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

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. The disclosure further relates to pharmaceutical compositions comprising such compounds and salts; uses of such compounds and salts for treating or preventing conditions mediated by the prolyl endopeptidase fibroblast activation protein (FAP); kits comprising such compounds and salts; and methods for making such compounds and salts. [Background technology]

[0002] FAP, a type II transmembrane serine protease, is expressed by fibroblast-like cells involved in tissue repair and healing. In the context of nonalcoholic 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 key aspect of NASH that predicts disease prognosis (Non-Patent Document 2). FAP can also exist as a shed plasma protease. Increased levels of circulating FAP are 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 activity. Known enzymatic activities include 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 collagen cleavage) on the cell surface of activated fibroblasts generates a profibrotic environment. FAP cleavage of α2AP results in more efficient cross-linking of α2AP to fibrin, leading to reduced fibrin clearance. FAP cleavage of FGF21 inactivates the metabolic effects of FGF21 (Non-Patent Document 5). All of these activities are associated with the worsening of NASH disease, and FAP inhibition has the potential to treat NASH and other pathologies by affecting multiple mechanisms.

[0004] Inhibition of FAP activity is currently an underdeveloped therapeutic approach for treating NASH and other diseases associated with such activity. No approved pharmacological agents that broadly inhibit or specifically inhibit FAP activity are currently available. Therefore, there is a need for FAP inhibitors, particularly FAP inhibitors that have pharmacologically appropriate selectivity and bioavailability and are therefore suitable for administration to subjects in need of such treatment. The present disclosure addresses this widespread unmet need by providing such compounds as well as corresponding pharmaceutical compositions and methods for treating or preventing NASH and related conditions. [Prior art documents] [Non-patent literature]

[0005] [Non-Patent Document 1] Hepatology 1999,29,1768 [Non-patent document 2] Gastroenterology 2020,158,1611 [Non-patent document 3] Diabetes Res Clin Pract 2015,108,466 [Non-patent document 4] Blood 2004 103,3783 [Non-patent document 5] Biochem J 2016,473,605 Summary of the Invention [Means for solving the problem]

[0006] In one aspect, the present disclosure provides a compound having the structure of formula (I): [ka] and pharmaceutically acceptable salts thereof, wherein X 1is selected from the group consisting of -S-, -S(O)-, and -S(O)2-; 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 (heterocyclyl rings are: (i) saturated, partially saturated, or fully unsaturated monocyclic or fused bicyclic rings; (ii) have 1, 2, or 3 nitrogen ring atoms, the remaining ring atoms being carbon; and (iii) are not 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) 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) 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 (heterocyclyl ring is: (i) 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) having no radicals selected from 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 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; and (c) spiroheterocyclyl containing a total of 6 to 11 ring atoms (spiroheterocyclyl: (i) contains two saturated rings; (ii) (a) has one or two nitrogen ring atoms, the remaining ring atoms being carbon, or (b) has one or two nitrogen ring atoms and one or two oxygen ring atoms, the remaining ring atoms being carbon, or (c) has one nitrogen ring atom and one sulfur ring atom, the remaining ring atoms being carbon, and (iii) does not contain 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 - selected from the group consisting of alkyl; R 4 is hydrogen, halogen, and C 1~3 - selected from the group consisting of alkyl; R 5 is hydrogen, halogen, and C 1~3 - selected from the group consisting of alkyl; and R 6 is hydrogen, halogen, and C 1~3 -alkyl).

[0007] In another aspect, the present disclosure provides compounds having the 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 pharmaceutically acceptable salts thereof.

[0008] In another aspect, the disclosure provides a pharmaceutical composition comprising a therapeutically effective amount 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, and a pharmaceutically acceptable carrier.

[0009] In another aspect, the disclosure provides a pharmaceutical composition comprising a therapeutically effective amount 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; 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 thereof a therapeutically effective amount 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. In a further aspect, the FAP-mediated condition is selected from the group consisting of liver disease, type 2 diabetes, a cardiovascular condition, obesity, an obesity-related condition, fibrosis, a keloid disorder, inflammation, and cancer. In a further aspect, the FAP-mediated condition is liver disease, particularly nonalcoholic steatohepatitis (NASH).

[0011] In another aspect, the 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 a condition mediated by FAP.

[0012] In another aspect, the disclosure provides 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 the preparation of a medicament for treating or preventing a condition mediated by FAP.

[0013] In another aspect, the 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 disclosure provides methods 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] Many embodiments are detailed throughout this specification and will be apparent to those skilled in the art, and this specification should not be construed as being limited to any particular embodiment described herein.

[0016] I. Definition With respect to the embodiments disclosed herein, 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, except where specified by number.

[0018] Unless the context otherwise requires, the words "comprise" or "comprises" or "comprising" are used with the clear understanding that they are to be interpreted inclusively and not exclusively, and that applicant intends each of those words to be so interpreted in interpreting this patent, including the claims that follow.

[0019] The term "halogen" (alone or in combination with another term(s)) 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(s)) means --OH.

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

[0022] The term "oxo" (alone or in combination with another term(s)) means an oxo group, which may be depicted 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 1 to about 20 carbon atoms, more typically 1 to about 12 carbon atoms, even more typically 1 to about 8 carbon atoms, and even more typically 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 carbocyclyl substituent containing 3 to about 14 carbon ring atoms, more typically 3 to about 12 carbon ring atoms, and even more typically 3 to about 8 carbon ring atoms. Cycloalkyls typically contain a single carbon ring containing 3 to 6 carbon ring atoms. Examples of single-ring cycloalkyls include cyclopropyl, cyclobutyl, cyclopentyl, and cyclohexyl.

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

[0026] The term "alkoxy" (alone or in combination with another term(s)) means an alkyl ether substituent, i.e., alkyl-O-. Examples of alkoxy include methoxy (CH3-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(s)) means an alkyl substituted with an alkoxy, such as "methoxymethyl," which may be shown as: [ka] ; (ii) The term "cycloalkylalkoxy" (alone or in combination with another term(s)) means an alkoxy substituted with cycloalkyl, such as "cyclopropylmethoxy", which may be shown as: [ka] ; (iii) The term “alkoxyalkoxy” (alone or in combination with another term(s)) means an alkoxy substituted with another alkoxy, such as “methoxyethoxy”, which may be shown as: [ka] ; (iv) The term "alkoxyalkoxyalkyl" (alone or in combination with another term(s)) means an alkyl substituted with an alkoxyalkoxy, such as "methoxyethoxymethyl", which may be shown as: [ka] ; (v) The term "alkoxyphenyl" (alone or in combination with another term(s)) means a phenyl substituted with alkoxy, such as "4-methoxyphenyl," which may be shown as: [ka] and (vi) The term "alkoxyphenylalkyl" (alone or in combination with another term(s)) means an alkyl substituted with an alkoxyphenyl, such as "4-methoxyphenylmethyl", which may be shown as: [ka] .

[0027] In some instances, 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. 1~6 "-alkyl" refers to an alkyl substituent containing 1 to 6 carbon atoms. 3~6 -Cycloalkyl refers to a cycloalkyl substituent containing from 3 to 6 carbon ring 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 refers to an alkyl substituent in which at least one hydrogen radical is replaced with a halogen group. When there are two or more hydrogens replaced with halogen, the halogens can 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" refers to an alkoxy substituent in which at least one hydrogen radical is replaced with a halogen group. When there are two or more hydrogens replaced with halogen, the halogens can 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(s)) means -C(O)-, which may also be represented as: [ka] So, for example, (i) The term “alkylcarbonyl” (alone or in combination with another term) means “methylcarbonyl” (i.e., acetyl), which may be represented as: [ka] ,and means alkyl-C(O)—, such as ethylcarbonyl, propylcarbonyl, butylcarbonyl, pentylcarbonyl, and other alkylcarbonyl substituents such as hexylcarbonyl; (ii) The term “alkylcarbonylalkyl” (alone or in combination with another term(s)) means an alkyl substituted with an alkylcarbonyl, such as “methylcarbonylmethyl,” which may be shown as: [ka] ; (iii) The term “cycloalkylcarbonyl” (alone or in combination with another term(s)) means cycloalkyl-C(O)—, such as “cyclopropylcarbonyl,” which may be shown as: [ka] and (iv) The term "cycloalkylcarbonylalkyl" (alone or in combination with another term(s)) means an alkyl substituted with a cycloalkylcarbonyl, such as "cyclopropylcarbonylmethyl," which may be shown as: [ka] .

[0030] The terms "thio" or "thia" (alone or in combination with another term(s)) mean a divalent sulfur atom which may also be designated as --S--.

[0031] The terms "sulfinyl" or "sulfoxide" (alone or in combination with another term(s)) mean --S(O)--, which may also be shown as follows: [ka]

[0032] The term "sulfonyl" (alone or in combination with another term(s)) means -S(O)2-, which may also be shown as: [ka] Thus, for example, "alkylsulfonyl" (alone or in combination with another term) means alkyl-S(O)-. Examples of alkylsulfonyl substituents include methylsulfonyl, ethylsulfonyl, and propylsulfonyl. Similarly, the term "alkylsulfonylalkyl" (alone or in combination with another term) means an alkyl substituted with an alkylsulfonyl, such as "methylsulfonylmethyl," which may be depicted as: [ka] .

[0033] The term "alkylcarbonylaminoalkyl" (alone or in combination with another term(s)) means alkyl-C(O)-N(H)-alkyl, such as "methylcarbonylaminomethyl", which may also be shown as: [ka] .

[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, wherein 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] Heterocyclyl includes, for example, monocyclic saturated, partially unsaturated, and fully unsaturated ring structures having 3 to 7 members, for example, 3 to 6 members, 5 to 7 members, for example, 5 or 6 members, in which at least one member and up to four 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, isothiazolyl, and isothiazolyl. Examples include pyranyl, thiazolidinyl, isothiazolidinyl, thiodiazolyl, 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] Heterocyclyl also includes bicyclic ring structures fused together (i.e., fused bicyclic) or two rings with only one common atom (i.e., spiro), wherein at least one such ring contains a heteroatom (i.e., nitrogen, oxygen, or sulfur) as a ring atom. Examples of heterocyclyls having two ring structures fused together include indolizinyl, pyrindinyl, pyranopyrrolyl, 4H-quinolidinyl, purinyl, naphthyridinyl, pyridopyridinyl, pteridinyl, indolyl, isoindolyl, indoleninyl, isoindazolyl, benzazinyl, phthalazinyl, quinoxalinyl, quinazolinyl, benzodiazinyl, benzopyranyl, benzothiopyranyl, benzoxazolyl, indoxazinyl, anthranilyl, benzodioxolyl, benzodioxanyl, benzoxadiazolyl, benzofuranyl, isobenzofuranyl, benzothienyl, isobenzothienyl, benzothiazolyl, benzothiadiazolyl, benzimidazolyl, benzotriazolyl, benzoxazinyl, benzisoxazinyl, 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 a 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 a hydrogen group on the alkyl substituent. For illustration, monofluoroalkyl is an alkyl substituted with one fluoro group, and difluoroalkyl is an alkyl substituted with two fluoro groups. When two or more substituents are present on a substituent, it should be recognized that 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 be (1) unsubstituted or (2) 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 of the hydrogens on the carbon (if present) may be replaced, separately and / or together, with an independently selected optional substituent. When a nitrogen of a substituent is described as being optionally substituted with one or more of a list of substituents, one or more of the hydrogens on the nitrogen (if present) may each be replaced with an independently selected optional substituent.

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

[0041] The term "pharmaceutically acceptable" is used adjectively herein to mean that the modified noun is appropriate for use as a pharmaceutical product or as part of a pharmaceutical product. For example, a "pharmaceutically acceptable salt" is a salt that is 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 that are suitable for use in mammals, particularly humans.

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

[0043] The term "prevent" is readily understood by an ordinarily skilled physician and may include those intended to have its standard meaning with respect to the treatment of a particular condition, including primary prevention, to prevent the onset of a disease, and secondary prevention, where the condition has already developed and the patient is temporarily or permanently protected against progression or worsening of the disease or the onset of new symptoms associated with the condition.

[0044] The term "treating" is readily understood by an ordinarily skilled physician and, with respect to the treatment of a particular condition, can include (1) reducing the extent or cause of the condition being treated, and / or (2) alleviating or ameliorating one or more symptoms associated with the condition. Treating liver disease can include, for example, in whole or in part, stabilizing (i.e., not getting worse), delaying, or slowing the spread or progression of liver disease; prolonging survival compared to expected survival in the absence of treatment; and / or otherwise ameliorating or reducing the severity of the cancer or liver disease.

[0045] II. Compounds In one embodiment, the present disclosure provides a compound having the structure of formula (I): [ka] and pharmaceutically acceptable salts thereof, wherein X 1 is selected from the group consisting of -S-, -S(O)-, and -S(O)2-; 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 (heterocyclyl rings are: (i) saturated, partially saturated, or fully unsaturated monocyclic or fused bicyclic rings; (ii) have 1, 2, or 3 nitrogen ring atoms, the remaining ring atoms being carbon; and (iii) are not 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) 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, C1~3 -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) 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 (heterocyclyl ring is: (i) 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) having no radicals selected from 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 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; and (c) spiroheterocyclyl containing a total of 6 to 11 ring atoms (spiroheterocyclyl: (i) contains two saturated rings; (ii) (a) has one or two nitrogen ring atoms, the remaining ring atoms being carbon, or (b) has one or two nitrogen ring atoms and one or two oxygen ring atoms, the remaining ring atoms being carbon, or (c) has one nitrogen ring atom and one sulfur ring atom, the remaining ring atoms being carbon, and (iii) does not contain 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 - selected from the group consisting of alkyl; R 4 is hydrogen, halogen, and C 1~3 - selected from the group consisting of alkyl; R 5 is hydrogen, halogen, and C 1~3 - selected from the group consisting of alkyl; and R 6 is hydrogen, halogen, and C 1~3 -alkyl).

[0046] In some embodiments, the present disclosure provides a compound having the structure of formula (II): [ka] and pharmaceutically acceptable salts thereof (wherein X 1 , R 1 , R 2 , R 3 , R 4 , R 5 , and R 6 is as defined above for compounds of formula (I). 1 is -S-. In another embodiment, X1 is -S(O)-. In another embodiment, X 1 is -S(O)2-.

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

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

[0049] In some embodiments, R 4 is hydrogen, halogen, and C 1~3 In one aspect, R 4 is hydrogen. 4 is chloro. In another embodiment, R 4 is fluoro. In another embodiment, R 4 is methyl.

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

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

[0052] In some embodiments, 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 The substituents are all hydrogen. 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 The substituents are all hydrogen. 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 The substituents are all hydrogen. 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 The substituents are all hydrogen. 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 The substituents are all hydrogen. 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 The substituents are all hydrogen.

[0053] In some embodiments, R 1 , R 3 , R 4 , R 5 , and R 6 At least two of the substituents are independently halogen and C 1~3 -alkyl, and the remaining R 1 , R 3 , R 4 , R 5 , and R 6 The substituents are all hydrogen. 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 The 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): [ka] and pharmaceutically acceptable salts thereof (wherein R 1 and R 2 is as defined in the various embodiments above).

[0058] In some embodiments, the present disclosure provides a compound having the structure of formula (III-B): [ka] and pharmaceutically acceptable salts thereof (wherein R 2 and R 3 is as defined in the various embodiments above).

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

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

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

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

[0063] In some embodiments, the present disclosure provides a compound having the structure of formula (IV-A): [ka] or a pharmaceutically acceptable salt thereof (wherein, R 2 is as defined above for compounds of formula (I).

[0064] AR 2 is a monocyclic or fused bicyclic heterocyclyl (nitrogen and carbon ring atoms) In some embodiments, the present disclosure provides compounds having the structure of Formula (I), (II), (III-A), (III-B), (III-C), (III-D), (III-E), (IV), or (IV-A), and pharmaceutically acceptable salts thereof, where R 2 is a heterocyclyl containing a total of 4 to 10 ring atoms, the heterocyclyl ring being (i) 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) containing no 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) 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) C 1~6 The alkyl may be further substituted with one or more hydroxy. 2 The heterocyclyl ring is a saturated monocyclic ring. 2 The heterocyclyl ring is a partially saturated monocyclic ring. 2 The heterocyclyl ring is a fully unsaturated monocyclic ring.2 The heterocyclyl ring is a saturated fused bicyclic ring. 2 The heterocyclyl ring is a partially saturated fused bicyclic ring. 2 The heterocyclyl ring is a fully unsaturated fused bicyclic ring. 2 The heterocyclyl ring has one nitrogen ring atom and the remaining ring atoms are carbon. 2 The heterocyclyl ring has two nitrogen ring atoms, and the remaining ring atoms are carbon. 2 The heterocyclyl ring has three nitrogen ring atoms, the remaining ring atoms being carbon.

[0065] In some embodiments, R 2 Heterocyclyl rings are: [ka] selected from the group consisting of: The heterocyclyl ring is substituted with 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-C1~3 -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) 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) C 1~6 The alkyl may be further substituted with one or more hydroxy.

[0066] In some embodiments, R 2 Heterocyclyl rings are: [ka] is selected from the group consisting of The heterocyclyl ring is substituted with 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) 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, C1~3 -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) C 1~6 The alkyl may be further substituted with one or more hydroxy.

[0067] In some embodiments, R 2 Heterocyclyl rings are: [ka] selected from the group consisting of: The heterocyclyl ring is substituted with 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) 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) C 1~6 The alkyl may be further substituted with one or more hydroxy.

[0068] In some embodiments, R 2 The heterocyclyl ring is substituted with 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; 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 further be substituted with one or more halogens.

[0069] In some embodiments, R 2 The heterocyclyl ring is substituted with halogen, hydroxy, oxo, C 1~3 -Alkyl, cyclopropyl, C 1~3 -alkoxy, and C 1~3 -Alkoxy-C 1~3 -alkyl, 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 1~3The alkyl may be further substituted with one or more halogens.

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

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

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

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

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

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

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

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

[0078] In some embodiments, R 2 The heterocyclyl ring may contain one or more C 3~6 -Cycloalkyl-C 1~3 -alkyl, optionally substituted with C 3~6 -Cycloalkyl-C 1~3 The alkyl may be further substituted with one or more halogens.

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

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

[0081] In some embodiments, R 2 The heterocyclyl ring may contain one or more C 1~3 -Alkoxy-C 1~3 -alkyl, optionally substituted with C 1~3 -Alkoxy-C 1~3 The alkyl may be further substituted with one or more halogens.

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

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

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

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

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

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

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

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

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

[0091] In some embodiments, R 2The 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.

[0092] In some embodiments, R 2 The heterocyclyl 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 Heterocyclyl rings are: [ka] and R 2 The heterocyclyl ring is free 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, 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 -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 may be further substituted with one or more halogens. 2 The heterocyclyl ring may be fluoro, hydroxy, C 1~3 -Alkyl, cyclopropyl, C 1~3 -alkoxy, and C 1~3 -Alkoxy-C 1~3 -alkyl, 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 be further substituted with one or more fluoro. 2 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. 2The 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.

[0094] In some embodiments, the compounds and pharmaceutically acceptable salts 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-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); (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 pharmaceutically acceptable salts thereof.

[0095] In some embodiments, the compounds and pharmaceutically acceptable salts 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 pharmaceutically acceptable salts thereof.

[0096] In some embodiments, R 2 Heterocyclyl rings are: [ka] and R 2 The heterocyclyl ring is substituted with 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, optionally substituted with one or more substituents independently selected from the group consisting of 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 may be further substituted with one or more halogens. 2The heterocyclyl ring may be 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, optionally substituted with one or more substituents independently selected from the group consisting of C 1~3 -Alkyl, Hydroxy-C 1~3 -Alkyl, cyclopropyl, C 1~3 -alkoxy, and C 1~3 -Alkoxy-C 1~3 -alkyl may be further substituted with one or more fluoro. 2 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. 2 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.

[0097] In some embodiments, the compounds and pharmaceutically acceptable salts 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 pharmaceutically acceptable salts thereof.

[0098] In some embodiments, R 2 Heterocyclyl rings are: [ka] and R 2 The heterocyclyl ring is free of halogen, hydroxy, C 1~6 -Alkyl, C 3~6 -cycloalkyl, C 1~6 -alkoxy, and C 1~3 -Alkoxy-C 1~3 -alkyl, 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, and C 1~3 -Alkoxy-C1~3 -alkyl may be further substituted with one or more halogens. 2 The heterocyclyl ring may be fluoro, hydroxy, C 1~3 -Alkyl, cyclopropyl, C 1~3 -alkoxy, and C 1~3 -Alkoxy-C 1~3 -alkyl, 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 be further substituted with one or more fluoro. 2 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. 2 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.

[0099] In some embodiments, the compounds and pharmaceutically acceptable salts 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-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); and pharmaceutically acceptable salts thereof.

[0100] In some embodiments, R 2 Heterocyclyl rings are: [ka] and R 2 The heterocyclyl ring is free 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; C 1~6 -Alkyl, Hydroxy-C 1~3 -Alkyl, C 3~6 -cycloalkyl, C 3~6 -Cycloalkyl-C 1~3 -Alkyl, C1~6 -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 -alkyl, phenyl, tetrahydrofuranyl, tetrahydropyranyl, and tetrahydrooxepanyl may be further substituted with one or more halogens. 2 The heterocyclyl ring is free 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; C 1~3 -Alkyl, C 3~6 -cycloalkyl, cyclopropyl-C 1~3 -Alkyl, C 1~3 -alkoxy, C 1~3 -Alkoxy-C 1~3 -alkyl, and tetrahydropyranyl may be further substituted with one or more halogens. 2 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. 2The 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.

[0101] In some embodiments, the compounds and pharmaceutically acceptable salts 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 pharmaceutically acceptable salts thereof.

[0102] In some embodiments, R 2 Heterocyclyl rings are: [ka] and R 2 The heterocyclyl ring is free 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; 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 -alkyl, phenyl, tetrahydrofuranyl, tetrahydropyranyl, and tetrahydrooxepanyl may be further substituted with one or more halogens. 2 The heterocyclyl ring is free 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; C 1~3 -Alkyl, C3~6 -cycloalkyl, cyclopropyl-C 1~3 -Alkyl, C 1~3 -alkoxy, C 1~3 -Alkoxy-C 1~3 -alkyl, and tetrahydropyranyl may be further substituted with one or more halogens. 2 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. 2 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.

[0103] In some embodiments, the compounds and pharmaceutically acceptable salts 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 pharmaceutically acceptable salts thereof.

[0104] In some embodiments, R 2 Heterocyclyl rings are: [ka] and R 2 The heterocyclyl ring is substituted with 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, optionally substituted with one or more substituents independently selected from the group consisting of 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 may be further substituted with one or more halogens. 2The heterocyclyl ring may be 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, optionally substituted with one or more substituents independently selected from the group consisting of C 1~3 -Alkyl, cyclopropyl, cyclopropyl-C 1~3 -Alkyl, C 1~3 -alkoxy, and C 1~3 -Alkoxy-C 1~3 -alkyl may be further substituted with one or more fluoro. 2 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. 2 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.

[0105] In some embodiments, the compounds and pharmaceutically acceptable salts 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-methyl-piperidin-1-yl)quinoline-4-carboxamide (Example 37); (R)—N-(2-(4-cyanothiazolidin-3-yl)-2-oxoethyl)-6-(4,4-difluoro-3,3-dimethyl-piperidin-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 pharmaceutically acceptable salts thereof.

[0106] In some embodiments, R 2 Heterocyclyl rings are: [ka] is.

[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 Heterocyclyl rings are: [ka] and R 2 The heterocyclyl ring is substituted with 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 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 may be further substituted with one or more halogens. 2 Heterocyclyl rings include 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, optionally substituted with one or more substituents independently selected from the group consisting of C 1~3 -Alkyl, cyclopropyl, cyclopropyl-C 1~3 -Alkyl, C 1~3 -alkoxy, and C 1~3 -Alkoxy-C 1~3 -alkyl may be further substituted with one or more fluoro. 2The 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. 2 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.

[0109] In some embodiments, the compound or pharmaceutically acceptable salt 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 Heterocyclyl rings are: [ka] and R 2 The heterocyclyl ring is free 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, 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 -Alkoxy-C 2~3 -alkoxy, and C 1~3 -Alkoxy-C 2~3 -Alkoxy-C 1~3 -alkyl may be further substituted with one or more halogens. 2 The heterocyclyl ring may be fluoro, hydroxy, C 1~3 -Alkyl, cyclopropyl, C 1~3 -alkoxy, and C 1~3 -Alkoxy-C 1~3 -alkyl, 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 be further substituted with one or more fluoro. 2 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. 2The 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.

[0111] In some embodiments, the compounds and pharmaceutically acceptable salts 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 pharmaceutically acceptable salts thereof.

[0112] In some embodiments, R 2 Heterocyclyl rings are: [ka] and R 2 The heterocyclyl ring is free of halogen, hydroxy, C 1~6 -Alkyl, Hydroxy-C 1~3 -Alkyl, C 3~6 -cycloalkyl, C 1~6 -alkoxy, C1~3 -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 optionally substituted with one or more substituents independently selected from the group consisting of alkyl, 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 -alkyloxy, and C 1~3 -Alkoxy-C 2~3 -Alkyloxy-C 1~3 The alkyl may be further substituted with one or more halogens. In one aspect, R 2 The heterocyclyl ring may be 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, 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 be further substituted with one or more fluoro. 2 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. 2The 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.

[0113] In some embodiments, the compounds and pharmaceutically acceptable salts 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 pharmaceutically acceptable salts thereof.

[0114] In some embodiments, R 2 Heterocyclyl rings are: [ka] and R 2 The heterocyclyl ring is free 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, 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 -Alkoxy-C 2~3 -alkoxy, and C 1~3 -Alkoxy-C 2~3 -Alkoxy-C 1~3 -alkyl may be further substituted with one or more halogens. 2 The heterocyclyl ring may be 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, 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 be further substituted with one or more fluoro. 2 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. 2The 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.

[0115] In some embodiments, the compound or pharmaceutically acceptable salt 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 Heterocyclyl rings are: [ka] and R 2 The heterocyclyl ring is free 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, 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 -Alkoxy-C 2~3 -alkoxy, and C 1~3-Alkoxy-C 2~3 -Alkoxy-C 1~3 -alkyl may be further substituted with one or more halogens. 2 The heterocyclyl ring may be 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, 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 be further substituted with one or more fluoro. 2 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. 2 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.

[0117] In some embodiments, the compound or pharmaceutically acceptable salt 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 compounds and pharmaceutically acceptable salts 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-methyl-piperidin-1-yl)quinoline-4-carboxamide (Example 37); (R)—N-(2-(4-cyanothiazolidin-3-yl)-2-oxoethyl)-6-(4,4-difluoro-3,3-dimethyl-piperidin-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 pharmaceutically acceptable salts thereof.

[0119] In some embodiments, the compounds and pharmaceutically acceptable salts 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-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); 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 pharmaceutically acceptable salts thereof.

[0120] BR 2 is a monocyclic or fused bicyclic heterocyclyl (nitrogen, oxygen (or sulfur), and carbon ring atoms) In some embodiments, the present disclosure provides compounds having the structure of Formula (I), (II), (III-A), (III-B), (III-C), (III-D), (III-E), (IV), or (IV-A), and pharmaceutically acceptable salts thereof, where R 2 is a heterocyclyl containing a total of 5 to 10 ring atoms, the heterocyclyl ring being (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) a heterocyclic ring containing no 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 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. 2 The heterocyclyl ring is a saturated monocyclic ring. 2 The heterocyclyl ring is a partially saturated monocyclic ring. 2 The heterocyclyl ring is a fully unsaturated monocyclic ring. 2 The heterocyclyl ring is a saturated fused bicyclic ring. 2 The heterocyclyl ring is a partially saturated fused bicyclic ring. 2 The heterocyclyl ring is a fully unsaturated fused bicyclic ring. 2 The heterocyclyl ring has one nitrogen ring atom and one oxygen ring atom, with the remaining ring atoms being carbon. 2 The heterocyclyl ring has one nitrogen ring atom and one sulfur ring atom, the remaining ring atoms being carbon.

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

[0122] In some embodiments, R 2 Heterocyclyl rings are: [ka] selected from the group consisting of: The heterocyclyl ring is substituted with 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, optionally substituted with one or more substituents independently selected from the group consisting of C 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 The alkyl may be further substituted with one or more halogens.

[0123] In some embodiments, R 2 Heterocyclyl rings are: [ka] selected from the group consisting of: The heterocyclyl ring is substituted with 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, optionally substituted with one or more substituents independently selected from the group consisting of C 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 The alkyl may be further substituted with one or more halogens.

[0124] In some embodiments, R 2 Heterocyclyl rings are: [ka] selected from the group consisting of: The heterocyclyl ring is substituted with 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, 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 C 1~3 -Alkylsulfonyl-C 1~3 The alkyl may be further substituted with one or more halogens.

[0125] In some embodiments, R 2 The heterocyclyl ring is substituted with 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, optionally substituted with one or more substituents independently selected from the group consisting of 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 The alkyl may be further substituted with one or more halogens.

[0126] In some embodiments, R 2 The heterocyclyl ring is substituted with 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, optionally substituted with one or more substituents independently selected from the group consisting of 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 The alkyl may be further substituted with one or more halogens.

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

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

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

[0130] In some embodiments, R 2 The heterocyclyl ring may contain one or more C 1~3 -Alkoxy-C 1~3 -alkyl, optionally substituted with C 1~3 -Alkoxy-C 1~3 The alkyl may be further substituted with one or more halogens.

[0131] In some embodiments, R 2 The heterocyclyl ring may contain one or more C 1~3 -Alkylsulfonyl-C 1~3 -alkyl, optionally substituted with C 1~3 -Alkylsulfonyl-C 1~3 The alkyl may be further substituted with one or more halogens.

[0132] In some embodiments, R 2 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.

[0133] In some embodiments, R 2 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.

[0134] In some embodiments, R 2 Heterocyclyl rings are: [ka] and R 2 The heterocyclyl ring is substituted with 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, 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 C 1~3 -Alkylsulfonyl-C 1~3 -alkyl may be further substituted with one or more halogens. 2 The heterocyclyl ring is substituted with 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 C1~3 -Alkylsulfonyl-C 1~3 -alkyl, optionally substituted with one or more substituents independently selected from the group consisting of 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 may be further substituted with one or more halogens. 2 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. 2 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.

[0135] In some embodiments, the compounds and pharmaceutically acceptable salts are (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-(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-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)-7-chloro-N-(2-(4-cyanothiazolidin-3-yl)-2-oxoethyl)-6-morpholinoquinoline-4-carboxamide (Example 179); (R)-8-chloro-N-(2-(4-cyanothiazolidin-3-yl)-2-oxoethyl)-6-morpholinoquinoline-4-carboxamide (Example 180); and pharmaceutically acceptable salts thereof.

[0136] In some embodiments, the compounds and pharmaceutically acceptable salts 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 pharmaceutically acceptable salts thereof.

[0137] In some embodiments, R 2 Heterocyclyl rings are: [ka] and The heterocyclyl ring is substituted with 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, 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 C 1~3 -Alkylsulfonyl-C 1~3 -alkyl may be further substituted with one or more halogens. 2 The heterocyclyl ring is substituted with 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, 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, C1~3 -Alkylcarbonyl-C 1~3 -alkyl, and C 1~3 -Alkylsulfonyl-C 1~3 -alkyl may be further substituted with one or more halogens. 2 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. 2 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.

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

[0139] In some embodiments, R 2 Heterocyclyl rings are: [ka] and The heterocyclyl ring is substituted with 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-C1~3 -alkyl, 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 C 1~3 -Alkylsulfonyl-C 1~3 -alkyl may be further substituted with one or more halogens. 2 The heterocyclyl ring is substituted with 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, 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 be further substituted with one or more halogens. 2The 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. 2 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.

[0140] In some embodiments, the compound or pharmaceutically acceptable salt 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 Heterocyclyl rings are: [ka] and The heterocyclyl ring is substituted with 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, 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, C1~3 -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. 2 The heterocyclyl ring is substituted with 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, 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 be further substituted with one or more halogens. 2 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. 2The 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. 2 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.

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

[0143] In some embodiments, R 2 Heterocyclyl rings are: [ka] and The heterocyclyl ring is substituted with 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, 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 C 1~3-Alkylsulfonyl-C 1~3 -alkyl may be further substituted with one or more halogens. 2 The heterocyclyl ring is substituted with 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, 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 be further substituted with one or more halogens. 2 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. 2 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.

[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 Heterocyclyl rings are: [ka] and The heterocyclyl ring is substituted with 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, 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 C 1~3 -Alkylsulfonyl-C 1~3 -alkyl may be further substituted with one or more halogens. 2 The heterocyclyl ring is substituted with 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-C1~3 -alkyl, 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 be further substituted with one or more halogens. 2 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. 2 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.

[0146] In some embodiments, the compounds and pharmaceutically acceptable salts 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 pharmaceutically acceptable salts thereof.

[0147] In some embodiments, R 2 Heterocyclyl rings are: [ka] and The heterocyclyl ring is substituted with 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, 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 C 1~3 -Alkylsulfonyl-C 1~3 -alkyl may be further substituted with one or more halogens. 2 The heterocyclyl ring is substituted with 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, 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 be further substituted with one or more halogens. 2 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. 2 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.

[0148] In some embodiments, the compound or pharmaceutically acceptable salt 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 Heterocyclyl rings are: [ka] and The heterocyclyl ring is substituted with 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-C1~3 -alkyl, 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 C 1~3 -Alkylsulfonyl-C 1~3 -alkyl may be further substituted with one or more halogens. 2 The heterocyclyl ring is substituted with 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, 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 be further substituted with one or more halogens. 2The 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. 2 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.

[0150] In some embodiments, the compound or pharmaceutically acceptable salt 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 Heterocyclyl rings are: [ka] and The heterocyclyl ring is substituted with 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, 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 C 1~3 -Alkylsulfonyl-C 1~3 -alkyl may be further substituted with one or more halogens. 2 The heterocyclyl ring is substituted with 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, 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 be further substituted with one or more halogens. 2 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. 2The 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.

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

[0153] In some embodiments, R 2 Heterocyclyl rings are: [ka] and The heterocyclyl ring is substituted with 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, 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 C 1~3 -Alkylsulfonyl-C 1~3 -alkyl may be further substituted with one or more halogens. 2 The heterocyclyl ring is substituted with halogen, cyano, C 1~3 -Alkyl, C 3~6 -cycloalkyl, C 1~3 -alkoxy, C1~3 -Alkoxy-C 1~3 -Alkyl, C 1~3 -Alkylcarbonyl-C 1~3 -alkyl, and C 1~3 -Alkylsulfonyl-C 1~3 -alkyl, 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 be further substituted with one or more halogens. 2 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. 2 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.

[0154] In some embodiments, the compounds and pharmaceutically acceptable salts 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 pharmaceutically acceptable salts thereof.

[0155] In some embodiments, R 2 Heterocyclyl rings are: [ka] and The heterocyclyl ring is substituted with 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, 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 be further substituted with one or more halogens. 2 The heterocyclyl ring is substituted with 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, 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 be further substituted with one or more halogens. 2 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. 2 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.

[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 compounds and pharmaceutically acceptable salts are (R)—N-(2-(4-cyanothiazolidin-3-yl)-2-oxoethyl)-6-(1,2-oxazinan-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-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); 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-oxazinan-3-yl)quinoline-4-carboxamide (Example 112); (R)-7-chloro-N-(2-(4-cyanothiazolidin-3-yl)-2-oxoethyl)-6-morpholinoquinoline-4-carboxamide (Example 179); (R)-8-chloro-N-(2-(4-cyanothiazolidin-3-yl)-2-oxoethyl)-6-morpholinoquinoline-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 pharmaceutically acceptable salts thereof.

[0158] In some embodiments, the compounds and pharmaceutically acceptable salts are (R)—N-(2-(4-cyanothiazolidin-3-yl)-2-oxoethyl)-6-(1,2-oxazinan-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-(2,2-difluoromorpholino)quinoline-4-carboxamide (Example 4); (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); 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-oxazinan-3-yl)quinoline-4-carboxamide (Example 112); and pharmaceutically acceptable salts thereof.

[0159] CR 2 is a spiroheterocyclyl 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), 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, with the remaining ring atoms being carbon, or (b) has one or two nitrogen ring atoms and one or two oxygen ring atoms, with the remaining ring atoms being carbon, or (c) has one nitrogen ring atom and one sulfur ring atom, with the remaining ring atoms being carbon; and (iii) does not contain 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, optionally substituted with one or more substituents independently selected from the group consisting of: 2 A spiroheterocyclyl has (a) one or two nitrogen ring atoms, the remaining ring atoms being carbon, or (b) one or two nitrogen ring atoms and one or two oxygen ring atoms, the remaining ring atoms being carbon. 2 A spiroheterocyclyl has one or two nitrogen ring atoms and optionally one or two oxygen ring atoms, with the remaining ring atoms being carbon. 2 A spiroheterocyclyl has one nitrogen ring atom and the remaining ring atoms are carbon. 2 A spiroheterocyclyl has two nitrogen ring atoms and the remaining ring atoms are carbon. 2 A spiroheterocyclyl has one nitrogen ring atom and one oxygen ring atom, with the remaining ring atoms being carbon. 2 A spiroheterocyclyl has one nitrogen ring atom and two oxygen ring atoms, the remaining ring atoms being carbon.

[0160] In some embodiments, R 2 The two saturated rings of a spiroheterocyclyl are: [ka] is selected from the group consisting of One or both of the rings may be halogen, C1~6 -Alkyl, C 1~6 -haloalkyl, C 1~6 -alkoxy, C 1~6 -haloalkoxy, and C 1~6 -alkylcarbonyl;

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

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

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

[0164] In some embodiments, R 2 The spiroheterocyclyl ring is substituted with 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. 2 The spiroheterocyclyl ring is optionally substituted with one or more fluoro.

[0166] In some embodiments, R 2 A spiroheterocyclyl ring may contain one or more C 1~3 - optionally substituted with alkyl.

[0167] In some embodiments, R 2 A spiroheterocyclyl ring may contain one or more C 1~3 - optionally substituted with haloalkyl.

[0168] In some embodiments, R 2 A spiroheterocyclyl ring may contain one or more C 1~3 - optionally substituted with alkoxy.

[0169] In some embodiments, R 2 A spiroheterocyclyl ring may contain one or more C1~3 - optionally substituted with haloalkoxy.

[0170] In some embodiments, R 2 A spiroheterocyclyl ring may contain one or more C 1~3 In one aspect, R 2 The spiroheterocyclyl ring is optionally substituted with one or more methylcarbonyls.

[0171] 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, 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 a spiroheterocyclyl are: [ka] 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 In one aspect, R is optionally substituted with one or more substituents independently selected from the group consisting of: -alkylcarbonyl; 2The spiroheterocyclyl ring is substituted with halogen, C 1~3 -Alkyl, C 1~3 -haloalkyl, C 1~3 -alkoxy, C 1~3 -haloalkoxy, and C 1~3 In another aspect, R is optionally substituted with one or more substituents independently selected from the group consisting of: -alkylcarbonyl; 2 The spiroheterocyclyl ring is substituted with halogen, C 1~3 -Alkyl, C 1~3 -haloalkyl, C 1~3 -alkoxy, C 1~3 -haloalkoxy, and C 1~3 In another aspect, R is optionally substituted with one or more substituents independently selected from the group consisting of: -alkylcarbonyl; 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. 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.

[0174] In some embodiments, the compounds and pharmaceutically acceptable salts 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 pharmaceutically acceptable salts thereof.

[0175] In some embodiments, R 2 The two saturated rings of a spiroheterocyclyl are: [ka] 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 In one aspect, R is optionally substituted with one or more substituents independently selected from the group consisting of: -alkylcarbonyl; 2 The spiroheterocyclyl ring is substituted with halogen, C 1~3 -Alkyl, C 1~3 -haloalkyl, C 1~3 -alkoxy, C 1~3 -haloalkoxy, and C 1~3 In another aspect, R is optionally substituted with one or more substituents independently selected from the group consisting of: -alkylcarbonyl; 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, and methylcarbonyl. 2The 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.

[0176] In some embodiments, the compound or pharmaceutically acceptable salt 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 a spiroheterocyclyl are: [ka] 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 In one aspect, R is optionally substituted with one or more substituents independently selected from the group consisting of: -alkylcarbonyl; 2 The spiroheterocyclyl ring is substituted with halogen, C 1~3 -Alkyl, C 1~3 -haloalkyl, C 1~3 -alkoxy, C 1~3 -haloalkoxy, and C 1~3 In another aspect, R is optionally substituted with one or more substituents independently selected from the group consisting of: -alkylcarbonyl; 2The 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. 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.

[0178] In some embodiments, the compound or pharmaceutically acceptable salt 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 a spiroheterocyclyl are: [ka] 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 In one aspect, R is optionally substituted with one or more substituents independently selected from the group consisting of: -alkylcarbonyl; 2 The spiroheterocyclyl ring is substituted with halogen, C 1~3 -Alkyl, C 1~3 -haloalkyl, C 1~3 -alkoxy, C 1~3 -haloalkoxy, and C 1~3In another aspect, R is optionally substituted with one or more substituents independently selected from the group consisting of: -alkylcarbonyl; 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. 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.

[0180] In some embodiments, the compounds and pharmaceutically acceptable salts 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 pharmaceutically acceptable salts thereof.

[0181] In some embodiments, R 2 The two saturated rings of a spiroheterocyclyl are: [ka] 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 1~6In one aspect, R is optionally substituted with one or more substituents independently selected from the group consisting of: -alkylcarbonyl; 2 The spiroheterocyclyl ring is substituted with halogen, C 1~3 -Alkyl, C 1~3 -haloalkyl, C 1~3 -alkoxy, C 1~3 -haloalkoxy, and C 1~3 In another aspect, R is optionally substituted with one or more substituents independently selected from the group consisting of: -alkylcarbonyl; 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. 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.

[0182] In some embodiments, the compound or pharmaceutically acceptable salt 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 a spiroheterocyclyl are: [ka] 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 In one aspect, R is optionally substituted with one or more substituents independently selected from the group consisting of: -alkylcarbonyl; 2 The spiroheterocyclyl ring is substituted with halogen, C 1~3 -Alkyl, C 1~3 -haloalkyl, C 1~3 -alkoxy, C 1~3 -haloalkoxy, and C 1~3 In another aspect, R is optionally substituted with one or more substituents independently selected from the group consisting of: -alkylcarbonyl; 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. 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.

[0184] In some embodiments, the compounds and pharmaceutically acceptable salts 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 pharmaceutically acceptable salts thereof.

[0185] In some embodiments, R 2 The two saturated rings of a spiroheterocyclyl are: [ka] 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 In one aspect, R is optionally substituted with one or more substituents independently selected from the group consisting of: -alkylcarbonyl; 2 The spiroheterocyclyl ring is substituted with halogen, C 1~3 -Alkyl, C 1~3 -haloalkyl, C 1~3 -alkoxy, C 1~3 -haloalkoxy, and C 1~3 In another aspect, R is optionally substituted with one or more substituents independently selected from the group consisting of: -alkylcarbonyl; 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. 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.

[0186] In some embodiments, the compound or pharmaceutically acceptable salt is (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), or a pharmaceutically acceptable salt thereof.

[0187] In some embodiments, R 2The two saturated rings of a spiroheterocyclyl are: [ka] 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 In one aspect, R is optionally substituted with one or more substituents independently selected from the group consisting of: -alkylcarbonyl; 2 The spiroheterocyclyl ring is substituted with halogen, C 1~3 -Alkyl, C 1~3 -haloalkyl, C 1~3 -alkoxy, C 1~3 -haloalkoxy, and C 1~3 In another aspect, R is optionally substituted with one or more substituents independently selected from the group consisting of: -alkylcarbonyl; 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. 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 a spiroheterocyclyl are: [ka] 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 In one aspect, R is optionally substituted with one or more substituents independently selected from the group consisting of: -alkylcarbonyl; 2 The spiroheterocyclyl ring is substituted with halogen, C 1~3 -Alkyl, C 1~3 -haloalkyl, C 1~3 -alkoxy, C 1~3 -haloalkoxy, and C 1~3 In another aspect, R is optionally substituted with one or more substituents independently selected from the group consisting of: -alkylcarbonyl; 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. 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 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 a spiroheterocyclyl are: [ka] 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 In one aspect, R is optionally substituted with one or more substituents independently selected from the group consisting of: -alkylcarbonyl; 2 The spiroheterocyclyl ring is substituted with halogen, C 1~3 -Alkyl, C 1~3 -haloalkyl, C 1~3 -alkoxy, C 1~3 -haloalkoxy, and C 1~3 In another aspect, R is optionally substituted with one or more substituents independently selected from the group consisting of: -alkylcarbonyl; 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. 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.

[0191] In some embodiments, the compound or pharmaceutically acceptable salt 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 a spiroheterocyclyl are: [ka] 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 In one aspect, R is optionally substituted with one or more substituents independently selected from the group consisting of: -alkylcarbonyl; 2 The spiroheterocyclyl ring is substituted with halogen, C 1~3 -Alkyl, C 1~3 -haloalkyl, C 1~3 -alkoxy, C 1~3 -haloalkoxy, and C 1~3 In another aspect, R is optionally substituted with one or more substituents independently selected from the group consisting of: -alkylcarbonyl; 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. 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.

[0193] In some embodiments, the compound or pharmaceutically acceptable salt is (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), or a pharmaceutically acceptable salt thereof.

[0194] In some embodiments, R 2 The two saturated rings of a spiroheterocyclyl are: [ka] 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 In one aspect, R is optionally substituted with one or more substituents independently selected from the group consisting of: -alkylcarbonyl; 2 The spiroheterocyclyl ring is substituted with halogen, C 1~3 -Alkyl, C 1~3 -haloalkyl, C 1~3 -alkoxy, C 1~3 -haloalkoxy, and C 1~3 In another aspect, R is optionally substituted with one or more substituents independently selected from the group consisting of: -alkylcarbonyl; 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. 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.

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

[0196] In some embodiments, R 2 The two saturated rings of a spiroheterocyclyl are: [ka] 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 In one aspect, R is optionally substituted with one or more substituents independently selected from the group consisting of: -alkylcarbonyl; 2 The spiroheterocyclyl ring is substituted with halogen, C 1~3 -Alkyl, C 1~3 -haloalkyl, C 1~3 -alkoxy, C 1~3 -haloalkoxy, and C 1~3 In another aspect, R is optionally substituted with one or more substituents independently selected from the group consisting of: -alkylcarbonyl; 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. 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.

[0197] In some embodiments, the compound or pharmaceutically acceptable salt 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 a spiroheterocyclyl are: [ka] 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 In one aspect, R is optionally substituted with one or more substituents independently selected from the group consisting of: -alkylcarbonyl; 2 The spiroheterocyclyl ring is substituted with halogen, C 1~3 -Alkyl, C 1~3 -haloalkyl, C 1~3 -alkoxy, C 1~3 -haloalkoxy, and C 1~3 In another aspect, R is optionally substituted with one or more substituents independently selected from the group consisting of: -alkylcarbonyl; 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. 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.

[0199] In some embodiments, the compound or pharmaceutically acceptable salt 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 a spiroheterocyclyl are: [ka] 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 In one aspect, R is optionally substituted with one or more substituents independently selected from the group consisting of: -alkylcarbonyl; 2 The spiroheterocyclyl ring is substituted with halogen, C 1~3 -Alkyl, C 1~3 -haloalkyl, C 1~3 -alkoxy, C 1~3 -haloalkoxy, and C 1~3 In another aspect, R is optionally substituted with one or more substituents independently selected from the group consisting of: -alkylcarbonyl; 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. 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.

[0201] In some embodiments, the compound or pharmaceutically acceptable salt is (R)—N-(2-(4-cyanothiazolidin-3-yl)-2-oxoethyl)-6-(1,4-dioxa-8-azaspiro[4.5]decan-8-yl)quinoline-4-carboxamide (Example 228), or a pharmaceutically acceptable salt thereof. 2 The two saturated rings of a spiroheterocyclyl are: [ka] 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 In one aspect, R is optionally substituted with one or more substituents independently selected from the group consisting of: -alkylcarbonyl; 2 The spiroheterocyclyl ring is substituted with halogen, C 1~3 -Alkyl, C 1~3 -haloalkyl, C 1~3 -alkoxy, C 1~3 -haloalkoxy, and C 1~3 In another aspect, R is optionally substituted with one or more substituents independently selected from the group consisting of: -alkylcarbonyl; 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. 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.

[0202] In some embodiments, the compound or pharmaceutically acceptable salt 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 compounds and pharmaceutically acceptable salts 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]decan-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]decan-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 pharmaceutically acceptable salts thereof.

[0204] In some embodiments, the compounds and pharmaceutically acceptable salts 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-dioxa-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-dioxa-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 pharmaceutically acceptable salts thereof.

[0205] DR 2 is azetidinyl In some embodiments, the present disclosure provides a compound having the structure of formula (V): [ka] and pharmaceutically acceptable salts thereof, wherein R1 , 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 - selected from the group consisting of 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 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, 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).

[0206] In some embodiments of 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 The substituents are all hydrogen. 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 The substituents are all hydrogen. 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 The substituents are all hydrogen. 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 The substituents are all hydrogen.

[0207] In some embodiments of compounds 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 a 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; 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 is independently selected from the group consisting of hydrogen and methyl.

[0209] In some embodiments of 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; C 1~3 -alkyl and C 1~3 The -alkoxy may be further substituted with one or more halogens.

[0210] In some embodiments, the compounds and pharmaceutically acceptable salts 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 pharmaceutically acceptable salts thereof.

[0211] ER 2 is morpholinyl In some embodiments, the present disclosure provides a compound having the structure of formula (VI): [ka] and pharmaceutically acceptable salts thereof, wherein 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 - selected from the group consisting of 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 - selected from the group consisting of alkyl; R 30e and R 30f are independently hydrogen, halogen, C 1~3 -Alkyl, Halo-C 1~3 -Alkyl, C1~3 -Alkoxy-C 1~3 -alkyl, and C 1~3 -Alkylsulfonyl-C 1~3 - selected from the group consisting of 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 -alkyl).

[0212] In some embodiments of 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 The substituents are all hydrogen. 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 The substituents are all hydrogen. 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 The substituents are all hydrogen. 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 The substituents are all hydrogen.

[0213] In some embodiments of compounds 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 a compound having the structure of Formula (VI), 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 - selected from the group consisting of 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 - selected from the group consisting of 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 - selected from the group consisting of alkyl; and R 30g and R 30h are independently hydrogen, C 1~2 -Alkyl, Halo-C 1~2 -alkyl, and C 1~2 -Alkoxy-C1~2 -alkyl.

[0215] In some embodiments, the compounds and pharmaceutically acceptable salts 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 pharmaceutically acceptable salts thereof.

[0216] FR 2 is piperidin-1-yl In some embodiments, the present disclosure provides a compound having the structure of formula (VII): [ka] and pharmaceutically acceptable salts thereof, wherein 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 - 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 - 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).

[0217] In some embodiments of 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 , R 3 , R 4 , R 5 , and R 6 The substituents are all hydrogen. 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 The substituents are all hydrogen. 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 The substituents are all hydrogen. 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 The substituents are all hydrogen.

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

[0219] In some embodiments of a 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 - selected from the group consisting of alkoxy; R 40e and R 40f are independently hydrogen, fluoro, hydroxy, 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.

[0220] In some embodiments of a compound having the structure of Formula (VII), R 40a and R 40b are independently hydrogen, C 1~2 -Alkyl and halo-C 1~2 - selected from the group consisting of 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 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; and R 40i and R 40j are independently hydrogen, C 1~2 -Alkyl and halo-C 1~2 -alkyl.

[0221] In some embodiments, the compounds and pharmaceutically acceptable salts 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 pharmaceutically acceptable salts thereof.

[0222] GR 2 is piperidin-4-yl In some embodiments, the present disclosure provides a compound having the structure of formula (VIII): [ka] and pharmaceutically acceptable salts thereof, wherein R 1 , R3 , 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.

[0223] In some embodiments of 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 The substituents are all hydrogen. 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 The substituents are all hydrogen. 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 The substituents are all hydrogen. 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 The substituents are all hydrogen.

[0224] In some embodiments of compounds 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 a 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 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 - selected from the group consisting of alkyl; R 50e is hydrogen, C 1~2 -Alkyl, Halo-C 1~2 -alkyl, and C 1~2 -Alkoxy-C 2~3 - selected from the group consisting of alkyl; R 50f and R 50g are independently hydrogen, C 1~2 -Alkyl and halo-C 1~2 - selected from the group consisting of 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 is selected from the group consisting of hydrogen and fluoro.

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

[0227] HR 2 is 3-oxomorpholinyl In some embodiments, the present disclosure provides a compound having the structure of formula (IX): [ka] and pharmaceutically acceptable salts thereof, wherein 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 - selected from the group consisting of alkyl; R 60c and R 60d are independently hydrogen and C 1~3 - selected from the group consisting of alkyl; and R 60e and R 60f are independently hydrogen and C 1~3 -alkyl).

[0228] In some embodiments of compounds having the structure of Formula (IX), 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 The substituents are all hydrogen. 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 The substituents are all hydrogen. 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 The substituents are all hydrogen. 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 The substituents are all hydrogen.

[0229] In some embodiments of compounds 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 a 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 a 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 hydrogen and C 1~2 - selected from the group consisting of alkyl; R 60c and R 60d are independently hydrogen and C 1~2- selected from the group consisting of alkyl; and R 60e and R 60f are independently hydrogen and C 1~2 -alkyl.

[0232] IR 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): [ka] and pharmaceutically acceptable salts thereof, wherein 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 - selected from the group consisting of alkyl; R 70c and R 70d are independently hydrogen and C 1~3 - selected from the group consisting of alkyl; R 70e and R 70f are independently hydrogen and C 1~3 - selected from the group consisting of alkyl; and R 70g and R 70h are independently hydrogen and C 1~3 -alkyl).

[0233] In some embodiments of compounds having the structure of Formula (X), 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 , R3 , R 4 , R 5 , and R 6 The substituents are all hydrogen. 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 The substituents are all hydrogen. 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 The substituents are all hydrogen. 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 The substituents are all hydrogen.

[0234] In some embodiments of compounds 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 a compound having the structure of Formula (X): R 1 , R 3 , R 4 , R 5 , and R 6 is selected from the group consisting of hydrogen, fluoro, and methyl; R70a and R 70b are independently hydrogen and C 1~2 - selected from the group consisting of alkyl; R 70c and R 70d are independently hydrogen and C 1~2 - selected from the group consisting of alkyl; R 70e and R 70f are independently hydrogen and C 1~2 - selected from the group consisting of alkyl; and R 70g and R 70h are independently hydrogen and C 1~2 -alkyl.

[0236] JR 2 is pyridin-3-yl In some embodiments, the present disclosure provides a compound having the structure of formula (XI): [ka] and pharmaceutically acceptable salts thereof, wherein 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).

[0237] In some embodiments of compounds 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 The substituents are all hydrogen. 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 The substituents are all hydrogen. 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 The substituents are all hydrogen. 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 The substituents are all hydrogen.

[0238] In some embodiments of compounds 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 a compound having the structure of Formula (XI), R 1 , R 3 , R 4 , R 5 , and R 6 is selected from the group consisting of hydrogen, fluoro, and methyl; R 80a is 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 is 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.

[0240] In some embodiments, the compound or pharmaceutically acceptable salt 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 this disclosure may be combined with any other suitable embodiment described herein to provide additional embodiments. For example, one embodiment may include a compound having R 1 , R 3 , R 4 , R 5 , and / or R 6 Possible groups for are described individually or together, and another embodiment is R 2 When describing possible groups for R, these embodiments can be combined to form 1 , R 3 , R 4 , R 5 , and / or R 6 The possible groups described for R 2 It is understood that additional embodiments can be provided that are described in conjunction with the possible groups described for R. In other words, for any of the compound embodiments described in this disclosure, R 2 The substituents are the following R 2 2. The compound of claim 1, wherein the compound is as defined in any of the embodiments of claim 1.

[0242] Compounds of the present disclosure have pharmaceutically acceptable FAP inhibitory activity as measured as described for the hFAP inhibition assay (tight binders) reported in the Examples below. In one embodiment, the compounds have an IC of less than about 100 nM. 50 In another embodiment, the compound has FAP inhibitory activity at an IC of less than about 50 nM. 50 In another embodiment, the compound has FAP inhibitory activity at an IC of less than about 10 nM. 50 In another embodiment, the compound has FAP inhibitory activity at an IC of less than about 1 nM. 50 It has FAP inhibitory activity at the following concentrations.

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

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

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

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

[0247] In some embodiments, 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 of less than about 300 μL / min / mg. int In another embodiment, the compound has an HLM CL of less than about 100 μL / min / mg. int In another embodiment, the compound has an HLM CL of less than about 50 μL / min / mg. int It has a value.

[0248] In some embodiments, 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 is administered at a flow rate of about 300 μL / min / 10 6 Subcellular rHep CL int In another embodiment, the compound has a flow rate of about 100 μL / min / 10 6 Subcellular rHep CL int In another embodiment, the compound has a flow rate of about 50 μL / min / 10 6 Subcellular rHep CL int It has a value.

[0249] In some embodiments, compounds of the present disclosure have a 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 a Caco-2 AB intrinsic permeability of at least about 0.1 x 10 6 In another embodiment, the compound has an apparent Caco-2 intrinsic permeability of at least about 0.5×10 cm / s. 6 In another embodiment, the compound has an apparent Caco-2 intrinsic permeability of at least about 1 x 10 6 It has an apparent Caco-2 intrinsic permeability of 10 ...

[0250] In some embodiments, compounds of the present disclosure have a pharmaceutically acceptable Caco-2 bidirectional (ABBA)A-B apparent permeability measured as described for the Caco-2 bidirectional (ABBA)A-B apparent permeability assay reported in the Examples below. In one aspect, the compound has a Caco-2 bidirectional (ABBA)A-B apparent permeability of at least about 0.1 x 10 6 In another embodiment, the compound has a Caco-2 bidirectional (ABBA) A-B apparent permeability of at least about 0.25 x 10 cm / s. 6 In another embodiment, the compound has a Caco-2 bidirectional (ABBA) A-B apparent permeability of at least about 0.5 x 10 6Caco-2 has a bidirectional (ABBA) A-B apparent permeability of 1000 cm / s.

[0251] In some embodiments, the compounds of the present disclosure have pharmaceutically acceptable kinetic solubility as measured by the kinetic solubility assay described 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 a salt form or a non-salt form (i.e., as a 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 embodiment, the acid addition salt is, for example, a trifluoroacetate salt, a formate salt, an acetate salt, or hydrochloric acid. Generally, base addition salts can be prepared using various inorganic or organic bases, for example, alkali or alkaline earth metal salts, such as sodium, calcium, or magnesium salts, or other metal salts, such as potassium or zinc, or ammonium salts, or organic bases, such as methylamine, dimethylamine, trimethylamine, piperidine, or morpholine. Those skilled in the art will be aware of the general principles and techniques of 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 diastereoisomeric forms, including, but not limited to, cis- and trans-forms, E- and Z-forms, and R-, S- and meso-forms. Unless otherwise specified, reference to a particular compound includes all such isomeric forms, including racemic and other mixtures. Where appropriate, such isomers can be separated from such 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) using, for example, chiral chromatographic separation. In other embodiments, a single stereoisomer is obtained, for example, by direct synthesis from chiral starting materials.

[0254] Particular 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 compound, or a pharmaceutically acceptable salt thereof, that is a single enantiomer present in an enantiomeric excess (% ee) of ≧90, ≧95, ≧96, ≧97, ≧98, or ≧99%, in association 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 the present disclosure encompasses all such tautomeric forms. A "tautomer" is a structural isomer that exists in equilibrium resulting from 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 the present disclosure encompasses all such solvates.

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

[0258] The compounds and salts of the present disclosure can be isotopically labeled (or "radiolabeled"). In this case, one or more atoms are replaced by atoms having an atomic mass or mass number different from the atomic mass or mass number typically found in nature. The present disclosure encompasses isotopically labeled forms of the compounds disclosed herein. Examples of isotopes that may be incorporated include: 2 H (also written as "D" for deuterium), 3 H (also written as "T" for tritium), 11 C. 13 C. 14 C. 13 N, 15 N, 15 O. 17 O. 18 O and 36 The isotope used will depend on the specific application of the radiolabeled derivative. For example, for in vitro receptor labeling and competition assays, 3 H or 14 C is 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 It is C.

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

[0260] III.How to use The disclosed compounds of the present disclosure, and pharmaceutically acceptable salts thereof, are inhibitors of the activity of the prolyl endopeptidase fibroblast activating protein (FAP). 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), a protein involved in regulating glucose and lipid metabolism (Biochem J 2016, 473, 605). Inhibition of FAP is hypothesized to increase endogenous FGF-21 levels and signaling, resulting in, for example, reduced adiposity, improved insulin sensitivity, improved glucose tolerance, weight loss, and / or reduced cardiovascular disease mortality.

[0262] FAP is also thought to cleave human α2-antiplasmin (α2AP), a protein involved in regulating fibrosis and fibrinolysis (Blood 2004 103, 3783). Tissue repair involves coagulation, which leads to fibrin deposition. Fibrin in blood clots is typically dissolved primarily by plasmin when converted from its inactive form (plasminogen) by plasminogen activators. 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 also thought to promote collagen production and deposition and play a role in increasing fibrosis through altered extracellular matrix (ECM) turnover (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 light of the above, it is hypothesized that inhibition of FAP collectively reduces fibrosis and inflammation by reducing hepatic stellate cell activity and increasing fibrinolysis, further resulting in positive metabolic effects via increased FGF21 signaling and improved glucose tolerance.

[0265] Thus, 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 methods for treating or preventing a condition characterized by overexpression of a 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), liver fibrosis, and cirrhosis. In another aspect, the liver disease is end-stage liver disease. In another aspect, the subject also suffers from or is susceptible to one or more conditions selected from the group consisting of obesity, dyslipidemia, insulin resistance, type 2 diabetes, and renal failure.

[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 liver disease of 27 kg / m 2 ~40kg / m 2 In one embodiment, the subject has a body mass index (BMI) of 30 kg / m 2 ~39.9kg / m 2 In another embodiment, the subject has a BMI of at least 40 kg / m 2 In another embodiment, the subject has a BMI of 0.01 to 0.05. In another embodiment, the subject is overweight. In another embodiment, the subject is obese. In another embodiment, the liver disease is NAFLD. In another embodiment, the liver disease is NASH. In another embodiment, the liver disease is liver fibrosis. In another embodiment, the liver disease is cirrhosis.

[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 suffers from or is prone to suffer from dyslipidemia.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.

[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 suffers from or is prone to suffer from 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 liver 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 suffers from or is prone to suffer from at least one of type 2 diabetes and renal failure.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.

[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 suffers from or is prone to suffer from 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 liver 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, and the subject also suffers from or is prone to suffer from renal failure.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 is suffering from or prone to NAFLD. In another aspect, the subject is suffering from or prone to NASH. In another aspect, the subject is suffering from or prone to liver fibrosis. In another aspect, the subject is suffering from or prone to cirrhosis. In another aspect, the subject is also suffering from or prone to one or more conditions selected from the group consisting of obesity, dyslipidemia, insulin resistance, type 2 diabetes, and renal failure.

[0275] In some embodiments, the present disclosure provides a method for treating or preventing nonalcoholic 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, e.g., "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 also suffers from or is susceptible to one or more conditions selected from the group consisting of obesity, dyslipidemia, insulin resistance, type 2 diabetes, and renal failure.

[0276] In some embodiments, the present disclosure provides a method for treating or preventing non-alcoholic fatty liver disease (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 also suffers from or is susceptible to one or more conditions selected from the group consisting of obesity, dyslipidemia, insulin resistance, type 2 diabetes, and renal failure.

[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 is afflicted with stage 3 liver fibrosis. In another aspect, the subject also is afflicted with or susceptible to one or more conditions selected from the group consisting of obesity, dyslipidemia, insulin resistance, type 2 diabetes, and renal failure.

[0278] In some embodiments, the present disclosure provides a method for treating or preventing liver 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 suffers from stage F4 liver cirrhosis. In another aspect, the subject also suffers from or is susceptible to one or more conditions selected from the group consisting of obesity, dyslipidemia, insulin resistance, type 2 diabetes, and renal failure.

[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 is suffering from renal failure. In another aspect, administration of the compound is an adjunct to diet and exercise. In another aspect, administration of the compound also reduces weight and / or treats obesity. In another aspect, the subject is a subject weighing less than 27 kg / m 2 ~40kg / m 2 In another embodiment, the subject has a BMI of 30 kg / m 2 ~39.9kg / m 2 In another embodiment, the subject has a BMI of at least 40 kg / m 2 In another embodiment, the subject is overweight. In another embodiment, 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 failure. In another aspect, administration of the compound is an adjunct to diet and exercise. In another aspect, administration of the compound also reduces weight and / or treats obesity. In another aspect, the subject is a subject weighing less than 27 kg / m 2 ~40kg / m 2 In another embodiment, the subject has a BMI of 30 kg / m 2 ~39.9kg / m 2 In another embodiment, the subject has a BMI of at least 40 kg / m 2 In another embodiment, the subject is overweight. In another embodiment, the subject is obese.

[0281] In some embodiments, the present disclosure provides a method of improving glycemic control in a subject with 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 weight and / or treats obesity. In another aspect, the subject has a weight of 27 kg / m 2 ~40kg / m 2 In another embodiment, the subject has a BMI of 30 kg / m 2 ~39.9kg / m 2 In another embodiment, the subject has a BMI of at least 40 kg / m 2 In another embodiment, the subject is overweight. In another embodiment, the subject is obese.

[0282] In some embodiments, the present disclosure provides a method of improving glycemic control in a subject with type 2 diabetes and renal failure 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 weight and / or treats obesity. In another aspect, the subject has a weight of 27 kg / m 2 ~40kg / m 2 In another embodiment, the subject has a BMI of 30 kg / m 2 ~39.9kg / m 2 In another embodiment, the subject has a BMI of at least 40 kg / m 2 In another embodiment, the subject is overweight. In another embodiment, the subject is obese.

[0283] In some embodiments, the present disclosure provides a method for 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 failure. Insulin resistance can be measured, for example, using the homeostatic model assessment of insulin resistance (HOMA-IR) and / or the MATSUDA index. HOMA-IR is described, for example, in Diabetologia 1985, 28, 412, the entire contents of which are incorporated herein by reference. The MATSUDA index is described, for example, in Diabetes Care 1999, 22, 1462, the entire contents of which are incorporated herein by reference.

[0284] In some embodiments, the present disclosure provides a method for 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 failure.

[0285] In some embodiments, the present disclosure provides a method of treating a cardiovascular condition 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 condition is selected from the group consisting of heart failure, cardiomyopathy, atherosclerosis, venous thromboembolism, and atrial fibrillation. In one aspect, the cardiovascular condition is heart failure. In another aspect, the cardiovascular condition is heart failure with preserved ejection fraction (HFpEF). In another aspect, the cardiomyopathy is a 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 condition is atherosclerosis. In another aspect, the cardiovascular condition is venous thromboembolism. In another aspect, the cardiovascular condition is atrial fibrillation.

[0286] In some embodiments, the present disclosure provides a method for treating obesity or an obesity-related condition 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 condition is an obesity-related metabolic condition. In another aspect, the obesity-related condition 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 condition is dyslipidemia. In another aspect, the obesity-related condition is a cardiovascular condition selected from the group consisting of heart failure, cardiomyopathy, atherosclerosis, venous thromboembolism, and atrial fibrillation. In another aspect, the obesity-related condition is renal disease.

[0287] In some embodiments, the present disclosure provides a method for reducing weight 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 failure. In another aspect, administration of the compound is an adjunct to diet and exercise. In another aspect, administration of the compound also reduces weight and / or treats obesity. In another aspect, the subject is a subject weighing less than 27 kg / m 2 ~40kg / m 2 In another embodiment, the subject has a BMI of 30 kg / m 2 ~39.9kg / m 2 In another embodiment, the subject has a BMI of at least 40 kg / m 2 In another embodiment, the subject is overweight. In another embodiment, the subject is obese. In another embodiment, the subject's weight is reduced, for example, by at least about 5%, 10%, 15%, 20%, 25%, 30%, 35%, or 40%.

[0288] In some embodiments, the present disclosure provides a method for reducing body 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 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 failure. In another aspect, administration of the compound is a supplement to diet and exercise. In another aspect, administration of the compound also reduces weight and / or treats obesity. In another aspect, the subject is a subject weighing less than 27 kg / m 2 ~40kg / m 2 In another embodiment, the subject has a BMI of 30 kg / m 2 ~39.9kg / m 2 In another embodiment, the subject has a BMI of at least 40 kg / m 2 In another embodiment, the subject is overweight. In another embodiment, the subject is obese. In another embodiment, the fat is liver fat.

[0289] In some embodiments, the present disclosure provides a method for treating or preventing 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 fibrosis is interstitial lung disease. In another aspect, the fibrosis is an 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 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 exacerbated cardiac tissue damage due to a myocardial infarction.

[0291] In some embodiments, the present disclosure provides a method of promoting wound healing and / or reducing adhesions 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, administration of the compound promotes wound healing and / or reduces adhesions via increased fibrinolysis.

[0292] In some embodiments, the present disclosure provides a method for treating or preventing a keloid 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 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 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 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 for 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, nasopharyngeal cancer, laryngeal cancer, myeloma cells, bladder cancer, cholangiocarcinoma, renal clear cell carcinoma, neuroendocrine tumor, tumor-induced osteomalacia, sarcoma, CUP (carcinoma of unknown primary), thymic carcinoma, desmoid tumor, glioma, astrocytoma, cervical cancer, and prostate cancer. In another aspect, the cancer is hepatocellular carcinoma.

[0295] The subject to be treated will usually 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 rhesus monkeys, macaques (also known as cynomolgus monkeys 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 pharmaceutical.

[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 condition mediated by FAP 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 condition mediated by FAP 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 the sole pharmacological agent or in combination with other pharmacological agents or procedures. Such combination therapy can be achieved by the 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 the other pharmacological agent(s) typically within their approved dosage ranges.

[0300] In some embodiments, the present disclosure provides a combination suitable for use in treating a condition selected from those previously discussed, 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 a combination suitable for use in treating a condition selected from those conditions discussed above, 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 a combination suitable for use in treating a condition selected from those previously discussed, 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 treating a condition selected from those previously discussed, 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 treating a condition selected from those previously discussed, 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 an SGLT2 inhibitor, metformin, a GLP1 agonist, a DPP4 inhibitor, and a PPAR agonist; and a pharmaceutically acceptable diluent or carrier. Such a combination can be used for the manufacture of a medicament for use in treating a condition selected from those previously discussed. 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 treating 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 an anti-PD-1 antibody, an anti-PD-L1 antibody, an anti-CTLA4 antibody, a TLR7 agonist, a CD40 agonist, a Lag-3 antagonist, and an OX40 agonist. 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), atezolizumab (Bavencio), durvalumab (Imfinzi), etc.). In another embodiment, the immune checkpoint inhibitor is an anti-CTLA4 antibody (e.g., ipilimumab (Yervoy), tremelimumab, etc.). In another embodiment, the cancer is selected from the group consisting of pancreatic cancer, colon cancer, and rectal cancer.

[0307] V. Pharmaceutical Compositions The compounds of the present disclosure, and their pharmaceutically acceptable salts, can be administered as pharmaceutical compositions containing one or more pharmaceutically acceptable excipients. Thus, in some embodiments, the present disclosure provides pharmaceutical compositions comprising the compounds of the present disclosure, or their pharmaceutically acceptable salts, 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 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, flavorings, colorings, fillers, binders, disintegrants, lubricants, glidants, thickeners, and coating agents. As those skilled in the art will recognize, a particular pharmaceutically acceptable excipient may perform more than one function, or may perform alternative functions, depending on the amount of the excipient present in the composition and which other excipients are present in the composition.

[0309] The compositions may be in a form suitable for oral use (e.g., as tablets, lozenges, hard or soft capsules, aqueous or oily suspensions, emulsions, dispersible powders or granules, syrups or elixirs), topical use (e.g., as creams, ointments, gels, or aqueous or oily solutions or suspensions), administration by inhalation (e.g., as a finely divided powder or liquid aerosol), administration by insufflation (e.g., as a finely divided powder), or parenteral administration (e.g., as a sterile aqueous or oily solution for intravenous, subcutaneous, or intramuscular administration), or as a suppository for rectal administration. The compositions may be obtained by conventional procedures using conventional pharmaceutical excipients well known in the art. Thus, compositions intended for oral use may contain, for example, one or more colorants, sweeteners, flavoring agents, and / or preservatives.

[0310] The total daily dose will necessarily vary depending on the subject being treated, the particular route of administration, any concurrent therapy, and the severity of the disease being treated, and may include single or multiple doses. A particular dosage may be adjusted depending, for example, on the condition being treated; the age, weight, general health, sex, and diet of the subject; the route of administration; the interval between doses; the rate of excretion; and other drugs being co-administered to the subject. A physician of ordinary skill, armed with the disclosure of this application, will be able to determine the appropriate dosage and regimen for administering a therapeutic agent to a subject and adjust such dosage and regimen as needed over the course of treatment, according to methods well known in the therapeutic arts. The compounds of the present disclosure, or pharmaceutically acceptable salts thereof, typically have a dosage of 2.5 to 5000 mg / m 2 (body area of ​​the animal), or approximately 0.05-100 mg / kg, will be administered to warm-blooded animals at a unit dose in the range of 0.05-100 mg / kg, which will usually provide a therapeutically effective dose. Unit dosage forms such as tablets or capsules may contain, for example, 0.1-500 mg, 0.1-250 mg, or 0.1-100 mg of 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 treating a FAP-mediated condition, 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, a cardiovascular condition, obesity, an obesity-related condition, fibrosis, a keloid disorder, inflammation, and cancer.

[0313] VI. Kit The present disclosure further provides kits comprising a unit dosage form comprising a compound of the present disclosure, or a pharmaceutically acceptable salt thereof, contained within 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 includes a unit dosage form containing a compound of the present disclosure, or a pharmaceutically acceptable salt thereof, contained within packaging materials, 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 FAP-mediated condition is 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 comprising a compound of the present disclosure, or a pharmaceutically acceptable salt thereof; (b) a second unit dosage form comprising 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 said 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 processes for the preparation of 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] Schemes 1-14 below illustrate the synthesis of compounds of formula (II), where 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 indicates a synthetic route to a leaving group (e.g., Cl, Br, I, or OTf). Those skilled in the art will appreciate that these methods are representative and do not encompass all possible methods for preparing the compounds of the present disclosure. X The substituents are as defined for the compounds of the present disclosure unless otherwise specified. It is understood that the processes for preparation described in Schemes 1-14 can be carried out starting from any enantiomer, or racemic mixture, of a compound of formula (2), (4), (6), (8), (9), (10), (11), (12), (13), or (14) to obtain a compound of formula (II) or any stereoisomer of formula (II).

[0318] Scheme 1 [ka] Scheme 1 shows a synthetic route to certain compounds of formula (II). Compounds of formula (2) may be reacted with compounds of formula (3) to give compounds of formula (II). The reaction may be carried out using a suitable coupling reagent (e.g., HATU, HOBt / EDC, or T3P) in the presence of a base (typically an organic base such as DIPEA or TEA) using a solvent such as DCM, DME, EtOAc, or MeCN, or a mixture thereof, and at a temperature typically ranging from 0°C to 60°C.

[0319] Scheme 2 [ka] Scheme 2 shows additional synthetic routes to certain compounds of formula (II). Compounds of formula (4) may be reacted with compounds of formula (5) to provide compounds of formula (II). The reaction may be carried out using a suitable coupling reagent (e.g., HATU, HOBt / EDC, or T3P) in the presence of a base (typically an organic base such as DIPEA or TEA) using a solvent such as DCM, DME, EtOAc, or MeCN, or a mixture thereof, and at a temperature typically ranging from 0°C to 60°C.

[0320] Scheme 3 [ka] Scheme 3 shows additional synthetic routes to certain compounds of formula (II). Compounds of formula (6) can be converted to compounds of formula (II) by dehydration using a suitable reagent (typically TFAA or T3P) in a solvent such as DCM, DMF, EtOAc or MeCN, or mixtures thereof, at temperatures typically ranging from 0° C. to 120° C.

[0321] Scheme 4 [ka] Scheme 4 shows a synthetic route to certain compounds of formula (2). Compounds of formula (4) may be reacted with (tert-butoxycarbonyl)-glycine (7) to give compounds of formula (8). The reaction may be carried out using a suitable coupling reagent (e.g., HATU, HOBt / EDC, or T3P) in the presence of a base (typically an organic base such as DIPEA or TEA) using a solvent such as DCM, DME, EtOAc, or MeCN, or a mixture thereof, and at a temperature typically ranging from 0°C to 120°C.

[0322] Compounds of formula (2) can be formed by reacting compounds 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, neat or in a solvent such as DCM, typically at temperatures ranging from 0° C. to 60° C.

[0323] Scheme 5 [ka] Scheme 5 shows a synthetic route to certain compounds of formula (4). Compounds of formula (10) can be formed by reacting compounds of formula (9) with neat NH or NH as a solution, for example, in water or MeOH, or an ammonia synthetic equivalent (e.g., NHCl). The reaction can be carried out using a suitable coupling reagent (e.g., HATU, HOBt / EDC, T3P, or BocO) in the presence of a base (typically an organic base such as DIPEA or TEA) using a solvent such as THF, DME, EtOAc, or MeCN, or a mixture thereof, and at a temperature typically ranging from 0°C to 120°C.

[0324] Compounds of formula (10) can be converted to compounds of formula (11) by dehydration using a suitable reagent (typically TFAA or T3P) in a solvent such as DCM, DMF, EtOAc or MeCN, or mixtures thereof, at temperatures typically ranging from 0°C to 120°C.

[0325] Compounds of formula (4) can be formed by reacting compounds 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 neat TFA or TFA in a solvent such as DCM, typically at temperatures ranging from 0°C to 60°C.

[0326] Scheme 6 [ka] Scheme 6 shows a synthetic route to certain compounds of formula (6). Compounds of formula (12) may be reacted with compounds of formula (3) to give compounds of formula (6). The reaction may be carried out under conditions described for the analogous reaction described in Scheme 1.

[0327] Scheme 7 [ka] Scheme 7 shows a synthetic route to certain compounds of formula (12). Compounds of formula (12) can be formed from compounds of formulas (13) and (7) via compounds of formula (14). The reaction can be carried out under conditions described for the analogous reaction described in Scheme 4.

[0328] Scheme 8 [ka] Scheme 8 shows a synthetic route to certain compounds of formula (5). Compounds of formula (3) may be reacted with compounds of formula (15) to give compounds of formula (16). The reaction may be carried out using a suitable coupling reagent (e.g., HATU, HOBt / EDC, or T3P) in the presence of a base (typically an organic base such as DIPEA or TEA) using a solvent such as DCM, DME, EtOAc, or MeCN, or a mixture thereof, and at a temperature typically ranging from 0°C to 120°C.

[0329] Compounds of formula (5) can be formed by reacting compounds 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 can be carried out at a temperature interval from 0° C. to reflux. Alternatively, R 7For compounds of formula (16) where HCl 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, neat or in a solvent such as DCM, typically at temperatures ranging from 0° C. to 60° C.

[0330] Scheme 9 [ka] Scheme 9 shows a synthetic route to certain compounds of formula (3). Compounds of formula (18) can be formed by reacting compounds of formula (17) with an alcohol (e.g., MeOH or EtOH) in the presence of an acid (e.g., HCl or H2SO4) in a suitable solvent, or using the alcohol as the solvent. Alternatively, the reaction can be facilitated by a reagent such as SOCl2 in a suitable solvent, or using the alcohol (e.g., MeOH or EtOH) as the solvent. Alternatively, compounds of formula (18) can be reacted with an alcohol (e.g., MeOH or EtOH), facilitated by coupling a reagent (e.g., EDC or TBTU) in the presence of a base (such as DIPEA, TEA, or DMAP) using a solvent such as DCM, DMF, EtOAc, or MeCN, or a mixture thereof, at temperatures typically ranging from 0°C to 120°C.

[0331] A compound of formula (19) (wherein R 2 is as defined in formula (I) and the point of attachment to the quinoline is through the nitrogen atom) can be reacted with a compound of formula (18) to form an amine HR 2 (20) (where R 2(I)) The reaction can be catalyzed with a suitable Pd-reagent, such as Pd(dba) with a suitable phosphine ligand (e.g., XPhos, CPhos, SPhos, RuPhos, DavePhos, or XantPhos), in the presence of a base (e.g., CsCO), in a suitable solvent (e.g., 1,4-dioxane), optionally in the presence of water, at a temperature ranging from room temperature to reflux.

[0332] A compound of formula (19) (wherein R 2 is as defined in formula (I) and the point of attachment to the quinoline is through the nitrogen atom) can be reacted with a compound of formula (18) to form an amine HR 2 (20) (where R 2 (I)) The reaction can be catalyzed by a suitable Cu-reagent (e.g., CuI or CuO) in the presence of a base (e.g., KCO or CsCO) in a suitable solvent (e.g., DMF) at a temperature ranging from room temperature to 160°C.

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

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

[0335] Scheme 10 [ka] Scheme 10 shows a synthetic route to certain compounds of formula (3). Compounds of formula (19) (wherein R 2 is as defined in formula (I) and the point of attachment to the quinoline is through the carbon atom) can be converted into a compound of formula (18) with the compound BR 2 (21) where B is a boronic acid, a boronic ester, or a trifluoroborate, and R 2 (I)) The reaction can be catalyzed by a suitable Pd-reagent (e.g., Pd(dppf)Cl) in the presence of a base (such as NaCO or KCO) in a suitable solvent (such as 1,4-dioxane), optionally in the presence of water, at a temperature ranging from room temperature to reflux.

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

[0337] Scheme 11 [ka] Scheme 11 shows a synthetic route to certain compounds of formula 19. Compounds of formula 22, where B is a boronic acid, boronic ester, or trifluoroborate, can be formed by reacting compounds of formula 18 with a bis-boronic acid species (e.g., B2(OH)4 (hypodiboric acid) or B2pin2 (4,4,4',4',5,5,5',5'-octamethyl-2,2'-bi(1,3,2-dioxaborolane)). The reaction can be catalyzed by a suitable Pd-reagent (e.g., Pd(dppf)Cl2) in the presence of a base (e.g., Na2CO3 or K2CO3) in a suitable solvent (e.g., ethanol or 1,4-dioxane), optionally in the presence of water, at a temperature ranging from room temperature to reflux.

[0338] A compound of formula (19) (wherein R 2 is as defined in formula (I) and the point of attachment to the quinoline is through a carbon atom), can be prepared by reacting a compound of formula (22) with an aryl halide or aryl pseudohalide of formula (23) 2 is as defined in formula (I) and X 3 is connected to R via the carbon atom 2 The reaction can be catalyzed by a suitable Pd-reagent (e.g., Pd(dppf)Cl) in the presence of a base (such as NaCO or KCO) in a suitable solvent (such as 1,4-dioxane), optionally in the presence of water, at a temperature ranging from room temperature to reflux.

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

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

[0341] Compounds of formula (19) can be formed by reacting compounds of formula (28) with carbon monoxide (1-10 atm) in a sealed vessel, typically at a temperature in the range of 80-120° C. and a pressure of typically 10 atm. The reaction can be catalyzed by a suitable Pd-reagent (e.g., Pd(dppf)Cl2) in the presence of a base (e.g., TEA) in the presence of a suitable alcohol (such as MeOH or EtOH) in a suitable solvent, or using the alcohol as the solvent.

[0342] Scheme 14 [ka] Scheme 14 shows a synthetic route to certain compounds of formula (31). Compounds of formula (29) (wherein R50 (wherein is as defined in formula (VIII)) can be formed from compounds of formula (27) by metal-halogen exchange using an organometallic reagent (e.g., BuLi) followed by reaction with an electrophile such as a ketone of formula (30). The reaction can be carried out in a solvent such as THF at temperatures typically ranging from −78° C. to room temperature.

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

[0344] Compounds of formula (31) can be converted to compounds of formula (VIII) using synthetic methodologies similar to those described in Schemes 13, 10 and 1.

[0345] It should be understood that (i) the organic reactions described in this disclosure are carried out according to laboratory standards known to those skilled in the art; (ii) some of the reactions described in this disclosure may optionally be carried out in a different order than that proposed herein; (iii) chiral isomers of the compounds in this disclosure may be resolved at any stage of the synthetic process using chiral resolving agents described in the literature and known to those skilled in the art, or chiral chromatography methods described in the literature and known to those skilled in the art, or as further described in the Examples; (iv) additional and / or other protecting groups may optionally be required in some of the above steps; and (v) deprotection steps may therefore 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. Hutz, Wiley-Interscience (1999), which is incorporated herein by reference. [Example]

[0346] VIII. Working Examples The following descriptions of experiments, procedures, examples, and intermediates are intended to illustrate embodiments of the present disclosure and are not intended to be limiting in any way. Other compounds of the present disclosure may be prepared using the methods illustrated 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 N2, unless otherwise stated; (ii) If the reaction involved 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, reaction steps were followed by thin layer chromatography (TLC) and / or analytical high performance liquid chromatography (HPLC or UPLC), usually coupled to a mass spectrometer (LCMC). (iv) Where necessary, organic solutions were dried over anhydrous MgSO or NaSO or by using an ISOLUTE® phase separator and work-up procedures were carried out using conventional phase separation techniques. (v) Evaporation was performed by rotary evaporation in vacuo or in a Genevac HT-4 / EZ-2 or Biotage V10; (vi) Unless otherwise stated, flash column chromatography was performed on normal phase silica using either Merck Silica Gel (Art. 9385) or pre-packed cartridges such as Biotage® SNAP cartridges (40-63 μm silica, 4-330 g), Biotage® Sfar Silica HC D cartridges (20 μm, 10-100 g), Interchim puriFlash™ cartridges (25 μm, 4-120 g), Interchim puriFlash™ cartridges (50 μm, 25-330 g), Grace® GraceResolv™ Silica Flash cartridges (4-120 g) or Agela Flash Column Silica-CS cartridges (80-330 g), or Agela Technologies manual or automated using the Grace Reveleris® X2 Flash system or similar system. C-18, carried out on reversed-phase silica using spherical cartridges (20–35 μm, 100 A, 80–330 g); (vii) Preparative reversed-phase HPLC and preparative reversed-phase SFC were performed using standard HPLC and SFC instruments, respectively, equipped with either MS and / or UV-driven fraction collection instruments, using isocratic or gradient mobile phases as described in the Experimental Section, and one of the following methods as described below:

[0348] HPLC preparative methods: Preparative method A: Compounds were purified by preparative HPLC on a YMC-Actus Triart C18 ExRS column (5 μm, 150 × 30 mm ID) using a gradient of MeCN / NH4HCO3 (10 mM) in HO as the mobile phase; Preparative method B: Compounds were purified by preparative HPLC on an XBridge™ C18 OBD column (5 μm, 150 × 30 mm ID) using a gradient of MeCN / NH4HCO3 (10 mM) / NH3 (0.1%, aq) buffer system in HO as the mobile phase; Preparative method C: Compounds were 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 HO as the mobile phase; Preparative method D: Compounds were purified by preparative HPLC on an XSelect CSH C18 OBD column (5 μm, 150 × 30 mm ID) using a gradient of MeCN / FA (0.1%) in HO as the mobile phase. Preparative Method E: Compounds were 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 HO as the mobile phase; Preparative Method F: Compounds were 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 HO as the mobile phase; Preparative Method G: Compounds were purified 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 HO as the mobile phase. Preparative Method H: Compounds were purified by preparative HPLC on a 1000 ketamine column (MeCN / MeCN / NH3 (95 / 5 / 0.01) in H2O as the mobile phase.Preparative Method I: Compounds were purified by preparative HPLC on an XBridge™ C18 column (10 μm, 250 × 50 mm ID) using a gradient of MeCN / NH4HCO3 (10 mM) in HO as the mobile phase; Preparative Method N: Compounds were purified by preparative HPLC on an XBridge™ C18 column (10 μm, 250 × 19 mm ID) using a gradient of MeCN / MeCN / NH3 (95 / 5 / 0.2) in HO as the mobile phase; Preparative Method O: Compounds were purified by preparative HPLC on an XBridge™ C18 column (5 μm, 250 × 19 mm ID) using a gradient of MeCN / NH4HCO3 (10 mM) in HO as the mobile phase. Preparative method P: Compounds were 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 HO as the mobile phase; Preparative method Q: Compounds were purified by preparative HPLC on an XBridge™ C18 ODB column (5 μm, 150 × 19 mm ID) using a gradient of MeCN / NH3 (0.2%, pH 10) buffer system in HO as the mobile phase; Preparative method R: Compounds were purified by preparative HPLC on an XBridge™ C18 OBD column (5 μm, 150 × 30 mm ID) using a gradient of MeCN / NH4HCO3 (10 mM) in HO as the mobile phase. Preparative Method T: Compounds were purified by preparative HPLC on an XBridge™ Shield C18 column (5 μm, 150 × 30 mm ID) using a gradient of MeCN / NH4CO3 (10 mM) / NH3 (0.1%, aq) buffer system in HO as the mobile phase; Preparative Method U: Compounds were purified by preparative HPLC on an XSelect CSH F-Phenyl OBD column (5 μm, 250 × 19 mm ID) using a gradient of MeCN / FA (0.1%) in HO as the mobile phase; Preparative Method V: Compounds were purified by preparative HPLC on an XBridge™ Shield C18 column (5 μm, 150 × 30 mm ID) using a gradient of MeCN / NH4CO3 (10 mM) / NH3 (0.1%, aq) buffer system in HO as the mobile phase.Preparative Method X: Compounds were 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 HO as the mobile phase;

[0349] SFC preparative methods: Preparative method SFC-A: Compounds were purified by preparative SFC on a Phenomenex Luna® HILIC column (5 μm, 250 × 30 mm ID) using EtOH / FA (20 mM) in CO2 as the mobile phase; Preparative method SFC-B: Compounds were purified by preparative SFC on a DAICEL DCpak® P4VP (5 μm, 250 × 20 mm ID) using MeOH in CO2 / 2M NH3 in MeOH (99.5 / 0.5) as the mobile phase; Preparative method SFC-C: Compounds were purified by preparative SFC on a Waters™ BEH (5 μm, 250 × 30 mm ID) using MeOH / HO (NH3 50 mM) (97 / 3) in CO2 as the mobile phase. Preparative method SFC-D: Compounds were purified by preparative SFC on a Waters™ BEH (5 μm, 30 × 250 mm ID) using EtOH / FA (20 mM) in CO as the mobile phase; Preparative method SFC-E: Compounds were purified by preparative SFC on a Waters™ BEH (5 μm, 250 × 30 mm ID) using MeOH / NH (20 mM) in CO as the mobile phase; Preparative method SFC-G: Compounds were purified by preparative SFC on a Waters™ BEH (3.5 μm, 100 × 3 mm ID) using MeOH / NH (20 mM) in CO as the mobile phase; Preparative method SFC-H: Compounds were purified by preparative SFC on a Phenomenex Luna® HILIC column (5 μm, 250 × 30 mm ID) using MeOH / NH (20 mM) in CO as the mobile phase. Purified by preparative SFC on a HPLC column.

[0350] The appropriate fractions were collected, combined and lyophilized to give the purified compound, or the appropriate fractions were collected, combined and concentrated under reduced pressure, extracted with DCM or EtOAc, and the organic phase was dried over Na2SO4 or by using a phase separator, followed by concentration under reduced pressure to give the purified compound; (viii) Chiral preparative chromatography was performed using HPLC or SFC on standard HPLC or SFC equipment, respectively, and using either isocratic or gradient run mobile phases as described in the Experimental section; (x) yields, if any, are not necessarily the maximum achievable and, if necessary, reactions were repeated if more reaction product was required; (xi) When a particular compound is obtained as an acid addition salt, e.g., a monohydrochloride or dihydrochloride, the stoichiometry of the salt is based on the number and nature of basic groups in the compound, and the exact stoichiometry of the salt has generally not been determined, e.g., by 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 spectrometry techniques; proton NMR chemical shift values ​​were 300, 400, 500 and 600 MHz, respectively. 1Measurements were made on a delta scale using a Bruker Avance III 300, 400, 500, and 600 spectrometer operating at H frequencies. Experiments were typically recorded at 25°C. Chemical shifts are given in ppm with the solvent as the internal standard. Protons on heteroatoms, such as NH and OH protons, may be missing, as they are reported only when detected in NMR. In certain instances, protons may be masked or partially masked by solvent peaks, and therefore will be missing, not reported, or reported as multiple overlaps with the solvent. The following abbreviations are used (and their derivatives, e.g., dd, doublet of doublet, etc.): s, singlet; d, doublet; t, triplet; q, quartet; m, multiplet; br, broad; qn, quintet; p, quintet. In some cases, the structure of the final product of formula (I) may appear as rotamers in the NMR spectrum, in which case only the peak of the major rotamer is reported. Electrospray mass spectral data are obtained using a Waters Acquity UPLC coupled to a Waters single quadrupole mass spectrometer or similar instrument that acquires both positive and negative ion data, and generally only ions associated with the parent structure are reported; high-resolution electrospray mass spectral data are obtained using a Waters Acquity XEVO qToF mass spectrometer or similar instrument that acquires both positive and negative ion data, and generally only ions associated with the parent structure are reported. (xiii) intermediates were not necessarily fully purified, but their structure and purity were assessed by TLC, analytical HPLC / UPLC, and / or NMR analysis and / or mass spectrometry; (xiv) Unless otherwise specified, compounds containing asymmetric carbon and / or sulfur atoms were not resolved; (xv) In general, the examples and intermediate compounds are named using ChemDraw Professional version 19.0.0.22 from PerkinElmer. ChemDraw Professional version 19.0.0.22 generates names for chemical structures using the Cahn-Ingold-Prelog (CIP) rules of stereochemistry and adheres as closely as possible to IUPAC rules when generating chemical names. Stereoisomers differ from each other in the stereodesignators referenced in the names 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 stereochemical centers present in a structure. In general, chemical structures of examples and intermediates containing the label "&" at a stereocenter mean that the configuration of such example or intermediate at that stereocenter is a mixture of both (R) and (S); the label "or" means that the configuration of such example or intermediate at that stereocenter is either (S) or (R). Absolute stereocenters, unspecified stereocenters, "&" stereocenters, and "or" stereocenters may all be present in a single structure.

[0352] In general, for example and intermediate structures where all of the stereocenters are designated as "&", the structures are named with a "rac-" prefix. For example and intermediate structures where all of the stereocenters are designated as "or", the structures are named with a "rel-" prefix.

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

[0354] In general, the designations (r) and (s) are used to denote the absolute configuration of any pseudo-chiral centers in the structures of the examples and intermediates.

[0355] Generally, the label "Isomer 1" corresponds to the isomer eluting first on a given chiral HPLC column, and "Isomer 2" corresponds to the isomer eluting second on a given chiral HPLC column, and is used to distinguish between two isomers containing one or more stereocenters with unknown absolute configuration. (xvi) When it is said that the reaction is degassed or purged, this can be done, for example, by purging the reaction solvent with a constant flow rate of nitrogen for a suitable period of time (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 [ka]

[0360] Step a) (R)-tert-butyl 4-carbamoylthiazolidine-3-carboxylate [ka] BocO (18.6 mL, 80.2 mmol) was added to a stirred solution of (R)-3-(tert-butoxycarbonyl)thiazolidine-4-carboxylic acid (17.0 g, 72.9 mmol) and pyridine (7.07 mL, 87.5 mmol) in EtOAc (170 mL), and the reaction mixture was stirred at room temperature for 3 h. A solution of NH (aq, 25%, 6 mL) was then added dropwise, and the mixture was stirred at room temperature overnight. The reaction mixture was diluted with EtOAc, the phases were separated, and the organic phase was washed with saturated NaCl, dried, filtered through a pad of silica gel, washed with EtOAc, and evaporated to give the crude title compound (16.9 g, 100%) as a colorless oil, which was used directly in the next step.

[0361] Step b) (R)-tert-butyl 4-cyanothiazolidine-3-carboxylate TFAA (12.4 mL, 87.5 mmol) as a solution in EtOAc (20 mL) was added to a solution of crude (R)-tert-butyl 4-carbamoylthiazolidine-3-carboxylate (16.9 g, 72.9 mmol) and pyridine (14.7 mL, 182 mmol) in EtOAc (150 mL) at room temperature. The mixture was stirred at room temperature for 4 hours, then diluted with EtOAc and washed with aq. HCl (1 M) and saturated NaHCO. The organic phase was dried, filtered through a pad of silica gel, washed with EtOAc, and evaporated to give a pale yellow oil that solidified on standing. The crude solid material was suspended in heptane:EtOAc (4:1, 50 mL) and stirred overnight at room temperature. The solid was filtered off, washed with heptane:EtOAc (4:1), and dried to give the title compound (12.0 g, 83%) as a colorless solid. 1 H NMR(400MHz,CDCl3)δ 5.20-4.79(m,1H),4.60-4.53(m,1H),4.53-4.36(m,1H),3.40-3.18(m,2H),1.51(s,9H).

[0362] Intermediate 2: (R)-Thiazolidine-4-carbonitrile hydrochloride [ka] A solution of aqueous HCl (12 M, 11 mL) in MeOH (140 mL) was slowly added to a solution of (R)-tert-butyl 4-cyanothiazolidine-3-carboxylate Intermediate 1 (6.0 g, 28 mmol) in MeOH (140 mL) at room temperature. The clear, colorless solution was stirred at room temperature for 2 hours. The solvent was evaporated to give the title compound (4.22 g, 100%) as a colorless solid. 1 H NMR(400MHz,CD3OD)δ 4.90(dd,1H),4.35-4.24(m,2H),3.37-3.24(m,2H).

[0363] Intermediate 3: (R)-(2-(4-cyanothiazolidin-3-yl)-2-oxoethyl)carbamate tert-butyl [ka] DIPEA (19.6 mL, 112 mmol) was added to a suspension of (R)-thiazolidine-4-carbonitrile hydrochloride intermediate 2 (4.22 g, 28 mmol), (tert-butoxycarbonyl)glycine (6.13 g, 35.0 mmol), and T3P (41.6 mL, 70.0 mmol, 50% solution in EtOAc) in EtOAc (120 mL). The mixture was heated at 60 °C for 4 h. The mixture was diluted with EtOAc and washed successively with water, aqueous HCl (1 M), and saturated NaHCO3. The organic phase was dried, filtered, and evaporated. The residue was filtered through a pad of silica gel, washed with heptane:EtOAc (1:1), and evaporated to give an oil, which was triturated with heptane:DCM to give the title compound (7.60 g, 100%) as a nearly colorless solid. 1 H NMR(400MHz,CDCl3)δ 5.36-5.25(m,2H),4.59-4.52(m,2H),4.14-3.90(m,2H),3.29(d,2H),1.45(s,9H).

[0364] Intermediate 4: (R)-3-glycylthiazolidine-4-carbonitrile hydrochloride [ka] A solution of aqueous HCl (12 M, 5.6 mL) in MeOH (140 mL) was slowly added to a solution of tert-butyl (R)-(2-(4-cyanothiazolidin-3-yl)-2-oxoethyl)carbamate Intermediate 3 (7.60 g, 28.0 mmol) in MeOH (140 mL), and the solution was then stirred at room temperature overnight. Evaporation of the solvent afforded the title compound (5.80 g, 100%) as a colorless solid. 1 H NMR(400MHz,CD3OD)δ 5.34(t,1H),4.72(d,1H),4.62(d,1H),4.11-3.94(m,2H),3.41-3.36(m,2H).

[0365] Intermediate 5: Ethyl 6-(1,2-oxazinan-2-yl)quinoline-4-carboxylate [ka] 1,2-Oxazinane hydrochloride (37 mg, 0.30 mmol) was added to a mixture of ethyl 6-bromoquinoline-4-carboxylate (56 mg, 0.20 mmol), Cs2CO3 (195 mg, 0.60 mmol), Pd2dba3 (9.0 mg, 10 μmol), and XPhos (9.5 mg, 0.02 mmol) in dioxane (1 mL). The flask was sealed, purged with N2 (g), and the mixture was heated at 90 °C overnight. The mixture was diluted with EtOAc and washed with water. The organic phase was dried, filtered, and evaporated. The residue was purified by normal-phase flash chromatography on silica (gradient: 20-50% EtOAc in heptane) to give the title compound (50 mg, 87%) as a yellow oil that solidified on standing; MS m / z (ESI) [M+H] + 287.2.

[0366] Intermediate 6: 6-(1,2-oxazinan-2-yl)quinoline-4-carboxylic acid [ka] Aq NaOH (1 M, 0.52 mL) was added to a solution of ethyl 6-(1,2-oxazinan-2-yl)quinoline-4-carboxylate intermediate 5 (50 mg, 0.17 mmol) in MeOH (2 mL) and water (1 mL). The mixture was stirred at room temperature for 3 h, then neutralized with aq HCl (1 M) and evaporated to give the title compound (45 mg, 100%) as a yellow-red semisolid; MS m / z (ESI), [M+H] + 259.1.

[0367] Intermediate 7: Ethyl 3-fluoro-6-morpholinoquinoline-4-carboxylate [ka] Morpholine (70 mg, 0.80 mmol) was added to a mixture of ethyl 6-chloro-3-fluoroquinoline-4-carboxylate (101 mg, 0.4 mmol), CsCO (0.391 g, 1.20 mmol), Pddba (18 mg, 0.02 mmol), and XPhos (19 mg, 0.04 mmol) in dioxane (2 mL). The flask was sealed and purged with N(g), and the mixture was heated at 90 °C for 1 h. The mixture was diluted with EtOAc and washed with water. The organic phase was dried, filtered, and evaporated to give the title compound (122 mg, 100%) as a yellow semi-solid; MS m / z (ESI) [M+H] + 305.2.

[0368] Intermediate 8: 3-Fluoro-6-morpholinoquinoline-4-carboxylic acid [ka] Aq NaOH (1 M, 1.25 mL) was added to a solution of ethyl 3-fluoro-6-morpholinoquinoline-4-carboxylate intermediate 7 (190 mg, 0.62 mmol) in MeOH (6 mL) and water (3 mL). The mixture was stirred at r...

Claims

1. A compound having the structure of formula (I): 【Chemical 1】 or a pharmaceutically acceptable salt thereof, wherein: 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 5 to 10 ring atoms, wherein 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) 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; 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 further be substituted with one or more halogens. (b) 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) has 1, 2, or 3 nitrogen ring atoms, the remaining ring atoms being carbon; and (iii) 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 The alkyl may be further substituted with one or more hydroxy; and (c) 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, the remaining ring atoms being carbon, or (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, optionally substituted with one or more substituents independently selected from the group consisting of selected from the group consisting of: R ３ is hydrogen, halogen, and C １～３ - selected from the group consisting of alkyl; R ４ is hydrogen, halogen, and C １～３ - selected from the group consisting of alkyl; R ５ is hydrogen, halogen, and C １～３ - selected from the group consisting of alkyl; and R ６ is hydrogen, halogen, and C １～３ -alkyl) However, the compound is not (R)—N-(2-(4-cyanothiazolidin-3-yl)-2-oxoethyl)-6-morpholinoquinoline-4-carboxamide.

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 pharmaceutically acceptable salt thereof.

3. X １ The compound according to claim 1 or 2, or a pharmaceutically acceptable salt thereof, wherein is -S-.

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

5. R ２ and (iii) a heterocyclyl containing a total of 5 to 10 ring atoms (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) having one or more of the following ring atoms: 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), or a pharmaceutically acceptable salt thereof.

6. The compound of claim 5, or a pharmaceutically acceptable salt thereof, wherein (a) the heterocyclyl ring is a saturated monocyclic ring, and / or (b) the heterocyclyl ring has one nitrogen ring atom and one oxygen ring atom, with the remaining ring atoms being carbon.

7. The heterocyclyl ring is 【Chemistry 4】 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 said 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 - the alkyl may be further substituted with one or more halogens; Optionally, said heterocyclyl ring is 【Chemistry 5】 is selected from the group consisting of said heterocyclyl ring is optionally substituted with one or more substituents independently 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 said 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 halogen; 6. The compound of claim 5, or a pharmaceutically acceptable salt thereof.

8. The heterocyclyl ring is 【Chemistry 6】 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 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 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 6. The compound of claim 5, or a pharmaceutically acceptable salt thereof, wherein -alkyl may be further substituted with one or more halogens.

9. The compound of claim 5, or a pharmaceutically acceptable salt thereof, selected from the group consisting of: (R)—N-(2-(4-cyanothiazolidin-3-yl)-2-oxoethyl)-6-(1,2-oxazinan-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); 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-oxazinan-3-yl)quinoline-4-carboxamide (Example 112); (R)-7-chloro-N-(2-(4-cyanothiazolidin-3-yl)-2-oxoethyl)-6-morpholinoquinoline-4-carboxamide (Example 179); (R)-8-chloro-N-(2-(4-cyanothiazolidin-3-yl)-2-oxoethyl)-6-morpholinoquinoline-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); or a pharmaceutically acceptable salt thereof.

10. R ２ and a heterocyclyl containing a total of 4 to 10 ring atoms (heterocyclyl rings are (i) saturated, partially saturated, or fully unsaturated monocyclic or fused bicyclic rings, (ii) having 1, 2, or 3 nitrogen ring atoms, the remaining ring atoms being 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 - 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 compound of any one of claims 1 to 4, or a pharmaceutically acceptable salt thereof, wherein alkyl may be further substituted with one or more hydroxy.

11. The heterocyclyl ring is 【Chemistry 7】 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) the C １～６ 11. The compound of claim 10, or a pharmaceutically acceptable salt thereof, wherein the alkyl is optionally further substituted with one or more hydroxy.

12. The compound of claim 10, or a pharmaceutically acceptable salt thereof, selected from the group consisting of: 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-methyl-piperidin-1-yl)quinoline-4-carboxamide (Example 37); (R)—N-(2-(4-cyanothiazolidin-3-yl)-2-oxoethyl)-6-(4,4-difluoro-3,3-dimethyl-piperidin-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); or a pharmaceutically acceptable salt thereof.

13. 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, the remaining ring atoms being carbon, or (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, or a pharmaceutically acceptable salt thereof.

14. The two saturated rings are 【Chemistry 8】 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 14. The compound of claim 13, or a pharmaceutically acceptable salt thereof, optionally substituted with one or more substituents independently selected from the group consisting of: - alkylcarbonyl.

15. The compound of claim 13, or a pharmaceutically acceptable salt thereof, selected from the group consisting of: (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]decan-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]decan-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); or a pharmaceutically acceptable salt thereof.

16. The compound has the structure of formula (V): 【Chemistry 9】 (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 - selected from the group consisting of 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 - the alkyl may be further substituted with one or more halogens, and R ２０ｅ and R ２０ｆ are independently hydrogen and C １～３ 10. The compound of claim 1, or a pharmaceutically acceptable salt thereof, wherein the compound has a substituent selected from the group consisting of: -alkyl;

17. The compound has the structure of formula (VI): 【Chemistry 10】 (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 - selected from the group consisting of 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 - selected from the group consisting of 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 - selected from the group consisting of 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 10. The compound of claim 1, or a pharmaceutically acceptable salt thereof, wherein the compound has a substituent selected from the group consisting of: -alkyl;

18. R １ , R ３ , R ４ , R ５ , and R ６ 18. The compound of claim 17, or a pharmaceutically acceptable salt thereof, wherein: are all hydrogen.

19. The compound has the structure of formula (VII): 【Chemistry 11】 (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 - 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 - 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 - selected from the group consisting of alkoxy; and R ４０ｉ and R ４０ｊ are independently hydrogen, C １～３ -alkyl and halo-C １～３ 10. The compound of claim 1, or a pharmaceutically acceptable salt thereof, wherein the compound has a substituent selected from the group consisting of: -alkyl;

20. The compound has the structure of formula (VIII): 【Chemistry 12】 (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 - selected from the group consisting of alkoxy; and R ５０ｊ is selected from the group consisting of hydrogen and fluoro, or a pharmaceutically acceptable salt thereof.

21. The compound has the structure of formula (IX): 【Chemistry 13】 (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 - selected from the group consisting of alkyl; R ６０ｃ and R ６０ｄ are independently hydrogen and C １～３ - selected from the group consisting of alkyl; and R ６０ｅ and R ６０ｆ are independently hydrogen and C １～３ 10. The compound of claim 1, or a pharmaceutically acceptable salt thereof, wherein the compound has a substituent selected from the group consisting of: -alkyl;

22. The compound has the structure of formula (X): 【Chemistry 14】 (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 - selected from the group consisting of alkyl; R ７０ｃ and R ７０ｄ are independently hydrogen and C １～３ - selected from the group consisting of alkyl; R ７０ｅ and R ７０ｆ are independently hydrogen and C １～３ - selected from the group consisting of alkyl; and R ７０ｇ and R ７０ｈ are independently hydrogen and C １～３ 10. The compound of claim 1, or a pharmaceutically acceptable salt thereof, wherein the compound has a substituent selected from the group consisting of: -alkyl;

23. The compound has the structure of formula (XI): 【Chemistry 15】 (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 - selected from the group consisting of alkoxy; and R ８０ｄ is hydrogen, fluoro, C １～３ -Alkyl, halo-C １～３ - alkyl, and C １～３ -alkoxy) or a pharmaceutically acceptable salt thereof.

24. A pharmaceutical composition comprising a compound according to any one of claims 1 to 23, or a pharmaceutically acceptable salt thereof, and one or more pharmaceutically acceptable excipients.

25. 24. A medicament for treating or preventing a FAP mediated condition in a subject suffering from or susceptible to said FAP mediated condition, comprising a compound according to any one of claims 1 to 23, or a pharmaceutically acceptable salt thereof.

26. 26. The method of claim 25, 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.

27. The method of claim 26, wherein the FAP-mediated pathology is liver disease.

28. The pharmaceutical described in claim 27, wherein the liver disease is non-alcoholic fatty liver disease (NAFLD), optionally wherein the NAFLD is selected from the group consisting of isolated steatosis, non-alcoholic steatohepatitis (NASH), hepatic fibrosis, and cirrhosis.

29. The method of claim 27, wherein the liver disease is non-alcoholic steatohepatitis.

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