N-(2-(4-cyanothiazolidin-3-yl)-2-oxoethyl)-quinoline-4-carboxamides

Abstract

To provide pharmaceuticals for treating or preventing Prolyl endopeptidase fibroblast activation protein (FAP)-mediated conditions.SOLUTION: The invention provides compounds having the structure of Formula (I) in the figure, pharmaceutically acceptable salts thereof, and pharmaceutical compositions comprising such compounds and salts.SELECTED DRAWING: None

Description

Technical Field

[0001] The present disclosure generally relates to N-(2-(4-cyanothiazolidin-3-yl)-2-oxoethyl)-quinoline-4-carboxamide and pharmaceutically acceptable salts thereof. This specification further relates to pharmaceutical compositions containing such compounds and salts; the use of such compounds and salts for treating or preventing fibroblast activation protein (FAP)-mediated pathologies; kits containing such compounds and salts; and methods for producing such compounds and salts.

Background Art

[0002] FAP, a type II transmembrane serine protease, is expressed by fibroblast-like cells involved in tissue repair and healing. In the context of non-alcoholic steatohepatitis (NASH), FAP is upregulated on the cell surface of activated hepatic stellate cells involved in fibrosis formation (Non-Patent Document 1), and is a major aspect of NASH that predicts disease prognosis (Non-Patent Document 2). FAP can also exist as a shed plasma protease. An increase in the level of circulating FAP is associated with the severity of NASH disease (Non-Patent Document 3).

[0003] FAP has a consensus cleavage motif after Gly-Pro and exhibits both endopeptidase and exopeptidase activities. Known enzyme activities include the cleavage of collagen (Non-Patent Document 1), α2-antiplasmin (α2AP) (Non-Patent Document 4), and fibroblast growth factor 21 (FGF21) (Non-Patent Document 5). FAP activity (including the cleavage of collagen) on the cell surface of activated fibroblasts generates a fibrosis-promoting environment. The FAP cleavage of α2AP results in more efficient cross-linking of α2AP to fibrin, causing a reduction in fibrin clearance. The FAP cleavage of FGF21 inactivates the metabolic effects of FGF21 (Non-Patent Document 5). All of these activities are associated with the exacerbation of NASH disease, and the inhibition of FAP has the potential to treat NASH and other pathologies by affecting multiple mechanisms.

[0004] Inhibition of FAP activity is an unmet therapeutic approach for treating NASH and other diseases associated with such activity. Approved pharmacological agents that broadly inhibit FAP activity or specifically inhibit FAP activity are not currently available. Accordingly, there is a need for FAP inhibitors, particularly those having appropriate pharmacological selectivity and bioavailability and thus suitable for administration to subjects in need of such treatment. The present disclosure addresses this broad unmet need by providing corresponding pharmaceutical compositions and methods together with such compounds for the treatment or prevention of NASH and related conditions.

Prior Art Documents

Non-Patent Documents

[0005]

Non-Patent Document 1

Non-Patent Document 2

Non-Patent Document 3

Non-Patent Document 4

Non-Patent Document 5

Summary of the Invention

Means for Solving the Problems

[0006] In one aspect, the present disclosure provides a compound having the structure of formula (I):

Chemical Formula

[0007] In another aspect, the present disclosure provides a compound having a structure of formula (II), (III-A), (III-B), (III-C), (III-D), (III-E), (IV), (IV-A), (V), (VI), (VII), (VIII), (IX), (X), or (XI) as further defined herein, and a pharmaceutically acceptable salt thereof.

[0008] In another aspect, the present disclosure provides a pharmaceutical composition comprising a therapeutically effective amount of a compound having a structure of formula (I), (II), (III-A), (III-B), (III-C), (III-D), (III-E), (IV), (IV-A), (V), (VI), (VII), (VIII), (IX), (X), or (XI), or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.

[0009] In another aspect, the present disclosure provides a pharmaceutical composition comprising a therapeutically effective amount of a compound having a structure of formula (I), (II), (III-A), (III-B), (III-C), (III-D), (III-E), (IV), (IV-A), (V), (VI), (VII), (VIII), (IX), (X), or (XI), or a pharmaceutically acceptable salt thereof; a second pharmacological agent; and a pharmaceutically acceptable carrier.

[0010] In another aspect, the present disclosure provides a method for treating or preventing a FAP-mediated condition by administering to a subject in need of a therapeutically effective amount of a compound having a structure of formula (I), (II), (III-A), (III-B), (III-C), (III-D), (III-E), (IV), (IV-A), (V), (VI), (VII), (VIII), (IX), (X), or (XI), or a pharmaceutically acceptable salt thereof. In a further aspect, the FAP-mediated condition is selected from the group consisting of liver disease, type 2 diabetes, cardiovascular conditions, obesity, obesity-related conditions, fibrosis, keloid disorders, inflammation, and cancer. In a further aspect, the FAP-mediated condition is liver disease, particularly non-alcoholic steatohepatitis (NASH).

[0011] In another aspect, the present disclosure provides a compound having the structure of formula (I), (II), (III-A), (III-B), (III-C), (III-D), (III-E), (IV), (IV-A), (V), (VI), (VII), (VIII), (IX), (X), or (XI), or a pharmaceutically acceptable salt thereof, for use as a medicament for treating or preventing FAP-mediated conditions.

[0012] In another aspect, the present disclosure provides the use of a compound having the structure of formula (I), (II), (III-A), (III-B), (III-C), (III-D), (III-E), (IV), (IV-A), (V), (VI), (VII), (VIII), (IX), (X), or (XI), or a pharmaceutically acceptable salt thereof, for preparing a medicament for treating or preventing FAP-mediated conditions.

[0013] In another aspect, the present disclosure provides a kit comprising a compound having the structure of formula (I), (II), (III-A), (III-B), (III-C), (III-D), (III-E), (IV), (IV-A), (V), (VI), (VII), (VIII), (IX), (X), or (XI), or a pharmaceutically acceptable salt thereof.

[0014] In another aspect, the present disclosure provides a method for preparing a compound having the structure of formula (I), (II), (III-A), (III-B), (III-C), (III-D), (III-E), (IV), (IV-A), (V), (VI), (VII), (VIII), (IX), (X), or (XI), or a pharmaceutically acceptable salt thereof.

DETAILED DESCRIPTION OF THE INVENTION

[0015] Numerous embodiments are detailed throughout this specification and will be apparent to those skilled in the art. This specification should not be construed as being limited to any particular embodiment described herein.

[0016] I. Definitions For the embodiments disclosed in this specification, the following terms have the following meanings.

[0017] References to "a" or "an" mean "one or more." Throughout, plural and singular forms should be treated as interchangeable unless a number designation is given.

[0018] Unless the context requires otherwise, the words "comprise," "comprises," and "comprising" are to be construed inclusively rather than exclusively, and are used based on and with the clear understanding that each of those words is intended to be so construed when the applicant interprets this patent including the following claims.

[0019] The term "halogen" (alone or in combination with another term) means a fluorine group (which may be represented as -F), a chlorine group (which may be represented as -Cl), a bromine group (which may be represented as -Br), or an iodine group (which may be represented as -I).

[0020] The term "hydroxy" (alone or in combination with another term) means -OH.

[0021] The term "cyano" (alone or in combination with another term) means -CN.

[0022] The term "oxo" (alone or in combination with another term) means an oxo group and may be represented as =O.

[0023] The term "alkyl" (alone or in combination with another term) means a straight-chain or branched-chain saturated hydrocarbyl substituent (i.e., a substituent containing only carbon and hydrogen). Alkyl typically contains from 1 to about 20 carbon atoms, more typically from 1 to about 12 carbon atoms, even more typically from 1 to about 8 carbon atoms, and even more typically from 1 to about 6 carbon atoms. Examples of such substituents include methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, pentyl, iso-amyl, 2,2-dimethylpropyl, hexyl, heptyl, and octyl.

[0024] The term "cycloalkyl" (alone or in combination with another term) means a saturated carbocyclic substituent containing from 3 to about 14 carbon ring atoms, more typically from 3 to about 12 carbon ring atoms, and even more typically from 3 to about 8 carbon ring atoms. Cycloalkyl typically includes a single carbon ring containing from 3 to 6 carbon ring atoms. Examples of monocyclic cycloalkyls include cyclopropyl, cyclobutyl, cyclopentyl, and cyclohexyl.

[0025] The term "cycloalkylalkyl" (alone or in combination with another term) means an alkyl substituted with cycloalkyl. Examples of such substituents include cyclopropylmethyl, cyclobutylmethyl, cyclopentylmethyl, and cyclohexylmethyl.

[0026] The term "alkoxy" (alone or in combination with another term) means an alkyl ether substituent, i.e., alkyl-O-. Examples of alkoxy include methoxy (CH 3 -O-), ethoxy, n-propoxy, iso-propoxy, n-butoxy, iso-butoxy, sec-butoxy, and tert-butoxy. Thus, for example, (i) The term "alkoxyalkyl" (alone or in combination with another term) means an alkyl substituted with alkoxy such as "methoxymethyl" which can be represented as follows: [Chemistry] ; (ii) The term "cycloalkylalkoxy" (alone or in combination with another term) means an alkoxy substituted with a cycloalkyl such as "cyclopropylmethoxy" which may be represented as follows: [Chemistry] ; (iii) The term "alkoxyalkoxy" (alone or in combination with another term) means an alkoxy substituted with another alkoxy such as "methoxyethoxy" which may be represented as follows: [Chemistry] ; (iv) The term "alkoxyalkoxyalkyl" (alone or in combination with another term) means an alkyl substituted with an alkoxyalkoxy such as "methoxyethoxymethyl" which may be represented as follows: [Chemistry] ; (v) The term "alkoxyphenyl" (alone or in combination with another term) means a phenyl substituted with an alkoxy such as "4 - methoxyphenyl" which may be represented as follows: [Chemistry] ; and (vi) The term "alkoxyphenylalkyl" (alone or in combination with another term) means an alkyl substituted with an alkoxyphenyl such as "4 - methoxyphenylmethyl" which may be represented as follows: [Chemistry] .

[0027] In some examples, the number of carbon atoms in a substituent (e.g., alkyl, cycloalkyl, etc.) is indicated by the prefix "C"x~y -」, where x is the minimum number of carbon atoms in the substituent and y is the maximum number of carbon atoms in the substituent. Thus, for example, "C 1~6 -alkyl" refers to an alkyl substituent containing 1 to 6 carbon atoms. Further exemplified, C 3~6 -cycloalkyl refers to a cycloalkyl substituent containing 3 to 6 carbocyclic atoms.

[0028] The prefix "halo" indicates that the substituent to which the prefix is attached is substituted with one or more independently selected halogen groups. For example, haloalkyl means an alkyl substituent in which at least one hydrogen group is replaced by a halogen group. When there are two or more hydrogens replaced by halogen, the halogens may be the same or different. Examples of haloalkyl include fluoromethyl, difluoromethyl, trifluoromethyl, difluoroethyl, 1,1,1-trifluoroethyl, pentafluoroethyl, difluoropropyl, heptafluoropropyl, chloromethyl, dichloromethyl, trichloromethyl, difluorochloromethyl, dichlorofluoromethyl, and dichloropropyl. Similarly, "haloalkoxy" means an alkoxy substituent in which at least one hydrogen group is replaced by a halogen group. When there are two or more hydrogens replaced by halogen, the halogens may be the same or different. Examples of haloalkoxy substituents include fluoromethoxy, difluoromethoxy, trifluoromethoxy (also known as "perfluoromethyloxy"), 1,1,1-trifluoroethoxy, and chloromethoxy.

[0029] The term "carbonyl" (alone or in combination with another term) means -C(O)-, which can also be shown as follows:

Chemical formula

[0030] The term "thio" or "thia" (alone or in combination with another term) means a divalent sulfur atom which can also be represented as -S-.

[0031] The term "sulfinyl" or "sulfoxide" (alone or in combination with another term) means -S(O)- which can also be represented as follows. [Chem.]

[0032] The term "sulfonyl" (alone or in combination with another term) may also be represented as -S(O) 2 - and means

Chem.

Chem.

[0033] The term "alkylcarbonylaminoalkyl" (alone or in combination with another term) may also be represented as alkyl-C(O)-N(H)-alkyl such as "methylcarbonylaminomethyl":

Chem.

[0034] The term "heterocyclyl" (alone or in combination with another term) means a saturated, partially saturated, or fully unsaturated (i.e., heteroaryl) ring structure containing a total of 3 to 14 ring atoms. At least one of the ring atoms is a heteroatom (i.e., oxygen, nitrogen, or sulfur), and the remaining ring atoms are independently selected from the group consisting of carbon, oxygen, nitrogen, and sulfur.

[0035] Examples of heterocyclyl include monocyclic saturated, partially unsaturated, and fully unsaturated ring structures having 3 to 7 members, such as 3 to 6 members, 5 to 7 members, such as 5 or 6 members. At least 1 member and up to 4 members, particularly 1, 2, or 3 members, of the ring are heteroatoms selected from N, O, and S in stable combinations known to those skilled in the art, and the remaining ring atoms are carbon atoms. Examples of monocyclic heterocyclyl include furanyl, dihydrofuranyl, tetrahydrofuranyl, thiophenyl, dihydrothiophenyl, tetrahydrothiophenyl, pyrrolyl, isopyrrolyl, pyrrolinyl, pyrrolidinyl, imidazolyl, isoimidazolyl, imidazolinyl, imidazolidinyl, pyrazolyl, pyrazolinyl, pyrazolidinyl, triazolyl, tetrazolyl, dithiolyl, oxathiolyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, thiazolinyl, isothiazolinyl, thiazolidinyl, isothiazolidinyl, thiadiazolyl, oxathiazolyl, dioxazolyl, oxathiazolyl, oxathiolyl, oxathiolanyl, pyranyl, dihydropyranyl, pyridinyl, piperidinyl, pyridazinyl, pyrimidinyl, pyrazinyl, piperazinyl, triazinyl, oxazinyl, isoxazolidinyl, oxazolidinyl, isoxazolidinyl, oxathiazinyl, morpholinyl, azepinyl, oxepinyl, thiepinyl, and diazepinyl.

[0036] The heterocyclyl further includes a bicyclic ring structure (i.e., a fused bicyclic) or a bicyclic having only one shared atom (i.e., a spiro) that are fused together, and at least one such ring contains a heteroatom (i.e., nitrogen, oxygen, or sulfur) as a ring atom. Examples of heterocyclyl having two fused ring structures together include indolizinyl, pyridinyl, pyranopyrrolyl, 4H-quinolizinyl, purinyl, naphthyridinyl, pyridopyridinyl, pteridinyl, indolyl, isoindolyl, indoleninyl, isoindazolyl, benzadiazinyl, phthalazinyl, quinoxalinyl, quinazolinyl, benzodiazinyl, benzopyranyl, benzothiopyranyl, benzoxazolyl, indoxazinyl, anthranilyl, benzodioxolyl, benzodioxanyl, benzoxadiazolyl, benzofuranyl, isobenzofuranyl, benzothienyl, isobenzothienyl, benzothiazolyl, benzothiadiazolyl, benzimidazolyl, benzotriazolyl, benzoxazinyl, benzoisoxazinyl, and tetrahydroisoquinolinyl.

[0037] A substituent is "substitutable" if it contains at least one carbon or nitrogen atom that is bonded to one or more hydrogen atoms. Thus, for example, hydrogen, halogen, and cyano are outside the scope of this definition.

[0038] When a substituent is described as being "substituted", a non-hydrogen group is present in place of the group on the carbon or nitrogen of the substituent. Thus, for example, a substituted alkyl substituent is an alkyl substituent and at least one non-hydrogen group is present in place of the hydrogen group on the alkyl substituent. By way of illustration, monofluoroalkyl is an alkyl substituted with one fluoro group and difluoroalkyl is an alkyl substituted with two fluoro groups. It should be recognized that when more than two substituents are present on a substituent, each non-hydrogen group may be the same or different (unless otherwise specified).

[0039] When a substituent is described as being "optionally substituted", the substituent may (1) not be substituted or (2) be substituted. When a carbon of a substituent is described as being optionally substituted with one or more of a list of substituents, one or more (as many as present) of the hydrogens on the carbon may be replaced, separately and / or together, with independently selected optional substituents. When a nitrogen of a substituent is described as being optionally substituted with one or more of a list of substituents, one or more (as many as present) of the hydrogens on the nitrogen may each be replaced with an independently selected optional substituent.

[0040] When a substituent is described as being "independently selected" from a group, each substituent is selected independently of the others. Thus, each substituent may be the same as or different from the other substituents.

[0041] The term "pharmaceutically acceptable" is used adjectivally herein to mean that the modified noun is suitable for use as or in a pharmaceutical. For example, a "pharmaceutically acceptable salt" is a salt suitable for use in mammals, particularly humans, and includes salts with inorganic bases, organic bases, inorganic acids, organic acids, or basic or acidic amino acids suitable for use in mammals, particularly humans.

[0042] A "therapeutically effective amount" of a pharmacological agent is an amount sufficient to produce an advantageous or desired result, including clinical results, and thus will depend on the circumstances in which it is administered. If a pharmacological agent is being administered to treat a liver disease, for example, the therapeutically effective amount of the agent is the amount of the agent that, alone or in combination with additional therapy, is sufficient to provide an anti-liver disease effect in the subject as compared to the response obtained without administration of the agent.

[0043] The term "prevent" can be understood by a normal and skilled physician and can include being intended to have its standard meaning with respect to the treatment of a particular medical condition, including primary prevention to prevent the onset of a disease, and secondary prevention where the medical condition has already occurred and the patient is temporarily or continuously protected against the worsening or deterioration of the disease or the onset of new symptoms associated with the medical condition.

[0044] The term "treat" can be understood by a normal and skilled physician and, with respect to the treatment of a particular medical condition, can include (1) reducing the degree or cause of the medical condition being treated, and / or (2) alleviating or remitting one or more symptoms associated with the medical condition. Treatment of a liver disease can include, for example, stabilizing (i.e., not worsening), delaying, or slowing the spread or progression of the liver disease, either wholly or in part; extending survival compared to what would be predicted in the absence of treatment; and / or, otherwise, alleviating or mitigating the severity of cancer or liver disease.

[0045] II. Compounds In one embodiment, the present disclosure provides a compound having the structure of formula (I):

Chemical formula

[0046] In some embodiments, the present disclosure provides a compound having the structure of formula (II):

Chemical formula

[0047] In some embodiments, R 1 is selected from the group consisting of hydrogen, halogen, and C 1~3 -alkyl. In one embodiment, R 1 is selected from the group consisting of hydrogen, chloro, fluoro, and methyl. In another embodiment, R 1 is hydrogen. In another embodiment, R 1 is chloro. In another embodiment, R 1 is fluoro. In another embodiment, R 1 is methyl.

[0048] In some embodiments, R 3 is selected from the group consisting of hydrogen, halogen, and C 1~3 -alkyl. In one embodiment, R 3 is selected from the group consisting of hydrogen, chloro, fluoro, and methyl. In another embodiment, R 3 is hydrogen. In another embodiment, R 3 is chloro. In another embodiment, R 3 is fluoro. In another embodiment, R 3 is methyl.

[0049] In some embodiments, R 4 is selected from the group consisting of hydrogen, halogen, and C 1~3 -alkyl. In one embodiment, R 4 is hydrogen. In another embodiment, R 4 is chloro. In another embodiment, R 4 is fluoro. In another embodiment, R 4 is methyl.

[0050] In some embodiments, R 5 is selected from the group consisting of hydrogen, halogen, and C 1~3 -alkyl. In one embodiment, R 5is selected from the group consisting of hydrogen, chloro, fluoro, and methyl. In another aspect, R 5 is hydrogen. In another aspect, R 5 is fluoro. In another aspect, R 5 is chloro. In another aspect, R 5 is methyl.

[0051] In some embodiments, R 6 is selected from the group consisting of hydrogen, halogen, and C 1~3 -alkyl. In one aspect, R 6 is selected from the group consisting of hydrogen, chloro, fluoro, and methyl. In another aspect, R 6 is hydrogen. In another embodiment, R 6 is chloro. In another aspect, R 6 is fluoro. In another aspect, R 6 is methyl.

[0052] In some embodiments, R 1 , R 3 , R 4 , R 5 , and R 6 Of the substituents, one is selected from the group consisting of halogen and C 1~3 -alkyl, and the remaining R 1 , R 3 , R 4 , R 5 , and R 6 Substituents are all hydrogen. In one aspect, R 1 , R 3 , R 4 , R 5 , and R 6 Of the substituents, one is selected from the group consisting of chloro, fluoro, and methyl, and the remaining R 1 , R 3 , R 4 , R 5 , and R 6 Substituents are all hydrogen. In another aspect, R 1 , R 3 , R 4 , R 5 , and R 6One of the substituents is selected from the group consisting of chloro and fluoro, and the remaining R 1 , R 3 , R 4 , R 5 , and R 6 substituents are all hydrogen. In another embodiment, R 1 , R 3 , R 4 , R 5 , and R 6 One of the substituents is chloro, and the remaining R 1 , R 3 , R 4 , R 5 , and R 6 substituents are all hydrogen. In another embodiment, R 1 , R 3 , R 4 , R 5 , and R 6 One of the substituents is fluoro, and the remaining R 1 , R 3 , R 4 , R 5 , and R 6 substituents are all hydrogen. In another embodiment, R 1 , R 3 , R 4 , R 5 , and R 6 One of the substituents is methyl, and the remaining R 1 , R 3 , R 4 , R 5 , and R 6 substituents are all hydrogen.

[0053] In some embodiments, at least two of the R 1 , R 3 , R 4 , R 5 , and R 6 substituents are independently selected from the group consisting of halogen and C 1~3 -alkyl, and the remaining R 1 , R 3 , R 4 , R 5 , and R 6 substituents are all hydrogen. In one embodiment, R 1 , R3 , R 4 , R 5 , and R 6 Two of the substituents are independently selected from the group consisting of chloro, fluoro, and methyl, and the remaining R 1 , R 3 , R 4 , R 5 , and R 6 substituents are all hydrogen.

[0054] In some embodiments, R 1 , R 3 , R 4 , R 5 , and R 6 At least one of the substituents is chloro.

[0055] In some embodiments, R 1 , R 3 , R 4 , R 5 , and R 6 At least one of the substituents is fluoro.

[0056] In some embodiments, R 1 , R 3 , R 4 , R 5 , and R 6 At least one of the substituents is methyl.

[0057] In some embodiments, the present disclosure provides a compound having the structure of formula (III-A):

Chemical formula

[0058] In some embodiments, the present disclosure provides a compound having the structure of formula (III-B):

Chemical formula

[0059] In some embodiments, the present disclosure provides a compound having the structure of formula (III-C): [Chemical formula] and its pharmaceutically acceptable salts (wherein R 2 and R 4 are as defined in the various embodiments above) are provided.

[0060] In some embodiments, the present disclosure provides a compound having the structure of formula (III-D): [Chemical formula] and its pharmaceutically acceptable salts (wherein R 2 and R 5 are as defined in the various embodiments above) are provided.

[0061] In some embodiments, the present disclosure provides a compound having the structure of formula (III-E): [Chemical formula] and its pharmaceutically acceptable salts (wherein R 2 and R 6 are as defined in the various embodiments above) are provided.

[0062] In some embodiments, the present disclosure provides a compound having the structure of formula (IV): [Chemical formula] and its pharmaceutically acceptable salts (wherein R 2 is as defined above for the compound of formula (I)) are provided.

[0063] In some embodiments, the present disclosure provides a compound having the structure of formula (IV-A):

Chemical formula

[0064] A.R 2 is a monocyclic or fused bicyclic heterocyclyl (nitrogen and carbon ring atoms) In some embodiments, the present disclosure provides a compound having the structure of formula (I), (II), (III-A), (III-B), (III-C), (III-D), (III-E), (IV), or (IV-A), and a pharmaceutically acceptable salt thereof (wherein R 2 is a heterocyclyl containing a total of 4 to 10 ring atoms, and the heterocyclyl ring is (i) a saturated, partially saturated, or fully unsaturated monocyclic or fused bicyclic ring, (ii) has 1, 2, or 3 nitrogen ring atoms, the remaining ring atoms are carbon, and (iii) halogen, hydroxy, oxo, cyano, C 1~6 -alkyl, C 3~6 -cycloalkyl, C 3~6 -cycloalkyl-C 1~3 -alkyl, C 1~6 -alkoxy, C 3~6 -cycloalkoxy, C 1~3 -alkoxy-C 1~3 -alkyl, C 1~3 -alkoxy-C 2~3 -alkoxy, C 1~3 -alkoxy-C 2~3 -alkoxy-C 1~3 -alkyl, C 1~3 -alkylcarbonyl, C 3~6 -cycloalkylcarbonyl, C 1~3 -alkyl-carbonylamino-C 1~3 -alkyl, C 1~3 -alkylsulfonyl-C 1~3 -alkyl, phenyl, tolyl, C 1~3-Alkoxyphenyl, phenyl-C 1~3 -Alkyl, C 1~3 -Alkoxyphenyl-C 1~3 -Alkyl, azetidinyl, pyrrolidinyl, piperidinyl, morpholinyl, tetrahydrofuranyl, tetrahydropyranyl, and tetrahydrooxepanyl, optionally substituted with one or more substituents independently selected from the group consisting of, and (a) C 1~6 -Alkyl, C 3~6 -Cycloalkyl, C 3~6 -Cycloalkyl-C 1~3 -Alkyl, C 1~6 -Alkoxy, C 3~6 -Cycloalkoxy, C 1~3 -Alkoxy-C 1~3 -Alkyl, C 1~3 -Alkoxy-C 2~3 -Alkoxy, C 1~3 -Alkoxy-C 2~3 -Alkoxy-C 1~3 -Alkyl, C 1~3 -Alkylcarbonyl, C 3~6 -Cycloalkylcarbonyl, C 1~3 -Alkyl-carbonylamino-C 1~3 -Alkyl, C 1~3 -Alkylsulfonyl-C 1~3 -Alkyl, phenyl, tolyl, C 1~3 -Alkoxyphenyl, phenyl-C 1~3 -Alkyl, C 1~3 -Alkoxyphenyl-C 1~3 -Alkyl, azetidinyl, pyrrolidinyl, piperidinyl, morpholinyl, tetrahydrofuranyl, tetrahydropyranyl, and tetrahydrooxepanyl may further be substituted with one or more halogens, and (b) C 1~6 Alkyl may further be substituted with one or more hydroxy) is provided. In one embodiment, R 2 The heterocyclic ring is a saturated monocyclic ring. In another embodiment, R 2 The heterocyclic ring is a partially saturated monocyclic ring. In another embodiment, R 2 The heterocyclic ring is a fully unsaturated monocyclic ring. In another embodiment, R2 The heterocyclic ring is a saturated fused bicyclic ring. In another aspect, R 2 The heterocyclic ring is a partially saturated fused bicyclic ring. In another aspect, R 2 The heterocyclic ring is a fully unsaturated fused bicyclic ring. In another aspect, R 2 The heterocyclic ring has one nitrogen ring atom and the remaining ring atoms are carbon. In another aspect, R 2 The heterocyclic ring has two nitrogen ring atoms and the remaining ring atoms are carbon. In another aspect, R 2 The heterocyclic ring has three nitrogen ring atoms and the remaining ring atoms are carbon.

[0065] In some embodiments, R 2 The heterocyclic ring is:

Chemical formula

[0066] In some embodiments, R 2 heterocyclic ring is:

Chemical formula

[0067] In some embodiments, R 2 heterocyclic ring is:

Chemical formula

[0068] In some embodiments, R 2 The heterocyclic ring is halogen, hydroxy, oxo, cyano, C 1~3 -Alkyl, C 3~6 -Cycloalkyl, C 1~3 -Alkoxy, C 1~3 -Alkylcarbonyl, C 3~6 -Cycloalkylcarbonyl, C 1~3-alkoxy-C 1~3 -alkyl, C 1~3 -alkoxy-C 2~3 -alkoxy, C 1~3 -alkoxy-C 2~3 -alkoxy-C 1~3 -alkyl, C 1~3 -alkyl-carbonylamino-C 1~3 -alkyl, C 1~3 -alkylsulfonyl-C 1~3 -alkyl, morpholinyl, tetrahydrofuranyl, tetrahydropyranyl, and tetrahydrooxepanyl, optionally substituted with one or more substituents independently selected from the group consisting of, C 1~3 -alkyl, C 3~6 -cycloalkyl, C 1~3 -alkoxy, C 1~3 -alkylcarbonyl, C 3~6 -cycloalkylcarbonyl, C 1~3 -alkoxy-C 1~3 -alkyl, C 1~3 -alkoxy-C 2~3 -alkoxy, C 1~3 -alkoxy-C 2~3 -alkoxy-C 1~3 -alkyl, C 1~3 -alkylsulfonyl-C 1~3 -alkyl, tetrahydrofuranyl, tetrahydropyranyl, and tetrahydrooxepanyl may be further substituted with one or more halogens.

[0069] In some embodiments, R 2 The heterocyclic ring is optionally substituted with one or more substituents independently selected from the group consisting of halogen, hydroxy, oxo, C 1~3 -alkyl, cyclopropyl, C 1~3 -alkoxy, and C 1~3 -alkoxy-C 1~3 -alkyl, and is C 1~3 -alkyl, cyclopropyl, C 1~3 -alkoxy, and C 1~3 -alkoxy-C 1~3-The alkyl may be further substituted with one or more halogens.

[0070] In some embodiments, R 2 The heterocyclic ring is optionally substituted with one or more substituents independently selected from the group consisting of azetidinyl, pyrrolidinyl, piperidinyl, and morpholinyl, and azetidinyl, pyrrolidinyl, piperidinyl, and morpholinyl may be further substituted with one or more halogens.

[0071] In some embodiments, R 2 The heterocyclic ring is optionally substituted with one or more substituents independently selected from the group consisting of tetrahydrofuranyl, tetrahydropyranyl, and tetrahydrooxepanyl, and tetrahydrofuranyl, tetrahydropyranyl, and tetrahydrooxepanyl may be further substituted with one or more halogens.

[0072] In some embodiments, R 2 The heterocyclic ring is optionally substituted with one or more halogens. In one aspect, R 2 The heterocyclic ring is optionally substituted with one or more chloro. In another aspect, R 2 The heterocyclic ring is optionally substituted with one or more fluoro.

[0073] In some embodiments, R 2 The heterocyclic ring is optionally substituted with one or more hydroxy.

[0074] In some embodiments, R 2 The heterocyclic ring is optionally substituted with one or more oxo.

[0075] In some embodiments, R 2 The heterocyclic ring is optionally substituted with one or more cyano.

[0076] In some embodiments, R 2The heterocyclic ring is optionally substituted with one or more C 1~3 -alkyl, and the C 1~3 -alkyl may be further substituted with one or more substituents independently selected from halogen and hydroxy.

[0077] In some embodiments, R 2 The heterocyclic ring is optionally substituted with one or more C 3~6 -cycloalkyl, and the C 3~6 -cycloalkyl may be further substituted with one or more halogens.

[0078] In some embodiments, R 2 The heterocyclic ring is optionally substituted with one or more C 3~6 -cycloalkyl-C 1~3 -alkyl, and the C 3~6 -cycloalkyl-C 1~3 -alkyl may be further substituted with one or more halogens.

[0079] In some embodiments, R 2 The heterocyclic ring is optionally substituted with one or more C 1~3 -alkoxy, and the C 1~3 -alkoxy may be further substituted with one or more halogens.

[0080] In some embodiments, R 2 The heterocyclic ring is optionally substituted with one or more C 3~6 -cycloalkoxy, and the C 3~6 -cycloalkoxy may be further substituted with one or more halogens.

[0081] In some embodiments, R 2 The heterocyclic ring is optionally substituted with one or more C 1~3 -alkoxy-C 1~3 -alkyl, and the C 1~3 -alkoxy-C 1~3 -alkyl may be further substituted with one or more halogens.

[0082] In some embodiments, R 2 The heterocyclic ring is optionally substituted with one or more C 1~3 -alkoxy-C 2~3 -alkoxy, and C 1~3 -alkoxy-C 2~3 -alkoxy may further be substituted with one or more halogens.

[0083] In some embodiments, R 2 The heterocyclic ring is optionally substituted with one or more C 1~3 -alkoxy-C 2~3 -alkoxy-C 1~3 -alkyl, and C 1~3 -alkoxy-C 2~3 -alkoxy-C 1~3 -alkyl may further be substituted with one or more halogens.

[0084] In some embodiments, R 2 The heterocyclic ring is optionally substituted with one or more C 1~3 -alkylcarbonyl, and C 1~3 -alkylcarbonyl may further be substituted with one or more halogens.

[0085] In some embodiments, R 2 The heterocyclic ring is optionally substituted with one or more C 3~6 -cycloalkylcarbonyl, and C 3~6 -cycloalkylcarbonyl may further be substituted with one or more halogens.

[0086] In some embodiments, R 2 The heterocyclic ring is optionally substituted with one or more C 1~3 -alkyl-carbonylamino-C 1~3 -alkyl, and C 1~3 -alkyl-carbonylamino-C 1~3 -alkyl may further be substituted with one or more halogens.

[0087] In some embodiments, R 2 The heterocyclic ring is optionally substituted with one or more C 1~3 -alkylsulfonyl-C 1~3 -alkyl, and C 1~3 -alkylsulfonyl-C 1~3 -alkyl may be further substituted with one or more halogens.

[0088] In some embodiments, R 2 The heterocyclic ring is optionally substituted with one or more substituents independently selected from the group consisting of phenyl, tolyl, C 1~3 -alkoxyphenyl, phenyl-C 1~3 -alkyl, and C 1~3 -alkoxyphenyl-C 1~3 -alkyl, and phenyl, tolyl, phenyl-C 1~3 -alkyl, and C 1~3 -alkoxyphenyl-C 1~3 -alkyl may be further substituted with one or more halogens.

[0089] In some embodiments, R 2 The heterocyclic ring is optionally substituted with one or more substituents independently selected from the group consisting of azetidinyl, pyrrolidinyl, piperidinyl, and morpholinyl, and azetidinyl, pyrrolidinyl, piperidinyl, and morpholinyl may be further substituted with one or more halogens.

[0090] In some embodiments, R 2 The heterocyclic ring is optionally substituted with one or more substituents independently selected from the group consisting of tetrahydrofuranyl, tetrahydropyranyl, and tetrahydrooxepanyl, and tetrahydrofuranyl, tetrahydropyranyl, and tetrahydrooxepanyl may be further substituted with one or more halogens.

[0091] In some embodiments, R 2The heterocyclic ring is optionally substituted with one or more substituents independently selected from the group consisting of fluoro, hydroxy, oxo, methyl, ethyl, propyl, isopropyl, cyclopropyl, fluoromethyl, difluoromethyl, trifluoromethyl, fluoroethyl, difluoroethyl, trifluoroethyl, difluoropropyl, trifluoropropyl, methoxy, ethoxy, isopropoxy, difluoromethoxy, trifluoromethoxy, methoxymethyl, trifluoromethoxymethyl, methylcarbonylaminomethyl, methylsulfonylmethyl, morpholinyl, and tetrahydropyranyl.

[0092] In some embodiments, R 2 The heterocyclic ring is optionally substituted with one or more substituents independently selected from the group consisting of fluoro, hydroxy, methyl, fluoromethyl, difluoromethyl, trifluoromethyl, difluoroethyl, difluoropropyl, cyclopropyl, methoxy, trifluoromethoxy, ethoxy, and methoxymethyl.

[0093] In some embodiments, R 2 The heterocyclic ring is:

Chemical formula

[0094] In some embodiments, the compound and the pharmaceutically acceptable salt are (R)-N-(2-(4-Cyanothiazolidin-3-yl)-2-oxoethyl)-6-(2,2-dimethylazetidin-1-yl)-quinoline-4-carboxamide (Example 20); (R)-N-(2-(4-Cyanothiazolidin-3-yl)-2-oxoethyl)-6-(3-fluoroazetidin-1-yl)quinoline-4-carboxamide (Example 21); (R)-N-(2-(4-Cyanothiazolidin-3-yl)-2-oxoethyl)-6-(3,3-dimethylazetidin-1-yl)-quinoline-4-carboxamide (Example 22); (R)-N-(2-(4-Cyanothiazolidin-3-yl)-2-oxoethyl)-6-(3,3-difluoroazetidin-1-yl)-quinoline-4-carboxamide (Example 23); (R)-N-(2-(4-Cyanothiazolidin-3-yl)-2-oxoethyl)-6-(3-fluoro-3-methylazetidin-1-yl)-quinoline-4-carboxamide (Example 24); (R)-N-(2-(4-Cyanothiazolidin-3-yl)-2-oxoethyl)-6-(3-methylazetidin-1-yl)quinoline-4-carboxamide (Example 25); (R)-N-(2-(4-Cyanothiazolidin-3-yl)-2-oxoethyl)-6-(3-(trifluoromethyl)azetidin-1-yl)-quinoline-4-carboxamide (Example 26); (R)-N-(2-(4-Cyanothiazolidin-3-yl)-2-oxoethyl)-6-(3-(fluoromethyl)-3-methylazetidin-1-yl)quinoline-4-carboxamide (Example 27); (R)-N-(2-(4-Cyanothiazolidin-3-yl)-2-oxoethyl)-6-(3-(difluoromethyl)azetidin-1-yl)-quinoline-4-carboxamide (Example 28); (R)-N-(2-(4-Cyanothiazolidin-3-yl)-2-oxoethyl)-6-(3-(methoxymethyl)-3-methyl-azetidin-1-yl)quinoline-4-carboxamide (Example 29); N-(2-((R)-4-Cyanothiazolidin-3-yl)-2-oxoethyl)-6-((2S,3R)-3-methoxy-2-methyl-azetidin-1-yl)quinoline-4-carboxamide (Example 30); (R)-N-(2-(4-Cyanothiazolidin-3-yl)-2-oxoethyl)-6-(3-cyclopropyl-3-fluoroazetidin-1-yl)quinoline-4-carboxamide (Example 31); (R)-N-(2-(4-Cyanothiazolidin-3-yl)-2-oxoethyl)-6-(3-methoxyazetidin-1-yl)quinoline-4-carboxamide (Example 66); (R)-N-(2-(4-Cyanothiazolidin-3-yl)-2-oxoethyl)-6-(3-(fluoromethyl)azetidin-1-yl)-quinoline-4-carboxamide (Example 113); (R)-N-(2-(4-Cyanothiazolidin-3-yl)-2-oxoethyl)-6-(3-morpholinoazetidin-1-yl)-quinoline-4-carboxamide (Example 122); (R)-N-(2-(4-Cyanothiazolidin-3-yl)-2-oxoethyl)-6-(3-((trifluoromethoxy)methyl)-azetidin-1-yl)quinoline-4-carboxamide (Example 130); (R)-N-(2-(4-Cyanothiazolidin-3-yl)-2-oxoethyl)-6-(3-methyl-3-(2,2,2-trifluoroethyl)azetidin-1-yl)quinoline-4-carboxamide (Example 131); (R)-N-(2-(4-Cyanothiazolidin-3-yl)-2-oxoethyl)-6-(3-(trifluoromethoxy)azetidin-1-yl)quinoline-4-carboxamide (Example 132); (R)-N-(2-(4-Cyanothiazolidin-3-yl)-2-oxoethyl)-6-(3-(2,2-difluoroethyl)-3-methylazetidin-1-yl)quinoline-4-carboxamide (Example 133); (R)-N-(2-(4-Cyanothiazolidin-3-yl)-2-oxoethyl)-6-(3-cyclopropyl-3-methylazetidin-1-yl)quinoline-4-carboxamide (Example 134); (R)-N-(2-(4-Cyanothiazolidin-3-yl)-2-oxoethyl)-6-(3-(difluoromethyl)-3-methylazetidin-1-yl)quinoline-4-carboxamide (Example 135); (R)-N-(2-(4-Cyanothiazolidin-3-yl)-2-oxoethyl)-6-(3-(difluoromethoxy)azetidin-1-yl)quinoline-4-carboxamide (Example 136); (R)-N-(2-(4-Cyanothiazolidin-3-yl)-2-oxoethyl)-6-(3-ethyl-3-methylazetidin-1-yl)quinoline-4-carboxamide (Example 137); (R)-N-(2-(4-Cyanothiazolidin-3-yl)-2-oxoethyl)-6-(3-ethyl-3-fluoroazetidin-1-yl)quinoline-4-carboxamide (Example 138); (R)-N-(2-(4-Cyanothiazolidin-3-yl)-2-oxoethyl)-6-(3-(2,2-difluoropropyl)azetidin-1-yl)quinoline-4-carboxamide (Example 140); (R)-N-(2-(4-Cyanothiazolidin-3-yl)-2-oxoethyl)-6-(3-(3,3,3-trifluoropropyl)azetidin-1-yl)quinoline-4-carboxamide (Example 142); (R)-N-(2-(4-Cyanothiazolidin-3-yl)-2-oxoethyl)-6-(3-fluoro-3-(trifluoromethyl)-azetidin-1-yl)quinoline-4-carboxamide (Example 143); (R)-N-(2-(4-Cyanothiazolidin-3-yl)-2-oxoethyl)-6-(3-(2,2-difluoroethyl)azetidin-1-yl)-quinoline-4-carboxamide (Example 144); (R)-N-(2-(4-Cyanothiazolidin-3-yl)-2-oxoethyl)-6-(3-cyclopropylazetidin-1-yl)-quinoline-4-carboxamide (Example 145); (R)-N-(2-(4-Cyanothiazolidin-3-yl)-2-oxoethyl)-6-(3-(2-fluoroethyl)azetidin-1-yl)-quinoline-4-carboxamide (Example 146); (R)-N-(2-(4-Cyanothiazolidin-3-yl)-2-oxoethyl)-6-(3-(1,1-difluoroethyl)azetidin-1-yl)-quinoline-4-carboxamide (Example 147); (R)-N-(2-(4-Cyanothiazolidin-3-yl)-2-oxoethyl)-6-(3-isopropylazetidin-1-yl)quinoline-4-carboxamide (Example 148); (R)-N-(2-(4-Cyanothiazolidin-3-yl)-2-oxoethyl)-6-(3-methoxy-3-methylazetidin-1-yl)-quinoline-4-carboxamide (Example 151); (R)-N-(2-(4-Cyanothiazolidin-3-yl)-2-oxoethyl)-6-(3-ethoxy-3-methylazetidin-1-yl)-quinoline-4-carboxamide (Example 152); (R)-N-(2-(4-Cyanothiazolidin-3-yl)-2-oxoethyl)-6-(3-ethyl-3-hydroxyazetidin-1-yl)quinoline-4-carboxamide (Example 154); (R)-N-(2-(4-Cyanothiazolidin-3-yl)-2-oxoethyl)-6-(3-fluoro-3-(fluoromethyl)azetidin-1-yl)quinoline-4-carboxamide (Example 157); (R)-N-(2-(4-Cyanothiazolidin-3-yl)-2-oxoethyl)-6-(3-(2,2,2-trifluoroethyl)azetidin-1-yl)quinoline-4-carboxamide (Example 158); N-(2-((R)-4-Cyanothiazolidin-3-yl)-2-oxoethyl)-6-(3,3-difluoro-2-methylazetidin-1-yl)quinoline-4-carboxamide (Example 159); (R)-N-(2-(4-Cyanothiazolidin-3-yl)-2-oxoethyl)-6-(3-hydroxy-3-methylazetidin-1-yl)quinoline-4-carboxamide (Example 165); (R)-6-(3-(Acetamidomethyl)-3-methylazetidin-1-yl)-N-(2-(4-cyanothiazolidin-3-yl)-2-oxoethyl)quinoline-4-carboxamide (Example 181); (R)-N-(2-(4-Cyanothiazolidin-3-yl)-2-oxoethyl)-6-(3-fluoro-3-phenylazetidin-1-yl)quinoline-4-carboxamide (Example 182); (R)-N-(2-(4-Cyanothiazolidin-3-yl)-2-oxoethyl)-6-(3-(p-tolyl)azetidin-1-yl)quinoline-4-carboxamide (Example 183); (R)-N-(2-(4-Cyanothiazolidin-3-yl)-2-oxoethyl)-6-(3-(4-fluorophenyl)azetidin-1-yl)quinoline-4-carboxamide (Example 185); (R)-N-(2-(4-Cyanothiazolidin-3-yl)-2-oxoethyl)-6-(3-(m-tolyl)azetidin-1-yl)quinoline-4-carboxamide (Example 186); (R)-6-(3-(4-Chlorobenzyl)azetidin-1-yl)-N-(2-(4-cyanothiazolidin-3-yl)-2-oxoethyl)-quinoline-4-carboxamide (Example 187); (R)-N-(2-(4-Cyanothiazolidin-3-yl)-2-oxoethyl)-6-(3-methyl-3-((methylsulfonyl)-methyl)azetidin-1-yl)quinoline-4-carboxamide (Example 188); and is selected from the group consisting of pharmaceutically acceptable salts thereof.

[0095] In some embodiments, the compound and the pharmaceutically acceptable salt are (R)-N-(2-(4-Cyanothiazolidin-3-yl)-2-oxoethyl)-6-(3,3-dimethylazetidin-1-yl)-quinoline-4-carboxamide (Example 22); (R)-N-(2-(4-Cyanothiazolidin-3-yl)-2-oxoethyl)-6-(3-fluoro-3-methylazetidin-1-yl)-quinoline-4-carboxamide (Example 24); (R)-N-(2-(4-Cyanothiazolidin-3-yl)-2-oxoethyl)-6-(3-(fluoromethyl)-3-methylazetidin-1-yl)quinoline-4-carboxamide (Example 27); (R)-N-(2-(4-Cyanothiazolidin-3-yl)-2-oxoethyl)-6-(3-(difluoromethyl)azetidin-1-yl)-quinoline-4-carboxamide (Example 28); (R)-N-(2-(4-Cyanothiazolidin-3-yl)-2-oxoethyl)-6-(3-(methoxymethyl)-3-methyl-azetidin-1-yl)quinoline-4-carboxamide (Example 29); N-(2-((R)-4-Cyanothiazolidin-3-yl)-2-oxoethyl)-6-((2S,3R)-3-methoxy-2-methyl-azetidin-1-yl)quinoline-4-carboxamide (Example 30); (R)-N-(2-(4-Cyanothiazolidin-3-yl)-2-oxoethyl)-6-(3-cyclopropyl-3-fluoroazetidin-1-yl)quinoline-4-carboxamide (Example 31); (R)-N-(2-(4-Cyanothiazolidin-3-yl)-2-oxoethyl)-6-(3-methoxyazetidin-1-yl)quinoline-4-carboxamide (Example 66); (R)-N-(2-(4-Cyanothiazolidin-3-yl)-2-oxoethyl)-6-(3-(fluoromethyl)azetidin-1-yl)-quinoline-4-carboxamide (Example 113); (R)-N-(2-(4-Cyanothiazolidin-3-yl)-2-oxoethyl)-6-(3-(difluoromethyl)-3-methyl-azetidin-1-yl)quinoline-4-carboxamide (Example 135); (R)-N-(2-(4-Cyanothiazolidin-3-yl)-2-oxoethyl)-6-(3-ethyl-3-fluoroazetidin-1-yl)-quinoline-4-carboxamide (Example 138); (R)-N-(2-(4-Cyanothiazolidin-3-yl)-2-oxoethyl)-6-(3-(2,2-difluoropropyl)azetidin-1-yl)quinoline-4-carboxamide (Example 140); (R)-N-(2-(4-Cyanothiazolidin-3-yl)-2-oxoethyl)-6-(3-fluoro-3-(trifluoromethyl)-azetidin-1-yl)quinoline-4-carboxamide (Example 143); (R)-N-(2-(4-Cyanothiazolidin-3-yl)-2-oxoethyl)-6-(3-(1,1-difluoroethyl)azetidin-1-yl)-quinoline-4-carboxamide (Example 147); (R)-N-(2-(4-Cyanothiazolidin-3-yl)-2-oxoethyl)-6-(3-methoxy-3-methylazetidin-1-yl)quinoline-4-carboxamide (Example 151); (R)-N-(2-(4-Cyanothiazolidin-3-yl)-2-oxoethyl)-6-(3-ethoxy-3-methylazetidin-1-yl)quinoline-4-carboxamide (Example 152); (R)-N-(2-(4-Cyanothiazolidin-3-yl)-2-oxoethyl)-6-(3-fluoro-3-(fluoromethyl)azetidin-1-yl)quinoline-4-carboxamide (Example 157); (R)-N-(2-(4-Cyanothiazolidin-3-yl)-2-oxoethyl)-6-(3-hydroxy-3-methylazetidin-1-yl)quinoline-4-carboxamide (Example 165); and is selected from the group consisting of pharmaceutically acceptable salts thereof.

[0096] In some embodiments, R 2 heterocyclic ring is:

Chemical formula

[0097] In some embodiments, the compound and the pharmaceutically acceptable salt are (R)-N-(2-(4-cyanothiazolidin-3-yl)-2-oxoethyl)-6-(3,3-difluoropyrrolidin-1-yl)-quinoline-4-carboxamide (Example 47); (R)-N-(2-(4-cyanothiazolidin-3-yl)-2-oxoethyl)-6-(3,3-dimethylpyrrolidin-1-yl)-quinoline-4-carboxamide (Example 48); N-(2-((R)-4-Cyanothiazolidin-3-yl)-2-oxoethyl)-6-((3R,4S)-3,4-difluoropyrrolidin-1-yl)-quinoline-4-carboxamide (Example 50); N-(2-((R)-4-Cyanothiazolidin-3-yl)-2-oxoethyl)-6-((S)-3-fluoropyrrolidin-1-yl)-quinoline-4-carboxamide (Example 51); N-(2-((R)-4-Cyanothiazolidin-3-yl)-2-oxoethyl)-6-((R)-3-fluoropyrrolidin-1-yl)-quinoline-4-carboxamide (Example 52); N-(2-((R)-4-Cyanothiazolidin-3-yl)-2-oxoethyl)-6-((S)-3-methylpyrrolidin-1-yl)-quinoline-4-carboxamide (Example 54); N-(2-((R)-4-Cyanothiazolidin-3-yl)-2-oxoethyl)-6-((R)-3-methylpyrrolidin-1-yl)-quinoline-4-carboxamide (Example 55); N-(2-((R)-4-Cyanothiazolidin-3-yl)-2-oxoethyl)-6-((S)-2-(trifluoromethyl)pyrrolidin-1-yl)quinoline-4-carboxamide (Example 56); (R)-N-(2-(4-Cyanothiazolidin-3-yl)-2-oxoethyl)-6-(2,2-dimethylpyrrolidin-1-yl)-quinoline-4-carboxamide (Example 57); N-(2-((R)-4-Cyanothiazolidin-3-yl)-2-oxoethyl)-6-((S)-2-methylpyrrolidin-1-yl)-quinoline-4-carboxamide (Example 65); N-(2-((R)-4-Cyanothiazolidin-3-yl)-2-oxoethyl)-6-((R)-3-methoxypyrrolidin-1-yl)-quinoline-4-carboxamide (Example 161); N-(2-((R)-4-Cyanothiazolidin-3-yl)-2-oxoethyl)-6-((R)-3-hydroxy-3-methylpyrrolidin-1-yl)quinoline-4-carboxamide (Example 167); N-(2-((R)-4-Cyanothiazolidin-3-yl)-2-oxoethyl)-6-((S)-3-hydroxy-3-methylpyrrolidin-1-yl)quinoline-4-carboxamide (Example 168); N-(2-((R)-4-Cyanothiazolidin-3-yl)-2-oxoethyl)-6-((RS)-3-fluoro-3-methylpyrrolidin-1-yl)quinoline-4-carboxamide (Example 198); N-(2-((R)-4-Cyanothiazolidin-3-yl)-2-oxoethyl)-6-((R*)-2-cyclopropylpyrrolidin-1-yl)quinoline-4-carboxamide isomer 1 (Example 199); N-(2-((R)-4-Cyanothiazolidin-3-yl)-2-oxoethyl)-6-((R*)-2-cyclopropylpyrrolidin-1-yl)quinoline-4-carboxamide isomer 2 (Example 200); N-(2-((R)-4-Cyanothiazolidin-3-yl)-2-oxoethyl)-6-((S)-3-methoxypyrrolidin-1-yl)-quinoline-4-carboxamide (Example 207); N-(2-((R)-4-Cyanothiazolidin-3-yl)-2-oxoethyl)-6-((R)-2-methylpyrrolidin-1-yl)-quinoline-4-carboxamide (Example 211); N-(2-((R)-4-Cyanothiazolidin-3-yl)-2-oxoethyl)-6-((S)-2-(methoxymethyl)pyrrolidin-1-yl)quinoline-4-carboxamide (Example 212); N-(2-((R)-4-Cyanothiazolidin-3-yl)-2-oxoethyl)-6-((3S,4S)-3,4-difluoropyrrolidin-1-yl)quinoline-4-carboxamide (Example 213); N-(2-((R)-4-Cyanothiazolidin-3-yl)-2-oxoethyl)-6-((3R,4R)-3,4-difluoropyrrolidin-1-yl)quinoline-4-carboxamide (Example 214); N-(2-((R)-4-Cyanothiazolidin-3-yl)-2-oxoethyl)-6-((R)-3-(hydroxymethyl)pyrrolidin-1-yl)quinoline-4-carboxamide (Example 220); N-(2-((R)-4-Cyanothiazolidin-3-yl)-2-oxoethyl)-6-((S)-3-(hydroxymethyl)pyrrolidin-1-yl)quinoline-4-carboxamide (Example 221); N-(2-((R)-4-Cyanothiazolidin-3-yl)-2-oxoethyl)-6-((RS)-3,3-difluoro-4-hydroxy-pyrrolidin-1-yl)quinoline-4-carboxamide (Example 224); N-(2-((R)-4-Cyanothiazolidin-3-yl)-2-oxoethyl)-6-((3R*,4R*)-3,4-dimethylpyrrolidin-1-yl)quinoline-4-carboxamide isomer 1 (Example 225); N-(2-((R)-4-Cyanothiazolidin-3-yl)-2-oxoethyl)-6-((3R*,4R*)-3,4-dimethylpyrrolidin-1-yl)quinoline-4-carboxamide isomer 2 (Example 226); and is selected from the group consisting of its pharmaceutically acceptable salts.

[0098] In some embodiments, R 2 The heterocyclic ring is: [Chemical formula] and R 2 The heterocyclic ring is optionally substituted with one or more substituents independently selected from the group consisting of halogen, hydroxy, C 1~6 -alkyl, C 3~6 -cycloalkyl, C 1~6 -alkoxy, and C 1~3 -alkoxy-C 1~3 -alkyl, and is C 1~6 -alkyl, C 3~6 -cycloalkyl, C 1~6 -alkoxy, and C 1~3 -alkoxy-C1~3 -Alkyl may further be substituted with one or more halogens. In one embodiment, R 2 The heterocyclic ring is optionally substituted with one or more substituents independently selected from the group consisting of fluoro, hydroxy, C 1~3 -Alkyl, cyclopropyl, C 1~3 -Alkoxy, and C 1~3 -Alkoxy-C 1~3 -Alkyl, and is optionally substituted with one or more substituents independently selected from the group consisting of C 1~3 -Alkyl, cyclopropyl, C 1~3 -Alkoxy, and C 1~3 -Alkoxy-C 1~3 -Alkyl may further be substituted with one or more fluoros. In another embodiment, R 2 The heterocyclic ring is optionally substituted with one or more substituents independently selected from the group consisting of fluoro, hydroxy, methyl, ethyl, fluoromethyl, difluoromethyl, trifluoromethyl, fluoroethyl, difluoroethyl, trifluoroethyl, difluoropropyl, cyclopropyl, methoxy, ethoxy, trifluoromethoxy, trifluoroethoxy, methoxymethyl, and trifluoromethoxymethyl. In another embodiment, R 2 The heterocyclic ring is optionally substituted with one or more substituents independently selected from the group consisting of fluoro, hydroxy, methyl, ethyl, fluoromethyl, methoxy, and trifluoromethoxy.

[0099] In some embodiments, the compound and the pharmaceutically acceptable salt are (R)-N-(2-(4-Cyanothiazolidin-3-yl)-2-oxoethyl)-6-(2-oxopyrrolidin-1-yl)quinoline-4-carboxamide (Example 11); (R)-N-(2-(4-Cyanothiazolidin-3-yl)-2-oxoethyl)-6-(3,3-dimethyl-2-oxopyrrolidin-1-yl)quinoline-4-carboxamide (Example 12); N-(2-((R)-4-Cyano-1,3-thiazolidin-3-yl)-2-oxoethyl)-6-((R*)-3-methyl-2-oxopyrrolidin-1-yl)quinoline-4-carboxamide isomer 1 (Example 201); N-(2-((R)-4-Cyano-1,3-thiazolidin-3-yl)-2-oxoethyl)-6-((R*)-3-methyl-2-oxopyrrolidin-1-yl)quinoline-4-carboxamide isomer 2 (Example 202); and is selected from the group consisting of its pharmaceutically acceptable salts.

[0100] In some embodiments, R 2 heterocyclic ring is:

Chemical formula

[0101] In some embodiments, the compound and the pharmaceutically acceptable salt are (R)-N-(2-(4-Cyanothiazolidin-3-yl)-2-oxoethyl)-6-(1-methyl-1H-pyrazol-4-yl)-quinoline-4-carboxamide (Example 129); (R)-N-(2-(4-Cyanothiazolidin-3-yl)-2-oxoethyl)-6-(1-cyclopropyl-1H-pyrazol-4-yl)-quinoline-4-carboxamide (Example 170); (R)-N-(2-(4-Cyanothiazolidin-3-yl)-2-oxoethyl)-6-(1,3-dimethyl-1H-pyrazol-4-yl)-quinoline-4-carboxamide (Example 171); (R)-N-(2-(4-Cyanothiazolidin-3-yl)-2-oxoethyl)-6-(3,5-dimethyl-1-(tetrahydro-2H-pyran-4-yl)-1H-pyrazol-4-yl)quinoline-4-carboxamide (Example 172); (R)-N-(2-(4-Cyanothiazolidin-3-yl)-2-oxoethyl)-6-(1-(tetrahydro-2H-pyran-4-yl)-1H-pyrazol-4-yl)quinoline-4-carboxamide (Example 173); and are selected from the group consisting of its pharmaceutically acceptable salts.

[0102] In some embodiments, R 2 The heterocyclic ring is:

Chemical formula

[0103] In some embodiments, the compound and the pharmaceutically acceptable salt are (R)-N-(2-(4-Cyanothiazolidin-3-yl)-2-oxoethyl)-6-(1-methyl-1H-pyrazol-5-yl)-quinoline-4-carboxamide (Example 174); N-(2-((R)-4-Cyanothiazolidin-3-yl)-2-oxoethyl)-6-(1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-5-yl)quinoline-4-carboxamide (Example 176); (R)-N-(2-(4-Cyanothiazolidin-3-yl)-2-oxoethyl)-6-(1H-pyrazol-5-yl)quinoline-4-carboxamide (Example 196); (R)-N-(2-(4-Cyanothiazolidin-3-yl)-2-oxoethyl)-6-(1-isopropyl-1H-pyrazol-5-yl)-quinoline-4-carboxamide (Example 197); and is selected from the group consisting of pharmaceutically acceptable salts thereof.

[0104] In some embodiments, R 2 heterocyclic ring is:

Chemical formula

[0105] In some embodiments, the compound and the pharmaceutically acceptable salt are N-(2-((R)-4-cyanothiazolidin-3-yl)-2-oxoethyl)-6-((3S,4S,5R)-4-hydroxy-3,5-dimethylpiperidin-1-yl)quinoline-4-carboxamide (Example 7); (R)-N-(2-(4-Cyanothiazolidin-3-yl)-2-oxoethyl)-6-(4-methoxypiperidin-1-yl)quinoline-4-carboxamide (Example 8); (R)-N-(2-(4-Cyanothiazolidin-3-yl)-2-oxoethyl)-6-(piperidin-1-yl)quinoline-4-carboxamide (Example 32); (R)-N-(2-(4-Cyanothiazolidin-3-yl)-2-oxoethyl)-6-(4,4-dimethylpiperidin-1-yl)quinoline-4-carboxamide (Example 33); (R)-N-(2-(4-Cyanothiazolidin-3-yl)-2-oxoethyl)-6-(4-fluoro-4-methylpiperidin-1-yl)quinoline-4-carboxamide (Example 34); (R)-N-(2-(4-Cyanothiazolidin-3-yl)-2-oxoethyl)-6-(4,4-difluoropiperidin-1-yl)quinoline-4-carboxamide (Example 35); (R)-N-(2-(4-Cyanothiazolidin-3-yl)-2-oxoethyl)-6-(3,3-difluoropiperidin-1-yl)quinoline-4-carboxamide (Example 36); (R)-N-(2-(4-Cyanothiazolidin-3-yl)-2-oxoethyl)-6-(4-(fluoromethyl)-4-methylpiperidin-1-yl)quinoline-4-carboxamide (Example 37); (R)-N-(2-(4-Cyanothiazolidin-3-yl)-2-oxoethyl)-6-(4,4-difluoro-3,3-dimethylpiperidin-1-yl)quinoline-4-carboxamide (Example 38); (R)-N-(2-(4-Cyanothiazolidin-3-yl)-2-oxoethyl)-6-(4-(trifluoromethyl)piperidin-1-yl)quinoline-4-carboxamide (Example 39); N-(2-((R)-4-Cyanothiazolidin-3-yl)-2-oxoethyl)-6-(3-fluoropiperidin-1-yl)quinoline-4-carboxamide (Example 40); N-(2-((R)-4-Cyanothiazolidin-3-yl)-2-oxoethyl)-6-(3-methoxypiperidin-1-yl)quinoline-4-carboxamide (Example 41); (R)-N-(2-(4-Cyanothiazolidin-3-yl)-2-oxoethyl)-6-(4-methoxy-4-methylpiperidin-1-yl)quinoline-4-carboxamide (Example 42); (R)-N-(2-(4-Cyanothiazolidin-3-yl)-2-oxoethyl)-6-(4-isopropoxypiperidin-1-yl)quinoline-4-carboxamide (Example 43); N-(2-((R)-4-Cyanothiazolidin-3-yl)-2-oxoethyl)-6-(4,4-difluoro-2-methylpiperidin-1-yl)quinoline-4-carboxamide (Example 44); N-(2-((R)-4-Cyanothiazolidin-3-yl)-2-oxoethyl)-6-((S)-2-(fluoromethyl)piperidin-1-yl)quinoline-4-carboxamide (Example 45); (R)-N-(2-(4-Cyanothiazolidin-3-yl)-2-oxoethyl)-6-(4-ethyl-4-hydroxypiperidin-1-yl)quinoline-4-carboxamide (Example 189); (R)-N-(2-(4-Cyanothiazolidin-3-yl)-2-oxoethyl)-6-(4-hydroxy-4-methylpiperidin-1-yl)quinoline-4-carboxamide (Example 190); (R)-N-(2-(4-Cyanothiazolidin-3-yl)-2-oxoethyl)-6-(4-ethyl-4-methoxypiperidin-1-yl)quinoline-4-carboxamide (Example 191); (R)-N-(2-(4-Cyanothiazolidin-3-yl)-2-oxoethyl)-6-(4-hydroxy-4-isopropylpiperidin-1-yl)quinoline-4-carboxamide (Example 192); N-(2-((R)-4-Cyanothiazolidin-3-yl)-2-oxoethyl)-6-((3R,4S,5S)-4-hydroxy-3,4,5-trimethylpiperidin-1-yl)quinoline-4-carboxamide (Example 193); (R)-N-(2-(4-Cyanothiazolidin-3-yl)-2-oxoethyl)-6-(4-fluoropiperidin-1-yl)quinoline-4-carboxamide (Example 205); (R)-N-(2-(4-Cyanothiazolidin-3-yl)-2-oxoethyl)-6-(4-fluoro-4-phenylpiperidin-1-yl)-quinoline-4-carboxamide (Example 223); and is selected from the group consisting of pharmaceutically acceptable salts thereof.

[0106] In some embodiments, R 2 heterocyclic ring is:

Chemical formula

[0107] In some embodiments, the compound or pharmaceutically acceptable salt is (R)-N-(2-(4-cyanothiazolidin-3-yl)-2-oxoethyl)-6-(4-oxopiperidin-1-yl)quinoline-4-carboxamide (Example 230), or a pharmaceutically acceptable salt thereof.

[0108] In some embodiments, R 2 heterocyclic ring is:

Chemical formula

[0109] In some embodiments, the compound or a pharmaceutically acceptable salt thereof is (R)-N-(2-(4-cyanothiazolidin-3-yl)-2-oxoethyl)-6-(4-fluoro-1-methylpiperidin-4-yl)quinoline-4-carboxamide (Example 195), or a pharmaceutically acceptable salt thereof.

[0110] In some embodiments, R 2 The heterocyclic ring is:

Chemical formula

[0111] In some embodiments, the compound and the pharmaceutically acceptable salt are (R)-N-(2-(4-cyanothiazolidin-3-yl)-2-oxoethyl)-6-(2-oxopiperidin-1-yl)quinoline-4-carboxamide (Example 14); (R)-N-(2-(4-cyanothiazolidin-3-yl)-2-oxoethyl)-6-(3,3-dimethyl-2-oxopiperidin-1-yl)-quinoline-4-carboxamide (Example 15); N-(2-((R)-4-cyanothiazolidin-3-yl)-2-oxoethyl)-6-((R*)-3-methyl-2-oxopiperidin-1-yl)quinoline-4-carboxamide isomer 1 (Example 203); N-(2-((R)-4-cyanothiazolidin-3-yl)-2-oxoethyl)-6-((R*)-3-methyl-2-oxopiperidin-1-yl)quinoline-4-carboxamide isomer 2 (Example 204); and are selected from the group consisting of its pharmaceutically acceptable salts.

[0112] In some embodiments, R 2 the heterocyclic ring is:

Chemical formula

[0113] In some embodiments, the compound and the pharmaceutically acceptable salt are (R)-N-(2-(4-Cyanothiazolidin-3-yl)-2-oxoethyl)-6-(pyridin-3-yl)quinoline-4-carboxamide (Example 126); (R)-N-(2-(4-Cyanothiazolidin-3-yl)-2-oxoethyl)-6-(2-methylpyridin-3-yl)quinoline-4-carboxamide (Example 128); (R)-N-(2-(4-Cyanothiazolidin-3-yl)-2-oxoethyl)-6-(6-(difluoromethyl)pyridin-3-yl)-quinoline-4-carboxamide (Example 169); (R)-N-(2-(4-Cyanothiazolidin-3-yl)-2-oxoethyl)-6-(6-methylpyridin-3-yl)quinoline-4-carboxamide (Example 177); (R)-N-(2-(4-Cyanothiazolidin-3-yl)-2-oxoethyl)-6-(6-methoxypyridin-3-yl)quinoline-4-carboxamide (Example 178); and are selected from the group consisting of its pharmaceutically acceptable salts.

[0114] In some embodiments, R 2 The heterocyclic ring is:

Chemical Structure

[0115] In some embodiments, the compound or pharmaceutically acceptable salt thereof is (R)-N-(2-(4-cyanothiazolidin-3-yl)-2-oxoethyl)-6-(5,5-dimethyl-5,6-dihydro-4H-pyrrolo[1,2-b]pyrazol-3-yl)quinoline-4-carboxamide (Example 123), or a pharmaceutically acceptable salt thereof.

[0116] In some embodiments, R 2 The heterocyclic ring is:

Chemical formula

[0117] In some embodiments, the compound or pharmaceutically acceptable salt thereof is (R)-N-(2-(4-cyanothiazolidin-3-yl)-2-oxoethyl)-6-(5,6,7,8-tetrahydroimidazo[1,2-a]pyridin-3-yl)quinoline-4-carboxamide (Example 175), or a pharmaceutically acceptable salt thereof.

[0118] In some embodiments, the compound and the pharmaceutically acceptable salt are N-(2-((R)-4-Cyanothiazolidin-3-yl)-2-oxoethyl)-6-((3S,4S,5R)-4-hydroxy-3,5-dimethylpiperidin-1-yl)quinoline-4-carboxamide (Example 7); (R)-N-(2-(4-Cyanothiazolidin-3-yl)-2-oxoethyl)-6-(4-methoxypiperidin-1-yl)-quinoline-4-carboxamide (Example 8); (R)-N-(2-(4-Cyanothiazolidin-3-yl)-2-oxoethyl)-6-(2-oxopyrrolidin-1-yl)quinoline-4-carboxamide (Example 11); (R)-N-(2-(4-Cyanothiazolidin-3-yl)-2-oxoethyl)-6-(3,3-dimethyl-2-oxopyrrolidin-1-yl)quinoline-4-carboxamide (Example 12); (R)-N-(2-(4-Cyanothiazolidin-3-yl)-2-oxoethyl)-6-(2-oxopiperidin-1-yl)quinoline-4-carboxamide (Example 14); (R)-N-(2-(4-Cyanothiazolidin-3-yl)-2-oxoethyl)-6-(3,3-dimethyl-2-oxopiperidin-1-yl)-quinoline-4-carboxamide (Example 15); (R)-N-(2-(4-Cyanothiazolidin-3-yl)-2-oxoethyl)-6-(2,2-dimethylazetidin-1-yl)-quinoline-4-carboxamide (Example 20); (R)-N-(2-(4-Cyanothiazolidin-3-yl)-2-oxoethyl)-6-(3-fluoroazetidin-1-yl)quinoline-4-carboxamide (Example 21); (R)-N-(2-(4-Cyanothiazolidin-3-yl)-2-oxoethyl)-6-(3,3-dimethylazetidin-1-yl)-quinoline-4-carboxamide (Example 22); (R)-N-(2-(4-Cyanothiazolidin-3-yl)-2-oxoethyl)-6-(3,3-difluoroazetidin-1-yl)quinoline-4-carboxamide (Example 23); (R)-N-(2-(4-Cyanothiazolidin-3-yl)-2-oxoethyl)-6-(3-fluoro-3-methylazetidin-1-yl)quinoline-4-carboxamide (Example 24); (R)-N-(2-(4-Cyanothiazolidin-3-yl)-2-oxoethyl)-6-(3-methylazetidin-1-yl)quinoline-4-carboxamide (Example 25); (R)-N-(2-(4-Cyanothiazolidin-3-yl)-2-oxoethyl)-6-(3-(trifluoromethyl)azetidin-1-yl)quinoline-4-carboxamide (Example 26); (R)-N-(2-(4-Cyanothiazolidin-3-yl)-2-oxoethyl)-6-(3-(fluoromethyl)-3-methylazetidin-1-yl)quinoline-4-carboxamide (Example 27); (R)-N-(2-(4-Cyanothiazolidin-3-yl)-2-oxoethyl)-6-(3-(difluoromethyl)azetidin-1-yl)quinoline-4-carboxamide (Example 28); (R)-N-(2-(4-Cyanothiazolidin-3-yl)-2-oxoethyl)-6-(3-(methoxymethyl)-3-methyl-azetidin-1-yl)quinoline-4-carboxamide (Example 29); N-(2-((R)-4-Cyanothiazolidin-3-yl)-2-oxoethyl)-6-((2S,3R)-3-methoxy-2-methyl-azetidin-1-yl)quinoline-4-carboxamide (Example 30); (R)-N-(2-(4-Cyanothiazolidin-3-yl)-2-oxoethyl)-6-(3-cyclopropyl-3-fluoroazetidin-1-yl)quinoline-4-carboxamide (Example 31); (R)-N-(2-(4-Cyanothiazolidin-3-yl)-2-oxoethyl)-6-(piperidin-1-yl)quinoline-4-carboxamide (Example 32); (R)-N-(2-(4-Cyanothiazolidin-3-yl)-2-oxoethyl)-6-(4,4-dimethylpiperidin-1-yl)quinoline-4-carboxamide (Example 33); (R)-N-(2-(4-Cyanothiazolidin-3-yl)-2-oxoethyl)-6-(4-fluoro-4-methylpiperidin-1-yl)quinoline-4-carboxamide (Example 34); (R)-N-(2-(4-Cyanothiazolidin-3-yl)-2-oxoethyl)-6-(4,4-difluoropiperidin-1-yl)quinoline-4-carboxamide (Example 35); (R)-N-(2-(4-Cyanothiazolidin-3-yl)-2-oxoethyl)-6-(3,3-difluoropiperidin-1-yl)quinoline-4-carboxamide (Example 36); (R)-N-(2-(4-Cyanothiazolidin-3-yl)-2-oxoethyl)-6-(4-(fluoromethyl)-4-methylpiperidin-1-yl)quinoline-4-carboxamide (Example 37); (R)-N-(2-(4-Cyanothiazolidin-3-yl)-2-oxoethyl)-6-(4,4-difluoro-3,3-dimethylpiperidin-1-yl)quinoline-4-carboxamide (Example 38); (R)-N-(2-(4-Cyanothiazolidin-3-yl)-2-oxoethyl)-6-(4-(trifluoromethyl)piperidin-1-yl)quinoline-4-carboxamide (Example 39); N-(2-((R)-4-Cyanothiazolidin-3-yl)-2-oxoethyl)-6-(3-fluoropiperidin-1-yl)quinoline-4-carboxamide (Example 40); N-(2-((R)-4-Cyanothiazolidin-3-yl)-2-oxoethyl)-6-(3-methoxypiperidin-1-yl)quinoline-4-carboxamide (Example 41); (R)-N-(2-(4-Cyanothiazolidin-3-yl)-2-oxoethyl)-6-(4-methoxy-4-methylpiperidin-1-yl)quinoline-4-carboxamide (Example 42); (R)-N-(2-(4-Cyanothiazolidin-3-yl)-2-oxoethyl)-6-(4-isopropoxypiperidin-1-yl)quinoline-4-carboxamide (Example 43); N-(2-((R)-4-Cyanothiazolidin-3-yl)-2-oxoethyl)-6-(4,4-difluoro-2-methylpiperidin-1-yl)quinoline-4-carboxamide (Example 44); N-(2-((R)-4-Cyanothiazolidin-3-yl)-2-oxoethyl)-6-((S)-2-(fluoromethyl)piperidin-1-yl)quinoline-4-carboxamide (Example 45); (R)-N-(2-(4-Cyanothiazolidin-3-yl)-2-oxoethyl)-6-(3,3-difluoropyrrolidin-1-yl)quinoline-4-carboxamide (Example 47); (R)-N-(2-(4-Cyanothiazolidin-3-yl)-2-oxoethyl)-6-(3,3-dimethylpyrrolidin-1-yl)quinoline-4-carboxamide (Example 48); N-(2-((R)-4-Cyanothiazolidin-3-yl)-2-oxoethyl)-6-((3R,4S)-3,4-difluoropyrrolidin-1-yl)quinoline-4-carboxamide (Example 50); N-(2-((R)-4-Cyanothiazolidin-3-yl)-2-oxoethyl)-6-((S)-3-fluoropyrrolidin-1-yl)quinoline-4-carboxamide (Example 51); N-(2-((R)-4-Cyanothiazolidin-3-yl)-2-oxoethyl)-6-((R)-3-fluoropyrrolidin-1-yl)quinoline-4-carboxamide (Example 52); N-(2-((R)-4-Cyanothiazolidin-3-yl)-2-oxoethyl)-6-(hexahydrocyclopenta[c]pyrrol-2(1H)-yl)quinoline-4-carboxamide (Example 53); N-(2-((R)-4-Cyanothiazolidin-3-yl)-2-oxoethyl)-6-((S)-3-methylpyrrolidin-1-yl)quinoline-4-carboxamide (Example 54); N-(2-((R)-4-Cyanothiazolidin-3-yl)-2-oxoethyl)-6-((R)-3-methylpyrrolidin-1-yl)quinoline-4-carboxamide (Example 55); N-(2-((R)-4-Cyanothiazolidin-3-yl)-2-oxoethyl)-6-((S)-2-(trifluoromethyl)pyrrolidin-1-yl)quinoline-4-carboxamide (Example 56); (R)-N-(2-(4-Cyanothiazolidin-3-yl)-2-oxoethyl)-6-(2,2-dimethylpyrrolidin-1-yl)quinoline-4-carboxamide (Example 57); N-(2-((R)-4-Cyanothiazolidin-3-yl)-2-oxoethyl)-6-((R)-3-fluoroazepan-1-yl)quinoline-4-carboxamide (Example 59); N-(2-((R)-4-Cyanothiazolidin-3-yl)-2-oxoethyl)-6-((S)-3-fluoroazepan-1-yl)quinoline-4-carboxamide (Example 60); N-(2-((R)-4-Cyanothiazolidin-3-yl)-2-oxoethyl)-6-((S)-2-methylpyrrolidin-1-yl)quinoline-4-carboxamide (Example 65); (R)-N-(2-(4-Cyanothiazolidin-3-yl)-2-oxoethyl)-6-(3-methoxyazetidin-1-yl)quinoline-4-carboxamide (Example 66); (R)-N-(2-(4-Cyanothiazolidin-3-yl)-2-oxoethyl)-6-(3-(fluoromethyl)azetidin-1-yl)quinoline-4-carboxamide (Example 113); (R)-N-(2-(4-Cyanothiazolidin-3-yl)-2-oxoethyl)-6-(4,5,6,7-tetrahydro-1H-indazol-1-yl)quinoline-4-carboxamide (Example 114); (R)-N-(2-(4-Cyanothiazolidin-3-yl)-2-oxoethyl)-6-(4,5,6,7-tetrahydro-2H-indazol-2-yl)quinoline-4-carboxamide (Example 115); (R)-N-(2-(4-Cyanothiazolidin-3-yl)-2-oxoethyl)-6-(5-methyl-3-(trifluoromethyl)-1H-pyrazol-1-yl)quinoline-4-carboxamide (Example 116); (R)-N-(2-(4-Cyanothiazolidin-3-yl)-2-oxoethyl)-6-(6,6-dimethyl-5,6-dihydrocyclopenta[c]pyrazol-2(4H)-yl)quinoline-4-carboxamide (Example 117); (R)-N-(2-(4-Cyanothiazolidin-3-yl)-2-oxoethyl)-6-(3-(trifluoromethyl)-1H-pyrazol-1-yl)quinoline-4-carboxamide (Example 118); (R)-N-(2-(4-Cyanothiazolidin-3-yl)-2-oxoethyl)-6-(4,6-difluoro-1H-indol-1-yl)-quinoline-4-carboxamide (Example 119); (R)-N-(2-(4-Cyanothiazolidin-3-yl)-2-oxoethyl)-6-(5-fluoro-1H-indol-1-yl)quinoline-4-carboxamide (Example 120); (R)-N-(2-(4-Cyanothiazolidin-3-yl)-2-oxoethyl)-6-(3-methyl-1H-pyrrol-1-yl)-quinoline-4-carboxamide (Example 121); (R)-N-(2-(4-Cyanothiazolidin-3-yl)-2-oxoethyl)-6-(3-morpholinoazetidin-1-yl)-quinoline-4-carboxamide (Example 122); (R)-N-(2-(4-Cyanothiazolidin-3-yl)-2-oxoethyl)-6-(5,5-dimethyl-5,6-dihydro-4H-pyrrolo[1,2-b]pyrazol-3-yl)quinoline-4-carboxamide (Example 123); (R)-N-(2-(4-Cyanothiazolidin-3-yl)-2-oxoethyl)-6-(2-fluoropyridin-4-yl)quinoline-4-carboxamide (Example 124); (R)-N-(2-(4-Cyanothiazolidin-3-yl)-2-oxoethyl)-6-(5-fluoropyridin-2-yl)quinoline-4-carboxamide (Example 125); (R)-N-(2-(4-Cyanothiazolidin-3-yl)-2-oxoethyl)-6-(pyridin-3-yl)quinoline-4-carboxamide (Example 126); (R)-N-(2-(4-Cyanothiazolidin-3-yl)-2-oxoethyl)-6-(pyrimidin-5-yl)quinoline-4-carboxamide (Example 127); (R)-N-(2-(4-Cyanothiazolidin-3-yl)-2-oxoethyl)-6-(2-methylpyridin-3-yl)quinoline-4-carboxamide (Example 128); (R)-N-(2-(4-Cyanothiazolidin-3-yl)-2-oxoethyl)-6-(1-methyl-1H-pyrazol-4-yl)-quinoline-4-carboxamide (Example 129); (R)-N-(2-(4-Cyanothiazolidin-3-yl)-2-oxoethyl)-6-(3-((trifluoromethoxy)methyl)-azetidin-1-yl)quinoline-4-carboxamide (Example 130); (R)-N-(2-(4-Cyanothiazolidin-3-yl)-2-oxoethyl)-6-(3-methyl-3-(2,2,2-trifluoroethyl)-azetidin-1-yl)quinoline-4-carboxamide (Example 131); (R)-N-(2-(4-Cyanothiazolidin-3-yl)-2-oxoethyl)-6-(3-(trifluoromethoxy)azetidin-1-yl)quinoline-4-carboxamide (Example 132); (R)-N-(2-(4-Cyanothiazolidin-3-yl)-2-oxoethyl)-6-(3-(2,2-difluoroethyl)-3-methyl-azetidin-1-yl)quinoline-4-carboxamide (Example 133); (R)-N-(2-(4-Cyanothiazolidin-3-yl)-2-oxoethyl)-6-(3-cyclopropyl-3-methylazetidin-1-yl)quinoline-4-carboxamide (Example 134); (R)-N-(2-(4-Cyanothiazolidin-3-yl)-2-oxoethyl)-6-(3-(difluoromethyl)-3-methyl-azetidin-1-yl)quinoline-4-carboxamide (Example 135); (R)-N-(2-(4-Cyanothiazolidin-3-yl)-2-oxoethyl)-6-(3-(difluoromethoxy)azetidin-1-yl)-quinoline-4-carboxamide (Example 136); (R)-N-(2-(4-Cyanothiazolidin-3-yl)-2-oxoethyl)-6-(3-ethyl-3-methylazetidin-1-yl)-quinoline-4-carboxamide (Example 137); (R)-N-(2-(4-Cyanothiazolidin-3-yl)-2-oxoethyl)-6-(3-ethyl-3-fluoroazetidin-1-yl)-quinoline-4-carboxamide (Example 138); (R)-N-(2-(4-Cyanothiazolidin-3-yl)-2-oxoethyl)-6-(3-(2,2-difluoropropyl)azetidin-1-yl)quinoline-4-carboxamide (Example 140); (R)-N-(2-(4-Cyanothiazolidin-3-yl)-2-oxoethyl)-6-(3-(3,3,3-trifluoropropyl)azetidin-1-yl)quinoline-4-carboxamide (Example 142); (R)-N-(2-(4-Cyanothiazolidin-3-yl)-2-oxoethyl)-6-(3-fluoro-3-(trifluoromethyl)-azetidin-1-yl)quinoline-4-carboxamide (Example 143); (R)-N-(2-(4-Cyanothiazolidin-3-yl)-2-oxoethyl)-6-(3-(2,2-difluoroethyl)azetidin-1-yl)-quinoline-4-carboxamide (Example 144); (R)-N-(2-(4-Cyanothiazolidin-3-yl)-2-oxoethyl)-6-(3-cyclopropylazetidin-1-yl)-quinoline-4-carboxamide (Example 145); (R)-N-(2-(4-Cyanothiazolidin-3-yl)-2-oxoethyl)-6-(3-(2-fluoroethyl)azetidin-1-yl)-quinoline-4-carboxamide (Example 146); (R)-N-(2-(4-Cyanothiazolidin-3-yl)-2-oxoethyl)-6-(3-(1,1-difluoroethyl)azetidin-1-yl)-quinoline-4-carboxamide (Example 147); (R)-N-(2-(4-Cyanothiazolidin-3-yl)-2-oxoethyl)-6-(3-isopropylazetidin-1-yl)quinoline-4-carboxamide (Example 148); (R)-N-(2-(4-Cyanothiazolidin-3-yl)-2-oxoethyl)-6-(3-methoxy-3-methylazetidin-1-yl)-quinoline-4-carboxamide (Example 151); (R)-N-(2-(4-Cyanothiazolidin-3-yl)-2-oxoethyl)-6-(3-ethoxy-3-methylazetidin-1-yl)-quinoline-4-carboxamide (Example 152); (R)-N-(2-(4-Cyanothiazolidin-3-yl)-2-oxoethyl)-6-(3-ethyl-3-hydroxyazetidin-1-yl)-quinoline-4-carboxamide (Example 154); 6-(6-Azabicyclo[3.2.0]heptan-6-yl)-N-(2-((R)-4-cyanothiazolidin-3-yl)-2-oxoethyl)-quinoline-4-carboxamide (Example 156); (R)-N-(2-(4-Cyanothiazolidin-3-yl)-2-oxoethyl)-6-(3-fluoro-3-(fluoromethyl)azetidin-1-yl)quinoline-4-carboxamide (Example 157); (R)-N-(2-(4-Cyanothiazolidin-3-yl)-2-oxoethyl)-6-(3-(2,2,2-trifluoroethyl)azetidin-1-yl)quinoline-4-carboxamide (Example 158); N-(2-((R)-4-Cyanothiazolidin-3-yl)-2-oxoethyl)-6-(3,3-difluoro-2-methylazetidin-1-yl)quinoline-4-carboxamide (Example 159); N-(2-((R)-4-Cyanothiazolidin-3-yl)-2-oxoethyl)-6-(6,6-difluoro-3-azabicyclo[3.1.0]hexan-3-yl)quinoline-4-carboxamide (Example 160); N-(2-((R)-4-Cyanothiazolidin-3-yl)-2-oxoethyl)-6-((R)-3-methoxypyrrolidin-1-yl)-quinoline-4-carboxamide (Example 161); (R)-N-(2-(4-Cyanothiazolidin-3-yl)-2-oxoethyl)-6-(3-hydroxy-3-methylazetidin-1-yl)-quinoline-4-carboxamide (Example 165); N-(2-((R)-4-Cyanothiazolidin-3-yl)-2-oxoethyl)-6-((R)-3-hydroxy-3-methylpyrrolidin-1-yl)quinoline-4-carboxamide (Example 167); N-(2-((R)-4-Cyanothiazolidin-3-yl)-2-oxoethyl)-6-((S)-3-hydroxy-3-methylpyrrolidin-1-yl)quinoline-4-carboxamide (Example 168); (R)-N-(2-(4-Cyanothiazolidin-3-yl)-2-oxoethyl)-6-(6-(difluoromethyl)pyridin-3-yl)-quinoline-4-carboxamide (Example 169); (R)-N-(2-(4-Cyanothiazolidin-3-yl)-2-oxoethyl)-6-(1-cyclopropyl-1H-pyrazol-4-yl)-quinoline-4-carboxamide (Example 170); (R)-N-(2-(4-Cyanothiazolidin-3-yl)-2-oxoethyl)-6-(1,3-dimethyl-1H-pyrazol-4-yl)-quinoline-4-carboxamide (Example 171); (R)-N-(2-(4-Cyanothiazolidin-3-yl)-2-oxoethyl)-6-(3,5-dimethyl-1-(tetrahydro-2H-pyran-4-yl)-1H-pyrazol-4-yl)quinoline-4-carboxamide (Example 172); (R)-N-(2-(4-Cyanothiazolidin-3-yl)-2-oxoethyl)-6-(1-(tetrahydro-2H-pyran-4-yl)-1H-pyrazol-4-yl)quinoline-4-carboxamide (Example 173); (R)-N-(2-(4-Cyanothiazolidin-3-yl)-2-oxoethyl)-6-(1-methyl-1H-pyrazol-5-yl)-quinoline-4-carboxamide (Example 174); (R)-N-(2-(4-Cyanothiazolidin-3-yl)-2-oxoethyl)-6-(5,6,7,8-tetrahydroimidazo[1,2-a]-pyridin-3-yl)quinoline-4-carboxamide (Example 175); N-(2-((R)-4-Cyanothiazolidin-3-yl)-2-oxoethyl)-6-(1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-5-yl)quinoline-4-carboxamide (Example 176); (R)-N-(2-(4-Cyanothiazolidin-3-yl)-2-oxoethyl)-6-(6-methylpyridin-3-yl)quinoline-4-carboxamide (Example 177); (R)-N-(2-(4-Cyanothiazolidin-3-yl)-2-oxoethyl)-6-(6-methoxypyridin-3-yl)quinoline-4-carboxamide (Example 178); (R)-6-(3-(Acetamidomethyl)-3-methylazetidin-1-yl)-N-(2-(4-cyanothiazolidin-3-yl)-2-oxoethyl)quinoline-4-carboxamide (Example 181); (R)-N-(2-(4-Cyanothiazolidin-3-yl)-2-oxoethyl)-6-(3-fluoro-3-phenylazetidin-1-yl)-quinoline-4-carboxamide (Example 182); (R)-N-(2-(4-Cyanothiazolidin-3-yl)-2-oxoethyl)-6-(3-(p-tolyl)azetidin-1-yl)quinoline-4-carboxamide (Example 183); (R)-N-(2-(4-Cyanothiazolidin-3-yl)-2-oxoethyl)-6-(3-(4-fluorophenyl)azetidin-1-yl)-quinoline-4-carboxamide (Example 185); (R)-N-(2-(4-Cyanothiazolidin-3-yl)-2-oxoethyl)-6-(3-(m-tolyl)azetidin-1-yl)quinoline-4-carboxamide (Example 186); (R)-6-(3-(4-Chlorobenzyl)azetidin-1-yl)-N-(2-(4-cyanothiazolidin-3-yl)-2-oxoethyl)-quinoline-4-carboxamide (Example 187); (R)-N-(2-(4-Cyanothiazolidin-3-yl)-2-oxoethyl)-6-(3-methyl-3-((methylsulfonyl)-methyl)azetidin-1-yl)quinoline-4-carboxamide (Example 188); (R)-N-(2-(4-Cyanothiazolidin-3-yl)-2-oxoethyl)-6-(4-ethyl-4-hydroxypiperidin-1-yl)-quinoline-4-carboxamide (Example 189); (R)-N-(2-(4-Cyanothiazolidin-3-yl)-2-oxoethyl)-6-(4-hydroxy-4-methylpiperidin-1-yl)quinoline-4-carboxamide (Example 190); (R)-N-(2-(4-Cyanothiazolidin-3-yl)-2-oxoethyl)-6-(4-ethyl-4-methoxypiperidin-1-yl)-quinoline-4-carboxamide (Example 191); (R)-N-(2-(4-Cyanothiazolidin-3-yl)-2-oxoethyl)-6-(4-hydroxy-4-isopropylpiperidin-1-yl)quinoline-4-carboxamide (Example 192); N-(2-((R)-4-Cyanothiazolidin-3-yl)-2-oxoethyl)-6-((3R,4S,5S)-4-hydroxy-3,4,5-trimethylpiperidin-1-yl)quinoline-4-carboxamide (Example 193); (R)-N-(2-(4-Cyanothiazolidin-3-yl)-2-oxoethyl)-6-(4-fluoro-1-methylpiperidin-4-yl)-quinoline-4-carboxamide (Example 195); (R)-N-(2-(4-Cyanothiazolidin-3-yl)-2-oxoethyl)-6-(1H-pyrazol-5-yl)quinoline-4-carboxamide (Example 196); (R)-N-(2-(4-Cyanothiazolidin-3-yl)-2-oxoethyl)-6-(1-isopropyl-1H-pyrazol-5-yl)-quinoline-4-carboxamide (Example 197); N-(2-((R)-4-Cyanothiazolidin-3-yl)-2-oxoethyl)-6-((RS)-3-fluoro-3-methylpyrrolidin-1-yl)quinoline-4-carboxamide (Example 198); N-(2-((R)-4-Cyanothiazolidin-3-yl)-2-oxoethyl)-6-((R*)-2-cyclopropylpyrrolidin-1-yl)quinoline-4-carboxamide isomer 1 (Example 199); N-(2-((R)-4-Cyanothiazolidin-3-yl)-2-oxoethyl)-6-((R*)-2-cyclopropylpyrrolidin-1-yl)quinoline-4-carboxamide isomer 2 (Example 200); N-(2-((R)-4-Cyanothiazolidin-3-yl)-2-oxoethyl)-6-((R*)-3-methyl-2-oxopyrrolidin-1-yl)quinoline-4-carboxamide isomer 1 (Example 201); N-(2-((R)-4-Cyanothiazolidin-3-yl)-2-oxoethyl)-6-((R*)-3-methyl-2-oxopyrrolidin-1-yl)quinoline-4-carboxamide isomer 2 (Example 202); N-(2-((R)-4-Cyanothiazolidin-3-yl)-2-oxoethyl)-6-((R*)-3-methyl-2-oxopiperidin-1-yl)quinoline-4-carboxamide isomer 1 (Example 203); N-(2-((R)-4-Cyanothiazolidin-3-yl)-2-oxoethyl)-6-((R*)-3-methyl-2-oxopiperidin-1-yl)quinoline-4-carboxamide isomer 2 (Example 204); (R)-N-(2-(4-Cyanothiazolidin-3-yl)-2-oxoethyl)-6-(4-fluoropiperidin-1-yl)quinoline-4-carboxamide (Example 205); 6-(3-Azabicyclo[3.1.0]hexan-3-yl)-N-(2-((R)-4-cyanothiazolidin-3-yl)-2-oxoethyl)-quinoline-4-carboxamide (Example 206); N-(2-((R)-4-Cyanothiazolidin-3-yl)-2-oxoethyl)-6-((S)-3-methoxypyrrolidin-1-yl)-quinoline-4-carboxamide (Example 207); N-(2-((R)-4-Cyanothiazolidin-3-yl)-2-oxoethyl)-6-((1R,5S,6R)-6-(trifluoromethyl)-3-azabicyclo[3.1.0]hexan-3-yl)quinoline-4-carboxamide (Example 208); (R)-6-(7-Azabicyclo[2.2.1]heptan-7-yl)-N-(2-(4-cyanothiazolidin-3-yl)-2-oxoethyl)-quinoline-4-carboxamide (Example 209); 6-(2-Azabicyclo[2.2.1]heptan-2-yl)-N-(2-((R)-4-cyanothiazolidin-3-yl)-2-oxoethyl)-quinoline-4-carboxamide (Example 210); N-(2-((R)-4-Cyanothiazolidin-3-yl)-2-oxoethyl)-6-((R)-2-methylpyrrolidin-1-yl)-quinoline-4-carboxamide (Example 211); N-(2-((R)-4-Cyanothiazolidin-3-yl)-2-oxoethyl)-6-((S)-2-(methoxymethyl)pyrrolidin-1-yl)quinoline-4-carboxamide (Example 212); N-(2-((R)-4-Cyanothiazolidin-3-yl)-2-oxoethyl)-6-((3S,4S)-3,4-difluoropyrrolidin-1-yl)quinoline-4-carboxamide (Example 213); N-(2-((R)-4-Cyanothiazolidin-3-yl)-2-oxoethyl)-6-((3R,4R)-3,4-difluoropyrrolidin-1-yl)quinoline-4-carboxamide (Example 214); (R)-N-(2-(4-Cyanothiazolidin-3-yl)-2-oxoethyl)-6-(2-phenyl-1H-imidazol-1-yl)-quinoline-4-carboxamide (Example 217); (R)-N-(2-(4-Cyanothiazolidin-3-yl)-2-oxoethyl)-6-(3-phenyl-1H-pyrrol-1-yl)-quinoline-4-carboxamide (Example 218); (R)-N-(2-(4-Cyanothiazolidin-3-yl)-2-oxoethyl)-6-(4,5,6,7-tetrahydro-1H-indol-1-yl)quinoline-4-carboxamide (Example 219); N-(2-((R)-4-Cyanothiazolidin-3-yl)-2-oxoethyl)-6-((R)-3-(hydroxymethyl)pyrrolidin-1-yl)quinoline-4-carboxamide (Example 220); N-(2-((R)-4-Cyanothiazolidin-3-yl)-2-oxoethyl)-6-((S)-3-(hydroxymethyl)pyrrolidin-1-yl)quinoline-4-carboxamide (Example 221); (R)-N-(2-(4-Cyanothiazolidin-3-yl)-2-oxoethyl)-6-(4-fluoro-4-phenylpiperidin-1-yl)-quinoline-4-carboxamide (Example 223); N-(2-((R)-4-Cyanothiazolidin-3-yl)-2-oxoethyl)-6-((RS)-3,3-difluoro-4-hydroxy-pyrrolidin-1-yl)quinoline-4-carboxamide (Example 224); N-(2-((R)-4-Cyanothiazolidin-3-yl)-2-oxoethyl)-6-((3R*,4R*)-3,4-dimethylpyrrolidin-1-yl)quinoline-4-carboxamide isomer 1 (Example 225); N-(2-((R)-4-Cyanothiazolidin-3-yl)-2-oxoethyl)-6-((3R*,4R*)-3,4-dimethylpyrrolidin-1-yl)quinoline-4-carboxamide isomer 2 (Example 226); (R)-N-(2-(4-Cyanothiazolidin-3-yl)-2-oxoethyl)-6-(4-oxopiperidin-1-yl)quinoline-4-carboxamide (Example 230); and is selected from the group consisting of its pharmaceutically acceptable salts.

[0119] In some embodiments, the compound and the pharmaceutically acceptable salt are N-(2-((R)-4-Cyanothiazolidin-3-yl)-2-oxoethyl)-6-((3S,4S,5R)-4-hydroxy-3,5-dimethylpiperidin-1-yl)quinoline-4-carboxamide (Example 7); (R)-N-(2-(4-Cyanothiazolidin-3-yl)-2-oxoethyl)-6-(4-methoxypiperidin-1-yl)-quinoline-4-carboxamide (Example 8); (R)-N-(2-(4-Cyanothiazolidin-3-yl)-2-oxoethyl)-6-(3,3-dimethyl-2-oxopyrrolidin-1-yl)quinoline-4-carboxamide (Example 12); (R)-N-(2-(4-Cyanothiazolidin-3-yl)-2-oxoethyl)-6-(3,3-dimethyl-2-oxopiperidin-1-yl)quinoline-4-carboxamide (Example 15); (R)-N-(2-(4-Cyanothiazolidin-3-yl)-2-oxoethyl)-6-(3,3-dimethylazetidin-1-yl)quinoline-4-carboxamide (Example 22); (R)-N-(2-(4-Cyanothiazolidin-3-yl)-2-oxoethyl)-6-(3-fluoro-3-methylazetidin-1-yl)quinoline-4-carboxamide (Example 24); (R)-N-(2-(4-Cyanothiazolidin-3-yl)-2-oxoethyl)-6-(3-(fluoromethyl)-3-methylazetidin-1-yl)quinoline-4-carboxamide (Example 27); (R)-N-(2-(4-Cyanothiazolidin-3-yl)-2-oxoethyl)-6-(3-(difluoromethyl)azetidin-1-yl)quinoline-4-carboxamide (Example 28); (R)-N-(2-(4-Cyanothiazolidin-3-yl)-2-oxoethyl)-6-(3-(methoxymethyl)-3-methyl-azetidin-1-yl)quinoline-4-carboxamide (Example 29); N-(2-((R)-4-Cyanothiazolidin-3-yl)-2-oxoethyl)-6-((2S,3R)-3-methoxy-2-methyl-azetidin-1-yl)quinoline-4-carboxamide (Example 30); (R)-N-(2-(4-Cyanothiazolidin-3-yl)-2-oxoethyl)-6-(3-cyclopropyl-3-fluoroazetidin-1-yl)quinoline-4-carboxamide (Example 31); (R)-N-(2-(4-Cyanothiazolidin-3-yl)-2-oxoethyl)-6-(piperidin-1-yl)quinoline-4-carboxamide (Example 32); (R)-N-(2-(4-Cyanothiazolidin-3-yl)-2-oxoethyl)-6-(4-fluoro-4-methylpiperidin-1-yl)quinoline-4-carboxamide (Example 34); N-(2-((R)-4-Cyanothiazolidin-3-yl)-2-oxoethyl)-6-(3-methoxypiperidin-1-yl)-quinoline-4-carboxamide (Example 41); (R)-N-(2-(4-Cyanothiazolidin-3-yl)-2-oxoethyl)-6-(4-methoxy-4-methylpiperidin-1-yl)quinoline-4-carboxamide (Example 42); (R)-N-(2-(4-Cyanothiazolidin-3-yl)-2-oxoethyl)-6-(4-isopropoxypiperidin-1-yl)quinoline-4-carboxamide (Example 43); N-(2-((R)-4-Cyanothiazolidin-3-yl)-2-oxoethyl)-6-((3R,4S)-3,4-difluoropyrrolidin-1-yl)quinoline-4-carboxamide (Example 50); N-(2-((R)-4-Cyanothiazolidin-3-yl)-2-oxoethyl)-6-((R)-3-fluoropyrrolidin-1-yl)quinoline-4-carboxamide (Example 52); (R)-N-(2-(4-Cyanothiazolidin-3-yl)-2-oxoethyl)-6-(3-methoxyazetidin-1-yl)quinoline-4-carboxamide (Example 66); (R)-N-(2-(4-Cyanothiazolidin-3-yl)-2-oxoethyl)-6-(3-(fluoromethyl)azetidin-1-yl)quinoline-4-carboxamide (Example 113); (R)-N-(2-(4-Cyanothiazolidin-3-yl)-2-oxoethyl)-6-(3-(difluoromethyl)-3-methylazetidin-1-yl)quinoline-4-carboxamide (Example 135); (R)-N-(2-(4-Cyanothiazolidin-3-yl)-2-oxoethyl)-6-(3-ethyl-3-fluoroazetidin-1-yl)quinoline-4-carboxamide (Example 138); (R)-N-(2-(4-Cyanothiazolidin-3-yl)-2-oxoethyl)-6-(3-(2,2-difluoropropyl)azetidin-1-yl)quinoline-4-carboxamide (Example 140); (R)-N-(2-(4-Cyanothiazolidin-3-yl)-2-oxoethyl)-6-(3-fluoro-3-(trifluoromethyl)azetidin-1-yl)quinoline-4-carboxamide (Example 143); (R)-N-(2-(4-Cyanothiazolidin-3-yl)-2-oxoethyl)-6-(3-(1,1-difluoroethyl)azetidin-1-yl)quinoline-4-carboxamide (Example 147); (R)-N-(2-(4-Cyanothiazolidin-3-yl)-2-oxoethyl)-6-(3-methoxy-3-methylazetidin-1-yl)quinoline-4-carboxamide (Example 151); (R)-N-(2-(4-Cyanothiazolidin-3-yl)-2-oxoethyl)-6-(3-ethoxy-3-methylazetidin-1-yl)quinoline-4-carboxamide (Example 152); (R)-N-(2-(4-Cyanothiazolidin-3-yl)-2-oxoethyl)-6-(3-fluoro-3-(fluoromethyl)azetidin-1-yl)quinoline-4-carboxamide (Example 157); N-(2-((R)-4-Cyanothiazolidin-3-yl)-2-oxoethyl)-6-((R)-3-methoxypyrrolidin-1-yl)quinoline-4-carboxamide (Example 161); (R)-N-(2-(4-Cyanothiazolidin-3-yl)-2-oxoethyl)-6-(3-hydroxy-3-methylazetidin-1-yl)quinoline-4-carboxamide (Example 165); (R)-N-(2-(4-Cyanothiazolidin-3-yl)-2-oxoethyl)-6-(6-(difluoromethyl)pyridin-3-yl)quinoline-4-carboxamide (Example 169); (R)-N-(2-(4-Cyanothiazolidin-3-yl)-2-oxoethyl)-6-(3,5-dimethyl-1-(tetrahydro-2H-pyran-4-yl)-1H-pyrazol-4-yl)quinoline-4-carboxamide (Example 172); (R)-N-(2-(4-Cyanothiazolidin-3-yl)-2-oxoethyl)-6-(5,6,7,8-tetrahydroimidazo[1,2-a]pyridin-3-yl)quinoline-4-carboxamide (Example 175); (R)-N-(2-(4-Cyanothiazolidin-3-yl)-2-oxoethyl)-6-(4-ethyl-4-hydroxypiperidin-1-yl)quinoline-4-carboxamide (Example 189); (R)-N-(2-(4-Cyanothiazolidin-3-yl)-2-oxoethyl)-6-(4-hydroxy-4-methylpiperidin-1-yl)quinoline-4-carboxamide (Example 190); (R)-N-(2-(4-Cyanothiazolidin-3-yl)-2-oxoethyl)-6-(4-fluoro-1-methylpiperidin-4-yl)-quinoline-4-carboxamide (Example 195); N-(2-((R)-4-Cyanothiazolidin-3-yl)-2-oxoethyl)-6-((RS)-3-fluoro-3-methylpyrrolidin-1-yl)quinoline-4-carboxamide (Example 198); N-(2-((R)-4-Cyanothiazolidin-3-yl)-2-oxoethyl)-6-((R*)-3-methyl-2-oxopyrrolidin-1-yl)quinoline-4-carboxamide Isomer 1 (Example 201); N-(2-((R)-4-Cyanothiazolidin-3-yl)-2-oxoethyl)-6-((R*)-3-methyl-2-oxopyrrolidin-1-yl)quinoline-4-carboxamide Isomer 2 (Example 202); N-(2-((R)-4-Cyanothiazolidin-3-yl)-2-oxoethyl)-6-((R*)-3-methyl-2-oxopiperidin-1-yl)quinoline-4-carboxamide Isomer 1 (Example 203); N-(2-((R)-4-Cyanothiazolidin-3-yl)-2-oxoethyl)-6-((R*)-3-methyl-2-oxopiperidin-1-yl)quinoline-4-carboxamide Isomer 2 (Example 204); (R)-N-(2-(4-Cyanothiazolidin-3-yl)-2-oxoethyl)-6-(4-fluoropiperidin-1-yl)quinoline-4-carboxamide (Example 205); N-(2-((R)-4-Cyanothiazolidin-3-yl)-2-oxoethyl)-6-((S)-3-methoxypyrrolidin-1-yl)quinoline-4-carboxamide (Example 207); N-(2-((R)-4-Cyanothiazolidin-3-yl)-2-oxoethyl)-6-((3S,4S)-3,4-difluoropyrrolidin-1-yl)quinoline-4-carboxamide (Example 213); N-(2-((R)-4-Cyanothiazolidin-3-yl)-2-oxoethyl)-6-((S)-3-(hydroxymethyl)pyrrolidin-1-yl)quinoline-4-carboxamide (Example 221); N-(2-((R)-4-Cyanothiazolidin-3-yl)-2-oxoethyl)-6-((RS)-3,3-difluoro-4-hydroxy-pyrrolidin-1-yl)quinoline-4-carboxamide (Example 224); and is selected from the group consisting of its pharmaceutically acceptable salts.

[0120] B.R 2 is a monocyclic or fused bicyclic heterocyclyl (nitrogen, oxygen (or sulfur), and carbon ring atoms) In some embodiments, the present disclosure provides a compound having a structure of formula (I), (II), (III-A), (III-B), (III-C), (III-D), (III-E), (IV), or (IV-A), and its pharmaceutically acceptable salts, wherein R 2 is a heterocyclyl containing a total of 5 to 10 ring atoms, and the heterocyclyl ring is (i) a saturated, partially saturated, or fully unsaturated monocyclic or fused bicyclic ring, (ii) (a) having one nitrogen ring atom and one oxygen ring atom, and the remaining ring atoms are carbon, or (b) having one nitrogen ring atom and one sulfur ring atom, and the remaining ring atoms are carbon, and (iii) halogen, cyano, oxo, C 1~6 -alkyl, C 3~6 -cycloalkyl, C 1~6 -alkoxy, C 1~3 -alkoxy-C 1~3 -alkyl, C 1~3 -alkylcarbonyl-C 1~3-Alkyl, and C 1~3 -Alkylsulfonyl-C 1~3 -Alkyl is optionally substituted with one or more substituents independently selected from the group consisting of, and C 1~6 -Alkyl, C 3~6 -Cycloalkyl, C 1~6 -Alkoxy, C 1~3 -Alkoxy-C 1~3 -Alkyl, C 1~3 -Alkylcarbonyl-C 1~3 -Alkyl, and C 1~3 -Alkylsulfonyl-C 1~3 -Alkyl may be further substituted with one or more halogens. In one embodiment, R 2 The heterocyclic ring is a saturated monocyclic ring. In another embodiment, R 2 The heterocyclic ring is a partially saturated monocyclic ring. In another embodiment, R 2 The heterocyclic ring is a fully unsaturated monocyclic ring. In another embodiment, R 2 The heterocyclic ring is a saturated fused bicyclic ring. In another embodiment, R 2 The heterocyclic ring is a partially saturated fused bicyclic ring. In another embodiment, R 2 The heterocyclic ring is a fully unsaturated fused bicyclic ring. In another embodiment, R 2 The heterocyclic ring has one nitrogen ring atom and one oxygen ring atom, and the remaining ring atoms are carbon. In another embodiment, R 2 The heterocyclic ring has one nitrogen ring atom and one sulfur ring atom, and the remaining ring atoms are carbon.

[0121] In some embodiments, R 2 The heterocyclic ring contains a total of 6 to 10 ring atoms.

[0122] In some embodiments, R 2 The heterocyclic ring is:

Chemical formula

[0123] In some embodiments, R 2 The heterocyclic ring is:

Chemical formula

[0124] In some embodiments, R 2 The heterocyclic ring is:

Chemical formula

[0125] In some embodiments, R 2 The heterocyclic ring is halogen, cyano, C 1~3 -Alkyl, C 3~5 -Cycloalkyl, C 1~3 -Alkoxy, C 1~3 -Alkoxy-C 1~3 -Alkyl, C 1~3 -Alkylcarbonyl-C 1~3 -Alkyl, and C 1~3 -Alkylsulfonyl-C 1~3Optionally substituted with one or more substituents independently selected from the group consisting of -alkyl, C 1~3 -alkyl, C 1~3 -alkoxy, C 1~3 -alkoxy-C 1~3 -alkyl, C 1~3 -alkylcarbonyl-C 1~3 -alkyl, C 3~5 -cycloalkyl, and C 1~3 -alkylsulfonyl-C 1~3 -alkyl may be further substituted with one or more halogens.

[0126] In some embodiments, R 2 The heterocyclic ring is halogen, cyano, C 1~2 -alkyl, C 3~4 -cycloalkyl, C 1~2 -alkoxy, C 1~2 -alkoxy-C 1~3 -alkyl, C 1~2 -alkylcarbonyl-C 1~2 -alkyl, and C 1~2 -alkylsulfonyl-C 1~2 Optionally substituted with one or more substituents independently selected from the group consisting of -alkyl, C 1~2 -alkyl, C 3~4 -cycloalkyl, C 1~2 -alkoxy, C 1~2 -alkoxy-C 1~2 -alkyl, C 1~2 -alkylcarbonyl-C 1~2 -alkyl, and C 1~2 -alkylsulfonyl-C 1~2 -alkyl may be further substituted with one or more halogens.

[0127] In some embodiments, R 2 The heterocyclic ring is optionally substituted with one or more halogens. In one aspect, R 2 The heterocyclic ring is optionally substituted with one or more fluoros.

[0128] In some embodiments, R 2 The heterocyclic ring is optionally substituted with one or more C 1~3 -alkyl, and the C 1~3 -alkyl may further be substituted with one or more halogens.

[0129] In some embodiments, R 2 The heterocyclic ring is optionally substituted with one or more C 3~6 -cycloalkyl, and the C 3~6 -cycloalkyl may further be substituted with one or more halogens.

[0130] In some embodiments, R 2 The heterocyclic ring is optionally substituted with one or more C 1~3 -alkoxy-C 1~3 -alkyl, and the C 1~3 -alkoxy-C 1~3 -alkyl may further be substituted with one or more halogens.

[0131] In some embodiments, R 2 The heterocyclic ring is optionally substituted with one or more C 1~3 -alkylsulfonyl-C 1~3 -alkyl, and the C 1~3 -alkylsulfonyl-C 1~3 -alkyl may further be substituted with one or more halogens.

[0132] In some embodiments, R 2 The heterocyclic ring is optionally substituted with one or more substituents independently selected from the group consisting of cyano, fluoro, methyl, ethyl, propyl, isopropyl, cyclopropyl, fluoromethyl, difluoromethyl, trifluoromethyl, fluoroethyl, difluoroethyl, trifluoroethyl, trifluoropropyl, methoxy, ethoxy, isopropoxy, trifluoromethoxy, trifluoroethoxy, methoxymethyl, methoxyethyl, trifluoromethoxymethyl, and methylsulfonylmethyl.

[0133] In some embodiments, R 2 The heterocyclic ring is optionally substituted with one or more substituents independently selected from the group consisting of fluoro, methyl, ethyl, isopropyl, cyclopropyl, fluoromethyl, difluoropropyl, methoxy, and trifluoromethoxy.

[0134] In some embodiments, R 2 The heterocyclic ring is:

Chemical formula

[0135] In some embodiments, the compound and the pharmaceutically acceptable salt are (R)-N-(2-(4-cyanothiazolidin-3-yl)-2-oxoethyl)-3-fluoro-6-morpholinquinoline-4-carboxamide (Example 2); (R)-N-(2-(4-cyanothiazolidin-3-yl)-2-oxoethyl)-6-(2,2-difluoromorpholino)quinoline-4-carboxamide (Example 4); (R)-N-(2-(4-Cyanothiazolidin-3-yl)-2-oxoethyl)-6-(2,2,6,6-tetrafluoromorpholino)-quinoline-4-carboxamide (Example 5); (R)-N-(2-(4-Cyanothiazolidin-3-yl)-2-oxoethyl)-8-methyl-6-morpholinoquinoline-4-carboxamide (Example 9); (R)-N-(2-(4-Cyanothiazolidin-3-yl)-2-oxoethyl)-7-methyl-6-morpholinoquinoline-4-carboxamide (Example 10); (R)-N-(2-(4-Cyanothiazolidin-3-yl)-2-oxoethyl)-6-(2,2-dimethyl-3-oxomorpholino)-quinoline-4-carboxamide (Example 16); (R)-N-(2-(4-Cyanothiazolidin-3-yl)-2-oxoethyl)-6-morpholinoquinoline-4-carboxamide (Example 67); N-(2-((R)-4-Cyanothiazolidin-3-yl)-2-oxoethyl)-6-((2R,6S)-2,6-dimethylmorpholino)-quinoline-4-carboxamide (Example 68); N-(2-((R)-4-Cyanothiazolidin-3-yl)-2-oxoethyl)-6-((R)-2-(fluoromethyl)morpholino)-quinoline-4-carboxamide (Example 69); N-(2-((R)-4-Cyanothiazolidin-3-yl)-2-oxoethyl)-6-((2R,6R)-2,6-dimethylmorpholino)-quinoline-4-carboxamide (Example 70); N-(2-((R)-4-Cyanothiazolidin-3-yl)-2-oxoethyl)-6-((S)-2-(fluoromethyl)morpholino)-quinoline-4-carboxamide (Example 71); N-(2-((R)-4-Cyanothiazolidin-3-yl)-2-oxoethyl)-6-((R)-2-methylmorpholino)-quinoline-4-carboxamide (Example 72); N-(2-((R)-4-Cyanothiazolidin-3-yl)-2-oxoethyl)-6-((R)-2-(trifluoromethyl)-morpholino)quinoline-4-carboxamide (Example 73); N-(2-((R)-4-Cyanothiazolidin-3-yl)-2-oxoethyl)-6-((S)-2-(trifluoromethyl)-morpholino)quinoline-4-carboxamide (Example 74); N-(2-((R)-4-Cyanothiazolidin-3-yl)-2-oxoethyl)-6-((2S,6S)-2,6-dimethylmorpholino)-quinoline-4-carboxamide (Example 78); N-(2-((R)-4-Cyanothiazolidin-3-yl)-2-oxoethyl)-6-((S)-2-methylmorpholino)quinoline-4-carboxamide (Example 80); N-(2-((R)-4-Cyanothiazolidin-3-yl)-2-oxoethyl)-6-((2R,3S)-2,3-dimethyl-morpholino)quinoline-4-carboxamide (Example 81); N-(2-((R)-4-Cyanothiazolidin-3-yl)-2-oxoethyl)-6-((2S,3S)-2,3-dimethylmorpholino)quinoline-4-carboxamide (Example 82); N-(2-((R)-4-Cyanothiazolidin-3-yl)-2-oxoethyl)-6-((2R,3R)-2,3-dimethyl-morpholino)quinoline-4-carboxamide (Example 83); N-(2-((R)-4-Cyanothiazolidin-3-yl)-2-oxoethyl)-6-((R*)-3-(trifluoromethyl)-morpholino)quinoline-4-carboxamide isomer 1 (Example 84); N-(2-((R)-4-Cyanothiazolidin-3-yl)-2-oxoethyl)-6-((R*)-3-(trifluoromethyl)-morpholino)quinoline-4-carboxamide isomer 2 (Example 85); N-(2-((R)-4-Cyanothiazolidin-3-yl)-2-oxoethyl)-6-((2R,5R)-2,5-dimethylmorpholino)quinoline-4-carboxamide (Example 87); (R)-N-(2-(4-Cyanothiazolidin-3-yl)-2-oxoethyl)-6-(2,2-dimethylmorpholino)-quinoline-4-carboxamide (Example 88); N-(2-((R)-4-Cyanothiazolidin-3-yl)-2-oxoethyl)-6-((S)-3-(methoxymethyl)-morpholino)quinoline-4-carboxamide (Example 89); N-(2-((R)-4-Cyanothiazolidin-3-yl)-2-oxoethyl)-6-((3S,5R)-3,5-dimethyl-morpholino)quinoline-4-carboxamide (Example 90); N-(2-((R)-4-Cyanothiazolidin-3-yl)-2-oxoethyl)-6-((R)-2-((methylsulfonyl)-methyl)morpholino)quinoline-4-carboxamide (Example 92); N-(2-((R)-4-Cyanothiazolidin-3-yl)-2-oxoethyl)-6-((S)-2-(methoxymethyl)-morpholino)quinoline-4-carboxamide (Example 93); N-(2-((R)-4-Cyanothiazolidin-3-yl)-2-oxoethyl)-6-((S)-2-((methylsulfonyl)-methyl)morpholino)quinoline-4-carboxamide (Example 94); N-(2-((R)-4-Cyanothiazolidin-3-yl)-2-oxoethyl)-6-((R)-3-(2-methoxyethyl)-morpholino)quinoline-4-carboxamide (Example 95); N-(2-((R)-4-Cyanothiazolidin-3-yl)-2-oxoethyl)-6-((2S,3S)-3-(methoxymethyl)-2-methylmorpholino)quinoline-4-carboxamide (Example 96); N-(2-((R)-4-Cyanothiazolidin-3-yl)-2-oxoethyl)-6-((2R,3R)-3-(methoxymethyl)-2-methylmorpholino)quinoline-4-carboxamide (Example 97); 7-Bromo-N-(2-((R)-4-cyanothiazolidin-3-yl)-2-oxoethyl)-6-((3S,5R)-3,5-dimethylmorpholino)quinoline-4-carboxamide (Example 100); (R)-5-Chloro-N-(2-(4-cyanothiazolidin-3-yl)-2-oxoethyl)-6-morpholinquinoline-4-carboxamide (Example 101); N-(2-((R)-4-Cyanothiazolidin-3-yl)-2-oxoethyl)-6-((S)-3-methylmorpholino)-quinoline-4-carboxamide (Example 102); N-(2-((R)-4-Cyanothiazolidin-3-yl)-2-oxoethyl)-6-((3S,5S)-3,5-dimethylmorpholino)-quinoline-4-carboxamide (Example 103); N-(2-((R)-4-Cyanothiazolidin-3-yl)-2-oxoethyl)-6-((3R,5R)-3,5-dimethylmorpholino)-quinoline-4-carboxamide (Example 105); N-(2-((R)-4-Cyanothiazolidin-3-yl)-2-oxoethyl)-6-((S)-3-ethylmorpholino)quinoline-4-carboxamide (Example 106); (R)-N-(2-(4-Cyanothiazolidin-3-yl)-2-oxoethyl)-6-(3,3-dimethylmorpholino)-quinoline-4-carboxamide (Example 107); N-(2-((R)-4-Cyanothiazolidin-3-yl)-2-oxoethyl)-6-((R)-3-methylmorpholino)-quinoline-4-carboxamide (Example 108); (R)-N-(2-(4-Cyanothiazolidin-3-yl)-2-oxoethyl)-2-methyl-6-morpholinquinoline-4-carboxamide (Example 109); (R)-7-Chloro-N-(2-(4-cyanothiazolidin-3-yl)-2-oxoethyl)-6-morpholinquinoline-4-carboxamide (Example 179); (R)-8-Chloro-N-(2-(4-cyanothiazolidin-3-yl)-2-oxoethyl)-6-morpholinquinoline-4-carboxamide (Example 180); and is selected from the group consisting of pharmaceutically acceptable salts thereof.

[0136] In some embodiments, the compound and the pharmaceutically acceptable salt are (R)-N-(2-(4-Cyanothiazolidin-3-yl)-2-oxoethyl)-8-methyl-6-morpholinoquinoline-4-carboxamide (Example 9); (R)-N-(2-(4-Cyanothiazolidin-3-yl)-2-oxoethyl)-6-morpholinoquinoline-4-carboxamide (Example 67); N-(2-((R)-4-Cyanothiazolidin-3-yl)-2-oxoethyl)-6-((2R,6S)-2,6-dimethylmorpholino)-quinoline-4-carboxamide (Example 68); N-(2-((R)-4-Cyanothiazolidin-3-yl)-2-oxoethyl)-6-((R)-2-(fluoromethyl)morpholino)-quinoline-4-carboxamide (Example 69); N-(2-((R)-4-Cyanothiazolidin-3-yl)-2-oxoethyl)-6-((2R,6R)-2,6-dimethylmorpholino)-quinoline-4-carboxamide (Example 70); N-(2-((R)-4-Cyanothiazolidin-3-yl)-2-oxoethyl)-6-((S)-2-(fluoromethyl)morpholino)-quinoline-4-carboxamide (Example 71); N-(2-((R)-4-Cyanothiazolidin-3-yl)-2-oxoethyl)-6-((R)-2-methylmorpholino)-quinoline-4-carboxamide (Example 72); N-(2-((R)-4-Cyanothiazolidin-3-yl)-2-oxoethyl)-6-((R)-2-(trifluoromethyl)-morpholino)quinoline-4-carboxamide (Example 73); N-(2-((R)-4-Cyanothiazolidin-3-yl)-2-oxoethyl)-6-((S)-2-(trifluoromethyl)-morpholino)quinoline-4-carboxamide (Example 74); N-(2-((R)-4-Cyanothiazolidin-3-yl)-2-oxoethyl)-6-((2S,6S)-2,6-dimethylmorpholino)-quinoline-4-carboxamide (Example 78); N-(2-((R)-4-Cyanothiazolidin-3-yl)-2-oxoethyl)-6-((S)-2-methylmorpholino)quinoline-4-carboxamide (Example 80); N-(2-((R)-4-Cyanothiazolidin-3-yl)-2-oxoethyl)-6-((2R,3S)-2,3-dimethylmorpholino)quinoline-4-carboxamide (Example 81); N-(2-((R)-4-Cyanothiazolidin-3-yl)-2-oxoethyl)-6-((2S,3S)-2,3-dimethylmorpholino)quinoline-4-carboxamide (Example 82); (R)-N-(2-(4-Cyanothiazolidin-3-yl)-2-oxoethyl)-6-(2,2-dimethylmorpholino)quinoline-4-carboxamide (Example 88); N-(2-((R)-4-Cyanothiazolidin-3-yl)-2-oxoethyl)-6-((S)-3-(methoxymethyl)morpholino)quinoline-4-carboxamide (Example 89); N-(2-((R)-4-Cyanothiazolidin-3-yl)-2-oxoethyl)-6-((S)-2-(methoxymethyl)morpholino)quinoline-4-carboxamide (Example 93); N-(2-((R)-4-Cyanothiazolidin-3-yl)-2-oxoethyl)-6-((2R,3R)-3-(methoxymethyl)-2-methylmorpholino)quinoline-4-carboxamide (Example 97); N-(2-((R)-4-Cyanothiazolidin-3-yl)-2-oxoethyl)-6-((S)-3-methylmorpholino)quinoline-4-carboxamide (Example 102); N-(2-((R)-4-Cyanothiazolidin-3-yl)-2-oxoethyl)-6-((S)-3-ethylmorpholino)quinoline-4-carboxamide (Example 106); (R)-N-(2-(4-Cyanothiazolidin-3-yl)-2-oxoethyl)-6-(3,3-dimethylmorpholino)quinoline-4-carboxamide (Example 107); and is selected from the group consisting of its pharmaceutically acceptable salts.

[0137] In some embodiments, R 2 The heterocyclic ring is:

Chemical formula

[0138] In some embodiments, the compound or pharmaceutically acceptable salt thereof is (R)-N-(2-(4-cyanothiazolidin-3-yl)-2-oxoethyl)-6-thiomorpholinonoquinoline-4-carboxamide (Example 3), or a pharmaceutically acceptable salt thereof.

[0139] In some embodiments, R 2 The heterocyclic ring is:

Chemical formula

[0140] In some embodiments, the compound or pharmaceutically acceptable salt thereof is (R)-N-(2-(4-cyanothiazolidin-3-yl)-2-oxoethyl)-6-(2,2-dimethyl-3-oxomorpholino)quinoline-4-carboxamide (Example 16), or a pharmaceutically acceptable salt thereof.

[0141] In some embodiments, R 2 The heterocyclic ring is:

Chemical formula

[0142] In some embodiments, the compound or pharmaceutically acceptable salt thereof is (R)-N-(2-(4-cyanothiazolidin-3-yl)-2-oxoethyl)-6-(6,6-dimethyl-2-oxo-1,3-oxazinane-3-yl)quinoline-4-carboxamide (Example 112), or a pharmaceutically acceptable salt thereof.

[0143] In some embodiments, R 2 The heterocyclic ring is:

Chemical formula

[0144] In some embodiments, the compound or pharmaceutically acceptable salt is 6-(6-oxa-3-azabicyclo[3.1.1]heptan-3-yl)-N-(2-((R)-4-cyanothiazolidin-3-yl)-2-oxoethyl)quinoline-4-carboxamide (Example 77), or a pharmaceutically acceptable salt thereof.

[0145] In some embodiments, R 2 The heterocyclic ring is:

Chemical formula

[0146] In some embodiments, the compound and the pharmaceutically acceptable salt are 6-((1S,4S)-2-oxa-5-azabicyclo[2.2.1]heptan-5-yl)-N-(2-((R)-4-cyanothiazolidin-3-yl)-2-oxoethyl)quinoline-4-carboxamide (Example 75); 6-((1R,4R)-2-oxa-5-azabicyclo[2.2.1]heptan-5-yl)-N-(2-((R)-4-cyanothiazolidin-3-yl)-2-oxoethyl)quinoline-4-carboxamide (Example 76); and are selected from the group consisting of its pharmaceutically acceptable salts.

[0147] In some embodiments, R 2 The heterocyclic ring is:

Chemical formula

[0148] In some embodiments, the compound or a pharmaceutically acceptable salt thereof is 6-(3-oxa-8-azabicyclo[3.2.1]octan-8-yl)-N-(2-((R)-4-cyanothiazolidin-3-yl)-2-oxoethyl)quinoline-4-carboxamide (Example 98), or a pharmaceutically acceptable salt thereof.

[0149] In some embodiments, R 2 The heterocyclic ring is:

Chemical formula

[0150] In some embodiments, the compound or pharmaceutically acceptable salt thereof is 6-(1R,5S)-9-oxa-3-azabicyclo[3.3.1]nonan-3-yl)-N-(2-((R)-4-cyanothiazolidin-3-yl)-2-oxoethyl)quinoline-4-carboxamide (Example 194), or a pharmaceutically acceptable salt thereof.

[0151] In some embodiments, R 2 The heterocyclic ring is:

Chemical formula

[0152] In some embodiments, the compound or pharmaceutically acceptable salt is (R)-N-(2-(4-cyanothiazolidin-3-yl)-2-oxoethyl)-6-(1,2-oxazinane-2-yl)quinoline-4-carboxamide (Example 1), or a pharmaceutically acceptable salt thereof.

[0153] In some embodiments, R 2 The heterocyclic ring is:

Chemical formula

[0154] In some embodiments, the compound and the pharmaceutically acceptable salt are N-(2-((R)-4-cyanothiazolidin-3-yl)-2-oxoethyl)-6-((R)-7-methyl-1,4-oxazepan-4-yl)quinoline-4-carboxamide (Example 61); N-(2-((R)-4-Cyanothiazolidin-3-yl)-2-oxoethyl)-6-((S)-7-methyl-1,4-oxazepan-4-yl)quinoline-4-carboxamide (Example 62); N-(2-((R)-4-Cyanothiazolidin-3-yl)-2-oxoethyl)-6-((S)-3-methyl-1,4-oxazepan-4-yl)quinoline-4-carboxamide (Example 63); N-(2-((R)-4-Cyanothiazolidin-3-yl)-2-oxoethyl)-6-((R)-2-methyl-1,4-oxazepan-4-yl)quinoline-4-carboxamide (Example 64); (R)-N-(2-(4-Cyanothiazolidin-3-yl)-2-oxoethyl)-6-(1,4-oxazepan-4-yl)quinoline-4-carboxamide (Example 91); and is selected from the group consisting of pharmaceutically acceptable salts thereof.

[0155] In some embodiments, R 2 The heterocyclic ring is: [Chemical formula] and The heterocyclic ring is optionally substituted with one or more substituents independently selected from the group consisting of halogen, cyano, oxo, C 1~6 -alkyl, C 3~6 -cycloalkyl, C 1~6 -alkoxy, C 1~3 -alkoxy-C 1~3 -alkyl, C 1~3 -alkylcarbonyl-C 1~3 -alkyl, and C 1~3 -alkylsulfonyl-C 1~3 -alkyl, and is optionally substituted with one or more substituents independently selected from the group consisting of C 1~6 -alkyl, C 3~6 -cycloalkyl, C 1~6 -alkoxy, C 1~3 -alkoxy-C 1~3 -alkyl, C 1~3 -alkylcarbonyl-C 1~3 -alkyl, and C1~3 -Alkylsulfonyl-C 1~3 -Alkyl may further be substituted with one or more halogens. In one embodiment, R 2 The heterocyclic ring is halogen, cyano, C 1~3 -Alkyl, C 3~6 -Cycloalkyl, C 1~3 -Alkoxy, C 1~3 -Alkoxy-C 1~3 -Alkyl, C 1~3 -Alkylcarbonyl-C 1~3 -Alkyl, and C 1~3 -Alkylsulfonyl-C 1~3 -Alkyl is optionally substituted with one or more substituents independently selected from the group consisting of C 1~3 -Alkyl, C 3~6 -Cycloalkyl, C 1~3 -Alkoxy, C 1~3 -Alkoxy-C 1~3 -Alkyl, C 1~3 -Alkylcarbonyl-C 1~3 -Alkyl, and C 1~3 -Alkylsulfonyl-C 1~3 -Alkyl may further be substituted with one or more halogens. In another embodiment, R 2 The heterocyclic ring is optionally substituted with one or more substituents independently selected from the group consisting of cyano, fluoro, methyl, ethyl, propyl, isopropyl, cyclopropyl, fluoromethyl, difluoromethyl, trifluoromethyl, fluoroethyl, difluoroethyl, trifluoroethyl, trifluoropropyl, methoxy, ethoxy, trifluoromethoxy, trifluoroethoxy, methoxymethyl, trifluoromethoxymethyl, and methylsulfonylmethyl. In another embodiment, R 2 The heterocyclic ring is optionally substituted with one or more substituents independently selected from the group consisting of fluoro, methyl, ethyl, fluoromethyl, difluoropropyl, methoxy, and trifluoromethoxy.

[0156] In some embodiments, the compound or pharmaceutically acceptable salt is 6-(8-oxa-3-azabicyclo[3.2.1]octan-3-yl)-N-(2-((R)-4-cyanothiazolidin-3-yl)-2-oxoethyl)quinoline-4-carboxamide (Example 79), or a pharmaceutically acceptable salt thereof.

[0157] In some embodiments, the compound and pharmaceutically acceptable salt are (R)-N-(2-(4-cyanothiazolidin-3-yl)-2-oxoethyl)-6-(1,2-oxazinane-2-yl)quinoline-4-carboxamide (Example 1); (R)-N-(2-(4-cyanothiazolidin-3-yl)-2-oxoethyl)-3-fluoro-6-morpholinoquinoline-4-carboxamide (Example 2); (R)-N-(2-(4-cyanothiazolidin-3-yl)-2-oxoethyl)-6-thiomorpholinoquinoline-4-carboxamide (Example 3); (R)-N-(2-(4-cyanothiazolidin-3-yl)-2-oxoethyl)-6-(2,2-difluoromorpholino)quinoline-4-carboxamide (Example 4); (R)-N-(2-(4-cyanothiazolidin-3-yl)-2-oxoethyl)-6-(2,2,6,6-tetrafluoromorpholino)-quinoline-4-carboxamide (Example 5); (R)-N-(2-(4-cyanothiazolidin-3-yl)-2-oxoethyl)-6-(2,3-dihydro-4H-benzo[b][1,4]oxazin-4-yl)quinoline-4-carboxamide (Example 6); (R)-N-(2-(4-cyanothiazolidin-3-yl)-2-oxoethyl)-8-methyl-6-morpholinoquinoline-4-carboxamide (Example 9); (R)-N-(2-(4-cyanothiazolidin-3-yl)-2-oxoethyl)-7-methyl-6-morpholinoquinoline-4-carboxamide (Example 10); (R)-N-(2-(4-Cyanothiazolidin-3-yl)-2-oxoethyl)-6-(5,5-dimethyl-2-oxooxazolidin-3-yl)quinoline-4-carboxamide (Example 13); (R)-N-(2-(4-Cyanothiazolidin-3-yl)-2-oxoethyl)-6-(2,2-dimethyl-3-oxomorpholino)-quinoline-4-carboxamide (Example 16); N-(2-((R)-4-Cyanothiazolidin-3-yl)-2-oxoethyl)-6-((R)-7-methyl-1,4-oxazepan-4-yl)-quinoline-4-carboxamide (Example 61); N-(2-((R)-4-Cyanothiazolidin-3-yl)-2-oxoethyl)-6-((S)-7-methyl-1,4-oxazepan-4-yl)-quinoline-4-carboxamide (Example 62); N-(2-((R)-4-Cyanothiazolidin-3-yl)-2-oxoethyl)-6-((S)-3-methyl-1,4-oxazepan-4-yl)-quinoline-4-carboxamide (Example 63); N-(2-((R)-4-Cyanothiazolidin-3-yl)-2-oxoethyl)-6-((R)-2-methyl-1,4-oxazepan-4-yl)-quinoline-4-carboxamide (Example 64); (R)-N-(2-(4-Cyanothiazolidin-3-yl)-2-oxoethyl)-6-morpholinquinoline-4-carboxamide (Example 67); N-(2-((R)-4-Cyanothiazolidin-3-yl)-2-oxoethyl)-6-((2R,6S)-2,6-dimethylmorpholino)-quinoline-4-carboxamide (Example 68); N-(2-((R)-4-Cyanothiazolidin-3-yl)-2-oxoethyl)-6-((R)-2-(fluoromethyl)-morpholino)quinoline-4-carboxamide (Example 69); N-(2-((R)-4-Cyanothiazolidin-3-yl)-2-oxoethyl)-6-((2R,6R)-2,6-dimethylmorpholino)-quinoline-4-carboxamide (Example 70); N-(2-((R)-4-Cyanothiazolidin-3-yl)-2-oxoethyl)-6-((S)-2-(fluoromethyl)-morpholino)quinoline-4-carboxamide (Example 71); N-(2-((R)-4-Cyanothiazolidin-3-yl)-2-oxoethyl)-6-((R)-2-methylmorpholino)-quinoline-4-carboxamide (Example 72); N-(2-((R)-4-Cyanothiazolidin-3-yl)-2-oxoethyl)-6-((R)-2-(trifluoromethyl)-morpholino)quinoline-4-carboxamide (Example 73); N-(2-((R)-4-Cyanothiazolidin-3-yl)-2-oxoethyl)-6-((S)-2-(trifluoromethyl)-morpholino)quinoline-4-carboxamide (Example 74); 6-((1S,4S)-2-oxa-5-azabicyclo[2.2.1]heptan-5-yl)-N-(2-((R)-4-cyanothiazolidin-3-yl)-2-oxoethyl)quinoline-4-carboxamide (Example 75); 6-((1R,4R)-2-oxa-5-azabicyclo[2.2.1]heptan-5-yl)-N-(2-((R)-4-cyanothiazolidin-3-yl)-2-oxoethyl)quinoline-4-carboxamide (Example 76); 6-(6-oxa-3-azabicyclo[3.1.1]heptan-3-yl)-N-(2-((R)-4-cyanothiazolidin-3-yl)-2-oxoethyl)quinoline-4-carboxamide (Example 77); N-(2-((R)-4-Cyanothiazolidin-3-yl)-2-oxoethyl)-6-((2S,6S)-2,6-dimethylmorpholino)-quinoline-4-carboxamide (Example 78); 6-(8-oxa-3-azabicyclo[3.2.1]octan-3-yl)-N-(2-((R)-4-cyanothiazolidin-3-yl)-2-oxoethyl)quinoline-4-carboxamide (Example 79); N-(2-((R)-4-Cyanothiazolidin-3-yl)-2-oxoethyl)-6-((S)-2-methylmorpholino)quinoline-4-carboxamide (Example 80); N-(2-((R)-4-Cyanothiazolidin-3-yl)-2-oxoethyl)-6-((2R,3S)-2,3-dimethylmorpholino)quinoline-4-carboxamide (Example 81); N-(2-((R)-4-Cyanothiazolidin-3-yl)-2-oxoethyl)-6-((2S,3S)-2,3-dimethylmorpholino)quinoline-4-carboxamide (Example 82); N-(2-((R)-4-Cyanothiazolidin-3-yl)-2-oxoethyl)-6-((2R,3R)-2,3-dimethylmorpholino)quinoline-4-carboxamide (Example 83); N-(2-((R)-4-Cyanothiazolidin-3-yl)-2-oxoethyl)-6-((R*)-3-(trifluoromethyl)morpholino)quinoline-4-carboxamide isomer 1 (Example 84); N-(2-((R)-4-Cyanothiazolidin-3-yl)-2-oxoethyl)-6-((R*)-3-(trifluoromethyl)morpholino)quinoline-4-carboxamide isomer 2 (Example 85); 6-(3-Oxa-9-azabicyclo[3.3.1]nonan-9-yl)-N-(2-((R)-4-cyanothiazolidin-3-yl)-2-oxoethyl)quinoline-4-carboxamide (Example 86); N-(2-((R)-4-Cyanothiazolidin-3-yl)-2-oxoethyl)-6-((2R,5R)-2,5-dimethylmorpholino)quinoline-4-carboxamide (Example 87); (R)-N-(2-(4-Cyanothiazolidin-3-yl)-2-oxoethyl)-6-(2,2-dimethylmorpholino)quinoline-4-carboxamide (Example 88); N-(2-((R)-4-Cyanothiazolidin-3-yl)-2-oxoethyl)-6-((S)-3-(methoxymethyl)morpholino)quinoline-4-carboxamide (Example 89); N-(2-((R)-4-Cyanothiazolidin-3-yl)-2-oxoethyl)-6-((3S,5R)-3,5-dimethyl-morpholino)quinoline-4-carboxamide (Example 90); (R)-N-(2-(4-Cyanothiazolidin-3-yl)-2-oxoethyl)-6-(1,4-oxazepan-4-yl)quinoline-4-carboxamide (Example 91); N-(2-((R)-4-Cyanothiazolidin-3-yl)-2-oxoethyl)-6-((R)-2-((methylsulfonyl)-methyl)morpholino)quinoline-4-carboxamide (Example 92); N-(2-((R)-4-Cyanothiazolidin-3-yl)-2-oxoethyl)-6-((S)-2-(methoxymethyl)-morpholino)quinoline-4-carboxamide (Example 93); N-(2-((R)-4-Cyanothiazolidin-3-yl)-2-oxoethyl)-6-((S)-2-((methylsulfonyl)-methyl)morpholino)quinoline-4-carboxamide (Example 94); N-(2-((R)-4-Cyanothiazolidin-3-yl)-2-oxoethyl)-6-((R)-3-(2-methoxyethyl)-morpholino)quinoline-4-carboxamide (Example 95); N-(2-((R)-4-Cyanothiazolidin-3-yl)-2-oxoethyl)-6-((2S,3S)-3-(methoxymethyl)-2-methylmorpholino)quinoline-4-carboxamide (Example 96); N-(2-((R)-4-Cyanothiazolidin-3-yl)-2-oxoethyl)-6-((2R,3R)-3-(methoxymethyl)-2-methylmorpholino)quinoline-4-carboxamide (Example 97); 6-(3-Oxa-8-azabicyclo[3.2.1]octan-8-yl)-N-(2-((R)-4-cyanothiazolidin-3-yl)-2-oxoethyl)quinoline-4-carboxamide (Example 98); 7-Bromo-N-(2-((R)-4-cyanothiazolidin-3-yl)-2-oxoethyl)-6-((3S,5R)-3,5-dimethyl-morpholino)quinoline-4-carboxamide (Example 100); (R)-5-Chloro-N-(2-(4-cyanothiazolidin-3-yl)-2-oxoethyl)-6-morpholinoquinoline-4-carboxamide (Example 101); N-(2-((R)-4-cyanothiazolidin-3-yl)-2-oxoethyl)-6-((S)-3-methylmorpholino)-quinoline-4-carboxamide (Example 102); N-(2-((R)-4-cyanothiazolidin-3-yl)-2-oxoethyl)-6-((3S,5S)-3,5-dimethylmorpholino)-quinoline-4-carboxamide (Example 103); N-(2-((R)-4-cyanothiazolidin-3-yl)-2-oxoethyl)-6-((3R,5R)-3,5-dimethylmorpholino)-quinoline-4-carboxamide (Example 105); N-(2-((R)-4-cyanothiazolidin-3-yl)-2-oxoethyl)-6-((S)-3-ethylmorpholino)quinoline-4-carboxamide (Example 106); (R)-N-(2-(4-cyanothiazolidin-3-yl)-2-oxoethyl)-6-(3,3-dimethylmorpholino)-quinoline-4-carboxamide (Example 107); N-(2-((R)-4-cyanothiazolidin-3-yl)-2-oxoethyl)-6-((R)-3-methylmorpholino)-quinoline-4-carboxamide (Example 108); (R)-N-(2-(4-cyanothiazolidin-3-yl)-2-oxoethyl)-2-methyl-6-morpholinoquinoline-4-carboxamide (Example 109); (R)-N-(2-(4-cyanothiazolidin-3-yl)-2-oxoethyl)-6-(6,6-dimethyl-2-oxo-1,3-oxazinane-3-yl)quinoline-4-carboxamide (Example 112); (R)-7-Chloro-N-(2-(4-cyanothiazolidin-3-yl)-2-oxoethyl)-6-morpholinquinoline-4-carboxamide (Example 179); (R)-8-Chloro-N-(2-(4-cyanothiazolidin-3-yl)-2-oxoethyl)-6-morpholinquinoline-4-carboxamide (Example 180); 6-((1R,5S)-9-oxa-3-azabicyclo[3.3.1]nonan-3-yl)-N-(2-((R)-4-cyanothiazolidin-3-yl)-2-oxoethyl)quinoline-4-carboxamide (Example 194); (R)-N-(2-(4-cyanothiazolidin-3-yl)-2-oxoethyl)-6-(2,4-dimethyloxazol-5-yl)quinoline-4-carboxamide (Example 215); (R)-N-(2-(4-cyanothiazolidin-3-yl)-2-oxoethyl)-6-(3,5-dimethylisoxazol-4-yl)quinoline-4-carboxamide (Example 216); and is selected from the group consisting of its pharmaceutically acceptable salts.

[0158] In some embodiments, the compound and the pharmaceutically acceptable salt are (R)-N-(2-(4-cyanothiazolidin-3-yl)-2-oxoethyl)-6-(1,2-oxazinane-2-yl)quinoline-4-carboxamide (Example 1); (R)-N-(2-(4-cyanothiazolidin-3-yl)-2-oxoethyl)-3-fluoro-6-morpholinquinoline-4-carboxamide (Example 2); (R)-N-(2-(4-cyanothiazolidin-3-yl)-2-oxoethyl)-6-(2,2-difluoromorpholino)quinoline-4-carboxamide (Example 4); (R)-N-(2-(4-cyanothiazolidin-3-yl)-2-oxoethyl)-8-methyl-6-morpholinquinoline-4-carboxamide (Example 9); (R)-N-(2-(4-Cyanothiazolidin-3-yl)-2-oxoethyl)-6-morpholinquinoline-4-carboxamide (Example 67); N-(2-((R)-4-Cyanothiazolidin-3-yl)-2-oxoethyl)-6-((2R,6S)-2,6-dimethylmorpholino)-quinoline-4-carboxamide (Example 68); N-(2-((R)-4-Cyanothiazolidin-3-yl)-2-oxoethyl)-6-((R)-2-(fluoromethyl)morpholino)-quinoline-4-carboxamide (Example 69); N-(2-((R)-4-Cyanothiazolidin-3-yl)-2-oxoethyl)-6-((2R,6R)-2,6-dimethylmorpholino)-quinoline-4-carboxamide (Example 70); N-(2-((R)-4-Cyanothiazolidin-3-yl)-2-oxoethyl)-6-((S)-2-(fluoromethyl)morpholino)-quinoline-4-carboxamide (Example 71); N-(2-((R)-4-Cyanothiazolidin-3-yl)-2-oxoethyl)-6-((R)-2-methylmorpholino)-quinoline-4-carboxamide (Example 72); N-(2-((R)-4-Cyanothiazolidin-3-yl)-2-oxoethyl)-6-((R)-2-(trifluoromethyl)-morpholino)quinoline-4-carboxamide (Example 73); N-(2-((R)-4-Cyanothiazolidin-3-yl)-2-oxoethyl)-6-((S)-2-(trifluoromethyl)-morpholino)quinoline-4-carboxamide (Example 74); 6-((1S,4S)-2-Oxa-5-azabicyclo[2.2.1]heptan-5-yl)-N-(2-((R)-4-cyanothiazolidin-3-yl)-2-oxoethyl)quinoline-4-carboxamide (Example 75); 6-((1R,4R)-2-Oxa-5-azabicyclo[2.2.1]heptan-5-yl)-N-(2-((R)-4-cyanothiazolidin-3-yl)-2-oxoethyl)quinoline-4-carboxamide (Example 76); 6-(6-Oxa-3-azabicyclo[3.1.1]heptan-3-yl)-N-(2-((R)-4-cyanothiazolidin-3-yl)-2-oxoethyl)quinoline-4-carboxamide (Example 77); N-(2-((R)-4-cyanothiazolidin-3-yl)-2-oxoethyl)-6-((2S,6S)-2,6-dimethylmorpholino)-quinoline-4-carboxamide (Example 78); 6-(8-Oxa-3-azabicyclo[3.2.1]octan-3-yl)-N-(2-((R)-4-cyanothiazolidin-3-yl)-2-oxoethyl)quinoline-4-carboxamide (Example 79); N-(2-((R)-4-cyanothiazolidin-3-yl)-2-oxoethyl)-6-((S)-2-methylmorpholino)-quinoline-4-carboxamide (Example 80); N-(2-((R)-4-cyanothiazolidin-3-yl)-2-oxoethyl)-6-((2R,3S)-2,3-dimethylmorpholino)-quinoline-4-carboxamide (Example 81); N-(2-((R)-4-cyanothiazolidin-3-yl)-2-oxoethyl)-6-((2S,3S)-2,3-dimethylmorpholino)-quinoline-4-carboxamide (Example 82); (R)-N-(2-(4-cyanothiazolidin-3-yl)-2-oxoethyl)-6-(2,2-dimethylmorpholino)-quinoline-4-carboxamide (Example 88); N-(2-((R)-4-cyanothiazolidin-3-yl)-2-oxoethyl)-6-((S)-3-(methoxymethyl)-morpholino)quinoline-4-carboxamide (Example 89); N-(2-((R)-4-cyanothiazolidin-3-yl)-2-oxoethyl)-6-((S)-2-(methoxymethyl)-morpholino)quinoline-4-carboxamide (Example 93); N-(2-((R)-4-cyanothiazolidin-3-yl)-2-oxoethyl)-6-((2R,3R)-3-(methoxymethyl)-2-methylmorpholino)quinoline-4-carboxamide (Example 97); 6-(3-Oxa-8-azabicyclo[3.2.1]octan-8-yl)-N-(2-((R)-4-cyanothiazolidin-3-yl)-2-oxoethyl)quinoline-4-carboxamide (Example 98); N-(2-((R)-4-Cyanothiazolidin-3-yl)-2-oxoethyl)-6-((S)-3-methylmorpholino)-quinoline-4-carboxamide (Example 102); N-(2-((R)-4-Cyanothiazolidin-3-yl)-2-oxoethyl)-6-((S)-3-ethylmorpholino)quinoline-4-carboxamide (Example 106); (R)-N-(2-(4-Cyanothiazolidin-3-yl)-2-oxoethyl)-6-(3,3-dimethylmorpholino)-quinoline-4-carboxamide (Example 107); (R)-N-(2-(4-Cyanothiazolidin-3-yl)-2-oxoethyl)-2-methyl-6-morpholinoquinoline-4-carboxamide (Example 109); (R)-N-(2-(4-Cyanothiazolidin-3-yl)-2-oxoethyl)-6-(6,6-dimethyl-2-oxo-1,3-oxazinane-3-yl)quinoline-4-carboxamide (Example 112); and is selected from the group consisting of its pharmaceutically acceptable salts.

[0159] C.R 2 is spiroheterocyclyl In some embodiments, the disclosure provides a compound having a structure of formula (I), (II), (III-A), (III-B), (III-C), (III-D), (III-E), (IV), or (IV-A), or a pharmaceutically acceptable salt thereof, wherein R 2is a spiroheterocyclyl containing a total of 6 to 11 ring atoms, wherein the spiroheterocyclyl: (i) contains two saturated rings; (ii) (a) has one or two nitrogen ring atoms and the remaining ring atoms are carbon, or (b) has one or two nitrogen ring atoms and one or two oxygen ring atoms and the remaining ring atoms are carbon, or (c) has one nitrogen ring atom and one sulfur ring atom and the remaining ring atoms are carbon; and (iii) is optionally substituted with one or more substituents independently selected from the group consisting of halogen, oxo, C 1~6 -alkyl, C 1~6 -haloalkyl, C 1~6 -alkoxy, C 1~6 -haloalkoxy, and C 1~6 -alkylcarbonyl. In one embodiment, R 2 The spiroheterocyclyl: (a) has one or two nitrogen ring atoms and the remaining ring atoms are carbon, or (b) has one or two nitrogen ring atoms and one or two oxygen ring atoms and the remaining ring atoms are carbon. In another embodiment, R 2 The spiroheterocyclyl has one or two nitrogen ring atoms and optionally one or two oxygen ring atoms, and the remaining ring atoms are carbon. In another embodiment, R 2 The spiroheterocyclyl has one nitrogen ring atom and the remaining ring atoms are carbon. In another embodiment, R 2 The spiroheterocyclyl has two nitrogen ring atoms and the remaining ring atoms are carbon. In another embodiment, R 2 The spiroheterocyclyl has one nitrogen ring atom and one oxygen ring atom and the remaining ring atoms are carbon. In another embodiment, R 2 The spiroheterocyclyl has one nitrogen ring atom and two oxygen ring atoms and the remaining ring atoms are carbon.

[0160] In some embodiments, R 2 The two saturated rings of the spiroheterocyclyl are:

Chemical formula

[0161] In some embodiments, R 2 The two saturated rings of spiroheterocyclyl are:

Chemical formula

[0162] In some embodiments, R 2 The two saturated rings of spiroheterocyclyl are:

Chemical formula

[0163] In some embodiments, R 2 The two saturated rings of spiroheterocyclyl are:

Chemical formula

[0164] In some embodiments, R 2 The spiroheterocyclyl ring is optionally substituted with one or more substituents independently selected from the group consisting of halogen, C 1~3 -alkyl, C 1~3 -haloalkyl, C 1~3 -alkoxy, C 1~3 -haloalkoxy, and C 1~3 -alkylcarbonyl.

[0165] In some embodiments, R 2 The spiroheterocyclyl ring is optionally substituted with one or more halogens. In one aspect, R 2 The spiroheterocyclyl ring is optionally substituted with one or more fluorines.

[0166] In some embodiments, R 2 The spiroheterocyclyl ring is optionally substituted with one or more C 1~3 -alkyls.

[0167] In some embodiments, R 2 The spiroheterocyclyl ring is optionally substituted with one or more C 1~3 -haloalkyls.

[0168] In some embodiments, R 2 The spiroheterocyclyl ring is optionally substituted with one or more C 1~3 -alkoxys.

[0169] In some embodiments, R 2 The spiroheterocyclyl ring is optionally substituted with one or more C1~3 - Optionally substituted with haloalkoxy.

[0170] In some embodiments, R 2 The spiroheterocyclyl ring has one or more C 1~3 - Optionally substituted with alkylcarbonyl. In one aspect, R 2 The spiroheterocyclyl ring is optionally substituted with one or more methylcarbonyls.

[0171] In another aspect, R 2 The spiroheterocyclyl ring is optionally substituted with one or more substituents independently selected from the group consisting of fluoro, methyl, ethyl, propyl, isopropyl, fluoromethyl, difluoromethyl, trifluoromethyl, fluoroethyl, difluoroethyl, trifluoroethyl, trifluoropropyl, methoxy, ethoxy, trifluoromethoxy, trifluoroethoxy, methoxycarbonyl, ethylcarbonyl, and isopropylcarbonyl.

[0172] In some embodiments, R 2 The spiroheterocyclyl ring is optionally substituted with one or more substituents independently selected from the group consisting of fluoro, methyl, ethyl, fluoromethyl, difluoromethyl, and trifluoromethyl.

[0173] In some embodiments, R 2 The two saturated rings of the spiroheterocyclyl are:

Chemical formula

[0174] In some embodiments, the compound and the pharmaceutically acceptable salt are (R)-N-(2-(4-cyanothiazolidin-3-yl)-2-oxoethyl)-6-(2-azaspiro[3.3]heptan-2-yl)-quinoline-4-carboxamide (Example 17); (R)-N-(2-(4-cyanothiazolidin-3-yl)-2-oxoethyl)-6-(6-fluoro-2-azaspiro[3.3]heptan-2-yl)quinoline-4-carboxamide (Example 155); (R)-N-(2-(4-Cyanothiazolidin-3-yl)-2-oxoethyl)-6-(6-(trifluoromethyl)-2-azaspiro[3.3]heptan-2-yl)quinoline-4-carboxamide (Example 150); (R)-N-(2-(4-Cyanothiazolidin-3-yl)-2-oxoethyl)-6-(6-methyl-2-azaspiro[3.3]heptan-2-yl)quinoline-4-carboxamide (Example 149); and is selected from the group consisting of pharmaceutically acceptable salts thereof.

[0175] In some embodiments, R 2 The two saturated rings of the spiroheterocyclyl are:

Chemical formula

[0176] In some embodiments, the compound or pharmaceutically acceptable salt thereof is (R)-6-(6-acetyl-2,6-diazaspiro[3.3]heptan-2-yl)-N-(2-(4-cyanothiazolidin-3-yl)-2-oxoethyl)quinoline-4-carboxamide (Example 184), or a pharmaceutically acceptable salt thereof.

[0177] In some embodiments, R 2 The two saturated rings of the spiroheterocyclyl are:

Chemical formula

[0178] In some embodiments, the compound or pharmaceutically acceptable salt thereof is (R)-N-(2-(4-cyanothiazolidin-3-yl)-2-oxoethyl)-6-(1-thia-6-azaspiro[3.3]heptan-6-yl)quinoline-4-carboxamide (Example 222), or a pharmaceutically acceptable salt thereof.

[0179] In some embodiments, R 2 The two saturated rings of the spiroheterocyclyl are:

Chemical formula

[0180] In some embodiments, the compound and the pharmaceutically acceptable salt are (R)-N-(2-(4-Cyanothiazolidin-3-yl)-2-oxoethyl)-6-(3,3-dimethyl-1-oxa-6-azaspiro[3.3]heptan-6-yl)quinoline-4-carboxamide (Example 18); (R)-N-(2-(4-Cyanothiazolidin-3-yl)-2-oxoethyl)-6-(1-oxa-6-azaspiro[3.3]heptan-6-yl)quinoline-4-carboxamide (Example 153); And selected from the group consisting of its pharmaceutically acceptable salts.

[0181] In some embodiments, R 2 The two saturated rings of the spiroheterocyclyl are:

Chemical formula

[0182] In some embodiments, the compound or pharmaceutically acceptable salt thereof is (R)-N-(2-(4-cyanothiazolidin-3-yl)-2-oxoethyl)-6-(2-oxa-6-azaspiro[3.3]heptan-6-yl)quinoline-4-carboxamide (Example 166), or a pharmaceutically acceptable salt thereof.

[0183] In some embodiments, R 2 The two saturated rings of the spiroheterocyclyl are:

Chemical formula

[0184] In some embodiments, the compound and the pharmaceutically acceptable salt are (R)-N-(2-(4-Cyanothiazolidin-3-yl)-2-oxoethyl)-6-(2-azaspiro[3.4]octan-2-yl)quinoline-4-carboxamide (Example 139); (R)-N-(2-(4-Cyanothiazolidin-3-yl)-2-oxoethyl)-6-(5,5-difluoro-2-azaspiro[3.4]octan-2-yl)quinoline-4-carboxamide (Example 141); And selected from the group consisting of its pharmaceutically acceptable salts.

[0185] In some embodiments, R 2 The two saturated rings of spiroheterocyclyl are: [Chemistry] and one or both of the rings are optionally substituted with one or more substituents independently selected from the group consisting of halogen, C -alkyl, C 1~6 -haloalkyl, C 1~6 -alkoxy, C 1~6 -haloalkoxy, and C 1~6 -alkylcarbonyl. In one embodiment, R 1~6 The spiroheterocyclyl ring is optionally substituted with one or more substituents independently selected from the group consisting of halogen, C 2 -alkyl, C 1~3 -haloalkyl, C 1~3 -alkoxy, C 1~3 -haloalkoxy, and C 1~3 -alkylcarbonyl. In another embodiment, R 1~3 The spiroheterocyclyl ring is optionally substituted with one or more substituents independently selected from the group consisting of fluoro, methyl, ethyl, propyl, fluoromethyl, difluoromethyl, trifluoromethyl, fluoroethyl, difluoroethyl, trifluoroethyl, trifluoropropyl, methoxy, ethoxy, trifluoromethoxy, trifluoroethoxy, methylcarbonyl, and ethylcarbonyl. In another embodiment, R 2 The spiroheterocyclyl ring is optionally substituted with one or more substituents independently selected from the group consisting of fluoro, methyl, ethyl, fluoromethyl, difluoromethyl, and trifluoromethyl. 2

[0186] In some embodiments, the compound or pharmaceutically acceptable salt thereof is (R)-N-(2-(4-cyanothiazolidin-3-yl)-2-oxoethyl)-6-(5,8-dioxo-2-azaspiro[3.4]octan-2-yl)quinoline-4-carboxamide (Example 163), or a pharmaceutically acceptable salt thereof.

[0187] In some embodiments, R 2The two saturated rings of spiroheterocyclyl are: [Chemical formula] and one or both of the rings are optionally substituted with one or more substituents independently selected from the group consisting of halogen, C 1~6 -alkyl, C 1~6 -haloalkyl, C 1~6 -alkoxy, C 1~6 -haloalkoxy, and C 1~6 -alkylcarbonyl. In one embodiment, R 2 the spiroheterocyclyl ring is optionally substituted with one or more substituents independently selected from the group consisting of halogen, C 1~3 -alkyl, C 1~3 -haloalkyl, C 1~3 -alkoxy, C 1~3 -haloalkoxy, and C 1~3 -alkylcarbonyl. In another embodiment, R 2 the spiroheterocyclyl ring is optionally substituted with one or more substituents independently selected from the group consisting of fluoro, methyl, ethyl, propyl, fluoromethyl, difluoromethyl, trifluoromethyl, fluoroethyl, difluoroethyl, trifluoroethyl, trifluoropropyl, methoxy, ethoxy, trifluoromethoxy, and trifluoroethoxy. In another embodiment, R 2 the spiroheterocyclyl ring is optionally substituted with one or more substituents independently selected from the group consisting of fluoro, methyl, ethyl, fluoromethyl, difluoromethyl, and trifluoromethyl.

[0188] In some embodiments, R 2 the two saturated rings of spiroheterocyclyl are: [Chemical formula] and one or both of the rings are halogen, C 1~6 -alkyl, C 1~6 -haloalkyl, C 1~6-alkoxy, C 1~6 -haloalkoxy, and C 1~6 -alkylcarbonyl, and is optionally substituted with one or more substituents independently selected from the group consisting of. In one embodiment, R 2 The spiroheterocyclyl ring is halogen, C 1~3 -alkyl, C 1~3 -haloalkyl, C 1~3 -alkoxy, C 1~3 -haloalkoxy, and C 1~3 -alkylcarbonyl, and is optionally substituted with one or more substituents independently selected from the group consisting of. In another embodiment, R 2 The spiroheterocyclyl ring is optionally substituted with one or more substituents independently selected from the group consisting of fluoro, methyl, ethyl, propyl, fluoromethyl, difluoromethyl, trifluoromethyl, fluoroethyl, difluoroethyl, trifluoroethyl, trifluoropropyl, methoxy, ethoxy, trifluoromethoxy, trifluoroethoxy, methylcarbonyl, and ethylcarbonyl. In another embodiment, R 2 The spiroheterocyclyl ring is optionally substituted with one or more substituents independently selected from the group consisting of fluoro, methyl, ethyl, fluoromethyl, difluoromethyl, and trifluoromethyl.

[0189] In some embodiments, the compound or pharmaceutically acceptable salt thereof is (R)-N-(2-(4-cyanothiazolidin-3-yl)-2-oxoethyl)-6-(8-oxa-5-azaspiro[3.5]nonan-5-yl)quinoline-4-carboxamide (Example 104), or a pharmaceutically acceptable salt thereof.

[0190] In some embodiments, R 2 The two saturated rings of the spiroheterocyclyl are:

Chemical formula

[0191] In some embodiments, the compound or pharmaceutically acceptable salt thereof is (R)-N-(2-(4-cyanothiazolidin-3-yl)-2-oxoethyl)-6-(3-oxa-9-azaspiro[5.5]undecan-9-yl)quinoline-4-carboxamide (Example 162), or a pharmaceutically acceptable salt thereof.

[0192] In some embodiments, R 2 The two saturated rings of spiroheterocyclyl are:

Chemical formula

[0193] In some embodiments, the compound or pharmaceutically acceptable salt thereof is (R)-N-(2-(4-cyanothiazolidin-3-yl)-2-oxoethyl)-6-(1,9-dioxo-4-azaspiro[5.5]undecan-4-yl)quinoline-4-carboxamide (Example 99), or a pharmaceutically acceptable salt thereof.

[0194] In some embodiments, R 2 The two saturated rings of spiroheterocyclyl are:

Chemical formula

[0195] In some embodiments, the compound or a pharmaceutically acceptable salt thereof is (R)-N-(2-(4-cyanothiazolidin-3-yl)-2-oxoethyl)-6-(7-oxo-6-oxa-8-azaspiro[4.5]dec-8-yl)quinoline-4-carboxamide (Example 111), or a pharmaceutically acceptable salt thereof.

[0196] In some embodiments, R 2 The two saturated rings of the spiroheterocyclyl are:

Chemical formula

[0197] In some embodiments, the compound or pharmaceutically acceptable salt thereof is (R)-N-(2-(4-cyanothiazolidin-3-yl)-2-oxoethyl)-6-(2-oxo-1-oxa-3-azaspiro[5.5]undecan-3-yl)quinoline-4-carboxamide (Example 110), or a pharmaceutically acceptable salt thereof.

[0198] In some embodiments, R 2 The two saturated rings of the spiroheterocyclyl are:

Chemical Structure

[0199] In some embodiments, the compound or pharmaceutically acceptable salt thereof is (R)-N-(2-(4-cyanothiazolidin-3-yl)-2-oxoethyl)-6-(2-oxa-7-azaspiro[3.5]nonan-7-yl)quinoline-4-carboxamide (Example 229), or a pharmaceutically acceptable salt thereof.

[0200] In some embodiments, R 2 The two saturated rings of the spiroheterocyclyl are:

Chemical formula

[0201] the two saturated rings of the spiroheterocyclyl are: 2

Chemical formula

Chem.

[0202] In some embodiments, the compound or pharmaceutically acceptable salt thereof is (R)-N-(2-(4-cyanothiazolidin-3-yl)-2-oxoethyl)-6-(1,5-dioxa-9-azaspiro[5.5]undecan-9-yl)quinoline-4-carboxamide (Example 227), or a pharmaceutically acceptable salt thereof.

[0203] In some embodiments, the compound and pharmaceutically acceptable salt thereof are (R)-N-(2-(4-Cyanothiazolidin-3-yl)-2-oxoethyl)-6-(2-azaspiro[3.3]heptan-2-yl)quinoline-4-carboxamide (Example 17); (R)-N-(2-(4-Cyanothiazolidin-3-yl)-2-oxoethyl)-6-(3,3-dimethyl-1-oxa-6-azaspiro[3.3]heptan-6-yl)quinoline-4-carboxamide (Example 18); (R)-N-(2-(4-Cyanothiazolidin-3-yl)-2-oxoethyl)-6-(1-azaspiro[3.3]heptan-1-yl)quinoline-4-carboxamide (Example 19); (R)-N-(2-(4-Cyanothiazolidin-3-yl)-2-oxoethyl)-6-(5-azaspiro[2.5]octan-5-yl)quinoline-4-carboxamide (Example 46); (R)-N-(2-(4-Cyanothiazolidin-3-yl)-2-oxoethyl)-6-(5-azaspiro[2.4]heptan-5-yl)quinoline-4-carboxamide (Example 49); N-(2-((R)-4-Cyanothiazolidin-3-yl)-2-oxoethyl)-6-((R)-6-(fluoromethyl)-5-azaspiro[2.4]heptan-5-yl)quinoline-4-carboxamide (Example 58); (R)-N-(2-(4-Cyanothiazolidin-3-yl)-2-oxoethyl)-6-(1,9-dioxa-4-azaspiro[5.5]undecan-4-yl)quinoline-4-carboxamide (Example 99); (R)-N-(2-(4-Cyanothiazolidin-3-yl)-2-oxoethyl)-6-(8-oxa-5-azaspiro[3.5]nonan-5-yl)quinoline-4-carboxamide (Example 104); (R)-N-(2-(4-Cyanothiazolidin-3-yl)-2-oxoethyl)-6-(2-oxo-1-oxa-3-azaspiro[5.5]undecan-3-yl)quinoline-4-carboxamide (Example 110); (R)-N-(2-(4-Cyanothiazolidin-3-yl)-2-oxoethyl)-6-(7-oxo-6-oxa-8-azaspiro[4.5]dec-8-yl)quinoline-4-carboxamide (Example 111); (R)-N-(2-(4-Cyanothiazolidin-3-yl)-2-oxoethyl)-6-(2-azaspiro[3.4]octan-2-yl)quinoline-4-carboxamide (Example 139); (R)-N-(2-(4-Cyanothiazolidin-3-yl)-2-oxoethyl)-6-(5,5-difluoro-2-azaspiro[3.4]octan-2-yl)quinoline-4-carboxamide (Example 141); (R)-N-(2-(4-Cyanothiazolidin-3-yl)-2-oxoethyl)-6-(6-methyl-2-azaspiro[3.3]heptan-2-yl)quinoline-4-carboxamide (Example 149); (R)-N-(2-(4-Cyanothiazolidin-3-yl)-2-oxoethyl)-6-(6-(trifluoromethyl)-2-azaspiro[3.3]heptan-2-yl)quinoline-4-carboxamide (Example 150); (R)-N-(2-(4-Cyanothiazolidin-3-yl)-2-oxoethyl)-6-(1-oxa-6-azaspiro[3.3]heptan-6-yl)quinoline-4-carboxamide (Example 153); (R)-N-(2-(4-Cyanothiazolidin-3-yl)-2-oxoethyl)-6-(6-fluoro-2-azaspiro[3.3]heptan-2-yl)quinoline-4-carboxamide (Example 155); (R)-N-(2-(4-Cyanothiazolidin-3-yl)-2-oxoethyl)-6-(3-oxa-9-azaspiro[5.5]undecan-9-yl)quinoline-4-carboxamide (Example 162); (R)-N-(2-(4-Cyanothiazolidin-3-yl)-2-oxoethyl)-6-(5,8-dioxa-2-azaspiro[3.4]octan-2-yl)quinoline-4-carboxamide (Example 163); (R)-N-(2-(4-Cyanothiazolidin-3-yl)-2-oxoethyl)-6-(5-azaspiro[2.3]hexan-5-yl)quinoline-4-carboxamide (Example 164); (R)-N-(2-(4-Cyanothiazolidin-3-yl)-2-oxoethyl)-6-(2-oxa-6-azaspiro[3.3]heptan-6-yl)quinoline-4-carboxamide (Example 166); (R)-6-(6-Acetyl-2,6-diazaspiro[3.3]heptan-2-yl)-N-(2-(4-cyanothiazolidin-3-yl)-2-oxoethyl)quinoline-4-carboxamide (Example 184); (R)-N-(2-(4-Cyanothiazolidin-3-yl)-2-oxoethyl)-6-(1-thia-6-azaspiro[3.3]heptan-6-yl)quinoline-4-carboxamide (Example 222); (R)-N-(2-(4-Cyanothiazolidin-3-yl)-2-oxoethyl)-6-(1,5-dioxa-9-azaspiro[5.5]undecan-9-yl)quinoline-4-carboxamide (Example 227); (R)-N-(2-(4-Cyanothiazolidin-3-yl)-2-oxoethyl)-6-(1,4-dioxa-8-azaspiro[4.5]decane-8-yl)quinoline-4-carboxamide (Example 228); (R)-N-(2-(4-Cyanothiazolidin-3-yl)-2-oxoethyl)-6-(2-oxa-7-azaspiro[3.5]nonan-7-yl)quinoline-4-carboxamide (Example 229); and is selected from the group consisting of the compound and its pharmaceutically acceptable salts.

[0204] In some embodiments, the compound and the pharmaceutically acceptable salt are (R)-N-(2-(4-Cyanothiazolidin-3-yl)-2-oxoethyl)-6-(3,3-dimethyl-1-oxa-6-azaspiro[3.3]heptan-6-yl)quinoline-4-carboxamide (Example 18); (R)-N-(2-(4-Cyanothiazolidin-3-yl)-2-oxoethyl)-6-(1,9-dioxo-4-azaspiro[5.5]undecan-4-yl)quinoline-4-carboxamide (Example 99); (R)-N-(2-(4-Cyanothiazolidin-3-yl)-2-oxoethyl)-6-(2-oxo-1-oxa-3-azaspiro[5.5]undecan-3-yl)quinoline-4-carboxamide (Example 110); (R)-N-(2-(4-Cyanothiazolidin-3-yl)-2-oxoethyl)-6-(6-(Trifluoromethyl)-2-azaspiro[3.3]heptan-2-yl)quinoline-4-carboxamide (Example 150); (R)-N-(2-(4-Cyanothiazolidin-3-yl)-2-oxoethyl)-6-(1-oxa-6-azaspiro[3.3]heptan-6-yl)quinoline-4-carboxamide (Example 153); (R)-N-(2-(4-Cyanothiazolidin-3-yl)-2-oxoethyl)-6-(5,8-dioxo-2-azaspiro[3.4]octan-2-yl)quinoline-4-carboxamide (Example 163); (R)-N-(2-(4-Cyanothiazolidin-3-yl)-2-oxoethyl)-6-(2-oxa-6-azaspiro[3.3]heptan-6-yl)quinoline-4-carboxamide (Example 166); (R)-N-(2-(4-Cyanothiazolidin-3-yl)-2-oxoethyl)-6-(1-thia-6-azaspiro[3.3]heptan-6-yl)quinoline-4-carboxamide (Example 222); and is selected from the group consisting of pharmaceutically acceptable salts thereof.

[0205] D.R 2 is azetidinyl In some embodiments, the disclosure provides a compound having the structure of formula (V):

Chemical formula

[0206] In some embodiments of the compounds having the structure of formula (V), R 1 , R 3 , R4 , R 5 , and R 6 One of the substituents is selected from the group consisting of chloro, fluoro, and methyl, and the remaining R 1 , R 3 , R 4 , R 5 , and R 6 substituents are all hydrogen. In one embodiment, R 1 , R 3 , R 4 , R 5 , and R 6 One of the substituents is chloro, and the remaining R 1 , R 3 , R 4 , R 5 , and R 6 substituents are all hydrogen. In another embodiment, R 1 , R 3 , R 4 , R 5 , and R 6 One of the substituents is fluoro, and the remaining R 1 , R 3 , R 4 , R 5 , and R 6 substituents are all hydrogen. In another embodiment, R 1 , R 3 , R 4 , R 5 , and R 6 One of the substituents is methyl, and the remaining R 1 , R 3 , R 4 , R 5 , and R 6 substituents are all hydrogen.

[0207] In some embodiments of the compound having the structure of formula (V), R 1 , R 3 , R 4 , R 5 , and R 6 are all hydrogen.

[0208] In some embodiments of the compound having the structure of formula (V), R 20a and R20b is independently selected from the group consisting of hydrogen and methyl; R 20c and R 20d are independently hydrogen, fluoro, hydroxy, C 1~3 -alkyl, C 3~6 -cycloalkyl, C 1~3 -alkoxy, C 1~3 -alkoxy-C 1~3 -alkyl, morpholinyl, C 1~3 -alkylsulfonyl-C 1~3 -alkyl, and C 1~3 -alkyl-carbonylamino-C 1~3 -alkyl selected from the group consisting of; C 1~3 -alkyl, C 3~6 -cycloalkyl, C 1~3 -alkoxy, and C 1~3 -alkoxy-C 1~3 -alkyl may be further substituted with one or more halogens; and R 20e and R 20f are independently selected from the group consisting of hydrogen and methyl.

[0209] In some embodiments of the compounds having the structure of formula (V), R 20c and R 20d are independently hydrogen, fluoro, C 1~3 -alkyl, C 1~3 -alkoxy, morpholinyl, and C 1~3 -alkyl-carbonylamino-C 1~3 -alkyl selected from the group consisting of; C 1~3 -alkyl and C 1~3 -alkoxy may be further substituted with one or more halogens.

[0210] In some embodiments, the compound and the pharmaceutically acceptable salt are (R)-N-(2-(4-cyanothiazolidin-3-yl)-2-oxoethyl)-6-(3-(fluoromethyl)-3-methylazetidin-1-yl)quinoline-4-carboxamide (Example 27); (R)-N-(2-(4-Cyanothiazolidin-3-yl)-2-oxoethyl)-6-(3-(fluoromethyl)azetidin-1-yl)quinoline-4-carboxamide (Example 113); (R)-N-(2-(4-Cyanothiazolidin-3-yl)-2-oxoethyl)-6-(3-methoxy-3-methylazetidin-1-yl)quinoline-4-carboxamide (Example 151); and is selected from the group consisting of the compound and its pharmaceutically acceptable salts.

[0211] E.R 2 is morpholinyl In some embodiments, the present disclosure provides a compound having the structure of formula (VI):

Chemical formula

[0212] In some embodiments of the compounds having the structure of formula (VI), R 1 , R 3 , R 4 , R 5 , and R 6 One of the substituents is selected from the group consisting of chloro, fluoro, and methyl, and the remaining R 1 , R 3 , R 4 , R 5 , and R 6 substituents are all hydrogen. In one aspect, R 1 , R 3 , R 4 , R 5 , and R 6 One of the substituents is chloro, and the remaining R 1 , R 3 , R 4 , R 5 , and R 6 substituents are all hydrogen. In another aspect, R 1 , R 3 , R 4 , R 5 , and R 6 One of the substituents is fluoro, and the remaining R 1 , R 3 , R 4 , R 5 , and R 6 substituents are all hydrogen. In another aspect, R 1 , R 3 , R 4 , R 5 , and R 6One of the substituents is methyl, and the remaining R 1 、R 3 、R 4 、R 5 、and R 6 substituents are all hydrogen.

[0213] In some embodiments of the compound having the structure of formula (VI), R 1 、R 3 、R 4 、R 5 、and R 6 are all hydrogen.

[0214] In some embodiments of the compound having the structure of formula (VI), R 30a and R 30b are independently selected from the group consisting of hydrogen, C 1~2 -alkyl, halo-C 1~2 -alkyl, and C 1~2 -alkoxy-C 1~2 -alkyl; R 30c and R 30d are independently selected from the group consisting of hydrogen, halogen, C 1~2 -alkyl, halo-C 1~2 -alkyl, C 1~2 -alkoxy-C 1~2 -alkyl, and C 1~2 -alkylsulfonyl-C 1~2 -alkyl; R 30e and R 30f are independently selected from the group consisting of hydrogen, halogen, C 1~2 -alkyl, halo-C 1~2 -alkyl, C 1~2 -alkoxy-C 1~2 -alkyl, and C 1~2 -alkylsulfonyl-C 1~2 -alkyl; and R 30g and R 30h are independently selected from the group consisting of hydrogen, C 1~2 -alkyl, halo-C 1~2 -alkyl, and C 1~2 -alkoxy-C1~2 is selected from the group consisting of -alkyl.

[0215] In some embodiments, the compound and the pharmaceutically acceptable salt are (R)-N-(2-(4-Cyanothiazolidin-3-yl)-2-oxoethyl)-8-methyl-6-morpholinoquinoline-4-carboxamide (Example 9); (R)-N-(2-(4-Cyanothiazolidin-3-yl)-2-oxoethyl)-6-morpholinoquinoline-4-carboxamide (Example 67); N-(2-((R)-4-Cyanothiazolidin-3-yl)-2-oxoethyl)-6-((2R,6S)-2,6-dimethylmorpholino)-quinoline-4-carboxamide (Example 68); N-(2-((R)-4-Cyanothiazolidin-3-yl)-2-oxoethyl)-6-((R)-2-(fluoromethyl)morpholino)-quinoline-4-carboxamide (Example 69); N-(2-((R)-4-Cyanothiazolidin-3-yl)-2-oxoethyl)-6-((2R,6R)-2,6-dimethylmorpholino)-quinoline-4-carboxamide (Example 70); N-(2-((R)-4-Cyanothiazolidin-3-yl)-2-oxoethyl)-6-((S)-2-(fluoromethyl)morpholino)-quinoline-4-carboxamide (Example 71); N-(2-((R)-4-Cyanothiazolidin-3-yl)-2-oxoethyl)-6-((R)-2-methylmorpholino)-quinoline-4-carboxamide (Example 72); N-(2-((R)-4-Cyanothiazolidin-3-yl)-2-oxoethyl)-6-((S)-2-methylmorpholino)-quinoline-4-carboxamide (Example 80); and is selected from the group consisting of its pharmaceutically acceptable salts.

[0216] F.R 2 is piperidin-1-yl In some embodiments, the present disclosure relates to a compound having the structure of formula (VII): [Chemical formula] and its pharmaceutically acceptable salts (wherein, R 1 R 3 R 4 R 5 and R 6 are independently selected from the group consisting of hydrogen, chloro, fluoro, and methyl; R 40a and R 40b are independently selected from the group consisting of hydrogen, C 1~3 -alkyl, and halo-C 1~3 -alkyl; R 40c and R 40d are independently selected from the group consisting of hydrogen, fluoro, C 1~3 -alkyl, halo-C 1~3 -alkyl, and C 1~3 -alkoxy; R 40e and R 40f are independently selected from the group consisting of hydrogen, fluoro, hydroxy, oxo, C 1~3 -alkyl, halo-C 1~3 -alkyl, cyclopropyl, and C 1~3 -alkoxy; R 40g and R 40h are independently selected from the group consisting of hydrogen, fluoro, C 1~3 -alkyl, halo-C 1~3 alkyl, and C 1~3 -alkoxy; and R 40i and R 40j are independently selected from the group consisting of hydrogen, C 1~3 -alkyl, and halo-C 1~3 -alkyl) are provided.

[0217] In some embodiments of the compounds having the structure of formula (VII), R 1 R 3 R 4 R 5 and R 6One of the substituents is selected from the group consisting of chloro, fluoro, and methyl, and the remaining R 1 's, R 3 's, R 4 's, R 5 's, and R 6 substituents are all hydrogen. In one embodiment, R 1 's, R 3 's, R 4 's, R 5 's, and R 6 One of the substituents is chloro, and the remaining R 1 's, R 3 's, R 4 's, R 5 's, and R 6 substituents are all hydrogen. In another embodiment, R 1 's, R 3 's, R 4 's, R 5 's, and R 6 One of the substituents is fluoro, and the remaining R 1 's, R 3 's, R 4 's, R 5 's, and R 6 substituents are all hydrogen. In another embodiment, R 1 's, R 3 's, R 4 's, R 5 's, and R 6 One of the substituents is methyl, and the remaining R 1 's, R 3 's, R 4 's, R 5 's, and R 6 substituents are all hydrogen.

[0218] In some embodiments of the compound having the structure of formula (VII), R 1 's, R 3 's, R 4 's, R 5 's, and R 6 are all hydrogen.

[0219] In some embodiments of the compound having the structure of formula (VII), R 40a and R 40b are, independently, hydrogen, C 1~3-Alkyl, and halo-C 1~3 selected from the group consisting of -alkyl; R 40c and R 40d are independently hydrogen, fluoro, C 1~3 -alkyl, halo-C 1~3 -alkyl, and C 1~3 -alkoxy selected from the group consisting of; R 40e and R 40f are independently hydrogen, fluoro, hydroxy, C 1~3 -alkyl, halo-C 1~3 -alkyl, cyclopropyl, and C 1~3 -alkoxy selected from the group consisting of; R 40g and R 40h are independently hydrogen, fluoro, C 1~3 -alkyl, halo-C 1~3 alkyl, and C 1~3 -alkoxy selected from the group consisting of; and R 40i and R 40j are independently hydrogen, C 1~3 -alkyl, and halo-C 1~3 -alkyl selected from the group consisting of.

[0220] In some embodiments of the compound having the structure of formula (VII), R 40a and R 40b are independently hydrogen, C 1~2 -alkyl, and halo-C 1~2 -alkyl selected from the group consisting of; R 40c and R 40d are independently hydrogen, fluoro, C 1~2 -alkyl, halo-C 1~2 -alkyl, and C 1~2 -alkoxy selected from the group consisting of; R 40e and R 40f are independently hydrogen, fluoro, hydroxy, C 1~2 -alkyl, halo-C 1~2 -alkyl, and C1~2 selected from the group consisting of -alkoxy; R 40g and R 40h are, independently, hydrogen, fluoro, C 1~2 -alkyl, halo-C 1~2 -alkyl, and C 1~2 -alkoxy selected from the group consisting of; and R 40i and R 40j are, independently, hydrogen, C 1~2 -alkyl, and halo-C 1~2 -alkyl selected from the group consisting of.

[0221] In some embodiments, the compound and the pharmaceutically acceptable salt are (R)-N-(2-(4-cyanothiazolidin-3-yl)-2-oxoethyl)-6-(4-methoxypiperidin-1-yl)quinoline-4-carboxamide (Example 8); (R)-N-(2-(4-cyanothiazolidin-3-yl)-2-oxoethyl)-6-(4-methoxy-4-methylpiperidin-1-yl)quinoline-4-carboxamide (Example 42); (R)-N-(2-(4-cyanothiazolidin-3-yl)-2-oxoethyl)-6-(4-fluoropiperidin-1-yl)quinoline-4-carboxamide (Example 205); (R)-N-(2-(4-cyanothiazolidin-3-yl)-2-oxoethyl)-6-(4-oxopiperidin-1-yl)quinoline-4-carboxamide (Example 230); and are selected from the group consisting of its pharmaceutically acceptable salts.

[0222] G.R 2 is piperidin-4-yl In some embodiments, the present disclosure relates to a compound having the structure of formula (VIII):

Chemical formula

[0223] In some embodiments of the compounds having the structure of formula (VIII), R 1 , R 3 , R 4 , R 5 , and R 6One of the substituents is selected from the group consisting of chloro, fluoro, and methyl, and the remaining R 1 , R 3 , R 4 , R 5 , and R 6 substituents are all hydrogen. In one embodiment, R 1 , R 3 , R 4 , R 5 , and R 6 one of the substituents is chloro, and the remaining R 1 , R 3 , R 4 , R 5 , and R 6 substituents are all hydrogen. In another embodiment, R 1 , R 3 , R 4 , R 5 , and R 6 one of the substituents is fluoro, and the remaining R 1 , R 3 , R 4 , R 5 , and R 6 substituents are all hydrogen. In another embodiment, R 1 , R 3 , R 4 , R 5 , and R 6 one of the substituents is methyl, and the remaining R 1 , R 3 , R 4 , R 5 , and R 6 substituents are all hydrogen.

[0224] In some embodiments of the compound having the structure of formula (VIII), R 1 , R 3 , R 4 , R 5 , and R 6 are all hydrogen.

[0225] In some embodiments of the compound having the structure of formula (VIII), R 1 , R 3 , R 4 , R 5, and R 6 is selected from the group consisting of hydrogen, fluoro, and methyl; R 50a and R 50b are independently selected from the group consisting of hydrogen, fluoro, C 1~2 -alkyl, halo-C 1~2 -alkyl, and C 1~2 -alkoxy; R 50c and R 50d are independently selected from the group consisting of hydrogen, C 1~2 -alkyl, and halo-C 1~2 -alkyl; R 50e is selected from the group consisting of hydrogen, C 1~2 -alkyl, halo-C 1~2 -alkyl, and C 1~2 -alkoxy-C 2~3 -alkyl; R 50f and R 50g are independently selected from the group consisting of hydrogen, C 1~2 -alkyl, and halo-C 1~2 -alkyl; R 50h and R 50i are independently selected from the group consisting of hydrogen, fluoro, C 1~2 -alkyl, halo-C 1~2 -alkyl, and C 1~2 -alkoxy; and R 50j is selected from the group consisting of hydrogen and fluoro.

[0226] In some embodiments of the compounds having the structure of formula (VIII), at least one of R 50a , R 50b , R 50h , R 50i , and R 50j is fluoro.

[0227] H.R 2 is 3-oxomorpholinyl In some embodiments, the present disclosure provides a compound having the structure of formula (IX): [Chemical formula] and its pharmaceutically acceptable salts (wherein, R 1 , R 3 , R 4 , R 5 , and R 6 are independently selected from the group consisting of hydrogen, chloro, fluoro, and methyl; R 60a and R 60b are independently selected from the group consisting of hydrogen and C 1~3 -alkyl; R 60c and R 60d are independently selected from the group consisting of hydrogen and C 1~3 -alkyl; and R 60e and R 60f are independently selected from the group consisting of hydrogen and C 1~3 -alkyl) is provided.

[0228] In some embodiments of the compound having the structure of formula (IX), one of the R 1 , R 3 , R 4 , R 5 , and R 6 substituents is selected from the group consisting of chloro, fluoro, and methyl, and the remaining R 1 , R 3 , R 4 , R 5 , and R 6 substituents are all hydrogen. In one aspect, one of the R 1 , R 3 , R 4 , R 5 , and R 6 substituents is chloro, and the remaining R 1 , R 3 , R 4 , R 5 , and R 6 substituents are all hydrogen. In another aspect, R 1 , R 3 , R 4 , R 5, and R 6 One of the substituents is fluoro, and the remaining R 1 , R 3 , R 4 , R 5 , and R 6 substituents are all hydrogen. In another embodiment, R 1 , R 3 , R 4 , R 5 , and R 6 One of the substituents is methyl, and the remaining R 1 , R 3 , R 4 , R 5 , and R 6 substituents are all hydrogen.

[0229] In some embodiments of the compound having the structure of formula (IX), R 1 , R 3 , R 4 , R 5 , and R 6 are all hydrogen.

[0230] In some embodiments of the compound having the structure of formula (IX), R 4 is methyl; and R 1 , R 3 , R 5 , and R 6 are all hydrogen.

[0231] In some embodiments of the compound having the structure of formula (IX), R 1 , R 3 , R 4 , R 5 , and R 6 is selected from the group consisting of hydrogen, fluoro, and methyl; R 60a and R 60b are independently selected from the group consisting of hydrogen and C 1~2 -alkyl; R 60c and R 60d are independently selected from the group consisting of hydrogen and C 1~2-selected from the group consisting of -alkyl; and R 60e and R 60f are, independently, selected from the group consisting of hydrogen and C 1~2 -alkyl.

[0232] I.R 2 is 5,8-dioxa-2-azaspiro[3.4]octan-2-yl In some embodiments, the present disclosure provides a compound having the structure of formula (X):

Chemical formula

[0233] In some embodiments of the compound having the structure of formula (X), one of the R 1 、R 3 、R 4 、R 5 、and R 6 substituents is selected from the group consisting of chloro, fluoro, and methyl, and the remaining R 1 、R3 , R 4 , R 5 , and R 6 substituents are all hydrogen. In one embodiment, R 1 , R 3 , R 4 , R 5 , and R 6 one of the substituents is chloro, and the remaining R 1 , R 3 , R 4 , R 5 , and R 6 substituents are all hydrogen. In another embodiment, R 1 , R 3 , R 4 , R 5 , and R 6 one of the substituents is fluoro, and the remaining R 1 , R 3 , R 4 , R 5 , and R 6 substituents are all hydrogen. In another embodiment, R 1 , R 3 , R 4 , R 5 , and R 6 one of the substituents is methyl, and the remaining R 1 , R 3 , R 4 , R 5 , and R 6 substituents are all hydrogen.

[0234] In some embodiments of the compound having the structure of formula (X), R 1 , R 3 , R 4 , R 5 , and R 6 are all hydrogen.

[0235] In some embodiments of the compound having the structure of formula (X), R 1 , R 3 , R 4 , R 5 , and R 6 are selected from the group consisting of hydrogen, fluoro, and methyl; R70a and R 70b are, independently, selected from the group consisting of hydrogen and C 1~2 -alkyl; R 70c and R 70d are, independently, selected from the group consisting of hydrogen and C 1~2 -alkyl; R 70e and R 70f are, independently, selected from the group consisting of hydrogen and C 1~2 -alkyl; and R 70g and R 70h are, independently, selected from the group consisting of hydrogen and C 1~2 -alkyl.

[0236] J.R 2 is pyridin-3-yl In some embodiments, the disclosure provides a compound having the structure of formula (XI):

Chemical formula

[0237] In some embodiments of the compound having the structure of formula (XI), R 1 , R 3 , R 4 , R 5 , and R 6 One of the substituents is selected from the group consisting of chloro, fluoro, and methyl, and the remaining R 1 , R 3 , R 4 , R 5 , and R 6 substituents are all hydrogen. In one aspect, R 1 , R 3 , R 4 , R 5 , and R 6 One of the substituents is chloro, and the remaining R 1 , R 3 , R 4 , R 5 , and R 6 substituents are all hydrogen. In another aspect, R 1 , R 3 , R 4 , R 5 , and R 6 One of the substituents is fluoro, and the remaining R 1 , R 3 , R 4 , R 5 , and R 6 substituents are all hydrogen. In another aspect, R 1 , R 3 , R 4 , R 5 , and R 6 One of the substituents is methyl, and the remaining R 1 , R 3 , R 4 , R 5 , and R 6 substituents are all hydrogen.

[0238] In some embodiments of the compound having the structure of formula (XI), R 1 , R 3 , R 4 , R 5 , and R 6 are all hydrogen.

[0239] In some embodiments of the compound having the structure of formula (XI), R 1 , R 3 , R 4 , R 5 , and R 6 are selected from the group consisting of hydrogen, fluoro, and methyl; R 80a is selected from the group consisting of hydrogen, fluoro, C 1~2 -alkyl, halo-C 1~2 -alkyl, and C 1~2 -alkoxy; R 80b is selected from the group consisting of hydrogen, fluoro, C 1~2 -alkyl, halo-C 1~2 -alkyl, and C 1~2 -alkoxy; R 80c is selected from the group consisting of hydrogen, fluoro, C 1~2 -alkyl, halo-C 1~2 -alkyl, and C 1~2 -alkoxy; and R 80d is selected from the group consisting of hydrogen, fluoro, C 1~2 -alkyl, halo-C 1~2 -alkyl, and C 1~2 -alkoxy.

[0240] In some embodiments, the compound or a pharmaceutically acceptable salt thereof is (R)-N-(2-(4-cyanothiazolidin-3-yl)-2-oxoethyl)-6-(6-(difluoromethyl)pyridin-3-yl)quinoline-4-carboxamide (Example 169), or a pharmaceutically acceptable salt thereof.

[0241] K. Additional Embodiments Any embodiment of the compounds described in the present disclosure can be combined with any other suitable embodiment described herein to provide additional embodiments. For example, if one embodiment describes the groups contemplated for R 1 , R 3 , R 4 , R 5 , and / or R 6 individually or in combination, and another embodiment describes the groups contemplated for R 2 , it is understood that these embodiments can be combined to provide additional embodiments that describe the groups contemplated for R 1 , R 3 , R 4 , R 5 , and / or R 6 in combination with the groups contemplated for R 2 . In other words, with respect to any of the embodiments of the compounds described in the present disclosure, the R 2 substituents can be as defined in any of the embodiments of the following R 2 .

[0242] The compounds of the present disclosure have pharmaceutically acceptable FAP inhibitory activity as measured as described for the hFAP inhibition assay (robust conjugate) reported in the examples below. In one aspect, the compound has FAP inhibitory activity at an IC 50 concentration of less than about 100 nM. In another aspect, the compound has FAP inhibitory activity at an IC 50 concentration of less than about 50 nM. In another aspect, the compound has FAP inhibitory activity at an IC 50 concentration of less than about 10 nM. In another aspect, the compound has FAP inhibitory activity at an IC 50 concentration of less than about 1 nM.

[0243] In some embodiments, the compounds of the present disclosure have pharmaceutically acceptable surface plasmon resonance (SPR) pK d values as measured as described for the SPR assay reported in the examples below. In one aspect, the compound has a surface plasmon resonance (SPR) pK greater than about 7d has a value. In another aspect, the compound has a surface plasmon resonance (SPR) pK greater than about 8 d has a value. In another aspect, the compound has an SPR pK greater than about 9 d has a value. In another aspect, the compound has an SPR pK greater than about 10 d has a value.

[0244] In some embodiments, the compounds of the present disclosure have a pharmaceutically acceptable selectivity for FAP over PREP as measured as described for the hFAP inhibition assay (robust conjugate) and hPREP inhibition assay reported in the examples below. In one aspect, the compound has at least about 50-fold higher selectivity for FAP over PREP. In another aspect, the compound has at least about 100-fold higher selectivity for FAP over PREP. In another aspect, the compound has at least about 1,000-fold higher selectivity for FAP over PREP. In another aspect, the compound has at least about 10,000-fold higher selectivity for FAP over PREP. In another aspect, the compound has a PREP IC greater than about 0.1 μM 50 has a value. In another aspect, the compound has a PREP IC greater than about 1.0 μM 50 has a value. In another aspect, the compound has a PREP IC greater than about 10.0 μM 50 has a value.

[0245] In some embodiments, the compounds of the present disclosure have pharmaceutically acceptable selectivity for FAP over DPP7 as measured as described for the hFAP inhibition assay (robust conjugate) and DPP7 selectivity assay reported in the examples below. In one aspect, the compound has at least about 50-fold higher selectivity for FAP over DPP7. In another aspect, the compound has at least about 100-fold higher selectivity for FAP over DPP7. In another aspect, the compound has at least about 1,000-fold higher selectivity for FAP over DPP7. In another aspect, the compound has at least about 10,000-fold higher selectivity for FAP over DPP7. In another aspect, the compound has an IC 50 value for DPP7 greater than about 0.1 μM. In another aspect, the compound has an IC 50 value for DPP7 greater than about 1 μM. In another aspect, the compound has an IC 50 value for DPP7 greater than about 10 μM.

[0246] In some embodiments, the compounds of the present disclosure have pharmaceutically acceptable selectivity for FAP over DPP8 and / or DPP9 as measured as described for the hFAP inhibition assay (robust conjugate), DPP8 selectivity assay, and DPP9 selectivity assay reported in the examples below. In one aspect, the compound has selectivity for FAP over DPP8. In another aspect, the compound has selectivity for FAP over DPP9. In another aspect, the compound has selectivity for FAP over both DPP8 and DPP9. In one aspect, the compound has at least about 50-fold higher selectivity for FAP over DPP8 and / or DPP9. In another aspect, the compound has at least about 100-fold higher selectivity for FAP over DPP8 and / or DPP9. In another aspect, the compound has at least about 500-fold higher selectivity for FAP over DPP8 and / or DPP9. In another aspect, the compound has at least about 1,000-fold higher selectivity for FAP over DPP8 and / or DPP9. In another aspect, the compound has an IC 50 value for DPP8 and / or DPP9 greater than about 0.01 μM. In another aspect, the compound has an IC 50 value for DPP8 and / or DPP9 greater than about 0.1 μM. In another aspect, the compound has an IC 50 value for DPP8 and / or DPP9 greater than about 0.4 μM.

[0247] In some embodiments, the compounds of the present disclosure have pharmaceutically acceptable metabolic stability as measured as described for the human liver microsome (HLM) assay reported in the examples below. In one aspect, the compound has an HLM CL int value less than about 300 μL / min / mg. In another aspect, the compound has an HLM CL int value less than about 100 μL / min / mg. In another aspect, the compound has an HLM CL int value less than about 50 μL / min / mg.

[0248] In some embodiments, the compounds of the present disclosure have pharmaceutically acceptable metabolic stability as measured as described for the rat hepatocyte (rHep) assay reported in the examples below. In one aspect, the compound has an rHep CL of less than about 300 μL / min / 10 6 cells int value. In another aspect, the compound has an rHep CL of less than about 100 μL / min / 10 6 cells int value. In another aspect, the compound has an rHep CL of less than about 50 μL / min / 10 6 cells int value.

[0249] In some embodiments, the compounds of the present disclosure have pharmaceutically acceptable Caco-2 AB intrinsic permeability as measured as described for the Caco-2 AB intrinsic permeability assay reported in the examples below. In one aspect, the compound has an apparent Caco-2 intrinsic permeability of at least about 0.1×10 6 cm / s. In another aspect, the compound has an apparent Caco-2 intrinsic permeability of at least about 0.5×10 6 cm / s. In another aspect, the compound has an apparent Caco-2 intrinsic permeability of at least about 1×10 6 cm / s.

[0250] In some embodiments, the compounds of the present disclosure have pharmaceutically acceptable Caco-2 bidirectional (ABBA) A-to-B apparent permeability as measured as described for the Caco-2 bidirectional (ABBA) A-to-B apparent permeability assay reported in the examples below. In one aspect, the compound has a Caco-2 bidirectional (ABBA) A-to-B apparent permeability of at least about 0.1×10 6 cm / s. In another aspect, the compound has a Caco-2 bidirectional (ABBA) A-to-B apparent permeability of at least about 0.25×10 6 cm / s. In another aspect, the compound has a Caco-2 bidirectional (ABBA) A-to-B apparent permeability of at least about 0.5×10 6It has a bidirectional (ABBA) apparent permeability of A to B in Caco-2 of cm / s.

[0251] In some embodiments, the compounds of the present disclosure have a pharmaceutically acceptable kinetic solubility as measured as described for the kinetic solubility assays reported in the examples below. In one aspect, the compound has a kinetic solubility of at least about 1 μM. In another aspect, the compound has a kinetic solubility of at least about 10 μM. In another aspect, the compound has a kinetic solubility of at least about 25 μM. In another aspect, the compound has a kinetic solubility of at least about 50 μM.

[0252] L. salt The compounds of the present disclosure may exist in salt or non-salt form (i.e., as free base), and the present disclosure encompasses both salt and non-salt forms. The compounds may form acid addition salts or base addition salts. Generally, acid addition salts can be prepared using various inorganic or organic acids. Such salts can typically be formed using various methods known in the art, for example, by mixing the compound with an acid (e.g., a stoichiometric amount of the acid). This mixing can occur in water, an organic solvent (e.g., ether, ethyl acetate, ethanol, methanol, isopropanol, or acetonitrile), or an aqueous / organic mixture. In another aspect, the acid addition salts are, for example, trifluoroacetate, formate, acetate, or hydrochloride. Generally, base addition salts can be prepared using various inorganic or organic bases, for example, alkali or alkaline earth metal salts, such as sodium salts, calcium salts, or magnesium salts, or other metal salts, such as potassium or zinc, or ammonium salts, or salts with organic bases, such as methylamine, dimethylamine, trimethylamine, piperidine, or morpholine. Those skilled in the art will recognize the general principles and techniques for preparing pharmaceutical salts, such as those described in J.Pharm.Sci. 1977 66, 1. Examples of pharmaceutically acceptable salts are also described in “Handbook of Pharmaceutical Salts: Properties, Selection, and Use” by Stahl and Wermuth (Wiley-VCH, Weinheim, Germany, 2002).

[0253] M. isomer The compounds and salts of the present disclosure may exist in one or more geometric, optical, enantiomeric, and diastereomeric forms including, but not limited to, cis- and trans-forms, E- and Z-forms, and R-, S-, and meso-forms. Unless otherwise specified, references to a particular compound include all such isomeric forms, including racemic mixtures and other mixtures. Where appropriate, such isomers can be separated from their mixtures by the application or adaptation of known methods (e.g., chromatographic and recrystallization techniques). Where appropriate, such isomers can be prepared by the application or adaptation of known methods. In some embodiments, a single stereoisomer is obtained by isolating it from a mixture of isomers (e.g., a racemate), for example, using chiral chromatographic separation. In other embodiments, a single stereoisomer is obtained, for example, by direct synthesis from a chiral starting material.

[0254] Certain enantiomers of the compounds described herein may be more active than other enantiomers of the same compound. In one embodiment, the compound, or a pharmaceutically acceptable salt thereof, is a single enantiomer present in an enantiomeric excess (%ee) of ≧90, ≧95%, ≧96%, ≧97, ≧98% or ≧99%.

[0255] In one aspect, the single enantiomer is present in an enantiomeric excess (%ee) of ≧99%. In another embodiment, the present disclosure relates to a pharmaceutical composition comprising a single enantiomer present in an enantiomeric excess (%ee) of ≧90, ≧95%, ≧96%, ≧97, ≧98% or ≧99%, or a pharmaceutically acceptable salt thereof, in combination with one or more pharmaceutically acceptable excipients. In one aspect, the single enantiomer is present in an enantiomeric excess (%ee) of ≧99%.

[0256] N. Additional Forms The compounds and salts of the present disclosure may exist in various tautomeric forms, and this specification encompasses all such tautomeric forms. A "tautomer" is a structural isomer that exists in equilibrium as a result of the migration of a hydrogen atom. The compounds of the present disclosure, and their pharmaceutically acceptable salts, may exist as solvates (such as hydrates) and non-solvated forms, and this specification encompasses all such solvates.

[0257] The compounds of the present disclosure, and their pharmaceutically acceptable salts, may exist in crystalline or amorphous forms, and this specification encompasses all such forms.

[0258] The compounds and salts of the present disclosure may be isotopically labeled (or "radiolabeled"). In such instances, one or more atoms are replaced by an atom having an atomic mass or mass number different from the atomic mass or mass number typically found in nature. This specification encompasses isotopically labeled forms of the compounds disclosed herein. Examples of isotopes that may be incorporated include 2 H (also described as "D" with respect to deuterium), 3 H (also described as "T" with respect to tritium), 11 C, 13 C, 14 C, 13 N, 15 N, 15 O, 17 O, 18 O and 36 Cl. The isotopes used will depend on the particular use of the radiolabeled derivative. For example, in the case of in vitro receptor labeling and competitive assays, 3 H or 14 C are often useful. For radioactive imaging applications, 11 C is often useful. In some embodiments, the radionuclide is 3 H. In some embodiments, the radionuclide is 14 C. In some embodiments, the radionuclide is 11 C.

[0259] O. Intermediate In some embodiments, the present disclosure provides additional compounds that are useful as intermediates for preparing the compounds of the present disclosure and pharmaceutically acceptable salts thereof.

[0260] III. Methods of Use The disclosed compounds of the present disclosure and pharmaceutically acceptable salts thereof are inhibitors of prolyl endopeptidase fibroblast activation protein (FAP) activity. FAP is an endopeptidase that enzymatically cleaves substances involved in glucose and lipid metabolism, fibrinolysis, and collagen production.

[0261] FAP is thought to cleave and inactivate human fibroblast growth factor 21 (FGF-21) (Biochem J 2016, 473, 605), a protein involved in the regulation of glucose and lipid metabolism. Inhibition of FAP is hypothesized to increase endogenous FGF-21 levels and signaling, resulting in, for example, a reduction in adiposity, an improvement in insulin sensitivity, an improvement in glucose tolerance, a reduction in body weight, and / or a reduction in cardiovascular disease mortality.

[0262] FAP is also thought to cleave human α2-antiplasmin (α2AP), a protein involved in the regulation of fibrosis and fibrinolysis (Blood 2004 103,3783). Tissue repair involves coagulation, which causes fibrin deposition. Fibrin in blood clots is usually lysed mainly by plasmin when it is converted from its inactive form (plasminogen) by plasminogen activator. Fibrinolysis is inhibited by plasminogen activator inhibitor-1 (PAI-1), plasminogen activator inhibitor-2 (PAI-2), and α2AP (Experimental & Molecular Medicine 2020,52,367), all of which are induced by tissue trauma. FAP converts α2AP to a more active form that reduces plasmin activity, increasing fibrin deposition at the site of injury. Inhibition of FAP is hypothesized to increase fibrinolysis and improve tissue regeneration at the site of injury (J Thromb Haemost 2013,11,2029;Proteomics Clin.Appl.2014,8,454).

[0263] FAP is further thought to play a role in promoting collagen production and deposition and increasing fibrosis via the turnover of the modified extracellular matrix (ECM) (J Biol Chem 2016,8,291). Inhibition of FAP is hypothesized to result in decreased collagen deposition and reduced inflammation (Inflamm Bowel Dis.2018,18,332).

[0264] In view of the above, it is hypothesized that inhibition of FAP reduces fibrosis and inflammation collectively by reducing hepatic stellate cell activity and increasing fibrinolysis, and further provides a positive metabolic effect through increased FGF21 signaling and improved glucose tolerance.

[0265] Accordingly, in some embodiments, the present disclosure provides a method for treating or preventing a FAP-mediated condition in a subject in need thereof by administering to the subject a therapeutically effective amount of a compound of Formula I, or a pharmaceutically acceptable salt thereof.

[0266] In some embodiments, the present disclosure provides a method for treating or preventing a condition characterized by overexpression of FAP in a subject in need thereof by administering to the subject a therapeutically effective amount of a compound of the present disclosure, or a pharmaceutically acceptable salt thereof.

[0267] In some embodiments, the present disclosure provides a method for treating or preventing liver disease in a subject in need thereof by administering to the subject a therapeutically effective amount of a compound of the present disclosure, or a pharmaceutically acceptable salt thereof. In one aspect, the liver disease is fatty liver disease. In another aspect, the liver disease is non-alcoholic fatty liver disease (NAFLD). In another aspect, the NAFLD is selected from the group consisting of isolated steatosis, non-alcoholic steatohepatitis (NASH), hepatic fibrosis, and cirrhosis. In another aspect, the liver disease is end-stage liver disease. In another aspect, the subject also has or is predisposed to one or more conditions selected from the group consisting of obesity, dyslipidemia, insulin resistance, type 2 diabetes, and renal insufficiency.

[0268] In some embodiments, the present disclosure provides a method for treating liver disease in a subject in need thereof by administering to the subject a therapeutically effective amount of a compound of the present disclosure, or a pharmaceutically acceptable salt thereof, wherein the subject has a body mass index (BMI) of 2 ~40 kg / m 2 In one aspect, the subject has a BMI of 2 ~39.9 kg / m 2 In another aspect, the subject has a BMI of at least 2 40 kg / m

[0269] In some embodiments, the present disclosure provides a method for treating liver disease in a subject in need thereof by administering to the subject a therapeutically effective amount of a compound of the present disclosure, or a pharmaceutically acceptable salt thereof, wherein the subject also has or is susceptible to dyslipidemia. In another aspect, the liver disease is NAFLD. In another aspect, the liver disease is NASH. In another aspect, the liver disease is hepatic fibrosis. In another aspect, the liver disease is cirrhosis.

[0270] In some embodiments, the present disclosure provides a method for treating liver disease in a subject in need thereof by administering to the subject a therapeutically effective amount of a compound of the present disclosure, or a pharmaceutically acceptable salt thereof, wherein the subject also has or is susceptible to insulin resistance. In another aspect, the liver disease is NAFLD. In another aspect, the liver disease is NASH. In another aspect, the liver disease is hepatic fibrosis. In another aspect, the liver disease is cirrhosis.

[0271] In some embodiments, the present disclosure provides a method for treating liver disease in a subject in need thereof by administering to the subject a therapeutically effective amount of a compound of the present disclosure, or a pharmaceutically acceptable salt thereof, wherein the subject also has or is susceptible to at least one of type 2 diabetes and renal insufficiency. In another aspect, the liver disease is NAFLD. In another aspect, the liver disease is NASH. In another aspect, the liver disease is hepatic fibrosis. In another aspect, the liver disease is cirrhosis.

[0272] In some embodiments, the present disclosure provides a method for treating liver disease in a subject in need thereof by administering to the subject a therapeutically effective amount of a compound of the present disclosure, or a pharmaceutically acceptable salt thereof, wherein the subject also has or is susceptible to type 2 diabetes. In another aspect, the liver disease is NAFLD. In another aspect, the liver disease is NASH. In another aspect, the liver disease is hepatic fibrosis. In another aspect, the liver disease is cirrhosis.

[0273] In some embodiments, the present disclosure provides a method for treating liver disease in a subject in need thereof by administering to the subject a therapeutically effective amount of a compound of the present disclosure, or a pharmaceutically acceptable salt thereof, wherein the subject also has or is at risk of having renal insufficiency. In another aspect, the liver disease is NAFLD. In another aspect, the liver disease is NASH. In another aspect, the liver disease is liver fibrosis. In another aspect, the liver disease is cirrhosis.

[0274] In some embodiments, the present disclosure provides a method for reducing liver fat in a subject in need thereof by administering to the subject a therapeutically effective amount of a compound of the present disclosure, or a pharmaceutically acceptable salt thereof. In one aspect, the subject has or is at risk of having NAFLD. In another aspect, the subject has or is at risk of having NASH. In another aspect, the subject has or is at risk of having liver fibrosis. In another aspect, the subject has or is at risk of having cirrhosis. In another aspect, the subject also has or is at risk of having one or more conditions selected from the group consisting of obesity, dyslipidemia, insulin resistance, type 2 diabetes, and renal insufficiency.

[0275] In some embodiments, the present disclosure provides a method for treating or preventing non-alcoholic fatty liver disease (NAFLD) in a subject in need thereof by administering to the subject a therapeutically effective amount of a compound of the present disclosure, or a pharmaceutically acceptable salt thereof. In one aspect, the NAFLD is stage 1 NAFLD. In another aspect, the NAFLD is stage 2 NAFLD. In another aspect, the NAFLD is stage 3 NAFLD. In another aspect, the NAFLD is stage 4 NAFLD. See, for example, “The Diagnosis and Management of Nonalcoholic Fatty Liver Disease: Practice Guidance From the American Association for the Study of Liver Diseases,” Hepatology, 2018, Vol. 67, No. 1. In another aspect, the subject is also suffering from or is susceptible to one or more conditions selected from the group consisting of obesity, dyslipidemia, insulin resistance, type 2 diabetes, and renal insufficiency.

[0276] In some embodiments, the present disclosure provides a method for treating or preventing non-alcoholic steatohepatitis (NASH) in a subject in need thereof by administering to the subject a therapeutically effective amount of a compound of the present disclosure, or a pharmaceutically acceptable salt thereof. In one aspect, the NASH is stage 1 NASH. In another aspect, the NASH is stage 2 NASH. In another aspect, the NASH is stage 3 NASH. In another aspect, the NASH is stage 4 NASH. In another aspect, the subject is also suffering from or is susceptible to one or more conditions selected from the group consisting of obesity, dyslipidemia, insulin resistance, type 2 diabetes, and renal insufficiency.

[0277] In some embodiments, the present disclosure provides a method for treating or preventing liver fibrosis in a subject in need thereof by administering to the subject a therapeutically effective amount of a compound of the present disclosure, or a pharmaceutically acceptable salt thereof. In one aspect, the subject has stage 3 liver fibrosis. In another aspect, the subject also has or is susceptible to one or more conditions selected from the group consisting of obesity, dyslipidemia, insulin resistance, type 2 diabetes, and renal insufficiency.

[0278] In some embodiments, the present disclosure provides a method for treating or preventing cirrhosis in a subject in need thereof by administering to the subject a therapeutically effective amount of a compound of the present disclosure, or a pharmaceutically acceptable salt thereof. In one aspect, the subject has stage F4 cirrhosis. In another aspect, the subject also has or is susceptible to one or more conditions selected from the group consisting of obesity, dyslipidemia, insulin resistance, type 2 diabetes, and renal insufficiency.

[0279] In some embodiments, the present disclosure provides a method for treating or preventing type 2 diabetes in a subject in need thereof by administering to the subject a therapeutically effective amount of a compound of the present disclosure, or a pharmaceutically acceptable salt thereof. In one aspect, the subject is a subject suffering from diabetic kidney disease. In another aspect, the subject has renal insufficiency. In another aspect, the administration of the compound is an adjunct to diet and exercise. In another aspect, the administration of the compound also reduces body weight and / or treats obesity. In another aspect, the subject has a BMI of 27 kg / m 2 ~40 kg / m 2 In another aspect, the subject has a BMI of 30 kg / m 2 ~39.9 kg / m 2 In another aspect, the subject has a BMI of at least 40 kg / m 2 In another aspect, the subject is overweight. In another aspect, the subject is obese.

[0280] In some embodiments, the present disclosure provides a method of improving glycemic control in a subject in need thereof by administering to the subject a therapeutically effective amount of a compound of the present disclosure, or a pharmaceutically acceptable salt thereof. In one aspect, the subject is a subject suffering from type 2 diabetes. In another aspect, the subject is a subject suffering from diabetic kidney disease. In another aspect, the subject is suffering from renal insufficiency. In another aspect, administration of the compound is an adjunct to diet and exercise. In another aspect, administration of the compound also reduces body weight and / or treats obesity. In another aspect, the subject has a BMI of 27 kg / m 2 to 40 kg / m 2 . In another aspect, the subject has a BMI of 30 kg / m 2 to 39.9 kg / m 2 . In another aspect, the subject has a BMI of at least 40 kg / m 2 . In another aspect, the subject is overweight. In another aspect, the subject is obese.

[0281] In some embodiments, the present disclosure provides a method of improving glycemic control in a subject having type 2 diabetes and diabetic kidney disease by administering to the subject a therapeutically effective amount of a compound of the present disclosure, or a pharmaceutically acceptable salt thereof. In one aspect, administration of the compound is an adjunct to diet and exercise. In another aspect, administration of the compound also reduces body weight and / or treats obesity. In another aspect, the subject has a BMI of 27 kg / m 2 to 40 kg / m 2 . In another aspect, the subject has a BMI of 30 kg / m 2 to 39.9 kg / m 2 . In another aspect, the subject has a BMI of at least 40 kg / m 2 . In another aspect, the subject is overweight. In another aspect, the subject is obese.

[0282] In some embodiments, the present disclosure provides a method of improving glycemic control in a subject having type 2 diabetes and renal insufficiency by administering to the subject a therapeutically effective amount of a compound of the present disclosure, or a pharmaceutically acceptable salt thereof. In one aspect, administration of the compound is an adjunct to diet and exercise. In another aspect, administration of the compound also reduces body weight and / or treats obesity. In another aspect, the subject has a BMI of 27 kg / m 2 to 40 kg / m 2 . In another aspect, the subject has a BMI of 30 kg / m 2 to 39.9 kg / m 2 . In another aspect, the subject has a BMI of at least 40 kg / m 2 . In another aspect, the subject is overweight. In another aspect, the subject is obese.

[0283] In some embodiments, the present disclosure provides a method of treating or preventing insulin resistance in a subject by administering to the subject a therapeutically effective amount of a compound of the present disclosure, or a pharmaceutically acceptable salt thereof. In another aspect, the subject is a subject suffering from type 2 diabetes. In another aspect, the subject is a subject suffering from diabetic kidney disease. In another aspect, the subject is suffering from renal insufficiency. Insulin resistance can be measured, for example, using the homeostasis model assessment of insulin resistance (HOMA-IR) and / or the Matsuda index. HOMA-IR is described, for example, in Diabetologia 1985, 28, 412, which is hereby incorporated by reference in its entirety. The Matsuda index is described, for example, in Diabetes Care 1999, 22, 1462, which is hereby incorporated by reference in its entirety.

[0284] In some embodiments, the present disclosure provides a method of treating or preventing glucose intolerance in a subject in need thereof by administering to the subject a therapeutically effective amount of a compound of the present disclosure, or a pharmaceutically acceptable salt thereof. In one aspect, the subject is a subject suffering from type 2 diabetes. In another aspect, the subject is a subject suffering from diabetic kidney disease. In another aspect, the subject is suffering from renal insufficiency.

[0285] In some embodiments, the present disclosure provides a method of treating a cardiovascular disorder in a subject in need thereof by administering to the subject a therapeutically effective amount of a compound of the present disclosure, or a pharmaceutically acceptable salt thereof. In one aspect, the cardiovascular disorder is selected from the group consisting of heart failure, cardiomyopathy, atherosclerosis, venous thromboembolism, and atrial fibrillation. In one aspect, the cardiovascular disorder is heart failure. In another aspect, the cardiovascular disorder is heart failure with preserved ejection fraction (HFpEF). In another aspect, the cardiovascular disorder is cardiomyopathy. In another aspect, the cardiomyopathy is selected from the group consisting of hypertrophic cardiomyopathy, dilated cardiomyopathy, restrictive cardiomyopathy, hypertrophic cardiomyopathy, ischemic cardiomyopathy, ischemic cardiomyopathy, dilated cardiomyopathy, and idiopathic cardiomyopathy. In another aspect, the cardiovascular disorder is atherosclerosis. In another aspect, the cardiovascular disorder is venous thromboembolism. In another aspect, the cardiovascular disorder is atrial fibrillation.

[0286] In some embodiments, the present disclosure provides a method of treating obesity or obesity-related disorders in a subject in need thereof by administering to the subject a therapeutically effective amount of a compound of the present disclosure, or a pharmaceutically acceptable salt thereof. In one aspect, the obesity-related disorder is an obesity-related metabolic disorder. In another aspect, the obesity-related disorder is selected from the group consisting of insulin resistance, prediabetes, type 2 diabetes, glucose intolerance, elevated fasting blood glucose, and glucagonoma. In another aspect, the obesity-related disorder is dyslipidemia. In another aspect, the obesity-related disorder is a cardiovascular disorder selected from the group consisting of heart failure, cardiomyopathy, atherosclerosis, venous thromboembolism, and atrial fibrillation. In another aspect, the obesity-related disorder is a kidney disease.

[0287] In some embodiments, the present disclosure provides a method of reducing body weight by administering to a subject in need thereof a therapeutically effective amount of a compound of the present disclosure, or a pharmaceutically acceptable salt thereof. In one aspect, the subject is a subject suffering from type 2 diabetes. In another aspect, the subject is a subject suffering from diabetic kidney disease. In another aspect, the subject is suffering from renal insufficiency. In another aspect, administration of the compound is an adjunct to diet and exercise. In another aspect, administration of the compound also reduces body weight and / or treats obesity. In another aspect, the subject has a BMI of 27 kg / m 2 to 40 kg / m 2 . In another aspect, the subject has a BMI of 30 kg / m 2 to 39.9 kg / m 2 . In another aspect, the subject has a BMI of at least 40 kg / m 2 . In another aspect, the subject is overweight. In another aspect, the subject is obese. In another aspect, the weight of the subject is reduced by, for example, at least about 5%, 10%, 15%, 20%, 25%, 30%, 35%, or 40%.

[0288] In some embodiments, the present disclosure provides a method of reducing body fat by administering to a subject in need thereof a therapeutically effective amount of a compound of the present disclosure, or a pharmaceutically acceptable salt thereof. In one aspect, the subject is a subject suffering from type 2 diabetes. In another aspect, the subject is a subject suffering from diabetic kidney disease. In another aspect, the subject is suffering from renal insufficiency. In another aspect, administration of the compound is an adjunct to diet and exercise. In another aspect, administration of the compound also reduces body weight and / or treats obesity. In another aspect, the subject has a BMI of 27 kg / m 2 to 40 kg / m 2 . In another aspect, the subject has a BMI of 30 kg / m 2 to 39.9 kg / m 2 . In another aspect, the subject has a BMI of at least 40 kg / m 2 . In another aspect, the subject is overweight. In another aspect, the subject is obese. In another aspect, the fat is liver fat.

[0289] In some embodiments, the present disclosure provides a method for treating or preventing fibrosis by administering to a subject in need thereof a therapeutically effective amount of a compound of the present disclosure, or a pharmaceutically acceptable salt thereof. In one aspect, the fibrosis is interstitial lung disease. In another aspect, the fibrosis is interstitial lung disease with progressive fibrosis. In another aspect, the interstitial lung disease is pulmonary fibrosis. In another aspect, the interstitial lung disease is idiopathic pulmonary fibrosis (IPF).

[0290] In some embodiments, the present disclosure provides a method for promoting tissue repair by administering to a subject in need thereof a therapeutically effective amount of a compound of the present disclosure, or a pharmaceutically acceptable salt thereof. In one aspect, the subject has deteriorated heart tissue damage resulting from myocardial infarction.

[0291] In some embodiments, the present disclosure provides a method for promoting wound healing and / or reducing adhesion by administering to a subject in need thereof a therapeutically effective amount of a compound of the present disclosure, or a pharmaceutically acceptable salt thereof. In one aspect, administration of the compound promotes wound healing and / or reduces adhesion via an increase in fibrinolysis.

[0292] In some embodiments, the present disclosure provides a method for treating or preventing keloid disorders by administering to a subject in need thereof a therapeutically effective amount of a compound of the present disclosure, or a pharmaceutically acceptable salt thereof. In one aspect, the keloid disorder is selected from the group consisting of scar formation, keloid tumors, and keloid scars.

[0293] In some embodiments, the present disclosure provides a method for treating or preventing inflammation by administering to a subject in need thereof a therapeutically effective amount of a compound of the present disclosure, or a pharmaceutically acceptable salt thereof. In one aspect, the inflammation is chronic inflammation. In one aspect, the chronic inflammation is selected from the group consisting of rheumatoid arthritis, osteoarthritis, and Crohn's disease. In another aspect, the chronic inflammation is rheumatoid arthritis.

[0294] In some embodiments, the present disclosure provides a method of treating cancer in a subject in need thereof by administering to the subject a therapeutically effective amount of a compound of the present disclosure, or a pharmaceutically acceptable salt thereof. In one aspect, the cancer is selected from the group consisting of breast cancer, pancreatic cancer, small intestine cancer, colon cancer, rectal cancer, lung cancer, head and neck cancer, ovarian cancer, hepatocellular carcinoma, esophageal cancer, hypopharyngeal cancer, oropharyngeal cancer, laryngeal cancer, multiple myeloma cells, bladder cancer, cholangiocarcinoma, renal clear cell carcinoma, neuroendocrine tumors, tumor-induced osteomalacia, sarcoma, CUP (cancer of unknown primary), thymic cancer, desmoid tumor, glioma, astrocytoma, cervical cancer, and prostate cancer. In another aspect, the cancer is hepatocellular carcinoma.

[0295] The subject to be treated will typically be a human or non-human mammal, particularly a human. Suitable subjects may also include domestic or wild animals; companion animals (including dogs, cats, etc.); livestock (including horses, cows and other ruminants, pigs, poultry, rabbits, etc.); primates (including monkeys such as macaques, cynomolgus monkeys (also known as crab-eating macaques or long-tailed macaques), marmosets, tamarins, chimpanzees, macaques, etc.); and rodents (including rats, mice, gerbils, guinea pigs, etc.).

[0296] In some embodiments, the present disclosure provides a compound of the present disclosure, or a pharmaceutically acceptable salt thereof, for use as a medicament.

[0297] In some embodiments, the present disclosure provides the use of a compound of formula I, or a pharmaceutically acceptable salt thereof, for treating or preventing a FAP-mediated condition as discussed above.

[0298] In some embodiments, the present disclosure provides the use of a compound of formula I, or a pharmaceutically acceptable salt thereof, for the manufacture of a medicament for treating or preventing a FAP-mediated condition as discussed above.

[0299] IV. Combination Therapy and Fixed Dose Combinations The compounds of the present disclosure can be used in the above methods as a single pharmacological agent or in combination with other pharmacological agents or techniques. Such combination therapies can be achieved by simultaneous, sequential, or separate administration of the individual components of the treatment. These combination therapies (and corresponding combination products) utilize the compounds of the present disclosure within the dosage ranges described in this application and typically other pharmacological agents within their approved dosage ranges.

[0300] In some embodiments, the present disclosure provides combinations suitable for use in the treatment of conditions selected from the conditions discussed previously, the combination comprising a compound of the present disclosure, or a pharmaceutically acceptable salt thereof, and a sodium-glucose transporter 2 (SGLT2) inhibitor. In one aspect, the SGLT2 inhibitor is selected from the group consisting of canagliflozin, dapagliflozin, empagliflozin, ertugliflozin, ipragliflozin, luseogliflozin, and remogliflozin. In another aspect, the SGLT2 inhibitor is dapagliflozin.

[0301] In some embodiments, the present disclosure provides combinations suitable for use in the treatment of conditions selected from the conditions discussed previously, the combination comprising a compound of the present disclosure, or a pharmaceutically acceptable salt thereof, and metformin.

[0302] In some embodiments, the present disclosure provides combinations suitable for use in the treatment of conditions selected from the conditions discussed previously, the combination comprising a compound of the present disclosure, or a pharmaceutically acceptable salt thereof, and a glucagon-like peptide-1 receptor (GLP1) agonist. In one aspect, the SGLT2 inhibitor is selected from the group consisting of exenatide, liraglutide, lixisenatide, albiglutide, dulaglutide, and semaglutide.

[0303] In some embodiments, the present disclosure provides a combination suitable for use in the treatment of a condition selected from the conditions discussed previously, the combination comprising a compound of the present disclosure, or a pharmaceutically acceptable salt thereof, and a dipeptidyl peptidase 4 (DPP4) inhibitor. In one aspect, the DPP4 inhibitor is selected from the group consisting of sitagliptin, vildagliptin, saxagliptin, linagliptin, gemigliptin, anagliptin, teneligliptin, alogliptin, trelagliptin, omarigliptin, evogliptin, gosogliptin, and dutogliptin.

[0304] In some embodiments, the present disclosure provides a combination suitable for use in the treatment of a condition selected from the conditions discussed previously, the combination comprising a compound of the present disclosure, or a pharmaceutically acceptable salt thereof, and a peroxisome proliferator-activated receptor (PPAR) agonist. In one aspect, the PPAR agonist is a PPARα agonist. In another aspect, the PPAR agonist is a PPARγ agonist. In another aspect, the PPAR agonist is a PPARα / γ agonist. In another aspect, the PPAR agonist is selected from the group consisting of clofibrate, gemfibrozil, ciprofibrate, bezafibrate, and fenofibrate. In another aspect, the PPAR agonist is a thiazolidinedione. In another aspect, the thiazolidinedione is selected from the group consisting of pioglitazone, rosiglitazone, lobeglitazone, and rivoglitazone. In another aspect, the PPAR agonist stimulates hepatic expression of FGF21.

[0305] In some embodiments, the present disclosure provides a pharmaceutical composition comprising a compound of the present disclosure, or a pharmaceutically acceptable salt thereof; one or more pharmacological agents selected from SGLT2 inhibitors, metformin, GLP1 agonists, DPP4 inhibitors, and PPAR agonists; and a pharmaceutically acceptable diluent or carrier. Such combinations can be used for the manufacture of a medicament for use in the treatment of a condition selected from the conditions discussed above. In one aspect, the pharmaceutical composition comprises an SGLT2 inhibitor. In another aspect, the pharmaceutical composition comprises metformin. In another aspect, the pharmaceutical composition comprises a GLP1 agonist. In another aspect, the pharmaceutical composition comprises a DPP4 inhibitor. In another aspect, the pharmaceutical composition comprises a PPAR agonist.

[0306] In some embodiments, the present disclosure provides a combination suitable for use in the treatment of cancer, the combination comprising a compound of the present disclosure, or a pharmaceutically acceptable salt thereof, and an immune checkpoint inhibitor. In one aspect, the immune checkpoint inhibitor is selected from the group consisting of anti-PD-1 antibodies, anti-PD-L1 antibodies, anti-CTLA4 antibodies, TLR7 agonists, CD40 agonists, Lag-3 antagonists, and OX40 agonists. In another aspect, the immune checkpoint inhibitor is an anti-PD-1 antibody (e.g., pembrolizumab (Keytruda), nivolumab (Opdivo), cemiplimab (Libtayo), etc.). In another aspect, the immune checkpoint inhibitor is an anti-PD-L1 antibody (e.g., atezolizumab (Tecentriq), avelumab (Bavencio), durvalumab (Imfinzi), etc.). In another aspect, the immune checkpoint inhibitor is an anti-CTLA4 antibody (e.g., ipilimumab (Yervoy), tremelimumab, etc.). In another aspect, the cancer is selected from the group consisting of pancreatic cancer, colon cancer, and rectal cancer.

[0307] V. Pharmaceutical Composition The compounds of the present disclosure, and pharmaceutically acceptable salts thereof, can be administered as a pharmaceutical composition comprising one or more pharmaceutically acceptable excipients. Accordingly, in some embodiments, the present disclosure provides a pharmaceutical composition comprising a compound of the present disclosure, or a pharmaceutically acceptable salt thereof, and at least one pharmaceutically acceptable excipient.

[0308] The excipients selected for inclusion in a particular composition will depend on factors such as the mode of administration and the form of the composition being provided. Suitable pharmaceutically acceptable excipients are well known to those skilled in the art and are described, for example, in Handbook of Pharmaceutical Excipients, Sixth Edition, Pharmaceutical Press, edited by Rowe, Ray C; Sheskey, Paul J; Quinn, Marian. Pharmaceutically acceptable excipients can function, for example, as adjuvants, diluents, carriers, stabilizers, flavoring agents, coloring agents, fillers, binders, disintegrants, lubricants, glidants, thickening agents, and coating agents. As will be appreciated by those skilled in the art, a particular pharmaceutically acceptable excipient may perform two or more functions, and may perform alternative functions, depending on the amount of excipient present in the composition and which other excipients are present in the composition.

[0309] The composition can be in a form suitable for oral use (for example, as tablets, lozenges, hard or soft capsules, aqueous or oily suspensions, emulsions, dispersible powders or granules, syrups or elixirs), topical use (for example, as creams, ointments, gels, or aqueous or oily solutions or suspensions), administration by inhalation (for example, as fine powders or liquid aerosols), administration by insufflation (for example, as fine powders), or parenteral administration (for example, as sterile aqueous or oily solutions for intravenous, subcutaneous or intramuscular administration), or as suppositories for rectal administration. The composition may be obtained by conventional procedures using conventional pharmaceutical excipients well known in the art. Accordingly, a composition intended for oral use may contain, for example, one or more coloring agents, sweetening agents, flavoring agents and / or preservatives.

[0310] The total daily dosage will necessarily vary depending on the subject being treated, the particular route of administration, any therapy being concurrently administered, and the severity of the disease being treated, and may include single or multiple dosages. The specific dosage can be adjusted, for example, according to the condition being treated; the age, weight, general health, gender, and diet of the subject; the route of administration; the dosing interval; the rate of excretion; and other drugs being co-administered to the subject. A normally skilled physician provided with the disclosure of the present application will be able to determine the appropriate dosage and regimen for the administration of the therapeutic agent to the subject and, in accordance with methods well known in the art of therapeutic drugs, adjust such dosage and regimen as necessary during the course of treatment. The compounds of the present disclosure, or pharmaceutically acceptable salts thereof, are usually administered to warm-blooded animals in unit dosages within the range of 2.5 - 5000 mg / m 2 (body surface area of the animal), or approximately 0.05 - 100 mg / kg, which will usually provide a therapeutically effective dosage. Unit dosage forms such as tablets or capsules may contain, for example, 0.1 - 500 mg, 0.1 - 250 mg, 0.1 - 100 mg of the active ingredient.

[0311] In some embodiments, the present disclosure provides a pharmaceutical composition for use in therapy, comprising a compound of the present disclosure, or a pharmaceutically acceptable salt thereof, and at least one pharmaceutically acceptable excipient.

[0312] In some embodiments, the present disclosure provides a pharmaceutical composition for use in the treatment of FAP-mediated conditions, comprising a compound of the present disclosure, or a pharmaceutically acceptable salt thereof, and at least one pharmaceutically acceptable excipient. In one aspect, the FAP-mediated condition is selected from the group consisting of liver disease, type 2 diabetes, cardiovascular conditions, obesity, obesity-related conditions, fibrosis, keloid disorders, inflammation, and cancer.

[0313] VI. Kit The present disclosure further provides a kit comprising a unit dosage form containing a compound of the present disclosure or a pharmaceutically acceptable salt thereof contained within a packaging material, and a label or package insert indicating that the unit dosage form can be used to treat one or more of the conditions discussed above.

[0314] In some embodiments, the kit comprises a unit dosage form containing a compound of the present disclosure or a pharmaceutically acceptable salt thereof contained within a packaging material, and a label or package insert indicating that the pharmaceutical composition can be used to treat a condition mediated by FAP. In another aspect, the condition mediated by FAP is a liver disease. In another aspect, the liver disease is selected from the group consisting of fatty liver disease, end-stage liver disease, and cirrhosis. In another aspect, the liver disease is selected from the group consisting of non-alcoholic steatohepatitis (NASH) and non-alcoholic fatty liver disease (NAFLD).

[0315] In some embodiments, the kit comprises: (a) a first unit dosage form containing a compound of the present disclosure or a pharmaceutically acceptable salt thereof; (b) a second unit dosage form containing a pharmacological agent selected from the group consisting of an SGLT2 inhibitor, metformin, a GLP1 agonist, a DPP4 inhibitor, and a PPAR agonist; (c) container means for containing the first dosage form and the second dosage form; and (d) a label or package insert indicating that the first unit dosage form and the second unit dosage form can be used to treat a condition mediated by FAP.

[0316] VII. Preparation Method The present disclosure further provides a process for the preparation of the compounds of formula (I), (II), (III-A), (III-B), (III-C), (III-D), (III-E), (IV), (IV-A), (V), (VI), (VII), (VIII), (IX), (X), and (XI), and pharmaceutically acceptable salts thereof.

[0317] The following Schemes 1-14 illustrate the preparation of the compound of formula (II) wherein R 1 , R 2 , R 3 , R 4 , R 5 , R6 and X 1 is as defined in formula (I), and R 7 is an alkyl group (e.g., methyl, ethyl, or tert-butyl), and X 2 , X 3 and X 4 is a leaving group (e.g., Cl, Br, I, or OTf)). The synthetic routes to) are shown. Those skilled in the art will understand that these methods are representative and do not encompass all possible methods for preparing the compounds of the present disclosure. The R X substituents in each scheme are as defined for the compounds of the present disclosure unless otherwise specified. The processes for the preparations described in Schemes 1 to 14 are carried out starting from any enantiomer, or racemic mixture of the compounds of formula (2), (4), (6), (8), (9), (10), (11), (12), (13) or (14) to obtain the compound of formula (II) or any stereoisomer of formula (II).

[0318] Scheme 1

Chemical formula

[0319] Scheme 2

Chemical formula

[0320] Scheme 3

Chemical formula

[0321] Scheme 4

Chemical formula

[0322] The compound of formula (2) can be formed by reacting the compound of formula (8) with a suitable acid (e.g., HCl) in a solvent such as 1,4-dioxane, EtOAc, MeOH, or water, or a mixture thereof. Alternatively, the reaction can be carried out using an acid such as TFA in a solvent such as neat TFA or DCM, typically at a temperature in the range of 0 °C to 60 °C.

[0323] Scheme 5

Chemical Structure

[0324] The compound of formula (10) can be converted to the compound of formula (11) by dehydration using a suitable reagent (typically TFAA or T3P) in a solvent such as DCM, DMF, EtOAc, or MeCN, or a mixture thereof, typically at a temperature in the range of 0 °C to 120 °C.

[0325] The compound of formula (4) can be formed by reacting the compound of formula (11) with a suitable acid (e.g., HCl or TsOH) in a solvent such as MeCN, 1,4-dioxane, EtOAc, MeOH, or water, or a mixture thereof. Alternatively, the reaction can be carried out using an acid such as TFA in a solvent such as neat TFA or DCM, typically at a temperature in the range of 0 °C to 60 °C.

[0326] Scheme 6

Chem.

[0327] Scheme 7

Chem.

[0328] Scheme 8

Chem.

[0329] The compound of formula (5) can be formed by reacting the compound of formula (16) with a base (e.g., NaOH or LiOH) in an organic solvent (e.g., dioxane, THF or MeOH, or a mixture thereof), optionally in the presence of water. The reaction may be carried out at a temperature interval from 0 °C to reflux. Alternatively, R 7Regarding the compound of formula (16) where it is tert-butyl, the reaction can be carried out with a suitable acid (e.g., HCl) in a solvent such as 1,4-dioxane, EtOAc, MeOH or water, or a mixture thereof. Alternatively, the reaction can be carried out using an acid such as TFA in a solvent such as neat TFA or DCM, typically at a temperature in the range of 0 °C to 60 °C.

[0330] Scheme 9

Chemical formula

[0331] The compound of formula (19) (wherein R 2 is as defined in formula (I) and the point of attachment to quinoline is via a nitrogen atom) can be formed by reacting the compound of formula (18) with an amine H-R 2 (20) (wherein R 2 is as defined in formula (I)). The reaction is carried out in a suitable solvent (such as 1,4-dioxane), optionally in the presence of water, at a temperature in the range from room temperature to reflux, with a base (Cs 2 CO 3In the presence of, etc., a suitable phosphine ligand (e.g., XPhos, CPhos, SPhos, RuPhos, DavePhos or XantPhos) together with a suitable Pd-reagent, e.g., Pd 2 (dba) 3 can be catalyzed.

[0332] The compound of formula (19) (wherein R 2 is as defined in formula (I) and the point of attachment to quinoline is via a nitrogen atom) can be formed by reacting the compound of formula (18) with an amine H-R 2 (20) (wherein R 2 is as defined in formula (I)). The reaction can be carried out in a suitable solvent (such as DMF) at a temperature in the range from room temperature to 160 °C in the presence of a base (K 2 CO 3 or Cs 2 CO 3 etc.) and can be catalyzed by a suitable Cu-reagent (e.g., CuI or Cu 2 O).

[0333] The compound of formula (3) can be formed by reacting a base (e.g., NaOH or LiOH) in an organic solvent (e.g., 1,4-dioxane, THF or MeOH, or a mixture thereof) with the compound of formula (19), optionally in the presence of water. The reaction may be carried out at a temperature interval from 0 °C to reflux. Alternatively, for the compound of formula (19) where R 7 = tert-butyl, the reaction can be carried out with a suitable acid (e.g., HCl) in a solvent such as 1,4-dioxane, EtOAc, MeOH or water, or a mixture thereof. Alternatively, for the compound of formula (19) (wherein R 7 = tert-butyl), the reaction can be carried out as such using an acid such as TFA or in a solvent such as DCM, typically at a temperature in the range from 0 °C to 60 °C.

[0334] Alternatively, for the compound of formula (3) (wherein R 2is as defined in formula (I) and the point of attachment to quinoline is via a nitrogen atom), is an amine H-R 2 (20) (wherein R 2 is as defined in formula (I)) can be formed directly from the compound of formula (17) by reaction with it. The reaction can be carried out under the conditions described for the similar reaction above in Scheme 9.

[0335] Scheme 10 [Chemical formula] Scheme 10 shows the synthetic route to a specific compound of formula (3). The compound of formula (19) (wherein R 2 is as defined in formula (I) and the point of attachment to quinoline is via a carbon atom) is obtained by reacting the compound of formula (18) with compound B-R 2 (21) (wherein B is a boronic acid, boronic acid ester or trifluoroborate, and R 2 is as defined in formula (I)). The reaction can be catalyzed by a suitable Pd-reagent (e.g., Pd(dppf)Cl 2 CO 3 or K 2 CO 3 etc.) in the presence of a base (Na 2 ) in a suitable solvent (such as 1,4-dioxane), optionally in the presence of water, at a temperature in the range from room temperature to reflux.

[0336] The compound of formula (3) can be formed by reacting the compound of formula (19) under the conditions described for the similar reaction described in Scheme 9. Alternatively, the compound of formula (3) (wherein R 2 is as defined in formula (I) and the point of attachment to quinoline is via a carbon atom) is the compound B-R 2 (21) (wherein B is a boronic acid, boronic acid ester or trifluoroborate, and R 2can be formed directly from the compound of formula (17) by reaction with (as defined in formula (I)). The reaction can be carried out under the conditions described for the similar reactions in Scheme 10.

[0337] Scheme 11

Chemical Structure

[0338] The compound of formula (19) (wherein R 2 is as defined in formula (I) and the point of attachment to quinoline is via a carbon atom) can be formed by reacting the compound of formula (22) with an aryl halide or aryl pseudohalide of formula (23) (wherein R 2 is as defined in formula (I) and X 3 is attached to R 2 via a carbon atom). The reaction can be carried out in a suitable solvent (such as 1,4-dioxane), optionally in the presence of water, at a temperature in the range from room temperature to reflux, in the presence of a base (Na 2 CO 3 or K 2 CO3 in the presence of, for example, a suitable Pd-reagent such as Pd(dppf)Cl 2 can be catalyzed by

[0339] Scheme 12 [Chemical formula] Scheme 12 shows the synthetic route to a certain compound of formula (17). The compound of formula (26) can be formed by reacting the compound of formula (24) with a 2-ketocarboxylic acid of formula (25) or a salt thereof (e.g., sodium salt) in water in the presence of a base (e.g., NaOH) at reflux temperature or typically at a high temperature in the range of 100 °C to 160 °C in a sealed vessel in a microwave reactor or a sealed tube. The compound of formula (17) can be formed by heating the compound of formula (26) as such or in a suitable solvent (e.g., water) typically at a high temperature in the range of 150 °C to 250 °C in a sealed vessel in a microwave reactor or a sealed tube.

[0340] Scheme 13 [Chemical formula] Scheme 13 shows the synthetic route to a certain compound of formula (19). The compound of formula (28) (wherein R 2 is as defined in formula (I) and the point of attachment to quinoline is via a nitrogen atom or a carbon atom) can be formed from the compound of formula (27) using a synthetic methodology carried out under the conditions described for the similar reactions described in Schemes 9, 10 and 11.

[0341] The compound of formula (19) can be formed by reacting the compound of formula (28) with carbon monoxide (1 - 10 atm) typically at a pressure of 10 atm at a temperature in the range of typically 80 - 120 °C in a sealed vessel. The reaction can be carried out in the presence of a suitable alcohol (such as MeOH or EtOH) in a suitable solvent or using an alcohol as the solvent, in the presence of a base (e.g., TEA), and catalyzed by a suitable Pd - reagent (e.g., Pd(dppf)Cl 2 ).

[0342] Scheme 14

Chemical formula

[0343] The compound of formula (31) (wherein R 50j is fluorine) can be formed by reacting the compound of formula (29) with a fluorinating agent (e.g., DAST) typically at a temperature in the range of - 20 °C to reflux in a solvent such as DCM.

[0344] The compound of formula (31) can be converted to the compound of formula (VIII) using a synthetic methodology similar to that described in Schemes 13, 10, and 1.

[0345] (i) The organic reactions described in the present disclosure are carried out according to laboratory standards known to those skilled in the art; (ii) Some of the reactions described in the present disclosure may, optionally, be carried out in an order different from that planned herein; (iii) The chiral isomers of the compounds in the present disclosure may be resolved using chiral resolving agents described in the literature and known to those skilled in the art, or using chiral chromatography methods described in the literature and known to those skilled in the art, or may be resolved at any stage of the synthetic process as further described in the examples; (iv) Additional protecting groups and / or other protecting groups may, optionally, be required in some of the above steps; and (v) Therefore, it should be understood that the deprotection step may, optionally, be carried out using methods described in the literature and known to those skilled in the art. Protection and deprotection of functional groups are described in “Protective Groups in Organic Synthesis” 3rd Ed, T.W. Greene and P.G.M. Wutz, Wiley-Interscience (1999), which publication is incorporated herein by reference.

Examples

[0346] VIII. Examples The following descriptions of experiments, procedures, examples, and intermediates are intended to illustrate, and in no way limit, embodiments of the present disclosure. Other compounds of the present disclosure may be prepared using the methods shown in these examples alone or in combination with techniques generally known in the art.

[0347] A. General Conditions Unless otherwise specified, (i) Operations were carried out at room temperature (rt), i.e., in the range of 17 - 25 °C, and under an atmosphere of an inert gas such as N 2 etc., unless otherwise specified; (ii) When the reaction relates to the use of a microwave reactor, one of the following microwave reactors was used: Biotage Initiator, Personal Chemistry Emrys Optimizer, Personal Chemistry Smith Creator, or CEM Explorer; (iii) Generally, after the reaction step, thin layer chromatography (TLC) and / or analytical high performance liquid chromatography (HPLC or UPLC) connected to a mass spectrometer (LCMC) were usually performed. (iv) If necessary, the organic solution was dried over anhydrous MgSO 4 or Na 2 SO 4 or by using an ISOLUTE® phase separator, and the work-up procedure was carried out using conventional phase separation techniques. (v) Evaporation was carried out in vacuo or by rotary evaporation in a Genevac HT-4 / EZ-2 or Biotage V10; (vi) Unless otherwise specified, flash column chromatography was carried out on normal phase silica using any of the prepacked cartridges such as Merck Silica Gel (Art.9385) or Biotage® SNAP Cartridge (40 - 63μm silica, 4 - 330g), Biotage® Sfar Silica HC D Cartridge (20μm, 10 - 100g), Interchim puriFlash® Cartridge (25μm, 4 - 120g), Interchim puriFlash® Cartridge (50μm, 25 - 330g), Grace® GraceResolv® Silica Flash Cartridge (4 - 120g) or Agela Flash Colum Silica-CS Cartridge (80 - 330g), or on reverse phase silica using an automated Agela Technologies C-18, spherical cartridge (20 - 35μm, 100A, 80 - 330g) using a manual or Grace Reveleris® X2 Flash system or a similar system; (vii) Preparative reversed-phase HPLC and preparative reversed-phase SFC were each performed using standard HPLC and SFC equipment equipped with a fraction collector operating with MS and / or UV, with a uniform concentration or gradient of the mobile phase as described in the experimental section and using one of the following methods as described below.

[0348] HPLC preparative method: Preparative method A: The compound was purified by preparative HPLC on a YMC-Actus Triart C18 ExRS column (5 μm, 150×30 mm ID) using a gradient of MeCN / NH 2 HCO 4 HCO 3 (10 mM) in H 2 O; Preparative method B: The compound was purified by preparative HPLC on an XBridge™ C18 OBD column (5 μm, 150×30 mm ID) using a gradient of MeCN / NH 4 HCO 3 (10 mM) / NH 3 (0.1%, aq) buffer system; Preparative method C: The compound was purified by preparative HPLC on an XSelect CSH OBD column (5 μm, 150×30 mm ID) using a gradient of MeCN / FA (0.1%) in H 2 O; Preparative method D: The compound was purified by preparative HPLC on an XSelect CSH C18 OBD column (5 μm, 250×19 mm ID) using a gradient of MeCN / FA (0.1%) in H 2 O; Preparative method E: The compound was purified by preparative HPLC on a Kromasil C8 column (10 μm, 250×20 mm ID) using a gradient of MeCN / MeCN / FA (95 / 5 / 0.2) in H 2 O; Preparative method F: The compound was purified by preparative HPLC on a Waters™ Sunfire™ C18 OBD column (5 μm, 150×30 mm ID) using a gradient of MeCN / FA (0.1%) in H 2 O; Preparative method G: The compound was purified by preparative HPLC on a column with mobile phase as H 2Purified by preparative HPLC on a Kromasil C8 column (10 μm, 250×50 mm ID) using a gradient of MeCN / MeCN / FA (95 / 5 / 0.2) in H2O; Preparative method H: The compound was eluted with H2O as the mobile phase 2 MeCN / MeCN / NH3 in H2O 3 (95 / 5 / 0.2) gradient and purified by preparative HPLC on an XBridge™ C18 column (10 μm, 250×50 mm ID); Preparative method I: The compound was eluted with H2O as the mobile phase 2 MeCN / NH3 in H2O 4 HCO2H 3 (10 mM) gradient and purified by preparative HPLC on an XBridge™ C18 OBD column (5 μm, 250×19 mm ID); Preparative method N: The compound was eluted with H2O as the mobile phase 2 MeCN / MeCN / NH3 in H2O 3 (95 / 5 / 0.2) gradient and purified by preparative HPLC on an XBridge™ C18 column (10 μm, 250×19 mm ID); Preparative method O: The compound was eluted with H2O as the mobile phase 2 MeCN / NH3 in H2O 4 HCO2H 3 (10 mM) gradient and purified by preparative HPLC on an XBridge™ C18 column (5 μm, 250×19 mm ID); Preparative method P: The compound was eluted with H2O as the mobile phase 2 Purified by preparative HPLC on an XBridge™ Shield C18 column (5 μm, 150×30 mm ID) using a gradient of MeCN / FA (0.1%) in H2O; Preparative method Q: The compound was eluted with H2O as the mobile phase 2 MeCN / NH3 in H2O 3 (0.2%, pH 10) buffer system gradient and purified by preparative HPLC on an XBridge™ C18 OBD column (5 μm, 150×19 mm ID); Preparative method R: The compound was eluted with H2O as the mobile phase 2 MeCN / NH3 in H2O 4 HCO2H 3(10 mM) gradient was used for purification by preparative HPLC on an XBridge™ C18 OBD column (5 μm, 150×30 mm ID); Preparative method T: The compound was eluted with a gradient of MeCN / NH 2 in H 4 O with NH 3 (10 mM) / NH 3 (0.1%, aq) buffer system on an XBridge™ Shield C18 column (5 μm, 150×30 mm ID); Preparative method U: The compound was eluted with a gradient of MeCN / FA (0.1%) in H 2 O on an XSelect CSH F-Phenyl OBD column (5 μm, 250×19 mm ID); Preparative method V: The compound was eluted with a gradient of MeCN / FA (0.1 M) in H 2 O on a Waters™ Sunfire™ C18 OBD column (5 μm, 150×30 mm ID); Preparative method X: The compound was eluted with a gradient of MeCN / FA (0.1%) in H2O on an XSelect CSH OBD column (5 μm, 150×30 mm ID);

[0349] SFC preparative method: Preparative method SFC-A: The compound was eluted with a gradient of EtOH / FA (20 mM) in CO 2 on a Phenomenex Luna® HILIC column (5 μm, 250×30 mm ID); Preparative method SFC-B: The compound was eluted with a gradient of MeOH / 2M NH 2 in MeOH (99.5 / 0.5) on a DAICEL DCpak® P4VP column (5 μm, 250×20 mm ID); Preparative method SFC-C: The compound was eluted with a gradient of MeOH / H 3 O (NH 2 in CO 2 3 ​Purified by preparative SFC on Waters™ BEH (5 μm, 250×30 mm ID) using (97 / 3) 50 mM; Preparative method SFC-D: The compound was eluted with CO 2 in EtOH / FA (20 mM) on Waters™ BEH (5 μm, 30×250 mm ID); Preparative method SFC-E: The compound was eluted with CO 2 in MeOH / NH 3 (20 mM) on Waters™ BEH (5 μm, 250×30 mm ID); Preparative method SFC-G: The compound was eluted with CO 2 in MeOH / NH 3 (20 mM) on Waters™ BEH (3.5 μm, 100×3 mm ID); Preparative method SFC-H: The compound was eluted with CO 2 in MeOH / NH 3 (20 mM) on Phenomenex Luna® HILIC column (5 μm, 250×30 mm ID).

[0350] The appropriate fractions were collected, combined, and lyophilized to obtain the purified compound or the appropriate fractions were collected, combined, concentrated under reduced pressure, extracted with DCM or EtOAc, and the organic phase was dried over Na 2 SO 4 or using a phase separator, and then concentrated under reduced pressure to obtain the purified compound; (viii) Chiral preparative chromatography was performed using either isocratic or gradient elution on standard HPLC or SFC equipment with the mobile phases as described in the experimental section; (x) Yields are not necessarily the maximum achievable and, if necessary, the reaction was repeated if larger amounts of reaction product were required; (xi) When a particular compound is obtained as an acid addition salt, such as a monohydrochloride or dihydrochloride, the stoichiometry of the salt is based on the number and nature of the basic groups in the compound, and the exact stoichiometry of the salt is generally not determined by, for example, elemental analysis data; (xii) In general, the structure of the final product of formula (I) was confirmed by nuclear magnetic resonance (NMR) and / or mass spectral techniques; the proton NMR chemical shift values were measured on the delta scale using Bruker Avance III 300, 400, 500 and 600 spectrometers operating at 1 H frequencies of 300, 400, 500 and 600 MHz. Experiments were usually recorded at 25 °C. Chemical shifts are given in ppm units by the solvent as an internal standard. Protons on heteroatoms such as NH and OH protons are only reported when detected by NMR and may therefore not be described. In certain examples, protons may be masked or partially masked by the solvent peak and therefore not described, not reported or reported as multiple overlaps with the solvent. The following abbreviations are used (and their derivatives, e.g., dd, doublet of doublets, etc.): s, singlet; d, doublet; t, triplet; q, quartet; m, multiplet; br, broad; qn, quintet; p, pentet. In some cases, the structure of the final product of formula (I) may appear as a rotamer in the NMR-spectrum, in which case only the peaks of the major rotamer are reported. Electrospray mass spectral data were obtained using a Waters single quadrupole mass spectrometer or a Waters Acquity UPLC connected to a similar device that acquires both positive and negative ion data, and generally only ions related to the parent structure are reported; high-resolution electrospray mass spectral data were obtained using a Waters Acquity XEVO qToF mass spectrometer or a similar device connected to a Waters Acquity UPLC that acquires both positive and negative ion data, and generally only ions related to the parent structure are reported. (xiii) The intermediates were not necessarily fully purified, but their structures and purities were evaluated by TLC, analytical HPLC / UPLC, and / or NMR analysis and / or mass spectrometry; (xiv) Unless otherwise specified, compounds containing asymmetric carbons and / or sulfur atoms were not resolved; (xv) In general, examples and intermediate compounds were named using ChemDraw Professional version 19.0.0.22 from PerkinElmer. ChemDraw Professional version 19.0.0.22 uses the Cahn-Ingold-Prelog (CIP) ranking rules for stereochemistry to generate the names of chemical structures and adheres as closely as possible to the IUPAC rules when generating chemical names. Stereoisomers have different stereodescriptors cited in the name and are assigned according to the CIP rules.

[0351] ChemDraw optionally uses labels in the graphical depiction of stereocenters, such as "&" and "or", to describe the configuration of the stereochemical centers present in the structure. In general, the chemical structures of examples and intermediates containing the label "&" at a stereocenter mean that the configuration of such an example or intermediate at that stereocenter is a mixture of both (R) and (S); the label "or" means that the configuration of such an example or intermediate at that stereocenter is either (S) or (R). Absolute stereocenters, unspecified stereocenters, "&" stereocenters, and "or" stereocenters can all exist in a single structure.

[0352] In general, with respect to the structures of examples and intermediates when all stereocenters are specified as "&", the structure is named with the "rac-" prefix. With respect to the structures of examples and intermediates when all stereocenters are specified as "or", the structure is named with the "rel-" prefix.

[0353] In general, examples and intermediate compounds are named to indicate the general " & " center for chemical structures having multiple chiral centers where only some are designated as " & " using the designations (RS) and (SR). The designations (R*) and (S*) are used to indicate the general "or" center for chemical structures having multiple chiral centers where only some are designated as "or".

[0354] In general, the designations (r) and (s) are used to describe the absolute configuration of any pseudoasymmetric center in the structures of the examples and intermediates.

[0355] In general, the label "isomer 1" corresponds to the isomer that elutes first on a given chiral HPLC column, "isomer 2" corresponds to the isomer that elutes second on a given chiral HPLC column, and is used to distinguish two isomers containing one or more stereocenters of unknown absolute configuration. (xvi) When referring to a reaction being degassed or purged, this can be accomplished, for example, by purging the reaction solvent with a constant flow rate of nitrogen for a suitable period (e.g., 5 - 10 minutes). (xvii) In addition to the above, the following abbreviations are used:

[0356]

Table 1

[0357]

Table 2

[0358]

Table 3

[0359] B. Intermediate Compounds Intermediate 1: (R)-tert-Butyl 4-cyanothiazolidine-3-carboxylate

Chemical Structure

[0360] Step a) (R)-4-Carbamoylthiazolidine-3-carboxylic acid tert-butyl

Chem.

Claims

1. A compound having the structure of formula (I): 【Chemistry 1】 or a pharma- ceutically acceptable salt thereof, X １ is -S-, -S(O)-, and -S(O) ２ - selected from the group consisting of; R １ is hydrogen, halogen, hydroxy, C １～３ -Alkyl, and C １～６ - selected from the group consisting of alkoxy; R ２ teeth, (a) heterocyclyl containing a total of 4 to 10 ring atoms, where the heterocyclyl ring is: (i) a saturated, partially saturated, or fully unsaturated monocyclic or fused bicyclic ring; (ii) having 1, 2, or 3 nitrogen ring atoms, the remaining ring atoms being carbon; and (iii) any of the following: halogen, hydroxy, oxo, cyano, C １～６ -Alkyl, C ３～６ -Cycloalkyl, C ３～６ -Cycloalkyl-C １～３ -Alkyl, C １～６ -Alkoxy, C ３～６ -cycloalkoxy, C １～３ -Alkoxy-C １～３ -Alkyl, C １～３ -Alkoxy-C ２～３ -Alkoxy, C １～３ -Alkoxy-C ２～３ -Alkoxy-C １～３ -Alkyl, C １～３ -Alkylcarbonyl, C ３～６ -Cycloalkylcarbonyl, C １～３ -Alkyl-carbonylamino-C １～３ -Alkyl, C １～３ -Alkylsulfonyl-C １～３ -Alkyl, phenyl, tolyl, C １～３ -Alkoxyphenyl, phenyl-C １～３ -Alkyl, C １～３ -Alkoxyphenyl-C １～３ - optionally substituted with one or more substituents independently selected from the group consisting of alkyl, azetidinyl, pyrrolidinyl, piperidinyl, morpholinyl, tetrahydrofuranyl, tetrahydropyranyl, and tetrahydrooxepanyl, and (a) said C １～６ -Alkyl, C ３～６ -Cycloalkyl, C ３～６ -Cycloalkyl-C １～３ -Alkyl, C １～６ -Alkoxy, C ３～６ -cycloalkoxy, C １～３ -Alkoxy-C １～３ -Alkyl, C １～３ -Alkoxy-C ２～３ -Alkoxy, C １～３ -Alkoxy-C ２～３ -Alkoxy-C １～３ -Alkyl, C １～３ -Alkylcarbonyl, C ３～６ -Cycloalkylcarbonyl, C １～３ -Alkyl-carbonylamino-C １～３ -Alkyl, C １～３ -Alkylsulfonyl-C １～３ -Alkyl, phenyl, tolyl, C １～３ -Alkoxyphenyl, phenyl-C １～３ -Alkyl, C １～３ -Alkoxyphenyl-C １～３ -alkyl, azetidinyl, pyrrolidinyl, piperidinyl, morpholinyl, tetrahydrofuranyl, tetrahydropyranyl, and tetrahydrooxepanyl may be further substituted with one or more halogens; and (b) said C １～６ The alkyl may be further substituted with one or more hydroxy; (b) heterocyclyl containing a total of 5 to 10 ring atoms, where the heterocyclyl ring is: (i) a saturated, partially saturated, or fully unsaturated monocyclic or fused bicyclic ring; (ii) (a) having one nitrogen ring atom and one oxygen ring atom, the remaining ring atoms being carbon, or (b) having one nitrogen ring atom and one sulfur ring atom, the remaining ring atoms being carbon, and (iii) any of the following radicals: halogen, cyano, oxo, C １～６ -Alkyl, C ３～６ -Cycloalkyl, C １～６ -Alkoxy, C １～３ -Alkoxy-C １～３ -Alkyl, C １～３ -Alkylcarbonyl-C １～３ -Alkyl, and C １～３ -Alkylsulfonyl-C １～３ -alkyl, and １～６ -Alkyl, C ３～６ -Cycloalkyl, C １～６ -Alkoxy, C １～３ -Alkoxy-C １～３ -Alkyl, C １～３ -Alkylcarbonyl-C １～３ -Alkyl, and C １～３ -Alkylsulfonyl-C １～３ -alkyl may be further substituted with one or more halogens; and (c) spiroheterocyclyls containing a total of 6 to 11 ring atoms, said spiroheterocyclyls: (i) containing two saturated rings; (ii) (a) having one or two nitrogen ring atoms, the remaining ring atoms being carbon; (b) having one or two nitrogen ring atoms and one or two oxygen ring atoms, the remaining ring atoms being carbon; or (c) having one nitrogen ring atom and one sulfur ring atom, the remaining ring atoms being carbon; and (iii) not containing any of halogen, oxo, C. １～６ -Alkyl, C １～６ -Haloalkyl, C １～６ -Alkoxy, C １～６ -haloalkoxy, and C １～６ -alkylcarbonyl, selected from the group consisting of: R ３ is hydrogen, halogen, and C １～３ - alkyl; R ４ is hydrogen, halogen, and C １～３ - alkyl; R ５ is hydrogen, halogen, and C １～３ - alkyl; and R ６ is hydrogen, halogen, and C １～３ -alkyl).

2. The compound has the structure of formula (II): 【Chemistry 2】 (In the formula, X １ , R １ , R ２ , R ３ , R ４ , R ５ , and R ６ is as defined in claim 1, or a pharma- ceutically acceptable salt thereof.

3. X １ The compound according to claim 1 or 2, or a pharma- ceutically acceptable salt thereof, wherein:

4. X １ The compound according to claim 1 or 2, wherein is -S(O)-, or a pharma- ceutically acceptable salt thereof.

5. X １ But -S(O) ２ 3. The compound according to claim 1 or 2, wherein: -, or a pharma- ceutically acceptable salt thereof.

6. R １ is hydrogen, halogen, and C １～３ -alkyl, or a pharma- ceutically acceptable salt thereof.

7. R １ The compound according to any one of claims 1 to 5, or a pharma- ceutically acceptable salt thereof, wherein is selected from the group consisting of hydrogen, chloro, fluoro, and methyl.

8. R １ The compound according to any one of claims 1 to 5, or a pharma- ceutically acceptable salt thereof, wherein is hydrogen.

9. R １ The compound according to any one of claims 1 to 5, or a pharma- ceutically acceptable salt thereof, wherein is chloro.

10. R １ The compound according to any one of claims 1 to 5, or a pharma- ceutically acceptable salt thereof, wherein is fluoro.

11. R １ The compound according to any one of claims 1 to 5, or a pharma- ceutically acceptable salt thereof, wherein is methyl.

12. R ３ is hydrogen, halogen, and C １～３ 12. The compound according to any one of claims 1 to 11, or a pharma- ceutically acceptable salt thereof, wherein the compound is selected from the group consisting of: -alkyl.

13. R ３ The compound according to any one of claims 1 to 11, or a pharma- ceutically acceptable salt thereof, wherein is selected from the group consisting of hydrogen, chloro, fluoro, and methyl.

14. R ３ The compound according to any one of claims 1 to 11, or a pharma- ceutically acceptable salt thereof, wherein is hydrogen.

15. R ３ The compound according to any one of claims 1 to 11, or a pharma- ceutically acceptable salt thereof, wherein is chloro.

16. R ３ The compound according to any one of claims 1 to 11, or a pharma- ceutically acceptable salt thereof, wherein is fluoro.

17. R ３ The compound according to any one of claims 1 to 11, or a pharma- ceutically acceptable salt thereof, wherein is methyl.

18. R ４ is hydrogen, halogen, and C １～３ 18. The compound according to any one of claims 1 to 17, or a pharma- ceutically acceptable salt thereof, wherein the compound is selected from the group consisting of: -alkyl.

19. R ４ The compound according to any one of claims 1 to 17, or a pharma- ceutically acceptable salt thereof, wherein is hydrogen.

20. R ４ The compound according to any one of claims 1 to 17, or a pharma- ceutically acceptable salt thereof, wherein is chloro.

21. R ４ The compound according to any one of claims 1 to 17, or a pharma- ceutically acceptable salt thereof, wherein is fluoro.

22. R ４ The compound according to any one of claims 1 to 17, or a pharma- ceutically acceptable salt thereof, wherein is methyl.

23. R ５ is hydrogen, halogen, and C １～３ -alkyl; or a pharma- ceutically acceptable salt thereof.

24. R ５ 23. The compound of any one of claims 1 to 22, or a pharma- ceutically acceptable salt thereof, wherein is selected from the group consisting of hydrogen, chloro, fluoro, and methyl.

25. R ５ The compound according to any one of claims 1 to 22, or a pharma- ceutically acceptable salt thereof, wherein is hydrogen.

26. R ５ The compound according to any one of claims 1 to 22, or a pharma- ceutically acceptable salt thereof, wherein is fluoro.

27. R ５ The compound according to any one of claims 1 to 22, or a pharma- ceutically acceptable salt thereof, wherein is chloro.

28. R ５ The compound according to any one of claims 1 to 22, or a pharma- ceutically acceptable salt thereof, wherein is methyl.

29. R ６ is hydrogen, halogen, and C １～３ 29. The compound according to any one of claims 1 to 28, or a pharma- ceutically acceptable salt thereof, wherein the compound is selected from the group consisting of: -alkyl.

30. R ６ 29. The compound of any one of claims 1 to 28, or a pharma- ceutically acceptable salt thereof, wherein is selected from the group consisting of hydrogen, chloro, fluoro, and methyl.

31. R ６ The compound according to any one of claims 1 to 28, or a pharma- ceutically acceptable salt thereof, wherein is hydrogen.

32. R ６ The compound according to any one of claims 1 to 28, or a pharma- ceutically acceptable salt thereof, wherein is chloro.

33. R ６ The compound according to any one of claims 1 to 28, or a pharma- ceutically acceptable salt thereof, wherein is fluoro.

34. R ６ The compound according to any one of claims 1 to 28, or a pharma- ceutically acceptable salt thereof, wherein is methyl.

35. The R １ , R ３ , R ４ , R ５ , and R ６ One of the substituents is a halogen and C １～３ -alkyl, and the remaining R １ , R ３ , R ４ , R ５ , and R ６ 6. The compound according to any one of claims 1 to 5, or a pharma- ceutically acceptable salt thereof, wherein all of the substituents are hydrogen.

36. The R １ , R ３ , R ４ , R ５ , and R ６ One of the substituents is selected from the group consisting of chloro, fluoro, and methyl, and the remaining R １ , R ３ , R ４ , R ５ , and R ６ 36. The compound of claim 35, or a pharma- ceutically acceptable salt thereof, wherein the substituents are all hydrogen.

37. The R １ , R ３ , R ４ , R ５ , and R ６ One of the substituents is selected from the group consisting of chloro and fluoro, and the remaining R １ , R ３ , R ４ , R ５ , and R ６ 36. The compound of claim 35, or a pharma- ceutically acceptable salt thereof, wherein the substituents are all hydrogen.

38. The R １ , R ３ , R ４ , R ５ , and R ６ One of the substituents is methyl, and the remaining R １ , R ３ , R ４ , R ５ , and R ６ 36. The compound of claim 35, or a pharma- ceutically acceptable salt thereof, wherein the substituents are all hydrogen.

39. The compound has the structure of formula (III-A): 【Chemistry 3】 (In the formula, R １ and R ２ is as defined in claim 1, or a pharma- ceutically acceptable salt thereof.

40. The compound has the structure of formula (III-B): 【Chemistry 4】 (In the formula, R ２ and R ３ is as defined in claim 1, or a pharma- ceutically acceptable salt thereof.

41. The compound has the structure of formula (III-C): 【Chemistry 5】 (In the formula, R ２ and R ４ is as defined in claim 1, or a pharma- ceutically acceptable salt thereof.

42. The compound has the structure of formula (III-D): 【Chemistry 6】 (In the formula, R ２ and R ５ is as defined in claim 1, or a pharma- ceutically acceptable salt thereof.

43. The compound has the structure of formula (III-E): 【Chemistry 7】 (In the formula, R ２ and R ６ is as defined in claim 1, or a pharma- ceutically acceptable salt thereof.

44. The R １ , R ３ , R ４ , R ５ , and R ６ At least two of the substituents are independently selected from halogen and C １～３ -alkyl, and the remaining R １ , R ３ , R ４ , R ５ , and R ６ 6. The compound according to any one of claims 1 to 5, or a pharma- ceutically acceptable salt thereof, wherein all of the substituents are hydrogen.

45. The R １ , R ３ , R ４ , R ５ , and R ６ Two of the substituents are independently selected from the group consisting of chloro, fluoro, and methyl, and the remaining R １ , R ３ , R ４ , R ５ , and R ６ 45. The compound of claim 44, or a pharma- ceutically acceptable salt thereof, wherein the substituents are all hydrogen.

46. The R １ , R ３ , R ４ , R ５ , and R ６ 46. ​​The compound of claim 45, or a pharma- ceutically acceptable salt thereof, wherein at least one of the substituents is chloro.

47. The R １ , R ３ , R ４ , R ５ , and R ６ 46. ​​The compound of claim 45, or a pharma- ceutically acceptable salt thereof, wherein at least one of the substituents is fluoro.

48. The R １ , R ３ , R ４ , R ５ , and R ６ 46. ​​The compound of claim 45, or a pharma- ceutically acceptable salt thereof, wherein at least one of the substituents is methyl.

49. The compound has the structure of formula (IV): 【Chemistry 8】 (In the formula, R ２ is as defined in claim 1, or a pharma- ceutically acceptable salt thereof.

50. The compound has the structure of formula (IV-A): 【Chemistry 9】 (In the formula, R ２ is as defined in claim 1, or a pharma- ceutically acceptable salt thereof.

51. R ２ and (iii) a heterocyclyl containing a total of 4 to 10 ring atoms, the heterocyclyl ring being (i) a saturated, partially saturated, or fully unsaturated monocyclic or fused bicyclic ring, (ii) having 1, 2, or 3 nitrogen ring atoms, the remaining ring atoms being carbon, and (iii) any of the following radicals: halogen, hydroxy, oxo, cyano, C １～６ -Alkyl, C ３～６ -Cycloalkyl, C ３～６ -Cycloalkyl-C １～３ -Alkyl, C １～６ -Alkoxy, C ３～６ -cycloalkoxy, C １～３ -Alkoxy-C １～３ -Alkyl, C １～３ -Alkoxy-C ２～３ -Alkoxy, C １～３ -Alkoxy-C ２～３ -Alkoxy-C １～３ -Alkyl, C １～３ -Alkylcarbonyl, C ３～６ -Cycloalkylcarbonyl, C １～３ -Alkyl-carbonylamino-C １～３ -Alkyl, C １～３ -Alkylsulfonyl-C １～３ -Alkyl, phenyl, tolyl, C １～３ -Alkoxyphenyl, phenyl-C １～３ -Alkyl, C １～３ -Alkoxyphenyl-C １～３ - optionally substituted with one or more substituents independently selected from the group consisting of alkyl, azetidinyl, pyrrolidinyl, piperidinyl, morpholinyl, tetrahydrofuranyl, tetrahydropyranyl, and tetrahydrooxepanyl, and (a) said C １～６ -Alkyl, C ３～６ -Cycloalkyl, C ３～６ -Cycloalkyl-C １～３ -Alkyl, C １～６ -Alkoxy, C ３～６ -cycloalkoxy, C １～３ -Alkoxy-C １～３ -Alkyl, C １～３ -Alkoxy-C ２～３ -Alkoxy, C １～３ -Alkoxy-C ２～３ -Alkoxy-C １～３ -Alkyl, C １～３ -Alkylcarbonyl, C ３～６ -Cycloalkylcarbonyl, C １～３ -Alkyl-carbonylamino-C １～３ -Alkyl, C １～３ -Alkylsulfonyl-C １～３ -Alkyl, phenyl, tolyl, C １～３ -Alkoxyphenyl, phenyl-C １～３ -Alkyl, C １～３ -Alkoxyphenyl-C １～３ -alkyl, azetidinyl, pyrrolidinyl, piperidinyl, morpholinyl, tetrahydrofuranyl, tetrahydropyranyl, and tetrahydrooxepanyl may be further substituted with one or more halogens; and (b) said C １～６ 51. The compound of any one of claims 1 to 50, or a pharma- ceutically acceptable salt thereof, wherein alkyl is optionally further substituted with one or more hydroxy.

52. 52. The compound of claim 51, or a pharma- ceutically acceptable salt thereof, wherein said heterocyclyl ring is a saturated monocyclic ring.

53. 52. The compound of claim 51, or a pharma- ceutically acceptable salt thereof, wherein said heterocyclyl ring is a partially saturated monocyclic ring.

54. 52. The compound of claim 51, or a pharma- ceutically acceptable salt thereof, wherein said heterocyclyl ring is a fully unsaturated monocyclic ring.

55. 52. The compound of claim 51, or a pharma- ceutically acceptable salt thereof, wherein said heterocyclyl ring is a saturated fused bicyclic ring.

56. 52. The compound of claim 51, or a pharma- ceutically acceptable salt thereof, wherein said heterocyclyl ring is a partially saturated fused bicyclic ring.

57. 52. The compound of claim 51, or a pharma- ceutically acceptable salt thereof, wherein said heterocyclyl ring is a fully unsaturated fused bicyclic ring.

58. 58. The compound of any one of claims 51 to 57, or a pharma- ceutically acceptable salt thereof, wherein the heterocyclyl ring has one nitrogen ring atom, the remaining ring atoms being carbon.

59. 58. The compound of any one of claims 51 to 57, or a pharma- ceutically acceptable salt thereof, wherein the heterocyclyl ring has two nitrogen ring atoms, the remaining ring atoms being carbon.

60. 58. The compound of any one of claims 51 to 57, or a pharma- ceutically acceptable salt thereof, wherein the heterocyclyl ring has three nitrogen ring atoms, the remaining ring atoms being carbon.

61. The heterocyclyl ring is 【Chemistry 10】 is selected from the group consisting of The heterocyclyl ring is selected from the group consisting of halogen, hydroxy, oxo, cyano, C １～６ -Alkyl, C ３～６ -Cycloalkyl, C ３～６ -Cycloalkyl-C １～３ -Alkyl, C １～６ -Alkoxy, C ３～６ -cycloalkoxy, C １～３ -Alkoxy-C １～３ -Alkyl, C １～３ -Alkoxy-C ２～３ -Alkoxy, C １～３ -Alkoxy-C ２～３ -Alkoxy-C １～３ -Alkyl, C １～３ -Alkylcarbonyl, C ３～６ -Cycloalkylcarbonyl, C １～３ -Alkyl-carbonylamino-C １～３ -Alkyl, C １～３ -Alkylsulfonyl-C １～３ -Alkyl, phenyl, tolyl, C １～３ -Alkoxyphenyl, phenyl-C １～３ -Alkyl, C １～３ -Alkoxyphenyl-C １～３ - optionally substituted with one or more substituents independently selected from the group consisting of alkyl, azetidinyl, pyrrolidinyl, piperidinyl, morpholinyl, tetrahydrofuranyl, tetrahydropyranyl, and tetrahydrooxepanyl, and (a) said C １～６ -Alkyl, C ３～６ -Cycloalkyl, C ３～６ -Cycloalkyl-C １～３ -Alkyl, C １～６ -Alkoxy, C ３～６ -cycloalkoxy, C １～３ -Alkoxy-C １～３ -Alkyl, C １～３ -Alkoxy-C ２～３ -Alkoxy, C １～３ -Alkoxy-C ２～３ -Alkoxy-C １～３ -Alkyl, C １～３ -Alkylcarbonyl, C ３～６ -Cycloalkylcarbonyl, C １～３ -Alkyl-carbonylamino-C １～３ -Alkyl, C １～３ -Alkylsulfonyl-C １～３ -Alkyl, phenyl, tolyl, C １～３ -Alkoxyphenyl, phenyl-C １～３ -Alkyl, C １～３ -Alkoxyphenyl-C １～３ -alkyl, azetidinyl, pyrrolidinyl, piperidinyl, morpholinyl, tetrahydrofuranyl, tetrahydropyranyl, and tetrahydrooxepanyl may be further substituted with one or more halogens, and (b) said C １～６ 52. The compound of claim 51, or a pharma- ceutically acceptable salt thereof, wherein the alkyl is optionally further substituted with one or more hydroxy.

62. The heterocyclyl ring is 【Chemistry 11】 is selected from the group consisting of The heterocyclyl ring is selected from the group consisting of halogen, hydroxy, oxo, cyano, C １～６ -Alkyl, C ３～６ -Cycloalkyl, C ３～６ -Cycloalkyl-C １～３ -Alkyl, C １～６ -Alkoxy, C ３～６ -cycloalkoxy, C １～３ -Alkoxy-C １～３ -Alkyl, C １～３ -Alkoxy-C ２～３ -Alkoxy, C １～３ -Alkoxy-C ２～３ -Alkoxy-C １～３ -Alkyl, C １～３ -Alkylcarbonyl, C ３～６ -Cycloalkylcarbonyl, C １～３ -Alkyl-carbonylamino-C １～３ -Alkyl, C １～３ -Alkylsulfonyl-C １～３ -Alkyl, phenyl, tolyl, C １～３ -Alkoxyphenyl, phenyl-C １～３ -Alkyl, C １～３ -Alkoxyphenyl-C １～３ - optionally substituted with one or more substituents independently selected from the group consisting of alkyl, azetidinyl, pyrrolidinyl, piperidinyl, morpholinyl, tetrahydrofuranyl, tetrahydropyranyl, and tetrahydrooxepanyl, and (a) said C １～６ -Alkyl, C ３～６ -Cycloalkyl, C ３～６ -Cycloalkyl-C １～３ -Alkyl, C １～６ -Alkoxy, C ３～６ -cycloalkoxy, C １～３ -Alkoxy-C １～３ -Alkyl, C １～３ -Alkoxy-C ２～３ -Alkoxy, C １～３ -Alkoxy-C ２～３ -Alkoxy-C １～３ -Alkyl, C １～３ -Alkylcarbonyl, C ３～６ -Cycloalkylcarbonyl, C １～３ -Alkyl-carbonylamino-C １～３ -Alkyl, C １～３ -Alkylsulfonyl-C １～３ -Alkyl, phenyl, tolyl, C １～３ -Alkoxyphenyl, phenyl-C １～３ -Alkyl, C １～３ -Alkoxyphenyl-C １～３ -alkyl, azetidinyl, pyrrolidinyl, piperidinyl, morpholinyl, tetrahydrofuranyl, tetrahydropyranyl, and tetrahydrooxepanyl may be further substituted with one or more halogens, and (b) said C １～６ 52. The compound of claim 51, or a pharma- ceutically acceptable salt thereof, wherein the alkyl is optionally further substituted with one or more hydroxy.

63. The heterocyclyl ring is 【Chemistry 12】 is selected from the group consisting of The heterocyclyl ring is selected from the group consisting of halogen, hydroxy, oxo, cyano, C １～６ -Alkyl, C ３～６ -Cycloalkyl, C ３～６ -Cycloalkyl-C １～３ -Alkyl, C １～６ -Alkoxy, C ３～６ -cycloalkoxy, C １～３ -Alkoxy-C １～３ -Alkyl, C １～３ -Alkoxy-C ２～３ -Alkoxy, C １～３ -Alkoxy-C ２～３ -Alkoxy-C １～３ -Alkyl, C １～３ -Alkylcarbonyl, C ３～６ -Cycloalkylcarbonyl, C １～３ -Alkyl-carbonylamino-C １～３ -Alkyl, C １～３ -Alkylsulfonyl-C １～３ -Alkyl, phenyl, tolyl, C １～３ -Alkoxyphenyl, phenyl-C １～３ -Alkyl, C １～３ -Alkoxyphenyl-C １～３ - optionally substituted with one or more substituents independently selected from the group consisting of alkyl, azetidinyl, pyrrolidinyl, piperidinyl, morpholinyl, tetrahydrofuranyl, tetrahydropyranyl, and tetrahydrooxepanyl, and (a) said C １～６ -Alkyl, C ３～６ -Cycloalkyl, C ３～６ -Cycloalkyl-C １～３ -Alkyl, C １～６ -Alkoxy, C ３～６ -cycloalkoxy, C １～３ -Alkoxy-C １～３ -Alkyl, C １～３ -Alkoxy-C ２～３ -Alkoxy, C １～３ -Alkoxy-C ２～３ -Alkoxy-C １～３ -Alkyl, C １～３ -Alkylcarbonyl, C ３～６ -Cycloalkylcarbonyl, C １～３ -Alkyl-carbonylamino-C １～３ -Alkyl, C １～３ -Alkylsulfonyl-C １～３ -Alkyl, phenyl, tolyl, C １～３ -Alkoxyphenyl, phenyl-C １～３ -Alkyl, C １～３ -Alkoxyphenyl-C １～３ -alkyl, azetidinyl, pyrrolidinyl, piperidinyl, morpholinyl, tetrahydrofuranyl, tetrahydropyranyl, and tetrahydrooxepanyl may be further substituted with one or more halogens, and (b) said C １～６ 52. The compound of claim 51, or a pharma- ceutically acceptable salt thereof, wherein the alkyl is optionally further substituted with one or more hydroxy.

64. The heterocyclyl ring is selected from the group consisting of halogen, hydroxy, oxo, cyano, C １～３ -Alkyl, C ３～６ -Cycloalkyl, C １～３ -Alkoxy, C １～３ -Alkylcarbonyl, C ３～６ -Cycloalkylcarbonyl, C １～３ -Alkoxy-C １～３ -Alkyl, C １～３ -Alkoxy-C ２～３ -Alkoxy, C １～３ -Alkoxy-C ２～３ -Alkoxy-C １～３ -Alkyl, C １～３ -Alkyl-carbonylamino-C １～３ -Alkyl, C １～３ -Alkylsulfonyl-C １～３ - optionally substituted with one or more substituents independently selected from the group consisting of alkyl, morpholinyl, tetrahydrofuranyl, tetrahydropyranyl, and tetrahydrooxepanyl; １～３ -Alkyl, C ３～６ -Cycloalkyl, C １～３ -Alkoxy, C １～３ -Alkylcarbonyl, C ３～６ -Cycloalkylcarbonyl, C １～３ -Alkoxy-C １～３ -Alkyl, C １～３ -Alkoxy-C ２～３ -Alkoxy, C １～３ -Alkoxy-C ２～３ -Alkoxy-C １～３ -Alkyl, C １～３ -Alkylsulfonyl-C １～３ 64. The compound according to any one of claims 51 to 63, or a pharma- ceutically acceptable salt thereof, wherein alkyl, tetrahydrofuranyl, tetrahydropyranyl, and tetrahydrooxepanyl may be further substituted with one or more halogens.

65. The heterocyclyl ring is selected from the group consisting of halogen, hydroxy, oxo, C １～３ -Alkyl, cyclopropyl, C １～３ -alkoxy, and C １～３ -Alkoxy-C １～３ -alkyl, wherein the C is optionally substituted with one or more substituents independently selected from the group consisting of １～３ -Alkyl, cyclopropyl, C １～３ -alkoxy, and C １～３ -Alkoxy-C １～３ 64. The compound according to any one of claims 51 to 63, or a pharma- ceutically acceptable salt thereof, wherein -alkyl is optionally further substituted with one or more halogens.

66. 64. The compound of any one of claims 51 to 63, or a pharma- ceutically acceptable salt thereof, wherein the heterocyclyl ring is optionally substituted with one or more substituents independently selected from the group consisting of tetrahydrofuranyl, tetrahydropyranyl, and tetrahydrooxepanyl, and the tetrahydrofuranyl, tetrahydropyranyl, and tetrahydrooxepanyl may be further substituted with one or more halogens.

67. 64. The compound of any one of claims 51 to 63, or a pharma- ceutically acceptable salt thereof, wherein said heterocyclyl ring is optionally substituted with one or more halogen.

68. 64. The compound of any one of claims 51 to 63, or a pharma- ceutically acceptable salt thereof, wherein said heterocyclyl ring is optionally substituted with one or more chloro.

69. 64. The compound of any one of claims 51 to 63, or a pharma- ceutically acceptable salt thereof, wherein said heterocyclyl ring is optionally substituted with one or more fluoro.

70. 64. The compound of any one of claims 51 to 63, or a pharma- ceutically acceptable salt thereof, wherein said heterocyclyl ring is optionally substituted with one or more hydroxy.

71. 64. The compound of any one of claims 51 to 63, or a pharma- ceutically acceptable salt thereof, wherein the heterocyclyl ring is optionally substituted with one or more oxo.

72. 64. The compound of any one of claims 51 to 63, or a pharma- ceutically acceptable salt thereof, wherein the heterocyclyl ring is optionally substituted with one or more cyano.

73. The heterocyclyl ring is one or more C １～３ - optionally substituted with alkyl, １～３ 64. The compound according to any one of claims 51 to 63, or a pharma- ceutically acceptable salt thereof, wherein -alkyl is optionally further substituted with one or more substituents independently selected from halogen and hydroxy.

74. The heterocyclyl ring is one or more C ３～６ - optionally substituted with cycloalkyl, ３～６ 64. The compound according to any one of claims 51 to 63, or a pharma- ceutically acceptable salt thereof, wherein cycloalkyl is optionally further substituted with one or more halogens.

75. The heterocyclyl ring is one or more C ３～６ -Cycloalkyl-C １～３ - optionally substituted with alkyl, ３～６ -Cycloalkyl-C １～３ 64. The compound according to any one of claims 51 to 63, or a pharma- ceutically acceptable salt thereof, wherein -alkyl is optionally further substituted with one or more halogens.

76. The heterocyclyl ring is one or more C １～３ - alkoxy optionally substituted, １～３ 64. The compound according to any one of claims 51 to 63, or a pharma- ceutically acceptable salt thereof, wherein -alkoxy is optionally further substituted with one or more halogens.

77. The heterocyclyl ring is one or more C ３～６ - cycloalkoxy optionally substituted, ３～６ 64. The compound according to any one of claims 51 to 63, or a pharma- ceutically acceptable salt thereof, wherein -cycloalkoxy is optionally further substituted with one or more halogens.

78. The heterocyclyl ring is one or more C １～３ -Alkoxy-C １～３ - optionally substituted with alkyl, １～３ -Alkoxy-C １～３ 64. The compound according to any one of claims 51 to 63, or a pharma- ceutically acceptable salt thereof, wherein -alkyl is optionally further substituted with one or more halogens.

79. The heterocyclyl ring is one or more C １～３ -Alkoxy-C ２～３ - alkoxy optionally substituted, １～３ -Alkoxy-C ２～３ 64. The compound according to any one of claims 51 to 63, or a pharma- ceutically acceptable salt thereof, wherein -alkoxy is optionally further substituted with one or more halogens.

80. The heterocyclyl ring is one or more C １～３ -Alkoxy-C ２～３ -Alkoxy-C １～３ - optionally substituted with alkyl, １～３ -Alkoxy-C ２～３ -Alkoxy-C １～３ 64. The compound according to any one of claims 51 to 63, or a pharma- ceutically acceptable salt thereof, wherein -alkyl is optionally further substituted with one or more halogens.

81. The heterocyclyl ring is one or more C １～３ - optionally substituted with alkylcarbonyl, １～３ 64. The compound according to any one of claims 51 to 63, or a pharma- ceutically acceptable salt thereof, wherein the alkylcarbonyl is optionally further substituted with one or more halogens.

82. The heterocyclyl ring is one or more C ３～６ - optionally substituted with cycloalkylcarbonyl, ３～６ 64. The compound according to any one of claims 51 to 63, or a pharma- ceutically acceptable salt thereof, wherein the cycloalkylcarbonyl is optionally further substituted with one or more halogens.

83. The heterocyclyl ring is one or more C １～３ -Alkyl-carbonylamino-C １～３ - optionally substituted with alkyl, １～３ -Alkyl-carbonylamino-C １～３ 64. The compound according to any one of claims 51 to 63, or a pharma- ceutically acceptable salt thereof, wherein -alkyl is optionally further substituted with one or more halogens.

84. The heterocyclyl ring is one or more C １～３ -Alkylsulfonyl-C １～３ - optionally substituted with alkyl, １～３ -Alkylsulfonyl-C １～３ 64. The compound according to any one of claims 51 to 63, or a pharma- ceutically acceptable salt thereof, wherein -alkyl is optionally further substituted with one or more halogens.

85. The heterocyclyl ring is selected from the group consisting of phenyl, tolyl, C １～３ -alkoxyphenyl, and phenyl-C １～３ -alkyl, optionally substituted with one or more substituents independently selected from the group consisting of phenyl, tolyl, and phenyl-C １～３ 64. The compound according to any one of claims 51 to 63, or a pharma- ceutically acceptable salt thereof, wherein -alkyl is optionally further substituted with one or more halogens.

86. 64. The compound of any one of claims 51 to 63, or a pharma- ceutically acceptable salt thereof, wherein the heterocyclyl ring is optionally substituted with one or more substituents independently selected from the group consisting of azetidinyl, pyrrolidinyl, piperidinyl, and morpholinyl, and the azetidinyl, pyrrolidinyl, piperidinyl, and morpholinyl may be further substituted with one or more halogens.

87. 64. The compound of any one of claims 51 to 63, or a pharma- ceutically acceptable salt thereof, wherein the heterocyclyl ring is optionally substituted with one or more substituents independently selected from the group consisting of tetrahydrofuranyl, tetrahydropyranyl, and tetrahydrooxepanyl, and the tetrahydrofuranyl, tetrahydropyranyl, and tetrahydrooxepanyl may be further substituted with one or more halogens.

88. 64. The compound of any one of claims 51 to 63, or a pharma- ceutically acceptable salt thereof, wherein the heterocyclyl ring is optionally substituted with one or more substituents independently selected from the group consisting of fluoro, hydroxy, oxo, methyl, ethyl, propyl, isopropyl, cyclopropyl, fluoromethyl, difluoromethyl, trifluoromethyl, fluoroethyl, difluoroethyl, trifluoroethyl, difluoropropyl, trifluoropropyl, methoxy, ethoxy, isopropoxy, difluoromethoxy, trifluoromethoxy, methoxymethyl, trifluoromethoxymethyl, methylcarbonylaminomethyl, methylsulfonylmethyl, morpholinyl, and tetrahydropyranyl.

89. 64. The compound of any one of claims 51 to 63, or a pharma- ceutically acceptable salt thereof, wherein the heterocyclyl ring is optionally substituted with one or more substituents independently selected from the group consisting of fluoro, hydroxy, methyl, fluoromethyl, difluoromethyl, trifluoromethyl, difluoropropyl, cyclopropyl, methoxy, trifluoromethoxy, ethoxy, and methoxymethyl.

90. The heterocyclyl ring is 【Chemistry 13】 and The heterocyclyl ring is selected from the group consisting of halogen, hydroxy, C １～６ -Alkyl, C ３～６ -Cycloalkyl, C １～６ -Alkoxy, C １～３ -Alkoxy-C １～３ -Alkyl, C １～３ -Alkyl-carbonylamino-C １～３ -Alkyl, C １～３ -Alkylsulfonyl-C １～３ -Alkyl, phenyl, tolyl, C １～３ -Alkoxyphenyl, phenyl-C １～３ -alkyl, and morpholinyl, １～６ -Alkyl, C ３～６ -Cycloalkyl, C １～６ -Alkoxy, C １～３ -Alkoxy-C １～３ -Alkyl, C １～３ -Alkyl-carbonylamino-C １～３ -Alkyl, C １～３ -Alkylsulfonyl-C １～３ -Alkyl, phenyl, tolyl, C １～３ -Alkoxyphenyl, phenyl-C １～３ 52. The compound of claim 51, or a pharma- ceutically acceptable salt thereof, wherein -alkyl, and morpholinyl may be further substituted with one or more halogens.

91. The heterocyclyl ring is selected from the group consisting of fluoro, hydroxy, C １～３ -Alkyl, cyclopropyl, C １～３ -alkoxy, and C １～３ -Alkoxy-C １～３ -alkyl, wherein the C is optionally substituted with one or more substituents independently selected from the group consisting of １～３ -Alkyl, cyclopropyl, C １～３ -alkoxy, and C １～３ -Alkoxy-C １～３ 91. The compound of claim 90, or a pharma- ceutically acceptable salt thereof, wherein -alkyl is optionally further substituted with one or more fluoro.

92. 91. The compound of claim 90, or a pharma- ceutically acceptable salt thereof, wherein the heterocyclyl ring is optionally substituted with one or more substituents independently selected from the group consisting of fluoro, hydroxy, methyl, ethyl, propyl, isopropyl, fluoromethyl, difluoromethyl, trifluoromethyl, fluoroethyl, difluoroethyl, trifluoroethyl, difluoropropyl, trifluoropropyl, cyclopropyl, methoxy, ethoxy, difluoromethoxy, trifluoromethoxy, trifluoroethoxy, methoxymethyl, trifluoromethoxymethyl, methylamidomethyl, methylsulfonylmethyl, and morpholinyl.

93. 91. The compound of claim 90, or a pharma- ceutically acceptable salt thereof, wherein the heterocyclyl ring is optionally substituted with one or more substituents independently selected from the group consisting of fluoro, hydroxy, methyl, ethyl, cyclopropyl, fluoromethyl, difluoromethyl, trifluoromethyl, difluoroethyl, trifluoroethyl, difluoropropyl, trifluoropropyl, methoxy, ethoxy, trifluoromethoxy, trifluoromethoxymethyl, methoxymethyl, methylamidomethyl, and morpholinyl.

94. The heterocyclyl ring is 【Chemistry 14】 and The heterocyclyl ring is selected from the group consisting of halogen, hydroxy, oxo, C １～６ -Alkyl, hydroxy-C １～３ -Alkyl, C ３～６ -Cycloalkyl, C １～６ -alkoxy, and C １～３ -Alkoxy-C １～３ -alkyl, wherein the C is optionally substituted with one or more substituents independently selected from the group consisting of １～６ -Alkyl, hydroxy-C １～３ -Alkyl, C ３～６ -Cycloalkyl, C １～６ -alkoxy, and C １～３ -Alkoxy-C １～３ 52. The compound of claim 51, or a pharma- ceutically acceptable salt thereof, wherein -alkyl is optionally further substituted with one or more halogens.

95. The heterocyclyl ring is selected from the group consisting of fluoro, hydroxy, C １～３ -Alkyl, hydroxy-C １～３ -Alkyl, cyclopropyl, C １～３ -alkoxy, and C １～３ -Alkoxy-C １～３ -alkyl, wherein the C is optionally substituted with one or more substituents independently selected from the group consisting of １～３ -Alkyl, hydroxy-C １～３ -Alkyl, cyclopropyl, C １～３ -alkoxy, and C １～３ -Alkoxy-C １～３ 95. The compound of claim 94, or a pharma- ceutically acceptable salt thereof, wherein -alkyl is optionally further substituted with one or more fluoro.

96. 95. The compound of claim 94, or a pharma- ceutically acceptable salt thereof, wherein the heterocyclyl ring is optionally substituted with one or more substituents independently selected from the group consisting of fluoro, hydroxy, methyl, ethyl, propyl, fluoromethyl, difluoromethyl, trifluoromethyl, fluoroethyl, difluoroethyl, trifluoroethyl, difluoropropyl, hydroxymethyl, cyclopropyl, methoxy, ethoxy, trifluoromethoxy, trifluoroethoxy, methoxymethyl, and trifluoromethoxymethyl.

97. 95. The compound of claim 94, or a pharma- ceutically acceptable salt thereof, wherein the heterocyclyl ring is optionally substituted with one or more substituents independently selected from the group consisting of fluoro, hydroxy, methyl, ethyl, fluoromethyl, hydroxymethyl, methoxy, and trifluoromethoxy.

98. The heterocyclyl ring is 【Chemistry 15】 and The heterocyclyl ring is selected from the group consisting of halogen, hydroxy, C １～６ -Alkyl, C ３～６ -Cycloalkyl, C １～６ -alkoxy, and C １～３ -Alkoxy-C １～３ -alkyl, wherein the C is optionally substituted with one or more substituents independently selected from the group consisting of １～６ -Alkyl, C ３～６ -Cycloalkyl, C １～６ -alkoxy, and C １～３ -Alkoxy-C １～３ 52. The compound of claim 51, or a pharma- ceutically acceptable salt thereof, wherein -alkyl is optionally further substituted with one or more halogens.

99. The heterocyclyl ring is selected from the group consisting of fluoro, hydroxy, C １～３ -Alkyl, cyclopropyl, C １～３ -alkoxy, and C １～３ -Alkoxy-C １～３ -alkyl, wherein the C is optionally substituted with one or more substituents independently selected from the group consisting of １～３ -Alkyl, cyclopropyl, C １～３ -alkoxy, and C １～３ -Alkoxy-C １～３ 99. The compound of claim 98, or a pharma- ceutically acceptable salt thereof, wherein -alkyl is optionally further substituted with one or more fluoro.

100. 99. The compound of claim 98, or a pharma- ceutically acceptable salt thereof, wherein the heterocyclyl ring is optionally substituted with one or more substituents independently selected from the group consisting of fluoro, hydroxy, methyl, ethyl, fluoromethyl, difluoromethyl, trifluoromethyl, fluoroethyl, difluoroethyl, trifluoroethyl, difluoropropyl, cyclopropyl, methoxy, ethoxy, trifluoromethoxy, trifluoroethoxy, methoxymethyl, and trifluoromethoxymethyl.

101. 99. The compound of claim 98, or a pharma- ceutically acceptable salt thereof, wherein the heterocyclyl ring is optionally substituted with one or more substituents independently selected from the group consisting of fluoro, hydroxy, methyl, ethyl, fluoromethyl, methoxy, and trifluoromethoxy.

102. The heterocyclyl ring is 【Chemistry 16】 and The heterocyclyl ring is selected from the group consisting of halogen, hydroxy, C １～６ -Alkyl, hydroxy-C １～３ -Alkyl, C ３～６ -Cycloalkyl, C ３～６ -Cycloalkyl-C １～３ -Alkyl, C １～６ -Alkoxy, C １～３ -Alkoxy-C １～３ -Alkyl, C １～３ -Alkoxy-C ２～３ -Alkoxy, C １～３ -Alkoxy-C ２～３ -Alkoxy-C １～３ -Alkyl, C １～３ -Alkyl-carbonylamino-C １～３ -Alkyl, C １～３ -Alkylsulfonyl-C １～３ - optionally substituted with one or more substituents independently selected from the group consisting of alkyl, phenyl, tetrahydrofuranyl, tetrahydropyranyl, and tetrahydrooxepanyl; １～６ -Alkyl, hydroxy-C １～３ -Alkyl, C ３～６ -Cycloalkyl, C ３～６ -Cycloalkyl-C １～３ -Alkyl, C １～６ -Alkoxy, C １～３ -Alkoxy-C １～３ -Alkyl, C １～３ -Alkoxy-C ２～３ -Alkoxy, C １～３ -Alkoxy-C ２～３ -Alkoxy-C １～３ -Alkyl, C １～３ -Alkyl-carbonylamino-C １～３ -Alkyl, C １～３ -Alkylsulfonyl-C １～３ 52. The compound of claim 51, or a pharma- ceutically acceptable salt thereof, wherein alkyl, phenyl, tetrahydrofuranyl, tetrahydropyranyl, and tetrahydrooxepanyl may be further substituted with one or more halogens.

103. The heterocyclyl ring is selected from the group consisting of halogen, hydroxy, C １～３ -Alkyl, C ３～６ -Cycloalkyl, cyclopropyl-C １～３ -Alkyl, C １～３ -Alkoxy, C １～３ -Alkoxy-C １～３ - optionally substituted with one or more substituents independently selected from the group consisting of alkyl, tetrahydrofuranyl, tetrahydropyranyl, and tetrahydrooxepanyl; １～３ -Alkyl, C ３～６ -Cycloalkyl, cyclopropyl-C １～３ -Alkyl, C １～３ -Alkoxy, C １～３ -Alkoxy-C １～３ 103. The compound of claim 102, or a pharma- ceutically acceptable salt thereof, wherein -alkyl, and tetrahydropyranyl may be further substituted with one or more halogens.

104. 103. The compound of claim 102, or a pharma- ceutically acceptable salt thereof, wherein the heterocyclyl ring is optionally substituted with one or more substituents independently selected from the group consisting of fluoro, methyl, ethyl, propyl, fluoromethyl, difluoromethyl, trifluoromethyl, fluoroethyl, difluoroethyl, trifluoroethyl, difluoropropyl, cyclopropyl, cyclopropylmethyl, methoxy, ethoxy, trifluoromethoxy, trifluoroethoxy, methoxymethyl, trifluoromethoxymethyl, and tetrahydropyranyl.

105. 103. The compound of claim 102, or a pharma- ceutically acceptable salt thereof, wherein the heterocyclyl ring is optionally substituted with one or more substituents independently selected from the group consisting of methyl, ethyl, propyl, fluoromethyl, difluoromethyl, trifluoromethyl, fluoroethyl, difluoroethyl, trifluoroethyl, difluoropropyl, cyclopropyl, and tetrahydropyranyl.

106. The heterocyclyl ring is 【Chemistry 17】 and The heterocyclyl ring is selected from the group consisting of halogen, hydroxy, C １～６ -Alkyl, C ３～６ -Cycloalkyl, C ３～６ -Cycloalkyl C １～３ -Alkyl, C １～６ -Alkoxy, C １～３ -Alkoxy-C １～３ -Alkyl, C １～３ -Alkoxy-C ２～３ -Alkoxy, C １～３ -Alkoxy-C ２～３ -Alkoxy-C １～３ -Alkyl, C １～３ -Alkylsulfonyl-C １～３ - optionally substituted with one or more substituents independently selected from the group consisting of alkyl, phenyl, tetrahydrofuranyl, tetrahydropyranyl, and tetrahydrooxepanyl; １～６ -Alkyl, C ３～６ -Cycloalkyl, C ３～６ -Cycloalkyl C １～３ -Alkyl, C １～６ -Alkoxy, C １～３ -Alkoxy-C １～３ -Alkyl, C １～３ -Alkoxy-C ２～３ -Alkoxy, C １～３ -Alkoxy-C ２～３ -Alkoxy-C １～３ -Alkyl, C １～３ -Alkylsulfonyl-C １～３ 52. The compound of claim 51, or a pharma- ceutically acceptable salt thereof, wherein alkyl, phenyl, tetrahydrofuranyl, tetrahydropyranyl, and tetrahydrooxepanyl may be further substituted with one or more halogens.

107. The heterocyclyl ring is selected from the group consisting of halogen, hydroxy, C １～３ -Alkyl, C ３～６ -Cycloalkyl, cyclopropyl-C １～３ -Alkyl, C １～３ -Alkoxy, C １～３ -Alkoxy-C １～３ - optionally substituted with one or more substituents independently selected from the group consisting of alkyl, tetrahydrofuranyl, tetrahydropyranyl, and tetrahydrooxepanyl; １～３ -Alkyl, C ３～６ -Cycloalkyl, cyclopropyl-C １～３ -Alkyl, C １～３ -Alkoxy, C １～３ -Alkoxy-C １～３ 107. The compound of claim 106, or a pharma- ceutically acceptable salt thereof, wherein -alkyl, and tetrahydropyranyl may be further substituted with one or more halogens.

108. 107. The compound of claim 106, or a pharma- ceutically acceptable salt thereof, wherein the heterocyclyl ring is optionally substituted with one or more substituents independently selected from the group consisting of fluoro, methyl, ethyl, propyl, isopropyl, fluoromethyl, difluoromethyl, trifluoromethyl, fluoroethyl, difluoroethyl, trifluoroethyl, difluoropropyl, cyclopropyl, methoxy, ethoxy, trifluoromethoxy, trifluoroethoxy, methoxymethyl, trifluoromethoxymethyl, and tetrahydropyranyl.

109. 107. The compound of claim 106, or a pharma- ceutically acceptable salt thereof, wherein the heterocyclyl ring is optionally substituted with one or more substituents independently selected from the group consisting of methyl, ethyl, propyl, isopropyl, fluoromethyl, difluoromethyl, trifluoromethyl, fluoroethyl, difluoroethyl, trifluoroethyl, difluoropropyl, cyclopropyl, and tetrahydropyranyl.

110. The heterocyclyl ring is 【Chemistry 18】 and The heterocyclyl ring is selected from the group consisting of halogen, hydroxy, oxo, C １～６ -Alkyl, C ３～６ -Cycloalkyl, C ３～６ -Cycloalkyl-C １～３ -Alkyl, C １～６ -Alkoxy, C １～３ -Alkoxy-C １～３ -Alkyl, C １～３ -Alkoxy-C ２～３ -Alkoxy, C １～３ -Alkoxy-C ２～３ -Alkoxy-C １～３ - alkyl, phenyl, tolyl, and C １～３ -alkoxyphenyl, wherein said C is optionally substituted with one or more substituents independently selected from the group consisting of １～６ -Alkyl, C ３～６ -Cycloalkyl, C ３～６ -Cycloalkyl-C １～３ -Alkyl, C １～６ -Alkoxy, C １～３ -Alkoxy-C １～３ -Alkyl, C １～３ -Alkoxy-C ２～３ -Alkoxy, C １～３ -Alkoxy-C ２～３ -Alkoxy-C １～３ - alkyl, phenyl, tolyl, and C １～３ 52. The compound of claim 51, or a pharma- ceutically acceptable salt thereof, wherein -alkoxyphenyl is optionally further substituted with one or more halogens.

111. The heterocyclyl ring is selected from the group consisting of fluoro, hydroxy, C １～３ -Alkyl, cyclopropyl, cyclopropyl-C １～３ -Alkyl, C １～３ -alkoxy, and C １～３ -Alkoxy-C １～３ -alkyl, wherein the C is optionally substituted with one or more substituents independently selected from the group consisting of １～３ -Alkyl, cyclopropyl, cyclopropyl-C １～３ -Alkyl, C １～３ -alkoxy, and C １～３ -Alkoxy-C １～３ 111. The compound of claim 110, or a pharma- ceutically acceptable salt thereof, wherein -alkyl is optionally further substituted with one or more fluoro.

112. 111. The compound of claim 110, or a pharma- ceutically acceptable salt thereof, wherein the heterocyclyl ring is optionally substituted with one or more substituents independently selected from the group consisting of fluoro, hydroxy, methyl, ethyl, propyl, isopropyl, fluoromethyl, difluoromethyl, trifluoromethyl, fluoroethyl, difluoroethyl, trifluoroethyl, cyclopropyl, cyclopropylmethyl, methoxy, ethoxy, propoxy, isopropoxy, trifluoromethoxy, trifluoroethoxy, methoxymethyl, and trifluoromethoxymethyl.

113. 111. The compound of claim 110, or a pharma- ceutically acceptable salt thereof, wherein the heterocyclyl ring is optionally substituted with one or more substituents independently selected from the group consisting of fluoro, hydroxy, methyl, ethyl, propyl, isopropyl, fluoromethyl, difluoromethyl, trifluoromethyl, fluoroethyl, difluoroethyl, trifluoroethyl, cyclopropyl, methoxy, ethoxy, propoxy, isopropoxy, trifluoromethoxy, and trifluoroethoxy.

114. The heterocyclyl ring is 【Chemistry 19】 and The heterocyclyl ring is selected from the group consisting of halogen, hydroxy, oxo, C １～６ -Alkyl, C ３～６ -Cycloalkyl, C ３～６ -Cycloalkyl-C １～３ -Alkyl, C １～６ -Alkoxy, C １～３ -Alkoxy-C １～３ -Alkyl, C １～３ -Alkoxy-C ２～３ -Alkoxy, C １～３ -Alkoxy-C ２～３ -Alkoxy-C １～３ -Alkyl, C １～３ -Alkylcarbonyl, C ３～６ -cycloalkylcarbonyl, and phenyl, optionally substituted with one or more substituents independently selected from the group consisting of １～６ -Alkyl, C ３～６ -Cycloalkyl, C ３～６ -Cycloalkyl-C １～３ -Alkyl, C １～６ -Alkoxy, C １～３ -Alkoxy-C １～３ -Alkyl, C １～３ -Alkoxy-C ２～３ -Alkoxy, C １～３ -Alkoxy-C ２～３ -Alkoxy-C １～３ -Alkyl, C １～３ -Alkylcarbonyl, C ３～６ 52. The compound of claim 51, or a pharma- ceutically acceptable salt thereof, wherein -cycloalkylcarbonyl, and phenyl may be further substituted with one or more halogens.

115. The heterocyclyl ring is selected from the group consisting of fluoro, hydroxy, oxo, C １～３ -Alkyl, cyclopropyl, cyclopropyl-C １～３ -Alkyl, C １～３ -alkoxy, and C １～３ -Alkoxy-C １～３ -alkyl, wherein the C is optionally substituted with one or more substituents independently selected from the group consisting of １～３ -Alkyl, cyclopropyl, cyclopropyl-C １～３ -Alkyl, C １～３ -alkoxy, and C １～３ -Alkoxy-C １～３ 115. The compound of claim 114, or a pharma- ceutically acceptable salt thereof, wherein -alkyl is optionally further substituted with one or more fluoro.

116. 115. The compound of claim 114, or a pharma- ceutically acceptable salt thereof, wherein the heterocyclyl ring is optionally substituted with one or more substituents independently selected from the group consisting of fluoro, hydroxy, oxo, methyl, ethyl, isopropyl, propyl, fluoromethyl, difluoromethyl, trifluoromethyl, fluoroethyl, difluoroethyl, trifluoroethyl, cyclopropyl, cyclopropylmethyl, methoxy, ethoxy, propoxy, trifluoromethoxy, trifluoroethoxy, methoxymethyl, and trifluoromethoxymethyl.

117. 115. The compound of claim 114, or a pharma- ceutically acceptable salt thereof, wherein the heterocyclyl ring is optionally substituted with one or more substituents independently selected from the group consisting of fluoro, hydroxy, oxo, methyl, ethyl, propyl, isopropyl, fluoromethyl, difluoromethyl, trifluoromethyl, fluoroethyl, difluoroethyl, trifluoroethyl, cyclopropyl, methoxy, ethoxy, trifluoromethoxy, trifluoroethoxy, and methoxymethyl.

118. The heterocyclyl ring is 【Chemistry 20】 and The heterocyclyl ring is selected from the group consisting of halogen, hydroxy, C １～６ -Alkyl, C ３～６ -Cycloalkyl, C １～６ -Alkoxy, C １～３ -Alkoxy-C １～３ -Alkyl, C １～３ -Alkoxy-C ２～３ -alkoxy, and C １～３ -Alkoxy-C ２～３ -Alkoxy-C １～３ -alkyl, wherein the C is optionally substituted with one or more substituents independently selected from the group consisting of １～６ -Alkyl, C ３～６ -Cycloalkyl, C １～６ -Alkoxy, C １～３ -Alkoxy-C １～３ -Alkyl, C １～３ -Alkoxy-C ２～３ -alkoxy, and C １～３ -Alkoxy-C ２～３ -Alkoxy-C １～３ 52. The compound of claim 51, or a pharma- ceutically acceptable salt thereof, wherein -alkyl is optionally further substituted with one or more halogens.

119. The heterocyclyl ring is selected from the group consisting of fluoro, hydroxy, C １～３ -Alkyl, cyclopropyl, C １～３ -alkoxy, and C １～３ -Alkoxy-C １～３ -alkyl, wherein the C is optionally substituted with one or more substituents independently selected from the group consisting of １～３ -Alkyl, cyclopropyl, C １～３ -alkoxy, and C １～３ -Alkoxy-C １～３ 119. The compound of claim 118, or a pharma- ceutically acceptable salt thereof, wherein -alkyl is optionally further substituted with one or more fluoro.

120. 119. The compound of claim 118, or a pharma- ceutically acceptable salt thereof, wherein the heterocyclyl ring is optionally substituted with one or more substituents independently selected from the group consisting of fluoro, hydroxy, methyl, ethyl, propyl, isopropyl, fluoromethyl, difluoromethyl, trifluoromethyl, fluoroethyl, difluoroethyl, trifluoroethyl, cyclopropyl, methoxy, ethoxy, propoxy, isopropoxy, trifluoromethoxy, trifluoroethoxy, methoxymethyl, and trifluoromethoxymethyl.

121. 119. The compound of claim 118, or a pharma- ceutically acceptable salt thereof, wherein the heterocyclyl ring is optionally substituted with one or more substituents independently selected from the group consisting of fluoro, hydroxy, methyl, ethyl, propyl, isopropyl, fluoromethyl, difluoromethyl, trifluoromethyl, fluoroethyl, difluoroethyl, trifluoroethyl, cyclopropyl, methoxy, ethoxy, isopropoxy, trifluoromethoxy, trifluoroethoxy, and methoxymethyl.

122. The heterocyclyl ring is 【Chemistry 21】 and The heterocyclyl ring is selected from the group consisting of halogen, hydroxy, C １～６ -Alkyl, hydroxy-C １～３ -Alkyl, C ３～６ -Cycloalkyl, C １～６ -Alkoxy, C １～３ -Alkoxy-C １～３ -Alkyl, C １～３ -Alkoxy-C ２～３ -alkoxy, and C １～３ -Alkoxy-C ２～３ -Alkoxy-C １～３ -alkyl, wherein the C is optionally substituted with one or more substituents independently selected from the group consisting of １～６ -Alkyl, C ３～６ -Cycloalkyl, C １～６ -Alkoxy, C １～３ -Alkoxy-C １～３ -Alkyl, C １～３ -Alkoxy-C ２～３ -alkoxy, and C １～３ -Alkoxy-C ２～３ -Alkoxy-C １～３ 52. The compound of claim 51, or a pharma- ceutically acceptable salt thereof, wherein -alkyl is optionally further substituted with one or more halogens.

123. The heterocyclyl ring is selected from the group consisting of fluoro, hydroxy, C １～３ -Alkyl, hydroxy-C １～３ -Alkyl, cyclopropyl, C １～３ -alkoxy, and C １～３ -Alkoxy-C １～３ -alkyl, wherein the C is optionally substituted with one or more substituents independently selected from the group consisting of １～３ -Alkyl, cyclopropyl, C １～３ -alkoxy, and C １～３ -Alkoxy-C １～３ 123. The compound of claim 122, or a pharma- ceutically acceptable salt thereof, wherein -alkyl is optionally further substituted with one or more fluoro.

124. 123. The compound of claim 122, or a pharma- ceutically acceptable salt thereof, wherein the heterocyclyl ring is optionally substituted with one or more substituents independently selected from the group consisting of fluoro, hydroxy, methyl, ethyl, propyl, fluoromethyl, difluoromethyl, trifluoromethyl, hydroxymethyl, fluoroethyl, difluoroethyl, trifluoroethyl, cyclopropyl, methoxy, ethoxy, propoxy, trifluoromethoxy, trifluoroethoxy, methoxymethyl, and trifluoromethoxymethyl.

125. 123. The compound of claim 122, or a pharma- ceutically acceptable salt thereof, wherein the heterocyclyl ring is optionally substituted with one or more substituents independently selected from the group consisting of fluoro, hydroxy, methyl, ethyl, propyl, fluoromethyl, difluoromethyl, trifluoromethyl, fluoroethyl, difluoroethyl, trifluoroethyl, cyclopropyl, methoxy, ethoxy, trifluoromethoxy, trifluoroethoxy, and methoxymethyl.

126. The heterocyclyl ring is 【Chemical 22】 and The heterocyclyl ring is selected from the group consisting of halogen, hydroxy, C １～６ -Alkyl, hydroxy-C １～３ -Alkyl, C ３～６ -Cycloalkyl, C １～６ -Alkoxy, C １～３ -Alkoxy-C １～３ -Alkyl, C １～３ -Alkoxy-C ２～３ -alkoxy, and C １～３ -Alkoxy-C ２～３ -Alkoxy-C １～３ -alkyl, wherein the C is optionally substituted with one or more substituents independently selected from the group consisting of １～６ -Alkyl, C ３～６ -Cycloalkyl, C １～６ -Alkoxy, C １～３ -Alkoxy-C １～３ -Alkyl, C １～３ -Alkoxy-C ２～３ -alkoxy, and C １～３ -Alkoxy-C ２～３ -Alkoxy-C １～３ 52. The compound of claim 51, or a pharma- ceutically acceptable salt thereof, wherein -alkyl is optionally further substituted with one or more halogens.

127. The heterocyclyl ring is selected from the group consisting of fluoro, hydroxy, C １～３ -Alkyl, hydroxy-C １～３ -Alkyl, cyclopropyl, C １～３ -alkoxy, and C １～３ -Alkoxy-C １～３ -alkyl, wherein the C is optionally substituted with one or more substituents independently selected from the group consisting of １～３ -Alkyl, cyclopropyl, C １～３ -alkoxy, and C １～３ -Alkoxy-C １～３ 127. The compound of claim 126, or a pharma- ceutically acceptable salt thereof, wherein -alkyl is optionally further substituted with one or more fluoro.

128. 127. The compound of claim 126, or a pharma- ceutically acceptable salt thereof, wherein the heterocyclyl ring is optionally substituted with one or more substituents independently selected from the group consisting of fluoro, hydroxy, methyl, ethyl, propyl, fluoromethyl, difluoromethyl, trifluoromethyl, hydroxymethyl, fluoroethyl, difluoroethyl, trifluoroethyl, cyclopropyl, methoxy, ethoxy, propoxy, trifluoromethoxy, trifluoroethoxy, methoxymethyl, and trifluoromethoxymethyl.

129. 127. The compound of claim 126, or a pharma- ceutically acceptable salt thereof, wherein the heterocyclyl ring is optionally substituted with one or more substituents independently selected from the group consisting of fluoro, hydroxy, methyl, ethyl, propyl, fluoromethyl, difluoromethyl, trifluoromethyl, fluoroethyl, difluoroethyl, trifluoroethyl, cyclopropyl, methoxy, ethoxy, trifluoromethoxy, trifluoroethoxy, and methoxymethyl.

130. The heterocyclyl ring is 【Chemistry 23】 and The heterocyclyl ring is selected from the group consisting of halogen, hydroxy, C １～６ -Alkyl, hydroxy-C １～３ -Alkyl, C ３～６ -Cycloalkyl, C １～６ -Alkoxy, C １～３ -Alkoxy-C １～３ -Alkyl, C １～３ -Alkoxy-C ２～３ -Alkyloxy, and C １～３ -Alkoxy-C ２～３ -Alkyloxy-C １～３ and optionally substituted with one or more substituents independently selected from the group consisting of alkyl, １～６ -Alkyl, C ３～６ -Cycloalkyl, C １～６ -Alkoxy, C １～３ -Alkoxy-C １～３ -Alkyl, C １～３ -Alkoxy-C ２～３ -Alkyloxy, and C １～３ -Alkoxy-C ２～３ -Alkyloxy-C １～３ 52. The compound of claim 51, or a pharma- ceutically acceptable salt thereof, wherein the alkyl is optionally further substituted with one or more halogens.

131. The heterocyclyl ring is selected from the group consisting of fluoro, hydroxy, C １～３ -Alkyl, hydroxy-C １～３ -Alkyl, cyclopropyl, C １～３ -alkoxy, and C １～３ -Alkoxy-C １～３ -alkyl, wherein the C is optionally substituted with one or more substituents independently selected from the group consisting of １～３ -Alkyl, cyclopropyl, C １～３ -alkoxy, and C １～３ -Alkoxy-C １～３ 131. The compound of claim 130, or a pharma- ceutically acceptable salt thereof, wherein -alkyl is optionally further substituted with one or more fluoro.

132. 131. The compound of claim 130, or a pharma- ceutically acceptable salt thereof, wherein the heterocyclyl ring is optionally substituted with one or more substituents independently selected from the group consisting of fluoro, hydroxy, methyl, ethyl, propyl, fluoromethyl, difluoromethyl, trifluoromethyl, hydroxymethyl, fluoroethyl, difluoroethyl, trifluoroethyl, cyclopropyl, methoxy, ethoxy, propoxy, trifluoromethoxy, trifluoroethoxy, methoxymethyl, and trifluoromethoxymethyl.

133. 131. The compound of claim 130, or a pharma- ceutically acceptable salt thereof, wherein the heterocyclyl ring is optionally substituted with one or more substituents independently selected from the group consisting of fluoro, hydroxy, methyl, ethyl, propyl, fluoromethyl, difluoromethyl, trifluoromethyl, fluoroethyl, difluoroethyl, trifluoroethyl, cyclopropyl, methoxy, ethoxy, trifluoromethoxy, trifluoroethoxy, and methoxymethyl.

134. R ２ and (ii) a heterocyclyl ring that is a saturated, partially saturated, or fully unsaturated monocyclic or fused bicyclic ring; (a) having one nitrogen ring atom and one oxygen ring atom, the remaining ring atoms being carbon, or (b) having one nitrogen ring atom and one sulfur ring atom, the remaining ring atoms being carbon, and (iii) a heterocyclyl ring that is a halogen atom, cyano, oxo, C １～６ -Alkyl, C ３～６ -Cycloalkyl, C １～６ -Alkoxy, C １～３ -Alkoxy-C １～３ -Alkyl, C １～３ -Alkylcarbonyl-C １～３ -Alkyl, and C １～３ -Alkylsulfonyl-C １～３ -alkyl, and １～６ -Alkyl, C ３～６ -Cycloalkyl, C １～６ -Alkoxy, C １～３ -Alkoxy-C １～３ -Alkyl, C １～３ -Alkylcarbonyl-C １～３ -Alkyl, and C １～３ -Alkylsulfonyl-C １～３ -alkyl may be further substituted with one or more halogens), or a pharma- ceutically acceptable salt thereof.

135. 135. The compound of claim 134, or a pharma- ceutically acceptable salt thereof, wherein said heterocyclyl ring is a saturated monocyclic ring.

136. 135. The compound of claim 134, or a pharma- ceutically acceptable salt thereof, wherein said heterocyclyl ring is a partially saturated monocyclic ring.

137. 135. The compound of claim 134, or a pharma- ceutically acceptable salt thereof, wherein said heterocyclyl ring is a fully unsaturated monocyclic ring.

138. 135. The compound of claim 134, or a pharma- ceutically acceptable salt thereof, wherein said heterocyclyl ring is a saturated fused bicyclic ring.

139. 135. The compound of claim 134, or a pharma- ceutically acceptable salt thereof, wherein said heterocyclyl ring is a partially saturated fused bicyclic ring.

140. 135. The compound of claim 134, or a pharma- ceutically acceptable salt thereof, wherein said heterocyclyl ring is a fully unsaturated fused bicyclic ring.

141. 141. The compound of any one of claims 134-140, or a pharma- ceutically acceptable salt thereof, wherein the heterocyclyl ring has one nitrogen ring atom and one oxygen ring atom, with the remaining ring atoms being carbon.

142. 141. The compound of any one of claims 134-140, wherein the heterocyclyl ring has one nitrogen ring atom and one sulfur ring atom, the remaining ring atoms being carbon, or a pharma- ceutically acceptable salt thereof.

143. The heterocyclyl ring is 【Chemistry 24】 is selected from the group consisting of The heterocyclyl ring is selected from the group consisting of halogen, cyano, C １～６ -Alkyl, C ３～６ -Cycloalkyl, C １～６ -Alkoxy, C １～３ -Alkoxy-C １～３ -Alkyl, C １～３ -Alkylcarbonyl-C １～３ -Alkyl, and C １～３ -Alkylsulfonyl-C １～３ -alkyl, wherein the C is optionally substituted with one or more substituents independently selected from the group consisting of １～６ -Alkyl, C １～６ -Alkoxy, C １～３ -Alkoxy-C １～３ -Alkyl, C ３～６ -Cycloalkyl, C １～３ -Alkylcarbonyl-C １～３ -Alkyl, and C １～３ -Alkylsulfonyl-C １～３ 135. The compound of claim 134, or a pharma- ceutically acceptable salt thereof, wherein -alkyl is optionally further substituted with one or more halogens.

144. The heterocyclyl ring is 【Chemistry 25】 is selected from the group consisting of The heterocyclyl ring is selected from the group consisting of halogen, cyano, C １～６ -Alkyl, C ３～６ -Cycloalkyl, C １～６ -Alkoxy, C １～３ -Alkoxy-C １～３ -Alkyl, C １～３ -Alkylcarbonyl-C １～３ -Alkyl, and C １～３ -Alkylsulfonyl-C １～３ -alkyl, wherein the C is optionally substituted with one or more substituents independently selected from the group consisting of １～６ -Alkyl, C １～６ -Alkoxy, C １～３ -Alkoxy-C １～３ -Alkyl, C ３～６ -Cycloalkyl, C １～３ -Alkylcarbonyl-C １～３ -Alkyl, and C １～３ -Alkylsulfonyl-C １～３ 135. The compound of claim 134, or a pharma- ceutically acceptable salt thereof, wherein -alkyl is optionally further substituted with one or more halogens.

145. The heterocyclyl ring is 【Chemistry 26】 is selected from the group consisting of The heterocyclyl ring is selected from the group consisting of halogen, cyano, C １～６ -Alkyl, C ３～６ -Cycloalkyl, C １～６ -Alkoxy, C １～３ -Alkoxy-C １～３ -Alkyl, C １～３ -Alkylcarbonyl-C １～３ -Alkyl, and C １～３ -Alkylsulfonyl-C １～３ -alkyl, wherein the C is optionally substituted with one or more substituents independently selected from the group consisting of １～６ -Alkyl, C ３～６ -Cycloalkyl, C １～６ -Alkoxy, C １～３ -Alkoxy-C １～３ -Alkyl, C １～３ -Alkylcarbonyl-C １～３ -Alkyl, and C １～３ -Alkylsulfonyl-C １～３ 135. The compound of claim 134, or a pharma- ceutically acceptable salt thereof, wherein -alkyl is optionally further substituted with one or more halogens.

146. The heterocyclyl ring is selected from the group consisting of halogen, cyano, C １～３ -Alkyl, C ３～５ -Cycloalkyl, C １～３ -Alkoxy, C １～３ -Alkoxy-C １～３ -Alkyl, C １～３ -Alkylcarbonyl-C １～３ -Alkyl, and C １～３ -Alkylsulfonyl-C １～３ -alkyl, wherein the C is optionally substituted with one or more substituents independently selected from the group consisting of １～３ -Alkyl, C １～３ -Alkoxy, C １～３ -Alkoxy-C １～３ -Alkyl, C １～３ -Alkylcarbonyl-C １～３ -Alkyl, C ３～５ -cycloalkyl, and C １～３ -Alkylsulfonyl-C １～３ 146. The compound of any one of claims 134 to 145, or a pharma- ceutically acceptable salt thereof, wherein -alkyl is optionally further substituted with one or more halogens.

147. The heterocyclyl ring is selected from the group consisting of halogen, cyano, C １～２ -Alkyl, C ３～４ -Cycloalkyl, C １～２ -Alkoxy, C １～２ -Alkoxy-C １～３ -Alkyl, C １～２ -Alkylcarbonyl-C １～２ -Alkyl, and C １～２ -Alkylsulfonyl-C １～２ -alkyl, wherein the C is optionally substituted with one or more substituents independently selected from the group consisting of １～２ -Alkyl, C ３～４ -Cycloalkyl, C １～２ -Alkoxy, C １～２ -Alkoxy-C １～２ -Alkyl, C １～２ -Alkylcarbonyl-C １～２ -Alkyl, and C １～２ -Alkylsulfonyl-C １～２ 146. The compound of any one of claims 134 to 145, or a pharma- ceutically acceptable salt thereof, wherein -alkyl is optionally further substituted with one or more halogens.

148. 146. The compound of any one of claims 134-145, or a pharma- ceutically acceptable salt thereof, wherein said heterocyclyl ring is optionally substituted with one or more halogens.

149. 146. The compound of any one of claims 134-145, or a pharma- ceutically acceptable salt thereof, wherein said heterocyclyl ring is optionally substituted with one or more fluoro.

150. The heterocyclyl ring is one or more C １～３ - optionally substituted with alkyl, １～３ 146. The compound of any one of claims 134 to 145, or a pharma- ceutically acceptable salt thereof, wherein -alkyl is optionally further substituted with one or more halogens.

151. The heterocyclyl ring is one or more C ３～６ - optionally substituted with cycloalkyl, ３～６ 146. The compound of any one of claims 134 to 145, or a pharma- ceutically acceptable salt thereof, wherein cycloalkyl is optionally further substituted with one or more halogens.

152. The heterocyclyl ring is one or more C １～３ -Alkoxy-C １～３ - optionally substituted with alkyl, １～３ -Alkoxy-C １～３ 146. The compound of any one of claims 134 to 145, or a pharma- ceutically acceptable salt thereof, wherein -alkyl is optionally further substituted with one or more halogens.

153. The heterocyclyl ring is one or more C １～３ -Alkylsulfonyl-C １～３ - optionally substituted with alkyl, １～３ -Alkylsulfonyl-C １～３ 146. The compound of any one of claims 134 to 145, or a pharma- ceutically acceptable salt thereof, wherein -alkyl is optionally further substituted with one or more halogens.

154. 146. The compound of any one of claims 134-145, or a pharma- ceutically acceptable salt thereof, wherein the heterocyclyl ring is optionally substituted with one or more substituents independently selected from the group consisting of cyano, fluoro, methyl, ethyl, propyl, isopropyl, cyclopropyl, fluoromethyl, difluoromethyl, trifluoromethyl, fluoroethyl, difluoroethyl, trifluoroethyl, trifluoropropyl, methoxy, ethoxy, isopropoxy, trifluoromethoxy, trifluoroethoxy, methoxymethyl, methoxyethyl, trifluoromethoxymethyl, and methylsulfonylmethyl.

155. 146. The compound of any one of claims 134-145, or a pharma- ceutically acceptable salt thereof, wherein said heterocyclyl ring is optionally substituted with one or more substituents independently selected from the group consisting of fluoro, methyl, ethyl, isopropyl, cyclopropyl, fluoromethyl, difluoropropyl, methoxy, and trifluoromethoxy.

156. The heterocyclyl ring is 【Chemistry 27】 and The heterocyclyl ring is selected from the group consisting of halogen, cyano, oxo, C １～６ -Alkyl, C ３～６ -Cycloalkyl, C １～６ -Alkoxy, C １～３ -Alkoxy-C １～３ -Alkyl, C １～３ -Alkylcarbonyl-C １～３ -Alkyl, and C １～３ -Alkylsulfonyl-C １～３ -alkyl, wherein the C is optionally substituted with one or more substituents independently selected from the group consisting of １～６ -Alkyl, C ３～６ -Cycloalkyl, C １～６ -Alkoxy, C １～３ -Alkoxy-C １～３ -Alkyl, C １～３ -Alkylcarbonyl-C １～３ -Alkyl, and C １～３ -Alkylsulfonyl-C １～３ 135. The compound of claim 134, or a pharma- ceutically acceptable salt thereof, wherein -alkyl is optionally further substituted with one or more halogens.

157. The heterocyclyl ring is selected from the group consisting of halogen, cyano, C １～３ -Alkyl, C ３～５ -Cycloalkyl, C １～３ -Alkoxy, C １～３ -Alkoxy-C １～３ -Alkyl, C １～３ -Alkylcarbonyl-C １～３ -Alkyl, and C １～３ -Alkylsulfonyl-C １～３ -alkyl, wherein the C is optionally substituted with one or more substituents independently selected from the group consisting of １～３ -Alkyl, C ３～５ -Cycloalkyl, C １～３ -Alkoxy, C １～３ -Alkoxy-C １～３ -Alkyl, C １～３ -Alkylcarbonyl-C １～３ -Alkyl, and C １～３ -Alkylsulfonyl-C １～３ 157. The compound of claim 156, or a pharma- ceutically acceptable salt thereof, wherein -alkyl is optionally further substituted with one or more halogens.

158. 157. The compound of claim 156, or a pharma- ceutically acceptable salt thereof, wherein the heterocyclyl ring is optionally substituted with one or more substituents independently selected from the group consisting of fluoro, cyano, methyl, ethyl, propyl, isopropyl, cyclopropyl, fluoromethyl, difluoromethyl, trifluoromethyl, fluoroethyl, difluoroethyl, trifluoroethyl, trifluoropropyl, methoxy, ethoxy, trifluoromethoxy, trifluoroethoxy, methoxymethyl, methoxyethyl, trifluoromethoxymethyl, and methylsulfonylmethyl.

159. 157. The compound of claim 156, or a pharma- ceutically acceptable salt thereof, wherein the heterocyclyl ring is optionally substituted with one or more substituents independently selected from the group consisting of fluoro, methyl, ethyl, fluoromethyl, trifluoromethyl, difluoropropyl, methoxy, trifluoromethoxy, and methoxymethyl.

160. The heterocyclyl ring is 【Chemistry 28】 and The heterocyclyl ring is selected from the group consisting of halogen, cyano, oxo, C １～６ -Alkyl, C ３～６ -Cycloalkyl, C １～６ -Alkoxy, C １～３ -Alkoxy-C １～３ -Alkyl, C １～３ -Alkylcarbonyl-C １～３ -Alkyl, and C １～３ -Alkylsulfonyl-C １～３ -alkyl, wherein the C is optionally substituted with one or more substituents independently selected from the group consisting of １～６ -Alkyl, C ３～６ -Cycloalkyl, C １～６ -Alkoxy, C １～３ -Alkoxy-C １～３ -Alkyl, C １～３ -Alkylcarbonyl-C １～３ -Alkyl, and C １～３ -Alkylsulfonyl-C １～３ 135. The compound of claim 134, or a pharma- ceutically acceptable salt thereof, wherein -alkyl is optionally further substituted with one or more halogens.

161. The heterocyclyl ring is selected from the group consisting of halogen, cyano, C １～３ -Alkyl, C ３～６ -Cycloalkyl, C １～３ -Alkoxy, C １～３ -Alkoxy-C １～３ -Alkyl, C １～３ -Alkylcarbonyl-C １～３ -Alkyl, and C １～３ -Alkylsulfonyl-C １～３ -alkyl, wherein the C is optionally substituted with one or more substituents independently selected from the group consisting of １～３ -Alkyl, C ３～６ -Cycloalkyl, C １～３ -Alkoxy, C １～３ -Alkoxy-C １～３ -Alkyl, C １～３ -Alkylcarbonyl-C １～３ -Alkyl, and C １～３ -Alkylsulfonyl-C １～３ 161. The compound of claim 160, or a pharma- ceutically acceptable salt thereof, wherein -alkyl is optionally further substituted with one or more halogens.

162. 161. The compound of claim 160, or a pharma- ceutically acceptable salt thereof, wherein the heterocyclyl ring is optionally substituted with one or more substituents independently selected from the group consisting of halogen, cyano, fluoro, methyl, ethyl, propyl, isopropyl, cyclopropyl, fluoromethyl, difluoromethyl, trifluoromethyl, fluoroethyl, difluoroethyl, trifluoroethyl, trifluoropropyl, methoxy, ethoxy, trifluoromethoxy, trifluoroethoxy, methoxymethyl, trifluoromethoxymethyl, and methylsulfonylmethyl.

163. 161. The compound of claim 160, or a pharma- ceutically acceptable salt thereof, wherein the heterocyclyl ring is optionally substituted with one or more substituents independently selected from the group consisting of fluoro, methyl, ethyl, isopropyl, cyclopropyl, fluoromethyl, difluoropropyl, methoxy, and trifluoromethoxy.

164. The heterocyclyl ring is 【Chemical 29】 and The heterocyclyl ring is selected from the group consisting of halogen, cyano, C １～６ -Alkyl, C ３～６ -Cycloalkyl, C １～６ -Alkoxy, C １～３ -Alkoxy-C １～３ -Alkyl, C １～３ -Alkylcarbonyl-C １～３ -Alkyl, and C １～３ -Alkylsulfonyl-C １～３ -alkyl, wherein the C is optionally substituted with one or more substituents independently selected from the group consisting of １～６ -Alkyl, C ３～６ -Cycloalkyl, C １～６ -Alkoxy, C １～３ -Alkoxy-C １～３ -Alkyl, C １～３ -Alkylcarbonyl-C １～３ -Alkyl, and C １～３ -Alkylsulfonyl-C １～３ 135. The compound of claim 134, or a pharma- ceutically acceptable salt thereof, wherein -alkyl is optionally further substituted with one or more halogens.

165. The heterocyclyl ring is selected from the group consisting of halogen, cyano, C １～３ -Alkyl, C ３～６ -Cycloalkyl, C １～３ -Alkoxy, C １～３ -Alkoxy-C １～３ -Alkyl, C １～３ -Alkylcarbonyl-C １～３ -Alkyl, and C １～３ -Alkylsulfonyl-C １～３ -alkyl, wherein the C is optionally substituted with one or more substituents independently selected from the group consisting of １～３ -Alkyl, C ３～６ -Cycloalkyl, C １～３ -Alkoxy, C １～３ -Alkoxy-C １～３ -Alkyl, C １～３ -Alkylcarbonyl-C １～３ -Alkyl, and C １～３ -Alkylsulfonyl-C １～３ 165. The compound of claim 164, or a pharma- ceutically acceptable salt thereof, wherein -alkyl is optionally further substituted with one or more halogens.

166. 165. The compound of claim 164, or a pharma- ceutically acceptable salt thereof, wherein the heterocyclyl ring is optionally substituted with one or more substituents independently selected from the group consisting of cyano, fluoro, methyl, ethyl, propyl, isopropyl, cyclopropyl, fluoromethyl, difluoromethyl, trifluoromethyl, fluoroethyl, difluoroethyl, trifluoroethyl, trifluoropropyl, methoxy, ethoxy, trifluoromethoxy, trifluoroethoxy, methoxymethyl, trifluoromethoxymethyl, and methylsulfonylmethyl.

167. 165. The compound of claim 164, or a pharma- ceutically acceptable salt thereof, wherein the heterocyclyl ring is optionally substituted with one or more substituents independently selected from the group consisting of fluoro, methyl, ethyl, isopropyl, cyclopropyl, fluoromethyl, difluoropropyl, methoxy, and trifluoromethoxy.

168. The heterocyclyl ring is 【Chemistry 30】 and The heterocyclyl ring is selected from the group consisting of halogen, cyano, C １～６ -Alkyl, C ３～６ -Cycloalkyl, C １～６ -Alkoxy, C １～３ -Alkoxy-C １～３ -Alkyl, C １～３ -Alkylcarbonyl-C １～３ -Alkyl, and C １～３ -Alkylsulfonyl-C １～３ -alkyl, wherein the C is optionally substituted with one or more substituents independently selected from the group consisting of １～６ -Alkyl, C ３～６ -Cycloalkyl, C １～６ -Alkoxy, C １～３ -Alkoxy-C １～３ -Alkyl, C １～３ -Alkylcarbonyl-C １～３ -Alkyl, and C １～３ -Alkylsulfonyl-C １～３ 135. The compound of claim 134, or a pharma- ceutically acceptable salt thereof, wherein -alkyl is optionally further substituted with one or more halogens.

169. The heterocyclyl ring is selected from the group consisting of halogen, cyano, C １～３ -Alkyl, C ３～６ -Cycloalkyl, C １～３ -Alkoxy, C １～３ -Alkoxy-C １～３ -Alkyl, C １～３ -Alkylcarbonyl-C １～３ -Alkyl, and C １～３ -Alkylsulfonyl-C １～３ -alkyl, wherein the C is optionally substituted with one or more substituents independently selected from the group consisting of １～３ -Alkyl, C ３～６ -Cycloalkyl, C １～３ -Alkoxy, C １～３ -Alkoxy-C １～３ -Alkyl, C １～３ -Alkylcarbonyl-C １～３ -Alkyl, and C １～３ -Alkylsulfonyl-C １～３ 169. The compound of claim 168, or a pharma- ceutically acceptable salt thereof, wherein -alkyl is optionally further substituted with one or more halogens.

170. 169. The compound of claim 168, or a pharma- ceutically acceptable salt thereof, wherein the heterocyclyl ring is optionally substituted with one or more substituents independently selected from the group consisting of cyano, fluoro, methyl, ethyl, propyl, isopropyl, cyclopropyl, fluoromethyl, difluoromethyl, trifluoromethyl, fluoroethyl, difluoroethyl, trifluoroethyl, trifluoropropyl, methoxy, ethoxy, trifluoromethoxy, trifluoroethoxy, methoxymethyl, trifluoromethoxymethyl, and methylsulfonylmethyl.

171. 169. The compound of claim 168, or a pharma- ceutically acceptable salt thereof, wherein the heterocyclyl ring is optionally substituted with one or more substituents independently selected from the group consisting of fluoro, methyl, ethyl, isopropyl, cyclopropyl, fluoromethyl, difluoropropyl, methoxy, and trifluoromethoxy.

172. 169. The compound of claim 168, or a pharma- ceutically acceptable salt thereof, wherein the heterocyclyl ring is optionally substituted with one or more substituents independently selected from the group consisting of fluoro, methyl, ethyl, fluoromethyl, difluoropropyl, methoxy, and trifluoromethoxy.

173. The heterocyclyl ring is 【Chemistry 31】 and The heterocyclyl ring is selected from the group consisting of halogen, cyano, oxo, C １～６ -Alkyl, C ３～６ -Cycloalkyl, C １～６ -Alkoxy, C １～３ -Alkoxy-C １～３ -Alkyl, C １～３ -Alkylcarbonyl-C １～３ -Alkyl, and C １～３ -Alkylsulfonyl-C １～３ -alkyl, wherein the C is optionally substituted with one or more substituents independently selected from the group consisting of １～６ -Alkyl, C ３～６ -Cycloalkyl, C １～６ -Alkoxy, C １～３ -Alkoxy-C １～３ -Alkyl, C １～３ -Alkylcarbonyl-C １～３ -Alkyl, and C １～３ -Alkylsulfonyl-C １～３ 135. The compound of claim 134, or a pharma- ceutically acceptable salt thereof, wherein -alkyl is optionally further substituted with one or more halogens.

174. The heterocyclyl ring is selected from the group consisting of halogen, cyano, C １～３ -Alkyl, C ３～６ -Cycloalkyl, C １～３ -Alkoxy, C １～３ -Alkoxy-C １～３ -Alkyl, C １～３ -Alkylcarbonyl-C １～３ -Alkyl, and C １～３ -Alkylsulfonyl-C １～３ -alkyl, wherein the C is optionally substituted with one or more substituents independently selected from the group consisting of １～３ -Alkyl, C ３～６ -Cycloalkyl, C １～３ -Alkoxy, C １～３ -Alkoxy-C １～３ -Alkyl, C １～３ -Alkylcarbonyl-C １～３ -Alkyl, and C １～３ -Alkylsulfonyl-C １～３ 174. The compound of claim 173, or a pharma- ceutically acceptable salt thereof, wherein -alkyl is optionally further substituted with one or more halogens.

175. 174. The compound of claim 173, or a pharma- ceutically acceptable salt thereof, wherein the heterocyclyl ring is optionally substituted with one or more substituents independently selected from the group consisting of cyano, fluoro, methyl, ethyl, propyl, isopropyl, cyclopropyl, fluoromethyl, difluoromethyl, trifluoromethyl, fluoroethyl, difluoroethyl, trifluoroethyl, trifluoropropyl, methoxy, ethoxy, trifluoromethoxy, trifluoroethoxy, methoxymethyl, trifluoromethoxymethyl, and methylsulfonylmethyl.

176. 174. The compound of claim 173, or a pharma- ceutically acceptable salt thereof, wherein the heterocyclyl ring is optionally substituted with one or more substituents independently selected from the group consisting of fluoro, methyl, ethyl, isopropyl, fluoromethyl, difluoropropyl, methoxy, and trifluoromethoxy.

177. The heterocyclyl ring is 【Chemistry 32】 and The heterocyclyl ring is selected from the group consisting of halogen, cyano, oxo, C １～６ -Alkyl, C ３～６ -Cycloalkyl, C １～６ -Alkoxy, C １～３ -Alkoxy-C １～３ -Alkyl, C １～３ -Alkylcarbonyl-C １～３ -Alkyl, and C １～３ -Alkylsulfonyl-C １～３ -alkyl, wherein the C is optionally substituted with one or more substituents independently selected from the group consisting of １～６ -Alkyl, C ３～６ -Cycloalkyl, C １～６ -Alkoxy, C １～３ -Alkoxy-C １～３ -Alkyl, C １～３ -Alkylcarbonyl-C １～３ -Alkyl, and C １～３ -Alkylsulfonyl-C １～３ 135. The compound of claim 134, or a pharma- ceutically acceptable salt thereof, wherein -alkyl is optionally further substituted with one or more halogens.

178. The heterocyclyl ring is selected from the group consisting of halogen, cyano, C １～３ -Alkyl, C ３～６ -Cycloalkyl, C １～３ -Alkoxy, C １～３ -Alkoxy-C １～３ -Alkyl, C １～３ -Alkylcarbonyl-C １～３ -Alkyl, and C １～３ -Alkylsulfonyl-C １～３ -alkyl, wherein the C is optionally substituted with one or more substituents independently selected from the group consisting of １～３ -Alkyl, C ３～６ -Cycloalkyl, C １～３ -Alkoxy, C １～３ -Alkoxy-C １～３ -Alkyl, C １～３ -Alkylcarbonyl-C １～３ -Alkyl, and C １～３ -Alkylsulfonyl-C １～３ 178. The compound of claim 177, or a pharma- ceutically acceptable salt thereof, wherein -alkyl is optionally further substituted with one or more halogens.

179. 178. The compound of claim 177, or a pharma- ceutically acceptable salt thereof, wherein the heterocyclyl ring is optionally substituted with one or more substituents independently selected from the group consisting of cyano, fluoro, methyl, ethyl, propyl, isopropyl, cyclopropyl, fluoromethyl, difluoromethyl, trifluoromethyl, fluoroethyl, difluoroethyl, trifluoroethyl, trifluoropropyl, methoxy, ethoxy, trifluoromethoxy, trifluoroethoxy, methoxymethyl, trifluoromethoxymethyl, and methylsulfonylmethyl.

180. 178. The compound of claim 177, or a pharma- ceutically acceptable salt thereof, wherein the heterocyclyl ring is optionally substituted with one or more substituents independently selected from the group consisting of fluoro, methyl, ethyl, fluoromethyl, difluoropropyl, methoxy, and trifluoromethoxy.

181. The heterocyclyl ring is 【Chemical Formula 33】 and The heterocyclyl ring is selected from the group consisting of halogen, cyano, oxo, C １～６ -Alkyl, C ３～６ -Cycloalkyl, C １～６ -Alkoxy, C １～３ -Alkoxy-C １～３ -Alkyl, C １～３ -Alkylcarbonyl-C １～３ -Alkyl, and C １～３ -Alkylsulfonyl-C １～３ -alkyl, wherein the C is optionally substituted with one or more substituents independently selected from the group consisting of １～６ -Alkyl, C ３～６ -Cycloalkyl, C １～６ -Alkoxy, C １～３ -Alkoxy-C １～３ -Alkyl, C １～３ -Alkylcarbonyl-C １～３ -Alkyl, and C １～３ -Alkylsulfonyl-C １～３ 135. The compound of claim 134, or a pharma- ceutically acceptable salt thereof, wherein -alkyl is optionally further substituted with one or more halogens.

182. The heterocyclyl ring is selected from the group consisting of halogen, cyano, C １～３ -Alkyl, C ３～６ -Cycloalkyl, C １～３ -Alkoxy, C １～３ -Alkoxy-C １～３ -Alkyl, C １～３ -Alkylcarbonyl-C １～３ -Alkyl, and C １～３ -Alkylsulfonyl-C １～３ -alkyl, wherein the C is optionally substituted with one or more substituents independently selected from the group consisting of １～３ -Alkyl, C ３～６ -Cycloalkyl, C １～３ -Alkoxy, C １～３ -Alkoxy-C １～３ -Alkyl, C １～３ -Alkylcarbonyl-C １～３ -Alkyl, and C １～３ -Alkylsulfonyl-C １～３ 182. The compound of claim 181, or a pharma- ceutically acceptable salt thereof, wherein -alkyl is optionally further substituted with one or more halogens.

183. 182. The compound of claim 181, or a pharma- ceutically acceptable salt thereof, wherein the heterocyclyl ring is optionally substituted with one or more substituents independently selected from the group consisting of cyano, fluoro, methyl, ethyl, propyl, isopropyl, cyclopropyl, fluoromethyl, difluoromethyl, trifluoromethyl, fluoroethyl, difluoroethyl, trifluoroethyl, trifluoropropyl, methoxy, ethoxy, trifluoromethoxy, trifluoroethoxy, methoxymethyl, trifluoromethoxymethyl, and methylsulfonylmethyl.

184. 182. The compound of claim 181, or a pharma- ceutically acceptable salt thereof, wherein the heterocyclyl ring is optionally substituted with one or more substituents independently selected from the group consisting of fluoro, methyl, ethyl, fluoromethyl, difluoropropyl, methoxy, and trifluoromethoxy.

185. The heterocyclyl ring is 【Chemical 34】 and The heterocyclyl ring is selected from the group consisting of halogen, cyano, oxo, C １～６ -Alkyl, C ３～６ -Cycloalkyl, C １～６ -Alkoxy, C １～３ -Alkoxy-C １～３ -Alkyl, C １～３ -Alkylcarbonyl-C １～３ -Alkyl, and C １～３ -Alkylsulfonyl-C １～３ -alkyl, wherein the C is optionally substituted with one or more substituents independently selected from the group consisting of １～６ -Alkyl, C ３～６ -Cycloalkyl, C １～６ -Alkoxy, C １～３ -Alkoxy-C １～３ -Alkyl, C １～３ -Alkylcarbonyl-C １～３ -Alkyl, and C １～３ -Alkylsulfonyl-C １～３ 135. The compound of claim 134, or a pharma- ceutically acceptable salt thereof, wherein -alkyl is optionally further substituted with one or more halogens.

186. The heterocyclyl ring is selected from the group consisting of halogen, cyano, C １～３ -Alkyl, C ３～６ -Cycloalkyl, C １～３ -Alkoxy, C １～３ -Alkoxy-C １～３ -Alkyl, C １～３ -Alkylcarbonyl-C １～３ -Alkyl, and C １～３ -Alkylsulfonyl-C １～３ -alkyl, wherein the C is optionally substituted with one or more substituents independently selected from the group consisting of １～３ -Alkyl, C ３～６ -Cycloalkyl, C １～３ -Alkoxy, C １～３ -Alkoxy-C １～３ -Alkyl, C １～３ -Alkylcarbonyl-C １～３ -Alkyl, and C １～３ -Alkylsulfonyl-C １～３ 186. The compound of claim 185, or a pharma- ceutically acceptable salt thereof, wherein -alkyl is optionally further substituted with one or more halogens.

187. 186. The compound of claim 185, or a pharma- ceutically acceptable salt thereof, wherein the heterocyclyl ring is optionally substituted with one or more substituents independently selected from the group consisting of cyano, fluoro, methyl, ethyl, propyl, isopropyl, cyclopropyl, fluoromethyl, difluoromethyl, trifluoromethyl, fluoroethyl, difluoroethyl, trifluoroethyl, trifluoropropyl, methoxy, ethoxy, trifluoromethoxy, trifluoroethoxy, methoxymethyl, trifluoromethoxymethyl, and methylsulfonylmethyl.

188. 186. The compound of claim 185, or a pharma- ceutically acceptable salt thereof, wherein the heterocyclyl ring is optionally substituted with one or more substituents independently selected from the group consisting of fluoro, methyl, ethyl, isopropyl, fluoromethyl, difluoropropyl, methoxy, and trifluoromethoxy.

189. The heterocyclyl ring is 【Chemistry 35】 and The heterocyclyl ring is selected from the group consisting of halogen, cyano, oxo, C １～６ -Alkyl, C ３～６ -Cycloalkyl, C １～６ -Alkoxy, C １～３ -Alkoxy-C １～３ -Alkyl, C １～３ -Alkylcarbonyl-C １～３ -Alkyl, and C １～３ -Alkylsulfonyl-C １～３ -alkyl, wherein the C is optionally substituted with one or more substituents independently selected from the group consisting of １～６ -Alkyl, C ３～６ -Cycloalkyl, C １～６ -Alkoxy, C １～３ -Alkoxy-C １～３ -Alkyl, C １～３ -Alkylcarbonyl-C １～３ -Alkyl, and C １～３ -Alkylsulfonyl-C １～３ 135. The compound of claim 134, or a pharma- ceutically acceptable salt thereof, wherein -alkyl is optionally further substituted with one or more halogens.

190. The heterocyclyl ring is selected from the group consisting of halogen, cyano, C １～３ -Alkyl, C ３～６ -Cycloalkyl, C １～３ -Alkoxy, C １～３ -Alkoxy-C １～３ -Alkyl, C １～３ -Alkylcarbonyl-C １～３ -Alkyl, and C １～３ -Alkylsulfonyl-C １～３ -alkyl, wherein the C is optionally substituted with one or more substituents independently selected from the group consisting of １～３ -Alkyl, C ３～６ -Cycloalkyl, C １～３ -Alkoxy, C １～３ -Alkoxy-C １～３ -Alkyl, C １～３ -Alkylcarbonyl-C １～３ -Alkyl, and C １～３ -Alkylsulfonyl-C １～３ 190. The compound of claim 189, or a pharma- ceutically acceptable salt thereof, wherein -alkyl is optionally further substituted with one or more halogens.

191. 190. The compound of claim 189, or a pharma- ceutically acceptable salt thereof, wherein the heterocyclyl ring is optionally substituted with one or more substituents independently selected from the group consisting of cyano, fluoro, methyl, ethyl, propyl, isopropyl, cyclopropyl, fluoromethyl, difluoromethyl, trifluoromethyl, fluoroethyl, difluoroethyl, trifluoroethyl, trifluoropropyl, methoxy, ethoxy, trifluoromethoxy, trifluoroethoxy, methoxymethyl, trifluoromethoxymethyl, and methylsulfonylmethyl.

192. 190. The compound of claim 189, or a pharma- ceutically acceptable salt thereof, wherein the heterocyclyl ring is optionally substituted with one or more substituents independently selected from the group consisting of fluoro, methyl, ethyl, fluoromethyl, difluoropropyl, methoxy, and trifluoromethoxy.

193. The heterocyclyl ring is 【Chemical Formula 36】 and The heterocyclyl ring is selected from the group consisting of halogen, cyano, oxo, C １～６ -Alkyl, C ３～６ -Cycloalkyl, C １～６ -Alkoxy, C １～３ -Alkoxy-C １～３ -Alkyl, C １～３ -Alkylcarbonyl-C １～３ -Alkyl, and C １～３ -Alkylsulfonyl-C １～３ -alkyl, wherein the C is optionally substituted with one or more substituents independently selected from the group consisting of １～６ -Alkyl, C ３～６ -Cycloalkyl, C １～６ -Alkoxy, C １～３ -Alkoxy-C １～３ -Alkyl, C １～３ -Alkylcarbonyl-C １～３ -Alkyl, and C １～３ -Alkylsulfonyl-C １～３ 135. The compound of claim 134, or a pharma- ceutically acceptable salt thereof, wherein -alkyl is optionally further substituted with one or more halogens.

194. The heterocyclyl ring is selected from the group consisting of halogen, cyano, C １～３ -Alkyl, C ３～６ -Cycloalkyl, C １～３ -Alkoxy, C １～３ -Alkoxy-C １～３ -Alkyl, C １～３ -Alkylcarbonyl-C １～３ -Alkyl, and C １～３ -Alkylsulfonyl-C １～３ -alkyl, wherein the C is optionally substituted with one or more substituents independently selected from the group consisting of １～３ -Alkyl, C ３～６ -Cycloalkyl, C １～３ -Alkoxy, C １～３ -Alkoxy-C １～３ -Alkyl, C １～３ -Alkylcarbonyl-C １～３ -Alkyl, and C １～３ -Alkylsulfonyl-C １～３ 194. The compound of claim 193, or a pharma- ceutically acceptable salt thereof, wherein -alkyl is optionally further substituted with one or more halogens.

195. 200. The compound of claim 193, or a pharma- ceutically acceptable salt thereof, wherein the heterocyclyl ring is optionally substituted with one or more substituents independently selected from the group consisting of cyano, fluoro, methyl, ethyl, propyl, isopropyl, cyclopropyl, fluoromethyl, difluoromethyl, trifluoromethyl, fluoroethyl, difluoroethyl, trifluoroethyl, trifluoropropyl, methoxy, ethoxy, trifluoromethoxy, trifluoroethoxy, methoxymethyl, trifluoromethoxymethyl, and methylsulfonylmethyl.

196. 200. The compound of claim 193, or a pharma- ceutically acceptable salt thereof, wherein the heterocyclyl ring is optionally substituted with one or more substituents independently selected from the group consisting of fluoro, methyl, ethyl, fluoromethyl, difluoropropyl, methoxy, and trifluoromethoxy.

197. The heterocyclyl ring is 【Chemical 37】 and The heterocyclyl ring is selected from the group consisting of halogen, cyano, oxo, C １～６ -Alkyl, C ３～６ -Cycloalkyl, C １～６ -Alkoxy, C １～３ -Alkoxy-C １～３ -Alkyl, C １～３ -Alkylcarbonyl-C １～３ -Alkyl, and C １～３ -Alkylsulfonyl-C １～３ -alkyl, wherein the C is optionally substituted with one or more substituents independently selected from the group consisting of １～６ -Alkyl, C ３～６ -Cycloalkyl, C １～６ -Alkoxy, C １～３ -Alkoxy-C １～３ -Alkyl, C １～３ -Alkylcarbonyl-C １～３ -Alkyl, and C １～３ -Alkylsulfonyl-C １～３ 135. The compound of claim 134, or a pharma- ceutically acceptable salt thereof, wherein -alkyl is optionally further substituted with one or more halogens.

198. The heterocyclyl ring is selected from the group consisting of halogen, cyano, C １～３ -Alkyl, C ３～６ -Cycloalkyl, C １～３ -Alkoxy, C １～３ -Alkoxy-C １～３ -Alkyl, C １～３ -Alkylcarbonyl-C １～３ -Alkyl, and C １～３ -Alkylsulfonyl-C １～３ -alkyl, wherein the C is optionally substituted with one or more substituents independently selected from the group consisting of １～３ -Alkyl, C ３～６ -Cycloalkyl, C １～３ -Alkoxy, C １～３ -Alkoxy-C １～３ -Alkyl, C １～３ -Alkylcarbonyl-C １～３ -Alkyl, and C １～３ -Alkylsulfonyl-C １～３ 200. The compound of claim 197, or a pharma- ceutically acceptable salt thereof, wherein -alkyl is optionally further substituted with one or more halogens.

199. 200. The compound of claim 197, or a pharma- ceutically acceptable salt thereof, wherein the heterocyclyl ring is optionally substituted with one or more substituents independently selected from the group consisting of cyano, fluoro, methyl, ethyl, propyl, isopropyl, cyclopropyl, fluoromethyl, difluoromethyl, trifluoromethyl, fluoroethyl, difluoroethyl, trifluoroethyl, trifluoropropyl, methoxy, ethoxy, trifluoromethoxy, trifluoroethoxy, methoxymethyl, trifluoromethoxymethyl, and methylsulfonylmethyl.

200. 200. The compound of claim 197, or a pharma- ceutically acceptable salt thereof, wherein the heterocyclyl ring is optionally substituted with one or more substituents independently selected from the group consisting of fluoro, methyl, ethyl, fluoromethyl, difluoropropyl, methoxy, and trifluoromethoxy.

201. R ２ a spiroheterocyclyl containing a total of 6 to 11 ring atoms, said spiroheterocyclyl (i) containing two saturated rings; (ii) (a) having one or two nitrogen ring atoms and the remaining ring atoms being carbon, or (b) having one or two nitrogen ring atoms and one or two oxygen ring atoms and the remaining ring atoms being carbon, or (c) having one nitrogen ring atom and one sulfur ring atom and the remaining ring atoms being carbon, and (iii) not containing any of halogen, oxo, C; １～６ -Alkyl, C １～６ -Haloalkyl, C １～６ -Alkoxy, C １～６ -haloalkoxy, and C １～６ -alkylcarbonyl, or a pharma- ceutically acceptable salt thereof.

202. R ２ is (a) a spiroheterocyclyl having one or two nitrogen ring atoms and the remaining ring atoms being carbon, or (b) a spiroheterocyclyl having one or two nitrogen ring atoms and one or two oxygen ring atoms and the remaining ring atoms being carbon, or a pharma- ceutically acceptable salt thereof.

203. 202. The compound of claim 201, or a pharma- ceutically acceptable salt thereof, wherein the spiroheterocyclyl has 1 or 2 nitrogen ring atoms, and optionally 1 or 2 oxygen ring atoms, the remaining ring atoms being carbon.

204. 202. The compound of claim 201, wherein said spiroheterocyclyl has one nitrogen ring atom and the remaining ring atoms are carbon; or a pharma- ceutically acceptable salt thereof.

205. 202. The compound of claim 201, wherein said spiroheterocyclyl has two nitrogen ring atoms and the remaining ring atoms are carbon; or a pharma- ceutically acceptable salt thereof.

206. 202. The compound of claim 201, wherein said spiroheterocyclyl has one nitrogen ring atom and one oxygen ring atom, with the remaining ring atoms being carbon; or a pharma- ceutically acceptable salt thereof.

207. 202. The compound of claim 201, wherein said spiroheterocyclyl has one nitrogen ring atom and two oxygen ring atoms, with the remaining ring atoms being carbon; or a pharma- ceutically acceptable salt thereof.

208. The two saturated rings are 【Chemical 38】 selected from the group consisting of: One or both of the rings may be halogen, C １～６ -Alkyl, C １～６ -Haloalkyl, C １～６ -Alkoxy, C １～６ -haloalkoxy, and C １～６ -alkylcarbonyl; or a pharma- ceutically acceptable salt thereof.

209. The two saturated rings are 【Chemical Formula 39】 is selected from the group consisting of One or both of the rings may be halogen, C １～６ -Alkyl, C １～６ -Haloalkyl, C １～６ -Alkoxy, C １～６ -haloalkoxy, and C １～６ -alkylcarbonyl; or a pharma- ceutically acceptable salt thereof.

210. The two saturated rings are 【Chemistry 40】 selected from the group consisting of: One or both of the rings may be halogen, C １～６ -Alkyl, C １～６ -Haloalkyl, C １～６ -Alkoxy, C １～６ -haloalkoxy, and C １～６ -alkylcarbonyl; or a pharma- ceutically acceptable salt thereof.

211. The spiroheterocyclyl ring is selected from the group consisting of halogen, C １～３ -Alkyl, C １～３ -Haloalkyl, C １～３ -Alkoxy, C １～３ -haloalkoxy, and C １～３ -alkylcarbonyl; or a pharma- ceutically acceptable salt thereof.

212. 211. The compound of any one of claims 201-210, or a pharma- ceutically acceptable salt thereof, wherein said spiroheterocyclyl ring is optionally substituted with one or more halogens.

213. 211. The compound of any one of claims 201-210, or a pharma- ceutically acceptable salt thereof, wherein said spiroheterocyclyl ring is optionally substituted with one or more fluoro.

214. The spiroheterocyclyl ring is １～３ 211. The compound of any one of claims 201 to 210, or a pharma- ceutically acceptable salt thereof, optionally substituted with -alkyl.

215. The spiroheterocyclyl ring is １～３ 211. The compound of any one of claims 201 to 210, or a pharma- ceutically acceptable salt thereof, optionally substituted with haloalkyl.

216. The spiroheterocyclyl ring is １～３ 211. The compound of any one of claims 201 to 210, or a pharma- ceutically acceptable salt thereof, optionally substituted with -alkoxy.

217. The spiroheterocyclyl ring is １～３ 211. The compound of any one of claims 201 to 210, or a pharma- ceutically acceptable salt thereof, optionally substituted with -haloalkoxy.

218. The spiroheterocyclyl ring is １～３ 211. The compound of any one of claims 201 to 210, or a pharma- ceutically acceptable salt thereof, optionally substituted with -alkylcarbonyl.

219. 211. The compound of any one of claims 201-210, or a pharma- ceutically acceptable salt thereof, wherein the spiroheterocyclyl ring is optionally substituted with one or more substituents independently selected from the group consisting of fluoro, methyl, ethyl, propyl, isopropyl, fluoromethyl, difluoromethyl, trifluoromethyl, fluoroethyl, difluoroethyl, trifluoroethyl, trifluoropropyl, methoxy, ethoxy, trifluoromethoxy, trifluoroethoxy, methylcarbonyl, ethylcarbonyl, and isopropylcarbonyl.

220. 211. The compound of any one of claims 201-210, or a pharma- ceutically acceptable salt thereof, wherein said spiroheterocyclyl ring is optionally substituted with one or more substituents independently selected from the group consisting of fluoro, methyl, ethyl, fluoromethyl, difluoromethyl, and trifluoromethyl.

221. The two saturated rings are 【Chemistry 41】 and One or both of the rings may be halogen, C １～６ -Alkyl, C １～６ -Haloalkyl, C １～６ -Alkoxy, C １～６ -haloalkoxy, and C １～６ -alkylcarbonyl; or a pharma- ceutically acceptable salt thereof.

222. The spiroheterocyclyl ring is selected from the group consisting of halogen, C １～３ -Alkyl, C １～３ -Haloalkyl, C １～３ -Alkoxy, C １～３ -haloalkoxy, and C １～３ -alkylcarbonyl; or a pharma- ceutically acceptable salt thereof.

223. 222. The compound of claim 221, or a pharma- ceutically acceptable salt thereof, wherein the spiroheterocyclyl ring is optionally substituted with one or more substituents independently selected from the group consisting of fluoro, methyl, ethyl, propyl, fluoromethyl, difluoromethyl, trifluoromethyl, fluoroethyl, difluoroethyl, trifluoroethyl, trifluoropropyl, methoxy, ethoxy, trifluoromethoxy, and trifluoroethoxy.

224. 222. The compound of claim 221, or a pharma- ceutically acceptable salt thereof, wherein the spiroheterocyclyl ring is optionally substituted with one or more substituents independently selected from the group consisting of fluoro, methyl, ethyl, fluoromethyl, difluoromethyl, and trifluoromethyl.

225. The two saturated rings are 【Chemistry 42】 and One or both of the rings may be halogen, C １～６ -Alkyl, C １～６ -Haloalkyl, C １～６ -Alkoxy, C １～６ -haloalkoxy, and C １～６ -alkylcarbonyl; or a pharma- ceutically acceptable salt thereof.

226. The spiroheterocyclyl ring is selected from the group consisting of halogen, C １～３ -Alkyl, C １～３ -Haloalkyl, C １～３ -Alkoxy, C １～３ -haloalkoxy, and C １～３ -alkylcarbonyl; or a pharma- ceutically acceptable salt thereof.

227. 226. The compound of claim 225, or a pharma- ceutically acceptable salt thereof, wherein the spiroheterocyclyl ring is optionally substituted with one or more substituents independently selected from the group consisting of fluoro, methyl, ethyl, propyl, fluoromethyl, difluoromethyl, trifluoromethyl, fluoroethyl, difluoroethyl, trifluoroethyl, trifluoropropyl, methoxy, ethoxy, trifluoromethoxy, trifluoroethoxy, and methylcarbonyl.

228. 226. The compound of claim 225, or a pharma- ceutically acceptable salt thereof, wherein the spiroheterocyclyl ring is optionally substituted with one or more substituents independently selected from the group consisting of fluoro, methyl, ethyl, fluoromethyl, difluoromethyl, trifluoromethyl, and methylcarbonyl.

229. The two saturated rings are 【Chemistry 43】 and One or both of the rings may be halogen, C １～６ -Alkyl, C １～６ -Haloalkyl, C １～６ -Alkoxy, C １～６ -haloalkoxy, and C １～６ -alkylcarbonyl; or a pharma- ceutically acceptable salt thereof.

230. The spiroheterocyclyl ring is selected from the group consisting of halogen, C １～３ -Alkyl, C １～３ -Haloalkyl, C １～３ -Alkoxy, C １～３ -haloalkoxy, and C １～３ 230. The compound of claim 229, or a pharma- ceutically acceptable salt thereof, optionally substituted with one or more substituents independently selected from the group consisting of: -alkylcarbonyl.

231. 230. The compound of claim 229, or a pharma- ceutically acceptable salt thereof, wherein the spiroheterocyclyl ring is optionally substituted with one or more substituents independently selected from the group consisting of fluoro, methyl, ethyl, propyl, fluoromethyl, difluoromethyl, trifluoromethyl, fluoroethyl, difluoroethyl, trifluoroethyl, trifluoropropyl, methoxy, ethoxy, trifluoromethoxy, trifluoroethoxy, methylcarbonyl, and ethylcarbonyl.

232. 230. The compound of claim 229, or a pharma- ceutically acceptable salt thereof, wherein the spiroheterocyclyl ring is optionally substituted with one or more substituents independently selected from the group consisting of fluoro, methyl, ethyl, fluoromethyl, difluoromethyl, and trifluoromethyl.

233. The two saturated rings are 【Chemistry 44】 and One or both of the rings may be halogen, C １～６ -Alkyl, C １～６ -Haloalkyl, C １～６ -Alkoxy, C １～６ -haloalkoxy, and C １～６ -alkylcarbonyl; or a pharma- ceutically acceptable salt thereof.

234. The spiroheterocyclyl ring is selected from the group consisting of halogen, C １～３ -Alkyl, C １～３ -Haloalkyl, C １～３ -Alkoxy, C １～３ -haloalkoxy, and C １～３ 234. The compound of claim 233, or a pharma- ceutically acceptable salt thereof, optionally substituted with one or more substituents independently selected from the group consisting of: -alkylcarbonyl.

235. 234. The compound of claim 233, or a pharma- ceutically acceptable salt thereof, wherein the spiroheterocyclyl ring is optionally substituted with one or more substituents independently selected from the group consisting of fluoro, methyl, ethyl, propyl, fluoromethyl, difluoromethyl, trifluoromethyl, fluoroethyl, difluoroethyl, trifluoroethyl, trifluoropropyl, methoxy, ethoxy, trifluoromethoxy, trifluoroethoxy, methylcarbonyl, and ethylcarbonyl.

236. 234. The compound of claim 233, or a pharma- ceutically acceptable salt thereof, wherein the spiroheterocyclyl ring is optionally substituted with one or more substituents independently selected from the group consisting of fluoro, methyl, ethyl, fluoromethyl, difluoromethyl, and trifluoromethyl.

237. The two saturated rings are 【Chemistry 45】 and One or both of the rings may be halogen, C １～６ -Alkyl, C １～６ -Haloalkyl, C １～６ -Alkoxy, C １～６ -haloalkoxy, and C １～６ -alkylcarbonyl; or a pharma- ceutically acceptable salt thereof.

238. The spiroheterocyclyl ring is selected from the group consisting of halogen, C １～３ -Alkyl, C １～３ -Haloalkyl, C １～３ -Alkoxy, C １～３ -haloalkoxy, and C １～３ 238. The compound of claim 237, or a pharma- ceutically acceptable salt thereof, optionally substituted with one or more substituents independently selected from the group consisting of: -alkylcarbonyl.

239. 238. The compound of claim 237, or a pharma- ceutically acceptable salt thereof, wherein the spiroheterocyclyl ring is optionally substituted with one or more substituents independently selected from the group consisting of fluoro, methyl, ethyl, propyl, fluoromethyl, difluoromethyl, trifluoromethyl, fluoroethyl, difluoroethyl, trifluoroethyl, trifluoropropyl, methoxy, ethoxy, trifluoromethoxy, trifluoroethoxy, methylcarbonyl, and ethylcarbonyl.

240. 238. The compound of claim 237, or a pharma- ceutically acceptable salt thereof, wherein the spiroheterocyclyl ring is optionally substituted with one or more substituents independently selected from the group consisting of fluoro, methyl, ethyl, fluoromethyl, difluoromethyl, and trifluoromethyl.

241. The two saturated rings are 【Chemistry 46】 and One or both of the rings may be halogen, C １～６ -Alkyl, C １～６ -Haloalkyl, C １～６ -Alkoxy, C １～６ -haloalkoxy, and C １～６ -alkylcarbonyl; or a pharma- ceutically acceptable salt thereof.

242. The spiroheterocyclyl ring is selected from the group consisting of halogen, C １～３ -Alkyl, C １～３ -Haloalkyl, C １～３ -Alkoxy, C １～３ -haloalkoxy, and C １～３ 242. The compound of claim 241, or a pharma- ceutically acceptable salt thereof, optionally substituted with one or more substituents independently selected from the group consisting of: -alkylcarbonyl.

243. 242. The compound of claim 241, or a pharma- ceutically acceptable salt thereof, wherein the spiroheterocyclyl ring is optionally substituted with one or more substituents independently selected from the group consisting of fluoro, methyl, ethyl, propyl, fluoromethyl, difluoromethyl, trifluoromethyl, fluoroethyl, difluoroethyl, trifluoroethyl, trifluoropropyl, methoxy, ethoxy, trifluoromethoxy, trifluoroethoxy, methylcarbonyl, and ethylcarbonyl.

244. 242. The compound of claim 241, or a pharma- ceutically acceptable salt thereof, wherein the spiroheterocyclyl ring is optionally substituted with one or more substituents independently selected from the group consisting of fluoro, methyl, ethyl, fluoromethyl, difluoromethyl, and trifluoromethyl.

245. The two saturated rings are 【Chemistry 47】 and One or both of the rings may be halogen, C １～６ -Alkyl, C １～６ -Haloalkyl, C １～６ -Alkoxy, C １～６ -haloalkoxy, and C １～６ -alkylcarbonyl; or a pharma- ceutically acceptable salt thereof.

246. The spiroheterocyclyl ring is selected from the group consisting of halogen, C １～３ -Alkyl, C １～３ -Haloalkyl, C １～３ -Alkoxy, C １～３ -haloalkoxy, and C １～３ 246. The compound of claim 245, or a pharma- ceutically acceptable salt thereof, optionally substituted with one or more substituents independently selected from the group consisting of: -alkylcarbonyl.

247. 246. The compound of claim 245, or a pharma- ceutically acceptable salt thereof, wherein the spiroheterocyclyl ring is optionally substituted with one or more substituents independently selected from the group consisting of fluoro, methyl, ethyl, propyl, fluoromethyl, difluoromethyl, trifluoromethyl, fluoroethyl, difluoroethyl, trifluoroethyl, trifluoropropyl, methoxy, ethoxy, trifluoromethoxy, trifluoroethoxy, methylcarbonyl, and ethylcarbonyl.

248. 246. The compound of claim 245, or a pharma- ceutically acceptable salt thereof, wherein the spiroheterocyclyl ring is optionally substituted with one or more substituents independently selected from the group consisting of fluoro, methyl, ethyl, fluoromethyl, difluoromethyl, and trifluoromethyl.

249. The two saturated rings are 【Chemistry 48】 and One or both of the rings may be halogen, C １～６ -Alkyl, C １～６ -Haloalkyl, C １～６ -Alkoxy, C １～６ -haloalkoxy, and C １～６ -alkylcarbonyl; or a pharma- ceutically acceptable salt thereof.

250. The spiroheterocyclyl ring is selected from the group consisting of halogen, C １～３ -Alkyl, C １～３ -Haloalkyl, C １～３ -Alkoxy, C １～３ -haloalkoxy, and C １～３ 250. The compound of claim 249, or a pharma- ceutically acceptable salt thereof, optionally substituted with one or more substituents independently selected from the group consisting of: -alkylcarbonyl.

251. 250. The compound of claim 249, or a pharma- ceutically acceptable salt thereof, wherein the spiroheterocyclyl ring is optionally substituted with one or more substituents independently selected from the group consisting of fluoro, methyl, ethyl, propyl, fluoromethyl, difluoromethyl, trifluoromethyl, fluoroethyl, difluoroethyl, trifluoroethyl, trifluoropropyl, methoxy, ethoxy, trifluoromethoxy, and trifluoroethoxy.

252. 250. The compound of claim 249, or a pharma- ceutically acceptable salt thereof, wherein the spiroheterocyclyl ring is optionally substituted with one or more substituents independently selected from the group consisting of fluoro, methyl, ethyl, fluoromethyl, difluoromethyl, and trifluoromethyl.

253. The two saturated rings are 【Chemistry 49】 and One or both of the rings may be halogen, C １～６ -Alkyl, C １～６ -Haloalkyl, C １～６ -Alkoxy, C １～６ -haloalkoxy, and C １～６ -alkylcarbonyl; or a pharma- ceutically acceptable salt thereof.

254. The spiroheterocyclyl ring is selected from the group consisting of halogen, C １～３ -Alkyl, C １～３ -Haloalkyl, C １～３ -Alkoxy, C １～３ -haloalkoxy, and C １～３ -alkylcarbonyl; or a pharma- ceutically acceptable salt thereof.

255. 254. The compound of claim 253, or a pharma- ceutically acceptable salt thereof, wherein the spiroheterocyclyl ring is optionally substituted with one or more substituents independently selected from the group consisting of fluoro, methyl, ethyl, propyl, fluoromethyl, difluoromethyl, trifluoromethyl, fluoroethyl, difluoroethyl, trifluoroethyl, trifluoropropyl, methoxy, ethoxy, trifluoromethoxy, trifluoroethoxy, methylcarbonyl, and ethylcarbonyl.

256. 254. The compound of claim 253, or a pharma- ceutically acceptable salt thereof, wherein the spiroheterocyclyl ring is optionally substituted with one or more substituents independently selected from the group consisting of fluoro, methyl, ethyl, fluoromethyl, difluoromethyl, and trifluoromethyl.

257. The two saturated rings are 【Chemistry 50】 and One or both of the rings may be halogen, C １～６ -Alkyl, C １～６ -Haloalkyl, C １～６ -Alkoxy, C １～６ -haloalkoxy, and C １～６ -alkylcarbonyl; or a pharma- ceutically acceptable salt thereof.

258. The spiroheterocyclyl ring is selected from the group consisting of halogen, C １～３ -Alkyl, C １～３ -Haloalkyl, C １～３ -Alkoxy, C １～３ -haloalkoxy, and C １～３ 258. The compound of claim 257, or a pharma- ceutically acceptable salt thereof, optionally substituted with one or more substituents independently selected from the group consisting of: -alkylcarbonyl.

259. 258. The compound of claim 257, or a pharma- ceutically acceptable salt thereof, wherein the spiroheterocyclyl ring is optionally substituted with one or more substituents independently selected from the group consisting of fluoro, methyl, ethyl, propyl, fluoromethyl, difluoromethyl, trifluoromethyl, fluoroethyl, difluoroethyl, trifluoroethyl, trifluoropropyl, methoxy, ethoxy, trifluoromethoxy, trifluoroethoxy, methylcarbonyl, and ethylcarbonyl.

260. 258. The compound of claim 257, or a pharma- ceutically acceptable salt thereof, wherein the spiroheterocyclyl ring is optionally substituted with one or more substituents independently selected from the group consisting of fluoro, methyl, ethyl, fluoromethyl, difluoromethyl, and trifluoromethyl.

261. The two saturated rings are 【Chemistry 51】 and One or both of the rings may be halogen, C １～６ -Alkyl, C １～６ -Haloalkyl, C １～６ -Alkoxy, C １～６ -haloalkoxy, and C １～６ -alkylcarbonyl; or a pharma- ceutically acceptable salt thereof.

262. The spiroheterocyclyl ring is selected from the group consisting of halogen, C １～３ -Alkyl, C １～３ -Haloalkyl, C １～３ -Alkoxy, C １～３ -haloalkoxy, and C １～３ 262. The compound of claim 261, or a pharma- ceutically acceptable salt thereof, optionally substituted with one or more substituents independently selected from the group consisting of: -alkylcarbonyl.

263. 262. The compound of claim 261, or a pharma- ceutically acceptable salt thereof, wherein the spiroheterocyclyl ring is optionally substituted with one or more substituents independently selected from the group consisting of fluoro, methyl, ethyl, propyl, fluoromethyl, difluoromethyl, trifluoromethyl, fluoroethyl, difluoroethyl, trifluoroethyl, trifluoropropyl, methoxy, ethoxy, trifluoromethoxy, trifluoroethoxy, methylcarbonyl, and ethylcarbonyl.

264. 262. The compound of claim 261, or a pharma- ceutically acceptable salt thereof, wherein the spiroheterocyclyl ring is optionally substituted with one or more substituents independently selected from the group consisting of fluoro, methyl, ethyl, fluoromethyl, difluoromethyl, and trifluoromethyl.

265. The two saturated rings are 【Chemistry 52】 and One or both of the rings may be halogen, C １～６ -Alkyl, C １～６ -Haloalkyl, C １～６ -Alkoxy, C １～６ -haloalkoxy, and C １～６ -alkylcarbonyl; or a pharma- ceutically acceptable salt thereof.

266. The spiroheterocyclyl ring is selected from the group consisting of halogen, C １～３ -Alkyl, C １～３ -Haloalkyl, C １～３ -Alkoxy, C １～３ -haloalkoxy, and C １～３ 266. The compound of claim 265, or a pharma- ceutically acceptable salt thereof, optionally substituted with one or more substituents independently selected from the group consisting of: -alkylcarbonyl.

267. 266. The compound of claim 265, or a pharma- ceutically acceptable salt thereof, wherein the spiroheterocyclyl ring is optionally substituted with one or more substituents independently selected from the group consisting of fluoro, methyl, ethyl, propyl, fluoromethyl, difluoromethyl, trifluoromethyl, fluoroethyl, difluoroethyl, trifluoroethyl, trifluoropropyl, methoxy, ethoxy, trifluoromethoxy, and trifluoroethoxy.

268. 266. The compound of claim 265, or a pharma- ceutically acceptable salt thereof, wherein the spiroheterocyclyl ring is optionally substituted with one or more substituents independently selected from the group consisting of fluoro, methyl, ethyl, fluoromethyl, difluoromethyl, and trifluoromethyl.

269. The two saturated rings are 【Chemistry 53】 and One or both of the rings may be halogen, C １～６ -Alkyl, C １～６ -Haloalkyl, C １～６ -Alkoxy, C １～６ -haloalkoxy, and C １～６ -alkylcarbonyl; or a pharma- ceutically acceptable salt thereof.

270. The spiroheterocyclyl ring is selected from the group consisting of halogen, C １～３ -Alkyl, C １～３ -Haloalkyl, C １～３ -Alkoxy, C １～３ -haloalkoxy, and C １～３ 270. The compound of claim 269, or a pharma- ceutically acceptable salt thereof, optionally substituted with one or more substituents independently selected from the group consisting of: -alkylcarbonyl.

271. 270. The compound of claim 269, or a pharma- ceutically acceptable salt thereof, wherein the spiroheterocyclyl ring is optionally substituted with one or more substituents independently selected from the group consisting of fluoro, methyl, ethyl, propyl, fluoromethyl, difluoromethyl, trifluoromethyl, fluoroethyl, difluoroethyl, trifluoroethyl, trifluoropropyl, methoxy, ethoxy, trifluoromethoxy, and trifluoroethoxy.

272. 270. The compound of claim 269, or a pharma- ceutically acceptable salt thereof, wherein the spiroheterocyclyl ring is optionally substituted with one or more substituents independently selected from the group consisting of fluoro, methyl, ethyl, fluoromethyl, difluoromethyl, and trifluoromethyl.

273. The two saturated rings are 【Chemical 54】 and One or both of the rings may be halogen, C １～６ -Alkyl, C １～６ -Haloalkyl, C １～６ -Alkoxy, C １～６ -haloalkoxy, and C １～６ -alkylcarbonyl; or a pharma- ceutically acceptable salt thereof.

274. The spiroheterocyclyl ring is selected from the group consisting of halogen, C １～３ -Alkyl, C １～３ -Haloalkyl, C １～３ -Alkoxy, C １～３ -haloalkoxy, and C １～３ 274. The compound of claim 273, or a pharma- ceutically acceptable salt thereof, optionally substituted with one or more substituents independently selected from the group consisting of: -alkylcarbonyl.

275. 274. The compound of claim 273, or a pharma- ceutically acceptable salt thereof, wherein the spiroheterocyclyl ring is optionally substituted with one or more substituents independently selected from the group consisting of fluoro, methyl, ethyl, propyl, fluoromethyl, difluoromethyl, trifluoromethyl, fluoroethyl, difluoroethyl, trifluoroethyl, trifluoropropyl, methoxy, ethoxy, trifluoromethoxy, trifluoroethoxy, methylcarbonyl, and ethylcarbonyl.

276. 274. The compound of claim 273, or a pharma- ceutically acceptable salt thereof, wherein the spiroheterocyclyl ring is optionally substituted with one or more substituents independently selected from the group consisting of fluoro, methyl, ethyl, fluoromethyl, difluoromethyl, and trifluoromethyl.

277. The compound has the structure of formula (V): 【Chemistry 55】 (In the formula, R １ , R ３ , R ４ , R ５ , and R ６ is independently selected from the group consisting of hydrogen, chloro, fluoro, and methyl; R ２０ａ and R ２０ｂ are independently hydrogen and C １～３ - alkyl; R ２０ｃ and R ２０ｄ are independently hydrogen, fluoro, hydroxy, C １～３ -Alkyl, C ３～６ -Cycloalkyl, C ３～６ -Cycloalkyl-C １～３ -Alkyl, C １～３ -Alkoxy, C ３～６ -cycloalkoxy, C １～３ -Alkoxy-C １～３ -Alkyl, phenyl, tolyl, phenyl-C １～３ -Alkyl, morpholinyl, C １～３ -Alkylsulfonyl-C １～３ -Alkyl, and C １～３ -Alkyl-carbonylamino-C １～３ -alkyl, and １～３ -Alkyl, C ３～６ -Cycloalkyl, C ３～６ -Cycloalkyl-C １～３ -Alkyl, C １～３ -Alkoxy, C ３～６ -cycloalkoxy, C １～３ -Alkoxy-C １～３ -alkyl, phenyl, and phenyl-C １～３ -alkyl may be further substituted with one or more halogens; and R ２０ｅ and R ２０ｆ are independently hydrogen and C １～３ -alkyl), or a pharma- ceutically acceptable salt thereof.

278. The R １ , R ３ , R ４ , R ５ , and R ６ One of the substituents is selected from the group consisting of chloro, fluoro, and methyl, and the remaining R １ , R ３ , R ４ , R ５ , and R ６ 278. The compound of claim 277, or a pharma- ceutically acceptable salt thereof, wherein the substituents are all hydrogen.

279. R １ , R ３ , R ４ , R ５ , and R ６ or a pharma- ceutically acceptable salt thereof.

278. The compound of claim 277, or a pharma- ceutically acceptable salt thereof, wherein:

280. R ２０ａ and R ２０ｂ is independently selected from the group consisting of hydrogen and methyl; R ２０ｃ and R ２０ｄ are independently hydrogen, fluoro, hydroxy, C １～３ -Alkyl, C ３～６ -Cycloalkyl, C １～３ -Alkoxy, C １～３ -Alkoxy-C １～３ -Alkyl, morpholinyl, C １～３ -Alkylsulfonyl-C １～３ -Alkyl, and C １～３ -Alkyl-carbonylamino-C １～３ -alkyl; １～３ -Alkyl, C ３～６ -Cycloalkyl, C １～３ -alkoxy, and C １～３ -Alkoxy-C １～３ - the alkyl may be further substituted with one or more halogens; and R ２０ｅ and R ２０ｆ is independently selected from the group consisting of hydrogen and methyl; or a pharma- ceutically acceptable salt thereof.

281. R ２０ｃ and R ２０ｄ are independently hydrogen, fluoro, C １～３ -Alkyl, C １～３ -alkoxy, morpholinyl, and C １～３ -Alkyl-carbonylamino-C １～３ -alkyl; １～３ -Alkyl and C １～３ 281. The compound of claim 280, or a pharma- ceutically acceptable salt thereof, wherein -alkoxy is optionally further substituted with one or more halogen.

282. The compound has the structure of formula (VI): 【Chemistry 56】 (In the formula, R １ , R ３ , R ４ , R ５ , and R ６ is independently selected from the group consisting of hydrogen, chloro, fluoro, and methyl; R ３０ａ and R ３０ｂ are independently hydrogen, C １～３ -Alkyl, halo-C １～３ -Alkyl, and C １～３ -Alkoxy-C １～３ - alkyl; R ３０ｃ and R ３０ｄ are independently hydrogen, halogen, C １～３ -Alkyl, halo-C １～３ -Alkyl, C １～３ -Alkoxy-C １～３ -Alkyl, and C １～３ -Alkylsulfonyl-C １～３ - alkyl; R ３０ｅ and R ３０ｆ are independently hydrogen, halogen, C １～３ -Alkyl, halo-C １～３ -Alkyl, C １～３ -Alkoxy-C １～３ -Alkyl, and C １～３ -Alkylsulfonyl-C １～３ - alkyl; and R ３０ｇ and R ３０ｈ are independently hydrogen, C １～３ -Alkyl, halo-C １～３ Alkyl, and C １～３ -Alkoxy-C １～３ 2. The compound of claim 1, wherein the compound is selected from the group consisting of: -alkyl, or a pharma- ceutically acceptable salt thereof.

283. The R １ , R ３ , R ４ , R ５ , and R ６ One of the substituents is selected from the group consisting of chloro, fluoro, and methyl, and the remaining R １ , R ３ , R ４ , R ５ , and R ６ 283. The compound of claim 282, or a pharma- ceutically acceptable salt thereof, wherein the substituents are all hydrogen.

284. R １ , R ３ , R ４ , R ５ , and R ６ or a pharma- ceutically acceptable salt thereof.

283. The compound of claim 282, or a pharma- ceutically acceptable salt thereof, wherein:

285. R ３０ａ and R ３０ｂ are independently hydrogen, C １～２ -Alkyl, halo-C １～２ -Alkyl, and C １～２ -Alkoxy-C １～２ - alkyl; R ３０ｃ and R ３０ｄ are independently hydrogen, halogen, C １～２ -Alkyl, halo-C １～２ -Alkyl, C １～２ -Alkoxy-C １～２ -Alkyl, and C １～２ -Alkylsulfonyl-C １～２ - alkyl; R ３０ｅ and R ３０ｆ are independently hydrogen, halogen, C １～２ -Alkyl, halo-C １～２ -Alkyl, C １～２ -Alkoxy-C １～２ -Alkyl, and C １～２ -Alkylsulfonyl-C １～２ - alkyl; and R ３０ｇ and R ３０ｈ are independently hydrogen, C １～２ -Alkyl, halo-C １～２ -Alkyl, and C １～２ -Alkoxy-C １～２ -alkyl; or a pharma- ceutically acceptable salt thereof.

286. The compound has the structure of formula (VII): 【Chemistry 57】 (In the formula, R １ , R ３ , R ４ , R ５ , and R ６ is independently selected from the group consisting of hydrogen, chloro, fluoro, and methyl; R ４０ａ and R ４０ｂ are independently hydrogen, C １～３ -alkyl and halo-C １～３ - alkyl; R ４０ｃ and R ４０ｄ are independently hydrogen, fluoro, C １～３ -Alkyl, halo-C １～３ -Alkyl, and C １～３ - selected from the group consisting of alkoxy; R ４０ｅ and R ４０ｆ are independently hydrogen, fluoro, hydroxy, oxo, C １～３ -Alkyl, halo-C １～３ -Alkyl, cyclopropyl, and C １～３ - selected from the group consisting of alkoxy; R ４０ｇ and R ４０ｈ are independently hydrogen, fluoro, C １～３ -Alkyl, halo-C １～３ Alkyl, and C １～３ -alkoxy; and R ４０ｉ and R ４０ｊ are independently hydrogen, C １～３ -Alkyl and halo-C １～３ -alkyl), or a pharma- ceutically acceptable salt thereof.

287. The R １ , R ３ , R ４ , R ５ , and R ６ One of the substituents is selected from the group consisting of chloro, fluoro, and methyl, and the remaining R １ , R ３ , R ４ , R ５ , and R ６ 287. The compound of claim 286, or a pharma- ceutically acceptable salt thereof, wherein the substituents are all hydrogen.

288. R １ , R ３ , R ４ , R ５ , and R ６ or a pharma- ceutically acceptable salt thereof.

287. The compound of claim 286, or a pharma- ceutically acceptable salt thereof, wherein:

289. R ４０ａ and R ４０ｂ are independently hydrogen, C １～２ -alkyl and halo-C １～２ - alkyl; R ４０ｃ and R ４０ｄ are independently hydrogen, fluoro, C １～２ -Alkyl, halo-C １～２ -Alkyl, and C １～２ - selected from the group consisting of alkoxy; R ４０ｅ and R ４０ｆ are independently hydrogen, fluoro, hydroxy, C １～２ -Alkyl, halo-C １～２ -Alkyl, and C １～２ - selected from the group consisting of alkoxy; R ４０ｇ and R ４０ｈ are independently hydrogen, fluoro, C １～２ -Alkyl, halo-C １～２ -Alkyl, and C １～２ -alkoxy; and R ４０ｉ and R ４０ｊ are independently hydrogen, C １～２ -alkyl and halo-C １～２ -alkyl; or a pharma- ceutically acceptable salt thereof.

290. The compound has the structure of formula (VIII): 【Chemistry 58】 (In the formula, R １ , R ３ , R ４ , R ５ , and R ６ is independently selected from the group consisting of hydrogen, chloro, fluoro, and methyl; R ５０ａ and R ５０ｂ are independently hydrogen, fluoro, C １～３ -Alkyl, halo-C １～３ -Alkyl, and C １～３ - selected from the group consisting of alkoxy; R ５０ｃ and R ５０ｄ are independently hydrogen, C １～３ -Alkyl and halo-C １～３ - alkyl or both are oxo; R ５０ｅ is hydrogen, C １～３ -Alkyl, halo-C １～３ -Alkyl, C １～３ -Alkoxy-C ２～３ -Alkyl, C １～３ -alkyl-carbonyl, and C ３～６ -cycloalkyl-carbonyl; R ５０ｆ and R ５０ｇ are independently hydrogen, C １～３ -Alkyl and halo-C １～３ - alkyl or both are oxo; R ５０ｈ and R ５０ｉ are independently hydrogen, fluoro, C １～３ -Alkyl, halo-C １～３ -Alkyl, and C １～３ -alkoxy; and R ５０ｊ is selected from the group consisting of hydrogen and fluoro, or a pharma- ceutically acceptable salt thereof.

291. The R １ , R ３ , R ４ , R ５ , and R ６ One of the substituents is selected from the group consisting of chloro, fluoro, and methyl, and the remaining R １ , R ３ , R ４ , R ５ , and R ６ 291. The compound of claim 290, or a pharma- ceutically acceptable salt thereof, wherein the substituents are all hydrogen.

292. R １ , R ３ , R ４ , R ５ , and R ６ or a pharma- ceutically acceptable salt thereof.

291. The compound of claim 290, wherein:

293. R １ , R ３ , R ４ , R ５ , and R ６ is independently selected from the group consisting of hydrogen, fluoro, and methyl; R ５０ａ and R ５０ｂ are independently hydrogen, fluoro, C １～２ -Alkyl, halo-C １～２ -Alkyl, and C １～２ - selected from the group consisting of alkoxy; R ５０ｃ and R ５０ｄ are independently hydrogen, C １～２ -Alkyl and halo-C １～２ - alkyl; R ５０ｅ is hydrogen, C １～２ -Alkyl, halo-C １～２ -Alkyl, and C １～２ -Alkoxy-C ２～３ - alkyl; R ５０ｆ and R ５０ｇ are independently hydrogen, C １～２ -Alkyl and halo-C １～２ - alkyl; R ５０ｈ and R ５０ｉ are independently hydrogen, fluoro, C １～２ -Alkyl, halo-C １～２ -Alkyl, and C １～２ -alkoxy; and R ５０ｊ 293. The compound of any one of claims 290 to 292, or a pharma- ceutically acceptable salt thereof, wherein is selected from the group consisting of hydrogen and fluoro.

294. R ５０ａ , R ５０ｂ , R ５０ｈ , R ５０ｉ , and R ５０ｊ or a pharma- ceutically acceptable salt thereof. The compound of any one of claims 290 to 293, wherein at least one of is fluoro.

295. The compound has the structure of formula (IX): 【Chemistry 59】 (In the formula, R １ , R ３ , R ４ , R ５ , and R ６ is independently selected from the group consisting of hydrogen, chloro, fluoro, and methyl; R ６０ａ and R ６０ｂ are independently hydrogen and C １～３ - alkyl; R ６０ｃ and R ６０ｄ are independently hydrogen and C １～３ - alkyl; and R ６０ｅ and R ６０ｆ are independently hydrogen and C １～３ -alkyl), or a pharma- ceutically acceptable salt thereof.

296. The R １ , R ３ , R ４ , R ５ , and R ６ One of the substituents is selected from the group consisting of chloro, fluoro, and methyl, and the remaining R １ , R ３ , R ４ , R ５ , and R ６ 300. The compound of claim 295, or a pharma- ceutically acceptable salt thereof, wherein the substituents are all hydrogen.

297. R １ , R ３ , R ４ , R ５ , and R ６ or a pharma- ceutically acceptable salt thereof.

296. The compound of claim 295, or a pharma- ceutically acceptable salt thereof, wherein:

298. R ４ is methyl, and R １ , R ３ , R ５ , and R ６ or a pharma- ceutically acceptable salt thereof.

296. The compound of claim 295, or a pharma- ceutically acceptable salt thereof, wherein:

299. R １ , R ３ , R ４ , R ５ , and R ６ is independently selected from the group consisting of hydrogen, fluoro, and methyl; R ６０ａ and R ６０ｂ are independently hydrogen and C １～２ - alkyl; R ６０ｃ and R ６０ｄ are independently hydrogen and C １～２ - alkyl; and R ６０ｅ and R ６０ｆ are independently hydrogen and C １～２ -alkyl; or a pharma- ceutically acceptable salt thereof.

300. The compound has the structure of formula (X): 【Chemistry 60】 (In the formula, R １ , R ３ , R ４ , R ５ , and R ６ is independently selected from the group consisting of hydrogen, chloro, fluoro, and methyl; R ７０ａ and R ７０ｂ are independently hydrogen and C １～３ - alkyl; R ７０ｃ and R ７０ｄ are independently hydrogen and C １～３ - alkyl; R ７０ｅ and R ７０ｆ are independently hydrogen and C １～３ - alkyl; and R ７０ｇ and R ７０ｈ are independently hydrogen and C １～３ -alkyl), or a pharma- ceutically acceptable salt thereof.

301. The R １ , R ３ , R ４ , R ５ , and R ６ One of the substituents is selected from the group consisting of chloro, fluoro, and methyl, and the remaining R １ , R ３ , R ４ , R ５ , and R ６ 301. The compound of claim 300, or a pharma- ceutically acceptable salt thereof, wherein all of the substituents are hydrogen.

302. R １ , R ３ , R ４ , R ５ , and R ６ or a pharma- ceutically acceptable salt thereof. The compound of claim 300, wherein:

303. R １ , R ３ , R ４ , R ５ , and R ６ is independently selected from the group consisting of hydrogen, fluoro, and methyl; R ７０ａ and R ７０ｂ are independently hydrogen and C １～２ - alkyl; R ７０ｃ and R ７０ｄ are independently hydrogen and C １～２ - alkyl; R ７０ｅ and R ７０ｆ are independently hydrogen and C １～２ - alkyl; and R ７０ｇ and R ７０ｈ are independently hydrogen and C １～２ -alkyl; or a pharma- ceutically acceptable salt thereof.

304. The compound has the structure of formula (XI): 【Chemistry 61】 (In the formula, R １ , R ３ , R ４ , R ５ , and R ６ is independently selected from the group consisting of hydrogen, chloro, fluoro, and methyl; R ８０ａ is hydrogen, fluoro, C １～３ -Alkyl, halo-C １～３ -Alkyl, and C １～３ - selected from the group consisting of alkoxy; R ８０ｂ is hydrogen, fluoro, C １～３ -Alkyl, halo-C １～３ -Alkyl, and C １～３ - selected from the group consisting of alkoxy; R ８０ｃ is hydrogen, fluoro, C １～３ -Alkyl, halo-C １～３ -Alkyl, and C １～３ -alkoxy; and R ８０ｄ is hydrogen, fluoro, C １～３ -Alkyl, halo-C １～３ -Alkyl, and C １～３ -alkoxy), or a pharma- ceutically acceptable salt thereof.

305. The R １ , R ３ , R ４ , R ５ , and R ６ One of the substituents is selected from the group consisting of chloro, fluoro, and methyl, and the remaining R １ , R ３ , R ４ , R ５ , and R ６ 305. The compound of claim 304, or a pharma- ceutically acceptable salt thereof, wherein the substituents are all hydrogen.

306. R １ , R ３ , R ４ , R ５ , and R ６ or a pharma- ceutically acceptable salt thereof.

305. The compound of claim 304, or a pharma- ceutically acceptable salt thereof, wherein:

307. R １ , R ３ , R ４ , R ５ , and R ６ is independently selected from the group consisting of hydrogen, fluoro, and methyl; R ８０ａ Hydrogen, Fluoro, C １～２ -Alkyl, halo-C １～２ -Alkyl, and C １～２ - selected from the group consisting of alkoxy; R ８０ｂ is hydrogen, fluoro, C １～２ -Alkyl, halo-C １～２ -Alkyl, and C １～２ - selected from the group consisting of alkoxy; R ８０ｃ Hydrogen, Fluoro, C １～２ -Alkyl, halo-C １～２ -Alkyl, and C １～２ -alkoxy; and R ８０ｄ is hydrogen, fluoro, C １～２ -Alkyl, halo-C １～２ -Alkyl, and C １～２ -alkoxy; or a pharma- ceutically acceptable salt thereof.

308. 308. A pharmaceutical composition comprising a compound according to any one of claims 1 to 307, or a pharma- ceutically acceptable salt thereof, and one or more pharma- ceutically acceptable excipients.

309. 307. A method of treating or preventing a FAP mediated condition in a subject suffering from or susceptible to said FAP mediated condition, comprising administering to said subject a therapeutically effective amount of a compound according to any one of claims 1 to 307, or a pharma- ceutically acceptable salt thereof.

310. 310. The method of claim 309, wherein the FAP-mediated condition is selected from the group consisting of liver disease, type 2 diabetes, cardiovascular conditions, obesity, obesity-related conditions, fibrosis, keloid disorders, inflammation, and cancer.

311. The method of claim 310, wherein the FAP-mediated condition is liver disease.

312. The method of claim 311, wherein the liver disease is non-alcoholic steatohepatitis.

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