HK1260831B - Novel biphenyl compound or salt thereof - Google Patents

Description

Novel biphenyl compound or its salt

Field of the Invention

CROSS-REFERENCE TO RELATED APPLICATIONS

This application claims the benefit of Japanese Patent Application No. 2015-232009, filed on November 27, 2015, and Japanese Patent Application No. 2016-117454, filed on June 13, 2016, which are hereby incorporated by reference herein in their entirety.

Histone methylation is one of the epigenetic mechanisms that regulate gene expression. Histone methylation regulates various processes, including cell maintenance, growth, and differentiation.

LSD1 (KDM1A) is an enzyme that regulates histone methylation modification. It is a FAD (flavin adenine dinucleotide)-dependent histone demethylase that primarily demethylates lysine residues at position 4 (K4) and lysine residues at position 9 (K9) of histone H3 (Non-Patent Literature (NPL) 1). With these functions, LSD1 is believed to positively or negatively regulate the transcription of various genes and regulate stem cell self-renewal and cell differentiation in various normal tissues.

In general, abnormalities in cell self-renewal or differentiation are thought to lead to cell carcinogenesis. Therefore, abnormal control of LSD1, which plays a key role in these processes, may lead to cell carcinogenesis. In fact, there are many reports on the correlation between LSD1 overexpression and its prognosis in various solid and blood cancers (NPL 2). In addition, in cell lines from cancer or non-clinical models, LSD1 inhibition has been reported to have led to cell differentiation induction, growth inhibition and in vivo anti-tumor effects (NPL 3 and NPL 4), which strongly suggests that LSD1 serves as one of the important target molecules in cancer treatment. These LSD1-involved cancers such as SCLC and AML have extremely short lifespans, and existing treatments cannot achieve satisfactory therapeutic effects.

Therefore, LSD1 inhibitory drugs are expected to provide effective therapeutic means based on novel mechanisms for intractable cancers for which there are currently no treatments.

In addition, according to some reports, LSD1, which is involved in neuronal programs and functions, may also serve as a target in the treatment of diseases other than cancer, such as Alzheimer's disease, Huntington's disease, Rett syndrome, and other cranial nerve disorders (NPL 2); herpes virus infection in which LSD1 function is implicated (NPL 5); and sickle cell disease (NPL 6).

Therefore, an object of the present invention is to provide novel compounds that exhibit selective and potent inhibitory activity against LSD1 and are useful for treating cancer and other LSD1-related diseases.

Reference List

Patent Literature

PTL 1: WO 2015/089192

PTL 2: WO 2015/168466

PTL 3: WO 2015/103060

PTL 4: WO 2010/077624

Non-patent literature

NPL 1: Biochim.Biophys.Acta,1829(10),pp.981-986(2013)

NPL 2: Epigenomics,7(4),pp.609-626(2015)

NPL 3: Cancer Cell,21(4),pp.473-487(2012)

NPL 4: Cancer Cell,28(1),pp.57-69(2015)

NPL 5: Sci.Transl.Med.,6(265),265ra169(2014)

NPL 6: Nat.Med.,19(3),pp.291-294(2013)

Summary of the Invention

Technical issues

The compound of the present invention is a novel biphenyl compound having excellent LSD1 inhibitory activity. More specifically, as shown in formula (I), the compound of the present invention is a novel biphenyl compound comprising:

(i) a benzene ring having an amide or thioamide group formed together with a cyclic amino group,

(ii) a benzene ring having a 4-nitro or 4-cyano group at the meta position relative to the amide or thioamide group,

(iii) The benzene ring further has an unsaturated hydrocarbon ring or an unsaturated heterocyclic ring at the para position relative to the amide or thioamide group.

PTL 1 and PTL 2 disclose substituted heterocyclic compounds as compounds having LSD1 inhibitory activity. Specifically, PTL 1 and PTL 2 disclose, for example, cyanobenzene-containing pyrimidine compounds, cyanobenzene-containing pyrazole compounds, or cyanobenzene-containing 6-oxo-1,6-dihydro-pyrimidine compounds. However, all of these compounds are significantly different from the compounds of the present invention because the compounds of the present invention contain a benzene ring having an amide or thioamide group formed together with a cyclic amino group, while the compounds of PTL 1 and PTL 2 contain a pyrimidine ring, a pyrazole ring, a 6-oxo-1,6-dihydro-pyrimidine ring, and the like. As shown in the following Comparative Examples, neither the compounds of the present invention whose benzene rings are substituted with a pyrimidine ring or a pyrazole ring (Comparative Examples 1, 2, and 3) nor the compound without an amide or thioamide group formed together with a cyclic amino group (Comparative Example 1) exhibited LSD1 inhibitory activity. Even when a phenyl compound has an amide or thioamide group formed together with a cyclic amino group, the compound does not exhibit LSD1 inhibitory activity unless it has an unsaturated hydrocarbon ring or an unsaturated heterocyclic ring at the para position relative to the amide or thioamide group (Comparative Example 4).

In addition, for example, PTL 3 also discloses compounds in which the phenyl moiety of the compound of the present invention is a 5-membered heterocyclic ring; however, PTL 3 does not disclose LSD1 inhibitory activity, and the compound of PTL 3 does not have LSD1 inhibitory activity, as described above with reference to the Comparative Examples. Furthermore, the compound specifically disclosed in this international publication, namely, a compound in which the 4-nitro- or 4-cyano-containing benzene ring of the compound of the present invention is substituted with a 4-trifluoromethyl-containing benzene ring, does not have LSD1 inhibitory activity, as shown in Comparative Example 5 below.

Furthermore, for example, PTL 4 discloses that a cyclic amino group and a carbonyl group, when combined, form a benzene ring having an amide group; however, PTL 4 does not disclose LSD1 inhibitory activity. Furthermore, the compound of PTL 4 is significantly different from the compound of the present invention because the moiety corresponding to R3 in formula (I) is a heterocyclic ring bonded directly to the cyclic amino group or via a linker. As shown in the following comparative examples, the compound in which a heterocyclic ring is bonded to the cyclic amino group (Comparative Example 6) does not exhibit LSD1 inhibitory activity.

Problem Solving

To address the above-mentioned issues, the present inventors conducted extensive research and discovered that the biphenyl compound of the present invention has excellent LSD1 inhibitory activity and cancer cell growth inhibitory activity, low toxicity, and can be used as an oral pharmaceutical preparation for treating cancer. This led to the completion of the present invention.

More specifically, the present invention provides the following:

Item 1. A compound represented by formula (I) or a salt thereof:

in,

Ring A represents a monocyclic, bridged or spirocyclic nitrogen-containing saturated heterocyclic group,

Ring B represents a monocyclic or bicyclic unsaturated hydrocarbon group or a monocyclic or bicyclic unsaturated heterocyclic group which may be substituted with oxo,

X represents O or S,

R1 represents a nitro group or a cyano group,

R2 represents a halogen atom,

R3 represents a substituted or unsubstituted amino group, a C1-C6 alkyl group, a halogen atom, a cyano group, an oxo group, a hydroxyl group, a carbamoyl group, a sulfo group, a C1-C6 alkoxy group or an amino (C1-C6 alkyl group),

R4 represents a halogen atom, a hydroxyl group, a nitro group, a cyano group, an amino group, a carboxyl group, a (C2-C7 acyl)amino group, a (C2-C7 acyl)oxy group, a substituted or unsubstituted C1-C8 alkyl group, a substituted or unsubstituted C2-C6 alkenyl group, a substituted or unsubstituted C1-C6 alkoxy group, a substituted or unsubstituted C3-C7 cycloalkyl group, a mono- or di-(C1-C6 alkyl)amino group, a substituted or unsubstituted carbamoyl group, a substituted or unsubstituted C2-C6 alkynyl group, a substituted or unsubstituted (C1-C6 alkyl)carbonyl group, a substituted or unsubstituted 4- to 14-membered nitrogen-containing saturated heterocyclic group, or a substituted or unsubstituted C6-C14 aromatic hydrocarbon group,

l is an integer from 0 to 2,

m is an integer from 0 to 2, and

n is an integer from 0 to 5,

wherein when l is 2, two R2 may be the same or different, when m is 2, two R3 may be the same or different, and when n is 2-5, 2 to 5 R4 may be the same or different.

Item 2. The compound or salt thereof according to Item 1, which satisfies the following conditions in formula (I):

Ring A represents a monocyclic, bridged or spirocyclic 4- to 14-membered nitrogen-containing saturated heterocyclic group having 1 to 3 nitrogen atoms, 0 to 1 sulfur atoms and 0 to 2 oxygen atoms as heteroatoms,

Ring B represents a monocyclic or bicyclic 5- to 14-membered unsaturated hydrocarbon group or a monocyclic or bicyclic 5- to 14-membered unsaturated heterocyclic group which may be substituted with oxo, the heterocyclic group having 0 to 4 nitrogen atoms, 0 to 2 sulfur atoms and 0 to 3 oxygen atoms as heteroatoms and having at least one of nitrogen, sulfur and oxygen,

R3 represents amino, mono- or di-(C1-C6 alkyl)amino, (C3-C7 cycloalkyl)amino, or C1-C6 alkyl, and

R4 represents a halogen atom, a nitro group, a cyano group, a carboxyl group, a substituted or unsubstituted C1-C8 alkyl group, a substituted or unsubstituted C2-C6 alkenyl group, a substituted or unsubstituted C1-C6 alkoxy group, a substituted or unsubstituted C3-C7 cycloalkyl group, a mono- or di-(C1-C6 alkyl)amino group, or a substituted or unsubstituted carbamoyl group,

wherein when at least one R4 represents a substituted C1-C8 alkyl group, a substituted C2-C6 alkenyl group, a substituted C1-C6 alkoxy group, a substituted C3-C7 cycloalkyl group or a substituted carbamoyl group, the substituent is a halogen atom, a carboxyl group, a C1-C6 alkoxy group, a hydroxyl group, a C1-C6 alkyl group which may be substituted with a hydroxyl group, a monocyclic 5- to 10-membered unsaturated hydrocarbon group, a carbamoyl group which may be substituted with a C1-C6 alkyl group or a monocyclic 5- to 10-membered unsaturated hydrocarbon group, a (C2-C7 acyl)oxy group, an amino group which may be substituted with a C1-C6 alkyl group or a C2-C7 acyl group, a C3-C7 cycloalkyl group which may be substituted with a hydroxyl group, or a (C1-C6 alkoxy) (C1-C6 alkyl) group, and when two or more substituents are present, the substituents may be the same or different.

Item 3. The compound or salt thereof according to Item 1 or 2, which satisfies the following conditions in formula (I):

Ring A represents pyrrolidinyl, piperidinyl, piperazinyl, azepanyl, diazepanyl,

2,7-diazaspiro[3.4]octyl, 3,7-diazaspiro[3.4]octyl, 2,7-diazaspiro[3.5]nonyl, 2,8-diazaspiro[3.5]nonyl, 3,7-diazaspiro[3.5]nonyl, 3,8-diazaspiro[4.4]nonyl, 3,8-diazaspiro[4.5]decyl, or 9-oxa-diazaspiro[3.5]nonyl, and

R3 represents amino, methylamino, ethylamino, isopropylamino, dimethylamino, cyclobutylamino, or methyl, wherein when there are two or more R3, R3 may be the same or different.

Item 4. The compound or salt thereof according to any one of Items 1 to 3, which satisfies the following conditions in formula (I):

R4 represents a halogen atom; a nitro group; a cyano group; a carboxyl group; a C1-C8 alkyl group which may be substituted by a halogen atom, an amino group, a hydroxyl group, a carboxyl group, a carbamoyl group, a (C1-C6 alkyl)carbamoyl group, a (C1-C6 alkyl)carbonylamino group, a C1-C6 alkoxy group, a (C1-C6 alkyl)carbonyl group, a C3-C7 cycloalkyl group, a hydroxyl group (C3-C7 cycloalkyl group) or a (C1-C6 alkyl)carbonyloxy group; a C2-C6 alkenyl group; a C1-C8 alkyl group which may be substituted by a hydroxyl group or a monocyclic 5- to 10-membered non-isocyanate group. C1-C6 alkoxy substituted with a saturated hydrocarbon group; C3-C7 cycloalkyl which may be substituted with a carbamoyl group substituted with hydroxy, hydroxy(C1-C4 alkyl), (C1-C4 alkoxy)(C1-C4 alkyl), hydroxy(C3-C7 cycloalkyl) or (C6-C14 aromatic hydrocarbon group); mono- or di-(C1-C6 alkyl)amino; or a carbamoyl group which may be substituted with a C1-C6 alkyl group, wherein when two or more R4 are present, R4 may be the same or different.

Item 5. The compound represented by formula (I) or a salt thereof according to any one of Items 1 to 4,

in

Ring A represents pyrrolidinyl, piperidinyl, piperazinyl, azepanyl, diazepanyl,

2,7-diazaspiro[3.4]octyl, 3,7-diazaspiro[3.4]octyl, 2,7-diazaspiro[3.5]nonyl, 2,8-diazaspiro[3.5]nonyl, 3,7-diazaspiro[3.5]nonyl, 3,8-diazaspiro[4.4]nonyl, 3,8-diazaspiro[4.5]decyl, or 9-oxa-diazaspiro[3.5]nonyl,

Ring B represents phenyl, naphthyl, pyridyl, pyrazolopyridyl, pyrazolopyrimidinyl, indolyl, dihydroindolinyl, 2-oxo-dihydroindolinyl, indazolyl, benzimidazolyl, benzisoxazolyl, benzothiazolyl, benzotriazolyl, imidazopyridyl, quinolyl, isoquinolyl, quinazolinyl, quinoxalinyl, phthalazinyl, 2-oxo-2,3-dihydrobenzo[d]oxazolyl, 1,3-dihydroisobenzofuranyl, dihydrobenzoxazinyl, benzodioxolyl, dihydrobenzodioxynyl, or 2-oxo-2,3-dihydrobenzo[d]thiazolyl,

X represents O or S,

R1 represents a nitro group or a cyano group,

R2 represents fluorine and is present in the ortho position relative to R1 on the phenyl group,

R3 represents amino, methylamino, ethylamino, isopropylamino, dimethylamino, cyclobutylamino, or methyl, wherein when there are two or more R3, R3 may be the same or different, and

R4 represents a fluorine atom, a chlorine atom, a bromine atom, an iodine atom, a nitro group, a cyano group, a carboxyl group, a methyl group, an ethyl group, an n-propyl group, an isopropyl group, a tert-butyl group, a difluoromethyl group, a trifluoromethyl group, a fluoroethyl group, an aminoethyl group, a hydroxymethyl group, a hydroxyethyl group, a hydroxypropyl group, a hydroxydimethylethyl group, a hydroxymethylpropyl group, a hydroxymethylbutyl group, a hydroxyethylbutyl group, a carboxymethyl group, a carbamoylmethyl group, a methylcarbamoylmethyl group, a dimethylcarbamoylmethyl group, an acetylaminoethyl group, a methoxyethyl group, a hydroxycyclopropylmethyl group, a hydroxycyclopropylmethyl group R4, methylamino, methylcarbamoyl, or dimethylcarbamoyl, wherein when two or more R4 are present, R4 may be the same or different, and n is an integer from 0 to 3, wherein when n is 2 to 3, 2 to 3 R4 may be the same or different.

Item 6. The compound according to any one of the following (1) to (24) or the salt of the compound according to any one of the following (1) to (24);

(1) 4-[5-[(3-exo)-3-amino-8-azabicyclo[3.2.1]octane-8-carbonyl]-2-[2-fluoro-4-(2-hydroxy-2-methyl-propyl)phenyl]phenyl]-2-fluoro-benzonitrile,

(2) 4-[5-[(3S)-3-aminopyrrolidine-1-carbonyl]-2-[2-fluoro-4-(2-hydroxy-2-methyl-propyl)phenyl]phenyl]-2-fluoro-benzonitrile,

(3) 4-[5-[(3-endo)-3-amino-8-azabicyclo[3.2.1]octane-8-carbonyl]-2-[2-fluoro-4-(2-hydroxy-2-methyl-propyl)phenyl]phenyl]-2-fluoro-benzonitrile,

(4) (S)-5'-(3-aminopyrrolidine-1-carbonyl)-3-fluoro-2'-(6-fluoro-1-(2-hydroxy-2-methylpropyl)-1H-indol-5-yl)-[1,1'-biphenyl]-4-carbonitrile,

(5) 5'-((3-endo)-3-amino-8-azabicyclo[3.2.1]octane-8-carbonyl)-2'-(6,7-difluoro-1-(2-hydroxy-2-methylpropyl)-1H-benzo[d][1,2,3]triazol-5-yl)-3-fluoro-[1,1'-biphenyl]-4-carbonitrile,

(6) 5'-((1S,2S,4R)-rel-2-amino-7-azabicyclo[2.2.1]heptane-7-carbonyl)-2",3-difluoro-4"-(2-hydroxy-2-methylpropyl)-[1,1':2',1"-terphenyl]-4-carbonitrile-isomer-B,

(7) 5'-((1S,2S,4R)-rel-2-amino-7-azabicyclo[2.2.1]heptane-7-carbonyl)-2'-(6,7-difluoro-1-methyl-1H-benzo[d][1,2,3]triazol-5-yl)-3-fluoro-[1,1'-biphenyl]-4-carbonitrile-isomer-B,

(8) 5'-((1S,2S,4R)-rel-2-amino-7-azabicyclo[2.2.1]heptane-7-carbonyl)-3-fluoro-2'-(6-fluoro-1-(2-hydroxy-2-methylpropyl)-1H-indazol-5-yl)-[1,1'-biphenyl]-4-carbonitrile-isomer-B,

(9) 5'-((1S,2S,4R)-rel-2-amino-7-azabicyclo[2.2.1]heptane-7-carbonyl)-2'-(6,7-difluoro-1-(2-hydroxy-2-methylpropyl)-1H-benzo[d][1,2,3]triazol-5-yl)-3-fluoro-[1,1'-biphenyl]-4-carbonitrile-isomer-B,

(10) 5'-((1S,2S,4R)-rel-2-amino-7-azabicyclo[2.2.1]heptane-7-carbonyl)-2'-(6,7-difluoro-1-(2-hydroxy-2-methylpropyl)-1H-benzo[d][1,2,3]triazol-5-yl)-3-fluoro-[1,1'-biphenyl]-4-carbonitrile,

(11) 5'-((1S,2S,4R)-rel-2-amino-7-azabicyclo[2.2.1]heptane-7-carbonyl)-2'-(7-chloro-6-fluoro-1-(2-hydroxy-2-methylpropyl)-1H-benzo[d][1,2,3]triazol-5-yl)-3-fluoro-[1,1'-biphenyl]-4-carbonitrile-isomer-X,

(12) 5'-((1S,2S,4R)-rel-2-amino-7-azabicyclo[2.2.1]heptane-7-carbonyl)-2'-(7-chloro-6-fluoro-1-(2-hydroxy-2-methylpropyl)-1H-benzo[d][1,2,3]triazol-5-yl)-3-fluoro-[1,1'-biphenyl]-4-carbonitrile,

(13) 5'-((1S,2S,4R)-rel-2-amino-7-azabicyclo[2.2.1]heptane-7-carbonyl)-2'-(1-(2-ethyl-2-hydroxybutyl)-6,7-difluoro-1H-benzo[d][1,2,3]triazol-5-yl)-3-fluoro-[1,1'-biphenyl]-4-carbonitrile-isomer-X,

(14) 5'-((1S,2S,4R)-rel-2-amino-7-azabicyclo[2.2.1]heptane-7-carbonyl)-2'-(1-(2-ethyl-2-hydroxybutyl)-6,7-difluoro-1H-benzo[d][1,2,3]triazol-5-yl)-3-fluoro-[1,1'-biphenyl]-4-carbonitrile,

(15) (S)-5'-(3-aminopyrrolidine-1-carbonyl)-3-fluoro-2'-(5-fluoro-3-(2-hydroxy-2-methylpropyl)benzo[d]isoxazol-6-yl)-[1,1'-biphenyl]-4-carbonitrile,

(16) 5'-((1S,2S,4R)-rel-2-amino-7-azabicyclo[2.2.1]heptane-7-carbonyl)-2'-(7-(difluoromethyl)-6-fluoro-1-(2-hydroxy-2-methylpropyl)-1H-benzo[d][1,2,3]triazol-5-yl)-3-fluoro-[1,1'-biphenyl]-4-carbonitrile-isomer-X,

(17) 5-(5-((1S,2S,4R)-rel-2-amino-7-azabicyclo[2.2.1]heptane-7-carbonyl)-4'-cyano-3'-fluoro-[1,1'-biphenyl]-2-yl)-6-fluoro-1-(2-hydroxy-2-methylpropyl)-1H-benzo[d][1,2,3]triazole-7-carbonitrile-isomer-X,

(18) 5'-((1S,2S,4R)-rel-2-amino-7-azabicyclo[2.2.1]heptane-7-carbonyl)-2'-(7-(difluoromethyl)-6-fluoro-1-(2-hydroxy-2-methylpropyl)-1H-benzo[d][1,2,3]triazol-5-yl)-3-fluoro-[1,1'-biphenyl]-4-carbonitrile,

(19) 5'-((3-endo)-3-amino-8-azabicyclo[3.2.1]octane-8-carbonyl)-2'-(7-chloro-6-fluoro-1-((1-hydroxycyclobutyl)methyl)-1H-benzo[d][1,2,3]triazol-5-yl)-3-fluoro-[1,1'-biphenyl]-4-carbonitrile,

(20) 5'-((3-endo)-3-amino-8-azabicyclo[3.2.1]octane-8-carbonyl)-2'-(7-(difluoromethyl)-6-fluoro-1-((1-hydroxycyclobutyl)methyl)-1H-benzo[d][1,2,3]triazol-5-yl)-3-fluoro-[1,1'-biphenyl]-4-carbonitrile,

(21) 5-(5-((1S,2S,4R)-rel-2-amino-7-azabicyclo[2.2.1]heptane-7-carbonyl)-4'-cyano-3'-fluoro-[1,1'-biphenyl]-2-yl)-6-fluoro-1-((1-hydroxycyclobutyl)methyl)-1H-benzo[d][1,2,3]triazole-7-carbonitrile-isomer-X,

(22) 5-(5-((1S,2S,4R)-rel-2-amino-7-azabicyclo[2.2.1]heptane-7-carbonyl)-4'-cyano-3'-fluoro-[1,1'-biphenyl]-2-yl)-6-fluoro-1-((1-hydroxycyclobutyl)methyl)-1H-benzo[d][1,2,3]triazole-7-carbonitrile,

(23) 5'-((1S,2S,4R)-rel-2-amino-7-azabicyclo[2.2.1]heptane-7-carbonyl)-2'-(7-bromo-6-fluoro-1-(2-hydroxy-2-methylpropyl)-1H-benzo[d][1,2,3]triazol-5-yl)-3-fluoro-[1,1'-biphenyl]-4-carbonitrile-isomer-X,

(24) 5′-((1S,2S,4R)-rel-2-amino-7-azabicyclo[2.2.1]heptane-7-carbonyl)-2′-(7-bromo-6-fluoro-1-(2-hydroxy-2-methylpropyl)-1H-benzo[d][1,2,3]triazol-5-yl)-3-fluoro-[1,1′-biphenyl]-4-carbonitrile.

Item 7. An LSD1 inhibitor comprising the compound according to any one of Items 1 to 6 or a salt thereof as an active ingredient.

Item 8. A pharmaceutical composition comprising the compound or salt thereof according to any one of Items 1 to 6.

Item 9. The pharmaceutical composition according to Item 8, which is an oral composition.

Item 10. An antitumor agent comprising the compound or a salt thereof according to any one of Items 1 to 6 as an active ingredient.

Item 11. A method for treating a cancer patient, comprising administering to the patient an effective amount of the compound according to any one of Items 1 to 6 or a salt thereof.

Item 12. The compound or salt thereof according to any one of Items 1 to 6, for use in treating a cancer patient.

Item 13. Use of the compound or salt thereof according to any one of Items 1 to 6 in the preparation of an antitumor agent.

Advantageous Effects of the Invention

The present invention provides a novel compound represented by the above formula (I) or a salt thereof, both of which are useful as LSD1 inhibitors.

It has been revealed that the compounds of the present invention or their salts have excellent LSD1 inhibitory activity and cancer cell growth inhibitory effects, are low in toxicity, and can be orally administered. Therefore, the compounds of the present invention or their salts are useful as preventive and/or therapeutic agents for cancer.

DETAILED DESCRIPTION

The compound represented by formula (I) of the present invention is a novel biphenyl compound comprising (i) a benzene ring having an amide or thioamide group formed together with a cyclic amino group, (ii) a benzene ring having a 4-nitro or 4-cyano group-containing benzene ring at the meta position relative to the amide or thioamide group, and (iii) the benzene ring further having an unsaturated hydrocarbon ring or an unsaturated heterocyclic ring at the para position relative to the amide or thioamide group.

In the present specification, unless otherwise specified, examples of the “substituent” include a halogen atom, a hydroxyl group, a cyano group, a nitro group, an alkyl group, a hydroxyalkyl group, a haloalkyl group, a cycloalkyl group, a hydroxycycloalkyl group, a cycloalkyl-alkyl group, an aralkyl group, an alkenyl group, an alkynyl group, an alkoxy group, a haloalkoxy group, a cycloalkyloxy group, a cycloalkyl-alkoxy group, an unsaturated hydrocarbon ring-alkoxy group, an alkylthio group, a cycloalkyl-alkylthio group, an amino group, a monoalkylamino group or a dialkylamino group, a cycloalkylamino group, a cycloalkyl-alkylamino group, an acyl group, an acyloxy group, an oxo group, a carboxyl group, an alkoxycarbonyl group, an aralkyloxycarbonyl group, a carbamoyl group which may be substituted with an unsaturated hydrocarbon ring, a saturated or unsaturated heterocyclic group, an unsaturated hydrocarbon ring (e.g., an aromatic hydrocarbon), or a saturated heterocyclic group, etc. When the substituent is present, the number thereof is generally one, two, or three.

In the present specification, examples of the "halogen atom" include a fluorine atom, a chlorine atom, a bromine atom, an iodine atom and the like, among which a fluorine atom, a chlorine atom, a bromine atom or an iodine atom is preferred, and a fluorine atom or a chlorine atom is more preferred.

In this specification, "alkyl" may be linear or branched. Examples include C1-C6 alkyl, such as methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, n-pentyl, isopentyl, tert-pentyl and n-hexyl.

In this specification, examples of "hydroxyalkyl" include the alkyl groups listed above having at least one hydroxyl group (e.g., one or two hydroxyl groups). Specific examples include hydroxymethyl, 2-hydroxyethyl, 1-hydroxyethyl, 3-hydroxypropyl, 2-hydroxypropyl, 1-methyl-2-hydroxyethyl, 4-hydroxybutyl, isobutyl, 2,2-dimethyl-2-hydroxyethyl, 5-hydroxypentyl, 3,3-dimethyl-3-hydroxypropyl, 6-hydroxyhexyl, dihydroxymethyl, 1,2-dihydroxyethyl, 2,3-dihydroxypropyl, 3,4-dihydroxybutyl, 4,5-dihydroxypentyl, 5,6-dihydroxyhexyl, etc., preferably a hydroxyalkyl group having one hydroxyl group.

In this specification, "haloalkyl" refers to a straight or branched C1-C6 alkyl group having 1 to 13 halogen atoms (halogenated C1-C6 alkyl group). Examples include halogenated C1-C6 alkyl groups such as fluoromethyl, difluoromethyl, trifluoromethyl, trichloromethyl, fluoroethyl, 1,1,1-trifluoroethyl, monofluoro-n-propyl, perfluoro-n-propyl, and perfluoroisopropyl. Halogenated C1-C4 alkyl groups are preferred, and halogenated C1-C4 alkyl groups having 1 to 7 halogen atoms are more preferred.

In the present specification, specific examples of the "cycloalkyl group" include a C3-C7 cycloalkyl group such as a cyclopropyl group, a cyclobutyl group, a cyclopentyl group, a cyclohexyl group and a cycloheptyl group.

In the present specification, specific examples of the "hydroxycycloalkyl" include the C3-C7 cycloalkyl groups listed above having at least one hydroxyl group (e.g., one or two hydroxyl groups). Specific examples include 1-hydroxycyclopropyl, 2-hydroxycyclopropyl, 1-hydroxycyclobutyl, 3-hydroxycyclobutyl, 1-hydroxycyclopentyl, 3,4-dihydroxycyclopentyl, 1-hydroxycyclohexyl, 4-hydroxycyclohexyl, 1-hydroxycycloheptyl, and the like, preferably a hydroxycycloalkyl group having one hydroxyl group.

In the present specification, examples of the "cycloalkyl-alkyl" include a C3-C7 cycloalkyl-substituted C1-C4 alkyl group such as a cyclopropylmethyl group, a cyclobutylmethyl group, a cyclopentylmethyl group, a cyclohexylmethyl group and a cycloheptylmethyl group.

In the present specification, examples of the "aralkyl group" include a C7-C13 aralkyl group such as a benzyl group, a phenethyl group, a naphthylmethyl group and a fluorenylmethyl group.

In this specification, "alkenyl" can be straight chain, branched or cyclic, and refers to an unsaturated hydrocarbon group having at least one double bond (e.g., one or two double bonds). Examples include C2-C6 alkenyl, such as vinyl, allyl, 1-propenyl, 2-methyl-2-propenyl, isopropenyl, 1-butenyl, 2-butenyl, 3-butenyl, isobutenyl, 2-pentenyl, 3-pentenyl, 4-pentenyl, 2-methyl-2-butenyl, 3-methyl-2-butenyl, 5-hexenyl, 1-cyclopentenyl, 1-cyclohexenyl, and 3-methyl-3-butenyl.

In this specification, "alkynyl" may be linear, branched, or cyclic, and refers to an unsaturated hydrocarbon group having at least one triple bond (e.g., one or two triple bonds). Examples include C2-C6 alkynyl groups such as ethynyl, 1-propynyl, 2-propynyl, 1-butynyl, 2-butynyl, 3-butynyl, and 1-methyl-2-propynyl.

In the present specification, "alkoxy" may be linear or branched. Examples include C1-C6 alkoxy groups such as methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, isobutoxy, sec-butoxy, tert-butoxy, pentyloxy, isopentyloxy, and hexyloxy.

In this specification, "halogenated alkoxy" refers to a linear or branched C1-C6 alkoxy group having 1 to 13 halogen atoms (halogenated C1-C6 alkoxy). Examples include halogenated C1-C6 alkoxy groups such as fluoromethoxy, difluoromethoxy, trifluoromethoxy, trichloromethoxy, fluoroethoxy, 1,1,1-trifluoroethoxy, monofluoro-n-propoxy, perfluoro-n-propoxy, and perfluoroisopropoxy, preferably halogenated C1-C4 alkoxy groups, more preferably halogenated C1-C4 alkoxy groups having 1 to 7 halogen atoms.

In the present specification, examples of the "cycloalkoxy group" include a C3-C7 cycloalkoxy group such as a cyclopropyloxy group, a cyclobutyloxy group, a cyclopentyloxy group, a cyclohexyloxy group, and a cycloheptyloxy group.

In the present specification, examples of the "cycloalkyl-alkoxy group" include a C3-C7 cycloalkyl-substituted C1-C4 alkoxy group such as a cyclopropylmethoxy group, a cyclobutylmethoxy group, a cyclopentylmethoxy group, a cyclohexylmethoxy group, and a cycloheptylmethoxy group.

In this specification, "alkylthio" may be linear or branched. Examples include C1-C6 alkylthio, such as methylthio, ethylthio, n-propylthio, isopropylthio, n-butylthio, isobutylthio, tert-butylthio, n-pentylthio, isopentylthio, and hexylthio.

In the present specification, examples of the "cycloalkyl-alkylthio group" include a C3-C7 cycloalkyl-substituted C1-C4 alkylthio group such as a cyclopropylmethylthio group, a cyclobutylmethylthio group, a cyclopentylmethylthio group, a cyclohexylmethylthio group, and a cycloheptylmethylthio group.

In the present specification, examples of the “monoalkylamino group” include an amino group monosubstituted by a linear or branched C1-C6 alkyl group, such as methylamino, ethylamino, n-propylamino, isopropylamino, n-butylamino, isobutylamino, tert-butylamino, n-pentylamino, isopentylamino, and hexylamino.

In the present specification, examples of the “dialkylamino group” include an amino group substituted by the same or different straight-chain or branched C1-C6 alkyl groups, such as dimethylamino, diethylamino, di-n-propylamino, diisopropylamino, di-n-butylamino, diisobutylamino, di-tert-butylamino, di-n-pentylamino, diisopentylamino, dihexylamino, methylethylamino, and methylisopropylamino.

In this specification, examples of "cycloalkylamino" include amino groups having one or two cycloalkyl groups as described above. Specific examples include N-cyclopropylamino, N,N-dicyclopropylamino, N-cyclobutylamino, N-cyclopentylamino, N-cyclohexylamino, N-cycloheptylamino, and the like.

In the present specification, examples of the "cycloalkyl-alkylamino group" include a C3-C7 cycloalkyl-substituted C1-C4 alkylamino group such as cyclopropylmethylamino, cyclobutylmethylamino, cyclopentylmethylamino, cyclohexylmethylamino, and cycloheptylmethylamino.

In the present specification, "acyl group" means an alkylcarbonyl group or an arylcarbonyl group.

In the present specification, examples of the “alkylcarbonyl group” include a linear or branched (C1-C6 alkyl)carbonyl group such as a methylcarbonyl group, an ethylcarbonyl group, an n-propylcarbonyl group, an isopropylcarbonyl group, an n-butylcarbonyl group, an isobutylcarbonyl group, a tert-butylcarbonyl group, an n-pentylcarbonyl group, an isopentylcarbonyl group, and a hexylcarbonyl group.

In the present specification, examples of the “arylcarbonyl group” include a (C6-C13 aryl)carbonyl group such as a phenylcarbonyl group, a naphthylcarbonyl group, a fluorenylcarbonyl group, an anthracenylcarbonyl group, a biphenylcarbonyl group, a tetrahydronaphthylcarbonyl group, a chromanylcarbonyl group, a 2,3-dihydro-1,4-dioxaphthalenylcarbonyl group, an indanylcarbonyl group, and a phenanthrylcarbonyl group.

In the present specification, the "acylamino group" refers to an alkylcarbonylamino group or an arylcarbonylamino group.

In the present specification, examples of the “alkylcarbonylamino group” include a linear or branched (C1-C6 alkyl)carbonylamino group, such as a methylcarbonylamino group, an ethylcarbonylamino group, an n-propylcarbonylamino group, an isopropylcarbonylamino group, an n-butylcarbonylamino group, an isobutylcarbonylamino group, a tert-butylcarbonylamino group, an n-pentylcarbonylamino group, an isopentylcarbonylamino group, and a hexylcarbonylamino group.

In the present specification, examples of the “arylcarbonylamino group” include a (C6-C13 aryl)carbonylamino group such as a phenylcarbonylamino group, a naphthylcarbonylamino group, a fluorenylcarbonylamino group, an anthracenylcarbonylamino group, a biphenylcarbonylamino group, a tetrahydronaphthylcarbonylamino group, a chromanylcarbonylamino group, a 2,3-dihydro-1,4-dioxaphthalenylcarbonylamino group, an indanylcarbonylamino group, and a phenanthrenylcarbonylamino group.

In the present specification, the "acyloxy group" refers to an alkylcarbonyloxy group or an arylcarbonyloxy group.

In the present specification, examples of the “alkylcarbonyloxy group” include a linear or branched (C1-C6 alkyl)carbonyloxy group such as a methylcarbonyloxy group, an ethylcarbonyloxy group, an n-propylcarbonyloxy group, an isopropylcarbonyloxy group, an n-butylcarbonyloxy group, an isobutylcarbonyloxy group, a tert-butylcarbonyloxy group, an n-pentylcarbonyloxy group, an isopentylcarbonyloxy group, and a hexylcarbonyloxy group.

In the present specification, examples of the “arylcarbonyloxy group” include a (C6-C13 aryl)carbonyloxy group such as a phenylcarbonyloxy group, a naphthylcarbonyloxy group, a fluorenylcarbonyloxy group, an anthracenylcarbonyloxy group, a biphenylcarbonyloxy group, a tetrahydronaphthylcarbonyloxy group, a chromanylcarbonyloxy group, a 2,3-dihydro-1,4-dioxaphthalenylcarbonyloxy group, an indanylcarbonyloxy group, and a phenanthrenylcarbonyloxy group.

In this specification, "alkoxycarbonyl" may be straight or branched. Examples include (C1-C6 alkoxy)carbonyl, such as methoxycarbonyl, ethoxycarbonyl, propoxycarbonyl, isopropoxycarbonyl, butoxycarbonyl, isobutoxycarbonyl, tert-butoxycarbonyl, pentyloxycarbonyl, isopentyloxycarbonyl, and hexyloxycarbonyl.

In the present specification, examples of the "aralkyloxycarbonyl group" include a (C7-C13aralkyl)oxycarbonyl group such as a benzyloxycarbonyl group, a phenethoxycarbonyl group, a naphthylmethoxycarbonyl group, and a fluorenylmethoxycarbonyl group.

In this specification, "saturated heterocyclic group" refers to a monocyclic or polycyclic saturated heterocyclic group having one or more (preferably 1-3) heteroatoms selected from nitrogen, oxygen and sulfur. Specific examples include morpholinyl, pyrrolidinyl, piperidinyl, piperazinyl, azepanyl, diazepanyl, tetrahydrofuranyl, tetrahydropyranyl, tetrahydrothienyl, thiazolidinyl, oxazolidinyl and the like.

In the present specification, the "unsaturated heterocyclic group" refers to a monocyclic or polycyclic, completely or partially unsaturated heterocyclic group having one or more (preferably 1 to 3) heteroatoms selected from nitrogen, oxygen and sulfur. Specific examples include imidazolyl, thienyl, furyl, pyrrolyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, thiadiazolyl, pyrazolyl, triazolyl, tetrazolyl, pyridinyl, pyrazinyl (pyrazyl), pyrimidinyl, pyridazinyl, pyrazolopyridinyl, pyrazolopyrimidinyl, indolyl, isoindolyl, indazolyl, triazolopyridinyl, benzimidazolyl, benzoxazolyl, benzisoxazolyl, benzothiazolyl, benzothienyl, benzofuranyl, 1,3-dihydroisobenzofuranyl, purinyl, benzotriazolyl, imidazopyridinyl, quinolyl, isoquinolyl, quinazolinyl, quinoxalinyl, phthalazinyl, methylenedioxyphenyl, ethylenedioxyphenyl, dihydrobenzofuranyl, and the like.

In the present specification, examples of the "unsaturated hydrocarbon group" include a monocyclic or polycyclic C5-14 hydrocarbon ring having at least one unsaturated bond (e.g., 1 to 8 unsaturated bonds), etc. The "unsaturated hydrocarbon group" is preferably an aromatic hydrocarbon group, or a monocyclic or bicyclic 5- to 14-membered unsaturated hydrocarbon group.

In the present specification, examples of the "aromatic hydrocarbon group" include C6-C14 aromatic hydrocarbon groups such as a phenyl group, a naphthyl group, an anthracenyl group, a phenanthrenyl group, a fluorenyl group, and a tetrahydronaphthyl group.

In the present specification, the "monocyclic or bicyclic 5- to 14-membered unsaturated hydrocarbon group" includes cyclopentadienyl, phenyl, naphthyl, tetrahydronaphthyl, azulenyl, heptalenyl and the like.

In the present specification, the "monocyclic 5- to 10-membered unsaturated hydrocarbon group" includes cyclopentadienyl, phenyl, cyclooctatetraenyl and the like.

In the present specification, the "saturated heterocyclic oxy group" refers to a saturated heterocyclic oxy group having a heteroatom selected from nitrogen, oxygen, and sulfur. Specific examples include morpholinyloxy, 1-pyrrolidinyloxy, piperidinyloxy, piperazinyloxy, 4-methyl-1-piperazinyloxy, tetrahydrofuranyloxy, tetrahydropyranyloxy, tetrahydrophenylthiooxy, thiazolidinyloxy, and oxazolidinyloxy groups, preferably a saturated heterocyclic oxy group having 1 to 3 heteroatoms selected from nitrogen, oxygen, and sulfur.

In this specification, the term "CA-CB" used in the description of a group indicates that the group has A to B carbon atoms. For example, a C1-C6 alkyl group refers to an alkyl group having 1 to 6 carbon atoms, and a "C6-C14 aromatic hydrocarbon group" refers to an oxygen bonded to a C6-C14 aromatic hydrocarbon group. Furthermore, the term "A to B membered" indicates that the number of atoms (ring atoms) constituting the ring is A to B. For example, a "4- to 10-membered nitrogen-containing saturated heterocyclic group" refers to a nitrogen-containing saturated heterocyclic group containing 4 to 10 ring atoms.

In the compound represented by formula (I) of the present invention, ring A refers to a nitrogen-containing saturated heterocyclic group, which may be cross-linked or spirocyclic. As shown in formula (I), the nitrogen on ring A is bonded to a carbonyl group or a carbothionyl group.

Examples of the monocyclic nitrogen-containing saturated heterocyclic group in the “monocyclic, bridged or spirocyclic nitrogen-containing saturated heterocyclic group” represented by ring A include monocyclic nitrogen-containing saturated heterocyclic groups such as pyrrolidinyl, piperidinyl, piperazinyl, azepanyl, diazepanyl and the like. The monocyclic nitrogen-containing saturated heterocyclic group is preferably a monocyclic nitrogen-containing saturated heterocyclic group having 1 to 3 nitrogen atoms, 0 to 1 sulfur atoms and 0 to 2 oxygen atoms as heteroatoms, more preferably a monocyclic nitrogen-containing saturated heterocyclic group having 1 to 2 nitrogen atoms as heteroatoms, more preferably a monocyclic 4- to 10-membered nitrogen-containing saturated heterocyclic group having 1 to 2 nitrogen atoms as heteroatoms, more preferably pyrrolidinyl, piperidinyl, piperazinyl, azepanyl or diazepanyl, still more preferably pyrrolidinyl, piperidinyl, azepanyl or diazepanyl, more preferably pyrrolidinyl or diazepanyl, more preferably pyrrolidinyl.

Examples of the bridged nitrogen-containing saturated heterocyclic group in the "monocyclic, bridged or spirocyclic nitrogen-containing saturated heterocyclic group" represented by ring A include:

The bridged nitrogen-containing saturated heterocyclic group is preferably

More preferred

More preferred

More preferred

And more preferably

Examples of the spiro nitrogen-containing saturated heterocyclic group in the "monocyclic, bridged or spiro nitrogen-containing saturated heterocyclic group" represented by ring A include a spiro ring having 0 to 2 oxygen atoms in which any two 4- to 7-membered nitrogen-containing saturated heterocyclic groups are bonded to each other. The spiro nitrogen-containing saturated heterocyclic group is preferably a 7- to 12-membered spirocyclic group having 2 nitrogen atoms and 0-1 oxygen atoms, and any two 4- to 7-membered nitrogen-containing saturated heterocyclic groups in the spirocyclic ring are bonded to each other, more preferably diazaspiroheptyl, diazaspirooctyl, diazaspirononyl, diazaspirodecanyl, diazaspiroundecyl, oxadiazaspiroheptyl, oxadiazaspirooctyl, oxadiazaspirononyl, oxadiazaspirodecanyl, or oxadiazaspiroundecyl, more preferably diazaspirooctyl, diazaspirononyl, diazaspirodecanyl, or oxadiazaspirononyl, more preferably 2,7-diazaspiro[3.4]octyl, 3,7-diazaspiro[3.4]octyl, 2,7-diazaspiro[3.5]nonyl, 2,8-diazaspiro[3.5]nonyl, 3,7-diazaspiro[3.5]nonyl, 3,8-diazaspiro[4.4]nonyl, 3,8-diazaspiro[3.5]decyl, or 9-oxa-diazaspiro[3.5]nonyl, more preferably 2,7-diazaspiro[3.4]octyl, 3,7-diazaspiro[3.4]octyl, 2,7-diazaspiro[3.5]nonyl, 2,8-diazaspiro[3.5]nonyl, or 9-oxa-diazaspiro[3.5]nonyl, more preferably 2,7-diazaspiro[3.4]octyl, 3,7-diazaspiro[3.4]octyl, or 2,8-diazaspiro[3.5]nonyl, more preferably 2,8-diazaspiro[3.5]nonyl.

The "monocyclic, bridged or spiro nitrogen-containing saturated heterocyclic group" represented by ring A is preferably a monocyclic, bridged or spiro nitrogen-containing saturated heterocyclic group having 1 to 3 nitrogen atoms, 0 to 1 sulfur atoms and 0 to 2 oxygen atoms as heteroatoms; more preferably a monocyclic 4 to 10-membered nitrogen-containing saturated heterocyclic group having 1 to 2 nitrogen atoms as heteroatoms. For example, the bridged nitrogen-containing saturated heterocyclic group is:

Alternatively, a spirocyclic group having 0-2 oxygen atoms, wherein any two 4- to 7-membered nitrogen-containing saturated heterocyclic groups in the spirocyclic ring are bonded to each other; more preferably, a monocyclic 4- to 10-membered nitrogen-containing saturated heterocyclic group having 1-2 nitrogen atoms as heteroatoms, a bridged nitrogen-containing saturated heterocyclic group such as:

Alternatively, a 7- to 12-membered spirocyclic group having 2 nitrogen atoms and 0-1 oxygen atoms, wherein any two 4- to 7-membered nitrogen-containing saturated heterocyclic rings in the spirocyclic ring are bonded to each other; more preferably, pyrrolidinyl, piperidinyl, piperazinyl, azepanyl, diazepanyl,

2,7-diazaspiro[3.4]octyl, 3,7-diazaspiro[3.4]octyl, 2,7-diazaspiro[3.5]nonyl, 2,8-diazaspiro[3.5]nonyl, 3,7-diazaspiro[3.5]nonyl, 3,8-diazaspiro[4.4]nonyl, 3,8-diazaspiro[4.5]decyl, or 9-oxa-diazaspiro[3.5]nonyl, more preferably pyrrolidinyl, piperidinyl, azepanyl, diazepanyl,

2,7-diazaspiro[3.4]octyl, 3,7-diazaspiro[3.4]octyl, 2,7-diazaspiro[3.5]nonyl, 2,8-diazaspiro[3.5]nonyl, or 9-oxa-diazaspiro[3.5]nonyl, more preferably pyrrolidinyl,

or 2,8-diazaspiro[3.5]nonyl; more preferably pyrrolidinyl,

In the compound represented by formula (I) of the present invention, ring B represents a monocyclic or bicyclic unsaturated hydrocarbon group, or a monocyclic or bicyclic unsaturated heterocyclic group.

The "monocyclic or bicyclic unsaturated hydrocarbon group" represented by ring B is preferably a monocyclic or bicyclic 5- to 14-membered unsaturated hydrocarbon group, more preferably a phenyl group or a naphthyl group, and still more preferably a phenyl group.

The "monocyclic or bicyclic unsaturated heterocyclic group" represented by ring B refers to a monocyclic or bicyclic, fully or partially unsaturated heterocyclic group having a heteroatom selected from nitrogen, oxygen and sulfur, preferably a 5-14-membered unsaturated heterocyclic group having 0-4 nitrogen atoms, 0-2 sulfur atoms and 0-3 oxygen atoms as heteroatoms and having at least one of nitrogen, sulfur and oxygen, more preferably an imidazolyl, thienyl, furyl, pyrrolyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, thiadiazolyl, pyrazolyl, triazolyl, tetrazolyl, pyridyl, pyrazinyl, pyrimidinyl, pyridazinyl, pyrazolopyridine phenyl, pyrazolopyrimidinyl, indolyl, isoindolyl, dihydroindolinyl, indazolyl, triazolopyridinyl, benzimidazolyl, benzoxazolyl, benzisoxazolyl, benzothiazolyl, benzotriazolyl, benzothiophenyl, benzofuranyl, purinyl, imidazopyridinyl, quinolinyl, isoquinolinyl, quinazolinyl, quinoxalinyl, phthalazinyl, methylenedioxyphenyl, ethylenedioxyphenyl, dihydrobenzofuranyl, 1,3-dihydroisobenzofuranyl, dihydrobenzoxazolyl (e.g., 2,3-dihydrobenzo[d]oxazolyl), dihydrobenzoxazinyl (e.g., 3,4- dihydro-2H-benzo[b][1,4]oxazinyl), benzodioxolyl (e.g., benzo[d][1,3]dioxolyl), dihydrobenzodioxolynyl (e.g., 2,3-dihydrobenzo[b][1,4]dioxolynyl), or dihydrobenzothiazolyl (e.g., 2,3-dihydrobenzo[d]thiazolyl), more preferably pyridyl, pyrazolopyridinyl, pyrazolopyrimidinyl, indolyl, dihydroindolinyl, indazolyl, benzimidazolyl, benzisoxazolyl, benzothiazolyl, benzotriazolyl, imidazopyridinyl, quinolinyl, isoquinolinyl, The monocyclic or bicyclic unsaturated heterocyclic group represented by ring B may be substituted with oxo. Examples of the monocyclic or bicyclic unsaturated heterocyclic group substituted with oxo include 2-oxo-indolinyl, ...

2-Oxo-2,3-dihydrobenzo[d]oxazolyl,

2-oxo-2,3-dihydrobenzo[d]thiazolyl,

The monocyclic or bicyclic unsaturated heterocyclic group substituted by oxygen is preferably 2-oxo-dihydroindole, 2-oxo-2,3-dihydrobenzo[d]oxazolyl, or 2-oxo-2,3-dihydrobenzo[d]thiazolyl, more preferably 2-oxo-2,3-dihydrobenzo[d]oxazolyl or 2-oxo-2,3-dihydrobenzo[d]thiazolyl.

Ring B is preferably a monocyclic or bicyclic 5- to 14-membered unsaturated hydrocarbon group or a monocyclic or bicyclic 5- to 14-membered unsaturated heterocyclic group which may be substituted with oxo, the heterocyclic group having 0 to 4 nitrogen atoms, 0 to 2 sulfur atoms, and 0 to 3 oxygen atoms as heteroatoms, and having at least one of nitrogen, sulfur and oxygen, and more preferably phenyl, naphthyl, pyridyl, pyrazolopyridyl, pyrazolopyrimidinyl, indolyl, dihydroindolinyl, 2-oxo-dihydroindolinyl, indazolyl, benzimidazolyl, benzisoxazolyl, benzothiazolyl, benzotriazolyl, imidazopyridyl, quinolyl, isoquinolyl, quinazolinyl, quinoxalinyl, phthalazinyl, 2-oxo-2,3-dihydro benzo[d]oxazolyl, 1,3-dihydroisobenzofuranyl, dihydrobenzoxazinyl, benzodioxolyl, dihydrobenzodioxolynyl, or 2-oxo-2,3-dihydrobenzo[d]thiazolyl, more preferably phenyl, naphthyl, pyridyl, pyrazolopyridinyl, indolyl, dihydroindolyl, indazolyl, benzimidazolyl, benzisoxazolyl, benzotriazolyl, quinolinyl, 2-oxo-2,3-dihydrobenzo[d]oxazolyl, 1,3-dihydroisobenzofuranyl, dihydrobenzoxazinyl, or 2-oxo-2,3-dihydrobenzo[d]thiazolyl, more preferably phenyl, indolyl, indazolyl, benzisoxazolyl, or benzotriazolyl.

In the compound represented by formula (I) of the present invention, X represents oxygen or sulfur, and preferably oxygen.

In the compound represented by formula (I) of the present invention, R1 represents a nitro group or a cyano group, and preferably a cyano group.

In the compound represented by formula (I) of the present invention, R2 represents a halogen atom, and preferably fluorine. When there are two or more R2, R2 may be the same or different.

In the compound represented by formula (I) of the present invention, 1 is an integer of 0-2, and preferably an integer of 0-1.

In the compound represented by formula (I) of the present invention, R3 represents substituted or unsubstituted amino, C1-C6 alkyl, halogen atom, cyano, oxo, hydroxyl, carbamoyl, sulfo, C1-C6 alkoxy or amino (C1-C6 alkyl). When there are two or more R3, R3 can be the same or different.

The "C1-C6 alkyl" represented by R3 may be linear or branched. Examples include methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, n-pentyl, isopentyl, hexyl, etc., preferably C1-C4 alkyl, more preferably methyl.

Examples of the “mono(C1-C6 alkyl)amino” represented by R3 include methylamino, ethylamino, n-propylamino, isopropylamino, n-butylamino, isobutylamino, tert-butylamino, n-pentylamino, isopentylamino, hexylamino, etc., preferably mono(C1-C4 alkyl)amino, more preferably methylamino, ethylamino or isopropylamino.

Examples of the “di(C1-C6 alkyl)amino group” represented by R3 include dimethylamino, diethylamino, di-n-propylamino, diisopropylamino, di-n-butylamino, diisobutylamino, di-t-butylamino, di-n-pentylamino, diisopentylamino, dihexylamino, methylethylamino, methylisopropylamino, and the like. The “di(C1-C6 alkyl)amino group” is preferably dimethylamino, diethylamino, di-n-propylamino, diisopropylamino, di-n-butylamino, diisobutylamino, di-t-butylamino, di-n-pentylamino, diisopentylamino, dihexylamino, methylethylamino, or methylisopropylamino, more preferably di(C1-C4 alkyl)amino, and still more preferably dimethylamino.

Examples of the "(C3-C7 cycloalkyl)amino" represented by R3 include (C3-C7 cycloalkyl)amino groups such as cyclopropylamino, cyclobutylamino, cyclopentylamino, cyclohexylamino, and cycloheptylamino. The "(C3-C7 cycloalkyl)amino" is preferably cyclopropylamino, cyclobutylamino, cyclopentylamino, cyclohexylamino, or cycloheptylamino, more preferably cyclobutylamino.

R3 is preferably a substituted or unsubstituted amino group, a C1-C6 alkyl group, a halogen atom, a cyano group, an oxo group, a hydroxyl group, a carbamoyl group, a sulfo group, a C1-C6 alkoxy group or an amino(C1-C6 alkyl group), more preferably an amino group, a C1-C6 alkyl group, a halogen atom, a cyano group, an oxo group, a hydroxyl group, a carbamoyl group, a sulfo group, a C1-C6 alkoxy group or an amino(C1-C6 alkyl group) which may be substituted by 1 to 2 C1-C6 alkyl groups or C3-C7 cycloalkyl groups, more preferably an amino group, a mono- or di-(C1-C6 alkyl)amino group, a (C3-C7 cycloalkyl)amino group or a C1-C6 alkyl group, more preferably an amino group, a methylamino group, an ethylamino group, an isopropylamino group, a dimethylamino group, a cyclobutylamino group or a methyl group, more preferably an amino group or a methyl group, and more preferably an amino group.

In the compound represented by formula (I) of the present invention, m is an integer of 0-2, and preferably an integer of 0-1.

In the compound represented by formula (I) of the present invention, R4 represents a halogen atom, a hydroxyl group, a nitro group, a cyano group, an amino group, a carboxyl group, a (C2-C7 acyl group) amino group, a (C2-C7 acyl group) oxygen group, a substituted or unsubstituted C1-C8 alkyl group, a substituted or unsubstituted C2-C6 alkenyl group, a substituted or unsubstituted C1-C6 alkoxy group, a substituted or unsubstituted C3-C7 cycloalkyl group, a single or double (C1-C6 alkyl) amino group, a substituted or unsubstituted carbamoyl group, a substituted or unsubstituted C2-C6 alkynyl group, a substituted or unsubstituted (C1-C6 alkyl) carbonyl group, a substituted or unsubstituted 4- to 14-membered nitrogen-containing saturated heterocyclic group, or a substituted or unsubstituted C6-C14 aromatic hydrocarbon group. When there are two or more R4, R4 can be identical or different.

In the present invention, when at least one R4 represents a substituted C1-C8 alkyl group, a substituted C2-C6 alkenyl group, a substituted C1-C6 alkoxy group, a substituted C3-C7 cycloalkyl group or a substituted carbamoyl group, examples of the substituent include a halogen atom, a carboxyl group, a C1-C6 alkoxy group, a hydroxyl group, a C1-C6 alkyl group which may be substituted with a hydroxyl group, a monocyclic 5- to 10-membered unsaturated hydrocarbon group, a carbamoyl group which may be substituted with a C1-C6 alkyl group or a monocyclic 5- to 10-membered unsaturated hydrocarbon group, a (C2-C7 acyl)oxy group, an amino group which may be substituted with a C1-C6 alkyl group or a C2-C7 acyl group, a C3-C7 cycloalkyl group which may be substituted with a hydroxyl group, a (C1-C6 alkoxy) (C1-C6 alkyl) group, etc. When two or more substituents are present, the substituents may be the same or different.

The "C1-C8 alkyl" in the "substituted or unsubstituted C1-C8 alkyl" represented by R4 is preferably a methyl group, an ethyl group, an n-propyl group, an isopropyl group, an n-butyl group, an isobutyl group, a sec-butyl group, a tert-butyl group, a pentyl group, a hexyl group, a heptyl group, or an octyl group, more preferably a C1-C6 alkyl group, more preferably a methyl group, an ethyl group, an n-propyl group, an isopropyl group, an n-butyl group, an isobutyl group, a sec-butyl group, a tert-butyl group, a pentyl group, or a hexyl group, more preferably a methyl group, an ethyl group, an n-propyl group, an isopropyl group, an n-butyl group, an isobutyl group, a sec-butyl group, or a tert-butyl group.

The substituents in the "substituted or unsubstituted C1-C8 alkyl group" represented by R4 may be, for example, the substituents described above, preferably a halogen atom, an amino group, a hydroxyl group, a carboxyl group, a carbamoyl group, an alkylcarbamoyl group, an acylamino group, an alkoxy group, a hydroxycycloalkyl group or an acyloxy group, more preferably a halogen atom, an amino group, a hydroxyl group, a carboxyl group, a carbamoyl group, a (C1-C6 alkyl)carbamoyl group, a (C2-C7 acyl)amino group, a C1-C6 alkoxy group, a C3-C7 cycloalkyl group, a hydroxyl group (C3-C7 cycloalkyl group) or a (C1-C6 alkoxy group a C2-C7 acyl)oxy group, more preferably a halogen atom, an amino group, a hydroxyl group, a carboxyl group, a carbamoyl group, a (C1-C6 alkyl)carbamoyl group, a (C1-C6 alkyl)carbonylamino group, a C1-C6 alkoxy group, a C3-C7 cycloalkyl group, a hydroxyl group (C3-C7 cycloalkyl group) or a (C1-C6 alkyl)carbonyloxy group, more preferably a fluorine atom, an amino group, a hydroxyl group, a carboxyl group, a carbamoyl group, a methylcarbamoyl group, a dimethylcarbamoyl group, an acetylamino group, a methoxy group, a hydroxycyclopropyl group or a methylcarbonyloxy group.

The “substituted or unsubstituted C1-C8 alkyl group” represented by R4 is preferably an unsubstituted C1-C8 alkyl group, or a C1-C8 alkyl group which may be substituted by a halogen atom, an amino group, a hydroxyl group, a carboxyl group, a carbamoyl group, a (C1-C6 alkyl)carbamoyl group, a (C1-C6 alkyl)carbonylamino group, a C1-C6 alkoxy group, a C3-C7 cycloalkyl group, a hydroxyl group (C3-C7 cycloalkyl group) or a (C1-C6 alkyl)carbonyloxy group, and more preferably a methyl group, an ethyl group, an n-propyl group, an isopropyl group, a tert-butyl group, a difluoromethyl group, a trifluoromethyl group, a fluoroethyl group, an aminoethyl group, a hydroxymethyl group, a hydroxyethyl group, a hydroxypropyl group, a hydroxydimethylethyl group, a hydroxymethylpropyl group, a hydroxymethylbutyl group, a hydroxyethylbutyl group, a carboxymethyl group, a carbamoylmethyl group, a methylcarbamoyl group methyl, dimethylcarbamoylmethyl, acetylaminoethyl, methoxyethyl, hydroxycyclopropylmethyl, hydroxycyclopropylethyl, hydroxycyclobutylmethyl or methylcarbonyloxyethyl, more preferably methyl, ethyl, n-propyl, tert-butyl, difluoromethyl, hydroxyethyl, hydroxymethylpropyl, hydroxymethylbutyl, hydroxyethylbutyl, carbamoylmethyl, methylcarbamoylmethyl, dimethylcarbamoylmethyl, methoxyethyl, hydroxycyclopropylmethyl, hydroxycyclobutylmethyl or methylcarbonyloxyethyl, more preferably methyl, difluoromethyl, hydroxymethylpropyl, hydroxymethylbutyl, hydroxycyclobutylmethyl, methoxyethyl or hydroxycyclobutylmethyl, more preferably methyl, difluoromethyl, hydroxymethylpropyl, hydroxyethylbutyl or hydroxycyclobutylmethyl.

The “substituted or unsubstituted C2-C6 alkenyl group” represented by R4 is preferably an unsubstituted C2-C6 alkenyl group, more preferably a vinyl group, an allyl group, a 1-propenyl group, a 2-methyl-2-propenyl group, an isopropenyl group, a 1-, 2- or 3-butenyl group, an isobutenyl group, a 2-, 3- or 4-pentenyl group, a 2-methyl-2-butenyl group, a 3-methyl-2-butenyl group, a 5-hexenyl group, a 1-cyclopentenyl group, a 1-cyclohexenyl group, or a 3-methyl-3-butenyl group, more preferably an isobutenyl group.

Examples of the “C2-C6 alkynyl group” in the “substituted or unsubstituted C2-C6 alkynyl group” represented by R4 include ethynyl, 1- or 2-propynyl, 1-, 2- or 3-butynyl, 1-methyl-2-propynyl, and the like. The “substituted or unsubstituted C2-C6 alkynyl group” is preferably an unsubstituted C2-C6 alkynyl group.

The “C1-C6 alkoxy group” in the “substituted or unsubstituted C1-C6 alkoxy group” represented by R4 is preferably a methoxy group, an ethoxy group, an n-propoxy group, an isopropoxy group, an n-butoxy group, an isobutoxy group, a sec-butoxy group, a tert-butoxy group, a pentyloxy group, or a hexyloxy group, and more preferably a methoxy group, an ethoxy group, an n-propoxy group, an isopropoxy group, an n-butoxy group, an isobutoxy group, a sec-butoxy group, and a tert-butoxy group.

The substituents in the "substituted or unsubstituted C1-C6 alkoxy group" represented by R4 may be, for example, those described above, preferably a hydroxyl group or a 5- to 14-membered unsaturated hydrocarbon group, more preferably a hydroxyl group or a monocyclic 5- to 10-membered unsaturated hydrocarbon group, more preferably a hydroxyl group or a phenyl group.

The "substituted or unsubstituted C1-C6 alkoxy group" represented by R4 is preferably a C1-C6 alkoxy group which may be substituted by a hydroxy group or a 5- to 14-membered unsaturated hydrocarbon group, more preferably a C1-C6 alkoxy group which may be substituted by a hydroxy group or a monocyclic 5- to 10-membered unsaturated hydrocarbon group, more preferably a C1-C6 alkoxy group which may be substituted by a hydroxy group or a phenyl group, and more preferably a methoxy group, a hydroxypropoxy group or a benzyloxy group.

The "substituted or unsubstituted C3-C7 cycloalkyl group" represented by R4 is preferably a C3-C7 cycloalkyl group which may be substituted by a hydroxyalkyl group, an alkoxyalkyl group, a hydroxycycloalkyl group or an unsaturated hydrocarbon group carbamoyl group, more preferably a C3-C7 cycloalkyl group which may be substituted by a hydroxy(C1-C4 alkyl group), a (C1-C4 alkoxy) (C1-C4 alkyl group), a hydroxy(C3-C7 cycloalkyl) or a (C6-C14 aromatic hydrocarbon group) carbamoyl group, more preferably a C3-C7 cycloalkyl group which may be substituted by a hydroxy(C1-C4 alkyl group), a (C1-C4 alkoxy) (C1-C4 alkyl group), a hydroxy(C3-C7 cycloalkyl) or a phenylcarbamoyl group, more preferably a cyclopropyl group, a hydroxymethylcyclopropyl group, a methoxymethylcyclopropyl group, a hydroxycyclopropylcyclopropyl group or a phenylcarbamoylcyclopropyl group, more preferably a cyclopropyl group or a hydroxymethylcyclopropyl group, more preferably a cyclopropyl group.

The “mono- or di-(C1-C6 alkyl)amino group” represented by R4 is preferably methylamino, ethylamino, n-propylamino, isopropylamino, n-butylamino, isobutylamino, tert-butylamino, n-pentylamino, isopentylamino, hexylamino, dimethylamino, diethylamino, di-n-propylamino, diisopropylamino, di-n-butylamino, diisobutylamino, di-tert-butylamino, di-n-pentylamino, diisopentylamino, dihexylamino, methylethylamino, or methylisopropylamino, more preferably methylamino, ethylamino, n-propylamino, isopropylamino, and n-butylamino, isobutylamino, tert-butylamino, dimethylamino, diethylamino, di-n-propylamino, diisopropylamino, di-n-butylamino, diisobutylamino, di-tert-butylamino, methylethylamino, or methylisopropylamino, more preferably dimethylamino.

The "substituted or unsubstituted carbamoyl group" represented by R4 is preferably a carbamoyl group which may be substituted by an alkyl group, more preferably a carbamoyl group which may be substituted by a C1-C6 alkyl group, and more preferably a carbamoyl group, a methylcarbamoyl group or a dimethylcarbamoyl group.

Examples of the alkylcarbonyl group of the “substituted or unsubstituted (C1-C6 alkyl)carbonyl group” represented by R4 include a linear or branched (C1-C6 alkyl)carbonyl group such as a methylcarbonyl group, an ethylcarbonyl group, an n-propylcarbonyl group, an isopropylcarbonyl group, an n-butylcarbonyl group, an isobutylcarbonyl group, a tert-butylcarbonyl group, an n-pentylcarbonyl group, an isopentylcarbonyl group and a hexylcarbonyl group.

Examples of the "nitrogen-containing saturated heterocyclic group" in the "substituted or unsubstituted 4- to 14-membered nitrogen-containing saturated heterocyclic group" represented by R4 include morpholinyl, azetidinyl, pyrrolidinyl, piperidinyl, piperazinyl and the like.

Examples of the "substituted or unsubstituted C6-C14 aromatic hydrocarbon group" represented by R4 include C6-C14 aromatic hydrocarbon groups which may be substituted with a methyl group, such as phenyl, tolyl, xylyl, naphthyl, anthracenyl, phenanthrenyl, fluorenyl and tetrahydronaphthyl.

R4 is preferably a halogen atom, a hydroxyl group, a nitro group, a cyano group, an amino group, a carboxyl group, a (C2-C7 acyl)amino group, a (C2-C7 acyl)oxy group, a substituted or unsubstituted C1-C8 alkyl group, a substituted or unsubstituted C2-C6 alkenyl group, a substituted or unsubstituted C1-C6 alkoxy group, a substituted or unsubstituted C3-C7 cycloalkyl group, a mono- or di-(C1-C6 alkyl)amino group, a substituted or unsubstituted carbamoyl group, a substituted or unsubstituted C2-C6 alkynyl group, a substituted or unsubstituted (C1-C6 alkyl)carbonyl group, a substituted or unsubstituted 4- to 14-membered nitrogen-containing saturated heterocyclic group, or a substituted or unsubstituted C6-C14 aromatic hydrocarbon group; more preferably a halogen atom, a nitro group, a cyano group, a carboxyl group, a substituted or unsubstituted C1-C8 alkyl group, a substituted or unsubstituted C2-C6 alkenyl group, a substituted or unsubstituted C1-C6 alkoxy group, a substituted or unsubstituted C3-C7 cycloalkyl group, a mono- or di-(C1-C6 alkyl)amino group, a substituted or unsubstituted carbamoyl group, a substituted or unsubstituted C2-C6 alkynyl group, a substituted or unsubstituted (C1-C6 alkyl)carbonyl group, a substituted or unsubstituted 4- to 14-membered nitrogen-containing saturated heterocyclic group, or a substituted or unsubstituted C6-C14 aromatic hydrocarbon group; or di(C1-C6 alkyl)amino, or substituted or unsubstituted carbamoyl; more preferably a halogen atom, a nitro group, a cyano group, a carboxyl group, a C1-C6 alkyl group which may be substituted by a halogen atom, an amino group, a hydroxyl group, a carboxyl group, a carbamoyl group, a (C1-C6 alkyl)carbamoyl group, a (C1-C6 alkyl)carbonylamino group, a C1-C6 alkoxy group, a C3-C7 cycloalkyl group, a hydroxyl group (C3-C7 cycloalkyl group) or a (C1-C6 alkyl)carbonyloxy group C1-C6 alkyl, C2-C6 alkenyl, C1-C6 alkoxy which may be substituted with hydroxy or a monocyclic 5- to 10-membered unsaturated hydrocarbon group, C3-C7 cycloalkyl, the C3-C7 cycloalkyl may be substituted with hydroxy, hydroxy(C1-C4 alkyl), (C1-C4 alkoxy)(C1-C4 alkyl), hydroxy(C3-C7 cycloalkyl) or (C6-C14 aromatic hydrocarbon) substituted carbamoyl, mono- or di-(C1-C6 alkyl)amino alkyl, or a carbamoyl group which may be substituted with a C1-C6 alkyl group; more preferably a fluorine atom, a chlorine atom, a bromine atom, an iodine atom, a nitro group, a cyano group, a carboxyl group, a methyl group, an ethyl group, an n-propyl group, an isopropyl group, a tert-butyl group, a difluoromethyl group, a trifluoromethyl group, a fluoroethyl group, an aminoethyl group, a hydroxymethyl group, a hydroxyethyl group, a hydroxypropyl group, a hydroxydimethylethyl group, a hydroxymethylpropyl group, a hydroxymethylbutyl group, a hydroxyethylbutyl group, a carboxylmethyl group, a carbamoylmethyl group, a methylcarbamoylmethyl group, a dimethylcarbamoylmethyl group, an acetylaminoethyl group, a methoxyethyl group, a hydroxycyclopropylmethyl group, a hydroxycyclopropylethyl group, a hydroxycyclobutylmethyl group, a methylcarbonyloxyethyl group, an isobutenyl group, a methoxy group, a hydroxypropyloxy group, a cyclopropyl group, a hydroxymethylcyclopropyl group, a methoxymethylcyclopropyl group, a hydroxycyclopropylcyclopropyl group, a phenylcarbamoylcyclopropyl group, a benzyloxy group, a dimethylamino group, a carbamoyl group, a methylcarbamoyl group, or a dimethyl carbamoyl; more preferably a fluorine atom, a chlorine atom, a bromine atom, a nitro group, a cyano group, a carboxyl group, a methyl group, an ethyl group, an n-propyl group, a tert-butyl group, a difluoromethyl group, a hydroxyethyl group, a hydroxymethylpropyl group, a hydroxymethylbutyl group, a hydroxyethylbutyl group, a carbamoylmethyl group, a methylcarbamoylmethyl group, a dimethylcarbamoylmethyl group, a methoxyethyl group, a hydroxycyclopropylmethyl group, a hydroxycyclobutylmethyl group, a methylcarbonyloxyethyl group, a methoxy group, a cyclopropyl group, a hydroxymethylcyclopropyl group, a dimethylamino group, a carbamoyl group, a methylcarbamoyl group, or a dimethylcarbamoyl group; more preferably a fluorine atom, a chlorine atom, a bromine atom, a cyano group, a methyl group, a difluoromethyl group, a hydroxymethylpropyl group, a hydroxymethylbutyl group, a hydroxyethylbutyl group, a methoxyethyl group, a hydroxycyclobutylmethyl group, or a cyclopropyl group; more preferably a fluorine atom, a chlorine atom, a bromine atom, a cyano group, a methyl group, a difluoromethyl group, a hydroxymethylpropyl group, a hydroxyethylbutyl group, or a hydroxycyclobutylmethyl group.

In the compound represented by formula (I) of the present invention, n is an integer of 0-5, and preferably an integer of 0-3.

As the compound of the present invention, preferred is a compound represented by formula (I) or a salt thereof, wherein

Ring A represents a monocyclic, bridged or spirocyclic nitrogen-containing saturated heterocyclic group,

Ring B represents a monocyclic or bicyclic unsaturated hydrocarbon group, or a monocyclic or bicyclic unsaturated heterocyclic group which may be substituted with oxo,

X represents O or S,

R1 represents a nitro group or a cyano group,

R2 represents a halogen atom,

R3 represents a substituted or unsubstituted amino group, a C1-C6 alkyl group, a halogen atom, a cyano group, an oxo group, a hydroxyl group, a carbamoyl group, a sulfo group, a C1-C6 alkoxy group or an amino (C1-C6 alkyl group),

R4 represents a halogen atom, a hydroxyl group, a nitro group, a cyano group, an amino group, a carboxyl group, a (C2-C7 acyl)amino group, a (C2-C7 acyl)oxy group, a substituted or unsubstituted C1-C8 alkyl group, a substituted or unsubstituted C2-C6 alkenyl group, a substituted or unsubstituted C1-C6 alkoxy group, a substituted or unsubstituted C3-C7 cycloalkyl group, a mono- or di-(C1-C6 alkyl)amino group, a substituted or unsubstituted carbamoyl group, a substituted or unsubstituted C2-C6 alkynyl group, a substituted or unsubstituted (C1-C6 alkyl)carbonyl group, a substituted or unsubstituted 4- to 14-membered nitrogen-containing saturated heterocyclic group, or a substituted or unsubstituted C6-C14 aromatic hydrocarbon group,

l is an integer from 0 to 2,

m is an integer from 0 to 2, and

n is an integer from 0 to 5,

When l is 2, the two R2 can be the same or different,

When m is 2, the two R3 may be the same or different, and

When n is 2-5, two to five R4 groups may be the same or different.

More preferred is a compound represented by formula (I) or a salt thereof, wherein

Ring A represents a monocyclic, bridged or spirocyclic 4- to 14-membered nitrogen-containing saturated heterocyclic group having 1 to 3 nitrogen atoms, 0 to 1 sulfur atoms and 0 to 2 oxygen atoms as heteroatoms,

Ring B represents a monocyclic or bicyclic 5- to 14-membered unsaturated hydrocarbon group, or a monocyclic or bicyclic 5- to 14-membered unsaturated heterocyclic group which may be substituted with oxo, the heterocyclic group having 0 to 4 nitrogen atoms, 0 to 2 sulfur atoms and 0 to 3 oxygen atoms as heteroatoms and having at least one of nitrogen, sulfur and oxygen,

X represents O or S,

R1 represents a nitro group or a cyano group,

R2 represents a halogen atom,

R3 represents amino, mono- or di-(C1-C6 alkyl)amino, (C3-C7 cycloalkyl)amino or C1-C6 alkyl,

R4 represents a halogen atom, a nitro group, a cyano group, a carboxyl group, a substituted or unsubstituted C1-C8 alkyl group, a substituted or unsubstituted C2-C6 alkenyl group, a substituted or unsubstituted C1-C6 alkoxy group, a substituted or unsubstituted C3-C7 cycloalkyl group, a mono- or di-(C1-C6 alkyl)amino group, or a substituted or unsubstituted carbamoyl group,

wherein when at least one R4 is a substituted C1-C8 alkyl group, a substituted C2-C6 alkenyl group, a substituted C1-C6 alkoxy group, a substituted C3-C7 cycloalkyl group, or a substituted carbamoyl group, the substituent is a halogen atom, a carboxyl group, a C1-C6 alkoxy group, a hydroxyl group, a C1-C6 alkyl group which may be substituted with a hydroxyl group, a monocyclic 5- to 10-membered unsaturated hydrocarbon group, a carbamoyl group which may be substituted with a C1-C6 alkyl group or a monocyclic 5- to 10-membered unsaturated hydrocarbon group, a (C2-C7 acyl)oxy group, an amino group which may be substituted with a C1-C6 alkyl group or a C2-C7 acyl group, a C3-C7 cycloalkyl group which may be substituted with a hydroxyl group, or a (C1-C6 alkoxy)(C1-C6 alkyl group), wherein when two or more substituents are present, the substituents may be the same or different,

l is an integer from 0 to 2,

m is an integer from 0 to 2, and

n is an integer from 0 to 5,

When l is 2, the two R2 can be the same or different,

When m is 2, the two R3 may be the same or different, and

When n is 2-5, two to five R4 groups may be the same or different.

More preferred is a compound represented by formula (I) or a salt thereof, wherein

Ring A represents pyrrolidinyl, piperidinyl, piperazinyl, azepanyl, diazepanyl,

2,7-diazaspiro[3.4]octyl, 3,7-diazaspiro[3.4]octyl, 2,7-diazaspiro[3.5]nonyl, 2,8-diazaspiro[3.5]nonyl, 3,7-diazaspiro[3.5]nonyl, 3,8-diazaspiro[4.4]nonyl, 3,8-diazaspiro[4.5]decyl, or 9-oxa-diazaspiro[3.5]nonyl,

Ring B represents a monocyclic or bicyclic 5- to 14-membered unsaturated hydrocarbon group, or a monocyclic or bicyclic 5- to 14-membered unsaturated heterocyclic group which may be substituted with oxo, the heterocyclic group having 0 to 4 nitrogen atoms, 0 to 2 sulfur atoms and 0 to 3 oxygen atoms as heteroatoms and having at least one of nitrogen, sulfur and oxygen,

X represents O or S,

R1 represents a nitro group or a cyano group,

R2 represents a halogen atom,

R3 represents amino, methylamino, ethylamino, isopropylamino, dimethylamino, cyclobutylamino or methyl,

R4 represents a halogen atom, a nitro group, a cyano group, a carboxyl group, a substituted or unsubstituted C1-C8 alkyl group, a substituted or unsubstituted C2-C6 alkenyl group, a substituted or unsubstituted C1-C6 alkoxy group, a substituted or unsubstituted C3-C7 cycloalkyl group, a mono- or di-(C1-C6 alkyl)amino group, or a substituted or unsubstituted carbamoyl group,

wherein when at least one R4 is a substituted C1-C8 alkyl group, a substituted C2-C6 alkenyl group, a substituted C1-C6 alkoxy group, a substituted C3-C7 cycloalkyl group, or a substituted carbamoyl group, the substituent is a halogen atom, a carboxyl group, a C1-C6 alkoxy group, a hydroxyl group, a C1-C6 alkyl group which may be substituted with a hydroxyl group, a monocyclic 5- to 10-membered unsaturated hydrocarbon group, a carbamoyl group which may be substituted with a C1-C6 alkyl group or a monocyclic 5- to 10-membered unsaturated hydrocarbon group, a C2-C7 acyl group, an amino group which may be substituted with a C1-C6 alkyl group or a C2-C7 acyl group, a C3-C7 cycloalkyl group which may be substituted with a hydroxyl group, or a (C1-C6 alkoxy) (C1-C6 alkyl group),

When two or more substituents are present, the substituents may be the same or different.

l is an integer from 0 to 2,

m is an integer from 0 to 2, and

n is an integer from 0 to 5,

When l is 2, the two R2 can be the same or different,

When m is 2, the two R3 may be the same or different, and

When n is 2-5, two to five R4 groups may be the same or different.

More preferred is a compound represented by formula (I) or a salt thereof, wherein

Ring A represents pyrrolidinyl, piperidinyl, piperazinyl, azepanyl, diazepanyl,

2,7-diazaspiro[3.4]octyl, 3,7-diazaspiro[3.4]octyl, 2,7-diazaspiro[3.5]nonyl, 2,8-diazaspiro[3.5]nonyl, 3,7-diazaspiro[3.5]nonyl, 3,8-diazaspiro[4.4]nonyl, 3,8-diazaspiro[4.5]decyl, or 9-oxa-diazaspiro[3.5]nonyl,

Ring B represents a monocyclic or bicyclic 5- to 14-membered unsaturated hydrocarbon group, or a monocyclic or bicyclic 5- to 14-membered unsaturated heterocyclic group which may be substituted with oxo, the heterocyclic group having 0 to 4 nitrogen atoms, 0 to 2 sulfur atoms and 0 to 3 oxygen atoms as heteroatoms and having at least one of nitrogen, sulfur and oxygen,

X represents O or S,

R1 represents a nitro group or a cyano group,

R2 represents a halogen atom,

R3 represents amino, methylamino, ethylamino, isopropylamino, dimethylamino, cyclobutylamino or methyl,

R4 represents a halogen atom; a nitro group; a cyano group; a carboxyl group; a C1-C8 alkyl group which may be substituted with a halogen atom, an amino group, a hydroxyl group, a carboxyl group, a carbamoyl group, a (C1-C6 alkyl)carbamoyl group, a (C1-C6 alkyl)carbonylamino group, a C1-C6 alkoxy group, a (C1-C6 alkyl)carbonyl group, a C3-C7 cycloalkyl group, a hydroxyl(C3-C7 cycloalkyl group) or a (C1-C6 alkyl)carbonyloxy group; a C2-C6 alkenyl group; a C1-C6 alkoxy group which may be substituted with a hydroxyl group or a monocyclic 5- to 10-membered unsaturated hydrocarbon group; a C3-C7 cycloalkyl group which may be substituted with a carbamoyl group which may be substituted with a hydroxyl group, a hydroxyl(C1-C4 alkyl group), a (C1-C4 alkoxy)(C1-C4 alkyl group), a hydroxyl(C3-C7 cycloalkyl group) or a (C6-C14 aromatic hydrocarbon group); a mono- or di-(C1-C6 alkyl)amino group; or a carbamoyl group which may be substituted with a C1-C6 alkyl group,

l is an integer from 0 to 2,

m is an integer from 0 to 2, and

n is an integer from 0 to 5,

When l is 2, the two R2 can be the same or different,

When m is 2, the two R3 may be the same or different, and

When n is 2-5, two to five R4 groups may be the same or different.

More preferred is a compound represented by formula (I) or a salt thereof, wherein

Ring A represents pyrrolidinyl, piperidinyl, piperazinyl, azepanyl, diazepanyl,

2,7-diazaspiro[3.4]octyl, 3,7-diazaspiro[3.4]octyl, 2,7-diazaspiro[3.5]nonyl, 2,8-diazaspiro[3.5]nonyl, 3,7-diazaspiro[3.5]nonyl, 3,8-diazaspiro[4.4]nonyl, 3,8-diazaspiro[4.5]decyl, or 9-oxa-diazaspiro[3.5]nonyl,

Ring B represents phenyl, naphthyl, pyridyl, pyrazolopyridyl, pyrazolopyrimidinyl, indolyl, dihydroindolinyl, 2-oxo-dihydroindolinyl, indazolyl, benzimidazolyl, benzisoxazolyl, benzothiazolyl, benzotriazolyl, imidazopyridyl, quinolyl, isoquinolyl, quinoxalinyl, quinazolinyl, phthalazinyl, 2-oxo-2,3-dihydrobenzo[d]oxazolyl, 1,3-dihydroisobenzofuranyl, dihydrobenzoxazinyl, benzodioxolyl, dihydrobenzodioxolynyl, or 2-oxo-2,3-dihydrobenzo[d]thiazolyl,

X represents O or S,

R1 represents a nitro group or a cyano group,

R2 represents fluorine and is present in the ortho position relative to R1 on the phenyl group,

R3 represents amino, methylamino, ethylamino, isopropylamino, dimethylamino, cyclobutylamino, or methyl (wherein when there are two or more R3, R3 may be the same or different),

R4 represents a fluorine atom, a chlorine atom, a bromine atom, an iodine atom, a nitro group, a cyano group, a carboxyl group, a methyl group, an ethyl group, an n-propyl group, an isopropyl group, a tert-butyl group, a difluoromethyl group, a trifluoromethyl group, a fluoroethyl group, an aminoethyl group, a hydroxymethyl group, a hydroxyethyl group, a hydroxypropyl group, a hydroxydimethylethyl group, a hydroxymethylpropyl group, a hydroxymethylbutyl group, a hydroxyethylbutyl group, a carboxymethyl group, a carbamoylmethyl group, a methylcarbamoylmethyl group, a dimethylcarbamoylmethyl group, an acetylaminoethyl group, a methoxyethyl group, a hydroxycyclopropylmethyl group, a hydroxycyclopropylethyl group, a hydroxycyclobutylmethyl group, a methylcarbonyloxyethyl group, an isobutenyl group, a methoxy group, a hydroxypropyloxy group, a cyclopropyl group, a hydroxymethylcyclopropyl group, a methoxymethylcyclopropyl group, a hydroxycyclopropylcyclopropyl group, a phenylcarbamoylcyclopropyl group, a benzyloxy group, a dimethylamino group, a carbamoyl group, a methylcarbamoyl group or a dimethylcarbamoyl group,

l is an integer from 0 to 2,

m is an integer from 0 to 2, and

n is an integer from 0 to 3,

When m is 2, the two R3 can be the same or different, and

When n is 2-3, two or three R4 groups may be the same or different.

More preferred is a compound represented by formula (I) or a salt thereof, wherein

Ring A represents pyrrolidinyl, piperidinyl, azepanyl, diazepanyl,

2,7-diazaspiro[3.4]octyl, 3,7-diazaspiro[3.4]octyl, 2,7-diazaspiro[3.5]nonyl, 2,8-diazaspiro[3.5]nonyl, or 9-oxa-diazaspiro[3.5]nonyl,

Ring B represents phenyl, naphthyl, pyridyl, pyrazolopyridyl, indolyl, dihydroindolinyl, indazolyl, benzimidazolyl, benzisoxazolyl, benzotriazolyl, quinolinyl, 2-oxo-2,3-dihydrobenzo[d]oxazolyl, 1,3-dihydroisobenzofuranyl, dihydrobenzoxazinyl, or 2-oxo-2,3-dihydrobenzo[d]thiazolyl,

X represents O or S,

R1 represents a cyano group,

R2 represents fluorine and is present in the ortho position relative to R1 on the benzene ring,

R3 represents amino, methylamino, ethylamino, isopropylamino, dimethylamino, cyclobutylamino or methyl (wherein when there are two or more R3, R3 may be the same or different),

R4 represents a fluorine atom, a chlorine atom, a bromine atom, a nitro group, a cyano group, a carboxyl group, a methyl group, an ethyl group, an n-propyl group, a tert-butyl group, a difluoromethyl group, a hydroxyethyl group, a hydroxymethylpropyl group, a hydroxymethylbutyl group, a hydroxyethylbutyl group, a carbamoylmethyl group, a methylcarbamoylmethyl group, a dimethylcarbamoylmethyl group, a methoxyethyl group, a hydroxycyclopropylmethyl group, a hydroxycyclobutylmethyl group, a methylcarbonyloxyethyl group, a methoxy group, a cyclopropyl group, a hydroxymethylcyclopropyl group, a dimethylamino group, a carbamoyl group, a methylcarbamoyl group or a dimethylcarbamoyl group,

l is an integer from 0 to 2,

m is an integer from 0 to 2, and

n is an integer from 0 to 3,

When m is 2, the two R3 can be the same or different, and

When n is 2-3, two or three R4 groups may be the same or different.

More preferred is a compound represented by formula (I) or a salt thereof, wherein

Ring A represents a pyrrolidinyl group,

or 2,8-diazaspiro[3.5]nonyl,

Ring B represents phenyl, indolyl, indazolyl, benzisoxazolyl, or benzotriazolyl,

X represents O,

R1 represents a cyano group,

R2 represents fluorine and is present in the ortho position relative to R1 on the benzene ring,

R3 represents amino or methyl (wherein when there are two or more R3, R3 may be the same or different),

R4 represents a fluorine atom, a chlorine atom, a bromine atom, a cyano group, a methyl group, a difluoromethyl group, a hydroxymethylpropyl group, a hydroxymethylbutyl group, a hydroxyethylbutyl group, a methoxyethyl group, a hydroxycyclobutylmethyl group, or a cyclopropyl group,

l is an integer from 0 to 2,

m is an integer from 0 to 2, and

n is an integer from 0 to 3,

When m is 2, the two R3 can be the same or different, and

When n is 2-3, two or three R4 groups may be the same or different.

More preferred is a compound represented by formula (I) or a salt thereof, wherein

Ring A represents a pyrrolidinyl group,

Ring B represents phenyl, indolyl, indazolyl, benzisoxazolyl, or benzotriazolyl,

X represents O,

R1 represents a cyano group,

R2 represents fluorine and is present in the ortho position relative to R1 on the benzene ring,

R3 represents an amino group (wherein when there are two or more R3, R3 may be the same or different),

R4 represents a fluorine atom, a chlorine atom, a bromine atom, a cyano group, a methyl group, a difluoromethyl group, a hydroxymethylpropyl group, a hydroxyethylbutyl group, or a hydroxycyclobutylmethyl group,

l is an integer from 0 to 2,

m is an integer from 0 to 2, and

n is an integer from 0 to 3,

When m is 2, the two R3 can be the same or different, and

When n is 2-3, two or three R4 groups may be the same or different.

Specific examples of the compounds of the present invention include, but are not limited to, the compounds prepared in the following examples.

The following are examples of preferred compounds of the present invention:

4-[5-[(3-exo)-3-amino-8-azabicyclo[3.2.1]octane-8-carbonyl]-2-[2-fluoro-4-(2-hydroxy-2-methyl-propyl)phenyl]phenyl]-2-fluoro-benzonitrile,

4-[5-[(3S)-3-aminopyrrolidine-1-carbonyl]-2-[2-fluoro-4-(2-hydroxy-2-methyl-propyl)phenyl]phenyl]-2-fluoro-benzonitrile,

4-[5-[(3-endo)-3-amino-8-azabicyclo[3.2.1]octane-8-carbonyl]-2-[2-fluoro-4-(2-hydroxy-2-methyl-propyl)phenyl]phenyl]-2-fluoro-benzonitrile,

(S)-5'-(3-aminopyrrolidine-1-carbonyl)-3-fluoro-2'-(6-fluoro-1-(2-hydroxy-2-methylpropyl)-1H-indol-5-yl)-[1,1'-biphenyl]-4-carbonitrile,

5'-((3-endo)-3-amino-8-azabicyclo[3.2.1]octane-8-carbonyl)-2'-(6,7-difluoro-1-(2-hydroxy-2-methylpropyl)-1H-benzo[d][1,2,3]triazol-5-yl)-3-fluoro-[1,1'-biphenyl]-4-carbonitrile,

5'-((1S,2S,4R)-rel-2-amino-7-azabicyclo[2.2.1]heptane-7-carbonyl)-2",3-difluoro-4"-(2-hydroxy-2-methylpropyl)-[1,1':2',1"-terphenyl]-4-carbonitrile-isomer-B,

5'-((1S,2S,4R)-rel-2-amino-7-azabicyclo[2.2.1]heptane-7-carbonyl)-2'-(6,7-difluoro-1-methyl-1H-benzo[d][1,2,3]triazol-5-yl)-3-fluoro-[1,1'-biphenyl]-4-carbonitrile-isomer-B,

5'-((1S,2S,4R)-rel-2-amino-7-azabicyclo[2.2.1]heptane-7-carbonyl)-3-fluoro-2'-(6-fluoro-1-(2-hydroxy-2-methylpropyl)-1H-indazol-5-yl)-[1,1'-biphenyl]-4-carbonitrile-isomer-B,

5'-((1S,2S,4R)-rel-2-amino-7-azabicyclo[2.2.1]heptane-7-carbonyl)-2'-(6,7-difluoro-1-(2-hydroxy-2-methylpropyl)-1H-benzo[d][1,2,3]triazol-5-yl)-3-fluoro-[1,1'-biphenyl]-4-carbonitrile-isomer-B,

5'-((1S,2S,4R)-rel-2-amino-7-azabicyclo[2.2.1]heptane-7-carbonyl)-2'-(6,7-difluoro-1-(2-hydroxy-2-methylpropyl)-1H-benzo[d][1,2,3]triazol-5-yl)-3-fluoro-[1,1'-biphenyl]-4-carbonitrile,

5'-((1S,2S,4R)-rel-2-amino-7-azabicyclo[2.2.1]heptane-7-carbonyl)-2'-(7-chloro-6-fluoro-1-(2-hydroxy-2-methylpropyl)-1H-benzo[d][1,2,3]triazol-5-yl)-3-fluoro-[1,1'-biphenyl]-4-carbonitrile-isomer-X,

5'-((1S,2S,4R)-rel-2-amino-7-azabicyclo[2.2.1]heptane-7-carbonyl)-2'-(7-chloro-6-fluoro-1-(2-hydroxy-2-methylpropyl)-1H-benzo[d][1,2,3]triazol-5-yl)-3-fluoro-[1,1'-biphenyl]-4-carbonitrile,

5'-((1S,2S,4R)-rel-2-amino-7-azabicyclo[2.2.1]heptane-7-carbonyl)-2'-(1-(2-ethyl-2-hydroxybutyl)-6,7-difluoro-1H-benzo[d][1,2,3]triazol-5-yl)-3-fluoro-[1,1'-biphenyl]-4-carbonitrile-isomer-X,

5'-((1S,2S,4R)-rel-2-amino-7-azabicyclo[2.2.1]heptane-7-carbonyl)-2'-(1-(2-ethyl-2-hydroxybutyl)-6,7-difluoro-1H-benzo[d][1,2,3]triazol-5-yl)-3-fluoro-[1,1'-biphenyl]-4-carbonitrile,

(S)-5'-(3-aminopyrrolidine-1-carbonyl)-3-fluoro-2'-(5-fluoro-3-(2-hydroxy-2-methylpropyl)benzo[d]isoxazol-6-yl)-[1,1'-biphenyl]-4-carbonitrile,

5'-((1S,2S,4R)-rel-2-amino-7-azabicyclo[2.2.1]heptane-7-carbonyl)-2'-(7-(difluoromethyl)-6-fluoro-1-(2-hydroxy-2-methylpropyl)-1H-benzo[d][1,2,3]triazol-5-yl)-3-fluoro-[1,1'-biphenyl]-4-carbonitrile-isomer-X,

5-(5-((1S,2S,4R)-rel-2-amino-7-azabicyclo[2.2.1]heptane-7-carbonyl)-4'-cyano-3'-fluoro-[1,1'-biphenyl]-2-yl)-6-fluoro-1-(2-hydroxy-2-methylpropyl)-1H-benzo[d][1,2,3]triazole-7-carbonitrile-isomer-X,

5'-((1S,2S,4R)-rel-2-amino-7-azabicyclo[2.2.1]heptane-7-carbonyl)-2'-(7-(difluoromethyl)-6-fluoro-1-(2-hydroxy-2-methylpropyl)-1H-benzo[d][1,2,3]triazol-5-yl)-3-fluoro-[1,1'-biphenyl]-4-carbonitrile,

5'-((3-endo)-3-amino-8-azabicyclo[3.2.1]octane-8-carbonyl)-2'-(7-chloro-6-fluoro-1-((1-hydroxycyclobutyl)methyl)-1H-benzo[d][1,2,3]triazol-5-yl)-3-fluoro-[1,1'-biphenyl]-4-carbonitrile,

5'-((3-endo)-3-amino-8-azabicyclo[3.2.1]octane-8-carbonyl)-2'-(7-(difluoromethyl)-6-fluoro-1-((1-hydroxycyclobutyl)methyl)-1H-benzo[d][1,2,3]triazol-5-yl)-3-fluoro-[1,1'-biphenyl]-4-carbonitrile,

5-(5-((1S,2S,4R)-rel-2-amino-7-azabicyclo[2.2.1]heptane-7-carbonyl)-4'-cyano-3'-fluoro-[1,1'-biphenyl]-2-yl)-6-fluoro-1-((1-hydroxycyclobutyl)methyl)-1H-benzo[d][1,2,3]triazole-7-carbonitrile-isomer-X,

5-(5-((1S,2S,4R)-rel-2-amino-7-azabicyclo[2.2.1]heptane-7-carbonyl)-4'-cyano-3'-fluoro-[1,1'-biphenyl]-2-yl)-6-fluoro-1-((1-hydroxycyclobutyl)methyl)-1H-benzo[d][1,2,3]triazole-7-carbonitrile,

5'-((1S,2S,4R)-rel-2-amino-7-azabicyclo[2.2.1]heptane-7-carbonyl)-2'-(7-bromo-6-fluoro-1-(2-hydroxy-2-methylpropyl)-1H-benzo[d][1,2,3]triazol-5-yl)-3-fluoro-[1,1'-biphenyl]-4-carbonitrile-isomer-X,

5'-((1S,2S,4R)-rel-2-amino-7-azabicyclo[2.2.1]heptane-7-carbonyl)-2'-(7-bromo-6-fluoro-1-(2-hydroxy-2-methylpropyl)-1H-benzo[d][1,2,3]triazol-5-yl)-3-fluoro-[1,1'-biphenyl]-4-carbonitrile.

Next, methods for preparing the compounds of the present invention are described.

The compound (I) of the present invention can be produced by, for example, the following production methods or the methods described in Examples. However, the method for producing the compound (I) of the present invention is not limited to these reaction examples.

In steps 1 to 5, in the chemical formula, L1, L2 and L3 each independently represent a leaving group, NH ₂ , or OH, and W represents a hydroxyl group, a C1-C6 alkoxy group or

Q1 means L1 or

Q2 means L2 or

and E1 represents hydrogen or a substituted or unsubstituted C1-C6 alkyl group, wherein when E1 is a substituted or unsubstituted C1-C6 alkyl group, E1 may form a ring together with BOO. X, Ring A, Ring B, R1, R2, R3, R4, l, m and n are as defined above.

Step 1: Suzuki reaction

This step represents a method for producing a compound represented by formula (IV) by Suzuki reaction using a compound represented by formula (II).

This step can be carried out according to a known method (for example, the method disclosed in Chemical Reviews, Vol. 95, p. 2457, 1995). Protection of substituents, removal or conversion of protecting groups, and conversion of leaving groups L1, L2, and L3 can be carried out as appropriate.

Examples of the leaving group represented by L1, L2 and L3 include a halogen atom such as a chlorine atom, a bromine atom and an iodine atom; an organic sulfonyloxy group such as a trifluoromethylsulfonyloxy group and a p-toluenesulfonyloxy group; and the like.

The amount of aromatic boronic acid or aromatic boronic acid ester (III) used may be 0.5-10 mol, preferably 0.8-3 mol, per mol of the compound represented by formula (II).

Examples of the transition metal catalyst include palladium catalysts such as palladium acetate, tetrakis(triphenylphosphine)palladium, 1,1'-bis(diphenylphosphino)ferrocene-dichloropalladium(II), bis(dibenzylideneacetone)dipalladium(0) and tris(dibenzylideneacetone)dipalladium(0); nickel catalysts such as nickel chloride; and the like.

As needed, a ligand can be added. Examples of ligands include triphenylphosphine, tricyclohexylphosphine, (diphenylphosphino) ferrocene, 2-dicyclohexylphosphino-2', 4', 6'-triisopropylbiphenyl, silica-SMAP, etc. The amount of the transition metal catalyst used varies according to the type of catalyst. Relative to each mole of the compound shown in formula (II), the amount of the transition metal catalyst used is generally 0.0001-1 mole, preferably 0.001-0.5 mole. Relative to each mole of the compound shown in formula (II), the amount of the ligand used is generally 0.0001-4 moles, preferably 0.01-2 moles.

Examples of the base include organic amines such as triethylamine; alkali metal salts such as sodium carbonate, potassium carbonate, cesium carbonate, sodium phosphate, tripotassium phosphate, sodium hydroxide, and potassium hydroxide; alkali metal alkoxides such as sodium methoxide, sodium ethoxide, sodium tert-butoxide, and potassium tert-butoxide, etc. The amount of the base used is generally 0.1 to 10 moles, preferably 1 to 5 moles, per mole of the compound represented by formula (II).

The solvent is not limited as long as it does not adversely affect the reaction. Examples include toluene, acetonitrile, 1,2-dimethoxyethane, tetrahydrofuran, 1,4-dioxane, ethanol, N,N-dimethylformamide, water, and mixed solvents thereof. The reaction time is 0.1 to 7 days, preferably 0.5 to 24 hours. The reaction temperature is 0°C to the boiling point of the solvent, preferably 20°C to 160°C.

The compound represented by formula (IV) thus obtained can be used for the subsequent step after isolation or purification by known separation and purification means such as concentration, vacuum concentration, crystallization, solvent extraction, reprecipitation and chromatography, or without isolation or purification.

Alternatively, the conversion of L2 into

reaction.

Step 2: Suzuki reaction

This step shows a method for producing a compound represented by formula (I') by using a compound represented by formula (IV) through Suzuki reaction.

This step can be carried out as in step 1. When L2 (or L1 if a reaction for converting L2 has been first carried out) is a boronic acid or boronic ester derivative, compound (VI) is used for the reaction.

L3 in (VI) is the same as L1 and L2 in step 1, and the amount of (VI) used is usually 1 to 10 moles, and preferably 1 to 5 moles, per mole of the compound represented by formula (IV).

Step 3: Boronation reaction

This step represents a method for preparing a compound represented by formula (IX), wherein L2 is converted into a borate ester by a borate esterification reaction using a compound represented by formula (IV) and a diborane compound (VIII) in the presence of a transition metal catalyst and a base, optionally using a ligand.

The amount of the diborane compound (VIII) to be used is 1 to 10 moles, and preferably 1 to 5 moles, per mole of the compound represented by the formula (IV).

The transition metal catalyst may be the same as that in step 1.

As the base, in addition to those described in Step 1, potassium acetate, sodium acetate, etc. can be used.

The ligand can be the same as in step 1, preferably silica-SMAP.

The solvent may be the same as in step 1.

The reaction temperature is usually 0-200° C., and preferably 50-160° C. The reaction time is usually 5 minutes to 3 days, preferably 5 minutes to 10 hours.

Before implementing step 3, you can first

Introduce into the compound represented by formula (II); then, the borate esterification reaction of L1 can be carried out as in step 3.

Step 4: Amidation reaction

This step represents a method for producing a compound represented by formula (XI) by amidation reaction using a carboxylic acid compound represented by formula (VII), an amine compound represented by formula (X) and a condensing agent.

The amount of the amine compound (X) used is 0.5 to 10 moles, and preferably 0.8 to 5 moles, per mole of the compound represented by the formula (VII).

Examples of the condensing agent include benzotriazol-1-yloxy-tris dimethylaminophosphonium salt, 4-(4,6-dimethoxy-1,3,5-triazin-2-yl)-4-methylmorpholinium chloride, a combination of 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide and 1-hydroxybenzotriazole, O-(7-azabenzotriazol-1-yl)-N,N,N',N'-tetramethylhexaurea hexafluorophosphate, etc. The amount added is usually 1 to 100 moles, and preferably 1 to 5 moles, per mole of the compound represented by formula (VII).

A base is optionally added during the above reaction. Examples of the base include organic bases such as triethylamine, diisopropylethylamine, and pyridine; and inorganic bases such as potassium carbonate. The amount added is generally 1 to 100 moles, preferably 1 to 10 moles, per mole of the compound represented by formula (VII).

The solvent is not particularly limited, and any solvent that does not adversely affect the reaction can be used. Examples of the solvent include toluene, chloroform, tetrahydrofuran, N,N-dimethylformamide, dimethylacetamide, N-methylpyrrolidin-2-one, mixtures thereof, and the like.

The reaction temperature is usually -78 to 200° C., and preferably 0 to 50° C. The reaction time is usually 5 minutes to 3 days, and preferably 5 minutes to 10 hours.

The compound represented by formula (XI) thus obtained can be used for the subsequent step after isolation or purification by known separation and purification means such as concentration, vacuum concentration, crystallization, solvent extraction, reprecipitation and chromatography, or without isolation or purification.

Step 5: Sulfurization reaction

This step represents a method for producing a thioamide compound represented by formula (XII) by reacting a compound represented by formula (XI) with a sulfurizing agent.

Examples of the sulfurizing agent include Lawesson's reagent, etc. The amount of the agent added may be 1 to 10 moles, and preferably 1 to 5 moles, per mole of the compound represented by formula (XI).

The solvent may be the same as in step 1.

The reaction temperature is usually 0 to 200° C., and preferably 0 to 100° C. The reaction time is usually 5 minutes to 3 days, and preferably 5 minutes to 10 hours.

The compound represented by formula (XII) thus obtained can be used for the subsequent step after isolation or purification by known separation and purification means such as concentration, vacuum concentration, crystallization, solvent extraction, reprecipitation and chromatography, or without isolation or purification.

The conversion of the substituents W and X, and the leaving groups L1, L2 and L3 can be carried out as appropriate.

In any of steps 1 to 5, protection of substituents and removal or conversion of protective groups may be appropriately performed. For example, for functional groups such as amino, imino, hydroxy, carboxyl, carbonyl, and amide groups, and functional groups having active protons such as indole, a protecting agent may be used, or a protecting group may be introduced into such a functional group according to conventional methods; thereafter, the protecting group may be removed in an appropriate step in each production method.

The protecting group of the amino group or the protecting group of the imino group is not particularly limited as long as it has a protective function. Examples of such protecting groups include aralkyl groups such as benzyl, p-methoxybenzyl, 3,4-dimethoxybenzyl, o-nitrobenzyl, p-nitrobenzyl, diphenylmethyl, triphenylmethyl and cumyl; lower alkanoyl groups such as formyl, acetyl, propionyl, butyryl, pivaloyl, trifluoroacetyl and trichloroacetyl; benzoyl; arylalkanoyl groups such as phenylacetyl and phenoxyacetyl; lower alkoxycarbonyl groups such as methoxycarbonyl, ethoxycarbonyl, propoxycarbonyl and tert-butoxycarbonyl; The present invention also includes alkylcarbonyl, arylcarbonyl, arylalkyloxycarbonyl, such as p-nitrobenzyloxycarbonyl and phenethoxycarbonyl, lower alkylsilyl, such as trimethylsilyl and tert-butyldimethylsilyl, tetrahydropyranyl, trimethylsilylethoxymethyl, lower alkylsulfonyl, such as methylsulfonyl, ethylsulfonyl and tert-butylsulfonyl, lower alkylsulfinyl, such as tert-butylsulfinyl, arylsulfonyl, such as benzylsulfonyl and toluenesulfonyl, and imino groups such as phthalimido. Specifically, trifluoroacetyl, acetyl, tert-butoxycarbonyl, benzyloxycarbonyl, trimethylsilylethoxymethyl, cumyl, etc. are preferred.

The protective group of the hydroxyl group is not particularly limited as long as it has a protective function. Examples of such protective groups include lower alkyl groups such as methyl, ethyl, propyl, isopropyl, and tert-butyl; lower alkylsilyl groups such as trimethylsilyl and tert-butyldimethylsilyl; lower alkoxymethyl groups such as methoxymethyl and 2-methoxyethoxymethyl; tetrahydropyranyl; trimethylsilylethoxymethyl; aralkyl groups such as benzyl, p-methoxybenzyl, 2,3-dimethoxybenzyl, o-nitrobenzyl, p-nitrobenzyl, and trityl; and acyl groups such as formyl, acetyl, and trifluoroacetyl. Particularly preferred are methyl, methoxymethyl, tetrahydropyranyl, trimethylsilylethoxymethyl, tert-butyldimethylsilyl, and acetyl.

The protective group of the carboxyl group is not particularly limited as long as it has a protective function. Examples of such protective groups include lower alkyl groups such as methyl, ethyl, propyl, isopropyl, and tert-butyl; halogenated lower alkyl groups such as 2,2,2-trichloroethyl; lower alkenyl groups such as allyl; trimethylsilylethoxymethyl; and aralkyl groups such as benzyl, p-methoxybenzyl, p-nitrobenzyl, diphenylmethyl, and triphenylmethyl. Particularly preferred are methyl, ethyl, tert-butyl, allyl, benzyl, p-methoxybenzyl, trimethylsilylethoxymethyl, and the like.

The protective group for the carbonyl group is not particularly limited as long as it has a protective function. Examples of such protective groups include ketals and acetals such as ethylene ketal, trimethylene ketal, dimethyl ketal, ethylene acetal, trimethylene acetal, and dimethyl acetal.

The protective group of the amide group or the functional group having an active proton, such as the protective group of the indole group, is not particularly limited as long as it has a protective function. Examples of such protective groups include lower alkyl groups such as methyl, ethyl, propyl, isopropyl, and tert-butyl; lower alkylsilyl groups such as trimethylsilyl and tert-butyldimethylsilyl; lower alkoxymethyl groups such as methoxymethyl and 2-methoxyethoxymethyl; tetrahydropyranyl; trimethylsilylethoxymethyl; aralkyl groups such as benzyl, p-methoxybenzyl, 2,3-dimethoxybenzyl, o-nitrobenzyl, p-nitrobenzyl, and trityl; and acyl groups such as formyl, acetyl, and trifluoroacetyl. Particularly preferred are methyl, methoxymethyl, tetrahydropyranyl, trimethylsilylethoxymethyl, tert-butyldimethylsilyl, and acetyl.

The method for removing such protecting groups may vary depending on the type of protecting group, the stability of the target compound (I), etc. For example, the following methods can be used: solvolysis using an acid or base according to the method disclosed in the publication (Protective Groups in Organic Synthesis, 3rd edition, T.W. Green, John Wiley & Sons (1999)) or a similar method, i.e., a method comprising reacting with 0.01 mole or a large excess of an acid, preferably trifluoroacetic acid, formic acid or hydrochloric acid, or with an equimolar to large excess of a base, preferably potassium hydroxide or calcium hydroxide; chemical reduction using a metal hydride complex; or catalytic reduction using a palladium-carbon catalyst or a Raney nickel catalyst;

The compounds of the present invention can be easily isolated and purified by common separation and purification means. Examples of such means include solvent extraction, recrystallization, preparative reverse-phase high performance liquid chromatography, column chromatography, preparative thin-layer chromatography, and the like.

When the compounds of this invention have isomers such as optical isomers, stereoisomers, rotational isomers and tautomers, unless otherwise stated, any isomer and mixture thereof are included in the scope of the compounds of this invention. For example, when the compounds of this invention have optical isomers, unless otherwise stated, the optical isomers separated by racemic mixture are also included in the scope of the compounds of this invention. By known synthesis and separation methods (such as concentration, solvent extraction and column chromatography, recrystallization) each such isomer can be obtained as a single compound.

As described above, unless otherwise indicated, the compounds of the present invention include all enantiomers and mixtures thereof. The compounds of the present invention may be mixtures of R and S enantiomers. Such mixtures may include mixtures containing 90% or more, 95% or more, or 99% or more of the R enantiomer; mixtures containing 90% or more, 95% or more, or 99% or more of the S enantiomer; and so on.

Chiral resolution methods include, for example, a diastereoisomer method in which a chiral resolving agent is allowed to act on the compound of the present invention to form a salt and one enantiomer is resolved using the difference in solubility of the resulting salt; a preferential crystallization method in which one enantiomer is added to a supersaturated solution of a racemate as a seed for crystallization; and column chromatography such as HPLC using a chiral column. The chiral resolving agent that can be used for the diastereoisomer method can be appropriately selected from, for example, acid resolving agents such as tartaric acid, malic acid, lactic acid, mandelic acid, 10-camphorsulfonic acid and its derivatives; and alkaline resolving agents such as alkaloids such as strychnine, quinine, amino acid derivatives, cinchona and α-methylbenzylamine. A single enantiomer of the compound of the present invention can be obtained not only by obtaining the compound of the present invention as a mixture of enantiomers as described above and then performing chiral resolution, but also by obtaining one enantiomer of the compound of the present invention by chiral resolution as described above or other methods and using it as a synthetic raw material for the compound of the present invention. Furthermore, the method for obtaining one enantiomer of the compound of the present invention or its starting compound includes a method for preferentially obtaining one enantiomer by adjusting the reaction conditions such as the catalyst in the reaction step for generating an asymmetric carbon.

The compound of the present invention or its salt can be a crystalline form. Single crystal and polymorphic crystal mixture are included in the scope of the compound of the present invention or its salt. This crystal can be prepared by crystallization according to crystallization methods known in the art. The compound of the present invention or its salt can be a solvate (such as a hydrate) or an ansolvate. Any such form is included in the scope of the compound of the present invention or its salt. Compounds labeled with isotopes (such as 3H, 14C, 35S and 125I) are also included in the scope of the compound of the present invention or its salt.

The salts of the compounds of the present invention or their intermediates refer to common salts used in the field of organic chemistry. Examples of such salts include base addition salts with carboxyl groups when the compound has a carboxyl group, and acid addition salts with amino groups or basic heterocyclic groups when the compound has an amino group or a basic heterocyclic group.

Examples of base addition salts include alkali metal salts such as sodium and potassium salts; alkaline earth metal salts such as calcium and magnesium salts; ammonium salts; and organic amine salts such as trimethylamine salts, triethylamine salts, dicyclohexylamine salts, ethanolamine salts, diethanolamine salts, triethanolamine salts, procaine salts, and N,N'-dibenzylethylenediamine salts.

Examples of acid addition salts include inorganic acid salts such as hydrochlorides, sulfates, nitrates, phosphates and perchlorates; organic acid salts such as acetates, formates, maleates, fumarates, tartrates, citrates, ascorbates and trifluoroacetates; and sulfonates such as methanesulfonates, isethionates, benzenesulfonates and p-toluenesulfonates.

Due to their excellent LSD1 inhibitory activity, the compounds of the present invention or salts thereof are useful as pharmaceutical preparations for preventing and treating LSD1-related diseases.

Examples of "LSD1-related diseases" include the following diseases: diseases whose incidence can be reduced and whose symptoms can be alleviated, relieved and/or completely cured by eliminating, preventing and/or inhibiting LSD1 function. Examples of these diseases include, but are not limited to, malignant tumors and the like. The types of malignant tumors that can be treated with the compounds of the present invention or their salts are not particularly limited. Examples of such malignant tumors include head and neck cancer, esophageal cancer, gastric cancer, colon cancer, rectal cancer, liver cancer, gallbladder cancer, bile duct cancer, biliary tract cancer, pancreatic cancer, lung cancer, breast cancer, ovarian cancer, cervical cancer, endometrial cancer, kidney cancer, bladder cancer, prostate cancer, testicular tumors, osteosarcoma, soft tissue sarcoma, leukemia, myelodysplastic syndrome, chronic myeloproliferative disease, malignant lymphoma, multiple myeloma, skin cancer, brain tumor, mesothelioma, and the like. Preferred examples include lung cancer (e.g., non-small cell lung cancer and small cell lung cancer), leukemia, and myelodysplastic syndrome.

When the compound of the present invention or its salt is used as a pharmaceutical preparation, a pharmaceutical carrier may be added if necessary to form a suitable dosage form according to the purpose of prevention and treatment. Examples of dosage forms include oral preparations, injections, suppositories, ointments, patches, etc. Among them, oral preparations are preferred. Such dosage forms can be formed by methods commonly known to those skilled in the art.

As pharmaceutical carriers, various conventional organic or inorganic carrier materials used as formulation materials can be blended in solid formulations as excipients, binders, disintegrants, lubricants or colorants; or blended in liquid formulations as solvents, solubilizers, suspending agents, isotonic agents, buffers or soothing agents. In addition, if necessary, pharmaceutical formulation additives such as preservatives, antioxidants, colorants, sweeteners and stabilizers can also be used.

Oral solid preparations are prepared as follows: After adding excipients, optionally with excipients, binders, disintegrants, lubricants, colorants, taste-masking agents or flavoring agents, etc., to the compound of the present invention, the resulting mixture is formulated into tablets, coated tablets, granules, powders, capsules, etc. by conventional methods.

Examples of excipients include lactose, sucrose, D-mannitol, glucose, starch, calcium carbonate, kaolin, microcrystalline cellulose, and silicic anhydride. Examples of binders include water, ethanol, 1-propanol, 2-propanol, simple syrup, liquid glucose, liquid α-starch, liquid gelatin, D-mannitol, carboxymethyl cellulose, hydroxypropyl cellulose, hydroxypropyl starch, methyl cellulose, ethyl cellulose, shellac, calcium phosphate, polyvinyl pyrrolidone, etc. Examples of disintegrants include dry starch, sodium alginate, agar powder, sodium bicarbonate, calcium carbonate, sodium lauryl sulfate, stearic acid monoglyceride, lactose, etc. Examples of lubricants include refined talc, sodium stearate, magnesium stearate, borax, polyethylene glycol, etc. Examples of colorants include titanium oxide, iron oxide, etc. Examples of taste masking agents or flavorings include sucrose, bitter orange peel, citric acid, tartaric acid, etc.

When preparing liquid preparations for oral administration, taste masking agents, buffers, stabilizers, flavoring agents, etc. can be added to the compounds of the present invention; and the resulting mixture can be formulated into oral liquid preparations, syrups, elixirs, etc. according to conventional methods.

In this case, the same taste masking agents or flavoring agents as those mentioned above can be used. The example of buffer comprises sodium citrate etc., and the example of stabilizer comprises tragacanth, gum arabic, gelatin etc. As required, these preparations for oral administration can be coated with enteric coating or other coating according to methods known in the art, to achieve the purpose of, for example, lasting effect. The example of this coating agent comprises hydroxypropyl methylcellulose, ethyl cellulose, hydroxymethyl cellulose, hydroxypropyl cellulose, polyoxyethylene glycol and Tween 80 (registered trademark).

When preparing injections, pH regulators, buffers, stabilizers, isotonic agents, local anesthetics, etc. may be added to the compound of the present invention as needed; and the resulting mixture may be formulated for subcutaneous, intramuscular and intravenous injection according to conventional methods.

Examples of usable pH adjusters and buffers include sodium citrate, sodium acetate, sodium phosphate, and the like. Examples of usable stabilizers include sodium metabisulfite, EDTA, thioglycolic acid, and thiolactic acid. Examples of usable local anesthetics include procaine hydrochloride, lidocaine hydrochloride, and the like. Examples of usable isotonic agents include sodium chloride, glucose, D-mannitol, glycerol, and the like.

The amount of the compound of the present invention incorporated in each of these dosage unit forms depends on the condition of the patient to whom the compound is administered, the dosage form, etc. In general, in the case of oral preparations, injections and suppositories, the amount of the compound of the present invention per dosage unit form is preferably 0.05-1000 mg, 0.01-500 mg and 1-1000 mg, respectively.

The daily dose of the drug in this dosage form depends on the patient's condition, body weight, age, sex, etc. and cannot be generalized. For example, for an adult (weighing 50 kg), the daily dose of the compound of the present invention can generally be 0.05-5000 mg, preferably 0.1-1000 mg, and is preferably administered once a day or in two to three divided doses.

Example

The present invention will be described in more detail below with reference to the following examples. However, the scope of the present invention is not limited to these examples. The present invention is fully described below by way of examples; however, it should be understood that various changes and modifications may be made by those skilled in the art. Therefore, such changes and modifications are intended to be included in the present invention without departing from the scope of the present invention.

Unless otherwise stated, the various reagents used in the examples were purchased from commercial suppliers. For silica gel column chromatography, SNAP-Ultra (registered trademark) silica pre-packed columns produced by Biotage were used. Alternatively, for basic silica gel column chromatography, KP-NH (registered trademark) pre-packed columns produced by Biotage were used. NMR spectra were measured using AL400 (400 MHz; produced by JEOL), Mercury 400 (400 MHz; produced by Agilent Technologies, Inc.) or 500-MHz Bruker Avance III HD NMR spectrometer (500 MHz; Bruker). When the deuterated solvent contained tetramethylsilane, tetramethylsilane was used as an internal standard. Otherwise, the NMR solvent was used as an internal standard. All δ values are expressed in ppm. Microwave reactions were performed using an Initiator produced by Biotage.

LCMS spectrum was measured using Acquity SQD (quadrupole) manufactured by Waters Corporation under the following conditions.

Column: Acquity UPLC (registered trademark) BEH C18, 2.1 x 50 mm, 1.7 μm (manufactured by Waters Corporation)

MS detection: ESI positive

UV detection: 254 and 280 nm

Column flow rate: 0.5 mL/min

Mobile phase: water/acetonitrile (0.1% formic acid)

Injection volume: 1 μL

Gradient (Table 1)

Time (min) Water Acetonitrile

0 95 5

0.1 95 5

2.1 5 95

3.0 Stop

Preparative reverse phase HPLC purification was performed using a preparative separation system from Gilson, Inc. under the following conditions.

Column: Xselect CSH Prep C18 5 μm OBD (19×50 mm) + (19×100 mm) manufactured by Waters Corporation

UV detection: 254nm

Column flow rate: 18 mL/min

Mobile phase: water/acetonitrile (0.1% formic acid)

Injection volume: 0.1-0.5 mL

The symbols are as follows.

s: single peak

d: Twin Peaks

t: triplet

q: quartet

dd: doublet

dt: double triplet

td: triplet doublet

tt: triple triplet

ddd: two sets of doublets

ddt: two sets of double triplets

dtd: two sets of three doublets

tdd: three sets of doublets

m: multiple peaks

br: width

brs: broad single peak

THF: Tetrahydrofuran

DMF: N,N-dimethylformamide

DME: 1,2-dimethoxyethane

DMSO: dimethyl sulfoxide

HATU: O-(7-azabenzotriazol-1-yl)-N,N,N',N'-tetramethylhexaurea hexafluorophosphate

TEA: triethylamine

WSC HCl: 1-Ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride

t-BuOH: tert-butyl alcohol

DMAP: N,N-dimethylaminopyridine

Pd(PPh ₃ ) ₄ : Tetrakis(triphenylphosphine)palladium(0)

Pd(dba) ₂ : Bis(dibenzylideneacetone)palladium(0)

PCy ₃ : tricyclohexylphosphine

TFA: trifluoroacetic acid

Pd(OAc) ₂ : palladium acetate

KOAc: potassium acetate

PdCl ₂ (dppf): [1,1'-bis(diphenylphosphino)ferrocene]palladium(II) dichloride

PdCl ₂ (dppf)CH ₂ Cl ₂ : [1,1'-bis(diphenylphosphino)ferrocene]palladium(II) dichloride dichloromethane complex

DMEAD: Di-2-methoxyethyl azodicarboxylate

PPh ₃ : triphenylphosphine

DMA: dimethylacetamide

MeMgBr: methylmagnesium bromide

EtMgBr: ethylmagnesium bromide

MTBE: Methyl tert-butyl ether

DCM: dichloromethane

Boc ₂ O: di-tert-butyl dicarboxylate

NBS: N-bromosuccinimide

X-phos: 2-dicyclohexylphosphino-2',4',6'-triisopropylbiphenyl

MeOH: methanol

EtOH: ethanol

IPE: diisopropyl ether

TBAF: Tetrabutylammonium fluoride

Example 1: Synthesis of 4-[5-[(3S)-3-aminopyrrolidine-1-carbonyl]-2-(p-tolyl)phenyl]benzonitrile

Step 1

3-Bromo-4-chloro-benzoic acid (19 g) was dissolved in DMF (160 mL). At 25° C., DMAP (20 g) and WSC HCl (31 g) were added, followed by t-BuOH (38 mL). The resulting mixture was stirred at room temperature overnight. Ethyl acetate was added, and the resulting mixture was washed with water and saturated brine in sequence. After drying the organic layer over anhydrous sodium sulfate, the solvent was evaporated. The residue was purified by silica gel column chromatography (mobile phase: hexane/ethyl acetate) to obtain tert-butyl 3-bromo-4-chloro-benzoate.

Step 2

tert-Butyl 3-bromo-4-chloro-benzoate (1.3 g) obtained in Step 1 above was dissolved in 1,4-dioxane (8.7 mL). (4-Cyanophenyl)boronic acid (768 mg), Pd(PPh ₃ ) ₄ (151 mg), and a 2M aqueous Na ₂ CO ₃ solution (5.4 mL) were added at room temperature, and the reaction solution was stirred in a microwave reactor at 120° C. for 30 minutes. The reaction solution was then concentrated in vacuo, and the residue was purified by silica gel column chromatography (mobile phase: hexane/ethyl acetate) to obtain tert-butyl 4-chloro-3-(4-cyanophenyl)benzoate.

Step 3

The tert-butyl 4-chloro-3-(4-cyanophenyl)benzoate (1.1 g) obtained in step 2 above was dissolved in 1,4-dioxane (17 mL). p-Tolylboronic acid (932 mg), Pd(dba) ₂ (157 mg), tripotassium phosphate (1.5 g) and a 1M PCy ₃ THF solution (0.57 mL) were added thereto at room temperature, and the reaction solution was stirred at 160° C. for 30 minutes in a microwave reactor. After adding chloroform, the insoluble matter was filtered off and the solvent was evaporated. The residue was purified by silica gel column chromatography (mobile phase: hexane/ethyl acetate), and the solvent was evaporated. The residue was dissolved in TFA (2 mL). The solvent was evaporated. Ethyl acetate was added thereto, and the mixture was washed with water and saturated brine in sequence. After the organic layer was dried over anhydrous sodium sulfate, the solvent was evaporated to obtain 3-(4-cyanophenyl)-4-(p-tolyl)benzoic acid.

Step 4

3-(4-cyanophenyl)-4-(p-tolyl)benzoic acid (10 mg), tert-butyl N-[(3S)-pyrrolidin-3-yl]carbamate (6 mg), and HATU (24 mg) obtained in Step 3 above were dissolved in THF (0.5 mL). TEA (0.013 mL) was added at room temperature, followed by stirring at 50°C overnight. The reaction solution was concentrated in vacuo, and the solvent was evaporated. The residue was purified by silica gel column chromatography (mobile phase: hexane/ethyl acetate) to obtain tert-butyl N-[(3S)-1-[3-(4-cyanophenyl)-4-(p-tolyl)benzoyl]pyrrolidin-3-yl]carbamate.

Step 5

tert-Butyl N-[(3S)-1-[3-(4-cyanophenyl)-4-(p-tolyl)benzoyl]pyrrolidin-3-yl]carbamate (15 mg) obtained in Step 4 above was dissolved in TFA (0.3 mL). The progress of the reaction was confirmed by LCMS, followed by vacuum concentration. The residue was purified by reverse-phase HPLC (mobile phase: water/acetonitrile) to obtain the title compound.

Example 2: 4-[5-[(3S)-3-aminopyrrolidine-1-thiocarbonyl]-2-(p-tolyl)phenyl]benzonitrile synthesis

4-[5-[(3S)-3-aminopyrrolidine-1-carbonyl]-2-(p-tolyl)phenyl]benzonitrile (6 mg) obtained in Example 1 (Step 5) was dissolved in THF (0.8 mL). Lawesson's reagent (3.8 mg) was added at room temperature, followed by stirring at room temperature for 30 minutes. Chloroform was added, and the mixture was partitioned with aqueous sodium bicarbonate. The organic layer was dried over anhydrous sodium sulfate, and the solvent was evaporated. The residue was purified by reverse-phase HPLC (mobile phase: water/acetonitrile) to obtain the title compound.

Example 3: Synthesis of 4-[5-(4-aminopiperidine-1-carbonyl)-2-(p-tolyl)phenyl]benzonitrile

Step 1

3-(4-Cyanophenyl)-4-(p-tolyl)benzoic acid (20 mg) obtained in Example 1 (Step 3) was dissolved in THF (1 mL). Tert-butyl N-(4-piperidinyl)carbamate (13 mg), HATU (49 mg), and TEA (0.027 mL) were added to the mixture at room temperature, followed by stirring at 50°C overnight. The reaction solution was concentrated in vacuo, and the solvent was evaporated. The residue was purified by silica gel column chromatography (mobile phase: hexane/ethyl acetate) to obtain tert-butyl N-[1-[3-(4-cyanophenyl)-4-(p-tolyl)benzoyl]-4-piperidinyl]carbamate.

Step 2

tert-Butyl N-[1-[3-(4-cyanophenyl)-4-(p-tolyl)benzoyl]-4-piperidinyl]carbamate (30 mg) obtained in Step 1 above was dissolved in TFA (0.3 mL). The progress of the reaction was confirmed by LCMS, followed by vacuum concentration. The residue was purified by reverse-phase HPLC (mobile phase: water/acetonitrile) to obtain the title compound.

Example 4: 4-[5-(2,8-diazaspiro[3.5]nonane-2-carbonyl)-2-(p-tolyl)phenyl]benzonitrile synthesis

The procedures of Steps 1 to 5 of Example 1 were repeated using tert-butyl 2,8-diazaspiro[3.5]nonane-8-carboxylate hydrochloride instead of tert-butyl N-[(3S)-pyrrolidin-3-yl]carbamate to give the title compound.

Example 5: 4-[5-(2,7-diazaspiro[3.4]octane-7-carbonyl)-2-(p-tolyl)phenyl]benzonitrile synthesis

The procedures of Steps 1 to 5 of Example 1 were repeated using tert-butyl 2,7-diazaspiro[3.4]octane-2-carboxylate instead of tert-butyl N-[(3S)-pyrrolidin-3-yl]carbamate to give the title compound.

Example 6: 4-[5-(3,8-diazaspiro[4.4]nonane-8-carbonyl)-2-(p-tolyl)phenyl]benzonitrile synthesis

The procedures of Steps 1 to 5 of Example 1 were repeated using tert-butyl 3,8-diazaspiro[4.4]nonane-8-carboxylate instead of tert-butyl N-[(3S)-pyrrolidin-3-yl]carbamate to give the title compound.

Example 7: 4-[5-[(3-exo)-3-amino-8-azabicyclo[3.2.1]octane-8-carbonyl]-2-(p-toluene Synthesis of [1,2-[(1,2-dimethyl)phenyl]benzonitrile

Step 1

3-Bromo-4-chloro-benzoic acid (500 mg) was dissolved in DMA (5.3 mL). HATU (1 g), TEA (0.59 mL), and tert-butyl N-[(3-exo)-8-azabicyclo[3.2.1]oct-3-yl]carbamate (480 mg) were added thereto at room temperature, followed by stirring at room temperature for 1 hour. Ethyl acetate was added thereto, and the resulting mixture was washed with water and saturated brine in sequence. After drying the organic layer over anhydrous sodium sulfate, the solvent was evaporated. The residue was purified by silica gel column chromatography (mobile phase: hexane/ethyl acetate) to obtain tert-butyl N-[(3-exo)-8-(3-bromo-4-chloro-benzoyl)-8-azabicyclo[3.2.1]oct-3-yl]carbamate.

Step 2

Tert-butyl N-[(3-exo)-8-(3-bromo-4-chloro-benzoyl)-8-azabicyclo[3.2.1]oct-3-yl]carbamate (200 mg) obtained in Step 1 above was dissolved in 1,4-dioxane (2.3 mL). (4-Cyanophenyl)boronic acid (60 mg), Pd(PPh₃) _₄ ( ₁₆ mg), and 2M _{aqueous Na₂CO₃} solution (1.1 mL) were added at room temperature, and the reaction solution was stirred in a microwave reactor at 120°C for 30 minutes. The solvent was evaporated, and the residue was purified by silica gel column chromatography (mobile phase: hexane/ethyl acetate) to obtain tert-butyl N-[(3-exo)-8-[4-chloro-3-(4-cyanophenyl)benzoyl]-8-azabicyclo[3.2.1]oct-3-yl]carbamate.

Step 3

Tert-butyl N-[(3-exo)-8-[4-chloro-3-(4-cyanophenyl)benzoyl]-8-azabicyclo[3.2.1]octan-3-yl]carbamate (15 mg) obtained in the above step 2 was dissolved in 1,4-dioxane (0.322 mL). p-Tolylboronic acid (5.3 mg), Pd(dba) ₂ (0.93 mg), 1M PCy ₃ in THF solution (0.003 mL), and tripotassium phosphate (21 mg) were added thereto at room temperature, and the reaction solution was stirred in a microwave reactor at 160° C. for 30 minutes. The solvent was evaporated and the residue was purified by silica gel column chromatography (mobile phase: hexane/ethyl acetate) to give tert-butyl N-[(3-exo)-8-[3-(4-cyanophenyl)-4-(p-tolyl)benzoyl]-8-azabicyclo[3.2.1]oct-3-yl]carbamate.

Step 4

Tert-butyl N-[(3-exo)-8-[3-(4-cyanophenyl)-4-(p-tolyl)benzoyl]-8-azabicyclo[3.2.1]octan-3-yl]carbamate (15 mg) obtained in Step 3 above was dissolved in TFA (0.3 mL). The progress of the reaction was confirmed by LCMS, followed by vacuum concentration. The residue was purified by reverse-phase HPLC (mobile phase: water/acetonitrile) to obtain the title compound.

Example 8: 4-[5-[(3S)-3-amino-3-methyl-pyrrolidine-1-carbonyl]-2-(p-tolyl)phenyl]benzyl Synthesis of Nitriles

The procedures of Steps 1 to 5 of Example 1 were repeated using tert-butyl N-[(3S)-3-methylpyrrolidin-3-yl]carbamate instead of tert-butyl N-[(3S)-pyrrolidin-3-yl]carbamate to give the title compound.

Example 9: 4-[5-[(3S)-3-aminopyrrolidine-1-carbonyl]-2-(2-chloro-4-methyl-phenyl)phenyl]benzyl Synthesis of Nitriles

Step 1

3-Bromo-4-chloro-benzoic acid (10 g) was dissolved in DMA (85 mL). HATU (24 g), TEA (12 mL) and tert-butyl N-[(3S)-pyrrolidin-3-yl]carbamate (8.7 g) were added thereto at room temperature, followed by stirring at room temperature for 1 hour. Ethyl acetate was added thereto, and the resulting mixture was washed with water and saturated brine in sequence. After drying the organic layer over anhydrous sodium sulfate, the solvent was evaporated. The residue was purified by silica gel column chromatography (mobile phase: hexane/ethyl acetate) to obtain tert-butyl N-[(3S)-1-(3-bromo-4-chloro-benzoyl)pyrrolidin-3-yl]carbamate.

Step 2

Dissolve tert-butyl N-[(3S)-1-(3-bromo-4-chlorobenzoyl)pyrrolidin-3-yl]carbamate (2.2 g) obtained in Step 1 above in 1,4-dioxane (13.6 mL). Add 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzonitrile (1.5 g), Pd(PPh ₃ ) ₄ (189 mg), and 2M aqueous Na ₂ CO ₃ solution (6.8 mL) at room temperature. Stir the reaction solution in a microwave reactor at 120°C for 30 minutes. Add ethyl acetate, and wash the resulting mixture sequentially with water and saturated brine. After drying the organic layer over anhydrous sodium sulfate, the solvent was evaporated. The residue was purified by silica gel column chromatography (mobile phase: hexane/ethyl acetate) to give tert-butyl N-[(3S)-1-[4-chloro-3-(4-cyanophenyl)benzoyl]pyrrolidin-3-yl]carbamate.

Step 3

tert-Butyl N-[(3S)-1-[4-chloro-3-(4-cyanophenyl)benzoyl]pyrrolidin-3-yl]carbamate (500 mg) obtained in Step 2 above was dissolved in 1,4-dioxane (9.8 mL). Pd(OAc) ₂ (26 mg), KOAc (346 mg), bis(pinacolato)diboron (596 mg), and silica-SMAP (150 mg) were added at room temperature, followed by stirring at 160° C. overnight. The mixture was passed through Celite, and the filtrate was concentrated in vacuo. The residue was purified by silica gel column chromatography (mobile phase: hexane/ethyl acetate) to obtain tert-butyl N-[(3S)-1-[3-(4-cyanophenyl)-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzoyl]pyrrolidin-3-yl]carbamate.

Step 4

Tert-butyl N-[(3S)-1-[3-(4-cyanophenyl)-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzoyl]pyrrolidin-3-yl]carbamate (15 mg), 1-bromo-2-chloro-4-methyl-benzene (12 mg), and Pd( _PPh₃ ) _₄ (1.7 mg) were suspended in 1,4-dioxane (1.5 mL). A _2M aqueous _Na₂CO₃ solution (0.7 mL) was added at room temperature, followed by stirring at 120°C for 30 minutes. The reaction mixture was filtered, and the solvent was evaporated to obtain tert-butyl N-[(3S)-1-[4-(2-chloro-4-methyl-phenyl)-3-(4-cyanophenyl)benzoyl]pyrrolidin-3-yl]carbamate.

Step 5

Tert-butyl N-[(3S)-1-[4-(2-chloro-4-methyl-phenyl)-3-(4-cyanophenyl)benzoyl]pyrrolidin-3-yl]carbamate (15 mg) obtained in Step 4 above was dissolved in TFA (0.3 mL). The progress of the reaction was confirmed by LCMS, followed by vacuum concentration. The residue was purified by reverse-phase HPLC (mobile phase: water/acetonitrile) to obtain the title compound.

Example 10: 4-[5-[(3S)-3-aminopyrrolidine-1-carbonyl]-2-(3-chloro-4-methyl-phenyl)phenyl]benzene Synthesis of Formonitrile

The procedures of Example 9 Steps 1 to 5 were repeated using 4-bromo-2-chloro-1-methyl-benzene instead of 1-bromo-2-chloro-4-methyl-benzene to give the title compound.

Example 11: 4-[5-[(3S)-3-aminopyrrolidine-1-carbonyl]-2-[3-fluoro-4-(trifluoromethyl)phenyl]benzene Synthesis of [1,2-dimethyl]benzonitrile

The procedures of Example 9, Steps 1 to 5, were repeated using 4-bromo-2-fluoro-1-(trifluoromethyl)benzene instead of 1-bromo-2-chloro-4-methyl-benzene to give the title compound.

Example 12: 4-[5-[(3S)-3-aminopyrrolidine-1-carbonyl]-2-(4-methyl-2-nitro-phenyl)phenyl] Synthesis of benzonitrile

Step 1

To this was added tert-butyl N-[(3S)-1-[4-chloro-3-(4-cyanophenyl)benzoyl]pyrrolidin-3-yl]carbamate (15 mg) obtained in Example 9 (Step 2), 4-methyl-2-nitrophenylboronic acid pinacol ester (18 mg), Pd(dba) ₂ (1.6 mg), a 1M THF solution of PCy ₃ (0.003 mL), and tripotassium phosphate (15 mg), and the reaction solution was stirred in a microwave reactor at 160° C. for 30 minutes. The solvent was evaporated, and the residue was purified by silica gel column chromatography (mobile phase: hexane/ethyl acetate) to obtain tert-butyl N-[(3S)-1-[3-(4-cyanophenyl)-4-(4-methyl-2-nitrophenyl)benzoyl]pyrrolidin-3-yl]carbamate.

Step 2

At room temperature, tert-butyl N-[(3S)-1-[3-(4-cyanophenyl)-4-(4-methyl-2-nitro-phenyl)benzoyl]pyrrolidin-3-yl]carbamate (10 mg) obtained in Step 1 above was dissolved in TFA (0.3 mL). The progress of the reaction was confirmed by LCMS, followed by vacuum concentration. The residue was purified by reverse phase HPLC (mobile phase: water/acetonitrile) to give the title compound.

Example 13: 4-[5-[(3S)-3-aminopyrrolidine-1-carbonyl]-2-[4-(difluoromethyl)phenyl]phenyl]benzene Synthesis of Formonitrile

The procedures of Steps 1 to 5 of Example 9 were repeated, substituting 1-bromo-4-(difluoromethyl)benzene for 1-bromo-2-chloro-4-methyl-benzene, to give the title compound.

Example 14: 4-[5-[(3S)-3-aminopyrrolidine-1-carbonyl]-2-[4-(trifluoromethyl)phenyl]phenyl]benzene Synthesis of Formonitrile

The procedures of Steps 1 to 2 of Example 12 were repeated using [4-(trifluoromethyl)phenyl]boronic acid instead of 4-methyl-2-nitrophenylboronic acid pinacol ester to give the title compound.

Example 15: 4-[5-[(3S)-3-aminopyrrolidine-1-carbonyl]-2-(2-fluoro-4-methyl-phenyl)phenyl]benzene Synthesis of Formonitrile

Step 1

Tert-butyl N-[(3S)-1-[4-chloro-3-(4-cyanophenyl)benzoyl]pyrrolidin-3-yl]carbamate (1.7 g) obtained in Example 9 (Step 2) was dissolved in 1,4-dioxane (20 mL). (2-Fluoro-4-methyl-phenyl)boronic acid (980 mg), Pd(dba) _₂ (110 mg), a 1M solution of _PCy₃ in THF (0.4 mL), and tripotassium phosphate (2.5 g) were added at room temperature, and the reaction solution was stirred in a microwave reactor at 160°C for 45 minutes. The mixture was purified using NH₆ silica gel, washed with methanol/ethyl acetate, and the solvent was evaporated to obtain tert-butyl N-[(3S)-1-[3-(4-cyanophenyl)-4-(2-fluoro-4-methyl-phenyl)benzoyl]pyrrolidin-3-yl]carbamate.

Step 2

Tert-butyl N-[(3S)-1-[3-(4-cyanophenyl)-4-(2-fluoro-4-methyl-phenyl)benzoyl]pyrrolidin-3-yl]carbamate (1.7 g) obtained in Step 1 above was dissolved in TFA (44 mL) and stirred for 10 minutes. The solvent was evaporated, and the residue was purified by reverse phase HPLC (mobile phase: water/acetonitrile) to obtain the title compound.

Example 16: 4-[5-[(3S)-3-aminopyrrolidine-1-carbonyl]-2-(p-tolyl)phenyl]-2-fluoro-benzyl Synthesis of Nitriles

Step 1

Tert-butyl N-[(3S)-1-(3-bromo-4-chloro-benzoyl)pyrrolidin-3-yl]carbamate (14 g) obtained in Example 9 (Step 1) was dissolved in 1,4-dioxane (87 mL). (4-Cyano-3-fluoro-phenyl)boric acid (6.3 g), Pd(PPh ₃ ) ₄ (1.2 g), and a 2M aqueous Na ₂ CO ₃ solution (44 mL) were added at room temperature, followed by stirring at 90°C overnight. Ethyl acetate was added, and the resulting mixture was washed sequentially with water and saturated brine. The organic layer was dried over anhydrous sodium sulfate, and the solvent was evaporated. The residue was purified by silica gel column chromatography (mobile phase: hexane/ethyl acetate) to obtain tert-butyl N-[(3S)-1-[4-chloro-3-(4-cyano-3-fluoro-phenyl)benzoyl]pyrrolidin-3-yl]carbamate.

Step 2

The tert-butyl N-[(3S)-1-[4-chloro-3-(4-cyano-3-fluoro-phenyl)benzoyl]pyrrolidin-3-yl]carbamate (48 mg) obtained in step 1 above was dissolved in 1,4-dioxane (0.5 mL). p-Tolylboronic acid (29 mg), Pd(dba) ₂ (3.1 mg), a 1M PCy ₃ solution in THF (0.005 mL), and tripotassium phosphate (68 mg) were added thereto at room temperature, and the reaction solution was stirred in a microwave reactor at 160° C. for 45 minutes. The mixture was purified by NH-silica gel and washed with methanol/ethyl acetate, and the solvent was evaporated to obtain tert-butyl N-[(3S)-1-[3-(4-cyano-3-fluoro-phenyl)-4-(p-tolyl)benzoyl]pyrrolidin-3-yl]carbamate.

Step 3

To tert-butyl N-[(3S)-1-[3-(4-cyano-3-fluoro-phenyl)-4-(p-tolyl)benzoyl]pyrrolidin-3-yl]carbamate (48 mg) obtained in step 2 above was added TFA (1.2 mL), followed by stirring for 10 minutes. The solvent was evaporated, and the residue was purified by reverse phase HPLC (mobile phase: water/acetonitrile) to obtain the title compound.

Example 17: 4-[5-[(3-endo)-3-amino-8-azabicyclo[3.2.1]octane-8-carbonyl]-2-(p-methyl Synthesis of [(phenyl)phenyl]-2-fluoro-benzonitrile

Step 1

3-Bromo-4-chloro-benzoic acid (700 mg) was dissolved in THF (15 mL). HATU (1.2 g), TEA (0.83 mL), and tert-butyl N-[(3-endo)-8-azabicyclo[3.2.1]oct-3-yl]carbamate (700 mg) were added at room temperature, followed by stirring at 50°C for 1 hour. The solvent was evaporated, and the residue was purified by silica gel column chromatography (mobile phase: hexane/ethyl acetate) to obtain tert-butyl N-[(3-endo)-8-(3-bromo-4-chloro-benzoyl)-8-azabicyclo[3.2.1]oct-3-yl]carbamate.

Step 2

Tert-butyl N-[(3-endo)-8-(3-bromo-4-chloro-benzoyl)-8-azabicyclo[3.2.1]octan-3-yl]carbamate (1.2 g) obtained in Step 1 above was dissolved in 1,4-dioxane (6.7 mL). (4-Cyano-3-fluorophenyl)boronic acid (461 mg), _PdCl₂ (dppf) (58 mg), and a 2M _{aqueous Na₂CO₃} solution (3.3 mL) were added at room temperature, followed by stirring at 95°C overnight. Ethyl acetate was added, and the resulting mixture was washed sequentially with water and saturated brine. The organic layer was dried over anhydrous sodium sulfate, and the solvent was evaporated. The residue was purified by silica gel column chromatography (mobile phase: hexane/ethyl acetate) to give tert-butyl N-[(3-endo)-8-[4-chloro-3-(4-cyano-3-fluoro-phenyl)benzoyl]-8-azabicyclo[3.2.1]oct-3-yl]carbamate.

Step 3

Tert-butyl N-[(3-endo)-8-[4-chloro-3-(4-cyano-3-fluoro-phenyl)benzoyl]-8-azabicyclo[3.2.1]octan-3-yl]carbamate (17 mg) obtained in step 2 above was dissolved in 1,4-dioxane (0.5 mL). p-Tolylboronic acid (9.6 mg), Pd(dba) ₂ (1.6 mg), tripotassium phosphate (15 mg) and a 1M THF solution of PCy ₃ (0.004 mL) were added thereto at room temperature, and the mixture was stirred in a microwave reactor at 160° C. for 30 minutes. The reaction solution was filtered through NH-silica gel, and the solvent of the filtrate was distilled off to obtain tert-butyl N-[(3-endo)-8-[3-(4-cyano-3-fluoro-phenyl)-4-(p-tolyl)benzoyl]-8-azabicyclo[3.2.1]oct-3-yl]carbamate.

Step 4

Tert-butyl N-[(3-endo)-8-[3-(4-cyano-3-fluoro-phenyl)-4-(p-tolyl)benzoyl]-8-azabicyclo[3.2.1]octan-3-yl]carbamate (15 mg) obtained in step 3 above was dissolved in TFA (0.3 mL). The progress of the reaction was confirmed by LCMS, followed by vacuum concentration. The residue was purified by reverse phase HPLC (mobile phase: water/acetonitrile) to give the title compound.

Example 18: 4-[5-[(3-exo)-3-amino-8-azabicyclo[3.2.1]octane-8-carbonyl]-2-(1-methyl Synthesis of [5-[(1-[(2 ...((-(-indol-5-yl)phenyl]-2-fluoro-benzonitrile

Step 1

Tert-butyl N-[(3-exo)-8-(3-bromo-4-chloro-benzoyl)-8-azabicyclo[3.2.1]octan-3-yl]carbamate (300 mg) obtained in Example 7 (Step 1) was dissolved in 1,4-dioxane (1.7 mL). (4-Cyano-3-fluorophenyl)boronic acid (123 mg), _PdCl₂ (dppf) (17 mg), and 2M _{aqueous Na₂CO₃} solution (0.85 mL) were added at room temperature, and the reaction solution was stirred in a microwave reactor at 120°C for 30 minutes. Ethyl acetate was added, and the resulting mixture was washed sequentially with water and saturated brine. After drying the organic layer over anhydrous sodium sulfate, the solvent was evaporated. The residue was purified by silica gel column chromatography (mobile phase: hexane/ethyl acetate) to give tert-butyl N-[(3-exo)-8-[4-chloro-3-(4-cyano-3-fluoro-phenyl)benzoyl]-8-azabicyclo[3.2.1]oct-3-yl]carbamate.

Step 2

Tert-butyl N-[(3-exo)-8-[4-chloro-3-(4-cyano-3-fluoro-phenyl)benzoyl]-8-azabicyclo[3.2.1]octan-3-yl]carbamate (10 mg) obtained in Step 1 above was dissolved in 1,4-dioxane (0.5 mL). (1-Methylindol-5-yl)boronic acid (7.2 mg), Pd(dba) ₂ (0.9 mg), tripotassium phosphate (8.8 mg), and a 1M solution of PCy ₃ in THF (0.002 mL) were added at room temperature, and the reaction solution was stirred in a microwave reactor at 160°C for 30 minutes. The reaction solution was filtered through NH silica gel, and the solvent in the filtrate was evaporated. The residue was purified by silica gel column chromatography (mobile phase: hexane/ethyl acetate) to give tert-butyl N-[(3-exo)-8-[3-(4-cyano-3-fluoro-phenyl)-4-(1-methylindol-5-yl)benzoyl]-8-azabicyclo[3.2.1]oct-3-yl]carbamate.

Step 3

Tert-butyl N-[(3-exo)-8-[3-(4-cyano-3-fluoro-phenyl)-4-(1-methylindol-5-yl)benzoyl]-8-azabicyclo[3.2.1]octan-3-yl]carbamate (15 mg) obtained in step 2 was dissolved in TFA (0.3 mL). The progress of the reaction was confirmed by LCMS, and the mixture was concentrated in vacuo. The residue was purified by reverse phase HPLC (mobile phase: water/acetonitrile) to give the title compound.

Example 19: 4-[5-[(3S)-3-aminopyrrolidine-1-carbonyl]-2-(p-tolyl)phenyl]-2,6-difluoro- Synthesis of benzonitrile

Step 1

4-Bromo-3-chloro-benzoic acid (2 g) was dissolved in DMA (17 mL). HATU (4.8 g), TEA (2.4 mL) and tert-butyl N-[(3S)-pyrrolidin-3-yl]carbamate (1.7 g) were added thereto at room temperature, followed by stirring at room temperature for 1 hour. Ethyl acetate was added thereto, and the resulting mixture was washed with water and saturated brine in sequence. After drying the organic layer over anhydrous sodium sulfate, the solvent was distilled off. The residue was purified by silica gel column chromatography (mobile phase: hexane/ethyl acetate) to obtain tert-butyl N-[(3S)-1-(4-bromo-3-chloro-benzoyl)pyrrolidin-3-yl]carbamate.

Step 2

The tert-butyl N-[(3S)-1-(4-bromo-3-chlorobenzoyl)pyrrolidin-3-yl]carbamate obtained in Step 1 above was dissolved in 1,4-dioxane (10.6 mL). Pd( _PPh₃ ) _₄ (147 mg), a 2M _{aqueous Na₂CO₃} solution (5.3 mL), and p-tolylboronic acid (693 mg) were added at room temperature, and the reaction solution was stirred in a microwave reactor at 120°C for 30 minutes. Ethyl acetate was added, and the resulting mixture was washed sequentially with water and saturated brine. After drying the organic layer over anhydrous sodium sulfate, the solvent was evaporated. The residue was purified by silica gel column chromatography (mobile phase: hexane/ethyl acetate) to obtain tert-butyl N-[(3S)-1-[3-chloro-4-(p-tolyl)benzoyl]pyrrolidin-3-yl]carbamate.

Step 3

tert-Butyl N-[(3S)-1-[3-chloro-4-(p-tolyl)benzoyl]pyrrolidin-3-yl]carbamate (666 mg) obtained in Step 2 above was dissolved in 1,4-dioxane (16 mL). Pd(OAc) _₂ (36 mg), KOAc (473 mg), bis(pinacolato)diboron (815 mg), and a 1M THF solution of _PCy₃ (0.24 mL) were added at room temperature. After degassing and nitrogen substitution, the mixture was stirred at 80°C overnight. The reaction solution was passed through Celite, and the solvent in the filtrate was evaporated. The residue was purified by silica gel column chromatography (mobile phase: hexane/ethyl acetate) to obtain tert-butyl N-[(3S)-1-[4-(p-tolyl)-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzoyl]pyrrolidin-3-yl]carbamate.

Step 4

Tert-butyl N-[(3S)-1-[4-(p-tolyl)-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzoyl]pyrrolidin-3-yl]carbamate (15 mg), 4-bromo-2,6-difluoro-benzonitrile (12.9 mg), and Pd(PPh ₃ ) ₄ (1.7 mg) obtained in Step 3 above were suspended in 1,4-dioxane (1.5 mL). A 2M aqueous _{Na 2} CO ₃ solution (0.7 mL) was added at room temperature, and the reaction solution was stirred in a microwave reactor at 120° C. for 30 minutes. The reaction solution was filtered, and the solvent was evaporated to obtain methyl N-[(3S)-1-[3-(4-cyano-3,5-difluoro-phenyl)-4-(p-tolyl)benzoyl]pyrrolidin-3-yl]carbamate.

Step 5

Methyl N-[(3S)-1-[3-(4-cyano-3,5-difluoro-phenyl)-4-(p-tolyl)benzoyl]pyrrolidin-3-yl]carbamate (15 mg) obtained in Step 4 above was dissolved in TFA (0.3 mL). The reaction was confirmed by LCMS and then concentrated in vacuo. The residue was purified by reverse phase HPLC (mobile phase: water/acetonitrile) to obtain the title compound.

Example 20: 4-[5-[(3S)-3-aminopyrrolidine-1-carbonyl]-2-[2-fluoro-4-(2-methoxyethyl)benzene Synthesis of [1,2-difluoro-1,2-dimethylphenyl]-2-fluoro-benzonitrile

Step 1

1-Bromo-2-fluoro-4-(2-methoxyethyl)benzene (4.5 g) was suspended in 1,4-dioxane (48 mL) and stirred. Bis(pinacolato)diboron (7.4 g), KOAc (3.8 g), and _PdCl₂ (dppf) (0.71 g) were then added, followed by stirring at 90°C overnight. Ethyl acetate was added, the mixture was passed through Celite, and the filtrate was washed sequentially with water and saturated brine. The organic layer was dried over anhydrous sodium sulfate, and the solvent was evaporated. The residue was purified by silica gel column chromatography (mobile phase: hexane/ethyl acetate) to yield 2-[2-fluoro-4-(2-methoxyethyl)phenyl]-4,4,5,5-tetramethyl-1,3,2-dioxaborolane.

Step 2

Tert-butyl N-[(3S)-1-[4-chloro-3-(4-cyano-3-fluoro-phenyl)benzoyl]pyrrolidin-3-yl]carbamate (150 mg) obtained in Example 16 (Step 1), 2-[2-fluoro-4-(2-methoxyethyl)phenyl]-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (189 mg) obtained in Step 1 above, Pd(dba) _₂ (15 mg), tripotassium phosphate (144 mg), and a 1M THF solution of _PCy₃ (0.034 mL) were dissolved in 1,4-dioxane (3.8 mL). The reaction solution was stirred in a microwave reactor at 160°C for 45 minutes. The reaction solution was filtered through NH₁-silica gel, and the solvent in the filtrate was evaporated. The residue was purified by silica gel column chromatography (mobile phase: hexane/ethyl acetate) to give tert-butyl N-[(3S)-1-[3-(4-cyanophenyl)-4-[2-fluoro-4-(2-methoxyethyl)phenyl]benzoyl]pyrrolidin-3-yl]carbamate.

Step 3

Tert-butyl N-[(3S)-1-[3-(4-cyanophenyl)-4-[2-fluoro-4-(2-methoxyethyl)phenyl]benzoyl]pyrrolidin-3-yl]carbamate (150 mg) obtained in Step 2 above was dissolved in TFA (10 mL). The reaction was confirmed by LCMS and then concentrated in vacuo. The residue was purified by reverse phase HPLC (mobile phase: water/acetonitrile) to give the title compound.

Example 21: 4-[5-[(3-endo)-3-amino-8-azabicyclo[3.2.1]octane-8-carbonyl]-2-(2-fluoro- Synthesis of [4-methyl-phenyl]-2-fluoro-benzonitrile

The procedures of Steps 1 to 4 of Example 17 were repeated using (2-fluoro-4-methyl-phenyl)boronic acid instead of p-tolylboronic acid to give the title compound.

Example 22: 4-[5-[(3-endo)-3-amino-8-azabicyclo[3.2.1]octane-8-carbonyl]-2-[2-fluoro- Synthesis of 4-(2-methoxyethyl)phenyl]phenyl]-2-fluoro-benzonitrile

Step 1

tert-Butyl 3-bromo-4-chloro-benzoate (1.00 g) obtained in Example 1 (Step 1) was dissolved in 1,4-dioxane (8.6 mL). (4-cyano-3-fluoro-phenyl)boric acid (509 mg), Pd(PPh ₃ ) ₄ (119 mg), and 2M Na ₂ CO ₃ aqueous solution (4.3 mL) were added at room temperature, and the reaction solution was stirred in a microwave reactor at 120° C. for 30 minutes. The reaction solution was filtered, and the solvent was evaporated. The residue was purified by silica gel column chromatography (mobile phase: hexane/ethyl acetate) to obtain tert-butyl 4-chloro-3-(4-cyano-3-fluoro-phenyl)benzoate.

Step 2

Tert-butyl 4-chloro-3-(4-cyano-3-fluoro-phenyl)benzoate (1.00 g) obtained in Step 1 above was dissolved in 1,4-dioxane (15 mL). 2-[2-Fluoro-4-(2-methoxyethyl)phenyl]-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (1.69 g), Pd(dba) ₂ (138 mg), tripotassium phosphate (1.28 g), and a 1M solution of PCy ₃ in THF (0.30 mL) were added to the mixture at room temperature, and the reaction solution was stirred in a microwave reactor at 160°C for 30 minutes. After adding chloroform, the insoluble matter was filtered off, and the solvent was evaporated. The residue was purified by silica gel column chromatography (mobile phase: hexane/ethyl acetate), and the solvent was evaporated. The residue was dissolved in TFA (2 mL), and the solvent was evaporated. Ethyl acetate was added thereto, and the mixture was washed with water and saturated brine in that order. After the organic layer was dried over anhydrous sodium sulfate, the solvent was distilled off to obtain 3-(4- cyano -3-fluoro-phenyl)-4-[2-fluoro-4-(2-methoxyethyl)phenyl]benzoic acid.

Step 3

3-(4-cyano-3-fluoro-phenyl)-4-[2-fluoro-4-(2-methoxyethyl)phenyl]benzoic acid (10 mg), tert-butyl N-[(3-endo)-8-azabicyclo[3.2.1]oct-3-yl]carbamate (5.8 mg), and HATU (19 mg) were dissolved in THF (0.5 mL). TEA (0.007 mL) was added at room temperature, followed by stirring at 50°C overnight. The reaction solution was concentrated in vacuo, and the solvent was evaporated. The residue was purified by silica gel column chromatography (mobile phase: hexane/ethyl acetate) to obtain tert-butyl N-[(3-endo)-8-[3-(4-cyano-3-fluoro-phenyl)-4-[2-fluoro-4-(2-methoxyethyl)phenyl]benzoyl]-8-azabicyclo[3.2.1]oct-3-yl]carbamate.

Step 4

Tert-butyl N-[(3-endo)-8-[3-(4-cyano-3-fluoro-phenyl)-4-[2-fluoro-4-(2-methoxyethyl)phenyl]benzoyl]-8-azabicyclo[3.2.1]octan-3-yl]carbamate (10.9 mg) obtained in Step 3 above was dissolved in TFA (0.3 mL). The reaction was confirmed by LCMS and then concentrated in vacuo. The residue was purified by reverse phase HPLC (mobile phase: water/acetonitrile) to give the title compound.

Example 23: 4-[5-[(3-exo)-3-amino-8-azabicyclo[3.2.1]octane-8-carbonyl]-2-(6-fluoro- Synthesis of 1-methyl-indol-5-yl)phenyl]-2-fluoro-benzonitrile

Step 1

Tert-butyl N-[(3-exo)-8-[4-chloro-3-(4-cyano-3-fluoro-phenyl)benzoyl]-8-azabicyclo[3.2.1]octan-3-yl]carbamate (270 mg) obtained in Example 18 (Step 1) was dissolved in 1,4-dioxane (2.8 mL). Pd(OAc) ₂ (2.5 mg), KOAc (164 mg), bis(pinacolato)diboron (283 mg), and silica-SMAP (4.6 mg) were added at room temperature, followed by stirring at 150° C. overnight. The mixture was passed through Celite, and the filtrate was concentrated in vacuo. The residue was purified by silica gel column chromatography (mobile phase: hexane/ethyl acetate) to give tert-butyl N-[(3-exo)-8-[3-(4-cyano-3-fluoro-phenyl)-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzoyl]-8-azabicyclo[3.2.1]oct-3-yl]carbamate.

Step 2

Tert-butyl N-[(3-exo)-8-[3-(4-cyano-3-fluoro-phenyl)-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzoyl]-8-azabicyclo[3.2.1]octan-3-yl]carbamate (10 mg) obtained in the above step 1, 5-bromo-6-fluoro-1-methyl-indole (4.8 mg) and PdCl ₂ (dppf) (0.71 mg) were suspended in 1,4-dioxane (0.5 mL). Tripotassium phosphate (11 mg) was added thereto at room temperature, followed by stirring at 125° C. for 45 minutes. After filtering the reaction solution, the solvent was distilled off to obtain tert-butyl N-[(3-exo)-8-[3-(4-cyano-3-fluoro-phenyl)-4-(6-fluoro-1-methyl-indol-5-yl)benzoyl]-8-azabicyclo[3.2.1]oct-3-yl]carbamate.

Step 3

Tert-butyl N-[(3-exo)-8-[3-(4-cyano-3-fluoro-phenyl)-4-(6-fluoro-1-methyl-indol-5-yl)benzoyl]-8-azabicyclo[3.2.1]octan-3-yl]carbamate (8 mg) obtained in Step 2 above was dissolved in TFA (0.3 mL). The reaction was confirmed by LCMS and then concentrated in vacuo. The residue was purified by reverse phase HPLC (mobile phase: water/acetonitrile) to give the title compound.

Example 24: 4-[5-[(3-exo)-3-amino-8-azabicyclo[3.2.1]octane-8-carbonyl]-2-(6-fluoro- Synthesis of [1-Methyl-indazol-5-yl)phenyl]-2-fluoro-benzonitrile

Step 1

Tert-butyl N-[(3-exo)-8-[3-(4-cyano-3-fluoro-phenyl)-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzoyl]-8-azabicyclo[3.2.1]octan-3-yl]carbamate (10 mg) obtained in Example 23 (Step 1) was dissolved in 1,4-dioxane (0.5 mL). 5-Bromo-6-fluoro-1-methyl-indazole (4.8 mg), PdCl ₂ (dppf) (0.71 mg), and tripotassium phosphate (11 mg) were added at room temperature, and the mixture was stirred in a microwave reactor at 125° C. for 45 minutes. The reaction solution was filtered and the solvent was distilled off to obtain tert-butyl N-[(3-exo)-8-[3-(4-cyano-3-fluoro-phenyl)-4-(6-fluoro-1-methyl-indazol-5-yl)benzoyl]-8-azabicyclo[3.2.1]oct-3-yl]carbamate.

Step 2

Tert-butyl N-[(3-exo)-8-[3-(4-cyano-3-fluoro-phenyl)-4-(6-fluoro-1-methyl-indazol-5-yl)benzoyl]-8-azabicyclo[3.2.1]octan-3-yl]carbamate (15 mg) obtained in Step 1 above was dissolved in TFA (0.3 mL). The reaction was confirmed by LCMS and then concentrated in vacuo. The residue was purified by reverse phase HPLC (mobile phase: water/acetonitrile) to give the title compound.

Example 25: 4-[5-[(3S)-3-amino-3-methyl-pyrrolidine-1-carbonyl]-2-[2-fluoro-4-(2-methoxy Synthesis of [ethyl]phenyl]phenyl]-2-fluoro-benzonitrile

Step 1

3-(4-Cyano-3-fluoro-phenyl)-4-[2-fluoro-4-(2- methoxyethyl )phenyl]benzoic acid (10 mg) obtained in Example 22 (Step 2) and tert-butyl N-[(3S)-3-methylpyrrolidin-3-yl]carbamate (5.1 mg) were dissolved in THF (0.5 mL). TEA (0.011 mL) and HATU (19 mg) were added thereto at room temperature, followed by stirring at 50°C overnight. The reaction solution was concentrated in vacuo, and the solvent was evaporated to obtain tert-butyl N-[(3S)-1-[3-(4-cyano-3-fluoro-phenyl)-4-[2-fluoro-4-(2-methoxyethyl)phenyl]benzoyl]-3-methyl-pyrrolidin-3-yl]carbamate.

Step 2

Tert-butyl N-[(3S)-1-[3-(4-cyano-3-fluoro-phenyl)-4-[2-fluoro-4-(2-methoxyethyl)phenyl]benzoyl]-3-methyl-pyrrolidin-3-yl]carbamate (15 mg) obtained in Step 1 above was dissolved in TFA (0.3 mL). The progress of the reaction was confirmed by LCMS, followed by vacuum concentration. The residue was purified by reverse phase HPLC (mobile phase: water/acetonitrile) to give the title compound.

Example 26: 4-[5-[(3-exo)-3-amino-8-azabicyclo[3.2.1]octane-8-carbonyl]-2-[2-fluoro- Synthesis of 4-(2-methoxyethyl)phenyl]phenyl]-2-fluoro-benzonitrile

Step 1

3-(4-Cyano-3-fluoro-phenyl)-4-[2-fluoro-4-(2- methoxyethyl )phenyl]benzoic acid (10 mg) and tert-butyl N-[(3-exo)-8-azabicyclo[3.2.1]oct-3-yl]carbamate (5.8 mg) obtained in Example 22 (Step 2) were dissolved in THF (0.5 mL). TEA (0.011 mL) and HATU (19 mg) were added at room temperature, followed by stirring at 50°C overnight. The reaction solution was concentrated in vacuo, and the solvent was evaporated to obtain tert-butyl N-[(3-exo)-8-[3-(4-cyano-3-fluoro-phenyl)-4-[2-fluoro-4-(2-methoxyethyl)phenyl]benzoyl]-8-azabicyclo[3.2.1]oct-3-yl]carbamate.

Step 2

Tert-butyl N-[(3-exo)-8-[3-(4-cyano-3-fluoro-phenyl)-4-[2-fluoro-4-(2-methoxyethyl)phenyl]benzoyl]-8-azabicyclo[3.2.1]octan-3-yl]carbamate (15 mg) obtained in Step 1 above was dissolved in TFA (0.3 mL). The reaction was confirmed by LCMS and then concentrated in vacuo. The residue was purified by reverse phase HPLC (mobile phase: water/acetonitrile) to give the title compound.

Example 27: 4-[5-(3,8-diazabicyclo[3.2.1]octane-8-carbonyl)-2-[2-fluoro-4-(2-methoxy Synthesis of [ethyl]phenyl]phenyl]-2-fluoro-benzonitrile

The procedures of Steps 1 to 4 of Example 22 were repeated using tert-butyl 3,8-diazabicyclo[3.2.1]octane-3-carboxylate instead of tert-butyl N-[(3-endo)-8-azabicyclo[3.2.1]oct-3-yl]carbamate to give the title compound.

Example 28: 4-[5-[(3-exo)-3-amino-8-azabicyclo[3.2.1]octane-8-carbonyl]-2-[2-fluoro- Synthesis of 4-(2-hydroxy-2-methyl-propyl)phenyl]phenyl]-2-fluoro-benzonitrile

Step 1

Methyl 2-(4-bromo-3-fluoro-phenyl)acetate (500 mg) was dissolved in THF (2.2 mL). A 3M solution of MeMgBr in diethyl ether (5.40 mL) was added dropwise at -30°C, and the mixture was stirred overnight at room temperature. The reaction solution was poured into an aqueous ammonium chloride solution, ethyl acetate was added, and the mixture was washed sequentially with water and saturated brine. The organic layer was dried over anhydrous sodium sulfate, and the solvent was evaporated. The residue was purified by silica gel column chromatography (mobile phase: hexane/ethyl acetate = 10% → 50%) to obtain 1-(4-bromo-3-fluoro-phenyl)-2-methyl-propan-2-ol.

Step 2

Tert-butyl N-[(3-exo)-8-[3-(4-cyano-3-fluoro-phenyl)-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzoyl]-8-azabicyclo[3.2.1]octan-3-yl]carbamate (68 mg) obtained in Example 23 (Step 1), 1-(4-bromo-3-fluoro-phenyl)-2-methyl-propan-2-ol (107 mg) obtained in Step 1 above, and Pd(PPh ₃ ) ₄ (6.42 mg) were suspended in 1,4-dioxane (0.93 mL). A 2M aqueous Na ₂ CO ₃ solution (0.46 mL) was added thereto at room temperature, followed by stirring at 125° C. for 45 minutes. After filtering the reaction solution, the solvent was distilled off to obtain tert-butyl N-[(3-exo)-8-[3-(4-cyano-3-fluoro-phenyl)-4-[2-fluoro-4-(2-hydroxy-2-methyl-propyl)phenyl]benzoyl]-8-azabicyclo[3.2.1]oct-3-yl]carbamate.

Step 3

Tert-butyl N-[(3-exo)-8-[3-(4-cyano-3-fluoro-phenyl)-4-[2-fluoro-4-(2-hydroxy-2-methyl-propyl)phenyl]benzoyl]-8-azabicyclo[3.2.1]octan-3-yl]carbamate (90 mg) obtained in step 2 above was dissolved in TFA (0.3 mL). The progress of the reaction was confirmed by LCMS, followed by vacuum concentration. The residue was purified by reverse phase HPLC (mobile phase: water/acetonitrile) to give the title compound.

Example 29: 4-[5-[(3S)-3-aminopyrrolidine-1-carbonyl]-2-[4-(hydroxymethyl)phenyl]phenyl]benzene Synthesis of Formonitrile

Step 1

[4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]methanol (500 mg) and DMAP (26 mg) were dissolved in THF (7.1 mL), followed by the addition of TEA (0.74 mL). Acetyl chloride (0.23 mL) was added at room temperature, followed by stirring for 1 hour. Ethyl acetate was added, and the resulting mixture was washed sequentially with water and saturated brine. After drying the organic layer over anhydrous sodium sulfate, the solvent was evaporated. The residue was purified by silica gel column chromatography (mobile phase: hexane/ethyl acetate) to obtain methyl [4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]acetate.

Step 2

Tert-butyl N-[(3S)-1-[4-chloro-3-(4-cyanophenyl)benzoyl]pyrrolidin-3-yl]carbamate (100 mg) obtained in Example 9 (Step 2) and methyl [4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]acetate (130 mg) obtained in Step 1 above were dissolved in 1,4-dioxane (1.2 mL). Pd(dba) _₂ (6.8 mg), tripotassium phosphate (100 mg), and a 1M THF solution of _PCy₃ (0.02 mL) were added at room temperature, and the mixture was stirred in a microwave reactor at 160°C for 1 hour. The reaction solution was filtered through NH₁-silica gel, and the solvent of the filtrate was evaporated. The residue was purified by silica gel column chromatography (mobile phase: hexane/ethyl acetate = 30% → 100%) to give methyl [4-[4-[(3S)-3-(tert-butoxycarbonylamino)pyrrolidine-1-carbonyl]-2-(4-cyanophenyl)phenyl]phenyl]acetate.

Step 3

Methyl [4-[4-[(3S)-3-(tert-butoxycarbonylamino)pyrrolidine-1-carbonyl]-2-(4-cyanophenyl)phenyl]phenyl]acetate (100 mg) obtained in Step 2 above was dissolved in MeOH (2 mL). _K₂CO₃ (65 mg ₎ was added at room temperature, followed by stirring at room temperature for 30 minutes. Chloroform was added, and the mixture was washed sequentially with saturated aqueous ammonium chloride and saturated brine, and dried over anhydrous sodium sulfate. The solvent was evaporated. The residue was purified by silica gel column chromatography (mobile phase: hexane/ethyl acetate = 40% → 100%) to obtain tert-butyl N-[(3S)-1-[3-(4-cyanophenyl)-4-[4-(hydroxymethyl)phenyl]benzoyl]pyrrolidin-3-yl]carbamate.

Step 4

Tert-butyl N-[(3S)-1-[3-(4-cyanophenyl)-4-[4-(hydroxymethyl)phenyl]benzoyl]pyrrolidin-3-yl]carbamate (15 mg) obtained in Step 3 above was dissolved in TFA (0.3 mL). The progress of the reaction was confirmed by LCMS, and then the mixture was concentrated in vacuo. The residue was purified by reverse phase HPLC (mobile phase: water/acetonitrile) to give the title compound.

Example 30: 4-[5-[(3S)-3-aminopyrrolidine-1-carbonyl]-2-[4-(2-methoxyethyl)phenyl]benzene Synthesis of [1,2-dimethyl]benzonitrile

Step 1

1-Bromo-4-(2-methoxyethyl)benzene (450 mg) was dissolved in 1,4-dioxane (5.2 mL). Bis(pinacolato)diboron (797 mg), KOAc (411 mg), and _PdCl₂ (dppf) (77 mg) were then added, followed by stirring at 90°C overnight. Ethyl acetate was added, the mixture was passed through Celite, and the filtrate was washed sequentially with water and saturated brine. The organic layer was dried over anhydrous sodium sulfate, and the solvent was evaporated. The residue was purified by silica gel column chromatography (mobile phase: hexane/ethyl acetate = 2% → 20%) to obtain 2-[4-(2-methoxyethyl)phenyl]-4,4,5,5-tetramethyl-1,3,2-dioxaborolane.

Step 2

Tert-butyl N-[(3S)-1-[4-chloro-3-(4-cyanophenyl)benzoyl]pyrrolidin-3-yl]carbamate (300 mg) obtained in Example 9 (Step 2) and 2-[4-(2-methoxyethyl)phenyl]-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (369 mg) obtained in Step 1 above were dissolved in 1,4-dioxane (2 mL). Pd(dba) _₂ (32 mg), tripotassium phosphate (300 mg), and a 1M THF solution of _PCy₃ (0.07 mL) were added at room temperature, and the mixture was stirred in a microwave reactor at 160°C for 45 minutes. The reaction solution was passed through Celite, and the solvent in the filtrate was evaporated. The residue was purified by reverse phase HPLC (mobile phase: water/acetonitrile) to give tert-butyl N-[(3S)-1-[3-(4-cyanophenyl)-4-[4-(2-methoxyethyl)phenyl]benzoyl]pyrrolidin-3-yl]carbamate.

Step 3

Tert-butyl N-[(3S)-1-[3-(4-cyanophenyl)-4-[4-(2-methoxyethyl)phenyl]benzoyl]pyrrolidin-3-yl]carbamate (15 mg) obtained in Step 2 above was dissolved in TFA (0.3 mL). The progress of the reaction was confirmed by LCMS, and then the mixture was concentrated in vacuo. The residue was purified by reverse phase HPLC (mobile phase: water/acetonitrile) to give the title compound.

Example 31: 4-[5-[(3S)-3-aminopyrrolidine-1-carbonyl]-2-[4-(2-hydroxyethyl)phenyl]phenyl] Synthesis of benzonitrile

The procedures of Steps 1 to 4 of Example 29 were repeated using 2-[4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]ethanol instead of [4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]methanol to give the title compound.

Example 32: 4-[5-[(3S)-3-aminopyrrolidine-1-carbonyl]-2-[4-(3-hydroxypropyl)phenyl]phenyl] Synthesis of benzonitrile

The procedures of Steps 1 to 4 of Example 29 were repeated using 3-[4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]propan-1-ol instead of [4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]methanol to give the title compound.

Example 33: 4-[5-[(3S)-3-aminopyrrolidine-1-carbonyl]-2-[4-[1-(hydroxymethyl)cyclopropyl]benzene Synthesis of [1,2-dimethyl]phenyl]benzonitrile

The procedures of Steps 1 to 5 of Example 9 were repeated using (1-(4-bromophenyl)cyclopropyl)methanol instead of 1-bromo-2-chloro-4-methyl-benzene to give the title compound.

Example 34: 4-[5-[(3S)-3-aminopyrrolidine-1-carbonyl]-2-[4-(2-hydroxy-2-methyl-propyl)benzene Synthesis of [1,2-dimethyl]phenyl]benzonitrile

The procedures of Steps 1 to 5 of Example 9 were repeated, substituting 1-(4-bromophenyl)-2-methylpropan-2-ol for 1-bromo-2-chloro-4-methyl-benzene, to give the title compound.

Example 35: 4-[5-[(3S)-3-aminopyrrolidine-1-carbonyl]-2-[4-(2-hydroxypropyloxy)phenyl]benzene Synthesis of [1,2-dimethyl]benzonitrile

Step 1

The procedure of Step 1 of Example 12 was repeated using (4-benzyloxyphenyl)boronic acid instead of 4-methyl-2-nitrophenylboronic acid pinacol ester to obtain tert-butyl N-[(3S)-1-[4-(4-benzyloxyphenyl)-3-(4-cyanophenyl)benzoyl]pyrrolidin-3-yl]carbamate.

Step 2

Tert-butyl N-[(3S)-1-[4-(4-benzyloxyphenyl)-3-(4-cyanophenyl)benzoyl]pyrrolidin-3-yl]carbamate (800 mg) and palladium hydroxide-carbon (160 mg) obtained in step 1 above were suspended in EtOH (20 mL), purged with hydrogen, and stirred at room temperature for 6 hours. The reaction solution was passed through celite, and the solvent was evaporated. The residue was purified by silica gel column chromatography (mobile phase: hexane/ethyl acetate) to obtain tert-butyl N-[(3S)-1-[3-(4-cyanophenyl)-4-(4-hydroxyphenyl)benzoyl]pyrrolidin-3-yl]carbamate.

Step 3

Tert-butyl N-[(3S)-1-[3-(4-cyanophenyl)-4-(4-hydroxyphenyl)benzoyl]pyrrolidin-3-yl]carbamate (15 mg) obtained in Step 2 above was dissolved in DMF (0.5 mL). _{K₂CO₃ (} 6.4 mg) and 2-methyloxirane (5.4 mg) were added at room temperature, followed by stirring at 120°C for 2 hours. Ethyl acetate was added, and the resulting mixture was washed sequentially with water and saturated brine, dried over anhydrous sodium sulfate, and the solvent was evaporated. The residue was purified by silica gel column chromatography (mobile phase: hexane/ethyl acetate) to obtain tert-butyl N-[(3S)-1-[3-(4-cyanophenyl)-4-[4-(2-hydroxypropyloxy)phenyl]benzoyl]pyrrolidin-3-yl]carbamate.

Step 4

Tert-butyl N-[(3S)-1-[3-(4-cyanophenyl)-4-[4-(2-hydroxypropyloxy)phenyl]benzoyl]pyrrolidin-3-yl]carbamate (15 mg) obtained in Step 3 above was dissolved in TFA (0.3 mL). The reaction was confirmed by LCMS and then concentrated in vacuo. The residue was purified by reverse phase HPLC (mobile phase: water/acetonitrile) to give the title compound.

Example 36: 4-[5-[(3S)-3-aminopyrrolidine-1-carbonyl]-2-(2-fluoro-4-methyl-phenyl)phenyl]-2- Synthesis of Fluoro-Benzonitrile

The procedures of Steps 1 to 3 of Example 16 were repeated using (2-fluoro-4-methyl-phenyl)boronic acid instead of p-tolylboronic acid to give the title compound.

Example 37: 4-[5-[(3S)-3-aminopyrrolidine-1-carbonyl]-2-[2-fluoro-4-(2-hydroxy-2-methyl-propane]- Synthesis of 2-fluoro-benzonitrile

Step 1

Tert-butyl N-[(3S)-1-[4-chloro-3-(4-cyano-3-fluoro-phenyl)benzoyl]pyrrolidin-3-yl]carbamate (4 g) obtained in Example 16 (Step 1) was dissolved in 1,4-dioxane (45 mL). Pd(OAc) ₂ (0.40 g), KOAc (2.7 g), bis(pinacolato)diboron (4.6 g), and silica-SMAP (0.72 g) were added at room temperature, followed by stirring at 150°C for 18 hours. The reaction solution was filtered, and the solvent was evaporated. The residue was purified by silica gel column chromatography (mobile phase: hexane/ethyl acetate) to give tert-butyl N-[(3S)-1-[3-(4-cyano-3-fluoro-phenyl)-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzoyl]pyrrolidin-3-yl]carbamate.

Step 2

Tert-butyl N-[(3S)-1-[3-(4-cyano-3-fluoro-phenyl)-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzoyl]pyrrolidin-3-yl]carbamate (30 mg) obtained in Step 1 above and 1-(4-bromo-3-fluoro-phenyl)-2-methyl-propan-2-ol (28 mg) obtained in Example 28 (Step 1) were dissolved in 1,4-dioxane (0.8 mL). Pd( _PPh₃ ) _₄ (3.2 mg) and 2M _{aqueous Na₂CO₃} solution (0.4 mL) were added at room temperature, and the mixture was stirred in a microwave reactor at 120°C for 30 minutes. The reaction solution was filtered, and the solvent was evaporated. Ethyl acetate was added, and the resulting mixture was washed sequentially with water and saturated brine, dried over anhydrous sodium sulfate, and the solvent was evaporated. The residue was purified by silica gel column chromatography (mobile phase: chloroform/methanol) to give tert-butyl N-[(3S)-1-[3-(4-cyano-3-fluoro-phenyl)-4-[2-fluoro-4-(2-hydroxy-2-methyl-propyl)phenyl]benzoyl]pyrrolidin-3-yl]carbamate.

Step 3

The tert-butyl N-[(3S)-1-[3-(4-cyano-3-fluoro-phenyl)-4-[2-fluoro-4-(2-hydroxy-2-methyl-propyl)phenyl]benzoyl]pyrrolidin-3-yl]carbamate (20 mg) obtained in step 2 above was dissolved in MeOH (1 mL). 12 M aqueous HCl solution (1 mL) was added thereto at room temperature, followed by stirring at room temperature for 30 minutes. The reaction solution was neutralized by adding water (1 mL) and 2 M aqueous sodium hydroxide solution (6 mL). Chloroform was added, and the mixture was washed with water and saturated brine in sequence and dried over anhydrous sodium sulfate. Afterwards, the solvent was distilled off to obtain the title compound.

Example 38: 2-Fluoro-4-[2-[2-fluoro-4-(2-methoxyethyl)phenyl]-5-(9-oxa-2,6-diazaspiro Synthesis of [3.5]nonane-2-carbonyl)phenyl]benzonitrile

The procedures of Steps 1 to 4 of Example 22 were repeated using tert-butyl 9-oxa-2,6-diazaspiro[3.5]nonane-6-carboxylate instead of tert-butyl N-[(3-endo)-8-azabicyclo[3.2.1]oct-3-yl]carbamate to give the title compound.

Example 39: 4-[5-(2,3,3a,4,6,6a-hexahydro-1H-pyrrolo[3,4-c]pyrrole-5-carbonyl)-2-[2- Synthesis of 4-(2-methoxyethyl)-phenyl-2-fluoro-benzonitrile

The procedures of Steps 1 to 4 of Example 22 were repeated using tert-butyl 2,3,3a,4,6,6a-hexahydro-1H-pyrrolo[3,4-c]pyrrole-5-carboxylate instead of tert-butyl N-[(3-endo)-8-azabicyclo[3.2.1]oct-3-yl]carbamate to give the title compound.

Example 40: 4-[5-[(3S)-3-aminopyrrolidine-1-carbonyl]-2-[4-(2-hydroxy-2-methyl-propyl)benzene Synthesis of [1,2-difluoro-1,2-dimethylphenyl]-2-fluoro-benzonitrile

The procedures of Steps 1 to 3 of Example 37 were repeated using 1-(4-bromophenyl)-2-methylpropan-2-ol instead of 1-(4-bromo-3-fluoro-phenyl)-2-methyl-propan-2-ol to give the title compound.

Example 41: 4-[5-[(3-endo)-3-amino-8-azabicyclo[3.2.1]octane-8-carbonyl]-2-[2-fluoro- Synthesis of 4-(2-hydroxy-2-methyl-propyl)phenyl]phenyl]-2-fluoro-benzonitrile

Step 1

tert-Butyl 4-chloro-3-(4-cyano-3-fluoro-phenyl)benzoate (300 mg) obtained in Example 22 (Step 1) was dissolved in 1,4-dioxane (5 mL). Pd(OAc) _₂ (40 mg), KOAc (300 mg), bis(pinacolato)diboron (500 mg), and silica-SMAP (50 mg) were added at room temperature, followed by stirring at 100°C for 26 hours. The reaction solution was filtered, and the solvent was evaporated. The residue was purified by silica gel column chromatography (mobile phase: hexane/ethyl acetate) to obtain tert-butyl 3-(4-cyano-3-fluoro-phenyl)-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzoate.

Step 2

Tert-butyl 3-(4-cyano-3-fluoro-phenyl)-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzoate (100 mg) obtained in step 1 above was dissolved in DCM (1.2 mL). TFA (1.00 mL) was added thereto at room temperature, followed by stirring at room temperature for 30 minutes. The reaction solution was concentrated in vacuo, and the solvent was evaporated. Chloroform was added, the mixture was washed with water and dried over anhydrous sodium sulfate, and the solvent was evaporated to obtain 3-(4-cyano-3-fluoro-phenyl)-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzoic acid.

Step 3

3-(4-Cyano-3-fluoro-phenyl)-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzoic acid (500 mg) obtained in the above step 2 and tert-butyl N-[(3-endo)-8-azabicyclo[3.2.1]octan-3-yl]carbamate (308 mg) were dissolved in THF (4.5 mL). TEA (0.57 mL) and HATU (1 g) were added thereto at room temperature, followed by stirring at 50° C. for 1 hour. The reaction solution was concentrated in vacuo, and the residue was purified by silica gel column chromatography (mobile phase: hexane/ethyl acetate) to give tert-butyl N-[(3-endo)-8-[3-(4-cyano-3-fluoro-phenyl)-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzoyl]-8-azabicyclo[3.2.1]oct-3-yl]carbamate.

Step 4

Tert-butyl N-[(3-endo)-8-[3-(4-cyano-3-fluoro-phenyl)-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzoyl]-8-azabicyclo[3.2.1]octan-3-yl]carbamate (30 mg) obtained in the above step 3 and 1-(4-bromo-3-fluoro-phenyl)-2-methyl-propan-2-ol (19 mg) obtained in Example 28 (step 1) were dissolved in 1,4-dioxane (0.5 mL). Pd(PPh ₃ ) ₄ (18 mg) and 2M Na ₂ CO ₃ aqueous solution (0.3 mL) were added thereto at room temperature, and the mixture was stirred in a microwave reactor at 120° C. for 30 minutes. The supernatant of the reaction solution was collected and filtered through NH-silica gel, and the solvent was evaporated to obtain tert-butyl N-[(3-endo)-8-[3-(4-cyano-3-fluoro-phenyl)-4-[2-fluoro-4-(2-hydroxy-2-methyl-propyl)phenyl]benzoyl]-8-azabicyclo[3.2.1]oct-3-yl]carbamate.

Step 5

The tert-butyl N-[(3-endo)-8-[3-(4-cyano-3-fluoro-phenyl)-4-[2-fluoro-4-(2-hydroxy-2-methyl-propyl)phenyl]benzoyl]-8-azabicyclo[3.2.1]octan-3-yl]carbamate (15 mg) obtained in step 4 above was dissolved in MeOH (0.5 mL). 12 M aqueous HCl solution (0.5 mL) was added thereto at room temperature, followed by stirring at room temperature for 30 minutes. Water and 2 M aqueous sodium hydroxide solution (3 mL) were then added thereto, the mixture was partitioned, and extracted with chloroform. After drying the organic layer over anhydrous sodium sulfate, the solvent was evaporated. The residue was purified by reverse phase HPLC (mobile phase: water/acetonitrile) to give the title compound.

Example 42: 4-[5-[(3S)-3-(methylamino)pyrrolidine-1-carbonyl]-2-(p-tolyl)phenyl]benzyl Synthesis of Nitriles

The procedures of Steps 1 to 5 of Example 1 were repeated using tert-butyl (S)-methyl(pyrrolidin-3-yl)carbamate instead of tert-butyl N-[(3S)-pyrrolidin-3-yl]carbamate to give the title compound.

Example 43: 4-[5-[(3S)-3-aminopyrrolidine-1-carbonyl]-2-(4-benzyloxyphenyl)phenyl]benzonitrile Synthesis

The procedures of Steps 1 to 5 of Example 9 were repeated, substituting 1-(benzyloxy)-4-bromobenzene for 1-bromo-2-chloro-4-methyl-benzene, to give the title compound.

Example 44: 1-[4-[4-[(3S)-3-aminopyrrolidine-1-carbonyl]-2-(4-cyanophenyl)phenyl]phenyl]- Synthesis of N-phenyl-cyclopropanecarboxamide

The procedures of Steps 1 to 5 of Example 9 were repeated using 1-(4-bromophenyl)-N-phenylcyclopropanecarboxamide instead of 1-bromo-2-chloro-4-methyl-benzene to give the title compound.

Example 45: 2-[4-[4-[(3S)-3-aminopyrrolidine-1-carbonyl]-2-(4-cyanophenyl)phenyl]phenyl] Synthesis of ethyl acetate

Step 1

The procedure of Step 1 of Example 29 was repeated using 2-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)ethanol instead of [4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]methanol to obtain phenylethyl 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)acetate.

Step 2

Using phenylethyl 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)acetate obtained in step 1 above instead of 4-methyl-2-nitrophenylboronic acid pinacol ester, the procedures of steps 1 to 2 of example 12 were repeated to give the title compound.

Example 46: 4-[2-[4-(2-hydroxyethyl)phenyl]-5-[(3S)-3-(methylamino)pyrrolidine-1-carbonyl] Synthesis of [phenyl]benzonitrile

Step 1

The procedures of Steps 1 to 5 of Example 1 were repeated, using phenylethyl 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)acetate obtained in Example 45 (Step 1) instead of p-tolylboronic acid, and using tert-butyl (S)-methyl(pyrrolidin-3-yl)carbamate instead of tert-butyl N-[(3S)-pyrrolidin-3-yl]carbamate, to obtain ethyl 2-[4-[2-(4-cyanophenyl)-4-[(3S)-3-(methylamino)pyrrolidine-1-carbonyl]phenyl]phenyl]acetate.

Step 2

The procedure of Step 3 of Example 29 was repeated using ethyl 2-[4-[2-(4-cyanophenyl)-4-[(3S)-3-(methylamino)pyrrolidine-1-carbonyl]phenyl]phenyl]acetate obtained in Step 1 above instead of methyl [4-[4-[(3S)-3-(tert-butoxycarbonylamino)pyrrolidine-1-carbonyl]-2-(4-cyanophenyl)phenyl]phenyl]acetate to give the title compound.

Example 47: 4-[2-[4-(2-methoxyethyl)phenyl]-5-[(3S)-3-(methylamino)pyrrolidine-1-carbonyl]- Synthesis of [1,2-dimethyl]phenyl]benzonitrile

Step 1

The procedures of Steps 1 to 5 of Example 1 were repeated using (4-(2-methoxyethyl)phenyl)boronic acid instead of p-tolylboronic acid and (S)-methyl(pyrrolidin-3-yl)carbamic acid tert-butyl ester instead of N-[(3S)-pyrrolidin-3-yl]carbamate to give the title compound.

Example 48: 4-[5-[(3S)-3-(dimethylamino)pyrrolidine-1-carbonyl]-2-[4-[1-(hydroxymethyl) Synthesis of [propyl]phenyl]phenyl]benzonitrile

The procedures of Steps 1 to 4 of Example 1 were repeated using [4-[1-(hydroxymethyl)cyclopropyl]phenyl]boronic acid instead of p-tolylboronic acid and (S)-N,N-dimethylpyrrolidin-3-amine instead of tert-butyl N-[(3S)-pyrrolidin-3-yl]carbamate to give the title compound.

Example 49: 4-[5-[(3S)-3-aminopyrrolidine-1-carbonyl]-2-(3-fluoro-4-methyl-phenyl)phenyl]benzene Synthesis of Formonitrile

The procedures of Steps 1 to 2 of Example 12 were repeated using (3-fluoro-4-methyl-phenyl)boronic acid instead of 4-methyl-2-nitrophenylboronic acid pinacol ester to give the title compound.

Example 50: Synthesis of 4-[5-[(3S)-3-aminopyrrolidine-1-carbonyl]-2-(4-chlorophenyl)phenyl]benzonitrile become

The procedures of Example 9 Steps 1 to 5 were repeated, substituting 1-bromo-4-chloro-benzene for 1-bromo-2-chloro-4-methyl-benzene, to give the title compound.

Example 51: Synthesis of 4-[5-[(3S)-3-aminopyrrolidine-1-carbonyl]-2-(4-bromophenyl)phenyl]benzonitrile become

The procedures of Steps 1 to 5 of Example 9 were repeated using 1,4-dibromobenzene instead of 1-bromo-2-chloro-4-methyl-benzene to give the title compound.

Example 52: 5'-((1S,4S)-2,5-diazabicyclo[2.2.1]heptane-2-carbonyl)-4"-methyl-[1,1': Synthesis of 2',1"-terphenyl-4-carbonitrile

The procedures of Steps 1 to 5 of Example 1 were repeated using tert-butyl (1S,4S)-2,5-diazabicyclo[2.2.1]heptane-2-carboxylate instead of tert-butyl N-[(3S)-pyrrolidin-3-yl]carbamate to give the title compound.

Example 53: 4-[2-[4-(2-aminoethyl)phenyl]-5-[(3S)-3-aminopyrrolidine-1-carbonyl]phenyl] Synthesis of benzonitrile

Step 1

Tert-butyl N-[(3S)-1-[3-(4-cyanophenyl)-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzoyl]pyrrolidin-3-yl]carbamate (50 mg) obtained in Example 9 (Step 3) was dissolved in 1,4-dioxane (0.48 mL). 2-(4-bromophenyl)ethanamine (29 mg), Pd(PPh ₃ ) ₄ (3.4 mg), and 2M aqueous _{Na 2} CO ₃ solution (0.24 mL) were added at room temperature, and the mixture was reacted in a microwave reactor at 120° C. for 30 minutes. The residue was purified by silica gel column chromatography (mobile phase: hexane/ethyl acetate) to give tert-butyl N-[(3S)-1-[4-[4-(2-aminoethyl)phenyl]-3-(4-cyanophenyl)benzoyl]pyrrolidin-3-yl]carbamate.

Step 2

Tert-butyl N-[(3S)-1-[4-[4-(2-aminoethyl)phenyl]-3-(4-cyanophenyl)benzoyl]pyrrolidin-3-yl]carbamate (15 mg) obtained in Step 1 was dissolved in TFA (0.3 mL). The progress of the reaction was confirmed by LCMS, followed by vacuum concentration. The residue was purified by reverse phase HPLC (mobile phase: water/acetonitrile) to give the title compound.

Example 54: Synthesis of 4-[5-[(3S)-3-aminopyrrolidine-1-carbonyl]-2-(4-iodophenyl)phenyl]benzonitrile become

The procedures of Steps 1 to 5 of Example 9 were repeated using 1,4-diiodobenzene instead of 1-bromo-2-chloro-4-methyl-benzene to give the title compound.

Example 55: N-[2-[4-[4-[(3S)-3-aminopyrrolidine-1-carbonyl]-2-(4-cyanophenyl)phenyl]benzene Synthesis of [3-amino]ethyl]acetamide

Tert-butyl N-[(3S)-1-[4-[4-(2-aminoethyl)phenyl]-3-(4-cyanophenyl)benzoyl]pyrrolidin-3-yl]carbamate (15 mg) obtained in Example 53 (Step 1) was dissolved in THF. TEA (0.02 mL) was added, followed by acetyl chloride (4.6 mg) at room temperature, and the mixture was stirred at room temperature for 1 hour. TFA was added to the residue, and the reaction was confirmed by LCMS, followed by vacuum concentration. The residue was purified by reverse phase HPLC (mobile phase: water/acetonitrile) to obtain the title compound.

Example 56: 4-[5-[(3S)-3-aminopyrrolidine-1-carbonyl]-2-(4-propylphenyl)phenyl]benzonitrile synthesis

The procedures of Steps 1 to 2 of Example 12 were repeated using (4-propylphenyl)boronic acid instead of 4-methyl-2-nitrophenylboronic acid pinacol ester to give the title compound.

Example 57: Synthesis of 4-[5-[(3S)-3-aminopyrrolidine-1-carbonyl]-2-(2-naphthyl)phenyl]benzonitrile

The procedures of Steps 1 to 2 of Example 12 were repeated using 2-naphthylboronic acid instead of 4-methyl-2-nitrophenylboronic acid pinacol ester to give the title compound.

Example 58: 4-[2-[4-[1-(Hydroxymethyl)cyclopropyl]phenyl]-5-[(3S)-3-(methylamino)pyrrole Synthesis of [1-alkyl]-1-carbonyl]phenyl]benzonitrile

The procedures of Steps 1 to 5 of Example 1 were repeated, using [4-[1-(hydroxymethyl)cyclopropyl]phenyl]boronic acid instead of p-tolylboronic acid and (S)-methyl(pyrrolidin-3-yl)carbamic acid tert-butyl ester instead of N-[(3S)-pyrrolidin-3-yl]carbamate, to give the title compound.

Example 59: 4-[5-[(3S)-3-aminopyrrolidine-1-carbonyl]-2-[4-[(1-hydroxycyclopropyl)methyl]benzene Synthesis of [1,2-dimethyl]phenyl]benzonitrile

The procedures of Steps 1 to 5 of Example 9 were repeated using 1-[(4-bromophenyl)methyl]cyclopropanol instead of 1-bromo-2-chloro-4-methyl-benzene to give the title compound.

Example 60: 4-[5-[(3S)-3-aminopyrrolidine-1-carbonyl]-2-[4-(2-methylprop-1-enyl)phenyl] Synthesis of [phenyl]benzonitrile

The procedures of Steps 1 to 5 of Example 9 were repeated, substituting 1-bromo-4-(2-methylprop-1-enyl)benzene for 1-bromo-2-chloro-4-methyl-benzene, to give the title compound.

Example 61: 4-[5-[(3S)-3-aminopyrrolidine-1-carbonyl]-2-[4-(3-hydroxy-3-methyl-butyl)benzene Synthesis of [1,2-dimethyl]phenyl]benzonitrile

The procedures of Steps 1 to 5 of Example 9 were repeated, substituting 4-(4-bromophenyl)-2-methyl-butan-2-ol for 1-bromo-2-chloro-4-methyl-benzene, to give the title compound.

Example 62: 4-[5-[(3S)-3-aminopyrrolidine-1-carbonyl]-2-[4-[2-(1-hydroxycyclopropyl)ethyl] Synthesis of [phenyl]phenyl]benzonitrile

The procedure of Steps 1 to 5 of Example 9 was repeated using 1-[2-(4-bromophenyl)ethyl]cyclopropanol instead of 1-bromo-2-chloro-4-methyl-benzene to give the title compound.

Example 63: 4-[5-[(3S)-3-aminopyrrolidine-1-carbonyl]-2-[4-(2-hydroxyethyl)phenyl]phenyl]- Synthesis of 2-Fluoro-benzonitrile

The procedures of Steps 1 to 3 of Example 37 were repeated using 2-(4-bromophenyl)ethanol instead of 1-(4-bromo-3-fluoro-phenyl)-2-methyl-propan-2-ol to give the title compound.

Example 64: 4-[5-[(3S)-3-aminopyrrolidine-1-carbonyl]-2-[2-fluoro-4-(2-hydroxy-2-methyl-propane]- Synthesis of [1,2-[4-(1-methyl)phenyl]phenyl]benzonitrile

The procedures of Steps 1 to 5 in Example 9 were repeated using 1-(4-bromo-3-fluoro-phenyl)-2-methyl-propan-2-ol obtained in Example 28 (Step 1) instead of 1-bromo-2-chloro-4-methyl-benzene to give the title compound.

Example 65: 4-[5-[(3S)-3-aminopyrrolidine-1-carbonyl]-2-[4-(3-hydroxy-3-methyl-butyl)benzene Synthesis of [1,2-difluoro-1,2-dimethylphenyl]-2-fluoro-benzonitrile

The procedures of Steps 1 to 3 of Example 16 were repeated using 2-methyl-4-[4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]butan-2-ol instead of p-tolylboronic acid to give the title compound.

Example 66: 4-[5-[(3S)-3-aminopyrrolidine-1-carbonyl]-2-[4-[1-(methoxymethyl)cyclopropyl] Synthesis of [phenyl]phenyl]benzonitrile

The procedures of Steps 1 to 5 of Example 9 were repeated, substituting 1-bromo-4-[1-(methoxymethyl)cyclopropyl]benzene for 1-bromo-2-chloro-4-methyl-benzene, to give the title compound.

Example 67: 4-[5-[(3S)-3-aminopyrrolidine-1-carbonyl]-2-[2-fluoro-4-[(1-hydroxycyclopropyl)methyl Synthesis of [1,2-dimethyl]phenyl]benzonitrile

Step 1

Methyl-2-(4-bromo-3-fluoro-phenyl)acetate (500 mg) and titanium isopropoxide (0.84 mL) were dissolved in THF (5 mL). A 3M solution of EtMgBr in diethyl ether (1.9 mL) was added dropwise at 0°C, and the mixture was stirred overnight at room temperature. Ethyl acetate was added, and the mixture was washed sequentially with water and saturated brine, dried over anhydrous sodium sulfate, and the solvent was evaporated. The residue was purified by silica gel column chromatography (mobile phase: hexane/ethyl acetate) to obtain 1-[(4-bromo-3-fluoro-phenyl)methyl]cyclopropanol.

Step 2

Using 1-[(4-bromo-3-fluoro-phenyl)methyl]cyclopropanol obtained in step 1 above instead of 1-bromo-2-chloro-4-methyl-benzene, the procedures of steps 1 to 5 of example 9 were repeated to give the title compound.

Example 68: 4-[5-[(3S)-3-aminopyrrolidine-1-carbonyl]-2-[4-[1-(1-hydroxycyclopropyl)cyclopropyl] Synthesis of [1,2-dimethyl]phenyl]phenyl]benzonitrile

Step 1

The procedure of Step 1 of Example 67 was repeated using methyl 1-(4-bromophenyl)cyclopropanecarboxylate in place of methyl-2-(4-bromo-3-fluoro-phenyl)acetate to give 1-[1-(4-bromophenyl)cyclopropyl]cyclopropanol.

Step 2

Using 1-[1-(4-bromophenyl)cyclopropyl]cyclopropanol obtained in step 1 above instead of 1-bromo-2-chloro-4-methyl-benzene, the procedures of steps 1 to 5 of example 9 were repeated to give the title compound.

Example 69: 4-[5-[(3S)-3-aminopyrrolidine-1-carbonyl]-2-[4-(2-methoxyethyl)phenyl]benzene Synthesis of 2-fluoro-benzonitrile

The procedures of Steps 1 to 3 of Example 16 were repeated using 2-[4-(2-methoxyethyl)phenyl]-4,4,5,5-tetramethyl-1,3,2-dioxaborolane obtained in Example 30 (Step 1) instead of p-tolylboronic acid to give the title compound.

Example 70: 4-[5-[(3S)-3-aminopyrrolidine-1-carbonyl]-2-[2-fluoro-4-(2-hydroxyethyl)phenyl] Synthesis of [phenyl]benzonitrile

The procedures of Example 9 Steps 1 to 5 were repeated using 2-(4-bromo-3-fluoro-phenyl)ethanol instead of 1-bromo-2-chloro-4-methyl-benzene to give the title compound.

Example 71: 4-[5-[(3S)-3-aminopyrrolidine-1-carbonyl]-2-[2-fluoro-4-(2-methoxyethyl)benzene Synthesis of [1,2-dimethyl]phenyl]benzonitrile

The procedures of Steps 1 to 5 of Example 9 were repeated, substituting 1-bromo-2-fluoro-4-(2-methoxyethyl)benzene for 1-bromo-2-chloro-4-methyl-benzene, to give the title compound.

Example 72: 4-[5-[(3S)-3-aminopyrrolidine-1-carbonyl]-2-[4-(2-hydroxy-1,1-dimethyl- Synthesis of [1,2-[4-(1-methyl)phenyl]phenyl]benzonitrile

The procedures of Steps 1 to 5 of Example 9 were repeated, substituting 2-(4-bromophenyl)-2-methyl-propan-1-ol for 1-bromo-2-chloro-4-methyl-benzene, to give the title compound.

Example 73: 4-[5-[(3S)-3-aminopyrrolidine-1-carbonyl]-2-[4-(2-fluoroethyl)phenyl]phenyl]benzene Synthesis of Formonitrile

The procedures of Steps 1 to 5 of Example 9 were repeated, substituting 1-bromo-4-(2-fluoroethyl)benzene for 1-bromo-2-chloro-4-methyl-benzene, to give the title compound.

Example 74: 4-[5-(2,7-diazaspiro[3.4]octane-7-carbonyl)-2-[2-fluoro-4-(2-methoxyethyl) Synthesis of [phenyl]phenyl]-2-fluoro-benzonitrile

The procedures of Steps 1 to 4 of Example 22 were repeated using tert-butyl 2,7-diazaspiro[3.4]octane-2-carboxylate instead of tert-butyl N-[(3-endo)-8-azabicyclo[3.2.1]oct-3-yl]carbamate to give the title compound.

Example 75: 4-[5-(2,8-diazaspiro[3.5]nonane-2-carbonyl)-2-[2-fluoro-4-(2-methoxyethyl) Synthesis of [phenyl]phenyl]-2-fluoro-benzonitrile

The procedures of Steps 1 to 4 of Example 22 were repeated using tert-butyl 2,8-diazaspiro[3.5]nonane-8-carboxylate instead of tert-butyl N-[(3-endo)-8-azabicyclo[3.2.1]oct-3-yl]carbamate to give the title compound.

Example 76: 4-[5-(2,7-diazaspiro[3.4]octane-7-carbonyl)-2-[2-fluoro-4-(2-hydroxy-2-methyl Synthesis of 2-fluoro-benzonitrile

The procedures of Steps 1 to 5 of Example 41 were repeated using tert-butyl 2,7-diazaspiro[3.4]octane-2-carboxylate instead of tert-butyl N-[(3-endo)-8-azabicyclo[3.2.1]oct-3-yl]carbamate to give the title compound.

Example 77: 4-[5-(2,8-diazaspiro[3.5]nonane-2-carbonyl)-2-[2-fluoro-4-(2-hydroxy-2-methyl Synthesis of 2-fluoro-benzonitrile

The procedures of Steps 1 to 5 of Example 41 were repeated using tert-butyl 2,8-diazaspiro[3.5]nonane-8-carboxylate instead of tert-butyl N-[(3-endo)-8-azabicyclo[3.2.1]oct-3-yl]carbamate to give the title compound.

Example 78: 4-[5-(3,8-diazaspiro[4.5]decane-8-carbonyl)-2-[2-fluoro-4-(2-methoxyethyl) Synthesis of [phenyl]phenyl]-2-fluoro-benzonitrile hydrochloride

The procedures of Steps 1 to 4 of Example 22 were repeated using tert-butyl 3,8-diazaspiro[4.5]decane-3-carboxylate instead of tert-butyl N-[(3-endo)-8-azabicyclo[3.2.1]oct-3-yl]carbamate to give the title compound.

Example 79: 4-[5-(2,8-diazaspiro[3.5]nonane-8-carbonyl)-2-[2-fluoro-4-(2-methoxyethyl) Synthesis of [phenyl]phenyl]-2-fluoro-benzonitrile

The procedures of Steps 1 to 4 of Example 22 were repeated using tert-butyl 2,8-diazaspiro[3.5]nonane-2-carboxylate instead of tert-butyl N-[(3-endo)-8-azabicyclo[3.2.1]oct-3-yl]carbamate to give the title compound.

Example 80: 4-[5-(1,4-diazepane-1-carbonyl)-2-[2-fluoro-4-(2-methoxyethyl)phenyl] Synthesis of [phenyl]-2-fluoro-benzonitrile hydrochloride

The procedures of Steps 1 to 4 of Example 22 were repeated using tert-butyl 1,4-diazepane-1-carboxylate instead of tert-butyl N-[(3-endo)-8-azabicyclo[3.2.1]oct-3-yl]carbamate to give the title compound.

Example 81: 4-[5-(3,7-diazaspiro[3.4]octane-7-carbonyl)-2-[2-fluoro-4-(2-methoxyethyl) Synthesis of [phenyl]phenyl]-2-fluoro-benzonitrile

The procedures of Steps 1 to 4 of Example 22 were repeated using tert-butyl 3,7-diazaspiro[3.4]octane-3-carboxylate instead of tert-butyl N-[(3-endo)-8-azabicyclo[3.2.1]oct-3-yl]carbamate to give the title compound.

Example 82: 4-[5-[(1S,4S)-2,5-diazabicyclo[2.2.1]heptane-2-carbonyl]-2-[2-fluoro-4- Synthesis of (2-methoxyethyl)phenyl]phenyl]-2-fluoro-benzonitrile

The procedures of Steps 1 to 4 of Example 22 were repeated using tert-butyl (1S,4S)-2,5-diazabicyclo[2.2.1]heptane-2-carboxylate instead of tert-butyl N-[(3-endo)-8-azabicyclo[3.2.1]oct-3-yl]carbamate to give the title compound.

Example 83: 4-[5-(3,7-diazaspiro[3.5]nonane-7-carbonyl)-2-[2-fluoro-4-(2-methoxyethyl) Synthesis of [phenyl]phenyl]-2-fluoro-benzonitrile

The procedures of Steps 1 to 4 of Example 22 were repeated using tert-butyl 3,7-diazaspiro[3.5]nonane-3-carboxylate instead of tert-butyl N-[(3-endo)-8-azabicyclo[3.2.1]oct-3-yl]carbamate to give the title compound.

Example 84: 4-[5-(2,7-diazaspiro[3.5]nonane-2-carbonyl)-2-[2-fluoro-4-(2-methoxyethyl) Synthesis of [phenyl]phenyl]-2-fluoro-benzonitrile

The procedures of Steps 1 to 4 of Example 22 were repeated using tert-butyl 2,7-diazaspiro[3.5]nonane-7-carboxylate hydrochloride instead of tert-butyl N-[(3-endo)-8-azabicyclo[3.2.1]oct-3-yl]carbamate to give the title compound.

Example 85: 4-[5-[(1R,4R)-2,5-diazabicyclo[2.2.1]heptane-2-carbonyl]-2-[2-fluoro-4- Synthesis of (2-methoxyethyl)phenyl]phenyl]-2-fluoro-benzonitrile

The procedures of Steps 1 to 4 of Example 22 were repeated using tert-butyl (1R,4R)-2,5-diazabicyclo[2.2.1]heptane-2-carboxylate instead of tert-butyl N-[(3-endo)-8-azabicyclo[3.2.1]oct-3-yl]carbamate to give the title compound.

Example 86: 2-Fluoro-4-[2-[2-fluoro-4-(2-methoxyethyl)phenyl]-5-[(1S,4S)-5-methyl-2,5- Synthesis of diazabicyclo[2.2.1]heptane-2-carbonyl]phenyl]benzonitrile

The procedures of Steps 1 to 4 of Example 22 were repeated using (1S,4S)-2-methyl-2,5-diazabicyclo[2.2.1]heptane instead of tert-butyl N-[(3-endo)-8-azabicyclo[3.2.1]oct-3-yl]carbamate to give the title compound.

Example 87: 2-Fluoro-4-[2-[2-fluoro-4-(2-methoxyethyl)phenyl]-5-[(1R,4R)-5-methyl-2,5- Synthesis of diazabicyclo[2.2.1]heptane-2-carbonyl]phenyl]benzonitrile

The procedures of Steps 1 to 4 of Example 22 were repeated using (1R,4R)-2-methyl-2,5-diazabicyclo[2.2.1]heptane instead of tert-butyl N-[(3-endo)-8-azabicyclo[3.2.1]oct-3-yl]carbamate to give the title compound.

Example 88: 4-[5-(3,8-diazabicyclo[3.2.1]octane-3-carbonyl)-2-[2-fluoro-4-(2-methoxy Synthesis of [ethyl]phenyl]phenyl]-2-fluoro-benzonitrile

The procedures of Steps 1 to 4 of Example 22 were repeated using tert-butyl 3,8-diazabicyclo[3.2.1]octane-8-carboxylate instead of tert-butyl N-[(3-endo)-8-azabicyclo[3.2.1]oct-3-yl]carbamate to give the title compound.

Example 89: 4-[5-[(3S)-3-aminopyrrolidine-1-carbonyl]-2-(1,3-benzothiazol-5-yl)phenyl]- Synthesis of 2-Fluoro-benzonitrile

The procedures of Steps 1 to 3 of Example 16 were repeated using 1,3-benzothiazol-5-ylboronic acid instead of p-tolylboronic acid to give the title compound.

Example 90: 4-[5-[(3S)-3-aminopyrrolidine-1-carbonyl]-2-(1-methylpyrazolo[3,4-b]pyridine- Synthesis of [5-(4-(4-(4-methyl)phenyl)-2-fluoro-benzonitrile]]

The procedures of Steps 1 to 3 of Example 16 were repeated using (1-methylpyrazolo[3,4-b]pyridin-5-yl)boronic acid instead of p-tolylboronic acid to give the title compound.

Example 91: 4-[5-[(3S)-3-aminopyrrolidine-1-carbonyl]-2-(1-methylbenzimidazol-5-yl)benzene Synthesis of 2-fluoro-benzonitrile

The procedures of Steps 1 to 3 of Example 37 were repeated using 5-bromo-1-methyl-benzimidazole instead of 1-(4-bromo-3-fluoro-phenyl)-2-methyl-propan-2-ol to give the title compound.

Example 92: 4-[5-[(3S)-3-aminopyrrolidine-1-carbonyl]-2-(1-methylindazol-5-yl)phenyl]-2- Synthesis of Fluoro-Benzonitrile

The procedures of Steps 1 to 3 of Example 16 were repeated using (1-methylindazol-5-yl)boronic acid instead of p-tolylboronic acid to give the title compound.

Example 93: 4-[5-[(3S)-3-aminopyrrolidine-1-carbonyl]-2-(2-methylindazol-5-yl)phenyl]-2- Synthesis of Fluoro-Benzonitrile

The procedure of Steps 1 to 3 of Example 16 was repeated using 2-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)indazole instead of p-tolylboronic acid to give the title compound.

Example 94: 4-[5-[(3S)-3-aminopyrrolidine-1-thiocarbonyl]-2-[2-fluoro-4-(2-methoxyethyl) Synthesis of [phenyl]phenyl]-2-fluoro-benzonitrile

The procedure of Example 2 was repeated using 4-[5-[(3S)-3-aminopyrrolidine-1-carbonyl]-2-[2-fluoro-4-(2-methoxyethyl)phenyl]phenyl]-2-fluoro-benzonitrile obtained in Example 20 (Step 3) instead of 4-[5-[(3S)-3-aminopyrrolidine-1-carbonyl]-2-(p-tolyl)phenyl]benzonitrile to give the title compound.

Example 95: 4-[5-[(3S)-3-aminopyrrolidine-1-carbonyl]-2-(6-fluoro-1-methyl-benzoimidazole-5- Synthesis of [1-(2-fluoro-1-methyl)phenyl]-2-fluoro-benzonitrile

The procedures of Steps 1 to 3 of Example 37 were repeated using 5-bromo-6-fluoro-1-methyl-benzimidazole instead of 1-(4-bromo-3-fluoro-phenyl)-2-methyl-propan-2-ol to give the title compound.

Example 96: 4-[5-[(3S)-3-aminopyrrolidine-1-carbonyl]-2-(6-fluoro-1-methyl-benzotriazole-5- Synthesis of [1-(2-fluoro-1-methyl)phenyl]-2-fluoro-benzonitrile

Step 1

Tert-butyl N-[(3S)-1-[3-(4-cyano-3-fluoro-phenyl)-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzoyl]pyrrolidin-3-yl]carbamate (15 mg) obtained in Example 37 (Step 1) was dissolved in 1,4-dioxane (0.5 mL). 5-Bromo-6-fluoro-1-methyl-benzotriazole (9.7 mg), PdCl ₂ (dppf) (1.0 mg), and tripotassium phosphate (18 mg) were added at room temperature, and the mixture was stirred in a microwave reactor at 125° C. for 30 minutes. Ethyl acetate was added, the mixture was poured onto NH-silica gel, and washed with ethyl acetate/methanol. The solvent was evaporated to obtain tert-butyl N-[(3S)-1-[3-(4-cyano-3-fluoro-phenyl)-4-(6-fluoro-1-methyl-benzotriazol-5-yl)benzoyl]pyrrolidin-3-yl]carbamate.

Step 2

Tert-butyl N-[(3S)-1-[3-(4-cyano-3-fluoro-phenyl)-4-(6-fluoro-1-methyl-benzotriazol-5-yl)benzoyl]pyrrolidin-3-yl]carbamate (15 mg) obtained in Step 1 above was dissolved in TFA (0.3 mL). The reaction was confirmed by LCMS and then concentrated in vacuo. The residue was purified by reverse phase HPLC (mobile phase: water/acetonitrile) to give the title compound.

Example 97: 4-[5-[(3-exo)-3-amino-8-azabicyclo[3.2.1]octane-8-carbonyl]-2-(4-fluoro Synthesis of [(phenyl)phenyl]benzonitrile

The procedures of Steps 1 to 3 of Example 23 were repeated using 1-bromo-4-fluorobenzene instead of 5-bromo-6-fluoro-1-methyl-indole to give the title compound.

Example 98: 4-[5-[(3-exo)-3-amino-8-azabicyclo[3.2.1]octane-8-carbonyl]-2-(4-chloro Synthesis of [(phenyl)phenyl]benzonitrile

The procedures of Steps 1 to 3 of Example 23 were repeated, substituting 1-bromo-4-chloro-benzene for 5-bromo-6-fluoro-1-methyl-indole, to give the title compound.

Example 99: [(3S)-3-aminopyrrolidin-1-yl]-[3-(4-nitrophenyl)-4-(p-tolyl)phenyl]methane Synthesis of ketones

The procedures of Steps 1 to 5 of Example 19 were repeated, substituting 1-bromo-4-nitro-benzene for 4-bromo-2,6-difluoro-benzonitrile, to give the title compound.

Example 100: 4-[5-[(3S)-3-aminopyrrolidine-1-carbonyl]-2-[6-(dimethylamino)-3-pyridinyl] Synthesis of [phenyl]-2-fluoro-benzonitrile

The procedures of Steps 1 to 3 of Example 37 were repeated using 5-bromo-N,N-dimethylpyridin-2-amine instead of 1-(4-bromo-3-fluoro-phenyl)-2-methyl-propan-2-ol to give the title compound.

Example 101: 4-[5-[(3S)-3-aminopyrrolidine-1-carbonyl]-2-(1-methylbenzotriazol-5-yl)benzene Synthesis of 2-fluoro-benzonitrile

The procedures of Steps 1 to 3 of Example 37 were repeated using 5-bromo-1-methyl-benzotriazole instead of 1-(4-bromo-3-fluoro-phenyl)-2-methyl-propan-2-ol to give the title compound.

Example 102: 4-[5-[(3S)-3-aminopyrrolidine-1-carbonyl]-2-(6,7-difluoro-1-methyl-benzimidazole Synthesis of [(5-oxazol-5-yl)phenyl]-2-fluoro-benzonitrile]

The procedures of Steps 1 to 3 of Example 37 were repeated using 5-bromo-6,7-difluoro-1-methyl-benzimidazole instead of 1-(4-bromo-3-fluoro-phenyl)-2-methyl-propan-2-ol to give the title compound.

Example 103: 4-[5-[(3S)-3-aminopyrrolidine-1-carbonyl]-2-(1,2-dimethylbenzimidazol-5-yl) Synthesis of [phenyl]-2-fluoro-benzonitrile

The procedures of Steps 1 to 3 of Example 37 were repeated using 5-bromo-1,2-dimethyl-benzimidazole instead of 1-(4-bromo-3-fluoro-phenyl)-2-methyl-propan-2-ol to give the title compound.

Example 104: 4-[5-[(3-exo)-3-amino-8-azabicyclo[3.2.1]octane-8-carbonyl]-2-(2-naphthalene Synthesis of [1-(2-fluoro-1-methyl)phenyl]-2-fluoro-benzonitrile

The procedures of Steps 1 to 3 of Example 23 were repeated using 2-bromonaphthalene instead of 5-bromo-6-fluoro-1-methyl-indole to give the title compound.

Example 105: 4-[5-[(3-exo)-3-amino-8-azabicyclo[3.2.1]octane-8-carbonyl]-2-(8- Synthesis of [7-fluoro-7-quinolinyl)phenyl]-2-fluoro-benzonitrile

The procedures of Steps 1 to 3 of Example 23 were repeated using 7-bromo-8-fluoroquinoline instead of 5-bromo-6-fluoro-1-methyl-indole to give the title compound.

Example 106: 4-[5-[(3-exo)-3-amino-8-azabicyclo[3.2.1]octane-8-carbonyl]-2-(4-methyl Synthesis of [2,3-dihydro-1,4-benzoxazin-7-yl]phenyl]-2-fluoro-benzonitrile

The procedures of Steps 1 to 3 of Example 23 were repeated using 7-bromo-4-methyl-3,4-dihydro-2H-benzo[b][1,4]oxazine instead of 5-bromo-6-fluoro-1-methyl-indole to give the title compound.

Example 107: 4-[5-[(3-exo)-3-amino-8-azabicyclo[3.2.1]octane-8-carbonyl]-2-(7-quinone Synthesis of [1-(2-fluoro-1-methyl)phenyl]-2-fluoro-benzonitrile

The procedures of Steps 1 to 3 of Example 23 were repeated using 7-bromoquinoline instead of 5-bromo-6-fluoro-1-methyl-indole to give the title compound.

Example 108: 4-[5-[(3-exo)-3-amino-8-azabicyclo[3.2.1]octane-8-carbonyl]-2-(6- Synthesis of [1-fluoro-1-methyl-benzimidazol-5-yl)phenyl]-2-fluoro-benzonitrile

The procedures of Steps 1 to 3 of Example 23 were repeated using 5-bromo-6-fluoro-1-methyl-benzimidazole instead of 5-bromo-6-fluoro-1-methyl-indole to give the title compound.

Example 109: 4-[5-[(3-exo)-3-amino-8-azabicyclo[3.2.1]octane-8-carbonyl]-2-(6- Synthesis of [1-fluoro-1-methyl-benzotriazol-5-yl)phenyl]-2-fluoro-benzonitrile

The procedures of Steps 1 to 3 of Example 23 were repeated using 5-bromo-6-fluoro-1-methyl-benzotriazole instead of 5-bromo-6-fluoro-1-methyl-indole to give the title compound.

Example 110: 4-[5-[(3-exo)-3-amino-8-azabicyclo[3.2.1]octane-8-carbonyl]-2-(4- Synthesis of [1-fluoro-1-methyl-indazol-5-yl)phenyl]-2-fluoro-benzonitrile

The procedures of Steps 1 to 3 of Example 23 were repeated using 5-bromo-4-fluoro-1-methyl-indazole instead of 5-bromo-6-fluoro-1-methyl-indole to give the title compound.

Example 111: 4-[5-[(3-exo)-3-amino-8-azabicyclo[3.2.1]octane-8-carbonyl]-2-(2-methyl Synthesis of [5-[(1-[(1-((2-( ...-(-(-(-(-(-(-(-(-(-(-(-(-(-(-(-(-(-(

The procedures of Steps 1 to 3 of Example 23 were repeated, substituting 5-bromo-2-methyl-2H-indazole for 5-bromo-6-fluoro-1-methyl-indole, to give the title compound.

Example 112: 2-Fluoro-4-[2-[2-fluoro-4-(2-methoxyethyl)phenyl]-5-[(3-exo)-3-(isopropyl)phenyl]- Synthesis of [3-amino]-8-azabicyclo[3.2.1]octane-8-carbonyl]phenyl]benzonitrile

Acetone (0.002 mL) was added to a dichloromethane solution (0.05 mL) of 4-[5-[(3-exo)-3-amino-8-azabicyclo[3.2.1]octane-8-carbonyl]-2-[2-fluoro-4-(2-methoxyethyl)phenyl]phenyl]-2-fluoro-benzonitrile obtained in Example 26 (Step 2) at 25°C. NaBH(OAc)3 (8.45 mg) was then added, followed by stirring at room temperature for 1 hour. MeOH was added, and the solvent was evaporated. The residue was then purified by reverse-phase HPLC (mobile phase: water/acetonitrile) to obtain the title compound.

Example 113: 2-Fluoro-4-[2-[2-fluoro-4-(2-hydroxy-2-methyl-propyl)phenyl]-5-[(3-exo)-3- Synthesis of (Isopropylamino)-8-azabicyclo[3.2.1]octane-8-carbonyl]phenyl]benzonitrile

The procedure of Example 112 was repeated using 4-[5-[(3-exo)-3-amino-8-azabicyclo[3.2.1]octane-8-carbonyl]-2-[2-fluoro-4-(2-hydroxy-2-methyl-propyl)phenyl]phenyl]-2-fluoro-benzonitrile obtained in Example 28 (Step 3) instead of 4-[5-[(3-exo)-3-amino-8-azabicyclo[3.2.1]octane-8-carbonyl]-2-[2-fluoro-4-(2-methoxyethyl)phenyl]phenyl]-2-fluoro-benzonitrile to give the title compound.

Example 114: 4-[5-[(3S)-3-(ethylamino)pyrrolidine-1-carbonyl]-2-(6-fluoro-1-methyl-benzotriazole Synthesis of [(5-oxazol-5-yl)phenyl]-2-fluoro-benzonitrile]

Step 1

Tert-butyl N-[(3S)-1-[3-(4-cyano-3-fluoro-phenyl)-4-(6-fluoro-1-methyl-benzotriazol-5-yl)benzoyl]pyrrolidin-3-yl]carbamate (10 mg) obtained in Example 96 (Step 1) was dissolved in THF (0.5 mL). Sodium hydride (0.85 mg) and then iodoethane (5.58 mg) were added at room temperature, and the mixture was stirred at 50°C overnight. The solvent was evaporated to obtain tert-butyl (S)-(1-(4'-cyano-3'-fluoro-6-(6-fluoro-1-methyl-1H-benzo[d][1,2,3]triazol-5-yl)-[1,1'-biphenyl]-3-carbonyl)pyrrolidin-3-yl)(ethyl)carbamate. The product thus obtained was used in the next step without purification.

Step 2

The procedure of Step 2 of Example 26 was repeated using (S)-(1-(4'-cyano-3'-fluoro-6-(6-fluoro-1-methyl-1H-benzo[d][1,2,3]triazol-5-yl)-[1,1'-biphenyl]-3-carbonyl)pyrrolidin-3-yl)(ethyl)carbamic acid tert-butyl ester obtained in Step 1 above instead of [(3-exo)-8-[3-(4-cyano-3-fluoro-phenyl)-4-[2-fluoro-4-(2-methoxyethyl)phenyl]benzoyl]-8-azabicyclo[3.2.1]oct-3-yl]carbamate to give the title compound.

Example 115: 2-Fluoro-4-[2-(6-fluoro-1-methyl-benzotriazol-5-yl)-5-[(3S)-3-(isopropylamino)- Synthesis of [1-[(1-[(1-( ...

The procedure of Example 112 was repeated using 4-[5-[(3S)-3-aminopyrrolidine-1-carbonyl]-2-(6-fluoro-1-methyl-benzotriazol-5-yl)phenyl]-2-fluoro-benzonitrile obtained in Example 96 (Step 2) instead of 4-[5-[(3-exo)-3-amino-8-azabicyclo[3.2.1]octane-8-carbonyl]-2-[2-fluoro-4-(2-methoxyethyl)phenyl]phenyl]-2-fluoro-benzonitrile to give the title compound.

Example 116: 4-[5-[(3S)-3-(cyclobutylamino)pyrrolidine-1-carbonyl]-2-(6-fluoro-1-methyl-benzo Synthesis of [5-triazol-1-yl]phenyl]-2-fluoro-benzonitrile

Using 4-[5-[(3S)-3-aminopyrrolidine-1-carbonyl]-2-(6-fluoro-1-methyl-benzotriazol-5-yl)phenyl]-2-fluoro-benzonitrile obtained in Example 96 (Step 2) instead of 4-[5-[(3-exo)-3-amino-8-azabicyclo[3.2.1]octane-8-carbonyl]-2-[2-fluoro-4-(2-methoxyethyl)phenyl]phenyl]-2-fluoro-benzonitrile and cyclobutanone instead of acetone, the procedure of Example 112 was repeated to give the title compound.

Example 117: 4-[5-[(3S)-3-aminopyrrolidine-1-carbonyl]-2-(1-methylindolin-5-yl)benzene Synthesis of 2-fluoro-benzonitrile

The procedures of Steps 1 to 3 of Example 37 were repeated using 5-bromo-1-methyl-indoline instead of 1-(4-bromo-3-fluoro-phenyl)-2-methyl-propan-2-ol to give the title compound.

Example 118: 4-[5-[(3S)-3-aminopyrrolidine-1-carbonyl]-2-(4-methyl-2,3-dihydro-1,4-benzo Synthesis of [(7-oxazin-7-yl)phenyl]-2-fluoro-benzonitrile]

The procedures of Steps 1 to 3 of Example 37 were repeated using 7-bromo-4-methyl-3,4-dihydro-2H-benzo[b][1,4]oxazine instead of 1-(4-bromo-3-fluoro-phenyl)-2-methyl-propan-2-ol to give the title compound.

Example 119: 4-[5-[(3S)-3-aminopyrrolidine-1-carbonyl]-2-(3-methyl-2-oxo-1,3-benzoxazol-1-yl)-1-nitro-1-nitro-2 ... Synthesis of [(1-(2-oxazol-6-yl)phenyl)-2-fluoro-benzonitrile]

The procedures of Steps 1 to 3 of Example 37 were repeated using 6-bromo-3-methyl-1,3-benzoxazol-2-one instead of 1-(4-bromo-3-fluoro-phenyl)-2-methyl-propan-2-ol to give the title compound.

Example 120: 4-[5-[(3S)-3-aminopyrrolidine-1-carbonyl]-2-(3-methyl-2-oxo-1,3-benzothiol) Synthesis of [(1-(2-oxazol-6-yl)phenyl)-2-fluoro-benzonitrile]

The procedures of Steps 1 to 3 of Example 37 were repeated using 6-bromo-3-methyl-1,3-benzothiazol-2-one instead of 1-(4-bromo-3-fluoro-phenyl)-2-methyl-propan-2-ol to give the title compound.

Example 121: 4-[5-[(3S)-3-aminopyrrolidine-1-carbonyl]-2-(2,3-dihydro-1,4-benzodioxin- Synthesis of [6-amino]phenyl]-2-fluoro-benzonitrile

The procedures of Steps 1 to 3 of Example 16 were repeated using 2,3-dihydro-1,4-benzodioxan-6-ylboronic acid instead of p-tolylboronic acid to give the title compound.

Example 122: 4-[5-[(3S)-3-aminopyrrolidine-1-carbonyl]-2-(1,3-benzodioxole-5- Synthesis of [1-(2-fluoro-1-methyl)phenyl]-2-fluoro-benzonitrile

The procedures of Steps 1 to 3 of Example 16 were repeated using 1,3-benzodioxol-5-ylboronic acid instead of p-tolylboronic acid to give the title compound.

Example 123: 4-[5-[(3-endo)-3-amino-8-azabicyclo[3.2.1]octane-8-carbonyl]-2-(6- Synthesis of [1-fluoro-1-methyl-indol-5-yl)phenyl]-2-fluoro-benzonitrile

The procedures of Steps 1 to 5 of Example 41 were repeated using 5-bromo-6-fluoro-1-methyl-indole instead of 1-(4-bromo-3-fluoro-phenyl)-2-methyl-propan-2-ol to give the title compound.

Example 124: 4-[5-[(3-endo)-3-amino-8-azabicyclo[3.2.1]octane-8-carbonyl]-2-(6- Synthesis of [1-fluoro-1-methyl-indazol-5-yl)phenyl]-2-fluoro-benzonitrile

The procedures of Steps 1 to 5 of Example 41 were repeated, substituting 5-bromo-6-fluoro-1-methyl-indazole for 1-(4-bromo-3-fluoro-phenyl)-2-methyl-propan-2-ol, to give the title compound.

Example 125: 4-[5-[(3-endo)-3-amino-8-azabicyclo[3.2.1]octane-8-carbonyl]-2-(6- Synthesis of [1-fluoro-1-methyl-benzotriazol-5-yl)phenyl]-2-fluoro-benzonitrile

The procedures of Steps 1 to 5 of Example 41 were repeated using 5-bromo-6-fluoro-1-methyl-benzotriazole instead of 1-(4-bromo-3-fluoro-phenyl)-2-methyl-propan-2-ol to give the title compound.

Example 126: 4-[5-[(3-endo)-3-amino-8-azabicyclo[3.2.1]octane-8-carbonyl]-2-(6,7- Synthesis of difluoro-1-methyl-benzimidazol-5-yl)phenyl]-2-fluoro-benzonitrile

The procedures of Steps 1 to 5 of Example 41 were repeated using 5-bromo-6,7-difluoro-1-methyl-benzimidazole instead of 1-(4-bromo-3-fluoro-phenyl)-2-methyl-propan-2-ol to give the title compound.

Example 127: 4-[5-[(3-exo)-3-amino-9-azabicyclo[3.3.1]nonane-9-carbonyl]-2-[2- Synthesis of 4-(2-methoxyethyl)-phenyl-2-fluoro-benzonitrile

The procedures of Steps 1 to 4 of Example 22 were repeated using tert-butyl N-[(3-exo)-9-azabicyclo[3.3.1]non-3-yl]carbamate instead of tert-butyl N-[(3-endo)-8-azabicyclo[3.2.1]oct-3-yl]carbamate to give the title compound.

Example 128: 4-[5-[(3-endo)-3-amino-8-azabicyclo[3.2.1]octane-8-carbonyl]-2-(4-methyl Synthesis of [2,3-dihydro-1,4-benzoxazin-7-yl]phenyl]-2-fluoro-benzonitrile

The procedures of Steps 1 to 5 of Example 41 were repeated using 7-bromo-4-methyl-3,4-dihydro-2H-benzo[b][1,4]oxazine instead of 1-(4-bromo-3-fluoro-phenyl)-2-methyl-propan-2-ol to give the title compound.

Example 129: 4-[5-[(3-endo)-3-amino-9-azabicyclo[3.3.1]nonane-9-carbonyl]-2-[2- Synthesis of 4-(2-methoxyethyl)-phenyl-2-fluoro-benzonitrile

The procedures of Steps 1 to 4 of Example 22 were repeated using tert-butyl N-[(3-endo)-9-azabicyclo[3.3.1]non-3-yl]carbamate instead of tert-butyl N-[(3-endo)-8-azabicyclo[3.2.1]oct-3-yl]carbamate to give the title compound.

Example 130: 4-[5-[(3-endo)-3-amino-8-azabicyclo[3.2.1]octane-8-carbonyl]-2-(6- Synthesis of [1-fluoro-1-methyl-benzimidazol-5-yl)phenyl]-2-fluoro-benzonitrile

The procedures of Steps 1 to 5 of Example 41 were repeated using 5-bromo-6-fluoro-1-methyl-benzimidazole instead of 1-(4-bromo-3-fluoro-phenyl)-2-methyl-propan-2-ol to give the title compound.

Example 131: 4-[5-[(3-endo)-3-amino-8-azabicyclo[3.2.1]octane-8-carbonyl]-2-[6- Synthesis of (dimethylamino)-3-pyridyl]phenyl]-2-fluoro-benzonitrile

The procedures of Steps 1 to 5 of Example 41 were repeated using 5-bromo-N,N-dimethylpyridin-2-amine instead of 1-(4-bromo-3-fluoro-phenyl)-2-methyl-propan-2-ol to give the title compound.

Example 132: 4-[5-[(3-endo)-3-amino-8-azabicyclo[3.2.1]octane-8-carbonyl]-2-(1,3, Synthesis of 3-trimethyl-2-oxo-indolin-5-yl)phenyl]-2-fluoro-benzonitrile

The procedures of Steps 1 to 5 of Example 41 were repeated using 5-bromo-1,3,3-trimethyl-indolin-2-one instead of 1-(4-bromo-3-fluoro-phenyl)-2-methyl-propan-2-ol to give the title compound.

Example 133: 4-[5-[(3-endo)-3-amino-8-azabicyclo[3.2.1]octane-8-carbonyl]-2-(3-methyl Synthesis of [2-fluoro-1,3-benzothiazol-6-yl]phenyl]-2-fluoro-benzonitrile

The procedures of Steps 1 to 5 of Example 41 were repeated using 6-bromo-3-methyl-1,3-benzothiazol-2-one instead of 1-(4-bromo-3-fluoro-phenyl)-2-methyl-propan-2-ol to give the title compound.

Example 134: (S)-5'-(3-aminopyrrolidine-1-carbonyl)-3-fluoro-2'-(6-fluoro-1-methyl-1H-indole- Synthesis of 5-(5-yl)-[1,1'-biphenyl]-4-carbonitrile

The procedures of Steps 1 to 3 of Example 37 were repeated using 5-bromo-6-fluoro-1-methyl-1H-indole instead of 1-(4-bromo-3-fluoro-phenyl)-2-methyl-propan-2-ol to give the title compound.

Example 135: (S)-5'-(3-aminopyrrolidine-1-carbonyl)-3-fluoro-2'-(6-fluoro-1-methyl-1H-indazole- Synthesis of 5-(5-yl)-[1,1'-biphenyl]-4-carbonitrile

The procedures of Steps 1 to 3 of Example 37 were repeated using 5-bromo-6-fluoro-1-methyl-1H-indazole instead of 1-(4-bromo-3-fluoro-phenyl)-2-methyl-propan-2-ol to give the title compound.

Example 136: 5'-((3-endo)-3-amino-8-azabicyclo[3.2.1]octane-8-carbonyl)-3-fluoro-2'- Synthesis of (6-fluoro-1-(2-hydroxy-2-methylpropyl)-1H-indol-5-yl)-[1,1'-biphenyl]-4-carbonitrile

Step 1

5-Bromo-6-fluoro-1H-indole (50 mg) was dissolved in DMF (0.78 mL). _Cs₂CO₃ (151 _mg ) and 2,2-dimethyloxirane (42 μL) were added at room temperature, followed by stirring at 90°C for 16 hours. The reaction was quenched with saturated aqueous _NH₄Cl solution, ethyl acetate was added, and the mixture was washed sequentially with water and saturated brine. The organic layer was dried over anhydrous sodium sulfate, and the solvent was evaporated. The residue was purified by silica gel column chromatography (mobile phase: hexane/ethyl acetate) to yield 1-(5-bromo-6-fluoro-indol-1-yl)-2-methyl-propan-2-ol.

Step 2

Using 1-(5-bromo-6-fluoro-indol-1-yl)-2-methyl-propan-2-ol obtained in the above step 1 instead of 1-(4-bromo-3-fluoro-phenyl)-2-methyl-propan-2-ol, the procedures of steps 1 to 5 of example 41 were repeated to give the title compound.

Example 137: 5'-((3-endo)-3-amino-8-azabicyclo[3.2.1]octane-8-carbonyl)-2'-(1,3- Synthesis of dihydroisobenzofuran-5-yl)-3-fluoro-[1,1'-biphenyl]-4-carbonitrile

The procedures of Steps 1 to 5 of Example 41 were repeated using 5-bromo-1,3-dihydroisobenzofuran instead of 1-(4-bromo-3-fluoro-phenyl)-2-methyl-propan-2-ol to give the title compound.

Example 138: 5'-((3-endo)-3-amino-8-azabicyclo[3.2.1]octane-8-carbonyl)-3-fluoro-2'- Synthesis of (3-Isopropyl-2-oxo-2,3-dihydrobenzo[d]thiazol-6-yl)-[1,1'-biphenyl]-4-carbonitrile

Step 1

6-Bromo-3H-1,3-benzothiazol-2-one (100 mg) was dissolved in DMF (0.87 mL). Potassium carbonate (90 mg) was added at room temperature, followed by stirring at 0°C for 15 minutes. 2-Bromopropane (0.082 mL) was added at room temperature, followed by stirring at 100°C for 3 hours. The reaction was quenched with saturated aqueous _NH₄Cl solution, ethyl acetate was added, and the resulting mixture was washed sequentially with water and saturated brine. The organic layer was dried over anhydrous sodium sulfate, and the solvent was evaporated. The residue was purified by silica gel column chromatography (mobile phase: hexane/ethyl acetate) to yield 6-bromo-3-isopropyl-1,3-benzothiazol-2-one.

Step 2

Using 6-bromo-3-isopropyl-1,3-benzothiazol-2-one obtained in step 1 above instead of 1-(4-bromo-3-fluoro-phenyl)-2-methyl-propan-2-ol, the procedures of steps 1 to 5 of example 41 were repeated to give the title compound.

Example 139: 5'-((3-endo)-3-amino-8-azabicyclo[3.2.1]octane-8-carbonyl)-2'-(1-(tert- Synthesis of 6-fluoro-1H-benzo[d][1,2,3]triazol-5-yl)-3-fluoro-[1,1'-biphenyl]-4-carbonitrile

The procedures of Steps 1 to 5 of Example 41 were repeated using 5-bromo-1-(tert-butyl)-6-fluoro-1H-benzo[d][1,2,3]triazole instead of 1-(4-bromo-3-fluoro-phenyl)-2-methyl-propan-2-ol to give the title compound.

Example 140: (S)-5'-(3-aminopyrrolidine-1-carbonyl)-2'-(1,3-dihydroisobenzofuran-5-yl)- Synthesis of 3-Fluoro-[1,1'-biphenyl]-4-carbonitrile

The procedures of Steps 1 to 3 of Example 37 were repeated using 5-bromo-1,3-dihydroisobenzofuran instead of 1-(4-bromo-3-fluoro-phenyl)-2-methyl-propan-2-ol to give the title compound.

Example 141: (S)-5'-(3-aminopyrrolidine-1-carbonyl)-3-fluoro-2'-(5-fluoro-3-methyl-2-oxo-2, Synthesis of 3-dihydrobenzo[d]thiazol-6-yl)-[1,1'-biphenyl]-4-carbonitrile

Step 1

5-Fluoro-3H-1,3-benzothiazol-2-one (200 mg) was suspended in MeCN (1 mL). N-bromosuccinimide (231 mg) was added to the suspension at room temperature, followed by stirring at room temperature for 1 hour. The solvent was concentrated in vacuo, and the residue was purified by silica gel column chromatography (mobile phase: hexane/ethyl acetate) to give 6-bromo-5-fluoro-3H-1,3-benzothiazol-2-one.

Step 2

6-Bromo-5-fluoro-3H-1,3-benzothiazol-2-one (100 mg) obtained in Step 1 above was dissolved in DMF (1.3 mL). Potassium carbonate (84 mg) was added at room temperature, followed by stirring at 0°C for 15 minutes. Iodomethane (0.050 mL) was added at room temperature, followed by stirring at room temperature for 0.5 hours. The reaction was quenched with saturated aqueous _NH₄Cl solution, ethyl acetate was added, and the resulting mixture was washed sequentially with water and saturated brine. The organic layer was dried over anhydrous sodium sulfate, and the solvent was evaporated. The residue was purified by silica gel column chromatography (mobile phase: hexane/ethyl acetate) to yield 6-bromo-5-fluoro-3-methyl-1,3-benzothiazol-2-one.

Step 3

The procedures of steps 1 to 3 of Example 37 were repeated using 6-bromo-5-fluoro-3-methyl-1,3-benzothiazol-2-one obtained in step 2 above instead of 1-(4-bromo-3-fluoro-phenyl)-2-methyl-propan-2-ol to give the title compound.

Example 142: 5'-((3-endo)-3-amino-8-azabicyclo[3.2.1]octane-8-carbonyl)-3-fluoro-2'- Synthesis of (6-fluoro-1-(2-hydroxy-2-methylpropyl)-1H-indazol-5-yl)-[1,1'-biphenyl]-4-carbonitrile

Step 1

5-Bromo-6-fluoro-1H-indazole (94 mg) was dissolved in DMF (1.5 mL). Cesium carbonate (285 mg) and 2,2-dimethyloxirane (0.078 mL) were added at room temperature, followed by stirring at 90°C for 16 hours. The reaction was quenched with saturated aqueous _NH₄Cl solution, ethyl acetate was added, and the resulting mixture was washed sequentially with water and saturated brine. The organic layer was dried over anhydrous sodium sulfate, and the solvent was evaporated. The residue was purified by silica gel column chromatography (mobile phase: hexane/ethyl acetate) to yield 1-(5-bromo-6-fluoro-indazol-1-yl)-2-methyl-propan-2-ol.

Step 2

Using 1-(5-bromo-6-fluoro-indazol-1-yl)-2-methyl-propan-2-ol obtained in step 1 above instead of 1-(4-bromo-3-fluoro-phenyl)-2-methyl-propan-2-ol, the procedures of steps 1 to 5 of example 41 were repeated to give the title compound.

Example 143: 4-[5-[(1S,3R,4R)-rel-3-amino-7-azabicyclo[2.2.1]heptane-7-carbonyl]- Synthesis of 2-[2-fluoro-4-(2-methoxyethyl)phenyl]phenyl]-2-fluoro-benzonitrile

Step 1

Tert-butyl (1S,3R,4R)-rel-3-amino-7-azabicyclo[2.2.1]heptane-7-carboxylate (50 mg) was dissolved in THF (1.2 mL). TEA (0.066 mL) and 2-nitrobenzenesulfonyl chloride (57 mg) were added at 0°C, followed by stirring at room temperature for 1 hour. Ethyl acetate was added, and the mixture was washed sequentially with water and saturated brine. The organic layer was dried over anhydrous sodium sulfate, and the solvent was evaporated. The residue was purified by silica gel column chromatography (mobile phase: hexane/ethyl acetate), and the solvent was evaporated. The residue was dissolved in 4N hydrochloric acid-ethyl acetate solution (2 mL) and stirred at room temperature for 30 minutes. The reaction solution was concentrated in vacuo to obtain N-[(1S,3R,4R)-rel-7-azabicyclo[2.2.1]hept-3-yl]-2-nitrobenzenesulfonamide hydrochloride.

Step 2

Using N-[(1S,3R,4R)-rel-7-azabicyclo[2.2.1]hept-3-yl]-2-nitrobenzenesulfonamide hydrochloride obtained in the above step 1 instead of tert-butyl N-[(3-endo)-8-azabicyclo[3.2.1]oct-3-yl]carbamate, the procedure of step 3 of Example 22 was repeated to obtain N-[(1S,3R,4R)-rel-7-[3-(4-cyano-3-fluoro-phenyl)-4-[2-fluoro-4-(2-methoxyethyl)phenyl]benzoyl]-7-azabicyclo[2.2.1]hept-3-yl]-2-nitrobenzenesulfonamide.

Step 3

N-[(1S,3R,4R)-rel-7-[3-(4-cyano-3-fluoro-phenyl)-4-[2-fluoro-4-(2-methoxyethyl)phenyl]benzoyl]-7-azabicyclo[2.2.1]hept-3-yl] _-2 -nitrobenzenesulfonamide (20 mg) obtained in Step 2 above was dissolved in DMF (0.5 mL). _K₂CO₃ (21 mg) and 4-mercaptobenzoic acid (12 mg) were added at room temperature, followed by stirring at 40°C for 12 hours. Ethyl acetate was added, and the mixture was washed sequentially with water and saturated brine. After drying the organic layer over anhydrous sodium sulfate, the solvent was evaporated. The residue was purified by reverse-phase HPLC (mobile phase: water/acetonitrile) to obtain the title compound.

Example 144: Synthesis of 5'-((3-endo)-3-amino-8-azabicyclo[3.2.1]octane-8-carbonyl)-2",3,3" -trifluoro-4 "-methyl-[1,1':2',1" -terphenyl]-4-carbonitrile

The procedures of Steps 1 to 5 of Example 41 were repeated using 1-bromo-2,3-difluoro-4-methyl-benzene instead of 1-(4-bromo-3-fluoro-phenyl)-2-methyl-propan-2-ol to give the title compound.

Example 145: 5'-((3-endo)-3-amino-8-azabicyclo[3.2.1]octane-8-carbonyl)-2'-(6,7- Synthesis of difluoro-1-methyl-1H-benzo[d][1,2,3]triazol-5-yl)-3-fluoro-[1,1'-biphenyl]-4-carbonitrile

Step 1

Tert-butyl N-[(3-endo)-8-[3-(4-cyano-3-fluoro-phenyl)-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzoyl]-8-azabicyclo[3.2.1]octan-3-yl]carbamate (200 mg) and 5-bromo-6,7-difluoro-1-methyl-benzotriazole (129 mg) were dissolved in 1,4-dioxane (1.74 mL). Pd(dba) _₂ (16.0 mg), X-phos (26.5 mg), and tripotassium phosphate (221 mg) were added at room temperature, and the mixture was stirred in a microwave reactor at 125°C for 1 hour. The reaction solution was filtered, and the solvent was evaporated. The residue was purified by silica gel column chromatography (mobile phase: ethyl acetate/hexane) to give tert-butyl N-[(3-endo)-8-[3-(4-cyano-3-fluoro-phenyl)-4-(6,7-difluoro-1-methyl-benzotriazol-5-yl)benzoyl]-8-azabicyclo[3.2.1]oct-3-yl]carbamate.

Step 2

Dissolve tert-butyl N-[(3-endo)-8-[3-(4-cyano-3-fluoro-phenyl)-4-(6,7-difluoro-1-methyl-benzotriazol-5-yl)benzoyl]-8-azabicyclo[3.2.1]octan-3-yl]carbamate (210 mg) obtained in Step 1 above in MeOH (1.60 mL). Add 4N hydrochloric acid-ethyl acetate solution (2.40 mL) at room temperature, followed by stirring at room temperature for 1 hour. The reaction solution is concentrated in vacuo, and the solvent is evaporated. The residue is purified by reverse phase HPLC (mobile phase: water/acetonitrile) to obtain the title compound.

Example 146: (S)-5'-(3-aminopyrrolidine-1-carbonyl)-3-fluoro-2'-(6-fluoro-1-(2-hydroxy-2-methyl) Synthesis of (1H-indol-5-yl)-[1,1'-biphenyl]-4-carbonitrile

Step 1

Tert-butyl N-[(3S)-1-[3-(4-cyano-3-fluoro-phenyl)-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzoyl]pyrrolidin-3-yl]carbamate (60 mg) obtained in Step 1 of Example 37 and 1-(5-bromo-6-fluoro-indol-1-yl)-2-methyl-propan-2-ol (48.1 mg) obtained in Step 1 of Example 136 were dissolved in 1,4-dioxane (0.50 mL). Pd(dba) ₂ (3.22 mg), X-phos (5.34 mg), and tripotassium phosphate (71.4 mg) were added at room temperature, and the mixture was stirred in a microwave reactor at 125°C for 1 hour. The reaction solution was filtered, and the solvent was evaporated. The residue was purified by silica gel column chromatography (mobile phase: chloroform/methanol) to give tert-butyl N-[(3S)-1-[3-(4-cyano-3-fluoro-phenyl)-4-[6-fluoro-1-(2-hydroxy-2-methyl-propyl)indol-5-yl]benzoyl]pyrrolidin-3-yl]carbamate.

Step 2

Dissolve tert-butyl N-[(3S)-1-[3-(4-cyano-3-fluoro-phenyl)-4-[6-fluoro-1-(2-hydroxy-2-methyl-propyl)indol-5-yl]benzoyl]pyrrolidin-3-yl]carbamate (68.0 mg) obtained in Step 1 above in MeOH (1.0 mL). 12N hydrochloric acid (1.0 mL) was added to the mixture at room temperature, followed by stirring at room temperature for 1 hour. 2N aqueous sodium hydroxide solution (6.00 mL) and chloroform were added, and the mixture was washed sequentially with water and saturated brine, dried over anhydrous sodium sulfate, and the solvent was evaporated. The residue was purified by reverse-phase HPLC (mobile phase: water/acetonitrile) to obtain the title compound.

Example 147: (S)-5'-(3-aminopyrrolidine-1-carbonyl)-3-fluoro-2'-(6-fluoro-1-(2-hydroxy-2-methyl) Synthesis of (1H-indazol-5-yl)-[1,1'-biphenyl]-4-carbonitrile

Step 1

Tert-butyl N-[(3S)-1-[3-(4-cyano-3-fluoro-phenyl)-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzoyl]pyrrolidin-3-yl]carbamate (70 mg) obtained in Step 1 of Example 37 and 1-(5-bromo-6-fluoro-indazol-1-yl)-2-methyl-propan-2-ol (56.3 mg) obtained in Step 1 of Example 142 were dissolved in 1,4-dioxane (0.50 mL). Pd(dba) ₂ (3.76 mg), X-phos (6.23 mg), and tripotassium phosphate (83.3 mg) were added at room temperature, and the mixture was stirred in a microwave reactor at 125°C for 1 hour. The reaction solution was filtered, and the solvent was evaporated. The residue was purified by silica gel column chromatography (mobile phase: chloroform/methanol) to give tert-butyl N-[(3S)-1-[3-(4-cyano-3-fluoro-phenyl)-4-[6-fluoro-1-(2-hydroxy-2-methyl-propyl)indazol-5-yl]benzoyl]pyrrolidin-3-yl]carbamate.

Step 2

Tert-butyl N-[(3S)-1-[3-(4-cyano-3-fluoro-phenyl)-4-[6-fluoro-1-(2-hydroxy-2-methyl-propyl)indazol-5-yl]benzoyl]pyrrolidin-3-yl]carbamate (70.0 mg) obtained in Step 1 above was dissolved in MeOH (1.0 mL). 12N hydrochloric acid (1.0 mL) was added to the mixture at room temperature, followed by stirring at room temperature for 1 hour. 2N aqueous sodium hydroxide solution (6.00 mL) and chloroform were added, and the mixture was washed sequentially with water and saturated brine, dried over anhydrous sodium sulfate, and the solvent was evaporated. The residue was purified by reverse-phase HPLC (mobile phase: water/acetonitrile) to obtain the title compound.

Example 148: 5'-((3-endo)-3-amino-8-azabicyclo[3.2.1]octane-8-carbonyl)-3-fluoro-2'- Synthesis of (Quinoxalin-6-yl)-[1,1'-biphenyl]-4-carbonitrile

The procedures of Steps 1 to 5 of Example 41 were repeated using 6-bromoquinoxaline instead of 1-(4-bromo-3-fluoro-phenyl)-2-methyl-propan-2-ol to give the title compound.

Example 149: 5'-((3-endo)-3-amino-8-azabicyclo[3.2.1]octane-8-carbonyl)-3-fluoro-2'- Synthesis of (Isoquinolin-6-yl)-[1,1'-biphenyl]-4-carbonitrile

The procedures of Steps 1 to 5 of Example 41 were repeated using 6-bromoisoquinoline instead of 1-(4-bromo-3-fluoro-phenyl)-2-methyl-propan-2-ol to give the title compound.

Example 150: 5'-((3-endo)-3-amino-8-azabicyclo[3.2.1]octane-8-carbonyl)-3-fluoro-2'- Synthesis of (Isoquinolin-7-yl)-[1,1'-biphenyl]-4-carbonitrile

The procedures of Steps 1 to 5 of Example 41 were repeated using 7-bromoisoquinoline instead of 1-(4-bromo-3-fluoro-phenyl)-2-methyl-propan-2-ol to give the title compound.

Example 151: 5'-((3-endo)-3-amino-8-azabicyclo[3.2.1]octane-8-carbonyl)-3-fluoro-2'- Synthesis of (Quinolin-6-yl)-[1,1'-biphenyl]-4-carbonitrile

The procedures of Steps 1 to 5 of Example 41 were repeated using 6-bromoquinoline instead of 1-(4-bromo-3-fluoro-phenyl)-2-methyl-propan-2-ol to give the title compound.

Example 152: 5'-((3-endo)-3-amino-8-azabicyclo[3.2.1]octane-8-carbonyl)-3-fluoro-2'- Synthesis of (Quinazolin-7-yl)-[1,1'-biphenyl]-4-carbonitrile

The procedures of Steps 1 to 5 of Example 41 were repeated using 7-bromoquinazoline instead of 1-(4-bromo-3-fluoro-phenyl)-2-methyl-propan-2-ol to give the title compound.

Example 153: 5'-((3-endo)-3-amino-8-azabicyclo[3.2.1]octane-8-carbonyl)-3-fluoro-2'- Synthesis of (Quinazolin-6-yl)-[1,1'-biphenyl]-4-carbonitrile

The procedures of Steps 1 to 5 of Example 41 were repeated using 6-bromoquinazoline instead of 1-(4-bromo-3-fluoro-phenyl)-2-methyl-propan-2-ol to give the title compound.

Example 154: 5'-((3-endo)-3-amino-8-azabicyclo[3.2.1]octane-8-carbonyl)-3-fluoro-2'- Synthesis of (phthalazin-6-yl)-[1,1'-biphenyl]-4-carbonitrile

The procedures of Steps 1 to 5 of Example 41 were repeated using 6-bromophthalazine instead of 1-(4-bromo-3-fluoro-phenyl)-2-methyl-propan-2-ol to give the title compound.

Example 155: 5'-((1R,2R,4S)-rel-2-amino-7-azabicyclo[2.2.1]heptane-7-carbonyl)-2", Synthesis of 3-difluoro-4"-(2-methoxyethyl)-[1,1':2',1"-terphenyl]-4-carbonitrile-Isomer-B

Step 1

Tert-butyl (1S,3R,4R)-rel-3-amino-7-azabicyclo[2.2.1]heptane-7-carboxylate (550 mg) was dissolved in THF (13.0 mL). TEA (0.720 mL) and 2,4-dinitrobenzenesulfonyl chloride (829 mg) were added at 0°C, followed by stirring at room temperature for 1 hour. Ethyl acetate was added, and the mixture was washed sequentially with water and saturated brine, dried over anhydrous sodium sulfate, and the solvent was evaporated. The residue was purified by silica gel column chromatography (mobile phase: hexane/ethyl acetate) to obtain tert-butyl (1S,3R,4R)-rel-3-[(2,4-dinitrophenyl)sulfonylamino]-7-azabicyclo[2.2.1]heptane-7-carboxylate.

Step 2

The (1S,3R,4R)-rel-3-[(2,4-dinitrophenyl)sulfonylamino]-7-azabicyclo[2.2.1]heptane-7-carboxylic acid tert-butyl ester (440 mg) obtained in step 1 was purified by SFC (apparatus: TharsFC prep 80 system, column: Chiralpak IE Chiral separation was performed using an HPLC-MS/MS elution column (20×250 mm, flow rate: 50 g/min, mobile phase: CO2/MeOH=90/10) to obtain (1S,3R,4R)-rel-3-[(2,4-dinitrophenyl)sulfonylamino]-7-azabicyclo[2.2.1]heptane-7-carboxylate isomer-A (the faster isomer) and (1S,3R,4R)-rel-3-[(2,4-dinitrophenyl)sulfonylamino]-7-azabicyclo[2.2.1]heptane-7-carboxylate isomer-B (the slower isomer).

Each isomer was analyzed under the following HPLC conditions.

Column: CHIRALPAK IE 4.6×150mm

Mobile phase: Hexane (0.1% triethylamine)/ethanol = 85/15

Flow rate: 1.0 mL/min

Retention time of each isomer:

(1S,3R,4R)-rel-3-[(2,4-dinitrophenyl)sulfonylamino]-7-azabicyclo[2.2.1]heptane-7-carboxylate-isomer-A: 10.903 minutes (faster isomer)

(1S,3R,4R)-rel-3-[(2,4-dinitrophenyl)sulfonylamino]-7-azabicyclo[2.2.1]heptane-7-carboxylate-isomer-B: 14.028 minutes (slower isomer)

Step 3

(1S,3R,4R)-rel-3-[(2,4-dinitrophenyl)sulfonylamino]-7-azabicyclo[2.2.1]heptane-7-carboxylate isomer B (200 mg) obtained in step 2 above was dissolved in ethyl acetate (1.00 mL). 4N hydrochloric acid-ethyl acetate solution (2.00 mL) was added thereto at room temperature, followed by stirring at room temperature for 2 hours. The reaction solution was concentrated in vacuo to obtain N-(( 1R,2R,4S )-rel-7-azabicyclo[2.2.1]hept-2-yl)-2,4-dinitrobenzenesulfonamide isomer B hydrochloride.

Step 4

3-(4-Cyano-3-fluoro-phenyl)-4-[2-fluoro-4-(2-methoxyethyl)phenyl]benzoic acid (8 mg) obtained in Step 2 of Example 22 and N-( (1R,2R,4S) -rel-7-azabicyclo[2.2.1]hept-2-yl)-2,4-dinitrobenzenesulfonamide-isomer-B hydrochloride (8.47 mg) obtained in Step 3 above were dissolved in THF (0.30 mL). TEA (8.49 μL) and HATU (15.5 mg) were added at room temperature, followed by stirring at 50°C for 1 hour. The solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (mobile phase: hexane/ethyl acetate) to give N-[(1S,3R,4R)-rel-7-[3-(4-cyano-3-fluoro-phenyl)-4-[2-fluoro-4-(2-methoxyethyl)phenyl]benzoyl]-7-azabicyclo[2.2.1]hept-3-yl]-2,4-dinitrobenzenesulfonamide-isomer-B.

Step 5

N-[(1S,3R,4R)-rel-7-[3-(4-cyano-3-fluoro-phenyl)-4-[2-fluoro-4-(2-methoxyethyl)phenyl]benzoyl]-7-azabicyclo[2.2.1]hept-3-yl]-2,4-dinitrobenzenesulfonamide-Isomer B (14.5 mg), obtained in Step 4 above, was dissolved in DCM (1 mL). Thioglycolic acid (2.83 μL) and TEA (7.49 μL) were added at 0°C, followed by stirring at room temperature for 2 hours. Chloroform was added, and the mixture was washed with 4N aqueous sodium hydroxide solution, dried over anhydrous sodium sulfate, and the solvent was evaporated. The residue was purified by reverse-phase HPLC (mobile phase: water/acetonitrile) to obtain the title compound.

Example 156: 5'-((1R,2R,4S)-rel-2-amino-7-azabicyclo[2.2.1]heptane-7-carbonyl)-2", Synthesis of 3-difluoro-4"-(2-methoxyethyl)-[1,1':2',1"-terphenyl]-4-carbonitrile-Isomer-A

Step 1

(1S,3R,4R)-rel-3-[(2,4-dinitrophenyl)sulfonylamino]-7-azabicyclo[2.2.1]heptane-7-carboxylate Isomer-A (200 mg) obtained in Step 2 of Example 155 was dissolved in ethyl acetate (1.00 mL). 4N hydrochloric acid-ethyl acetate solution (2.00 mL) was added to the mixture at room temperature, followed by stirring at room temperature for 2 hours. The reaction solution was concentrated in vacuo to obtain N-((1R,2R,4S)-rel-7-azabicyclo[2.2.1]hept-2-yl)-2,4-dinitrobenzenesulfonamide Isomer-A hydrochloride.

Step 2

3-(4-Cyano-3-fluoro-phenyl)-4-[2-fluoro-4-(2-methoxyethyl)phenyl]benzoic acid (8 mg) obtained in Step 2 of Example 22 and N-((1r,2r,4s)-rel-7-azabicyclo[2.2.1]hept-2-yl)-2,4-dinitrobenzenesulfonamide-Isomer-A hydrochloride (8.47 mg) obtained in Step 1 above were dissolved in THF (0.30 mL). TEA (8.49 μL) and HATU (15.5 mg) were added at room temperature, followed by stirring at 50°C for 1 hour. The solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (mobile phase: hexane/ethyl acetate) to give N-[(1S,3R,4R)-rel-7-[3-(4-cyano-3-fluoro-phenyl)-4-[2-fluoro-4-(2-methoxyethyl)phenyl]benzoyl]-7-azabicyclo[2.2.1]hept-3-yl]-2,4-dinitrobenzenesulfonamide-isomer-A.

Step 3

N-[(1S,3R,4R)-rel-7-[3-(4-cyano-3-fluoro-phenyl)-4-[2-fluoro-4-(2-methoxyethyl)phenyl]benzoyl]-7-azabicyclo[2.2.1]hept-3-yl]-2,4-dinitrobenzenesulfonamide-Isomer-A (14.5 mg), obtained in Step 2 above, was dissolved in DCM (1 mL). Thioglycolic acid (2.83 μL) and TEA (7.49 μL) were added at 0°C, and the mixture was stirred at room temperature for 2 hours. Chloroform was added, and the mixture was washed with 4N aqueous sodium hydroxide solution, dried over anhydrous sodium sulfate, and the solvent was evaporated. The residue was purified by reverse-phase HPLC (mobile phase: water/acetonitrile) to obtain the title compound.

Example 157: 5'-((3-endo)-3-amino-8-azabicyclo[3.2.1]octane-8-carbonyl)-3-fluoro-2'- Synthesis of (3-Methylimidazo[1,5-a]pyridin-7-yl)-[1,1'-biphenyl]-4-carbonitrile

The procedures of Steps 1 to 5 of Example 41 were repeated using 7-bromo-3-methyl-imidazo[1,5-a]pyridine instead of 1-(4-bromo-3-fluoro-phenyl)-2-methyl-propan-2-ol to give the title compound.

Example 158: 5'-((3-endo)-3-amino-8-azabicyclo[3.2.1]octane-8-carbonyl)-3-fluoro-2'- Synthesis of (3-methylpyrazolo[1,5-a]pyrimidin-6-yl)-[1,1'-biphenyl]-4-carbonitrile

The procedures of Steps 1 to 5 of Example 41 were repeated using 6-bromo-3-methyl-pyrazolo[1,5-a]pyrimidine instead of 1-(4-bromo-3-fluoro-phenyl)-2-methyl-propan-2-ol to give the title compound.

Example 159: 5'-((3-endo)-3-amino-8-azabicyclo[3.2.1]octane-8-carbonyl)-3-fluoro-2'- Synthesis of (6-fluoro-2-(2-hydroxy-2-methylpropyl)-2H-indazol-5-yl)-[1,1'-biphenyl]-4-carbonitrile

Step 1

5-Bromo-6-fluoro-1H-indazole (94 mg) was dissolved in DMF (1.5 mL). Cesium carbonate (285 mg) and 2,2-dimethyloxirane (0.078 mL) were added at room temperature, followed by stirring at 90°C for 16 hours. The reaction was quenched with saturated aqueous _NH₄Cl solution, ethyl acetate was added, and the resulting mixture was washed sequentially with water and saturated brine. The organic layer was dried over anhydrous sodium sulfate, and the solvent was evaporated. The residue was purified by silica gel column chromatography (mobile phase: hexane/ethyl acetate) to yield 1-(5-bromo-6-fluoro-indazol-2-yl)-2-methyl-propan-2-ol.

Step 2

Using 1-(5-bromo-6-fluoro-indazol-2-yl)-2-methyl-propan-2-ol obtained in the above step 1 instead of 1-(4-bromo-3-fluoro-phenyl)-2-methyl-propan-2-ol, the procedures of steps 1 to 5 of example 41 were repeated to give the title compound.

Example 160: 5'-((3-endo)-3-amino-8-azabicyclo[3.2.1]octane-8-carbonyl)-2'-(1-ethyl Synthesis of 6-fluoro-1H-benzo[d][1,2,3]triazol-5-yl)-3-fluoro-[1,1'-biphenyl]-4-carbonitrile

The procedures of Steps 1 to 5 of Example 41 were repeated using 5-bromo-1-ethyl-6-fluoro-benzotriazole instead of 1-(4-bromo-3-fluoro-phenyl)-2-methyl-propan-2-ol to give the title compound.

Example 161: 5'-((3-endo)-3-amino-8-azabicyclo[3.2.1]octane-8-carbonyl)-2'-(6,7- difluoro-1-(2-hydroxy-2-methylpropyl)-1H-benzo[d][1,2,3]triazol-5-yl)-3-fluoro-[1,1'-biphenyl]-4- Synthesis of Formonitrile

Step 1

1-(2,3-difluoro-6-nitro-anilino)-2-methyl-propan-2-ol (6.20 g) was dissolved in DMF (84.0 mL). N-bromosuccinimide (5.80 g) was added at room temperature, followed by stirring at 90°C for 1 hour. Ethyl acetate was added, and the mixture was washed sequentially with water and saturated brine, dried over anhydrous sodium sulfate, and the solvent was evaporated. The residue was purified by silica gel column chromatography (mobile phase: hexane/ethyl acetate) to obtain 1-(4-bromo-2,3-difluoro-6-nitro-anilino)-2-methyl-propan-2-ol.

Step 2

1-(4-Bromo-2,3-difluoro-6-nitro-anilino)-2-methyl-propan-2-ol (5.67 g) obtained in Step 1 above was dissolved in ethanol (87.2 mL). Ammonium chloride (5.67 g), iron (5.67 g), and water (87.2 mL) were added at room temperature, followed by stirring at 60°C overnight. The reaction solution was passed through Celite and washed with ethyl acetate. The filtrate was concentrated in vacuo, ethyl acetate was added, and the mixture was washed sequentially with water and saturated brine, dried over anhydrous sodium sulfate, and the solvent was evaporated. The residue was purified by silica gel column chromatography (mobile phase: hexane/ethyl acetate) to obtain 1-(6-amino-4-bromo-2,3-difluoro-anilino)-2-methyl-propan-2-ol.

Step 3

1-(6-Amino-4-bromo-2,3-difluoro-anilino)-2-methyl-propan-2-ol (4.36 g) obtained in Step 2 above was dissolved in water (28.4 mL) and THF (28.4 mL). 12N hydrochloric acid (28.4 mL) and sodium nitrite (1.80 g) were added at 0°C, followed by stirring at room temperature for 1 hour. Ethyl acetate was added, and the mixture was washed sequentially with water and saturated brine, dried over anhydrous sodium sulfate, and the solvent was evaporated. The residue was purified by silica gel column chromatography (mobile phase: hexane/ethyl acetate) to obtain 1-(5-bromo-6,7-difluoro-benzotriazol-1-yl)-2-methyl-propan-2-ol.

Step 4

Tert-butyl N-[(3-endo)-8-[3-(4-cyano-3-fluoro-phenyl)-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzoyl]-8-azabicyclo[3.2.1]octan-3-yl]carbamate (50 mg) obtained in Step 3 of Example 41 and 1-(5-bromo-6,7-difluoro-benzotriazol-1-yl)-2-methyl-propan-2-ol (39.9 mg) obtained in Step 3 above were dissolved in 1,4-dioxane (0.50 mL). Pd(dba) ₂ (2.50 mg), X-phos (4.14 mg), and tripotassium phosphate (55.3 mg) were added at room temperature, and the mixture was stirred in a microwave reactor at 125°C for 1 hour. The reaction solution was filtered, and the solvent was evaporated. The residue was purified by silica gel column chromatography (mobile phase: chloroform/methanol) to give tert-butyl N-[(3-endo)-8-[3-(4-cyano-3-fluoro-phenyl)-4-[6,7-difluoro-1-(2-hydroxy-2-methyl-propyl)benzotriazol-5-yl]benzoyl]-8-azabicyclo[3.2.1]oct-3-yl]carbamate.

Step 5

Dissolve tert-butyl N-[(3-endo)-8-[3-(4-cyano-3-fluoro-phenyl)-4-[6,7-difluoro-1-(2-hydroxy-2-methyl-propyl)benzotriazol-5-yl]benzoyl]-8-azabicyclo[3.2.1]octan-3-yl]carbamate (55.0 mg) obtained in Step 4 above in MeOH (1.0 mL). Add 12N hydrochloric acid (1.0 mL) at room temperature, followed by stirring at room temperature for 1 hour. Add 2N aqueous sodium hydroxide solution (6.00 mL) and chloroform, and the mixture is washed sequentially with water and saturated brine, dried over anhydrous sodium sulfate, and the solvent is evaporated. The residue is purified by reverse-phase HPLC (mobile phase: water/acetonitrile) to obtain the title compound.

Example 162: (S)-5'-(3-aminopyrrolidine-1-carbonyl)-2'-(6,7-difluoro-1-(2-hydroxy-2-methyl) Synthesis of (1,1'-biphenyl)-4-[(1,2,3'-propyl)-1H-benzo[d][1,2,3]triazol-5-yl]-3-fluoro-[1,1'-biphenyl]carbonitrile

Step 1

Tert-butyl N-[(3S)-1-[3-(4-cyano-3-fluoro-phenyl)-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzoyl]pyrrolidin-3-yl]carbamate (100 mg), obtained in Step 1 of Example 37, and 1-(5-bromo-6,7-difluoro-benzotriazol-1-yl)-2-methyl-propan-2-ol (85.8 mg), obtained in Step 3 of Example 161, were dissolved in 1,4-dioxane (0.934 mL). Pd(dba) ₂ (5.37 mg), X-phos (8.90 mg), and tripotassium phosphate (119 mg) were added at room temperature, and the mixture was stirred in a microwave reactor at 125°C for 1 hour. The reaction solution was filtered, and the solvent was evaporated. The residue was purified by silica gel column chromatography (mobile phase: chloroform/methanol) to give tert-butyl N-[(3S)-1-[3-(4-cyano-3-fluoro-phenyl)-4-[6,7-difluoro-1-(2-hydroxy-2-methyl-propyl)benzotriazol-5-yl]benzoyl]pyrrolidin-3-yl]carbamate.

Step 2

Dissolve tert-butyl N-[(3S)-1-[3-(4-cyano-3-fluoro-phenyl)-4-[6,7-difluoro-1-(2-hydroxy-2-methyl-propyl)benzotriazol-5-yl]benzoyl]pyrrolidin-3-yl]carbamate (99.8 mg) obtained in Step 1 above in MeOH (1.0 mL). Add 12N hydrochloric acid (1.0 mL) at room temperature, followed by stirring at room temperature for 1 hour. Then, add 2N aqueous sodium hydroxide solution (6.00 mL) and chloroform, and wash the mixture sequentially with water and saturated brine, dry over anhydrous sodium sulfate, and evaporate the solvent. The residue is purified by reverse-phase HPLC (mobile phase: water/acetonitrile) to obtain the title compound.

Example 163: 2",3-difluoro-4"-(2-methoxyethyl)-5'-(piperazine-1-carbonyl)-[1,1':2',1"-trifluoromethyl]-piperazine [Biphenyl]-4-carbonitrile

The procedures of Steps 1 to 4 of Example 22 were repeated using tert-butyl piperazine-1-carboxylate instead of tert-butyl N-[(3-endo)-8-azabicyclo[3.2.1]oct-3-yl]carbamate to give the title compound.

Example 164: (R)-5'-(3-aminopiperidine-1-carbonyl)-2",3-difluoro-4"-(2-methoxyethyl)-[1, Synthesis of 1':2',1"-terphenyl]-4-carbonitrile

The procedures of Steps 1 to 4 of Example 22 were repeated using tert-butyl N-[(3R)-3-piperidinyl]carbamate instead of tert-butyl N-[(3-endo)-8-azabicyclo[3.2.1]oct-3-yl]carbamate to give the title compound.

Example 165: 5'-(4-aminoazepanyl-1-carbonyl)-2",3-difluoro-4"-(2-methoxyethyl)- Synthesis of [1,1':2',1"-terphenyl]-4-carbonitrile

The procedures of Steps 1 to 4 of Example 22 were repeated using tert-butyl N-(azepan-4-yl)carbamate instead of tert-butyl N-[(3-endo)-8-azabicyclo[3.2.1]oct-3-yl]carbamate to give the title compound.

Example 166: 5'-((1S,2S,4R)-rel-2-amino-7-azabicyclo[2.2.1]heptane-7-carbonyl)-2", Synthesis of 3-difluoro-4"-(2-hydroxy-2-methylpropyl)-[1,1':2',1"-terphenyl]-4-carbonitrile-Isomer B

Step 1

tert-Butyl 3-(4-cyano-3-fluoro-phenyl)-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzoate (500 mg) obtained in Step 1 of Example 41 and 1-(4-bromo-3-fluoro-phenyl)-2-methyl-propan-2-ol (379 mg) obtained in Step 1 of Example 28 were dissolved in 1,4-dioxane (5.9 mL). Pd(dba) _₂ (68 mg), X-phos (113 mg), and tripotassium phosphate (752 mg) were added at room temperature, followed by stirring at 100°C overnight. The solvent was evaporated, and the residue was purified by silica gel column chromatography (mobile phase: hexane/ethyl acetate) to obtain tert-butyl 3-(4-cyano-3-fluoro-phenyl)-4-[2-fluoro-4-(2-hydroxy-2-methyl-propyl)phenyl]benzoate.

Step 2

Tert-butyl 3-(4-cyano-3-fluoro-phenyl)-4-[2-fluoro-4-(2-hydroxy-2-methyl-propyl)phenyl]benzoate (300 mg) obtained in Step 1 above was dissolved in THF (0.9 mL). 12N hydrochloric acid (0.9 mL) was added at 0°C, followed by stirring at room temperature for 2 hours. MTBE was then added, the mixture was washed with water and dried over anhydrous sodium sulfate, and the solvent was evaporated to obtain 3-(4-cyano-3-fluoro-phenyl)-4-[2-fluoro-4-(2-hydroxy-2-methyl-propyl)phenyl]benzoic acid.

Step 3

The 3-(4-cyano-3-fluoro-phenyl)-4-[2-fluoro-4-(2-hydroxy-2-methyl-propyl)phenyl]benzoic acid (10 mg) obtained in Step 2 above and N-((1R,2R,4S)-rel-7-azabicyclo[2.2.1]hept-2-yl)-2,4-dinitrobenzenesulfonamide-isomer-B hydrochloride (10.2 mg) obtained in Step 3 of Example 155 were dissolved in THF (0.12 mL). TEA (0.014 mL) and HATU (18.7 mg) were added thereto at room temperature, followed by stirring at 50° C. for 1 hour. The reaction solution was concentrated in vacuo, and the residue was purified by silica gel column chromatography (mobile phase: hexane/ethyl acetate) to give N-[(1S,3R,4R)-rel-7-[3-(4-cyano-3-fluoro-phenyl)-4-[2-fluoro-4-(2-hydroxy-2-methyl-propyl)phenyl]benzoyl]-7-azabicyclo[2.2.1]hept-3-yl]-2,4-dinitrobenzenesulfonamide-isomer-B.

Step 4

N-[(1S,3R,4R)-rel-7-[3-(4-cyano-3-fluoro-phenyl)-4-[2-fluoro-4-(2-hydroxy-2-methyl-propyl)phenyl]benzoyl]-7-azabicyclo[2.2.1]hept-3-yl]-2,4-dinitrobenzenesulfonamide-Isomer-B (15 mg) obtained in Step 3 above was dissolved in DCM (0.2 mL). Thioglycolic acid (2 μL) and TEA (8.6 μL) were added at 0°C, followed by stirring at room temperature for 2 hours. Ethyl acetate was added, and the mixture was washed sequentially with water and saturated brine. After drying the organic layer over anhydrous sodium sulfate, the solvent was evaporated. The residue was purified by reverse phase HPLC (mobile phase: water/acetonitrile) to obtain the title compound.

Example 167: (S)-5'-(3-aminopyrrolidine-1-carbonyl)-2'-(6,7-difluoro-1-methyl-1H-benzo[d] Synthesis of [1,2,3]triazol-5-yl)-3-fluoro-[1,1'-biphenyl]-4-carbonitrile

Step 1

Tert-butyl N-[(3S)-1-[3-(4-cyano-3-fluoro-phenyl)-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzoyl]pyrrolidin-3-yl]carbamate (60 mg) and 5-bromo-6,7-difluoro-1-methyl-benzotriazole (41.7 mg) obtained in Step 1 of Example 37 were dissolved in 1,4-dioxane (0.56 mL). Pd(dba) ₂ (3.22 mg), X-phos (5.34 mg), and tripotassium phosphate (71.4 mg) were added at room temperature, and the mixture was stirred in a microwave reactor at 125°C for 1 hour. The reaction solution was filtered, and the solvent was evaporated. The residue was purified by silica gel column chromatography (mobile phase: chloroform/methanol) to give tert-butyl N-[(3S)-1-[3-(4-cyano-3-fluoro-phenyl)-4-(6,7-difluoro-1-methyl-benzotriazol-5-yl)benzoyl]pyrrolidin-3-yl]carbamate.

Step 2

The tert-butyl N-[(3S)-1-[3-(4-cyano-3-fluoro-phenyl)-4-(6,7-difluoro-1-methyl-benzotriazol-5-yl)benzoyl]pyrrolidin-3-yl]carbamate (20 mg) obtained in step 1 above was dissolved in TFA (0.40 mL) and stirred at room temperature for 5 minutes. After confirming the completion of the reaction by LCMS, DMSO (1.60 mL) was added thereto and purified by reverse phase HPLC (mobile phase: water/acetonitrile) to give the title compound.

Example 168: 5'-((3-endo)-3-amino-8-azabicyclo[3.2.1]octane-8-carbonyl)-3-fluoro-2'- Synthesis of (6-fluoro-1-propyl-1H-benzo[d][1,2,3]triazol-5-yl)-[1,1'-biphenyl]-4-carbonitrile

The procedures of Steps 1 to 5 of Example 41 were repeated using 5-bromo-6-fluoro-1-propyl-benzotriazole instead of 1-(4-bromo-3-fluoro-phenyl)-2-methyl-propan-2-ol to give the title compound.

Example 169: (S)-5'-(3-aminopyrrolidine-1-carbonyl)-2'-(6,7-difluoro-1-(2-methoxyethyl)- Synthesis of 1H-benzo[d][1,2,3]triazol-5-yl)-3-fluoro-[1,1'-biphenyl]-4-carbonitrile

Step 1

The procedures of Steps 1 to 3 of Example 161 were repeated using 2,3-difluoro-N-(2-methoxyethyl)-6-nitro-aniline instead of 1-(2,3-difluoro-6-nitro-anilino)-2-methyl-propan-2-ol to give 5-bromo-6,7-difluoro-1-(2-methoxyethyl)benzotriazole.

Step 2

Using 5-bromo-6,7-difluoro-1-(2-methoxyethyl)benzotriazole obtained in step 1 above instead of 1-(4-bromo-3-fluoro-phenyl)-2-methyl-propan-2-ol, the procedures of steps 1 to 3 of example 37 were repeated to give the title compound.

Example 170: (S)-5'-(3-aminopyrrolidine-1-carbonyl)-3-fluoro-2'-(6-fluoro-1-(2-hydroxyethyl)- Synthesis of 1H-indol-5-yl)-[1,1'-biphenyl]-4-carbonitrile

The procedures of Steps 1 to 3 of Example 37 were repeated using 2-(5-bromo-6-fluoro-indol-1-yl)ethanol instead of 1-(4-bromo-3-fluoro-phenyl)-2-methyl-propan-2-ol to give the title compound.

Example 171: 5'-((1R,2R,4S)-rel-2-amino-7-azabicyclo[2.2.1]heptane-7-carbonyl)-3- Fluoro-2'-(6-fluoro-1-(2-hydroxy-2-methylpropyl)-1H-indol-5-yl)-[1,1'-biphenyl]-4-carbonitrile-isomer-B Synthesis

Step 1

Tert-butyl 3-(4-cyano-3-fluoro-phenyl)-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzoate (2.3 g) obtained in Step 1 of Example 41 and 1-(5-bromo-6-fluoro-indol-1-yl)-2-methyl-propan-2-ol (2.02 g) obtained in Step 1 of Example 136 were dissolved in 1,4-dioxane (18.1 mL). Pd(dba) _₂ (250 mg), X-phos (414 mg), and tripotassium phosphate (3.46 g) were added at room temperature, followed by stirring at 100°C overnight. The solvent was evaporated, and the residue was purified by silica gel column chromatography (mobile phase: hexane/ethyl acetate). The solvent was evaporated, and the residue was dissolved in THF (40.0 mL). 12N hydrochloric acid (30.0 mL) was added thereto at 0°C, followed by stirring at room temperature for 2 hours. Then, MTBE was added thereto, the mixture was washed with water and dried over anhydrous sodium sulfate, and the solvent was distilled off to obtain 3-(4-cyano-3-fluoro-phenyl)-4-[6-fluoro-1-(2-hydroxy-2-methyl-propyl)indol-5-yl]benzoic acid.

Step 2

3-(4-Cyano-3-fluoro-phenyl)-4-[6-fluoro-1-(2-hydroxy-2-methyl-propyl)indol-5-yl]benzoic acid (8 mg) obtained in Step 1 above and N-((1R,2R,4S)-rel-7-azabicyclo[2.2.1]hept-2-yl)-2,4-dinitrobenzenesulfonamide-isomer-B hydrochloride (7.47 mg) obtained in Step 3 of Example 155 were dissolved in THF (0.30 mL). TEA (0.00748 mL) and HATU (13.6 mg) were added thereto at room temperature, followed by stirring at 50° C. for 1 hour. The reaction solution was concentrated in vacuo, and the residue was purified by silica gel column chromatography (mobile phase: hexane/ethyl acetate) to give N-[(1S,3R,4R)-rel-7-[3-(4-cyano-3-fluoro-phenyl)-4-[6-fluoro-1-(2-hydroxy-2-methyl-propyl)indol-5-yl]benzoyl]-7-azabicyclo[2.2.1]hept-3-yl]-2,4-dinitrobenzenesulfonamide-isomer-B.

Step 3

N-[(1S,3R,4R)-rel-7-[3-(4-cyano-3-fluoro-phenyl)-4-[6-fluoro-1-(2-hydroxy-2-methyl-propyl)indol-5-yl]benzoyl]-7-azabicyclo[2.2.1]hept-3-yl]-2,4-dinitrobenzenesulfonamide-isomer-B (13.8 mg) obtained in step 2 above was dissolved in DCM (1.0 mL). Thioglycolic acid (2.49 μL) and TEA (7.48 μL) were added at 0°C, followed by stirring at room temperature for 1 hour. Chloroform and 4N sodium hydroxide were added, and the mixture was washed sequentially with water and saturated brine. After drying the organic layer over anhydrous sodium sulfate, the solvent was evaporated. The residue was purified by reverse phase HPLC (mobile phase: water/acetonitrile) to obtain the title compound.

Example 172: (S)-5'-(3-aminopyrrolidine-1-carbonyl)-2'-(6,7-difluoro-1-(2-hydroxy-2-methyl) Synthesis of (1H-indol-5-yl)-3-fluoro-[1,1'-biphenyl]-4-carbonitrile

Step 1

5-Bromo-6,7-difluoro-1H-indole (300 mg) was dissolved in DMF (4.31 mL). _Cs₂CO₃ (843 _mg ) and 2,2-dimethyloxirane (0.230 mL) were added at room temperature, followed by stirring at 80°C for 3 hours. The reaction mixture was filtered, and the solvent was evaporated. Ethyl acetate was added, and the mixture was washed sequentially with saturated aqueous ammonium chloride, water, and saturated brine, dried over anhydrous sodium sulfate, and the solvent was evaporated. The residue was purified by silica gel column chromatography (mobile phase: hexane/ethyl acetate) to obtain 1-(5-bromo-6,7-difluoro-indol-1-yl)-2-methyl-propan-2-ol.

Step 2

Tert-butyl 3-(4-cyano-3-fluoro-phenyl)-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzoate (210 mg) obtained in Step 1 of Example 41 and 1-(5-bromo-6,7-difluoro-indol-1-yl)-2-methyl-propan-2-ol (196 mg) obtained in Step 1 above were dissolved in 1,4-dioxane (1.65 mL). Pd(dba) ₂ (22.8 mg), X-phos (37.8 mg), and tripotassium phosphate (316 mg) were added at room temperature, followed by stirring at 100°C overnight. The solvent was evaporated, and the residue was purified by silica gel column chromatography (mobile phase: hexane/ethyl acetate). The solvent was evaporated, and the residue was dissolved in THF (2.63 mL). 12N hydrochloric acid (2.1 mL) was added thereto at 0°C, followed by stirring at room temperature for 2 hours. MTBE was added thereto, the mixture was washed with water, dried over anhydrous sodium sulfate, and the solvent was distilled off to obtain 3-(4-cyano-3-fluoro-phenyl)-4-[6,7-difluoro-1-(2-hydroxy-2-methyl-propyl)indol-5-yl]benzoic acid.

Step 3

3-(4-Cyano-3-fluoro-phenyl)-4-[6,7-difluoro-1-(2-hydroxy-2-methyl-propyl)indol-5-yl]benzoic acid (30 mg) and tert-butyl N-[(3S)-pyrrolidin-3-yl]carbamate (13.2 mg) were dissolved in THF (0.323 mL). TEA (0.027 mL) and HATU (49.1 mg) were added at room temperature, followed by stirring at 50°C for 1 hour. The solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (mobile phase: hexane/ethyl acetate) to obtain tert-butyl N-[(3S)-1-[3-(4-cyano-3-fluoro-phenyl)-4-[6,7-difluoro-1-(2-hydroxy-2-methyl-propyl)indol-5-yl]benzoyl]pyrrolidin-3-yl]carbamate.

Step 4

Dissolve tert-butyl N-[(3S)-1-[3-(4-cyano-3-fluoro-phenyl)-4-[6,7-difluoro-1-(2-hydroxy-2-methyl-propyl)indol-5-yl]benzoyl]pyrrolidin-3-yl]carbamate (40 mg) obtained in Step 3 above in MeOH (0.80 mL). Add 4N hydrochloric acid in 1,4-dioxane (0.80 mL) at room temperature, and stir at room temperature for 1 hour. Add chloroform and 2N aqueous sodium hydroxide solution (1.6 mL), wash the mixture with water, dry over anhydrous sodium sulfate, and evaporate the solvent. The residue is purified by reverse-phase HPLC (mobile phase: water/acetonitrile) to obtain the title compound.

Example 173: 5'-(7-amino-2-azabicyclo[2.2.1]heptane-2-carbonyl)-3-fluoro-2'-(6-fluoro-1- Synthesis of (2-Hydroxy-2-methylpropyl)-1H-indol-5-yl)-[1,1'-biphenyl]-4-carbonitrile

The 3-(4-cyano-3-fluoro-phenyl)-4-[6-fluoro-1-(2-hydroxy-2-methyl-propyl) indol-5-yl] benzoic acid (8 mg) obtained in step 1 of Example 171 was dissolved in THF (0.3 mL). At room temperature, tert-butyl N-(3-azabicyclo[2.2.1]hept-7-yl)carbamate (3.80 mg), TEA (0.0075 mL) and HATU (13.6 mg) were added thereto, followed by stirring at 50 ° C for 3 hours. After the reaction was confirmed to be complete by LCMS, the reaction solution was concentrated. TFA (0.20 mL) was added to the residue, followed by stirring at room temperature for 5 minutes. After the reaction was confirmed to be complete by LCMS, DMSO (0.8 mL) was added to the reaction solution, and the title compound was purified by reverse phase HPLC (mobile phase: water/acetonitrile) to give the title compound.

Example 174: 5'-(7-amino-2-azabicyclo[2.2.1]heptane-2-carbonyl)-2",3-difluoro-4"-(2-hydroxy Synthesis of (1,1':2',1"-terphenyl)-4-carbonitrile

Step 1

3-(4-Cyano-3-fluoro-phenyl)-4-[2-fluoro-4-(2-hydroxy-2-methyl-propyl)phenyl]benzoic acid (100 mg) obtained in Step 2 of Example 166 was dissolved in THF (0.982 mL). Tert-butyl N-(3-azabicyclo[2.2.1]hept-7-yl)carbamate (52.1 mg), TEA (0.103 mL), and HATU (187 mg) were added at room temperature, followed by stirring at 50°C for 3 hours. The residue was purified by silica gel column chromatography (mobile phase: hexane/ethyl acetate) to give tert-butyl N-[3-[3-(4-cyano-3-fluoro-phenyl)-4-[2-fluoro-4-(2-hydroxy-2-methyl-propyl)phenyl]benzoyl]-3-azabicyclo[2.2.1]hept-7-yl]carbamate.

Step 2

Tert-butyl N-[3-[3-(4-cyano-3-fluoro-phenyl)-4-[2-fluoro-4-(2-hydroxy-2-methyl-propyl)phenyl]benzoyl]-3-azabicyclo[2.2.1]hept-7-yl]carbamate (30 mg) obtained in step 1 above was dissolved in MeOH (0.5 mL). 12N hydrochloric acid (0.5 mL) was added thereto at room temperature. After the mixture was stirred at room temperature for 0.5 hours, water and 2N aqueous sodium hydroxide solution (3.0 mL) were added thereto. The mixture was extracted with chloroform, and the solvent was evaporated. The residue was purified by reverse phase HPLC (mobile phase: water/acetonitrile) to obtain the title compound.

Example 175: 5'-((1S,2S,4R)-rel-2-amino-7-azabicyclo[2.2.1]heptane-7-carbonyl)-2'- (6,7-Difluoro-1-methyl-1H-benzo[d][1,2,3]triazol-5-yl)-3-fluoro-[1,1'-biphenyl]-4-carbonitrile-isomer Synthesis of body-B

Step 1

Tert-butyl 3-(4-cyano-3-fluoro-phenyl)-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzoate (90 mg) and 5-bromo-6,7-difluoro-1-methyl-benzotriazole (68.6 mg) obtained in Step 1 of Example 41 were dissolved in 1,4-dioxane (0.71 mL). Pd(dba) ₂ (9.8 mg), X-phos (16 mg), and tripotassium phosphate (135 mg) were added at room temperature, followed by stirring at 100°C overnight. The solvent was evaporated, and the residue was purified by silica gel column chromatography (mobile phase: hexane/ethyl acetate), and the solvent was evaporated. The residue was dissolved in TFA (1.0 mL) and stirred at room temperature for 2 hours. MTBE was added thereto, and the mixture was washed with water and dried over anhydrous sodium sulfate. The solvent was distilled off to obtain 3-(4-cyano-3-fluoro-phenyl)-4-(6,7-difluoro-1-methyl-benzotriazol-5-yl)benzoic acid.

Step 2

3-(4-Cyano-3-fluoro-phenyl)-4-(6,7-difluoro-1-methyl-benzotriazol-5-yl)benzoic acid (30 mg) obtained in Step 1 above and N-((1R,2R,4S)-rel-7-azabicyclo[2.2.1]hept-2-yl)-2,4-dinitrobenzenesulfonamide-Isomer B hydrochloride (30.6 mg) obtained in Step 3 of Example 155 were dissolved in THF (0.367 mL). TEA (0.042 mL) and HATU (55.9 mg) were added thereto at room temperature, followed by stirring at 50° C. for 1 hour. The reaction solution was concentrated in vacuo, and the residue was purified by silica gel column chromatography (mobile phase: hexane/ethyl acetate) to give N-[(1R,3S,4S)-rel-7-[3-(4-cyano-3-fluoro-phenyl)-4-(6,7-difluoro-1-methyl-benzotriazol-5-yl)benzoyl]-7-azabicyclo[2.2.1]hept-3-yl]-2,4-dinitrobenzenesulfonamide-isomer-B.

Step 3

N-[(1R,3S,4S)-rel-7-[3-(4-cyano-3-fluoro-phenyl)-4-(6,7-difluoro-1-methyl-benzotriazol-5-yl)benzoyl]-7-azabicyclo[2.2.1]hept-3-yl]-2,4-dinitrobenzenesulfonamide-Isomer-B (51 mg), obtained in Step 2 above, was dissolved in DCM (0.70 mL). Thioglycolic acid (5.8 μL) and TEA (29.1 μL) were added at 0°C, followed by stirring at room temperature for 2 hours. Ethyl acetate was added, and the mixture was washed sequentially with water and saturated brine. The organic layer was dried over anhydrous sodium sulfate, and the solvent was evaporated. The residue was purified by reverse-phase HPLC (mobile phase: water/acetonitrile) to obtain the title compound.

Example 176: 5'-((1S,2S,4R)-rel-2-amino-7-azabicyclo[2.2.1]heptane-7-carbonyl)-3- Fluoro-2'-(6-fluoro-1-(2-hydroxy-2-methylpropyl)-1H-indazol-5-yl)-[1,1'-biphenyl]-4-carbonitrile-isomer-B Synthesis

Step 1

tert-Butyl 3-(4-cyano-3-fluoro-phenyl)-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzoate (2.3 g) obtained in Step 1 of Example 41 and 1-(5-bromo-6-fluoro-1H-indazol-1-yl)-2-methylpropan-2-ol (2.03 g) obtained in Step 1 of Example 142 were dissolved in 1,4-dioxane (18.7 mL). Pd(dba) _₂ (250 mg), X-phos (414 mg), and tripotassium phosphate (3.46 g) were added at room temperature, followed by stirring at 100°C overnight. The solvent was evaporated, and the residue was purified by silica gel column chromatography (mobile phase: hexane/ethyl acetate). The solvent was evaporated, and the residue was dissolved in THF (10.0 mL). 12N hydrochloric acid (10.0 mL) was added thereto at 0°C, followed by stirring at room temperature for 2 hours. MTBE was added thereto, the mixture was washed with water and dried over anhydrous sodium sulfate, and the solvent was distilled off to obtain 3-(4-cyano-3-fluoro-phenyl)-4-[6-fluoro-1-(2-hydroxy-2-methyl-propyl)indazol-5-yl]benzoic acid.

Step 2

3-(4-Cyano-3-fluoro-phenyl)-4-[6-fluoro-1-(2-hydroxy-2-methyl-propyl)indazol-5-yl]benzoic acid (30 mg) obtained in Step 1 above and N-((1R,2R,4S)-rel-7-azabicyclo[2.2.1]hept-2-yl)-2,4-dinitrobenzenesulfonamide-isomer-B hydrochloride (27.9 mg) obtained in Step 3 of Example 155 were dissolved in THF (0.34 mL). TEA (0.038 mL) and HATU (51.0 mg) were added thereto at room temperature, followed by stirring at 50° C. for 1 hour. The reaction solution was concentrated in vacuo, and the residue was purified by silica gel column chromatography (mobile phase: hexane/ethyl acetate) to give N-[(1S,3R,4R)-rel-7-[3-(4-cyano-3-fluoro-phenyl)-4-[6-fluoro-1-(2-hydroxy-2-methyl-propyl)indazol-5-yl]benzoyl]-7-azabicyclo[2.2.1]hept-3-yl]-2,4-dinitrobenzenesulfonamide-isomer-B.

Step 3

N-[(1S,3R,4R)-rel-7-[3-(4-cyano-3-fluoro-phenyl)-4-[6-fluoro-1-(2-hydroxy-2-methyl-propyl)indazol-5-yl]benzoyl]-7-azabicyclo[2.2.1]hept-3-yl]-2,4-dinitrobenzenesulfonamide-isomer-B (45 mg) obtained in step 2 above was dissolved in DCM (0.58 mL). Thioglycolic acid (4.9 μL) and TEA (24 μL) were added at 0°C, followed by stirring at room temperature for 2 hours. Ethyl acetate was added, and the mixture was washed sequentially with water and saturated brine. After drying the organic layer over anhydrous sodium sulfate, the solvent was evaporated. The residue was purified by reverse phase HPLC (mobile phase: water/acetonitrile) to obtain the title compound.

Example 177: 5'-((1S,2S,4R)-rel-2-amino-7-azabicyclo[2.2.1]heptane-7-carbonyl)-2'- (6,7-difluoro-1-(2-hydroxy-2-methylpropyl)-1H-benzo[d][1,2,3]triazol-5-yl)-3-fluoro-[1,1'-biphenyl Synthesis of 4-[[(4-(2-methyl-1-nitropropane)]-4-carbonitrile-isomer-B]]

Step 1

Tert-butyl 3-(4-cyano-3-fluoro-phenyl)-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzoate (3.2 g) obtained in Step 1 of Example 41 and 1-(5-bromo-6,7-difluoro-benzotriazol-1-yl)-2-methyl-propan-2-ol (3.01 g) obtained in Step 3 of Example 161 were dissolved in 1,4-dioxane (25.2 mL). Pd(dba) _₂ (348 mg), X-phos (577 mg), and tripotassium phosphate (4.81 g) were added at room temperature, followed by stirring at 100°C overnight. The solvent was evaporated, and the residue was purified by silica gel column chromatography (mobile phase: hexane/ethyl acetate). The solvent was evaporated, and the residue was dissolved in THF (15.0 mL). 12N hydrochloric acid (15.0 mL) was added thereto at 0°C, followed by stirring at room temperature for 2 hours. MTBE was added thereto, the mixture was washed with water and dried over anhydrous sodium sulfate, and the solvent was distilled off to obtain 3-(4-cyano-3-fluoro-phenyl)-4-[6,7-difluoro-1-(2-hydroxy-2-methyl-propyl)benzotriazol-5-yl]benzoic acid.

Step 2

3-(4-Cyano-3-fluoro-phenyl)-4-[6,7-difluoro-1-(2-hydroxy-2-methyl-propyl)benzotriazol-5-yl]benzoic acid (30 mg) obtained in Step 1 above and N-((1S,2S,4R)-rel-7-azabicyclo[2.2.1]hept-2-yl)-2,4-dinitrobenzenesulfonamide-isomer-B hydrochloride (26.8 mg) obtained in Step 3 of Example 155 were dissolved in THF (0.33 mL). TEA (0.037 mL) and HATU (48.9 mg) were added thereto at room temperature, followed by stirring at 50° C. for 1 hour. The reaction solution was concentrated in vacuo, and the residue was purified by silica gel column chromatography (mobile phase: hexane/ethyl acetate) to give N-[(1S,2S,4R)-rel-7-[3-(4-cyano-3-fluoro-phenyl)-4-[6,7-difluoro-1-(2-hydroxy-2-methyl-propyl)benzotriazol-5-yl]benzoyl]-7-azabicyclo[2.2.1]hept-3-yl]-2,4-dinitrobenzenesulfonamide-isomer-B.

Step 3

The N-[(1S,2S,4R)-rel-7-[3-(4-cyano-3-fluoro-phenyl)-4-[6,7-difluoro-1-(2-hydroxy-2-methyl-propyl)benzotriazol-5-yl]benzoyl]-7-azabicyclo[2.2.1]hept-3-yl]-2,4-dinitrobenzenesulfonamide-isomer-B (43 mg) obtained in step 2 above was dissolved in DCM (0.54 mL). At 0°C, thioglycolic acid (4.5 μL) and TEA (22.7 μL) were added thereto, followed by stirring at room temperature for 2 hours. Ethyl acetate was added, and the mixture was washed sequentially with water and saturated brine. After drying the organic layer over anhydrous sodium sulfate, the solvent was evaporated. The residue was purified by reverse phase HPLC (mobile phase: water/acetonitrile) to obtain the title compound.

Example 178: 5'-((3-endo)-3-amino-8-azabicyclo[3.2.1]octane-8-carbonyl)-2'-(3-bromo- Synthesis of 6-fluoro-1-(2-hydroxy-2-methylpropyl)-1H-indazol-5-yl)-3-fluoro-[1,1'-biphenyl]-4-carbonitrile

Step 1

Using 1-(5-bromo-6-fluoro-indazol-1-yl)-2-methyl-propan-2-ol obtained in Step 1 of Example 142 instead of 1-(4-bromo-3-fluoro-phenyl)-2-methyl-propan-2-ol, the procedures of Steps 1-4 of Example 41 were repeated to obtain tert-butyl N-((3-endo)-8-(4'-cyano-3'-fluoro-6-(6-fluoro-1-(2-hydroxy-2-methylpropyl)-1H-indazol-5-yl-[1,1'-biphenyl]-3-carbonyl)-8-azabicyclo[3.2.1]oct-3-yl)carbamate.

Step 2

Tert-butyl N-((3-endo)-8-(4'-cyano-3'-fluoro-6-(6-fluoro-1-(2-hydroxy-2-methylpropyl)-1H-indazol-5-yl-[1,1'-biphenyl]-3-carbonyl)-8-azabicyclo[3.2.1]octan-3-yl)carbamate (10 mg) obtained in the above step 1 was dissolved in DMF (0.076 mL). NBS (3.5 mg) was added thereto, followed by stirring at 80° C. overnight. The reaction solution was diluted to 1 mL with DMSO and purified by reverse phase HPLC (mobile phase: water/acetonitrile) to give the title compound.

Example 179: 5'-((3-endo)-3-amino-8-azabicyclo[3.2.1]octane-8-carbonyl)-3-fluoro-2'- Synthesis of (5-fluoro-3-methylbenzo[d]isoxazol-6-yl)-[1,1'-biphenyl]-4-carbonitrile

Step 1

3-Bromo-4-fluorophenol (5 g) was dissolved in dichloromethane (114 mL). TEA (5.5 mL) was added thereto at 0° C., and acetyl chloride (2.8 mL) was added dropwise thereto. The reaction solution was stirred at 20° C. for 30 minutes and diluted with dichloromethane (100 mL). The resulting product was washed with 0.5 N hydrochloric acid, saturated aqueous sodium bicarbonate solution, and saturated brine, and the solvent was distilled off to obtain 3-bromo-4-fluorophenyl acetate.

Step 2

Boron trifluoride-acetic acid complex (53mL) is added to the 3-bromo-4-fluorophenyl acetate (6.2g) obtained in the above step 1, and then stirred at 155 ℃ for 14 hours. The reaction solution is cooled to 0 ℃, and ice is added thereto. The precipitate is collected by filtration, washed with water at 0 ℃ and dried. The resulting solid is purified by silica gel column chromatography (mobile phase: hexane/ethyl acetate) to obtain 1-(4-bromo-5-fluoro-2-hydroxyphenyl) ethanone.

Step 3

MeOH (30 mL) was added to 1-(4-bromo-5-fluoro-2-hydroxyphenyl)ethanone (2.16 g), hydroxylamine hydrochloride (1.29 g), and sodium acetate (1.14 g) obtained in Step 2 above, followed by stirring at 60°C for 1 hour. Ice water was added to the reaction solution, and the precipitate was collected by filtration, washed with water, and dried. The resulting solid was dissolved in THF (31 mL), and TEA (1.68 mL) and N,N'-carbonyldiimidazole (1.65 g) were added, followed by stirring at 70°C for 1 hour. The solvent was evaporated, and the residue was purified by silica gel column chromatography (mobile phase: chloroform/ethyl acetate) to obtain 6-bromo-5-fluoro-3-methylbenzo[d]isoxazole.

Step 4

Using 6-bromo-5-fluoro-3-methylbenzo[d]isoxazole obtained in step 3 above instead of 1-(4-bromo-3-fluoro-phenyl)-2-methyl-propan-2-ol, the procedures of steps 1 to 5 of example 41 were repeated to give the title compound.

Example 180: (S)-5'-(3-aminopyrrolidine-1-carbonyl)-3-fluoro-2'-(5-fluoro-3-methylbenzo[d]iso Synthesis of 6-oxazol-[1,1'-biphenyl]-4-carbonitrile

The procedures of Steps 1 to 3 of Example 37 were repeated using 6-bromo-5-fluoro-3-methylbenzo[d]isoxazole obtained in Step 3 of Example 179 instead of 1-(4-bromo-3-fluoro-phenyl)-2-methyl-propan-2-ol to give the title compound.

Example 181: 5'-((3-endo)-3-amino-8-azabicyclo[3.2.1]octane-8-carbonyl)-3-fluoro-2'- Synthesis of (6-fluoro-1-(2-hydroxy-2-methylpropyl)-3-methyl-1H-indazol-5-yl)-[1,1'-biphenyl]-4-carbonitrile

Step 1

Tert-butyl N-((3-endo)-8-(4'-cyano-3'-fluoro-6-(6-fluoro-1-(2-hydroxy-2-methylpropyl)-1H-indazol-5-yl-[1,1'-biphenyl]-3-carbonyl)-8-azabicyclo[3.2.1]oct-3-yl)carbamate (69 mg) obtained in Step 1 of Example 178 was dissolved in DMF (0.53 mL), and NBS (38 mg) was added thereto, followed by stirring at 80° C. overnight. The mixture was cooled to room temperature, and Boc _{2 O} was added thereto. O (200 mg) and DMAP (1 mg), then stirred at room temperature for 2 hours. Ethyl acetate was added thereto, and the resulting mixture was washed with water and saturated brine in sequence. After the organic layer was dried over anhydrous sodium sulfate, the solvent was distilled off. The solvent was distilled off, and the residue was purified by silica gel column chromatography (mobile phase: hexane/ethyl acetate) to obtain tert-butyl ((3-endo)-8-(4'-cyano-3'-fluoro-6-(6-fluoro-1-(2-hydroxy-2-methylpropyl)-1H-indazole-5-yl)-[1,1'-biphenyl]-3-carbonyl)-8-azabicyclo[3.2.1]oct-3-yl)carbamate.

Step 2

Tert-butyl ((3-endo)-8-(4'-cyano-3'-fluoro-6-(6-fluoro-1-(2-hydroxy-2-methylpropyl)-1H-indazol-5-yl)-[1,1'-biphenyl]-3-carbonyl)-8-azabicyclo[3.2.1]octan-3-yl)carbamate (15 mg), trimethylboroxine (7.7 mg), _PdCl₂ (dppf) _{CH₂Cl₂ (} 1 mg), and cesium carbonate (20 mg) were suspended in 1,4-dioxane and stirred at 125°C for 30 minutes under microwave irradiation. The solvent was evaporated, and trifluoroacetic acid (0.2 mL) was added to the residue, followed by stirring at room temperature for 10 minutes. The reaction solution was diluted to 1 mL with DMSO and purified by reverse-phase HPLC (mobile phase: water/acetonitrile) to obtain the title compound.

Example 182: 5'-((1R,2S,4S)-rel-2-amino-7-azabicyclo[2.2.1]heptane-7-carbonyl)-2", Synthesis of 3-difluoro-4"-(2-hydroxy-2-methylpropyl)-[1,1':2',1"-terphenyl]-4-carbonitrile

Step 1

Tert-butyl (1S,3S,4R)-rel-3-amino-7-azabicyclo[2.2.1]heptane-7-carboxylate (919 mg) was dissolved in THF (14.4 mL). TEA (1.81 mL) and 2,4-dinitrobenzenesulfonyl chloride (1.73 g) were added at 0°C, followed by stirring at room temperature overnight. Ethyl acetate was added, and the mixture was washed sequentially with water and saturated brine, dried over anhydrous sodium sulfate, and the solvent was evaporated. The residue was purified by silica gel column chromatography (mobile phase: hexane/ethyl acetate) to obtain tert-butyl (1S,3S,4R)-rel-3-[(2,4-dinitrophenyl)sulfonylamino]-7-azabicyclo[2.2.1]heptane-7-carboxylate.

Step 2

Dissolve tert-butyl (1S,3S,4R)-rel-3-[(2,4-dinitrophenyl)sulfonylamino]-7-azabicyclo[2.2.1]heptane-7-carboxylate (100 mg) obtained in step 1 above in ethyl acetate (1.00 mL). Add 4N hydrochloric acid-ethyl acetate solution (2.00 mL) at room temperature, followed by stirring at room temperature for 1 hour. The reaction solution is concentrated in vacuo to obtain N-[(1S,3S,4R)-rel-7-azabicyclo[2.2.1]hept-3-yl]-2,4-dinitrobenzenesulfonamide hydrochloride.

Step 3

3-(4-Cyano-3-fluoro-phenyl)-4-[2-fluoro-4-(2-hydroxy-2-methyl-propyl)phenyl]benzoic acid (30 mg) obtained in Step 2 of Example 166 and N-[(1S,3S,4R)-rel-7-azabicyclo[2.2.1]hept-3-yl]-2,4-dinitrobenzenesulfonamide hydrochloride (30.7 mg) obtained in Step 2 above were dissolved in THF (0.40 mL). TEA (0.0420 mL) and HATU (56.0 mg) were added thereto at room temperature, followed by stirring at 50° C. for 1 hour. The reaction solution was concentrated in vacuo, and the residue was purified by silica gel column chromatography (mobile phase: hexane/ethyl acetate) to give N-[(1S,3S,4R)-rel-7-[3-(4-cyano-3-fluoro-phenyl)-4-[2-fluoro-4-(2-hydroxy-2-methyl-propyl)phenyl]benzoyl]-7-azabicyclo[2.2.1]hept-3-yl]-2,4-dinitrobenzenesulfonamide.

Step 4

N-[(1S,3S,4R)-rel-7-[3-(4-cyano-3-fluoro-phenyl)-4-[2-fluoro-4-(2-hydroxy-2-methyl-propyl)phenyl]benzoyl]-7-azabicyclo[2.2.1]hept-3-yl]-2,4-dinitrobenzenesulfonamide (55 mg) obtained in Step 3 above was dissolved in DCM (0.752 mL). Thioglycolic acid (6.27 μL) and TEA (31.4 μL) were added at 0°C, followed by stirring at room temperature for 2 hours. Chloroform was added, and the mixture was washed with 4N aqueous sodium hydroxide solution, dried over anhydrous sodium sulfate, and the solvent was evaporated. The residue was purified by reverse-phase HPLC (mobile phase: water/acetonitrile) to obtain the title compound.

Example 183: 5'-((3-endo)-3-amino-8-azabicyclo[3.2.1]octane-8-carbonyl)-2'-(6,7- Synthesis of difluoro-1-(2-hydroxy-2-methylpropyl)-1H-indol-5-yl)-3-fluoro-[1,1'-biphenyl]-4-carbonitrile

Step 1

3-(4-Cyano-3-fluoro-phenyl)-4-[6,7-difluoro-1-(2-hydroxy-2-methyl-propyl)indol-5-yl]benzoic acid (30 mg) obtained in Step 2 of Example 172 and tert-butyl N-[(3-endo)-8-azabicyclo[3.2.1]octan-3-yl]carbamate (16.1 mg) were dissolved in THF (0.323 mL). TEA (0.027 mL) and HATU (49.1 mg) were added at room temperature, followed by stirring at 50°C for 1 hour. The solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (mobile phase: hexane/ethyl acetate) to give tert-butyl N-[(3-endo)-8-[3-(4-cyano-3-fluoro-phenyl)-4-[6,7-difluoro-1-(2-hydroxy-2-methyl-propyl)indol-5-yl]benzoyl]-8-azabicyclo[3.2.1]oct-3-yl]carbamate.

Step 2

Dissolve tert-butyl N-[(3-endo)-8-[3-(4-cyano-3-fluoro-phenyl)-4-[6,7-difluoro-1-(2-hydroxy-2-methyl-propyl)indol-5-yl]benzoyl]-8-azabicyclo[3.2.1]octan-3-yl]carbamate (42 mg) obtained in Step 1 above in MeOH (0.84 mL). Add 4N hydrochloric acid-1,4-dioxane solution (0.84 mL) at room temperature, followed by stirring at room temperature for 1 hour. Add chloroform and 2N aqueous sodium hydroxide solution (1.68 mL), wash the mixture with water, dry it over anhydrous sodium sulfate, and evaporate the solvent. The residue is purified by reverse-phase HPLC (mobile phase: water/acetonitrile) to obtain the title compound.

Example 184: 5'-((1R,2S,4S)-rel-2-amino-7-azabicyclo[2.2.1]heptane-7-carbonyl)-3- Synthesis of Fluoro-2'-(6-fluoro-1-(2-hydroxy-2-methylpropyl)-1H-indol-5-yl)-[1,1'-biphenyl]-4-carbonitrile

The procedures of Steps 1 to 3 of Example 171 were repeated using N-[(1R,2S,4S)-rel-7-azabicyclo[2.2.1]hept-3-yl]-2,4-dinitrobenzenesulfonamide hydrochloride obtained in Step 2 of Example 182 instead of N-((1R,2R,4S)-rel-7-azabicyclo[2.2.1]hept-2-yl)-2,4-dinitrobenzenesulfonamide-isomer-B hydrochloride to give the title compound.

Example 185: 5'-((1S,2S,4R)-rel-2-amino-7-azabicyclo[2.2.1]heptane-7-carbonyl)-2'- Synthesis of (6,7-difluoro-1-methyl-1H-benzo[d][1,2,3]triazol-5-yl)-3-fluoro-[1,1'-biphenyl]-4-carbonitrile

The procedures of Steps 3-4 of Example 172 were repeated using 3-(4-cyano-3-fluoro-phenyl)-4-(6,7-difluoro-1-methyl-benzotriazol-5-yl)benzoic acid obtained in Step 1 of Example 175 instead of 3-(4-cyano-3-fluoro-phenyl)-4-[6,7-difluoro-1-(2-hydroxy-2-methyl-propyl)indol-5-yl]benzoic acid, and tert-butyl ((1S,2S,4R)-rel-7-azabicyclo[2.2.1]hept-2-yl)carbamate hydrochloride instead of tert-butyl N-[(3S)-pyrrolidin-3-yl]carbamate to give the title compound.

Example 186: 5'-((3-endo)-3-amino-8-azabicyclo[3.2.1]octane-8-carbonyl)-3-fluoro-2'- Synthesis of (6-fluoro-1-(2-hydroxy-2-methylpropyl)-7-methoxy-1H-indazol-5-yl)-[1,1'-biphenyl]-4-carbonitrile

Step 1

5-Bromo-2,3,4-trifluoro-benzaldehyde (480 mg) was dissolved in 1,2-dimethoxyethane (4.8 mL). Hydrazine monohydrate (7.68 mL) was added at room temperature, followed by stirring at 80°C for 5 hours. Ethyl acetate was added, and the mixture was washed sequentially with water and saturated brine, dried over anhydrous sodium sulfate, and the solvent was evaporated. The residue was purified by silica gel column chromatography (mobile phase: hexane/ethyl acetate) to obtain 5-bromo-6,7-difluoro-1H-indazole.

Step 2

5-Bromo-6,7-difluoro-1H-indazole (97 mg) obtained in Step 1 above was dissolved in DMF (1.38 mL). Methanol (0.1 mL), cesium carbonate (271 mg), and 2,2-dimethyloxirane (0.074 mL) were added at room temperature, followed by stirring at 80°C for 1 hour. Ethyl acetate was added, and the mixture was washed sequentially with water and saturated brine, dried over anhydrous sodium sulfate, and the solvent was evaporated. The residue was purified by silica gel column chromatography (mobile phase: hexane/ethyl acetate) to obtain 1-(5-bromo-6-fluoro-7-methoxy-indazol-1-yl)-2-methyl-propan-2-ol.

Step 3

Step 41: tert-Butyl 3-(4-cyano-3-fluoro-phenyl)-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzoate (45.0 mg) obtained in Step 1 and 1-(5-bromo-6-fluoro-7-methoxy-indazol-1-yl)-2-methyl-propan-2-ol (43.8 mg) obtained in Step 2 above were dissolved in 1,4-dioxane (0.50 mL). Pd(dba) ₂ (4.89 mg), X-phos (8.11 mg), and tripotassium phosphate (67.7 mg) were added at room temperature, followed by stirring at 100°C overnight. The solvent was evaporated, and the residue was purified by silica gel column chromatography (mobile phase: hexane/ethyl acetate), and the solvent was evaporated. The residue was dissolved in THF (0.45 mL). 12N hydrochloric acid (0.56 mL) was added at 0°C, followed by stirring at room temperature for 2 hours. MTBE was added, and the mixture was washed with water and dried over anhydrous sodium sulfate. Thereafter, the solvent was distilled off to obtain 3-(4-cyano-3-fluoro-phenyl)-4-[6-fluoro-1-(2-hydroxy-2-methyl-propyl)-7-methoxy-indazol-5-yl]benzoic acid.

Step 4

The procedures of Steps 3-4 of Example 172 were repeated using 3-(4-cyano-3-fluoro-phenyl)-4-[6-fluoro-1-(2-hydroxy-2-methyl-propyl)-7-methoxy-indazol-5-yl]benzoic acid obtained in Step 3 above instead of 3-(4-cyano-3-fluoro-phenyl)-4-[6,7-difluoro-1-(2-hydroxy-2-methyl-propyl)indol-5-yl]benzoic acid, and tert-butyl ((3-endo)-8-azabicyclo[3.2.1]octan-3-yl)carbamate instead of tert-butyl N-[(3S)-pyrrolidin-3-yl]carbamate to give the title compound.

Example 187: (S)-5'-(3-aminopyrrolidine-1-carbonyl)-2'-(6,7-difluoro-1-(2-hydroxy-2-methyl) Synthesis of (1H-indazol-5-yl)-3-fluoro-[1,1'-biphenyl]-4-carbonitrile

Step 1

5-Bromo-6,7-difluoro-1H-indazole (101 mg) obtained in Step 1 of Example 186 was dissolved in DMF (1.44 mL). Cesium carbonate (283 mg) and 2,2-dimethyloxirane (0.077 mL) were added at room temperature, followed by stirring at 80°C overnight. Ethyl acetate was added, and the mixture was washed sequentially with water and saturated brine, and dried over anhydrous sodium sulfate. Thereafter, the solvent was evaporated. The residue was purified by silica gel column chromatography (mobile phase: hexane/ethyl acetate) to obtain 1-(5-bromo-6,7-difluoro-indazol-1-yl)-2-methyl-propan-2-ol.

Step 2

The procedures of Steps 2 to 4 of Example 172 were repeated using 1-(5-bromo-6,7-difluoro-indazole-1-yl)-2-methyl-propan-2-ol obtained in Step 1 above instead of 1-(5-bromo-6,7-difluoro-indol-1-yl)-2-methyl-propan-2-ol to give the title compound.

Example 188: 5'-((3-endo)-3-amino-8-azabicyclo[3.2.1]octane-8-carbonyl)-2'-(6,7- Synthesis of difluoro-1-(2-hydroxy-2-methylpropyl)-1H-indazol-5-yl)-3-fluoro-[1,1'-biphenyl]-4-carbonitrile

The procedures of Steps 2 to 4 of Example 172 were repeated, using 1-(5-bromo-6,7-difluoro-indole-1-yl)-2-methyl-propan-2-ol obtained in Step 1 of Example 187 instead of 1-(5-bromo-6,7-difluoro-indol-1-yl)-2-methyl-propan-2-ol, and tert-butyl ((3-endo)-8-azabicyclo[3.2.1]octan-3-yl)carbamate instead of tert-butyl N-[(3S)-pyrrolidin-3-yl]carbamate to give the title compound.

Example 189: 5'-((1S,2S,4R)-rel-2-amino-7-azabicyclo[2.2.1]heptane-7-carbonyl)-3- Synthesis of Fluoro-2'-(6-fluoro-1-(2-hydroxy-2-methylpropyl)-1H-indazol-5-yl)-[1,1'-biphenyl]-4-carbonitrile

The procedures of Steps 2 to 4 of Example 172 were repeated using 1-(5-bromo-6-fluoro-indazol-1-yl)-2-methyl-propan-2-ol obtained in Step 1 of Example 142 instead of 1-(5-bromo-6,7-difluoro-indol-1-yl)-2-methyl-propan-2-ol, and tert-butyl N-[(3S)-pyrrolidin-3-yl]carbamate was replaced with tert-butyl ((1S,2S,4R)-rel-7-azabicyclo[2.2.1]hept-2-yl)carbamate hydrochloride to give the title compound.

Example 190: (S)-5'-(3-amino-3-methylpyrrolidine-1-carbonyl)-3-fluoro-2'-(6-fluoro-1-(2-hydroxy Synthesis of (1H-indol-5-yl)-[1,1'-biphenyl]-4-carbonitrile

Using 1-(5-bromo-6-fluoro-indol-1-yl)-2-methyl-propan-2-ol obtained in step 1 of example 136 instead of 1-(5-bromo-6,7-difluoro-indol-1-yl)-2-methyl-propan-2-ol, and using (S)-(3-methylpyrrolidin-3-yl)carbamic acid tert-butyl ester instead of N-[(3S)-pyrrolidin-3-yl]carbamic acid tert-butyl ester, the procedures of steps 2 to 4 of example 172 were repeated to give the title compound.

Example 191: (S)-5'-(3-amino-3-methylpyrrolidine-1-carbonyl)-2'-(6,7-difluoro-1-(2-hydroxy- Synthesis of (2-methylpropyl)-1H-benzo[d][1,2,3]triazol-5-yl)-3-fluoro-[1,1'-biphenyl]-4-carbonitrile

Using 3-(4-cyano-3-fluoro-phenyl)-4-[6,7-difluoro-1-(2-hydroxy-2-methyl-propyl)benzotriazol-5-yl]benzoic acid obtained in step 1 of example 177 instead of 3-(4-cyano-3-fluoro-phenyl)-4-[6,7-difluoro-1-(2-hydroxy-2-methyl-propyl)indol-5-yl]benzoic acid, and using (S)-(3-methylpyrrolidin-3-yl)carbamic acid tert-butyl ester instead of N-[(3S)-pyrrolidin-3-yl]carbamic acid tert-butyl ester, the procedures of steps 3-4 of example 172 were repeated to give the title compound.

Example 192: 5'-((1S,2S,4R)-rel-2-amino-7-azabicyclo[2.2.1]heptane-7-carbonyl)-2'- (6,7-difluoro-1-(2-hydroxy-2-methylpropyl)-1H-benzo[d][1,2,3]triazol-5-yl)-3-fluoro-[1,1'-biphenyl Synthesis of [4-Methyl]-4-carbonitrile

The procedures of Steps 3-4 of Example 172 were repeated using 3-(4-cyano-3-fluoro-phenyl)-4-[6,7-difluoro-1-(2-hydroxy-2-methyl-propyl)benzotriazol-5-yl]benzoic acid obtained in Step 1 of Example 177 to replace 3-(4-cyano-3-fluoro-phenyl)-4-[6,7-difluoro-1-(2-hydroxy-2-methyl-propyl)indol-5-yl]benzoic acid, and tert-butyl N-[(3S)-pyrrolidin-3-yl]carbamate was replaced with tert-butyl ((1S,2S,4R)-rel-7-azabicyclo[2.2.1]hept-2-yl)carbamate hydrochloride to give the title compound.

Example 193: 5'-((1S,2S,4R)-rel-2-amino-7-azabicyclo[2.2.1]heptane-7-carbonyl)-2", Synthesis of 3-difluoro-4"-(2-hydroxy-2-methylpropyl)-[1,1':2',1"-terphenyl]-4-carbonitrile

Using 3-(4-cyano-3-fluoro-phenyl)-4-[2-fluoro-4-(2-hydroxy-2-methyl-propyl)phenyl]benzoic acid obtained in step 2 of Example 166 instead of 3-(4-cyano-3-fluoro-phenyl)-4-[6,7-difluoro-1-(2-hydroxy-2-methyl-propyl)indol-5-yl]benzoic acid, and using tert-butyl ((1S,2S,4R)-rel-7-azabicyclo[2.2.1]hept-2-yl)carbamate hydrochloride instead of tert-butyl N-[(3S)-pyrrolidin-3-yl]carbamate, the procedures of steps 3-4 of 172 were repeated to give the title compound.

Example 194: 5'-((3-endo)-3-amino-8-azabicyclo[3.2.1]octane-8-carbonyl)-3-fluoro-2'- Synthesis of (6-fluoro-1-(3-hydroxy-3-methylbutyl)-1H-indazol-5-yl)-[1,1'-biphenyl]-4-carbonitrile

Step 1

5-Bromo-6-fluoro-1H-indazole (200 mg) was dissolved in DMF (3.1 mL). Cesium carbonate (606 mg) and 3-hydroxy-3-methyl-butyl 4-methylbenzenesulfonate (481 mg) were added thereto at room temperature, and then stirred at 90° C. for 16 hours. Ethyl acetate was added thereto, and the mixture was washed with water and saturated brine in sequence and dried over anhydrous sodium sulfate. Thereafter, the solvent was distilled off. The residue was purified by silica gel column chromatography (mobile phase: hexane/ethyl acetate) to obtain 4-(5-bromo-6-fluoro-indazole-1-yl)-2-methyl-butan-2-ol.

Step 2

Replace 1-(5-bromo-6,7-difluoro-indol-1-yl)-2-methyl-propan-2-ol with 4-(5-bromo-6-fluoro-indazol-1-yl)-2-methyl-butan-2-ol obtained in the above step 1, and replace N-[(3S)-pyrrolidin-3-yl]carbamic acid tert-butyl ester with ((3-endo)-8-azabicyclo[3.2.1]octan-3-yl)carbamic acid tert-butyl ester, and repeat the procedures of steps 2-4 of 172 to give the title compound.

Example 195: 5'-((1S,2S,4R)-rel-2-amino-7-azabicyclo[2.2.1]heptane-7-carbonyl)-2'- Synthesis of (6,7-difluoro-1-(2-hydroxy-2-methylpropyl)-1H-indazol-5-yl)-3-fluoro-[1,1'-biphenyl]-4-carbonitrile

Using 1-(5-bromo-6,7-difluoro-indole-1-yl)-2-methyl-propan-2-ol obtained in Step 1 of Example 187 instead of 1-(5-bromo-6,7-difluoro-indol-1-yl)-2-methyl-propan-2-ol, and using tert-butyl ((1S,2S,4R)-rel-7-azabicyclo[2.2.1]hept-2-yl)carbamate hydrochloride instead of tert-butyl N-[(3S)-pyrrolidin-3-yl]carbamate, the procedures of Step 2-4 of 172 were repeated to give the title compound.

Example 196: 5'-((1S,2S,4R)-rel-2-amino-7-azabicyclo[2.2.1]heptane-7-carbonyl)-2'- Synthesis of (6,7-difluoro-1-(2-hydroxy-2-methylpropyl)-1H-indol-5-yl)-3-fluoro-[1,1'-biphenyl]-4-carbonitrile

The procedures of steps 1-4 of 172 were repeated using tert-butyl ((1S,2S,4R)-rel-7-azabicyclo[2.2.1]hept-2-yl)carbamate hydrochloride instead of tert-butyl N-[(3S)-pyrrolidin-3-yl]carbamate to give the title compound.

Example 197: (S)-5'-(3-amino-3-methylpyrrolidine-1-carbonyl)-2'-(6,7-difluoro-1-(2-hydroxy- Synthesis of (2-methylpropyl)-1H-indazol-5-yl)-3-fluoro-[1,1'-biphenyl]-4-carbonitrile

Using 1-(5-bromo-6,7-difluoro-indole-1-yl)-2-methyl-propan-2-ol obtained in Step 1 of Example 187 instead of 1-(5-bromo-6,7-difluoro-indol-1-yl)-2-methyl-propan-2-ol, and using (S)-(3-methylpyrrolidin-3-yl)carbamic acid tert-butyl ester instead of N-[(3S)-pyrrolidin-3-yl]carbamic acid tert-butyl ester, the procedures of Step 2-4 of 172 were repeated to give the title compound.

Example 198: (S)-5'-(3-amino-3-methylpyrrolidine-1-carbonyl)-2'-(6,7-difluoro-1-(2-hydroxy- Synthesis of (2-methylpropyl)-1H-indol-5-yl)-3-fluoro-[1,1'-biphenyl]-4-carbonitrile

The procedure of Steps 1 to 4 of 172 was repeated using tert-butyl (S)-(3-methylpyrrolidin-3-yl)carbamate instead of tert-butyl N-[(3S)-pyrrolidin-3-yl]carbamate to give the title compound.

Example 199: 3-Fluoro-2'-(6-fluoro-1-(2-hydroxy-2-methylpropyl)-1H-indazol-5-yl)-5'-(2,7- Synthesis of Diazaspiro[3.4]octane-6-carbonyl)-[1,1'-biphenyl]-4-carbonitrile

Using 1-(5-bromo-6-fluoro-indazol-1-yl)-2-methyl-propan-2-ol obtained in Step 1 of Example 142 instead of 1-(5-bromo-6,7-difluoro-indol-1-yl)-2-methyl-propan-2-ol, and using tert-butyl 2,7-diazaspiro[3.4]octane-2-carboxylate instead of tert-butyl N-[(3S)-pyrrolidin-3-yl]carbamate, the procedures of Step 2-4 of 172 were repeated to give the title compound.

Example 200: 2'-(6,7-difluoro-1-(2-hydroxy-2-methylpropyl)-1H-indol-5-yl)-3-fluoro-5'- Synthesis of (2,7-diazaspiro[3.4]octane-6-carbonyl)-[1,1'-biphenyl]-4-carbonitrile

The procedure of steps 1-4 of 172 was repeated using tert-butyl 2,7-diazaspiro[3.4]octane-2-carboxylate instead of tert-butyl N-[(3S)-pyrrolidin-3-yl]carbamate to give the title compound.

Example 201: 2'-(6,7-difluoro-1-(2-hydroxy-2-methylpropyl)-1H-indol-5-yl)-3-fluoro-5'- Synthesis of (2,8-diazaspiro[3.5]nonane-2-carbonyl)-[1,1'-biphenyl]-4-carbonitrile

The procedure of steps 1 to 4 of 172 was repeated using tert-butyl 2,8-diazaspiro[3.5]nonane-6-carboxylate instead of tert-butyl N-[(3S)-pyrrolidin-3-yl]carbamate to give the title compound.

Example 202: 5'-((1S,2S,4R)-rel-2-amino-7-azabicyclo[2.2.1]heptane-7-carbonyl)-3- Synthesis of Fluoro-2'-(5-fluoro-3-methylbenzo[d]isoxazol-6-yl)-[1,1'-biphenyl]-4-carbonitrile-Isomer-X

Step 1

Tert-butyl ((1S,2S,4R)-rel-7-azabicyclo[2.2.1]hept-2-yl)carbamate hydrochloride (36 mg) was dissolved in DCM (2.89 mL). TEA (40 μL) and benzyl chloroformate (25 μL) were added to the mixture at room temperature, followed by stirring at room temperature for 1 hour. The solvent was evaporated, and chloroform and water were added. The mixture was extracted twice with chloroform and washed with water and saturated brine. The solvent was evaporated, and the residue was purified by silica gel column chromatography (mobile phase: hexane/ethyl acetate) to obtain benzyl (1S,2S,4R)-rel-2-((tert-butoxycarbonyl)amino)-7-azabicyclo[2.2.1]heptane-7-carboxylate.

Benzyl (1S,2S,4R)-rel-2-((tert-butoxycarbonyl)amino)-7-azabicyclo[2.2.1]heptane-7-carboxylate was obtained as a 10 mg/mL solution in ethanol and separated under the following conditions.

The isomer with a shorter retention time was defined as "Isomer-X", and the isomer with a longer retention time was defined as "Isomer-Y".

Column: Daicel CHIRALPAK IC 2.0×25cm

Mobile phase: hexane/2-propanol = 85/15

Flow rate: 12.5 mL/min

Retention time of each isomer:

(1S,2S,4R)-rel-2-((tert-butoxycarbonyl)amino)-7-azabicyclo[2.2.1]heptane-7-carboxylic acid benzyl ester-isomer-X: 16.93 minutes

(1S,2S,4R)-rel-2-((tert-butoxycarbonyl)amino)-7-azabicyclo[2.2.1]heptane-7-carboxylic acid benzyl ester-isomer-Y: 23.82 minutes.

Chiral analysis conditions:

Column: CHIRALPAK IC 4.6×150mm

Mobile phase: hexane/2-propanol = 85/15

Flow rate: 1.0 mL/min

Retention time of each isomer:

(1S,2S,4R)-rel-2-((tert-butoxycarbonyl)amino)-7-azabicyclo[2.2.1]heptane-7-carboxylic acid benzyl ester-isomer-X: 6.972 minutes

(1S,2S,4R)-rel-2-((tert-butoxycarbonyl)amino)-7-azabicyclo[2.2.1]heptane-7-carboxylic acid benzyl ester-isomer-Y: 9.895 minutes.

Step 2

Benzyl (1S,2S,4R)-rel-2-((tert-butoxycarbonyl)amino)-7-azabicyclo[2.2.1]heptane-7-carboxylate, isomer-X (93 g) and 10% Pd/C (10 g) obtained in Step 1 above were suspended in methanol (1.0 L). Under a hydrogen atmosphere (50 psi), the mixture was stirred at room temperature for 5 hours. The reaction solution was filtered, and the filtrate was concentrated to obtain tert-butyl ((1S,2S,4R)-rel-7-azabicyclo[2.2.1]hept-2-yl)carbamate, isomer-X.

Step 3

The procedures of Steps 2 to 4 of Example 172 were repeated using 6-bromo-5-fluoro-3-methylbenzo[d]isoxazole obtained in Step 3 of Example 179 instead of 1-(5-bromo-6,7-difluoro-indol-1-yl)-2-methyl-propan-2-ol, and ((1S,2S,4R)-rel-7-azabicyclo[2.2.1]hept-2-yl)carbamic acid tert-butyl ester-isomer-X obtained in Step 2 above instead of N-[(3S)-pyrrolidin-3-yl]carbamic acid tert-butyl ester to give the title compound.

Example 203: 2'-(6,7-difluoro-1-(2-hydroxy-2-methylpropyl)-1H-indol-5-yl)-3-fluoro-5'- Synthesis of (Octahydropyrrolo[3,4-c]pyrrole-2-carbonyl)-[1,1'-biphenyl]-4-carbonitrile

The procedures of Steps 1 to 4 of Example 172 were repeated using tert-butyl hexahydropyrrolo[3,4-c]pyrrole-2(1H)-carboxylate instead of tert-butyl N-[(3S)-pyrrolidin-3-yl]carbamate to give the title compound.

Example 204: (S)-5'-(3-aminopyrrolidine-1-carbonyl)-2'-(1-(2-ethyl-2-hydroxybutyl)-6-fluoro- Synthesis of 1H-indazol-5-yl)-3-fluoro-[1,1'-biphenyl]-4-carbonitrile

Step 1

5-Bromo-6-fluoro-1H-indazole (300 mg) was dissolved in DMF (4.65 mL). Cesium carbonate (90.9 mg) and 2,2-diethyloxirane (0.20 mL) were added at room temperature, followed by stirring at 90°C for 16 hours. Ethyl acetate was added, and the mixture was washed sequentially with water and saturated brine, and dried over anhydrous sodium sulfate. The solvent was then evaporated. The residue was purified by silica gel column chromatography (mobile phase: hexane/ethyl acetate) to obtain 3-[(5-bromo-6-fluoro-indazol-1-yl)methyl]pentan-3-ol.

Step 2

The procedures of Steps 2 to 4 of Example 172 were repeated using 3-[(5-bromo-6-fluoro-indazol-1-yl)methyl]pentan-3-ol obtained in Step 1 instead of 1-(5-bromo-6,7-difluoro-indol-1-yl)-2-methyl-propan-2-ol to give the title compound.

Example 205: 5'-((3-endo)-3-amino-8-azabicyclo[3.2.1]octane-8-carbonyl)-2'-(1-(2- Synthesis of (2-(Ethyl)-6-fluoro-1H-indazol-5-yl)-3-fluoro-[1,1'-biphenyl]-4-carbonitrile

The procedures of Steps 2 to 4 of Example 172 were repeated using 3-[(5-bromo-6-fluoro-indazol-1-yl)methyl]pentan-3-ol obtained in Step 1 of Example 204 instead of 1-(5-bromo-6,7-difluoro-indol-1-yl)-2-methyl-propan-2-ol, and tert-butyl ((3-endo)-8-azabicyclo[3.2.1]octan-3-yl)carbamate instead of tert-butyl N-[(3S)-pyrrolidin-3-yl]carbamate to give the title compound.

Example 206: 5'-((1S,2S,4R)-rel-2-amino-7-azabicyclo[2.2.1]heptane-7-carbonyl)-2'- (1-(2-Ethyl-2-hydroxybutyl)-6-fluoro-1H-indazol-5-yl)-3-fluoro-[1,1'-biphenyl]-4-carbonitrile-isomer-X Synthesis

The procedures of Steps 2-4 of Example 172 were repeated using 3-[(5-bromo-6-fluoro-indazol-1-yl)methyl]pentan-3-ol obtained in Step 1 of Example 204 instead of 1-(5-bromo-6,7-difluoro-indol-1-yl)-2-methyl-propan-2-ol, and ((1S,2S,4R)-rel-7-azabicyclo[2.2.1]hept-2-yl)carbamic acid tert-butyl ester-isomer-X obtained in Step 2 of Example 202 instead of N-[(3S)-pyrrolidin-3-yl]carbamic acid tert-butyl ester to give the title compound.

Example 207: 2-(5-(5-((1S,2S,4R)-rel-2-amino-7-azabicyclo[2.2.1]heptane-7-carbonyl Synthesis of 4'-cyano-3'-fluoro-[1,1'-biphenyl]-2-yl)-6-fluoro-1H-indol-1-yl)acetic acid isomer X

Step 1

5-Bromo-6-fluoro-1H-indole (500 mg) was dissolved in DMF (7.79 mL). Cesium carbonate (1.67 g) and ethyl 2-chloroacetate (573 mg) were added thereto at room temperature, and then stirred at 90° C. for 16 hours. The reaction was terminated with a saturated aqueous ammonium chloride solution. Ethyl acetate was added, and the mixture was washed with water and saturated brine in sequence, and dried over anhydrous sodium sulfate. Thereafter, the solvent was distilled off. The residue was purified by silica gel column chromatography (mobile phase: hexane/ethyl acetate) to obtain ethyl 2-(5-bromo-6-fluoro-indol-1-yl)acetate.

Step 2

3-(4-Cyano-3-fluoro-phenyl)-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzoic acid (2 g) obtained in Step 2 of Example 41 and tert-butyl ((1S,2S,4R)-rel-7-azabicyclo[2.2.1]hept-2-yl)carbamate-isomer-X (1.24 g) obtained in Step 2 of Example 202 were dissolved in THF (21.8 mL). TEA (1.52 mL) and HATU (2.28 g) were added thereto at room temperature, followed by stirring at 50°C for 1 hour. The reaction solution was concentrated in vacuo, and the residue was purified by silica gel column chromatography (mobile phase: hexane/ethyl acetate) to give tert-butyl ((1S,2S,4R)-rel-7-(4'-cyano-3'-fluoro-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-[1,1'-biphenyl]-3-carbonyl)-7-azabicyclo[2.2.1]hept-2-yl)carbamate-isomer-X.

Step 3

Tert-butyl ((1S,2S,4R)-rel-7-(4'-cyano-3'-fluoro-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-[1,1'-biphenyl]-3-carbonyl)-7-azabicyclo[2.2.1]hept-2-yl)carbamate-isomer-X (100 mg) obtained in the above step 2 and ethyl 2-(5-bromo-6-fluoro-indol-1-yl)acetate (69.5 mg) obtained in the above step 1 were suspended in 1,4-dioxane (0.59 mL). Pd(dba) ₂ (8.2 mg), X-phos (13.6 mg), and tripotassium phosphate (113 mg) were added thereto at room temperature, followed by degassing and replacement with nitrogen. Under a nitrogen atmosphere, the mixture was stirred at an external temperature of 100° C. overnight. The solvent was evaporated and the residue was purified by silica gel column chromatography (mobile phase: chloroform/methanol). The residue was dissolved in MeOH (1.0 mL), 5N sodium hydroxide aqueous solution (1.0 mL) was added, and then stirred for 1 hour. MTBE was added and the aqueous layer was extracted. The aqueous layer was acidified with hydrochloric acid, MTBE was added thereto, and the resulting mixture was washed with water and saturated brine in sequence. After the organic layer was dried over anhydrous sodium sulfate, the solvent was evaporated to obtain 2-(5-(5-((1S,2S,4R)-rel-2-((tert-butoxycarbonyl)amino)-7-azabicyclo[2.2.1]heptane-7-carbonyl)-4'-cyano-3'-fluoro-[1,1'-biphenyl]-2-yl-6-fluoro-1H-indol-1-yl)acetic acid-isomer-X

Step 4

Acetonitrile (1.0 mL) and 4N hydrochloric acid-1,4-dioxane solution (1.0 mL) were added to 2-(5-(5-((1S,2S,4R)-rel-2-((tert-butoxycarbonyl)amino)-7-azabicyclo[2.2.1]heptane-7-carbonyl)-4'-cyano-3'-fluoro-[1,1'-biphenyl]-2-yl-6-fluoro-1H-indol-1-yl)acetic acid-isomer-X (10 mg) obtained in the above step 3, followed by stirring for 30 minutes. The solvent was distilled off, and the residue was purified by reverse phase HPLC (mobile phase: water/acetonitrile) to obtain the title compound.

Example 208: 2-(4'-((1S,2S,4R)-rel-2-amino-7-azabicyclo[2.2.1]heptane-7-carbonyl)- Synthesis of 4"-cyano-2,3"-difluoro-[1,1':2',1"-terphenyl]-4-yl)acetic acid-isomer-X

The procedures of Steps 3-4 of Example 207 were repeated using methyl 2-(4-bromo-3-fluorophenyl)acetate instead of ethyl 2-(5-bromo-6-fluoro-indol-1-yl)acetate to give the title compound.

Example 209: 5'-((1S,2S,4R)-rel-2-amino-7-azabicyclo[2.2.1]heptane-7-carbonyl)-2'- (7-Chloro-6-fluoro-1-(2-hydroxy-2-methylpropyl)-1H-benzo[d][1,2,3]triazol-5-yl)-3-fluoro-[1,1'-biphenyl Synthesis of [4-[(2-Methyl]-4-carbonitrile-Isomer-X]]

Step 1

2-Chloro-1,3-difluoro-4-nitro-benzene (1 g) was dissolved in THF (12.9 mL). TEA (1.08 mL) and 1-amino-2-methyl-propan-2-ol (0.59 mL) were added, followed by stirring at room temperature for 1 hour. Ethyl acetate was added, and the mixture was washed sequentially with water and saturated brine. The organic layer was dried over anhydrous sodium sulfate, and the solvent was evaporated to obtain 1-(2-chloro-3-fluoro-6-nitro-anilino)-2-methyl-propan-2-ol.

Step 2

1-(2-chloro-3-fluoro-6-nitro-anilino)-2-methyl-propan-2-ol (1.3 g) obtained in step 1 above was dissolved in DMF (9.9 mL). N-bromosuccinimide (1.1 g) was added thereto at room temperature, followed by stirring at 90°C for 1 hour. Ethyl acetate was added, and the mixture was washed sequentially with water and saturated brine, and dried over anhydrous sodium sulfate. Thereafter, the solvent was distilled off. The residue was crystallized from IPE:hexane = 1:1 and washed twice with hexane to obtain 1-(4-bromo-2-chloro-3-fluoro-6-nitro-anilino)-2-methyl-propan-2-ol.

Step 3

1-(4-Bromo-2-chloro-3-fluoro-6-nitro-anilino)-2-methyl-propan-2-ol (1.6 g), _NH₄Cl (1.6 g), and iron (0.8 g) obtained in Step 2 above were suspended in EtOH (7.81 mL) and water (7.81 mL), followed by stirring at 60°C overnight. MTBE was added, and the mixture was passed through Celite. MTBE was added, and the mixture was washed sequentially with water and saturated brine, and dried over anhydrous sodium sulfate. The solvent was then evaporated to yield 1-(6-amino-4-bromo-2-chloro-3-fluoro-anilino)-2-methyl-propan-2-ol.

Step 4

1-(6-Amino-4-bromo-2-chloro-3-fluoro-anilino)-2-methyl-propan-2-ol (352 mg) obtained in Step 3 above was dissolved in water (0.70 mL) and THF (1.76 mL). 12N hydrochloric acid (1.06 mL) and sodium nitrite (aqueous solution (0.3 mL) containing 101 mg of sodium nitrite) were added dropwise at 0°C, followed by stirring at room temperature for 1 hour. MTBE was added, and the mixture was washed sequentially with water and saturated brine, then dried over anhydrous sodium sulfate. The solvent was then evaporated. IPE:hexane = 1:1 (68 mL) was added to the residue, and the target compound was collected by filtration and washed with IPE:hexane = 1:1 to obtain 1-(5-bromo-7-chloro-6-fluoro-benzotriazol-1-yl)-2-methyl-propan-2-ol.

Step 5

Tert-butyl ((1S,2S,4R)-rel-7-(4'-cyano-3'-fluoro-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-[1,1'-biphenyl]-3-carbonyl)-7-azabicyclo[2.2.1]hept-2-yl)carbamate-isomer-X (50 mg) obtained in Step 2 of Example 207 and 1-(5-bromo-7-chloro-6-fluoro-benzotriazol-1-yl)-2-methyl-propan-2-ol (37.4 mg) obtained in Step 4 above were suspended in 1,4-dioxane (0.3 mL). Pd(dba) ₂ (4.1 mg), X-phos (6.8 mg), and tripotassium phosphate (56.7 mg) were added thereto at room temperature. After nitrogen substitution, the mixture was stirred at 100° C. for 2 hours. Ethyl acetate was added, and the mixture was placed on NH-silica gel and washed with ethyl acetate:methanol = 10:1. The solvent was evaporated, and acetonitrile (1.0 mL) and 4N hydrochloric acid-1,4-dioxane solution (1.0 mL) were added to the residue, followed by stirring for 10 minutes. The solvent was evaporated, and the residue was dissolved in DMSO and purified by reverse-phase HPLC (mobile phase: water/acetonitrile) to obtain the title compound.

Example 210: (S)-5'-(3-aminopyrrolidine-1-carbonyl)-2'-(7-chloro-6-fluoro-1-(2-hydroxy-2-methyl)- Synthesis of (1,1'-biphenyl)-4-[(1,2,3'-propyl)-1H-benzo[d][1,2,3]triazol-5-yl]-3-fluoro-[1,1'-biphenyl]carbonitrile

The procedures of Steps 1 to 5 of Example 209 were repeated using tert-butyl N-[(3S)-1-[3-(4-cyano-3-fluoro-phenyl)-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzoyl]pyrrolidin-3-yl]carbamate obtained in Step 1 of Example 37 instead of tert-butyl ((1S,2S,4R)-rel-7-(4'-cyano-3'-fluoro-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-[1,1'-biphenyl]-3-carbonyl)-7-azabicyclo[2.2.1]hept-2-yl)carbamate-isomer-X to give the title compound.

Example 211: 5'-((3-endo)-3-amino-8-azabicyclo[3.2.1]octane-8-carbonyl)-2'-(7-chloro- 6-fluoro-1-(2-hydroxy-2-methylpropyl)-1H-benzo[d][1,2,3]triazol-5-yl)-3-fluoro-[1,1'-biphenyl]-4- Synthesis of Formonitrile

The procedures of Steps 1 to 5 of Example 209 were repeated using tert-butyl N-[(3-endo)-8-[3-(4-cyano-3-fluoro-phenyl)-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzoyl]-8-azabicyclo[3.2.1]oct-3-yl]carbamate obtained in Step 3 of Example 41 instead of tert-butyl ((1S,2S,4R)-rel-7-(4'-cyano-3'-fluoro-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-[1,1'-biphenyl]-3-carbonyl)-7-azabicyclo[2.2.1]hept-2-yl)carbamate-isomer-X to give the title compound.

Example 212: 5-(5-((1S,2S,4R)-rel-2-amino-7-azabicyclo[2.2.1]heptane-7-carbonyl)- 4'-cyano-3'-fluoro-[1,1'-biphenyl]-2-yl)-6-fluoro-1-(2-hydroxy-2-methylpropyl)-1H-indazole-3-carboxylic acid Synthesis of Isomer-X

Step 1

3-(4-Cyano-3-fluoro-phenyl)-4-[6-fluoro-1-(2-hydroxy-2-methyl-propyl)indazol-5-yl]benzoic acid (250 mg) obtained in Step 1 of Example 176 was dissolved in THF (2.24 mL). HATU (234 mg), tert-butyl ((1S,2S,4R)-rel-7-azabicyclo[2.2.1]hept-2-yl)carbamate-isomer-X (125 mg) obtained in Step 2 of Example 202, and TEA (0.156 mL) were added at room temperature, followed by stirring at 50°C for 1 hour. The solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (mobile phase: chloroform/methanol) to give tert-butyl ((1S,2S,4R)-rel-7-(4'-cyano-3'-fluoro-6-(6-fluoro-1-(2-hydroxy-2-methylpropyl)-1H-indazol-5-yl)-[1,1'-biphenyl]-3-carbonyl)-7-azabicyclo[2.2.1]hept-2-yl)carbamate-isomer-X.

Step 2

Tert-butyl ((1S,2S,4R)-rel-7-(4'-cyano-3'-fluoro-6-(6-fluoro-1-(2-hydroxy-2-methylpropyl)-1H-indazol-5-yl)-[1,1'-biphenyl]-3-carbonyl)-7-azabicyclo[2.2.1]hept-2-yl)carbamate-isomer-X (289 mg) obtained in step 1 above was dissolved in DMF (4.50 mL). NBS (120 mg) was added thereto at room temperature, followed by stirring at room temperature for 1 hour. Ethyl acetate was added thereto, and the mixture was washed sequentially with water and saturated brine. After drying the organic layer over anhydrous sodium sulfate, the solvent was evaporated. The residue was purified by silica gel column chromatography (mobile phase: hexane/ethyl acetate) to give tert-butyl ((1S,2S,4R)-rel-7-(6-(3-bromo-6-fluoro-1-(2-hydroxy-2-methylpropyl)-1H-indazol-5-yl)-4'-cyano-3'-fluoro-[1,1'-biphenyl]-3-carbonyl)-7-azabicyclo[2.2.1]hept-2-yl)carbamate-isomer-X.

Step 3

Tert-butyl ((1S,2S,4R)-rel-7-(6-(3-bromo-6-fluoro-1-(2-hydroxy-2-methylpropyl)-1H-indazol-5-yl)-4'-cyano-3'-fluoro-[1,1'-biphenyl]-3-carbonyl)-7-azabicyclo[2.2.1]hept _{-2-yl)carbamate-isomer-X (50 mg) and PdCl₂(PPh₃)₂ ( 2.4} mg) obtained in Step 2 above were suspended in 1-methyl-2-pyrrolidone (0.5 mL). N,N-dimethylethanolamine (0.046 mL) was added thereto at room temperature, and after CO₂ replacement, the mixture was stirred at 125°C for 1 hour. To the reaction solution were added tert-butanol (0.5 mL) and a 2N aqueous sodium hydroxide solution (0.25 mL), and stirred at room temperature for 1 hour. MTBE was added thereto and the aqueous layer was separated. The aqueous layer was acidified with hydrochloric acid and extracted with MTBE. After drying the organic layer over anhydrous sodium sulfate, the solvent was evaporated. Acetonitrile (0.5 mL) and 4N hydrochloric acid-1,4-dioxane solution (0.5 mL) were added to the residue, followed by stirring for 10 minutes. The reaction solution was concentrated and the residue was purified by reverse phase HPLC (mobile phase: water/acetonitrile) to obtain the title compound.

Example 213: 5'-((1S,2S,4R)-rel-2-amino-7-azabicyclo[2.2.1]heptane-7-carbonyl)-2'- (7-Chloro-6-fluoro-1-(2-hydroxy-2-methylpropyl)-1H-benzo[d][1,2,3]triazol-5-yl-3-fluoro-[1,1'-biphenyl Synthesis of [4-Methyl]-4-carbonitrile

Step 1

3-(4-Cyano-3-fluoro-phenyl)-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzoic acid (500 mg) obtained in Step 2 of Example 41 and tert-butyl ((1S,2S,4R)-rel-7-azabicyclo[2.2.1]hept-2-yl)carbamate hydrochloride (303.5 mg) were dissolved in THF (5.45 mL). TEA (0.379 mL) and (569.5 mg) were added at room temperature, followed by stirring at 50°C for 1 hour. The reaction solution was concentrated in vacuo, and the residue was purified by silica gel column chromatography (mobile phase: hexane/ethyl acetate) to give tert-butyl ((1S,2S,4R)-rel-7-(4'-cyano-3'-fluoro-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-[1,1'-biphenyl]-3-carbonyl)-7-azabicyclo[2.2.1]hept-2-yl)carbamate.

Step 2

The procedures of Steps 1 to 5 of Example 209 were repeated using tert-butyl ((1S,2S,4R)-rel-7-(4'-cyano-3'-fluoro-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-[1,1'-biphenyl]-3-carbonyl)-7-azabicyclo[2.2.1]hept-2-yl)carbamate obtained in Step 1 above instead of tert-butyl ((1S,2S,4R)-rel-7-(4'-cyano-3'-fluoro-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-[1,1'-biphenyl]-3-carbonyl)-7-azabicyclo[2.2.1]hept-2-yl)carbamate-isomer-X to give the title compound.

Example 214: 5'-((1S,2S,4R)-rel-2-amino-7-azabicyclo[2.2.1]heptane-7-carbonyl)-2'- (1-(2-ethyl-2-hydroxybutyl)-6,7-difluoro-1H-benzo[d][1,2,3]triazol-5-yl)-3-fluoro-[1,1'-biphenyl Synthesis of [4-[(2-Methyl]-4-carbonitrile-Isomer-X]]

3-[(2,3-difluoro-6-nitro-anilino)methyl]pentan-3-ol was used instead of 1-(2,3-difluoro-6-nitro-anilino)-2-methyl-propan-2-ol, and ((1S,2S,4R)-rel-7-(4'-cyano-3'-fluoro-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-[1,1'-biphenyl]-3-carbonyl)-1-[[[[[[[[[[[[[[[[[[[[[[[[[[[[[[[[[[[[[[[[[[[[[[[[[[[[[[[[[[[[[[[[[[[[[[[[[[[[[[[[[[[[[[[[[[[[[[[[[[[[[[[[[[[[[[[[[[[[[[[[[[[[ The procedures of Steps 1 to 5 of Example 161 were repeated to give the title compound by replacing tert-butyl N-[(3-endo)-8-[3-(4-cyano-3-fluoro-phenyl)-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzoyl]-8-azabicyclo[3.2.1]oct-3-yl]carbamate with tert-butyl)-7-azabicyclo[2.2.1]hept-2-yl)carbamate-isomer-X.

Example 215: (S)-5'-(3-aminopyrrolidine-1-carbonyl)-2'-(1-(2-ethyl-2-hydroxybutyl)-6,7- Synthesis of difluoro-1H-benzo[d][1,2,3]triazol-5-yl)-3-fluoro-[1,1'-biphenyl]-4-carbonitrile

3-[(2,3-difluoro-6-nitro-anilino)methyl]pentan-3-ol was used instead of 1-(2,3-difluoro-6-nitro-anilino)-2-methyl-propan-2-ol, and N-[(3S)-1-[3-(4-cyano-3-fluoro-phenyl)-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzyl] The procedures of Steps 1 to 5 of Example 161 were repeated using tert-butyl N-[(3-endo)-8-[3-(4-cyano-3-fluoro-phenyl)-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzoyl]-8-azabicyclo[3.2.1]oct-3-yl]carbamate to give the title compound.

Example 216: 5'-((3-endo)-3-amino-8-azabicyclo[3.2.1]octane-8-carbonyl)-2'-(1-(2- ethyl-2-hydroxybutyl)-6,7-difluoro-1H-benzo[d][1,2,3]triazol-5-yl)-3-fluoro-[1,1'-biphenyl]-4-carboxylic Synthesis of Nitriles

The procedures of Steps 1 to 5 of Example 161 were repeated using 3-[(2,3-difluoro-6-nitro-anilino)methyl]pentan-3-ol instead of 1-(2,3-difluoro-6-nitro-anilino)-2-methyl-propan-2-ol to give the title compound.

Example 217: 5'-((1S,2S,4R)-rel-2-amino-7-azabicyclo[2.2.1]heptane-7-carbonyl)-2'- (1-(2-ethyl-2-hydroxybutyl)-6,7-difluoro-1H-benzo[d][1,2,3]triazol-5-yl)-3-fluoro-[1,1'-biphenyl Synthesis of [4-Methyl]-4-carbonitrile

3-[(2,3-difluoro-6-nitro-anilino)methyl]pentan-3-ol was used instead of 1-(2,3-difluoro-6-nitro-anilino)-2-methyl-propan-2-ol, and ((1S,2S,4R)-rel-7-(4'-cyano-3'-fluoro-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-[1,1'-biphenyl]- The procedures of Steps 1 to 5 of Example 161 were repeated using tert-butyl N-[(3-endo)-8-[3-(4-cyano-3-fluoro-phenyl)-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzoyl]-8-azabicyclo[3.2.1]oct-3-yl]carbamate to give the title compound.

Example 218: 5'-((1S,2S,4R)-rel-2-amino-7-azabicyclo[2.2.1]heptane-7-carbonyl)-2'- (7-Chloro-1-(2-ethyl-2-hydroxybutyl)-6-fluoro-1H-benzo[d][1,2,3]triazol-5-yl)-3-fluoro-[1,1'-biphenyl Synthesis of [4-[(2-Methyl]-4-carbonitrile-Isomer-X]]

The procedures of Steps 1 to 5 of Example 209 were repeated using 3-(aminomethyl)pentan-3-ol instead of 1-amino-2-methyl-propan-2-ol to give the title compound.

Example 219: (S)-5'-(3-aminopyrrolidine-1-carbonyl)-2'-(7-chloro-1-(2-ethyl-2-hydroxybutyryl)-1-yl)-2-nitro-1-nitro-1-nitro-2 ... Synthesis of 6-fluoro-1H-benzo[d][1,2,3]triazol-5-yl)-3-fluoro-[1,1'-biphenyl]-4-carbonitrile

The procedures of Steps 1 to 5 of Example 209 were repeated using 3-(aminomethyl)pentan-3-ol instead of 1-amino-2-methyl-propan-2-ol and tert-butyl N-[(3S)-1-[3-(4-cyano-3-fluoro-phenyl)-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzoyl]pyrrolidin-3-yl]carbamate obtained in Step 1 of Example 37 instead of tert-butyl ((1S,2S,4R)-rel-7-(4'-cyano-3'-fluoro-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-[1,1'-biphenyl]-3-carbonyl)-7-azabicyclo[2.2.1]hept-2-yl)carbamate-isomer-X to give the title compound.

Example 220: 5'-((3-endo)-3-amino-8-azabicyclo[3.2.1]octane-8-carbonyl)-2'-(7-chloro- 1-(2-Ethyl-2-hydroxybutyl)-6-fluoro-1H-benzo[d][1,2,3]triazol-5-yl)-3-fluoro-[1,1'-biphenyl]-4- Synthesis of Formonitrile

1-Amino-2-methyl-propan-2-ol was replaced with 3-(aminomethyl)pentan-3-ol, and tert-butyl N-[(3-endo)-8-[3-(4-cyano-3-fluoro-phenyl)-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzoyl]-8-azabicyclo[3.2.1]oct-3-yl]carbamate obtained in step 3 of Example 41 was used. The procedures of Steps 1 to 5 of Example 209 were repeated to give the title compound by replacing tert-butyl ((1S,2S,4R)-rel-7-(4'-cyano-3'-fluoro-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-[1,1'-biphenyl]-3-carbonyl)-7-azabicyclo[2.2.1]hept-2-yl)carbamate-isomer-X.

Example 221: 5'-((1S,2S,4R)-rel-2-amino-7-azabicyclo[2.2.1]heptane-7-carbonyl)-2'- (7-Chloro-1-(2-ethyl-2-hydroxybutyl)-6-fluoro-1H-benzo[d][1,2,3]triazol-5-yl)-3-fluoro-[1,1'-biphenyl Synthesis of [4-Methyl]-4-carbonitrile

3-(Aminomethyl)pentan-3-ol was used instead of 1-amino-2-methyl-propan-2-ol, and ((1S,2S,4R)-rel-7-(4'-cyano-3'-fluoro-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-[1,1'-biphenyl]-3-carbonyl)-7-azabicyclo[2.2.1]hept-2-yl) obtained in Step 1 of Example 213 was used. The procedures of Steps 1 to 5 of Example 209 were repeated using tert-butyl carbamate instead of ((1S,2S,4R)-rel-7-(4'-cyano-3'-fluoro-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-[1,1'-biphenyl]-3-carbonyl)-7-azabicyclo[2.2.1]hept-2-yl)carbamate-isomer-X to give the title compound.

Example 222: 5-(5-((1S,2S,4R)-rel-2-amino-7-azabicyclo[2.2.1]heptane-7-carbonyl)- 4'-cyano-3'-fluoro-[1,1'-biphenyl]-2-yl)-6-fluoro-1-(2-hydroxy-2-methylpropyl)-1H-indole-3-carboxylic acid Synthesis of Isomer-X

Step 1

3-(4-Cyano-3-fluoro-phenyl)-4-[6-fluoro-1-(2-hydroxy-2-methyl-propyl)indol-5-yl]benzoic acid (250 mg) obtained in Step 1 of Example 171 was dissolved in THF (2.24 mL). HATU (234 mg), tert-butyl ((1S,2S,4R)-rel-7-azabicyclo[2.2.1]hept-2-yl)carbamate-isomer-X (125 mg) obtained in Step 2 of Example 202, and TEA (0.156 mL) were added at room temperature, followed by stirring at 50°C for 1 hour. The solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (mobile phase: chloroform/methanol) to give tert-butyl ((1S,2S,4R)-rel-7-(4'-cyano-3'-fluoro-6-(6-fluoro-1-(2-hydroxy-2-methylpropyl)-1H-indol-5-yl)-[1,1'-biphenyl]-3-carbonyl)-7-azabicyclo[2.2.1]hept-2-yl)carbamate-isomer-X.

Step 2

Tert-butyl ((1S,2S,4R)-rel-7-(4'-cyano-3'-fluoro-6-(6-fluoro-1-(2-hydroxy-2-methylpropyl)-1H-indol-5-yl)-[1,1'-biphenyl]-3-carbonyl)-7-azabicyclo[2.2.1]hept-2-yl)carbamate-isomer-X (289 mg) obtained in step 1 above was dissolved in DMF (4.50 mL). N-iodosuccinimide (120 mg) was added thereto at room temperature, followed by stirring at room temperature for 1 hour. Ethyl acetate was added, and the mixture was washed sequentially with water and saturated brine. After drying the organic layer over anhydrous sodium sulfate, the solvent was evaporated. The residue was purified by silica gel column chromatography (mobile phase: hexane/ethyl acetate) to give tert-butyl ((1S,2S,4R)-rel-7-(4'-cyano-3'-fluoro-6-(6-fluoro-1-(2-hydroxy-2-methylpropyl)-3-iodo-1H-indol-5-yl)-[1,1'-biphenyl]-3-carbonyl)-7-azabicyclo[2.2.1]hept-2-yl)carbamate-isomer-X.

Step 3

Tert-butyl ((1S,2S,4R)-rel-7-(4'-cyano-3'-fluoro-6-(6-fluoro-1-(2-hydroxy-2-methylpropyl)-3-iodo-1H-indol-5-yl)-[1,1'-biphenyl]-3-carbonyl)-7-azabicyclo[2.2.1]hept-2-yl)carbamate-isomer-X (20 mg) and Pd(PPh ₃ ) ₄ (0.92 mg) obtained in Step 2 above were suspended in 1-methyl-2-pyrrolidone (0.2 mL). N,N-diethylethanolamine (0.0173 mL) was added thereto at room temperature, and after CO purging, the mixture was stirred at 100°C for 1 hour. Tert-butanol (0.2 mL) and a 2N aqueous sodium hydroxide solution (0.2 mL) were added to the reaction solution, followed by stirring at room temperature overnight. MTBE was added, and the aqueous layer was separated. The aqueous layer was acidified with hydrochloric acid and extracted with MTBE. The organic layer was dried over anhydrous sodium sulfate and the solvent was evaporated. Acetonitrile (0.5 mL) and 4N hydrochloric acid-1,4-dioxane solution (0.5 mL) were added to the residue, followed by stirring for 10 minutes. The reaction solution was concentrated, and the residue was purified by reverse-phase HPLC (mobile phase: water/acetonitrile) to obtain the title compound.

Example 223: 5-(5-((1S,2S,4R)-rel-2-amino-7-azabicyclo[2.2.1]heptane-7-carbonyl)- Synthesis of 4'-cyano-3'-fluoro-[1,1'-biphenyl]-2-yl)-6-fluoro-1-methyl-1H-indazole-3-carboxylic acid isomer X

Step 1

Tert-butyl ((1S,2S,4R)-rel-7-(4'-cyano-3'-fluoro-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-[1,1'-biphenyl]-3-carbonyl)-7-azabicyclo[2.2.1]hept-2-yl)carbamate-isomer-X (350 mg) and 5-bromo-6-fluoro-1-methyl-indazole (186 mg) were suspended in 1,4-dioxane (2.08 mL). Pd(dba) ₂ (28.7 mg), X-phos (47.6 mg), and tripotassium phosphate (397 mg) were added at room temperature, followed by degassing and replacement with nitrogen. Under a nitrogen atmosphere, the mixture was stirred at an external temperature of 100°C overnight. The solvent was evaporated, and the residue was purified by silica gel column chromatography (mobile phase: chloroform/methanol) to give tert-butyl ((1S,2S,4R)-rel-7-(4'-cyano-3'-fluoro-6-(6-fluoro-1-methyl-1H-indazol-5-yl)-[1,1'-biphenyl]-3-carbonyl)-7-azabicyclo[2.2.1]hept-2-yl)carbamate-isomer-X.

Step 2

The procedures of Steps 2-3 of Example 212 were repeated using tert-butyl ((1S,2S,4R)-rel-7-(4'-cyano-3'-fluoro-6-(6-fluoro-1-methyl-1H-indazol-5-yl)-[1,1'-biphenyl]-3-carbonyl)-7-azabicyclo[2.2.1]hept-2-yl)carbamate-isomer-X obtained in Step 1 above instead of tert-butyl ((1S,2S,4R)-rel-7-(4'-cyano-3'-fluoro-6-(6-fluoro-1-(2-hydroxy-2-methylpropyl)-1H-indazol-5-yl)-[1,1'-biphenyl]-3-carbonyl)-7-azabicyclo[2.2.1]hept-2-yl)carbamate-isomer-X to give the title compound.

Example 224: 5-(5-((1S,2S,4R)-rel-2-amino-7-azabicyclo[2.2.1]heptane-7-carbonyl)- Synthesis of 4'-cyano-3'-fluoro-[1,1'-biphenyl]-2-yl)-6-fluoro-1-methyl-1H-indole-3-carboxylic acid isomer X

Step 1

Tert-butyl ((1S,2S,4R)-rel-7-(4'-cyano-3'-fluoro-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-[1,1'-biphenyl]-3-carbonyl)-7-azabicyclo[2.2.1]hept-2-yl)carbamate-isomer-X (350 mg) and 5-bromo-6-fluoro-1-methyl-indole (185 mg) were suspended in 1,4-dioxane (2.08 mL). Pd(dba) ₂ (28.7 mg), X-phos (47.6 mg), and tripotassium phosphate (397 mg) were added at room temperature, followed by degassing and replacement with nitrogen. Under a nitrogen atmosphere, the mixture was stirred at an external temperature of 100°C overnight. The solvent was evaporated, and the residue was purified by silica gel column chromatography (mobile phase: chloroform/methanol) to obtain tert-butyl ((1S,2S,4R)-rel-7-(4'-cyano-3'-fluoro-6-(6-fluoro-1-methyl-1H-indol-5-yl)-[1,1'-biphenyl]-3-carbonyl)-7-azabicyclo[2.2.1]hept-2-ylcarbamate-isomer-X.

Step 2

Tert-butyl ((1S,2S,4R)-rel-7-(4'-cyano-3'-fluoro-6-(6-fluoro-1-methyl-1H-indol-5-yl)-[1,1'-biphenyl]-3-carbonyl)-7-azabicyclo[2.2.1]hept-2-ylcarbamate-isomer-X (209 mg) obtained in the above step 1 was dissolved in DMF (3.6 mL). N-iodosuccinimide (121 mg) was added thereto at room temperature, followed by stirring at room temperature for 1 hour. Ethyl acetate was added. Ester, and the resulting mixture was washed with water and saturated brine in sequence. After drying the organic layer over anhydrous sodium sulfate, the solvent was distilled off. The residue was purified by silica gel column chromatography (mobile phase: hexane/ethyl acetate) to obtain ((1S,2S,4R)-rel-7-(4'-cyano-3'-fluoro-6-(6-fluoro-3-iodo-1-methyl-1H-indol-5-yl)-[1,1'-biphenyl]-3-carbonyl)-7-azabicyclo[2.2.1]hept-2-yl)carbamic acid tert-butyl ester-isomer-X.

Step 3

Tert-butyl ((1S,2S,4R)-rel-7-(4'-cyano-3'-fluoro-6-(6-fluoro-3-iodo-1-methyl-1H-indol-5-yl)-[1,1'-biphenyl]-3-carbonyl)-7-azabicyclo[2.2.1]hept-2-yl)carbamate-isomer-X (211 mg) and PdCl₂( _PPh₃ ) _{₂ (} 10.5 mg) obtained in Step 2 above were suspended in 1-methyl-2-pyrrolidone (2.11 mL). N,N-diethylethanolamine (0.197 mL) was added at room temperature. After CO₃ replacement, the mixture was stirred at 100°C for 1 hour. Tert-butanol (0.2 mL) and 2N aqueous sodium hydroxide solution (0.2 mL) were added to the reaction solution, and the resulting mixture was stirred at room temperature overnight. MTBE was added, and the aqueous layer was separated. The aqueous layer was acidified with hydrochloric acid and extracted with MTBE. The organic layer was dried over anhydrous sodium sulfate, and the solvent was evaporated to obtain 5-(5-((1S,2S,4R)-rel-2-((tert-butoxycarbonyl)amino)-7-azabicyclo[2.2.1]heptane-7-carbonyl)-4'-cyano-3'-fluoro-[1,1'-biphenyl]-2-yl)-6-fluoro-1-methyl-1H-indole-3-carboxylic acid isomer X.

Step 4

Acetonitrile (0.5 mL) and a 4N hydrochloric acid-1,4-dioxane solution (0.5 mL) were added to 5-(5-((1S,2S,4R)-rel-2-((tert-butoxycarbonyl)amino)-7-azabicyclo[2.2.1]heptane-7-carbonyl)-4'-cyano-3'-fluoro-[1,1'-biphenyl]-2-yl)-6-fluoro-1-methyl-1H-indole-3-carboxylic acid isomer-X (10 mg) obtained in Example 3 above, followed by stirring for 10 minutes. The reaction solution was concentrated, and the residue was purified by reverse phase HPLC (mobile phase: water/acetonitrile) to obtain the title compound.

Example 225: 5'-((1S,2S,4R)-rel-2-amino-7-azabicyclo[2.2.1]heptane-7-carbonyl)-2'- Synthesis of (1-(2-ethyl-2-hydroxybutyl)-6-fluoro-1H-indazol-5-yl)-3-fluoro-[1,1'-biphenyl]-4-carbonitrile

Tert-butyl ((1S,2S,4R)-rel-7-(4'-cyano-3'-fluoro-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-[1,1'-biphenyl]-3-carbonyl)-7-azabicyclo[2.2.1]hept-2-yl)carbamate (40 mg) obtained in Step 1 of Example 213 and 3-[(5-bromo-6-fluoro-indazol-1-yl)methyl]pentan-3-ol (29.2 mg) obtained in Step 1 of Example 204 were suspended in 1,4-dioxane (0.5 mL). Pd(dba) ₂ (3.3 mg), X-phos (5.5 mg), and tripotassium phosphate (45.4 mg) were added at room temperature, followed by stirring at 100°C for 1 hour. The reaction solution was filtered, and the solvent was evaporated. The residue was dissolved in acetonitrile (0.5 mL). 4N hydrochloric acid-1,4-dioxane solution (0.5 mL) was added thereto at room temperature, followed by stirring at room temperature for 5 minutes. The reaction solution was concentrated, and the residue was purified by reverse phase HPLC (mobile phase: water/acetonitrile) to obtain the title compound.

Example 226: 5'-((1S,2S,4R)-rel-2-amino-7-azabicyclo[2.2.1]heptane-7-carbonyl)-3- Fluoro-2'-(6-fluoro-1-(2-hydroxy-2-methylpropyl)-1,3-dihydroisobenzofuran-5-yl)-[1,1'-biphenyl]-4-carboxylic Synthesis of Nitrile-Isomer-X

Step 1

5-Bromo-4-fluoro-2-iodo-benzoic acid methyl ester (2 g) was dissolved in diethyl ether (55.7 mL). 2.0 M LiBH ₄ in THF (6.13 mL) and MeOH (0.56 mL) were added thereto at 0° C., followed by stirring at 0° C. for 1 hour. MTBE was added, and the mixture was washed with water and saturated brine in sequence, and dried over anhydrous sodium sulfate. Thereafter, the solvent was distilled off. The residue was purified by silica gel column chromatography (mobile phase: hexane/ethyl acetate) to obtain (5-bromo-4-fluoro-2-iodo-phenyl)methanol.

Step 2

(5-Bromo-4-fluoro-2-iodophenyl)methanol (1.39 g) obtained in Step 1 above and 3,4-dihydro-2H-pyran (0.419 mL) were dissolved in _CH₂Cl₂ (8.4 _mL ). Pyridinium p-toluenesulfonate (106 mg) was added at room temperature, followed by stirring overnight at room temperature. Ethyl acetate was added, and the mixture was washed sequentially with water and saturated brine, and dried over anhydrous sodium sulfate. The solvent was then evaporated. The residue was purified by silica gel column chromatography (mobile phase: hexane/ethyl acetate) to obtain 2-[(5-bromo-4-fluoro-2-iodophenyl)methoxy]tetrahydropyran.

Step 3

2-[(5-Bromo-4-fluoro-2-iodo-phenyl)methoxy]tetrahydropyran (1.5 g), _PdCl₂ ( _PPh₃ ) _₂ (130 mg), and CuI (34 mg) obtained in Step 2 above were suspended in THF (18 mL). TEA (18 mL) and 2-methyl-3-butyn-2-ol (0.42 mL) were added at room temperature, followed by stirring at room temperature for 4 hours. The reaction solution was filtered, and the solvent was evaporated. The residue was purified by silica gel column chromatography (mobile phase: hexane/ethyl acetate) to obtain 4-[4-bromo-5-fluoro-2-(tetrahydropyran-2-yloxymethyl)phenyl]-2-methyl-3-butyn-2-ol.

Step 4

Tert-butyl ((1S,2S,4R)-rel-7-(4'-cyano-3'-fluoro-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-[1,1'-biphenyl]-3-carbonyl)-7-azabicyclo[2.2.1]hept-2-yl)carbamate, isomer X (150 mg) obtained in Step 2 of Example 207 and 4-[4-bromo-5-fluoro-2-(tetrahydropyran-2-yloxymethyl)phenyl]-2-methyl-3-butyn-2-ol (129 mg) obtained in Step 3 above were suspended in 1,4-dioxane (0.89 mL). Pd(dba) ₂ (12.3 mg) and X-phos (20.4 mg) were added at room temperature, followed by stirring at 100°C for 1 hour. The reaction solution was filtered, and the solvent was evaporated. The residue was purified by silica gel column chromatography (mobile phase: hexane/ethyl acetate). The residue was dissolved in THF (0.92 mL) and water (0.46 mL). p-Toluenesulfonic acid monohydrate (6.9 mg) was added at room temperature, followed by stirring at 70°C for 1 hour. Ethyl acetate was added, and the mixture was washed sequentially with water and saturated brine, and dried over anhydrous sodium sulfate. The solvent was then evaporated. The residue was purified by silica gel column chromatography (mobile phase: hexane/ethyl acetate) to obtain tert-butyl ((1S,2S,4R)-rel-7-(4"-cyano-2,3"-difluoro-4-(3-hydroxy-3-methyl-1-butyn-1-yl)-5-(hydroxymethyl)-[1,1':2',1"-terphenyl]-4'-carbonyl-7-azabicyclo[2.2.1]hept-2-yl)carbamate-isomer X.

Step 5

Tert-butyl ((1S,2S,4R)-rel-7-(4″-cyano-2,3″-difluoro-4-(3-hydroxy-3-methyl-1-butyn-1-yl)-5-(hydroxymethyl)-[1,1′:2′,1″-terphenyl]-4′-carbonyl-7-azabicyclo[2.2.1]hept-2-yl)carbamate-isomer-X (30 mg) obtained in the above step 4 was dissolved in 1,4-dioxane (0.24 mL). 1.0 M of HCl was added thereto at room temperature. A THF solution of TBAF (0.14 mL) was added, and then stirred at 100°C for 1 hour. EtOH (0.12 mL) and 10% Pd/C (30 mg) were added to the reaction solution. After hydrogen replacement, the mixture was stirred at 70°C for 30 minutes. The reaction solution was filtered and the filtrate was concentrated. The residue was dissolved in THF. TEA (0.013 mL), DMAP (1.1 mg) and Boc ₂ were added thereto at room temperature. O (20.4 mg), and then stirred at 70 ° C for 1 hour. Ethyl acetate was added thereto, and the mixture was washed 5 times with phosphoric acid at a concentration of about 0.5 mol / L, washed with saturated brine, and dried over anhydrous sodium sulfate. Thereafter, the solvent was distilled off. The residue was dissolved in acetonitrile (0.5 mL). At room temperature, 4N hydrochloric acid-1,4-dioxane solution (0.5 mL) was added thereto, and then stirred at room temperature for 5 minutes. After confirming the completion of the reaction by LCMS, the solvent was distilled off. The residue was purified by reverse phase HPLC (mobile phase: water / acetonitrile) to obtain the title compound.

Example 227: 5'-((S)-3-aminopyrrolidine-1-carbonyl)-3-fluoro-2'-(6-fluoro-1-(2-hydroxy-2-methyl) Synthesis of 1,3-dihydroisobenzofuran-5-yl)-[1,1'-biphenyl]-4-carbonitrile

Step 1

Tert-butyl 3-(4-cyano-3-fluoro-phenyl)-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzoate (400 mg) obtained in Step 1 of Example 41 and 4-[4-bromo-5-fluoro-2-(tetrahydropyran-2-yloxymethyl)phenyl]-2-methyl-3-butyn-2-ol (456 mg) obtained in Step 3 of Example 226 were suspended in 1,4-dioxane (3.15 mL). Pd(dba) ₂ (43.5 mg), X-phos (144 mg), and tripotassium phosphate (601 mg) were added at room temperature, followed by stirring at 100°C for 1 hour. The reaction solution was filtered, and the solvent was evaporated. The residue was purified by silica gel column chromatography (mobile phase: chloroform/methanol). The residue was dissolved in THF (1.62 mL). Water (0.81 mL) and p-toluenesulfonic acid monohydrate (12.3 mg) were added at room temperature, followed by stirring at 70°C for 1 hour. Ethyl acetate was added, and the mixture was washed with water and saturated brine in that order and dried over anhydrous sodium sulfate. Thereafter, the solvent was distilled off. The residue was purified by silica gel column chromatography (mobile phase: hexane/ethyl acetate) to obtain tert-butyl 3-(4-cyano-3-fluoro-phenyl)-4-[2-fluoro-5-(hydroxymethyl)-4-(3-hydroxy-3-methyl-1-butenyl)phenyl]benzoate.

Step 2

Tert-butyl 3-(4-cyano-3-fluoro-phenyl)-4-[2-fluoro-5-(hydroxymethyl)-4-(3-hydroxy-3-methyl-1-butenyl)phenyl]benzoate (90 mg) obtained in step 1 above was dissolved in 1,4-dioxane (0.9 mL). A 1.0 M TBAF solution in THF (0.54 mL) was added at room temperature, followed by stirring at 100°C for 2 hours. EtOH (0.30 mL) and 10% Pd/C (90 mg) were added to the reaction solution, and after hydrogen substitution, the mixture was stirred at 70°C overnight. The reaction solution was filtered, and the solvent was evaporated. The residue was purified by silica gel column chromatography (mobile phase: hexane/ethyl acetate). The residue was dissolved in THF (1.0 mL). 12N hydrochloric acid (0.5 mL) was added at room temperature, followed by stirring at room temperature for 1.5 hours. MTBE was added, and the mixture was extracted twice with a 2N aqueous sodium hydroxide solution. The aqueous layer was acidified with 2N hydrochloric acid and extracted twice with MTBE. The organic layer was then washed with saturated brine and dried over anhydrous sodium sulfate. The solvent was evaporated to obtain 3-(4-cyano-3-fluoro-phenyl)-4-[6-fluoro-1-(2-hydroxy-2-methyl-propyl)-1,3-dihydroisobenzofuran-5-yl]benzoic acid.

Step 3

3-(4-Cyano-3-fluoro-phenyl)-4-[6-fluoro-1-(2-hydroxy-2-methyl-propyl)-1,3-dihydroisobenzofuran-5-yl]benzoic acid (10 mg) obtained in Step 2 above was dissolved in THF (0.5 mL). HATU (9.31 mg), tert-butyl N-[(3S)-pyrrolidin-3-yl]carbamate (43.5 mg), and TEA (6.2 μL) were added at room temperature, followed by stirring at 50°C for 1 hour. The solvent was evaporated, and MeOH (0.5 mL) and a 4N hydrochloric acid solution in 1,4-dioxane (0.5 mL) were added, followed by stirring at room temperature for 30 minutes. The solvent was evaporated, and the residue was purified by reverse-phase HPLC (mobile phase: water/acetonitrile) to obtain the title compound.

Example 228: 5'-((1S,2S,4R)-rel-2-amino-7-azabicyclo[2.2.1]heptane-7-carbonyl)-3- Fluoro-2'-(6-fluoro-1-(2-hydroxy-2-methylpropyl)-7-methyl-1H-benzo[d][1,2,3]triazol-5-yl)-[1,1'- Synthesis of [phenyl]-4-carbonitrile-isomer-X

The procedures of Steps 1 to 5 of Example 209 were repeated, substituting 1,3-difluoro-2-methyl-4-nitro-benzene for 2-chloro-1,3-difluoro-4-nitro-benzene, to give the title compound.

Example 229: (S)-5'-(3-aminopyrrolidine-1-carbonyl)-3-fluoro-2'-(5-fluoro-3-(2-hydroxy-2-methyl) Synthesis of (1,1'-biphenyl)-4-[(1,1'-propyl)benzo[d]isoxazol-6-yl]carbonitrile

Step 1

1-(4-Bromo-5-fluoro-2-hydroxyphenyl)ethanone (150 mg) obtained in Step 2 of Example 179 was dissolved in THF (3.2 mL). Lithium diisopropylamide (1.0 M, THF solution) (3.2 mL) was added at -25°C, followed by stirring at -25°C for 1 hour. The mixture was cooled to -40°C, acetone (0.118 mL) was added, and the mixture was stirred at -40°C for 1 hour. After adding aqueous phosphoric acid, ethyl acetate was added, and the mixture was washed sequentially with water and saturated brine. After drying the organic layer over anhydrous sodium sulfate, the solvent was evaporated. The residue was purified by silica gel column chromatography (mobile phase: hexane/ethyl acetate) to obtain 1-(4-bromo-5-fluoro-2-hydroxy-phenyl)-3-hydroxy-3-methyl-butan-1-one.

Step 2

1-(4-Bromo-5-fluoro-2-hydroxy-phenyl)-3-hydroxy-3-methyl-butan-1-one (60 mg), hydroxylamine hydrochloride (28.6 mg), and sodium acetate (25.4 mg) obtained in Step 1 above were dissolved in methanol (0.69 mL) and stirred at 60°C overnight. MTBE was added, and the mixture was washed sequentially with water and saturated brine. The organic layer was dried over anhydrous sodium sulfate, and the solvent was evaporated. The residue was dissolved in THF (0.69 mL), and N,N'-carbonyldiimidazole (36.8 mg) and TEA (0.037 mL) were added, followed by stirring at 70°C for 1 hour. The solvent was evaporated, and the residue was purified by silica gel column chromatography (mobile phase: hexane/ethyl acetate) to obtain 1-(6-bromo-5-fluoro-1,2-benzoxazol-3-yl)-2-methyl-propan-2-ol.

Step 3

The procedures of Steps 1 to 3 of Example 37 were repeated using 1-(6-bromo-5-fluoro-1,2-benzoxazol-3-yl)-2-methyl-propan-2-ol obtained in Step 2 above instead of 1-(4-bromo-3-fluoro-phenyl)-2-methyl-propan-2-ol to give the title compound.

Example 230: 2-(5-(5-((1S,2S,4R)-rel-2-amino-7-azabicyclo[2.2.1]heptane-7-carbonyl Synthesis of 4'-cyano-3'-fluoro-[1,1'-biphenyl]-2-yl)-6-fluoro-1H-indol-1-yl)acetamide

Step 1

Tert-butyl ((1S,2S,4R)-rel-7-(4'-cyano-3'-fluoro-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-[1,1'-biphenyl]-3-carbonyl)-7-azabicyclo[2.2.1]hept-2-yl)carbamate (100 mg) obtained in Step 1 of Example 213 and ethyl 2-(5-bromo-6-fluoro-indol-1-yl)acetate (69.5 mg) obtained in Step 1 of Example 207 were suspended in 1,4-dioxane (0.59 mL). Pd(dba) ₂ (8.2 mg), X-phos (13.6 mg), and tripotassium phosphate (113 mg) were added at room temperature, followed by degassing and replacement with nitrogen. Under a nitrogen atmosphere, the mixture was stirred at an external temperature of 100°C overnight. The solvent was evaporated, and the residue was purified by silica gel column chromatography (mobile phase: chloroform/methanol). The residue was dissolved in MeOH (1.0 mL), and 5N aqueous sodium hydroxide solution (1.0 mL) was added, followed by stirring for 1 hour. MTBE was added, and the aqueous layer was extracted. The aqueous layer was acidified with hydrochloric acid, MTBE was added, and the mixture was washed sequentially with water and saturated brine. The organic layer was dried over anhydrous sodium sulfate, and the solvent was evaporated to obtain 2-(5-(5-((1S,2S,4R)-rel-2-((tert-butoxycarbonyl)amino)-7-azabicyclo[2.2.1]heptane-7-carbonyl)-4'-cyano-3'-fluoro-[1,1'-biphenyl]-2-yl)-6-fluoro-1H-indol-1-yl)acetic acid.

Step 2

2-(5-(5-((1S,2S,4R)-rel-2-((tert-butoxycarbonyl)amino)-7-azabicyclo[2.2.1]heptane-7-carbonyl)-4'-cyano-3'-fluoro-[1,1'-biphenyl]-2-yl)-6-fluoro-1H-indol-1-yl)acetic acid (10 mg) obtained in Step 1 above was dissolved in THF (0.32 mL). N,N'-carbonyldiimidazole (5.2 mg) was then added, and the mixture was stirred at room temperature for 20 minutes. 28% aqueous ammonia (0.06 mL) was added, and the mixture was stirred at room temperature for 20 minutes. The solvent was evaporated, and acetonitrile (0.2 mL) and a 4N hydrochloric acid-1,4-dioxane solution (0.2 mL) were added to the residue, followed by stirring for 30 minutes. The solvent was evaporated and the residue was purified by reverse phase HPLC (mobile phase: water/acetonitrile) to give the title compound.

Example 231: 2-(5-(5-((1S,2S,4R)-rel-2-amino-7-azabicyclo[2.2.1]heptane-7-carbonyl Synthesis of 4'-cyano-3'-fluoro-[1,1'-biphenyl]-2-yl)-6-fluoro-1H-indol-1-yl)-N-methylacetamide

2-(5-(5-((1S,2S,4R)-rel-2-((tert-butoxycarbonyl)amino)-7-azabicyclo[2.2.1]heptane-7-carbonyl)-4'-cyano-3'-fluoro-[1,1'-biphenyl]-2-yl)-6-fluoro-1H-indol-1-yl)acetic acid (10 mg) obtained in Step 1 of Example 230 was dissolved in THF (0.064 mL). HATU (6.7 mg), methylamine hydrochloride (2.2 mg), and TEA (6.7 μL) were added at room temperature, followed by stirring at 50°C for 1 hour. The solvent was evaporated, and acetonitrile (1.0 mL) and a 4N hydrochloric acid-1,4-dioxane solution (1.0 mL) were added to the residue, followed by stirring for 10 minutes. The solvent was evaporated and the residue was dissolved in DMSO and purified by reverse phase HPLC (mobile phase: water/acetonitrile) to give the title compound.

Example 232: 2-(5-(5-((1S,2S,4R)-rel-2-amino-7-azabicyclo[2.2.1]heptane-7-carbonyl Synthesis of 4'-cyano-3'-fluoro-[1,1'-biphenyl]-2-yl)-6-fluoro-1H-indol-1-yl)-N,N-dimethylacetamide become

The procedure of Example 231 was repeated using dimethylamine hydrochloride instead of methylamine hydrochloride to give the title compound.

Example 233: 2-(4'-((1S,2S,4R)-rel-2-amino-7-azabicyclo[2.2.1]heptane-7-carbonyl)- Synthesis of 4"-cyano-2,3"-difluoro-[1,1':2',1"-terphenyl]-4-yl)acetamide

Step 1

2-(4-Bromo-3-fluoro-phenyl)acetic acid (600 mg) was dissolved in THF (10.3 mL). HATU (1.08 g), NH ₄ Cl (275.4 mg), and TEA (1.08 mL) were added at room temperature, followed by stirring at 50°C for 1 hour. The solvent was evaporated, and the residue was purified by silica gel column chromatography (mobile phase: chloroform/methanol) to obtain 2-(4-bromo-3-fluoro-phenyl)acetamide.

Step 2

The procedure of Example 225 was repeated using 2-(4-bromo-3-fluoro-phenyl)acetamide obtained in step 1 above instead of 3-[(5-bromo-6-fluoro-indazol-1-yl)methyl]pentan-3-ol to give the title compound.

Example 234: 2-(4'-((1S,2S,4R)-rel-2-amino-7-azabicyclo[2.2.1]heptane-7-carbonyl)- Synthesis of 4"-cyano-2,3"-difluoro-[1,1':2',1"-terphenyl]-4-yl)-N-methylacetamide

Step 1

2-(4-Bromo-3-fluoro-phenyl)acetic acid (600 mg) was dissolved in THF (10.3 mL). HATU (1.08 g), methylamine (approximately 9.8 mol/L in MeOH) (0.525 mL), and TEA (1.08 mL) were added at room temperature, followed by stirring at 50°C for 1 hour. The solvent was evaporated, and the residue was purified by silica gel column chromatography (mobile phase: chloroform/methanol) to obtain 2-(4-bromo-3-fluoro-phenyl)-N-methyl-acetamide.

Step 2

The procedure of Example 225 was repeated using 2-(4-bromo-3-fluoro-phenyl)-N-methyl-acetamide obtained in step 1 above instead of 3-[(5-bromo-6-fluoro-indazol-1-yl)methyl]pentan-3-ol to give the title compound.

Example 235: 2-(4'-((1S,2S,4R)-rel-2-amino-7-azabicyclo[2.2.1]heptane-7-carbonyl)- Synthesis of 4"-cyano-2,3"-difluoro-[1,1':2',1"-terphenyl]-4-yl)-N,N-dimethylacetamide

Step 1

2-(4-Bromo-3-fluoro-phenyl)acetic acid (600 mg) was dissolved in THF (10.3 mL). HATU (1.08 g), dimethylamine hydrochloride (419.9 mg), and TEA (1.08 mL) were added at room temperature, followed by stirring at 50°C for 1 hour. The solvent was evaporated, and the residue was purified by silica gel column chromatography (mobile phase: chloroform/methanol) to obtain 2-(4-bromo-3-fluoro-phenyl)-N,N-dimethyl-acetamide.

Step 2

The procedure of Example 225 was repeated using 2-(4-bromo-3-fluoro-phenyl)-N,N-dimethyl-acetamide obtained in step 1 above instead of 3-[(5-bromo-6-fluoro-indazol-1-yl)methyl]pentan-3-ol to give the title compound.

Example 236: 5-(5-((1S,2S,4R)-rel-2-amino-7-azabicyclo[2.2.1]heptane-7-carbonyl)- Synthesis of 4'-cyano-3'-fluoro-[1,1'-biphenyl]-2-yl)-6-fluoro-1-methyl-1H-indole-3-carboxamide-Isomer-X

5-(5-((1S,2S,4R)-rel-2-((tert-butoxycarbonyl)amino)-7-azabicyclo[2.2.1]heptane-7-carbonyl)-4'-cyano-3'-fluoro-[1,1'-biphenyl]-2-yl)-6-fluoro-1-methyl-1H-indole-3-carboxylic acid-isomer-X (10 mg) obtained in Step 3 of Example 224 was dissolved in THF (0.32 mL). Then, N,N'-carbonyldiimidazole (5.2 mg) was added thereto, and the mixture was stirred at room temperature for 20 minutes. 28% aqueous ammonia (0.1 mL) was added thereto, and the mixture was stirred at room temperature for 20 minutes. The solvent was evaporated, and acetonitrile (0.2 mL) and a 4N hydrochloric acid-1,4-dioxane solution (0.2 mL) were added to the residue, followed by stirring for 30 minutes. The solvent was evaporated and the residue was purified by reverse phase HPLC (mobile phase: water/acetonitrile) to give the title compound.

Example 237: 5-(5-((1S,2S,4R)-rel-2-amino-7-azabicyclo[2.2.1]heptane-7-carbonyl)- 4'-cyano-3'-fluoro-[1,1'-biphenyl]-2-yl)-6-fluoro-N,1-dimethyl-1H-indole-3-carboxamide-isomer-X synthesis

5-(5-((1S,2S,4R)-rel-2-((tert-butoxycarbonyl)amino)-7-azabicyclo[2.2.1]heptane-7-carbonyl)-4'-cyano-3'-fluoro-[1,1'-biphenyl]-2-yl)-6-fluoro-1-methyl-1H-indole-3-carboxylic acid isomer X (10 mg) obtained in Step 3 of Example 224 was dissolved in THF (0.064 mL). HATU (6.7 mg), methylamine hydrochloride (2.2 mg), and TEA (6.7 μL) were added at room temperature, followed by stirring at 50°C for 1 hour. After evaporating the solvent, acetonitrile (0.5 mL) and a 4N hydrochloric acid-1,4-dioxane solution (0.5 mL) were added to the residue, followed by stirring for 10 minutes. The solvent was evaporated, and the residue was dissolved in DMSO and purified by reverse phase HPLC (mobile phase: water/acetonitrile) to give the title compound.

Example 238: 5-(5-((1S,2S,4R)-rel-2-amino-7-azabicyclo[2.2.1]heptane-7-carbonyl)- 4'-Cyano-3'-fluoro-[1,1'-biphenyl]-2-yl)-6-fluoro-N,N,1-trimethyl-1H-indole-3-carboxamide-isomer-X Synthesis

The procedure of Example 237 was repeated using dimethylamine hydrochloride instead of methylamine hydrochloride to give the title compound.

Example 239: (S)-5'-(3-aminopyrrolidine-1-carbonyl)-3-fluoro-2'-(6-fluoro-1-(2-hydroxy-2-methyl) Synthesis of 7-methyl-1H-benzo[d][1,2,3]triazol-5-yl-[1,1'-biphenyl]-4-carbonitrile

1,3-difluoro-2-methyl-4-nitro-benzene was used instead of 2-chloro-1,3-difluoro-4-nitro-benzene, and tert-butyl N-[(3S)-1-[3-(4-cyano-3-fluoro-phenyl)-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzoyl]pyrrolidin-3-yl]carbamate obtained in step 1 of Example 37 was used instead of (( The procedures of Steps 1 to 5 of Example 209 were repeated to prepare tert-butyl 1S,2S,4R)-rel-7-(4'-cyano-3'-fluoro-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-[1,1'-biphenyl]-3-carbonyl)-7-azabicyclo[2.2.1]hept-2-yl)carbamate-isomer-X to give the title compound.

Example 240: 5'-((3-endo)-3-amino-8-azabicyclo[3.2.1]octane-8-carbonyl)-3-fluoro-2'- (6-Fluoro-1-(2-hydroxy-2-methylpropyl)-7-methyl-1H-benzo[d][1,2,3]triazol-5-yl)-[1,1'-biphenyl]- Synthesis of 4-carbonitrile

2-Chloro-1,3-difluoro-4-nitro-benzene was replaced with 1,3-difluoro-2-methyl-4-nitro-benzene, and N-[(3-endo)-8-[3-(4-cyano-3-fluoro-phenyl)-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzoyl]-8-azabicyclo[3.2.1]oct-3-yl]carbamic acid obtained in step 3 of Example 41 was used. The procedures of Steps 1 to 5 of Example 209 were repeated to give the title compound by replacing tert-butyl ((1S,2S,4R)-rel-7-(4'-cyano-3'-fluoro-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-[1,1'-biphenyl]-3-carbonyl)-7-azabicyclo[2.2.1]hept-2-yl)carbamate-isomer-X with tert-butyl ester.

Example 241: 5'-((1S,2S,4R)-rel-2-amino-7-azabicyclo[2.2.1]heptane-7-carbonyl)-3- Fluoro-2'-(6-fluoro-1-(2-hydroxy-2-methylpropyl)-7-methyl-1H-benzo[d][1,2,3]triazol-5-yl)-[1,1'- Synthesis of [phenyl]-4-carbonitrile

2-Chloro-1,3-difluoro-4-nitro-benzene was replaced with 1,3-difluoro-2-methyl-4-nitro-benzene, and ((1S,2S,4R)-rel-7-(4'-cyano-3'-fluoro-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-[1,1'-biphenyl]-3-carbonyl)-7-azabicyclo[2.2.1]heptyl-2-yl)-3-nitro-1,3-difluoro-2-nitro-benzene obtained in Step 1 of Example 213 was used. The procedures of Steps 1 to 5 of Example 209 were repeated to give the title compound by replacing tert-butyl ((1S,2S,4R)-rel-7-(4'-cyano-3'-fluoro-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-[1,1'-biphenyl]-3-carbonyl)-7-azabicyclo[2.2.1]hept-2-yl)carbamate-isomer-X with tert-butyl ((1S,2S,4R)-rel-7-(4'-cyano-3'-fluoro-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-[1,1'-biphenyl]-3-carbonyl)-7-azabicyclo[2.2.1]hept-2-yl)carbamate-isomer-X.

Example 242: 5-(5-((1S,2S,4R)-rel-2-amino-7-azabicyclo[2.2.1]heptane-7-carbonyl)- Synthesis of 4'-cyano-3'-fluoro-[1,1'-biphenyl]-2-yl)-6-fluoro-1-methyl-1H-indole-3-carboxylic acid

Step 1

Tert-butyl ((1S,2S,4R)-rel-7-(4'-cyano-3'-fluoro-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-[1,1'-biphenyl]-3-carbonyl)-7-azabicyclo[2.2.1]hept-2-yl)carbamate (200 mg) and 5-bromo-6-fluoro-1-methyl-indole (105.6 mg) were suspended in 1,4-dioxane (1.19 mL). Pd(dba) ₂ (16.4 mg), X-phos (27.2 mg), and tripotassium phosphate (226.9 mg) were added at room temperature, followed by degassing and replacement with nitrogen. Under a nitrogen atmosphere, the mixture was stirred at an external temperature of 100°C overnight. The solvent was evaporated, and the residue was purified by silica gel column chromatography (mobile phase: chloroform/methanol) to give tert-butyl ((1S,2S,4R)-rel-7-(4'-cyano-3'-fluoro-6-(6-fluoro-1-methyl-1H-indol-5-yl)-[1,1'-biphenyl]-3-carbonyl)-7-azabicyclo[2.2.1]hept-2-yl)carbamate.

Step 2

Tert-butyl ((1S,2S,4R)-rel-7-(4'-cyano-3'-fluoro-6-(6-fluoro-1-methyl-1H-indol-5-yl)-[1,1'-biphenyl]-3-carbonyl)-7-azabicyclo[2.2.1]hept-2-yl)carbamate (209 mg) obtained in step 1 above was dissolved in DMF (3.6 mL). N-iodosuccinimide (121 mg) was added thereto at room temperature, followed by stirring at room temperature for 1 hour. Ethyl acetate was added thereto, and the resulting mixture was washed sequentially with water and saturated brine. After drying the organic layer over anhydrous sodium sulfate, the solvent was evaporated. The residue was purified by silica gel column chromatography (mobile phase: hexane/ethyl acetate) to give tert-butyl ((1S,2S,4R)-rel-7-(4'-cyano-3'-fluoro-6-(6-fluoro-3-iodo-1-methyl-1H-indol-5-yl)-[1,1'-biphenyl]-3-carbonyl)-7-azabicyclo[2.2.1]hept-2-yl)carbamate.

Step 3

Tert-butyl ((1S,2S,4R)-rel-7-(4'-cyano-3'-fluoro-6-(6-fluoro-3-iodo-1-methyl-1H-indol-5-yl)-[1,1'-biphenyl]-3-carbonyl)-7-azabicyclo[2.2.1]hept-2-yl)carbamate (211 mg) and _PdCl₂ ( _PPh₃ ) _₂ (10.5 mg) obtained in Step 2 above were suspended in 1-methyl-2-pyrrolidone (2.11 mL). N,N-diethylethanolamine (0.197 mL) was added at room temperature. After CO₂ substitution, the mixture was stirred at 100°C for 1 hour. Tert-butanol (0.2 mL) and 2N aqueous sodium hydroxide solution (0.2 mL) were added to the reaction solution, and the resulting mixture was stirred at room temperature overnight. MTBE was added, and the aqueous layer was separated. The aqueous layer was acidified with hydrochloric acid and extracted with MTBE. The organic layer was dried over anhydrous sodium sulfate, and the solvent was evaporated to obtain 5-(5-((1S,2S,4R)-rel-2-((tert-butoxycarbonyl)amino)-7-azabicyclo[2.2.1]heptane-7-carbonyl)-4'-cyano-3'-fluoro-[1,1'-biphenyl]-2-yl)-6-fluoro-1-methyl-1H-indole-3-carboxylic acid.

Step 4

Acetonitrile (0.5 mL) and a 4N hydrochloric acid-1,4-dioxane solution (0.5 mL) were added to 5-(5-((1S,2S,4R)-rel-2-((tert-butoxycarbonyl)amino)-7-azabicyclo[2.2.1]heptane-7-carbonyl)-4'-cyano-3'-fluoro-[1,1'-biphenyl]-2-yl)-6-fluoro-1-methyl-1H-indole-3-carboxylic acid (10 mg) obtained in Step 3 above, followed by stirring for 10 minutes. The reaction solution was concentrated, and the residue was purified by reverse phase HPLC (mobile phase: water/acetonitrile) to obtain the title compound.

Example 243: 5-(5-((1S,2S,4R)-rel-2-amino-7-azabicyclo[2.2.1]heptane-7-carbonyl)- Synthesis of 4'-cyano-3'-fluoro-[1,1'-biphenyl]-2-yl)-6-fluoro-N,1-dimethyl-1H-indole-3-carboxamide

The procedure of Example 237 was repeated using 5-(5-((1S,2S,4R)-rel-2-((tert-butoxycarbonyl)amino)-7-azabicyclo[2.2.1]heptane-7-carbonyl)-4'-cyano-3'-fluoro-[1,1'-biphenyl]-2-yl)-6-fluoro-1-methyl-1H-indole-3-carboxylic acid obtained in Step 3 of Example 242 instead of 5-(5-((1S,2S,4R)-rel-2-((tert-butoxycarbonyl)amino)-7-azabicyclo[2.2.1]heptane-7-carbonyl)-4'-cyano-3'-fluoro-[1,1'-biphenyl]-2-yl)-6-fluoro-1-methyl-1H-indole-3-carboxylic acid Isomer-X to give the title compound.

Example 244: 5-(5-((1S,2S,4R)-rel-2-amino-7-azabicyclo[2.2.1]heptane-7-carbonyl)- Synthesis of 4'-cyano-3'-fluoro-[1,1'-biphenyl]-2-yl)-6-fluoro-N,N,1-trimethyl-1H-indole-3-carboxamide

The procedure of Example 237 was repeated using 5-(5-((1S,2S,4R)-rel-2-((tert-butoxycarbonyl)amino)-7-azabicyclo[2.2.1]heptane-7-carbonyl)-4'-cyano-3'-fluoro-[1,1'-biphenyl]-2-yl)-6-fluoro-1-methyl-1H-indole-3-carboxylic acid obtained in Step 3 of Example 242 instead of 5-(5-((1S,2S,4R)-rel-2-((tert-butoxycarbonyl)amino)-7-azabicyclo[2.2.1]heptane-7-carbonyl)-4'-cyano-3'-fluoro-[1,1'-biphenyl]-2-yl)-6-fluoro-1-methyl-1H-indole-3-carboxylic acid Isomer-X and using dimethylamine hydrochloride instead of methylamine hydrochloride to give the title compound.

Example 245: 5-(5-((1S,2S,4R)-rel-2-amino-7-azabicyclo[2.2.1]heptane-7-carbonyl)- Synthesis of 4'-cyano-3'-fluoro-[1,1'-biphenyl]-2-yl)-6-fluoro-1-methyl-1H-indole-3-carboxamide

The procedure of Example 236 was repeated using 5-(5-((1S,2S,4R)-rel-2-((tert-butoxycarbonyl)amino)-7-azabicyclo[2.2.1]heptane-7-carbonyl)-4'-cyano-3'-fluoro-[1,1'-biphenyl]-2-yl)-6-fluoro-1-methyl-1H-indole-3-carboxylic acid obtained in Step 3 of Example 242 instead of 5-(5-((1S,2S,4R)-rel-2-((tert-butoxycarbonyl)amino)-7-azabicyclo[2.2.1]heptane-7-carbonyl)-4'-cyano-3'-fluoro-[1,1'-biphenyl]-2-yl)-6-fluoro-1-methyl-1H-indole-3-carboxylic acid Isomer-X to give the title compound.

Example 246: 5'-((1S,2S,4R)-rel-2-amino-7-azabicyclo[2.2.1]heptane-7-carbonyl)-2'- (7-(Difluoromethyl)-6-fluoro-1-(2-hydroxy-2-methylpropyl)-1H-benzo[d][1,2,3]triazol-5-yl)-3-fluoro-[1, Synthesis of 1'-biphenyl]-4-carbonitrile-isomer-X

The procedures of Steps 1 to 5 of Example 209 were repeated, substituting 2-(difluoromethyl)-1,3-difluoro-4-nitro-benzene for 2-chloro-1,3-difluoro-4-nitro-benzene, to give the title compound.

Example 247: 5-(5-((1S,2S,4R)-rel-2-amino-7-azabicyclo[2.2.1]heptane-7-carbonyl)- 4'-cyano-3'-fluoro-[1,1'-biphenyl]-2-yl)-6-fluoro-1-(2-hydroxy-2-methylpropyl)-1H-benzo[d][1,2, 3] Synthesis of triazole-7-carbonitrile-isomer-X

The procedures of Example 209 Steps 1-5 were repeated, substituting 2,6-difluoro-3-nitro-benzonitrile for 2-chloro-1,3-difluoro-4-nitro-benzene, and THF for EtOH, to give the title compound.

Example 248: (S)-5'-(3-aminopyrrolidine-1-carbonyl)-2'-(7-(difluoromethyl)-6-fluoro-1-(2-hydroxy Synthesis of (1H-benzo[d][1,2,3]triazol-5-yl)-3-fluoro-[1,1'-biphenyl]-4-carbonitrile

2-(Difluoromethyl)-1,3-difluoro-4-nitro-benzene was used instead of 2-chloro-1,3-difluoro-4-nitro-benzene, and tert-butyl N-[(3S)-1-[3-(4-cyano-3-fluoro-phenyl)-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzoyl]pyrrolidin-3-yl]carbamate obtained in step 1 of Example 37 was used instead of The procedures of Steps 1 to 5 of Example 209 were repeated to give tert-butyl ((1S,2S,4R)-rel-7-(4'-cyano-3'-fluoro-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-[1,1'-biphenyl]-3-carbonyl)-7-azabicyclo[2.2.1]hept-2-yl)carbamate-isomer-X to give the title compound.

Example 249: (S)-5-(5-(3-aminopyrrolidine-1-carbonyl)-4'-cyano-3'-fluoro-[1,1'-biphenyl]- Synthesis of 2-fluoro-6-(2-hydroxy-2-methylpropyl)-1H-benzo[d][1,2,3]triazole-7-carbonitrile

2-Chloro-1,3-difluoro-4-nitro-benzene was replaced with 2,6-difluoro-3-nitro-benzonitrile, EtOH was replaced with THF, and tert-butyl N-[(3S)-1-[3-(4-cyano-3-fluoro-phenyl)-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzoyl]pyrrolidin-3-yl]carbamate obtained in step 1 of Example 37 was used. The procedures of Steps 1 to 5 of Example 209 were repeated to give the title compound by replacing tert-butyl ((1S,2S,4R)-rel-7-(4'-cyano-3'-fluoro-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-[1,1'-biphenyl]-3-carbonyl)-7-azabicyclo[2.2.1]hept-2-yl)carbamate-isomer-X.

Example 250: 5'-((3-endo)-3-amino-8-azabicyclo[3.2.1]octane-8-carbonyl)-2'-(7-(di fluoromethyl)-6-fluoro-1-(2-hydroxy-2-methylpropyl)-1H-benzo[d][1,2,3]triazol-5-yl)-3-fluoro-[1,1'- Synthesis of [phenyl]-4-carbonitrile

2-(Difluoromethyl)-1,3-difluoro-4-nitro-benzene was used instead of 2-chloro-1,3-difluoro-4-nitro-benzene, and N-[(3-endo)-8-[3-(4-cyano-3-fluoro-phenyl)-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzoyl]-8-azabicyclo[3.2.1]oct-3-yl]amino]-1,3-difluoro-4-nitro-benzene obtained in Step 3 of Example 41 was used. The procedures of Steps 1 to 5 of Example 209 were repeated using tert-butyl formate instead of tert-butyl ((1S,2S,4R)-rel-7-(4'-cyano-3'-fluoro-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-[1,1'-biphenyl]-3-carbonyl)-7-azabicyclo[2.2.1]hept-2-yl)carbamate-isomer-X to give the title compound.

Example 251: 5-(5-((3-endo)-3-amino-8-azabicyclo[3.2.1]octane-8-carbonyl)-4'-cyano 1-(2-hydroxy-2-methylpropyl)-1H-benzo[d][1,2,3]triazol-3'-fluoro-[1,1'-biphenyl]-2-yl)-6-fluoro-1-(2-hydroxy-2-methylpropyl)-1H-benzo[d][1,2,3]triazol-3'-fluoro-[1,1'-biphenyl]-2-yl) Synthesis of oxazole-7-carbonitrile

2-Chloro-1,3-difluoro-4-nitro-benzene was replaced with 2,6-difluoro-3-nitro-benzonitrile, EtOH was replaced with THF, and N-[(3-endo)-8-[3-(4-cyano-3-fluoro-phenyl)-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzoyl]-8-azabicyclo[3.2.1]octan-3-yl] obtained in step 3 of Example 41 was used. The procedures of Steps 1 to 5 of Example 209 were repeated using tert-butyl carbamate instead of ((1S,2S,4R)-rel-7-(4'-cyano-3'-fluoro-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-[1,1'-biphenyl]-3-carbonyl)-7-azabicyclo[2.2.1]hept-2-yl)carbamate-isomer-X to give the title compound.

Example 252: 5'-((1S,2S,4R)-rel-2-amino-7-azabicyclo[2.2.1]heptane-7-carbonyl)-2'- (7-(Difluoromethyl)-6-fluoro-1-(2-hydroxy-2-methylpropyl)-1H-benzo[d][1,2,3]triazol-5-yl-3-fluoro-[1, Synthesis of 1'-biphenyl]-4-carbonitrile

2-(Difluoromethyl)-1,3-difluoro-4-nitro-benzene was used instead of 2-chloro-1,3-difluoro-4-nitro-benzene, and ((1S,2S,4R)-rel-7-(4'-cyano-3'-fluoro-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-[1,1'-biphenyl]-3-carbonyl)-7-azabicyclo[2.2.1]heptyl)-1,4-difluoro-2-nitro-1-yl)-2-nitro-3-nitro-1-yl)-3-nitro-2 ... The procedures of Steps 1 to 5 of Example 209 were repeated to give the title compound by replacing tert-butyl ((1S,2S,4R)-rel-7-(4'-cyano-3'-fluoro-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-[1,1'-biphenyl]-3-carbonyl)-7-azabicyclo[2.2.1]hept-2-yl)carbamate-isomer-X with tert-butyl ((1S,2S,4R)-rel-7-(4'-cyano-3'-fluoro-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-[1,1'-biphenyl]-3-carbonyl)-7-azabicyclo[2.2.1]hept-2-yl)carbamate-isomer-X.

Example 253: 5-(5-((1S,2S,4R)-rel-2-amino-7-azabicyclo[2.2.1]heptane-7-carbonyl)- 4'-cyano-3'-fluoro-[1,1'-biphenyl]-2-yl)-6-fluoro-1-(2-hydroxy-2-methylpropyl)-1H-benzo[d][1,2, 3] Synthesis of triazole-7-carbonitrile

2-Chloro-1,3-difluoro-4-nitro-benzene was replaced by 2,6-difluoro-3-nitro-benzonitrile, EtOH was replaced by THF, and ((1S,2S,4R)-rel-7-(4'-cyano-3'-fluoro-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-[1,1'-biphenyl]-3-carbonyl)-7-azabicyclo[2.2.1 obtained in step 1 of Example 213 was used. The procedures of Steps 1 to 5 of Example 209 were repeated to give tert-butyl ((1S,2S,4R)-rel-7-(4'-cyano-3'-fluoro-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-[1,1'-biphenyl]-3-carbonyl)-7-azabicyclo[2.2.1]hept-2-yl)carbamate-isomer-X to give the title compound.

Example 254: 5'-((1S,2S,4R)-rel-2-amino-7-azabicyclo[2.2.1]heptane-7-carbonyl)-2'- (6,7-difluoro-1-((1-hydroxycyclobutyl)methyl)-1H-benzo[d][1,2,3]triazol-5-yl)-3-fluoro-[1,1'-biphenyl Synthesis of 4-[[(4-(2-methyl-1-nitropropane)]-4-carbonitrile-isomer-X]]

The procedures of Steps 1 to 5 of Example 209 were repeated using 1,2,3-trifluoro-4-nitro-benzene instead of 2-chloro-1,3-difluoro-4-nitro-benzene and 1-(aminomethyl)cyclobutanol instead of 1-amino-2-methyl-propan-2-ol to give the title compound.

Example 255: (S)-5'-(3-aminopyrrolidine-1-carbonyl)-2'-(6,7-difluoro-1-((1-hydroxycyclobutyl) Synthesis of 1H-benzo[d][1,2,3]triazol-5-yl)-3-fluoro-[1,1'-biphenyl]-4-carbonitrile

2-Chloro-1,3-difluoro-4-nitro-benzene was replaced by 1,2,3-trifluoro-4-nitro-benzene, 1-amino-2-methyl-propan-2-ol was replaced by 1-(aminomethyl)cyclobutanol, and N-[(3S)-1-[3-(4-cyano-3-fluoro-phenyl)-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzoyl]pyrrolidine-3-ol obtained in step 1 of Example 37 was used. The procedures of Steps 1 to 5 of Example 209 were repeated to give the title compound by replacing tert-butyl ((1S,2S,4R)-rel-7-(4'-cyano-3'-fluoro-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-[1,1'-biphenyl]-3-carbonyl)-7-azabicyclo[2.2.1]hept-2-yl)carbamate-isomer-X with tert-butyl ((1S,2S,4R)-rel-7-(4'-cyano-3'-fluoro-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-[1,1'-biphenyl]-3-carbonyl)-7-azabicyclo[2.2.1]hept-2-yl)carbamate-isomer-X.

Example 256: 5'-((3-endo)-3-amino-8-azabicyclo[3.2.1]octane-8-carbonyl)-2'-(6,7- difluoro-1-((1-hydroxycyclobutyl)methyl)-1H-benzo[d][1,2,3]triazol-5-yl)-3-fluoro-[1,1'-biphenyl]-4- Synthesis of Formonitrile

1,2,3-trifluoro-4-nitro-benzene was used instead of 2-chloro-1,3-difluoro-4-nitro-benzene, 1-(aminomethyl)cyclobutanol was used instead of 1-amino-2-methyl-propan-2-ol, and N-[(3-endo)-8-[3-(4-cyano-3-fluoro-phenyl)-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzoyl]-8-azabicyclo[3. The procedures of Steps 1 to 5 of Example 209 were repeated using tert-butyl ((1S,2S,4R)-rel-7-(4'-cyano-3'-fluoro-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-[1,1'-biphenyl]-3-carbonyl)-7-azabicyclo[2.2.1]hept-2-yl)carbamate to give the title compound.

Example 257: 5'-((1S,2S,4R)-rel-2-amino-7-azabicyclo[2.2.1]heptane-7-carbonyl)-2'- (7-Chloro-6-fluoro-1-((1-hydroxycyclobutyl)methyl)-1H-benzo[d][1,2,3]triazol-5-yl)-3-fluoro-[1,1'-biphenyl Synthesis of 4-[[(4-(2-methyl-1-nitropropane)]-4-carbonitrile-isomer-X]]

The procedures of Steps 1 to 5 of Example 209 were repeated using 1-(aminomethyl)cyclobutanol instead of 1-amino-2-methyl-propan-2-ol to give the title compound.

Example 258: (S)-5'-(3-aminopyrrolidine-1-carbonyl)-2'-(7-chloro-6-fluoro-1-((1-hydroxycyclobutane) Synthesis of 1H-benzo[d][1,2,3]triazol-5-yl)-3-fluoro-[1,1'-biphenyl]-4-carbonitrile

The procedures of Steps 1 to 5 of Example 209 were repeated using 1-(aminomethyl)cyclobutanol instead of 1-amino-2-methyl-propan-2-ol and tert-butyl N-[(3S)-1-[3-(4-cyano-3-fluoro-phenyl)-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzoyl]pyrrolidin-3-yl]carbamate obtained in Step 1 of Example 37 instead of tert-butyl ((1S,2S,4R)-rel-7-(4'-cyano-3'-fluoro-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-[1,1'-biphenyl]-3-carbonyl)-7-azabicyclo[2.2.1]hept-2-yl)carbamate-isomer-X to give the title compound.

Example 259: 5'-((3-endo)-3-amino-8-azabicyclo[3.2.1]octane-8-carbonyl)-2'-(7-chloro- 6-Fluoro-1-((1-hydroxycyclobutyl)methyl)-1H-benzo[d][1,2,3]triazol-5-yl)-3-fluoro-[1,1'-biphenyl]-4- Synthesis of Formonitrile

1-(Aminomethyl)cyclobutanol was used instead of 1-amino-2-methyl-propan-2-ol, and tert-butyl N-[(3-endo)-8-[3-(4-cyano-3-fluoro-phenyl)-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzoyl]-8-azabicyclo[3.2.1]oct-3-yl]carbamate obtained in step 3 of Example 41 was used instead. Instead of tert-butyl ((1S,2S,4R)-rel-7-(4'-cyano-3'-fluoro-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-[1,1'-biphenyl]-3-carbonyl)-7-azabicyclo[2.2.1]hept-2-yl)carbamate-isomer-X, the procedures of Steps 1 to 5 of Example 209 were repeated to give the title compound.

Example 260: 5'-((1S,2S,4R)-rel-2-amino-7-azabicyclo[2.2.1]heptane-7-carbonyl)-2'- (7-(Difluoromethyl)-6-fluoro-1-((1-hydroxycyclobutyl)methyl)-1H-benzo[d][1,2,3]triazol-5-yl)-3-fluoro- Synthesis of [1,1'-biphenyl]-4-carbonitrile-isomer-X

The procedures of Steps 1 to 5 of Example 209 were repeated using 2-(difluoromethyl)-1,3-difluoro-4-nitro-benzene instead of 2-chloro-1,3-difluoro-4-nitro-benzene and 1-(aminomethyl)cyclobutanol instead of 1-amino-2-methyl-propan-2-ol to give the title compound.

Example 261: (S)-5'-(3-aminopyrrolidine-1-carbonyl)-2'-(7-(difluoromethyl)-6-fluoro-1-((1-hydroxy Synthesis of (4-(2-(2-(4-((2-((4 ...

2-(Difluoromethyl)-1,3-difluoro-4-nitro-benzene was used instead of 2-chloro-1,3-difluoro-4-nitro-benzene, 1-(aminomethyl)cyclobutanol was used instead of 1-amino-2-methyl-propan-2-ol, and N-[(3S)-1-[3-(4-cyano-3-fluoro-phenyl)-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzoyl]pyrrole obtained in Step 1 of Example 37 was used. The procedures of Steps 1 to 5 of Example 209 were repeated to give the title compound by replacing tert-butyl ((1S,2S,4R)-rel-7-(4'-cyano-3'-fluoro-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-[1,1'-biphenyl]-3-carbonyl)-7-azabicyclo[2.2.1]hept-2-yl)carbamate-isomer-X.

Example 262: 5'-((3-endo)-3-amino-8-azabicyclo[3.2.1]octane-8-carbonyl)-2'-(7-(di fluoromethyl)-6-fluoro-1-((1-hydroxycyclobutyl)methyl)-1H-benzo[d][1,2,3]triazol-5-yl)-3-fluoro-[1,1'- Synthesis of [phenyl]-4-carbonitrile

2-(Difluoromethyl)-1,3-difluoro-4-nitro-benzene was substituted for 2-chloro-1,3-difluoro-4-nitro-benzene, 1-(aminomethyl)cyclobutanol was substituted for 1-amino-2-methyl-propan-2-ol, and N-[(3-endo)-8-[3-(4-cyano-3-fluoro-phenyl)-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzoyl]-8-azabicyclo ... The procedures of Steps 1 to 5 of Example 209 were repeated to give the title compound by substituting tert-butyl ((1S,2S,4R)-rel-7-(4'-cyano-3'-fluoro-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-[1,1'-biphenyl]-3-carbonyl)-7-azabicyclo[2.2.1]hept-2-yl)carbamate-isomer-X for tert-butyl ((1S,2S,4R)-rel-7-(4'-cyano-3'-fluoro-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-[1,1'-biphenyl]-3-carbonyl)-7-azabicyclo[2.2.1]hept-2-yl)carbamate.

Example 263: 5'-((1S,2S,4R)-rel-2-amino-7-azabicyclo[2.2.1]heptane-7-carbonyl)-2'- (7-(Difluoromethyl)-6-fluoro-1-((1-hydroxycyclobutyl)methyl)-1H-benzo[d][1,2,3]triazol-5-yl)-3-fluoro- Synthesis of [1,1'-biphenyl]-4-carbonitrile

2-(Difluoromethyl)-1,3-difluoro-4-nitro-benzene was substituted for 2-chloro-1,3-difluoro-4-nitro-benzene, 1-(Aminomethyl)cyclobutanol was substituted for 1-amino-2-methyl-propan-2-ol, and (1S,2S,4R)-rel-7-(4'-cyano-3'-fluoro-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-[1,1'-biphenyl]-3-carbonyl)-1-[ ... The procedures of Steps 1 to 5 of Example 209 were repeated to give the title compound by replacing tert-butyl ((1S,2S,4R)-rel-7-(4'-cyano-3'-fluoro-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-[1,1'-biphenyl]-3-carbonyl)-7-azabicyclo[2.2.1]hept-2-yl)carbamate-isomer-X with tert-butyl ((1S,2S,4R)-rel-7-(4'-cyano-3'-fluoro-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-[1,1'-biphenyl]-3-carbonyl)-7-azabicyclo[2.2.1]hept-2-yl)carbamate.

Example 264: 5-(5-((1S,2S,4R)-rel-2-amino-7-azabicyclo[2.2.1]heptane-7-carbonyl)- 4'-cyano-3'-fluoro-[1,1'-biphenyl]-2-yl)-6-fluoro-1-((1-hydroxycyclobutyl)methyl)-1H-benzo[d][1,2, 3] Synthesis of triazole-7-carbonitrile-isomer-X

The procedures of Steps 1 to 5 of Example 209 were repeated using 2,6-difluoro-3-nitro-benzonitrile instead of 2-chloro-1,3-difluoro-4-nitro-benzene and 1-(aminomethyl)cyclobutanol instead of 1-amino-2-methyl-propan-2-ol to give the title compound.

Example 265: (S)-5-(5-(3-aminopyrrolidine-1-carbonyl)-4'-cyano-3'-fluoro-[1,1'-biphenyl]- Synthesis of 2-(2-yl)-6-fluoro-1-((1-hydroxycyclobutyl)methyl)-1H-benzo[d][1,2,3]triazole-7-carbonitrile

2-Chloro-1,3-difluoro-4-nitro-benzene was replaced with 2,6-difluoro-3-nitro-benzonitrile, 1-amino-2-methyl-propan-2-ol was replaced with 1-(aminomethyl)cyclobutanol, and N-[(3S)-1-[3-(4-cyano-3-fluoro-phenyl)-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzoyl]pyrrolidine-3-ol obtained in step 1 of Example 37 was used. The procedures of Steps 1 to 5 of Example 209 were repeated to give the title compound by replacing tert-butyl ((1S,2S,4R)-rel-7-(4'-cyano-3'-fluoro-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-[1,1'-biphenyl]-3-carbonyl)-7-azabicyclo[2.2.1]hept-2-yl)carbamate-isomer-X with tert-butyl ((1S,2S,4R)-rel-7-(4'-cyano-3'-fluoro-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-[1,1'-biphenyl]-3-carbonyl)-7-azabicyclo[2.2.1]hept-2-yl)carbamate-isomer-X.

Example 266: 5-(5-((3-endo)-3-amino-8-azabicyclo[3.2.1]octane-8-carbonyl)-4'-cyano 3'-fluoro-[1,1'-biphenyl]-2-yl)-6-fluoro-1-((1-hydroxycyclobutyl)methyl)-1H-benzo[d][1,2,3]triazol-2-yl Synthesis of oxazole-7-carbonitrile

2-Chloro-1,3-difluoro-4-nitro-benzene was replaced by 2,6-difluoro-3-nitro-benzonitrile, 1-amino-2-methyl-propan-2-ol was replaced by 1-(aminomethyl)cyclobutanol, and N-[(3-endo)-8-[3-(4-cyano-3-fluoro-phenyl)-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzoyl]-8-azabicyclo[3. The procedures of Steps 1 to 5 of Example 209 were repeated using tert-butyl ((1S,2S,4R)-rel-7-(4'-cyano-3'-fluoro-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-[1,1'-biphenyl]-3-carbonyl)-7-azabicyclo[2.2.1]hept-2-yl)carbamate to give the title compound.

Example 267: 5-(5-((1S,2S,4R)-rel-2-amino-7-azabicyclo[2.2.1]heptane-7-carbonyl)- 4'-cyano-3'-fluoro-[1,1'-biphenyl]-2-yl)-6-fluoro-1-((1-hydroxycyclobutyl)methyl)-1H-benzo[d][1,2, 3] Synthesis of triazole-7-carbonitrile

2-Chloro-1,3-difluoro-4-nitro-benzene was replaced with 2,6-difluoro-3-nitro-benzonitrile, 1-amino-2-methyl-propan-2-ol was replaced with 1-(aminomethyl)cyclobutanol, and ((1S,2S,4R)-rel-7-(4'-cyano-3'-fluoro-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-[1,1'-biphenyl]-3-carbonyl)-7-(4'-cyano-3'-fluoro-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-[1,1'-biphenyl]-3-carbonyl)-7-(4'-cyano-3'-fluoro-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)- The procedures of Steps 1 to 5 of Example 209 were repeated to give the title compound by replacing tert-butyl ((1S,2S,4R)-rel-7-(4'-cyano-3'-fluoro-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-[1,1'-biphenyl]-3-carbonyl)-7-azabicyclo[2.2.1]hept-2-yl)carbamate isomer-X with tert-butyl ((1S,2S,4R)-rel-7-(4'-cyano-3'-fluoro-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-[1,1'-biphenyl]-3-carbonyl)-7-azabicyclo[2.2.1]hept-2-yl)carbamate.

Example 268: 5'-((1S,2S,4R)-rel-2-amino-7-azabicyclo[2.2.1]heptane-7-carbonyl)-2'- (6,7-difluoro-1-((1-hydroxycyclobutyl)methyl)-1H-benzo[d][1,2,3]triazol-5-yl)-3-fluoro-[1,1'-biphenyl Synthesis of [4-Methyl]-4-carbonitrile

2-Chloro-1,3-difluoro-4-nitro-benzene was replaced by 1,2,3-trifluoro-4-nitro-benzene, 1-amino-2-methyl-propan-2-ol was replaced by 1-(aminomethyl)cyclobutanol, and ((1S,2S,4R)-rel-7-(4'-cyano-3'-fluoro-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-[1,1'-biphenyl]-3-carbonyl)-7- The procedures of Steps 1 to 5 of Example 209 were repeated to give the title compound by replacing tert-butyl ((1S,2S,4R)-rel-7-(4'-cyano-3'-fluoro-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-[1,1'-biphenyl]-3-carbonyl)-7-azabicyclo[2.2.1]hept-2-yl)carbamate isomer-X with tert-butyl ((1S,2S,4R)-rel-7-(4'-cyano-3'-fluoro-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-[1,1'-biphenyl]-3-carbonyl)-7-azabicyclo[2.2.1]hept-2-yl)carbamate.

Example 269: 5'-((1S,2S,4R)-rel-2-amino-7-azabicyclo[2.2.1]heptane-7-carbonyl)-2'- (7-Chloro-6-fluoro-1-((1-hydroxycyclobutyl)methyl)-1H-benzo[d][1,2,3]triazol-5-yl)-3-fluoro-[1,1'-biphenyl base]-4-carbonitrile

1-(Aminomethyl)cyclobutanol was used in place of 1-amino-2-methyl-propan-2-ol, and ((1S,2S,4R)-rel-7-(4'-cyano-3'-fluoro-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-[1,1'-biphenyl]-3-carbonyl)-7-azabicyclo[2.2.1]hept-2-yl)amino The procedures of Steps 1 to 5 of Example 209 were repeated to give the title compound by replacing tert-butyl ((1S,2S,4R)-rel-7-(4'-cyano-3'-fluoro-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-[1,1'-biphenyl]-3-carbonyl)-7-azabicyclo[2.2.1]hept-2-yl)carbamate-isomer-X with tert-butyl ((1S,2S,4R)-rel-7-(4'-cyano-3'-fluoro-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-[1,1'-biphenyl]-3-carbonyl)-7-azabicyclo[2.2.1]hept-2-yl)carbamate-isomer-X.

Example 270: 5'-((1S,2S,4R)-rel-2-amino-7-azabicyclo[2.2.1]heptane-7-carbonyl)-3- Fluoro-2'-(6-fluoro-1-((1-hydroxycyclobutyl)methyl)-7-methyl-1H-benzo[d][1,2,3]triazol-5-yl)-[1,1'- Synthesis of [Biphenyl]-4-carbonitrile-Isomer-X

The procedures of Steps 1 to 5 of Example 209 were repeated, substituting 1,3-difluoro-2-methyl-4-nitro-benzene for 2-chloro-1,3-difluoro-4-nitro-benzene and 1-(aminomethyl)cyclobutanol for 1-amino-2-methyl-propan-2-ol, to give the title compound.

Example 271: (S)-5'-(3-aminopyrrolidine-1-carbonyl)-3-fluoro-2'-(6-fluoro-1-((1-hydroxycyclobutane Synthesis of 7-methyl-1H-benzo[d][1,2,3]triazol-5-yl)-[1,1'-biphenyl]-4-carbonitrile

2-Chloro-1,3-difluoro-4-nitro-benzene was replaced by 1,3-difluoro-2-methyl-4-nitro-benzene, 1-amino-2-methyl-propan-2-ol was replaced by 1-(aminomethyl)cyclobutanol, and N-[(3S)-1-[3-(4-cyano-3-fluoro-phenyl)-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzoyl]pyrrolidine- The procedures of Steps 1 to 5 of Example 209 were repeated to give the title compound by replacing tert-butyl ((1S,2S,4R)-rel-7-(4'-cyano-3'-fluoro-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-[1,1'-biphenyl]-3-carbonyl)-7-azabicyclo[2.2.1]hept-2-yl)carbamate-isomer-X.

Example 272: 5'-((3-endo)-3-amino-8-azabicyclo[3.2.1]octane-8-carbonyl)-3-fluoro-2'- (6-Fluoro-1-((1-hydroxycyclobutyl)methyl)-7-methyl-1H-benzo[d][1,2,3]triazol-5-yl)-[1,1'-biphenyl Synthesis of [4-Methyl]-4-carbonitrile

1,3-difluoro-2-methyl-4-nitro-benzene was used instead of 2-chloro-1,3-difluoro-4-nitro-benzene, 1-amino-2-methyl-propan-2-ol was used instead of 1-(aminomethyl)cyclobutanol, and N-[(3-endo)-8-[3-(4-cyano-3-fluoro-phenyl)-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzoyl]-8-azabicyclo[ The procedures of Steps 1 to 5 of Example 209 were repeated to give tert-butyl ((1S,2S,4R)-rel-7-(4'-cyano-3'-fluoro-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-[1,1'-biphenyl]-3-carbonyl)-7-azabicyclo[2.2.1]hept-2-yl)carbamate-isomer-X to give the title compound.

Example 273: 5'-((1S,2S,4R)-rel-2-amino-7-azabicyclo[2.2.1]heptane-7-carbonyl)-2'- (7-Bromo-6-fluoro-1-(2-hydroxy-2-methylpropyl)-1H-benzo[d][1,2,3]triazol-5-yl)-3-fluoro-[1,1'-biphenyl Synthesis of 4-[[(4-(2-methyl-1-nitropropane)]-4-carbonitrile-isomer-X]]

Step 1

2-Bromo-1,3-difluoro-4-nitro-benzene (3 g) was dissolved in THF (31.5 mL). TEA (2.6 mL) and 1-amino-2-methyl-propan-2-ol (1.4 mL) were added thereto, followed by stirring at room temperature for 1 hour. Ethyl acetate was added, and the resulting mixture was washed with water and saturated brine in sequence. After drying the organic layer over anhydrous sodium sulfate, the solvent was evaporated. The residue was purified by silica gel column chromatography (mobile phase: hexane/ethyl acetate) to obtain 1-(2-bromo-3-fluoro-6-nitro-anilino)-2-methyl-propan-2-ol.

Step 2

1-(2-Bromo-3-fluoro-6-nitro-anilino)-2-methyl-propan-2-ol (1.03 g) obtained in Step 1 above was dissolved in acetic acid (6.7 mL). N-iodosuccinimide (981 mg) was added thereto at room temperature, followed by stirring at 50° C. for 3 hours. MTBE and water were added thereto, and the mixture was extracted twice with MTBE. The combined organic layers were dried over anhydrous sodium sulfate, and the solvent was evaporated. The residue was purified by silica gel column chromatography (mobile phase: hexane/ethyl acetate) to obtain 1-(2-Bromo-3-fluoro-4-iodo-6-nitro-anilino)-2-methyl-propan-2-ol.

Step 3

1-(2-Bromo-3-fluoro-4-iodo-6-nitro-anilino)-2-methyl-propan-2-ol (1.33 g) and iron (1.33 g) obtained in Step 2 above were dissolved in THF (10.2 mL) and 2N hydrochloric acid (10.2 mL), followed by stirring at 60°C for 1 hour. MTBE was added, and the mixture was passed through Celite. MTBE was added, and the mixture was washed sequentially with water and saturated brine, and dried over anhydrous sodium sulfate. Thereafter, the solvent was evaporated. The residue was purified by silica gel column chromatography (mobile phase: hexane/ethyl acetate) to obtain 1-(6-amino-2-bromo-3-fluoro-4-iodo-anilino)-2-methyl-propan-2-ol.

Step 4

1-(6-amino-2-bromo-3-fluoro-4-iodo-anilino)-2-methyl-propan-2-ol (940 mg) obtained in Step 3 above was dissolved in water (1.88 mL) and THF (4.7 mL). 12N hydrochloric acid (2.82 mL) and an aqueous sodium nitrite solution (prepared by dissolving 209 mg of sodium nitrite in 0.63 mL of water) were added dropwise at 0°C, followed by stirring at room temperature for 1 hour. MTBE was added, and the mixture was washed sequentially with water and saturated brine, and dried over anhydrous sodium sulfate. Thereafter, the solvent was evaporated. The residue was purified by silica gel column chromatography (mobile phase: hexane/ethyl acetate) to obtain 1-(7-bromo-6-fluoro-5-iodo-benzotriazol-1-yl)-2-methyl-propan-2-ol.

Step 5

Tert-butyl ((1S,2S,4R)-rel-7-(4'-cyano-3'-fluoro-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-[1,1'-biphenyl]-3-carbonyl)-7-azabicyclo[2.2.1]hept-2-yl)carbamate-isomer-X (50 mg) obtained in Step 2 of Example 207 and 1-(7-bromo-6-fluoro-5-iodo-benzotriazol-1-yl)-2-methyl-propan-2-ol (47.9 mg) obtained in Step 4 above were dissolved in 1,4-dioxane (0.3 mL). Pd(dba) ₂ (4.1 mg), X-phos (6.8 mg), and tripotassium phosphate (56.7 mg) were added thereto at room temperature. After nitrogen substitution, the mixture was stirred at 90° C. overnight. Ethyl acetate was added, and the mixture was placed on NH-silica gel and washed with ethyl acetate:methanol = 10:1. The solvent was evaporated, and acetonitrile (1.0 mL) and 4N hydrochloric acid-1,4-dioxane solution (1.0 mL) were added to the residue, followed by stirring for 10 minutes. The solvent was evaporated, and the residue was dissolved in DMSO and purified by reverse-phase HPLC (mobile phase: water/acetonitrile) to obtain the title compound.

Example 274: (S)-5'-(3-aminopyrrolidine-1-carbonyl)-2'-(7-bromo-6-fluoro-1-(2-hydroxy-2-methyl)- Synthesis of (1H-benzo[d][1,2,3]triazol-5-yl)-3-fluoro-[1,1'-biphenyl]-4-carbonitrile

The procedures of Steps 1 to 5 of Example 273 were repeated using tert-butyl N-[(3S)-1-[3-(4-cyano-3-fluoro-phenyl)-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzoyl]pyrrolidin-3-yl]carbamate obtained in Step 1 of Example 37 instead of tert-butyl ((1S,2S,4R)-rel-7-(4'-cyano-3'-fluoro-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-[1,1'-biphenyl]-3-carbonyl)-7-azabicyclo[2.2.1]hept-2-yl)carbamate-isomer-X to give the title compound.

Example 275: 5'-((3-endo)-3-amino-8-azabicyclo[3.2.1]octane-8-carbonyl)-2'-(7-bromo- 6-fluoro-1-(2-hydroxy-2-methylpropyl)-1H-benzo[d][1,2,3]triazol-5-yl)-3-fluoro-[1,1'-biphenyl]-4- Synthesis of Formonitrile

The procedures of Steps 1 to 5 of Example 273 were repeated using tert-butyl N-[(3-endo)-8-[3-(4-cyano-3-fluoro-phenyl)-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzoyl]-8-azabicyclo[3.2.1]oct-3-yl]carbamate obtained in Step 3 of Example 41 instead of tert-butyl ((1S,2S,4R)-rel-7-(4'-cyano-3'-fluoro-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-[1,1'-biphenyl]-3-carbonyl)-7-azabicyclo[2.2.1]hept-2-yl)carbamate-isomer-X to give the title compound.

Example 276: 5'-((1S,2S,4R)-rel-2-amino-7-azabicyclo[2.2.1]heptane-7-carbonyl)-3- Fluoro-2'-(6-fluoro-1-((1-hydroxycyclobutyl)methyl)-7-methyl-1H-benzo[d][1,2,3]triazol-5-yl)-[1,1'- Synthesis of [Biphenyl]-4-carbonitrile

2-Chloro-1,3-difluoro-4-nitro-benzene was replaced by 1,3-difluoro-2-methyl-4-nitro-benzene, 1-amino-2-methyl-propan-2-ol was replaced by 1-(aminomethyl)cyclobutanol, and ((1S,2S,4R)-rel-7-(4'-cyano-3'-fluoro-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-[1,1'-biphenyl]-3-carbonyl)-7 obtained in step 1 of Example 213 was used. The procedures of Steps 1 to 5 of Example 209 were repeated to give the title compound by replacing tert-butyl ((1S,2S,4R)-rel-7-(4'-cyano-3'-fluoro-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-[1,1'-biphenyl]-3-carbonyl)-7-azabicyclo[2.2.1]hept-2-yl)carbamate-isomer-X with tert-butyl ((1S,2S,4R)-rel-7-(4'-cyano-3'-fluoro-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-[1,1'-biphenyl]-3-carbonyl)-7-azabicyclo[2.2.1]hept-2-yl)carbamate.

Example 277: 5'-((1S,2S,4R)-rel-2-amino-7-azabicyclo[2.2.1]heptane-7-carbonyl)-2'- (7-Bromo-6-fluoro-1-(2-hydroxy-2-methylpropyl)-1H-benzo[d][1,2,3]triazol-5-yl)-3-fluoro-[1,1'-biphenyl Synthesis of [4-Methyl]-4-carbonitrile

The procedures of Steps 1 to 5 of Example 273 were repeated using tert-butyl ((1S,2S,4R)-rel-7-(4'-cyano-3'-fluoro-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-[1,1'-biphenyl]-3-carbonyl)-7-azabicyclo[2.2.1]hept-2-yl)carbamate obtained in Step 1 of Example 213 instead of tert-butyl ((1S,2S,4R)-rel-7-(4'-cyano-3'-fluoro-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-[1,1'-biphenyl]-3-carbonyl)-7-azabicyclo[2.2.1]hept-2-yl)carbamate-isomer-X to give the title compound.

Example 278: 5'-((1R,2R,4S)-rel-2-amino-7-azabicyclo[2.2.1]heptane-7-carbonyl)-2'- (7-cyclopropyl-6-fluoro-1-(2-hydroxy-2-methylpropyl)-1H-benzo[d][1,2,3]triazol-5-yl)-3-fluoro-[1,1'- Synthesis of [Biphenyl]-4-carbonitrile

Step 1

1-(2-Bromo-3-fluoro-6-nitro-anilino)-2-methyl-propan-2-ol (975 mg) obtained in Step 1 of Example 273 was dissolved in 1,4-dioxane (10.6 mL). Dichlorobis(tricyclohexylphosphine)palladium(II) (234 mg), cyclopropylboronic acid (464 mg), and tripotassium phosphate (2.02 g) were added at room temperature, followed by stirring at 10°C overnight. The solvent was evaporated, and the residue was purified by silica gel column chromatography (mobile phase: hexane/ethyl acetate) to obtain 1-((2-cyclopropyl-3-fluoro-6-nitrophenyl)amino)-2-methylpropan-2-ol.

Step 2

1-((2-cyclopropyl-3-fluoro-6-nitrophenyl)amino)-2-methylpropan-2-ol (204 mg) obtained in Step 1 above was dissolved in acetonitrile (1.5 mL). N-bromosuccinimide (196 mg) was added at room temperature, followed by stirring at 50°C for 1 hour. The solvent was evaporated, and the residue was purified by silica gel column chromatography (mobile phase: hexane/ethyl acetate) to obtain 1-((4-bromo-2-cyclopropyl-3-fluoro-6-nitrophenyl)amino)-2-methylpropan-2-ol.

Step 3

1-((4-bromo-2-cyclopropyl-3-fluoro-6-nitrophenyl)amino)-2-methylpropan-2-ol (250 mg) obtained in the above step 2 and iron (250 mg) were dissolved in THF (2.4 mL) and 2N hydrochloric acid (2.4 mL), followed by stirring at 60° C. for 1 hour. Ethyl acetate was added thereto, and the mixture was passed through celite. Ethyl acetate was added thereto, and the mixture was washed sequentially with water and saturated brine, and dried over anhydrous sodium sulfate. Thereafter, the solvent was distilled off. The residue was purified by silica gel column chromatography (mobile phase: hexane/ethyl acetate) to obtain 1-((6-amino-4-bromo-2-cyclopropyl-3-fluorophenyl)amino)-2-methylpropan-2-ol.

Step 4

1-((6-amino-4-bromo-2-cyclopropyl-3-fluorophenyl)amino)-2-methylpropan-2-ol (192 mg) obtained in step 3 above was dissolved in THF (2.0 mL) and 2N hydrochloric acid (2.0 mL). An aqueous sodium nitrite solution (54 mg of sodium nitrite dissolved in 0.16 mL of water) was added dropwise thereto, followed by stirring at room temperature for 1 hour. Ethyl acetate was added thereto, and the mixture was washed with water and saturated brine in sequence, and dried over anhydrous sodium sulfate. Thereafter, the solvent was evaporated. The residue was purified by silica gel column chromatography (mobile phase: hexane/ethyl acetate) to obtain 1-(5-bromo-7-cyclopropyl-6-fluoro-1H-benzo[d][1,2,3]triazol-1-yl)-2-methylpropan-2-ol.

Step 5

Tert-butyl ((1S,2S,4R)-rel-7-(4'-cyano-3'-fluoro-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-[1,1'-biphenyl]-3-carbonyl)-7-azabicyclo[2.2.1]hept-2-yl)carbamate (15 mg) obtained in Step 1 of Example 213 and 1-(5-bromo-7-cyclopropyl-6-fluoro-1H-benzo[d][1,2,3]triazol-1-yl)-2-methylpropan-2-ol (10.5 mg) obtained in Step 4 above were dissolved in 1,4-dioxane (0.2 mL). Pd(dba) ₂ (1.2 mg), X-phos (2.0 mg) and tripotassium phosphate (17 mg) were added thereto. After nitrogen substitution, the mixture was stirred at 100° C. overnight. Ethyl acetate was added, and the mixture was placed on NH-silica gel and washed with ethyl acetate:methanol = 10:1. The solvent was evaporated, and acetonitrile (1.0 mL) and 4N hydrochloric acid-1,4-dioxane solution (1.0 mL) were added to the residue, followed by stirring for 10 minutes. The solvent was evaporated, and the residue was dissolved in DMSO and purified by reverse-phase HPLC (mobile phase: water/acetonitrile) to obtain the title compound.

Example 279: 5'-((1R,2R,4S)-rel-2-amino-7-azabicyclo[2.2.1]heptane-7-carbonyl)-2'- (7-cyclopropyl-6-fluoro-1-(2-hydroxy-2-methylpropyl)-1H-benzo[d][1,2,3]triazol-5-yl)-3-fluoro-[1,1'- Synthesis of [Biphenyl]-4-carbonitrile-Isomer-X

The procedures of Steps 1 to 5 of Example 278 were repeated using tert-butyl ((1S,2S,4R)-rel-7-(4'-cyano-3'-fluoro-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-[1,1'-biphenyl]-3-carbonyl)-7-azabicyclo[2.2.1]hept-2-yl)carbamate-isomer-X obtained in Step 2 of Example 207 instead of tert-butyl ((1S,2S,4R)-rel-7-(4'-cyano-3'-fluoro-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-[1,1'-biphenyl]-3-carbonyl)-7-azabicyclo[2.2.1]hept-2-yl)carbamate.

Example 280: (S)-5'-(3-aminopyrrolidine-1-carbonyl)-2'-(7-cyclopropyl-6-fluoro-1-(2-hydroxy-2- Synthesis of (1H-benzo[d][1,2,3]triazol-5-yl)-3-fluoro-[1,1'-biphenyl]-4-carbonitrile

The procedures of Steps 1 to 5 of Example 278 were repeated using tert-butyl N-[(3S)-1-[3-(4-cyano-3-fluoro-phenyl)-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzoyl]pyrrolidin-3-yl]carbamate obtained in Step 1 of Example 37 instead of tert-butyl ((1S,2S,4R)-rel-7-(4'-cyano-3'-fluoro-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-[1,1'-biphenyl]-3-carbonyl)-7-azabicyclo[2.2.1]hept-2-yl)carbamate to give the title compound.

Example 281: 5'-((3-endo)-3-amino-8-azabicyclo[3.2.1]octane-8-carbonyl)-2'-(7-cyclo Propyl-6-fluoro-1-(2-hydroxy-2-methylpropyl)-1H-benzo[d][1,2,3]triazol-5-yl)-3-fluoro-[1,1'-biphenyl Synthesis of [4-Methyl]-4-carbonitrile

The procedures of Steps 1 to 5 of Example 278 were repeated using tert-butyl N-[(3-endo)-8-[3-(4-cyano-3-fluoro-phenyl)-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzoyl]-8-azabicyclo[3.2.1]oct-3-yl]carbamate obtained in Step 3 of Example 41 instead of tert-butyl ((1S,2S,4R)-rel-7-(4'-cyano-3'-fluoro-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-[1,1'-biphenyl]-3-carbonyl)-7-azabicyclo[2.2.1]hept-2-yl)carbamate to give the title compound.

Comparative Example 1: 4-(2-((3-exo)-3-amino-8-azabicyclo[3.2.1]octan-8-yl)-5-(2-methyl-2H- Synthesis of (indazol-5-yl)pyrimidin-4-yl)benzonitrile

The procedure of Example 59 disclosed in Patent Document (PTL) 1 was repeated using (4-cyanophenyl)boronic acid instead of (4-cyano-3-fluorophenyl)boronic acid and tert-butyl N-[(3-exo)-8-azabicyclo[3.2.1]oct-3-yl]carbamate instead of 4-Boc-aminopiperidine to give the title compound.

Comparative Example 2: (S)-4-(3-(3-aminopyrrolidine-1-carbonyl)-5-(4-fluorophenyl)-1H-pyrazol-1-yl)benzene Synthesis of Nitriles

Step 1

Using 1-(4-fluorophenyl)ethanone as C-1, 4-hydrazinobenzonitrile instead of (4-(trifluoromethyl)phenyl)hydrazine, and (S)-pyrrolidin-3-ylcarbamic acid tert-butyl ester instead of 1-(4-fluorophenyl)-1,3,8-triazaspiro[4.5]decan-4-one, the procedure of the synthetic method of Scheme C disclosed in PTL 3 was repeated to obtain (S)-tert-butyl (1-(1-(4-cyanophenyl)-5-(4-fluorophenyl)-1H-pyrazole-3-carbonyl)pyrrolidin-3-yl)carbamate.

Step 2

Using (S)-(1-(1-(4-cyanophenyl)-5-(4-fluorophenyl)-1H-pyrazole-3-carbonyl)pyrrolidin-3-yl)carbamic acid tert-butyl ester obtained in the above step 1 instead of N-[(3S)-1-[3-(4-cyanophenyl)-4-(p-tolyl)benzoyl]pyrrolidin-3-yl]carbamate, the procedure of step 5 of Example 1 was repeated to give the title compound.

Comparative Example 3: 4-(5-(4-fluorophenyl)-3-(2,6-diazaspiro[3.5]nonane-6-carbonyl)-1H-pyrazole-1- Synthesis of (4-methyl)benzonitrile

Step 1

Using 1-(4-fluorophenyl)ethanone as C-1, 4-hydrazinobenzonitrile instead of (4-(trifluoromethyl)phenyl)hydrazine, and tert-butyl 2,6-diazaspiro[3.5]nonane-2-carboxylate instead of 1-(4-fluorophenyl)-1,3,8-triazaspiro[4.5]decan-4-one, the procedure of the synthetic method of Scheme C disclosed in PTL 3 was repeated to obtain tert-butyl 6-(1-(4-cyanophenyl)-5-(4-fluorophenyl)-1H-pyrazole-3-carbonyl)-2,6-diazaspiro[3.5]nonane-2-carboxylate.

Step 2

The procedure of Step 5 of Example 1 was repeated using tert-butyl 6-(1-(4-cyanophenyl)-5-(4-fluorophenyl)-1H-pyrazole-3-carbonyl)-2,6-diazaspiro[3.5]nonane-2-carboxylate obtained in Step 1 above instead of tert-butyl N-[(3S)-1-[3-(4-cyanophenyl)-4-(p-tolyl)benzoyl]pyrrolidin-3-yl]carbamate to give the title compound.

Comparative Example 4: 4-[5-[(3R)-3-aminopiperidine-1-carbonyl]-2-(3-pyridylmethoxy)phenyl]benzonitrile synthesis

Step 1

Using 3-bromo-4-methoxybenzoic acid instead of 3-bromo-4-chloro-benzoic acid and using tert-butyl (R)-piperidin-3-ylcarbamate instead of tert-butyl N-[(3S)-pyrrolidin-3-yl]carbamate, the procedures of Steps 1-2 of Example 9 were repeated to obtain tert-butyl (R)-(1-(4'-cyano-6-methoxy-[1,1'-biphenyl]-3-carbonyl)piperidin-3-yl)carbamate.

Step 2

tert-Butyl (R)-(1-(4'-cyano-6-methoxy-[1,1'-biphenyl]-3-carbonyl)piperidin-3-yl)carbamate (430 mg) obtained in Step 1 above was dissolved in dichloromethane (10 mL). A solution of 1M _BBr₃ in dichloromethane (2.17 mL) was added dropwise at 0°C, followed by stirring at room temperature for 30 minutes. Saturated aqueous sodium bicarbonate (17 mL), water (4 mL), and _CH₂Cl₂ (8 mL) were added, followed by stirring for 10 minutes. _BoC₂O (0.2370 g ₎ was added, followed by stirring at room temperature for 1 hour. The organic layer was dried over anhydrous sodium sulfate, and the solvent was evaporated. The residue was purified by silica gel column chromatography (mobile phase: hexane/ethyl acetate) to give tert-butyl N-[(3R)-1-[3-(4-cyanophenyl)-4-hydroxy-benzoyl]-3-piperidinyl]carbamate.

Step 3

Tert-butyl N-[(3R)-1-[3-(4-cyanophenyl)-4-hydroxybenzoyl]-3-piperidinyl]carbamate (10 mg) obtained in Step 2 above was dissolved in THF (0.500 mL). 3-Pyridylmethanol (7 mg), polymer-supported _PPh₃ (30 mg), and DMEAD (27.8 mg) were added at 25°C, followed by stirring at 50°C for 3 hours. Ethyl acetate was added, and the resulting mixture was washed sequentially with water and saturated brine. The organic layer was dried over anhydrous sodium sulfate, and the solvent was evaporated. The residue was purified by silica gel column chromatography (mobile phase: chloroform/methanol) to obtain tert-butyl (S)-(1-(4'-cyano-6-(pyridin-3-ylmethoxy)-[1,1'-biphenyl]-3-carbonyl)piperidin-3-yl)carbamate.

Step 4

Using (S)-(1-(4'-cyano-6-(pyridin-3-ylmethoxy)-[1,1'-biphenyl]-3-carbonyl)piperidin-3-yl)carbamic acid tert-butyl ester obtained in the above step 3 instead of N-[(3S)-1-[3-(4-cyanophenyl)-4-(p-tolyl)benzoyl]pyrrolidin-3-yl]carbamate, the procedure of step 5 of Example 1 was repeated to give the title compound.

Comparative Example 5: (S)-(3-aminopyrrolidin-1-yl)(4-methyl-4"-(trifluoromethyl)-[1,1':2',1"-trifluoromethyl]- Synthesis of [4-[(4-phenyl]-4'-yl)methanone]

The procedures of Steps 1 to 5 of Example 19 were repeated using 1-bromo-4-(trifluoromethyl)benzene instead of 4-bromo-2,6-difluoro-benzonitrile to give the title compound.

Comparative Example 6: 4"-methyl-5'-(3-(pyridin-3-yl)pyrrolidine-1-carbonyl)-[1,1':2',1"-terphenyl Synthesis of [4-Methyl]-4-carbonitrile

Using 3-(pyrrolidin-3-yl)pyridine instead of tert-butyl N-[(3S)-pyrrolidin-3-yl]carbamate, the steps 1-5 of Example 1 were repeated to obtain 4″-methyl-5′-(3-(pyridin-3-yl)pyrrolidine-1-carbonyl)-[1,1′:2′,1″-terphenyl]-4-carbonitrile.

Comparative Example 7: Synthesis of 4-(3-(4-aminopiperidine-1-carbonyl)-5-(p-tolyl)-1H-pyrazol-1-yl)benzonitrile become

Step 1

The procedure of the synthetic method of Scheme C disclosed in WO2015/103060 was repeated using 1-(4-methylphenyl)ethanone as C-1, 4-hydrazinobenzonitrile instead of (4-(trifluoromethyl)phenyl)hydrazine, and tert-butyl piperidin-4-ylcarbamate instead of 1-(4-fluorophenyl)-1,3,8-triazaspiro[4.5]decan-4-one to obtain tert-butyl (1-(1-(4-cyanophenyl)-5-(p-tolyl)-1H-pyrazole-3-carbonyl)piperidin-4-yl)carbamate.

Step 2

Using tert-butyl (1-(1-(4-cyanophenyl)-5-(p-tolyl)-1H-pyrazole-3-carbonyl)piperidin-4-yl)carbamate obtained in the above step 1 instead of N-[(3S)-1-[3-(4-cyanophenyl)-4-(p-tolyl)benzoyl]pyrrolidin-3-yl]carbamate, the procedure of step 5 of example 1 was repeated to give the title compound.

The following is a list of compounds of Examples 1-281 and Comparative Examples 1-7.

In the following table, if the structure:

As shown below:

Then a compound represents a mixture of compounds having the following structures:

If the structure looks like this:

Then a compound represents a mixture of compounds having the following structures:

And if the structure looks like this:

Then the compound has one of the following structures:

Table 1

Table 2

Table 3

Table 4

Table 5

Table 6

Table 7

Table 8

Table 9

Table 10

Table 11

Table 12

Table 13

Table 14

Table 15

Table 16

Table 17

Table 18

Table 19

Table 20

Table 21

Table 22

Table 23

Table 24

Table 25

Table 26

Table 27

Table 28

Table 29

Table 30

Table 31

Test Example 1: Determination of LSD1 inhibitory activity (in vitro)

The conditions for measuring the inhibitory activity of the compounds on LSD1 activity were determined with reference to a document available from the PerkinElmer website (U-TRF#38) and a patent of GlaxoSmithKline (WO2012135113).

To determine inhibitory activity, the compounds of the present invention were first serially diluted in dimethyl sulfoxide (DMSO). Subsequently, a solution of the compounds of the present invention in DMSO (final concentration: 5%) and human LSD1 protein (Abcam, ab80379) were added to a reaction buffer (25 mM Tris-HCl (pH 7.5), 50 mM KCl, 2 mM CHAPS, 1 mM DTT, 0.02% BSA). The mixture was preincubated at 25°C for 30 minutes. An H3K4(Me1)-biotin-labeled peptide (Anaspec #64355) was then added (final concentration: 200 nM) and allowed to react for 60 minutes. Tranylcypromine (final concentration: 3 mM) was then added to terminate the reaction. Afterwards, a detection solution containing an Eu-labeled anti-H3K4 antibody (PerkinElmer, TRF0404) and streptavidin Alexa Fluor 647 (Thermo Fisher Scientific, S21374) was added thereto, and the mixture was left at room temperature for 1 hour. Finally, the fluorescence intensity under excitation light of 337 nm was measured at two wavelengths of 620 nm and 665 nm using a PHERAstar FS (BMG Labtech). The demethylation level was calculated based on the ratio of the fluorescence intensities at the two wavelengths, and the concentration of the compound at which demethylation was inhibited by 50% was defined as IC 50 (nM). The following table shows the results.

Table 32

Table 33

The test results show that the compounds of the present invention exhibit LSD1 inhibitory activity.

Test Example 2: Cell growth inhibition test

In vitro cell growth inhibition assays were performed on HEL cells (human acute myeloid leukemia cell line), NCI-H1417 cells (human small cell lung cancer cell line) and NCI-H146 cells (human small cell lung cancer cell line) under the following conditions.

HEL cells (JCRB, catalog number: JCRB0062), NCI-H1417 cells (ATCC, catalog number: CRL-5869) or NCI-H146 cells (ATCC, catalog number: HTB-173) cultured in RPMI1640 (Thermo Fisher Scientific, catalog number: A10491-01) containing 10% FBS were seeded in 96-well flat-bottom microplates (Thermo Fisher Scientific, catalog number: 165305) so that each well contained 1500 HEL cells (100 μL), 5000 NCI-H1417 cells (100 μL) or 1200 NCI-H146 cells (100 μL). The compounds of the present invention were serially diluted in dimethyl sulfoxide (DMSO) to a concentration 500 times higher than the final concentration. The serially diluted compound of the present invention or dimethyl sulfoxide alone was added to RPMI1640 culture medium containing 10% FBS to a concentration twice the final concentration, and the resulting product was added to each well of a culture plate containing HEL cells, NCI-H1417 cells or NCI-H146 cells in an amount of 100 μL so that the final concentrations of the compound of the present invention were 3000, 1000, 300, 100, 30, 10, 3, 1, 0.3, 0.1, 0.03 and 0.01 nM, respectively. The final concentration of dimethyl sulfoxide was adjusted to 0.2%. Cells with the compound of the present invention or only dimethyl sulfoxide were cultured at 37°C in an incubator containing 5% carbon dioxide for 5 days (HEL cells) or 10 days (NCI-H1417 cells and NCI-H146 cells). After cultivation, the plate was placed at room temperature for 30 minutes, and 100 μL of supernatant was removed from each well, leaving 100 μL of cell culture fluid. An equal amount of CellTiter-Glo 2.0 Assay (Promega, catalog number: G9242) was added to each well containing the remaining 100 μL of cell culture medium. The microplate was shaken for 1 minute using a plate mixer and then allowed to stand in the dark for 10 minutes. Thereafter, the luminescence intensity of the viable cells in each well was measured using a microplate reader (PerkinElmer, EnSpire). The cell growth rate was determined according to the following formula: the concentration at which the cell growth rate was 50%, i.e., the concentration of each compound of the present invention that inhibited cell growth by 50% (IC 50 (nM)), was determined.

Cell growth rate (%) = T/C x 100

T: Luminescence intensity (counts per second) in the well to which the compound of the present invention was added

C: Luminescence intensity (counts per second) in the well to which only dimethyl sulfoxide was added

The table below shows the results.

Table 34

Cell growth inhibition assay: HEL cells

Ex.No. IC50(nM) Ex.No. IC50(nM) Ex.No. IC50(nM) Ex.No. IC50(nM) 1 39.8 49 32.1 125 7.57 177 0.38 4 28.8 59 33.0 126 5.39 178 3.57 5 34.5 63 28.3 128 5.70 179 1.52 7 14.8 65 23.9 130 22.2 180 1.16 8 42.7 69 29.9 131 15.2 181 9.06 9 38.7 71 19.5 133 17.7 182 22.4 10 31.7 74 20.4 134 1.06 183 0.54 12 36.7 75 5.78 135 2.37 184 2.26 15 17.3 77 12.6 136 0.90 185 0.68 16 34.3 80 43.6 139 16.9 186 5.30 18 3.55 81 11.7 141 1.50 187 1.99 19 24.4 82 11.1 142 3.86 188 1.95 20 7.73 84 41.7 143 0.95 189 0.59 twenty one 8.34 85 32.2 144 6.37 190 0.41 twenty two 3.51 86 13.4 145 1.61 191 3.91 twenty three 0.73 87 17.4 146 1.15 192 1.11 twenty four 3.56 92 9.91 147 3.04 193 2.31 25 4.72 94 25.4 155 0.83 194 15.5 26 4.83 96 11.0 160 7.03 195 0.45 27 24.7 102 12.8 161 6.88 196 0.33 28 15.7 104 28.8 162 17.7 197 1.0 30 27.1 106 5.74 166 0.62 198 0.43 36 15.4 108 36.4 167 4.05 199 22.0 37 10.1 109 15.1 168 5.29 200 3.72 38 34.0 110 7.41 170 3.44 201 1.55 39 17.4 113 9.00 171 0.090 202 0.24 40 27.2 117 8.54 172 0.47 203 2.48 41 4.98 120 7.60 173 1.65 204 2.14 47 29.3 123 1.39 175 0.20 205 4.95 48 28.9 124 2.84 176 0.20 206 0.40

Table 35

Cell growth inhibition assay: HEL cells

Table 36

Cell growth inhibition assay: NCI-H1417 cells

Table 37

Cell growth inhibition assay: NCI-H1417 cells

Table 38

Cell growth inhibition assay: NCI-H146 cells

The test results show that the compounds of the present invention exhibit in vitro cell growth inhibition effects. The compounds of the present invention not only inhibit the activity of recombinant human LSD1 protein, but also inhibit the growth of cancer cells, indicating that the compounds can be used as antitumor agents.

Test Example 3: Anti-tumor effect test using NCI-H146 cells (human small cell lung cancer cell line)

NCI-H146 cells (3.5×10 ⁶ cells (100 μL)) were subcutaneously implanted into BALB/cAJcl-nu/nu mice, and mice with tumor volumes ranging from 100-300 mm ³ were grouped so that the groups had uniform tumor volumes. Five mice per group were orally administered with a vehicle (0.5% hydroxymethylpropylcellulose containing 0.1N HCL) or each example compound. Dosing was performed once a day for 21 consecutive days (Example Compound 41) or 28 consecutive days (Example Compounds 37, 161, 166, 175, 176, and 177). The long and short axes of the tumor were measured twice a week with an electric caliper to calculate the tumor volume (TV). Based on the tumor volume thus obtained, the relative tumor volume (RTV) and relative tumor volume change (T/C (%)) were calculated. TV, RTV, and T/C (%) were calculated using the following equations.

Tumor volume TV (mm ³ ) = (long axis, mm) x (short axis, mm) x (short axis, mm)/2

Relative tumor volume RTV = TV/(TV on the day of grouping)

T/C (%)=(average RTV of the drug-administered group)/(average RTV of the vehicle-administered group)×100.

The table below shows the results.

Table 39

Example Compound No. Dosage (mg/kg) T/C (%) 37 50 twenty two 41 25 19 161 40 14 166 20 19 175 2 41 176 20 27 177 10 twenty two

The final measurement day is the day after the last administration. The compounds of the present invention showed antitumor effects in the above efficacy evaluation model, and the body weight loss percentage on the final measurement day was less than 20% of the body weight before administration (Day 0).

The results show that the compounds of the present invention or their salts have excellent LSD1 inhibitory activity, exhibit cancer cell growth inhibitory effects, have low toxicity, and can be orally administered. Therefore, the compounds of the present invention or their salts are useful as preventive and/or therapeutic agents for cancer.

Claims (7)

1. A compound or a salt thereof represented by formula (I): in Ring A represents pyrrolidinyl, piperidinyl, piperazinyl, aziridine-heptyl, diazacycloheptanyl, etc. 2,7-Dazaspiro[3.4]octyl, 3,7-Dazaspiro[3.4]octyl, 2,7-Dazaspiro[3.5]nonyl, 2,8-Dazaspiro[3.5]nonyl, 3,7-Dazaspiro[3.5]nonyl, 3,8-Dazaspiro[4.4]nonyl, 3,8-Dazaspiro[4.5]decyl, or 9-oxa-diazaspiro[3.5]nonyl, Ring B represents phenyl, naphthyl, pyridinyl, pyrazolopyridinyl, pyrazolopyrimidinyl, indole, dihydroindole, 2-oxo-dihydroindole, indazole, benzimidazolyl, benzisoxazolyl, benzothiazolyl, benzotriazolyl, imidazopyridinyl, quinolinyl, isoquinolinyl, quinoxolinyl, quinazolinyl, phthalazinyl, 2-oxo-2,3-dihydrobenzo[d]oxazolyl, 1,3-dihydroisobenzofuranyl, dihydrobenzooxazinyl, benzodioxolyl, dihydrobenzodioxynyl, or 2-oxo-2,3-dihydrobenzo[d]thiazolyl. X represents O or S. R1 represents nitro or cyano. R2 represents a fluorine atom and is located in the ortho position relative to R1 on the phenyl group. R3 represents amino, methylamino, ethylamino, isopropylamino, dimethylamino, cyclobutylamino, or methyl. When two or more R3s are present, the R3s can be the same or different. R4 is selected from fluorine, chlorine, bromine, iodine, nitro, cyano, carboxyl, methyl, ethyl, n-propyl, isopropyl, tert-butyl, difluoromethyl, trifluoromethyl, fluoroethyl, aminoethyl, hydroxymethyl, hydroxyethyl, hydroxypropyl, hydroxydimethylethyl, hydroxymethylpropyl, hydroxymethylbutyl, hydroxyethylbutyl, carboxymethyl, carbamoylmethyl, methylcarbamoylmethyl, dimethylcarbamoylmethyl, acetylaminoethyl, methoxyethyl, hydroxycyclopropylmethyl, hydroxycyclopropylethyl, hydroxycyclobutylmethyl, methylcarbonyloxyethyl, isobutylenyl, methoxy, hydroxypropoxy, cyclopropyl, hydroxymethylcyclopropyl, methoxymethylcyclopropyl, hydroxycyclopropylcyclopropyl, phenylcarbamoylcyclopropyl, benzyloxy, dimethylamino, carbamoyl, methylcarbamoyl, or dimethylcarbamoyl. When two or more R4s are present, R4s can be the same or different, and n is an integer from 0 to 3. l is an integer between 0 and 2. m is an integer between 0 and 2, and n is an integer between 0 and 3. When l is 2, the two R2s can be the same or different; when m is 2, the two R3s can be the same or different; and when n is 2-3, the two to three R4s can be the same or different. 2. A salt of a compound according to any one of (1)-(24) below or a compound according to any one of (1)-(24) below; (1) 4-[5-[(3-exo)-3-amino-8-azabicyclo[3.2.1]octane-8-carbonyl]-2-[2-fluoro-4-(2-hydroxy-2-methyl-propyl)phenyl]phenyl]-2-fluorobenzonitrile, (2) 4-[5-[(3S)-3-aminopyrrolidone-1-carbonyl]-2-[2-fluoro-4-(2-hydroxy-2-methyl-propyl)phenyl]phenyl]-2-fluorobenzonitrile, (3) 4-[5-[(3-endo)-3-amino-8-azabicyclo[3.2.1]octane-8-carbonyl]-2-[2-fluoro-4-(2-hydroxy-2-methyl-propyl)phenyl]phenyl]-2-fluorobenzonitrile, (4)(S)-5'-(3-aminopyrrolidone-1-carbonyl)-3-fluoro-2'-(6-fluoro-1-(2-hydroxy-2-methylpropyl)-1H-indol-5-yl)-[1,1'-biphenyl]-4-carboxynitrile, (5) 5'-((3-endo)-3-amino-8-azabicyclo[3.2.1]octane-8-carbonyl)-2'-(6,7-difluoro-1-(2-hydroxy-2-methylpropyl)-1H-benzo[d][1,2,3]triazol-5-yl)-3-fluoro-[1,1'-biphenyl]-4-carboxynitrile, (6) 5'-((1S,2S,4R)-rel-2-amino-7-azabicyclo[2.2.1]heptane-7-carbonyl)-2”,3-difluoro-4”-(2-hydroxy-2-methylpropyl)-[1,1':2',1”-terphenyl]-4-carboxynitrile-isomer-B, (7) 5'-((1S,2S,4R)-rel-2-amino-7-azabicyclo[2.2.1]heptane-7-carbonyl)-2'-(6,7-difluoro-1-methyl-1H-benzo[d][1,2,3]triazol-5-yl)-3-fluoro-[1,1'-biphenyl]-4-carboxynitrile-isomer-B, (8) 5'-((1S,2S,4R)-rel-2-amino-7-azabicyclo[2.2.1]heptane-7-carbonyl)-3-fluoro-2'-(6-fluoro-1-(2-hydroxy-2-methylpropyl)-1H-indazol-5-yl)-[1,1'-biphenyl]-4-carboxynitrile-isomer-B, (9) 5'-((1S,2S,4R)-rel-2-amino-7-azabicyclo[2.2.1]heptane-7-carbonyl)-2'-(6,7-difluoro-1-(2-hydroxy-2-methylpropyl)-1H-benzo[d][1,2,3]triazol-5-yl)-3-fluoro-[1,1'-biphenyl]-4-carboxynitrile-isomer-B, (10) 5'-((1S,2S,4R)-rel-2-amino-7-azabicyclo[2.2.1]heptane-7-carbonyl)-2'-(6,7-difluoro-1-(2-hydroxy-2-methylpropyl)-1H-benzo[d][1,2,3]triazol-5-yl)-3-fluoro-[1,1'-biphenyl]-4-carboxynitrile, (11) 5'-((1S,2S,4R)-rel-2-amino-7-azabicyclo[2.2.1]heptane-7-carbonyl)-2'-(7-chloro-6-fluoro-1-(2-hydroxy-2-methylpropyl)-1H-benzo[d][1,2,3]triazol-5-yl)-3-fluoro-[1,1'-biphenyl]-4-carboxynitrile-isomer-X, (12) 5'-((1S,2S,4R)-rel-2-amino-7-azabicyclo[2.2.1]heptane-7-carbonyl)-2'-(7-chloro-6-fluoro-1-(2-hydroxy-2-methylpropyl)-1H-benzo[d][1,2,3]triazol-5-yl)-3-fluoro-[1,1'-biphenyl]-4-carboxynitrile, (13) 5'-((1S,2S,4R)-rel-2-amino-7-azabicyclo[2.2.1]heptane-7-carbonyl)-2'-(1-(2-ethyl-2-hydroxybutyl)-6,7-difluoro-1H-benzo[d][1,2,3]triazol-5-yl)-3-fluoro-[1,1'-biphenyl]-4-carboxynitrile-isomer-X, (14) 5'-((1S,2S,4R)-rel-2-amino-7-azabicyclo[2.2.1]heptane-7-carbonyl)-2'-(1-(2-ethyl-2-hydroxybutyl)-6,7-difluoro-1H-benzo[d][1,2,3]triazol-5-yl)-3-fluoro-[1,1'-biphenyl]-4-carboxynitrile, (15)(S)-5'-(3-aminopyrrolidine-1-carbonyl)-3-fluoro-2'-(5-fluoro-3-(2-hydroxy-2-methylpropyl)benzo[d]isoxazo-6-yl)-[1,1'-biphenyl]-4-carboxynitrile, (16) 5'-((1S,2S,4R)-rel-2-amino-7-azabicyclo[2.2.1]heptane-7-carbonyl)-2'-(7-(difluoromethyl)-6-fluoro-1-(2-hydroxy-2-methylpropyl)-1H-benzo[d][1,2,3]triazol-5-yl)-3-fluoro-[1,1'-biphenyl]-4-carboxynitrile-isomer-X, (17) 5-(5-((1S,2S,4R)-rel-2-amino-7-azabicyclo[2.2.1]heptane-7-carbonyl)-4'-cyano-3'-fluoro-[1,1'-biphenyl]-2-yl)-6-fluoro-1-(2-hydroxy-2-methylpropyl)-1H-benzo[d][1,2,3]triazole-7-carboxynitrile-isomer-X, (18) 5'-((1S,2S,4R)-rel-2-amino-7-azabicyclo[2.2.1]heptane-7-carbonyl)-2'-(7-(difluoromethyl)-6-fluoro-1-(2-hydroxy-2-methylpropyl)-1H-benzo[d][1,2,3]triazol-5-yl)-3-fluoro-[1,1'-biphenyl]-4-carboxynitrile, (19) 5'-((3-endo)-3-amino-8-azabicyclo[3.2.1]octane-8-carbonyl)-2'-(7-chloro-6-fluoro-1-((1-hydroxycyclobutyl)methyl)-1H-benzo[d][1,2,3]triazol-5-yl)-3-fluoro-[1,1'-biphenyl]-4-carboxynitrile, (20)5'-((3-endo)-3-amino-8-azabicyclo[3.2.1]octane-8-carbonyl)-2'-(7-(difluoromethyl)-6-fluoro-1-((1-hydroxycyclobutyl)methyl)-1H-benzo[d][1,2,3]triazol-5-yl)-3-fluoro-[1,1'-biphenyl]-4-carboxynitrile, (21) 5-(5-((1S,2S,4R)-rel-2-amino-7-azabicyclo[2.2.1]heptane-7-carbonyl)-4'-cyano-3'-fluoro-[1,1'-biphenyl]-2-yl)-6-fluoro-1-((1-hydroxycyclobutyl)methyl)-1H-benzo[d][1,2,3]triazole-7-carboxynitrile-isomer-X, (22) 5-(5-((1S,2S,4R)-rel-2-amino-7-azabicyclo[2.2.1]heptane-7-carbonyl)-4'-cyano-3'-fluoro-[1,1'-biphenyl]-2-yl)-6-fluoro-1-((1-hydroxycyclobutyl)methyl)-1H-benzo[d][1,2,3]triazol-7-carboxynitrile, (23) 5'-((1S,2S,4R)-rel-2-amino-7-azabicyclo[2.2.1]heptane-7-carbonyl)-2'-(7-bromo-6-fluoro-1-(2-hydroxy-2-methylpropyl)-1H-benzo[d][1,2,3]triazol-5-yl)-3-fluoro-[1,1'-biphenyl]-4-carboxynitrile-isomer-X, (24)5'-((1S,2S,4R)-rel-2-amino-7-azabicyclo[2.2.1]heptane-7-carbonyl)-2'-(7-bromo-6-fluoro-1-(2-hydroxy-2-methylpropyl)-1H-benzo[d][1,2,3]triazol-5-yl)-3-fluoro-[1,1'-biphenyl]-4-carboxynitrile. 3. An LSD1 inhibitor comprising the compound or a salt thereof according to claim 1 or 2 as the active ingredient. 4. A pharmaceutical composition comprising the compound or a salt thereof according to claim 1 or 2. 5. The pharmaceutical composition according to claim 4, in combination with a carrier suitable for oral administration. 6. An antitumor agent comprising, as an active ingredient, the compound or a salt thereof according to claim 1 or 2. 7. Use of the compound or its salt according to claim 1 or 2 in the preparation of an antitumor agent.