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

Abstract

Compounds having the structure of formula (I) and pharmaceutically acceptable salts thereof, wherein X 1 , R 1 , R 2 , R 3 , R 4 , R 5 , and R 6 is as defined herein, compounds and pharmaceutically acceptable salts thereof; pharmaceutical compositions comprising such compounds and salts; use of such compounds and salts for treating or preventing prolyl endopeptidase fibroblast activation protein (FAP) mediated conditions; kits comprising such compounds and salts; and methods for preparing such compounds and salts. [Formula 1] JPEG2025525344000321.jpg56128

Description

[Technical Field]

[0001] (CROSS-REFERENCE TO RELATED APPLICATIONS) This application claims the benefit of priority to U.S. Provisional Patent Application No. 63 / 366,699, filed June 21, 2022. The entire text of the above-referenced patent application is incorporated herein by reference.

[0002] The present disclosure relates generally 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 prolyl endopeptidase fibroblast activating protein (FAP)-mediated conditions; kits comprising such compounds and salts; and methods for making such compounds and salts. [Background technology]

[0003] FAP, a type II transmembrane serine protease, is expressed by fibroblast-like cells involved in tissue remodeling and healing. In the context of nonalcoholic steatohepatitis (NASH), FAP is upregulated on the cell surface of activated hepatic stellate cells, which are involved in fibrogenesis, a key aspect of NASH that predicts disease outcome (Gastroenterology 2020, 158, 1611) (Hepatology 1999, 29, 1768). FAP can also exist as a shed plasma protease. Increased circulating FAP levels are associated with NASH disease severity (Diabetes Res Clin Pract 2015, 108, 466).

[0004] FAP has a consensus cleavage motif after Gly-Pro and exhibits both endopeptidase and exopeptidase activity. Its known enzymatic activities include cleavage of collagen (Hepatology 1999, 29, 1768), α2-antiplasmin (α2AP) (Blood 2004, 103, 3783), and fibroblast growth factor 21 (FGF21) (Biochem J 2016, 473, 605). FAP activity (including collagen cleavage) on the cell surface of activated fibroblasts creates a profibrotic environment. FAP cleavage of α2AP results in more efficient cross-linking of α2AP to fibrin, resulting in reduced fibrin clearance. FAP cleavage of FGF21 inactivates the metabolic effects of FGF21 (Biochem J 2016, 473, 605). All of these activities are associated with NASH disease progression, and inhibiting FAPs has the potential to treat NASH and other conditions by affecting multiple mechanisms.

[0005] Inhibition of FAP activity is currently an underutilized therapeutic approach for treating NASH and other diseases associated with such activity.No approved pharmaceutical agent that generally inhibits FAP activity or specifically inhibits FAP activity is 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 requiring such treatment.The present disclosure addresses this significant unmet need by providing such compounds together with corresponding pharmaceutical compositions and methods for treating or preventing NASH and related conditions. Summary of the Invention

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

[0007] [ka] or a pharmaceutically acceptable salt thereof, 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)C 1~6 -alkyl, optionally containing halogen, hydroxy, cyano, C 3~6 -cycloalkyl, halo-C 3~6 -cycloalkyl, C 1~6 -Alkoxy, Halo-C 1~6 -alkoxy, C 3~6 -Cycloalkoxy, halo-C 3~6 -cycloalkoxy, C 1~6 -Alkoxy-C 1~6 -substituted with one or more substituents independently selected from the group consisting of alkoxy, oxetanyl, tetrahydrofuranyl, tetrahydrofuranyloxy, tetrahydropyranyl, morpholinyl, pyrazolyl, isoxazolyl, triazolyl, and pyridinyl; oxetanyl, tetrahydrofuranyl, tetrahydrofuranyloxy, tetrahydropyranyl, morpholinyl, pyrazolyl, isoxazolyl, triazolyl, and pyridinyl are optionally substituted with one or more substituents independently selected from the group consisting of halogen, cyano, C 1~6 -Alkyl and halo-C 1~6 -substituted with one or more substituents independently selected from the group consisting of alkyl, C 1~6 - alkyl; (b)C 3~6 -cycloalkyl, optionally containing halogen, hydroxy, cyano, C 1~6 -Alkyl, Halo-C 1~6 -Alkyl, C 1~6 -Alkoxy, Halo-C 1~6 -substituted with one or more substituents independently selected from the group consisting of alkoxy, isoxazolyl, and pyridinyl; isoxazolyl and pyridinyl are optionally substituted with halogen, C 1~6 -Alkyl and halo-C 1~6 -substituted with one or more substituents independently selected from the group consisting of alkyl, C3~6 -cycloalkyl; (c) phenyl, optionally containing halogen, cyano, C 1~6 -Alkyl, Halo-C 1~6 -Alkyl, C 1~6 -Alkoxy, Halo-C 1~6 -alkoxy, and C 1~6 -Alkoxy-C 1~6 -phenyl substituted with one or more substituents independently selected from the group consisting of alkoxy; (d) a 4-, 5-, 6-, or 7-membered heterocyclyl that (i) is saturated, partially saturated, or fully unsaturated, monocyclic or fused bicyclic, (ii) has one or two oxygen ring atoms, the remaining ring atoms being carbon, and (iii) optionally contains halogen, hydroxy, cyano, C 1~6 -Alkyl, Halo-C 1~6 -Alkyl, C 2~6 -alkynyl, C 1~6 -alkoxy and halo-C 1~6 -heterocyclyl substituted with one or more substituents independently selected from the group consisting of alkoxy; and (e)-OR 7 and R 7 But C 1~6 - selected from the group consisting of alkyl, phenyl, and tetrahydropyranyl; (I C 1~6 -Alkyl is optionally substituted with halogen, cyano, C 3~6 -cycloalkyl, halo-C 3~6 -cycloalkyl, C 1~6 -alkoxy and halo-C 1~6 -substituted with one or more substituents independently selected from the group consisting of alkoxy; (ii) phenyl optionally containing halogen, C 1~6 -Alkyl, Halo-C 1~6 -Alkyl, C 1~6 -alkoxy and halo-C 1~6 -substituted with one or more substituents independently selected from the group consisting of alkoxy; (iii) tetrahydropyranyl optionally containing halogen, C 1~6 -Alkyl, Halo-C1~6 -Alkyl, C 1~6 -alkoxy and halo-C 1~6 -OR substituted with one or more substituents independently selected from the group consisting of -alkoxy; 7 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; R 6 is hydrogen, halogen, and C 1~3 -alkyl, or a pharmaceutically acceptable salt thereof.

[0008] 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), or (IV-A), as further defined herein, and pharmaceutically acceptable salts thereof.

[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), or (IV-A), as further defined herein, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.

[0010] 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), or (IV-A), as further defined herein, or a pharmaceutically acceptable salt thereof; a second pharmaceutical agent; and a pharmaceutically acceptable carrier.

[0011] In another aspect, the present disclosure provides a method for treating or preventing a FAP-mediated condition by administering 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), or (IV-A), as further defined herein, or a pharmaceutically acceptable salt thereof, to a subject in need thereof. In one aspect, the FAP-mediated condition is selected from the group consisting of liver disease, type 2 diabetes mellitus, a cardiovascular condition, obesity, an obesity-related condition, fibrosis, a keloid disorder, inflammation, and cancer. In another aspect, the FAP-mediated condition is a liver disease, particularly nonalcoholic steatohepatitis (NASH).

[0012] 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), or (IV-A), as further defined herein, or a pharmaceutically acceptable salt thereof, for use as a medicament for treating or preventing a FAP-mediated condition.

[0013] In another aspect, the disclosure provides the use of a compound having the structure of Formula (I), (II), (III-A), (III-B), (III-C), (III-D), (III-E), (IV), or (IV-A), as further defined herein, or a pharmaceutically acceptable salt thereof, for the preparation of a medicament for treating or preventing a FAP-mediated condition.

[0014] In another aspect, the present disclosure provides a kit comprising a compound having the structure of Formula (I), (II), (III-A), (III-B), (III-C), (III-D), (III-E), (IV), or (IV-A), as further defined herein, or a pharmaceutically acceptable salt thereof.

[0015] In another aspect, the disclosure provides methods for preparing compounds having the structure of Formula (I), (II), (III-A), (III-B), (III-C), (III-D), (III-E), (IV), or (IV-A), as further defined herein, or a pharmaceutically acceptable salt thereof. DETAILED DESCRIPTION OF THE INVENTION

[0016] 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.

[0017] I. Definition With respect to the embodiments disclosed herein, the following terms have the meanings set forth below.

[0018] References to "a" or "an" mean "one or more." Throughout, plural and singular forms should be treated as interchangeable except for references to number.

[0019] Unless the context requires otherwise, the words "comprise" or "comprises" or "comprising" are to be interpreted inclusively and not exclusively, and are used with the understanding and express understanding that Applicant intends each of these words to be so interpreted in interpreting this patent, including the claims that follow.

[0020] The term "halogen" (alone or in combination with another term(s)) means a fluorine radical (which may be represented as -F), a chlorine radical (which may be represented as -Cl), a bromine radical (which may be represented as -Br), or an iodine radical (which may be represented as -I).

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

[0022] The term "cyano" (alone or in combination with another term(s)) means --CN.

[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, propyl (including n-propyl and isopropyl), butyl (including n-butyl, isobutyl, sec-butyl, and tert-butyl), pentyl (including n-pentyl, iso-amyl, and 2,2-dimethylpropyl), and hexyl.

[0024] The term "cycloalkyl" (alone or in combination with another term(s)) 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 "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, for example, "methoxymethyl", which means

[0026] [ka] can be expressed as (ii) the term "cycloalkylalkoxy" (alone or in combination with another term(s)) means an alkoxy substituted with a cycloalkyl, for example, "cyclopropylmethoxy", which means

[0027] [ka] It can be expressed as:

[0028] The term "cycloalkoxy" (alone or in combination with another term) means a cycloalkyl ether substituent, i.e., cycloalkyl-O-. Examples of cycloalkoxy include cyclopropoxy, cyclobutoxy, cyclopentoxy, and cyclohexoxy. Thus, for example, the term "alkylcycloalkoxy" (alone or in combination with another term) means an alkyl-substituted cycloalkoxy, such as "methylcyclopropoxy," which means

[0029] [ka] It can be expressed as:

[0030] In some instances, the number of carbon atoms in a substituent (e.g., alkyl, cycloalkyl, etc.) is indicated by the prefix "Cx-y-" where x is the minimum number of carbon atoms in the substituent and y is the maximum number. Thus, for example, "Ci_6-alkyl" refers to an alkyl substituent containing from 1 to 6 carbon atoms. To illustrate further, C3_6-cycloalkyl refers to a cycloalkyl substituent containing from 3 to 6 carbon ring atoms.

[0031] The prefix "halo" indicates that the substituent to which the prefix is attached is substituted with one or more independently selected halogen radicals. For example, haloalkyl refers to an alkyl substituent in which at least one hydrogen radical is replaced with a halogen radical. When two or more hydrogens are replaced with halogens, the halogens can be the same or different. Examples of haloalkyl include fluoromethyl, difluoromethyl, trifluoromethyl, difluoroethyl, 1,1,1-trifluoroethyl, pentafluoroethyl, difluoropropyl, heptafluoropropylchloromethyl, 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 radical. When two or more hydrogens are replaced with halogens, 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.

[0032] The term "heterocyclyl" (alone or in combination with another term) refers to a saturated, partially saturated, or fully unsaturated (i.e., "heteroaryl") ring structure containing a total of 3 to 14 ring atoms. At least one of the ring atoms is a heteroatom (i.e., oxygen, nitrogen, or sulfur), and the remaining ring atoms are independently selected from the group consisting of carbon, oxygen, nitrogen, and sulfur. Heterocyclyl includes monocyclic saturated, partially unsaturated, and fully unsaturated ring structures having, for example, 4 to 7 members, e.g., 4 to 6 members, 5 to 7 members, or 5 or 6 members, in any stable combination known to those skilled in the art, in which at least one and up to four, particularly 1, 2, or 3, members of the ring are heteroatoms selected from N, O, and S, and the remaining ring atoms are carbon atoms. Heterocyclyl also includes bicyclic ring structures fused together (i.e., fused bicyclic rings) in which at least one such ring contains a heteroatom (i.e., nitrogen, oxygen, or sulfur) as a ring atom.

[0033] 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 not included in this definition.

[0034] When a substituent is described as "substituted," a non-hydrogen radical is present in place of a hydrogen radical on the carbon or nitrogen of the substituent. Thus, for example, a substituted alkyl substituent is an alkyl substituent in which at least one non-hydrogen radical is present in place of a hydrogen radical on the alkyl substituent. For example, a monofluoroalkyl is an alkyl substituted with a fluoro radical, and a difluoroalkyl is an alkyl substituted with two fluoro radicals. When two or more substitutions are present on a substituent, it should be recognized that each non-hydrogen radical may be the same or different (unless otherwise specified).

[0035] When a substituent is described as "optionally substituted," the substituent can be (1) unsubstituted or (2) substituted. When a carbon of a substituent is described as optionally substituted with one or more of a list of substituents, one or more of the hydrogens on the carbon (to the extent present) can be replaced separately and / or together with any independently selected substituents. When a nitrogen of a substituent is described as optionally substituted with one or more of a list of substituents, one or more of the hydrogens on the nitrogen (to the extent present) can each be replaced with any independently selected substituents.

[0036] When substituents are described as being "independently selected" from a group, each substituent is selected independently of the other. Thus, each substituent can be the same or different from the other substituents.

[0037] The term "pharmaceutically acceptable" is used adjectively herein to mean that the modified noun is appropriate for use as a pharmaceutical product or part of a pharmaceutical product. For example, a "pharmaceutically acceptable salt" is a salt suitable for use in mammals, particularly humans, and includes salts with inorganic bases, organic bases, inorganic acids, organic acids, or basic or acidic amino acids that are suitable for use in mammals, particularly humans.

[0038] A "therapeutically effective amount" of a pharmaceutical agent is an amount sufficient to produce beneficial or desired results, including clinical results, and thus depends on the context in which it is administered. For example, when a pharmaceutical agent is administered to treat liver disease, a therapeutically effective amount of the pharmaceutical agent is the amount of the agent, either 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.

[0039] The term "prevent" is readily understood by an ordinarily skilled physician and is intended to have its ordinary meaning with respect to the treatment of a particular condition, and may include primary prevention, to prevent the onset of the condition, and secondary prevention, where the condition has already occurred and the patient is protected, either temporarily or permanently, from exacerbation or worsening of the disease or the onset of new symptoms associated with the condition.

[0040] 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, stabilizing (i.e., not worsening), slowing, or delaying the spread or progression of liver disease; prolonging survival compared to expected survival in the absence of treatment; and / or ameliorating or alleviating, in whole or in part, the severity of the cancer or liver disease.

[0041] II. Compounds A. Compounds of Formula (I) In one embodiment, the present disclosure provides a compound having the structure of formula (I):

[0042] [ka] or a pharmaceutically acceptable salt thereof, 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)C 1~6 -alkyl, optionally containing halogen, hydroxy, cyano, C 3~6 -cycloalkyl, halo-C 3~6 -cycloalkyl, C 1~6 -Alkoxy, Halo-C 1~6 -alkoxy, C 3~6 -Cycloalkoxy, halo-C 3~6 -cycloalkoxy, C 1~6 -Alkoxy-C 1~6 -substituted with one or more substituents independently selected from the group consisting of alkoxy, oxetanyl, tetrahydrofuranyl, tetrahydrofuranyloxy, tetrahydropyranyl, morpholinyl, pyrazolyl, isoxazolyl, triazolyl, and pyridinyl; oxetanyl, tetrahydrofuranyl, tetrahydrofuranyloxy, tetrahydropyranyl, morpholinyl, pyrazolyl, isoxazolyl, triazolyl, and pyridinyl are optionally substituted with one or more substituents independently selected from the group consisting of halogen, cyano, C 1~6 -Alkyl and halo-C 1~6 -substituted with one or more substituents independently selected from the group consisting of alkyl, C 1~6 - alkyl; (b)C 3~6 -cycloalkyl, optionally containing halogen, hydroxy, cyano, C 1~6 -Alkyl, Halo-C 1~6 -Alkyl, C 1~6 -Alkoxy, Halo-C 1~6-substituted with one or more substituents independently selected from the group consisting of alkoxy, isoxazolyl, and pyridinyl; isoxazolyl and pyridinyl are optionally substituted with halogen, C 1~6 -Alkyl and halo-C 1~6 -substituted with one or more substituents independently selected from the group consisting of alkyl, C 3~6 -cycloalkyl; (c) phenyl, optionally containing halogen, cyano, C 1~6 -Alkyl, Halo-C 1~6 -Alkyl, C 1~6 -Alkoxy, Halo-C 1~6 -alkoxy, and C 1~6 -Alkoxy-C 1~6 -phenyl substituted with one or more substituents independently selected from the group consisting of alkoxy; (d) a 4-, 5-, 6-, or 7-membered heterocyclyl that (i) is saturated, partially saturated, or fully unsaturated, monocyclic or fused bicyclic, (ii) has one or two oxygen ring atoms, the remaining ring atoms being carbon, and (iii) optionally contains halogen, hydroxy, cyano, C 1~6 -Alkyl, Halo-C 1~6 -Alkyl, C 2~6 -alkynyl, C 1~6 -alkoxy and halo-C 1~6 -heterocyclyl substituted with one or more substituents independently selected from the group consisting of alkoxy; and (e)-OR 7 and R 7 But C 1~6 - selected from the group consisting of alkyl, phenyl, and tetrahydropyranyl; (I C 1~6 -Alkyl is optionally substituted with halogen, cyano, C 3~6 -cycloalkyl, halo-C 3~6 -cycloalkyl, C 1~6 -alkoxy and halo-C 1~6 -substituted with one or more substituents independently selected from the group consisting of alkoxy; (ii) phenyl optionally containing halogen, C 1~6 -Alkyl, Halo-C1~6 -Alkyl, C 1~6 -alkoxy and halo-C 1~6 -substituted with one or more substituents independently selected from the group consisting of alkoxy; (iii) tetrahydropyranyl optionally containing halogen, C 1~6 -Alkyl, Halo-C 1~6 -Alkyl, C 1~6 -alkoxy and halo-C 1~6 -OR substituted with one or more substituents independently selected from the group consisting of -alkoxy; 7 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; R 6 is hydrogen, halogen, and C 1~3 -alkyl, or a pharmaceutically acceptable salt thereof.

[0043] In some embodiments, the present disclosure provides a compound having the structure of formula (II):

[0044] [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), and pharmaceutically acceptable salts thereof. 1 is -S-. In another embodiment, X 1 is -S(O)-. In another embodiment, X1 is -S(O)2-.

[0045] 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. In another embodiment, R 1 is chloro. In another embodiment, R 1 is fluoro. In another embodiment, R 1 is methyl.

[0046] In some embodiments, R 3 is selected from the group consisting of hydrogen, chloro, fluoro, and methyl. 3 is hydrogen. In another embodiment, R 3 is chloro. In another embodiment, R 3 is fluoro. In another embodiment, R 3 is methyl.

[0047] In some embodiments, R 4 is selected from the group consisting of hydrogen, halogen, and methyl. 4 is hydrogen. In another embodiment, R 4 is chloro. In another embodiment, R 4 is fluoro. In another embodiment, R 4 is methyl.

[0048] In some embodiments, R 5 is selected from the group consisting of hydrogen, chloro, fluoro, and methyl. 5 is hydrogen. In another embodiment, R 5 is fluoro. In another embodiment, R 5 is chloro. In another embodiment, R 5 is methyl.

[0049] In some embodiments, R6 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.

[0050] 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 6 One of the substituents is selected from the group consisting of chloro and fluoro, and the remaining R 1 , R 3 , R 4 , R 5 , and R 6 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 , R5 , and R 6 The substituents are all hydrogen.

[0051] In some embodiments, R 1 , R 3 , R 4 , R 5 , and R 6 At least two of the substituents are 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.

[0052] In some embodiments, R 1 , R 3 , R 4 , R 5 , and R 6 Two of the substituents are independently selected from the group consisting of chloro, fluoro, and methyl, and the remaining R 1 , R 3 , R 4 , R 5 , and R 6 The substituents are all hydrogen.

[0053] In some embodiments, R 1 , R 3 , R 4 , R 5 , and R 6 At least one of the substituents is chloro.

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

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

[0056] In some embodiments, R 1 , R 3 , R 4 , R 5 , and R 6 The substituents are hydrogen, and X 1 is selected from the group consisting of -S-, -S(O)-, and -S(O)2-.

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

[0058] [ka] and pharmaceutically acceptable salts thereof, wherein R 1 and R 2 provides compounds and pharmaceutically acceptable salts thereof, as defined in the various embodiments above.

[0059] In some embodiments, the present disclosure provides a compound having the structure of formula (III-B):

[0060] [ka] and pharmaceutically acceptable salts thereof, wherein R 2 and R 3 provides compounds and pharmaceutically acceptable salts thereof, as defined in the various embodiments above.

[0061] In some embodiments, the present disclosure provides a compound having the structure of formula (III-C):

[0062] [ka] and pharmaceutically acceptable salts thereof, wherein R 2 and R 4provides compounds and pharmaceutically acceptable salts thereof, as defined in the various embodiments above.

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

[0064] [ka] and pharmaceutically acceptable salts thereof, wherein R 2 and R 5 provides compounds and pharmaceutically acceptable salts thereof, as defined in the various embodiments above.

[0065] In some embodiments, the present disclosure provides a compound having the structure of formula (III-E):

[0066] [ka] and pharmaceutically acceptable salts thereof, wherein R 2 and R 6 provides compounds and pharmaceutically acceptable salts thereof, as defined in the various embodiments above.

[0067] In some embodiments, the present disclosure provides a compound having the structure of formula (IV):

[0068] [ka] and pharmaceutically acceptable salts thereof, wherein R 2 provides compounds and pharmaceutically acceptable salts thereof, as defined in the various embodiments above.

[0069] In some embodiments, the present disclosure provides a compound having the structure of formula (IV-A):

[0070] [ka] and pharmaceutically acceptable salts thereof, wherein R 2 provides compounds and pharmaceutically acceptable salts thereof, as defined in the various embodiments above.

[0071] BR 2 is C 1~6 - alkyl 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 2 is C 1~6 -alkyl, C 1~6 -Alkyl is optionally substituted with halogen, hydroxy, cyano, C 3~6 -cycloalkyl, halo-C 3~6 -cycloalkyl, C 1~6 -Alkoxy, Halo-C 1~6 -alkoxy, C 3~6 -Cycloalkoxy, halo-C 3~6 -cycloalkoxy, C 1~6 -Alkoxy-C 1~6 -substituted with one or more substituents independently selected from the group consisting of alkoxy, oxetanyl, tetrahydrofuranyl, tetrahydrofuranyloxy, tetrahydropyranyl, morpholinyl, pyrazolyl, isoxazolyl, triazolyl, and pyridinyl; oxetanyl, tetrahydrofuranyl, tetrahydrofuranyloxy, tetrahydropyranyl, morpholinyl, pyrazolyl, isoxazolyl, triazolyl, and pyridinyl are optionally substituted with one or more substituents independently selected from the group consisting of halogen, C 1~6 -Alkyl and halo-C 1~6 In one aspect, the present invention provides a compound or a pharmaceutically acceptable salt thereof, wherein R is substituted with one or more substituents independently selected from the group consisting of: 2 is C 1~3 -alkyl, C 1~3 -Alkyl is optionally substituted with halogen, hydroxy, cyano, C 3~6 -cycloalkyl, halo-C 3~6 -cycloalkyl, C 1~3-Alkoxy, Halo-C 1~3 -alkoxy, C 3~6 -Cycloalkoxy, halo-C 3~6 -cycloalkoxy, C 1~3 -Alkoxy-C 1~3 -substituted with one or more substituents independently selected from the group consisting of alkoxy, oxetanyl, tetrahydrofuranyl, tetrahydrofuranyloxy, tetrahydropyranyl, morpholinyl, pyrazolyl, isoxazolyl, triazolyl, and pyridinyl; oxetanyl, tetrahydrofuranyl, tetrahydrofuranyloxy, tetrahydropyranyl, morpholinyl, pyrazolyl, isoxazolyl, triazolyl, and pyridinyl are optionally substituted with one or more substituents independently selected from the group consisting of halogen, C 1~3 -Alkyl and halo-C 1~3 In another embodiment, R is substituted with one or more substituents independently selected from the group consisting of: -alkyl. 2 is C 1~6 -alkyl, C 1~6 -Alkyl is optionally substituted with halogen, hydroxy, C 1~6 -Alkoxy, Halo-C 1~6 -alkoxy, C 3~6 -cycloalkoxy, C 1~6 -Alkoxy-C 1~6 -substituted with one or more substituents independently selected from the group consisting of alkoxy, tetrahydrofuranyl, tetrahydrofuranyloxy, tetrahydropyranyl, morpholinyl, pyrazolyl, isoxazolyl, triazolyl, and pyridinyl; tetrahydrofuranyl, tetrahydrofuranyloxy, tetrahydropyranyl, morpholinyl, pyrazolyl, isoxazolyl, triazolyl, and pyridinyl are optionally substituted with one or more substituents independently selected from the group consisting of halogen, C 1~6 -Alkyl and halo-C 1~6 In another embodiment, R is substituted with one or more substituents independently selected from the group consisting of: -alkyl. 2 is C 1~3 -alkyl, C 1~3 -Alkyl is optionally substituted with halogen, hydroxy, C 1~3 -Alkoxy, Halo-C 1~3 -alkoxy, C 3~6 -cycloalkoxy, C1~3 -Alkoxy-C 1~3 -substituted with one or more substituents independently selected from the group consisting of alkoxy, tetrahydrofuranyl, tetrahydrofuranyloxy, tetrahydropyranyl, morpholinyl, pyrazolyl, isoxazolyl, triazolyl, and pyridinyl; tetrahydrofuranyl, tetrahydrofuranyloxy, tetrahydropyranyl, morpholinyl, pyrazolyl, isoxazolyl, triazolyl, and pyridinyl are optionally substituted with one or more substituents independently selected from the group consisting of halogen, C 1~3 -Alkyl and halo-C 1~6 -substituted with one or more substituents independently selected from the group consisting of alkyl;

[0072] In some embodiments, R 2 is C 1~6 -alkyl. In one aspect, R 2 is C 1~3 -alkyl. In one aspect, R 2 is methyl.

[0073] In some embodiments, R 2 is C 1~6 -alkyl, C 1~6 -alkyl is optionally substituted with one or more halogens. 2 is C 1~6 -alkyl, C 1~6 The -alkyl is optionally substituted with one or more fluoro.

[0074] In some embodiments, R 2 is C 1~6 -alkyl, C 1~6 The -alkyl is optionally substituted with one or more hydroxy.

[0075] In some embodiments, R 2 is C 1~6 -alkyl, C 1~6 -Alkyl optionally has one or more C 1~6 -substituted with alkoxy.

[0076] In some embodiments, R 2 is C 1~6 -alkyl, C 1~6 -alkyl optionally contains one or more halo-C 1~6 -substituted with alkoxy.

[0077] In some embodiments, R 2 is C 1~6 -alkyl, C 1~6 -Alkyl optionally has one or more C 3~6 -substituted with cycloalkoxy.

[0078] In some embodiments, R 2 is C 1~6 -alkyl, C 1~6 -Alkyl optionally has one or more C 1~6 -Alkoxy-C 1~6 -substituted with alkoxy.

[0079] In some embodiments, R 2 is C 1~6 -alkyl, C 1~6 -alkyl is optionally substituted with one or more tetrahydrofuranyls, and the tetrahydrofuranyls are optionally substituted with halogen, C 1~6 -Alkyl and halo-C 1~6 -substituted with one or more substituents independently selected from the group consisting of alkyl;

[0080] In some embodiments, R 2 is C 1~6 -alkyl, C 1~6 -alkyl is optionally substituted with one or more tetrahydrofuranyloxy, which is optionally substituted with halogen, C 1~6 -Alkyl and halo-C 1~6 -substituted with one or more substituents independently selected from the group consisting of alkyl;

[0081] In some embodiments, R 2 is C 1~6 -alkyl, C 1~6-alkyl is optionally substituted with one or more tetrahydropyranyls, which are optionally substituted with halogen, C 1~6 -Alkyl and halo-C 1~6 -substituted with one or more substituents independently selected from the group consisting of alkyl;

[0082] In some embodiments, R 2 is C 1~6 -alkyl, C 1~6 -alkyl is optionally substituted with one or more morpholinyls, and the morpholinyls are optionally substituted with halogen, C 1~6 -Alkyl and halo-C 1~6 -substituted with one or more substituents independently selected from the group consisting of alkyl;

[0083] In some embodiments, R 2 is C 1~6 -alkyl, C 1~6 -alkyl is optionally substituted with one or more pyrazolyls, the pyrazolyls are optionally substituted with halogen, C 1~6 -Alkyl and halo-C 1~6 -substituted with one or more substituents independently selected from the group consisting of alkyl;

[0084] In some embodiments, R 2 is C 1~6 -alkyl, C 1~6 -alkyl is optionally substituted with one or more isoxazolyl, and the isoxazolyl is optionally substituted with halogen, C 1~6 -Alkyl and halo-C 1~6 -substituted with one or more substituents independently selected from the group consisting of alkyl;

[0085] In some embodiments, R 2 is C 1~6 -alkyl, C 1~6 -alkyl is optionally substituted with one or more triazolyls, and the triazolyls are optionally substituted with halogen, C 1~6 -Alkyl and halo-C 1~6-substituted with one or more substituents independently selected from the group consisting of alkyl;

[0086] In some embodiments, R 2 is C 1~6 -alkyl, C 1~6 -alkyl is optionally substituted with one or more pyridinyls, and pyridinyls are optionally substituted with halogen, C 1~6 -Alkyl and halo-C 1~6 -substituted with one or more substituents independently selected from the group consisting of alkyl;

[0087] In some embodiments, R 2 is selected from the group consisting of methyl, fluoromethyl, difluoromethyl, trifluoromethyl, hydroxylethyl, hydroxypropyl, ethoxymethyl, difluoroethoxymethyl, methoxyethyl, dimethoxyethyl, difluoropropyl, trifluoropropyl, methoxypropyl, methoxyethoxymethyl, cyclopropoxymethyl, morpholinylmethyl, tetrahydrofuranylmethyl, tetrahydrofuranyloxymethyl, tetrahydropyranylmethyl, pyrazolylmethyl, dimethylpyrazolylmethyl, methylisoxazolylmethyl, methylisoxazolylethyl, methyltriazolylmethyl, dimethyltriazolylmethyl, dimethylpyridinylmethyl, methylpyridinylethyl, fluoropyridinylethyl, chloropyridinylethyl, and trifluoromethylpyridinylethyl.

[0088] In some embodiments, the compounds and pharmaceutically acceptable salts are N-(2-((R)-4-cyanothiazolidin-3-yl)-2-oxoethyl)-6-((RS)-1-(3-fluoropyridin-2-yl)-ethyl)quinoline-4-carboxamide (Example 12); (R)—N-(2-(4-cyanothiazolidin-3-yl)-2-oxoethyl)-6-(2-hydroxypropan-2-yl)quinoline-4-carboxamide (Example 16); (R)—N-(2-(4-cyanothiazolidin-3-yl)-2-oxoethyl)-6-(trifluoromethyl)-quinoline-4-carboxamide (Example 17); (R)—N-(2-(4-cyanothiazolidin-3-yl)-2-oxoethyl)-6-(2-methoxypropan-2-yl)quinoline-4-carboxamide (Example 18); (R)—N-(2-(4-cyanothiazolidin-3-yl)-2-oxoethyl)-6-((2,5-dimethyl-2H-1,2,3-triazol-4-yl)-methyl)quinoline-4-carboxamide (Example 19); (R)—N-(2-(4-cyanothiazolidin-3-yl)-2-oxoethyl)-6-(morpholino-methyl)quinoline-4-carboxamide (Example 24); N-(2-((R)-4-cyanothiazolidin-3-yl)-2-oxoethyl)-6-((RS)-1-hydroxyethyl)quinoline-4-carboxamide (Example 25); N-(2-((R)-4-cyanothiazolidin-3-yl)-2-oxoethyl)-6-((RS)-1-methoxyethyl)quinoline-4-carboxamide (Example 26); (R)—N-(2-(4-cyanothiazolidin-3-yl)-2-oxoethyl)-6-(ethoxymethyl)-quinoline-4-carboxamide (Example 27); (R)—N-(2-(4-cyanothiazolidin-3-yl)-2-oxoethyl)-6-methylquinoline-4-carboxamide (Example 28); (R)—N-(2-(4-cyanothiazolidin-3-yl)-2-oxoethyl)-6-(fluoromethyl)-quinoline-4-carboxamide (Example 29); N-(2-((R)-4-cyanothiazolidin-3-yl)-2-oxoethyl)-6-((RS)-1,2-dimethoxyethyl)quinoline-4-carboxamide (Example 30); (R)—N-(2-(4-cyanothiazolidin-3-yl)-2-oxoethyl)-6-((2-methoxyethoxy)-methyl)quinoline-4-carboxamide (Example 31); N-(2-((R)-4-cyanothiazolidin-3-yl)-2-oxoethyl)-6-(((RS)-tetrahydrofuran-3-yl)oxy)-methyl)quinoline-4-carboxamide (Example 35); (R)—N-(2-(4-cyanothiazolidin-3-yl)-2-oxoethyl)-6-((2,2-difluoroethoxy)methyl)quinoline-4-carboxamide (Example 36); (R)—N-(2-(4-cyanothiazolidin-3-yl)-2-oxoethyl)-6-(cyclopropoxy-methyl)quinoline-4-carboxamide (Example 37); (R)—N-(2-(4-cyanothiazolidin-3-yl)-2-oxoethyl)-6-((4-methylisoxazol-3-yl)methyl)-quinoline-4-carboxamide (Example 38); (R)—N-(2-(4-cyanothiazolidin-3-yl)-2-oxoethyl)-6-((4,6-dimethylpyridin-3-yl)-methyl)quinoline-4-carboxamide (Example 39); (R)—N-(2-(4-cyanothiazolidin-3-yl)-2-oxoethyl)-6-((1,3-dimethyl-1H-pyrazol-5-yl)-methyl)quinoline-4-carboxamide (Example 40); (R)—N-(2-(4-cyanothiazolidin-3-yl)-2-oxoethyl)-6-((2-methyl-2H-1,2,3-triazol-4-yl)-methyl)quinoline-4-carboxamide (Example 41); (R)—N-(2-(4-cyanothiazolidin-3-yl)-2-oxoethyl)-6-((5-methylisoxazol-3-yl)-methyl)quinoline-4-carboxamide (Example 42); N-(2-((R)-4-cyanothiazolidin-3-yl)-2-oxoethyl)-6-((RS)-1-(5-methylisoxazol-3-yl)-ethyl)quinoline-4-carboxamide (Example 46); 6-((RS)-1-(5-chloropyridin-2-yl)ethyl)-N-(2-((R)-4-cyanothiazolidin-3-yl)-2-oxoethyl)quinoline-4-carboxamide (Example 48); N-(2-((R)-4-cyanothiazolidin-3-yl)-2-oxoethyl)-6-((RS)-1-(3-methylisoxazol-5-yl)-ethyl)quinoline-4-carboxamide (Example 49); N-(2-((R)-4-cyanothiazolidin-3-yl)-2-oxoethyl)-6-((RS)-1-(6-methylpyridin-3-yl)-ethyl)quinoline-4-carboxamide (Example 51); N-(2-((R)-4-cyanothiazolidin-3-yl)-2-oxoethyl)-6-((RS)-1-(2-(trifluoromethyl)pyridin-4-yl)-ethyl)quinoline-4-carboxamide (Example 52); (R)—N-(2-(4-cyanothiazolidin-3-yl)-2-oxoethyl)-6-(2,2-difluoropropyl)quinoline-4-carboxamide (Example 53); (R)—N-(2-(4-cyanothiazolidin-3-yl)-2-oxoethyl)-6-(tetrahydro-2H-pyran-4-yl)-methyl)quinoline-4-carboxamide (Example 56); (R)—N-(2-(4-cyanothiazolidin-3-yl)-2-oxoethyl)-6-(3,3,3-trifluoropropyl)quinoline-4-carboxamide (Example 58); N-(2-((R)-4-cyanothiazolidin-3-yl)-2-oxoethyl)-6-(((RS)-tetrahydrofuran-3-yl)-methyl)quinoline-4-carboxamide (Example 65); (R)—N-(2-(4-cyanothiazolidin-3-yl)-2-oxoethyl)-6-(difluoromethyl)-quinoline-4-carboxamide (Example 71); (R)-6-((1H-pyrazol-1-yl)methyl)-N-(2-(4-cyanothiazolidin-3-yl)-2-oxoethyl)quinoline-4-carboxamide (Example 80); (R)—N-(2-(4-cyanothiazolidin-3-yl)-2-oxoethyl)-6-(3-methoxypropyl)quinoline-4-carboxamide (Example 81); (R)—N-(2-(4-cyanothiazolidin-3-yl)-2-oxoethyl)-6-(2-methoxyethyl)quinoline-4-carboxamide (Example 82); and pharmaceutically acceptable salts thereof.

[0089] CR 2 is C 3~6 -cycloalkyl In some embodiments, the 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 2 is C 3~6 -cycloalkyl, C 3~6 -cycloalkyl is optionally substituted with halogen, hydroxy, cyano, C 1~6 -Alkyl, Halo-C 1~6 -Alkyl, C 1~6 -Alkoxy, Halo-C 1~6 -substituted with one or more substituents independently selected from the group consisting of alkoxy, isoxazolyl, and pyridinyl; isoxazolyl and pyridinyl are optionally substituted with halogen, C 1~6 -Alkyl and halo-C 1~6 In one aspect, R is substituted with one or more substituents independently selected from the group consisting of: -alkyl. 2 is C 3~6 -cycloalkyl, C 3~6 -cycloalkyl is optionally substituted with halogen, hydroxy, cyano, C 1~3 -Alkyl, Halo-C 1~3 -Alkyl, C 1~3 -Alkoxy, Halo-C 1~3 -substituted with one or more substituents independently selected from the group consisting of alkoxy, isoxazolyl, and pyridinyl; isoxazolyl and pyridinyl are optionally substituted with halogen, C 1~3 -Alkyl and halo-C1~3 In another embodiment, R is substituted with one or more substituents independently selected from the group consisting of: -alkyl. 2 is C 3~6 -cycloalkyl, C 3~6 -cycloalkyl is optionally substituted with halogen, cyano, C 1~6 -substituted with one or more substituents independently selected from the group consisting of alkoxy, isoxazolyl, and pyridinyl; isoxazolyl and pyridinyl are optionally substituted with halogen, C 1~6 -Alkyl and halo-C 1~6 In another embodiment, R is substituted with one or more substituents independently selected from the group consisting of: -alkyl. 2 is C 3~6 -cycloalkyl, C 3~6 -cycloalkyl is optionally substituted with halogen, cyano, C 1~3 -substituted with one or more substituents independently selected from the group consisting of alkoxy, isoxazolyl, and pyridinyl; isoxazolyl and pyridinyl are optionally substituted with halogen, C 1~3 -Alkyl and halo-C 1~3 -substituted with one or more substituents independently selected from the group consisting of alkyl;

[0090] In some embodiments, R 2 is optionally substituted cyclopropyl.

[0091] In some embodiments, R 2 is optionally substituted cyclobutyl.

[0092] In some embodiments, R 2 is optionally substituted cyclopentyl.

[0093] In some embodiments, R 2 is optionally substituted cyclohexyl.

[0094] In some embodiments, R 2 is the unsubstituted C 3~6 -cycloalkyl.

[0095] In some embodiments, R 2 is C 3~6 -cycloalkyl, C 3~6 -cycloalkyl is optionally substituted with one or more halogens.

[0096] In some embodiments, R 2 is C 3~6 -cycloalkyl, C 3~6 -cycloalkyl is optionally substituted with one or more cyano.

[0097] In some embodiments, R 2 is C 3~6 -cycloalkyl, C 3~6 -cycloalkyl optionally includes one or more C 1~6 -substituted with alkoxy.

[0098] In some embodiments, R 2 is C 3~6 -cycloalkyl, C 3~6 -cycloalkyl is optionally substituted with one or more isoxazolyl, wherein the isoxazolyl is optionally substituted with halogen, C 1~6 -Alkyl and halo-C 1~6 -substituted with one or more substituents independently selected from the group consisting of alkyl;

[0099] In some embodiments, R 2 is C 3~6 -cycloalkyl, C 3~6 -cycloalkyl is optionally substituted with one or more pyridinyls, wherein the pyridinyls are optionally substituted with halogen, C 1~6 -Alkyl and halo-C 1~6 -substituted with one or more substituents independently selected from the group consisting of alkyl;

[0100] In some embodiments, R 2is selected from the group consisting of cyclopropyl, cyanocyclopropyl, ethoxycyclopropyl, methylisoxazolylcyclopropyl, methylpyridinylcyclopropyl, chloropyridinylcyclopropyl, fluoropyridinylcyclopropyl, trifluoropyridinylcyclopropyl, fluorocyclobutyl, (fluoro)(methoxy)cyclobutyl, methoxycyclohexyl, and cyanocyclohexyl.

[0101] In some embodiments, the compounds and pharmaceutically acceptable salts are (R)—N-(2-(4-cyanothiazolidin-3-yl)-2-oxoethyl)-6-(1-(2-(trifluoromethyl)pyridin-4-yl)-cyclopropyl)quinoline-4-carboxamide (Example 13); (R)—N-(2-(4-cyanothiazolidin-3-yl)-2-oxoethyl)-6-(1-(6-methylpyridin-3-yl)-cyclopropyl)quinoline-4-carboxamide (Example 43); (R)—N-(2-(4-cyanothiazolidin-3-yl)-2-oxoethyl)-6-(1-(3-fluoropyridin-2-yl)-cyclopropyl)quinoline-4-carboxamide (Example 44); (R)—N-(2-(4-cyanothiazolidin-3-yl)-2-oxoethyl)-6-(1-(5-methylisoxazol-3-yl)-cyclopropyl)quinoline-4-carboxamide (Example 45); (R)-6-(1-(5-chloropyridin-2-yl)cyclopropyl)-N-(2-(4-cyanothiazolidin-3-yl)-2-oxoethyl)quinoline-4-carboxamide (Example 47); (R)—N-(2-(4-cyanothiazolidin-3-yl)-2-oxoethyl)-6-(1-(3-methylisoxazol-5-yl)-cyclopropyl)quinoline-4-carboxamide (Example 50); 6-((1r,4R *)-4-cyanocyclohexyl)-N-(2-((R-4-cyanothiazolidin-3-yl)-2-oxoethyl)-quinoline-4-carboxamide Isomer 1 (Example 54); 6-((1r,4R * )-4-cyanocyclohexyl)-N-(2-((R)-4-cyanothiazolidin-3-yl)-2-oxoethyl)-quinoline-4-carboxamide Isomer 2 (Example 55); (R)-6-(1-cyanocyclohexyl)-N-(2-(4-cyanothiazolidin-3-yl)-2-oxoethyl)quinoline-4-carboxamide (Example 60); N-(2-((R)-4-cyanothiazolidin-3-yl)-2-oxoethyl)-6-((1r,3R * )-1-fluoro-3-methoxy-cyclobutyl)quinoline-4-carboxamide Isomer 1 (Example 62); N-(2-((R)-4-cyanothiazolidin-3-yl)-2-oxoethyl)-6-((1r,3R * )-1-fluoro-3-methoxy-cyclobutyl)quinoline-4-carboxamide Isomer 2 (Example 63); (R)-6-(1-cyanocyclopropyl)-N-(2-(4-cyanothiazolidin-3-yl)-2-oxoethyl)quinoline-4-carboxamide (Example 70); (R)—N-(2-(4-cyanothiazolidin-3-yl)-2-oxoethyl)-6-(1-fluoro-cyclobutyl)quinoline-4-carboxamide (Example 75); (R)—N-(2-(4-cyanothiazolidin-3-yl)-2-oxoethyl)-6-(1-ethoxycyclopropyl)quinoline-4-carboxamide (Example 76); (R)—N-(2-(4-cyanothiazolidin-3-yl)-2-oxoethyl)-6-cyclopropylquinoline-4-carboxamide (Example 77); N-(2-((R)-4-cyanothiazolidin-3-yl)-2-oxoethyl)-6-((1r,4R * )-4-Methoxycyclohexyl)-quinoline-4-carboxamide Isomer 1 (Example 78); N-(2-((R)-4-cyanothiazolidin-3-yl)-2-oxoethyl)-6-((1r,4R * )-4-Methoxycyclohexyl)-quinoline-4-carboxamide Isomer 2 (Example 79); and pharmaceutically acceptable salts thereof.

[0102] DR 2 is phenyl In some embodiments, the 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 2 is phenyl, and the phenyl is optionally selected from halogen, cyano, C 1~6 -Alkyl, Halo-C 1~6 -Alkyl, C 1~6 -Alkoxy, Halo-C 1~6 -alkoxy, and C 1~6 -Alkoxy-C 1~6 In one aspect, R is substituted with one or more substituents independently selected from the group consisting of: -alkoxy. 2 is phenyl, and the phenyl is optionally selected from halogen, cyano, C 1~3 -Alkyl, Halo-C 1~3 -Alkyl, C 1~3 -Alkoxy, Halo-C 1~3 -alkoxy, and C 1~3 -Alkoxy-C 1~3 -substituted with one or more substituents independently selected from the group consisting of: -alkoxy;

[0103] In some embodiments, R 2 is phenyl, which is optionally substituted with one or more halogens.

[0104] In some embodiments, R 2 is phenyl, and the phenyl optionally has one or more C 1~6 -substituted with alkyl.

[0105] In some embodiments, R 2 is phenyl, which optionally contains one or more halo-C 1~6 -substituted with alkyl.

[0106] In some embodiments, R 2 is phenyl, and the phenyl optionally has one or more C 1~6 -substituted with alkoxy.

[0107] In some embodiments, R 2 is phenyl, which optionally contains one or more halo-C 1~6 -substituted with alkoxy.

[0108] In some embodiments, R 2 is phenyl, and the phenyl optionally has one or more C 1~6 -Alkoxy-C 1~6 -substituted with alkoxy.

[0109] In some embodiments, the compound is (R)—N-(2-(4-cyanothiazolidin-3-yl)-2-oxoethyl)-6-(4-(3-methoxy-propoxy)phenyl)quinoline-4-carboxamide, or a pharmaceutically acceptable salt thereof (Example 72).

[0110] ER 2 is a 5-, 6-, or 7-membered heterocyclyl In some embodiments, the 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 2 is a 4-, 5-, 6-, or 7-membered heterocyclyl, wherein the heterocyclyl ring (i) is a saturated, partially saturated, or fully unsaturated monocyclic or fused bicyclic ring; (ii) has one or two oxygen ring atoms, the remaining ring atoms being carbon; and (iii) optionally contains halogen, hydroxy, cyano, C 1~6 -Alkyl, Halo-C 1~6-Alkyl, C 2~6 -alkynyl, C 1~6 -alkoxy and halo-C 1~6 In one aspect, R is substituted with one or more substituents independently selected from the group consisting of: -alkoxy. 2 is a 4-, 5-, 6-, or 7-membered heterocyclyl, wherein the heterocyclyl ring (i) is a saturated, partially saturated, or fully unsaturated monocyclic or fused bicyclic ring; (ii) has one or two oxygen ring atoms, the remaining ring atoms being carbon; and (iii) optionally contains halogen, hydroxy, cyano, C 1~3 -Alkyl, Halo-C 1~3 -Alkyl, C 2~3 -alkynyl, C 1~3 -alkoxy and halo-C 1~-3 -substituted with one or more substituents independently selected from the group consisting of: -alkoxy;

[0111] In some embodiments, R 2 is a 5- or 6-membered heterocyclyl, the heterocyclyl ring being (i) a saturated, partially saturated, or fully unsaturated monocyclic or fused bicyclic ring; (ii) having one or two oxygen ring atoms with the remaining ring atoms being carbon; and (iii) optionally containing halogen, hydroxy, cyano, C 1~3 -Alkyl, C 2~3 -alkynyl, and C 1~3 -substituted with one or more substituents independently selected from the group consisting of: -alkoxy;

[0112] In some embodiments, R 2 is a 4-membered heterocyclyl, the heterocyclyl ring being (i) a saturated or partially saturated monocyclic ring, (ii) having one oxygen ring atom with the remaining ring atoms being carbon, and (iii) optionally containing halogen, hydroxy, cyano, C 1~6 -Alkyl, Halo-C 1~6 -Alkyl, C 2~6 -alkynyl, C 1~6 -alkoxy and halo-C 1~6 In one aspect, R is substituted with one or more substituents independently selected from the group consisting of: -alkoxy. 2is a 4-membered heterocyclyl, the heterocyclyl ring being (i) a saturated or partially saturated monocyclic ring, (ii) having one oxygen ring atom with the remaining ring atoms being carbon, and (iii) optionally containing halogen, hydroxy, cyano, C 1~3 -Alkyl, Halo-C 1~3 -Alkyl, C 2~3 -alkynyl, C 1~3 -alkoxy and halo-C 1~3 -substituted with one or more substituents independently selected from the group consisting of: -alkoxy;

[0113] In some embodiments, R 2 is a 5-membered heterocyclyl, the heterocyclyl ring (i) being a saturated, partially saturated, or fully unsaturated monocyclic ring; (ii) having one or two oxygen ring atoms, the remaining ring atoms being carbon; and (iii) optionally containing halogen, hydroxy, cyano, C 1~6 -Alkyl, Halo-C 1~6 -Alkyl, C 2~6 -alkynyl, C 1~6 -alkoxy and halo-C 1~6 In one aspect, R is substituted with one or more substituents independently selected from the group consisting of: -alkoxy. 2 is a 5-membered heterocyclyl, the heterocyclyl ring (i) being a saturated, partially saturated, or fully unsaturated monocyclic ring; (ii) having one or two oxygen ring atoms, the remaining ring atoms being carbon; and (iii) optionally containing halogen, hydroxy, cyano, C 1~3 -Alkyl, Halo-C 1~3 -Alkyl, C 2~3 -alkynyl, C 1~3 -alkoxy and halo-C 1~3 -substituted with one or more substituents independently selected from the group consisting of: -alkoxy;

[0114] In some embodiments, R 2is a 6-membered heterocyclyl, the heterocyclyl ring (i) being a saturated, partially saturated, or fully unsaturated monocyclic ring; (ii) having one or two oxygen ring atoms, the remaining ring atoms being carbon; and (iii) optionally containing halogen, hydroxy, cyano, C 1~6 -Alkyl, Halo-C 1~6 -Alkyl, C 2~6 -alkynyl, C 1~6 -alkoxy and halo-C 1~6 In one aspect, R is substituted with one or more substituents independently selected from the group consisting of: -alkoxy. 2 is a 6-membered heterocyclyl, the heterocyclyl ring (i) being a saturated, partially saturated, or fully unsaturated monocyclic ring; (ii) having one or two oxygen ring atoms, the remaining ring atoms being carbon; and (iii) optionally containing halogen, hydroxy, cyano, C 1~3 -Alkyl, Halo-C 1~3 -Alkyl, C 2~3 -alkynyl, C 1~3 -alkoxy and halo-C 1~3 -substituted with one or more substituents independently selected from the group consisting of: -alkoxy;

[0115] In some embodiments, R 2 is a seven-membered heterocyclyl, the heterocyclyl ring (i) being saturated, partially saturated, or fully unsaturated, monocyclic or fused bicyclic ring; (ii) having one or two oxygen ring atoms, the remaining ring atoms being carbon; and (iii) optionally containing halogen, hydroxy, cyano, C 1~6 -Alkyl, Halo-C 1~6 -Alkyl, C 2~6 -alkynyl, C 1~6 -alkoxy and halo-C 1~6 In one aspect, R is substituted with one or more substituents independently selected from the group consisting of: -alkoxy. 2 is a seven-membered heterocyclyl, the heterocyclyl ring (i) being saturated, partially saturated, or fully unsaturated, monocyclic or fused bicyclic ring; (ii) having one or two oxygen ring atoms, the remaining ring atoms being carbon; and (iii) optionally containing halogen, hydroxy, cyano, C 1~3-Alkyl, Halo-C 1~3 -Alkyl, C 2~3 -alkynyl, C 1~3 -alkoxy and halo-C 1~3 -substituted with one or more substituents independently selected from the group consisting of: -alkoxy;

[0116] In some embodiments, R 2 is selected from the group consisting of tetrahydrofuranyl, furanyl, dihydropyranyl, tetrahydropyranyl, 1,4-dioxanyl, and 3-oxabicyclo[4.1.0]heptane, wherein tetrahydrofuranyl, dihydropyranyl, tetrahydropyranyl, 1,4-dioxanyl, and 3-oxabicyclo[4.1.0]heptane are optionally selected from the group consisting of halogen, hydroxy, cyano, C 1~6 -Alkyl, Halo-C 1~6 -Alkyl, C 2~6 -alkynyl, C 1~6 -alkoxy and halo-C 1~6 In one aspect, R is substituted with one or more substituents independently selected from the group consisting of: -alkoxy. 2 is selected from the group consisting of tetrahydrofuranyl, furanyl, dihydropyranyl, tetrahydropyranyl, 1,4-dioxanyl, and 3-oxabicyclo[4.1.0]heptane, wherein tetrahydrofuranyl, dihydropyranyl, tetrahydropyranyl, 1,4-dioxanyl, and 3-oxabicyclo[4.1.0]heptane are optionally selected from the group consisting of halogen, hydroxy, cyano, C 1~3 -Alkyl, Halo-C 1~3 -Alkyl, C 2~3 -alkynyl, C 1~3 -alkoxy and halo-C 1~3 -substituted with one or more substituents independently selected from the group consisting of: -alkoxy;

[0117] In some embodiments, R 2 is substituted with tetrahydrofuranyl, which is optionally substituted with halogen, hydroxy, cyano, C 1~6 -Alkyl, Halo-C 1~6 -Alkyl, C 2~6-alkynyl, C 1~6 -alkoxy and halo-C 1~6 -substituted with one or more substituents independently selected from the group consisting of: -alkoxy;

[0118] In some embodiments, R 2 is substituted with tetrahydropyranyl, which is optionally substituted with halogen, hydroxy, cyano, C 1~6 -Alkyl, Halo-C 1~6 -Alkyl, C 2~6 -alkynyl, C 1~6 -alkoxy and halo-C 1~6 -substituted with one or more substituents independently selected from the group consisting of: -alkoxy;

[0119] In some embodiments, R 2 is substituted with dihydropyranyl, which is optionally substituted with halogen, hydroxy, cyano, C 1~6 -Alkyl, Halo-C 1~6 -Alkyl, C 2~6 -alkynyl, C 1~6 -alkoxy and halo-C 1~6 -substituted with one or more substituents independently selected from the group consisting of: -alkoxy;

[0120] In some embodiments, R 2 is substituted with 1,4-dioxanyl, and the 1,4-dioxanyl is optionally substituted with halogen, hydroxy, cyano, C 1~6 -Alkyl, Halo-C 1~6 -Alkyl, C 2~6 -alkynyl, C 1~6 -alkoxy and halo-C 1~6 -substituted with one or more substituents independently selected from the group consisting of: -alkoxy;

[0121] In some embodiments, R 2 is substituted with 3-oxabicyclo[4.1.0]heptane, which is optionally substituted with halogen, hydroxy, cyano, C 1~6 -Alkyl, Halo-C1~6 -Alkyl, C 2~6 -alkynyl, C 1~6 -alkoxy and halo-C 1~6 -substituted with one or more substituents independently selected from the group consisting of: -alkoxy;

[0122] In some embodiments, R 2 is selected from the group consisting of tetrahydrofuranyl, furanyl, dimethyltetrahydrofuranyl, dihydropyranyl, tetrahydropyranyl, hydroxytetrahydropyranyl, fluorotetrahydropyranyl, cyanotetrahydropyranyl, methyltetrahydropyranyl, dimethyltetrahydropyranyl, methoxytetrahydropyranyl, ethoxytetrahydropyranyl, 1,4-dioxanyl, and 3-oxabicyclo[4.1.0]heptane.

[0123] In some embodiments, the compounds and pharmaceutically acceptable salts are (R)—N-(2-(4-cyanothiazolidin-3-yl)-2-oxoethyl)-6-(furan-3-yl)quinoline-4-carboxamide (Example 14); (R)—N-(2-(4-cyanothiazolidin-3-yl)-2-oxoethyl)-6-(4-hydroxy-tetrahydro-2H-pyran-4-yl)-quinoline-4-carboxamide (Example 15); (R)—N-(2-(4-cyanothiazolidin-3-yl)-2-oxoethyl)-6-(tetrahydro-2H-pyran-4-yl)quinoline-4-carboxamide (Example 20); (R)—N-(2-(4-cyanothiazolidin-3-yl)-2-oxoethyl)-6-(4-methyl-tetrahydro-2H-pyran-4-yl)-quinoline-4-carboxamide (Example 21); (R)—N-(2-(4-cyanothiazolidin-3-yl)-2-oxoethyl)-6-(3,6-dihydro-2H-pyran-4-yl)quinoline-4-carboxamide (Example 22); (R)—N-(2-(4-cyanothiazolidin-3-yl)-2-oxoethyl)-6-(4-ethoxytetrahydro-2H-pyran-4-yl)-quinoline-4-carboxamide (Example 23); N-(2-((R)-4-cyanothiazolidin-3-yl)-2-oxoethyl)-6-((RS)-tetrahydro-2H-pyran-2-yl)-quinoline-4-carboxamide (Example 32); N-(2-((R)-4-cyanothiazolidin-3-yl)-2-oxoethyl)-6-((RS)-1,4-dioxan-2-yl)quinoline-4-carboxamide (Example 33); N-(2-((R)-4-cyanothiazolidin-3-yl)-2-oxoethyl)-6-((RS)-tetrahydrofuran-2-yl)quinoline-4-carboxamide (Example 34); (R)—N-(2-(4-cyanothiazolidin-3-yl)-2-oxoethyl)-6-(4-ethynyl-tetrahydro-2H-pyran-4-yl)-quinoline-4-carboxamide (Example 57); (R)-6-(4-cyanotetrahydro-2H-pyran-4-yl)-N-(2-(4-cyanothiazolidin-3-yl)-2-oxoethyl)-quinoline-4-carboxamide (Example 59); N-(2-((R-4-cyanothiazolidin-3-yl)-2-oxoethyl)-6-(5,5-dimethyltetrahydrofuran-3-yl)-quinoline-4-carboxamide (Example 61); (R)—N-(2-(4-cyanothiazolidin-3-yl)-2-oxoethyl)-6-(4-fluorotetrahydro-2H-pyran-4-yl)-quinoline-4-carboxamide (Example 64); (R)—N-(2-(4-cyanothiazolidin-3-yl)-2-oxoethyl)-6-(4-methoxy-tetrahydro-2H-pyran-4-yl)quinoline-4-carboxamide (Example 66); N-(2-((R-4-cyanothiazolidin-3-yl)-2-oxoethyl)-6-((RS)-tetrahydrofuran-3-yl)quinoline-4-carboxamide (Example 67); N-(2-((R)-4-cyanothiazolidin-3-yl)-2-oxoethyl)-6-((RS)-2,2-dimethyltetrahydro-2H-pyran-4-yl)quinoline-4-carboxamide (Example 68); 6-((1RS,6SR)-3-oxabicyclo[4.1.0]heptan-6-yl)-N-(2-((R)-4-cyanothiazolidin-3-yl)-2-oxoethyl)quinoline-4-carboxamide (Example 69); and pharmaceutically acceptable salts thereof.

[0124] FR 2 -OR 7 is In some embodiments, the 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 2 -OR 7 and R 7 is C 1~6 - selected from the group consisting of alkyl, phenyl and tetrahydropyranyl; (I C 1~6 -Alkyl is optionally substituted with halogen, cyano, C 3~6 -cycloalkyl, halo-C 3~6 -cycloalkyl, C 1~6 -alkoxy and halo-C 1~6 -substituted with one or more substituents independently selected from the group consisting of alkoxy; (ii) phenyl optionally containing halogen, C 1~6 -Alkyl, Halo-C 1~6 -Alkyl, C 1~6 -alkoxy and halo-C 1~6 -substituted with one or more substituents independently selected from the group consisting of alkoxy; (iii) tetrahydropyranyl optionally containing halogen, C 1~6 -Alkyl, Halo-C 1~6 -Alkyl, C 1~6 -alkoxy and halo-C 1~6-substituted with one or more substituents independently selected from the group consisting of: -alkoxy;

[0125] In some embodiments, R 2 -OR 7 and R 7 is C 1~4 - selected from the group consisting of alkyl, phenyl, and tetrahydropyranyl; (I C 1~4 -Alkyl is optionally substituted with halogen, cyano, C 3~6 -cycloalkyl, halo-C 3~6 -cycloalkyl, C 1~3 -alkoxy and halo-C 1~3 -substituted with one or more substituents independently selected from the group consisting of alkoxy; (ii) phenyl optionally containing halogen, C 1~3 -Alkyl, Halo-C 1~3 -Alkyl, C 1~3 -alkoxy and halo-C 1~3 -substituted with one or more substituents independently selected from the group consisting of alkoxy; (iii) tetrahydropyranyl optionally containing halogen, C 1~3 -Alkyl, Halo-C 1~3 -Alkyl, C 1~3 -alkoxy and halo-C 1~3 -substituted with one or more substituents independently selected from the group consisting of: -alkoxy;

[0126] In some embodiments, R 2 -OR 7 and R 7 is C 1~6 - selected from the group consisting of alkyl, phenyl, and tetrahydropyranyl; (I C 1~6 -Alkyl is optionally substituted with halogen, cyano, C 3~6 -cycloalkyl, halo-C 3~6 -cycloalkyl, and C 1~6 -substituted with one or more substituents independently selected from the group consisting of alkoxy; (ii) tetrahydropyranyl is optionally one or C 1~6 -substituted with alkyl.

[0127] In some embodiments, R 2 -OR 7 and R 7 is C 1~4 - selected from the group consisting of alkyl, phenyl, and tetrahydropyranyl; (I C 1~4 -Alkyl is optionally substituted with halogen, cyano, C 3~6 -cycloalkyl, halo-C 3~6 -cycloalkyl, and C 1~3 -substituted with one or more substituents independently selected from the group consisting of alkoxy; (ii) tetrahydropyranyl is optionally one or C 1~3 -substituted with alkyl.

[0128] In some embodiments, R 2 -OR 7 and R 7 is C 1~6 -alkyl, C 1~6 -Alkyl is optionally substituted with halogen, cyano, C 3~6 -cycloalkyl, halo-C 3~6 -cycloalkyl, C 1~6 -alkoxy and halo-C 1~6 -substituted with one or more substituents independently selected from the group consisting of: -alkoxy;

[0129] In some embodiments, R 2 -OR 7 and R 7 is C 1~4 -alkyl, C 1~4 -Alkyl is optionally substituted with halogen, cyano, C 3~6 -cycloalkyl, halo-C 3~6 -cycloalkyl, and C 1~3 -substituted with one or more substituents independently selected from the group consisting of: -alkoxy;

[0130] In some embodiments, R 2 -OR 7 and R 7 is C 1~4 -alkyl, C 1~4 The -alkyl is optionally substituted with one or more substituents independently selected from the group consisting of fluoro.

[0131] In some embodiments, R 2 -OR 7 and R 7 is phenyl, and the phenyl is optionally selected from halogen, C 1~6 -Alkyl, Halo-C 1~6 -Alkyl, C 1~6 -alkoxy and halo-C 1~6 -substituted with one or more substituents independently selected from the group consisting of: -alkoxy;

[0132] In some embodiments, R 2 -OR 7 and R 7 is phenyl.

[0133] In some embodiments, R 2 -OR 7 and R 7 is tetrahydropyranyl; tetrahydropyranyl optionally contains halogen, C 1~6 -Alkyl, Halo-C 1~6 -Alkyl, C 1~6 -alkoxy and halo-C 1~6 -substituted with one or more substituents independently selected from the group consisting of: -alkoxy;

[0134] In some embodiments, R 2 -OR 7 and R 7 is tetrahydropyranyl; tetrahydropyranyl optionally has one or more C 1~3 -substituted with alkyl.

[0135] In some embodiments, R 2 -OR7 and R 7 is tetrahydropyranyl.

[0136] In some embodiments, R 2 -OR 7 and R 7 is selected from the group consisting of cyanomethyl, fluoroethyl, difluoroethyl, propyl, difluoropropyl, fluorobutyl, methoxyethyl, cyclopropylmethyl, difluorocyclobutylmethyl, phenyl, tetrahydropyranyl, and dimethyltetrahydropyranyl.

[0137] In some embodiments, the compounds and pharmaceutically acceptable salts are RN-(2-(4-cyanothiazolidin-3-yl)-2-oxoethyl)-6-phenoxyquinoline-4-carboxamide (Example 1); (R)—N-(2-(4-cyanothiazolidin-3-yl)-2-oxoethyl)-6-(2,2-difluoroethoxy)quinoline-4-carboxamide (Example 2); (R)—N-(2-(4-cyanothiazolidin-3-yl)-2-oxoethyl)-6-(2-fluoro-2-methylpropoxy)quinoline-4-carboxamide (Example 3); (R)—N-(2-(4-cyanothiazolidin-3-yl)-2-oxoethyl)-6-(2-methoxyethoxy)quinoline-4-carboxamide (Example 4); (R)—N-(2-(4-cyanothiazolidin-3-yl)-2-oxoethyl)-6-(cyclopropyl-methoxy)quinoline-4-carboxamide (Example 5); (R)—N-(2-(4-cyanothiazolidin-3-yl)-2-oxoethyl)-6-(tetrahydro-2H-pyran-4-yl)oxy)-quinoline-4-carboxamide (Example 6); (R)—N-(2-(4-cyanothiazolidin-3-yl)-2-oxoethyl)-6-((1,3-difluoropropan-2-yl)oxy)-quinoline-4-carboxamide (Example 7); (R)—N-(2-(4-cyanothiazolidin-3-yl)-2-oxoethyl)-6-((3,3-difluorocyclobutyl)-methoxy)quinoline-4-carboxamide (Example 8); N-(2-((R-4-cyanothiazolidin-3-yl)-2-oxoethyl)-6-(((RS)-2,2-dimethyltetrahydro-2H-pyran-4-yl)oxy)quinoline-4-carboxamide (Example 9); (R)-6-(cyanomethoxy)-N-(2-(4-cyanothiazolidin-3-yl)-2-oxoethyl)quinoline-4-carboxamide (Example 10); (R)—N-(2-(4-cyanothiazolidin-3-yl)-2-oxoethyl)-6-(2,2-difluoropropoxy)quinoline-4-carboxamide (Example 11); (R)—N-(2-(4-cyanothiazolidin-3-yl)-2-oxoethyl)-6-propoxyquinoline-4-carboxamide (Example 73); (R)—N-(2-(4-cyanothiazolidin-3-yl)-2-oxoethyl)-6-(2-fluoroethoxy)-quinoline-4-carboxamide (Example 74); and pharmaceutically acceptable salts thereof.

[0138] G. Additional Embodiments In some embodiments, the 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 2 teeth, (a)C 1~3 -alkyl, optionally containing halogen, hydroxy, cyano, C 3~6 -cycloalkyl, halo-C 3~6 -cycloalkyl, C 1~3 -Alkoxy, Halo-C 1~3 -alkoxy, C 3~6 -Cycloalkoxy, halo-C 3~6 -cycloalkoxy, C 1~3 -Alkoxy-C1~3 -substituted with one or more substituents independently selected from the group consisting of alkoxy, oxetanyl, tetrahydrofuranyl, tetrahydrofuranyloxy, tetrahydropyranyl, morpholinyl, pyrazolyl, isoxazolyl, triazolyl, and pyridinyl; oxetanyl, tetrahydrofuranyl, tetrahydrofuranyloxy, tetrahydropyranyl, morpholinyl, pyrazolyl, isoxazolyl, triazolyl, and pyridinyl are optionally substituted with one or more substituents independently selected from the group consisting of halogen, C 1~3 -Alkyl and halo-C 1~3 -substituted with one or more substituents independently selected from the group consisting of alkyl, C 1~3 - alkyl; (b)C 3~6 -cycloalkyl, optionally containing halogen, cyano, C 1~3 -Alkyl, Halo-C 1~3 -Alkyl, C 1~3 -Alkoxy, Halo-C 1~3 -substituted with one or more substituents independently selected from the group consisting of alkoxy, isoxazolyl, and pyridinyl; isoxazolyl and pyridinyl are optionally substituted with halogen, C 1~3 -Alkyl and halo-C 1~3 -substituted with one or more substituents independently selected from the group consisting of alkyl, C 3~6 -cycloalkyl; (c) phenyl, optionally containing halogen, C 1~3 -Alkyl, Halo-C 1~3 -Alkyl, C 1~3 -Alkoxy, Halo-C 1~3 -alkoxy, and C 1~3 -Alkoxy-C 1~3 -phenyl substituted with one or more substituents independently selected from the group consisting of alkoxy; (d) a 4-, 5-, 6-, or 7-membered heterocyclyl that (i) is saturated or partially saturated, monocyclic or fused bicyclic, (ii) has one or two oxygen ring atoms, the remaining ring atoms being carbon, and (iii) optionally contains halogen, hydroxy, cyano, C 1~3 -Alkyl, Halo-C 1~3 -Alkyl, C2~3 -alkynyl, C 1~3 -alkoxy and halo-C 1~3 -heterocyclyl substituted with one or more substituents independently selected from the group consisting of alkoxy; and (e)-OR 7 and R 7 But C 1~4 - selected from the group consisting of alkyl, phenyl, and tetrahydropyranyl; (I C 1~4 -Alkyl is optionally substituted with halogen, cyano, C 3~6 -cycloalkyl, halo-C 3~6 -cycloalkyl, C 1~3 -alkoxy and halo-C 1~3 -substituted with one or more substituents independently selected from the group consisting of alkoxy; (ii) phenyl optionally containing halogen, C 1~3 -Alkyl, Halo-C 1~3 -Alkyl, C 1~3 -alkoxy and halo-C 1~3 -substituted with one or more substituents independently selected from the group consisting of alkoxy; (iii) tetrahydropyranyl optionally containing halogen, C 1~3 -Alkyl, Halo-C 1~3 -Alkyl, C 1~3 -alkoxy and halo-C 1~3 -OR substituted with one or more substituents independently selected from the group consisting of -alkoxy; 7 , are selected from the group consisting of.

[0139] In some embodiments, the 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 2 teeth, (a)C 3~6 -cycloalkyl, optionally containing halogen, cyano, C 1~3 -Alkyl, Halo-C 1~3 -Alkyl, C 1~3-Alkoxy, Halo-C 1~3 -substituted with one or more substituents independently selected from the group consisting of alkoxy, isoxazolyl, and pyridinyl; isoxazolyl and pyridinyl are optionally substituted with halogen, C 1~3 -Alkyl and halo-C 1~3 -substituted with one or more substituents independently selected from the group consisting of alkyl, C 3~6 -cycloalkyl; (b) a 4-, 5-, 6-, or 7-membered heterocyclyl that (i) is saturated or partially saturated, monocyclic or fused bicyclic, (ii) has one or two oxygen ring atoms, the remaining ring atoms being carbon, and (iii) optionally contains halogen, hydroxy, cyano, C 1~3 -Alkyl, Halo-C 1~3 -Alkyl, C 2~3 -alkynyl, C 1~3 -alkoxy and halo-C 1~3 -heterocyclyl substituted with one or more substituents independently selected from the group consisting of alkoxy; and (c)-OR 7 and R 7 But C 1~4 - selected from the group consisting of alkyl, phenyl, and tetrahydropyranyl; (I C 1~4 -Alkyl is optionally substituted with halogen, cyano, C 3~6 -cycloalkyl, halo-C 3~6 -cycloalkyl, C 1~3 -alkoxy and halo-C 1~3 -substituted with one or more substituents independently selected from the group consisting of alkoxy; (ii) phenyl optionally containing halogen, C 1~3 -Alkyl, Halo-C 1~3 -Alkyl, C 1~3 -alkoxy and halo-C 1~3 -substituted with one or more substituents independently selected from the group consisting of alkoxy; (iii) tetrahydropyranyl optionally containing halogen, C 1~3 -Alkyl, Halo-C 1~3 -Alkyl, C 1~3-alkoxy and halo-C 1~3 -OR substituted with one or more substituents independently selected from the group consisting of -alkoxy; 7 , are selected from the group consisting of.

[0140] In some embodiments, the 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 2 teeth, (a)C 1~6 -alkyl, optionally containing halogen, hydroxy, C 1~6 -Alkoxy, Halo-C 1~6 -alkoxy, C 3~6 -cycloalkoxy, C 1~6 -Alkoxy-C 1~6 -substituted with one or more substituents independently selected from the group consisting of alkoxy, tetrahydrofuranyl, tetrahydrofuranyloxy, tetrahydropyranyl, morpholinyl, pyrazolyl, isoxazolyl, triazolyl, and pyridinyl; tetrahydrofuranyl, tetrahydrofuranyloxy, tetrahydropyranyl, morpholinyl, pyrazolyl, isoxazolyl, triazolyl, and pyridinyl are optionally substituted with one or more substituents independently selected from the group consisting of halogen, C 1~6 -Alkyl and halo-C 1~6 -substituted with one or more substituents independently selected from the group consisting of alkyl, C 1~6 - alkyl; (b)C 3~6 -cycloalkyl, optionally containing halogen, cyano, C 1~6 -substituted with one or more substituents independently selected from the group consisting of alkoxy, isoxazolyl, and pyridinyl; isoxazolyl and pyridinyl are optionally substituted with halogen, C 1~6 -Alkyl and halo-C 1~6 -substituted with one or more substituents independently selected from the group consisting of alkyl, C 3~6 -cycloalkyl; (c) phenyl, optionally containing halogen, C 1~3-Alkyl, Halo-C 1~3 -Alkyl, C 1~3 -Alkoxy, Halo-C 1~3 -alkoxy, and C 1~3 -Alkoxy-C 1~3 -phenyl substituted with one or more substituents independently selected from the group consisting of alkoxy; (d) a 5-, 6-, or 7-membered heterocyclyl that (i) is saturated or partially saturated, monocyclic or fused bicyclic, (ii) has one or two oxygen ring atoms, the remaining ring atoms being carbon, and (iii) optionally contains halogen, hydroxy, cyano, C 1~3 -Alkyl, C 2~3 -alkynyl, and C 1~3 -heterocyclyl substituted with one or more substituents independently selected from the group consisting of alkoxy; and (e)-OR 7 and R 7 But C 1~6 - selected from the group consisting of alkyl, phenyl, and tetrahydropyranyl; (I C 1~6 -Alkyl is optionally substituted with halogen, cyano, C 3~6 -cycloalkyl, halo-C 3~6 -cycloalkyl, and C 1~6 -substituted with one or more substituents independently selected from the group consisting of alkoxy; (ii) tetrahydropyranyl is optionally one or C 1~6 -substituted with alkyl, -OR 7 , are selected from the group consisting of.

[0141] In some embodiments, the 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 2 teeth, (a)C 3~6 -cycloalkyl, optionally containing halogen, cyano, C 1~6-substituted with one or more substituents independently selected from the group consisting of alkoxy, isoxazolyl, and pyridinyl; isoxazolyl and pyridinyl are optionally substituted with halogen, C 1~6 -Alkyl and halo-C 1~6 -substituted with one or more substituents independently selected from the group consisting of alkyl, C 3~6 -cycloalkyl; (b) a 5-, 6-, or 7-membered heterocyclyl that (i) is saturated or partially saturated, monocyclic or fused bicyclic, (ii) has one or two oxygen ring atoms, the remaining ring atoms being carbon, and (iii) optionally contains halogen, hydroxy, cyano, C 1~3 -Alkyl, C 2~3 -alkynyl, and C 1~3 -heterocyclyl substituted with one or more substituents independently selected from the group consisting of alkoxy; and (c)-OR 7 and R 7 But C 1~6 - selected from the group consisting of alkyl, phenyl, and tetrahydropyranyl; (I C 1~6 -Alkyl is optionally substituted with halogen, cyano, C 3~6 -cycloalkyl, halo-C 3~6 -cycloalkyl, and C 1~6 -substituted with one or more substituents independently selected from the group consisting of alkoxy; (ii) tetrahydropyranyl is optionally one or C 1~6 -substituted with alkyl, -OR 7 , are selected from the group consisting of.

[0142] In one aspect, R 2 is a 4-membered heterocyclyl, the heterocyclyl ring being (i) a saturated or partially saturated monocyclic ring, (ii) having one oxygen ring atom with the remaining ring atoms being carbon, and (iii) optionally containing halogen, hydroxy, cyano, C 1~3 -Alkyl, C 2~3 -alkynyl, and C 1~3In another embodiment, R is substituted with one or more substituents independently selected from the group consisting of: -alkoxy. 2 is a 5-membered heterocyclyl, the heterocyclyl ring (i) being a saturated or partially saturated monocyclic ring, (ii) having one or two oxygen ring atoms with the remaining ring atoms being carbon, and (iii) optionally containing halogen, hydroxy, cyano, C 1~3 -alkyl, and C 2~3 -alkynyl, C 1~3 In another embodiment, R is substituted with one or more substituents independently selected from the group consisting of: -alkoxy. 2 is a 6-membered heterocyclyl, the heterocyclyl ring (i) being a saturated or partially saturated monocyclic ring, (ii) having one or two oxygen ring atoms with the remaining ring atoms being carbon, and (iii) optionally containing halogen, hydroxy, cyano, C 1~3 -Alkyl, C 2~3 -alkynyl, and C 1~3 In another embodiment, R is substituted with one or more substituents independently selected from the group consisting of: -alkoxy. 2 is a seven-membered heterocyclyl, the heterocyclyl ring (i) being saturated or partially saturated, monocyclic or fused bicyclic, (ii) having one or two oxygen ring atoms, the remaining ring atoms being carbon, and (iii) optionally containing halogen, hydroxy, cyano, C 1~3 -Alkyl, C 2~3 -alkynyl, and C 1~3 -substituted with one or more substituents independently selected from the group consisting of: -alkoxy;

[0143] In some embodiments, the 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 2 teeth, (a)C 1~3 -alkyl, optionally containing halogen, hydroxy, C 1~3 -Alkoxy, Halo-C 1~3 -alkoxy, C 3~6 -cycloalkoxy, C 1~3-Alkoxy-C 1~3 -substituted with one or more substituents independently selected from the group consisting of alkoxy, tetrahydrofuranyl, tetrahydrofuranyloxy, tetrahydropyranyl, morpholinyl, pyrazolyl, isoxazolyl, triazolyl, and pyridinyl; tetrahydrofuranyl, tetrahydrofuranyloxy, tetrahydropyranyl, morpholinyl, pyrazolyl, isoxazolyl, triazolyl, and pyridinyl are optionally substituted with one or more substituents independently selected from the group consisting of halogen, C 1~3 -Alkyl and halo-C 1~6 -substituted with one or more substituents independently selected from the group consisting of alkyl, C 1~3 - alkyl; (b)C 3~6 -cycloalkyl, optionally containing halogen, cyano, C 1~3 -substituted with one or more substituents independently selected from the group consisting of alkoxy, isoxazolyl, and pyridinyl; isoxazolyl and pyridinyl are optionally substituted with halogen, C 1~3 -Alkyl and halo-C 1~3 -substituted with one or more substituents independently selected from the group consisting of alkyl, C 3~6 -cycloalkyl; (c) phenyl, optionally containing halogen, C 1~3 -Alkyl, Halo-C 1~3 -Alkyl, C 1~3 -Alkoxy, Halo-C 1~3 -alkoxy, and C 1~3 -Alkoxy-C 1~3 -phenyl substituted with one or more substituents independently selected from the group consisting of alkoxy; (d) a 5-, 6-, or 7-membered heterocyclyl selected from the group consisting of tetrahydrofuranyl, dihydropyranyl, tetrahydropyranyl, 1,4-dioxanyl, and 3-oxabicyclo[4.1.0]heptane, wherein tetrahydrofuranyl, dihydropyranyl, tetrahydropyranyl, 1,4-dioxanyl, and 3-oxabicyclo[4.1.0]heptane are optionally substituted with halogen, hydroxy, cyano, C 1~6 -Alkyl, Halo-C 1~6 -Alkyl, C2~6 -alkynyl, C 1~6 -alkoxy and halo-C 1~6 - a 5-, 6-, or 7-membered heterocyclyl substituted with one or more substituents independently selected from the group consisting of alkoxy; and (e)-OR 7 and R 7 But C 1~4 - selected from the group consisting of alkyl, phenyl, and tetrahydropyranyl; (I C 1~4 -Alkyl is optionally substituted with halogen, cyano, C 3~6 -cycloalkyl, halo-C 3~6 -cycloalkyl, and C 1~3 -substituted with one or more substituents independently selected from the group consisting of alkoxy; (ii) tetrahydropyranyl is optionally one or C 1~3 -substituted with alkyl, -OR 7 , are selected from the group consisting of.

[0144] In some embodiments, the 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 2 teeth, (a)C 3~6 -cycloalkyl, optionally containing halogen, cyano, C 1~3 -substituted with one or more substituents independently selected from the group consisting of alkoxy, isoxazolyl, and pyridinyl; isoxazolyl and pyridinyl are optionally substituted with halogen, C 1~3 -Alkyl and halo-C 1~3 -substituted with one or more substituents independently selected from the group consisting of alkyl, C 3~6 -cycloalkyl; (b) a 5-, 6-, or 7-membered heterocyclyl selected from the group consisting of tetrahydrofuranyl, dihydropyranyl, tetrahydropyranyl, 1,4-dioxanyl, and 3-oxabicyclo[4.1.0]heptane, wherein tetrahydrofuranyl, dihydropyranyl, tetrahydropyranyl, 1,4-dioxanyl, and 3-oxabicyclo[4.1.0]heptane are optionally substituted with halogen, hydroxy, cyano, C 1~6 -Alkyl, Halo-C 1~6 -Alkyl, C 2~6 -alkynyl, C 1~6 -alkoxy and halo-C 1~6 - a 5-, 6-, or 7-membered heterocyclyl substituted with one or more substituents independently selected from the group consisting of alkoxy; and (c)-OR 7 and R 7 But C 1~4 - selected from the group consisting of alkyl, phenyl, and tetrahydropyranyl; (I C 1~4 -Alkyl is optionally substituted with halogen, cyano, C 3~6 -cycloalkyl, halo-C 3~6 -cycloalkyl, and C 1~3 -substituted with one or more substituents independently selected from the group consisting of alkoxy; (ii) tetrahydropyranyl is optionally one or C 1~3 -substituted with alkyl, -OR 7 , are selected from the group consisting of.

[0145] In one aspect, R 2 is optionally substituted cyclopropyl. In another embodiment, R 2 is optionally substituted cyclobutyl. In another embodiment, R 2 is optionally substituted cyclopentyl. In another embodiment, R 2 is optionally substituted cyclohexyl.

[0146] In some embodiments, the 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 2 teeth, (a) an optionally substituted C selected from the group consisting of methyl, fluoromethyl, difluoromethyl, trifluoromethyl, hydroxylethyl, hydroxypropyl, ethoxymethyl, difluoroethoxymethyl, methoxyethyl, dimethoxyethyl, difluoropropyl, trifluoropropyl, methoxypropyl, methoxyethoxymethyl, cyclopropoxymethyl, morpholinylmethyl, tetrahydrofuranylmethyl, tetrahydrofuranyloxymethyl, tetrahydropyranylmethyl, pyrazolylmethyl, dimethylpyrazolylmethyl, methylisoxazolylmethyl, methylisoxazolylethyl, methyltriazolylmethyl, dimethyltriazolylmethyl, dimethylpyridinylmethyl, methylpyridinylethyl, fluoropyridinylethyl, chloropyridinylethyl, and trifluoromethylpyridinylethyl; 1~3 - alkyl; (b) an optionally substituted C selected from the group consisting of cyclopropyl, cyanocyclopropyl, ethoxycyclopropyl, methylisoxazolylcyclopropyl, methylpyridinylcyclopropyl, chloropyridinylcyclopropyl, fluoropyridinylcyclopropyl, trifluoropyridinylcyclopropyl, fluorocyclobutyl, (fluoro)(methoxy)cyclobutyl, methoxycyclohexyl, and cyanocyclohexyl. 3~6 -cycloalkyl; (c) an optionally substituted 5-, 6-, or 7-membered heterocyclyl selected from the group consisting of tetrahydrofuranyl, dimethyltetrahydrofuranyl, dihydropyranyl, tetrahydropyranyl, hydroxytetrahydropyranyl, fluorotetrahydropyranyl, cyanotetrahydropyranyl, methyltetrahydropyranyl, dimethyltetrahydropyranyl, methoxytetrahydropyranyl, ethoxytetrahydropyranyl, 1,4-dioxanyl, and 3-oxabicyclo[4.1.0]heptane; and (d)-OR 7 and R 7 is selected from the group consisting of cyanomethyl, fluoroethyl, difluoroethyl, propyl, difluoropropyl, fluorobutyl, methoxyethyl, cyclopropylmethyl, difluorocyclobutylmethyl, phenyl, tetrahydropyranyl, and dimethyltetrahydropyranyl; 7 , are selected from the group consisting of.

[0147] In some embodiments, the 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 2 teeth, (a) an optionally substituted C selected from the group consisting of cyclopropyl, cyanocyclopropyl, ethoxycyclopropyl, methylisoxazolylcyclopropyl, methylpyridinylcyclopropyl, chloropyridinylcyclopropyl, fluoropyridinylcyclopropyl, trifluoropyridinylcyclopropyl, fluorocyclobutyl, (fluoro)(methoxy)cyclobutyl, methoxycyclohexyl, and cyanocyclohexyl; 3~6 -cycloalkyl; (b) an optionally substituted 5-, 6-, or 7-membered heterocyclyl selected from the group consisting of tetrahydrofuranyl, dimethyltetrahydrofuranyl, dihydropyranyl, tetrahydropyranyl, hydroxytetrahydropyranyl, fluorotetrahydropyranyl, cyanotetrahydropyranyl, methyltetrahydropyranyl, dimethyltetrahydropyranyl, methoxytetrahydropyranyl, ethoxytetrahydropyranyl, 1,4-dioxanyl, and 3-oxabicyclo[4.1.0]heptane; and (c)-OR 7 and R 7 is selected from the group consisting of cyanomethyl, fluoroethyl, difluoroethyl, propyl, difluoropropyl, fluorobutyl, methoxyethyl, cyclopropylmethyl, difluorocyclobutylmethyl, phenyl, tetrahydropyranyl, and dimethyltetrahydropyranyl; 7 , are selected from the group consisting of.

[0148] In some embodiments, the 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 2 is selected from the group consisting of methoxycyclohexyl, tetrahydropyranyl, fluorobutoxy, and tetrahydropyranyloxy.

[0149] H. Combination of Embodiments Any embodiment of the compounds described in this disclosure can be combined with any other suitable embodiment described herein to provide additional embodiments. For example, one embodiment may include R 1 , R 2 , R 3 , R 4 , R 5 and / or R 6 The possible groups for R are described individually or collectively, and another embodiment is R 2 When describing possible groups for R, these embodiments can be combined to form 1 , R2 , 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 may be any of the R groups described herein. 2 may be as defined in any of the embodiments.

[0150] I. Further Embodiments 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 certain concentrations.

[0151] 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.

[0152] In some embodiments, compounds of the present disclosure have pharmaceutically acceptable selectivity for FAP relative to 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 is at least about 50-fold selective for FAP relative to PREP. In another aspect, a compound is at least about 100-fold selective for FAP relative to PREP. In another aspect, a compound is at least about 1,000-fold selective for FAP relative to PREP. In another aspect, a compound is at least about 10,000-fold selective for FAP relative to 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.

[0153] In some embodiments, compounds of the present disclosure have pharmaceutically acceptable selectivity for a FAP relative to DPP7, as measured as described for the hFAP inhibition assay (tight binder) and the DPP7 selectivity assay reported in the Examples below. In one aspect, a compound is at least about 50-fold selective for a FAP relative to DPP7. In another aspect, a compound is at least about 100-fold selective for a FAP relative to DPP7. In another aspect, a compound is at least about 1,000-fold selective for a FAP relative to DPP7. In another aspect, a compound is at least about 10,000-fold selective for a FAP relative to DPP7. In another aspect, a compound has an IC of greater than about 0.1 μM for DPP7. 50 In another embodiment, the compound has an IC value of greater than about 1 μM against DPP7. 50 In another embodiment, the compound has an IC value for DPP7 of greater than about 10 μM. 50 It has a value.

[0154] In some embodiments, compounds of the present disclosure have pharmaceutically acceptable selectivity for a FAP relative to 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 is selective for a FAP relative to DPP8. In another aspect, a compound is selective for a FAP relative to DPP9. In another aspect, a compound is selective for a FAP relative to both DPP8 and DPP9. In one aspect, a compound is at least about 50-fold selective for a FAP relative to DPP8 and / or DPP9. In another aspect, a compound is at least about 100-fold selective for a FAP relative to DPP8 and / or DPP9. In another aspect, a compound is at least about 500-fold selective for a FAP relative to DPP8 and / or DPP9. In another aspect, a compound is at least about 1,000-fold selective for a FAP relative to DPP8 and / or DPP9. In another embodiment, the compound has an IC value of greater than about 0.01 μM against DPP8 and / or DPP9. 50 In another embodiment, the compound has an IC value of greater than about 0.1 μM against DPP8 and / or DPP9. 50 In another embodiment, the compound has an IC value of greater than about 0.4 μM against DPP8 and / or DPP9. 50 It has a value.

[0155] 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.

[0156] 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.

[0157] 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 a Caco-2 specific apparent permeability of at least about 0.5×10 cm / s. 6 In another embodiment, the compound has a Caco-2 specific apparent permeability of at least about 1×10 cm / s. 6 Caco-2 has a specific apparent permeability of 1.0 cm / s.

[0158] In some embodiments, compounds of the present disclosure have a pharmaceutically acceptable Caco-2 bidirectional (ABBA) A to B apparent permeability as measured as described for the Caco-2 bidirectional (ABBA) A to B apparent permeability assay reported in the Examples below. In one aspect, the compound has a Caco-2 bidirectional (ABBA) A to B apparent permeability of at least about 0.1 x 10 6 In another embodiment, the compound has a Caco-2 bidirectional (ABBA) A to 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 to B apparent permeability of at least about 0.5 x 10 cm / s. 6 Caco-2 bidirectional (ABBA) A to B apparent permeability of 1000 nm / s.

[0159] 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 compounds have a kinetic solubility of at least about 1 μM.In another aspect, the compounds have a kinetic solubility of at least about 10 μM.In another aspect, the compounds have a kinetic solubility of at least about 25 μM.In another aspect, the compounds have a kinetic solubility of at least about 50 μM.

[0160] J. 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, for example, by mixing the compound with an acid (e.g., a stoichiometric amount of the acid) using various methods known in the art. This mixing can be carried out 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 a hydrochloride salt. Generally, base addition salts can be prepared using salts with various inorganic or organic bases, such as alkali metal or alkaline earth metal salts, e.g., sodium, calcium, or magnesium salts, or other metal salts, e.g., potassium or zinc, or ammonium salts, or organic bases, such as methylamine, dimethylamine, trimethylamine, piperidine, or morpholine. Those skilled in the art are aware of the general principles and techniques for preparing pharmaceutical salts, which are described, for example, 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).

[0161] K. Isomers The compounds and salts of the present disclosure may exist in one or more geometric, optical, enantiomeric, and diastereomeric forms, including, but not limited to, cis- and trans-forms, E- and Z-forms, and R-, S-, and meso-forms. Unless otherwise specified, reference to a particular compound includes all such isomeric forms, including racemates and other mixtures. Where appropriate, such isomers can be separated from their mixtures by the application or adaptation of known methods (e.g., chromatographic and recrystallization techniques). Where appropriate, such isomers can be prepared by the application or adaptation of known methods. In some embodiments, a single stereoisomer is obtained by isolation 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.

[0162] A particular enantiomer of a compound 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 with an enantiomeric excess (% ee) of ≧90%, ≧95%, ≧96%, ≧97%, ≧98%, or ≧99%. In one aspect, the single enantiomer is present in an enantiomeric excess (% ee) of ≧99%.

[0163] In another embodiment, the present disclosure relates to a pharmaceutical composition comprising a compound or a pharmaceutically acceptable salt thereof, or a pharmaceutically acceptable salt thereof, that is a single enantiomer in an enantiomeric excess (% ee) of ≧90, ≧95%, ≧96%, ≧97, ≧98%, or ≧99%, together with one or more pharmaceutically acceptable excipients. In one aspect, the single enantiomer is present in an enantiomeric excess (% ee) of ≧99%.

[0164] L. Additional Forms The compounds and salts of the present disclosure may exist in various tautomeric forms, and the present specification includes all such tautomeric forms. "Tautomers" are structural isomers that exist in equilibrium resulting from the migration of a hydrogen atom.

[0165] The compounds of the present disclosure and their pharmaceutically acceptable salts may exist in solvated (such as hydrated) as well as unsolvated forms, and the present specification includes all such solvates.

[0166] 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.

[0167] The compounds and salts of the present disclosure may be isotopically labeled (or "radiolabeled"). In that case, one or more atoms are replaced by an atom having an atomic mass or mass number different from the atomic mass or mass number typically found in nature. 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, in 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.

[0168] M. intermediate In some embodiments, the present disclosure provides additional compounds useful as intermediates for preparing the disclosed compounds and pharmaceutically acceptable salts thereof.

[0169] III.How to use The disclosed compounds and pharmaceutically acceptable salts thereof are inhibitors of the activity of the prolyl endopeptidase fibroblast activation protein (FAP). FAP is an endopeptidase that enzymatically cleaves substrates involved in glucose and lipid metabolism, fibrinolysis, and collagen production.

[0170] FAP is believed 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.

[0171] 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 results in fibrin deposition. Fibrin in blood clots is typically dissolved primarily by plasmin, once 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 effectively fibrin-bound form, which reduces plasmin degradation of fibrin 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).

[0172] FAP is also thought to promote collagen production and deposition and play a role in increasing fibrosis through alterations in 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).

[0173] In view of the above, it is hypothesized that inhibition of FAP collectively reduces fibrosis and inflammation by decreasing hepatic stellate cell activity and increasing fibrinolysis, and further provides positive metabolic effects via increased FGF21 signaling and improved glucose tolerance.

[0174] Thus, in some embodiments, the present disclosure provides methods of 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.

[0175] In some embodiments, the present disclosure provides methods of 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.

[0176] In some embodiments, the present disclosure provides a method for treating or preventing liver disease in a subject in need thereof by administering a therapeutically effective amount of a compound of the present disclosure or a pharmaceutically acceptable salt thereof to the subject. 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.

[0177] In some embodiments, the present disclosure provides a method of 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.

[0178] In some embodiments, the present disclosure provides a method for treating liver disease in a subject in need thereof by administering a therapeutically effective amount of a compound of the present disclosure or a pharmaceutically acceptable salt thereof to the subject, 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.

[0179] In some embodiments, the present disclosure provides a method for treating liver disease in a subject in need thereof by administering a therapeutically effective amount of a compound of the present disclosure or a pharmaceutically acceptable salt thereof to the subject, wherein the subject also suffers from or is susceptible to insulin resistance.In another aspect, the liver disease is NAFLD.In another aspect, the liver disease is NASH.In another aspect, the liver disease is liver fibrosis.In another aspect, the liver disease is cirrhosis.

[0180] In some embodiments, the present disclosure provides a method for treating liver disease in a subject in need thereof by administering a therapeutically effective amount of a compound of the present disclosure or a pharmaceutically acceptable salt thereof to the subject, wherein the subject suffers from or is prone to 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.

[0181] In some embodiments, the present disclosure provides a method for treating liver disease in a subject in need thereof by administering a therapeutically effective amount of a compound of the present disclosure or a pharmaceutically acceptable salt thereof to the subject, wherein the subject also suffers from or is susceptible to type 2 diabetes. In another aspect, the liver disease is NAFLD. In another aspect, the liver disease is NASH. In another aspect, the liver disease is liver fibrosis. In another aspect, the liver disease is cirrhosis.

[0182] In some embodiments, the present disclosure provides a method for treating liver disease in a subject in need thereof by administering a therapeutically effective amount of a compound of the present disclosure or a pharmaceutically acceptable salt thereof to the subject, wherein 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.

[0183] In some embodiments, the present disclosure provides a method for reducing liver fat in a subject in need thereof by administering a therapeutically effective amount of a compound of the present disclosure or a pharmaceutically acceptable salt thereof to the subject. 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.

[0184] 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.

[0185] In some embodiments, the present disclosure provides methods of treating or preventing non-alcoholic steatohepatitis (NASH) in a subject in need thereof by administering to the subject a therapeutically effective amount of a compound of the present disclosure, or a pharmaceutically acceptable salt thereof. In one aspect, the NASH is stage 1 NASH. In another aspect, the NASH is stage 2 NASH. In another aspect, the NASH is stage 3 NASH. In another aspect, the NASH is stage 4 NASH. In another aspect, the subject 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.

[0186] In some embodiments, the present disclosure provides a method of 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.

[0187] In some embodiments, the present disclosure provides a method for treating or preventing cirrhosis in a subject in need thereof by administering a therapeutically effective amount of a compound of the present disclosure or a pharmaceutically acceptable salt thereof to the subject. In one aspect, the subject is suffering from stage F4 cirrhosis. In another aspect, the subject is also suffering from or susceptible to one or more conditions selected from the group consisting of obesity, dyslipidemia, insulin resistance, type 2 diabetes, and renal failure.

[0188] In some embodiments, the present disclosure provides a method of treating or preventing type 2 diabetes mellitus 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 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.

[0189] In some embodiments, the present disclosure provides a method for 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 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.

[0190] In some embodiments, the present disclosure provides methods for 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 is ≥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.

[0191] 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 is ≥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.

[0192] In some embodiments, the present disclosure provides a method for treating or preventing insulin resistance in a subject by administering a therapeutically effective amount of a compound of the present disclosure or a pharmaceutically acceptable salt thereof to the subject. 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, which is incorporated herein by reference in its entirety. The MATSUDA index is described, for example, in Diabetes Care 1999, 22, 1462, which is incorporated herein by reference in its entirety.

[0193] In some embodiments, the present disclosure provides a method for treating or preventing impaired glucose tolerance in a subject in need thereof by administering a therapeutically effective amount of a compound of the present disclosure or a pharmaceutically acceptable salt thereof to the subject. 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.

[0194] In some embodiments, the present disclosure provides a method for treating or preventing 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.

[0195] 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, impaired glucose tolerance, elevated fasting 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.

[0196] In some embodiments, the present disclosure provides a method for reducing weight in a subject in need thereof by administering a therapeutically effective amount of a compound of the present disclosure or a pharmaceutically acceptable salt thereof to the subject. 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 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 has a BMI of 0.05%. 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%.

[0197] In some embodiments, the present disclosure provides a method for reducing body fat in a subject in need of treatment by administering a therapeutically effective amount of a compound of the present disclosure or a pharmaceutically acceptable salt thereof to the subject. 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.

[0198] 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).

[0199] In some embodiments, the present disclosure provides methods of promoting tissue remodeling 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 suffered cardiac tissue damage due to myocardial infarction.

[0200] In some embodiments, the present disclosure provides methods 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 through increased fibrinolysis.

[0201] In some embodiments, the present disclosure provides a method of 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.

[0202] In some embodiments, the present disclosure provides a method for treating or preventing inflammation in a subject in need thereof by administering a therapeutically effective amount of a compound of the present disclosure or a pharmaceutically acceptable salt thereof to the subject. 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.

[0203] In some embodiments, the present disclosure provides a method for treating cancer in a subject in need thereof by administering a therapeutically effective amount of a compound of the present disclosure or a pharmaceutically acceptable salt thereof to the subject. 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 carcinoma, pharyngeal carcinoma, myeloma cells, bladder cancer, cholangiocarcinoma, renal clear cell carcinoma, neuroendocrine tumor, tumor-induced osteomalacia, sarcoma, CUP (cancer of unknown primary), thymic carcinoma, desmoid tumor, glioma, astrocytoma, cervical cancer, and prostate cancer. In another aspect, the cancer is hepatocellular carcinoma.

[0204] The subject to be treated is typically a human or non-human mammal, particularly a human. Suitable subjects may include domestic or wild animals; companion animals (including dogs, cats, etc.); livestock (including horses, cattle and other ruminants, pigs, poultry, rabbits, etc.); primates (including monkeys such as rhesus monkeys, cynomolgus monkeys (also known as cynomolgus or long-tailed monkeys), marmosets, tamarins, chimpanzees, macaques, etc.); and rodents (including rats, mice, gerbils, guinea pigs, etc.).

[0205] In some embodiments, the present disclosure provides compounds of the present disclosure, and pharmaceutically acceptable salts thereof, for use as pharmaceuticals.

[0206] In some embodiments, the present disclosure provides the use of a compound of formula I, or a pharmaceutically acceptable salt thereof, for treating or preventing a FAP-mediated condition, such as those discussed above.

[0207] In some embodiments, the present disclosure provides the use of a compound of formula I or a pharmaceutically acceptable salt thereof for the manufacture of a medicament for treating or preventing a FAP-mediated condition, as discussed above.

[0208] IV. Combination Therapy and Fixed-Dose Combinations The compounds of the present disclosure can be used in the above methods either as single pharmaceutical agents or in combination with other pharmaceutical agents or techniques. Such combination therapy can be achieved by simultaneous, separate, or sequential administration of the individual components of the treatment. These combination therapies (and corresponding combination products) use the compounds of the present disclosure within the dosage ranges described herein and the other pharmaceutical agents, typically within their approved dosage ranges.

[0209] In some embodiments, the present disclosure provides a combination suitable for use in treating a condition selected from those discussed above, the combination comprising a compound of the present disclosure or a pharmaceutically acceptable salt thereof and a sodium-glucose transport protein 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.

[0210] In some embodiments, the present disclosure provides a combination suitable for use in treating a condition selected from the conditions discussed above, the combination comprising a compound of the present disclosure or a pharmaceutically acceptable salt thereof, and metformin.

[0211] In some embodiments, the present disclosure provides a combination suitable for use in treating a condition selected from those discussed above, 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 GLP1 agonist is selected from the group consisting of exenatide, liraglutide, lixisenatide, albiglutide, dulaglutide, and semaglutide.

[0212] In some embodiments, the present disclosure provides a combination suitable for use in treating a condition selected from those discussed above, 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.

[0213] In some embodiments, the present disclosure provides a combination suitable for use in treating a condition selected from those discussed above, 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.

[0214] 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 pharmaceutical 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 in the manufacture of a medicament for use in treating a condition selected from the conditions discussed above. In one aspect, the pharmaceutical composition comprises an SGLT2 inhibitor. In another aspect, the pharmaceutical composition comprises metformin. In another aspect, the pharmaceutical composition comprises a GLP1 agonist. In another aspect, the pharmaceutical composition comprises a DPP4 inhibitor. In another aspect, the pharmaceutical composition comprises a PPAR agonist.

[0215] 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-LI 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-LI antibody (e.g., atezolizumab (Tecentriq), avelumab (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.

[0216] 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 a compound of the present disclosure or a pharmaceutically acceptable salt thereof and at least one pharmaceutically acceptable excipient.

[0217] The excipients selected for inclusion in a particular composition depend on factors such as the mode of administration and the form of the composition provided. Suitable pharmaceutically acceptable excipients are known to those skilled in the art and are described, for example, in Handbook of Pharmaceutical Excipients, Sixth Edition, Pharmaceutical Press, edited by Rowe, Ray C; Sheskey, Paul J; Quinn, Marian. Pharmaceutically acceptable excipients can function, for example, as adjuvants, diluents, carriers, stabilizers, flavoring agents, coloring agents, fillers, binders, disintegrants, lubricants, glidants, thickeners, and coating agents. As those skilled in the art will understand, a particular pharmaceutically acceptable excipient can perform more than one function, and can perform different functions, depending on how much of the excipient is present in the composition and which other excipients are present in the composition.

[0218] 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 finely divided powders or liquid aerosols), administration by insufflation (e.g., as finely divided powders), or parenteral administration (e.g., as sterile aqueous or oily solutions for intravenous, subcutaneous, or intramuscular administration), or as suppositories for rectal administration. The compositions may be obtained by conventional procedures using conventional pharmaceutical excipients known in the art. Thus, compositions intended for oral use may contain, for example, one or more colorants, sweeteners, flavoring agents, and / or preservatives.

[0219] The total daily dose will necessarily vary depending on the subject being treated, the particular route of administration, any co-administered therapies, and the severity of the disease being treated, and may include single or multiple doses. The specific dosage can be adjusted depending, for example, on the condition being treated; the subject's age, weight, general health, sex, and diet; the route of administration; the interval between doses; the rate of excretion; and other drugs co-administered to the subject. A physician of ordinary skill, given the disclosure of this application, can determine the appropriate dosage and regimen for administering a therapeutic agent to a subject, and can adjust such dosage and regimen as necessary during the course of treatment, according to methods well known in the therapeutic arts. The compounds of the present disclosure, or pharmaceutically acceptable salts thereof, are typically administered in a dose range of 2.5 to 5,000 mg / m of an animal's body area. 2 or a unit dose in the range of about 0.05-100 mg / kg, which will normally provide a therapeutically effective dose.

[0220] 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.

[0221] 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 mellitus, a cardiovascular condition, obesity, an obesity-related condition, fibrosis, a keloid disorder, inflammation, and cancer.

[0222] VI. Kit The present disclosure further provides a kit 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 previously described.

[0223] 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 material, and a label or package insert indicating that the pharmaceutical composition can be used to treat a FAP-mediated condition. In another aspect, the FAP-mediated condition is a liver disease. In another aspect, the liver disease is selected from the group consisting of fatty liver disease, end-stage liver disease, and cirrhosis. In another aspect, the liver disease is selected from the group consisting of non-alcoholic steatohepatitis (NASH) and non-alcoholic fatty liver disease (NAFLD).

[0224] 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 pharmaceutical 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 and second dosage forms; 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 FAP-mediated condition.

[0225] 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), and (IV-A), and pharmaceutically acceptable salts thereof. Reaction Schemes 1-10 illustrate synthetic routes to these compounds, and unless otherwise indicated, R 1 , R 2 , R 3 , R 5 , and R 6 is as defined in formula (I); R 7 is an alkyl group (e.g., methyl, ethyl, tert-butyl, etc.); R 8 and R 9 is an alkyl group, an aryl group, or hydrogen; X 1 is S, S(O) or S(O)2; X 2 and X 3 is a leaving group (e.g., Cl, Br, I, OMs, OTs, OTf, etc.); PG1 is a protecting group. 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.

[0226] [ka]

[0227] Scheme 1 shows a synthetic route to a particular compound of formula (I). A compound of formula (2) can be reacted with a compound of formula (3) to give a compound of formula (I). The reaction can be carried out using a suitable coupling reagent (e.g., HATU, HOBt / EDC, T3P, etc.) in the presence of a base, typically an organic base (e.g., DIPEA or TEA), using a solvent (e.g., DCM, DMF, EtOAc, MeCN, or a mixture thereof), typically at a temperature ranging from 0°C to 60°C.

[0228] [ka]

[0229] Scheme 2 shows a synthetic route to certain compounds of formula (2). Compounds of formula (2) can be formed by reacting compounds of formula (4) with a base (e.g., NaOH, LiOH, etc.) in an organic solvent (e.g., 1,4-dioxane, THF, 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 (4) where CI = tert-butyl, the reaction can be carried out using a suitable acid (such as HCl) in a solvent (such as 1,4-dioxane, EtOAc, MeOH, water, or mixtures thereof). Alternatively, the reaction can be carried out using a carboxylic acid (such as TFA) either neat or in a solvent (such as DCM), typically at temperatures ranging from 0°C to 60°C.

[0230] [ka]

[0231] Scheme 3 shows a synthetic route to certain compounds of formula (4). Compounds of formula (5) can be prepared by reacting R 2 is as defined in formula (I), and Y 1 can be converted to a compound of formula (4) by reacting with an alkyl halide of formula (6), typically an alkyl bromide, where X is as defined above. The reaction can be catalyzed using a Ni catalyst (such as NiBr2DME) and a suitable ligand (such as dtbbpy), and a suitable photoredox catalyst (such as Ir[dF(CF3)ppy]2(dtbbpy)PF6), in the presence of HSi(SiMe3)3 and a base (such as Na2CO3), in a suitable solvent (such as DME), typically at 20 °C, under illumination with a blue light LED.

[0232] Alternatively, compounds of formula (4) can be formed by reacting compounds of formula (5) with alkyl halides of formula (6) using the methodology and conditions described in the following publications: MacMillan DW Cet. al. J. Am. Chem. Soc. 2020, 142, 11691-11697; Weix DJ Et. al. J. Am. Chem. Soc. 2010, 132, 920-921; Weix DJ Et. al. Nat. Chem. 2016, 8, 1126-1130; Gong H. et. al. J. Am. Chem. Soc. 2015, 137, 11562-11565 and Gong H. et. al. J. Am. Chem. Soc. 2018, 140, 14490-14497.

[0233] Alternatively, the compound of formula (4) can be prepared by reacting a compound of formula (5) with R 2 is as defined in formula (I), and Y 1with an alkyl ether of formula (6), where R is hydrogen. The reaction can be catalyzed using a Ni catalyst (such as NiBr2dtbbpy) and a suitable photoredox catalyst (such as TBADT) in the presence of a base (such as K3PO4) in a suitable solvent (such as MeCN), typically at 20°C, under illumination with a blue light LED.

[0234] Alternatively, the compound of formula (4) can be prepared by reacting a compound of formula (5) with R 2 is as defined in formula (I), and Y 1 With an aryl or alkylboron reagent of formula (6), where R is a boron derivative (e.g., boronic acid, trifluoroborate, etc.). The reaction can be catalyzed by a Pd catalyst (e.g., PdCl(dppf)DCM, etc.) in the presence of a base (e.g., KCO, NaCO, etc.) in a suitable solvent (e.g., 1,4-dioxane, THF, etc.) at temperatures typically ranging from 20°C to reflux.

[0235] Alternatively, compounds of formula (4) can be prepared by reacting compounds of formula (5) with R using the methodology and conditions described in the following publication: Harris MR et. al. Org. Lett. 2018, 20, 2867-2871. 2 is as defined in formula (I), and Y 1 can be formed by reacting with an alkylboron reagent of formula (6), which is a boron derivative (boronic acid, trifluoroborate, etc.).

[0236] Alternatively, the compound of formula (4) may be R 2 is as defined in formula (I), and Y 1 can be formed from compounds of formula (5) by reaction with an alcohol or phenol of formula (6) where is hydrogen. The reaction can be carried out in the presence of a base (e.g., KPO), in a suitable solvent (e.g., toluene, 1,4-dioxane, etc.), catalyzed by a suitable Pd reagent (e.g., Pd(OAc)), with a suitable phosphine ligand (e.g., XPhos, t-BuXPhos, etc.), at elevated temperatures.

[0237] Alternatively, the compound of formula (4) may be R 2 is as defined in formula (I), and Y 1 can be formed from compounds of formula (5) by reaction with an alcohol or phenol of formula (6) where is hydrogen. The reaction can be facilitated using a suitable Cu reagent (such as CuBr) in a suitable solvent (such as DMF) at elevated temperature in the presence of a base (such as KCO, CsCO, etc.) and a radical initiator (such as AIBN).

[0238] Alternatively, the compound of formula (4) can be prepared by reacting a compound of formula (5) with R 2 is as defined in formula (I), and Y 1 is hydrogen, the reaction can be carried out in the presence of a base (e.g., NaHMDS, Cs2CO3, etc.), in a suitable solvent (e.g., 1,4-dioxane, etc.), with a suitable phosphine ligand (e.g., BINAP, SPhos, etc.), catalyzed by a suitable Pd reagent (e.g., Pd(OAc)2, etc.), at elevated temperatures.

[0239] [ka]

[0240] Scheme 4 shows a synthetic route to certain compounds of formula (4). Compounds of formula (8) can be prepared by reacting R 8 is hydrogen or an alkyl group, and R 9 It can be formed from a compound of formula (7) where is hydrogen by reaction with an oxidizing reagent (such as Dess-Martin periodinane). The reaction can be carried out in a suitable solvent (such as DCM) at a temperature typically in the range of 0°C to 40°C.

[0241] R 2Compounds of formula (4), wherein R is as defined in formula (I), can be formed by reacting compounds of formula (8) with a fluorinating reagent (such as DAST) in a suitable solvent (such as DCM, THF) at temperatures typically ranging from 0°C to 60°C.

[0242] Alternatively, compounds of formula (4) can be formed from compounds of formula (8) by reduction with a reducing agent such as sodium borohydride. The reaction can be carried out in a solvent such as methanol at temperatures typically ranging from 0°C to 40°C.

[0243] Alternatively, compounds of formula (4) can be formed from compounds of formula (8) by reaction with a Grignard reagent (e.g., MeMgCl, MeMgBr, etc.) The reaction can be carried out in a suitable solvent (e.g., diethyl ether, THF, etc.) at temperatures typically ranging from -78°C to 40°C.

[0244] Alternatively, compounds of formula (4) can be formed from compounds of formula (8) by condensation with a sulfonyl hydrazide (e.g., 4-methylbenzene-sulfonohydrazide) in a suitable solvent (e.g., 1,4-dioxane). The intermediate hydrazone can then be reacted with a boronic acid. The reaction can be carried out in the presence of a base (e.g., K2CO3 or Na2CO3) in a suitable solvent (e.g., 1,4-dioxane), typically at reflux temperature, according to the procedure described in Barluenga J. et al. Nat. Chem. 2009, 1, 494-499.

[0245] Alternatively, R 2 Compounds of formula (4), wherein R is as defined in formula (I), can be formed by reacting compounds of formula (7) with a fluorinating reagent (such as DAST) in a suitable solvent (such as DCM, THF) at temperatures typically ranging from 0°C to 60°C.

[0246] Alternatively, compounds of formula (4) can be formed from compounds of formula (7) by reaction with an alkyl halide (e.g., MeI, etc.) or another alkylating agent (e.g., alkyl sulfonate, alkyl triflate, etc.). The reaction can be carried out using a base (e.g., NaH, etc.) in a solvent (e.g., THF, 1,4-dioxane, etc.).

[0247] [ka]

[0248] Scheme 5 shows a synthetic route to certain compounds of formula (7). 8 Compounds of formula (8), in which is an alkyl group (such as a methyl group), can be formed by reacting compounds of formula (5) with a trialkyl(1-alkoxyvinyl)tin reagent (such as tributyl(1-ethoxyvinyl)tin). The reaction can be catalyzed by a Pd reagent (such as PdCl(dppf)DCM, Pd(PPh)), in a suitable solvent (such as toluene, 1,4-dioxane), typically at temperatures ranging from 80°C to reflux.

[0249] Alternatively, R 8 Compounds of formula (8), in which is hydrogen, can be formed by reacting compounds of formula (5) with formic acid and acetic anhydride. The reaction can be carried out with a Pd reagent (such as PdOAc) in a suitable solvent (such as DMF) at a temperature typically ranging from 80° C. to 120° C., along with a suitable ligand (such as butyl-1-adamantylphosphine), NaHCO3, and TEA.

[0250] R 8 and R 9Compounds of formula (7) where is hydrogen can be formed by reacting compounds of formula (5) with a (trialkylstannyl)methanol reagent (e.g., (tributylstannyl)methanol, etc.). The reaction can be catalyzed by a Pd reagent (e.g., PdCl(dppf)DCM, Pd(PPh) and the like) in a suitable solvent (e.g., toluene, 1,4-dioxane, etc.) at temperatures typically ranging from 80°C to reflux.

[0251] Alternatively, R 9 Compounds of formula (7), where is hydrogen, can be formed from compounds of formula (8) by reduction with a reducing agent such as sodium borohydride. The reaction can be carried out in a solvent such as methanol, typically at temperatures ranging from 0°C to 40°C.

[0252] Alternatively, R 9 Compounds of formula (7), where is an alkyl group, can be formed from compounds of formula (8) by reaction with a Grignard reagent (e.g., MeMgCl, MeMgBr, etc.). The reaction can be carried out in a suitable solvent (e.g., diethyl ether, THF, etc.) at temperatures typically ranging from -78°C to 40°C.

[0253] [ka]

[0254] Scheme 6 shows a synthetic route to certain compounds of formula (4). Compounds of formula (9) can be prepared by reacting R 8 and R 9 It can be formed from a compound of formula (7) where is hydrogen or an alkyl group by reaction with a suitable reagent (such as thionyl chloride, MsCl, etc.) The reaction can be carried out in a suitable solvent (such as DCM) at a temperature typically in the range of 0°C to 40°C.

[0255] The compound of formula (4) is R 8 and R 9It can be formed from a compound of formula (9) where is hydrogen or an alkyl group by reaction with an alcohol. The reaction can be carried out in a suitable solvent (e.g., THF, DMF, etc.) in the presence of a base (e.g., NaH, etc.) typically at 0°C to 40°C.

[0256] Alternatively, the compound of formula (4) may be R 8 and R 9 It can be formed from a compound of formula (9) where is hydrogen or an alkyl group by reaction with an amine. The reaction can be carried out in a suitable solvent (e.g., MeCN, DMF, etc.) in the presence of a base (e.g., TEA, Cs2CO3, etc.) with or without an additive (e.g., KI, etc.) typically at temperatures between 0°C and 80°C.

[0257] [ka]

[0258] Scheme 7 shows a synthetic route to certain compounds of formula (4). Compounds of formula (4) can be prepared by reacting Y 2 is a boron derivative (e.g., boronic acid, boronic ester, trifluoroborate, etc.), 2 is as defined in formula (I), and X 2 is a leaving group as defined above. The reaction can be catalyzed by a Pd-reagent (e.g., PdCl(dppf)DCM, trans-bromo(N-succinimidyl)-bis(triphenylphosphine)palladium(II), etc.) in a suitable solvent (e.g., toluene, 1,4-dioxane, etc.), with or without water, at temperatures typically ranging from 80° C. to 120° C.

[0259] Alternatively, the compound of formula (4) may be Y 2The compound of formula (10), wherein R is a boronic acid, can be formed by reaction with a sulfonylhydrazone of an aldehyde or ketone, typically a tosylhydrazone. The reaction can be carried out in a suitable solvent (e.g., 1,4-dioxane, etc.) in the presence of a base (e.g., KCO, NaCO, etc.), typically at reflux temperature, according to the procedure described in Barluenga J. et.al. Nat. Chem. 2009, 1, 494-499.

[0260] [ka]

[0261] Scheme 8 shows a synthetic route to certain compounds of formula (4). 2 Compounds of formula (4), wherein R is as defined in formula (I), can be formed from compounds of formula (12) by reaction with an alkyl halide, alkyl sulfonate, or alkyl triflate of formula (11). The reaction can be promoted by a base (e.g., Cs2CO3, K2CO3, etc.) in a suitable solvent (e.g., DMF, etc.) at temperatures typically ranging from 20°C to 100°C.

[0262] Alternatively, the compound of formula (4) may be R 2 is as defined in formula (I), and X 2 The compound of formula (12) can be formed from a compound of formula (12) by reaction with an alcohol of formula (11) in which R is a hydroxyl group. The reaction can be carried out in the presence of a phosphine (such as PhP) and an azodicarboxylate (such as DIAD) in a suitable solvent (such as THF) at a temperature typically in the range of 20°C to 60°C.

[0263] [ka]

[0264] Scheme 9 shows a synthetic route to certain compounds of formula (12). 2The compound of formula (10) in which X is a boron derivative (e.g., boronic acid, boronic ester, trifluoroborate, etc.) can be 2 is a leaving group as defined above, and a boron reagent (such as B2(OH)4 or B2pin2). The reaction can be catalyzed by a Pd-reagent (such as PdCl2(dppf)DCM) and a base (such as KOAc) in a suitable solvent (such as toluene, 1,4-dioxane, EtOH) at temperatures typically ranging from 80°C to 120°C.

[0265] The compound of formula (12) is Y 2 is a boron derivative (e.g., boronic acid, boronic ester, etc.). The reaction can be facilitated by a suitable reagent (e.g., NaBO3, etc.) in a suitable solvent (e.g., THF / water mixture, etc.), typically at room temperature.

[0266] [ka]

[0267] Scheme 10 shows a synthetic route to certain compounds of formula (7). Compounds of formula (14) can be prepared by reacting X 2 and X 3 can be formed from a compound of formula (13) as defined above, and X 2 is selectively reacted with an organometallic reagent (e.g., BuLi), and then R 8 and R 9 can be selected such that it can react with an aldehyde or ketone of formula (15) as defined above. The reaction can be carried out in a suitable solvent (such as THF) and is typically carried out at low temperatures between -78°C and 0°C.

[0268] Compounds of formula (7) can be formed by reacting compounds of formula (14) with carbon monoxide, typically at a pressure of 1-10 atm, in a sealed vessel at a temperature typically ranging from 80° C. to 120° C. The reaction can be catalyzed with a suitable Pd reagent (such as Pd(dppf)Cl2) in the presence of a base (such as TEA), in a suitable solvent in the presence of a suitable alcohol (such as MeOH, EtOH), or using a suitable alcohol as the solvent.

[0269] It is understood that the organic reactions described herein are carried out according to laboratory practice known to those skilled in the art. It is understood that some of the reactions described herein can be optionally carried out in a different order from that shown herein, if necessary. It is understood that the chiral isomers of the compounds herein can 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.

[0270] It is further understood that additional protecting groups may optionally be required in some of the above steps, and therefore deprotection steps may optionally be performed 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" 3 rd Ed., TW Greene and PG M Hutz, Wiley-Interscience (1999), which publication is incorporated herein by reference.

[0271] VIII. Numbered Embodiments Embodiment 1. A compound having the structure of formula (I)

[0272] [ka] or a pharmaceutically acceptable salt thereof, 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)C 1~6 -alkyl, optionally containing halogen, hydroxy, cyano, C 3~6 -cycloalkyl, halo-C 3~6 -cycloalkyl, C 1~6 -Alkoxy, Halo-C 1~6 -alkoxy, C 3~6 -Cycloalkoxy, halo-C 3~6 -cycloalkoxy, C 1~6 -Alkoxy-C 1~6 -substituted with one or more substituents independently selected from the group consisting of alkoxy, oxetanyl, tetrahydrofuranyl, tetrahydrofuranyloxy, tetrahydropyranyl, morpholinyl, pyrazolyl, isoxazolyl, triazolyl, and pyridinyl; oxetanyl, tetrahydrofuranyl, tetrahydrofuranyloxy, tetrahydropyranyl, morpholinyl, pyrazolyl, isoxazolyl, triazolyl, and pyridinyl are optionally substituted with one or more substituents independently selected from the group consisting of halogen, cyano, C 1~6 -Alkyl and halo-C 1~6 -substituted with one or more substituents independently selected from the group consisting of alkyl, C 1~6 - alkyl; (b)C 3~6 -cycloalkyl, optionally containing halogen, hydroxy, cyano, C 1~6 -Alkyl, Halo-C 1~6 -Alkyl, C 1~6 -Alkoxy, Halo-C 1~6 -substituted with one or more substituents independently selected from the group consisting of alkoxy, isoxazolyl, and pyridinyl; isoxazolyl and pyridinyl are optionally substituted with halogen, C 1~6 -Alkyl and halo-C 1~6 -substituted with one or more substituents independently selected from the group consisting of alkyl, C3~6 -cycloalkyl; (c) phenyl, optionally containing halogen, cyano, C 1~6 -Alkyl, Halo-C 1~6 -Alkyl, C 1~6 -Alkoxy, Halo-C 1~6 -alkoxy, and C 1~6 -Alkoxy-C 1~6 -phenyl substituted with one or more substituents independently selected from the group consisting of alkoxy; (d) a 4-, 5-, 6-, or 7-membered heterocyclyl that (i) is saturated, partially saturated, or fully unsaturated, monocyclic or fused bicyclic, (ii) has one or two oxygen ring atoms, the remaining ring atoms being carbon, and (iii) optionally contains halogen, hydroxy, cyano, C 1~6 -Alkyl, Halo-C 1~6 -Alkyl, C 2~6 -alkynyl, C 1~6 -alkoxy and halo-C 1~6 -heterocyclyl substituted with one or more substituents independently selected from the group consisting of alkoxy; and (e)-OR 7 and R 7 But C 1~6 - selected from the group consisting of alkyl, phenyl, and tetrahydropyranyl; (I C 1~6 -Alkyl is optionally substituted with halogen, cyano, C 3~6 -cycloalkyl, halo-C 3~6 -cycloalkyl, C 1~6 -alkoxy and halo-C 1~6 -substituted with one or more substituents independently selected from the group consisting of alkoxy; (ii) phenyl optionally containing halogen, C 1~6 -Alkyl, Halo-C 1~6 -Alkyl, C 1~6 -alkoxy and halo-C 1~6 -substituted with one or more substituents independently selected from the group consisting of alkoxy; (iii) tetrahydropyranyl optionally containing halogen, C 1~6 -Alkyl, Halo-C1~6 -Alkyl, C 1~6 -alkoxy and halo-C 1~6 -substituted with one or more substituents independently selected from the group consisting of alkoxy, OR 7 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; R 6 is hydrogen, halogen, and C 1~3 -alkyl, or a pharmaceutically acceptable salt thereof.

[0273] Embodiment 2. The compound has the structure of formula (II):

[0274] [ka] In the formula, X 1 , R 1 , R 2 , R 3 , R 4 , R 5 and R 6 is as defined in embodiment 1, or a pharmaceutically acceptable salt thereof.

[0275] Embodiment 3.X 1 is -S-; or a pharmaceutically acceptable salt thereof.

[0276] Embodiment 4.X 1 is —S(O)—; or a pharmaceutically acceptable salt thereof.

[0277] Embodiment 5.X 1is —S(O)2—; or a pharmaceutically acceptable salt thereof.

[0278] Embodiment 6.R 1 is hydrogen, halogen, and C 1~3 6. The compound of any one of embodiments 1-5, or a pharmaceutically acceptable salt thereof, wherein the compound is selected from the group consisting of: -alkyl.

[0279] Embodiment 7.R 1 is selected from the group consisting of hydrogen, chloro, fluoro, and methyl; or a pharmaceutically acceptable salt thereof.

[0280] Embodiment 8.R 1 6. The compound of any one of embodiments 1-5, or a pharmaceutically acceptable salt thereof, wherein:

[0281] Embodiment 9.R 1 or a pharmaceutically acceptable salt thereof.

[0282] Embodiment 10.R 1 or a pharmaceutically acceptable salt thereof.

[0283] Embodiment 11.R 1 6. The compound of any one of embodiments 1-5, or a pharmaceutically acceptable salt thereof, wherein:

[0284] Embodiment 12.R 3 is selected from the group consisting of hydrogen, chloro, fluoro, and methyl; or a pharmaceutically acceptable salt thereof.

[0285] Embodiment 13.R 3 12. The compound of any one of embodiments 1-11, or a pharmaceutically acceptable salt thereof, wherein:

[0286] Embodiment 14.R 3 12. The compound of any one of embodiments 1-11, or a pharmaceutically acceptable salt thereof, wherein is chloro.

[0287] Embodiment 15.R 3 12. The compound of any one of embodiments 1-11, or a pharmaceutically acceptable salt thereof, wherein is fluoro.

[0288] Embodiment 16.R 3 12. The compound of any one of embodiments 1-11, or a pharmaceutically acceptable salt thereof, wherein:

[0289] Embodiment 17.R 4 is selected from the group consisting of hydrogen, halogen, and methyl; or a pharmaceutically acceptable salt thereof.

[0290] Embodiment 18.R 4 17. The compound of any one of embodiments 1-16, or a pharmaceutically acceptable salt thereof, wherein: is hydrogen.

[0291] Embodiment 19.R 4 17. The compound of any one of embodiments 1-16, or a pharmaceutically acceptable salt thereof, wherein is chloro.

[0292] Embodiment 20.R 4 17. The compound of any one of embodiments 1-16, or a pharmaceutically acceptable salt thereof, wherein is fluoro.

[0293] Embodiment 21.R 4 17. The compound of any one of embodiments 1-16, or a pharmaceutically acceptable salt thereof, wherein:

[0294] Embodiment 22.R 5 22. The compound of any one of embodiments 1-21, or a pharmaceutically acceptable salt thereof, wherein is selected from the group consisting of hydrogen, chloro, fluoro, and methyl.

[0295] Embodiment 23.R 5 22. The compound of any one of embodiments 1-21, or a pharmaceutically acceptable salt thereof, wherein:

[0296] Embodiment 24.R 5 22. The compound of any one of embodiments 1-21, or a pharmaceutically acceptable salt thereof, wherein: is fluoro.

[0297] Embodiment 25.R 5 22. The compound of any one of embodiments 1-21, or a pharmaceutically acceptable salt thereof, wherein:

[0298] Embodiment 26.R 5 22. The compound of any one of embodiments 1-21, or a pharmaceutically acceptable salt thereof, wherein:

[0299] Embodiment 27.R 6 is selected from the group consisting of hydrogen, chloro, fluoro, and methyl; or a pharmaceutically acceptable salt thereof.

[0300] Embodiment 28.R 6 27. The compound of any one of embodiments 1-26, or a pharmaceutically acceptable salt thereof, wherein: is hydrogen.

[0301] Embodiment 29.R 6 27. The compound of any one of embodiments 1-26, or a pharmaceutically acceptable salt thereof, wherein is chloro.

[0302] Embodiment 30.R 6 27. The compound of any one of embodiments 1-26, or a pharmaceutically acceptable salt thereof, wherein is fluoro.

[0303] Embodiment 31.R 6 27. The compound of any one of embodiments 1-26, or a pharmaceutically acceptable salt thereof, wherein:

[0304] Embodiment 32.R 1 , R3 , R 4 , R 5 , and R 6 One of the substituents is a halogen and C 1~3 -alkyl, and the remaining R 1 , R 3 , R 4 , R 5 , and R 6 6. The compound of any one of embodiments 1 to 5, or a pharmaceutically acceptable salt thereof, wherein the substituents are all hydrogen.

[0305] Embodiment 33.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 compound of embodiment 32, or a pharmaceutically acceptable salt thereof, wherein the substituents are all hydrogen.

[0306] Embodiment 34.R 1 , R 3 , R 4 , R 5 , and R 6 One of the substituents is selected from the group consisting of chloro and fluoro, and the remaining R 1 , R 3 , R 4 , R 5 , and R 6 The compound of embodiment 32, or a pharmaceutically acceptable salt thereof, wherein the substituents are all hydrogen.

[0307] Embodiment 35.R 1 , R 3 , R 4 , R 5 , and R 6 One of the substituents is methyl and the remaining R 1 , R 3 , R 4 , R 5 , and R6 The compound of embodiment 32, or a pharmaceutically acceptable salt thereof, wherein the substituents are all hydrogen.

[0308] Embodiment 36. The compound has the structure of formula (III-A):

[0309] [ka] In the formula, R 1 and R 2 The compound of any one of embodiments 32 to 35, or a pharmaceutically acceptable salt thereof, wherein is as defined in embodiment 1.

[0310] Embodiment 37. The compound has the structure of formula (III-B):

[0311] [ka] In the formula, R 2 and R 3 The compound of any one of embodiments 32 to 35, or a pharmaceutically acceptable salt thereof, wherein is as defined in embodiment 1.

[0312] Embodiment 38. The compound has the structure of Formula (III-C):

[0313] [ka] In the formula, R 2 and R 4 The compound of any one of embodiments 32 to 35, or a pharmaceutically acceptable salt thereof, wherein is as defined in embodiment 1.

[0314] Embodiment 39. The compound has the structure of formula (III-D):

[0315] [ka] In the formula, R 2 and R 5The compound of any one of embodiments 32 to 35, or a pharmaceutically acceptable salt thereof, wherein is as defined in embodiment 1.

[0316] Embodiment 40. The compound has the structure of formula (III-E):

[0317] [ka] In the formula, R 2 and R 6 The compound of any one of embodiments 32 to 35, or a pharmaceutically acceptable salt thereof, wherein is as defined in embodiment 1.

[0318] Embodiment 41.R 1 , R 3 , R 4 , R 5 , and R 6 At least two of the substituents are halogen and C 1~3 -alkyl, and the remaining R 1 , R 3 , R 4 , R 5 , and R 6 6. The compound of any one of embodiments 1 to 5, or a pharmaceutically acceptable salt thereof, wherein the substituents are all hydrogen.

[0319] Embodiment 42.R 1 , R 3 , R 4 , R 5 , and R 6 Two of the substituents are independently selected from the group consisting of chloro, fluoro, and methyl, and the remaining R 1 , R 3 , R 4 , R 5 , and R 6 The compound of embodiment 41, or a pharmaceutically acceptable salt thereof, wherein the substituents are all hydrogen.

[0320] Embodiment 43.R 1 , R 3 , R 4 , R 5and R 6 43. The compound of embodiment 42, or a pharmaceutically acceptable salt thereof, wherein at least one of the substituents is chloro.

[0321] Embodiment 44.R 1 , R 3 , R 4 , R 5 and R 6 43. The compound of embodiment 42, or a pharmaceutically acceptable salt thereof, wherein at least one of the substituents is fluoro.

[0322] Embodiment 45.R 1 , R 3 , R 4 , R 5 and R 6 43. The compound of embodiment 42, or a pharmaceutically acceptable salt thereof, wherein at least one of the substituents is methyl.

[0323] Embodiment 46. The compound has the structure of formula (IV):

[0324] [ka] In the formula, R 2 is as defined in embodiment 1, or a pharmaceutically acceptable salt thereof.

[0325] Embodiment 47. The compound has the structure of formula (IV-A):

[0326] [ka] In the formula, R 2 is as defined in embodiment 1, or a pharmaceutically acceptable salt thereof.

[0327] Embodiment 48.R 2 is C 1~6 -alkyl, C 1~6 -Alkyl is optionally substituted with halogen, hydroxy, cyano, C 3~6 -cycloalkyl, halo-C3~6 -cycloalkyl, C 1~6 -Alkoxy, Halo-C 1~6 -alkoxy, C 3~6 -Cycloalkoxy, halo-C 3~6 -cycloalkoxy, C 1~6 -Alkoxy-C 1~6 -substituted with one or more substituents independently selected from the group consisting of alkoxy, oxetanyl, tetrahydrofuranyl, tetrahydrofuranyloxy, tetrahydropyranyl, morpholinyl, pyrazolyl, isoxazolyl, triazolyl, and pyridinyl; oxetanyl, tetrahydrofuranyl, tetrahydrofuranyloxy, tetrahydropyranyl, morpholinyl, pyrazolyl, isoxazolyl, triazolyl, and pyridinyl are optionally substituted with one or more substituents independently selected from the group consisting of halogen, C 1~6 -Alkyl and halo-C 1~6 48. The compound of any one of embodiments 1-47, or a pharmaceutically acceptable salt thereof, substituted with one or more substituents independently selected from the group consisting of: -alkyl.

[0328] Embodiment 49.R 2 is C 1~3 -alkyl, C 1~3 -Alkyl is optionally substituted with halogen, hydroxy, cyano, C 3~6 -cycloalkyl, halo-C 3~6 -cycloalkyl, C 1~3 -Alkoxy, Halo-C 1~3 -alkoxy, C 3~6 -Cycloalkoxy, halo-C 3~6 -cycloalkoxy, C 1~3 -Alkoxy-C 1~3 -substituted with one or more substituents independently selected from the group consisting of alkoxy, oxetanyl, tetrahydrofuranyl, tetrahydrofuranyloxy, tetrahydropyranyl, morpholinyl, pyrazolyl, isoxazolyl, triazolyl, and pyridinyl; oxetanyl, tetrahydrofuranyl, tetrahydrofuranyloxy, tetrahydropyranyl, morpholinyl, pyrazolyl, isoxazolyl, triazolyl, and pyridinyl are optionally substituted with one or more substituents independently selected from the group consisting of halogen, C 1~3 -Alkyl and halo-C1~3 48. The compound of any one of embodiments 1-47, or a pharmaceutically acceptable salt thereof, substituted with one or more substituents independently selected from the group consisting of: -alkyl.

[0329] Embodiment 50.R 2 is C 1~6 -alkyl, C 1~6 -Alkyl is optionally substituted with halogen, hydroxy, C 1~6 -Alkoxy, Halo-C 1~6 -alkoxy, C 3~6 -cycloalkoxy, C 1~6 -Alkoxy-C 1~6 -substituted with one or more substituents independently selected from the group consisting of alkoxy, tetrahydrofuranyl, tetrahydrofuranyloxy, tetrahydropyranyl, morpholinyl, pyrazolyl, isoxazolyl, triazolyl, and pyridinyl; tetrahydrofuranyl, tetrahydrofuranyloxy, tetrahydropyranyl, morpholinyl, pyrazolyl, isoxazolyl, triazolyl, and pyridinyl are optionally substituted with one or more substituents independently selected from the group consisting of halogen, C 1~6 -Alkyl and halo-C 1~6 48. The compound of any one of embodiments 1-47, or a pharmaceutically acceptable salt thereof, substituted with one or more substituents independently selected from the group consisting of: -alkyl.

[0330] Embodiment 51.R 2 is C 1~3 -alkyl, C 1~3 -Alkyl is optionally substituted with halogen, hydroxy, C 1~3 -Alkoxy, Halo-C 1~3 -alkoxy, C 3~6 -cycloalkoxy, C 1~3 -Alkoxy-C 1~3-substituted with one or more substituents independently selected from the group consisting of alkoxy, tetrahydrofuranyl, tetrahydrofuranyloxy, tetrahydropyranyl, morpholinyl, pyrazolyl, isoxazolyl, triazolyl, and pyridinyl; tetrahydrofuranyl, tetrahydrofuranyloxy, tetrahydropyranyl, morpholinyl, pyrazolyl, isoxazolyl, triazolyl, and pyridinyl are optionally substituted with one or more substituents independently selected from the group consisting of halogen, C 1~3 -Alkyl and halo-C 1~6 48. The compound of any one of embodiments 1-47, or a pharmaceutically acceptable salt thereof, substituted with one or more substituents independently selected from the group consisting of: -alkyl.

[0331] Embodiment 52.R 2 is C 1~6 48. The compound of any one of embodiments 1-47, or a pharmaceutically acceptable salt thereof, wherein - is -alkyl.

[0332] Embodiment 53.R 2 is C 1~6 -alkyl, C 1~6 48. The compound of any one of embodiments 1-47, or a pharmaceutically acceptable salt thereof, wherein -alkyl is optionally substituted with one or more halogens.

[0333] Embodiment 54.R 2 is C 1~6 -alkyl, C 1~6 48. The compound of any one of embodiments 1-47, or a pharmaceutically acceptable salt thereof, wherein -alkyl is optionally substituted with one or more fluoro.

[0334] Embodiment 55.R 2 is C 1~6 -alkyl, C 1~6 48. The compound of any one of embodiments 1-47, or a pharmaceutically acceptable salt thereof, wherein -alkyl is optionally substituted with one or more hydroxy.

[0335] Embodiment 56.R 2 is C 1~6 -alkyl, C1~6 -Alkyl optionally has one or more C 1~6 48. The compound of any one of embodiments 1-47, or a pharmaceutically acceptable salt thereof, substituted with -alkoxy.

[0336] Embodiment 57.R 2 is C 1~6 -alkyl, C 1~6 -alkyl optionally contains one or more halo-C 1~6 48. The compound of any one of embodiments 1-47, or a pharmaceutically acceptable salt thereof, substituted with -alkoxy.

[0337] Embodiment 58.R 2 is C 1~6 -alkyl, C 1~6 -Alkyl optionally has one or more C 3~6 48. The compound of any one of embodiments 1-47, or a pharmaceutically acceptable salt thereof, substituted with -cycloalkoxy.

[0338] Embodiment 59.R 2 is C 1~6 -alkyl, C 1~6 -Alkyl optionally has one or more C 1~6 -Alkoxy-C 1-6 48. The compound of any one of embodiments 1-47, or a pharmaceutically acceptable salt thereof, substituted with -alkoxy.

[0339] Embodiment 60.R 2 is C 1~6 -alkyl, C 1~6 -alkyl is optionally substituted with one or more tetrahydrofuranyls, and the tetrahydrofuranyls are optionally substituted with halogen, C 1~6 -Alkyl and halo-C 1~6 48. The compound of any one of embodiments 1-47, or a pharmaceutically acceptable salt thereof, substituted with one or more substituents independently selected from the group consisting of: -alkyl.

[0340] Embodiment 61.R 2 is C 1~6 -alkyl, C1~6 -alkyl is optionally substituted with one or more tetrahydrofuranyloxy, which is optionally substituted with halogen, C 1~6 -Alkyl and halo-C 1~6 48. The compound of any one of embodiments 1-47, or a pharmaceutically acceptable salt thereof, substituted with one or more substituents independently selected from the group consisting of: -alkyl.

[0341] Embodiment 62.R 2 is C 1~6 -alkyl, C 1~6 -alkyl is optionally substituted with one or more tetrahydropyranyls, which are optionally substituted with halogen, C 1~6 -Alkyl and halo-C 1~6 48. The compound of any one of embodiments 1-47, or a pharmaceutically acceptable salt thereof, substituted with one or more substituents independently selected from the group consisting of: -alkyl.

[0342] Embodiment 63.R 2 is C 1~6 -alkyl, C 1~6 -alkyl is optionally substituted with one or more morpholinyls, and the morpholinyls are optionally substituted with halogen, C 1~6 -Alkyl and halo-C 1~6 48. The compound of any one of embodiments 1-47, or a pharmaceutically acceptable salt thereof, substituted with one or more substituents independently selected from the group consisting of: -alkyl.

[0343] Embodiment 64.R 2 is C 1~6 -alkyl, C 1~6 -alkyl is optionally substituted with one or more pyrazolyls, the pyrazolyls are optionally substituted with halogen, C 1~6 -Alkyl and halo-C 1~6 48. The compound of any one of embodiments 1-47, or a pharmaceutically acceptable salt thereof, substituted with one or more substituents independently selected from the group consisting of: -alkyl.

[0344] Embodiment 65.R2 is C 1~6 -alkyl, C 1~6 -alkyl is optionally substituted with one or more isoxazolyl, and the isoxazolyl is optionally substituted with halogen, C 1~6 -Alkyl and halo-C 1~6 48. The compound of any one of embodiments 1-47, or a pharmaceutically acceptable salt thereof, substituted with one or more substituents independently selected from the group consisting of: -alkyl.

[0345] Embodiment 66.R 2 is C 1~6 -alkyl, C 1~6 -alkyl is optionally substituted with one or more triazolyls, and the triazolyls are optionally substituted with halogen, C 1~6 -Alkyl and halo-C 1~6 48. The compound of any one of embodiments 1-47, or a pharmaceutically acceptable salt thereof, substituted with one or more substituents independently selected from the group consisting of: -alkyl.

[0346] Embodiment 67.R 2 is C 1~6 -alkyl, C 1~6 -alkyl is optionally substituted with one or more pyridinyls, and pyridinyls are optionally substituted with halogen, C 1~6 -Alkyl and halo-C 1~6 48. The compound of any one of embodiments 1-47, or a pharmaceutically acceptable salt thereof, substituted with one or more substituents independently selected from the group consisting of: -alkyl.

[0347] Embodiment 68.R 2or a pharmaceutically acceptable salt thereof.

[0348] Embodiment 69. The compound is N-(2-((R)-4-cyanothiazolidin-3-yl)-2-oxoethyl)-6-((RS)-1-(3-fluoropyridin-2-yl)-ethyl)quinoline-4-carboxamide; (R)-N-(2-(4-cyanothiazolidin-3-yl)-2-oxoethyl)-6-(2-hydroxypropan-2-yl)quinoline-4-carboxamide; (R)-N-(2-(4-cyanothiazolidin-3-yl)-2-oxoethyl)-6-(trifluoromethyl)-quinoline-4-carboxamide; (R)-N-(2-(4-cyanothiazolidin-3-yl)-2-oxoethyl)-6-(2-methoxypropan-2-yl)quinoline-4-carboxamide; (R)—N-(2-(4-cyanothiazolidin-3-yl)-2-oxoethyl)-6-((2,5-dimethyl-2H-1,2,3-triazol-4-yl)-methyl)quinoline-4-carboxamide; (R)-N-(2-(4-cyanothiazolidin-3-yl)-2-oxoethyl)-6-(morpholino-methyl)quinoline-4-carboxamide; N-(2-((R)-4-cyanothiazolidin-3-yl)-2-oxoethyl)-6-((RS)-1-hydroxyethyl)quinoline-4-carboxamide; N-(2-((R)-4-cyanothiazolidin-3-yl)-2-oxoethyl)-6-((RS)-1-methoxyethyl)quinoline-4-carboxamide; (R)-N-(2-(4-cyanothiazolidin-3-yl)-2-oxoethyl)-6-(ethoxymethyl)-quinoline-4-carboxamide; (R)-N-(2-(4-cyanothiazolidin-3-yl)-2-oxoethyl)-6-methylquinoline-4-carboxamide; (R)-N-(2-(4-cyanothiazolidin-3-yl)-2-oxoethyl)-6-(fluoromethyl)-quinoline-4-carboxamide; N-(2-((R)-4-cyanothiazolidin-3-yl)-2-oxoethyl)-6-((RS)-1,2-dimethoxyethyl)quinoline-4-carboxamide; (R)-N-(2-(4-cyanothiazolidin-3-yl)-2-oxoethyl)-6-((2-methoxyethoxy)-methyl)quinoline-4-carboxamide; N-(2-((R)-4-cyanothiazolidin-3-yl)-2-oxoethyl)-6-((((RS)-tetrahydrofuran-3-yl)oxy)-methyl)quinoline-4-carboxamide; (R)—N-(2-(4-cyanothiazolidin-3-yl)-2-oxoethyl)-6-((2,2-difluoroethoxy)methyl)quinoline-4-carboxamide; (R)-N-(2-(4-cyanothiazolidin-3-yl)-2-oxoethyl)-6-(cyclopropoxy-methyl)quinoline-4-carboxamide; (R)—N-(2-(4-cyanothiazolidin-3-yl)-2-oxoethyl)-6-((4-methylisoxazol-3-yl)methyl)-quinoline-4-carboxamide; (R)—N-(2-(4-cyanothiazolidin-3-yl)-2-oxoethyl)-6-((4,6-dimethylpyridin-3-yl)-methyl)quinoline-4-carboxamide; (R)—N-(2-(4-cyanothiazolidin-3-yl)-2-oxoethyl)-6-((1,3-dimethyl-1H-pyrazol-5-yl)-methyl)quinoline-4-carboxamide; (R)—N-(2-(4-cyanothiazolidin-3-yl)-2-oxoethyl)-6-((2-methyl-2H-1,2,3-triazol-4-yl)-methyl)quinoline-4-carboxamide; (R)-N-(2-(4-cyanothiazolidin-3-yl)-2-oxoethyl)-6-((5-methylisoxazol-3-yl)-methyl)quinoline-4-carboxamide; N-(2-((R)-4-cyanothiazolidin-3-yl)-2-oxoethyl)-6-((RS)-1-(5-methylisoxazol-3-yl)-ethyl)quinoline-4-carboxamide; 6-((RS)-1-(5-chloropyridin-2-yl)ethyl)-N-(2-((R)-4-cyanothiazolidin-3-yl)-2-oxoethyl)quinoline-4-carboxamide; N-(2-((R)-4-cyanothiazolidin-3-yl)-2-oxoethyl)-6-((RS)-1-(3-methylisoxazol-5-yl)-ethyl)quinoline-4-carboxamide; N-(2-((R)-4-cyanothiazolidin-3-yl)-2-oxoethyl)-6-((RS)-1-(6-methylpyridin-3-yl)-ethyl)quinoline-4-carboxamide; N-(2-((R)-4-cyanothiazolidin-3-yl)-2-oxoethyl)-6-((RS)-1-(2-(trifluoromethyl)pyridin-4-yl)ethyl)quinoline-4-carboxamide; (R)—N-(2-(4-cyanothiazolidin-3-yl)-2-oxoethyl)-6-(2,2-difluoropropyl)quinoline-4-carboxamide; (R)—N-(2-(4-cyanothiazolidin-3-yl)-2-oxoethyl)-6-((tetrahydro-2H-pyran-4-yl)-methyl)quinoline-4-carboxamide; (R)—N-(2-(4-cyanothiazolidin-3-yl)-2-oxoethyl)-6-(3,3,3-trifluoropropyl)quinoline-4-carboxamide; N-(2-((R)-4-cyanothiazolidin-3-yl)-2-oxoethyl)-6-(((RS)-tetrahydrofuran-3-yl)-methyl)quinoline-4-carboxamide; (R)-N-(2-(4-cyanothiazolidin-3-yl)-2-oxoethyl)-6-(difluoromethyl)-quinoline-4-carboxamide; (R)-6-((1H-pyrazol-1-yl)methyl)-N-(2-(4-cyanothiazolidin-3-yl)-2-oxoethyl)quinoline-4-carboxamide; (R)—N-(2-(4-cyanothiazolidin-3-yl)-2-oxoethyl)-6-(3-methoxypropyl)quinoline-4-carboxamide; and The compound of embodiment 1, selected from the group consisting of: (R)—N-(2-(4-cyanothiazolidin-3-yl)-2-oxoethyl)-6-(2-methoxyethyl)quinoline-4-carboxamide; or a pharmaceutically acceptable salt thereof.

[0349] Embodiment 70.R 2 is C 3~6 -cycloalkyl, C 3~6 -cycloalkyl is optionally substituted with halogen, hydroxy, cyano, C 1~6 -Alkyl, Halo-C 1~6 -Alkyl, C 1~6 -Alkoxy, Halo-C 1~6 -substituted with one or more substituents independently selected from the group consisting of alkoxy, isoxazolyl, and pyridinyl, wherein the isoxazolyl and pyridinyl are optionally substituted with one or more substituents independently selected from the group consisting of halogen, C 1~6 -Alkyl and halo-C 1~648. The compound of any one of embodiments 1-47, or a pharmaceutically acceptable salt thereof, substituted with one or more substituents independently selected from the group consisting of: -alkyl.

[0350] Embodiment 71.R 2 is C 3~6 -cycloalkyl, C 3~6 -cycloalkyl is optionally substituted with halogen, hydroxy, cyano, C 1~3 -Alkyl, Halo-C 1~3 -Alkyl, C 1~3 -Alkoxy, Halo-C 1~3 -substituted with one or more substituents independently selected from the group consisting of alkoxy, isoxazolyl, and pyridinyl, wherein the isoxazolyl and pyridinyl are optionally substituted with one or more substituents independently selected from the group consisting of halogen, C 1~3 -Alkyl and halo-C 1~3 48. The compound of any one of embodiments 1-47, or a pharmaceutically acceptable salt thereof, substituted with one or more substituents independently selected from the group consisting of: -alkyl.

[0351] Embodiment 72.R 2 is C 3~6 -cycloalkyl, C 3~6 -cycloalkyl is optionally substituted with halogen, cyano, C 1~6 -substituted with one or more substituents independently selected from the group consisting of alkoxy, isoxazolyl, and pyridinyl, wherein the isoxazolyl and pyridinyl are optionally substituted with one or more substituents independently selected from the group consisting of halogen, C 1~6 -Alkyl and halo-C 1~6 48. The compound of any one of embodiments 1-47, or a pharmaceutically acceptable salt thereof, substituted with one or more substituents independently selected from the group consisting of: -alkyl.

[0352] Embodiment 73.R 2 is C 3~6 -cycloalkyl, C 3~6 -cycloalkyl is optionally substituted with halogen, cyano, C 1~3-substituted with one or more substituents independently selected from the group consisting of alkoxy, isoxazolyl, and pyridinyl, wherein the isoxazolyl and pyridinyl are optionally substituted with one or more substituents independently selected from the group consisting of halogen, C 1~3 -Alkyl and halo-C 1~3 48. The compound of any one of embodiments 1-47, or a pharmaceutically acceptable salt thereof, substituted with one or more substituents independently selected from the group consisting of: -alkyl.

[0353] Embodiment 74.R 2 is C 3~6 48. The compound of any one of embodiments 1-47, or a pharmaceutically acceptable salt thereof, wherein -cycloalkyl.

[0354] Embodiment 75.R 2 is C 3~6 -cycloalkyl, C 3~6 48. The compound of any one of embodiments 1-47, or a pharmaceutically acceptable salt thereof, wherein -alkyl is optionally substituted with one or more halogens.

[0355] Embodiment 76.R 2 is C 3~6 -cycloalkyl, C 3~6 48. The compound of any one of embodiments 1-47, or a pharmaceutically acceptable salt thereof, wherein -alkyl is optionally substituted with one or more cyano.

[0356] Embodiment 77.R 2 is C 3~6 -cycloalkyl, C 3~6 -Alkyl optionally has one or more C 1~6 48. The compound of any one of embodiments 1-47, or a pharmaceutically acceptable salt thereof, substituted with -alkoxy.

[0357] Embodiment 78.R 2 is C 3~6 -cycloalkyl, C 3~6 -cycloalkyl is optionally substituted with one or more isoxazolyl, wherein the isoxazolyl is optionally substituted with halogen, C 1~6 -Alkyl and halo-C1~6 48. The compound of any one of embodiments 1-47, or a pharmaceutically acceptable salt thereof, substituted with one or more substituents independently selected from the group consisting of: -alkyl.

[0358] Embodiment 79.R 2 is C 3~6 -cycloalkyl, C 3~6 -cycloalkyl is optionally substituted with one or more pyridinyls, wherein the pyridinyls are optionally substituted with halogen, C 1~6 -Alkyl and halo-C 1~6 48. The compound of any one of embodiments 1-47, or a pharmaceutically acceptable salt thereof, substituted with one or more substituents independently selected from the group consisting of: -alkyl.

[0359] Embodiment 80.R 2 80. The compound of any one of embodiments 70-79, or a pharmaceutically acceptable salt thereof, wherein is optionally substituted cyclopropyl.

[0360] Embodiment 81.R 2 Embodiment 79. The compound of any one of embodiments 70-79, or a pharmaceutically acceptable salt thereof, wherein is optionally substituted cyclobutyl.

[0361] Embodiment 82.R 2 80. The compound of any one of embodiments 70-79, or a pharmaceutically acceptable salt thereof, wherein is optionally substituted cyclopentyl.

[0362] Embodiment 83.R 2 80. The compound of any one of embodiments 70-79, or a pharmaceutically acceptable salt thereof, wherein is optionally substituted cyclohexyl.

[0363] Embodiment 84.R 2is selected from the group consisting of cyclopropyl, cyanocyclopropyl, ethoxycyclopropyl, methylisoxazolylcyclopropyl, methylpyridinylcyclopropyl, chloropyridinylcyclopropyl, fluoropyridinylcyclopropyl, trifluoropyridinylcyclopropyl, fluorocyclobutyl, (fluoro)(methoxy)cyclobutyl, methoxycyclohexyl, and cyanocyclohexyl; or a pharmaceutically acceptable salt thereof.

[0364] Embodiment 85. The compound is (R)—N-(2-(4-cyanothiazolidin-3-yl)-2-oxoethyl)-6-(1-(2-(trifluoromethyl)pyridin-4-yl)-cyclopropyl)quinoline-4-carboxamide; (R)—N-(2-(4-cyanothiazolidin-3-yl)-2-oxoethyl)-6-(1-(6-methylpyridin-3-yl)-cyclopropyl)quinoline-4-carboxamide; (R)—N-(2-(4-cyanothiazolidin-3-yl)-2-oxoethyl)-6-(1-(3-fluoropyridin-2-yl)-cyclopropyl)quinoline-4-carboxamide; (R)—N-(2-(4-cyanothiazolidin-3-yl)-2-oxoethyl)-6-(1-(5-methylisoxazol-3-yl)-cyclopropyl)quinoline-4-carboxamide; (R)-6-(1-(5-chloropyridin-2-yl)cyclopropyl)-N-(2-(4-cyanothiazolidin-3-yl)-2-oxoethyl)quinoline-4-carboxamide; (R)-N-(2-(4-cyanothiazolidin-3-yl)-2-oxoethyl)-6-(1-(3-methylisoxazol-5-yl)-cyclopropyl)quinoline-4-carboxamide; 6-((1r,4R * )-4-cyanocyclohexyl)-N-(2-((R-4-cyanothiazolidin-3-yl)-2-oxoethyl)-quinoline-4-carboxamide; 6-((1r,4R* )-4-cyanocyclohexyl)-N-(2-((R-4-cyanothiazolidin-3-yl)-2-oxoethyl)-quinoline-4-carboxamide; (R)-6-(1-cyanocyclohexyl)-N-(2-(4-cyanothiazolidin-3-yl)-2-oxoethyl)quinoline-4-carboxamide; N-(2-((R)-4-cyanothiazolidin-3-yl)-2-oxoethyl)-6-((1r,3R * )-1-fluoro-3-methoxy-cyclobutyl)quinoline-4-carboxamide isomer 1; N-(2-((R)-4-cyanothiazolidin-3-yl)-2-oxoethyl)-6-((1r,3R * )-1-fluoro-3-methoxy-cyclobutyl)quinoline-4-carboxamide isomer 2; (R)-6-(1-cyanocyclopropyl)-N-(2-(4-cyanothiazolidin-3-yl)-2-oxoethyl)quinoline-4-carboxamide; (R)-N-(2-(4-cyanothiazolidin-3-yl)-2-oxoethyl)-6-(1-fluoro-cyclobutyl)quinoline-4-carboxamide; (R)-N-(2-(4-cyanothiazolidin-3-yl)-2-oxoethyl)-6-(1-ethoxycyclopropyl)quinoline-4-carboxamide; (R)-N-(2-(4-cyanothiazolidin-3-yl)-2-oxoethyl)-6-cyclopropylquinoline-4-carboxamide; N-(2-((R)-4-cyanothiazolidin-3-yl)-2-oxoethyl)-6-((1r,4R * )-4-Methoxycyclohexyl)-quinoline-4-carboxamide isomer 1; and N-(2-((R)-4-cyanothiazolidin-3-yl)-2-oxoethyl)-6-((1r,4R * 2. The compound of embodiment 1, or a pharmaceutically acceptable salt thereof, selected from the group consisting of: 1)-4-methoxycyclohexyl)-quinoline-4-carboxamide isomer 2;

[0365] Embodiment 86.R 2 is phenyl, and the phenyl is optionally selected from halogen, cyano, C 1~6 -Alkyl, Halo-C 1~6 -Alkyl, C 1~6 -Alkoxy, Halo-C 1~6 -alkoxy and C 1~6 -Alkoxy-C 1~6 48. The compound of any one of embodiments 1-47, or a pharmaceutically acceptable salt thereof, substituted with one or more substituents independently selected from the group consisting of: -alkoxy.

[0366] Embodiment 87.R 2 is phenyl, and the phenyl is optionally selected from halogen, cyano, C 1~3 -Alkyl, Halo-C 1~3 -Alkyl, C 1~3 -Alkoxy, Halo-C 1~3 -alkoxy and C 1~3 -Alkoxy-C 1~3 48. The compound of any one of embodiments 1-47, or a pharmaceutically acceptable salt thereof, substituted with one or more substituents independently selected from the group consisting of: -alkoxy.

[0367] Embodiment 88.R 2 The compound of any one of embodiments 1-47, or a pharmaceutically acceptable salt thereof, wherein is phenyl, wherein phenyl is optionally substituted with one or more halogens.

[0368] Embodiment 89.R 2 is phenyl, and the phenyl optionally has one or more C 1~6 48. The compound of any one of embodiments 1-47, or a pharmaceutically acceptable salt thereof, substituted with -alkyl.

[0369] Embodiment 90.R 2 is phenyl, which optionally contains one or more halo-C 1~6 48. The compound of any one of embodiments 1-47, or a pharmaceutically acceptable salt thereof, substituted with -alkyl.

[0370] Embodiment 91.R 2 is phenyl, and the phenyl optionally has one or more C 1~6 48. The compound of any one of embodiments 1-47, or a pharmaceutically acceptable salt thereof, substituted with -alkoxy.

[0371] Embodiment 92.R 2 is phenyl, which optionally contains one or more halo-C 1~6 48. The compound of any one of embodiments 1-47, or a pharmaceutically acceptable salt thereof, substituted with -alkoxy.

[0372] Embodiment 93.R 2 is phenyl, and the phenyl optionally has one or more C 1~6 -Alkoxy-C 1~6 48. The compound of any one of embodiments 1-47, or a pharmaceutically acceptable salt thereof, substituted with -alkoxy.

[0373] Embodiment 94. The compound of embodiment 1, wherein the compound is (R)—N-(2-(4-cyanothiazolidin-3-yl)-2-oxoethyl)-6-(4-(3-methoxy-propoxy)-phenyl)quinoline-4-carboxamide, or a pharmaceutically acceptable salt thereof.

[0374] Embodiment 95.R 2 is a 4-, 5-, 6-, or 7-membered heterocyclyl, wherein the heterocyclyl ring (i) is a saturated, partially saturated, or fully unsaturated monocyclic or fused bicyclic ring; (ii) has one or two oxygen ring atoms, the remaining ring atoms being carbon; and (iii) optionally contains halogen, hydroxy, cyano, C 1~6 -Alkyl, Halo-C 1~6 -Alkyl, C 2~6 -alkynyl, C 1~6 -alkoxy and halo-C 1~6 48. The compound of any one of embodiments 1-47, or a pharmaceutically acceptable salt thereof, substituted with one or more substituents independently selected from the group consisting of: -alkoxy.

[0375] Embodiment 96.R 2 is a 4-, 5-, 6-, or 7-membered heterocyclyl, wherein the heterocyclyl ring (i) is a saturated, partially saturated, or fully unsaturated monocyclic or fused bicyclic ring; (ii) has one or two oxygen ring atoms, the remaining ring atoms being carbon; and (iii) optionally contains halogen, hydroxy, cyano, C 1~3 -Alkyl, Halo-C 1~3 -Alkyl, C 2~3 -alkynyl, C 1~3 -alkoxy and halo-C 1~3 48. The compound of any one of embodiments 1-47, or a pharmaceutically acceptable salt thereof, substituted with one or more substituents independently selected from the group consisting of: -alkoxy.

[0376] Embodiment 97.R 2 is a 5- or 6-membered heterocyclyl, the heterocyclyl ring being (i) a saturated, partially saturated, or fully unsaturated monocyclic or fused bicyclic ring; (ii) having one or two oxygen ring atoms with the remaining ring atoms being carbon; and (iii) optionally containing halogen, hydroxy, cyano, C 1~3 -Alkyl, C 2~3 -alkynyl, and C 1~3 48. The compound of any one of embodiments 1-47, or a pharmaceutically acceptable salt thereof, substituted with one or more substituents independently selected from the group consisting of: -alkoxy.

[0377] Embodiment 98.R 2 is a 4-membered heterocyclyl, the heterocyclyl ring being (i) a saturated or partially saturated monocyclic ring, (ii) having one oxygen ring atom with the remaining ring atoms being carbon, and (iii) optionally containing halogen, hydroxy, cyano, C 1~6 -Alkyl, Halo-C 1~6 -Alkyl, C 2~6 -alkynyl, C 1~6 -alkoxy and halo-C 1~6 48. The compound of any one of embodiments 1-47, or a pharmaceutically acceptable salt thereof, substituted with one or more substituents independently selected from the group consisting of: -alkoxy.

[0378] Embodiment 99.R 2 is a 4-membered heterocyclyl, the heterocyclyl ring being (i) a saturated or partially saturated monocyclic ring, (ii) having one oxygen ring atom with the remaining ring atoms being carbon, and (iii) optionally containing halogen, hydroxy, cyano, C 1~3 -Alkyl, Halo-C 1~3 -Alkyl, C 2~3 -alkynyl, C 1~3 -alkoxy and halo-C 1~3 48. The compound of any one of embodiments 1-47, or a pharmaceutically acceptable salt thereof, substituted with one or more substituents independently selected from the group consisting of: -alkoxy.

[0379] Embodiment 100.R 2 is a 5-membered heterocyclyl, the heterocyclyl ring (i) being a saturated, partially saturated, or fully unsaturated monocyclic ring; (ii) having one or two oxygen ring atoms, the remaining ring atoms being carbon; and (iii) optionally containing halogen, hydroxy, cyano, C 1~6 -Alkyl, Halo-C 1~6 -Alkyl, C 2~6 -alkynyl, C 1~6 -alkoxy and halo-C 1~6 48. The compound of any one of embodiments 1-47, or a pharmaceutically acceptable salt thereof, substituted with one or more substituents independently selected from the group consisting of: -alkoxy.

[0380] Embodiment 101.R 2 is a 5-membered heterocyclyl, the heterocyclyl ring (i) being a saturated, partially saturated, or fully unsaturated monocyclic ring; (ii) having one or two oxygen ring atoms, the remaining ring atoms being carbon; and (iii) optionally containing halogen, hydroxy, cyano, C 1~3 -Alkyl, Halo-C 1~3 -Alkyl, C 2~3 -alkynyl, C 1~3 -alkoxy and halo-C 1~348. The compound of any one of embodiments 1-47, or a pharmaceutically acceptable salt thereof, substituted with one or more substituents independently selected from the group consisting of: -alkoxy.

[0381] Embodiment 102.R 2 is a 6-membered heterocyclyl, the heterocyclyl ring (i) being a saturated, partially saturated, or fully unsaturated monocyclic ring; (ii) having one or two oxygen ring atoms, the remaining ring atoms being carbon; and (iii) optionally containing halogen, hydroxy, cyano, C 1~6 -Alkyl, Halo-C 1~6 -Alkyl, C 2~6 -alkynyl, C 1~6 -alkoxy and halo-C 1~6 48. The compound of any one of embodiments 1-47, or a pharmaceutically acceptable salt thereof, substituted with one or more substituents independently selected from the group consisting of: -alkoxy.

[0382] Embodiment 103.R 2 is a 6-membered heterocyclyl, the heterocyclyl ring (i) being a saturated, partially saturated, or fully unsaturated monocyclic ring; (ii) having one or two oxygen ring atoms, the remaining ring atoms being carbon; and (iii) optionally containing halogen, hydroxy, cyano, C 1~3 -Alkyl, Halo-C 1~3 -Alkyl, C 2~3 -alkynyl, C 1~3 -alkoxy and halo-C 1~3 48. The compound of any one of embodiments 1-47, or a pharmaceutically acceptable salt thereof, substituted with one or more substituents independently selected from the group consisting of: -alkoxy.

[0383] Embodiment 104.R 2 is a seven-membered heterocyclyl, the heterocyclyl ring (i) being saturated, partially saturated, or fully unsaturated, monocyclic or fused bicyclic ring; (ii) having one or two oxygen ring atoms, the remaining ring atoms being carbon; and (iii) optionally containing halogen, hydroxy, cyano, C 1~6 -Alkyl, Halo-C 1~6 -Alkyl, C2~6 -alkynyl, C 1~6 -alkoxy and halo-C 1~6 48. The compound of any one of embodiments 1-47, or a pharmaceutically acceptable salt thereof, substituted with one or more substituents independently selected from the group consisting of: -alkoxy.

[0384] Embodiment 105.R 2 is a seven-membered heterocyclyl, the heterocyclyl ring (i) being saturated, partially saturated, or fully unsaturated, monocyclic or fused bicyclic ring; (ii) having one or two oxygen ring atoms, the remaining ring atoms being carbon; and (iii) optionally containing halogen, hydroxy, cyano, C 1~3 -Alkyl, Halo-C 1~3 -Alkyl, C 2~3 -alkynyl, C 1~3 -alkoxy and halo-C 1~3 48. The compound of any one of embodiments 1-47, or a pharmaceutically acceptable salt thereof, substituted with one or more substituents independently selected from the group consisting of: -alkoxy.

[0385] Embodiment 106.R 2 is selected from the group consisting of tetrahydrofuranyl, furanyl, dihydropyranyl, tetrahydropyranyl, 1,4-dioxanyl, and 3-oxabicyclo[4.1.0]heptane, wherein tetrahydrofuranyl, dihydropyranyl, tetrahydropyranyl, 1,4-dioxanyl, and 3-oxabicyclo[4.1.0]heptane are optionally selected from the group consisting of halogen, hydroxy, cyano, C 1~6 -Alkyl, Halo-C 1~6 -Alkyl, C 2~6 -alkynyl, C 1~6 -alkoxy and halo-C 1~6 48. The compound of any one of embodiments 1-47, or a pharmaceutically acceptable salt thereof, substituted with one or more substituents independently selected from the group consisting of: -alkoxy.

[0386] Embodiment 107.R 2is selected from the group consisting of tetrahydrofuranyl, furanyl, dihydropyranyl, tetrahydropyranyl, 1,4-dioxanyl, and 3-oxabicyclo[4.1.0]heptane, wherein tetrahydrofuranyl, dihydropyranyl, tetrahydropyranyl, 1,4-dioxanyl, and 3-oxabicyclo[4.1.0]heptane are optionally selected from the group consisting of halogen, hydroxy, cyano, C 1~3 -Alkyl, Halo-C 1~3 -Alkyl, C 2~3 -alkynyl, C 1~3 -alkoxy and halo-C 1~3 48. The compound of any one of embodiments 1-47, or a pharmaceutically acceptable salt thereof, substituted with one or more substituents independently selected from the group consisting of: -alkoxy.

[0387] Embodiment 108.R 2 is tetrahydrofuranyl, which is optionally substituted with halogen, hydroxy, cyano, C 1~6 -Alkyl, Halo-C 1~6 -Alkyl, C 2~6 -alkynyl, C 1~6 -alkoxy and halo-C 1~6 48. The compound of any one of embodiments 1-47, or a pharmaceutically acceptable salt thereof, substituted with one or more substituents independently selected from the group consisting of: -alkoxy.

[0388] Embodiment 109.R 2 is tetrahydropyranyl, which is optionally substituted with halogen, hydroxy, cyano, C 1~6 -Alkyl, Halo-C 1~6 -Alkyl, C 2~6 -alkynyl, C 1~6 -alkoxy and halo-C 1~6 48. The compound of any one of embodiments 1-47, or a pharmaceutically acceptable salt thereof, substituted with one or more substituents independently selected from the group consisting of: -alkoxy.

[0389] Embodiment 110.R 2is dihydropyranyl, which optionally contains halogen, hydroxy, cyano, C 1~6 -Alkyl, Halo-C 1~6 -Alkyl, C 2~6 -alkynyl, C 1~6 -alkoxy and halo-C 1~6 48. The compound of any one of embodiments 1-47, or a pharmaceutically acceptable salt thereof, substituted with one or more substituents independently selected from the group consisting of: -alkoxy.

[0390] Embodiment 111.R 2 is 1,4-dioxanyl, and 1,4-dioxanyl is optionally substituted with halogen, hydroxy, cyano, C 1~6 -Alkyl, Halo-C 1~6 -Alkyl, C 2~6 -alkynyl, C 1~6 -alkoxy and halo-C 1~6 48. The compound of any one of embodiments 1-47, or a pharmaceutically acceptable salt thereof, substituted with one or more substituents independently selected from the group consisting of: -alkoxy.

[0391] Embodiment 112.R 2 is 3-oxabicyclo[4.1.0]heptane, which optionally contains halogen, hydroxy, cyano, C 1~6 -Alkyl, Halo-C 1~6 -Alkyl, C 2~6 -alkynyl, C 1~6 -alkoxy and halo-C 1~6 48. The compound of any one of embodiments 1-47, or a pharmaceutically acceptable salt thereof, substituted with one or more substituents independently selected from the group consisting of: -alkoxy.

[0392] Embodiment 113.R 2or a pharmaceutically acceptable salt thereof.

[0393] Embodiment 114. The compound is (R)-N-(2-(4-cyanothiazolidin-3-yl)-2-oxoethyl)-6-(furan-3-yl)quinoline-4-carboxamide; (R)-N-(2-(4-cyanothiazolidin-3-yl)-2-oxoethyl)-6-(4-hydroxy-tetrahydro-2H-pyran-4-yl)-quinoline-4-carboxamide; (R)—N-(2-(4-cyanothiazolidin-3-yl)-2-oxoethyl)-6-(tetrahydro-2H-pyran-4-yl)quinoline-4-carboxamide; (R)-N-(2-(4-cyanothiazolidin-3-yl)-2-oxoethyl)-6-(4-methyl-tetrahydro-2H-pyran-4-yl)-quinoline-4-carboxamide; (R)—N-(2-(4-cyanothiazolidin-3-yl)-2-oxoethyl)-6-(3,6-dihydro-2H-pyran-4-yl)quinoline-4-carboxamide; (R)-N-(2-(4-cyanothiazolidin-3-yl)-2-oxoethyl)-6-(4-ethoxytetrahydro-2H-pyran-4-yl)-quinoline-4-carboxamide; N-(2-((R)-4-cyanothiazolidin-3-yl)-2-oxoethyl)-6-((RS)-tetrahydro-2H-pyran-2-yl)-quinoline-4-carboxamide; N-(2-((R)-4-cyanothiazolidin-3-yl)-2-oxoethyl)-6-((RS)-1,4-dioxan-2-yl)quinoline-4-carboxamide; N-(2-((R)-4-cyanothiazolidin-3-yl)-2-oxoethyl)-6-((RS)-tetrahydrofuran-2-yl)quinoline-4-carboxamide; (R)-N-(2-(4-cyanothiazolidin-3-yl)-2-oxoethyl)-6-(4-ethynyl-tetrahydro-2H-pyran-4-yl)-quinoline-4-carboxamide; (R)-6-(4-cyanotetrahydro-2H-pyran-4-yl)-N-(2-(4-cyanothiazolidin-3-yl)-2-oxoethyl)-quinoline-4-carboxamide; N-(2-((R-4-cyanothiazolidin-3-yl)-2-oxoethyl)-6-(5,5-dimethyltetrahydrofuran-3-yl)-quinoline-4-carboxamide; (R)—N-(2-(4-cyanothiazolidin-3-yl)-2-oxoethyl)-6-(4-fluorotetrahydro-2H-pyran-4-yl)-quinoline-4-carboxamide; (R)—N-(2-(4-cyanothiazolidin-3-yl)-2-oxoethyl)-6-(4-methoxy-tetrahydro-2H-pyran-4-yl)quinoline-4-carboxamide; N-(2-((R-4-cyanothiazolidin-3-yl)-2-oxoethyl)-6-((RS)-tetrahydrofuran-3-yl)quinoline-4-carboxamide; N-(2-((R-4-cyanothiazolidin-3-yl)-2-oxoethyl)-6-((RS)-2,2-dimethyltetrahydro-2H-pyran-4-yl)quinoline-4-carboxamide; and 6-((1RS,6SR)-3-oxabicyclo[4.1.0]heptan-6-yl)-N-(2-((R)-4-cyanothiazolidin-3-yl)-2-oxoethyl)quinoline-4-carboxamide; or a pharmaceutically acceptable salt thereof.

[0394] Embodiment 115.R 2 -OR 7 and R 7 is C 1~6 - selected from the group consisting of alkyl, phenyl, and tetrahydropyranyl; (I C 1~6 -Alkyl is optionally substituted with halogen, cyano, C 3~6 -cycloalkyl, halo-C 3~6 -cycloalkyl, C 1~6 -alkoxy and halo-C 1~6 -substituted with one or more substituents independently selected from the group consisting of alkoxy; (ii) phenyl optionally containing halogen, C 1~6 -Alkyl, Halo-C 1~6 -Alkyl, C 1~6 -alkoxy and halo-C 1~6 -substituted with one or more substituents independently selected from the group consisting of alkoxy; (iii) tetrahydropyranyl optionally containing halogen, C 1~6 -Alkyl, Halo-C 1~6 -Alkyl, C 1~6 -alkoxy and halo-C 1~6 48. The compound of any one of embodiments 1-47, or a pharmaceutically acceptable salt thereof, substituted with one or more substituents independently selected from the group consisting of: -alkoxy.

[0395] Embodiment 116.R 2 -OR 7 and R 7 is C 1~4 - selected from the group consisting of alkyl, phenyl, and tetrahydropyranyl; (I C 1~4 -Alkyl is optionally substituted with halogen, cyano, C 3~6 -cycloalkyl, halo-C 3~6 -cycloalkyl, C 1~3 -alkoxy and halo-C 1~3 -substituted with one or more substituents independently selected from the group consisting of alkoxy; (ii) phenyl optionally containing halogen, C1~3 -Alkyl, Halo-C 1~3 -Alkyl, C 1~3 -alkoxy and halo-C 1~3 -substituted with one or more substituents independently selected from the group consisting of alkoxy; (iii) tetrahydropyranyl optionally containing halogen, C 1~3 -Alkyl, Halo-C 1~3 -Alkyl, C 1~3 -alkoxy and halo-C 1~3 48. The compound of any one of embodiments 1-47, or a pharmaceutically acceptable salt thereof, substituted with one or more substituents independently selected from the group consisting of: -alkoxy.

[0396] Embodiment 117.R 2 -OR 7 and R 7 is C 1~6 - selected from the group consisting of alkyl, phenyl, and tetrahydropyranyl; (I C 1~6 -Alkyl is optionally substituted with halogen, cyano, C 3~6 -cycloalkyl, halo-C 3~6 -cycloalkyl, and C 1~6 -substituted with one or more substituents independently selected from the group consisting of alkoxy; (ii) tetrahydropyranyl is optionally one or C 1~6 48. The compound of any one of embodiments 1-47, or a pharmaceutically acceptable salt thereof, substituted with -alkyl.

[0397] Embodiment 118.R 2 -OR 7 and R 7 is C 1~4 - selected from the group consisting of alkyl, phenyl, and tetrahydropyranyl; (I C 1~4 -Alkyl is optionally substituted with halogen, cyano, C 3~6 -cycloalkyl, halo-C 3~6 -cycloalkyl, and C 1~3-substituted with one or more substituents independently selected from the group consisting of alkoxy; (ii) tetrahydropyranyl is optionally one or C 1~3 48. The compound of any one of embodiments 1-47, or a pharmaceutically acceptable salt thereof, substituted with -alkyl.

[0398] Embodiment 119.R 2 -OR 7 and R 7 is C 1~6 -alkyl, C 1~6 -Alkyl is optionally substituted with halogen, cyano, C 3-6 -cycloalkyl, halo-C 3-6 -cycloalkyl, C 1-6 -alkoxy and halo-C 1-6 48. The compound of any one of embodiments 1-47, or a pharmaceutically acceptable salt thereof, substituted with one or more substituents independently selected from the group consisting of: -alkoxy.

[0399] Embodiment 120.R 2 -OR 7 and R 7 is C 1~4 -alkyl, C 1~4 -Alkyl is optionally substituted with halogen, cyano, C 3~6 -cycloalkyl, halo-C 3~6 -cycloalkyl, and C 1~3 48. The compound of any one of embodiments 1-47, or a pharmaceutically acceptable salt thereof, substituted with one or more substituents independently selected from the group consisting of: -alkoxy.

[0400] Embodiment 121.R 2 -OR 7 and R 7 is C 1~4 -alkyl, C 1~4 48. The compound of any one of embodiments 1-47, or a pharmaceutically acceptable salt thereof, wherein -alkyl is optionally substituted with one or more substituents independently selected from the group consisting of: fluoro.

[0401] Embodiment 122.R 2 -OR 7 and R 7 is phenyl, and the phenyl is optionally selected from halogen, C 1~6 -Alkyl, Halo-C 1~6 -Alkyl, C 1~6 -alkoxy and halo-C 1~6 48. The compound of any one of embodiments 1-47, or a pharmaceutically acceptable salt thereof, substituted with one or more substituents independently selected from the group consisting of: -alkoxy.

[0402] Embodiment 123.R 2 -OR 7 and R 7 The compound of any one of embodiments 1-47, or a pharmaceutically acceptable salt thereof, wherein is phenyl.

[0403] Embodiment 124.R 2 -OR 7 and R 7 is tetrahydropyranyl; tetrahydropyranyl optionally contains halogen, C 1~6 -Alkyl, Halo-C 1~6 -Alkyl, C 1~6 -alkoxy and halo-C 1~6 48. The compound of any one of embodiments 1-47, or a pharmaceutically acceptable salt thereof, substituted with one or more substituents independently selected from the group consisting of: -alkoxy.

[0404] Embodiment 125.R 2 -OR 7 and R 7 is tetrahydropyranyl; tetrahydropyranyl optionally has one or more C 1~3 48. The compound of any one of embodiments 1-47, or a pharmaceutically acceptable salt thereof, substituted with -alkyl.

[0405] Embodiment 126.R 2 -OR 7 and R 7is tetrahydropyranyl; or a pharmaceutically acceptable salt thereof.

[0406] Embodiment 127.R 2 -OR 7 and R 7 is selected from the group consisting of cyanomethyl, fluoroethyl, difluoroethyl, propyl, difluoropropyl, fluorobutyl, methoxyethyl, cyclopropylmethyl, difluorocyclobutylmethyl, phenyl, tetrahydropyranyl, and dimethyltetrahydropyranyl; or a pharmaceutically acceptable salt thereof.

[0407] Embodiment 128. The compound is (R)-N-(2-(4-cyanothiazolidin-3-yl)-2-oxoethyl)-6-phenoxyquinoline-4-carboxamide; (R)-N-(2-(4-cyanothiazolidin-3-yl)-2-oxoethyl)-6-(2,2-difluoroethoxy)quinoline-4-carboxamide; (R)-N-(2-(4-cyanothiazolidin-3-yl)-2-oxoethyl)-6-(2-fluoro-2-methylpropoxy)quinoline-4-carboxamide; (R)-N-(2-(4-cyanothiazolidin-3-yl)-2-oxoethyl)-6-(2-methoxyethoxy)quinoline-4-carboxamide; (R)-N-(2-(4-cyanothiazolidin-3-yl)-2-oxoethyl)-6-(cyclopropyl-methoxy)quinoline-4-carboxamide; (R)—N-(2-(4-cyanothiazolidin-3-yl)-2-oxoethyl)-6-(tetrahydro-2H-pyran-4-yl)oxy)-quinoline-4-carboxamide; (R)—N-(2-(4-cyanothiazolidin-3-yl)-2-oxoethyl)-6-((1,3-difluoropropan-2-yl)oxy)-quinoline-4-carboxamide; (R)-N-(2-(4-cyanothiazolidin-3-yl)-2-oxoethyl)-6-((3,3-difluorocyclobutyl)-methoxy)quinoline-4-carboxamide; N-(2-((R-4-cyanothiazolidin-3-yl)-2-oxoethyl)-6-(((RS)-2,2-dimethyltetrahydro-2H-pyran-4-yl)oxy)quinoline-4-carboxamide; (R)-6-(cyanomethoxy)-N-(2-(4-cyanothiazolidin-3-yl)-2-oxoethyl)quinoline-4-carboxamide; (R)-N-(2-(4-cyanothiazolidin-3-yl)-2-oxoethyl)-6-(2,2-difluoropropoxy)quinoline-4-carboxamide; (R)—N-(2-(4-cyanothiazolidin-3-yl)-2-oxoethyl)-6-propoxyquinoline-4-carboxamide; and The compound of embodiment 1, selected from the group consisting of: (R)—N-(2-(4-cyanothiazolidin-3-yl)-2-oxoethyl)-6-(2-fluoroethoxy)-quinoline-4-carboxamide; or a pharmaceutically acceptable salt thereof.

[0408] Embodiment 129.R 2 teeth, (a)C 1~3 -alkyl, optionally containing halogen, hydroxy, cyano, C 3~6 -cycloalkyl, halo-C 3~6 -cycloalkyl, C 1~3 -Alkoxy, Halo-C 1~3 -alkoxy, C 3~6 -Cycloalkoxy, halo-C 3~6 -cycloalkoxy, C 1~3 -Alkoxy-C 1~3-substituted with one or more substituents independently selected from the group consisting of alkoxy, oxetanyl, tetrahydrofuranyl, tetrahydrofuranyloxy, tetrahydropyranyl, morpholinyl, pyrazolyl, isoxazolyl, triazolyl, and pyridinyl; oxetanyl, tetrahydrofuranyl, tetrahydrofuranyloxy, tetrahydropyranyl, morpholinyl, pyrazolyl, isoxazolyl, triazolyl, and pyridinyl are optionally substituted with one or more substituents independently selected from the group consisting of halogen, C 1~3 -Alkyl and halo-C 1~3 -substituted with one or more substituents independently selected from the group consisting of alkyl, C 1~3 - alkyl; (b)C 3~6 -cycloalkyl, optionally containing halogen, cyano, C 1~3 -Alkyl, Halo-C 1~3 -Alkyl, C 1~3 -Alkoxy, Halo-C 1~3 -substituted with one or more substituents independently selected from the group consisting of alkoxy, isoxazolyl, and pyridinyl; isoxazolyl and pyridinyl are optionally substituted with halogen, C 1~3 -Alkyl and halo-C 1~3 -substituted with one or more substituents independently selected from the group consisting of alkyl, C 3~6 -cycloalkyl; (c) phenyl, optionally containing halogen, C 1~3 -Alkyl, Halo-C 1~3 -Alkyl, C 1~3 -Alkoxy, Halo-C 1~3 -alkoxy, and C 1~3 -Alkoxy-C 1~3 -phenyl substituted with one or more substituents independently selected from the group consisting of alkoxy; (d) a 4-, 5-, 6-, or 7-membered heterocyclyl that (i) is saturated or partially saturated, monocyclic or fused bicyclic, (ii) has one or two oxygen ring atoms, the remaining ring atoms being carbon, and (iii) optionally contains halogen, hydroxy, cyano, C 1~3 -Alkyl, Halo-C 1~3 -Alkyl, C 2~3-alkynyl, C 1~3 -alkoxy and halo-C 1~3 -heterocyclyl substituted with one or more substituents independently selected from the group consisting of alkoxy; and (e)-OR 7 and R 7 But C 1~4 - selected from the group consisting of alkyl, phenyl, and tetrahydropyranyl; (I C 1~4 -Alkyl is optionally substituted with halogen, cyano, C 3~6 -cycloalkyl, halo-C 3~6 -cycloalkyl, C 1~3 -alkoxy and halo-C 1~3 -substituted with one or more substituents independently selected from the group consisting of alkoxy; (ii) phenyl optionally containing halogen, C 1~3 -Alkyl, Halo-C 1~3 -Alkyl, C 1~3 -alkoxy and halo-C 1~3 -substituted with one or more substituents independently selected from the group consisting of alkoxy; (iii) tetrahydropyranyl optionally containing halogen, C 1~3 -Alkyl, Halo-C 1~3 -Alkyl, C 1~3 -alkoxy and halo-C 1~3 -OR substituted with one or more substituents independently selected from the group consisting of -alkoxy; 7 or a pharmaceutically acceptable salt thereof.

[0409] Embodiment 130.R 2 teeth, (a)C 3~6 -cycloalkyl, optionally containing halogen, cyano, C 1~3 -Alkyl, Halo-C 1~3 -Alkyl, C 1~3 -Alkoxy, Halo-C 1~3-substituted with one or more substituents independently selected from the group consisting of alkoxy, isoxazolyl, and pyridinyl; isoxazolyl and pyridinyl are optionally substituted with halogen, C 1~3 -Alkyl and halo-C 1~3 -substituted with one or more substituents independently selected from the group consisting of alkyl, C 3~6 -cycloalkyl; (b) a 4-, 5-, 6-, or 7-membered heterocyclyl that (i) is saturated or partially saturated, monocyclic or fused bicyclic, (ii) has one or two oxygen ring atoms, the remaining ring atoms being carbon, and (iii) optionally contains halogen, hydroxy, cyano, C 1~3 -Alkyl, Halo-C 1~3 -Alkyl, C 2~3 -alkynyl, C 1~3 -alkoxy and halo-C 1~3 -a heterocyclyl ring substituted with one or more substituents independently selected from the group consisting of alkoxy; and (c)-OR 7 and R 7 But C 1~4 - selected from the group consisting of alkyl, phenyl, and tetrahydropyranyl; (I C 1~4 -Alkyl is optionally substituted with halogen, cyano, C 3~6 -cycloalkyl, halo-C 3~6 -cycloalkyl, C 1~3 -alkoxy and halo-C 1~3 -substituted with one or more substituents independently selected from the group consisting of alkoxy; (ii) phenyl optionally containing halogen, C 1~3 -Alkyl, Halo-C 1~3 -Alkyl, C 1~3 -alkoxy and halo-C 1~3 -substituted with one or more substituents independently selected from the group consisting of alkoxy; (iii) tetrahydropyranyl optionally containing halogen, C 1~3 -Alkyl, Halo-C 1~3 -Alkyl, C 1~3 -alkoxy and halo-C1~3 -OR substituted with one or more substituents independently selected from the group consisting of -alkoxy; 7 or a pharmaceutically acceptable salt thereof.

[0410] Embodiment 131.R 2 teeth, (a)C 1~6 -alkyl, optionally containing halogen, hydroxy, C 1~6 -Alkoxy, Halo-C 1~6 -alkoxy, C 3~6 -cycloalkoxy, C 1~6 -Alkoxy-C 1~6 -substituted with one or more substituents independently selected from the group consisting of alkoxy, tetrahydrofuranyl, tetrahydrofuranyloxy, tetrahydropyranyl, morpholinyl, pyrazolyl, isoxazolyl, triazolyl, and pyridinyl; tetrahydrofuranyl, tetrahydrofuranyloxy, tetrahydropyranyl, morpholinyl, pyrazolyl, isoxazolyl, triazolyl, and pyridinyl are optionally substituted with one or more substituents independently selected from the group consisting of halogen, C 1~6 -Alkyl and halo-C 1~6 -substituted with one or more substituents independently selected from the group consisting of alkyl, C 1~6 - alkyl; (b)C 3~6 -cycloalkyl, optionally containing halogen, cyano, C 1~6 -substituted with one or more substituents independently selected from the group consisting of alkoxy, isoxazolyl, and pyridinyl; isoxazolyl and pyridinyl are optionally substituted with halogen, C 1~6 -Alkyl and halo-C 1~6 -substituted with one or more substituents independently selected from the group consisting of alkyl, C 3~6 -cycloalkyl; (c) phenyl, optionally containing halogen, C 1~3 -Alkyl, Halo-C 1~3 -Alkyl, C 1~3 -Alkoxy, Halo-C 1~3 -alkoxy, and C1~3 -Alkoxy-C 1~3 -phenyl substituted with one or more substituents independently selected from the group consisting of alkoxy; (d) a 5-, 6-, or 7-membered heterocyclyl that (i) is saturated or partially saturated, monocyclic or fused bicyclic, (ii) has one or two oxygen ring atoms, the remaining ring atoms being carbon, and (iii) optionally contains halogen, hydroxy, cyano, C 1~3 -Alkyl, C 2~3 -alkynyl, and C 1~3 -heterocyclyl substituted with one or more substituents independently selected from the group consisting of alkoxy; and (e)-OR 7 and R 7 But C 1~6 - selected from the group consisting of alkyl, phenyl, and tetrahydropyranyl; (I C 1~6 -Alkyl is optionally substituted with halogen, cyano, C 3~6 -cycloalkyl, halo-C 3~6 -cycloalkyl, and C 1~6 -substituted with one or more substituents independently selected from the group consisting of alkoxy; (ii) tetrahydropyranyl is optionally one or C 1~6 -substituted with alkyl, -OR 7 or a pharmaceutically acceptable salt thereof.

[0411] Embodiment 132.R 2 teeth, (a)C 3~6 -cycloalkyl, optionally containing halogen, cyano, C 1~6 -substituted with one or more substituents independently selected from the group consisting of alkoxy, isoxazolyl, and pyridinyl; isoxazolyl and pyridinyl are optionally substituted with halogen, C 1~6 -Alkyl and halo-C 1~6 -substituted with one or more substituents independently selected from the group consisting of alkyl, C 3~6 -cycloalkyl; (b) a 5-, 6-, or 7-membered heterocyclyl that (i) is saturated or partially saturated, monocyclic or fused bicyclic, (ii) has one or two oxygen ring atoms, the remaining ring atoms being carbon, and (iii) optionally contains halogen, hydroxy, cyano, C 1~3 -Alkyl, C 2~3 -alkynyl, and C 1~3 -heterocyclyl substituted with one or more substituents independently selected from the group consisting of alkoxy; and (c)-OR 7 and R 7 But C 1~6 - selected from the group consisting of alkyl, phenyl, and tetrahydropyranyl; (I C 1~6 -Alkyl is optionally substituted with halogen, cyano, C 3~6 -cycloalkyl, halo-C 3~6 -cycloalkyl, and C 1~6 -substituted with one or more substituents independently selected from the group consisting of alkoxy; (ii) tetrahydropyranyl is optionally one or C 1~6 -substituted with alkyl, -OR 7 or a pharmaceutically acceptable salt thereof.

[0412] Embodiment 133.R 2 is a 4-membered heterocyclyl, the heterocyclyl ring being (i) a saturated or partially saturated monocyclic ring, (ii) having one oxygen ring atom with the remaining ring atoms being carbon, and (iii) optionally containing halogen, hydroxy, cyano, C 1~3 -Alkyl, C 2~3 -alkynyl, and C 1~3 133. The compound of any one of embodiments 129-132, or a pharmaceutically acceptable salt thereof, substituted with one or more substituents independently selected from the group consisting of: -alkoxy.

[0413] Embodiment 134.R 2is a 5-membered heterocyclyl, the heterocyclyl ring (i) being a saturated or partially saturated monocyclic ring, (ii) having one or two oxygen ring atoms with the remaining ring atoms being carbon, and (iii) optionally containing halogen, hydroxy, cyano, C 1~3 -alkyl, and C 2~3 -alkynyl, C 1~3 133. The compound of any one of embodiments 129-132, or a pharmaceutically acceptable salt thereof, substituted with one or more substituents independently selected from the group consisting of: -alkoxy.

[0414] Embodiment 135.R 2 is a 6-membered heterocyclyl, the heterocyclyl ring (i) being a saturated or partially saturated monocyclic ring, (ii) having one or two oxygen ring atoms with the remaining ring atoms being carbon, and (iii) optionally containing halogen, hydroxy, cyano, C 1~3 -Alkyl, C 2~3 -alkynyl, and C 1~3 133. The compound of any one of embodiments 129-132, or a pharmaceutically acceptable salt thereof, substituted with one or more substituents independently selected from the group consisting of: -alkoxy.

[0415] Embodiment 136.R 2 is a seven-membered heterocyclyl, the heterocyclyl ring (i) being saturated or partially saturated, monocyclic or fused bicyclic, (ii) having one or two oxygen ring atoms, the remaining ring atoms being carbon, and (iii) optionally containing halogen, hydroxy, cyano, C 1~3 -Alkyl, C 2~3 -alkynyl, and C 1~3 133. The compound of any one of embodiments 129-132, or a pharmaceutically acceptable salt thereof, substituted with one or more substituents independently selected from the group consisting of: -alkoxy.

[0416] Embodiment 137.R 2 teeth, (a)C 1~3 -alkyl, optionally containing halogen, hydroxy, C 1~3 -Alkoxy, Halo-C 1~3-alkoxy, C 3~6 -cycloalkoxy, C 1~3 -Alkoxy-C 1~3 -substituted with one or more substituents independently selected from the group consisting of alkoxy, tetrahydrofuranyl, tetrahydrofuranyloxy, tetrahydropyranyl, morpholinyl, pyrazolyl, isoxazolyl, triazolyl, and pyridinyl; tetrahydrofuranyl, tetrahydrofuranyloxy, tetrahydropyranyl, morpholinyl, pyrazolyl, isoxazolyl, triazolyl, and pyridinyl are optionally substituted with one or more substituents independently selected from the group consisting of halogen, C 1~3 -Alkyl and halo-C 1~6 -substituted with one or more substituents independently selected from the group consisting of alkyl, C 1~3 - alkyl; (b)C 3~6 -cycloalkyl, optionally containing halogen, cyano, C 1~3 -substituted with one or more substituents independently selected from the group consisting of alkoxy, isoxazolyl, and pyridinyl; isoxazolyl and pyridinyl are optionally substituted with halogen, C 1~3 -Alkyl and halo-C 1~3 -substituted with one or more substituents independently selected from the group consisting of alkyl, C 3~6 -cycloalkyl; (c) phenyl, optionally containing halogen, C 1~3 -Alkyl, Halo-C 1~3 -Alkyl, C 1~3 -Alkoxy, Halo-C 1~3 -alkoxy, and C 1~3 -Alkoxy-C 1~3 -phenyl substituted with one or more substituents independently selected from the group consisting of alkoxy; (d) a 5-, 6-, or 7-membered heterocyclyl selected from the group consisting of tetrahydrofuranyl, dihydropyranyl, tetrahydropyranyl, 1,4-dioxanyl, and 3-oxabicyclo[4.1.0]heptane, wherein tetrahydrofuranyl, dihydropyranyl, tetrahydropyranyl, 1,4-dioxanyl, and 3-oxabicyclo[4.1.0]heptane are optionally substituted with halogen, hydroxy, cyano, C1~6 -Alkyl, Halo-C 1~6 -Alkyl, C 2~6 -alkynyl, C 1~6 -alkoxy and halo-C 1~6 -a 5-, 6-, or 7-membered heterocyclyl substituted with one or more substituents independently selected from the group consisting of alkoxy; (e)-OR 7 and R 7 But C 1~4 - selected from the group consisting of alkyl, phenyl, and tetrahydropyranyl; (I C 1~4 -Alkyl is optionally substituted with halogen, cyano, C 3~6 -cycloalkyl, halo-C 3~6 -cycloalkyl, and C 1~3 -substituted with one or more substituents independently selected from the group consisting of alkoxy; (ii) tetrahydropyranyl is optionally one or C 1~3 -substituted with alkyl, -OR 7 or a pharmaceutically acceptable salt thereof.

[0417] Embodiment 138.R 2 teeth, (a)C 3~6 -cycloalkyl, optionally containing halogen, cyano, C 1~3 -substituted with one or more substituents independently selected from the group consisting of alkoxy, isoxazolyl, and pyridinyl; isoxazolyl and pyridinyl are optionally substituted with halogen, C 1~3 -Alkyl and halo-C 1~3 -substituted with one or more substituents independently selected from the group consisting of alkyl, C 3~6 -cycloalkyl; (b) a 5-, 6-, or 7-membered heterocyclyl selected from the group consisting of tetrahydrofuranyl, dihydropyranyl, tetrahydropyranyl, 1,4-dioxanyl, and 3-oxabicyclo[4.1.0]heptane, wherein tetrahydrofuranyl, dihydropyranyl, tetrahydropyranyl, 1,4-dioxanyl, and 3-oxabicyclo[4.1.0]heptane are optionally substituted with halogen, hydroxy, cyano, C 1~6 -Alkyl, Halo-C 1~6 -Alkyl, C 2~6 -alkynyl, C 1~6 -alkoxy and halo-C 1~6 - a 5-, 6-, or 7-membered heterocyclyl substituted with one or more substituents independently selected from the group consisting of alkoxy; and (c)-OR 7 and R 7 But C 1~4 - selected from the group consisting of alkyl, phenyl, and tetrahydropyranyl; (I C 1~4 -Alkyl is optionally substituted with halogen, cyano, C 3~6 -cycloalkyl, halo-C 3~6 -cycloalkyl, and C 1~3 -substituted with one or more substituents independently selected from the group consisting of alkoxy; (ii) tetrahydropyranyl is optionally one or C 1~3 -substituted with alkyl, -OR 7 or a pharmaceutically acceptable salt thereof.

[0418] Embodiment 139.R 2 The compound of any one of embodiments 129-138, or a pharmaceutically acceptable salt thereof, wherein is optionally substituted cyclopropyl.

[0419] Embodiment 140.R 2 The compound of any one of embodiments 129-138, or a pharmaceutically acceptable salt thereof, wherein is optionally substituted cyclobutyl.

[0420] Embodiment 141.R 2 The compound of any one of embodiments 129-138, or a pharmaceutically acceptable salt thereof, wherein is optionally substituted cyclopentyl.

[0421] Embodiment 142.R 2 139. The compound of any one of embodiments 129-138, or a pharmaceutically acceptable salt thereof, wherein is optionally substituted cyclohexyl.

[0422] Embodiment 143.R 2 teeth, (a) an optionally substituted C selected from the group consisting of methyl, fluoromethyl, difluoromethyl, trifluoromethyl, hydroxylethyl, hydroxypropyl, ethoxymethyl, difluoroethoxymethyl, methoxyethyl, dimethoxyethyl, difluoropropyl, trifluoropropyl, methoxypropyl, methoxyethoxymethyl, cyclopropoxymethyl, morpholinylmethyl, tetrahydrofuranylmethyl, tetrahydrofuranyloxymethyl, tetrahydropyranylmethyl, pyrazolylmethyl, dimethylpyrazolylmethyl, methylisoxazolylmethyl, methylisoxazolylethyl, methyltriazolylmethyl, dimethyltriazolylmethyl, dimethylpyridinylmethyl, methylpyridinylethyl, fluoropyridinylethyl, chloropyridinylethyl, and trifluoromethylpyridinylethyl; 1~3 - alkyl; (b) an optionally substituted C selected from the group consisting of cyclopropyl, cyanocyclopropyl, ethoxycyclopropyl, methylisoxazolylcyclopropyl, methylpyridinylcyclopropyl, chloropyridinylcyclopropyl, fluoropyridinylcyclopropyl, trifluoropyridinylcyclopropyl, fluorocyclobutyl, (fluoro)(methoxy)cyclobutyl, methoxycyclohexyl, and cyanocyclohexyl. 3~6 -cycloalkyl; (c) an optionally substituted 5-, 6-, or 7-membered heterocyclyl selected from the group consisting of tetrahydrofuranyl, dimethyltetrahydrofuranyl, dihydropyranyl, tetrahydropyranyl, hydroxytetrahydropyranyl, fluorotetrahydropyranyl, cyanotetrahydropyranyl, methyltetrahydropyranyl, dimethyltetrahydropyranyl, methoxytetrahydropyranyl, ethoxytetrahydropyranyl, 1,4-dioxanyl, and 3-oxabicyclo[4.1.0]heptane; and (d)-OR 7 and R 7 is selected from the group consisting of cyanomethyl, fluoroethyl, difluoroethyl, propyl, difluoropropyl, fluorobutyl, methoxyethyl, cyclopropylmethyl, difluorocyclobutylmethyl, phenyl, tetrahydropyranyl, and dimethyltetrahydropyranyl; 7 or a pharmaceutically acceptable salt thereof.

[0423] Embodiment 144.R 2 teeth, (a) an optionally substituted C selected from the group consisting of cyclopropyl, cyanocyclopropyl, ethoxycyclopropyl, methylisoxazolylcyclopropyl, methylpyridinylcyclopropyl, chloropyridinylcyclopropyl, fluoropyridinylcyclopropyl, trifluoropyridinylcyclopropyl, fluorocyclobutyl, (fluoro)(methoxy)cyclobutyl, methoxycyclohexyl, and cyanocyclohexyl; 3~6 -cycloalkyl; (b) an optionally substituted 5-, 6-, or 7-membered heterocyclyl selected from the group consisting of tetrahydrofuranyl, dimethyltetrahydrofuranyl, dihydropyranyl, tetrahydropyranyl, hydroxytetrahydropyranyl, fluorotetrahydropyranyl, cyanotetrahydropyranyl, methyltetrahydropyranyl, dimethyltetrahydropyranyl, methoxytetrahydropyranyl, ethoxytetrahydropyranyl, 1,4-dioxanyl, and 3-oxabicyclo[4.1.0]heptane; and (c)-OR 7 and R 7 is selected from the group consisting of cyanomethyl, fluoroethyl, difluoroethyl, propyl, difluoropropyl, fluorobutyl, methoxyethyl, cyclopropylmethyl, difluorocyclobutylmethyl, phenyl, tetrahydropyranyl, and dimethyltetrahydropyranyl; 7 or a pharmaceutically acceptable salt thereof.

[0424] Embodiment 145.R 2 is selected from the group consisting of methoxycyclohexyl, tetrahydropyranyl, fluorobutoxy, and tetrahydropyranyloxy; or a pharmaceutically acceptable salt thereof.

[0425] Embodiment 146. A pharmaceutical composition comprising a compound according to any one of embodiments 1 to 145 or a pharmaceutically acceptable salt thereof, and one or more pharmaceutically acceptable excipients.

[0426] Embodiment 147. A method for treating or preventing a FAP-mediated condition in a subject suffering from or susceptible to a FAP-mediated condition, comprising administering to the subject a therapeutically effective amount of a compound of any one of embodiments 1 to 145, or a pharmaceutically acceptable salt thereof.

[0427] Embodiment 148. The method of embodiment 147, wherein the FAP-mediated condition is selected from the group consisting of liver disease, type 2 diabetes mellitus, cardiovascular conditions, obesity, obesity-related conditions, fibrosis, keloid disorders, inflammation, and cancer.

[0428] Embodiment 149. The method of embodiment 148, wherein the FAP-mediated condition is a liver disease.

[0429] Embodiment 150. The method of embodiment 149, wherein the liver disease is nonalcoholic steatohepatitis.

[0430] Embodiment 151 Use of a compound according to any one of embodiments 1 to 145, or a pharmaceutically acceptable salt thereof, for the manufacture of a medicament for treating or preventing a FAP-mediated condition.

[0431] VIX Example 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 can be prepared using the methods illustrated in these examples either alone or in combination with techniques generally known in the art.

[0432] A. General conditions Unless otherwise stated: (i) The operations were carried out at room temperature (rt), i.e., in the range of 17-25°C, under an atmosphere of an inert gas such as N2; (ii) Where a reaction refers to the use of a microwave reactor, one of the following microwave reactors was used: Biotage Initiator, Personal Chemistry Emrys Optimizer, Personal Chemistry Smith Creator, or CEM Explorer; (iii) When the reaction refers to the use of irradiation with LEDs, a commercially available standardized EvoluChem™ PhotoRedOx Box Photoreactor from HepatoChem equipped with a Kessil H150 blue LED (456 nm, 34 W) or a commercially available standardized Photoreactor m2 from Penn Photon Devices equipped with an LED module (365 nm) was used; (iv) In general, the course of reactions was followed by thin-layer chromatography (TLC) and / or analytical high-performance liquid chromatography (HPLC or UPLC), usually coupled to a mass spectrometer (LCMS); (v) If necessary, the organic solution was dried over anhydrous MgSO4 or Na2SO4 or using an ISOLUTE® phase separator and work-up procedures were carried out using traditional phase separation techniques; (vi) evaporation was performed in a rotary evaporator vacuum or on either a Genevac HT-4 / EZ-2 or a Biotage V10; (vii) Unless otherwise stated, flash column chromatography was performed on normal-phase silica using either Merck Silica Gel (Art. 9385) or preparatively 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 on reverse-phase silica, spherical cartridges (20-35 μm, 100 A, 80-330 g) using Agela Technologies C-18. performed manually or automated using the Reveleris® X2 Flash System or similar system; (viii) Preparative reversed-phase HPLC and preparative reversed-phase SFC were performed using standard HPLC and SFC equipment, respectively, equipped with either MS and / or UV-triggered fraction collection equipment, using either isocratic or gradient mobile phase as described in the Experimental Section, and one of the following methods as described below; (vii) Preparative reversed-phase HPLC and preparative reversed-phase SFC were performed using standard HPLC and SFC equipment, respectively, equipped with either MS and / or UV-triggered fraction collection equipment, using either isocratic or gradient mobile phase as described in the Experimental Section, and one of the following methods as described below; HPLC preparative methods: Preparative method A: Compounds were purified by preparative HPLC on a Kromasil C8 column (10 μm, 250 × 50 mm ID) using a gradient of MeCN in HO / MeCN / FA (95 / 5 / 0.2) as the mobile phase; Preparative method B: Compounds were purified by preparative HPLC on an XSelect CSH C18 OBD column (5 μm, 150 × 30 mm ID) using a gradient of MeCN in HO / TFA (0.05%) as the mobile phase; Preparative method C: Compounds were purified by preparative HPLC on a Kromasil C8 column (10 μm, 250 × 20 mm ID) using a gradient of MeCN in HO / MeCN / FA (95 / 5 / 0.2) as the mobile phase; Preparative method D: Compounds were purified by preparative HPLC on an XSelect CSH OBD column (5 μm, 150 × 30 mm ID) using a gradient of MeCN in HO / TFA (0.05%) as the mobile phase. Preparative Method E: Compounds were purified by preparative HPLC on an XBridge C18 column (10 μm, 250 × 19 mm ID) using a gradient of MeCN in HO / MeCN / NH3 (95 / 5 / 0.2) as the mobile phase; Preparative Method F: Compounds were purified by preparative HPLC on a Sunfire prep C18 column (5 μm, 150 × 30 mm ID) using a gradient of MeCN in HO / FA (0.1%) as the mobile phase; Preparative Method G: Compounds were purified by preparative HPLC on a Waters Sunfire C18 ODB column (5 μm, 150 × 30 mm ID) using a gradient of MeCN in HO / FA (0.1 M) as the mobile phase; Preparative Method H: Compounds were purified by preparative HPLC on an XBridge Prep OBD Preparative HPLC was performed on a C18 column (5 μm, 150 × 30 mm ID) using H2O / NH4HCO3 (10 mM) + NH3 (0.Preparative Method I: Compounds were purified by preparative HPLC on an XBridge Prep OBD C18 column (5 μm, 150 × 30 mm ID) using a gradient of MeCN in HO / NH4HCO3 (10 mM) as the mobile phase; Preparative Method J: Compounds were purified by preparative HPLC on an XSelect CSH Prep C18 OBD column (5 μm, 250 × 19 mm ID) using a gradient of MeCN in HO / TFA (0.05%) as the mobile phase; Preparative Method K: Compounds were purified by preparative HPLC on a Sunfire C18 OBD Prep column (5 μm, 250 × 19 mm ID) using a gradient of MeCN in HO / NH4HCO3 (10 mM) as the mobile phase; Preparative Method L: Compounds were purified by preparative HPLC on a Kinetex EVO C18 column (5 μm, 150 × 30 mm ID) using a gradient of MeCN in HO / NH4HCO3 (10 mM) as the mobile phase. Preparative Method M: Compounds were purified by preparative HPLC on an XBridge C18 ODB column (5 μm, 150 × 30 mm ID) using a gradient of MeCN in HO / NH3 (0.2%) as the mobile phase; Preparative Method N: Compounds were purified by preparative HPLC on an XSelect CSH Fluorophenyl column (5 μm, 150 × 30 mm ID) using a gradient of MeCN in HO / TFA (0.1%) as the mobile phase; Preparative Method O: Compounds were purified by preparative HPLC on an XSelect CSH Fluorophenyl OBD column (5 μm, 250 × 19 mm ID) using a gradient of MeCN in HO / TFA (0.05%) as the mobile phase; Preparative Method P: Compounds were purified by preparative HPLC on a CSH Prep C18 OBD column (5 μm, 250 × 19 mm ID) using a gradient of MeCN in HO / TFA (0.05%) as the mobile phase. Preparative Method Q: Compounds were purified by preparative HPLC on a CHIRALPAK IA column (5 μm, 250 × 50 mm ID) using a gradient of MeCN in HO / TFA (0.1%) as the mobile phase; Preparative Method Q: Compounds were purified by preparative HPLC on a CHIRALPAK IA column (5 μm, 250 × 50 mm ID) using a gradient of MeCN in HO / TFA (0.1%) as the mobile phase;Preparative Method R: Compounds were purified by preparative HPLC on an XSelect CSH OBD column (5 μm, 150×30 mm ID) using a gradient of MeCN in HO / TFA (0.1%) as the mobile phase; Preparative Method S: Compounds were purified by preparative HPLC on an XBridge Prep OBD C18 column (5 μm, 150×30 mm ID) using a gradient of MeCN in HO / FA (0.1%) as the mobile phase; Preparative Method T: Compounds were purified by preparative HPLC on an XSelect CSH C18 OBD column (5 μm, 150×30 mm ID) using a gradient of MeCN in HO / FA (0.1%) as the mobile phase; Preparative Method U: Compounds were purified by preparative HPLC on a CHIRALPAK IA-3 column (3 μm, 50×4.6 mm ID) using a gradient of MeCN in HO / TFA (0.1%) as the mobile phase. ID) using a gradient of EtOH in hexane / DCM (3:1, 0.1% DEA) as the mobile phase; Preparative Method V: Compounds were purified by preparative HPLC on an XSelect CSH Prep C18 OBD column (5 μm, 250 × 19 mm ID) using a gradient of MeCN in HO / FA (0.1%) as the mobile phase; SFC preparative methods: Preparative method SFC-A compounds were purified by preparative SFC on a Waters BEH 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 Phenomenex Luna Hilic column (5 μm, 250×30 mm ID) using EtOH / FA (20 mM) in CO2 as the mobile phase; Preparative method SFC-C: compounds were purified by preparative SFC on a Phenomenex Luna Hilic column (5 μm, 250×30 mm ID) using MeOH / NH3 (20 mM) in CO2 as the mobile phase; The relevant fractions were collected, combined and lyophilized to give the purified compound, or the relevant fractions were collected, combined and concentrated under reduced pressure, extracted with DCM or EtOAc, and the organic phase was dried either over Na2SO4 or by using a phase separator, and then concentrated under reduced pressure to give the purified compound; (ix) Chiral preparative chromatography was performed using HPLC or SFC on standard HPLC or SFC equipment, respectively, using either isocratic or gradient runs with mobile phases as described in the Experimental Section; (x) yields, if any, are not necessarily the maximum achievable and, if necessary, reactions were repeated when larger amounts of reaction product were required; (xi) When a particular compound was obtained as an acid addition salt (e.g., a monohydrochloride or dihydrochloride), the stoichiometry of the salt was based on the number and nature of basic groups in the compound, and the exact stoichiometry of the salt was generally not determined, for example, 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 Bruker Avance III 300, 400, 500, and 600 spectrometer operating at H frequencies on the delta scale. 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, are reported only if detected in the NMR and may therefore be missing. In certain instances, protons may be masked or partially masked by the solvent peak and therefore either missing and not reported, or reported as a multiplet overlapping with the solvent. The following abbreviations (and their derivatives, e.g., dd, doublet of doublets, etc.) are used: s, singlet; d, doublet; t, triplet; q, quartet; m, multiplet; br, broad; qn, quintet; and p, pentet. 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 were obtained using a Waters Acquity UPLC coupled to a Waters single quadrupole mass spectrometer or similar instrument, acquiring both positive and negative ion data, generally only ions associated with the parent structure being reported; high-resolution electrospray mass spectral data were obtained using a Waters XEVO qToF mass spectrometer or similar instrument, acquiring either positive or negative ion data, generally only ions associated with the parent structure being reported; (xiii) intermediates were not necessarily completely 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 or 20.0.2.51 from PerkinElmer. ChemDraw Professional versions 19.0.0.22 and 20.0.2.51 generate names of chemical structures using the Cahn-Ingold-Prelog (CIP) rules for stereochemistry and follow IUPAC rules whenever possible when generating chemical names. Stereoisomers are cited by name and distinguished from one another by stereodescriptors assigned according to the CIP rules.

[0433] ---ChemDraw optionally uses labels in the graphical representation 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 is either (S) or (R) at the stereocenter. All absolute, unspecified "&" and "or" stereocenters may be present in a single structure.

[0434] ---In general, for structures of examples and intermediates where all of the stereocenters are designated as "&", the structures are named with the prefix "rac-". For structures of examples and intermediates where all of the stereocenters are designated as "or", the structures are named with the prefix "rel-".

[0435] Generally, the examples and intermediate compounds are named using the descriptors (RS) and (SR) to indicate the common "&" center of a chemical structure having multiple chiral centers, only some of which are designated "&". * ) and (S * ) is used to indicate a general "or" center for chemical structures with multiple chiral centers, only some of which are designated as "or."

[0436] --- In general, the descriptors (r) and (s) are used to describe the absolute configuration of any pseudo-asymmetric centers in the structures of the examples and intermediates.

[0437] ---Generally, the label "Isomer 1" corresponds to the first eluting isomer and "Isomer 2" corresponds to the second eluting isomer on a given chiral HPLC column and eluent, and is used to distinguish between two isomers containing one or more stereocenters with an absolute unknown configuration at one or more stereocenters; (xvi) when the reaction is referred to as being degassed or purged, this can be done, for example, by purging the reaction solvent with a constant flow of nitrogen for a suitable period of time (e.g., 5-10 minutes); (xvii) When the reaction refers to the application of an evacuation-refill cycle, this can be done by evacuating the reaction vessel by applying a vacuum to the reaction vessel and then refilling it with an inert gas, typically N2 or argon. This process is generally repeated, typically three times; (xvii) In addition to the above, the following abbreviations are used: (xvii) In addition to the above, the following abbreviations are used:

[0438] [Table 1-1]

[0439] [Table 1-2]

[0440] [Table 1-3]

[0441] [Table 2]

[0442] B. Intermediate compounds Intermediate 1: tert-butyl (R)-4-cyanothiazolidine-3-carboxylate

[0443] [ka]

[0444] Step a) tert-Butyl (R)-4-carbamoylthiazolidine-3-carboxylate

[0445] [ka]

[0446] BocO (18.6 mL, 80.2 mmol) was added to a stirred solution of tert-butyl (R)-4-carbamoylthiazolidine-3-carboxylate (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. Then, a solution of NH (aqueous, 25%, 6 mL) was 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.

[0447] Step b) tert-butyl (R)-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 tert-butyl (R)-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 HCl (1 M, aq.) and saturated NaHCO3 (aq.). The organic phase was dried, filtered through a pad of silica gel, washed with EtOAc, and evaporated to give a light yellow oil that solidified upon 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) δ5.20-4.79(m,1H),4.60-4.53(m,1H),4.53-4.36(m,1H),3.40-3.18(m,2H),1.51(s,9H).

[0448] Intermediate 2: (R)-Thiazolidine-4-carbonitrile hydrochloride

[0449] [ka]

[0450] A solution of concentrated HCl (11 mL) in MeOH (140 mL) was slowly added to a solution of tert-butyl (R)-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) δ4.90 (dd, 1H), 4.35-4.24 (m, 2H), 3.37-3.24 (m, 2H).

[0451] Intermediate 3: tert-butyl (R)-(2-(4-cyanothiazolidin-3-yl)-2-oxoethyl)carbamate

[0452] [ka]

[0453] 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 (42 mL, 70 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, HCl (1 M, aq.) and saturated NaHCO3 (aq.). 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 (7.6 g, 100%) as a nearly colorless solid; 1 H NMR (400MHz, CDCl3) δ5.36-5.25(m,2H),4.59-4.52(m,2H),4.14-3.90(m,2H),3.29(d,2H),1.45(s,9H).

[0454] Intermediate 4: (R)-3-glycylthiazolidine-4-carbonitrile hydrochloride

[0455] [ka]

[0456] A solution of concentrated HCl (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 (7.6 g, 28 mmol) in MeOH (140 mL), and the solution was stirred at room temperature overnight. The solvent was evaporated to give the title compound (5.8 g, 100%) as a colorless solid. 1 H NMR (400MHz, CD3OD) δ5.34(t,1H),4.72(d,1H),4.62(d,1H),4.11-3.94(m,2H),3.41-3.36(m,2H).

[0457] Intermediate 5: Methyl 6-acetylquinoline-4-carboxylate

[0458] [ka]

[0459] Tributyl(1-ethoxyvinyl)stannane (1.63 g, 4.51 mmol) was added to methyl 6-bromoquinoline-4-carboxylate (1.0 g, 3.8 mmol) and Pd(dppf)Cl·DCM (0.307 g, 0.38 mmol) in degassed 1,4-dioxane (25 mL) at 20 °C under N (g). The resulting mixture was stirred at 80 °C for 18 h. The mixture was diluted with MeCN (3 mL), 10 drops of 3 N HCl (aq) were added, and stirring was continued for 30 min. The reaction mixture was diluted with water (10 mL) and extracted with EtOAc (3 × 10 mL). The organic layer was dried over NaSO, filtered, and concentrated. The residue was purified by preparative TLC (pentane: EtOAc 1:1) to give the title compound (0.70 g, 81%) as a white solid; MS (ESI) m / z [M+H] + 230.

[0460] Intermediate 6: Methyl 6-(2-hydroxypropan-2-yl)quinoline-4-carboxylate

[0461] [ka]

[0462] CHCl (3 M in THF, 0.87 mL, 2.6 mmol) was added dropwise to a solution of methyl 6-acetylquinoline-4-carboxylate intermediate 5 (0.30 g, 1.3 mmol) in THF (3 mL) at 0 °C under an atmosphere of N (g), and the reaction mixture was stirred at 0 °C for 3 h. The reaction was quenched with saturated NHCl (aqueous, 20 mL), and the mixture was extracted with DCM (3 × 20 mL). The combined organic layers were dried over NaSO, filtered, and evaporated under reduced pressure. The residue was purified by preparative TLC (DCM:MeOH, 10:1) to give the title compound (0.20 g, 62%) as an orange gum; MS (ESI) m / z [M+H] + 246.

[0463] Intermediate 7: Methyl 6-(hydroxymethyl)quinoline-4-carboxylate

[0464] [ka]

[0465] (Tributylstannyl)methanol (1.45 g, 4.51 mmol) was added to a suspension of methyl 6-bromoquinoline-4-carboxylate (1.0 g, 3.8 mmol) and Pd(PPh3)4 (0.43 g, 0.38 mmol) in degassed toluene (25 mL) at 20 °C under an atmosphere of N2 (g), and the reaction mixture was stirred at 80 °C for 18 h. The solvent was removed under reduced pressure, and the residue was purified by preparative TLC (EtOAc:pentane 3:2) to give the title compound (0.62 g, 76%) as a pale yellow solid; MS (ESI) m / z [M+H] + 218.

[0466] Intermediate 8: Methyl 6-formylquinoline-4-carboxylate

[0467] [ka]

[0468] Dess-Martin periodinane (4.64 g, 10.9 mmol) was added to a solution of methyl 6-(hydroxymethyl)quinoline-4-carboxylate intermediate 7 (950 mg, 4.37 mmol) in DCM (20 mL), and the reaction mixture was stirred for 2 h at 25° C. The reaction mixture was concentrated in vacuo, and the crude product was purified by preparative TLC (EtOAc:petroleum ether, 1:1) to give the title compound (850 mg, 90%) as a yellow solid: MS (ESI) m / z [M+H] + 215.

[0469] Intermediate 9: Methyl 6-(chloromethyl)quinoline-4-carboxylate

[0470] [ka]

[0471] Methyl 6-(hydroxymethyl)quinoline-4-carboxylate intermediate 7 (0.37 g, 1.7 mmol) was added to SOCl (0.26 mL, 3.6 mmol) in DCM (18 mL) at 20 °C. The resulting mixture was stirred at 20 °C for 16 h. The material was diluted with EtOAc and filtered through silica. The solvent was removed under reduced pressure to give the title compound (0.44 g) as a pale yellow solid: MS (ESI) m / z [M+H] + 236.

[0472] Intermediate 10: 6-((1H-pyrazol-1-yl)methyl)quinoline-4-carboxylic acid

[0473] [ka]

[0474] Intermediate 9 (220 mg, 0.93 mmol) was added to a mixture of 1H-pyrazole (76 mg, 1.1 mmol), CsCO (1.52 g, 4.67 mmol), and KI (465 mg, 2.80 mmol) in MeCN (25 mL) at 20 °C. The resulting mixture was stirred at 80 °C for 16 h. The reaction mixture was acidified with HCl (0.1 M), and the volatiles were removed under reduced pressure. The dried solid was triturated with DCM (2 × 50 mL), filtered, and concentrated under reduced pressure. The residue was purified by preparative HPLC Prep Method F (gradient: 1-21%) to give the title compound (40 mg, 17%) as a white solid: MS (ESI) m / z [M+H] + 254.

[0475] Intermediate 11: tert-butyl 6-(3-methoxypropyl)quinoline-4-carboxylate

[0476] [ka]

[0477] NiBrO(CHCHOCH) (30 mg, 0.10 mmol) was added to a mixture of tert-butyl 6-bromoquinoline-4-carboxylate (WO2019154886) (300 mg, 0.97 mmol), 1-bromo-3-methoxypropane (298 mg, 1.95 mmol), Zn (127 mg, 1.95 mmol), 4,4'-dimethoxy-2,2'-bipyridyl (21 mg, 0.10 mmol), and NaI (146 mg, 0.97 mmol) in DMPU (8 mL). The reaction was stirred at 80 °C for 2 h, diluted with EtOAc, and washed with water. The organic layer was dried over NaSO, filtered, and evaporated under reduced pressure. The residue was purified by preparative TLC (EtOAc:petroleum ether; 1:5) to give the title compound (0.12 g, 41%) as a pale yellow gum: MS (ESI) m / z [M+H] + 302.

[0478] Intermediate 12: 6-(3-methoxypropyl)quinoline-4-carboxylic acid

[0479] [ka]

[0480] tert-Butyl 6-(3-methoxypropyl)quinoline-4-carboxylate intermediate 11 (160 mg, 0.53 mmol) was added to a mixture of TFA (4 mL) in DCM (10 mL) and stirred at room temperature for 2 h. The volatiles were removed under reduced pressure and the solid was further dried under vacuum to give the title compound (0.13 g) as a pale yellow gum: MS (ESI) m / z [M+H] + 246.

[0481] Intermediate 13: tert-butyl 6-(2-methoxyethyl)quinoline-4-carboxylate

[0482] [ka]

[0483] NiBrO(CHCHOCH) (45 mg, 0.15 mmol) was added to a mixture of tert-butyl 6-bromoquinoline-4-carboxylate (WO2019154886) (300 mg, 0.97 mmol), 1-bromo-2-methoxyethane (271 mg, 1.95 mmol), Zn (127 mg, 1.95 mmol), 4,4'-dimethoxy-2,2'-bipyridyl (21 mg, 0.10 mmol), and NaI (146 mg, 0.97 mmol) in DMPU (10 mL). The reaction was stirred at 80 °C for 2 h, diluted with EtOAc, and washed with water. The organic layer was dried over NaSO, filtered, and evaporated. The residue was purified by preparative TLC (EtOAc:petroleum ether; 1:4) to give the title compound (80 mg, 29%) as a pale yellow solid: MS (ESI) m / z [M+H] + 288.

[0484] Intermediate 14: 6-(2-methoxyethyl)quinoline-4-carboxylic acid

[0485] [ka]

[0486] tert-Butyl 6-(2-methoxyethyl)quinoline-4-carboxylate intermediate 13 (80 mg, 0.28 mmol) was added to a mixture of TFA (2 mL) in DCM (5 mL) and stirred at room temperature for 2 h. The volatiles were removed under reduced pressure and the solid was further dried under vacuum to give the title compound (64 mg, 99%) as a pale yellow gum: MS (ESI) m / z [M+H] + 232.

[0487] Intermediate 15: Methyl 6-(cyanomethyl)quinoline-4-carboxylate

[0488] [ka]

[0489] Pd(dba)·CHCl (194 mg, 0.19 mmol) was added in one portion to a suspension of methyl 6-bromoquinoline-4-carboxylate (500 mg, 1.88 mmol), 2-(trimethylsilyl)acetonitrile (277 mg, 2.44 mmol), ZnF (136 mg, 1.32 mmol), and XantPhos (109 mg, 0.19 mmol) in DMF (8 mL) under an atmosphere of N (g) at 20 °C, and the reaction mixture was stirred at 105 °C for 10 h. The reaction mixture was diluted with EtOAc (100 mL) and washed with saturated brine (3 × 50 mL). The organic layer was dried over NaSO, filtered, and evaporated in vacuo, and the residue was purified by preparative TLC (EtOAc:petroleum ether, 1:2) to give the title compound (340 mg, 80%) as a yellow solid: MS (ESI) m / z [M+H] + 227.

[0490] Intermediate 16: Methyl 6-(1-cyanocyclopropyl)quinoline-4-carboxylate

[0491] [ka]

[0492] NaH (32 mg, 1.3 mmol) was added portionwise to a solution of methyl 6-(cyanomethyl)quinoline-4-carboxylate intermediate 15 (300 mg, 1.33 mmol) in DMF (2 mL), and the reaction mixture was stirred at room temperature for 1 h. 1,2-Dibromoethane (249 mg, 1.33 mmol) was added, and the reaction mixture was stirred at 20 °C for 2 h. The reaction mixture was diluted with EtOAc (50 mL) and washed with water (2 × 20 mL). The organic layer was dried over Na SO , filtered, evaporated, and the residue was purified by preparative TLC (EtOAc:petroleum ether, 1:2) to give the title compound (200 mg, 60%) as a yellow solid: MS (ESI) m / z [M+H] + 253.

[0493] Intermediate 17: 6-(1-cyanocyclopropyl)quinoline-4-carboxylic acid

[0494] [ka]

[0495] A solution of methyl 6-(1-cyanocyclopropyl)quinoline-4-carboxylate intermediate 16 (130 mg, 0.52 mmol) and LiOH (25 mg, 1.0 mmol) in THF (6 mL) and water (1 mL) was stirred at room temperature for 2 h. The solvent was removed under reduced pressure. The reaction mixture was acidified with 2 M HCl (aq), and the precipitate was collected by filtration and washed with water to give the crude title compound (70 mg, 57%) as a white solid. MS (ESI) m / z [M+H] + 239.

[0496] Intermediate 18: Methyl 6-(2-methoxyethoxy)quinoline-4-carboxylate

[0497] [ka]

[0498] To a stirred solution of methyl 6-hydroxyquinoline-4-carboxylate (200 mg, 0.98 mmol) in DMF (5 mL) was added 1-bromo-2-methoxyethane (137 mg, 0.98 mmol) and CsCO (802 mg, 2.46 mmol). The resulting mixture was stirred at 25 °C for 2 h. The reaction mixture was filtered through Celite®. The solvent was removed under reduced pressure. The residue was purified by preparative TLC (petroleum ether: EtOAc, 2:1) to give the title compound (0.19 g, 73%) as a colorless oil; MS m / z (ESI), [M+H] + 262.0.

[0499] Intermediate 19: 6-(2-methoxyethoxy)quinoline-4-carboxylic acid

[0500] [ka]

[0501] LiOH (55 mg, 2.3 mmol) was added to methyl 6-(2-methoxyethoxy)quinoline-4-carboxylate intermediate 18 (150 mg, 0.57 mmol) in THF (2 mL) and water (2 mL) at 25° C. The resulting suspension was stirred at 25° C. for 3 h. The reaction mixture was adjusted to pH 5 with 2 M HCl (aq). The solvent was removed under reduced pressure to give the crude product as a pale yellow solid; MS m / z (ESI), [M+H] + 248.0.

[0502] Intermediate 20: Methyl 6-(cyclopropylmethoxy)quinoline-4-carboxylate

[0503] [ka]

[0504] K2CO3 (340 mg, 2.46 mmol) was added to methyl 6-hydroxyquinoline-4-carboxylate (200 mg, 0.98 mmol) and (bromomethyl)cyclopropane (199 mg, 1.48 mmol) in DMF (3 mL) at 30 °C. The resulting suspension was stirred at 60 °C under N2(g) for 3 h. The solvent was removed under reduced pressure. The residue was purified by preparative TLC (EtOAc:petroleum ether, 1:1) to give the title compound (197 mg, 78%) as a yellow solid; MS m / z (ESI), [M+H] + 258.2.

[0505] Intermediate 21: 6-(cyclopropylmethoxy)quinoline-4-carboxylic acid

[0506] [ka]

[0507] NaOH (148 mg, 3.7 mmol) was added to methyl 6-(cyclopropylmethoxy)quinoline-4-carboxylate intermediate 20 (191 mg, 0.74 mmol) in MeOH (9 mL) and water (3 mL) at 25° C. The resulting solution was stirred at 25° C. for 1 h. The solvent was removed under reduced pressure. The residue was diluted with water (50 mL) and adjusted to pH 3 with 1 M HCl (aq). The aqueous phase was extracted with EtOAc (3×50 mL), and the organic layer was dried over NaSO, filtered, and evaporated to give the title compound (173 mg, 96%) as a white solid, which was used directly in the next step without further purification; MS m / z (ESI), [M+H] + 244.0.

[0508] Intermediate 22: Methyl 6-((tetrahydro-2H-pyran-4-yl)oxy)quinoline-4-carboxylate

[0509] [ka]

[0510] DIAD (574 μL, 2.95 mmol) was slowly added to methyl 6-hydroxyquinoline-4-carboxylate (120 mg, 0.59 mmol), tetrahydro-2H-pyran-4-ol (302 mg, 2.95 mmol), and triphenylphosphine (774 mg, 2.95 mmol) in THF (5 mL) at 60° C. The resulting suspension was stirred at 60° C. for 15 min. The solvent was removed under reduced pressure. The residue was purified by preparative TLC (EtOAc:petroleum ether, 1:2) to give the crude title compound (1.1 g) as a yellow solid; MS m / z (ESI), [M+H] + 288.2.

[0511] Intermediate 23: 6-((tetrahydro-2H-pyran-4-yl)oxy)quinoline-4-carboxylic acid

[0512] [ka]

[0513] NaOH (762 mg, 19.1 mmol) was added to methyl 6-((tetrahydro-2H-pyran-4-yl)oxy)quinoline-4-carboxylate intermediate 22 (1.10 g, 3.81 mmol) in MeOH (9 mL) and water (3 mL) at 25 °C. The resulting solution was stirred at 25 °C for 1 h. The solvent was removed under reduced pressure. The residue was diluted with saturated NaHCO (aq, 50 mL) and extracted with EtOAc (3 × 50 mL). The aqueous layer was adjusted to pH 3 with 1 M HCl (aq) and then extracted with EtOAc (3 × 100 mL). The combined organic layers were dried over NaSO, filtered, and evaporated to give the title compound (161 mg, 15%) as a white solid. The product was used directly in the next step without further purification; MS m / z (ESI), [M+H] + 274.1.

[0514] Intermediate 24: Methyl 6-((1,3-difluoropropan-2-yl)oxy)quinoline-4-carboxylate

[0515] [ka]

[0516] DIAD (0.896 g, 4.43 mmol) was added dropwise to methyl 6-hydroxyquinoline-4-carboxylate (0.15 g, 0.74 mmol), 1,3-difluoropropan-2-ol (0.426 g, 4.43 mmol), and triphenylphosphine (1.16 g, 4.43 mmol) in THF (15 mL) at 60 °C. The resulting solution was stirred at 60 °C for 15 min. The solvent was removed under reduced pressure. The crude product was purified by flash chromatography on silica (gradient: 1 to 50% EtOAc in petroleum ether) to give the crude title compound (1 g) as a pale yellow solid, which was used in the next step; MS m / z (ESI), [M+H] + 282.1.

[0517] Intermediate 25: 6-((1,3-difluoropropan-2-yl)oxy)quinoline-4-carboxylic acid

[0518] [ka]

[0519] NaOH (722 mg, 18.0 mmol) was added to methyl 6-((1,3-difluoropropan-2-yl)oxy)quinoline-4-carboxylate intermediate 24 (1015 mg, 3.61 mmol) in MeOH (9 mL) and water (3 mL) at 25 °C. The resulting solution was stirred under air at 25 °C for 1 h. The solvent was removed under reduced pressure. The residue was diluted with saturated NaHCO (aq, 50 mL) and extracted with EtOAc (3 × 50 mL). The aqueous layer was adjusted to pH 3 with 1 M HCl (aq) and extracted with EtOAc (3 × 50 mL). The organic layer was dried over NaSO, filtered, and evaporated to give the title compound (174 mg, 18%) as a pale yellow solid, which was used directly in the next step without further purification; MS m / z (ESI), [M+H] + 268.0.

[0520] Intermediate 26: Methyl 6-((3,3-difluorocyclobutyl)methoxy)quinoline-4-carboxylate

[0521] [ka]

[0522] Cs2CO3 (802 mg, 2.46 mmol) was added to methyl 6-hydroxyquinoline-4-carboxylate (200 mg, 0.98 mmol) and 3-(bromomethyl)-1,1-difluorocyclobutane (273 mg, 1.48 mmol) in DMF (3 mL) at 25 °C. The resulting suspension was stirred at 55 °C under N2(g) for 3 h. The solvent was removed under reduced pressure. The residue was diluted with water (50 mL) and extracted with EtOAc (3 × 50 mL). The organic layer was dried over Na2SO4, filtered, and evaporated. The residue was purified by preparative TLC (EtOAc:petroleum ether, 1:2) to give the title compound (132 mg, 43%) as a brown gum; MS m / z (ESI), [M+H] + 308.0.

[0523] Intermediate 27: 6-((3,3-difluorocyclobutyl)methoxy)quinoline-4-carboxylic acid

[0524] [ka]

[0525] NaOH (83 mg, 2.1 mmol) was added to methyl 6-((3,3-difluorocyclobutyl)methoxy)-quinoline-4-carboxylate intermediate 26 (127 mg, 0.41 mmol) in MeOH (9 mL) and water (3 mL) at 25° C. The resulting solution was stirred at 25° C. for 1 h. The solvent was removed under reduced pressure and the mixture was diluted with water (50 mL). The pH was adjusted to pH 3 with 1 M HCl (aq). The aqueous phase was extracted with EtOAc (3×50 mL). The organic phase was dried over Na2SO4, filtered and evaporated to give the title compound (120 mg, 99%) as a white solid, which was used directly in the next step without further purification; MS m / z (ESI), [M+H] + 294.0.

[0526] Intermediate 28: rac-methyl (R)-6-((2,2-dimethyltetrahydro-2H-pyran-4-yl)oxy)quinoline-4-carboxylate

[0527] [ka]

[0528] DIAD (718 μL, 3.69 mmol) was slowly added to methyl 6-hydroxyquinoline-4-carboxylate (150 mg, 0.74 mmol), rac-(R)-2,2-dimethyltetrahydro-2H-pyran-4-ol (WO2012021591) (481 mg, 3.69 mmol), and triphenylphosphine (968 mg, 3.69 mmol) in THF (10 mL) at 60° C. The resulting suspension was stirred at 60° C. for 15 min. The solvent was removed under reduced pressure. The residue was triturated with EtO (2×15 mL) and filtered. The residue was purified by preparative TLC (EtOAc:petroleum ether, 1:2) to give the crude title compound (365 mg) as a yellow gum, which was used in the next step; MS m / z (ESI), [M+H] + 316.0.

[0529] Intermediate 29: rac-(R)-6-((2,2-dimethyltetrahydro-2H-pyran-4-yl)oxy)quinoline-4-carboxylic acid

[0530] [ka]

[0531] NaOH (224 mg, 5.60 mmol) was added to rac-methyl (R)-6-((2,2-dimethyltetrahydro-2H-pyran-4-yl)oxy)quinoline-4-carboxylate intermediate 28 (353 mg, 1.12 mmol) in MeOH (9 mL) and water (3 mL) at 25 °C. The resulting solution was stirred at 25 °C for 1 h. The solvent was removed under reduced pressure. The residue was diluted with saturated NaHCO (aq, 50 mL) and extracted with EtOAc (3 × 50 mL). The pH of the aqueous layer was adjusted to pH 3 with 1 M HCl (aq) and then extracted with EtOAc (3 × 50 mL). The organic layer was dried over NaSO, filtered, and evaporated to give the title compound (194 mg, 57%) as a white solid, which was used directly in the next step without further purification; MS m / z (ESI), [M+H] + 302.2.

[0532] Intermediate 30: tert-butyl 6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)quinoline-4-carboxylate

[0533] [ka]

[0534] Pd(dppf)Cl (137 mg, 0.19 mmol) was added to tert-butyl 6-bromoquinoline-4-carboxylate (WO2019154886) (640 mg, 2.08 mmol), KOAc (549 mg, 5.59 mmol), and bis(pinacolato)diboron (711 mg, 2.80 mmol) in 1,4-dioxane (10 mL). The resulting solution was stirred at 80 °C under N (g) for 3 h. The solvent was removed under reduced pressure. The mixture was diluted with EtOAc (50 mL) and washed sequentially with water (3 × 25 mL). The organic layer was dried over NaSO, filtered, and evaporated. The residue was purified by preparative TLC (EtOAc:petroleum ether, 2:1) to give the title compound (540 mg, 73%) as a yellow solid; MS m / z (ESI), [M+H] + 356.1.

[0535] Intermediate 31: tert-Butyl 6-hydroxyquinoline-4-carboxylate

[0536] [ka]

[0537] Sodium perborate tetrahydrate (458 mg, 2.98 mmol) was added to tert-butyl 6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)quinoline-4-carboxylate Intermediate 30 (580 mg, 1.63 mmol) in THF (8 mL) and water (4 mL). The resulting solution was stirred at 20° C. for 6 hours. The solvent was removed under reduced pressure. The residue was purified by preparative TLC (EtOAc:petroleum ether, 1:2) to give the title compound (350 mg, 87%) as a yellow solid; MS m / z (ESI), [M+H] + 246.0.

[0538] Intermediate 32: tert-butyl 6-(cyanomethoxy)quinoline-4-carboxylate

[0539] [ka]

[0540] Bromoacetonitrile (257 mg, 2.14 mmol) was added to tert-butyl 6-hydroxyquinoline-4-carboxylate intermediate 31 (350 mg, 1.43 mmol) and K2CO3 (493 mg, 3.57 mmol) in DMF (20 mL). The resulting solution was stirred at 60 °C under N2(g) for 6 h. The solvent was removed under reduced pressure. The residue was purified by preparative TLC (EtOAc:petroleum ether, 1:1) to give the title compound (320 mg, 79%) as a yellow solid; MS m / z (ESI), [M+H] + 285.1.

[0541] Intermediate 33: 6-(cyanomethoxy)quinoline-4-carboxylic acid

[0542] [ka]

[0543] TFA (650 μL, 8.44 mmol) was slowly added to a solution of tert-butyl 6-(cyanomethoxy)quinoline-4-carboxylate intermediate 32 (300 mg, 1.06 mmol) in DCM (3 mL). The resulting solution was stirred at 20° C. for 18 h. The solvent was removed under reduced pressure to give the crude title compound (300 mg, 83%); MS m / z (ESI), [M+H] + 229.1.

[0544] Intermediate 34: Methyl 6-(2-oxopropoxy)quinoline-4-carboxylate

[0545] [ka]

[0546] A solution of methyl 6-hydroxyquinoline-4-carboxylate (200 mg, 0.98 mmol), 1-bromopropan-2-one (270 mg, 1.97 mmol), and CsCO (641 mg, 1.97 mmol) in THF (8 mL) was stirred at 50 °C for 20 h. The solvent was removed under reduced pressure. The reaction mixture was diluted with EtOAc (25 mL) and washed with water (3 × 10 mL). The organic layer was dried over NaSO, filtered, and evaporated. The crude product was purified by preparative TLC (petroleum ether: EtOAc, 3:2) to give the title compound (220 mg, 86%) as a white solid; MS m / z (ESI), [M+H] + 260.0.

[0547] Intermediate 35: Methyl 6-(2,2-difluoropropoxy)quinoline-4-carboxylate

[0548] [ka]

[0549] DAST (561 μL, 4.24 mmol) was added to a solution of methyl 6-(2-oxopropoxy)quinoline-4-carboxylate intermediate 34 (220 mg, 0.85 mmol) in DCM (10 mL) at 0° C. The reaction was stirred at 25° C. for 20 h. The solvent was removed under reduced pressure. The residue was purified by preparative TLC (petroleum ether: EtOAc, 3:2) to give the title compound (180 mg, 75%) as a white solid; MS m / z (ESI), [M+H] + 282.1.

[0550] Intermediate 36: 6-(2,2-difluoropropoxy)quinoline-4-carboxylic acid

[0551] [ka]

[0552] A solution of methyl 6-(2,2-difluoropropoxy)quinoline-4-carboxylate intermediate 35 (170 mg, 0.60 mmol) and LiOH (29 mg, 1.2 mmol) in MeOH (6 mL) and water (1 mL) was stirred at 25° C. for 3 h. The solvent was removed under reduced pressure. The mixture was diluted with water (10 mL) and the pH was adjusted to pH 6 with 1 M HCl (aq). The precipitate was collected by filtration, washed with water (25 mL), and dried under vacuum to give the title compound (150 mg, 93%) as a white solid, which was used without further purification; MS m / z (ESI), [M+H] + 268.0.

[0553] Intermediate 37: rac-(R)-1-(4-chloroquinolin-6-yl)-1-(3-fluoropyridin-2-yl)ethan-1-ol

[0554] [ka]

[0555] n-BuLi (4.95 mL, 12.4 mmol, 2.5 M in hexanes) was slowly added to 6-bromo-4-chloroquinoline (2.0 g, 8.3 mmol) in THF (20 mL) at −78° C. under N2(g). The resulting solution was stirred at −78° C. under N2(g) for 3 h. 1-(3-fluoropyridin-2-yl)ethan-1-one (1.15 g, 8.25 mmol) was slowly added over 15 min to the stirred mixture warmed to −40° C. The resulting solution was stirred at −40° C. under N2(g) for 2 h. The reaction mixture was quenched with saturated NH4Cl (aq, 20 mL) and extracted with EtOAc (3×50 mL). The organic layer was dried over Na2SO4, filtered, and evaporated. The crude product was purified by flash chromatography on C18 (gradient: 40-45% MeCN in water) to give, after evaporation of the pure fractions, the title compound (687 mg, 27%) as a brown gum; MS m / z (ESI), [M+H] + 303.2.

[0556] Intermediate 38: rac-methyl (R)-6-(1-(3-fluoropyridin-2-yl)-1-hydroxyethyl)quinoline-4-carboxylate

[0557] [ka]

[0558] Pd(OAc) (54 mg, 0.24 mmol) and Pd(dppf)Cl (88 mg, 0.12 mmol) were added to a mixture of rac-(R)-1-(4-chloroquinolin-6-yl)-1-(3-fluoropyridin-2-yl)ethan-1-ol intermediate 37 (727 mg, 2.40 mmol), TEA (1.0 mL, 7.2 mmol), and dppf (200 mg, 0.36 mmol) in MeOH (5 mL) under N (g). The resulting mixture was stirred at 100 °C under a CO (g) atmosphere (20 atm) for 12 h. The solvent was removed under reduced pressure. The residue was diluted with water (50 mL) and extracted with EtOAc (3 × 50 mL). The organic layer was dried over Na SO , filtered, and evaporated. The crude product was purified by flash chromatography on silica (gradient: 50-80% EtOAc in petroleum ether) to give, after evaporation of the pure fractions, the title compound (537 mg, 68%) as a brown gum; MS m / z (ESI), [M+H] + 327.2.

[0559] Intermediate 39: rac-methyl (R)-6-(1-(3-fluoropyridin-2-yl)ethyl)quinoline-4-carboxylate

[0560] [ka]

[0561] rac-Methyl (R)-6-(1-(3-fluoropyridin-2-yl)-1-hydroxyethyl)quinoline-4-carboxylate intermediate 38 (120 mg, 0.37 mmol) was added to triethylsilane (5 mL) and TFA (5 mL) at 13 °C. The resulting solution was stirred at 100 °C under N (g) for 2 days. Additional triethylsilane (1 mL) and TFA (1 mL) were added, and the reaction was stirred at 100 °C for 1 day. The solvent was removed under reduced pressure. The residue was diluted with saturated NaHCO (aq, 50 mL) and extracted with EtOAc (3 × 100 mL). The organic layer was dried over NaSO, filtered, and evaporated. The crude product was purified by flash chromatography on C18 (gradient: 40-60% MeCN in water) to give, after evaporation of the pure fractions, the title compound (12 mg, 10%) as a yellow gum; MS m / z (ESI), [M+H] + 311.1.

[0562] Intermediate 40: rac-(R)-6-(1-(3-fluoropyridin-2-yl)ethyl)quinoline-4-carboxylic acid

[0563] [ka]

[0564] NaOH (32 mg, 0.79 mmol) was added to rac-methyl (R)-6-(1-(3-fluoropyridin-2-yl)ethyl)quinoline-4-carboxylate intermediate 39 (49 mg, 0.16 mmol) in MeOH (3 mL) and water (1 mL) at 15 °C. The resulting solution was stirred under N2(g) at 15 °C for 1 h. The solvent was removed under reduced pressure. The mixture was diluted with water (10 mL) and the pH was adjusted to pH 3 with 1 M HCl (aq). The aqueous phase was extracted with EtOAc (3 × 50 mL). The organic layer was dried over Na2SO4, filtered, and evaporated to give the crude title compound (100 mg) as a colorless gum, which was used directly in the next step; MS m / z (ESI), [M+H] + 297.2.

[0565] Intermediate 41: 2,2'-(cyclopropane-1,1-diyl)bis(4,4,5,5-tetramethyl-1,3,2-dioxaborolane)

[0566] [ka]

[0567] Bromocyclopropane (7.0 g, 58 mmol) and 4,4,4',4',5,5,5',5'-octamethyl-2,2'-bi(1,3,2-dioxaborolane) (14.1 g, 55.6 mmol) in THF (50 mL) were added dropwise over 30 min to lithium 2,2,6,6-tetramethylpiperidin-1-ide (11.9 g, 81.0 mmol) in THF (100 mL) under N2 (g) and cooled to -78 °C. The resulting solution was stirred at -80 °C for 1 h. The reaction mixture was poured into saturated NaHCO3 (aq, 300 mL) and extracted with EtOAc (3 x 200 mL). The organic layer was dried over Na2SO4, filtered, and evaporated. The crude product was purified by flash chromatography on silica (gradient: 0-2% EtOAc in petroleum ether) to give, after evaporation of the pure fractions, the title compound (7.2 g, 42%) as a white solid; 1 H NMR (300MHz, CDCl3): δ1.20 (s, 24H), 0.78 (s, 4H).

[0568] Intermediate 42: 4-chloro-6-(1-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)cyclopropyl)quinoline

[0569] [ka]

[0570] CataCXium® A Pd G3 (0.557 g, 0.77 mmol) was added to 2,2'-(cyclopropane-1,1-diyl)bis(4,4,5,5-tetramethyl-1,3,2-dioxaborolane) in 1,4-dioxane (20 mL) and water (2 mL). Intermediate 41 (5.0 g, 17 mmol), 6-bromo-4-chloroquinoline (5.36 g, 22.1 mmol), and Cs2CO3 (11.1 g, 34.0 mmol) were added at 20 °C. The resulting solution was stirred at 100 °C under N2 (g) for 20 h. The reaction mixture was diluted with EtOAc, dried over Na2SO4, filtered, and evaporated to give a brown gum. The crude product was purified by flash chromatography on silica (gradient 2-20% EtOAc in petroleum ether) to give the title compound (3.8 g, 67%) as a pale yellow oil that solidified on standing; MS m / z (ESI), [M+H] + 330.3.

[0571] Intermediate 43: Potassium (1-(4-chloroquinolin-6-yl)cyclopropyl)-trifluoroborate

[0572] [ka]

[0573] KHF2 (5.40 g, 69.2 mmol) was added to 4-chloro-6-(1-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)cyclopropyl)quinoline intermediate 42 (3.8 g, 12 mmol) in MeOH (20 mL) at 20 °C. The resulting solution was stirred at 80 °C under N2 (g) for 14 h. The reaction mixture was evaporated. The crude white solid was triturated with petroleum ether:TBME, 1:1, to give a solid. The precipitate was collected by filtration and washed with hot MeCN (100 mL). The filtrate was concentrated to give the title compound (2.3 g, 64%) as a yellow solid, which was used without further purification; MS m / z (ESI), [M+H] + 269.9.

[0574] Intermediate 44: 4-chloro-6-(1-(2-(trifluoromethyl)pyridin-4-yl)cyclopropyl)-quinoline

[0575] [ka]

[0576] CataCXium® A Pd G3 (57 mg, 0.08 mmol) was added to 4-bromo-2-(trifluoromethyl)pyridine (263 mg, 1.16 mmol), potassium (1-(4-chloroquinolin-6-yl)cyclopropyl)trifluoroborate Intermediate 43 (300 mg, 0.97 mmol), and Cs2CO3 (632 mg, 1.94 mmol) in 1,4-dioxane (10 mL) and water (1 mL) at 20 °C. The resulting solution was stirred at 100 °C under N2(g) for 14 h. The reaction mixture was dried over Na2SO4 and filtered through Celite®. The filter cake was washed with DCM (20 mL). The solvent was removed under reduced pressure. The residue was purified by preparative TLC (EtOAc:petroleum ether, 1:1) to give the title compound (256 mg, 76%) as a pale yellow gum. MS m / z (ESI), [M+H] + 349.0.

[0577] Intermediate 45: Methyl 6-(1-(2-(trifluoromethyl)pyridin-4-yl)cyclopropyl)-quinoline-4-carboxylate

[0578] [ka]

[0579] TEA (318 μL, 2.28 mmol) was added to 4-chloro-6-(1-(2-(trifluoromethyl)pyridin-4-yl)cyclopropyl)quinoline intermediate 44 (265 mg, 0.76 mmol), Pd(OAc) (17 mg, 0.08 mmol), Pd(dppf)Cl (28 mg, 0.04 mmol), and dppf (63 mg, 0.11 mmol) in MeOH (5 mL) at 13 °C. The resulting solution was stirred at 100 °C under a CO(g) atmosphere (20 atm) for 12 h. The solvent was removed under reduced pressure. The residue was diluted with water (50 mL) and extracted with EtOAc (3 × 50 mL). The organic layer was dried over NaSO, filtered, and evaporated. The residue was purified by preparative TLC (EtOAc:petroleum ether, 1:1) to give the title compound (161 mg, 56%) as a brown gum; MS m / z (ESI), [M+H] + 373.1.

[0580] Intermediate 46: 6-(1-(2-(trifluoromethyl)pyridin-4-yl)cyclopropyl)quinoline-4-carboxylic acid

[0581] [ka]

[0582] NaOH (86 mg, 2.2 mmol) was added to methyl 6-(1-(2-(trifluoromethyl)pyridin-4-yl)cyclopropyl)quinoline-4-carboxylate intermediate 45 (160 mg, 0.43 mmol) in MeOH (6 mL) and water (2 mL) at 15° C. The resulting solution was stirred at 15° C. for 1 h. The solvent was removed under reduced pressure. The residue was diluted with water (10 mL) and the pH was adjusted to pH 3 with 1 M HCl (aq). The aqueous phase was extracted with EtOAc (3×50 mL), and the organic layer was dried over NaSO, filtered, and evaporated to give the crude title compound (158 mg) as an orange solid, which was used directly in the next step without further purification; MS m / z (ESI), [M+H] + 359.0.

[0583] Intermediate 47: 6-(furan-3-yl)quinoline-4-carboxylic acid

[0584] [ka]

[0585] 6-Bromoquinoline-4-carboxylic acid (250 mg, 0.99 mmol), furan-3-ylboronic acid (111 mg, 0.99 mmol), Pd(dppf)Cl (65 mg, 0.10 mmol), and CsCO (969 mg, 2.98 mmol) were mixed in 1,4-dioxane (6 mL) and water (1.5 mL). The mixture was bubbled with N(g) for 10 min and then stirred at room temperature under N(g) for 19 h. HCl (3.8 M, 783 μL, 2.98 mmol) and DMSO (5 mL) were added, and the 1,4-dioxane was evaporated. The mixture was filtered through a syringe filter and purified by preparative HPLC, Prep Method A (gradient 5-40%) to give, after evaporation of the solvent and co-evaporation with EtOH (1x), the title compound (137 mg, 58%) as a solid; MS m / z (ESI), [M+H] + 240.0.

[0586] Intermediate 48: 4-(4-chloroquinolin-6-yl)tetrahydro-2H-pyran-4-ol

[0587] [ka]

[0588] 6-Bromo-4-chloroquinoline (10 g, 41 mmol) was dissolved in THF (200 mL) in a dry, two-necked flask under an argon atmosphere and cooled to −70° C. n-BuLi (2.5 M in hexanes, 24.7 mL, 61.9 mmol) was added dropwise slowly so that the internal temperature did not exceed −65° C. The reaction mixture was stirred at −70° C. for 1 h. Tetrahydro-4H-pyran-4-one (6.19 g, 61.9 mmol) in THF (10 mL) was added dropwise slowly so that the internal temperature did not exceed −65° C. The reaction solution was stirred at −70° C. for 1 h, then warmed to room temperature and stirred for 3 h. The reaction mixture was poured into saturated NH4Cl (100 mL) and extracted with EtOAc (4 × 100 mL). The organic layer was dried over Na2SO4, filtered, and evaporated. The crude product was purified by flash chromatography on silica (gradient: 10-50% EtOAc in petroleum ether) to give the title compound (3.5 g, 32%) as a pale yellow solid; MS m / z (ESI), [M+H] + 264.0.

[0589] Intermediate 49: Methyl 6-(4-hydroxytetrahydro-2H-pyran-4-yl)quinoline-4-carboxylate

[0590] [ka]

[0591] Pd(OAc) (0.17 g, 0.76 mmol) and Pd(dppf)Cl·DCM (0.31 g, 0.38 mmol) were added to a mixture of 4-(4-chloroquinolin-6-yl)tetrahydro-2H-pyran-4-ol intermediate 48 (2.0 g, 7.6 mmol), dppf (0.63 g, 1.1 mmol), and TEA (3.2 mL, 23 mmol) in MeOH (20 mL) under N (g). The resulting mixture was stirred at 100 °C under a CO (g) atmosphere (10 atm) for 12 h. The solvent was removed under reduced pressure. The reaction mixture was diluted with EtOAc (50 mL) and washed sequentially with water (3 × 25 mL). The organic layer was dried over Na SO , filtered, and evaporated. The crude product was purified by flash chromatography on silica (gradient: 10-50% EtOAc in petroleum ether) to give the title compound (1.6 g, 73%) as a pale yellow solid; MS m / z (ESI), [M+H] + 288.1.

[0592] Intermediate 50: 6-(4-hydroxytetrahydro-2H-pyran-4-yl)quinoline-4-carboxylic acid

[0593] [ka]

[0594] A solution of methyl 6-(4-hydroxytetrahydro-2H-pyran-4-yl)quinoline-4-carboxylate intermediate 49 (180 mg, 0.63 mmol) and LiOH (45 mg, 1.9 mmol) in MeOH (8 mL) and water (2 mL) was stirred at 30° C. for 2 h. The solvent was removed under reduced pressure. The mixture was diluted with water (10 mL) and the pH was adjusted to pH 6 with 1 M HCl. The reaction mixture was diluted with water (20 mL) and extracted with EtOAc (3×25 mL). The organic layer was dried over NaSO, filtered, and evaporated to give the title compound (100 mg, 58%) as an orange solid, which was used directly in the next step; MS m / z (ESI), [M+H] + 274.1.

[0595] Intermediate 51: 6-(2-hydroxypropan-2-yl)quinoline-4-carboxylic acid

[0596] [ka]

[0597] A solution of methyl 6-(2-hydroxypropan-2-yl)quinoline-4-carboxylate intermediate 6 (80 mg, 0.33 mmol) and LiOH (16 mg, 0.65 mmol) in THF (4 mL) and water (0.5 mL) was stirred at room temperature for 1 h. The solvent was removed under reduced pressure. The mixture was acidified with 2 M HCl, diluted with EtOAc, and then washed with water. The organic layer was dried over Na2SO4, filtered, and evaporated to give the title compound (60 mg, 80%), which was used directly in the next step without further purification. MS m / z (ESI), [M+H] + 232.0.

[0598] Intermediate 52: 6-(trifluoromethyl)quinoline-4-carboxylic acid

[0599] [ka]

[0600] A mixture of 4-bromo-6-(trifluoromethyl)quinoline (150 mg, 0.54 mmol), Pd(OAc) (12 mg, 0.05 mmol), XantPhos (47 mg, 0.08 mmol), DCC (224 mg, 1.09 mmol), TEA (0.227 mL, 1.63 mmol), and acetic formic anhydride (335 mg, 3.80 mmol) was stirred at 100 °C for 2 h. The solvent was removed under reduced pressure. The mixture was diluted with EtOAc and washed with water. Evaporation of the aqueous layer gave the title compound (80 mg, 61%) as a pale yellow product, which was used directly in the next step without further purification; MS m / z (ESI), [M+H] + 242.0.

[0601] Intermediate 53: Ethyl 6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)quinoline-4-carboxylate

[0602] [ka]

[0603] Ethyl 6-bromoquinoline-4-carboxylate (1.0 g, 3.6 mmol), 4,4,4',4',5,5,5',5'-octamethyl-2,2'-bi(1,3,2-dioxaborolane) (0.997 g, 3.93 mmol), KOAc (0.701 g, 7.14 mmol), and Pd(dppf)Cl₂·DCM (0.146 g, 0.18 mmol) were added to a microwave vial. The mixture was flushed with N₂(g), 1,4-dioxane (12 mL) was added, and the mixture was bubbled with N₂(g) for 10 minutes. The vial was capped and heated in an oil bath at 80 °C overnight. After cooling to room temperature, the reaction was diluted with EtOAc (100 mL), washed with water (2×) and brine (2×), dried (MgSO₄), and evaporated. The residue was purified by automated flash chromatography (25 g silica column, gradient: 5-50% EtOAc in heptane over 25 column volumes, wavelength: 240 nm) to give the title compound (1.13 g, 97%) as a syrup after evaporation of the solvent and keeping under vacuum for 3 days. The compound solidified on standing; MS m / z (ESI), [M+H] + 328.2.

[0604] Intermediate 54: Ethyl 6-((2,5-dimethyl-2H-1,2,3-triazol-4-yl)methyl)quinoline-4-carboxylate

[0605] [ka]

[0606] Ethyl 6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)quinoline-4-carboxylate Intermediate 53 (200 mg, 0.61 mmol), 4-(bromomethyl)-2,5-dimethyl-2H-1,2,3-triazole (WO 2007096576) (128 mg, 0.67 mmol), NaCO (259 mg, 2.45 mmol), and trans-bromo(N-succinimidyl)-bis(triphenylphosphine)palladium(II) (25 mg, 0.03 mmol) were added to a microwave vial. Toluene (5 mL) and water (1 mL) were added. The mixture was bubbled with N (g) for 10 minutes. The vial was capped and heated in a microwave oven at 100 °C for 2 hours. DCM and water were added, and the mixture was stirred, filtered through a phase separator, and evaporated. The residue was purified by automated flash chromatography (10 g Biotage® KP-SIL column, gradient: 20 to 100% EtOAc in heptane over 40 column volumes, wavelength: 245 nm) to give the title compound (96 mg, 50%); MS m / z (ESI), [M+H] + 311.3.

[0607] Intermediate 55: tert-butyl 6-(tetrahydro-2H-pyran-4-yl)quinoline-4-carboxylate

[0608] [ka]

[0609] (4-(tert-Butoxycarbonyl)quinolin-6-yl)boronic acid intermediate 169 (814 mg, 2.98 mmol) was added to 4-methyl-N'-(tetrahydro-4H-pyran-4-ylidene)benzenesulfonohydrazide (J Org Chem. 2014 79,328.) (400 mg, 1.49 mmol) and K2CO3 (824 mg, 5.96 mmol) in 1,4-dioxane (150 mL) at 20 °C. The resulting solution was stirred at 110 °C for 15 h. The solvent was removed under reduced pressure. The mixture was poured into saturated NaHCO3 (aq, 150 mL) and extracted with EtOAc (3 × 150 mL). The organic layer was dried over Na2SO4, filtered, and evaporated. The residue was purified by preparative TLC (petroleum ether: EtOAc, 2:1) to give the title compound (100 mg, 21%) as a pale yellow gum; MS m / z (ESI), [M+H] + 314.1.

[0610] Intermediate 56: 4-Carboxy-6-(tetrahydro-2H-pyran-4-yl)quinolin-1-ium 2,2,2-trifluoroacetate

[0611] [ka]

[0612] TFA (1.0 mL, 13 mmol) was added to tert-butyl 6-(tetrahydro-2H-pyran-4-yl)quinoline-4-carboxylate intermediate 55 (99 mg, 0.32 mmol) in DCM (2 mL) at 20° C. The resulting solution was stirred at 20° C. for 16 h. The solvent was removed under reduced pressure to give the title compound (0.234 g, 99%) containing 3.3 equivalents of TFA as a brown gum, which was used directly in the next step without further purification. MS m / z (ESI), [M+H] + 258.2.

[0613] Intermediate 57: tert-butyl 6-(4-methyltetrahydro-2H-pyran-4-yl)quinoline-4-carboxylate

[0614] [ka]

[0615] 1,3-Di-tert-butyl-1H-imidazol-3-ium chloride (33 mg, 0.15 mmol) was added to a solution of tert-butyl 6-bromoquinoline-4-carboxylate (WO 2019154886) (200 mg, 0.65 mmol), 4-bromo-4-methyltetrahydro-2H-pyran (J Am Chem Soc. 2015 137, 11562.) (89 mg, 0.50 mmol), nickel(II)(Z)-4-oxopent-2-en-2-olate (26 mg, 0.10 mmol), magnesium chloride (71 mg, 0.75 mmol), Zn (65 mg, 1.0 mmol), and DMAP (73 mg, 0.60 mmol) in DMA (8 mL) at 20 °C. The resulting suspension was stirred under N2(g) at 25 °C for 18 h. The reaction mixture was diluted with EtOAc (60 mL) and filtered through Celite®. The organic layers were combined and washed with brine (2 x 50 mL). The organic layers were dried over Na2SO4, filtered, and evaporated to give a yellow oil. The residue was purified by preparative TLC (petroleum ether: EtOAc, 4:1) to give the crude title compound as a pale yellow oil. The crude product was further purified by preparative HPLC Prep Method B to give the title compound (25 mg, 15%) as a yellow oil; MS m / z (ESI), [M+H] + 328.1.

[0616] Intermediate 58: 6-(4-methyltetrahydro-2H-pyran-4-yl)quinoline-4-carboxylic acid

[0617] [ka]

[0618] TFA (0.50 mL, 6.5 mmol) was added to tert-butyl 6-(4-methyltetrahydro-2H-pyran-4-yl)quinoline-4-carboxylate intermediate 57 (25 mg, 0.08 mmol) in DCM (5 mL) at 20° C. The resulting solution was stirred at 20° C. for 15 h. The solvent was removed under reduced pressure to give the title compound (20 mg, 97%) as a yellow gum. The product was used directly in the next step without further purification; MS m / z (ESI), [M+H] + 272.3.

[0619] Intermediate 59: 6-(3,6-dihydro-2H-pyran-4-yl)quinoline-4-carboxylic acid

[0620] [ka]

[0621] Tetramethyl 6-bromoquinoline-4-carboxylate (100 mg, 0.40 mmol), 2-(3,6-dihydro-2H-pyran-4-yl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (ACS Med Chem Lett. 2016 7,666.) (92 mg, 0.44 mmol), Pd(dtbpf)Cl (26 mg, 0.04 mmol), and CsCO (388 mg, 1.19 mmol) were mixed in 1,4-dioxane (3 mL) and water (0.75 mL). The mixture was bubbled with N(g) for 10 minutes and then stirred overnight at room temperature under N(g). DMSO (2 mL) was added, and the 1,4-dioxane was evaporated. The mixture was filtered through a syringe filter and purified by preparative HPLC: Preparative Method C (gradient 0-30%). MeCN was evaporated and the remaining aqueous phase was lyophilized to give the title compound (30 mg, 29%) as a solid; MS m / z (ESI), [M+H] + 256.1.

[0622] Intermediate 60: 6-(4-ethoxytetrahydro-2H-pyran-4-yl)quinoline-4-carboxylic acid

[0623] [ka]

[0624] NaH (56 mg, 1.4 mmol, 60 wt%) was added to a stirred solution of methyl 6-(4-hydroxytetrahydro-2H-pyran-4-yl)quinoline-4-carboxylate intermediate 49 (200 mg, 0.70 mmol) in DMF (2 mL) cooled to 0°C. The resulting suspension was stirred at 10°C for 30 min. Ethyl iodide (139 μL, 1.74 mmol) was added slowly to the above suspension at 10°C. The resulting solution was stirred at 10°C for 1 h. Additional ethyl iodide (139 μL, 1.74 mmol) was added, and the suspension was stirred at 10°C for 1 h. NaOH (56 mg, 1.4 mmol) was added slowly to the above mixture at 10°C. The resulting solution was stirred at 10°C for 1 h. The reaction mixture was adjusted to pH ∼6 with 1 M aqueous HCl and filtered through Celite®. The filtrate was directly purified by preparative HPLC method D (gradient 10-35%) to give the title compound (130 mg, 62%) as a white solid; MS m / z (ESI), [M+H] + 302.1.

[0625] Intermediate 61: Methyl 6-(morpholinomethyl)quinoline-4-carboxylate

[0626] [ka]

[0627] Morpholine (222 μL, 2.55 mmol) was added to methyl 6-(chloromethyl)quinoline-4-carboxylate intermediate 9 (200 mg, 0.85 mmol), TEA (591 μL, 4.24 mmol), and KI (282 mg, 1.70 mmol) in MeCN (18 mL) at 20° C. The resulting mixture was stirred at 20° C. for 15 h. The reaction mixture was diluted with DCM (100 mL) and washed sequentially with saturated NaHCO (aq., 3×100 mL). The organic layer was dried over NaSO, filtered, and evaporated. The residue was purified by preparative TLC (EtOAc:petroleum ether, 1:1) to give the title compound (0.15 g, 61%) as a pale yellow oil; MS m / z (ESI), [M+H] + 287.0.

[0628] Intermediate 62: 6-(morpholinomethyl)quinoline-4-carboxylic acid

[0629] [ka]

[0630] Methyl 6-(morpholinomethyl)quinoline-4-carboxylate intermediate 61 (120 mg, 0.42 mmol) was added to LiOH (240 mg, 10.0 mmol) in water (6 mL) and MeOH (18 mL) at 20° C. The resulting mixture was stirred at 20° C. for 16 h. The reaction mixture was adjusted to pH 3 with 1 M HCl. The solution was filtered and dried over Na2SO4. The solvent was removed under reduced pressure to give the title compound (100 mg, 88%) as a pale yellow solid, which was used directly in the next step without further purification; MS m / z (ESI), [M+H] + 272.9.

[0631] Intermediate 63: rac-methyl (R)-6-(1-hydroxyethyl)quinoline-4-carboxylate

[0632] [ka]

[0633] NaBH4 (27 mg, 0.65 mmol) was added to a solution of methyl 6-acetylquinoline-4-carboxylate intermediate 5 (300 mg, 1.31 mmol) in MeOH (5 mL), and the reaction mixture was stirred at 25 °C for 2 h. The reaction mixture was concentrated in vacuo, and the crude product was purified by preparative TLC (EtOAc:pentane, 1:1) to give the title compound (200 mg, 66%) as a yellow solid; MS (ESI) m / z [M+H] + 232.

[0634] Intermediate 64: rac-(R)-6-(1-hydroxyethyl)quinoline-4-carboxylic acid

[0635] [ka]

[0636] A solution of rac-methyl (R)-6-(1-hydroxyethyl)quinoline-4-carboxylate intermediate 63 (130 mg, 0.56 mmol) and LiOH (27 mg, 1.1 mmol) in THF (6 mL) and water (1 mL) was stirred at room temperature for 1 h. The solvent was removed under reduced pressure. The reaction mixture was acidified with 0.1 M HCl, diluted with EtOAc, and washed with water. The organic layer was dried over Na2SO4, filtered, and evaporated to give the title compound (85 mg, 69%), which was used directly in the next step without further purification; MS m / z (ESI), [M+H] + 218.3.

[0637] Intermediate 65: Methyl 6-(ethoxymethyl)quinoline-4-carboxylate

[0638] [ka]

[0639] CsCO (918 mg, 2.82 mmol) was added to methyl 6-bromoquinoline-4-carboxylate (300 mg, 1.13 mmol), potassium (ethoxymethyl)trifluoroborate (374 mg, 2.25 mmol), Pd(OAc) (25 mg, 0.11 mmol) in 1,4-dioxane (10 mL) and water (1 mL) at 25 °C. The resulting suspension was stirred at 100 °C under N (g) for 16 h. The solvent was removed under reduced pressure. The residue was diluted with water (50 mL) and extracted with EtOAc (3 × 50 mL), and the organic layer was dried over NaSO, filtered, and evaporated. The residue was purified by preparative TLC (EtOAc:petroleum ether 1:2) to give the title compound (0.165 g, 60%) as a brown gum; MS (ESI) m / z [M+H] + 246.

[0640] Intermediate 66: 6-(ethoxymethyl)quinoline-4-carboxylic acid

[0641] [ka]

[0642] NaOH (130 mg, 3.26 mmol) was added to methyl 6-(ethoxymethyl)quinoline-4-carboxylate intermediate 65 (160 mg, 0.65 mmol) in MeOH (9 mL) and water (3 mL) at 25 °C. The resulting solution was stirred under N2(g) at 25 °C for 1 h. The solvent was removed under reduced pressure. The residue was diluted with water (50 mL) and adjusted to pH 3 with 1 M HCl (aq). The aqueous phase was extracted with EtOAc (3 × 50 mL), and the organic layer was dried over Na2SO4, filtered, and evaporated to give the title compound (0.133 g, 88%) as a pale yellow solid; MS (ESI) m / z [M+H] + 232.1.

[0643] Intermediate 67: Methyl 6-(fluoromethyl)quinoline-4-carboxylate

[0644] [ka]

[0645] DAST (0.365 mL, 2.76 mmol) was added to methyl 6-(hydroxymethyl)quinoline-4-carboxylate intermediate 7 (300 mg, 1.38 mmol) in DCM (10 mL) at room temperature. The resulting mixture was stirred at room temperature for 2 hours. The solvent was removed under reduced pressure, and the residue was purified by preparative TLC (pentane: EtOAc, 2:1) to give the title compound (200 mg, 66%) as a pale yellow solid; MS (ESI) m / z [M+H] + 220.

[0646] Intermediate 68: 6-(Fluoromethyl)quinoline-4-carboxylic acid

[0647] [ka]

[0648] A solution of methyl 6-(fluoromethyl)quinoline-4-carboxylate intermediate 67 (160 mg, 0.73 mmol) and LiOH (35 mg, 1.5 mmol) in THF (5 mL) and water (1 mL) was stirred at room temperature for 1 h. The solvent was removed under reduced pressure. The reaction mixture was diluted with HO (5 mL) and acidified with 0.1 M HCl. The precipitate was collected by filtration and washed with water to give the title compound (80 mg, 53%) as a white solid; MS (ESI) m / z [M+H] + 206.

[0649] Intermediate 69: Methyl 6-((2-methoxyethoxy)methyl)quinoline-4-carboxylate and Intermediate 70: rac-methyl (R)-6-(1,2-dimethoxyethyl)quinoline-4-carboxylate

[0650] [ka]

[0651] A mixture of methyl 6-bromoquinoline-4-carboxylate (133 mg, 0.5 mmol), NiBr₂·dtbbpy (12 mg, 0.03 mmol), and TBADT (17 mg, 5.0 μmol) in a 5 mL microwave vial was placed in a glovebox. MeCN (5 mL) was added. The resulting solution was then added to a 5 mL microwave vial containing K₃PO₄ (117 mg, 0.55 mmol). 1,2-Dimethoxyethane (0.26 mL, 2.5 mmol) was added to the resulting suspension. The vial was then capped, removed from the glovebox, placed in a photoreactor, and irradiated at 365 nm for 18 h. The cap was removed, and the mixture was stirred open to air for 15 min, then filtered and concentrated. The resulting residue was purified using preparative HPLC method E, (gradient 15-55%) to give a mixture of the title compounds (46 mg, 34%); MS (ESI) m / z [M+H] + 276.1.

[0652] Intermediate 71: 6-((2-methoxyethoxy)methyl)quinoline-4-carboxylic acid and Intermediate 72: rac-(R)-6-(1,2-dimethoxyethyl)quinoline-4-carboxylic acid

[0653] [ka]

[0654] Aqueous LiOH (574 μL, 0.57 mmol, 1 M) was added to a mixture of 6-((2-methoxyethoxy)-methyl)quinoline-4-carboxylic acid intermediate 69 and rac-methyl (R)-6-(1,2-dimethoxyethyl)quinoline-4-carboxylate intermediate 70 (79 mg, 0.29 mmol) in THF (2.3 mL). The reaction was stirred overnight at room temperature and then concentrated. The residue was purified by preparative HPLC, Preparative Method C, (gradient: 0-30%) to give a mixture of the title compounds intermediate 71 and intermediate 72 (60 mg, 80%); MS (ESI) m / z [M+H] + 262.2.

[0655] Intermediate 73: rac-methyl (R)-6-(tetrahydro-2H-pyran-2-yl)quinoline-4-carboxylate

[0656] [ka]

[0657] A solution of methyl 6-bromoquinoline-4-carboxylate (133 mg, 0.5 mmol), TBADT (17 mg, 5.0 μmol), and NiBr₂·dtbbpy (12 mg, 0.03 mmol) in deoxygenated MeCN (5 mL) in a microwave vial (2–5 mL size) was added under N₂(g) to a vial containing K₃PO₄ (117 mg, 0.55 mmol) (ground with a mortar and pestle and dried by heating with a heat gun under vacuum in a microwave vial). The resulting suspension was bubbled with N₂(g) for 10 min while cooling at 0 °C. Degassed tetrahydro-2H-pyran (0.25 mL, 2.5 mmol) was then added, and the reaction vial was placed in a photoreactor and irradiated at 365 nm for 18 h. The reaction mixture was stirred open to air for 15 min and then filtered through a syringe filter. The filter was washed several times with EtOAc. The resulting solution was concentrated and the residue was purified by normal phase flash chromatography on silica (gradient: 25-50% EtOAc in heptane) to give the title compound (20 mg, 15%) as a film; MS (ESI) m / z [M+H] + 272.1.

[0658] Intermediate 74: rac-methyl (R)-6-(1,4-dioxan-2-yl)quinoline-4-carboxylate

[0659] [ka]

[0660] A solution of methyl 6-bromoquinoline-4-carboxylate (133 mg, 0.5 mmol), TBADT (17 mg, 5.0 μmol), and NiBr₂·dtbbpy (12 mg, 0.03 mmol) in deoxygenated MeCN (5 mL) was added under N₂(g) to a vial containing K₃PO₄ (117 mg, 0.55 mmol), which had been crushed with a mortar and pestle and dried by heating with a heat gun under vacuum. The resulting suspension was cooled to 0 °C and bubbled with N₂(g) for 10 min. Degassed 1,4-dioxane (0.21 mL, 2.5 mmol) was then added, and the reaction vial was placed in a photoreactor and irradiated at 365 nm for 18 h. The reaction mixture was stirred open to air for 15 min, filtered, and the filter was washed several times with EtOAc. The combined filtrates were concentrated and the residue was purified by flash chromatography using a gradient of 25-50% EtOAc in heptane to give the title compound (45 mg, 33%) as a yellow film; MS (ESI) m / z [M+H] + 274.0.

[0661] Intermediate 75: rac-methyl (R)-6-(tetrahydrofuran-2-yl)quinoline-4-carboxylate

[0662] [ka]

[0663] A solution of methyl 6-bromoquinoline-4-carboxylate (106 mg, 0.4 mmol), TBADT (13 mg, 4.0 μmol), and NiBr₂·dtbbpy (10 mg, 0.02 mmol) in deoxygenated MeCN (4 mL) was added to a vial containing K₃PO₄ (93 mg, 0.44 mmol) under N₂(g). The resulting suspension was bubbled with N₂(g) for 10 min while cooled at 0 °C. THF (0.16 mL, 2.0 mmol) was then added, and the reaction vial was placed in a photoreactor and irradiated at 365 nm for 18 h. The reaction mixture was then filtered through a syringe filter, and the filter was washed several times with EtOAc. The combined filtrate was concentrated and the residue was purified by preparative HPLC, Prep Method E, (gradient: 15-55%) to give the title compound (26 mg, 25%) as a yellow film; MS (ESI) m / z [M+H] + 258.1.

[0664] Intermediate 76: rac-(R)-6-(tetrahydrofuran-2-yl)quinoline-4-carboxylic acid

[0665] [ka]

[0666] Aqueous LiOH (505 μL, 0.51 mmol, 1 M) was added to a solution of rac-methyl (R)-6-(tetrahydrofuran-2-yl)quinoline-4-carboxylate intermediate 75 (65 mg, 0.25 mmol) in THF (2 mL). The mixture was stirred at room temperature for 2 h and then concentrated. The residue was purified by preparative HPLC, Preparative Method C, (gradient: 0-30%) to give the title compound (43 mg, 70%) as a white solid; MS (ESI) m / z [M+H] + 244.0.

[0667] Intermediate 77: rac-(R)-6-(((tetrahydrofuran-3-yl)oxy)methyl)quinoline-4-carboxylic acid

[0668] [ka]

[0669] A solution of NaH (38 mg, 0.95 mmol; 60 wt% in oil) and tetrahydrofuran-3-ol (84 mg, 0.95 mmol) in DMF (5 mL) was stirred at 0° C. for 10 min. Then, methyl 6-(chloromethyl)-quinoline-4-carboxylate intermediate 9 (75 mg, 0.32 mmol) was added. The reaction was stirred at 0° C. for 1 h. Water (1 mL) was added and the reaction was stirred at 0° C. for 30 min. The solvent was removed under reduced pressure. The residue was diluted with water. The mixture was adjusted to pH 6 with 0.1 M HCl, diluted with EtOAc (20 mL), and washed with water (3×10 mL). The organic layer was dried over Na2SO4, filtered, and concentrated to give the title compound (70 mg, 80%); MS (ESI) m / z [M+H] + 274.

[0670] Intermediate 78: 6-((2,2-difluoroethoxy)methyl)quinoline-4-carboxylic acid

[0671] [ka]

[0672] 2,2-Difluoroethan-1-ol (89 mg, 1.1 mmol) and methyl 6-(chloromethyl)quinoline-4-carboxylate intermediate 9 (85 mg, 0.36 mmol) were treated in a similar manner as described for compound intermediate 77 to give the title compound (90 mg, 93%); MS (ESI) m / z [M+H] + 268.

[0673] Intermediate 79: 6-((4-methylisoxazol-3-yl)methyl)quinoline-4-carboxylic acid

[0674] [ka]

[0675] A microwave vial was charged with 6-bromoquinoline-4-carboxylic acid (83 mg, 0.33 mmol), 4,4,4',4',5,5,5',5'-octamethyl-2,2'-bi(1,3,2-dioxaborolane) (92 mg, 0.36 mmol), KOAc (97 mg, 0.99 mmol), Pd(dppf)Cl·DCM (40 mg, 0.05 mmol), and 1,4-dioxane (2 mL). The vial was capped, evacuated, and refilled with N(g) three times. The vial was then heated in a microwave reactor at 120 °C for 30 min. The vial was cooled to room temperature, and 3-(bromomethyl)-4-methylisoxazole (58 mg, 0.33 mmol), Pd(dtbpf)Cl (32 mg, 0.05 mmol), and aqueous KCO (659 μL, 1.32 mmol, 2 M) were added. The reaction mixture was stirred overnight at room temperature under N (g). The mixture was partitioned between water and EtOAc, and the pH of the aqueous phase was adjusted to slightly acidic with 2 M HCl (aq). The organic phase was collected, and the aqueous phase was extracted once more with EtOAc. The combined organic phases were evaporated, and the compound was purified by preparative HPLC, Prep Method C, (gradient: 5-40%) to give the title compound (17 mg, 19%); MS (ESI) m / z [M+H] + 269.

[0676] Intermediate 80: Ethyl 6-((4,6-dimethylpyridin-3-yl)methyl)quinoline-4-carboxylate

[0677] [ka]

[0678] A vial was charged with ethyl 6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)quinoline-4-carboxylate Intermediate 53 (200 mg, 0.61 mmol), 5-(bromomethyl)-2,4-dimethylpyridine (135 mg, 0.67 mmol), NaCO (259 mg, 2.45 mmol), and trans-bromo(N-succinimidyl)-bis(triphenylphosphine)palladium(II) (25 mg, 0.03 mmol). Toluene (5 mL) and water (1 mL) were added, and the mixture was bubbled with N (g) for 10 minutes. The vial was capped and heated at 100 °C for 2 hours. The reaction mixture was partitioned between DCM and water, and the layers were separated using a phase separator. The organic layer was concentrated and the residue was purified by normal phase flash chromatography on silica (gradient: 20-100% EtOAc in heptane) to give the title compound (50 mg, 26%); MS (ESI) m / z [M+H] + 321.4.

[0679] Intermediate 81: Ethyl 6-((1,3-dimethyl-1H-pyrazol-5-yl)methyl)quinoline-4-carboxylate

[0680] [ka]

[0681] The title compound was prepared in a similar manner as described for Intermediate 80 using ethyl 6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)quinoline-4-carboxylate Intermediate 53 (190 mg, 0.58 mmol) and 5-(bro...

Claims

1. Compounds having the structure of formula (I) 【Chemistry 1】 or a pharmaceutically acceptable salt thereof X １ -S-, -S(O)-, and -S(O) ２ Selected from the group consisting of: R １ is hydrogen, halogen, hydroxyl, C １～３ - Alkyl and C １～６ - Selected from the group consisting of alkoxys; R ２ teeth, (a) C １～６ -alkyl, optionally substituted with one or more substituents independently selected from the group consisting of halogen, hydroxy, cyano, C ３～６ -cycloalkyl, halo-C ３～６ -cycloalkyl, C １～６ -alkoxy, halo-C １～６ -alkoxy, C ３～６ -cycloalkoxy, halo-C ３～６ -cycloalkoxy, C １～６ -alkoxy-C １～６ -alkoxy, oxetanyl, tetrahydrofuranyl, tetrahydrofuranyloxy, tetrahydropyranyl, morpholinyl, pyrazolyl, isoxazolyl, triazolyl, and pyridinyl; said oxetanyl, tetrahydrofuranyl, tetrahydrofuranyloxy, tetrahydropyranyl, morpholinyl, pyrazolyl, isoxazolyl, triazolyl, and pyridinyl are optionally substituted with one or more substituents independently selected from the group consisting of halogen, cyano, C １～６ -alkyl, and halo-C １～６ -alkyl, C １～６ -alkyl; (b) C ３～６ - A cycloalkyl group, optionally containing halogen, hydroxy, cyano, C １～６ -Alkyl, Halo-C １～６ - Alkyl, C １～６ - Alkoxy, Halo-C １～６ - Substituted with one or more substituents independently selected from the group consisting of alkoxy, isoxazolyl, and pyridinyl; the isoxazolyl and pyridinyl are optionally halogens, C １～６ -Alkyl and halo-C １～６ - Substituted with one or more substituents independently selected from the group consisting of alkyl groups, C ３～６ - Cycloalkyl; (c) Phenyl, optionally halogen, cyano, C １～６ -Alkyl, Halo-C １～６ - Alkyl, C １～６ - Alkoxy, Halo-C １～６ - Alkoxy, and C １～６ -Alkoxy-C １～６ - Phenyl substituted with one or more substituents independently selected from the group consisting of alkoxys. (d) a four-membered, five-membered, six-membered, or seven-membered heterocyclyl, (i) a saturated, partially saturated, or fully unsaturated monocyclic or fused bicyclic ring, (ii) having one or two oxygen ring atoms and the remaining ring atoms being carbon, and (iii) optionally halogen, hydroxyl, cyano, C １～６ -Alkyl, Halo-C １～６ - Alkyl, C ２～６ - Alkinyl, C １～６ - Alkoxy and halo-C １～６ - Heterocyclines substituted with one or more substituents independently selected from the group consisting of alkoxys; and (e) - OR ７ And R ７ However, C １～６ - Selected from the group consisting of alkyl, phenyl, and tetrahydropyranyl, (i) Said C １～６ - Alkyl can be optionally halogen, cyano, or C ３～６ -Cycloalkyl, Halo-C ３～６ - Cycloalkyl, C １～６ - Alkoxy and halo-C １～６ - Substituted with one or more substituents independently selected from the group consisting of alkoxys; (ii) The phenyl may optionally be a halogen, C １～６ -Alkyl, Halo-C １～６ - Alkyl, C １～６ - Alkoxy and halo-C １～６ - Substituted with one or more substituents independently selected from the group consisting of alkoxys; (iii) The tetrahydropyranyl may optionally be a halogen, C １～６ -Alkyl, Halo-C １～６ - Alkyl, C １～６ - Alkoxy and halo-C １～６ - Substituted with one or more substituents independently selected from the group consisting of alkoxys, -OR ７ Selected from the group consisting of; R ３ These are hydrogen, halogens and C １～３ - Selected from the group consisting of alkyl groups; R ４ These are hydrogen, halogens and C １～３ - Selected from the group consisting of alkyl groups; R ５ These are hydrogen, halogens, and C １～３ - Selected from the group consisting of alkyl groups; R ６ These are hydrogen, halogens, and C １～３ - A compound or a pharmaceutically acceptable salt thereof, selected from the group consisting of alkyl groups.

2. The aforementioned 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 The compound according to claim 1 or a pharmaceutically acceptable salt thereof, as defined in claim 1.

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

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

5. R ２ C １～６ - Alkyl, and the C １～６ - Alkyl can be optionally halogen, hydroxyl, cyano, or C ３～６ -Cycloalkyl, Halo-C ３～６ - Cycloalkyl, C １～６ - Alkoxy, Halo-C １～６ - Alkoxy, C ３～６ -Cycloalkoxy, Halo-C ３～６ - Cycloalkoxy, C １～６ -Alkoxy-C １～６ - Substituted with one or more substituents independently selected from the group consisting of alkoxy, oxetanyl, tetrahydrofuranyl, tetrahydrofuranyloxy, tetrahydropyranyl, morpholinyl, pyrazolyl, isoxazolyl, triazolyl, and pyridinyl; the oxetanyl, tetrahydrofuranyl, tetrahydrofuranyloxy, tetrahydropyranyl, morpholinyl, pyrazolyl, isoxazolyl, triazolyl, and pyridinyl may optionally be halogens, C １～６ -Alkyl and halo-C １～６ - The compound according to claim 1 or a pharmaceutically acceptable salt thereof, substituted with one or more substituents independently selected from the group consisting of alkyl groups.

6. The aforementioned compound, N-(2-((R)-4-cyanothiazolidined-3-yl)-2-oxoethyl)-6-((RS)-1-(3-fluoropyridine-2-yl)-ethyl)quinoline-4-carboxamide; (R)-N-(2-(4-cyanothiazolidined-3-yl)-2-oxoethyl)-6-(2-hydroxypropane-2-yl)quinoline-4-carboxamide; (R)-N-(2-(4-cyanothiazolidined-3-yl)-2-oxoethyl)-6-(trifluoromethyl)-quinoline-4-carboxamide; (R)-N-(2-(4-cyanothiazolidined-3-yl)-2-oxoethyl)-6-(2-methoxypropane-2-yl)quinoline-4-carboxamide; (R)-N-(2-(4-cyanothiazolidined-3-yl)-2-oxoethyl)-6-((2,5-dimethyl-2H-1,2,3-triazole-4-yl)-methyl)quinoline-4-carboxamide; (R)-N-(2-(4-cyanothiazolidined-3-yl)-2-oxoethyl)-6-(morpholino-methyl)quinoline-4-carboxamide; N-(2-((R)-4-cyanothiazolidined-3-yl)-2-oxoethyl)-6-((RS)-1-hydroxyethyl)quinoline-4-carboxamide; N-(2-((R)-4-cyanothiazolidined-3-yl)-2-oxoethyl)-6-((RS)-1-methoxyethyl)quinoline-4-carboxamide; (R)-N-(2-(4-cyanothiazolidined-3-yl)-2-oxoethyl)-6-(ethoxymethyl)-quinoline-4-carboxamide; R-N-(2-(4-cyanothiazolidined-3-yl)-2-oxoethyl)-6-methylquinoline-4-carboxamide; (R)-N-(2-(4-cyanothiazolidined-3-yl)-2-oxoethyl)-6-(fluoromethyl)-quinoline-4-carboxamide; N-(2-((R)-4-cyanothiazolidined-3-yl)-2-oxoethyl)-6-((RS)-1,2-dimethoxyethyl)quinoline-4-carboxamide; (R)-N-(2-(4-cyanothiazolidined-3-yl)-2-oxoethyl)-6-((2-methoxyethoxy)-methyl)quinoline-4-carboxamide; N-(2-((R)-4-cyanothiazolidined-3-yl)-2-oxoethyl)-6-(((RS)-tetrahydrofuran-3-yl)oxy)-methyl)quinoline-4-carboxamide; (R)-N-(2-(4-cyanothiazolidined-3-yl)-2-oxoethyl)-6-((2,2-difluoroethoxy)methyl)quinoline-4-carboxamide; (R)-N-(2-(4-cyanothiazolidined-3-yl)-2-oxoethyl)-6-(cyclopropoxymethyl)quinoline-4-carboxamide; (R)-N-(2-(4-cyanothiazolidined-3-yl)-2-oxoethyl)-6-((4-methylisoxazole-3-yl)methyl)-quinoline-4-carboxamide; (R)-N-(2-(4-cyanothiazolidined-3-yl)-2-oxoethyl)-6-((4,6-dimethylpyridine-3-yl)-methyl)quinoline-4-carboxamide; (R)-N-(2-(4-cyanothiazolidined-3-yl)-2-oxoethyl)-6-((1,3-dimethyl-1H-pyrazole-5-yl)-methyl)quinoline-4-carboxamide; (R)-N-(2-(4-cyanothiazolidined-3-yl)-2-oxoethyl)-6-((2-methyl-2H-1,2,3-triazole-4-yl)-methyl)quinoline-4-carboxamide; (R)-N-(2-(4-cyanothiazolidined-3-yl)-2-oxoethyl)-6-((5-methylisoxazole-3-yl)-methyl)quinoline-4-carboxamide; N-(2-((R)-4-cyanothiazolidined-3-yl)-2-oxoethyl)-6-((RS)-1-(5-methylisoxazole-3-yl)-ethyl)quinoline-4-carboxamide; 6-((RS)-1-(5-chloropyridine-2-yl)ethyl)-N-(2-((R)-4-cyanothiazolidined-3-yl)-2-oxoethyl)quinoline-4-carboxamide; N-(2-((R)-4-cyanothiazolidined-3-yl)-2-oxoethyl)-6-((RS)-1-(3-methylisoxazole-5-yl)-ethyl)quinoline-4-carboxamide; N-(2-((R)-4-cyanothiazolidined-3-yl)-2-oxoethyl)-6-((RS)-1-(6-methylpyridine-3-yl)-ethyl)quinoline-4-carboxamide; N-(2-((R)-4-cyanothiazolidined-3-yl)-2-oxoethyl)-6-((RS)-1-(2-(trifluoromethyl)pyridine-4-yl)ethyl)quinoline-4-carboxamide; (R)-N-(2-(4-cyanothiazolidined-3-yl)-2-oxoethyl)-6-(2,2-difluoropropyl)quinoline-4-carboxamide; (R)-N-(2-(4-cyanothiazolidined-3-yl)-2-oxoethyl)-6-((tetrahydro-2H-pyran-4-yl)-methyl)quinoline-4-carboxamide; (R)-N-(2-(4-cyanothiazolidined-3-yl)-2-oxoethyl)-6-(3,3,3-trifluoropropyl)quinoline-4-carboxamide; N-(2-((R)-4-cyanothiazolidined-3-yl)-2-oxoethyl)-6-(((RS)-tetrahydrofuran-3-yl)-methyl)quinoline-4-carboxamide; (R)-N-(2-(4-cyanothiazolidined-3-yl)-2-oxoethyl)-6-(difluoromethyl)-quinoline-4-carboxamide; (R)-6-((1H-pyrazole-1-yl)methyl)-N-(2-(4-cyanothiazolidined-3-yl)-2-oxoethyl)quinoline-4-carboxamide; (R)-N-(2-(4-cyanothiazolidined-3-yl)-2-oxoethyl)-6-(3-methoxypropyl)quinoline-4-carboxamide; and A compound according to claim 1, selected from the group consisting of (R)-N-(2-(4-cyanothiazolidined-3-yl)-2-oxoethyl)-6-(2-methoxyethyl)quinoline-4-carboxamide, or a pharmaceutically acceptable salt thereof.

7. R ２ is a C ３～６ -cycloalkyl, and the C ３～６ -cycloalkyl is optionally substituted with one or more substituents independently selected from the group consisting of halogen, hydroxy, cyano, C １～６ -alkyl, halo-C １～６ -alkyl, C １～６ -alkoxy, halo-C １～６ -alkoxy, isoxazolyl, and pyridinyl, and the isoxazolyl and pyridinyl are optionally substituted with one or more substituents independently selected from the group consisting of halogen, C １～６ -alkyl and halo-C １～６ -alkyl, the compound according to claim 1 or a pharmaceutically acceptable salt thereof.

8. The aforementioned compound, (R)-N-(2-(4-cyanothiazolidined-3-yl)-2-oxoethyl)-6-(1-(2-(trifluoromethyl)pyridine-4-yl)-cyclopropyl)quinoline-4-carboxamide; (R)-N-(2-(4-cyanothiazolidined-3-yl)-2-oxoethyl)-6-(1-(6-methylpyridine-3-yl)-cyclopropyl)quinoline-4-carboxamide; (R)-N-(2-(4-cyanothiazolidined-3-yl)-2-oxoethyl)-6-(1-(3-fluoropyridine-2-yl)-cyclopropyl)quinoline-4-carboxamide; (R)-N-(2-(4-cyanothiazolidined-3-yl)-2-oxoethyl)-6-(1-(5-methylisoxazole-3-yl)-cyclopropyl)quinoline-4-carboxamide; (R)-6-(1-(5-chloropyridine-2-yl)cyclopropyl)-N-(2-(4-cyanothiazolidined-3-yl)-2-oxoethyl)quinoline-4-carboxamide; (R)-N-(2-(4-cyanothiazolidined-3-yl)-2-oxoethyl)-6-(1-(3-methylisoxazole-5-yl)-cyclopropyl)quinoline-4-carboxamide; 6-((1st round, 4th round) ＊ )-4-cyanocyclohexyl)-N-(2-((R-4-cyanothiazolidined-3-yl)-2-oxoethyl)-quinoline-4-carboxamide; 6-((1st round, 4th round) ＊ )-4-cyanocyclohexyl)-N-(2-((R-4-cyanothiazolidined-3-yl)-2-oxoethyl)-quinoline-4-carboxamide; (R)-6-(1-cyanocyclohexyl)-N-(2-(4-cyanothiazolidined-3-yl)-2-oxoethyl)quinoline-4-carboxamide; N-(2-((R)-4-cyanothiazolidined-3-yl)-2-oxoethyl)-6-((1r,3R ＊ )-1-fluoro-3-methoxy-cyclobutyl)quinoline-4-carboxamide isomer 1; N-(2-((R)-4-Cyanothiazolidin-3-yl)-2-oxoethyl)-6-((1r,3R ＊ )-1-Fluoro-3-methoxy-cyclobutyl)quinoline-4-carboxamide isomer 2; (R)-6-(1-cyanocyclopropyl)-N-(2-(4-cyanothiazolidined-3-yl)-2-oxoethyl)quinoline-4-carboxamide; (R)-N-(2-(4-cyanothiazolidined-3-yl)-2-oxoethyl)-6-(1-fluorocyclobutyl)quinoline-4-carboxamide; (R)-N-(2-(4-cyanothiazolidined-3-yl)-2-oxoethyl)-6-(1-ethoxycyclopropyl)quinoline-4-carboxamide; (R)-N-(2-(4-cyanothiazolidined-3-yl)-2-oxoethyl)-6-cyclopropylquinoline-4-carboxamide; N-(2-((R)-4-cyanothiazolidined-3-yl)-2-oxoethyl)-6-((1r,4R ＊ )-4-methoxycyclohexyl)-quinoline-4-carboxamide isomer 1; and N-(2-((R)-4-cyanothiazolidined-3-yl)-2-oxoethyl)-6-((1r,4R ＊ A compound according to claim 1, or a pharmaceutically acceptable salt thereof, selected from the group consisting of )-4-methoxycyclohexyl)-quinoline-4-carboxamide isomer 2.

9. R ２ is phenyl, and the phenyl may optionally be a halogen, cyano, or C １～６ -Alkyl, Halo-C １～６ - Alkyl, C １～６ - Alkoxy, Halo-C １～６ - Alkoxy and C １～６ -Alkoxy-C １～６ - The compound according to claim 1 or a pharmaceutically acceptable salt thereof, substituted with one or more substituents independently selected from the group consisting of alkoxys.

10. R ２ The heterocycline ring is a four-membered, five-membered, six-membered, or seven-membered heterocycline, wherein the heterocycline ring is (i) a saturated, partially saturated, or fully unsaturated monocyclic or fused bicyclic ring, (ii) has one or two oxygen ring atoms and the remaining ring atoms are carbon, and (iii) optionally contains halogen, hydroxyl, cyano, or C １～６ -Alkyl, Halo-C １～６ - Alkyl, C ２～６ - Alkinyl, C １～６ - Alkoxy and halo-C １～６ - The compound according to claim 1 or a pharmaceutically acceptable salt thereof, substituted with one or more substituents independently selected from the group consisting of alkoxys.

11. R ２ The compound according to claim 1 or a pharmaceutically acceptable salt thereof, selected from the group consisting of tetrahydrofuranil, furanil, dimethyltetrahydrofuranil, dihydropyranil, tetrahydropyranil, hydroxytetrahydropyranil, fluorotetrahydropyranil, cyanotetrahydropyranil, methyltetrahydropyranil, dimethyltetrahydropyranil, methoxytetrahydropyranil, ethoxytetrahydropyranil, 1,4-dioxanil, and 3-oxabicyclo[4.1.0]heptane.

12. The aforementioned compound, (R)-N-(2-(4-cyanothiazolidined-3-yl)-2-oxoethyl)-6-(furan-3-yl)quinoline-4-carboxamide; (R)-N-(2-(4-cyanothiazolidined-3-yl)-2-oxoethyl)-6-(4-hydroxytetrahydro-2H-pyran-4-yl)-quinoline-4-carboxamide; (R)-N-(2-(4-cyanothiazolidined-3-yl)-2-oxoethyl)-6-(tetrahydro-2H-pyran-4-yl)quinoline-4-carboxamide; (R)-N-(2-(4-cyanothiazolidined-3-yl)-2-oxoethyl)-6-(4-methyl-tetrahydro-2H-pyran-4-yl)-quinoline-4-carboxamide; (R)-N-(2-(4-cyanothiazolidined-3-yl)-2-oxoethyl)-6-(3,6-dihydro-2H-pyran-4-yl)quinoline-4-carboxamide; (R)-N-(2-(4-cyanothiazolidined-3-yl)-2-oxoethyl)-6-(4-ethoxytetrahydro-2H-pyran-4-yl)-quinoline-4-carboxamide; N-(2-((R)-4-cyanothiazolidined-3-yl)-2-oxoethyl)-6-((RS)-tetrahydro-2H-pyran-2-yl)-quinoline-4-carboxamide; N-(2-((R)-4-cyanothiazolidined-3-yl)-2-oxoethyl)-6-((RS)-1,4-dioxan-2-yl)quinoline-4-carboxamide; N-(2-((R)-4-cyanothiazolidined-3-yl)-2-oxoethyl)-6-((RS)-tetrahydrofuran-2-yl)quinoline-4-carboxamide; (R)-N-(2-(4-cyanothiazolidined-3-yl)-2-oxoethyl)-6-(4-ethynyl-tetrahydro-2H-pyran-4-yl)-quinoline-4-carboxamide; (R)-6-(4-cyanotetrahydro-2H-pyran-4-yl)-N-(2-(4-cyanothiazolidined-3-yl)-2-oxoethyl)-quinoline-4-carboxamide; N-(2-((R-4-cyanothiazolidined-3-yl)-2-oxoethyl)-6-(5,5-dimethyltetrahydrofuran-3-yl)-quinoline-4-carboxamide; (R)-N-(2-(4-cyanothiazolidined-3-yl)-2-oxoethyl)-6-(4-fluorotetrahydro-2H-pyran-4-yl)-quinoline-4-carboxamide; (R)-N-(2-(4-cyanothiazolidined-3-yl)-2-oxoethyl)-6-(4-methoxytetrahydro-2H-pyran-4-yl)quinoline-4-carboxamide; N-(2-((R-4-cyanothiazolidined-3-yl)-2-oxoethyl)-6-((RS)-tetrahydrofuran-3-yl)quinoline-4-carboxamide; N-(2-((R-4-cyanothiazolidined-3-yl)-2-oxoethyl)-6-((RS)-2,2-dimethyltetrahydro-2H-pyran-4-yl)quinoline-4-carboxamide; and A compound according to claim 1, or a pharmaceutically acceptable salt thereof, selected from the group consisting of 6-((1RS,6SR)-3-oxabicyclo[4.1.0]heptan-6-yl)-N-(2-((R)-4-cyanothiazolidined-3-yl)-2-oxoethyl)quinoline-4-carboxamide.

13. R ２ is, -OR ７ And R ７ C １～６ - Selected from the group consisting of alkyl, phenyl, and tetrahydropyranyl; (i) Said C １～６ - Alkyl can be optionally halogen, cyano, or C ３～６ -Cycloalkyl, Halo-C ３～６ - Cycloalkyl, C １～６ - Alkoxy and halo-C １～６ - Substituted with one or more substituents independently selected from the group consisting of alkoxys; (ii) The phenyl may optionally be a halogen, C １～６ -Alkyl, Halo-C １～６ - Alkyl, C １～６ - Alkoxy and halo-C １～６ - Substituted with one or more substituents independently selected from the group consisting of alkoxys; (iii) The tetrahydropyranyl may optionally be a halogen, C １～６ -Alkyl, Halo-C １～６ - Alkyl, C １～６ - Alkoxy and halo-C １～６ - The compound according to claim 1 or a pharmaceutically acceptable salt thereof, substituted with one or more substituents independently selected from the group consisting of alkoxys.

14. R ２ is, -OR ７ And R ７ The compound described in claim 1 or a pharmaceutically acceptable salt thereof, selected from the group consisting of cyanomethyl, fluoroethyl, difluoroethyl, propyl, difluoropropyl, fluorobutyl, methoxyethyl, cyclopropylmethyl, difluorocyclobutylmethyl, phenyl, tetrahydropyranyl, and dimethyltetrahydropyranyl.

15. The aforementioned compound, (R)-N-(2-(4-cyanothiazolidined-3-yl)-2-oxoethyl)-6-phenoxyquinoline-4-carboxamide; (R)-N-(2-(4-cyanothiazolidined-3-yl)-2-oxoethyl)-6-(2,2-difluoroethoxy)quinoline-4-carboxamide; (R)-N-(2-(4-cyanothiazolidined-3-yl)-2-oxoethyl)-6-(2-fluoro-2-methylpropoxy)quinoline-4-carboxamide; (R)-N-(2-(4-cyanothiazolidined-3-yl)-2-oxoethyl)-6-(2-methoxyethoxy)quinoline-4-carboxamide; (R)-N-(2-(4-cyanothiazolidined-3-yl)-2-oxoethyl)-6-(cyclopropyl-methoxy)quinoline-4-carboxamide; (R)-N-(2-(4-cyanothiazolidined-3-yl)-2-oxoethyl)-6-(tetrahydro-2H-pyran-4-yl)oxy)-quinoline-4-carboxamide; (R)-N-(2-(4-cyanothiazolidined-3-yl)-2-oxoethyl)-6-((1,3-difluoropropane-2-yl)oxy)-quinoline-4-carboxamide; (R)-N-(2-(4-cyanothiazolidined-3-yl)-2-oxoethyl)-6-((3,3-difluorocyclobutyl)-methoxy)quinoline-4-carboxamide; N-(2-((R-4-cyanothiazolidined-3-yl)-2-oxoethyl)-6-(((RS)-2,2-dimethyltetrahydro-2H-pyran-4-yl)oxy)quinoline-4-carboxamide; (R)-6-(cyanomethoxy)-N-(2-(4-cyanothiazolidined-3-yl)-2-oxoethyl)quinoline-4-carboxamide; (R)-N-(2-(4-cyanothiazolidined-3-yl)-2-oxoethyl)-6-(2,2-difluoropropoxy)quinoline-4-carboxamide; (R)-N-(2-(4-cyanothiazolidined-3-yl)-2-oxoethyl)-6-propoxyquinoline-4-carboxamide; and A compound according to claim 1, selected from the group consisting of R-N-(2-(4-cyanothiazolidined-3-yl)-2-oxoethyl)-6-(2-fluoroethoxy)-quinoline-4-carboxamide, or a pharmaceutically acceptable salt thereof.

16. R ２ teeth, (a) C １～３ - Alkyl, optionally halogen, hydroxy, cyano, C ３～６ -Cycloalkyl, Halo-C ３～６ - Cycloalkyl, C １～３ - Alkoxy, Halo-C １～３ - Alkoxy, C ３～６ -Cycloalkoxy, Halo-C ３～６ - Cycloalkoxy, C １～３ -Alkoxy-C １～３ - Substituted with one or more substituents independently selected from the group consisting of alkoxy, oxetanyl, tetrahydrofuranyl, tetrahydrofuranyloxy, tetrahydropyranyl, morpholinyl, pyrazolyl, isoxazolyl, triazolyl, and pyridinyl; the oxetanyl, tetrahydrofuranyl, tetrahydrofuranyloxy, tetrahydropyranyl, morpholinyl, pyrazolyl, isoxazolyl, triazolyl, and pyridinyl may optionally be halogens, C １～３ -Alkyl and halo-C １～３ - Substituted with one or more substituents independently selected from the group consisting of alkyl groups, C １～３ - Alkyl; (b) C ３～６ - A cycloalkyl group, optionally containing halogen, cyano, C １～３ -Alkyl, Halo-C １～３ - Alkyl, C １～３ - Alkoxy, Halo-C １～３ - Substituted with one or more substituents independently selected from the group consisting of alkoxy, isoxazolyl, and pyridinyl; the isoxazolyl and pyridinyl are optionally halogens, C １～３ -Alkyl and halo-C １～３ - Substituted with one or more substituents independently selected from the group consisting of alkyl groups, C ３～６ - Cycloalkyl; (c) Phenyl, optionally a halogen, C １～３ -Alkyl, Halo-C １～３ - Alkyl, C １～３ - Alkoxy, Halo-C １～３ - Alkoxy, and C １～３ -Alkoxy-C １～３ - Phenyl substituted with one or more substituents independently selected from the group consisting of alkoxys; (d) A four-membered, five-membered, six-membered, or seven-membered heterocyclyl, (i) a saturated or partially saturated monocyclic or fused bicyclic ring, (ii) having one or two oxygen ring atoms and the remaining ring atoms being carbon, and (iii) optionally a halogen, hydroxyl, cyano, or C １～３ -Alkyl, Halo-C １～３ - Alkyl, C ２～３ - Alkinyl, C １～３ - Alkoxy and halo-C １～３ - Heterocyclines substituted with one or more substituents independently selected from the group consisting of alkoxys; and (e) - OR ７ And R ７ However, C １～４ - Selected from the group consisting of alkyl, phenyl, and tetrahydropyranyl, (i) Said C １～４ - Alkyl can be optionally halogen, cyano, or C ３～６ -Cycloalkyl, Halo-C ３～６ - Cycloalkyl, C １～３ - Alkoxy and halo-C １～３ - Substituted with one or more substituents independently selected from the group consisting of alkoxys; (ii) The phenyl may optionally be a halogen, C １～３ -Alkyl, Halo-C １～３ - Alkyl, C １～３ - Alkoxy and halo-C １～３ - Substituted with one or more substituents independently selected from the group consisting of alkoxys; (iii) The tetrahydropyranyl may optionally be a halogen, C １～３ -Alkyl, Halo-C １～３ - Alkyl, C １～３ - Alkoxy and halo-C １～３ - Substituted with one or more substituents independently selected from the group consisting of alkoxys, -OR ７ A compound according to claim 1 or a pharmaceutically acceptable salt thereof, selected from the group consisting of ,

17. R ２ teeth, (a) C ３～６ - A cycloalkyl group, optionally containing halogen, cyano, C １～３ -Alkyl, Halo-C １～３ - Alkyl, C １～３ - Alkoxy, Halo-C １～３ - Substituted with one or more substituents independently selected from the group consisting of alkoxy, isoxazolyl, and pyridinyl; the isoxazolyl and pyridinyl are optionally halogens, C １～３ -Alkyl and halo-C １～３ - Substituted with one or more substituents independently selected from the group consisting of alkyl groups, C ３～６ - Cycloalkyl; (b) A four-membered, five-membered, six-membered, or seven-membered heterocyclyl, (i) a saturated or partially saturated monocyclic or fused bicyclic ring, (ii) having one or two oxygen ring atoms and the remaining ring atoms being carbon, and (iii) optionally a halogen, hydroxyl, cyano, C １～３ -Alkyl, Halo-C １～３ - Alkyl, C ２～３ - Alkinyl, C １～３ - Alkoxy and halo-C １～３ - Heterocyclines substituted with one or more substituents independently selected from the group consisting of alkoxys; and (c)-OR ７ And R ７ However, C １～４ - Selected from the group consisting of alkyl, phenyl, and tetrahydropyranyl, (i) Said C １～４ - Alkyl can be optionally halogen, cyano, or C ３～６ -Cycloalkyl, Halo-C ３～６ - Cycloalkyl, C １～３ - Alkoxy and halo-C １～３ - Substituted with one or more substituents independently selected from the group consisting of alkoxys; (ii) The phenyl may optionally be a halogen, C １～３ -Alkyl, Halo-C １～３ - Alkyl, C １～３ - Alkoxy and halo-C １～３ - Substituted with one or more substituents independently selected from the group consisting of alkoxys; (iii) The tetrahydropyranyl may optionally be a halogen, C １～３ -Alkyl, Halo-C １～３ - Alkyl, C １～３ - Alkoxy and halo-C １～３ - Substituted with one or more substituents independently selected from the group consisting of alkoxys, -OR ７ A compound according to claim 1 or a pharmaceutically acceptable salt thereof, selected from the group consisting of ,

18. R ２ teeth, (a) C ３～６ - A cycloalkyl group, optionally containing halogen, cyano, C １～６ - Substituted with one or more substituents independently selected from the group consisting of alkoxy, isoxazolyl, and pyridinyl; the isoxazolyl and pyridinyl are optionally halogens, C １～６ -Alkyl and halo-C １～６ - Substituted with one or more substituents independently selected from the group consisting of alkyl groups, C ３～６ - Cycloalkyl; (b) a five-membered, six-membered, or seven-membered heterocyclyl, (i) a saturated or partially saturated monocyclic or fused bicyclic ring, (ii) having one or two oxygen ring atoms and the remaining ring atoms being carbon, and (iii) optionally a halogen, hydroxyl, cyano, C １～３ - Alkyl, C ２～３ - Alkinyl, and C １～３ - Heterocyclines substituted with one or more substituents independently selected from the group consisting of alkoxys; and (c)-OR ７ And R ７ However, C １～６ - Selected from the group consisting of alkyl, phenyl, and tetrahydropyranyl, (i) Said C １～６ - Alkyl can be optionally halogen, cyano, or C ３～６ -Cycloalkyl, Halo-C ３～６ -Cycloalkyl and C １～６ - Substituted with one or more substituents independently selected from the group consisting of alkoxys; (ii) The tetrahydropyranyl can be any one or C １～６ - Substituted with alkyl, - OR ７ A compound according to claim 1 or a pharmaceutically acceptable salt thereof, selected from the group consisting of ,

19. R ２ teeth, (a) C ３～６ - A cycloalkyl group, optionally containing halogen, cyano, C １～３ - Substituted with one or more substituents independently selected from the group consisting of alkoxy, isoxazolyl, and pyridinyl; the isoxazolyl and pyridinyl are optionally halogens, C １～３ -Alkyl and halo-C １～３ - Substituted with one or more substituents independently selected from the group consisting of alkyl groups, C ３～６ - Cycloalkyl; (b) A five-membered, six-membered, or seven-membered heterocyclyl selected from the group consisting of tetrahydrofuranil, dihydropyranil, tetrahydropyranil, 1,4-dioxanil, and 3-oxabicyclo[4.1.0]heptane, wherein the tetrahydrofuranil, dihydropyranil, tetrahydropyranil, 1,4-dioxanil, and 3-oxabicyclo[4.1.0]heptane may optionally be halogen, hydroxyl, cyano, or C １～６ -Alkyl, Halo-C １～６ - Alkyl, C ２～６ - Alkinyl, C １～６ - Alkoxy and halo-C １～６ - Heterocyclines substituted with one or more substituents independently selected from the group consisting of alkoxys; and (c)-OR ７ And R ７ However, C １～４ - Selected from the group consisting of alkyl, phenyl, and tetrahydropyranyl, (i) Said C １～４ - Alkyl can be optionally halogen, cyano, or C ３～６ -Cycloalkyl, Halo-C ３～６ -Cycloalkyl and C １～３ - Substituted with one or more substituents independently selected from the group consisting of alkoxys; (ii) The tetrahydropyranyl can be any one or C １～３ - Substituted with alkyl, - OR ７ A compound according to claim 1 or a pharmaceutically acceptable salt thereof, selected from the group consisting of ,

20. R ２ teeth, (a) A optionally substituted C selected from the group consisting of cyclopropyl, cyanocyclopropyl, ethoxycyclopropyl, methylisoxazolylcyclopropyl, methylpyridinylcyclopropyl, chloropyridinylcyclopropyl, fluoropyridinylcyclopropyl, trifluoropyridinylcyclopropyl, fluorocyclobutyl, (fluoro)(methoxy)cyclobutyl, methoxycyclohexyl, and cyanocyclohexyl. ３～６ - Cycloalkyl; (b) optionally substituted five-membered, six-membered, or seven-membered heterocyclyls selected from the group consisting of tetrahydrofuranyl, dimethyltetrahydrofuranyl, dihydropyranyl, tetrahydropyranyl, hydroxytetrahydropyranyl, fluorotetrahydropyranyl, cyanotetrahydropyranyl, methyltetrahydropyranyl, dimethyltetrahydropyranyl, methoxytetrahydropyranyl, ethoxytetrahydropyranyl, 1,4-dioxanyl, and 3-oxabicyclo[4.1.0]heptane; and (c)-OR ７ And R ７ -OR selected from the group consisting of cyanomethyl, fluoroethyl, difluoroethyl, propyl, difluoropropyl, fluorobutyl, methoxyethyl, cyclopropylmethyl, difluorocyclobutylmethyl, phenyl, tetrahydropyranyl, and dimethyltetrahydropyranyl ７ A compound according to claim 1 or a pharmaceutically acceptable salt thereof, selected from the group consisting of ,

21. A pharmaceutical composition comprising a compound according to any one of claims 1 to 20 or a pharmaceutically acceptable salt thereof, and one or more pharmaceutically acceptable excipients.

22. A pharmaceutical agent for treating or preventing a FAP-mediated condition, comprising a compound according to any one of claims 1 to 20 or a pharmaceutically acceptable salt thereof.

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