphorans and the like. Alkylidenophosphorans can be prepared according to a method known per se, for example, by reacting a phosphonium salt with a strong base.
[00225] [00225] When the Horner-Emmons reaction is performed at each step, Examples of the reagent to be used include phosphonoacetates such as methyl dimethylphosphonoacetate, ethyl diethylphosphonoacetate and the like; and bases such as alkali metal hydrides, organic lithium and the like.
[00226] [00226] When the Friedel-Crafts reaction is carried out at each step, a combination of a Lewis acid and an acid chloride is used or a combination of a Lewis acid and an alkylating agent (for example, a halide of alkyl, an alcohol, an olefin etc.) as a reagent. Alternatively, an organic acid or an inorganic acid can also be used instead of a Lewis acid, and an anhydride like acetic anhydride and the like can also be used instead of an acid chloride.
[00227] [00227] When the aromatic nucleophilic substitution reaction is carried out at each stage, a nucleophile (for example, an amine, imidazole, etc.) and a base (for example, an organic base, etc.) are used as the reagent.
[00228] [00228] When the reaction of adding nucleophiles by a carbanion, the reaction of adding 1.4 nucleophiles (Michael's addition reaction) by a reaction of replacing a carbonanion or nucleophilic by a carbonanion is carried out at each step, and Examples of the base to be used to generate the carbonanion include organic lithium, metal alkoxides, inorganic bases, organic bases and the like.
[00229] [00229] When the Grignard reaction is performed at each step, Examples of the Grignard reagent to be used include arylmagnesium halides such as phenylmagnesium bromide and the like; and alkylmagnesium halides such as methylmagnesium bromide and the like. The Grignard reagent can be prepared according to a method known per se, for example, by reacting an alkyl halide or an aryl halide with a metal magnesium in an ether or tetrahydrofuran as a solvent.
[00230] [00230] When the Knoevenagel condensation reaction is carried out at each stage, a compound with an activated methylene group with two electron withdrawing groups (for example, malonic acid, diethyl malonate, malononitrile, etc.) and a base ( for example, an organic base, a metal alkoxide, an inorganic base) are used as a reagent.
[00231] [00231] When the Vilsmeier-Haack reaction is carried out at each step, phosphoryl chloride and an amide derivative (for example, N, N-dimethylformamide, etc.) are used as the reagent.
[00232] [00232] When the azidation reaction of an alcohol, an alkyl halide or a sulfonate is carried out at each step, Examples of the azidation agent to be used include diphenylphosphoryl azide (DPPA), trimethylsilylazide, sodium azide and the like. For example, for the azidation reaction of a
[00233] [00233] When the reductive amination reaction is carried out in each step, Examples of the reducing agent to be used include sodium triacetoxyborohydride, sodium cyanoborohydride, hydrogen, formic acid and the like. When the substrate is an amine compound, Examples of the carbonyl compound to be used include paraformaldehyde, aldehydes such as acetaldehyde and the like and ketones such as cyclohexanone and the like. When the substrate is a carbonyl compound, Examples of the amine to be used include ammonia, primary amines, such as methylamine and the like; secondary amines, such as dimethylamine and the like, and the like.
[00234] [00234] When the Mitsunobu reaction is carried out at each step, an azodicarboxylate (eg, diethyl azodicarboxylate (DEAD), diisopropyl azodicarboxylate (DIAD), etc.) and triphenylphosphine are used as the reagent.
[00235] [00235] When the esterification reaction, the amidation reaction or the urea formation reaction is carried out at each step, Examples of the reagent to be used include acyl halides such as acid chlorides, acid bromides and the like; activated carboxylic acids such as acid anhydrides, activated esters, sulfates and the like. Examples of the carboxylic acid activating agent include carbodiimide condensing agents such as 1-ethyl-3- (3-dimethylaminopropyl) carbodiimide hydrochloride (WSCD) and the like; triazine condensing agents such as 4- (4,6-dimethoxy-1,3,5-triazin-2-yl) -4-methylmorpholine (DMT-MM) chloride n-hydrate and the like; carbonate condensing agents such as 1,1-carbonyldiidimidazole (CDI) and the like; diphenylphosphoryl azide (DPPA); benzotriazole-1-yloxy-trisdimethylaminophosphonium salt (BOP reagent); 2-chloro-1-methylpyridinium iodide (Mukaiyama reagent); thionyl chloride; alkyl haloforms
[00236] [00236] When the coupling reaction is carried out at each step, Examples of the metal catalyst to be used include palladium compounds such as palladium (II) acetate, tetrakis (triphenylphosphine) palladium (0), dichlorobis (triphenylphosphine) palladium ( II), dichlorobis (triethylphosphine) palladium (II), tris (dibenzylidenoacetone) dipaladium (0), 1,1'-bis (diphenylphosphine) ferrocene palladium (II), bis (tri-tert-butylphosphine) palladium (0) and the like; nickel compounds such as tetrakis (triphenylphosphine) nickel (0) and the like; rhodium compounds such as tris (triphenylphosphine) rhodium (III) chloride and the like; cobalt compounds; copper compounds such as copper oxide, copper (I) iodide and the like; platinum compounds and the like. In addition, a base can be added to the reaction system and Examples of the same include inorganic bases and the like.
[00237] [00237] When the thiocarbonylation reaction is carried out at each stage, phosphorus pentasulfide is typically used as a thiocarbonylation agent. Alternatively, a reagent with a 1,3,2,4-dithiadiphosphethane-2,4-disulfide structure (e.g., 2,4-bis (4-methoxyphenyl) -1,3,2,4-dithiadiphosphethane-2,4 -disulfide (Lawesson's reagent) etc.) can also be used instead of phosphorus pentasulfide.
[00238] [00238] When the Wohl-Ziegler reaction is performed at each step, Examples of the halogenating agent to be used include N-iodosuccinimide, N-bromosuccinimide (NBS), N-chlorosuccinimide (NCS), bromine, sulfuryl chloride and the like . In addition, the reaction can be accelerated by subjecting a radical initiator such as heat, light, benzoyl peroxide,
[00239] [00239] When the halogenation reaction of a hydroxy group is carried out at each step, Examples of the halogenating agent to be used include hydrohalogenated acids and acid halides of inorganic acids, specifically hydrochloric acid, thionyl chloride, phosphorus oxychloride and the like for chlorination, 48% hydrobromic acid and the like for bromination. In addition, an alkyl halide production method can be used by reacting an alcohol with triphenylphosphine and carbon tetrachloride or carbon tetrabromide or the like. Alternatively, a method of producing an alkyl halide by means of two steps comprising converting an alcohol into the corresponding sulfonate and then reacting the sulfonate with lithium bromide, lithium chloride or sodium iodide can be used.
[00240] [00240] When the Arbuzov reaction is carried out at each step, Examples of the reagent to be used include alkyl halides such as ethyl bromoacetate and the like; and phosphites such as triethyl phosphite, tri (isopropyl) phosphite and the like.
[00241] [00241] When the sulfonate esterification reaction is carried out at each step, Examples of the sulfonation agent to be used include methanesulfonyl chloride, p-toluenesulfonyl chloride, methanesulfonic anhydride, p-toluenesulfonic anhydride and the like.
[00242] [00242] When the hydrolysis reaction is carried out in each step, an acid or a base is used as a reagent. For the acid hydrolysis reaction of the tert-butyl ester, formic acid, triethylsilane and the like can be added to reductively capture the tert-butyl cation, which is underproduced.
[00243] [00243] When the dehydration reaction is carried out at each step, Examples of the dehydrating agent to be used include sulfuric acid, diphosphorus pentaoxide, phosphorus oxychloride, N, N'-dicyclohexylcarbodimide, alumina, polyphosphoric acid and the like .
[00244] [00244] The compound (7) used in reaction scheme 3 mentioned below can be produced from compound (1) according to the method shown in reaction scheme 1 below. As used herein, M is a magnesium halide or an alkali metal such as lithium and the like, and the other symbols are as defined above.
[00245] [00245] The compound (1) can be commercially available or can be produced according to a method known per se or a method analogous thereto.
[00246] [00246] Compound (3) can be produced by subjecting compound (2) to a nucleophilic addition reaction with an organometallic reagent. Examples of the organometallic reagent to be used include organic magnesium halides, organic lithium and the like. The organometallic reagent can be prepared according to a method known per se.
[00247] [00247] Compound (4) can be produced, for example, by subjecting compound (3) in which R4 is a hydrogen atom to an oxidation reaction.
[00248] [00248] The compound (5) in which R5 is a hydrogen atom can be produced, for example, by subjecting the compound (3) to a reduction reaction.
[00249] [00249] The compound (5) in which R5 is a C1-6 alkoxy group can be produced, for example, by subjecting the compound (3) to a nucleophilic substitution reaction with an electrophile in the presence of a base. Examples of the electrophile to be used include alkyl halides and the like. Examples of the base to be used include alkali metal hydrides and the like.
[00250] [00250] The compound (5) in which R4 and R5 are both fluorine atoms can be produced, for example, by subjecting the compound (4) to a fluorination reaction. Examples of the reagent to be used include fluorine agents, such as diethylamino sulfur trifluoride (DAST), bis (2-methoxyethyl) amino sulfur trifluoride (BAST), 1,1,2,2-tetrafluoroethyl-N, N-dimethylamine (TFEDMA) and similar.
[00251] [00251] Compound (7) can be produced by subjecting compound (5) and compound (6) to a coupling reaction. The compound (6) can be commercially available or can be produced according to a method known per se or a method analogous thereto.
[00252] [00252] Compound (7) can also be produced from compound (8) according to the method shown in reaction scheme 2 below. As used here, Hal is a halogen atom, LG1 and LG2 are each independently an output group, and the other symbols are as defined above.
[00253] [00253] Examples of the "leaving group" represented by LG1 or LG2 include halogen atoms, optionally halogenated C1-6 alkylsulfonyloxy groups (e.g., methanesulfonyloxy, ethanesulfonyloxy, trifluoromethanesulfonyloxy), C6-14 arylsulfonyloxy groups optionally substituted with C1- (for example, benzenesulfonyloxy, toluenesulfonyloxy) and the like.
[00254] [00254] The compound (8) can be commercially available or can be produced according to a method known per se or a method analogous thereto.
[00255] [00255] The compound (11) can be produced by subjecting the compound (9) to a nucleophilic substitution reaction with the compound (10). Examples of the compound (10) to be used include cyclic amines (for example, pyrrolidine, piperidine), pyrazole and the like. In addition, a base can be added to the reaction system. Examples of the base include inorganic bases, organic bases, alkali metal hydrides and the like.
[00256] [00256] The compound (14) can be produced by subjecting the compound (12) to a sulfonamidation reaction with the compound (13) in the presence of a base. Examples of the base to be used include organic bases and the like. Compound (13) can be commercially available or can be produced according to a method known per se.
[00257] [00257] The compound (7) can be produced by subjecting the compound (14) to a nucleophilic substitution reaction with an electrophile in the presence of a base. Examples of the electrophile to be used include alkyl halides and the like. Examples of the base to be used include alkali metal hydrides and the like.
[00258] [00258] Compound (Ia) and compound (Ib), which are compound (I) in which ring A is a piperidine ring, can be produced from compound (7) according to the method shown in the scheme reaction 3 below. As used here, LG3 is an output group, and the other symbols are as defined above.
[00259] [00259] Examples of the "leaving group" represented by LG3 include those exemplified as the "leaving group" represented by LG1 or LG2.
[00260] [00260] The compound (Ia) can be produced by subjecting the compound (7) to a reduction reaction. Examples of the reducing agent to be used include catalysts such as palladium carbon, rhodium carbon, platinum carbon and the like.
[00261] [00261] The compound (Ib) can be produced by subjecting the compound (Ia) and the compound (15) to a condensation reaction. Examples of the compound (15) to be used include acyl halides, such as acid chlorides, acid bromides, alkyl chloroformates, carbamoyl chlorides and the like; activated carboxylic acids, such as acid anhydrides, activated esters, sulfate esters and the like. Examples of the activating agent for carboxylic acid include carbodiimide condensing agents such as 1-
[00262] [00262] The compound (Ic) and the compound (Id), which are the compound (I) in which R2 is a hydrogen atom, and the compound (I) can be produced from the compound (16) according to the method shown in reaction scheme 4 below. As used here, P1 is a protecting group, LG4 is an output group, and the other symbols are as defined above.
[00263] [00263] Examples of the "protecting group" represented by P1 include those exemplified as the "protecting group for an amino group and an aromatic heterocycle, such as imidazole, pyrrole, indole and the like" mentioned above.
[00264] [00264] Examples of the "leaving group" represented by LG4 include those exemplified as the "leaving group" represented by LG1 or LG2.
[00265] [00265] Compound (16) and compound (17) may be commercially available or may be produced according to a method known per se or a method analogous thereto.
[00266] [00266] The compound (18) can be produced by subjecting the compound (16) to a nucleophilic substitution reaction with the compound (17) in the presence of a base. Examples of the base to be used include alkali metal hydrides, organic lithium and the like. Alternatively, the compound (18) can also be produced by reaction in two steps, that is, by converting the compound (16) into the corresponding enamine and then by reacting the enamine with the compound (17).
[00267] [00267] Examples of the amine to be used for the formation of enamine include pyrrolidine, morpholine, N, N-dimethylhydrazine and the like. A base can be added to the reaction system of the enamine and the compound (17). Examples of the base include alkali metal hydrides, organic lithium and the like. In addition, a catalyst can be added to the reaction system to promote the reaction. Examples of the catalyst to be used include tetrabutylammonium iodide and the like.
[00268] [00268] Compound (19) can be produced by subjecting compound (18) to a reductive amination reaction. Examples of the reducing agent to be used include sodium triacetoxyborohydride, sodium cyanoborohydride, hydrogen, formic acid and the like. Examples of the amine to be used include ammonia and the like. In addition, a metal catalyst can be
[00269] [00269] Compound (21) can be produced by subjecting compound (19) to a sulfonamidation reaction with compound (20) in the presence of a base. Examples of the base to be used include organic bases and the like. Compound (20) can be commercially available or can be produced according to a method known per se.
[00270] [00270] The compound (Id) can be produced by subjecting the compound (Ic) and the compound (15) to a condensation reaction. Examples of the compound (15) to be used include acyl halides, such as acid chlorides, acid bromides, alkyl chloroformates, carbamoyl chlorides and the like; activated carboxylic acids, such as acid anhydrides, activated esters, sulfate esters and the like. Examples of the activating agent for carboxylic acid include carbodiimide condensing agents such as 1-ethyl-3- (3-dimethylaminopropyl) carbodiimide hydrochloride (WSCD) and the like; triazine condensing agents such as 4- (4,6-dimethoxy-1,3,5-triazin-2-yl) -4-methylmorpholine (DMT-MM) chloride n-hydrate (DMT-MM) and the like; carbonate ester condensing agents such as 1,1-carbonyldiimidazole (CDI) and the like; diphenylphosphoryl azide (DPPA); benzotriazol-1-yloxy-trisdimethylaminophosphonium salt (BOP reagent); 2-chloro-1-methyl-pyridinium iodide
[00271] [00271] The compound (I) can be produced by subjecting the compound (Id) to a nucleophilic substitution reaction with an electrophile in the presence of a base. Examples of the electrophile to be used include alkyl halide and the like. Examples of the base to be used include alkali metal hydrides and the like.
[00272] [00272] In the compound (I) thus obtained, an intramolecular functional group can also be converted into an object functional group by a combination of chemical reactions known per se. Examples of the chemical reaction include oxidation reaction, reduction reaction, alkylation reaction, acylation reaction, urea reaction, hydrolysis reaction, amination reaction, esterification reaction, aryl coupling reaction, deprotection reaction and the like.
[00273] [00273] In the production method mentioned above, when a starting compound has an amino group, a carboxyl group, a hydroxy group, a carbonyl group or a mercapto group as a substituent, a protecting group generally used in peptide chemistry can be introduced in these groups and the object compound can be obtained by removing the protecting group as needed after the reaction.
[00274] [00274] The compound (I) obtained by the production method mentioned above can be isolated and purified by a known means, such as extraction
[00275] [00275] When compound (I) contains an optical isomer, a stereoisomer, a regioisomer and a rotamer, these compounds are also included in compound (I) and each can be obtained as a single product by a method of synthesis and or a separation method known per se. For example, when an optical isomer exists in compound (I), an optical isomer resolved from the compound is also covered in compound (I).
[00276] [00276] Here, an optical isomer can be produced by a method known per se.
[00277] [00277] The compound (I) can be a crystal.
[00278] [00278] A crystal of compound (I) (hereinafter abbreviated as the crystal of the present invention) can be produced by crystallization of compound (I), applying a crystallization method known per se.
[00279] [00279] In this specification, the melting point means a melting point measured, for example, by micro melting point devices (Yanako, MP-500D or Buchi, B-545), DSC devices (differential calorimetry analysis scanners) (METTLER TOLEDO, DSC1) and the like.
[00280] [00280] Generally, the melting point sometimes varies depending on the measuring device, measuring condition and the like. The crystal in this specification can be a crystal showing a melting point different from the values described in this specification, as long as the difference is within a general error range.
[00281] [00281] The crystal of the present invention is superior in physical-chemical properties (for example, melting point, solubility, stability) and biological properties (for example, pharmacokinetics (absorption, distribution, metabolism, excretion)), expression of effectiveness ) and is
[00282] [00282] Compound (I) can be used as a prodrug. A prodrug of the compound (I) means a compound that is converted to the compound (I) of the present invention with a reaction due to an enzyme, a gastric acid, etc. under the physiological condition in the living body, that is, a compound that is converted to the compound (I) of the present invention with oxidation, reduction, hydrolysis, etc. according to an enzyme; a compound that is converted to the compound (I) of the present invention by hydrolysis, etc. due to gastric acid, etc.
[00283] [00283] A prodrug of compound (I) can be a compound obtained by subjecting an amino group in compound (I) to acylation, alkylation or phosphorylation (for example, a compound obtained by subjecting an amino group in compound (I) to an eicosanoylation, alanylation, pentylaminocarbonylation, (5-methyl-2-oxo-1,3-dioxolen-4-yl) methoxycarbonylation, tetrahydrofuranylation, pyrrolidylmethylation, pivaloyloxymethylation and tert-butylation, etc.); a compound obtained by subjecting a hydroxy group in compound (I) to acylation, alkylation, phosphorylation or boron (for example, a compound obtained by subjecting a hydroxy group in compound (I) to acetylation, palmitoylation, propaneylation, pivaloylation, succinylation, fumarylation , alanylation, dimethylaminomethylcarbonylation, etc.); a compound obtained by subjecting a carboxyl group in compound (I) to an esterification or amidation (for example, a compound obtained by subjecting a carboxyl group in compound (I) to an ethyl esterification, phenyl esterification, carboxymethyl esterification, dimethylaminomethyl esterification , esterification of pivaloyloxymethyl, esterification of ethoxycarbonyloxyethyl, esterification of phthalidyl, esterification of (5-methyl-2-oxo-1,3-dioxolen-4-yl) methyl, esterification of cyclohexyloxycarbonylethyl and methylamidation, etc.)
[00284] [00284] A prodrug for compound (I) can also be one that is converted to compound (I) under physiological condition as described in IYAKUHIN in KAIHATSU (Development of Pharmaceuticals), Vol.7, Design of Molecules, p. 163-198, published by HIROKAWA SHOTEN (1990).
[00285] [00285] In the present specification, a prodrug can form a salt and, as such, those exemplified as a salt of the compound represented by the formula (I) mentioned above can be mentioned.
[00286] [00286] Compound (I) can be labeled with an isotope (for example, 3H, 13C, 14C, 18F, 35S, 125I) and the like.
[00287] [00287] The compound (I) marked with or replaced with an isotope can be used, for example, as a marker used for Positron Emission Tomography (PET) (PET marker), and is useful in the field of medical diagnosis and the like .
[00288] [00288] In addition, compound (I) can be a hydrate or a non-hydrate, or a non-solvate (for example, anhydride) or a solvate (for example, hydrate).
[00289] [00289] Compound (I) also encompasses a form of deuterium conversion in which 1H is converted to 2H (D).
[00290] [00290] Furthermore, compound (I) can be a pharmaceutically acceptable cocrystal or cocrystal salt. Cocrystal or cocrystal salt means a crystalline substance consisting of two or more special solids at room temperature, each with different physical properties (for example, Structure, melting point, heat of melting, hygroscopicity, solubility and stability). The cocrystal or cocrystal salt can be produced by a cocrystallization method known per se.
[00291] [00291] The compound (I) or a prodrug thereof (hereinafter, sometimes, simply abbreviated as the compound of this
[00292] [00292] As pharmacologically acceptable carriers, various organic or inorganic carrier substances conventionally used as preparation materials can be used. These are incorporated as an excipient, lubricant, binder and disintegrant for solid preparations; or solvent, solubilizing agent, suspending agent, isotonicity agent, buffer and soothing agent for liquid preparations; and the like; and preparation ADDITIVES such as preservative, antioxidant, dye, sweetener and the like can be added as needed.
[00293] [00293] Preferred examples of the excipient include lactose, sucrose, D-mannitol, D-sorbitol, starch, gelatinized starch, dextrin, crystalline cellulose, low substituted hydroxypropylcellulose, sodium carboxymethylcellulose, arabic gum, pullulan, light anhydrous silicic acid synthetic aluminum and aluminum and magnesium metasilicate.
[00294] [00294] Preferable examples of the lubricant include magnesium stearate, calcium stearate, talc and colloidal silica.
[00295] Preferred examples of the binder include gelatinized starch, sucrose, gelatin, gum arabic, methylcellulose, carboxymethylcellulose, sodium carboxymethylcellulose, crystalline cellulose, sucrose, D-mannitol, trehalose, dextrin, pullulan, hydroxypropylcellulose, hydroxypropylmethyl cellulose and hydroxypropylmethyl hydroxylmethyl cellulose and hydroxypropylmethyl cellulose.
[00296] [00296] Preferable examples of the disintegrant include lactose, sucrose, starch, carboxymethylcellulose, calcium carboxymethylcellulose, croscarmellose sodium, sodium carboxymethyl starch, anhydrous light silicic acid
[00297] [00297] Preferable examples of the solvent include water for injection, physiological brine, Ringer's solution, alcohol, propylene glycol, polyethylene glycol, sesame oil, corn oil, olive oil and cottonseed oil.
[00298] [00298] Preferable examples of the solubilizing agent include polyethylene glycol, propylene glycol, D-mannitol, trehalose, benzyl benzoate, ethanol, trisaminomethane, cholesterol, triethanolamine, sodium carbonate, sodium citrate, sodium salicylate and sodium acetate.
[00299] Preferred examples of the suspending agent include surfactants such as stearyltriethanolamine, sodium lauryl sulfate, lauryl aminopropionate, lecithin, benzalkonium chloride, benzethonium chloride, glycerol monostearate and the like; hydrophilic polymers such as poly (vinyl alcohol), polyvinylpyrrolidone, sodium carboxymethylcellulose, methylcellulose, hydroxymethylcellulose, hydroxyethylcellulose, hydroxypropylcellulose and the like, polysorbates; and polyoxyethylene hydrogenated castor oil.
[00300] Preferred examples of the isotonicity agent include sodium chloride, glycerol, D-mannitol, D-sorbitol and glucose.
[00301] Preferable examples of the buffer include phosphate, acetate, carbonate, citrate buffers, etc.
[00302] [00302] Preferable examples of the calming agent include benzyl alcohol.
[00303] Preferable examples of the preservative include esters of p-oxybenzoate, chlorobutanol, benzyl alcohol, phenethyl alcohol, dehydroacetic acid and sorbic acid.
[00304] Preferred examples of the antioxidant include sulfite salts and ascorbate salts.
[00305] [00305] Preferred examples of the dye include aqueous tar food dyes (for example, food dyes such as red food dyes 2 and 3, yellow food dyes 4 and 5,
[00306] Preferred examples of the sweetening agent include sodium saccharin, dipotassium glycyrrhizinate, aspartame and stevia.
[00307] [00307] Examples of the dosage form of the pharmaceutical composition mentioned above include oral preparations, such as tablets (including sugar-coated tablets, film-coated tablets, sublingual tablets, oral disintegrating tablets, oral tablets), capsules (including soft capsules) , microcapsules), pill, granule, powder, troches, syrup, liquid, emulsion, suspension, aerosol, films (eg, oral disintegrable films, adhesive film for oral mucosa) and the like; and parenteral agents, such as injection (for example, subcutaneous injection, intravenous injection, intramuscular injection, intraperitoneal injection, drip infusion), external preparation (for example, preparation of the transdermal absorption type, ointment, lotion, adhesive preparation), suppository ( for example, rectal suppository, vaginal suppository), lozenge, nasal preparation, pulmonary preparation (inhalant), eye drops and the like. The compound and medicament of the present invention can be safely orally or parenterally administered respectively (e.g., intrarectal, intravenous, intraarterial, intramuscular, subcutaneous, intraorganic, intranasal, intradermal, intradermal, intravaginal, intraperitoneal, intraperitoneal, intraperitoneal administration. , intratumoral, proximal, and administration to the lesion).
[00308] [00308] These preparations can be a release control preparation (eg, extended release microcapsule), such as an immediate release preparation, an extended release preparation and the like.
[00309] [00309] The pharmaceutical composition can be produced according to
[00310] [00310] Although the content of the compound of the present invention in the pharmaceutical composition of the present invention varies depending on the dosage form, the dose of the compound of the present invention and the like, it is, for example, about 0.1 to 100% by weight.
[00311] [00311] When an oral preparation is produced, the coating can be applied whenever necessary in order to mask flavor, enteric solubility or sustainability.
[00312] [00312] Examples of the coating base used for coating include sugar coating base, water soluble film coating base, enteric film coating base and extended release film coating base.
[00313] [00313] As a sugar coating base, sucrose is used, and one or more selected types of talc, and precipitated calcium carbonate, gelatin, gum arabic, pullulan, carnauba wax and the like can also be used in combination.
[00314] [00314] Examples of the water soluble film coating base include cellulose polymers, such as hydroxypropyl cellulose, hydroxypropylmethylcellulose, hydroxyethylcellulose, methylhydroxyethylcellulose and the like; synthetic polymers such as polyvinylacetal diethylaminoacetate, aminoalkylmethacrylate E [Eudragit E (trade name)] copolymer, polyvinylpyrrolidone and the like; and polysaccharides such as pullulan and the like.
[00315] [00315] Examples of the enteric film coating base include cellulose polymers, such as hydroxypropylmethylcellulose phthalate, hydroxypropylmethylcellulose acetate succinate, carboxymethylethylcellulose, cellulose acetate phthalate and the like; acrylic acid polymers, such as methacrylic acid copolymer L [Eudragit L (trade name)], acid copolymer
[00316] [00316] Examples of the extended release film coating base include cellulose polymers such as ethyl cellulose and the like; and acrylic acid polymers, such as aminoalkylmethacrylate copolymer RS [Eudragit RS (trade name)], suspension of ethyl acrylate-methyl methacrylate copolymer [Eudragit NE (trade name)] and the like.
[00317] [00317] Two or more types of the coating bases mentioned above can be used in a mixture at an appropriate ratio. In addition, for example, light protection agents, such as titanium oxide, red ferric oxide and the like, can also be used during coating.
[00318] [00318] As the compound of the present invention shows low toxicity (e.g. acute toxicity, chronic toxicity, genetic toxicity, reproductive toxicity, cardiotoxicity, carcinogenicity) and less side effects, it can be used as a prophylactic or therapeutic agent or as diagnosis for various diseases in mammals (eg, human, bovine, horse, dog, cat, monkey, mouse, rat).
[00319] [00319] The compound of the present invention has excellent type 2 orexin receptor agonist activity and can treat, prevent or improve the risk of various neurological and psychiatric diseases associated with a type 2 orexin receptor. The compound of the present invention is useful as an agent for prophylaxis or treatment of various diseases, such as narcolepsy, idiopathic hypersomnia, hypersomnia, sleep apnea syndrome, narcolepsy syndrome accompanied by symptoms similar to narcolepsy, hypersomnia syndrome accompanied by daytime hypersomnia (eg Kleine Levin syndrome , major depression with hypersomnia, Lewy body dementia,
[00320] [00320] In particular, the compound of the present invention is useful as an agent for prophylaxis or treatment of narcolepsy, idiopathic hypersomnia, hypersomnia, sleep apnea syndrome, narcolepsy syndrome accompanied by symptoms similar to narcolepsy, hypersomnia syndrome accompanied by daytime hypersomnia (for example, Parkinson's disease, Guillain-Barre syndrome and Kleine Levin syndrome), Alzheimer's disease, obesity, insulin resistance syndrome, heart failure, diseases related to bone loss, sepsis, consciousness disorder like coma and the like , side effects and complications due to anesthesia and the like, or anesthetic antagonist.
[00321] [00321] Although the dose of the compound of the present invention varies depending on the individual of administration, route of administration, target disease, symptom and the like, for example, when the compound of the present invention is administered orally or parenterally to an adult patient, its dose is, for example, about 0.01 to 100 mg / kg of body weight per dose, preferably 0.1 to 50 mg / kg of body weight per dose and more preferably 0.5 to 20 mg / kg of weight per dose. This amount is desirably administered in one to three servings daily.
[00322] [00322] The compound of the present invention can be used in combination with other drugs (hereinafter abbreviated as a concomitant drug).
[00323] [00323] By combining the compound of the present invention and a concomitant drug, a superior effect can be achieved, for example, (1) the dose can be reduced compared to
[00324] [00324] In the present specification, the compound of the present invention and a concomitant drug used in combination are called the "combining agent of the present invention".
[00325] [00325] When using the combination agent of the present invention, the time of administration of the compound of the present invention and the concomitant drug is not restricted and the compound of the present invention or a pharmaceutical composition thereof, or the concomitant drug or a pharmaceutical composition of the same can be administered simultaneously to an individual of the administration, or can be administered at different times. The concomitant drug dosage can be determined according to the dose used clinically and can be appropriately selected depending on an individual of administration, route of administration, disease, combination and the like.
[00326] [00326] The mode of administration of the combination agent of the present invention and the concomitant drug is not particularly limited,
[00327] [00327] The dose of the concomitant drug can be properly determined based on the dose used in clinical situations. The mixing ratio of the compound of the present invention and a concomitant drug can be suitably determined depending on the individual of administration, route of administration, target disease, symptom, combination and the like.
[00328] [00328] For example, the content of the compound of the present invention in the combining agent of the present invention differs depending on the form of a preparation, and generally from about 0.01 to about 100% by weight, preferably from about 0, 1 to about 50% by weight, more preferably from about 0.5 to about 20% by weight, based on the complete preparation.
[00329] [00329] The content of the concomitant drug in the combining agent of the present invention differs depending on the form of a preparation, and generally from about 0.01 to about 100% by weight, preferably from about 0.1 to about 50 % by weight, more preferably from about 0.5 to about 20% by weight, based on the complete preparation.
[00330] [00330] The content of ADDITIVES such as a carrier and the like in the combination agent of the present invention differs depending on the form of a preparation, and generally from about 1 to about 99.99% by weight, preferably from about 10 to about 90% by weight, based on the preparation.
[00331] [00331] Similar contents can be used even when the compound of the present invention and a concomitant drug are formulated separately in preparations.
[00332] [00332] Examples of the concomitant drug include the following. A therapeutic drug for narcolepsy (for example, methylphenidate, amphetamine, pemoline, phenelzine, protriptyline, sodium oxybate, modafinil, caffeine), anti-obesity drug (amphetamine, benzfetamine, bromocriptine, bupropion, diethylpropion, exenathyride, lithaminamine, exhenatyrine, lyridaminone , methamphetamine, octreotide, octreotide, orlistat, phendimetrazine, phendimetrazine, phenmetrazine, phentermine, Qnexa (trademark), phenylpropanolamine, pramlintide, propylhexedrine, recombinant leptin, sibutramine, topiramate, zimelidine, acetaminamine, zimelidine, acetaminamine, ziselidine, acetaminophen, zinc, acetone esterase (eg donepezil, rivastigmine, galantamine, zanapezil, idebenone, tacrine), anti-dementia agent (eg memantine), inhibitor of production, secretion, accumulation, aggregation and / or deposition of β amyloid proteins, β secretase inhibitor ( for example, 6- (4-biphenylyl) methoxy-2- [2- (N, N-dimethylamino) ethyl] tetraline, 6- (4-biphenylyl) methoxy-2- (N, N-dimethylamino) methyl tetraline, 6- (4-biphenylyl) methoxy- 2- (N, N-dipropylamino) methyltetraline, 2- (N, N-dimethylamino) methyl-6- (4'-
[00333] [00333] Two or more types of the concomitant drug mentioned above can be used in a mixture at an appropriate ratio.
[00334] [00334] When the compound of the present invention is applied to each of the diseases mentioned above, it can also be used in combination with biological products (for example, antibody drug, nucleic acid or nucleic acid derivative, aptamer drug, vaccine preparation ) or can be used in combination with a method of gene therapy and the like, or can also be used in combination with treatment in the psychiatric field without the use of drugs.
[00335] [00335] Examples of the antibody drug and vaccine preparation include angiotensin II vaccine preparation, CETP vaccine preparation, CETP antibody, TNFα antibody and other cytokines, amyloid β vaccine preparation, type 1 diabetes vaccine (for example , Peptor DIAPEP-277), anti-HIV antibody and HIV vaccine preparation, as well as antibodies or cytokine vaccine preparations, renin-angiotensin enzymes and their products, antibodies or vaccine preparations against enzymes or proteins involved in the blood lipid metabolism, antibodies or vaccines related to enzymes and proteins involved in the blood coagulation or fibrinolysis system, antibodies or vaccine preparations against proteins involved in sugar metabolism and insulin resistance, and the like. In addition, it can be used in combination with biological products related to growth factors such as GH, IGF and the like.
[00336] [00336] Examples of the gene therapy method include a treatment method using the gene related to the cytokine, enzyme of the type renin-angiotensin and its product, protein G, protein-conjugated receptor and phosphorylating enzyme thereof, a treatment method using a DNA decoy, such as the NFκB decoy and the like, a treatment method using antisense, a treatment method using a gene related to an enzyme or protein involved in blood lipid metabolism (eg, a gene related to metabolism, excretion and absorption of cholesterol or triglyceride or HDL cholesterol or phospholipid in the blood), a treatment method using a gene related to an enzyme or protein involved in angiogenesis therapy for peripheral vascular obstruction and the like (eg, growth factors like HGF, VEGF etc. .), a treatment method using a gene related to a protein involved in glucose metabolism and insulin resistance, antisense against cytokines like TNF etc., and the like.
[00337] [00337] Examples of the treatment method in the psychiatric field without the use of drugs include modified electroconvulsive therapy, deep brain stimulation therapy, repetitive transcranial magnetic stimulation therapy, psychotherapy including cognitive behavioral therapy and the like.
[00338] [00338] The compound of the present invention can also be used in combination with various methods of organ regeneration, such as cardiac regeneration, renal regeneration, pancreatic regeneration, revascularization and the like, cell transplant therapy using bone marrow cells (derived mononuclear cell bone marrow, myelogenic stem cell) or artificial organ using tissue engineering (eg artificial blood vessel, cardiomyocyte sheet). Examples
[00339] [00339] The present invention is explained in detail below, with reference to the Examples, Experimental Examples and Formulation Examples. However, the Examples do not limit the present invention and the Examples can be modified within the scope of the present invention.
[00340] [00340] The "room temperature" in the Examples below is generally about 10 ° C to about 35 ° C. The ratio for mixed solvent is, unless otherwise specified, a mixing ratio of volume and% means% by weight, unless otherwise specified.
[00341] [00341] Elution by column chromatography in the Examples was performed under observation by TLC (Thin Layer Chromatography), unless otherwise specified. In TLC observation, 60 F254 manufactured by Merck was used as a TLC plate, the solvent used as the elution solvent in column chromatography was used as the eluent and the UV detector was used for detection. In silica gel column chromatography, the indication of NH means use of silica gel bound to aminopropylsilane and the indication of Diol means use of silica gel attached to
[00342] [00342] The 1H NMR was measured by Fourier transform NMR. For the analysis of 1H NMR, ACD / SpecManager software (trade name) and similar were used. Peaks of a hydroxyl group, an amino group and the like, with a very light proton peak, are sometimes not described.
[00343] [00343] MS was measured by LC / MS. As the ionization method, ESI method or APCI method was used. The data indicates the actual measured (found) value. While the peak of the molecular ion is generally observed, an ion fragment is sometimes observed. In the case of a salt, a peak of molecular ions or a free-form fragmented ion peak is usually observed.
[00344] [00344] The unit of concentration of the sample (c) for optical rotation ([α] D) is g / 100 mL.
[00345] [00345] The value of the elementary analysis (Anal.) Is described as calculated value (Calcd) and actual measured value (Found).
[00346] [00346] In the Example, the expression cis / trans contained in the name of the compound basically means a cis or trans mixture of two types of optical isomers when the corresponding partial structure contains two asymmetric centers. Exceptionally, the term cis / trans means a single optical isomer when indicated as an “optional asset”.
[00347] [00347] X-ray powder diffraction peaks in the Examples mean peaks measured at room temperature using Ultima IV (Rigaku Corporation, Japan) using Cu Kα radiation as a radiation source. The measurement conditions are as follows.
[00348] [00348] Electric pressure / electric current: 40 kV / 50 mA Scanning speed: 6 degrees / min
[00349] [00349] In the following Examples, the following abbreviations are used. mp: melting point MS: mass spectrum M: molar concentration N: normality CDCl3: deuterochloroform DMSO-d6: deuterodimethyl sulfoxide 1 H NMR: proton nuclear magnetic resonance LC / MS: mass spectrometer for ESI liquid chromatography: electrospray ionization , ionization by electron spray APCI: chemical ionization of atmospheric pressure, chemical ionization of atmospheric pressure Pd2 (dba) 3: tris (dibenzylidene acetone) di-palladium (0) TFA: trifluoroacetic acid DIPEA: N-ethyl-N-isopropylpropan- 2-amine DMF: N, N-dimethylformamide THF: tetrahydrofuran CH3CN: acetonitrile DME: 1,2-dimethoxyethane MeOH: methanol EtoH: ethanol t-AmOH: 2-methyl-2-butanol Pd (PPh3) 4: palladium- triphenylphosphine (1: 4) tBuXphos: 2-di-tert-butylphosphino-2 ', 4', 6'-triisopropylbiphenyl XPhos Pd G3: (2-dicyclohexylphosphino- methanesulfonate
[00350] [00350] A mixture of (chloromethyl) benzene (3.78 g), boronic acid (3-bromophenyl) (6.00 g), Pd (PPh3) 4 (1.73 g), sodium carbonate (3.16 g) g), DME (60 ml) and water (30 ml) was stirred at 100 ° C for 15 h. The reaction mixture was added to the water, and the mixture was extracted with ethyl acetate. The organic layer was separated, washed with saturated brine, dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (petroleum ether) to give the title compound (4.50 g). 1 H NMR (400 MHz, CDCl 3) δ3.94 (2H, s), 7.10-7.25 (5H, m), 7.28-7.40 (4H, m).
[00351] [00351] To a mixture of magnesium (147 mg) and THF (10 ml) was added iodine (catalytic amount) and 1-benzyl-3-bromobenzene (1.49 g). The mixture was heated under reflux for 1 h, and cooled to 20 ° C. To the mixture, 3-bromopyridine-2-carbaldehyde (750 mg) was added, and the mixture was stirred under a nitrogen atmosphere at 20 ° C for 15 h. The reaction mixture was added to the saturated aqueous ammonium chloride solution, and the mixture was extracted with ethyl acetate. The organic layer was separated, washed with saturated brine, dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate / petroleum ether) to give the title compound (900 mg). 1 H NMR (400 MHz, CDCl3) δ 3.97 (2H, s), 5.23 (1H, d, J = 6.8 Hz), 5.94 (1H, d, J = 5.2 Hz) , 7.03-7.08 (1H, m), 7.10-7.31 (9H, m), 7.83-7.90 (1H, m), 8.59 (1H, dd, J = 4.4, 1.2 Hz). C) 2- (3-benzylbenzyl) -3-bromopyridine
[00352] [00352] To a mixture of (3-benzylphenyl) (3-bromopyridin-2-yl) methanol (900 mg) and TFA (5 ml), triethylsilane (10 ml) was added. The mixture was stirred at 60 ° C for 40 h, and the reaction mixture was concentrated under reduced pressure. The obtained residue was basified to pH7 at 8 with saturated aqueous sodium hydrogen carbonate solution and the mixture was extracted with ethyl acetate . The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate / petroleum ether) to give the title compound (1.10 g). 1 H NMR (400 MHz, CDCl3) δ3.95 (2H, s), 4.32 (2H, s), 7.00-7.08 (2H, m), 7.10-7.23 (6H, m), 7.25-7.30 (2H, m), 8.83 (1H, dd, J = 8.0, 1.6 Hz), 8.50 (1H, dd, J = 4.8, 1.6 Hz). D) N- (2- (3-benzylbenzyl) pyridin-3-yl) methanesulfonamide
[00353] [00353] A mixture of 2- (3-benzylbenzyl) -3-bromopyridine (1.10 g), methanesulfonamide (464 mg), tBuXphos (166 mg), Pd2 (dba) 3 (149 mg), cesium carbonate ( 1.59 g) and DME (20 mL) was stirred under nitrogen at 85 ° C for 15 h. The reaction mixture was added to the water, and the mixture was extracted with ethyl acetate. The organic layer was separated, washed with saturated brine, dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate / petroleum ether) to give the title compound (260 mg). 1 H NMR (400 MHz, CDCl3) δ2.39 (3H, s), 3.93 (2H, s), 4.22 (2H, s), 6.21 (1H, brs), 7.00-7 , 35 (10H, m), 8.87 (1H, d, J = 7.2 Hz), 8.44 (1H, d, J = 3.6 Hz). E) N- (cis-2- (3-benzylbenzyl) piperidin-3-yl) methanesulfonamide
[00354] [00354] A mixture of N- (2- (3-benzylbenzyl) pyridin-3-yl) methanesulfonamide (200 mg), 5% rhodium on carbon (350 mg), THF (9 ml) and AcOH (1 ml) was stirred under a 35 psi (241.3 kPa) hydrogen atmosphere at 20 ° C for 15 h. The reaction mixture was filtered and the filtrate was added to the water. The mixture was neutralized with a saturated aqueous solution of sodium hydrogen carbonate and extracted with ethyl acetate. The organic layer was separated, washed with saturated brine, dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (dichloromethane / methanol) and preparative thin layer chromatography to give the title compound (30 mg). MS: [M + H] + 359.0. F) cis-2- (3-benzylbenzyl) -N-ethyl-3 - ((methylsulfonyl) amino)) piperidine-1-carboxamide
[00355] [00355] A mixture of N- (cis-2- (3-benzylbenzyl) piperidin-3-yl) methanesulfonamide (30 mg), TEA (25 mg) and isocyanatoethane (8 mg) in
[00356] [00356] To a mixture of tert-butyl 3-oxopiperidine-1-carboxylate (3.49 g) and toluene (38 ml), pyrrolidine (1.87 g) was added at room temperature. The mixture was stirred at room temperature for 30 min, heated under reflux for 1 hour using Dean-Stark apparatus and concentrated under reduced pressure. The obtained residue was mixed with CH3CN (38 ml), and 3- (bromomethyl) biphenyl (5.19 g) was added thereto at room temperature. The mixture was heated under reflux for 1 h, and the reaction mixture was poured into water, and the mixture was extracted with ethyl acetate. The organic layer was separated, washed with water and saturated brine, dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate / hexane) to give the title compound (3.42 g). MS: [M + H- (tBu)] + 310.2. B) tert-butyl cis-3-amino-2- (biphenyl-3-ylmethyl) piperidine-1-carboxylate
[00357] [00357] To a mixture of 2- (biphenyl-3-ylmethyl) -3-oxopiperidine-1-tert-butyl carboxylate (3.41 g), THF (25 ml) and MeOH (25 ml), was added ammonium acetate (7.19 g) at room temperature. The mixture was stirred at room temperature for 1 h and sodium triacetoxyborohydride (3.56 g) was added thereto. The mixture was stirred at room temperature for 18h. The reaction mixture was poured into saturated aqueous sodium hydrogen carbonate solution at 0 ° C, and the mixture was extracted with ethyl acetate. The organic layer was separated, washed with water and saturated brine, dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (methanol / ethyl acetate) to give the title compound (1.67 g). MS: [M + H] + 367.2. C) tert-butyl cis-2- (biphenyl-3-ylmethyl) -3 - ((methylsulfonyl) amino)) piperidine-1-carboxylate
[00358] [00358] To a mixture of cis-3-amino-2- (biphenyl-3-ylmethyl) piperidine-1-tert-butyl carboxylate (1.66 g), THF (15 ml) and TEA (0.917 g), methanesulfonyl chloride (0.623 g) was added at 0 ° C. The mixture was stirred at room temperature for 1 h, poured into ice water and extracted with ethyl acetate. The organic layer was separated, washed with aqueous sodium hydrogen carbonate solution and saturated brine, dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate / hexane) to give the title compound (1.75 g). 1 H NMR (300 MHz, CDCl3) δ 1.11 (9H, s), 1.61-1.74 (2H, m), 1.75-1.84 (1H, m), 1.88-1 , 97 (1H, m), 2.83-2.98 (3H, m), 3.00 (3H, s), 3.57-3.68 (1H, m), 4.04-4.12 (1H, m), 4.41 (1H, d, J = 7.9 Hz), 4.73-4.83 (1H, m), 7.17 (1H, d, J = 7.2 Hz) , 7.30-7.39 (3H, m), 7.39-7.46 (3H, m), 7.52-7.58 (2H, m). Example 24 cis-2- (3-iodobenzyl) -3 - ((methylsulfonyl) amino)) piperidine-1-carboxylate
[00359] [00359] To a mixture of tert-butyl 3-oxopiperidine-1-carboxylate (10 g) and toluene (100 ml), pyrrolidine (4.28 g) was added at room temperature. The mixture was stirred at room temperature for 30 min and concentrated under reduced pressure. The residue was mixed with CH3CN (100 ml), and 1- (bromomethyl) -3-iodobenzene (17.9 g) was added to the mixture. The mixture was stirred overnight at 80 ° C, and the reaction mixture was concentrated under reduced pressure. The residue was dissolved in ethyl acetate and 1M hydrochloric acid, and the solution was stirred for 30 min and extracted with ethyl acetate. The separated organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate / hexane) to give the title compound (14.7 g). MS: [M + H-Boc] + 316.0. B) tert-butyl cis-3-amino-2- (3-iodobenzyl) piperidine-1-carboxylate
[00360] [00360] To a mixture of 2- (3-iodobenzyl) -3-oxopiperidine-1-tert-butyl carboxylate (3.9 g), MeOH (40 ml) and THF (40 ml), was added acetate ammonium (7.24 g) at room temperature. The mixture was stirred at room temperature for 1 h, sodium triacetoxyborohydride (3.58 g) was added and the mixture was stirred at room temperature for 18 h. The reaction mixture was added to the saturated aqueous sodium hydrogen carbonate solution under ice-cooling and the mixture was extracted with ethyl acetate. The separated organic layer was washed with water and saturated brine, dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (NH, ethyl acetate / hexane) to give the title compound (2.14 g). MS: [M + H] +417.1. C) cis-2- (3-iodobenzyl) -3 - ((methylsulfonyl) amino)) piperidine-1-carboxylate
[00361] [00361] To a mixture of tert-butyl cis-3-amino-2- (3-iodobenzyl) piperidine-1-carboxylate (2.00 g) and THF (20 ml), TEA (0.972 g) and methanesulfonyl chloride (0.660 g) at 0 ° C. The mixture was stirred at room temperature for 1 h. To the mixture, saturated aqueous sodium hydrogen carbonate solution was added and the mixture was extracted with ethyl acetate. The organic layer was separated, washed with water and saturated brine, dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate / hexane) to give the title compound (1.66 g). MS: [M-H] - 493.1. D) N- (cis-2- (3-iodobenzyl) piperidin-3-yl) methanesulfonamide hydrochloride
[00362] [00362] To a mixture of tert-butyl cis-2- (3-iodobenzyl) -3- ((methylsulfonyl) amino)) piperidine-1-carboxylate (1.66 g) and THF (8 ml) if 4M ethyl acetate / hydrogen chloride solution (8.39 mL) at room temperature. The mixture was stirred overnight at room temperature, and concentrated under reduced pressure. The residue was suspended in ethyl acetate and the solid was collected by filtration. The obtained solid was washed with ethyl acetate to give the title compound (1.29 g). MS: [M + H] + 395.0. E) methyl cis-2- (3-iodobenzyl) -3 - ((methylsulfonyl) amino)) piperidine-1-carboxylate
[00363] [00363] To a mixture of N- (cis-2- (3-iodobenzyl) piperidin-3-yl) methanesulfonamide hydrochloride (1.3 g), TEA (1.22 g) and THF (20 ml) was added methyl carbonochlorhydrate (0.570 g) at room temperature. The mixture was stirred at room temperature for 10 min and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate / hexane) to give the title compound (1.30 g).
[00364] [00364] A mixture of methyl cis-2- (3-iodobenzyl) -3- ((methylsulfonyl) amino)) piperidine-1-carboxylate (40 mg), pyrrolidine (12.6 mg), Pd2 (dba) 3 (8.10 mg), dicyclohexyl (2 ', 6'-diisopropoxybiphenyl-2-yl) phosphine (12.4 mg), cesium carbonate (86 mg) and t-AmOH (1 ml) were subjected to irradiation by microwave at 100 ° C for 1 h. The mixture was poured into water and extracted with ethyl acetate. The organic layer was separated, washed with saturated brine, dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (NH, ethyl acetate / hexane) to give the title compound (19.0 mg). 1 H NMR (300 MHz, DMSO-d6) δ 1.32-1.57 (1H, m), 1.61-1.76 (3H, m), 1.86-1.99 (4H, m) , 2.68-2.84 (2H, m), 2.90-3.03 (4H, m), 3.08-3.23 (5H, m), 3.34-3.52 (2H, m), 3.61 to 3.89 (1H, m), 4.39 to 4.71 (1H, m), 6.23 to 6.47 (3H, m), 6.92 to 7.06 ( 1H, m), 7.28-7.40 (1H, m). Example 64 cis-3 - ((methylsulfonyl) amino)) - 2 - ((6-phenylpyridin-2-yl) methyl) isopropyl A-piperidine-1-carboxylate A) (6-phenylpyridin-2-yl) methanol
[00365] [00365] A mixture of (6-bromopyridin-2-yl) methanol (5.10 g), phenylboronic acid (4.96 g), Pd (PPh3) 4 (1.25 g), aqueous sodium carbonate solution 2M (33.9 mL) and DME (55 mL) was heated under reflux for 15 h under an argon atmosphere. The reaction mixture was poured into water, and the mixture
[00366] [00366] To a mixture of (6-phenylpyridin-2-yl) methanol (3.74 g), PPh3 (6.36 g) and benzotrifluoride (150 ml) was added tetrabromomethane (8.04 g) at 0 ° C . The mixture was stirred at 0 ° C for 3 h, and the insoluble substance was removed by filtration and washed with ethyl acetate. The filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate / hexane) to give the title compound (4.03 g). MS: [M + H] + 248.0. C) tert-Butyl 3-oxo-2 - ((6-phenylpyridin-2-yl) methyl) piperidine-1-carboxylate
[00367] [00367] To a mixture of tert-butyl 3-oxopiperidine-1-carboxylate (2.69 g) and toluene (29 ml), pyrrolidine (1.44 g) was added at room temperature. The mixture was stirred at room temperature for 30 min, heated under reflux for 1 hour using Dean-Stark apparatus and concentrated under reduced pressure. The residue was mixed with CH3CN (29 ml), and 2- (bromomethyl) -6-phenylpyridine (4.02 g) was added to the mixture at room temperature. The mixture was stirred at room temperature for 15 h, and the reaction mixture was poured into water, and the mixture was extracted with ethyl acetate. The organic layer was separated, washed with water and saturated brine, dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate / hexane) to give the title compound (2.56 g).
[00368] [00368] To a mixture of tert-butyl 3-oxo-2 - ((6-phenylpyridin-2-yl) methyl) piperidine-1-carboxylate (2.55 g), MeOH (19 mL) and THF (19 ml), ammonium acetate (5.36 g) was added at room temperature. The mixture was stirred at room temperature for 1 h and sodium triacetoxyborohydride (2.65 g) was added thereto. The mixture was stirred at room temperature for 3 h. The reaction mixture was poured into a saturated aqueous solution of sodium hydrogen carbonate under ice cooling, and the mixture was extracted with ethyl acetate. The organic layer was separated, washed with water and saturated brine, dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (methanol / ethyl acetate) to give the title compound (977 mg). MS: [M + H] + 368.2. E) cis-3 - ((methylsulfonyl) amino)) - 2 (tert-butyl (6-phenylpyridin-2-yl) methyl) piperidine-1-carboxylate
[00369] [00369] To a mixture of cis-3-amino-2 - ((6-phenylpyridin-2-yl) methyl) tert-butyl piperidine-1-carboxylate (973 mg), TEA (536 mg) and THF (9 ml), methanesulfonyl chloride (364 mg) was added at 0 ° C. The mixture was stirred at room temperature for 1 h, and the reaction mixture was poured into ice water, and the mixture was extracted with ethyl acetate. The organic layer was separated, washed with aqueous sodium hydrogen carbonate solution and saturated brine, dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate / hexane) to give the title compound (1.05 g). MS: [M + H] + 446.2.
[00370] [00370] To a mixture of tert-butyl cis-3 - ((methylsulfonyl) amino)) - 2 - ((6-phenylpyridin-2-yl) methyl) piperidine-1-carboxylate (991 mg) and toluene (11 ml), TFA (11 ml) was added at room temperature. The mixture was stirred at room temperature for 1 h, and the reaction mixture was poured into a saturated aqueous solution of sodium hydrogen carbonate under ice-cooling. The mixture was basified to pH = 8 with potassium carbonate and extracted with ethyl acetate / THF. The organic layer was separated, washed with water and saturated brine, dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The obtained solid was collected by filtration and washed with diisopropyl ether to give the title compound (671 mg). MS: [M + H] + 346.1. G) cis-3 - ((methylsulfonyl) amino)) - 2 ((6-phenylpyridin-2-yl) methyl) isopropyl piperidine-1-carboxylate
[00371] [00371] To a mixture of N- (cis-2 - ((6-phenylpyridin-2-yl) methyl) piperidin-3-yl) methanesulfonamide (150 mg) and THF (2.17 ml) was added TEA ( 132 mg) and isopropyl carbonochloride (0.326 ml) at room temperature. The mixture was stirred at room temperature for 1 h, and the reaction mixture was poured into water, and the mixture was extracted with ethyl acetate. The organic layer was separated, dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate / hexane) to give the title compound (157 mg). 1 H NMR (300 MHz, CDCl3) δ 1.12 (6H, d, J = 6.4 Hz), 1.75 (4H, brs), 2.05-2.19 (1H, m), 2, 67-2.90 (3H, m), 2.88-3.06 (2H, m), 3.35 (1H, dd, J = 13.9, 5.7 Hz), 3.53-3, 68 (1H, m), 3.96-4.14 (1H, m), 4.84 (2H, d, J = 5.7 Hz), 7.14- 7.22 (1H, m), 7 , 38-7.52 (3H, m), 7.55-7.59 (1H, m), 7.66-7.74 (1H, m), 7.90-7.98 (2H, m) .
[00372] [00372] To a mixture of tert-butyl 3-oxopyrrolidine-1-carboxylate (3.5 g) and toluene (30 ml), pyrrolidine (1.61 g) was added at room temperature. The mixture was stirred at 100 ° C for 3 h, and concentrated. CH3CN (30 mL) and 3- (bromomethyl) biphenyl (4.67 g) were added thereto at room temperature. The mixture was stirred overnight under nitrogen at 80 ° C, and concentrated. The residue obtained was diluted with water, and the mixture was extracted with ethyl acetate. The organic layer was dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate / hexane) to give the title compound (2.92 g). MS: [M + H-Boc] + 252.2. B) tert-butyl cis-2- (biphenyl-3-ylmethyl) -3 - ((1-phenylethyl) amino) pyrrolidine-1-carboxylate
[00373] [00373] A mixture of tert-butyl 2- (biphenyl-3-ylmethyl) -3-oxopyrrolidine-1-carboxylate (2.38 g), 1-phenylethanamine (0.903 g), tris (trifluoromethanesulfonate) (3 +) (0.420 g) and toluene (20 ml) was stirred at 100 ° C for 4 h. The reaction mixture was partitioned between ethyl acetate-water, and the organic layer was washed with saturated brine and concentrated under reduced pressure. To a mixture of the obtained residue (3.08 g), CH 3 CN (30 ml) and AcOH (5 ml) was added sodium triacetoxyborohydride (4.30 g) at 0 ° C. The mixture was stirred at room temperature for 1 h and neutralized with 4M aqueous sodium hydroxide solution. The obtained mixture was partitioned between ethyl acetate-aqueous sodium hydrogen carbonate solution, and the organic layer was washed with saturated brine and concentrated under reduced pressure. The residue was purified by chromatography
[00374] [00374] A mixture of tert-butyl cis-2- (biphenyl-3-ylmethyl) -3 - ((1-phenylethyl) amino) pyrrolidine-1-carboxylate (2.29 g), 20% palladium hydroxide on carbon (3.52 g), 1M hydrochloric acid (10.0 ml) and MeOH (50 ml) was stirred overnight under normal hydrogen atmosphere at room temperature. The catalyst was removed by filtration, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (NH, ethyl acetate / hexane) to give the title compound (865 mg). MS, found: 297.2. D) tert-butyl cis-2- (biphenyl-3-ylmethyl) -3 - ((methylsulfonyl) amino)) pyrrolidine-1-carboxylate
[00375] [00375] To a mixture of tert-butyl cis-3-amino-2- (biphenyl-3-ylmethyl) pyrrolidine-1-carboxylate (865 mg), TEA (497 mg) and THF (50 ml) methanesulfonyl chloride (337 mg) at 0 ° C. The mixture was stirred at room temperature for 1 h, poured into ice water and extracted with ethyl acetate. The organic layer was separated, washed with saturated aqueous sodium hydrogen carbonate solution and saturated brine, dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate / hexane) to give the title compound (750 mg). MS: [M-H] - 429.2. E) N- (cis-2- (biphenyl-3-ylmethyl) pyrrolidin-3-yl) methanesulfonamide hydrochloride
[00376] [00376] A mixture of tert-butyl cis-2- (biphenyl-3-ylmethyl) -3- ((methylsulfonyl) amino)) pyrrolidine-1-carboxylate (750 mg) and ethyl acetate / hydrogen chloride solution 4M (20 mL) was stirred at
[00377] [00377] To a mixture of N- (cis-2- (biphenyl-3-ylmethyl) pyrrolidin-3-yl) methanesulfonamide hydrochloride (40 mg), TEA (33.1 mg) and THF (3 ml) was added ethyl carbonochloride (23.7 mg) at room temperature. The mixture was stirred at room temperature for 30 min, the reaction solution was poured into saturated aqueous sodium hydrogen carbonate solution at room temperature, and the mixture was extracted with ethyl acetate. The organic layer was separated, washed with saturated brine, dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The obtained solid was crystallized from ethyl acetate-heptane to give the title compound (32.0 mg). 1 H NMR (300 MHz, DMSO-d6) δ 0.64-1.23 (3H, m), 1.72-2.25 (2H, m), 2.60-3.48 (8H, m) , 3.54-4.25 (3H, m), 7.11-7.69 (10H, m). Example 76 cis-3 - ((methylsulfonyl) amino)) - 2 - ((6-phenylpyridin-2-yl) methyl) piperidine-1-optically active isopropyl carboxylate
[00378] [00378] A racemate (120 mg) of cis-3 - ((methylsulfonyl) amino)) - 2 - ((6-phenylpyridin-2-yl) methyl) piperidine-1-carboxylate was resolved by HPLC (column: CHIRALPAK AD-H (UG065), 4.6 mmID × 250 mmL, manufactured by Daicel Chemical Industries, mobile phase: hexane / 2-propanol = 700/300) to give the title compound (49.4 mg) with a time of lower retention. The title compound was purified by HPLC (C18, mobile phase: water / acetonitrile (containing 0.1% TFA)), and to the obtained fraction was added saturated aqueous sodium hydrogen carbonate solution, and the mixture was extracted with ethyl acetate . The extract was dried over magnesium sulfate
[00379] [00379] A mixture of tert-butyl cis-2- (biphenyl-3-ylmethyl) -3- ((methylsulfonyl) amino)) pyrrolidine-1-carboxylate (0.950 g), TFA (3.08 g) and dichloromethane (10 mL) was stirred under a nitrogen atmosphere at 15 ° C for 2 h. The reaction solution was neutralized (pH = 7) with saturated aqueous sodium hydrogen carbonate solution. The aqueous layer was extracted with dichloromethane, and the combined organic layers were washed with saturated brine, dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (EtoH / ethyl acetate) to give the title compound (0.378 g). 1 H NMR (400 MHz, CDCl3) δ 1.85-1.96 (1H, m), 2.22-2.34 (1H, m), 2.74-2.86 (2H, m), 2 , 94 (3H, s), 3.00-3.15 (2H, m), 3.25-3.33 (1H, m), 3.90-3.96 (1H, m), 7.18 -7.25 (1H, m), 7.30-7.48 (6H, m), 7.54-7.63 (2H, m). Example 88 cis-3 - ((methylsulfonyl) amino)) - 2 - (tert-butyl (2-phenyl-1,3-thiazol-4-yl) methyl) piperidine-1-carboxylate A) 4- (chloromethyl) -2-phenyl-1,3-thiazole
[00380] [00380] A mixture of benzenocarbothioamide (6.86 g), 1,3-dichloroacetone (6.35 g) and toluene (50 ml) was heated under reflux for 3 h. The reaction mixture was cooled and water was added to it. The mixture was extracted with ethyl acetate, and the extract was washed with water and brine
[00381] [00381] To a mixture of tert-butyl 3-oxopiperidine-1-carboxylate (0.950 g) and toluene (10 ml), pyrrolidine (0.50 g) was added at room temperature. The mixture was stirred at room temperature for 30 min, and concentrated. The residue was mixed with CH3CN (10 ml), and 4- (chloromethyl) - 2-phenyl-1,3-thiazole (1 g) and TBAI (0.352 g) were added to the mixture at room temperature. The mixture was stirred overnight at 80 ° C, and the reaction mixture was concentrated. The residue obtained was partitioned between ethyl acetate-water, and extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate / hexane) to give the title compound (0.580 g). MS: [M + H] + 373.1. C) tert-butyl cis-3-amino-2 - ((2-phenyl-1,3-thiazol-4-yl) methyl) piperidine-1-carboxylate
[00382] [00382] To a mixture of tert-butyl 3-oxo-2 - ((2-phenyl-1,3-thiazol-4-yl) methyl) piperidine-1-carboxylate (580 mg), ammonium acetate (1200 mg), MeOH (5 ml) and THF (5 ml), sodium triacetoxyborohydride (495 mg) was added at room temperature. The mixture was stirred overnight at room temperature, and concentrated. The obtained residue was mixed with a saturated aqueous solution of sodium hydrogen carbonate, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate and concentrated under
[00383] [00383] To a mixture of tert-butyl cis-3-amino-2 - ((2-phenyl-1,3-thiazol-4-yl) methyl) piperidine-1-carboxylate (212 mg), TEA (86 mg) and THF (5 ml), methanesulfonic anhydride (119 mg) was added at room temperature. The mixture was stirred at room temperature for 10 min, and the reaction mixture was concentrated. The residue was purified by silica gel column chromatography (ethyl acetate / hexane) to give the title compound (212 mg). 1 H NMR (300 MHz, CDCl3) δ 1.33 (9H, s), 1.58-1.83 (3H, m), 2.00-2.11 (1H, m), 2.75-3 , 07 (5H, m), 3.27 (1H, dd, J = 14.4, 6.1 Hz), 3.54-3.69 (1H, m), 4.01 (1H, d, J = 11.4 Hz), 4.75 (1H, q, J = 5.8 Hz), 6.14 (1H, brs), 7.01 (1H, s), 7.39-7.49 (3H , m), 7.86-8.01 (2H, m). Example 89 cis-3 - ((methylsulfonyl) amino)) - 2 - ((2-phenyl-1,3-thiazol-4-yl) methyl) isopropyl piperidine-1-carboxylate A) N- (cis- 2 - (((2-phenyl-1,3-thiazol-4-yl) methyl) piperidin-3-yl) methanesulfonamide
[00384] [00384] To a mixture of tert-butyl cis-3 - ((methylsulfonyl) amino)) - 2 - ((2-phenyl-1,3-thiazol-4-yl) methyl) piperidine-1-carboxylate (207 mg) and ethyl acetate (5 ml), 4M ethyl acetate / hydrogen chloride solution (2 ml) was added at room temperature. The mixture was stirred overnight at room temperature and the reaction mixture was concentrated to give the title compound (200 mg). MS: [M + H] + 352.1. B) cis-3 - ((methylsulfonyl) amino)) - 2 - ((2-phenyl-1,3-thiazol-4-yl) methyl) piperidine-1-
[00385] [00385] To a mixture of N- (cis-2 - ((2-phenyl-1,3-thiazol-4-yl) methyl) piperidin-3-yl) methanesulfonamide dihydrochloride (60 mg), TEA (71, 5 mg) and THF (2 ml) 2M toluene / isopropyl carbonochlorhydrate solution (0.106 ml) was added at room temperature. The mixture was stirred at room temperature for 3 h and the reaction mixture was purified directly by column chromatography on silica gel (ethyl acetate / hexane) to give the title compound (43.0 mg). 1 H NMR (300 MHz, CDCl3) δ1.04.04.21 (6H, m), 1.59-1.83 (3H, m), 2.03-2.15 (1H, m), 2, 81-3.05 (5H, m), 3.30 (1H, dd, J = 14.8, 6.4 Hz), 3.53-3.71 (1H, m), 3.98-4, 09 (1H, m), 4.69-4.91 (2H, m), 6.38 (1H, brs), 7.02 (1H, s), 7.38-7.53 (3H, m) , 7.90-8.02 (2H, m). Example 93 N- (cis-2- (biphenyl-3-ylmethyl) -1- (cyclopropylcarbonyl) piperidin-3-yl) methanesulfonamide
[00386] [00386] To a mixture of N- (cis-2- (biphenyl-3-ylmethyl) piperidin-3-yl) methanesulfonamide (100 mg), TEA (58.8 mg) and dichloromethane (1 ml) was added chloride cyclopropanocarbonyl (45.5 mg) under nitrogen atmosphere at 0 ° C. The mixture was stirred at 0 ° C for 1 h. Saturated aqueous sodium hydrogen carbonate solution was added to the mixture, and the mixture was extracted with dichloromethane. The organic layer was separated, washed with saturated brine, dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was purified by HPLC (column: Phenomenex Gemini, mobile phase: water / CH3CN (containing 0.05% NH3-H2O)) to give the title compound (56.0 mg). 1 H NMR (400 MHz, DMSO-d6) δ 0.53-0.40 (4H, m), 1.26-1.76 (5H, m), 2.90-3.05 (6H, m) , 3.23-3.52 (1H, m), 4.28-4.66 (1H, m), 4.88-5.18 (1H, m), 7.16 (1H, d, J = 7.6 Hz), 7.27-7.47 (7H, m), 7.57-7.62 (2H, m). Example 100
[00387] [00387] To a mixture of 1-benzyl piperidin-3-one hydrochloride (15.0 g), TEA (7.40 g) and CH3CN (100 ml) was added dropwise a solution of toluene / carbonochlorhydrate of 2M isopropyl (59.8 ml) at 0 ° C. The mixture was stirred at room temperature for 2 h, and the insoluble substance was removed by filtration and washed with CH3CN. The filtrate was concentrated under reduced pressure. The residue was diluted with a saturated aqueous solution of sodium hydrogen carbonate, and the mixture was extracted with ethyl acetate. The organic layer was separated, washed with saturated brine, dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate / hexane) to give the title compound (11.0 g). 1 H NMR (300 MHz, CDCl3) δ 1.25 (6H, d, J = 6.4 Hz), 1.95-2.04 (2H, m), 2.48 (2H, t, J = 6 , 6 Hz), 3.60-3.66 (2H, m), 4.04 (2H, s), 4.94 (1H, spt, J = 6.2 Hz). B) 2-bromo-6- (bromomethyl) pyridine
[00388] [00388] To a mixture of (6-bromopyridin-2-yl) methanol (5.22 g), PPh3 (8.74 g) and benzotrifluoride (210 ml) was added tetrabromomethane (11.1 g) at 0 ° C . The mixture was stirred at 0 ° C for 2 h, and the insoluble substance was removed by filtration and washed with ethyl acetate / diethyl ether. The filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate / hexane) to give the title compound (7.33 g). 1 H NMR (300 MHz, CDCl 3) δ 4.50 (2H, s), 7.39-7.45 (2H, m), 7.52-7.60 (1H, m). C) Isopropyl 2 - ((6-bromopyridin-2-yl) methyl) -3-oxopiperidine-1-carboxylate
[00389] [00389] To a mixture of isopropyl 3-oxopiperidine-1-carboxylate
[00390] [00390] To a mixture of isopropyl 2 - ((6-bromopyridin-2-yl) methyl) -3-oxopiperidine-1-carboxylate (2.71 g), MeOH (23 mL), and THF (23 mL), ammonium acetate (5.88 g) was added at room temperature. The mixture was stirred at room temperature for 1 h and sodium triacetoxyborohydride (3.23 g) was added thereto. The mixture was stirred at room temperature for 15 h. The mixture was poured into a saturated aqueous solution of sodium hydrogen carbonate under ice cooling, and the mixture was extracted with ethyl acetate. The organic layer was separated, washed with water and saturated brine, dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (methanol / ethyl acetate) to give the title compound (373 mg). MS: [M + H] + 356.0. E) cis-2 - ((6-bromopyridin-2-yl) methyl) -3 - ((methylsulfonyl) amino)) isopropyl piperidine-1-carboxylate
[00391] [00391] Isopropyl cis-3-amino-2 - ((6-bromopyridin-2-yl) methyl) piperidine-1-carboxylate (369 mg), TEA (210 mg) and THF (3.5 ml), methanesulfonyl chloride (142 mg) was added at room temperature. The mixture was stirred at room temperature for 1 h, and the reaction solution was poured into water and the mixture was extracted with ethyl acetate. The organic layer was separated, washed with aqueous sodium hydrogen carbonate solution and saturated brine, dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate / hexane) to give the title compound (340 mg). MS: [M + H] + 434.0. F) cis-2 - ((6- (2,5-difluorophenyl) pyridin-2-yl) methyl) -3- ((methylsulfonyl) amino)) isopropyl piperidine-1-carboxylate
[00392] [00392] A mixture of cis-2 - ((6-bromopyridin-2-yl) methyl) -3- ((methylsulfonyl) amino)) isopropyl piperidine-1-carboxylate (73 mg), acid (2.5- difluorophenyl) boronic acid (39.8 mg), 2M aqueous sodium carbonate solution (0.210 mL) and DME (1.1 mL) was heated under reflux under an argon atmosphere for 9 h. The mixture was poured into water and extracted with ethyl acetate. The organic layer was separated, washed with water and saturated brine, dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate / hexane) to give the title compound (58.6 mg). 1 H NMR (300 MHz, CDCl3) δ 0.92-1.12 (6H, m), 1.60-1.83 (3H, m), 2.02-2.07 (1H, m), 2 , 91 (3H, s), 2.94-3.06 (2H, m), 3.30 (1H, dd, J = 14.0, 5.7 Hz), 3.57-3.68 (1H , m), 3.99-4.13 (1H, m), 4.73 (1H, spt, J = 6.2 Hz), 4.84-4.92 (1H, m), 5.64 ( 1H, brs), 7.01-7.16 (2H, m), 7.22-7.26 (1H, m), 7.62-7.74 (3H, m). Example 101 (2S, 3S) -2- (biphenyl-3-ylmethyl) -3 - ((methylsulfonyl) amino)) pyrrolidine-1-
[00393] [00393] An ethyl cis-2- (biphenyl-3-ylmethyl) -3- ((methylsulfonyl) amino)) pyrrolidine-1-carboxylate racemate (146 mg) was resolved by HPLC (column: CHIRALCEL OD (IK001) , 50 mmID × 500 mmL, manufactured by Daicel Chemical Industries, mobile phase: hexane / 2-propanol = 450/550) to give the title compound (47 mg) with a shorter retention time. 1 H NMR (300 MHz, DMSO-d6) δ 0.62-1.16 (3H, m), 1.71-2.23 (2H, m), 2.67-3.50 (8H, m) , 3.55-4.26 (3H, m), 7.10-7.68 (10H, m). Example 116 isopropyl cis-2 - ((2 ', 3'-difluorobiphenyl-3-yl) methyl) -3 - ((methylsulfonyl) amino)) piperidine-1-carboxylate
[00394] [00394] A mixture of cis-2- (3-iodobenzyl) -3- ((methylsulfonyl) amino)) isopropyl piperidine-1-carboxylate (96 mg), boronic acid (2,3-difluorophenyl) (95 mg) , XPhos Pd G3 (8.46 mg), 1M aqueous solution of tripotassium phosphate (0.6 ml) and THF (1 ml) was heated under reflux for 1 h. The mixture was diluted with ethyl acetate, washed with water and saturated brine, dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate / hexane) to give the title compound (71.0 mg). 1 H NMR (300 MHz, CDCl3) δ 0.82 (3H, brs), 1.03 (3H, d, J = 6.4 Hz), 1.59 - 1.99 (4H, m), 2, 98 (6H, s), 3.56-3.73 (1H, m), 4.01-4.13 (1H, m), 4.38 (1H, d, J = 7.6 Hz), 4 , 54-4.69 (1H, m), 4.74-4.89 (1H, m), 7.07-7.25 (4H, m), 7.30- 7.42 (3H, m) Example 117 isopropyl cis-2- (3-iodobenzyl) -3 - ((methylsulfonyl) amino)) piperidine-1-carboxylate
[00395] [00395] To a mixture of N- (cis-2- (3-iodobenzyl) piperidin-3-yl) methanesulfonamide hydrochloride (1.29 g), TEA (0.909 g) and THF (15 ml) was added toluene / isopropyl carbonochloride 2M
[00396] [00396] A mixture of 2- (bromomethyl) -3-nitropyridine (100 mg), 3-phenyl-1H-pyrazole (69.8 mg) and DMF (2 ml) was stirred at 60 ° C for 17 h. The mixture was partitioned between ethyl acetate-water, and the organic layer was washed with saturated brine and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (NH, ethyl acetate / hexane) to give the title compound (87 mg). MS: [M + H] + 281.0. B) 2 - ((3-phenyl-1H-pyrazol-1-yl) methyl) pyridin-3-amine
[00397] [00397] A mixture of 3-nitro-2 - ((3-phenyl-1H-pyrazol-1-yl) methyl) pyridine (793 mg), 10% palladium on carbon (301 mg) and EtoH (35 ml) it was stirred under a normal hydrogen atmosphere at room temperature for 1 h. The catalyst was removed by filtration, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate / hexane) to give the title compound (509 mg). MS: [M + H] + 251.0. C) N- (2 - ((3-phenyl-1H-pyrazol-1-yl) methyl) pyridin-3-yl) methanesulfonamide
[00398] [00398] A mixture of 2 - ((3-phenyl-1H-pyrazol-1-yl) methyl) pyridin-3-
[00399] [00399] A mixture of N- (2 - ((3-phenyl-1H-pyrazol-1-yl) methyl) pyridin-3-yl) methanesulfonamide (648 mg), 5% platinum on carbon (150 mg), 35% hydrochloric acid (411 mg), MeOH (23 ml) and water (7 ml) was stirred under a 3MPa hydrogen atmosphere at 50 ° C for 2 h. To the mixture, 5% platinum on carbon (75 mg) was added and the mixture was stirred under a 3MPa hydrogen atmosphere at 50 ° C for 2 h. The catalyst was removed by filtration, and the filtrate was concentrated under reduced pressure. The residue obtained was partitioned between THF-aqueous sodium hydrogen carbonate solution, and the organic layer was washed with saturated brine and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (NH, ethyl acetate / hexane) and crystallized from ethyl acetate to give the title compound (110 mg). MS: [M + H] + 335.1. E) cis-3 - ((methylsulfonyl) amino)) - 2 - ((3-phenyl-1H-pyrazol-1-yl) methyl) isopropyl piperidine-1-carboxylate
[00400] [00400] A mixture of N- (cis-2 - ((3-phenyl-1H-pyrazol-1-yl) methyl) piperidin-3-yl) methanesulfonamide (110 mg), TEA (66.6 mg), solution of toluene / isopropyl carbonochloridate 2 M (0.247 ml) and THF (3 ml) was stirred at room temperature for 30 min. The mixture was partitioned between
[00401] [00401] To a mixture of cis-3-amino-2 - ((6-phenylpyridin-2-yl) methyl) tert-butyl piperidine-1-carboxylate (1.05 g), sodium hydrogen carbonate (0.360 g) , THF (7 ml) and water (7 ml), 1- (((benzyloxy) carbonyl) oxy) pyrrolidine-2,5-dione (0.748 g) was added at room temperature. The mixture was vigorously stirred at room temperature for 2 h, poured into water and extracted with ethyl acetate. The organic layer was separated, washed with water and saturated brine, dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate / hexane) to give the title compound (1.37 g). MS: [M + H] + 502.2. B) benzyl carbamate (cis-2 - ((6-phenylpyridin-2-yl) methyl) piperidin-3-yl)
[00402] [00402] To a mixture of tert-butyl cis-3 - (((benzyloxy) carbonyl) amino) -2 - ((6-phenylpyridin-2-yl) methyl) piperidine-1-carboxylate (1.37 g) and toluene (15 ml), TFA (15 ml) was added at room temperature. THE
[00403] [00403] To a mixture of benzyl (cis-2 - ((6-phenylpyridin-2-yl) methyl) piperidin-3-yl) carbamate (960 mg), TEA (726 mg) and THF (20 ml) added - a 2M solution of toluene / isopropyl carbonochloride (2.39 mL) at room temperature. The mixture was stirred at room temperature for 1 h, added to the aqueous sodium hydrogen carbonate solution and extracted with ethyl acetate. The organic layer was separated, washed with water and saturated brine, dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate / hexane) to give the title compound (1.11 g). MS: [M + H] + 488.2. D) isopropyl cis-3-amino-2 - ((6-phenylpyridin-2-yl) methyl) piperidine-1-carboxylate
[00404] [00404] A mixture of isopropyl cis-3 - (((benzyloxy) carbonyl) amino) -2 - ((6-phenylpyridin-2-yl) methyl) piperidine-1-carboxylate (1.09 g), hydroxide 10% palladium on carbon (0.36 g) and MeOH (22 mL) was stirred under a normal hydrogen atmosphere at room temperature for 1.5 h. The catalyst was removed by filtration, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (methanol / ethyl acetate) to give the title compound (703 mg).
[00405] [00405] To a mixture of isopropyl cis-3-amino-2 - ((6-phenylpyridin-2-yl) methyl) piperidine-1-carboxylate (28 mg), TEA (0.00971 mg) and THF (1 , 0 mL), cyclopropanesulfonyl chloride (13.5 mg) was added. The mixture was stirred at room temperature for 3 h, and the reaction mixture was poured into water, and the mixture was extracted with ethyl acetate. The organic layer was filtered using an upper phase separation filter tube and the filtrate was concentrated by blowing air at 60 ° C. The residue was purified by HPLC (YMCTriartC18, mobile phase: water / MeCN (10 mM ammonium bicarbonate)). The fraction obtained was concentrated by blowing air at 60 ° C to give the title compound (12.7 mg). MS: [M + H] + 458.1. Example 206 N- (cis-2- (biphenyl-3-ylmethyl) -1- (cyclopropylcarbonyl) pyrrolidin-3-yl) methanesulfonamide
[00406] [00406] To a mixture of N- (cis-2- (biphenyl-3-ylmethyl) pyrrolidin-3-yl) methanesulfonamide (52.0 mg), TEA (47.8 mg) and THF (1.2 ml) cyclopropanecarbonyl chloride (32.9 mg) was added at room temperature. The mixture was stirred at room temperature for 50 min, and poured into aqueous sodium hydrogen carbonate solution and extracted with ethyl acetate. The organic layer was separated, washed with saturated brine, dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (methanol / ethyl acetate) to give a solid. The solid was collected by filtration and washed with isopropyl ether / hexane to give the title compound (38.0 mg). 1 H NMR (300 MHz, CDCl3) δ0.07-0.62 (2H, m), 0.72-1.08 (3H, m), 1.71
[00407] [00407] To a mixture of N- (cis-2- (biphenyl-3-ylmethyl) pyrrolidin-3-yl) methanesulfonamide (51.2 mg), TEA (47.0 mg) and THF (2 ml) was added if 2-methylpropanoyl chloride (24.8 mg) at 0 ° C. The mixture was stirred at 0 ° C for 30 min, and water was added to 0 ° C, and the mixture was extracted with ethyl acetate. The organic layer was separated, washed with saturated brine, dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (methanol / ethyl acetate). The obtained solid was recrystallized from ethyl acetate / hexane to give the title compound (29.0 mg). 1 H NMR (300 MHz, CDCl3) δ 0.50-1.19 (6H, m), 1.71-2.51 (4H, m), 2.54-2.74 (1H, m), 2 , 87-3.09 (2H, m), 3.11-3.27 (1H, m), 3.38-3.84 (2H, m), 3.91 4.09 (1H, m) , 4.23-4.55 (1H, m), 4.57-4.74 (1H, m), 7.09-7.62 (9H, m). Example 210 cis-3 - ((methylsulfonyl) amino)) - 2 - ((2-phenyl-1,3-thiazol-4-yl) methyl) optically active isopropyl piperidine-1-carboxylate
[00408] An isopropyl cis-3 - ((methylsulfonyl) amino)) - 2 - ((2-phenyl-1,3-thiazol-4-yl) methyl) piperidine-1-carboxylate racemate (82 mg) was resolved by SFC (column: CHIRALCEL ODH (TB001), 4.6 mmID × 150 mmL, manufactured by Daicel Chemical Industries, mobile phase: carbon dioxide / methanol = 770/230) to give the title compound (381 mg) with a longer retention time. 1 H NMR (300 MHz, CDCl3) δ 0.96-1.24 (6H, m), 1.60-1.87 (3H, m), 2.08 (1H, d, J = 9.5 Hz ), 2.78-3.07 (5H, m), 3.30 (1H, dd, J = 14.6, 6.2 Hz), 3.52 - 3.76 (1H, m), 4, 05 (1H, d, J = 14.8 Hz), 4.67-4.90 (2H, m), 6.31 (1H, brs),
[00409] [00409] To a mixture of tert-butyl 3-oxopiperidine-1-carboxylate (2.00 g) and toluene (20 ml), pyrrolidine (0.857 g) was added at room temperature. The mixture was stirred for 15 min, and concentrated under reduced pressure. The residue was dissolved in CH3CN (20 ml), and 2-chloro-5- (chloromethyl) pyridine (1.63 g) and TBAI (0.742 g) were added to it. The mixture was heated under reflux for 1 h, and the reaction mixture was diluted with water. The mixture was extracted with ethyl acetate, and the extract was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate / hexane) to give the title compound (1.61 g). MS: [M + H] + 325.3. B) cis-3-amino-2 - (tert-butyl (6-chloropyridin-3-yl) methyl) piperidine-1-carboxylate
[00410] [00410] To a mixture of tert-butyl 2 - ((6-chloropyridin-3-yl) methyl) -3-oxopiperidine-1-carboxylate (1.61 g), THF (15 mL) and MeOH (15 mL ), ammonium acetate (3.82 g) was added at room temperature. The mixture was stirred at room temperature for 1 h and sodium triacetoxyborohydride (2.10 g) was added thereto. The mixture was stirred overnight at room temperature, poured into a saturated aqueous solution of sodium hydrogen carbonate under ice-cooling and extracted with ethyl acetate. The organic layer was separated, washed with water and saturated brine, dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (NH, methanol / ethyl acetate) to give the title compound (567 mg).
[00411] [00411] To a mixture of cis-3-amino-2 - ((6-chloropyridin-3-yl) methyl) tert-butyl piperidine-1-carboxylate (567 mg), TEA (264 mg) and THF (8 ml), methanesulfonic anhydride (364 mg) was added at room temperature. The mixture was stirred at room temperature for 2 h, and the reaction solution was concentrated. The residue was purified by silica gel column chromatography (ethyl acetate / hexane) to give the title compound (650 mg). MS: [M + H] + 404.2. D) N- (cis-2 - ((6-chloropyridin-3-yl) methyl) piperidin-3-yl) methanesulfonamide dihydrochloride
[00412] [00412] A mixture of tert-butyl cis-2 - ((6-chloropyridin-3-yl) methyl) -3- ((methylsulfonyl) amino)) piperidine-1-carboxylate (645 mg) and methanol / hydrogen chloride (776 mg) was stirred overnight at room temperature. The mixture was concentrated under reduced pressure to give the title compound (557 mg). MS: [M + H] + 304.1. E) cis-2 - ((6-chloropyridin-3-yl) methyl) -3 - ((methylsulfonyl) amino)) isopropyl piperidine-1-carboxylate
[00413] [00413] To a mixture of N- (cis-2 - ((6-chloropyridin-3-yl) methyl) piperidin-3-yl) methanesulfonamide (200 mg), TEA (215 mg) and THF (5 ml ) 2M isopropyl toluene / carbonochlorhydrate solution (0.319 mL) was added at room temperature. The mixture was stirred overnight at room temperature. To the mixture, saturated aqueous sodium hydrogen carbonate solution was added and the mixture was extracted with ethyl acetate. The organic layer was separated, washed with saturated brine, dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue was
[00414] [00414] A mixture of isopropyl cis-2 - ((6-chloropyridin-3-yl) methyl) -3- ((methylsulfonyl) amino)) piperidine-1-carboxylate (91.0 mg), 5% carbon (30 mg) and EtoH (5 mL) was stirred under a normal hydrogen atmosphere at room temperature for 2 days. The catalyst was removed by filtration, and the filtrate was concentrated under reduced pressure. The similar reaction was carried out using cis-2 - ((6-chloropyridin-3-yl) methyl) -3- ((methylsulfonyl) amino)) isopropyl piperidine-1-carboxylate (117 mg) and 5.5% palladium on carbon (40 mg) and EtoH (5 ml). The combined residues were purified by silica gel column chromatography (NH, ethyl acetate / hexane) to give the title compound (144 mg). 1 H NMR (300 MHz, DMSO-d6) δ0.49-1.13 (6H, m), 1.49 (1H, brs), 1.60-1.82 (3H, m), 2.81 2.91 (2H, m), 2.92-3.07 (4H, m), 3.35-3.50 (1H, m), 3.85 (1H, d, J = 14.4 Hz) , 4.26-4.67 (2H, m), 7.27 (1H, brs), 7.39 (1H, brs), 7.54 (1H, dt, J = 7.8, 2.0 Hz ), 8.36 (2H, d, J = 2.3 Hz). Example 214 cis-3 - ((methylsulfonyl) amino)) - 2 ((1-phenylpiperidin-3-yl) methyl) isopropyl piperidine-1-carboxylate A) cis-3 - ((methylsulfonyl) amino)) - 2- (piperidin-3-ylmethyl) isopropyl piperidine-1-carboxylate
[00415] [00415] Isopropyl cis-3 - ((methylsulfonyl) amino)) - 2- (pyridin-3-ylmethyl) piperidine-1-carboxylate (142 mg), 5% rhodium on carbon (50% wet, 30 mg), MeOH (25 ml) and AcOH (5 ml) was stirred under a 3MPa hydrogen atmosphere at 50 ° C for 3 h. The catalyst was removed by filtration, and the filtrate was concentrated under reduced pressure. The residue was
[00416] [00416] To a mixture of isopropyl cis-3 - ((methylsulfonyl) amino)) - 2- (piperidin-3-ylmethyl) piperidine-1-carboxylate (28.6 mg), bromobenzene (24.8 mg), Cesium carbonate (103 mg) and t-AmOH (1 mL) were added Pd2 (dba) 3 (7.24 mg) and dicyclohexyl (2 ', 6'-diisopropoxyphenyl-2-yl) phosphine (7 , 38 mg) at room temperature. The mixture was heated under reflux under a nitrogen atmosphere for 4 h. Water was added to the mixture, and the mixture was extracted with ethyl acetate. The organic layer was separated, washed with saturated brine, dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate / hexane) to give the title compound (23.6 mg). 1 H NMR (300 MHz, DMSO-d6) δ0.92-2.04 (18H, m), 2.22-2.45 (1H, m), 2.55-2.87 (2H, m), 2.92 (3H, s), 3.20-3.64 (2H, m), 3.79 (1H, brs), 4.43 (1H, brs), 4.76 (1H, quin, J = 6.2 Hz), 6.72 (1H, t, J = 7.2 Hz), 6.90 (2H, dd, J = 8.5, 3.2 Hz), 7.09-7.27 ( 3H, m). Example 227 N- (cis-2- (biphenyl-3-ylmethyl) -1- (2,2-dimethylpropanoyl) pyrrolidin-3-yl) methanesulfonamide
[00417] [00417] To a mixture of N- (cis-2- (biphenyl-3-ylmethyl) pyrrolidin-3-yl) methanesulfonamide (40 mg), pivalic acid (13.4 mg), HATU (49.7 mg ) and DMF (0.5 ml) TEA (33.1 mg) was added at 0 ° C. The mixture was stirred at room temperature for 30 min, and saturated aqueous sodium hydrogen carbonate solution was added to the mixture, and the mixture was extracted with ethyl acetate. The organic layer was separated, washed with water and saturated brine, dried over anhydrous sodium sulfate and concentrated
[00418] [00418] H NMR (300 MHz, CDCl3) δ 1.26 (9H, s), 1.89-2.05 (1H, m), 2.20-2.34 (1H, m), 2.45 (3H, s), 2.78-2.93 (1H, m), 3.19-3.29 (1H, m), 3.62-3.77 (2H, m), 3.89-4 , 04 (1H, m), 4.45 (1H, d, J = 8.3 Hz), 4.70-4.80 (1H, m), 7.30-7.49 (6H, m), 7.52-7.62 (3H, m). Example 254 N- (cis-1- (cyclobutylcarbonyl) -2 - ((2- (3-fluorophenyl) -1,3-thiazol-4-yl) methyl) pyrrolidin-3-yl) methanesulfonamide A) 2-bromo- 4- (bromomethyl) -1,3-thiazole
[00419] [00419] To a mixture of (2-bromo-1,3-thiazol-4-yl) methanol (5.0 g) and THF (50 ml) was added phosphorus tribromide (6.97 g) at 0 ° Ç. The mixture was stirred overnight under a nitrogen atmosphere at room temperature. The mixture was poured into ice water at room temperature and extracted with ethyl acetate. The organic layer was separated, washed with a saturated aqueous solution of sodium hydrogen carbonate and water, dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate / hexane) to give the title compound (3.90 g). MS: [M + H] + 255.7. B) tert-Butyl 2 - ((2-bromo-1,3-thiazol-4-yl) methyl) -3-oxopyrrolidine-1-carboxylate
[00420] [00420] To a mixture of tert-butyl 3-oxopyrrolidine-1-carboxylate (20.2 g) and toluene (200 ml), pyrrolidine (8.53 g) was added at room temperature. The mixture was heated to reflux overnight, and the reaction solution was concentrated. The residue was mixed with CH3CN (200 ml), and a mixture of 2-bromo-4- (bromomethyl) -1,3-thiazole (14.0 g), TBAI (4.03 g) and CH3CN (200 ml) was added thereto at 80 ° C. The mixture was stirred under a nitrogen atmosphere at 80 ° C for 3 h, and concentrated under reduced pressure.
[00421] [00421] To a mixture of tert-butyl 2 - ((2-bromo-1,3-thiazol-4-yl) methyl) -3-oxopyrrolidine-1-carboxylate (13.6 g), ammonium formate ( 25.0 g) and MeOH (40 ml) chlorine [N- [4- (dimethylamino) phenyl] -2-pyridinecarboxamidate] (pentamethylcyclopentadienyl) iridium (III) (0.454 g) was added at room temperature. The mixture was heated under reflux for 2 h. The reaction solution was concentrated. The residue obtained was diluted with ethyl acetate and the mixture was washed with a mixture of saturated brine and saturated aqueous sodium hydrogen carbonate solution, dried over anhydrous sodium sulfate and concentrated under reduced pressure to give the title compound (6.18 g ). MS: [M + H] + 362.1. D) cis-2 - (tert-butyl (2-bromo-1,3-thiazol-4-yl) methyl) -3 - ((methylsulfonyl) amino)) pyrrolidine-1-carboxylate
[00422] [00422] A mixture of tert-butyl cis-3-amino-2 - ((2-bromo-1,3-thiazol-4-yl) methyl) pyrrolidine-1-carboxylate (145 mg), TEA (81 mg ) and THF (2 ml) was stirred at 0 ° C, and methanesulfonic anhydride (91 mg) was added to it at 0 ° C. The reaction mixture was concentrated under reduced pressure and the residue was purified by column chromatography on silica gel (ethyl acetate / hexane) to give the title compound (53 mg). MS: [M + H] + 440.0. E) N- (cis-2 - ((2-bromo-1,3-thiazol-4-yl) methyl) -1- (cyclobutylcarbonyl) pyrrolidin-3-yl) methanesulfonamide
[00423] [00423] Cis-2 - ((2-bromo-1,3-thiazol-4-yl) methyl) -3- ((methylsulfonyl) amino)) tert-butyl pyrrolidine-1-carboxylate (650 mg) and solution of ethyl acetate / 4M hydrogen chloride (7.38 ml) were mixed at room temperature. After 30 min, the reaction solution was concentrated. The obtained residue was mixed with THF (7.5 ml), and TEA (747 mg) and cyclobutanocarbonyl chloride (262 mg) at 0 ° C were added to it. The mixture was stirred at room temperature for 1 h, to the reaction solution was added saturated brine, and the mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate / hexane) to give the title compound (422 mg). MS: [M + H] + 422.1. F) N- (cis-1- (cyclobutylcarbonyl) -2 - ((2- (3-fluorophenyl) -1,3-thiazol-4-yl) methyl) pyrrolidin-3-yl) methanesulfonamide
[00424] [00424] To a mixture of N- (cis-2 - ((2-bromo-1,3-thiazol-4-yl) methyl) -1- (cyclobutylcarbonyl) pyrrolidin-3-yl) methanesulfonamide (60.0 mg ), (3-fluorophenyl) boronic acid (29.8 mg), potassium carbonate (40.2 mg), water (0.40 ml) and DME (1.2 ml), were added (A-taPhos) 2PdCl2 (5.7 mg) at room temperature. The mixture was stirred under a nitrogen atmosphere at 80 ° C for 3 h. The reaction mixture was purified by silica gel column chromatography (NH, ethyl acetate / hexane) and silica gel column chromatography (ethyl acetate / hexane), and the obtained compound was triturated in diethyl ether / hexane to give the title compound (35.2 mg). 1 H NMR (300 MHz, CDCl3) δ 1.33-1.52 (1H, m), 1.81-2.58 (7H, m), 2.94-3.45 (7H, m), 3 , 61 (1H, dd, J = 14.8, 6.1 Hz), 4.00-4.21 (1H, m), 4.30-4.59 (1H, m), 6.94-7 , 04 (1H, m), 7.10-7.20 (1H, m), 7.39-7.51 (1H, m), 7.59-7.68 (1H, m), 7.69 -7.79 (1H, m), 8.12 (1H, d, J = 9.1 Hz). Example 255 N- (cis-1- (cyclobutylcarbonyl) -2 - ((2- (2-fluorophenyl) -1,3-thiazol-4-yl) methyl) pyrrolidin-3-yl) methanesulfonamide
[00425] [00425] To a mixture of N- (cis-2 - ((2-bromo-1,3-thiazol-4-yl) methyl) -1- (cyclobutylcarbonyl) pyrrolidin-3-yl) methanesulfonamide (60.0 mg ), boronic acid (2-fluorophenyl) (30.0 mg), potassium carbonate (40.1 mg), water (0.40 ml) and DME (1.2 ml), were added (A-taPhos) 2PdCl2 (6.0 mg) at room temperature. The mixture was stirred under a nitrogen atmosphere at 80 ° C for 3 h. The reaction mixture was purified by silica gel column chromatography (NH, ethyl acetate / hexane) and silica gel column chromatography (ethyl acetate / hexane), and the obtained compound was triturated in diethyl ether / hexane to give the title compound (38.2 mg). 1 H NMR (300 MHz, CDCl3) δ 1.23-1.43 (1H, m), 1.82-2.59 (7H, m), 2.94-3.46 (7H, m), 3 , 66 (1H, dd, J = 14.8, 5.7 Hz), 4.01-4.19 (1H, m), 4.30-4.62 (1H, m), 7.02-7 , 12 (1H, m), 7.16-7.25 (1H, m), 7.28-7.36 (1H, m), 7.38-7.49 (1H, m), 8.14 -8.29 (2H, m). Example 256 N- (cis-1- (cyclobutylcarbonyl) -2 - ((2- (2,3-difluorophenyl) -1,3-thiazol-4-yl) methyl) pyrrolidin-3-yl) methanesulfonamide
[00426] [00426] To a mixture of N- (cis-2 - ((2-bromo-1,3-thiazol-4-yl) methyl) -1- (cyclobutylcarbonyl) pyrrolidin-3-yl) methanesulfonamide (60.0 mg ), boronic acid (2,3-difluorophenyl) (35.0 mg), potassium carbonate (40.1 mg), water (0.40 ml) and DME (1.2 ml), added (A- taPhos) 2PdCl2 (6.0 mg) at room temperature. The mixture was stirred under a nitrogen atmosphere at 80 ° C for 3 h. The reaction mixture was purified by silica gel column chromatography (NH, ethyl acetate / hexane) and silica gel column chromatography (ethyl acetate / hexane), and the obtained compound was triturated in diethyl ether / hexane to give the title compound (38.4 mg). 1 H NMR (300 MHz, CDCl3) δ 1.20-1.44 (1H, m), 1.81-2.03 (2H, m), 2.06-2.61 (5H, m), 2 , 94-3.44 (7H, m), 3.67 (1H, dd, J = 14.6, 5.9 Hz), 4.00-4.19 (1H, m), 4.30-4 , 60 (1H, m), 7.05-7.51 (3H, m), 7.89-8.12 (2H, m). Example 258
[00427] [00427] To a mixture of N- (cis-2 - ((2-bromo-1,3-thiazol-4-yl) methyl) -1- (cyclobutylcarbonyl) pyrrolidin-3-yl) methanesulfonamide (51.1 mg ), boronic acid (3,5-difluorophenyl) (25.3 mg), potassium carbonate (35.1 mg), water (0.40 ml) and DME (1.2 ml), added (A- taPhos) 2PdCl2 (3.7 mg) at room temperature. The mixture was stirred overnight under nitrogen at 80 ° C. The reaction mixture was purified by silica gel column chromatography (NH, ethyl acetate / hexane) and silica gel column chromatography (ethyl acetate / hexane), and the obtained compound was triturated in diethyl ether / hexane to give the title compound (30.2 mg). 1 H NMR (300 MHz, CDCl3) δ 1.33-1.52 (1H, m), 1.80-2.03 (2H, m), 2.06-2.58 (5H, m), 2 , 96-3.05 (3H, m), 3.07-3.45 (4H, m), 3.60 (1H, dd, J = 14.8, 6.4 Hz), 3.98-4 , 20 (1H, m), 4.30-4.57 (1H, m), 6.84-6.95 (1H, m), 6.99-7.10 (1H, m), 7.42 -7.53 (2H, m), 7.94 (1H, d, J = 8.7 Hz). Example 259 N- (cis-1- (cyclobutylcarbonyl) -2 - ((2-phenyl-1,3-thiazol-4-yl) methyl) pyrrolidin-3-yl) cyclopropanesulfonamide A) 3-oxo-2 - (( Tert-Butyl 2-phenyl-1,3-thiazol-4-yl) methyl) pyrrolidine-1-carboxylate
[00428] [00428] To a mixture of tert-butyl 3-oxopyrrolidine-1-carboxylate (185 mg) and toluene (2.00 ml) was added pyrrolidine (85 mg) at room temperature. The mixture was stirred at room temperature for 15 min and concentrated under reduced pressure. The residue was mixed with CH3CN (2 ml), and 4- (chloromethyl) -2-phenyl-1,3-thiazole (105 mg) and TBAI (36.9 mg) were added to it. The mixture was heated under reflux for 1.5 h, and the reaction mixture was diluted with water. The mixture was extracted with ethyl acetate, and the extract was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (acetate)
[00429] [00429] To a mixture of tert-butyl 3-oxo-2 - ((2-phenyl-1,3-thiazol-4-yl) methyl) pyrrolidine-1-carboxylate (3.66 g), ammonium formate (6.44 g) and MeOH (30ml) chlorine [N- [4- (dimethylamino) phenyl] -2-pyridinecarboxamidate] (pentamethylcyclopentadienyl) iridium (III) (123 mg) was added at room temperature. The mixture was stirred under an argon atmosphere at 70 ° C for 2 h. The mixture was concentrated under reduced pressure and the residue was diluted with ethyl acetate, and the mixture was washed with saturated aqueous sodium hydrogen carbonate solution and saturated brine and concentrated under reduced pressure to give the title compound (3.42 g). MS: [M + H] + 360.1. C) tert-butyl cis-3 - ((cyclopropylsulfonyl) amino) -2 - ((2-phenyl-1,3-thiazol-4-yl) methyl) pyrrolidine-1-carboxylate
[00430] [00430] To a mixture of tert-butyl cis-3-amino-2 - ((2-phenyl-1,3-thiazol-4-yl) methyl) pyrrolidine-1-carboxylate (810 mg), TEA (0 , 81 ml), DMAP (91.0 mg), THF (5.0 ml) and DMF (6.0 ml), cyclopropanesulfonyl chloride (0.57 ml) was added at room temperature. The mixture was stirred at room temperature for 2 h. To the reaction mixture, 5% aqueous acetic acid solution was added and the mixture was extracted with ethyl acetate. The organic layer was separated, washed with water and saturated brine, dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate / hexane) to give the title compound (317 mg). MS: [M + H] + 464.3. D) N- (cis-1- (cyclobutylcarbonyl) -2 - ((2-phenyl-1,3-thiazol-4-yl) methyl) pyrrolidin-3-yl) cyclopropanesulfonamide
[00431] [00431] To a mixture of tert-butyl cis-3 - ((cyclopropylsulfonyl) amino) -2 - ((2-phenyl-1,3-thiazol-4-yl) methyl) pyrrolidine-1-carboxylate (72, 0 mg), cyclopentyl methyl ether (2.0 ml) and MeOH (2.0 ml), 4M cyclopentyl methyl ether / hydrogen chloride solution (2.0 ml) was added at room temperature. The mixture was stirred at room temperature for 2 h and concentrated under reduced pressure. To the residue were added DMF (2.0 ml), THF (2.0 ml), TEA (0.088 ml) and cyclobutanocarbonyl chloride (0.050 ml) and the mixture was stirred overnight at room temperature. To the reaction mixture, water was added, and the mixture was extracted with ethyl acetate. The organic layer was separated, washed with water and saturated brine, dried over sodium sulfate and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (NH, ethyl acetate / hexane) and silica gel column chromatography (ethyl acetate / hexane). The compound obtained was purified by HPLC (C18, mobile phase: water / acetonitrile (containing 0.1% TFA)), and to the fraction obtained, saturated aqueous sodium hydrogen carbonate solution was added, and the mixture was extracted with ethyl acetate. . The extract was dried over sodium sulfate and concentrated under reduced pressure, and the obtained compound was triturated in diethyl ether / hexane to give the title compound (15.5 mg). 1 H NMR (300 MHz, CDCl3) δ 0.81 - 1.44 (6H, m), 1.80-2.53 (7H, m), 3.03 - 3.53 (4H, m), 3 , 65 (1H, dd, J = 14.8, 5.7 Hz), 4.03-4.21 (1H, m), 4.45-4.58 (1H, m), 6.88-6 , 98 (1H, m), 7.41-7.52 (3H, m), 7.88-8.00 (2H, m), 8.11 (1H, d, J = 9.5 Hz). Example 261 N - ((2S, 3S) -2- (biphenyl-3-ylmethyl) -1- (cyclobutylcarbonyl) pyrrolidin-3-yl) methanesulfonamide A) 2- (3-bromobenzyl) -3-oxopyrrolidine-1-carboxylate from tert-butyl
[00432] [00432] To a mixture of tert-butyl 3-oxopyrrolidine-1-carboxylate (5.4 g) and toluene (50.0 ml) was added pyrrolidine (2.49 g) at temperature
[00433] [00433] To a mixture of 2- (3-bromobenzyl) -3-oxopyrrolidine-1-tert-butyl carboxylate (1.54 g), ammonium formate (1.37 g) and MeOH (25 ml) was added chlorine [N- [4- (dimethylamino) phenyl] -2-pyridinecarboxamidate] (pentamethylcyclopentadienyl) iridium (III) (0.026 g) at room temperature. The mixture was stirred under a nitrogen atmosphere at 70 ° C for 2 h. The mixture was neutralized with a saturated aqueous solution of sodium hydrogen carbonate at 0 ° C, and concentrated under reduced pressure. The mixture was extracted with ethyl acetate. The organic layer was separated, washed with saturated brine, dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (methanol / ethyl acetate) to give the title compound (565 mg). MS, found: 299.2. C) tert-butyl (2S, 3S) -3-amino-2- (3-bromobenzyl) pyrrolidine-1-carboxylate
[00434] [00434] A racemate (1.5 g) of tert-butyl cis-3-amino-2- (3-bromobenzyl) pyrrolidine-1-carboxylate was resolved by HPLC (column: CHIRALPAK AD (AK001), 50 mmID × 500 mmL, manufactured by Daicel Chemical Industries, mobile phase: hexane / ethanol / diethylamine = 850/150/1) to give the title compound (650 mg) with a shorter retention time.
[00435] [00435] A mixture of tert-butyl (2S, 3S) -3-amino-2- (3-bromobenzyl) pyrrolidine-1-carboxylate (920 mg), TEA (786 mg) and THF (10 ml) was stirred and methanesulfonic anhydride (541 mg) was added at room temperature. After 0.5 h, the reaction mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate / hexane) to give the title compound (1.05 g). MS, found: 333.1. E) N - ((2S, 3S) -2- (3-bromobenzyl) pyrrolidin-3-yl) methanesulfonamide hydrochloride
[00436] [00436] To the 4M ethyl acetate / hydrogen chloride solution (5.42 mL), (2S, 3S) -2- (3-bromobenzyl) -3- ((methylsulfonyl) amino)) pyrrolidine-1 was added tert-butyl carboxylate (470 mg) at room temperature. The mixture was stirred for 1 h, and the reaction solution was concentrated to give the title compound (370 mg). MS: [M + H] + 333.1. F) N - ((2S, 3S) -2- (3-bromobenzyl) -1- (cyclobutylcarbonyl) pyrrolidin-3-yl) methanesulfonamide
[00437] [00437] To a mixture of N - ((2S, 3S) -2- (3-bromobenzyl) pyrrolidin-3-yl) methanesulfonamide hydrochloride (200 mg), TEA (274 mg) and THF (5 ml) was added cyclobutanocarbonyl chloride (96 mg) at room temperature. The mixture was stirred at room temperature for 2 h. To the mixture, saturated aqueous sodium hydrogen carbonate solution was added and the mixture was extracted with ethyl acetate. The organic layer was separated, washed with saturated brine, dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue was purified by
[00438] [00438] A mixture of N - ((2S, 3S) -2- (3-bromobenzyl) -1- (cyclobutylcarbonyl) pyrrolidin-3-yl) methanesulfonamide (55 mg), phenylboronic acid (48.4 mg), XPhos Pd G3 (5.60 mg), 1M aqueous solution of tripotassium phosphate (0.397 ml) and THF (1 ml) was heated under reflux for 1 h. The reaction mixture was concentrated under reduced pressure and the residue was diluted with ethyl acetate. The mixture was washed with saturated aqueous sodium hydrogen carbonate solution and purified by column chromatography on silica gel (methanol / ethyl acetate). The obtained solid was crystallized from ethyl acetate-diisopropyl ether-hexane to give the title compound (31 mg). 1 H NMR (300 MHz, CDCl3) δ 1.31-3.01 (11H, m), 3.04-3.79 (4H, m), 3.89- 4.74 (3H, m), 7 , 07-7.63 (10H, m). Example 262 N - (((2S, 3S) -1- (cyclobutylcarbonyl) -2 - (((3'-fluorobiphenyl-3-yl) methyl) pyrrolidin-3-yl) methanesulfonamide A) (2S, 3S) -2- ( Tert-butyl (3'-fluorobiphenyl-3-yl) methyl) -3- ((methylsulfonyl) amino)) pyrrolidine-1-carboxylate
[00439] [00439] A mixture of tert-butyl (2S, 3S) -2- (3-bromobenzyl) -3- ((methylsulfonyl) amino)) pyrrolidine-1-carboxylate (2.38 g), acid (3-fluorophenyl) ) boronic acid (1.15 g), XPhos Pd G3 (0.139 g), 1M aqueous solution of tripotassium phosphate (16.5 ml) and THF (50 ml) was stirred at 70 ° C for 2 h. The mixture was concentrated under reduced pressure, and the residue was diluted with saturated aqueous sodium hydrogen carbonate solution, and the mixture was extracted with ethyl acetate. The organic layer was washed with brine
[00440] [00440] To a mixture of tert-butyl (2S, 3S) -2 - ((3'-fluorobiphenyl-3-yl) methyl) -3- ((methylsulfonyl) amino)) pyrrolidine-1-carboxylate (2, 37 g) and ethyl acetate (10 ml) 4M ethyl acetate / hydrogen chloride solution (26.4 ml) was added at room temperature. The mixture was stirred at room temperature for 2 h. The mixture was concentrated under reduced pressure and the obtained solid was collected by filtration with ethyl acetate. The obtained solid was washed with ethyl acetate and dried to give the title compound (1.88 g). MS: [M + H] + 349.3. C) N - ((2S, 3S) -1- (cyclobutylcarbonyl) -2 - (((3'-fluorobiphenyl-3-yl) methyl) pyrrolidin-3-yl) methanesulfonamide
[00441] [00441] To a mixture of N - ((2S, 3S) -2 - (((3'-fluorobiphenyl-3-yl) methyl) pyrrolidin-3-yl) methanesulfonamide hydrochloride (1.10 g), TEA (1 , 45 g) and THF (20 ml) was added dropwise cyclobutanocarbonyl chloride (0.508 g) at 0 ° C. The mixture was stirred at room temperature for 1 h. To the mixture, saturated aqueous sodium hydrogen carbonate solution was added, and the mixture was concentrated under reduced pressure to remove THF. The remaining aqueous layer was extracted with ethyl acetate. The organic layer was separated, washed with saturated brine, dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate / hexane). The residue was crystallized from ethyl acetate-hexane to give the title compound (1.10 g).
[00442] [00442] To a mixture of N - ((2S, 3S) -2- (3-bromobenzyl) pyrrolidin-3-yl) methanesulfonamide (100 mg), 1-fluorocyclobutanecarboxylic acid (50 mg) and DMF (2 ml ) HATU (154 mg) and DIPEA (105 mg) were added at room temperature. The mixture was stirred at room temperature for 2 h. To the mixture, saturated aqueous sodium hydrogen carbonate solution was added and the mixture was extracted with ethyl acetate. The organic layer was separated, washed with water and saturated brine, dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate / hexane) to give the title compound (109 mg). MS: [M + H] + 433.1. B) N - (((2S, 3S) -2 - (((3'-fluorobiphenyl-3-yl) methyl) -1 - (((1-fluorocyclobutyl) carbonyl) pyrrolidin-3-yl) methanesulfonamide
[00443] [00443] A mixture of N - ((2S, 3S) -2- (3-bromobenzyl) -1 - ((1-fluorocyclobutyl) carbonyl) pyrrolidin-3-yl) methanesulfonamide (54.4 mg), acid (3 -fluorophenyl) boron (52.7 mg), XPhos Pd G3 (5.31 mg), 1M tripotassium phosphate (0.377 ml) and THF (1 ml) was stirred at 70 ° C for 2 h. To the mixture, saturated aqueous sodium hydrogen carbonate solution was added and the mixture was extracted with ethyl acetate. The organic layer was separated, washed with saturated brine, dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (NH, ethyl acetate / hexane). The residue was
[00444] [00444] To a mixture of tert-butyl cis-3-amino-2 - ((2-phenyl-1,3-thiazol-4-yl) methyl) pyrrolidine-1-carboxylate (108 mg), DIPEA (58 , 2 mg) and THF (1 ml), fluoromethanesulfonyl chloride (31.8 mg) was added at 0 ° C. To the reaction mixture, water was added, and the mixture was concentrated under reduced pressure. The residue was diluted with ethyl acetate, and the mixture was washed with saturated brine, dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate / hexane) to give the title compound (62.5 mg). MS: [M + H] + 456.1. B) N- (cis-1- (cyclobutylcarbonyl) -2 - ((2-phenyl-1,3-thiazol-4-yl) methyl) pyrrolidin-3-yl) -1-fluoromethanesulfonamide
[00445] [00445] To a mixture of tert-butyl cis-3 - (((fluoromethyl) sulfonyl) amino) -2 - ((2-phenyl-1,3-thiazol-4-yl) methyl) pyrrolidine-1-carboxylate (31.2 mg) and MeOH (0.200 ml), 4M cyclopentyl methyl ether / hydrogen chloride solution (0.342 ml) was added at room temperature. The mixture was stirred at room temperature for 1 h, and the reaction solution was concentrated. The residue was mixed with THF (0.7 ml), and TEA (34.7 mg) and chloride
[00446] [00446] To a mixture of (3-bromo-2-fluorophenyl) methanol (5.13 g), PPh3 (7.88 g) and trifluoromethylbenzene (180 ml) was added tetrabromomethane (9.96 g) at 0 ° Ç. The mixture was stirred at 0 ° C for 2 h, and the insoluble substance was removed by filtration and washed with diethyl ether. The filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate / hexane) to give the title compound (6.70 g). 1 H NMR (300 MHz, CDCl3) δ 4.51 (2H, d, J = 1.1 Hz), 7.02 (1H, td, J = 8.0, 1.4 Hz), 7.30- 7.37 (1H, m), 7.51 (1H, ddd, J = 8.1, 6.4, 1.7 Hz). B) tert-Butyl 2- (3-bromo-2-fluorobenzyl) -3-oxopyrrolidine-1-carboxylate
[00447] [00447] To a mixture of tert-butyl 3-oxopyrrolidine-1-carboxylate (3.30 g) and toluene (28 ml) was added pyrrolidine (1.52 g) at room temperature. The mixture was stirred at room temperature for 30 min, heated under reflux using Dean-Stark apparatus for 30 min and concentrated under reduced pressure. The residue was mixed with CH3CN (28 ml), and 1-bromo-3- (bromomethyl) -2-fluorobenzene (4.77 g) and TBAI (1.32 g) were added to the
[00448] [00448] A mixture of tert-butyl 2- (3-bromo-2-fluorobenzyl) -3-oxopyrrolidine-1-carboxylate (941 mg), ammonium formate (1.28 g), chlorine [N- [4 - (dimethylamino) phenyl] -2-pyridinecarboxamidate] (pentamethylcyclopentadienyl) iridium (III) (30.5 mg) and MeOH (20 ml) was stirred under an argon atmosphere at 70 ° C for 2.5 h. The reaction mixture was poured into a saturated aqueous solution of sodium hydrogen carbonate under ice cooling, and the mixture was extracted with ethyl acetate. The organic layer was washed with water and saturated brine, dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (methanol / ethyl acetate) to give the title compound (427 mg). MS: [M + H- (tBu)] + 316.9. D) tert-butyl cis-2- (3-bromo-2-fluorobenzyl) -3 - ((methylsulfonyl) amino)) pyrrolidine-1-carboxylate
[00449] [00449] To a mixture of cis-3-amino-2- (3-bromo-2-fluorobenzyl) pyrrolidine-1-carboxylate (421 mg), TEA (228 mg) and THF (4 ml), methanesulfonyl chloride (155 mg) was added at room temperature. The mixture was stirred at room temperature for 1 h, and
[00450] [00450] To a mixture of tert-butyl cis-2- (3-bromo-2-fluorobenzyl) -3- ((methylsulfonyl) amino)) pyrrolidine-1-carboxylate (434 mg) and toluene (4.8 ml ), TFA (4.8 ml) was added at room temperature. The mixture was stirred at room temperature for 1 h, and the reaction mixture was poured into a saturated aqueous solution of sodium hydrogen carbonate under ice-cooling. The mixture was basified at pH = 8 with potassium carbonate and extracted with ethyl acetate. The organic layer was washed with water and saturated brine, dried over anhydrous magnesium sulfate and concentrated under reduced pressure to give crystals. The crystals were collected by filtration and washed with diisopropyl ether-hexane to give the title compound (245 mg). MS: [M + H] + 350.9. F) N- (cis-2- (3-bromo-2-fluorobenzyl) -1-isobutyryl pyrrolidin-3-yl) methanesulfonamide
[00451] [00451] To a mixture of N- (cis-2- (3-bromo-2-fluorobenzyl) pyrrolidin-3-yl) methanesulfonamide (120 mg), TEA (104 mg) and THF (3 ml) was added 2-methylpropanoyl (72.8 mg) at room temperature. The mixture was stirred at room temperature for 1 h, added to the aqueous sodium hydrogen carbonate solution and extracted with THF-ethyl acetate. The organic layer was washed with water and saturated brine, dried over anhydrous magnesium sulfate and concentrated under pressure
[00452] [00452] A mixture of N- (cis-2- (3-bromo-2-fluorobenzyl) -1-isobutyryl pyrrolidin-3-yl) methanesulfonamide (63 mg), phenylboronic acid (36.5 mg), XPhos Pd G3 (6.33 mg), 1 M aqueous solution of tripotassium phosphate (0.449 ml) and THF (1.5 ml) was stirred under an argon atmosphere at 70 ° C for 1 h. The mixture was poured into an aqueous sodium hydrogen carbonate solution and extracted with THF-ethyl acetate. The organic layer was washed with water and saturated brine, dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (methanol / ethyl acetate) to give the title compound (52.8 mg). 1 H NMR (300 MHz, CDCl3) δ 0.57-1.14 (6H, m), 1.83-2.13 (1H, m), 2.27-2.41 (1H, m), 2 , 53-3.20 (6H, m), 3.40-3.55 (2H, m), 3.65-4.11 (1H, m), 4.35- 4.67 (1H, m) , 4.81-4.89 (1H, m), 7.10-7.20 (1H, m), 7.28-7.54 (7H, m). Example 294 N- (cis-2 - ((2,3'-difluorobiphenyl-3-yl) methyl) -1-isobutyryl pyrrolidin-3-yl) methanesulfonamide
[00453] [00453] A mixture of N- (cis-2- (3-bromo-2-fluorobenzyl) -1-isobutyryl pyrrolidin-3-yl) methanesulfonamide (62 mg), boronic acid (3-fluorophenyl) (41.2 mg ), Xphos Pd G3 (6.23 mg), aqueous solution of 1 M tripotassium phosphate (0.441 ml) and THF (1.5 ml) was stirred under an argon atmosphere at 70 ° C for 1 h. The mixture was poured into an aqueous sodium hydrogen carbonate solution and extracted with THF-ethyl acetate. The organic layer was washed with water and saturated brine, dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (methanol / ethyl acetate) to give the compound
[00454] [00454] To a mixture of tert-butyl 3-oxopyrrolidine-1-carboxylate (3.44 g) and toluene (30 ml) was added pyrrolidine (1.59 g) at room temperature. The mixture was stirred at room temperature for 20 min, heated under reflux for 20 min using a Dean-Stark apparatus, and concentrated under reduced pressure. The residue was mixed with CH3CN (30 ml), and 1-bromo-3- (bromomethyl) -5-fluorobenzene (4.98 g) and TBAI (1.37 g) were added to the mixture at room temperature. The mixture was heated under reflux for 4.5 h, and the reaction mixture was poured into water, and the mixture was extracted with ethyl acetate. The organic layer was washed with water and saturated brine, dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate / hexane) to give the title compound (2.83 g). MS: [M + H-Boc] + 271.9. B) tert-butyl cis-3-amino-2- (3-bromo-5-fluorobenzyl) pyrrolidine-1-carboxylate
[00455] [00455] A mixture of 2- (3-bromo-5-fluorobenzyl) -3-oxopyrrolidine-1-tert-butyl carboxylate (2.82 g), ammonium formate (3.82 g), chlorine [N- [4- (dimethylamino) phenyl] -2-pyridinecarboxamidate] (pentamethylcyclopentadienyl) iridium (III) (0.069 g) and MeOH (60 ml) was stirred under an argon atmosphere at 70 ° C for 2.5 h. THE
[00456] [00456] To a mixture of tert-butyl cis-3-amino-2- (3-bromo-5-fluorobenzyl) pyrrolidine-1-carboxylate (1.06 g), TEA (0.575 g) and THF (10 ml ), methanesulfonyl chloride (0.390 g) was added at room temperature. The mixture was stirred at room temperature for 1 h, and the reaction mixture was poured into water, and the mixture was extracted with ethyl acetate. The organic layer was washed with aqueous sodium hydrogen carbonate solution and saturated brine, dried over anhydrous magnesium sulfate and concentrated under reduced pressure to give crystals. The crystals were collected by filtration and washed with diisopropyl ether-hexane to give the title compound (1.09 g). MS: [M-H] - 448.8. D) N- (cis-2- (3-bromo-5-fluorobenzyl) pyrrolidin-3-yl) methanesulfonamide
[00457] [00457] To a mixture of tert-butyl cis-2- (3-bromo-5-fluorobenzyl) -3- ((methylsulfonyl) amino)) pyrrolidine-1-carboxylate (1.09 g) and toluene (12 ml ), TFA (12 ml) was added at room temperature. The mixture was stirred at room temperature for 1 h and poured into a saturated aqueous solution of sodium hydrogen carbonate under ice-cooling. The mixture was basified at pH = 8 with potassium carbonate and extracted with ethyl acetate. The organic layer was washed with water and saturated brine, dried over anhydrous magnesium sulfate and concentrated under reduced pressure.
[00458] [00458] To a mixture of N- (cis-2- (3-bromo-5-fluorobenzyl) pyrrolidin-3-yl) methanesulfonamide (229 mg), TEA (198 mg) and THF (5.6 ml) was added cyclobutanocarbonyl chloride (155 mg) at room temperature. The mixture was stirred at room temperature for 1 h, added to the aqueous sodium hydrogen carbonate solution and extracted with THF-ethyl acetate. The organic layer was washed with water and saturated brine, dried over anhydrous magnesium sulfate and concentrated under reduced pressure to give crystals. The crystals were collected by filtration and washed with diisopropyl ether-hexane to give the title compound (261 mg). MS: [M + H] + 433.0. F) N- (cis-1- (cyclobutylcarbonyl) -2 - ((5-fluorobiphenyl-3-yl) methyl) pyrrolidin-3-yl) methanesulfonamide
[00459] [00459] A mixture of N- (cis-2- (3-bromo-5-fluorobenzyl) -1- (cyclobutylcarbonyl) pyrrolidin-3-yl) methanesulfonamide (128 mg), phenylboronic acid (72.0 mg), XPhos Pd G3 (12.5 mg), aqueous solution of 1 M tripotassium phosphate (0.886 ml) and THF (3 ml) was stirred under an argon atmosphere at 70 ° C for 1 h. The mixture was poured into an aqueous sodium hydrogen carbonate solution and extracted with THF-ethyl acetate. The organic layer was washed with water and saturated brine, dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (methanol / ethyl acetate) to give the title compound (107 mg). 1 H NMR (300 MHz, CDCl3) δ 1.66-2.39 (8H, m), 2.47-3.22 (6H, m), 3.28-3.78 (2H, m), 3 , 89-4.04 (1H, m), 4.23-4.81 (2H, m), 6.84-7.10 (1H, m), 7.11
[00460] [00460] A mixture of N- (cis-2- (3-bromo-5-fluorobenzyl) -1- (cyclobutylcarbonyl) pyrrolidin-3-yl) methanesulfonamide (126 mg), boronic acid (3-fluorophenyl) (81 mg ), XPhos Pd G3 (12.3 mg), aqueous solution of 1 M tripotassium phosphate (0.872 ml) and THF (2.9 ml) was stirred under an argon atmosphere at 70 ° C for 1 h. The mixture was poured into an aqueous sodium hydrogen carbonate solution and extracted with THF-ethyl acetate. The organic layer was washed with water and saturated brine, dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (methanol / ethyl acetate) to give the title compound (118 mg). 1 H NMR (300 MHz, CDCl3) δ 1.67-2.38 (8H, m), 2.43-3.22 (6H, m), 3.28-3.82 (2H, m), 3 , 89-4.06 (1H, m), 4.22-4.66 (1H, m), 4.68-4.84 (1H, m), 6.88- 7.24 (4H, m) , 7.27-7.45 (3H, m). Example 303 N- (cis-1- (cyclobutylcarbonyl) -2 - ((6-fluorobiphenyl-3-yl) methyl) pyrrolidin-3-yl) methanesulfonamide A) 2- (3-bromo-4-fluorobenzyl) -3- tert-butyl oxopyrrolidine-1-carboxylate
[00461] [00461] To a mixture of tert-butyl 3-oxopyrrolidine-1-carboxylate (3.46 g) and toluene (30 ml) was added pyrrolidine (1.59 g) at room temperature. The mixture was stirred at room temperature for 30 min, heated under reflux for 30 min using Dean-Stark apparatus, and concentrated under reduced pressure. The residue was mixed with CH3CN (30 ml), and 2-bromo-4- (bromomethyl) -1-fluorobenzene (5.00 g) and TBAI (1.38 g) were added to the mixture at room temperature. The mixture was heated under reflux for 4 h, and the reaction mixture was poured into water, and the mixture was extracted with
[00462] [00462] A mixture of 2- (3-bromo-4-fluorobenzyl) -3-oxopyrrolidine-1-tert-butyl carboxylate (1.59 g), ammonium formate (1.35 g), chlorine [N- [4- (dimethylamino) phenyl] -2-pyridinecarboxamidate] (pentamethylcyclopentadienyl) iridium (III) (0.026 g) and MeOH (25 ml) was stirred under an argon atmosphere at 70 ° C for 2.5 h. The reaction mixture was poured into a saturated aqueous solution of sodium hydrogen carbonate under ice cooling, and the mixture was extracted with ethyl acetate. The organic layer was washed with water and saturated brine, dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (methanol / ethyl acetate) to give the title compound (548 mg). MS: [M + H- (tBu)] + 317.0. C) tert-butyl cis-2- (3-bromo-4-fluorobenzyl) -3 - ((methylsulfonyl) amino)) pyrrolidine-1-carboxylate
[00463] [00463] To a mixture of tert-butyl cis-3-amino-2- (3-bromo-4-fluorobenzyl) pyrrolidine-1-carboxylate (542 mg), TEA (294 mg) and THF (5.1 ml ), methanesulfonyl chloride (200 mg) was added at room temperature. The mixture was stirred at room temperature for 1 h, and the reaction mixture was poured into water, and the mixture was extracted with ethyl acetate. The organic layer was washed with aqueous sodium hydrogen carbonate solution and saturated brine, dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue was purified
[00464] [00464] To a mixture of tert-butyl cis-2- (3-bromo-4-fluorobenzyl) -3- ((methylsulfonyl) amino)) pyrrolidine-1-carboxylate (477 mg) and toluene (5.3 ml ), TFA (5.3 ml) was added at room temperature. The mixture was stirred at room temperature for 1 h and poured into a saturated aqueous solution of sodium hydrogen carbonate under ice-cooling. The mixture was basified at pH = 8 with potassium carbonate and extracted with ethyl acetate. The organic layer was washed with water and saturated brine, dried over anhydrous magnesium sulfate and concentrated under reduced pressure to give crystals. The crystals were collected by filtration and washed with diisopropyl ether-hexane to give the title compound (323 mg). MS: [M + H] + 350.9. E) N- (cis-2- (3-bromo-4-fluorobenzyl) -1- (cyclobutylcarbonyl) pyrrolidin-3-yl) methanesulfonamide
[00465] [00465] To a mixture of N- (cis-2- (3-bromo-4-fluorobenzyl) pyrrolidin-3-yl) methanesulfonamide (160 mg), TEA (138 mg) and THF (3.9 ml) was added cyclobutanocarbonyl chloride (108 mg) at room temperature. The mixture was stirred at room temperature for 1 h, added to the aqueous sodium hydrogen carbonate solution and extracted with THF-ethyl acetate. The organic layer was washed with water and saturated brine, dried over anhydrous magnesium sulfate and concentrated under reduced pressure to give crystals. The crystals were collected by filtration and washed with diisopropyl ether-hexane to give the title compound (149 mg). MS: [M + H] + 433.0. F) N- (cis-1- (cyclobutylcarbonyl) -2 - ((6-fluorobiphenyl-3-yl) methyl) pyrrolidin-3-yl) methanesulfonamide
[00466] [00466] A mixture of N- (cis-2- (3-bromo-4-fluorobenzyl) -1- (cyclobutylcarbonyl) pyrrolidin-3-yl) methanesulfonamide (72 mg), phenylboronic acid (40.5 mg), XPhos Pd G3 (7.03 mg), 1 M aqueous solution of tripotassium phosphate (0.498 ml) and THF (1.7 ml) was stirred under an argon atmosphere at 70 ° C for 1 h. The mixture was poured into an aqueous sodium hydrogen carbonate solution and extracted with THF-ethyl acetate. The organic layer was washed with water and saturated brine, dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (methanol / ethyl acetate) to give the title compound (61.3 mg). 1 H NMR (300 MHz, CDCl3) δ 1.65-2.58 (9H, m), 2.60-3.20 (5H, m), 3.30-3.80 (2H, m), 3 , 88-4.04 (1H, m), 4.18-4.76 (2H, m), 7.06-7.21 (2H, m), 7.28- 7.54 (6H, m) . Example 304 N- (cis-1- (cyclobutylcarbonyl) -2 - (((3 ', 6-difluorobiphenyl-3-yl) methyl) pyrrolidin-3-yl) methanesulfonamide
[00467] [00467] A mixture of N- (cis-2- (3-bromo-4-fluorobenzyl) -1- (cyclobutylcarbonyl) pyrrolidin-3-yl) methanesulfonamide (71 mg), boronic acid (3-fluorophenyl) (45, 9 mg), XPhos Pd G3 (6.93 mg), aqueous solution of 1 M tripotassium phosphate (0.492 ml) and THF (1.7 ml) was stirred under an argon atmosphere at 70 ° C for 1 h. The mixture was poured into an aqueous sodium hydrogen carbonate solution and extracted with THF-ethyl acetate. The organic layer was washed with water and saturated brine, dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (methanol / ethyl acetate) to give crystals. The crystals were collected by filtration and washed with diisopropyl ether-hexane to give the title compound (59.6 mg). 1 H NMR (300 MHz, CDCl3) δ 1.68-2.57 (9H, m), 2.65-3.20 (5H, m), 3.28-3.81 (2H, m), 3 , 88-4.05 (1H, m), 4.19-4.74 (2H, m), 7.02-7.26 (4H, m), 7.28-
[00468] [00468] To a mixture of N - ((2S, 3S) -2 - (((3'-fluorobiphenyl-3-yl) methyl) pyrrolidin-3-yl) methanesulfonamide (50 mg), 1-methylcyclobutanecarboxylic acid ( 17.8 mg), TEA (65.7 mg) and DMF (2 ml), HATU (59.3 mg) was added at room temperature, and the mixture was stirred at room temperature for 30 min. To the mixture, saturated aqueous sodium hydrogen carbonate solution was added and the mixture was extracted with ethyl acetate. The organic layer was separated, washed with saturated brine, dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate / hexane) and crystallized from ethanol and water to give the title compound (50 mg). 1 H NMR (300 MHz, CDCl3) δ 1.41 (3H, s), 1.60-2.06 (5H, m), 2.19-2.32 (1H, m), 2.33-2 , 49 (2H, m), 2.55 (3H, s), 2.85-3.02 (1H, m), 3.09-3.25 (1H, m), 3.26-3.49 (2H, m), 3.86-4.04 (1H, m), 4.35-4.49 (1H, m), 4.60-4.74 (1H, m), 6.92-7 , 13 (1H, m), 7.27-7.58 (7H, m). Example 306 N - (((2S, 3S) -1- (bicyclo [1.1.1] pent-1-ylcarbonyl) -2 - (((3'-fluorobiphenyl-3-yl) methyl) pyrrolidin-3-yl) methanesulfonamide
[00469] [00469] To a hydrochloride mixture of N - ((2S, 3S) -2 - (((3'-fluorobiphenyl-3-yl) methyl) pyrrolidin-3-yl) methanesulfonamide (50 mg), bicyclic acid [1.1. 1] pentane-1-carboxylic (17.5 mg), TEA (65.7 mg) and DMF (2 ml), HATU (59.3 mg) was added at room temperature, and the mixture was stirred at room temperature for 30 min. To the mixture, saturated aqueous sodium hydrogen carbonate solution was added and the mixture was extracted with ethyl acetate. The organic layer was separated, washed with brine
[00470] [00470] To a mixture of N - ((2S, 3S) -2- (3-bromobenzyl) pyrrolidin-3-yl) methanesulfonamide (240 mg), bicyclo [1.1.1] pentane-1-carboxylic acid ( 80 mg), TEA (328 mg) and DMF (2 ml), HATU (296 mg) was added at room temperature, and the mixture was stirred at room temperature for 30 min. To the mixture, saturated aqueous sodium hydrogen carbonate solution was added and the mixture was extracted with ethyl acetate. The organic layer was separated, washed with saturated brine, dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (methanol / ethyl acetate) to give the title compound (270 mg). MS: [M + H] + 427.2. B) N - ((2S, 3S) -1- (bicyclo [1.1.1] pent-1-ylcarbonyl) -2 - ((3 ', 5'-difluorobiphenyl-3-yl) methyl) pyrrolidin-3-yl ) methanesulfonamide
[00471] [00471] A mixture of N - ((2S, 3S) -1- (bicyclo [1.1.1] pent-1-ylcarbonyl) -2- (3-bromobenzyl) pyrrolidin-3-yl) methanesulfonamide (55 mg), boronic acid (3,5-difluorophenyl) (61.0 mg), XPhos Pd G3 (5.45 mg), 1M aqueous solution of tripotassium phosphate (0.356 ml) and THF (1 ml) was heated
[00472] [00472] To a hydrochloride mixture of N - ((2S, 3S) -2 - (((3'-fluorobiphenyl-3-yl) methyl) pyrrolidin-3-yl) methanesulfonamide (49.6 mg), 1- hydroxycyclobutanecarboxylic (18.0 mg) and DMF (1 ml) were added HATU (73.5 mg) and DIPEA (50.0 mg) at room temperature. The mixture was stirred overnight at room temperature. To the mixture, saturated aqueous sodium hydrogen carbonate solution was added and the mixture was extracted with ethyl acetate. The organic layer was separated, washed with water and saturated brine, dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate / hexane) to give the title compound (45.5 mg). 1 H NMR (300 MHz, DMSO-d6) δ 1.28 (1H, dd, J = 19.1, 8.5 Hz), 1.55-2.14 (5H, m), 2.36-2 , 46 (2H, m), 2.62-2.74 (3H, m), 2.80 (1H, dd, J = 13.6, 4.9 Hz), 2.91-3.06 (1H , m), 3.48-3.68 (2H, m), 3.84 (1H, brs), 4.36-4.72 (1H, m), 5.63-6.07 (1H, m ), 7.12-7.23 (1H, m), 7.31-7.42 (2H, m), 7.45-7.57 (5H, m), 7.64 (1H, s). Example 309 N - ((2S, 3S) -2 - (((3'-fluorobiphenyl-3-yl) methyl) -1 - ((1-
[00473] [00473] To a mixture of N - (((2S, 3S) -2 - (((3'-fluorobiphenyl-3-yl) methyl) pyrrolidin-3-yl) methanesulfonamide hydrochloride (51.0 mg), 1- (trifluoromethyl) cyclobutanecarboxylic (26.7 mg) and DMF (1 ml) were added HATU (76 mg) and DIPEA (51.4 mg) at room temperature. The mixture was stirred overnight at room temperature. To the mixture, saturated aqueous sodium hydrogen carbonate solution was added and the mixture was extracted with ethyl acetate. The organic layer was separated, washed with water and saturated brine, dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate / hexane) to give the title compound (54.5 mg). 1 H NMR (300 MHz, DMSO-d6) δ 1.40 (1H, d, J = 10.6 Hz), 1.74-2.08 (2H, m), 2.11-2.37 (4H , m), 2.53-2.66 (1H, m), 2.68-2.83 (4H, m), 2.98 (1H, dd, J = 13.8, 6.6 Hz), 3.32-3.41 (1H, m), 3.45-3.61 (1H, m), 3.86 (1H, d, J = 9.8 Hz), 4.53 (1H, q, J = 7.3 Hz), 7.12-7.24 (1H, m), 7.30-7.41 (2H, m), 7.43-7.56 (4H, m), 7.59 (1H, s), 7.63 (1H, s). Example 310 N - (((2S, 3S) -1- (cyclobutylcarbonyl) -2 - (((3 ', 5'-difluorobiphenyl-3-yl) methyl) pyrrolidin-3-yl) methanesulfonamide
[00474] [00474] A mixture of N - ((2S, 3S) -2- (3-bromobenzyl) -1- (cyclobutylcarbonyl) pyrrolidin-3-yl) methanesulfonamide (49.5 mg), acid (3,5-difluorophenyl) boronic acid (28.2 mg), 1M aqueous solution of tripotassium phosphate (0.358 ml), XPhos Pd G3 (3.03 mg) and THF (2 ml) was stirred under nitrogen at 70 ° C for 1 h. To the mixture, saturated aqueous sodium hydrogen carbonate solution was added and the mixture was extracted with ethyl acetate. The organic layer was separated, washed with saturated brine, dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (NH,
[00475] [00475] A mixture of N - ((2S, 3S) -2- (3-bromobenzyl) -1- (cyclobutylcarbonyl) pyrrolidin-3-yl) methanesulfonamide (51.4 mg), (3-methylphenyl) boronic acid ( 25.2 mg), 1M aqueous solution of tripotassium phosphate (0.371 ml), XPhos Pd G3 (3.14 mg) and THF (2 ml) was stirred under nitrogen at 70 ° C for 1 h. To the mixture, saturated aqueous sodium hydrogen carbonate solution was added and the mixture was extracted with ethyl acetate. The organic layer was separated, washed with saturated brine, dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (NH, ethyl acetate / hexane) to give the title compound (52.0 mg). 1 H NMR (300 MHz, DMSO-d6) δ 0.91 - 2.36 (8H, m), 2.37 (3H, s), 2.64-3.07 (5H, m), 3.11 -3.60 (3H, m), 3.73-3.97 (1H, m), 4.01-4.45 (1H, m), 7.09-7.69 (9H, m). Example 312 N - (((2S, 3S) -1- (cyclobutylcarbonyl) -2 - (((3'-fluorobiphenyl-3-yl) methyl) pyrrolidin-3-yl) -1-methoxymethanesulfonamide A) (2S, 3S) - 2- (3-bromobenzyl) -3 - (((bromomethyl) sulfonyl) amino) tert-butyl pyrrolidine-1-carboxylate
[00476] [00476] To a mixture of tert-butyl (2S, 3S) -3-amino-2- (3-bromobenzyl) pyrrolidine-1-carboxylate (900 mg) and THF (3 ml) were added DIPEA (1.33 ml) and bromomethanesulfonyl chloride (0.392 ml) at 0 ° C. The mixture was stirred for 30 min, and the mixture was
[00477] [00477] A mixture of tert-butyl (2S, 3S) -2- (3-bromobenzyl) -3- (((bromomethyl) sulfonyl) amino) pyrrolidine-1-carboxylate (1.20 g), silver carbonate (I) (3.23 g) and MeOH (3 ml) was heated in a sealed tube at 100 ° C. The mixture was stirred for 3 h and filtered saturated aqueous sodium hydrogen carbonate solution was added, and the mixture was extracted with ethyl acetate. The organic layer was separated, dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate / hexane) to give the title compound (640 mg). MS: [MH] +460.9 C) (2S, 3S) -2 - (((3'-fluorobiphenyl-3-yl) methyl) -3- ((((methoxymethyl) sulfonyl) amino) pyrrolidine-1-carboxylate tert-butyl
[00478] [00478] A mixture of tert-butyl (2S, 3S) -2- (3-bromobenzyl) -3- (((methoxymethyl) sulfonyl) amino) pyrrolidine-1-carboxylate (342 mg), acid (3-fluorophenyl) ) boronic acid (155 mg), XPhos Pd G3 (125 mg), 1M aqueous solution of tripotassium phosphate (1 ml) and THF (1 ml) was stirred at 60 ° C for 1 h. To the mixture, saturated aqueous sodium hydrogen carbonate solution was added and the mixture was extracted with ethyl acetate. The organic layer was separated, dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate / hexane) to give the title compound (286 mg).
[00479] [00479] Ao (2S, 3S) -2 - (((3'-fluorobiphenyl-3-yl) methyl) -3- (((methoxymethyl) sulfonyl) amino) pyrrolidine-1-carboxylate (58 mg) 4M ethyl acetate / hydrogen chloride solution (1 ml) was added and the mixture was stirred for 1 h. The reaction solution was concentrated, and to a mixture of the residue and THF (1 ml) were added TEA (0.084 ml) and cyclobutanocarbonyl chloride (17.2 mg) at room temperature. The mixture was stirred for 30 min, and to the mixture was added saturated aqueous sodium hydrogen carbonate solution, and the mixture was extracted with ethyl acetate. The organic layer was separated, dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate / hexane) to give the title compound (28 mg). 1 H NMR (300 MHz, CDCl3) δ 1.63-2.01 (4H, m), 2.07-2.67 (5H, m), 3.00 - 3.23 (2H, m), 3 , 26-3.53 (2H, m), 3.55-3.71 (3H, m), 3.92-4.27 (3H, m), 4.50 (2H, s), 6.93 -7.24 (2H, m), 7.29-7.55 (6H, m). Example 313 N - (((2S, 3S) -1- (azetidin-1-ylcarbonyl) -2 - ((3'-fluorobiphenyl-3-yl) methyl) pyrrolidin-3-yl) methanesulfonamide
[00480] [00480] To a mixture of N - (((2S, 3S) -2 - (((3'-fluorobiphenyl-3-yl) methyl) pyrrolidin-3-yl) methanesulfonamide (50.2 mg) and THF (2 ml) bis (trichloromethyl) carbonate (31.0 mg) and DIPEA (33.7 mg) were added at 0 ° C. The mixture was stirred at 0 ° C for 10 min, and the reaction solution was concentrated. To the obtained residue, THF (2 ml) and azetidine (22.3 mg) were added. The mixture was stirred at room temperature for 2 h. To the mixture, saturated aqueous sodium hydrogen carbonate solution was added and the mixture was extracted with ethyl acetate. The organic layer was
[00481] [00481] To a mixture of N - ((2S, 3S) -2 - (((3'-fluorobiphenyl-3-yl) methyl) pyrrolidin-3-yl) methanesulfonamide (50 mg), 1-methoxycyclobutanecarboxylic acid ( 20.3 mg), TEA (65.7 mg) and DMF (2 ml), HATU (59.3 mg) was added at room temperature, and the mixture was stirred at room temperature for 30 min. To the mixture, saturated aqueous sodium hydrogen carbonate solution was added and the mixture was extracted with ethyl acetate. The organic layer was separated, washed with saturated brine, dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate / hexane) and crystallized from ethyl acetate, diisopropyl ether and hexane to give the title compound (53 mg). 1 H NMR (300 MHz, CDCl3) δ 1.60-2.03 (3H, m), 2.03-2.20 (2H, m), 2.20-2.37 (1H, m), 2 , 42-2.61 (5H, m), 2.85-2.98 (1H, m), 3.08 (3H, s), 3.19-3.30 (1H, m), 3.52 -3.66 (2H, m), 3.91-4.09 (1H, m), 4.36-4.48 (1H, m), 4.68-4.80 (1H, m), 6 , 98-7.09 (1H, m), 7.26-7.48 (6H, m), 7.53-7.58 (1H, m). Example 315
[00482] [00482] To a mixture of tert-butyl cis-3-amino-2 - ((2-bromo-1,3-thiazol-4-yl) methyl) pyrrolidine-1-carboxylate (500 mg), TEA (209 mg) and THF (5 ml), ethanesulfonyl chloride (213 mg) was added at room temperature. The mixture was stirred at room temperature for 1 h and diluted with ethyl acetate. The insoluble substance was removed by filtration and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate / hexane) to give the title compound (610 mg). MS: [M + H] + 454.1. B) cis-tert-butyl cis-2 - ((2- (3,5-difluorophenyl) -1,3-thiazol-4-yl) methyl) -3- ((ethylsulfonyl) amino)) pyrrolidine-1-carboxylate
[00483] [00483] A mixture of tert-butyl cis-2 - ((2-bromo-1,3-thiazol-4-yl) methyl) -3- ((ethylsulfonyl) amino)) pyrrolidine-1-carboxylate (610 mg ), (3,5-difluorophenyl) boronic acid (318 mg), (A-taPhos) 2PdCl2 (90 mg), potassium carbonate (371 mg), DME (4.8 ml) and water (1.6 ml) was stirred under nitrogen at 90 ° C for 30 min. The mixture was purified by column chromatography on silica gel (NH, ethyl acetate / hexane) to give the title compound (595 mg). MS: [M + H] + 488.3. C) N- (cis-2 - ((2- (3,5-difluorophenyl) -1,3-thiazol-4-yl) methyl) pyrrolidin-3-yl) ethanesulfonamide dihydrochloride
[00484] [00484] To a mixture of cis-2 - ((2- (3,5-difluorophenyl) -1,3-thiazol-4-yl) methyl) -3 - ((ethylsulfonyl) amino)) pyrrolidine-1-carboxylate tert-butyl (595 mg) and MeOH (2 ml), 4M cyclopentyl methyl ether / hydrogen chloride solution (8 ml) was added at room temperature. The mixture was stirred at
[00485] [00485] To a mixture of N- (cis-2 - ((2- (3,5-difluorophenyl) -1,3-thiazol-4-yl) methyl) pyrrolidin-3-yl) ethanesulfonamide dihydrochloride (100 mg ), TEA (110 mg) and THF (2 ml), cyclobutanocarbonyl chloride (38.6 mg) was added at room temperature. The mixture was stirred at room temperature for 1 h, and the reaction mixture was diluted with ethyl acetate. The insoluble substance was removed by filtration and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate / hexane) to give the title compound (73 mg). 1 H NMR (300 MHz, DMSO-d6) δ 1.16 (3H, s), 1.28-2.23 (8H, m), 2.65-3.47 (7H, m), 3.77 -3.96 (1H, m), 4.15-4.49 (1H, m), 7.31-7.74 (5H, m). Example 316 N- (cis-2 - ((2- (3,5-difluorophenyl) -1,3-thiazol-4-yl) methyl) -1 - ((1-methylcyclobutyl) carbonyl) pyrrolidin-3-yl) ethanesulfonamide
[00486] [00486] To a mixture of N- (cis-2 - ((2- (3,5-difluorophenyl) -1,3-thiazol-4-yl) methyl) pyrrolidin-3-yl) ethanesulfonamide dihydrochloride (100 mg ), 1-methylcyclobutanecarboxylic acid (29.8 mg), TEA (110 mg) and DMF (2 ml), HATU (99 mg) was added at room temperature, and the mixture was stirred at room temperature for 30 min. To the mixture, saturated aqueous sodium hydrogen carbonate solution was added and the mixture was extracted with ethyl acetate. The organic layer was separated, washed with saturated brine, dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate / hexane) and crystallized from ethyl acetate, ether
[00487] [00487] To a mixture of N- (cis-2 - ((2- (3,5-difluorophenyl) -1,3-thiazol-4-yl) methyl) pyrrolidin-3-yl) ethanesulfonamide dihydrochloride (100 mg ), 1-hydroxycyclobutanecarboxylic acid (30.3 mg), TEA (110 mg) and DMF (2 ml), HATU (99 mg) was added at room temperature, and the mixture was stirred at room temperature for 30 min. To the mixture, saturated aqueous sodium hydrogen carbonate solution was added and the mixture was extracted with ethyl acetate. The organic layer was separated, washed with saturated brine, dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate / hexane) and crystallized from ethyl acetate, diisopropyl ether and hexane to give the title compound (56 mg). 1 H NMR (300 MHz, DMSO-d6) δ 1.16 (3H, t, J = 7.4 Hz), 1.22-1.49 (1H, m), 1.55-1.82 (2H , m), 1.83-2.17 (3H, m), 2.31-2.47 (2H, m), 2.87-3.28 (4H, m), 3.37-3.52 (1H, m), 3.54-3.71 (1H, m), 3.73-3.94 (1H, m), 4.39-4.57 (1H, m), 5.73 (1H , s), 7.31-7.43 (1H, m), 7.47 (1H, s), 7.51-7.58 (1H, m), 7.59-7.68 (2H, m ). Example 318 N- (cis-1- (bicyclo [1.1.1] pent-1-ylcarbonyl) -2 - ((2- (3,5-difluorobiphenyl) -1,3-thiazol-4-yl) methyl) pyrrolidin -3-yl) ethanesulfonamide
[00488] [00488] To a mixture of N- (cis-2 - ((2- (3,5-difluorophenyl) -1,3-thiazol-4-yl) methyl) pyrrolidin-3-yl) ethanesulfonamide dihydrochloride (100
[00489] [00489] To a mixture of tert-butyl cis-3-amino-2 - ((2-phenyl-1,3-thiazol-4-yl) methyl) pyrrolidine-1-carboxylate (45.3 mg), TEA (25.5 mg) and THF (1 ml), methanesulfonic anhydride (28.5 mg) was added at 0 ° C, and the reaction solution was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate / hexane) to give the title compound (44.3 mg). MS: [M + H] + 438.2. B) N- (cis-1- (cyclobutylcarbonyl) -2 - ((2-phenyl-1,3-thiazol-4-yl) methyl) pyrrolidin-3-yl) methanesulfonamide
[00490] [00490] A mixture of tert-butyl cis-3 - ((methylsulfonyl) amino)) - 2 - ((2-phenyl-1,3-thiazol-4-yl) methyl) pyrrolidine-1-carboxylate (44, 3 mg),
[00491] [00491] A racemate (123 mg) of N- (cis-1- (cyclobutylcarbonyl) -2 - ((2- (3-fluorophenyl) -1,3-thiazol-4-yl) methyl) pyrrolidin-3-yl ) methanesulfonamide was resolved by HPLC (column: CHIRALPAK OD (IK001), 50 mmID × 500 mmL, manufactured by Daicel Chemical Industries, mobile phase: hexane / ethanol = 600/400) to give a compound with a shorter retention time. The obtained compound was triturated in diethyl ether / hexane to give the title compound (43.2 mg). 1 H NMR (300 MHz, CDCl3) δ 1.35-1.50 (1H, m), 1.82-2.47 (7H, m), 2.95-3.40 (7H, m), 3 , 61 (1H, dd, J = 14.7, 6.0 Hz), 3.88-4.19 (1H, m), 4.30-4.57 (1H, m), 6.89-7 , 05 (1H, m), 7.10-7.20 (1H, m), 7.40-7.50 (1H, m), 7.59-7.68 (1H, m), 7.70 -7.78 (1H, m), 8.12 (1H, d, J = 9.1 Hz). Example 321 N - (((2S, 3S) -1- (cyclobutylcarbonyl) -2 - (((2-phenyl-1,3-thiazol-4-yl) methyl) pyrrolidin-3-
[00492] [00492] A racemate (234 mg) of N- (cis-1- (cyclobutylcarbonyl) -2 - ((2-phenyl-1,3-thiazol-4-yl) methyl) pyrrolidin-3-yl) cyclopropanesulfonamide was resolved by HPLC (column: CHIRALPAK AS (CC001), 50 mmID × 500 mmL, manufactured by Daicel Chemical Industries, mobile phase: hexane / ethanol = 700/300) to give a compound with a longer retention time. The obtained compound was triturated in diethyl ether / hexane to give the title compound (42.6 mg). 1 H NMR (300 MHz, CDCl3) δ 0.80-1.44 (5H, m), 1.81-2.50 (8H, m), 3.02-3.39 (4H, m), 3 , 65 (1H, dd, J = 14.8, 5.7 Hz), 4.03-4.21 (1H, m), 4.43-4.57 (1H, m), 6.89-6 , 97 (1H, m), 7.41-7.57 (3H, m), 7.90-7.96 (2H, m), 8.11 (1H, d, J = 9.8 Hz). Example 322 N- (cis-2 - ((2- (3,5-difluorophenyl) -1,3-thiazol-4-yl) methyl) -1 - ((1-methylcyclobutyl) carbonyl) pyrrolidin-3-yl) methanesulfonamide A) cis-2 - tert-butyl (-2 ((2- (3,5-difluorophenyl) -1,3-thiazol-4-yl) methyl) -3- ((methylsulfonyl) amino)) pyrrolidine-1-carboxylate
[00493] [00493] A mixture of tert-butyl cis-2 - ((2-bromo-1,3-thiazol-4-yl) methyl) -3- ((methylsulfonyl) amino)) pyrrolidine-1-carboxylate (430 mg ), (3,5-difluorophenyl) boronic acid (231 mg), (A-taPhos) 2PdCl2 (32.8 mg), potassium carbonate (270 mg), DME (4 ml) and water (1 ml) was stirred under nitrogen atmosphere at 80 ° C for 30 min. The reaction solution was concentrated under reduced pressure, and the residue was purified by column chromatography on silica gel (ethyl acetate / hexane) to give the title compound (379 mg). MS: [M + H] + 474.1. B) N- (cis-2 - ((2- (3,5-difluorophenyl) -1,3-thiazol-4-yl) methyl) pyrrolidin-3-yl) methanesulfonamide dihydrochloride
[00494] [00494] A mixture of cis-2 - ((2- (3,5-difluorophenyl) -1,3-thiazole-4-
[00495] [00495] To a mixture of N- (cis-2 - ((2- (3,5-difluorophenyl) -1,3-thiazol-4-yl) methyl) pyrrolidin-3-yl) methanesulfonamide dihydrochloride (80 mg ) and DMF (1 ml), TEA (0.106 ml), 1-methylcyclobutanecarboxylic acid (20.9 mg) and HATU (69.5 mg) were added at room temperature. The mixture was stirred for 1 h, and to the mixture was added saturated aqueous sodium hydrogen carbonate solution, and the mixture was extracted with ethyl acetate. The organic layer was separated, washed with saturated brine, dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate / hexane) to give the title compound (60.7 mg). 1 H NMR (300 MHz, CDCl3) δ 1.33 (3H, s), 1.64-1.85 (4H, m), 1.88-2.00 (1H, m), 2.06-2 , 20 (1H, m), 2.22-2.55 (2H, m), 2.98-3.31 (6H, m), 3.68 (1H, dd, J = 14.7, 6, 4 Hz), 4.01-4.24 (1H, m), 4.51 (1H, t, J = 6.6 Hz), 6.76-7.00 (1H, m), 7.08 ( 1H, s), 7.38-7.63 (2H, m), 8.21 (1H, d, J = 8.7 Hz). Example 323 N- (cis-2 - ((2- (3,5-difluorophenyl) -1,3-thiazol-4-yl) methyl) -1 - ((1-hydroxycyclobutyl) carbonyl) pyrrolidin-3-yl) methanesulfonamide
[00496] [00496] To a mixture of N- (cis-2 - ((2- (3,5-difluorophenyl) -1,3-thiazol-4-yl) methyl) pyrrolidin-3-yl) methanesulfonamide dihydrochloride (80 mg ) and DMF (1 ml), TEA (0.106 ml), 1-hydroxycyclobutanecarboxylic acid (21.2 mg) and HATU (69.5 mg) were added at temperature
[00497] [00497] A mixture of tert-butyl (2S, 3S) -2- (3-bromobenzyl) -3- (((methoxymethyl) sulfonyl) amino) pyrrolidine-1-carboxylate (200 mg), phenylboronic acid (79 mg ), XPhos Pd G3 (73.2 mg), 1M aqueous solution of tripotassium phosphate (1 ml) and THF (1 ml) was stirred at 60 ° C for 30 min. To the mixture, saturated aqueous sodium hydrogen carbonate solution was added and the mixture was extracted with ethyl acetate. The organic layer was separated, dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate / hexane) to give the title compound (188 mg). MS: [M-H] +459.0. B) N - ((2S, 3S) -2- (biphenyl-3-ylmethyl) -1- (cyclobutylcarbonyl) pyrrolidin-3-yl) -1- methoxymethanesulfonamide
[00498] [00498] Ao (2S, 3S) -2- (biphenyl-3-ylmethyl) -3 - (((methoxymethyl) sulfonyl)
[00499] [00499] To a hydrochloride mixture of N - ((2S, 3S) -2 - (((3'-fluorobiphenyl-3-yl) methyl) pyrrolidin-3-yl) methanesulfonamide (50 mg), oxetane-2- carboxylic (15.9 mg), TEA (65.7 mg) and DMF (1 ml), HATU (59.3 mg) was added at room temperature, and the mixture was stirred at room temperature for 30 min. To the mixture, saturated aqueous sodium hydrogen carbonate solution was added and the mixture was extracted with ethyl acetate. The organic layer was separated, washed with saturated brine, dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (methanol / ethyl acetate) and crystallized from ethyl acetate, diisopropyl ether and hexane to give the title compound (40 mg). 1 H NMR (300 MHz, DMSO-d6) δ 1.75-2.44 (4H, m), 2.54-3.10 (6H, m),
[00500] [00500] A mixture of (6-bromopyridin-2-yl) methanol (10.0 g), (3-fluorophenyl) boronic acid (12.0 g), (A-taPhos) 2PdCl2 (2.10 g), 2M aqueous sodium carbonate solution (100 mL) and DME (300 mL) was stirred under nitrogen at 70 ° C for 5 h. The reaction mixture was poured into water, and the mixture was extracted with ethyl acetate. The organic layer was separated, washed with water and saturated brine, dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate / hexane) to give the title compound (10.8 g). MS: [M + H] + 204.2. B) 2- (bromomethyl) -6- (3-fluorophenyl) pyridine
[00501] [00501] To a mixture of (6- (3-fluorophenyl) pyridin-2-yl) methanol (10.8 g) and THF (300 ml) was added phosphorus tribromide (43.2 g) at 0 ° C . The mixture was stirred under a nitrogen atmosphere overnight at room temperature. The reaction mixture was poured into ice water, and the mixture was extracted with ethyl acetate. The organic layer was separated, washed with a saturated aqueous solution of sodium hydrogen carbonate and water, dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate / hexane) to give the title compound (13.5 g). MS: [M + H] + 265.9. C) tert-Butyl 2 - ((6- (3-fluorophenyl) pyridin-2-yl) methyl) -3-oxopyrrolidine-1-carboxylate
[00502] [00502] A mixture of pyrrolidine (7.74 g), 3-oxopyrrolidine-1-
[00503] [00503] A mixture of ammonium formate (40 g), chlorine [N- [4- (dimethylamino) phenyl] -2-pyridinecarboxamidate] (pentamethylcyclopentadienyl) iridium (III) (0.521 g), 2 - ((6- ( Tert-Butyl 3-fluorophenyl) pyridin-2-yl) methyl) -3-oxopyrrolidine-1-carboxylate (16.0 g) and MeOH (500 mL) was refluxed for 5 h. The reaction mixture was concentrated, and the residue was poured into saturated brine at room temperature, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated aqueous sodium hydrogen carbonate solution, dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (methanol / ethyl acetate) to give the title compound (9.00 g). MS: [M + H] + 372.1. E) cis-2 - tert-butyl cis-2 - ((6- (3-fluorophenyl) pyridin-2-yl) methyl) -3 - ((methylsulfonyl) amino)) pyrrolidine-1-carboxylate
[00504] [00504] To a mixture of cis-3-amino-2 - ((6- (3-fluorophenyl) pyridin-2-
[00505] [00505] To a mixture of tert-butyl cis-2 - ((6- (3-fluorophenyl) pyridin-2-yl) methyl) -3- ((methylsulfonyl) amino)) pyrrolidine-1-carboxylate (1, 10 g) and cyclopentylmethyl ether (10 ml), 4M cyclopentylmethyl ether / hydrogen chloride solution (10 ml) was added at 0 ° C. The mixture was stirred overnight under a nitrogen atmosphere at room temperature and the reaction mixture was concentrated to give the title compound (1.00 g). MS: [M + H] + 350.0. G) N- (cis-1- (azetidin-1-ylcarbonyl) -2 - ((6- (3-fluorophenyl) pyridin-2-yl) methyl) pyrrolidin-3-yl) methanesulfonamide
[00506] [00506] To a mixture of bis (trichloromethyl) carbonate (69.5 mg) and THF (7 ml) was added a mixture of N- (cis-2 - ((6- (3-fluorophenyl) pyridine dihydrochloride) -2-yl) methyl) pyrrolidin-3-yl) methanesulfonamide (120 mg), DIPEA (148 mg) and THF (7 ml) at 0 ° C. The mixture was stirred at 0 ° C for 20 min, and concentrated under reduced pressure to give an intermediate. To a mixture of the obtained intermediate and THF (7 ml) was added azetidine (85 mg) at 0 ° C. The mixture was stirred under a nitrogen atmosphere at room temperature for 1 h and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (methanol / ethyl acetate) to give the title compound (85 mg). 1 H NMR (300 MHz, CDCl3) δ 1.24-1.46 (1H, m), 1.94-2.09 (1H, m), 2.11
[00507] [00507] To a mixture of N- (cis-2 - ((6- (3-fluorophenyl) pyridin-2-yl) methyl) pyrrolidin-3-yl) methanesulfonamide (51.1 mg), 1- hydroxycyclobutanecarboxylic acid (24.3 mg), TEA (72.6 mg) and DMF (1.0 ml), HATU (54.2 mg) was added at room temperature. The mixture was stirred at room temperature for 1 h, to the reaction mixture was added saturated aqueous sodium hydrogen carbonate solution, and the mixture was extracted with ethyl acetate. The organic layer was separated, washed with water and saturated brine, dried over sodium sulfate and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate / hexane), triturated in diethyl ether and hexane to give the title compound (27.3 mg). 1 H NMR (300 MHz, CDCl3) δ 1.29-1.43 (1H, m), 1.58-1.74 (1H, m), 1.86-2.21 (5H, m), 2 , 38-2.53 (1H, m), 2.61-2.95 (4H, m), 3.21-3.37 (2H, m), 3.41- 3.58 (1H, m) , 3.72 (1H, dd, J = 14.0, 6.4 Hz), 4.05-4.21 (1H, m), 4.62 (1H, t, J = 6.6 Hz), 7.10-7.21 (2H, m), 7.43-7.83 (5H, m), 8.73 (1H, d, J = 8.7 Hz). Example 339 N - (((2S, 3S) -2 - ((2- (3,5-difluorophenyl) -1,3-thiazol-4-yl) methyl) -1 - ((1-hydroxycyclobutyl) carbonyl) pyrrolidin- Tert-butyl 3-yl) methanesulfonamide A) (2S, 3S) -3-amino-2 - ((2-bromo-1,3-thiazol-4-yl) methyl) pyrrolidine-1-carboxylate
[00508] A cis-3-amino-2 - ((2-bromo-1,3-thiazol-4-yl) methyl) pyrrolidine-1-carboxylate racemate (550 mg) was resolved by HPLC ( column: CHIRALPAK AD (NF001), 50 mm ID × 500 mmL, manufactured
[00509] [00509] To a mixture of tert-butyl (2S, 3S) -3-amino-2 - ((2-bromo-1,3-thiazol-4-yl) methyl) pyrrolidine-1-carboxylate (150 mg) and THF (1 ml), TEA (126 mg) and methanesulfonic anhydride (87 mg) were added at room temperature. The mixture was stirred for 30 min, and to the mixture was added saturated aqueous sodium hydrogen carbonate solution, and the mixture was extracted with ethyl acetate. The organic layer was separated, dried over anhydrous sodium sulfate and concentrated under reduced pressure to give the title compound (184 mg). MS: [M-H] +437.8. C) (2S, 3S) -2 - ((2- (3,5-difluorophenyl) -1,3-thiazol-4-yl) methyl) -3 - (((methylsulfonyl) amino)) pyrrolidine-1-carboxylate tert-butyl
[00510] [00510] A mixture of (2S, 3S) -2 - ((2-bromo-1,3-thiazol-4-yl) methyl) -3- ((methylsulfonyl) amino)) pyrrolidine-1-carboxylate butyl (182 mg), boronic acid (3,5-difluorophenyl) (131 mg), potassium carbonate (114 mg), (AtaPhos) 2PdCl2 (13.9 mg), DME (4 mL) and water (1 ml) was stirred at 60 ° C for 30 min. To the mixture, water was added, and the mixture was extracted with ethyl acetate. The organic layer was separated, dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate / hexane) to give the title compound (172 mg). MS: [M-H] -471.9. D) N - ((2S, 3S) -2 - ((2- (3,5-difluorophenyl) -1,3-thiazol-4-yl) methyl) pyrrolidin-3-yl) methanesulfonamide dihydrochloride
[00511] [00511] To a mixture of (2S, 3S) -2 - ((2- (3,5-difluorophenyl) -1,3-thiazole-
[00512] [00512] To a mixture of N - ((2S, 3S) -2 - ((2- (3,5-difluorophenyl) -1,3-thiazol-4-yl) methyl) pyrrolidin-3-yl dihydrochloride) methanesulfonamide (72.6 mg) and DMF (1 ml), TEA (82 mg), 1-hydroxycyclobutanecarboxylic acid (22.7 mg) and HATU (74.2 mg) were added at room temperature. The mixture was stirred for 1 h, and to the mixture was added saturated aqueous sodium hydrogen carbonate solution, and the mixture was extracted with ethyl acetate. The organic layer was separated, washed with saturated brine, dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate / hexane) to give the title compound (68.5 mg). 1 H NMR (300 MHz, CDCl3) δ 1.43-1.54 (1H, m), 1.62-1.73 (1H, m), 1.88-2.22 (5H, m), 2 , 40-2.57 (1H, m), 2.59-2.75 (1H, m), 3.02 (3H, s), 3.21 (1H, s), 3.30-3.45 (1H, m), 3.47-3.60 (1H, m), 3.66 (1H, dd, J = 14.9, 6.6 Hz), 4.00-4.21 (1H, m ), 4.53 (1H, t, J = 6.6 Hz), 6.84-6.95 (1H, m), 7.10 (1H, s), 7.44-7.50 (2H, m), 8.02 (1H, d, J = 9.0 Hz). Example 340 N - (((2S, 3S) -1- (azetidin-1-ylcarbonyl) -2 - ((2- (3,5-difluorobiphenyl) -1,3-thiazol-4-yl) methyl) pyrrolidin-3 -yl) methanesulfonamide
[00513] [00513] To a mixture of N - ((2S, 3S) -2 - ((2- (3,5-difluorophenyl) -1,3-thiazol-4-yl) methyl) pyrrolidin-3-yl dihydrochloride) methanesulfonamide (92.6 mg) and THF (1 ml) were added bis (trichloromethyl) carbonate (30.8 mg) and DIPEA (53.6 mg) at 0 ° C. The mixture was stirred for 30 min, and the mixture
[00514] [00514] To a mixture of N - (((2S, 3S) -2 - (((3'-fluorobiphenyl-3-yl) methyl) pyrrolidin-3-yl) methanesulfonamide (101 mg) and THF (2 ml) Bis (trichloromethyl) carbonate (62.3 mg) and DIPEA (67.8 mg) were added at 0 ° C. The mixture was stirred at 0 ° C for 15 min, and the reaction solution was concentrated under reduced pressure to give the title compound (152 mg). MS: [M + H] + 411.2. B) N - (((2S, 3S) -1 - (((3-fluoroazetidin-1-yl) carbonyl) -2 - (((3'-fluorobiphenyl-3-yl) methyl) pyrrolidin-3-yl) methanesulfonamide
[00515] [00515] To a mixture of (2S, 3S) -2 - (((3'-fluorobiphenyl-3-yl) methyl) -3 - (((methylsulfonyl) amino)) pyrrolidine-1-carbonyl (50 mg) and THF (1 mL) 3-fluoroazetidine hydrochloride (19.3 mg) and DIPEA were added
[00516] [00516] To a mixture of 3,3-difluoroazetidine hydrochloride (22.4 mg), DIPEA (33.5 mg) and THF (0.5 ml) was added a mixture of (2S, 3S) -2 chloride - (((3'-fluorobiphenyl-3-yl) methyl) -3 - (((methylsulfonyl) amino)) pyrrolidine-1-carbonyl (50 mg) and THF (0.5 ml) at room temperature. The mixture was stirred at room temperature for 2 h. To the mixture, saturated aqueous sodium hydrogen carbonate solution was added and the mixture was extracted with ethyl acetate. The organic layer was separated, washed with saturated brine, dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (NH, ethyl acetate / hexane), and the obtained solid was crystallized from ethyl acetate / hexane to give the title compound (28.4 mg). 1 H NMR (300 MHz, DMSO-d6) δ 1.84-2.02 (1H, m), 2.07-2.20 (1H, m), 2.74 (1H, dd, J = 13, 4, 7.4 Hz), 2.84 (3H, s), 2.87-2.99 (1H, m), 3.16-3.27 (1H, m),
[00517] [00517] To a mixture of 2-methylazetidine hydrochloride (46.5 mg), DIPEA (112 mg) and THF (0.5 ml) was added a mixture of (2S, 3S) -2 - ((3 '-fluorobiphenyl-3-yl) methyl) -3 - ((methylsulfonyl) amino)) pyrrolidine-1-carbonyl (50 mg) and THF (0.5 ml) at room temperature. The mixture was stirred at room temperature for 5 h. To the mixture, saturated aqueous sodium hydrogen carbonate solution was added and the mixture was extracted with ethyl acetate. The organic layer was separated, washed with saturated brine, dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (NH, ethyl acetate / hexane) to give the title compound (31.1 mg). 1 H NMR (300 MHz, DMSO-d6) δ 1.03-1.24 (3H, m), 1.55-1.94 (2H, m), 1.97-2.23 (2H, m) , 2.68-2.89 (4H, m), 2.90-3.05 (1H, m), 3.14 (1H, t, J = 8.9 Hz), 3.23-3.39 (1H, m), 3.40-3.75 (1H, m), 3.75-3.91 (2H, m), 3.97-4.40 (2H, m), 7.13-7 , 23 (1H, m), 7.23-7.41 (2H, m), 7.44-7.63 (6H, m). Example 344 N - ((2S, 3S) -2 - ((3 ', 5'-difluorobiphenyl-3-yl) methyl) -1 - ((1-hydroxycyclobutyl) carbonyl) pyrrolidin-3-yl) methanesulfonamide A) N - (((2S, 3S) -2- (3-bromobenzyl) -1 - ((1-hydroxycyclobutyl) carbonyl) pyrrolidin-3-yl) methanesulfonamide
[00518] [00518] To a mixture of N - ((2S, 3S) -2- (3-bromobenzyl) pyrrolidin-3-yl) methanesulfonamide (101 mg), 1-hydroxycyclobutanecarboxylic acid (38.1 mg) and DMF ( 1 ml) HATU (156 mg) and DIPEA (106 mg) were added at room temperature. The mixture was
[00519] [00519] A mixture of N - ((2S, 3S) -2- (3-bromobenzyl) -1 - ((1-hydroxycyclobutyl) carbonyl) pyrrolidin-3-yl) methanesulfonamide (49.5 mg), acid (3 , 5-difluorophenyl) boronic acid (27.2 mg), XPhos Pd G3 (2.91 mg), 1M aqueous solution of tripotassium phosphate (0.344 ml) and THF (2 ml) was stirred at 70 ° C for 1 h. To the mixture, saturated aqueous sodium hydrogen carbonate solution was added and the mixture was extracted with ethyl acetate. The organic layer was separated, washed with saturated brine, dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (NH, ethyl acetate / hexane), and the obtained solid was collected by filtration with hexane to give the title compound (33.2 mg). 1 H NMR (300 MHz, DMSO-d6) δ 1.16-1.37 (2H, m), 1.57-1.72 (1H, m), 1.82-1.97 (2H, m) , 2.08 (1H, brs), 2.35-2.47 (2H, m), 2.63-2.75 (3H, m), 2.75-2.86 (1H, m), 2 , 91-3.04 (1H, m), 3.45-3.67 (2H, m), 3.75-3.93 (1H, m), 4.33-4.72 (1H, m) , 5.71 - 6.02 (1H, m), 7.20 (1H, tt, J = 9.2, 2.3 Hz), 7.37 (1H, d, J = 7.2 Hz), 7.39-7.47 (3H, m), 7.48-7.57 (2H, m), 7.65 (1H, s). Example 345 N - (((2S, 3S) -1- (azetidin-1-ylcarbonyl) -2 - ((3 ', 5'-difluorobiphenyl-3-yl) methyl) pyrrolidin-3-yl) methanesulfonamide A) N- ((2S, 3S) -1- (azetidin-1-ylcarbonyl) -2- (3-bromobenzyl) pyrrolidin-3-
[00520] [00520] To a mixture of N - ((2S, 3S) -2- (3-bromobenzyl) pyrrolidin-3-yl) methanesulfonamide (101 mg) and THF (2 ml) was added bis (trichloromethyl) carbonate (64.9 mg) and DIPEA (70.6 mg) at 0 ° C. The mixture was stirred at 0 ° C for 15 min, and the reaction solution was concentrated under reduced pressure. To the residue, THF (2 ml) and azetidine (46.8 mg) were added, and the mixture was stirred at room temperature for 2 h. To the mixture, saturated aqueous sodium hydrogen carbonate solution was added and the mixture was extracted with ethyl acetate. The organic layer was separated, washed with water and saturated brine, dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (methanol / ethyl acetate) to give the title compound (78.4 mg). MS: [M + H] + 416.2. B) N - (((2S, 3S) -1- (azetidin-1-ylcarbonyl) -2 - ((3 ', 5'-difluorobiphenyl-3-yl) methyl) pyrrolidin-3-yl) methanesulfonamide
[00521] [00521] A mixture of N - ((2S, 3S) -1- (azetidin-1-ylcarbonyl) -2- (3-bromobenzyl) pyrrolidin-3-yl) methanesulfonamide (46.8 mg), acid (3, 5- difluorophenyl) boronic acid (26.6 mg), XPhos Pd G3 (2.85 mg), 1M aqueous solution of tripotassium phosphate (0.337 mL) and THF (2 mL) was stirred at 70 ° C for 1 h. To the mixture, saturated aqueous sodium hydrogen carbonate solution was added and the mixture was extracted with ethyl acetate. The organic layer was separated, washed with saturated brine, dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (NH, ethyl acetate / hexane), and the obtained solid was crystallized from ethyl acetate / hexane to give the title compound (35.8 mg). 1 H NMR (300 MHz, DMSO-d6) δ 1.83-2.14 (4H, m), 2.69-2.80 (1H, m), 2.83 (3H, s), 2.86 -2.97 (1H, m), 3.09-3.21 (1H, m, J = 9.5 Hz), 3.34 (1H, brs), 3.61
[00522] [00522] To a mixture of N - ((2S, 3S) -2 - (((3'-fluorobiphenyl-3-yl) methyl) pyrrolidin-3-yl) methanesulfonamide (30 mg), 1-cyanocyclobutanecarboxylic acid ( 11.7 mg) and DMF (1 ml) were added HATU (44.5 mg) and DIPEA (30.2 mg) at room temperature. The mixture was stirred overnight at room temperature. To the mixture, saturated aqueous sodium hydrogen carbonate solution was added and the mixture was extracted with ethyl acetate. The organic layer was separated, washed with water and saturated brine, dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate / hexane), and the obtained solid was crystallized from ethyl acetate / hexane to give the title compound (28.7 mg). 1 H NMR (300 MHz, DMSO-d6) δ 1.58-1.75 (1H, m), 1.94-2.11 (2H, m), 2.14-2.25 (1H, m) , 2.37-2.48 (3H, m), 2.52-2.59 (1H, m), 2.71-2.83 (4H, m), 3.01 (1H, dd, J = 13.6, 6.4 Hz), 3.37-3.45 (1H, m), 3.48-3.61 (1H, m), 3.85- 4.05 (1H, m), 4 , 46 (1H, q, J = 6.4 Hz), 7.09-7.23 (1H, m), 7.26-7.38 (2H, m), 7.42-7.56 (4H , m), 7.58-7.67 (2H, m). Example 347 N - (((2S, 3S) -1- (5-azaspiro [2.3] hex-5-ylcarbonyl) -2 - (((3'-fluorobiphenyl-3-yl) methyl) pyrrolidin-3-yl) methanesulfonamide
[00523] [00523] To a mixture of N - (((2S, 3S) -2 - (((3'-fluorobiphenyl-3-yl) methyl) pyrrolidin-3-yl) methanesulfonamide (30.3 mg) and THF (2 ml), bis (trichloromethyl) carbonate (18.7 mg) and
[00524] [00524] To a mixture of tert-butyl (2S, 3S) -3-amino-2 - ((2-bromo-1,3-thiazol-4-yl) methyl) pyrrolidine-1-carboxylate (300 mg) , TEA (126 mg) and THF (3 ml), ethanesulfonyl chloride (128 mg) was added at room temperature. The mixture was stirred at room temperature for 1 h and diluted with ethyl acetate. The insoluble substance was removed by filtration and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate / hexane) to give the title compound (240 mg).
[00525] [00525] A mixture of (2S, 3S) -2 - ((2-bromo-1,3-thiazol-4-yl) methyl) -3- ((ethylsulfonyl) amino)) pyrrolidine-1-carboxylate butyl (240 mg), boronic acid (3,5-difluorophenyl) (125 mg), (A-taPhos) 2PdCl2 (35.5 mg), potassium carbonate (146 mg), DME (2.4 ml) and water (0.8 mL) was stirred under nitrogen at 90 ° C for 30 min. The mixture was purified by column chromatography over silica gel (NH, ethyl acetate / hexane) to give the title compound (240 mg). MS: [M + H] + 488.2. C) N - ((2S, 3S) -2 - ((2- (3,5-difluorophenyl) -1,3-thiazol-4-yl) methyl) pyrrolidin-3-yl) ethanesulfonamide dihydrochloride
[00526] [00526] To a mixture of (2S, 3S) -2 - ((2- (3,5-difluorophenyl) -1,3-thiazol-4-yl) methyl) -3 - ((ethylsulfonyl) amino)) pyrrolidine Tert-butyl -1-carboxylate (240 mg) and MeOH (1 ml), 4M cyclopentyl methyl ether / hydrogen chloride solution (4 ml) was added at room temperature. The mixture was stirred at room temperature for 30 min, and the reaction mixture was concentrated to give the title compound (226 mg). MS: [M + H] + 388.2. D) N - (((2S, 3S) -1- (azetidin-1-ylcarbonyl) -2 - ((2- (3,5-difluorobiphenyl) -1,3-thiazol-4-yl) methyl) pyrrolidin-3 -yl) ethanesulfonamide
[00527] [00527] A mixture of N - ((2S, 3S) -2 - ((2- (3,5-difluorophenyl) -1,3-thiazol-4-yl) methyl) pyrrolidin-3-yl) ethanesulfonamide dihydrochloride (70 mg), DIPEA (79 mg) and THF (5 ml) a solution of bis (trichloromethyl) carbonate (36.1 mg) in THF (5 ml) was added at 0 ° C. The mixture was stirred at 0 ° C for 20 min, and the reaction solution was concentrated. To the obtained residue were added THF (5 ml) and azetidine (43.4 mg). The mixture was stirred at room temperature for 1 h. The reaction mixture was concentrated under
[00528] [00528] A tert-butyl cis-3-amino-2- (3-bromo-2-fluorobenzyl) pyrrolidine-1-carboxylate racemate (848 mg) was resolved by HPLC (column: CHIRALPAK AD (AK001), 50 mmID × 500 mmL, manufactured by Daicel Chemical Industries, mobile phase: hexane / ethanol = 850/150) to give the title compound (352 mg) with a shorter retention time. MS: [M + H-tBu] + 316.9. B) tert-butyl (2S, 3S) -2- (3-bromo-2-fluorobenzyl) -3 - ((methylsulfonyl) amino)) pyrrolidine-1-carboxylate
[00529] [00529] To a mixture of tert-butyl (2S, 3S) -3-amino-2- (3-bromo-2-fluorobenzyl) pyrrolidine-1-carboxylate (349 mg), TEA (189 mg) and THF ( 3.3 ml), methanesulfonyl chloride (129 mg) was added at room temperature. The mixture was stirred at room temperature for 1 h, and the reaction mixture was poured into water, and the mixture was extracted with ethyl acetate. The organic layer was washed with aqueous sodium hydrogen carbonate solution and saturated brine, dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate / hexane) to give the title compound (386 mg).
[00530] [00530] A mixture of tert-butyl (2S, 3S) -2- (3-bromo-2-fluorobenzyl) -3- ((methylsulfonyl) amino)) pyrrolidine-1-carboxylate (380 mg), acid (3 -fluorophenyl) boronic acid (236 mg), XPhos Pd G3 (35.6 mg), 1 M aqueous solution of tripotassium phosphate (2.53 ml) and THF (9 ml) was stirred under an argon atmosphere at 70 ° C for 1 h. The mixture was poured into an aqueous solution of sodium hydrogen carbonate, and extracted with ethyl acetate. The organic layer was washed with water and saturated brine, dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate / hexane) to give crystals. The crystals were collected by filtration and washed with diisopropyl ether-hexane to give the title compound (353 mg). MS: [M-H] - 465.0. D) N - ((2S, 3S) -2 - (((2,3'-difluorobiphenyl-3-yl) methyl) pyrrolidin-3-yl) methanesulfonamide
[00531] [00531] To a mixture of tert-butyl (2S, 3S) -2 - ((2,3'-difluorobiphenyl-3-yl) methyl) - 3 - ((methylsulfonyl) amino)) pyrrolidine-1-carboxylate ( 349 mg) and toluene (3.8 ml), TFA (3.8 ml) was added at room temperature. The mixture was stirred at room temperature for 1 h and poured into a saturated aqueous solution of sodium hydrogen carbonate under ice-cooling. The mixture was basified to pH = 8 with potassium carbonate and extracted with ethyl acetate-THF. The organic layer was washed with water and saturated brine, dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (NH, methanol / ethyl acetate) to give the title compound (283 mg). MS: [M + H] + 367.2. E) N - ((2S, 3S) -2 - ((2,3'-difluorobiphenyl-3-yl) methyl) -1- (2,2-
[00532] [00532] To a mixture of N - ((2S, 3S) -2 - ((2,3'-difluorobiphenyl-3-yl) methyl) pyrrolidin-3-yl) methanesulfonamide (68 mg), TEA (75 mg) and THF (1.6 ml) 2,2-dimethylpropanoyl chloride (67.1 mg) was added at room temperature. The mixture was stirred at room temperature for 3 h, added to the aqueous sodium hydrogen carbonate solution and extracted with ethyl acetate-THF. The organic layer was washed with water and saturated brine, dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate / hexane) to give the title compound (68.9 mg). 1 H NMR (300 MHz, CDCl3) δ 1.25 (9H, s), 1.95-2.04 (1H, m), 2.28-2.39 (1H, m), 2.53 (3H , s), 2.92-3.08 (2H, m), 3.64-3.71 (2H, m), 3.92-4.05 (1H, m), 4.65-4.75 (2H, m), 7.03-7.11 (1H, m), 7.15-7.26 (2H, m), 7.27-7.32 (2H, m), 7.36-7 , 45 (1H, m), 7.53 (1H, td, J = 7.1, 1.7 Hz). Example 350 N - (((2S, 3S) -1- (cyclobutylcarbonyl) -2 - (((2,3'-difluorobiphenyl-3-yl) methyl) pyrrolidin-3-yl) methanesulfonamide
[00533] [00533] To a mixture of N - ((2S, 3S) -2 - ((2,3'-difluorobiphenyl-3-yl) methyl) pyrrolidin-3-yl) methanesulfonamide (66 mg), TEA (54.7 mg) and THF (1.6 ml) cyclobutanocarbonyl chloride (42.7 mg) was added at room temperature. The mixture was stirred at room temperature for 2 h, added to the aqueous sodium hydrogen carbonate solution and extracted with ethyl acetate-THF. The organic layer was washed with water and saturated brine, dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (methanol / ethyl acetate) to give crystals. The crystals were collected by filtration and washed with diisopropyl ether-hexane to give the title compound (49.9 mg). 1 H NMR (300 MHz, CDCl3) δ 1.67-2.40 (8H, m), 2.57-3.22 (6H, m), 3.27-
[00534] [00534] To a solution of N - ((2S, 3S) -2 - ((2,3'-difluorobiphenyl-3-yl) methyl) pyrrolidin-3-yl) methanesulfonamide (66 mg), 1-methylcyclopropanecarboxylic acid ( 23.4 mg), DIPEA (46.6 mg) and DMF (1 ml) were added HATU (103 mg) at room temperature. The mixture was stirred at room temperature for 3 h, added to the aqueous sodium hydrogen carbonate solution and extracted with ethyl acetate-THF. The organic layer was washed with water and saturated brine, dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate / hexane) to give the title compound (54.5 mg). 1 H NMR (300 MHz, CDCl3) δ 0.46-0.61 (2H, m), 0.71-0.80 (1H, m), 0.94-1.03 (1H, m), 1 , 25 (3H, s), 1.88-2.02 (1H, m), 2.27-2.39 (1H, m), 2.70 (3H, s), 2.91-2.99 (1H, m), 3.05 (1H, dd, J = 14.2, 7.4 Hz), 3.58-3.76 (2H, m), 3.94-4.06 (1H, m ), 4.66 (1H, q, J = 6.5 Hz), 4.77 (1H, dd, J = 9.3, 4.4 Hz), 7.03-7.11 (1H, m) , 7.17 (1H, t, J = 7.8 Hz), 7.20-7.25 (1H, m), 7.27-7.44 (4H, m). Example 352 N - (((2S, 3S) -1- (azetidin-1-ylcarbonyl) -2 - ((2,3'-difluorobiphenyl-3-yl) methyl) pyrrolidin-3-yl) methanesulfonamide
[00535] [00535] To a mixture of N - ((2S, 3S) -2 - ((2,3'-difluorobiphenyl-3-yl) methyl) pyrrolidin-3-yl) methanesulfonamide hydrochloride (68 mg), DIPEA (48 , 0 mg) and THF (1.6 ml) bis (trichloromethyl) carbonate (44.1 mg) was added at 0 ° C. The mixture was stirred at 0 ° C for 20 min, and the reaction mixture was concentrated under reduced pressure. The residue was diluted with THF
[00536] [00536] To a mixture of tert-butyl (2S, 3S) -3-amino-2- (3-bromobenzyl) pyrrolidine-1-carboxylate (3.2 g), TEA (1.37 g) and THF ( 50 ml), ethanesulfonyl chloride (1.39 g) was added at room temperature. The mixture was stirred at room temperature for 1 h. The insoluble substance was removed by filtration and washed with ethyl acetate. The filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate / hexane). The obtained oil was crystallized from ethyl acetate, and diluted with hexane. The precipitate was collected by filtration to give the title compound (3.46 g). MS: [M + H-Boc] + 347.2. B) tert-butyl (2S, 3S) -2- (biphenyl-3-ylmethyl) -3 - ((ethylsulfonyl) amino)) pyrrolidine-1-carboxylate
[00537] [00537] A mixture of (2S, 3S) -2- (3-bromobenzyl) -3-
[00538] [00538] A mixture of tert-butyl (2S, 3S) -2- (biphenyl-3-ylmethyl) -3- ((ethylsulfonyl) amino)) pyrrolidine-1-carboxylate (714 mg), ethyl acetate solution / 4M hydrogen chloride (5 ml) and ethyl acetate (10 ml) was stirred overnight at room temperature. The mixture was diluted with ethyl acetate, and the precipitate was collected by filtration to give the title compound (576 mg). MS: [M + H] + 345.3. D) N - ((2S, 3S) -1- (azetidin-1-ylcarbonyl) -2- (biphenyl-3-ylmethyl) pyrrolidin-3-yl) ethanesulfonamide
[00539] [00539] A mixture of N - ((2S, 3S) -2- (biphenyl-3-ylmethyl) pyrrolidin-3-yl) ethanesulfonamide (576 mg), DIPEA (391 mg) and THF (10 ml) hydrochloride was added dropwise to a mixture of bis (trichloromethyl) carbonate (359 mg) and THF (10 ml), and the mixture was stirred at room temperature for 30 min, and concentrated. The residue was partitioned between ethyl acetate and saturated aqueous sodium hydrogen carbonate solution, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate and
[00540] [00540] A mixture of tert-butyl (2S, 3S) -2- (3-bromobenzyl) -3- ((methylsulfonyl) amino)) pyrrolidine-1-carboxylate (1.73 g) -difluorophenyl) boronic (0.947 g), potassium carbonate (1.11 g), (A-TaPhos) 2PdCl2 (0.135 g), DME (20 ml) and water (4 ml) was stirred at 70 ° C for 2 h . The mixture was concentrated under reduced pressure and the residue was purified by column chromatography on silica gel (NH, ethyl acetate / hexane) to give the title compound (1.74 g). MS: [M + Na] + 489.3. B) N - ((2S, 3S) -2 - ((3 ', 5'-difluorobiphenyl-3-yl) methyl) pyrrolidin-3-yl) methanesulfonamide hydrochloride
[00541] [00541] A mixture of tert-butyl (2S, 3S) -2 - ((3 ', 5'-difluorobiphenyl-3-yl) methyl) -3- ((methylsulfonyl) amino)) pyrrolidine-1-carboxylate ( 1.74 g), 4M CPME / hydrogen chloride solution (18.7 mL) and methanol (10 mL) was stirred at room temperature for 2 h. The reaction mixture was concentrated under reduced pressure. The obtained solid was washed with ethyl acetate to give the title compound (1.47 g). MS: [M + H] + 367.2. C) (2S, 3S) -2 - ((3 ', 5'-difluorobiphenyl-3-yl) methyl) -N, N-dimethyl-3 - ((methylsulfonyl) amino)) pyrrolidine-1-carboxamide
[00542] [00542] To a mixture of N - ((2S, 3S) -2 - (((3 ', 5'-difluorobiphenyl-3-yl) methyl) pyrrolidin-3-yl) methanesulfonamide hydrochloride (1.47 g) and THF (20 mL) TEA (1.29 g) and dimethylcarbamoyl chloride (0.589 g) were added at room temperature. The mixture was stirred at room temperature for 1 h, and to the mixture was added saturated brine, and the mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (NH, ethyl acetate / hexane) to give the title compound (1.49 g). 1 H NMR (400 MHz, CDCl3) δ 2.03-2.11 (2H, m), 2.63-2.72 (1H, m), 2.73 (3H, s), 2.85 (6H , s), 3.23-3.38 (2H, m), 3.56-3.65 (1H, m), 3.85-3.93 (1H, m), 4.41 - 4.50 (1H, m), 4.69 (1H, d, J = 8.6 Hz), 6.73-6.81 (1H, m), 7.06-7.15 (2H, m), 7, 32-7.41 (3H, m), 7.49 (1H, s). Example 373 (2S, 3S) -2 - ((2,3'-difluorobiphenyl-3-yl) methyl) -3 - ((ethylsulfonyl) amino)) - N, N-dimethylpyrrolidine-1-carboxamide A) (2S, 3S) tert-butyl -2- (3-bromo-2-fluorobenzyl) -3 - ((ethylsulfonyl) amino)) pyrrolidine-1-carboxylate
[00543] [00543] To a mixture of tert-butyl (2S, 3S) -3-amino-2- (3-bromo-2-fluorobenzyl) pyrrolidine-1-carboxylate (1.20 g), TEA (0.651 g), DMAP (0.118 g) and THF (11.5 ml), ethanesulfonyl chloride was added
[00544] [00544] A mixture of tert-butyl (2S, 3S) -2- (3-bromo-2-fluorobenzyl) -3- ((ethylsulfonyl) amino)) pyrrolidine-1-carboxylate (465 mg), acid (3 -fluorophenyl) boron (280 mg), XPhos Pd G3 (42.3 mg), 1 M aqueous tripotassium phosphate solution (3.00 ml) and THF (11 ml) was stirred under an argon atmosphere at 70 ° C for 1 h. The reaction mixture was poured into an aqueous sodium hydrogen carbonate solution and the mixture was extracted with ethyl acetate. The organic layer was washed with water and saturated brine, dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate / hexane) to give the title compound (449 mg). MS: [M-H] - 479.2. C) N - ((2S, 3S) -2 - (((2,3'-difluorobiphenyl-3-yl) methyl) pyrrolidin-3-yl) ethanesulfonamide
[00545] [00545] To a mixture of tert-butyl (2S, 3S) -2 - ((2,3'-difluorobiphenyl-3-yl) methyl) - 3 - ((ethylsulfonyl) amino)) pyrrolidine-1-carboxylate ( 444 mg) and toluene (4.8 ml), TFA (4.8 ml) was added at room temperature. The mixture was stirred at room temperature for 1 h, and the reaction solution was poured into a saturated aqueous solution of sodium hydrogen carbonate under ice-cooling. The mixture was basified to pH = 8 with carbonate
[00546] [00546] To a hydrochloride mixture of N - ((2S, 3S) -2 - ((2,3'-difluorobiphenyl-3-yl) methyl) pyrrolidin-3-yl) ethanesulfonamide (215 mg), DIPEA (146 mg) and THF (4.8 ml) bis (trichloromethyl) carbonate (134 mg) was added at 0 ° C. The mixture was stirred at 0 ° C for 10 min, and then at room temperature for 10 min. The mixture was poured into water and extracted with ethyl acetate. The organic layer was separated, washed with water and saturated brine, dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate / hexane), and the obtained crystals were collected by filtration and washed with diisopropyl ether / hexane to give the title compound (223 mg). MS: [M-H] - 441.1. E) (2S, 3S) -2 - ((2,3'-difluorobiphenyl-3-yl) methyl) -3 - ((ethylsulfonyl) amino)) - N, N-dimethylpyrrolidine-1-carboxamide
[00547] [00547] To a mixture of (2S, 3S) -2 - ((2,3'-difluorobiphenyl-3-yl) methyl) -3 - ((ethylsulfonyl) amino)) pyrrolidine-1-carbonyl (110 mg ) and THF (1.9 mL) 2M THF / dimethylamine solution (0.373 mL) was added at room temperature. The mixture was stirred at room temperature for 30 min, and then at 70 ° C for 10 min. The mixture was poured into an aqueous sodium hydrogen carbonate solution and extracted with ethyl acetate / THF. The organic layer was separated, washed with water and saturated brine, dried
[00548] [00548] To a mixture of N - ((2S, 3S) -2 - ((2,3'-difluorobiphenyl-3-yl) methyl) pyrrolidin-3-yl) methanesulfonamide (60 mg), hydroxy-2- methylpropanoic (22.2 mg), DIPEA (42.3 mg) and DMF (1 ml) was added HATU (93 mg) at room temperature. The mixture was stirred at room temperature for 3 h, and the reaction mixture was poured into aqueous sodium hydrogen carbonate solution, and the mixture was extracted with ethyl acetate / THF. The organic layer was separated, washed with water and saturated brine, dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (methanol / ethyl acetate) to give the title compound (63.8 mg). 1 H NMR (300 MHz, CDCl3) δ1.41 (3H, s), 1.43 (3H, s), 1.89-2.01 (1H, m), 2.29-2.41 (1H, m), 2.66 (3H, s), 2.91-3.00 (1H, m), 3.06-3.16 (1H, m), 3.68 (2H, brs), 3.84 (1H, brs), 3.97-4.10 (1H, m), 4.74 (2H, brs), 7.07 (1H, tdd, J = 8.4, 2.6, 1.0 Hz ), 7.16-7.25 (2H, m), 7.26-7.33 (2H, m), 7.36-7.45 (2H, m). Example 389 N - (((2S, 3S) -2 - (((2,3'-difluorobiphenyl-3-yl) methyl) -1- (2-hydroxy-2-methylpropanoyl) pyrrolidin-3-yl) ethanesulfonamide
[00549] [00549] To a mixture of N - ((2S, 3S) -2 - ((2,3'-difluorobiphenyl-3-
[00550] [00550] A mixture of tert-butyl (2S, 3S) -2- (3-bromo-2-fluorobenzyl) -3- ((methylsulfonyl) amino)) pyrrolidine-1-carboxylate (450 mg), acid (3 , 5-difluorophenyl) boronic acid (315 mg), XPhos Pd G3 (42.2 mg), 1 M aqueous tripotassium phosphate solution (2.99 ml) and THF (11 ml) was stirred under an argon atmosphere at 70 ° C for 1 h. The reaction mixture was poured into an aqueous sodium hydrogen carbonate solution and the mixture was extracted with ethyl acetate. The organic layer was washed with water and saturated brine, dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate / hexane) to give the title compound (482 mg).
[00551] [00551] To a mixture of tert (2S, 3S) -3 - ((methylsulfonyl) amino)) - 2- ((2,3 ', 5'-trifluorobiphenyl-3-yl) methyl) pyrrolidine-1-carboxylate -butyl (477 mg) and toluene (5.2 ml), TFA (5.2 ml) was added at room temperature. The mixture was stirred at room temperature for 1 h, and the reaction mixture was poured into a saturated aqueous solution of sodium hydrogen carbonate under ice-cooling. The mixture was basified to pH = 8 with potassium carbonate and extracted with ethyl acetate / THF. The organic layer was washed with water and saturated brine, dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (NH, methanol / ethyl acetate) to give the title compound (339 mg). MS: [M + H] + 385.2. C) N - (((2S, 3S) -1- (2-hydroxy-2-methylpropanoyl) -2 - ((2,3 ', 5'-trifluorobiphenyl-3-yl) methyl) pyrrolidin-3-yl) methanesulfonamide
[00552] [00552] To a mixture of N - ((2S, 3S) -2 - ((2,3 ', 5'-trifluorobiphenyl-3-yl) methyl) pyrrolidin-3-yl) methanesulfonamide (60 mg), hydroxy acid -2-methylpropanoic (21.1 mg), DIPEA (40.3 mg) and DMF (1 ml) was added HATU (89 mg) at room temperature. The mixture was stirred at room temperature for 3 h, and the reaction mixture was poured into aqueous sodium hydrogen carbonate solution, and the mixture was extracted with ethyl acetate / THF. The organic layer was separated, washed with water and saturated brine, dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (methanol / ethyl acetate) to give the title compound (63.1 mg). 1 H NMR (300 MHz, CDCl3) δ 1.40 (3H, s), 1.42 (3H, s), 1.91-2.03 (1H, m), 2.30-2.42 (1H , m), 2.70 (3H, s), 2.89-2.97 (1H, m), 3.10 (1H, dd, J = 14.0, 8.0
[00553] [00553] To a mixture of tert-butyl (2S, 3S) -2- (3-bromo-2-fluorobenzyl) -3- ((ethylsulfonyl) amino)) pyrrolidine-1-carboxylate (340 mg) and MeOH ( 1 ml), 4M CPME / hydrogen chloride solution (3.65 ml) was added at room temperature. The mixture was stirred for 1 h, and the reaction solution was concentrated under reduced pressure. The obtained residue was mixed with THF (4 ml). To the mixture, TEA (739 mg) and dimethylcarbamoyl chloride (393 mg) were added at room temperature. The mixture was stirred at 70 ° C for 1 h. To the reaction mixture, saturated brine was added, and the mixture was extracted with ethyl acetate. The extract was dried over anhydrous sodium sulfate and concentrated under reduced pressure. The obtained solid was washed with ethyl acetate to give the title compound (327 mg). MS: [M + H] + 436.2. B) (2S, 3S) -3 - ((ethylsulfonyl) amino)) - N, N-dimethyl-2 - (((2,3 ', 5'-trifluorobiphenyl-3-yl) methyl) pyrrolidine-1-carboxamide
[00554] [00554] A mixture of (2S, 3S) -2- (3-bromo-2-fluorobenzyl) -3- ((ethylsulfonyl) amino)) - N, N-dimethylpyrrolidine-1-carboxamide (70.4 mg), boronic acid (3,5-difluorophenyl) (38.2 mg), XPhos Pd G3 (4.10 mg), 1 M aqueous tripotassium phosphate solution (0.484 ml) and THF (2 ml) was stirred at 70 ° C for 1.5 h. To the mixture, saturated aqueous sodium hydrogen carbonate solution was added and the mixture was extracted with ethyl acetate. The organic layer was separated, washed with saturated brine, dried over
[00555] [00555] To a mixture of N - ((2S, 3S) -2 - ((2,3 ', 5'-trifluorobiphenyl-3-yl) methyl) pyrrolidin-3-yl) methanesulfonamide (60 mg), TEA ( 47.4 mg) and THF (1.4 ml) 2-methylpropanoyl chloride (33.3 mg) was added at room temperature. The mixture was stirred at room temperature for 1 h, poured into aqueous sodium hydrogen carbonate solution and extracted with ethyl acetate / THF. The organic layer was washed with water and saturated brine, dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (methanol / ethyl acetate), and the obtained solid was collected by filtration and washed with diisopropyl ether / hexane to give the title compound (56.7 mg). 1 H NMR (300 MHz, CDCl3) δ 0.56-1.12 (6H, m), 1.86-2.05 (1H, m), 2.31 2.43 (1H, m), 2 , 54-3.21 (6H, m), 3.42-3.79 (2H, m), 3.96-4.10 (1H, m), 4.36- 4.68 (1H, m) , 4.72-4.80 (1H, m), 6.77-6.86 (1H, m), 6.98-7.53 (5H, m). Example 404 N - ((2S, 3S) -2 - ((3 ', 5'-difluorobiphenyl-3-yl) methyl) -1- (2-hydroxy-2-methylpropanoyl) pyrrolidin-3-yl) ethanesulfonamide A) (2S, 3S) -2 - ((3 ', 5'-difluorobiphenyl-3-yl) methyl) -3 - ((ethylsulfonyl) amino)) pyrrolidine-1-carboxylate
[00556] [00556] A mixture of tert-butyl (2S, 3S) -2- (3-bromobenzyl) -3- ((ethylsulfonyl) amino)) pyrrolidine-1-carboxylate (1.00 g), acid (3.5 -difluorophenyl) boronic acid (0.529 g), XPhos Pd G3 (0.057 g), 1 M aqueous solution of tripotassium phosphate (6.71 ml) and THF (20 ml) was stirred at 70 ° C for 2 h. The reaction mixture was concentrated under reduced pressure, the residue was diluted with a saturated aqueous solution of sodium hydrogen carbonate and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (NH, ethyl acetate / hexane) to give the title compound (1.08 g). MS: [M + H-Boc] + 381.3. B) N - (((2S, 3S) -2 - (((3 ', 5'-difluorobiphenyl-3-yl) methyl) pyrrolidin-3-yl) ethanesulfonamide hydrochloride
[00557] [00557] To a mixture of tert-butyl (2S, 3S) -2 - ((3 ', 5'-difluorobiphenyl-3-yl) methyl) - 3 - ((ethylsulfonyl) amino)) pyrrolidine-1-carboxylate (1.10 g) and ethyl acetate (5 ml) 4M ethyl acetate / hydrogen chloride solution (11.2 ml) was added at room temperature. The mixture was stirred at room temperature for 2 h and concentrated under reduced pressure. The obtained solid was collected by filtration with ethyl acetate and dried to give the title compound (875 mg). MS: [M + H] + 381.3. C) N - ((2S, 3S) -2 - ((3 ', 5'-difluorobiphenyl-3-yl) methyl) -1- (2-hydroxy-2-methylpropanoyl) pyrrolidin-3-yl) ethanesulfonamide
[00558] [00558] To a mixture of N - ((2S, 3S) -2 - (((3 ', 5'-difluorobiphenyl-3-yl) methyl) pyrrolidin-3-yl) ethanesulfonamide (100 mg), acid 2 - hydroxy-2-methylpropanoic (32.5 mg), DIPEA (62.0 mg) and DMF (1 ml) was added HATU (137 mg) at room temperature. The mixture was stirred at room temperature for 3 h, water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with
[00559] [00559] To a mixture of tert-butyl (2S, 3S) -3-amino-2- (3-bromo-2-fluorobenzyl) pyrrolidine-1-carboxylate (1.24 g), DIPEA (0.859 g) and THF (11 mL) was added fluoromethanesulfonyl chloride (0.484 g) at 0 ° C. The mixture was stirred at room temperature for 1 h, poured into water, and extracted with ethyl acetate. The organic layer was washed with aqueous sodium hydrogen carbonate solution and saturated brine, dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate / hexane) to give the title compound (1.49 g). MS: [M-H] - 466.9. B) N - ((2S, 3S) -2- (3-bromo-2-fluorobenzyl) pyrrolidin-3-yl) -1- fluoromethanesulfonamide
[00560] [00560] To a mixture of tert-butyl (2S, 3S) -2- (3-bromo-2-fluorobenzyl) -3- (((fluoromethyl) sulfonyl) amino) pyrrolidine-1-carboxylate (1.48 g ) and toluene (16 ml) were added TFA (16 ml) at room temperature. The mixture was stirred at room temperature for 1 h, and the reaction solution was poured into a saturated aqueous solution of sodium hydrogen carbonate under
[00561] [00561] To a mixture of N - ((2S, 3S) -2- (3-bromo-2-fluorobenzyl) pyrrolidin-3-yl) -1-fluoromethanesulfonamide (556 mg), 2-hydroxy-2-methylpropanoic acid (204 mg), DIPEA (389 mg) and DMF (10 ml) were added HATU (859 mg) at room temperature. The mixture was stirred at room temperature for 3.5 h, and the reaction mixture was poured into aqueous sodium hydrogen carbonate solution, and the mixture was extracted with ethyl acetate / THF. The organic layer was washed with water and saturated brine, dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The obtained solid was collected by filtration and washed with diisopropyl ether to give the title compound (627 mg). MS: [M + H] + 455.0. D) N - ((2S, 3S) -2 - (((2,3'-difluorobiphenyl-3-yl) methyl) -1- (2-hydroxy-2-methylpropanoyl) pyrrolidin-3-yl) -1-fluoromethanesulfonamide
[00562] [00562] A mixture of N - ((2S, 3S) -2- (3-bromo-2-fluorobenzyl) -1- (2-hydroxy-2-methylpropanoyl) pyrrolidin-3-yl) -1-fluoromethanesulfonamide (73 mg), boronic acid (3-fluorophenyl) (44.9 mg), XPhos Pd G3 (6.79 mg), 1 M aqueous tripotassium phosphate solution (0.481 ml) and THF (1.6 ml) was stirred under argon atmosphere at 70 ° C for 1 h. The reaction mixture was poured into an aqueous sodium hydrogen carbonate solution and the mixture was extracted with ethyl acetate. The organic layer was washed with water and
[00563] [00563] To a mixture of tert-butyl (2S, 3S) -3-amino-2- (3-bromobenzyl) pyrrolidine-1-carboxylate (1.22 g), DIPEA (0.888 g) and THF (12 mL ) fluoromethanesulfonyl chloride (0.501 g) was added at 0 ° C. The mixture was stirred at room temperature for 1.5 h, poured into water, and extracted with ethyl acetate. The organic layer was washed with aqueous sodium hydrogen carbonate solution and saturated brine, dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate / hexane) to give the title compound (1.46 g). MS: [M + H-Boc] + 350.9. B) N - ((2S, 3S) -2- (3-bromobenzyl) pyrrolidin-3-yl) -1-fluoromethanesulfonamide
[00564] [00564] To a mixture of tert-butyl (2S, 3S) -2- (3-bromobenzyl) -3- (((fluoromethyl) sulfonyl) amino) pyrrolidine-1-carboxylate (1.45 g) and toluene ( 15.5 ml) TFA (15.5 ml) was added at room temperature. The mixture was stirred at room temperature for 1 h, and the reaction solution was poured into a saturated aqueous solution of sodium hydrogen carbonate under ice-cooling. The mixture was basified to pH = 8 with carbonate
[00565] [00565] To a mixture of N - ((2S, 3S) -2- (3-bromobenzyl) pyrrolidin-3-yl) -1-fluoromethanesulfonamide (692 mg), 2-hydroxy-2-methylpropanoic acid (267 mg) , DIPEA (509 mg) and DMF (13 ml) were added HATU (1.12 g) at room temperature. The mixture was stirred at room temperature for 3.5 h, and the reaction mixture was poured into aqueous sodium hydrogen carbonate solution, and the mixture was extracted with ethyl acetate / THF. The organic layer was washed with water and saturated brine, dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate / hexane) to give the title compound (788 mg). MS: [M + H] + 437.0. D) N - ((2S, 3S) -2 - ((3 ', 5'-difluorobiphenyl-3-yl) methyl) -1- (2-hydroxy-2-methylpropanoyl) pyrrolidin-3-yl) -1- fluoromethanesulfonamide
[00566] [00566] A mixture of N - ((2S, 3S) -2- (3-bromobenzyl) -1- (2-hydroxy-2-methylpropanoyl) pyrrolidin-3-yl) -1-fluoromethanesulfonamide (71 mg), acid (3,5-difluorophenyl) boronic acid (51.3 mg), XPhos Pd G3 (6.87 mg), aqueous solution of 1 M tripotassium phosphate (0.477 ml) and THF (1.6 ml) was stirred under an atmosphere of argon at 70 ° C for 1 h. The reaction mixture was poured into an aqueous sodium hydrogen carbonate solution and the mixture was extracted with ethyl acetate. The organic layer was washed with water and saturated brine, dried over anhydrous magnesium sulfate and concentrated under pressure
[00567] [00567] A mixture of N - ((2S, 3S) -2- (3-bromo-2-fluorobenzyl) -1- (2-hydroxy-2-methylpropanoyl) pyrrolidin-3-yl) -1-fluoromethanesulfonamide (73 mg), boronic acid (3,5-difluorophenyl) (50.6 mg), XPhos Pd G3 (6.79 mg), 1 M aqueous tripotassium phosphate solution (0.481 ml) and THF (1.6 ml) stirred under an argon atmosphere at 70 ° C for 1 h. The reaction mixture was poured into an aqueous sodium hydrogen carbonate solution and the mixture was extracted with ethyl acetate. The organic layer was washed with water and saturated brine, dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate / hexane) to give the title compound (44.4 mg). 1 H NMR (300 MHz, CDCl3) δ 1.41 (3H, s), 1.43 (3H, s), 1.89-2.03 (1H, m), 2.30-2.41 (1H , m), 2.93-3.01 (1H, m), 3.12 (1H, dd, J = 14.0, 7.6 Hz), 3.63 - 3.83 (3H, m), 4.02-4.13 (1H, m), 4.65-4.86 (2H, m), 4.87-5.08 (2H, m), 6.82 (1H, tt, J = 8 , 9, 2.5 Hz), 7.01-7.10 (2H, m), 7.21 (1H, t, J = 7.6 Hz), 7.27-7.32 (1H, m) , 7.41-7.48 (1H, m). Example 424 1,1-difluoro-N - ((2S, 3S) -1- (2-hydroxy-2-methylpropanoyl) -2 - ((2,3 ', 5'-trifluorobiphenyl-3-yl) methyl) pyrrolidin -3-yl) methanesulfonamide A) (2S, 3S) -2- (3-bromo-2-fluorobenzyl) -3 - tert-butyl (((difluoromethyl) sulfonyl) amino) pyrrolidine-1-carboxylate
[00568] [00568] To a mixture of (2S, 3S) -3-amino-2- (3-bromo-2-
[00569] [00569] To a mixture of tert-butyl (2S, 3S) -2- (3-bromo-2-fluorobenzyl) -3- (((difluoromethyl) sulfonyl) amino) pyrrolidine-1-carboxylate (949 mg) and toluene (10.2 ml) TFA (10.2 ml) was added at room temperature. The mixture was stirred at room temperature for 1 h, and the reaction solution was poured into a saturated aqueous solution of sodium hydrogen carbonate under ice-cooling. The mixture was basified to pH = 8 with potassium carbonate and extracted with ethyl acetate / THF. The organic layer was washed with water and saturated brine, dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (NH, methanol / ethyl acetate) to give the title compound (643 mg). MS: [M + H] + 386.9. C) N - ((2S, 3S) -2- (3-bromo-2-fluorobenzyl) -1- (2-hydroxy-2-methylpropanoyl) pyrrolidin-3-yl) -1,1-difluoromethanesulfonamide
[00570] [00570] To a mixture of N - ((2S, 3S) -2- (3-bromo-2-fluorobenzyl) pyrrolidin-3-yl) -1,1-difluoromethanesulfonamide (639 mg), 2-hydroxy-2 acid -methylpropanoic (223 mg), DIPEA (427 mg) and DMF (11 ml) were added HATU (941 mg) at room temperature. The mixture was stirred at
[00571] [00571] A mixture of N - ((2S, 3S) -2- (3-bromo-2-fluorobenzyl) -1- (2-hydroxy-2-methylpropanoyl) pyrrolidin-3-yl) -1,1-difluoromethanesulfonamide (76 mg), boronic acid (3,5-difluorophenyl) (50.7 mg), XPhos Pd G3 (6.80 mg), 1 M aqueous tripotassium phosphate solution (0.482 ml) and THF (1.6 ml ) was stirred under an argon atmosphere at 70 ° C for 1 h. The reaction mixture was poured into an aqueous sodium hydrogen carbonate solution and the mixture was extracted with ethyl acetate. The organic layer was washed with water and saturated brine, dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate / hexane) to give the title compound (63.6 mg). 1 H NMR (300 MHz, CDCl3) δ 1.42 (3H, s), 1.43 (3H, s), 1.88-2.03 (1H, m), 2.36-2.42 (1H , m), 2.94-3.02 (1H, m), 3.13 (1H, dd, J = 14.0, 7.8 Hz), 3.64-3.80 (3H, m), 4.11 - 4.22 (1H, m), 4.75 (1H, brs), 5.10 (1H, brs), 6.04 (1H, t, J = 54.0 Hz), 6.83 (1H, tt, J = 8.9, 2.3 Hz), 7.01-7.09 (2H, m), 7.21 (1H, t, J = 7.6 Hz), 7.26- 7.32 (1H, m), 7.43 (1H, t, J = 6.4 Hz). Example 428 N - ((2S, 3S) -2 - (((3'-chloro-2,5'-difluorobiphenyl-3-yl) methyl) -1- (2-hydroxy-2-methylpropanoyl) pyrrolidin-3-yl ) methanesulfonamide A) N - ((2S, 3S) -2- (3-bromo-2-fluorobenzyl) pyrrolidin-3-yl) methanesulfonamide hydrochloride
[00572] [00572] A tert-butyl (2S, 3S) -2- (3-bromo-2-fluorobenzyl) -3- ((methylsulfonyl) amino)) pyrrolidine-1-carboxylate (5 g) ethyl acetate / 4M hydrogen chloride (22.2 mL) at room temperature. The mixture was stirred at room temperature for 10 h, and the reaction solution was concentrated under reduced pressure. The obtained solid was washed with diisopropyl ether to give the title compound (4.11 g). MS: [M + H] + 351.1. B) N - ((2S, 3S) -2- (3-bromo-2-fluorobenzyl) -1- (2-hydroxy-2-methylpropanoyl) pyrrolidin-3-yl) methanesulfonamide
[00573] [00573] To a mixture of N - ((2S, 3S) -2- (3-bromo-2-fluorobenzyl) pyrrolidin-3-yl) methanesulfonamide (4.11 g), 2-hydroxy-2- acid methylpropanoic (1.32 g) and DMF (40 ml) were added HATU (4.84 g) and TEA (4.29 g) at room temperature. The mixture was stirred overnight at room temperature, to the reaction mixture saturated aqueous sodium hydrogen carbonate solution was added and the mixture was extracted with ethyl acetate. The organic layer was separated, washed with water and saturated brine, dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate / hexane) to give the title compound (3.30 g). MS: [M + H] + 437.2. C) N - ((2S, 3S) -2 - (((3'-chloro-2,5'-difluorobiphenyl-3-yl) methyl) -1- (2-hydroxy-2-methylpropanoyl) pyrrolidin-3-yl ) methanesulfonamide
[00574] [00574] A mixture of N - ((2S, 3S) -2- (3-bromo-2-fluorobenzyl) -1- (2-hydroxy-2-methylpropanoyl) pyrrolidin-3-yl) methanesulfonamide (70 mg), boronic acid (3-chloro-5-fluorophenyl) (41.9 mg), XPhos Pd G3 (4.06 mg), 1 M aqueous tripotassium phosphate solution (0.480 mL) and THF (2 mL) was stirred at 70 ° C for 1 h. The reaction mixture was purified by column chromatography on silica gel (NH, ethyl acetate / hexane) and then purified by HPLC (C18, mobile phase: water / acetonitrile (containing 0.1% TFA)). THE
[00575] [00575] A tert-butyl (2S, 3S) -2- (3-bromo-2-fluorobenzyl) -3- ((ethylsulfonyl) amino)) pyrrolidine-1-carboxylate (847 mg) ethyl acetate / 4M hydrogen chloride (8 mL) at room temperature. The mixture was stirred at room temperature for 1 h, and the reaction mixture was concentrated under reduced pressure. The obtained solid was washed with ethyl acetate to give the title compound (527 mg). MS: [M + H] + 364.9. B) N - ((2S, 3S) -2- (3-bromo-2-fluorobenzyl) -1- (2-hydroxy-2-methylpropanoyl) pyrrolidin-3-yl) ethanesulfonamide
[00576] [00576] To a mixture of N - ((2S, 3S) -2- (3-bromo-2-fluorobenzyl) pyrrolidin-3-yl) ethanesulfonamide (727 mg), 2-hydroxy-2-methylpropanoic acid ( 227 mg) and DMF (5 ml) were added HATU (1.03 g) and TEA (549 mg) at room temperature. The mixture was stirred at room temperature for 2 h, to the reaction mixture was added saturated aqueous sodium hydrogen carbonate solution, and the mixture was extracted with ethyl acetate. The organic layer was separated, washed with water and saturated brine, dried
[00577] [00577] A mixture of N - ((2S, 3S) -2- (3-bromo-2-fluorobenzyl) -1- (2-hydroxy-2-methylpropanoyl) pyrrolidin-3-yl) ethanesulfonamide (60 mg), boronic acid (3-chlorophenyl) (31.2 mg), XPhos Pd G3 (3.38 mg), 1 M aqueous solution of tripotassium phosphate (0.399 ml) and THF (2 ml) was stirred at 70 ° C for 1 H. The reaction mixture was purified by column chromatography on silica gel (NH, ethyl acetate / hexane) and then purified by HPLC (C18, mobile phase: water / acetonitrile (containing 0.1% TFA)). To the fraction obtained, saturated aqueous sodium hydrogen carbonate solution was added and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate and concentrated under reduced pressure to give the title compound (38 mg). 1 H NMR (400 MHz, DMSO-d6) δ 1.03-1.17 (6H, m), 1.18-1.23 (3H, m), 1.99-2.23 (2H, m) , 2.54-2.67 (1H, m), 2.95-3.11 (3H, m), 3.62-3.83 (2H, m), 3.84-3.98 (1H, m), 4.53-4.73 (1H, m), 4.89-5.04 (1H, m), 7.07-7.17 (1H, m), 7.26-7.39 ( 2H, m), 7.41-7.52 (4H, m), 7.54-7.62 (1H, m). Example 435 N - (((2S, 3S) -1- (2-hydroxy-2-methylpropanoyl) -2 - ((2,3 ', 5'-trifluorobiphenyl-3-yl) methyl) pyrrolidin-3-yl) ethanesulfonamide
[00578] [00578] A mixture of N - ((2S, 3S) -2- (3-bromo-2-fluorobenzyl) -1- (2-hydroxy-2-methylpropanoyl) pyrrolidin-3-yl) ethanesulfonamide (70 mg), boronic (3,5-difluorophenyl) acid (36.7 mg), XPhos Pd G3 (3.94 mg), 1 M aqueous tripotassium phosphate solution (0.465 mL) and THF (3 mL) was stirred at 70 ° C for 1.5 h. The reaction mixture was partitioned between ethyl acetate and
[00579] [00579] A mixture of N - ((2S, 3S) -2- (3-bromo-2-fluorobenzyl) -1- (2-hydroxy-2-methylpropanoyl) pyrrolidin-3-yl) ethanesulfonamide (70 mg), boronic acid (3-chloro-5-fluorophenyl) (40.6 mg), XPhos Pd G3 (3.94 mg), 1 M aqueous tripotassium phosphate solution (0.465 mL) and THF (3 mL) was stirred at 70 ° C for 2.5 h. The reaction mixture was partitioned between ethyl acetate and water, and the mixture was extracted with ethyl acetate. The organic layer was washed with aqueous sodium hydrogen carbonate solution and saturated brine, dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (NH, methanol / ethyl acetate). The obtained solid was recrystallized from ethyl acetate / hexane / water to give the title compound (10 mg). 1 H NMR (400 MHz, CDCl3) δ1.24 (3H, t, J = 6.8 Hz), 1.40 (3H, s), 1.41 (3H, brs), 1.82-2.04 (1H, m), 2.25-2.44 (1H, m), 2.77-3.01 (3H, m), 3.05-3.23 (1H, m), 3.68 (2H , brs), 3.81 (1H, brs), 3.90-4.08 (1H, m), 4.39-4.58 (1H, m), 4.75 (1H, brs), 7, 04-7.22 (3H, m), 7.23-7.35 (2H, m), 7.37-7.47 (1H, m).
[00580] [00580] To a mixture of tert-butyl (2S, 3S) -3-amino-2- (3-bromo-2-fluorobenzyl) pyrrolidine-1-carboxylate (1 g), TEA (0.542 g), DMAP ( 0.327 g) and THF (10 ml) were added cyclopropanesulfonyl chloride (0.753 g) at room temperature. The mixture was stirred at 50 ° C for 3.5 h, and to the reaction mixture was added ethyl acetate. The insoluble substance was removed by filtration and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate / hexane) to give the title compound (1.2 g). MS: [M + H-Boc] + 377.1. B) N - ((2S, 3S) -2- (3-bromo-2-fluorobenzyl) pyrrolidin-3-yl) cyclopropanesulfonamide hydrochloride
[00581] [00581] To tert-butyl (2S, 3S) -2- (3-bromo-2-fluorobenzyl) -3 - ((cyclopropylsulfonyl) amino) pyrrolidine-1-carboxylate (722 mg), acetate solution was added of ethyl / hydrogen chloride 4M (7.56 mL) at room temperature. The mixture was stirred at room temperature for 2 h and concentrated under reduced pressure. The residue was washed with diisopropyl ether to give the title compound (617 mg). MS: [M + H] + 377.1. C) N - ((2S, 3S) -2- (3-bromo-2-fluorobenzyl) -1- (2-hydroxy-2-methylpropanoyl) pyrrolidin-3-yl) cyclopropanesulfonamide
[00582] [00582] To a mixture of N - ((2S, 3S) -2- (3-bromo-2-fluorobenzyl) pyrrolidin-3-yl) cyclopropanesulfonamide (607 mg), 2-hydroxy-2-methylpropanoic acid ( 183 mg) and DMF (10 ml) were added HATU (837 mg) and TEA (445 mg) at room temperature. The mixture was
[00583] [00583] A mixture of N - ((2S, 3S) -2- (3-bromo-2-fluorobenzyl) -1- (2-hydroxy-2-methylpropanoyl) pyrrolidin-3-yl) cyclopropanesulfonamide (73.3 mg ), boronic acid (3,5-difluorophenyl) (37.5 mg), XPhos Pd G3 (4.02 mg), 1 M aqueous tripotassium phosphate solution (0.475 mL) and THF (3 mL) was stirred at 70 ° C for 1.5 h. The reaction mixture was partitioned between ethyl acetate and water, and the mixture was extracted with ethyl acetate. The organic layer was washed with aqueous sodium hydrogen carbonate solution and saturated brine, dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (NH, ethyl acetate / hexane) to give the title compound (35.8 mg). 1 H NMR (400 MHz, CDCl3) δ0.83-0.98 (2H, m), 1.10 (2H, brs), 1.38 (3H, brs), 1.40 (3H, brs), 1 , 93-2.14 (2H, m), 2.25-2.45 (1H, m), 2.80-2.99 (1H, m), 3.05-3.23 (1H, m) , 3.71 (2H, brs), 3.86 (1H, brs), 3.95-4.06 (1H, m), 4.78 (1H, brs), 4.96 (1H, d, J = 7.1 Hz), 6.81 (1H, t, J = 8.4 Hz), 6.99-7.11 (2H, m), 7.12-7.20 (1H, m), 7 , 22-7.31 (1H, m), 7.40 (1H, brs). Example 362 N - (((2S, 3S) -1- (azetidin-1-ylcarbonyl) -2 - ((3 ', 5'-difluorobiphenyl-3-yl) methyl) pyrrolidin-3-yl) ethanesulfonamide A) chloride (2S, 3S) -2 - ((3 ', 5'-difluoro [biphenyl] -3-yl) methyl) -3 - ((ethylsulfonyl)
[00584] [00584] To a mixture of N - (((2S, 3S) -2 - (((3 ', 5'-difluorobiphenyl-3-yl) methyl) pyrrolidin-3-yl) ethanesulfonamide hydrochloride (1.0 g), DIPEA (0.620 g) and THF (30 ml) were added bis (trichloromethyl) carbonate (0.569 g) in THF (5 ml) at 0 ° C. After being stirred at 0 ° C for 10 min, the mixture was warmed to room temperature and stirred for 3 h. The mixture was concentrated in vacuo. The residue was triturated with ethyl acetate and the insoluble substance was removed by filtration. The filtrate was concentrated in vacuo. The residue was purified by silica gel column chromatography (ethyl acetate / hexane) to give the title compound (1.06 g). MS: [M-H] - 441.2. B) N - (((2S, 3S) -1- (azetidin-1-ylcarbonyl) -2 - ((3 ', 5'-difluorobiphenyl-3-yl) methyl) pyrrolidin-3-yl) ethanesulfonamide
[00585] [00585] To a mixture of (2S, 3S) -2 - ((3 ', 5'-difluoro [biphenyl] -3-yl) methyl) -3 - (((ethylsulfonyl) amino)) pyrrolidine-1- carbonyl (500 mg), azetidine (129 mg) and THF (10 ml) TEA (343 mg) was added at room temperature. The mixture was stirred at room temperature for 3 h, then diluted with THF and the insoluble substance was removed by filtration. The filtrate was concentrated in vacuo. The residue was purified by silica gel column chromatography (methanol / ethyl acetate) and recrystallized from ethyl acetate / hexane to give the title compound (380 mg). 1 H NMR (300 MHz, CDCl3) δ 1.18-1.28 (3H, m), 1.75-1.90 (1H, m), 2.08-2.25 (3H, m), 2 , 81-2.99 (3H, m), 3.16 (1H, dd, J = 14.0, 4.9 Hz), 3.26-3.43 (2H, m), 3.80-4 .08 (5H, m), 4.36 (1H, d, J = 8.7 Hz), 4.43-4.53 (1H, m), 6.78 (1H, tt, J = 8.9 , 2.3 Hz), 7.07-7.17 (2H, m), 7.31-7.43 (3H, m), 7.46-7.50 (1H, m). Example 372 N - (((2S, 3S) -1- (azetidin-1-ylcarbonyl) -2 - ((2,3'-difluorobiphenyl-3-yl) methyl) pyrrolidin-3-yl) ethanesulfonamide
[00586] [00586] Azetidine (244 mg) was added to a stirred mixture of (2S, 3S) -2 - ((2,3'-difluorobiphenyl-3-yl) methyl) -3- ((ethylsulfonyl) amino)) pyrrolidine-1-carbonyl (632 mg) and THF (6 ml) at room temperature. After being stirred for 30 min, the reaction mixture was concentrated in vacuo. The residue was diluted with ethyl acetate, washed with saturated brine, dried over anhydrous sodium sulfate, filtered and concentrated in vacuo. The obtained solid was crystallized from ethyl acetate / ethanol to give the title compound (416 mg). 1 H NMR (400 MHz, CDCl3) δ 1.23 (3H, t, J = 7.4 Hz), 1.82-1.97 (1H, m), 2.08-2.30 (3H, m ), 2.78-2.91 (2H, m), 2.92-3.06 (2H, m), 3.22-3.40 (2H, m), 3.74-4.02 (5H , m), 4.46-4.61 (2H, m), 7.03-7.11 (1H, m), 7.14-7.25 (2H, m), 7.26-7.44 (4H, m). Example 377 (2S, 3S) -2 - ((2,3'-difluorobiphenyl-3-yl) methyl) -3 - ((dimethylsulfamoyl) amino) -N, N-dimethylpyrrolidine-1-carboxamide A) (2S, 3S Tert-butyl -2- (3-bromo-2-fluorobenzyl) -3 - ((dimethylsulfamoyl) amino) pyrrolidine-1-carboxylate
[00587] [00587] Dimethylsulfamoyl chloride (2.31 g) was added to a mixture of tert-butyl (2S, 3S) -3-amino-2- (3-bromo-2-fluorobenzyl) pyrrolidine-1-carboxylate (2 , 5 g), TEA (1.36 g), DMAP (0.982 g) and THF (25 ml) at room temperature. After being stirred at 50 ° C for 4 h, the reaction mixture was poured into water and extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate and concentrated in vacuo. The residue was purified by silica gel column chromatography (ethyl acetate / hexane) to give the title compound (2.4 g). MS: [M + H-Boc] + 380.0. B) diamide hydrochloride N '- ((2S, 3S) -2- (3-bromo-2-fluorobenzyl) pyrrolidin-3-yl) -N, N-dimethylsulfuric
[00588] [00588] A mixture of tert-butyl (2S, 3S) -2- (3-bromo-2-fluorobenzyl) -3- ((dimethylsulfamoyl) amino) pyrrolidine-1-carboxylate (2.4 g) 4M ethyl acetate / hydrogen chloride (12.5 mL) was stirred at room temperature under a dry atmosphere (Cacl2 tube) overnight. The mixture was concentrated in vacuo. The residue was washed with diisopropyl ether to give the title compound (1.78 g). MS: [M + H] + 379.9. C) (2S, 3S) -2- (3-bromo-2-fluorobenzyl) -3 - ((dimethylsulfamoyl) amino) -N, N-dimethylpyrrolidine-1-carboxamide
[00589] [00589] To a mixture of diamide hydrochloride N '- ((2S, 3S) -2- (3-bromo-2-fluorobenzyl) pyrrolidin-3-yl) -N, N-dimethylsulfuric (1.78 g), TEA (4.32 g) and THF (20 ml) were added dimethylcarbamoyl chloride (2.30 g) at room temperature. The mixture was refluxed for 3 h. The mixture was quenched with a saturated aqueous solution of sodium hydrogen carbonate and extracted with ethyl acetate. The organic layer was separated, washed with saturated brine, dried over anhydrous magnesium sulfate and concentrated in vacuo. The residue was purified by silica gel column chromatography (NH, ethyl acetate / hexane) to give the title compound (1.9 g). MS: [M + H] + 451.0. D) (2S, 3S) -2 - ((2,3'-difluorobiphenyl-3-yl) methyl) -3 - ((dimethylsulfamoyl) amino) - N, N-dimethylpyrrolidine-1-carboxamide
[00590] [00590] A mixture of (2S, 3S) -2- (3-bromo-2-fluorobenzyl) -3- ((dimethylsulfamoyl) amino) -N, N-dimethylpyrrolidine-1-carboxamide (600 mg), acid (3 -fluorophenyl) boron (242 mg), XPhos Pd G3 (16.9 mg), 1M aqueous solution of tripotassium phosphate (3.99 ml) and THF (6 ml) was stirred at 70 ° C for 1 h. The aqueous phase was removed and the organic layer was concentrated in vacuo. The residue was purified by silica gel column chromatography (NH, ethyl acetate / hexane) and the resulting solid was
[00591] [00591] To a stirred mixture of N - ((2S, 3S) -2- (biphenyl-3-ylmethyl) pyrrolidin-3-yl) ethanesulfonamide (293 mg), DIPEA (298 mg) and THF (3 ml ) methoxy (methyl) carbamoyl chloride (143 mg) was added at room temperature. After 15 min, the reaction mixture was concentrated in vacuo. The residue was diluted with ethyl acetate, washed with saturated brine, and purified by silica gel column chromatography (ethyl acetate / hexane) and recrystallized from ethyl acetate / hexane to give the title compound (302 mg) . 1 H NMR (400 MHz, CDCl3) δ 1.19 (3H, t, J = 7.4 Hz), 1.83-1.94 (1H, m), 2.06-2.23 (1H, m ), 2.72-2.94 (3H, m), 2.98 (3H, s), 3.17-3.27 (1H, m), 3.42-3.52 (1H, m), 3.55 (3H, s), 3.60-3.70 (1H, m), 3.86-4.02 (1H, m), 4.40 (1H, d, J = 8.8 Hz) , 4.52-4.68 (1H, m), 7.27-7.62 (9H, m). Example 441 N - {(2S, 3S) -1- (oxethane-2-carbonyl) -2 - [(2,3 ', 5'-trifluoro [1,1'-biphenyl] -3-yl) methyl] pyrrolidin -3-yl} methanesulfonamide A) N - ((2S, 3S) -2- (3-bromo-2-fluorobenzyl) -1- (oxetan-2-ylcarbonyl) pyrrolidin-3-yl) methanesulfonamide
[00592] [00592] HATU (374 mg) was added to a mixture of N - ((2S, 3S) -2- (3-bromo-2-fluorobenzyl) pyrrolidin-3-yl) methanesulfonamide (318 mg), oxetane acid -2-carboxylic (100 mg), TEA (415 mg) and DMF (6
[00593] [00593] A mixture of N - ((2S, 3S) -2- (3-bromo-2-fluorobenzyl) -1- (oxetan-2-ylcarbonyl) pyrrolidin-3-yl) methanesulfonamide (76.5 mg), boronic acid (3,5-difluorophenyl) (41.6 mg), Xphos Pd G3 (4.46 mg), 1M aqueous solution of tripotassium phosphate (0.527 ml) and THF (3 ml) was stirred at 70 ° C for 1.5 h. The mixture was partitioned between ethyl acetate and water and extracted with ethyl acetate. The extract was washed with aqueous sodium hydrogen carbonate solution and saturated brine, dried over anhydrous magnesium sulfate, filtered and concentrated in vacuo to give a solid. The residue was purified by silica gel column chromatography (NH, methanol / ethyl acetate) to give the title compound (42.4 mg). 1 H NMR (400 MHz, CDCl3) δ 1.82-1.98 (1H, m), 2.25-2.63 (2H, m), 2.69-3.03 (5H, m), 3 , 06-3.16 (1H, m), 3.25-3.81 (2H, m), 3.93-4.58 (3H, m), 4.62-5.25 (3H, m) , 6.76-7.55 (6H, m). Example 450 N - [(2S, 3S) -2 - [(2,3'-difluoro [1,1'-biphenyl] -3-yl) methyl] -1- (2-hydroxy-2-methylpropanoyl) pyrrolidin- 3-yl] -1-fluorocyclopropane-1-sulfonamide A) (2S, 3S) -3 - ((cyclopropylsulfonyl) amino) -2 - ((2,3'-difluoro [biphenyl] -3-yl) methyl) pyrrolidine Tert-butyl -1-carboxylate
[00594] [00594] A mixture of tert-butyl (2S, 3S) -2- (3-bromo-2-fluorobenzyl) -3- ((cyclopropylsulfonyl) amino) pyrrolidine-1-carboxylate (1.17 g) 3-fluorophenyl) boronic (0.514 g), XPhos Pd G3 (0.207 g), 1M aqueous solution of tripotassium phosphate (7.35 ml) and THF (10 ml) was stirred at 70 ° C for 1 h. The mixture was poured into water at room temperature and extracted with ethyl acetate. The organic layer was separated, washed with saturated brine, dried over anhydrous magnesium sulfate and concentrated in vacuo. The residue was purified by silica gel column chromatography (NH, ethyl acetate / Hexane) to give the title compound (1.02 g). MS: [M + H-Boc] + 393.1. B) tert- butyl
[00595] [00595] To a mixture of (2S, 3S) -3 - ((cyclopropylsulfonyl) amino) -2- ((2,3'-difluoro [biphenyl] -3-yl) methyl) pyrrolidine-1-carboxylate butyl (156 mg) and THF (3 ml) 2.6M hexane / n-butylithium solution (0.268 ml) was added dropwise at -78 ° C. After being stirred at -78 ° C for 1 h, a solution of N-fluoro-N- (phenylsulfonyl) benzenesulfonamide (120 mg) in THF (1 ml) was added dropwise to the reaction mixture. The mixture was stirred at 0 ° C under a nitrogen atmosphere for 1 h and then at room temperature for 2 h. The mixture was quenched with a saturated aqueous solution of ammonium chloride and extracted with ethyl acetate. The organic layer was separated, washed with water and saturated brine, dried over anhydrous magnesium sulfate and concentrated in vacuo. The residue was purified by silica gel column chromatography (ethyl acetate / hexane) to give the title compound (81.9 mg). MS: [M + H-Boc] + 411.3. C) N - ((2S, 3S) -2 - ((2,3'-difluoro [biphenyl] -3-yl) methyl) pyrrolidin-3-yl) -1-fluorocyclopropanesulfonamide hydrochloride
[00596] [00596] To a mixture of (2S, 3S) -2 - ((2,3'-difluoro [biphenyl] -3-
[00597] [00597] A mixture of N - (((2S, 3S) -2 - (((2,3'-difluoro [biphenyl] -3-yl) methyl) pyrrolidin-3-yl) -1-fluorocyclopropanesulfonamide hydrochloride (447 mg ), DIPEA (1.29 g) and THF (5 ml) was stirred at room temperature for 30 min. To the suspension, 1-chloro-2-methyl-1-oxopropan-2-yl acetate (198 mg) was added dropwise at 0 ° C, and the mixture was stirred at the same temperature for 1 h. To the mixture, water (2 ml) and 4M aqueous lithium hydroxide solution (2.00 ml) were added and the mixture was stirred at room temperature overnight. The mixture was diluted with saturated brine and extracted with ethyl acetate. The organic layer was separated, dried over anhydrous magnesium sulfate and concentrated in vacuo. The residue was purified by column chromatography on silica gel (NH, ethyl acetate / hexane) and then preparative HPLC (C18, mobile phase: water / acetonitrile (containing 0.1% TFA)). The desired fraction was neutralized with a saturated aqueous solution of sodium hydrogen carbonate and extracted with ethyl acetate. The organic layer was separated, washed with water and saturated brine, dried over anhydrous magnesium sulfate and concentrated in vacuo. The solid was crystallized from ethanol / water to give the title compound (140 mg). 1 H NMR (400 MHz, CDCl3) δ 1.14-1.52 (10H, m), 1.79-2.03 (1H, m), 2.28-2.22 (1H, m), 2 , 91-3.04 (1H, m), 3.11-3.26 (1H, m), 3.52-3.95 (3H, m), 4.07- 4.24 (1H, m) , 4.69-5.06 (2H, m), 7.03-7.10 (1H, m), 7.15-7.25 (2H, m), 7.27- 7.44 (4H, m).
[00598] [00598] A mixture of tert-butyl (2S, 3S) -2- (3-bromo-2-fluorobenzyl) -3- ((ethylsulfonyl) amino)) pyrrolidine-1-carboxylate (0.698 g), phenylboronic acid ( 0.238 g), XPhos Pd G3 (0.019 g), 2M aqueous solution of tripotassium phosphate (2.25 ml) and THF (3 ml) was stirred at 70 ° C for 1 h. The aqueous phase was removed and the organic layer was concentrated in vacuo. The residue was purified by silica gel column chromatography (NH, ethyl acetate / hexane) to give a solid. 4M ethyl acetate / hydrogen chloride solution (7.50 mL) was added to a stirred mixture of the solid (694 mg) and ethyl acetate (2 mL) at room temperature. After 18 h, the reaction mixture was concentrated in vacuo, and the resulting solid was collected by filtration to give the title compound (568 mg). MS: [M + H] + 363.3. B) N - {(2S, 3S) -1- (azetidine-1-carbonyl) -2 - [(2-fluoro [1,1'-biphenyl] -3-yl) methyl] pyrrolidin-3-yl} ethanesulfonamide
[00599] [00599] To a stirred mixture of N - ((2S, 3S) -2 - ((2-fluoro [biphenyl] -3-yl) methyl) pyrrolidin-3-yl) ethanesulfonamide (568 mg), carbonate bis (trichloromethyl) (254 mg) and THF (6 ml) were added DIPEA (368 mg) at 0 ° C. After being stirred at room temperature for 30 min, the reaction mixture was concentrated in vacuo. The residue was diluted with ethyl acetate, washed with saturated brine and purified by column chromatography on silica gel (ethyl acetate / hexane) to give an oil. Azetidine (243 mg) was added to a stirred mixture of the oil (603 mg) and THF (7 ml) at room temperature. After being stirred for 30 min, the reaction mixture was concentrated in vacuo. The residue was diluted with acetate
[00600] [00600] A mixture of (2S, 3S) -3 - ((methylsulfonyl) amino)) - 2 - ((2,3 ', 5'-trifluorobiphenyl-3-yl) methyl) pyrrolidine-1-carboxylate butyl (1.67 g), 4M ethyl acetate / hydrogen chloride solution (20 mL) and ethyl acetate (20 mL) was stirred at room temperature overnight. The mixture was diluted with ethyl acetate and the precipitate was collected by filtration to give the title compound (1.37 g). MS: [M + H] + 385.2. B) N - {(2S, 3S) -1- (3-hydroxy-2,2-dimethylpropanoyl) -2 - [(2,3 ', 5'-trifluoro [1,1'-biphenyl] -3-yl ) methyl] pyrrolidin-3-yl} methanesulfonamide
[00601] [00601] HATU (67.8 mg) was added to a mixture of N - ((2S, 3S) -2 - ((2,3 ', 5'-trifluorobiphenyl-3-yl) methyl) pyrrolidin-3 hydrochloride - yl) methanesulfonamide (50 mg), 3-hydroxy-2,2-dimethylpropanoic acid (18.2 mg), DIPEA (77 mg) and DMF (1 ml) at room temperature. After being stirred at room temperature for 7 h, the reaction mixture was diluted with water and extracted with ethyl acetate. The extract was washed with a saturated aqueous solution of sodium hydrogen carbonate and saturated brine, dried over
[00602] [00602] To a mixture of tert-butyl (2S, 3S) -3-amino-2- (3-bromobenzyl) pyrrolidine-1-carboxylate (10.7 g), 2M aqueous sodium hydroxide solution (19 mL ) and THF (100 mL) benzyl carbonochloride (5.98 g) was added at 0 ° C. The mixture was stirred at room temperature for 30 min. To the mixture, saturated aqueous sodium hydrogen carbonate solution was added and extracted with ethyl acetate. The organic layer was separated, washed with water and saturated brine, dried over anhydrous sodium sulfate and concentrated in vacuo. To a mixture of the obtained residue and ethyl acetate (20 ml) was added 4M ethyl acetate / hydrogen chloride solution (75 ml) at room temperature. The mixture was stirred at room temperature overnight. The mixture was concentrated in vacuo. The residue was triturated with ethyl acetate and the precipitate was collected by filtration to give the title compound (12.8 g). MS: [M + H] + 389.0.
[00603] [00603] To a mixture of benzyl ((2S, 3S) -2- (3-bromobenzyl) pyrrolidin-3-yl) carbamate hydrochloride (5 g) and THF (100 ml) was added bis (trichloromethyl) carbonate ) (2.79 g) and DIPEA (3.04 g) at 0 ° C. After being stirred at 0 ° C for 20 min, the mixture was concentrated in vacuo. To the residue were added THF (100 ml) and azetidine (5.36 g). The mixture was stirred at room temperature overnight. The mixture was quenched with a saturated aqueous solution of sodium hydrogen carbonate at room temperature and extracted with ethyl acetate. The organic layer was separated, washed with saturated brine, dried over anhydrous magnesium sulfate and concentrated in vacuo. The solid was crystallized from ethyl acetate / diisopropyl ether to give the title compound (4.74 g). MS: [M + H] + 472.1. C) ((2S, 3S) -1- (azetidin-1-ylcarbonyl) -2 - ((3'-fluoro [biphenyl] -3-yl) methyl) pyrrolidin-3-yl) benzyl carbamate
[00604] [00604] A mixture of benzyl ((2S, 3S) -1- (azetidin-1-ylcarbonyl) -2- (3-bromobenzyl) pyrrolidin-3-yl) carbamate (1.4 g), acid (3- fluorophenyl) boron (0.539 g), XPhos Pd G3 (0.038 g), 1M aqueous solution of tripotassium phosphate (8.89 ml) and THF (20 ml) was stirred at 70 ° C for 5 h. After cooling, the insoluble substance was removed by filtration, and the filtrate was concentrated in vacuo. The residue was extracted with ethyl acetate / THF. The organic layer was separated, washed with saturated brine, passed through NH silica gel and concentrated in vacuo. The obtained solid was washed with ethyl acetate and diisopropyl ether to give the title compound (1.25 g). MS: [M + H] + 488.2. D) ((2S, 3S) -3-amino-2 - (((3'-fluoro [biphenyl] -3-yl) methyl) pyrrolidin-1-yl) (azetidin-1-yl) methanone
[00605] [00605] A mixture of benzyl ((2S, 3S) -1- (azetidin-1-ylcarbonyl) -2 - ((3'-fluoro [biphenyl] -3-yl) methyl) pyrrolidin-3-yl) carbamate (1.25 g), 10% palladium on carbon (0.12 g), EtoH (20 ml) and THF (20 ml) was hydrogenated under balloon pressure at room temperature for 1 h. The catalyst was removed by filtration and the filtrate was concentrated in vacuo. The residue was purified by silica gel column chromatography (NH, methanol / ethyl acetate) to give the title compound (900 mg). MS: [M + H] + 354.0. E) N - {(2S, 3S) -1- (azetidine-1-carbonyl) -2 - [(3'-fluoro [1,1'-biphenyl] -3-yl) methyl] pyrrolidin-3-yl} -1-fluoromethanesulfonamide
[00606] [00606] To a mixture of ((2S, 3S) -3-amino-2 - (((3'-fluoro [biphenyl] -3-yl) methyl) pyrrolidin-1-yl) (azetidin-1-yl) methanone (100 mg) and THF (2 ml) were added DIPEA (47.5 mg) and fluoromethanesulfonyl chloride (41.3 mg) at room temperature. After being stirred for 30 min, the mixture was concentrated in vacuo. The residue was purified by silica gel column chromatography (ethyl acetate / hexane). The solid was crystallized from ethyl acetate / hexane to give the title compound (58 mg). 1 H NMR (400 MHz, DMSO-d6) δ 1.86-2.00 (3H, m), 2.02-2.16 (1H, m), 2.70-2.82 (1H, m) , 2.85-2.95 (1H, m), 3.10-3.21 (1H, m), 3.32-3.38 (1H, m), 3.52-3.64 (2H, m), 3.72-3.88 (3H, m), 4.20-4.31 (1H, m), 5.17-5.50 (2H, m), 7.14-7.22 ( 1H, m), 7.26-7.30 (1H, m), 7.33-7.39 (1H, m), 7.46-7.58 (5H, m), 8.22 (1H, brs). Example 460 N - {(2S, 3S) -1- (azetidine-1-carbonyl) -2 - [([1,1'-biphenyl] -3-yl) methyl] pyrrolidin-3-yl} -1-fluoromethanesulfonamide A) ((2S, 3S) -1- (azetidin-1-ylcarbonyl) -2 - ([biphenyl] -3-ylmethyl) pyrrolidin-3-yl) benzyl carbamate
[00607] [00607] A mixture of ((2S, 3S) -1- (azetidin-1-ylcarbonyl) -2- (3-bromobenzyl) pyrrolidin-3-yl) benzyl carbamate (1.4 g), phenylboronic acid
[0001] [0001] B) ((2S, 3S) -3-amino-2 - ([biphenyl] -3-ylmethyl) pyrrolidin-1-yl) (azetidin-1-yl) methanone
[00608] [00608] A mixture of benzyl (((2S, 3S) -1- (azetidin-1-ylcarbonyl) -2 - ([biphenyl] - 3-ylmethyl) pyrrolidin-3-yl) carbamate (1.08 g), 10% palladium on carbon (0.10 g), EtoH (20 ml) and THF (20 ml) was hydrogenated under balloon pressure at room temperature for 1 h. The catalyst was removed by filtration and the filtrate was concentrated in vacuo. The residue was purified by silica gel column chromatography (NH, methanol / ethyl acetate) to give the title compound (700 mg). MS: [M + H] + 336.1. C) N - {(2S, 3S) -1- (azetidine-1-carbonyl) -2 - [([1,1'-biphenyl] -3-yl) methyl] pyrrolidin-3-yl} -1-fluoromethanesulfonamide
[00609] [00609] To a mixture of ((2S, 3S) -3-amino-2 - ([biphenyl] -3-ylmethyl) pyrrolidin-1-yl) (azetidin-1-yl) methanone (100 mg) in THF ( 2 ml) DIPEA (50.1 mg) and fluoromethanesulfonyl chloride (43.5 mg) 0 ° C were added. After being stirred for 30 min, the mixture was concentrated in vacuo. The residue was purified by silica gel column chromatography (ethyl acetate / hexane). The solid was crystallized from ethyl acetate / hexane to give the title compound (98 mg). 1 H NMR (400 MHz, DMSO-d6) δ 1.85-1.99 (3H, m), 2.03-2.14 (1H, m),
[00610] [00610] To a mixture of ((2S, 3S) -3-amino-2 - (((3'-fluoro [biphenyl] -3-yl) methyl) pyrrolidin-1-yl) (azetidin-1-yl) methanone (200 mg) and THF (4 ml) were added DIPEA (95 mg), DMAP (69.1 mg) and cyclopropanesulfonyl chloride (88 mg) at room temperature. After being stirred for 10 h, the mixture was quenched with a saturated aqueous solution of sodium hydrogen carbonate and extracted with ethyl acetate. The organic layer was separated, dried over anhydrous sodium sulfate and concentrated in vacuo. The residue was purified by silica gel column chromatography (methanol / ethyl acetate). The solid was crystallized from ethyl acetate / diisopropyl ether to give the title compound (221 mg). 1 H NMR (400 MHz, DMSO-d6) δ 0.77-1.00 (4H, m), 1.88-2.03 (3H, m), 2.03-2.16 (1H, m) , 2.37-2.48 (1H, m), 2.70-2.81 (1H, m), 2.88-2.97 (1H, m), 3.13-3.23 (1H, m), 3.33-3.39 (1H, m), 3.53-3.65 (2H, m), 3.72-3.86 (3H, m), 4.21 - 4.30 ( 1H, m), 7.13-7.23 (1H, m), 7.26-7.39 (2H, m), 7.45-7.61 (6H, m). Example 463 N - {(2S, 3S) -1- (azetidine-1-carbonyl) -2 - [([1,1'-biphenyl] -3-yl) methyl] pyrrolidin-3-yl} cyclopropanesulfonamide
[00611] [00611] To a mixture of ((2S, 3S) -3-amino-2 - ([biphenyl] -3-ylmethyl) pyrrolidin-1-yl) (azetidin-1-yl) methanone (200 mg) and THF ( 4 ml) DIPEA (100 mg), DMAP (14.6 mg) and cyclopropanesulfonyl chloride (92 mg) were added at room temperature. After being stirred overnight, the mixture was quenched with an aqueous solution
[00612] [00612] To a mixture of tert-butyl (2S, 3S) -3-amino-2- (3-bromo-2-fluorobenzyl) pyrrolidine-1-carboxylate (1.43 g), aqueous sodium hydroxide solution 2M (2.30 ml) and THF (20 ml) benzyl carbonochlorohydrate (0.719 g) was added at 0 ° C. The mixture was stirred at room temperature for 30 min. To the mixture, saturated aqueous sodium hydrogen carbonate solution was added and extracted with ethyl acetate. The organic layer was separated, washed with water and saturated brine, dried over anhydrous sodium sulfate and concentrated in vacuo to give the title compound (2.03 g). MS: [M + H-Boc] + 407.0. B) benzyl ((2S, 3S) -2- (3-bromo-2-fluorobenzyl) pyrrolidin-3-yl) hydrochloride
[00613] [00613] A mixture of tert-butyl (2S, 3S) -3 - ((((benzyloxy) carbonyl) amino) -2- (3-bromo-2-fluorobenzyl) pyrrolidine-1-carboxylate (1.94 g) and
[00614] [00614] To a mixture of benzyl ((2S, 3S) -2- (3-bromo-2-fluorobenzyl) pyrrolidin-3-yl) carbamate hydrochloride (1.54 g) and THF (30 ml) were added bis (trichloromethyl) carbonate (0.824 g) and DIPEA (0.897 g) at 0 ° C. After being stirred at 0 ° C for 20 min, the mixture was concentrated in vacuo. To the residue were added THF (30 ml) and azetidine (0.991 g). The mixture was stirred at room temperature overnight. The mixture was quenched with a saturated aqueous solution of sodium hydrogen carbonate at room temperature and extracted with ethyl acetate. The organic layer was separated, washed with saturated brine, dried over anhydrous magnesium sulfate and concentrated in vacuo. The solid was crystallized from ethyl acetate / diisopropyl ether to give the title compound (1.64 g). MS: [M + H] + 490.1. D) benzyl carbamate ((2S, 3S) -1- (azetidin-1-ylcarbonyl) -2 - ((2-fluoro [biphenyl] -3-yl) methyl) pyrrolidin-3-yl)
[00615] [00615] A mixture of benzyl ((2S, 3S) -1- (azetidin-1-yl-carbonyl) -2- (3-bromo-2-fluorobenzyl) pyrrolidin-3-yl) carbamate (600 mg), phenylboronic acid (194 mg), XPhos Pd G3 (15.5 mg), 1M aqueous solution of tripotassium phosphate (3.67 ml) and THF (20 ml) was stirred at 70 ° C for 5 h. After cooling, the insoluble substance was removed by filtration, and the filtrate was concentrated in vacuo. The residue was extracted with ethyl acetate / THF. The organic layer was separated, washed with saturated brine, passed through
[00616] [00616] A mixture of benzyl (((2S, 3S) -1- (azetidin-1-ylcarbonyl) -2 - (((2-fluoro [biphenyl] -3-yl) methyl) pyrrolidin-3-yl) carbamate ( 500 mg), 10% palladium on carbon (50 mg), EtoH (20 ml) and THF (20 ml) was hydrogenated under balloon pressure at room temperature for 1 h. The catalyst was removed by filtration and the filtrate was concentrated in vacuo. The residue was purified by silica gel column chromatography (NH, methanol / ethyl acetate) to give the title compound (360 mg). MS: [M + H] + 354.0. F) N - {(2S, 3S) -1- (azetidine-1-carbonyl) -2 - [(2-fluoro [1,1'-biphenyl] -3-yl) methyl] pyrrolidin-3-yl} - 1-fluoromethanesulfonamide
[00617] [00617] To a mixture of ((2S, 3S) -3-amino-2 - (((2-fluoro [biphenyl] -3-yl) methyl) pyrrolidin-1-yl) (azetidin-1-yl) methanone ( 100 mg) and THF (2 ml) were added DIPEA (47.5 mg) and fluoromethanesulfonyl chloride (41.3 mg) at 0 ° C. After being stirred for 30 min, the mixture was concentrated in vacuo. The residue was purified by silica gel column chromatography (ethyl acetate / hexane). The solid was crystallized from ethyl acetate / hexane to give the title compound (98 mg). 1 H NMR (400 MHz, DMSO-d6) δ 1.90-2.19 (4H, m), 2.60-2.71 (1H, m), 2.86-2.97 (1H, m) , 3.09-3.20 (1H, m), 3.32-3.39 (1H, m), 3.43-3.53 (2H, m), 3.66-3.77 (2H, m), 3.80-3.89 (1H, m), 4.34-4.46 (1H, m), 5.22-5.55 (2H, m), 7.13-7.20 ( 1H, m), 7.25-7.34 (2H, m), 7.35-7.42 (1H, m), 7.44-7.51 (2H, m), 7.52-7, 57 (2H, m), 8.15-8.34 (1H, m). Example 467 N - {(2S, 3S) -1- (azetidine-1-carbonyl) -2 - [(2,3'-difluoro [1,1'-biphenyl] -3-
[00618] [00618] A mixture of benzyl ((2S, 3S) -1- (azetidin-1-ylcarbonyl) -2- (3-bromo-2-fluorobenzyl) pyrrolidin-3-yl) carbamate (600 mg) 3- fluorophenyl) boronic (223 mg), XPhos Pd G3 (15.5 mg), 1M aqueous solution of tripotassium phosphate (3.67 mL) and THF (20 mL) was stirred at 70 ° C for 5 h. After cooling, the insoluble substance was removed by filtration, and the filtrate was concentrated in vacuo. The residue was extracted with ethyl acetate / THF. The organic layer was separated, washed with saturated brine, passed through NH silica gel and concentrated in vacuo. The obtained solid was washed with ethyl acetate and diisopropyl ether to give the title compound (475 mg). MS: [M + H] + 506.2. B) ((2S, 3S) -3-amino-2 - (((2,3'-difluoro [biphenyl] -3-yl) methyl) pyrrolidin-1-yl) (azetidin-1-yl) methanone
[00619] [00619] A mixture of ((2S, 3S) -1- (azetidin-1-ylcarbonyl) -2 - ((2,3'-difluoro [biphenyl] -3-yl) methyl) pyrrolidin-3-yl) carbamate benzyl (475 mg), 10% palladium on carbon (0.47 g), EtoH (20 ml) and THF (20 ml) was hydrogenated under balloon pressure at room temperature for 1 h. The catalyst was removed by filtration and the filtrate was concentrated in vacuo. The residue was purified by silica gel column chromatography (NH, methanol / ethyl acetate) to give the title compound (330 mg). MS: [M + H] + 372.1. C) N - {(2S, 3S) -1- (azetidine-1-carbonyl) -2 - [(2,3'-difluoro [1,1'-biphenyl] -3-yl) methyl] pyrrolidin-3- il} -1-fluoromethanesulfonamide
[00620] [00620] To a mixture of ((2S, 3S) -3-amino-2 - (((2,3'-difluoro [biphenyl] - 3-yl) methyl) pyrrolidin-1-yl) (azetidin-1-yl ) methanone (100 mg) and THF (2 ml) were added DIPEA (45.2 mg) and fluoromethanesulfonyl chloride
[00621] [00621] To a mixture of N - ((2S, 3S) -2- (biphenyl-3-ylmethyl) pyrrolidin-3-yl) ethanesulfonamide (100 mg), cyclobutanecarboxylic acid (31.5 mg), HATU ( 120 mg) and DMF (1 ml) TEA (80 mg) was added at 0 ° C. The mixture was stirred at room temperature for 30 min. To the mixture, saturated aqueous sodium hydrogen carbonate solution was added and extracted with ethyl acetate. The organic layer was separated, washed with water and saturated brine, dried over anhydrous sodium sulfate and concentrated in vacuo. The residue was purified by silica gel column chromatography (methanol / ethyl acetate). The residue was crystallized from ethyl acetate / diisopropyl ether to give the title compound (75 mg). 1 H NMR (400 MHz, DMSO-d6) δ 0.91-1.30 (5H, m), 1.38-2.36 (8H, m), 2.63-3.31 (5H, m) , 3.38-3.88 (2H, m), 3.99-4.39 (1H, m), 7.12-7.68 (9H, m). Example 474 (2S, 3S) -3 - [(ethanesulfonyl) amino] -2 - [(3'-fluoro [1,1'-biphenyl] -3-yl) methyl] -N- methoxy-N-methylpyrrolidine-1 -carboxamide A) (2S, 3S) -3 - ((ethylsulfonyl) amino)) - 2 - (tert-butyl (3'-fluoro [biphenyl] -3-yl) methyl) pyrrolidine-1-carboxylate
[00622] [00622] A mixture of (2S, 3S) -2- (3-bromobenzyl) -3-
[00623] [00623] 4M ethyl acetate / hydrogen chloride solution (7.46 mL) was added to a stirred mixture of (2S, 3S) -3 - ((ethylsulfonyl) amino)) - 2 - ((3'-fluoro tert-butyl [biphenyl] -3-yl) methyl) pyrrolidine-1-carboxylate (0.690 g) and ethyl acetate (3 ml) at room temperature. After 1 h, the resulting solid was collected by filtration to give the title compound (508 mg). MS: [M + H] + 363.2. C) (2S, 3S) -3 - ((ethylsulfonyl) amino)) - 2 - ((3'-fluoro [biphenyl] -3-yl) methyl) pyrrolidine-1-carbonyl
[00624] [00624] To a mixture of N - ((2S, 3S) -2 - (((3-fluoro [biphenyl] -3-yl) methyl) pyrrolidin-3-yl) ethanesulfonamide (508 mg), bis carbonate (trichloromethyl) (302 mg) and THF (6 ml) DIPEA (329 mg) was added at 0 ° C. After being stirred at room temperature for 30 min, the reaction mixture was concentrated in vacuo. The residue was diluted with ethyl acetate, washed with saturated brine and purified by silica gel column chromatography (ethyl acetate / hexane) to give the title compound (542 mg). MS: [M-H] - 423.2. D) (2S, 3S) -3 - [(ethanesulfonyl) amino] -2 - [(3'-fluoro [1,1'-biphenyl] -3-yl) methyl] - N-methoxy-N-methylpyrrolidine-1 -carboxamide
[00625] [00625] DIPEA (330 mg) was added to a stirred mixture of (2S, 3S) -3 - ((ethylsulfonyl) amino)) - 2 - ((3'-fluoro [biphenyl] -3-yl) methyl ) pyrrolidine-1-carbonyl (271 mg), N-methoxymethanamine hydrochloride (124 mg) and THF (3 ml) at room temperature. After being stirred at 60 ° C for 2 h, the reaction mixture was cooled to room temperature, quenched with saturated brine and concentrated in vacuo. The residue was purified by silica gel column chromatography (ethyl acetate / hexane) to give a solid. The solid was crystallized from ethyl acetate / hexane to give the title compound (248 mg). 1 H NMR (400 MHz, CDCl3) δ 1.23 (3H, t, J = 7.4 Hz), 1.80-1.92 (1H, m), 2.09-2.23 (1H, m ), 2.86 (2H, q, J = 7.3 Hz), 2.90-2.97 (1H, m), 2.98 (3H, s), 3.14-3.22 (1H, m), 3.42-3.52 (1H, m), 3.56 (3H, s), 3.60-3.70 (1H, m), 3.89- 4.01 (1H, m) , 4.35 (1H, d, J = 8.8 Hz), 4.53-4.66 (1H, m), 6.98-7.07 (1H, m), 7.27-7.45 (6H, m), 7.50 (1H, s). Example 475 (2S, 3S) -3 - [(dimethylsulfamoyl) amino] -2 - [(2-fluoro [1,1'-biphenyl] -3-yl) methyl] - N, N-dimethylpyrrolidine-1-carboxamide
[00626] [00626] A mixture of (2S, 3S) -2- (3-bromo-2-fluorobenzyl) -3- ((dimethylsulfamoyl) amino) -N, N-dimethylpyrrolidine-1-carboxamide (650 mg), phenylboronic acid ( 228 mg), XPhos Pd G3 (18.3 mg), 1M aqueous solution of tripotassium phosphate (4.32 ml) and THF (3.6 ml) was stirred at 70 ° C for 1 h. The mixture was diluted with a saturated aqueous solution of sodium hydrogen carbonate and extracted with ethyl acetate. The organic layer was separated, washed with saturated brine, dried over anhydrous magnesium sulfate and concentrated in vacuo. The residue was purified by column chromatography (NH, ethyl acetate / hexane). The solid was crystallized from ethyl acetate / hexane to give the title compound (560 mg). 1 H NMR (400 MHz, CDCl3) δ 2.05-2.22 (2H, m), 2.71 (6H, s), 2.77 (6H, s),
[00627] [00627] A mixture of (2S, 3S) -2- (3-bromo-2-fluorobenzyl) -3- ((dimethylsulfamoyl) amino) -N, N-dimethylpyrrolidine-1-carboxamide (650 mg), acid (3 , 5-difluorophenyl) boronic acid (296 mg), XPhos Pd G3 (18.3 mg), 1M aqueous solution of tripotassium phosphate (4.32 mL) and THF (3.6 mL) was stirred at 70 ° C for 1 H. The mixture was diluted with a saturated aqueous solution of sodium hydrogen carbonate and extracted with ethyl acetate. The organic layer was separated, washed with saturated brine, dried over anhydrous magnesium sulfate and concentrated in vacuo. The residue was purified by silica gel column chromatography (NH, ethyl acetate / hexane). The solid was crystallized from ethyl acetate / hexane to give the title compound (600 mg). 1 H NMR (400 MHz, CDCl3) δ 2.03-2.21 (2H, m), 2.75 (6H, s), 2.77 (6H, s), 2.83-2.93 (1H , m), 2.94-3.04 (1H, m), 3.20-3.32 (1H, m), 3.54-3.65 (1H, m), 3.81-3.92 (1H, m), 4.30-4.40 (1H, m), 4.52-4.63 (1H, m), 6.76-6.84 (1H, m), 7.02-7 , 10 (2H, m), 7.13-7.20 (1H, m), 7.21-7.25 (1H, m), 7.34-7.41 (1H, m). Example 477 (2S, 3S) -2 - [(3 ', 5'-difluoro [1,1'-biphenyl] -3-yl) methyl] -3 - [(ethanesulfonyl) amino] - N-methoxy-N- methylpyrrolidine-1-carboxamide
[00628] [00628] To a mixture of N - ((2S, 3S) -2 - (((3 ', 5'-difluorobiphenyl-3-yl) methyl) pyrrolidin-3-yl) ethanesulfonamide (500 mg), TEA ( 607 mg) and THF (10 ml) N-methoxy-N-methylcarbamoyl chloride (310 mg) was added at room temperature. The mixture was refluxed for 15 min. The mixture was diluted with THF and the precipitate was
[00629] [00629] A mixture of tert-butyl (2S, 3S) -2- (3-bromo-2-fluorobenzyl) -3- ((cyclopropylsulfonyl) amino) pyrrolidine-1-carboxylate (500 mg), phenylboronic acid (153 mg), XPhos Pd G3 (8.87 mg), 1M aqueous solution of tripotassium phosphate (3.14 ml) and THF (2 ml) was stirred at 70 ° C for 1 h. The mixture was poured into water at room temperature and extracted with ethyl acetate. The organic layer was separated, washed with saturated brine, dried over anhydrous magnesium sulfate and concentrated in vacuo. The residue was purified by silica gel column chromatography (NH, ethyl acetate / hexane) to give the title compound (490 mg). MS: [M + H-Boc] + 375.1. B) 1-fluoro-N - [(2S, 3S) -2 - [(2-fluoro [1,1'-biphenyl] -3-yl) methyl] -1- (2-hydroxy-2-methylpropanoyl) pyrrolidin -3-yl] cyclopropane-1-sulfonamide
[00630] [00630] To a mixture of tert-butyl (2S, 3S) -3 - ((cyclopropylsulfonyl) amino) -2- ((2-fluoro [biphenyl] -3-yl) methyl) pyrrolidine-1-carboxylate (490 mg) and THF (4 ml) 2.6M hexane / n-butylithium solution (1.39 ml) was added
[00631] [00631] A mixture of tert-butyl (2S, 3S) -2- (3-bromo-2-fluorobenzyl) -3- ((cyclopropylsulfonyl) amino) pyrrolidine-1-carboxylate (500 mg), 5-difluorophenyl) boronic acid (248 mg), XPhos Pd G3 (44.3 mg), 1M aqueous solution of tripotassium phosphate (3.14 ml) and THF (2 ml) was stirred at 70 ° C for 2 h. The mixture was poured into water at room temperature and extracted with ethyl acetate. The organic layer was separated, washed with saturated brine, dried over anhydrous magnesium sulfate and concentrated in vacuo. The residue was purified by silica gel column chromatography (NH, ethyl acetate / hexane) to give the title compound (488 mg). MS: [M-H] - 509.2. B) 1-fluoro-N - {(2S, 3S) -1- (2-hydroxy-2-methylpropanoyl) -2 - [(2,3 ', 5'-trifluoro [1,1'-biphenyl] -3 -yl) methyl] pyrrolidin-3-yl} cyclopropane-1-sulfonamide
[00632] [00632] To a mixture of (2S, 3S) -3 - ((cyclopropylsulfonyl) amino) -2- ((2,3 ', 5'-trifluoro [biphenyl] -3-yl) methyl) pyrrolidine-1-carboxylate of tert-butyl (453 mg) and THF (6 ml) was added 2.6M hexane / n-butyllithium solution (1.19 ml) dropwise at -78 ° C. After being stirred at -78 ° C for 30 min, a mixture of N-fluoro-N- (phenylsulfonyl) benzenesulfonamide (699 mg) and THF (12 ml) was added dropwise to the reaction mixture. The mixture was slowly warmed to room temperature and stirred under a nitrogen atmosphere overnight. The mixture was quenched with a saturated aqueous solution of ammonium chloride and extracted with ethyl acetate. The organic layer was separated, washed with water and saturated brine, dried over anhydrous magnesium sulfate and concentrated in vacuo. The residue was purified by silica gel column chromatography (acetate)
[00633] [00633] To a mixture of tert-butyl (2S, 3S) -2 - ((2,3'-difluorobiphenyl-3-yl) methyl) - 3 - ((ethylsulfonyl) amino)) pyrrolidine-1-carboxylate ( 5.69 g) and MeOH (10 mL) 4M ethyl acetate / hydrogen chloride solution (35.5 mL) was added at room temperature. The mixture was stirred at room temperature overnight. The solvent was removed in vacuo and the resulting solid was triturated with diisopropyl ether. The precipitate was collected by
[00634] [00634] A mixture of N - (((2S, 3S) -2 - (((2,3'-difluorobiphenyl-3-yl) methyl) pyrrolidin-3-yl) ethanesulfonamide (4.87 g), DIPEA ( 7.55 g) and THF (50 mL) was stirred at room temperature for 30 min. To the suspension, 1-chloro-2-methyl-1-oxopropan-2-yl acetate (2.31 g) was added dropwise at 0 ° C, and the mixture was stirred at the same temperature for 1 h. To the mixture, water (30 ml), 2-propanol (10 ml) and 4M aqueous lithium hydroxide solution (14.6 ml) were added and the mixture was stirred at room temperature overnight. 4M aqueous lithium hydroxide solution (4.38 mL) was added to the mixture. The mixture was stirred at room temperature for 2 h. The mixture was diluted with saturated brine and extracted with ethyl acetate. The organic layer was separated, dried over anhydrous magnesium sulfate and concentrated in vacuo. The residue was purified by silica gel column chromatography (ethyl acetate / hexane). The residue was crystallized from ethanol / water to give the title compound (4.75 g) as its hydrate. 1 H NMR (400 MHz, CDCl3) δ 1.22 (3H, t, J = 7.2 Hz), 1.33-1.47 (6H, m), 1.80-2.03 (1H, m ), 2.27-2.42 (1H, m), 2.78-2.92 (2H, m), 2.96 (1H, dd, J = 14.4, 5.5 Hz), 3, 13 (1H, dd, J = 14.4, 7.6 Hz), 3.66 (2H, brs), 3.90 (1H, brs), 3.94-4.06 (1H, m), 4 , 55 (1H, brs), 4.73 (1H, brs), 7.04-7.11 (1H, m), 7.16- 7.21 (1H, m), 7.21-7.25 (1H, m), 7.27-7.33 (2H, m), 7.35-7.44 (2H, m). Anal. Calcd for C23H28F2N2O4S · 0.3H2O: C, 58.53; H, 6.11; N, 5.94. Found: C, 58.42; H, 6.35; N, 6.00. Example 483 N - ((2S, 3S) -1- (2-hydroxy-2-methylpropanoyl) -2 - ((2,3 ', 5'-trifluorobiphenyl-3-
[00635] [00635] A mixture of N - ((2S, 3S) -2 - ((2,3 ', 5'-trifluorobiphenyl-3-yl) methyl) pyrrolidin-3-yl) methanesulfonamide hydrochloride (8.5 g) , DIPEA (13.1 g) and THF (81 ml) was stirred at room temperature for 30 min. To the suspension, 1-chloro-2-methyl-1-oxopropan-2-yl acetate (3.99 g) was added dropwise at 0 ° C and stirred at the same temperature overnight. To the mixture, water (53.9 ml) and 4M aqueous lithium hydroxide solution (25.2 ml) were added and the mixture was stirred at room temperature overnight. The mixture was quenched with a saturated aqueous solution of sodium hydrogen carbonate and extracted with ethyl acetate. The extract was washed with saturated brine and passed through a block of silica gel. The solution was purified by silica gel column chromatography (NH, ethyl acetate / hexane). The product obtained was crystallized from ethanol / water to give the title compound (5.27 g) as its hydrate. 1 H NMR (400 MHz, DMSO-d6) δ 1.04-1.19 (6H, m), 1.90-2.07 (1H, m), 2.11-2.23 (1H, m) , 2.59-2.70 (1H, m), 2.85-2.95 (3H, m), 2.95-3.10 (1H, m), 3.69-3.99 (3H, m), 4.50-4.68 (1H, m), 5.00 (1H, s), 7.08-7.18 (1H, m), 7.21- 7.51 (6H, m) . Anal. Calcd for C24H27F3N2O5S · 1.5H2O: C, 53.11; H, 5.67; N, 5.63. Found: C, 53.19; H, 5.65; N, 5.61. Example 484 N - (((2S, 3S) -1- (2-hydroxy-2-methylpropanoyl) -2 - ((2,3 ', 5'-trifluorobiphenyl-3-yl) methyl) pyrrolidin-3-yl) ethanesulfonamide A) N - ((2S, 3S) -2 - ((2,3 ', 5'-trifluorobiphenyl-3-yl) methyl) pyrrolidin-3-yl) ethanesulfonamide hydrochloride
[00636] [00636] To a mixture of tert-butyl (2S, 3S) -2- (3-bromo-2-fluorobenzyl) -3- ((ethylsulfonyl) amino)) pyrrolidine-1-carboxylate (10 g) 3,5-difluorophenyl) boronic acid (5.09 g), tripotassium phosphate (13.7 g), THF (50 ml) and water (30 ml) XPhos Pd G3 (0.273 g) was added at temperature
[00637] [00637] A mixture of N - ((2S, 3S) -2 - ((2,3 ', 5'-trifluorobiphenyl-3-yl) methyl) pyrrolidin-3-yl) ethanesulfonamide hydrochloride (8.81 g) , DIPEA (7.85 g) and THF (100 ml) was stirred at room temperature for 30 min. To the suspension, 1-chloro-2-methyl-1-oxopropan-2-yl acetate (4.00 g) was added dropwise at 0 ° C. After being stirred for 1 h at room temperature, water (10 mL) and 4M aqueous lithium hydroxide solution (25.3 mL) were added to the reaction mixture. After 48 h, the mixture was quenched with saturated aqueous sodium hydrogen carbonate solution, diluted with ethyl acetate, washed with saturated brine, filtered and concentrated in vacuo. The residue was purified by silica gel column chromatography (ethyl acetate) and crystallized from ethyl acetate / hexane to give the title compound (8.71 g). 1 H NMR (400 MHz, CDCl3) δ 1.24 (3H, t, J = 7.3 Hz), 1.39 (3H, s), 1.41 (3H, s), 1.83-2, 03 (1H, m), 2.23-2.43 (1H, m), 2.83-2.97 (3H, m), 3.12 (1H, dd, J = 14.0, 7.5 Hz), 3.58-3.76 (2H, m), 3.84 (1H, brs), 3.91 - 4.07 (1H, m), 4.45-4.63 (1H, m) , 4.67-4.89 (1H, m), 6.77-6.87 (1H, m), 6.99-7.10 (2H, m), 7.16-7.22 (1H, m), 7.26-7.30 (1H, m), 7.37-7.46 (1H, m).
[00638] [00638] N - (((2S, 3S) -1- (2-Hydroxy-2-methylpropanoyl) -2 - ((2,3 ', 5'-trifluorobiphenyl-3-yl) methyl) pyrrolidin-3-yl) ethanesulfonamide (550 mg) was
[00639] [00639] To a mixture of tert-butyl (2S, 3S) -2 - ((2,3'-difluorobiphenyl-3-yl) methyl) - 3 - ((methylsulfonyl) amino)) pyrrolidine-1-carboxylate ( 1.77 g) and ethyl acetate (20 ml) 4M ethyl acetate / hydrogen chloride solution (28.5 ml) was added at room temperature. The mixture was stirred at room temperature for 2 h and then at 60 ° C for 1 h. After evaporation, the solid was collected by filtration with diisopropyl ether to give the title compound (1.44 g). MS: [M + H] + 367.0. B) (2S, 3S) -2 - (((2,3'-difluorobiphenyl-3-yl) methyl) -3- ((methylsulfonyl) amino)) pyrrolidine-1-carbonyl chloride
[00640] [00640] To a mixture of N - ((2S, 3S) -2 - ((2,3'-difluorobiphenyl-3-yl) methyl) pyrrolidin-3-yl) methanesulfonamide hydrochloride (492 mg), bis carbonate (trichloromethyl) (217 mg) and THF (6 ml) DIPEA (316 mg) was added at 0 ° C. After being stirred at room temperature for 30 min, the reaction mixture was concentrated in vacuo. The residue was diluted with ethyl acetate, washed with saturated brine and purified by column chromatography on silica gel (ethyl acetate / hexane) to give the title compound (548 mg). MS: [M-H] - 427.2. C) N - (((2S, 3S) -1- (azetidin-1-ylcarbonyl) -2 - ((2,3'-difluorobiphenyl-3-yl) methyl) pyrrolidin-3-yl) methanesulfonamide
[00641] [00641] Azetidine (209 mg) was added to a stirred mixture of (2S, 3S) -2 - ((2,3'-difluorobiphenyl-3-yl) methyl) -3- ((methylsulfonyl) amino)) pyrrolidine-1-carbonyl (524 mg) and THF (6 ml) at room temperature. After being stirred for 30 min, the reaction mixture was concentrated in vacuo. The residue was diluted with ethyl acetate, washed with saturated brine, dried over anhydrous sodium sulfate, filtered and concentrated in vacuo. The obtained solid was crystallized from ethyl acetate / EtoH to give the title compound (404 mg). 1 H NMR (400 MHz, CDCl3) δ 1.87-2.00 (1H, m), 2.09-2.32 (3H, m), 2.69 (3H, s), 2.91-2 , 99 (1H, m), 3.01-3.10 (1H, m), 3.24-3.41 (2H, m), 3.84 (2H, q, J = 7.8 Hz), 3.90-4.07 (3H, m), 4.53 (1H, q, J = 6.5 Hz), 4.68 (1H, d, J = 6.6 Hz), 7.01-7 , 11 (1H, m), 7.14-7.25 (2H, m), 7.27-7.33 (2H, m), 7.35-7.46 (2H, m). Example 486 (2S, 3S) -2 - ((2,3'-difluorobiphenyl-3-yl) methyl) -3 - ((ethylsulfonyl) amino)) - N, N-dimethylpyrrolidine-1-carboxamide
[00642] [00642] (2S, 3S) -2 - (((2,3'-Difluorobiphenyl-3-yl) methyl) -3- ((ethylsulfonyl) amino)) - N, N-dimethylpyrrolidine-1-carboxamide (200 mg) it was recrystallized from ethyl acetate / hexane to give the title compound (152 mg). 1 H NMR (300 MHz, CDCl3) δ 1.26 (3H, t, J = 7.4 Hz), 1.99-2.26 (2H, m), 2.80 (6H, s), 2, 81-2.96 (3H, m), 2.99-3.12 (1H, m), 3.28 (1H, ddd, J = 10.4, 8.3, 4.4 Hz), 3, 61 (1H, dt, J = 10.4, 7.7 Hz), 3.87-3.98 (1H, m), 4.44 (1H, d, J = 8.3 Hz), 4.50 -4.60 (1H, m), 7.01-7.10 (1H, m), 7.12-7.19 (1H, m), 7.20- 7.31 (3H, m), 7 , 32-7.44 (2H, m). Example 487 (2S, 3S) -3 - ((ethylsulfonyl) amino)) - N, N-dimethyl-2 - ((2,3 ', 5'-trifluorobiphenyl-3-yl) methyl) pyrrolidine-1-carboxamide
[00643] [00643] (2S, 3S) -3 - ((Ethylsulfonyl) amino)) - N, N-dimethyl-2 - ((2,3 ', 5'-
[00644] [00644] A mixture of N - ((2S, 3S) -2 - ((2,3'-difluorobiphenyl-3-yl) methyl) -1- (2-hydroxy-2-methylpropanoyl) pyrrolidin-3-yl) ethanesulfonamide (1.00 g) and diisopropyl ether (15 ml) was stirred at room temperature for 6 days. The precipitate was collected by filtration and dried to give the title compound (0.973 g). 1 H NMR (400 MHz, CDCl3) δ 1.22 (3H, t, J = 7.2 Hz), 1.36-1.46 (6H, m), 1.80-2.03 (1H, m ), 2.28-2.43 (1H, m), 2.76-2.91 (2H, m), 2.96 (1H, dd, J = 14.5, 4.6 Hz), 3, 13 (1H, dd, J = 14.4, 7.2 Hz), 3.66 (2H, brs), 3.89 (1H, brs), 3.94-4.05 (1H, m), 4 , 54 (1H, brs), 4.73 (1H, brs), 7.04-7.11 (1H, m), 7.16- 7.21 (1H, m), 7.21-7.25 (1H, m), 7.27-7.33 (2H, m), 7.35-7.45 (2H, m). mp 89 ° C
[00645] [00645] The compounds of the Examples are shown in the following tables. MS in the tables means actual measured value. The compounds of Examples 2 to 18, 20 to 23, 25, 26, 28 to 63, 65 to 74, 77 to 80, 82 to 87, 90 to 92, 94 to 99, 102 to 115, 118 to 121, 123 to 177, 179 to 205, 207, 208, 211, 212, 215 to 226, 228 to 253, 257, 260, 263 to 265, 267, 268, 270 to 292, 295 to 298, 301, 302, 325 to 327, 329 to 332, 334 to 337, 353 to 361, 363, 365, 367 to 371, 374 to 376, 378 to 386, 388, 390 to 394, 396 to 398, 400, 401, 403, 405, 406, 408 to 416, 418 to 420, 422, 425 to 427, 429, 430, 432 to 434, 436, 438, 440, 442 a
[00646] [00646] To obtain a cell clone that stably expresses human type 2 orexin receptor, the type 2 human orexin receptor cDNA was inserted into the plasmid vector pcDNA3.1 (+) (Invitrogen) and a plasmid DNA for expression of the receptor of human orexin type 2 (pcDNA3.1 (+) / hOX2R) was cloned. Plasmid DNA was introduced into the CHO-dhfr cell by an electroporation method, and cells from the clone expressing the human orexin receptor type 2 were obtained by the
[00647] [00647] CHO cells that forcefully express the human OX2 receptor were seeded in each well of the 384-well black transparent bottom plate (BD Falcon) at 7,500 cells / well, and cultured for one day in a 5% CO2 incubator at 37 ° C. After removing the medium in the cell plate, assay buffer A containing a calcium indicator (HBSS (Thermo Fisher Scientific), 20 mM HEPES (Thermo Fisher Scientific), 0.1% BSA (Wako Pure Chemical Industries, Ltd. or Sigma-Aldrich), 2.5 µg / mL Fluo-4 AM (DOJINDO Chemical), 0.08% Pluronic F127 (DOJINDO Chemical), probable 1.25 mM (DOJINDO Chemical)) were added to 30 µL / well. The plate was kept for 30 min in a 5% CO2 incubator at 37 ° C, and subsequently kept at room temperature for 30 min. A test compound prepared by dilution with assay buffer B (HBSS, 20 mM HEPES, 0.1% BSA) was added at 10 μL / well, and the fluorescence value was measured by FDSSμCELL (Hamamatsu Photonics KK) each second for 1 min, and then every two seconds for 1 min 40 sec. The activity (%) of the test compound was calculated assuming that the change in fluorescence value when DMSO was added instead of the test compound was 0% and the change in fluorescence value when orexin A (human) (PEPTIDE INSTITUTE , INC.) Was added at the final concentration of 10 nM was 100%. The activity of each compound at a concentration of 3 μM was shown in Table 2. As is evident from the results, it was demonstrated that the compound of the present invention has an agonist activity at the type 2 human orexin receptor.
[00648] [00648] Human liver microsomes were purchased from Xenotech, LLC (Lenexa, KS). An incubation mixture consisted of microsomes in 50 mmol / L of phosphate buffer KH2PO4 - K2HPO4 (pH 7.4) and 1 µmol / L of test compound. The concentration of microsomal protein was 0.2 mg / mL. A NADPH generator system (5 mmol / L of MgCl2, 5 mmol / L of glucose-6-phosphate, 0.5 mmol / L of beta-NADP + and 1.5 units / mL of glucose-6-phosphate dehydrogenase) was added to the incubation mixture with half a volume of the reaction mixture to initiate the enzymatic reaction. The reaction was terminated 15 and 30 minutes after the start of the reaction by mixing the reaction mixture with acetonitrile, followed by centrifugation at 2500 rpm for 10 min. The supernatant was subjected to analysis by LC / MS / MS. Metabolic velocity was calculated as the slope of the concentration-time graph. In vitro intrinsic metabolic clearance was calculated by dividing the initial metabolic rate by the concentration of the test compound in the incubation mixture. The results were shown in Table 3. Table 3 Debug Test compound (μL / min / mg) Example 450 78 Example 482 26 Example 483 6 Example 484 23
[00649] [00649] As is evident from the results, the debugging
[00650] [00650] The promoter effects of wakefulness were assessed by measuring the electroencephalogram (EEG), electromyogram (EMG) and electro-oculogram (EOG) in cynomolgus monkeys. Under isoflurane anesthesia (1- 5%, Pfizer Japan Inc., Tokyo, Japan), cynomolgus monkeys (3 to 5 years, Hamri Co., Ltd., Ibaraki, Japan) were surgically implanted with radio-telemetry transmitters (TL10M3 -D70-EEE, Data Sciences International Inc., MN, USA). The EEG electrodes were placed stereotaxically in the parietal area and fixed to the skull with stainless steel screws in contact with the dura mater. The unilateral EOG electrodes were positioned in the upper orbital margin of an eye and fixed with stainless steel screws. Bilateral EMG electrodes were implanted in the rear cervical muscles. After surgery, each monkey received penicillin (100,000 units / head, im, Meiji Seika Pharma Co., Ltd., Tokyo, Japan), buprenorphine (0.02 mg / kg, im, Otsuka Pharmaceutical Co., Ltd., Tokyo , Japan) and prednisolone (1 mg / kg, sc, Kyoritsu Seiyaku Co., Ltd., Tokyo, Japan) daily for one week. After at least a recovery period of one month in domestic cages, the monkeys were accustomed to the recording chamber (an acrylic cage of 60L x 55P x 75A (cm)) located in a soundproof and electrically protected room. After confirming that the monkeys slept enough in the experimental room, the cortical signals from EEG, EMG and EOG were recorded using Dataquest ART software (Data Sciences International Inc., MN, USA). The signals were marked semiautomatically over 20-second periods by a sleep scoring system (SleepSign, Kissei Comtec Co., Ltd., Nagano, Japan). This preliminary score was visually inspected and corrected, if
[00651] [00651] As is evident from the results, the test compounds of the present invention increased the wake time compared to the vehicle treatment group in cynomolgus monkeys. That is, these compounds proved to be effective in the treatment of narcolepsy. Formulation Example 1 (capsule production) 1) compound of Example 1 30 mg 2) crystalline cellulose 10 mg 3) lactose 19 mg 4) magnesium stearate 1 mg total 60 mg
[00652] [00652] 1), 2), 3) and 4) are mixed and placed in a capsule
[00653] [00653] The total quantity of 1), 2), 3) and 30 g of 4) are mixed with water, vacuum dried and sieved. The sieved powder is mixed with 14 g of 4) and 1 g of 5) and the mixture is punctured by a tablet machine. In this way, 1000 tablets are obtained containing 30 mg of the compound of Example 1 per tablet. Industrial applicability
[00654] [00654] The compound of the present invention has a type 2 orexin receptor agonist activity and is useful as an agent for prophylaxis or treatment of narcolepsy.
[00655] [00655] This application is based on patent applications No. 2017-150685 filed on August 3, 2017 and No. 2017-248495 filed on December 25, 2017 in Japan, whose contents are covered in full here.

权利要求:
Claims (8)
[1]
1. Compound, characterized by the fact that it is represented by the formula:
O O 2
B R S N R1 R5 (I)
The R4
N R3 where R1 is (1) a C1-6 alkyl group optionally substituted with 1 to 3 substituents selected from (a) a halogen atom, and (b) a C1-6 alkoxy group, (2) a C3- 6 cycloalkyl optionally substituted with 1 to 3 halogen atoms, or (3) a mono- or di-C1-6 alkylamino group; R2 is a hydrogen atom; R3 is (1) a C1-6 alkoxycarbonyl group, (2) a C1-6 alkylcarbonyl group optionally substituted with 1 to 3 hydroxy groups, (3) a mono- or di-C1-6 alkylcarbamoyl group , (4) an N-C1-6 alkyl-N-C1-6 alkoxy-carbamoyl group, (5) a C3-6 cycloalkyl-carbonyl group (the C3-6 cycloalkyl in the C3-6 cycloalkyl-carbonyl group can be a group of bridged rings) optionally substituted with 1 to 3 substituents selected from (a) a halogen atom,
(b) a C1-6 alkyl group optionally substituted with 1 to 3 halogen atoms, (c) a hydroxy group, (d) a C1-6 alkoxy group, and (e) a cyano group, (6) an oxetanylcarbonyl group , (7) an azetidinylcarbonyl group optionally substituted with 1 to 3 substituents selected from (a) a halogen atom, and (b) a C1-6 alkyl group, or (8) a 5-azaspiro [2.3] hexylcarbonyl group; R4 and R5 are both hydrogen atoms; ring A is (1) a pyrrolidine ring, or (2) a piperidine ring; and ring B is (1) a benzene ring additionally substituted with a phenyl group optionally substituted with 1 to 3 substituents selected from (i) a halogen atom, and (ii) a C1-6 alkyl group, and optionally substituted with a halogen atom, (2) a pyridine ring additionally substituted with a phenyl group optionally substituted with 1 to 3 halogen atoms, (3) a thiazole ring additionally substituted with a phenyl group optionally substituted with 1 to 3 halogen atoms, ( 4) a piperidine ring additionally substituted with a phenyl group or a salt thereof.
[2]
A compound or salt according to claim 1, characterized in that R1 is (1) a C1-6 alkyl group, (2) a C3-6 cycloalkyl group optionally substituted with 1 to 3 halogen atoms, or ( 3) a mono- or di-C 1-6 alkylamino group; R2 is a hydrogen atom; R3 is (1) a C1-6 alkylcarbonyl group optionally substituted with 1 to 3 hydroxy groups, (2) a mono- or di-C1-6 alkylcarbamoyl group, (3) an N-C1-6 alkyl group -N-C1-6 alkoxy carbamoyl, or (4) an azetidinylcarbonyl group; R4 and R5 are both hydrogen atoms; ring A is a pyrrolidine ring; and ring B is a benzene ring additionally substituted with a phenyl group optionally substituted with 1 to 3 halogen atoms, and optionally substituted additionally with a halogen atom.
[3]
Compound or salt according to claim 1, characterized in that it is N - ((2S, 3S) -2 - ((2,3'-difluorobiphenyl-3-yl) methyl) - 1- (2-hydroxy -2-methylpropanoyl) pyrrolidin-3-yl) ethanesulfonamide or a salt thereof.
[4]
Compound or salt according to claim 1, characterized in that it is N - ((2S, 3S) -1- (2-hydroxy-2-methylpropanoyl) -2- ((2,3 ', 5'- trifluorobiphenyl-3-yl) methyl) pyrrolidin-3-yl) methanesulfonamide or a salt thereof.
[5]
Compound or salt according to claim 1, characterized in that it is N - ((2S, 3S) -1- (2-hydroxy-2-methylpropanoyl) -2- ((2,3 ', 5'- trifluorobiphenyl-3-yl) methyl) pyrrolidin-3-yl) ethanesulfonamide or a salt thereof.
[6]
6. Compound or salt according to claim 1, characterized in that it is selected from (1) N - ((2S, 3S) -1- (azetidin-1-ylcarbonyl) -2 - ((2,3'- difluorobiphenyl-3-yl) methyl) pyrrolidin-3-yl) methanesulfonamide, (2) N - ((2S, 3S) -1- (azetidin-1-ylcarbonyl) -2 - ((3 ', 5'- difluorobiphenyl- 3-yl) methyl) pyrrolidin-3-yl) ethanesulfonamide, (3) N - ((2S, 3S) -1- (azetidin-1-ylcarbonyl) -2- (biphenyl-3-ylmethyl) pyrrolidin-3-yl ) ethanesulfonamide, (4) N - ((2S, 3S) -1- (azetidin-1-ylcarbonyl) -2 - ((2,3'-difluorobiphenyl-3-yl) methyl) pyrrolidin-3-yl) ethanesulfonamide, (5) (2S, 3S) -2 - ((2,3'-difluorobiphenyl-3-yl) methyl) -3- ((ethylsulfonyl) amino)) - N, N-dimethylpyrrolidine-1-carboxamide, (6) (2S, 3S) -2 - ((2,3'-difluorobiphenyl-3-yl) methyl) -3- ((dimethylsulfamoyl) amino) -N, N-dimethylpyrrolidine-1-carboxamide, (7) (2S, 3S ) -3 - ((ethylsulfonyl) amino)) - N, N-dimethyl-2 - (((2,3 ', 5'-trifluorobiphenyl-3-yl) methyl) pyrrolidine-1-carboxamide, (8) (2S, 3S) -2- (biphenyl-3-ylmethyl) -3 - ((ethylsulfonyl) amino)) - N- methoxy-N-methylpyrrolidine-1-carboxamide, (9) N - [(2S, 3S) -2 - [(2,3'-difluoro [1,1'-biphenyl] -3-yl) methyl] -1- (2-hydroxy-2-methylpropanoyl) pyrrolidin-3-yl] -1-fluorocyclopropane-1 -sulfonamide, (10) N - {(2S, 3S) -1- (azetidine-1-carbonyl) -2 - [(2-fluoro [1,1'-biphenyl] -3-yl) methyl] pyrrolidin-3 -yl} ethanesulfonamide, (11) (2S, 3S) -3 - [(ethanesulfonyl) amino] -2 - [(3'-fluoro [1,1'-biphenyl] -3-yl) methyl] -N-methoxy -N-methylpyrrolidine-1-carboxamide,
(12) (2S, 3S) -3 - [(dimethylsulfamoyl) amino] -2 - [(2-fluoro [1,1'-biphenyl] -3-yl) methyl] -N, N-dimethylpyrrolidine-1-carboxamide , (13) (2S, 3S) -3 - [(dimethylsulfamoyl) amino] -N, N-dimethyl-2- [(2,3 ', 5'-trifluoro [1,1'-biphenyl] -3-yl ) methyl] pyrrolidine-1-carboxamide, and (14) (2S, 3S) -2 - [(3 ', 5'-difluoro [1,1'-biphenyl] -3-yl) methyl] -3- [( ethanesulfonyl) amino] -N-methoxy-N-methylpyrrolidine-1-carboxamide or a salt thereof.
[7]
7. Medicament, characterized by the fact that it comprises the compound or salt as defined in claim 1.
[8]
8. Compound or salt according to claim 1, characterized by the fact that it is for use in the prophylaxis or treatment of narcolepsy.

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引用文献:

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公开号 | 申请日 | 公开日 | 申请人 | 专利标题

---

---

JP2001500852A|1996-08-27|2001-01-23|プレーシスファーマスーティカルズインコーポレイテッド|Modulator of aggregation of β-amyloid peptide containing D-amino acids|

---

US6166193A|1997-07-25|2000-12-26|Board Of Regents, University Of Texas System|Polynucleotides encoding MY1 receptor|

---

WO2001000663A2|1999-06-28|2001-01-04|Oklahoma Medical Research Foundation|Catalytically active recombinant memapsin and methods of use thereof|

---

AU6615300A|1999-07-30|2001-02-19|Board Of Trustees Of The Leland Stanford Junior University|Hypocretin and hypocretin receptors in regulation of sleep and related disorders|

---

US6204245B1|1999-09-17|2001-03-20|The Regents Of The University Of California|Treatment of narcolepsy with immunosuppressants|

---

WO2001074162A1|2000-04-04|2001-10-11|The Regents Of The University Of California|Treatment of sleep disorders with hypocretin-1|

---

US7112566B1|1999-09-17|2006-09-26|The Regents Of The University Of California|Systemic administration of Hypocretin-1|

---

US20080260744A1|2002-09-09|2008-10-23|Omeros Corporation|G protein coupled receptors and uses thereof|

---

JP2006513702A|2002-09-09|2006-04-27|ヌラインコーポレーティッド|G protein-coupled receptor and use thereof|

---

DK1572133T3|2002-12-13|2008-07-14|Janssen Pharmaceutica Nv|Method for identifying modulators of the human orexin-2 receptor|

---

WO2009049215A1|2007-10-10|2009-04-16|Wake Forest University Health Sciences|Methods to reduce the effects of sleep deprivation|

---

EP2092825A1|2008-02-21|2009-08-26|Bayer CropScience Aktiengesellschaft|Herbicidal combinations comprising a herbicide of the class of the diamino-s-triazines|

---

JP5976011B2|2011-04-05|2016-08-23|武田薬品工業株式会社|Sulfonamide derivatives and uses thereof|

---

WO2014170343A1|2013-04-15|2014-10-23|Icm |Depolarizing agents and nicotinic acetylcholine receptor modulators for treating dopaminergic-related disorders|

---

US20160250224A1|2013-09-24|2016-09-01|The Board Of Regents Of The University Of Texas System|Orexin-control of bone formation and loss|

---

CA2930693A1|2013-11-15|2015-05-21|The Board Of Trustees Of The Leland Stanford Junior Unversity|Methods of treating heart failure with agonists of hypocretin receptor 2|

---

KR20160105812A|2013-12-12|2016-09-07|고쿠리쯔 다이가쿠 호징 츠쿠바 다이가쿠|Sulfonamide derivative or pharmaceutically acceptable acid addition salt thereof|

---

WO2015147240A1|2014-03-28|2015-10-01|国立大学法人筑波大学|Prophylactic and therapeutic agent for septicemia|

---

JP6746107B2|2015-02-19|2020-08-26|国立大学法人 筑波大学|Sulfonamide derivative or pharmaceutically acceptable acid addition salt thereof|

---

CA2989146A1|2015-06-12|2016-12-15|Board Of Regents, The University Of Texas System|Sulfonamide derivative and pharmaceutically acceptable acid addition salt thereof|

---

US10980755B2|2015-09-10|2021-04-20|The Regents Of The University Of California|LRH-1 modulators|

---

TWI594181B|2015-12-29|2017-08-01|宏正自動科技股份有限公司|Method for increasing the compatibility of displayport|

---

SG11201806429PA|2016-02-04|2018-08-30|Takeda Pharmaceuticals Co|Substituted piperidine compound and use thereof|

---

EP3594202B1|2017-03-08|2021-08-11|Takeda Pharmaceutical Company Limited|Substituted pyrrolidine compound and use thereof|

---

JP6957598B2|2017-03-08|2021-11-02|武田薬品工業株式会社|Substituted pyrrolidine compounds and their uses|

---

US20200385346A1|2017-08-03|2020-12-10|Takeda Pharmaceutical Company Limited|Heterocyclic compound and application thereof|US20210269420A1|2018-06-29|2021-09-02|Takeda Pharmaceutical Company Limited|Heterocyclic compound and application thereof|

---

US20210198240A1|2018-06-29|2021-07-01|Takeda Pharmaceutical Company Limited|Heterocyclic compound and use thereof|

---

EP3896060A1|2018-12-12|2021-10-20|Takeda Pharmaceutical Company Limited|Heterocyclic compound|

---

JPWO2020122092A1|2018-12-12|2021-10-21|武田薬品工業株式会社|Heterocyclic compound|

---

SG11202106791XA|2019-01-31|2021-07-29|Takeda Pharmaceuticals Co|Heterocyclic compound and use thereof|

---

TW202045476A|2019-02-13|2020-12-16|美商默沙東藥廠|5-alkyl pyrrolidine orexin receptor agonists|

---

EP3923933A1|2019-02-13|2021-12-22|Merck Sharp & Dohme Corp.|Pyrrolidine orexin receptor agonists|

---

WO2021100730A1|2019-11-19|2021-05-27|武田薬品工業株式会社|Method for producing pyrrolidine compound|

---

US20210155636A1|2019-11-25|2021-05-27|Alkermes, Inc.|Substituted Macrocyclic Compounds and Related Methods of Treatment|

---

TW202134229A|2019-11-27|2021-09-16|日商大日本住友製藥股份有限公司|Cycloalkylurea derivative|

---

WO2021166934A1|2020-02-18|2021-08-26|武田薬品工業株式会社|Production method for pyrrolidine compound|

---

WO2022040070A1|2020-08-18|2022-02-24|Merck Sharp & Dohme Corp.|Bicycloheptane pyrrolidine orexin receptor agonists|

法律状态:
2021-11-03| B350| Update of information on the portal [chapter 15.35 patent gazette]|

优先权:

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申请号 | 申请日 | 专利标题

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JP2017150685|2017-08-03|

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JP2017-150685|2017-08-03|

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JP2017248495|2017-12-25|

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JP2017-248495|2017-12-25|

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PCT/JP2018/029696|WO2019027058A1|2017-08-03|2018-08-02|Heterocyclic compound and use thereof|

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