RU2803455C1 - Pyrrolidine and piperidine compounds - Google Patents

Abstract

FIELD: pharmaceuticals.

SUBSTANCE: invention relates to compounds of formula 1, where R₂ and R₃ are defined in the claims, or their pharmaceutically acceptable salts, methods of their preparation, pharmaceutical compositions containing them, and the use of compounds for the treatment and prevention of FAP-mediated diseases.

R₁ is selected from:

EFFECT: obtaining pyrrolidine and piperidine compounds.

11 cl, 8 tbl, 439 ex

Description

TECHNICAL FIELD

[0001] The present technology relates to pyrrolidine and piperidine compounds, their stereoisomers and pharmaceutically acceptable salts having fibroblast activation protein (FAP) inhibitory activity. Methods of preparation, pharmaceutical compositions and methods of use are also provided.

BACKGROUND OF THE ART

[0002] Fibroblast activation protein (FAP) is a homodimeric type II integral membrane serine protease belonging to the dipeptidyl peptidase-4 group (dipeptidyl peptidase IV, DPP4). This group of proteins includes proteins of other subtypes such as DPP7, 8, 9, etc. FAP and DPP4 share approximately 50% amino acid sequence similarity. However, unlike DPP4, which is expressed in most biological tissues, FAP is expressed in sites of tissue remodeling, including, but not limited to, cancer, fibrosis, atherosclerosis, and arthritis.

[0003] FAP, like DPP4, has dipeptidyl peptidase activity, capable of cleaving a post-proline bond at two or more residues from the N-terminus, but, unlike DPP4, FAP also has specific endopeptidase enzymatic activity, capable of cleaving the glycine-proline bond present in the substrate (Aertgeerts et al., J. Biol. Chem., 2005, 280, 19441). In addition, FAP has collagenase activity, capable of degrading gelatin and collagen type 1 (CN-1) (Fuming Zi et al., Molecular Medicine Reports, November 2015, 3203).

[0004] FAP is expressed where tissue remodeling occurs, for example, in liver fibrosis (Levy et al., Hepatol, 1999, 29:1768). In patients with liver fibrosis due to alcohol abuse or a viral infection, cells have been found to express large amounts of FAP, which is associated with excessive scarring and liver disease. As an example, FAP expression has been reported to be increased in activated hepatic stellate cells (hereinafter “aHSC”) and myofibroblasts, which play an important role in liver fibrosis (Levy et al., Hepatol., 1999, 29, 1768; Lay AJ et al. , Front. Biosci. [Landmark Ed] 2019, 24, 1-17).

[0005] Substrates cleaved by FAP include α2-antiplasmin, Sprouty-2 protein, and gelatin and collagen type 1 (CN-1). Recently, it was reported that fibroblast growth factor-21 (FGF21), which is one of the non-mitogenic hepatokines, is also a substrate cleaved by FAP (D.R. Dunshee et al., J. Biol. Chem., 2016, 291, 5986).

[0006] Accordingly, there is a need for FAP inhibitors that can be successfully used for the prevention and treatment of diseases.

DISCLOSURE OF THE INVENTION

[0007] Presented herein in one aspect is a compound of formula 1:

Where

n is 1 or 2;

R ₁ is selected from the group consisting of formulas I, II, III, IV, and IV;

R ₂ represents hydrogen or C _1-3 alkyl;

R ₃ represents a 5-12 membered heteroaryl, wherein said heteroaryl contains from 1 to 3 heteroatoms selected from O, N and S, and is optionally substituted with 1-3 Z,

a 3-12 membered non-aromatic heterocycle, wherein said heterocycle contains from 1 to 3 heteroatoms selected from O, N and S, and is optionally substituted with 1-3 Z,

-NR ₄ R ₅ , -OR ₄ , -C(O)NHR ₄ , -NHC(O)(CH ₂ ) _m R ₄ , -NHS(O) ₂ R ₄ , -(CH ₂ ) _m CH ₂ R ₄ , or -(CH ₂ ) _m NHR ₄ ,

where m represents 0 or 1;

R ₄ is phenyl substituted with 1-3 Z,

heterocycle selected from the group consisting of benzo[d][1,3]dioxolyl,

dihydrobenzo[1,4]dioxynyl, 2,3-dihydrobenzofuranyl, 2-oxo-1,2-dihydroquinolinyl and 2-oxo-1,2,3,4-tetrahydroquinolinyl, wherein said heterocycle is optionally substituted with 1-3 Z,

naphthyl, optionally substituted with 1-3 Z or

heteroaryl selected from the group consisting of pyridinyl, pyrimidinyl, pyrazinyl, imidazolyl, pyrazolyl, triazolyl, oxazolyl, thiazolyl, furanyl, pyrrolyl, thiophenyl, quinolinyl, isoquinolinyl, chromenonyl, quinazolinyl, benzoxazolyl, benzofuranyl, benzothiophenyl, indolyl, indolinyl, benzime idazolyl, benzoxazolyl, benzothiazolyl, indazolyl, furo[3,2-c]pyridinyl, thieno[2,3-d]pyrimidinyl, thieno[3,2-c]pyridinyl, isoxazolyl, acridinyl and naphthyridinyl, wherein said heteroaryl is optionally substituted 1-3 Z;

R ₅ represents hydrogen or C _1-3 alkyl; And

each Z is independently selected from the group consisting of hydroxy, amino, halogen, cyano, nitro, carboxylic acid, C _1-5 alkyl, optionally substituted with 1-3 Z ¹ , C _2-6 alkenyl, optionally substituted with Z ¹ , C _{2- 6} alkynyl, optionally substituted with Z ¹ , C _1-5 alkoxy, optionally substituted with 1-3 Z ¹ , C _1-5 alkylthio, optionally substituted with Z ¹ , mono- or di-C _1-5 alkylamino, optionally substituted with Z ¹ , piperazinyl , optionally substituted with Z ¹ , C _1-5 alkylsulfonylamino, optionally substituted with Z ¹ , C _1-5 alkylcarbonylamino, optionally substituted with Z ¹ , aminosulfonyl, optionally substituted with Z ¹ , aminocarbonyl, optionally substituted with Z ¹ , C _1-5 alkylaminocarbonyl, optionally substituted Z ¹ , phenyl, optionally substituted with Z ¹ , phenoxy, optionally substituted with Z ¹ , benzyl, optionally substituted with Z ¹ , benzoyl, optionally substituted with Z ¹ , phenylaminocarbonyl, optionally substituted with Z ¹ , pyrazolyl, optionally substituted with Z ¹ , benzoxazolyl, optionally substituted with Z ¹ , C _1-5 alkoxycarbonyl, optionally substituted with Z ¹ , benzyloxy, optionally substituted with Z ¹ , C _1-5 alkylsulfonyl, optionally substituted with Z ¹ acetyl, morpholinyl, optionally substituted with Z ¹ , -NR ₆ C(O)R ₇ and - C(O)NR ₆ R ₇ ;

where each Z ¹ is independently selected from halogen, hydroxyl, amino, C _1-5 alkylamino, cyano, acetyl, C _1-5 alkyl, C _1-5 haloalkyl, C _3-6 carbocycle, C _3-6 heterocycle, wherein the specified The C _3-6 carbocycle and said C _3-6 heterocycle are optionally substituted with halogen, hydroxyl, C _1-5 alkyl or C _1-5 haloalkyl;

R ₆ represents hydrogen or a C _1-3 alkyl group;

R ₇ represents a C _1-3 alkyl group, optionally substituted with phenyl,

phenyl, optionally substituted with 1-3 Z ² or

heteroaryl selected from the group consisting of pyridinyl, pyrimidinyl, pyrazinyl, imidazolyl, pyrazolyl, triazolyl, oxazolyl, thiazolyl, furanyl, pyrrolyl, thiophenyl, quinolinyl, isoquinolinyl, chromenonyl, quinazolinyl, benzoxazolyl, benzofuranyl, benzothiophenyl, indolyl, indolinyl, benzime idazolyl, benzoxazolyl, benzothiazolyl, indazolyl, furo[3,2-c]pyridinyl, thieno[2,3-d]pyrimidinyl, thieno[3,2-c]pyridinyl, isoxazolyl, acridinyl and naphthyridinyl, wherein said heteroaryl is optionally substituted 1-3 ^Z2 ; And

each Z ² is independently selected from the group consisting of hydroxy, amino, halogen, cyano, nitro, hydroxycarbonyl, C _1-5 alkyl, optionally substituted 1-3 Z ³ , C _2-6 alkenyl, C _2-6 alkynyl, C _{1 -5} alkoxy, optionally substituted with 1-3 Z ³ , C _1-5 alkylthio, mono- or di-C _1-5 alkylamino, piperazinyl, optionally substituted with Z ³ , C _1-5 alkylsulfonylamino, C _1-5 alkylcarbonylamino, aminosulfonyl, aminocarbonyl, C _1-5 alkylaminocarbonyl, phenyl, phenoxy, benzyl, benzoyl, phenylaminocarbonyl, pyrazolyl and benzoxazolyl;

wherein each Z ³ is independently selected from halogen, amino or acetyl;

or a stereoisomer, or a mixture of stereoisomers, or a pharmaceutically acceptable salt thereof.

[0008] In some embodiments, R ₁ is selected from the group consisting of compounds of formulas I, II, III and V:

[0009] In some embodiments, R ₁ is a compound of Formula I. . In some embodiments, R ₁ is a compound of Formula II. . In some embodiments, R ₁ is a compound of Formula III. . In some embodiments, R ₁ is a compound of Formula IV. . In some embodiments, R ₁ is a compound of Formula V .

[0010] In some embodiments, R ₁ is a substituent selected from the group consisting of compounds of formulas Ia-Va,

[0011] In some embodiments, R ₁ is a substituent selected from the group consisting of compounds of formulas Ia, IIa, IIIa, and Va:

[0012] In some embodiments, R ₁ is a compound of Formula Ia: . In some embodiments, R ₁ is a compound of Formula IIa: . In some embodiments, R ₁ is a compound of formula IIIa: . In some embodiments, R ₁ is a compound of Formula IVa: . In some embodiments, R ₁ is a compound of Formula Va: .

[0013] In some embodiments, R ₂ is hydrogen. In some embodiments, R ₂ is C _1-3 alkyl.

[0014] In some embodiments, the compound, or a stereoisomer or mixture of stereoisomers, or a pharmaceutically acceptable salt thereof has the structure of formula 1a:

In additional embodiments, R ₅ is hydrogen. In other embodiments, R ₅ is C _1-3 alkyl.

[0015] In some embodiments, the compound, or a stereoisomer or mixture of stereoisomers, or a pharmaceutically acceptable salt thereof has the structure of Formula 1b:

[0016] In some embodiments, the compound, or a stereoisomer or mixture of stereoisomers, or a pharmaceutically acceptable salt thereof has the structure of formula 1c:

[0017] In some embodiments, the compound, or a stereoisomer or mixture of stereoisomers, or a pharmaceutically acceptable salt thereof has the structure of formula 1d:

In additional embodiments, m is 0. In other embodiments, m is 1.

[0018] In some embodiments, the compound, or a stereoisomer or mixture of stereoisomers, or a pharmaceutically acceptable salt thereof has the structure of formula 1e:

[0019] In some embodiments, R ₃ is a substituent selected from the group consisting of -NR ₄ R ₅ , -OR ₄ , -C(O)NHR ₄ , -NHC(O)(CH ₂ ) _m R ₄ , and -NHS(O) ₂ R ₄ . In some embodiments, R ₃ is a substituent selected from the group consisting of -NR ₄ R ₅ , -OR ₄ , and -NHC(O)(CH ₂ ) _m R ₄ . In some embodiments, R ₃ is a substituent selected from the group consisting of -NR ₄ R ₅ and -OR ₄ .

[0020] In some embodiments, R ₄ is phenyl substituted with 1-3 Z, each Z being independently selected from the group consisting of hydroxy, amino, halogen, cyano, nitro, carboxylic acid, C _1-5 alkyl, optional substituted with 1-3 halogens or amino group, C _2-6 alkenyl, C _2-6 alkynyl, C _1-5 alkoxy, C _1-5 alkylthio, mono- or di-C _1-5 alkylamino, piperazinyl, optionally substituted with acetyl, C _1-5 alkylsulfonylamino, C _1-5 alkylcarbonylamino, aminosulfonyl, aminocarbonyl, C _1-5 alkylaminocarbonyl, phenyl, phenoxy, benzyl, benzoyl, phenylaminocarbonyl, pyrazolyl and benzoxazolyl. In additional embodiments, R ₄ is phenyl substituted with a substituent selected from the group consisting of piperazinyl, optionally substituted with acetyl, phenyl, phenoxy, benzyl, benzoyl, phenylaminocarbonyl, pyrazolyl, and benzoxazolyl.

[0021] In some embodiments, R ₄ is a heterocycle selected from the group consisting of benzo[d][1,3]dioxolyl, dihydrobenzo[1,4]dioxynyl, 2,3-dihydrobenzofuranyl, 2-oxo-1 ,2-dihydroquinolinyl and 2-oxo-1,2,3,4-tetrahydroquinolinyl, wherein said heterocycle is optionally substituted with 1-3 Z. In further embodiments, R ₄ is a heterocycle selected from the group consisting of benzo[d][ 1,3]dioxolyl, 2,3-dihydrobenzofuranyl, 2-oxo-1,2-dihydroquinolinyl and 2-oxo-1,2,3,4-tetrahydroquinolinyl.

[0022] In some embodiments, R ₄ is naphthyl, optionally substituted with halogen.

[0023] In some embodiments, R ₄ is heteroaryl selected from the group consisting of pyridinyl, pyrimidinyl, pyrazinyl, imidazolyl, pyrazolyl, triazolyl, oxazolyl, thiazolyl, furanyl, pyrrolyl, thiophenyl, quinolinyl, isoquinolinyl, chromenonyl, quinazolinyl, benzoxazolyl, benzofuranyl, benzothiophenyl, indolyl, indolinyl, benzimidazolyl, benzoxazolyl, benzothiazolyl, indazolyl, furo[3,2-c]pyridinyl, thieno[2,3-d]pyrimidinyl, thieno[3,2-c]pyridinyl, isoxazolyl, acridinyl and naphthyridinyl, wherein said heteroaryl is optionally substituted with 1-3 Z, wherein each Z is independently selected from the group consisting of hydroxy, amino, di-C _1-5 alkylamino, cyano, nitro, halogen, C _1-5 alkyl, optionally substituted 1-3 halogens, C _1-5 alkoxy, optionally substituted with 1 to 3 halogens, C _1-5 alkoxycarbonyl, benzyloxy, phenyl, optionally substituted with halogen, acetyl, C _1-5 alkylsulfonyl, morpholinyl, -NR ₆ C(O) R ₇ and -C(O)NR ₆ R ₇ . In additional embodiments, R ₄ is heteroaryl selected from the group consisting of pyridinyl, quinolinyl, isoquinolinyl, chromenonyl, quinazolinyl, benzofuranyl, indolinyl, benzimidazolyl, benzothiophenyl, benzothiazolyl, furo[3,2-c]pyridinyl, thieno[2, 3-d]pyrimidinyl, thieno[3,2-c]pyridinyl, isoxazolyl, acridinyl and naphthyridinyl, wherein said heteroaryl is optionally substituted with 1-3 Z, each Z being independently selected from the group consisting of hydroxy, halogen, C _1-5 alkyl, optionally substituted with 1-3 halogens, C _1-5 alkoxy, optionally substituted with 1-3 halogens, C _1-5 alkoxycarbonyl, benzyloxy, acetyl, morpholinyl, -NR ₆ C(O)R ₇ , -C(O)NR ₆ R ₇ and phenyl, optionally substituted with halogen; where R ₆ represents hydrogen or a C _1-3 alkyl group; and R ₇ represents a C _1-3 alkyl group, optionally substituted with phenyl, phenyl or heteroaryl selected from the group consisting of pyridinyl, pyrimidinyl and isoxazolyl.

[0024] In other embodiments, R ₄ is phenyl substituted with a substituent selected from the group consisting of piperazinyl, optionally substituted with acetyl, phenyl, phenoxy, benzyl, benzoyl, phenylaminocarbonyl, pyrazolyl, and benzoxazolyl;

a heterocycle selected from the group consisting of benzo[d][1,3]dioxolyl, 2,3-dihydrobenzofuranyl, 2-oxo-1,2-dihydroquinolinyl and 2-oxo-1,2,3,4-tetrahydroquinolinyl;

naphthyl, optionally substituted with halogen; or

heteroaryl selected from the group consisting of pyridinyl, quinolinyl, isoquinolinyl, chromium, quinazolinyl, benzofuranyl, indolinyl, benzimidazolyl, benzothiophenyl, benzothiazolyl, furo[3,2-c]pyridinyl, thieno[2,3-d]pyrimidinyl, thieno[ 3,2-c]pyridinyl, isoxazolyl, acridinyl and naphthyridinyl, wherein said heteroaryl is optionally substituted with 1-3 Z, wherein each Z is independently selected from the group consisting of hydroxy, halogen, C _1-5 alkyl, optionally substituted with 1-3 halogens , C _1-5 alkoxy, optionally substituted with 1-3 halogens, C _1-5 alkoxycarbonyl, benzyloxy, acetyl, morpholinyl, -NR ₆ C(O)R ₇ , -C(O)NR ₆ R ₇ and phenyl, optionally substituted halogen; where R ₆ represents hydrogen or a C _1-3 alkyl group; and R ₇ represents a C _1-3 alkyl group, optionally substituted with phenyl, phenyl or heteroaryl selected from the group consisting of pyridinyl, pyrimidinyl and isoxazolyl.

[0025] In some embodiments, R ₄ is phenyl substituted with phenyl; naphthyl; heteroaryl selected from the group consisting of pyridinyl, quinolinyl, isoquinolinyl, chromenonyl, quinazolinyl, benzofuranyl, indolinyl, benzimidazolyl, benzothiophenyl, benzothiazolyl, furo[3,2-c]pyridinyl and naphthyridinyl, wherein said heteroaryl is optionally substituted with 1-3 Z, wherein each Z is independently selected from the group consisting of hydroxy, cyano, nitro, halogen, C _1-5 alkyl, optionally substituted with 1-3 halogens, C _1-5 alkoxy, optionally substituted with 1-3 halogens, benzyloxy, acetyl, morpholinyl, -NR ₆ C(O)R ₇ , -C(O)NR ₆ R ₇ . In additional embodiments, R ₄ is phenyl substituted with phenyl. In other embodiments, R ₄ is naphthyl. In other embodiments, R ₄ is heteroaryl selected from the group consisting of pyridinyl, quinolinyl, isoquinolinyl, chromium, quinazolinyl, benzofuranyl, indolinyl, benzimidazolyl, benzothiophenyl, benzothiazolyl, furo[3,2-c]pyridinyl and naphthyridinyl, wherein said heteroaryl is optionally substituted with 1-3 Z, each Z being independently selected from the group consisting of hydroxy, cyano, nitro, halogen, C _1-5 alkyl, optionally substituted with 1-3 halogens, C _1-5 alkoxy, optionally substituted with 1- 3 halogens, benzyloxy, acetyl, morpholinyl, -NR ₆ C(O)R ₇ , -C(O)NR ₆ R ₇ . R ₆ represents hydrogen or a C _1-3 alkyl group; and R ₇ represents a C _1-3 alkyl group, optionally substituted with phenyl, phenyl or heteroaryl selected from the group consisting of pyridinyl, pyrimidinyl and isoxazolyl. In additional embodiments, R ₄ is quinolinyl or isoquinolinyl, each of which is optionally substituted with 1-3 Z's, each Z being independently selected from the group consisting of hydroxy, cyano, nitro, halogen, C _1-5 alkyl, optionally substituted with 1- 3 halogens, C _1-5 alkoxy, optionally substituted with 1-3 halogens, benzyloxy, acetyl, morpholinyl, -NR ₆ C(O)R ₇ and -C(O)NR ₆ R ₇ . In additional embodiments, R ₄ is quinolinyl, optionally substituted with 1-3 Z, with each Z independently selected from the group consisting of hydroxy, cyano, nitro, halogen, C _1-5 alkyl, optionally substituted with 1-3 halogen, C _{1 -5} alkoxy, optionally substituted with 1-3 halogens, benzyloxy, acetyl, morpholinyl, -NR ₆ C(O)R ₇ and -C(O)NR ₆ R ₇ . In other embodiments, R ₄ is benzofuranyl, benzothiophenyl or furo[3,2-c]pyridinyl, each of which is optionally substituted with 1-3 Z, each Z being independently selected from the group consisting of halogen, C _1-5 alkyl and C _1-5 alkoxy. In further embodiments, R ₄ is benzofuranyl or benzothiophenyl, each of which is optionally substituted with 1-3 Z, each Z being independently selected from the group consisting of halogen, C _1-5 alkyl and C _1-5 alkoxy.

[0026] In other embodiments, R ₄ is phenyl substituted with a substituent selected from the group consisting of piperazinyl, optionally substituted with acetyl, phenyl, phenoxy, benzyl, benzoyl, phenylaminocarbonyl, pyrazolyl, and benzoxazolyl;

a heterocycle selected from the group consisting of benzo[d][1,3]dioxolyl, 2,3-dihydrobenzofuranyl, 2-oxo-1,2-dihydroquinolinyl and 2-oxo-1,2,3,4-tetrahydroquinolinyl;

naphthyl, optionally substituted with halogen; or

heteroaryl selected from the group consisting of pyridinyl, quinolinyl, isoquinolinyl, quinazolinyl, thieno[2,3-d]pyrimidinyl, isoxazolyl and acridinyl, wherein said heteroaryl is optionally substituted with 1-3 Z, each Z being independently selected from the group consisting of cyano, halogen, C _1-5 alkyl, optionally substituted with 1-3 halogens, C _1-5 alkoxy, optionally substituted with 1-3 halogens, benzyloxy and phenyl, optionally substituted with halogen. In additional embodiments, R ₄ is phenyl substituted with a substituent selected from the group consisting of piperazinyl, optionally substituted with acetyl, phenyl, phenoxy, benzyl, benzoyl, phenylaminocarbonyl, pyrazolyl, and benzoxazolyl. In other embodiments, R ₄ is a heterocycle selected from the group consisting of benzo[d][1,3]dioxolyl, 2,3-dihydrobenzofuranyl, 2-oxo-1,2-dihydroquinolinyl and 2-oxo-1, 2,3,4-. In other embodiments, R ₄ is naphthyl, optionally substituted with halogen. In other embodiments, R ₄ is a heteroaryl selected from the group consisting of pyridinyl, quinolinyl, isoquinolinyl, quinazolinyl, thieno[2,3-d]pyrimidinyl, isoxazolyl and acridinyl, wherein said heteroaryl is optionally substituted with 1-3 Z, wherein each Z is independently selected from the group consisting of cyano, halogen, C _1-5 alkyl, optionally substituted with 1-3 halogens, C _1-5 alkoxy, optionally substituted with 1-3 halogens, benzyloxy, and phenyl, optionally substituted with halogen. In additional embodiments, R ₄ is quinolinyl, isoquinolinyl, or quinazolinyl, each optionally substituted with 1-3 Z, each Z independently selected from the group consisting of cyano, halogen, C _1-5 alkyl, optionally substituted with 1-3 halogens , and C _1-5 alkoxy, optionally substituted with 1-3 halogens.

[0027] In some embodiments, R ₄ is quinolinyl.

[0028] In some embodiments, R ₄ is phenyl substituted with phenyl; naphthyl; or heteroaryl selected from the group consisting of quinolinyl, isoquinolinyl, benzofuranyl and benzothiophenyl, wherein said heteroaryl is optionally substituted with 1-3 Z, each Z being independently selected from the group consisting of hydroxy, halogen, C _1-5 alkyl and C _{1- 5} alkoxy. In additional embodiments, R ₄ is phenyl substituted with phenyl. In other embodiments, R ₄ is naphthyl. In other embodiments, R ₄ is a heteroaryl selected from the group consisting of quinolinyl, isoquinolinyl, benzofuranyl and benzothiophenyl, wherein said heteroaryl is optionally substituted with 1-3 Z, each Z being independently selected from the group consisting of hydroxy, halogen, C _1-5 alkyl and C _1-5 alkoxy. In additional embodiments, R ₄ is benzofuranyl, optionally substituted with 1-3 Z, with each Z independently selected from the group consisting of hydroxy, halogen, C _1-5 alkyl and C _1-5 alkoxy. In other embodiments, R ₄ is quinolinyl or isoquinolinyl, each of which is optionally substituted with 1-3 Z, each Z being independently selected from the group consisting of hydroxy, halogen, C _1-5 alkyl and C _1-5 alkoxy.

[0029] In some embodiments, R ₄ is benzofuranyl or benzothiophenyl.

[0030] In some embodiments, R ₃ is a 3-12 membered non-aromatic heterocycle containing nitrogen, wherein said heterocycle is optionally substituted with 1-3 Z. In some embodiments, R ₃ is a 5-12 membered heteroaryl, optionally substituted 1-5 Z. In some embodiments, R ₃ is 2-oxo-2,3-dihydro-1H-benzo[d]imidazol-1-yl.

[0031] In some embodiments, n is 1 or 2; R ₁ represents a substituent selected from the group consisting of compounds of formulas I, II, III, and V; R ₂ represents hydrogen; R ₃ is a substituent selected from the group consisting of -NR ₄ R ₅ , -OR ₄ , -C(O)NHR ₄ , -NHC(O)(CH ₂ ) _m R ₄ , and -NHS(O) _{2 R4} ; where m represents 0 or 1; where R ₁ represents phenyl substituted with a substituent selected from the group consisting of piperazinyl, optionally substituted with acetyl, phenyl, phenoxy, benzyl, benzoyl, phenylaminocarbonyl, pyrazolyl and benzoxazolyl; a heterocycle selected from the group consisting of benzo[d][1,3]dioxolyl, 2,3-dihydrobenzofuranyl, 2-oxo-1,2-dihydroquinolinyl and 2-oxo-1,2,3,4-tetrahydroquinolinyl; naphthyl, optionally substituted with halogen; or heteroaryl selected from the group consisting of pyridinyl, quinolinyl, isoquinolinyl, quinazolinyl, benzofuranyl, benzothiophenyl, furo[3,2-c]pyridinyl, thieno[2,3-d]pyrimidinyl, thieno[3,2-c]pyridinyl , isoxazolyl and acridinyl, wherein said heteroaryl is optionally substituted with 1-3 Z, each Z being independently selected from the group consisting of hydroxy, halogen, C _1-5 alkyl, optionally substituted with 1-3 halogens, C _1-5 alkoxy, optionally substituted 1-3 halogens, C _1-5 alkoxycarbonyl, benzyloxy and phenyl, optionally substituted with halogen; and R ₅ represents hydrogen.

[0032] In some embodiments, n is 1. In some embodiments, n is 2.

[0033] In some embodiments, the compound or a stereoisomer or mixture of stereoisomers or a pharmaceutically acceptable salt thereof is selected from Table 1 or stereoisomers or a mixture of stereoisomers or a pharmaceutically acceptable salt thereof.

[0034] Provided herein in another aspect is a pharmaceutical composition comprising a compound described herein, or a stereoisomer or mixture of stereoisomers, or a pharmaceutically acceptable salt thereof, and at least one pharmaceutically acceptable excipient.

[0035] Provided herein in another aspect is a method of inhibiting fibroblast activation protein in a mammal, comprising administering to the mammal a therapeutically effective amount of a compound or stereoisomers thereof or a mixture of stereoisomers or a pharmaceutically acceptable salt thereof described herein.

[0036] In another aspect, provided herein is a method of treating non-alcoholic steatohepatitis (NASH) in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of a compound described herein, or stereoisomers thereof, or a mixture of stereoisomers, or a pharmaceutically acceptable salt thereof, or a therapeutically effective amount of the pharmaceutical composition described herein.

[0037] This document provides in another aspect the use of a compound described herein, or a stereoisomer or mixture of stereoisomers, or a pharmaceutically acceptable salt thereof, for the manufacture of a medicament for the treatment of NASH.

[0038] In another aspect, provided herein is a compound described herein, or a stereoisomer or mixture of stereoisomers, or a pharmaceutically acceptable salt thereof, for use in the treatment of NASH.

[0039] Provided herein in another aspect is a composition described herein for use in the treatment of NASH.

[0040] Provided herein in another aspect is a compound described herein, or a stereoisomer or mixture of stereoisomers thereof, or a pharmaceutically acceptable salt thereof for use in inhibiting fibroblast activation protein.

[0041] Provided herein in another aspect is a composition described herein for use in inhibiting fibroblast activation protein.

[0042] In another aspect, provided herein is a method of treating fibroblast activation protein-mediated disease in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of a compound described herein, or stereoisomers thereof, or a mixture of stereoisomers, or a pharmaceutically acceptable salt thereof, or a therapeutically effective amount of the pharmaceutical composition described herein. In some embodiments, the fibroblast activation protein-mediated disease is selected from the group consisting of lipid and lipoprotein disorders, conditions and diseases that result from chronic fatty and fibrous degeneration of organs due to the accumulation of lipids and, in particular, triglycerides, and subsequent activation of profibrotic pathways, diabetes mellitus type I or II and clinical complications of diabetes mellitus type I and II, chronic intrahepatic or some forms of extrahepatic cholestatic conditions, liver fibrosis, acute intrahepatic cholestatic conditions, obstructive or chronic inflammatory diseases arising due to abnormal composition of bile, gastrointestinal - intestinal diseases with reduced absorption of dietary fats and fat-soluble dietary vitamins, inflammatory bowel diseases, obesity and metabolic syndrome (a combination of dyslipidemia, diabetes and an abnormally high body mass index), persistent infections with intracellular bacteria or parasitic protozoa, non-malignant hyperproliferative diseases, malignant hyperproliferative diseases, adenocarcinoma of the colon and hepatocellular carcinoma, in particular hepatic steatosis and associated syndromes, hepatitis B infection, hepatitis C infection and/or cholestatic and fibrotic effects that are associated with alcoholic cirrhosis of the liver or with viral forms of hepatitis, liver failure or dysfunction liver as a result of chronic liver disease or surgical resection of the liver, acute myocardial infarction, acute stroke, thrombosis occurring as an end point of chronic obstructive atherosclerosis, osteoarthritis, rheumatoid arthritis, psoriasis and ischemic stroke, alone or any combination thereof.

[0043] Provided herein in another aspect is a compound described herein, or a stereoisomer or mixture of stereoisomers thereof, or a pharmaceutically acceptable salt thereof for use in the treatment of fibroblast activation protein-mediated disease. In some embodiments, the fibroblast activation protein-mediated disease is selected from the group consisting of lipid and lipoprotein disorders, conditions and diseases that result from chronic fatty and fibrous degeneration of organs due to the accumulation of lipids and, in particular, triglycerides, and subsequent activation of profibrotic pathways, diabetes mellitus type I or II and clinical complications of diabetes mellitus type I and II, chronic intrahepatic or some forms of extrahepatic cholestatic conditions, liver fibrosis, acute intrahepatic cholestatic conditions, obstructive or chronic inflammatory diseases arising due to abnormal composition of bile, gastrointestinal - intestinal diseases with reduced absorption of dietary fats and fat-soluble dietary vitamins, inflammatory bowel diseases, obesity and metabolic syndrome (a combination of dyslipidemia, diabetes and an abnormally high body mass index), persistent infections with intracellular bacteria or parasitic protozoa, non-malignant hyperproliferative diseases, malignant hyperproliferative diseases, adenocarcinoma of the colon and hepatocellular carcinoma, in particular hepatic steatosis and associated syndromes, hepatitis B infection, hepatitis C infection and/or cholestatic and fibrotic effects that are associated with alcoholic cirrhosis of the liver or with viral forms of hepatitis, liver failure or dysfunction liver as a result of chronic liver disease or surgical resection of the liver, acute myocardial infarction, acute stroke, thrombosis occurring as an end point of chronic obstructive atherosclerosis, osteoarthritis, rheumatoid arthritis, psoriasis and ischemic stroke, alone or any combination thereof.

[0044] Herein, in another aspect, there is provided a method of treating cancer in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of a compound described herein, or stereoisomers thereof or a mixture of stereoisomers or a pharmaceutically acceptable salt thereof or a therapeutically effective amount of a pharmaceutical composition described in this document.

[0045] Provided herein in another aspect is a compound described herein, or a stereoisomer or mixture of stereoisomers thereof, or a pharmaceutically acceptable salt thereof for use in the treatment of cancer.

[0046] In another aspect, provided herein is a method of inhibiting the degradation of fibroblast growth factor-21 in a subject, comprising administering to the subject a therapeutically effective amount of a compound, or a stereoisomer thereof, or a mixture of stereoisomers, or a pharmaceutically acceptable salt thereof, as described herein.

[0047] Provided herein in another aspect is a compound described herein, or a stereoisomer or mixture of stereoisomers thereof, or a pharmaceutically acceptable salt thereof for use in inhibiting the degradation of fibroblast growth factor-21.

[0048] This document provides in another aspect a method for preparing a compound of formula 1a,

or a stereoisomer thereof or a mixture of stereoisomers or a pharmaceutically acceptable salt thereof, said method comprising

reacting a compound of formula 2a with a compound of formula 2aa under metal-mediated conditions to produce a compound of formula 3a:

removal of Boc from a compound of formula 3a under reaction conditions to give a compound of formula 4a:

And

reacting a compound of formula 4a with a compound of formula 5 to produce a compound of formula 1a or an isomer thereof or a pharmaceutically acceptable salt thereof:

where n represents 1 or 2.

where X represents a halogen,

where R ₁ represents a substituent selected from the group consisting of compounds of formula IV,

where R ₂ represents hydrogen or C _1-3 alkyl,

where R ₄ represents phenyl substituted with 1-3 Z, each Z being independently selected from the group consisting of hydroxy, amino, halogen, cyano, nitro, carboxylic acid, C _1-5 alkyl, optionally substituted with 1-3 halogens or amino group , C _2-6 alkenyl, C _2-6 alkynyl, C _1-5 alkoxy, C _1-5 alkylthio, mono- or di-C _1-5 alkylamino, piperazinyl, optionally substituted with acetyl, C _1-5 alkylsulfonylamino, C _{1 -5} alkylcarbonylamino, aminosulfonyl, aminocarbonyl, C _1-5 alkylaminocarbonyl, phenyl, phenoxy, benzyl, benzoyl, phenylaminocarbonyl, pyrazolyl and benzoxazolyl;

heterocycle selected from the group consisting of benzo[d][1,3]dioxolyl, dihydrobenzo[1,4]dioxynyl, 2,3-dihydrobenzofuranyl, 2-oxo-1,2-dihydroquinolinyl and 2-oxo-1,2 ,3,4-tetrahydroquinolinyl;

naphthyl, optionally substituted with halogen; or

heteroaryl selected from the group consisting of pyridinyl, pyrimidinyl, pyrazinyl, imidazolyl, pyrazolyl, triazolyl, oxazolyl, thiazolyl, furanyl, pyrrolyl, thiophenyl, quinolinyl, isoquinolinyl, chromenonyl, quinazolinyl, benzoxazolyl, benzofuranyl, benzothiophenyl, indolyl, indolinyl, benzime idazolyl, benzoxazolyl, benzothiazolyl, indazolyl, furo[3,2-c]pyridinyl, thieno[2,3-d]pyrimidinyl, thieno[3,2-c]pyridinyl, isoxazolyl, acridinyl and naphthyridinyl, wherein said heteroaryl is optionally substituted 1-3 Z, wherein each Z is independently selected from the group consisting of hydroxy, amino, di-C _1-5 alkylamino, cyano, nitro, halogen, C _1-5 alkyl optionally substituted with 1-3 halogens, C _1-5 alkoxy, C _1-5 alkoxycarbonyl, benzyloxy, phenyl, optionally substituted with halogen, acetyl, C _1-5 alkylsulfonyl, morpholinyl, -NR ₆ C(O)R ₇ , and -C(O)NR ₆ R ₇ ;

where R ₅ represents hydrogen or C _1-3 alkyl;

where R ₆ represents hydrogen or a C _1-3 alkyl group; And

where R ₇ represents a C _1-3 alkyl group, optionally substituted with phenyl; phenyl; or heteroaryl selected from the group consisting of pyridinyl, pyrimidinyl and isoxazolyl.

[0049] This document provides in another aspect a method for preparing a compound of formula 1a,

or a stereoisomer thereof or a mixture of stereoisomers or a pharmaceutically acceptable salt thereof, said method comprising

reacting a compound of formula 2a with a compound of formula 2aa under metal-mediated conditions to produce a compound of formula 3a:

removal of Boc from a compound of formula 3a under reaction conditions to give a compound of formula 4a:

And

reacting a compound of formula 4a with a compound of formula 5 to produce a compound of formula 1a or an isomer thereof or a pharmaceutically acceptable salt thereof:

where n represents 1 or 2.

where X represents a halogen,

where R ₁ represents a substituent selected from the group consisting of compounds of formula IV,

where R ₂ represents hydrogen or C _1-3 alkyl,

where R ₄ represents phenyl substituted with 1-3 Z, each Z being independently selected from the group consisting of hydroxy, amino, halogen, cyano, nitro, carboxylic acid, C _1-5 alkyl, optionally substituted with 1-3 halogens or amino group , C _2-6 alkenyl, C _2-6 alkynyl, C _1-5 alkoxy, C _1-5 alkylthio, mono- or di-C _1-5 alkylamino, piperazinyl, optionally substituted with acetyl, C _1-5 alkylsulfonylamino, C _{1 -5} alkylcarbonylamino, aminosulfonyl, aminocarbonyl, C _1-5 alkylaminocarbonyl, phenyl, phenoxy, benzyl, benzoin, phenylaminocarbonyl, pyrazolyl and benzoxazolyl;

heterocycle selected from the group consisting of benzo[d][1,3]dioxolyl, dihydrobenzo[1,4]dioxynyl, 2,3-dihydrobenzofuranyl, 2-oxo-1,2-dihydroquinolinyl and 2-oxo-1,2 ,3,4-tetrahydroquinolinyl;

naphthyl, optionally substituted with halogen; or

heteroaryl selected from the group consisting of pyridinyl, pyrimidinyl, pyrazinyl, imidazolyl, pyrazolyl, triazolyl, oxazolyl, thiazolyl, furanyl, pyrrolyl, thiophenyl, quinolinyl, isoquinolinyl, chromenonyl, quinazolinyl, benzoxazolyl, benzofuranyl, benzothiophenyl, indolyl, indolinyl, benzime idazolyl, benzoxazolyl, benzothiazolyl, indazolyl, furo[3,2-c]pyridinyl, thieno[2,3-d]pyrimidinyl, thieno[3,2-c]pyridinyl, isoxazolyl and acridinyl, wherein said heteroaryl is optionally substituted with 1-3 Z, wherein each Z is independently selected from the group consisting of hydroxy, amino, di-C _1-5 alkylamino, cyano, nitro, halogen, C _1-5 alkyl optionally substituted with 1-3 halogens, C _1-5 alkoxy, C _{1- 5} alkoxycarbonyl, benzyloxy, phenyl, optionally substituted with halogen, acetyl and C _1-5 alkylsulfonyl, and

where R ₅ represents hydrogen or C _1-3 alkyl.

[0050] In some embodiments, the metal-mediated conditions contain a palladium catalyst, a ligand, and a base at a reaction temperature ranging from 50°C to 150°C.

[0051] This document provides in another aspect a method for preparing a compound of formula 1b,

or a stereoisomer thereof or a mixture of stereoisomers or a pharmaceutically acceptable salt thereof, said method comprising

reacting a compound of formula 2b with a compound of formula 2ba under Mitsunobu reaction conditions to give a compound of formula 3b:

removal of Boc from a compound of formula 3b under reaction conditions to give a compound of formula 4b:

And

reacting a compound of formula 4b with a compound of formula 5 to produce a compound of formula 1b or isomers thereof or a pharmaceutically acceptable salt thereof:

where n represents 1 or 2.

where R ₁ represents a substituent selected from the group consisting of compounds of formula IV,

where R ₂ represents hydrogen or C _1-3 alkyl and

where R ₄ is phenyl substituted with 1-3 Z, each Z being independently selected from the group consisting of hydroxy, amino, halogen, cyano, nitro, carboxylic acid, C _1-5 alkyl, optionally substituted with 1-3 halogens or amino group , C _2-6 alkenyl, C _2-6 alkynyl, C _1-5 alkoxy, C _1-5 alkylthio, mono- or di-C _1-5 alkylamino, piperazinyl, optionally substituted with acetyl, C _1-5 alkylsulfonylamino, C _{1 -5} alkylcarbonylamino, aminosulfonyl, aminocarbonyl, C _1-5 alkylaminocarbonyl, phenyl, phenoxy, benzyl, benzoyl, phenylaminocarbonyl, pyrazolyl and benzoxazolyl;

heterocycle selected from the group consisting of benzo[d][1,3]dioxolyl, dihydrobenzo[1,4]dioxynyl, 2,3-dihydrobenzofuranyl, 2-oxo-1,2-dihydroquinolinyl and 2-oxo-1,2 ,3,4-tetrahydroquinolinyl;

naphthyl, optionally substituted with halogen; or

heteroaryl selected from the group consisting of pyridinyl, pyrimidinyl, pyrazinyl, imidazolyl, pyrazolyl, triazolyl, oxazolyl, thiazolyl, furanyl, pyrrolyl, thiophenyl, quinolinyl, isoquinolinyl, chromenonyl, quinazolinyl, benzoxazolyl, benzofuranyl, benzothiophenyl, indolyl, indolinyl, benzime idazolyl, benzoxazolyl, benzothiazolyl, indazolyl, furo[3,2-c]pyridinyl, thieno[2,3-d]pyrimidinyl, thieno[3,2-c]pyridinyl, isoxazolyl, acridinyl and naphthyridinyl, wherein said heteroaryl is optionally substituted 1-3 Z, wherein each Z is independently selected from the group consisting of hydroxy, amino, di-C _1-5 alkylamino, cyano, nitro, halogen, C _1-5 alkyl optionally substituted with 1-3 halogens, C _1-5 alkoxy, C _1-5 alkoxycarbonyl, benzyloxy, phenyl, optionally substituted with halogen, acetyl, C _1-5 alkylsulfonyl, morpholinyl, -NR ₆ C(O)R ₇ , and -C(O)NR ₆ R ₇ ;

where R ₆ represents hydrogen or a C _1-3 alkyl group; And

where R ₇ represents a C _1-3 alkyl group, optionally substituted with phenyl; phenyl; or heteroaryl selected from the group consisting of pyridinyl, pyrimidinyl and isoxazolyl.

[0052] This document provides in another aspect a method for preparing a compound of formula 1b,

or a stereoisomer thereof or a mixture of stereoisomers or a pharmaceutically acceptable salt thereof, said method comprising

reacting a compound of formula 2b with a compound of formula 2ba under Mitsunobu reaction conditions to give a compound of formula 3b:

removal of Boc from a compound of formula 3b under reaction conditions to give a compound of formula 4b:

And

reacting a compound of formula 4b with a compound of formula 5 to produce a compound of formula 1b or isomers thereof or a pharmaceutically acceptable salt thereof:

where n represents 1 or 2.

where R ₁ represents a substituent selected from the group consisting of compounds of formula IV,

where R ₂ represents hydrogen or C _1-3 alkyl and

where R ₄ represents phenyl substituted with 1-3 Z, each Z being independently selected from the group consisting of hydroxy, amino, halogen, cyano, nitro, carboxylic acid, C _1-5 alkyl, optionally substituted with 1-3 halogens or amino group , C _2-6 alkenyl, C _2-6 alkynyl, C _1-5 alkoxy, C _1-5 alkylthio, mono- or di-C _1-5 alkylamino, piperazinyl, optionally substituted with acetyl, C _1-5 alkylsulfonylamino, C _{1 -5} alkylcarbonylamino, aminosulfonyl, aminocarbonyl, C _1-5 alkylaminocarbonyl, phenyl, phenoxy, benzyl, benzoyl, phenylaminocarbonyl, pyrazolyl and benzoxazolyl;

heterocycle selected from the group consisting of benzo[d][1,3]dioxolyl, dihydrobenzo[1,4]dioxynyl, 2,3-dihydrobenzofuranyl, 2-oxo-1,2-dihydroquinolinyl and 2-oxo-1,2 ,3,4-tetrahydroquinolinyl;

naphthyl, optionally substituted with halogen; or

heteroaryl selected from the group consisting of pyridinyl, pyrimidinyl, pyrazinyl, imidazolyl, pyrazolyl, triazolyl, oxazolyl, thiazolyl, furanyl, pyrrolyl, thiophenyl, quinolinyl, isoquinolinyl, chromenonyl, quinazolinyl, benzoxazolyl, benzofuranyl, benzothiophenyl, indolyl, indolinyl, benzime idazolyl, benzoxazolyl, benzothiazolyl, indazolyl, furo[3,2-c]pyridinyl, thieno[2,3-d]pyrimidinyl, thieno[3,2-c]pyridinyl, isoxazolyl and acridinyl, wherein said heteroaryl is optionally substituted with 1-3 Z, wherein each Z is independently selected from the group consisting of hydroxy, amino, di-C _1-5 alkylamino, cyano, nitro, halogen, C _1-5 alkyl optionally substituted with 1-3 halogens, C _1-5 alkoxy, C _{1- 5} alkoxycarbonyl, benzyloxy, phenyl, optionally substituted with halogen, acetyl and C _1-5 alkylsulfonyl.

[0053] This document provides in another aspect a method for preparing a compound of formula 1c,

or a stereoisomer thereof or a mixture of stereoisomers or a pharmaceutically acceptable salt thereof, said method comprising

reacting a compound of formula 2c with a compound of formula 2ca under amide coupling conditions to produce a compound of formula 3c:

removal of Boc from a compound of formula 3c under reaction conditions to give a compound of formula 4c:

And

reacting a compound of formula 4c with a compound of formula 5 to produce a compound of formula 1c or isomers thereof or a pharmaceutically acceptable salt thereof:

where n represents 1 or 2.

where R ₁ represents a substituent selected from the group consisting of compounds of formula IV,

where R ₂ represents hydrogen or C _1-3 alkyl and

where R ₄ represents phenyl substituted with 1-3 Z, each Z being independently selected from the group consisting of hydroxy, amino, halogen, cyano, nitro, carboxylic acid, C _1-5 alkyl, optionally substituted with 1-3 halogens or amino group , C _2-6 alkenyl, C _2-6 alkynyl, C _1-5 alkoxy, C _1-5 alkylthio, mono- or di-C _1-5 alkylamino, piperazinyl, optionally substituted with acetyl, C _1-5 alkylsulfonylamino, C _{1 -5} alkylcarbonylamino, aminosulfonyl, aminocarbonyl, C _1-5 alkylaminocarbonyl, phenyl, phenoxy, benzyl, benzoyl, phenylaminocarbonyl, pyrazolyl and benzoxazolyl;

heterocycle selected from the group consisting of benzo[d][1,3]dioxolyl, dihydrobenzo[1,4]dioxynyl, 2,3-dihydrobenzofuranyl, 2-oxo-1,2-dihydroquinolinyl and 2-oxo-1,2 ,3,4-tetrahydroquinolinyl;

naphthyl, optionally substituted with halogen; or

heteroaryl selected from the group consisting of pyridinyl, pyrimidinyl, pyrazinyl, imidazolyl, pyrazolyl, triazolyl, oxazolyl, thiazolyl, furanyl, pyrrolyl, thiophenyl, quinolinyl, isoquinolinyl, chromenonyl, quinazolinyl, benzoxazolyl, benzofuranyl, benzothiophenyl, indolyl, indolinyl, benzime idazolyl, benzoxazolyl, benzothiazolyl, indazolyl, furo[3,2-c]pyridinyl, thieno[2,3-d]pyrimidinyl, thieno[3,2-c]pyridinyl, isoxazolyl, acridinyl and naphthyridinyl, wherein said heteroaryl is optionally substituted 1-3 Z, wherein each Z is independently selected from the group consisting of hydroxy, amino, di-C _1-5 alkylamino, cyano, nitro, halogen, C _1-5 alkyl optionally substituted with 1-3 halogens, C _1-5 alkoxy, C _1-5 alkoxycarbonyl, benzyloxy, phenyl, optionally substituted with halogen, acetyl, C _1-5 alkylsulfonyl, morpholinyl, -NR ₆ C(O)R ₇ , and -C(O)NR ₆ R ₇ ;

where R ₆ represents hydrogen or a C _1-3 alkyl group; And

where R ₇ represents a C _1-3 alkyl group, optionally substituted with phenyl; phenyl; or heteroaryl selected from the group consisting of pyridinyl, pyrimidinyl and isoxazolyl.

[0054] This document provides in another aspect a method for preparing a compound of formula 1c,

or a stereoisomer thereof or a mixture of stereoisomers or a pharmaceutically acceptable salt thereof, said method comprising

reacting a compound of formula 2c with a compound of formula 2ca under amide coupling conditions to produce a compound of formula 3c:

removal of Boc from a compound of formula 3c under reaction conditions to give a compound of formula 4c:

And

reacting a compound of formula 4c with a compound of formula 5 to produce a compound of formula 1c or isomers thereof or a pharmaceutically acceptable salt thereof:

where n represents 1 or 2.

where R ₁ represents a substituent selected from the group consisting of compounds of formula IV,

where R ₂ represents hydrogen or C _1-3 alkyl and

where R ₄ represents phenyl substituted with 1-3 Z, each Z being independently selected from the group consisting of hydroxy, amino, halogen, cyano, nitro, carboxylic acid, C _1-5 alkyl, optionally substituted with 1-3 halogens or amino group , C _2-6 alkenyl, C _2-6 alkynyl, C _1-5 alkoxy, C _1-5 alkylthio, mono- or di-C _1-5 alkylamino, piperazinyl, optionally substituted with acetyl, C _1-5 alkylsulfonylamino, C _{1 -5} alkylcarbonylamino, aminosulfonyl, aminocarbonyl, C _1-5 alkylaminocarbonyl, phenyl, phenoxy, benzyl, benzoyl, phenylaminocarbonyl, pyrazolyl and benzoxazolyl;

heterocycle selected from the group consisting of benzo[d][1,3]dioxolyl, dihydrobenzo[1,4]dioxynyl, 2,3-dihydrobenzofuranyl, 2-oxo-1,2-dihydroquinolinyl and 2-oxo-1,2 ,3,4-tetrahydroquinolinyl;

naphthyl, optionally substituted with halogen; or

heteroaryl selected from the group consisting of pyridinyl, pyrimidinyl, pyrazinyl, imidazolyl, pyrazolyl, triazolyl, oxazolyl, thiazolyl, furanyl, pyrrolyl, thiophenyl, quinolinyl, isoquinolinyl, chromenonyl, quinazolinyl, benzoxazolyl, benzofuranyl, benzothiophenyl, indolyl, indolinyl, benzime idazolyl, benzoxazolyl, benzothiazolyl, indazolyl, furo[3,2-c]pyridinyl, thieno[2,3-d]pyrimidinyl, thieno[3,2-c]pyridinyl, isoxazolyl and acridinyl, wherein said heteroaryl is optionally substituted with 1-3 Z, wherein each Z is independently selected from the group consisting of hydroxy, amino, di-C _1-5 alkylamino, cyano, nitro, halogen, C _1-5 alkyl optionally substituted with 1-3 halogens, C _1-5 alkoxy, C _{1- 5} alkoxycarbonyl, benzyloxy, phenyl, optionally substituted with halogen, acetyl and C _1-5 alkylsulfonyl.

[0055] This document provides in another aspect a method for preparing a compound of formula 1d,

or a stereoisomer thereof or a mixture of stereoisomers or a pharmaceutically acceptable salt thereof, said method comprising

reacting a compound of formula 5 with a compound of formula 9 to produce a compound of formula 10:

removal of Boc from a compound of formula 10 under reaction conditions to give a compound of formula 11:

And

reacting a compound of formula 11 with a compound of formula 11a to produce a compound of formula 1d or an isomer thereof or a pharmaceutically acceptable salt thereof:

where n represents 1 or 2.

where R ₁ represents a substituent selected from the group consisting of compounds of formula IV,

where R ₂ represents hydrogen or C _1-3 alkyl,

where m represents 0 or 1, and

where R ₄ represents phenyl substituted with 1-3 Z, each Z being independently selected from the group consisting of hydroxy, amino, halogen, cyano, nitro, carboxylic acid, C _1-5 alkyl, optionally substituted with 1-3 halogens or amino group , C _2-6 alkenyl, C _2-6 alkynyl, C _1-5 alkoxy, C _1-5 alkylthio, mono- or di-C _1-5 alkylamino, piperazinyl, optionally substituted with acetyl, C _1-5 alkylsulfonylamino, C _{1 -5} alkylcarbonylamino, aminosulfonyl, aminocarbonyl, C _1-5 alkylaminocarbonyl, phenyl, phenoxy, benzyl, benzoyl, phenylaminocarbonyl, pyrazolyl and benzoxazolyl;

heterocycle selected from the group consisting of benzo[d][1,3]dioxolyl, dihydrobenzo[1,4]dioxynyl, 2,3-dihydrobenzofuranyl, 2-oxo-1,2-dihydroquinolinyl and 2-oxo-1,2 ,3,4-tetrahydroquinolinyl;

naphthyl, optionally substituted with halogen; or

heteroaryl selected from the group consisting of pyridinyl, pyrimidinyl, pyrazinyl, imidazolyl, pyrazolyl, triazolyl, oxazolyl, thiazolyl, furanyl, pyrrolyl, thiophenyl, quinolinyl, isoquinolinyl, chromenonyl, quinazolinyl, benzoxazolyl, benzofuranyl, benzothiophenyl, indolyl, indolinyl, benzime idazolyl, benzoxazolyl, benzothiazolyl, indazolyl, furo[3,2-c]pyridinyl, thieno[2,3-d]pyrimidinyl, thieno[3,2-c]pyridinyl, isoxazolyl, acridinyl and naphthyridinyl, wherein said heteroaryl is optionally substituted 1-3 Z, wherein each Z is independently selected from the group consisting of hydroxy, amino, di-C _1-5 alkylamino, cyano, nitro, halogen, C _1-5 alkyl optionally substituted with 1-3 halogens, C _1-5 alkoxy, C _1-5 alkoxycarbonyl, benzyloxy, phenyl, optionally substituted with halogen, acetyl, C _1-5 alkylsulfonyl, morpholinyl, -NR ₆ C(O)R ₇ , and -C(O)NR ₆ R ₇ ;

where R ₆ represents hydrogen or a C _1-3 alkyl group; And

where R ₇ represents a C _1-3 alkyl group, optionally substituted with phenyl; phenyl; or heteroaryl selected from the group consisting of pyridinyl, pyrimidinyl and isoxazolyl.

[0056] This document provides in another aspect a method for preparing a compound of formula 1d,

or a stereoisomer thereof or a mixture of stereoisomers or a pharmaceutically acceptable salt thereof, said method comprising

reacting a compound of formula 5 with a compound of formula 9 to produce a compound of formula 10:

removal of Boc from a compound of formula 10 under reaction conditions to give a compound of formula 11:

And

reacting a compound of formula 11 with a compound of formula 11a to produce a compound of formula 1d or an isomer thereof or a pharmaceutically acceptable salt thereof:

where n represents 1 or 2.

where R ₁ represents a substituent selected from the group consisting of compounds of formula IV,

where R ₂ represents hydrogen or C _1-3 alkyl,

where m represents 0 or 1, and

where R ₄ is phenyl substituted with 1-3 Z, each Z being independently selected from the group consisting of hydroxy, amino, halogen, cyano, nitro, carboxylic acid, C _1-5 alkyl, optionally substituted with 1-3 halogens or amino group , C _2-6 alkenyl, C _2-6 alkynyl, C _1-5 alkoxy, C _1-5 alkylthio, mono- or di-C _1-5 alkylamino, piperazinyl, optionally substituted with acetyl, C _1-5 alkylsulfonylamino, C _{1 -5} alkylcarbonylamino, aminosulfonyl, aminocarbonyl, C _1-5 alkylaminocarbonyl, phenyl, phenoxy, benzyl, benzoyl, phenylaminocarbonyl, pyrazolyl and benzoxazolyl;

heterocycle selected from the group consisting of benzo[d][1,3]dioxolyl, dihydrobenzo[1,4]dioxynyl, 2,3-dihydrobenzofuranyl, 2-oxo-1,2-dihydroquinolinyl and 2-oxo-1,2 ,3,4-tetrahydroquinolinyl;

naphthyl, optionally substituted with halogen; or

heteroaryl selected from the group consisting of pyridinyl, pyrimidinyl, pyrazinyl, imidazolyl, pyrazolyl, triazolyl, oxazolyl, thiazolyl, furanyl, pyrrolyl, thiophenyl, quinolinyl, isoquinolinyl, chromenonyl, quinazolinyl, benzoxazolyl, benzofuranyl, benzothiophenyl, indolyl, indolinyl, benzime idazolyl, benzoxazolyl, benzothiazolyl, indazolyl, furo[3,2-c]pyridinyl, thieno[2,3-d]pyrimidinyl, thieno[3,2-c]pyridinyl, isoxazolyl and acridinyl, wherein said heteroaryl is optionally substituted with 1-3 Z, wherein each Z is independently selected from the group consisting of hydroxy, amino, di-C _1-5 alkylamino, cyano, nitro, halogen, C _1-5 alkyl optionally substituted with 1-3 halogens, C _1-5 alkoxy, C _{1- 5} alkoxycarbonyl, benzyloxy, phenyl, optionally substituted with halogen, acetyl and C _1-5 alkylsulfonyl.

[0057] This document provides in another aspect a method for preparing a compound of formula 1e,

or a stereoisomer thereof or a mixture of stereoisomers or a pharmaceutically acceptable salt thereof, said method comprising

reacting a compound of formula 5 with a compound of formula 9 to produce a compound of formula 10:

removal of Boc from a compound of formula 10 under reaction conditions to give a compound of formula 11:

And

reacting a compound of formula 11 with a compound of formula 11b to produce a compound of formula 1d or isomers thereof or a pharmaceutically acceptable salt thereof:

where n represents 1 or 2.

where R ₁ represents a substituent selected from the group consisting of compounds of formula IV,

where R ₂ represents hydrogen or C _1-3 alkyl and

where R ₄ represents phenyl substituted with 1-3 Z, each Z being independently selected from the group consisting of hydroxy, amino, halogen, cyano, nitro, carboxylic acid, C _1-5 alkyl, optionally substituted with 1-3 halogens or amino group , C _2-6 alkenyl, C _2-6 alkynyl, C _1-5 alkoxy, C _1-5 alkylthio, mono- or di-C _1-5 alkylamino, piperazinyl, optionally substituted with acetyl, C _1-5 alkylsulfonylamino, C _{1 -5} alkylcarbonylamino, aminosulfonyl, aminocarbonyl, C _1-5 alkylaminocarbonyl, phenyl, phenoxy, benzyl, benzoyl, phenylaminocarbonyl, pyrazolyl and benzoxazolyl;

heterocycle selected from the group consisting of benzo[d][1,3]dioxolyl, dihydrobenzo[1,4]dioxynyl, 2,3-dihydrobenzofuranyl, 2-oxo-1,2-dihydroquinolinyl and 2-oxo-1,2 ,3,4-tetrahydroquinolinyl;

naphthyl, optionally substituted with halogen; or

heteroaryl selected from the group consisting of pyridinyl, pyrimidinyl, pyrazinyl, imidazolyl, pyrazolyl, triazolyl, oxazolyl, thiazolyl, furanyl, pyrrolyl, thiophenyl, quinolinyl, isoquinolinyl, chromenonyl, quinazolinyl, benzoxazolyl, benzofuranyl, benzothiophenyl, indolyl, indolinyl, benzime idazolyl, benzoxazolyl, benzothiazolyl, indazolyl, furo[3,2-c]pyridinyl, thieno[2,3-d]pyrimidinyl, thieno[3,2-c]pyridinyl, isoxazolyl, acridinyl and naphthyridinyl, wherein said heteroaryl is optionally substituted 1-3 Z, wherein each Z is independently selected from the group consisting of hydroxy, amino, di-C _1-5 alkylamino, cyano, nitro, halogen, C _1-5 alkyl optionally substituted with 1-3 halogens, C _1-5 alkoxy, C _1-5 alkoxycarbonyl, benzyloxy, phenyl, optionally substituted with halogen, acetyl, C _1-5 alkylsulfonyl, morpholinyl, -NR ₆ C(O)R ₇ , and -C(O)NR ₆ R ₇ ;

where R ₆ represents hydrogen or a C _1-3 alkyl group; And

where R ₇ represents a C _1-3 alkyl group, optionally substituted with phenyl; phenyl; or heteroaryl selected from the group consisting of pyridinyl, pyrimidinyl and isoxazolyl.

[0058] This document provides in another aspect a method for preparing a compound of formula 1e,

or a stereoisomer thereof or a mixture of stereoisomers or a pharmaceutically acceptable salt thereof, said method comprising

reacting a compound of formula 5 with a compound of formula 9 to produce a compound of formula 10:

removal of Boc from a compound of formula 10 under reaction conditions to give a compound of formula 11:

And

reacting a compound of formula 11 with a compound of formula 11b to produce a compound of formula 1d or isomers thereof or a pharmaceutically acceptable salt thereof:

where n represents 1 or 2.

where R ₁ represents a substituent selected from the group consisting of compounds of formula IV,

where R ₂ represents hydrogen or C _1-3 alkyl and

where R ₄ represents phenyl substituted with 1-3 Z, each Z being independently selected from the group consisting of hydroxy, amino, halogen, cyano, nitro, carboxylic acid, C _1-5 alkyl, optionally substituted with 1-3 halogens or amino group , C _2-6 alkenyl, C _2-6 alkynyl, C _1-5 alkoxy, C _1-5 alkylthio, mono- or di-C _1-5 alkylamino, piperazinyl, optionally substituted with acetyl, C _1-5 alkylsulfonylamino, C _{1 -5} alkylcarbonylamino, aminosulfonyl, aminocarbonyl, C _1-5 alkylaminocarbonyl, phenyl, phenoxy, benzyl, benzoyl, phenylaminocarbonyl, pyrazolyl and benzoxazolyl;

heterocycle selected from the group consisting of benzo[d][1,3]dioxolyl, dihydrobenzo[1,4]dioxynyl, 2,3-dihydrobenzofuranyl, 2-oxo-1,2-dihydroquinolinyl and 2-oxo-1,2 ,3,4-tetrahydroquinolinyl;

naphthyl, optionally substituted with halogen; or

heteroaryl selected from the group consisting of pyridinyl, pyrimidinyl, pyrazinyl, imidazolyl, pyrazolyl, triazolyl, oxazolyl, thiazolyl, furanyl, pyrrolyl, thiophenyl, quinolinyl, isoquinolinyl, chromenonyl, quinazolinyl, benzoxazolyl, benzofuranyl, benzothiophenyl, indolyl, indolinyl, benzime idazolyl, benzoxazolyl, benzothiazolyl, indazolyl, furo[3,2-c]pyridinyl, thieno[2,3-d]pyrimidinyl, thieno[3,2-c]pyridinyl, isoxazolyl and acridinyl, wherein said heteroaryl is optionally substituted with 1-3 Z, wherein each Z is independently selected from the group consisting of hydroxy, amino, di-C _1-5 alkylamino, cyano, nitro, halogen, C _1-5 alkyl optionally substituted with 1-3 halogens, C _1-5 alkoxy, C _{1- 5} alkoxycarbonyl, benzyloxy, phenyl, optionally substituted with halogen, acetyl and C _1-5 alkylsulfonyl.

[0059] In some embodiments, a compound of Formula 5 is prepared by reacting a compound of Formula 6 with a compound of any of the formulas R ₁ aR ₁ e to produce a compound of Formula 5:

[0060] This document provides in another aspect a method for preparing a compound of formula 1b,

or a stereoisomer thereof or a mixture of stereoisomers or a pharmaceutically acceptable salt thereof, said method comprising

reacting a compound of formula 5 with a compound of formula 7 to produce a compound of formula 8:

And

reacting a compound of formula 8 with a compound of formula 2ba under Mitsunobu reaction conditions to obtain a compound of formula 1b or an isomer thereof or a pharmaceutically acceptable salt thereof:

where n represents 1 or 2.

where R ₁ represents a substituent selected from the group consisting of compounds of formula IV,

where R ₂ represents hydrogen or C _1-3 alkyl,

where R ₄ represents phenyl substituted with 1-3 Z, each Z being independently selected from the group consisting of hydroxy, amino, halogen, cyano, nitro, carboxylic acid, C _1-5 alkyl, optionally substituted with 1-3 halogens or amino group , C _2-6 alkenyl, C _2-6 alkynyl, C _1-5 alkoxy, C _1-5 alkylthio, mono- or di-C _1-5 alkylamino, piperazinyl, optionally substituted with acetyl, C _1-5 alkylsulfonylamino, C _{1 -5} alkylcarbonylamino, aminosulfonyl, aminocarbonyl, C _1-5 alkylaminocarbonyl, phenyl, phenoxy, benzyl, benzoyl, phenylaminocarbonyl, pyrazolyl and benzoxazolyl;

heterocycle selected from the group consisting of benzo[d][1,3]dioxolyl, dihydrobenzo[1,4]dioxynyl, 2,3-dihydrobenzofuranyl, 2-oxo-1,2-dihydroquinolinyl and 2-oxo-1,2 ,3,4-tetrahydroquinolinyl;

naphthyl, optionally substituted with halogen; or

heteroaryl selected from the group consisting of pyridinyl, pyrimidinyl, pyrazinyl, imidazolyl, pyrazolyl, triazolyl, oxazolyl, thiazolyl, furanyl, pyrrolyl, thiophenyl, quinolinyl, isoquinolinyl, chromenonyl, quinazolinyl, benzoxazolyl, benzofuranyl, benzothiophenyl, indolyl, indolinyl, benzime idazolyl, benzoxazolyl, benzothiazolyl, indazolyl, furo[3,2-c]pyridinyl, thieno[2,3-d]pyrimidinyl, thieno[3,2-c]pyridinyl, isoxazolyl, acridinyl and naphthyridinyl, wherein said heteroaryl is optionally substituted 1-3 Z, wherein each Z is independently selected from the group consisting of hydroxy, amino, di-C _1-5 alkylamino, cyano, nitro, halogen, C _1-5 alkyl optionally substituted with 1-3 halogens, C _1-5 alkoxy, C _1-5 alkoxycarbonyl, benzyloxy, phenyl, optionally substituted with halogen, acetyl, C _1-5 alkylsulfonyl, morpholinyl, -NR ₆ C(O)R ₇ , and -C(O)NR ₆ R ₇ ;

where R ₆ represents hydrogen or a C _1-3 alkyl group; And

where R ₇ represents a C _1-3 alkyl group, optionally substituted with phenyl; phenyl; or heteroaryl selected from the group consisting of pyridinyl, pyrimidinyl and isoxazolyl.

[0061] This document provides in another aspect a method for preparing a compound of formula 1b,

or a stereoisomer thereof or a mixture of stereoisomers or a pharmaceutically acceptable salt thereof, said method comprising

reacting a compound of formula 5 with a compound of formula 7 to produce a compound of formula 8:

And

reacting a compound of formula 8 with a compound of formula 2ba under Mitsunobu reaction conditions to obtain a compound of formula lb or an isomer thereof or a pharmaceutically acceptable salt thereof:

where n represents 1 or 2.

where R ₁ represents a substituent selected from the group consisting of compounds of formula IV,

where R ₂ represents hydrogen or C _1-3 alkyl,

where R ₄ is phenyl substituted with 1-3 Z, each Z being independently selected from the group consisting of hydroxy, amino, halogen, cyano, nitro, carboxylic acid, C _1-5 alkyl, optionally substituted with 1-3 halogens or amino group , C _2-6 alkenyl, C _2-6 alkynyl, C _1-5 alkoxy, C _1-5 alkylthio, mono- or di-C _1-5 alkylamino, piperazinyl, optionally substituted with acetyl, C _1-5 alkylsulfonylamino, C _{1 -5} alkylcarbonylamino, aminosulfonyl, aminocarbonyl, C _1-5 alkylaminocarbonyl, phenyl, phenoxy, benzyl, benzoyl, phenylaminocarbonyl, pyrazolyl and benzoxazolyl;

heterocycle selected from the group consisting of benzo[d][1,3]dioxolyl, dihydrobenzo[1,4]dioxynyl, 2,3-dihydrobenzofuranyl, 2-oxo-1,2-dihydroquinolinyl and 2-oxo-1,2 ,3,4-tetrahydroquinolinyl;

naphthyl, optionally substituted with halogen; or

heteroaryl selected from the group consisting of pyridinyl, pyrimidinyl, pyrazinyl, imidazolyl, pyrazolyl, triazolyl, oxazolyl, thiazolyl, furanyl, pyrrolyl, thiophenyl, quinolinyl, isoquinolinyl, chromenonyl, quinazolinyl, benzoxazolyl, benzofuranyl, benzothiophenyl, indolyl, indolinyl, benzime idazolyl, benzoxazolyl, benzothiazolyl, indazolyl, furo[3,2-c]pyridinyl, thieno[2,3-d]pyrimidinyl, thieno[3,2-c]pyridinyl, isoxazolyl and acridinyl, wherein said heteroaryl is optionally substituted with 1-3 Z, wherein each Z is independently selected from the group consisting of hydroxy, amino, di-C _1-5 alkylamino, cyano, nitro, halogen, C _1-5 alkyl optionally substituted with 1-3 halogens, C _1-5 alkoxy, C _{1- 5} alkoxycarbonyl, benzyloxy, phenyl, optionally substituted with halogen, acetyl and C _1-5 alkylsulfonyl.

DETAILED DESCRIPTION OF THE INVENTION

[0062] It should be noted that as used herein and in the appended claims, the singular forms of the singular include references to the plural unless the context clearly requires otherwise. In addition, it should be noted that the claims may be drafted in such a way as to exclude any optional element. As such, this statement is intended to serve as a precursor to the use of exclusive terminology such as “solely,” “only,” etc. in connection with the recitation of claims or the use of a “negative” limitation.

[0063] As used herein, the term “comprising” or “comprises” is intended to indicate that the compositions and methods include the listed elements, but are not exclusive of others. A composition or process “consisting essentially of” elements, as defined herein, is not exclusive of other materials or steps that do not significantly affect the essential and novel characteristics of the claimed technology. The term "consisting of" means excluding more trace elements from other ingredients and essential process steps. Embodiments defined by each of these transitional terms are within the scope of this technology. If an embodiment is defined by one of these terms (for example, “comprising”), it should be understood that this disclosure also includes alternative embodiments such as “consisting essentially of” and “consisting of” for the specified embodiment.

[0064] The term "substantially" means almost all or completely, for example, 95%, 96%, 97%, 98%, 99% or more of some given amount.

[0065] As used herein, the term “about” will be understood by those skilled in the art and will vary to some extent depending on the context in which it is used. If terms are used that are not obvious to those skilled in the art given the context in which it is used, "about" will mean up to plus or minus 10% of the specific value.

[0066] Specific ranges are provided herein with numerical values preceded by the term “about.” The term "about" is used herein to provide literal support for the exact number that it precedes, as well as a number that closely or approximately matches the number that the term precedes. In determining whether a number is close or approximate to a specifically named number, a close or approximate unnamed number may be a number that, in the context presented, provides a substantial equivalent to the specifically named number.

[0067] Where a range of values is specified, it is understood that every intermediate value, to the nearest tenth of a lower limit unit, unless the context clearly indicates otherwise, between the upper and lower limits of that range and any other specified or intermediate value within the specified range is covered by the present technology . The upper and lower limits of these smaller ranges may be independently included in the smaller ranges and are also covered by this technology, subject to any specifically excluded limit within the specified range. If a specified range includes one or both limits, ranges excluding one or both of those included limits are also included in this technology.

[0068] Generally, the term “substituted” refers to an organic group (eg, an alkyl group) in which one or more bonds to a hydrogen atom contained therein are replaced by bonds to atoms other than hydrogen or carbon. Substituted groups also include groups in which one or more bonds to a carbon(s) or hydrogen atom(s) are replaced by one or more bonds, including double or triple bonds, to a heteroatom. It should be understood that the present invention includes embodiments in which, for example, "substituted alkyl" optionally contains one or more alkenes and/or alkynes. A substituted group will be replaced by one or more substituents unless otherwise specified. In some embodiments, the substituted group is substituted with 1, 2, 3, 4, 5, or 6 substituents. Examples of substituent groups include: alkyls, halogenated alkyls, halogens (ie F, Cl, Br and I); hydroxyls; alkoxy, alkenoxy, alkynoxy, aryloxy, aralkyloxy, heterocyclyloxy and heterocyclylalkoxy groups; aryl groups; heteroaryl groups; cycloalkyl groups; heterocyclyl groups; carbonyls (oxo); carboxyls; esters; carbamates; urethanes; urea; oximes; hydroxylamines; alkoxyamines; aralkoxyamines; thiols; sulfides; sulfoxides; sulfones; sulfonyls; sulfonamides; amines; N-oxides; hydrazines; hydrazides; hydrazones; azides; amides; urea; amidines; guanidines; enamines; imides; isocyanates; isothiocyanates; cyanates; thiocyanates; imines; nitro groups; nitriles (ie CN); and so on. As used herein, “optionally substituted group” refers to a group that is substituted or unsubstituted. Thus, "optionally substituted" and "substituted or unsubstituted" can be used interchangeably.

[0069] Substituted ring groups, such as substituted carbocyclic, substituted cycloalkyl, substituted aryl, substituted heterocyclic and substituted heteroaryl groups, also include rings and joined ring systems in which the bond to a hydrogen atom is replaced by a bond to a carbon atom. Therefore, substituted carbocyclic, substituted cycloalkyl, substituted aryl, substituted heterocyclic and substituted heteroaryl groups may also be substituted by substituted or unsubstituted alkyl, alkenyl and alkynyl groups as defined below.

[0070] As used herein, the term “carbocyclic group” or “carbocycle” includes aromatic (also called aryl) and non-aromatic ring compounds (such as cycloalkyl) containing 3 or more ring members and not containing any heteroatomic ring members. In some embodiments, the carbocycle has 3 to 20 cycles, while other such groups have 3 to 6, 3 to 10, 3 to 12, 3 to 15, or 5 to 12 cycles.

[0071] As used herein, “aryl group” refers to a cyclic aromatic hydrocarbon that does not contain heteroatoms. Aryl groups include monocyclic, bicyclic and polycyclic ring systems. Thus, aryl groups include, without limitation, phenyl, azulenyl, heptalenyl, biphenylenyl, indacyl, fluorenyl, phenanthrine, triphenylenyl, pyrenyl, naphthazenyl, chryosyl, biphenyl, anthracenyl, indenyl, indanyl, pentalenyl, and naphthyl groups. In some embodiments, aryl groups contain 6-14 carbon atoms, and in others, 6-12 or even 6-10 carbon atoms in the ring portions of the groups. Although the phrase "aryl groups" includes groups containing joined rings, such as fused aromatic-aliphatic ring systems (e.g., indanyl, tetrahydronaphthyl, etc.), it does not include aryl groups, which have other groups, such as alkyl or halogen groups. groups associated with one of the ring elements. Rather, groups such as tolyl are called substituted aryl groups. Exemplary substituted aryl groups may be monosubstituted or substituted more than once. For example, monosubstituted aryl groups include, but are not limited to, 2-, 3-, 4-, 5-, or 6-substituted phenyl or naphthyl groups, which may be substituted with substituents such as those listed above.

[0072] As used herein, the term “cycloalkyl group” refers to a cyclic alkyl group, such as, but not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl and cyclooctyl groups. In some embodiments, the cycloalkyl group has from 3 to 8 ring carbon atoms, while in other embodiments, the number of ring carbon atoms ranges from 3 to 5, 3 to 6, or 3 to 7. Cycloalkyl groups further include mono -, bicyclic and polycyclic ring systems, such as, for example, bridged cycloalkyl groups, as described below, and linked rings, such as, without limitation, decalinyl and the like. In some embodiments, the polycyclic cycloalkyl groups have three rings. Substituted cycloalkyl groups may be substituted one or more times with non-hydrogen and non-carbon groups as defined above. However, substituted cycloalkyl groups also include rings that are substituted with straight or branched alkyl groups as defined above. Exemplary substituted cycloalkyl groups may be monosubstituted or more than once substituted, such as, but not limited to, 2,2-, 2,3-, 2,4-, 2,5-, or 2,6-di-substituted cyclohexyl groups, which may be replaced by substituents such as those listed above. In some embodiments, the cycloalkyl group has one or more alkene bonds but is not aromatic.

[0073] As used herein, the term “heterocyclic group” or “heterocycle” includes aromatic (also called heteroaryl) and non-aromatic ring compounds containing 3 or more ring units, one or more of which is a heteroatom, such as, but not limited to, N, O, S, or B. In some embodiments, heterocyclic groups have 3 to 20 ring members, while other such groups have 3 to 6, 3 to 10, 3 to 12, 3 to 15, or 5 up to 12 ring members. Heterocyclic groups include unsaturated, partially saturated and saturated ring systems, such as, for example, imidazolyl, imidazolinyl and imidazolidinyl groups. The phrase “heterocyclic group” includes ring-jointed compounds, including those containing fused aromatic and non-aromatic groups, such as, for example, benzotriazolyl, 2,3-dihydrobenzo[1,4]dioxynyl and benzo[1,3]dioxolyl. The phrase also includes bridged polycyclic ring systems containing a heteroatom, such as, but not limited to, quinuclidyl. However, this phrase does not include heterocyclic groups that contain other groups, such as alkyl, oxo or halogen groups, attached to one of the ring members. Rather, they are called "substituted heterocyclic groups." Heterocyclic groups include, but are not limited to, acridinyl, aziridinyl, azetidinyl, pyrrolidinyl, imidazolidinyl, pyrazolidinyl, thiazolidinyl, tetrahydrothiophenyl, tetrahydrofuranyl, dioxolyl, furanyl, thiophenyl, pyrrolyl, pyrrolinyl, imidazolyl, imidazolinyl, pyrazolyl, pyrazolinyl, triazolyl, tetrazolyl, oxazolyl , isoxazolyl, thiazolyl, thiazolinyl, isothiazolyl, thiadiazolyl, oxadiazolyl, chromenonyl, piperidyl, piperazinyl, morpholinyl, thiomorpholinyl, tetrahydropyranyl, tetrahydrothiopyranyl, oxathianyl, dioxyl, dithianyl, pyranyl, pyridyl, pyrimidinyl, pyridazinyl, pyrazinyl, triazinyl, dihydropyridyl, dihydrodithinyl, dihydrodithionyl , homopiperazinyl, quinuclidyl, indolyl, indolinyl, isoindolyl, azaindolyl (pyrrolopyridyl), indazolyl, indolizinyl, benzotriazolyl, benzimidazolyl, benzofuranyl, benzothiophenyl, benzthiazolyl, benzoxadiazolyl, benzoxazinyl, benzodithinyl, benzoxathiinyl, benzothiazinyl, benzoxazolyl, benzoti azolyl, benzothiadiazolyl, benzo[1, 3]dioxolyl, dihydrobenzo[1,4]dioxynyl, 2,3-dihydrobenzofuranyl, 2-oxo-1,2-dihydroquinolinyl, 2-oxo-1,2,3,4-tetrahydroquinolinyl, pyrazolopyridyl, imidazopyridyl (azabenzimidazolyl), triazolopyridyl , isoxazolopyridyl, furo[3,2-c]pyridinyl, thieno[2,3-d]pyrimidinyl, thieno[3,2-c]pyridinyl, purinyl, xanthinyl, adeninyl, guaninyl, quinolinyl, isoquinolinyl, quinolizinyl, quinoxalinyl, quinazolinyl , cinnolinyl, phthalazinyl, naphthyridinyl, pteridinyl, thianaphthalinyl, dihydrobenzothiazinyl, dihydrobenzofuranyl, dihydroindolyl, dihydrobenzodioxynyl, tetrahydroindolyl, tetrahydroindazolyl, tetrahydrobenzimidazolyl, tetrahydrobenzotriazolyl, tetrahydropyrrolopyridyl, tetrahydropyridyl opirazolopyridyl, tetrahydroimidazopyridyl, tetrahydrotriazolopyridyl and tetrahydroquinolinyl groups. Representative substituted heterocyclic groups may be monosubstituted or substituted more than once, for example, pyridyl or piperazinyl groups, which are 2-, 3-, 4-, 5-, or 6-substituted or disubstituted with various substituents such as those listed above. In some embodiments, the term “naphthyridinyl” refers to 1,8-naphthyridinyl; 2,6-naphthyridinyl; or 1,5-naphthyridinyl or any combination of two or more of them.

[0074] As used herein, the term “heteroaryl group” refers to an aromatic ring compound containing 5 or more ring members, one or more of which are heteroatoms such as, but not limited to, N, O, S or B. in some embodiments, one or more heteroatoms are independently selected from N, O, or S. In some embodiments, from 1 to 4 heteroatoms are independently selected from N, O, or S. In some embodiments, from 1 to 5 heteroatoms are independently selected from N, O, or S. In some embodiments, heteroaryl groups include 5 to 14 ring members, while other such groups contain 5 to 6, 5 to 9, 5 to 10, 6 to 9, 6 to 10, or 6 to 14 ring members. For example, a 5-membered heteroaryl group has 5 ring members; A 6-membered heteroaryl group has 6 ring members; and a 9-membered heteroaryl group has 9 ring members (eg, but not limited to, benzothiophene). Heteroaryl groups include, but are not limited to, pyrrolyl, pyrazolyl, triazolyl, tetrazolyl, oxazolyl, isoxazolyl, thiazolyl, pyridyl, pyridazinyl, pyrimidinyl, pyrazinyl, thiophenyl, benzothiophenyl, furanyl, benzofuranyl, indolyl, azaindolyl (pyrrolopyridyl), indazolyl, benzimidazolyl, imidazopyridyl (azabenzimidazolyl), pyrazolopyridyl, triazolopyridyl, benzotriazolyl, benzoxazolyl, benzothiazolyl, benzothiadiazolyl, imidazopyridyl, isoxazolopyridyl, thianaphthalenyl, purinyl, xanthinyl, adeninyl, guaninyl, naphthyridinyl, quinolinyl, iso quinolinyl, tetrahydroquinolinyl, quinoxalinyl and quinazolinyl. Although the phrase "heteroaryl groups" includes ring-jointed compounds such as indolyl and 2,3-dihydroindolyl, the phrase does not include heteroaryl groups that have other groups attached to one of the ring members, such as alkyl groups. Rather, heteroaryl groups with such substitution are called "substituted heteroaryl groups." Typical substituted heteroaryl groups may be substituted one or more times with various substituents such as those listed above. An azolyl group is a 5-membered heteroaryl group containing a nitrogen atom and at least one other atom selected from nitrogen, sulfur and oxygen in the ring. Azolyl groups include imidazole, pyrazole, 1,2,3-triazole, 1,2,4-triazole, tetrazole, pentazole, oxazole, isoxazole, 1,2,4-oxadiazole, 1,2,5-oxadiazole, 1,3 ,4-oxadiazole, thiazole, isothiazole, 1,2,3-thiadiazole, 1,2,4-thiadiazole, 1,2,5-thiadiazole and 1,3,4-thiadiazole.

[0075] As used herein, the term “alkyl” refers to an aliphatic hydrocarbon radical, which includes both straight and branched hydrocarbon radicals. In some embodiments, alkyl has from 1 to about 20 carbon atoms, from 1 to 12 carbon atoms, from 1 to 8 carbon atoms, from 1 to 6 carbon atoms, or from 1 to 4 carbon atoms. For example, C _1-6 alkyl refers to an aliphatic hydrocarbon having from 1 to 6 carbon atoms, which includes methyl, ethyl, propyl, n-butyl, n-pentyl, n-hexyl, isopropyl, isobutyl, sec-butyl, tert- butyl, neopentyl, isopentyl, etc.

[0076] Additionally, as used herein, the term “hydroxy” is defined as -OH.

[0077] As used herein, the term “alkoxy,” unless otherwise noted, refers to a radical formed by replacing the hydrogen atom of a hydroxyl group with an alkyl, as defined above. For example, C _1-6 alkoxy includes methoxy, ethoxy, propoxy, n-butoxy, n-pentaloxy, isopropoxy, sec-butoxy, t-butoxy, neopentyloxy, isopentyloxy and the like.

[0078] In addition, as used herein, the term “halogen” refers to fluorine, bromine, chlorine and iodine.

[0079] Additionally, as used herein, the term “amino” is defined as -NH ₂ and the term “alkylamino” refers to a mono- or dialkyl substituted amine. For example, C _1-6 alkylamino includes mono- or di-C _1-6 alkyl-substituted amino.

[0080] Additionally, as used herein, the term “alkylthio” is defined as -SR* (where R* is alkyl) and the term “cyano” is defined as -CN.

[0081] Those skilled in the art will appreciate that the compounds of the present technology may exhibit tautomerism, conformational isomerism, geometric isomerism, and/or optical isomerism. Since the claim drawings and claims may represent only one of the possible tautomeric, conformational isomeric, optical isomeric, or geometric isomeric forms, it should be understood that the present technology covers any tautomeric, conformational isomeric, optical isomeric, and/or geometric isomeric forms of compounds having one or more of the agents described herein, as well as mixtures of these different forms. As used herein, the term “isomer” refers to a tautomer, a conformational isomer, an optical isomer, a geometric isomer of a compound, or any combination thereof.

[0082] As will be appreciated by one skilled in the art, a wide range of functional groups and other structures can exhibit tautomerism, and all tautomers of compounds as described herein are within the scope of the present technology.

[0083] Stereoisomers of compounds, also known as "optical isomers", include all chiral, diastereomeric and racemic forms of the structure unless explicitly stated otherwise. Thus, the compounds used in the present technology include enriched or separated optical isomers at any or all stereogenic atoms, as seen in the images. Both racemic and diastereomeric mixtures, as well as individual optical isomers, can be isolated or synthesized so that they are substantially free of their enantiomeric or diastereomeric partners, and all are within the scope of the present technology.

[0084] By “pharmaceutically acceptable” is meant a material that is not biologically or otherwise undesirable, for example, the material can be included in a pharmaceutical composition administered to a patient without causing undesirable biological effects or harmful interaction with any of the other components of the composition, in which it is contained. When the term "pharmaceutically acceptable" is used to refer to a pharmaceutical carrier or excipient, it is intended that the carrier or excipient meets required toxicological and manufacturing testing standards or is included in the Inactive Ingredients Handbook prepared by the US Food and Drug Administration.

[0085] Typically, reference to a specific moiety that may be protected (such as hydroxy, amine, carbonyl, etc.) includes protected groups in some embodiments. For example, in some embodiments, the -OH moiety included herein also includes -OP, wherein P is a protecting group. Protecting groups mentioned herein may be selected by one skilled in the art and include groups and strategies taught in the art, such as those described in R. Larock, Comprehensive Organic Transformations, VCH Publishers (1989); T.W. Greene and P.G.M. Wuts, Greene's protective groups in organic synthesis, John Wiley & Sons (2006); L. Fieser and M. Fieser, Fieser and Fieser's Reagents for Organic Synthesis, John Wiley and Sons (1994); and L. Paquette, ed., Encyclopedia of Reagents for Organic Synthesis, John Wiley and Sons (1995), and subsequent editions thereof.

[0086] The term "subject" refers to an animal, such as a mammal (including a human), that has been or will be the subject of treatment, observation or experiment. "Subject" and "patient" may be used interchangeably unless otherwise noted. The methods described herein can be used in human and/or veterinary medicine. In some embodiments, the subject is a mammal. In some embodiments, the subject is a human.

[0087] The terms "therapeutically effective amount" and "effective amount" are used interchangeably and refer to an amount of a compound that is sufficient to provide treatment, as defined below, when administered to a patient (e.g., a human) in need of such treatment in one or more doses The therapeutically effective amount will vary depending on the patient, the disease being treated, the weight and/or age of the patient, the severity of the disease, or the route of administration as determined by the qualified physician or caregiver.

[0088] The term “treatment” means the administration of a compound described herein for the purpose of (i) delaying the onset of a disease, that is, preventing or delaying the development of clinical symptoms of a disease; (ii) inhibiting the disease, that is, stopping the development of clinical symptoms; and/or (iii) alleviation of the disease, that is, causing regression of clinical symptoms or their severity.

[0089] Unless otherwise specified, all technical and scientific terms used herein have the same meaning as commonly understood by one skilled in the art to which this technology relates. Although any methods and materials similar or equivalent to those described herein may also be used in the practice or testing of the present technology, representative illustrative methods and materials are described herein.

[0090] The present inventors have discovered that specific pyrrolidine or piperidine compounds, although exhibiting low inhibitory activity against other DPP family enzymes (DPP4, DPP7, DPP8, DPP9, PREP), exhibit selective inhibitory activity against FAP. Thus, pyrrolidine or piperidine compounds or their salts can be effectively used for the treatment and prevention of various FAP-mediated diseases, such as cancer, wound healing, obesity, diabetes, steatosis, non-alcoholic steatohepatitis (NASH) and liver cirrhosis.

[0091] Thus, the present technology provides pyrrolidine and piperidine compounds, stereoisomers thereof, or pharmaceutically acceptable salts thereof, methods for their preparation, pharmaceutical compositions containing them, and uses thereof.

[0092] In accordance with one aspect of the present technology, a pyrrolidine or piperidine compound, a stereoisomer or mixture of stereoisomers thereof, or a pharmaceutically acceptable salt thereof is provided.

[0093] In accordance with another aspect of the present technology, a method for preparing pyrrolidine or piperidine is provided.

[0094] In accordance with another aspect of the present technology, a pharmaceutical composition is provided containing pyrrolidine or piperidine as an active ingredient.

[0095] In accordance with another aspect of the present technology, a method of treatment is provided, comprising administering pyrrolidine or a piperidine solution described herein.

[0096] Another aspect of the present technology provides the use of a pyrrolidine or a piperidine compound or a stereoisomer or mixture of stereoisomers thereof or a pharmaceutically acceptable salt thereof in the manufacture of a medicament for inhibiting fibroblast activation proteins.

[0097] In the present technology, it has been found that the compounds according to the present technology, i.e. pyrrolidine or piperidine, or stereoisomers thereof, or pharmaceutically acceptable salts thereof exhibit FAP inhibitory activity. Thus, the compounds of the present technology or their stereoisomers or their pharmaceutically acceptable salts can be effectively used for the treatment and prevention of various FAP-mediated diseases, for example, cancer, wound healing, obesity, diabetes, steatosis, non-alcoholic steatohepatitis (NASH) and cirrhosis liver.

[0098] In one aspect, provided herein is a compound of Formula X, or a stereoisomer or mixture of stereoisomers thereof, or a pharmaceutically acceptable salt thereof:

Where

n is 1 or 2;

R ₁ represents a substituent selected from the group consisting of compounds of formula IV,

R ₂ represents hydrogen or C _1-3 alkyl;

R ₃ represents a 5-12 membered substituted or unsubstituted heteroaryl, where said heteroaryl contains from 1 to 3 heteroatoms independently selected from O, N and S,

A 3-12 membered substituted or unsubstituted non-aromatic heterocycle, wherein said heterocycle contains from 1 to 3 heteroatoms independently selected from O, N and S,

-NR ₄ R ₅ , -OR ₄ , -C(O)NHR ₄ , -NHC(O)(CH ₂ ) _m R ₄ , or -NHS(O) ₂ R ₄ ,

where m represents 0 or 1;

R ₄ represents substituted phenyl; substituted or unsubstituted naphthyl; substituted or unsubstituted non-aromatic heterocycle; or substituted or unsubstituted heteroaryl; And

R ₅ represents hydrogen or C _{1 3} .

[0099] In another aspect, provided herein is a compound of Formula Xa, or a stereoisomer or mixture of stereoisomers, or a pharmaceutically acceptable salt thereof:

Where

n represents 1 or 2,

R ₁ represents a substituent selected from the group consisting of compounds of formula IV,

R ₁ represents hydrogen or C _1-3 alkyl;

R ₃ represents a 5-12 membered substituted or unsubstituted heteroaryl, where said heteroaryl contains from 1 to 3 heteroatoms independently selected from O, N and S,

A 3-12 membered substituted or unsubstituted non-aromatic heterocycle, wherein said heterocycle contains from 1 to 3 heteroatoms independently selected from O, N and S,

-NR ₄ R ₃ , -OR ₄ , -C(O)NHR ₄ , -NHC(O)(CH ₂ ) _m R ₄ , or -NHS(O) ₂ R ₄ ,

where m represents 0 or 1;

R ₄ represents substituted phenyl; substituted or unsubstituted naphthyl; substituted or unsubstituted non-aromatic heterocycle; or substituted or unsubstituted heteroaryl; And

R ₅ represents hydrogen or C _1-3 .

[0100] In another aspect, provided herein is a compound of Formula Xb, or a stereoisomer or mixture of stereoisomers, or a pharmaceutically acceptable salt thereof:

Where

n is 1 or 2;

R ₁ represents a substituent selected from the group consisting of compounds of formula IV,

R ₂ represents hydrogen or C _1-3 alkyl;

R ₃ represents a 5-12 membered substituted or unsubstituted heteroaryl, where said heteroaryl contains from 1 to 3 heteroatoms independently selected from O, N and S,

A 3-12 membered substituted or unsubstituted non-aromatic heterocycle, wherein said heterocycle contains from 1 to 3 heteroatoms independently selected from O, N and S,

-NR ₄ R ₅ , -OR ₄ , -C(O)NHR ₄ , -NHC(O)(CH ₂ ) _m R ₄ , or -NHS(O) ₂ R ₄ ,

where m represents 0 or 1;

R ₄ represents substituted phenyl; substituted or unsubstituted naphthyl; substituted or unsubstituted non-aromatic heterocycle; or substituted or unsubstituted heteroaryl; And

R ₅ represents hydrogen or C _1-3 .

[0101] In another aspect, provided herein is a compound of formula 1a, or a stereoisomer or mixture of stereoisomers, or a pharmaceutically acceptable salt thereof:

where R ₁ , R ₂ , R ₄ , R ₅ and n are as defined in the embodiments above or below.

[0102] In another aspect, provided herein is a compound of Formula 1b, or a stereoisomer or mixture of stereoisomers, or a pharmaceutically acceptable salt thereof:

where R ₁ , R ₂ , R ₄ and n are as defined in the embodiments above or below.

[0103] In another aspect, provided herein is a compound of Formula 1c, or a stereoisomer or mixture of stereoisomers, or a pharmaceutically acceptable salt thereof:

where R ₁ , R ₂ , R ₄ and n are as defined in the embodiments above or below.

[0104] In another aspect, provided herein is a compound of Formula 1d, or a stereoisomer or mixture of stereoisomers, or a pharmaceutically acceptable salt thereof:

where R ₁ , R ₂ , R ₄ , m and n are as defined in the embodiments above or below.

[0105] In another aspect, provided herein is a compound of Formula 1e, or a stereoisomer or mixture of stereoisomers, or a pharmaceutically acceptable salt thereof:

where R ₁ , R ₂ , R ₄ and n are as defined in the embodiments above or below.

[0106] In some embodiments of Formulas X, Xa, Xb, 1a, 1b, 1c, 1d, and 1e, R ₄ is

phenyl substituted with 1-3 Z; heterocycle selected from the group consisting of benzo[d][1,3]dioxolyl, dihydrobenzo[1,4]dioxynyl, 2,3-dihydrobenzofuranyl, 2-oxo-1,2-dihydroquinolinyl and 2-oxo-1,2 ,3,4-tetrahydroquinolinyl, wherein said heterocycle is optionally substituted with 1-3 Z,

naphthyl, optionally substituted with 1-3 Z or

heteroaryl selected from the group consisting of pyridinyl, pyrimidinyl, pyrazinyl, imidazolyl, pyrazolyl, triazolyl, oxazolyl, thiazolyl, furanyl, pyrrolyl, thiophenyl, quinolinyl, isoquinolinyl, chromenonyl, quinazolinyl, benzoxazolyl, benzofuranyl, benzothiophenyl, indolyl, indolinyl, benzime idazolyl benzoxazolyl , benzothiazolyl, indazolyl, furo[3,2-c]pyridinyl, thieno[2,3-d]pyrimidinyl, thieno[3,2-c]pyridinyl, isoxazolyl and acridinyl, wherein said heteroaryl is optionally substituted with 1-3 Z; And

each Z is independently selected from the group consisting of hydroxy, amino, halogen, cyano, nitro, carboxylic acid, C _1-5 alkyl, optionally substituted with 1-3 Z ¹ , C _2-6 alkenyl, optionally substituted with Z ¹ , C _{2- 6} alkynyl, optionally substituted with Z ¹ , C _1-5 alkoxy, optionally substituted with 1-3 Z ¹ , C _1-5 alkylthio, optionally substituted with Z ¹ , mono- or di-C _1-5 alkylamino, optionally substituted with Z ¹ , piperazinyl , optionally substituted with Z ¹ , C _1-5 alkylsulfonylamino, optionally substituted with Z ¹ , C _1-5 alkylcarbonylamino, optionally substituted with Z ¹ , aminosulfonyl, optionally substituted with Z ¹ , aminocarbonyl, optionally substituted with Z ¹ , C _1-5 alkylaminocarbonyl, optionally substituted Z ¹ , phenyl, optionally substituted with Z ¹ , phenoxy, optionally substituted with Z ¹ , benzyl, optionally substituted with Z ¹ , benzoyl, optionally substituted with Z ¹ , phenylaminocarbonyl, optionally substituted with Z ¹ , pyrazolyl, optionally substituted with Z ¹ , benzoxazolyl, optionally substituted with Z ¹ , C _1-5 alkoxycarbonyl, optionally substituted with Z ¹ , benzyloxy, optionally substituted with Z ¹ , C _1-5 alkylsulfonyl, optionally substituted with Z ¹ ;

where each Z ¹ is independently selected from halogen, hydroxyl, amino, C _1-5 alkylamino, cyano, acetyl, C _1-5 alkyl, C _1-5 haloalkyl, C _3-6 carbocycle, C _3-6 heterocycle, wherein the specified The C _3-6 carbocycle and said C _3-6 heterocycle are optionally substituted with halogen, hydroxyl, C _1-5 galkyl or C _1-5 haloalkyl.

[0107] In some embodiments of formulas X, Xa, Xb, 1a, 1b, 1c, 1d, and 1e, R ₄ is phenyl substituted with 1-3 Z, each Z being independently selected from the group consisting of hydroxy, amino, halogen, cyano, nitro, carboxylic acid, C _1-5 alkyl, optionally substituted with 1-3 halogens or amino group, C _2-6 alkenyl, C _2-6 alkynyl, C _1-5 alkoxy, C _1-5 alkylthio, mono- or di-C _1-5 alkylamino, piperazinyl, optionally substituted with acetyl, C _1-5 alkylsulfonylamino, C _1-5 alkylcarbonylamino, aminosulfonyl, aminocarbonyl, C _1-5 alkylaminocarbonyl, phenyl, phenoxy, benzyl, benzoyl, phenylaminocarbonyl, pyrazolyl and benzoxazolyl; or

R ₄ is a heterocycle selected from the group consisting of benzo[d][1,3]dioxolyl, dihydrobenzo[1,4]dioxynyl, 2,3-dihydrobenzofuranyl, 2-oxo-1,2-dihydroquinolinyl and 2-oxo -1,2,3,4-tetrahydroquinolinyl; or

R ₄ is naphthyl, optionally substituted with halogen; or

R ₄ is heteroaryl selected from the group consisting of pyridinyl, pyrimidinyl, pyrazinyl, imidazolyl, pyrazolyl, triazolyl, oxazolyl, thiazolyl, furanyl, pyrrolyl, thiophenyl, quinolinyl, isoquinolinyl, chromenonyl, quinazolinyl, benzoxazolyl, benzofuranyl, benzothiophenyl, indolyl, indolinyl, benzimidazolyl, benzoxazolyl, benzothiazolyl, indazolyl, furo[3,2-c]pyridinyl, thieno[2,3-d]pyrimidinyl, thieno[3,2-c]pyridinyl, isoxazolyl and acridinyl, wherein the heteroaryl is optionally substituted with 1- 3 Z, wherein each Z is independently selected from the group consisting of hydroxy, amino, di-C _1-5 alkylamino, cyano, nitro, halogen, C _1-5 alkyl optionally substituted with 1-3 halogens, C _1-5 alkoxy, optionally substituted with 1-3 halogens, C _1-5 alkoxycarbonyl, benzyloxy, phenyl, optionally substituted with halogen, acetyl and C _1-5 alkylsulfonyl.

[0108] In another aspect, the present technology provides a compound having inhibitory activity against FAP, or a salt thereof, that is, a compound of Formula 1, or a stereoisomer thereof, or a mixture of stereoisomers, or a pharmaceutically acceptable salt thereof:

Where

n is 1 or 2;

R ₁ is selected from the group consisting of formulas I, II, III, IV, and IV;

R ₂ represents hydrogen or C _1-3 alkyl;

R ₃ is a 5-12 membered heteroaryl, wherein said heteroaryl contains from 1 to 3 heteroatoms independently selected from O, N and S, and is optionally substituted with a 1-3 Z, 3-12 membered non-aromatic heterocycle, wherein said heterocycle contains from 1 to 3 heteroatoms independently selected from O, N and S, and optionally substituted with 1-3 Z, -NR ₄ R ₃ , -OR ₄ , -C(O)NHR ₄ , -NHC(O)(CH ₂ ) _m R ₄ , -NHS(O) ₂ R ₄ , -(CH ₂ ) _m CH ₂ R ₄ , or -(CH ₂ ) _m NHR ₄ ,

where m represents 0 or 1;

R ₄ is phenyl substituted with 1-3 Z,

heterocycle selected from the group consisting of benzo[d][1,3]dioxolyl, dihydrobenzo[1,4]dioxynyl, 2,3-dihydrobenzofuranyl, 2-oxo-1,2-dihydroquinolinyl and 2-oxo-1,2, 3,4-tetrahydroquinolinyl, wherein said heterocycle is optionally substituted with 1-3 Z, naphthyl, optionally substituted with 1-3 Z, or

heteroaryl selected from the group consisting of pyridinyl, pyrimidinyl, pyrazinyl, imidazolyl, pyrazolyl, triazolyl, oxazolyl, thiazolyl, furanyl, pyrrolyl, thiophenyl, quinolinyl, isoquinolinyl, chromenonyl, quinazolinyl, benzoxazolyl, benzofuranyl, benzothiophenyl, indolyl, indolinyl, benzime idazolyl benzoxazolyl , benzothiazolyl, indazolyl, furo[3,2-c]pyridinyl, thieno[2,3-d]pyrimidinyl, thieno[3,2-c]pyridinyl, isoxazolyl, acridinyl and naphthyridinyl, wherein said heteroaryl is optionally substituted with 1-3 Z ;

R ₅ represents hydrogen or C _1-3 alkyl; And

each Z is independently selected from the group consisting of hydroxy, amino, halogen, cyano, nitro, carboxylic acid, C _1-5 alkyl, optionally substituted 1-3 Z ¹ , C _2-6 alkenyl, optionally substituted Z ¹ , C _{2- 6} alkynyl, optionally substituted with Z ¹ , C _1-5 alkoxy, optionally substituted with 1-3 Z ¹ , C _1-5 alkylthio, optionally substituted with Z ¹ , mono- or di-C _1-5 alkylamino, optionally substituted with Z ¹ , piperazinyl , optionally substituted with Z ¹ , C _1-5 alkylsulfonylamino, optionally substituted with Z ¹ , C _1-5 alkylcarbonylamino, optionally substituted with Z ¹ , aminosulfonyl, optionally substituted with Z ¹ , aminocarbonyl, optionally substituted with Z ¹ , C _1-5 alkylaminocarbonyl, optionally substituted Z ¹ , phenyl, optionally substituted with Z ¹ , phenoxy, optionally substituted with Z ¹ , benzyl, optionally substituted with Z ¹ , benzoin, optionally substituted with Z ¹ , phenylaminocarbonyl, optionally substituted with Z ¹ , pyrazolyl, optionally substituted with Z ¹ , benzoxazolyl, optionally substituted with Z ¹ , C _1-5 alkoxycarbonyl, optionally substituted with Z ¹ , benzyloxy, optionally substituted with Z ¹ , C _1-5 alkylsulfonyl, optionally substituted with Z ¹ , acetyl, morpholinyl, optionally substituted with Z ¹ , -NR ₆ C(O)R ₇ , and -C(O)NR ₆ R ₇ ;

where each Z ¹ is independently selected from halogen, hydroxyl, amino, C _1-5 alkylamino, cyano, acetyl, C _1-5 alkyl, C _1-5 haloalkyl, C _3-6 carbocycle, C _3-6 heterocycle, wherein the specified The C _3-6 carbocycle and said C _3-6 heterocycle are optionally substituted with halogen, hydroxyl, C _1-5 alkyl or C _1-5 ;

R ₆ represents hydrogen or a C _1-3 alkyl group;

R ₇ represents a C _1-3 alkyl group optionally substituted with phenyl, phenyl optionally substituted with 1-3 Z ² or

heteroaryl selected from the group consisting of pyridinyl, pyrimidinyl, pyrazinyl, imidazolyl, pyrazolyl, triazolyl, oxazolyl, thiazolyl, furanyl, pyrrolyl, thiophenyl, quinolinyl, isoquinolinyl, chromenonyl, quinazolinyl, benzoxazolyl, benzofuranyl, benzothiophenyl, indolyl, indolinyl, benzime idazolyl benzoxazolyl , benzothiazolyl, indazolyl, furo[3,2-c]pyridinyl, thieno[2,3-d]pyrimidinyl, thieno[3,2-c]pyridinyl, isoxazolyl, acridinyl and naphthyridinyl, wherein said heteroaryl is optionally substituted with 1-3 Z ² ; And

each Z ² is independently selected from the group consisting of hydroxy, amino, halogen, cyano, nitro, hydroxycarbonyl, C _1-5 alkyl, optionally substituted 1-3 Z ³ , C _2-6 alkenyl, C _2-6 alkynyl, C _{1 -5} alkoxy, optionally substituted with 1-3 Z ³ , C _1-5 alkylthio, mono- or di-C _1-5 alkylamino, piperazinyl, optionally substituted with Z ³ , C _1-5 alkylsulfonylamino, C _1-5 alkylcarbonylamino, aminosulfonyl, aminocarbonyl, C _1-5 alkylaminocarbonyl, phenyl, phenoxy, benzyl, benzoyl, phenylaminocarbonyl, pyrazolyl and benzoxazolyl;

wherein each Z ³ is independently selected from halogen, amino or acetyl.

[0109] In some embodiments, a compound of Formula 1, or a stereoisomer or mixture of stereoisomers, or a pharmaceutically acceptable salt thereof:

n is 1 or 2;

R ₁ is selected from the group consisting of formulas I, II, III, IV and V:

R ₂ represents hydrogen or C _1-3 alkyl;

R ₃ is a 5-12 membered heteroaryl, wherein said heteroaryl contains from 1 to 3 heteroatoms independently selected from O, N and S, and is optionally substituted with a 1-3 Z, 3-12 membered non-aromatic heterocycle, wherein said heterocycle contains from 1 to 3 heteroatoms independently selected from O, N and S, and optionally substituted with 1-3 Z, -NR ₄ R ₅ , -OR ₄ , -C(O)NHR ₄ , -NHC(O)(CH ₂ ) _m R ₄ , or -NHS(O) ₂ R ₄ ,

where m represents 0 or 1;

R ₄ is phenyl substituted with 1-3 Z,

heterocycle selected from the group consisting of benzo[d][1,3]dioxolyl, dihydrobenzo[1,4]dioxynyl, 2,3-dihydrobenzofuranyl, 2-oxo-1,2-dihydroquinolinyl and 2-oxo-1,2 ,3,4-tetrahydroquinolinyl, wherein said heterocycle is optionally substituted with 1-3 Z, naphthyl, optionally substituted with 1-3 Z, or

heteroaryl selected from the group consisting of pyridinyl, pyrimidinyl, pyrazinyl, imidazolyl, pyrazolyl, triazolyl, oxazolyl, thiazolyl, furanyl, pyrrolyl, thiophenyl, quinolinyl, isoquinolinyl, chromenonyl, quinazolinyl, benzoxazolyl, benzofuranyl, benzothiophenyl, indolyl, indolinyl, benzime idazolyl, benzoxazolyl, benzothiazolyl, indazolyl, furo[3,2-c]pyridinyl, thieno[2,3-d]pyrimidinyl, thieno[3,2-c]pyridinyl, isoxazolyl and acridinyl, wherein said heteroaryl is optionally substituted with 1-3 Z;

R ₅ represents hydrogen or C _1-3 alkyl; And

each Z is independently selected from the group consisting of hydroxy, amino, halogen, cyano, nitro, carboxylic acid, C _1-5 alkyl, optionally substituted with 1-3 Z ¹ , C _2-6 alkenyl, optionally substituted with Z ¹ , C _{2- 6} alkynyl, optionally substituted with Z ¹ , C _1-5 alkoxy, optionally substituted with 1-3 Z ¹ , C _1-5 alkylthio, optionally substituted with Z ¹ , mono- or di-C _1-5 alkylamino, optionally substituted with Z ¹ , piperazinyl , optionally substituted with Z ¹ , C _1-5 alkylsulfonylamino, optionally substituted with Z ¹ , C _1-5 alkylcarbonylamino, optionally substituted with Z ¹ , aminosulfonyl, optionally substituted with Z ¹ , aminocarbonyl, optionally substituted with Z ¹ , C _1-5 alkylaminocarbonyl, optionally substituted Z ¹ , phenyl, optionally substituted with Z ¹ , phenoxy, optionally substituted with Z ¹ , benzyl, optionally substituted with Z ¹ , benzoin, optionally substituted with Z ¹ , phenylaminocarbonyl, optionally substituted with Z ¹ , pyrazolyl, optionally substituted with Z ¹ , benzoxazolyl, optionally substituted with Z ¹ , C _1-5 alkoxycarbonyl, optionally substituted with Z ¹ , benzyloxy, optionally substituted with Z ¹ , C _1-5 alkylsulfonyl, optionally substituted with Z ¹ ;

where each Z ¹ is independently selected from halogen, hydroxyl, amino, C _1-5 alkylamino, cyano, acetyl, C _1-5 alkyl, C _1-5 haloalkyl, C _3-6 carbocycle, C _3-6 heterocycle, wherein the specified The C _3-6 carbocycle and said C _3-6 heterocycle are optionally substituted with halogen, hydroxyl, C _1-5 alkyl or C _1-5 haloalkyl.

[0110] In some embodiments, R ₁ is selected from the group consisting of compounds of formulas I, II, III and V:

In some embodiments, R ₁ is a substituent of Formula I. In some embodiments, R ₁ is a substituent of Formula P. In some embodiments, R ₁ is a substituent of Formula III. In some embodiments, R ₁ is a substituent of Formula IV. In some embodiments, R ₁ is a substituent of Formula V.

[0111] In some embodiments, R ₁ is a substituent selected from the group consisting of compounds of formulas Ia-Va,

[0112] In some embodiments, R ₁ is a substituent selected from the group consisting of compounds of formulas Ia, IIa, IIIa, and Va:

[0113] In some embodiments, R ₁ is a compound of Formula Ia:

[0114] In some embodiments, R ₁ is a compound of Formula IIa:

[0115] In some embodiments, R ₁ is a compound of formula IIIa:

[0116] In some embodiments, R ₁ is a compound of Formula IVa:

[0117] In some embodiments, R ₁ is a compound of Formula Va:

[0118] In some embodiments, R ₂ is hydrogen. In some embodiments, R ₂ is C _1-3 alkyl.

[0119] In some embodiments, m is 0. In some embodiments, m is 1.

[0120] In some embodiments, n is 1. In some embodiments, n is 2.

[0121] In some embodiments, R ₃ is a substituent selected from the group consisting of -NR ₄ R ₃ , -OR ₄ , -C(O)NHR ₄ , -NHC(O)(CH ₂ ) _m R ₄ , and -NHS(O) ₂ R ₄ . In some embodiments, R ₃ is a substituent selected from the group consisting of -NR ₄ R ₃ , -OR ₄ , and -NHC(O)(CH ₂ ) _m R ₄ . In some embodiments, R ₃ is a substituent selected from the group consisting of -NR ₄ R ₅ and -OR ₄ . In some embodiments, R ₃ is -NR ₄ R ₃ . In some embodiments, R ₃ is -OR ₄ . In some embodiments, R ₃ is -C(O)NHR ₄ . In some embodiments, R ₃ is -NHC(O)(CH ₂ ) _m R ₄ . In some embodiments, R ₃ is -NHS(O) ₂ R ₄ .

[0122] In some embodiments, R ₃ is a 3-12 membered non-aromatic heterocycle, 1-3 nitrogen atoms, wherein said heterocycle is optionally substituted with 1-3 Z. In some embodiments, R ₃ is a 5-12 membered heteroaryl , optionally substituted with 1-5 Z. In some embodiments, R ₃ is 2-oxo-2,3-dihydro-1H-benzo[d]imidazol-1-yl.

[0123] In other embodiments, R ₄ is phenyl substituted with a substituent selected from the group consisting of piperazinyl, optionally substituted with acetyl, phenyl, phenoxy, benzyl, benzoyl, phenylaminocarbonyl, pyrazolyl, and benzoxazolyl; or R ₄ is a heterocycle selected from the group consisting of benzo[d][1,3]dioxolyl, 2,3-dihydrobenzofuranyl, 2-oxo-1,2-dihydroquinolinyl and 2-oxo-1,2,3, 4-tetrahydroquinolinyl; or R ₄ is naphthyl, optionally substituted with halogen; or R ₄ is heteroaryl selected from the group consisting of pyridinyl, quinolinyl, isoquinolinyl, quinazolinyl, benzofuranyl, benzothiophenyl, furo[3,2-c]pyridinyl, thieno[2,3-d]pyrimidinyl, thieno[3,2 -c]pyridinyl, isoxazolyl and acridinyl, wherein said heteroaryl is optionally substituted with 1-3 Z, each Z independently selected from the group consisting of hydroxy, halogen, C _1-5 alkyl, optionally substituted with 1-3 halogens, C _1-5 alkoxy, optionally substituted with 1-3 halogens, C _1-5 alkoxycarbonyl, benzyloxy and phenyl, optionally substituted with halogen.

[0124] In some embodiments, R ₄ is phenyl substituted with phenyl; or R ₄ is naphthyl; or R ₄ is a heteroaryl selected from the group consisting of quinolinyl, isoquinolinyl, benzofuranyl, benzothiophenyl and furo[3,2-c]pyridinyl, wherein said heteroaryl is optionally substituted with 1-3 Z, each Z being independently selected from the group consisting of of halogen, C _1-5 alkyl, optionally substituted with 1-3 halogens, and C _1-5 alkoxy, optionally substituted with 1-3 halogens.

[0125] In some embodiments, R ₄ is phenyl substituted with phenyl; or R ₄ is naphthyl; or R ₄ is a heteroaryl selected from the group consisting of quinolinyl, isoquinolinyl, benzofuranyl and benzothiophenyl, wherein said heteroaryl is optionally substituted with 1-3 Z, each Z being independently selected from the group consisting of hydroxy, halogen, C _1-5 alkyl and C _1-5 alkoxy.

[0126] In other embodiments, R ₄ is phenyl substituted with a substituent selected from the group consisting of piperazinyl, optionally substituted with acetyl, phenyl, phenoxy, benzyl, benzoyl, phenylaminocarbonyl, pyrazolyl, and benzoxazolyl; or R ₄ is a heterocycle selected from the group consisting of benzo[d][1,3]dioxolyl, 2,3-dihydrobenzofuranyl, 2-oxo-1,2-dihydroquinolinyl and 2-oxo-1,2,3, 4-tetrahydroquinolinyl; or R ₄ is naphthyl, optionally substituted with halogen; or R ₄ is a heteroaryl selected from the group consisting of pyridinyl, quinolinyl, isoquinolinyl, quinazolinyl, thieno[2,3-d]pyrimidinyl, isoxazolyl and acridinyl, wherein said heteroaryl is optionally substituted with 1-3 Z, each Z being independently selected from the group consisting of halogen, C _1-5 alkyl, optionally substituted with 1-3 halogens, C _1-5 alkoxy, optionally substituted with 1-3 halogens, benzyloxy and phenyl, optionally substituted with halogen.

[0127] In some embodiments, R ₄ is phenyl substituted with 1-3 Z, each Z being independently selected from the group consisting of hydroxy, amino, halogen, cyano, nitro, carboxylic acid, C _1-5 alkyl, optional substituted with 1-3 halogens or amino group, C _2-6 alkenyl, C _2-6 alkynyl, C _1-5 alkoxy, C _1-5 alkylthio, mono- or di-C _1-5 alkylamino, piperazinyl, optionally substituted with acetyl, C _1-5 alkylsulfonylamino, C _1-5 alkylcarbonylamino, aminosulfonyl, aminocarbonyl, C _1-5 alkylaminocarbonyl, phenyl, phenoxy, benzyl, benzoyl, phenylaminocarbonyl, pyrazolyl and benzoxazolyl.

[0128] In other embodiments, R ₄ is phenyl substituted with a substituent selected from the group consisting of piperazinyl, optionally substituted with acetyl, phenyl, phenoxy, benzyl, benzoyl, phenylaminocarbonyl, pyrazolyl, and benzoxazolyl. In some embodiments, R ₄ is phenyl substituted with phenyl.

[0129] In some embodiments, R ₄ is a heterocycle selected from the group consisting of benzo[d][1,3]dioxolyl, dihydrobenzo[1,4]dioxynyl, 2,3-dihydrobenzofuranyl, 2-oxo- 1,2-dihydroquinolinyl and 2-oxo-1,2,3,4-tetrahydroquinolinyl. In other embodiments, R ₄ is a heterocycle selected from the group consisting of benzo[d][1,3]dioxolyl, 2,3-dihydrobenzofuranyl, 2-oxo-1,2-dihydroquinolinyl and 2-oxo-1, 2,3,4-.

[0130] In some embodiments, R ₄ is naphthyl, optionally substituted with halogen. In other embodiments, R ₄ is naphthyl.

[0131] In some embodiments, R ₄ is a heteroaryl selected from the group consisting of pyridinyl, pyrimidinyl, pyrazinyl, imidazolyl, pyrazolyl, triazolip, oxazolyl, thiazolip, furanip, pyrrolyl, thiophenip, quinolinyl, isoquinolinip, chromenonyl, quinazolinip, benzoxazolyl, benzofuranyl, benzothiophenyl, indolyl, indolinyl, benzimidazolyl, benzoxazolyl, benzothiazolyl, indazolyl, furo[3,2-c]pyridinyl, thieno[2,3-d]pyrimidinyl, thieno[3,2-c]pyridinyl, isoxazolyl, acridinip and naphthyridinyl, wherein said heteroaryl is optionally substituted with 1-3 Z, wherein each Z is independently selected from the group consisting of hydroxy, amino, di-C _1-5 alkylamino, cyano, nitro, halogen, C _1-5 alkyl, optionally substituted 1-3 halogens, C _1-5 alkoxy, optionally substituted with 1 to 3 halogens, C _1-5 alkoxycarbonyl, benzyloxy, phenyl, optionally substituted with halogen, acetyl, C _1-5 alkylsulfonyl, morpholine, -NR ₆ C(O) R ₇ , and -C(O)NR ₆ R ₇ . In some embodiments, R ₄ is a heteroaryl selected from the group consisting of pyridinyl, quinolinyl, isoquinolinyl, chromium, quinazolinyl, benzofuranyl, indolinyl, benzimidazolyl, benzothiophenyl, benzothiazolyl, furo[3,2-c]pyridinyl, thieno[2, 3-d]pyrimidinyl, thieno[3,2-c]pyridinyl, isoxazolyl, acridinyl and naphthyridinyl, wherein said heteroaryl is optionally substituted with 1-3 Z, each Z being independently selected from the group consisting of hydroxy, cyano, nitro, halogen, C _1-5 alkyl, optionally substituted with 1-3 halogens, C _1-5 alkoxy, optionally substituted with 1-3 halogens, C _1-5 alkoxycarbonyl, benzyloxy, acetyl, morpholine, -NR ₆ C(O)R ₇ , -C (O)NR ₆ R ₇ and phenyl, optionally substituted with halogen; R ₆ represents hydrogen or a C _1-5 alkyl group; and R ₇ represents a C _1-5 alkyl group, optionally substituted with phenyl, phenyl or heteroaryl selected from the group consisting of pyridinyl, pyrimidinyl and isoxazolyl. In some embodiments, R ₄ is a heteroaryl selected from the group consisting of pyridinyl, quinolinyl, isoquinolinyl, chromium, quinazolinyl, benzofuranyl, indolinyl, benzimidazolyl, benzothiophenyl, benzothiazolyl, furo[3,2-c]pyridinyl and naphthyridinyl, wherein said heteroaryl is optionally substituted with 1-3 Z, each Z being independently selected from the group consisting of hydroxy, cyano, nitro, halogen, C _1-5 alkyl, optionally substituted with 1-3 halogens, C _1-5 alkoxy, optionally substituted with 1- 3 halogens, benzyloxy, acetyl, morpholinyl, -NR ₆ C(O)R ₇ , -C(O)NR ₆ R ₇ In some embodiments, R ₄ is heteroaryl selected from the group consisting of pyridinyl, quinolinyl, isoquinolinyl , chromium, quinazolinyl, benzofuranyl, indolinyl, benzimidazolyl, benzothiophenyl, benzothiazolyl, furo[3,2-c]pyridinyl and naphthyridinyl, wherein said heteroaryl is optionally substituted with 1-3 Z, each Z being independently selected from the group consisting of hydroxy, cyano , nitro, halogen, C _1-5 alkyl, optionally substituted with 1-3 halogens, C _1-5 alkoxy, optionally substituted with 1-3 halogens, benzyloxy, acetyl, morpholinyl, -NR ₆ C(O)R ₇ , -C( O)NR ₆ R ₇ ; R ₆ represents hydrogen or a C _1-3 alkyl group; and R ₇ represents a C _1-3 alkyl group, optionally substituted with phenyl, phenyl or heteroaryl selected from the group consisting of pyridinyl, pyrimidinyl and isoxazolyl.

[0132] In some embodiments, R ₄ is quinolinyl or isoquinolinyl, each of which is optionally substituted with 1-3 Z's, each Z being independently selected from the group consisting of hydroxy, cyano, nitro, halogen, C _1-5 alkyl, optionally substituted with 1-3 halogens, C _1-5 alkoxy, optionally substituted with 1-3 halogens, benzyloxy, acetyl, morpholinyl, -NR ₆ C(O)R ₇ , -C(O)NR ₆ R ₇ ; R ₆ represents hydrogen or a C _1-3 alkyl group; and R ₇ represents a C _1-3 alkyl group, optionally substituted with phenyl, phenyl or heteroaryl selected from the group consisting of pyridinyl, pyrimidinyl and isoxazolyl. In some embodiments, R ₄ is quinolinyl, optionally substituted with 1-3 Z, each Z independently selected from the group consisting of hydroxy, cyano, nitro, halogen, C _1-5 alkyl, optionally substituted with 1-3 halogen, C _1-5 alkoxy, optionally substituted with 1-3 halogens, benzyloxy, acetyl, morpholinyl, -NR ₆ C(O)R ₇ , -C(O)NR ₆ R ₇ ; R ₆ represents hydrogen or a C _1-3 alkyl group; and R ₇ represents a C _1-3 alkyl group, optionally substituted with phenyl, phenyl or heteroaryl selected from the group consisting of pyridinyl, pyrimidinyl and isoxazolyl.

[0133] In some embodiments, R ₄ is a heteroaryl selected from the group consisting of pyridinyl, pyrimidinyl, pyrazinyl, imidazolyl, pyrazolyl, triazolyl, oxazolyl, thiazolyl, furanyl, pyrrolyl, thiophenyl, quinolinyl, isoquinolinyl, chromenonyl, quinazolinyl, benzoxazolyl, benzofuranyl, benzothiophenyl, indolyl, indolinyl, benzimidazolyl, benzoxazolyl, benzothiazolyl, indazolyl, furo[3,2-c]pyridinyl, thieno[2,3-d]pyrimidinyl, thieno[3,2-c]pyridinyl, isoxazolyl and acridinyl, wherein the heteroaryl is optionally substituted with 1-3 Z, wherein each Z is independently selected from the group consisting of hydroxy, amino, di- _C1-5 alkylamino, cyano, nitro, halogen, _C1-5 alkyl, optionally substituted with 1-3 halogens, C _1-5 alkoxy, optionally substituted with 1-3 halogens, C _1-5 alkoxycarbonyl, benzyloxy, phenyl, optionally substituted with halogen, acetyl and C _1-5 alkylsulfonyl. In some embodiments, R ₄ is heteroaryl selected from the group consisting of pyridinyl, quinolinyl, isoquinolinyl, quinazolinyl, benzofuranyl, benzothiophenyl, furo[3,2-c]pyridinyl, thieno[2,3-d]pyrimidinyl, thieno [3,2-c]pyridinyl, isoxazolyl and acridinyl, wherein said heteroaryl is optionally substituted with 1-3 Z, each Z being independently selected from the group consisting of hydroxy, halogen, C _1-5 alkyl, optionally substituted with 1-3 halogens, C _1-5 alkoxy, optionally substituted with 1-3 halogens, C _1-5 alkoxycarbonyl, benzyloxy and phenyl, optionally substituted with halogen. In some embodiments, R ₄ is a heteroaryl selected from the group consisting of quinolinyl, isoquinolinyl, benzofuranyl, benzothiophenyl, and furo[3,2-c]pyridinyl, wherein said heteroaryl is optionally substituted with 1-3 Z's, each Z being independently selected from the group consisting of halogen, C _1-5 alkyl, optionally substituted with 1-3 halogens, and C _1-5 alkoxy, optionally substituted with 1-3 halogens.

[0134] In some embodiments, R ₄ is a heteroaryl selected from the group consisting of quinolinyl, isoquinolinyl, benzofuranyl and benzothiophenyl, wherein said heteroaryl is optionally substituted with 1-3 Zs, each Z being independently selected from the group consisting of hydroxy, halogen, C _1-5 alkyl and C _1-5 alkoxy.

[0135] In some embodiments, R ₄ is a heteroaryl selected from the group consisting of pyridinyl, quinolinyl, isoquinolinyl, quinazolinyl, thieno[2,3-d]pyrimidinyl, isoxazolyl, and acridinyl, wherein said heteroaryl is optionally substituted with 1-3 Z, wherein each Z is independently selected from the group consisting of cyano, halogen, C _1-5 alkyl, optionally substituted with 1-3 halogens, C _1-5 alkoxy, optionally substituted with 1-3 halogens, benzyloxy, and phenyl, optionally substituted with halogen. In some embodiments, R ₄ is a heteroaryl selected from the group consisting of pyridinyl, quinolinyl, isoquinolinyl, quinazolinyl, thieno[2,3-d]pyrimidinyl, isoxazolyl and acridinyl, wherein said heteroaryl is optionally substituted with 1-3 Z, wherein each Z is independently selected from the group consisting of halogen, C _1-5 alkyl, optionally substituted with 1-3 halogens, C _1-5 alkoxy, optionally substituted with 1-3 halogens, benzyloxy, and phenyl, optionally substituted with halogen.

[0136] In some embodiments, R ₄ is quinolinyl, isoquinolinyl, or quinazolinyl, each optionally substituted with 1-3 Zs, each Z independently selected from the group consisting of cyano, halogen, C _1-5 alkyl, optionally substituted with 1 -3 halogens, and C _1-5 alkoxy, optionally substituted with 1-3 halogens. In some embodiments, R ₄ is quinolinyl, isoquinolinyl, or quinazolinyl, each optionally substituted with 1-3 Z's, each Z independently selected from the group consisting of halogen, C _1-5 alkyl, optionally substituted with 1-3 halogens, and With _1-5 alkoxy, optionally substituted with 1-3 halogens.

[0137] In some embodiments, R ₄ is quinolinyl or isoquinolinyl, each optionally substituted with 1-3 Zs, each Z independently selected from the group consisting of halogen, C _1-5 alkyl, optionally substituted with 1-3 halogens, and C _1-5 alkoxy, optionally substituted with 1-3 halogens.

[0138] In some embodiments, R ₄ is quinolinyl or isoquinolinyl, each of which is optionally substituted with 1-3 Zs, each Z being independently selected from the group consisting of hydroxy, halogen, C _1-5 alkyl, and C _1-5 alkoxy. In some embodiments, R ₄ is quinolinyl, optionally substituted with 1-3 Z, with each Z independently selected from the group consisting of halogen, C _1-5 alkyl, optionally substituted with 1-3 halogens, and C _1-5 alkoxy, optionally substituted with 1-3 halogens.

[0139] In some embodiments, R ₄ is benzofuranyl, benzothiophenyl, or furo[3,2-c]pyridinyl, each of which is optionally substituted with 1-3 Zs, each Z being independently selected from the group consisting of halogen, C _{1 -5} alkyl and C _1-5 alkoxy. In some embodiments, R ₄ is benzofuranyl or benzothiophenyl, each of which is optionally substituted with 1-3 Z, each Z being independently selected from the group consisting of halogen, C _1-5 alkyl, and C _1-5 alkoxy. In some embodiments, R ₄ is benzofuranyl, optionally substituted with 1-3 Zs, each Z being independently selected from the group consisting of hydroxy, halogen, C _1-5 alkyl, and C _1-5 alkoxy. In some embodiments, R ₄ is benzofuranyl or benzothiophenyl.

[0140] In some embodiments, R ₄ is pyridinyl, wherein said R ₄ is an optionally substituted 1-3 Z, wherein each Z is independently selected from the group consisting of hydroxy, amino, di-C _1-5 alkylamino, cyano , nigro, halogen, C _1-5 alkyl, optionally substituted with 1-3 halogens, C _1-5 alkoxy, optionally substituted with 1-3 halogens, C _1-5 alkoxycarbonyl, benzyloxy, phenyl, optionally substituted with halogen, acetyl, C _{1- 5} alkylsulfonyl, morpholinyl, -NR ₆ C(O)R ₇ and -C(O)NR ₆ R ₇ . In some embodiments, R ₄ is pyridinyl, wherein said R ₄ is optionally substituted with 1-3 Z, each Z being independently selected from the group consisting of hydroxy, amino, di-C _1-5 alkylamino, cyano, nitro, halogen, C _1-5 alkyl, optionally substituted with 1-3 halogens, C _1-5 alkoxy, optionally substituted with 1-3 halogens, C _1-5 alkoxycarbonyl, benzyloxy, phenyl, optionally substituted with halogen, acetyl, C _1-5 alkylsulfonyl, morpholinyl, -NR ₆ C(O)R ₇ and -C(O)NR ₆ R ₇ ; R ₆ represents hydrogen or a C _1-3 alkyl group; and R ₇ represents a C _1-3 alkyl group, optionally substituted with phenyl, phenyl or heteroaryl selected from the group consisting of pyridinyl, pyrimidinyl and isoxazolyl.

[0141] In some embodiments, R ₄ is chromenonyl, wherein said R ₄ is an optionally substituted 1-3 Z, wherein each Z is independently selected from the group consisting of hydroxy, amino, di-C _1-5 alkylamino, cyano , nigro, halogen, C _1-5 alkyl, optionally substituted with 1-3 halogens, C _1-5 alkoxy, optionally substituted with 1-3 halogens, C _1-5 alkoxycarbonyl, benzyloxy, phenyl, optionally substituted with halogen, acetyl, C _{1- 5} alkylsulfonyl, morpholinyl, -NR ₆ C(O)R ₇ and -C(O)NR ₆ R ₇ . In some embodiments, R ₄ is chromenonyl, wherein said R ₄ is optionally substituted with 1-3 Z, each Z being independently selected from the group consisting of hydroxy, amino, di-C _1-5 alkylamino, cyano, nitro, halogen, C _1-5 alkyl, optionally substituted with 1-3 halogens, C _1-5 alkoxy, optionally substituted with 1-3 halogens, C _1-3 alkoxycarbonyl, benzyloxy, phenyl, optionally substituted with halogen, acetyl, C _1-3 alkylsulfonyl, morpholinyl, -NR ₆ C(O)R ₇ , and -C(O)NR ₆ R ₇ . R ₆ represents hydrogen or a C _1-3 alkyl group; and R ₇ represents a C _1-3 alkyl group, optionally substituted with phenyl, phenyl or heteroaryl selected from the group consisting of pyridinyl, pyrimidinyl and isoxazolyl.

[0142] In some embodiments, R ₄ is quinazolinyl, wherein said R ₄ is an optionally substituted 1-3 Z, wherein each Z is independently selected from the group consisting of hydroxy, amino, di-C _1-5 alkylamino, cyano , nitro, halogen, C _1-5 alkyl, optionally substituted with 1-3 halogens, C _1-5 alkoxy, optionally substituted with 1-3 halogens, C _1-5 alkoxycarbonyl, benzyloxy, phenyl, optionally substituted with halogen, acetyl, C _{1- 5} alkylsulfonyl, morpholinyl, -NR ₆ C(O)R ₇ , and -C(O)NR ₆ R ₇ . In some embodiments, R ₄ is quinazolinyl, wherein said R ₄ is optionally substituted with 1-3 Z, each Z being independently selected from the group consisting of hydroxy, amino, di-C _1-5 alkylamino, cyano, nitro, halogen, C _1-5 alkyl, optionally substituted with 1-3 halogens, C _1-5 alkoxy, optionally substituted with 1-3 halogens, C _1-5 alkoxycarbonyl, benzyloxy, phenyl, optionally substituted with halogen, acetyl, C _1-5 alkylsulfonyl, morpholinyl, -NR ₆ C(O)R ₇ , and -C(O)NR ₆ R ₇ ; R ₆ represents hydrogen or a C _1-3 alkyl group; and R ₇ represents a C _1-3 alkyl group, optionally substituted with phenyl, phenyl or heteroaryl selected from the group consisting of pyridinyl, pyrimidinyl and isoxazolyl.

[0143] In some embodiments, R ₄ is benzothiophenyl, wherein said R ₄ is an optionally substituted 1-3 Z, wherein each Z is independently selected from the group consisting of hydroxy, amino, di-C _1-5 alkylamino, cyano , nitro, halogen, C _1-5 alkyl, optionally substituted with 1-3 halogens, C _1-5 alkoxy, optionally substituted with 1-3 halogens, C _1-5 alkoxycarbonyl, benzyloxy, phenyl, optionally substituted with halogen, acetyl, C _{1- 5} alkylsulfonyl, morpholinyl, -NR ₆ C(O)R ₇ , and -C(O)NR ₆ R ₇ . In some embodiments, R ₄ is benzothiophenyl, wherein said R ₄ is optionally substituted with 1-3 Z, each Z being independently selected from the group consisting of hydroxy, amino, di-C _1-5 alkylamino, cyano, nitro, halogen, C _1-5 alkyl, optionally substituted with 1-3 halogens, C _1-5 alkoxy, optionally substituted with 1-3 halogens, C _1-5 alkoxycarbonyl, benzyloxy, phenyl, optionally substituted with halogen, acetyl, C _1-5 alkylsulfonyl, morpholinyl, -NR ₆ C(O)R ₇ , and -C(O)NR ₆ R ₇ ; R ₆ represents hydrogen or a C _1-3 alkyl group; and R ₇ represents a C _1-3 alkyl group, optionally substituted with phenyl, phenyl or heteroaryl selected from the group consisting of pyridinyl, pyrimidinyl and isoxazolyl.

[0144] In some embodiments, R ₄ is indolinyl, wherein said R ₄ is an optionally substituted 1-3 Z, wherein each Z is independently selected from the group consisting of hydroxy, amino, di-C _1-5 alkylamino, cyano , nitro, halogen, C _1-5 alkyl, optionally substituted with 1-3 halogens, C _1-5 alkoxy, optionally substituted with 1-3 halogens, C _1-5 alkoxycarbonyl, benzyloxy, phenyl, optionally substituted with halogen, acetyl, C _{1- 5} alkylsulfonyl, morpholinyl, -NR ₆ C(O)R ₇ , and -C(O)NR ₆ R ₇ . In some embodiments, R ₄ is indolinyl, wherein said R ₄ is an optionally substituted 1-3 Z, with each Z independently selected from the group consisting of hydroxy, amino, di-C _1-5 alkylamino, cyano, nitro, halogen, C _1-5 alkyl, optionally substituted with 1-3 halogens, C _1-5 alkoxy, optionally substituted with 1-3 halogens, C _1-5 alkoxycarbonyl, benzyloxy, phenyl, optionally substituted with halogen, acetyl, C _1-5 alkylsulfonyl, morpholinyl, -NR ₆ C(O)R ₇ , and -C(O)NR ₆ R ₇ ; R ₆ represents hydrogen or a C _1-3 alkyl group; and R ₇ represents a C _1-3 alkyl group, optionally substituted with phenyl, phenyl or heteroaryl selected from the group consisting of pyridinyl, pyrimidinyl and isoxazolyl.

[0145] In some embodiments, R ₄ is benzothiazolyl, wherein said R ₄ is an optionally substituted 1-3 Z, wherein each Z is independently selected from the group consisting of hydroxy, amino, di-C _1-5 alkylamino, cyano , nitro, halogen, C _1-5 alkyl, optionally substituted with 1-3 halogens, C _1-5 alkoxy, optionally substituted with 1-3 halogens, C _1-5 alkoxycarbonyl, benzyloxy, phenyl, optionally substituted with halogen, acetyl, C _{1- 5} alkylsulfonyl, morpholinyl, -NR ₆ C(O)R ₇ , and -C(O)NR ₆ R ₇ . In some embodiments, R ₄ is benzothiazolyl, wherein said R ₄ is optionally substituted with 1-3 Z, each Z being independently selected from the group consisting of hydroxy, amino, di-C _1-5 alkylamino, cyano, nitro, halogen, C _1-5 alkyl, optionally substituted with 1-3 halogens, C _1-5 alkoxy, optionally substituted with 1-3 halogens, C _1-5 alkoxycarbonyl, benzyloxy, phenyl, optionally substituted with halogen, acetyl, C _1-5 alkylsulfonyl, morpholinyl, -NR ₆ C(O)R ₇ , and -C(O)NR ₆ R ₇ ; R ₆ represents hydrogen or a C _1-3 alkyl group; and R ₇ represents a C _1-3 alkyl group, optionally substituted with phenyl, phenyl or heteroaryl selected from the group consisting of pyridinyl, pyrimidinyl and isoxazolyl.

[0146] In some embodiments, R ₄ is furo[3,2-c]pyridinyl, wherein said R ₄ is an optionally substituted 1-3 Z, each Z being independently selected from the group consisting of hydroxy, amino, di -C _1-3 alkylamino, cyano, nitro, halogen, C _1-3 alkyl, optionally substituted with 1-3 halogens, C _1-5 alkoxy, optionally substituted with 1-3 halogens, C _1-5 alkoxycarbonyl, benzyloxy, phenyl, optional halogen-substituted, acetyl, C _1-5 alkylsulfonyl, morpholinyl, -NR ₆ C(O)R ₇ , and -C(O)NR ₆ R ₇ . In some embodiments, R ₄ is furo[3,2-c]pyridinyl, wherein said R ₄ is an optionally substituted 1-3 Z, wherein each Z is independently selected from the group consisting of hydroxy, amino, di-C _{1 -5} alkylamino, cyano, nitro, halogen, C _1-5 alkyl, optionally substituted with 1-3 halogens, C _1-5 alkoxy, optionally substituted with 1-3 halogens, C _1-5 alkoxycarbonyl, benzyloxy, phenyl, optionally substituted with halogen, acetyl, C _1-5 alkylsulfonyl, morpholinyl, -NR ₆ C(O)R ₇ , and -C(O)NR ₆ R ₇ ; R ₆ represents hydrogen or a C _1-3 alkyl group; and R ₇ represents a C _1-3 alkyl group, optionally substituted with phenyl, phenyl or heteroaryl selected from the group consisting of pyridinyl, pyrimidinyl and isoxazolyl.

[0147] In some embodiments, R ₄ is naphthyridinyl, wherein said R ₄ is an optionally substituted 1-3 Z, wherein each Z is independently selected from the group consisting of hydroxy, amino, di-C _1-5 alkylamino, cyano , nitro, halogen, C _1-5 alkyl, optionally substituted with 1-3 halogens, C _1-5 alkoxy, optionally substituted with 1-3 halogens, C _1-5 alkoxycarbonyl, benzyloxy, phenyl, optionally substituted with halogen, acetyl, C _{1- 5} alkylsulfonyl, morpholinyl, -NR ₆ C(O)R ₇ , and -C(O)NR ₆ R ₇ . In some embodiments, R ₄ is naphthyridinyl, wherein said R ₄ is optionally substituted with 1-3 Z, each Z being independently selected from the group consisting of hydroxy, amino, di-C _1-5 alkylamino, cyano, nitro, halogen, C _1-5 alkyl, optionally substituted with 1-3 halogens, C _1-5 alkoxy, optionally substituted with 1-3 halogens, C _1-5 alkoxycarbonyl, benzyloxy, phenyl, optionally substituted with halogen, acetyl, C _1-5 alkylsulfonyl, morpholinyl, -NR ₆ C(O)R ₇ , and -C(O)NR ₆ R ₇ ; R ₆ represents hydrogen or a C _1-3 alkyl group; and R ₇ represents a C _1-3 alkyl group, optionally substituted with phenyl, phenyl or heteroaryl selected from the group consisting of pyridinyl, pyrimidinyl and isoxazolyl.

[0148] In some embodiments, R ₄ is substituted or unsubstituted pyridinyl. In some embodiments, R ₄ is substituted or unsubstituted pyrimidinyl. In some embodiments, R ₄ is substituted or unsubstituted pyrazinyl. In some embodiments, R ₄ is substituted or unsubstituted imidazolyl. In some embodiments, R ₄ is substituted or unsubstituted pyrazolyl. In some embodiments, R ₄ is a substituted or unsubstituted triazolyl. In some embodiments, R ₄ is substituted or unsubstituted oxazolyl. In some embodiments, R ₄ is substituted or unsubstituted oxazolyl. In some embodiments, R ₄ is substituted or unsubstituted furanyl. In some embodiments, R ₄ is substituted or unsubstituted pyrrolyl. In some embodiments, R ₄ is substituted or unsubstituted thiophenyl. In some embodiments, R ₄ is substituted or unsubstituted quinolinyl. In some embodiments, R ₄ is substituted or unsubstituted isoquinolinyl. In some embodiments, R ₄ is substituted or unsubstituted chromenonyl. In some embodiments, R ₄ is substituted or unsubstituted quinazolinyl. In some embodiments, R ₄ is substituted or unsubstituted benzoxazolyl. In some embodiments, R ₄ is substituted or unsubstituted benzofuranyl. In some embodiments, R ₄ is substituted or unsubstituted benzothiophenyl. In some embodiments, R ₄ is substituted or unsubstituted indolyl. In some embodiments, R ₄ is substituted or unsubstituted indolinyl. In some embodiments, R ₄ is substituted or unsubstituted benzimidazolyl. In some embodiments, R ₄ is substituted or unsubstituted benzoxazolyl. In some embodiments, R ₄ is substituted or unsubstituted benzothiazolyl. In some embodiments, R ₄ is substituted or unsubstituted indazolyl. In some embodiments, R ₄ is substituted or unsubstituted furo[3,2-c]pyridinyl. In some embodiments, R ₄ is substituted or unsubstituted thieno[2,3-d]pyrimidinyl. In some embodiments, R ₄ is substituted or unsubstituted thieno[3,2-c]pyridinyl. In some embodiments, R ₄ is substituted or unsubstituted isoxazolyl. In some embodiments, R ₄ is substituted or unsubstituted acridinyl. In some embodiments, R ₄ is substituted or unsubstituted naphthyridinyl.

[0149] In other embodiments, R ₄ is phenyl substituted with a substituent selected from the group consisting of piperazinyl, optionally substituted with acetyl, phenyl, phenoxy, benzyl, benzoyl, phenylaminocarbonyl, pyrazolyl, and benzoxazolyl;

a heterocycle selected from the group consisting of benzo[d][1,3]dioxolyl, 2,3-dihydrobenzofuranyl, 2-oxo-1,2-dihydroquinolinyl and 2-oxo-1,2,3,4-tetrahydroquinolinyl;

naphthyl, optionally substituted with halogen; or

heteroaryl selected from the group consisting of pyridinyl, quinolinyl, isoquinolinyl, chromium, quinazolinyl, benzofuranyl, indolinyl, benzimidazolyl, benzothiophenyl, benzothiazolyl, furo[3,2-c]pyridinyl, thieno[2,3-d]pyrimidinyl, thieno[ 3,2-c]pyridinyl, isoxazolyl, acridinyl and naphthyridinyl, wherein said heteroaryl is optionally substituted with 1-3 Z, wherein each Z is independently selected from the group consisting of hydroxy, cyano, nitro, halogen, C _1-5 alkyl, optionally substituted 1-3 halogens, C _1-5 alkoxy, optionally substituted with 1-3 halogens, C _1-5 alkoxycarbonyl, benzyloxy, acetyl, morpholinyl, -NR ₆ C(O)R ₇ , -C(O)NR ₆ R ₇ and phenyl, optionally substituted with halogen;

where R ₆ represents hydrogen or a C _1-3 alkyl group; and R ₇ represents a C _1-3 alkyl group, optionally substituted with phenyl, phenyl or

heteroaryl selected from the group consisting of pyridinyl, pyrimidinyl and isoxazolyl.

[0150] In other embodiments, R ₄ is phenyl substituted with a substituent selected from the group consisting of piperazinyl, optionally substituted with acetyl, phenyl, phenoxy, benzyl, benzoyl, phenylaminocarbonyl, pyrazolyl, and benzoxazolyl;

a heterocycle selected from the group consisting of benzo[d][1,3]dioxolyl, 2,3-dihydrobenzofuranyl, 2-oxo-1,2-dihydroquinolinyl and 2-oxo-1,2,3,4-tetrahydroquinolinyl;

naphthyl, optionally substituted with halogen; or

or heteroaryl selected from the group consisting of pyridinyl, quinolinyl, isoquinolinyl, quinazolinyl, benzofuranyl, benzothiophenyl, furo[3,2-c]pyridinyl, thieno[2,3-d]pyrimidinyl, thieno[3,2-c]pyridinyl , isoxazolyl and acridinyl, wherein said heteroaryl is optionally substituted with 1-3 Z, each Z being independently selected from the group consisting of hydroxy, halogen, C _1-5 alkyl, optionally substituted with 1-3 halogens, C _1-5 alkoxy, optionally substituted 1-3 halogens, C _1-3 alkoxycarbonyl, benzyloxy and phenyl, optionally substituted with halogen.

[0151] In some embodiments, R ₄ is phenyl substituted with phenyl;

naphthyl; or

heteroaryl selected from the group consisting of pyridinyl, quinolinyl, isoquinolinyl, chromium, quinazolinyl, benzofuranyl, indolinyl, benzimidazolyl, benzothiophenyl, benzothiazolyl, furo[3,2-c]pyridinyl and naphthyridinyl, wherein said heteroaryl is optionally substituted with 1-3 Z, wherein each Z is independently selected from the group consisting of hydroxy, cyano, nitro, halogen, C _1-5 alkyl, optionally substituted with 1-3 halogens, C _1-5 alkoxy, optionally substituted with 1-3 halogens, benzyloxy, acetyl, morpholinyl, -NR ₆ C(O)R ₇ , -C(O)NR ₆ R ₇ .

[0152] In some embodiments, R ₄ is phenyl substituted with phenyl;

naphthyl; or

heteroaryl selected from the group consisting of quinolinyl, isoquinolinyl, benzofuranyl, benzothiophenyl and furo[3,2-c]pyridinyl, wherein said heteroaryl is optionally substituted with 1-3 Z, each Z being independently selected from the group consisting of halogen, C _{1 -5} -alkyl, optionally substituted with 1-3 halogens, and C _1-5 alkoxy, optionally substituted with 1-3 halogens.

[0153] In some embodiments, R ₅ is hydrogen. In some embodiments, R ₅ is C _1-3 alkyl.

[0154] In some embodiments, R ₆ is hydrogen. In some embodiments, R ₆ is a C _1-3 alkyl group.

[0155] In some embodiments, R ₇ is a C _1-3 alkyl group, optionally substituted with phenyl.

[0156] In some embodiments, R ₇ is phenyl, optionally substituted with 1-3 Z ² ;

wherein each Z ² is independently selected from the group consisting of hydroxy, amino, halogen, cyano, nitro, hydroxycarbonyl, C _1-5 alkyl, optionally substituted 1-3 Z ³ , C _2-6 alkenyl, C _2-6 alkynyl, C _1-5 alkoxy, optionally substituted 1-3 Z ³ , C _1-5 alkylthio, mono- or di-C _1-5 alkylamino, piperazinyl, optionally substituted Z ³ , C _1-5 alkylsulfonylamino, C _1-5 alkylcarbonylamino, aminosulfonyl , aminocarbonyl, C _1-5 alkylaminocarbonyl, phenyl, phenoxy, benzyl, benzoyl, phenylaminocarbonyl, pyrazolyl and benzoxazolyl; where each Z ³ is independently selected from halogen, amino or acetyl

[0157] In some embodiments, R ₇ is a heteroaryl selected from the group consisting of pyridinyl, pyrimidinyl, pyrazinyl, imidazolyl, pyrazolyl, triazolyl, oxazolyl, thiazolyl, furanyl, pyrrolyl, thiophenyl, quinolinyl, isoquinolinyl, chromenonyl, quinazolinyl, benzoxazolyl, benzofuranyl, benzothiophenyl, indolyl, indolinyl, benzimidazolyl benzoxazolyl, benzothiazolyl, indazolyl, furo[3,2-c]pyridinyl, thieno[2,3-d]pyrimidinyl, thieno[3,2-c]pyridinyl, isoxazolyl, acridinyl and naphthyridinyl, wherein said heteroaryl is optionally substituted with 1-3 Z ² ;

wherein each Z ² is independently selected from the group consisting of hydroxy, amino, halogen, cyano, nitro, hydroxycarbonyl, C _1-5 alkyl, optionally substituted 1-3 Z ³ , C _2-6 alkenyl, C _2-6 alkynyl, C _1-5 alkoxy, optionally substituted 1-3 Z ³ , C _1-5 alkylthio, mono- or di-C _1-5 alkylamino, piperazinyl, optionally substituted Z ³ , C _1-5 alkylsulfonylamino, C _1-5 alkylcarbonylamino, amino sulfonyl, aminocarbonyl, C _1-5 alkylaminocarbonyl, phenyl, phenoxy, benzyl, benzoyl, phenylaminocarbonyl, pyrazolyl and benzoxazolyl; wherein each Z ³ is independently selected from halogen, amino or acetyl.

[0158] In some embodiments, R ₆ is hydrogen or a C _1-3 alkyl group, and R ₇ is a C _1-3 alkyl group, optionally substituted with phenyl, phenyl, or heteroaryl selected from the group consisting of pyridinyl, pyrimidinyl, and isoxazolyl.

[0159] One embodiment of the present technology provides a compound of formulas X, Xa, Xb, 1, 1a, 1b, 1c, 1d, or 1e, or a stereoisomer or mixture of stereoisomers or a pharmaceutically acceptable salt thereof, wherein

n is 1 or 2;

R ₁ represents a substituent selected from the group consisting of formulas I, II, III, and V;

R ₂ represents hydrogen;

R ₃ is a substituent selected from the group consisting of -NR ₄ R ₅ , -OR ₄ , -C(O)NHR ₄ , -NHC(O)(CH ₂ ) _m R ₄ , and -NHS(O) _{2 R4} ,

where m represents 0 or 1;

R ₄ is phenyl substituted with a substituent selected from the group consisting of piperazinyl, optionally substituted with acetyl, phenyl, phenoxy, benzyl, benzoyl, phenylaminocarbonyl, pyrazolyl and benzoxazolyl;

naphthyl, optionally substituted with halogen; or

or heteroaryl selected from the group consisting of pyridinyl, quinolinyl, isoquinolinyl, 2-oxo-1,2-dihydroquinolinyl, 2-oxo-1,2,3,4-tetrahydroquinolinyl, quinazolinyl, benzofuranyl, 2,3-dihydrobenzofuranyl, benzothiophenyl , benzo[d][1,3]dioxolyl, furo[3,2-c]pyridinyl, thieno[2,3-d]pyrimidinyl, thieno[3,2-c]pyridinyl, isoxazolyl and acridinyl, optionally said heteroaryl substituted with 1-3 Z's, each Z being independently selected from the group consisting of hydroxy, halogen, C _1-5 alkyl, optionally substituted with 1-3 halogens, C _1-5 alkoxy, optionally substituted with 1-3 halogens, C _1-5 alkoxycarbonyl, benzyloxy and phenyl, optionally substituted with halogen, and

R ₅ represents hydrogen.

[0160] In another aspect, a compound of formulas X, Xa, Xb, 1, 1, 1a, 1b, 1c, 1d, or 1e or a stereoisomer or mixture of stereoisomers thereof or a pharmaceutically acceptable salt thereof is selected from the following compounds or a stereoisomer or a pharmaceutically acceptable salt thereof salt:

(R)-1-(2-((S)-2-cyanopyrrolidin-1-yl)-2-oxoethyl)-N-(quinolin-3-yl)pyrrolidin-3-carboxamide;

(R)-1-(2-((S)-2-cyanopyrrolidin-1-yl)-2-oxoethyl)-N-(quinolin-4-yl)pyrrolidin-3-carboxamide;

(S)-1-(2-((S)-2-cyanopyrrolidin-1-yl)-2-oxoethyl)-N-(quinolin-3-yl)pyrrolidin-3-carboxamide;

(S)-1-(2-((S)-2-cyanopyrrolidin-1-yl)-2-oxoethyl)-N-(quinolin-4-yl)pyrrolidin-3-carboxamide;

(S)-1-(2-((S)-3-(quinolin-4-ylamino)pyrrolidin-1-yl)acetyl)pyrrolidin-2-carbonitrile;

(S)-4,4-difluoro-1-(2-((S)-3-(quinolin-3-ylamino)pyrrolidin-1-yl)acetyl)pyrrolidin-2-carbonitrile;

(S)-4,4-difluoro-1-(2-((S)-3-(quinolin-4-ylamino)pyrrolidin-1-yl)acetyl)pyrrolidin-2-carbonitrile;

(S)-4,4-difluoro-1-(2-((S)-3-(isoquinolin-4-ylamino)pyrrolidin-1-yl)acetyl)pyrrolidin-2-carbonitrile;

(S)-1-(2-((S)-3-(benzo[b]thiophen-4-ylamino)pyrrolidin-1-yl)acetyl)-4,4-difluoropyrrolidine-2-carbonitrile;

(S)-1-(2-((S)-3-(benzo[b]thiophen-7-ylamino)pyrrolidin-1-yl)acetyl)-4,4-difluoropyrrolidine-2-carbonitrile;

(S)-1-(2-((S)-3-(benzofuran-7-ylamino)pyrrolidin-1-yl)acetyl)-4,4-difluoropyrrolidine-2-carbonitrile;

(S)-4,4-difluoro-1-(2-(SS)-3-(furo[3,2-c]pyridin-7-ylamino)pyrrolidin-1-yl)acetyl)pyrrolidin-2-carbonitrile;

(S)-1-(2-((S)-3-([1,1'-biphenyl]-2-ylamino)pyrrolidin-1-yl)acetyl)-4,4-difluoropyrrolidine-2-carbonitrile;

(S)-1-(2-((S)-3-([1,1'-biphenyl]-4-ylamino)pyrrolidin-1-yl)acetyl)-4,4-difluoropyrrolidine-2-carbonitrile;

(S)-4,4-difluoro-1-(2-((S)-3-(naphthalene-2-ylamino)pyrrolidin-1-yl)acetyl)pyrrolidin-2-carbonitrile;

(S)-1-(2-((S)-3-([1,1'-biphenyl]-3-ylamino)pyrrolidin-1-yl)acetyl)-4,4-difluoropyrrolidine-2-carbonitrile;

(S)-1-(2-((R)-3-(quinolin-3-ylamino)pyrrolidin-1-yl)acetyl)pyrrolidin-2-carbonitrile;

(S)-1-(2-((R)-3-([1,1'-biphenyl]-3-ylamino)pyrrolidin-1-yl)acetyl)pyrrolidin-2-carbonitrile;

(S)-1-(2-((S)-3-(isoquinolin-4-ylamino)pyrrolidin-1-yl)acetyl)pyrrolidin-2-carbonitrile;

(S)-1-(2-((S)-3-(benzo[b]thiophen-4-ylamino)pyrrolidin-1-yl)acetyl)pyrrolidin-2-carbonitrile;

(S)-1-(2-((S)-3-(benzo[b]thiophen-7-ylamino)pyrrolidin-1-yl)acetyl)pyrrolidin-2-carbonitrile;

(S)-1-(2-((S)-3-(benzofuran-7-ylamino)pyrrolidin-1-yl)acetyl)pyrrolidin-2-carbonitrile;

(S)-1-(2-((S)-3-(furo[3,2-c]pyridin-7-ylamino)pyrrolidin-1-yl)acetyl)pyrrolidin-2-carbonitrile;

(S)-1-(2-((R)-3-(isoquinolin-4-ylamino)pyrrolidin-1-yl)acetyl)pyrrolidin-2-carbonitrile;

(S)-1-(2-((R)-3-(benzo[b]thiophen-7-ylamino)pyrrolidin-1-yl)acetyl)pyrrolidin-2-carbonitrile;

(1S,3S,5S)-2-(2-((S)-3-(furo[3,2-c]pyridin-7-ylamino)pyrrolidin-1-yl)acetyl)-2-azabicyclo[3.1. 0]hexane-3-carbonitrile;

(S)-1-(2-((S)-3-(quinolin-5-ylamino)pyrrolidin-1-yl)acetyl)pyrrolidin-2-carbonitrile;

(2S,4S)-4-fluoro-1-(2-((S)-3-(furo[3,2-c]pyridin-7-ylamino)pyrrolidin-1-yl)acetyl)pyrrolidin-2-carbonitrile ;

N-((S)-1-(2-(2S,4S)-2-cyano-4-fluoropyrrolidin-1-yl)-2-oxoethyl)pyrrolidin-3-yl)-6-fluorobenzofuran-3-carboxamide;

N-((S)-1-(2-((S)-2-cyanopyrrolidin-1-yl)-2-oxoethyl)pyrrolidin-3-yl)quinoline-4-carboxamide;

N-((S)-1-(2-((S)-2-cyanopyrrolidin-1-yl)-2-oxoethyl)pyrrolidin-3-yl)quinoline-3-carboxamide;

N-((S)-1-(2-((S)-2-cyanopyrrolidin-1-yl)-2-oxoethyl)pyrrolidin-3-yl)quinoline-5-carboxamide;

N-((S)-1-(2-((S)-2-cyanopyrrolidin-1-yl)-2-oxoethyl)pyrrolidin-3-yl)quinoline-2-carboxamide;

N-((S)-1-(2-((S)-2-cyanopyrrolidin-1-yl)-2-oxoethyl)pyrrolidin-3-yl)quinoline-8-carboxamide;

N-((S)-1-(2-((S)-2-cyanopyrrolidin-1-yl)-2-oxoethyl)pyrrolidin-3-yl)isoquinoline-1-carboxamide;

N-((S)-1-(2-((S)-2-cyanopyrrolidin-1-yl)-2-oxoethyl)pyrrolidin-3-yl)benzo[b]thiophene-2-carboxamide;

N-((S)-1-(2-((S)-2-cyanopyrrolidin-1-yl)-2-oxoethyl)pyrrolidin-3-yl)benzofuran-3-carboxamide;

N-((S)-1-(2-((S)-2-cyanopyrrolidin-1-yl)-2-oxoethyl)pyrrolidin-3-yl)-2-(naphthalene-1-yl)acetamide;

N-((S)-1-(2-((S)-2-cyanopyrrolidin-1-yl)-2-oxoethyl)pyrrolidin-3-yl)-[1,1'-biphenyl]-2-carboxamide;

N-((S)-1-(2-((S)-2-cyanopyrrolidin-1-yl)-2-oxoethyl)pyrrolidin-3-yl)benzofuran-2-carboxamide;

N-((S)-1-(2-((S)-2-cyanopyrrolidin-1-yl)-2-oxoethyl)pyrrolidin-3-yl)benzo[b]thiophene-3-carboxamide;

N-((S)-1-(2-((S)-2-cyanopyrrolidin-1-yl)-2-oxoethyl)pyrrolidin-3-yl)-2-methylbenzofuran-3-carboxamide;

N-((S)-1-(2-((S)-2-cyanopyrrolidin-1-yl)-2-oxoethyl)pyrrolidin-3-yl)-5-fluorobenzofuran-3-carboxamide;

N-((S)-1-(2-((S)-2-cyanopyrrolidin-1-yl)-2-oxoethyl)pyrrolidin-3-yl)-6-fluorobenzofuran-3-carboxamide;

N-((S)-1-(2-((S)-2-cyanopyrrolidin-1-yl)-2-oxoethyl)pyrrolidin-3-yl)-7-methylbenzofuran-3-carboxamide;

N-((S)-1-(2-((S)-2-cyanopyrrolidin-1-yl)-2-oxoethyl)pyrrolidin-3-yl)-5-methoxybenzofuran-3-carboxamide;

N-((S)-1-(2-((S)-2-cyanopyrrolidin-1-yl)-2-oxoethyl)pyrrolidin-3-yl)-7-methoxybenzofuran-3-carboxamide;

N-((S)-1-(2-((S)-2-cyanopyrrolidin-1-yl)-2-oxoethyl)pyrrolidin-3-yl)-4-hydroxybenzofuran-3-carboxamide;

N-((S)-1-(2-((S)-2-cyanopyrrolidin-1-yl)-2-oxoethyl)pyrrolidin-3-yl)-6-hydroxybenzofuran-3-carboxamide;

N-((S)-1-(2-((S)-2-cyanopyrrolidin-1-yl)-2-oxoethyl)pyrrolidin-3-yl)-7-fluorobenzofuran-3-carboxamide;

N-((S)-1-(2-((S)-2-cyanopyrrolidin-1-yl)-2-oxoethyl)pyrrolidin-3-yl)-5,7-difluorobenzofuran-3-carboxamide;

N-((S)-1-(2-((S)-2-cyanopyrrolidin-1-yl)-2-oxoethyl)pyrrolidin-3-yl)-5-methylbenzofuran-3-carboxamide;

N-((S)-1-(2-((S)-2-cyanopyrrolidin-1-yl)-2-oxoethyl)pyrrolidin-3-yl)-6-methylbenzofuran-3-carboxamide;

N-((S)-1-(2-((S)-2-cyanopyrrolidin-1-yl)-2-oxoethyl)pyrrolidin-3-yl)-6-methoxybenzofuran-3-carboxamide;

N-((S)-1-(2-((S)-2-cyanopyrrolidin-1-yl)-2-oxoethyl)pyrrolidin-3-yl)benzofuran-4-carboxamide;

N-((S)-1-(2-((S)-2-cyanopyrrolidin-1-yl)-2-oxoethyl)pyrrolidin-3-yl)benzofuran-5-carboxamide;

N-((S)-1-(2-((S)-2-cyanopyrrolidin-1-yl)-2-oxoethyl)pyrrolidin-3-yl)benzofuran-6-carboxamide;

N-((S)-1-(2-((S)-2-cyanopyrrolidin-1-yl)-2-oxoethyl)pyrrolidin-3-yl)benzofuran-7-carboxamide;

N-((S)-1-(2-((S)-2-cyanopyrrolidin-1-yl)-2-oxoethyl)pyrrolidin-3-yl)benzofuran-2-sulfonamide;

N-((S)-1-(2-((S)-2-cyanopyrrolidin-1-yl)-2-oxoethyl)pyrrolidin-3-yl)benzo[b]thiophene-2-sulfonamide;

(S)-1-(2-((S)-3-(quinolin-4-yloxy)pyrrolidin-1-yl)acetyl)pyrrolidin-2-carbonitrile;

(S)-1-(2-(((S))-3-(naphthalene-1-yloxy)pyrrolidin-1-yl)acetyl)pyrrolidin-2-carbonitrile;

(S)-1-(2-(((S))-3-(quinolin-6-yloxy)pyrrolidin-1-yl)acetyl)pyrrolidin-2-carbonitrile;

((S))-1-(2-((S)-3-(quinolin-8-yloxy)pyrrolidin-1-yl)acetyl)pyrrolidin-2-carbonitrile;

((S))-1-(2-(((S))-(S)-(isoquinolin-5-yloxy)pyrrolidin-1-yl)acetyl)pyrrolidine-2carbonitrile;

(S)-1-(2-((S)-3-(quinolin-5-yloxy)pyrrolidin-1-yl)acetyl)pyrrolidin-2-carbonitrile;

(S)-1-(2-((S)-3-(benzo[d][1,3]dioxol-5-yloxy)pyrrolidin-1-yl)acetyl)pyrrolidin-2-carbonitrile;

(S)-1-(2-((S)-3-(thieno[2,3-d]pyrimidin-4-yloxy)pyrrolidin-1-yl)acetyl)pyrrolidin-2-carbonitrile;

(S)-1-(2-((S)-3-(isoquinolin-3-yloxy)pyrroldin-1-yl)acetyl)pyrrolidine-2-carbonitrile;

(S)-1-(2-((S)-3-(3-bromothieno[3,2-c]pyrrolidin-4-yl)oxy)pyrrolidin-1-yl)acetyl)pyrrolidin-2-carbonitrile;

(S)-1-(2-((S)-3-(4-chloronaphthalene-1-yl)oxy)pyrrolidin-1-yl)acetyl)pyrrolidin-2-carbonitrile;

(S)-1-(2-((S)-3-(2-(1H-pyrazol-3-yl)phenoxy)pyrrolidin-1-yl)acetyl)pyrrolidin-2-carbonitrile;

(S)-1-(2-((S)-3-(4-chloroquinazolin-8-yl)oxy)pyrrolidin-1-yl)acetyl)pyrrolidin-2-carbonitrile;

(S)-1-(2-((S)-3-(4-chloroquinazolin-6-yl)oxy)pyrrolidin-1-yl)acetyl)pyrrolidin-2-carbonitrile;

(S)-1-(2-((S)-3-(2-oxo-1,2-dihydroquinolin-5-yl)oxy)pyrrolidin-1-yl)acetyl)pyrrolidin-2-carbonitrile;

(S)-1-(2-((S)-3-(2-oxo-1,2,3,4-tetrahydroquinolin-5-yl)oxy)pyrrolidin-1-yl)acetyl)pyrrolidin-2-carbonitrile ;

(S)-1-(2-((S)-3-(2-oxo-1,2,3,4-tetrahydroquinolin-6-yl)oxy)pyrrolidin-1-yl)acetyl)pyrrolidin-2-carbonitrile ;

(S)-1-(2-((S)-3-(2-methylquinolin-8-yl)oxy)pyrrolidin-1-yl)acetyl)pyrrolidin-2-carbonitrile;

(S)-1-(2-((S)-3-((7-chloroquinolin-4-yl)oxy)pyrrolidin-1-yl)acetyl)pyrrolidin-2-carbonitrile;

(S)-1-(2-((S)-3-(7-bromoquinolin-4-yl)oxy)pyrrolidin-1-yl)acetyl)pyrrolidin-2-carbonitrile;

(S)-1-(2-((S)-3-(5-chloroquinolin-8-yl)oxy)pyrrolidin-1-yl)acetyl)pyrrolidin-2-carbonitrile;

(S)-1-(2-((S)-3-([1,1'-biphenyl]-3-yloxy)pyrrolidin-1-yl)acetyl)pyrrolidin-2-carbonitrile;

(S)-1-(2-((S)-3-([1,1'-biphenyl]-4-yloxy)pyrrolidin-1-yl)acetyl)pyrrolidin-2-carbonitrile;

(S)-1-(2-((S)-3-(6-methoxyquinolin-4-yl)oxy)pyrrolidin-1-yl)acetyl)pyrrolidin-2-carbonitrile;

(S)-1-(2-((S)-3-(7,8-difluoroquinolin-4-yl)oxy)pyrrolidin-1-yl)acetyl)pyrrolidin-2-carbonitrile;

methyl 6-((S)-1-(2-((S)-2-cyanopyrrolidin-1-yl)-2-oxoethyl)pyrrolidin-3-yl)oxy)-2,3-dihydrobenzofuran-2-carboxylate ;

(S)-1-(2-((S)-3-(4-phenoxyphenoxy)pyrrolidin-1-yl)acetyl)pyrrolidine-2-carbonitrile;

(S)-1-(2-((S)-3-(3-phenoxyphenoxy)pyrrolidin-1-yl)acetyl)pyrrolidine-2-carbonitrile;

(S)-1-(2-((S)-3-(4-benzylphenoxy)pyrrolidin-1-yl)acetyl)pyrrolidine-2-carbonitrile;

(S)-1-(2-((S)-3-(2-benzylphenoxy)pyrrolidin-1-yl)acetyl)pyrrolidine-2-carbonitrile;

(S)-1-(2-((S)-3-(3-benzoylphenoxy)pyrroldin-1-yl)acetyl)pyrrolidine-2-carbonitrile;

(S)-1-(2-((S)-3-(4-benzoylphenoxy)pyrroldin-1-yl)acetyl)pyrrolidine-2-carbonitrile;

(S)-1-(2-((S)-3-(4-(benzenoxy)pyridin-2-yl)oxy)pyrrolidin-1-yl)acetyl)pyrrolidin-2-carbonitrile;

(S)-1-(2-((S)-3-(7-(trifluoromethyl)quinolin-4-yl)oxy)pyrrolidin-1-yl)acetyl)pyrrolidin-2-carbonitrile;

(S)-1-(2-((S)-3-(8-(trifluoromethyl)quinolin-4-yl)oxy)pyrrolidin-1-yl)acetyl)pyrrolidin-2-carbonitrile;

(S)-1-(2-((S)-3-(acridin-4-yloxy)pyrrolidin-1-yl)acetyl)pyrrolidin-2-carbonitrile;

(S)-1-(2-((S)-3-(2-(benzo[d]oxazol-2-yl)phenoxy)pyrrolidin-1-yl)acetyl)pyrrolidin-2-carbonitrile;

(S)-1-(2-((S)-3-(4-(4-acetylpiperazin-1-yl)phenoxy)pyrrolidin-1-yl)acetyl)pyrrolidin-2-carbonitrile;

2-((S)-1-(2-((S)-2-cyanopyrrolidin-1-yl)-2-oxoethyl)pyrrolidin-3-yl)oxy)-N-phenylbenzamide;

(S)-1-(2-((S)-3-(7-methoxyquinolin-4-yl)oxy)pyrrolidin-1-yl)acetyl)pyrrolidin-2-carbonitrile;

(S)-1-(2-((S)-3-(6,7-dimethoxyquinolin-4-yl)oxy)pyrrolidin-1-yl)acetyl)pyrrolidin-2-carbonitrile;

(S)-1-(2-((S)-3-(3-(4-bromophenyl)isoxazol-5-yl)oxy)pyrrolidin-1-yl)acetyl)pyrrolidin-2-carbonitrile;

(S)-4,4-difluoro-1-(2-((S)-3-(6-methoxyquinolin-4-yl)oxy)pyrrolidin-1-yl)acetyl)pyrrolidin-2-carbonitrile;

(S)-4,4-difluoro-1-(2-((S)-3-(8-(trifluoromethyl)quinolin-4-yl)oxy)pyrrolidin-1-yl)acetyl)pyrrolidin-2-carbonitrile;

(S)-4,4-difluoro-1-(2-((S)-3-(quinolin-5-yloxy)pyrrolidin-1-yl)acetyl)pyrrolidin-2-carbonitrile;

(S)-4,4-difluoro-1-(2-((S)-3-(isoquinolin-5-yloxy)pyrrolidin-1-yl)acetyl)pyrrolidin-2-carbonitrile;

(S)-1-(2-((S)-3-(7-chloroquinolin-4-yl)oxy)pyrrolidin-1-yl)acetyl)-4,4-difluoropyrrolidine-2-carbonitrile;

(S)-4,4-difluoro-1-(2-((S)-3-(2-oxo-1,2-dihydroquinolin-5-yl)oxy)pyrrolidin-1-yl)acetyl)pyrrolidin-2 -carbonitrile;

(S)-1-(2-((S)-3-(5-chloroquinolin-8-yl)oxy)pyrrolidin-1-yl)acetyl)-4,4-difluoropyrrolidine-2-carbonitrile;

(S)-1-(2-(4-(quinolin-5-ylamino)piperidin-1-yl)acetyl)pyrrolidine-2-carbonitrile;

(S)-1-(2-(4-(quinolin-4-ylamino)piperidin-1-yl)acetyl)pyrrolidine-2-carbonitrile;

(1S,3S,5S)-2-(2-(4-(quinolin-4-ylamino)piperidin-1-yl)acetyl)-2-azabicyclo[3.1.0]hexane-3-carbonitrile;

(2S,4S)-4-fluoro-1-(2-(4-(quinolin-5-ylamino)piperidin-1-yl)acetyl)pyrrolidine-2-carbonitrile;

(S)-4,4-difluoro-1-(2-(4-(quinolin-5-ylamino)piperidin-1-yl)acetyl)pyrrolidine-2-carbonitrile;

(1S,3S,5S)-2-(2-(4-(quinolin-5-ylamino)piperidin-1-yl)acetyl)-2-azabicyclo[3.1.0]hexane-3-carbonitrile;

(S)-1-(2-(4-(furo[3,2-c]pyridin-7-ylamino)piperidin-1-yl)acetyl)pyrrolidine-2-carbonitrile;

(S)-1-(2-(4-(quinolin-3-yloxy)piperidin-1-yl)acetyl)pyrrolidine-2-carbonitrile;

(S)-1-(2-(4-(quinolin-4-yloxy)piperidin-1-yl)acetyl)pyrrolidine-2-carbonitrile;

(S)-1-(2-(4-(quinolin-5-yloxy)piperidin-1-yl)acetyl)pyrrolidine-2-carbonitrile;

(S)-1-(2-(4-(quinolin-6-yloxy)piperidin-1-yl)acetyl)pyrrolidine-2-carbonitrile;

(S)-1-(2-(4-(3-methylquinolin-5-yl)amino)piperidin-1-yl)acetyl)pyrrolidine-2-carbonitrile;

(S)-1-(2-(4-(b-methylquinolin-5-yl)amino)piperidin-1-yl)acetyl)pyrrolidine-2-carbonitrile;

(S)-1-(2-(4-(7-fluoroquinolin-5-yl)amino)piperidin-1-yl)acetyl)pyrrolidine-2-carbonitrile;

(S)-1-(2-(4-(7-methoxyquinolin-5-yl)amino)piperidin-1-yl)acetyl)pyrrolidine-2-carbonitrile;

(S)-1-(2-(4-(8-methoxyquinolin-5-yl)amino)piperidin-1-yl)acetyl)pyrrolidine-2-carbonitrile;

(2S,4S)-4-fluoro-1-(2-(4-((b-fluoroquinolin-4-yl)oxy)piperidin-1-yl)acetyl)pyrrolidine-2-carbonitrile;

(2S,4S)-1-(2-(4-((6-chloroquinolin-4-yl)oxy)piperidin-1-yl)acetyl)-4-fluoropyrrolidine-2-carbonitrile;

(2S,4S)-4-fluoro-1-(2-(4-((b-methoxyquinolin-4-yl)oxy)piperidin-1-yl)acetyl)pyrrolidine-2-carbonitrile;

(2S,4S)-4-fluoro-1-(2-(4-((7-methoxyquinolin-4-yl)oxy)piperidin-1-yl)acetyl)pyrrolidine-2-carbonitrile;

(2S,4S)-1-(2-(4-((6,7-dimethoxyquinolin-4-yl)oxy)piperidin-1-yl)acetyl)-4-fluoropyrrolidine-2-carbonitrile;

(2S,4S)-4-fluoro-1-(2-(4-((3-methylquinolin-5-yl)amino)piperidin-1-yl)acetyl)pyrrolidine-2-carbonitrile;

(2S,4S)-4-fluoro-1-(2-(4-((7-fluoroquinolin-5-yl)amino)piperidin-1-yl)acetyl)pyrrolidin-2-carbonitrile;

(2S,4S)-4-fluoro-1-(2-(4-((7-methoxyquinolin-5-yl)amino)piperidin-1-yl)acetyl)pyrrolidine-2-carbonitrile;

(2S,4S)-4-fluoro-1-(2-(4-((6-methylquinolin-5-yl)amino)piperidin-1-yl)acetyl)pyrrolidine-2-carbonitrile;and

(2S,4S)-4-fluoro-1-(2-(4-((8-methoxyquinolin-5-yl)amino)piperidin-1-yl)acetyl)pyrrolidine-2-carbonitrile.

[0161] In another aspect, a compound of formulas X, Xa, Xb, 1, 1, 1a, 1b, 1c, 1d or 1e, or a stereoisomer or mixture of stereoisomers or a pharmaceutically acceptable salt thereof is selected from compounds or stereoisomers or a mixture of stereoisomers, or pharmaceutically acceptable salts listed in Table 1.

[0162] A compound of formulas X, Xa, Xb, 1, 1a, 1b, 1c, 1d or 1e, or a pharmaceutically acceptable salt thereof, may have a substituent containing an asymmetric carbon atom (eg, an R ₂ substituent). In this case, the compound of formula 1 or a salt thereof may exist as an optical isomer such as (R) or (S), or a racemate (RS). Thus, unless otherwise indicated, a compound of Formula 1 or a salt thereof contains an optical isomer such as (R) or (S) and a racemate (RS). Additionally, in some embodiments, a compound of Formula 1 or a salt thereof may exist as a geometric isomer with a cis or trans double bond structure depending on the substituent. Thus, in some embodiments, unless otherwise indicated, the compound of Formula 1 or a salt thereof contains both geometric isomers of cis and trans structures. In addition, the compound of Formula 1 or a salt thereof may exist as a diastereomer and, unless otherwise indicated, contains both diastereomers and mixtures thereof.

[0163] The compounds presented herein are FAP inhibitors. FAP inhibition can be measured, for example, by determining the half-maximal inhibition concentration (IC ₅₀ ). One way to determine the IC ₅₀ for FAP is in the experimental section.

[0164] In some embodiments, the compounds are selective FAP inhibitors. Selectivity can be determined, for example, by comparing FAP inhibition with inhibition of other DPP families, such as DPP7 (dipeptidyl peptidase 7), DPP8 (dipeptidyl peptidase 8), DPP9 (dipeptidyl peptidase 9) or PREP (prolyl oligopepase). In one embodiment, "selective inhibitory activity" means that the IC ₅₀ for FAP, obtained from an in vitro enzyme assay (in vitro enzyme assay), is at least 100 times lower than the IC 50 for DPP7, at least 100 times lower than the IC ₅₀ for DPP7. times lower than ICjo for DPP8, at least 100 times lower than IC ₅₀ of DPP9, or at least 100 times lower than IC ₅₀ of PREP. In an alternative embodiment, "selective inhibitory activity" means that the IC ₅₀ for FAP obtained from an in vitro enzyme assay (in vitro enzyme assay) is at least 100 times lower than the IC 50 for DPP7, at least 100 times lower than the IC ₅₀ for DPP7. times lower than the IC ₅₀ of DPP8, at least 100 times lower than the IC ₅₀ of DPP9, and at least 100 times lower than the IC ₅₀ of PREP.

[0165] The compound of Formula 1 of the present technology may be in the form of a pharmaceutically acceptable salt. As used herein, the term "pharmaceutically acceptable salt" refers to salts or zwitterionic forms of compounds of the present technology that are soluble or dispersible in water or oil; which are suitable for the treatment of diseases without unwanted toxicity, irritation and allergic response; that are commensurate with a reasonable benefit/risk ratio and that are effective for their intended use. Salts can be obtained during the final isolation and purification of the compounds or separately, for example, by reacting the corresponding compound in free base form with a suitable acid. Such salts include conventional acid addition salts, for example, a salt derived from an inorganic acid such as hydrochloric acid, bromic acid, sulfuric acid, sulfamic acid, phosphoric acid or nitric acid, and a salt derived from an organic acid such as acetic acid , propionic acid, succinic acid, glycolic acid, stearic acid, citric acid, maleic acid, malonic acid, methanesulfonic acid, tartaric acid, malic acid, phenylacetic acid, glutamic acid, benzoic acid, salicylic acid, 2-acetoxybenzoic acid, fumaric acid , p-toluenesulfonic acid, oxalic acid or trifluoroacetic acid. In addition, these salts include standard types of metal salt, for example, a salt derived from a metal such as lithium, sodium, potassium, magnesium or calcium. Said acid addition salt or metal salt can be prepared according to conventional methods.

[0166] The compound of formula 1 or a salt thereof in accordance with this technology can be obtained in various ways. For example, a compound of formula 1a in which R ₃ of formula 1 is -NR ₄ R ₅ or a salt thereof can be prepared by a process comprising the step of reacting a compound of formula 2a with R ₄ X to produce a compound of formula 3a; the step of carrying out a deprotection reaction of the compound of formula 3a above to obtain the compound of formula 4a or a salt thereof; and the step of reacting a compound of formula 4a or a salt thereof with a compound of formula 5 to form a compound of formula 1a.

In these formulas 1a, 2a, 3a, 4a and 5, X represents a halogen (e.g., Br, F, Cl, Br, or I), Boe represents an amine protecting group (e.g., tert-butoxycarbonyl, 9-fluoromethyloxycarbonyl (FMOC) ), benzyloxycarbonyl (CBZ), triphenylmethyl (trityl), etc.), and R ₁ , P ₂ , P ₄ , P ₅ and n are the same as defined above.

[0167] The compound of formula 2a is commercially available. The reaction of the compound of formula 2a above with R ₄ X can be carried out using a palladium catalyst via the Buchwald-Hartwig reaction. The palladium catalyst includes palladium diacetate (Pd(OAc) ₂ ), tris(dibenzylideneacetone)dipalladium (Pd ₂ (dba) ₃ ), tetrakis(triphenylphosphine)palladium (Pd(PPh ₃ ) ₄ ), or palladium di[1,1'-bis( diphenylphosphino)ferrocene]dichloride (PdCl ₂ (dppf) ₂ ), etc. Moreover, in addition to the palladium catalyst, a ligand and a base can be added. The ligand includes (S)-2,2-bis(diphenylphosphino)-1,1-binaphthyl (BINAP), 1,1'-bis(diphenylphosphino)ferrocene(dppf) or (tri-O-tolyl)phosphine(P( O-Tol) ₃ ), etc., and said base includes an inorganic base such as cesium carbonate (Cs ₂ CO ₃ ), sodium carbonate (Na ₂ CO ₃ ), potassium carbonate (K ₂ CO ₃ ), potassium fluoride (KF), cesium fluoride (CsF), sodium hydroxide (NaOH), potassium phosphonate (K ₃ PO ₄ ), sodium tert-butoxide (tert-BuONa), tert-butoxide potassium (tert-BuOK) or the like . The reaction can be carried out in a non-polar organic solvent such as benzene or toluene, or a polar organic solvent such as dioxane, tetrahydrofuran, acetonitrile, 1,2-dimethoxyethane, N,N-dimethylformamide or the like, at a temperature ranging from 50 °C to 150°C, preferably from 80°C to 110°C. Other reaction conditions, including, for example, reaction time, can be determined in accordance with known Buchwald-Hartwig reaction methods (Barbara Czako et al, STRATEGIC APPLICATIONS of NAMED REACTIONS in ORGANIC SYNTHESIS, 2005).

[0168] In some embodiments, the reaction of a compound of formula 2a with R ₄ X is carried out via nucleophilic substitution. The nucleophilic substitution reaction can be carried out at room temperature or under boiling conditions (20°C to 120°C) using a base such as cesium carbonate, potassium carbonate, etc., in a solvent such as acetonitrile, dichloromethane, or the like. P.

[0169] Deprotection of the compound of formula 3a can be accomplished by conventional amine deprotection methods. For example, said amine protecting group in an organic solvent such as dichloromethane, etc., can be removed using an acid such as trifluoroacetic acid, or can be removed in the form of a hydrochloride salt using hydrogen chloride dissolved in organic solvents such as such as diethyl ether, 1,4-dioxane, etc.

[0170] The reaction of a compound of formula 4a above or a salt thereof with a compound of formula 5 can be accomplished by nucleophilic substitution. The nucleophilic substitution reaction can be carried out at room temperature or moderately warm temperature (20°C to 60°C) using a base such as cesium carbonate, potassium carbonate, etc., in a solvent such as acetonitrile, dichloromethane, or the like. P.

[0171] The compound of formula 5 above can be prepared by reacting the compound of formula 6 with compounds of formulas R ₁ aR ₁ e, respectively.

In the above formula 6, R ₂ is the same as defined above.

[0172] The compound of formula 6 and the compounds of formulas R ₁ aR ₁ e are commercially available. The reaction of a compound of formula 6 with compounds of formulas R ₁ aR ₁ e can be converted to a compound of formula 5 by nucleophilic acyl substitution. The nucleophilic acyl substitution reaction can be carried out using cesium carbonate, potassium carbonate, etc. in a solvent such as acetonitrile, dichloromethane and the like, and it can be carried out at a temperature of 0°C to room temperature.

[0173] In addition, the present technology includes a process for preparing a compound of formula 1b, in which R ₃ represents -OR ₄ or a stereoisomer or a mixture of stereoisomers or a pharmaceutically acceptable salt thereof. Thus, the present technology includes a process for preparing a compound of formula 1b or a stereoisomer or mixture of stereoisomers or a pharmaceutically acceptable salt thereof, comprising the step of reacting a compound of formula 2b with R ₄ -OH to produce a compound of formula 3b; the step of carrying out a deprotection reaction of the compound of formula 3b above to obtain the compound of formula 4b or a salt thereof; and the step of reacting a compound of formula 4b or a salt thereof with a compound of formula 5 to produce a compound of formula 1b.

In these formulas 1b, 2b, 3b, 4b and 5, Boc represents an amine protecting group (e.g. tert-butoxycarbonyl, 9-fluorenylmethyloxycarbonyl (FMOC), benzyloxycarbonyl (CBZ), triphenylmethyl (trityl), etc.), and R ₁ , R ₂ , R ₄ and n are the same as defined above.

[0174] The compound of formula 2b is commercially available. The reaction of the compound of the above formula 2b with R ₄ -OH can be carried out according to the Mitsunobu reaction. The Mitsunobu reaction can be carried out at room temperature or under mildly warm temperature conditions (20°C to 60°C) using a dialkyl azodicarboxylate such as diethyl azodicarboxylate (DEAD), diisopropyl azodicarboxylate (DTAD), di-2-methoxyethyl azodicarboxylate (DMEAD), 1. 1'-(azodicarbonyl)dipiperidine, etc. and trialkylphosphine or triarylphosphine such as triphenylphosphine (PPh ₃ ), tributylphosphine (PBu ₃ ), etc. Other reaction conditions, including, for example, reaction time, can be determined in accordance with known methods for the Mitsunobu reaction (Barbara Czako and Laszlo Kurti, STRATEGIC APPLICATIONS of NAMED REACTIONS in ORGANIC SYNTHESIS, 2005).

[0175] Deprotection of the compound of formula 3b can be accomplished by conventional amine deprotection methods. For example, said amine protecting group in an organic solvent such as dichloromethane, etc., can be removed using an acid such as trifluoroacetic acid, or can be removed in the form of a hydrochloride salt using hydrogen chloride dissolved in organic solvents such as such as diethyl ether, 1,4-dioxane, etc.

[0176] The reaction of a compound of formula 4b above or a salt thereof with a compound of formula 5 can be accomplished by nucleophilic substitution. The nucleophilic substitution reaction can be carried out at room temperature or moderately warm temperature (20°C to 60°C) using a base such as cesium carbonate, potassium carbonate, etc., in a solvent such as acetonitrile, dichloromethane, or the like. P.

[0177] The present technology includes a process for preparing a compound of formula 1b or a stereoisomer or mixture of stereoisomers or a pharmaceutically acceptable salt thereof, comprising the step of reacting a compound of formula 5 with a compound of formula 7 to produce a compound of formula 8; the step of reacting a compound of formula 8 with R ₄ -OH to obtain a compound of formula 1b.

In the above formulas 1b, 5, 7 and 8, R ₁ , R ₂ , R ₄ and n are the same as defined above.

[0178] The compound of formula 7 is commercially available. The reaction of a compound of formula 5 above or a salt thereof with a compound of formula 7 can be accomplished by nucleophilic substitution. The nucleophilic substitution reaction can be carried out at room temperature or moderately warm temperature (20°C to 60°C) using a base such as cesium carbonate, potassium carbonate, etc., in a solvent such as acetonitrile, dichloromethane, or the like. P.

[0179] The reaction of the compound of the above formula 8 with R ₄ -OH can be carried out by the Mitsunobu reaction.

[0180] In addition, the present technology includes a process for preparing a compound of formula 1c, in which R ₃ of formula 1 is -C(ONHR ₄ or a stereoisomer or mixture of stereoisomers or a pharmaceutically acceptable salt thereof. Thus, the present technology includes a process for preparing a compound of formula 1c or a stereoisomer or a mixture of stereoisomers or a pharmaceutically acceptable salt thereof, comprising the step of reacting a compound of formula 2c with R ₄ -NH ₂ to produce a compound of formula 3c; the step of performing a deprotection reaction of a compound of formula 3c above to produce a compound of formula 4c or salt; and the step of reacting a compound of formula 4c or a salt thereof with a compound of formula 5 to produce a compound of formula 1c.

In the above formulas 1c, 2c, 3c, 4c and 5, Boc represents an amine protecting group (e.g., tert-butoxycarbonyl, 9-fluorenylmethyloxycarbonyl (FMOC), benzyloxycarbonyl (CBZ), triphenylmethyl (trityl), etc.), and R ₁ , R ₂ , R ₄ and 11 are the same as defined above.

[0181] The compound of formula 2c is commercially available. The reaction of the compound of formula 2c above with R ₄ -NH ₂ can be carried out via an amide coupling reaction. Said amide coupling reaction can be carried out using a base such as diisopropylamine, diisopropylethylamine, triethylamine, etc., and a coupling reagent such as O-(7-azabenzotriazol-1-yl)-N,N,N',N '-tetramethylurinium hexafluorophosphate (HATU), O-(benzotriazol-1-yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate (HBTU), etc. Said coupling reaction can be carried out in organic solvents such as dichloromethane, N,N-dimethylformamide, etc., and can be carried out at room temperature or under warm-temperature conditions (20° C. to 60° C.).

[0182] Deprotection of the compound of Formula 3c can be accomplished by conventional amine deprotection methods. For example, said amine protecting group in an organic solvent such as dichloromethane, etc., can be removed using an acid such as trifluoroacetic acid, or can be removed in the form of a hydrochloride salt using hydrogen chloride dissolved in organic solvents such as such as diethyl ether, 1,4-dioxane, etc.

[0183] The reaction of a compound of formula 4c above or a salt thereof with a compound of formula 5 can be accomplished by nucleophilic substitution. The nucleophilic substitution reaction can be carried out at room temperature or moderately warm temperature (20°C to 60°C) using a base such as cesium carbonate, potassium carbonate, etc., in a solvent such as acetonitrile, dichloromethane, or the like. P.

[0184] In addition, the present technology includes a process for preparing a compound of formula 1d, in which formula 1 is -NHC(O)(CH ₂ ) _m R ₄ or a stereoisomer thereof or a mixture of stereoisomers or a pharmaceutically acceptable salt thereof. Thus, the present technology includes a process for preparing a compound of formula 1d or a stereoisomer or mixture of stereoisomers or a pharmaceutically acceptable salt thereof, comprising the step of reacting a compound of formula 5 with a compound of formula 9 to produce a compound of formula 10; a step of carrying out a deprotection reaction of the compound of the above formula 10 to obtain the compound of formula 11 or a salt thereof; and the step of reacting the compound of formula 11 with R ₄ -(CH ₂ ) _m COOH to obtain the compound of formula 1d.

In these formulas 1d, 5, 9, 10 and 11, Boc represents an amine protecting group (e.g., tert-butoxycarbonyl, 9-fluorenylmethyloxycarbonyl (FMOC), benzyloxycarbonyl (CBZ), triphenylmethyl (trityl), etc.), and R ₁ , R ₂ , R ₄ , pit are the same as defined above.

[0185] The compound of formula 9 is commercially available. The reaction of a compound of formula 5 above with a compound of formula 9 can be accomplished by nucleophilic substitution. The nucleophilic substitution reaction can be carried out at room temperature or moderately warm temperature (20°C to 60°C) using a base such as cesium carbonate, potassium carbonate, etc., in a solvent such as acetonitrile, dichloromethane, or the like. P.

[0186] Deprotection of the compound of Formula 10 can be accomplished by conventional amine deprotection methods. For example, said amine protecting group in an organic solvent such as dichloromethane, etc., can be removed using an acid such as trifluoroacetic acid, or can be removed in the form of a hydrochloride salt using hydrogen chloride dissolved in organic solvents such as such as diethyl ether, 1,4-dioxane, etc.

[0187] The reaction of the compound of the above formula 11 with R ₄ -(CH ₂ ) _m COOH can be carried out through an amide coupling reaction. Said amide coupling reaction can be carried out using a base such as diisopropylamine, diisopropylethylamine, triethylamine, etc., and a coupling reagent such as O-(7-azabenzotriazol-1-yl)-N,N,N',N '-tetramethylurinium hexafluorophosphate (HATU), O-(benzotriazol-1-yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate (HBTU), etc. Said coupling reaction can be carried out in organic solvents such as dichloromethane, N,N-dimethylformamide, etc., and can be carried out at room temperature or under warm-temperature conditions (20° C. to 60° C.).

[0188] In addition, the present technology includes a process for preparing a compound of formula 1e, in which R ₃ of formula 1 is -NHS(O) ₂ R ₄ or a stereoisomer thereof or a mixture of stereoisomers or a pharmaceutically acceptable salt thereof. Thus, the present technology includes a process for preparing a compound of formula 1e or a stereoisomer or mixture of stereoisomers or a pharmaceutically acceptable salt thereof, comprising the step of reacting a compound of formula 11 provided herein with R ₄ -S(O) ₂ Cl to produce a compound of formula 1e.

In the above formulas 1e and 11, R ₁ , R ₂ , R ₄ and n are the same as defined above.

[0189] The reaction of a compound of formula 11 above or a salt thereof with R ₄ -S(O) ₂ Cl can be carried out via nucleophilic substitution. The nucleophilic substitution reaction can be carried out at room temperature or moderately warm temperature (20°C to 60°C) using a base such as cesium carbonate, potassium carbonate, etc., in a solvent such as acetonitrile, dichloromethane, or the like. P.

[0190] In general, FAP is not expressed in normal tissues, but its expression is increased in stromal fibroblasts of malignant tumors such as breast cancer, colorectal cancer, ovarian cancer, and the like. (Garin-Chesa et al., Proc. Natl. Acad. Sci., 1990, 87: 7235). Accordingly, inhibition of FAP may be a target for the treatment of malignant tumors. In fact, ValboroPro (PT-100, Talobostat), known as a FAP inhibitor, when administered orally, has been reported to exhibit anticancer activity in mice by delaying tumor proliferation and causing degeneration of tumors (Adams et al., Cancer Res., 2004, 64:5471). However, Val-boroPro (PT-100, talabostat), known as a FAP inhibitor, also has inhibitory activity against DPP4, PREP, etc. Therefore, the poor selectivity for FAP needs to be improved. (O. Ryabtsova et al. Bioorg. Med. Chem. Lett., 2012, 3412-3417).

[0191] In addition, since FAP regulates metabolic functions and is expressed in activated hepatic stellate cells (aHSCs) and sites of tissue remodeling associated with liver fibrosis, inhibition of FAP may be useful for the treatment of non-alcoholic fatty liver disease (NAFLD). Non-alcoholic fatty liver disease (NAFLD) histologically includes simple steatosis, non-alcoholic steatohepatitis (NASH) and cirrhosis. Among them, unlike simple steatosis (non-alcoholic fatty liver, NAFLD), NASH can potentially progress to liver cirrhosis and hepatocellular carcinoma. In addition to insulin resistance, oxidative stress, the inflammatory cascade, and fibrosis are known to play important roles in the progression of NASH. Thus, inhibition of FAP may improve insulin resistance, which is one of the key factors of NASH, and may regulate the hepatoprotective effect and function of activated hepatic stellate cells (aHSC) through the regulation of FGF21 and thus may have potential for the treatment of NASH (Lay AJ et al., Front Biosci (Landmark Ed), 2019, 24, 1-17).

[0192] Pyrrolidine and piperidine in accordance with the present technology, i.e. a compound of formula X, Xa, Xb, 1, 1a, 1b, 1c, 1d or 1e, or a stereoisomer or mixture of stereoisomers thereof, or a pharmaceutically acceptable salt thereof, has FAP inhibitory activity and can thus be usefully used for prevention or treatment of fibroblast activation protein (FAP)-mediated disease. Preferably, the compound of formula 1 in accordance with the present technology or a stereoisomer or mixture of stereoisomers or a pharmaceutically acceptable salt thereof can be effectively used for the prevention or treatment of obesity, diabetes, steatosis and non-alcoholic steatohepatitis (NAST).

[0193] Some embodiments of the present invention provide the use of pyrrolidine and piperidine compounds in accordance with the present technology, i.e. a compound of formulas X, Xa, Xb, 1, 1a, 1b, 1c, 1d or 1e, or a stereoisomer or a mixture of stereoisomers thereof, or a pharmaceutically acceptable salt thereof, in the preparation of a medicament for the prevention and/or treatment of lipid and lipoprotein disorders (such as , without limitation, hypercholesterolemia, hypertriglyceridemia and atherosclerosis), conditions and diseases that arise due to the accumulation of lipids and, in particular, triglycerides, and subsequent activation of profibrotic pathways (such as, but not limited to, hypercholesterolemia, hypertriglyceridemia and atherosclerosis) , conditions and diseases resulting from chronic fatty and fibrous organ degeneration due to the accumulation of lipids and in particular triglycerides and subsequent activation of profibrotic pathways (such as, but not limited to, NASH and chronic cholestatic conditions in the liver, glomerulosclerosis and diabetic nephropathy in the kidneys, macular degeneration and diabetic retinopathy in the eyes and neurodegenerative diseases such as Alzheimer's disease in the brain or diabetic neuropathy of the peripheral nervous system), type I or type II diabetes and clinical complications of type I and type II diabetes (such as but not limited to, diabetic nephropathy, diabetic retinopathy, diabetic neuropathy or peripheral arterial occlusive disease (PAOD), chronic intrahepatic or some forms of extrahepatic cholestatic conditions, liver fibrosis, acute intrahepatic cholestatic conditions, obstructive or chronic inflammatory diseases arising from for abnormal bile composition (such as, but not limited to, cholelithiasis, also known as cholesterol gallstones), gastrointestinal diseases with reduced intake of dietary fats and fat-soluble dietary vitamins, inflammatory bowel disease, obesity and metabolic syndrome (a combination of dyslipidemia , diabetes and abnormally high body mass index), persistent infections with intracellular bacteria or parasitic protozoa, non-malignant hyperproliferative diseases, malignant hyperproliferative diseases (such as, but not limited to, various forms of cancer, especially certain forms of breast, liver or colon cancer, or diseases selected from the group consisting of hepatocellular carcinoma, colon adenoma and polyposis), colon adenocarcinoma and hepatocellular carcinoma, in particular hepatic steatosis and associated syndromes, hepatitis B infection, hepatitis C infection and/or cholestatic and fibrotic effects, associated with alcoholic cirrhosis or viral forms of hepatitis, liver failure or impaired liver function as a result of chronic liver disease or surgical resection of the liver, acute myocardial infarction, acute stroke, thrombosis, which is the end point of chronic obstructive atherosclerosis, osteoarthritis, rheumatoid arthritis, psoriasis or ischemic stroke , individually or in any combination thereof.

[0194] In some embodiments, the compounds and/or pharmaceutical compositions described herein are used for the prevention and/or treatment of chronic intrahepatic conditions, such as primary cirrhosis (PBC), primary sclerosing cholangitis (PSC), progressive hereditary intrahepatic cholestasis (PFIC), alcoholic cirrhosis and related cholestasis, and some forms of extrahepatic cholestatic conditions or liver fibrosis.

[0195] In some embodiments, the present invention provides a method of treating chronic intrahepatic cholestatic conditions and/or certain forms of extrahepatic cholestatic conditions in a patient in need thereof, the method comprising, essentially consisting of, or consisting of administering to the patient a therapeutically effective amount of a compound or a composition described herein. In some embodiments, the chronic intrahepatic conditions are selected from PBC, PSC, PFIC, and alcoholic cirrhosis and nymphholestasis-related.

[0196] In some embodiments, the present invention provides a method of treating liver fibrosis in a patient in need thereof, the method comprising, essentially consisting of, or consisting of administering to the patient a therapeutically effective amount of a compound or composition described herein.

[0197] In some embodiments, the present invention provides a method of treating a lipid or lipoprotein metabolic disorder in a patient in need thereof, the method comprising, essentially consisting of, or consisting of administering to the patient a therapeutically effective amount of a compound or composition described herein . In some embodiments, the lipid or lipoprotein metabolic disorder is selected from hypercholesterolemia, hypertriglyceridemia, and atherosclerosis.

[0198] In some embodiments, provided herein is a method of treating a condition or disease resulting from chronic fatty and fibrous organ degeneration due to lipid accumulation and, in particular, triglyceride accumulation and subsequent activation of profibrotic pathways in a patient in need thereof, wherein the method includes, essentially consists of, or consists of administering to a patient a therapeutically effective amount of a compound or composition described herein. In some embodiments, the condition or disease resulting from chronic fatty and fibrotic degeneration of organs due to lipid accumulation and, in particular, triglyceride accumulation and subsequent activation of profibrotic pathways is selected from NASH and chronic cholestatic liver conditions, glomerulosclerosis and diabetic kidney nephropathy, luteal degeneration spots and diabetic eye retinopathy, as well as neurodegenerative diseases. In some additional embodiments, the neurodegenerative diseases are selected from Alzheimer's disease in the brain and diabetic neuropathies in the peripheral nervous system.

[0199] In some embodiments, the present invention provides a method of treating type I or II diabetes and the clinical complications of type I and type II diabetes in a patient in need thereof, wherein the method includes, essentially consists of, or consists of administering to the patient a therapeutically effective the amount of a compound or composition described herein. In some embodiments, the present invention provides a method of treating type I diabetes in a patient in need thereof, the method comprising, essentially consisting of, or consisting of administering to the patient a therapeutically effective amount of a compound or composition described herein. In some embodiments, the present invention provides a method of treating type I diabetes in a patient in need thereof, the method comprising, essentially consisting of, or consisting of administering to the patient a therapeutically effective amount of a compound or composition described herein. In some embodiments, the present invention provides a method of treating one or more clinical complications of type I or type II diabetes in a patient in need thereof, the method comprising, essentially consisting of, or consisting of administering to the patient a therapeutically effective amount of a compound or composition, described in this document. In some embodiments, the clinical complications of type I and type II diabetes are selected from diabetic nephropathy, diabetic retinopathy, diabetic neuropathy and peripheral arterial disease (PAOD), or any combination thereof.

[0200] In some embodiments, the present invention provides a method of treating acute intrahepatic cholestatic conditions in a patient in need thereof, the method comprising, essentially consisting of, or consisting of administering to the patient a therapeutically effective amount of a compound or composition described herein.

[0201] In some embodiments, provided herein is a method of treating obstructive or chronic inflammatory diseases resulting from abnormal bile composition in a patient in need thereof, the method including, essentially consisting of, or consisting of administering to the patient a therapeutically effective the amount of a compound or composition described herein. In some embodiments, obstructive or chronic inflammatory diseases resulting from abnormal bile composition are gallstones, also known as cholesterol gallstones.

[0202] In some embodiments, the present invention provides a method of treating gastrointestinal diseases associated with reduced intake of dietary fat and fat-soluble dietary vitamins in a patient in need thereof, the method including, essentially consisting of, or consisting of administering to the patient therapeutically an effective amount of a compound or composition described herein.

[0203] In some embodiments, the present invention provides a method of treating inflammatory bowel disease in a patient in need thereof, the method comprising, essentially consisting of, or consisting of administering to the patient a therapeutically effective amount of a compound or composition described herein .

[0204] In some embodiments, the present invention provides a method of treating obesity and metabolic syndrome in a patient in need thereof, the method comprising, substantially consisting of, or consisting of administering to the patient a therapeutically effective amount of a compound or composition described herein document.

[0205] In some embodiments, provided herein is a method of treating persistent infections caused by intracellular bacteria or parasitic protozoa in a patient in need thereof, the method comprising, essentially consisting of, or consisting of administering to the patient a therapeutically effective amount of a compound or compositions described herein.

[0206] In some embodiments, the present invention provides a method of treating non-malignant hyperproliferative disorders in a patient in need thereof, the method comprising, essentially consisting of, or consisting of administering to the patient a therapeutically effective amount of a compound or composition described herein .

[0207] In some embodiments, the present invention provides a method of treating a malignant hyperproliferative disorder in a patient in need thereof, the method comprising, essentially consisting of, or consisting of administering to the patient a therapeutically effective amount of a compound or composition described herein . In some embodiments, the malignant hyperproliferative disorder is selected from various forms of cancer, particularly certain forms of breast, liver, or colon cancer, or a disorder selected from the group consisting of hepatocellular carcinoma, colon adenoma, and polyposis.

[0208] In some embodiments, the present invention provides a method of treating colon adenocarcinoma in a patient in need thereof, the method comprising, essentially consisting of, or consisting of administering to the patient a therapeutically effective amount of a compound or composition described herein.

[0209] In some embodiments, the present invention provides a method of treating hepatocellular carcinoma in a patient in need thereof, the method comprising, essentially consisting of, or consisting of administering to the patient a therapeutically effective amount of a compound or composition described herein.

[0210] In some embodiments, the present invention provides a method of treating hepatic steatosis and related syndromes in a patient in need thereof, the method comprising, substantially consisting of, or consisting of administering to the patient a therapeutically effective amount of a compound or composition, described in this document.

[0211] In some embodiments, the present invention provides a method of treating hepatitis B infection in a patient in need thereof, the method comprising, essentially consisting of, or consisting of administering to the patient a therapeutically effective amount of a compound or composition described herein .

[0212] In some embodiments, the present invention provides a method of treating hepatitis C infection in a patient in need thereof, the method comprising, essentially consisting of, or consisting of administering to the patient a therapeutically effective amount of a compound or composition described herein .

[0213] In some embodiments, provided herein is a method of treating the cholestatic and fibrotic effects associated with alcohol-induced cirrhosis of the liver or viral forms of hepatitis in a patient in need thereof, the method including, essentially consisting of, or consisting of administering to the patient a therapeutically effective amount of a compound or composition described herein.

[0214] In some embodiments, provided herein is a method of treating liver failure or liver dysfunction resulting from chronic liver disease or surgical liver resection in a patient in need thereof, the method including, substantially consisting of, or consisting of administering to the patient a therapeutically effective amount of a compound or composition described herein.

[0215] In some embodiments, the present invention provides a method of treating acute myocardial infarction in a patient in need thereof, the method comprising, essentially consisting of, or consisting of administering to the patient a therapeutically effective amount of a compound or composition described herein.

[0216] In some embodiments, the present invention provides a method of treating acute stroke in a patient in need thereof, the method comprising, essentially consisting of, or consisting of administering to the patient a therapeutically effective amount of a compound or composition described herein.

[0217] In some embodiments, provided herein is a method of treating thrombosis that occurs as an endpoint of chronic obstructive atherosclerosis in a patient in need thereof, the method comprising, essentially consisting of, or consisting of administering to the patient a therapeutically effective amount of a compound or compositions described herein.

[0218] In some embodiments, the present invention provides a method of treating osteoarthritis in a patient in need thereof, the method comprising, substantially consisting of, or consisting of administering to the patient a therapeutically effective amount of a compound or composition described herein.

[0219] In some embodiments, the present invention provides a method of treating rheumatoid arthritis in a patient in need thereof, the method comprising, essentially consisting of, or consisting of administering to the patient a therapeutically effective amount of a compound or composition described herein.

[0220] In some embodiments, the present invention provides a method of treating psoriasis in a patient in need thereof, the method comprising, essentially consisting of, or consisting of administering to the patient a therapeutically effective amount of a compound or composition described herein.

[0221] In some embodiments, provided herein is a method of treating ischemic stroke in a patient in need thereof, the method including, essentially consisting of, or consisting of administering to the patient a therapeutically effective amount of a compound or composition described herein.

[0222] FAP is expressed not only in a form attached to the cell membrane, but also in a form secreted from the cell and circulating in the blood (circulating FAP, hereafter “c-FAP”), and both forms have the same enzymatic activity. c-FAP can be quantified at the antigen level using an enzyme-linked immunosorbent assay (ELISA) or can be quantified at the enzymatic activity level using a FAP-specific substrate, and this quantitation of FAP has shown that these levels correlate with the degree of induction of the indicated diseases (Ultte de Willige S et al, PLoS One, June 5, 2017, 12). That is, c-FAP can be used as an indicator for diagnosing a disease such as chronic liver disease, malignant tumor, etc. Accordingly, in another aspect, provided herein are methods of using the compounds described herein to detect c-FAP. In some embodiments, provided herein are methods of diagnosing a disease described herein in a subject, the method comprising contacting the subject's blood with a compound described herein and determining the concentration of c-FAP in the blood.

[0223] FGF-21 is known to have effects against obesity and diabetes (M.J. Potthoff et al., Nature Reviews Endocrinology, 2017, 13, and 74), the effect of regulating lipid metabolism (Murata Y et al. J Nutr Metab . 2011; 2011: 981315), and is known to have a powerful hepatoprotective effect (Y. Yu et al, molecular & Cellular Biochemistry, 2015, 403, 287). Thus, inhibition of FAP activity may regulate the degradation of FGF-21 by FAP and may be useful for the treatment of metabolic syndromes such as obesity, diabetes, etc.

[0224] Accordingly, in another aspect, provided herein are methods of regulating the degradation of FGF-21 by inhibiting FAP using a compound described herein.

[0225] Thus, the present technology includes a pharmaceutical composition for inhibiting FAP containing a therapeutically effective amount of a compound of formulas X, Xa, Xb, 1, 1a, 1b, 1c, 1d or 1e, or a stereoisomer or mixture of stereoisomers thereof, or a pharmaceutically acceptable salts as active ingredient. In one embodiment, the present technology provides a pharmaceutical composition for the prevention or treatment of obesity, diabetes, steatosis and non-alcoholic steatohepatitis (NASH) containing a therapeutically effective amount of a compound of formulas X, Xa, Xb, 1, 1a, 1b, 1c, 1d or 1e, or a stereoisomer or mixture of stereoisomers thereof, or a pharmaceutically acceptable salt thereof as an active ingredient.

[0226] In some embodiments, the compounds of this invention may be combined with one or more additional agents for the prevention or treatment of a disease or condition suitable for treatment by FAP inhibition.

[0227] In some embodiments, the compositions described herein contain at least one additional active agent.

[0228] Examples of additional active agents include, but are not limited to, one or more of an ACE inhibitor, an acetyl-CoA carboxylase inhibitor (e.g., firsocostat), an adenosine A3 receptor agonist, an adiponectin receptor agonist, an AKT protein kinase inhibitor, an AMP-activated protein kinase (AMPK), amylin receptor agonist, angiotensin II AT-1 receptor antagonist, apoptosis signaling kinase 1 inhibitor, autotaxin inhibitors, bioactive lipids, calcitonin agonists, caspase inhibitor, caspase-3 stimulator, cathepsin inhibitor, caveolin 1 inhibitor, CCR2 chemokine antagonist, CCR3 chemokine antagonist, CCR5 chemokine antagonist, CCR2/CCR5 dual antagonist (eg, cenicriviroc), chloride channel stimulator, CNR1 inhibitor, cyclin D1 inhibitor, cytochrome P450 7A1 inhibitor, DGAT1/2 inhibitor, dipeptidyl peptidase IV inhibitor, endosialin modulator, eotaxin ligand inhibitor , extracellular matrix protein modulator, farnesoid X receptor agonist (eg, obetacholic acid, tropofexor or cilofexor), fatty acid synthase inhibitor, FGF1 receptor agonists, pegylated FGF21 ligands, fibroblast growth factor (FGF-15, FGF-19, FGF-21) , galectin-3 inhibitor, glucagon receptor agonist, glucagon-like peptide 1 agonist, G protein-coupled bile acid receptor 1 agonists, Hedgehog (Hh) modulator, hepatitis C virus NS3 protease inhibitor, hepatocyte nuclear factor 4 alpha (TTNF4A) modulator, hepatocyte growth factor modulator, HMG CoA reductase inhibitor, IL-10 agonist, IL-17 antagonist, ileal sodium bile acid cotransporter inhibitors, insulin sensitizer, integrin modulator, interleukin-1 receptor-associated kinase 4 (IRAK4) inhibitor, tyrosine kinase inhibitor Jak2, ketohexokinase inhibitors, Klotho beta stimulator, 5-lipoxygenase inhibitor, lipoprotein lipase inhibitor, liver X receptor, LPL gene stimulator, lysophosphatidate-1 receptor antagonist, lysyl oxidase homolog 2 inhibitor, matrix metalloproteinases (MMPs) inhibitor, MEKK-5 protein kinase inhibitor, membrane copper amine oxidase (VAP-1) inhibitors, methionine aminopeptidase inhibitor-2, methyl CpG-binding protein 2 modulator, microRNA-21 (miR-21) inhibitor, mitochondrial uncoupler, myelin basic protein stimulators, PYD domain protein 3 inhibitor NACHT LRR PYD (NLRP3), sirtuin NAD-dependent deacetylase stimulators, NADPH oxidase (NOX) inhibitor, nicotinic acid receptor 1 agonist, P2Y13 purinoceptor stimulator, PDE-3 inhibitor, PDE-4 inhibitor, PDE-5 inhibitor, PDGF receptor beta modulator, phospholipase C inhibitor, PPAR alpha agonist, PPAR delta agonist, PPAR gamma agonist, PPAR gamma modulator (eg, elafibrinor), protease-activated receptor-2 antagonist, protein kinase modulator, Rho-associated protein kinase inhibitor, sodium glucose transporter inhibitor -2, SREBP transcription factor inhibitor, STAT-1 inhibitor, stearoyl-CoA desaturase inhibitor-1, suppressor of stimulator of cytokine signaling-1, suppressor of stimulator of cytokine signaling-3, β-selective thyroid hormone receptor agonists such as M GL-3196, transforming growth factor β (TGF-β), transforming growth factor β-activated kinase 1 (TAK1), thyroid hormone receptor beta-agonist, TLR-4 antagonist, transglutaminase inhibitor, receptor tyrosine kinase modulator, GPCR modulator, nuclear modulator hormone receptors, WNT modulator and YAP/TAZ modulator. Examples of JAK inhibitors include, but are not limited to, filgotonib and tofacitinib. A non-limiting example of an apoptosis signaling kinase inhibitor is selonsertib.

[0229] A compound of formulas X, Xa, Xb, 1, 1a, 1b, 1c, 1d or 1e, or a stereoisomer or mixture of stereoisomers thereof, or a pharmaceutically acceptable salt thereof, and at least one additional active agent can be administered in any order or even simultaneously. Multiple active agents may be provided in one unit form or in multiple forms (by way of example only, either as a single tablet or as two separate tablets). One of the active agents may be administered in multiple doses, or both may be administered in multiple doses. If non-simultaneous administration is used, the time between multiple doses may vary from more than zero weeks to less than four weeks. In addition, combination methods, compositions and formulations should not be limited to the use of only two agents.

[0230] The pharmaceutical composition of the present technology may contain a pharmaceutically acceptable carrier such as diluents, disintegrating agents, sweeteners, glidants or flavoring agents, and may be formulated into an oral dosage form such as tablets, capsules, powders, granules, suspensions, emulsions or syrups; or parenteral administration, such as topical liquids, topical suspensions, topical emulsions, gels (ointments, etc.), inhalants, nebulizers, injections, etc. These dosage forms can be prepared in various forms, for example, in the form of a dosage form for single administration or for multiple administration.

[0231] The pharmaceutical composition of the present technology may contain excipients such as lactose, corn starch or the like, glidants such as magnesium stearate, etc., emulsifying agents, suspending agents, stabilizers and isotonic agents, etc. Sweetener and/or flavoring may be added as needed. Examples of excipients include, but are not limited to, polyethylene glycol (PEG), hydrogenated castor oil (HCO), chromophores, carbohydrates, starches (eg, corn starch), inorganic salts, antimicrobial agents, antioxidants, binders/fillers, surfactants, lubricants (e.g. calcium or magnesium stearate), glidants such as talc, tablet disintegrating agents, diluents, buffers, acids, bases, film coatings, combinations thereof, etc.

[0232] Specific carbohydrate excipients include, for example: monosaccharides such as fructose, maltose, galactose, glucose, d-mannose, sorbose, and the like; disaccharides such as lactose, sucrose, trehalose, cellobiose and the like; polysaccharides such as raffinose, melezitose, maltodextrins, dextran, starches and the like; and alditols such as mannitol, xylitol, maltitol, lactitol, xylitol, sorbitol (glucyl), pyranosyl sorbitol, myoinositol and the like;

[0233] Inorganic salts or buffers include, but are not limited to, citric acid, sodium chloride, potassium chloride, sodium sulfate, potassium nitrate, monosodium phosphate, dibasic sodium phosphate, and combinations thereof.

[0234] Suitable antioxidants for use herein include, for example, ascorbyl palmitate, butylated hydroxyanisole, butylated hydroxytoluene, hypophosphoric acid, monothiogaicerin, propyl gallate, sodium bisulfite, sodium sulfoxylate, sodium metabisulfite, and combinations thereof.

[0235] Additional illustrative excipients include surfactants such as polysorbates, for example, "Tween 20" and "Tween 80", and pluronics, such as F68 and F88 (both available from BASF, Mount Olive, NJ), esters sorbitan, lipids (eg, phospholipids such as lecithin and other phosphatidylcholines and phosphatidylethanolamines), fatty acids and fatty acid esters, steroids such as cholesterol, and chelating agents such as zinc EDTD and other such suitable cations.

[0236] In addition, the composition described herein may optionally contain one or more acids or bases. Non-limiting examples of acids that can be used include acids selected from the group consisting of hydrochloric acid, acetic acid, phosphoric acid, citric acid, malic acid, lactic acid, formic acid, trichloroacetic acid, nitric acid, perchloric acid, phosphoric acid, sulfuric acid, fumaric acid and combinations thereof. Non-limiting examples of suitable bases include bases selected from the group consisting of sodium hydroxide, sodium acetate, ammonium hydroxide, potassium hydroxide, ammonium acetate, potassium acetate, sodium phosphate, potassium phosphate, sodium citrate, sodium formate, sodium sulfate, sulfate potassium, potassium fumarate and combinations thereof.

[0237] The amount of any individual excipient in the composition will vary depending on the role of the excipient, the dosage requirements of the active agent components, and the specific needs of the composition.

[0238] However, generally, the excipient will be present in the composition in an amount of from about 1% to about 99% by weight, preferably from about 5% to about 98% by weight, more preferably from about 15 to about 95% by weight of the excipient . Typically, the amount of excipient present in the composition of the present invention is selected from the following: at least about 2%, 5%, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45% , 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90% or even 95% by weight.

[0239] The composition of the present technology can be administered orally or parenterally, including inhalation, intravenous, intraperitoneal, subcutaneous, rectal and topical administration. Therefore, the composition of the present technology can be prepared in various forms, such as tablets, capsules, aqueous solutions, suspensions, etc. In the case of tablets for oral administration, carriers such as lactose, corn starch and lubricants such as magnesium stearate may be added. In the case of capsules for oral administration, lactose and/or dried corn starch can be used as a diluent. When an aqueous suspension is required for oral administration, the active ingredient can be combined with emulsifying and/or suspending agents. Some sweeteners and/or flavorings may be added if necessary. For intramuscular, intraperitoneal, subcutaneous and intravenous administration, sterile solutions of the active ingredient are usually prepared; the pH of the solutions should be adjusted and buffered accordingly. When administered intravenously, the concentration of solutes should be monitored to make the drug isotonic. The composition of the present technology may be in the form of an aqueous solution containing pharmaceutically acceptable carriers, for example saline solution having a pH level of 7.4. Solutions can be administered into the patient's intramuscular circulation by local bolus injection.

[0240] Said pyrrolidine or piperidine compound, that is, a compound of formulas X, Xa, Xb, 1, 1a, 1b, 1c, 1d or 1e, or a stereoisomer thereof, or a mixture of stereoisomers, or a pharmaceutically acceptable salt thereof, can be administered to a patient in an effective amount from about 0.001 mg/kg to about 100 mg/kg per day. Of course, the dosage may be adjusted according to the age, weight, sensitivity of the patient, symptoms or clinical effectiveness of the compound. This includes 0.001, 0.0025, 0.005, 0.0075, 0.01, 0.025, 0.05, 0.075, 0.1, 0.25, 0.5, 0.75, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 15, 20, 25, 30, 35, 40, 45, 50, 55, 60, 65, 70, 75, 80, 85, 90, 95 or 100 mg/kg .

[0241] Generally, a therapeutically effective amount of a compound of formulas X, Xa, Xb, 1, 1a, 1b, 1c, 1d or 1e, or a stereoisomer or mixtures of stereoisomers thereof, or a pharmaceutically acceptable salt thereof, will range from a total daily dose of about 0.1 mg/day up to 1000 mg/day, about 30-720 mg/day, about 60-600 mg/day, or about 100-480 mg/day or more. In some embodiments, a therapeutically effective amount of a compound of formulas X, Xa, Xb, 1, 1a, 1b, 1c, 1d, or 1e, or a pharmaceutically acceptable salt thereof, will be in the range of about 1-240 mg/day, about 30-240 mg/day , about 30-200 mg/day, about 30-120 mg/day, about 1-120 mg/day, about 50-150 mg/day, about 60-150 mg/day, about 60-120 mg/day or about 60-100 mg/day when administered either as a single dose or as multiple doses. In some embodiments, the multiple doses include two, three, or four doses per day.

[0242] In some embodiments, the therapeutically effective amount of a compound of formulas X, Xa, Xb, 1, 1a, 1b, 1c, 1d, or 1e, or a stereoisomer thereof, or a mixture of stereoisomers, or a pharmaceutically acceptable salt thereof is at least 0.1 mg/day, at least 0.5 mg/day, at least 1 mg/day, at least 5 mg/day, at least 10 mg/day, at least 20 mg/day, at least 30 mg/day, at least 40 mg/day, at least 50 mg/day, at least 60 mg/day, at least 70 mg/day, at least 80 mg/day, at least 90 mg/day day, at least 100 mg/day, at least 110 mg/day, at least 120 mg/day, at least 130 mg/day, at least 140 mg/day, at least 150 mg/day, at least 160 mg/day, at least 170 mg/day, at least 180 mg/day, at least 190 mg/day, at least 200 mg/day, at least 225 mg/day, at least at least 250 mg/day, at least 275 mg/day, at least 300 mg/day, at least 325 mg/day, at least 350 mg/day, at least 375 mg/day, at least 400 mg/day, at least 425 mg/day, at least 450 mg/day, at least 475 mg/day, at least 500 mg/day, at least 525 mg/day, at least 550 mg/day day, at least 575 mg/day, at least 600 mg/day, at least 625 mg/day, at least 650 mg/day, at least 675 mg/day, at least 700 mg/day, at least 725 mg/day, at least 750 mg/day, at least 775 mg/day, at least 800 mg/day, at least 825 mg/day, at least 850 mg/day, at least at least 875 mg/day, at least 900 mg/day, at least 925 mg/day, at least 950 mg/day, at least 975 mg/day or at least 1000 mg/day.

[0243] The present technology also includes a method of inhibiting fibroblast activation protein (FAP) in a mammal, comprising administering to the mammal a therapeutically effective amount of a compound of formulas X, Xa, Xb, 1, 1a, 1b, 1c, 1d or 1e, or a stereoisomer or mixture of stereoisomers, or pharmaceutically acceptable salt. In one embodiment, the present invention provides a method of treating obesity, diabetes, steatosis and non-alcoholic steatohepatitis (NASH), comprising administering to a mammal a therapeutically effective amount of a compound of formulas X, Xa, Xb, 1, 1a, 1b, 1c, 1d or 1e or stereoisomers or a mixture stereoisomers or a pharmaceutically acceptable salt thereof. In some embodiments, the present invention provides a method of treating NASH in a subject in need thereof, the method comprising, essentially consisting of, or consisting of administering to the subject a therapeutically effective amount of a compound of formulas X, Xa, Xb, 1, 1a, 1b , 1c, 1d or 1e or a stereoisomer thereof or a mixture of stereoisomers or a pharmaceutically acceptable salt thereof. Mammals include, but are not limited to, mice, rodents, rats, monkeys, humans, farm animals, dogs, cats, sporting animals and pets.

[0244] The present technology provides the use of a compound of formulas X, Xa, Xb, 1, 1a, 1b, 1c, 1d or 1e or stereoisomers or a mixture of stereoisomers or a pharmaceutically acceptable salt thereof in the manufacture of a medicament for inhibiting fibroblast activation (FAP) in mammals . In one embodiment, the present technology provides the use of a compound of formulas X, Xa, Xb, 1, 1a, 1b, 1c, 1d or 1e or stereoisomers or a mixture of stereoisomers or a pharmaceutically acceptable salt thereof in the manufacture of a medicament for the treatment or prevention of obesity, diabetes, steatosis and non-alcoholic steatohepatitis (NASH).

[0245] Next, the present technology is supplemented with examples and experimental examples. However, the following examples and experimental examples are provided for purposes of illustration only and are not intended to limit the scope of the invention.

[0246] As will be apparent to those skilled in the art upon reading this specification, each of the individual embodiments described and illustrated herein has distinct components and features that can be readily separated from or combined with features of any of the other several embodiments without deviations from the scope or essence of this technology. Any specified method may be carried out in the specified order or in any other order that is logically possible.

EXAMPLES

[0247] Analyzes of the compounds obtained in the following examples were performed as follows: Nuclear magnetic resonance (NMR) spectrum analysis was performed using a Bruker 400 MHz spectrometer and an Agilent 600 MHz spectrometer and their chemical shifts in ppm. In addition, the indicated molecular weights were measured using an Agilent 1260 Infinity liquid chromatography/mass selective detector (MSD) equipped with an electrostatic spray interface (using single quadrupole analysis, this indicates the ESI m/z value (ESI-MS (cation), which is represented by the [M+H]+ peak. Column chromatography was performed on silica gel (Merck, 70-230 mesh) (W.C. Still, J. Org. Chem., 43, 2923, 1978). In addition, the abbreviations used in the following examples are as follows: Me is methyl, Et is ethyl, Ph is phenyl, and Boc is tert-butyloxycarbonyl. In addition, the starting materials in each example [0248] [0249] are known compounds that were synthesized in accordance with literature or purchased, for example, from Sigma-Aldrich.

[0250] Reference Example 1: (S)-1-(2-chloroacetyl)pyrrolidine-2-carbonitrile

[0251](S)-pyrrolidine-2-carbonitrile hydrochloride (7 g, 52.8 mmol) was dissolved in dichloromethane (264 ml). The resulting solution was added with triethylamine (22.1 ml, 158.3 mmol) and then cooled to 0°C. A solution in which 2-chloroacetyl chloride (4.63 mL, 58.1 mmol) was dissolved in dichloromethane (10 mL) was slowly added dropwise to the reaction mixture. The reaction mixture was stirred for 2 hours at 0°C and then water was added to extract the aqueous layer with dichloromethane. The extracted organic layer was dried and filtered over anhydrous magnesium sulfate. The filtered solution was concentrated and then purified by silica gel column chromatography (ethyl acetate/n-hexane = 2/1, v/v) to give the title compound (7.6 g). ¹ H-NMR (CDCl ₃ , 400 MHz) δ 4.81 (d, 1 H), 4.24-4.11 (m, 2 H), 3.73 (s, 2 H), 3.61 ( s, 1 N), 3.61 (s, 1 N) 2.42-2.05 (m, 4 N)

[0252] Reference Example 2: (2S,4S)-1-(2-chloroacetyl)-4-fluoropyrrolidine-2-carbonitrile

[0253] The title compound as a solid (6.31 g) was prepared in the same manner as Example 1 except that (2S,4S)- 4-fluoropyrrolidine-2-carbonitrile hydrochloride (7.95 g, 52.8 mmol). ¹ H-NMR (CDCl ₃ , 400 MHz) δ 5.52-5.31 (m, 1 H), 5.06-4.94 (m, 1 H), 4.26-3.84 (m, 3 N) 2.80-2.68 (m, 1 N), 2.42-2.32 (m, 1 N)

[0254] Reference Example 3: (2S)-1-(2-chloroacetyl)-4,4-difluoropyrrolidine-2-carbonitrile

[0255] The title compound as a solid (8.57 g) was prepared in the same manner as Example 1 except that (2S)-4 was used instead of (S)-pyrrolidine-2-carbonitrile hydrochloride. 4-difluoropyrrolidine-2-carbonitrile 4-methylbenzenesulfonate (16.1 g, 52.8 mmol). ¹ H-NMR (CDCl ₃ , 400 MHz) δ 4.97 (s, 1 H), 4.04 (s, 3 H), 2.79 (s, 2 H), 1.55 (s, 1 H )

[0256] Reference Example 4: (1S,3S,5S)-2-(2-chloroacetyl)-2-azabicyclo[3.1.0]hexane-3-carbonitrile

[0257] The title compound as a liquid (8 g) was prepared in the same manner as Example 1 except that (1S,3S,5S)-2 was used instead of (S)-pyrrolidine-2-carbonitrile hydrochloride -azabicyclo[3.1.0]hexane-3-carbonitrile 4-methylbenzenesulfonate (14.8 g, 52.8 mmol). ¹ H-NMR (CDCl ₃ , 400 MHz) δ 4.96 (d, 1 H), 4.25-1.14 (m, 2 H), 3.62-3.58 (m, 1 H), 2.65-2.58 (m, 1 N), 2.42 (d, 1 N), 1.94-1.90 (m, 1 N), 1.16-1.05 (m, 2 N )

[0258] Reference Example 5: (S)-N-(pyrrolidin-3-yl)quinolin-4-amine hydrochloride

[0259] Step 1: tert-butyl (S)-3-(quinolin-4-ylamino)pyrrolidine-1-carboxylate

[0260] Tert-Butyl (S)-3-aminopyrrolidine-1-carboxylate (500 mg, 2.68 mmol) was dissolved in anhydrous toluene. To the resulting solution was added 4-bromoquinoline (670.2 mg, 3.22 mmol), cesium carbonate (1.31 g, 4.02 mmol), tris(dibenzylideneacetone)diyalladium(0) (245.8 mg, 0.27 mmol), and (+/-)-2,2'-bis(diphenylphosphino)-1,1'-binaphthalene (167.1 mg, 0.27 mmol). The reaction mixture was refluxed and stirred at 100°C overnight. After completion of the reaction, the reaction mixture was cooled to room temperature, and then water was added to extract the aqueous layer with ethyl acetate. The extracted organic layer was dried and filtered over anhydrous magnesium sulfate. The filtered solution was concentrated and then purified by silica gel column chromatography (ethyl acetate/n-hexane = 1/1, v/v) to give the title compound (633.5 mg). ¹ H-NMR (CDCl ₃ , 400 MHz) δ 8.53 (d, 1H), 8.14 (d, 1H), 7.99 (d, 1H), 7.60 (t, 1H), 7. 36 (t, 1H), 6.47 (d, 1H), 4.80 (m, 1H), 4.39 (m, 1H), 3.89-3.98 (m, 1H), 3.79 -3.89 (m, 1H), 3.63-3.74 (m, 1H), 3.51-3.63 (m, 1H), 2.21-2.30 (m, 1H), 1 .96-2.08 (m, 1H), 1.46 (s, 9H)

[0261] Step 2: (S)-N-(pyrrolidin-3-yl)quinoline-4-amine hydrochloride

[0262] Tert-Butyl (S)-3-(quinolin-4-ylamino)pyrrolidine-1-carboxylate (472 mg, 1.51 mmol) obtained in step 1 was dissolved in dichloromethane (8.4 ml), and then an excess of 4.0 M hydrochloric acid dissolved in 1,4-dioxane was added dropwise. The reaction mixture was stirred overnight at room temperature. After completion of the reaction, the resulting solid was filtered, washed and dried in vacuo to give the title compound (394.5 mg). ¹ H-NMR ((CD ₃ ) ₂ SO, 400 MHz) δ 14.6 (s, 1H), 9.75 (s, 1H), 9.46 (d, 1H), 8.98 (d, 1H ), 8.66 (d, 1H), 8.08 (d, 1H), 8.00 (dd, 1H), 7.74 (dd, 1H), 6.98 (d, 1H), 4.74 -4.82 (m, 1H), 3.35-3.59 (m, 2H), 2.23-2.32 (m, 1H), 2.18-2.28 (m, 1H)

[0263] Reference Example 6: (S)-N-(pyrrolidin-3-yl)quinolin-3-amine hydrochloride

[0264] Step 1: tert-butyl-((S)-3-(quinolin-3-ylamino)pyrrolidine-1-carboxylate

[0265] The title compound (576.3 mg) was prepared in the same manner as Step 1 of Reference Example 5 except that 3-bromoquinoline (670.2 mg, 3.22 mmol) was used instead of 4-bromoquinoline. ^1H -NMR ( _CDCl3 , 400 MHz) δ 8.40-8.53 (m, 1H), 7.88-8.02 (m, 1H), 7.60-7.74 (m, 1H) , 7.34-7.55 (m, 2H), 6.95-7.09 (m, 1H), 4.17-4.33 (m, 1H), 3.80 (m, 1H), 3 .42-3.64 (m, 2H), 3.21-3.41 (m, 1H), 2.13-2.42 (m, 2H), 1.87-2.02 (m, 1H) , 1.34-1.60 (m, 9H)

[0266] Step 2: (S)-N-(pyrrolidin-3-yl)quinoline-3-amine hydrochloride

[0267] The title compound (473.5 mg) was prepared in the same manner as in Step 2 of Reference Example 5 and used in the next step without any further purification.

[0268] Reference Example 7: (S)-N-(pyrrolidin-3-yl)isoquinolin-4-amine hydrochloride

[0269] Step 1: tert-butyl-(S)-3-(isoquinolin-4-ylamino)pyrrolidine-1-carboxylate

[0270] The title compound (457.9 mg) was prepared in the same manner as Step 1 of Reference Example 5 except that 4-bromoquinoline (670.2 mg, 3.22 mmol) was used instead of 4-bromoquinoline. . ¹ H-NMR (CDCl ₃ , 400 MHz) δ 8.85 (s, 1H), 8.11 (d, 1H), 8.01-8.15 (m, 1H), 7.93 (d, 1H ), 7.54-7.68 (m, 2H), 4.91-4.94 (m, 1H), 4.39-4.48 (m, 1H), 3.62-3.86 (m , 2H), 3.29-3.43 (m, 2H), 2.31-2.41 (m, 1H), 1.90-1.99 (m, 1H), 1.47 (s, 9H )

[0271] Step 2: (S)-N-(pyrrolidin-3-yl)isoquinolin-4-amine hydrochloride

[0272] The title compound (343.2 mg) was prepared in the same manner as in Step 2 of Reference Example 5 and used in the next step without further purification.

[0273] Reference Example 8: (S)-N-(benzo[b]thiophen-4-yl)pyrrolidin-3-amine hydrochloride

[0274] Step 1: tert-butyl-(S)-3-(benzo[b]thiophen-4-ylamino)pyrrolidine-1-carboxylate

[0275] The title compound (351.6 mg) was prepared in the same manner as Step 1 of Reference Example 5 except that 4-bromobenzo[b]thiophene (686.2 mg, 3 .22 mmol). ^1H -NMR ( _CDCl3 , 400 MHz) δ 7.26-7.37 (m, 2H), 7.15-7.24 (m, 2H), 6.53 (d, 1H), 4.07 -4.25 (m, 2H), 3.77-3.82 (m, 1H), 3.43-3.63 (m, 2H), 3.26-3.42 (m, 1H), 2 .25-2.35 (m, 1H), 1.93-2.07 (m, 1H), 1.42-1.52 (m, 9H)

[0276] Step 2: (S)-N-(benzo[b]thiophen-4-yl)pyrrolidin-3-amine hydrochloride

[0277] The title compound (200.3 mg) was prepared in the same manner as in Step 2 of Reference Example 5 and used in the next step without further purification.

[0278] Reference Example 9: (S)-N-(benzo[b]thiophen-7-yl)pyrrolidin-3-amine hydrochloride

[0279] Step 1: tert-butyl-(S)-3-(benzo[b]thiophen-7-ylamino)pyrrolidine-1-carboxylate

[0280] The title compound (264.5 mg) was prepared in the same manner as Step 1 of Reference Example 5 except that 7-bromobenzo[b]thiophene (686.2 mg, 3 .22 mmol). ¹ H-NMR (CDCl ₃ , 400 MHz) δ 7.34-7.40 (m, 1H), 7.26-7.33 (m, 3H), 6.59 (d, 1H), 4.23 -4.32 (m, 1H), 3.79-3.88 (m, 1H), 3.70-3.82 (m, 1H), 3.46-3.61 (m, 2H), 3 .24-3.42 (m, 1H), 2.24-2.32 (m, 1H), 1.90-2.04 (m, 1H), 1.47 (s, 9H)

[0281] Step 2: (S)-N-(benzo[b]thiophen-7-yl)pyrrolidin-3-amine hydrochloride

[0282] The title compound (172 mg) was prepared in the same manner as in step 2

reference example 5, and used in the next step without further purification.

[0283] Reference Example 10. (S)-N-(Benzofuran-7-yl)pyrrolidin-3-amine hydrochloride

[0284] Step 1: tert-butyl-(S)-3-(benzofuran-7-ylamino)pyrrolidine-1-carboxylate

[0285] The title compound (555.9 mg) was prepared in the same manner as Step 1 of Reference Example 5 except that 7-bromobenzofuran (641.2 mg, 3.22 mmol) was used instead of 4-bromoquinoline ). ^1H -NMR ( _CDCl3 , 400 MHz) δ 7.55-7.67 (m, 1H), 7.10-7.35 (m, 1H), 6.99-7.05 (m, 1H) , 6.72-6.85 (m, 1H), 6.54 (d, 1H), 4.19-4.31 (m, 2H), 3.69-3.82 (m, 1H), 3 .48-3.62 (m, 2H), 3.27-3.43 (m, 1H), 2.18-2.27 (m, 1H), 1.97-2.03 (m, 1H) , 1.46 (s, 9H)

[0286] Step 2: (S)-N-(benzofuran-7-yl)pyrrolidin-3-amine hydrochloride

[0287] The title compound (342.8 mg) was prepared in the same manner as in Step 2 of Reference Example 5 [0288] and used in the next step without further purification.

[0289] Reference Example 11: (S)-N-(pyrrolidin-3-yl)furo[3,2-c]pyridin-7-amine hydrochloride

[0290] Step 1: tert-butyl-(S)-3-(furo[3,2-c]pyridin-7-ylamino)pyrrolidine-1-carboxylate

[0291] The title compound (171.5 mg) was prepared in the same manner as Step 1 of Reference Example 5 except that 7-bromofuro[3,2-c]pyridine (640, 2 mg, 3.22 mmol). ^1H -NMR ( _CDCl3 , 400 MHz) δ 8.40 (s, 1H), 7.91 (s, 1H), 7.60 (d, 1H), 6.81 (d, 1H), 4, 30-4.45 (m, 1H), 4.07-4.29 (m, 1H), 3.76-3.89 (m, 1H), 3.47-3.60 (m, 2H), 3.28-3.44 (m, 1H), 2.43-2.65 (m, 1H), 2.19-2.34 (m, 11H), 1.94-2.03 (m, 1H ), 1.46 (s, 9H)

[0292] Step 2: (S)-N-(pyrrolidin-3-yl)furo[3,2-c]pyridin-7-amine hydrochloride

[0293] The title compound (100.9 mg) was prepared in the same manner as in Step 2 of Reference Example 5 and used in the next step without further purification.

[0294] Reference Example 12: (S)-N-([1,1'-Biphenyl]-2-yl)tphrolidin-3-amine hydrochloride

[0295] Step 1: tert-butyl (S)-3-([1,1'-biphenyl]-2-ylamino)pyrrolidine-1-carboxylate

[0296] The title compound (836.3 mg) was prepared in the same manner as Step 1 of Reference Example 5 except that 2-bromobiphenyl (750.0 mg, 3.22 mmol) was used instead of 4-bromoquinoline ). ^1H -NMR ( _CDCl3 , 400 MHz) δ 7.40-7.58 (m, 2H), 7.32-7.40 (m, 3H), 7.18-7.24 (m, 1H) , 7.04-7.13 (m, 1H), 6.75-6.86 (m, 1H), 6.66-6.72 (m, 1H), 4.03-4.10 (m, 1H), 3.93-4.01 (m, 1H), 3.67-3.75 (m, 1H), 3.27-3.47 (m, 2H), 3.11-3.25 ( m, 1H), 2.09-2.19 (m, 1H), 1.48-1.58 (m, 1H), 1.38-1.47 (s, 9H)

[0297] Step 2: (S)-N-([1,1'-biphenyl]-2-yl)pyrrolidin-3-amine hydrochloride

[0298] The title compound (562 mg) was prepared in the same manner as in Step 2 of Reference Example 5 and used in the next step without further purification.

[0299] Reference Example 13: (S)-N-([1,1'-Biphenyl]-4-yl)tphrolidin-3-amine hydrochloride

[0300] Step 1: tert-butyl (S)-3-([1,1'-biphenyl]-4-ylamino)pyrrolidine-1-carboxylate

[0301] The title compound (756.5 mg) was prepared in the same manner as Step 1 of Reference Example 5 except that 4-bromobiphenyl (750.0 mg, 3.22 mmol) was used instead of 4-bromoquinoline ). ¹ H-NMR (CDCl ₃ , 400 MHz) δ 7.47-7.56 (m, 2H), 7.40-7.46 (m, 2H), 7.35-7.40 (m, 2H) , 7.22-7.29 (m, 2H), 6.66-6.68 (m, 1H), 3.99-4.08 (m, 1H), 3.87-3.91 (m, 1H), 3.70-3.85 (m, 1H), 3.42-3.54 (m, 2H), 3.18-3.32 (m, 1H), 2.13-2.21 ( m, 1H), 1.42-1.51 (m, 9H)

[0302] Step 2: (S)-N-([1,1'-biphenyl]-4-yl)pyrrolidin-3-amine hydrochloride

[0303] The title compound (414 mg) was prepared in the same manner as in Step 2 of Reference Example 5 and used in the next step without further purification.

[0304] Reference Example 14: (S)-N-(naphthalene-2-yl)pyrrolidin-3-amine

[0305] Step 1: tert-butyl (S)-3-(naphthalene-2-ylamino)pyrrolidine-1-carboxylate

[0306] Tert-Butyl (S)-3-aminopyrrolidine-1-carboxylate (500 mg, 2.68 mmol) was dissolved in anhydrous toluene. To the resulting solution add 2-bromonaphthalene (665.2 mg, 3.22 mmol), cesium carbonate (1.31 g, 4.02 mmol), tris(dibenzylideneacetone)dipalladium(0) (245.8 mg, 0.27 mmol), and (+/-)-2,2'-bis(diphenylphosphino)-1,1'-binaphthalene (167.1 mg, 0.27 mmol). The reaction mixture was refluxed and stirred at 100°C overnight. After completion of the reaction, the reaction mixture was cooled to room temperature, and then water was added to extract the aqueous layer with ethyl acetate. The extracted organic layer was dried and filtered over anhydrous magnesium sulfate. The filtered solution was concentrated and then purified by silica gel column chromatography (ethyl acetate/n-hexane = 1/1, v/v) to give the title compound (633.5 mg). MS (IER) m/z - 312.4 (M+H)+

[0307] Step 2: (S)-N-(naphthalene-2-yl)pyrrolidin-3-amine

[0308] Tert-Butyl (S)-3-(naphthalene-2-ylamino)pyrrolidine-1-carboxylate (633.5 mg, 2.02 mmol) obtained in step 1 was dissolved in dichloromethane (11.2 ml) , and then an excess of 4.0 M hydrochloric acid dissolved in 1,4-dioxane was added dropwise. The reaction mixture was stirred overnight at room temperature. After completion of the reaction, the residue obtained by concentration under reduced pressure was dissolved in dichloromethane, the solution was washed with 1N aqueous sodium hydroxide and brine, dried over anhydrous magnesium sulfate, and then concentrated under reduced pressure to obtain the title compound (318.6 mg). ^1H -NMR ( _CDCl3 , 400 MHz) δ 7.58-7.71 (m, 3H), 7.36 (dd, 1H), 7.19 (dd, 1H), 6.84 (dd, 1H ), 6.74-6.82 (m, 1H), 4.01-4.12 (m, 1H), 3.88-3.98 (m, 0.9H), 3.73-3.79 (m, 0.2H), 3.57-3.65 (m, 0.3H), 3.04-3.30 (m, 2H), 2.81-3.00 (m, 2H), 2 ,16-2.28 (m, 1H), 1.64-1.78 (m, 1H)

[0309] Reference Example 15. (S)-N-([1,1'-Biphenyl]-3-yl)pyrrolidin-3-amine hydrochloride

[0310] Step 1: tert-butyl (S)-3-([1,1'-biphenyl]-3-ylamino)pyrrolidine-1-carboxylate

[0311] The title compound (562.4 mg) was prepared in the same manner as Step 1 of Reference Example 5 except that 3-bromobiphenyl (750.0 mg, 3.22 mmol) was used instead of 4-bromoquinoline ). ¹ H-NMR (CDCl ₃ , 400 MHz) δ 7.52-7.60 (m, 2H), 7.36-7.47 (m, 3H), 7.31-7.35 (m, 1H) , 6.96-7.05 (m, 1H), 6.80-6.93 (m, 1H), 6.60-6.75 (m, 1H), 4.03-4.15 (m, 1H), 3.84-3.95 (m, 1H), 3.65-3.77 (m, 1H), 3.47-3.52 (m, 1H), 3.18-3.35 ( m, 1H), 2.15-2.25 (m, 1H), 1.86-1.98 (m, 1H), 1.40-1.52 (m, 9H)

[0312] Step 2: (S)-N-([1,1'-biphenyl]-3-yl)pyrrolidin-3-amine hydrochloride

[0313] The title compound (342.2 mg) was prepared in the same manner as in Step 2 of Reference Example 5 and used in the next step without further purification.

[0314] Reference Example 16: (S)-N-(pyrrolidin-3-yl)quinoline-5-amine hydrochloride

[0315] Step 1: tert-butyl (S)-3-(quinolin-5-ylamino)pyrrolidine-1-carboxylate

[0316] The title compound (297.4 mg) was prepared in the same manner as Step 1 of Reference Example 5 except that 5-bromoquinoline (670.2 mg, 3.22 mmol) was used instead of 4-bromoquinoline ). ¹ H-NMR (CD ₃ OD, 400 MHz) δ 9.67-9.72 (m, 1H), 9.06-9.21 (m, 1H), 7.90-8.00 (m, 2H ), 7.46-7.52 (m, 1H), 7.01-7.11 (m, 1H), 4.58 (m, 1H), 3.60-3.75 (m, 2H), 3.53-3.59 (m, 2H), 2.45-2.52 (m, 1H), 2.37-2.42 (m, 1H)

[0317] Step 2: (S)-N-(pyrrolidin-3-yl)quinoline-5-amine hydrochloride

[0318] The title compound (342.2 mg) was prepared in the same manner as in Step 2 of Reference Example 5 and used in the next step without further purification.

[0319] Reference Example 17: (R)-N-(pyrrolidin-3-yl)quinolin-3-amine hydrochloride

[0320] Step 1: tert-butyl-(R)-3-(quinolin-3-ylamino)pyrrolidine-1-carboxylate

[0321] Tert-Butyl (R)-3-aminopyrrolidine-1-carboxylate (500 mg, 2.68 mmol) was dissolved in anhydrous toluene. To the resulting solution add 3-bromoquinoline (670.2 mg, 3.22 mmol), cesium carbonate (1.31 g, 4.02 mmol), tris(dibenzyldenacetone)dipalladium(0) (245.8 mg, 0.27 mmol), and (+/-)-2,2'-bis(diphenylphosphino)-1,1'-binaphthalene (167.1 mg, 0.27 mmol). The reaction mixture was refluxed and stirred at 100°C overnight. After completion of the reaction, the reaction mixture was cooled to room temperature, and then water was added to extract the aqueous layer with ethyl acetate. The extracted organic layer was dried and filtered over anhydrous magnesium sulfate. The filtered solution was concentrated and then purified by silica gel column chromatography (ethyl acetate/n-hexane = 1/1, v/v) to give the title compound (472 mg). ^1H -NMR ( _CDCl3 , 400 MHz) δ 8.41-8.52 (m, 1H), 7.94-8.11 (m, 1H), 7.57-7.68 (m, 1H) , 7.38-7.51 (m, 2H), 7.02-7.13 (m, 1H), 4.27 (m, 1H), 3.89-3.92 (m, 1H), 3 .51-3.75 (m, 2H), 3.32-3.42 (m, 1H), 2.26-2.31 (m, 1H), 1.90-2.13 (m, 2H) , 1.40-1.60 (m, 9H)

[0322] Step 2: (R)-N-(pyrrolidin-3-yl)quinoline-3-amine hydrochloride

[0323] The title compound (344.7 mg) was prepared in the same manner as in Step 2 of Reference Example 5 and used in the next step without further purification.

[0324] Reference Example 18: (R)-N-([1,1'-Biphenyl]-3-yl)pyrrolidin-3-amine hydrochloride

[0325] Step 1: tert-butyl (R)-3-([1,1'-biphenyl]-3-yl)pyrrolidin-1-carboxylate

[0326] The title compound (621.3 mg) was prepared in the same manner as Step 1 of Reference Example 17, except that 3-bromobiphenyl (750.0 mg, 3.22 mmol) was used instead of 3-bromoquinoline. ¹ H-NMR (CDCl ₃ , 400 MHz) δ 7.55-7.68 (m, 2H), 7.38-7.53 (m, 2H), 7.30-7.35 (m, 1H) , 7.23-7.28 (m, 1H), 6.94-7.08 (m, 1H), 6.79-6.84 (m, 1H), 6.58-6.63 (m, 1H), 4.04-4.12 (m, 1H), 3.90-4.03 (m, 1H), 3.71-3.85 (m, 1H), 3.46-3.52 ( m, 2H), 3.15-3.35 (m, 1H), 2.16-2.20 (m, 1H), 1.82-1.98 (m, 1H), 1.46-1, 58 (m, 9N)

[0327] Step 2: (R)-N-([1,1'-biphenyl]-3-yl)pyrrolidin-3-amine hydrochloride

[0328] The title compound (383.7 mg) was prepared in the same manner as in Step 2 of Reference Example 5 and used in the next step without further purification.

[0329] Reference Example 19: (R)-N-(pyrrolidin-3-yl)isoquinolin-4-amine hydrochloride

[0330] Step 1: tert-butyl-(R)-3-(isoquinolin-4-ylamino)pyrrolidine-1-carboxylate

[0331] The title compound (447.7 mg) was prepared in the same manner as Step 1 of Reference Example 17 except that 3-bromoquinoline (670.2 mg, 3.22 mmol) was used instead of 4-bromoquinoline. . MS (IER) m/z - 314.2 (M+H)+

[0332] Step 2: (R)-N-(pyrrolidin-3-yl)isoquinolin-4-amine hydrochloride

[0333] The title compound (299.7 mg) was prepared in the same manner as Step 2 of Reference Example 5. MS (ESI) m/z - 214.2 (M+H)+

[0334] Reference Example 20: (R)-N-(benzo[b]thiophen-7-yl)pyrrolidin-3-amine hydrochloride

[0335] Step 1: tert-butyl-(R)-3-(benzo[b]thiophen-7-ylamino)pyrrolidine-1-carboxylate

[0336] The title compound (128 mg) was prepared in the same manner as Step 1 of Reference Example 17 except that 7-bromobenzo[b]thiophene (685.0 mg, 3.22 mmol). ^1H -NMR ( _CDCl3 , 400 MHz) δ 7.21-7.45 (m, 4H), 6.57-6.62 (m, 1H), 4.21-4.31 (m, 1H ), 3.73-3.82 (m, 2H), 3.44-3.60 (m, 2H), 3.26-3.40 (m, 1H), 2.23-2.25 (m , 1H), 1.97-2.21 (m, 1H), 1.40-1.56 (m, 9H)

[0337] Step 2: (R)-N-(benzo[b]thiophen-7-yl)pyrrolidin-3-amine hydrochloride

[0338] The title compound (79.0 mg) was prepared in the same manner as in Step 2 of Reference Example 5 and used in the next step without further purification.

[0339] Reference Example 21: (S)-N-(quinolin-4-yl)pyrrolidin-3-carboxamide hydrochloride

[0340] Step 1: tert-butyl (S)-3-(quinolin-4-ylcamamoyl)pyrrolidine-1-carboxylate

[0341] (S)-1-(tert-Butoxycarbonyl)pyrrolidine-3-carboxylic acid (300 mg, 1.39 mmol) was dissolved in dichloromethane. To the resulting solution was added 4-aminoquinoline (200.9 mg, 1.39 mmol), HATU (O-(7-azabenzotriazol-1-yl)-N,N,N',N'-tetramethyluran hexafluorophosphate) (794.9 mg, 2.09 mmol) and diisopropylethylamine (0.49 ml, 2.79 mmol). The reaction mixture was stirred overnight at room temperature. After completion of the reaction, water was added to the reaction mixture. The aqueous layer of the reaction mixture was extracted with dichloromethane. The extracted organic layer was dried and filtered over anhydrous magnesium sulfate. The filtered solution was concentrated and then purified by silica gel column chromatography (dichloromethane/methanol = 20/1, v/v) to give the title compound (250 mg). ^1H -NMR ( _CDCl3 , 400 MHz) δ 9.05 (s, 1H), 8.80 (s, 1H), 8.63 (s, 1H), 8.38 (s, 1H), 7, 95 (d, 2H), 7.71 (s, 1H), 3.71-3.46 (m, 5 N), 2.83 (s, 10 N), 2.32-2.18 (m, 2H), 1.50-1.43 (d, 9H)

[0342] Step 2: (S)-N-(quinolin-4-yl)pyrrolidin-3-carboxamide hydrochloride

[0343] Tert-Butyl (S)-3-(quinolin-4-ylcamamoyl)pyrrolidine-1-carboxylate (450 mg, 1.32 mmol) prepared in step 1 was dissolved in dichloromethane (7.3 ml), and then an excess of 4.0 M hydrochloric acid dissolved in 1,4-dioxane was added dropwise. The reaction mixture was stirred overnight at room temperature. After completion of the reaction, the resulting solid was filtered and dried to obtain the title compound (220 mg). The title compound was used in the next step without further purification.

[0344] Reference Example 22: (S)-N-(quinolin-3-yl)pyrrolidin-3-carboxamide hydrochloride

[0345] Step 1: tert-butyl (S)-3-(quinolin-3-ylcamamoyl)pyrrolidine-1-carboxylate

[0346] The title compound (100 mg) was prepared in the same manner as Step 1 of Reference Example 21 except that 3-aminoquinoline (200.9 mg, 1.39 mmol) was used instead of 4-aminoquinoline. MS (IER) m/z - 342.4 (M + H)+

[0347] Step 2: (S)-N-(quinolin-3-yl)pyrrolidin-3-carboxamide hydrochloride

[0348] The title compound (190.7 mg) was prepared in the same manner as in Step 2 of Reference Example 21 and used in the next step without further purification.

[0349] Reference Example 23: (R)-N-(quinolin-4-yl)pyrrolidin-3-carboxamide hydrochloride

[0350] Step 1: tert-butyl (R)-3-(quinolin-4-ylcamamoyl)pyrrolidine-1-carboxylate

[0351] The title compound (340 mg g) was prepared in the same manner as Step 1 of Reference Example 21 except that (S)-1-(tert-butoxycarbonyl)pyrrolidine-3-carboxylic acid was used ( R)-1-(tert-butoxycarbonyl)pyrrolidine-3-carboxylic acid (300 mg, 1.39 mmol). ^1H -NMR ( _CDCl3 , 400 MHz) δ 9.05 (s, 1H), 8.80 (s, 1H), 8.63 (s, 1H), 8.38 (s, 1H), 7, 95 (d, 2H), 7.71 (s, 1H), 3.71-3.46 (m, 5H), 2.83 (s, 10H), 2.32-2.18 (m, 2H ), 1.50-1.43 (d, 9H)

[0352] Step 2: (R)-N-(quinolin-4-yl)pyrrolidin-3-carboxamide hydrochloride

[0353] The title compound (260 mg) was prepared in the same manner as in Step 2 of Reference Example 21 and used in the next step without further purification.

[0354] Reference Example 24: (R)-N-(quinolin-3-yl)pyrrolidin-3-carboxamide hydrochloride

[0355] Step 1: tert-butyl (R)-3-(quinolin-3-ylcamamoyl)pyrrolidine-1-carboxylate

[0356] The title compound (450 mg) was prepared in the same manner as in step 1

Reference Example 21, except that 3-aminoquinoline (200.9 mg, 1.39 mmol) was used instead of 4-aminoquinoline. MS (IER) m/z - 342.4 (M+H)+

[0357] Step 2: (R)-N-(quinolin-3-yl)pyrrolidin-3-carboxamide hydrochloride

[0358] The title compound (310.7 mg) was prepared in the same manner as in Step 2 of Reference Example 21 and used in the next step without further purification.

[0359] Reference Example 25: (S)-1-(2-((S)-3-aminopyrrolidin-1-yl)acetyl)pyrrolidin-2-carbonitrile trifluoroacetate

[0360] Step 1: tert-butyl (S)-1-(2-((S)-2-cyanopyrrolidin-1-yl)-2-oxoethyl)pyrrolidin-3-yl)carbamate

[0361](S)-1-(2-Chloroacetyl)pyrrolidine-2-carbonitrile (3 g, 17.4 mmol) obtained in Reference Example 1 was dissolved in anhydrous dichloromethane (34.8 ml). (3S)-(-)-3-(tert-Butoxycarbonylamino)pyrrolidine (3.56 g, 19.1 mmol) and potassium carbonate (4.8 g, 34.8 mmol) were added to the resulting solution. The reaction mixture was stirred overnight at room temperature. After completion of the reaction, water was added to the reaction mixture. The aqueous layer of the reaction mixture was extracted with dichloromethane. The extracted organic layer was dried and filtered over anhydrous magnesium sulfate. The filtered solution was concentrated and then purified by silica gel column chromatography (ethyl acetate/n-hexane = 4/1, v/v) to give the title compound (2.33 g) ¹ H-NMR (CDCl ₃ , 400 MHz) δ 4.77-4.82 (m, 1H), 3.60-3.74 (m, 1H), 3.30-3.55 (m, 6H), 3.05-3.28 (m, 1H), 2.10-2.44 (m, 4H), 1.68-1.86 (m, 4H), 1.41-1.54 (m, 9H)

[0362] Step 2: (S)-1-(2-((S)-3-aminohyrrolidin-1-yl)acetyl)pyrrolidin-2-carbonitrile trifluoroacetate

[0363] Tert-butyl (S)-1-(2-((S)-2-cyanopyrrolidin-1-yl)-2-oxoethyl)pyrrolidin-3-yl)carbamate (2.6 g, 8.06 mmol ) prepared in step 1 was dissolved in dichloromethane (44.8 ml) and excess trifluoroacetic acid was added dropwise. The reaction mixture was stirred overnight at room temperature and concentrated to give the title compound (1.3 g). ¹ H-NMR (CD ₃ OD, 400 MHz) δ 4.79-4.91 (m, 1H), 4.41 (q, 2H), 4.09-4.21 (m, 1H), 3, 96-4.05 (m, 1H), 3.54-3.81 (m, 5H), 2.55-2.67 (m, 1H), 2.10-2.31 (m, 5H)

[0364] Reference Example 26: (S)-1-(2-((R)-3-hydroxypyrrolidin-1-yl)acetyl)pyrrolidin-2-carbonitrile

[0365](S)-1-(2-chloroacetyl)pyrrolidine-2-carbonitrile (2 g, 11.6 mmol) obtained in Reference Example 1 was dissolved in anhydrous acetonitrile (23.2 ml). (R)-3-pyrrolidinol (1.12 mL, 13.9 mmol) and potassium carbonate (4 g, 28.9 mmol) were added to the resulting solution. The reaction mixture was stirred overnight at room temperature. After completion of the reaction, the reaction mixture was filtered. The filtered solution was concentrated and then purified by silica gel column chromatography (ethyl acetate/n-hexane = 1/1, v/v) to give the title compound (2.42 g). ^1H -NMR ( _CDCl3 , 400 MHz) δ 4.74(d, 1H), 4.35(s, 1H), 3.65-3.63(m, 1H), 3.51-3.33 (m, 3H), 3.11-2.96(m, 2H), 2.88-2.80(m, 2H), 2.55-2.47(m, 1H), 2.35-2 .16(m, 5N), 1.90-1.75(m, 1N)

[0366] Reference Example 27: (S)-4,4-difluoro-1-(2-((R)-3-hydroxypyrrolidin-1-yl)-2-oxoethyl)pyrrolidine-2-carbonitrile

[0367] The title compound (2.52 g) was prepared in the same manner as Reference Example 26 except that (2S) was used instead of (S)-1-(2-chloroacetyl)pyrrolidine-2-carbonitrile. -1-(2-chloroacetyl)-4,4-difluoropyrrolidine-2-carbonitrile (1.4 g, 11.6 mmol) obtained in reference example 3. MS (ESI) m/z - 260.2 (M+ H)+

[0368] Reference Example 28: N-(Piperidin-4-yl)quinolin-4-amine hydrochloride

[0369] Step 1: tert-butyl 4-(quinolin-4-ylamino)piperidine-1-carboxylate

[0370] Tert-butyl-4-aminopiperidine-1-carboxylate (500 mg, 2.68 mmol) was dissolved in anhydrous toluene. To the resulting solution add 4-bromoquinoline (670.2 mg, 3.22 mmol), cesium carbonate (1.31 g, 4.02 mmol), tris(dibenzylideneacetone)diyalladium(0) (245.8 mg, 0.27 mmol), and (+/-)-2,2'-bis(diphenylphosphino)-1,1'-binaphthalene (167.1 mg, 0.27 mmol). The reaction mixture was refluxed and stirred at 100°C overnight. After completion of the reaction, the reaction mixture was cooled to room temperature, and then water was added to extract the aqueous layer with ethyl acetate. The extracted organic layer was dried and filtered over anhydrous magnesium sulfate. The filtered solution was concentrated and then purified by silica gel column chromatography (ethyl acetate/n-hexane=1/1, v/v) to obtain the title compound (720 mg). ^1H -NMR ( _CDCl3 , 400 MHz) δ 8.56 (d, 1H), 7.99 (d, 1H), 7.72 (d, 1H), 7.63 (t, 1H), 7. 43 (t, 1H), 6.47 (d, 1H), 4.93 (d, 1H), 4.12 (d, 2H), 3.68 (s, 1H), 3.00 (t, 1H ), 2.17-2.14 (m, 2H), 1.53-1.44 (m, 12H)

[0371] Step 2: T^-(piperidin-4-yl)quinoline-4-amine hydrochloride

[0372] Tert-Butyl 4-(quinolin-4-ylamino)piperidin-1-carboxylate (720 mg, 2.20 mmol) prepared

in step 1, dissolved in dichloromethane (12.2 ml). An excess of 4.0 M hydrochloric acid dissolved in 1,4-dioxane was added dropwise to the resulting solution. The reaction mixture was stirred overnight at room temperature. After completion of the reaction, the resulting solid was filtered and dried to obtain the title compound (320 mg). The title compound was used in the next step without further purification.

[0373] Reference Example 29.1M-(Piperidin-4-yl)quinolin-5-amine hydrochloride

[0374] Step 1: tert-butyl 4-(quinolin-5-ylamino)piperidine-1-carboxylate

[0375] The title compound (500 mg) was prepared in the same manner as Step 1 of Reference Example 28 except that 5-bromoquinoline (500 mg, 2.50 mmol) was used instead of 4-bromoquinoline. ¹ H-NMR (CDCl ₃ , 400 MHz) δ 8.87 (s, 1H), 8.15 (d, 1H), 7.58-7.49 (m, 2H), 7.34-7.32 (m, 1H), 6.69 (d, 1H), 4.17 (d, 3H), 3.64 (s, 1H), 3.02 (t, 2H), 2.18-2.15 ( m, 2H), 1.49-1.45 (m, 11H)

[0376] Step 2: N-(piperidin-4-yl)quinoline-5-amine hydrochloride

[0377] The title compound (390 mg) was prepared in the same manner as in Step 2 of Reference Example 28 and used in the next step without further purification.

[0378] Reference Example 30: N-(piperidin-4-yl)furo[3,2-c]pyridin-7-amine hydrochloride

[0379] The title compound (324 mg) was prepared in the same manner as Reference Example 28 except that 7-bromofuro[3,2-c]pyridine (495.1 mg) was used instead of 4-bromoquinoline in Step 1 , 2.50 mmol). ¹ H-NMR (CD ₃ OD, 400 MHz) δ 8.6 (s, 1H), 8.26 (s, 1H), 8.17 (s, 1H), 7.29 (s, 1H), 4 .00 (s, 1H), 3.52 (d, 2H), 3.24 (t, 2H), 2.32 (d, 2H), 1.91 (sq, 2H)

[0380] Reference Example 31: 3-(Piperidin-4-yloxy)quinoline hydrochloride

[0381] Step 1: tert-butyl 4-(quinolin-3-yloxy)piperidine-1-carboxylate

[0382] Tert-butyl-4-hydroxypiperidine-1-carboxylate (200 mg, 1.0 mmol) was dissolved in

tetrahydrofuran (4.97 ml). 3-quinolinol (144.25 mg, 1.0 mmol) and triphenylphosphine (391 mg, 1.5 mmol) were added to the resulting solution. The mixture was cooled to 0°C and then DIAD (diisopropyl azodicarboxylate) (0.29 ml, 1.5 mmol) was slowly added dropwise over 15 minutes. The reaction mixture was stirred for 12 hours at room temperature. After completion of the reaction, a saturated ammonium chloride solution and a saturated sodium hydrogen carbonate solution were added to the reaction mixture. The aqueous layer of the reaction mixture was extracted with ethyl acetate. The extracted organic layer was dried and filtered over anhydrous magnesium sulfate. The filtered solution was concentrated and then purified by silica gel column chromatography (dichloromethane/methanol = 10/1, v/v) to give the title compound (280 mg) MS (ESI) m/z - 330.2 ( M + N)+

[0383] Step 2: 3-(piperidin-4-yloxy)quinoline hydrochloride

[0384] Tert-Butyl 4-(quinolin-3-yloxy)piperidin-1-carboxylate (280 mg, 0.85 mmol) was dissolved in dichloromethane (4.7 ml). An excess of 4.0 M hydrochloric acid dissolved in 1,4-dioxane was added dropwise to the resulting solution. The reaction mixture was stirred overnight at room temperature. After completion of the reaction, the resulting solid was filtered and dried to obtain the title compound (47 mg). The title compound was used in the next step without further purification. MS (IER) m/z - 230.1 (M+H)+

[0385] Reference Example 32: 4-(Piperidin-4-yloxy)quinoline hydrochloride

[0386] The title compound (100 mg) was prepared in the same manner as Example 31 except that 4-quinolinol (144.25 mg, 1.0 mmol) was used instead of 3-quinolinol in Step 1. MS (IER) m/z - 230.1 (M+H)+

[0387] Reference Example 33: 5-(Piperidin-4-yloxy)quinoline hydrochloride

[0388] The title compound (60 mg) was prepared in the same manner as Example 31 except that 5-quinolinol (144.25 mg, 1.0 mmol) was used instead of 3-quinolinol in Step 1. The title compound was used in the next step without further purification. MS (IER) m/z - 230.1 (M+H)+

[0389] Reference Example 34: 6-(Piperidin-4-yloxy)quinoline hydrochloride

[0390] The title compound (40 mg) was prepared in the same manner as Example 31 except that 6-quinolinol (144.25 mg, 1.0 mmol) was used instead of 3-quinolinol in Step 1. The title compound was used in the next step without further purification. MS (IER) m/z - 230.1 (M+H)+

[0391] Reference Example 35: 3-Methyl-N-(piperidin-4-yl)quinolin-5-amine hydrochloride

[0392] The title compound (81.8 mg) was prepared in the same manner as Example 28 except that 5-bromo-3-methylquinoline (554.4 mg, 2 .50 mmol). The title compound was used in the next step without further purification. MS (IER) m/z - 242.3 (M+H)+

[0393] Reference Example 36: 6-Methyl-N-(piperidin-4-yl)quinolin-5-amine hydrochloride

[0394] The title compound (40.2 mg) was prepared in the same manner as Example 28 except that 5-bromo-6-methylquinoline (554.4 mg, 2 .50 mmol). The title compound was used in the next step without further purification. MS (IER) m/z - 242.3 (M+H)+

[0395] Reference Example 37: 7-Fluoro-N-(piperidin-4-yl)quinoline-5-amine hydrochloride

[0396] The title compound (251 mg) was prepared in the same manner as Example 28, except that 5-bromo-7-fluoroquinoline (564 mg, 2.50 mmol) was used instead of 4-bromoquinoline in Step 1. . The title compound was used in the next step without further purification. MS (IER) m/z - 246.3 (M+H)+

[0397] Reference Example 38: 7-methoxy-N-(piperidin-4-yl)quinolin-5-amine hydrochloride

[0398] The title compound (106 mg) was prepared in the same manner as Example 28, except that 5-bromo-7-methoxyquinoline (594 mg, 2.50 mmol) was used instead of 4-bromoquinoline in Step 1. . The title compound was used in the next step without further purification. MS (IER) m/z - 258.3 (M+H)+

[0399] Reference Example 39: 8-methoxy-g-T-(piperidin-4-yl)quinolin-5-amine hydrochloride

[0400] The title compound (27 mg) was prepared in the same manner as Example 28 except that 5-bromo-8-methoxyquinoline (594 mg, 2.50 mmol) was used instead of 4-bromoquinoline in Step 1. . The title compound was used in the next step without further purification. MS (IER) m/z - 258.3 (M+H)+

[0401] Reference Example 40: 6-Fluoro-4-(piperidin-4-yloxy)quinoline hydrochloride

[0402] The title compound (214 mg) was prepared in the same manner as Example 31 except that 6-fluoroquinolin-4-ol (202.6 mg, 1.2 mmol). The title compound was used in the next step without further purification. MS (IER) m/z - 246.3 (M+H)+

[0403] Reference Example 41: 6-Chloro-4-(piperidin-4-yloxy)quinoline hydrochloride

[0404] The title compound (197 mg) was prepared in the same manner as Example 31 except that 6-chloroquinolin-4-ol (223.1 mg, 1.2 mmol). The title compound was used in the next step without further purification. MS (IER) m/z - 262.8 (M+H)+

[0405] Reference Example 42: 6-methoxy-4-(piperidin-4-yloxy)quinoline hydrochloride

[0406] The title compound (108.6 mg) was prepared in the same manner as Example 31 except that 6-methoxyquinolin-4-ol (217.6 mg, 1 .2 mmol). The title compound was used in the next step without further purification. MS (IER) m/z - 258.3 (M+H)+

[0407] Reference Example 43: 7-methoxy-4-(piperidin-4-yloxy)quinoline hydrochloride

[0408] The title compound (39.2 mg) was prepared in the same manner as Example 31 except that 7-methoxyquinolin-4-ol (217.6 mg, 1 .2 mmol). The title compound was used in the next step without further purification. MS (IER) m/z - 258.3 (M+H)+

[0409] Reference Example 44: 6,7-Dimethoxy-4-(piperidin-4-yloxy)quinoline hydrochloride

[0410] The title compound (24.7 mg) was prepared in the same manner as Example 31 except that 6,7-dimethoxyquinolin-4-ol (254.9 mg) was used instead of 3-quinolinol in Step 1 , 1.2 mmol). The title compound was used in the next step without further purification. MS (IER) m/z - 288.3 (M+H)+

[0411] Reference Example 45: (S)-6-Fluoro-N-(pyrrolidin-3-yl)benzofuran-3-carboxamide hydrochloride

[0412] Step 1: tert-butyl (S)-3-(6-fluorobenzofuran-3-carboxamido)pyrrolidine-1-carboxylate

[0413] Tert-Butyl (S)-3-aminopyrrolidine-1-carboxylate (500 mg, 2.68 mmol) was dissolved in dimethylformamide (5.4 ml). To the resulting solution was added 6-fluorobenzofuran-3-carboxylic acid (725.4 mg, 4.02 mmol), HATU (O-(7-azabenzotriazol-1-yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate) (1541.4 mg, 4.05 mmol) idiisopropylethylamine (4.67 ml, 26.8 mmol). The reaction mixture was stirred overnight at room temperature. After completion of the reaction, water was added to the reaction mixture. The aqueous layer of the reaction mixture was extracted with ethyl acetate. The extracted organic layer was dried and filtered over anhydrous magnesium sulfate. The filtered solution was concentrated and then purified by silica gel column chromatography (hexane/ethyl acetate = 1/4, v/v) to give the title compound (766 mg). ^1H -NMR ( _CDCl3 , 400 MHz) δ 8.17 (s, 1H), 7.95 (s, 1H), 7.22 (d, 1H), 7.10 (t, 1H), 6, 73-6.52 (m, 1H), 4.67 (s, 1H), 3.70 (d, 1H), 3.47 (d, 2H), 3.32 (s, 1H), 2.23 (s, 1H), 2.00 (d, 1H), 1.46 (s, 9H)

[0414] Step 2: (S)-6-fluoro-N-(pyrrolidin-3-yl)benzofuran-3-carboxamide hydrochloride

[0415] Tert-Butyl (S)-3-(6-fluorobenzofuran-3-carboxamido)pyrrolidine-1-carboxylate (280 mg, 0.85 mmol) was dissolved in dichloromethane (4.7 ml) and then added thereto (dropwise) in excess of 4.0 M hydrochloric acid dissolved in 1,4-dioxane. The reaction mixture was stirred overnight at room temperature. After completion of the reaction, the resulting solid was filtered and dried to obtain the title compound (47 mg). The title compound was used in the next step without further purification. MS (IER) m/z - 249.2 (M+H)+

[0416] Reference Example 46: (S)-6-methoxy-N-(pyrrolidin-3-yl)benzofuran-3-carboxamide hydrochloride

[0417] Step 1: tert-butyl (S)-3-(6-methoxybenzofuran-3-carboxamido)pyrrolidine-1-carboxylate

[0418] The title compound (399.3 mg, 41.3%) was prepared in the same manner as Step 1 of Reference Example 45 except that 6-methoxybenzofuran was used instead of 6-fluorobenzofuran-3-carboxylic acid -3-carboxylic acid (772.5 mg, 4.02 mmol). ^1H NMR ( _CDCl3 , 400 MHz) δ 8.06 (s, 1H), 7.78 (d, 1H), 7.03 (s, 1H), 6.97 (d, 1H), 4.68 (s, 1H), 3.86 (s, 3H), 3.72 (s, 1H), 3.51-3.32 (m, 3H), 2.26-2.25 (m, 1H), 1.98-1.83 (m, 2H), 1.47 (s, 9H).

[0419] Step 2: (S)-6-methoxy-N-(pyrrolidin-3-yl)benzofuran-3-carboxamide hydrochloride

[0420] The title compound (295.9 mg, 90.0%) was prepared in the same manner as in Step 2 of Reference Example 5 and used in the next step without further purification. ^1H NMR ( _MeOD4 , 400 MHz) δ 8.35 (s, 1H), 7.90 (s, 1H), 7.14 (s, 1H), 697, (d, 1H), 4.63- 4.62 (m, 1H), 3.85 (s, 3H), 3.61-3.58 (m, 2H), 3.43-3.41 (m, 2H), 2.45-2, 40 (m, 1H), 2.23-2.22 (m, 1H).

[0421] Reference Example 47: (R)-N-methyl-N-(pyrrolidin-3-yl)quinolin-2-amine hydrochloride

[0422] Step 1: tert-butyl-(R)-3-(methyl(quinolin-2-yl)amino)pyrrolidine-1-carboxylate

[0423] (R)-tert-Butyl 3-(methylamino)pyrrolidine-1-carboxylate (250.0 mg, 1.25 mmol) was dissolved in anhydrous toluene. To the resulting solution was added 2-bromoquinoline (259.7 mg, 1.25 mmol), cesium carbonate (488.1 mg, 1.50 mmol), tris(dibenzylideneacetone) dipalladium (0) (114.3 mg, 0.13 mmol) and (+/-)-2,2'-bis(diphenylphospino)-1,1'-binaphthalene (93.3 mg, 0.15 mmol). The reaction mixture was refluxed and stirred at 100°C overnight. After completion of the reaction, the reaction mixture was cooled to room temperature, and then water was added to extract the aqueous layer with ethyl acetate. The extracted organic layer was dried and filtered over anhydrous magnesium sulfate. The filtered solution was concentrated and then purified by silica gel column chromatography (ethyl acetate/n-hexane = 1/1, v/v) to give the title compound (56.4 mg, 13.8%). MS (IER) m/z - 328.2 (M+H)+

[0424] Step 2: (R)-N-methyl-N-(pyrrolidin-3-yl)quinolin-2-amine hydrochloride

[0425] The title compound (25.5 mg, 100.0%) was prepared in the same manner as in Step 2 of Reference Example 5 and used in the next step without further purification.

[0426] Reference Example 48: (R)-N-Methyl-N-(pyrrolidin-3-yl)quinolin-3-amine hydrochloride

[0427] Step 1: tert-butyl-(R)-3-(methyl (quinolin-3-yl)amino)pyrrolidine-1-carboxylate

[0428] The title compound (220.4 mg, 53.9%) was prepared in the same manner as Step 1 of Reference Example 47 except that 3-bromoquinoline (259.7 mg) was used instead of 2-bromoquinoline , 1.25 mmol). MS (IER) m/z - 328.2 (M+H)+

[0429] Step 2: (R)-N-methyl-N-(pyrrolidin-3-yl)quinolin-3-amine hydrochloride

[0430] The title compound (168.8 mg, 100.0%) was prepared in the same manner as in Step 2 of Reference Example 5 and used in the next step without further purification.

[0431] Reference Example 49: (R)-N-methyl-N-(pyrrolidin-3-yl)quinolin-5-amine hydrochloride

[0432] Step 1: tert-butyl-(R)-3-(methyl(quinolin-5-yl)amino)pyrrolidine-1-carboxylate

[0433] The title compound (109.4 mg, 26.8%) was prepared in the same manner as Step 1 of Reference Example 47 except that 5-bromoquinoline (259.7 mg, 1.25 mmol). MS (IER) m/z - 328.1 (M+H)+

[0434] Step 2: (R)-N-methyl-N-(pyrrolidin-3-yl)quinolin-5-amine hydrochloride

[0435] The title compound (88.1 mg, 100.0%) was prepared in the same manner as in Step 2 of Reference Example 5 and used in the next step without further purification.

[0436] Reference Example 50: (R)-N-methyl-N-(pyrrolidin-3-yl)quinolin-6-amine hydrochloride

[0437] Step 1: tert-butyl (R)-3-(methyl(quinolin-6-yl)amino)pyrrolidine-1-carboxylate

[0438] The title compound (73.9 mg, 18.1%) was prepared in the same manner as Step 1 of Reference Example 47 except that 6-bromoquinoline (259.7 mg) was used instead of 2-bromoquinoline , 1.25 mmol). MS (IER) m/z - 328.3 (M+H)+

[0439] Step 2: (R)-N-methyl-N-(pyrrolidin-3-yl)quinolin-6-amine hydrochloride

[0440] The title compound (59.5 mg, 100.0%) was prepared in the same manner as in Step 2 of Reference Example 5 and used in the next step without further purification.

[0441] Reference Example 51: (R)-N-methyl-N-(pyrrolidin-3-yl)quinolin-7-amine hydrochloride

[0442] Step 1: tert-butyl-(R)-3-(methyl(quinolin-7-yl)amino)pyrrolidine-1-carboxylate

[0443] The title compound (131.9 mg, 32.3%) was prepared in the same manner as Step 1 of Reference Example 47 except that 7-bromoquinoline (259.7 mg, 1.25 mmol). MS (IER) m/z - 358.2 (M+H)+

[0444] Step 2: (R)-N-methyl-N-(pyrrolidin-3-yl)quinolin-7-amine hydrochloride

[0445] The title compound (106.3 mg, 100.0%) was prepared in the same manner as in Step 2 of Reference Example 5 and used in the next step without further purification.

[0446] Reference Example 52: (S)-N-methyl-N-(pyrrolidin-3-yl)quinolin-3-amine hydrochloride

[0447] Step 1: tert-butyl (S)-3-((methyl(quinolin-3-yl)amino)pyrrolidine-1-carboxylate

[0448] (S)-tert-Butyl 3-(methylamino)pyrrolidine-1-carboxylate (250.0 mg, 1.25 mmol) was dissolved in anhydrous toluene. To the resulting solution was added 3-bromoquinoline (259.7 mg, 1.25 mmol), cesium carbonate (488.1 mg, 1.50 mmol), tris(dibenzylideneacetone) dipalladium (0) (114.3 mg, 0.13 mmol) and (+/-)-2,2'-bis(diphenylphospino)-1,1'-binaphthalene (93.3 mg, 0.15 mmol). The reaction mixture was refluxed and stirred at 100°C overnight. After completion of the reaction, the reaction mixture was cooled to room temperature, and then water was added to extract the aqueous layer with ethyl acetate. The extracted organic layer was dried and filtered over anhydrous magnesium sulfate. The filtered solution was concentrated and then purified by silica gel column chromatography (ethyl acetate/n-hexane = 1/1, v/v) to obtain the title compound (252.5 mg, 61.8%). MS (IER) m/z - 328.3 (M+H)+

[0449] Step 2: (S)-N-methyl-N-(pyrrolidin-3-yl)quinolin-3-amine hydrochloride

[0450] The title compound (203.4 mg, 100.0%) was prepared in the same manner as in Step 2 of Reference Example 5 and used in the next step without further purification.

[0451] Reference Example 53: (S)-N-methyl-N-(pyrrolidin-3-yl)quinolin-4-amine hydrochloride

[0452] Step 1: tert-butyl (S)-3-((methyl (quinolin-4-yl)amino)pyrrolidine-1-carboxylate

[0453] The title compound (74.2 mg, 18.2%) was prepared in the same manner as Step 1 of Reference Example 52 except that 4-bromoquinoline (259.7 mg) was used instead of 3-bromoquinoline , 1.25 mmol). MS (IER) m/z - 328.3 (M+H)+

[0454] Step 2: (S)-N-methyl-N-(pyrrolidin-3-yl)quinolin-4-amine hydrochloride

[0455] The title compound (59.8 mg, 100.0%) was prepared in the same manner as in Step 2 of Reference Example 5 and used in the next step without further purification.

[0456] Reference Example 54: (S)-N-methyl-N-(pyrrolidin-3-yl)quinolin-5-amine hydrochloride

[0457] Step 1: tert-butyl (S)-3-((methyl(quinolin-5-yl)amino)pyrrolidine-1-carboxylate

[0458] The title compound (124.2 mg, 30.4%) was prepared in the same manner as Step 1 of Reference Example 52 except that 5-bromoquinoline (259.7 mg) was used instead of 3-bromoquinoline , 1.25 mmol). MS (ESI) m/z - 328.2 (M + H)+

[0459] Step 2: (S)-N-methyl-N-(pyrrolidin-3-yl)quinolin-5-amine hydrochloride

[0460] The title compound (100.1 mg, 100.0%) was prepared in the same manner as in Step 2 of Reference Example 5 and used in the next step without further purification.

[0461] Reference Example 55: (S)-N-methyl-N-(pyrrolidin-3-yl)quinolin-6-amine hydrochloride

[0462] Step 1: tert-butyl (S)-3-((methyl (quinolin-6-yl)amino)pyrrolidin-1-carboxylate

[0463] The title compound (120.5 mg, 29.5%) was prepared in the same manner as Step 1 of Reference Example 52 except that 6-bromoquinoline (259.7 mg) was used instead of 3-bromoquinoline , 1.25 mmol). MS (IER) m/z - 328.3 (M+H)+

[0464] Step 2: (S)-N-methyl-N-(pyrrolidin-3-yl)quinolin-6-amine hydrochloride

[0465] The title compound (97.1 mg, 100.0%) was prepared in the same manner as in Step 2 of Reference Example 5 and used in the next step without further purification.

[0466] Reference Example 56: (S)-N-methyl-N-(pyrrolidin-3-yl)quinolin-7-amine hydrochloride

[0467] Step 1: tert-butyl (S)-3-((methyl(quinolin-7-yl)amino)pyrrolidine-1-carboxylate

[0468] The title compound (260.0 mg, 63.6%) was prepared in the same manner as Step 1 of Reference Example 52 except that 7-bromoquinoline (259.7 mg) was used instead of 3-bromoquinoline , 1.25 mmol). MS (IER) m/z - 328.2 (M+H)+

[0469] Step 2: (S)-N-methyl-N-(pyrrolidin-3-yl)quinolin-7-amine hydrochloride

[0470] The title compound (209.5 mg, 100.0%) was prepared in the same manner as in Step 2 of Reference Example 5 and used in the next step without further purification.

[0471] Reference Example 57: (S)-N-methyl-N-(pyrrolidin-3-yl)isoquinolin-4-amine hydrochloride

[0472] Step 1: tert-butyl (S)-3-((isoquinolin-4-yl(methyl)amino)pyrrolidine-1-carboxylate

[0473] The title compound (69.0 mg, 16.9%) was prepared in the same manner as Step 1 of Reference Example 52 except that 4-bromoquinoline (259.7 mg) was used instead of 3-bromoquinoline , 1.25 mmol). MS (IER) m/z - 328.3 (M+H)+

[0474] Step 2: (S)-N-methyl-N-(pyrrolidin-3-yl)isoquinolin-4-amine hydrochloride

[0475] The title compound (55.6 mg, 100.0%) was prepared in the same manner as in Step 2 of Reference Example 21 and used in the next step without further purification.

[0476] Reference Example 58: (S)-N-methyl-N-(pyrrolidin-3-yl)isoquinolin-5-amine hydrochloride

[0477] Step 1: tert-butyl (S)-3-((isoquinolin-5-yl(methyl)amino)pyrrolidine-1-carboxylate

[0478] The title compound (87.8 mg, 21.5%) was prepared in the same manner as Step 1 of Reference Example 52 except that 5-bromoquinoline (259.7 mg) was used instead of 3-bromoquinoline , 1.25 mmol). MS (IER) m/z - 328.3 (M+H)+

[0479] Step 2: (S)-N-methyl-N-(pyrroldin-3-yl)isoquinolin-5-amine hydrochloride

[0480] The title compound (70.7 mg, 100.0%) was prepared in the same manner as in Step 2 of Reference Example 5 and used in the next step without further purification.

[0481] Reference Example 59: (S)-N,4-dimethyl-N-(pyrrolidin-3-yl)quinolin-3-amine hydrochloride

[0482] Step 1: tert-butyl (S)-3-(methyl(4-methylquinolin-3-yl)amino)pyrrolidine-1-carboxylate

[0483] The title compound (60.4 mg, 14.2%) was prepared in the same manner as Step 1 of Reference Example 52 except that 3-bromo-4-methylquinoline ( 3-bromo-4-methylquinoline) was used instead of 3-bromoquinoline 277.2 mg, 1.25 mmol). MS (IER) m/z - 342.2 (M+H)+

[0484] Step 2: (S)-N,4-dimethyl-N-(pyrrolidin-3-yl)quinolin-3-amine hydrochloride

[0485] The title compound (49.1 mg, 100.0%) was prepared in the same manner as in Step 2 of Reference Example 5 and used in the next step without further purification.

[0486] Reference Example 60: (S)-N,6-dimethyl-N-(pyrrolidin-3-yl)quinolin-3-amine hydrochloride

[0487] Step 1: tert-butyl (S)-3-(methyl(6-methylquinolin-3-yl)amino)pyrrolidine-1-carboxylate

[0488] The title compound (244.0 mg, 57.3%) was prepared in the same manner as Step 1 of Reference Example 52 except that 3-bromo-6-methylquinoline was used instead of 3-bromoquinoline 277.2 mg, 1.25 mmol). MS (IER) m/z - 342.2 (M+H)+

[0489] Step 2: (S)-N,6-dimethyl-N-(pyrrolidin-3-yl)quinolin-3-amine hydrochloride

[0490] The title compound (198.5 mg, 100.0%) was prepared in the same manner as in Step 2 of Reference Example 5 and used in the next step without further purification.

[0491] Reference Example 61: (S)-6-Fluoro-N-methyl-N-(pyrrolidin-3-yl)quinolin-3-amine hydrochloride

[0492] Step 1: tert-butyl (S)-3-((6-fluoroquinolin-3-yl)(methyl)amino)pyrrolidine-1-carboxylate

[0493] The title compound (314.7 mg, 73.0%) was prepared in the same manner as Step 1 of Reference Example 52 except that 3-bromo-6-fluoroquinoline was used instead of 3-bromoquinoline 282.2 mg, 1.25 mmol). MS (IER) m/z - 346.3 (M+H)+

[0494] Step 2: (S)-6-fluoro-N-methyl-N-(pyrrolidin-3-yl)quinolin-3-amine hydrochloride

[0495] The title compound (256.7 mg, 100.0%) was prepared in the same manner as in Step 2 of Reference Example 5 and used in the next step without further purification.

[0496] Reference Example 62: (S)-6-methoxy-N-methyl-N-(pyrrolidin-3-yl)quinolin-3-amine hydrochloride

[0497] Step 1: tert-butyl (S)-3-((6-methoxyquinolin-3-yl)(methyl)amino)pyrrolidine-1-carboxylate

[0498] The title compound (264.3 mg, 59.2%) was prepared in the same manner as Step 1 of Reference Example 52 except that 3-bromo-6-methoxyquinoline was used instead of 3-bromoquinoline 297.2 mg, 1.25 mmol). MS (IER) m/z - 358.2 (M+H)+

[0499] Step 2: (S)-6-methoxy-N-methyl-N-(pyrrolidin-3-yl)quinolin-3-amine hydrochloride

[0500] The title compound (217.2 mg, 100.0%) was prepared in the same manner as in Step 2 of Reference Example 5 and used in the next step without further purification.

[0501] Reference Example 63: (S)-7-methoxy-N-methyl-N-(pyrroldin-3-yl)quinolin-3-amine hydrochloride

[0502] Step 1: tert-butyl (S)-3-((7-methoxyquinolin-3-yl)(methyl)amino)pyrrolidine-1-carboxylate

[0503] The title compound (177.0 mg, 39.7%) was prepared in the same manner as Step 1 of Reference Example 52 except that 3-bromo-7-methoxyquinoline was used instead of 3-bromoquinoline 297.2 mg, 1.25 mmol). MS (IER) m/z - 358.2 (M+H)+

[0504] Step 2: (S)-7-methoxy-N-methyl-N-(pyrrolidin-3-yl)quinolin-3-amine hydrochloride

[0505] The title compound (145.5 mg, 100.0%) was prepared in the same manner as in Step 2 of Reference Example 5 and used in the next step without further purification.

[0506] Reference Example 64: (S)-8-methoxy-N-methyl-N-(pyrrolidin-3-yl)quinolin-3-amine hydrochloride

[0507] Step 1: tert-butyl (S)-3-((8-methoxyquinolin-3-yl)(methyl)amino)pyrrolidine-1-carboxylate

[0508] The title compound (359.9 mg, 80.7%) was prepared in the same manner as Step 1 of Reference Example 52 except that 3-bromo-8-methoxyquinoline (3-bromo-8-methoxyquinoline) was used instead of 3-bromoquinoline 297.2 mg, 1.25 mmol). MS (IER) m/z - 358.2 (M+H)+

[0509] Step 2: (S)-8-methoxy-N-methyl-N-(pyrrolidin-3-yl)quinolin-3-amine hydrochloride

[0510] The title compound (295.8 mg, 100.0%) was prepared in the same manner as in Step 2 of Reference Example 5 and used in the next step without further purification.

[0511] Reference Example 65: (S)-N,3-dimethyl-N-(pyrrolidin-3-yl)quinolin-5-amine hydrochloride

[0512] Step 1: tert-butyl (S)-3-((methyl (3-methylquinolin-5-yl)amino)pyrrolidine-1-carboxylate

[0513] The title compound (115.1 mg, 27.0%) was prepared in the same manner as Step 1 of Reference Example 52 except that 5-bromo-3-methylquinoline (5-bromo-3-methylquinoline) was used instead of 3-bromoquinoline 277.2 mg, 1.25 mmol). MS (IER) m/z - 342.2 (M+H)+

[0514] Step 2: (S)-N,3-dimethyl-N-(pyrrolidin-3-yl)quinolin-5-amine hydrochloride

[0515] The title compound (93.6 mg, 100.0%) was prepared in the same manner as in Step 2 of Reference Example 5 and used in the next step without further purification.

[0516] Reference Example 66: (S)-3-Fluoro-N-methyl-N-(pyrrolidin-3-yl)quinolin-5-amine hydrochloride

[0517] Step 1: tert-butyl (S)-3-((3-fluoroquinolin-5-yl)(methyl)amino)pyrrolidine-1-carboxylate

[0518] The title compound (286.6 mg, 66.5%) was prepared in the same manner as Step 1 of Reference Example 52 except that 5-bromo-3-fluoroquinoline (5-bromo-3-fluoroquinoline) was used instead of 3-bromoquinoline 282.2 mg, 1.25 mmol). MS (IER) m/z - 346.2 (M+H)+

[0519] Step 2: (S)-3-fluoro-N-methyl-N-(pyrrolidin-3-yl)quinolin-5-amine hydrochloride

[0520] The title compound (233.8 mg, 100.0%) was prepared in the same manner as in Step 2 of Reference Example 5 and used in the next step without further purification.

[0521] Reference Example 67: (S)-7-Fluoro-N-methyl-N-(pyrrolidin-3-yl)quinolin-5-amine hydrochloride

[0522] Step 1: tert-butyl (S)-3-((7-fluoroquinolin-5-yl)(methyl)amino)pyrrolidine-1-carboxylate

[0523] The title compound (223.7 mg, 51.9%) was prepared in the same manner as Step 1 of Reference Example 52 except that 5-bromo-7-fluoroquinoline (5-bromo-7-fluoroquinoline) was used instead of 3-bromoquinoline 282.2 mg, 1.25 mmol). MS (IER) m/z - 346.2 (M+H)+

[0524] Step 2: (S)-7-fluoro-N-methyl-N-(pyrrolidin-3-yl)quinolin-5-amine hydrochloride

[0525] The title compound (182.5 mg, 100.0%) was prepared in the same manner as in Step 2 of Reference Example 5 and used in the next step without further purification.

[0526] Reference Example 68: (S)-8-Fluoro-N-methyl-N-(pyrrolidin-3-yl)quinolin-5-amine hydrochloride

[0527] Step 1: tert-butyl (S)-3-((8-fluoroquinolin-5-yl)(methyl)amino)pyrrolidine-1-carboxylate

[0528] The title compound (209.9 mg, 48.7%) was prepared in the same manner as Step 1 of Reference Example 52 except that 5-bromo-8-fluoroquinoline (5-bromo-8-fluoroquinoline) was used instead of 3-bromoquinoline 282.2 mg, 1.25 mmol). MS (IER) m/z - 346.2 (M+H)+

[0529] Step 2: (S)-8-fluoro-N-methyl-N-(pyrrolidin-3-yl)quinolin-5-amine hydrochloride

[0530] The title compound (171.2 mg, 100.0%) was prepared in the same manner as in Step 2 of Reference Example 5 and used in the next step without further purification.

[0531] Reference Example 69: (S)-N-Methyl-N-(pyrrolidin-3-yl)-8-(trifluoromethyl)quinoline-5-amine hydrochloride

[0532] Step 1: tert-butyl (S)-3-((methyl(8-(trifluoromethyl)quinolin-5-yl)amino)pyrrolidine-1-carboxylate

[0533] The title compound (416.4 mg, 84.4%) was prepared in the same manner as Step 1 of Reference Example 52 except that 5-bromo-8-(trifluoromethyl) was used instead of 3-bromoquinoline )quinoline (344.6 mg, 1.25 mmol). MS (IER) m/z - 396.2 (M + H)+

[0534] Step 2: (S)-N-methyl-N-(pyrrolidin-3-yl)-8-(trifluoromethyl)quinoline-5-amine hydrochloride

[0535] The title compound (349.4 mg, 100.0%) was prepared in the same manner as in Step 2 of Reference Example 5 and used in the next step without further purification.

[0536] Reference Example 70: (S)-N-Methyl-N-(pyrroldin-3-yl)-8-(trifluoromethoxy)quinoline-5-amine hydrochloride

[0537] Step 1: tert-butyl (S)-3-((methyl(8-(trifluoromethoxy)quinolin-5-yl)amino)pyrrolidine-1-carboxylate

[0538] The title compound (432.5 mg, 84.2%) was prepared in the same manner as Step 1 of Reference Example 52 except that 5-bromo-8-trifluoromethoxyquinoline (5-bromo-8-trifluoromethoxyquinoline) was used instead of 3-bromoquinoline 364.6 mg, 1.25 mmol). MS (IER) m/z - 412.2 (M+H)+

[0539] Step 2: (S)-N-methyl-N-(pyrrolidin-3-yl)-8-(trifluoromethoxy)quinoline-5-amine hydrochloride

[0540] The title compound (365.6 mg, 100.0%) was prepared in the same manner as in Step 2 of Reference Example 5 and used in the next step without further purification.

[0541] Reference Example 71: (R)-N-(pyrrolidin-3-yl)quinoline-5-amine hydrochloride

[0542] Step 1: tert-butyl-(R)-3-(quinolin-5-ylamino)pyrrolidine-1-carboxylate

[0543] The title compound (589.6 mg, 70.0%) was prepared in the same manner as Step 1 of Reference Example 17 except that 5-bromoquinoline (558.5 mg) was used instead of 3-bromoquinoline , 2.68 mmol). MS (IER) m/z - 314.2 (M+H)+

[0544] Step 2: (R)-N-(pyrrolidin-3-yl)quinoline-5-amine hydrochloride

[0545] The title compound (466.5 mg, 86.6%) was prepared in the same manner as Step 2 of Reference Example 5. MS (ESI) m/z - 214.2 (M+H)+

[0546] Reference Example 72: (R)-N-(pyrrolidin-3-yl)quinolin-6-amine hydrochloride

[0547] Step 1: tert-butyl-(R)-3-(quinolin-6-ylamino)pyrrolidine-1-carboxylate

[0548] The title compound (389.3 mg, 46.3%) was prepared in the same manner as Step 1 of Reference Example 17 except that 6-bromoquinoline (558.5 mg) was used instead of 3-bromoquinoline , 2.68 mmol). MS (IER) m/z - 314.2 (M+H)+

[0549] Step 2: (R)-N-(pyrrolidin-3-yl)quinoline-6-amine hydrochloride

[0550] The title compound (298.1 mg, 94.1%) was prepared in the same manner as Step 2 of Reference Example 5. MS (ESI) m/z - 214.2 (M+H)+

[0551] Reference Example 73: (R)-N-(pyrrolidin-3-yl)quinoline-7-amine hydrochloride

[0552] Step 1: tert-butyl-(R)-3-(quinolin-7-ylamino)pyrrolidine-1-carboxylate

[0553] The title compound (356.5 mg, 42.4%) was prepared in the same manner as Step 1 of Reference Example 17 except that 7-bromoquinoline (558.5 mg) was used instead of 3-bromoquinoline , 2.68 mmol). MS (IER) m/z - 314.2 (M + H)+

[0554] Step 2: (R)-N-(pyrrolidin-3-yl)quinoline-7-amine hydrochloride

[0555] The title compound (261.9 mg, 82.6%) was prepared in the same manner as Step 2 of Reference Example 5. MS (ESI) m/z - 214.2 (M+H)+

[0556] Reference Example 74: (R)-N-(pyrrolidin-3-yl)quinoline-8-amine hydrochloride

[0557] Step 1: tert-butyl-(R)-3-(quinolin-8-ylamino)pyrrolidine-1-carboxylate

[0558] The title compound (692.6 mg, 82.3%) was prepared in the same manner as Step 1 of Reference Example 17 except that 8-bromoquinoline (558.5 mg) was used instead of 3-bromoquinoline , 2.68 mmol). MS (IER) m/z - 314.2 (M+H)+

[0559] Step 2: (R)-N-(pyrrolidin-3-yl)quinoline-8-amine hydrochloride

[0560] The title compound (589.4 mg, 93.1%) was prepared in the same manner as Step 2 of Reference Example 5. MS (ESI) m/z - 214.2 (M+H)+

[0561] Reference Example 75: (R)-N-(pyrrolidin-3-yl)quinolin-4-amine hydrochloride

[0562] Step 1: tert-butyl-(R)-3-(quinolin-4-ylamino)pyrrolidine-1-carboxylate

[0563] The title compound (490.9 mg, 58.4%) was prepared in the same manner as Step 1 of Reference Example 17 except that 4-bromoquinoline (558.5 mg) was used instead of 3-bromoquinoline , 2.68 mmol). MS (IER) m/z - 314.2 (M+H)+

[0564] Step 2: (R)-N-(pyrrolidin-3-yl)quinoline-4-amine hydrochloride

[0565] The title compound (195.4 mg, 43.6%) was prepared in the same manner as Step 2 of Reference Example 5. MS (ESI) m/z - 214.2 (M+H)+

[0566] Reference Example 76: (R)-N-(pyrrolidin-3-yl)-1,8-naphthyridin-3-amine hydrochloride

[0567] Step 1: tert-butyl (R)-3-((1,8-naphthyridin-3-yl)amino)pyrrolidine-1-carboxylate

[0568] The title compound (278.2 mg, 65.9%) was prepared in the same manner as Step 1 of Reference Example 17 except that 3-bromo-1,8- was used instead of 3-bromoquinoline naphthyridine (280.6 mg, 1.34 mmol). MS (IER) m/z - 315.1 (M+H)+

[0569] Step 2: (R)-N-(pyrrolidin-3-yl)-1,8-naphthyridin-3-amine hydrochloride

[0570] The title compound (254.2 mg, 100.0%) was prepared in the same manner as in Step 2 of Reference Example 5 and used in the next step without further purification.

[0571] Reference Example 77: (R)-7-chloro-N-(pyrrolidin-3-yl)-1,8-naphthyridin-3-amine hydrochloride

[0572] Step 1: tert-butyl (R)-3-((7-chloro-1,8-naphthyridin-3-yl)amino)pyrrolidine-1-carboxylate

[0573] The title compound (174.8 mg, 37.3%) was prepared in the same manner as Step 1 of Reference Example 17 except that 6-bromo-2-chloro-1 was used instead of 3-bromoquinoline ,8-naphthyridine (326.8 mg, 1.34 mmol). MS (IER) m/z - 349.1 (M + H)+

[0574] Step 2: (R)-7-chloro-N-(pyrrolidin-3-yl)-1,8-naphthyridin-3-amine hydrochloride

[0575] The title compound (161.2 mg, 100.0%) was prepared in the same manner as in Step 2 of Reference Example 5 and used in the next step without further purification.

[0576] Reference Example 78: (R)-6-Fluoro-N-(pyrrolidin-3-yl)quinolin-5-amine hydrochloride

[0577] Step 1: tert-butyl (R)-3-((6-fluoroquinolin-5-yl)amino)pyrrolidine-1-carboxylate

[0578] The title compound (187.1 mg, 42.1%) was prepared in the same manner as Step 1 of Reference Example 17 except that 5-bromo-6-fluoroquinoline (5-bromo-6-fluoroquinoline) was used instead of 3-bromoquinoline 303.4 mg, 1.34 mmol). MS (IER) m/z - 332.2 (M+H)+

[0579] Step 2: (R)-6-fluoro-N-(pyrrolidin-3-yl)quinoline-5-amine hydrochloride

[0580] The title compound (171.9 mg, 100.0%) was prepared in the same manner as in Step 2 of Reference Example 5 and used in the next step without further purification.

[0581] Reference Example 79: (R)-7-Fluoro-N-(pyrrolidin-3-yl)quinolin-5-amine hydrochloride

[0582] Step 1: tert-butyl (R)-3-((7-fluoroquinolin-5-yl)amino)pyrrolidine-1-carboxylate

[0583] The title compound (129.4 mg, 29.1%) was prepared in the same manner as Step 1 of Reference Example 17 except that 5-bromo-7-fluoroquinoline (5-bromo-7-fluoroquinoline) was used instead of 3-bromoquinoline 303.4 mg, 1.34 mmol). MS (IER) m/z - 332.2 (M+H)+

[0584] Step 2: (R)-7-fluoro-N-(pyrrolidin-3-yl)quinoline-5-amine hydrochloride

[0585] The title compound (118.6 mg, 100.0%) was prepared in the same manner as in Step 2 of Reference Example 5 and used in the next step without further purification.

[0586] Reference Example 80: (R)-8-Fluoro-N-(pyrrolidin-3-yl)quinolin-5-amine hydrochloride

[0587] Step 1: tert-butyl (R)-3-((8-fluoroquinolin-5-yl)amino)pyrrolidine-1-carboxylate

[0588] The title compound (330.4 mg, 74.3%) was prepared in the same manner as Step 1 of Reference Example 17 except that 5-bromo-8-fluoroquinoline (5-bromo-8-fluoroquinoline) was used instead of 3-bromoquinoline 303.4 mg, 1.34 mmol). MS (IER) m/z - 332.2 (M+H)+

[0589] Step 2: (R)-8-fluoro-N-(pyrrolidin-3-yl)quinoline-5-amine hydrochloride

[0590] The title compound (303.3 mg, 100.0%) was prepared in the same manner as in Step 2 of Reference Example 5 and used in the next step without further purification.

[0591] Reference Example 81: (R)-6-methoxy-N-(pyrrolidin-3-yl)quinolin-5-amine hydrochloride

[0592] Step 1: tert-butyl (R)-3-((6-methoxyquinolin-5-yl)amino)pyrrolidine-1-carboxylate

[0593] The title compound (427.4 mg, 92.7%) was prepared in the same manner as Step 1 of Reference Example 17 except that 5-bromo-6-methoxyquinoline (319) was used instead of 3-bromoquinoline .6 mg, 1.34 mmol). MS (IER) m/z - 344.2 (M + H)+

[0594] Step 2: (R)-6-methoxy-N-(pyrrolidin-3-yl)quinolin-5-amine hydrochloride

[0595] The title compound (393.7 mg, 100.0%) was prepared in the same manner as in Step 2 of Reference Example 5 and used in the next step without further purification.

[0596] Reference Example 82: (R)-7-methoxy-N-(pyrrolidin-3-yl)quinolin-5-amine hydrochloride

[0597] Step 1: tert-butyl (R)-3-((7-methoxyquinolin-5-yl)amino)pyrrolidine-1-carboxylate

[0598] The title compound (460.9 mg, 100.0%) was prepared in the same manner as Step 1 of Reference Example 17 except that 5-bromo-7 methoxyquinoline (319, 6 mg, 1.34 mmol). MS (IER) m/z - 344.2 (M+H)+

[0599] Step 2: (R)-7-methoxy-N-(pyrrolidin-3-yl)quinolin-5-amine hydrochloride

[0600] The title compound (424.4 mg, 100.0%) was prepared in the same manner as in Step 2 of Reference Example 5 and used in the next step without further purification.

[0601] Reference Example 83: (R)-8-methoxy-N-(pyrrolidin-3-yl)quinolin-5-amine hydrochloride

[0602] Step 1: tert-butyl (R)-3-((8-methoxyquinolin-5-yl)amino)pyrrolidine-1-carboxylate

[0603] The title compound (180.0 mg, 39.1%) was prepared in the same manner as Step 1 of Reference Example 17 except that 5-bromo-8 methoxyquinoline (319) was used instead of 3-bromoquinoline .6 mg, 1.34 mmol). MS (IER) m/z - 344.2 (M+H)+

[0604] Step 2: (R)-8-methoxy-N-(pyrrolidin-3-yl)quinoline-5-amine hydrochloride

[0605] The title compound (165.7 mg, 100.0%) was prepared in the same manner as in Step 2 of Reference Example 5 and used in the next step without further purification.

[0606] Reference Example 84: (R)-3-Methyl-N-(pyrrolidin-3-yl)quinolin-5-amine hydrochloride

[0607] Step 1: tert-butyl (R)-3-((3-methylquinolin-5-yl)amino)pyrrolidin-1-carboxylate

[0608] The title compound (314.2 mg, 71.5%) was prepared in the same manner as Step 1 of Reference Example 17 except that 5-bromo-3 methylquinoline (298) was used instead of 3-bromoquinoline .1 mg, 1.34 mmol). MS (IER) m/z - 328.2 (M+H)+

[0609] Step 2: (R)-3-methyl-N-(pyrrolidin-3-yl)quinolin-5-amine hydrochloride

[0610] The title compound (288.2 mg, 100.0%) was prepared in the same manner as in Step 2 of Reference Example 5 and used in the next step without further purification.

[0611] Reference Example 85: (R)-6-Methyl-N-(pyrrolidin-3-yl)quinolin-5-amine hydrochloride

[0612] Step 1: tert-butyl (R)-3-((6-methoxyquinolin-5-yl)amino)pyrrolidine-1-carboxylate

[0613] The title compound (419.0 mg, 95.3%) was prepared in the same manner as Step 1 of Reference Example 17 except that 5-bromo-6-methoxyquinoline (298) was used instead of 3-bromoquinoline .1 mg, 1.34 mmol). MS (IER) m/z - 328.2 (M + H)+

[0614] Step 2: (R)-6-methyl-N-(pyrrolidin-3-yl)quinolin-5-amine hydrochloride

[0615] The title compound (384.3 mg, 100.0%) was prepared in the same manner as in Step 2 of Reference Example 5 and used in the next step without further purification.

[0616] Reference Example 86: (R)-8-Methyl-N-(pyrrolidin-3-yl)quinolin-5-amine hydrochloride

[0617] Step 1: tert-butyl (R)-3-((8-methylquinolin-5-yl)amino)pyrrolidine-1-carboxylate

[0618] The title compound (290.5 mg, 66.1%) was prepared in the same manner as Step 1 of Reference Example 17 except that 5-bromo-8-methylquinoline was used instead of 3-bromoquinoline 298.1 mg, 1.34 mmol). MS (IER) m/z - 328.2 (M+H)+

[0619] Step 2: (R)-8-methyl-N-(pyrrolidin-3-yl)quinolin-5-amine hydrochloride

[0620] The title compound (266.3 mg, 100.0%) was prepared in the same manner as in Step 2 of Reference Example 5 and used in the next step without further purification.

[0621] Reference Example 87: (R)-N-(pyrrolidin-3-yl)-7-(trifluoromethyl)quinoline-5-amine hydrochloride

[0622] Step 1: tert-butyl (R)-3-((7-(trifluoromethyl)quinolin-5-yl)amino)pyrrolidine-1-carboxylate

[0623] The title compound (424.1 mg, 82.8%) was prepared in the same manner as Step 1 of Reference Example 17 except that 5-bromo-7-(trifluoromethyl) was used instead of 3-bromoquinoline quinoline (370.5 mg, 1.34 mmol). MS (IER) m/z - 382.2 (M+H)+

[0624] Step 2: (R)-N-(pyrrolidin-3-yl)-7-(trifluoromethyl)quinoline-5-amine hydrochloride

[0625] The title compound (393.9 mg, 100.0%) was prepared in the same manner as in Step 2 of Reference Example 5 and used in the next step without further purification.

[0626] Reference Example 88: (R)-N-(pyrrolidin-3-yl)-8-(trifluoromethyl)quinoline-5-amine hydrochloride

[0627] Step 1: tert-butyl (R)-3-((8-(trifluoromethyl)quinolin-5-yl)amino)pyrrolidine-1-carboxylate

[0628] The title compound (186.5 mg, 36.4%) was prepared in the same manner as Step 1 of Reference Example 17 except that 5-bromo-8-(trifluoromethyl) was used instead of 3-bromoquinoline )quinoline (370.5 mg, 1.34 mmol). MS (IER) m/z - 382.2 (M+H)+

[0629] Step 2: (R)-N-(pyrrolidin-3-yl)-8-(trifluoromethyl)quinoline-5-amine hydrochloride

[0630] The title compound (173.2 mg, 100.0%) was prepared in the same manner as in Step 2 of Reference Example 5 and used in the next step without further purification.

[0631] Reference Example 89: (R)-3-Fluoro-N-(pyrrolidin-3-yl)quinolin-5-amine hydrochloride

[0632] Step 1: tert-butyl (R)-3-((3-fluoroquinolin-5-yl)amino)pyrrolidine-1-carboxylate

[0633] The title compound (251.6 mg, 56.6%) was prepared in the same manner as Step 1 of Reference Example 17 except that 5-bromo-3-fluoroquinoline (303) was used instead of 3-bromoquinoline .4 mg, 1.34 mmol). MS (IER) m/z - 332.2 (M + H)+

[0634] Step 2: (R)-3-fluoro-N-(pyrrolidin-3-yl)quinoline-5-amine hydrochloride

[0635] The title compound (230.9 mg, 100.0%) was prepared in the same manner as in Step 2 of Reference Example 5 and used in the next step without further purification.

[0636] Reference Example 90: (R)-3-chloro-N-(pyrrolidin-3-yl)quinolin-5-amine hydrochloride

[0637] Step 1: tert-butyl (R)-3-((3-chloroquinolin-5-yl)amino)pyrrolidine-1-carboxylate

[0638] The title compound (320.1 mg, 68.6%) was prepared in the same manner as Step 1 of Reference Example 17 except that 5-bromo-3-chloroquinoline (5-bromo-3-chloroquinoline) was used instead of 3-bromoquinoline 325.5 mg, 1.34 mmol). MS (IER) m/z - 348.2 (M+H)+

[0639] Step 2: (R)-3-chloro-N-(pyrrolidin-3-yl)quinoline-5-amine hydrochloride

[0640] The title compound (295.0 mg, 100.0%) was prepared in the same manner as in Step 2 of Reference Example 5 and used in the next step without further purification.

[0641] Reference Example 91: (R)-N-(pyrrolidin-3-yl)-8-(trifluoromethoxy)quinoline-5-amine hydrochloride

[0642] Step 1: tert-butyl (R)-3-((8-(trifluoromethoxy)quinolin-5-yl)amino)pyrrolidine-1-carboxylate

[0643] The title compound (470.2 mg, 88.2%) was prepared in the same manner as Step 1 of Reference Example 17 except that 5-bromo-8-trifluoromethoxyquinoline (5-bromo-8-trifluoromethoxyquinoline) was used instead of 3-bromoquinoline 392.0 mg, 1.34 mmol). MS (IER) m/z - 398.2 (M+H)+

[0644] Step 2: (R)-N-(pyrrolidin-3-yl)-8-(trifluoromethoxy)quinoline-5-amine hydrochloride

[0645] The title compound (438.0 mg, 100.0%) was prepared in the same manner as in Step 2 of Reference Example 5 and used in the next step without further purification.

[0646] Reference Example 92: (R)-6-Methyl-N-(pyrrolidin-3-yl)quinolin-4-amine hydrochloride

[0647] Step 1: tert-butyl (R)-3-((6-methylquinolin-4-yl)amino)pyrrolidine-1-carboxylate

[0648] The title compound (47.1 mg, 10.7%) was prepared in the same manner as Step 1 of Reference Example 17 except that 4-bromo-6-methylquinoline ( 4-bromo-6-methylquinoline) was used instead of 3-bromoquinoline 298.1 mg, 1.34 mmol). MS (IER) m/z - 328.2 (M+H)+

[0649] Step 2: (R)-6-methyl-N-(pyrrolidin-3-yl)quinolin-4-amine hydrochloride

[0650] The title compound (43.2 mg, 100.0%) was prepared in the same manner as in Step 2 of Reference Example 5 and used in the next step without further purification.

[0651] Reference Example 93: (R)-6-methoxy-N-(pyrrolidin-3-yl)quinolin-4-amine hydrochloride

[0652] Step 1: tert-butyl (R)-3-((6-methoxyquinolin-4-yl)amino)pyrrolidine-1-carboxylate

[0653] The title compound (326.8 mg, 70.9%) was prepared in the same manner as Step 1 of Reference Example 17 except that 4-bromo-6-methoxyquinoline (319) was used instead of 3-bromoquinoline .6 mg, 1.34 mmol). MS (IER) m/z - 344.1 (M + H)+

[0654] Step 2: (R)-6-methoxy-N-(pyrrolidin-3-yl)quinolin-4-amine hydrochloride

[0655] The title compound (301.1 mg, 100.0%) was prepared in the same manner as in Step 2 of Reference Example 5 and used in the next step without further purification.

[0656] Reference Example 94: (R)-8-chloro-N-(pyrrolidin-3-yl)quinolin-4-amine hydrochloride

[0657] Step 1: tert-butyl (R)-3-((8-chloroquinolin-4-yl)amino)pyrrolidine-1-carboxylate

[0658] The title compound (126.9 mg, 27.2%) was prepared in the same manner as Step 1 of Reference Example 17 except that 4-bromo-8-chloroquinoline was used instead of 3-bromoquinoline 325.5 mg, 1.34 mmol). MS (IER) m/z - 348.2 (M+H)+

[0659] Step 2: (R)-8-chloro-N-(pyrrolidin-3-yl)quinoline-4-amine hydrochloride

[0660] The title compound (117.0 mg, 100.0%) was prepared in the same manner as in Step 2 of Reference Example 5 and used in the next step without further purification.

[0661] Reference Example 95: (R)-8-Methyl-N-(pyrrolidin-3-yl)quinolin-4-amine hydrochloride

[0662] Step 1: tert-butyl (R)-3-((8-methylquinolin-4-yl)amino)pyrrolidine-1-carboxylate

[0663] The title compound (425.0 mg, 96.7%) was prepared in the same manner as Step 1 of Reference Example 17 except that 4-bromo-8-methylquinoline was used instead of 3-bromoquinoline 298.1 mg, 1.34 mmol). MS (IER) m/z - 328.2 (M+H)+

[0664] Step 2: (R)-8-methyl-N-(pyrrolidin-3-yl)quinolin-4-amine hydrochloride

[0665] The title compound (406.2 mg, 100.0%) was prepared in the same manner as in Step 2 of Reference Example 5 and used in the next step without further purification.

[0666] Reference Example 96: (R)-6-Fluoro-N-(pyrrolidin-3-yl)quinolin-4-amine hydrochloride

[0667] Step 1: tert-butyl (R)-3-((6-fluoroquinolin-4-yl)amino)pyrrolidine-1-carboxylate

[0668] The title compound (367.0 mg, 82.7%) was prepared in the same manner as Step 1 of Reference Example 17 except that 4-bromo-6-fluoroquinoline ( 4-bromo-6-fluoroquinoline) was used instead of 3-bromoquinoline 303.4 mg, 1.34 mmol). MS (IER) m/z - 332.2 (M+H)+

[0669] Step 2: (R)-6-fluoro-N-(pyrrolidin-3-yl)quinoline-4-amine hydrochloride

[0670] The title compound (337.7 mg, 100.0%) was prepared in the same manner as in Step 2 of Reference Example 5 and used in the next step without further purification.

[0671] Reference Example 97: (R)-6-chloro-N-(pyrrolidin-3-yl)quinolin-4-amine hydrochloride

[0672] Step 1: tert-butyl (R)-3-((6-chloroquinolin-4-yl)amino)pyrrolidine-1-carboxylate

[0673] The title compound (298.1 mg, 63.9%) was prepared in the same manner as Step 1 of Reference Example 17 except that 4-bromo-6-chloroquinoline was used instead of 3-bromoquinoline 325.5 mg, 1.34 mmol). MS (IER) m/z - 348.1 (M+H)+

[0674] Step 2: (R)-6-chloro-N-(pyrrolidin-3-yl)quinoline-4-amine hydrochloride

[0675] The title compound (274.8 mg, 100.0%) was prepared in the same manner as in Step 2 of Reference Example 5 and used in the next step without further purification.

[0676] Reference Example 98: (R)-7-methoxy-N-(pyrrolidin-3-yl)quinolin-4-amine hydrochloride

[0677] Step 1: tert-butyl (R)-3-((7-methoxyquinolin-4-yl)amino)pyrrolidine-1-carboxylate

[0678] The title compound (423.5 mg, 91.9%) was prepared in the same manner as Step 1 of Reference Example 17 except that 4-bromo-7-methoxy- quinoline (319.6 mg, 1.34 mmol). MS (IER) m/z - 344.2 (M+H)+

[0679] Step 2: (R)-7-methoxy-N-(pyrrolidin-3-yl)quinolin-4-amine hydrochloride

[0680] The title compound (358.2 mg, 100.0%) was prepared in the same manner as in Step 2 of Reference Example 5 and used in the next step without further purification.

[0681] Reference Example 99: (R)-8-Fluoro-N-(pyrrolidin-3-yl)quinolin-4-amine hydrochloride

[0682] Step 1: tert-butyl (R)-3-((8-fluoroquinolin-4-yl)amino)pyrrolidine-1-carboxylate

[0683] The title compound (444.7 mg, 100.0%) was prepared in the same manner as Step 1 of Reference Example 17 except that 4-bromo-8-fluoroquinoline ( 4-bromo-8-fluoroquinoline) was used instead of 3-bromoquinoline 303.4 mg, 1.34 mmol). MS (IER) m/z - 332.2 (M+H)+

[0684] Step 2: (R)-8-fluoro-N-(pyrrolidin-3-yl)quinoline-4-amine hydrochloride

[0685] The title compound (418.0 mg, 100.0%) was prepared in the same manner as in Step 2 of Reference Example 5 and used in the next step without further purification.

[0686] Reference Example 100: (R)-8-methoxy-N-(pyrrolidin-3-yl)quinolin-4-amine hydrochloride

[0687] Step 1: tert-butyl (R)-3-((8-methoxyquinolin-4-yl)amino)pyrrolidine-1-carboxylate

[0688] The title compound (348.5 mg, 75.6%) was prepared in the same manner as Step 1 of Reference Example 17 except that 4-bromo-8-methoxyquinoline was used instead of 3-bromoquinoline 319.6 mg, 1.34 mmol). MS (IER) m/z - 344.2 (M+H)+

[0689] Step 2: (R)-8-methoxy-N-(pyrrolidin-3-yl)quinolin-4-amine hydrochloride

[0690] The title compound (316.4 mg, 100.0%) was prepared in the same manner as in Step 2 of Reference Example 5 and used in the next step without further purification.

[0691] Reference Example 101: (R)-N-(pyrrolidin-3-yl)-8-(trifluoromethyl)quinoline-4-amine hydrochloride

[0692] Step 1: tert-butyl (R)-3-((8-(trifluoromethyl)quinolin-4-yl)amino)pyrrolidine-1-carboxylate

[0693] The title compound (511.8 mg, 100.0%) was prepared in the same manner as Step 1 of Reference Example 17 except that 4-bromo-8(trifluoromethyl) was used instead of 3-bromoquinoline quinoline (370.5 mg, 1.34 mmol). MS (IER) m/z - 382.2 (M+H)+

[0694] Step 2: (R)-N-(pyrrolidin-3-yl)-8-(trifluoromethyl)quinoline-4-amine hydrochloride

[0695] The title compound (499.4 mg, 100.0%) was prepared in the same manner as in Step 2 of Reference Example 5 and used in the next step without further purification.

[0696] Reference Example 102: (R)-3-methoxy-N-(pyrrolidin-3-yl)quinolin-5-amine hydrochloride

[0697] Step 1: tert-butyl (R)-3-((3-methoxyquinolin-5-yl)amino)pyrrolidine-1-carboxylate

[0698] The title compound (662.7 mg, 71.9%) was prepared in the same manner as Step 1 of Reference Example 17 except that 5-bromo-3-methoxyquinoline was used instead of 3-bromoquinoline 639.1 mg, 2.69 mmol). MS (IER) m/z - 344.2 (M+H)+

[0699] Step 2: (R)-3-methoxy-N-(pyrrolidin-3-yl)quinolin-5-amine hydrochloride

[0700] The title compound (610.3 mg, 100.0%) was prepared in the same manner as in Step 2 of Reference Example 5 and used in the next step without further purification.

[0701] Reference Example 103: (R)-2-chloro-N-(pyrrolidin-3-yl)quinolin-6-amine hydrochloride

[0702] Step 1: tert-butyl (R)-3-((2-chloroquinolin-6-yl)amino)pyrrolidine-1-carboxylate

[0703] The title compound (720.5 mg, 77.2%) was prepared in the same manner as Step 1 of Reference Example 17 except that 2-chloro-6-bromoquinoline was used instead of 3-bromoquinoline ( 651.0 mg, 2.69 mmol). MS (IER) m/z - 348.2 (M+H)+

[0704] Step 2: (R)-2-chloro-N-(pyrrolidine-3-ip)quinoline-6-amine hydrochloride

[0705] The title compound (618.5 mg, 100.0%) was prepared in the same manner as in Step 2 of Reference Example 5 and used in the next step without further purification.

[0706] Reference Example 104: (R)-N-(pyrrolidin-3-yl)-2-(trifluoromethyl)quinoline-6-amine hydrochloride

[0707] Step 1: tert-butyl (R)-3-((2-(trifluoromethyl)quinolin-6-yl)amino)pyrrolidine-1-carboxylate

[0708] The title compound (408.1 mg, 79.7%) was prepared in the same manner as Step 1 of Reference Example 17 except that 6-bromo-2-(trifluoromethyl) was used instead of 3-bromoquinoline )quinoline (370.5 mg, 1.34 mmol). MS (IER) m/z - 382.2 (M+H)+

[0709] Step 2: (R)-N-(1 hydrolidin-3-yl)-2-(trifluoromethyl)quinoline-6-amine hydrochloride

[0710] The title compound (379.0 mg, 100.0%) was prepared in the same manner as in Step 2 of Reference Example 5 and used in the next step without further purification.

[0711] Reference Example 105: (R)-3-Methyl-N-(pyrrolidin-3-yl)quinolin-6-amine hydrochloride

[0712] Step 1: tert-butyl (R)-3-((3-methylquinolin-6-yl)amino)pyrrolidine-1-carboxylate

[0713] The title compound (328.0 mg, 74.6%) was prepared in the same manner as Step 1 of Reference Example 17 except that 6-bromo-3-methylquinoline was used instead of 3-bromoquinoline 298.1 mg, 1.34 mmol). MS (IER) m/z - 328.2 (M+H)+

[0714] Step 2: (R)-3-methyl-N-(pyrrolidin-3-yl)quinolin-6-amine hydrochloride

[0715] The title compound (300.8 mg, 100.0%) was prepared in the same manner as in Step 2 of Reference Example 5 and used in the next step without further purification.

[0716] Reference Example 106: (R)-4-methoxy-N-(pyrrolidin-3-yl)quinolin-6-amine hydrochloride

[0717] Step 1: tert-butyl (R)-3-((4-methoxyquinolin-7-yl)amino)pyrrolidine-1-carboxylate

[0718] The title compound (239.7 mg, 52.0%) was prepared in the same manner as Step 1 of Reference Example 17 except that 6-bromo-4-methoxy- quinoline (319.6 mg, 1.34 mmol). MS (IER) m/z - 344.2 (M+H)+

[0719] Step 2: (R)-4-methoxy-N-(pyrrolidin-3-yl)quinolin-6-amine hydrochloride

[0720] The title compound (220.7 mg, 100.0%) was prepared in the same manner as in Step 2 of Reference Example 5 and used in the next step without further purification.

[0721] Reference Example 107: (R)-8-Methyl-N-(pyrrolidin-3-yl)quinolin-6-amine hydrochloride

[0722] Step 1: tert-butyl (R)-3-((8-methylquinolin-6-yl)amino)pyrrolidine-1-carboxylate

[0723] The title compound (258.6 mg, 58.8%) was prepared in the same manner as Step 1 of Reference Example 17 except that 6-bromo-8-methylquinoline ( 6-bromo-8-methylquinoline) was used instead of 3-bromoquinoline 298.1 mg, 1.34 mmol). MS (IER) m/z - 328.2 (M+H)+

[0724] Step 2: (R)-8-methyl-N-(pyrrolidin-3-yl)quinolin-6-amine hydrochloride

[0725] The title compound (238.2 mg, 100.0%) was prepared in the same manner as in Step 2 of Reference Example 5 and used in the next step without further purification.

[0726] Reference Example 108: (R)-8-chloro-N-(pyrrolidin-3-yl)quinolin-6-amine hydrochloride

[0727] Step 1: tert-butyl (R)-3-((8-chloroquinolin-6-yl)amino)pyrrolidine-1-carboxylate

[0728] The title compound (311.9 mg, 66.8%) was prepared in the same manner as Step 1 of Reference Example 17 except that 6-bromo-8-chloroquinoline was used instead of 3-bromoquinoline 325.5 mg, 1.34 mmol). MS (IER) m/z - 348.1 (M+H)+

[0729] Step 2: (R)-8-chloro-N-(pyrrolidin-3-yl)quinoline-6-amine hydrochloride

[0730] The title compound (287.6 mg, 100.0%) was prepared in the same manner as in Step 2 of Reference Example 5 and used in the next step without further purification.

[0731] Reference Example 109: (R)-N-(pyrrolidin-3-yl)-8-(trifluoromethyl)quinoline-6-amine hydrochloride

[0732] Step 1: tert-butyl (R)-3-((8-(trifluoromethyl)quinolin-6-yl)amino)pyrrolidine-1-carboxylate

[0733] The title compound (424.5 mg, 82.9%) was prepared in the same manner as Step 1 of Reference Example 17 except that 6-bromo-8-(trifluoromethyl) was used instead of 3-bromoquinoline )quinoline (370.5 mg, 1.34 mmol). MS (IER) m/z - 382.1 (M+H)+

[0734] Step 2: (R)-N-(pyrrolidin-3-yl)-8-(trifluoromethyl)quinoline-6-amine hydrochloride

[0735] The title compound (394.2 mg, 100.0%) was prepared in the same manner as in Step 2 of Reference Example 5 and used in the next step without further purification.

[0736] Reference Example 110: (R)-8-Fluoro-N-(pyrrolidin-3-yl)quinolin-6-amine hydrochloride

[0737] Step 1: tert-butyl (R)-3-((8-fluoroquinolin-6-yl)amino)pyrrolidine-1-carboxylate

[0738] The title compound (167.0 mg, 37.5%) was prepared in the same manner as Step 1 of Reference Example 17 except that 6-bromo-8-fluoroquinoline ( 6-bromo-8-fluoroquinoline) was used instead of 3-bromoquinoline 303.4 mg, 1.34 mmol). MS (IER) m/z - 332.2 (M+H)+

[0739] Step 2: (R)-8-fluoro-N-(pyrrolidin-3-yl)quinoline-6-amine hydrochloride

[0740] The title compound (153.3 mg, 100.0%) was prepared in the same manner as in Step 2 of Reference Example 5 and used in the next step without further purification.

[0741] Reference Example 111: (S)-N-(pyrrolidin-3-yl)quinoline-6-amine hydrochloride

[0742] Step 1: tert-butyl (S)-3-(quinolin-6-ylamino)pyrrolidine-1-carboxylate

[0743] The title compound (610.0 mg, 72.5%) was prepared in the same manner as Step 1 of Reference Example 5 except that 6-bromoquinoline (558.5 mg) was used instead of 4-bromoquinoline , 2.68 mmol). MS (IER) m/z - 314.2 (M+H)+

[0744] Step 2: (S)-T^-(pyrrolidin-3-yl)quinolin-6-amine hydrochloride

[0745] The title compound (102.0 mg, 61.3%) was prepared in the same manner as in Step 2 of Reference Example 5 and used in the next step without further purification. MS (IER) m/z - 214.2 (M+H)+

[0746] Reference Example 112: (S)-5-(pyrrolidin-3-ylamino)quinoline-2-carbonitrile hydrochloride

[0747] Step 1: tert-butyl (S)-3-((2-cyanoquinolin-5-yl)amino)pyrrolidin-1-carboxylate

[0748] The title compound (818 mg, 90.0%) was prepared in the same manner as Step 1 of Reference Example 5 except that 5-bromoquinoline-2-carbonitrile (625, 6 mg, 2.68 mmol). MS (IER) m/z - 339.2 (M+H)+

[0749] Step 2: (S)-5-(pyrrolidin-3-ylamino)quinoline-2-carbonitrile hydrochloride

[0750] The title compound (200.2 mg, 66.5%) was prepared in the same manner as in Step 2 of Reference Example 5 and used in the next step without further purification.

[0751] Reference Example 113: (S)-5-(pyrrolidin-3-ylamino)quinoline-3-carbonitrile hydrochloride

[0752] Step 1: tert-butyl (S)-3-((3-cyanoquinolin-5-yl)amino)pyrrolidine-1-carboxylate

[0753] The title compound (698.0 mg, 76.8%) was prepared in the same manner as Step 1 of Reference Example 5 except that 5-bromoquinoline-3-carbonitrile was used instead of 4-bromoquinoline 625.6 mg, 2.68 mmol). MS (IER) m/z - 339.2 (M+H)+

[0754] Step 2: (S)-5-(pyrrolidin-3-ylamino)quinoline-3-carbonitrile hydrochloride

[0755] The title compound (143.2 mg, 47.9%) was prepared in the same manner as Step 2 of Reference Example 5 and used in the next step without further purification

[0756] Reference Example 114: (S)-3-methoxy-N-(pyrrolidin-3-yl)quinolin-5-amine hydrochloride

[0757] Step 1: tert-butyl (S)-3-((3-methoxyquinolin-5-yl)amino)pyrrolidine-1-carboxylate

[0758] The title compound (446.2 mg, 48.4%) was prepared in the same manner as Step 1 of Reference Example 5 except that 5-bromo-3-methoxyquinoline (5-bromo-3-methoxyquinoline) was used instead of 4-bromoquinoline 639.2 mg, 2.68 mmol). MS (IER) m/z - 344.2 (M+H)+

[0759] Step 2: (S)-3-methoxy-N-(pyrrolidin-3-yl)quinolin-5-amine hydrochloride

[0760] The title compound (187.5 mg, 59.3%) was prepared in the same manner as Step 2 of Reference Example 5 and used in the next step without further purification

[0761] Reference Example 115: (S)-3-Fluoro-N-(pyrrolidin-3-yl)quinolin-5-amine hydrochloride

[0762] Step 1: tert-butyl (S)-3-((3-fluoroquinolin-5-yl)amino)pyrrolidine-1-carboxylate

[0763] The title compound (668.7 mg, 75.1%) was prepared in the same manner as Step 1 of Reference Example 5 except that 5-bromo-3-fluoroquinoline (5-bromo-3-fluoroquinoline) was used instead of 4-bromoquinoline 606.8 mg, 2.68 mmol). MS (IER) m/z - 333.1 (M+H)+

[0764] Stage 2:. (S)-3-fluoro-N-(pyrrolidin-3-yl)quinoline-5-amine hydrochloride

[0765] The title compound (392.5 mg, 63.9%) was prepared in the same manner as Step 2 of Reference Example 5 and used in the next step without further purification

[0766] Reference Example 116: (S)-3-chloro-1M-(pyrrolidin-3-yl)quinolin-5-amine hydrochloride

[0767] Step 1: tert-butyl (S)-3-((3-chloroquinolin-5-yl)amino)pyrrolidine-1-carboxylate

[0768] The title compound (613.0 mg, 65.6%) was prepared in the same manner as Step 1 of Reference Example 5 except that 5-bromo-3-chloroquinoline (5-bromo-3-chloroquinoline) was used instead of 4-bromoquinoline 651.0 mg, 2.68 mmol). MS (IER) m/z - 348.2 (M+H)+

[0769] Step 2: (S)-3-chloro-N-(pyrrolidin-3-yl)quinoline-5-amine hydrochloride

[0770] The title compound (163.7 mg, 28.9%) was prepared in the same manner as Step 2 of Reference Example 5 and used in the next step without further purification

[0771] Reference Example 117: (S)-7-Fluoro-N-(pyrrolidin-3-yl)quinolin-5-amine hydrochloride

[0772] Step 1: tert-butyl (S)-3-((7-fluoroquinolin-5-yl)amino)pyrrolidine-1-carboxylate

[0773] The title compound (875.0 mg, 98.3%) was prepared in the same manner as Step 1 of Reference Example 5, except that 5-bromo-7-fluoroquinoline (5-bromo-7-fluoroquinoline) was used instead of 4-bromoquinoline 606.8 mg, 2.68 mmol). MS (IER) m/z - 333.1 (M+H)+

[0774] Step 2: (S)-7-fluoro-N-(pyrrolidin-3-yl)quinoline-5-amine hydrochloride

[0775] The title compound (250.0 mg, 38.3%) was prepared in the same manner as in Step 2 of Reference Example 5 and used in the next step without further purification

[0776] Reference Example 118: (S)-7-methoxy-N-(pyrrolidin-3-yl)quinolin-5-amine hydrochloride

[0777] Step 1: tert-butyl (S)-3-((7-methoxyquinolin-5-yl)amino)pyrrolidine-1-carboxylate

[0778] The title compound (848.2 mg, 92.0%) was prepared in the same manner as Step 1 of Reference Example 5 except that 5-bromo-7-methoxyquinoline (5-bromo-7-methoxyquinoline) was used instead of 4-bromoquinoline 639.2 mg, 2.68 mmol). ^1H -NMR ( _CDCl3 , 400 MHz) δ 8.78 (d, 1H), 8.02 (d, 1H), 7.19 (dd, 1H), 6.89 (s, 1H), 6, 28 (s, 1H), 4.43 (d, 1H), 4.15 (s, 1H), 3.93 (s, 3H), 3.79 (s, 1H), 3.56-3.36 (m, 3H), 2.27 (s, 1H), 2.05-1.93 (m, 1H), 1.47 (s, 9H).

[0779] Step 2: (S)-7-methoxy-N-(pyrrolidin-3-yl)quinoline-5-amine hydrochloride

[0780] The title compound (485.0 mg, 62.0%) was prepared in the same manner as in Step 2 of Reference Example 5 and used in the next step without further purification

[0781] Reference Example 119: (S)-N-(pyrrolidin-3-yl)-7-(trifluoromethyl)quinoline-5-amine hydrochloride

[0782] Step 1: tert-butyl (S)-3-((7-(trifluoromethyl)quinolin-5-yl)amino)pyrrolidine-1-carboxylate

[0783] The title compound (888.5 mg, 86.7%) was prepared in the same manner as Step 1 of Reference Example 5 except that 5-bromo-7-(trifluoromethyl) was used instead of 4-bromoquinoline )quinoline (741.1 mg, 2.68 mmol). ^1H -NMR ( _CDCl3 , 400 MHz) δ 8.97 (d, 1H), 8.19 (d, 1H), 7.80 (s, 1H), 7.47-7.44 (m, 1H ), 6.73 (s, 1H), 4.63 (s, 1H), 4.26 (s, 1H), 3.83 (s, 1H), 3.59-3.39 (m, 3H) , 2.37-2.29 (m, 1H) 2.07-2.05 (m, 1H), 1.49 (s, 9H).

[0784] Step 2: (S)-N-(pyrrolidin-3-yl)-7-(trifluoromethyl)quinoline-5-amine hydrochloride

[0785] The title compound (325.0 mg, 39.3%) was prepared in the same manner as in Step 2 of Reference Example 5 and used in the next step without further purification

[0786] Reference Example 120: (S)-6-Methyl-N-(pyrrolidin-3-yl)quinolin-5-amine hydrochloride

[0787] Step 1: tert-butyl (S)-3-((6-methylquinolin-5-yl)amino)pyrrolidine-1-carboxylate

[0788] The title compound (683.2 mg, 77.7%) was prepared in the same manner as Step 1 of Reference Example 5 except that 5-bromo-6-methylquinoline (5-bromo-6-methylquinoline) was used instead of 4-bromoquinoline 596.2 mg, 2.68 mmol). ^1H -NMR ( _CDCl3 , 400 MHz) δ 8.84 (d, 1H), 8.39 (d, 1H), 7.75 (d, 1H), 7.52 (d, 1H), 7. 37 (d, 1H), 3.97 (s, 1H), 3.64-3.29 (m, 5H), 2.43 (s, 3H), 2.15-1.97 (m, 2H ), 1.48-1.45 (s, 9H)

[0789] Step 2: (S)-6-methyl-N-(pyrrolidin-3-yl)quinoline-5-amine hydrochloride

[0790] The title compound (495.0 mg, 79.0%) was prepared in the same manner as Step 2 of Reference Example 5 and used in the next step without further purification

[0791] Reference Example 121: (S)-6-methoxy-N-(pyrrolidin-3-yl)quinolin-5-amine hydrochloride

[0792] Step 1: tert-butyl (S)-3-((6-methoxyquinolin-5-yl)amino)pyrrolidine-1-carboxylate

[0793] The title compound (378.5 mg, 41.0%) was prepared in the same manner as Step 1 of Reference Example 5 except that 5-bromo-6-methoxyquinoline (5-bromo-6-methoxyquinoline) was used instead of 4-bromoquinoline 639.2 mg, 2.68 mmol). ^1H -NMR ( _CDCl3 , 400 MHz) δ 8.78 (s, 1H), 8.39 (d, 1H), 7.83 (d, 1H), 7.48 (d, 1H), 7. 35-7.33 (m, 1H), 4.00-3.97 (m, 4 N), 3.61-3.31 (m, 5 N), 2.05-1.90 (m, 2H ), 1.48-1.46 (s, 9H).

[0794] Step 2: (S)-6-methoxy-N-(pyrrolidin-3-yl)quinoline-5-amine hydrochloride

[0795] The title compound (248.5 mg, 71.2%) was prepared in the same manner as in Step 2 of Reference Example 5 and used in the next step without further purification

[0796] Reference Example 122: (S)-6-Fluoro-N-(pyrrolidin-3-yl)quinolin-5-amine hydrochloride

[0797] Step 1: tert-butyl (S)-3-((6-fluoroquinolin-5-yl)amino)pyrrolidine-1-carboxylate

[0798] The title compound (344.7 mg, 38.7%) was prepared in the same manner as Step 1 of Reference Example 5 except that 5-bromo-6-fluoroquinoline (5-bromo-6-fluoroquinoline) was used instead of 4-bromoquinoline 606.8 mg, 2.68 mmol). ^1H -NMR ( _CDCl3 , 400 MHz) δ 8.88 (s, 1H), 8.37 (d, 1H), 7.75 (s, 1H), 7.49 (t, 1H), 7. 41 (dd, 1H), 4.14 (d, 1H), 3.69-3.36 (m, 5H), 2.16-2.08 (m, 1H), 1.93 (s, 1H ), 1.48-1.46 (m, 9H).

[0799] Step 2: (S)-6-fluoro-N-(pyrrolidin-3-yl)quinoline-5-amine hydrochloride

[0800] The title compound (251.7 mg, 79.5%) was prepared in the same manner as in Step 2 of Reference Example 5 and used in the next step without further purification

[0801] Reference Example 123: (S)-8-Methyl-N-(pyrrolidin-3-yl)quinolin-5-amine hydrochloride

[0802] Step 1: tert-butyl (S)-3-((8-methylquinolin-5-yl)amino)pyrrolidine-1-carboxylate

[0803] The title compound (631.0 mg, 71.7%) was prepared in the same manner as Step 1 of Reference Example 5 except that 5-bromo-8-methylquinoline (5-bromo-8-methylquinoline) was used instead of 4-bromoquinoline 596.2 mg, 2.68 mmol). ^1H -NMR ( _CDCl3 , 400 MHz) δ 8.94 (d, 1H), 8.17 (d, 1H), 7.41 (s, 1H), 7.36 (dd, 1H), 6, 60 (d, 1H), 4.19 (s, 2H), 3.83-3.78 (m, 1H), 3.56-3.48 (m, 2H), 3.40-3.32 ( m, 1H), 2.69 (s, 3H), 2.27 (m, 1H), 2.04 (s, 1H), 1.47 (s, 9H).

[0804] Step 2: (S)-8-methyl-N-(pyrrolidin-3-yl)quinoline-5-amine hydrochloride

[0805] The title compound (489.3 mg, 84.5%) was prepared in the same manner as Step 2 of Reference Example 5 and used in the next step without further purification

[0806] Reference Example 124: (S)-8-methoxy-N-(pyrrolidin-3-yl)quinolin-5-amine hydrochloride

[0807] Step 1: tert-butyl (S)-3-((8-methoxyquinolin-5-yl)amino)pyrrolidine-1-carboxylate

[0808] The title compound (712.0 mg, 77.2%) was prepared in the same manner as Step 1 of Reference Example 5 except that 5-bromo-8-methoxyquinoline (5-bromo-8-methoxyquinoline) was used instead of 4-bromoquinoline 639.2 mg, 2.68 mmol). ^1H -NMR ( _CDCl3 , 400 MHz) δ 8.94 (d, 1H), 8.20 (d, 1H), 7.42 (dd, 1H), 6.96 (s, 1H), 6, 64 (d, 1H), 4.15-4.13 (m, 1H), 4.04 (s, 3H), 3.88-3.76 (m, 2H), 3.49-3.33 ( m, 3H), 2.29-2.24 (m, 1H), 2.05-2.02 (m, 1H), 1.47 (s, 9H).

[0809] Step 2: (S)-8-methoxy-N-(pyrrolidin-3-yl)quinoline-5-amine hydrochloride

[0810] The title compound (505.5 mg, 77.0%) was prepared in the same manner as in Step 2 of Reference Example 5 and used in the next step without further purification

[0811] Reference Example 125: (S)-8-Fluoro-N-(pyrrolidin-3-yl)quinolin-5-amine hydrochloride

[0812] Step 1: tert-butyl (S)-3-((8-fluoroquinolin-5-yl)amino)pyrrolidine-1-carboxylate

[0813] The title compound (852.0 mg, 95.7%) was prepared in the same manner as Step 1 of Reference Example 5 except that 5-bromo-8-fluoroquinoline (5-bromo-8-fluoroquinoline) was used instead of 4-bromoquinoline 606.8 mg, 2.68 mmol). ^1H -NMR ( _CDCl3 , 400 MHz) δ 8.95 (d, 1H), 8.20 (d, 1H), 7.43 (dd, 1H), 7.29 (t, 1H), 6, 55 (dd, 1H), 4.17 (s, 2H), 3.81 (s, 1H), 3.56-3.35 (m, 3H), 2.28 (s, 1H), 2.04 (s, 1H), 1.47 (s, 9H).

[0814] Step 2: (S)-8-fluoro-1M-(pyrrolidin-3-yl)quinoline-5-amine hydrochloride

[0815] The title compound (556.6 mg, 71.2%) was prepared in the same manner as Step 2 of Reference Example 5 and used in the next step without further purification

[0816] Reference Example 126: (S)-N-(pyrrolidin-3-yl)-8-(trifluoromethyl)quinoline-5-amine hydrochloride

[0817] Step 1: tert-butyl (S)-3-((8-(trifluoromethyl)quinolin-5-yl)amino)pyrrolidine-1-carboxylate

[0818] The title compound (318.0 mg, 31.0%) was prepared in the same manner as Step 1 of Reference Example 5 except that 5-bromo-8-(trifluoromethyl) was used instead of 4-bromoquinoline )quinoline (741.1 mg, 2.68 mmol). ^1H -NMR ( _CDCl3 , 400 MHz) δ 9.04 (d, 1H), 8.16 (d, 1H), 7.92 (d, 1H), 7.43 (dd, 1H), 6, 59 (d, 1H), 4.78 (s, 1H), 4.26 (s, 1H), 3.84 (s, 1H), 3.59-3.37 (m, 3H), 2.37 -2.32 (m, 1H), 2.07-2.05 (m, 1H), 1.48 (s, 9H).

[0819] Step 2: (S)-N-(pyrrolidin-3-yl)-8-(trifluoromethyl)quinoline-5-amine hydrochloride

[0820] The title compound (175.0 mg, 59.3%) was prepared in the same manner as Step 2 of Reference Example 5 and used in the next step without further purification

[0821] Reference Example 127: (S)-N-(pyrrolidin-3-yl)-8-(trifluoromethoxy)quinoline-5-amine hydrochloride

[0822] Step 1: tert-butyl (S)-3-((8-(trifluoromethoxy)quinolin-5-yl)amino)pyrrolidine-1-carboxylate

[0823] The title compound (844.5 mg, 79.1%) was prepared in the same manner as Step 1 of Reference Example 5 except that 5-bromo-8-(trifluoromethoxy) was used instead of 4-bromoquinoline )quinoline (784.0 mg, 2.68 mmol). ^1H -NMR ( _CDCl3 , 400 MHz) δ 8.99 (d, 1H), 8.19 (d, 1H), 7.51 (d, 1H), 7.42 (dd, 1H), 6, 56 (d, 1H), 4.50 (s, 1H), 4.19 (s, 1H), 3.81 (s, 1H), 3.56-3.36 (m, 2H), 2.35 -2.25 (m, 1H), 2.05 (s, 1H), 1.48 (s, 9H).

[0824] Step 2: (S)-N-(pyrrolidin-3-yl)-8-(trifluoromethoxy)quinoline-5-amine hydrochloride

[0825] The title compound (505.3 mg, 64.2%) was prepared in the same manner as Step 2 of Reference Example 5 and used in the next step without further purification

[0826] Reference Example 128: (S)-5-(pyrrolidin-3-ylamino)quinoline-8-carbonitrile hydrochloride

[0827] Step 1: tert-butyl (S)-3-((8-cyanoquinolin-5-yl)amino)pyrrolidine-1-carboxylate

[0828] The title compound (800.0 mg, 88.0%) was prepared in the same manner as Step 1 of Reference Example 5 except that 5-bromoquinoline-8-carbonitrile was used instead of 4-bromoquinoline 625.6 mg, 2.68 mmol). ^1H -NMR ( _CDCl3 , 400 MHz) δ 9.01 (d, 1H), 8.26 (d, 1H), 7.94 (d, 1H), 7.42 (dd, 1H), 6, 60 (d, 1H), 5.30-5.25 (m, 1H), 4.27 (s, 1H), 3.83 (s, 1H), 3.57-3.40 (m, 3H) , 2.38-2.31 (m, 1H), 2.11 (s, 1H), 1.48 (s, 9H).

[0829] Step 2: (S)-5-(pyrrolidin-3-ylamino)quinoline-8-carbonitrile hydrochloride

[0830] The title compound (525.0 mg, 71.3%) was prepared in the same manner as Step 2 of Reference Example 5 and used in the next step without further purification

[0831] Reference Example 129. (S)-8-(Benzyloxy)-N-(pyrroldin-3-yl)quinolin-5-amine hydrochloride

[0832] Step 1: tert-butyl (S)-3-((8-(benzyloxy)quinolin-5-yl)amino)pyrrolidine-1-carboxylate

[0833] The title compound (1120.0 mg, 99.6%) was prepared in the same manner as Step 1 of Reference Example 5 except that 8-(benzyloxy)-5- was used instead of 4-bromoquinoline bromoquinoline (843.4 mg, 2.68 mmol). ^1H -NMR ( _CDCl3 , 400 MHz) δ 8.97 (d, 1H), 8.19 (d, 1H), 7.50 (d, 2H), 7.41 (dd, 1H), 7. 35 (t, 2H), 7.29 (d, 1H), 6.93 (d, 1H), 6.51 (d, 1H), 5.38 (s, 2H), 4.13-4.08 (m, 1H), 3.93 (s, 1H), 3.76-3.72 (m, 1H), 3.53-3.47 (m, 2H), 3.39-3.28 (m , 1H), 2.25-2.20 (m, 1H), 1.99 (s, 1H), 1.46 (s, 9H).

[0834] Step 2: (S)-8-(benzyloxy)-N-(pyrrolidin-3-yl)quinolin-5-amine hydrochloride

[0835] The title compound (1000.0 mg, 79.7%) was prepared in the same manner as in Step 2 of Reference Example 5 and used in the next step without further purification

[0836] Reference Example 130: (S)-N-(pyrrolidin-3-yl)quinoline-7-amine hydrochloride

[0837] Step 1: tert-butyl (S)-3-(quinolin-7-ylamino)pyrrolidine-1-carboxylate

[0838] The title compound (631.5 mg, 75.0%) was prepared in the same manner as Step 1 of Reference Example 5 except that 7-bromoquinoline (558.5 mg) was used instead of 4-bromoquinoline , 2.68 mmol). MS (IER) m/z - 314.2 (M+H)+

[0839] Step 2: (S)-N-(pyrrolidin-3-yl)quinoline-7-amine hydrochloride

[0840] The title compound (110.0 mg, 64.1%) was prepared in the same manner as in Step 2 of Reference Example 5 and used in the next step without further purification. MS (IER) m/z - 214.2 (M+H)+

[0841] Reference Example 131: (S)-N-(pyrrolidin-3-yl)-8-(trifluoromethyl)quinoline-4-amine hydrochloride

[0842] Step 1: tert-butyl (S)-3-((8-(trifluoromethyl)quinolin-4-yl)amino)pyrrolidine-1-carboxylate

[0843] The title compound (384.0 mg, 37.5%) was prepared in the same manner as Step 1 of Reference Example 5 except that 4-bromo-8-(trifluoromethyl) was used instead of 4-bromoquinoline )quinoline (741.0 mg, 2.68 mmol). MS (IER) m/z - 382.2 (M+H)+

[0844] Step 2: (S)-N-(pyrrolidin-3-yl)-8-(trifluoromethyl)quinoline-4-amine hydrochloride

[0845] The title compound (254.0 mg, 71.2%) was prepared in the same manner as in Step 2 of Reference Example 5 and used in the next step without further purification. MS (IER) m/z - 282.2 (M+H)+

[0846] Reference Example 132: (S)-N-(pyrrolidin-3-yl)-1,8-naphthyridin-3-amine hydrochloride

[0847] Step 1: tert-butyl (S)-3-((1,8-naphthyridin-3-yl)amino)pyrrolidine-1-carboxylate

[0848] The title compound (215.3 mg, 51.0%) was prepared in the same manner as Step 1 of Reference Example 5 except that 3-bromo-1,8- was used instead of 4-bromoquinoline naphthyridine (280.6 mg, 1.34 mmol). MS (IER) m/z - 315.1 (M+H)+

[0849] Step 2: (S)-N-(pyrrolidin-3-yl)-1,8-naphthyridin-3-amine hydrochloride

[0850] The title compound (196.7 mg, 100.0%) was prepared in the same manner as in Step 2 of Reference Example 5 and used in the next step without further purification.

[0851] Reference Example 133: (S)-7-chloro-N-(pyrrolidin-3-yl)-1,8-naphthyridin-3-amine hydrochloride

[0852] Step 1: tert-butyl (S)-3-((7-chloro-1,8-naphthyridin-3-yl)amino)pyrrolidine-1-carboxylate

[0853] The title compound (168.8 mg, 36.1%) was prepared in the same manner as Step 1 of Reference Example 5 except that 6-bromo-2-chloro- 1,8-naphthyridine (326.8 mg, 1.34 mmol). MS (IER) m/z - 349.2 (M+H)+

[0854] Step 2: (S)-7-chloro-N-(pyrrolidin-3-yl)-1,8-naphthyridin-3-amine hydrochloride

[0855] The title compound (155.6 mg, 100.0%) was prepared in the same manner as in Step 2 of Reference Example 5 and used in the next step without further purification.

[0856] Reference Example 134: (S)-8-Ethoxy-N-(pyrrolidin-3-yl)quinolin-5-amine hydrochloride

[0857] Step 1: tert-butyl (S)-3-((8-ethoxyquinolin-5-yl)amino)pyrrolidine-1-carboxylate

[0858] The title compound (561.0 mg, 58.4%) was prepared in the same manner as Step 1 of Reference Example 5 except that 5-bromo-8-ethoxyquinoline (5-bromo-8-ethoxyquinoline) was used instead of 4-bromoquinoline 676.8 mg, 2.68 mmol). MS (IER) m/z - 358.2 (M+H)+

[0859] Step 2: (S)-8-ethoxy-N-(pyrrolidin-3-yl)quinolin-5-amine hydrochloride

[0860] The title compound (321.0 mg, 61.9%) was prepared in the same manner as in Step 2 of Reference Example 5 and used in the next step without further purification. MS (IER) m/z - 258.2 (M+H)+

[0861] Reference Example 135: (S)-5-(pyrrolidin-3-ylamino)quinolin-8-ol hydrochloride

[0862] Step 1: 5-bromo-8-(tert-butyldimethylsilyl)oxy)quinoline

[0863] 5-Bromoquinolin-8-ol (1 g, 4.46 mmol) was dissolved in anhydrous dichloromethane. Tert-butyldimethylsilyl chloride (0.74 g, 4.91 mmol) and imidazole (0.67 g, 9.819 mmol) were added to the resulting solution. The reaction mixture was stirred overnight at room temperature. After completion of the reaction, the reaction mixture was diluted with dichloromethane, and then water was added to extract the aqueous layer. The extracted organic layer was dried and filtered over anhydrous magnesium sulfate. The filtered solution was concentrated and then purified by silica gel column chromatography (n-hexane only) to give the title compound (1.16 g, 76.8%). ^1H -NMR ( _CDCl3 , 400 MHz) δ 8.88 (dd, 1H), 8.47 (dd, 1H), 7.68 (d, 1H), 7.49 (q, 1H), 7. 07 (d, 1N), 1.07 (s, 9N), 0.27 (s, 6N)

[0864] Step 2: tert-butyl (S)-3-((8-(tert-butyldimethylsilyl)oxy)quinolin-5-yl)amino)pyrrolidine-1-carboxylate

[0865] 5-bromo-8-(tert-butyldimethylsilyl)oxy)quinoline (500 mg, 1.47 mmol) obtained in step 1 was dissolved in anhydrous toluene. Tert-butyl (S)-3-aminopyrrolidine-1-carboxylate (275.3 mg, 1.47 mmol), cesium carbonate (578 mg, 1.77 mmol), tris(dibenzylideneacetone)dipalladium (0) were added to the resulting solution. (162.4 mg, 0.17 mmol) nRuphos (82.7 mg, 0.17 mmol). The reaction mixture was refluxed and stirred at 100°C overnight. After completion of the reaction, the reaction mixture was cooled to room temperature, and then water was added to extract the aqueous layer with ethyl acetate. The extracted organic layer was dried and filtered over anhydrous magnesium sulfate. The filtered solution was concentrated and then purified by silica gel column chromatography (ethyl acetate/n-hexane = 1/1, v/v) to obtain the title compound (655.3 mg, 99.9%). MS (IER) m/z - 444.3 (M+H)+

[0866] Step 3. (S)-5-(pyrrolidin-3-ylamino)quinolin-8-ol hydrochloride

[0867] tert-butyl (S)-3-((8-(tert-butyldimethylsilyl)oxy)quinolin-5-yl)amino)pyrrolidine-1-carboxylate (655.3 mg, 1.47 mmol), prepared from stage 2, was dissolved in dichloromethane (8.4 ml), and then 4.0 M hydrochloric acid dissolved in 1,4-dioxane was added dropwise in excess. The reaction mixture was stirred overnight at room temperature. After completion of the reaction, the resulting solid was filtered, washed and vacuum dried to obtain the title compound (405.2 mg, 91.2%). ¹ H-NMR ((CD ₃ ) ₂ SO, 400 MHz) δ 9.55 (d, 1H), 8.99 (d, 1H), 7.98 (q, 1H), 7.43 (d, 1H ), 6.96 (d, 1H), 4.48-4.46 (m, 1H), 3.67-3.61 (m, 2H), 3.53-3.47 (m, 2H), 2.53-2.44 (m, 1H), 2.36-2.29 (m, 1H).

[0868] Reference Example 136: (S)-8-Methyl-N-(pyrrolidin-3-yl)quinolin-6-amine hydrochloride

[0869] Step 1: tert-butyl (S)-3-((8-methylquinolin-6-yl)amino)pyrrolidine-1-carboxylate

[0870] The title compound (261.6 mg, 59.5%) was prepared in the same manner as Step 1 of Reference Example 5 except that 6-bromo-8-methylquinoline was used instead of 4-bromoquinoline 298.1 mg, 1.34 mmol). MS (IER) m/z - 328.2 (M+H)+

[0871] Step 2: (S)-8-methyl-N-(pyrrolidin-3-yl)quinolin-6-amine hydrochloride

[0872] The title compound (238.2 mg, 100.0%) was prepared in the same manner as in Step 2 of Reference Example 5 and used in the next step without further purification.

[0873] Reference Example 137: (S)-8-Fluoro-N-(pyrrolidin-3-yl)quinolin-6-amine hydrochloride

[0874] Step 1: tert-butyl (S)-3-((8-fluoroquinolin-6-yl)amino)pyrrolidine-1-carboxylate

[0875] The title compound (391.1 mg, 87.9%) was prepared in the same manner as Step 1 of Reference Example 5 except that 6-bromo-8-fluoroquinoline (6-bromo-8-fluoroquinoline) was used instead of 4-bromoquinoline 303.4 mg, 1.34 mmol). MS (IER) m/z - 332.2 (M+H)+

[0876] Step 2: (S)-8-fluoro-N-(pyrrolidin-3-yl)quinoline-6-amine hydrochloride

[0877] The title compound (294.2 mg, 100.0%) was prepared in the same manner as in Step 2 of Reference Example 5 and used in the next step without further purification.

[0878] Reference Example 138: (S)-8-chloro-N-(pyrrolidin-3-yl)quinolin-6-amine hydrochloride

[0879] Step 1: tert-butyl (S)-3-((8-chloroquinolin-6-yl)amino)pyrrolidin-1-carboxylate

[0880] The title compound (316.5 mg, 67.8%) was prepared in the same manner as Step 1 of Reference Example 5 except that 6-bromo-8-chloroquinoline (6-bromo-8-chloroquinoline) was used instead of 4-bromoquinoline 325.5 mg, 1.34 mmol). MS (IER) m/z - 348.1 (M+H)+

[0881] Step 2: (S)-8-chloro-N-(pyrrolidin-3-yl)quinoline-6-amine hydrochloride

[0882] The title compound (287.6 mg, 100.0%) was prepared in the same manner as in Step 2 of Reference Example 5 and used in the next step without further purification.

[0883] Reference Example 139: (S)-N-(pyrrolidin-3-yl)-8-(trifluoromethyl)quinoline-6-amine hydrochloride

[0884] Step 1: tert-butyl (S)-3-((8-(trifluoromethyl)quinolin-6-yl)amino)pyrrolidine-1-carboxylate

[0885] The title compound (232.4 mg, 45.4%) was prepared in the same manner as Step 1 of Reference Example 5 except that 6-bromo-8-(trifluoromethyl) was used instead of 4-bromoquinoline )quinoline (370.5 mg, 1.34 mmol). MS (IER) m/z - 382.1 (M+H)+

[0886] Step 2: (S)-N-(pyrrolidin-3-yl)-8-(trifluoromethyl)quinoline-6-amine hydrochloride

[0887] The title compound (394.2 mg, 100.0%) was prepared in the same manner as Step 2 of Reference Example 5 and used in the next step without further purification

[0888] Reference Example 140: (S)-N-methyl-5-(pyrrolidin-3-ylamino)quinoline-8-carboxamide hydrochloride

[0889] Step 1: 5-Bromo-N-methylquinoline-8-carboxamide

[0890] 5-Bromoquinoline-8-carboxylic acid (300 mg, 1.19 mmol) was dissolved in dimethylformamide.

Methanamine (0.06 ml, 1.42 mmol), HATU (O-(7-azabenzotriazol-1-yl)-N,N,N',N'-tetramethyluran hexafluorophosphate) (633.6 mg, 1.67 mmol) and diisopropylethylamine (769.16 mg, 5.95 mmol). The reaction mixture was stirred overnight at room temperature. After completion of the reaction, water was added to the reaction mixture. The aqueous layer of the reaction mixture was extracted with dichloromethane. The extracted organic layer was dried and filtered over anhydrous magnesium sulfate. The filtered solution was concentrated and then purified by silica gel column chromatography (ethyl acetate/n-hexane = 1/1, v/v) to obtain the title compound (229.8 mg, 72.8%). ^1H -NMR ( _CDCl3 , 400 MHz) δ 8.96 (dd, 1H), 8.74 (d, 1H), 8.72 (dd, 1H), 7.99 (d, 1H), 7. 60 (q, 1H), 3.16 (d, 3H).

[0891] Step 2: tert-butyl (S)-3-((8-(methylcarbamoyl)quinolin-5-yl)amino)pyrrolidine-1-carboxylate

[0892] 5-Bromo-N-methylquinoline-8-carboxamide (192 mg, 0.72 mmol) obtained in step 1 was dissolved in anhydrous toluene. Tert-butyl (S)-3-aminopyrrolidine-1-carboxylate (135.0 mg, 0.72 mmol), cesium carbonate (192.4 mg, 0.591 mmol), tris(dibenzylideneacetone)dipalladium (0) were added to the resulting solution. (49.2 mg, 0.05 mmol) and (+/-)-2,2'-bis(diphenylphospino)-1,1'-binaphthalene (40.1 mg, 0.06 mmol). The reaction mixture was refluxed and stirred at 100°C overnight. After completion of the reaction, the reaction mixture was cooled to room temperature, and then water was added to extract the aqueous layer with ethyl acetate. The extracted organic layer was dried and filtered over anhydrous magnesium sulfate. The filtered solution was concentrated and then purified by silica gel column chromatography (ethyl acetate/n-hexane = 1/1, v/v) to give the title compound (106.3 mg, 39.6%). MS (IER) m/z - 371.2 (M+H)+

[0893] Step 3. (S)-N-methyl-5-(pyrrolidin-3-ylamino)quinoline-8-carboxamide hydrochloride

[0894] tert-butyl (S)-3-((8-(methylcarbamoyl)quinolin-5-yl)amino)pyrrolidine-1-carboxylate (106.3 mg, 0.287 mmol) obtained in step 2 was dissolved in dichloromethane (8.4 ml), and then an excess of 4.0 M hydrochloric acid dissolved in 1,4-dioxane was added dropwise. The reaction mixture was stirred overnight at room temperature. After completion of the reaction, the resulting solid was filtered, washed and vacuum dried to obtain the title compound (12.5 mg, 16.1%). MS (IER) m/z - 271.1 (M+H)+

[0895] Reference Example 141: (S)-N,N-dimethyl-5-(pyrrolidin-3-ylamino)quinoline-8-carboxamide

[0896] Step 1: 5-Bromo-N,N-dimethylquinoline-8-carboxamide

[0897] The title compound (179.1 mg, 53.9%) was prepared in the same manner as Step 1 of Reference Example 140 except that dimethylamine (64.1 mg, 1.42%) was used instead of methamine mmol). ^1H -NMR ( _CDCl3 , 400 MHz) δ 8.95 (dd, 1H), 8.55 (dd, 1H), 7.86 (d, 1H), 7.56-7.52 (m, 2H ), 3.24 (s, 3H), 2.77 (s, 3H).

[0898] Step 2: tert-butyl (S)-3-((8-(dimethylcarbamoyl)quinolin-5-yl)amino)pyrrolidine-1-carboxylate

[0899] The title compound (86.2 mg, 23.2%) was prepared in the same manner as Step 2 of Reference Example 140. MS (ESI) m/z - 385.2 (M+H)+

[0900] Step 3. (S)-N,N-dimethyl-5-(pyrrolidin-3-ylamino)quinoline-8-carboxamide hydrochloride

[0901] The title compound (57.0 mg, 71.4%) was prepared in the same manner as Step 3 of Reference Example 140 and used in the next step without further purification. MS (IER) m/z - 285.1 (M+H)+

[0902] Reference Example 142: (S)-N-Phenyl-5-(pyrrolidin-3-ylamino)quinoline-8-carboxamide hydrochloride

[0903] Step 1: 5-Bromo-N-phenylquinoline-8-carboxamide

[0904] The title compound (348.12 mg, 89.4%) was prepared in the same manner as Step 1 of Reference Example 140 except that aniline (132.2 mg, 1.42 mmol). ¹ H-NMR (CDCl ₃ , 400 MHz) δ 13.41 (s, 1H), 9.03 (d, 1H), 8.80 (d, 1H), 8.75 (d, 1H), 8. 02 (d, 1H), 7.87 (d, 2H), 7.64 (q, 1H), 7.42 (t, 2H), 7.16 (t, 1H).

[0905] Step 2: tert-butyl (S)-3-((8-(phenylcarbamoyl)quinolin-5-yl)amino)pyrrolidine-1-carboxylate

[0906] The title compound (54.0 mg, 38.3%) was prepared in the same manner as Step 2 of Reference Example 140. MS (ESI) m/z - 433.2 (M+H)+

[0907] Step 3. (S)-N-phenyl-5-(pyrrolidin-3-ylamino)quinoline-8-carboxamide hydrochloride

[0908] The title compound (47.4 mg, 93.6%) was prepared in the same manner as Step 3 of Reference Example 140 and used in the next step without further purification. MS (IER) m/z - 333.2 (M+H)+

[0909] Reference Example 143: (S)-N-Methyl-N-phenyl-5-(pyrrolidin-3-ylamino)quinoline-8-carboxamide hydrochloride

[0910] Step 1: 5-Bromo-N-methyl-N-phenylquinoline-8-carboxamide

[0911] The title compound (365.2 mg, 89.9%) was prepared in the same manner as Step 1 of Reference Example 140 except that N-methylaniline (152.2 mg, 1 .42 mmol). ^1H -NMR ( _CDCl3 , 400 MHz) δ 8.95 (dd, 1H), 8.35 (dd, 1H), 7.56 (d, 1H), 7.41 (q, 1H), 7, 30 (d, 1H), 7.05 (d, 2H), 6.97-6.91 (m, 3H), 3.59 (s, 3H)

[0912] Step 2: tert-butyl (S)-3-((8-(methyl(phenyl)carbamoyl)quinolin-5-yl)amino)pyrrolidine-1-carboxylate

[0913] The title compound (92.2 mg, 36.4%) was prepared in the same manner as Step 2 of Reference Example 140. MS (ESI) m/z - 447.2 (M+H)+

[0914] Step 3. (S)-N-methyl-N-phenyl-5-(pyrrolidin-3-ylamino)quinoline-8-carboxamide hydrochloride

[0915] The title compound (85 mg, 98.5%) was prepared in the same manner as in Step 3 of Reference Example 140 and used in the next step without further purification. MS (IER) m/z - 347.2 (M+H)+

[0916] Reference Example 144: (S)-N-Benzyl-N-methyl-5-(pyrrolidin-3-ylamino)quinoline-8-carboxamide hydrochloride

[0917] Step 1: N-benzyl-5-bromo-N-methylquinoline-8-carboxamide

[0918] The title compound (382.5 mg, 90.4%) was prepared in the same manner as Step 1 of Reference Example 140 except that N-methyl-1-phenylmethanamine (172, 0 mg, 1.42 mmol). ^1H -NMR ( _CDCl3 , 400 MHz) δ 8.99-8.98 (m, 1H), 8.54-8.49 (m, 1H), 7.86-7.78 (m, 1H) , 7.59-7.50 (m, 3H), 7.41-7.37 (m, 1H), 7.31-7.19 (m, 3H), 4.93 (s, 1H), 4 .29 (s, 1H), 3.15 (s, 1.5H), 2.65 (s, 1.5H)

[0919] Step 2: tert-butyl (S)-3-((8-(benzyl(methyl)carbamoyl)quinolin-5-yl)amino)pyrrolidine-1-carboxylate

[0920] The title compound (90.1 mg, 31.2%) was prepared in the same manner as Step 2 of Reference Example 140. MS (ESI) m/z - 461.2 (M+H)+

[0921] Step 3. (S)-N-Benzyl-N-methyl-5-(pyrrolidin-3-ylamino)quinoline-8-carboxamide hydrochloride

[0922] The title compound (76.0 mg, 89.2%) was prepared in the same manner as Step 3 of Reference Example 140 and used in the next step without further purification. MS (IER) m/z - 361.2 (M+H)+

[0923] Reference Example 145: (S)-N-(pyridin-3-yl)-5-(pyrrolidin-3-ylamino)quinoline-8-carboxamide hydrochloride

[0924] Step 1: 5-Bromo-N-(pyrid-3-yl)quinoline-8-carboxamide

[0925] The title compound (259.5 mg, 66.4%) was prepared in the same manner as Step 1 of Reference Example 140 except that 3-aminopyridine (123.2 mg, 1 .42 mmol). ^1H -NMR ( _CDCl3 , 400 MHz) δ 9.09 (dd, 1H), 8.88 (d, 1H), 8.83-8.79 (m, 2H), 8.51 (dt, 1H ), 8.41 (dd, 1H), 8.07 (d, 1H), 7.70 (dd, 1H), 7.36 (dd, 1H).

[0926] Step 2: tert-butyl (S)-3-((8-(pyridin-3-ylcarbamoyp)quinolin-5-yl)amino)pyrrolidine-1-carboxylate

[0927] The title compound (273.9 mg, 79.9%) was prepared in the same manner as Step 2 of Reference Example 140. MS (ESI) m/z - 434.2 (M + H)+

[0928] Step 3. (S)-N-(pyridin-3-yl)-5-(pyrrolidin-3-ylamino)quinoline-8-carboxamide hydrochloride

[0929] The title compound (221.4 mg, 86.2%) was prepared in the same manner as Step 3 of Reference Example 140 and used in the next step without further purification.

[0930] Reference Example 146: (S)-N-(pyrrolidin-4-yl)-5-(pyrrolidin-3-ylamino)quinoline-8-carboxamide hydrochloride

[0931] Step 1: 5-Bromo-N-(pyrid-4-yl)quinoline-8-carboxamide

[0932] The title compound (325.5 mg, 83.3%) was prepared in the same manner as Step 1 of Reference Example 140 except that 4-aminopyridine (123.2 mg, 1 .42 mmol). ^1H -NMR ( _CDCl3 , 400 MHz) δ 9.07 (dd, 1H), 8.81 (d, 2H), 8.59 (d, 2H), 8.07 (d, 1H), 7 .79 (d, 2 I), 7.71 (dd, 1H).

[0933] Step 2: tert-butyl (S)-3-((8-(pyridin-4-ylcarbamoyl)quinolin-5-yl)amino)pyrrolidine-1-carboxylate

[0934] The title compound (363.6 mg, 84.5%) was prepared in the same manner as Step 2 of Reference Example 140. MS (ESI) m/z - 434.2 (M+H)+

[0935] Step 3. (S)-N-(pyrrolidin-4-yl)-5-(pyrrolidin-3-ylamino)quinoline-8-carboxamide hydrochloride

[0936] The title compound (330.0 mg, 96.7%) was prepared in the same manner as Step 3 of Reference Example 140 and used in the next step without further purification.

[0937] Reference Example 147: (S)-N-(pyrrodin-2-yl)-5-(pyrrolidin-3-ylamino)quinoline-8-carboxamide hydrochloride

[0938] Step 1: 5-Bromo-N-(pyrid-2-yl)quinoline-8-carboxamide

[0939] The title compound (262.5 mg, 67.2%) was prepared in the same manner as Step 1 of Reference Example 140 except that 2-aminopyridine (123.2 mg, 1 .42 mmol). ^1H -NMR ( _CDCl3 , 400 MHz) δ 9.19 (dd, 1H), 8.82 (d, 1H), 8.77 (dd, 1H), 8.52 (d, 1H), 8. 44 (dd, 1H), 8.05 (d, 1H), 7.78 (td, 1H), 7.68 (dd, 1H), 7.10 (dd, 1H).

[0940] Step 2: tert-butyl (S)-3-((8-(pyridin-2-ylcarbamoyl)quinolin-5-yl)amino)pyrrolidine-1-carboxylate

[0941] The title compound (318.9 mg, 91.9%) was prepared in the same manner as Step 2 of Reference Example 140. MS (ESI) m/z - 434.2 (M+H)+

[0942] Step 3: (S)-N-(pyrvdin-2-yl)-5-(pyrrolidin-3-ylamino)quinoline-8-carboxamide

[0943] The title compound (287.1 mg, 96.0%) was prepared in the same manner as Step 3 of Reference Example 140 and used in the next step without further purification.

[0944] Reference Example 148: (S)-N-(5-(pyrrolidin-3-ylamino)quinolin-8-yl)acetamide hydrochloride

[0945] Step 1: tert-butyl (S)-3-((8-acetamidoquinolin-5-yl)amino)pyrrolidine-1-carboxylate

[0946] The title compound (434.0 mg, 43.6%) was prepared in the same manner as Step 1 of Reference Example 5 except that N-(5-bromoquinoline-8 -yl) acetamide (711.7 mg, 2.68 mmol). MS (IER) m/z - 371.2 (M+H)+

[0947] Step 2: (S)-N-(5-(pyrrolidin-3-ylamino)quinolin-8-yl)acetamide hydrochloride

[0948] The title compound (300.5 mg, 74.6%) was prepared in the same manner as in Step 2 of Reference Example 5 and used in the next step without further purification. MS (IER) m/z - 271.2 (M+H)+

[0949] Reference Example 149: (S)-N-(5-(pyrrolidin-3-ylamino)quinolin-8-yl)benzamide hydrochloride

[0950] Step 1: N-(5-bromoquinolin-8-yl)benzamide

[0951] 5-Bromoquinoline-8-amine (500 mg, 2.24 mmol) was dissolved in dimethylformamide. To the resulting solution was added benzoic acid (355.8 mg, 2.91 mmol), HATU (O-(7-azabenzotriazol-1-yl)-N,N,N',N'-tetramethyluran hexafluorophosphate) (1278.4 mg , 8.96 mmol) and diisopropylethylamine (11158.83 mg, 8.96 mmol). The reaction mixture was stirred overnight at room temperature. After completion of the reaction, water was added to the reaction mixture. The aqueous layer of the reaction mixture was extracted with dichloromethane. The extracted organic layer was dried and filtered over anhydrous magnesium sulfate. The filtered solution was concentrated and then purified by silica gel column chromatography (ethyl acetate/n-hexane = 1/1, v/v) to give the title compound (88.3 mg, 12.0%). MS (IER) m/z - 327.0 (M+H)+

[0952] Step 2: tert-butyl (S)-3-((8-(phenylcarbamoyl)quinolin-5-yl)amino)pyrrolidine-1-carboxylate

[0953] The title compound (72.4 mg, 31.1%) was prepared in the same manner as Step 2 of Reference Example 140 except that 5-bromo-N-methylquinoline-8-carboxamide was used instead N-(5-bromoquinolin-8-yl)benzamide (192 mg, 0.58 mmol). MS (IER) m/z - 433.2 (M+H)+

[0954] Step 3. (S)-N-(5-(pyrrolidin-3-ylamino)quinolin-8-yl)benzamide hydrochloride

[0955] The title compound (60.1 mg, 88.6%) was prepared in the same manner as Step 3 of Reference Example 140 and used in the next step without further purification. MS (IER) m/z - 333.1 (M+H)+

[0956] Reference Example 150: (S)-6-methoxy-4-(pyrrolidin-3-yloxy)quinoline hydrochloride

[0957] Step 1: tert-butyl (S)-3-((6-methoxyquinolin-4-yl)oxy)pyrrolidine-1-carboxylate

[0958] Tert-Butyl (R)-3-hydroxypyrrolidine-1-carboxylate (187 mg, 1.0 mmol) was dissolved in tetrahydrofuran (5.0 ml). 4-hydroxy-6-methoxyquinoline (175 mg, 1.0 mmol) and triphenylphosphine (393 mg, 1.5 mmol) were added to the resulting solution. The mixture was cooled to 0°C. DIAD (diisopropyl azodicarboxylate) (0.29 mL, 1.5 mmol) was then added dropwise slowly over 15 minutes. The reaction mixture was stirred for 12 hours at room temperature. After completion of the reaction, the reaction mixture was evaporated in vacuo and then purified by silica gel column chromatography (ethyl acetate/methanol = 10/1, v/v) to obtain the title compound (275 mg, 80%). MS (IER) m/z - 345.2 (M+H)+

[0959] Step 2: (S)-6-methoxy-4-(pyrrolidin-3-yloxy)quinoline hydrochloride

[0960] tert-butyl (S)-3-((6-methoxyquinolin-4-yl)oxy)pyrrolidine-1-carboxylate (275 mg, 0.80 mmol) prepared in step 1 was dissolved in dichloromethane (2, 4 ml) and methanol (0.2 ml). An excess of 4.0 M hydrochloric acid dissolved in 1,4-dioxane was added dropwise to the resulting solution. The reaction mixture was stirred overnight at room temperature. After completion of the reaction, the resulting solid was filtered and dried to obtain the title compound (224 mg, 100%). The title compound was used in the next step without further purification.

[0961] Reference Example 151: (S)-6,7-dimethoxy-4-(pyrrolidin-3-yloxy)quinoline hydrochloride

[0962] Step 1: tert-butyl-(S)-3-((6,7-dimethoxyquinolin-4-yl)oxy)pyrrolidine-1-carboxylate

[0963] Tert-Butyl (R)-3-hydroxypyrrolidine-1-carboxylate (187 mg, 1.0 mmol) was dissolved in tetrahydrofuran (5.0 ml). 4-hydroxy-6,7-dimethoxyquinoline (205 mg, 1.0 mmol) and triphenylphosphine (393 mg, 1.5 mmol) were added to the resulting solution. The mixture was cooled to 0°C. DIAD (diisopropyl azodicarboxylate) (0.29 mL, 1.5 mmol) was then added dropwise slowly over 15 minutes. The reaction mixture was stirred for 12 hours at room temperature. After completion of the reaction, the reaction mixture was evaporated in vacuo and then purified by silica gel column chromatography (ethyl acetate/methanol = 10/1, v/v) to obtain the title compound (138 mg, 37%). MS (IER) m/z - 375.2 (M+H)+

[0964] Step 2: (S)-6,7-dimethoxy-4-(pyrrolidin-3-yloxy)quinoline hydrochloride

[0965] tert-butyl-(S)-3-((b,7-dimethoxyquinolin-4-yl)oxy)pyrrolidine-1-carboxylate (138 mg, 0.37 mmol) obtained in step 1 was dissolved in dichloromethane (1.0 ml) and methanol (0.1 ml). An excess of 4.0 M hydrochloric acid dissolved in 1,4-dioxane was added dropwise to the resulting solution. The reaction mixture was stirred overnight at room temperature. After completion of the reaction, the resulting solid was filtered and dried to obtain the title compound (114 mg, 100%)). The title compound was used in the next step without further purification.

[0966] Reference Example 152: N-(Piperidin-4-yl)quinoline-8-carboxamide hydrochloride

[0967] Step 1: tert-butyl 4-(quinoline-8-carboxamido) piperidine-1-carboxylate

[0968] 4-Amino-1-tert-butoxycarbonylpiperidine (250.0 mg, 1.25 mmol) was dissolved in dichloromethane.

To the resulting solution was added 8-quinolinecarboxylic acid (216.2 mg, 1.25 mmol), 1-hydroxybenzotriazole hydrate (337.3 mg, 2.50 mmol), EDAC (N-(3-dimethylaminopropyl) hydrochloride-N'- ethylcarbodiimide) (478.6 mg, 2.50 mmol) and triethylamine (0.35 ml, 2.50 mmol). The reaction mixture was stirred overnight at room temperature. After completion of the reaction, water was added to the reaction mixture. The aqueous layer of the reaction mixture was extracted with dichloromethane. The extracted organic layer was dried and filtered over anhydrous magnesium sulfate. The filtered solution was concentrated and then purified by silica gel column chromatography (ethyl acetate/n-hexane = 1/1, v/v) to obtain the title compound (443.6 mg, 99.9%). MS (IER) m/z - 356.2 (M+H)+

[0969] Step 2: N-(piperidin-4-yl)quinoline-8-carboxamide hydrochloride

[0970] Tert-Butyl 4-(quinoline-8-carboxamido)piperidine-1-carboxylate (443.6 mg, 1.25 mmol) prepared in step 1 was dissolved in dichloromethane (5.0 ml) and then an excess of 4.0 M hydrochloric acid dissolved in 1,4-dioxane was added (dropwise). The reaction mixture was stirred overnight at room temperature. After completion of the reaction, the resulting solid was filtered and dried to obtain the title compound (409.7 mg, 100.0%). The title compound was used in the next step without further purification.

[0971] Reference Example 153: N-ethyl-N-(piperidin-4-yl)quinolin-3-amine hydrochloride

[0972] Step 1: tert-butyl 4-(ethyl(quinolin-3-yl)amino)piperidine-1-carboxylate

[0973] Tert-Butyl 4-(ethylamino)piperidine-1-carboxylate (109.7 mg, 0.48 mmol) was dissolved in anhydrous toluene. To the resulting solution was added 3-bromoquinoline (100.0 mg, 0.48 mmol), cesium carbonate (187.9 mg, 0.58 mmol), tris(dibenzylideneacetone) dipalladium (0) (44.0 mg, 0.04 mmol) and (+/-)-2,2'-bis(diphenylphospino)-1,1'-binaphthalene (29.9 mg, 0.27 mmol). The reaction mixture was refluxed and stirred at 100°C overnight. After completion of the reaction, the reaction mixture was cooled to room temperature, and then water was added to extract the aqueous layer with ethyl acetate. The extracted organic layer was dried and filtered over anhydrous magnesium sulfate. The filtered solution was concentrated and then purified by silica gel column chromatography (ethyl acetate/n-hexane = 1/1, v/v) to obtain the title compound (120.0 mg, 70.2%). MS (IER) m/z - 356.2 (M+H)+

[0974] Step 2: N-ethyl-N-(piperidin-4-yl)quinoline-3-amine hydrochloride

[0975] tert-butyl 4-(ethyl(quinolin-3-yl)amino)piperidine-1-carboxylate (120 mg, 0.34 mmol) obtained in step 1 was dissolved in dichloromethane (2.2 ml), and then an excess of 4.0 M hydrochloric acid dissolved in 1,4-dioxane was added dropwise. The reaction mixture was stirred overnight at room temperature. After completion of the reaction, the resulting solid was filtered, washed and vacuum dried to give the title compound (72.7 mg, 65.6%) and used in the next step without further purification.

[0976] Reference Example 154: N-ethyl-N-(piperidin-4-i)quinoline-6-amine hydrochloride

[0977] Step 1: tert-butyl 4-(ethyl(quinolin-6-yl)amino)pyrrolidine-1-carboxylate

[0978] The title compound (97.3 mg, 56.9%) was prepared in the same manner as Step 1 of Reference Example 153 except that 6-bromoquinoline (100.0 mg) was used instead of 3-bromoquinoline , 0.48 mmol). MS (IER) m/z - 356.2 (M+H)+

[0979] Step 2: N-ethyl-N-(piperidin-4-yl)quinoline-6-amine hydrochloride

[0980] The title compound (67.0 mg, 77.8%) was prepared in the same manner as Step 2 of Reference Example 153 and used in the next step without further purification.

[0981] Reference Example 155: N-ethyl-N-(piperidin-4-yl)quinoline-5-amine hydrochloride

[0982] Step 1: tert-butyl 4-(ethyl(quinolin-5-yl)amino)piperidine-1-carboxylate

[0983] The title compound (93.1 mg, 54.4%) was prepared in the same manner as Step 1 of Reference Example 153 except that 5-bromoquinoline (100.0 mg) was used instead of 3-bromoquinoline , 0.48 mmol). MS (IER) m/z - 356.2 (M+H)+

[0984] Step 2: K-ethyl-N-(piperidin-4-yl)quinoline-5-amine hydrochloride

[0985] The title compound (68.6 mg, 76.5%) was prepared in the same manner as Step 2 of Reference Example 153 and used in the next step without further purification.

[0986] Reference Example 156: N-Methyl-N-(piperidin-4-yl)quinolin-2-amine hydrochloride

[0987] Step 1: tert-butyl 4-(methyl(quinolin-2-yl)amino)piperidine-1-carboxylate

[0988] Tert-Butyl 4-(methylamino)piperidine-1-carboxylate (500.0 mg, 2.33 mmol) was dissolved in anhydrous toluene. 2-bromoquinoline (485.4 mg, 2.33 mmol), cesium carbonate (910 mg, 2.80 mmol), tris(dibenzylideneacetone) dipalladium (0) (210.0 mg, 0.23 mmol) were added to the resulting solution. and (+/-)-2,2'-bis(diphenylphospino)-1,1'-binaphthalene (170.0 mg, 0.28 mmol). The reaction mixture was refluxed and stirred at 100°C overnight. After completion of the reaction, the reaction mixture was cooled to room temperature, and then water was added to extract the aqueous layer with ethyl acetate. The extracted organic layer was dried and filtered over anhydrous magnesium sulfate. The filtered solution was concentrated and then purified by silica gel column chromatography (ethyl acetate/n-hexane = 1/1, v/v) to obtain the title compound (203.8 mg, 25.5%). MS (IER) m/z - 342.3 (M+H)+

[0989] Step 2: N-methyl-N-(piperidin-4-yl)quinolin-2-amine hydrochloride

[0990] Tert-Butyl 4-(methyl(quinolin-2-yl)amino)piperidine-1-carboxylate (203.8 mg, 0.34 mmol) obtained in step 1 was dissolved in dichloromethane (3.1 ml) , and then an excess of 4.0 M hydrochloric acid dissolved in 1,4-dioxane was added dropwise. The reaction mixture was stirred overnight at room temperature. After completion of the reaction, the resulting solid was filtered, washed and vacuum dried to give the title compound (128.8 mg, 68.6%) and used in the next step without further purification.

[0992] Step 1: tert-butyl 4-(methyl(quinolin-4-yl)amino)piperidine-1-carboxylate

[0993] The title compound (85.2 mg, 15.5%) was prepared in the same manner as Step 1 of Reference Example 156 except that 4-bromoquinoline (485.4 mg, 2.33 mmol). MS (IER) m/z - 342.3 (M+H)+

[0994] Step 2: N-methyl-N-(piperidin-4-yl)quinolin-4-amine hydrochloride

[0995] The title compound (85.2 mg, 74.6%) was prepared in the same manner as Step 2 of Reference Example 156 and used in the next step without further purification.

[0996] Reference Example 158: N-Methyl-N-(piperidin-4-yl)quinolin-5-amine hydrochloride

[0997] Step 1: tert-butyl 4-(methyl(quinolin-5-yl)amino)piperidine-1-carboxylate

[0998] The title compound (154.7 mg, 19.4%) was prepared in the same manner as Step 1 of Reference Example 156 except that 5-bromoquinoline (485.4 mg, 2.33 mmol). MS (IER) m/z - 342.3 (M+H)+

[0999] Step 2: N-methyl-N-(piperidin-4-yl)quinolin-5-amine hydrochloride

[1000] The title compound (141.0 mg, 99.1%) was prepared in the same manner as in Step 2 of Reference Example 156 and used in the next step without further purification.

[1001] Reference Example 159: N-Methyl-N-(piperidin-4-yl)quinolin-6-amine hydrochloride

[1002] Step 1: tert-butyl 4-(methyl(quinolin-6-yl)amino)piperidine-1-carboxylate

[1003] The title compound (184.2 mg, 23.1%) was prepared in the same manner as Step 1 of Reference Example 156 except that 6-bromoquinoline (485.4 mg, 2.33 mmol). MS (IER) m/z - 342.3 (M+H)+

[1004] Step 2: N-methyl-N-(piperidin-4-yl)quinolin-6-amine hydrochloride

[1005] The title compound (155.4 mg, 91.6%) was prepared in the same manner as Step 2 of Reference Example 156 and used in the next step without further purification.

[1006] Reference Example 160: N-Methyl-N-(piperidin-4-yl)quinolin-7-amine hydrochloride

[1007] Step 1: tert-butyl 4-(methyl(quinolin-7-yl)amino)piperidine-1-carboxylate

[1008] The title compound (220.4 mg, 27.6%) was prepared in the same manner as Step 1 of Reference Example 156 except that 7-bromoquinoline (485.4 mg) was used instead of 2-bromoquinoline , 2.33 mmol). MS (IER) m/z - 342.3 (M+H)+

[1009] Step 2: N-methyl-N-(piperidin-4-yl)quinolin-7-amine hydrochloride

[1010] The title compound (198.0 mg, 97.6%) was prepared in the same manner as Step 2 of Reference Example 156 and used in the next step without further purification.

[1011] Reference Example 161: N-Methyl-N-(piperidin-4-yl)furo[3,2-c]pyridin-7-amine hydrochloride

[1012] Step 1: tert-butyl 4-(furo[3,2-c]pyridin-7-yl (methyl)amino)piperidine-1-carboxylate

[1013] The title compound (230.8 mg, 29.8%) was prepared in the same manner as Step 1 of Reference Example 156 except that 7-bromofuro[3,2-c was used instead of 2-bromoquinoline ]pyridine (462.0 mg, 2.33 mmol). MS (IER) m/z - 332.3 (M+H)+

[1014] Step 2: N-methyl-N-(piperidin-4-yl)furo[3,2-c]pyridin-7-amine hydrochloride

[1015] The title compound (153.7 mg, 72.5%) was prepared in the same manner as Step 2 of Reference Example 156 and used in the next step without further purification.

[1016] Reference Example 162: N-Methyl-N-(piperidin-4-yl)isoquinolin-5-amine hydrochloride

[1017] Step 1: tert-butyl 4-(methyl(isoquinolin-5-yl)amino)piperidine-1-carboxylate

[1018] The title compound (228.0 mg, 28.6%) was prepared in the same manner as Step 1 of Reference Example 156 except that 5-bromoquinoline (485.4 mg, 2.33 mmol). MS (IER) m/z - 342.3 (M+H)+

[1019] Step 2: N-methyl-N-(piperidin-4-yl)isoquinolin-5-amine hydrochloride

[1020] The title compound (126.6 mg, 60.4%) was prepared in the same manner as Step 2 of Reference Example 156 and used in the next step without further purification.

[1021] Reference Example 163: N-Methyl-N-(piperidin-4-yl)isoquinolin-6-amine hydrochloride

[1022] Step 1: tert-butyl 4-(methyl(isoquinolin-6-yl)amino)piperidine-1-carboxylate

[1023] The title compound (165.0 mg, 20.7%) was prepared in the same manner as Step 1 of Reference Example 156 except that 6-bromoquinoline (485.4 mg, 2.33 mmol). MS (IER) m/z - 342.3 (M+H)+

[1024] Step 2: N-methyl-N-(piperidin-4-yl)isoquinolin-6-amine hydrochloride

[1025] The title compound (119.0 mg, 47.6%) was prepared in the same manner as Step 2 of Reference Example 156 and used in the next step without further purification.

[1026] Reference Example 164: N-Methyl-N-(piperidin-4-yl)quinolin-3-amine hydrochloride

[1027] Step 1: tert-butyl 4-(methyl(quinolin-3-yl)amino)piperidine-1-carboxylate

[1028] The title compound (124.0 mg, 15.5%) was prepared in the same manner as Step 1 of Reference Example 156 except that 3-bromoquinoline (485.4 mg, 2.33 mmol). MS (IER) m/z - 342.3 (M+H)+

[1029] Step 2: N-methyl-N-(piperidin-4-yl)quinolin-3-amine hydrochloride

[1030] The title compound (69.5 mg, 60.9%) was prepared in the same manner as Step 2 of Reference Example 156 and used in the next step without further purification.

[1031] Reference Example 165: N-Methyl-N-(piperidin-4-yl)isoquinolin-3-amine hydrochloride

[1032] Step 1: tert-butyl 4-(methyl(isoquinolin-3-yl)amino)piperidine-1-carboxylate

[1033] The title compound (406.5 mg, 51.0%) was prepared in the same manner as Step 1 of Reference Example 156 except that 3-bromoquinoline (485.4 mg, 2.33 mmol). MS (IER) m/z - 342.3 (M+H)+

[1034] Step 2: N-methyl-N-(piperidin-4-yl)isoquinolin-3-amine hydrochloride

[1035] The title compound (238.6 mg, 63.8%) was prepared in the same manner as Step 2 of Reference Example 156 and used in the next step without further purification.

[1036] Reference Example 166: N-Methyl-N-(piperidin-4-yl)isoquinolin-7-amine hydrochloride

[1037] Step 1: tert-butyl 4-(methyl(isoquinolin-7-yl)amino)piperidine-1-carboxylate

[1038] The title compound (245.0 mg, 30.7%) was prepared in the same manner as Step 1 of Reference Example 156 except that 7-bromoquinoline (485.4 mg) was used instead of 2-bromoquinoline , 2.33 mmol). MS (IER) m/z - 342.3 (M+H)+

[1039] Step 2: N-methyl-N-(piperidin-4-yl)isoquinolin-7-amine hydrochloride

[1040] The title compound (132.7 mg, 58.3%) was prepared in the same manner as Step 2 of Reference Example 156 and used in the next step without further purification.

[1041] Reference Example 167: N-Methyl-N-(piperidin-4-yl)isoquinolin-8-amine hydrochloride

[1042] Step 1: tert-butyl 4-(methyl(isoquinolin-8-yl)amino)piperidine-1-carboxylate

[1043] The title compound (514.5 mg, 64.6%) was prepared in the same manner as Step 1 of Reference Example 156 except that 8-bromoquinoline (485.4 mg, 2.33 mmol). MS (IER) m/z - 342.3 (M+H)+

[1044] Step 2: N-methyl-N-(piperidin-4-yl)isoquinolin-8-amine hydrochloride

[1045] The title compound (303.3 mg, 64.1%) was prepared in the same manner as Step 2 of Reference Example 156 and used in the next step without further purification.

[1046] Reference Example 168 N,6-dimethyl-N-(piperidin-4-yl)quinolin-3-amine hydrochloride

[1047] Step 1: tert-butyl 4-(methyl(6-methylquinolin-3-yl)amino)piperidine-1-carboxylate

[1048] The title compound (750.3 mg, 45.2%) was prepared in the same manner as Step 1 of Reference Example 156 except that 3-bromo-6-methylquinoline was used instead of 2-bromoquinoline 518.1 mg, 2.33 mmol). MS (IER) m/z - 356.2 (M+H)+

[1049] Step 2: N,6-dimethyl-N-(piperidin-4-yl)quinolin-3-amine hydrochloride

[1050] The title compound (525.6 mg, 75.8%) was prepared in the same manner as in Step 2 of Reference Example 156 and used in the next step without further purification. MS (IER) m/z - 256.2 (M+H)+

[1051] Reference Example 169: 6-methoxy-N-methyl-N-(piperidin-4-yl)quinolin-3-amine hydrochloride

[1052] Step 1: tert-butyl 4-(methyl(6-methoxyquinolin-3-yl)amino)piperidine-1-carboxylate

[1053] The title compound (781.3 mg, 45.2%) was prepared in the same manner as Step 1 of Reference Example 156 except that 3-bromo-6-methoxyquinoline (555 .5 mg, 2.33 mmol). MS (IER) m/z - 372.2 (M+H)+

[1054] Step 2: 6-methoxy-N-methyl-N-(piperidin-4-yl)quinolin-3-amine hydrochloride

[1055] The title compound (420.3 mg, 57.8%) was prepared in the same manner as Step 2 of Reference Example 156 and used in the next step without further purification. MS (IER) m/z - 272.1 (M+H)+

[1056] Reference Example 170: 7-methoxy-N-methyl-N-(piperidin-4-yl)quinolin-3-amine hydrochloride

[1057] Step 1: tert-butyl 4-(methyl(7-methoxyquinolin-3-yl)amino)piperidine-1-carboxylate

[1058] The title compound (778.3 mg, 44.9%) was prepared in the same manner as Step 1 of Reference Example 156 except that 3-bromo-7-methoxyquinoline (555 .5 mg, 2.33 mmol). MS (IER) m/z - 372.2 (M+H)+

[1059] Step 2: 7-methoxy-N-methyl-N-(piperidin-4-yl)quinolin-3-amine hydrochloride

[1060] The title compound (303.3 mg, 41.7%) was prepared in the same manner as Step 2 of Reference Example 156 and used in the next step without further purification. MS (IER) m/z - 272.2 (M+H)+

[1061] Reference Example 171: 8-methoxy-N-methyl-N-(piperidin-4-yl)quinolin-3-amine hydrochloride

[1062] Step 1: tert-butyl 4-(methyl(8-methoxyquinolin-3-yl)amino)piperidine-1-carboxylate

[1063] The title compound (780.0 mg, 45.0%) was prepared in the same manner as Step 1 of Reference Example 156 except that 3-bromo-8-methoxyquinoline (555 .5 mg, 2.33 mmol). MS (IER) m/z - 372.2 (M+H)+

[1064] Step 2: 8-methoxy-N-methyl-N-(piperidin-4-yl)quinolin-3-amine hydrochloride

[1065] The title compound (645.5 mg, 88.8%) was prepared in the same manner as Step 2 of Reference Example 156 and used in the next step without further purification. MS (IER) m/z - 272.2 (M+H)+

[1066] Reference Example 172: 8-Fluoro-N-(piperidin-4-yl)quinoline-5-amine hydrochloride

[1067] Step 1: tert-butyl 4-((8-fluoroquinolin-5-yl)amino)piperidine-1-carboxylate

[1068] The title compound (163.9 mg, 38.0%) was prepared in the same manner as Step 1 of Reference Example 28 except that 5-bromo-8-fluoroquinoline (5-bromo-8-fluoroquinoline) was used instead of 4-bromoquinoline 282.2 mg, 1.25 mmol). MS (IER) m/z - 293.1 (M+H)+

[1069] Step 2: 8-fluoro-N-(piperidin-4-yl)quinoline-5-amine hydrochloride

[1070] The title compound (151.0 mg, 100.0%) was prepared in the same manner as in Step 2 of Reference Example 28 and used in the next step without further purification.

[1071] Reference Example 173: 8-Methyl-N-(piperidin-4-yl)quinolin-5-amine hydrochloride

[1072] Step 1: tert-butyl 4-((8-methylquinolin-5-yl)amino)piperidine-1-carboxylate

[1073] The title compound (66.5 mg, 15.6%) was prepared in the same manner as Step 1 of Reference Example 28 except that 5-bromo-8-methylquinoline was used instead of 4-bromoquinoline 277.2 mg, 1.25 mmol). MS (IER) m/z - 342.3 (M+H)+

[1074] Step 2: 8-methyl-N-(piperidin-4-yl)quinolin-5-amine hydrochloride

[1075] The title compound (61.2 mg, 100.0%) was prepared in the same manner as in Step 2 of Reference Example 28 and used in the next step without further purification.

[1076] Reference Example 174 8-(Benzyloxy)-N-(piperidin-4-yl)quinolin-5-amine hydrochloride

[1077] Step 1: tert-butyl 4-((8-(benzyloxy)quinolin-5-yl)amino)piperidine-1-carboxylate

[1078] The title compound (143.2 mg, 26.5%) was prepared in the same manner as Step 1 of Reference Example 28 except that 8-(benzyloxy)-5- was used instead of 4-bromoquinoline bromoquinoline (392.2 mg, 1.25 mmol). MS (IER) m/z - 434.3 (M+H)+

[1079] Step 2: 8-(benzyloxy)-N-(piperidin-4-yl)quinolin-5-amine hydrochloride

[1080] The title compound (134.2 mg, 100.0%) was prepared in the same manner as in Step 2 of Reference Example 28 and used in the next step without further purification.

[1081] Reference Example 175: 3-Chloro-N-(piperidin-4-yl)quinoline-5-amine hydrochloride

[1082] Step 1: tert-butyl 4-((3-chloroquinolin-5-yl)amino)piperidine-1-carboxylate

[1083] The title compound (261.0 mg, 57.8%) was prepared in the same manner as Step 1 of Reference Example 28 except that 5-bromo-3-chloroquinoline (5-bromo-3-chloroquinoline) was used instead of 4-bromoquinoline 302.7 mg, 1.25 mmol). MS (IER) m/z - 262.1 (M+H)+

[1084] Step 2: 3-chloro-N-(piperidin-4-yl)quinoline-5-amine hydrochloride

[1085] The title compound (241.4 mg, 100.0%) was prepared in the same manner as in Step 2 of Reference Example 28 and used in the next step without further purification.

[1086] Reference Example 176 N-(piperidin-4-yl)-8-(trifluoromethyl)quinoline-5-amine hydrochloride

[1087] Step 1: tert-butyl 4-((8-(trifluoromethyl)quinolin-5-yl)amino)piperidine-1-carboxylate

[1088] The title compound (147.6 mg, 29.9%) was prepared in the same manner as Step 1 of Reference Example 28 except that 5-bromo-8-(trifluoromethyl) was used instead of 4-bromoquinoline )quinoline (344.6 mg, 1.25 mmol). MS (IER) m/z - 396.2 (M+H)+

[1089] Step 2: N-(piperidin-4-yl)-8-(trifluoromethyl)quinoline-5-amine hydrochloride

[1090] The title compound (137.5 mg, 100.0%) was prepared in the same manner as in Step 2 of Reference Example 28 and used in the next step without further purification.

[1091] Reference Example 177 5-(Piperidin-4-ylamino)quinoline-2-carbonitrile hydrochloride

[1092] Step 1: tert-butyl 4-((8-(trifluoromethyl)quinolin-5-yl)amino)piperidine-1-carboxylate

[1093] The title compound (324.8 mg, 73.8%) was prepared in the same manner as Step 1 of Reference Example 28 except that 5-bromoquinoline-2-carbonitrile was used instead of 4-bromoquinoline 290.9 mg, 1.25 mmol). MS (IER) m/z -353.2 (M+H)+

[1094] Step 2: 5-(piperidin-4-ylamino)quinoline-2-carbonitrile hydrochloride

[1095] The title compound (299.7 mg, 100.0%) was prepared in the same manner as in Step 2 of Reference Example 28 and used in the next step without further purification.

[1096] Reference Example 178 N-(benzo[b]thiophen-4-yl)piperidin-4-amine hydrochloride

[1097] Step 1: tert-butyl 4-(benzo[b]thiophen-4-ylamino)piperidine-1-carboxylate

[1098] The title compound (220.4 mg, 53.1%) was prepared in the same manner as Step 1 of Reference Example 28 except that 4-bromobenzo[b]thiophene ( 4-bromobenzo[b]thiophene) was used instead of 4-bromoquinoline 266.0 mg, 1.25 mmol). MS (IER) m/z - 333.1 (M+H)+

[1099] Step 2: N-(benzo[b]thiophen-4-yl)piperidin-4-amine hydrochloride

[1100] The title compound (220.4 mg, 100.0%) was prepared in the same manner as in Step 2 of Reference Example 28 and used in the next step without further purification.

[1101] Reference Example 179: 6-Fluoro-N-(piperidin-4-yl)quinoline-4-amine hydrochloride

[1102] Step 1: tert-butyl 4-((6-fluoroquinolin-4-yl)amino)piperidine-1-carboxylate

[1103] The title compound (167.7 mg, 38.9%) was prepared in the same manner as Step 1 of Reference Example 28 except that 4-bromo-6-fluoroquinoline was used instead of 4-bromoquinoline 282.2 mg, 1.25 mmol). MS (IER) m/z - 346.2 (M+H)+

[1104] Step 2: 6-fluoro-N-(piperidin-4-yl)quinoline-4-amine hydrochloride

[1105] The title compound (154.5 mg, 100.0%) was prepared in the same manner as in Step 2 of Reference Example 28 and used in the next step without further purification.

[1106] Reference Example 180: 6-Chloro-N-(piperidin-4-yl)quinoline-4-amine hydrochloride

[1107] Step 1: tert-butyl 4-((6-chloroquinolin-4-yl)amino)piperidine-1-carboxylate

[1108] The title compound (210.0 mg, 46.5%) was prepared in the same manner as Step 1 of Reference Example 28 except that 4-bromo-6-chloroquinoline ( 4-bromo-6-chloroquinoline) was used instead of 4-bromoquinoline 302.7 mg, 1.25 mmol). MS (IER) m/z - 362.2 (M+H)+

[1109] Step 2: 6-chloro-N-(piperidin-4-yl)quinoline-4-amine hydrochloride

[1110] The title compound (194.2 mg, 100.0%) was prepared in the same manner as in Step 2 of Reference Example 28 and used in the next step without further purification.

[1111] Reference Example 181 N-(piperidin-4-yl)isoquinolin-4-amine hydrochloride

[1112] Step 1: tert-butyl 4-(isoquinolin-4-ylamino)piperidine-1-carboxylate

[1113] The title compound (381.7 mg, 93.4%) was prepared in the same manner as Step 1 of Reference Example 28 except that 4-bromoquinoline (259.7 mg) was used instead of 4-bromoquinoline , 1.25 mmol). MS (IER) m/z - 328.2 (M+H)+

[1114] Step 2: N-(piperidin-4-yl)isoquinoline-4-amine hydrochloride

[1115] The title compound (350.0 mg, 100.0%) was prepared in the same manner as in Step 2 of Reference Example 28 and used in the next step without further purification.

[1116] Reference Example 182 N-(piperidin-4-yl)isoquinolin-5-amine hydrochloride

[1117] Step 1: tert-butyl 4-(isoquinolin-5-ylamino)piperidine-1-carboxylate

[1118] The title compound (333.6 mg, 81.6%) was prepared in the same manner as Step 1 of Reference Example 28 except that 5-bromoquinoline (259.7 mg) was used instead of 4-bromoquinoline , 1.25 mmol). MS (IER) m/z - 328.2 (M+H)+

[1119] Step 2: N-(piperidin-4-yl)isoquinoline-5-amine hydrochloride

[1120] The title compound (305.9 mg, 100.0%) was prepared in the same manner as in Step 2 of Reference Example 28 and used in the next step without further purification.

[1121] Reference Example 183 N-(piperidin-4-yl)isoquinolin-6-amine hydrochloride

[1122] Step 1: tert-butyl 4-(isoquinolin-6-ylamino)piperidine-1-carboxylate

[1123] The title compound (150.1 mg, 36.7%) was prepared in the same manner as Step 1 of Reference Example 28 except that 6-bromoquinoline (259.7 mg) was used instead of 4-bromoquinoline , 1.25 mmol). MS (IER) m/z - 328.2 (M+H)+

[1124] Step 2: N-(piperidin-4-yl)isoquinoline-6-amine hydrochloride

[1125] The title compound (137.6 mg, 100.0%) was prepared in the same manner as in Step 2 of Reference Example 28 and used in the next step without further purification.

[1126] Reference Example 184 N-(piperidin-4-yl)isoquinolin-8-amine hydrochloride

[1127] Step 1: tert-butyl 4-(isoquinolin-8-ylamino)piperidine-1-carboxylate

[1128] The title compound (408.7 mg, 99.9%) was prepared in the same manner as Step 1 of Reference Example 28 except that 8-bromoquinoline (259.7 mg) was used instead of 4-bromoquinoline , 1.25 mmol). MS (IER) m/z - 328.2 (M+H)+

[1129] Step 2: N-(piperidin-4-yl)isoquinoline-8-amine hydrochloride

[1130] The title compound (374.8 mg, 100.0%) was prepared in the same manner as in Step 2 of Reference Example 28 and used in the next step without further purification.

[1131] Reference Example 185: 8-Methyl-N-(piperidin-4-yl)quinolin-4-amine hydrochloride

[1132] Step 1: tert-butyl 4-((8-methylquinolin-4-yl)amino)piperidine-1-carboxylate

[1133] The title compound (336.4 mg, 78.9%) was prepared in the same manner as Step 1 of Reference Example 28 except that 4-bromo-8-methylquinoline was used instead of 4-bromoquinoline ( 277.2 mg, 1.25 mmol). MS (IER) m/z - 342.2 (M+H)+

[1134] Step 2: 8-methyl-N-(piperidin-4-yl)quinolin-4-amine hydrochloride

[1135] The title compound (309.6 mg, 100.0%) was prepared in the same manner as in Step 2 of Reference Example 28 and used in the next step without further purification.

[1136] Reference Example 186: 8-Chloro-N-(piperidin-4-yl)quinolin-4-amine hydrochloride

[1137] Step 1: tert-butyl 4-((8-chloroquinolin-4-yl)amino)piperidine-1-carboxylate

[1138] The title compound (75.8 mg, 16.8%) was prepared in the same manner as Step 1 of Reference Example 28 except that 4-bromo-8-chloroquinoline was used instead of 4-bromoquinoline 302.7 mg, 1.25 mmol). MS (IER) m/z - 362.2 (M+H)+

[1139] Step 2: 8-chloro-N-(piperidin-4-yl)quinoline-4-amine hydrochloride

[1140] The title compound (70.1 mg, 100.0%) was prepared in the same manner as in Step 2 of Reference Example 28 and used in the next step without further purification.

[1141] Reference Example 187: 8-Fluoro-N-(piperidin-4-yl)quinoline-4-amine hydrochloride

[1142] Step 1: tert-butyl 4-((8-fluoroquinolin-4-yl)amino)piperidine-1-carboxylate

[1143] The title compound (209.4 mg, 48.6%) was prepared in the same manner as Step 1 of Reference Example 28 except that 4-bromo-8-fluoroquinoline ( 4-bromo-8-fluoroquinoline) was used instead of 4-bromoquinoline 282.2 mg, 1.25 mmol). MS (IER) m/z - 346.2 (M+H)+

[1144] Step 2: 8-fluoro-N-(piperidin-4-yl)quinoline-4-amine hydrochloride

[1145] The title compound (192.9 mg, 100.0%) was prepared in the same manner as in Step 2 of Reference Example 28 and used in the next step without further purification.

[1146] Reference Example 188 N-(piperidin-4-yl)-8-(trifluoromethyl)quinoline-4-amine hydrochloride

[1147] Step 1: tert-butyl 4-((8-(trifluoromethyl)quinolin-4-yl)amino)piperidine-1-carboxylate

[1148] The title compound (366.5 mg, 74.3%) was prepared in the same manner as Step 1 of Reference Example 28 except that 4-bromo-8-(trifluoromethyl) was used instead of 4-bromoquinoline )quinoline (344.6 mg, 1.25 mmol). MS (IER) m/z -396.2 (M+H)+

[1149] Step 2: N-(piperidin-4-yl)-8-(trifluoromethyl)quinoline-4-amine hydrochloride

[1150] The title compound (341.3 mg, 100.0%) was prepared in the same manner as in Step 2 of Reference Example 28 and used in the next step without further purification.

[1151] Reference Example 189 N-(piperidin-4-yl)-8-(trifluoromethoxy)quinoline-5-amine hydrochloride

[1152] Step 1: tert-butyl 4-((8-(trifluoromethoxy)quinolin-5-yl)amino)piperidine-1-carboxylate

[1153] The title compound (437.1 mg, 85.1%) was prepared in the same manner as Step 1 of Reference Example 28 except that 5-bromo-8-trifluoromethoxyquinoline (5-bromo-8-trifluoromethoxyquinoline) was used instead of 4-bromoquinoline 364.6 mg, 1.25 mmol). MS (IER) m/z - 412.2 (M+H)+

[1154] Step 2: N-(piperidin-4-yl)-8-(trifluoromethoxy)quinoline-5-amine hydrochloride

[1155] The title compound (408.2 mg, 100.0%) was prepared in the same manner as in Step 2 of Reference Example 28 and used in the next step without further purification.

[1156] Reference Example 190: 3-methoxy-N-(piperidin-4-yl)quinolin-5-amine hydrochloride

[1157] Step 1: tert-butyl 4-((3-methoxyquinolin-5-yl)amino)piperidine-1-carboxylate

[1158] The title compound (327.6 mg, 73.4%) was prepared in the same manner as Step 1 of Reference Example 28 except that 5-bromo-3-methoxyquinoline was used instead of 4-bromoquinoline ( 297.2 mg, 1.25 mmol). MS (IER) m/z - 358.2 (M+H)+

[1159] Step 2: 3-methoxy-N-(piperidin-4-yl)quinolin-5-amine hydrochloride

[1160] The title compound (302.7 mg, 100.0%) was prepared in the same manner as in Step 2 of Reference Example 28 and used in the next step without further purification.

[1161] Reference Example 191: 3-Fluoro-N-(piperidin-4-yl)quinoline-5-amine hydrochloride

[1162] Step 1: tert-butyl 4-((3-fluoroquinolin-5-yl)amino)piperidine-1-carboxylate

[1163] The title compound (343.7 mg, 79.7%) was prepared in the same manner as Step 1 of Reference Example 28 except that 5-bromo-3-fluoroquinoline was used instead of 4-bromoquinoline ( 282.2 mg, 1.25 mmol). MS (IER) m/z - 346.2 (M+H)+

[1164] Step 2: 3-fluoro-N-(piperidin-4-yl)quinoline-5-amine hydrochloride

[1165] The title compound (316.6 mg, 100.0%) was prepared in the same manner as in Step 2 of Reference Example 28 and used in the next step without further purification.

[1166] Reference Example 192: 1-Chloro-N-(piperidin-4-yl)isoquinolin-5-amine hydrochloride

[1167] Step 1: tert-butyl 4-((1-chloroisoquinolin-5-yl)amino)piperidine-1-carboxylate

[1168] The title compound (49.5 mg, 11.0%) was prepared in the same manner as Step 1 of Reference Example 28 except that 5-bromo-1-chloroisoquinoline was used instead of 4-bromoquinoline 302.7 mg, 1.25 mmol). MS (IER) m/z - 362.2 (M+H)+

[1169] Step 2: 1-chloro-N-(piperidin-4-yl)isoquinoline-5-amine hydrochloride

[1170] The title compound (45.8 mg, 100.0%) was prepared in the same manner as in Step 2 of Reference Example 28 and used in the next step without further purification.

[1171] Reference Example 193: 3-Chloro-N-(piperidin-4-yl)isoquinolin-5-amine hydrochloride

[1172] Step 1: tert-butyl 4-((3-chloroisoquinolin-5-yl)amino)piperidine-1-carboxylate

[1173] The title compound (332.2 mg, 73.5%) was prepared in the same manner as Step 1 of Reference Example 28 except that 5-bromo-3-chloroisoquinoline was used instead of 4-bromoquinoline 302.7 mg, 1.25 mmol). MS (IER) m/z - 362.2 (M+H)+

[1174] Step 2: 3-chloro-N-(piperidin-4-yl)isoquinoline-5-amine hydrochloride

[1175] The title compound (307.2 mg, 100.0%) was prepared in the same manner as in Step 2 of Reference Example 28 and used in the next step without further purification.

[1176] Reference Example 194: 8-Chloro-N-(piperidin-4-yl)isoquinolin-5-amine hydrochloride

[1177] Step 1: tert-butyl 4-((8-chloroisoquinolin-5-yl)amino)piperidine-1-carboxylate

[1178] The title compound (265.1 mg, 58.7%) was prepared in the same manner as Step 1 of Reference Example 28 except that 5-bromo-8-chloroisoquinoline was used instead of 4-bromoquinoline 302.7 mg, 1.25 mmol). MS (IER) m/z - 362.2 (M+H)+

[1179] Step 2: 8-chloro-N-(piperidin-4-yl)isoquinoline-5-amine hydrochloride

[1180] The title compound (245.2 mg, 100.0%) was prepared in the same manner as in Step 2 of Reference Example 28 and used in the next step without further purification.

[1181] Reference Example 195: 4-Methyl-N-(piperidin-4-yl)isoquinolin-5-amine hydrochloride

[1182] Step 1: tert-butyl 4-((4-methylisoquinolin-5-yl)amino)piperidine-1-carboxylate

[1183] The title compound (284.3 mg, 66.7%) was prepared in the same manner as Step 1 of Reference Example 28 except that 5-bromo-4-methylisoquinoline (5-bromo-4-methylisoquinoline) was used instead of 4-bromoquinoline 277.2 mg, 1.25 mmol). MS (IER) m/z - 342.2 (M+H)+

[1184] Step 2: 4-methyl-N-(piperidin-4-yl)isoquinolin-5-amine hydrochloride

[1185] The title compound (261.6 mg, 100.0%) was prepared in the same manner as in Step 2 of Reference Example 28 and used in the next step without further purification.

[1186] Reference Example 196: 3-methoxy-N-(piperidin-4-yl)isoquinolin-5-amine hydrochloride

[1187] Step 1: tert-butyl 4-((3-methoxyisoquinolin-5-yl)amino)piperidine-1-carboxylate

[1188] The title compound (407.0 mg, 91.2%) was prepared in the same manner as Step 1 of Reference Example 28 except that 5-bromo-3-methoxyisoquinoline (5-bromo-3-methoxyisoquinoline) was used instead of 4-bromoquinoline 297.2 mg, 1.25 mmol). MS (IER) m/z - 358.2 (M+H)+

[1189] Step 2: 3-methoxy-N-(piperidin-4-yl)isoquinolin-5-amine hydrochloride

[1190] The title compound (376.0 mg, 100.0%) was prepared in the same manner as in Step 2 of Reference Example 28 and used in the next step without further purification.

[1191] Reference Example 197: 8-nitro-N-(piperidin-4-yl)isoquinolin-5-amine hydrochloride

[1192] Step 1: tert-butyl 4-((8-nitroisoquinolin-5-yl)amino)piperidine-1-carboxylate

[1193] The title compound (178.1 mg, 38.2%) was prepared in the same manner as Step 1 of Reference Example 28 except that 5-bromo-8-nitroisoquinoline (5-bromo-8-nitroisoquinoline) was used instead of 4-bromoquinoline 315.9 mg, 1.25 mmol). MS (IER) m/z - 373.2 (M+H)+

[1194] Step 2: 8-nitro-N-(piperidin-4-yl)isoquinoline-5-amine hydrochloride

[1195] The title compound (165.1 mg, 100.0%) was prepared in the same manner as in Step 2 of Reference Example 28 and used in the next step without further purification.

[1196] Reference Example 198: 8-Fluoro-N-(piperidin-4-yl)isoquinolin-5-amine hydrochloride

[1197] Step 1: tert-butyl 4-((8-fluoroisoquinolin-5-yl)amino)piperidine-1-carboxylate

[1198] The title compound (377.9 mg, 87.7%) was prepared in the same manner as Step 1 of Reference Example 28 except that 5-bromo-8-fluoroisoquinoline was used instead of 4-bromoquinoline 282.2 mg, 1.25 mmol). MS (IER) m/z - 346.2 (M+H)+

[1199] Step 2: 8-fluoro-N-(piperidin-4-yl)isoquinoline-5-amine hydrochloride

[1200] The title compound (348.2 mg, 100.0%) was prepared in the same manner as in Step 2 of Reference Example 28 and used in the next step without further purification.

[1201] Reference Example 199: 2-Chloro-6,7-dimethoxy-N-(piperidin-4-yl)quinazolin-4-amine hydrochloride

[1202] Step 1: tert-butyl 4-((2-chloro-6,7-dimethoxyquinazolin-4-yl)amino)piperidine-1-carboxylate

[1203] Tert-Butyl 4-aminopiperidine-1-carboxylate (250.0 mg, 1.25 mmol) dissolved in anhydrous dichloromethane. 2,4-Dichloro-6,7-dimethoxyquinazoline (291.1 mg, 1.12 mmol) and triethylamine (0.35 ml, 2.50 mmol) were added to the resulting solution. The reaction mixture was stirred overnight at room temperature. After completion of the reaction, a saturated aqueous solution of NH ₄ Cl was added to the reaction mixture. The aqueous layer of the reaction mixture was extracted with dichloromethane. The extracted organic layer was dried and filtered over anhydrous magnesium sulfate. The filtered solution was concentrated and then purified by silica gel column chromatography (ethyl acetate/n-hexane = 1/1, v/v) to obtain the title compound (204.0 mg, 38.6%). MS (IER) m/z - 423.2 (M+H)+

[1204] Step 2: 2-chloro-6,7-dimethoxy-N-(piperidin-4-yl)quinazolin-4-amine hydrochloride

[1205] tert-butyl 4-((2-chloro-6,7-dimethoxyquinazolin-4-yl)amino)piperidine-1-carboxylate (204.0 mg, 0.48 mmol), prepared in step 1, was dissolved in dichloromethane (5.0 ml). An excess of 4.0 M hydrochloric acid dissolved in 1,4-dioxane was added dropwise to the resulting solution. The reaction mixture was stirred overnight at room temperature. After completion of the reaction, the resulting solid was filtered and dried to obtain the title compound (190.9 mg, 100.0%). The title compound was used in the next step without further purification.

[1206] Reference Example 200: 2-Chloro-8-methyl-N-(piperidin-4-yl)quinazolin-4-amine hydrochloride

[1207] Step 1: tert-butyl 4-((2-chloro-8-methylquinazolin-4-yl)amino)piperidine-1-carboxylate

[1208] The title compound (138.7 mg, 29.5%) was prepared in the same manner as Step 1 of Reference Example 199 except that instead of 2,4-dichloro-6,7-dimethoxyquinazoline, 2,4-dichloro-8-methylquinazoline (239.4 mg, 1.25 mmol). MS (IER) m/z - 377.2 (M+H)+

[1209] Step 2: 2-chloro-8-methyl-N-(piperidin-4-yl)quinazolin-4-amine hydrochloride

[1210] The title compound (128.7 mg, 100.0%) was prepared in the same manner as Step 2 of Reference Example 199 and used in the next step without further purification.

[1211] Reference Example 201 N-(piperidin-4-yl)-2,6-naphthyridin-4-amine hydrochloride

[1212] Step 1: tert-butyl 4-((2,6-naphthyridin-4-yl)amino)piperidine-1-carboxylate

[1213] The title compound (113.5 mg, 27.7%) was prepared in the same manner as Step 1 of Reference Example 28 except that 4-bromo-2,6- was used instead of 4-bromoquinoline. naphthyridine (260.9 mg, 1.25 mmol). MS (IER) m/z - 329.2 (M+H)+

[1214] Step 2: N-(piperidin-4-yl)-2,6-naphthyridin-4-amine hydrochloride

[1215] The title compound (104.1 mg, 100.0%) was prepared in the same manner as in Step 2 of Reference Example 28 and used in the next step without further purification.

[1216] Reference Example 202: 8-Chloro-N-(piperidin-4-yl)isoquinolin-4-amine hydrochloride

[1217] Step 1: tert-butyl 4-((8-chloroisoquinolin-4-yl)amino)piperidine-1-carboxylate

[1218] The title compound (102.8 mg, 22.8%) was prepared in the same manner as Step 1 of Reference Example 28 except that 4-bromo-8-chloroisoquinoline was used instead of 4-bromoquinoline 302.7 mg, 1.25 mmol). MS (IER) m/z - 362.2 (M+H)+

[1219] Step 2: 8-chloro-N-(piperidin-4-yl)isoquinoline-4-amine hydrochloride

[1220] The title compound (95.1 mg, 100.0%) was prepared in the same manner as in Step 2 of Reference Example 28 and used in the next step without further purification.

[1221] Reference Example 203: N-(piperidin-4-yl)quinolin-3-amine hydrochloride [1222] Step 1: tert-butyl 4-(quinolin-3-ylamino)piperidine-1-carboxylate

[1223] The title compound (212.5 mg, 99.9%) was prepared in the same manner as Step 1 of Reference Example 28 except that 3-bromoquinoline (135.0 mg) was used instead of 4-bromoquinoline , 0.65 mmol). MS (IER) m/z - 328.2 (M+H)+

[1224] Step 2: N-(piperidin-4-yl)quinoline-3-amine hydrochloride

[1225] The title compound (202.9 mg, 100.0%) was prepared in the same manner as in Step 2 of Reference Example 28 and used in the next step without further purification.

[1226] Reference Example 204: 6-Methyl-N-(piperidin-4-yl)quinolin-3-amine hydrochloride

[1227] Step 1: tert-butyl 4-((6-methylquinolin-3-yl)amino)piperidine-1-carboxylate

[1228] The title compound (143.3 mg, 64.7%) was prepared in the same manner as Step 1 of Reference Example 28 except that 3-bromo-6-methylquinoline was used instead of 4-bromoquinoline 144.2 mg, 0.65 mmol). MS (IER) m/z - 342.3 (M+H)+

[1229] Step 2: 6-methyl-N-(piperidin-4-yl)quinolin-3-amine hydrochloride

[1230] The title compound (131.9 mg, 100.0%) was prepared in the same manner as in Step 2 of Reference Example 28 and used in the next step without further purification.

[1231] Reference Example 205: 6-Fluoro-N-(piperidin-4-yl)quinoline-3-amine hydrochloride

[1232] Step 1: tert-butyl 4-((6-fluoroquinolin-3-yl)amino)piperidine-1-carboxylate

[1233] The title compound (218.3 mg, 64.7%) was prepared in the same manner as Step 1 of Reference Example 28 except that 3-bromo-6-fluoroquinoline was used instead of 4-bromoquinoline ( 146.7 mg, 0.65 mmol). MS (IER) m/z - 346.2 (M+H)+

[1234] Step 2: 6-fluoro-N-(piperidin-4-yl)quinoline-3-amine hydrochloride

[1235] The title compound (201.1 mg, 100.0%) was prepared in the same manner as in Step 2 of Reference Example 28 and used in the next step without further purification.

[1236] Reference Example 206: 6-methoxy-N-(piperidin-4-yl)quinolin-3-amine hydrochloride

[1237] Step 1: tert-butyl 4-((6-methoxyquinolin-3-yl)amino)piperidine-1-carboxylate

[1238] The title compound (194.2 mg, 83.7%) was prepared in the same manner as Step 1 of Reference Example 28 except that 3-bromo-6-methoxyquinoline was used instead of 4-bromoquinoline 154.5 mg, 0.65 mmol). MS (IER) m/z - 358.2 (M+H)+

[1239] Step 2: 6-methoxy-N-(piperidin-4-yl)quinolin-3-amine hydrochloride

[1240] The title compound (179.4 mg, 100.0%) was prepared in the same manner as in Step 2 of Reference Example 28 and used in the next step without further purification.

[1241] Reference Example 207: 7-methoxy-N-(piperidin-4-yl)quinolin-3-amine hydrochloride

[1242] Step 1: tert-butyl 4-((7-methoxyquinolin-3-yl)amino)piperidine-1-carboxylate

[1243] The title compound (66.0 mg, 28.5%) was prepared in the same manner as Step 1 of Reference Example 28 except that 3-bromo-7-methoxyquinoline (3-bromo-7-methoxyquinoline) was used instead of 4-bromoquinoline 154.5 mg, 0.65 mmol). MS (IER) m/z - 358.2 (M+H)+

[1244] Step 2: 7-methoxy-N-(piperidin-4-yl)quinolin-3-amine hydrochloride

[1245] The title compound (61.0 mg, 100.0%) was prepared in the same manner as in Step 2 of Reference Example 28 and used in the next step without further purification.

[1246] Reference Example 208: 8-methoxy-N-(piperidin-4-yl)quinolin-3-amine hydrochloride

[1247] Step 1: tert-butyl 4-((8-methoxyquinolin-3-yl)amino)piperidine-1-carboxylate

[1248] The title compound (78.5 mg, 33.8%) was prepared in the same manner as Step 1 of Reference Example 28 except that 3-bromo-8-methoxyquinoline (3-bromo-8-methoxyquinoline) was used instead of 4-bromoquinoline 154.5 mg, 0.65 mmol). MS (IER) m/z - 358.1 (M+H)+

[1249] Step 2: 8-methoxy-N-(piperidin-4-yl)quinolin-3-amine hydrochloride

[1250] The title compound (72.5 mg, 100.0%) was prepared in the same manner as in Step 2 of Reference Example 28 and used in the next step without further purification.

[1251] Reference Example 209 N-(piperidin-4-yl)-1,8-naphthyridin-3-amine hydrochloride

[1252] Step 1: tert-butyl 4-((1,8-naphthyridin-3-yl)amino)piperidine-1-carboxylate

[1253] The title compound (189.1 mg, 46.1%) was prepared in the same manner as Step 1 of Reference Example 28 except that 3-bromo-1,8- was used instead of 4-bromoquinoline. naphthyridine (260.9 mg, 1.25 mmol). MS (IER) m/z - 329.2 (M+H)+

[1254] Step 2: N-(piperidin-4-yl)-1,8-naphthyridin-3-amine hydrochloride

[1255] The title compound (173.4 mg, 100.0%) was prepared in the same manner as in Step 2 of Reference Example 28 and used in the next step without further purification.

[1256] Reference Example 210: 7-Chloro-N-(piperidin-4-yl)-1,8-naphthyridin-3-amine hydrochloride

[1257] Step 1: tert-butyl 4-((7-chloro-1,8-naphthyridin-3-yl)amino)piperidine-1-carboxylate

[1258] The title compound (57.9 mg, 12.8%) was prepared in the same manner as Step 1 of Reference Example 28 except that 6-bromo-2-chloro- 1,8-naphthyridine (303.9 mg, 1.25 mmol). MS (IER) m/z - 363.2 (M+H)+

[1259] Step 2: 7-chloro-N-(piperidin-4-yl)-1,8-naphthyridin-3-amine hydrochloride

[1260] The title compound (53.6 mg, 100.0%) was prepared in the same manner as in Step 2 of Reference Example 28 and used in the next step without further purification.

[1261] Reference Example 211: 8-Ethoxy-N-(piperidin-4-yl)quinolin-5-amine hydrochloride

[1262] Step 1: tert-butyl 4-((8-ethoxyquinolin-5-yl)amino)piperidine-1-carboxylate

[1263] The title compound (776.4 mg, 83.7%) was prepared in the same manner as Step 1 of Reference Example 28 except that 5-bromo-8-ethoxyquinoline (5-bromo-8-ethoxyquinoline) was used instead of 4-bromoquinoline 629.4 mg, 2.49 mmol). MS (IER) m/z - 372.2 (M+H)+

[1264] Step 2: 8-ethoxy-N-(piperidin-4-yl)quinolin-5-amine hydrochloride

[1265] The title compound (432.6 mg, 60.1%) was prepared in the same manner as Step 2 of Reference Example 28 and used in the next step without further purification. MS (IER) m/z - 272.2 (M+H)+

[1266] Reference Example 212 N-(piperidin-4-yl)benzo[d]thiazol-7-amine hydrochloride

[1267] Step 1: tert-butyl 4-(1,3-benzothiazol-7-ylamino)piperidine-1-carboxylate

[1268] 1-Boc-4-piperidone (250.0 mg, 1.26 mmol) was dissolved in anhydrous dichloromethane. Benzo[d]thiazol-7-amine (188.5 mg, 1.26 mmol), acetic acid (0.15 ml) and sodium triacetoxyborohydride (265.9 mg, 1.26 mmol) were added to the resulting solution. The reaction mixture was stirred overnight at room temperature. After completion of the reaction, a saturated aqueous sodium carbonate solution was added to the reaction mixture. The aqueous layer of the reaction mixture was extracted with dichloromethane. The extracted organic layer was dried and filtered over anhydrous magnesium sulfate. The filtered solution was concentrated and then purified by silica gel column chromatography (ethyl acetate/n-hexane = 1/1, v/v) to obtain the title compound (375.3 mg, 89.7%). MS (IER) m/z - 334.2 (M+H)+

[1269] Step 2: N-(piperidin-4-yl)benzo[d]thiazol-7-amine hydrochloride

[1270] Tert-Butyl 4-(1,3-benzothiazol-7-ylamino)piperidin-1-carboxylate (375.3 mg, 1.13 mmol) obtained in step 1 was dissolved in dichloromethane (5.0 ml) . An excess of 4.0 M hydrochloric acid dissolved in 1,4-dioxane was added dropwise to the resulting solution. The reaction mixture was stirred overnight at room temperature. After completion of the reaction, the resulting solid was filtered and dried to obtain the title compound (344.8 mg, 100.0%). The title compound was used in the next step without further purification.

[1271] Reference Example 213 1-(4-(piperidin-4-ylamino)indolin-1-yl)ethan-1-one hydrochloride

[1272] Step 1: tert-butyl 4-[(1-acetylindolin-4-yl)amino]piperidine-1-carboxylate

[1273] The title compound (310.2 mg, 68.8%) was prepared in the same manner as Step 1 of Reference Example 212 except that 1-( 4-aminoindolin-1-yl)ethanone (221.1 mg, 1.26 mmol). MS (IER) m/z - 360.2 (M+H)+

[1274] Step 2: 1-(4-(piperidin-4-ylamino)indolin-1-yl)ethan-1-one hydrochloride

[1275] The title compound (286.8 mg, 100.0%) was prepared in the same manner as Step 2 of Reference Example 212 and used in the next step without further purification.

[1276] Reference Example 214: 8-Methyl-N-(piperidin-4-yl)quinolin-6-amine hydrochloride

[1277] Step 1: tert-butyl 4-((8-methylquinolin-6-yl)amino)piperidine-1-carboxylate

[1278] The title compound (196.4 mg, 50.1%) was prepared in the same manner as Step 1 of Reference Example 28 except that 6-bromo-8-methylquinoline was used instead of 4-bromoquinoline 255.0 mg, 1.15 mmol). MS (IER) m/z - 342.2 (M+H)+

[1279] Step 2: 8-methyl-N-(piperidin-4-yl)quinolin-6-amine hydrochloride

[1280] The title compound (180.7 mg, 100.0%) was prepared in the same manner as in Step 2 of Reference Example 28 and used in the next step without further purification.

[1281] Reference Example 215: 8-Fluoro-N-(piperidin-4-yl)quinoline-6-amine hydrochloride

[1282] Step 1: tert-butyl 4-((8-fluoroquinolin-6-yl)amino)piperidine-1-carboxylate

[1283] The title compound (317.3 mg, 80.0%) was prepared in the same manner as Step 1 of Reference Example 28 except that 6-bromo-8-fluoroquinoline was used instead of 4-bromoquinoline 259.6 mg, 1.15 mmol). MS (IER) m/z - 346.2 (M+H)+

[1284] Step 2: 8-fluoro-N-(piperidin-4-yl)quinoline-6-amine hydrochloride

[1285] The title compound (292.4 mg, 100.0%) was prepared in the same manner as in Step 2 of Reference Example 28 and used in the next step without further purification.

[1286] Reference Example 216: 8-Chloro-N-(piperidin-4-yl)quinoline-6-amine hydrochloride

[1287] Step 1: tert-butyl 4-((8-chloroquinolin-6-yl)amino)piperidine-1-carboxylate

[1288] The title compound (369.5 mg, 88.9%) was prepared in the same manner as Step 1 of Reference Example 28 except that 6-bromo-8-chloroquinoline was used instead of 4-bromoquinoline 278.5 mg, 1.15 mmol). MS (IER) m/z - 362.2 (M+H)+

[1289] Step 2: 8-chloro-N-(piperidin-4-yl)quinoline-6-amine hydrochloride

[1290] The title compound (341.7 mg, 100.0%) was prepared in the same manner as in Step 2 of Reference Example 28 and used in the next step without further purification.

[1291] Reference Example 217 N-(piperidin-4-yl)-8-(trifluoromethyl)quinoline-6-amine hydrochloride

[1292] Step 1: tert-butyl 4-((8-(trifluoromethyl)quinolin-6-yl)amino)piperidine-1-carboxylate

[1293] The title compound (284.3 mg, 62.6%) was prepared in the same manner as Step 1 of Reference Example 28 except that 6-bromo-8-(trifluoromethyl) was used instead of 4-bromoquinoline )quinoline (317.0 mg, 1.15 mmol). MS (IER) m/z - 396.2 (M+H)+

[1294] Step 2: N-(piperidin-4-yl)-8-(trifluoromethyl)quinoline-6-amine hydrochloride

[1295] The title compound (264.8 mg, 100.0%) was prepared in the same manner as in Step 2 of Reference Example 28 and used in the next step without further purification.

[1296] Reference Example 218 4-(Piperidin-4-ylamino)-2H-chromen-2-one hydrochloride

[1297] Step 1: tert-butyl 4-((2-oxo-2H-chromen-4-yl)amino)piperidine-1-carboxylate

[1298] Tert-Butyl 4-aminopiperidine-1-carboxylate (300 mg, 1.4 mmol) was dissolved in anhydrous DMF. 4-bromo-2H-chromen-2-one (337.1 mg, 1.49 mmol) and potassium carbonate (414.0 mg, 2.996 mmol) were added to the resulting solution. The reaction mixture was stirred at 100°C overnight. After completion of the reaction, the reaction mixture was cooled to room temperature, and then water was added to extract the aqueous layer with ethyl acetate. The extracted organic layer was dried and filtered over anhydrous magnesium sulfate. The filtered solution was concentrated and then purified by silica gel column chromatography (ethyl acetate/n-hexane = 1/1, v/v) to obtain the title compound (300 mg, 58.1%). ¹ H-NMR ( _MeOD4 , 400 MHz) δ 8.01 (dd, 1H), 7.61 (td, 1H), 7.36-7.32 (m, 2H), 5.41 (s, 1H ), 4.16 (d, 2H), 3.77-3.75 (m, 1H), 2.97 (s, 2H), 2.07-2.02 (m, 2H), 1.60- 1.53 (m, 2H), 1.49 (s, 9H).

[1299] Step 2: 4-(piperidin-4-ylamino)-2H-chromen-2-one hydrochloride

[1300] The title compound (210.0 mg, 76.0%) was prepared in the same manner as in Step 2 of Reference Example 28 and used in the next step without further purification. ¹ H-NMR ( _MeOD4 , 400 MHz) δ 8.05 (dd, 1H), 7.63 (td, 1H), 7.38-7.33 (m, 2H), 5.45 (s, 1H ), 3.95-3.89 (m, 1H), 3.53 (d, 2H), 3.22 (td, 2H), 2.33 (d, 2H), 2.00-1.89 ( m, 2H).

[1301] Reference Example 219 N-(piperidin-4-yl)-1,5-naphthyridin-4-amine hydrochloride

[1302] Step 1: tert-butyl 4-((1,5-naphthyridin-4-yl)amino)piperidine-1-carboxylate

[1303] The title compound (700.0 mg, 85.4%) was prepared in the same manner as Step 1 of Reference Example 28 except that 4-bromo-1,5- was used instead of 4-bromoquinoline. naphthyridine (521.8 mg, 2.49 mmol). MS (IER) m/z - 329.2 (M+H)+

[1304] Step 2: N-(piperidin-4-yl)-1,5-naphthyridin-4-amine hydrochloride

[1305] The title compound (321.0 mg, 80.6%) was prepared in the same manner as Step 2 of Reference Example 28 and used in the next step without further purification. MS (IER) m/z - 229.2 (M+H)+

[1306] Reference Example 220 N-(piperidin-4-yl)-2-(trifluoromethyl)quinoline-6-amine hydrochloride

[1307] Step 1: tert-butyl 4-((2-(trifluoromethyl)quinolin-6-yl)amino)piperidine-1-carboxylate

[1308] The title compound (462.5 mg, 93.7%) was prepared in the same manner as Step 1 of Reference Example 28 except that 6-bromo-2-(trifluoromethyl) was used instead of 4-bromoquinoline )quinoline (344.6 mg, 1.25 mmol). MS (IER) m/z - 396.2 (M+H)+

[1309] Step 2: N-(piperidin-4-yl)-2-(trifluoromethyl)quinoline-6-amine hydrochloride

[1310] The title compound (430.8 mg, 100.0%) was prepared in the same manner as in Step 2 of Reference Example 28 and used in the next step without further purification.

[1311] Reference Example 221: 4-methoxy-N-(piperidin-4-yl)quinolin-6-amine hydrochloride

[1312] Step 1: tert-butyl 4-((4-methoxyquinolin-6-yl)amino)piperidine-1-carboxylate

[1313] The title compound (110.2 mg, 24.7%) was prepared in the same manner as Step 1 of Reference Example 28 except that 6-bromo-4-methoxy- quinoline (297.2 mg, 1.25 mmol). MS (IER) m/z - 358.2 (M+H)+

[1314] Step 2: 4-methoxy-N-(piperidin-4-yl)quinolin-6-amine hydrochloride

[1315] The title compound (101.7 mg, 100.0%) was prepared in the same manner as in Step 2 of Reference Example 28 and used in the next step without further purification.

[1316] Reference Example 222: 2-Bromo-N-(piperidin-4-yl)pyridin-4-amine hydrochloride

[1317] Step 1: tert-butyl 4-[(2-bromo-4-pyridyl)amino]piperidine-1-carboxylate

[1318] The title compound (257.0 mg, 57.5%) was prepared in the same manner as Step 1 of Reference Example 212 except that 4-amino was used instead of benzo[d]thiazol-7-amine -2-bromopyridine (217.1 mg, 1.26 mmol). MS (IER) m/z - 358.1 (M+H)+

[1319] Step 2: 2-bromo-N-(piperidin-4-yl)pyridin-4-amine hydrochloride

[1320] The title compound (237.3 mg, 100.0%) was prepared in the same manner as Step 2 of Reference Example 212 and used in the next step without further purification.

[1321] Reference Example 223 N-(piperidin-4-yl)-1H-benzo[d]imidazol-7-amine hydrochloride

[1322] Step 1: tert-butyl 4-((1H-benzo[d]imidazol-7-yl)amino)piperidine-1-carboxylate

[1323] The title compound (319.6 mg, 80.5%) was prepared in the same manner as Step 1 of Reference Example 212 except that 3H- benzo[d]imidazol-4-amine (167.1 mg, 1.26 mmol). MS (IER) m/z - 317.2 (M+H)+

[1324] Step 2: N-(piperidin-4-yl)-1H-benzo[d]imidazol-7-amine hydrochloride

[1325] The title compound (292.1 mg, 100.0%) was prepared in the same manner as in Step 2 of Reference Example 212 and used in the next step without further purification.

[1326] Reference Example 224: 2-Chloro-6-morpholino-N-(piperidin-4-yl)pyridin-4-amine hydrochloride

[1327] Step 1: tert-butyl 4-((2-chloro-6-morpholinopyridin-4-yl)amino)piperidine-1-carboxylate

[1328] The title compound (463.1 mg, 93.0%) was prepared in the same manner as Step 1 of Reference Example 212 except that 4-amino was used instead of benzo[d]thiazol-7-amine -2-chloro-6-morpholinopyridine (268.1 mg, 1.26 mmol). MS (IER) m/z - 397.2 (M+H)+

[1329] Step 2: 2-chloro-6-morpholino-N-(piperidin-4-yl)pyridin-4-amine hydrochloride

[1330] The title compound (431.5 mg, 100.0%) was prepared in the same manner as Step 2 of Reference Example 212 and used in the next step without further purification.

[1331] Reference Example 225 N-(piperidin-4-yl)-3-(trifluoromethyl)quinoline-5-amine hydrochloride

[1332] Step 1: tert-butyl 4-((3-(trifluoromethyl)quinolin-5-yl)amino)piperidine-1-carboxylate

[1333] The title compound (853.9 mg, 86.5%) was prepared in the same manner as Step 1 of Reference Example 28 except that 5-bromo-3-(trifluoromethyl) was used instead of 4-bromoquinoline )quinoline (689.2 mg, 2.50 mmol). MS (IER) m/z - 396.1 (M+H)+

[1334] Step 2: N-(piperidin-4-yl)-3-(trifluoromethyl)quinoline-5-amine hydrochloride

[1335] The title compound (795.0 mg, 100.0%) was prepared in the same manner as in Step 2 of Reference Example 28 and used in the next step without further purification.

[1336] Reference Example 226: N-Phenyl-5-(piperidin-4-ylamino)quinoline-3-carboxamide hydrochloride

[1337] Step 1: 5-bromo-N-phenylquinoline-3-carboxamide

[1338] 5-Bromoquinoline-3-carboxylic acid (300 mg, 1.19 mmol) was dissolved in dimethylformamide. Aniline (133.0 mg, 1.42 mmol), HATU (O-(7-azabenzotriazol-1-yl)-N,N,N',N'-tetramethyluran hexafluorophosphate) (633.6 mg, 1.67 mmol) and diisopropylethylamine (769.16 mg, 5.95 mmol). The reaction mixture was stirred overnight at room temperature. After completion of the reaction, water was added to the reaction mixture. The aqueous layer of the reaction mixture was extracted with dichloromethane. The extracted organic layer was dried and filtered over anhydrous magnesium sulfate. The filtered solution was concentrated and then purified by silica gel column chromatography (ethyl acetate/n-hexane = 1/1, v/v) to give the title compound (144.0 mg, 36.9%). ¹ H-NMR (CDCl ₃ , 400 MHz) δ 9.40 (dd, 1H), 8.97 (d, 1H), 8.16 (d, 1H), 7.99 (s, 1H), 7, 94 (d, 1H), 7.73-7.68 (m, 3H)m 7.44 (t, 2H), 7.23 (t, 1H).

[1339] Step 2: tert-butyl 4-(3-(phenylcarbamoyl)quinolin-5-yl)amino)piperidine-1-carboxylate

[1340] 5-Bromo-N-phenylquinoline-3-carboxamide (144.0 mg, 0.44 mmol) obtained in step 1 was dissolved in anhydrous toluene. To the resulting solution was added tert-butyl-4-aminopiperidine-1-carboxylate (88.2 mg, 0.44 mmol), cesium carbonate (103.1 mg, 0.53 mmol), tris(dibenzylideneacetone)dipalladium(0) ( 36.6 mg, 0.04 mmol) and (+/-)-2,2'-bis(diphenylphospino)-1,1'-binaphthalene (32.9 mg, 0.05 mmol). The reaction mixture was refluxed and stirred at 100°C overnight. After completion of the reaction, the reaction mixture was cooled to room temperature, and then water was added to extract the aqueous layer with ethyl acetate.

The extracted organic layer was dried and filtered over anhydrous magnesium sulfate. The filtered solution was concentrated and then purified by silica gel column chromatography (ethyl acetate/n-hexane = 1/1, v/v) to give the title compound (81.4 mg, 41.4%). MS (IER) m/z - 447.2 (M+H)+

[1341] Step 3: N-phenyl-5-(piperidin-4-ylamino)quinoline-3-carboxamide hydrochloride

[1342] tert-butyl 4-((3-(phenylcarbamoyl)quinolin-5-yl)amino)piperidine-1-carboxylate (81.4 mg, 0.18 mmol) obtained in step 2 was dissolved in dichloromethane (8 .4 ml), and then an excess of 4.0 M hydrochloric acid dissolved in 1,4-dioxane was added dropwise. The reaction mixture was stirred overnight at room temperature. After completion of the reaction, the resulting solid was filtered, washed and dried in vacuo to obtain the title compound (5.4 mg, 7.2%).

[1343] Reference Example 227: N-Benzyl-N-methyl-5-(piperidin-4-ylamino)quinoline-3-carboxamide hydrochloride

[1344] Step 1: N-benzyl-5-bromo-N-methylquinoline-3-carboxamide

[1345] The title compound (172.2 mg, 40.7%) was prepared in the same manner as Step 1 of Reference Example 226 except that N-methyl-1-phenylmethanamine (173, 0 mg, 1.42 mmol). ¹ H-NMR (CDCl ₃ , 400 MHz) δ 9.04 (s, 1H), 8.64 (s, 1H), 8.11 (s, 1H), 7.89,7.86 (m, 1H ), 7.64-7.62 (m, 1H), 7.43-7.35 (m, 4H), 7.24-7.23 (m, 1H), 4.73 (d, 2H), 3.08 (d, 3H).

[1346] Step 2: tert-butyl 4-(3-(benzyl(methyl)carbamoyl)quinolin-5-yl)amino)piperidine-1-carboxylate

[1347] The title compound (120.8 mg, 52.4%) was prepared in the same manner as Step 2 of Reference Example 226. MS (ESI) m/z - 475.3 (M+H)+

[1348] Step 3: N-benzyl-N-methyl-5-(piperidin-4-ylamino)quinoline-3-carboxamide hydrochloride

[1349] The title compound (105.3 mg, 92.4%) was prepared in the same manner as Step 3 of Reference Example 226 and used in the next step without further purification.

[1350] Reference Example 228: N-Methyl-5-(piperidin-4-ylamino)quinoline-8-carboxamide hydrochloride

[1351] Step 1: tert-butyl 4-((8-(methylcarbamoyl)quinolin-5-yl)amino)piperidine-1-carboxylate

[1352] The title compound (116.9 mg, 42.0%) was prepared in the same manner as Step 2 of Example 140 except that instead of tert-butyl (S)-3-aminopyrrolidine-1- carboxylate, tert-butyl-4-aminopiperidine-1-carboxylate (144.2 mg, 0.72 mmol) was used. MS (IER) m/z - 385.2 (M+H)+

[1353] Step 2: N-methyl-5-(piperidin-4-ylamino)quinoline-8-carboxamide hydrochloride

[1354] The title compound (71.3 mg, 85.6%) was prepared in the same manner as Step 3 of Reference Example 140 and used in the next step without further purification.

[1355] Reference Example 229: N,N-Dimethyl-5-(piperidin-4-ylamino)quinoline-8-carboxamide hydrochloride

[1356] Step 1: tert-butyl 4-((8-(dimethylcarbamoyl)quinolin-5-yl)amino)piperidine-1-carboxylate

[1357] The title compound (84.9 mg, 32.9%) was prepared in the same manner as Step 2 of Example 141 except that instead of tert-butyl (S)-3-aminopyrrolidine-1-carboxylate tert-butyl-4-aminopiperidine-1-carboxylate (128.0 mg, 0.64 mmol) was used. MS (IER) m/z - 399.2 (M+H)+

[1358] Step 2: N,N-dimethyl-5-(piperidin-4-ylamino)quinoline-8-carboxamide hydrochloride

[1359] The title compound (60.1 mg, 23.4%) was prepared in the same manner as Step 3 of Reference Example 141 and used in the next step without further purification

[1360] Reference Example 230: N-Methyl-N-phenyl-5-(piperidin-4-ylamino)quinoline-8-carboxamide hydrochloride

[1361] Step 1: tert-butyl 4-((8-(methyl (phenyl)carbamoyl)quinolin-5-yl)amino)piperidine-1-carboxylate

[1362] The title compound (196.6 mg, 39.9%) was prepared in the same manner as Step 2 of Example 143 except that instead of tert-butyl (5)-3-aminopyrrolidine-1-carboxylate tert-butyl-4-aminopiperidine-1-carboxylate (128.0 mg, 0.64 mmol) was used. MS (IER) m/z - 461.3 (M+H)+

[1363] Step 2: N-methyl-N-phenyl-5-(piperidin-4-ylamino)quinoline-8-carboxamide hydrochloride

[1364] The title compound (134.2 mg, 72.6%) was prepared in the same manner as Step 3 of Reference Example 143 and used in the next step without further purification

[1365] Reference Example 231: N-Benzyl-N-methyl-5-(piperidin-4-ylamino)quinoline-8-carboxamide hydrochloride

[1366] Step 1: tert-butyl 4-((8-(benzyl(methyl)carbamoyl)quinolin-5-yl)amino)piperidine-1-carboxylate

[1367] The title compound (218.1 mg, 32.4%) was prepared in the same manner as Step 2 of Example 144 except that instead of tert-butyl(5)-3-aminopyrrolidine-1- carboxylate, tert-butyl-4-aminopiperidine-1-carboxylate (215.0 mg, 1.07 mmol) was used. MS (IER) m/z - 475.3 (M+H)+

[1368] Step 2: N-methyl-N-phenyl-5-(piperidin-4-ylamino)quinoline-8-carboxamide hydrochloride

[1369] The title compound (179.2 mg, 87.1%) was prepared in the same manner as Step 3 of Reference Example 144 and used in the next step without further purification

[1370] Reference Example 232: N-Phenyl-5-(piperidin-4-ylamino)quinoline-8-carboxamide hydrochloride

[1371] Step 1: tert-butyl 4-((8-(phenylcarbamoyl)quinolin-5-yl)amino)piperidine-1-carboxylate

[1372] The title compound (196.9 mg, 41.6%) was prepared in the same manner as Step 2 of Example 142 except that instead of tert-butyl (S)-3-aminopyrrolidine-1-carboxylate tert-butyl-4-aminopiperidine-1-carboxylate (213.0 mg, 1.06 mmol) was used. MS (IER) m/z - 447.2 (M+H)+

[1373] Step 2: N-phenyl-5-(piperidin-4-ylamino)quinoline-8-carboxamide hydrochloride

[1374] The title compound (100.8 mg, 54.4%) was prepared in the same manner as Step 3 of Reference Example 142 and used in the next step without further purification

[1375] Reference Example 233: 5-(Piperidin-4-ylamino)-K-(pyridin-2-yl)quinoline-8-carboxamide hydrochloride

[1376] Step 1: tert-butyl 4-((8-(pyridin-2-ylcarbamoyl)quinolin-5-yl)amino)piperidine-1-carboxylate

[1377] The title compound (100.6 mg, 45.0%) was prepared in the same manner as Step 2 of Example 147 except that instead of tert-butyl (S)-3-aminopyrrolidine-1-carboxylate tert-butyl-4-aminopiperidine-1-carboxylate (100.0 mg, 0.50 mmol) was used. MS (IER) m/z - 448.2 (M+H)+

[1378] Step 2: 5-(piperidin-4-ylamino)-N-(pyridin-2-yl)quinoline-8-carboxamide hydrochloride

[1379] The title compound (63.5 mg, 67.6%) was prepared in the same manner as Step 3 of Reference Example 147 and used in the next step without further purification. ^1H -NMR ( _MeOD4 , 400 MHz) δ 9.40 (s, 1H), 9.18 (dd, 1H), 8.84 (d, 1H), 8.53-8.49 (m, 2H ), 8.02 (d, 1H), 7.89 (dd, 1H), 7.67 (t, 1H), 7.17 (d, 1H), 4.22-4.17 (m, 1H) , 3.58 (d, 2H), 3.30-3.26 (m, 2H), 2.39 (d, 2H), 2.12-2.02 (m, 2H).

[1380] Reference Example 234 5-(Piperidin-4-ylamino)-N-(pyridin-3-yl)quinoline-8-carboxamide hydrochloride

[1381] Step 1: tert-butyl 4-((8-(pyridin-3-ylcarbamoyl)quinolin-5-yl)amino)piperidine-1-carboxylate

[1382] The title compound (210.3 mg, 94.1%) was prepared in the same manner as Step 2 of Example 145 except that instead of tert-butyl (S)-3-aminopyrrolidine-1- carboxylate, tert-butyl-4-aminopiperidine-1-carboxylate (100.0 mg, 0.50 mmol) was used. MS (IER) m/z - 448.2 (M+H)+

[1383] Step 2: 5-(piperidin-4-ylamino)-N-(pyridin-3-yl)quinoline-8-carboxamide hydrochloride

[1384] The title compound (195.3 mg, 98.9%) was prepared in the same manner as Step 3 of Reference Example 145 and used in the next step without further purification. ¹ H-NMR (MeOD4, 400 MHz) δ 9.66 (d, 1H), 9.16 (dd, 1H), 8.88 (d, 1H), 8.80 (d, 1H), 8.73 -8.71 (m, 1H), 8.63 (d, 1H), 8.14-8.11 (m, 1H), 7.94-7.88 (m, 1H), 7.17 (d , 1H), 4.22-4.17 (m, 1H), 3.58 (d, 2H), 3.27 (d, 2H), 2.40 (d, 2H), 2.03 (d, 2H).

[1385] Reference Example 235 5-(Piperidin-4-ylamino)-N-(pyridin-4-yl)quinoline-8-carboxamide hydrochloride

[1386] Step 1: tert-butyl 4-((8-(pyridin-4-ylcarbamoyl)quinolin-5-yl)amino)piperidine-1-carboxylate

[1387] The title compound (130.1 mg, 58.2%) was prepared in the same manner as Step 2 of Example 146 except that instead of tert-butyl (5)-3-aminopyrrolidine-1-carboxylate tert-butyl-4-aminopiperidine-1-carboxylate (100.0 mg, 0.50 mmol) was used. MS (IER) m/z - 448.2 (M+H)+

[1388] Step 2: 5-(piperidin-4-ylamino)-N-(pyridin-4-yl)quinoline-8-carboxamide hydrochloride

[1389] The title compound (68.6 mg, 56.0%) was prepared in the same manner as Step 3 of Reference Example 146 and used in the next step without further purification. ^1H -NMR ( _MeOD4 , 400 MHz) δ 9.34-9.24 (m, 1H), 9.15 (d, 1H), 8.79 (d, 1H), 8.67 (d, 2H ), 8.47 (d, 2H), 7.84 (s, 1H), 7.12 (d, 1H), 4.18-4.12 (m, 1H), 3.57 (d, 2H) , 3.26 (d, 2H), 2.40 (d, 2H), 2.07-1.96 (m, 2H).

[1390] Reference Example 236: 5-(Piperidin-4-ylamino)-N-(pyrimidin-2-yl)quinoline-8-carboxamide hydrochloride

[1391] Step 1: 5-Bromo-N-(pyrimidin-2-yl)quinoline-8-carboxamide

[1392] The title compound (140.1 mg, 21.4%) was prepared in the same manner as Step 1 of Reference Example 140 except that pyrimidin-2-amine (188.6 mg) was used instead of methamine , 1.98 mmol). ¹ H-NMR (CDCl ₃ , 400 MHz) δ 9.16 (dd, 1H), 8.87 (d, 1H), 8.79 (dd, 1H), 8.76 (d, 2H), 8. 07 (d, 1H), 7.69 (dd, 1H), 7.08 (t, 1H).

[1393] Step 2: tert-butyl 4-(8-(pyrimidin-2-ylcarbamoyl)quinolin-5-yl)amino)piperidine-1-carboxylate

[1394] The title compound (144.4 mg, 75.8%) was prepared in the same manner as Step 1 of Reference Example 233 except that instead of 5-bromo-N-(pyridin-2-yl )quinoline-8-carboxamide (140.3 mg, 0.43 mmol) obtained in step 1, 5-bromo-N-(pyrimidin-2-yl)quinoline-8-carboxamide was used. MS (IER) m/z - 449.2 (M+H)+

[1395] Step 3: (S)-N-(pyridin-4-yl)-5-(pyrrolidin-3-ylamino)quinoline-8-carboxamide hydrochloride

[1396] The title compound (63.6 mg, 46.9%) was prepared in the same manner as Step 2 of Reference Example 233 and used in the next step without further purification. ¹ H-NMR ( _MeOD4 , 400 MHz) δ 9.32 (d, 1H), 9.13 (d, 1H), 9.01 (d, 2H), 8.78 (d, 1H), 7. 85 (dd, 1H), 7.61 (t, 1H), 7.14 (d, 1H), 4.20-4.14 (m, 1H), 3.58 (d, 2H), 3.27 (d, 2H), 2.40 (d, 2H), 2.10-2.00 (m, 2H).

[1397] Reference Example 237 N-(isoxazol-3-yl)-5-(piperidin-4-ylamino)quinoline-8-carboxamide hydrochloride

[1398] Step 1: 5-Bromo-N-(isoxazol-3-yl)quinoline-8-carboxamide

[1399] The title compound (158.8 mg, 41.9%) was prepared in the same manner as Step 1 of Reference Example 140 except that isoxazol-3-amine (118.0 mg) was used instead of methamine , 1.42 mmol). ¹ H-NMR (CDCl ₃ , 400 MHz) δ 9.09 (dd, 1H), 8.78 (dd, 2H), 8.38 (dd, 1H), 8.05 (dd, 1H), 7, 69 (dd, 1H), 7.29 (d, 1H).

[1400] Step 2: tert-butyl 4-(8-(isoxazol-3-ylcarbamoyl)quinolin-5-yl)amino)piperidine-1-carboxylate

[1401] The title compound (84.9 mg, 38.8%) was prepared in the same manner as Step 1 of Reference Example 233 except that instead of 5-bromo-N-(pyridin-2-yl) quinoline-8-carboxamide 5-bromo-N-(isoxazol-3-yl)quinoline-8-carboxamide (158.8 mg, 0.5 mmol) was used. MS (IER) m/z - 438.2 (M+H)+

[1402] Step 3: N-(isoxazol-3-yl)-5-(piperidin-4-ylamino)quinoline-8-carboxamide hydrochloride

[1403] The title compound (21.6 mg, 27.3%) was prepared in the same manner as Step 2 of Reference Example 233 and used in the next step without further purification.

[1404] Reference Example 238 N-(5-(piperidin-4-ylamino)quinolin-8-yl)acetamide hydrochloride

[1405] Step 1: tert-butyl 4-((8-acetamidoquinolin-5-yl)amino)piperidine-1-carboxylate

[1406] The title compound (264.2 mg, 27.5%) was prepared in the same manner as Step 1 of Reference Example 28 except that N-(5-bromoquinoline-8 -yl) acetamide (661.8 mg, 2.49 mmol). MS (IER) m/z - 385.2 (M+H)+

[1407] Step 2: N-(5-(piperidin-4-ylamino)quinolin-8-yl)acetamide hydrochloride

[1408] The title compound (204.2 mg, 83.1%) was prepared in the same manner as Step 2 of Reference Example 28 and used in the next step without further purification. ¹ H-NMR ( _MeOD4 , 400 MHz) δ 9.54 (dd, 1H), 9.00 (dd, 1H), 7.95 (dd, 1H), 7.79 (d, 1H), 7, 08 (d, 1H), 4.02-3.05 (m, 1H), 3.55 (m, 2H), 3.25 (td, 2H), 2.39 (d, 2H), 2.30 (s, 3H), 2.00-1.89 (m, 2H).

[1409] Reference Example 239: 6-Methyl-4-(piperidin-4-yloxy)quinoline hydrochloride

[1410] Step 1: tert-butyl 4-((6-methylquinolin-4-yl)oxy)piperidine-1-carboxylate

[1411] The title compound (425.3 mg, 100.0%) was prepared in the same manner as Step 1 of Reference Example 31 except that 4-hydroxy-6-methylquinoline was used instead of 3-quinolinol. 197.7 mg, 1.24 mmol). MS (IER) m/z - 343.2 (M+H)+

[1412] Step 2: 6-methyl-4-(piperidin-4-yloxy)quinoline hydrochloride

[1413] The title compound (346.3 mg, 100.0%) was prepared in the same manner as in Step 2 of Reference Example 31 and used in the next step without further purification.

[1414] Reference Example 240 4-(Piperidin-4-yloxy)-6-(trifluoromethyl)quinoline hydrochloride

[1415] Step 1: tert-butyl 4-((6-(trifluoromethyl)quinolin-4-yl)oxy)piperidine-1-carboxylate

[1416] The title compound (492.3 mg, 100.0%) was prepared in the same manner as Step 1 of Reference Example 31 except that 6-(trifluoromethyl)quinoline-4 was used instead of 3-quinolinol -ol (264.8 mg, 1.24 mmol). MS (IER) m/z -397.1 (M+H)+

[1417] Step 2: 4-(piperidin-4-yloxy)-6-(trifluoromethyl)quinoline hydrochloride

[1418] The title compound (413.3 mg, 100.0%) was prepared in the same manner as in Step 2 of Reference Example 31 and used in the next step without further purification.

[1419] Reference Example 241 4-(Piperidin-4-yloxy)-2-(trifluoromethyl)quinoline hydrochloride

[1420] Step 1: tert-butyl 4-((2-(trifluoromethyl)quinolin-4-yl)oxy)piperidine-1-carboxylate

[1421] The title compound (347.0 mg, 70.5%) was prepared in the same manner as Step 1 of Reference Example 31 except that 4-hydroxy-2-trifluoromethylquinoline was used instead of 3-quinolinol. 264.8 mg, 1.24 mmol). MS (IER) m/z - 397.1 (M+H)+

[1422] Step 2: 4-(piperidin-4-yloxy)-2-(trifluoromethyl)quinoline hydrochloride

[1423] The title compound (291.3 mg, 100.0%) was prepared in the same manner as in Step 2 of Reference Example 31 and used in the next step without further purification.

[1424] Reference Example 242: 6-Fluoro-4-(piperidin-4-yloxy)-2-(trifluoromethyl)quinoline hydrochloride

[1425] Step 1: tert-butyl 4-((6-fluoro-2-(trifluoromethyl)quinolin-4-yl)oxy)piperidine-1-carboxylate

[1426] The title compound (302.0 mg, 58.7%) was prepared in the same manner as Step 1 of Reference Example 31 except that 6-fluoro-2-(trifluoromethyl) was used instead of 3-quinolinol. quinolin-4-ol (287.1 mg, 1.24 mmol). MS (IER) m/z - 415.2 (M+H)+

[1427] Step 2: 6-fluoro-4-(piperidin-4-yloxy)-2-(trifluoromethyl)quinoline hydrochloride

[1428] The title compound (255.6 mg, 100.0%) was prepared in the same manner as in Step 2 of Reference Example 31 and used in the next step without further purification.

[1429] Reference Example 243: 6-methoxy-4-(piperidin-4-yloxy)-2-(trifluoromethyl)quinoline hydrochloride

[1430] Step 1: tert-butyl 4-((6-methoxy-2-(trifluoromethyl)quinolin-4-yl)oxy)piperidine-1-carboxylate

[1431] The title compound (357.1 mg, 67.4%) was prepared in the same manner as Step 1 of Reference Example 31 except that 6-methoxy-2-(trifluoromethyl) was used instead of 3-quinolinol )quinolin-4-ol (302.1 mg, 1.24 mmol). MS (IER) m/z - 427.2 (M+H)+

[1432] Step 2: 6-methoxy-4-(piperidin-4-yloxy)-2-(trifluoromethyl)quinoline hydrochloride

[1433] The title compound (303.8 mg, 100.0%) was prepared in the same manner as in Step 2 of Reference Example 31 and used in the next step without further purification.

[1434] Reference Example 244 8-methoxy-4-(piperidin-4-yloxy)-2-(trifluoromethyl)quinoline hydrochloride

[1435] Step 1: tert-butyl 4-((8-methoxy-2-(trifluoromethyl)quinolin-4-yl)oxy)piperidine-1-carboxylate

[1436] The title compound (487.7 mg, 92.1%) was prepared in the same manner as Step 1 of Reference Example 31 except that 8-methoxy-2-(trifluoromethyl) was used instead of 3-quinolinol. quinolin-4-ol (302.1 mg, 1.24 mmol). MS (IER) m/z - 427.2 (M+H)+

[1437] Step 2: 8-methoxy-4-(piperidin-4-yloxy)-2-(trifluoromethyl)quinoline hydrochloride

[1438] The title compound (414.9 mg, 100.0%) was prepared in the same manner as in Step 2 of Reference Example 31 and used in the next step without further purification.

[1439] Reference Example 245: 3-Fluoro-5-(piperidin-4-yloxy)quinoline hydrochloride

[1440] Step 1: tert-butyl 4-((3-fluoroquinolin-5-yl)oxy)piperidine-1-carboxylate

[1441] The title compound (430.2 mg, 100.0%) was prepared in the same manner as Step 1 of Reference Example 31 except that 3-fluoroquinolin-5-ol was used instead of 3-quinolinol ( 202.7 mg, 1.24 mmol). MS (IER) m/z - 347.2 (M+H)+

[1442] Step 2: 3-fluoro-5-(piperidin-4-yloxy)quinoline hydrochloride

[1443] The title compound (442.2 mg, 100.0%) was prepared in the same manner as in Step 2 of Reference Example 31 and used in the next step without further purification.

[1444] Reference Example 246: 5-(Piperidin-4-yloxy)quinoline-2-carbonitrile hydrochloride

[1445] Step 1: tert-butyl 4-((2-cyanoquinolin-5-yl)oxy)piperidine-1-carboxylate

[1446] The title compound (438.9 mg, 100.0%) was prepared in the same manner as Step 1 of Reference Example 31 except that 5-hydroxyquinoline-2-carbonitrile was used instead of 3-quinolinol. 211.4 mg, 1.24 mmol). MS (IER) m/z - 354.2 (M+H)+

[1447] Step 2: 5-(piperidin-4-yloxy)quinoline-2-carbonitrile hydrochloride

[1448] The title compound (381.6 mg, 100.0%) was prepared in the same manner as in Step 2 of Reference Example 31 and used in the next step without further purification.

[1449] Reference Example 247: 8-Chloro-5-(piperidin-4-yloxy)quinoline hydrochloride

[1450] Step 1: tert-butyl 4-((8-chloroquinolin-5-yl)oxy)piperidine-1-carboxylate

[1451] The title compound (450.7 mg, 100.0%) was prepared in the same manner as Step 1 of Reference Example 31 except that 8-chloroquinolin-5-ol was used instead of 3-quinolinol ( 223.1 mg, 1.24 mmol). MS (IER) m/z - 363.2 (M+H)+

[1452] Step 2: 8-chloro-5-(piperidin-4-yloxy)quinoline hydrochloride

[1453] The title compound (660.6 mg, 100.0%) was prepared in the same manner as in Step 2 of Reference Example 31 and used in the next step without further purification.

[1454] Reference Example 248 1-(Piperidin-4-yloxy)isoquinoline hydrochloride

[1455] Step 1: tert-butyl 4-(isoquinolin-1-yloxy)piperidine-1-carboxylate

[1456] The title compound (155.8 mg, 38.2%) was prepared in the same manner as Step 1 of Reference Example 31 except that 1-hydroxyisoquinoline (180.3 mg) was used instead of 3-quinolinol , 1.24 mmol). MS (IER) m/z - 329.2 (M+H)+

[1457] Step 2: 1-(piperidin-4-yloxy)isoquinoline hydrochloride

[1458] The title compound (125.6 mg, 100.0%) was prepared in the same manner as in Step 2 of Reference Example 31 and used in the next step without further purification.

[1459] Reference Example 249: 4-(Piperidin-4-yloxy)isoquinoline hydrochloride

[1460] Step 1: tert-butyl 4-(isoquinolin-4-yloxy)piperidine-1-carboxylate

[1461] The title compound (407.9 mg, 100.0%) was prepared in the same manner as Step 1 of Reference Example 31 except that 4-hydroxyisoquinoline (180.3 mg) was used instead of 3-quinolinol , 1.24 mmol). MS (IER) m/z - 329.1 (M+H)+

[1462] Step 2: 4-(piperidin-4-yloxy) isoquinoline hydrochloride

[1463] The title compound (328.8 mg, 100.0%) was prepared in the same manner as in Step 2 of Reference Example 31 and used in the next step without further purification.

[1464] Reference Example 250: 5-(Piperidin-4-yloxy)isoquinoline hydrochloride

[1465] Step 1: tert-butyl 4-(isoquinolin-5-yloxy)piperidine-1-carboxylate

[1466] The title compound (194.1 mg, 47.6%) was prepared in the same manner as Step 1 of Reference Example 31 except that 5-hydroxyisoquinoline (180.3 mg) was used instead of 3-quinolinol , 1.24 mmol). MS (IER) m/z - 329.1 (M+H)+

[1467] Step 2: 5-(piperidin-4-yloxy) isoquinoline hydrochloride

[1468] The title compound (156.5 mg, 100.0%) was prepared in the same manner as in Step 2 of Reference Example 31 and used in the next step without further purification.

[1469] Reference Example 251 6-(Piperidin-4-yloxy)isoquinoline hydrochloride

[1470] Step 1: tert-butyl 4-(isoquinolin-6-yloxy)piperidine-1-carboxylate

[1471] The title compound (407.9 mg, 100.0%) was prepared in the same manner as Step 1 of Reference Example 31 except that 6-hydroxyisoquinoline (180.3 mg) was used instead of 3-quinolinol , 1.24 mmol). MS (IER) m/z - 329.2 (M+H)+

[1472] Step 2: 6-(piperidin-4-yloxy) isoquinoline hydrochloride

[1473] The title compound (328.9 mg, 100.0%) was prepared in the same manner as in Step 2 of Reference Example 31 and used in the next step without further purification.

[1474] Reference Example 252 7-(Piperidin-4-yloxy)isoquinoline hydrochloride

[1475] Step 1: tert-butyl 4-(isoquinolin-7-yloxy)piperidine-1-carboxylate

[1476] The title compound (407.9 mg, 100.0%) was prepared in the same manner as Step 1 of Reference Example 31 except that 7-hydroxyisoquinoline (180.3 mg) was used instead of 3-quinolinol , 1.24 mmol). MS (IER) m/z - 329.2 (M+H)+

[1477] Step 2: 7-(piperidin-4-yloxy) isoquinoline hydrochloride

[1478] The title compound (328.9 mg, 100.0%) was prepared in the same manner as in Step 2 of Reference Example 31 and used in the next step without further purification.

[1479] Reference Example 253: 6-methoxy-2-methyl-4-(piperidin-4-yloxy)quinoline hydrochloride

[1480] Step 1: tert-butyl 4-((6-methoxy-2-methylquinolin-4-yl)oxy)piperidine-1-carboxylate

[1481] The title compound (462.6 mg, 100.0%) was prepared in the same manner as Step 1 of Reference Example 31 except that 6-methoxy-2-methylquinoline- 4-ol (235.0 mg, 1.24 mmol). MS (IER) m/z - 373.2 (M+H)+

[1482] Step 2: 6-methoxy-2-methyl-4-(piperidin-4-yloxy)quinoline hydrochloride

[1483] The title compound (383.6 mg, 100.0%) was prepared in the same manner as in Step 2 of Reference Example 31 and used in the next step without further purification.

[1484] Reference Example 254: 7-Chloro-4-(piperidin-4-yloxy)quinoline hydrochloride

[1485] Step 1: tert-butyl 4-((7-chloroquinolin-4-yl)oxy)piperidine-1-carboxylate

[1486] The title compound (450.7 mg, 99.9%) was prepared in the same manner as Step 1 of Reference Example 31 except that 7-chloroquinolin-4-ol was used instead of 3-quinolinol ( 223.1 mg, 1.24 mmol). MS (IER) m/z - 363.2 (M+H)+

[1487] Step 2: 7-chloro-4-(piperidin-4-yloxy)quinoline hydrochloride

[1488] The title compound (371.6 mg, 100.0%) was prepared in the same manner as in Step 2 of Reference Example 31 and used in the next step without further purification.

[1489] Reference Example 255: 7-Methyl-4-(piperidin-4-yloxy)quinoline hydrochloride

[1490] Step 1: tert-butyl 4-((7-methylquinolin-4-yl)oxy)piperidine-1-carboxylate

[1491] The title compound (500.0 mg, 98.0%) was prepared in the same manner as Step 1 of Reference Example 31 except that 7-methylquinolin-4-ol was used instead of 3-quinolinol ( 237.3 mg, 1.49 mmol). MS (IER) m/z - 343.3 (M+H)+

[1492] Step 2: 7-methyl-4-(piperidin-4-yloxy)quinoline hydrochloride

[1493] The title compound (407.0 mg, 100.0%) was prepared in the same manner as in Step 2 of Reference Example 31 and used in the next step without further purification.

[1494] Reference Example 256: 7-Fluoro-4-(piperidin-4-yloxy)quinoline hydrochloride

[1495] Step 1: tert-butyl 4-((7-fluoroquinolin-4-yl)oxy)piperidine-1-carboxylate

[1496] The title compound (516.0 mg, 99.9%) was prepared in the same manner as Step 1 of Reference Example 31 except that 7-fluoroquinolin-4-ol was used instead of 3-quinolinol ( 243.2 mg, 1.49 mmol). MS (IER) m/z - 347.2 (M+H)+

[1497] Step 2: 7-fluoro-4-(piperidin-4-yloxy)quinoline hydrochloride

[1498] The title compound (421.3 mg, 100.0%) was prepared in the same manner as in Step 2 of Reference Example 31 and used in the next step without further purification.

[1499] Reference Example 257 4-(Piperidin-4-yloxy)quinoline-8-carbonitrile hydrochloride

[1500] Step 1: tert-butyl 4-((8-cyanoquinolin-4-yl)oxy)piperidine-1-carboxylate

[1501] The title compound (505.4 mg, 95.9%) was prepared in the same manner as Step 1 of Reference Example 31 except that 4-hydroxyquinoline-8-carbonitrile ( 4-hydroxyquinoline-8-carbonitrile) was used instead of 3-quinolinol. 253.7 mg, 1.49 mmol). MS (IER) m/z - 354.2 (M+H)+

[1502] Step 2: 4-(piperidin-4-yloxy)quinoline-8-carbonitrile hydrochloride

[1503] The title compound (414.4 mg, 100.0%) was prepared in the same manner as in Step 2 of Reference Example 31 and used in the next step without further purification.

[1504] Reference Example 258: 8-Fluoro-4-(piperidin-4-yloxy)quinoline hydrochloride

[1505] Step 1: tert-butyl 4-((8-fluoroquinolin-4-yl)oxy)piperidine-1-carboxylate

[1506] The title compound (516.0 mg, 99.9%) was prepared in the same manner as Step 1 of Reference Example 31 except that 8-fluoro-4-hydroxyquinoline was used instead of 3-quinolinol. 243.2 mg, 1.49 mmol). MS (IER) m/z - 347.1 (M+H)+

[1507] Step 2: 8-fluoro-4-(piperidin-4-yloxy)quinoline hydrochloride

[1508] The title compound (421.3 mg, 100.0%) was prepared in the same manner as in Step 2 of Reference Example 31 and used in the next step without further purification.

[1509] Reference Example 259: 2-Methyl-4-(piperidin-4-yloxy)quinoline hydrochloride

[1510] Step 1: tert-butyl 4-((2-methylquinolin-4-yl)oxy)piperidine-1-carboxylate

[1511] The title compound (510.0 mg, 99.9%) was prepared in the same manner as Step 1 of Reference Example 31 except that 4-hydroxy-2-methylquinoline ( 237.3 mg, 1.49 mmol). MS (IER) m/z - 343.2 (M+H)+

[1512] Step 2: 2-methyl-4-(piperidin-4-yloxy)quinoline hydrochloride

[1513] The title compound (415.4 mg, 100.0%) was prepared in the same manner as in Step 2 of Reference Example 31 and used in the next step without further purification.

[1514] Reference Example 260: 6-Fluoro-2-methyl-4-(piperidin-4-yloxy)quinoline hydrochloride

[1515] Step 1: tert-butyl 4-((6-fluoro-2-methylquinolin-4-yl)oxy)piperidine-1-carboxylate

[1516] The title compound (537.0 mg, 99.9%) was prepared in the same manner as Step 1 of Reference Example 31 except that 6-fluoro-2-methylquinoline- 4 (264.1 mg, 1.49 mmol). MS (IER) m/z - 361.2 (M+H)+

[1517] Step 2: 6-fluoro-2-methyl-4-(piperidin-4-yloxy)quinoline hydrochloride

[1518] The title compound (442.2 mg, 100.0%) was prepared in the same manner as in Step 2 of Reference Example 31 and used in the next step without further purification.

[1519] Reference Example 261: 8-methoxy-4-(piperidin-4-yloxy)quinoline hydrochloride

[1520] Step 1: tert-butyl 4-((8-methoxyquinolin-4-yl)oxy)piperidine-1-carboxylate

[1521] The title compound (118.7 mg, 22.2%) was prepared in the same manner as Step 1 of Reference Example 31 except that 4-hydroxy-8-methoxyquinoline was used instead of 3-quinolinol. 261.1 mg, 1.49 mmol). MS (IER) m/z - 359.2 (M+H)+

[1522] Step 2: 8-methoxy-4-(piperidin-4-yloxy)quinoline hydrochloride

[1523] The title compound (97.6 mg, 100.0%) was prepared in the same manner as in Step 2 of Reference Example 31 and used in the next step without further purification.

[1524] Reference Example 262: 8-Methyl-4-(piperidin-4-yloxy)quinoline hydrochloride

[1525] Step 1: tert-butyl 4-((8-methylquinolin-4-yl)oxy)piperidine-1-carboxylate

[1526] The title compound (510.0 mg, 99.9%) was prepared in the same manner as Step 1 of Reference Example 31 except that 8-methylquinolin-4-ol was used instead of 3-quinolinol. 237.3 mg, 1.49 mmol). MS (IER) m/z - 343.2 (M+H)+

[1527] Step 2: 8-methyl-4-(piperidin-4-yloxy)quinoline hydrochloride

[1528] The title compound (415.4 mg, 100.0%) was prepared in the same manner as in Step 2 of Reference Example 31 and used in the next step without further purification.

[1529] Example 1: (R)-1-(2-((S)-2-cyanopyrrolidin-1-yl)-2-oxoethyl)-N-(quinolin-3-yl)pyrrolidin-3-carboxamide

[1530](S)-1-(2-chloroacetyl)pyrrolidine-2-carbonitrile (30 mg, 0.17 mmol) obtained in Reference Example 1 was dissolved in anhydrous dichloromethane (1.2 ml). To the resulting solution, (R)-N-(quinolin-3-yl)pyrrolidin-3-carboxamide hydrochloride (54.6 mg, 0.19 mmol) obtained in Reference Example 24 and potassium carbonate (96.0 mg, 0.69 mmol). The reaction mixture was stirred overnight at room temperature. After completion of the reaction, water was added to the reaction mixture. The aqueous layer of the reaction mixture was extracted with dichloromethane. The extracted organic layer was dried and filtered over anhydrous magnesium sulfate. The filtered solution was concentrated and then purified by silica gel column chromatography (ethyl acetate/methanol = 10/1, v/v) to give the title compound (31.6 mg). ¹ H-NMR (CDCl ₃ , 400 MHz) δ 10.45 (s, 1H), 9.12 (s, 1H), 8.75 (s, 1H), 7.97 (d, 1H), 7. 73 (d, 1H), 7.55-7.46 (m, 2H), 4.78 (s, 1H), 3.74-3.18 (m, 7H), 2.82 (s, 1H) , 2.59-2.18 (m, 8H)

[1531] Example 2: (R)-1-(2-((S)-2-cyanopyrrolidin-1-yl)-2-oxoethyl)-N-(quinolin-4-yl)pyrrolidin-3-carboxamide

[1532] The title compound (33.3 mg) was prepared in the same manner as Example 1 except that (R)-N-(quinolin-3-yl)pyrrolidin-3-carboxamide hydrochloride was used instead (R)-N-(quinolin-4-yl)pyrrolidin-3-carboxamide hydrochloride (54.6 mg, 0.19 mmol) prepared in reference example 23. ¹ H-NMR (CDCl ₃ , 400 MHz) δ 10 .62 (s, 1H), 8.78 (s, 1H), 8.31-8.26 (m, 2H), 8.05 (d, 1H), 7.71-7.62 (m, 2H ), 4.78 (d, 1H), 3.71-3.19 (m, 8H), 2.82 (s, 1H), 2.62-2.05 (m, 8H)

[1533] Example 3: (S)-1-(2-((S)-2-cyanopyrrolidin-1-yl)-2-oxoethyl)-N-(quinolin-3-yl)pyrrolidin-3-carboxamide

[1534] The title compound (6.3 mg) was prepared in the same manner as Example 1 except that (R)-N-(quinolin-3-yl)pyrrolidin-3-carboxamide hydrochloride was used instead (S)-N-(quinolin-3-yl)pyrrolidin-3-carboxamide hydrochloride (54.6 mg, 0.19 mmol) prepared in Reference Example 22. ¹ H-NMR (CDCl ₃ , 400 MHz) δ 10 .36 (d, 1H), 9.11 (d, 1H), 8.84 (d, 1H), 8.02 (t, 1H), 7.81 (d, 1H), 7.60-7, 47 (m, 2H), 4.83 (d, 1H), 3.69-3.04 (m, 7 N), 2.56-2.05 (m, 10H)

[1535] Example 4: (S)-1-(2-((3)-2-cyanopyrrolidin-1-yl)-2-oxoethyl)-N-(quinolin-4-yl)pyrrolidin-3-carboxamide

[1536] The title compound (14.3 mg) was prepared in the same manner as Example 1 except that (R)-N-(quinolin-3-yl)pyrrolidin-3-carboxamide hydrochloride was used ( S)-N-(quinolin-4-yl)pyrrolidin-3-carboxamide hydrochloride (54.6 mg, 0.19 mmol) prepared in reference example 21. ¹ H-NMR (CDCl ₃ , 400 MHz) δ 10, 42 (s, 1H), 8.77 (d, 1H), 8.35-8.03 (m, 3H), 7.71-7.58 (m, 2H), 4.79 (d, 1H) , 3.70-3.35 (m, 6H), 3.22 (s, 1H), 2.48-2.05 (m, 9H)

[1537] Example 5 (S)-1-(2-((S)-3-(quinolin-4-ylamino)pyrrolidin-1-yl)acetyl)pyrrolidin-2-carbonitrile

[1538](S)-1-(2-chloroacetyl)pyrrolidine-2-carbonitrile (20 mg, 0.12 mmol) obtained in Reference Example 1 was dissolved in anhydrous dichloromethane (4 ml). To the resulting solution, (S)-N-(pyrrolidin-3-yl)quinolin-4-amine hydrochloride (39.8 mg, 0.14 mmol) obtained in Reference Example 5 and potassium carbonate (48.0 mg, 0.35 mmol). The reaction mixture was stirred overnight at room temperature. After completion of the reaction, water was added to the reaction mixture. The aqueous layer of the reaction mixture was extracted with dichloromethane. The extracted organic layer was dried and filtered over anhydrous magnesium sulfate. The filtered solution was concentrated and then purified by silica gel column chromatography (dichloromethane/methanol = 10/1, v/v) to give the title compound (11.4 mg). ¹ H-NMR (CDCl ₃ , 400 MHz) δ 8.65-8.72 (m, 1H), 8.00 (d, 1H), 7.87-7.93 (m, 1H), 7.77 -7.82 (m, 1H), 7.67-7.75 (m, 1H), 7.58-7.62 (m, 1H), 4.75-4.82 (m, 1H), 4 .25-4.31 (m, 1H), 3.63-3.70 (m, 1H), 3.44-3.52 (m, 2H), 3.12-3.22 (m, 1H) , 3.08 (d, 1H), 2.80 (dd, 0.3 N), 2.64-2.71 (m, 0.5 N), 2.26-2.36 (m, 2H) , 2.13-2.25 (m, 2H)

[1539] Example 6 (S)-4,4-difluoro-1-(2-((S)-3-(quinolin-3-ylamino)pyrrolidin-1-yl)acetyl)pyrrolidin-2-carbonitrile

[1540](2S)-1-(2-chloroacetyl)-4,4-difluoropyrrolidine-2-carbonitrile (25.0 mg 0.12 mmol) obtained in Reference Example 3 was dissolved in anhydrous dichloromethane (4 ml). To the resulting solution was added (S)-N-(pyrrolidin-3-yl)quinolin-3-amine hydrochloride (34.3 mg, 0.12 mmol) obtained in Reference Example 6 and potassium carbonate (48.0 mg, 0.12 mmol). 35 mmol). The reaction mixture was stirred overnight at room temperature. After completion of the reaction, water was added to the reaction mixture. The aqueous layer of the reaction mixture was extracted with dichloromethane. The extracted organic layer was dried and filtered over anhydrous magnesium sulfate. The filtered solution was concentrated and then purified by silica gel column chromatography (dichloromethane/methanol = 10/1, v/v) to give the title compound (6.1 mg). ¹ H-NMR (CDCl ₃ , 400 MHz) δ 8.42 (s, 1H), 7.85-7.96 (m, 1H), 7.50-7.64 (m, 1H), 7.36 -7.46 (m, 2H), 6.96 (s, 1H), 5.17-5.28 (m, 0.4H), 4.89-5.01 (m, 0.6H), 4 .32-4.56 (m, 1H), 4.05-4.19 (m, 2H), 3.37-3.55 (m, 1H), 3.30-3.36 (m, 1H) , 2.91-3.11 (m, 2H), 2.68-2.86 (m, 3H), 2.33-2.53 (m, 2H), 1.78-1.99 (m, 2H)

[1541] Example 7: (S)-4,4-difluoro-1-(2-((S)-3-(quinolin-4-ylamino)pyrrolidin-1-yl)acetyl)pyrrolidin-2-carbonitrile

[1542] The title compound (5.3 mg) was prepared in the same manner as Example 6 except that (S)-N-(pyrrolidin-3-yl)quinolin-3-amine hydrochloride was used instead (S)-N-(pyrrolidin-3-yl)quinolin-4-amine hydrochloride (34.3 mg 0.12 mmol) obtained in reference example 5. ¹ H-NMR (CDCl ₃ , 400 MHz) δ 8, 68 (s, 1H), 7.90 (d, 1H), 7.85 (d, 1H), 7.76-7.83 (m, 1H), 7.62-7.72 (m, 1H) , 7.54-7.62 (m, 1H), 5.13-5.21 (m, 0.4H), 4.91-5.02 (m, 0.6H), 4.65-4, 80 (m, 1H), 4.26 (m, 1H), 3.98-4.15 (m, 2H), 3.78-3.91 (m, 0.5H), 3.47-3, 59 (m, 0.5H), 3.34-3.43 (m, 1.5H), 2.87-3.14 (m, 3H), 2.59-2.81 (m, 3H), 2.35-2.59 (m, 1.5N)

[1543] Example 8 (S)-4,4-difluoro-1-(2-((S)-3-(isoquinolin-4-ylamino)pyrrolidin-1-yl)acetyl)pyrrolidin-2-carbonitrile

[1544] The title compound (16.3 mg) was prepared in the same manner as Example 6 except that (S)-N-(pyrrolidin-3-yl)quinolin-3-amine hydrochloride was used (S)-N-(pyrrolidin-3-yl)isoquinolin-4-amine hydrochloride (34.3 mg, 0.12 mmol) prepared in Reference Example 7. ¹ H-NMR (CDCl ₃ , 400 MHz) δ 8 .51 (d, 1H), 7.96 (d, 1H), 7.83-7.91 (m, 1H), 7.59-7.65 (m, 1H), 7.42 (t, 1H ), 5.92 (d, 0.6N), 5.69 (d, 0.4N), 5.11 (dd, 0.4N), 4.91 (t, 0.6N), 4.16- 4.28 (m, 1H), 3.72-4.12 (m, 2H), 3.59 (d, 0.5H), 3.37 (s, 1H), 3.31 (d, 0. 5H), 3.07-3.18 (m, 0.5H), 2.99-3.07 (m, 1H), 2.89-2.95 (m, 1H), 2.55-2, 76 (m, 5H), 2.44-2.55 (m, 0.5H), 2.30-2.41 (m, 1H), 1.92 (m, 1H)

[1545] Example 9 (S)-1-(2-((S)-3-(benzo[b]thiophen-4-ylamino)pyrrolidin-1-yl)acetyl)-4,4-difluoropyrrolidin-2- carbonitrile

[1546] The title compound (5.62 mg) was prepared in the same manner as Example 6 except that (S)-N-(pyrrolidin-3-yl)quinolin-3-amine hydrochloride was used instead (S)-N-(benzo[b]thiophen-4-yl)pyrrolidin-3-amine hydrochloride (26.2 mg, 0.12 mmol) obtained in Reference Example 8. ¹ H-NMR (CDCl ₃ , 400 MHz) δ 7.23-7.36 (m, 3H), 7.16-7.23 (m, 1H), 6.35 (s, 1H), 5.15 (d, 0.4H), 4 .88 (t, 0.6N), 4.18 (s, 1H), 3.94-4.05 (m, 1.6N), 3.81-3.91 (m, 0.5N), 3 .44-3.53 (m, 0.5H), 3.31-3.40 (m, 0.5H), 3.25-3.31 (m, 1H), 3.03-3.11 ( m, 0.4H), 2.86-2.99 (m, 1.6H), 2.76-2.82 (m, 0.5H), 2.29-2.72 (m, 5H), 1.79-1.98 (m, 1H)

[1547] Example 10 -carbonitrile

[1548] The title compound (10.9 mg) was prepared in the same manner as Example 6 except that (S)-N-(pyrrolidin-3-yl)quinolin-3-amine hydrochloride was used (S)-N-(benzo[b]thiophen-7-yl)pyrrolidin-3-amine hydrochloride (26.2 mg, 0.12 mmol) obtained in Reference Example 9. ¹ H-NMR (CDCl ₃ , 400 MHz) δ 7.34-7.41 (m, 1H), 7.20-7.34 (m, 4H), 6.47-6.57 (m, 1H), 5.37 (d, 0 ,5H), 4.89 (t, 0.7H), 4.17-4.28 (m, 1H), 3.75-4.08 (m, 3H), 3.35-3.55 (m , 1H), 3.21-3.35 (m, 1H), 2.78-3.13 (m, 2H), 2.55-2.73 (m, 4H), 2.31-2.53 (m, 2H), 1.78-1.97 (m, 1H)

[1549] Example 11: (S)-1-(2-((S)-3-(benzofuran-7-ylamino)pyrrolidin-1-yl)acetyl)-4,4-difluoropyrrolide in-2-carbonitrile

[1550] The title compound (6.91 mg) was prepared in the same manner as Example 6 except that (S)-N-(pyrrolidin-3-yl)quinolin-3-amine hydrochloride was used (S)-N-(benzofuran-7-yl)pyrrolidin-3-amine hydrochloride (24.27 mg, 0.12 mmol) obtained in Reference Example 10. ¹ H-NMR (CDCl ₃ , 400 MHz) δ 7 .55 (s, 1H), 7.08 (t, 1H), 6.97 (d, 1H), 6.72 (s, 1H), 6.45-6.50 (m, 1H), 5. 44 (d, 0.3H), 4.90 (dd, 0.6H), 4.13-4.29 (m, 1H), 3.75-4.08 (m, 2H), 3.32- 3.59 (m, 1H), 3.23-3.32 (m, 1H), 2.85-3.08 (m, 2H), 2.55-2.78 (m, 4H), 2. 32-2.53 (m, 1H), 1.72-1.93 (m, 1H)

[1551] Example 12 (S)-4,4-difluoro-1-(2-((S)-3-(furo[3,2-c]pyridin-7-ylamino)pyrrolidin-1-yl)acetyl )pyrrolidine-2-carbonitrile

[1552] The title compound (4.59 mg) was prepared in the same manner as Example 6 except that (S)-N-(pyrrolidin-3-yl)quinolin-3-amine hydrochloride was used (S)-N-(pyrrolidin-3-yl)furo[3,2-c]pyridin-7-amine hydrochloride (24.4 mg, 0.12 mmol) obtained in Reference Example 11. ¹ H-NMR ( CDCl ₃ , 400 MHz) δ 8.39 (s, 1H), 7.87 (s, 1H), 7.61-7.72 (m, 1H), 6.82-6.98 (m, 1H) , 5.31-5.41 (m, 0.4H), 4.92-5.03 (m, 0.7H), 4.21-4.45 (m, 2H), 3.49-3, 62 (m, 1H), 3.33-3.40 (m, 1H), 2.94-3.12 (m, 2H), 2.58-2.87 (m, 6H), 2.37 -2.54 (m, 2H), 1.77-2.00 (m, 1H)

[1553] Example 13: (S)-1-(2-((S)-3-([1,1'-biphenyl]-2-ylamino)pyrrolidin-1-yl)acetyl)-4,4-difluoropyrrolidine -2-carbonitrile

[1554] The title compound (14.9 mg) was prepared in the same manner as Example 6 except that (S)-N-(pyrrolidin-3-yl)quinolin-3-amine hydrochloride was used instead (S)-N-([1,1'-Biphenyl]-2-yl)pyrrolidin-3-amine hydrochloride (28.6 mg, 0.12 mmol) obtained in Reference Example 12. ¹ H-NMR (CDCl ₃ , 400 MHz) δ 7.32-7.48 (m, 5H), 7.19-7.26 (m, 1H), 7.09 (d, 1H), 6.78 (ush t, 1H), 6.64 (d, 1H), 5.36 (wt, 0.3H), 4.87-4.92 (m, 0.6N), 3.75-4.22 (m, 4H), 3 .57 (b.d., 0.5N), 3.20-3.30 (m, 1.6N), 2.79-2.93 (m, 1H), 2.62-2.76 (m, 2H ), 2.43-2.61 (m, 2H), 2.24-2.35 (m, 1H), 1.56-1.70 (m, 1H)

[1555] Example 14 (S)-1-(2-((S)-3-([1,1'-biphenyl]-4-ylamino)pyrrolidin-1-yl)acetyl)-4,4-difluoropyrrolidine -2-carbonitrile

[1556] The title compound (13.3 mg) was prepared in the same manner as Example 6 except that (S)-N-(pyrrolidin-3-yl)quinolin-3-amine hydrochloride was used (S)-N-([1,1'-Biphenyl]-4-yl)pyrrolidin-3-amine hydrochloride (28.6 mg, 0.12 mmol) prepared in Reference Example 13. ¹ H-NMR (CDCl ₃ , 400 MHz) δ 7.53 (d, 2H), 7.41-7.51 (m, 2H), 7.39 (t, 2H), 7.22-7.30 (m, 1H), 6 .65 (d, 2H), 5.31-5.48 (s, 0.4H), 4.95-5.12 (m, 0.6H), 3.96-4.17 (m, 3H) , 3.33-3.52 (m, 1H), 2.84-3.08 (m, 2H), 2.56-2.81 (m, 4H), 2.27-2.53 (m, 2H), 1.78-1.85 (m, 1H)

[1557] Example 15 (S)-4,4-difluoro-1-(2-((S)-3-(naphthalene-2-ylamino)pyrrolidin-1-yl)acetyl)pyrrolidin-2-carbonitrile

[1558] The title compound (13.8 mg) was prepared in the same manner as Example 6 except that (S)-N-(pyrrolidin-3-yl)quinolin-3-amine hydrochloride was used (S)-N-(naphthalene-2-yl)pyrrolidin-3-amine (25.5 mg, 0.12 mmol) obtained in reference example 14. ¹ H-NMR (CDCl ₃ , 400 MHz) δ 7.58 -7.68 (m, 3H), 7.36 (t, 1H), 7.16-7.26 (m, 1H), 6.85 (d, 1H), 6.73-6.81 (m , 1H), 5.26 (d, 0.3H), 4.89 (t, 0.6H), 4.08-4.19 (m, 1H), 3.82-3.92 (m, 0 ,5H), 3.37-3.57 (m, 1H), 3.23-3.33 (m, 1H), 2.87-3.04 (m, 1.5H), 2.55-2 .83 (m, 4H), 2.30-2.47 (m, 1H), 1.81-1.93 (m, 1H)

[1559] Example 16 (S)-1-(2-((S)-3-([1,1'-biphenyl]-3-ylamino)pyrrolidin-1-yl)acetyl)-4,4-difluoropyrrolidine -2-carbonitrile

[1560] The title compound (8.3 mg) was prepared in the same manner as Example 6 except (S)-N-([1,1'-biphenyl]-3-yl)pyrrolidine -3-amine hydrochloride (28.6 mg, 0.12 mmol) obtained in Reference Example 15 was used instead of (S)-N-(pyrrolidin-3-yl)quinolin-3-amine hydrochloride. ¹ H-NMR (CDCl ₃ , 400 MHz) δ 7.55 (d, 2H), 7.41 (t, 2H), 7.30-7.35 (m, 1H), 7.20-7.25 (m, 1H), 6.93 (d, 1H), 6.77 (s, 1H), 6.54-6.62 (m, 1H), 5.28 (m, 0.3H), 4. 90 (m, 0.6H), 3.95-4.14 (m, 3H), 3.77-3.87 (m, 0.4H), 3.42-3.52 (m, 0.6H ), 3.23-3.29 (m, 1H), 2.84-3.01 (m, 1H), 2.54-2.78 (m, 4H), 2.29-2.44 (m , 1H), 1.68-1.84(m, 1H)

[1561] Example 17 (S)-1-(2-((R)-3-(quinolin-3-ylamino)pyrrolidin-1-yl)acetyl)pyrrolidin-2-carbonitrile

[1562] (S)-1-(2-chloroacetyl)pyrrolidine-2-carbonitrile (25.0 mg 0.12 mmol) obtained in Reference Example 1 was dissolved in anhydrous dichloromethane (4 ml). To the resulting solution was added (R)-N-(pyrrolidin-3-yl)quinolin-3-amine hydrochloride (34.3 mg, 0.12 mmol) obtained in Reference Example 17 and potassium carbonate (48.0 mg, 0 .35 mmol). The reaction mixture was stirred overnight at room temperature. After completion of the reaction, water was added to the reaction mixture. The aqueous layer of the reaction mixture was extracted with dichloromethane. The extracted organic layer was dried and filtered over anhydrous magnesium sulfate. The filtered solution was concentrated and then purified by silica gel column chromatography (dichloromethane/methanol = 10/1, v/v) to give the title compound (6.1 mg). ¹ H-NMR (CDCl ₁ , 400 MHz) δ 8.39-8.54 (m, 1H), 7.93 (d, 1H), 7.60-7.72 (m, 1H), 7.37 -7.44 (m, 2.0H), 6.96 (s, 1H), 4.83-4.91 (m, 0.4H), 4.76-4.81 (m, 1H), 4 .50 (m, 0.6H), 3.67-3.81 (m, 1H), 3.46-3.56 (m, 1H), 3.28-3.43 (m, 2H), 3 .02-3.12 (m, 2H), 2.80-2.90 (m, 1H), 2.52-2.73 (m, 1H), 2.10-2.48 (m, 5H) , 1.81 (m, 2H)

[1563] Example 18 (S)-1-(2-((R)-3-([1,1'-biphenyl]-3-ylamino)pyrrolidin-1-yl)acetyl)pyrrolidin-2-carbonitrile

[1564] The title compound (6.92 mg) was prepared in the same manner as Example 17 except that (R)-N-(pyrrolidin-3-yl)quinolin-3-amine hydrochloride was used (R)-N-([1,1'-biphenyl]-3-yl)pyrrolidin-3-amine hydrochloride (28.6 mg, 0.12 mmol) obtained in Reference Example 18. ¹ H-NMR (CDCl ₃ , 400 MHz) δ 7.56 (d, 2H), 7.41 (t, 2H), 7.33 (d, 1H), 7.20-7.32 (m, 1H), 6.92 (d , 1H), 6.79 (s, 1H), 6.58 (d, 1H), 4.89-4.96 (m, 0.3H), 4.74 (m, 0.7H), 4, 11-4.24 (m, 1H), 3.65-3.72 (m, 1H), 3.29-3.56 (m, 4H), 2.88-3.02 (m, 2H), 2.79-2.85 (m, 1H), 2.63-2.71 (m, 1H), 2.04-2.45 (m, 5H), 1.78-1.85 (m, 1H )

[1565] Example 19 (S)-1-(2-((S)-3-(isoquinolin-4-ylamino)pyrrolidin-1-yl)acetyl)pyrrolidin-2-carbonitrile

[1566] The title compound (4.78 mg) was prepared in the same manner as Example 5 except that (S)-N-(pyrrolidin-3-yl)quinolin-4-amine hydrochloride was used instead (S)-N-(pyrrolidin-3-yl)isoquinolin-4-amine hydrochloride (25.6 mg, 0.12 mmol) obtained in reference example 7. ¹ H-NMR (CDCl ₂ , 400 MHz) δ 8 .41-8.54 (m, 1H), 7.93-8.22 (m, 2H), 7.65-7.75 (m, 1H), 7.39-7.53 (m, 1H) , 7.36-7.41 (m, 0.5H), 6.34-6.44 (m, 1H), 6.22-6.32 (m, 0.4H), 4.72-4, 86 (m, 1H), 4.24-4.34 (m, 1H), 3.43-3.72 (m, 4H), 3.24-3.36 (m, 1H), 2.98- 3.17 (m, 2H), 2.83-2.94 (m, 1H), 1.93-2.54 (m, 7H)

[1567] Example 20: (S)-1-(2-((S)-3-(benzo[b]thiophen-4-ylamino)pyrrolidin-1-yl)acetyl)pyrrolidin-2-carbonitrile

[1568] The title compound (8.46 mg) was prepared in the same manner as Example 5 except that (S)-N-(pyrrolidin-3-yl)quinolin-4-amine hydrochloride was used instead (S)-N-(benzo[b]thiophen-4-yl)pyrrolidin-3-amine hydrochloride (26.2 mg, 0.12 mmol) obtained in Reference Example 8. ¹ H-NMR (CDCl ₃ , 400 MHz) δ 7.33-7.42 (m, 1H), 7.28-7.32 (m, 1H), 7.20-7.25 (m, 1H), 7.17-7.20 ( m, 1H), 6.44 (dd, 1H), 4.63-4.88 (m, 1H), 4.19-4.24 (m, 1H), 3.26-3.69 (m, 4H), 2.98-3.18 (m, 1H), 2.82-2.95 (m, 1H), 2.62-2.76 (m, 1H), 1.83-2.52 ( m, 7N)

[1569] Example 21 (S)-1-(2-((S)-3-(benzo[b]thiophen-7-ylamino)pyrrolidin-1-yl)acetyl)pyrrolidin-2-carbonitrile

[1570] The title compound (6.55 mg) was prepared in the same manner as Example 5 except that (S)-N-(pyrrolidin-3-yl)quinolin-4-amine hydrochloride was used instead (S)-N-(benzo[b]thiophen-7-yl)pyrrolidin-3-amine hydrochloride (26.2 mg, 0.12 mmol) obtained in Reference Example 9. ¹ H-NMR (CDCl ₃ , 400 MHz) δ 7.24-7.37 (m, 4H), 6.50-6.72 (m, 1H), 4.99-5.02 (m, 0.4H), 4.74-4, 82 (m, 0.6H), 4.24-4.32 (m, 1H), 3.97-4.13 (m, 1H), 3.57-3.68 (m, 1H), 3. 24-3.52 (m, 3H), 3.03-3.10 (m, 1H), 2.95-3.01 (m, 0.6H), 2.75-2.84 (m, 1H ), 2.62-2.71 (m, 0.6H), 2.34-2.46 (m, 1H), 1.75-2.28 (m, 5H)

[1571] Example 22 (S)-1-(2-((3)-3-(benzofuran-7-ylamino)pyrrolidin-1-yl)acetyl)pyrrolidin-2-carbonitrile

[1572] The title compound (22.5 mg) was prepared in the same manner as Example 5 except that (S)-N-(pyrrolidin-3-yl)quinolin-4-amine hydrochloride was used instead (S)-N-(Benzofuran-7-yl)pyrrolidin-3-amine hydrochloride (24.27 mg, 0.12 mmol) obtained in Reference Example 10. ¹ H-NMR (CDCl ₃ , 400 MHz) δ 7 .54-7.65 (m, 1H), 7.08 (t, 1H), 6.96 (d, 1H), 6.72 (s, 1H), 6.47-6.52 (m, 1H ), 5.06-5.12 (m, 0.3 N), 4.74-4.85 (m, 0.6 N), 4.18-4.30 (m, 1H), 3.58 -3.68 (m, 1H), 3.44-3.56 (m, 1H), 3.24-3.42 (m, 2H), 2.89-3.14 (m, 2H), 2 .65-2.87 (m, 2H), 2.33-2.51 (m, 1H), 1.94-2.29 (m, 4H), 1.78-1.91 (m, 1H )

[1573] Example 23

[1574] The title compound (14.0 mg) was prepared in the same manner as Example 5 except that (S)-N-(pyrrolidin-4-yl)quinolin-3-amine hydrochloride was used instead (S)-N-(pyrrolidin-3-yl)furo[3,2-c]pyridin-7-amine hydrochloride (24.4 mg, 0.12 mmol) obtained in Reference Example 11. ¹ H-NMR ( CDCl ₃ , 400 MHz) δ 8.37 (s, 1H), 7.87 (s, 1H), 7.60-7.71 (m, 1H), 6.80-6.95 (m, 1H) , 4.96-5.02 (m, 0.3 N), 4.77-4.88 (m, 0.7 N), 4.37-4.51 (m, 1H), 4.30- 4.35 (m, 1H), 3.59-3.72 (m, 1H), 3.40-3.55 (m, 1H), 2.97-3.11 (m, 2H), 2. 80-2.89 (m, 1.4H), 2.60-2.68 (m, 0.6N), 2.04-2.55 (m, 6H), 1.81-1.95 (m , 1H)

[1575] Example 24: (S)-1-(2-((R)-3-(isoquinolin-4-ylamino)pyrrolidin-1-yl)acetyl)pyrrolidin-2-carbonitrile

[1576] The title compound (12.4 mg) was prepared in the same manner as Example 17 except that (R)-N-(pyrrolidin-3-yl)quinolin-3-amine hydrochloride was used ( R)-N-(pyrrolidin-3-yl)isoquinolin-4-amine hydrochloride obtained in reference example 19. ¹ H-NMR (CDCl ₃ , 400 MHz) δ 8.52-8.62 (m, 1H), 7.94-8.01 (m, 2H), 7.59-7.65 (m, 1H), 7.39-7.47 (m, 1H), 6.38-6.54 (m, 1H ), 4.76-4.84 (m, 1H), 4.14-4.35 (m, 1H), 3.60-3.68 (m, 1H), 3.33-3.58 (m , 3H), 3.13-3.23 (m, 1H), 2.90-3.10 (m, 2H), 2.58-2.78 (m, 1H), 2.08-2.50 (m, 5H), 1.87-2.00 (m, 1H)

[1577] Example 25

[1578] The title compound (4.5 mg) was prepared in the same manner as Example 17 except that (R)-N-(pyrrolidin-3-yl)quinolin-3-amine hydrochloride was used (R)-N-(benzo[b]thiophen-7-yl)pyrrolidin-3-amine hydrochloride (26.2 mg, 0.12 mmol) obtained in Reference Example 20. ¹ H-NMR (CDCl ₃ , 400 MHz) δ 7.24-7.38 (m, 4H), 6.54-6.72 (m, 1H), 5.02-5.12 (m, 0.4H), 4.75-4, 82 (m, 0.7H), 4.25-4.32 (m, 1H), 3.61-3.88 (m, 1H), 3.47-3.58 (m, 1H), 3. 28-3.46 (m, 2H), 2.87-3.10 (m, 2H), 2.79-2.87 (m, 1H), 2.59-2.73 (m, 1H), 2.32-2.50 (m, 1H), 2.04-2.30 (m, 4H), 1.79-1.93 (m, 1H)

[1579] Example 26. (1S,3S,5S)-2-(2-((S)-3-(furo[3,2-c]pyridin-7-ylamino)pyrrolidin-1-yl)acetyl)- 2-azabicyclo[3.1.0]hexane-3-carbonitrile

[1580](1S,3S,5S)-2-(2-chloroacetyl)-2-azabicyclo[3.1.0]hexane-3-carbonitrile (22.2 mg, 0.12 mmol) prepared in Reference Example 4, dissolved in anhydrous acetonitrile (4 ml). To the resulting solution was added (S)-N-(pyrrolidin-3-yl)furo[3,2-c]pyridin-7-amine hydrochloride (33.1 mg, 0.12 mmol) obtained in Reference Example 11 and carbonate potassium (48.0 mg, 0.35 mmol). The reaction mixture was stirred overnight at room temperature. After completion of the reaction, water was added to the reaction mixture. The aqueous layer of the reaction mixture was extracted with dichloromethane. The extracted organic layer was dried and filtered over anhydrous magnesium sulfate. The filtered solution was concentrated and then purified by silica gel column chromatography (dichloromethane/methanol = 10/1, v/v) to give the title compound (1.8 mg). ¹ H-NMR (CDCl ₃ , 400 MHz) δ 8.84 (m, 1H), 8.37 (d, 0.6H), 8.28 (d, 0.4H), 7.54-7.72 (m, 1H), 7.46-7.52 (m, 1H), 7.33-7.42 (m, 1H), 6.56-6.72 (m, 1H), 5.42-5 .51 (m, 0.6H), 5.09-5.24 (m, 0.4H), 4.75-4.92 (m, 1H), 4.20-4.31 (m, 1H) , 3.62-3.78 (m, 1H), 3.24-3.57 (m, 3H), 2.92-3.20 (m, 3H), 2.59-2.76 (m, 1H), 1.86-2.49 (m, 6H)

[1581] Example 27 (S)-1-(2-((3)-3-(quinolin-5-ylamino)pyrrolidin-1-yl)acetyl)pyrrolidin-2-carbonitrile

[1582] The title compound (18.1 mg) was prepared in the same manner as Example 5 except that (S)-N-(pyrrolidin-3-yl)quinolin-4-amine hydrochloride was used instead (S)-N-(pyrrolidin-3-yl)quinolin-5-amine hydrochloride (34.3 mg 0.12 mmol) obtained in reference example 16. ¹ H-NMR (CDCl ₃ , 400 MHz) δ 8, 84 (m, 1H), 8.37 (d, 0.6H), 8.28 (d, 0.4H), 7.54-7.72 (m, 1H), 7.46-7.52 ( m, 1H), 7.33-7.42 (m, 1H), 6.56-6.72 (m, 1H), 5.42-5.51 (m, 0.6H), 5.09- 5.24 (m, 0.4H), 4.75-4.92 (m, 1H), 4.20-4.31 (m, 1H), 3.62-3.78 (m, 1H), 3.24-3.57 (m, 3H), 2.92-3.20 (m, 3H), 2.59-2.76 (m, 1H), 1.86-2.49 (m, 6H )

[1583] Example 28: (2S,4S)-4-fluoro-1-(2-((S)-3-(furo[3,2-c]pyridin-7-ylamino)pyrrolidin-1-yl)acetyl )pyrrolidine-2-carbonitrile;

[1584](2S,4S)-1-(2-chloroacetyl)-4-fluoropyrrolidine-2-carbonitrile (20.0 mg, 0.10 mmol) obtained in Reference Example 2 was dissolved in anhydrous dichloromethane (4 ml) . To the resulting solution was added (S)-N-(pyrrolidin-3-yl)furo[3,2-c]pyridin-7-amine hydrochloride (31.8 mg 0.12 mmol) obtained in Reference Example 11 and potassium carbonate (29.0 mg, 0.21 mmol). The reaction mixture was stirred overnight at room temperature. After completion of the reaction, water was added to the reaction mixture. The aqueous layer of the reaction mixture was extracted with dichloromethane. The extracted organic layer was dried and filtered over anhydrous magnesium sulfate. The filtered solution was concentrated and then purified by silica gel column chromatography (dichloromethane/methanol = 10/1, v/v) to give the title compound (27.7 mg). ¹ H-NMR (CD ₃ OD, 400 MHz) δ 8.36 (s, 1H), 7.89 (d, 1H), 7.13 (s, 1H), 6.98 (d, 1H), 5 .51-5.38 (m, 1H), 5.00 (s, 1H), 4.03 (s, 1H), 3.85-3.73 (m, 1H), 3.58-3.39 (m, 2H), 3.07-3.04 (m, 1H) 2.92-2.84 (m, 2H), 2.69-2.31 (m, 4H), 1.88-1, 86 (m, 1H)

[1585] Example 29 N-((S)-1-(2-(2S,4S)-2-cyano-4-fluoropyrrolidin-1-yl)-2-oxoethyl)pyrrolidin-3-yl)-6- fluorobenzofuran-3-carboxamide;

[1586](2S,4S)-1-(2-chloroacetyl)-4-fluoropyrrolidine-2-carbonitrile (20.0 mg, 0.10 mmol) obtained in Reference Example 2 was dissolved in anhydrous acetonitrile (1 ml) . To the resulting solution was added (S)-6-fluoro-N-(pyrrolidin-3-yl)benzofuran-3-carboxamide hydrochloride (32.8 mg 0.12 mmol) obtained in Reference Example 45 and potassium carbonate (29.0 mg, 0.21 mmol). The reaction mixture was stirred overnight at room temperature. After completion of the reaction, water was added to the reaction mixture. The aqueous layer of the reaction mixture was extracted with dichloromethane. The extracted organic layer was dried and filtered over anhydrous magnesium sulfate. The filtered solution was concentrated and then purified by silica gel column chromatography (dichloromethane/methanol = 10/1, v/v) to give the title compound (4.3 mg). ^1H NMR (CD ₃ OD, 400 MHz) δ 8.36 (s, 1H), 8.03 (s, 1H), 7.35 (d, 1H), 7.15 (t, 1H), 5, 51-5.38 (m, 1H), 5.00 (dd, 1H), 4.60 (s, 1H), 4.03 (dd, 1H), 3.85-3.73 (m, 1H) , 3.64-3.36 (m, 2H), 3.07-3.04 (m, 1H) 2.92-2.86 (m, 2H), 2.69-2.32 (m, 4H ), 1.88-1.86 (m, 1H)

[1587] Example 30 N-((S)-1-(2-((S)-2-cyanopyrrolidin-1-yl)-2-oxoethyl)pyrrolidin-3-yl)quinoline-4-carboxamide

[1588] (S)-1-(2-((S)-3-Aminopyrrolidin-1-yl)acetyl)pyrrolidine-2-carbonitrile trifluoroacetate (20 mg, 0.09 mmol) prepared in Reference Example 25 was dissolved in dimethylformamide (2 ml). To the resulting solution was added quinoline-4-carboxylic acid (31.2 mg, 0.18 mmol), HATU (O-(7-azabenzotriazol-1-yl)-N,N,N',N'-tetramethyluranium hexafluorophosphate) ( 24.9 mg, 0.18 mmol) and diisopropylethylamine (47 μl, 0.27 mmol). The reaction mixture was stirred overnight at room temperature. After completion of the reaction, water was added to the reaction mixture. The aqueous layer of the reaction mixture was extracted with ethyl acetate. The extracted organic layer was dried and filtered over anhydrous magnesium sulfate. The filtered solution was concentrated and then purified by silica gel column chromatography (dichloromethane/methanol = 20/1, v/v) to give the title compound (7 mg). ^1H -NMR ( _CDCl3 , 400 MHz) δ 8.92-9.01 (m, 1H), 8.33 (d, 1H), 8.14 (d, 1H), 7.76 (t, 1H ), 7.49-7.69 (m, 2H), 4.77-7.89 (m, 1H), 4.68-4.75 (m, 1H), 3.55-3.67 (m , 1H), 3.43 (kv, 2H), 3.18 (m, 1H), 2.99 (m, 2H), 2.58-2.83 (m, 1H), 2.07-2, 51 (m, 5H), 1.78-2.02 (m, 3H)

[1589] Example 31 N-((S)-1-(2-((S)-2-cyanopyrrolidin-1-yl)-2-oxoethyl)pyrrolidin-3-yl)quinoline-3-carboxamide

[1590] The title compound (7.23 mg) was prepared in the same manner as Example 30 except that quinoline-3-carboxylic acid (31.2 mg, 0 .18 mmol). ¹ H-NMR (CDCl ₃ , 400 MHz) δ 9.41-9.50 (m, 1H), 8.73-8.85 (m, 1H), 8.12-8.21 (m, 1H) , 7.97-8.11 (m, 1H), 7.78-7.95 (m, 1H), 7.60-7.72 (m, 1H), 4.74-4.88 (m, 2H), 3.36-3.78 (m, 4H), 3.26-3.32 (m, 2H), 3.02-3.12 (m, 1H), 2.73-2.82 ( m, 1H), 2.13-2.45 (m, 5H), 2.05-2.12 (m, 2H)

[1591] Example 32 N-((S)-1-(2-((S)-2-cinopyrrolidin-1-yl)-2-oxoethyl)pyrrolidin-3-yl)quinoline-5-carboxamide

[1592] The title compound (11.7 mg) was prepared in the same manner as Example 30 except that quinoline-5-carboxylic acid (31.2 mg, 0 .18 mmol). ¹ H-NMR (CD ₃ OD, 400 MHz): Shift = 9.23 (d, 0.3H), 8.83-8.94 (m, 1H), 8.76 (d, 0.7H), 8.12 (d, 1H), 7.81-7.92 (m, 2H), 7.67-7.80 (m, 1H), 5.78-4.87 (m, 0.5H), 4.6-4.77 (m, 0.7H), 3.66-3.75 (m, 1H), 3.66-3.65 (m, 2H), 3.43-3.42 (m , 1H), 2.72-3.23 (m, 4H), 1.89-2.26 (m, 4H), 1.24-1.26 (m, 4H), 1.24-1.40 (m, 2H)

[1593] Example 33 N-((S)-1-(2-((S)-2-cyanopyrrolidin-1-yl)-2-oxoethyl)pyrrolidin-3-yl)quinoline-2-carboxamide

[1594] The title compound (14.4 mg) was prepared in the same manner as Example 30 except that quinoline-2-carboxylic acid (31.2 mg, 0 .18 mmol). ¹ H-NMR (CDCl ₃ , 400 MHz) δ 8.67-8.81 (m, 1H), 8.29-8.42 (m, 2H), 8.12-8.24 (m, 1H) , 7.87-8.10 (m, 1H), 7.77-7.86 (m, 1H), 7.62-7.72 (m, 1H), 5.11-5.19 (m, 0.3H), 4.78-7.85 (m, 1.7H), 3.60-3.77 (m, 1H), 3.54-3.59 (m, 1H), 3.42- 3.51 (m, 2H), 3.27-3.42 (m, 1H), 3.01-3.11 (m, 1H), 2.82-2.92 (m, 1H), 2. 62-2.72 (m, 1H), 2.54-2.60 (m, 1H), 2.17-2.42 (m, 4H), 1.94-2.02 (m, 1H), 1.44-1.59 (m, 1H)

[1595] Example 34 N-((S)-1-(2-((S)-2-cyanopyrrolidin-1-yl)-2-oxoethyl)pyrrolidin-3-yl)quinoline-8-carboxamide

[1596] The title compound (4.82 mg) was prepared in the same manner as Example 30 except that quinoline-8-carboxylic acid (31.2 mg, 0 .18 mmol). ¹ H-NMR (CDCl ₃ , 400 MHz) δ 8.92-9.02 (m, 1H), 8.75-8.88 (m, 1H), 8.21-8.34 (m, 1H) , 7.92-8.03 (m, 1H), 7.61-7.73 (m, 1H), 7.45-7.59 (m, 1H), 4.61-4.91 (m, 1.7H), 3.33-3.82 (m, 4H), 2.73-3.24 (m, 3H), 2.41-2.63 (m, 1H), 1.87-2, 34 (m, 6N)

[1597] Example 35 N-((S)-1-(2-((S)-2-cyanopyrrolidin-1-yl)-2-oxoethyl)pyrrolidin-3-yl)isoquinoline-1-carboxamide

[1598] The title compound (4.9 mg) was prepared in the same manner as Example 30 except that isoquinoline-1-carboxylic acid (31.2 mg, 0 .18 mmol). ¹ H-NMR (CDCl ₃ , 400 MHz) δ 9.55-9.68 (m, 1H), 8.45-8.58 (m, 2H), 7.83-7.98 (m, 1H) , 7.75-7.81 (m, 1H), 7.61-7.74 (m, 2H), 5.18-5.26 (m, 0.3H), 4.77-4.87 ( m, 0.7H), 4.64-4.74 (m, 1H), 3.57-3.71 (m, 2H), 3.40-3.55 (m, 1H), 3.10- 3.28 (m, 1H), 2.85-2.96 (m, 2H), 2.39-2.72 (m, 2H), 2.17-2.35 (m, 3H), 1. 84-2.10 (m, 2H)

[1599] Example 36 N-((S)-1 -(2-((S)-2-cyanopyrrolidin-1-yl)-2-oxoethyl)pyrrolidin-3-yl)benzo[b]thiophene-2- carboxamide

[1600] The title compound (8.0 mg) was prepared in the same manner as Example 30 except that benzo[b]thiophene-2-carboxylic acid (32, 6 mg, 0.18 mmol). ¹ H-NMR (CDCl ₃ , 400 MHz) δ 8.20-8.29 (m, 0.5H), 7.97-8.12 (m, 0.6H), 7.80-7.89 ( m, 2H), 7.39-7.52 (m, 2H), 4.77-4.89 (m, 1H), 4.67-4.72 (m, 1H), 3.39-3, 73 (m, 3H), 3.06-3.25 (m, 2H), 2.93-3.00 (m, 1H), 2.71-2.82 (m, 1H), 2.13- 2.47 (m, 5H), 1.95 (m, 1H)

[1601] Example 37 N-((S)-1-(2-((S)-2-cyanopyrrolidin-1-yl)-2-oxoethyl)pyrrolidin-3-yl)benzofuran-3-carboxamide

[1602] The title compound (6.4 mg) was prepared in the same manner as Example 30 except that benzofuran-3-carboxylic acid (29.2 mg, 0 .18 mmol). ¹ H-NMR (CDCl ₂ , 400 MHz) δ 8.26-8.36 (m, 0.7H), 8.14-8.21 (m, 1.4H), 7.81-7.92 ( m, 0.6H), 7.52-7.68 (m, 1H), 7.35-7.51 (m, 2H), 7.05-7.13 (m, 0.3H), 4, 75-4.82 (m, 2H), 3.64-3.82 (m, 2H), 3.39-3.52 (m, 3H), 3.00-3.26 (m, 2H), 2.94-3.00 (m, 1H), 2.69-2.85 (m, 1H), 2.11-2.46 (m, 6H), 1.87-2.02 (m, 1H )

[1603] Example 38 N-((S)-1-(2-((S)-2-cyanopyrrolidin-1-yl)-2-oxoethyl)pyrrolidin-3-yl)-2-(naphthalene-1- yl)acetamide

[1604] The title compound (6.6 mg) was prepared in the same manner as Example 30 except that 2-(naphthalene-1-yl)acetic acid (31) was used instead of quinoline-4-carboxylic acid .2 mg, 0.18 mmol). ¹ H-NMR (CDCl ₃ , 400 MHz) δ 7.95-8.03 (m, 1H), 7.79-7.90 (m, 2H), 7.41-7.57 (m, 4H) , 6.06-6.33 (m, 1H), 4.62 (m, 0.6H), 4.45 (m, 1H), 3.92-4.07 (m, 2H), 3.36 -3.52 (m, 1H), 3.18-3.30 (m, 2H), 2.64-3.08 (m, 2H), 2.32-2.55 (m, 2H), 2 .07-2.30 (m, 4H), 1.48-1.58 (m, 1H)

[1605] Example 39 N-((S)-1-(2-((S)-2-cyanopyrrolidin-1-yl)-2-oxoethyl)pyrrolidin-3-yl)-[1,1'-biphenyl ]-2-carboxamide

[1606] The title compound (7.6 mg) was prepared in the same manner as Example 30 except that [1,1'-biphenyl]-2-carboxylic acid was used instead of quinoline-4-carboxylic acid (35.7 mg, 0.18 mmol). ¹ H-NMR (CDCl ₃ , 400 MHz) δ 7.66-7.76 (m, 1H), 7.34-7.50 (m, 8H), 5.87-6.07 (m, 1H) , 4.40-4.78 (m, 2H), 3.56-3.72 (m, 2H), 3.06-3.30 (m, 2H), 2.65-2.81 (m, 1H), 2.58-2.64 (m, 1H), 2.19-2.39 (m, 3H), 2.03-2.18 (m, 4H), 1.25-1.35 ( m, 2N)

[1607] Example 40 N-((S)-1-(2-((S)-2-cyanopyrrolidin-1-yl)-2-oxoethyl)pyrrolidin-3-yl)benzofuran-2-carbooxamide

[1608] The title compound (8.4 mg) was prepared in the same manner as Example 30 except that benzofuran-2-carboxylic acid (29.2 mg, 0 .18 mmol). ¹ H-NMR (CDCl ₃ , 400 MHz) δ 7.66-7.75 (m, 1H), 7.49-7.59 (m, 1H), 7.37-7.49 (m, 2H) , 7.27-7.33 (m, 1H), 4.91 (m, 0.3H), 4.79 (m, 0.7H), 4.71-4.78 (m, 1H), 3 .62-3.71 (m, 1H), 3.41-3.60 (m, 2H), 3.08-3.28 (m, 1H), 2.88-2.98 (m, 2H) , 2.52-2.83 (m, 1H), 2.03-2.42 (m, 5H), 1.79-1.98 (m, 1H)

[1609] Example 41 N-((S)-1-(2-((3)-2-cyanopyrrolidin-1-yl)-2-oxoethyl)pyrrolidin-3-yl)benzo[b]thiophene-3- carboxamide

[1610] The title compound (10.4 mg) was prepared in the same manner as Example 30 except that benzo[b]thiophene-3-carboxylic acid (32, 1 mg, 0.18 mmol). ¹ H-NMR (CDCl ₃ , 400 MHz) δ 8.49-8.58 (m, 1H), 8.08 (s, 0.6H), 7.96 (s, 0.4H), 7.85 -7.95 (m, 1H), 7.68-7.82 (m, 0.6H), 7.34-7.48 (m, 2H), 7.10 (m, 0.4H), 4 .72-4.82 (m, 2H), 3.39-3.75 (m, 4H), 3.10-3.26 (m, 1H), 2.88-3.07 (m, 2H) , 2.56-2.77 (m, 1H), 2.09-2.50 (m, 5H), 1.86-2.02 (m, 1H)

[1611] Example 42 N-((S)-1-(2-((S)-2-cyanopyrrolidin-1-yl)-2-oxoethyl)pyrrolidin-3-yl)-2-methylbenzofuran-3-carboxamide

[1612] The title compound (14.4 mg) was prepared in the same manner as Example 30 except that 2-methylbenzofuran-3-carboxylic acid (31.7 mg) was used instead of quinoline-4-carboxylic acid , 0.18 mmol). ¹ H-NMR (CDCl ₃ , 400 MHz) δ 7.68-7.82 (m, 1H), 7.43-7.52 (m, 1H), 7.27-7.33 (m, 1H) , 6.97-7.12 (m, 0.7H), 6.58-6.71 (m, 0.3H), 4.69-4.91 (m, 2H), 3.60-3, 73 (m, 1H), 3.32-3.59 (m, 3H), 3.08-3.24 (m, 1H), 2.92-3.05 (m, 2H), 2.78- 2.90 (m, 1H), 2.71-2.75 (m, 3H), 2.65-2.71 (m, 1H), 2.08-2.49 (m, 5H), 1. 86-2.00 (m, 1H)

[1613] Example 43 N-((S)-1-(2-((S)-2-cyanopyrrolidin-1-yl)-2-oxoethyl)pyrrolidin-3-yl)-5-fluorobenzofuran-3-carboxamide

[1614] The title compound (6.5 mg) was prepared in the same manner as Example 30 except that 5-fluorobenzofuran-3-carboxylic acid (32.4 mg) was used instead of quinoline-4-carboxylic acid , 0.18 mmol). ¹ H-NMR (CDCl ₃ , 400 MHz) δ 8.33 (s, 0.6H), 8.16-8.22 (m, 0.3H), 8.12-8.14 (m, 0. 7H), 7.74-7.92 (m, 1H), 7.43-7.52 (m, 1H), 6.95-7.17 (m, 1H), 4.64-4.86 ( m, 2H), 3.49-3.72 (m, 3H), 3.43 (m, 1H), 3.21-3.35 (m, 1H), 3.16 (m, 1H), 2 .91-3.10 (m, 1H), 2.69-2.86 (m, 1H), 2.13-2.40 (m, 5H)

[1615] Example 44 N-((S)-1-(2-((S)-2-cyanopyrrolidin-1-yl)-2-oxoethyl)pyrrolidin-3-yl)-6-fluorobenzofuran-3-carboxamide

[1616] The title compound (9.8 mg) was prepared in the same manner as Example 30 except that 6-fluorobenzofuran-3-carboxylic acid (32.4 mg) was used instead of quinoline-4-carboxylic acid , 0.18 mmol). ¹ H-NMR (CDCl ₃ , 400 MHz) δ 8.29 (s, 1H), 8.01-8.18 (m, 2H), 7.21-7.40 (m, 1H), 7.05 -7.17 (m, 1H), 4.73-4.85 (m, 2H), 3.48-3.71 (m, 3H), 3.36-3.47 (m, 1H), 3 .06-3.29 (m, 2H), 2.94-3.05 (m, 1H), 2.66-2.80 (m, 1H), 2.11-2.39 (m, 5H) , 1.84-2.03 (m, 1H)

[1617] Example 45 N-((S)-1-(2-((S)-2-cyanopyrrolidin-1-yl)-2-oxoethyl)pyrrolidin-3-yl)-7-methylbenzofuran-3-carboxamide

[1618] The title compound (8.5 mg) was prepared in the same manner as Example 30 except that 7-methylbenzofuran-3-carboxylic acid (31.7 mg) was used instead of quinoline-4-carboxylic acid , 0.18 mmol). ¹ H-NMR (CDCl ₃ , 400 MHz) δ 8.29 (s, 0.7H), 8.17 (s, 0.4H), 7.80-8.00 (m, 2H), 7.20 -7.25 (m, 1H), 7.14-7.18 (m, 1H), 4.69-4.84 (m, 2H), 3.53-3.69 (m, 3H), 3 .27-3.49 (m, 2H), 3.11-3.25 (m, 1H), 2.77-2.97 (m, 1H), 2.52-2.62 (s, 3H) , 2.10-2.42 (m, 5H), 1.99-2.04 (m, 1H)

[1619] Example 46 N-((S)-1-(2-((S)-2-cyanopyrrolidin-1-yl)-2-oxoethyl)pyrrolidin-3-yl)-5-methoxybenzofuran-3-carboxamide

[1620] The title compound (5.9 mg) was prepared in the same manner as Example 30 except that 5-methoxybenzofuran-3-carboxylic acid (34.6 mg) was used instead of quinoline-4-carboxylic acid , 0.18 mmol). ¹ H-NMR (CDCl ₃ , 400 MHz) δ 8.27 (s, 0.7H), 8.12 (s, 0.4H), 8.00 (d, 0.7H), 7.60-7 .69 (m, 1H), 7.38 (d, 1H), 7.09-7.24 (m, 0.4H), 6.93 (d, J-9.1, 1H), 4.68 -4.81 (m, 2H), 3.88 (s, 3H), 3.50-3.70 (m, 3H), 3.25-3.49 (m, 2H), 2.98-3 .23 (m, 2H), 2.68-2.79 (m, 1H), 2.11-2.41 (m, 5H), 1.97-2.03 (m, 1H)

[1621] Example 47 N-((S)-1-(2-((S)-2-cyanopyrrolidin-1-yl)-2-oxoethyl)pyrrolidin-3-yl)-7-methoxybenzofuran-3-carboxamide

[1622] The title compound (1.1 mg) was prepared in the same manner as Example 30 except that 7-methoxybenzofuran-3-carboxylic acid (34.6 mg) was used instead of quinoline-4-carboxylic acid , 0.18 mmol). ¹ H-NMR (CDCl ₃ , 400 MHz) δ 8.28 (s, 0.6H), 8.16 (s, 0.5H), 7.79-8.15 (m, 0.5H), 7 ,61-7.74 (m, 1H), 7.28-7.33 (m, 0.6H), 6.86 (d, 1.), 4.76-4.87 (m, 2H), 4.01-4.21 (s, 3H), 3.52-3.72 (m, 3H), 3.44-3.51 (m, 1H), 3.33-3.42 (m, 1H ), 3.16-3.32 (m, 1H), 3.08-3.15 (m, 1H), 2.73-2.86 (m, 1H), 2.11-2.45 (m , 5H), 1.90-2.04 (m, 1H)

[1623] Example 48 N-((S)-1-(2-((S)-2-cyanopyrrolidin-1-yl)-2-oxoethyl)pyrrolidin-3-yl)-4-hydroxybenzofuran-3-carboxamide

[1624] The title compound (1.8 mg) was prepared in the same manner as Example 30 except that 4-hydroxybenzofuran-3-carboxylic acid (32.1 mg) was used instead of quinoline-4-carboxylic acid , 0.18 mmol). ¹ H-NMR (CDCl ₂ , 400 MHz) δ 9.15-9.21 (m, 0.8H), 8.36 (s, 0.7H), 8.13 (s, 0.3H), 7 .88 (m, 0.2H), 7.19-7.25 (m, 1H), 6.98-7.12 (m, 1H), 6.76 (d, 1H), 4.77-4 .88 (m, 1H), 4.67-4.76 (m, 1H), 3.54-3.75 (m, 3H), 3.35-3.51 (m, 1H), 3.15 -3.28 (m, 2H), 3.02 (m, 1H), 2.67-2.90 (m, 1H), 2.14-2.42 (m, 5H), 2.05 (s , 1H)

[1625] Example 49 N-((S)-1-(2-((S)-2-cyanopyrrolidin-1-yl)-2-oxoethyl)pyrrolidin-3-yl)-6-hydroxybenzofuran-3-carboxamide

[1626] The title compound (7.6 mg) was prepared in the same manner as Example 30 except that 6-hydroxybenzofuran-3-carboxylic acid (32.1 mg) was used instead of quinoline-4-carboxylic acid , 0.18 mmol). ¹ H-NMR (CDCl ₃ , 400 MHz) δ 8.05-8.12 (m, 1H), 7.80-7.98 (m, 1H), 7.64-7.78 (m, 1H) , 6.99-7.12 (m, 1H), 6.82-6.98 (m, 1H), 4.76-4.82 (m, 2H), 3.48-3.84 (m, 3H), 3.41-3.47 (m, 1H), 3.31-3.40 (m, 1H), 2.91-3.23 (m, 2H), 2.62-2.81 ( m, 1H), 2.11-2.40 (m, 5H), 1.86-2.01 (m, 1H)

[1627] Example 50 N-((S)-1-(2-((S)-2-cyanopyrrolidin-1-yl)-2-oxoethyl)pyrrolidin-3-yl)-7-fluorobenzofuran-3-carboxamide

[1628] The title compound (9.6 mg) was prepared in the same manner as Example 30 except that 7-fluorobenzofuran-3-carboxylic acid (32.4 mg) was used instead of quinoline-4-carboxylic acid , 0.18 mmol). ¹ H-NMR (CDCl ₃ , 400 MHz) δ 8.32 (s, 0.6H), 8.18 (s, 0.3H), 8.04-8.12 (m, 0.6H), 7 .88-7.98 (m, 1.0H), 7.18-7.34 (m, 1.4H), 7.03-7.14 (m, 1H), 4.67-4.85 ( m, 2H), 3.35-3.78 (m, 4H), 3.05-3.27 (m, 2H), 2.98-3.03 (m, 1H), 2.66-2, 79 (m, 1H), 2.12-2.48 (m, 5H), 1.87-2.03 (m, 1H)

[1629] Example 51 N-((S)-1-(2-((5)-2-cisnopyrrolidin-1-yl)-2-oxoethyl)pyrrolidin-3-yl)-5,7-difluorobenzofuran-3 -carboxamide

[1630] The title compound (12 mg) was prepared in the same manner as Example 30 except that 5,7-difluorobenzofuran-3-carboxylic acid (35.6 mg) was used instead of quinoline-4-carboxylic acid , 0.18 mmol). ¹ H-NMR (CDCl ₃ , 400 MHz) δ 8.38 (s, 0.7H), 8.31 (d, 0.6H), 8.21 (s, 0.3H), 7.67-7 .77 (m, 1H), 7.36 (d, 0.3H), 6.88 (t, 1H), 4.77-4.89 (m, 1H), 4.65-4.73 (m , 1H), 3.36-3.74 (m, 4H), 3.08-3.28 (m, 2H), 3.00-3.07 (m, 1H), 2.69-2.82 (m, 1H), 2.13-2.41 (m, 5H), 1.86-2.05 (m, 1H)

[1631] Example 52 N-((S)-1-(2-((S)-2-cyanopyrrolidin-1-yl)-2-oxoethyl)pyrrolidin-3-yl)-5-methylbenzofuran-3-carboxamide

[1632] The title compound (6.2 mg) was prepared in the same manner as Example 30 except that 5-methylbenzofuran-3-carboxylic acid (31.7 mg) was used instead of quinoline-4-carboxylic acid , 0.18 mmol). ¹ H-NMR (CDCl ₃ , 400 MHz) δ 8.22 (s, 0.6H), 8.10 (s, 0.4H), 7.91 (s, 1H), 7.69 (m, 0 ,7H), 7.38 (d, 1H), 7.15 (d, 1H), 7.03 (m, 0.3H), 4.67-4.82 (m, 2H), 3.37- 3.77 (m, 4H), 2.89-3.32 (m, 3H), 2.63-2.85 (m, 1H), 2.45-2.50 (m, 3H), 2. 12-2.39 (m, 5H), 1.97-2.11 (m, 1H)

[1633] Example 53 N-((S)-1-(2-((S)-2-cyanopyrrolidin-1-yl)-2-oxoethyl)pyrrolidin-3-yl)-6-methylbenzofuran-3-carboxamide

[1634] The title compound (3.3 mg) was prepared in the same manner as Example 30 except that 6-methylbenzofuran-3-carboxylic acid (31.7 mg) was used instead of quinoline-4-carboxylic acid , 0.18 mmol). ¹ H-NMR (CDCl ₃ , 400 MHz) δ 8.20 (s, 0.7H), 8.08 (s, 0.3H), 7.88-8.04 (m, 1H), 7.75 (m, 0.7H), 7.28-7.36 (m, 1H), 7.10-7.21 (m, 1H), 7.04 (m, 0.3H), 4.67-4 .81 (m, 2H), 3.52-3.74 (m, 3H), 3.38-3.52 (m, 1H), 3.22-3.36 (m, 1H), 2.96 -3.21 (m, 2H), 2.72-2.83 (m, 1H), 2.48 (s, 3H), 2.12-2.39 (m, 5H), 2.00-2 .11 (m, 1H)

[1635] Example 54 N-((S)-1-(2-((S)-2-cyanopyrrolidin-1-yl)-2-oxoethyl)pyrrolidin-3-yl)-6-methoxybenzofuran-3-carboxamide

[1636] The title compound (1.8 mg) was prepared in the same manner as Example 30 except that 6-methoxybenzofuran-3-carboxylic acid (34.6 mg) was used instead of quinoline-4-carboxylic acid , 0.18 mmol). ¹ H-NMR (CDCl ₃ , 400 MHz) δ 8.16 (s, 0.7H), 7.93-8.08 (m, 1.4H), 7.75 (m, 0.7H), 6 .94-7.08 (m, 2.4H), 4.67-4.83 (m, 2H), 3.86 (s, 3H), 3.50-3.71 (m, 3H), 3 .44-3.49 (m, 1H), 2.94-3.32 (m, 3H), 2.73-2.91 (m, 1H), 2.12-2.40 (m, 5H) , 1.99-2.11 (m, 1H)

[1637] Example 55 N-((S)-1-(2-((S)-2-cyanopyrrolidin-1-yl)-2-oxoethyl)pyrrolidin-3-yl)benzofuran-4-carboxamide

[1638] The title compound (7.0 mg) was prepared in the same manner as Example 30 except that benzofuran-4-carboxylic acid (29.2 mg) was used instead of the quinoline-4-carboxylic acid of Example 28 , 0.18 mmol). ¹ H-NMR (CDCl ₃ , 400 MHz) δ 7.50-7.74 (m, 3H), 7.29-7.44 (m, 2H), 4.75-4.86 (m, 2H) , 3.35-3.71 (m, 4H), 2.93-3.34 (m, 3H), 2.62-2.80 (m, 1H), 2.32-2.52 (m, 3H), 2.17-2.31 (m, 3H), 1.95-2.13 (m, 2H)

[1639] Example 56 N-((S)-1-(2-((S)-2-cyanopyrrolidin-1-yl)-2-oxoethyl)pyrrolidin-3-yl)benzofuran-5-carboxamide

[1640] The title compound (10.6 mg) was prepared in the same manner as Example 30 except that benzofuran-5-carboxylic acid (29.2 mg, 0 .18 mmol). ¹ H-NMR (CDCl ₃ , 400 MHz) δ 8.11-8.24 (m, 1H), 7.76-7.99 (m, 1.7H), 7.66-7.75 (m, 1H), 7.53-7.62 (m, 1H), 7.06-7.24 (m, 0.4H), 6.80-6.90 (m, 1H), 4.75 (m, 2H), 3.39-3.73 (m, 4H), 2.84-3.31 (m, 4H), 2.70-2.82 (m, 1H), 2.09-2.47 ( m, 5H), 1.94-2.08 (m, 1H)

[1641] Example 57 N-((S)-1-(2-((S)-2-cyanopyrrolidin-1-yl)-2-oxoethyl)pyrrolidin-3-yl)benzofuran-6-carboxamide

[1642] The title compound (15.0 mg) was prepared in the same manner as Example 30 except that benzofuran-6-carboxylic acid (29.2 mg, 0 .18 mmol). ¹ H-NMR (CDCl ₃ , 400 MHz) δ 8.00-8.15 (m, 1H), 7.57-7.87 (m, 3.7H), 7.15-7.24 (m, 0.4H), 6.80-6.92 (m, 1H), 4.76-4.86 (m, 2H), 3.38-3.75 (m, 4H), 3.10-3, 27 (m, 1H), 2.80-3.05 (m, 2H), 2.56-2.78 (m, 1H), 2.07-2.47 (m, 6H), 1.93- 2.05 (m, 1H)

[1643] Example 58 N-((S)-1-(2-((S)-2-cyanopyrrolidin-1-yl)-2-oxoethyl)pyrrolidin-3-yl)benzofuran-7-carboxamide

[1644] The title compound (11.2 mg) was prepared in the same manner as Example 30 except that benzofuran-7-carboxylic acid (29.2 mg, 0 .18 mmol). ¹ H-NMR (CDCl ₃ , 400 MHz) δ 8.08 (m, 1H), 7.68-7.95 (m, 3H), 7.30-7.41 (m, 1H), 6.87 (s, 1H), 5.06 (m, 0.4H), 4.78-4.89 (m, 1.6H), 3.59-3.78 (m, 1H), 3.30-3 .55 (m, 3H), 3.14-3.28 (m, 1H), 2.77-3.03 (m, 2H), 2.38-2.69 (m, 2H), 2.01 -2.35 (m, 5H), 1.93-2.00 (m, 1H)

[1645] Example 59 N-((S)-1-(2-((S)-2-cyanopyrrolidin-1-yl)-2-oxoethyl)pyrrolidin-3-yl)benzofuran-2-sulfonamide

[1646] (S)-1-(2-((S)-3-Aminopyrrolidin-1-yl)acetyl)pyrrolidine-2-carbonitrile trifluoroacetate (30 mg, 0.13 mmol) prepared in Reference Example 25 was dissolved in anhydrous dichloromethane (2 ml). Triethylamine (60 μL, 0.40 mmol) and benzofuran 2-sulfonyl chloride (32.2 mg, 0.15 mmol) were added to the resulting solution. The reaction mixture was stirred overnight at room temperature. After completion of the reaction, water was added to the reaction mixture. The aqueous layer of the reaction mixture was extracted with dichloromethane. The extracted organic layer was dried and filtered over anhydrous magnesium sulfate. The filtered solution was concentrated and then purified by silica gel column chromatography (ethyl acetate/methanol = 20/1, v/v) to give the title compound (7.3 mg). ¹ H-NMR (CDCl ₃ , 400 MHz) δ 7.68-7.79 (m, 1H), 7.56-7.62 (m, 1H), 7.46-7.55 (m, 1H) , 7.31-7.40 (m, 2H), 4.68-4.80 (m, 1H), 4.09-4.12 (m, 1H), 3.55-3.77 (m, 1H), 3.21-3.53 (m, 3H), 2.74-3.16 (m, 3H), 2.42-2.69 (m, 1H), 2.02-2.40 ( m, 7H), 1.76-1.86 (m, 1H)

[1647] Example 60 N-((S)-1-(2-((S)-2-cyanopyrrolidin-1-yl)-2-oxoethyl)pyrrolidin-3-yl)benzo[b]thiophene-2- sulfonamide

[1648] The title compound (8.7 mg) was prepared in the same manner as Example 59 except that benzo[b]thiophene-2-sulfonyl chloride (34.6 mg, 0.15 mmol). ¹ H-NMR (CDCl ₃ , 400 MHz) δ 7.87-7.99 (m, 3H), 7.46-7.58 (m, 2H), 4.73-4.82 (m, 1H) , 4.03-4.12 (m, 1H), 3.57-3.62 (m, 1H), 3.24-3.42 (m, 2H), 3.09-3.21 (m, 1H), 2.53-2.88 (m, 2H), 2.41-2.51 (m, 1H), 2.09-2.31 (m, 6H), 1.67-1.85 ( m, 1N)

[1649] Example 61: (S)-1-(2-((S)-3-(quinolin-4-yloxy)pyrrolidin-1-yl)acetyl)pyrrolidin-2-carbonitrile

[1650](S)-1-(2-((R)-3-hydroxypyrrolidin-1-yl)acetyl)pyrrolidine-2-carbonitrile (242 mg, 1.08 mmol) prepared in Reference Example 26 was dissolved in tetrahydrofuran (9.03 ml). 4-quinolinol (15.7.34 mg, 1.08 mmol) and triphenylphosphine (568.6 mg, 2.17 mmol) were added to the resulting solution. The mixture solution was cooled to 0°C. DIAD (diisopropyl azodicarboxylate) (0.43 mL, 2.17 mmol) was then added dropwise slowly over 15 minutes. The reaction mixture was stirred for 12 hours at room temperature. After completion of the reaction, a saturated ammonium chloride solution and a saturated sodium hydrogen carbonate solution were added to the reaction mixture. The aqueous layer of the reaction mixture was extracted with ethyl acetate. The extracted organic spruce was dried and filtered over anhydrous magnesium sulfate. The filtered solution was concentrated and then purified by silica gel column chromatography (dichloromethane/methanol = 10/1, v/v) to give the title compound (18.5 mg). ¹ H-NMR (CDCl ₃ , 400 MHz) δ 8.73 (d, 1H), 8.19 (t, 1H), 8.04 (d, 1H), 7.70 (t, 1H), 7. 51 (m, 1H), 6.64 (d, 1H), 5.16-5.09 (m, 1.3H), 4.76 (d, 0.7H), 3.71-3.63 ( m, 2H), 3.53-3.51 (m, 1H), 3.41-3.37 (m, 1H), 3.15-2.72 (m, 3H), 2.46-2, 29 (m, 1H), 2.27-1.98 (m, 6H)

[1651] Example 62: (S)-1-(2-((S)-3-(naphthalene-1-yloxy)pyrrolidin-1-yl)acetyl)pyrrolidin-2-carbonitrile

[1652] The title compound (68 mg) was prepared in the same manner as Example 61 except that naphthalene-1-ol (160 mg, 1.08 mmol) was used instead of 4-quinolinol. ¹ H-NMR (CDCl ₃ , 400 MHz) δ 8.23 (t, 1H), 7.80 (d, 1H), 7.46-7.40 (m, 3H), 7.32 (t, 1H ), 6.72 (d, 1H), 5.27 (d, 0.3H), 5.05 (m, 1H), 4.76 (m, 0.7H), 3.72-3.31 ( m, 5H), 3.05-3.03 (m, 1H), 2.95-2.91 (m, 2H), 2.41-2.38 (m, 1H), 2.25-2, 14 (m, 4H), 2.02-1.98 (m, 1H), 1.89 (m, 1H)

[1653] Example 63: (S)-1-(2-((S)-3-(quinolin-6-yloxy)pyrrolidin-1-yl)acetyl)pyrrolidin-2-carbonitrile

[1654] The title compound (87 mg) was prepared in the same manner as Example 61 except that 6-quinolinol (160 mg, 1.08 mmol) was used instead of 4-quinolinol. ¹ H-NMR (CDCl ₃ , 400 MHz) δ 8.76 (s, 1H), 8.04-7.98 (m, 2H), 7.35-7.27 (m, 2H), 6.97 (s, 1H), 5.24-4.76 (m, 2H), 3.68-3.34 (m, 5H), 3.01-2.89 (m, 3H), 2.44-2 .10 (m, 7N)

[1655] Example 64: (S)-1-(2-((S)-3-(quinolin-8-yloxy)pyrrolidin-1-yl)acetyl)pyrrolidin-2-carbonitrile

[1656] The title compound (57 mg) was prepared in the same manner as Example 61 except that 8-quinolinol (160 mg, 1.08 mmol) was used instead of 4-quinolinol. ¹ H-NMR (CDCl ₃ , 400 MHz) δ 8.93 (s, 1H), 8.14 (d, 1H), 7.44-7.38 (m, 3H), 7.00-6.96 (m, 1H), 5.47 (d, 0.4H), 5.14 (s, 1H), 4.75 (d, 0.6H), 3.79-3.66 (m, 2H), 3.64-3.30 (m, 3H), 3.09-2.84 (m, 3H), 2.47-2.43 (m, 1H), 2.28-2.03 (m, 6H )

[1657] Example 65: (S)-1-(2-((S)-3-(isoquinolin-5-yloxy)pyrrolidin-1-yl)acetyl)pyrrolidin-2-carbonitrile

[1658] The title compound (62 mg) was prepared in the same manner as Example 61 except that 5-isoquinolinol (160 mg, 1.08 mmol) was used instead of 4-quinolinol. ¹ H-NMR (CDCl ₃ , 400 MHz) δ 9.20 (s, 1H), 8.51 (s, 1H), 8.00-7.99 (m, 1H), 7.54-7.46 (m, 2H), 6.91 (d, 1H), 5.19 (d, 0.3H), 5.05 (s, 1H), 4.76 (d, 0.7H), 3.71- 3.63 (m, 2H), 3.53-3.51 (m, 1H), 3.42-3.38 (m, 2H), 3.13-2.91 (m, 3H), 2. 48-2.41 (m, 1H), 2.34-1.99 (m, 6H)

[1659] Example 66: (S)-1-(2-((S)-3-(quinolin-5-yloxy)pyrrolidin-1-yl)acetyl)pyrrolidin-2-carbonitrile

[1660] The title compound (89 mg) was prepared in the same manner as Example 61 except that 5-quinolinol (160 mg, 1.08 mmol) was used instead of 4-quinolinol. ¹ H-NMR (CDCl ₃ , 400 MHz) δ 8.90 (s, 1H), 8.59 (t, 1H), 7.69 (d, 1H), 7.58 (t, 1H), 7. 37 (s, 1H), 6.76 (d, 1H), 5.15 (m, 0.3H), 5.05 (m, 1H), 4.76 (m, 0.7H), 3.71 -3.61 (m, 2H), 3.50 (m, 1H), 3.41-3.37 (m, 1H), 3.00-2.86 (m, 3H), 2.45-2 .40 (m, 1H), 2.28-2.07 (m, 6H)

[1661] Example 67: (S)-1-(2-((S)-3-(benzo[d][1,3]dioxol-5-yloxy)pyrrolidin-1-yl)acetyl)pyrrolidin-2- carbonitrile

[1662] The title compound (76 mg) was prepared in the same manner as Example 61 except that benzo[d][1,3]dioxol-5-ol (150 mg, 1.08 mmol). ¹ H-NMR (CDCl ₃ , 400 MHz) δ 6.69 (d, 1H), 6.44 (d, 1H), 6.24 (t, 1H), 5.90 (s, 2H), 5, 28 (d, 0.3H), 4.94-4.92 (m, 1H), 4.75 (m, 0.7H), 3.72-3.63 (m, 2H), 3.52- 3.50 (m, 1H), 3.37-3.21 (m, 1H), 2.94-2.74 (m, 3H), 2.33-2.00 (m, 7H)

[1663] Example 68

[1664] The title compound (63 mg) was prepared in the same manner as Example 61 except that thieno[2,3-d]pyrimidin-4-ol (160 mg, 1 .08 mmol). ¹ H-NMR (CDCl ₃ , 400 MHz) δ 8.62 (s, 1H), 7.38 (s, 2H), 5.72 (m, 1H), 5.20 (d, 0.3H), 4.76 (m, 0.7H), 3.71-3.62 (m, 2H), 3.53-3.52 (m, 1H), 3.45-3.35 (m, 1H), 3.27-3.22 (m, 1H), 3.04 (d, 2H), 2.49-2.44 (m, 1H), 2.42-2.04 (m, 6H)

[1665] Example 69: (S)-1-(2-((S)-3-(isoquinolin-3-yloxy)pyrrolidin-1-yl)acetyl)pyrrolidin-2-carbonitrile

[1666] The title compound (123 mg) was prepared in the same manner as Example 61 except that 3-isoquinolinol (151 mg, 1.08 mmol) was used instead of 4-quinolinol. ^1H -NMR ( _CDCl3 , 400 MHz) δ 8.89 (s, 1H), 7.84 (d, 1H), 7.65 (d, 1H), 7.54 (m, 1H), 7. 34 (m, 1H), 6.96 (m, 1H), 5.47 (m, 1H), 4.71 (m, 1H), 3.68-3.37 (m, 4H), 3.07 -2.89 (m, 3H), 2.41-2.01 (m, 7H)

[1667] Example 70: (S)-1-(2-((S)-3-(3-bromothieno[3,2-c]pyridin-4-yl)oxy)pyrrolidin-1-yl)acetyl)pyrrolidine -2-carbonitrile

[1668] The title compound (70.2 mg) was prepared in the same manner as Example 61 except that 3-bromothieno[3,2-c]pyridin-4-ol ( 151 mg, 1.08 mmol). ¹ H-NMR (CDCl ₃ , 400 MHz) δ 7.92 (s, 1H), 7.34 (m, 2H), 5.62 (m, 1H), 4.75 (m, 1H), 3, 72-3.39 (m, 4H), 3.04-2.91 (m, 3H), 2.42 (m, 1H), 2.27-2.19 (m, 6H)

[1669] Example 71: (S)-1-(2-((S)-3-(4-chloronaphthalene-1-yl)oxy)pyrrolidin-1-yl)acetyl)pyrrolidin-2-carbonitrile

[1670] The title compound (94.0 mg) was prepared in the same manner as Example 61 except that 4-chloronaphthalene-1-ol (194 mg, 1.08 mmol) was used instead of 4-quinolinol. . ¹ H-NMR (CDCl ₃ , 400 MHz) δ 8.27 (d, 1H), 8.16 (d, 1H), 7.58 (m, 1H), 7.52 (m, 1H), 7. 40 (d, 1H), 6.60 (d, 1H), 4.90 (m, 1H), 4.70 (m, 1H), 3.61-3.27 (m, 4H), 2.97 -2.69 (m, 3H), 2.39-1.93 (m, 7H)

[1671] Example 72

[1672] The title compound (81 mg) was prepared in the same manner as Example 61 except that 2-(1H-pyrazol-3-yl)phenol (173 mg, 1. 08 mmol). ¹ H-NMR (CDCl ₃ , 400 MHz) δ 7.63 (d, 1H), 7.56 (s, 1H), 7.25 (m, 1H), 7.04 (m, 1H), 6, 97 (d, 1H), 6.58 (s, 1H), 5.03 (s, 1H), 4.72 (s, 1H), 3.59 (d, 2H), 3.44-3.40 (m, 2H), 3.22-3.02 (m, 3H), 2.31-2.30 (m, 1H), 2.20-1.98 (m, 6H)

[1673] Example 73: (S)-1-(2-((S)-3-(4-chloroquinazolin-8-yl)oxy)pyrrolidin-1-yl)acetyl)pyrrolidin-2-carbonitrile

[1674] The title compound (72 mg) was prepared in the same manner as Example 61 except that 4-chloroquinazolin-8-ol (194 mg, 1.08 mmol) was used instead of 4-quinolinol in Example 59 ). ¹ H-NMR (CDCl ₃ , 400 MHz) δ 7.85-7.47 (m, 3H), 7.20 (m, 1H), 5.03 (s, 1H), 4.76 (s, 1H ), 3.66-3.54 (m, 4H), 3.18-2.96 (m, 4H), 2.49-2.05 (m, 6H)

[1675] Example 74: (S)-1-(2-((S)-3-(4-chloroquinazolin-6-yl)oxy)pyrrolidin-1-yl)acetyl)pyrrolidin-2-carbonitrile

[1676] The title compound (90.7 mg) was prepared in the same manner as Example 61 except that 4-chloroquinazolin-6-ol (194 mg, 1.08 mmol) was used instead of 4-quinolinol. . ^1H -NMR ( _CDCl3 , 400 MHz) δ 7.97 (m, 1H), 7.62-7.54 (m, 2H), 7.37 (d, 1H), 5.06 (s, 1H ), 4.75 (s, 1H), 3.69-3.36 (m, 4H), 3.10-2.92 (m, 4H), 2.49-2.18 (m, 6H)

[1677] Example 75: (S)-1-(2-((S)-3-(2-oxo-1,2-dihydroquinolin-5-yl)oxy)pyrrolidin-1-yl)acetyl)pyrrolidin-2 -carbonitrile

[1678] The title compound (93.9 mg) was prepared in the same manner as Example 61 except that 5-hydroxyquinolin-2(1H)-one (176 mg, 1. 08 mmol). ¹ H-NMR (CDCl ₃ , 400 MHz) δ 11.68 (m, 1H), 8.17 (m, 1H), 7.37-7.26 (m, 1H), 6.61 (m, 1H ), 6.49 (m, 1H), 5.10 (s, 2H), 3.70-3.30 (m, 4H), 2.96-2.85 (m, 3H), 2.38- 1.92 (m, 7N)

[1679] Example 76: (S)-1-(2-((S)-3-(2-oxo-1,2,3,4-tetrahydroquinolin-5-yl)oxy)pyrrolidin-1-yl)acetyl )pyrrolidine-2-carbonitrile

[1680] The title compound (112.3 mg) was prepared in the same manner as Example 61 except that 5-hydroxy-3,4-dihydroquinolin-2(1H)-one was used instead of 4-quinolinol (176 mg, 1.08 mmol). ¹ H-NMR (CDCl ₃ , 400 MHz) δ 9.71 (s, 0.5H), 8.49 (s, 0.5H), 7.07 (t, 1H), 6.44 (m, 2H ), 4.87 (s, 1H), 4.76 (s, 1H), 3.69-3.30 (m, 4H), 2.92-2.79 (m, 5H), 2.70- 2.57 (m, 2H), 2.33-2.06 (m, 7H)

[1681] Example 77: (S)-1-(2-((S)-3-(2-oxo-1,2,3,4-tetrahydroquinolin-6-yl)oxy)pyrrolidin-1-yl)acetyl )pyrrolidine-2-carbonitrile

[1682] The title compound (94.0 mg) was prepared in the same manner as Example 61 except that 6-hydroxy-3,4-dihydroquinolin-2(1H)-one was used instead of 4-quinolinol (176 mg, 1.08 mmol). ¹ H-NMR (CDCl ₃ , 400 MHz) δ 9.02 (s, 1H), 6.76 (d, 1H), 6.64 (m, 2H), 4.79-4.75 (m, 2H ), 3.68-3.24 (m, 5H), 2.90-2.59 (m, 7H), 2.27-2.02 (m, 6H)

[1683] Example 78 (S)-1-(2-((S)-3-(2-methylquinolin-8-yl)oxy)pyrrolidin-1-yl)acetyl)pyrrolidin-2-carbonitrile

[1684] The title compound (74.5 mg) was prepared in the same manner as Example 61 except that 2-methylquinolin-8-ol (171.7 mg, 1.08 mmol). ^1H NMR ( _CDCl3 , 400 MHz) δ 8.28 (s, 1H), 7.52 (s, 1H), 7.34 (d, 2H), 6.89 (d, 1H), 5.09 (s, 1H), 4.98 (s, 1H), 3.78-3.53 (m, 4H), 3.42-3.16 (m, 3H), 2.80-2.75 (m , 4H), 2.43-2.04 (m, 6H)

[1685] Example 79: (S)-1-(2-((S)-3-((7-chloroquinolin-4-yl)oxy)pyrrolidin-1-yl)acetyl)pyrrolidin-2-carbonitrile

[1686] The title compound (50.7 mg) was prepared in the same manner as Example 61 except that 7-chloroquinolin-4-ol (194 mg, 1.08 mmol) was used instead of 4-quinolinol. . ¹ H-NMR (CDCl ₃ , 400 MHz) δ 8.69 (s, 1H), 8.13 (d, 1H), 8.00 (s, 1H), 7.43 (d, 1H), 6, 62 (s, 1H), 5.07 (s, 1.3H), 4.75 (s, 0.7H), 3.69-3.27 (m, 4H), 3.09-2.86 ( m, 3H), 2.46-2.45 (m, 1H), 2.28-2.00 (m, 6H)

[1687] Example 80: (S)-1-(2-((S)-3-(7-bromoquinolin-4-yl)oxy)pyrrolidin-1-yl)acetyl)pyrrolidin-2-carbonitrile

[1688] The title compound (48.6 mg) was prepared in the same manner as Example 61 except that 7-bromoquinolin-4-ol (237 mg, 1.08 mmol) was used instead of 4-quinolinol. . ¹ H-NMR (CDCl ₃ , 400 MHz) δ 8.67 (s, 1H), 8.17 (s, 1H), 8.05 (d, 1H), 7.55 (d, 1H), 6, 63 (s, 1H), 5.06 (s, 1.3H), 4.75 (s, 0.7H), 3.71-3.26 (m, 4H), 3.03-2.85 ( m, 3H), 2.45-2.44 (m, 1H), 2.31-1.99 (m, 6H)

[1689] Example 81: (S)-1-(2-((S)-3-(5-chloroquinolin-8-yl)oxy)pyrrolidin-1-yl)acetyl)pyrrolidin-2-carbonitrile

[1690] The title compound (41 mg) was prepared in the same manner as Example 61 except that 5-chloroquinolin-8-ol (194 mg, 1.08 mmol) was used instead of 4-quinolinol. ^1H -NMR ( _CDCl3 , 400 MHz) δ 8.95 (s, 1H), 8.53 (d, 1H), 7.53-7.49 (m, 2H), 6.92 (d, 1H ), 5.11 (s, 1H), 4.75 (s, 1H), 3.79-3.35 (m, 5H), 3.16-2.93 (m, 2H), 2.45 ( m, 1H), 2.22-2.04 (m, 6H)

[1691] Example 82: (S)-1-(2-((S)-3-([1,1'-biphenyl]-3-yloxy)pyrrolidin-1-yl)acetyl)pyrrolidin-2-carbonitrile

[1692] The title compound (81 mg) was prepared in the same manner as Example 61 except that [1,1'-biphenyl]-3-ol (184 mg, 1. 08 mmol). ¹ H-NMR (CDCl ₃ , 400 MHz) δ 7.56-7.48 (m, 2H), 7.42-7.27 (m, 4H), 7.17-7.06 (m, 2H) , 6.90-6.67 (m, 1H), 4.91 (s, 1H), 4.72 (s, 1H), 3.74-3.27 (m, 5H), 2.88-2 .83 (m, 2H), 2.31 (m, 1H), 2.30-2.11 (m, 6H)

[1693] Example 83: (S)-1-(2-((S)-3-([1,1'-biphenyl]-4-yloxy)pyrrolidin-1-yl)acetyl)pyrrolidin-2-carbonitrile

[1694] The title compound (63.7 mg) was prepared in the same manner as Example 61 except that [1,1'-biphenyl]-4-ol (184 mg, 1.08 mmol). ^1H -NMR ( _CDCl3 , 400 MHz) δ 7.53-7.48 (m, 4H), 7.39 (t, 2H), 7.28 (t, 1H), 6.90 (d, 2H ), 4.88 (s, 1H), 4.72 (s, 1H), 3.74-3.28 (m, 5H), 2.87-2.80 (m, 2H), 2.31 ( m, 1H), 2.12-1.97 (m, 6H)

[1695] Example 84: (S)-1-(2-((S)-3-(6-methoxyquinolin-4-yl)oxy)pyrrolidin-1-yl)acetyl)pyrrolidin-2-carbonitrile

[1696] The title compound (70.2 mg) was prepared in the same manner as Example 61 except that 6-methoxyquinolin-4-ol (183 mg, 1.08 mmol) was used instead of 4-quinolinol. . ¹ H-NMR (CDCl ₃ , 400 MHz) δ 8.57 (s, 1H), 7.94 (d, 1H), 7.43 (s, 1H), 7.34 (d, 1H), 6, 60 (s, 1H), 5.06 (s, 1.4H), 4.75 (s, 0.6H), 3.93 (s, 3H), 3.71-3.69 (m, 2H) , 3.63-3.25 (m, 3H), 3.04-2.84 (m, 2H), 2.45 (m, 1H), 2.27-1.98 (m, 6H)

[1697] Example 85 (S)-1-(2-((S)-3-(7,8-difluoroquinolin-4-yl)oxy)pyrrolidin-1-yl)acetyl)pyrrolidin-2-carbonitrile

[1698] The title compound (62.6 mg) was prepared in the same manner as Example 61 except that 7,8-difluoroquinolin-4-ol (194 mg, 1.08 mmol). ¹ H-NMR (CDCl ₃ , 400 MHz) δ 8.75 (s, 1H), 7.94 (s, 1H), 7.33 (d, 1H), 6.67 (s, 1H), 5, 09 (s, 1.4H), 4.76 (s, 0.6H), 3.93 (s, 3H), 3.71-3.66 (m, 2H), 3.56-3.27 ( m, 3H), 3.06-2.86 (m, 2H), 2.48-2.45 (m, 1H), 2.29-2.00 (m, 6H)

[1699] Example 86 Methyl 6-((S)-1-(2-((S)-2-cyanopyrrolidin-1-yl)-2-oxoethyl)pyrrolidin-3-yl)oxy)-2,3 -dihydrobenzofuran-2-carboxylate

[1700] The title compound (85.3 mg) was prepared in the same manner as Example 61 except that methyl 6-hydroxy-2,3-dihydrobenzofuran-2-carboxylate ( 205 mg, 1.08 mmol). ¹ H-NMR (CDCl ₃ , 400 MHz) δ 7.02 (d, 1H), 6.41-6.36 (m, 2H), 5.23 (t, 1H), 4.80 (s, 1H ), 4.72 (s, 1H), 4.08 (m, 1H), 3.80 (s, 3H), 3.74-3.65 (m, 2H), 3.51-3.39 ( m, 3H), 3.33-3.25 (m, 2H), 2.91-2.86 (m, 2H), 2.25-2.04 (m, 6H)

[1701] Example 87 (S)-1-(2-((S)-3-(4-phenoxyphenoxy)pyrrolidin-1-yl)acetyl)pyrrolidin-2-carbonitrile

[1702] The title compound (50.7 mg) was prepared in the same manner as Example 61 except that 4-phenoxyphenol (205 mg, 1.08 mmol) was used instead of 4-quinolinol. ^1H -NMR ( _CDCl3 , 400 MHz) δ 7.29-2.27 (m, 2H), 7.03 (s, 1H), 6.94 (s, 4H), 6.82 (d, 2H ), 4.81-4.69 (m, 2H), 3.74-3.62 (m, 2H), 3.51-3.43 (m, 1H), 3.39-3.35 (m , 1H), 3.32-3.24 (m, 1H), 2.87-2.82 (t, 2H), 2.29-2.04 (m, 7H)

[1703] Example 88 (S)-1-(2-((S)-3-(3-phenoxyphenoxy)pyrrolidin-1-yl)acetyl)pyrrolidin-2-carbonitrile

[1704] The title compound (95 mg) was prepared in the same manner as Example 61 except that 3-phenoxyphenol (205 mg, 1.08 mmol) was used instead of 4-quinolinol. ¹ H-NMR (CDCl ₃ , 400 MHz) δ 7.34 (t, 2H), 7.19 (t, 1H), 7.13 (t, 1H), 7.02 (d, 2H), 6, 57 (d, 2H), 6.49 (s, 1H), 4.81 (s, 1H), 4.74 (s, 1H), 3.71-3.63 (m, 1H), 3.51 -3.49 (m, 1H), 3.38-3.23 (m, 2H), 2.86-2.62 (m, 3H), 2.27-2.02 (m, 7H)

[1705] Example 89 (S)-1-(2-((S)-3-(4-benzylphenoxy)pyrrolidin-1-yl)acetyl)pyrrolidin-2-carbonitrile

[1706] The title compound (96.1 mg) was prepared in the same manner as Example 61 except that 4-benzylphenol (194 mg, 1.08 mmol) was used instead of 4-quinolinol. ¹ H-NMR (CDCl ₃ , 400 MHz) δ 7.26 (s, 2H), 7.17 (t, 3H), 7.08 (d, 2H), 6.76 (d, 2H), 4, 81 (s, 1H), 4.74 (s, 1H), 3.90 (s, 2H), 3.73-3.67 (m, 2H), 3.51-3.27 (m, 2H) , 2.85-2.76 (m, 3H), 2.26-2.02 (m, 7H)

[1707] Example 90 (S)-1-(2-((S)-3-(2-benzylphenoxy)pyrrolidin-1-yl)acetyl)pyrrolidin-2-carbonitrile

[1708] The title compound (69.1 mg) was prepared in the same manner as Example 61 except that 2-benzylphenol (194 mg, 1.08 mmol) was used instead of 4-quinolinol. ^1H -NMR ( _CDCl3 , 400 MHz) δ 7.26-7.09 (m, 7H), 6.87 (t, 1H), 6.74 (d, 1H), 4.93 (s, 1H ), 4.73 (s, 1H), 3.94 (s, 2H), 3.71-3.64 (m, 1H), 3.57-3.48 (m, 1H), 3.32- 3.24 (m, 2H), 2.84-2.64 (m, 3H), 2.23-1.97 (m, 7H)

[1709] Example 91: (S)-1-(2-((S)-3-(3-benzoylphenoxy)pyrrolidin-1-yl)acetyl)pyrrolidin-2-carbonitrile

[1710] The title compound (93.9 mg) was prepared in the same manner as Example 61 except that 3-hydroxybenzophenone (216 mg, 1.08 mmol) was used instead of 4-quinolinol. ¹ H-NMR (CDCl ₃ , 400 MHz) δ 7.79 (d, 2H), 7.59 (d, 1H), 7.50 (t, 2H), 7.37-7.27 (m, 3H ), 7.09 (d, 1H), 4.93 (s, 1H), 4.47 (s, 1H), 3.73-3.65 (m, 2H), 3.56-3.30 ( m, 2H), 2.97-2.86 (m, 3H), 2.34-1.98 (m, 7H)

[1711] Example 92: (S)-1-(2-((S)-3-(4-benzoylphenoxy)pyrrolidin-1-yl)acetyl)pyrrolidin-2-carbonitrile

[1712] The title compound (49.7 mg) was prepared in the same manner as Example 61 except that 4-hydroxybenzophenone (216 mg, 1.08 mmol) was used instead of 4-quinolinol. ¹ H-NMR (CDCl ₃ , 400 MHz) δ 7.80 (d, 2H), 7.74 (d, 2H), 7.56 (d, 1H), 7.48 (d, 2H), 6, 91 (d, 2H), 4.97 (s, 1H), 4.73 (s, 1H), 3.75-3.65 (m, 2H), 3.57-3.40 (m, 2H) , 3.00-2.88 (m, 3H), 2.38-2.36 (m, 1H), 2.18-1.99 (m, 6H)

[1713] Example 93 (S)-1-(2-((S)-3-(4-(benzyloxy)pyridin-2-yl)oxy)pyrrolidin-1-yl)acetyl)pyrrolidin-2-carbonitrile

[1714] The title compound (95.0 mg) was prepared in the same manner as Example 61 except that 4-(benzyloxy)pyridin-2-ol (216 mg, 1. 08 mmol). ^1H -NMR ( _CDCl3 , 400 MHz) δ 7.92 (d, 1H), 7.38-7.34 (m, 6H), 6.51 (s, 1H), 5.43 (s, 1H ), 5.03 (s, 2H), 4.72 (s, 1H), 3.72-3.44 (m, 2H), 3.38-3.28 (m, 2H), 3.17- 3.13 (m, 1H), 2.96-2.87 (m, 1H), 2.80-2.71 (m, 1H), 2.35-2.30 (m, 1H), 2. 19-1.97 (m, 6N)

[1715] Example 94

[1716] The title compound (97.2 mg) was prepared in the same manner as Example 61 except that 7-(trifluoromethyl)quinolin-4-ol (227 mg, 1. 08 mmol). ¹ H-NMR (CDCl ₃ , 400 MHz) δ 8.78 (s, 1H), 8.30 (s, 2H), 7.64 (d, 1H), 6.74 (d, 1H), 5, 10 (s, 1H), 4.76 (s, 1H), 3.72-3.24 (m, 4H), 3.13-2.96 (m, 2H), 2.86 (m, 1H) , 2.50-2.45 (m, 1H), 2.18-1.99 (m, 6H)

[1717] Example 95

[1718] The title compound (57.2 mg) was prepared in the same manner as Example 61 except that 8-(trifluoromethyl)quinolin-4-ol (227 mg, 1. 08 mmol). ¹ H-NMR (CDCl ₃ , 400 MHz) δ 8.84 (d, 1H), 8.43 (d, 1H), 8.03 (d, 1H), 7.53 (t, 1H), 6, 74 (s, 1H), 5.08 (s, 1H), 4.75 (s, 1H), 3.72-3.38 (m, 4H), 3.29-2.82 (m, 3H) , 2.47-2.45 (m, 1H), 2.26-1.98 (m, 6H)

[1719] Example 96: (S)-1-(2-((S)-3-(acridin-4-yloxy)pyrrolidin-1-yl)acetyl)pyrrolidin-2-carbonitrile

[1720] The title compound (51.8 mg) was prepared in the same manner as Example 61 except that acridin-4-ol (205 mg, 1.08 mmol) was used instead of 4-quinolinol. ¹ H-NMR (CDCl ₃ , 400 MHz) δ 8.67 (s, 1H), 8.31 (d, 1H), 7.92 (d, 1H), 7.69 (m, 1H), 7. 52-7.48 (t, 2H), 7.36 (t, 1H), 6.92 (d, 1H), 5.01 (s, 1H), 4.76 (s, 1H), 3.76 -3.27 (m, 6H), 2.85 (m, 1H), 2.45 (m, 1H), 2.21-1.96 (m, 6H)

[1721] Example 97 (S)-1-(2-((S)-3-(2-(benzo[d]oxazol-2-yl)phenoxy)pyrrolidin-1-yl)acetyl)pyrrolidin-2- carbonitrile

[1722] The title compound (71.3 mg) was prepared in the same manner as Example 61 except that 2-(benzo[d]oxazol-2-yl)-phenol was used instead of the 4-quinolinol of Example 61 (227 mg, 1.08 mmol). ¹ H-NMR (CDCl ₃ , 400 MHz) δ 8.09 (d, 1H), 7.77 (s, 1H), 7.58 (s, 1H), 7.44 (t, 1H), 7. 34 (m, 2H), 7.06 (t, 1H), 6.96 (d, 1H), 4.99 (s, 1H), 4.69 (s, 1H), 3.69-3.54 (m, 1H), 3.48-3.27 (m, 3H), 3.03-2.84 (m, 3H), 2.37-2.32 (m, 1H), 2.17-1 .88 (m, 6N)

[1723] Example 98 (S)-1-(2-((S)-3-(4-(4-acetylpiperazin-1-yl)phenoxy)pyrrolidin-1-yl)acetyl)pyrrolidin-2-carbonitrile

[1724] The title compound (85.3 mg) was prepared in the same manner as Example 61 except that 4-(4-acetylpiperazin-1-yl)phenol (238 mg, 1.08 mmol). ^1H -NMR ( _CDCl3 , 400 MHz) δ 6.88 (d, 2H), 6.79 (d, 2H), 4.78 (s, 1.4H), 4.47 (s, 0.6H ), 3.74-3.68 (m, 3H), 3.60-3.50 (m, 3H), 3.36-3.34 (m, 1H), 3.17-3.15 (m , 1H), 3.04-3.01 (m, 5H), 2.84-2.77 (m, 2H), 2.28-1.99 (m, 10H)

[1725] Example 99 2-((S)-1-(2-((S)-2-cyanopyrrolidin-1-yl)-2-oxoethyl)pyrrolidin-3-yl)oxy)-N-phenylbenzamide

[1726] The title compound (40.0 mg) was prepared in the same manner as Example 61 except that 2-hydroxy-N-phenylbenzamide (227 mg, 1.08 mmol) was used instead of 4-quinolinol. . ^1H -NMR ( _CDCl3 , 400 MHz) δ 10.06-9.94 (m, 1H), 8.21 (d, 1H), 7.73 (d, 2H), 7.41 (t, 1H ), 7.33 (m, 2H), 7.09 (d, 2H), 6.91 (d, 1H), 5.06 (s, 1H), 4.58 (s, 1H), 3.61 -3.26 (m, 4H), 3.07-2.99 (m, 2H), 2.69-2.67 (m, 1H), 2.40-2.38 (m, 1H), 2 .10-1.80 (m, 6N)

[1727] Example 100: (S)-1-(2-((S)-3-(7-methoxyquinolin-4-yl)oxy)pyrrolidin-1-yl)acetyl)pyrrolidin-2-carbonitrile

[1728] The title compound (58.3 mg) was prepared in the same manner as Example 61 except that 7-methoxyquinolin-4-ol (183 mg, 1.08 mmol) was used instead of 4-quinolinol. . ¹ H-NMR (CDCl ₃ , 400 MHz) δ 8.60 (s, 1H), 8.07 (d, 1H), 7.34 (s, 1H), 7.12 (d, 1H), 6, 51 (s, 1H), 5.02 (m, 1.2H), 4.72 (s, 0.8H), 3.91 (s, 4H), 3.64-3.57 (m, 1H ), 3.46-3.28 (m, 3H), 2.99-2.80 (m, 2H), 2.40 (m, 1H), 2.12-2.10 (m, 6H)

[1729] Example 101 (S)-1-(2-((S)-3-(6,7-dimethoxyquinolin-4-yl)oxy)pyrrolidin-1-yl)acetyl)pyrrolidin-2-carbonitrile

[1730] The title compound (73.4 mg) was prepared in the same manner as Example 61 except that 6,7-dimethoxyquinolin-4-ol (216 mg, 1.08 mmol). ¹ H-NMR (CDCl ₃ , 400 MHz) δ 8.52 (d, 1H), 7.40 (s, 1H), 7.35 (s, 1H), 6.54 (s, 1H), 5, 04-5.03 (m, 1H), 4.73 (s, 1H), 4.02 (d, 6H), 3.80-3.51 (m, 1H), 3.48-3.26 ( m, 3H), 3.05-2.93 (m, 2H), 2.80-2.79 (m, 1H), 2.47-2.42 (m, 1H), 2.24-1, 99 (m, 6N)

[1731] Example 102: (S)-1-(2-((S)-3-(3-(4-bromophenyl)isoxazol-5-yl)oxy)pyrrolidin-1-yl)acetyl)pyrrolidin-2- carbonitrile

[1732] The title compound (79.9 mg) was prepared in the same manner as Example 61 except that (3-(4-bromophenyl)isoxazol-5-ol (258 mg) was used instead of 4-quinolinol , 1.08 mmol) ¹ H-NMR (CDCl ₃ , 400 MHz) δ 7.61-7.50 (m, 5H), 5.04 (s, 1H), 4.74 (s, 1H), 3.65-3.61 (m, 1H), 3.50-3.41 (m, 2H), 3.17-2.86 (m, 4H), 2.38 (m, 1H), 2. 26-2.08 (m, 6N)

[1733] Example 103: (S)-4,4-difluoro-1-(2-((S)-3-(6-methoxyquinolin-4-yl)oxy)pyrrolidin-1-yl)acetyl)pyrrolidin-2 -carbonitrile

[1734] (S)-4,4-Difluoro-1-(2-(R)-3-hydroxypyrrolidin-1-yl)-2-oxoethyl)pyrrolidine-2-carbonitrile (260 mg, 1.00 mmol), obtained in Reference Example 27 was dissolved in tetrahydrofuran (10 ml). 6-methoxyquinolin-4-ol (180 mg, 1.0 mmol) and triphenylphosphine (520 mg, 2.0 mmol) were added to the resulting solution. The mixture solution was cooled to 0°C. DIAD (diisopropyl azodicarboxylate) (0.39 mL, 2.0 mmol) was then added dropwise slowly over 15 minutes. The reaction mixture was stirred for 12 hours at room temperature. After completion of the reaction, a saturated ammonium chloride solution and a saturated sodium hydrogen carbonate solution were added to the reaction mixture. The aqueous layer of the reaction mixture was extracted with ethyl acetate. The extracted organic layer was dried and filtered over anhydrous magnesium sulfate. The filtered solution was concentrated and then purified by silica gel column chromatography (dichloromethane/methanol = 10/1, v/v) to give the title compound (45 mg). ¹ H-NMR (CDCl ₃ , 400 MHz) δ 8.54 (d, 1H), 7.92 (d, 1H), 7.43-7.38 (m, 1H), 7.33-7.26 (m, 1H), 6.55 (s, 1H), 4.99-4.95 (m, 2H), 4.13-.98 (m, 1H), 3.91-3.85 (m, 4H), 3.70-3.58 (m, 1H), 3.50-3.35 (m, 1H), 3.11-2.96 (m, 3H), 2.70-2.66 ( m, 3H), 2.44-.40 (m, 1H), 2.12-2.09 (m 1H)

[1735] Example 104 (S)-4,4-difluoro-1-(2-((S)-3-(8-(trifluoromethyl)quinolin-4-yl)oxy)pyrrolidin-1-yl)acetyl) pyrrolidine-2-carbonitrile

[1736] The title compound (87 mg) was prepared in the same manner as Example 103 except that 8-(trifluoromethyl)quinolin-4-ol (210 mg, 1.0 mmol). ¹ H-NMR (CDCl ₃ , 400 MHz) δ 8.82 (s, 1H), 8.41 (d, 1H), 8.02 (d, 1H), 6.71 (s, 1H), 5, 11-4.98 (m, 2H), 4.16-4.06 (m, 2H), 3.65-3.42 (m, 2H), 3.16-2.99 (m, 3H), 2.73-2.72 (m, 3H), 2.43 (m, 1H), 2.12-2.01 (m, 1H)

[1737] Example 105 (S)-4,4-difluoro-1-(2-((S)-3-(quinolin-5-yloxy)pyrrolidin-1-yl)acetyl)pyrrolidin-2-carbonitrile

[1738] The title compound (68 mg) was prepared in the same manner as Example 103 except that quinolin-5-ol (150 mg, 1.0 mmol) was used instead of 6-methoxyquinolin-4-ol. . ^1H -NMR ( _CDCl3 , 400 MHz) δ 8.87 (s, 1H), 8.55 (d, 1H), 7.68 (d, 1H), 7.56 (t, 1H), 7. 36 (s, 1H), 6.73 (d, 1H), 4.97 (m, 2H), 4.13-3.97 (m, 2H), 3.68-3.36 (m, 2H) , 3.09 (m, 1H), 2.99-2.91 (m, 2H), 2.68 (m, 3H), 2.39-2.36 (m, 1H), 2.21-2 .03 (m, 1H)

[1739] Example 106 (S)-4,4-difluoro-1-(2-((S)-3-(isoquinolin-5-yloxy)pyrrolidin-1-yl)acetyl)pyrrolidin-2-carbonitrile

[1740] The title compound (59 mg) was prepared in the same manner as Example 103 except isoquinolin-5-ol (150 mg, 1.0 mmol) was used instead of 6-methoxyquinolin-4-ol. . ^1H -NMR ( _CDCl3 , 400 MHz) δ 9.17 (s, 1H), 8.49 (d, 1H), 7.98 (d, 1H), 7.50-7.44 (m, 2H ), 6.89 (d, 1H), 4.99 (m, 2H), 4.12-3.69 (m, 2H), 3.44-3.39 (m, 2H), 3.16- 2.93 (m, 3H), 2.72-2.70 (m, 3H), 2.41-2.38 (m, 1H), 2.24-2.13 (m, 1H)

[1741] Example 107 (S)-1-(2-((S)-3-(7-chloroquinolin-4-yl)oxy)pyrrolidin-1-yl)acetyl)-4,4-difluoropyrrolidin-2- carbonitrile

[1742] The title compound (37 mg) was prepared in the same manner as Example 103 except that 7-chloroquinolin-4-ol (180 mg, 1.0 mmol). ¹ H-NMR (CDCl ₃ , 400 MHz) δ 8.65 (s, 1H), 8.06 (d, 1H), 7.96 (s, 1H), 7.47-7.31 (m, 1H ), 6.58 (d, 1H), 5.01-4.97 (m, 2H), 4.17-3.99 (m, 2H), 3.86-3.35 (m, 2H), 3.12-3.11 (m, 1H), 3.02-2.97 (m, 2H), 2.77-2.71 (m, 3H), 2.42-2.41 (m, 1H ), 2.12-2.10 (m, 1H)

[1743] Example 108 (S)-4,4-difluoro-1-(2-((S)-3-(2-oxo-1,2-dihydroquinolin-5-yl)oxy)pyrrolidin-1-yl )acetyl)pyrrolidine-2-carbonitrile

[1744] The title compound (64 mg) was prepared in the same manner as Example 103 except that 5-hydroxyquinolin-2(1H)-one (160 mg, 1.0 mmol). ¹ H-NMR (CDCl ₃ , 400 MHz) δ 12.24 (s, 1H), 8.18 (d, 1H), 7.37 (m, 1H), 7.01 (s, 1H), 6, 62 (d, 1H), 6.50 (d, 1H), 4.97 (s, 2H), 4.15-4.00 (m, 2H), 3.39 (m, 2H), 3.12 -3.03 (m, 3H), 2.92-2.72 (m, 3H), 2.53-2.36 (m, 1H), 2.09 (m, 1H)

[1745] Example 109 carbonitrile

[1746] The title compound (81 mg) was prepared in the same manner as Example 103 except that 5-chloroquinolin-8-ol (180 mg, 1.0 mmol) was used instead of 6-methoxyquinolin-4-ol ). ^1H -NMR ( _CDCl3 , 400 MHz) δ 8.91 (s, 1H), 8.50 (d, 1H), 7.52-7.46 (m, 2H), 6.86 (d, 1H ), 5.06-4.99 (m, 2H), 4.10-3.84 (m, 3H), 3.51-3.32 (m, 1H), 3.09-3.07 (m , 3H), 2.87-2.57 (m, 3H), 2.39 (m, 1H), 2.21 (m, 1H)

[1747] Example 110: (S)-1-(2-(4-(quinolin-5-ylamino)piperidin-1-yl)acetyl)pyrrolidine-2-carbonitrile

[1748](S)-1-(2-chloroacetyl)pyrrolidine-2-carbonitrile (28.75 mg, 0.16 mmol) obtained in Reference Example 1 was dissolved in anhydrous dichloromethane (4 ml). N-(piperidin-4-yl)quinolin-5-amine hydrochloride (50.0 mg, 0.16 mmol) obtained in Reference Example 29 and potassium carbonate (115.0 mg, 0.83 mmol) were added to the resulting solution. . The reaction mixture was stirred overnight at room temperature. After completion of the reaction, water was added to the reaction mixture. The aqueous layer of the reaction mixture was extracted with dichloromethane. The extracted organic layer was dried and filtered over anhydrous magnesium sulfate. The filtered solution was concentrated and then purified by silica gel column chromatography (dichloromethane/methanol = 10/1, v/v) to give the title compound (12 mg). ^1H -NMR ( _CDCl3 , 400 MHz) δ 8.83 (d, 1H), 8.25 (d, 1H), 7.54-7.42 (m, 2H), 7.28 (s, 1H ), 6.52 (d, 1H), 5.15 (d, 0.3H), 4.80 (s, 0.7H), 4.12 (d, 1H), 3.69-2.90 ( m, 8H), 2.37-2.04 (m, 8H), 1.79-1.64 (m, 2H)

[1749] Example 111: (S)-1-(2-(4-(quinolin-4-ylamino)piperidin-1-yl)acetyl)pyrrolidine-2-carbonitrile

[1750] The title compound (19.8 mg) was prepared in the same manner as Example 110 except that N-(piperidin-4-yl)quinolin-5-amine hydrochloride was used instead of N-(piperidin-4-yl)quinolin-5-amine hydrochloride. 4-yl)quinolin-4-amine hydrochloride (50.0 mg, 0.16 mmol) prepared in reference example 28. ¹ H-NMR (CD ₃ OD, 400 MHz) δ 8.35-8.32 (m , 2H), 7.81 (s, 2H), 7.59 (s, 1H), 6.79 (d, 1H), 4.80 (s, 1H), 3.78 (s, 2H), 3 .60-3.35 (m, 2H), 3.08 (d, 2H), 2.42-1.82 (m, 11H), 1.28 (s, 1H)

[1751] Example 112 (1S,3S,5S)-2-(2-(4-(quinolin-4-ylamino)piperidin-1-yl)acetyl)-2-azabicyclo[3.1.0]hexane-3- carbonitrile

[1752](1S,3S,5S)-2-(2-chloroacetyl)-2-azabicyclo[3.1.0]hexane-3-carbonitrile (25 mg, 0.14 mmol) obtained in Reference Example 4 was dissolved in anhydrous acetonitrile (3.5 ml). To the resulting solution was added N-(piperidin-4-yl)quinolin-4-amine hydrochloride (50.0 mg, 0.16 mmol) obtained in Reference Example 28 and potassium carbonate (115.0 mg, 0.83 mmol ). The reaction mixture was stirred overnight at room temperature. After completion of the reaction, water was added to the reaction mixture. The aqueous layer of the reaction mixture was extracted with dichloromethane. The extracted organic layer was dried and filtered over anhydrous magnesium sulfate. The filtered solution was concentrated and then purified by silica gel column chromatography (dichloromethane/methanol = 10/1, v/v) to give the title compound (11.9 mg). ¹ H-NMR (CD ₃ OD, 400 MHz) δ 8.39 (d, 2H), 7.84 (s, 2H), 7.64 (s, 1H), 6.88 (s, 1H), 5 .04 (s, 1H), 3.84 (s, 2H), 3.57-3.46 (m, 2H), 3.10 (s, 2H), 2.63 (s, 1H), 2, 43 (d, 2H), 2.30 (d, 1H), 2.03-2.18 (m, 1H), 2.10-1.75 (m, 4H), 1.25-0.92 ( s, 3H)

[1753] Example 113 (2S,4S)-4-fluoro-1-(2-(4-(quinolin-5-ylamino)piperidin-1-yl)acetyl)pyrrolidine-2-carbonitrile

[1754] The title compound (29.9 mg) was prepared in the same manner as Example 110 except (2S,4S)-1-(2-chloroacetyl)-4-fluoropyrrolidine-2-carbonitrile (25.4 mg, 0.14 mmol) obtained in Reference Example 2 was used instead of (S)-1-(2-chloroacetyl)pyrrolidine-2-carbonitrile. ¹ H-NMR (CD ₃ OD, 400 MHz) δ 8.72 (s, 1H), 8.63 (d, 1H), 7.56 (t, 1H), 7.42 (s, 1H), 7 .28 (d, 1H), 6.73 (d, 1H), 5.45 (d, 1H), 4.99 (d, 1H), 3.91-3.78 (m, 1H), 3. 61-3.43 (m, 3H), 3.16-3.08 (m, 2H), 2.61-2.45 (m, 4H), 2.18 (kv, 2H), 2.01- 1.78 (m, 4H)

[1755] Example 114 (S)-4,4-difluoro-1-(2-(4-(quinolin-5-ylamino)piperidin-1-yl)acetyl)pyrrolidine-2-carbonitrile

[1756] The title compound (12.6 mg) was prepared in the same manner as Example 110 except (2S)-1-(2-chloroacetyl)-4,4-difluoropyrrolidine-2-carbonitrile (27.8 mg, 0.14 mmol) obtained in Reference Example 3 was used instead of (S)-1-(2-chloroacetyl)pyrrolidine-2-carbonitrile. ¹ H-NMR (CD ₃ OD, 400 MHz) δ 8.72 (d, 1H), 8.62 (d, 1H), 7.54 (t, 1H), 7.40 (d, 1H), 7 .27 (d, 1H), 6.71 (d, 1H), 5.58-5.05 (m, 1H), 4.25-4.09 (m, 2H), 3.53-3.24 (m, 3H), 3.00 (d, 2H), 2.90-2.74 (m, 2H), 2.39 (t, 2H), 2.13 (d, 2H), 1.72 ( d, 2H), 1.28 (s, 1H)

[1757] Example 115 (1S,3S,5S)-2-(2-(4-(quinolin-5-ylamino)piperidin-1-yl)acetyl)-2-azabicyclo[3.1.0]hexane-3- carbonitrile

[1758] The title compound (33.6 mg) was prepared in the same manner as Example 112 except that N-(piperidin-4-yl)quinolin-4-amine hydrochloride was used instead of N-(piperidin-4-yl)hydrochloride -4-yl)quinolin-5-amine hydrochloride (50.0 mg, 0.16 mmol) obtained in reference example 29. ¹ H-NMR (CD ₃ OD, 400 MHz) δ 8.72 (s, 1H) , 8.66 (d, 1H), 7.56 (t, 1H), 7.41 (d, 1H), 7.29 (d, 1H), 6.73 (d, 1H), 5.56- 5.05 (m, 1H), 3.81 (s, 1H), 3.77 (s, 1H), 3.65 (d, 2H), 3.22-3.06 (m, 2H), 2 .64 (t, 3H), 2.47-1.81 (m, 7H), 1.28-1.07 (m, 2H)

[1759] Example 116 (S)-1-(2-(4-(furo[3,2-c]pyridin-7-ylamino)piperidin-1-yl)acetyl)pyrrolidine-2-carbonitrile

[1760] The title compound (21.6 mg) was prepared in the same manner as Example 110 except that N-(piperidin-4-yl)quinolin-5-amine hydrochloride was used instead of N-(piperidin-4-yl)quinolin-5-amine hydrochloride -4-yl)furo[3,2-c]pyridin-7-amine hydrochloride (40.6 g, 0.16 mmol) obtained in Reference Example 30. ¹ H-NMR (CDCl ₃ , 400 MHz) δ 8 .35 (s, 1H), 7.91 (s, 1H), 7.61 (s, 1H), 6.81 (s, 1H), 4.76 (s, 1H), 3.94 (s, 1H), 3.74 (s, 1H), 3.57 (d, 2H), 3.43-3.36 (m, 1H), 3.24 (s, 1H), 2.84-3.03 (m, 2H), 2.44-2.14 (m, 7H), 1.87-1.52 (m, 2H)

[1761] Example 117 (S)-1-(2-(4-(quinolin-3-yloxy)piperidin-1-yl)acetyl)pyrrolidine-2-carbonitrile

[1762](S)-1-(2-chloroacetyl)pyrrolidine-2-carbonitrile (60 mg, 0.35 mmol) obtained in Reference Example 1 was dissolved in anhydrous dichloromethane (2.4 ml). To the resulting solution, 3-(piperidin-4-yloxy)quinoline hydrochloride (104.7 mg, 0.35 mmol) obtained in Reference Example 31 and potassium carbonate (192.2 mg, 1.39 mmol) were added. The reaction mixture was stirred overnight at room temperature. After completion of the reaction, water was added to the reaction mixture. The aqueous layer of the reaction mixture was extracted with dichloromethane. The extracted organic layer was dried and filtered over anhydrous magnesium sulfate. The filtered solution was concentrated and then purified by silica gel column chromatography (dichloromethane/methanol = 10/1, v/v) to give the title compound (22.1 mg). ^1H -NMR ( _CDCl3 , 400 MHz) δ 8.66 (d, 1H), 8.04 (d, 1H), 7.71 (d, 1H), 7.57-7.49 (m, 2H ) 7.40 (s, 1H), 5.20 (d, 0.3H), 4.76 (d, 0.6H), 4.52 (s, 1H), 3.75-3.54 (m , 2H), 3.44-3.24 (m, 2H) 2.82-2.51 (m, 5H) 2.28-1.94 (m, 8H)

[1763] Example 118 (S)-1-(2-(4-(quinolin-4-yloxy)piperidin-1-yl)acetyl)pyrrolidine-2-carbonitrile

[1764] The title compound (23.6 mg) was prepared in the same manner as Example 117 except that 4-(piperidin-4-yloxy) was used instead of 3-(piperidin-4-yloxy)quinoline hydrochloride )quinoline hydrochloride (104.7 mg, 0.35 mmol) obtained in reference example 32. ¹ H-NMR (CDCl ₃ , 400 MHz) δ 8.72 (d, 1H), 8.23 (d, 1H) , 8.03 (d, 1H), 7.70 (t, 1H), 7.52 (t, 1H), 6.72 (d, 1H) 5.17 (d, 0.3H), 4.76 (d, 0.6H), 4.69 (s, 1H), 3.75-3.55 (m, 2H), 3.43-3.24 (m, 2H) 2.93-2.36 ( m, 5H) 2.28-2.05 (m, 8H)

[1765] Example 119 (S)-1-(2-(4-(quinolin-5-yloxy)piperidin-1-yl)acetyl)pyrrolidine-2-carbonitrile

[1766] The title compound (20.2 mg) was prepared in the same manner as Example 117 except that 5-(piperidin-4-yloxy) was used instead of 3-(piperidin-4-yloxy)quinoline hydrochloride )quinoline hydrochloride (104.7 mg, 0.35 mmol) obtained in reference example 33. ¹ H-NMR (CDCl ₃ , 400 MHz) δ 8.90 (s, 1H), 8.61 (d, 1H) , 7.68 (d, 1H), 7.60 (t, 1H), 7.39 (kv, 1H), 6.88 (d, 1H) 5.21 (d, 0.3H), 4.76 (s, 0.6H), 4.61 (s, 1H), 3.76-3.54 (m, 2H), 3.44-3.23 (m, 2H) 2.83-2.58 ( m, 5H) 2.28-2.01 (m, 8H)

[1767] Example 120: (S)-1-(2-(4-(quinolin-6-yloxy)piperidin-1-yl)acetyl)pyrrolidine-2-carbonitrile

[1768] The title compound (24.4 mg) was prepared in the same manner as Example 117 except that 6-(piperidin-4-yloxy) was used instead of 3-(piperidin-4-yloxy)quinoline hydrochloride )quinoline hydrochloride (104.7 mg, 0.35 mmol) obtained in reference example 34. ¹ H-NMR (CDCl ₃ , 400 MHz) δ 8.76 (d, 1H), 8.05-8.00 ( m, 2H), 7.38-7.34 (m, 2H), 7.10 (s, 1H), 5.24 (d, 0.3 N), 4.76 (s, 0.6 N) , 4.53 (s, 1H), 3.75-3.54 (m, 2H), 3.46-3.23 (m, 2H) 2.86 (s, 2H) 2.62-2.50 (m, 3H), 2.35-1.96 (m, 8H)

[1769] Example 121 (S)-1-(2-(4-(3-methylquinolin-5-yl)amino)piperidin-1-yl)acetyl)pyrrolidin-2-carbonitrile

[1770](S)-1-(2-chloroacetyl)pyrrolidine-2-carbonitrile (152.05 mg, 0.88 mmol) obtained in Reference Example 1 was dissolved in anhydrous acetonitrile (4.4 ml). To the resulting solution was added 3-methyl-N-(piperidin-4-yl)quinolin-5-amine hydrochloride (308.94 mg, 0.88 mmol) obtained in Reference Example 35, potassium carbonate (487.0 mg, 3 .52 mmol) and potassium iodide (1.46 mg, 0.01 mmol). The reaction mixture was stirred overnight at room temperature. After completion of the reaction, water was added to the reaction mixture. The aqueous layer of the reaction mixture was extracted with dichloromethane. The extracted organic layer was dried and filtered over anhydrous magnesium sulfate. The filtered solution was concentrated and then purified by silica gel column chromatography (dichloromethane/methanol = 10/1, v/v) to give the title compound (72 mg). ¹ H-NMR (CDCl ₃ , 400 MHz) δ 8.70 (s, 1H), 7.93 (s, 1H), 7.47-7.41 (m, 2H), 6.62 (d, 1H ), 5.15 (d, 1H), 4.74 (s, 1H), 3.72-3.18 (m, 4H), 2.98-2.89 (m, 2H), 2.65 ( s, 1H), 2.50 (s, 3H), 2.39-2.04 (m, 8H), 1.68-1.66 (m, 2H)

[1771] Example 122 (S)-1-(2-(4-(6-methylquinolin-5-yl)amino)piperidin-1-yl)acetyl)pyrrolidin-2-carbonitrile

[1772] The title compound (21.8 mg) was prepared similarly to Example 121 except that 6 was used instead of 3-methyl-N-(piperidin-4-yl)quinolin-5-amine hydrochloride -methyl-N-(piperidin-4-yl)quinolin-5-amine hydrochloride (268.4 mg, 0.96 mmol) obtained in reference example 36. ¹ H-NMR (CDCl ₃ , 400 MHz) δ 8, 82 (s, 1H), 8.38 (d, 1H), 7.70 (d, 1H), 7.49 (d, 1H), 7.35 (s, 1H), 4.74 (s, 1H ), 3.72-3.52 (m, 2H), 3.34-2.93 (m, 5H), 2.44 (s, 3H), 2.27-1.63 (m, 9H), 1.26 (m, 2H)

[1773] Example 123: (S)-1-(2-(4-(7-fluoroquinolin-5-yl)amino)piperidin-1-yl)acetyl)pyrrolidin-2-carbonitrile

[1774] The title compound (36.4 mg) was prepared analogously to that described in Example 121 except that 7 was used instead of 3-methyl-N-(piperidin-4-yl)quinolin-5-amine hydrochloride -fluoro-N-(piperidin-4-yl)quinolin-5-amine hydrochloride (329.36 mg, 0.93 mmol) obtained in reference example 37. ¹ H-NMR (CDCl ₃ , 400 MHz) δ 8, 82 (s, 1H), 8.10 (d, 1H), 7.26 (s, 1H), 7.05 (d, 1H), 6.37 (d, 1H), 4.75 (s, 1H ), 4.59 (s, 1H), 3.74-3.22 (m, 5H), 3.00-2.90 (m, 2H), 2.39-1.67 (m, 8H), 1.26 (m, 2H)

[1775] Example 124 (S)-1-(2-(4-(7-methoxyquinolin-5-yl)amino)piperidin-1-yl)acetyl)pyrrolidin-2-carbonitrile

[1776] The title compound (4.6 mg) was prepared in the same manner as in Example 121 except that 7 was used instead of 3-methyl-N-(piperidin-4-yl)quinolin-5-amine hydrochloride -methoxy-N-(piperidin-4-yl)quinolin-5-amine hydrochloride (291.0 mg, 0.88 mmol) obtained in reference example 38. ¹ H-NMR (CDCl ₃ , 400 MHz) δ 8, 76 (s, 1H), 8.04 (s, 1H), 7.19 (s, 1H), 6.87 (s, 1H), 6.28 (s, 1H), 4.77 (s, 1H ), 3.75 (s, 3H), 3.65-3.15 (m, 5H), 2.99-2.90 (m, 2H), 2.40-1.46 (m, 9H) , 1.26 (m, 2H)

[1777] Example 125: (S)-1-(2-(4-(8-methoxyquinolin-5-yl)amino)piperidin-1-yl)acetyl)pyrrolidin-2-carbonitrile

[1778] The title compound (6.1 mg) was prepared analogously to that described in Example 121 except that 8 was used instead of 3-methyl-N-(piperidin-4-yl)quinolin-5-amine hydrochloride -methoxy-N-(piperidin-4-yl)quinolin-5-amine hydrochloride (291.0 mg, 0.88 mmol) obtained in reference example 39. ¹ H-NMR (CDCl ₃ , 400 MHz) δ 8, 93 (s, 1H), 8.24 (s, 1H), 7.41 (s, 1H), 6.94 (s, 1H), 6.65 (s, 1H), 4.76 (s, 1H ), 4.03 (s, 3H), 3.73-3.14 (m, 7H), 3.02-2.05 (m, 9H), 1.63 (m, 2H)

[1779] Example 126

[1780](2S,4S)-1-(2-chloroacetyl)-4-fluoropyrrolidine-2-carbonitrile (214 mg, 1.12 mmol) obtained in Reference Example 2 was dissolved in anhydrous acetonitrile (4 ml). To the resulting solution, 6-fluoro-4-(piperidin-4-yloxy)quinoline hydrochloride (400 mg, 1.12 mmol) obtained in Reference Example 40, potassium carbonate (621.8 mg, 5.00 mmol) and iodide were added potassium (1.87 mg, 0.011 mmol). The reaction mixture was stirred overnight at room temperature. After completion of the reaction, water was added to the reaction mixture. The aqueous layer of the reaction mixture was extracted with dichloromethane. The extracted organic layer was dried and filtered over anhydrous magnesium sulfate. The filtered solution was concentrated and then purified by silica gel column chromatography (dichloromethane/methanol = 10/1, v/v) to give the title compound (20 mg). ¹ H-NMR (CDCl ₃ , 400 MHz) δ 8.69 (s, 1H), 8.02 (d, 1H), 7.80 (d, 1H), 7.47 (t, 1H), 6, 73 (s, 1H), 5.50-5.30 (m, 1H), 4.95 (d, 1H), 4.69 (s, 1H), 4.24-3.77 (m, 2H) , 3.51-3.22 (m, 2H), 2.80-2.15 (m, 10H)

[1781] Example 127 (2S,4S)-1-(2-(4-((6-chloroquinolin-4-yl)oxy)piperidin-1-yl)acetyl)-4-fluoropyrrolidine-2-carbonitrile

[1782] The title compound (17.0 mg) was prepared in the same manner as Example 126 except that 6-chloro-4 was used instead of 6-fluoro-4-(piperidin-4-yloxy)quinoline hydrochloride -(piperidin-4-yloxy)quinoline hydrochloride (336.7 mg, 1.12 mmol) obtained in reference example 41. ¹ H-NMR (CDCl ₃ , 400 MHz) δ 8.71 (s, 1H), 8 .17 (s, 1H), 7.96 (s, 1H), 7.62 (s, 1H), 6.74 (s, 1H), 5.43 (t, 1H), 4.95 (s, 1H), 4.68 (s, 1H), 4.24-3.70 (m, 2H), 3.53-3.27 (m, 2H), 2.82-1.84 (m, 10H)

[1783] Example 128

[1784] The title compound (24.1 mg) was prepared in the same manner as described in Example 126 except that 6-methoxy-quinoline was used instead of 6-fluoro-4-(piperidin-4-yloxy)quinoline hydrochloride. 4-(piperidin-4-yloxy)quinoline hydrochloride (410.0 mg, 1.12 mmol) obtained in reference example 42. ¹ H-NMR (CDCl ₃ , 400 MHz) δ 8.95 (d, 1H), 7.94 (d, 1H), 7.47 (s, 1H), 7.35 (d, 1H), 6.70 (d, 1H), 5.49-5.30 (m, 1H), 4 .94 (d, 1H), 4.68 (s, 1H), 4.25-4.10 (m, 1H), 3.95 (s, 3H), 3.92-3.21 (m, 3H ), 2.86-2.13 (m, 10N)

[1785] Example 129

[1786] The title compound (4.5 mg) was prepared in the same manner as in Example 126 except that 7-methoxy-quinoline was used instead of 6-fluoro-4-(piperidin-4-yloxy)quinoline hydrochloride. 4-(piperidin-4-yloxy)quinoline hydrochloride (331.7 mg, 1.12 mmol) obtained in reference example 43. ¹ H-NMR (CDCl ₃ , 400 MHz) δ 8.64 (s, 1H), 8.10 (d, 1H), 7.37 (s, 1H), 7.15 (d, 1H), 6.62 (s, 1H), 5.49-5.30 (m, 1H), 4 .95 (d, 1H), 4.68 (s, 1H), 4.25-4.11 (m, 1H), 3.95 (s, 3H), 3.89-3.71 (m, 1H ), 3.52-3.25 (m, 2H), 2.80-2.05 (m, 10H)

[1787] Example 130 (2S,4S)-1-(2-(4-((6,7-dimethoxyquinolin-4-yl)oxy)piperidin-1-yl)acetyl)-4-fluoropyrrolidine-2-carbonitrile

[1788] The title compound (4.7 mg) was prepared in the same manner as Example 126 except that 6,7- dimethoxy-4-(piperidin-4-yloxy)quinoline hydrochloride (407.1 mg, 1.12 mmol) obtained in reference example 44. ¹ H-NMR (CDCl ₃ , 400 MHz) δ 8.55 (s, 1H ), 7.43 (d, 1H), 7.39 (s, 1H), 6.65 (s, 1H), 5.49-5.37 (m, 1H), 4.95 (d, 1H) , 4.68 (s, 1H), 4.28-4.11 (m, 1H), 4.00 (s, 6H), 3.87-3.78 (m, 1H), 3.52-3 .22 (m, 2N), 2.88-2.01 (m, 10N)

[1789] Example 131: (2S,4S)-4-fluoro-1-(2-(4-((3-methylquinolin-5-yl)amino)piperidin-1-yl)acetyl)pyrrolidine-2-carbonitrile

[1790](2S,4S)-1-(2-chloroacetyl)-4-fluoropyrrolidine-2-carbonitrile (20.5 mg, 0.11 mmol) obtained in Reference Example 2 was dissolved in anhydrous acetonitrile (4 ml) . To the resulting solution was added 3-methyl-N-(piperidin-4-yl)quinolin-5-amine hydrochloride (37.7 mg, 0.11 mmol) obtained in Reference Example 35, potassium carbonate (59.38 mg, 0 .43 mmol) and potassium iodide (0.18 mg, 0.001 mmol). The reaction mixture was stirred overnight at room temperature. After completion of the reaction, water was added to the reaction mixture. The aqueous layer of the reaction mixture was extracted with dichloromethane. The extracted organic layer was dried and filtered over anhydrous magnesium sulfate. The filtered solution was concentrated and then purified by silica gel column chromatography (dichloromethane/methanol = 10/1, v/v) to give the title compound (3 mg). ¹ H-NMR (CDCl ₃ , 400 MHz) δ 8.73 (s, 1H), 7.89 (s, 1H), 7.48-7.45 (m, 2H), 6.63 (d, 1H ), 5.49-5.29 (m, 1H), 4.96 (d, 1H), 4.28-3.25 (m, 5H), 2.98-2.65 (m, 3H), 2.54 (s, 3H), 2.41-2.05 (m, 5H), 1.88-1.26 (m, 3H)

[1791] Example 132

[1792] The title compound (14 mg) was prepared analogously to that described in Example 131, except that 7-fluoro was used instead of 3-methyl-N-(piperidin-4-yl)quinolin-5-amine hydrochloride -N-(piperidin-4-yl)quinolin-5-amine hydrochloride (30.12 mg, 0.11 mmol) obtained in reference example 37. ¹ H-NMR (CDCl ₃ , 400 MHz) δ 8.85 ( s, 1H), 8.08 (d, 1H), 7.07 (d, 1H), 6.39 (d, 1H), 5.49-5.37 (m, 1H), 4.95 (d , 1H), 4.50-3.74 (m, 3H), 3.47-3.20 (m, 3H), 3.00-2.64 (m, 3H), 2.44-2.05 (m, 6H), 1.85-1.64 (m, 2H)

[1793] Example 133

[1794] The title compound (4 mg) was prepared analogously to that described in Example 131, except that 7-methoxy was used instead of 3-methyl-N-(piperidin-4-yl)quinolin-5-amine hydrochloride -N-(piperidin-4-yl)quinolin-5-amine hydrochloride (35.3 mg, 0.11 mmol) prepared in reference example 38. ¹ H-NMR (CDCl ₃ , 400 MHz) δ 8.78 ( s, 1H), 8.01 (d, 1H), 7.20-7.18 (m, 1H), 6.86 (s, 1H), 6.27 (s, 1H), 5.49-5 .36 (m, 1H), 4.95 (d, 1H), 4.26-3.98 (m, 1H), 3.93 (s, 3H), 3.87-3.70 (m, 1H ), 3.38-3.16 (m, 3H), 2.94-2.64 (m, 3H), 2.39-2.05 (m, 6H), 1.82-1.64 (m , 2H)

[1795] Example 134 (2S,4S)-4-fluoro-1-(2-(4-((6-methylquinolin-5-yl)amino)piperidin-1-yl)acetyl)pyrrolidine-2-carbonitrile

[1796] The title compound (14.1 mg) was prepared analogously to that described in Example 131 except that 6 was used instead of 3-methyl-N-(piperidin-4-yl)quinolin-5-amine hydrochloride -methyl-N-(piperidin-4-yl)quinolin-5-amine (34.6 mg, 0.11 mmol) obtained in reference example 36. ¹ H-NMR (CDCl ₃ , 400 MHz) δ 8.83 (s, 1H), 8.38 (d, 1H), 7.71 (d, 1H), 7.50 (d, 1H), 7.37-7.35 (m, 1H), 5.48- 5.35 (m, 1H), 4.93 (d, 1H), 4.22-3.72 (m, 2H), 3.42-3.15 (m, 3H), 2.96-2, 63 (m, 3H), 2.44 (s, 3H), 2.36-1.26 (m, 8H)

[1797] Example 135

[1798] The title compound (1.67 mg) was prepared analogously to that described in Example 131 except that 8 was used instead of 3-methyl-N-(piperidin-4-yl)quinolin-5-amine hydrochloride -methoxy-N-(piperidin-4-yl)quinolin-5-amine hydrochloride (35.3 mg, 0.11 mmol) prepared in reference example 39. ¹ H-NMR (CDCl ₃ , 400 MHz) δ 8, 94 (s, 1H), 8.20 (d, 1H), 7.42 (d, 1H), 6.96 (d, 1H), 6.65 (d, 1H), 5.48-5.36 (m, 1H), 4.95 (d, 1H), 4.27-4.13 (m, 1H), 4.03 (s, 3H), 3.99-3.77 (m, 1H), 3.49-2.64 (m, 7H), 2.38-1.26 (m, 7H).

[1799] Example 136 6-methoxy-N-[(3S)-1-[2-oxo-2-[(2S,4S)-2-cyano-4-fluoropyrrolidin-1-yl]ethyl]pyrrolidin-3 -yl]benzofuran-3-carboxamide

[1800] The title compound (10.0 mg, 23.1%) was prepared in the same manner as Example 29 except that instead of (S)-6-fluoro-N-(pyrrolidine-3- yl)benzofuran-3-carboxamide hydrochloride (S)-6-methoxy-N-(pyrrolidin-3-yl)benzofuran-3-carboxamide hydrochloride (37.9 mg, 0.12 mmol) was used in Reference Example 46. ¹ H -NMR ( _CDCl3 , 400 MHz) δ 8.24 (s, 1H), 7.89 (d, 1H), 7.13 (s, 1H), 6.97 (d, 1H), 5.51- 4.98 (m, 2H), 4.60 (s, 1H), 4.07-3.99 (m, 1H), 3.85 (s, 3H), 3.82-3.39 (m, 3H), 3.07 (s, 1H), 2.87 (s, 2H), 2.61-2.36 (m, 3H), 1.87 (s, 1H)

[1801] Example 137 (2S)-1-[2-[(3R)-3-[methyl(2-quinolyl)amino]pyrrolidin-1-yl]acetyl]pyrrolidin-2-carbonitrile

[1802] The title compound (24.0 mg, 38.3%) was prepared in the same manner as Example 17 except that instead of (R)-N-(pyrrolidin-3-yl)quinoline- 3-amine hydrochloride (R)-N-methyl-N-(pyrrolidin-3-yl)quinolin-2-amine hydrochloride (45.5 mg, 0.17 mmol) obtained in Reference Example 47 was used. ¹ H-NMR ( _CDCl3 , 400 MHz) δ 7.88 (d, 1H), 7.68 (d, 1H), 7.60 (d, 1H), 7.53 (t, 1H), 7.19 (t, 1H), 6.91 (d, 1H), 5.70-5.50 (m, 1H), 5.25-4.79 (m, 1H), 3.76-3.56 (m, 2H) , 3.44-3.28 (m, 2H), 3.16 (s, 3H), 3.13-2.97 (m, 2H), 2.88-2.58 (m, 2H), 2 .40-2.20 (m, 3H), 2.20-2.13 (m, 2H), 1.94-1.89 (m, 1H)

[1803] Example 138 (2S)-1-[2-[(3R)-3-[methyl(3-quinolyl)amino]pyrrolidin-1-yl]acetyl]pyrrolidin-2-carbonitrile

[1804] The title compound (109.3 mg, 47.0%) was prepared in the same manner as Example 17 except that instead of (R)-N-(pyrrolidin-3-yl)quinoline- 3-amine hydrochloride (R)-N-methyl-N-(pyrrolidin-3-yl)quinolin-3-amine hydrochloride (168.8 mg, 0.64 mmol) obtained in Reference Example 48 was used. ¹ H-NMR ( _CDCl3 , 400 MHz) δ 8.77 (s, 1H), 7.96 (d, 1H), 7.64 (d, 1H), 7.45-7.28 (m, 2H), 7. 23 (s, 1H), 5.15-4.77 (m, 1H), 4.70-4.50 (m, 1H), 3.73-3.70 (m, 1H), 3.60- 3.52 (m, 1H), 3.48-3.26 (m, 2H), 3.04 (s, 3H), 3.03-2.88 (m, 1H), 2.86-2, 77 (m, 2H), 2.64 (dd, 1H), 2.40-2.20 (m, 3H), 2.20-2.05 (m, 2H), 1.97-1.91 ( m, 1N)

[1805] Example 139 (2S)-1-[2-[(3R)-3-[methyl(5-quinolyl)amino]pyrrolidin-1-yl]acetyl]pyrrolidin-2-carbonitrile

[1806] The title compound (1.5 mg, 12.0%) was prepared in the same manner as Example 17 except that (R)-N-methyl-N-(pyrrolidin-3-yl) Quinoline-5-amine hydrochloride (88.1 mg, 0.33 mmol) prepared in Reference Example 49 was used in place of (R)-N-(pyrrolidin-3-yl)quinoline-3-amine hydrochloride. ¹ H-NMR (CDCl ₃ , 400 MHz) δ 8.91 (d, 1H), 8.63 (d, 1H), 7.84 (d, 1H), 7.64 (t, 1H), 7. 41 (t, 1H), 7.21 (d, 1H), 5.20-4.70 (m, 1H), 4.10-3.90 (m, 1H), 3.80-3.66 ( m, 1H), 3.60-3.40 (m, 2H), 3.38-3.20 (m, 2H), 3.00-2.88 (m, 1H), 2.81 (s, 3H), 2.81-2.70 (m, 2H), 2.40-2.20 (m, 2H), 2.20-2.00 (m, 3H), 2.00-1.80 ( m, 1N)

[1807] Example 140 (2S)-1-[2-[(3R)-3-[methyl(6-quinolyl)amino]pyrrolidin-1-yl]acetyl]pyrrolidin-2-carbonitrile

[1808] The title compound (16.5 mg, 19.9%) was prepared in the same manner as Example 17 except that (R)-N-methyl-N-(pyrrolidin-3-yl )quinoline-6-amine hydrochloride (59.5 mg, 0.23 mmol) obtained in Reference Example 50 was used instead of (R)-N-(pyrrolidin-3-yl)quinoline-3-amine hydrochloride. ¹ H-NMR (CDCl ₃ , 400 MHz) δ 8.64 (d, 1H), 8.00-7.94 (m, 2H), 7.44 (d, 1H), 7.30-7.20 (m, 1H), 6.88 (d, 1H), 5.15-4.73 (m, 1H), 4.73-4.58 (m, 1H), 3.80-3.62 (m , 1H), 3.62-3.45 (m, 2H), 3.46-3.20 (m, 2H), 3.04 (s, 3H), 3.03-2.78 (m, 2H ), 2.78-2.58 (m, 1H), 2.48-2.22 (m, 3H), 2.22-2.10 (m, 2H), 2.01-1.82 (m , 1H)

[1809] Example 141 (2S)-1-[2-[(3R)-3-[methyl(7-quinolyl)amino]pyrrolidin-1-yl]acetyl]pyrrolidin-2-carbonitrile

[1810] The title compound (74.9 mg, 51.1%) was prepared in the same manner as Example 17 except (R)-N-methyl-N-(pyrrolidin-3-yl )quinoline-7-amine hydrochloride (106.3 mg, 0.40 mmol) obtained in Reference Example 51 was used instead of (R)-N-(pyrrolidin-3-yl)quinoline-3-amine hydrochloride. ¹ H-NMR (CDCl ₃ , 400 MHz) δ 8.75 (s, 1H), 7.97 (d, 1H), 7.65 (d, 1H), 7.28-7.23 (m, 2H ), 7.12 (t, 1H), 5.20-4.74 (m, 1H), 4.74-4.61 (m, 1H), 3.82-3.64 (m, 1H), 3.64-3.50 (m, 1H), 3.46-3.24 (m, 2H), 3.07 (s, 3H), 3.07-2.83 (m, 2H), 2. 83-2.66 (m, 1H), 2.60 (kv, 1H), 2.46-2.22 (m, 3H), 2.22-2.10 (m, 2H), 2.00- 1.92 (m, 1H)

[1811] Example 142 (2S)-1-[2-[(3S)-3-[methyl(3-quinolyl)amino]pyrrolidin-1-yl]acetyl]pyrrolidin-2-carbonitrile

[1812] The title compound (165.8 mg, 59.1%) was prepared in the same manner as Example 5 except that instead of (S)-N-(pyrrolidin-3-yl)quinoline- 4-amine hydrochloride (S)-N-methyl-N-(pyrrolidin-3-yl)quinolin-3-amine hydrochloride (203.4 mg, 0.77 mmol) obtained in Reference Example 52 was used. ¹ H-NMR ( _CDCl3 , 400 MHz) δ 8.75 (s, 1H), 7.94 (d 1H), 7.63 (t, 1H), 7.44-7.41 (m, 2H), 7.22 (s, 1H), 5.16-4.70 (m, 1H), 4.70-4.52 (m, 1H), 3.80-3.60 (m, 1H), 3.60-3 .48 (m, 1H), 3.48-3.18 (m, 2H), 3.02 (s, 3H), 3.02-2.70 (m, 2H), 2.60 (dd, 1H ), 2.50-2.34 (m, 1H), 2.34-2.20 (m, 3H), 2.20-2.04 (m, 2H), 2.04-1.88 (m , 1H)

[1813] Example 143 (2S)-1-[2-[(3S)-3-[methyl(4-quinolyl)amino]pyrrolidin-1-yl]acetyl]pyrrolidin-2-carbonitrile

[1814] The title compound (60.3 mg, 73.1%) was prepared in the same manner as Example 5 except that instead of (S)-N-(pyrrolidin-3-yl)quinoline- 4-amine hydrochloride (S)-N-methyl-N-(pyrrolidin-3-yl)quinolin-4-amine hydrochloride (59.8 mg, 0.23 mmol) obtained in Reference Example 53 was used. ¹ H-NMR (CDCl ₃ , 400 MHz) δ 8.69 (d, 1H), 8.06-8.04 (m, 2H), 7.66 (t, 1H), 7.48 (t, 1H), 6, 84 (d, 1H), 5.18-4.76 (m, 1H), 4.48-4.30 (m, 1H), 3.82-3.60 (m, 1H), 3.60- 3.44 (m, 1H), 3.44-3.20 (m, 2H), 3.01 (s, 3H), 3.01-2.90 (m, 2H), 2.90-2, 80 (m, 1H), 2.70-2.58 (m, 1H), 2.40-2.30 (m, 1H), 2.30-2.20 (m, 3H), 2.20- 1.94 (m, 2H)

[1815] Example 144 (2S)-1-[2-[(3S)-3-[methyl(5-quinolyl)amino]pyrrolidin-1-yl]acetyl]pyrrolidin-2-carbonitrile

[1816] The title compound (22.9 mg, 16.6%) was prepared in the same manner as Example 5 except that instead of (S)-N-(pyrrolidin-3-yl)quinoline- 4-amine hydrochloride was used (S)-N-methyl-N-(pyrrolidin-3-yl)quinolin-5-amine hydrochloride (100.1 mg, 0.38 mmol) obtained in Reference Example 54 was used. ¹ H-NMR (CDCl ₃ , 400 MHz) δ 8.90 (d, 1H), 8.62 (d, 1H), 7.83 (d, 1H), 7.63 (t, 1H), 7. 41 (t, 1H), 7.21 (d, 1H), 5.20-4.70 (m, 1H), 4.12-3.98 (m, 1H), 3.80-3.60 ( m, 1H), 3.60-3.40 (m, 1H), 3.40-3.20 (m, 2H), 3.02-2.90 (m, 1H), 2.79 (s, 3H), 2.78-2.60 (m, 3H), 2.40-2.20 (m, 2H), 2.20-2.00 (m, 3H), 2.00-1.84 ( m, 1N)

[1817] Example 145 (2S)-1-[2-[(3S)-3-[methyl(6-quinolyl)amino]pyrrolidin-1-yl]acetyl]pyrrolidin-2-carbonitrile

[1818] The title compound (85.9 mg, 64.1%) was prepared in the same manner as Example 5 except that instead of (S)-N-(pyrrolidin-3-yl)quinoline- 4-amine hydrochloride (S)-N-methyl-N-(pyrrolidin-3-yl)quinolin-6-amine hydrochloride (97.1 mg, 0.37 mmol) obtained in Reference Example 55 was used. ¹ H-NMR ( _CDCl3 , 400 MHz) δ 8.62 (d, 1H), 8.08-7.90 (m, 2H), 7.42 (d, 1H), 7.28-7.25 (m, 1H ), 6.87 (d, 1H), 5.20-4.74 (m, 1H), 4.74-4.50 (m, 1H), 3.80-3.60 (m, 1H), 3.60-3.48 (m, 1H), 3.48-3.20 (m, 2H), 3.10 (s, 3H), 3.10-2.90 (m, 2H), 2, 90-2.72 (m, 1H), 2.70-2.50 (m, 1H), 2.50-2.23 (m, 2H), 2.23-2.05 (m, 3H), 2.05-1.80 (m, 1H)

[1819] Example 146: (2S)-1-[2-[(3S)-3-[methyl(7-quinolyl)amino]pyrrolidin-1-yl]acetyl]pyrrolidin-2-carbonitrile

[1820] The title compound (142.4 mg, 49.4%) was prepared in the same manner as Example 5 except that instead of (S)-N-(pyrrolidin-3-yl)quinoline- 4-amine hydrochloride (S)-N-methyl-N-(pyrrolidin-3-yl)quinolin-7-amine hydrochloride (209.5 mg, 0.79 mmol) obtained in Reference Example 56 was used. ¹ H-NMR ( _CDCl3 , 400 MHz) δ 8.73 (s, 1H), 7.98 (d, 1H), 7.65 (d, 1H), 7.28-7.23 (m, 2H), 7. 14-7.10 (m, 1H), 5.20-4.74 (m, 1H), 4.74-4.60 (m, 1H), 3.80-3.60 (m, 1H), 3.60-3.48 (m, 1H), 3.48-3.20 (m, 2H), 3.07 (s, 3H), 3.07-2.90 (m, 1H), 2. 90-2.72 (m, 1H), 2.70-2.50 (m, 1H), 2.50-2.20 (m, 3H), 2.20-2.00 (m, 3H), 2.00-1.85 (m, 1H)

[1821] Example 147 (2S)-1-[2-[(3S)-3-[4-isoquinolyl(methyl)amino]pyrrolidin-1-yl]acetyl]pyrrolidin-2-carbonitrile

[1822] The title compound (2.4 mg, 3.3%) was prepared in the same manner as Example 5 except that instead of (S)-N-(pyrrolidin-3-yl)quinoline- 4-amine hydrochloride (S)-N-methyl-N-(pyrrolidin-3-yl)isoquinolin-4-amine hydrochloride (55.6 mg, 0.21 mmol) obtained in Reference Example 57 was used. ¹ H-NMR ( _CDCl3 , 400 MHz) δ 8.98 (s, 1H), 8.24 (s, 1H), 8.19 (d, 1H), 7.97 (d, 1H), 7.70 (t, 1H), 7.61 (t, 1H), 5.25-4.74 (m, 1H), 4.23-4.10 (m, 1H), 3.80-3.60 (m, 1H) , 3.60-3.40 (m, 1H), 3.40-3.20 (m, 2H), 3.05-2.90 (m, 1H), 2.86 (s, 3H), 2 .86-2.78 (m, 2H), 2.78-2.66 (m, 1H), 2.40-2.24 (m, 2H), 2.24-2.10 (m, 3H) , 2.05-1.90 (m, 1H)

[1823] Example 148 (2S)-1-[2-[(3S)-3-[5-isoquinolyl(methyl)amino]pyrrolidin-1-yl]acetyl]pyrrolidin-2-carbonitrile

[1824] The title compound (10.9 mg, 11.2%) was prepared in the same manner as Example 5 except that instead of (S)-N-(pyrrolidin-3-yl)quinoline- 4-amine hydrochloride (S)-N-methyl-N-(pyrrolidin-3-yl)isoquinolin-5-amine hydrochloride (70.7 mg, 0.27 mmol) obtained in Reference Example 58 was used. ¹ H-NMR ( _CDCl3 , 400 MHz) δ 9.22 (s, 1H), 8.53 (d, 1H), 8.00 (d, 1H), 7.68 (d, 1H), 7.52 (t, 1H), 7.33 (d, 1H), 5.20-4.70 (m, 1H), 4.18-4.00 (m, 1H), 3.80-3.60 (m, 1H) , 3.60-3.42 (m, 1H), 3.42-3.20 (m, 2H), 3.00-2.88 (m, 1H), 2.80 (s, 3H), 2 ,80-2.70 (m, 2H), 2.70-2.60 (m, 1H), 2.40-2.20 (m, 2H), 2.20-2.05 (m, 3H) , 2.00-1.85 (m, 1H)

[1825] Example 149 (2S)-1-[2-[(3S)-3-[methyl-(4-methyl-3-quinolyl)amino]pyrrolidin-1-yl]acetyl]pyrrolidin-2-carbonitrile

[1826] The title compound (37.4 mg, 55.9%) was prepared in the same manner as Example 5 except that instead of (S)-N-(pyrrolidin-3-yl)quinoline- 4-amine hydrochloride (S)-N,4-dimethyl-N-(pyrrolidin-3-yl)quinolin-3-amine hydrochloride (49.1 mg, 0.18 mmol) prepared in Reference Example 59 was used. ¹ H -NMR ( _CDCl3 , 400 MHz) δ 8.79 (s, 1H), 8.05 (d, 1H), 7.99 (d, 1H), 7.64 (t, 1H), 7.55 ( t, 1H), 5.20-4.70 (m, 1H), 4.10-3.96 (m, 1H), 3.78-3.60 (m, 1H), 3.60-3, 44 (m, 1H), 3.40-3.20 (m, 2H), 3.04-2.90 (m, 1H), 2.90-2.78 (m, 1H), 2.74 ( s, 3H), 2.74-2.70 (m, 1H), 2.68 (s, 3H), 2.68-2.50 (m, 1H), 2.34-2.20 (m, 2H), 2.20-2.00 (m, 3H), 2.00-1.74 (m, 1H)

[1827] Example 150 (2S)-1-[2-[(3S)-3-[methyl-(6-methyl-3-quinolyl)amino]pyrrolidin-1-yl]acetyl]pyrrolidin-2-carbonitrile

[1828] The title compound (224.5 mg, 83.2%) was prepared in the same manner as Example 5 except that instead of (S)-N-(pyrrolidin-3-yl)quinoline- 4-amine hydrochloride (S)-N,6-dimethyl-N-(pyrrolidin-3-yl)quinolin-3-amine hydrochloride (198.5 mg, 0.72 mmol) prepared in Reference Example 60 was used. ¹ H -NMR ( _CDCl3 , 400 MHz) δ 8.67 (s, 1H), 7.83 (d, 1H), 7.40 (s, 1H), 7.28 (d, 1H), 7.15 ( s, 1H), 5.18-4.74 (m, 1H), 4.70-4.50 (m, 1H), 3.80-3.60 (m, 1H), 3.60-3, 48 (m, 1H), 3.48-3.20 (m, 2H), 3.01 (s, 3H), 3.01-2.90 (m, 2H), 2.90-2.72 ( m, 1H), 2.68-2.52 (m, 1H), 2.50 (s, 3H), 2.45-2.24 (m, 2H), 2.24-2.08 (m, 3H), 2.08-1.88 (m, 1H)

[1829] Example 151 (S)-1-(2-((S)-3-((6-fluoroquinolin-3-yl)(methyl)amino)pyrrolidin-1-yl)acetyl)pyrrolidin-2-carbonitrile

[1830] The title compound (273.7 mg, 78.8%) was prepared in the same manner as Example 5 except that instead of (S)-N-(pyrrolidin-3-yl)quinoline- 4-amine hydrochloride (S)-6-fluoro-N-methyl-N-(pyrrolidin-3-yl)quinolin-3-amine hydrochloride (256.7 mg, 0.91 mmol) prepared in Reference Example 61 was used. ¹ H-NMR (CDCl ₃ , 400 MHz) δ 8.69 (s, 1H), 7.91 (d, 1H), 7.22-7.13 (m, 2H), 7.10 (s, 1H ), 5.12-4.72 (m, 1H), 4.72-4.58 (m, 1H), 3.82-3.60 (m, 1H), 3.60-3.48 (m , 1H), 3.48-3.20 (m, 2H), 3.04 (s, 3H), 3.04-2.90 (m, 2H), 2.90-2.70 (m, 1H ), 2.68-2.52 (m, 1H), 2.45-2.24 (m, 2H), 2.24-2.06 (m, 3H), 2.06-1.85 (m , 1H)

[1831] Example 152: (S)-1-(2-((S)-3-((6-methoxyquinolin-3-yl)(methyl)amino)pyrrolidin-1-yl)acetyl)pyrrolidin-2-carbonitrile

[1832] The title compound (196.9 mg, 67.7%) was prepared in the same manner as Example 5 except that instead of (S)-N-(pyrrolidin-3-yl)quinoline- 4-amine hydrochloride (S)-6-methoxy-N-methyl-N-(pyrrolidin-3-yl)quinolin-3-amine hydrochloride (217.2 mg, 0.74 mmol) prepared in Reference Example 62 was used. ¹ H-NMR (CDCl ₃ , 400 MHz) δ 8.59 (s, 1H), 7.83 (d, 1H), 7.14 (s, 1H), 7.08 (d, 1H), 6, 93 (s, 1H), 5.16-4.74 (m, 1H), 4.70-4.55 (m, 1H), 3.91 (s, 3H), 3.88-3.62 ( m, 1H), 3.62-3.48 (m, 1H), 3.48-3.20 (m, 2H), 3.02 (s, 3H), 3.02-2.90 (m, 2H), 2.90-2.73 (m, 1H), 2.68-2.55 (m, 1H), 2.42-2.24 (m, 2H), 2.24-2.08 ( m, 3H), 2.08-1.86 (m, 1H)

[1833] Example 153: (S)-1-(2-((S)-3-((7-methoxyquinolin-3-yl)(methyl)amino)pyrrolidin-1-yl)acetyl)pyrrolidin-2-carbonitrile

[1834] The title compound (61.5 mg, 31.5%) was prepared in the same manner as Example 5 except that instead of (S)-N-(pyrrolidin-3-yl)quinoline- 4-amine hydrochloride (S)-7-methoxy-N-methyl-N-(pyrrolidin-3-yl)quinolin-3-amine hydrochloride (145.5 mg, 0.50 mmol) prepared in Reference Example 63 was used. ¹ H-NMR (CDCl ₃ , 400 MHz) δ 8.70 (s, 1H), 7.55 (d, 1H), 7.33 (s, 1H), 7.28 (s, 1H), 7. 14 (d, 1H), 5.20-4.72 (m, 1H), 4.62-4.49 (m, 1H), 3.93 (s, 3H), 3.88-3.62 ( m, 1H), 3.62-3.50 (m, 1H), 3.50-3.20 (m, 2H), 2.99 (s, 3H), 2.99-2.90 (m, 2H), 2.90-2.73 (m, 1H), 2.73-2.56 (m, 1H), 2.46-2.05 (m, 5H), 2.05-1.82 ( m, 1N)

[1835] Example 154 (S)-1-(2-((S)-3-((8-methoxyquinolin-3-yl)(methyl)amino)pyrrolidin-1-yl)acetyl)pyrrolidin-2-carbonitrile

[1836] The title compound (180.2 mg, 45.5%) was prepared in the same manner as Example 5 except that (S)-8-methoxy-N-methyl-N-(pyrrolidine -3-yl)quinolin-3-amine hydrochloride (295.8 mg, 1.01 mmol) prepared in Reference Example 64 was used in place of (S)-N-(pyrrolidin-3-yl)quinolin-4-amine hydrochloride . ¹ H-NMR (CDCl ₃ , 400 MHz) δ 8.73 (s, 1H), 7.35 (t, 1H), 7.22-7.19 (m, 2H), 6.79 (d, 1H ), 5.18-4.72 (m, 1H), 4.70-4.50 (m, 1H), 4.06 (s, 3H), 3.82-3.60 (m, 1H), 3.60-3.49 (m, 1H), 3.49-3.18 (m, 2H), 3.03 (s, 3H), 3.03-2.90 (m, 2H), 2. 90-2.70 (m, 1H), 2.66-2.52 (m, 1H), 2.40-2.22 (m, 2H), 2.22-2.08 (m, 3H), 2.05-1.82 (m, 1H)

[1837] Example 155 (2S,4S)-4-fluoro-1-[2-[(3S)-3-[methyl-(3-methyl-5-quinolyl)amino]pyrrolidin-1-yl]acetyl] pyrrolidine-2-carbonitrile

[1838] The title compound (38.9 mg, 29.1%) was prepared in the same manner as Example 28 except that instead of (S)-N-(pyrrolidin-3-yl)furo[ 3,2-c]pyridin-7-amine hydrochloride (S)-N,3-dimethyl-N-(pyrrolidin-3-yl)quinolin-5-amine hydrochloride (93.6 mg, 0.34 mmol) was used. obtained in reference example 65. ¹ H-NMR (CDCl ₃ , 600 MHz) δ 8.72 (s, 1H), 8.34 (s, 1H), 7.77 (d, 1H), 7.53 (t , 1H), 7.15 (d, 1H), 5.46-4.90 (m, 2H), 4.20-3.98 (m, 2H), 3.80-3.60 (m, 1H ), 3.40-3.25 (m, 2H), 3.02-2.90 (m, 1H), 2.90-2.75 (m, 1H), 2.75 (s, 3H), 2.75-2.60 (m, 3H), 2.53 (s, 3H), 2.40-2.20 (m, 1H), 2.15-2.05 (m, 1H), 1, 98-1.80 (m, 1H)

[1839] Example 156: (2S,4S)-4-fluoro-1-(2-((S)-3-((3-fluoroquinolin-5-yl)(methyl)amino)pyrrolidin-1-yl)acetyl )pyrrolidine-2-carbonitrile

[1840] The title compound (264.4 mg, 79.8%) was prepared in the same manner as Example 28 except that instead of (S)-N-(pyrrolidin-3-yl)furo[ 3,2-c]pyridin-7-amine hydrochloride used (S)-3-fluoro-N-methyl-N-(pyrrolidin-3-yl)quinolin-5-amine hydrochloride (233.8 mg, 0.83 mmol ), prepared in reference example 66. ¹ H-NMR (CDCl ₃ , 600 MHz) δ 8.77 (s, 1H), 8.20 (d, 1H), 7.82 (d, 1H), 7.58 (t, 1H), 7.24 (d, 1H), 5.50-4.90 (m, 2H), 4.20-3.98 (m, 2H), 3.80-3.68 (m , 1H), 3.60-3.18 (m, 2H), 2.98-2.76 (m, 2H), 2.76 (s, 3H), 2.76-2.50 (m, 3H ), 2.40-2.20 (m, 1H), 2.18-2.05 (m, 1H), 1.94-1.78 (m, 1H)

[1841] Example 157: (2S,4S)-4-fluoro-1-(2-((S)-3-((7-fluoroquinolin-5-yl)(methyl)amino)pyrrolidin-1-yl)acetyl )pyrrolidine-2-carbonitrile

[1842] The title compound (238.2 mg, 92.0%) was prepared in the same manner as Example 28 except that instead of (S)-N-(pyrrolidin-3-yl)furo[ 3,2-c]pyridin-7-amine hydrochloride (S)-7-fluoro-N-methyl-N-(pyrrolidin-3-yl)quinolin-5-amine hydrochloride (182.5 mg, 0.65 mmol) was used ), prepared in reference example 67. ¹ H-NMR (CDCl ₃ , 600 MHz) δ 8.85 (d, 1H), 8.47 (d, 1H), 7.39 (t, 1H), 7.33 (s, 1H), 6.92 (s, 1H), 5.48-4.90 (m, 2H), 4.20-3.88 (m, 2H), 3.80-3.68 (m , 1H), 3.60-3.18 (m, 2H), 2.98-2.80 (m, 2H), 2.76 (s, 3H), 2.76-2.60 (m, 3H ), 2.40-2.20 (m, 1H), 2.18-2.08 (m, 1H), 2.00-1.88 (m, 1H)

[1843] Example 158: (2S,4S)-4-fluoro-1-(2-((S)-3-((8-fluoroquinolin-5-yl)(methyl)amino)pyrrolidin-1-yl)acetyl )pyrrolidine-2-carbonitrile

[1844] The title compound (196.6 mg, 80.9%) was prepared in the same manner as Example 28 except that instead of (S)-N-(pyrrolidin-3-yl)furo[ 3,2-c]pyridin-7-amine hydrochloride (S)-8-fluoro-N-methyl-N-(pyrrolidin-3-yl)quinolin-5-amine hydrochloride (171.2 mg, 0.61 mmol) was used ), obtained in reference example 68. ¹ H-NMR (CDCl ₃ , 600 MHz) δ 8.92 (s, 1H), 8.61 (d, 1H), 7.45 (d, 1H), 7.29 (t, 1H), 7.12 (d, 1H), 5.48-4.90 (m, 2H), 4.20-3.84 (m, 2H), 3.78-3.64 (m , 1H), 3.60-3.14 (m, 2H), 3.00-2.72 (m, 2H), 2.72 (s, 3H), 2.72-2.50 (m, 3H ), 2.38-2.20 (m, 1H), 2.12-2.00 (m, 1H), 1.90-1.80 (m, 1H)

[1845] Example 159 (2S,4S)-4-fluoro-1-[2-[(3S)-3-[methyl-[8-(trifluoromethyl)-5-quinolyl]amino]pyrrolidin-1-yl] acetyl]pyrrolidine-2-carbonitrile

[1846] The title compound (324.1 mg, 68.5%) was prepared in the same manner as Example 28 except that instead of S)-N-(pyrrolidin-3-yl)furo[3 ,2-c]pyridin-7-amine hydrochloride (S)-N-methyl-N-(pyrrolidin-3-yl)-8-(trifluoromethyl)quinoline-5-amine hydrochloride (349.4 mg, 1.05 mmol) obtained in reference example 69. ¹ H-NMR (CDCl ₃ , 600 MHz) δ 9.02 (d, 1H), 8.54 (d, 1H), 7.95 (d, 1H), 7. 46 (t, 1H), 7.10 (d, 1H), 5.50-4.90 (m, 2H), 4.26-3.90 (m, 2H), 3.82-3.68 ( m, 1H), 3.70-3.16 (m, 2H), 3.00-2.85 (m, 1H), 2.85 (s, 3H), 2.85-2.78 (m, 2H), 2.78-2.60 (m, 2H), 2.40-2.24 (m, 1H), 2.20-2.10 (m, 1H), 2.00-1.90 ( m, 1N)

[1847] Example 160: (2S,4S)-4-fluoro-1-[2-[(3S)-3-[methyl-[8-(trifluoromethoxy)-5-quinolyl]amino]pyrrolidin-1-yl] acetyl]pyrrolidine-2-carbonitrile

[1848] The title compound (271.0 mg, 55.4%) was prepared in the same manner as Example 28 except that instead of S)-N-(pyrrolidin-3-yl)furo[3 ,2-c]pyridin-7-amine hydrochloride (S)-N-methyl-N-(pyrrolidin-3-yl)-8-(trifluoromethoxy)quinolin-5-amine hydrochloride (365.6 mg, 1.05 mmol) obtained in reference example 70. ¹ H-NMR (CDCl ₃ , 600 MHz) δ 9.00 (d, 1H), 8.59 (d, 1H), 7.52 (d, 1H), 7. 47 (t, 1H), 7.13 (d, 1H), 5.48-4.90 (m, 2H), 4.24-3.88 (m, 2H), 3.80-3.68 ( m, 1H), 3.60-3.16 (m, 2H), 3.05-2.78 (m, 2H), 2.78 (s, 3H), 2.78-2.60 (m, 3H), 2.40-2.22 (m, 1H), 2.20-2.10 (m, 1H), 1.98-1.85 (m, 1H)

[1849] Example 161: (S)-1-(2-((R)-3-(quinolin-5-ylamino)pyrrolidin-1-yl)acetyl)pyrrolidin-2-carbonitrile

[1850] The title compound (2.5 mg, 5.19%) was prepared in the same manner as Example 17 except that instead of (R)-N-(pyrrolidin-3-yl)quinolin-hydrochloride 3-amine hydrochloride was used (R)-N-(pyrrolidin-3-yl)quinolin-5-amine (25.6 mg, 0.12 mmol) prepared in reference example 71. ¹ H-NMR (CDCl ₃ , 400 MHz) δ 8.87 (s, 1H), 8.31 (dd, 1H), 7.55 (t, 1H), 7.47 (d, 1H), 7.36-7.30 (m, 1H ), 6.57 (d, 1H), 4.82 (dd, 1H), 4.21 (s, 1H), 3.69-3.35 (m, 4H), 3.14-2.47 ( m, 4H), 2.41-1.90 (m, 7H)

[1851] Example 162

[1852] The title compound (11.4 mg, 22.5%) was prepared in the same manner as Example 17 except that instead of (R)-N-(pyrrolidin-3-yl)quinoline- 3-amine hydrochloride (R)-N-(pyrrolidin-3-yl)quinolin-6-amine hydrochloride (25.6 mg, 0.12 mmol) prepared in reference example 72 was used. ¹ H-NMR (CDCl ₃ , 400 MHz) δ 8.57 (d, 1H), 7.86 (dd, 2H), 7.25-7.22 (m, 1H), 7.07 (dd, 1H), 6.62 (s, 1H), 4.87-4.62 (m, 2H), 4.11 (s, 1H), 3.66-3.28 (m, 4H), 3.01-2.82 (m, 3H) , 2.64-2.09 (m, 6H), 1.83-1.79 (m, 1H)

[1853] Example 163

[1854] The title compound (3.4 mg, 6.72%) was prepared in the same manner as Example 17 except that instead of (R)-N-(pyrrolidin-3-yl)quinoline- 3-amine hydrochloride (R)-N-(pyrrolidin-3-yl)quinolin-7-amine hydrochloride (25.6 mg, 0.12 mmol) obtained in reference example 73 was used. ¹ H-NMR (CDCl ₃ , 400 MHz) δ 8.71 (d, 1H), 7.94 (d, 1H), 7.57-7.54 (m, 1H), 7.10 (kv, 1H), 6.99 (d, 1H), 6.93-6.90 (m, 1H), 4.93-4.73 (m, 2H), 4.18 (s, 1H), 3.69-3.31 (m, 4H) , 3.09-2.85 (m, 3H), 2.60-2.16 (m, 6H), 1.86 (m, 1H)

[1855] Example 164 (2S)-1-[2-[(3R)-3-(8-quinolylamino)pyrrolidin-1-yl]acetyl]pyrrolidin-2-carbonitrile

[1856] The title compound (9.5 mg, 18.7%) was prepared in the same manner as Example 17 except that instead of (R)-N-(pyrrolidin-3-yl)quinoline- 3-amine hydrochloride (R)-N-(pyrrolidin-3-yl)quinolin-8-amine (25.6 mg, 0.12 mmol) obtained in reference example 74 was used. ¹ H-NMR (CDCl ₃ , 400 MHz) δ 8.70-8.69 (m, 1H), 8.05 (d, 1H), 7.39-7.35 (m, 2H), 7.08-7.05 (m, 1H) , 6.64 (d, 1H), 6.29 (d, 1H), 5.24-4.71 (m, 1H), 4.23 (s, 1H), 3.75-3.52 (m , 2.3H), 3.36-3.28 (m, 1.7H), 3.15-3.11 (m, 1H), 2.91-2.74 (m, 3H), 2.49 -2.07 (m, 5H), 1.93-1.190 (m, 1H)

[1857] Example 165

[1858] The title compound (15.3 mg, 39.7%) was prepared in the same manner as Example 28 except that instead of (S)-N-(pyrrolidin-3-yl)furo[3 ,2-c]pyridin-7-amine hydrochloride (R)-N-(pyrrolidin-3-yl)quinolin-3-amine hydrochloride (25.6 mg, 0.12 mmol) prepared in Reference Example ¹⁷ was used. H-NMR ( _CDCl3 , 400 MHz) δ 8.42-8.39 (m, 1H), 7.88 (d, 1H), 7.57 (d, 1H), 7.40-7.34 ( m, 2H), 6.90-6.89 (m, 1H), 5.36-5.20 (m, 1H), 5.06-4.83 (m, 2H), 4.07-3, 54 (m, 3H), 3.40-3.23 (m, 1H), 2.96-2.95 (m, 2H), 2.88-2.80 (m, 2H), 2.67- 2.51 (m, 2H), 2.40-2.10 (m, 2H), 1.77-1.76 (m, 1H)

[1859] Example 166

[1860] The title compound (16.9 mg, 44.0%) was prepared in the same manner as in Example 28 except that instead of (S)-N-(pyrrolidin-3-yl)furo[ 3,2-c]pyridin-7-amine hydrochloride (R)-N-(pyrrolidin-3-yl)quinolin-5-amine hydrochloride (25.6 mg, 0.12 mmol) prepared in Reference Example 71 was used. ^1H -NMR ( _CDCl3 , 400 MHz) δ 8.53 (d, 1H), 7.85 (d, 1H), 7.79 (d, 1H), 7.21-7.18 (m, 1H ), 7.05-7.03 (m, 1H), 6.58-6.56 (m, 1H), 5.34-5.18 (m, 1H), 5.07-4.72 (m , 2H), 4.09-3.20 (m, 5H), 2.90-2.73 (m, 3H), 2.64-2.47 (m, 2H), 2.37-2.09 (m, 2H), 1.73-1.70 (m, 1H)

[1861] Example 167

[1862] The title compound (1.2 mg, 3.1%) was prepared in the same manner as Example 28 except that instead of (S)-N-(pyrrolidin-3-yl)furo[3 ,2-c]pyridin-7-amine hydrochloride (R)-N-(pyrrolidin-3-yl)quinolin-6-amine hydrochloride (25.6 mg, 0.12 mmol) prepared in Reference Example 72 was used ^{. 1} H NMR (CD ₃ OD, 400 MHz) δ 8.75 (dd, 1H), 8.67-8.60 (m, 1H), 7.60-7.56 (m, 1H), 7.46- 7.43 (m, 1H), 7.33-7.31 (d, 1H), 6.69-6.66 (m, 1H), 5.51 (s, 1H), 5.39-5, 31 (m, 1H), 5.00 (d, 1H), 4.25-4.24 (m, 1H), 4.09-4.00 (m, 1H), 3.87-3.74 ( m, 1H), 3.59-3.42 (m, 1H), 3.09-3.04 (m, 2H), 2.95-2.88 (m, 1H), 2.71-2, 39 (m, 4H), 1.97-1.91 (m, 1H).

[1863] Example 168

[1864] The title compound (1.5 mg, 3.9%) was prepared in the same manner as described in Example 28 except that instead of (S)-N-(pyrrolidin-3-yl)furo[ 3,2-c]pyridin-7-amine hydrochloride (R)-N-(pyrrolidin-3-yl)quinolin-7-amine hydrochloride (25.6 mg, 0.12 mmol) prepared in Reference Example 73 was used. ¹ H-NMR (CDCl ₃ , 400 MHz) δ 8.72-8.71 (m, 1H), 7.96 (d, 1H), 7.58-7.55 (m, 1H), 7.13 -7.10 (m, 1H), 6.99 (s, 1H), 6.92-6.90 (m, 1H), 5.48-5.29 (m, 1H), 5.18-4 .93 (m, 1H), 4.77-4.61 (m, 1H), 4.23-4.18 (m, 1H), 4.11-3.79 (m, 2H), 3.48 -3.32 (m, 2H), 3.04-2.22 (m, 7H), 1.90-1.85 (m, 1H)

[1865] Example 169

[1866] The title compound (16.7 mg, 43.2%) was prepared in the same manner as in Example 28 except that instead of (S)-N-(pyrrolidin-3-yl)furo[ 3,2-c]pyridin-7-amine hydrochloride (R)-N-(pyrrolidin-3-yl)quinolin-8-amine hydrochloride (25.6 mg, 0.12 mmol) prepared in Reference Example 74 was used. ¹ H-NMR (CDCl ₃ , 400 MHz) δ 8.69-8.67 (m, 1H), 8.05-8.03 (m, 1H), 7.39-7.34 (m, 2H) , 7.08-7.04 (m, 1H), 6.64-6.61 (m, 1H), 6.25 (d, 1H), 5.44-5.19 (m, 1.3H) , 4.83 (d, 0.7H), 4.19-4.17 (m, 1H), 4.05-3.65 (m, 2H), 3.39-3.07 (m, 2H) , 3.00-2.02 (m, 7H), 1.92-1.85 (m, 1H)

[1867] Example 170: (2S,4S)-4-fluoro-1-[2-[(3R)-3-(4-quinolidin-1-yl]acetyl]pyrrolidin-2-carbonitrile

[1868] The title compound (1.1 mg, 2.91%) was prepared in the same manner as Example 28 except (R)-N-(pyrrolidin-3-yl)quinoline-4- amine hydrochloride (25.6 mg, 0.12 mmol) prepared in Reference Example 75 was used in place of (S)-N-(pyrrolidin-3-yl)furo[3,2-c]pyridin-7-amine hydrochloride. ^1H NMR ( _CDOD3 , 400 MHz) δ 8.38 (dd, 1H), 8.22-8.15 (m, 1H), 7.83 (d, 1H), 7.66 (t, 1H) , 7.49-7.45 (m, 1H), 6.53 (d, 1H), 5.51-5.00 (m, 2H), 4.35-4.31 (m, 1H), 4 .08-4.00 (m, 1H), 3.86-3.74 (m, 1H), 3.62-3.57 (m, 1H), 3.45 (d, 1H), 3.13 -2.92 (m, 3H), 2.67-2.36 (m, 4H), 1.97-1.90 (m, 1H)

[1869] Example 171 -carbonitrile

[1870](2S)-1-(2-chloroacetyl)-4-fluoropyrrolidine-2-carbonitrile (168.7 mg, 0.89 mmol) obtained in Reference Example 2 was dissolved in anhydrous dichloromethane (4 ml). To the resulting solution was added (R)-N-(pyrrolidin-3-yl)-1,8-naphthyridin-3-amine hydrochloride (254.1 mg 0.89 mmol) obtained in Reference Example 76 and potassium carbonate (492, 0 mg, 3.56 mmol). The reaction mixture was stirred overnight at room temperature. After completion of the reaction, water was added to the reaction mixture. The aqueous layer of the reaction mixture was extracted with dichloromethane. The extracted organic layer was dried and filtered over anhydrous magnesium sulfate. The filtered solution was concentrated and then purified by silica gel column chromatography (dichloromethane/methanol = 10/1, v/v) to give the title compound (50.1 mg, 15.4%). ¹ H-NMR (CDCl ₃ , 600 MHz) δ 8.79 (s, 1H), 8.61 (d, 1H), 7.96 (d, 1H), 7.35 (t, 1H), 6, 90 (d, 1H), 5.50-5.28 (m, 1H), 5.10-4.70 (m, 1H), 4.20-4.00 (m, 2H), 3.98- 3.70 (m, 1H), 3.60-3.30 (m, 2H), 3.10-2.98 (m, 2H), 2.95-2.82 (m, 2H), 2, 80-2.55 (m, 2H), 2.50-2.20 (m, 2H), 1.90-1.80 (m, 1H)

[1871] Example 172 (2S,4S)-4-fluoro-1-[2-[(3R)-3-[(7-chloro-1,8-naphthyridin-3-yl)amino]pyrrolidin-1- yl]acetyl]pyrrolidine-2-carbonitrile

[1872] The title compound (8.5 mg, 4.2%) was prepared in the same manner as Example 171 except that instead of (R)-N-(pyrrolidin-3-yl)-1 ,8-naphthyridin-3-amine hydrochloride (R)-7-chloro-N-(pyrrolidin-3-yl)-1,8-naphthyridin-3-amine hydrochloride (161.2 mg, 0.50 mmol) was used. obtained in reference example 77. ¹ H-NMR (CDCl ₃ , 600 MHz) δ 8.58 (s, 1H), 7.91 (d, 1H), 7.35 (d, 1H), 6.91 (s , 1H), 5.50-5.30 (m, 1H), 5.08-4.75 (m, 1H), 4.20-4.00 (m, 2H), 3.96-3.68 (m, 1H), 3.65-3.30 (m, 2H), 3.14-3.00 (m, 2H), 2.98-2.72 (m, 2H), 2.72-2 .50 (m, 2H), 2.50-2.25 (m, 2H), 1.90-1.80 (m, 1H)

[1873] Example 173 (2S,4S)-4-fluoro-1-[2-[(3R)-3-[(6-fluoro-5-quinolyl)amino]pyrrolidin-1-yl]acetyl]pyrrolidin- 2-carbonitrile

[1874] The title compound (138.8 mg, 63.7%) was prepared in the same manner as Example 171 except that instead of (R)-N-(pyrrolidin-3-yl)-1 ,8-naphthyridin-3-amine hydrochloride (R)-6-fluoro-N-(pyrrolidin-3-yl)quinolin-5-amine hydrochloride (171.9 mg, 0.57 mmol) prepared in Reference Example 78 was used ^.1H -NMR ( _CDCl3 , 400 MHz) δ 8.86 (d, 1H), 8.43 (d, 1H), 7.68 (d, 1H), 7.47-7.39 (m, 2H), 5.52-5.35 (m, 1H), 5.35-4.94 (m, 1H), 4.30-4.06 (m, 2H), 4.04-3.70 ( m, 1H), 3.70-3.38 (m, 2H), 3.18-3.00 (m, 1H), 2.98-2.85 (m, 1H), 2.82-2, 60 (m, 2H), 2.60-2.40 (m, 2H), 2.40-2.20 (m, 2H), 2.00-1.85 (m, 1H)

[1875] Example 174 (2S,4S)-4-fluoro-1-[2-[(3R)-3-[(7-fluoro-5-quinolyl)amino]pyrrolidin-1-yl]acetyl]pyrrolidin- 2-carbonitrile

[1876] The title compound (54.9 mg, 36.4%) was prepared in the same manner as Example 171 except that instead of (R)-N-(pyrrolidin-3-yl)-1 ,8-naphthyridin-3-amine hydrochloride (R)-7-fluoro-N-(pyrrolidin-3-yl)quinolin-5-amine hydrochloride (118.6 mg, 0.39 mmol) prepared in Reference Example 79 was used ^.1H -NMR ( _CDCl3 , 400 MHz) δ 8.84 (d, 1H), 8.29 (d, 1H), 7.31-7.25 (m, 1H), 7.08 (s, 1H), 6.33 (s, 1H), 5.70-5.34 (m, 1H), 5.10-4.93 (m, 1H), 4.30-3.70 (m, 3H) , 3.70-3.40 (m, 2H), 3.20-3.00 (m, 2H), 2.98-2.42 (m, 4H), 2.42-2.22 (m, 2H), 2.00-1.85 (m, 1H)

[1877] Example 175 2-carbonitrile

[1878] The title compound (45.6 mg, 11.8%) was prepared in the same manner as Example 171 except that (R)-8-fluoro-N-(pyrrolidin-3-yl )quinoline-5-amine hydrochloride (303.3 mg, 1.00 mmol) prepared in Reference Example 80 was used in place of (R)-N-(pyrrolidin-3-yl)-1,8-naphthyridin-3-amine hydrochloride. ^1H -NMR ( _CDCl3 , 400 MHz) δ 8.95 (d, 1H), 8.32 (d, 1H), 7.42 (t, 1H), 7.32-7.22 (m, 1H ), 6.46 (d, 1H), 5.50-5.30 (m, 1H), 5.10-4.90 (m, 1H), 4.30-3.74 (m, 3H), 3.74-3.35 (m, 2H), 3.15-2.85 (m, 2H), 2.80-2.58 (m, 4H), 2.58-2.20 (m, 2H ), 2.00-1.85 (m, 1H)

[1879] Example 176 2-carbonitrile

[1880] The title compound (132.2 mg, 26.7%) was prepared in the same manner as Example 171 except that instead of (R)-N-(pyrrolidin-3-yl)-1 ,8-naphthyridin-3-amine hydrochloride (R)-6-methoxy-N-(pyrrolidin-3-yl)quinolin-5-amine hydrochloride (393.7 mg, 1.25 mmol) prepared in Reference Example 81 was used ^.1H -NMR ( _CDCl3 , 400 MHz) δ 8.76 (d, 1H), 8.39 (d, 1H), 7.79 (d, 1H), 7.46 (d, 1H), 7 .33 (t, 1H), 5.50-5.24 (m, 1H), 5.24-4.90 (m, 1H), 4.25-4.00 (m, 2H), 3.96 (s, 3H), 3.96-3.70 (m, 1H), 3.70-3.30 (m, 2H), 3.10-3.00 (m, 1H), 3.00-2 .82 (m, 1H), 2.80-2.32 (m, 4H), 2.32-1.95 (m, 2H), 1.90-1.78 (m, 1H)

[1881] Example 177 (2S,4S)-4-fluoro-1-[2-[(3R)-3-[(7-methoxy-5-quinolyl)amino]pyrrolidin-1-yl]acetyl]pyrrolidin- 2-carbonitrile

[1882] The title compound (107.8 mg, 20.2%) was prepared in the same manner as Example 171 except that instead of (R)-N-(pyrrolidin-3-yl)-1, 8-Naphthyridin-3-amine hydrochloride (R)-7-methoxy-N-(pyrrolidin-3-yl)quinolin-5-amine hydrochloride (424.4 mg, 1.34 mmol) prepared in Reference Example 82 was used. ¹ H-NMR (CDCl ₃ , 400 MHz) δ 8.78 (d, 1H), 8.14 (d, 1H), 7.19 (t, 1H), 6.86 (s, 1H), 6, 21 (s, 1H), 5.50-5.28 (m, 1H), 5.12-4.92 (m, 1H), 4.28-3.95 (m, 2H), 3.93 ( s, 3H), 3.90-3.62 (m, 1H), 3.50-3.33 (m, 2H), 3.10-2.90 (m, 2H), 2.80-2, 42 (m, 4H), 2.42-2.20 (m, 2H), 2.00-1.85 (m, 1H)

[1883] Example 178 (2S,4S)-4-fluoro-1-[2-[(3R)-3-[(8-methoxy-5-quinolyl)amino]pyrrolidin-1-yl]acetyl]pyrrolidin- 2-carbonitrile

[1884] The title compound (11.1 mg, 5.3%) was prepared in the same manner as Example 171 except that (R)-8-methoxy-N-(pyrrolidin-3-yl) Quinoline-5-amine hydrochloride (165.7 mg, 0.52 mmol) prepared in Reference Example 83 was used in place of (R)-N-(pyrrolidin-3-yl)-1,8-naphthyridin-3-amine hydrochloride . ^1H -NMR ( _CDCl3 , 400 MHz) δ 8.94 (d, 1H), 8.27 (d, 1H), 7.43 (t, 1H), 6.96 (d, 1H), 6, 54 (d, 1H), 5.49-5.28 (m, 1H), 5.19-4.92 (m, 1H), 4.28-4.10 (m, 2H), 4.06 ( s, 3H), 4.00-3.80 (m, 1H), 3.78-3.33 (m, 2H), 3.10-3.00 (m, 2H), 3.00-2, 96 (m, 1H), 2.96-2.60 (m, 3H), 2.60-2.30 (m, 2H), 1.95-1.85 (m, 1H)

[1885] Example 179 (2S,4S)-4-fluoro-1-[2-[(3R)-3-[(3-methyl-5-quinolyl)amino]pyrrolidin-1-yl]acetyl]pyrrolidin- 2-carbonitrile

[1886] The title compound (258.9 mg, 70.7%) was prepared in the same manner as Example 171 except that instead of (R)-N-(pyrrolidin-3-yl)-1 ,8-naphthyridin-3-amine hydrochloride (R)-3-methyl-N-(pyrrolidin-3-yl)quinolin-5-amine hydrochloride (288.2 mg, 0.96 mmol) prepared in Reference Example 84 was used ^.1H -NMR ( _CDCl3 , 400 MHz) δ 8.72 (d, 1H), 8.06 (s, 1H), 7.50-7.42 (m, 2H), 6.54 (d, 1H), 5.48-5.28 (m, 1H), 5.15-4.98 (m, 1H), 4.30-3.62 (m, 3H), 3.60-3.32 ( m, 2H), 3.12-3.00 (m, 2H), 3.00-2.90 (m, 1H), 2.80-2.60 (m, 2H), 2.53 (s, 3H), 2.53-2.40 (m, 1H), 2.40-2.18 (m, 2H), 2.00-1.85 (m, 1H)

[1887] Example 180: (2S,4S)-4-fluoro-1-[2-[(3R)-3-[(6-methyl-5-quinolyl)amino]pyrrolidin-1-yl]acetyl]pyrrolidin- 2-carbonitrile

[1888] The title compound (206.3 mg, 42.3%) was prepared in the same manner as Example 171 except that instead of (R)-N-(pyrrolidin-3-yl)-1 ,8-naphthyridin-3-amine hydrochloride (R)-6-methyl-N-(pyrrolidin-3-yl)quinolin-5-amine hydrochloride (384.3 mg, 1.28 mmol) prepared in Reference Example 85 was used ^.1H -NMR ( _CDCl3 , 400 MHz) δ 8.82 (d, 1H), 8.43 (d, 1H), 7.70 (d, 1H), 7.50 (d, 1H), 7 .37 (t, 1H), 5.50-5.28 (m, 1H), 5.20-4.90 (m, 1H), 4.20-4.00 (m, 2H), 4.00 -3.70 (m, 2H), 3.54-3.28 (m, 2H), 3.20-3.00 (m, 1H), 2.90-2.64 (m, 2H), 2 .64-2.50 (m, 2H), 2.46 (s, 3H), 2.46-2.15 (m, 2H), 1.98-1.80 (m, 1H)

[1889] Example 181 (2S,4S)-4-fluoro-1-[2-[(3R)-3-[(8-methyl-5-quinolyl)amino]pyrrolidin-1-yl]acetyl]pyrrolidin- 2-carbonitrile

[1890] The title compound (106.3 mg, 31.5%) was prepared in the same manner as Example 171 except that instead of (R)-N-(pyrrolidin-3-yl)-1 ,8-naphthyridin-3-amine hydrochloride (R)-8-methyl-N-(pyrrolidin-3-yl)quinolin-5-amine hydrochloride (266.3 mg, 0.89 mmol) prepared in Reference Example 86 was used ^.1H -NMR ( _CDCl3 , 400 MHz) δ 8.93 (d, 1H), 8.25 (d, 1H), 7.42-7.33 (m, 2H), 6.51 (d, 1H), 5.49-5.28 (m, 1H), 5.18-4.90 (m, 1H), 4.30-4.00 (m, 2H), 4.00-3.64 ( m, 2H), 3.60-3.34 (m, 2H), 3.10-3.00 (m, 2H), 3.00-2.90 (m, 1H), 2.80-2, 69 (m, 1H), 2.69 (s, 3H), 2.69-2.18 (m, 3H), 1.98-1.85 (m, 1H)

[1891] Example 182 (2S,4S)-4-fluoro-1-[2-[(3R)-3-[[7-(trifluoromethyl)-5-quinolyl]amino]pyrrolidin-1-yl]acetyl] pyrrolidine-2-carbonitrile

[1892] The title compound (184.3 mg, 38.0%) was prepared in the same manner as Example 171 except that instead of (R)-N-(pyrrolidin-3-yl)-1 ,8-naphthyridin-3-amine hydrochloride (R)-N-(pyrrolidin-3-yl)-7-(trifluoromethyl)quinoline-5-amine hydrochloride (393.9 mg, 1.11 mmol) prepared in the reference example 87. ¹ H-NMR (CDCl ₃ , 400 MHz) δ 8.95 (d, 1H), 8.40 (d, 1H), 7.74 (s, 1H), 7.44 (t, 1H) , 6.64 (s, 1H), 5.78-5.40 (m, 1H), 5.03-4.97 (m, 1H), 4.38-4.20 (m, 1H), 4 ,10-3.74 (m, 2H), 3.70-3.35 (m, 2H), 3.22-2.85 (m, 3H), 2.82-2.42 (m, 3H) , 2.42-2.22 (m, 2H), 2.05-1.88 (m, 1H)

[1893] Example 183: (2S,4S)-4-fluoro-1-[2-[(3R)-3-[[8-(trifluoromethyl)-5-quinolyl]amino]pyrrolidin-1-yl]acetyl] pyrrolidine-2-carbonitrile

[1894] The title compound (116.0 mg, 54.4%) was prepared in the same manner as Example 171 except that instead of (R)-N-(pyrrolidin-3-yl)-1 ,8-naphthyridin-3-amine hydrochloride (R)-N-(pyrrolidin-3-yl)-8-(trifluoromethyl)quinoline-5-amine hydrochloride (173.2 mg, 0.49 mmol) prepared in the reference example 88. ¹ H-NMR (CDCl ₃ , 400 MHz) δ 9.01 (d, 1H), 8.41 (d, 1H), 7.90 (d, 1H), 7.41 (t, 1H) , 6.49 (d, 1H), 5.52-5.28 (m, 1H), 5.05-4.93 (m, 1H), 4.38-4.20 (m, 1H), 4 ,10-3.94 (m, 1H), 3.94-3.70 (m, 1H), 3.70-3.35 (m, 2H), 3.25-2.95 (m, 3H) , 2.95-2.55 (m, 3H), 2.55-2.22 (m, 2H), 2.05-1.85 (m, 1H)

[1895] Example 184 (2S,4S)-4-fluoro-1-[2-[(3R)-3-[(3-fluoro-5-quinolyl)amino]pyrrolidin-1-yl]acetyl]pyrrolidin- 2-carbonitrile

[1896] The title compound (255.8 mg, 87.5%) was prepared in the same manner as Example 171 except that instead of (R)-N-(pyrrolidin-3-yl)-1 ,8-naphthyridin-3-amine hydrochloride (R)-3-fluoro-N-(pyrrolidin-3-yl)quinolin-5-amine hydrochloride (230.9 mg, 0.76 mmol) prepared in Reference Example 89 was used ^.1H -NMR ( _CDCl3 , 400 MHz) δ 8.77 (s, 1H), 7.99 (d, 1H), 7.52-7.49 (m, 2H), 6.61 (d, 1H), 5.54-5.28 (m, 1H), 5.10-4.95 (m, 1H), 4.30-4.14 (m, 1H), 4.10-3.94 ( m, 1H), 3.94-3.65 (m, 1H), 3.65-3.37 (m, 2H), 3.18-2.88 (m, 3H), 2.85-2, 58 (m, 2H), 2.55-2.20 (m, 3H), 2.00-1.95 (m, 1H)

[1897] Example 185 (2S,4S)-4-fluoro-1-[2-[(3R)-3-[(3-chloro-5-quinolyl)amino]pyrrolidin-1-yl]acetyl]pyrrolidin- 2-carbonitrile

[1898] The title compound (27.4 mg, 7.4%) was prepared in the same manner as Example 171 except that instead of (R)-N-(pyrrolidin-3-yl)-1 ,8-naphthyridin-3-amine hydrochloride (R)-3-chloro-N-(pyrrolidin-3-yl)quinolin-5-amine hydrochloride (295.0 mg, 0.92 mmol) prepared in Reference Example 90 was used ^.1H -NMR ( _CDCl3 , 400 MHz) δ 8.78 (s, 1H), 8.36 (s, 1H), 7.54 (t, 1H), 7.45 (d, 1H), 6 .61 (d, 1H), 5.54-5.25 (m, 1H), 5.10-4.95 (m, 1H), 4.30-4.15 (m, 1H), 4.10 -3.84 (m, 1H), 3.84-3.65 (m, 1H), 3.65-3.40 (m, 2H), 3.20-2.90 (m, 3H), 2 .84-2.40 (m, 3H), 2.40-2.20 (m, 2H), 2.00-1.86 (m, 1H)

[1899] Example 186 (2S,4S)-4-fluoro-1-[2-[(3R)-3-[[8-(trifluoromethoxy)-5-quinolyl]amino]pyrrolidin-1-yl]acetyl] pyrrolidine-2-carbonitrile

[1900] The title compound (200.3 mg, 37.5%) was prepared in the same manner as Example 171 except that instead of (R)-N-(pyrrolidin-3-yl)-1 ,8-naphthyridin-3-amine hydrochloride (R)-N-(pyrrolidin-3-yl)-8-(trifluoromethoxy)quinoline-5-amine hydrochloride (438.0 mg, 1.18 mmol) obtained from the reference example 91. ¹ H-NMR (CDCl ₃ , 400 MHz) δ 9.00 (d, 1H), 8.35 (d, 1H), 7.50-7.41 (m, 2H), 6.48 ( d, 1H), 5.52-5.24 (m, 1H), 5.10-4.92 (m, 1H), 4.30-4.15 (m, 1H), 4.15-3, 98 (m, 1H), 3.98-3.70 (m, 1H), 3.70-3.38 (m, 2H), 3.20-2.88 (m, 3H), 2.84- 2.40 (m, 3H), 2.40-2.20 (m, 2H), 2.00-1.85 (m, 1H)

[1901] Example 187 (2S,4S)-4-fluoro-1-[2-[(3R)-3-[(6-methyl-4-quinolyl)amino]pyrrolidin-1-yl]acetyl]pyrrolidin- 2-carbonitrile

[1902] The title compound (3.7 mg, 6.7%) was prepared in the same manner as Example 171 except that instead of (R)-N-(pyrrolidin-3-yl)-1 ,8-naphthyridin-3-amine hydrochloride (R)-6-methyl-N-(pyrrolidin-3-yl)quinolin-4-amine hydrochloride (43.2 mg, 0.14 mmol) prepared in Reference Example 92 was used ^.1H -NMR ( _CDCl3 , 400 MHz) δ 8.27-8.23 (m, 3H), 7.57 (d, 1H), 6.43 (d, 1H), 5.60-5, 40 (m, 1H), 5.14-5.06 (m, 1H), 4.30-4.20 (m, 1H), 4.05-3.90 (m, 1H), 3.90- 3.80 (m, 1H), 3.80-3.60 (m, 2H), 3.54-3.45 (m, 1H), 3.32-3.05 (m, 3H), 3. 05-2.70 (m, 2H), 2.59 (s, 3H), 2.59-2.38 (m, 1H), 2.28-2.16 (m, 1H), 2.08- 1.98 (m, 1H)

[1903] Example 188. (2S,4S)-4-fluoro-1-[2-[(3R)-3-[(6-methoxy-4-quinolyl)amino]pyrrolidin-1-yl]acetyl]pyrrolidin- 2-carbonitrile

[1904] The title compound (37.8 mg, 10.0%) was prepared as described in Example 171 except that instead of (R)-N-(pyrrolidin-3-yl)-1, 8-Naphthyridin-3-amine hydrochloride (R)-6-methoxy-N-(pyrrolidin-3-yl)quinolin-4-amine hydrochloride (301.1 mg, 0.95 mmol) prepared in Reference Example 93 was used. ^1H -NMR ( _CDCl3 , 400 MHz) δ 8.19 (d, 1H), 8.13 (d, 1H), 7.48 (s, 1H), 7.30-7.20 (m, 1H ), 6.39 (d, 1H), 5.58-5.40 (m, 1H), 5.20-5.10 (m, 1H), 4.34-4.20 (m, 1H), 4.06 (s, 3H), 4.00-3.88 (m, 1H), 3.88-3.70 (m, 1H), 3.70-3.60 (m, 2H), 3. 49-3.40 (m, 1H), 3.38-3.00 (m, 3H), 3.00-2.84 (m, 1H), 2.84-2.72 (m, 1H), 2.72-2.30 (m, 1H), 2.30-2.10 (m, 1H), 2.10-1.95 (m, 1H)

[1905] Example 189. (2S,4S)-4-fluoro-1-[2-[(3R)-3-[(8-chloro-4-quinolyl)amino]pyrrolidin-1-yl]acetyl]pyrrolidin- 2-carbonitrile

[1906] The title compound (60.4 mg, 41.1%) was prepared in the same manner as Example 171 except that instead of (R)-N-(pyrrolidin-3-yl)-1 ,8-naphthyridin-3-amine hydrochloride (R)-8-chloro-N-(pyrrolidin-3-yl)quinolin-4-amine hydrochloride (117.0 mg, 0.37 mmol) prepared in Reference Example 94 was used ^.1H -NMR ( _CDCl3 , 400 MHz) δ 8.55 (d, 1H), 7.48-7.41 (m, 3H), 6.67 (d, 1H), 5.54-5, 38 (m, 1H), 5.30-4.88 (m, 1H), 4.30-4.18 (m, 1H), 4.18-3.90 (m, 1H), 3.90- 3.70 (m, 1H), 3.50-3.30 (m, 2H), 3.20-3.00 (m, 1H), 3.00-2.85 (m, 1H), 2, 85-2.58 (m, 3H), 2.58-2.30 (m, 2H), 2.30-2.10 (m, 1H), 2.00-1.86 (m, 1H)

[1907] Example 190. (2S,4S)-4-fluoro-1-[2-[(3R)-3-[(8-methyl-4-quinolyl)amino]pyrrolidin-1-yl]acetyl]pyrrolidin- 2-carbonitrile

[1908] The title compound (140.6 mg, 27.3%) was prepared in the same manner as Example 171 except that instead of (R)-N-(pyrrolidin-3-yl)-1 ,8-naphthyridin-3-amine hydrochloride (R)-8-methyl-N-(pyrrolidin-3-yl)quinolin-4-amine hydrochloride (406.2 mg, 1.35 mmol) prepared in Reference Example 95 was used ^.1H -NMR ( _CDCl3 , 400 MHz) δ 8.61 (d, 1H), 7.74 (d, 1H), 7.50 (d, 1H), 7.35 (t, 1H), 6 .41 (d, 1H), 5.50-5.30 (m, 1H), 5.10-4.90 (m, 1H), 4.34-4.18 (m, 1H), 4.18 -3.82 (m, 1H), 3.82-3.60 (m, 1H), 3.60-3.40 (m, 2H), 3.18-2.94 (m, 3H), 2 .77 (s, 3H), 2.77-2.42 (m, 3H), 2.42-2.18 (m, 2H), 2.00-1.8 8 (m, 1H)

[1909] Example 191. (2S,4S)-4-fluoro-1-[2-[(3R)-3-[(6-fluoro-4-quinolyl)amino]pyrrolidin-1-yl]acetyl]pyrrolidin- 2-carbonitrile

[1910] The title compound (65.2 mg, 15.2%) was prepared in the same manner as Example 171 except that instead of (R)-N-(pyrrolidin-3-yl)-1 ,8-naphthyridin-3-amine hydrochloride (R)-6-fluoro-N-(pyrrolidin-3-yl)quinolin-4-amine hydrochloride (337.7 mg, 1.11 mmol) prepared in Reference Example 96 was used ^.1H -NMR ( _CDCl3 , 400 MHz) δ 8.51 (s, 1H), 7.96 (d, 1H), 7.66 (d, 1H), 7.40 (d, 1H), 6 .40 (d, 1H), 5.52-5.30 (m, 1H), 5.05-4.95 (m, 1H), 4.34-4.18 (m, 1H), 4.10 -3.94 (m, 1H), 3.94-3.74 (m, 1H), 3.70-3.40 (m, 2H), 3.25-3.10 (m, 1H), 3 ,10-2.95 (m, 2H), 2.85-2.60 (m, 2H), 2.52-2.24 (m, 3H), 2.00-1.90 (m, 1H)

[1911] Example 192. (2S,4S)-4-fluoro-1-[2-[(3R)-3-[(6-chloro-4-quinolyl)amino]pyrrolidin-1-yl]acetyl]pyrrolidin- 2-carbonitrile

[1912] The title compound (109.4 mg, 31.7%) was prepared in the same manner as Example 171 except that instead of (R)-N-(pyrrolidin-3-yl)-1 ,8-naphthyridin-3-amine hydrochloride (R)-6-chloro-N-(pyrrolidin-3-yl)quinolin-4-amine hydrochloride (274.8 mg, 0.86 mmol) prepared in Reference Example 97 was used ^1H -NMR ( _CDCl3 , 400 MHz) δ 8.51 (d, 1H), 8.07 (s, 1H), 7.90 (d, 1H), 7.55 (d, 1H), 6 .38 (d, 1H), 5.55-5.30 (m, 1H), 5.08-4.95 (m, 1H), 4.30-4.15 (m, 1H), 4.08 -3.70 (m, 1H), 3.70-3.40 (m, 2H), 3.30-3.20 (m, 1H), 3.15-3.00 (m, 2H), 2 .85-2.65 (m, 2H), 2.52-2.20 (m, 3H), 2.00-1.90 (m, 1H)

[1913] Example 193. (2S,4S)-4-fluoro-1-[2-[(3R)-3-[(7-methoxy-4-quinolyl)amino]pyrrolidin-1-yl]acetyl]pyrrolidin- 2-carbonitrile

[1914] The title compound (159.2 mg, 35.4%) was prepared in the same manner as described in Example 171 except that instead of (R)-N-(pyrrolidin-3-yl)-1 ,8-naphthyridin-3-amine hydrochloride (R)-7-methoxy-N-(pyrrolidin-3-yl)quinolin-4-amine hydrochloride (358.2 mg, 1.13 mmol) prepared in Reference Example 98 was used ^.1H -NMR ( _CDCl3 , 400 MHz) δ 8.47 (d, 1H), 7.81 (d, 1H), 7.33 (s, 1H), 7.11 (d, 1H), 6 .31 (d, 1H), 5.50-5.30 (m, 1H), 5.10-4.94 (m, 1H), 4.35-4.20 (m, 1H), 4.10 -3.94 (m, 1H), 3.94 (s, 3H), 3.94-3.66 (m, 2H), 3.66-3.40 (m, 2H), 3.15-2 .90 (m, 2H), 2.80-2.40 (m, 2H), 2.40-2.20 (m, 3H), 2.00-1.85 (m, 1H)

[1915] Example 194. (2S,4S)-4-fluoro-1-[2-[(3R)-3-[(8-fluoro-4-quinolyl)amino]pyrrolidin-1-yl]acetyl]pyrrolidin- 2-carbonitrile

[1916] The title compound (29.9 mg, 5.7%) was prepared in the same manner as Example 171 except that instead of (R)-N-(pyrrolidin-3-yl)-1 ,8-naphthyridin-3-amine hydrochloride (R)-8-fluoro-N-(pyrrolidin-3-yl)quinolin-4-amine hydrochloride (418.0 mg, 1.37 mmol) prepared in Reference Example 99 was used ^.1H -NMR (MeOD, 400 MHz) δ 8.41 (d, 1H), 8.03 (d, 1H), 7.44-7.39 (m, 2H), 6.62 (d, 1H ), 5.55-5.30 (m, 1H), 5.05-4.96 (m, 1H), 4.40-4.30 (m, 1H), 4.10-4.00 (m , 1H), 3.90-3.70 (m, 1H), 3.65-3.40 (m, 2H), 3.16-3.00 (m, 3H), 2.75-2.60 (m, 2H), 2.60-2.35 (m, 3H), 2.05-1.90 (m, 1H)

[1917] Example 195 (2S,4S)-4-fluoro-1-[2-[(3R)-3-[(8-methoxy-4-quinolyl)amino]pyrrolidin-1-yl]acetyl]pyrrolidin- 2-carbonitrile

[1918] The title compound (13.2 mg, 3.3%) was prepared in the same manner as Example 171 except that instead of (R)-N-(pyrrolidin-3-yl)-1, 8-Naphthyridin-3-amine hydrochloride (R)-8-methoxy-N-(pyrrolidin-3-yl)quinolin-4-amine hydrochloride (316.4 mg, 1.00 mmol) prepared in Reference Example 100 was used. ¹ H-NMR (CDCl ₃ , 400 MHz) δ 8.57 (d, 1H), 7.67 (d, 1H), 7.41 (t, 1H), 7.05 (d, 1H), 6, 44 (d, 1H), 5.55-5.30 (m, 1H), 5.20-5.00 (m, 1H), 4.35-4.20 (m, 1H), 4.07 ( s, 3H), 4.07-3.90 (m, 1H), 3.90-3.70 (m, 1H), 3.70-3.45 (m, 2H), 3.25-3, 15 (m, 1H), 3.15-2.90 (m, 3H), 2.84-2.50 (m, 2H), 2.50-2.25 (m, 2H), 2.06- 1.90 (m, 1H)

[1919] Example 196 (2S,4S)-4-fluoro-1-[2-[(3R)-3-[[8-(trifluoromethyl)-4-quinolyl]amino]pyrrolidin-1-yl]acetyl] pyrrolidine-2-carbonitrile

The title compound (30.8 mg, 5.0%) was prepared in the same manner as Example 171 except that instead of (R)-N-(pyrrolidin-3-yl)-1,8- naphthyridin-3-amine hydrochloride (R)-N-(pyrrolidin-3-yl)-8-(trifluoromethyl)quinoline-4-amine hydrochloride (499.4 mg, 1.41 mmol) prepared in Reference Example 101 was used. ¹ H-NMR (CDCl ₃ , 400 MHz) δ 8.64 (d, 1H), 8.22 (d, 1H), 7.97 (d, 1H), 7.44 (t, 1H), 6, 43 (d, 1H), 5.52-5.28 (m, 1H), 5.00-4.90 (m, 1H), 4.30-4.15 (m, 1H), 4.04- 3.84 (m, 1H), 3.80-3.60 (m, 1H), 3.60-3.35 (m, 2H), 3.20-2.85 (m, 3H), 2. 80-2.40 (m, 3H), 2.40-2.30 (m, 1H), 2.30-2.20 (m, 1H), 2.00-1.85 (m, 1H)

[1920] Example 197 (2S)-1-[2-[(3R)-3-[(7-fluoro-5-quinolyl)amino]pyrrolidin-1-yl]acetyl]pyrrolidin-2-carbonitrile

[1921] The title compound (207.1 mg, 90.3%) was prepared in the same manner as Example 17 except that instead of (R)-N-(pyrrolidin-3-yl)quinolin- 3-amine hydrochloride (R)-7-fluoro-N-(pyrrolidin-3-yl)quinolin-5-amine hydrochloride (189.8 mg, 0.62 mmol) obtained in Reference Example 79 was used. ¹ H-NMR ( _CDCl3 , 400 MHz) δ 8.81 (d, 1H), 8.33 (d, 1H), 7.27 (t, 1H), 7.04 (s, 1H), 6.31 (s, 1H), 5.95-5.50 (m, 1H), 4.85-4.75 (m, 1H), 4.24-4.08 (m, 1H), 3.70-3.55 ( m, 2H), 3.55-3.30 (m, 2H), 3.20-2.80 (m, 3H), 2.75-2.50 (m, 1H), 2.50-2, 20 (m, 4H), 2.20-2.00 (m, 2H), 2.00-1.85 (m, 1H)

[1922] Example 198 (2S)-1-[2-[(3R)-3-[(7-methoxy-5-quinolyl)amino]pyrrolidin-1-yl]acetyl]pyrrolidin-2-carbonitrile

[1923] The title compound (287.5 mg, 59.0%) was prepared in the same manner as Example 17 except that instead of (R)-N-(pyrrolidin-3-yl)quinoline- 3-amine hydrochloride (R)-7-methoxy-N-(pyrrolidin-3-yl)quinolin-5-amine hydrochloride (406.4 mg, 1.29 mmol) obtained in Reference Example 82 was used. ¹ H-NMR ( _CDCl3 , 400 MHz) δ 8.76 (d, 1H), 8.20 (d, 1H), 7.18 (t, 1H), 6.84 (s, 1H), 6.20 (s, 1H), 5.35-5.10 (m, 1H), 4.90-4.70 (m, 1H), 4.25-4.10 (m, 1H), 3.92 (s, 3H) , 3.70-3.60 (m, 1H), 3.60-3.30 (m, 3H), 3.15-2.85 (m, 3H), 2.70-2.40 (m, 1H), 2.40-2.20 (m, 2H), 2.20-2.00 (m, 2H), 2.00-1.85 (m, 1H)

[1924] Example 199 (2S)-1-[2-[(3R)-3-[(8-fluoro-5-quinolyl)amino]pyrrolidin-1-yl]acetyl]pyrrolidin-2-carbonitrile

[1925] The title compound (91.5 mg, 23.6%) was prepared in the same manner as Example 17 except that instead of (R)-N-(pyrrolidin-3-yl)quinoline- 3-amine hydrochloride (R)-8-fluoro-N-(pyrrolidin-3-yl)quinolin-5-amine hydrochloride (320.6 mg, 1.05 mmol) obtained in Reference Example 80 was used. ¹ H-NMR ( _CDCl3 , 400 MHz) δ 8.93 (d, 1H), 8.36 (d, 1H), 7.42 (d, 1H), 7.29-7.24 (m, 1H), 6, 44 (s, 1H), 5.18-4.90 (m, 1H), 4.90-4.70 (m, 1H), 4.30-4.10 (m, 1H), 3.70- 3.60 (m, 1H), 3.60-3.30 (m, 3H), 3.20-2.80 (m, 3H), 2.75-2.50 (m, 1H), 2, 50-2.10 (m, 4H), 2.00-1.80 (m, 1H)

[1926] Example 200: (2S)-1-[2-[(3R)-3-[(8-methyl-5-quinolyl)amino]pyrrolidin-1-yl]acetyl]pyrrolidin-2-carbonitrile

[1927] The title compound (172.5 mg, 51.9%) was prepared in the same manner as Example 17 except that instead of (R)-N-(pyrrolidin-3-yl)quinolin- 3-amine hydrochloride (R)-8-methyl-N-(pyrrolidin-3-yl)quinolin-5-amine hydrochloride (275.0 mg, 0.92 mmol) obtained in Reference Example 86 was used. ¹ H-NMR ( _CDCl3 , 400 MHz) δ 8.92 (d, 1H), 8.31 (d, 1H), 7.40 (d, 1H), 7.35 (t, 1H), 6.51 (d, 1H), 4.95-4.74 (m, 1H), 4.30-4.15 (m, 1H), 3.70-3.60 (m, 1H), 3.60-3.35 ( m, 3H), 3.15-2.85 (m, 3H), 2.68 (s, 3H), 2.68-2.40 (m, 2H), 2.40-2.30 (m, 1H), 2.30-2.20 (m, 1H), 2.20-2.00 (m, 2H), 2.00-1.80 (m, 1H)

[1928] Example 201

[1929] The title compound (118.4 mg, 62.7%) was prepared in the same manner as Example 17 except that instead of (R)-N-(pyrrolidin-3-yl)quinoline- 3-amine hydrochloride (R)-N-(pyrrolidin-3-yl)-8-(trifluoromethyl)quinoline-5-amine hydrochloride (160.5 mg, 0.45 mmol) prepared in Reference Example 88 was used. ¹ H -NMR ( _CDCl3 , 400 MHz) δ 9.00 (d, 1H), 8.48 (d, 1H), 7.88 (d, 1H), 7.42 (t, 1H), 6.47 ( d, 1H), 6.30-5.70 (m, 1H), 4.85-4.75 (m, 1H), 4.30-4.15 (m, 1H), 3.70-3, 60 (m, 1H), 3.60-3.30 (m, 3H), 3.28-3.15 (m, 1H), 3.15-2.80 (m, 2H), 2.80- 2.50 (m, 1H), 2.50-2.10 (m, 4H), 2.10-1.85 (m, 1H)

[1930] Example 202

[1931] The title compound (97.5 mg, 17.9%) was prepared in the same manner as Example 17 except that instead of (R)-N-(pyrrolidin-3-yl)quinoline- 3-amine hydrochloride (R)-N-(pyrrolidin-3-yl)-8-(trifluoromethoxy)quinoline-5-amine hydrochloride (464.2 mg, 1.25 mmol) prepared in Reference Example 91 was used. ¹ H -NMR ( _CDCl3 , 400 MHz) δ 8.98 (d, 1H), 8.42 (d, 1H), 7.49 (d, 1H), 7.43 (t, 1H), 6.45 ( d, 1H), 5.70-5.30 (m, 1H), 4.85-4.75 (m, 1H), 4.30-4.15 (m, 1H), 3.70-3, 56 (m, 1H), 3.56-3.30 (m, 3H), 3.20-3.00 (m, 3H), 2.90-2.70 (m, 1H), 2.60- 2.40 (m, 1H), 2.40-2.08 (m, 3H), 2.05-1.88 (m, 1H)

[1932] Example 203 (2S)-1-[2-[(3R)-3-[(3-chloro-5-quinolyl)amino]pyrrolidin-1-yl]acetyl]pyrrolidin-2-carbonitrile

[1933] The title compound (265.9 mg, 76.4%) was prepared in the same manner as Example 17 except that instead of (R)-N-(pyrrolidin-3-yl)quinoline- 3-amine hydrochloride (R)-3-chloro-N-(pyrrolidin-3-yl)quinolin-5-amine hydrochloride (290.8 mg, 0.91 mmol) obtained in Reference Example 90 was used. ¹ H-NMR ( _CDCl3 , 400 MHz) δ 8.75 (d, 1H), 8.43 (s, 1H), 7.53 (d, 1H), 7.43 (t, 1H), 6.59 (s, 1H), 5.60-5.20 (m, 1H), 4.85-4.75 (m, 1H), 4.30-4.15 (m, 1H), 3.70-3.60 ( m, 1H), 3.60-3.30 (m, 3H), 3.20-3.10 (m, 1H), 3.10-2.95 (m, 2H), 2.80-2, 50 (m, 1H), 2.50-2.20 (m, 3H), 2.20-2.00 (m, 1H), 2.00-1.85 (m, 1H)

[1934] Example 204 (2S)-1-[2-[(3R)-3-[(3-methoxy-5-quinolyl)amino]pyrrolidin-1-yl]acetyl]pyrrolidin-2-carbonitrile

[1935] The title compound (338.5 mg, 92.4%) was prepared in the same manner as Example 17 except that instead of (R)-N-(pyrrolidin-3-yl)quinoline- 3-amine hydrochloride (R)-3-methoxy-N-(pyrrolidin-3-yl)quinolin-5-amine hydrochloride (305.2 mg, 0.97 mmol) obtained in Reference Example 102 was used. ¹ H-NMR ( _CDCl3 , 400 MHz) δ 8.62 (d, 1H), 7.65 (s, 1H), 7.42-7.38 (m, 2H), 6.57 (d, 1H), 5, 55-5.10 (m, 1H), 4.85-4.70 (m, 1H), 4.30-4.15 (m, 1H), 4.01 (s, 3H), 3.65- 3.55 (m, 1H), 3.55-3.40 (m, 3H), 3.35-3.15 (m, 1H), 3.10-2.95 (m, 2H), 2, 85-2.60 (m, 1H), 2.40-2.20 (m, 2H), 2.20-2.05 (m, 2H), 2.05-1.85 (m, 1H)

[1936] Example 205 2-carbonitrile

[1937] The title compound (349.0 mg, 91.0%) was prepared in the same manner as Example 171 except that instead of (R)-N-(pyrrolidin-3-yl)-1 ,8-naphthyridin-3-amine hydrochloride (R)-3-methoxy-N-(pyrrolidin-3-yl)quinolin-5-amine hydrochloride (305.2 mg, 0.97 mmol) prepared in Reference Example 102 was used ^.1H -NMR ( _CDCl3 , 400 MHz) δ 8.65 (d, 1H), 7.59 (s, 1H), 7.46-7.38 (m, 2H), 6.59 (d, 1H), 5.55-5.25 (m, 1H), 5.10-4.90 (m, 1H), 4.35-4.20 (m, 1H), 4.02 (s, 3H) , 4.00-3.80 (m, 3H), 3.80-3.60 (m, 1H), 3.60-3.35 (m, 2H), 3.25-3.00 (m, 2H), 2.90-2.60 (m, 2H), 2.60-2.20 (m, 2H), 2.05-1.90 (m, 1H)

[1938] Example 206

[1939] The title compound (61.1 mg, 20.3%) was prepared in the same manner as Example 17 except that instead of (R)-N-(pyrrolidin-3-yl)quinoline-3 -amine hydrochloride (R)-2-chloro-N-(pyrrolidin-3-yl)quinolin-6-amine hydrochloride (251.8 mg, 0.79 mmol) obtained in Reference Example 103 was used. ¹ H-NMR ( CDCl ₃ , 400 MHz) δ 7.86 (d, 1H), 7.78 (d, 1H), 7.27-7.23 (m, 1H), 7.09 (d, 1H), 6.64 (s, 1H), 4.90-4.75 (m, 1H), 4.20-4.10 (m, 1H), 3.75-3.60 (m, 1H), 3.60-3 .30 (m, 3H), 3.10-3.00 (m, 2H), 2.90-2.65 (m, 2H), 2.60-2.20 (m, 3H), 2.20 -2.10 (m, 2H), 1.88-1.78 (m, 1H)

[1940] Example 207 (2S,4S)-4-fluoro-1-[2-[(3R)-3-[(2-chloro-6-quinolyl)amino]pyrrolidin-1-yl]acetyl]pyrrolidin- 2-carbonitrile

[1941] The title compound (54.3 mg, 17.2%) was prepared in the same manner as described in Example 171 except that instead of (R)-N-(pyrrolidin-3-yl)-1 ,8-naphthyridin-3-amine hydrochloride (R)-2-chloro-N-(pyrrolidin-3-yl)quinolin-6-amine hydrochloride (251.8 mg, 0.79 mmol) prepared in Reference Example 103 was used ^.1H -NMR ( _CDCl3 , 400 MHz) δ 7.86 (d, 1H), 7.79 (d, 1H), 7.27-7.23 (m, 1H), 7.09 (d, 1H), 6.64 (s, 1H), 5.54-5.30 (m, 1H), 5.10-4.90 (m, 1H), 4.22-4.04 (m, 1H) , 4.00-3.70(m, 1H), 3.60-3.30 (m, 3H), 3.10-2.90 (m, 2H), 2.90-2.58 (m, 3H), 2.55-2.20 (m, 3H), 1.90-1.75 (m, 1H)

[1942] Example 208 (2S)-1-[2-[(3R)-3-[(3-methyl-5-quinolyl)amino]pyrrolidin-1-yl]acetyl]pyrrolidin-2-carbonitrile

[1943] The title compound (4.3 mg, 4.0%) was prepared in the same manner as Example 17 except that instead of (R)-N-(pyrrolidin-3-yl)quinoline- 3-amine hydrochloride (R)-3-methyl-N-(pyrrolidin-3-yl)quinolin-5-amine hydrochloride (89.8 mg, 0.30 mmol) obtained in Reference Example 84 was used. ¹ H-NMR ( _CDCl3 , 400 MHz) δ 8.73 (s, 1H), 8.10 (s, 1H), 7.50-7.42 (m, 2H), 6.56 (d, 1H), 5, 25-4.90 (m, 1H), 4.90-4.75 (m, 1H), 4.30-4.15 (m, 1H), 3.74-3.60 (m, 1H), 3.60-3.38 (m, 3H), 3.20-2.90 (m, 3H), 2.75-2.60 (m, 1H), 2.72 (s, 3H), 2. 40-2.26 (m, 2H), 2.26-2.00 (m, 2H), 2.00-1.85 (m, 1H)

[1944] Example 209

[1945] The title compound (73.0 mg, 66.5%) was prepared in the same manner as Example 17 except that instead of (R)-N-(pyrrolidin-3-yl)quinoline- 3-amine hydrochloride (R)-3-fluoro-N-(pyrrolidin-3-yl)quinolin-5-amine hydrochloride (120.5 mg, 0.40 mmol) prepared in Reference Example 89 was used. ¹ H-NMR ( _CDCl3 , 400 MHz) δ 8.77 (s, 1H), 8.04 (d, 1H), 7.52-7.46 (m, 2H), 6.62 (d, 1H), 5, 30-5.05 (m, 1H), 4.88-4.78 (m, 1H), 4.30-4.15 (m, 1H), 3.74-3.60 (m, 1H), 3.60-3.30 (m, 3H), 3.20-2.85 (m, 3H), 2.80-2.50 (m, 1H), 2.40-2.24 (m, 2H ), 2.24-2.10 (m, 2H), 2.00-1.85 (m, 1H)

[1946] Example 210: (2S,4S)-4-fluoro-1-[2-[(3R)-3-[[2-(trifluoromethyl)-6-quinolyl]amino]pyrrolidin-1-yl]acetyl] pyrrolidine-2-carbonitrile

[1947] The title compound (84.0 mg, 18.0%) was prepared in the same manner as Example 171 except that instead of (R)-N-(pyrrolidin-3-yl)-1 ,8-naphthyridin-3-amine hydrochloride (R)-N-(pyrrolidin-3-yl)-2-(trifluoromethyl)quinoline-6-amine hydrochloride (379.0 mg, 1.07 mmol) prepared in the reference example 104. ¹ H-NMR (CDCl ₃ , 400 MHz) δ 8.03 (d, 1H), 7.96 (d, 1H), 7.58 (d, 1H), 7.16 (d, 1H) , 6.66 (s, 1H), 5.52-5.30 (m, 1H), 5.10-4.90 (m, 1H), 4.30-4.10 (m, 1H), 4 ,10-3.65(m, 3H), 3.65-3.34 (m, 2H), 3.12-3.00 (m, 2H), 3.00-2.80 (m, 1H) , 2.80-2.58 (m, 2H), 2.54-2.20 (m, 2H), 1.98-1.80 (m, 1H)

[1948] Example 211 (25.45)-4-fluoro-1-[2-[(3R)-3-[(3-methyl-6-quinolyl)amino]pyrrolidin-1-yl]acetyl]pyrrolidin- 2-carbonitrile

[1949] The title compound (98.8 mg, 25.9%) was prepared in the same manner as described in Example 171 except that instead of (R)-N-(pyrrolidin-3-yl)-1 ,8-naphthyridin-3-amine hydrochloride (R)-3-methyl-N-(pyrrolidin-3-yl)quinolin-6-amine hydrochloride (300.8 mg, 1.00 mmol) prepared in Reference Example 105 was used ^.1H -NMR ( _CDCl3 , 400 MHz) δ 8.47 (s, 1H), 7.82 (d, 1H), 7.68 (s, 1H), 7.00 (d, 1H), 6 .59 (s, 1H), 5.50-5.25 (m, 1H), 5.15-4.90 (m, 1H), 4.40-4.15 (m, 1H), 4.15 -3.70(m, 3H), 3.54-3.30 (m, 2H), 3.05-2.94 (m, 2H), 2.94-2.60 (m, 3H), 2 .45 (s, 3H), 2.45-2.20 (m, 2H), 1.90-1.75 (m, 1H)

[1950] Example 212 2-carbonitrile

[1951] The title compound (44.8 mg, 16.2%) was prepared in the same manner as Example 171 except that instead of (R)-N-(pyrrolidin-3-yl)-1 ,8-naphthyridin-3-amine hydrochloride (R)-4-methoxy-N-(pyrrolidin-3-yl)quinolin-6-amine hydrochloride (220.7 mg, 0.70 mmol) prepared in Reference Example 106 was used ^.1H -NMR ( _CDCl3 , 400 MHz) δ 8.50 (d, 1H), 7.82 (d, 1H), 7.08-7.03 (m, 2H), 6.66 (d, 1H), 5.50-5.30 (m, 1H), 5.20-4.90 (m, 1H), 4.30-4.18 (m, 1H), 4.18-4.05( m, 1H), 4.03 (s, 3H), 4.03-3.70 (m, 2H), 3.05-2.95 (m, 2H), 2.95-2.80 (m, 2H), 2.80-2.58 (m, 2H), 2.55-2.20 (m, 3H), 1.90-1.75 (m, 1H)

[1952] Example 213. (2S,4S)-4-fluoro-1-[2-[(3R)-3-[(8-methyl-6-quinolyl)amino]pyrrolidin-1-yl]acetyl]pyrrolidin- 2-carbonitrile

[1953] The title compound (95.3 mg, 31.6%) was prepared in the same manner as Example 171 except that instead of (R)-N-(pyrrolidin-3-yl)-1 ,8-naphthyridin-3-amine hydrochloride (R)-8-methyl-N-(pyrrolidin-3-yl)quinolin-6-amine hydrochloride (237.2 mg, 0.79 mmol) prepared in Reference Example 107 was used ^.1H -NMR ( _CDCl3 , 400 MHz) δ 8.65 (d, 1H), 7.88 (d, 1H), 7.29-7.24 (m, 1H), 6.96 (s, 1H), 6.52 (s, 1H), 5.50-5.28 (m, 1H), 5.20-4.90 (m, 1H), 4.25-4.15 (m, 1H) , 4.15-3.70 (m, 3H), 3.55-3.30 (m, 2H), 3.05-2.95 (m, 2H), 2.95-2.75 (m, 2H), 2.72 (s, 3H), 2.72-2.55 (m, 1H), 2.50-2.20 (m, 2H), 1.90-1.75 (m, 1H)

[1954] Example 214 2-carbonitrile

[1955] The title compound (220.7 mg, 59.3%) was prepared in the same manner as Example 171 except that instead of (R)-N-(pyrrolidin-3-yl)-1 ,8-naphthyridin-3-amine hydrochloride (R)-8-fluoro-N-(pyrrolidin-3-yl)quinolin-6-amine hydrochloride (294.2 mg, 0.97 mmol) prepared in Reference Example 110 was used ^.1H -NMR ( _CDCl3 , 400 MHz) δ 8.63 (s, 1H), 7.90 (d, 1H), 7.32-7.27 (m, 1H), 6.82 (d, 1H), 6.45 (s, 1H), 5.50-5.30 (m, 1H), 5.14-4.90 (m, 1H), 4.20-4.00 (m, 2H) , 4.00-3.65 (m, 2H), 3.60-3.30 (m, 2H), 3.10-2.90 (m, 2H), 2.90-2.70 (m, 2H), 2.70-2.50 (m, 1H), 2.50-2.20 (m, 2H), 1.90-1.70 (m, 1H)

[1956] Example 215 (2S,4S)-4-fluoro-1-[2-[(3R)-3-[(8-chloro-6-quinolyl)amino]pyrrolidin-1-yl]acetyl]pyrrolidin- 2-carbonitrile

[1957] The title compound (59.4 mg, 16.5%) was prepared in the same manner as Example 171 except that (R)-8-chloro-N-(pyrrolidin-3-yl )quinoline-6-amine hydrochloride (287.6 mg, 0.90 mmol) prepared in Reference Example 108 was used in place of (R)-N-(pyrrolidin-3-yl)-1,8-naphthyridin-3-amine hydrochloride. ^1H -NMR ( _CDCl3 , 400 MHz) δ 8.73 (s, 1H), 7.92 (d, 1H), 7.32 (t, 1H), 7.27-7.25 (m, 1H ), 6.59 (s, 1H), 5.52-5.28 (m, 1H), 5.10-4.90 (m, 1H), 4.25-4.00 (m, 2H), 4.00-3.68 (m, 2H), 3.60-3.30 (m, 2H), 3.10-3.00 (m, 2H), 2.95-2.55 (m, 3H ), 2.50-2.20 (m, 2H), 1.90-1.70 (m, 1H)

[1958] Example 216 (2S,4S)-4-fluoro-1-[2-[(3R)-3-[[8-(trifluoromethyl)-6-quinolyl]amino]pyrrolidin-1-yl]acetyl] pyrrolidine-2-carbonitrile

[1959] The title compound (18.0 mg, 3.7%) was prepared in the same manner as Example 171 except that instead of (R)-N-(pyrrolidin-3-yl)-1 ,8-naphthyridin-3-amine hydrochloride (R)-N-(pyrrolidin-3-yl)-8-(trifluoromethyl)quinoline-6-amine hydrochloride (394.2 mg, 1.11 mmol) prepared in the reference example 109. ¹ H-NMR (CDCl ₃ , 400 MHz) δ 8.77 (d, 1H), 7.95 (d, 1H), 7.46 (s, 1H), 7.35 (t, 1H) , 6.79 (s, 1H), 5.55-5.30 (m, 1H), 5.10-4.90 (m, 1H), 4.30-4.02 (m, 2H), 4 .02-3.65 (m, 2H), 3.60-3.30 (m, 2H), 3.12-2.98 (m, 2H), 2.95-2.60 (m, 3H) , 2.55-2.20 (m, 2H), 1.90-1.80 (m, 1H)

[1960] Example 217

[1961] The title compound (17.6 mg, 4.6%) was prepared in the same manner as Example 17 except that instead of (R)-N-(pyrrolidin-3-yl)quinoline- 3-amine hydrochloride (R)-N-(pyrrolidin-3-yl)-2-(trifluoromethyl)quinoline-6-amine hydrochloride (324.5 mg, 0.92 mmol) prepared in Reference Example 104 was used. ¹ H -NMR ( _CDCl3 , 400 MHz) δ 8.04 (d, 1H), 7.96 (d, 1H), 7.58 (d, 1H), 7.17 (d, 1H), 6.67 ( s, 1H), 4.90-4.75 (m, 1H), 4.25-4.15 (m, 1H), 3.75-3.60 (m, 1H), 3.60-3, 45 (m, 2H), 3.45-3.30 (m, 2H), 3.10-3.00 (m, 2H), 2.95-2.55 (m, 2H), 2.50- 2.10 (m, 4H), 1.95-1.80 (m, 1H)

[1962] Example 218 (2S)-1-[2-[(3R)-3-[(3-methyl-6-quinolyl)amino]pyrrolidin-1-yl]acetyl]pyrrolidin-2-carbonitrile

[1963] The title compound (224.2 mg, 55.4%) was prepared as described in Example 17 except that instead of (R)-N-(pyrrolidin-3-yl)quinoline-3 -amine hydrochloride (R)-3-methyl-N-(pyrrolidin-3-yl)quinolin-6-amine hydrochloride (334.2 mg, 1.11 mmol) obtained in Reference Example 105 was used. ¹ H-NMR ( CDCl ₃ , 400 MHz) δ 8.45 (s, 1H), 7.82 (d, 1H), 7.67 (s, 1H), 7.01 (d, 1H), 6.58 (s, 1H ), 4.95-4.70 (m, 1H), 4.25-4.10 (m, 1H), 3.75-3.40 (m, 3H), 3.40-3.30 (m , 2H), 3.10-2.95 (m, 2H), 2.90-2.55 (m, 2H), 2.44 (s, 3H), 2.44-2.20 (m, 2H ), 2.20-1.90 (m, 2H), 1.90-1.75 (m, 1H)

[1964] Example 219 (2S)-1-[2-[(3R)-3-[(4-methoxy-6-quinolyl)amino]pyrrolidin-1-yl]acetyl]pyrrolidin-2-carbonitrile

[1965] The title compound (143.4 mg, 44.5%) was prepared in the same manner as Example 17 except that instead of (R)-N-(pyrrolidin-3-yl)quinoline- 3-amine hydrochloride (R)-4-methoxy-N-(pyrrolidin-3-yl)quinolin-6-amine hydrochloride (268.8 mg, 0.85 mmol) obtained in Reference Example 106 was used. ¹ H-NMR ( _CDCl3 , 400 MHz) δ 8.48 (d, 1H), 7.81 (d, 1H), 7.07-7.02 (m, 2H), 6.65 (d, 1H), 4, 95-4.75 (m, 1H), 4.30-4.15 (m, 1H), 4.02 (s, 3H), 3.75-3.45 (m, 3H), 3.45- 3.30 (m, 2H), 3.10-2.95 (m, 2H), 2.90-2.50 (m, 2H), 2.50-2.30 (m, 2H), 2, 30-2.00 (m, 2H), 1.90-1.75 (m, 1H)

[1966] Example 220: (2S)-1-[2-[(3R)-3-[(8-methyl-6-quinolyl)amino]pyrrolidin-1-yl]acetyl]pyrrolidin-2-carbonitrile

[1967] The title compound (200.6 mg, 97.0%) was prepared in the same manner as Example 17 except that instead of (R)-N-(pyrrolidin-3-yl)quinoline- 3-amine hydrochloride (R)-8-methyl-N-(pyrrolidin-3-yl)quinolin-6-amine hydrochloride (170.8 mg, 0.57 mmol) obtained in Reference Example 107 was used. ¹ H-NMR ( _CDCl3 , 400 MHz) δ 8.64 (d, 1H), 7.88 (d, 1H), 7.26-7.24 (m, 1H), 6.95 (s, 1H), 6, 52 (s, 1H), 4.95-4.75 (m, 1H), 4.25-4.10 (m, 1H), 3.75-3.45 (m, 3H), 3.45- 3.30 (m, 2H), 3.10-2.95 (m, 2H), 2.90-2.80 (m, 1H), 2.72 (s, 3H), 2.70-2, 50 (m, 1H), 2.50-2.30 (m, 1H), 2.30-2.10 (m, 3H), 1.90-1.75 (m, 1H)

[1968] Example 221 (2S)-1-[2-[(3R)-3-[(8-fluoro-6-quinolyl)amino]pyrrolidin-1-yl]acetyl]pyrrolidin-2-carbonitrile

[1969] The title compound (121.2 mg, 65.5%) was prepared in the same manner as Example 17 except that instead of (R)-N-(pyrrolidin-3-yl)quinoline- 3-amine hydrochloride (R)-8-fluoro-N-(pyrrolidin-3-yl)quinolin-6-amine hydrochloride (153.3 mg, 0.50 mmol) prepared in Reference Example 110 was used. ¹ H-NMR ( _CDCl3 , 400 MHz) δ 8.62 (s, 1H), 7.89 (d, 1H), 7.29 (t, 1H), 6.82 (d, 1H), 6.45 (s, 1H), 4.90-4.75 (m, 1H), 4.25-4.05 (m, 1H), 3.75-3.60 (m, 1H), 3.60-3.44 ( m, 2H), 3.44-3.30 (m, 2H), 3.10-2.95 (m, 2H), 2.95-2.50 (m, 2H), 2.50-2, 10 (m, 4H), 1.90-1.75 (m, 1H)

[1970] Example 222 (2S)-1-[2-[(3R)-3-[(8-chloro-6-quinolyl)amino]pyrrolidin-1-yl]acetyl]pyrrolidin-2-carbonitrile

[1971] The title compound (77.7 mg, 57.4%) was prepared in the same manner as Example 17 except that (R)-8-chloro-N-(pyrrolidin-3-yl )quinoline-6-amine hydrochloride (112.9 mg, 0.35 mmol) obtained in Reference Example 108 was used instead of (R)-N-(pyrrolidin-3-yl)quinoline-3-amine hydrochloride. ¹ H-NMR (CDCl ₃ , 400 MHz) δ 8.72 (d, 1H), 7.91 (d, 1H), 7.33-7.25 (m, 2H), 6.58 (s, 1H ), 4.90-4.75 (m, 1H), 4.20-4.10 (m, 1H), 3.74-3.60 (m, 1H), 3.60-3.42 (m , 2H), 3.42-3.30 (m, 2H), 3.10-2.95 (m, 2H), 2.90-2.50 (m, 2H), 2.50-2.20 (m, 2H), 2.20-2.05 (m, 2H), 1.90-1.75 (m, 1H)

[1972] Example 223: (2S)-1-[2-[(3R)-3-[(6-methyl-4-quinolyl)amino]pyrrolidin-1-yl]acetyl]pyrrolidin-2-carbonitrile

[1973] The title compound (233.0 mg, 64.8%) was prepared in the same manner as Example 17 except that instead of (R)-N-(pyrrolidin-3-yl)quinoline-3 -amine hydrochloride (R)-6-methyl-N-(pyrrolidin-3-yl)quinolin-4-amine hydrochloride (297.2 mg, 0.99 mmol) obtained in Reference Example 92 was used. ¹ H-NMR ( CDCl ₃ , 400 MHz) δ 8.43 (d, 1H), 7.99 (d, 1H), 7.91 (s, 1H), 7.50 (d, 1H), 6.38 (d, 1H ), 4.90-4.75 (m, 1H), 4.35-4.20 (m, 1H), 3.72-3.60 (m, 2H), 3.60-3.40 (m , 3H), 3.35-3.25 (m, 1H), 3.20-2.98 (m, 2H), 2.85-2.75 (m, 1H), 2.57 (s, 3H ), 2.50-2.10 (m, 4H), 2.10-1.90 (m, 1H)

[1974] Example 224 (2S)-1-[2-[(3R)-3-[(6-methoxy-4-quinolyl)amino]pyrrolidin-1-yl]acetyl]pyrrolidin-2-carbonitrile

[1975] The title compound (340.7 mg, 73.1%) was prepared in the same manner as Example 17 except that instead of (R)-N-(pyrrolidin-3-yl)quinoline- 3-amine hydrochloride (R)-6-methoxy-N-(pyrrolidin-3-yl)quinolin-4-amine hydrochloride (388.7 mg, 1.23 mmol) obtained in Reference Example 93 was used. ¹ H-NMR ( _CDCl3 , 400 MHz) δ 8.39 (d, 1H), 7.99 (d, 1H), 7.42 (s, 1H), 7.32 (d, 1H), 6.39 (d, 1H), 4.85-4.75 (m, 1H), 4.35-4.20 (m, 1H), 4.04 (s, 3H), 3.75-3.50 (m, 3H) , 3.50-3.30 (m, 2H), 3.25-2.85 (m, 3H), 2.85-2.60 (m, 1H), 2.50-2.10 (m, 4H), 2.10-1.90 (m, 1H)

[1976] Example 225: (2S)-1-[2-[(3R)-3-[(6-fluoro-4-quinolyl)amino]pyrrolidin-1-yl]acetyl]pyrrolidin-2-carbonitrile

[1977] The title compound (267.8 mg, 64.0%) was prepared in the same manner as Example 17 except that instead of (R)-N-(pyrrolidin-3-yl)quinoline- 3-amine hydrochloride (R)-6-fluoro-N-(pyrrolidin-3-yl)quinolin-4-amine hydrochloride (346.5 mg, 1.14 mmol) obtained in Reference Example 96 was used. ¹ H-NMR ( _CDCl3 , 400 MHz) δ 8.50 (d, 1H), 7.95 (d, 1H), 7.72 (d, 1H), 7.38 (s, 1H), 6.39 (d, 1H), 4.90-4.75 (m, 1H), 4.35-4.15 (m, 1H), 3.75-3.60 (m, 1H), 3.60-3.35 ( m, 3H), 3.25-3.15 (m, 1H), 3.15-2.90 (m, 2H), 2.80-2.60 (m, 1H), 2.50-2, 35 (m, 1H), 2.35-2.10 (m, 4H), 2.00-1.85 (m, 1H)

[1978] Example 226: (2S)-1-[2-[(3R)-3-[(6-chloro-4-quinolyl)amino]pyrrolidin-1-yl]acetyl]pyrrolidin-2-carbonitrile

[1979] The title compound (335.8 mg, 70.7%) was prepared in the same manner as Example 17 except that instead of (R)-N-(pyrrolidin-3-yl)quinoline-3 -amine hydrochloride (R)-6-chloro-N-(pyrrolidin-3-yl)quinolin-4-amine hydrochloride (397.0 mg, 1.24 mmol) obtained in Reference Example 97 was used. ¹ H-NMR ( CDCl ₃ , 400 MHz) δ 8.50 (d, 1H), 8.14 (s, 1H), 7.88 (d, 1H), 7.54 (d, 1H), 6.38 (d, 1H ), 4.90-4.75 (m, 1H), 4.30-4.15 (m, 1H), 3.75-3.55 (m, 2H), 3.55-3.35 (m , 3H), 3.30-3.20 (m, 1H), 3.18-2.90 (m, 2H), 2.85-2.60 (m, 1H), 2.50-2.10 (m, 4H), 2.00-1.85 (m, 1H)

[1980] Example 227 (2S)-1-[2-[(3R)-3-[(8-fluoro-4-quinolyl)amino]pyrrolidin-1-yl]acetyl]pyrrolidin-2-carbonitrile

[1981] The title compound (59.4 mg, 12.1%) was prepared in the same manner as Example 17 except that instead of (R)-N-(pyrrolidin-3-yl)quinoline- 3-amine hydrochloride (R)-8-fluoro-N-(pyrrolidin-3-yl)quinolin-4-amine hydrochloride (407.6 mg, 1.34 mmol) obtained in Reference Example 99 was used. ¹ H-NMR ( _CDCl3 , 400 MHz) δ 8.59 (d, 1H), 7.81 (d, 1H), 7.38-7.31 (m, 2H), 6.44 (d, 1H), 4, 85-4.75 (m, 1H), 4.40-4.20 (m, 1H), 3.75-3.60 (m, 2H), 3.60-3.35 (m, 3H), 3.30-3.20 (m, 1H), 3.18-2.90 (m, 2H), 2.85-2.60 (m, 1H), 2.55-2.15 (m, 4H ), 2.00-1.85 (m, 1H)

[1982] Example 228

[1983] (2S,4S)-1-(2-chloroacetyl)-4-fluoropyrrolidine-2-carbonitrile (20.0 mg, 0.10 mmol) prepared in Reference Example 2 was dissolved in anhydrous dichloromethane (4 ml) . To the resulting solution was added (S)-N-(pyrrolidin-3-yl)quinolin-5-amine hydrochloride (36.0 mg, 0.12 mmol) obtained in Reference Example 16 and potassium carbonate (29.0 mg, 0.12 mmol). 21 mmol). The reaction mixture was stirred overnight at room temperature. After completion of the reaction, water was added to the reaction mixture. The aqueous layer of the reaction mixture was extracted with dichloromethane. The extracted organic layer was dried and filtered over anhydrous magnesium sulfate. The filtered solution was concentrated and then purified by silica gel column chromatography (dichloromethane/methanol = 10/1, v/v) to give the title compound (5.3 mg, 13.7%). ¹ H-NMR (CDCl ₃ , 400 MHz) δ 8.86 (m, 1H), 8.30 (m, 1H), 7.48-7.54 (m, 2H), 7.33 (m, 1H ), 6.55 (m, 1H), 5.25-5.49 (m, 1H), 4.97 (m, 1H), 4.31 (m, 1H), 3.82-3.92 ( m, 1H), 3.62-3.80 (m, 1H), 3.32-3.60 (m, 2H), 3.01-3.25 (m, 2H), 2.62-2, 82 (m, 2H), 2.21-2.42 (m, 2H), 1.96-2.19 (m, 3H)

[1984] Example 229

[1985] The title compound (7.7 mg, 38.3%) was prepared in the same manner as Example 5 except that instead of (S)-N-(pyrrolidin-3-yl)quinoline- 4-amine hydrochloride (S)-N-(pyrrolidin-3-yl)quinolin-3-amine hydrochloride (25.6 mg, 0.12 mmol) obtained in Reference Example 6 was used. ¹ H-NMR (CDCl ₃ , 400 MHz) δ 8.44 (d, 1H), 7.93 (d, 1H), 7.60 (d, 1H), 7.41-7.39 (m, 2H), 6.96 (d, 1H), 4.87-4.67 (m, 2H), 4.12-4.11 (m, 1H), 3.65-3.62 (m, 1H), 3.55-3.41 ( m, 2H), 3.09-3.00 (m, 2H), 2.86-2.79 (m, 1H), 2.67-2.05 (m, 7H), 1.88-1, 79 (m, 1H).

[1986] Example 230: (2S)-1-[2-[(3S)-3-(6-quinolylamino)pyrrolidin-1-yl]acetyl]pyrrolidin-2-carbonitrile

[1987] The title compound (11.4 mg, 56.5%) was prepared in the same manner as Example 5 except that instead of (S)-N-(pyrrolidin-3-yl)quinoline- 4-amine hydrochloride (S)-N-(pyrrolidin-3-yl)quinolin-6-amine hydrochloride (25.6 mg, 0.12 mmol) obtained in reference example 111 was used. ¹ H-NMR (CDCl ₃ , 400 MHz) δ 8.58 (d, 1H), 7.90 (d, 1H), 7.84 (d, 1H), 7.26-1.23 (m, 1H), 7.10-7, 08 (m, 1H), 6.63 (s, 1H), 4.90-4.65 (m, 2H), 4.12-4.11 (m, 1H), 3.62-3.32 ( m, 3H), 3.02-3.01 (m, 2H), 2.82-2.79 (m, 2H), 2.66-2.04 (m, 6H), 1.85-1, 80 (m, 1H).

[1988] Example 231 5-[(3S)-1-[2-oxo-2-[(2S)-2-cyanopyrrolidin-1-yl]ethyl]pyrrolidin-3-yl]amino]quinoline-2-carbonitrile

[1989] The title compound (3.0 mg, 13.8%) was prepared in the same manner as Example 5 except that instead of (S)-N-(pyrrolidin-3-yl)quinoline-4 -amine hydrochloride (S)-5-(pyrrolidin-3-ylamino)quinoline-2-carbonitrile hydrochloride (37.3 mg, 0.12 mmol) obtained in reference example 112 was used. ¹ H-NMR (CDCl ₃ , 400 MHz) δ 8.62-8.42 (m, 1H), 7.66-7.58 (m, 2H), 7.49-7.43 (m, 1H), 6.67-6.63 ( m, 1H), 6.06 (d, 0.6H), 5.34 (d, 0.4H), 4.79-4.71 (m, 1H), 4.25-4.20 (m, 1H), 3.70-3.43 (m, 3H), 3.28-2.99 (m, 3H), 2.79-2.73 (m, 1H), 2.48-2.13 ( m, 5H), 2.05-1.95 (m, 2H).

[1990] Example 232 5-[(3S)-1-[2-oxo-2-[(2S)-2-cyanopyrrolidin-1-yl]ethyl]pyrrolidin-3-yl]amino]quinoline-3-carbonitrile

[1991] The title compound (1.9 mg, 13.8%) was prepared in the same manner as Example 5 except that instead of (S)-N-(pyrrolidin-3-yl)quinoline-4 -amine hydrochloride (S)-5-(pyrrolidin-3-ylamino)quinoline-3-carbonitrile hydrochloride (37.3 mg, 0.12 mmol) obtained in reference example 113 was used. ¹ H-NMR (CDCl ₃ , 400 MHz) δ 8.95-8.93 (m, 1.6H), 8.79 (s, 0.4H), 7.71-7.65 (m, 1H), 7.45-7.39 ( m, 1H), 6.64-6.61 (m, 1H), 6.45 (d, 0.7H), 5.79 (d, 0.3H), 4.87-4.70 (m, 1H), 4.25-4.16 (m, 1H), 3.72-3.64 (m, 1H), 3.58-3.54 (m, 1.3H), 3.49-3, 43 (m, 0.7H), 3.35-3.28 (m, 1H), 3.15-3.09 (m, 1H), 3.05-3.00 (m, 1H), 2. 93-2.77 (m, 1H), 2.42-2.11 (m, 5H), 2.03-1.96 (m, 1H), 1.85-1.82 (m, 1H).

[1992] Example 233: (2S)-1-[2-[(3S)-3-[(3-methoxy-5-quinolyl)amino]pyrrolidin-1-yl]acetyl]pyrrolidin-2-carbonitrile

[1993] The title compound (10.6 mg, 24.2%) was prepared in the same manner as Example 5 except that instead of (S)-N-(pyrrolidin-3-yl)quinoline- 4-amine hydrochloride (S)-3-methoxy-N-(pyrrolidin-3-yl)quinolin-5-amine hydrochloride (37.9 mg, 0.12 mmol) prepared in Reference Example 114 was used. ¹ H-NMR ( _CDCl3 , 400 MHz) δ 8.63 (d, 1H), 7.64-7.53 (m, 1H), 7.45-7.37 (m, 2H), 6.57 (q, 1H ), 5.39-5.38 (m, 0.5H), 5.02-5.00 (m, 0.5H), 4.72 (t, 1H), 4.21 (s, 1H), 4.01 (s, 1.7H), 3.94 (s, 1.3H), 3.64-3.39 (m, 3H), 3.23-3.14 (m, 2H), 3. 03-2.98 (m, 1H), 2.73-2.68 (m, 1H), 2.48-2.00 (m, 7H).

[1994] Example 234: (2S)-1-[2-[(3S)-3-[(3-fluoro-5-quinolyl)amino]pyrrolidin-1-yl]acetyl]pyrrolidin-2-carbonitrile

[1995] The title compound (5.7 mg, 13.3%) was prepared in the same manner as Example 5 except that instead of (S)-N-(pyrrolidin-3-yl)quinoline-4 -amine hydrochloride (S)-3-fluoro-N-(pyrrolidin-3-yl)quinolin-5-amine hydrochloride (36.5 mg, 0.12 mmol) obtained in Reference Example 115 was used. ¹ H-NMR ( CDCl ₃ , 400 MHz) δ 8.76 (s, 1H), 7.99 (dd, 1H), 7.52-7.46 (m, 2H), 6.60 (t, 1H), 4.97 -4.79 (m, 1H), 4.21-4.19 (m, 1H), 3.67-3.43 (m, 4H), 3.31-3.07 (m, 2H), 2 .96 (d, 1H), 2.81-2.71 (m, 1H), 2.48-1.94 (m, 7H).

[1996] Example 235: (2S)-1-[2-[(3S)-3-[(3-chloro-5-quinolyl)amino]pyrrolidin-1-yl]acetyl]pyrrolidin-2-carbonitrile

[1997] The title compound (13.7 mg, 34.4%) was prepared in the same manner as Example 5 except that instead of (S)-N-(pyrrolidin-3-yl)quinoline- 4-amine hydrochloride (S)-3-chloro-N-(pyrrolidin-3-yl)quinolin-5-amine hydrochloride (38.4 mg, 0.12 mmol) prepared in Reference Example 116 was used. ¹ H-NMR (CDCl ₃ , 400 MHz) δ 8.75 (s, 1H), 8.41-8.30 (m, 1H), 7.55-7.50 (m, 1H), 7.44-7.40 (m, 1H), 6.57 (d, 1H), 5.53 (d, 0.7H), 5.12 (d, 0.3H), 4.79 (d, 1H), 4.21- 4.16 (m, 1H), 3.67-3.41 (m, 3H), 3.34-3.08 (m, 2H), 2.94 (d, 1H), 2.84-2, 68 (m, 1H), 2.45-1.92 (m, 7H).

[1998] Example 236: (2S)-1-[2-[(3S)-3-[(7-fluoro-5-quinolyl)amino]pyrrolidin-1-yl]acetyl]pyrrolidin-2-carbonitrile

[1999] The title compound (6.8 mg, 16.1%) was prepared in the same manner as Example 5 except that instead of (S)-N-(pyrrolidin-3-yl)quinoline-4 -amine hydrochloride (S)-7-fluoro-N-(pyrrolidin-3-yl)quinolin-5-amine hydrochloride (36.5 mg, 0.12 mmol) obtained in Reference Example 117 was used. ¹ H-NMR ( CDCl ₃ , 400 MHz) δ 8.82 (s, 1H), 8.37-8.21 (m, 1H), 7.30-7.24 (m, 1H), 7.06-7.02 ( m, 1H), 6.32-6.27 (m, 1H), 5.94 (d, 0.7H), 5.40 (d, 0.3H), 4.75 (dd, 1H), 4 .18-4.13 (m, 1H), 3.67-3.43 (m, 3H), 3.28-2.98 (m, 3H), 2.77-2.67 (m, 1H) , 2.52-1.92 (m, 7H).

[2000] Example 237: (2S)-1-[2-[(3S)-3-[(7-methoxy-5-quinolyl)amino]pyrrolidin-1-yl]acetyl]pyrrolidin-2-carbonitrile

[2001] The title compound (10.1 mg, 16.1%) was prepared in the same manner as Example 5 except that instead of (S)-N-(pyrrolidin-3-yl)quinoline- 4-amine hydrochloride (S)-7-methoxy-N-(pyrrolidin-3-yl)quinolin-5-amine hydrochloride (37.9 mg, 0.12 mmol) prepared in reference example 118 was used. ¹ H-NMR ( _CDCl3 , 400 MHz) δ 8.75 (s, 1H), 8.25-8.14 (m, 1H), 7.20-7.16 (m, 1H), 6.83 (s, 1H ), 6.18 (d, 1H), 5.45 (d, 0.6H), 5.11 (d, 0.3H), 4.78-4.75 (m, 1H), 4.14- 4.13 (m, 1H), 3.92 (s, 3H), 3.65-3.27 (m, 4H), 3.13-2.95 (m, 2H), 2.74-2, 60 (m, 1H), 2.37-1.94 (m, 7H).

[2002] Example 238

[2003] The title compound (15.0 mg, 31.0%) was prepared in the same manner as Example 5 except that instead of (S)-N-(pyrrolidin-3-yl)quinoline- 4-amine hydrochloride (S)-N-(pyrrolidin-3-yl)-7-(trifluoromethyl)quinoline-5-amine hydrochloride (42.5 mg, 0.12 mmol) prepared in Reference Example 119 was used. ¹ H -NMR (CDCl ₃ , 400 MHz) δ 8.93-8.90 (m, 1H), 8.51-8.33 (m, 1H), 7.70 (d, 1H), 7.45-7 .40 (m, 1H), 6.61 (d, 1H), 6.15 (d, 0.7H), 5.51 (d, 0.3H), 4.77-4.72 (m, 1H ), 4.25-4.20 (m, 1H), 3.69-3.24 (m, 4H), 3.18-3.01 (m, 2H), 2.79-2.65 (m , 1H), 2.57-1.95 (m, 7H).

[2004] Example 239 (2S)-1-[2-[(3S)-3-[(6-methyl-5-quinolyl)amino]pyrrolidin-1-yl]acetyl]pyrrolidin-2-carbonitrile

[2005] The title compound (3.3 mg, 7.9%) was prepared in the same manner as Example 5 except that instead of (S)-N-(pyrrolidin-3-yl)quinoline- 4-amine hydrochloride (S)-6-methyl-N-(pyrrolidin-3-yl)quinolin-5-amine hydrochloride (36.0 mg, 0.12 mmol) prepared in Reference Example 120 was used. ¹ H-NMR ( _CDCl3 , 400 MHz) δ 8.82 (s, 1H), 8.47-8.41 (m, 1H), 7.69 (d, 1H), 7.50 (d, 1H), 7. 36 (q, 1H), 4.98-4.77 (m, 1H), 4.02 (s, 1H), 3.73-3.66 (m, 1H), 3.57-3.29 ( m, 3H), 3.19-3.11 (m, 1H), 2.87-2.79 (m, 1H), 2.60-2.39 (m, 5H), 2.29-2, 15 (m, 5H), 1.93-1.84 (m, 2H).

[2006] Example 240: (2S)-1-[2-[(3S)-3-[(6-methoxy-5-quinolyl)amino]pyrrolidin-1-yl]acetyl]pyrrolidin-2-carbonitrile

[2007] The title compound (5.1 mg, 11.6%) was prepared in the same manner as Example 5 except that instead of (S)-N-(pyrrolidin-3-yl)quinoline-4 -amine hydrochloride (S)-6-methoxy-N-(pyrrolidin-3-yl)quinolin-5-amine hydrochloride (37.9 mg, 0.12 mmol) obtained in Reference Example 121 was used. ¹ H-NMR ( CDCl ₃ , 400 MHz) δ 8.77 (s, 1H), 8.43-8.38 (m, 1H), 7.77 (d, 1H), 7.47 (d, 1H), 7.34 (q, 1H), 5.13-4.76 (m, 1H), 4.11-4.05 (m, 1H), 3.98 (s, 3H), 3.75-3.65 (m , 1H), 3.58-3.35 (m, 3H), 3.04-2.98 (m, 1H), 2.81-2.78 (m, 1H), 2.70-2.36 (m, 2H), 2.32-2.05 (m, 5H), 1.97-1.82 (m, 2H).

[2008] Example 241: (2S)-1-[2-[(3S)-3-[(6-fluoro-5-quinolyl)amino]pyrrolidin-1-yl]acetyl]pyrrolidin-2-carbonitrile

[2009] The title compound (12.8 mg, 30.1%) was prepared in the same manner as Example 5 except that instead of (S)-N-(pyrrolidin-3-yl)quinoline- 4-amine hydrochloride (S)-6-fluoro-N-(pyrrolidin-3-yl)quinolin-5-amine hydrochloride (36.5 mg, 0.12 mmol) prepared in Reference Example 122 was used. ¹ H-NMR (CDCl ₃ , 400 MHz) δ 8.86-8.83 (m, 1H), 8.55-8.42 (m, 1H), 7.70-7.63 (m, 1H), 7.48 -7.38 (m, 2H), 5.03-4.76 (m, 1H), 4.65-4.17 (m, 2H), 3.73-3.64 (m, 1H), 3 .58-3.37 (m, 3H), 3.16-3.09 (m, 1H), 2.94-2.81 (m, 1H), 2.59-2.47 (m, 1H) , 2.38-2.11 (m, 6H), 2.02-1.83 (m, 1H).

[2010] Example 242. (2S)-1-[2-[(3S)-3-[(8-methyl-5-quinolyl)amino]pyrrolidin-1-yl]acetyl]pyrrolidin-2-carbonitrile

[2011] The title compound (15.6 mg, 37.2%) was prepared in the same manner as Example 5 except that instead of (S)-N-(pyrrolidin-3-yl)quinoline- 4-amine hydrochloride (S)-8-methyl-N-(pyrrolidin-3-yl)quinolin-5-amine hydrochloride (36.0 mg, 0.12 mmol) prepared in reference example 123 was used. ¹ H-NMR (CDCl ₃ , 400 MHz) δ 8.91 (s, 1H), 8.34-8.26 (m, 1H), 7.40-7.33 (m, 2H), 6.51-6.47 (m, 1H), 5.03-4.74 (m, 2H), 4.22-4.14 (m, 1H), 3.69-3.28 (m, 4H), 3.10-3 .05 (m, 1H), 2.94-2.92 (m, 1H), 2.76-2.63 (m, 4H), 2.47-1.91 (m, 7H)

[2012] Example 243. (2S)-1-[2-[(3S)-3-[(8-methoxy-5-quinolyl)amino]pyrrolidin-1-yl]acetyl]pyrrolidin-2-carbonitrile

[2013] The title compound (3.7 mg, 8.5%) was prepared in the same manner as Example 5 except that instead of (S)-N-(pyrrolidin-3-yl)quinoline- 4-amine hydrochloride (S)-8-methoxy-N-(pyrrolidin-3-yl)quinolin-5-amine hydrochloride (37.9 mg, 0.12 mmol) prepared in Reference Example 124 was used. ¹ H-NMR ( _CDCl3 , 400 MHz) δ 8.93 (s, 1H), 8.34-8.27 (m, 1H), 7.43-7.40 (m, 1H), 6.95 (d, 1H ), 6.55-6.50 (m, 1H), 4.86-4.77 (m, 1H), 4.20-4.13 (m, 1H), 4.02 (s, 3H), 3.69-3.32 (m, 4H), 3.14-3.11 (m, 1H), 2.95-2.92 (m, 1H), 2.79-2.68 (m, 1H ), 2.43-1.83 (m, 8H)

[2014] Example 244: (2S)-1-[2-[(3S)-3-[(8-fluoro-5-quinolyl)amino]pyrrolidin-1-yl]acetyl]pyrrolidin-2-carbonitrile

[2015] The title compound (1.9 mg, 4.3%) was prepared in the same manner as Example 5 except that instead of (S)-N-(pyrrolidin-3-yl)quinoline-4 -amine hydrochloride (S)-8-fluoro-N-(pyrrolidin-3-yl)quinolin-5-amine hydrochloride (36.5 mg, 0.12 mmol) obtained in Reference Example 125 was used. ¹ H-NMR ( CDCl ₃ , 400 MHz) δ 8.93 (s, 1H), 8.42-8.29 (m, 1H), 7.44-7.41 (m, 1H), 7.29-7.24 ( m, 1H), 6.46-6.41 (m, 1H), 4.79-4.77 (m, 1H), 4.17 (s, 1H), 3.74-3.31 (m, 1H), 4H), 3.31-3.11 (m, 2H), 3.03-2.95 (m, 1H), 2.78-2.73 (m, 1H), 2.49-1.92 ( m, 7N)

[2016] Example 245

[2017] The title compound (9.9 mg, 20.4%) was prepared in the same manner as Example 5 except that instead of (S)-N-(pyrrolidin-3-yl)quinoline- 4-amine hydrochloride (S)-N-(pyrrolidin-3-yl)-8-(trifluoromethyl)quinoline-5-amine hydrochloride (42.5 mg, 0.12 mmol) prepared in Reference Example 126 was used. ¹ H -NMR (CDCl ₃ , 400 MHz) δ 8.99 (d, 1H), 8.51-8.31 (m, 1H), 7.89-7.86 (m, 1H), 7.44-7 .38 (m, 1H), 6.49-6.45 (m, 1H), 6.37 (d, 0.6H), 6.65 (d, 0.4H), 4.78-4.69 (m, 1H), 4.25-4.19 (m, 1H), 3.68-3.41 (m, 3H), 3.28-2.98 (m, 3H), 2.79-2 .71 (m, 1H), 2.49-1.92 (m, 7H)

[2018] Example 246

[2019] The title compound (23.6 mg, 46.9%) was prepared in the same manner as Example 5 except that instead of (S)-N-(pyrrolidin-3-yl)quinoline- 4-amine hydrochloride (S)-N-(pyrrolidin-3-yl)-8-(trifluoromethoxy)quinoline-5-amine hydrochloride (44.4 mg, 0.12 mmol) prepared in Reference Example 127 was used. ¹ H -NMR (CDCl ₃ , 400 MHz) δ 8.97-8.95 (m, 1H), 8.45-8.30 (m, 1H), 7.46 (d, 1H), 7.42-7 .38 (m, 1H), 6.43 (t, 1H), 5.76 (d, 0.6H), 5.25 (d, 0.4H), 4.76 (s, 1H), 4. 17 (s, 1H), 3.63-3.24 (m, 3H), 3.13-2.95 (m, 3H), 2.77-2.66 (m, 1H), 2.47- 1.92 (m, 7N)

[2020] Example 247 5-[(3S)-1-[2-oxo-2-[(2S)-2-cyanopyrrolidin-1-yl]ethyl]pyrrolidin-3-yl]amino]quinoline-8-carbonitrile

[2021] The title compound (1.2 mg, 2.8%) was prepared in the same manner as Example 5 except instead of (S)-N-(pyrrolidin-3-yl)quinoline-4 -amine hydrochloride (S)-5-(pyrrolidin-3-ylamino)quinoline-8-carbonitrile hydrochloride (37.3 mg, 0.12 mmol) obtained in reference example 128 was used. ¹ H-NMR (CDCl ₃ , 400 MHz) δ 9.02-9.00 (m, 1H), 8.62-8.34 (m, 1H), 7.92 (t, 1H), 7.14 (d, 1H), 6.51 -6.48 (m, 1H), 4.80-4.67 (m, 1H), 4.26-4.22 (m, 1H), 3.75-3.43 (m, 4H), 3 .31-3.14 (m, 3H), 2.85-2.80 (m, 1H), 2.44-2.01 (m, 7H)

[2022] Example 248

[2023] The title compound (19.5 mg, 29.3%) was prepared in the same manner as Example 5 except that instead of (S)-N-(pyrrolidin-3-yl)quinoline- 4-amine hydrochloride (S)-8-(benzyloxy)-N-(pyrrolidin-3-yl)quinolin-5-amine hydrochloride (47.1 mg, 0.12 mmol) prepared in Reference Example 129 was used. ¹ H -NMR (CDCl ₃ , 400 MHz) δ 8.95 (s, 1H), 8.33-8.26 (m, 1H), 7.50 (d, 2H), 7.41-7.33 (m , 3H), 7.29-7.26 (m, 1H), 6.91 (d, 1H), 6.42-6.37 (m, 1H), 5.35 (s, 2H), 4, 82-4.73 (m, 1H), 4.08 (s, 1H), 3.61-3.60 (m, 1H), 3.50-3.27 (m, 3H), 3.05- 3.01 (m, 1.6 N), 2.89-2.86 (m, 1H), 2.72-2.61 (m, 1H), 2.42-1.86 (m, 7. 4 N)

[2024] Example 249

[2025] The title compound (10.2 mg, 26.6%) was prepared in the same manner as Example 28 except (S)-N-(pyrrolidin-3-yl)quinoline-4- amine hydrochloride (25.6 mg, 0.12 mmol) obtained in Reference Example 5 was used in place of (S)-N-(pyrrolidin-3-yl)furo[3,2-c]pyridin-7-amine hydrochloride. ^1H NMR ( _MeOD4 , 400 MHz) δ 8.40 (d, 1H), 7.80 (d, 1H), 7.67 (d, 1H), 7.43-7.38 (m, 2H) , 7.12 (s, 1H), 5.49-4.96 (m, 2H), 4.17-3.73 (m, 3H), 3.61-3.37 (m, 2H), 3 ,10-2.91 (m, 2H), 2.74-2.35 (m, 5H), 1.84-1.76 (m, 1H).

[2026] Example 250

[2027] The title compound (4.9 mg, 12.8%) was prepared in the same manner as Example 28 except that instead of (S)-N-(pyrrolidin-3-yl)furo[3 ,2-c]pyridin-7-amine hydrochloride (S)-N-(pyrrolidin-3-yl)quinolin-6-amine hydrochloride (25.6 mg, 0.12 mmol) prepared in Reference Example 111 was used. ¹ H-NMR ( _CDCl3 , 400 MHz) δ 8.60 (d, 1H), 7.91-7.84 (m, 2H), 7.27-7.25 (m, 1H), 7.09 ( t, 1H), 6.63 (s, 1H), 5.46-5.13 (m, 1H), 5.15-4.90 (m, 1H), 4.59-4.47 (m, 1H), 4.17-3.66 (m, 3H), 3.52-3.32 (m, 2H), 3.10-2.99 (m, 1H), 2.88-2.61 ( m, 3H), 2.48-2.21 (m, 3H), 1.88-1.81 (m, 1H).

[2028] Example 251

[2029] The title compound (12.2 mg, 31.6%) was prepared in the same manner as in Example 28 except that instead of (S)-N-(pyrrolidin-3-yl)furo[ 3,2-c]pyridin-7-amine hydrochloride (S)-N-(pyrrolidin-3-yl)quinolin-7-amine hydrochloride (25.6 mg, 0.12 mmol) prepared in Reference Example 130 was used. ^1H NMR ( _MeOD4 , 400 MHz) δ 8.56 (s, 1H), 8.07 (d, 1H), 7.62 (d, 1H), 7.16-7.13 (m, 1H) , 7.05 (d, 1H), 6.84 (s, 1H), 5.49-4.95 (m, 2H), 4.19-3.71 (m, 3H), 3.59-3 .37 (m, 2H), 3.05-2.95 (m, 2H), 2.81-2.35 (m, 5H), 1.87-1.78 (m, 1H).

[2030] Example 252 5-[(3S)-1-[2-oxo-2-[(2S,4S)-2-cyano-4-fluoropyrrolidin-1-yl]ethyl]pyrrolidin-3-yl]amino ]quinoline-2-carbonitrile

[2031] The title compound (3.8 mg, 9.2%) was prepared in the same manner as in Example 28 except that instead of (S)-N-(pyrrolidin-3-yl)furo[ 3,2-c]pyridin-7-amine hydrochloride (S)-5-(pyrrolidin-3-ylamino)quinoline-2-carbonitrile (37.3 mg, 0.12 mmol) prepared in Reference Example ¹¹² was used. H NMR ( _MeOD4 , 400 MHz) δ 8.77-8.71 (m, 1H), 7.72-7.64 (m, 2H), 7.34 (d, 1H), 6.73 (d , 1H), 5.49-4.99 (m, 2H), 4.20-3.73 (m, 3H), 3.66-3.40 (m, 2H), 3.05-2.87 (m, 3H), 2.70-2.39 (m, 4H), 1.94-1.86 (m, 1H).

[2032] Example 253 5-[(3S)-1-[2-oxo-2-[(2S,4S)-2-cyano-4-fluoropyrrolidin-1-yl]ethyl]pyrrolidin-3-yl]amino ]quinoline-3-carbonitrile

[2033] The title compound (4.4 mg, 10.7%) was prepared in the same manner as Example 28 except that instead of (S)-N-(pyrrolidin-3-yl)furo[3 ,2-c]pyridin-7-amine hydrochloride (S)-5-(pyrrolidin-3-ylamino)quinoline-3-carbonitrile hydrochloride (37.3 mg, 0.12 mmol) prepared in Reference Example ¹¹³ was used. H NMR ( _MeOD4 , 400 MHz) δ 9.12 (d, 1H), 8.92 (s, 1H), 7.73 (t, 1H), 7.33 (d, 1H), 6.74 ( d, 1H), 5.52-4.99 (m, 2H), 4.30-3.74 (m, 3H), 3.66-3.42 (m, 2H), 3.11-2, 89 (m, 3H), 2.70-2.37 (m, 4H), 1.97-1.89 (m, 1H).

[2034] Example 254. (2S,4S)-4-fluoro-1-[2-[(3S)-3-[(3-methoxy-5-quinolyl)amino]pyrrolidin-1-yl]acetyl]pyrrolidin- 2-carbonitrile

[2035] The title compound (2.3 mg, 5.4%) was prepared in the same manner as Example 28 except that instead of (S)-N-(pyrrolidin-3-yl)furo[ 3,2-c]pyridin-7-amine hydrochloride (S)-3-methoxy-N-(pyrrolidin-3-yl)quinolin-5-amine hydrochloride (37.9 mg, 0.12 mmol) obtained in reference example 114. ^1H NMR ( _MeOD4 , 400 MHz) δ 8.51 (s, 1H), 7.97 (t, 1H), 7.43-7.28 (m, 2H), 6.76- 6.68 (m, 1H), 5.50-4.99 (m, 2H), 4.30-3.92 (m, 5H), 3.82-3.42 (m, 4H), 3. 14-2.91 (m, 2H), 2.70-2.31 (m, 4H), 2.23-1.92 (m, 1H).

[2036] Example 255 2-carbonitrile

[2037] The title compound (4.7 mg, 11.7%) was prepared in the same manner as Example 28 except that instead of (S)-N-(pyrrolidin-3-yl)furo[ 3,2-c]pyridin-7-amine hydrochloride (S)-3-fluoro-N-(pyrrolidin-3-yl)quinolin-5-amine hydrochloride (36.5 mg, 0.12 mmol) prepared in reference example 115. ^1H NMR ( _MeOD4 , 400 MHz) δ 8.70 (d, 1H), 8.39-8.32 (m, 1H), 7.51 (t, 1H), 7.34 ( d, 1H), 6.64 (d, 1H), 5.49-4.97 (m, 2H), 4.23-4.15 (m, 1H), 4.05-3.38 (m, 4H), 3.07-2.85 (m, 3H), 2.67-2.35 (m, 4H), 1.92-1.85 (m, 1H).

[2038] Example 256 2-carbonitrile

[2039] The title compound (4.9 mg, 11.8%) was prepared in the same manner as Example 28 except that instead of (S)-N-(pyrrolidin-3-yl)furo[ 3,2-c]pyridin-7-amine hydrochloride (S)-3-chloro-N-(pyrrolidin-3-yl)quinolin-5-amine hydrochloride (38.4 mg, 0.12 mmol) obtained in reference example 116. ^1H NMR ( _MeOD4 , 400 MHz) δ 8.69-8.67 (m, 2H), 7.55 (t, 1H), 7.29 (d, 1H), 6.64 ( d, 1H), 5.49-4.97 (m, 2H), 4.23-4.15 (m, 1H), 4.05-3.71 (m, 2H), 3.63-3, 38 (m, 2H), 3.08-2.89 (m, 3H), 2.66-2.36 (m, 4H), 1.90-1.87 (m, 1H).

[2040] Example 257. (2S,4S)-4-fluoro-1-[2-[(3S)-3-[(7-methoxy-5-quinolyl)amino]pyrrolidin-1-yl]acetyl]pyrrolidin- 2-carbonitrile

[2041] The title compound (3.0 mg, 7.2%) was prepared in the same manner as Example 28 except that instead of (S)-N-(pyrrolidin-3-yl)furo[ 3,2-c]pyridin-7-amine hydrochloride (S)-7-methoxy-N-(pyrrolidin-3-yl)quinolin-5-amine hydrochloride (37.9 mg, 0.12 mmol) obtained in reference example 118. ^1H NMR ( _MeOD4 , 400 MHz) δ 8.60 (d, 1H), 8.48-8.42 (m, 1H), 7.24 (q, 1H), 6.70 ( s, 1H), 6.19 (s, 1H), 5.49-4.95 (m, 2H), 4.13-4.09 (m, 1H), 4.00-3.91 (dd, 1H), 3.89 (s, 3H), 3.81-3.66 (m, 1H), 3.61-3.36 (m, 2H), 3.04-2.88 (m, 3H) , 2.60-2.32 (m, 4H), 1.88-1.85 (m, 1H).

[2042] Example 258 (2S,4S)-4-fluoro-1-[2-[(3S)-3-[[7-(trifluoromethyl)-5-quinolyl]amino]pyrrolidin-1-yl]acetyl] pyrrolidine-2-carbonitrile

[2043] The title compound (3.5 mg, 7.7%) was prepared in the same manner as Example 28 except that instead of (S)-N-(pyrrolidin-3-yl)furo[ 3,2-c]pyridin-7-amine hydrochloride (S)-N-(pyrrolidin-3-yl)-7-(trifluoromethyl)quinoline-5-amine hydrochloride (42.5 mg, 0.12 mmol) was used. obtained in reference example 119. ^1H NMR ( _MeOD4 , 400 MHz) δ 8.87 (d, 1H), 8.74-8.67 (m, 1H), 7.58-7.55 (m, 2H ), 6.68 (s, 1H), 5.51-4.99 (m, 2H), 4.29-4.24 (m, 1H), 4.07-3.98 (dd, 1H), 3.85-3.73(m, 1H), 3.68-3.42 (m, 2H), 3.12-2.92 (m, 3H), 2.71-2.37 (m, 4H ), 1.97-1.90 (m, 1H).

[2044] Example 259 2-carbonitrile

[2045] The title compound (5.3 mg, 13.3%) was prepared in the same manner as Example 28 except that instead of (S)-N-(pyrrolidin-3-yl)furo[3 ,2-c]pyridin-7-amine hydrochloride (S)-6-methyl-N-(pyrrolidin-3-yl)quinolin-5-amine hydrochloride (36.0 mg, 0.12 mmol) prepared in the reference example 120. ¹ H NMR (MeOD ₄ , 400 MHz) δ 8.71 (d, 1H), 8.67-8.61 (m, 1H), 7.57 (sq, 2H), 7.48 (sq , 1H), 5.49-4.96 (m, 2H), 4.08-3.99 (m, 2H), 3.83-3.71 (m, 1H), 3.59-3.42 (m, 1H), 3.32-3.28 (m, 1H), 3.12-3.05 (m, 1H), 2.86-2.80 (m, 1H), 2.70-2 .32 (m, 7H), 2.25-2.16 (m, 1H), 1.92-1.81 (m, 1H).

[2046] Example 260: (2S,4S)-4-fluoro-1-[2-[(3S)-3-[(6-methoxy-5-quinolyl)amino]pyrrolidin-1-yl]acetyl]pyrrolidin- 2-carbonitrile

[2047] The title compound (2.5 mg, 5.9%) was prepared in the same manner as Example 28 except that instead of (S)-N-(pyrrolidin-3-yl)furo[ 3,2-c]pyridin-7-amine hydrochloride (S)-6-methoxy-N-(pyrrolidin-3-yl)quinolin-5-amine hydrochloride (37.9 mg, 0.12 mmol) obtained in reference example 121. ^1H NMR ( _MeOD4 , 400 MHz) δ 8.67 (d, 1H), 8.58-8.53 (m, 1H), 7.70 (d, 1H), 7.65- 7.62 (m, 1H), 7.45 (dd, 1H), 5.49-4.96 (m, 2H), 4.12-4.00 (m, 5H), 3.87-3, 75 (m, 1H), 3.62-3.32 (m, 2H), 3.04-2.99 (m, 1H), 2.85-2.36 (m, 5H), 2.23- 2.09 (m, 1H), 1.95-1.76 (m, 1H).

[2048] Example 261 2-carbonitrile

[2049] The title compound (4.6 mg, 11.3%) was prepared in the same manner as Example 28 except that instead of (S)-N-(pyrrolidin-3-yl)furo[ 3,2-c]pyridin-7-amine hydrochloride (S)-6-fluoro-N-(pyrrolidin-3-yl)quinolin-5-amine hydrochloride (36.5 mg, 0.12 mmol) obtained in reference example 122. ¹ H NMR (MeOD ₄ , 400 MHz) δ 8.75-8.64 (m, 2H), 7.54-7.50 (m, 3H), 5.49-4.98 (m , 2H), 4.35 (br. s, 1H), 4.06-3.72 (m, 2H), 3.61-3.32 (m, 2H), 3.12-3.06 (m , 1H), 2.95-2.68 (m, 2H), 2.64-2.19 (m, 4H), 1.94-1.82 (m, 1H).

[2050] Example 262 2-carbonitrile

[2051] The title compound (8.6 mg, 21.6%) was prepared in the same manner as Example 28 except that instead of (S)-N-(pyrrolidin-3-yl)furo[ 3,2-c]pyridin-7-amine hydrochloride (S)-8-methyl-N-(pyrrolidin-3-yl)quinolin-5-amine hydrochloride (36.0 mg, 0.12 mmol) obtained in reference example 123. ¹ H NMR (MeOD ₄ , 400 MHz) δ 8.78 (s, 1 H), 8.60-8.58 (m, 1 H), 7.41 (br. s, 2 H) , 6.56 (d, 1 N), 5.49-4.96 (m, 2 N), 4.17 (br. s, 1 N), 4.06-3.71 (m, 2 N) , 3.58-3.38 (m, 2 N), 3.00-2.88 (m, 3 N), 2.64-2.39 (m, 7 N), 1.94-1.84 (m, 1 N).

[2052] Example 263 2-carbonitrile

[2053] The title compound (11.5 mg, 27.6%) was prepared in the same manner as Example 28 except that instead of (S)-N-(pyrrolidin-3-yl)furo[ 3,2-c]pyridin-7-amine hydrochloride (S)-8-methoxy-N-(pyrrolidin-3-yl)quinolin-5-amine hydrochloride (37.9 mg, 0.12 mmol) obtained in reference example 124. ¹ H-NMR (CDCl ₃ , 400 MHz) δ 8.93 (s, 1 H), 8.29 (d, 1 H), 7.43-7.40 (m, 1 H), 6.95 (d, 1 N), 6.52 (dd, 1 N), 5.49-4.95 (m, 2 N), 4.19-3.67 (m, 6 N), 3. 55-3.36 (m, 2 N), 3.17-2.89 (m, 2 N), 2.77-2.61 (m, 2 N), 2.52-2.13 (m, 3 N), 2.05-1.86 (m, 2 N).

[2054] Example 264: (2S,4S)-4-fluoro-1-[2-[(3S)-3-[(8-fluoro-5-quinolyl)amino]pyrrolidin-1-yl]acetyl]pyrrolidin- 2-carbonitrile

[2055] The title compound (1.8 mg, 4.5%) was prepared in the same manner as Iv

Example 28, except that (S)-8-fluoro-N-(pyrrolidin- 3-yl)quinolin-5-amine hydrochloride (36.5 mg, 0.12 mmol) obtained from reference example 125. ¹ H NMR (MeOD ₄ , 400 MHz) δ 8.82 (d, 1 H), 8 .69-8.63 (m, 1 N), 7.54 (dd, 1 N), 7.33 (t, 1 N), 6.57 (dd, 1 N), 5.50-5.38 (m, 1 N), 5.32-4.98 (m, 1 N), 4.24-4.17 (m, 1 N), 4.14-3.99 (m, 1 N), 3 .86-3.73 (m, 1 N), 3.67-3.44 (m, 2 N), 3.09-2.88 (m, 3 N), 2.75-2.33 (m , 4 N), 1.93-1.88 (m, 1 N).

[2056] Example 265: (2S,4S)-4-fluoro-1-[2-[(3S)-3-[[8-(trifluoromethyl)-5-quinolyl]amino]pyrrolidin-1-yl]acetyl] pyrrolidine-2-carbonitrile

[2057] The title compound (3.9 mg, 8.6%) was prepared in the same manner as Example 28 except that instead of (S)-N-(pyrrolidin-3-yl)furo[ 3,2-c]pyridin-7-amine hydrochloride (S)-N-(pyrrolidin-3-yl)-8-(trifluoromethyl)quinoline-5-amine hydrochloride (42.5 mg, 0.12 mmol) was used. obtained in example 126. ¹ H NMR (MeOD ₄ , 400 MHz) δ 8.85 (d, 1 H), 8.69-8.62 (m, 1 N), 7.88 (d, 1 H), 7.49 (dd, 1 N), 6.58 (d, 1 N), 5.49-4.98 (m, 2 N), 4.24 (br. s, 1 N), 4.06- 3.97 (m, 1 N), 3.83-3.40 (m, 3 N), 3.09-2.90 (m, 3 N), 2.68-2.36 (m, 4 N ), 1.98-1.88 (m, 1 N).

[2058] Example 266 (2S,4S)-4-fluoro-1-[2-[(3S)-3-[[8-(trifluoromethoxy)-5-quinolyl]amino]pyrrolidin-1-yl]acetyl] pyrrolidine-2-carbonitrile

[2059] The title compound (5.5 mg, 11.7%) was prepared in the same manner as Example 28 except that instead of (S)-N-(pyrrolidin-3-yl)furo[ 3,2-c]pyridin-7-amine hydrochloride (S)-N-(pyrroldin-3-yl)-8-(trifluoromethoxy)quinoline-5-amine hydrochloride (44.4 mg, 0.12 mmol) was used. obtained in example 127. ¹ H NMR (MeOD ₄ , 400 MHz) δ 8.84 (d, 1 H), 8.69-8.63 (m, 1 H), 7.53-7.50 (m, 2 N), 6.56 (d, 1 N), 5.49-5.37 (m, 1 N), 5.30-4.98 (m, 1 N), 4.19 (br. s, 1 N), 4.06-3.97 (m, 1 N), 3.83-3.72 (m, 1 N), 3.66-3.40 (m, 2 N), 3.08- 2.88 (m, 3 N), 2.69-2.36 (m, 4 N), 1.91-1.88 (m, 1 N).

[2060] Example 267 5-[(3S)-1-[2-oxo-2-[(2S,4S)-2-cyano-4-fluoropyrrolidin-1-yl]ethyl]pyrrolidin-3-yl]amino ]quinoline-8-carbonitrile

[2061] The title compound (2.6 mg, 6.3%) was prepared in the same manner as Example 28 except that instead of (S)-N-(pyrrolidin-3-yl)furo[ 3,2-c]pyridin-7-amine hydrochloride (S)-5-(pyrrolidin-3-ylamino)quinoline-8-carbonitrile hydrochloride (37.3 mg, 0.12 mmol) prepared in Reference Example 128 was used. ^1H NMR ( _MeOD4 , 400 MHz) δ 8.89 (d, 1 H), 8.77-8.69 (m, 1 H), 7.98 (d, 1 H), 7.53 (dd , 1 N), 6.68 (d, 1 N), 5.50-5.38 (m, 1 N), 5.31-5.00 (m, 1 N), 4.38-4.30 (m, 1 N), 4.09-4.00 (m, 1 N), 3.86-3.43 (m, 3 N), 3.13-2.92 (m, 3 N), 2 .72-2.41 (m, 4 N), 2.02-1.96 (m, 1 N).

[2062] Example 268: (2S,4S)-4-fluoro-1-[2-[(3S)-3-[(8-benzyloxy-5-quinolyl)amino]pyrrolidin-1-yl]acetyl]pyrrolidin- 2-carbonitrile

[2063] The title compound (3.2 mg, 6.4%) was prepared in the same manner as Example 28 except that instead of (S)-N-(pyrrolidin-3-yl)furo[ 3,2-c]pyridin-7-amine hydrochloride (S)-8-(benzyloxy)-N-(pyrrolidin-3-yl)quinolin-5-amine hydrochloride (47.1 mg, 0.12 mmol) was used. obtained in reference example 129. ^1H NMR ( _MeOD4 , 400 MHz) δ 8.78 (d, 1 N), 8.58-8.53 (m, 1 N), 7.51-7.45 (m , 3 N), 7.35-7.25 (m, 3 N), 7.03 (d, 1 N), 6.47 (d, 1 N), 5.49-5.25 (m, 3 ,2 N), 4.95-4.93 (m, 0.8 N), 4.04-3.64 (m, 3 N), 3.58-3.29 (m, 2 N), 2 .97-2.80 (m, 3 N), 2.58-2.28 (m, 4 N), 1.87-1.80 (m, 1 N).

[2064] Example 269 2-carbonitrile

[2065] The title compound (7.2 mg, 15.9%) was prepared in the same manner as Example 28 except that instead of (S)-N-(pyrroldin-3-yl)furo[ 3,2-c]pyridin-7-amine hydrochloride (S)-7-fluoro-N-(pyrrolidin-3-yl)quinolin-5-amine hydrochloride (36.5 mg, 0.12 mmol) obtained in reference example 117. ¹ H NMR (CDCl ₃ , 400 MHz) δ 8.79 (t, 1 Η), 8.30-8.22 (m, 1 Η), 7.26-7.23 (m, 1 Η), 7.04-7.00 (m, 1 Η), 6.28 (m, 1 Η), 5.71-5.46 (m, 1 Η), 5.38-5.25 (m , 1 Η), 4.89 (t, 1 Η), 4.15-3.44 (m, 3 Η), 3.34-3.26 (m, 1 Η), 3.17-2.94 (m, 2 Η), 2.73-2.22 (m, 6 Η), 2.03-1.91 (m, 1 Η).

[2066] Example 270

[2067] The title compound (12.2 mg, 24.3%) was prepared in the same manner as Example 5 except that instead of (S)-N-(pyrrolidin-3-yl)quinoline- 4-amine hydrochloride (S)-N-(pyrrolidin-3-yl)-8-(trifluoromethyl)quinoline-4-amine hydrochloride (42.5 mg, 0.12 mmol) prepared in Reference Example 131 was used. ¹ H NMR ( _CDCl3 , 400 MHz) δ 8.68 (t, 1 H), 8.18 (dd, 1 H), 8.00 (t, 1 H), 7.47 (t, 1 H), 6 .45 (t, 1 N), 6.21 (dd, 1 N), 5.52-5.30 (m, 1 N), 4.93 (dd, 1 N), 4.26-3.54 (m, 4 N), 3.45-3.02 (m, 3.5 N), 2.78-2.26 (m, 4.5 N), 2.10-1.88 (m, 1 N).

[2068] Example 271 (2S,4S)-4-fluoro-1-[2-[(3S)-3-[[8-(trifluoromethyl)-4-quinolyl]amino]pyrrolidin-1-yl]acetyl] pyrrolidine-2-carbonitrile

[2069] The title compound (8.0 mg, 15.4%) was prepared in the same manner as Example 28 except that instead of (S)-N-(pyrrolidin-3-yl)furo[ 3,2-c]pyridin-7-amine hydrochloride (S)-N-(pyrroldin-3-yl)-8-(trifluoromethyl)quinoline-4-amine hydrochloride (42.5 mg, 0.12 mmol) was used. obtained in reference example 131. ^1H NMR ( _CDCl3 , 400 MHz) δ 8.68 (t, 1 Η), 8.22 (dd, 1 Η), 8.00 (t, 1 Η), 7.47 (dd, 1 Η), 6.47 (t, 1 Η), 6.42 (dd, 1 Η), 4.82-4.69 (m, 1 Η), 4.24 (d, 1 Η) , 3.66-3.45 (m, 3 Η), 3.30-3.01 (m, 3 Η), 2.82-2.76 (m, 1 Η), 2.50-2.13 (m, 5 Η), 2.06-1.99 (m, 1 Η).

[2070] Example 272 -carbonitrile

[2071] The title compound (67.7 mg, 26.6%) was prepared in the same manner as Example 28 except that instead of (S)-N-(pyrrolidin-3-yl)furo[ 3,2-c]pyridin-7-amine hydrochloride (S)-N-(pyrrolidin-3-yl)-1,8-naphthyridin-3-amine hydrochloride (196.7 mg, 0.69 mmol) was used, obtained in reference example 132. ¹ H-NMR (CDCl ₃ , 600 MHz) δ 8.79 (d, 1 H), 8.62 (s, 1 H), 7.96 (d, 1 H), 7.35 (t, 1 N), 6.90 (s, 1 N), 5.50-5.30 (m, 1 N), 5.10-4.70 (m, 1 N), 4.20-4 .05 (m, 1 N), 3.95-3.70 (m, 2 N), 3.60-3.35 (m, 2 N), 3.15-3.00 (m, 2 N) , 2.90-2.65 (m, 3 N), 2.50-2.25 (m, 3 N), 1.95-1.80 (m, 1 N)

[2072] Example 273 (2S,4S)-4-fluoro-1-[2-[(3S)-3-[(7-chloro-1,8-naphthyridin-3-yl)amino]pyrrolidin-1- yl]acetyl]pyrrolidine-2-carbonitrile

[2073] The title compound (10.1 mg, 5.2%) was prepared in the same manner as Example 28 except that instead of (S)-N-(pyrrolidin-3-yl)furo[ 3,2-c]pyridin-7-amine hydrochloride (S)-7-chloro-N-(pyrrolidin-3-yl)-1,8-naphthyridin-3-amine hydrochloride (155.6 mg, 0.48 mmol) obtained in reference example 13S. ¹ H-NMR (CDCl ₃ , 600 MHz) δ 8.58 (s, 1 H), 7.90 (d, 1 H), 7.34 (d, 1 H), 6.90 (s, 1 H ), 5.50-5.30 (m, 1 N), 5.10-4.90 (m, 1 N), 4.20-4.00 (m, 2 N), 4.00-3, 65 (m, 1 N), 3.60-3.30 (m, 2 N), 3.20-3.00 (m, 2 N), 2.90-2.60 (m, 3 N), 2.50-2.25 (m, 3 N), 1.95-1.80 (m, 1 N)

[2074] Example 274 (2S)-1-[2-[(3S)-3-[(8-ethoxy-5-quinolyl)amino]pyrrolidin-1-yl]acetyl]pyrrolidin-2-carbonitrile

[2075] The title compound (3.4 mg, 7.5%) was prepared in the same manner as Example 5 except that instead of (S)-N-(pyrrolidin-3-yl)quinoline- 4-amine hydrochloride (S)-8-ethoxy-N-(pyrrolidin-3-yl)quinolin-5-amine hydrochloride (39.6 mg, 0.12 mmol) obtained in reference example 134 was used. ¹ H NMR ( CDCl ₃ , 400 MHz) δ 8.93-8.91 (m, 1 N), 8.31-8.24 (m, 1 N), 7.39-7.35 (m, 1 N), 6 .94 (d, 1 N), 6.49 (dd, 1 N), 4.85-4.72 (m, 1 N), 4.66^1.45 (m, 1 N), 4.23 (sq, 2 N), 4.13-4.09 (m, 1 N), 3.65-3.28 (m, 4 N), 3.09-2.99 (m, 1 N), 2 .89-2.86 (m, 1 N), 2.75-2.63 (m, 1 N), 2.45-1.83 (m, 7 N), 1.56 (t, 3 N) .

[2076] Example 275: (2S,4S)-4-fluoro-1-[2-[(3S)-3-[(8-ethoxy-5-quinolyl)amino]pyrrolidin-1-yl]acetyl]pyrrolidin- 2-carbonitrile

[2077] The title compound (3.5 mg, 8.0%) was prepared in the same manner as Example 28 except that instead of (S)-N-(pyrrolidin-3-yl)furo[3 ,2-c]pyridin-7-amine hydrochloride (S)-8-ethoxy-N-(pyrrolidin-3-yl)quinolin-5-amine hydrochloride (39.6 mg, 0.12 mmol) prepared in the reference example 134. ¹ H NMR (CDCl ₃ , 400 MHz) δ 8.90 (t, 1 Η), 8.26 (d, 1 Η), 7.37-7.33 (m, 1 Η), 6, 93 (d, 1 Η), 6.46 (dd, 1 Η), 5.41-5.17 (m, 1 Η), 5.07-4.84 (m, 1 Η), 4.54- 4.39 (m, 1 Η), 4.20 (sq, 2 Η), 4.13-3.99 (m, 1.5 Η), 3.89-3.58 (m, 1.5 Η ), 3.50-3.25 (m, 2 Η), 3.09-2.81 (m, 2 Η), 2.72-2.08 (m, 5 Η), 1.98-1, 80 (m, 1 Η), 1.54 (td, 3 N).

[2078] Example 276 2-carbonitrile

[2079] The title compound (2.5 mg, 5.4%) was prepared in the same manner as Example 28 except that instead of (S)-N-(pyrrolidin-3-yl)furo[ 3,2-c]pyridin-7-amine hydrochloride (S)-5-(pyrrolidin-3-ylamino)quinolin-8-ol hydrochloride (36.2 mg, 0.12 mmol) prepared in Reference Example 135 was used. ¹ H NMR (CDCl ₃ , 400 MHz) δ 8.78 (s, 1 H), 8.31 (d, 1 H), 7.69 (br. s, 1 H), 7.42 (dd, 1 N), 7.06 (d, 1 N), 6.53 (dd, 1 N), 5.50-5.24 (m, 1 N), 5.07-4.95 (m, 1 N) , 4.19-4.11 (m, 2 N), 3.96-3.69 (m, 2 N), 3.56-3.34 (m, 2 N), 3.50-3.25 (m , 2 N), 3.16-2.89 (m, 2 N), 2.76-2.16 (m, 5 N), 2.05-1.87 (m, 1 N).

[2080] Example 277 (2S,4S)-4-fluoro-1-[2-[(3S)-3-[(8-methyl-6-quinolyl)amino]pyrrolidin-1-yl]acetyl]pyrrolidin- 2-carbonitrile

[2081] The title compound (122.9 mg, 40.3%) was prepared in the same manner as Example 28 except that instead of (S)-N-(pyrrolidin-3-yl)furo[ 3,2-c]pyridin-7-amine hydrochloride (S)-8-methyl-N-(pyrrolidin-3-yl)quinolin-6-amine hydrochloride (239.9 mg, 0.80 mmol) obtained in reference example 136. ¹ H-NMR (CDCl ₃ , 600 MHz) δ 8.63 (s, 1 H), 7.88 (d, 1 H), 7.27-7.24 (m, 1 H), 6.95 (d, 1 N), 6.50 (s, 1 N), 5.50-5.25 (m, 1 N), 5.20-4.90 (m, 1 N), 4. 20-4.05 (m, 2 N), 4.00-3.70 (m, 1 N), 3.55-3.30 (m, 2 N), 3.15-3.00 (m, 2 N ), 2.95-2.75 (m, 2 N), 2.71 (s, 3 N), 2.71-2.60 (m, 1 N), 2.50-2.20 (m, 3 N), 1.95-1.80 (m, 1 N)

[2082] Example 278: (2S,4S)-4-fluoro-1-[2-[(3S)-3-[(8-fluoro-6-quinolyl)amino]pyrrolidin-1-yl]acetyl]pyrrolidin- 2-carbonitrile

[2083] The title compound (222.3 mg, 48.9%) was prepared in the same manner as Example 28 except that instead of (S)-N-(pyrrolidin-3-yl)furo[ 3,2-c]pyridin-7-amine hydrochloride (S)-8-fluoro-N-(pyrrolidin-3-yl)quinolin-6-amine hydrochloride (358.9 mg, 1.18 mmol) obtained in reference example 137. ¹ H-NMR (CDCl ₃ , 600 MHz) δ 8.62 (s, 1 H), 7.89 (d, 1 H), 7.29 (d, 1 H), 6.80 ( t, 1 N), 6.44 (s, 1 N), 5.50-5.35 (m, 1 N), 5.10-4.90 (m, 1 N), 4.20-4, 05 (m, 2 N), 3.95-3.70 (m, 1 N), 3.60-3.30 (m, 2 N), 3.15-2.95 (m, 2 N), 2.90-2.60 (m, 3 N), 2.50-2.20 (m, 3 N), 1.90-1.75 (m, 1 N)

[2084] Example 279: (2S,4S)-4-fluoro-1-[2-[(3S)-3-[(8-chloro-6-quinolyl)amino]pyrrolidin-1-yl]acetyl]pyrrolidin- 2-carbonitrile

[2085] The title compound (314.5 mg, 86.0%) was prepared in the same manner as Example 28 except that instead of (S)-N-(pyrrolidin-3-yl)furo[ 3,2-c]pyridin-7-amine hydrochloride (S)-8-chloro-N-(pyrrolidin-3-yl)quinolin-6-amine hydrochloride (291.8 mg, 0.91 mmol) obtained in reference example 138. ¹ H-NMR (CDCl ₃ , 600 MHz) δ 8.68 (s, 1 H), 7.88 (d, 1 H), 7.29-7.22 (m, 2 H), 6.54 (s, 1 N), 5.50-5.25 (m, 1 N), 5.10-4.85 (m, 1 N), 4.20-4.00 (m, 2 N ), 3.95-3.65 (m, 1 N), 3.55-3.25 (m, 2 N), 3.10-2.90 (m, 2 N), 2.90-2, 55 (m, 3 N), 2.45-2.20 (m, 3 N), 1.90-1.75 (m, 1 N)

[2086] Example 280: (2S,4S)-4-fluoro-1-[2-[(3S)-3-[[8-(trifluoromethyl)-6-quinolyl]amino]pyrrolidin-1-yl]acetyl] pyrrolidine-2-carbonitrile

[2087] The title compound (72.1 mg, 27.3%) was prepared in the same manner as Example 28 except that instead of (S)-N-(pyrroldin-3-yl)furo[ 3,2-c]pyridin-7-amine hydrochloride (S)-N-(pyrroldin-3-yl)-8-(trifluoromethyl)quinoline-6-amine hydrochloride (215.7 mg, 0.61 mmol) was used. obtained in reference example 139. ¹ H-NMR (CDCl ₃ , 600 MHz) δ 8.75 (s, 1 H), 7.94 (d, 1 H), 7.45 (d, 1 H), 7. 34 (t, 1 N), 6.77 (s, 1 N), 5.50-5.35 (m, 1 N), 5.10-4.90 (m, 1 N), 4.20- 4.05 (m, 2 N), 3.95-3.65 (m, 1 N), 3.60-3.30 (m, 2 N), 3.15-3.00 (m, 2 N ), 2.90-2.60 (m, 3 N), 2.50-2.20 (m, 3 N), 1.95-1.80 (m, 1 N)

[2088] Example 281 N-methyl-5-[[(3S)-1-[2-oxo-2-[(2S,4S)-2-cyano-4-fluoropyrrolidin-1-yl]ethyl]pyrrolidin- 3-yl]amino]quinoline-8-carboxamide

[2089] The title compound (8.6 mg, 16.9%) was prepared in the same manner as in Example 28 except that instead of (S)-N-(pyrrolidin-3-yl)furo[ 3,2-c]pyridin-7-amine hydrochloride (S)-N-methyl-5-(pyrrolidin-3-ylamino)quinoline-8-carboxamide (41.0 mg, 0.12 mmol) prepared in the reference example 140. ¹ H NMR (CDCl ₃ , 400 MHz) δ 10.95 (t, 1 Η), 8.87-8.85 (m, 1 Η), 8.72 (dd, 1 Η), 8, 42 (dd, 1 Η), 7.41-7.36 (m, 1 Η), 6.61 (dd, 1 Η), 5.93-5.62 (m, 1 Η), 5.53- 5.27 (m, 1 Η), 4.94 (dd, 1 Η), 4.30-4.22 (m, 1 Η), 4.16-4.07 (m, 1 Η), 3, 92-3.69 (m, 2 Η), 3.67-3.38 (m, 2 Η), 3.29-3.03 (m, 6 Η), 2.75-2.63 (m, 2 Η), 2.54-2.20 (m, 1 Η), 2.10-1.95 (m, 1 Η).

[2090] Example 282 N,N-dimethyl-5-[[(3S)-1-[2-oxo-2-[(2S,4S)-2-cyano-4-fluoropyrrolidin-1-yl]ethyl] pyrrolidin-3-yl]amino]quinoline-8-carboxamide

[2091] The title compound (10.0 mg, 19.0%) was prepared in the same manner as in Example 28 except that instead of (S)-N-(pyrrolidin-3-yl)furo[ 3,2-c]pyridin-7-amine hydrochloride (S)-N,N-dimethyl-5-(pyrrolidin-3-ylamino)quinoline-8-carboxamide hydrochloride (42.7 mg, 0.12 mmol) was used. obtained in reference example 141. ¹ H NMR (CDCl ₃ , 400 MHz) δ 8.86-8.84 (m, 1 N), 8.31-8.26 (m, 1 N), 7.46 (d , 1 N), 7.30-7.28 (m, 1 N), 6.49-6.44 (m, 1 N), 5.62-4.80 (m, 3 N), 4.16 -4.14 (m, 1 N), 3.96-3.63 (m, 2 N), 3.60-3.25 (m, 2 N), 3.22 (d, 3 N), 3 .17-2.87 (m, 2 N), 2.80 (d, 3 N), 2.62-2.20 (m, 5 N), 2.03-1.95 (m, 1 N).

[2092] Example 283 N-phenyl-5-[[(3S)-1-[2-oxo-2-[(2S,4S)-2-cyano-4-fluoropyrrolidin-1-yl]ethyl]pyrrolidin- 3-yl]amino]quinoline-8-carboxamide

[2093] The title compound (12.0 mg, 21.2%) was prepared in the same manner as in Example 28 except that instead of (S)-N-(pyrroldin-3-yl)furo[ 3,2-c]pyridin-7-amine hydrochloride (S)-N-phenyl-5-(pyrrolidin-3-ylamino)quinoline-8-carboxamide hydrochloride (48.5 mg, 0.12 mmol) prepared in reference example 142. ¹ H NMR (CDCl ₃ , 400 MHz) δ 8.88 (t, 1 Η), 8.74-8.71 (m, 1 Η), 7.43 (d, 1 Η), 7 .85 (d, 2 Η), 7.39-7.35 (m, 3 Η), 7.11-7.07 (m, 1 Η), 6.57 (dd, 1 Η), 6.28 -5.81 (m, 1 Η), 5.43-5.24 (m, 1 Η), 4.91 (dd, 1 Η), 4.23-4.15 (m, 1 Η), 4 .03-3.15 (m, 5 Η), 3.08-2.99 (m, 2 Η), 2.75-2.18 (m, 5 Η), 2.03-1.95 (m , 1 Η).

[2094] Example 284 N-methyl-N-phenyl-5-[[(3S)-1-[2-oxo-2-[(2S,4S)-2-cyano-4-fluoropyrrolidin-1-yl] ethyl]pyrrolidin-3-yl]amino]quinoline-8-carboxamide

[2095] The title compound (17.6 mg, 28.6%) was prepared similarly to Example 28 except that instead of (S)-N-(pyrrolidin-3-yl)furo[3 ,2-c]pyridin-7-amine hydrochloride used (S)-N-methyl-N-phenyl-5-(pyrroldin-3-ylamino)quinoline-8-carboxamide hydrochloride (50.21 mg, 0.12 mmol) , obtained in reference example 143. ¹ H NMR (CDCl ₃ , 400 MHz) δ 8.85-8.81 (m, 1 N), 8.21-8.15 (m, 1 N), 7.29- 7.00 (m, 7 N), 6.27-6.22 (m, 1 N), 5.38-5.15 (m, 1 N), 4.89 (dd, 1 N), 4. 02-3.66 (m, 2 N), 3.59-3.50 (m, 2 N), 3.42 (s, 3 N), 3.35-3.22 (m, 2 N), 3.06-2.79 (m, 2 N), 2.61-1.98 (m, 5 N), 1.89-1.78 (m, 1 N).

[2096] Example 285 N-Benzyl-N-methyl-5-[[(3S)-1-[2-oxo-2-[(2S,4S)-2-cyano-4-fluoropyrrolidin-1-yl] ethyl]pyrrolidin-3-yl]amino]quinoline-8-carboxamide

[2097] The title compound (11.0 mg, 17.8%) was prepared in the same manner as in Example 28 except that instead of (S)-N-(pyrrolidin-3-yl)furo[ 3,2-c]pyridin-7-amine hydrochloride (S)-N-benzyl-N-methyl-5-(pyrrolidin-3-ylamino)quinoline-8-carboxamide hydrochloride (51.89 mg, 0.12 mmol) was used ), obtained in reference example 144. ¹ H NMR (CDCl ₃ , 400 MHz) δ 8.88-8.85 (m, 1 H), 8.35-8.27 (m, 1 H), 7.51 (t, 2 N), 7.37 (t, 1 N), 7.29-7.17 (m, 4 N), 6.48-6.40 (m, 1 N), 5.79-5 .13 (m, 3 N), 5.05-4.76 (m, 1 N), 4.40-4.11 (m, 2 N), 3.84-3.58 (m, 2 N), 3.42 (s, 3 N), 3.35-3.20 (m, 2 N), 3.08 (s, 2 N), 3.02-2.16 (m, 5 N), 1. 98-1.86 (m, 1 N).

[2098] Example 286 N-methyl-5-[[(3S)-1-[2-oxo-2-[(23)-2-cyanopyrrolidin-1-yl]ethyl]pyrrolidin-3-yl] amino] quinoline-8-carboxamide

[2099] The title compound (10.1 mg, 29.7%) was prepared in the same manner as Example 5 except that instead of (S)-N-(pyrrolidin-3-yl)quinoline- 4-amine hydrochloride (S)-N-methyl-5-(pyrrolidin-3-ylamino)quinoline-8-carboxamide (29.0 mg, 0.084 mmol) obtained in reference example 140 was used. ¹ H NMR (CDCl ₃ , 400 MHz) δ 10.98-10.94 (m, 1 N), 8.85-8.83 (m, 1 N), 8.70 (dd, 1 N), 8.48 (dd, 1 N ), 7.40-7.34 (m, 1 N), 6.60 (dd, 1 N), 6.39-5.65 (m, 1 N), 4.78-4.73 (m, 1 N), 4.27-4.24 (m, 1 N), 3.66-3.42 (m, 3 N), 3.29-3.01 (m, 5 N), 2.79- 2.70 (m, 1 N), 2.49-2.36 (m, 1 N), 2.33-1.96 (m, 7 N)

[2100] Example 287 N-phenyl-5-[[(3S)-1-[2-oxo-2-[(2S)-2-cyanopyrrolidin-1-yl]ethyl]pyrrolidin-3-yl] amino] quinoline-8-carboxamide

[2101] The title compound (4.4 mg, 12.1%) was prepared in the same manner as Example 5 except that instead of (S)-N-(pyrrolidin-3-yl)quinoline- 4-amine hydrochloride (S)-N-phenyl-5-(pyrrolidin-3-ylamino)quinoline-8-carboxamide hydrochloride (30.0 mg, 0.074 mmol) obtained in reference example 142 was used. ¹ H NMR (CDCl ₃ , 400 MHz) δ 8.88 (t, 1 Η), 8.72 (dd, 1 Η), 8.43 (dd, 1 Η), 7.85 (d, 2 Η), 7.39-7 .35 (m, 3 Η), 7.09 (t, 1 Η), 6.57 (dd, 1 Η), 6.28-5.81 (m, 1 Η), 5.44-5.24 (m, 1 Η), 4.91 (dd, 1 Η), 4.23-4.15 (m, 1 Η), 4.04-3.17 (m, 5 Η), 3.08-2 .99 (m, 2 Η), 2.75-2.60 (m, 2 Η), 2.39-2.18 (m, 2 Η), 2.05-1.93 (m, 1 H)

[2102] Example 288 N-benzyl-N-methyl-5-[[(3S)-1-[2-oxo-2-[(2S)-2-cyanopyrrolidin-1-yl]ethyl]pyrrolidin-3- yl]amino]quinoline-8-carboxamide

[2103] The title compound (6.89 mg, 11.5%) was prepared in the same manner as Example 5 except that instead of (S)-N-(pyrrolidin-3-yl)quinoline- 4-amine hydrochloride (S)-N-benzyl-N-methyl-5-(pyrrolidin-3-ylamino)quinoline-8-carboxamide hydrochloride (52.0 mg, 0.12 mmol) prepared in Reference Example 144 was used. ^1H NMR ( _CDCl3 , 400 MHz) δ 8.91-8.88 (m, 1 H), 8.33 (dt, 1 H), 7.53 (dd, 2 H), 7.40 (t , 1 N), 7.33-7.25 (m, 2 N), 7.23-7.19 (m, 2 N), 6.52-6.43 (m, 1 N), 5.80 -5.32(m, 1 Η), 4.99-4.74 (m, 1 Η), 4.38-4.32 (m, 1 Η), 4.22-4.13 (m, 1 Η), 3.63-3.43 (m, 4 Η), 3.10 (s, 3 Η), 2.99-2.94 (m, 1 Η), 2.70-2.66 (m , 3 Η), 2.45-1.92 (m, 7 Η).

[2104] Example 289 N-methyl-N-phenyl-5-[[(3S)-1-[2-oxo-2-[(2S)-2-cyanopyrrolidin-1-yl]ethyl]pyrrolidin-3- yl]amino]quinoline-8-carboxamide

[2105] The title compound (5.9 mg, 10.2%) was prepared in the same manner as Example 5 except that instead of (S)-N-(pyrrolidin-3-yl)quinoline- 4-amine hydrochloride (S)-N-methyl-M-phenyl-5-(pyrrolidin-3-ylamino)quinoline-8-carboxamide hydrochloride (50.3 mg, 0.12 mmol) prepared in Reference Example 143 was used. ¹ H NMR (CDCl ₃ , 400 MHz) δ 8.86-8.82 (dd, 1 H), 8.38-8.28 (m, 2 H), 7.29-7.25 (m, 2 N), 7.05-7.00 (m, 4 N), 6.18 (d, 1 N), 4.76 (d, 1 N), 4.09 (br. s, 1 N), 3 .98-3.70 (m, 2 N), 3.66-3.15 (m, 7 N), 3.03 (br.s., 1 N), 2.32-2.07 (m, 4 N), 2.02-1.96 (m, 1 N).

[2106] Example 290 N-(3-pyridyl)-5-[[(3S)-1-[2-oxo-2-[(2S)-2-cyanopyrrolidin-1-yl]ethyl]pyrrolidin-3- yl]amino]quinoline-8-carboxamide

[2107] The title compound (21.8 mg, 50.5%) was prepared in the same manner as Example 5 except that instead of (S)-N-(pyrrolidin-3-yl)quinoline- 4-amine hydrochloride (S)-N-(pyridin-3-yl)-5-(pyrrolidin-3-ylamino)quinoline-8-carboxamide hydrochloride (36.9 mg, 0.09 mmol) prepared in the reference example was used 145. ¹ H NMR (CDCl ₃ , 400 MHz) δ 8.91-8.88 (m, 1 H), 8.86-8.84 (m, 1 H), 8.75-8.71 (m , 1 N), 8.67 (d, 0.7 N), 8.46-8.44 (m, 1.3 N), 8.31 (d, 1 N), 7.44-7.39 (m, 1 N), 7.31-7.28 (m, 1 N), 6.87 (d, 0.7 N), 6.62 (d, 1 N), 5.95 (d, 0 ,3 N), 4.78-4.70 (m, 1 N), 4.24 (s, 1 N), 3.67-3.40 (m, 3 N), 3.17-3.11 (m, 2 N), 2.81-2.69 (m, 1 N), 2.49-2.12 (m, 8 N), 2.04-1.97 (m, 1 N).

[2108] Example 291 N-(4-pyridyl)-5-[[(3S)-1-[2-oxo-2-[(2S)-2-cyanopyrrolidin-1-yl]ethyl]pyrrolidin-3- yl]amino]quinoline-8-carboxamide

[2109] The title compound (11.2 mg, 19.8%) was prepared in the same manner as Example 5 except that instead of (S)-N-(pyrrolidin-3-yl)quinoline- 4-amine hydrochloride (S)-N-(pyridin-4-yl)-5-(pyrrolidin-3-ylamino)quinoline-8-carboxamide hydrochloride (48.7 mg, 0.12 mmol) prepared in the reference example was used 146. ¹ H NMR (CDCl ₃ , 400 MHz) δ 8.91-8.87 (m, 1 H), 8.74-8.67 (m, 1.7 H), 8.49-8.44 (dd, 2.3 N), 7.76 (d, 2 N), 7.45-7.39 (m, 1 N), 7.00 (d, 0.7 N), 6.62 (d , 1 N), 6.01 (d, 0.3 N), 4.78-4.70 (m, 1 N), 4.25 (s, 1 N), 3.67-3.40 (m , 3 N), 3.19-3.12 (m, 2 N), 2.82-2.70 (m, 1 N), 2.49-2.08 (m, 8 N), 2.04- 1.97 (m, 1 N).

[2110] Example 292 N-(4-pyridyl)-5-[[(3S)-1-[2-oxo-2-[(2S,4S)-2-cyano-4-fluoropyrrolidin-1-yl] ethyl]pyrrolidin-3-yl]amino]quinoline-8-carboxamide

[2111] The title compound (8.4 mg, 14.3%) was prepared in the same manner as in Example 28 except that instead of (S)-N-(pyrrolidin-3-yl)furo[ 3,2-c]pyridin-7-amine hydrochloride (S)-N-(pyridin-4-yl)-5-(pyrrolidin-3-ylamino)quinoline-8-carboxamide hydrochloride (48.7 mg, 0. 12 mmol) obtained in reference example 146. ¹ H NMR (CDCl ₃ , 400 MHz) δ 8.92-8.89 (m, 1 N), 8.72 (t, 1 H), 8.59-8 .43 (m, 3 N), 7.76-7.74 (m, 2 N), 7.45-7.41 (m, 1 N), 6.63 (d, 1 N), 6.54 (d, 0.6 N), 5.97 (d, 0.4 N), 5.52-5.28 (m, 1 N), 4.93 (dd, 1 N), 4.30-4 .25 (m, 1 N), 4.01-3.39 (m, 4 N), 3.29-3.06 (m, 3 N), 2.79-2.65 (m, 2 N) , 2.53-2.24 (m, 2 N), 2.11-1.99 (m, 1 N).

[2112] Example 293 N-(2-pyridyl)-5-[[(35)-1-[2-oxo-2-[(25)-2-cyanopyrrolidin-1-yl]ethyl]pyrrolidin-3- yl]amino]quinoline-8-carboxamide

[2113] The title compound (4.3 mg, 7.6%) was prepared in the same manner as Example 5 except that instead of (S)-N-(pyrrolidin-3-yl)quinoline- 4-amine hydrochloride (S)-N-(pyridin-2-yl)-5-(pyrrolidin-3-ylamino)quinoline-8-carboxamide hydrochloride (48.7 mg, 0.12 mmol) prepared in the reference example was used 147. ¹ H NMR (CDCl ₃ , 400 MHz) δ 9.06 (td, 1 H), 8.80 (dd, 1 H), 8.64 (dd, 0.6 H), 8.54 (d , 1 N), 8.44-8.40 (m, 1.4 N), 7.76-7.71 (m, 1 N), 7.48-7.41 (m, 1 N), 7 .04-7.00 (m, 1 N), 6.74-6.65 (m, 1.6 N), 5.85 (d, 0.4 N), 4.81-4.70 (m , 1 N), 4.30-4.28 (m, 1 N), 3.68-3.43 (m, 4 N), 3.28-3.04 (m, 3 N), 2.82 -2.76 (m, 1 N), 2.51-2.11 (m, 6 N), 2.03-2.00 (m, 1 N).

[2114] Example 294 N-(2-pyridyl)-5-[[(3S)-1-[2-oxo-2-[(2S,4S)-2-cyano-4-fluoropyrrolidin-1-yl] ethyl]pyrrolidin-3-yl]amino]quinoline-8-carboxamide

[2115] The title compound (1.7 mg, 2.9%) was prepared in the same manner as in Example 28 except that instead of (S)-N-(pyrrolidin-3-yl)furo[ 3,2-c]pyridin-7-amine hydrochloride (S)-N-(pyrrolidin-2-yl)-5-(pyrrolidin-3-ylamino)quinoline-8-carboxamide hydrochloride (48.7 mg, 0. 12 mmol) obtained in reference example 147. ¹ H NMR (CDCl ₃ , 400 MHz) δ 9.06 (td, 1 H), 8.79 (dd, 1 H), 8.54-8.40 (m , 3 N), 7.76-7.71 (m, 1 N), 7.45-7.41 (m, 1 N), 7.04-7.00 (m, 1 N), 6.65 (t, 1 N), 6.28 (d, 0.5 N), 5.85 (d, 0.5 N), 5.51-5.28 (m, 1 N), 4.93 (dd , 1 N), 4.32-4.26 (m, 1 N), 4.13-3.39 (m, 4 N), 3.29-3.05 (m, 3 N), 2.78 -2.64 (m, 2 N), 2.57-2.21 (m, 3 N), 2.12-1.97 (m, 1 N).

[2116] Example 295 N-(3-pyridyl)-5-[[(3S)-1-[2-oxo-2-[(2S,4S)-2-cyano-4-fluoropyrrolidin-1-yl] ethyl]pyrrolidin-3-yl]amino]quinoline-8-carboxamide

[2117] The title compound (2.6 mg, 5.5%) was prepared in the same manner as in Example 28 except that instead of (S)-N-(pyrrolidin-3-yl)furo[ 3,2-c]pyridin-7-amine hydrochloride (S)-N-(pyridin-3-yl)-5-(pyrrolidin-3-ylamino)quinoline-8-carboxamide hydrochloride (36.9 mg, 0. 09 mmol) obtained in reference example 145. ¹ H NMR (CDCl ₃ , 400 MHz) δ 8.96-8.95 (m, 1 N), 8.86 (t, 1 H), 8.80-8 .77 (m, 1 N), 8.59-8.45 (m, 2 N), 8.33-8.32 (m, 1 N), 7.49-7.44 (m, 1 N) , 7.34-7.30 (m, 1 N), 6.67 (t, 1 N), 6.38 (d, 0.5 N), 5.89 (d, 0.5 N), 5 .54-5.30 (m, 1 N), 4.94 (dd, 1 N), 4.34-4.28 (m, 1 N), 4.15-3.39 (m, 4 N) , 3.29-3.07 (m, 3 N), 2.80-2.67 (m, 2 N), 2.58-2.23 (m, 3 N), 2.13-1.99 (m, 1 N).

[2118] Example 296 N-[5-[[(3S)-1-[2-oxo-2-[(2S)-2-cyanopyrrolidin-1-yl]ethyl]pyrrolidin-3-yl] amino]- 8-quinolyl] acetamide

[2119] The title compound (5.9 mg, 12.2%) was prepared in the same manner as Example 5 except that instead of (S)-N-(pyrrolidin-3-yl)quinoline- 4-amine hydrochloride (S)-N-(5-(pyrrolidin-3-ylamino)quinolin-8-yl)acetamide hydrochloride (41.2 mg, 0.12 mmol) prepared in Reference Example 148 was used. ¹ H NMR (CDCl ₃ , 400 MHz) δ 9.47 (s, 1 H), 8.76-8.74 (m, 1 H), 8.59-8.57 (m, 1 H), 8.39-8, 28 (m, 1 N), 7.40-7.36 (m, 1 N), 6.52 (t, 1 N), 4.79-4.72 (m, 1 N), 4.17- 4.09 (m, 1 N), 3.64-3.58 (m, 1 N), 3.54-3.23 (m, 3 N), 3.09-2.91 (m, 3 N), 2.74-2.59 (m, 1 N), 2.47-2.02 (m, 9 N), 1.96-1.86 (m, 1 N).

[2120] Example 297 N-[5-[[(3S)-1-[2-oxo-2-[(2S,4S)-2-cyano-4-fluoropyrrolidin-1-yl]ethyl]pyrrolidin-3 -yl]amino]-8-quinolyl]acetamide

[2121] The title compound (3.9 mg, 7.6%) was prepared in the same manner as Example 28 except that instead of (S)-N-(pyrroldin-3-yl)furo[ 3,2-c]pyridin-7-amine hydrochloride (S)-N-(5-(pyrrolidin-3-ylamino)quinolin-8-yl) acetamide hydrochloride (41.2 mg, 0.12 mmol) obtained in reference example 148. ¹ H NMR (CDCl ₃ , 400 MHz) δ 9.47-9.46 (m, 1 H), 8.77-8.74 (m, 1 H), 8.56 (d, 1 N), 8.3S-8.29 (m, 1 N), 7.39-7.36 (m, 1 N), 6.52-6.48 (m, 1 N), 5.45- 5.21 (m, 1 N), 5.01-4.88 (m, 2 N), 4.17-4.12 (m, 1 N), 4.08-3.38 (m, 3 N ), 3.31-3.26 (m, 1 N), 3.14-3.01 (m, 1 N), 2.96-2.89 (m, 1 N), 2.71-2, 54 (m, 2 N), 2.47-2.18 (m, 5 N), 2.00-1.83 (m, 1 N).

[2122] Example 298 N-[5-[[(3S)-1-[2-oxo-2-[(2S,4S)-2-cyano-4-fluoropyrrolidin-1-yl]ethyl]pyrrolidin-3 -yl]amino]-8-quinolyl]benzamide

[2123] The title compound (9.8 mg, 16.8%) was prepared in the same manner as Example 28 except that instead of (S)-N-(pyrrolidin-3-yl)furo[ 3,2-c]pyridin-7-amine hydrochloride (S)-N-(5-(pyrrolidin-3-ylamino)quinolin-8-yl)benzamide hydrochloride (48.5 mg, 0.12 mmol) obtained in reference example 149. ^1H NMR ( _CDCl3 , 400 MHz) δ 10.46 (s, 1H), 8.83-8.78 (m, 2H), 8.36-8.3S (m, 1 N), 8.06-8.02 (m, 2 N), 7.60-7.48 (m, 3 N), 7.43-7.40 (m, 1 N), 6.59 ( t, 1 N), 5.47-5.23 (m, 1 N), 5.02-4.91 (m, 2 N), 4.22-4.18 (m, 1 N), 4, 15-3.55 (m, 3 N), 3.48-3.13 (m, 1 N), 3.10-2.93 (m, 2 N), 2.75-2.59 (m, 2 N), 2.53-2.16 (m, 2.5 N), 2.05-1.88 (m, 1.5 N).

[2124] Example 299: (2S,4S)-4-fluoro-1-[2-[(3S)-3-[(6-methoxy-4-quinolyl)oxy]pyrrolidin-1-yl]acetyl]pyrrolidin- 2-carbonitrile

[2125](2S,4S)-1-(2-chloroacetyl)-4-fluoropyrrolidine-2-carbonitrile (152 mg, 0.80 mmol) obtained in Reference Example 2 was dissolved in anhydrous acetonitrile (4.0 ml) . To the resulting solution was added (S)-6-methoxy-4-(pyrrolidin-3-yloxy)quinoline hydrochloride (224 mg, 0.80 mmol) obtained in Reference Example 150, potassium carbonate (441 mg, 3.2 mmol) . The reaction mixture was stirred overnight at room temperature. After completion of the reaction, water was added to the reaction mixture. The aqueous layer of the reaction mixture was extracted with dichloromethane. The extracted organic layer was dried and filtered over anhydrous magnesium sulfate. The filtered solution was concentrated and then purified by silica gel column chromatography (dichloromethane/methanol = 10/1, v/v) to give the title compound (76 mg, 24%). ^1H NMR ( _CDCl3 , 600 MHz) δ 8.54 (d, 1 H), 7.89 (d, 1 H), 7.41 (s, 1 H), 7.32 (d, 1 H) , 6.56 (d, 1 N), 5.41-5.17 (m, 1.3 N), 5.12-5.00 (m, 1 N), 4.91 (d, 0.7 N), 4.17-4.04 (m, 1 N), 3.91 (s, 3 N), 3.79-3.29 (m, 3 N), 3.23-3.09 (m , 1 N), 3.07-2.89 (m, 2 N), 2.75-2.54 (m, 2 N), 2.48-2.40 (m, 1 N), 2.32 -2.09 (m, 2 N)

[2126] Example 300: (2S,4S)-4-fluoro-1-[2-[(3S)-3-[(6,7-dimethoxy-4-quinolyl)oxy]pyrrolidin-1-yl]acetyl] pyrrolidine-2-carbonitrile

[2127](2S,4S)-1-(2-chloroacetyl)-4-fluoropyrrolidine-2-carbonitrile (71 mg, 0.37 mmol) obtained in Reference Example 2 was dissolved in anhydrous acetonitrile (2.0 ml) . To the resulting solution was added (S)-6,7-dimethoxy-4-(pyrrolidin-3-yloxy)quinoline hydrochloride (114 mg, 0.37 mmol) obtained in Reference Example 151, potassium carbonate (204 mg, 1.5 mmol). The reaction mixture was stirred overnight at room temperature. After completion of the reaction, water was added to the reaction mixture. The aqueous layer of the reaction mixture was extracted with dichloromethane. The extracted organic layer was dried and filtered over anhydrous magnesium sulfate. The filtered solution was concentrated and then purified by silica gel column chromatography (dichloromethane/methanol = 10/1, v/v) to give the title compound (40 mg, 25%). ^1H NMR ( _CDCl3 , 600 MHz) δ 8.52 (d, 1 H), 7.39 (s, 1 H), 7.35 (s, 1 H), 6.53 (d, 1 H) , 5.46-5.20 (m, 1.4 N), 5.14-5.01 (m, 1 N), 4.94 (d, 0.6 N), 4.23-4.12 (m, 1 N), 4.01 (d, 6 N), 3.96-3.60 (m, 2 N), 3.47-2.91 (m, 4 N), 2.80-2 .57 (m, 2 N), 2.50-2.40 (m, 1 N), 2.37-2.10 (m, 2 N)

[2128] Example 301 N-[1-[2-oxo-2-[(25)-2-cyanopyrrolidin-1-yl]ethyl]-4-piperidyl]quinoline-8-carboxamide

[2129] The title compound (424.3 mg, 86.9%) was prepared in the same manner as Example 110 except that N-(piperidin-4-yl)quinolin-5-amine hydrochloride was used instead of N-(piperidin-4-yl)quinoline-8-carboxamide hydrochloride (409.7 mg, 1.25 mmol) obtained in reference example 152. ¹ H-NMR (CDCl ₃ , 400 MHz) δ 11.47 (s , 1 N), 8.92 (d, 1 N), 8.83 (d, 1 N), 8.28 (d, 1 N), 7.96 (d, 1 N), 7.66 (t , 1 N), 7.49 (t, 1 N), 5.40-4.70 (m, 1 N), 4.30-4.10 (m, 1 N), 3.85-3.50 (m, 2 N), 3.50-3.10 (m, 2 N), 3.00-2.75 (m, 2 N), 2.55-2.20 (m, 4 N), 2 .20-2.00 (m, 4 N), 2.00-1.70 (m, 2 N)

[2130] Example 302: (2S)-1-[2-[4-[ethyl(3-quinolyl)amino]-1-piperidyl]acetyl]pyrrolidine-2-carbonitrile

[2131] The title compound (132.5 mg, 38.4%) was prepared similarly to Example 121 except that instead of 3-methyl-N-(piperidin-4-yl)quinoline-5 -amine hydrochloride N-ethyl-N-(piperidin-4-yl)quinolin-3-amine hydrochloride (230.4 mg, 0.88 mmol) obtained in reference example 153 was used. ¹ H NMR (CDCl ₃ , 400 MHz ) δ 8.67 (d, 1 N), 7.92-7.90 (m, 1 N), 7.61-7.59 (m, 1 N), 7.41-7.36 (m, 2 N), 7.14 (d, 1 N), 5.07-4.73 (m, 1 N), 3.74-3.61 (m, 2 N), 3.56-3.47 ( m, 1 N), 3.44-3.38 (m, 2 N), 3.36-3.19 (m, 2 N), 3.08-2.96 (m, 2 N), 2. 33-2.03 (m, 7 N), 1.90-1.85 (m, 3 N), 1.21 (t, 3 N).

[2132] Example 303: (2S)-1-[2-[4-[ethyl(6-quinolyl)amino]-1-piperidyl]acetyl]pyrrolidine-2-carbonitrile

[2133] The title compound (274.8 mg, 79.7%) was prepared as described in Example 121 except that instead of 3-methyl-N-(piperidin-4-yl)quinoline-5 -amine hydrochloride N-ethyl-N-(piperidin-4-yl)quinolin-6-amine hydrochloride (230.4 mg, 0.88 mmol) obtained in reference example 154 was used. ¹ H NMR (CDCl ₃ , 400 MHz ) δ 8.54 (dd, 1 N), 7.90-7.86 (m, 2 N), 7.30 (dd, 1 N), 7.19 (kv, 1 N), 6.77 ( d, 1 N), 5.06-4.79 (m, 1 N), 3.71-3.58 (m, 2 N), 3.53-3.43 (m, 1 N), 3. 39-3.3S (m, 2 N), 3.29-3.12 (m, 2 N), 3.04-2.93 (m, 2 N), 2.31-1.96 (m, 6 N), 1.86-1.78 (m, 4 N), 1.18 (t, 3 N).

[2134] Example 304: (2S,4S)-1-[2-[4-[ethyl(3-quinolyl)amino]-1-piperidyl]acetyl]-4-fluoropyrrolidine-2-carbonitrile

[2135] The title compound (12.4 mg, 27.5%) was prepared in the same manner as Example 131 except that instead of 3-methyl-N-(piperidin-4-yl)quinolin- 5-amine hydrochloride N-ethyl-N-(piperidin-4-yl)quinolin-3-amine hydrochloride (36.1 mg, 0.11 mmol) obtained in reference example 153 was used. ¹ H NMR (CDCl ₃ , 400 MHz) δ 8.69 (d, 1 N), 7.95-7.92 (m, 1 N), 7.63-7.61 (m, 1 N), 7.44-7.40 (m , 2 N), 7.17 (s, 1 N), 5.51-4.94 (m, 2 N), 4.21-4.12 (m, 1 N), 4.02-3.71 (m, 2 N), 3.47-3.40 (m, 3 N), 3.30-3.19 (m, 2 N), 3.12-2.99 (m, 2 N), 2 .80-2.64 (m, 1 N), 2.50-2.24 (m, 3 N), 1.89-1.88 (m, 3 N), 1.23 (t, 3 N) .

[2136] Example 305: (2S,4S)-1-[2-[4-[ethyl(5-quinolyl)amino]-1-piperidyl]acetyl]-4-fluoropyrrolidine-2-carbonitrile

[2137] The title compound (39.8 mg, 88.5%) was prepared in the same manner as Example 131 except that instead of 3-methyl-N-(piperidin-4-yl)quinolin- 5-amine hydrochloride N-ethyl-N-(piperidin-4-yl)quinolin-5-amine hydrochloride (36.1 mg, 0.11 mmol) obtained in reference example 155 was used. ¹ H NMR (CDCl ₃ , 400 MHz) δ 8.84 (d, 1 N), 8.63 (m, 1 N), 7.83 (d, 1 N), 7.61 (t, 1 N), 7.35 (sq, 1 N), 7.26 (d 1 Η), 5.44-4.83 (m, 2 Η), 4.10-3.83 (m, 1 Η), 3.79-3.66 (m, 1 Η), 3.37-3.06 (m, 4 Η), 2.99-2.94 (m, 1 Η), 2.90-2.76 (m, 2 Η), 2.69- 2.20 (m, 2 Η), 2.07-2.00 (m, 2 Η), 1.81-1.59 (m, 4 Η), 0.86 (t, 3 Η).

[2138] Example 306: (2S,4S)-1-[2-[4-[ethyl(6-quinolyl)amino]-1-piperidyl]acetyl]-4-fluoropyrrolidine-2-carbonitrile

[2139] The title compound (35.4 mg, 78.6%) was prepared in the same manner as Example 131 except that instead of 3-methyl-N-(piperidin-4-yl)quinolin- 5-amine hydrochloride N-ethyl-N-(piperidin-4-yl)quinolin-6-amine hydrochloride (36.1 mg, 0.11 mmol) obtained in reference example 154 was used. ¹ H NMR (CDCl ₃ , 400 MHz) δ 8.54 (dd, 1 N), 7.90 (s, 1 N), 7.87 (s, 1 N), 7.32-7.29 (m, 1 N), 7.20 (kv, 1 N), 6.78-6.77 (m, 1 N), 5.44-4.87 (m, 2 N), 4.13-4.04 (m, 1 N), 3 .95-3.64 (m, 2 N), 3.39-3.34 (m, 2 N), 3.26-3.13 (m, 2 N), 3.06-2.94 (m , 2 N), 2.36-2.22 (m, 3 N), 1.86-1.82 (m, 4 N), 1.18 (t, 3 N).

[2140] Example 307 (2S)-1-[2-[4-[methyl(2-quinolyl)amino]-1-piperidyl]acetyl]pyrrolidine-2-carbonitrile

[2141] The title compound (45.7 mg, 13.7%) was prepared as described in Example 121 except that instead of 3-methyl-N-(piperidin-4-yl)quinoline-5 -amine hydrochloride N-methyl-N-(piperidin-4-yl)quinolin-2-amine hydrochloride (276.5 mg, 0.88 mmol) obtained in reference example 156 was used. ¹ H NMR (CDCl ₃ , 400 MHz ) δ 7.86 (d, 1 N), 7.67 (d, 1 N), 7.58 (d, 1 N), 7.51 (t, 1 N), 7.17 (t, 1 N ), 6.88 (d, 1 N), 5.19-4.71 (m, 2 N), 3.81-3.73 (m, 2 N), 3.59-3.55 (m, 1 N), 3.42-3.22 (m, 2 N), 3.08-3.04 (m, 4 N), 2.39 (t, 2 N), 2.29-2.11 ( m, 4 N), 1.96-1.90 (m, 2 N), 1.76 (d, 2 N).

[2142] Example 308 (2S)-1-[2-[4-[methyl(4-quinolyl)amino]-1-piperidyl]acetyl]pyrrolidine-2-carbonitrile

[2143] The title compound (79.5 mg, 23.9%) was prepared in the same manner as Example 121 except that instead of 3-methyl-N-(piperidin-4-yl)quinoline-5 -amine hydrochloride N-methyl-N-(piperidin-4-yl)quinolin-4-amine hydrochloride (276.5 mg, 0.88 mmol) obtained in reference example 157 was used. ¹ H NMR (CDCl ₃ , 400 MHz ) δ 8.67 (d, 1 N), 8.04 (d, 1 N), 7.94 (d, 1 N), 7.65 (t, 1 N), 7.46 (t, 1 N ), 6.85 (d, 1 N), 5.09-4.75 (m, 1 N), 3.70-3.48 (m, 3 N), 3.31-3.12 (m, 4 N), 2.89 (s, 3 N), 2.29-2.01 (m, 8 N), 1.80 (d, 2 N).

[2144] Example 309 (2S)-1-[2-[4-[methyl(5-quinolyl)amino]-1-piperidyl]acetyl]pyrrolidine-2-carbonitrile

[2145] The title compound (220.8 mg, 66.4%) was prepared as described in Example 121 except that instead of 3-methyl-N-(piperidin-4-yl)quinoline-5 -amine hydrochloride N-methyl-N-(piperidin-4-yl)quinolin-5-amine hydrochloride (276.5 mg, 0.88 mmol) obtained in reference example 158 was used. ¹ H NMR (CDCl ₃ , 400 MHz ) δ 8.88 (d, 1 N), 8.51 (d, 1 N), 7.80 (d, 1 N), 7.62 (t, 1 N), 7.38 (sq, 1 N ), 7.20 (d, 1 N), 5.18-4.72 (m, 1 N), 3.72-3.48 (m, 2 N), 3.33-3.02 (m, 3 N), 2.95-2.81 (m, 5 N), 2.34-2.06 (m, 6 N), 2.01-1.80 (m, 4 N).

[2146] Example 310: (2S)-1-[2-[4-[methyl(6-quinolyl)amino]-1-piperidyl]acetyl]pyrrolidine-2-carbonitrile

[2147] The title compound (171.0 mg, 51.4%) was prepared similarly to Example 121 except that instead of 3-methyl-N-(piperidin-4-yl)quinoline-5 -amine hydrochloride N-methyl-N-(piperidin-4-yl)quinolin-6-amine hydrochloride (276.5 mg, 0.88 mmol) prepared in reference example 159 was used. ¹ H NMR (CDCl ₃ , 400 MHz ) δ 8.62 (d, 1 N), 7.93 (d, 2 N), 7.42 (d, 1 N), 7.26 (kv, 1 N), 6.85 (d, 1 N ), 5.11-4.75 (m, 1 N), 3.79-3.63 (m, 2 N), 3.58-3.49 (m, 1 N), 3.38-3, 20 (m, 2 N), 3.16-2.97 (m, 2 N), 3.29 (s, 3 N), 2.35-2.08 (m, 7 N), 1.99- 1.88 (m, 1 N), 1.78-1.75 (m, 2 N).

[2148] Example 311 (2S)-1-[2-[4-[methyl(7-quinolyl)amino]-1-piperidyl]acetyl]pyrrolidine-2-carbonitrile

[2149] The title compound (35.8 mg, 10.7%) was prepared as described in Example 121 except that instead of 3-methyl-N-(piperidin-4-yl)quinoline-5 -amine hydrochloride N-methyl-N-(piperidin-4-yl)quinolin-7-amine hydrochloride (276.5 mg, 0.88 mmol) obtained in reference example 160 was used. ¹ H NMR (CDCl ₃ , 400 MHz ) δ 8.73 (d, 1 N), 7.96 (d, 1 N), 7.64 (d, 1 N), 7.22 (d, 2 N), 7.10 (sq, 1 N ), 5.14-4.77 (m, 1 N), 3.86-3.55 (m, 3 N), 3.39-3.00 (m, 4 N), 2.94 (s, 3 N), 2.45-2.09 (m, 6 N), 2.03-1.89 (m, 2 N), 1.81-1.78 (m, 2 N).

[2150] Example 312

[2151] The title compound (139.4 mg, 43.1%) was prepared in the same manner as Example 121 except that instead of 3-methyl-N-(piperidin-4-yl)quinolin- 5-amine hydrochloride N-methyl-N-(piperidin-4-yl)furo[3,2-c]pyridin-7-amine hydrochloride (267.7 mg, 0.88 mmol) prepared in Reference Example 161 was used. ^1H NMR ( _CDCl3 , 400 MHz) δ 8.46 (s, 1 H), 7.98 (s, 1 H), 7.63 (s, 1 H), 6.81 (s, 1 H) , 5.17-4.75 (m, 1 N), 3.96-3.90 (m, 1 N), 3.76-3.64 (m, 1 N), 3.57-3.51 (m, 1 N), 3.39-3.19 (m, 2 N), 3.04-2.95 (m, 5 N), 2.36-1.92 (m, 8 N), 1 .81-1.78 (m, 2 N).

[2152] Example 313 (2S)-1-[2-[4-[5-Isoquinolyl(methyl)amino]-1-piperidyl]acetyl]pyrrolidine-2-carbonitrile

[2153] The title compound (28.4 mg, 8.5%) was prepared in the same manner as Example 121 except that instead of 3-methyl-N-(piperidin-4-yl)quinoline- 5-amine hydrochloride N-methyl-N-(piperidin-4-yl)isoquinolin-5-amine hydrochloride (267.7 mg, 0.88 mmol) obtained in reference example 162 was used. ¹ H NMR (MeOD ₄ , 400 MHz) δ 9.18 (s, 1 N), 8.42 (d, 1 N), 8.06 (d, 1 N), 7.75 (d, 1 N), 7.64-7.51 (m, 2 N), 4.74-4.64 (m, 1 N), 3.73-3.50 (m, 2 N), 3.26-2.85 (m, 8 N), 2 .22-2.09 (m, 6 N), 1.95-1.80 (m, 4 N).

[2154] Example 314: (2S)-1-(2-(4-(isoquinolin-6-yl(methyl)amino)piperidin-1-yl)acetyl)pyrrolidin-2-carbonitrile

[2155] The title compound (146.1 mg, 44.0%) was prepared in the same manner as Example 121 except that instead of 3-methyl-N-(piperidin-4-yl)quinolin- 5-amine hydrochloride N-methyl-N-(piperidin-4-yl)isoquinolin-6-amine hydrochloride (267.7 mg, 0.88 mmol) obtained in reference example 163 was used. ¹ H NMR (MeOD ₄ , 400 MHz) δ 8.84 (s, 1 N), 8.13 (d, 1 N), 7.86 (d, 1 N), 7.51 (d, 1 N), 7.41-7.38 (m, 1 N), 6.92 (s, 1 N), 5.17-4.76 (m, 1 N), 3.96-3.90 (m, 1 N), 3.78-3 .73 (m, 1 N), 3.61-3.53 (m, 1 N), 3.45-3.22 (m, 3 N), 3.10-3.08 (m, 2 N) , 2.96 (s, 3 N), 2.39-2.33 (m, 2 N), 2.28-2.12 (m, 4 N), 2.05-1.96 (m, 1 1.74-1.71 (m, 2 N).

[2156] Example 315: (2S,4S)-4-fluoro-1-[2-[4-[methyl(b-quinolyl)amino]-1-piperidyl]acetyl]pyrrolidine-2-carbonitrile

[2157] The title compound (4.4 mg, 10.2%) was prepared in the same manner as Example 131 except that instead of 3-methyl-N-(piperidin-4-yl)quinoline- 5-amine hydrochloride N-methyl-N-(piperidin-4-yl)quinolin-6-amine hydrochloride (34.5 mg, 0.11 mmol) obtained in reference example 159 was used. ¹ H NMR (CDCl ₃ , 400 MHz) δ 8.62 (d, 1 N), 7.94 (d, 2 N), 7.41 (d, 1 N), 7.27 (t, 1 N), 6.85 (s, 1 N), 5.49-4.93 (m, 2 N), 4.21-3.91 (m, 1 N), 3.87-3.75 (m, 2 N), 3.46-3 .18 (m, 2 N), 3.11-2.98 (m, 2 N), 2.91 (s, 3 N), 2.80-2.63 (m, 1 N), 2.40 -2.24 (m, 3 N), 2.15-1.90 (m, 2 N), 1.79-1.76 (m, 2 N).

[2158] Example 316: (2S,4S)-4-fluoro-1-[2-[4-[methyl(3-quinolyl)amino]-1-piperidyl]acetyl]pyrrolidine-2-carbonitrile

[2159] The title compound (12.0 mg, 27.5%) was prepared in the same manner as Example 131 except that instead of 3-methyl-N-(piperidin-4-yl)quinolin- 5-amine hydrochloride N-methyl-N-(piperidin-4-yl)quinolin-3-amine hydrochloride (34.5 mg, 0.11 mmol) obtained in reference example 164 was used. ¹ H NMR (CDCl ₃ , 400 MHz) δ 8.76 (d, 1 N), 7.97-7.95 (m, 1 N), 7.66-7.64 (m, 1 N), 7.46-7.43 (m , 2 N), 7.22 (d, 1 N), 5.51-4.95 (m, 2 N), 4.22-3.92 (m, 1 N), 3.88-3.75 (m, 2 N), 3.46-3.19 (m, 2 N), 3.12-3.00 (m, 2 N), 2.92 (s, 3 N), 2.81-2 .65 (m, 1 N), 2.41-2.24 (m, 3 N), 2.18-1.79 (m, 4 N).

[2160] Example 317 (2S,4S)-4-fluoro-1-[2-[4-[3-isoquinolyl(methyl)amino]-1-piperidyl]acetyl]pyrrolidine-2-carbonitrile

[2161] The title compound (18.7 mg, 43.1%) was prepared in the same manner as Example 131 except that instead of 3-methyl-N-(piperidin-4-yl)quinolin- 5-amine hydrochloride N-methyl-N-(piperidin-4-yl)isoquinolin-3-amine hydrochloride (34.5 mg, 0.11 mmol) obtained in reference example 165 was used. ¹ H NMR (CDCl ₃ , 400 MHz) δ 8.75 (d, 1 N), 7.95 (kv, 1 N), 7.65-7.63 (m, 1 N), 7.43 (kv, 2 N), 7.21 (d, 1 N), 5.49-4.93 (m, 2 N), 4.20-3.91 (m, 1 N), 3.87-3.73 (m, 2 N), 3 .45-3.17 (m, 2 N), 3.11-2.99 (m, 2 N), 2.91 (s, 3 N), 2.76-2.63 (m, 1 N) , 2.40-2.24 (m, 3 N), 2.13-1.77 (m, 4 N).

[2162] Example 318 (2S,4S)-4-fluoro-1-[2-[4-[5-isoquinolyl(methyl)amino]-1-piperide yl]acetyl]pyrrolidine-2-carbonitrile

[2163] The title compound (28.4 mg, 65.4%) was prepared in the same manner as Example 131 except that instead of 3-methyl-N-(piperidin-4-yl)quinolin- 5-amine hydrochloride N-methyl-N-(piperidin-4-yl)yuoquinolin-5-amine hydrochloride (34.5 mg, 0.11 mmol) obtained in reference example 162 was used. ¹ H NMR (CDCl ₃ , 400 MHz) δ 9.21 (s, 1 N), 8.51 (dd, 1 N), 7.91 (d, 1 N), 7.65 (d, 1 Η), 7.52 (t, 1 Η), 7.33 (d, 1 Η), 5.47-4.91 (m, 2 Η), 4.18-3.90 (m, 1 Η), 3.85-3.72 (m , 1 Η), 3.42-3.13 (m, 3 Η), 2.99-2.86 (m, 2 Η), 2.82 (s, 3 Η), 2.78-2.61 (m, 1 Η), 2.38-1.82 (m, 7 Η).

[2164] Example 319 (2S,4S)-4-fluoro-1-[2-[4-[7-isoquinolyl(methyl)amino]-1-piperidyl]acetyl]pyrrolidine-2-carbonitrile

[2165] The title compound (14.0 mg, 32.1%) was prepared in the same manner as Example 131 except that instead of 3-methyl-N-(piperidin-4-yl)quinolin- 5-amine hydrochloride N-methyl-N-(piperidin-4-yl)yuoquinolin-7-amine hydrochloride (34.5 mg, 0.11 mmol) obtained in reference example 166 was used. ¹ H NMR (CDCl ₃ , 400 MHz) δ 9.06 (s, 1 N), 8.27 (dd, 1 N), 7.69 (d, 1 N), 7.49 (d, 1 N), 7.40 (d, 1 N), 7.02 (s, 1 N), 5.51-4.95 (m, 2 N), 4.23-3.92 (m, 1 N), 3.88-3.75 (m , 2 N), 3.47-3.23 (m, 2 N), 3.12-3.00 (m, 2 N), 2.92 (s, 3 N), 2.77-2.65 (m, 1 N), 2.41-2.29 (m, 3 N), 2.05-1.89 (m, 2 N), 1.80-1.77 (m, 2 H).

[2166] Example 320: (2S,4S)-4-fluoro-1-[2-[4-[8-isoquinolyl(methyl)amino]-1-piperidyl]acetyl]pyrrolidine-2-carbonitrile

[2167] The title compound (20.4 mg, 46.9%) was prepared in the same manner as Example 131 except that instead of 3-methyl-N-(piperidin-4-yl)quinolin- 5-amine hydrochloride N-methyl-N-(piperidin-4-yl)yuoquinolin-8-amine hydrochloride (34.5 mg, 0.11 mmol) obtained in reference example 166 was used. ¹ H NMR (CDCl ₃ , 400 MHz) δ 9.51 (s, 1 N), 8.45 (dd, 1 N), 7.59-7.43 (m, 3 N), 7.17 (d, 1 N), 5.45 -4.87 (m, 2 N), 4.11-3.70 (m, 2 N), 3.47-3.09 (m, 3 N), 2.92-2.89 (m, 2 N), 2.82 (s, 3 N), 2.74-2.57 (m, 2 N), 2.37-2.22 (m, 2 N), 2.09-2.03 (m , 2 N), 1.88-1.81 (m, 2 N).

[2168] Example 321 (2S)-1-[2-[4-[3-Isoquinolyl(methyl)amino]-1-piperidyl]acetyl]pyrrolidine-2-carbonitrile

[2169] The title compound (97.5 mg, 28.0%) was prepared in the same manner as Example 121 except that instead of 3-methyl-N-(piperidin-4-yl)quinolin- 5-amine hydrochloride N-methyl-N-(piperidin-4-yl)isoquinolin-3-amine hydrochloride (276.5 mg, 0.88 mmol) obtained in reference example 165 was used. ¹ H NMR (CDCl ₃ , 400 MHz) δ 8.75 (d, 1 N), 7.96-7.93 (m, 1 N), 7.65-7.63 (m, 1 N), 7.44-7.42 (m , 2 N), 7.20 (d, 1 N), 5.10-4.76 (m, 1 N), 3.79-3.65 (m, 2 N), 3.57-3.51 (m, 1 N), 3.38-3.17 (m, 2 N), 3.12-3.07 (m, 2 N), 2.91 (s, 3 N), 2.37-1 .79 (m, 10 N).

[2170] Example 322 (2S)-1-[2-[4-[methyl-(6-methyl-3-quinolyl)amino]-1-piperidyl]acetyl]pyrrolidine-2-carbonitrile

[2171] The title compound (75.9 mg, 22.0%) was prepared similarly to Example 121 except that instead of 3-methyl-N-(piperidin-4-yl)quinoline-5 -amine hydrochloride N, 6-dimethyl-N-(piperidin-4-yl)quinolin-3-amine hydrochloride (344.5 mg, 0.88 mmol) obtained in reference example 168 was used. ¹ H NMR (CDCl ₃ , 400 MHz) δ 8.65 (d, 1 N), 7.82 (d, 1 N), 7.39 (s, 1 N), 7.24 (d, 1 N), 7.11 (d, 1 N), 5.09-4.75 (m, 1 N), 4.21-3.96 (m, 2 N), 3.67-3.50 (m, 3 N), 3.3S- 3.18 (m, 2H), 3.06-2.96 (m, 2 N), 2.88 (s, 3 N), 2.47 (s, 3 N), 2.30-2.06 (m, 5 N), 1.98-1.87 (m, 3 N).

[2172] Example 323: (S)-1-(2-(4-((b-methoxyquinolin-3-yl)(methyl)amino)piperidin-1-yl)acetyl)pyrrolide in-2-carbonitrile

[2173] The title compound (55.8 mg, 15.5%) was prepared in the same manner as Example 121 except that instead of 3-methyl-N-(piperidin-4-yl)quinolin- 5-amine hydrochloride 6-methoxy-N-methyl-N-(piperidin-4-yl)quinolin-3-amine hydrochloride (344.5 mg, 0.88 mmol) obtained in reference example 169 was used. ¹ H NMR ( CDCl ₃ , 400 MHz) δ 8.54 (d, 1 N), 7.80 (d, 1 N), 7.09 (d, 1 N), 7.04 (dd, 1 N), 6.69 (d, 1 N), 5.06-4.72 (m, 1 N), 3.87 (s, 3 N), 3.75-3.60 (m, 2 N), 3.55-3 .46 (m, 1 N), 3.34-3.13 (m, 2 N), 3.05-2.94 (m, 2 N), 2.87 (s, 3 N), 2.36 -1.86 (m, 8 N), 1.74 (d, 2 N).

[2174] Example 324: (2S)-1-[2-[4-[(7-methoxy-3-quinolyl)-methyl-amino]-1-piperidyl]acetyl]pyrrolide in-2-carbonitrile

[2175] The title compound (59.0 mg, 16.4%) was prepared as described in Example 121 except that instead of 3-methyl-N-(piperidin-4-yl)quinoline-5 -amine hydrochloride 7-methoxy-N-methyl-N-(piperidin-4-yl)quinolin-3-amine hydrochloride (344.5 mg, 0.88 mmol) obtained in Reference Example 170 was used. ¹ H NMR (CDCl ₃ , 400 MHz) δ 8.68 (d, 1 N), 7.55 (d, 1 N), 7.32 (d, 1 N), 7.24 (d, 1 N), 7.13 ( d, 1 N), 5.13-4.78 (m, 1 N), 4.15-3.96 (m, 1 N), 3.92 (s, 3 N), 3.71-3, 49 (m, 3 N), 3.35-3.17 (m, 2 N), 3.07-2.97 (m, 2 N), 2.88 (s, 3 N), 2.47 ( s, 3 N), 2.33-1.87 (m, 10 N).

[2176] Example 325

[2177] The title compound (53.3 mg, 14.8%) was prepared as described in Example 121 except that instead of 3-methyl-N-(piperidin-4-yl)quinoline-5 -amine hydrochloride 8-methoxy-N-methyl-N-(piperidin-4-yl)quinolin-3-amine hydrochloride (344.5 mg, 0.88 mmol) prepared in Reference Example 171 was used. ¹ H NMR (CDCl ₃ , 400 MHz) δ 8.65 (d, 1 N), 7.27 (t, 1 N), 7.14 (d, 1 N), 7.10 (d, 1 N), 6.71 ( d, 1 N), 5.02-4.67 (m, 1 N), 3.97 (s, 3 N), 3.71-3.40 (m, 3 N), 3.29-3, 08 (m, 2 N), 3.00-2.90 (m, 2 N), 2.83 (s, 3 N), 2.31-1.97 (m, 6 N), 1.92-1, 82 (m, 2H), 1.71-1.68 (m, 2H).

[2178] Example 326: (2S,4S)-4-fluoro-1-[2-[4-[methyl-(6-methyl-3-quinolyl)amino]-1-piperidyl]acetyl]pyrrolidine-2-carbonitrile

[2179] The title compound (13.0 mg, 28.9%) was prepared similarly to Example 131 except that instead of 3-methyl-N-(piperidin-4-yl)quinoline-5 -amine hydrochloride N,6-dimethyl-N-(piperidin-4-yl)quinolin-3-amine hydrochloride N-hydrochloride (36.1 mg, 0.11 mmol) obtained in Reference Example 168 was used. ^1H NMR ( CDCl ₃ , 400 MHz) δ 8.66 (d, 1 N), 7.83 (d, 1 N), 7.40 (s, 1 N), 7.27-7.24 (m, 1 N) , 7.12 (d, 1 N), 5.49-4.93 (m, 2 N), 4.19-4.01 (m, 1 N), 3.81-3.70 (m, 2 N), 3.29-3.15 (m, 2 N), 3.09-2.93 (m, 2 N), 2.88 (s, 3 N), 2.47 (s, 3 N) , 2.24-1.89 (m, 6 N), 1.79-1.76 (m, 2 N).

[2180] Example 327 (2S,4S)-4-fluoro-1-(2-(4-((6-methoxyquinolin-3-yl)(methyl)amino)piperidin-1-yl)acetyl)pyrrolidin-2 -carbonitrile

[2181] The title compound (7.3 mg, 15.5%) was prepared in the same manner as Example 131 except that instead of 3-methyl-N-(piperidin-4-yl)quinolin- 5-amine hydrochloride 6-methoxy-N-methyl-N-(piperidin-4-yl)quinolin-3-amine hydrochloride (37.8 mg, 0.11 mmol) obtained in reference example 169 was used. ¹ H NMR ( CDCl ₃ , 400 MHz) δ 8.54 (d, 1 N), 7.80 (d, 1 N), 7.09 (d, 1 N), 7.04 (dd, 1 N), 6.90 (d, 1 N), 5.46-5.24 (m, 2 N), 4.14-3.90 (m, 1 N), 3.87 (s, 3 N), 3.84-3 .68 (m, 2 N), 3.40-3.13 (m, 2 Η), 3.07-2.92 (m, 2 Η), 2.86 (s, 3 Η), 2.75 -2.57 (m, 1 Η), 2.37-2.20 (m, 3 Η), 2.10-1.84 (m, 2 Η), 1.76-1.63 (m, 2 Η).

[2182] Example 328 (2S,4S)-4-fluoro-1-(2-(4-((7-methoxyquinolin-3-yl)(methyl)amino)piperidin-1-yl)acetyl)pyrrolidin-2 -carbonitrile

[2183] The title compound (11.6 mg, 24.7%) was prepared in the same manner as Example 131 except that instead of 3-methyl-N-(piperidin-4-yl)quinolin- 5-amine hydrochloride 7-methoxy-N-methyl-N-(piperidin-4-yl)quinolin-3-amine hydrochloride (37.8 mg, 0.11 mmol) obtained in Reference Example 170 was used. ¹ H NMR ( CDCl ₃ , 400 MHz) δ 8.68 (s, 1 H), 7.55 (d, 1 H), 7.32 (d, 1 H), 7.24 (d, 1 H), 7.13 (dd, 1 N), 5.50-4.94 (m, 2 N), 4.21-4.12 (m, 1 N), 3.87 (s, 3 N), 3.78-3 .64 (m, 2 N), 3.46-3.17 (m, 2 N), 3.10-2.97 (m, 2 N), 2.88 (s, 3 N), 2.80 -2.64 (m, 1 N), 2.49-2.24 (m, 3 N), 2.12-2.02 (m, 1 N), 1.97-1.84 (m, 3 N).

[2184] Example 329: (2S,4S)-4-fluoro-1-[2-[4-[(8-methoxy-3-quinolyl)-methyl-amino]-1-piperidyl]acetyl]pyrrolide in-2 -carbonitrile

[2185] The title compound (3.8 mg, 8.0%) was prepared as described in Example 131 except that instead of 3-methyl-M-(piperidin-4-yl)quinoline-5 -amine hydrochloride 8-methoxy-N-methyl-N-(piperidin-4-yl)quinolin-3-amine hydrochloride (37.8 mg, 0.11 mmol) prepared in Reference Example 171 was used. ¹ H NMR (CDCl ₃ , 400 MHz) δ 8.72 (d, 1 N), 7.35 (t, 1 N), 7.22 (d, 1 N), 7.18 (d, 1 N), 6.80 ( d, 1 N), 5.50-4.94 (m, 2 N), 4.21-4.12 (m, 1 N), 4.06 (s, 3 N), 3.88-3, 73 (m, 2 N), 3.46-3.21 (m, 2 N), 3.11-2.96 (m, 2 N), 2.91 (s, 3 N), 2.80- 2.65 (m, 1 N), 2.50-2.22 (m, 3 N), 2.15-1.86 (m, 2 N), 1.81-1.78 (m, 3 N ).

[2186] Example 330: (2S,4S)-4-fluoro-1-[2-[4-[(8-fluoro-5-quinolyl)amino]-1-piperidyl]acetyl]pyrrolide in-2-carbonitrile

[2187](2S,4S)-1-(2-chloroacetyl)-4-fluoropyrrolidine-2-carbonitrile (90.4 mg, 0.47 mmol) obtained in Reference Example 2 was dissolved in anhydrous acetonitrile (4 ml) . To the resulting solution, 8-fluoro-N-(piperidin-4-yl)quinolin-5-amine hydrochloride (151.0 mg, 0.47 mmol) obtained in Reference Example 172 and potassium carbonate (262.3 mg, 1.90 mmol). The reaction mixture was stirred overnight at room temperature. After completion of the reaction, water was added to the reaction mixture. The aqueous layer of the reaction mixture was extracted with ethyl acetate. The extracted organic layer was dried and filtered over anhydrous magnesium sulfate. The filtered solution was concentrated and then purified by silica gel column chromatography (dichloromethane/methanol = 10/1, v/v) to give the title compound (76.2 mg, 40.2%). ¹ H-NMR (CD ₃ OD, 400 MHz) δ 8.94 (d, 1 H), 8.18 (d, 1 H), 7.42 (d, 1 H), 7.30-7.26 (m, 1 N), 6.55 (d, 1 N), 5.50-5.30 (m, 1 N), 5.10-4.80 (m, 1 N), 4.30-4 .15 (m, 1 N), 4.05-3.85 (m, 1 N), 3.85-3.70 (m, 2 N), 3.55-3.15 (m, 2 N) , 3.05-2.85 (m, 2 N), 2.80-2.60 (m, 1 N), 2.50-2.30 (m, 2 N), 2.20-2.05 (m, 2 N), 1.90-1.55 (m, 3 N)

[2188] Example 331: (2S,4S)-4-fluoro-1-[2-[4-[(8-methyl-5-quinolyl)amino]-1-piperidyl]acetyl]pyrrolide in-2-carbonitrile

[2189] The title compound (46.7 mg, 24.9%) was prepared in the same manner as in Example 330 except that instead of 8-fluoro-N-(piperidin-4-yl)quinolin- 5-amine hydrochloride 8-methyl-N-(piperidin-4-yl)quinolin-5-amine hydrochloride (61.2 mg, 0.20 mmol) obtained in reference example 173 was used. ¹ H-NMR (CDCl ₃ , 400 MHz) δ 8.93 (d, 1 N), 8.17 (d, 1 N), 7.42-7.33 (m, 2 N), 6.60 (d, 1 N), 5, 55-5.30 (m, 1 N), 5.05-4.90 (m, 1 N), 4.30-4.10 (m, 1 N), 4.05-3.65 (m, 2 N), 3.55-3.16 (m, 3 N), 3.05-2.85 (m, 2 N), 2.80-2.68 (m, 1 N), 2.68 ( s, 3 N), 2.50-2.25 (m, 2 N), 2.25-2.05 (m, 2 N), 1.95-1.50 (m, 3 N)

[2190] Example 332 (2S,4S)-1-[2-[4-[(8-Benzyloxy-5-quinolyl)amino]-1-piperidyl]acetyl]-4-fluoropyrrolidine-2-carbonitrile

[2191] The title compound (109.7 mg, 47.4%) was prepared in the same manner as Example 330 except that instead of 8-fluoro-N-(piperidin-4-yl)quinolin- 5-amine hydrochloride 8-(benzyloxy)-N-(piperidin-4-yl)quinolin-5-amine hydrochloride (134.2 mg, 0.3S mmol) obtained in Reference Example 174 was used. ¹ H-NMR (CDCl ₃ , 400 MHz) δ 8.97 (d, 1 N), 8.19 (d, 1 N), 7.51-7.49 (m, 2 N), 7.41-7.26 (m, 4 N), 6.92 (d, 1 N), 6.53 (d, 1 N), 5.55-5.30 (m, 1 N), 5.48 (s, 2 N), 5. 00-4.85 (m, 1 N), 4.30-4.10 (m, 1 N), 4.05-3.70 (m, 2 N), 3.55-3.20 (m, 3 N), 3.05-2.80 (m, 2 N), 2.80-2.60 (m, 1 N), 2.50-2.25 (m, 2 N), 2.25- 2.05 (m, 2 N), 1.80-1.50 (m, 3 N)

[2192] Example 333 (2S,4S)-1-[2-[4-[(3-chloro-5-quinolyl)amino]-1-piperidyl]acetyl]-4-fluoropyrrolidine-2-carbonitrile

[2193] The title compound (191.7 mg, 97.1%) was prepared in the same manner as Example 330 except that instead of 8-fluoro-N-(piperidin-4-yl)quinolin- 5-amine hydrochloride 3-chloro-N-(piperidin-4-yl)quinolin-5-amine hydrochloride (241.4 mg, 0.72 mmol) obtained in reference example 175 was used. ¹ H-NMR (CDCl ₃ , 400 MHz) δ 8.80 (s, 1 N), 8.13 (s, 1 N), 7.55 (t, 1 N), 7.45 (d, 1 N), 6.68 (d, 1 N), 5.50-5.30 (m, 1 N), 5.00-4.85 (m, 1 N), 4.30-4.15 (m, 1 N), 4.10- 3.70 (m, 2N), 3.60-3.10 (m, 3 N), 3.10-2.85 (m, 2 N), 2.85-2.60 (m, 1 N) , 2.50-2.30 (m, 2 N), 2.30-2.10 (m, 2 N), 1.90-1.50 (m, 3 N)

[2194] Example 334: (2S,4S)-4-fluoro-1-[2-[4-[[8-(trifluoromethyl)-5-quinolyl]amino]-1-piperidyl]acetyl]pyrrolidine-2-carbonitrile

[2195] The title compound (116.6 mg, 54.7%) was prepared in the same manner as in Example 330 except that instead of 8-fluoro-N-(piperidin-4-yl)quinolin- 5-amine hydrochloride N-(piperidin-4-yl)-8-(trifluoromethyl)quinoline-5-amine hydrochloride (137.5 mg, 0.37 mmol) obtained in reference example 176 was used. ¹ H-NMR (CDCl ₃ , 400 MHz) δ 9.01 (d, 1 N), 8.16 (d, 1 N), 7.89 (d, 1 N), 7.41 (t, 1 N), 6.56 ( d, 1 N), 5.55-5.30 (m, 1 N), 5.00-4.90 (m, 1 N), 4.30-4.10 (m, 1 N), 4, 05-3.70 (m, 2 N), 3.70-3.15 (m, 3 N), 3.10-2.85 (m, 2 N), 2.80-2.55 (m, 1 N), 2.50-2.35 (m, 2 N), 2.35-2.10 (m, 2 N), 1.95-1.55 (m, 3 N)

[2196] Example 335 5-[[1-[2-oxo-2-[(2S,4S)-2-cyano-4-fluoropyrrolidin-1-yl]ethyl]-4-piperidyl]amino]quinoline-2 -carbonitrile

[2197] The title compound (42.1 mg, 21.8%) was prepared in the same manner as Example 330 except that instead of 8-fluoro-N-(piperidin-4-yl)quinolin- 5-amine hydrochloride 5-(piperidin-4-ylamino)quinoline-2-carbonitrile hydrochloride (299.7 mg, 0.92 mmol) obtained in reference example 177 was used. ¹ H-NMR (CDCl ₃ , 400 MHz) δ 8.29 (d, 1 N), 7.68-7.59 (m, 2 N), 7.50 (d, 1 N), 6.76 (d, 1 N), 5.60-5, 30 (m, 1 N), 5.00-4.90 (m, 1 N), 4.30-4.10 (m, 1 N), 4.10-3.70 (m, 2 N), 3.60-3.20 (m, 3 N), 3.10-2.90 (m, 2 N), 2.80-2.60 (m, 1 N), 2.50-2.30 ( m, 2 N), 2.30-2.10 (m, 2 N), 1.90-1.55 (m, 3 N)

[2198] Example 336 (2S,4S)-1-(2-(4-(benzo[b]thiophen-4-ylamino)piperidin-1-yl)acetyl)-4-fluoropyrrolidine-2-carbonitrile

[2199] The title compound (239.9 mg, 93.6%) was prepared in the same manner as in Example 330 except that instead of 8-fluoro-N-(piperidin-4-yl)quinolin- 5-amine hydrochloride N-(benzo[b]thiophen-4-yl)piperidin-4-amine hydrochloride (202.4 mg, 0.66 mmol) obtained in reference example 178 was used. ¹ H-NMR (CDCl ₃ , 400 MHz) δ 7.31 (s, 1 N), 7.31-7.17 (m, 3 N), 6.52 (d, 1 N), 5.50-5.25 (m, 1 N ), 4.95-4.85 (m, 1 N), 4.25-4.15 (m, 1 N), 4.15-3.70 (m, 2 N), 3.55-3, 10 (m, 3 N), 3.00-2.80 (m, 2 N), 2.75-2.60 (m, 1 N), 2.40-2.25 (m, 2 N), 2.20-2.05 (m, 2 N), 1.85-1.50 (m, 3 N)

[2200] Example 337 (2S,4S)-4-fluoro-1-[2-[4-[(6-fluoro-4-quinolyl)amino]-1-piperidyl]acetyl]pyrrolidine-2-carbonitrile

[2201] The title compound (22.9 mg, 23.2%) was prepared in the same manner as in Example 330 except that instead of 8-fluoro-N-(piperidin-4-yl)quinolin- 5-amine hydrochloride 6-fluoro-N-(piperidin-4-yl)quinolin-4-amine hydrochloride (154.5 mg, 0.49 mmol) obtained in reference example 179 was used. ¹ H-NMR (CDCl ₃ , 400 MHz) δ 8.53 (d, 1 N), 7.97 (d, 1 N), 7.40 (s, 1 N), 7.33 (d, 1 N), 6.46 (d, 1 N), 5.55-5.35 (m, 1 N), 5.05-4.95 (m, 1 N), 4.30-4.10 (m, 1 N), 3.90- 3.50 (m, 3 N), 3.50-3.10 (m, 2 N), 3.05-2.90 (m, 2 N), 2.85-2.70 (m, 1 N ), 2.50-2.35 (m, 2 N), 2.25-2.10 (m, 2 N), 1.80-1.60 (m, 3 N)

[2202] Example 3S8. (2S,4S)-1-[2-[4-[(6-chloro-4-quinolyl)amino]-1-piperidyl]acetyl]-4-fluoropyrrolidine-2-carbonitrile

[2203] The title compound (35.0 mg, 34.0%) was prepared in the same manner as in Example 330 except that instead of 8-fluoro-N-(piperidin-4-yl)quinolin- 5-amine hydrochloride 6-chloro-N-(piperidin-4-yl)quinolin-4-amine hydrochloride (194.2 mg, 0.58 mmol) obtained in reference example 180 was used. ¹ H-NMR (CDCl ₃ , 400 MHz) δ 8.54 (d, 1 N), 7.92 (d, 1 N), 7.69 (s, 1 N), 7.57 (d, 1 N), 6.46 (d, 1 N), 5.55-5.30 (m, 1 N), 5.00-4.90 (m, 1 N), 4.35-4.20 (m, 1 N), 4.05- 3.70 (m, 2 N), 3.65-3.20 (m, 3 N), 3.05-2.90 (m, 2 N), 2.80-2.60 (m, 1 N ), 2.50-2.30 (m, 2 N), 2.20-2.10 (m, 2 N), 1.90-1.60 (m, 3 N)

[2204] Example 339: (2S,4S)-4-fluoro-1-[2-[4-(4-isoquinolamine)-1-piperidyl]acetyl]pyrrolidine-2-carbonitrile

[2205] The title compound (180.2 mg, 40.5%) was prepared in the same manner as in Example 330 except that instead of 8-fluoro-N-(piperidin-4-yl)quinolin- 5-amine hydrochloride N-(piperidin-4-yl)isoquinolin-4-amine hydrochloride (350.0 mg, 1.17 mmol) obtained in reference example 181 was used. ¹ H-NMR (CDCl ₃ , 400 MHz) δ 8.68 (s, 1 N), 7.92-7.88 (m, 2 N), 7.78 (d, 1 N), 7.66 (t, 1 N), 7.58 (t, 1 N), 5.55-5.25 (m, 1 N), 5.00-4.90 (m, 1 N), 4.30-4.15 (m, 1 N), 4.15- 3.70 (m, 2 N), 3.65-3.20 (m, 3 N), 3.10-2.85 (m, 2 N), 2.80-2.60 (m, 1 N ), 2.50-2.30 (m, 2 N), 2.30-2.15 (m, 2 N), 1.90-1.65 (m, 3 N)

[2206] Example 340: (2S,4S)-4-fluoro-1-[2-[4-(5-isoquinolamine)-1-piperidyl]acetyl]pyrrolidine-2-carbonitrile

[2207] The title compound (153.2 mg, 34.5%) was prepared in the same manner as in Example 330 except that instead of 8-fluoro-N-(piperidin-4-yl)quinolin- 5-amine hydrochloride N-(piperidin-4-yl)isoquinolin-5-amine hydrochloride (305.9 mg, 1.02 mmol) obtained in reference example 182 was used. ¹ H-NMR (CDCl ₃ , 400 MHz) δ 9.15 (s, 1 Η), 8.47 (d, 1 Η), 7.54 (d, 1 Η), 7.45 (t, 1 Η), 7.31 (d, 1 Η), 6, 78 (d, 1 Η), 5.55-5.25 (m, 1 Η), 5.00-4.85 (m, 1 Η), 4.30-4.15 (m, 1 Η), 4.10-3.70 (m, 2 Η), 3.60-3.15 (m, 3 Η), 3.05-2.85 (m, 2 Η), 2.80-2.60 ( m, 1 Η), 2.50-2.30 (m, 2 Η), 2.30-2.10 (m, 2 Η), 1.90-1.55 (m, 3 Η)

[2208] Example 341: (2S,4S)-4-fluoro-1-[2-[4-(6-isoquinolamine)-1-piperidyl]acetyl]pyrrolidine-2-carbonitrile

[2209] The title compound (28.4 mg, 6.4%) was prepared in the same manner as in Example 330 except that instead of 8-fluoro-N-(piperidin-4-yl)quinolin- 5-amine hydrochloride N-(piperidin-4-yl)isoquinolin-6-amine hydrochloride (137.6 mg, 0.46 mmol) obtained in reference example 183 was used. ¹ H-NMR (CDCl ₃ , 400 MHz) δ 8.93 (s, 1 N), 8.31 (d, 1 N), 7.71 (d, 1 N), 7.37 (d, 1 N), 6.89 (d, 1 N), 6.65 (s, 1 N), 5.55-5.25 (m, 1 N), 5.00-4.85 (m, 1 N), 4.35-4.15 (m, 1 N ), 4.15-3.70 (m, 2 N), 3.55-3.15 (m, 3 N), 3.05-2.85 (m, 2 N), 2.80-2, 60 (m, 1 N), 2.50-2.30 (m, 2 N), 2.25-2.05 (m, 2 N), 1.75-1.50 (m, 3 N)

[2210] Example 342: (2S,4S)-4-fluoro-1-[2-[4-(8-isoquinolamine)-1-piperidyl]acetyl]pyrrolidine-2-carbonitrile

[2211] The title compound (40.8 mg, 9.2%) was prepared in the same manner as Example 330 except that instead of 8-fluoro-N-(piperidin-4-yl)quinolin- 5-amine hydrochloride N-(piperidin-4-yl)isoquinolin-8-amine hydrochloride (374.8 mg, 1.25 mmol) obtained in reference example 184 was used. ¹ H-NMR (CDCl ₃ , 400 MHz) δ 9.32 (s, 1 N), 8.45 (d, 1 N), 7.57-7.50 (m, 2 N), 7.12 (d, 1 N), 6.68 (d, 1 N), 5.60-5.25 (m, 1 N), 5.00-4.90 (m, 1 N), 4.30-4.15 (m, 1 N), 4.05- 3.70 (m, 2 N), 3.60-3.20 (m, 3 N), 3.05-2.85 (m, 2 N), 2.85-2.60 (m, 1 N ), 2.55-2.30 (m, 2 N), 2.30-2.10 (m, 2 N), 1.90-1.60 (m, 3 N)

[2212] Example 343 (2S,4S)-4-fluoro-1-[2-[4-[(8-methyl-4-quinolyl)amino]-1-piperidyl]acetyl]pyrrolidine-2-carbonitrile

[2213] The title compound (205.7 mg, 52.8%) was prepared in the same manner as in Example 330 except that instead of 8-fluoro-N-(piperidin-4-yl)quinolin- 5-amine hydrochloride 8-methyl-N-(piperidin-4-yl)quinolin-4-amine hydrochloride (309.6 mg, 0.99 mmol) obtained in reference example 185 was used. ¹ H-NMR (CDCl ₃ , 400 MHz) δ 8.58 (d, 1 N), 7.58 (d, 1 N), 7.50 (d, 1 N), 7.32 (t, 1 N), 6.46 (d, 1 N ), 5.50-5.25 (m, 1 N), 5.00-4.80 (m, 1 N), 4.30-4.10 (m, 1 N), 4.05-3, 70 (m, 2 N), 3.65-3.15 (m, 3 N), 3.05-2.85 (m, 2 N), 2.76 (s, 3 N), 2.76- 2.55 (m, 1 N), 2.45-2.30 (m, 2 N), 2.20-2.05 (m, 2 N), 1.85-1.55 (m, 3 N)

[2214] Example 344 (2S,4S)-1-[2-[4-[(8-chloro-4-quinolyl)amino]-1-piperidyl]acetyl]-4-fluoropyrrolidine-2-carbonitrile

[2215] The title compound (16.6 mg, 4.1%) was prepared in the same manner as in Example 330 except that instead of 8-fluoro-N-(piperidin-4-yl)quinolin- 5-amine hydrochloride 8-chloro-N-(piperidin-4-yl)quinolin-4-amine hydrochloride (70.1 mg, 0.21 mmol) obtained in reference example 186 was used. ¹ H-NMR (CDCl ₃ , 400 MHz) δ 8.54 (d, 1 N), 7.46-7.37 (m, 3 N), 6.71 (d, 1 N), 5.70-5.20 (m, 1 N ), 5.05-4.85 (m, 1 N), 4.30-4.10 (m, 1 N), 4.05-3.70 (m, 2 N), 3.60-3, 15 (m, 3 N), 3.00-2.80 (m, 2 N), 2.80-2.60 (m, 1 N), 2.50-2.30 (m, 2 N), 2.20-2.05 (m, 2 N), 1.90-1.50 (m, 3 N)

[2216] Example 345: (2S,4S)-4-fluoro-1-[2-[4-[(8-fluoro-4-quinolyl)amino]-1-piperidyl]acetyl]pyrrolide in-2-carbonitrile

[2217] The title compound (18.7 mg, 4.8%) was prepared in the same manner as in Example 330 except that instead of 8-fluoro-N-(piperidin-4-yl)quinolin- 5-amine hydrochloride 8-fluoro-N-(piperidin-4-yl)quinolin-4-amine hydrochloride (192.9 mg, 0.61 mmol) obtained in reference example 187 was used. ¹ H-NMR (CDCl ₃ , 400 MHz) δ 8.59 (d, 1 N), 7.49 (d, 1 N), 7.36-7.33 (m, 2 N), 6.50 (d, 1 N), 5, 55-5.25 (m, 1 N), 5.05-4.90 (m, 1 N), 4.30-4.15 (m, 1 N), 4.05-3.70 (m, 2 N), 3.65-3.20 (m, 3 N), 3.10-2.85 (m, 2 N), 2.80-2.60 (m, 1 N), 2.50- 2.30 (m, 2 N), 2.20-2.05 (m, 2 N), 1.90-1.50 (m, 3 N)

[2218] Example 346: (2S,4S)-4-fluoro-1-[2-[4-[[8-(trifluoromethyl)-4-quinolyl]amino]-1-piperidyl]acetyl]pyrrolidine-2-carbonitrile

[2219] The title compound (347.4 mg, 78.5%) was prepared in the same manner as in Example 330 except that instead of 8-fluoro-N-(piperidin-4-yl)quinolin- 5-amine hydrochloride N-(piperidin-4-yl)-8-(trifluoromethyl)quinoline-4-amine hydrochloride (341.3 mg, 0.93 mmol) obtained in reference example 188 was used. ¹ H-NMR (CDCl ₃ , 400 MHz) δ 8.65 (d, 1 N), 7.99-7.95 (m, 2 N), 7.44 (t, 1 N), 6.51 (d, 1 N), 5.50-5.20 (m, 1 N), 5.10-4.85 (m, 1 N), 4.30-4.10 (m, 1 N), 4.00-3.65 ( m, 2 N), 3.60-3.10 (m, 3 N), 3.05-2.80 (m, 2 N), 2.75-2.55 (m, 1 N), 2. 50-2.25 (m, 2 N), 2.25-2.05 (m, 2 N), 1.90-1.55 (m, 3 N)

[2220] Example 347 (2S,4S)-4-fluoro-1-[2-[4-[[8-(trifluoromethoxy)-5-quinolyl]amino]-1-piperidyl]acetyl]pyrrolidine-2-carbonitrile

[2221] The title compound (125.5 mg, 82.2%) was prepared in the same manner as Example 330 except that instead of 8-fluoro-N-(piperidin-4-yl)quinolin- 5-amine hydrochloride N-(piperidin-4-yl)-8-(trifluoromethoxy)quinoline-5-amine hydrochloride (408.2 mg, 1.06 mmol) obtained in reference example 189 was used. ¹ H-NMR (CDCl ₃ , 400 MHz) δ 9.00 (d, 1 N), 8.18 (d, 1 N), 7.50 (d, 1 N), 7.43 (t, 1 N), 6.56 ( d, 1 N), 5.55-5.25 (m, 1 N), 5.05-4.90 (m, 1 N), 4.30-4.15 (m, 1 N), 4, 05-3.70 (m, 2 N), 3.60-3.20 (m, 3 N), 3.10-2.90 (m, 2 N), 2.80-2.60 (m, 1 N), 2.50-2.35 (m, 2 N), 2.35-2.10 (m, 2 N), 1.90-1.60 (m, 3 N)

[2222] Example 348: (2S,4S)-4-fluoro-1-[2-[4-[(3-methoxy-5-quinolyl)amino]-1-piperidyl]acetyl]pyrrolidine-2-carbonitrile

[2223] The title compound (284.9 mg, 75.5%) was prepared in the same manner as in Example 330 except that instead of 8-fluoro-N-(piperidin-4-yl)quinolin- 5-amine hydrochloride 3-methoxy-N-(piperidin-4-yl)quinolin-5-amine hydrochloride (302.7 mg, 0.92 mmol) obtained in Reference Example 190 was used. ¹ H-NMR (CDCl ₃ , 400 MHz) δ 8.65 (s, 1 N), 7.47-7.38 (m, 2 N), 7.34 (s, 1 N), 6.68 (d, 1 N), 5, 50-5.20 (m, 1 N), 5.00-4.85 (m, 1 N), 4.30-4.15 (m, 1 N), 3.90 (s, 3 N), 4.10-3.70 (m, 2 N), 3.55-3.10 (m, 3 N), 3.05-2.85 (m, 2 N), 2.80-2.60 ( m, 1 N), 2.45-2.30 (m, 2 N), 2.30-2.10 (m, 2 N), 1.95-1.55 (m, 3 N)

[2224] Example 349: (2S,4S)-4-fluoro-1-[2-[4-[(3-fluoro-5-quinolyl)amino]-1-piperidyl]acetyl]pyrrolidine-2-carbonitrile

[2225] The title compound (147.1 mg, 37.0%) was prepared in the same manner as in Example 330 except that instead of 8-fluoro-N-(piperidin-4-yl)quinolin- 5-amine hydrochloride 3-fluoro-N-(piperidin-4-yl)quinolin-5-amine hydrochloride (316.6 mg, 1.00 mmol) obtained in reference example 191 was used. ¹ H-NMR (CDCl ₃ , 400 MHz) δ 8.75 (s, 1 N), 7.81 (d, 1 N), 7.54-7.47 (m, 2 N), 6.69 (d, 1 N), 5, 50-5.20 (m, 1 N), 5.00-4.80 (m, 1 N), 4.30-4.10 (m, 1 N), 4.10-3.70 (m, 2 N), 3.60-3.10 (m, 3 N), 3.00-2.80 (m, 2 N), 2.80-2.55 (m, 1 N), 2.50- 2.30 (m, 2 N), 2.30-2.10 (m, 2 N), 1.85-1.50 (m, 3 N)

[2226] Example 350: (2S,4S)-4-fluoro-1-[2-[4-[furo[3,2-c]pyridin-7-yl(methyl)amino]-1-piperidyl]acetyl] pyrrolidine-2-carbonitrile

[2227] The title compound (8.9 mg, 21.0%) was prepared in the same manner as Example 131 except that instead of 3-methyl-N-(piperidin-4-yl)quinoline- 5-amine hydrochloride N-methyl-N-(piperidin-4-yl)furo[3,2-c]pyridin-7-amine hydrochloride (3S.4 mg, 0.11 mmol) prepared in Reference Example 161 was used. ^1H NMR ( _MeOD4 , 400 MHz) δ 8.35 (s, 1 H), 7.87 (d, 2 H), 6.96 (d, 1 H), 5.51-4.96 (m , 2 N), 4.15-3.75 (m, 3 N), 3.42-3.20 (m, 2 N), 3.06-3.01 (m, 2 N), 2.95 (s, 3 N), 2.66-2.40 (m, 2 N), 2.29-2.23 (m, 2 N), 2.04-1.95 (m, 2 N), 1 .75-1.73 (m, 2 N).

[2228] Example 351: (2S,4S)-1-[2-[4-[(1-chloro-5-isoquinolyl)amino]-1-piperidyl]acetyl]-4-fluoropyrrolidine-2-carbonitrile

[2229] The title compound (34.6 mg, 60.8%) was prepared in the same manner as Example 330 except that instead of 8-fluoro-N-(piperidin-4-yl)quinolin- 5-amine hydrochloride 1-chloro-N-(piperidin-4-yl)isoquinolin-5-amine hydrochloride (45.8 mg, 0.14 mmol) obtained in reference example 192 was used. ¹ H-NMR (CDCl ₃ , 400 MHz) δ 8.21 (d, 1 N), 8.06 (d, 1 N), 7.88-7.49 (m, 2 N), 6.83 (d, 1 N), 5, 55-5.25 (m, 1 N), 5.00-4.85 (m, 1 N), 4.30-4.15 (m, 1 N), 4.15-3.70 (m, 2 N), 3.60-3.20 (m, 3 N), 3.05-2.85 (m, 2 N), 2.80-2.60 (m, 1 N), 2.50- 2.30 (m, 2 N), 2.30-2.10 (m, 2 N), 1.85-1.55 (m, 3 N)

[2230] Example 352: (2S,4S)-1-[2-[4-[(3-chloro-5-isoquinolyl)amino]-1-piperidyl]acetyl]-4-fluoropyrrolidine-2-carbonitrile

[2231] The title compound (194.4 mg, 50.9%) was prepared in the same manner as in Example 330 except that instead of 8-fluoro-N-(piperidin-4-yl)quinolin- 5-amine hydrochloride 3-chloro-N-(piperidin-4-yl)isoquinolin-5-amine hydrochloride (307.2 mg, 0.92 mmol) obtained in reference example 193 was used. ¹ H-NMR (CDCl ₃ , 400 MHz) δ 8.95 (s, 1 N), 7.66 (s, 1 N), 7.43 (t, 1 N), 7.28 (d, 1 N), 6.76 (d, 1 N), 5.55-5.35 (m, 1 N), 5.00-4.85 (m, 1 N), 4.30-4.10 (m, 1 N), 4.00- 3.70 (m, 2 N), 3.55-3.15 (m, 3 N), 3.05-2.85 (m, 2 N), 2.80-2.60 (m, 1 N ), 2.50-2.25 (m, 2 N), 2.25-2.10 (m, 2 N), 1.90-1.50 (m, 3 N)

[2232] Example 353: (2S,4S)-1-[2-[4-[(8-chloro-5-isoquinolyl)amino]-1-piperidyl]acetyl]-4-fluoropyrrolidine-2-carbonitrile

[2233] The title compound (193.7 mg, 63.6%) was prepared in the same manner as in Example 330 except that instead of 8-fluoro-N-(piperidin-4-yl)quinoline- 5-amine hydrochloride 8-chloro-N-(piperidin-4-yl)isoquinolin-5-amine hydrochloride (245.2 mg, 0.73 mmol) obtained in reference example 194 was used. ¹ H-NMR (CDCl ₃ , 400 MHz) δ 9.58 (s, 1 N), 8.57 (d, 1 N), 7.54 (d, 1 N), 7.45 (d, 1 N), 6.67 (d, 1 N), 5.55-5.25 (m, 1 N), 5.00-4.90 (m, 1 N), 4.30-4.10 (m, 1 N), 4.00- 3.65 (m, 2 N), 3.60-3.20 (m, 3 N), 3.10-2.85 (m, 2 N), 2.85-2.60 (m, 1 N ), 2.50-2.30 (m, 2 N), 2.30-2.10 (m, 2 N), 1.90-1.55 (m, 3 N)

[2234] Example 354: (2S,4S)-4-fluoro-1-[2-[4-[(4-methyl-5-isoquinolyl)amino]-1-piperidyl]acetyl]pyrrolidine-2-carbonitrile

[2235] The title compound (307.2 mg, 93.3%) was prepared in the same manner as Example 330 except that instead of 8-fluoro-N-(piperidin-4-yl)quinoline- 5-amine hydrochloride 4-methyl-N-(piperidin-4-yl)isoquinolin-5-amine hydrochloride (261.6 mg, 0.83 mmol) obtained in reference example 195 was used. ¹ H-NMR (CDCl ₃ , 400 MHz) δ 8.93 (s, 1 N), 8.11 (s, 1 N), 7.39 (t, 1 N), 7.27-7.23 (m, 1 N), 6, 73 (d, 1 N), 5.50-5.20 (m, 1 N), 5.00-4.80 (m, 1 N), 4.30-4.10 (m, 1 N), 4.05-3.70 (m, 2 N), 3.55-3.15 (m, 3 N), 2.91 (s, 3 N), 2.91-2.80 (m, 2 N ), 2.80-2.60 (m, 1 N), 2.55-2.30 (m, 2 N), 2.30-2.10 (m, 2 N), 1.85-1, 50(m, 3 N)

[2236] Example 355: (2S,4S)-4-fluoro-1-[2-[4-[(3-methoxy-5-isoquinolyl)amino]-1-piperidyl]acetyl]pyrrolidine-2-carbonitrile

[2237] The title compound (76.0 mg, 16.2%) was prepared in the same manner as in Example 330 except that instead of 8-fluoro-N-(piperidin-4-yl)quinolin- 5-amine hydrochloride 3-methoxy-N-(piperidin-4-yl)isoquinolin-5-amine hydrochloride (376.0 mg, 1.14 mmol) obtained in reference example 196 was used. ¹ H-NMR (CDCl ₃ , 400 MHz) δ 8.86 (s, 1 N), 7.48-7.21 (m, 2 N), 6.91 (s, 1 N), 6.66 (d, 1 N), 5, 60-5.30 (m, 1 N), 5.00-4.90 (m, 1 N), 4.30-4.10 (m, 1 N), 4.05 (s, 3 N), 4.05-3.70 (m, 2 N), 3.60-3.20 (m, 3 N), 3.10-2.90 (m, 2 N), 2.80-2.60 ( m, 1 N), 2.60-2.30 (m, 2 N), 2.30-2.10 (m, 2 N), 1.85-1.50 (m, 3 N)

[2238] Example 356: (2S,4S)-4-fluoro-1-[2-[4-[(8-nitro-5-isoquinolyl)amino]-1-piperidyl]acetyl]pyrrolidine-2-carbonitrile

[2239] The title compound (95.6 mg, 19.7%) was prepared in the same manner as in Example 330 except that instead of 8-fluoro-N-(piperidin-4-yl)quinolin- 5-amine hydrochloride 8-nitro-N-(piperidin-4-yl)isoquinolin-5-amine hydrochloride (165.1 mg, 0.48 mmol) obtained in reference example 197 was used. ¹ H-NMR (CDCl ₃ , 400 MHz) δ 8.66 (d, 1 N), 8.50 (d, 1 N), 7.58 (d, 1 N), 7.26 (s, 1 N), 6.66 (d, 1 N), 5.60-5.20 (m, 1 N), 5.00-4.85 (m, 1 N), 4.30-4.10 (m, 1 N), 4.00- 3.70 (m, 2 N), 3.70-3.15 (m, 3 N), 3.10-2.90 (m, 2 N), 2.85-2.60 (m, 1 N ), 2.55-2.30 (m, 2 N), 2.30-2.10 (m, 2 N), 1.85-1.50 (m, 3 N)

[2240] Example 357: (2S,4S)-4-fluoro-1-[2-[4-[(8-fluoro-5-isoquinolyl)amino]-1-piperidyl]acetyl]pyrrolidine-2-carbonitrile

[2241] The title compound (225.9 mg, 49.7%) was prepared in the same manner as Example 3S0 except that instead of 8-fluoro-N-(piperidin-4-yl)quinolin- 5-amine hydrochloride 8-fluoro-N-(piperidin-4-yl)isoquinolin-5-amine hydrochloride (348.2 mg, 1.09 mmol) obtained in reference example 198 was used. ¹ H-NMR (CDCl ₃ , 400 MHz) δ 9.45 (s, 1 N), 8.56 (d, 1 N), 7.57 (d, 1 N), 7.10 (d, 1 N), 6.66 (d, 1 N), 5.55-5.25 (m, 1 N), 5.00-4.85 (m, 1 N), 4.30-4.10 (m, 1 N), 4.05- 3.70 (m, 2 N), 3.55-3.15 (m, 3 N), 3.05-2.85 (m, 2 N), 2.80-2.60 (m, 1 N ), 2.55-2.30 (m, 2 N), 2.25-2.05 (m, 2 N), 1.85-1.55 (m, 3 N)

[2242] Example 358 (2S)-1-[2-[4-[(2-Chloro-6,7-dimethoxy-quinazolin-4-yl)amino]-1-piperidyl]acetyl]pyrrolidine-2-carbonitrile

[2243] The title compound (210.7 mg, 95.2%) was prepared in the same manner as in Example 110 except that instead of N-(piperidin-4-yl)quinolin-5-amine hydrochloride used 2-chloro-6,7-dimethoxy-N-(piperidin-4-yl)quinazolin-4-amine hydrochloride (190.9 mg, 0.48 mmol) obtained in reference example 199. ¹ H-NMR ( CDCl ₃ , 400 MHz) δ 7.07-7.02 (m, 2 N), 6.20-6.10 (m, 1 N), 5.00-4.70 (m, 1 N), 4 .40-4.20 (m, 1 N), 3.95 (s, 3 N), 3.93 (s, 3 N), 3.75-3.40 (m, 2 N), 3.35 -3.10 (m, 2 N), 3.05-2.85 (m, 2 N), 2.45-2.25 (m, 3 N), 2.25-2.00 (m, 4 N), 1.90-1.60 (m, 3 N)

[2244] Example 359 (2S)-1-[2-[4-[(2-Chloro-8-methylquinazolin-4-yl)amino]-1-piperidyl]acetyl]pyrrolidine-2-carbonitrile

[2245] The title compound (148.0 mg, 74.3%) was prepared in the same manner as Example 110 except that instead of N-(piperidin-4-yl)quinolin-5-amine hydrochloride used 2-chloro-8-methyl-N-(piperidin-4-yl)quinazolin-4-amine hydrochloride (128.7 mg, 0.37 mmol) obtained in Reference Example 200. ¹ H-NMR (CDCl ₃ , 400 MHz) δ 7.59-7.54 (m, 2 N), 7.34 (t, 1 N), 5.90-5.75 (m, 1 N), 5.10-4.70 ( m, 1 N), 4.40-4.20 (m, 1 N), 3.80-3.50 (m, 2 N), 3.40-3.10 (m, 2 N), 3. 10-2.85 (m, 2 N), 2.64 (s, 3 N), 2.50-2.20 (m, 3 N), 2.20-2.00 (m, 4 N), 1.90-1.60 (m, 3 N)

[2246] Example 360: (2S,4S)-4-fluoro-1-[2-[4-(2,b-naphthyridin-4-ylamino)-1-piperidyl]acetyl]pyrrolidine-2-carbonitrile

[2247] The title compound (55.6 mg, 42.1%) was prepared in the same manner as in Example 330 except that instead of 8-fluoro-N-(piperidin-4-yl)quinolin- 5-amine hydrochloride N-(piperidin-4-yl)-2,6-naphthyridin-4-amine hydrochloride (104.1 mg, 0.35 mmol) obtained in Reference Example 201 was used. ¹ H-NMR (CDCl ₃ , 400 MHz) δ 9.10 (s, 1 N), 8.58 (d, 1 N), 8.11 (d, 1 N), 7.54 (s, 1 N), 7.00 (s , 1 N), 5.55-5.25 (m, 1 N), 5.05-4.90 (m, 1 N), 4.30-4.15 (m, 1 N), 4.05 -3.70 (m, 2 N), 3.50-3.15 (m, 3 N), 3.05-2.85 (m, 2 N), 2.80-2.60 (m, 1 N), 2.50-2.30 (m, 2 N), 2.30-2.10 (m, 2 N), 1.95-1.60 (m, 3 N)

[2248] Example 361: (2S,4S)-1-[2-[4-[(8-chloro-4-isoquinolyl)amino]-1-piperidyl]acetyl]-4-fluoropyrrolidine-2-carbonitrile

[2249] The title compound (91.6 mg, 63.7%) was prepared in the same manner as in Example 330 except that instead of 8-fluoro-N-(piperidin-4-yl)quinolin- 5-amine hydrochloride 8-chloro-N-(piperidin-4-yl)isoquinolin-4-amine hydrochloride (95.1 mg, 0.28 mmol) obtained in reference example 202 was used. ¹ H-NMR (CDCl ₃ , 400 MHz) δ 8.29 (d, 1 N), 7.81-7.66 (m, 3 N), 7.61 (s, 1 N), 5.55-5.30 (m, 1 N ), 5.00-4.90 (m, 1 N), 4.30-4.15 (m, 1 N), 4.15-3.70 (m, 2 N), 3.60-3, 20 (m, 3 N), 3.10-2.90 (m, 2 N), 2.85-2.65 (m, 1 N), 2.50-2.35 (m, 2 N), 2.35-2.15 (m, 2 N), 1.90-1.60 (m, 3 N)

[2250] Example 362: (2S,4S)-4-fluoro-1-[2-[4-(3-quinollamino)-1-piperidyl]acetyl]pyrrolidine-2-carbonitrile

[2251] The title compound (154.9 mg, 60.1%) was prepared in the same manner as in Example 330 except that instead of 8-fluoro-N-(piperidin-4-yl)quinolin- 5-amine hydrochloride N-(piperidin-4-yl)quinolin-3-amine hydrochloride (202.9 mg, 0.68 mmol) obtained in reference example 203 was used. ¹ H-NMR (CDCl ₃ , 400 MHz) δ 8.44 (s, 1 N), 7.95 (d, 1 N), 7.62 (d, 1 N), 7.44-7.43 (m, 2 N), 7.03 (s, 1 N), 5.50-5.30 (m, 1 N), 5.00-4.90 (m, 1 N), 4.30-4.15 (m, 1 N), 4.15- 3.70 (m, 2 N), 3.55-3.20 (m, 3 N), 3.10-2.90 (m, 2 N), 2.85-2.60 (m, 1 N ), 2.55-2.35 (m, 3 N), 2.35-2.10 (m, 2 N), 1.80-1.50 (m, 2 N)

[2252] Example 363: (2S,4S)-4-fluoro-1-[2-[4-[(6-methyl-3-quinolyl)amino]-1-piperidyl]acetyl]pyrrolidine-2-carbonitrile

[2253] The title compound (102.5 mg, 38.4%) was prepared in the same manner as in Example 330 except that instead of 8-fluoro-N-(piperidin-4-yl)quinolin- 5-amine hydrochloride 6-methyl-N-(piperidin-4-yl)quinolin-3-amine hydrochloride (131.9 mg, 0.42 mmol) obtained in reference example 204 was used. ¹ H-NMR (CDCl ₃ , 400 MHz) δ 8.35 (s, 1 N), 7.82 (d, 1 N), 7.38 (s, 1 N), 7.24 (d, 1 N), 6.95 (s, 1 N), 5.55-5.25 (m, 1 N), 5.00-4.90 (m, 1 N), 4.30-4.10 (m, 1 N), 4.05- 3.70 (m, 2 N), 3.55-3.20 (m, 3 N), 3.05-2.80 (m, 2 N), 2.80-2.60 (m, 1 N ), 2.45 (s, 3 N), 2.45-2.20 (m, 3 N), 2.20-2.10 (m, 2 N), 1.80-1.50 (m, 2 N)

[2254] Example 364: (2S,4S)-4-fluoro-1-[2-[4-[(6-fluoro-3-quinolyl)amino]-1-piperidyl]acetyl]pyrrolidine-2-carbonitrile

[2255] The title compound (167.9 mg, 62.2%) was prepared in the same manner as in Example 330 except that instead of 8-fluoro-N-(piperidin-4-yl)quinolin- 5-amine hydrochloride 6-fluoro-N-(piperidin-4-yl)quinolin-3-amine hydrochloride (201.1 mg, 0.63 mmol) obtained in Reference Example 205 was used. ¹ H-NMR (CDCl ₃ , 400 MHz) δ 8.35 (s, 1 N), 7.90 (d, 1 N), 7.23-7.13 (m, 2 N), 6.93 (s, 1 N), 5, 55-5.30 (m, 1 N), 5.05-4.95 (m, 1 N), 4.30-4.10 (m, 1 N), 4.05-3.75 (m, 2 N), 3.55-3.20 (m, 3 N), 3.10-2.90 (m, 2 N), 2.85-2.60 (m, 1 N), 2.50- 2.25 (m, 3 N), 2.25-2.10 (m, 2 N), 1.85-1.50 (m, 2 N)

[2256] Example 365: (2S,4S)-4-fluoro-1-[2-[4-[(6-methoxy-3-quinolyl)amino]-1-piperidyl]acetyl]pyrrolidine-2-carbonitrile

[2257] The title compound (85.7 mg, 30.8%) was prepared in the same manner as in Example 330 except that instead of 8-fluoro-N-(piperidin-4-yl)quinolin- 5-amine hydrochloride 6-methoxy-N-(piperidin-4-yl)quinolin-3-amine hydrochloride (179.4 mg, 0.54 mmol) obtained in Reference Example 206 was used. ¹ H-NMR (CDCl ₃ , 400 MHz) δ 8.26 (s, 1 N), 7.82 (d, 1 N), 7.06 (d, 1 N), 6.93 (s, 1 N), 6.91 (s, 1 N), 5.50-5.25 (m, 1 N), 5.00-4.90 (m, 1 N), 4.30-4.10 (m, 1 N), 3.90 ( s, 3 N), 4.05-3.70 (m, 2 N), 3.55-3.20 (m, 3 N), 3.05-2.85 (m, 2 N), 2, 80-2.60 (m, 1 N), 2.50-2.30 (m, 3 N), 2.30-2.10 (m, 2 N), 1.85-1.50 (m, 2 N)

[2258] Example 366: (2S,4S)-4-fluoro-1-[2-[4-[(7-methoxy-3-quinolyl)amino]-1-piperidyl]acetyl]pyrrolidine-2-carbonitrile

[2259] The title compound (39.6 mg, 14.2%) was prepared in the same manner as in Example 330 except that instead of 8-fluoro-N-(piperidin-4-yl)quinolin- 5-amine hydrochloride 7-methoxy-N-(piperidin-4-yl)quinolin-3-amine hydrochloride (61.0 mg, 0.19 mmol) obtained in Reference Example 207 was used. ¹ H-NMR (CDCl ₃ , 400 MHz) δ 8.38 (s, 1 N), 7.52 (d, 1 N), 7.31 (s, 1 N), 7.13 (d, 1 N), 7.05 (s, 1 N), 5.55-5.30 (m, 1 N), 5.00-4.90 (m, 1 N), 4.25-4.10 (m, 1 N), 3.90 ( s, 3 N), 4.05-3.70 (m, 2 N), 3.55-3.20 (m, 3 N), 3.05-2.85 (m, 2 N), 2, 80-2.60 (m, 1 N), 2.50-2.25 (m, 3 N), 2.25-2.05 (m, 2 N), 1.80-1.50 (m, 2 N)

[2260] Example 367 (2S,4S)-4-fluoro-1-[2-[4-[(8-methoxy-3-quinolyl)amino]-1-piperidyl]acetyl]pyrrolidine-2-carbonitrile

[2261] The title compound (29.5 mg, 10.6%) was prepared in the same manner as described in Example 330 except that instead of 8-fluoro-N-(piperidin-4-yl)quinolin- 5-amine hydrochloride 8-methoxy-N-(piperidin-4-yl)quinolin-3-amine hydrochloride (72.5 mg, 0.22 mmol) obtained in Reference Example 208 was used. ¹ H-NMR (CDCl ₃ , 400 MHz) δ 8.42 (s, 1 N), 7.36 (t, 1 N), 7.19 (d, 1 N), 7.00 (s, 1 N), 6.79 (d, 1 N), 5.55-5.30 (m, 1 N), 5.05-4.90 (m, 1 N), 4.30-4.10 (m, 1 N), 4.06 ( s, 3 N), 4.06-3.70 (m, 2 N), 3.60-3.25 (m, 3 N), 3.10-2.90 (m, 2 N), 2, 85-2.60 (m, 1 N), 2.60-2.35 (m, 3 N), 2.35-2.10 (m, 2 N), 1.80-1.55 (m, 2 N)

[2262] Example 368: (2S,4S)-4-fluoro-1-[2-[4-(1,8-naphthyridin-3-ylamino)-1-piperidyl]acetyl]pyrrolidine-2-carbonitrile

[2263] The title compound (109.4 mg, 49.7%) was prepared in the same manner as Example 330 except that instead of 8-fluoro-N-(piperidin-4-yl)quinolin- 5-amine hydrochloride N-(piperidin-4-yl)-1,8-naphthyridin-3-amine hydrochloride (173.4 mg, 0.58 mmol) obtained in reference example 209 was used. ¹ H-NMR (CDCl ₃ , 600 MHz) δ 8.79 (d, 1 N), 8.59 (s, 1 N), 7.96 (d, 1 N), 7.35 (t, 1 N), 6.95 (s , 1 N), 5.50-5.30 (m, 1 N), 5.00-4.90 (m, 1 N), 4.25-4.15 (m, 1 N), 4.00 -3.70 (m, 2 N), 3.50-3.20 (m, 3 N), 3.05-2.85 (m, 2 N), 2.80-2.60 (m, 1 N), 2.50-2.30 (m, 3 N), 2.20-2.10 (m, 2 N), 1.80-1.55 (m, 2 N)

[2264] Example 369: (2S,4S)-1-[2-[4-[(7-chloro-1,8-naphthyridin-3-yl)amino]-1-piperidyl]acetyl]-4-fluoropyrrolidin- 2-carbonitrile

[2265] The title compound (13.8 mg, 20.6%) was prepared in the same manner as Example 330 except that instead of 8-fluoro-N-(piperidin-4-yl)quinolin- 5-amine hydrochloride 7-chloro-N-(piperidin-4-yl)-1,8-naphthyridin-3-amine hydrochloride (53.6 mg, 0.16 mmol) prepared in Reference Example 210 was used. ¹ H- NMR ( _CDCl3 , 600 MHz) δ 8.55 (s, 1 H), 7.90 (d, 1 H), 7.35 (d, 1 H), 6.95 (s, 1 H), 5 .50-5.30 (m, 1 N), 5.00-4.90 (m, 1 N), 4.30-4.10 (m, 1 N), 4.00-3.70 (m , 2 N), 3.50-3.20 (m, 3 N), 3.05-2.90 (m, 2 N), 2.80-2.65 (m, 1 N), 2.50 -2.30 (m, 3 N), 2.20-2.10 (m, 2 N), 1.80-1.55 (m, 2 N)

[2266] Example 370: (2S)-1-[2-[4-[(8-Ethoxy-5-quinolyl)amino]-1-piperidyl]acetyl]pyrrolidine-2-carbonitrile

[2267] The title compound (35.4 mg, 9.8%) was prepared as described in Example 121 except that instead of 3-methyl-N-(piperidin-4-yl)quinoline-5 -amine hydrochloride 8-ethoxy-N-(piperidin-4-yl)quinolin-5-amine hydrochloride (302.9 mg, 0.88 mmol) obtained in reference example 211 was used. ¹ H NMR (CDCl ₃ , 400 MHz ) δ 8.90 (dd, 1 N), 8.18 (dd, 1 N), 7.34 (kv, 1 N), 6.93 (d, 1 N), 6.59 (d, 1 N ), 5.17-4.69 (m, 1 N), 4.21 (sq, 2 N), 3.73-3.58 (m, 2 N), 3.53-3.46 (m, 1 N), 3.37-3.13 (m, 3 N), 2.93-2.83 (m, 2 N), 2.35-2.00 (m, 8 N), 1.73- 1.56 (m, 2 N), 1.53 (t, 3 N).

[2268] Example 371: (2S,4S)-1-[2-[4-[(8-ethoxy-5-quinolyl)amino]-1-piperidyl]acetyl]-4-fluoropyrrolidine-2-carbonitrile

[2269] The title compound (2.4 mg, 5.0%) was prepared as described in Example 131 except that instead of 3-methyl-N-(piperidin-4-yl)quinoline-5 -amine hydrochloride 8-ethoxy-N-(piperidin-4-yl)quinolin-5-amine hydrochloride (37.8 mg, 0.11 mmol) obtained in reference example 211 was used. ¹ H NMR (CDCl ₃ , 400 MHz ) δ 8.90 (dd, 1 N), 8.18 (dd, 1 N), 7.36 (kv, 1 N), 6.94 (d, 1 Η), 6.60 (d, 1 Η ), 5.46-4.87 (m, 2 Η), 4.22 (sq, 2 Η), 4.17-3.67 (m, 1 Η), 3.83-3.68 (m, 2 Η), 3.44-3.21 (m, 2 Η), 3.18 (s, 1 Η), 2.96-2.84 (m, 2 Η), 2.73-2.56 ( m, 1 Η), 2.35-2.10 (m, 5 Η), 1.75-1.53 (m, 5 Η).

[2270] Example 372 (2S,4S)-1-[2-[4-(1,3-Benzothiazol-7-ylamino)-1-piperidyl]acetyl]-4-fluoropyrrolidine-2-carbonitrile

[2271] The title compound (266.8 mg, 61.2%) was prepared in the same manner as in Example 330 except that instead of 8-fluoro-N-(piperidin-4-yl)quinolin- 5-amine hydrochloride N-(piperidin-4-yl)benzo[d]thiazol-7-amine hydrochloride (344.8 mg, 1.13 mmol) obtained in reference example 212 was used. ¹ H-NMR (CDCl ₃ , 600 MHz) δ 8.92 (s, 1 N), 7.56 (d, 1 N), 7.38 (t, 1 N), 6.66 (d, 1 N), 5.50-5, 30 (m, 1 N), 5.00-4.90 (m, 1 N), 4.25-4.15 (m, 1 N), 4.00-3.70 (m, 2 N), 3.60-3.15 (m, 3 N), 3.00-2.80 (m, 2 N), 2.80-2.60 (m, 1 N), 2.50-2.20 ( m, 3 N), 2.20-2.10 (m, 2 N), 1.85-1.50 (m, 2 N)

[2272] Example 373 (2S,4S)-1-[2-[4-[(1-acetylindolin-4-yl)amino]-1-rsperidyl]acetyl]-4-fluoropyrrolidine-2-carbonitrile

[2273] The title compound (45.8 mg, 12.8%) was prepared in the same manner as Example 330 except that instead of 8-fluoro-N-(piperidin-4-yl)quinolin- 5-amine hydrochloride 1-(4-(piperidin-4-ylamino)indolin-1-yl)ethan-1-one hydrochloride (286.8 mg, 0.86 mmol) prepared in Reference Example 213 was used. ¹ H- NMR ( _CDCl3 , 400 MHz) δ 7.63 (d, 1 H), 7.10 (t, 1 H), 6.36 (d, 1 H), 5.50-5.25 (m, 1 N), 5.00-4.90 (m, 1 N), 4.30-4.10 (m, 1 N), 4.09 (t, 2 N), 4.00-3.70 (m , 2H), 3.50-3.15 (m, 3 N), 3.00-2.80 (m, 4 N), 2.80-2.60 (m, 1 N), 2.45- 2.25 (m, 3 N), 2.21 (s, 3 N), 2.20-2.00 (m, 2 N), 1.75-1.45 (m, 2 N)

[2274] Example 374: (2S,4S)-4-fluoro-1-[2-[4-[(8-methyl-6-quinolyl)amino]-1-piperidyl]acetyl]pyrrolidine-2-carbonitrile

[2275] The title compound (149.1 mg, 65.6%) was prepared in the same manner as in Example 330 except that instead of 8-fluoro-N-(piperidin-4-yl)quinolin- 5-amine hydrochloride 8-methyl-N-(piperidin-4-yl)quinolin-6-amine hydrochloride (180.7 mg, 0.58 mmol) obtained in reference example 214 was used. ¹ H-NMR (CDCl ₃ , 400 MHz) δ 8.64 (d, 1 N), 7.88 (d, 1 N), 7.28-7.24 (m, 1 N), 6.94 (s, 1 N), 6, 57 (s, 1 N), 5.50-5.25 (m, 1 N), 5.00-4.90 (m, 1 N), 4.30-4.15 (m, 1 N), 4.05-3.70 (m, 2 N), 3.50-3.20 (m, 3 N), 3.00-2.85 (m, 2 N), 2.80-2.60 ( m, 1 N), 2.72 (s, 3 N), 2.50-2.20 (m, 3 N), 2.20-2.10 (m, 2 N), 1.80-1, 50 (m, 2 N)

[2276] Example 375: (2S,4S)-4-fluoro-1-[2-[4-[(8-fluoro-6-quinolyl)amino]-1-piperidyl]acetyl]pyrrolide in-2-carbonitrile

[2277] The title compound (305.3 mg, 83.1%) was prepared in the same manner as in Example 330 except that instead of 8-fluoro-N-(piperidin-4-yl)quinolin- 5-amine hydrochloride 8-fluoro-N-(piperidin-4-yl)quinolin-6-amine hydrochloride (292.4 mg, 0.92 mmol) obtained in Reference Example 215 was used. ¹ H-NMR (CDCl ₃ , 400 MHz) δ 8.63 (s, 1 N), 7.89 (d, 1 N), 7.32-7.28 (m, 1 N), 6.80 (d, 1 N), 6, 50 (s, 1 N), 5.50-5.25 (m, 1 N), 5.00-4.90 (m, 1 N), 4.30-4.15 (m, 1 N), 4.05-3.70 (m, 2 N), 3.50-3.20 (m, 3 N), 3.05-2.85 (m, 2 N), 2.80-2.60 ( m, 1 N), 2.50-2.20 (m, 3 N), 2.20-2.05 (m, 2 N), 1.80-1.50 (m, 2 N)

[2278] Example 376: (2S,4S)-1-[2-[4-[(8-chloro-6-quinolyl)amino]-1-piperidyl]acetyl]-4-fluoropyrrolidine-2-carbonitrile

[2279] The title compound (265.9 mg, 62.6%) was prepared in the same manner as in Example 330 except that instead of 8-fluoro-N-(piperidin-4-yl)quinolin- 5-amine hydrochloride 8-chloro-N-(piperidin-4-yl)quinolin-6-amine hydrochloride (341.7 mg, 1.02 mmol) obtained in Reference Example 216 was used. ¹ H-NMR (CDCl ₃ , 400 MHz) δ 8.80 (d, 1 N), 8.71 (d, 1 N), 7.32 (t, 1 N), 7.24 (s, 1 N), 6.62 (s, 1 N), 5.50-5.25 (m, 1 N), 5.00-4.90 (m, 1 N), 4.30-4.10 (m, 1 N), 4.05- 3.70 (m, 2 N), 3.50-3.20 (m, 3 N), 3.00-2.85 (m, 2 N), 2.80-2.60 (m, 1 N ), 2.50-2.20 (m, 3 N), 2.20-2.05 (m, 2 N), 1.80-1.50 (m, 2 N)

[2280] Example 377 (2S,4S)-4-fluoro-1-[2-[4-[[8-(trifluoromethyl)-6-quinolyl]amino]-1-piperidyl]acetyl]pyrrolidine-2-carbonitrile

[2281] The title compound (270.6 mg, 83.7%) was prepared in the same manner as in Example 330 except that instead of 8-fluoro-N-(piperidin-4-yl)quinolin- 5-amine hydrochloride N-(piperidin-4-yl)-8-(trifluoromethyl)quinoline-6-amine hydrochloride (264.8 mg, 0.72 mmol) obtained in Reference Example 217 was used. ¹ H-NMR (CDCl ₃ , 400 MHz) δ 8.75 (d, 1 N), 7.95 (d, 1 N), 7.44 (s, 1 N), 7.35 (t, 1 N), 6.83 ( s, 1 N), 5.50-5.30 (m, 1 N), 5.00-4.90 (m, 1 N), 4.30-4.10 (m, 1 N), 4, 05-3.70 (m, 2 N), 3.55-3.20 (m, 3 N), 3.05-2.85 (m, 2 N), 2.80-2.60 (m, 1 N), 2.50-2.20 (m, 3 N), 2.20-2.05 (m, 2 N), 1.80-1.50 (m, 2 N)

[2282] Example 378 (2S)-1-[2-[4-[(2-Oxochromen-4-yl)amino]-1-piperidyl]acetyl]pyrrolidine-2-carbonitrile

[2283] The title compound (25.9 mg, 72.0%) was prepared in the same manner as Example 121 except that instead of 3-methyl-N-(piperidin-4-yl)quinolin- 5-amine hydrochloride 4-(piperidin-4-ylamino)-2H-chromen-2-one hydrochloride (30.0 mg, 0.09 mmol) obtained in reference example 218 was used. ¹ H NMR (CDCl ₃ , 400 MHz ) δ 7.55-7.47 (m, 2 N), 7.33 (d, 1 N), 7.28-7.24 (m, 1 N), 5.34 (d, 1 N), 5.22-5.15 (m, 1 N), 5.03-4.75 (m, 1 N), 3.75-3.63 (m, 1 N), 3.60-3.42 ( m, 2 N), 3.32-3.17 (m, 2 N), 3.04-2.91 (m, 2 N), 2.39-2.06 (m, 8 N), 1. 92-1.66 (m, 2 N).

[2284] Example 379: (2S,4S)-4-fluoro-1-[2-[4-[(2-oxochromen-4-yl)amino]-1-piperidyl]acetyl]pyrrolidine-2-carbonitrile

[2285] The title compound (20.3 mg, 53.8%) was prepared as described in Example 131 except that instead of 3-methyl-N-(piperidin-4-yl)quinoline-5 -amine hydrochloride 4-(piperidin-4-ylamino)-2H-chromen-2-one hydrochloride (30.0 mg, 0.09 mmol) obtained in reference example 218 was used. ¹ H NMR (CDCl ₃ , 400 MHz) δ 7.56-7.47 (m, 2 N), 7.33 (d, 1 N), 7.28-7.24 (m, 1 N), 5.50-5.25 (m, 2 .4 N), 5.20-5.14 (m, 1 N), 4.95 (d, 0.6 N), 4.22-4.16 (m, 1.5 N), 4.00 -3.72 (m, 1.5 N), 3.49-3.41 (m, 1 N), 3.37-3.17 (m, 2 N), 3.03-2.92 (m , 2 N), 2.79-2.64 (m, 1 N), 2.41-2.31 (m, 3 N), 2.17-2.07 (m, 2 N), 1.94 -1.64 (m, 2 N).

[2286] Example 380: (2S,4S)-4-fluoro-1-[2-[4-(1,5-naphthyridin-4-ylamino)-1-piperidyl]acetyl]pyrrolidine-2-carbonitrile

[2287] The title compound (4.3 mg, 10.2%) was prepared as described in Example 131 except that instead of 3-methyl-N-(piperidin-4-yl)quinoline-5 -amine hydrochloride N-(piperidin-4-yl)-1,5-naphthyridin-4-amine hydrochloride (33.1 mg, 0.11 mmol) prepared in standard example 219 was used. ¹ H NMR (CDCl ₃ , 400 MHz) δ 8.69 (dd, 1 N), 8.54 (d, 1 N), 8.22 (dd, 1 N), 7.57 (kv, 1 Η), 6.65-6.62 (m, 1 Η), 6.53 (d, 1 Η), 5.51-4.94 (m, 2 Η), 4.26-3.93 (m, 1 Η), 3.90-3 .73 (m, 1 Η), 3.59-3.26 (m, 2 Η), 3.25 (s, 1 Η), 3.03-2.90 (m, 2 Η), 2.80 -2.64 (m, 1 Η), 2.49-2.16 (m, 4 Η), 1.89-1.67 (m, 3 Η).

[2288] Example 381: (2S,4S)-4-fluoro-1-[2-[4-[[2-(trifluoromethyl)-6-quinolyl]amino]-1-piperidyl]acetyl]pyrrolidine-2-carbonitrile

[2289] The title compound (429.7 mg, 81.7%) was prepared in the same manner as in Example 330 except that instead of 8-fluoro-N-(piperidin-4-yl)quinolin- 5-amine hydrochloride N-(piperidin-4-yl)-2-(trifluoromethyl)quinoline-6-amine hydrochloride (430.8 mg, 1.17 mmol) obtained in Reference Example 220 was used. ¹ H-NMR (CDCl ₃ , 400 MHz) δ 8.02 (d, 1 N), 7.95 (d, 1 N), 7.57 (d, 1 N), 7.13 (d, 1 N), 6.70 ( s, 1 N), 5.50-5.25 (m, 1 N), 5.00-4.90 (m, 1 N), 4.30-4.10 (m, 1 N), 4, 05-3.70 (m, 2 N), 3.55-3.20 (m, 3 N), 3.05-2.85 (m, 2 N), 2.80-2.60 (m, 1 N), 2.50-2.20 (m, 3 N), 2.20-2.10 (m, 2 N), 1.85-1.55 (m, 2 N)

[2290] Example 382: (2S,4S)-4-fluoro-1-[2-[4-[(4-methoxy-6-quinolyl)amino]-1-piperidyl]acetyl]pyrrolidine-2-carbonitrile

[2291] The title compound (25.9 mg, 20.5%) was prepared in the same manner as in Example 330 except that instead of 8-fluoro-N-(piperidin-4-yl)quinolin- 5-amine hydrochloride 4-methoxy-N-(piperidin-4-yl)quinolin-6-amine hydrochloride (101.7 mg, 0.31 mmol) obtained in reference example 221 was used. ¹ H-NMR (CDCl ₃ , 400 MHz) δ 8.49 (d, 1 N), 7.83 (d, 1 N), 7.08-7.03 (m, 2 N), 6.66 (d, 1 N), 5, 50-5.25 (m, 1 N), 5.00-4.90 (m, 1 N), 4.30-4.15 (m, 1 N), 4.03 (s, 3 N), 4.00-3.70 (m, 2 N), 3.55-3.20 (m, 3 N), 3.05-2.85 (m, 2 N), 2.80-2.60 ( m, 1 N), 2.50-2.25 (m, 3 N), 2.20-2.10 (m, 2 N), 1.85-1.50 (m, 2 H)

[2292] Example 383: (2S,4S)-1-[2-[4-[(2-bromo-4-pyridyl)amino]-1-piperidyl]acetyl]-4-fluoropyrrolidine-2-carbonitrile

[2293] The title compound (65.4 mg, 22.1%) was prepared in the same manner as Example 330 except that instead of 8-fluoro-N-(piperidin-4-yl)quinolin- 5-amine hydrochloride 2-bromo-N-(piperidin-4-yl)pyridin-4-amine hydrochloride (237.3 mg, 0.72 mmol) obtained in Example 222 was used. ¹ H-NMR (CDCl ₃ , 400 MHz) δ 7.91 (d, 1 N), 6.59 (s, 1 N), 6.36 (d, 1 N), 5.50-5.25 (m, 1 N), 5.00 -4.90 (m, 1 N), 4.25-4.10 (m, 1 N), 4.05-3.70 (m, 2 N), 3.45-3.15 (m, 3 N), 3.05-2.80 (m, 2 N), 2.80-2.60 (m, 1 N), 2.50-2.25 (m, 3 N), 2.05-2 .00 (m, 2 N), 1.80-1.50 (m, 2 N)

[2294] Example 384: (2S,4S)-1-[2-[4-(3H-benzimidazol-4-ylamino)-1-piperidyl]acetyl]-4-fluoropyrrolidine-2-carbonitrile

[2295] The title compound (363.5 mg, 97.2%) was prepared in the same manner as in Example 330 except that instead of 8-fluoro-N-(piperidin-4-yl)quinoline- 5-amine hydrochloride N-(piperidin-4-yl)-1H-benzo[d]imidazol-7-amine hydrochloride (292.1 mg, 1.01 mmol) obtained in reference example 223 was used. ¹ H-NMR ( MeOD, 400 MHz) δ 7.99 (s, 1 N), 7.08 (t, 1 N), 6.85 (d, 1 N), 6.45 (d, 1 N), 5.55- 5.30 (m, 1 N), 5.00-4.90 (m, 1 N), 4.20-4.05 (m, 1 N), 3.95-3.70 (m, 2 N ), 3.60-3.20 (m, 3 N), 3.00-2.90 (m, 2 N), 2.70-2.55 (m, 1 N), 2.55-2, 30 (m, 3 N), 2.20-2.05 (m, 2 N), 1.85-1.60 (m, 2 N)

[2296] Example 385: (2S,4S)-1-[2-[4-[(2-chloro-6-morpholino-4-pyridyl)amino]-1-piperidyl]acetyl]-4-fluoropyrrolidine-2- carbonitrile

[2297] The title compound (157.9 mg, 29.9%) was prepared in the same manner as Example 330 except that instead of 8-fluoro-N-(piperidin-4-yl)quinolin- 5-amine hydrochloride 2-chloro-6-morpholino-N-(piperidin-4-yl)pyridin-4-amine hydrochloride (431.5 mg, 1.17 mmol) prepared in Reference Example 224 was used. ¹ H-NMR (CDCl ₃ , 400 MHz) δ 5.95 (s, 1 Η), 5.56 (s, 1 Η), 5.50-5.25 (m, 1 Η), 5.00-4.90 ( m, 1 Η), 4.25-4.05 (m, 1 Η), 4.00-3.70 (m, 6 Η), 3.50-3.40 (m, 4 Η), 3, 40-3.15 (m, 3 Η), 3.00-2.80 (m, 2 Η), 2.80-2.60 (m, 1 Η), 2.50-2.20 (m, 3 Η), 2.10-1.95 (m, 2 Η), 1.70-1.45 (m, 2 Η)

[2298] Example 386: (2S,4S)-4-fluoro-1-[2-[4-[[3-(trifluoromethyl)-5-quinolyl]amino]-1-piperidyl]acetyl]pyrrolidine-2-carbonitrile

[2299] The title compound (450.5 mg, 92.9%) was prepared in the same manner as Example 330 except that instead of 8-fluoro-N-(piperidin-4-yl)quinolin- 5-amine hydrochloride N-(piperidin-4-yl)-3-(trifluoromethyl)quinoline-5-amine hydrochloride (397.5 mg, 1.08 mmol) obtained in Reference Example 225 was used. ¹ H-NMR (CDCl ₃ , 400 MHz) δ 9.03 (s, 1 N), 8.43 (s, 1 N), 7.67 (t, 1 N), 7.50 (d, 1 N), 6.73 ( d, 1 N), 5.55-5.25 (m, 1 N), 5.00-4.90 (m, 1 N), 4.30-4.15 (m, 1 N), 4, 05-3.70 (m, 2 N), 3.60-3.20 (m, 3 N), 3.10-2.90 (m, 2 N), 2.80-2.60 (m, 1 N), 2.50-2.25 (m, 3 N), 2.25-2.10 (m, 2 N), 1.90-1.60 (m, 2 N)

[2300] Example 387 (2S)-1-[2-[4-[[3-(trifluoromethyl)-5-quinolyl]amino]-1-piperidyl]acetyl]pyrrolidine-2-carbonitrile

[2301] The title compound (324.7 mg, 69.7%) was prepared in the same manner as Example 110 except that N-(piperidin-4-yl)quinolin-5-amine hydrochloride was used instead of N-(piperidin-4-yl)quinolin-5-amine hydrochloride -(piperidin-4-yl)-3-(trifluoromethyl)quinoline-5-amine hydrochloride (397.5 mg, 1.08 mmol) obtained in reference example 225. ¹ H-NMR (CDCl ₃ , 400 MHz) δ 9 .03 (s, 1 N), 8.42 (s, 1 N), 7.67 (t, 1 N), 7.51 (d, 1 N), 6.73 (d, 1 N), 5 .20-4.70 (m, 1 N), 4.50-4.35 (m, 1 N), 3.85-3.60 (m, 1 N), 3.60-3.45 (m , 3 N), 3.45-3.20 (m, 2 N), 3.10-2.90 (m, 2 N), 2.50-2.35 (m, 2 N), 2.35 -2.10 (m, 5 N), 1.90-1.60 (m, 2 N)

[2302] Example 388 5-[[1-[2-oxo-2-[(2S,4S)-2-cyano-4-fluoropyrrolidin-1-yl]ethyl]-4-piperidyl]amino]-N- phenylquinoline-3-carboxamide

[2303] The title compound (29.3 mg, 53.3%) was prepared similarly to Example 131 except that instead of 3-methyl-N-(piperidin-4-yl)quinoline-5 -amine hydrochloride used N-phenyl-5-(piperidin-4-ylamino)quinoline-3-carboxamide hydrochloride (46.0 mg, 0.11 mmol) obtained in reference example 226. ¹ H NMR (CDCl ₃ , 400 MHz ) δ 9.33 (d, 1 N), 8.91 (d, 1 N), 8.69 (d, 1 N), 7.72-7.70 (m, 2 H), 7.64-7 .59 (m, 1 N), 7.46-7.43 (m, 1 N), 7.38 (sq, 2 N), 7.18 (sq, 1 N), 6.67-6.62 (m, 1 N), 5.48-4.92 (m, 2 N), 4.03-3.70 (m, 2 N), 3.47-3.23 (m, 2 N), 3 .19 (d, 1 N), 3.00-2.61 (m, 3 N), 2.40-2.28 (m, 3 N), 2.17-2.01 (m, 2 N) , 1.65-1.46 (m, 3 N).

[2304] Example 389 N-benzyl-N-methyl-5-[[1-[2-oxo-2-[(2S,4S)-2-ctno-4-fluoropyrrolidin-1-yl]ethyl]-4 -piperidyl]amino]quinoline-3-carboxamide

[2305] The title compound (42.1 mg, 72.4%) was prepared as described in Example 131 except that instead of 3-methyl-N-(piperidin-4-yl)quinoline-5 -amine hydrochloride N-benzyl-N-methyl-5-(piperidin-4-ylamino)quinoline-3-carboxamide hydrochloride (50.2 mg, 0.11 mmol) obtained in reference example 227 was used. ¹ H NMR (CDCl ₃ , 400 MHz) δ 8.90 (s, 1 N), 8.37 (d, 1 N), 7.55 (s, 1 Η), 7.36-7.19 (m, 6 Η), 6.60 (s, 1 Η), 5.45-4.89 (m, 2 Η), 4.76-3.73 (m, 5 Η), 3.44-2.88 (m, 8 Η ), 2.73-2.60 (m, 1 Η), 2.47-2.22 (m, 3 Η), 2.09-2.01 (m, 2 Η), 1.75-1, 48 (m, 2 Η).

[2306] Example 390 N-methyl-5-[[1-[2-oxo-2-[(2S,4S)-2-cyano-4-fluoropyrrolidin-1-yl]ethyl]-4-piperidyl]amino ]quinoline-8-carboxamide

[2307] The title compound (11.7 mg, 24.4%) was prepared as described in Example 131 except that instead of 3-methyl-N-(piperidin-4-yl)quinoline-5 -amine hydrochloride N-methyl-5-(piperidin-4-ylamino)quinoline-8-carboxamide hydrochloride (39.2 mg, 0.11 mmol) obtained in reference example 228 was used. ¹ H NMR (CDCl ₃ , 400 MHz ) δ 10.92 (d, 1 N), 8.83 (dd, 1 N), 8.68 (d, 1 N), 8.26 (d, 1 N), 7.36-7.33 ( m, 1 N), 6.65 (dd, 1 N), 5.47-4.91 (m, 2 N), 4.89-4.85 (m, 1 N), 4.21-3, 71 (m, 2 N), 3.60-3.50 (m, 1 N), 3.42-3.16 (m, 3 N), 3.09 (d, 3 N), 3.00- 2.89 (m, 2 N), 2.74-2.60 (m, 1 N), 2.40-1.58 (m, 6 N).

[2308] Example 391 N,N-dimethyl-5-[[1-[2-oxo-2-[(2S,4S)-2-cyano-4-fluoropyrrolidin-1-yl]ethyl]-4-piperidyl ]amino]quinoline-8-carboxamide

[2309] The title compound (24.2 mg, 48.7%) was prepared as described in Example 131 except that instead of 3-methyl-N-(piperidin-4-yl)quinoline-5 -amine hydrochloride used N,N-dimethyl-5-(piperidin-4-ylamino)quinoline-8-carboxamide hydrochloride (40.7 mg, 0.11 mmol) obtained in example 229. ¹ H NMR (CDCl ₃ , 400 MHz) δ 8.82 (dd, 1 N), 8.16 (d, 1 N), 7.45 (d, 1 N), 7.27-7.23 (m, 1 N), 6.54 (d, 1 N), 5.44-4.86 (m, 2 N), 4.63 (d, 1 N), 4.19-3.71 (m, 2 N), 3.46-3, 47 (m, 3 N), 3.28-3.13 (m, 4 N), 2.91-2.86 (m, 2 N), 2.78 (s, 3 N), 2.70- 2.54 (m, 1 N), 2.74-2.60 (m, 1 N), 2.46-2.02 (m, 5 N).

[2310] Example 392 N-methyl-5-[[1-[2-oxo-2-[(2S,4S)-2-cyano-4-fluoropyrrolidin-1-yl]ethyl]-4-piperidyl]amino ]-N-phenylquinoline-8-carboxamide

[2311] The title compound (11.4 mg, 20.3%) was prepared as described in Example 131 except that instead of 3-methyl-N-(piperidin-4-yl)quinoline-5 -amine hydrochloride N-methyl-N-phenyl-5-(piperidin-4-ylamino)quinoline-8-carboxamide hydrochloride (47.5 mg, 0.11 mmol) obtained in Reference Example 230 was used. ¹ H NMR (CDCl ₃ , 400 MHz) δ 8.84-8.83 (m, 1 N), 8.04-8.02 (d, 1 N), 7.27-6.99 (m, 7 N), 6, 34 (s, 1 N), 5.41-5.20 (m, 2 N), 4.48 (s, 1 N), 4.14-3.82 (m, 1 N), 3.80-3 .65 (m, 1 N), 3.63-3.41 (m, 3 N), 3.37-3.21 (m, 2 N), 3.17-3.10 (m, 1 N) , 2.91-2.79 (m, 2 N), 2.66-2.51 (m, 1 N), 2.36-2.00 (m, 5 N), 1.74-1.51 ( m, 2H).

[2312] Example 393 N-benzyl-N-methyl-5-[[1-[2-oxo-2-[(2S,4S)-2-cyano-4-fluoropyrrolidin-1-yl]ethyl]-4 -piperidyl]amino]quinoline-8-carboxamide

[2313] The title compound (12.5 mg, 21.5%) was prepared as described in Example 131 except that instead of 3-methyl-N-(piperidin-4-yl)quinoline-5 -amine hydrochloride N-benzyl-N-methyl-5-(piperidin-4-ylamino)quinoline-8-carboxamide hydrochloride (49.1 mg, 0.11 mmol) obtained in reference example 231 was used. ¹ H NMR (CDCl ₃ , 400 MHz) δ 8.81 (s, 1 N), 8.22-8.16 (m, 1 N), 7.49 (t, 2 N), 7.34 (t, 1 N), 7.27-7.14 (m, 4 N), 6.50 (kv, 1 N), 5.39-4.89 (m, 2 N), 4.30 (kv, 1 N), 4. 08-4.01 (m, 1 N), 3.88-3.61 (m, 2 N), 3.40-3.20 (m, 2 N), 3.16-3.05 (m, 3 N), 2.83-2.82 (m, 2 N), 2.65-2.45 (m, 3 N), 2.39-2.00 (m, 5 N), 1.77- 1.58 (m, 2 N).

[2314] Example 394 5-[[1-[2-oxo-2-[(2S,4S)-2-cyano-4-fluoropyrrolidin-1-yl]ethyl]-4-piperidyl]amino]-N- phenylquinoline-8-carboxamide

[2315] The title compound (29.6 mg, 53.7%) was prepared similarly to Example 131 except that N-phenyl-5-(piperidin-4-ylamino)quinoline-8- The carboxamide (54.0 mg, 0.11 mmol) obtained in Reference Example 232 was used in place of 3-methyl-N-(piperidin-4-yl)quinolin-5-amine hydrochloride. ^1H NMR ( _CDCl3 , 400 MHz) δ 13.47 (s, 1H), 8.87-8.85 (m, 1H), 8.71 (dd, 1H), 8.28 (dd , 1 N), 7.83 (d, 2 N), 7.38-7.32 (m, 3 N), 7.09 (t, 1 N), 6.64 (t, 1 N), 5 .42-4.88 (m, 3 N), 4.14-3.86 (m, 1 N), 3.84-3.65 (m, 1 N), 3.58-3.47 (m , 1 N), 3.34-3.12 (m, 2 N), 2.99-2.87 (m, 2 N), 2.69-2.56 (m, 1 N), 2.43 -2.10 (m, 5 N), 1.90-1.63 (m, 2 N).

[2316] Example 395 N-methyl-5-[[1-[2-oxo-2-[(2S)-2-cyanopyrrolidin-1-yl]ethyl]-4-piperidyl]amino]quinoline-8-carboxamide

[2317] The title compound (243.0 mg, 65.6%) was prepared similarly to Example 121 except that instead of 3-methyl-N-(piperidin-4-yl)quinoline-5 -amine hydrochloride N-methyl-5-(piperidin-4-ylamino)quinoline-8-carboxamide hydrochloride (313.6 mg, 0.88 mmol) obtained in reference example 228 was used. ¹ H NMR (CDCl ₃ , 400 MHz ) δ 10.91 (d, 1 N), 8.84 (dd, 1 N), 8.70 (d, 1 N), 8.25 (d, 1 N), 7.37-7.34 ( m, 1 N), 6.67 (d, 1 N), 5.10-4.74 (m, 2 N), 3.76-3.49 (m, 3 N), 3.37-3, 17 (m, 2 N), 3.09 (d, 3 N), 3.01-2.89 (m, 2 N), 2.42-2.07 (m, 8 N), 1.88- 1.63 (m, 2 N)

[2318] Example 396 5-[[1-[2-oxo-2-[(2S)-2-cyanopyrrolidin-1-yl]ethyl]-4-piperidyl]amino]-N-phenylquinoline-8-carboxamide

[2319] The title compound (185.5 mg, 43.6%) was prepared as described in Example 121 except that instead of 3-methyl-N-(piperidin-4-yl)quinoline-5 -amine hydrochloride was used N-phenyl-5-(piperidin-4-ylamino)quinoline-8-carboxamide hydrochloride (369.0 mg, 0.88 mmol) obtained in reference example 232. ¹ H NMR (CDCl ₃ , 400 MHz ) δ 13.46 (s, 1 N), 8.89 (d, 1 N), 8.75 (d, 1 N), 8.27 (d, 1 N), 7.85 (d, 2 N ), 7.39-7.35 (m, 3 N), 7.09 (t, 1 N), 6.70-6.66 (m, 1 N), 5.08-4.74 (m, 2 N), 3.73-3.47 (m, 3 N), 3.36-3.16 (m, 2 N), 2.99-2.89 (m, 2 N), 2.41- 2.13 (m, 8 N), 1.90-1.64 (m, 2 N)

[2320] Example 397 N-benzyl-N-methyl-5-[[1-[2-oxo-2-[(2S)-2-cyanopyrrolidin-1-yl]ethyl]-4-piperidyl]amino]quinoline -8-carboxamide

[2321] The title compound (256.2 mg, 57.0%) was prepared similarly to Example 121 except that instead of 3-methyl-N-(piperidin-4-yl)quinoline-5 -amine hydrochloride N-benzyl-N-methyl-5-(piperidin-4-ylamino)quinoline-8-carboxamide hydrochloride (393.7 mg, 0.88 mmol) obtained in reference example 231 was used. ¹ H NMR (CDCl ₃ , 400 MHz) δ 8.89-8.86 (m, 1 N), 8.17-8.12 (m, 1 N), 7.53 (d, 2 N), 7.38 (t, 1 N), 7.30-7.18 (m, 4 N), 6.56 (dd, 1 N), 5.17-4.73 (m, 2 N), 4.56 (s, 1 N ), 4.34 (dd, 1 N), 3.73-3.47 (m, 3 N), 3.39-3.15 (m, 2 N), 3.10 (s, 1.5 N ), 2.99-2.85 (m, 2 N), 2.68 (s, 1.5 N), 2.42-2.03 (m, 9 N), 1.80-1.59 (m , 2 N).

[2322] Example 398 N-methyl-5-[[1-[2-oxo-2-[(2S)-2-cyanopyrrolidin-1-yl]ethyl]-4-piperidyl]amino]-N-phenylquinoline- 8-carboxamide

[2323] The title compound (45.5 mg, 10.4%) was prepared as described in Example 121 except that instead of 3-methyl-N-(piperidin-4-yl)quinoline-5 -amine hydrochloride N-methyl-N-phenyl-5-(piperidin-4-ylamino)quinoline-8-carboxamide hydrochloride (381.3 mg, 0.88 mmol) obtained in Reference Example 230 was used. ¹ H NMR (CDCl ₃ , 400 MHz) δ 8.88 (dd, 1 N), 8.00 (d, 1 N), 7.30-6.95 (m, 7 N), 6.38 (s, 1 N), 5.14-4.73 (m, 1 N), 3.76-3.70 (m, 1 N), 3.66-3.50 (m, 4 N), 3.40-3.15 ( m, 3 N), 2.93-2.84 (m, 2 N), 2.37-1.99 (m, 9 N), 1.76-1.57 (m, 2 N)

[2324] Example 399 5-[[1-[2-oxo-2-[(2S)-2-cyanopyrrolidin-1-yl]ethyl]-4-piperidyl]amino]-N-(2-pyridyl)quinoline -8-carboxamide

[2325] The title compound (340.4 mg, 80.0%) was prepared in the same manner as Example 121 except that instead of 3-methyl-N-(piperidin-4-yl)quinolin- The 5-amine hydrochloride used was 5-(piperidin-4-ylamino)-N-(pyridin-2-yl)quinoline-8-carboxamide hydrochloride (369.9 mg, 0.88 mmol) prepared in Reference Example 233. ¹ H NMR ( _CDCl3 , 400 MHz) δ 9.04 (d, 1 H), 8.78 (d, 1 H), 8.53 (d, 1 H), 8.40 (d, 1 H), 8 .26 (d, 1 N), 7.72 (t, 1 N), 7.41 (sq, 1 N), 7.01 (dd, 1 N), 6.72 (d, 1 N), 5 .09-4.75 (m, 2 N), 3.76-3.51 (m, 3 N), 3.38-3.18 (m, 2 N), 3.02-2.88 (m , 2 N), 2.45-2.35 (m, 2 N), 2.31-2.07 (m, 6 N), 1.75-1.65 (m, 2 N).

[2326] Example 400 5-[[1-[2-oxo-2-[(2S)-2-cyanopyrrolidin-1-yl]ethyl]-4-piperidyl]amino]-N-(3-pyridyl)quinoline -8-carboxamide

[2327] The title compound (316.8 mg, 74.4%) was prepared in the same manner as Example 121 except that instead of 3-methyl-N-(piperidin-4-yl)quinoline-5 -amine hydrochloride, 5-(piperidin-4-ylamino)-N-(pyridin-3-yl)quinoline-8-carboxamide hydrochloride (369.9 mg, 0.88 mmol) prepared in Reference Example 234 was used. ¹ H NMR ( _CDCl3 , 400 MHz) δ 8.92 (d, 1 H), 8.84 (s, 1 H), 8.84 (d, 1 H), 8.46 (d, 1 H), 8. 31-8.29 (m, 2 N), 7.41 (sq, 1 N), 7.29 (dd, 1 N), 6.71 (dd, 1 N), 5.07-4.74 ( m, 2 N), 3.76-3.49 (m, 3 N), 3.37-3.18 (m, 2 N), 3.01-2.91 (m, 2 N), 2. 44-2.35 (m, 2 N), 2.31-2.07 (m, 6 N), 1.91-1.65 (m, 2 N).

[2328] Example 401 5-[[1-[2-oxo-2-[(2S)-2-cyanopyrrolidin-1-yl]ethyl]-4-piperidyl]amino]-N-(4-pyridyl)quinoline -8-carboxamide

[2329] The title compound (85.1 mg, 20.0%) was prepared in the same manner as Example 121 except that instead of 3-methyl-N-(piperidin-4-yl)quinolin- The 5-amine hydrochloride used was 5-(piperidin-4-ylamino)-N-(pyridin-4-yl)quinoline-8-carboxamide hydrochloride (369.9 mg, 0.88 mmol) prepared in Reference Example 235. ¹ H NMR ( _CDCl3 , 400 MHz) δ 8.97 (dd, 1 H), 8.78 (d, 1 H), 8.52 (d, 2 H), 8.29 (d, 1 H), 7 .78 (d, 2 N), 7.47 (sq, 1 N), 6.76 (d, 1 N), 5.06-4.77 (m, 2 N), 3.78-3.50 (m, 3 N), 3.39-3.21 (m, 2 N), 3.07-2.94 (m, 2 N), 2.47-2.37 (m, 2 N), 2 .34-2.09 (m, 6 N), 1.94-1.76 (m, 2 N).

[2330] Example 402 5-[[1-[2-oxo-2-[(2S)-2-cyanopyrrolidin-1-yl]ethyl]-4-piperidyl]amino]-N-pyrimidin-2-yl- quinoline-8-carboxamide

[2331] The title compound (324.4 mg, 76.0%) was prepared as described in Example 121 except that instead of 3-methyl-N-(piperidin-4-yl)quinoline-5 -amine hydrochloride, 5-(piperidin-4-ylamino)-N-(pyrimidin-2-yl)quinoline-8-carboxamide hydrochloride (370.7 mg, 0.88 mmol) prepared in Reference Example 236 was used. ¹ H NMR (CDCl ₃ , 400 MHz) δ 9.00 (t, 1 Η), 8.81 (d, 1 Η), 8.68 (dd, 2 Η), 8.29 (d, 1 Η), 7, 41-7.39 (m, 1 Η), 6.98 (t, 1 Η), 6.70 (d, 1 Η), 5.09-4.99 (m, 1.4 Η), 5, 76-4.75 (m, 0.6 Η), 3.72-3.51 (m, 3 Η), 3.48 (s, 1 Η), 3.34-3.17 (m, 2 Η ), 3.00-2.87 (m, 2 Η), 2.43-2.34 (m, 2 Η), 2.30-2.08 (m, 6 Η), 1.75-1, 65 (m, 2 Η).

[2332] Example 403 5-[1-[2-oxo-2-[(2S,4S)-2-cyano-4-fluoropyrrolidin-1-yl]ethyl]-4-piperidyl]amino]-]-N -pyrimidin-2-yl-quinoline-8-carboxamide.

[2333] The title compound (16.3 mg, 29.5%) was prepared as described in Example 131 except that instead of 3-methyl-N-(piperidin-4-yl)quinoline-5 -amine hydrochloride, 5-(piperidin-4-ylamino)-N-(pyrimidin-2-yl)quinoline-8-carboxamide hydrochloride (46.3 mg, 0.11 mmol) prepared in Reference Example 236 was used. ¹ H NMR ( _CDCl3 , 400 MHz) δ 8.99 (d, 1 N), 8.79 (d, 1 N), 8.68 (d, 2 N), 8.32-8.29 (m, 1 N ), 7.39 (sq, 1 N), 6.98 (t, 1 N), 6.70-6.67 (m, 1 N), 5.48-5.27 (m, 1.4 N ), 5.09-4.92 (m, 1.6 N), 4.20-3.72 (m, 2 N), 3.62-3.56 (m, 1 N), 3.48 ( s, 1 N), 3.43-3.17 (m, 2 N), 3.01-2.87 (m, 2 N), 2.49-1.83 (m, 6 N), 1, 75-1.55 (m, 2 N).

[2334] Example 404 5-[[1-[2-oxo-2-[(2S,4S)-2-cyano-4-fluoropyrrolidin-1-yl]ethyl]-4-piperidyl]amino]-N- (2-pyridyl)quinoline-8-carboxamide

[2335] The title compound (45.5 mg, 82.6%) was prepared in the same manner as in Example 131 except that instead of 3-methyl-N-(piperidin-4-yl)quinolin- The 5-amine hydrochloride used was 5-(piperidin-4-ylamino)-N-(pyridin-2-yl)quinoline-8-carboxamide hydrochloride (46.3 mg, 0.11 mmol) prepared in reference example 23S. ^1H NMR ( _CDCl3 , 400 MHz) δ 8.99 (d, 1 H), 8.72 (d, 1 H), 8.50 (d, 1 H), 8.38 (d, 1 H) , 8.30-8.27 (m, 1 N), 7.71 (t, 1 N), 7.36 (sq, 1 N), 7.02-6.99 (m, 1 N), 6 .69-6.56 (m, 1 N), 5.45-5.25 (m, 1.4 N), 5.12-4.90 (m, 1.6 N), 4.18-3 .69 (m, 2 N), 3.57-3.55 (m, 1 N), 3.41-3.14 (m, 2 N), 3.00-2.88 (m, 2 N) , 2.74-2.59 (m, 1 N), 2.38-2.12 (m, 7 N), 1.68-1.63 (m, 2 N).

[2336] Example 405 5-[[1-[2-oxo-2-[(2S,4S)-2-cyano-4-fluoropyrrolidin-1-yl]ethyl]-4-piperidyl]amino]-N- (3-pyridyl)quinoline-8-carboxamide

[2337] The title compound (6.8 mg, 12.3%) was prepared as described in Example 131 except that instead of 3-methyl-N-(piperidin-4-yl)quinoline-5 -amine hydrochloride, 5-(piperidin-4-ylamino)-N-(pyridin-3-yl)quinoline-8-carboxamide hydrochloride (46.3 mg, 0.11 mmol) prepared in Reference Example 234 was used. ¹ H NMR ( _CDCl3 , 400 MHz) δ 8.92 (d, 1 H), 8.85 (s, 1 H), 8.44 (d, 1 H), 8.31-8.29 (m, 2 H) , 7.41 (kv, 1 N), 7.30 (kv, 1 N), 6.72-6.68 (m, 1 N), 5.49-5.29 (m, 1.4 N) , 5.06-4.93 (m, 1.6 N), 4.23-4.13 (dd, 0.6 N), 3.95-3.71 (m, 1.4 N), 3 .61-3.58 (m, 1 N), 3.42-3.18 (m, 2 N), 3.03-2.92 (m, 2 N), 2.77-2.62 (m , 1 N), 2.48-2.15 (m, 5 N), 1.88-1.67 (m, 2 N)

[2338] Example 406 5-[[1-[2-oxo-2-[(2S,4S)-2-cyano-4-fluoropyrrolidin-1-yl]ethyl]-4-piperidyl]amino]-N- (4-pyridyl)quinoline-8-carboxamide

[2339] The title compound (1.3 mg, 2.3%) was prepared in the same manner as Example 131 except that instead of 3-methyl-N-(piperidin-4-yl)quinoline- The 5-amine hydrochloride used was 5-(piperidin-4-ylamino)-N-(pyridin-4-yl)quinoline-8-carboxamide hydrochloride (46.3 mg, 0.11 mmol) prepared in Reference Example 235. ¹ H NMR ( _CDCl3 , 400 MHz) δ 8.98 (d, 1 H), 8.80 (d, 1 H), 8.53 (d, 2 H), 8.28 (d, 1 H), 7 .78 (d, 1 N), 7.48 (kv, 1 N), 6.77 (d, 1 N), 5.50-5.30 (m, 1 N), 5.29 (d, 0 .4 N), 4.97 (d, 0.6 Η), 4.86 (t, 1 Η), 4.23-3.66 (m, 3 Η), 3.44-3.21 (m , 2 Η), 3.06-2.95 (m, 2 Η), 2.81-2.66 (m, 1 Η), 2.49-2.23 (m, 5 Η), 2.05 -2.00 (m, 1 Η) 1.94-1.67 (m, 1 Η).

[2340] Example 407 N-isoxazol-3-yl-5-[[1-[2-oxo-2-[(2S,4S)-2-cyano-4-fluoropyrrolidin-1-yl]ethyl]-4 -piperidyl]amino]quinoline-8-carboxamide

[2341] The title compound (20.4 mg, 37.7%) was prepared as described in Example 131 except that instead of 3-methyl-N-(piperidin-4-yl)quinoline-5 -amine hydrochloride N-(isoxazol-3-yl)-5-(piperidin-4-ylamino)quinoline-8-carboxamide hydrochloride (45.3 mg, 0.11 mmol) prepared in Reference Example 237 was used. ¹ H NMR ( _CDCl3 , 400 MHz) δ 8.91 (d, 1 H), 8.71 (d, 1 H), 8.33 (s, 1 H), 8.27 (d, 1 H), 7. 42-7.39 (m, 1 N), 7.29 (s, 1 N), 6.70 (d, 1 N), 5.49-5.29 (m, 1.4 N), 5. 03 (t, 1 N), 4.94 (d, 0.6 N), 4.20 (dd, 0.5 N), 4.00-3.72 (m, 1.5 N), 3, 62-3.61 (m, 1 N), 3.44-3.19 (m, 2 N), 2.98 (sq, 2 N), 2.78-2.63 (m, 1 N), 2.48-2.16 (m, 4 N), 1.80-1.66 (m, 4 N)

[2342] Example 408 N-[5-[[1-[2-oxo-2-[(2S)-2-cyanopyrrolidin-1-yl]ethyl]-4-piperidyl]amino]-8-quinolyl] acetamide

[2343] The title compound (33.6 mg, 9.0%) was prepared as described in Example 121 except that instead of 3-methyl-N-(piperidin-4-yl)quinoline-5 -amine hydrochloride N-(5-(piperidin-4-ylamino)quinolin-8-yl)acetamide hydrochloride (314.4 mg, 0.88 mmol) obtained in reference example 238 was used. ¹ H NMR (CDCl ₃ , 400 MHz) δ 8.91 (d, 1 N), 8.78 (dd, 1 N), 8.60 (d, 1 N), 8.20 (dd, 1 N), 7.40 (kv, 1 N), 6.64(d, 1 N) 5.49-5.27 (m, 1.4 N), 4.93 (d, 0.6 N), 4.23-3.73 (m, 3 N), 3.48-3.42 (m, 1.4 N), 3.29-3.17 (m, 1.6 N), 2.99-2.87 (m, 2 N), 2.77-2.61 (m, 1 N), 2.47-2.33 (m, 3 N), 2.30 (s, 3 N), 2.21-2.13 (m, 2. 5 N), 1.80-1.55 (m, 2.5 N)

[2344] Example 409 N-[5-[[1-[2-oxo-2-[(2S,4S)-2-cyano-4-fluoropyrrolidin-1-yl]ethyl]-4-piperidyl]amino] -8-quinolyl]acetamide

[2345] The title compound (3.7 mg, 7.7%) was prepared as described in Example 131 except that instead of 3-methyl-N-(piperidin-4-yl)quinoline-5 -amine hydrochloride used N-(5-(piperidin-4-ylamino)quinolin-8-yl)acetamide hydrochloride (39.3 mg, 0.11 mmol) obtained in reference example 238. ¹ H NMR (CDCl ₃ , 400 MHz) δ 9.49 (s, 1 N), 8.78 (dd, 1 N), 8.60 (d, 1 N), 8.20 (dd, 1 N), 7.40 (kv, 1 N), 6.64(d, 1 N) 5.49-5.27 (m, 1.4 N), 4.93 (d, 0.6 N), 4.23-3.73 (m, 2.5 N), 3.48-3.25 (m, 2.5 N), 3.21 (d, 1 N), 2.99-2.87 (m, 2 N), 2.77- 2.61 (m, 1 N), 2.40-2.33 (m, 2.6 N), 2.30 (s, 3 N), 2.21-2.13 (m, 2 N), 1 .83-1.55 (m, 2.4 N)

[2346] Example 410: (2S,4S)-4-fluoro-1-[2-[4-[(6-methyl-4-quinolyl)oxy]-1-piperidyl]acetyl]pyrrolidine-2-carbonitrile

[2347] The title compound (190.9 mg, 38.8%) was prepared in the same manner as in Example 330 except that instead of 8-fluoro-N-(piperidin-4-yl)quinoline- 5-amine hydrochloride used 6-methyl-4-(piperidin-4-yloxy)quinoline (346.3 mg, 1.24 mmol) obtained in reference example 239. ¹ H-NMR (CDCl ₃ , 400 MHz) δ 8 .65 (d, 1 N), 7.97 (s, 1 N), 7.92 (d, 1 N), 7.53 (d, 1 N), 6.69 (d, 1 N), 5 .50-5.25 (m, 1 N), 5.00-4.90 (m, 1 N), 4.75-4.60 (m, 1 N), 4.30-4.10 (m , 1 N), 4.05-3.70 (m, 2 N), 3.60-3.20 (m, 2 N), 2.90-2.80 (m, 2 N), 2.80 -2.65 (m, 1 N), 2.65-2.55 (m, 2 N), 2.55 (s, 3 N), 2.40-2.05 (m, 2 N), 2 .05-1.95 (m, 2 H)

[2348] Example 411: (2S,4S)-4-fluoro-1-[2-[4-[[6-(trifluoromethyl)-4-quinolyl]oxy]-1-piperidyl] acetyl]pyrrolidine-2-carbonitrile

[2349] The title compound (245.4 mg, 43.9%) was prepared in the same manner as in Example 330 except that instead of 8-fluoro-N-(piperidin-4-yl)quinolin- 5-amine hydrochloride 4-(piperidin-4-yloxy)-6-(trifluoromethyl)quinoline hydrochloride (413.3 mg, 1.24 mmol) obtained in reference example 240 was used. ¹ H-NMR (CDCl ₃ , 400 MHz) δ 8.83 (d, 1 N), 8.51 (s, 1 N), 8.13 (d, 1 N), 7.87 (d, 1 N), 6.81 (d, 1 N) , 5.55-5.35 (m, 1 N), 5.00-4.90 (m, 1 N), 4.75-4.65 (m, 1 N), 4.30-4.10 (m, 1 N), 4.05-3.70 (m, 2 N), 3.55-3.20 (m, 2 N), 3.00-2.80 (m, 2 N), 2 .80-2.60 (m, 1 N), 2.60-2.50 (m, 2 N), 2.30-2.10 (m, 2 N), 2.10-1.95 (m , 2 N)

[2350] Example 412: (2S,4S)-4-fluoro-1-[2-[4-[[2-(trifluoromethyl)-4-quinolyl]oxy]-1-piperidyl]acetyl]pyrrolidine-2-carbonitrile

[2351] The title compound (312.7 mg, 55.9%) was prepared in the same manner as Example 330 except that instead of 8-fluoro-N-(piperidin-4-yl)quinolin- 5-amine hydrochloride 4-(piperidin-4-yloxy)-2-(trifluoromethyl)quinoline hydrochloride (291.3 mg, 0.88 mmol) obtained in reference example 241 was used. ¹ H-NMR (CDCl ₃ , 400 MHz) δ 8.27 (d, 1 N), 8.14 (d, 1 N), 7.80 (t, 1 N), 7.62 (t, 1 N), 7.02 (s, 1 N) , 5.50-5.25 (m, 1 N), 5.00-4.90 (m, 1 N), 4.85-4.70 (m, 1 N), 4.30-4.15 (m, 1 N), 4.05-3.70 (m, 2 N), 3.55-3.15 (m, 2 N), 2.95-2.80 (m, 2 N), 2 .80-2.65 (m, 1 N), 2.65-2.55 (m, 2 N), 2.30-2.10 (m, 2 N), 2.10-1.95 (m ,2H)

[2352] Example 413: (2S,4S)-4-fluoro-1-[2-[4-[[6-fluoro-2-(trifluoromethyl)-4-quinolyl]oxy]-1-piperidyl]acetyl]pyrrolidine -2-carbonitrile

[2353] The title compound (243.7 mg, 41.9%) was prepared in the same manner as Example 330 except that instead of 8-fluoro-N-(piperidin-4-yl)quinolin- 5-amine hydrochloride 6-fluoro-4-(piperidin-4-yloxy)-2-(trifluoromethyl)quinoline hydrochloride (255.6 mg, 0.73 mmol) obtained in Reference Example 242 was used. ¹ H-NMR (CDCl ₃ , 400 MHz) δ 8.15 (d, 1 N), 7.84 (d, 1 N), 7.56 (s, 1 N), 7.03 (s, 1 N), 5.50- 5.20 (m, 1 N), 5.00-4.90 (m, 1 N), 4.85-4.70 (m, 1 N), 4.30-4.15 (m, 1 N ), 4.05-3.70 (m, 2 N), 3.55-3.20 (m, 2 N), 2.95-2.80 (m, 2 N), 2.80-2, 65 (m, 1 N), 2.65-2.55 (m, 2 N), 2.30-2.10 (m, 2 N), 2.10-1.95 (m, 2 N)

[2354] Example 414: (2S,4S)-4-fluoro-1-[2-[4-[[b-methoxy-2-(trifluoromethyl)-4-quinolyl]oxy]-1-piperidyl]acetyl]pyrrolidine -2-carbonitrile

[2355] The title compound (266.4 mg, 44.6%) was prepared in the same manner as Example 330 except that instead of 8-fluoro-N-(piperidin-4-yl)quinolin- 5-amine hydrochloride 6-methoxy-4-(piperidin-4-yloxy)-2-(trifluoromethyl)quinoline hydrochloride (303.8 mg, 0.84 mmol) obtained in Reference Example 243 was used. ¹ H-NMR (CDCl ₃ , 400 MHz) δ 8.04 (d, 1 N), 7.48-7.42 (m, 2 N), 7.00 (s, 1 N), 5.55-5.25 (m, 1 N), 5.00-4.90 (m, 1 N), 4.85-4.70 (m, 1 N), 4.35-4.20 (m, 1 N), 3.98 ( s, 3 N), 3.98-3.70 (m, 2 N), 3.50-3.20 (m, 2 N), 2.95-2.85 (m, 2 N), 2, 85-2.60 (m, 1 N), 2.70-2.55 (m, 2 N), 2.30-2.10 (m, 2 N), 2.10-2.00 (m, 2 N)

[2356] Example 415: (2S,4S)-4-fluoro-1-[2-[4-[[8-methoxy-2-(trifluoromethyl)-4-quinolyl]oxy]-1-piperidyl]acetyl]pyrrolidine -2-carbonitrile

[2357] The title compound (429.0 mg, 71.9%) was prepared in the same manner as in Example 330 except that instead of 8-fluoro-N-(piperidin-4-yl)quinolin- 5-amine hydrochloride 8-methoxy-4-(piperidin-4-yloxy)-2-(trifluoromethyl)quinoline hydrochloride (414.9 mg, 1.14 mmol) obtained in Reference Example 244 was used. ¹ H-NMR (CDCl ₃ , 400 MHz) δ 7.81 (d, 1 N), 7.54 (t, 1 N), 7.14 (d, 1 N), 7.05 (s, 1 N), 5.55- 5.35 (m, 1 N), 5.00-4.90 (m, 1 N), 4.85-4.70 (m, 1 N), 4.30-4.15 (m, 1 N ), 4.09 (s, 3 N), 4.05-3.70 (m, 2 N), 3.55-3.20 (m, 2 N), 2.90-2.80 (m, 2 N), 2.80-2.70 (m, 1 N), 2.70-2.55 (m, 2 N), 2.35-2.10 (m, 2 N), 2.10- 2.00 (m, 2 N)

[2358] Example 416: (2S,4S)-4-fluoro-1-[2-[4-[(3-fluoro-5-quinolyl)oxy]-1-piperidyl]acetyl]pyrrolidine-2-carbonitrile

[2359] The title compound (179.0 mg, 36.0%) was prepared in the same manner as in Example 330 except that instead of 8-fluoro-N-(piperidin-4-yl)quinolin- 5-amine hydrochloride used 3-fluoro-5-(piperidin-4-yloxy)quinoline (351.2 mg, 1.24 mmol) obtained in reference example 245. ¹ H-NMR (CDCl ₃ , 400 MHz) δ 8 .79 (s, 1 N), 8.17 (d, 1 N), 7.68 (s, 1 N), 7.56 (t, 1 N), 6.91 (d, 1 N), 5 .55-5.30 (m, 1 N), 5.05-4.85 (m, 1 N), 4.70-4.50 (m, 1 N), 4.30-4.10 (m , 1 N), 4.00-3.70 (m, 2 N), 3.55-3.20 (m, 2 N), 2.90-2.75 (m, 2 N), 2.75 -2.60 (m, 1 N), 2.60-2.50 (m, 2 N), 2.35-2.10 (m, 2 N), 2.10-1.90 (m, 2 N)

[2360] Example 417 5-[[1-[2-oxo-2-[(2S,4S)-2-cyano-4-fluoropyrrolidin-1-yl]ethyl]-4-piperidyl]oxy]quinoline-2 -carbonitrile

[2361] The title compound (70.2 mg, 13.9%) was prepared in the same manner as Example 330 except that instead of 8-fluoro-N-(piperidin-4-yl)quinolin- 5-amine hydrochloride 5-(piperidin-4-yloxy)quinoline-2-carbonitrile hydrochloride (359.9 mg, 1.24 mmol) obtained in reference example 246 was used. ¹ H-NMR (CDCl ₃ , 400 MHz) δ 8.73 (d, 1 N), 7.73-7.64 (m, 3 N), 6.99 (d, 1 N), 5.55-5.35 (m, 1 N), 5. 00-4.90 (m, 1 N), 4.70-4.55 (m, 1 N), 4.30-4.15 (m, 1 N), 4.05-3.70 (m, 2 N), 3.55-3.20 (m, 2 N), 2.90-2.80 (m, 2 N), 2.80-2.65 (m, 1 N), 2.65- 2.50 (m, 2 N), 2.35-2.05 (m, 2 N), 2.05-1.95 (m, 2 N)

[2362] Example 418 (2S,4S)-1-[2-[4-[(8-chloro-5-quinolyl)oxy]-1-piperidyl]acetyl]-4-fluoropyrrolidine-2-carbonitrile

[2363] The title compound (304.0 mg, 58.7%) was prepared in the same manner as in Example 330 except that instead of 8-fluoro-N-(piperidin-4-yl)quinolin- 5-amine hydrochloride used 8-chloro-5-(piperidin-4-yloxy)quinoline (371.7 mg, 1.24 mmol) obtained in reference example 247. ¹ H-NMR (CDCl ₃ , 400 MHz) δ 8 .99 (d, 1 N), 8.53 (d, 1 N), 7.53-7.50 (m, 2 N), 7.04 (d, 1 N), 5.75-5.20 (m, 1 N), 5.00-4.90 (m, 1 N), 4.70-4.50 (m, 1 N), 4.30-4.10 (m, 1 N), 4 ,10-3.65 (m, 2 N), 3.65-3.20 (m, 2 N), 3.10-2.80 (m, 2 N), 2.80-2.55 (m , 1 N), 2.55-2.40 (m, 2 N), 2.40-2.15 (m, 2 N), 2.15-1.90 (m, 2 N)

[2364] Example 419 (2S,4S)-4-fluoro-1-[2-[4-(1-isoquinoloxy)-1-piperidyl]acetyl]pyrrolidine-2-carbonitrile

[2365] The title compound (156.9 mg, 86.5%) was prepared in the same manner as Example 330 except that instead of 8-fluoro-N-(piperidin-4-yl)quinolin- 5-amine hydrochloride 1-(piperidin-4-yloxy)isoquinoline hydrochloride (125.6 mg, 0.47 mmol) obtained in reference example 248 was used. ¹ H-NMR (CDCl ₃ , 400 MHz) δ 8.25 ( d, 1 N), 7.96 (d, 1 N), 7.73 (d, 1 N), 7.66 (t, 1 N), 7.54 (t, 1 N), 7.19 ( d, 1 Η), 5.75-5.25 (m, 2 Η), 5.00-4.90 (m, 1 Η), 4.30-4.15 (m, 1 Η), 4, 10-3.70 (m, 2 Η), 3.60-3.20 (m, 2 Η), 2.90-2.80 (m, 2 Η), 2.80-2.65 (m, 1 Η), 2.65-2.50 (m, 2 Η), 2.35-2.10 (m, 2 Η), 2.10-1.90 (m, 2 Η)

[2366] Example 420: (2S,4S)-4-fluoro-1-[2-[4-(4-isoquinoloxy)-1-piperidyl]acetyl]pyrrolidine-2-carbonitrile

[2367] The title compound (39.9 mg, 22.0%) was prepared in the same manner as in Example 330 except that instead of 8-fluoro-N-(piperidin-4-yl)quinolin- 5-amine hydrochloride used 4-(piperidin-4-yloxy)isoquinoline hydrochloride (328.9 mg, 1.24 mmol) obtained in reference example 249. ¹ H-NMR (CDCl ₃ , 400 MHz) δ 8.90 ( s, 1 N), 8.22 (d, 1 N), 8.10 (s, 1 N), 7.94 (d, 1 N), 7.71 (t, 1 N), 7.63 ( t, 1 N), 5.60-5.25 (m, 1 N), 5.00-4.90 (m, 1 N), 4.80-4.60 (m, 1 N), 4, 30-4.15 (m, 1 N), 4.05-3.70 (m, 2 N), 3.60-3.15 (m, 2 N), 2.95-2.80 (m, 2 N), 2.80-2.60 (m, 1 N), 2.60-2.50 (m, 2 N), 2.30-2.10 (m, 2 N), 2.10- 1.90 (m, 2 N)

[2368] Example 421: (2S,4S)-4-fluoro-1-[2-[4-(5-isoquinoloxy)-1-piperidyl]acetyl]pyrrolidine-2-carbonitrile

[2369] The title compound (107.7 mg, 59.4%) was prepared in the same manner as Example 330 except that instead of 8-fluoro-N-(piperidin-4-yl)quinolin- 5-amine hydrochloride 5-(piperidin-4-yloxy)isoquinoline hydrochloride (156.5 mg, 0.59 mmol) obtained in reference example 250 was used. ¹ H-NMR (CDCl ₃ , 400 MHz) δ 9.20 ( s, 1 N), 8.53 (d, 1 N), 8.03 (d, 1 N), 7.55-7.47 (m, 2 N), 7.02 (d, 1 N), 5.55-5.20 (m, 1 N), 5.00-4.85 (m, 1 N), 4.70-4.50 (m, 1 N), 4.30-4.15 ( m, 1 N), 4.05-3.70 (m, 2 N), 3.60-3.20 (m, 2 N), 2.90-2.80 (m, 2 N), 2, 80-2.60 (m, 1 N), 2.60-2.50 (m, 2 N), 2.30-2.10 (m, 2 N), 2.10-1.90 (m, 2 N)

[2370] Example 422: (2S,4S)-4-fluoro-1-[2-[4-(6-isoquinoloxy)-1-piperidyl]acetyl]pyrrolidine-2-carbonitrile

[2371] The title compound (73.3 mg, 40.4%) was prepared in the same manner as Example 330 except that instead of 8-fluoro-N-(piperidin-4-yl)quinolin- 5-amine hydrochloride 6-(piperidin-4-yloxy)isoquinoline hydrochloride (328.9 mg, 1.24 mmol) obtained in reference example 251 was used. ¹ H-NMR (CDCl ₃ , 400 MHz) δ 9.10 ( s, 1 N), 8.43 (d, 1 N), 7.87 (d, 1 N), 7.52 (d, 1 N), 7.23 (d, 1 N), 7.06 ( s, 1 N), 5.55-5.25 (m, 1 N), 5.00-4.90 (m, 1 N), 4.65-4.50 (m, 1 N), 4, 30-4.15 (m, 1 N), 4.05-3.70 (m, 2 N), 3.60-3.15 (m, 2 N), 2.90-2.80 (m, 2 N), 2.80-2.60 (m, 1 N), 2.60-2.45 (m, 2 N), 2.30-2.10 (m, 2 N), 2.00- 1.80 (m, 2 N)

[2372] Example 423 (2S,4S)-4-fluoro-1-[2-[4-(7-isoquinoloxy)-1-piperidyl]acetyl]pyrrolidine-2-carbonitrile

[2373] The title compound (140.7 mg, 77.6%) was prepared in the same manner as in Example 330 except that instead of 8-fluoro-N-(piperidin-4-yl)quinolin- 5-amine hydrochloride 7-(piperidin-4-yloxy)isoquinoline hydrochloride (328.9 mg, 1.24 mmol) obtained in reference example 252 was used. ¹ H-NMR (CDCl ₃ , 400 MHz) δ 9.15 ( s, 1 N), 8.41 (d, 1 N), 7.75 (d, 1 N), 7.58 (d, 1 N), 7.35 (d, 1 N), 7.23 ( s, 1 N), 5.55-5.25 (m, 1 N), 5.00-4.90 (m, 1 N), 4.60-4.45 (m, 1 N), 4, 25-4.10 (m, 1 N), 4.05-3.70 (m, 2 N), 3.65-3.20 (m, 2 N), 2.90-2.80 (m, 2 N), 2.80-2.60 (m, 1 N), 2.60-2.45 (m, 2 N), 2.30-2.05 (m, 2 N), 2.00- 1.85 (m, 2 N)

[2374] Example 424: (2S,4S)-4-fluoro-1-[2-[4-[(b-methoxy-2-methyl-4-quinolyl)oxy]-1-piperidyl]acetyl]pyrrolidine-2 -carbonitrile

[2375] The title compound (141.2 mg, 69.8%) was prepared in the same manner as Example 330 except that instead of 8-fluoro-N-(piperidin-4-yl)quinolin- 5-amine hydrochloride 6-methoxy-2-methyl-4-(piperidin-4-yloxy)quinoline hydrochloride (383.6 mg, 1.24 mmol) obtained in reference example 253 was used. ¹ H-NMR (CDCl ₃ , 400 MHz) δ 7.85 (d, 1 N), 7.42 (s, 1 N), 7.32 (d, 1 N), 6.59 (s, 1 N), 5.55-5, 20 (m, 1 N), 5.00-4.90 (m, 1 N), 4.70-4.60 (m, 1 N), 4.30-4.15 (m, 1 N), 4.05-3.70 (m, 2 N), 3.94 (s, 3 N), 3.55-3.20 (m, 2 N), 2.90-2.80 (m, 2 N ), 2.80-2.65 (m, 1 N), 2.65 (s, 3 N), 2.65-2.50 (m, 2 N), 2.30-2.10 (m, 2 N), 2.10-1.95 (m, 2 N)

[2376] Example 425: (2S,4S)-4-fluoro-1-[2-[4-(5-quinoloxy)-1-piperidyl]acetyl]pyrrolidine-2-carbonitrile

[2377] The title compound (161.4 mg, 37.0%) was prepared in the same manner as in Example 330 except that instead of 8-fluoro-N-(piperidin-4-yl)quinolin- 5-amine hydrochloride 5-(piperidin-4-yloxy)quinoline hydrochloride (383.6 mg, 1.24 mmol) prepared in Reference Example 3S was used. ^1H -NMR ( _CDCl3 , 400 MHz) δ 8.91 (d, 1 H), 8.60 (d, 1 H), 7.69 (d, 1 H), 7.60 (t, 1 H ), 7.40 (t, 1 N), 6.89 (d, 1 N), 5.55-5.25 (m, 1 N), 5.00-4.90 (m, 1 N), 4.80-4.70 (m, 1 N), 4.30-4.15 (m, 1 N), 4.05-3.70 (m, 2 N), 3.55-3.20 ( m, 2 N), 2.95-2.80 (m, 2 N), 2.80-2.65 (m, 1 N), 2.65-2.50 (m, 2 N), 2. 30-2.10 (m, 2 N), 2.10-1.95 (m, 2 N)

[2378] Example 426: (2S)-1-[2-[4-[(6-Methoxy-4-quinolyl)oxy]-1-piperidyl]acetyl]pyrrolidine-2-carbonitrile

[2379] The title compound (127.1 mg, 25.9%) was prepared as described in Example 110 except that N-(piperidin-4-yl)quinolin-5-amine hydrochloride was used instead of 6-methoxy-4-(piperidin-4-yloxy)quinoline hydrochloride (366.1 mg, 1.24 mmol) obtained in reference example 42. ¹ H-NMR (CDCl ₃ , 400 MHz) δ 8.59 (d , 1 N), 7.93 (d, 1 N), 7.47 (s, 1 N), 7.34 (d, 1 N), 6.70 (d, 1 N), 5.20-4 .70 (m, 1 N), 4.70-4.60 (m, 1 N), 3.95 (s, 3 N), 3.80-3.60 (m, 1 N), 3.60 -3.50 (m, 1 N), 3.45-3.20 (m, 2 N), 2.95-2.75 (m, 2 N), 2.70-2.50 (m, 2 N), 2.40-2.10 (m, 6 N), 2.10-1.95 (m, 2 N)

[2380] Example 427 (2S)-1-[2-[4-[(6-Fluoro-4-quinolyl)oxy]-1-piperidyl]acetyl]pyrrolidine-2-carbonitrile

[2381] The title compound (51.1 mg, 10.8%) was prepared as described in Example 110 except that N-(piperidin-4-yl)quinolin-5-amine hydrochloride was used instead of 6-Fluoro-4-(piperidin-4-yloxy)quinoline hydrochloride (351.2 mg, 1.24 mmol) obtained in reference example 40. ¹ H-NMR (CDCl ₃ , 400 MHz) δ 8.69 (d , 1 N), 8.02 (d, 1 N), 7.81 (d, 1 N), 7.46 (s, 1 N), 6.74 (d, 1 N), 5.20-4 .75 (m, 1 N), 4.75-4.60 (m, 1 N), 3.80-3.60 (m, 1 N), 3.60-3.50 (m, 1 N) , 3.50-3.20 (m, 2 N), 2.95-2.75 (m, 2 N), 2.70-2.50 (m, 2 N), 2.40-2.10 (m, 6 N), 2.10-1.95 (m, 2 N)

[2382] Example 428: (2S)-1-[2-[4-[(7-chloro-4-quinolyl)oxy]-1-piperidyl]acetyl]pyrrolidine-2-carbonitrile

[2383] The title compound (272.5 mg, 55.0%) was prepared as described in Example 110 except that N-(piperidin-4-yl)quinolin-5-amine hydrochloride was used instead of 7-chloro-4-(piperidin-4-yloxy)quinoline hydrochloride (371.6 mg, 1.24 mmol) obtained from reference example 254. ¹ H-NMR (CDCl ₃ , 400 MHz) δ 8.70 (d , 1 N), 8.14 (d, 1 N), 8.00 (s, 1 N), 7.43 (d, 1 N), 6.70 (d, 1 N), 5.20-4 .75 (m, 1 N), 4.75-4.60 (m, 1 N), 3.80-3.60 (m, 1 N), 3.60-3.50 (m, 1 N) , 3.45-3.15 (m, 2 N), 2.90-2.75 (m, 2 N), 2.70-2.50 (m, 2 N), 2.40-2.10 (m, 6 N), 2.10-1.95 (m, 2 N)

[2384] Example 429: (2S)-1-[2-[4-[(3-Fluoro-5-quinolyl)oxy]-1-piperidyl]acetyl]pyrrolidine-2-carbonitrile

[2385] The title compound (419.4 mg, 88.3%) was prepared in the same manner as in Example 110 except that instead of N-(piperidin-4-yl)quinolin-5-amine hydrochloride used 3-fluoro-5-(piperidin-4-yloxy)quinoline hydrochloride (351.2 mg, 1.24 mmol) obtained in reference example 245. ¹ H-NMR (CDCl ₃ , 400 MHz) δ 8.79 ( s, 1 N), 8.19 (s, 1 N), 7.68 (d, 1 N), 7.55 (t, 1 N), 6.91 (d, 1 N), 5.25- 4.70 (m, 1 N), 4.65-4.55 (m, 1 N), 3.80-3.60 (m, 1 N), 3.60-3.50 (m, 1 N ), 3.50-3.10 (m, 2 N), 2.90-2.75 (m, 2 N), 2.65-2.50 (m, 2 N), 2.45-2, 10 (m, 6 N), 2.10-1.95 (m, 2 N)

[2386] Example 430 5-[[1-[2-oxo-2-[(2S)-2-cyanopyrrolidin-1-yl]ethyl]-4-piperidyl]oxy]quinoline-2-carbonitrile

[2387] The title compound (198.9 mg, 41.1%) was prepared in the same manner as Example 110 except that instead of N-(piperidin-4-yl)quinolin-5-amine hydrochloride used 5-(piperidin-4-yloxy)quinolin-2-carbonitrile hydrochloride (359.9 mg, 1.24 mmol) obtained in reference example 246. ¹ H-NMR (CDCl ₃ , 400 MHz) δ 8.74 (d , 1 N), 7.72-7.66 (m, 3 N), 7.01 (d, 1 N), 5.20-4.75 (m, 1 N), 4.70-4.60 (m, 1 N), 3.80-3.60 (m, 1 N), 3.60-3.50 (m, 1 N), 3.45-3.20 (m, 2 N), 2 .90-2.80 (m, 2 N), 2.70-2.50 (m, 2 N), 2.40-2.10 (m, 6 N), 2.10-1.95 (m , 2 N)

[2388] Example 431: (2S)-1-[2-[4-[(8-chloro-5-quinolyl)oxy]-1-piperidyl]acetyl]pyrrolidine-2-carbonitrile

[2389] The title compound (383.5 mg, 77.4%) was prepared as described in Example 110 except that N-(piperidin-4-yl)quinolin-5-amine hydrochloride was used instead of 8-chloro-5-(piperidin-4-yloxy)quinoline hydrochloride (371.6 mg, 1.24 mmol) obtained from reference example 247. ¹ H-NMR (CDCl ₃ , 400 MHz) δ 9.00 (d , 1 N), 8.54 (d, 1 N), 7.56-7.51 (m, 2 N), 7.05 (d, 1 N), 5.45-4.70 (m, 1 N), 4.65-4.55 (m, 1 N), 3.85-3.65 (m, 1 N), 3.65-3.55 (m, 1 N), 3.55-3 .20 (m, 2 N), 3.05-2.85 (m, 2 N), 2.60-2.40 (m, 2 N), 2.40-2.00 (m, 8 N)

[2390] Example 432: (2S,4S)-4-fluoro-1-[2-[4-[(7-methyl-4-quinolyl)oxy]-1-piperidyl]acetyl]pyrrolidine-2-carbonitrile

[2391] The title compound (129.3 mg, 22.3%) was prepared in the same manner as in Example 330 except that instead of 8-fluoro-N-(piperidin-4-yl)quinolin- 5-amine hydrochloride 7-methyl-4-(piperidin-4-yloxy)quinoline hydrochloride (407.0 mg, 1.46 mmol) obtained in reference example 255 was used. ¹ H-NMR (CDCl ₃ , 400 MHz) δ 8 .68 (d, 1 N), 8.11 (d, 1 N), 7.80 (s, 1 N), 7.34 (d, 1 N), 6.67 (d, 1 N), 5 .50-5.25 (m, 1 N), 5.00-4.90 (m, 1 N), 4.75-4.65 (m, 1 N), 4.30-4.15 (m , 1 N), 4.05-3.70 (m, 2 N), 3.55-3.20 (m, 2 Η), 2.95-2.75 (m, 2 Η), 2.75 -2.65 (m, 1 Η), 2.65-2.56 (m, 2 Η), 2.56 (s, 3 Η), 2.30-2.10 (m, 2 Η), 2 .10-1.95 (m, 2 Η)

[2392] Example 43S. (2S,4S)-4-fluoro-1-[2-[4-[(7-fluoro-4-quinolyl)oxy]-1-piperidyl]acetyl]pyrrolidine-2-carbonitrile

[2393] The title compound (239.1 mg, 40.9%) was prepared in the same manner as in Example 330 except that instead of 8-fluoro-N-(piperidin-4-yl)quinolin- 5-amine hydrochloride 7-fluoro-4-(piperidin-4-yloxy)quinoline hydrochloride (421.3 mg, 1.49 mmol) obtained in reference example 256 was used. ¹ H-NMR (CDCl ₃ , 400 MHz) δ 8.71 (d, 1 N), 8.22 (d, 1 N), 7.64 (d, 1 N), 7.27 (s, 1 N), 6.69 (d, 1 N), 5. 50-5.25 (m, 1 N), 5.00-4.90 (m, 1 N), 4.75-4.65 (m, 1 N), 4.30-4.15 (m, 1 N), 4.05-3.70 (m, 2 N), 3.50-3.20 (m, 2 N), 2.95-2.80 (m, 2 N), 2.80- 2.65 (m, 1 N), 2.65-2.50 (m, 2 N), 2.30-2.10 (m, 2 N), 2.10-1.95 (m, 2 H )

[2394] Example 434 4-[[1-[2-oxo-2-[(2S,4S)-2-cyano-4-fluoropyrrolidin-1-yl]ethyl]-4-piperidyl]oxy]quinoline-8 -carbonitrile

[2395] The title compound (277.0 mg, 46.6%) was prepared in the same manner as Example 330 except that instead of 8-fluoro-N-(piperidin-4-yl)quinolin- 5-amine hydrochloride 4-(piperidin-4-yloxy)quinoline-8-carbonitrile hydrochloride (414.4 mg, 1.43 mmol) obtained in reference example 257 was used. ¹ H-NMR (CDCl ₃ , 400 MHz) δ 8.87 (d, 1 N), 8.46 (d, 1 N), 8.09 (d, 1 N), 7.54 (t, 1 N), 6.84 (d, 1 N), 5.55-5.25 (m, 1 N), 5.00-4.90 (m, 1 N), 4.80-4.65 (m, 1 N), 4.30-4.15 ( m, 1 N), 4.00-3.70 (m, 2 N), 3.50-3.20 (m, 2 N), 2.90-2.80 (m, 2 N), 2.80- 2.65 (m, 1 N), 2.65-2.50 (m, 2 N), 2.30-2.10 (m, 2 N), 2.10-1.95 (m, 2 N )

[2396] Example 435: (2S,4S)-4-fluoro-1-[2-[4-[(8-fluoro-4-quinolyl)oxy]-1-piperidyl]acetyl]pyrrolidine-2-carbonitrile

[2397] The title compound (301.2 mg, 50.5%) was prepared in the same manner as in Example 330 except that instead of 8-fluoro-N-(piperidin-4-yl)quinolin- 5-amine hydrochloride 8-fluoro-4-(piperidin-4-yloxy)quinoline hydrochloride (421.3 mg, 1.49 mmol) obtained in reference example 258 was used. ¹ H-NMR (CDCl ₃ , 400 MHz) δ 8.77 (d, 1 N), 8.00 (d, 1 N), 7.44-7.37 (m, 2 N), 6.78 (d, 1 N), 5.55-5, 25 (m, 1 N), 5.00-4.90 (m, 1 N), 4.80-4.65 (m, 1 N), 4.30-4.15 (m, 1 N), 4.05-3.70 (m, 2 N), 3.55-3.20 (m, 2 N), 2.95-2.75 (m, 2 N), 2.75-2.65 ( m, 1 N), 2.65-2.50 (m, 2 N), 2.30-2.10 (m, 2 N), 2.10-1.95 (m, 2 N)

[2398] Example 436: (2S,4S)-4-fluoro-1-[2-[4-[(2-methyl-4-quinolyl)oxy]-1-piperidyl]acetyl]pyrrolidine-2-carbonitrile

[2399] The title compound (79.9 mg, 13.5%) was prepared in the same manner as described in Example 3S0 except that instead of 8-fluoro-N-(piperidin-4-yl)quinolin- 5-amine hydrochloride 2-methyl-4-(piperidin-4-yloxy)quinoline hydrochloride (415.4 mg, 1.49 mmol) obtained in reference example 259 was used. ¹ H-NMR (CDCl ₃ , 400 MHz) δ 8.16 (d, 1 N), 7.94 (d, 1 N), 7.66 (t, 1 N), 7.44 (t, 1 N), 6.61 (s, 1 N), 5.50-5.25 (m, 1 N), 5.00-4.90 (m, 1 N), 4.75-4.65 (m, 1 N), 4.30-4.15 ( m, 1 N), 4.05-3.70 (m, 2 N), 3.55-3.20 (m, 2 N), 2.95-2.80 (m, 2 N), 2. 80-2.69 (m, 1 N), 2.69 (s, 3 N), 2.69-2.55 (m, 2 N), 2.30-2.10 (m, 2 N), 2.10-1.95 (m, 2 N)

[2400] Example 437: (2S,4S)-4-fluoro-1-[2-[4-[(b-fluoro-2-methyl-4-quinolyl)oxy]-1-piperidyl]acetyl]pyrrolidine-2 -carbonitrile

[2401] The title compound (403.6 mg, 65.4%) was prepared in the same manner as in Example 330 except that instead of 8-fluoro-N-(piperidin-4-yl)quinolin- 5-amine hydrochloride 6-fluoro-2-methyl-4-(piperidin-4-yloxy)quinoline hydrochloride (442.2 mg, 1.49 mmol) obtained in Reference Example 260 was used. ¹ H-NMR (CDCl ₃ , 400 MHz) δ 7.90 (d, 1 N), 7.72 (d, 1 N), 7.39 (s, 1 N), 6.60 (s, 1 N), 5.50-5, 25 (m, 1 N), 5.00-4.90 (m, 1 N), 4.70-4.60 (m, 1 N), 4.30-4.15 (m, 1 N), 4.05-3.70 (m, 2 N), 3.50-3.20 (m, 2 N), 2.90-2.75 (m, 2 N), 2.75-2.65 ( m, 1 N), 2.65 (s, 3 N), 2.65-2.55 (m, 2 N), 2.30-2.10 (m, 2 N), 2.10-1, 95 (m, 2 N)

[2402] Example 438: (2S,4S)-4-fluoro-1-[2-[4-[(8-methoxy-4-quinolyl)oxy]-1-piperidyl]acetyl]pyrrolidine-2-carbonitrile

[2403] The title compound (65.9 mg, 10.7%) was prepared in the same manner as in Example 330 except that instead of 8-fluoro-N-(piperidin-4-yl)quinolin- 5-amine hydrochloride 8-methoxy-4-(piperidin-4-yloxy)quinoline hydrochloride (97.6 mg, 0.3S mmol) obtained in reference example 261 was used. ¹ H-NMR (CDCl ₃ , 400 MHz) δ 8.74 (d, 1 N), 7.79 (d, 1 N), 7.43 (t, 1 N), 7.06 (d, 1 N), 6.76 (d, 1 N), 5.50-5.25 (m, 1 N), 5.00-4.90 (m, 1 N), 4.75-4.65 (m, 1 N), 4.30-4.15 ( m, 1 N), 4.08 (s, 3 N), 4.08-3.70 (m, 2 N), 3.55-3.20 (m, 2 N), 2.90-2, 75 (m, 2 N), 2.75-2.65 (m, 1 N), 2.65-2.55 (m, 2 N), 2.30-2.10 (m, 2 N), 2.10-1.95 (m, 2 N)

[2404] Example 439: (2S,4S)-4-fluoro-1-[2-[4-[(8-methyl-4-quinolyl)oxy]-1-piperidyl]acetyl]pyrrolidine-2-carbonitrile

[2405] The title compound (450.4 mg, 76.3%) was prepared in the same manner as in Example 330 except that instead of 8-fluoro-N-(piperidin-4-yl)quinolin- 5-amine hydrochloride 8-methyl-4-(piperidin-4-yloxy)quinoline hydrochloride (415.4 mg, 1.49 mmol) obtained in reference example 262 was used. ¹ H-NMR (CDCl ₃ , 400 MHz) δ 8.75 (d, 1 N), 8.08 (d, 1 N), 7.54 (d, 1 N), 7.38 (t, 1 N), 6.72 (d, 1 N), 5.50-5.25 (m, 1 N), 5.00-4.90 (m, 1 N), 4.75-4.65 (m, 1 N), 4.25-4.10 ( m, 1 N), 4.05-3.70 (m, 2 N), 3.50-3.20 (m, 2 N), 2.90-2.78 (m, 2 N), 2. 78 (s, 3 N), 2.78-2.60 (m, 1 N), 2.60-2.50 (m, 2 N), 2.30-2.10 (m, 2 N), 2.10-1.95 (m,2N)

[2406] The structures of the compounds are shown in Table 1. Chemical names were determined using ChemDraw.

[2407]

[2408] Experimental Example 1: Evaluation of the inhibitory effect on the activity of dipeptidyl peptidases including FAP

[2409] Compounds of the present technology were evaluated for their inhibitory effect on the activity of dipeptidyl peptidases, including FAP, using a fluorescent-producing substrate upon enzymatic degradation. The test was performed at 25°C to obtain a final reaction volume of 100 μl in a 96-well black plate. Each of the dipeptidyl peptidases was reacted with test compounds (compounds of the present technology) or Talabostat for 10 minutes and then digested with enzymes for 10 minutes to measure the level of fluorescent substances released from them. Briefly, test compounds were dissolved in dimethyl sulfoxide (DMSO) at a concentration of 20 mM and then subjected to serial dilution, thereby generating an 8-point curve. For the control group, a 6-point curve was used, obtained by serially diluting Talabostat in the same buffer solution. Fluorescence intensity was measured using a microplate reader (Flexstation3, Molecular Devices) at a wavelength of 380 nm and emission was read at 460 nm. The inhibitory effect of the test compounds was measured as the reduction (%) in signal rate compared to a control group without any inhibitor. Data were fit to a four-variable logistic model and IC ₅₀ values were calculated using GraphPad Prism software.

[2410] Recombinant human FAP (R&D Systems) was diluted in 50 mM Tris (pH 7.5) buffer containing 1 M sodium chloride and 1 mg/ml bovine serum albumin (BSA), which was 10 ng per final reaction. Test compounds were serially diluted in buffer containing up to 0.1% DMSO. Z-Gly-Pro-AMC (Bachem) was used as a substrate. Dissolved in DMSO and then diluted in the same buffer, substrate was added to 50 µM for the final reaction.

[2411] For recombinant human DPP4 (R&D Systems), 25 mM Tris (pH 8.0) buffer was used as the buffer solution and H-Gly-Pro-AMC (Bachem) as the substrate. For recombinant human DPP7 (R&D Systems), 25 mM MES buffer (pH 6.0) was used as the buffer solution and Lys-Pro-AMC (Bachem) as the substrate. For recombinant human DPP8 (PBS Bioscience), a buffer containing 10 mM magnesium chloride and 0.05% Tween 20 and Z-Ala-Pro-AMC (BPS Bioscience) was used as a 10 mM Tris buffer solution (pH 7.4). as a substrate. For recombinant human DPP9 (R&D Systems), 25 mM Tris buffer (pH 8.0) was used as a buffer solution and H-Gly-Pro-AMC (Bachem) as a substrate. For recombinant human PREP (R&D System), the buffer solution used is 25 mM Tris buffer (pH 7.5) containing 250 mM sodium chloride and 2.5 mM DTT (dithiol threitol), and Z-Gly-Pro-AMC (Bachem) as a substrate. Evaluation was performed using 10 HrDPP4, PDD7 and PREP, 20 HrDPP8 and 50 ng DPP9 based on the final reaction. When assessing DPP4, test compounds were subjected to serial dilution in buffer under conditions containing up to 0.1% DMSO. When assessing DPP7, DPP8, DPP9 and PREP, test compounds were subjected to serial dilutions in each buffer under conditions containing up to 0.5% DMSO.

[2412] For the FAP FRET assay, recombinant human FAP (R&D systems) was diluted in 50 mM HEPES buffer (pH 7.2) containing 150 mM sodium chloride, 0.1 mg/mL bovine serum albumin (BSA), and 1 mM EDTA to obtain 10 ng for final reaction. Test compounds were serially diluted in buffer containing up to 0.1% DMSO. The substrate used was FRET peptides containing the human FGF21 sequence (VGPSQGK) conjugated to HyLite Fluor 488 and QXL 520 dark quencher (Anaspec). Dissolved in DMSO and then diluted with the same buffer, the substrate was added to a concentration of 6 μM per final reaction. All FRET assay reactions were performed at 37°C.

[2413] The results obtained by evaluating the inhibitory effect on the activity of dipeptidyl peptidase, including FAP, as indicated above, are shown in tables 2-8 below.

Claims (62)

1. Compound of formula 1: or a stereoisomer thereof, a mixture of stereoisomers, or a pharmaceutically acceptable salt, wherein n is 1 or 2; R ₁ is selected from the group consisting of formulas I, II, III, IV and V: ; R ₂ represents hydrogen; R ₃ represents -NR ₄ R ₅ , -OR ₄ , -C(O)NHR ₄ , -NHC(O)(CH ₂ ) _m R ₄ , -NHS(O) ₂ R ₄ , -(CH ₂ ) _m CH ₂ R ₄ or -(CH ₂ ) _m NHR ₄ , where m represents 0 or 1; R₄ is phenyl substituted with 1-3 Z, heterocycle selected from the group consisting of benzo[d][1,3]dioxolyl, dihydrobenzo[1,4]dioxynyl, 2,3-dihydrobenzofuranyl, 2-oxo-1,2-dihydroquinolinyl and 2-oxo-1,2 ,3,4-tetrahydroquinolinyl, wherein said heterocycle is optionally substituted with 1-3 Z, naphthyl, optionally substituted with 1-3 Z, or heteroaryl selected from the group consisting of pyridinyl, pyrimidinyl, pyrazinyl, imidazolyl, pyrazolyl, triazolyl, oxazolyl, thiazolyl, furanyl, pyrrolyl, thiophenyl, quinolinyl, isoquinolinyl, chromenonyl, quinazolinyl, benzoxazolyl, benzofuranyl, benzothiophenyl, indolyl, indolinyl, benzime idazolyl, benzoxazolyl, benzothiazolyl, indazolyl, furo[3,2-c]pyridinyl, thieno[2,3-d]pyrimidinyl, thieno[3,2-c]pyridinyl, isoxazolyl, acridinyl and naphthyridinyl, wherein said heteroaryl is optionally substituted 1-3 Z; R₅ represents hydrogen or C_1-3alkyl; And each Z is independently selected from the group consisting of hydroxy, amino, halogen, cyano, nitro, carboxylic acid, C_1-5alkyl, optionally substituted with 1-3 Z¹, WITH_2-6alkenyl, C_2-6alkynyl, C_1-5alkoxy, optionally substituted with 1-3 Z¹, WITH_1-5alkylthio, mono- or di-C_1-5alkylamino, piperazinyl, optionally substituted with Z¹, WITH_1-5alkylsulfonylamino, C_1-5alkylcarbonylamino, aminosulfonyl, aminocarbonyl, C_1-5alkylaminocarbonyl, phenyl, optionally substituted with Z¹, phenoxy, optionally substituted Z¹, benzyl, optionally substituted with Z¹, benzoyl, optionally substituted with Z¹, phenylaminocarbonyl, pyrazolyl, optionally substituted with Z¹, benzoxazolyl, optionally substituted with Z¹, WITH_1-5alkoxycarbonyl, optionally substituted with Z¹, benzyloxy, optionally substituted with Z¹, WITH_1-5alkylsulfonyl, optionally substituted with Z¹, acetyl, morpholinyl, optionally substituted with Z¹, -NR₆C(O)R₇ and -C(O)NR₆R₇; wherein each Z ¹ is independently selected from halogen, hydroxyl, amino, C _1-5 alkylamino, cyano, acetyl, C _1-5 alkyl, C _1-5 haloalkyl, C _3-6 carbocycle and C _3-6 heterocycle; R ₆ represents hydrogen or a C _1-3 alkyl group; And R ₇ represents a C _1-3 alkyl group, optionally substituted with phenyl, phenyl, or heteroaryl selected from the group consisting of pyridinyl, pyrimidinyl and isoxazolyl. 2. A compound according to claim 1 or a stereoisomer thereof, a mixture of stereoisomers or a pharmaceutically acceptable salt thereof, wherein R ₁ is selected from the group consisting of compounds of formula Ia, IIa, IIIa, IVa and Va: . 3. Connection according to any one of paragraphs. 1-2 or a stereoisomer thereof, a mixture of stereoisomers or a pharmaceutically acceptable salt thereof having the structure of formula 1a: or having the structure of formula 1b: or having the structure of formula 1c: or having the structure of formula 1d: or having the structure of formula 1e: 4. Connection according to any one of paragraphs. 1-3 or a stereoisomer thereof, a mixture of stereoisomers or a pharmaceutically acceptable salt thereof, wherein R ₄ is phenyl substituted with 1-3 Zs, each Z being independently selected from the group consisting of hydroxy, amino, halogen, cyano, nitro, carboxylic acid, C _1-5 alkyl, optionally substituted with 1-3 halogens or amino group, C _2-6 alkenyl, C _2-6 alkynyl, C _1-5 alkoxy, C _1-5 alkylthio, mono- or di-C _1-5 alkylamino, piperazinyl, optionally substituted with acetyl, C _1-5 alkylsulfonylamino, C _1-5 alkylcarbonylamino, aminosulfonyl, aminocarbonyl, C _1-5 alkylaminocarbonyl, phenyl, phenoxy, benzyl, benzoyl, phenylaminocarbonyl, pyrazolyl and benzoxazolyl; wherein optionally R ₄ is phenyl substituted with a substituent selected from the group consisting of piperazinyl, optionally substituted with acetyl, phenyl, phenoxy, benzyl, benzoyl, phenylaminocarbonyl, pyrazolyl and benzoxazolyl; or wherein optionally R ₄ is naphthyl, optionally substituted with halogen. 5. Connection according to any one of paragraphs. 1-3 or a stereoisomer thereof, a mixture of stereoisomers or a pharmaceutically acceptable salt thereof, in which R ₄ represents a heterocycle selected from the group consisting of benzo[d][1,3]dioxolyl, dihydrobenzo[1,4]dioxynyl, 2, 3-dihydrobenzofuranyl, 2-oxo-1,2-dihydroquinolinyl and 2-oxo-1,2,3,4-tetrahydroquinolinyl, wherein said heterocycle is optionally substituted with 1-3 Z; wherein optionally R ₄ represents a heterocycle selected from the group consisting of benzo[d][1,3]dioxolyl, 2,3-dihydrobenzofuranyl, 2-oxo-1,2-dihydroquinolinyl and 2-oxo-1,2, 3,4-tetrahydroquinolinyl. 6. Connection according to any one of paragraphs. 1-3 or a stereoisomer thereof, a mixture of stereoisomers or a pharmaceutically acceptable salt thereof, wherein R ₄ is a heteroaryl selected from the group consisting of pyridinyl, pyrimidinyl, pyrazinyl, imidazolyl, pyrazolyl, triazolyl, oxazolyl, thiazolyl, furanyl, pyrrolyl, thiophenyl , quinolinyl, isoquinolinyl, chromenonyl, quinazolinyl, benzoxazolyl, benzofuranyl, benzothiophenyl, indolyl, indolinyl, benzimidazolyl, benzoxazolyl, benzothiazolyl, indazolyl, furo[3,2-c]pyridinyl, thieno[2,3-d]pyrimidinyl, thieno[3 ,2-c]pyridinyl, isoxazolyl, acridinyl and naphthyridinyl, wherein said heteroaryl is optionally substituted with 1-3 Z, each Z being independently selected from the group consisting of hydroxy, amino, di-C _1-5 alkylamino, cyano, nitro, halogen , C _1-5 alkyl, optionally substituted with 1-3 halogens, C _1-5 alkoxy, optionally substituted with 1-3 halogens, C _1-5 alkoxycarbonyl, benzyloxy, phenyl, optionally substituted with halogen, acetyl, C _1-5 alkylsulfonyl, morpholinyl , -NR ₆ C(O)R ₇ and -C(O)NR ₆ R ₇ ; or optionally R₄is a heteroaryl selected from the group consisting of pyridinyl, quinolinyl, isoquinolinyl, chromenonyl, quinazolinyl, benzofuranyl, indolinyl, benzimidazolyl, benzothiophenyl, benzothiazolyl, furo[3,2-c]pyridinyl, thieno[2,3-d]pyrimidinyl, thieno[3,2-c]pyridinyl, isoxazolyl, acridinyl and naphthyridinyl, wherein said heteroaryl is optionally substituted with 1-3 Z, each Z being independently selected from the group consisting of hydroxy, cyano, nitro, halogen, C_1-5alkyl, optionally substituted with 1-3 halogens, C_1-5alkoxy, optionally substituted with 1-3 halogens, C_1-5alkoxycarbonyl, benzyloxy, acetyl, morpholinyl, -NR₆C(O)R₇, -C(O)NR₆R₇ and phenyl, optionally substituted with halogen; where R ₆ represents hydrogen or a C _1-3 alkyl group; And R ₇ represents a C _1-3 alkyl group, optionally substituted with phenyl, phenyl or heteroaryl selected from the group consisting of pyridinyl, pyrimidinyl and isoxazolyl. 7. Connection according to any one of paragraphs. 1-3 or a stereoisomer thereof, a mixture of stereoisomers or a pharmaceutically acceptable salt thereof, wherein R ₄ is phenyl substituted with a substituent selected from the group consisting of piperazinyl, optionally substituted with acetyl, phenyl, phenoxy, benzyl, benzoyl, phenylaminocarbonyl, pyrazolyl and benzoxazolyl; a heterocycle selected from the group consisting of benzo[d][1,3]dioxolyl, 2,3-dihydrobenzofuranyl, 2-oxo-1,2-dihydroquinolinyl and 2-oxo-1,2,3,4-tetrahydroquinolinyl; naphthyl, optionally substituted with halogen; or heteroaryl selected from the group consisting of pyridinyl, quinolinyl, isoquinolinyl, chromenonyl, quinazolinyl, benzofuranyl, indolinyl, benzimidazolyl, benzothiophenyl, benzothiazolyl, furo[3,2-c]pyridinyl, thieno[2,3-d]pyrimidinyl, thieno[ 3,2-c]pyridinyl, isoxazolyl, acridinyl and naphthyridinyl, wherein said heteroaryl is optionally substituted with 1-3 Z, each Z being independently selected from the group consisting of hydroxy, cyano, nitro, halogen, C_1-5alkyl, optionally substituted with 1-3 halogens, C_1-5alkoxy, optionally substituted with 1-3 halogens, C_1-5alkoxycarbonyl, benzyloxy, acetyl, morpholinyl, -NR₆C(O)R₇, -C(O)NR₆R₇ and phenyl, optionally substituted with halogen; R ₆ represents hydrogen or a C _1-3 alkyl group; And R ₇ represents a C _1-3 alkyl group, optionally substituted with phenyl, phenyl or heteroaryl selected from the group consisting of pyridinyl, pyrimidinyl and isoxazolyl. 8. A compound according to claim 1 or a stereoisomer thereof, a mixture of stereoisomers or a pharmaceutically acceptable salt thereof, in which R ₁ represents a substituent selected from the group consisting of compounds of formulas I, II, III and V, R ₃ is a substituent selected from the group consisting of -NR ₄ R ₅ , -OR ₄ , -C(O)NHR ₄ , -NHC(O)(CH ₂ ) _m R ₄ and -NHS(O) ₂ R ₄ , wherein R ₄ is phenyl substituted with a substituent selected from the group consisting of piperazinyl, optionally substituted with acetyl, phenyl, phenoxy, benzyl, benzoyl, phenylaminocarbonyl, pyrazolyl and benzoxazolyl; a heterocycle selected from the group consisting of benzo[d][1,3]dioxolyl, 2,3-dihydrobenzofuranyl, 2-oxo-1,2-dihydroquinolinyl and 2-oxo-1,2,3,4-tetrahydroquinolinyl; naphthyl, optionally substituted with halogen; or heteroaryl selected from the group consisting of pyridinyl, quinolinyl, isoquinolinyl, quinazolinyl, benzofuranyl, benzothiophenyl, furo[3,2-c]pyridinyl, thieno[2,3-d]pyrimidinyl, thieno[3,2-c]pyridinyl, isoxazolyl and acridinyl, wherein said heteroaryl is optionally substituted with 1-3 Z, each Z being independently selected from the group consisting of hydroxy, halogen, C _1-5 alkyl, optionally substituted with 1-3 halogens, C _1-5 alkoxy, optionally substituted with 1 -3 halogens, C _1-5 alkoxycarbonyl, benzyloxy and phenyl, optionally substituted with halogen, and R ₅ represents hydrogen. 9. A compound having the following structure: (R)-1-(2-((S)-2-cyanopyrrolidin-1-yl)-2-oxoethyl)-N-(quinolin-3-yl)pyrrolidin-3-carboxamide (R)-1-(2-((S)-2-cyanopyrrolidin-1-yl)-2-oxoethyl)-N-(quinolin-4-yl)pyrrolidin-3-carboxamide (S)-1-(2-((S)-2-cyanopyrrolidin-1-yl)-2-oxoethyl)-N-(quinolin-3-yl)pyrrolidin-3-carboxamide (S)-1-(2-((S)-2-cyanopyrrolidin-1-yl)-2-oxoethyl)-N-(quinolin-4-yl)pyrrolidin-3-carboxamide (S)-1-(2-((S)-3-(quinolin-4-ylamino)pyrrolidin-1-yl)acetyl)pyrrolidin-2-carbonitrile (S)-4,4-difluoro-1-(2-((S)-3-(quinolin-3-ylamino)pyrrolidin-1-yl)acetyl)pyrrolidin-2-carbonitrile (S)-4,4-difluoro-1-(2-((S)-3-(quinolin-4-ylamino)pyrrolidin-1-yl)acetyl)pyrrolidin-2-carbonitrile (S)-4,4-difluoro-1-(2-((S)-3-(isoquinolin-4-ylamino)pyrrolidin-1-yl)acetyl)pyrrolidin-2-carbonitrile (S)-1-(2-((S)-3-(benzo[b]thiophen-4-ylamino)pyrrolidin-1-yl)acetyl)-4,4-difluoropyrrolidine-2-carbonitrile (S)-1-(2-((S)-3-(benzo[b]thiophen-7-ylamino)pyrrolidin-1-yl)acetyl)-4,4-difluoropyrrolidine-2-carbonitrile (S)-1-(2-((S)-3-(benzofuran-7-ylamino)pyrrolidin-1-yl)acetyl)-4,4-difluoropyrrolidine-2-carbonitrile (S)-4,4-difluoro-1-(2-((S)-3-(furo[3,2-c]pyridin-7-ylamino)pyrrolidin-1-yl)acetyl)pyrrolidin-2-carbonitrile (S)-1-(2-((S)-3-([1,1'-biphenyl]-2-ylamino)pyrrolidin-1-yl)acetyl)-4,4-difluoropyrrolidine-2-carbonitrile (S)-1-(2-((S)-3-([1,1'-biphenyl]-4-ylamino)pyrrolidin-1-yl)acetyl)-4,4-difluoropyrrolidine-2-carbonitrile (S)-4,4-difluoro-1-(2-((S)-3-(naphthalene-2-ylamino)pyrrolidin-1-yl)acetyl)pyrrolidin-2-carbonitrile (S)-1-(2-((S)-3-([1,1'-biphenyl]-3-ylamino)pyrrolidin-1-yl)acetyl)-4,4-difluoropyrrolidine-2-carbonitrile (S)-1-(2-((R)-3-(quinolin-3-ylamino)pyrrolidin-1-yl)acetyl)pyrrolidin-2-carbonitrile (S)-1-(2-((R)-3-([1,1'-biphenyl]-3-ylamino)pyrrolidin-1-yl)acetyl)pyrrolidin-2-carbonitrile (S)-1-(2-((S)-3-(isoquinolin-4-ylamino)pyrrolidin-1-yl)acetyl)pyrrolidin-2-carbonitrile (S)-1-(2-((S)-3-(benzo[b]thiophen-4-ylamino)pyrrolidin-1-yl)acetyl)pyrrolidin-2-carbonitrile (S)-1-(2-((S)-3-(benzo[b]thiophen-7-ylamino)pyrrolidin-1-yl)acetyl)pyrrolidin-2-carbonitrile (S)-1-(2-((S)-3-(benzofuran-7-ylamino)pyrrolidin-1-yl)acetyl)pyrrolidin-2-carbonitrile (S)-1-(2-((S)-3-(furo[3,2-c]pyridin-7-ylamino)pyrrolidin-1-yl)acetyl)pyrrolidin-2-carbonitrile (S)-1-(2-((R)-3-(isoquinolin-4-ylamino)pyrrolidin-1-yl)acetyl)pyrrolidin-2-carbonitrile (S)-1-(2-((R)-3-(benzo[b]thiophen-7-ylamino)pyrrolidin-1-yl)acetyl)pyrrolidin-2-carbonitrile (1S,3S,5S)-2-(2-((S)-3-(furo[3,2-c]pyridin-7-ylamino)pyrrolidin-1-yl)acetyl)-2-azabicyclo[3.1. 0]hexane-3-carbonitrile (S)-1-(2-((S)-3-(quinolin-5-ylamino)pyrrolidin-1-yl)acetyl)pyrrolidin-2-carbonitrile (2S,4S)-4-fluoro-1-(2-((S)-3-(furo[3,2-c]pyridin-7-ylamino)pyrrolidin-1-yl)acetyl)pyrrolidin-2-carbonitrile N-((S)-1-(2-(2S,4S)-2-cyano-4-fluoropyrrolidin-1-yl)-2-oxoethyl)pyrrolidin-3-yl)-6-fluorobenzofuran-3-carboxamide N-((S)-1-(2-((S)-2-cyanopyrrolidin-1-yl)-2-oxoethyl)pyrrolidin-3-yl)quinoline-4-carboxamide N-((S)-1-(2-((S)-2-cyanopyrrolidin-1-yl)-2-oxoethyl)pyrrolidin-3-yl)quinoline-3-carboxamide N-((S)-1-(2-((S)-2-cyanopyrrolidin-1-yl)-2-oxoethyl)pyrrolidin-3-yl)quinoline-5-carboxamide N-((S)-1-(2-((S)-2-cyanopyrrolidin-1-yl)-2-oxoethyl)pyrrolidin-3-yl)quinoline-2-carboxamide N-((S)-1-(2-((S)-2-cyanopyrrolidin-1-yl)-2-oxoethyl)pyrrolidin-3-yl)quinoline-8-carboxamide N-((S)-1-(2-((S)-2-cyanopyrrolidin-1-yl)-2-oxoethyl)pyrrolidin-3-yl)isoquinoline-1-carboxamide N-((S)-1-(2-((S)-2-cyanopyrrolidin-1-yl)-2-oxoethyl)pyrrolidin-3-yl)benzo[b]thiophene-2-carboxamide N-((S)-1-(2-((S)-2-cyanopyrrolidin-1-yl)-2-oxoethyl)pyrrolidin-3-yl)benzofuran-3-carboxamide N-((S)-1-(2-((S)-2-cyanopyrrolidin-1-yl)-2-oxoethyl)pyrrolidin-3-yl)-2-(naphthalene-1-yl)acetamide N-((S)-1-(2-((S)-2-cyanopyrrolidin-1-yl)-2-oxoethyl)pyrrolidin-3-yl)-[1,1'-biphenyl]-2-carboxamide N-((S)-1-(2-((S)-2-cyanopyrrolidin-1-yl)-2-oxoethyl)pyrrolidin-3-yl)benzofuran-2-carboxamide N-((S)-1-(2-((S)-2-cyanopyrrolidin-1-yl)-2-oxoethyl)pyrrolidin-3-yl)benzo[b]thiophene-3-carboxamide N-((S)-1-(2-((S)-2-cyanopyrrolidin-1-yl)-2-oxoethyl)pyrrolidin-3-yl)-2-methylbenzofuran-3-carboxamide N-((S)-1-(2-((S)-2-cyanopyrrolidin-1-yl)-2-oxoethyl)pyrrolidin-3-yl)-5-fluorobenzofuran-3-carboxamide N-((S)-1-(2-((S)-2-cyanopyrrolidin-1-yl)-2-oxoethyl)pyrrolidin-3-yl)-6-fluorobenzofuran-3-carboxamide N-((S)-1-(2-((S)-2-cyanopyrrolidin-1-yl)-2-oxoethyl)pyrrolidin-3-yl)-7-methylbenzofuran-3-carboxamide N-((S)-1-(2-((S)-2-cyanopyrrolidin-1-yl)-2-oxoethyl)pyrrolidin-3-yl)-5-methoxybenzofuran-3-carboxamide N-((S)-1-(2-((S)-2-cyanopyrrolidin-1-yl)-2-oxoethyl)pyrrolidin-3-yl)-7-methoxybenzofuran-3-carboxamide N-((S)-1-(2-((S)-2-cyanopyrrolidin-1-yl)-2-oxoethyl)pyrrolidin-3-yl)-4-hydroxybenzofuran-3-carboxamide N-((S)-1-(2-((S)-2-cyanopyrrolidin-1-yl)-2-oxoethyl)pyrrolidin-3-yl)-6-hydroxybenzofuran-3-carboxamide N-((S)-1-(2-((S)-2-cyanopyrrolidin-1-yl)-2-oxoethyl)pyrrolidin-3-yl)-7-fluorobenzofuran-3-carboxamide N-((S)-1-(2-((S)-2-cyanopyrrolidin-1-yl)-2-oxoethyl)pyrrolidin-3-yl)-5,7-difluorobenzofuran-3-carboxamide N-((S)-1-(2-((S)-2-cyanopyrrolidin-1-yl)-2-oxoethyl)pyrrolidin-3-yl)-5-methylbenzofuran-3-carboxamide N-((S)-1-(2-((S)-2-cyanopyrrolidin-1-yl)-2-oxoethyl)pyrrolidin-3-yl)-6-methylbenzofuran-3-carboxamide N-((S)-1-(2-((S)-2-cyanopyrrolidin-1-yl)-2-oxoethyl)pyrrolidin-3-yl)-6-methoxybenzofuran-3-carboxamide N-((S)-1-(2-((S)-2-cyanopyrrolidin-1-yl)-2-oxoethyl)pyrrolidin-3-yl)benzofuran-4-carboxamide N-((S)-1-(2-((S)-2-cyanopyrrolidin-1-yl)-2-oxoethyl)pyrrolidin-3-yl)benzofuran-5-carboxamide N-((S)-1-(2-((S)-2-cyanopyrrolidin-1-yl)-2-oxoethyl)pyrrolidin-3-yl)benzofuran-6-carboxamide N-((S)-1-(2-((S)-2-cyanopyrrolidin-1-yl)-2-oxoethyl)pyrrolidin-3-yl)benzofuran-7-carboxamide N-((S)-1-(2-((S)-2-cyanopyrrolidin-1-yl)-2-oxoethyl)pyrrolidin-3-yl)benzofuran-2-sulfonamide N-((S)-1-(2-((S)-2-cyanopyrrolidin-1-yl)-2-oxoethyl)pyrrolidin-3-yl)benzo[b]thiophene-2-sulfonamide (S)-1-(2-((S)-3-(quinolin-4-yloxy)pyrrolidin-1-yl)acetyl)pyrrolidin-2-carbonitrile (S)-1-(2-((S)-3-(naphthalene-1-yloxy)pyrrolidin-1-yl)acetyl)pyrrolidin-2-carbonitrile (S)-1-(2-((S)-3-(quinolin-6-yloxy)pyrrolidin-1-yl)acetyl)pyrrolidin-2-carbonitrile (S)-1-(2-((S)-3-(quinolin-8-yloxy)pyrrolidin-1-yl)acetyl)pyrrolidin-2-carbonitrile (S)-1-(2-((S)-3-(isoquinolin-5-yloxy)pyrrolidin-1-yl)acetyl)pyrrolidin-2-carbonitrile (S)-1-(2-((S)-3-(quinolin-5-yloxy)pyrrolidin-1-yl)acetyl)pyrrolidin-2-carbonitrile (S)-1-(2-((S)-3-(benzo[d][1,3]dioxol-5-yloxy)pyrrolidin-1-yl)acetyl)pyrrolidin-2-carbonitrile (S)-1-(2-((S)-3-(thieno[2,3-d]pyrimidin-4-yloxy)pyrrolidin-1-yl)acetyl)pyrrolidin-2-carbonitrile (S)-1-(2-((S)-3-(isoquinolin-3-yloxy)pyrrolidin-1-yl)acetyl)pyrrolidin-2-carbonitrile (S)-1-(2-((S)-3-(3-bromothieno[3,2-c]pyridin-4-yl)oxy)pyrrolidin-1-yl)acetyl)pyrrolidin-2-carbonitrile (S)-1-(2-((S)-3-(4-chloronaphthalene-1-yl)oxy)pyrrolidin-1-yl)acetyl)pyrrolidin-2-carbonitrile (S)-1-(2-((S)-3-(2-(1H-pyrazol-3-yl)phenoxy)pyrrolidin-1-yl)acetyl)pyrrolidin-2-carbonitrile (S)-1-(2-((S)-3-((4-chloroquinazolin-8-yl)oxy)pyrrolidin-1-yl)acetyl)pyrrolidin-2-carbonitrile (S)-1-(2-((S)-3-((4-chloroquinazolin-6-yl)oxy)pyrrolidin-1-yl)acetyl)pyrrolidin-2-carbonitrile (S)-1-(2-((S)-3-((2-oxo-1,2-dihydroquinolin-5-yl)oxy)pyrrolidin-1-yl)acetyl)pyrrolidin-2-carbonitrile (S)-1-(2-((S)-3-((2-oxo-1,2,3,4-tetrahydroquinolin-5-yl)oxy)pyrrolidin-1-yl)acetyl)pyrrolidin-2- carbonitrile (S)-1-(2-((S)-3-((2-oxo-1,2,3,4-tetrahydroquinolin-6-yl)oxy)pyrrolidin-1-yl)acetyl)pyrrolidin-2- carbonitrile (S)-1-(2-((S)-3-((2-methylquinolin-8-yl)oxy)pyrrolidin-1-yl)acetyl)pyrrolidin-2-carbonitrile (S)-1-(2-((S)-3-((7-chloroquinolin-4-yl)oxy)pyrrolidin-1-yl)acetyl)pyrrolidin-2-carbonitrile (S)-1-(2-((S)-3-((7-bromoquinolin-4-yl)oxy)pyrrolidin-1-yl)acetyl)pyrrolidin-2-carbonitrile (S)-1-(2-((S)-3-((5-chloroquinolin-8-yl)oxy)pyrrolidin-1-yl)acetyl)pyrrolidin-2-carbonitrile (S)-1-(2-((S)-3-([1,1'-biphenyl]-3-yloxy)pyrrolidin-1-yl)acetyl)pyrrolidin-2-carbonitrile (S)-1-(2-((S)-3-([1,1'-biphenyl]-4-yloxy)pyrrolidin-1-yl)acetyl)pyrrolidin-2-carbonitrile (S)-1-(2-((S)-3-((6-methoxyquinolin-4-yl)oxy)pyrrolidin-1-yl)acetyl)pyrrolidin-2-carbonitrile (S)-1-(2-((S)-3-((7,8-difluoroquinolin-4-yl)oxy)pyrrolidin-1-yl)acetyl)pyrrolidin-2-carbonitrile methyl-6-(((S)-1-(2-((S)-2-cyanopyrrolidin-1-yl)-2-oxoethyl)pyrrolidin-3-yl)oxy)-2,3-dihydrobenzofuran-2- carboxylate (S)-1-(2-((S)-3-(4-phenoxyphenoxy)pyrrolidin-1-yl)acetyl)pyrrolidine-2-carbonitrile (S)-1-(2-((S)-3-(3-phenoxyphenoxy)pyrrolidin-1-yl)acetyl)pyrrolidine-2-carbonitrile (S)-1-(2-((S)-3-(4-benzylphenoxy)pyrrolidin-1-yl)acetyl)pyrrolidine-2-carbonitrile (S)-1-(2-((S)-3-(2-benzylphenoxy)pyrrolidin-1-yl)acetyl)pyrrolidine-2-carbonitrile (S)-1-(2-((S)-3-(3-benzoylphenoxy)pyrrolidin-1-yl)acetyl)pyrrolidine-2-carbonitrile (S)-1-(2-((S)-3-(4-benzoylphenoxy)pyrrolidin-1-yl)acetyl)pyrrolidine-2-carbonitrile (S)-1-(2-((S)-3-((4-(benzyloxy)pyridin-2-yl)oxy)pyrrolidin-1-yl)acetyl)pyrrolidin-2-carbonitrile (S)-1-(2-((S)-3-((7-(trifluoromethyl)quinolin-4-yl)oxy)pyrrolidin-1-yl)acetyl)pyrrolidin-2-carbonitrile (S)-1-(2-((S)-3-((8-(trifluoromethyl)quinolin-4-yl)oxy)pyrrolidin-1-yl)acetyl)pyrrolidin-2-carbonitrile (S)-1-(2-((S)-3-(acridin-4-yloxy)pyrrolidin-1-yl)acetyl)pyrrolidin-2-carbonitrile (S)-1-(2-((S)-3-(2-(benzo[d]oxazol-2-yl)phenoxy)pyrrolidin-1-yl)acetyl)pyrrolidin-2-carbonitrile (S)-1-(2-((S)-3-(4-(4-acetylpiperazin-1-yl)phenoxy)pyrrolidin-1-yl)acetyl)pyrrolidin-2-carbonitrile 2-(((S)-1-(2-((S)-2-cyanopyrrolidin-1-yl)-2-oxoethyl)pyrrolidin-3-yl)oxy)-N-phenylbenzamide (S)-1-(2-((S)-3-(7-methoxyquinolin-4-yl)oxy)pyrrolidin-1-yl)acetyl)pyrrolidin-2-carbonitrile (S)-1-(2-((S)-3-((6,7-dimethoxyquinolin-4-yl)oxy)pyrrolidin-1-yl)acetyl)pyrrolidin-2-carbonitrile (S)-1-(2-((S)-3-(3-(4-bromophenyl)isoxazol-5-yl)oxy)pyrrolidin-1-yl)acetyl)pyrrolidin-2-carbonitrile (S)-4,4-difluoro-1-(2-((S)-3-(6-methoxyquinolin-4-yl)oxy)pyrrolidin-1-yl)acetyl)pyrrolidin-2-carbonitrile (S)-4,4-difluoro-1-(2-((S)-3-((8-(trifluoromethyl)quinolin-4-yl)oxy)pyrrolidin-1-yl)acetyl)pyrrolidin-2-carbonitrile (S)-4,4-difluoro-1-(2-((S)-3-(quinolin-5-yloxy)pyrrolidin-1-yl)acetyl)pyrrolidin-2-carbonitrile (S)-4,4-difluoro-1-(2-((S)-3-(isoquinolin-5-yloxy)pyrrolidin-1-yl)acetyl)pyrrolidin-2-carbonitrile (S)-1-(2-((S)-3-((7-chloroquinolin-4-yl)oxy)pyrrolidin-1-yl)acetyl)-4,4-difluoropyrrolidine-2-carbonitrile (S)-4,4-difluoro-1-(2-((S)-3-((2-oxo-1,2-dihydroquinolin-5-yl)oxy)pyrrolidin-1-yl)acetyl)pyrrolidin- 2-carbonitrile (S)-1-(2-((S)-3-((5-chloroquinolin-8-yl)oxy)pyrrolidin-1-yl)acetyl)-4,4-difluoropyrrolidine-2-carbonitrile (S)-1-(2-(4-(quinolin-5-ylamino)piperidin-1-yl)acetyl)pyrrolidine-2-carbonitrile (S)-1-(2-(4-(quinolin-4-ylamino)piperidin-1-yl)acetyl)pyrrolidine-2-carbonitrile (1S,3S,5S)-2-(2-(4-(quinolin-4-ylamino)piperidin-1-yl)acetyl)-2-azabicyclo[3.1.0]hexane-3-carbonitrile (2S,4S)-4-fluoro-1-(2-(4-(quinolin-5-ylamino)piperidin-1-yl)acetyl)pyrrolidine-2-carbonitrile (S)-4,4-difluoro-1-(2-(4-(quinolin-5-ylamino)piperidin-1-yl)acetyl)pyrrolidine-2-carbonitrile (1S,3S,5S)-2-(2-(4-(quinolin-5-ylamino)piperidin-1-yl)acetyl)-2-azabicyclo[3.1.0]hexane-3-carbonitrile (S)-1-(2-(4-(furo[3,2-c]pyridin-7-ylamino)piperidin-1-yl)acetyl)pyrrolidine-2-carbonitrile (S)-1-(2-(4-(quinolin-3-yloxy)piperidin-1-yl)acetyl)pyrrolidine-2-carbonitrile (S)-1-(2-(4-(quinolin-4-yloxy)piperidin-1-yl)acetyl)pyrrolidine-2-carbonitrile (S)-1-(2-(4-(quinolin-5-yloxy)piperidin-1-yl)acetyl)pyrrolidine-2-carbonitrile (S)-1-(2-(4-(quinolin-6-yloxy)piperidin-1-yl)acetyl)pyrrolidine-2-carbonitrile (S)-1-(2-(4-((3-methylquinolin-5-yl)amino)piperidin-1-yl)acetyl)pyrrolidine-2-carbonitrile (S)-1-(2-(4-((6-methylquinolin-5-yl)amino)piperidin-1-yl)acetyl)pyrrolidine-2-carbonitrile (S)-1-(2-(4-((7-fluoroquinolin-5-yl)amino)piperidin-1-yl)acetyl)pyrrolidine-2-carbonitrile (S)-1-(2-(4-((7-methoxyquinolin-5-yl)amino)piperidin-1-yl)acetyl)pyrrolidine-2-carbonitrile (S)-1-(2-(4-((8-methoxyquinolin-5-yl)amino)piperidin-1-yl)acetyl)pyrrolidine-2-carbonitrile (2S,4S)-4-fluoro-1-(2-(4-((6-fluoroquinolin-4-yl)oxy)piperidin-1-yl)acetyl)pyrrolidin-2-carbonitrile (2S,4S)-1-(2-(4-((6-chloroquinolin-4-yl)oxy)piperidin-1-yl)acetyl)-4-fluoropyrrolidine-2-carbonitrile (2S,4S)-4-fluoro-1-(2-(4-((6-methoxyquinolin-4-yl)oxy)piperidin-1-yl)acetyl)pyrrolidine-2-carbonitrile (2S,4S)-4-fluoro-1-(2-(4-((7-methoxyquinolin-4-yl)oxy)piperidin-1-yl)acetyl)pyrrolidine-2-carbonitrile (2S,4S)-1-(2-(4-((6,7-dimethoxyquinolin-4-yl)oxy)piperidin-1-yl)acetyl)-4-fluoropyrrolidine-2-carbonitrile (2S,4S)-4-fluoro-1-(2-(4-((3-methylquinolin-5-yl)amino)piperidin-1-yl)acetyl)pyrrolidine-2-carbonitrile (2S,4S)-4-fluoro-1-(2-(4-((7-fluoroquinolin-5-yl)amino)piperidin-1-yl)acetyl)pyrrolidin-2-carbonitrile (2S,4S)-4-fluoro-1-(2-(4-((7-methoxyquinolin-5-yl)amino)piperidin-1-yl)acetyl)pyrrolidin-2-carbonitrile (2S,4S)-4-fluoro-1-(2-(4-((6-methylquinolin-5-yl)amino)piperidin-1-yl)acetyl)pyrrolidine-2-carbonitrile (2S,4S)-4-fluoro-1-(2-(4-((8-methoxyquinolin-5-yl)amino)piperidin-1-yl)acetyl)pyrrolidin-2-carbonitrile 6-methoxy-N-[(3S)-1-[2-oxo-2-[(2S,4S)-2-cyano-4-fluoropyrrolidin-1-yl]ethyl]pyrrolidin-3-yl]benzofuran-3 -carboxamide (2S)-1-[2-[(3R)-3-[methyl(2-quinolyl)amino]pyrrolidin-1-yl]acetyl]pyrrolidin-2-carbonitrile (2S)-1-[2-[(3R)-3-[methyl(3-quinolyl)amino]pyrrolidin-1-yl]acetyl]pyrrolidin-2-carbonitrile (2S)-1-[2-[(3R)-3-[methyl(5-quinolyl)amino]pyrrolidin-1-yl]acetyl]pyrrolidin-2-carbonitrile (2S)-1-[2-[(3R)-3-[methyl(6-quinolyl)amino]pyrrolidin-1-yl]acetyl]pyrrolidin-2-carbonitrile (2S)-1-[2-[(3R)-3-[methyl(7-quinolyl)amino]pyrrolidin-1-yl]acetyl]pyrrolidin-2-carbonitrile (2S)-1-[2-[(3S)-3-[methyl(3-quinolyl)amino]pyrrolidin-1-yl]acetyl]pyrrolidin-2-carbonitrile (2S)-1-[2-[(3S)-3-[methyl(4-quinolyl)amino]pyrrolidin-1-yl]acetyl]pyrrolidin-2-carbonitrile (2S)-1-[2-[(3S)-3-[methyl(5-quinolyl)amino]pyrrolidin-1-yl]acetyl]pyrrolidin-2-carbonitrile (2S)-1-[2-[(3S)-3-[methyl(6-quinolyl)amino]pyrrolidin-1-yl]acetyl]pyrrolidin-2-carbonitrile (2S)-1-[2-[(3S)-3-[methyl(7-quinolyl)amino]pyrrolidin-1-yl]acetyl]pyrrolidin-2-carbonitrile (2S)-1-[2-[(3S)-3-[4-isoquinolyl(methyl)amino]pyrrolidin-1-yl]acetyl]pyrrolidin-2-carbonitrile (2S)-1-[2-[(3S)-3-[5-isoquinolyl(methyl)amino]pyrrolidin-1-yl]acetyl]pyrrolidin-2-carbonitrile (2S)-1-[2-[(3S)-3-[methyl-(4-methyl-3-quinolyl)amino]pyrrolidin-1-yl]acetyl]pyrrolidin-2-carbonitrile (2S)-1-[2-[(3S)-3-[methyl-(6-methyl-3-quinolyl)amino]pyrrolidin-1-yl]acetyl]pyrrolidin-2-carbonitrile (S)-1-(2-((S)-3-((6-fluoroquinolin-3-yl)(methyl)amino)pyrrolidin-1-yl)acetyl)pyrrolidin-2-carbonitrile (S)-1-(2-((S)-3-((6-methoxyquinolin-3-yl)(methyl)amino)pyrrolidin-1-yl)acetyl)pyrrolidin-2-carbonitrile (S)-1-(2-((S)-3-((7-methoxyquinolin-3-yl)(methyl)amino)pyrrolidin-1-yl)acetyl)pyrrolidin-2-carbonitrile (S)-1-(2-((S)-3-((8-methoxyquinolin-3-yl)(methyl)amino)pyrrolidin-1-yl)acetyl)pyrrolidin-2-carbonitrile (2S,4S)-4-fluoro-1-[2-[(3S)-3-[methyl-(3-methyl-5-quinolyl)amino]pyrrolidin-1-yl]acetyl]pyrrolidin-2-carbonitrile (2S,4S)-4-fluoro-1-(2-((S)-3-((3-fluoroquinolin-5-yl)(methyl)amino)pyrrolidin-1-yl)acetyl)pyrrolidin-2-carbonitrile (2S,4S)-4-fluoro-1-(2-((S)-3-((7-fluoroquinolin-5-yl)(methyl)amino)pyrrolidin-1-yl)acetyl)pyrrolidin-2-carbonitrile (2S,4S)-4-fluoro-1-(2-((S)-3-((8-fluoroquinolin-5-yl)(methyl)amino)pyrrolidin-1-yl)acetyl)pyrrolidin-2-carbonitrile (2S,4S)-4-fluoro-1-[2-[(3S)-3-[methyl-[8-(trifluoromethyl)-5-quinolyl]amino]pyrrolidin-1-yl]acetyl]pyrrolidin-2- carbonitrile (2S,4S)-4-fluoro-1-[2-[(3S)-3-[methyl-[8-(trifluoromethoxy)-5-quinolyl]amino]pyrrolidin-1-yl]acetyl]pyrrolidin-2- carbonitrile (2S)-1-[2-[(3R)-3-(5-quinolylamino)pyrrolidin-1-yl]acetyl]pyrrolidine-2-carbonitrile (2S)-1-[2-[(3R)-3-(6-quinolylamino)pyrrolidin-1-yl]acetyl]pyrrolidine-2-carbonitrile (2S)-1-[2-[(3R)-3-(7-quinolylamino)pyrrolidin-1-yl]acetyl]pyrrolidine-2-carbonitrile (2S)-1-[2-[(3R)-3-(8-quinolylamino)pyrrolidin-1-yl]acetyl]pyrrolidine-2-carbonitrile (2S,4S)-4-fluoro-1-[2-[(3R)-3-(3-quinolylamino)pyrrolidin-1-yl]acetyl]pyrrolidin-2-carbonitrile (2S,4S)-4-fluoro-1-[2-[(3R)-3-(5-quinolylamino)pyrrolidin-1-yl]acetyl]pyrrolidin-2-carbonitrile (2S,4S)-4-fluoro-1-[2-[(3R)-3-(6-quinolylamino)pyrrolidin-1-yl]acetyl]pyrrolidin-2-carbonitrile (2S,4S)-4-fluoro-1-[2-[(3R)-3-(7-quinolylamino)pyrrolidin-1-yl]acetyl]pyrrolidin-2-carbonitrile (2S,4S)-4-fluoro-1-[2-[(3R)-3-(8-quinolylamino)pyrrolidin-1-yl]acetyl]pyrrolidin-2-carbonitrile (2S,4S)-4-fluoro-1-[2-[(3R)-3-(4-quinolylamino)pyrrolidin-1-yl]acetyl]pyrrolidin-2-carbonitrile (2S,4S)-4-fluoro-1-[2-[(3R)-3-(1,8-naphthyridin-3-ylamino)pyrrolidin-1-yl]acetyl]pyrrolidin-2-carbonitrile (2S,4S)-4-fluoro-1-[2-[(3R)-3-[(7-chloro-1,8-naphthyridin-3-yl)amino]pyrrolidin-1-yl]acetyl]pyrrolidin- 2-carbonitrile (2S,4S)-4-fluoro-1-[2-[(3R)-3-[(6-fluoro-5-quinolyl)amino]pyrrolidin-1-yl]acetyl]pyrrolidin-2-carbonitrile (2S,4S)-4-fluoro-1-[2-[(3R)-3-[(7-fluoro-5-quinolyl)amino]pyrrolidin-1-yl]acetyl]pyrrolidin-2-carbonitrile (2S,4S)-4-fluoro-1-[2-[(3R)-3-[(8-fluoro-5-quinolyl)amino]pyrrolidin-1-yl]acetyl]pyrrolidin-2-carbonitrile (2S,4S)-4-fluoro-1-[2-[(3R)-3-[(6-methoxy-5-quinolyl)amino]pyrrolidin-1-yl]acetyl]pyrrolidin-2-carbonitrile (2S,4S)-4-fluoro-1-[2-[(3R)-3-[(7-methoxy-5-quinolyl)amino]pyrrolidin-1-yl]acetyl]pyrrolidin-2-carbonitrile (2S,4S)-4-fluoro-1-[2-[(3R)-3-[(8-methoxy-5-quinolyl)amino]pyrrolidin-1-yl]acetyl]pyrrolidin-2-carbonitrile (2S,4S)-4-fluoro-1-[2-[(3R)-3-[(3-methyl-5-quinolyl)amino]pyrrolidin-1-yl]acetyl]pyrrolidin-2-carbonitrile (2S,4S)-4-fluoro-1-[2-[(3R)-3-[(6-methyl-5-quinolyl)amino]pyrrolidin-1-yl]acetyl]pyrrolidin-2-carbonitrile (2S,4S)-4-fluoro-1-[2-[(3R)-3-[(8-methyl-5-quinolyl)amino]pyrrolidin-1-yl]acetyl]pyrrolidin-2-carbonitrile (2S,4S)-4-fluoro-1-[2-[(3R)-3-[[7-(trifluoromethyl)-5-quinolyl]amino]pyrrolidin-1-yl]acetyl]pyrrolidin-2-carbonitrile (2S,4S)-4-fluoro-1-[2-[(3R)-3-[[8-(trifluoromethyl)-5-quinolyl]amino]pyrrolidin-1-yl]acetyl]pyrrolidin-2-carbonitrile (2S,4S)-4-fluoro-1-[2-[(3R)-3-[(3-fluoro-5-quinolyl)amino]pyrrolidin-1-yl]acetyl]pyrrolidin-2-carbonitrile (2S,4S)-4-fluoro-1-[2-[(3R)-3-[(3-chloro-5-quinolyl)amino]pyrrolidin-1-yl]acetyl]pyrrolidin-2-carbonitrile (2S,4S)-4-fluoro-1-[2-[(3R)-3-[[8-(trifluoromethoxy)-5-quinolyl]amino]pyrrolidin-1-yl]acetyl]pyrrolidin-2-carbonitrile (2S,4S)-4-fluoro-1-[2-[(3R)-3-[(6-methyl-4-quinolyl)amino]pyrrolidin-1-yl]acetyl]pyrrolidin-2-carbonitrile (2S,4S)-4-fluoro-1-[2-[(3R)-3-[(6-methoxy-4-quinolyl)amino]pyrrolidin-1-yl]acetyl]pyrrolidin-2-carbonitrile (2S,4S)-4-fluoro-1-[2-[(3R)-3-[(8-chloro-4-quinolyl)amino]pyrrolidin-1-yl]acetyl]pyrrolidin-2-carbonitrile (2S,4S)-4-fluoro-1-[2-[(3R)-3-[(8-methyl-4-quinolyl)amino]pyrrolidin-1-yl]acetyl]pyrrolidin-2-carbonitrile (2S,4S)-4-fluoro-1-[2-[(3R)-3-[(6-fluoro-4-quinolyl)amino]pyrrolidin-1-yl]acetyl]pyrrolidin-2-carbonitrile (2S,4S)-4-fluoro-1-[2-[(3R)-3-[(6-chloro-4-quinolyl)amino]pyrrolidin-1-yl]acetyl]pyrrolidin-2-carbonitrile (2S,4S)-4-fluoro-1-[2-[(3R)-3-[(7-methoxy-4-quinolyl)amino]pyrrolidin-1-yl]acetyl]pyrrolidin-2-carbonitrile (2S,4S)-4-fluoro-1-[2-[(3R)-3-[(8-fluoro-4-quinolyl)amino]pyrrolidin-1-yl]acetyl]pyrrolidin-2-carbonitrile (2S,4S)-4-fluoro-1-[2-[(3R)-3-[(8-methoxy-4-quinolyl)amino]pyrrolidin-1-yl]acetyl]pyrrolidin-2-carbonitrile (2S,4S)-4-fluoro-1-[2-[(3R)-3-[[8-(trifluoromethyl)-4-quinolyl]amino]pyrrolidin-1-yl]acetyl]pyrrolidin-2-carbonitrile (2S)-1-[2-[(3R)-3-[(7-fluoro-5-quinolyl)amino]pyrrolidin-1-yl]acetyl]pyrrolidin-2-carbonitrile (2S)-1-[2-[(3R)-3-[(7-methoxy-5-quinolyl)amino]pyrrolidin-1-yl]acetyl]pyrrolidin-2-carbonitrile (2S)-1-[2-[(3R)-3-[(8-fluoro-5-quinolyl)amino]pyrrolidin-1-yl]acetyl]pyrrolidin-2-carbonitrile (2S)-1-[2-[(3R)-3-[(8-methyl-5-quinolyl)amino]pyrrolidin-1-yl]acetyl]pyrrolidin-2-carbonitrile (2S)-1-[2-[(3R)-3-[[8-(trifluoromethyl)-5-quinolyl]amino]pyrrolidin-1-yl]acetyl]pyrrolidin-2-carbonitrile (2S)-1-[2-[(3R)-3-[[8-(trifluoromethoxy)-5-quinolyl]amino]pyrrolidin-1-yl]acetyl]pyrrolidin-2-carbonitrile (2S)-1-[2-[(3R)-3-[(3-chloro-5-quinolyl)amino]pyrrolidin-1-yl]acetyl]pyrrolidin-2-carbonitrile (2S)-1-[2-[(3R)-3-[(3-methoxy-5-quinolyl)amino]pyrrolidin-1-yl]acetyl]pyrrolidin-2-carbonitrile (2S,4S)-4-fluoro-1-[2-[(3R)-3-[(3-methoxy-5-quinolyl)amino]pyrrolidin-1-yl]acetyl]pyrrolidin-2-carbonitrile (2S)-1-[2-[(3R)-3-[(2-chloro-6-quinolyl)amino]pyrrolidin-1-yl]acetyl]pyrrolidin-2-carbonitrile (2S,4S)-4-fluoro-1-[2-[(3R)-3-[(2-chloro-6-quinolyl)amino]pyrrolidin-1-yl]acetyl]pyrrolidin-2-carbonitrile (2S)-1-[2-[(3R)-3-[(3-methyl-5-quinolyl)amino]pyrrolidin-1-yl]acetyl]pyrrolidin-2-carbonitrile (2S)-1-[2-[(3R)-3-[(3-fluoro-5-quinolyl)amino]pyrrolidin-1-yl]acetyl]pyrrolidin-2-carbonitrile (2S,4S)-4-fluoro-1-[2-[(3R)-3-[[2-(trifluoromethyl)-6-quinolyl]amino]pyrrolidin-1-yl]acetyl]pyrrolidin-2-carbonitrile (2S,4S)-4-fluoro-1-[2-[(3R)-3-[(3-methyl-6-quinolyl)amino]pyrrolidin-1-yl]acetyl]pyrrolidin-2-carbonitrile (2S,4S)-4-fluoro-1-[2-[(3R)-3-[(4-methoxy-6-quinolyl)amino]pyrrolidin-1-yl]acetyl]pyrrolidin-2-carbonitrile (2S,4S)-4-fluoro-1-[2-[(3R)-3-[(8-methyl-6-quinolyl)amino]pyrrolidin-1-yl]acetyl]pyrrolidin-2-carbonitrile (2S,4S)-4-fluoro-1-[2-[(3R)-3-[(8-fluoro-6-quinolyl)amino]pyrrolidin-1-yl]acetyl]pyrrolidin-2-carbonitrile (2S,4S)-4-fluoro-1-[2-[(3R)-3-[(8-chloro-6-quinolyl)amino]pyrrolidin-1-yl]acetyl]pyrrolidin-2-carbonitrile (2S,4S)-4-fluoro-1-[2-[(3R)-3-[[8-(trifluoromethyl)-6-quinolyl]amino]pyrrolidin-1-yl]acetyl]pyrrolidin-2-carbonitrile (2S)-1-[2-[(3R)-3-[2-(trifluoromethyl)-6-quinolyl]amino]pyrrolidin-1-yl]acetyl]pyrrolidin-2-carbonitrile (2S)-1-[2-[(3R)-3-[(3-methyl-6-quinolyl)amino]pyrrolidin-1-yl]acetyl]pyrrolidin-2-carbonitrile (2S)-1-[2-[(3R)-3-[(4-methoxy-6-quinolyl)amino]pyrrolidin-1-yl]acetyl]pyrrolidin-2-carbonitrile (2S)-1-[2-[(3R)-3-[(8-methyl-6-quinolyl)amino]pyrrolidin-1-yl]acetyl]pyrrolidin-2-carbonitrile (2S)-1-[2-[(3R)-3-[(8-fluoro-6-quinolyl)amino]pyrrolidin-1-yl]acetyl]pyrrolidin-2-carbonitrile (2S)-1-[2-[(3R)-3-[(8-chloro-6-quinolyl)amino]pyrrolidin-1-yl]acetyl]pyrrolidin-2-carbonitrile (2S)-1-[2-[(3R)-3-[(6-methyl-4-quinolyl)amino]pyrrolidin-1-yl]acetyl]pyrrolidin-2-carbonitrile (2S)-1-[2-[(3R)-3-[(6-methoxy-4-quinolyl)amino]pyrrolidin-1-yl]acetyl]pyrrolidin-2-carbonitrile (2S)-1-[2-[(3R)-3-[(6-fluoro-4-quinolyl)amino]pyrrolidin-1-yl]acetyl]pyrrolidin-2-carbonitrile (2S)-1-[2-[(3R)-3-[(6-chloro-4-quinolyl)amino]pyrrolidin-1-yl]acetyl]pyrrolidin-2-carbonitrile (2S)-1-[2-[(3R)-3-[(8-fluoro-4-quinolyl)amino]pyrrolidin-1-yl]acetyl]pyrrolidin-2-carbonitrile (2S,4S)-4-fluoro-1-[2-[(3S)-3-(5-quinolylamino)pyrrolidin-1-yl]acetyl]pyrrolidin-2-carbonitrile (2S)-1-[2-[(3S)-3-(3-quinolylamino)pyrrolidin-1-yl]acetyl]pyrrolidine-2-carbonitrile (2S)-1-[2-[(3S)-3-(6-quinolylamino)pyrrolidin-1-yl]acetyl]pyrrolidine-2-carbonitrile 5-[[(3S)-1-[2-oxo-2-[(2S)-2-cyanopyrrolidin-1-yl]ethyl]pyrrolidin-3-yl]amino]quinoline-2-carbonitrile 5-[[(3S)-1-[2-oxo-2-[(2S)-2-cyanopyrrolidin-1-yl]ethyl]pyrrolidin-3-yl]amino]quinoline-3-carbonitrile (2S)-1-[2-[(3S)-3-[(3-methoxy-5-quinolyl)amino]pyrrolidin-1-yl]acetyl]pyrrolidin-2-carbonitrile (2S)-1-[2-[(3S)-3-[(3-fluoro-5-quinolyl)amino]pyrrolidin-1-yl]acetyl]pyrrolidin-2-carbonitrile (2S)-1-[2-[(3S)-3-[(3-chloro-5-quinolyl)amino]pyrrolidin-1-yl]acetyl]pyrrolidin-2-carbonitrile (2S)-1-[2-[(3S)-3-[(7-fluoro-5-quinolyl)amino]pyrrolidin-1-yl]acetyl]pyrrolidin-2-carbonitrile (2S)-1-[2-[(3S)-3-[(7-methoxy-5-quinolyl)amino]pyrrolidin-1-yl]acetyl]pyrrolidin-2-carbonitrile (2S)-1-[2-[(3S)-3-[[7-(trifluoromethyl)-5-quinolyl]amino]pyrrolidin-1-yl]acetyl]pyrrolidin-2-carbonitrile (2S)-1-[2-[(3S)-3-[(6-methyl-5-quinolyl)amino]pyrrolidin-1-yl]acetyl]pyrrolidin-2-carbonitrile (2S)-1-[2-[(3S)-3-[(6-methoxy-5-quinolyl)amino]pyrrolidin-1-yl]acetyl]pyrrolidin-2-carbonitrile (2S)-1-[2-[(3S)-3-[(6-fluoro-5-quinolyl)amino]pyrrolidin-1-yl]acetyl]pyrrolidin-2-carbonitrile (2S)-1-[2-[(3S)-3-[(8-methyl-5-quinolyl)amino]pyrrolidin-1-yl]acetyl]pyrrolidin-2-carbonitrile (2S)-1-[2-[(3S)-3-[(8-methoxy-5-quinolyl)amino]pyrrolidin-1-yl]acetyl]pyrrolidin-2-carbonitrile (2S)-1-[2-[(3S)-3-[(8-fluoro-5-quinolyl)amino]pyrrolidin-1-yl]acetyl]pyrrolidin-2-carbonitrile (2S)-1-[2-[(3S)-3-[[8-(trifluoromethyl)-5-quinolyl]amino]pyrrolidin-1-yl]acetyl]pyrrolidin-2-carbonitrile (2S)-1-[2-[(3S)-3-[[8-(trifluoromethoxy)-5-quinolyl]amino]pyrrolidin-1-yl]acetyl]pyrrolidin-2-carbonitrile 5-[[(3S)-1-[2-oxo-2-[(2S)-2-cyanopyrrolidin-1-yl]ethyl]pyrrolidin-3-yl]amino]quinoline-8-carbonitrile (2S)-1-[2-[(3S)-3-[(8-benzyloxy-5-quinolyl)amino]pyrrolidin-1-yl]acetyl]pyrrolidin-2-carbonitrile (2S,4S)-4-fluoro-1-[2-[(3S)-3-(3-quinolylamino)pyrrolidin-1-yl]acetyl]pyrrolidin-2-carbonitrile (2S,4S)-4-fluoro-1-[2-[(3S)-3-(6-quinolylamino)pyrrolidin-1-yl]acetyl]pyrrolidin-2-carbonitrile (2S,4S)-4-fluoro-1-[2-[(3S)-3-(7-quinolylamino)pyrrolidin-1-yl]acetyl]pyrrolidin-2-carbonitrile 5-[[(3S)-1-[2-oxo-2-[(2S,4S)-2-cyano-4-fluoropyrrolidin-1-yl]ethyl]pyrrolidin-3-yl]amino]quinoline-2- carbonitrile 5-[[(3S)-1-[2-oxo-2-[(2S,4S)-2-cyano-4-fluoropyrrolidin-1-yl]ethyl]pyrrolidin-3-yl]amino]quinoline-3- carbonitrile (2S,4S)-4-fluoro-1-[2-[(3S)-3-[(3-methoxy-5-quinolyl)amino]pyrrolidin-1-yl]acetyl]pyrrolidin-2-carbonitrile (2S,4S)-4-fluoro-1-[2-[(3S)-3-[(3-fluoro-5-quinolyl)amino]pyrrolidin-1-yl]acetyl]pyrrolidin-2-carbonitrile (2S,4S)-4-fluoro-1-[2-[(3S)-3-[(3-chloro-5-quinolyl)amino]pyrrolidin-1-yl]acetyl]pyrrolidin-2-carbonitrile (2S,4S)-4-fluoro-1-[2-[(3S)-3-[(7-methoxy-5-quinolyl)amino]pyrrolidin-1-yl]acetyl]pyrrolidin-2-carbonitrile (2S,4S)-4-fluoro-1-[2-[(3S)-3-[[7-(trifluoromethyl)-5-quinolyl]amino]pyrrolidin-1-yl]acetyl]pyrrolidin-2-carbonitrile (2S,4S)-4-fluoro-1-[2-[(3S)-3-[(6-methyl-5-quinolyl)amino]pyrrolidin-1-yl]acetyl]pyrrolidin-2-carbonitrile (2S,4S)-4-fluoro-1-[2-[(3S)-3-[(6-methoxy-5-quinolyl)amino]pyrrolidin-1-yl]acetyl]pyrrolidin-2-carbonitrile (2S,4S)-4-fluoro-1-[2-[(3S)-3-[(6-fluoro-5-quinolyl)amino]pyrrolidin-1-yl]acetyl]pyrrolidin-2-carbonitrile (2S,4S)-4-fluoro-1-[2-[(3S)-3-[(8-methyl-5-quinolyl)amino]pyrrolidin-1-yl]acetyl]pyrrolidin-2-carbonitrile (2S,4S)-4-fluoro-1-[2-[(3S)-3-[(8-methoxy-5-quinolyl)amino]pyrrolidin-1-yl]acetyl]pyrrolidin-2-carbonitrile (2S,4S)-4-fluoro-1-[2-[(3S)-3-[(8-fluoro-5-quinolyl)amino]pyrrolidin-1-yl]acetyl]pyrrolidin-2-carbonitrile (2S,4S)-4-fluoro-1-[2-[(3S)-3-[[8-(trifluoromethyl)-5-quinolyl]amino]pyrrolidin-1-yl]acetyl]pyrrolidin-2-carbonitrile (2S,4S)-4-fluoro-1-[2-[(3S)-3-[[8-(trifluoromethoxy)-5-quinolyl]amino]pyrrolidin-1-yl]acetyl]pyrrolidin-2-carbonitrile 5-[[(3S)-1-[2-oxo-2-[(2S,4S)-2-cyano-4-fluoropyrrolidin-1-yl]ethyl]pyrrolidin-3-yl]amino]quinoline-8- carbonitrile (2S,4S)-4-fluoro-1-[2-[(3S)-3-[(8-benzyloxy-5-quinolyl)amino]pyrrolidin-1-yl]acetyl]pyrrolidin-2-carbonitrile (2S,4S)-4-fluoro-1-[2-[(3S)-3-[(7-fluoro-5-quinolyl)amino]pyrrolidin-1-yl]acetyl]pyrrolidin-2-carbonitrile (2S)-1-[2-[(3S)-3-[[8-(trifluoromethyl)-4-quinolyl]amino]pyrrolidin-1-yl]acetyl]pyrrolidin-2-carbonitrile (2S,4S)-4-fluoro-1-[2-[(3S)-3-[[8-(trifluoromethyl)-4-quinolyl]amino]pyrrolidin-1-yl]acetyl]pyrrolidin-2-carbonitrile (2S,4S)-4-fluoro-1-[2-[(3S)-3-(1,8-naphthyridin-3-ylamino)pyrrolidin-1-yl]acetyl]pyrrolidin-2-carbonitrile (2S,4S)-4-fluoro-1-[2-[(3S)-3-[(7-chloro-1,8-naphthyridin-3-yl)amino]pyrrolidin-1-yl]acetyl]pyrrolidin- 2-carbonitrile (2S)-1-[2-[(3S)-3-[(8-ethoxy-5-quinolyl)amino]pyrrolidin-1-yl]acetyl]pyrrolidin-2-carbonitrile (2S,4S)-4-fluoro-1-[2-[(3S)-3-[(8-ethoxy-5-quinolyl)amino]pyrrolidin-1-yl]acetyl]pyrrolidin-2-carbonitrile (2S,4S)-4-fluoro-1-[2-[(3S)-3-[(8-hydroxy-5-quinolyl)amino]pyrrolidin-1-yl]acetyl]pyrrolidin-2-carbonitrile (2S,4S)-4-fluoro-1-[2-[(3S)-3-[(8-methyl-6-quinolyl)amino]pyrrolidin-1-yl]acetyl]pyrrolidin-2-carbonitrile (2S,4S)-4-fluoro-1-[2-[(3S)-3-[(8-fluoro-6-quinolyl)amino]pyrrolidin-1-yl]acetyl]pyrrolidin-2-carbonitrile (2S,4S)-4-fluoro-1-[2-[(3S)-3-[(8-chloro-6-quinolyl)amino]pyrrolidin-1-yl]acetyl]pyrrolidin-2-carbonitrile (2S,4S)-4-fluoro-1-[2-[(3S)-3-[[8-(trifluoromethyl)-6-quinolyl]amino]pyrrolidin-1-yl]acetyl]pyrrolidin-2-carbonitrile N-methyl-5-[[(3S)-1-[2-oxo-2-[(2S,4S)-2-cyano-4-fluoropyrrolidin-1-yl]ethyl]pyrrolidin-3-yl]amino] quinoline-8-carboxamide N,N-dimethyl-5-[[(3S)-1-[2-oxo-2-[(2S,4S)-2-cyano-4-fluoropyrrolidin-1-yl]ethyl]pyrrolidin-3-yl] amino]quinoline-8-carboxamide N-phenyl-5-[[(3S)-1-[2-oxo-2-[(2S,4S)-2-cyano-4-fluoropyrrolidin-1-yl]ethyl]pyrrolidin-3-yl]amino] quinoline-8-carboxamide N-methyl-N-phenyl-5-[[(3S)-1-[2-oxo-2-[(2S,4S)-2-cyano-4-fluoropyrrolidin-1-yl]ethyl]pyrrolidin-3- yl]amino]quinoline-8-carboxamide N-benzyl-N-methyl-5-[[(3S)-1-[2-oxo-2-[(2S,4S)-2-cyano-4-fluoropyrrolidin-1-yl]ethyl]pyrrolidin-3- yl]amino]quinoline-8-carboxamide N-methyl-5-[[(3S)-1-[2-oxo-2-[(2S)-2-cyanopyrrolidin-1-yl]ethyl]pyrrolidin-3-yl]amino]quinoline-8-carboxamide N-phenyl-5-[[(3S)-1-[2-oxo-2-[(2S)-2-cyanopyrrolidin-1-yl]ethyl]pyrrolidin-3-yl]amino]quinoline-8-carboxamide N-benzyl-N-methyl-5-[[(3S)-1-[2-oxo-2-[(2S)-2-cyanopyrrolidin-1-yl]ethyl]pyrrolidin-3-yl]amino]quinoline- 8-carboxamide N-methyl-N-phenyl-5-[[(3S)-1-[2-oxo-2-[(2S)-2-cyanopyrrolidin-1-yl]ethyl]pyrrolidin-3-yl]amino]quinoline- 8-carboxamide N-(3-pyridyl)-5-[[(3S)-1-[2-oxo-2-[(2S)-2-cyanopyrrolidin-1-yl]ethyl]pyrrolidin-3-yl]amino]quinoline- 8-carboxamide N-(4-pyridyl)-5-[[(3S)-1-[2-oxo-2-[(2S)-2-cyanopyrrolidin-1-yl]ethyl]pyrrolidin-3-yl]amino]quinoline- 8-carboxamide N-(4-pyridyl)-5-[[(3S)-1-[2-oxo-2-[(2S,4S)-2-cyano-4-fluoropyrrolidin-1-yl]ethyl]pyrrolidin-3- yl]amino]quinoline-8-carboxamide N-(2-pyridyl)-5-[[(3S)-1-[2-oxo-2-[(2S)-2-cyanopyrrolidin-1-yl]ethyl]pyrrolidin-3-yl]amino]quinoline- 8-carboxamide N-(2-pyridyl)-5-[[(3S)-1-[2-oxo-2-[(2S,4S)-2-cyano-4-fluoropyrrolidin-1-yl]ethyl]pyrrolidin-3- yl]amino]quinoline-8-carboxamide N-(3-pyridyl)-5-[[(3S)-1-[2-oxo-2-[(2S,4S)-2-cyano-4-fluoropyrrolidin-1-yl]ethyl]pyrrolidin-3- yl]amino]quinoline-8-carboxamide N-[5-[[(3S)-1-[2-oxo-2-[(2S)-2-cyanopyrrolidin-1-yl]ethyl]pyrrolidin-3-yl]amino]-8-quinolyl]acetamide N-[5-[[(3S)-1-[2-oxo-2-[(2S,4S)-2-cyano-4-fluoropyrrolidin-1-yl]ethyl]pyrrolidin-3-yl]amino]- 8-quinolyl]acetamide N-[5-[[(3S)-1-[2-oxo-2-[(2S,4S)-2-cyano-4-fluoropyrrolidin-1-yl]ethyl]pyrrolidin-3-yl]amino]- 8-quinolyl]benzamide (2S,4S)-4-fluoro-1-[2-[(3S)-3-[(6-methoxy-4-quinolyl)oxy]pyrrolidin-1-yl]acetyl]pyrrolidin-2-carbonitrile (2S,4S)-4-fluoro-1-[2-[(3S)-3-[(6,7-dimethoxy-4-quinolyl)oxy]pyrrolidin-1-yl]acetyl]pyrrolidin-2-carbonitrile N-[1-[2-oxo-2-[(2S)-2-cyanopyrrolidin-1-yl]ethyl]-4-piperidyl]quinoline-8-carboxamide (2S)-1-[2-[4-[ethyl(3-quinolyl)amino]-1-piperidyl]acetyl]pyrrolidine-2-carbonitrile (2S)-1-[2-[4-[ethyl(6-quinolyl)amino]-1-piperidyl]acetyl]pyrrolidine-2-carbonitrile (2S,4S)-1-[2-[4-[ethyl(3-quinolyl)amino]-1-piperidyl]acetyl]-4-fluoropyrrolidine-2-carbonitrile (2S,4S)-1-[2-[4-[ethyl(5-quinolyl)amino]-1-piperidyl]acetyl]-4-fluoropyrrolidine-2-carbonitrile (2S,4S)-1-[2-[4-[ethyl(6-quinolyl)amino]-1-piperidyl]acetyl]-4-fluoropyrrolidine-2-carbonitrile (2S)-1-[2-[4-[methyl(2-quinolyl)amino]-1-piperidyl]acetyl]pyrrolidine-2-carbonitrile (2S)-1-[2-[4-[methyl(4-quinolyl)amino]-1-piperidyl]acetyl]pyrrolidine-2-carbonitrile (2S)-1-[2-[4-[methyl(5-quinolyl)amino]-1-piperidyl]acetyl]pyrrolidine-2-carbonitrile (2S)-1-[2-[4-[methyl(6-quinolyl)amino]-1-piperidyl]acetyl]pyrrolidine-2-carbonitrile (2S)-1-[2-[4-[methyl(7-quinolyl)amino]-1-piperidyl]acetyl]pyrrolidine-2-carbonitrile (2S)-1-[2-[4-[furo[3,2-c]pyridin-7-yl(methyl)amino]-1-piperidyl]acetyl]pyrrolidine-2-carbonitrile (2S)-1-[2-[4-[5-isoquinolyl(methyl)amino]-1-piperidyl]acetyl]pyrrolidine-2-carbonitrile (2S)-1-(2-(4-(isoquinolin-6-yl(methyl)amino)piperidin-1-yl)acetyl)pyrrolidin-2-carbonitrile (2S,4S)-4-fluoro-1-[2-[4-[methyl(6-quinolyl)amino]-1-piperidyl]acetyl]pyrrolidine-2-carbonitrile (2S,4S)-4-fluoro-1-[2-[4-[methyl(3-quinolyl)amino]-1-piperidyl]acetyl]pyrrolidine-2-carbonitrile (2S,4S)-4-fluoro-1-[2-[4-[3-isoquinolyl(methyl)amino]-1-piperidyl]acetyl]pyrrolidine-2-carbonitrile (2S,4S)-4-fluoro-1-[2-[4-[5-isoquinolyl(methyl)amino]-1-piperidyl]acetyl]pyrrolidine-2-carbonitrile (2S,4S)-4-fluoro-1-[2-[4-[7-isoquinolyl(methyl)amino]-1-piperidyl]acetyl]pyrrolidine-2-carbonitrile (2S,4S)-4-fluoro-1-[2-[4-[8-isoquinolyl(methyl)amino]-1-piperidyl]acetyl]pyrrolidine-2-carbonitrile (2S)-1-[2-[4-[3-isoquinolyl(methyl)amino]-1-piperidyl]acetyl]pyrrolidine-2-carbonitrile (2S)-1-[2-[4-[methyl-(6-methyl-3-quinolyl)amino]-1-piperidyl]acetyl]pyrrolidine-2-carbonitrile (S)-1-(2-(4-((6-methoxyquinolin-3-yl)(methyl)amino)piperidin-1-yl)acetyl)pyrrolidine-2-carbonitrile (2S)-1-[2-[4-[(7-methoxy-3-quinolyl)-methyl-amino]-1-piperidyl]acetyl]pyrrolidine-2-carbonitrile (2S)-1-[2-[4-[(8-methoxy-3-quinolyl)-methyl-amino]-1-piperidyl]acetyl]pyrrolidine-2-carbonitrile (2S,4S)-4-fluoro-1-[2-[4-[methyl-(6-methyl-3-quinolyl)amino]-1-piperidyl]acetyl]pyrrolidine-2-carbonitrile (2S,4S)-4-fluoro-1-(2-(4-((6-methoxyquinolin-3-yl)(methyl)amino)piperidin-1-yl)acetyl)pyrrolidin-2-carbonitrile (2S,4S)-4-fluoro-1-(2-(4-((7-methoxyquinolin-3-yl)(methyl)amino)piperidin-1-yl)acetyl)pyrrolidin-2-carbonitrile (2S,4S)-4-fluoro-1-[2-[4-[(8-methoxy-3-quinolyl)-methyl-amino]-1-piperidyl]acetyl]pyrrolidine-2-carbonitrile (2S,4S)-4-fluoro-1-[2-[4-[(8-fluoro-5-quinolyl)amino]-1-piperidyl]acetyl]pyrrolidine-2-carbonitrile (2S,4S)-4-fluoro-1-[2-[4-[(8-methyl-5-quinolyl)amino]-1-piperidyl]acetyl]pyrrolidine-2-carbonitrile (2S,4S)-1-[2-[4-[(8-benzyloxy-5-quinolyl)amino]-1-piperidyl]acetyl]-4-fluoropyrrolidine-2-carbonitrile (2S,4S)-1-[2-[4-[(3-chloro-5-quinolyl)amino]-1-piperidyl]acetyl]-4-fluoropyrrolidine-2-carbonitrile (2S,4S)-4-fluoro-1-[2-[4-[[8-(trifluoromethyl)-5-quinolyl]amino]-1-piperidyl]acetyl]pyrrolidine-2-carbonitrile 5-[[1-[2-oxo-2-[(2S,4S)-2-cyano-4-fluoropyrrolidin-1-yl]ethyl]-4-piperidyl]amino]quinoline-2-carbonitrile (2S,4S)-1-(2-(4-(benzo[b]thiophen-4-ylamino)piperidin-1-yl)acetyl)-4-fluoropyrrolidine-2-carbonitrile (2S,4S)-4-fluoro-1-[2-[4-[(6-fluoro-4-quinolyl)amino]-1-piperidyl]acetyl]pyrrolidine-2-carbonitrile (2S,4S)-1-[2-[4-[(6-chloro-4-quinolyl)amino]-1-piperidyl]acetyl]-4-fluoropyrrolidine-2-carbonitrile (2S,4S)-4-fluoro-1-[2-[4-(4-isoquinolylamino)-1-piperidyl]acetyl]pyrrolidine-2-carbonitrile (2S,4S)-4-fluoro-1-[2-[4-(5-isoquinolylamino)-1-piperidyl]acetyl]pyrrolidine-2-carbonitrile (2S,4S)-4-fluoro-1-[2-[4-(6-isoquinolylamino)-1-piperidyl]acetyl]pyrrolidine-2-carbonitrile (2S,4S)-4-fluoro-1-[2-[4-(8-isoquinolylamino)-1-piperidyl]acetyl]pyrrolidine-2-carbonitrile (2S,4S)-4-fluoro-1-[2-[4-[(8-methyl-4-quinolyl)amino]-1-piperidyl]acetyl]pyrrolidine-2-carbonitrile (2S,4S)-1-[2-[4-[(8-chloro-4-quinolyl)amino]-1-piperidyl]acetyl]-4-fluoropyrrolidine-2-carbonitrile (2S,4S)-4-fluoro-1-[2-[4-[(8-fluoro-4-quinolyl)amino]-1-piperidyl]acetyl]pyrrolidine-2-carbonitrile (2S,4S)-4-fluoro-1-[2-[4-[[8-(trifluoromethyl)-4-quinolyl]amino]-1-piperidyl]acetyl]pyrrolidine-2-carbonitrile (2S,4S)-4-fluoro-1-[2-[4-[[8-(trifluoromethoxy)-5-quinolyl]amino]-1-piperidyl]acetyl]pyrrolidine-2-carbonitrile (2S,4S)-4-fluoro-1-[2-[4-[(3-methoxy-5-quinolyl)amino]-1-piperidyl]acetyl]pyrrolidine-2-carbonitrile (2S,4S)-4-fluoro-1-[2-[4-[(3-fluoro-5-quinolyl)amino]-1-piperidyl]acetyl]pyrrolidine-2-carbonitrile (2S,4S)-4-fluoro-1-[2-[4-[furo[3,2-c]pyridin-7-yl(methyl)amino]-1-piperidyl]acetyl]pyrrolidine-2-carbonitrile (2S,4S)-1-[2-[4-[(1-chloro-5-isoquinolyl)amino]-1-piperidyl]acetyl]-4-fluoropyrrolidine-2-carbonitrile (2S,4S)-1-[2-[4-[(3-chloro-5-isoquinolyl)amino]-1-piperidyl]acetyl]-4-fluoropyrrolidine-2-carbonitrile (2S,4S)-1-[2-[4-[(8-chloro-5-isoquinolyl)amino]-1-piperidyl]acetyl]-4-fluoropyrrolidine-2-carbonitrile (2S,4S)-4-fluoro-1-[2-[4-[(4-methyl-5-isoquinolyl)amino]-1-piperidyl]acetyl]pyrrolidine-2-carbonitrile (2S,4S)-4-fluoro-1-[2-[4-[(3-methoxy-5-isoquinolyl)amino]-1-piperidyl]acetyl]pyrrolidine-2-carbonitrile (2S,4S)-4-fluoro-1-[2-[4-[(8-nitro-5-isoquinolyl)amino]-1-piperidyl]acetyl]pyrrolidine-2-carbonitrile (2S,4S)-4-fluoro-1-[2-[4-[(8-fluoro-5-isoquinolyl)amino]-1-piperidyl]acetyl]pyrrolidine-2-carbonitrile (2S)-1-[2-[4-[(2-chloro-6,7-dimethoxy-quinazolin-4-yl)amino]-1-piperidyl]acetyl]pyrrolidine-2-carbonitrile (2S)-1-[2-[4-[(2-chloro-8-methylquinazolin-4-yl)amino]-1-piperidyl]acetyl]pyrrolidine-2-carbonitrile (2S,4S)-4-fluoro-1-[2-[4-(2,6-naphthyridin-4-ylamino)-1-piperidyl]acetyl]pyrrolidine-2-carbonitrile (2S,4S)-1-[2-[4-[(8-chloro-4-isoquinolyl)amino]-1-piperidyl]acetyl]-4-fluoropyrrolidine-2-carbonitrile (2S,4S)-4-fluoro-1-[2-[4-(3-quinollamino)-1-piperidyl]acetyl]pyrrolidine-2-carbonitrile (2S,4S)-4-fluoro-1-[2-[4-[(6-methyl-3-quinolyl)amino]-1-piperidyl]acetyl]pyrrolidine-2-carbonitrile (2S,4S)-4-fluoro-1-[2-[4-[(6-fluoro-3-quinolyl)amino]-1-piperidyl]acetyl]pyrrolidine-2-carbonitrile (2S,4S)-4-fluoro-1-[2-[4-[(6-methoxy-3-quinolyl)amino]-1-piperidyl]acetyl]pyrrolidine-2-carbonitrile (2S,4S)-4-fluoro-1-[2-[4-[(7-methoxy-3-quinolyl)amino]-1-piperidyl]acetyl]pyrrolidine-2-carbonitrile (2S,4S)-4-fluoro-1-[2-[4-[(8-methoxy-3-quinolyl)amino]-1-piperidyl]acetyl]pyrrolidine-2-carbonitrile (2S,4S)-4-fluoro-1-[2-[4-(1,8-naphthyridin-3-ylamino)-1-piperidyl]acetyl]pyrrolidine-2-carbonitrile (2S,4S)-1-[2-[4-[(7-chloro-1,8-naphthyridin-3-yl)amino]-1-piperidyl]acetyl]-4-fluoropyrrolidine-2-carbonitrile (2S)-1-[2-[4-[(8-ethoxy-5-quinolyl)amino]-1-piperidyl]acetyl]pyrrolidine-2-carbonitrile (2S,4S)-1-[2-[4-[(8-ethoxy-5-quinolyl)amino]-1-piperidyl]acetyl]-4-fluoropyrrolidine-2-carbonitrile (2S,4S)-1-[2-[4-(1,3-benzothiazol-7-ylamino)-1-piperidyl]acetyl]-4-fluoropyrrolidine-2-carbonitrile (2S,4S)-1-[2-[4-[(1-acetylindolin-4-yl)amino]-1-piperidyl]acetyl]-4-fluoropyrrolidine-2-carbonitrile (2S,4S)-4-fluoro-1-[2-[4-[(8-methyl-6-quinolyl)amino]-1-piperidyl]acetyl]pyrrolidine-2-carbonitrile (2S,4S)-4-fluoro-1-[2-[4-[(8-fluoro-6-quinolyl)amino]-1-piperidyl]acetyl]pyrrolidine-2-carbonitrile (2S,4S)-1-[2-[4-[(8-chloro-6-quinolyl)amino]-1-piperidyl]acetyl]-4-fluoropyrrolidine-2-carbonitrile (2S,4S)-4-fluoro-1-[2-[4-[[8-(trifluoromethyl)-6-quinolyl]amino]-1-piperidyl]acetyl]pyrrolidine-2-carbonitrile (2S)-1-[2-[4-[(2-oxochromen-4-yl)amino]-1-piperidyl]acetyl]pyrrolidine-2-carbonitrile (2S,4S)-4-fluoro-1-[2-[4-[(2-oxochromen-4-yl)amino]-1-piperidyl]acetyl]pyrrolidine-2-carbonitrile (2S,4S)-4-fluoro-1-[2-[4-(1,5-naphthyridin-4-ylamino)-1-piperidyl]acetyl]pyrrolidine-2-carbonitrile (2S,4S)-4-fluoro-1-[2-[4-[[2-(trifluoromethyl)-6-quinolyl]amino]-1-piperidyl]acetyl]pyrrolidine-2-carbonitrile (2S,4S)-4-fluoro-1-[2-[4-[(4-methoxy-6-quinolyl)amino]-1-piperidyl]acetyl]pyrrolidine-2-carbonitrile (2S,4S)-1-[2-[4-[(2-bromo-4-pyridyl)amino]-1-piperidyl]acetyl]-4-fluoropyrrolidine-2-carbonitrile (2S,4S)-1-[2-[4-(3H-benzimidazol-4-ylamino)-1-piperidyl]acetyl]-4-fluoropyrrolidine-2-carbonitrile (2S,4S)-1-[2-[4-[(2-chloro-6-morpholino-4-pyridyl)amino]-1-piperidyl]acetyl]-4-fluoropyrrolidine-2-carbonitrile (2S,4S)-4-fluoro-1-[2-[4-[[3-(trifluoromethyl)-5-quinolyl]amino]-1-piperidyl]acetyl]pyrrolidine-2-carbonitrile (2S)-1-[2-[4-[[3-(trifluoromethyl)-5-quinolyl]amino]-1-piperidyl]acetyl]pyrrolidine-2-carbonitrile 5-[[1-[2-oxo-2-[(2S,4S)-2-cyano-4-fluoropyrrolidin-1-yl]ethyl]-4-piperidyl]amino]-N-phenylquinoline-3-carboxamide N-benzyl-N-methyl-5-[[1-[2-oxo-2-[(2S,4S)-2-cyano-4-fluoropyrrolidin-1-yl]ethyl]-4-piperidyl]amino]quinoline -3-carboxamide N-methyl-5-[[1-[2-oxo-2-[(2S,4S)-2-cyano-4-fluoropyrrolidin-1-yl]ethyl]-4-piperidyl]amino]quinoline-8-carboxamide N,N-dimethyl-5-[[1-[2-oxo-2-[(2S,4S)-2-cyano-4-fluoropyrrolidin-1-yl]ethyl]-4-piperidyl]amino]quinoline-8 -carboxamide N-methyl-5-[[1-[2-oxo-2-[(2S,4S)-2-cyano-4-fluoropyrrolidin-1-yl]ethyl]-4-piperidyl]amino]-N-phenylquinoline- 8-carboxamide N-benzyl-N-methyl-5-[[1-[2-oxo-2-[(2S,4S)-2-cyano-4-fluoropyrrolidin-1-yl]ethyl]-4-piperidyl]amino]quinoline -8-carboxamide 5-[[1-[2-oxo-2-[(2S,4S)-2-cyano-4-fluoropyrrolidin-1-yl]ethyl]-4-piperidyl]amino]-N-phenylquinoline-8-carboxamide N-methyl-5-[[1-[2-oxo-2-[(2S)-2-cyanopyrrolidin-1-yl]ethyl]-4-piperidyl]amino]quinoline-8-carboxamide 5-[[1-[2-oxo-2-[(2S)-2-cyanopyrrolidin-1-yl]ethyl]-4-piperidyl]amino]-N-phenylquinoline-8-carboxamide N-benzyl-N-methyl-5-[[1-[2-oxo-2-[(2S)-2-cyanopyrrolidin-1-yl]ethyl]-4-piperidyl]amino]quinoline-8-carboxamide N-methyl-5-[[1-[2-oxo-2-[(2S)-2-cyanopyrrolidin-1-yl]ethyl]-4-piperidyl]amino]-N-phenylquinoline-8-carboxamide 5-[[1-[2-oxo-2-[(2S)-2-cyanopyrrolidin-1-yl]ethyl]-4-piperidyl]amino]-N-(2-pyridyl)quinoline-8-carboxamide 5-[[1-[2-oxo-2-[(2S)-2-cyanopyrrolidin-1-yl]ethyl]-4-piperidyl]amino]-N-(3-pyridyl)quinoline-8-carboxamide 5-[[1-[2-oxo-2-[(2S)-2-cyanopyrrolidin-1-yl]ethyl]-4-piperidyl]amino]-N-(4-pyridyl)quinoline-8-carboxamide 5-[[1-[2-oxo-2-[(2S)-2-cyanopyrrolidin-1-yl]ethyl]-4-piperidyl]amino]-N-pyrimidin-2-yl-quinoline-8-carboxamide 5-[[1-[2-oxo-2-[(2S,4S)-2-cyano-4-fluoropyrrolidin-1-yl]ethyl]-4-piperidyl]amino]-N-pyrimidin-2-yl- quinoline-8-carboxamide 5-[[1-[2-oxo-2-[(2S,4S)-2-cyano-4-fluoropyrrolidin-1-yl]ethyl]-4-piperidyl]amino]-N-(2-pyridyl)quinoline -8-carboxamide 5-[[1-[2-oxo-2-[(2S,4S)-2-cyano-4-fluoropyrrolidin-1-yl]ethyl]-4-piperidyl]amino]-N-(3-pyridyl)quinoline -8-carboxamide 5-[[1-[2-oxo-2-[(2S,4S)-2-cyano-4-fluoropyrrolidin-1-yl]ethyl]-4-piperidyl]amino]-N-(4-pyridyl)quinoline -8-carboxamide N-isoxazol-3-yl-5-[[1-[2-oxo-2-[(2S,4S)-2-cyano-4-fluoropyrrolidin-1-yl]ethyl]-4-piperidyl]amino]quinoline -8-carboxamide N-[5-[[1-[2-oxo-2-[(2S)-2-cyanopyrrolidin-1-yl]ethyl]-4-piperidyl]amino]-8-quinolyl]acetamide N-[5-[[1-[2-oxo-2-[(2S,4S)-2-cyano-4-fluoropyrrolidin-1-yl]ethyl]-4-piperidyl]amino]-8-quinolyl]acetamide (2S,4S)-4-fluoro-1-[2-[4-[(6-methyl-4-quinolyl)oxy]-1-piperidyl]acetyl]pyrrolidine-2-carbonitrile (2S,4S)-4-fluoro-1-[2-[4-[[6-(trifluoromethyl)-4-quinolyl]oxy]-1-piperidyl]acetyl]pyrrolidine-2-carbonitrile (2S,4S)-4-fluoro-1-[2-[4-[[2-(trifluoromethyl)-4-quinolyl]oxy]-1-piperidyl]acetyl]pyrrolidine-2-carbonitrile (2S,4S)-4-fluoro-1-[2-[4-[[6-fluoro-2-(trifluoromethyl)-4-quinolyl]oxy]-1-piperidyl]acetyl]pyrrolidine-2-carbonitrile (2S,4S)-4-fluoro-1-[2-[4-[[6-methoxy-2-(trifluoromethyl)-4-quinolyl]oxy]-1-piperidyl]acetyl]pyrrolidine-2-carbonitrile (2S,4S)-4-fluoro-1-[2-[4-[[8-methoxy-2-(trifluoromethyl)-4-quinolyl]oxy]-1-piperidyl]acetyl]pyrrolidine-2-carbonitrile (2S,4S)-4-fluoro-1-[2-[4-[(3-fluoro-5-quinolyl)oxy]-1-piperidyl]acetyl]pyrrolidine-2-carbonitrile 5-[[1-[2-oxo-2-[(2S,4S)-2-cyano-4-fluoropyrrolidin-1-yl]ethyl]-4-piperidyl]oxy]quinoline-2-carbonitrile (2S,4S)-1-[2-[4-[(8-chloro-5-quinolyl)oxy]-1-piperidyl]acetyl]-4-fluoropyrrolidine-2-carbonitrile (2S,4S)-4-fluoro-1-[2-[4-(1-isoquinolyloxy)-1-piperidyl]acetyl]pyrrolidine-2-carbonitrile (2S,4S)-4-fluoro-1-[2-[4-(4-isoquinolyloxy)-1-piperidyl]acetyl]pyrrolidine-2-carbonitrile (2S,4S)-4-fluoro-1-[2-[4-(5-isoquinolyloxy)-1-piperidyl]acetyl]pyrrolidine-2-carbonitrile (2S,4S)-4-fluoro-1-[2-[4-(6-isoquinolyloxy)-1-piperidyl]acetyl]pyrrolidine-2-carbonitrile (2S,4S)-4-fluoro-1-[2-[4-(7-isoquinolyloxy)-1-piperidyl]acetyl]pyrrolidine-2-carbonitrile (2S,4S)-4-fluoro-1-[2-[4-[(6-methoxy-2-methyl-4-quinolyl)oxy]-1-piperidyl]acetyl]pyrrolidine-2-carbonitrile (2S,4S)-4-fluoro-1-[2-[4-(5-quinolyloxy)-1-piperidyl]acetyl]pyrrolidine-2-carbonitrile (2S)-1-[2-[4-[(6-methoxy-4-quinolyl)oxy]-1-piperidyl]acetyl]pyrrolidine-2-carbonitrile (2S)-1-[2-[4-[(6-fluoro-4-quinolyl)oxy]-1-piperidyl]acetyl]pyrrolidine-2-carbonitrile (2S)-1-[2-[4-[(7-chloro-4-quinolyl)oxy]-1-piperidyl]acetyl]pyrrolidine-2-carbonitrile (2S)-1-[2-[4-[(3-fluoro-5-quinolyl)oxy]-1-piperidyl]acetyl]pyrrolidine-2-carbonitrile 5-[[1-[2-oxo-2-[(2S)-2-cyanopyrrolidin-1-yl]ethyl]-4-piperidyl]oxy]quinoline-2-carbonitrile (2S)-1-[2-[4-[(8-chloro-5-quinolyl)oxy]-1-piperidyl]acetyl]pyrrolidine-2-carbonitrile (2S,4S)-4-fluoro-1-[2-[4-[(7-methyl-4-quinolyl)oxy]-1-piperidyl]acetyl]pyrrolidine-2-carbonitrile (2S,4S)-4-fluoro-1-[2-[4-[(7-fluoro-4-quinolyl)oxy]-1-piperidyl]acetyl]pyrrolidine-2-carbonitrile 4-[[1-[2-oxo-2-[(2S,4S)-2-cyano-4-fluoropyrrolidin-1-yl]ethyl]-4-piperidyl]oxy]quinoline-8-carbonitrile (2S,4S)-4-fluoro-1-[2-[4-[(8-fluoro-4-quinolyl)oxy]-1-piperidyl]acetyl]pyrrolidine-2-carbonitrile (2S,4S)-4-fluoro-1-[2-[4-[(2-methyl-4-quinolyl)oxy]-1-piperidyl]acetyl]pyrrolidine-2-carbonitrile (2S,4S)-4-fluoro-1-[2-[4-[(6-fluoro-2-methyl-4-quinolyl)oxy]-1-piperidyl]acetyl]pyrrolidine-2-carbonitrile (2S,4S)-4-fluoro-1-[2-[4-[(8-methoxy-4-quinolyl)oxy]-1-piperidyl]acetyl]pyrrolidine-2-carbonitrile (2S,4S)-4-fluoro-1-[2-[4-[(8-methyl-4-quinolyl)oxy]-1-piperidyl]acetyl]pyrrolidine-2-carbonitrile or a stereoisomer thereof, a mixture of stereoisomers or a pharmaceutically acceptable salt thereof. 10. Pharmaceutical composition for the treatment of a disease mediated by fibroblast activation protein, containing a therapeutically effective amount of a compound according to any one of claims. 1-9 or a stereoisomer thereof, a mixture of stereoisomers or a pharmaceutically acceptable salt thereof and at least one pharmaceutically acceptable excipient. 11. A method of treating a fibroblast activation protein-mediated disease in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of a compound according to any one of claims. 1-9 or a stereoisomer thereof, a mixture of stereoisomers or a pharmaceutically acceptable salt thereof or a therapeutically effective amount of the pharmaceutical composition according to claim 10, wherein the fibroblast activation protein-mediated disease is selected from the group consisting of a lipid disorder, a lipoprotein disorder, a condition or a disease, which arise as a result of chronic fatty and fibrous degeneration of organs due to the accumulation of lipids and, in particular, triglycerides, and subsequent activation of the profibrotic pathway, type I or II diabetes mellitus, clinical complications of type I and II diabetes mellitus, chronic intrahepatic cholestatic condition, extrahepatic cholestatic condition , liver fibrosis, acute intrahepatic cholestatic condition, obstructive or chronic inflammatory disorder resulting from abnormal bile composition, gastrointestinal condition with reduced absorption of dietary fats and fat-soluble dietary vitamins, inflammatory bowel disease, obesity, metabolic syndrome, combination of dyslipidemia conditions, diabetes and abnormally high body mass index, persistent infection with intracellular bacteria or parasitic protozoa, non-malignant hyperproliferative disorder, malignant hyperproliferative disorder, colon adenocarcinoma and hepatocellular carcinoma, hepatic steatosis or related syndromes, hepatitis B infection, hepatitis C infection, cholestatic and fibrotic effects that are associated with alcoholic cirrhosis or with viral forms of hepatitis, liver failure or liver dysfunction resulting from chronic liver disease or surgical resection of the liver, acute myocardial infarction, acute stroke, thrombosis occurring as an end point of chronic obstructive atherosclerosis, osteoarthritis, rheumatoid arthritis , psoriasis and ischemic stroke, individually or any combination thereof.