N-(2-(3-cyano-2-azabicyclo[3.1.0]hexan-2-yl)-2-oxoethyl)-quinoline-4-carboxamide

Abstract

Compounds having the structure of formula (I) and pharmaceutically acceptable salts thereof, wherein R 2 , R 3 , R 5 , R 6 , R 7 and R 8 are as defined herein; pharmaceutical compositions comprising such compounds and salts; uses 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] JPEG2025525345000191.jpg38128

Description

[Technical Field]

[0001] (CROSS-REFERENCE TO RELATED APPLICATIONS) This application claims the benefit of priority to U.S. Provisional Patent Application No. 63 / 366,700, 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-(3-cyano-2-azabicyclo-[3.1.0]hexan-2-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 activation protein (FAP)-mediated conditions; kits comprising such compounds and salts; and methods for preparing 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 (Hepatology 1999, 29, 1768) (Gastroenterology 2020, 158, 1611). 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. 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 generates 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 pharmacological 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] and pharmaceutically acceptable salts thereof, wherein: R 2is selected from the group consisting of hydrogen, halogen, and methyl; R 3 is hydrogen or halogen; R 5 is selected from the group consisting of hydrogen, hydroxy, halogen, methyl, and methoxy; R 6 and R 7 is hydrogen and R 6 and R 7 The other is, (a) halogen; (b) Halogen, hydroxy, C 1~6 -Alkoxy, Halo-C 1~6 -alkoxy, C 3~6 -cycloalkyl, and C 3~6 -cycloalkoxy, C optionally substituted with one or more substituents independently selected from the group consisting of 1~6 - alkyl; (c) Cyano, Fluoro, C 1~6 -Alkyl, Halo-C 1~6 -alkyl, and C 1~6 -cyclopropyl, optionally substituted with one or more substituents independently selected from the group consisting of alkoxy; (d) C optionally substituted with one or more substituents independently selected from the group consisting of halogen and cyclopropyl. 1~6 -alkoxy; and (e) Halogens and C 1~3 -C optionally substituted with one or more substituents independently selected from the group consisting of alkyl, 3~6 -cycloalkoxy, R 8 is selected from the group consisting of hydrogen, halogen, and methyl, or a pharmaceutically acceptable salt thereof.

[0008] In another aspect, the disclosure provides compounds having the structure of Formula (II-A), (II-B), (II-C), (III-A), (III-B), or (III-C), 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-A), (II-B), (II-C), (III-A), (III-B), or (III-C), as further defined, 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-A), (II-B), (II-C), (III-A), (III-B), or (III-C), as further defined, or a pharmaceutically acceptable salt thereof, a second pharmacological 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-A), (II-B), (II-C), (III-A), (III-B), or (III-C), as further defined, 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-A), (II-B), (II-C), (III-A), (III-B), or (III-C), 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-A), (II-B), (II-C), (III-A), (III-B), or (III-C), 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-A), (II-B), (II-C), (III-A), (III-B), or (III-C), 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-A), (II-B), (II-C), (III-A), (III-B), or (III-C), 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. References to "a" or "an" mean "one or more." Throughout, plural and singular forms should be treated as interchangeable except for references to number.

[0018] 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.

[0019] 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).

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

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

[0022] The term "alkyl" (alone or in combination with another term) means a straight- 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 (n-pentyl, iso-amyl, and 2,2-dimethylpropyl), and hexyl.

[0023] 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.

[0024] 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

[0025] [ka] It 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 is

[0026] [ka] can be expressed as; 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

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

[0028] In some instances, the number of carbon atoms in a substituent (e.g., alkyl, cycloalkyl, etc.) is indicated by the prefix "C x~y -" where x is the minimum number of carbon atoms in the substituent and y is the maximum number. 1~6 "-alkyl" refers to an alkyl substituent containing 1 to 6 carbon atoms. 3~6 -Cycloalkyl refers to a cycloalkyl substituent containing from 3 to 6 carbon ring atoms.

[0029] 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 has been 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, heptafluoropropyl, chloromethyl, dichloromethyl, trichloromethyl, difluorochloromethyl, dichlorofluoromethyl, and dichloropropyl. Similarly, "haloalkoxy" refers to an alkoxy substituent in which at least one hydrogen radical has been 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.

[0030] 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.

[0031] When a substituent is described as being "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).

[0032] When a substituent is described as "optionally substituted," the substituent may be either (1) unsubstituted or (2) substituted. When a carbon of a substituent is described as being optionally substituted with one or more of a list of substituents, one or more of the hydrogens on the carbon (to the extent present) may be replaced separately and / or together with independently selected optional substituents. When a nitrogen of a substituent is described as being optionally substituted with one or more of a list of substituents, one or more of the hydrogens on the nitrogen (to the extent present) may each be replaced with an independently selected optional substituent.

[0033] 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.

[0034] 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.

[0035] A "therapeutically effective amount" of a pharmacological agent is an amount sufficient to produce beneficial or desired results, including clinical results, and thus will depend on the context in which it is administered. For example, when a pharmacological agent is administered to treat liver disease, a therapeutically effective amount of the 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.

[0036] 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.

[0037] 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), delaying, or slowing the spread or progression of liver disease; prolonging survival compared to expected survival in the absence of treatment; and / or otherwise ameliorating or alleviating the severity of cancer or liver disease, in whole or in part.

[0038] II. Compounds A. Compounds of Formula (I) In one embodiment, the present disclosure provides a compound having the structure of formula (I):

[0039] [ka] and pharmaceutically acceptable salts thereof, wherein: R 2 is selected from the group consisting of hydrogen, halogen, and methyl; R 3 is hydrogen or halogen; R 5 is selected from the group consisting of hydrogen, hydroxy, halogen, methyl, and methoxy; R 6 and R 7 is hydrogen and R 6 and R 7 The other is, (a) halogen; (b) Halogen, hydroxy, C 1~6-Alkoxy, Halo-C 1~6 -alkoxy, C 3~6 -cycloalkyl, and C 3~6 -cycloalkoxy, C optionally substituted with one or more substituents independently selected from the group consisting of 1~6 - alkyl; (c) Cyano, Fluoro, C 1~6 -Alkyl, Halo-C 1~6 -alkyl, and C 1~6 -cyclopropyl, optionally substituted with one or more substituents independently selected from the group consisting of alkoxy; (d) C optionally substituted with one or more substituents independently selected from the group consisting of halogen and cyclopropyl. 1~6 -alkoxy; and (e) Halogens and C 1~3 -C optionally substituted with one or more substituents independently selected from the group consisting of alkyl, 3~6 -cycloalkoxy, R 8 is selected from the group consisting of hydrogen, halogen, and methyl, or a pharmaceutically acceptable salt thereof.

[0040] In some embodiments, R 2 is selected from the group consisting of hydrogen, chloro, fluoro, and methyl. 2 is selected from the group consisting of hydrogen, chloro, and methyl. 2 is selected from the group consisting of hydrogen, fluoro, and methyl. 2 is hydrogen or halogen. 2 is hydrogen or chloro. 2 is hydrogen or fluoro. 2 is hydrogen or methyl. In another embodiment, R 2 is hydrogen. In another embodiment, R 2 is halogen. In another embodiment, R 2 is chloro. In another embodiment, R 2 is fluoro. In another embodiment, R2 is methyl.

[0041] In some embodiments, R 3 is selected from the group consisting of hydrogen, chloro, and fluoro. 3 is hydrogen or chloro. 3 is hydrogen or fluoro. 3 is hydrogen. In another embodiment, R 3 is halogen. In another embodiment, R 3 is chloro. In another embodiment, R 3 is fluoro.

[0042] In some embodiments, R 5 is selected from the group consisting of hydrogen, hydroxy, chloro, fluoro, methyl, and methoxy. 5 is selected from the group consisting of hydrogen, chloro, and methyl. 5 is selected from the group consisting of hydrogen, fluoro, and methyl. 5 is hydrogen or halogen. 5 is hydrogen or chloro. 5 is hydrogen or fluoro. 5 is hydrogen or methyl. In another embodiment, R 5 is hydrogen. In another embodiment, R 5 is hydroxy. In another embodiment, R 5 is halogen. In another embodiment, R 5 is chloro. In another embodiment, R 5 is fluoro. In another embodiment, R 5 is methyl. In another embodiment, R 5 is methoxy.

[0043] In some embodiments, R 8 is selected from the group consisting of hydrogen, chloro, fluoro, and methyl. 8is hydrogen or chloro. 8 is hydrogen or fluoro. 8 is hydrogen or methyl. In another embodiment, R 8 is hydrogen. In another embodiment, R 8 is halogen. In another embodiment, R 8 is chloro. In another embodiment, R 8 is fluoro. In another embodiment, R 8 is methyl.

[0044] In some embodiments, R 2 is selected from the group consisting of hydrogen, chloro, fluoro, and methyl. 3 is selected from the group consisting of hydrogen, chloro, and fluoro; R 5 is selected from the group consisting of hydrogen, hydroxy, chloro, fluoro, methyl, and methoxy; R 8 is selected from the group consisting of hydrogen, chloro, fluoro, and methyl.

[0045] In some embodiments, R 2 is selected from the group consisting of hydrogen, chloro, fluoro, and methyl. 3 is selected from the group consisting of hydrogen, chloro, and fluoro; R 5 is selected from the group consisting of hydrogen, chloro, and fluoro; R 8 is selected from the group consisting of hydrogen, chloro, and fluoro.

[0046] In some embodiments, R 2 is selected from the group consisting of hydrogen, fluoro, and methyl; R 3 is hydrogen or fluoro; R 5 is hydrogen or fluoro; R 8 is hydrogen or fluoro.

[0047] In some embodiments, R 2 is hydrogen or methyl; R 3 is selected from the group consisting of hydrogen, chloro, and fluoro; R5 is selected from the group consisting of hydrogen, chloro, and fluoro; R 8 is selected from the group consisting of hydrogen, chloro, and fluoro.

[0048] In some embodiments, R 2 , R 3 , R 5 , and R 8 is independently selected from hydrogen and fluoro.

[0049] In some embodiments, R 2 , R 3 , R 5 and R 8 Two of the substituents are other than hydrogen and the remaining R 2 , R 3 , R 5 and R 8 The substituents are all hydrogen.

[0050] In some embodiments, R 2 , R 3 , R 5 and R 8 One of the substituents is other than hydrogen and the remaining R 2 , R 3 , R 5 and R 8 The substituents are all hydrogen.

[0051] In some embodiments, R 2 , R 3 , R 5 and R 8 The substituents are all hydrogen.

[0052] In some embodiments, R 6 and R 7 is other than hydrogen, and R 6 and R 7 The other of R is hydrogen. 6 is other than hydrogen, and R 7 is hydrogen. In another embodiment, R 6 is hydrogen and R 7 is other than hydrogen.

[0053] In some embodiments, R 6 and R 7 One of R is hydrogen and the other is halogen. 6 and R 7 In another embodiment, one of R is hydrogen and the other is chloro. 6 and R 7 In another embodiment, one of R is hydrogen and the other is fluoro. 6 and R 7 In another embodiment, one of R is hydrogen and the other is bromo. 6 and R 7 One of them is hydrogen and the other is iodine.

[0054] In some embodiments, R 6 and R 7 One of them is hydrogen and the other 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 -cycloalkyl, and C 3~6 In one aspect, R is substituted with one or more substituents independently selected from the group consisting of: -cycloalkoxy; 6 and R 7 One of them is hydrogen and the other 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 -cycloalkyl, and C 3~6 In another embodiment, R is substituted with one or more substituents independently selected from the group consisting of: -cycloalkoxy; 6 and R 7 One of them is hydrogen and the other is C 1~3 -alkyl, C 1~3 -alkyl is optionally substituted with one or more substituents independently selected from the group consisting of halogen, hydroxy, methoxy, and halomethoxy.6 and R 7 One of them is hydrogen and the other is C 1~3 -alkyl, C 1~3 -alkyl is optionally substituted with one or more substituents independently selected from the group consisting of fluoro, hydroxy, methoxy, and fluoromethoxy. 6 and R 7 One of them is hydrogen and the other is C 1~3 -alkyl, C 1~3 -alkyl is optionally substituted with one or more substituents independently selected from the group consisting of fluoro and methoxy. 6 and R 7 One of them is hydrogen and the other is C 1~6 -alkyl, C 1~6 -alkyl optionally containing halogen and C 1~6 In another embodiment, R is substituted with one or more substituents independently selected from the group consisting of: -alkoxy. 6 and R 7 One of them is hydrogen and the other is C 1~3 -alkyl, C 1~3 -alkyl optionally containing halogen and C 1~3 -substituted with one or more substituents independently selected from the group consisting of: -alkoxy;

[0055] In some embodiments, R 6 and R 7 One of them is hydrogen and the other is C 1~6 -alkyl. In one aspect, R 6 and R 7 One of them is hydrogen and the other is C 1~3 In another embodiment, R 6 and R 7 One of the groups is hydrogen and the other is methyl.

[0056] In some embodiments, R 6 and R 7 One of them is hydrogen and the other is C 1~6 -alkyl, C 1~6-alkyl is optionally substituted with one or more halogens. 6 and R 7 One of them is hydrogen and the other is C 1~3 -alkyl, C 1~3 The -alkyl is optionally substituted with one or more fluoro.

[0057] In some embodiments, R 6 and R 7 One of them is hydrogen and the other is C 1~6 -alkyl, C 1~6 -alkyl is optionally substituted with one or more hydroxy. 6 and R 7 One of them is hydrogen and the other is C 1~3 -alkyl, C 1~3 The -alkyl is optionally substituted with one or more hydroxy.

[0058] In some embodiments, R 6 and R 7 One of them is hydrogen and the other is C 1~6 -alkyl, C 1~6 -Alkyl optionally has one or more C 1~6 In one aspect, R 6 and R 7 One of them is hydrogen and the other is C 1~3 -alkyl, C 1~3 -Alkyl optionally has one or more C 1~3 -substituted with alkoxy.

[0059] In some embodiments, R 6 and R 7 One of them is hydrogen and the other is C 1~6 -alkyl, C 1~6 -alkyl optionally contains one or more halo-C 1~6 In one aspect, R 6 and R 7 One of them is hydrogen and the other is C 1~3 -alkyl, C 1~3 -alkyl optionally contains one or more halo-C1~3 In another embodiment, R 6 and R 7 is hydrogen and the other is C 1~3 -alkyl, 1~3 -alkyl optionally has one or more fluoro-C 1~3 -substituted with alkoxy.

[0060] In some embodiments, R 6 and R 7 One of them is hydrogen and the other is C 1~6 -alkyl, C 1~6 -Alkyl optionally has one or more C 3~6 -cycloalkyl. In one aspect, R 6 and R 7 One of them is hydrogen and the other is C 1~3 -alkyl, C 1~3 -Alkyl optionally has one or more C 3~6 -substituted with cycloalkyl.

[0061] In some embodiments, R 6 and R 7 One of them is hydrogen and the other is C 1~6 -alkyl, C 1~6 -Alkyl optionally has one or more C 3~6 In one aspect, R 6 and R 7 One of them is hydrogen and the other is C 1~3 -alkyl, C 1~3 -Alkyl optionally has one or more C 3~6 -substituted with cycloalkoxy.

[0062] In some embodiments, R 6 and R 7 is hydrogen and the other is selected from the group consisting of methyl, ethyl, fluoromethyl, difluoromethyl, trifluoromethyl, fluoropropyl, hydroxyethyl, hydroxypropyl, methoxyethyl, methoxypropyl, trifluoromethoxymethyl, and trifluoromethoxyethyl.6 and R 7 is hydrogen and the other is selected from the group consisting of methyl, ethyl, fluoromethyl, difluoromethyl, trifluoromethyl, fluoropropyl, methoxyethyl, and methoxypropyl.

[0063] In some embodiments, R 6 and R 7 is hydrogen and the other is cyclopropyl, and cyclopropyl is optionally cyano, fluoro, C 1~6 -Alkyl, Halo-C 1~6 -alkyl, and C 1~6 In one aspect, R is substituted with one or more substituents independently selected from the group consisting of: -alkoxy. 6 and R 7 is hydrogen and the other is cyclopropyl, and cyclopropyl is optionally cyano, fluoro, C 1~3 -Alkyl, Halo-C 1~3 -alkyl, and C 1~3 In another embodiment, R is substituted with one or more substituents independently selected from the group consisting of: -alkoxy. 6 and R 7 one of which is hydrogen and the other is cyclopropyl, and cyclopropyl is optionally cyano, C 1~3 -Alkyl, Fluoro-C 1~3 -alkyl, and C 1~3 -substituted with one or more substituents independently selected from the group consisting of: -alkoxy;

[0064] In some embodiments, R 6 and R 7 One of the groups is hydrogen and the other is cyclopropyl.

[0065] In some embodiments, R 6 and R 7 One of the groups is hydrogen and the other is cyclopropyl, which is optionally substituted with one or more cyanos.

[0066] In some embodiments, R 6and R 7 One of is hydrogen and the other is cyclopropyl, which is optionally substituted with one or more fluoro.

[0067] In some embodiments, R 6 and R 7 one of which is hydrogen and the other is cyclopropyl, and the cyclopropyl optionally has one or more C 1~6 In one aspect, R 6 and R 7 one of which is hydrogen and the other is cyclopropyl, and the cyclopropyl optionally has one or more C 1~3 -substituted with alkyl.

[0068] In some embodiments, R 6 and R 7 one of which is hydrogen and the other is cyclopropyl, and the cyclopropyl optionally has one or more halo-C 1~6 In one aspect, R 6 and R 7 one of which is hydrogen and the other is cyclopropyl, and the cyclopropyl optionally has one or more halo-C 1~3 In another embodiment, R 6 and R 7 is hydrogen and the other is cyclopropyl, and the cyclopropyl optionally has one or more fluoro-C 1~3 -substituted with alkyl.

[0069] In some embodiments, R 6 and R 7 one of which is hydrogen and the other is cyclopropyl, and the cyclopropyl optionally has one or more C 1~6 In another embodiment, R 6 and R 7 one of which is hydrogen and the other is cyclopropyl, and the cyclopropyl optionally has one or more C 1~3 -substituted with alkoxy.

[0070] In some embodiments, R6 and R 7 one of which is hydrogen and the other is cyclopropyl, which is optionally substituted with one or more substituents independently selected from the group consisting of cyano, methyl, trifluoromethyl, and ethoxy.

[0071] In some embodiments, R 6 and R 7 One of them is hydrogen and the other is C 1~6 -alkoxy, C 1~6 -alkoxy is optionally substituted with one or more substituents independently selected from the group consisting of halogen and cyclopropyl. 6 and R 7 One of them is hydrogen and the other is C 1~3 -alkoxy 1~3 The -alkoxy is optionally substituted with one or more substituents independently selected from the group consisting of halogen and cyclopropyl.

[0072] In some embodiments, R 6 and R 7 One of them is hydrogen and the other is C 1~6 In one aspect, R 6 and R 7 One of them is hydrogen and the other is C 1~3 -alkoxy.

[0073] In some embodiments, R 6 and R 7 One of them is hydrogen and the other is C 1~6 -alkoxy, C 1~6 -alkoxy is optionally substituted with one or more halogens. 6 and R 7 One of them is hydrogen and the other is C 1~3 -alkoxy, C 1~3 -alkoxy is optionally substituted with one or more halogens. 6 and R 7 One of them is hydrogen and the other is C 1~3 -alkoxy, C 1~3The -alkoxy is optionally substituted with one or more fluoro.

[0074] In some embodiments, R 6 and R 7 One of them is hydrogen and the other is C 1~6 -alkoxy, C 1~6 -alkoxy is optionally substituted with one or more cyclopropyl. 6 and R 7 One of them is hydrogen and the other is C 1~3 -alkoxy, C 1~3 The -alkoxy is optionally substituted with one or more cyclopropyl.

[0075] In some embodiments, R 6 and R 7 One of these is hydrogen and the other is selected from the group consisting of methoxy, propoxy, trifluoroethoxy, and cyclopropylmethoxy.

[0076] In some embodiments, R 6 and R 7 One of them is hydrogen and the other is C 3~6 -cycloalkoxy, C 3~6 -cycloalkoxy optionally includes one or more C 1~3 -substituted with alkyl.

[0077] In some embodiments, R 6 and R 7 One of them is hydrogen and the other is C 3~6 -cycloalkoxy, C 3~6 -cycloalkoxy is optionally substituted with one or more halogens. 6 and R 7 One of them is hydrogen and the other is C 3~6 -cycloalkoxy, C 3~6 -cycloalkoxy is optionally substituted with one or more fluoro. 6 and R 7In another embodiment, one of R is hydrogen and the other is cyclohexyloxy, which is optionally substituted with one or more halogens. 6 and R 7 is hydrogen and the other is cyclohexyloxy, which is optionally substituted with one or more fluoro. 6 and R 7 In another embodiment, one of R is hydrogen and the other is cyclopropoxy, which is optionally substituted with one or more halogens. 6 and R 7 One of the groups is hydrogen and the other is cyclopropoxy, which is optionally substituted with one or more fluoro.

[0078] In some embodiments, R 6 and R 7 One of them is hydrogen and the other is C 3~6 In one aspect, R 6 and R 7 In another embodiment, one of R is hydrogen and the other is cyclopropoxy. 6 and R 7 One of these is hydrogen and the other is cyclohexyloxy.

[0079] In some embodiments, the compound, and pharmaceutically acceptable salts thereof, has the structure of Formula (II-A):

[0080] [ka] In the formula, R 6 and R 7 is as defined in various embodiments herein.

[0081] In some embodiments, the compound and pharmaceutically acceptable salts thereof have the structure of Formula (II-B):

[0082] [ka] In the formula, R 7 is as defined in various embodiments herein.

[0083] In some embodiments, the compound and pharmaceutically acceptable salts thereof have the structure of Formula (II-C):

[0084] [ka] In the formula, R 6 is as defined in various embodiments herein.

[0085] In some embodiments, the compound and pharmaceutically acceptable salts thereof have the structure of Formula (III-A):

[0086] [ka] In the formula, R 6 and R 7 is as defined in various embodiments herein.

[0087] In some embodiments, the compound and pharmaceutically acceptable salts thereof have the structure of Formula (III-B):

[0088] [ka] In the formula, R 7 is as defined in various embodiments herein.

[0089] In some embodiments, the compound and pharmaceutically acceptable salts thereof have the structure of Formula (III-C):

[0090] [ka] In the formula, R 6 is as defined in various embodiments herein.

[0091] B. Embodiment Embodiment 1: A compound having the structure of Formula (I) or a pharmaceutically acceptable salt thereof, wherein R 6 and R 7 is hydrogen and R 6 and R 7 The other is, (a) halogen; (b) Halogen, hydroxy, C 1~6 -Alkoxy, Halo-C 1~6 -alkoxy, C 3~6 -cycloalkyl, and C 3~6 -cycloalkoxy, C optionally substituted with one or more substituents independently selected from the group consisting of 1~6 -alkyl; and (c) Cyano, Fluoro, C 1~6 -Alkyl, Halo-C 1~6 -alkyl, and C 1~6 -cyclopropyl, optionally substituted with one or more substituents independently selected from the group consisting of alkoxy; or a pharmaceutically acceptable salt thereof.

[0092] Embodiment 2: A compound having the structure of Formula (I) or a pharmaceutically acceptable salt thereof: R 2 is selected from the group consisting of hydrogen, halogen, and methyl; R 3 is hydrogen or halogen; R 5 is selected from the group consisting of hydrogen, hydroxy, halogen, methyl, and methoxy; R 6 and R 7 is hydrogen and R 6 and R 7 The other is, (a) halogen; (b) Halogen, hydroxy, C 1~6 -alkoxy and halo-C 1~6 -C optionally substituted with one or more substituents independently selected from the group consisting of alkoxy; 1~6 -alkyl; and (c) Cyano, C 1~6 -Alkyl, Halo-C 1~6 -alkyl and C 1~6 -cyclopropyl, optionally substituted with one or more substituents independently selected from the group consisting of alkoxy; R 8 is hydrogen or halogen, or a pharmaceutically acceptable salt thereof.

[0093] Embodiment 3: A compound having the structure of Formula (I) or a pharmaceutically acceptable salt thereof: R 2 is selected from the group consisting of hydrogen, chloro, fluoro, and methyl; R 3 is selected from the group consisting of hydrogen, chloro, and fluoro; R 5 is selected from the group consisting of hydrogen, hydroxy, chloro, fluoro, methyl, and methoxy; R 6 and R 7 is hydrogen and R 6 and R 7 The other is, (a) halogen; (b) Halogen, hydroxy, C 1~6 -alkoxy and halo-C 1~6 -C optionally substituted with one or more substituents independently selected from the group consisting of alkoxy; 1~6 -alkyl; and (c) Cyano, C 1~6 -Alkyl, Halo-C 1~6 -alkyl and C 1~6 -cyclopropyl, optionally substituted with one or more substituents independently selected from the group consisting of alkoxy; R 8 is selected from the group consisting of hydrogen, chloro, and fluoro, or a pharmaceutically acceptable salt thereof.

[0094] Embodiment 4: A compound having the structure of Formula (I) or a pharmaceutically acceptable salt thereof: R2 is selected from the group consisting of hydrogen, chloro, and methyl; R 3 is hydrogen or chloro; R 5 is hydrogen or chloro; R 6 and R 7 is hydrogen and R 6 and R 7 The other is, (a) halogen; (b) Halogen, hydroxy, C 1~6 -alkoxy and halo-C 1~6 -C optionally substituted with one or more substituents independently selected from the group consisting of alkoxy; 1~6 -alkyl; and (c) Cyano, C 1~6 -Alkyl, Halo-C 1~6 -alkyl and C 1~6 -cyclopropyl, optionally substituted with one or more substituents independently selected from the group consisting of alkoxy; R 8 is hydrogen or chloro, or a pharmaceutically acceptable salt thereof.

[0095] Embodiment 5: A compound having the structure of Formula (I) or a pharmaceutically acceptable salt thereof: R 2 is selected from the group consisting of hydrogen, fluoro, and methyl; R 3 is hydrogen or fluoro; R 5 is hydrogen or fluoro; R 6 and R 7 is hydrogen and R 6 and R 7 The other is, (a) halogen; (b) Halogen, hydroxy, C 1~6 -alkoxy and halo-C 1~6 -C optionally substituted with one or more substituents independently selected from the group consisting of alkoxy; 1~6-alkyl; and (c) Cyano, C 1~6 -Alkyl, Halo-C 1~6 -alkyl and C 1~6 -cyclopropyl, optionally substituted with one or more substituents independently selected from the group consisting of alkoxy; R 8 is hydrogen or fluoro, or a pharmaceutically acceptable salt thereof.

[0096] Embodiment 6: A compound having the structure of Formula (I) or a pharmaceutically acceptable salt thereof, wherein R 6 and R 7 is hydrogen and R 6 and R 7 The other is, (a) halogen; (b) Halogen, hydroxy, C 1~3 -alkoxy and halo-C 1~3 -C optionally substituted with one or more substituents independently selected from the group consisting of alkoxy; 1~3 -alkyl; and (c) Cyano, C 1~3 -Alkyl, Halo-C 1~3 -alkyl and C 1~3 -cyclopropyl, optionally substituted with one or more substituents independently selected from the group consisting of alkoxy; or a pharmaceutically acceptable salt thereof.

[0097] Embodiment 7: R 6 and R 7 The compound of any of embodiments 1-6, or a pharmaceutically acceptable salt thereof, wherein one of is hydrogen and the other is halogen.

[0098] Embodiment 8: R 6 and R 7 or a pharmaceutically acceptable salt thereof.

[0099] Embodiment 9:R 6 and R 7or a pharmaceutically acceptable salt thereof.

[0100] Embodiment 10:R 6 and R 7 or a pharmaceutically acceptable salt thereof.

[0101] Embodiment 11:R 6 and R 7 The compound of any of embodiments 1-6, or a pharmaceutically acceptable salt thereof, wherein one of is hydrogen and the other is iodo.

[0102] Embodiment 12:R 6 and R 7 One of them is hydrogen and the other is C 1~6 -alkyl, C 1~6 -alkyl optionally containing halogen, hydroxy, C 1~6 -alkoxy and halo-C 1~6 6. The compound of any of embodiments 1-5, or a pharmaceutically acceptable salt thereof, substituted with one or more substituents independently selected from the group consisting of: -alkoxy.

[0103] Embodiment 13:R 6 and R 7 One of them is hydrogen and the other is C 1~3 -alkyl, C 1~3 -alkyl optionally containing halogen, hydroxy, C 1~3 -alkoxy and halo-C 1~3 7. The compound of any of embodiments 1-6, or a pharmaceutically acceptable salt thereof, substituted with one or more substituents independently selected from the group consisting of: -alkoxy.

[0104] Embodiment 14:R 6 and R 7 One of them is hydrogen and the other is C 1~3 -alkyl, C 1~3The compound of any of embodiments 1-6, or a pharmaceutically acceptable salt thereof, wherein -alkyl is optionally substituted with one or more substituents independently selected from the group consisting of halogen, hydroxy, methoxy, and halomethoxy.

[0105] Embodiment 15:R 6 and R 7 One of them is hydrogen and the other is C 1~3 -alkyl, C 1~3 The compound of any of embodiments 1-6, or a pharmaceutically acceptable salt thereof, wherein -alkyl is optionally substituted with one or more substituents independently selected from the group consisting of fluoro, hydroxy, methoxy, and fluoromethoxy.

[0106] Embodiment 16:R 6 and R 7 One of them is hydrogen and the other is C 1~3 -alkyl, C 1~3 The compound of any of embodiments 1-6, or a pharmaceutically acceptable salt thereof, wherein -alkyl is optionally substituted with one or more substituents independently selected from the group consisting of fluoro, and methoxy.

[0107] Embodiment 17:R 6 and R 7 One of them is hydrogen and the other is C 1~6 -alkyl, C 1~6 -alkyl optionally containing halogen and C 1~6 6. The compound of any of embodiments 1-5, or a pharmaceutically acceptable salt thereof, substituted with one or more substituents independently selected from the group consisting of: -alkoxy.

[0108] Embodiment 18:R 6 and R 7 One of them is hydrogen and the other is C 1~3 -alkyl, C 1~3 -alkyl optionally containing halogen and C 1~3 7. The compound of any of embodiments 1-6, or a pharmaceutically acceptable salt thereof, substituted with one or more substituents independently selected from the group consisting of: -alkoxy.

[0109] Embodiment 19:R 6 and R 7 One of them is hydrogen and the other is C 1~6 6. The compound of any of embodiments 1-5, or a pharmaceutically acceptable salt thereof, wherein - is -alkyl.

[0110] Embodiment 20:R 6 and R 7 One of them is hydrogen and the other is C 1~3 7. The compound of any of embodiments 1-6, or a pharmaceutically acceptable salt thereof, wherein - is -alkyl.

[0111] Embodiment 21:R 6 and R 7 or a pharmaceutically acceptable salt thereof. 7. The compound of any of embodiments 1-6, wherein one of is hydrogen and the other is methyl.

[0112] Embodiment 22:R 6 and R 7 One of them is hydrogen and the other is C 1~6 -alkyl, C 1~6 The compound of any of embodiments 1-5, or a pharmaceutically acceptable salt thereof, wherein - alkyl is optionally substituted with one or more halogens.

[0113] Embodiment 23:R 6 and R 7 One of them is hydrogen and the other is C 1~3 -alkyl, C 1~3 The compound of any of embodiments 1-6, or a pharmaceutically acceptable salt thereof, wherein -alkyl is optionally substituted with one or more fluoro.

[0114] Embodiment 24:R 6 and R 7 One of them is hydrogen and the other is C 1~6 -alkyl, C 1~6 The compound of any of embodiments 1-5, or a pharmaceutically acceptable salt thereof, wherein -alkyl is optionally substituted with one or more hydroxy.

[0115] Embodiment 25:R6 and R 7 One of them is hydrogen and the other is C 1~3 -alkyl, C 1~3 The compound of any of embodiments 1-6, or a pharmaceutically acceptable salt thereof, wherein -alkyl is optionally substituted with one or more hydroxy.

[0116] Embodiment 26:R 6 and R 7 One of them is hydrogen and the other is C 1~6 -alkyl, C 1~6 -alkyl optionally having one or more C 1~6 6. The compound of any of embodiments 1-5, or a pharmaceutically acceptable salt thereof, substituted with -alkoxy.

[0117] Embodiment 27:R 6 and R 7 One of them is hydrogen and the other is C 1~3 -alkyl, C 1~3 -alkyl optionally having one or more C 1~3 The compound of any of embodiments 1-6, or a pharmaceutically acceptable salt thereof, substituted with -alkoxy.

[0118] Embodiment 28:R 6 and R 7 One of them is hydrogen and the other is C 1~6 -alkyl, C 1~6 -alkyl optionally containing one or more halo-C 1~6 6. The compound of any of embodiments 1-5, or a pharmaceutically acceptable salt thereof, substituted with -alkoxy.

[0119] Embodiment 29:R 6 and R 7 One of them is hydrogen and the other is C 1~3 -alkyl, C 1~3 -alkyl optionally containing one or more halo-C 1~3 The compound of any of embodiments 1-6, or a pharmaceutically acceptable salt thereof, substituted with -alkoxy.

[0120] Embodiment 30:R 6 and R7 One of them is hydrogen and the other is C 1~3 -alkyl, C 1~3 -alkyl optionally having one or more fluoro-C 1~3 The compound of any of embodiments 1-6, or a pharmaceutically acceptable salt thereof, substituted with -alkoxy.

[0121] Embodiment 31:R 6 and R 7 or a pharmaceutically acceptable salt thereof.

[0122] Embodiment 32:R 6 and R 7 or a pharmaceutically acceptable salt thereof.

[0123] Embodiment 33:R 6 and R 7 one of which is hydrogen and the other is cyclopropyl, and cyclopropyl is optionally cyano, C 1~6 -Alkyl, Halo-C 1~6 -alkyl, and C 1~6 6. The compound of any of embodiments 1-5, or a pharmaceutically acceptable salt thereof, substituted with one or more substituents independently selected from the group consisting of: -alkoxy.

[0124] Embodiment 34:R 6 and R 7 one of which is hydrogen and the other is cyclopropyl, and cyclopropyl is optionally cyano, C 1~3 -Alkyl, Halo-C 1~3 -alkyl, and C 1~37. The compound of any of embodiments 1-6, or a pharmaceutically acceptable salt thereof, substituted with one or more substituents independently selected from the group consisting of: -alkoxy.

[0125] Embodiment 35:R 6 and R 7 one of which is hydrogen and the other is cyclopropyl, and cyclopropyl is optionally cyano, C 1~3 -Alkyl, Fluoro-C 1~3 -alkyl, and C 1~3 7. The compound of any of embodiments 1-6, or a pharmaceutically acceptable salt thereof, substituted with one or more substituents independently selected from the group consisting of: -alkoxy.

[0126] Embodiment 36:R 6 and R 7 or a pharmaceutically acceptable salt thereof.

[0127] Embodiment 37:R 6 and R 7 or a pharmaceutically acceptable salt thereof.

[0128] Embodiment 38:R 6 and R 7 one of which is hydrogen and the other is cyclopropyl, and the cyclopropyl is optionally selected from one or more C 1~6 6. The compound of any of embodiments 1-5, or a pharmaceutically acceptable salt thereof, substituted with -alkyl.

[0129] Embodiment 39:R 6 and R 7 one of which is hydrogen and the other is cyclopropyl, and the cyclopropyl is optionally selected from one or more C 1~3 The compound of any of embodiments 1-6, or a pharmaceutically acceptable salt thereof, substituted with -alkyl.

[0130] Embodiment 40:R6 and R 7 one of which is hydrogen and the other is cyclopropyl, and the cyclopropyl optionally contains one or more halo-C 1~6 6. The compound of any of embodiments 1-5, or a pharmaceutically acceptable salt thereof, substituted with -alkyl.

[0131] Embodiment 41:R 6 and R 7 one of which is hydrogen and the other is cyclopropyl, and the cyclopropyl optionally contains one or more halo-C 1~3 The compound of any of embodiments 1-6, or a pharmaceutically acceptable salt thereof, substituted with -alkyl.

[0132] Embodiment 42:R 6 and R 7 one of which is hydrogen and the other is cyclopropyl, and the cyclopropyl optionally has one or more fluoro-C 1~3 The compound of any of embodiments 1-6, or a pharmaceutically acceptable salt thereof, substituted with -alkyl.

[0133] Embodiment 43:R 6 and R 7 one of which is hydrogen and the other is cyclopropyl, and the cyclopropyl is optionally selected from one or more C 1~6 6. The compound of any of embodiments 1-5, or a pharmaceutically acceptable salt thereof, substituted with -alkoxy.

[0134] Embodiment 44:R 6 and R 7 one of which is hydrogen and the other is cyclopropyl, and the cyclopropyl is optionally selected from one or more C 1~3 The compound of any of embodiments 1-6, or a pharmaceutically acceptable salt thereof, substituted with -alkoxy.

[0135] Embodiment 45:R 6 and R 7or a pharmaceutically acceptable salt thereof.

[0136] Embodiment 46:R 6 and R 7 is hydrogen and R 6 and R 7 The other one is, (a) the group consisting of chloro, fluoro, bromo, and iodo; (b) Halogen, hydroxy, C 1~3 -alkoxy and halo-C 1~3 -C optionally substituted with one or more substituents independently selected from the group consisting of alkoxy; 1~3 -alkyl; and (c) Cyano, C 1~3 -Alkyl, Halo-C 1~3 -alkyl and C 1~3 -cyclopropyl, optionally substituted with one or more substituents independently selected from the group consisting of alkoxy;

[0137] Embodiment 47:R 6 and R 7 is hydrogen and R 6 and R 7 The other one is, (a) the group consisting of chloro, fluoro, bromo, and iodo; (b) C optionally substituted with one or more substituents independently selected from the group consisting of halogen, hydroxy, methoxy, and halomethoxy. 1~3 -alkyl; and (c) Cyano, C 1~3 -Alkyl, Halo-C 1~3 -alkyl and C 1~3-cyclopropyl, optionally substituted with one or more substituents independently selected from the group consisting of alkoxy;

[0138] Embodiment 48:R 6 and R 7 is hydrogen and R 6 and R 7 The other one is, (a) the group consisting of chloro, fluoro, bromo, and iodo; (b) Halogens and C 1~6 -C optionally substituted with one or more substituents independently selected from the group consisting of alkoxy; 1~6 -alkyl; and (c) Cyano, C 1~3 -Alkyl, Halo-C 1~3 -alkyl and C 1~3 -cyclopropyl, optionally substituted with one or more substituents independently selected from the group consisting of alkoxy;

[0139] Embodiment 49:R 6 and R 7 is hydrogen and R 6 and R 7 The other one is, (a) the group consisting of chloro, fluoro, bromo, and iodo; (b) Halogens and C 1~3 -C optionally substituted with one or more substituents independently selected from the group consisting of alkoxy; 1~3 -alkyl; and (c) Cyano, C 1~3 -Alkyl, Halo-C 1~3 -alkyl and C 1~3 -cyclopropyl, optionally substituted with one or more substituents independently selected from the group consisting of alkoxy;

[0140] Embodiment 50:R6 and R 7 is hydrogen and R 6 and R 7 The other one is, (a) the group consisting of chloro, fluoro, bromo, and iodo; (b) Halogen, hydroxy, C 1~3 -alkoxy and halo-C 1~3 -C optionally substituted with one or more substituents independently selected from the group consisting of alkoxy; 1~3 -alkyl; and (c) The compound of any of embodiments 1-6, or a pharmaceutically acceptable salt thereof, wherein the cyclopropyl group is optionally substituted with one or more substituents independently selected from the group consisting of cyano, methyl, trifluoromethyl, and ethoxy.

[0141] Embodiment 51:R 6 and R 7 is hydrogen and R 6 and R 7 The other one is, (a) the group consisting of chloro, fluoro, bromo, and iodo; (b) Halogens and C 1~3 -C optionally substituted with one or more substituents independently selected from the group consisting of alkoxy; 1~3 -alkyl; and (c) The compound of any of embodiments 1-6, or a pharmaceutically acceptable salt thereof, wherein the cyclopropyl group is optionally substituted with one or more substituents independently selected from the group consisting of cyano, methyl, trifluoromethyl, and ethoxy.

[0142] Embodiment 52:R 6 and R 7 is hydrogen and R 6 and R 7 The other one is, (a) the group consisting of chloro and fluoro; (b) C optionally substituted with one or more substituents independently selected from the group consisting of halogen, hydroxy, methoxy, and halomethoxy. 1~3 -alkyl; and (c) The compound of any of embodiments 1-6, or a pharmaceutically acceptable salt thereof, wherein the cyclopropyl group is optionally substituted with one or more substituents independently selected from the group consisting of cyano, methyl, trifluoromethyl, and ethoxy.

[0143] Embodiment 53:R 6 and R 7 is hydrogen and R 6 and R 7 The other one is, (a) the group consisting of chloro and fluoro; (b) C optionally substituted with one or more substituents independently selected from the group consisting of fluoro, hydroxy, methoxy, and fluoromethoxy. 1~3 -alkyl; and (c) The compound of any of embodiments 1-6, or a pharmaceutically acceptable salt thereof, wherein the cyclopropyl group is optionally substituted with one or more substituents independently selected from the group consisting of cyano, methyl, trifluoromethyl, and ethoxy.

[0144] Embodiment 54:R 6 and R 7 is hydrogen and R 6 and R 7 The other one is, (a) the group consisting of chloro and fluoro; (b) C optionally substituted with one or more substituents independently selected from the group consisting of methyl, ethyl, propyl, fluoromethyl, difluoromethyl, trifluoromethyl, fluoropropyl, hydroxyethyl, hydroxypropyl, methoxyethyl, methoxypropyl, trifluoromethoxymethyl, and trifluoromethoxyethyl. 1~3 -alkyl; and (c) The compound of any of embodiments 1-6, or a pharmaceutically acceptable salt thereof, wherein the cyclopropyl group is optionally substituted with one or more substituents independently selected from the group consisting of cyano, methyl, trifluoromethyl, and ethoxy.

[0145] Embodiment 55:R 6 and R 7 is hydrogen and R 6 and R 7 The other one is, (a) the group consisting of chloro and fluoro; (b) C optionally substituted with one or more substituents independently selected from the group consisting of methyl, ethyl, propyl, fluoromethyl, difluoromethyl, trifluoromethyl, fluoropropyl, methoxyethyl, and methoxypropyl. 1~3 -alkyl; and (c) The compound of any of embodiments 1-6, or a pharmaceutically acceptable salt thereof, wherein the cyclopropyl group is optionally substituted with one or more substituents independently selected from the group consisting of cyano, methyl, trifluoromethyl, and ethoxy.

[0146] Embodiment 56:R 6 and R 7 is hydrogen and R 6 and R 7 The other one is, (a) the group consisting of chloro and fluoro; (b) C optionally substituted with one or more substituents independently selected from the group consisting of chloro, fluoro, and methoxy. 1~6 -alkyl; and (c) The compound of any of embodiments 1-5, or a pharmaceutically acceptable salt thereof, wherein the compound is selected from the group consisting of cyclopropyl, optionally substituted with one or more cyano.

[0147] Embodiment 57:R 6 57. The compound of any of embodiments 1-56, or a pharmaceutically acceptable salt thereof, wherein is hydrogen.

[0148] Embodiment 58:R 7 57. The compound of any of embodiments 1-56, or a pharmaceutically acceptable salt thereof, wherein is hydrogen.

[0149] Embodiment 59: The compound of any of embodiments 1-6, wherein the compound has the structure of formula (II-A): or a pharmaceutically acceptable salt thereof.

[0150] Embodiment 60: The compound of any of embodiments 1-6, wherein the compound has the structure of formula (II-B): or a pharmaceutically acceptable salt thereof.

[0151] Embodiment 61: The compound of any of embodiments 1-6, wherein the compound has the structure of formula (II-C): or a pharmaceutically acceptable salt thereof.

[0152] Embodiment 62: The compound of any of embodiments 1-6, wherein the compound has the structure of formula (III-A): or a pharmaceutically acceptable salt thereof.

[0153] Embodiment 63: The compound of any of embodiments 1-6, wherein the compound has the structure of Formula (III-B): or a pharmaceutically acceptable salt thereof.

[0154] Embodiment 64: The compound of any of embodiments 1-6, or a pharmaceutically acceptable salt thereof, wherein the compound has the structure of Formula III-C), as further defined herein.

[0155] Embodiment 65: A compound of Formula (I) or a pharmaceutically acceptable salt thereof, wherein the compound is 6-bromo-N-(2-((1S,3S,5S)-3-cyano-2-azabicyclo[3.1.0]hexan-2-yl)-2-oxoethyl)quinoline-4-carboxamide (Example 1); 7-chloro-N-(2-((1S,3S,5S)-3-cyano-2-azabicyclo[3.1.0]hexan-2-yl)-2-oxoethyl)quinoline-4-carboxamide (Example 2); 7-bromo-N-(2-((1S,3S,5S)-3-cyano-2-azabicyclo[3.1.0]hexan-2-yl)-2-oxoethyl)quinoline-4-carboxamide (Example 3); N-(2-((1S,3S,5S)-3-cyano-2-azabicyclo[3.1.0]hexan-2-yl)-2-oxoethyl)-6-fluoro-2-methylquinoline-4-carboxamide (Example 4); 6-chloro-N-(2-((1S,3S,5S)-3-cyano-2-azabicyclo[3.1.0]hexan-2-yl)-2-oxoethyl)-2-methylquinoline-4-carboxamide (Example 5); 6-bromo-N-(2-((1S,3S,5S)-3-cyano-2-azabicyclo[3.1.0]hexan-2-yl)-2-oxoethyl)-2-methylquinoline-4-carboxamide (Example 6); N-(2-((1S,3S,5S)-3-cyano-2-azabicyclo[3.1.0]hexan-2-yl)-2-oxoethyl)-6-iodo-2-methylquinoline-4-carboxamide (Example 7); and N-(2-((1S,3S,5S)-3-cyano-2-azabicyclo[3.1.0]hexan-2-yl)-2-oxoethyl)-7-fluoro-2-methylquinoline-4-carboxamide (Example 8), or a pharmaceutically acceptable salt thereof.

[0156] Embodiment 66: A compound of Formula (I) or a pharmaceutically acceptable salt thereof, wherein the compound is 6-bromo-N-(2-((1S,3S,5S)-3-cyano-2-azabicyclo[3.1.0]hexan-2-yl)-2-oxoethyl)quinoline-4-carboxamide (Example 1); N-(2-((1S,3S,5S)-3-cyano-2-azabicyclo[3.1.0]hexan-2-yl)-2-oxoethyl)-6-fluoro-2-methylquinoline-4-carboxamide (Example 4); 6-chloro-N-(2-((1S,3S,5S)-3-cyano-2-azabicyclo[3.1.0]hexan-2-yl)-2-oxoethyl)-2-methylquinoline-4-carboxamide (Example 5); 6-bromo-N-(2-((1S,3S,5S)-3-cyano-2-azabicyclo[3.1.0]hexan-2-yl)-2-oxoethyl)-2-methylquinoline-4-carboxamide (Example 6); and N-(2-((1S,3S,5S)-3-cyano-2-azabicyclo[3.1.0]hexan-2-yl)-2-oxoethyl)-6-iodo-2-methylquinoline-4-carboxamide (Example 7), or a pharmaceutically acceptable salt thereof.

[0157] Embodiment 67: A compound of Formula (I) or a pharmaceutically acceptable salt thereof, wherein the compound is 7-chloro-N-(2-((1S,3S,5S)-3-cyano-2-azabicyclo[3.1.0]hexan-2-yl)-2-oxoethyl)quinoline-4-carboxamide (Example 2); 7-bromo-N-(2-((1S,3S,5S)-3-cyano-2-azabicyclo[3.1.0]hexan-2-yl)-2-oxoethyl)quinoline-4-carboxamide (Example 3); and N-(2-((1S,3S,5S)-3-cyano-2-azabicyclo[3.1.0]hexan-2-yl)-2-oxoethyl)-7-fluoro-2-methylquinoline-4-carboxamide (Example 8), or a pharmaceutically acceptable salt thereof.

[0158] Embodiment 68: A compound of Formula (I) or a pharmaceutically acceptable salt thereof, wherein the compound is N-(2-((1S,3S,5S)-3-cyano-2-azabicyclo[3.1.0]hexan-2-yl)-2-oxoethyl)-6-methylquinoline-4-carboxamide (Example 9); N-(2-((1S,3S,5S)-3-cyano-2-azabicyclo[3.1.0]hexan-2-yl)-2-oxoethyl)-6-(trifluoromethyl)quinoline-4-carboxamide (Example 10); N-(2-((1S,3S,5S)-3-cyano-2-azabicyclo[3.1.0]hexan-2-yl)-2-oxoethyl)-6-(fluoromethyl)quinoline-4-carboxamide (Example 11); N-(2-((1S,3S,5S)-3-cyano-2-azabicyclo[3.1.0]hexan-2-yl)-2-oxoethyl)-6-(2-fluoropropan-2-yl)quinoline-4-carboxamide (Example 12); N-(2-((1S,3S,5S)-3-cyano-2-azabicyclo[3.1.0]hexan-2-yl)-2-oxoethyl)-6-(2-hydroxypropan-2-yl)quinoline-4-carboxamide (Example 13); N-(2-((1S,3S,5S)-3-cyano-2-azabicyclo[3.1.0]hexan-2-yl)-2-oxoethyl)-6-(1-hydroxyethyl)quinoline-4-carboxamide (Example 14); N-(2-((1S,3S,5S)-3-cyano-2-azabicyclo[3.1.0]hexan-2-yl)-2-oxoethyl)-6-(1-methoxyethyl)quinoline-4-carboxamide (Example 15); N-(2-((1S,3S,5S)-3-cyano-2-azabicyclo[3.1.0]hexan-2-yl)-2-oxoethyl)-6-(2-methoxypropan-2-yl)quinoline-4-carboxamide (Example 16); N-(2-((1S,3S,5S)-3-cyano-2-azabicyclo[3.1.0]hexan-2-yl)-2-oxoethyl)-6-((trifluoromethoxy)methyl)quinoline-4-carboxamide (Example 17); N-(2-((1S,3S,5S)-3-cyano-2-azabicyclo[3.1.0]hexan-2-yl)-2-oxoethyl)-6-ethyl-2-methylquinoline-4-carboxamide (Example 18); N-(2-((1S,3S,5S)-3-cyano-2-azabicyclo[3.1.0]hexan-2-yl)-2-oxoethyl)-2,6-dimethylquinoline-4-carboxamide (Example 19); N-(2-((1S,3S,5S)-3-cyano-2-azabicyclo[3.1.0]hexan-2-yl)-2-oxoethyl)-7-methylquinoline-4-carboxamide (Example 20); N-(2-((1S,3S,5S)-3-cyano-2-azabicyclo[3.1.0]hexan-2-yl)-2-oxoethyl)-7-(2-fluoropropan-2-yl)quinoline-4-carboxamide (Example 21); N-(2-((1S,3S,5S)-3-cyano-2-azabicyclo[3.1.0]hexan-2-yl)-2-oxoethyl)-7-(difluoromethyl)quinoline-4-carboxamide (Example 22); N-(2-((1S,3S,5S)-3-cyano-2-azabicyclo[3.1.0]hexan-2-yl)-2-oxoethyl)-7-(trifluoromethyl)quinoline-4-carboxamide (Example 23); N-(2-((1S,3S,5S)-3-cyano-2-azabicyclo[3.1.0]hexan-2-yl)-2-oxoethyl)-7-(fluoromethyl)quinoline-4-carboxamide (Example 24); N-(2-((1S,3S,5S)-3-cyano-2-azabicyclo[3.1.0]hexan-2-yl)-2-oxoethyl)-7-(1-hydroxyethyl)quinoline-4-carboxamide (Example 25); N-(2-((1S,3S,5S)-3-cyano-2-azabicyclo[3.1.0]hexan-2-yl)-2-oxoethyl)-7-(2-hydroxypropan-2-yl)quinoline-4-carboxamide (Example 26); N-(2-((1S,3S,5S)-3-cyano-2-azabicyclo[3.1.0]hexan-2-yl)-2-oxoethyl)-7-(1-methoxyethyl)quinoline-4-carboxamide (Example 27); N-(2-((1S,3S,5S)-3-cyano-2-azabicyclo[3.1.0]hexan-2-yl)-2-oxoethyl)-7-(2-methoxypropan-2-yl)quinoline-4-carboxamide (Example 28); N-(2-((1S,3S,5S)-3-cyano-2-azabicyclo[3.1.0]hexan-2-yl)-2-oxoethyl)-7-((trifluoromethoxy)methyl)quinoline-4-carboxamide (Example 29); N-(2-((1S,3S,5S)-3-cyano-2-azabicyclo[3.1.0]hexan-2-yl)-2-oxoethyl)-7-(1-(trifluoromethoxy)ethyl)quinoline-4-carboxamide (Example 30); and N-(2-((1S,3S,5S)-3-cyano-2-azabicyclo[3.1.0]hexan-2-yl)-2-oxoethyl)-2,7-dimethylquinoline-4-carboxamide (Example 31), or a pharmaceutically acceptable salt thereof.

[0159] Embodiment 69: A compound of Formula (I) or a pharmaceutically acceptable salt thereof, wherein the compound is N-(2-((1S,3S,5S)-3-cyano-2-azabicyclo[3.1.0]hexan-2-yl)-2-oxoethyl)-6-methylquinoline-4-carboxamide (Example 9); N-(2-((1S,3S,5S)-3-cyano-2-azabicyclo[3.1.0]hexan-2-yl)-2-oxoethyl)-6-(trifluoromethyl)quinoline-4-carboxamide (Example 10); N-(2-((1S,3S,5S)-3-cyano-2-azabicyclo[3.1.0]hexan-2-yl)-2-oxoethyl)-6-(fluoromethyl)quinoline-4-carboxamide (Example 11); N-(2-((1S,3S,5S)-3-cyano-2-azabicyclo[3.1.0]hexan-2-yl)-2-oxoethyl)-6-(2-fluoropropan-2-yl)quinoline-4-carboxamide (Example 12); N-(2-((1S,3S,5S)-3-cyano-2-azabicyclo[3.1.0]hexan-2-yl)-2-oxoethyl)-6-(2-hydroxypropan-2-yl)quinoline-4-carboxamide (Example 13); N-(2-((1S,3S,5S)-3-cyano-2-azabicyclo[3.1.0]hexan-2-yl)-2-oxoethyl)-6-(1-hydroxyethyl)quinoline-4-carboxamide (Example 14); N-(2-((1S,3S,5S)-3-cyano-2-azabicyclo[3.1.0]hexan-2-yl)-2-oxoethyl)-6-(1-methoxyethyl)quinoline-4-carboxamide (Example 15); N-(2-((1S,3S,5S)-3-cyano-2-azabicyclo[3.1.0]hexan-2-yl)-2-oxoethyl)-6-(2-methoxypropan-2-yl)quinoline-4-carboxamide (Example 16); N-(2-((1S,3S,5S)-3-cyano-2-azabicyclo[3.1.0]hexan-2-yl)-2-oxoethyl)-6-((trifluoromethoxy)methyl)quinoline-4-carboxamide (Example 17); N-(2-((1S,3S,5S)-3-cyano-2-azabicyclo[3.1.0]hexan-2-yl)-2-oxoethyl)-6-ethyl-2-methylquinoline-4-carboxamide (Example 18); and N-(2-((1S,3S,5S)-3-cyano-2-azabicyclo[3.1.0]hexan-2-yl)-2-oxoethyl)-2,6-dimethylquinoline-4-carboxamide (Example 19), or a pharmaceutically acceptable salt thereof.

[0160] Embodiment 70: A compound of Formula (I) or a pharmaceutically acceptable salt thereof, wherein the compound is N-(2-((1S,3S,5S)-3-cyano-2-azabicyclo[3.1.0]hexan-2-yl)-2-oxoethyl)-7-methylquinoline-4-carboxamide (Example 20); N-(2-((1S,3S,5S)-3-cyano-2-azabicyclo[3.1.0]hexan-2-yl)-2-oxoethyl)-7-(2-fluoropropan-2-yl)quinoline-4-carboxamide (Example 21); N-(2-((1S,3S,5S)-3-cyano-2-azabicyclo[3.1.0]hexan-2-yl)-2-oxoethyl)-7-(difluoromethyl)quinoline-4-carboxamide (Example 22); N-(2-((1S,3S,5S)-3-cyano-2-azabicyclo[3.1.0]hexan-2-yl)-2-oxoethyl)-7-(trifluoromethyl)quinoline-4-carboxamide (Example 23); N-(2-((1S,3S,5S)-3-cyano-2-azabicyclo[3.1.0]hexan-2-yl)-2-oxoethyl)-7-(fluoromethyl)quinoline-4-carboxamide (Example 24); N-(2-((1S,3S,5S)-3-cyano-2-azabicyclo[3.1.0]hexan-2-yl)-2-oxoethyl)-7-(1-hydroxyethyl)quinoline-4-carboxamide (Example 25); N-(2-((1S,3S,5S)-3-cyano-2-azabicyclo[3.1.0]hexan-2-yl)-2-oxoethyl)-7-(2-hydroxypropan-2-yl)quinoline-4-carboxamide (Example 26); N-(2-((1S,3S,5S)-3-cyano-2-azabicyclo[3.1.0]hexan-2-yl)-2-oxoethyl)-7-(1-methoxyethyl)quinoline-4-carboxamide (Example 27); N-(2-((1S,3S,5S)-3-cyano-2-azabicyclo[3.1.0]hexan-2-yl)-2-oxoethyl)-7-(2-methoxypropan-2-yl)quinoline-4-carboxamide (Example 28); N-(2-((1S,3S,5S)-3-cyano-2-azabicyclo[3.1.0]hexan-2-yl)-2-oxoethyl)-7-((trifluoromethoxy)methyl)quinoline-4-carboxamide (Example 29); N-(2-((1S,3S,5S)-3-cyano-2-azabicyclo[3.1.0]hexan-2-yl)-2-oxoethyl)-7-(1-(trifluoromethoxy)ethyl)quinoline-4-carboxamide (Example 30); and N-(2-((1S,3S,5S)-3-cyano-2-azabicyclo[3.1.0]hexan-2-yl)-2-oxoethyl)-2,7-dimethylquinoline-4-carboxamide (Example 31), or a pharmaceutically acceptable salt thereof.

[0161] Embodiment 71: A compound of Formula (I) or a pharmaceutically acceptable salt thereof, wherein the compound is N-(2-((1S,3S,5S)-3-cyano-2-azabicyclo[3.1.0]hexan-2-yl)-2-oxoethyl)-7-(1-cyanocyclopropyl)quinoline-4-carboxamide (Example 40); N-(2-((1S,3S,5S)-3-cyano-2-azabicyclo[3.1.0]hexan-2-yl)-2-oxoethyl)-6-cyclopropylquinoline-4-carboxamide (Example 42); N-(2-((1S,3S,5S)-3-cyano-2-azabicyclo[3.1.0]hexan-2-yl)-2-oxoethyl)-6-(1-methylcyclopropyl)quinoline-4-carboxamide (Example 43); N-(2-((1S,3S,5S)-3-cyano-2-azabicyclo[3.1.0]hexan-2-yl)-2-oxoethyl)-6-(1-(trifluoromethyl)cyclopropyl)quinoline-4-carboxamide (Example 44); N-(2-((1S,3S,5S)-3-cyano-2-azabicyclo[3.1.0]hexan-2-yl)-2-oxoethyl)-6-(1-ethoxycyclopropyl)quinoline-4-carboxamide (Example 45); N-(2-((1S,3S,5S)-3-cyano-2-azabicyclo[3.1.0]hexan-2-yl)-2-oxoethyl)-6-(1-cyanocyclopropyl)quinoline-4-carboxamide (Example 46); N-(2-((1S,3S,5S)-3-cyano-2-azabicyclo[3.1.0]hexan-2-yl)-2-oxoethyl)-7-cyclopropylquinoline-4-carboxamide (Example 47); N-(2-((1S,3S,5S)-3-cyano-2-azabicyclo[3.1.0]hexan-2-yl)-2-oxoethyl)-7-(1-methylcyclopropyl)quinoline-4-carboxamide (Example 32); N-(2-((1S,3S,5S)-3-cyano-2-azabicyclo[3.1.0]hexan-2-yl)-2-oxoethyl)-7-(1-(trifluoromethyl)cyclopropyl)quinoline-4-carboxamide (Example 36); and N-(2-((1S,3S,5S)-3-cyano-2-azabicyclo[3.1.0]hexan-2-yl)-2-oxoethyl)-7-(1-ethoxycyclopropyl)quinoline-4-carboxamide (Example 39), or a pharmaceutically acceptable salt thereof.

[0162] Embodiment 72: A compound of Formula (I) or a pharmaceutically acceptable salt thereof, wherein the compound is N-(2-((1S,3S,5S)-3-cyano-2-azabicyclo[3.1.0]hexan-2-yl)-2-oxoethyl)-6-cyclopropylquinoline-4-carboxamide (Example 42); N-(2-((1S,3S,5S)-3-cyano-2-azabicyclo[3.1.0]hexan-2-yl)-2-oxoethyl)-6-(1-methylcyclopropyl)quinoline-4-carboxamide (Example 43); N-(2-((1S,3S,5S)-3-cyano-2-azabicyclo[3.1.0]hexan-2-yl)-2-oxoethyl)-6-(1-(trifluoromethyl)cyclopropyl)quinoline-4-carboxamide (Example 44); N-(2-((1S,3S,5S)-3-cyano-2-azabicyclo[3.1.0]hexan-2-yl)-2-oxoethyl)-6-(1-ethoxycyclopropyl)quinoline-4-carboxamide (Example 45); and N-(2-((1S,3S,5S)-3-cyano-2-azabicyclo[3.1.0]hexan-2-yl)-2-oxoethyl)-6-(1-cyanocyclopropyl)quinoline-4-carboxamide (Example 46), or a pharmaceutically acceptable salt thereof.

[0163] Embodiment 73: A compound of Formula (I) or a pharmaceutically acceptable salt thereof, wherein the compound is N-(2-((1S,3S,5S)-3-cyano-2-azabicyclo[3.1.0]hexan-2-yl)-2-oxoethyl)-7-(1-cyanocyclopropyl)quinoline-4-carboxamide (Example 40); N-(2-((1S,3S,5S)-3-cyano-2-azabicyclo[3.1.0]hexan-2-yl)-2-oxoethyl)-7-cyclopropylquinoline-4-carboxamide (Example 47); N-(2-((1S,3S,5S)-3-cyano-2-azabicyclo[3.1.0]hexan-2-yl)-2-oxoethyl)-7-(1-methylcyclopropyl)quinoline-4-carboxamide (Example 32); N-(2-((1S,3S,5S)-3-cyano-2-azabicyclo[3.1.0]hexan-2-yl)-2-oxoethyl)-7-(1-(trifluoromethyl)cyclopropyl)quinoline-4-carboxamide (Example 36); and N-(2-((1S,3S,5S)-3-cyano-2-azabicyclo[3.1.0]hexan-2-yl)-2-oxoethyl)-7-(1-ethoxycyclopropyl)quinoline-4-carboxamide (Example 39), or a pharmaceutically acceptable salt thereof.

[0164] Embodiment 74: A compound of Formula (I) or a pharmaceutically acceptable salt thereof, wherein the compound is N-(2-((1S,3S,5S)-3-cyano-2-azabicyclo[3.1.0]hexan-2-yl)-2-oxoethyl)-6-(2,2,2-trifluoroethoxy)quinoline-4-carboxamide (Example 33); N-(2-((1S,3S,5S)-3-cyano-2-azabicyclo[3.1.0]hexan-2-yl)-2-oxoethyl)-6-isopropoxyquinoline-4-carboxamide (Example 34); N-(2-((1S,3S,5S)-3-cyano-2-azabicyclo[3.1.0]hexan-2-yl)-2-oxoethyl)-6-(cyclopropylmethoxy)quinoline-4-carboxamide (Example 35); and N-(2-((1S,3S,5S)-3-cyano-2-azabicyclo[3.1.0]hexan-2-yl)-2-oxoethyl)-7-methoxy-2-methylquinoline-4-carboxamide (Example 41), or a pharmaceutically acceptable salt thereof.

[0165] Embodiment 75: A compound of Formula (I) or a pharmaceutically acceptable salt thereof, wherein the compound is N-(2-((1S,3S,5S)-3-cyano-2-azabicyclo[3.1.0]hexan-2-yl)-2-oxoethyl)-6-(2,2,2-trifluoroethoxy)quinoline-4-carboxamide (Example 33); N-(2-((1S,3S,5S)-3-cyano-2-azabicyclo[3.1.0]hexan-2-yl)-2-oxoethyl)-6-isopropoxyquinoline-4-carboxamide (Example 34); and N-(2-((1S,3S,5S)-3-cyano-2-azabicyclo[3.1.0]hexan-2-yl)-2-oxoethyl)-6-(cyclopropylmethoxy)quinoline-4-carboxamide (Example 35), or a pharmaceutically acceptable salt thereof.

[0166] Embodiment 76: N-(2-((1S,3S,5S)-3-cyano-2-azabicyclo[3.1.0]hexan-2-yl)-2-oxoethyl)-7-methoxy-2-methylquinoline-4-carboxamide, or a pharmaceutically acceptable salt thereof (Example 41).

[0167] Embodiment 77: A compound of Formula (I) or a pharmaceutically acceptable salt thereof, wherein the compound is N-(2-((1S,3S,5S)-3-cyano-2-azabicyclo[3.1.0]hexan-2-yl)-2-oxoethyl)-6-cyclopropoxyquinoline-4-carboxamide (Example 37); and N-(2-((1S,3S,5S)-3-cyano-2-azabicyclo[3.1.0]hexan-2-yl)-2-oxoethyl)-6-((4,4-difluorocyclohexyl)oxy)quinoline-4-carboxamide (Example 38), or a pharmaceutically acceptable salt thereof.

[0168] Embodiment 78: A compound of Formula (I) or a pharmaceutically acceptable salt thereof, wherein the compound is N-(2-((1S,3S,5S)-3-cyano-2-azabicyclo[3.1.0]hexan-2-yl)-2-oxoethyl)-2,7-dimethylquinoline-4-carboxamide (Example 31); 6-bromo-N-(2-((1S,3S,5S)-3-cyano-2-azabicyclo[3.1.0]hexan-2-yl)-2-oxoethyl)-2-methylquinoline-4-carboxamide (Example 6); N-(2-((1S,3S,5S)-3-cyano-2-azabicyclo[3.1.0]hexan-2-yl)-2-oxoethyl)-7-fluoro-2-methylquinoline-4-carboxamide (Example 8); N-(2-((1S,3S,5S)-3-cyano-2-azabicyclo[3.1.0]hexan-2-yl)-2-oxoethyl)-7-methoxy-2-methylquinoline-4-carboxamide (Example 41); N-(2-((1S,3S,5S)-3-cyano-2-azabicyclo[3.1.0]hexan-2-yl)-2-oxoethyl)-6-ethyl-2-methylquinoline-4-carboxamide (Example 18); N-(2-((1S,3S,5S)-3-cyano-2-azabicyclo[3.1.0]hexan-2-yl)-2-oxoethyl)-6-iodo-2-methylquinoline-4-carboxamide (Example 7); N-(2-((1S,3S,5S)-3-cyano-2-azabicyclo[3.1.0]hexan-2-yl)-2-oxoethyl)-2,6-dimethylquinoline-4-carboxamide (Example 19); 6-chloro-N-(2-((1S,3S,5S)-3-cyano-2-azabicyclo[3.1.0]hexan-2-yl)-2-oxoethyl)-2-methylquinoline-4-carboxamide (Example 5); and N-(2-((1S,3S,5S)-3-cyano-2-azabicyclo[3.1.0]hexan-2-yl)-2-oxoethyl)-6-fluoro-2-methylquinoline-4-carboxamide (Example 4), or a pharmaceutically acceptable salt thereof.

[0169] Embodiment A-1: A compound having the structure of formula (I):

[0170] [ka] or a pharmaceutically acceptable salt thereof, wherein: R 2 is selected from the group consisting of hydrogen, halogen, and methyl; R 3 is hydrogen or halogen; R 5 is selected from the group consisting of hydrogen, hydroxy, halogen, methyl, and methoxy; R 6 and R 7 is hydrogen and R 6 and R 7 The other is, (a) halogen; (b) Halogen, hydroxy, C 1~6 -Alkoxy, Halo-C 1~6 -alkoxy, C 3~6 -cycloalkyl, and C 3~6 -cycloalkoxy, C optionally substituted with one or more substituents independently selected from the group consisting of 1~6 - alkyl; (c) Cyano, Fluoro, C 1~6-Alkyl, Halo-C 1~6 -alkyl, and C 1~6 -cyclopropyl, optionally substituted with one or more substituents independently selected from the group consisting of alkoxy; (d) C optionally substituted with one or more substituents independently selected from the group consisting of halogen and cyclopropyl. 1~6 -alkoxy; and (e) Halogens and C 1~3 -C optionally substituted with one or more substituents independently selected from the group consisting of alkyl, 3~6 -cycloalkoxy, R 8 is selected from the group consisting of hydrogen, halogen and methyl.

[0171] Embodiment A-2:R 2 A compound of embodiment A-1, or a pharmaceutically acceptable salt thereof, wherein is selected from the group consisting of hydrogen, chloro, fluoro, and methyl.

[0172] Embodiment A-3:R 2 A compound of embodiment A-1, or a pharmaceutically acceptable salt thereof, wherein is selected from the group consisting of hydrogen, chloro, and methyl.

[0173] Embodiment A-4:R 2 A compound of embodiment A-1, or a pharmaceutically acceptable salt thereof, wherein is selected from the group consisting of hydrogen, fluoro, and methyl.

[0174] Embodiment A-5:R 2 A compound of embodiment A-1, or a pharmaceutically acceptable salt thereof, wherein is hydrogen or halogen.

[0175] Embodiment A-6:R 2 A compound of embodiment A-1, or a pharmaceutically acceptable salt thereof, wherein is hydrogen or chloro.

[0176] Embodiment A-7:R 2 A compound of embodiment A-1, or a pharmaceutically acceptable salt thereof, wherein is hydrogen or fluoro.

[0177] Embodiment A-8:R 2 A compound of embodiment A-1, or a pharmaceutically acceptable salt thereof, wherein is hydrogen or methyl.

[0178] Embodiment A-9:R 2 A compound of embodiment A-1, or a pharmaceutically acceptable salt thereof, wherein is hydrogen.

[0179] Embodiment A-10:R 2 A compound of embodiment A-1, or a pharmaceutically acceptable salt thereof, wherein is halogen.

[0180] Embodiment A-11:R 2 The compound of embodiment A-1, or a pharmaceutically acceptable salt thereof, wherein is chloro.

[0181] Embodiment A-12:R 2 The compound of embodiment A-1, or a pharmaceutically acceptable salt thereof, wherein is fluoro.

[0182] Embodiment A-13:R 2 The compound of embodiment A-1, or a pharmaceutically acceptable salt thereof, wherein is methyl.

[0183] Embodiment A-14:R 3 A compound of any of embodiments A-1 to A-13, or a pharmaceutically acceptable salt thereof, wherein is selected from the group consisting of hydrogen, chloro, and fluoro.

[0184] Embodiment A-15:R 3 A compound of any of embodiments A-1 to A-13, or a pharmaceutically acceptable salt thereof, wherein is hydrogen or chloro.

[0185] Embodiment A-16:R 3 A compound of any of embodiments A-1 to A-13, or a pharmaceutically acceptable salt thereof, wherein is hydrogen or fluoro.

[0186] Embodiment A-17:R 3The compound of any of embodiments A-1 to A-13, or a pharmaceutically acceptable salt thereof, wherein is hydrogen.

[0187] Embodiment A-18:R 3 The compound of any of embodiments A-1 to A-13, or a pharmaceutically acceptable salt thereof, wherein is halogen.

[0188] Embodiment A-19:R 3 The compound of any of embodiments A-1 to A-13, or a pharmaceutically acceptable salt thereof, wherein is chloro.

[0189] Embodiment A-20:R 3 The compound of any of embodiments A-1 to A-13, or a pharmaceutically acceptable salt thereof, wherein is fluoro.

[0190] Embodiment A-21:R 5 The compound of any of embodiments A-1 to A-20, or a pharmaceutically acceptable salt thereof, wherein is selected from the group consisting of hydrogen, hydroxy, chloro, fluoro, methyl, and methoxy.

[0191] Embodiment A-22:R 5 The compound of any of embodiments A-1 to A-20, or a pharmaceutically acceptable salt thereof, wherein is selected from the group consisting of hydrogen, chloro, and methyl.

[0192] Embodiment A-23:R 5 The compound of any of embodiments A-1 to A-20, or a pharmaceutically acceptable salt thereof, wherein is selected from the group consisting of hydrogen, fluoro, and methyl.

[0193] Embodiment A-24:R 5 The compound of any of embodiments A-1 to A-20, or a pharmaceutically acceptable salt thereof, wherein is hydrogen or halogen.

[0194] Embodiment A-25:R 5 A compound of any of embodiments A-1 to A-20, or a pharmaceutically acceptable salt thereof, wherein is hydrogen or chloro.

[0195] Embodiment A-26:R 5 The compound of any of embodiments A-1 to A-20, or a pharmaceutically acceptable salt thereof, wherein is hydrogen or fluoro.

[0196] Embodiment A-27:R 5 The compound of any of embodiments A-1 to A-20, or a pharmaceutically acceptable salt thereof, wherein is hydrogen or methyl.

[0197] Embodiment A-28:R 5 The compound of any of embodiments A-1 to A-20, or a pharmaceutically acceptable salt thereof, wherein is hydrogen.

[0198] Embodiment A-29:R 5 The compound of any of embodiments A-1 to A-20, or a pharmaceutically acceptable salt thereof, wherein is hydroxy.

[0199] Embodiment A-30:R 5 The compound of any of embodiments A-1 to A-20, or a pharmaceutically acceptable salt thereof, wherein is halogen.

[0200] Embodiment A-31:R 5 The compound of any of embodiments A-1 to A-20, or a pharmaceutically acceptable salt thereof, wherein is chloro.

[0201] Embodiment A-32:R 5 The compound of any of embodiments A-1 to A-20, or a pharmaceutically acceptable salt thereof, wherein is fluoro.

[0202] Embodiment A-33:R 5 The compound of any of embodiments A-1 to A-20, or a pharmaceutically acceptable salt thereof, wherein is methyl.

[0203] Embodiment A-34:R 5 The compound of any of embodiments A-1 to A-20, or a pharmaceutically acceptable salt thereof, wherein is methoxy.

[0204] Embodiment A-35:R 8 A compound of any of embodiments A-1 to A-34, or a pharmaceutically acceptable salt thereof, wherein is selected from the group consisting of hydrogen, chloro, fluoro, and methyl.

[0205] Embodiment A-36:R 8 A compound of any of embodiments A-1 to A-34, or a pharmaceutically acceptable salt thereof, wherein is hydrogen or chloro.

[0206] Embodiment A-37:R 8 A compound of any of embodiments A-1 to A-34, or a pharmaceutically acceptable salt thereof, wherein is hydrogen or fluoro.

[0207] Embodiment A-38:R 8 The compound of any of embodiments A-1 to A-34, or a pharmaceutically acceptable salt thereof, wherein is hydrogen or methyl.

[0208] Embodiment A-39:R 8 The compound of any of embodiments A-1 to A-34, or a pharmaceutically acceptable salt thereof, wherein is hydrogen.

[0209] Embodiment A-40:R 8 The compound of any of embodiments A-1 to A-34, or a pharmaceutically acceptable salt thereof, wherein is halogen.

[0210] Embodiment A-41:R 8 The compound of any of embodiments A-1 to A-34, or a pharmaceutically acceptable salt thereof, wherein is chloro.

[0211] Embodiment A-42:R 8 The compound of any of embodiments A-1 to A-34, or a pharmaceutically acceptable salt thereof, wherein is fluoro.

[0212] Embodiment A-43:R 8 The compound of any of embodiments A-1 to A-34, or a pharmaceutically acceptable salt thereof, wherein is methyl.

[0213] Embodiment A-44: A compound of embodiment A-1 or a pharmaceutically acceptable salt thereof, wherein: R 2 is selected from the group consisting of hydrogen, chloro, fluoro, and methyl; R 3 is selected from the group consisting of hydrogen, chloro, and fluoro; R 5 is selected from the group consisting of hydrogen, hydroxy, chloro, fluoro, methyl, and methoxy; R 8 A compound of embodiment A-1, or a pharmaceutically acceptable salt thereof, wherein is selected from the group consisting of hydrogen, chloro, fluoro, and methyl.

[0214] Embodiment A-45: A compound of embodiment A-1 or a pharmaceutically acceptable salt thereof, wherein: R 2 is selected from the group consisting of hydrogen, chloro, fluoro, and methyl; R 3 is selected from the group consisting of hydrogen, chloro, and fluoro; R 5 is selected from the group consisting of hydrogen, chloro, and fluoro; R 8 A compound of embodiment A-1, or a pharmaceutically acceptable salt thereof, wherein is selected from the group consisting of hydrogen, chloro, and fluoro.

[0215] Embodiment A-46: A compound of embodiment A-1 or a pharmaceutically acceptable salt thereof, wherein: R 2 is selected from the group consisting of hydrogen, fluoro, and methyl; R 3 is hydrogen or fluoro; R 5 is hydrogen or fluoro; R 8 A compound of embodiment A-1, or a pharmaceutically acceptable salt thereof, wherein is hydrogen or fluoro.

[0216] Embodiment A-47: A compound of embodiment A-1 or a pharmaceutically acceptable salt thereof, wherein: R2 is hydrogen or methyl; R 3 is selected from the group consisting of hydrogen, chloro, and fluoro; R 5 is selected from the group consisting of hydrogen, chloro, and fluoro; R 8 A compound of embodiment A-1, or a pharmaceutically acceptable salt thereof, wherein is selected from the group consisting of hydrogen, chloro, and fluoro.

[0217] Embodiment A-48:R 2 , R 3 , R 5 , and R 8 The compound of embodiment A-1, or a pharmaceutically acceptable salt thereof, wherein is independently selected from hydrogen and fluoro.

[0218] Embodiment A-49:R 2 , R 3 , R 5 and R 8 One of the substituents is other than hydrogen and the remaining R 2 , R 3 , R 5 and R 8 The compound of any of embodiments A-1 to A-48, or a pharmaceutically acceptable salt thereof, wherein the substituents are all hydrogen.

[0219] Embodiment A-50:R 6 and R 7 or a pharmaceutically acceptable salt thereof. The compound of any of embodiments A-1 to A-49, wherein one of is hydrogen and the other is chloro.

[0220] Embodiment A-51:R 6 and R 7 or a pharmaceutically acceptable salt thereof. The compound of any of embodiments A-1 to A-49, wherein one of is hydrogen and the other is fluoro.

[0221] Embodiment A-52:R 6 and R 7The compound of any of embodiments A-1 to A-49, wherein one of is hydrogen and the other is bromo; or a pharmaceutically acceptable salt thereof.

[0222] Embodiment A-53:R 6 and R 7 The compound of any of embodiments A-1 to A-49, or a pharmaceutically acceptable salt thereof, wherein one of is hydrogen and the other is iodo.

[0223] Embodiment A-54:R 6 and R 7 One of them is hydrogen and the other 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 -cycloalkyl, and C 3~6 The compound of any of embodiments A-1 through A-49, or a pharmaceutically acceptable salt thereof, substituted with one or more substituents independently selected from the group consisting of: -cycloalkoxy.

[0224] Embodiment A-55:R 6 and R 7 One of them is hydrogen and the other is C 1~3 -alkyl, C 1~3 -alkyl optionally containing halogen, hydroxy, C 1~3 -Alkoxy, Halo-C 1~3 -alkoxy, C 3~6 -cycloalkyl, and C 3~6 The compound of any of embodiments A-1 through A-49, or a pharmaceutically acceptable salt thereof, substituted with one or more substituents independently selected from the group consisting of: -cycloalkoxy.

[0225] Embodiment A-56:R 6 and R 7 One of them is hydrogen and the other is C 1~3 -alkyl, C 1~3The compound of any of embodiments A-1 through A-49, or a pharmaceutically acceptable salt thereof, wherein -alkyl is optionally substituted with one or more substituents independently selected from the group consisting of halogen, hydroxy, methoxy, and halomethoxy.

[0226] Embodiment A-57:R 6 and R 7 One of them is hydrogen and the other is C 1~3 -alkyl, C 1~3 The compound of any of embodiments A-1 through A-49, or a pharmaceutically acceptable salt thereof, wherein -alkyl is optionally substituted with one or more substituents independently selected from the group consisting of fluoro, hydroxy, methoxy, and fluoromethoxy.

[0227] Embodiment A-58:R 6 and R 7 One of them is hydrogen and the other is C 1~3 -alkyl, C 1~3 The compound of any of embodiments A-1 through A-49, or a pharmaceutically acceptable salt thereof, wherein alkyl is optionally substituted with one or more substituents independently selected from the group consisting of fluoro, and methoxy.

[0228] Embodiment A-59:R 6 and R 7 One of them is hydrogen and the other is C 1~6 -alkyl, C 1~6 -alkyl optionally containing halogen and C 1~6 The compound of any of embodiments A-1 through A-49, or a pharmaceutically acceptable salt thereof, substituted with one or more substituents independently selected from the group consisting of: -alkoxy.

[0229] Embodiment A-60:R 6 and R 7 One of them is hydrogen and the other is C 1~3 -alkyl, C 1~3 -alkyl optionally containing halogen and C 1~3The compound of any of embodiments A-1 through A-49, or a pharmaceutically acceptable salt thereof, substituted with one or more substituents independently selected from the group consisting of: -alkoxy.

[0230] Embodiment A-61:R 6 and R 7 One of them is hydrogen and the other is C 1~6 The compound of any of embodiments A-1 to A-49, or a pharmaceutically acceptable salt thereof, wherein - is alkyl.

[0231] Embodiment A-62:R 6 and R 7 One of them is hydrogen and the other is C 1~3 The compound of any of embodiments A-1 to A-49, or a pharmaceutically acceptable salt thereof, wherein - is alkyl.

[0232] Embodiment A-63:R 6 and R 7 The compound of any of embodiments A-1 to A-49, wherein one of is hydrogen and the other is methyl; or a pharmaceutically acceptable salt thereof.

[0233] Embodiment A-64:R 6 and R 7 One of them is hydrogen and the other is C 1~6 -alkyl, C 1~6 The compound of any of embodiments A-1 through A-49, or a pharmaceutically acceptable salt thereof, wherein alkyl is optionally substituted with one or more halogen.

[0234] Embodiment A-65:R 6 and R 7 One of them is hydrogen and the other is C 1~3 -alkyl, C 1~3 The compound of any of embodiments A-1 through A-49, or a pharmaceutically acceptable salt thereof, wherein alkyl is optionally substituted with one or more fluoro.

[0235] Embodiment A-66:R 6 and R 7 One of them is hydrogen and the other is C 1~6-alkyl, C 1~6 The compound of any of embodiments A-1 through A-49, or a pharmaceutically acceptable salt thereof, wherein alkyl is optionally substituted with one or more hydroxy.

[0236] Embodiment A-67:R 6 and R 7 One of them is hydrogen and the other is C 1~3 -alkyl, C 1~3 The compound of any of embodiments A-1 through A-49, or a pharmaceutically acceptable salt thereof, wherein alkyl is optionally substituted with one or more hydroxy.

[0237] Embodiment A-68:R 6 and R 7 One of them is hydrogen and the other is C 1~6 -alkyl, C 1~6 -alkyl optionally having one or more C 1~6 The compound of any of embodiments A-1 to A-49, or a pharmaceutically acceptable salt thereof, substituted with -alkoxy.

[0238] Embodiment A-69:R 6 and R 7 One of them is hydrogen and the other is C 1~3 -alkyl, C 1~6 -alkyl optionally having one or more C 1~3 The compound of any of embodiments A-1 to A-49, or a pharmaceutically acceptable salt thereof, substituted with -alkoxy.

[0239] Embodiment A-70:R 6 and R 7 One of them is hydrogen and the other is C 1~6 -alkyl, C 1~6 -alkyl optionally containing one or more halo-C 1~6 The compound of any of embodiments A-1 to A-49, or a pharmaceutically acceptable salt thereof, substituted with -alkoxy.

[0240] Embodiment A-71:R 6 and R 7 One of them is hydrogen and the other is C 1~3-alkyl, C 1~3 -alkyl optionally containing one or more halo-C 1~3 The compound of any of embodiments A-1 to A-49, or a pharmaceutically acceptable salt thereof, substituted with -alkoxy.

[0241] Embodiment A-72:R 6 and R 7 One of them is hydrogen and the other is C 1~3 -alkyl, C 1~3 -alkyl optionally having one or more fluoro-C 1~3 The compound of any of embodiments A-1 to A-49, or a pharmaceutically acceptable salt thereof, substituted with -alkoxy.

[0242] Embodiment A-73:R 6 and R 7 One of them is hydrogen and the other is C 1~6 -alkyl, C 1~6 -alkyl optionally having one or more C 3~6 The compound of any of embodiments A-1 to A-49, or a pharmaceutically acceptable salt thereof, which is substituted with -cycloalkyl.

[0243] Embodiment A-74:R 6 and R 7 One of them is hydrogen and the other is C 1~3 -alkyl, C 1~3 -alkyl optionally having one or more C 3~6 The compound of any of embodiments A-1 to A-49, or a pharmaceutically acceptable salt thereof, which is substituted with -cycloalkyl.

[0244] Embodiment A-75:R 6 and R 7 One of them is hydrogen and the other is C 1~6 -alkyl, C 1~6 -alkyl optionally having one or more C 3~6 The compound of any of embodiments A-1 to A-49, or a pharmaceutically acceptable salt thereof, substituted with -cycloalkoxy.

[0245] Embodiment A-76:R 6and R 7 One of them is hydrogen and the other is C 1~3 -alkyl, C 1~3 -alkyl optionally having one or more C 3~6 The compound of any of embodiments A-1 to A-49, or a pharmaceutically acceptable salt thereof, substituted with -cycloalkoxy.

[0246] Embodiment A-77:R 6 and R 7 or a pharmaceutically acceptable salt thereof.

[0247] Embodiment A-78:R 6 and R 7 or a pharmaceutically acceptable salt thereof.

[0248] Embodiment A-79:R 6 and R 7 one of which is hydrogen and the other is cyclopropyl, and cyclopropyl is optionally cyano, fluoro, C 1~6 -Alkyl, Halo-C 1~6 -alkyl, and C 1~6 The compound of any of embodiments A-1 to A-49, or a pharmaceutically acceptable salt thereof, substituted with one or more substituents independently selected from the group consisting of: -alkoxy.

[0249] Embodiment A-80:R 6 and R 7 one of which is hydrogen and the other is cyclopropyl, and cyclopropyl is optionally cyano, fluoro, C 1~3 -Alkyl, Halo-C1~3 -alkyl, and C 1~3 The compound of any of embodiments A-1 to A-49, or a pharmaceutically acceptable salt thereof, substituted with one or more substituents independently selected from the group consisting of: -alkoxy.

[0250] Embodiment A-81:R 6 and R 7 one of which is hydrogen and the other is cyclopropyl, and cyclopropyl is optionally cyano, C 1~3 -Alkyl, Fluoro-C 1~3 -alkyl, and C 1~3 The compound of any of embodiments A-1 to A-49, or a pharmaceutically acceptable salt thereof, substituted with one or more substituents independently selected from the group consisting of: -alkoxy.

[0251] Embodiment A-82:R 6 and R 7 or a pharmaceutically acceptable salt thereof. The compound of any of embodiments A-1 to A-49, wherein one of is hydrogen and the other is cyclopropyl;

[0252] Embodiment A-83:R 6 and R 7 or a pharmaceutically acceptable salt thereof. The compound of any of embodiments A-1 through A-49, wherein one of is hydrogen and the other is cyclopropyl, which is optionally substituted with one or more cyano.

[0253] Embodiment A-84:R 6 and R 7 The compound of any one of Embodiments A-1 to A-49, wherein one of is hydrogen and the other is cyclopropyl, which is optionally substituted with one or more fluoro; or a pharmaceutically acceptable salt thereof.

[0254] Embodiment A-85:R 6 and R 7 one of which is hydrogen and the other is cyclopropyl, and the cyclopropyl is optionally selected from one or more C 1~6The compound of any of embodiments A-1 to A-49, or a pharmaceutically acceptable salt thereof, which is substituted with -alkyl.

[0255] Embodiment A-86:R 6 and R 7 one of which is hydrogen and the other is cyclopropyl, and the cyclopropyl is optionally selected from one or more C 1~3 The compound of any of embodiments A-1 to A-49, or a pharmaceutically acceptable salt thereof, which is substituted with -alkyl.

[0256] Embodiment A-87:R 6 and R 7 one of which is hydrogen and the other is cyclopropyl, and the cyclopropyl optionally contains one or more halo-C 1~6 The compound of any of embodiments A-1 to A-49, or a pharmaceutically acceptable salt thereof, which is substituted with -alkyl.

[0257] Embodiment A-88:R 6 and R 7 one of which is hydrogen and the other is cyclopropyl, and the cyclopropyl optionally contains one or more halo-C 1~3 The compound of any of embodiments A-1 to A-49, or a pharmaceutically acceptable salt thereof, which is substituted with -alkyl.

[0258] Embodiment A-89:R 6 and R 7 one of which is hydrogen and the other is cyclopropyl, and the cyclopropyl optionally has one or more fluoro-C 1~3 The compound of any of embodiments A-1 to A-49, or a pharmaceutically acceptable salt thereof, which is substituted with -alkyl.

[0259] Embodiment A-90:R 6 and R 7 one of which is hydrogen and the other is cyclopropyl, and the cyclopropyl is optionally selected from one or more C 1~6 The compound of any of embodiments A-1 to A-49, or a pharmaceutically acceptable salt thereof, substituted with -alkoxy.

[0260] Embodiment A-91:R 6 and R 7 one of which is hydrogen and the other is cyclopropyl, and the cyclopropyl is optionally selected from one or more C 1~3 The compound of any of embodiments A-1 to A-49, or a pharmaceutically acceptable salt thereof, substituted with -alkoxy.

[0261] Embodiment A-92:R 6 and R 7 or a pharmaceutically acceptable salt thereof.

[0262] Embodiment A-93:R 6 and R 7 One of them is hydrogen and the other is C 1~6 -alkoxy, C 1~6 The compound of any of embodiments A-1 through A-49, or a pharmaceutically acceptable salt thereof, wherein alkoxy is optionally substituted with one or more substituents independently selected from the group consisting of halogen, and cyclopropyl.

[0263] Embodiment A-94:R 6 and R 7 One of them is hydrogen and the other is C 1~3 -alkoxy, C 1~3 The compound of any of embodiments A-1 through A-49, or a pharmaceutically acceptable salt thereof, wherein alkoxy is optionally substituted with one or more substituents independently selected from the group consisting of halogen, and cyclopropyl.

[0264] Embodiment A-95:R 6 and R 7 One of them is hydrogen and the other is C 1~6 The compound of any of embodiments A-1 to A-49, or a pharmaceutically acceptable salt thereof, wherein -alkoxy.

[0265] Embodiment A-96:R 6 and R 7 One of them is hydrogen and the other is C 1~3 The compound of any of embodiments A-1 to A-49, or a pharmaceutically acceptable salt thereof, wherein -alkoxy.

[0266] Embodiment A-97:R 6 and R 7 One of them is hydrogen and the other is C 1~6 -alkoxy, C 1~6 The compound of any of embodiments A-1 through A-49, or a pharmaceutically acceptable salt thereof, wherein alkoxy is optionally substituted with one or more halogen.

[0267] Embodiment A-98:R 6 and R 7 One of them is hydrogen and the other is C 1~3 -alkoxy, C 1~3 The compound of any of embodiments A-1 through A-49, or a pharmaceutically acceptable salt thereof, wherein alkoxy is optionally substituted with one or more halogen.

[0268] Embodiment A-99:R 6 and R 7 One of them is hydrogen and the other is C 1~3 -alkoxy, C 1~3 The compound of any of embodiments A-1 through A-49, or a pharmaceutically acceptable salt thereof, wherein -alkoxy is optionally substituted with one or more fluoro.

[0269] Embodiment A-100:R 6 and R 7 One of them is hydrogen and the other is C 1~6 -alkoxy, C 1~6 The compound of any of embodiments A-1 through A-49, or a pharmaceutically acceptable salt thereof, wherein alkoxy is optionally substituted with one or more cyclopropyl.

[0270] Embodiment A-101:R 6 and R 7 One of them is hydrogen and the other is C 1~3 -alkoxy, C1~3 The compound of any of embodiments A-1 through A-49, or a pharmaceutically acceptable salt thereof, wherein alkoxy is optionally substituted with one or more cyclopropyl.

[0271] Embodiment A-102:R 6 and R 7 or a pharmaceutically acceptable salt thereof. The compound of any of embodiments A-1 to A-49, wherein one of is hydrogen and the other is selected from the group consisting of methoxy, propoxy, trifluoroethoxy, and cyclopropylmethoxy;

[0272] Embodiment A-103:R 6 and R 7 One of them is hydrogen and the other is C 3~6 -cycloalkoxy, C 3~6 A compound of any of embodiments A-1 through A-49, or a pharmaceutically acceptable salt thereof, wherein cycloalkoxy is optionally substituted with one or more halogens.

[0273] Embodiment A-104:R 6 and R 7 One of them is hydrogen and the other is C 3~6 -cycloalkoxy, C 3~6 -cycloalkoxy optionally has one or more C 1~3 The compound of any of embodiments A-1 to A-49, or a pharmaceutically acceptable salt thereof, which is substituted with -alkyl.

[0274] Embodiment A-105:R 6 and R 7 One of them is hydrogen and the other is C 3~6 The compound of any of embodiments A-1 to A-49, or a pharmaceutically acceptable salt thereof, is -cycloalkoxy.

[0275] Embodiment A-106:R 6 and R 7 The compound of any of embodiments A-1 through A-49, wherein one of is hydrogen and the other is cyclopropoxy; or a pharmaceutically acceptable salt thereof.

[0276] Embodiment A-107:R 6 and R 7 The compound of any of embodiments A-1 to A-49, wherein one of is hydrogen and the other is cyclohexyloxy; or a pharmaceutically acceptable salt thereof.

[0277] Embodiment A-108:R 6 and R 7 One of them is hydrogen and the other is C 3~6 -cycloalkoxy, C 3~6 A compound of any of embodiments A-1 through A-49, or a pharmaceutically acceptable salt thereof, wherein cycloalkoxy is optionally substituted with one or more fluoro.

[0278] Embodiment A-109:R 6 and R 7 or a pharmaceutically acceptable salt thereof. The compound of any of embodiments A-1 through A-49, wherein one of is hydrogen and the other is cyclohexyloxy, which cyclohexyloxy is optionally substituted with one or more halogens.

[0279] Embodiment A-110:R 6 and R 7 or a pharmaceutically acceptable salt thereof. The compound of any of embodiments A-1 through A-49, wherein one of is hydrogen and the other is cyclohexyloxy, which cyclohexyloxy is optionally substituted with one or more fluoro.

[0280] Embodiment A-111:R 6 and R 7 or a pharmaceutically acceptable salt thereof. The compound of any of embodiments A-1 through A-49, wherein one of is hydrogen and the other is cyclopropoxy, which cyclopropoxy is optionally substituted with one or more halogens.

[0281] Embodiment A-112: The compound of embodiment 1, wherein the compound is N-(2-((1S,3S,5S)-3-cyano-2-azabicyclo[3.1.0]hexan-2-yl)-2-oxoethyl)-7-methylquinoline-4-carboxamide; or a pharmaceutically acceptable salt thereof.

[0282] Embodiment B-1:R 6 and R 7 or a pharmaceutically acceptable salt thereof.

[0283] Embodiment C-1: A pharmaceutical composition comprising a compound of any of embodiments 1 to 78 or A-1 to A-112, or a pharmaceutically acceptable salt thereof, and one or more pharmaceutically acceptable excipients.

[0284] Embodiment C-2: 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 of embodiments 1 to 78 or A-1 to A-112, or a pharmaceutically acceptable salt thereof.

[0285] Embodiment C-3: The method of embodiment C-2, wherein 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.

[0286] Embodiment C-4: The method of embodiment C-3, wherein the FAP-mediated condition is a liver disease.

[0287] Embodiment C-5: The method of embodiment C-4, wherein the liver disease is non-alcoholic steatohepatitis.

[0288] Embodiment C-6: Use of a compound according to any of embodiments 1 to 78 or A-1 to A-112, or a pharmaceutically acceptable salt thereof, for the manufacture of a medicament for treating or preventing a FAP-mediated condition.

[0289] C. 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 a compound having R 2 , R 3 , R 5 , R 6 , R 7 and / or R 8 The possible groups for R are described individually or collectively, and another embodiment is 7 When describing possible groups for R, these embodiments can be combined to form 2 , R 3 , R 5 , R 6 , R 7 and / or R 8 The possible groups described for R 7 It is understood that additional embodiments can be provided that are described with the possible groups described for R. In other words, for any of the compound embodiments described in this disclosure, R 7 The substituents may be any of the R groups described herein. 7 may be as defined in any of the embodiments.

[0290] D. 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.

[0291] 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 6. d In another embodiment, the compound has a surface plasmon resonance (SPR) pK value of greater than about 7. d In another embodiment, the compound has an 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 It has a value.

[0292] 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.

[0293] 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 of greater than about 10 μM against DPP7. 50 It has a value.

[0294] 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.

[0295] 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.

[0296] 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.

[0297] 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 intrinsic apparent permeability of at least about 0.5×10 cm / s. 6 In another embodiment, the compound has a Caco-2 intrinsic apparent permeability of at least about 1 x 10 6 Caco-2 has an intrinsic apparent permeability of 10 ...

[0298] In some embodiments, compounds of the present disclosure have a pharmaceutically acceptable Caco-2 bidirectional (ABBA) A-B apparent permeability as measured as described for the Caco-2 bidirectional (ABBA) A-B apparent permeability assay reported in the Examples below. In one aspect, the compound has a Caco-2 bidirectional (ABBA) A-B apparent permeability of at least about 0.1 x 10 6 In another embodiment, the compound has a Caco-2 bidirectional (ABBA) A-B apparent permeability of at least about 0.25 x 10 cm / s. 6 In another embodiment, the compound has a Caco-2 bidirectional (ABBA) A-B apparent permeability of at least about 0.5 x 10 cm / s. 6Caco-2 has a bidirectional (ABBA) A-B apparent permeability of 10 ...

[0299] 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 embodiment, the compounds have a kinetic solubility of at least about 1 μM.In another embodiment, the compounds have a kinetic solubility of at least about 10 μM.In another embodiment, the compounds have a kinetic solubility of at least about 25 μM.In another embodiment, the compounds have a kinetic solubility of at least about 50 μM.

[0300] E. 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).

[0301] F. 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.

[0302] 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 having 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%.

[0303] 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%.

[0304] G. 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.

[0305] 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.

[0306] 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.

[0307] 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.

[0308] H. Intermediates In some embodiments, the present disclosure provides additional compounds useful as intermediates for preparing the disclosed compounds and pharmaceutically acceptable salts thereof.

[0309] III.How to use The disclosed compounds of the present disclosure, and pharmaceutically acceptable salts thereof, are inhibitors of the activity of the prolyl endopeptidase fibroblast activation protein (FAP). FAP is an endopeptidase that enzymatically cleaves substrates involved in glucose and lipid metabolism, fibrinolysis, and collagen production.

[0310] 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.

[0311] 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 when converted from its inactive form (plasminogen) by plasminogen activators. Fibrinolysis is inhibited by plasminogen activator inhibitor-1 (PAI-1), plasminogen activator inhibitor-2 (PAI-2), and α2AP (Experimental & Molecular Medicine 2020, 52, 367), all of which are induced by tissue trauma. FAP converts α2AP to a more effectively fibrin-bound form, which reduces plasmin degradation of fibrin at the site of injury. It is hypothesized that inhibition of FAP increases fibrinolysis and improves tissue regeneration at the site of injury (J. Thromb. Haemost. 2013, 11, 2029; Proteomics Clin. Appl. 2014, 8, 454).

[0312] FAP is also thought to promote collagen production and deposition and play a role in increasing fibrosis through altered extracellular matrix (ECM) turnover (J Biol Chem 2016, 8, 291). Inhibition of FAP is hypothesized to result in decreased collagen deposition and reduced inflammation (Inflamm. Bowel Dis. 2018, 18, 332).

[0313] 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.

[0314] Thus, in some embodiments, the present disclosure provides methods for treating or preventing a FAP-mediated condition in a subject in need thereof by administering to the subject a therapeutically effective amount of a compound of formula I, or a pharmaceutically acceptable salt thereof.

[0315] In some embodiments, the present disclosure provides methods for treating or preventing a condition characterized by overexpression of a FAP in a subject in need thereof by administering to the subject a therapeutically effective amount of a compound of the present disclosure, or a pharmaceutically acceptable salt thereof.

[0316] 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.

[0317] In some embodiments, the present disclosure provides a method for treating liver disease in a subject in need thereof by administering to the subject a therapeutically effective amount of a compound of the present disclosure, or a pharmaceutically acceptable salt thereof, wherein the subject has a liver disease of 27 kg / m 2 ~40kg / m 2 In one embodiment, the subject has a body mass index (BMI) of 30 kg / m 2 ~39.9kg / m 2 In another embodiment, the subject has a BMI of at least 40 kg / m 2 In another embodiment, the subject has a BMI of 0.05 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.

[0318] 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 the compound of the present disclosure or its pharmaceutically acceptable salt to the subject, and the subject also suffers from or is likely to suffer from dyslipidemia.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.

[0319] 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 the compound of the present disclosure or its pharmaceutically acceptable salt to the subject, and the subject also suffers from or is likely to suffer from insulin resistance.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.

[0320] 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 the compound of the present disclosure or its pharmaceutically acceptable salt to the subject, and the subject also suffers from or is likely to suffer from at least one of type 2 diabetes and renal failure.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.

[0321] 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 the compound of the present disclosure or its pharmaceutically acceptable salt to the subject, and the subject also suffers from or is likely to suffer from type 2 diabetes.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.

[0322] 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 the compound of the present disclosure or its pharmaceutically acceptable salt to the subject, and the subject also suffers from or is likely to suffer from renal failure.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.

[0323] 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.

[0324] 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 a therapeutically effective amount of a compound of the present disclosure or a pharmaceutically acceptable salt thereof to the subject. 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.

[0325] In some embodiments, the present disclosure provides a method for treating or preventing non-alcoholic steatohepatitis (NASH) in a subject in need thereof by administering to the subject a therapeutically effective amount of a compound of the present disclosure or a pharmaceutically acceptable salt thereof. In one aspect, the NASH is stage 1 NASH. In another aspect, the NASH is stage 2 NASH. In another aspect, the NASH is stage 3 NASH. In another aspect, the NASH is stage 4 NASH. In another aspect, the subject 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.

[0326] In some embodiments, the present disclosure provides a method for treating or preventing liver fibrosis in a subject in need thereof by administering to the subject a therapeutically effective amount of a compound of the present disclosure or a pharmaceutically acceptable salt thereof. In one aspect, the subject is afflicted with stage 3 liver fibrosis. In another aspect, the subject also is afflicted with or susceptible to one or more conditions selected from the group consisting of obesity, dyslipidemia, insulin resistance, type 2 diabetes, and renal failure.

[0327] 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.

[0328] In some embodiments, the present disclosure provides a method for treating or preventing type 2 diabetes mellitus 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 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.

[0329] In some embodiments, the present disclosure provides a method for improving glycemic control 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 is overweight. In another embodiment, the subject is obese.

[0330] In some embodiments, the present disclosure provides a method 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.

[0331] In some embodiments, the present disclosure provides a method for 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 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 ≥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.

[0332] 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.

[0333] 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.

[0334] In some embodiments, the present disclosure provides a method for treating a cardiovascular condition in a subject in need thereof by administering to the subject a therapeutically effective amount of a compound of the present disclosure or a pharmaceutically acceptable salt thereof. In one aspect, the cardiovascular condition is selected from the group consisting of heart failure, cardiomyopathy, atherosclerosis, venous thromboembolism, and atrial fibrillation. In one aspect, the cardiovascular condition is heart failure. In another aspect, the cardiovascular condition is heart failure with preserved ejection fraction (HFpEF). In another aspect, the cardiomyopathy is a cardiomyopathy. In another aspect, the cardiomyopathy is selected from the group consisting of hypertrophic cardiomyopathy, dilated cardiomyopathy, restrictive cardiomyopathy, hypertrophic cardiomyopathy, ischemic cardiomyopathy, ischemic cardiomyopathy, dilated cardiomyopathy, and idiopathic cardiomyopathy. In another aspect, the cardiovascular condition is atherosclerosis. In another aspect, the cardiovascular condition is venous thromboembolism. In another aspect, the cardiovascular condition is atrial fibrillation.

[0335] 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 a therapeutically effective amount of a compound of the present disclosure or a pharmaceutically acceptable salt thereof to the subject. 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, increased 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.

[0336] 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% or less. In another embodiment, the subject is overweight. In another embodiment, the subject is obese. In another embodiment, the subject's weight is reduced by, for example, at least about 5%, 10%, 15%, 20%, 25%, 30%, 35%, or 40%.

[0337] 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.

[0338] In some embodiments, the present disclosure provides a method for treating or preventing fibrosis 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 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).

[0339] In some embodiments, the present disclosure provides a method for 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.

[0340] 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.

[0341] In some embodiments, the present disclosure provides a method for treating or preventing a keloid disorder in a subject in need thereof by administering to the subject a therapeutically effective amount of a compound of the present disclosure or a pharmaceutically acceptable salt thereof. In one aspect, the keloid disorder is selected from the group consisting of scar formation, keloid tumors, and keloid scars.

[0342] 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.

[0343] 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, laryngeal cancer, myeloma cells, bladder cancer, cholangiocarcinoma, clear cell renal carcinoma, neuroendocrine tumor, oncogenetic 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.

[0344] The subject to be treated is typically a human or non-human mammal, particularly a human. Suitable subjects also 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 (also known as crab-eating or long-tailed), marmosets, tamarins, chimpanzees, macaques, etc.); and rodents (including rats, mice, gerbils, guinea pigs, etc.).

[0345] In some embodiments, the present disclosure provides a compound of the present disclosure, or a pharmaceutically acceptable salt thereof, for use as a pharmaceutical.

[0346] In some embodiments, the 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 described above.

[0347] In some embodiments, the 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, such as those described above.

[0348] IV. Combination Therapy and Fixed-Dose Combinations The compounds of the present disclosure can be used in the above methods either as single pharmacological agents or in combination with other pharmacological agents or techniques. Such combination therapy can be achieved by simultaneous, sequential, or separate 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 in this application and the other pharmacological agents, typically within their approved dosage ranges.

[0349] In some embodiments, the present disclosure provides a combination suitable for use in treating a condition selected from those discussed above, wherein the combination comprises 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.

[0350] 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.

[0351] 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.

[0352] 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.

[0353] 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.

[0354] In some embodiments, the present disclosure provides a pharmaceutical composition comprising a compound of the present disclosure or a pharmaceutically acceptable salt thereof; one or more pharmacological agents selected from an SGLT2 inhibitor, metformin, a GLP1 agonist, a DPP4 inhibitor, and a PPAR agonist; and a pharmaceutically acceptable diluent or carrier. Such a combination can be used 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.

[0355] In some embodiments, the present disclosure provides a combination suitable for use in treating cancer, the combination comprising a compound of the present disclosure or a pharmaceutically acceptable salt thereof, and an immune checkpoint inhibitor. In one aspect, the immune checkpoint inhibitor is selected from the group consisting of an anti-PD-1 antibody, an anti-PD-L1 antibody, an anti-CTLA4 antibody, a TLR7 agonist, a CD40 agonist, a Lag-3 antagonist, and an OX40 agonist. In another aspect, the immune checkpoint inhibitor is an anti-PD-1 antibody (e.g., pembrolizumab (Keytruda), nivolumab (Opdivo), cemiplimab (Libtayo), etc.). In another aspect, the immune checkpoint inhibitor is an anti-PD-L1 antibody (e.g., atezolizumab (Tecentriq), 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.

[0356] 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.

[0357] 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 well known to those skilled in the art and are described, for example, in Handbook of Pharmaceutical Excipients, Sixth Edition, Pharmaceutical Press, edited by Rowe, Ray C; Sheskey, Paul J; Quinn, Marian. Pharmaceutically acceptable excipients can function, for example, as adjuvants, diluents, carriers, stabilizers, flavoring agents, coloring agents, fillers, binders, disintegrants, lubricants, glidants, 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.

[0358] 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 well known in the art. Thus, compositions intended for oral use may contain, for example, one or more colorants, sweeteners, flavoring agents, and / or preservatives.

[0359] 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 according to methods well known in the therapeutic arts, and can adjust such dosage and regimen as necessary during the course of treatment. The compounds of the present disclosure, or pharmaceutically acceptable salts thereof, typically deliver 2.5 to 5,000 mg / m of body area of an animal. 2 or a unit dose in the range of about 0.05-100 mg / kg, which will normally provide a therapeutically effective dose.

[0360] 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.

[0361] 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.

[0362] 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.

[0363] 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).

[0364] In some embodiments, the kit comprises: (a) a first unit dosage form comprising a compound of the present disclosure or a pharmaceutically acceptable salt thereof; (b) a second unit dosage form comprising a pharmacological agent selected from the group consisting of an SGLT2 inhibitor, metformin, a GLP1 agonist, a DPP4 inhibitor, and a PPAR agonist; (c) container means for containing the 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.

[0365] VII. Preparation method The present disclosure further provides processes for the preparation of compounds of Formula (I), (II-A), (II-B), (II-C), (III-A), (III-B), or (III-C), and pharmaceutically acceptable salts thereof. Reaction Schemes 1-30 illustrate synthetic routes to these compounds, and unless otherwise indicated, R 2 , R 3 , R 5 , R 6 , R 7 , and R 8 is as defined in formula (I); R 9 is alkyl (e.g., methyl, ethyl, tert-butyl, etc.); R 10 and R 11 is hydrogen or alkyl; X 1 , X 2 and X 3is a leaving group (e.g., Cl, Br, I, OTf, etc.). One of skill 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.

[0366] [ka]

[0367] Scheme 1 shows a synthetic route to certain compounds of formula (I). Compounds of formula (2) can be reacted with compounds of formula (3) or a salt thereof to give compounds of formula (I). The reaction can be carried out in the presence of a base, typically an organic base (DIPEA, TEA, etc.), using a solvent (DCM, DMF, EtOAc, MeCN, or a mixture thereof, etc.), at a temperature typically ranging from 0° C. to 60° C., using a suitable coupling reagent (HATU, HOBt / EDC, T3P, etc.).

[0368] [ka]

[0369] 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 9 For compounds of formula (4) where ═ = 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.

[0370] [ka]

[0371] Scheme 3 shows a synthetic route to certain compounds of formula (I). Compounds of formula (5) can be reacted with compounds of formula (6) to give compounds of formula (I). The reaction can be carried out in the presence of a base, typically an organic base (DIPEA, TEA, etc.), using a solvent (DCM, DMF, EtOAc, MeCN, or mixtures thereof, etc.), at a temperature typically ranging from 0° C. to 60° C., using a suitable coupling reagent (HATU, HOBt / EDC, T3P, etc.).

[0372] [ka]

[0373] Scheme 4 shows a synthetic route to a particular compound of formula (5). A compound of formula (2) can be reacted with a compound of formula (7) to give a compound of formula (8). The reaction can be carried out in the presence of a base, typically an organic base (DIPEA, TEA, etc.), using a solvent (DCM, DMF, EtOAc, MeCN, or a mixture thereof, etc.), typically at a temperature ranging from 0° C. to 120° C., using a suitable coupling reagent (HATU, HOBt / EDC, T3P, etc.).

[0374] Compounds of formula (5) can be formed by reacting compounds of formula (8) with a base (e.g., NaOH, LiOH, etc.) in an organic solvent (e.g., 1,4-dioxane, THF, MeOH, or mixtures thereof), optionally in the presence of water. The reaction can be carried out at a temperature interval from 0° C. to reflux. Alternatively, R 9 For compounds of formula (8) where ═H═ ...

[0375] [ka]

[0376] Scheme 5 shows a synthetic route to certain compounds of formula (I). Compounds of formula (9) can be converted to compounds of formula (I) by reaction with an alkylzinc reagent of formula (10), where R 6 is as defined in groups (b) and (c) of formula (I), and Y 1 is a monoalkyl or halide derivative of zinc (e.g., diethylzinc). The reaction can be catalyzed by a Pd catalyst (e.g., PdCl(dppf)·DCM) in a suitable solvent (e.g., 1,4-dioxane, THF, etc.) at temperatures typically ranging from 20 °C to reflux.

[0377] Alternatively, the compound of formula (9) may be R 6 is as defined in groups (b) and (c) of formula (I), and Y 1 The compound of formula (I) can be converted to a compound of formula (I) by reaction with an alkylboron reagent of formula (10), where ≡ is boron or a derivative thereof (e.g., trimethylboroxine). 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.

[0378] Alternatively, compounds of formula (9) can be converted to compounds of formula (I) by reaction with an alkyl halide of formula (10), wherein R 6 is as defined in groups (b) and (c) of formula (I), and Y 1is a halogen, typically an alkyl bromide. The reaction can be catalyzed with a Ni catalyst (e.g., NiCl2·DCM) and a suitable ligand (e.g., bbbpy), and a suitable photoredox catalyst (e.g., Ir[dF(CF3)ppy]2(dtbbpy)PF6), in the presence of HSi(SiMe3)3 and a base (e.g., Na2CO3), in a suitable solvent (e.g., DME), typically at 20 °C, while being illuminated with a blue light LED.

[0379] Alternatively, compounds of formula (9) can be converted to compounds of formula (I) by reaction with an alcohol of formula (10), wherein R 6 is as defined in groups (d) and (e) of formula (I), and Y 1 is hydrogen. The reaction can be catalyzed using a suitable Pd reagent (such as Pd(OAc)) with a suitable phosphine ligand (such as XPhos, t-BuXPhos) in a suitable solvent (such as toluene, 1,4-dioxane) in the presence of a base (such as KPO) at elevated temperatures.

[0380] Alternatively, compounds of formula (9) can be converted to compounds of formula (I) by reaction with an alcohol of formula (10), wherein R 6 is as defined in groups (d) and (e) of formula (I), and Y 1 is hydrogen. The reaction can be carried out in the presence of a base (e.g., K2CO3, Cs2CO3, etc.) and a radical initiator (e.g., AIBN, etc.) in a suitable solvent (e.g., DMF, etc.) and promoted with a suitable Cu reagent (e.g., CuBr, etc.) at elevated temperatures.

[0381] Alternatively, compounds of formula (9) can be converted to compounds of formula (I) by reaction with an alcohol of formula (10), wherein R 6 is as defined in groups (d) and (e) of formula (I), and Y 1is hydrogen. The reaction can be catalyzed using a Ni-catalyst (such as NiCl·DCM) and a suitable ligand (such as bbbpy) and a suitable photoredox catalyst (such as Ir[dF(CF)ppy](dtbbpy)PF) in the presence of quinuclidine and a base (such as KCO) in a suitable solvent (such as acetonitrile), typically at 20 °C, under illumination with a blue-light LED.

[0382] [ka]

[0383] Scheme 6 shows a synthetic route to a specific compound of formula (9). A compound of formula (11) can be reacted with a compound of formula (3) to give a compound of formula (9). The reaction can be carried out under the conditions described for the analogous reaction described in Scheme 1.

[0384] [ka]

[0385] Scheme 7 shows a synthetic route to a specific compound of formula (9). A compound of formula (12) can be reacted with a compound of formula (6) to give a compound of formula (9). The reaction can be carried out under the conditions described for the analogous reaction described in Scheme 3.

[0386] [ka]

[0387] Scheme 8 shows a synthetic route to a specific compound of formula (12). A compound of formula (11) can be reacted with a compound of formula (7) to give a compound of formula (13). A compound of formula (12) can be formed from a compound of formula (13). The reaction can be carried out under the conditions described for the analogous reaction described in Scheme 4.

[0388] [ka]

[0389] Scheme 9 shows a synthetic route to certain compounds of formula (I). Compounds of formula (14) can be converted to compounds of formula (I) by reaction with an alkylzinc reagent of formula (15), where R 7 is as defined in groups (b) and (c) of formula (I), and Y 1 is a monoalkyl or halide derivative of zinc (e.g., diethylzinc). The reaction can be catalyzed by a Pd catalyst (e.g., PdCl(dppf)·DCM) in a suitable solvent (e.g., 1,4-dioxane, THF, etc.) at temperatures typically ranging from 20 °C to reflux.

[0390] Alternatively, the compound of formula (14) may be R 7 is as defined in groups (b) and (c) of formula (I), and Y 1 The compound of formula (I) can be converted to a compound of formula (I) by reaction with an alkylboron reagent of formula (15), where ≡ is boron or a derivative thereof (e.g., trimethylboroxine). 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.

[0391] Alternatively, compounds of formula (14) can be converted to compounds of formula (I) by reaction with an alkyl halide of formula (15), wherein R 7 is as defined in groups (b) and (c) of formula (I), and Y 1 is a halogen, typically an alkyl bromide. The reaction can be catalyzed with a Ni catalyst (e.g., NiCl2·DCM) and a suitable ligand (e.g., bbbpy), and a suitable photoredox catalyst (e.g., Ir[dF(CF3)ppy]2(dtbbpy)PF6), in the presence of HSi(SiMe3)3 and a base (e.g., Na2CO3), in a suitable solvent (e.g., DME), typically at 20 °C, while being illuminated with a blue light LED.

[0392] Alternatively, compounds of formula (14) can be converted to compounds of formula (I) by reaction with an alcohol of formula (15), wherein R 7 is as defined in groups (d) and (e) of formula (I), and Y 1 is hydrogen. The reaction can be catalyzed using a suitable Pd reagent (such as Pd(OAc)) with a suitable phosphine ligand (such as XPhos, t-BuXPhos) in a suitable solvent (such as toluene, 1,4-dioxane) in the presence of a base (such as KPO) at elevated temperatures.

[0393] Alternatively, compounds of formula (14) can be converted to compounds of formula (I) by reaction with an alcohol of formula (15), wherein R 7 is as defined in groups (d) and (e) of formula (I), and Y 1 is hydrogen. This reaction can be carried out in the presence of a base (e.g., K2CO3, Cs2CO3, etc.) and a radical initiator (e.g., AIBN, etc.) in a suitable solvent (e.g., DMF, etc.) and is promoted with a suitable Cu reagent (e.g., CuBr, etc.) at elevated temperatures.

[0394] Alternatively, compounds of formula (14) can be converted to compounds of formula (I) by reaction with an alcohol of formula (15), wherein R 7 is as defined in groups (d) and (e) of formula (I), and Y 1 is hydrogen. The reaction can be catalyzed using a Ni catalyst (e.g., NiCl·DCM) and a suitable ligand (e.g., bbbpy) and a suitable photoredox catalyst (e.g., Ir[dF(CF)ppy](dtbbpy)PF) in the presence of quinuclidine and a base (e.g., KCO) in a suitable solvent (e.g., acetonitrile), typically at 20 °C, under illumination with a blue light LED.

[0395] [ka]

[0396] Scheme 10 shows a synthetic route to a specific compound of formula (14). Compounds of formula (14) can be formed from compounds of formula (16) and formula (3). The reaction can be carried out under conditions described for the analogous reaction described in Scheme 1.

[0397] [ka]

[0398] Scheme 11 shows a synthetic route to a specific compound of formula (14). Compounds of formula (14) can be formed from compounds of formula (17) and formula (6). The reaction can be carried out under the conditions described for the analogous reaction described in Scheme 3.

[0399] [ka]

[0400] Scheme 12 shows a synthetic route to a specific compound of formula (17). A compound of formula (16) can be reacted with a compound of formula (7) to give a compound of formula (18). A compound of formula (17) can be formed from a compound of formula (18). The reaction can be carried out under the conditions described for the analogous reaction described in Scheme 4.

[0401] [ka]

[0402] Scheme 13 shows a synthetic route to certain compounds of formula (8). Compounds of formula (13) can be converted to compounds of formula (8) by reaction with compounds of formula (10), where R 6 is as defined in groups (b), (c), (d) and (e) of formula (I), and Y 1 is as defined in Scheme 5. The reaction can be carried out under the conditions described for the analogous reaction described in Scheme 5.

[0403] [ka]

[0404] Scheme 14 shows a synthetic route to certain compounds of formula (4). Compounds of formula (19) can be converted to compounds of formula (4) by reaction with compounds of formula (10), where R 6 is as defined in groups (b), (c), (d) and (e) of formula (I), and Y 1 is as defined in Scheme 5. The reaction can be carried out under the conditions described for the analogous reaction described in Scheme 5.

[0405] [ka]

[0406] Scheme 15 shows a synthetic route to certain compounds of formula (8). Compounds of formula (18) can be converted to compounds of formula (8) by reaction with compounds of formula (15), where R 7 is as defined in groups (b), (c), (d) and (e) of formula (I), and Y 1 is as defined in Scheme 9. The reaction can be carried out under the conditions described for the analogous reaction described in Scheme 9.

[0407] [ka]

[0408] Scheme 16 shows a synthetic route to certain compounds of formula (4). Compounds of formula (20) can be converted to compounds of formula (4) by reaction with compounds of formula (15), where R 7 is as defined in groups (b), (c), (d) and (e) of formula (I), and Y 1is as defined in Scheme 9. The reaction can be carried out under the conditions described for the analogous reaction described in Scheme 9.

[0409] [ka]

[0410] Scheme 17 shows a synthetic route to certain compounds of formula (8). 10 The compound of formula (22) where R is hydrogen or alkyl is 10 is hydrogen or alkyl, and R 11 It can be formed from compounds of formula (21) 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 temperatures typically ranging from 0°C to 40°C.

[0411] R 6 Compounds of formula (8), wherein is as defined in group (b) of formula (I), can be formed by reacting compounds of formula (22) 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.

[0412] Alternatively, R 6 Compounds of formula (8), wherein is as defined in group (b) of formula (I), can be formed from compounds of formula (22) 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.

[0413] Alternatively, R 6 Compounds of formula (8), wherein R is as defined in group (b) of formula (I), can be formed from compounds of formula (22) by reaction with a Grignard reagent (e.g., CHMgCl, CHMgBr, 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.

[0414] Alternatively, R 6 Compounds of formula (8), wherein R is as defined in group (b) of formula (I), can be formed by reacting compounds of formula (21) 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.

[0415] Alternatively, R 6 Compounds of formula (8), wherein R is as defined in group (b) of formula (I), can be formed by reacting compounds of formula (21) with (trifluoromethyl)trimethylsilane. The reaction can be carried out in the presence of KF, AgOTf, Selectfluor, and 2-fluoropyridine in a suitable solvent (such as EtOAc) at temperatures typically ranging from 0° C. to 25° C.

[0416] Alternatively, R 6 Compounds of formula (8), wherein R is as defined in group (b) of formula (I), can be formed from compounds of formula (21) by reaction with an alkyl halide (such as MeI) or another alkylating agent (such as an alkyl sulfonate or alkyl triflate). The reaction can be carried out using a base (such as NaH) in a suitable solvent (such as THF or DMF) at temperatures typically ranging from 0° C. to 25° C.

[0417] [ka]

[0418] Scheme 18 shows a synthetic route to certain compounds of formula (21). 10 Compounds of formula (22), where R is alkyl (e.g., methyl), can be formed by reacting compounds of formula (13) with a trialkyl(1-alkoxyvinyl)tin reagent (e.g., tributyl(1-ethoxyvinyl)tin). The reaction can be catalyzed by a Pd reagent (e.g., PdCl(dppf)·DCM, Pd(PPh)), in a suitable solvent (e.g., toluene, 1,4-dioxane), typically at temperatures ranging from 80 °C to reflux.

[0419] Alternatively, R 10 Compounds of formula (22), where is hydrogen, can be formed by reacting compounds of formula (13) with formic acid and acetic anhydride. The reaction can be carried out using a Pd reagent (such as Pd(OAc)) with a suitable ligand (such as butyl-1-adamantylphosphine) in a suitable solvent (such as DMF) at a temperature typically ranging from 80° C. to 120° C., along with NaHCO and TEA.

[0420] R 10 and R 11 Compounds of formula (21), where is hydrogen, can be formed by reacting compounds of formula (13) 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)), etc.) in a suitable solvent (e.g., toluene, 1,4-dioxane, etc.) at temperatures typically ranging from 80 °C to reflux.

[0421] Alternatively, R 10 is alkyl, and R 11 Compounds of formula (21), where is hydrogen, can be formed from compounds of formula (22) 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.

[0422] Alternatively, R 10 and R 11 Compounds of formula (21), where is alkyl, can be formed from compounds of formula (22) by reaction with a Grignard reagent (such as CHMgCl or CHMgBr). The reaction can be carried out in a suitable solvent (such as diethyl ether or THF) at temperatures typically ranging from -78°C to 40°C.

[0423] [ka]

[0424] Scheme 19 shows a synthetic route to certain compounds of formula (4). 6 is as defined in group (b) of formula (I), the compound of formula (4) is 10 and R 11 can be formed from a compound of formula (23) or formula (24), wherein:

[0425] [ka]

[0426] Scheme 20 shows a synthetic route to certain compounds of formula (23). Compounds of formula (23) can be formed from compounds of formula (19) or formula (24), where R 10 and R 11 is as defined in Scheme 18. The reaction can be carried out under the conditions described for the analogous reaction described in Scheme 18.

[0427] [ka]

[0428] Scheme 21 shows a synthetic route to certain compounds of formula (8). 7 is as defined in group (b) of formula (I), the compound of formula (8) is 10 and R 11 can be formed from a compound of formula (25) or formula (26), wherein:

[0429] [ka]

[0430] Scheme 22 shows a synthetic route to certain compounds of formula (25). Compounds of formula (25) can be formed from compounds of formula (18) or formula (26), where R 10 and R 11 is as defined in Scheme 18. The reaction can be carried out under the conditions described for the analogous reaction described in Scheme 18.

[0431] [ka]

[0432] Scheme 23 shows a synthetic route to certain compounds of formula (4). 7 is as defined in group (b) of formula (I), the compound of formula (4) is 10 and R 11 can be formed from compounds of formula (27) or (28), where:

[0433] [ka]

[0434] Scheme 24 shows a synthetic route to certain compounds of formula (27). Compounds of formula (27) can be formed from compounds of formula (20) or formula (28), where R 10 and R 11 is as defined in Scheme 18. The reaction can be carried out under the conditions described for the analogous reaction described in Scheme 18.

[0435] [ka]

[0436] Scheme 25 shows a synthetic route to certain compounds of formula (8). Compounds of formula (29) can be prepared by reaction with an alkyl halide, alkyl sulfonate, or alkyl triflate, R6 can be converted to a compound of formula (8), wherein:

[0437] [ka]

[0438] Scheme 26 shows a synthetic route to certain compounds of formula (4). 6 Compounds of formula (4), wherein R is as defined in groups (d) and (e) of formula (I), can be formed from compounds of formula (30). The reaction can be carried out under conditions described for the analogous reaction described in Scheme 25.

[0439] [ka]

[0440] Scheme 27 shows a synthetic route to certain compounds of formula (8). 7 Compounds of formula (8), wherein R is as defined in groups (d) and (e) of formula (I), can be formed from compounds of formula (31). The reaction can be carried out under conditions described for the analogous reaction described in Scheme 25.

[0441] [ka]

[0442] Scheme 28 shows a synthetic route to certain compounds of formula (4). 7 Compounds of formula (4), wherein R is as defined in groups (d) and (e) of formula (I), can be formed from compounds of formula (32). The reaction can be carried out under conditions described for the analogous reaction described in Scheme 25.

[0443] [ka]

[0444] Scheme 29 shows a synthetic route to certain compounds of formula (4). 6 and R 7 Compounds of formula (35), wherein is as defined in formula (I), can be formed from either compounds of formula (33) or compounds of formula (34) using synthetic methods carried out under the conditions described for the analogous reactions described in Schemes 5, 9, 17 and 18.

[0445] Compounds of formula (4) can be formed by reacting compounds of formula (35) with carbon monoxide, typically at a pressure of 10 atmospheres, 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 (e.g., Pd(dppf)Cl2DCM, etc.) in the presence of a base (e.g., TEA, etc.), in the presence of a suitable alcohol (e.g., MeOH, EtOH, etc.), in a suitable solvent, or using the alcohol as the suitable solvent.

[0446] [ka]

[0447] Scheme 30 shows a synthetic route to certain compounds of formula (2). Compounds of formula (38) can be formed by reacting compounds of formula (36) with a 2-ketocarboxylic acid of formula (37), or a salt thereof (such as the sodium salt), in the presence of a base (such as NaOH) in water at reflux or at elevated temperatures, typically in the range of 100°C to 160°C, in a sealed vessel or in a sealed tube in a microwave reactor.

[0448] Compounds of formula (2) can be formed by heating compounds of formula (38), either neat or in a suitable solvent (such as water), at elevated temperatures, typically in the range of 150°C to 250°C, in a sealed vessel or in a sealed tube in a microwave oven.

[0449] It should be understood that: (ii) the organic reactions described in this disclosure are carried out in accordance with laboratory practice known to those skilled in the art; (iii) some of the reactions described in this disclosure may optionally be carried out in a different order than described herein; (iv) chiral isomers of the compounds of this disclosure may be resolved at any stage of the synthetic process using chiral resolving agents described in the literature and known to those skilled in the art, using chiral chromatography methods described in the literature and known to those skilled in the art, or as further described in the Examples; (iv) additional and / or other protecting groups may optionally be required in some of the above steps; and thus, (v) deprotection steps may optionally be carried out using methods described in the literature and known to those skilled in the art. Protection and deprotection of functional groups may be carried out using methods described in, for example, "Protective Groups in Organic Synthesis" 3 rd Ed., TW Greene and PG M Hutz, Wiley-Interscience (1999), which publication is incorporated herein by reference.

[0450] VIII. Working Examples The following descriptions of experiments, procedures, examples, and intermediates are intended to illustrate embodiments of the present disclosure and are not intended to be limiting in any way. Other compounds of the present disclosure can be prepared using the methods illustrated in these examples, either alone or in combination with techniques generally known in the art.

[0451] 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, organic solutions were dried over anhydrous MgSO4 or Na2SO4 or dried using an ISOLUTE® phase separator and work-up procedures were carried out using traditional phase separation techniques; (vi) evaporation was performed either in vacuo or by rotary evaporation on a Genevac HT-4 / EZ-2 or 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, 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 OBD column (5 μm, 150×30 mm ID) using a gradient of MeCN (0.05%) in HO / TFA as the mobile phase; Preparative method C: Compounds were purified by preparative HPLC on an XSelect CSH OBD column (5 μm, 150×30 mm ID) using a gradient of MeCN (0.1%) in HO / FA as the mobile phase; Preparative method D: Compounds were purified by preparative HPLC on a Waters™ BEH 2-EP column (5 μm, 250×30 mm ID) using MeOH / HO (NH3 20 mM) in CO2 as the mobile phase. Preparative Method E: Compounds were purified by preparative SFC on a Phenomenex Luna Hilic column (5 μm, 250×30 mm ID) using MeOH / H2O (NH3 20 mM) in CO2 as the mobile phase; Preparative Method F: Compounds were purified by preparative HPLC on an XBridge™ OBD C18 column (5 μm, 150×30 mm ID) using a gradient of MeCN (0.05%) in H2O / NH3 as the mobile phase; Preparative Method G: Compounds were purified by preparative HPLC on an Atlantis Prep T3 OBD column (10 μm, 250×19 mm ID) using a gradient of MeCN (0.05%) in H2O / TFA as the mobile phase; Preparative Method H: Compounds were purified by preparative SFC on an XBridge™ OBD column (10 μm, 250×19 mm ID) using a gradient of MeCN (0.1%) in H2O / TFA as the mobile phase. Purification was performed by preparative HPLC on a C18 column (5 μm, 250 × 19 mm ID); Preparative Method I: Compounds were purified by preparative HPLC on an XBridge™ OBD C18 column (5 μm, 150 × 30 mm ID) using a gradient of MeCN (0.1%) in HO / NH3 as the mobile phase; Preparative Method J: Compounds were purified by preparative HPLC on an XBridge™ OBD C18 column (5 μm, 150 × 30 mm ID) using a gradient of MeCN (0.1%) in HO / NH3 as the mobile phase.Preparative Method K: Compounds were purified by preparative HPLC on an XBridge™ OBD C18 column (5 μm, 250 × 19 mm ID) using a gradient of MeCN (0.1%, aq.) in a HO / NH4HCO3 (10 mM) / NH3 buffer system as the mobile phase; Preparative Method L: Compounds were purified by preparative HPLC on an XBridge™ C18 OBD column (5 μm, 150 × 30 mm ID) using a gradient of MeCN (10 mM) in HO / NH4HCO3 (10 mM) / NH3 buffer system as the mobile phase; Preparative Method M: Compounds were purified by preparative HPLC on an XBridge™ C18 OBD column (5 μm, 150 × 30 mm ID) using a gradient of MeCN (0.1%, aq.) in a HO / NH4HCO3 (10 mM) / NH3 buffer system as the mobile phase. Preparative Method N: Compounds were purified by preparative HPLC on an XBridge™ C18 OBD column (5 μm, 250 × 19 mm ID) using a gradient of MeCN (0.1%, aq.) in HO / NHHCO (10 mM) / NH buffer system as mobile phase; Preparative Method O: Compounds were purified by preparative SFC on a Waters™ Acquity UPC2 BEH 2-EP column, (3.5 μm, 100 × 3 mm ID) using MeOH / HO (NH 20 mM) in CO as mobile phase; Preparative Method P: Compounds were purified by preparative SFC on a Waters™ BEH column (5 μm, 250 × 30 mm ID) using MeOH / HO (NH 20 mM) in CO as mobile phase. Preparative method R: Compounds were purified by preparative SFC on a 0.1% ethanol solution in MeCN (0.1%) in HO / FA as the mobile phase.Preparative Method S: Compounds were purified by preparative HPLC on a Waters™ Sunfire™ C18 OBD column (5 μm, 150×30 mm ID) using a gradient of MeCN in HO (pH 10) as the mobile phase; Preparative Method T: Compounds were purified by preparative SFC on a CHIRAL ART amylose-SA (5 μm, 250×20 mm ID) using MeOH / HO 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) is confirmed by nuclear magnetic resonance (NMR) and / or mass spectrometry techniques; proton NMR chemical shift values are 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 spectrum 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 are used (and their derivatives, e.g., dd, doublet of doublets, etc.): s, singlet; d, doublet; t, triplet; q, quartet; m, multiplet; br, broad; qn, quintet; 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.

[0452] 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.

[0453] 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-".

[0454] In general, 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, where only some are indicated as "or."

[0455] 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.

[0456] 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 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) Where 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 N or argon. This process is generally repeated, typically three times. (xvii) In addition to the above, the following abbreviations are used:

[0457] [Table 1-1]

[0458] [Table 1-2]

[0459] [Table 2]

[0460] B. Intermediate compounds Intermediate 1: tert-butyl (2-((1S,3S,5S)-3-cyano-2-azabicyclo[3.1.0]hexan-2-yl)-2-oxoethyl)carbamate

[0461] [ka]

[0462] DIPEA (3.0 mL, 17 mmol) and HATU (2.28 g, 5.99 mmol) were added to a solution of (tert-butoxycarbonyl)glycine (1.0 g, 5.7 mmol) in DMF (17.2 mL) at 0 °C, and the reaction mixture was stirred at room temperature for 15 min. A solution of (1S,3S,5S)-2-azabicyclo[3.1.0]hexane-3-carbonitrile 4-methylbenzenesulfonate (WO2007029086) (1.6 g, 5.7 mmol) in DMF (11.5 mL) was added, and the reaction mixture was stirred at room temperature overnight. The reaction mixture was diluted with EtOAc, and the organic phase was washed sequentially with 1 M citric acid (aqueous solution, containing 0.5 mL of brine) and 1 M aqueous citric acid, and then washed three times with saturated aqueous NaHCO3. The organic phase was dried using a phase separator and evaporated in vacuo. The crude product was purified by normal phase flash chromatography on silica (gradient: 10 to 100% EtOAc in heptane). The compound-containing fractions were collected, concentrated in vacuo, and purified by normal phase flash chromatography on silica (gradient: 0 to 100% EtOAc in heptane) to give the title compound (1.24 g, 82%): 1 H NMR(400MHz,CD3OD)δ5.03(dd,1H),4.22-4.12(m,1H),3.99(d,1H),3.66(s,1H),2.71-2.54( m,1H),2.31(dd,1H),1.97-1.80(m,1H),1.46(s,9H),1.11-0.98(m,1H),0.98-0.82(m,1H)).

[0463] Intermediate 2: (1S,3S,5S)-2-glycyl-2-azabicyclo[3.1.0]hexane-3-carbonitrile 4-methylbenzenesulfonate

[0464] [ka]

[0465] tert-Butyl (2-((1S,3S,5S)-3-cyano-2-azabicyclo[3.1.0]hexan-2-yl)-2-oxoethyl)carbamate intermediate 1 (1.24 g, 4.67 mmol) was dissolved in MeCN (12 mL) and the reaction mixture was cooled on an ice bath. 4-Methylbenzenesulfonic acid hydrate (1.24 g, 6.54 mmol) was added and the reaction mixture was stirred at 0° C. for 15 minutes, then allowed to reach room temperature and stirred at room temperature for 29 hours. The reaction mixture was evaporated in vacuo and the residue was suspended twice in DCM and evaporated to give a brown-beige meringue. The residue was suspended in cold EtOAc while keeping the ice bath. The solid was allowed to settle and the EtOAc was removed using a Pasteur pipette. The solid was once again suspended in cold EtOAc, allowed to settle and the organic phase was removed. The solid was dried in vacuo to give the title compound (1.51 g) as a beige foam: MS (ESI) m / z [M+H] + 166.2.

[0466] Intermediate 3: (1S,3S,5S)-2-Glycyl-2-azabicyclo[3.1.0]hexane-3-carbonitrile hydrochloride

[0467] [ka]

[0468] 12M HCl (aqueous, 1.13 mL, 13.6 mmol) was added to a solution of tert-butyl (2-((1S,3S,5S)-3-cyano-2-azabicyclo[3.1.0]hexan-2-yl)-2-oxoethyl)carbamate Intermediate 1 (1.2 g, 4.5 mmol) in MeOH (10.2 mL), and the clear, colorless solution was stirred at room temperature for 20 hours. The reaction mixture was concentrated in vacuo to give the title compound (0.80 g, 88%) as a beige foam. 1 H NMR(500MHz,CD3OD)δ5.11(dd,1H),4.26-3.97(m,2H),3.65(td,1H),2.68( ddd,1H),2.35(dd,1H),1.97(dq,1H),1.12-1.04(m,1H),0.98-0.90(m,1H).

[0469] Intermediate 4: (1S,3S,5S)-2-glycyl-2-azabicyclo[3.1.0]hexane-3-carbonitrile

[0470] [ka]

[0471] tert-Butyl (2-((1S,3S,5S)-3-cyano-2-azabicyclo[3.1.0]hexan-2-yl)-2-oxoethyl)carbamate Intermediate 1 (3.0 g, 11 mmol) and TFA (0.87 mL, 11 mmol) were dissolved in DCM (300 mL), and the reaction mixture was stirred at 20 °C for 2 h. The reaction mixture was concentrated in vacuo, and the crude product was purified by reverse-phase flash chromatography on a C18 column (gradient: 0-50% MeCN in water) to give the title compound (1.50 g, 80%); MS (ESI) m / z [M+H] + 166; 1 H NMR (300MHz, CD3OD) δ5.12(dd,1H),4.21(d,1H),4.05(d,1H),3.65(td,1H),2.78-2.62(m,1H),2.38(dd,1H),1.99(dq,1H),1.18-0.89(m,2H).

[0472] Intermediate 5: tert-butyl (6-bromoquinoline-4-carbonyl)glycinate

[0473] [ka]

[0474] DIPEA (2.08 mL, 11.9 mmol) was added to a mixture of 6-bromoquinoline-4-carboxylic acid (1.0 g, 4.0 mmol), tert-butyl glycinate hydrochloride (0.80 g, 4.8 mmol), EDC (0.913 g, 4.76 mmol), and HOBt (0.729 g, 4.76 mmol) in DMF (10 mL) at 20 °C, and the reaction mixture was stirred at 20 °C for 16 h. The reaction mixture was quenched with saturated NaHCO (aq, 20 mL) and water (20 mL), and the suspension was filtered. The solid was washed with water and dried under vacuum to give the title compound (1.40 g, 97%); MS (ESI) m / z [M+H] + 365 / 367.

[0475] Intermediate 6: (6-Bromoquinoline-4-carbonyl)glycine

[0476] [ka]

[0477] TFA (1.0 mL, 13 mmol) was added to a solution of tert-butyl (6-bromoquinoline-4-carbonyl)glycinate intermediate 5 (0.25 g, 0.68 mmol) in DCM (1 mL) at 20 °C, and the reaction mixture was stirred at 20 °C for 4 h. The solvent was removed under reduced pressure. The residue was dissolved in water and basified with saturated aqueous NaHCO3 to pH = 5-6. The reaction mixture was filtered, and the solid was washed with water and dried under vacuum to give the title compound (0.130 g, 61%); MS (ESI) m / z [M+H] + 309 / 311.

[0478] Intermediate 7: tert-butyl (7-bromoquinoline-4-carbonyl)glycinate

[0479] [ka]

[0480] A solution of 7-bromoquinoline-4-carboxylic acid (4.50 g, 17.9 mmol), tert-butyl glycinate hydrochloride (4.49 g, 26.8 mmol), EDC (5.13 g, 26.8 mmol), HOBt (3.62 g, 26.8 mmol), and DIPEA (9.35 mL, 53.6 mmol) in THF (80 mL) was stirred at 30 °C for 15 h. The solvent was removed under reduced pressure, and the reaction mixture was diluted with EtOAc (80 mL). The organic phase was washed sequentially with saturated NaHCO (aqueous, 2 × 35 mL) and water (35 mL). The organic layer was dried over NaSO, filtered, and evaporated. The crude product was purified by normal-phase flash chromatography on silica (gradient: 5–55% EtOAc in petroleum ether) to give the title compound (6.0 g, 92%); MS (ESI) m / z [M+H] + 365.

[0481] Intermediate 8: (7-Bromoquinoline-4-carbonyl)glycine

[0482] [ka]

[0483] TFA (40.5 mL, 526 mmol) was added to a solution of tert-butyl (7-bromoquinoline-4-carbonyl)glycinate intermediate 7 (1.20 g, 3.29 mmol) in DCM (5 mL), and the reaction mixture was stirred at room temperature for 2 hours. The solvent was removed under reduced pressure to give the title compound (1.0 g, 98%); MS (ESI) m / z [M+H] + 311.

[0484] Intermediate 9: tert-butyl (6-(trifluoromethyl)quinoline-4-carbonyl)glycinate

[0485] [ka]

[0486] DIPEA (0.39 mL, 2.2 mmol) was added to a suspension of 6-(trifluoromethyl)quinoline-4-carboxylic acid (0.18 g, 0.75 mmol), tert-butyl glycinate hydrochloride (0.15 g, 0.90 mmol), EDC (0.215 g, 1.12 mmol), and HOBt (0.171 g, 1.12 mmol) in DMF (2 mL), and the reaction mixture was stirred at 20 °C for 4 h. The reaction mixture was quenched with saturated NaHCO (aq, 20 mL), and the reaction mixture was filtered. The solid was dried under vacuum to give the title compound (0.220 g, 83%); MS (ESI) m / z [M+H] + 335.

[0487] Intermediate 10: (6-(trifluoromethyl)quinoline-4-carbonyl)glycine

[0488] [ka]

[0489] TFA (0.478 mL, 6.21 mmol) was added to a solution of tert-butyl (6-(trifluoromethyl)quinoline-4-carbonyl)glycinate intermediate 9 (220 mg, 0.62 mmol) in DCM (1 mL) at 0° C., and the reaction mixture was stirred at 20° C. for 4 h. The solvent was removed under reduced pressure to give the crude title compound (120 mg); MS (ESI) m / z [M+H] + 299.

[0490] Intermediate 11: tert-butyl (6-(hydroxymethyl)quinoline-4-carbonyl)glycinate

[0491] [ka]

[0492] Tributylstannyl)methanol (0.527 g, 1.64 mmol) was added to a mixture of tert-butyl (6-bromoquinoline-4-carbonyl)glycinate intermediate 5 (0.50 g, 1.4 mmol) and Pd(PPh) (0.158 g, 0.14 mmol) in degassed 1,4-dioxane (5 mL) under an atmosphere of N at 20 °C, and the reaction mixture was stirred at 80 °C for 18 h. The reaction was quenched with water (20 mL), and the mixture was extracted with EtOAc (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 (0.350 g, 81%) as a pale yellow oil; MS (ESI) m / z [M+H] + 317.

[0493] Intermediate 12: tert-butyl (6-(fluoromethyl)quinoline-4-carbonyl)glycinate

[0494] [ka]

[0495] DAST (0.125 mL, 0.95 mmol) was added to a solution of tert-butyl (6-(hydroxymethyl)quinoline-4-carbonyl)glycinate intermediate 11 (0.15 g, 0.47 mmol) in DCM (3 mL), and the reaction mixture was stirred at 18° C. for 4 h. The solvent was removed under reduced pressure, and the residue was purified by preparative TLC (DCM:MeOH, 10:1) to give the title compound (0.077 g, 51%) as an orange gum; MS (ESI) m / z [M+H] + 319.

[0496] Intermediate 13: (6-(fluoromethyl)quinoline-4-carbonyl)glycine

[0497] [ka]

[0498] 4M HCl in 1,4-dioxane (1.20 mL, 4.84 mmol) was added dropwise to tert-butyl (6-(fluoromethyl)quinoline-4-carbonyl)glycinate intermediate 12 (77 mg, 0.24 mmol) at 20 °C under an atmosphere of N2 (g), and the reaction mixture was stirred at 20 °C for 20 h. The solvent was removed under reduced pressure, and the crude product was dissolved in MeOH (2 mL) and water (0.67 mL). LiOH (30 mg, 1.3 mmol) was added to the reaction mixture, which was stirred at 20 °C for 4 h. The solvent was removed under reduced pressure, the residue was dissolved in water (5 mL), and the mixture was acidified to pH 6-7 with 3M HCl (aq). The aqueous layer was washed with DCM and then concentrated in vacuo to give the crude title compound (103 mg); MS (ESI) m / z [M+H] + 263.

[0499] Intermediate 14: tert-butyl (6-acetylquinoline-4-carbonyl)glycinate

[0500] [ka]

[0501] Tributyl(1-ethoxyvinyl)stannane (0.593 g, 1.64 mmol) was added to a mixture of tert-butyl(6-bromoquinoline-4-carbonyl)glycinate intermediate 5 (0.50 g, 1.4 mmol) and Pd(dppf)Cl·DCM (0.112 g, 0.14 mmol) in degassed toluene (5 mL) under an atmosphere of N (g) at 20 °C, and the reaction mixture was stirred at 100 °C for 18 h. The reaction mixture was diluted with MeCN (5 mL). 6 M HCl (aq, 0.1 mL) was added, and the reaction mixture was stirred for 20 min. The reaction was quenched with water (15 mL) and extracted with EtOAc (3 × 15 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 (0.430 g, 96%) as an orange gum; MS (ESI) m / z [M+H] + 329.

[0502] Intermediate 15: tert-butyl (6-(2-hydroxypropan-2-yl)quinoline-4-carbonyl)glycinate

[0503] [ka]

[0504] CHMgCl in THF (3 M in THF, 0.51 mL, 1.5 mmol) was added to a solution of tert-butyl (6-acetylquinoline-4-carbonyl)glycinate intermediate 14 (0.20 g, 0.61 mmol) in THF (5 mL) under an atmosphere of N2 (g) at 0 °C, and the reaction mixture was stirred at 0 °C for 3 h. The reaction was quenched with saturated NH4Cl (aqueous, 20 mL) and extracted with DCM (3 × 20 mL). The combined organic layers were dried over Na2SO4, filtered, and evaporated under reduced pressure. The residue was purified by preparative TLC (DCM:MeOH, 10:1) to give the title compound (0.070 g, 33%) as an orange gum; MS (ESI) m / z [M+H] + 345.

[0505] Intermediate 16: tert-butyl (6-(2-fluoropropan-2-yl)quinoline-4-carbonyl)glycinate

[0506] [ka]

[0507] DAST (0.153 mL, 1.16 mmol) was added to a solution of tert-butyl (7-(2-hydroxypropan-2-yl)quinoline-4-carbonyl)glycinate intermediate 15 (100 mg, 0.29 mmol) in DCM (2 mL) at 19 °C, and the reaction mixture was stirred at 20 °C for 19 h. The solvent was removed under reduced pressure, and the residue was purified by preparative TLC (DCM:MeOH, 10:1) to give the title compound (30 mg, crude) as a pale yellow gum; MS (ESI) m / z [M+H] + 347.

[0508] Intermediate 17: (6-(2-fluoropropan-2-yl)quinoline-4-carbonyl)glycine

[0509] [ka]

[0510] TFA (0.267 mL, 3.46 mmol) was added to a solution of crude tert-butyl (6-(2-fluoropropan-2-yl)quinoline-4-carbonyl)glycinate intermediate 16 (30 mg) in DCM (0.5 mL) at 20° C., and the reaction mixture was stirred at 20° C. for 4 h. The solvent was removed under reduced pressure, and the residue was dried under vacuum to give the crude title compound (30 mg) as an orange gum; MS (ESI) m / z [M+H] + 291.

[0511] Intermediate 18: (6-(2-hydroxypropan-2-yl)quinoline-4-carbonyl)glycine

[0512] [ka]

[0513] TFA (0.215 mL, 2.79 mmol) was added to a solution of tert-butyl (7-(2-hydroxypropan-2-yl)quinoline-4-carbonyl)glycinate intermediate 15 (48 mg, 0.14 mmol) in DCM (0.5 mL) at 20° C., and the reaction mixture was stirred at 20° C. for 3 h. The solvent was removed under reduced pressure, and the residue was dried under vacuum to give the crude title compound (50 mg, 89%) as a pale orange gum; 1 H NMR (400MHz, CD3OD) δ9.12(d,1H),8.62(d,1H),8.31(dd,1H),8.19(d,1H),7.93(d,1H),4.26(s,2H),1.67(s,6H).

[0514] Intermediate 19: tert-butyl (6-(1-hydroxyethyl)quinoline-4-carbonyl)glycinate

[0515] [ka]

[0516] NaBH4 (42 mg, 1.1 mmol) was added to a solution of tert-butyl (6-acetylquinoline-4-carbonyl)glycinate intermediate 14 (120 mg, 0.37 mmol) in THF (1 mL), and the reaction mixture was stirred at 20 °C for 4 h. The reaction was quenched with water (10 mL) and extracted with EtOAc (3 × 10 mL). The combined organic layers were dried over Na2SO4, filtered, and concentrated in vacuo, and the residue was purified by preparative TLC (DCM:MeOH, 10:1) to give the title compound (90 mg, 74%); MS (ESI) m / z [M+H] + 331.

[0517] Intermediate 20: (6-(1-hydroxyethyl)quinoline-4-carbonyl)glycine

[0518] [ka]

[0519] TFA (0.117 mL, 1.51 mmol) was added to a solution of tert-butyl (6-(1-hydroxyethyl)quinoline-4-carbonyl)glycinate intermediate 19 (100 mg, 0.30 mmol) in DCM (1 mL), and the reaction mixture was stirred at 20° C. for 4 h. The solvent was removed under reduced pressure to give the crude title compound (100 mg); MS (ESI) m / z [M+H] + 289.1.

[0520] Intermediate 21: Methyl 6-acetylquinoline-4-carboxylate

[0521] [ka]

[0522] Tributyl(1-ethoxyvinyl)stannane (1.63 g, 4.51 mmol) was added in one portion to a suspension of methyl 6-bromoquinoline-4-carboxylate (0.80 g, 3.0 mmol) and Pd(dppf)Cl·DCM (0.22 g, 0.30 mmol) in toluene (10 mL) at 20 °C under a N2(g) atmosphere, and the reaction mixture was stirred at 100 °C for 4 h. The reaction mixture was diluted with 4 M HCl in 1,4-dioxane and stirred at 20 °C for 30 min. 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 (610 mg, 89%); MS (ESI) m / z [M+H] + 229.

[0523] Intermediate 22: Methyl 6-(1-hydroxyethyl)quinoline-4-carboxylate

[0524] [ka]

[0525] NaBH4 (27 mg, 0.65 mmol) was added to a solution of methyl 6-acetylquinoline-4-carboxylate intermediate 21 (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%); MS (ESI) m / z [M+H] + 232.

[0526] Intermediate 23: Methyl 6-(1-methoxyethyl)quinoline-4-carboxylate

[0527] [ka]

[0528] NaH (60% in oil, 42 mg, 1.0 mmol) was added to a solution of methyl 6-(1-hydroxyethyl)quinoline-4-carboxylate intermediate 22 (120 mg, 0.52 mmol) in DMF (3 mL) at 0° C., and the reaction mixture was stirred at 0° C. for 10 min. CHCl (110 mg, 0.78 mmol) was added to the reaction mixture, which was stirred at 0° C. for 1 h. The solvent was removed under reduced pressure, and the residue was purified by preparative TLC (EtOAc:petroleum ether, 1:1) to give the title compound (80 mg, 63%); MS (ESI) m / z [M+H] + 246.

[0529] Intermediate 24: 6-(1-methoxyethyl)quinoline-4-carboxylic acid

[0530] [ka]

[0531] LiOH (12 mg, 0.49 mmol) was added to a solution of methyl 6-(1-methoxyethyl)quinoline-4-carboxylate intermediate 23 (30 mg, 0.12 mmol) in MeOH (0.9 mL) and water (0.3 mL), and the reaction mixture was stirred at 20 °C for 3 h. The solvent was removed under reduced pressure, and the residue was acidified with 2 M HCl (aq) to pH 6-7. The aqueous phase was washed with DCM and concentrated in vacuo to give the crude title compound (30 mg); MS (ESI) m / z [M+H] + 232.

[0532] Intermediate 25: Methyl 6-(2-hydroxypropan-2-yl)quinoline-4-carboxylate

[0533] [ka]

[0534] CHCl (3 M in THF, 0.87 mL, 2.6 mmol) was added dropwise to a solution of methyl 6-acetylquinoline-4-carboxylate intermediate 21 (0.30 g, 1.3 mmol) in THF (3 mL) under an atmosphere of N2(g), and the reaction mixture was stirred at 0 °C for 3 h. The reaction was quenched with saturated NH4Cl (aqueous, 20 mL), and the mixture was extracted with DCM (3 × 20 mL). The combined organic layers were dried over Na2SO4, 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.

[0535] Intermediate 26: Methyl 6-(2-methoxypropan-2-yl)quinoline-4-carboxylate

[0536] [ka]

[0537] NaH (60% in oil, 24 mg, 0.61 mmol) was added to a solution of methyl 6-(2-hydroxypropan-2-yl)quinoline-4-carboxylate intermediate 25 (100 mg, 0.41 mmol) in DMF (1 mL), and the reaction mixture was stirred at 20 °C for 30 min. CHCl (0.051 mL, 0.82 mmol) was added to the reaction mixture, which was stirred at room temperature for 16 h. An additional batch was prepared as above using (70 mg, 0.29 mmol) of intermediate 25. The reaction mixtures from both batches were combined, and the reaction was quenched with water (10 mL) and extracted with EtOAc (3 × 10 mL). The combined organic layers were dried over NaSO, filtered, and evaporated. The residue was purified by preparative TLC (DCM:MeOH, 10:1) to give the title compound (70 mg, 48%) as a brown gum; MS (ESI) m / z [M+H] + 260.1.

[0538] Intermediate 27: 6-(2-methoxypropan-2-yl)quinoline-4-carboxylic acid

[0539] [ka]

[0540] LiOH (9 mg, 0.4 mmol) was added to a solution of methyl 6-(2-methoxypropan-2-yl)quinoline-4-carboxylate intermediate 26 (50 mg, 0.19 mmol) in MeOH (0.9 mL) and water (0.3 mL), and the reaction mixture was stirred at 20° C. for 4 h. The reaction mixture was acidified with 2 M HCl (aq) to pH 5-6, and the reaction mixture was concentrated to dryness to give the crude title compound (60 mg); MS (ESI) m / z [M+H] + 246.

[0541] Intermediate 28: Methyl 6-(hydroxymethyl)quinoline-4-carboxylate

[0542] [ka]

[0543] (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) under an atmosphere of N2 (g) at 20 °C, 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%); MS (ESI) m / z [M+H] + 218.

[0544] Intermediate 29: Methyl 6-((trifluoromethoxy)methyl)quinoline-4-carboxylate

[0545] [ka]

[0546] AgOTf (1.04 g, 4.05 mmol), Selectfluor (1.08 g, 3.04 mmol), and 2-fluoropyridine (393 mg, 4.05 mmol) were added to a solution of methyl 6-(hydroxymethyl)-quinoline-4-carboxylate intermediate 28 (440 mg, 2.03 mmol), (CH)SiCF (576 mg, 4.05 mmol), and KF (353 mg, 6.08 mmol) in EtOAc (9.4 mL) under an atmosphere of N(g) at 25 °C, and the reaction mixture was stirred at 25 °C for 12 h. The reaction mixture was concentrated in vacuo, and the residue was purified by preparative TLC (EtOAc:(petroleum ether, 1:2)) to give the title compound (240 mg, 42%); MS (ESI) m / z [M+H] + 285.

[0547] Intermediate 30: 6-((trifluoromethoxy)methyl)quinoline-4-carboxylic acid

[0548] [ka]

[0549] NaOH (194 mg, 4.84 mmol) was added to a solution of methyl 6-((trifluoromethoxy)methyl)-quinoline-4-carboxylate intermediate 29 (230 mg, 0.81 mmol) in MeOH (4 mL) and water (1 mL), and the reaction mixture was stirred at 25° C. for 2 h. The reaction mixture was concentrated in vacuo, and the residue was purified by preparative TLC (EtOAc:(petroleum ether, 1:1) to give the title compound (170 mg, 78%); MS (ESI) m / z [M+H] + 271.

[0550] Intermediate 31: Methyl 7-acetylquinoline-4-carboxylate

[0551] [ka]

[0552] Pd(PPh3)4 (1.18 g, 1.02 mmol) was added to a solution of methyl 7-bromoquinoline-4-carboxylic acid carboxylate (2.72 g, 10.2 mmol) and tributyl(1-ethoxyvinyl)stannane (4.81 g, 13.3 mmol) in 1,4-dioxane (50 mL) under an atmosphere of N2 (g), and the reaction mixture was stirred at 80 °C for 16 h. The reaction mixture was cooled and diluted with MeCN (20 mL). 2 M HCl (aq, 10 mL) was added, and the reaction mixture was stirred for 30 min. The reaction mixture was poured into water (50 mL), and the mixture was extracted with EtOAc (3 × 60 mL). The combined organic phases were dried over Na2SO4, filtered, and concentrated under reduced pressure. The crude product was purified by normal phase flash chromatography on silica (gradient: 0-50% EtOAc in petroleum ether) to give the title compound (2.1 g, 89%); MS (ESI) m / z [M+H] + 230.

[0553] Intermediate 32: Methyl 7-(2-hydroxypropan-2-yl)quinoline-4-carboxylate

[0554] [ka]

[0555] MeMgBr (3.2 M in THF, 1.64 mL, 5.23 mmol) was added dropwise to a solution of methyl 7-acetylquinoline-4-carboxylate intermediate 31 (300 mg, 1.31 mmol) in THF (5 mL), and the reaction mixture was stirred at 0° C. for 4 hours. The reaction was quenched with saturated NH4Cl (aqueous, 5 mL), and the mixture was extracted with EtOAc (3×20 mL). The combined organic layers were dried over Na2SO4, filtered, and evaporated under reduced pressure. The crude product was purified by preparative TLC (DCM:MeOH, 10:1) to give the title compound (120 mg, 37%); 1 H NMR (400MHz, CD3OD) δ8.97(d,1H),8.73(dd,1H),8.23(dd,1H),7.96(d,1H),7.89(dd,1H),4.06(s,3H),1.66(s,6H).

[0556] Intermediate 33: Methyl 7-(2-fluoropropan-2-yl)quinoline-4-carboxylate

[0557] [ka]

[0558] DAST (0.404 mL, 3.06 mmol) was added to a solution of methyl 7-(2-hydroxypropan-2-yl)quinoline-4-carboxylate intermediate 32 (150 mg, 0.61 mmol) in DCM (2 mL), and the reaction mixture was stirred at 20 °C for 16 h. The mixture was quenched with water (20 mL), and the mixture was extracted with EtOAc (2 × 50 mL). The combined organic layers were dried over Na SO , filtered, concentrated in vacuo, and the crude product was purified by preparative TLC (DCM:MeOH, 20:1) to give the title compound (60 mg, 40%); MS (ESI) m / z [M+H] + 248.

[0559] Intermediate 34: 7-(2-fluoropropan-2-yl)quinoline-4-carboxylic acid

[0560] [ka]

[0561] Methyl 7-(2-fluoropropan-2-yl)quinoline-4-carboxylate intermediate 33 (60 mg, 0.24 mmol) and NaOH (48 mg, 1.2 mmol) were dissolved in a mixture of MeOH (2 mL) and water (0.5 mL), and the reaction mixture was stirred at 35 °C for 3 h. The pH of the reaction mixture was adjusted to 5 with 2 M HCl (aq, 1 mL). The mixture was diluted with EtOAc (20 mL) and washed sequentially with saturated brine (2 × 10 mL). The organic layer was dried over Na SO , filtered, and evaporated in vacuo to give the crude title compound (30 mg); MS (ESI) m / z [M+H] + 234.

[0562] Intermediate 35: tert-butyl (7-(hydroxymethyl)quinoline-4-carbonyl)glycinate

[0563] [ka]

[0564] Pd(dppf)Cl·DCM (112 mg, 0.14 mmol) was added in one portion to a solution of tert-butyl (7-bromoquinoline-4-carbonyl)glycinate intermediate 7 (500 mg, 1.37 mmol) and (tributylstannyl)methanol (484 mg, 1.51 mmol) in 1,4-dioxane (5 mL) at 20 °C under an atmosphere of N (g), and the reaction mixture was stirred at 80 °C for 16 h. 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 (350 mg, 81%). 1 H NMR (400 MHz, CD3OD) δ 8.93 (d, 1H), 8.35 (d, 1H), 8.10 (s, 1H), 7.69 (dd, 1H), 7.61 (d, 1H), 4.12 (s, 2H), 3.36 (m, solvent overlap), 1.56 (s, 9H).

[0565] Intermediate 36: tert-butyl (7-(difluoromethyl)quinoline-4-carbonyl)glycinate

[0566] [ka]

[0567] Step a) tert-butyl (7-formylquinoline-4-carbonyl)glycinate

[0568] [ka]

[0569] Dess-Martin periodinane (1488 mg, 3.51 mmol) was added portionwise to a solution of tert-butyl (7-(hydroxymethyl)quinoline-4-carbonyl)glycinate intermediate 35 (370 mg, 1.17 mmol) in DCM (6 mL), and the reaction mixture was stirred at 35° C. for 5 h. The reaction mixture was diluted with EtOAc (100 mL) and washed with water (2×100 mL). The organic layer was dried over NaSO, filtered, evaporated in vacuo, and the residue was purified by preparative TLC (EtOAc:petroleum ether, 1:1) to give the subtitle compound of step a) (250 mg, crude).

[0570] Step b) tert-butyl (7-(difluoromethyl)quinoline-4-carbonyl)glycinate DAST (0.841 mL, 6.36 mmol) was added dropwise to a solution of tert-butyl (7-formylquinoline-4-carbonyl)glycinate intermediate step a) (250 mg, 0.80 mmol) in DCM (5 mL), and the reaction mixture was stirred at 0° C. for 16 h. The reaction mixture was diluted with EtOAc (20 mL) and washed with saturated brine (2×20 mL). The organic layer was dried over NaSO, filtered, evaporated in vacuo, and the crude product was purified by preparative TLC (EtOAc:petroleum ether, 1:1) to give the title compound (100 mg, 37%) as a yellow liquid; MS (ESI) m / z [M+H] + 337.

[0571] Intermediate 37: (7-(difluoromethyl)quinoline-4-carbonyl)glycine

[0572] [ka]

[0573] 4M HCl in 1,4-dioxane (0.037 mL, 1.5 mmol) was added dropwise to a solution of tert-butyl (7-(difluoromethyl)quinoline-4-carbonyl)glycinate intermediate 36 (100 mg, 0.30 mmol) in 1,4-dioxane (2 mL), and the reaction mixture was stirred at 35° C. for 2 hours. The reaction mixture was concentrated in vacuo to give the crude title compound (50 mg); MS (ESI) m / z [M+H] + 284.

[0574] Intermediate 38: tert-butyl (7-(trifluoromethyl)quinoline-4-carbonyl)glycinate

[0575] [ka]

[0576] DIPEA (0.369 mL, 2.11 mmol) was added to a solution of 7-(trifluoromethyl)-quinoline-4-carboxylic acid (0.17 g, 0.70 mmol), tert-butyl glycinate hydrochloride (0.142 g, 0.85 mmol), EDC (0.203 g, 1.06 mmol), and HOBt (0.162 g, 1.06 mmol) in DMF (2 mL), and the reaction mixture was stirred at 20 °C for 4 h. The reaction was quenched with saturated NaHCO (aq, 20 mL) and extracted with EtOAc (3 × 20 mL). The combined organic layers were dried over NaSO, filtered, and evaporated under reduced pressure. The residue was purified by preparative TLC (EtOAc:petroleum ether, 1:2) to give the title compound (0.150 g, 60%); MS (ESI) m / z [M+H] + 355.

[0577] Intermediate 39: (7-(trifluoromethyl)quinoline-4-carbonyl)glycine

[0578] [ka]

[0579] 4M HCl in 1,4-dioxane (1.06 mL, 4.23 mmol) was added to a solution of tert-butyl (7-(trifluoromethyl)quinoline-4-carbonyl)glycinate intermediate 38 (150 mg, 0.42 mmol) in DCM (1 mL) at 0° C., and the reaction mixture was stirred at 20° C. for 4 h. The solvent was removed under reduced pressure to give the crude title compound (0.180 g); MS (ESI) m / z [M+H] + 299.

[0580] Intermediate 40: tert-butyl (7-(fluoromethyl)quinoline-4-carbonyl)glycinate

[0581] [ka]

[0582] DAST (550 mg, 3.41 mmol) was added to a solution of tert-butyl (7-(hydroxymethyl)quinoline-4-carbonyl)glycinate intermediate 35 (540 mg, 1.71 mmol) in DCM (10 mL) at 0 °C, and the reaction mixture was stirred at 25 °C for 4 h. The reaction mixture was poured into saturated NaHCO (aq, 100 mL), and the mixture was extracted with DCM (3 × 50 mL). The combined organic layers were dried over NaSO, filtered, evaporated in vacuo, and the residue was purified by preparative TLC (EtOAc:petroleum ether, 1:1) to give the title compound (250 mg, 46%); MS (ESI) m / z [M+H] + 318.

[0583] Intermediate 41: (7-(fluoromethyl)quinoline-4-carbonyl)glycine

[0584] [ka]

[0585] 4M HCl in 1,4-dioxane (2.0 mL, 2.5 mmol) was added to a solution of tert-butyl (7-(fluoromethyl)quinoline-4-carbonyl)glycinate intermediate 40 (200 mg, 0.63 mmol) in 1,4-dioxane (2 mL), and the reaction mixture was stirred at 25° C. for 3 hours. The reaction mixture was concentrated in vacuo to give the crude title compound (105 mg); MS (ESI) m / z [M+H] + 262.

[0586] Intermediate 42: tert-butyl (7-acetylquinoline-4-carbonyl)glycinate

[0587] [ka]

[0588] tert-Butyl (7-bromoquinoline-4-carbonyl)glycinate intermediate 7 (800 mg, 2.19 mmol), tributyl(1-ethoxyvinyl)stannane (949 mg, 2.63 mmol), and Pd(dppf)Cl·DCM (160 mg, 0.22 mmol) were suspended in toluene (10 mL) under a N2(g) atmosphere, and the reaction mixture was stirred at 100 °C for 12 h. The reaction mixture was acidified to pH 6 with 2 M HCl (aq), and the mixture was concentrated under reduced pressure. The residue was purified by preparative TLC (EtOAc:petroleum ether, 2:1) to give the title compound (400 mg, 56%); MS (ESI) m / z [M+H] + 329.

[0589] Intermediate 43: tert-butyl (7-(1-hydroxyethyl)quinoline-4-carbonyl)glycinate

[0590] [ka]

[0591] NaBH4 (28 mg, 0.73 mmol) was added to a solution of tert-butyl (7-acetylquinoline-4-carbonyl)glycinate intermediate 42 (120 mg, 0.37 mmol) in THF (1 mL), and the reaction mixture was stirred at 20 °C for 2 h. The reaction mixture was diluted with EtOAc (10 mL) and washed successively with saturated aqueous NaHCO3, saturated aqueous NaCl, and water. The organic layer was dried over Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by preparative TLC (EtOAc:petroleum ether, 3:2) to give the title compound (98 mg, 81%); MS (ESI) m / z [M+H] + 331.

[0592] Intermediate 44: (7-(1-hydroxyethyl)quinoline-4-carbonyl)glycine

[0593] [ka]

[0594] TFA (0.069 mL, 0.89 mmol) was added to a solution of tert-butyl (7-(1-hydroxyethyl)quinoline-4-carbonyl)glycinate intermediate 43 (98 mg, 0.30 mmol) in DCM (1 mL), and the reaction mixture was stirred at 20° C. for 4 h. The solvent was removed under reduced pressure to give the crude title compound (100 mg); MS (ESI) m / z [M+H] + 275.

[0595] Intermediate 45: tert-butyl (7-(2-hydroxypropan-2-yl)quinoline-4-carbonyl)glycinate

[0596] [ka]

[0597] MeMgCl (3 M in THF, 0.25 mL, 0.76 mmol) was added to a solution of tert-butyl (6-acetylquinoline-4-carbonyl)glycinate intermediate 42 (100 mg, 0.30 mmol) in THF (1 mL) under an atmosphere of N2(g) at 0 °C, and the reaction mixture was stirred at 0 °C for 3 h. The reaction was quenched with saturated NH4Cl (aqueous, 10 mL), and the mixture was extracted with EtOAc (3 × 10 mL). The combined organic layers were dried over Na2SO4, filtered, and evaporated under reduced pressure. The residue was purified by preparative TLC (DCM:MeOH, 10:1) to give the title compound (6.0 mg, 57%) as an orange gum; MS (ESI) m / z [M+H] + 345.

[0598] Intermediate 46: (7-(2-hydroxypropan-2-yl)quinoline-4-carbonyl)glycine

[0599] [ka]

[0600] TFA (5.0 mL, 65 mmol) was slowly added to a solution of tert-butyl (7-(2-hydroxypropan-2-yl)quinoline-4-carbonyl)glycinate intermediate 45 (110 mg, 0.32 mmol) in DCM (1 mL), and the reaction mixture was stirred at 25° C. for 2 hours. The reaction mixture was concentrated under reduced pressure to give the crude title compound (75 mg); MS (ESI) m / z [M+H] + 289.

[0601] Intermediate 47: Methyl 7-(1-hydroxyethyl)quinoline-4-carboxylate

[0602] [ka]

[0603] NaBH4 (136 mg, 3.60 mmol) was added to a solution of methyl 7-acetylquinoline-4-carboxylate intermediate 31 (550 mg, 2.40 mmol) in MeOH (10 mL) at 0 °C, and the reaction mixture was stirred at room temperature for 2 h. The reaction mixture was diluted with water (50 mL) and extracted with EtOAc (3 × 50 mL). The organic layer was dried over Na2SO4, filtered, and evaporated under reduced pressure. The residue was purified by preparative TLC (DCM:MeOH, 10:1) to give the title compound (420 mg, 76%) as a yellow oil; MS (ESI) m / z [M+H] + 232.

[0604] Intermediate 48: Methyl 7-(1-methoxyethyl)quinoline-4-carboxylate

[0605] [ka]

[0606] NaH (60% in oil, 26 mg, 0.65 mmol) was added to a solution of methyl 7-(1-hydroxyethyl)quinoline-4-carboxylate intermediate 47 (100 mg, 0.43 mmol) in DMF (1.5 mL) under an atmosphere of N2(g) at 0 °C, and the reaction mixture was stirred at 20 °C for 30 min. The reaction mixture was cooled to 0 °C, CHI (0.054 mL, 0.86 mmol) was added, and the reaction mixture was allowed to warm slowly to room temperature and then stirred at room temperature for 2 h. The reaction was quenched with water (10 mL), and the mixture was extracted with EtOAc (3 × 10 mL). The combined organic layers were dried over Na2SO4, filtered, and evaporated under reduced pressure. The residue was purified by preparative TLC (DCM:MeOH, 10:1) to give the title compound (60 mg, 57%) as a pale yellow gum; MS (ESI) m / z [M+H] + 246.

[0607] Intermediate 49: 7-(1-methoxyethyl)quinoline-4-carboxylic acid

[0608] [ka]

[0609] LiOH (18 mg, 0.73 mmol) was added to a solution of methyl 7-(1-methoxyethyl)quinoline-4-carboxylate intermediate 48 (60 mg, 0.24 mmol) in MeOH (0.9 mL) and water (0.3 mL) under an atmosphere of N2(g), and the reaction mixture was stirred at 20 °C for 3 h. The solvent was removed under reduced pressure, and the residue was dissolved in water and acidified to pH 5-6 with 2 M HCl (aq). The mixture was washed with DCM, and the aqueous layer was concentrated under reduced pressure to give the crude title compound (60 mg); MS (ESI) m / z [M+H] + 232.

[0610] Intermediate 50: Methyl 7-(2-methoxypropan-2-yl)quinoline-4-carboxylate

[0611] [ka]

[0612] NaH (60% in oil, 42 mg, 1.06 mmol) was added portionwise to a solution of methyl 7-(2-hydroxypropan-2-yl)quinoline-4-carboxylate intermediate 32 (130 mg, 0.53 mmol) in DMF (4 mL) at 0° C., and the reaction mixture was stirred at 0° C. for 30 minutes. CHCl (226 mg, 1.59 mmol) was added, and the reaction mixture was stirred at 20° C. for 2 hours. The reaction mixture was diluted with EtOAc (20 mL) and washed with saturated NHCl (aq, 2×20 mL). The organic layer was dried over NaSO, filtered, and evaporated under reduced pressure to give the title compound (80 mg, 58%); 1 H NMR (400MHz, CD3OD) δ8.99(d,1H),8.77(dd,1H),8.12(d,1H),7.99(d,1H),7.85(dd,1H),4.06(s,3H),3.15(s,3H),1.66(s,6H).

[0613] Intermediate 51: 7-(2-methoxypropan-2-yl)quinoline-4-carboxylic acid

[0614] [ka]

[0615] Methyl 7-(2-methoxypropan-2-yl)quinoline-4-carboxylate intermediate 50 (100 mg, 0.39 mmol) and NaOH (77 mg, 1.9 mmol) were dissolved in MeOH (4 mL) and water (1 mL), and the reaction mixture was stirred at 20° C. for 1 h. The mixture was concentrated in vacuo to give the crude title compound (60 mg); MS (ESI) m / z [M+H] + 246.

[0616] Intermediate 52: Methyl 7-(hydroxymethyl)quinoline-4-carboxylate

[0617] [ka]

[0618] Methyl 7-bromoquinoline-4-carboxylate (600 mg, 2.25 mmol), (tributylstannyl)-methanol (1.08 g, 3.38 mmol), and Pd(PPh3)4 (261 mg, 0.23 mmol) were suspended in 1,4-dioxane (10 mL) at 20 °C, and the reaction mixture was stirred at 80 °C for 16 h. The reaction mixture was concentrated in vacuo, and the residue was purified by preparative TLC (EtOAc) to give the title compound (450 mg, 92%); MS (ESI) m / z [M+H] + 218.

[0619] Intermediate 53: Methyl 7-((trifluoromethoxy)methyl)quinoline-4-carboxylate

[0620] [ka]

[0621] AgOTf (710 mg, 2.76 mmol), Selectfluor (734 mg, 2.07 mmol), KF (241 mg, 4.14 mmol), and methyl 7-(hydroxymethyl)quinoline-4-carboxylate intermediate 52 (300 mg, 1.38 mmol) were dissolved in EtOAc (4 mL) under an atmosphere of N2 (g), and the reaction mixture was stirred at room temperature for 2 min. 2-Fluoropyridine (268 mg, 2.76 mmol) and (CH3)3SiCF3 (393 mg, 2.76 mmol) were added, and the reaction mixture was stirred at 20 °C for 12 h. The reaction mixture was filtered through Celite. The filtrate was concentrated in vacuo, and the residue was purified by preparative TLC (EtOAc:petroleum ether, 1:1) to give the title compound (200 mg, 51%); MS (ESI) m / z [M+H] + 286.

[0622] Intermediate 54: Methyl 7-(1-(trifluoromethoxy)ethyl)quinoline-4-carboxylate

[0623] [ka]

[0624] (CH)SiCF (1.48 g, 10.4 mmol) was added to a solution of methyl 7-(1-hydroxyethyl)quinoline-4-carboxylate intermediate 47 (800 mg, 3.46 mmol), Selectfluor (1.84 g, 5.19 mmol), AgOTf (2.67 g, 10.4 mmol), 2-fluoropyridine (0.892 mL, 10.4 mmol), 2,6-di-tert-butylphenol (357 mg, 1.73 mmol), and KF (804 mg, 13.8 mmol) in EtOAc (100 mL) at 20 °C under an atmosphere of N (g), and the reaction mixture was stirred at 20 °C for 96 h. The reaction mixture was filtered through Celite. The filtrate was washed with water (2 × 60 mL), and the organic layer was dried over NaSO and concentrated in vacuo. The residue was purified by preparative TLC (EtOAc:petroleum ether, 1:2) to give the title compound (152 mg, 15%); MS (ESI) m / z [M+H] + 300.

[0625] Intermediate 55: 7-(1-(trifluoromethoxy)ethyl)quinoline-4-carboxylic acid

[0626] [ka]

[0627] NaOH (40 mg, 1.0 mmol) was added to a solution of methyl 7-(1-(trifluoromethoxy)ethyl)quinoline-4-carboxylate intermediate 54 (150 mg, 0.50 mmol) in EtOH (20 mL), and the reaction mixture was stirred at 40° C. for 3 h. The solvent was removed in vacuo to give the crude title compound (150 mg); MS (ESI) m / z [M+H] + 286.

[0628] Intermediate 56: tert-butyl (7-(1-ethoxyvinyl)quinoline-4-carbonyl)glycinate

[0629] [ka]

[0630] Pd(dppf)Cl·DCM (112 mg, 0.14 mmol) was added in one portion to a solution of tert-butyl (7-bromoquinoline-4-carbonyl)glycinate intermediate 7 (500 mg, 1.37 mmol) and tributyl(1-ethoxyvinyl)stannane (593 mg, 1.64 mmol) in toluene (8 mL) at 19 °C and under an atmosphere of N (g), and the reaction mixture was stirred at 100 °C for 8 h. The reaction mixture was concentrated in vacuo, and the residue was diluted with EtOAc (100 mL). The organic layer was washed with saturated brine (2 × 100 mL), dried over NaSO, filtered, and concentrated under reduced pressure. The crude product was purified by preparative TLC (EtOAc:petroleum ether, 1:1) to give the title compound (350 mg, 72%). 1H NMR(400MHz,CD3OD)δ8.93(d,1H),8.38-8.28(m,2H),7.97(dd,1H),7.60(d,1H) ,5.01(d,1H),4.51(d,1H),4.12(s,2H),4.04(q,2H),1.56(s,9H),1.50(t,3H).

[0631] Intermediate 57: tert-butyl (7-(1-ethoxycyclopropyl)quinoline-4-carbonyl)glycinate

[0632] [ka]

[0633] A solution of CHI (451 mg, 1.68 mmol) in DCM (1 mL) was added to a solution of EtZn (15 wt% in hexane, 693 mg, 0.84 mmol) in DCM (4 mL) at −78 °C under an atmosphere of N (g), and the reaction mixture was stirred at −15 °C for 30 min. A solution of TFA (65 μL, 0.84 mmol) in DCM (1 mL) was added, and the reaction mixture was stirred at −15 °C for 30 min. A solution of tert-butyl (7-(1-ethoxyvinyl)quinoline-4-carbonyl)glycinate intermediate 56 (300 mg, 0.84 mmol) in DCM (0.5 mL) was added at −15 °C, and the reaction mixture was stirred at room temperature for 3 h. The reaction mixture was diluted with DCM (50 mL) and washed with saturated NHCl (4 × 20 mL). The organic layer was dried over Na2SO4, filtered and evaporated under reduced pressure to give the crude title product: (200 mg): MS (ESI) m / z [M+H] + 371.

[0634] Intermediate 58: (7-(1-ethoxycyclopropyl)quinoline-4-carbonyl)glycine

[0635] [ka]

[0636] 4M HCl in 1,4-dioxane (4.0 mL, 16 mmol) was added to tert-butyl (7-(1-ethoxycyclopropyl)quinoline-4-carbonyl)glycinate intermediate 57 (200 mg, 0.54 mmol), and the reaction mixture was stirred at 35° C. for 3 hours. The reaction mixture was concentrated in vacuo to give the crude title compound (100 mg); MS (ESI) m / z [M+H] + 315.

[0637] Intermediate 59: tert-butyl (6-(1-methylcyclopropyl)quinoline-4-carbonyl)glycinate

[0638] [ka]

[0639] Dtbbpy (0.022 g, 0.08 mmol) was added to a mixture of NiCl₂·DME (0.012 g, 0.05 mmol) in degassed DME (12 mL) at 20 °C under an atmosphere of N₂ (g), and the resulting mixture was stirred at 20 °C for 30 min. Tris(trimethylsilyl)silane (0.272 g, 1.10 mmol), tert-butyl(6-bromoquinoline-4-carbonyl)glycinate intermediate 5 (0.20 g, 0.55 mmol), 1-bromo-1-methylcyclopropane (0.148 g, 1.10 mmol), Na₂CO₃ (0.174 g, 1.64 mmol), and [Ir(dF(CF₃)ppy}₂(dtbbpy)]PF₆ (0.012 g, 11 μmol). was added, and the reaction mixture was stirred under an atmosphere of N2(g) at room temperature for 20 h under 34 W blue LED light irradiation. The reaction was quenched with water (20 mL), and the mixture was extracted with EtOAc (3 x 20 mL). The organic layer was dried over Na2SO4, filtered, and evaporated. The residue was purified twice by preparative TLC (DCM:MeOH, 10:1) to give the title compound (0.21 g) as a light orange gum: MS (ESI) m / z [M+H] + 341.

[0640] Intermediate 60: (6-(1-methylcyclopropyl)quinoline-4-carbonyl)glycine

[0641] [ka]

[0642] TFA (0.905 mL, 11.8 mmol) was added to a solution of tert-butyl (6-(1-methylcyclopropyl)quinoline-4-carbonyl)glycinate intermediate 59 (0.20 g, 0.59 mmol) in DCM (2 mL) at 20° C., and the reaction mixture was stirred at 20° C. for 3 h. The solvent was removed under reduced pressure, and the crude product was purified by preparative HPLC, Prep Method B, (gradient: 13-23%) to give the title compound (0.045 g, 27%): MS (ESI) m / z [M+H] + 285.

[0643] Intermediate 61: Methyl 6-formylquinoline-4-carboxylate

[0644] [ka]

[0645] Dess-Martin periodinane (4.64 g, 10.9 mmol) was added to a solution of methyl 6-(hydroxymethyl)quinoline-4-carboxylate intermediate 28 (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%): MS (ESI) m / z [M+H] + 215.

[0646] Intermediate 62: Methyl 6-(3-(trimethylsilyl)propanoyl)quinoline-4-carboxylate

[0647] [ka]

[0648] RhCl(PPh) (344 mg, 0.37 mmol) and benzoic acid (91 mg, 0.74 mmol) were added to a solution of methyl 6-formylquinoline-4-carboxylate intermediate 61 (800 mg, 3.72 mmol), 3-methylpyridin-2-amine (402 mg, 3.72 mmol), and trimethyl(vinyl)silane (3.73 mg, 37.2 mmol) in toluene (10 mL) under an atmosphere of N (g) at 25 °C, and the reaction mixture was heated at 150 °C for 2 h. The reaction mixture was concentrated in vacuo, and the residue was purified by preparative TLC (EtOAc:petroleum ether, 1:2) to give the title compound (700 mg, 60%): MS (ESI) m / z [M+H] + 315.

[0649] Intermediate 63: Methyl 6-(1,1,1-trifluoro-2-hydroxy-4-(trimethylsilyl)butan-2-yl)quinoline-4-carboxylate

[0650] [ka]

[0651] (CH)SiCF (0.793 g, 5.58 mmol) was added to a solution of methyl 6-(3-(trimethylsilyl)propanoyl)quinoline-4-carboxylate intermediate 62 (1.1 g, 3.5 mmol) and CsF (0.026 g, 0.17 mmol) in THF (15 mL), and the reaction mixture was stirred at 25 °C for 4 h. Water (0.377 g, 20.9 mmol) and TBAF (1 M in THF, 0.697 mL, 0.70 mmol) were added, and the reaction mixture was stirred at 25 °C for 12 h. The reaction mixture was poured into saturated brine (50 mL) and extracted with EtOAc (3 × 50 mL), and the combined organic layers were dried over NaSO, filtered, and evaporated under reduced pressure. The residue was purified by preparative TLC (EtOAc:petroleum ether, 1:2) to give the title compound (450 mg, 33%); MS (ESI) m / z [M+H] + 386.15.

[0652] Intermediate 64: Methyl 6-(1,1,1-trifluoro-2-((methylsulfonyl)oxy)-4-(trimethylsilyl)butan-2-yl)quinoline-4-carboxylate

[0653] [ka]

[0654] Methanesulfonyl chloride (61 mg, 0.53 mmol) was added to a solution of methyl 6-(1,1,1-trifluoro-2-hydroxy-4-(trimethylsilyl)butan-2-yl)quinoline-4-carboxylate intermediate 63 (170 mg, 0.44 mmol) and TEA (89 mg, 0.88 mmol) in DCM (5 mL) at 0° C., and the reaction mixture was stirred at 0° C. for 20 min and then at 25° C. for 2 h. The reaction mixture was concentrated in vacuo, and the residue was purified by preparative TLC (EtOAc:petroleum ether, 1:1) to give the title compound (90 mg, 44%): MS (ESI) m / z [M+H] + 463.

[0655] Intermediate 65: 6-(1-(trifluoromethyl)cyclopropyl)quinoline-4-carboxylic acid

[0656] [ka]

[0657] Step a) Methyl 6-(1-(trifluoromethyl)cyclopropyl)quinoline-4-carboxylate

[0658] [ka]

[0659] Pyridine (61 mg, 0.78 mmol) was added to a solution of methyl 6-(1,1,1-trifluoro-2-((methylsulfonyl)oxy)-4-(trimethylsilyl)butan-2-yl)quinoline-4-carboxylate intermediate 64 (180 mg, 0.39 mmol) in HFIP (2 mL), and the reaction mixture was stirred at 25° C. for 2 h. The reaction mixture was poured into 0.5 M citric acid (aq, 50 mL) and extracted with EtOAc (3×50 mL). The combined organic layers were dried over NaSO, filtered, and evaporated to give the title compound (100 mg, 87%) as a yellow oil; MS (ESI) m / z [M+H] + 296.1.

[0660] Step b) 6-(1-(trifluoromethyl)cyclopropyl)quinoline-4-carboxylic acid NaOH (12 mg, 0.30 mmol) was added to a solution of methyl 6-(1-(trifluoromethyl)cyclopropyl)quinoline-4-carboxylate step a) (90 mg, 0.30 mmol) in MeOH (3 mL) and water (0.75 mL) at 25° C., and the reaction mixture was heated at 40° C. for 2 h. The reaction mixture was poured into water (50 mL), the pH was adjusted to pH 3 with 2 M HCl (aq), and the mixture was extracted with EtOAc (3×50 mL). The combined organic layers were dried over NaSO, filtered, and evaporated to give the title compound (80 mg, 93%) as a yellow oil; MS (ESI) m / z [M+H] + 282.0.

[0661] Intermediate 66: Methyl 6-(1-ethoxyvinyl)quinoline-4-carboxylate

[0662] [ka]

[0663] A solution of methyl 6-bromoquinoline-4-carboxylate (400 mg, 1.50 mmol), tributyl(1-ethoxyvinyl)stannane (651 mg, 1.80 mmol), and Pd(dppf)2·DCM (123 mg, 0.15 mmol) in 1,4-dioxane (15 mL) was stirred at 80 °C for 15 h. The solvent was removed under reduced pressure, and the residue was dried under vacuum. The residue was purified by preparative TLC (EtOAc:pentane, 1:4) to give the title compound (300 mg, 78%): MS (ESI) m / z [M+H] + 258.

[0664] Intermediate 67: Methyl 6-(1-ethoxycyclopropyl)quinoline-4-carboxylate

[0665] [ka]

[0666] A solution of CHI (1.25 g, 4.66 mmol) in DCM (1 mL) was added to a solution of EtZn (15 wt% in hexanes, 288 mg, 2.33 mmol) in DCM (4 mL) at −78 °C under an atmosphere of N (g). After the addition was complete, the reaction mixture was stirred at −15 °C for 30 min. A solution of TFA (0.180 mL, 2.33 mmol) in DCM (1 mL) was added at −15 °C, and the reaction mixture was stirred at −15 °C for 30 min. Methyl 6-(1-ethoxyvinyl)-quinoline-4-carboxylate intermediate 66 (300 mg, 1.17 mmol) in DCM (0.5 mL) was added at −5 °C, and the reaction mixture was stirred at 20 °C for 3 h. The reaction mixture was poured into water (50 mL) and extracted with DCM (2 x 100 mL), and the combined organic layers were dried over Na2SO4, filtered, and evaporated in vacuo. The residue was purified by preparative TLC (EtOAc:petroleum ether, 1:2) to give the title compound (120 mg, 38%): MS (ESI) m / z [M+H] + 272.

[0667] Intermediate 68: 6-(1-ethoxycyclopropyl)quinoline-4-carboxylic acid

[0668] [ka]

[0669] Methyl 6-(1-ethoxycyclopropyl)quinoline-4-carboxylate intermediate 67 (120 mg, 0.44 mmol) and NaOH (88 mg, 2.21 mmol) were dissolved in MeOH (2 mL) and water (0.5 mL), and the reaction mixture was stirred at 35° C. for 2 h. The pH of the reaction mixture was adjusted to 6 with 0.1 M HCl (aq), and the mixture was concentrated in vacuo to give the crude title compound (100 mg): MS (ESI) m / z [M+H] + 258.

[0670] Intermediate 69: Methyl 6-(cyanomethyl)quinoline-4-carboxylate

[0671] [ka]

[0672] 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) at 20 °C under a N (g) atmosphere, 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, evaporated in vacuo, and the residue was purified by preparative TLC (EtOAc:petroleum ether, 1:2) to give the title compound (340 mg, 80%): MS (ESI) m / z [M+H] + 227.

[0673] Intermediate 70: Methyl 6-(1-cyanocyclopropyl)quinoline-4-carboxylate

[0674] [ka]

[0675] NaH (60% in mineral oil, 53 mg, 1.3 mmol) was added portionwise to a solution of methyl 6-(cyanomethyl)quinoline-4-carboxylate intermediate 69 (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%): MS (ESI) m / z [M+H] + 253.

[0676] Intermediate 71: 6-(1-cyanocyclopropyl)quinoline-4-carboxylic acid

[0677] [ka]

[0678] A solution of methyl 6-(1-cyanocyclopropyl)quinoline-4-carboxylate intermediate 70 (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 hours. 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). MS (ESI) m / z [M+H] + 239.

[0679] Intermediate 72: tert-butyl (7-(1-methylcyclopropyl)quinoline-4-carbonyl)glycinate

[0680] [ka]

[0681] Dtbbpy (0.022 g, 0.08 mmol) was added to a solution of NiCl₂·DME (0.012 g, 0.05 mmol) in degassed DME (12 mL) at 20 °C under a N₂ atmosphere, and the mixture was stirred at 20 °C for 30 min. Tris(trimethylsilyl)silane (0.272 g, 1.10 mmol), tert-butyl(7-bromoquinoline-4-carbonyl)glycinate intermediate 7 (0.20 g, 0.55 mmol), 1-bromo-1-methylcyclopropane (0.148 g, 1.10 mmol), Na₂CO₃ (0.174 g, 1.64 mmol), and [Ir(dF(CF₃)ppy}₂(dtbbpy)]PF₆ (0.012 g, 11 μmol) were added. The reaction mixture was stirred for 20 h at room temperature under an atmosphere of N2(g) and 34 W blue LED light. The reaction was quenched with water (20 mL) and extracted with DCM (3 x 20 mL). The organic layer was dried over Na2SO4, filtered, and evaporated under reduced pressure. The residue was purified by preparative TLC (EtOAc:petroleum ether, 1:1) to give the title compound (0.045 g, 24%) as a pale yellow gum: MS (ESI) m / z [M+H] + 341.

[0682] Intermediate 73: (7-(1-methylcyclopropyl)quinoline-4-carbonyl)glycine

[0683] [ka]

[0684] TFA (0.362 mL, 4.70 mmol) was added to tert-butyl (7-(1-methylcyclopropyl)-quinoline-4-carbonyl)glycinate Intermediate 72 (40 mg, 0.12 mmol) in DCM (0.5 mL) at 20° C., and the reaction mixture was stirred at 20° C. for 4 h. The solvent was removed under reduced pressure, and the residue was dried under vacuum to give the crude title compound (40 mg) as a pale orange gum; MS (ESI) m / z [M+H]+ 285.

[0685] Intermediate 74: Methyl 7-formylquinoline-4-carboxylate

[0686] [ka]

[0687] Dess-Martin periodinane (2.93 g, 6.91 mmol) was added portionwise to a solution of methyl 7-(hydroxymethyl)quinoline-4-carboxylate intermediate 52 (600 mg, 2.76 mmol) in DCM (10 mL) at 25° C., and the reaction mixture was stirred for 3 h at 25° C. The reaction mixture was concentrated in vacuo, and the residue was purified by preparative TLC (petroleum ether: EtOAc, 1:1) to give the title compound (510 mg, 86%); MS (ESI) m / z [M+H] + 215.

[0688] Intermediate 75: Methyl 7-(3-(trimethylsilyl)propanoyl)quinoline-4-carboxylate

[0689] [ka]

[0690] RhCl(PPh) (365 mg, 0.39 mmol) and trimethyl(vinyl)silane (3.96 g, 39.5 mmol) were added to a solution of benzoic acid (96 mg, 0.79 mmol), methyl 7-formylquinoline-4-carboxylate intermediate 74 (850 mg, 3.95 mmol), and 3-methylpyridin-2-amine (427 mg, 3.95 mmol) in toluene (10 mL) under an atmosphere of N (g) at 25 °C, and the reaction mixture was stirred at 150 °C for 2 h. The reaction mixture was concentrated in vacuo, and the residue was purified by preparative TLC (petroleum ether: EtOAc, 2:1) to give the title compound (700 mg, 56%): MS (ESI) m / z [M+H] + 315.

[0691] Intermediate 76: Methyl 7-(1,1,1-trifluoro-2-hydroxy-4-(trimethylsilyl)butan-2-yl)quinoline-4-carboxylate

[0692] [ka]

[0693] (CH)SiCF (176 mg, 1.24 mmol) and CsF (7 mg, 0.05 mmol) were added to a mixture of methyl 7-(3-(trimethylsilyl)propanoyl)quinoline-4-carboxylate intermediate 75 (300 mg, 0.95 mmol), TBAF (50 mg, 0.19 mmol), and water (103 mg, 5.71 mmol) in THF (10 mL) at 25 °C under a N (g) atmosphere. The reaction mixture was stirred at 25 °C for 12 h and then concentrated in vacuo. The residue was purified by preparative TLC (petroleum ether: EtOAc, 2:1) to give the title compound (110 mg, 29%): MS (ESI) m / z [M+H] + 386.2.

[0694] Intermediate 77: Methyl 7-(1,1,1-trifluoro-2-((methylsulfonyl)oxy)-4-(trimethylsilyl)butan-2-yl)quinoline-4-carboxylate

[0695] [ka]

[0696] Methanesulfonyl chloride (96 mg, 0.84 mmol) was added to a solution of methyl 7-(1,1,1-trifluoro-2-hydroxy-4-(trimethylsilyl)butan-2-yl)quinoline-4-carboxylate intermediate 76 (270 mg, 0.70 mmol) and TEA (142 mg, 1.40 mmol) in DCM (10 mL), and the reaction mixture was stirred at 25 °C for 2 h. The reaction mixture was poured into saturated NaHCO (aq, 50 mL) and extracted with DCM (3 × 50 mL). The combined organic layers were dried over NaSO, filtered, and evaporated under reduced pressure to give the title product (300 mg, 92%) as a yellow oil; MS (ESI) m / z [M+H] + 464.1.

[0697] Intermediate 78: Methyl 7-(1-(trifluoromethyl)cyclopropyl)quinoline-4-carboxylate

[0698] [ka]

[0699] Pyridine (63 mg, 0.80 mmol) was added to a solution of methyl 7-(1,1,1-trifluoro-2-((methylsulfonyl)oxy)-4-(trimethylsilyl)butan-2-yl)quinoline-4-carboxylate intermediate 77 (185 mg, 0.40 mmol) in HFIP (2 mL), and the reaction mixture was stirred at 25° C. for 2 h. The reaction mixture was poured into 0.5 M citric acid (aq, 50 mL) and extracted with EtOAc (3×50 mL). The combined organic layers were dried over NaSO, filtered, and evaporated under reduced pressure to give the title compound (170 mg) as a crude product; MS (ESI) m / z [M+H] + 296.1.

[0700] Intermediate 79: 7-(1-(trifluoromethyl)cyclopropyl)quinoline-4-carboxylic acid

[0701] [ka]

[0702] NaOH (22 mg, 0.56 mmol) was added to a solution of methyl 7-(1-(trifluoromethyl)-cyclopropyl)quinoline-4-carboxylate intermediate 78 (165 mg, 0.56 mmol) in MeOH (2 mL) and water (0.5 mL) at 25° C., and the reaction mixture was stirred at 40° C. for 2 h. The reaction mixture was poured into water (50 mL) and the pH was adjusted to 3 with 2 M HCl (aq). The mixture was extracted with EtOAc (3×50 mL), and the combined organic layers were dried over NaSO, filtered, and evaporated under reduced pressure to give the title compound (150 mg, 95%); MS (ESI) m / z [M+H] + 282.0.

[0703] Intermediate 80: Methyl 7-(1-cyanocyclopropyl)quinoline-4-carboxylate

[0704] [ka]

[0705] A solution of methyl 7-bromoquinoline-4-carboxylate (500 mg, 1.88 mmol), bis(pinacolato)diboron (716 mg, 2.82 mmol), Pd(dppf)Cl·DCM (153 mg, 0.19 mmol), and potassium acetate (369 mg, 3.76 mmol) in 1,4-dioxane (8 mL) was stirred at 80 °C for 2 h under a N2(g) atmosphere. 1-Bromocyclopropane-1-carbonitrile (549 mg, 3.76 mmol), K2CO3 (519 mg, 3.76 mmol), and water (2 mL) were added, and the reaction mixture was stirred overnight at 80 °C under a N2(g) atmosphere. The solids were filtered off, and the filtrate was concentrated in vacuo. The residue was purified by preparative TLC (petroleum ether: EtOAc, 3:2) to give the title compound (240 mg, 51%): MS (ESI) m / z [M+H] + 253.

[0706] Intermediate 81: 7-(1-cyanocyclopropyl)quinoline-4-carboxylic acid

[0707] [ka]

[0708] A solution of methyl 7-(1-cyanocyclopropyl)quinoline-4-carboxylate intermediate 80 (300 mg, 1.19 mmol) and LiOH (85 mg, 3.6 mmol) in THF (8 mL) and water (2 mL) was stirred at room temperature for 2 h. The reaction mixture was concentrated under reduced pressure, and the residue was diluted with water. The pH of the mixture was adjusted to 6 with 2 M HCl (aq). The precipitate was collected by filtration and washed with water to give the crude title compound (200 mg): MS (ESI) m / z [M+H] + 239.

[0709] C. Final compound Example 1: 6-Bromo-N-(2-((1S,3S,5S)-3-cyano-2-azabicyclo[3.1.0]hexan-2-yl)-2-oxoethyl)quinoline-4-carboxamide

[0710] [ka]

[0711] DIPEA (0.12 mL, 0.68 mmol) was added to a solution of (1S,3S,5S)-2-azabicyclo[3.1.0]hexane-3-carbonitrile 4-methylbenzenesulfonate WO2007029086 (95 mg, 0.34 mmol), Intermediate 6 (6-bromoquinoline-4-carbonyl)glycine (70 mg, 0.23 mmol), EDC (65 mg, 0.34 mmol), and HOBt (52 mg, 0.34 mmol) in DMF (1 mL) at 20 °C, and the reaction mixture was stirred at 20 °C for 18 h. The reaction was quenched with saturated NaHCO (aq, 10 mL) and extracted with EtOAc (3 × 15 mL). The combined organic layers were dried over NaSO, filtered, and evaporated. The crude product was purified by preparative HPLC, Prep Method C (gradient: 28-38%) to give the title compound (38 mg, 42%); HRMS (ESI) m / z [M+H] + C 18 H 16 Calculated for BrN4O2: 399.0452, Found: 399.0454; 1 H NMR(400MHz,DMSO-d6)δ9.20(t,1H),9.04(d,1H),8.60(d,1H),8.05(d,1H),7.96(dd,1H),7.65(d,1H),5.18(dd,1H),4.58(d d,1H),4.23(dd,1H),3.87(td,1H),2.65-2.53(m,1H),2.25(dd,1H),1.96-1.85(m,1H),1.07-0.94(m,1H),0.84-0.76(m,1H).

[0712] Example 2: 7-chloro-N-(2-((1S,3S,5S)-3-cyano-2-azabicyclo[3.1.0]hexan-2-yl)-2-oxoethyl)quinoline-4-carboxamide

[0713] [ka]

[0714] HATU (0.063 g, 0.17 mmol) and DIPEA (0.105 mL, 0.60 mmol) were added to a suspension of 7-chloroquinoline-4-carboxylic acid (0.033 g, 0.16 mmol) and (1S,3S,5S)-2-glycyl-2-azabicyclo[3.1.0]hexane-3-carbonitrile hydrochloride intermediate 3 (0.030 g, 0.15 mmol) in a mixture of DCM (1 mL) and MeCN (0.2 mL), and the reaction mixture was stirred at room temperature overnight. The mixture was diluted with DCM and washed with saturated aqueous NaHCO3. The aqueous phase was extracted twice with EtOAc, and the combined organic phases were dried using a phase separator and evaporated in vacuo. The crude product was purified by preparative SFC, Prep Method D (gradient: 15-20%) to give the title compound (20 mg, 38%); HRMS (ESI) m / z [M+H] + C 18 H 16 Calculated for ClN4O2: 355.0956, Found: 355.0934; 1 H NMR(600MHz,DMSO-d6)δ9.19(t,1H),9.05(d,1H),8.41(d,1H),8.17(d,1H),7.76(dd,1H),7.63(d,1H),5.17(dd,1H),4.57(d d,1H),4.23(dd,1H),3.87(td,1H),2.64-2.55(m,1H),2.26(dd,1H),1.94-1.87(m,1H),1.05-0.99(m,1H),0.83-0.77(m,1H).

[0715] Example 3: 7-Bromo-N-(2-((1S,3S,5S)-3-cyano-2-azabicyclo[3.1.0]hexan-2-yl)-2-oxoethyl)quinoline-4-carboxamide

[0716] [ka]

[0717] DIPEA (0.17 mL, 0.97 mmol) was added to a solution of (1S,3S,5S)-2-azabicyclo[3.1.0]hexane-3-carbonitrile 4-methylbenzenesulfonate WO2007029086 (136 mg, 0.49 mmol), (7-bromoquinoline-4-carbonyl)glycine intermediate 8 (100 mg, 0.32 mmol), EDC (93 mg, 0.49 mmol), and HOBt (74 mg, 0.49 mmol) in DMF (1 mL) at 20 °C, and the reaction mixture was stirred at 20 °C for 18 h. The reaction was quenched with saturated NaHCO (aq, 10 mL) and extracted with EtOAc (3 × 15 mL). The organic layer was dried over NaSO, filtered, and evaporated. The crude product was purified by preparative HPLC, Prep Method C (gradient: 25-36%) to give the title compound (74 mg, 57%); HRMS (ESI) m / z [M+H] + C 18 H 16 Calculated for BrN4O2: 399.0452, Found: 399.0454; 1 H NMR(400MHz,DMSO-d6)δ9.18(t,1H),9.03(d,1H),8.35-8.28(m,2H),7.86(dd,1H),7.64(d,1H),5.16(dd,1H),4.57(dd,1 H),4.23(dd,1H),3.87(td,1H),2.66-2.54(m,1H),2.25(dd,1H),1.96-1.85(m,1H),1.06-0.96(m,1H),0.84-0.76(m,1H).

[0718] Example 4: N-(2-((1S,3S,5S)-3-cyano-2-azabicyclo[3.1.0]hexan-2-yl)-2-oxoethyl)-6-fluoro-2-methylquinoline-4-carboxamide

[0719] [ka]

[0720] HATU (59 mg, 0.15 mmol) was added to a suspension of 6-fluoro-2-methylquinoline-4-carboxylic acid (29 mg, 0.14 mmol) in DCM (1 mL), and the reaction mixture was stirred at room temperature for 15 min. (1S,3S,5S)-2-glycyl-2-azabicyclo[3.1.0]hexane-3-carbonitrile hydrochloride intermediate 3 (28 mg, 0.14 mmol) and DIPEA (0.073 mL, 0.42 mmol), followed by MeCN (0.2 mL), were added, and the reaction mixture was stirred at room temperature overnight. The mixture was diluted with DCM and washed with saturated aqueous NaHCO3. The organic phase was dried using a phase separator and evaporated in vacuo. The crude product was purified by preparative SFC, preparative method D (gradient: 12-17%) to give the title compound (25 mg, 51%); HRMS (ESI) m / z [M+H] + C 19 H 18 Calculated value for FN4O2: 353.1408, Measured value: 353.1402; 1 H NMR(600MHz,DMSO-d6)δ9.12(t,1H),8.09(dd,1H),8.05(dd,1H),7.69(ddd,1H),7.55(s,1H),5.17(dd,1H),4.54(dd,1H),4.21 (dd,1H),3.86(td,1H),2.69(s,3H),2.63-2.55(m,1H),2.25(dd,1H),1.94-1.86(m,1H),1.06-0.93(m,1H),0.82-0.75(m,1H).

[0721] Example 5: 6-chloro-N-(2-((1S,3S,5S)-3-cyano-2-azabicyclo[3.1.0]hexan-2-yl)-2-oxoethyl)-2-methylquinoline-4-carboxamide

[0722] [ka]

[0723] HATU (59 mg, 0.15 mmol) was added to a suspension of 6-chloro-2-methylquinoline-4-carboxylic acid (31 mg, 0.14 mmol) in DCM (1 mL), and the reaction mixture was stirred at room temperature for 15 min. (1S,3S,5S)-2-glycyl-2-azabicyclo[3.1.0]hexane-3-carbonitrile hydrochloride intermediate 3 (28 mg, 0.14 mmol) and DIPEA (0.073 mL, 0.42 mmol), followed by DCM (0.5 mL) and MeCN (0.2 mL) were added, and the reaction mixture was stirred at room temperature overnight. The reaction mixture was diluted with DCM and washed with saturated aqueous NaHCO3. The organic phase was dried using a phase separator and evaporated in vacuo. The crude product was purified by preparative SFC, preparative method D (gradient: 15-20%) to give the title compound (29 mg, 57%); HRMS (ESI) m / z [M+H] + C 19 H 18 Calculated for ClN4O2: 369.1112, Found: 369.1118; 1 H NMR(600MHz,DMSO-d6)δ9.16(t,1H),8.37(d,1H),8.00(d,1H),7.79(dd,1H),7.56(s,1H),5.17(dd,1H),4.55(dd,1H),4.22( dd,1H),3.86(td,1H),2.70(s,3H),2.63-2.56(m,1H),2.24(dd,1H),1.94-1.87(m,1H),1.06-0.91(m,1H),0.85-0.75(m,1H).

[0724] Example 6: 6-BromoN-(2-((1S,3S,5S)-3-cyano-2-azabicyclo[3.1.0]hexan-2-yl)-2-oxoethyl)-2-methylquinoline-4-carboxamide

[0725] [ka]

[0726] HATU (59 mg, 0.15 mmol) and DIPEA (0.073 mL, 0.42 mmol) were added to a suspension of 6-bromo-2-methylquinoline-4-carboxylic acid (37 mg, 0.14 mmol) in DCM (1 mL), and the reaction mixture was stirred at room temperature for 15 min. A solution of (1S,3S,5S)-2-glycyl-2-azabicyclo[3.1.0]hexane-3-carbonitrile hydrochloride intermediate 3 (28 mg, 0.14 mmol) in DCM (1 mL) was added, followed by MeCN (0.2 mL), and the reaction mixture was stirred at room temperature for 2 h. The reaction mixture was diluted with DCM and washed with saturated aqueous NaHCO3. The organic phase was dried using a phase separator and evaporated in vacuo. The crude product was purified by preparative SFC, Prep Method E (gradient: 15-20%) to give the title compound (15 mg, 26%); HRMS (ESI) m / z [M+H] + C 19 H 18 Calculated for BrN4O2: 413.0608, Found: 413.0630; 1 H NMR(600MHz,DMSO-d6)δ9.16(t,1H),8.51(d,1H),8.02-7.83(m,2H),7.55(s,1H),5.17(dd,1H),4.55(dd,1H),4.22(dd ,1H),3.86(td,1H),2.69(s,3H),2.62-2.55(m,1H),2.24(dd,1H),1.94-1.86(m,1H),1.05-0.99(m,1H),0.79(ddd,1H).

[0727] Example 7: N-(2-((1S,3S,5S)-3-cyano-2-azabicyclo[3.1.0]hexan-2-yl)-2-oxoethyl)-6-iodo-2-methylquinoline-4-carboxamide

[0728] [ka]

[0729] HATU (59 mg, 0.15 mmol) was added to a suspension of 6-iodo-2-methylquinoline-4-carboxylic acid (44 mg, 0.14 mmol) in DCM (1 mL), and the reaction mixture was stirred at room temperature for 15 minutes. (1S,3S,5S)-2-Glycyl-2-azabicyclo[3.1.0]hexane-3-carbonitrile hydrochloride intermediate 3 (28 mg, 0.14 mmol) and DIPEA (0.073 mL, 0.42 mmol) were added to the reaction mixture, followed by DCM (0.5 mL) and MeCN (0.2 mL). The reaction mixture was stirred at room temperature overnight. The reaction mixture was diluted with DCM and washed with saturated aqueous NaHCO3. The organic phase was dried using a phase separator and evaporated in vacuo. The crude product was purified by preparative SFC, preparative method D (gradient: 15-20%) to give the title compound (33 mg, 52%); HRMS (ESI) m / z [M+H] + C 19 H 18 Calculated value for IN4O2: 461.0468, Measured value: 461.0460; 1 H NMR(600MHz,DMSO-d6)δ9.14(t,1H),8.67(d,1H),8.02(dd,1H),7.76(d,1H),7.52(s,1H),5.16(dd,1H),4.55(dd,1H),4.21( dd,1H),3.85(td,1H),2.68(s,3H),2.63-2.56(m,1H),2.24(dd,1H),1.94-1.86(m,1H),1.06-0.93(m,1H),0.85-0.73(m,1H).

[0730] Example 8: N-(2-((1S,3S,5S)-3-cyano-2-azabicyclo[3.1.0]hexan-2-yl)-2-oxoethyl)-7-fluoro-2-methylquinoline-4-carboxamide

[0731] [ka]

[0732] HATU (59 mg, 0.15 mmol) was added to a suspension of 7-fluoro-2-methylquinoline-4-carboxylic acid (29 mg, 0.14 mmol) in DCM (1 mL), and the reaction mixture was stirred at room temperature for 15 min. (1S,3S,5S)-2-glycyl-2-azabicyclo[3.1.0]hexane-3-carbonitrile hydrochloride intermediate 3 (28 mg, 0.14 mmol) and DIPEA (0.073 mL, 0.42 mmol), followed by DCM (0.5 mL) and MeCN (0.2 mL) were added, and the reaction mixture was stirred at room temperature overnight. The reaction mixture was diluted with DCM, washed with saturated aqueous NaHCO3, and the organic phase was dried using a phase separator and evaporated in vacuo. The crude product was purified by preparative SFC, preparative method D (gradient: 12-17%) to give the title compound (29 mg, 58%); HRMS (ESI) m / z [M+H] + C 19 H 18 Calculated value for FN4O2: 353.1408, Measured value: 353.1406; 1 H NMR(600MHz,DMSO-d6)δ9.12(t,1H),8.38(dd,1H),7.72(dd,1H),7.55(td,1H),7.48(s,1H),5.15(dd,1H),4.54(dd,1H),4.21 (dd,1H),3.86(td,1H),2.70(s,3H),2.62-2.55(m,1H),2.25(dd,1H),1.94-1.86(m,1H),1.07-0.89(m,1H),0.84-0.66(m,1H).

[0733] Example 9: N-(2-((1S,3S,5S)-3-cyano-2-azabicyclo[3.1.0]hexan-2-yl)-2-oxoethyl)-6-methylquinoline-4-carboxamide

[0734] [ka]

[0735] Pd(dppf)₂·DCM (12 mg, 0.02 mmol) was added to a suspension of 6-bromo-N-(2-((1S,3S,5S)-3-cyano-2-azabicyclo[3.1.0]hexan-2-yl)-2-oxoethyl)quinoline-4-carboxamide Example 1 (120 mg, 0.30 mmol), TMB (113 mg, 0.90 mmol), and K₂CO₃ (125 mg, 0.90 mmol) in 1,4-dioxane (2 mL), and the reaction mixture was stirred at 80 °C for 4 h. The reaction mixture was diluted with EtOAc (10 mL), and the mixture was washed sequentially with saturated aqueous NaHCO₃, saturated aqueous NaCl, and HO. The organic layer was dried over Na₂SO₄, filtered, and concentrated in vacuo, and the residue was purified by preparative TLC (MeOH:DCM, 1:10). The crude product was purified by preparative HPLC, Prep Method F (gradient: 15-40%) to give the title compound (50 mg, 50%); HRMS (ESI) m / z [M+H] + C 19 H 19 Calculated value for N4O2: 335.1502, Measured value: 335.1506; 1 H NMR(400MHz,CD3OD)δ8.87(d,1H),8.22-8.15(m,1H),8.00(d,1H),7.69(dd,1H),7.64(d,1H),5.12(dd,1H),4.64(d,1H),4.42 (d,1H),3.82(td,1H),2.76-2.65(m,1H),2.57(s,3H),2.38(dd,1H),2.03-1.91(m,1H),1.15-1.07(m,1H),1.05-0.95(m,1H).

[0736] Example 10: N-(2-((1S,3S,5S)-3-cyano-2-azabicyclo[3.1.0]hexan-2-yl)-2-oxoethyl)-6-(trifluoromethyl)quinoline-4-carboxamide

[0737] [ka]

[0738] EDC (85 mg, 0.44 mmol) and DIPEA (0.14 mL, 0.80 mmol) were added to a solution of HOBt (68 mg, 0.44 mmol), (1S,3S,5S)-2-azabicyclo[3.1.0]hexane-3-carbonitrile 4-methylbenzenesulfonate WO2007029086 (124 mg, 0.44 mmol), and (6-(trifluoromethyl)-quinoline-4-carbonyl)glycine intermediate 10 (120 mg, 0.40 mmol) in DMF (2 mL) at 0 °C. The reaction mixture was stirred at 20 °C for 4 h. The reaction mixture was diluted with EtOAc (10 mL) and washed successively with saturated aqueous NaHCO, saturated aqueous NaCl, and water. The organic layer was dried over NaSO, filtered, and concentrated in vacuo. The crude product was purified by preparative HPLC, Prep Method F (gradient: 15-40%) to give the title compound (50 mg, 32%); HRMS (ESI) m / z [M+H] + C 19 H 16 Calculated value for F3N4O2: 389.1220, Measured value: 389.1224; 1 H NMR(300MHz,CD3OD)δ9.11(d,1H),8.85-8.78(m,1H),8.41-8.25(m,1H),8.04(dd,1H),7.84(d,1H),5.12(dd,1H) ,4.67(d,1H),4.44(d,1H),3.81(td,1H),2.77-2.61(m,1H),2.36(dd,1H),2.05-1.90(m,1H),1.25-0.93(m,2H).

[0739] Example 11: N-(2-((1S,3S,5S)-3-cyano-2-azabicyclo[3.1.0]hexan-2-yl)-2-oxoethyl)-6-(fluoromethyl)quinoline-4-carboxamide

[0740] [ka]

[0741] DIPEA (0.174 mL, 1.00 mmol) was added to a solution of (1S,3S,5S)-2-azabicyclo[3.1.0]hexane-3-carbonitrile 4-methylbenzenesulfonate WO2007029086 (70 mg, 0.25 mmol), (6-(fluoromethyl)quinoline-4-carbonyl)glycine intermediate 13 (103 mg), and T3P (50% in EtOAc, 477 mg, 0.75 mmol) in EtOAc (1 mL) at 20 °C, and the reaction mixture was stirred at 20 °C for 4 h. The reaction mixture was quenched with saturated NaHCO (aq, 15 mL) and extracted with DCM (3 × 15 mL). The combined organic layers were dried over NaSO, filtered, and evaporated under reduced pressure. The crude product was purified by preparative HPLC, Prep Method F (isocratic 34%) to give the title compound (6.5 mg, 5%); HRMS (ESI) m / z [M+H] + C 19 H 18 Calculated value for FN4O2: 353.1408, Measured value: 353.1388; 1 H NMR(400MHz,CD3OD)δ9.03(d,1H),8.51-8.43(m,1H),8.17(d,1H),7.94(dd,1H),7.81(d,1H),5.62(d,2H),5.13(dd,1H),4.65 (d,1H),4.45(d,1H),3.81(td,1H),2.78-2.63(m,1H),2.37(dd,1H),2.06-1.90(m,1H),1.17-1.06(m,1H),1.05-0.96(m,1H).

[0742] Example 12: N-(2-((1S,3S,5S)-3-cyano-2-azabicyclo[3.1.0]hexan-2-yl)-2-oxoethyl)-6-(2-fluoropropan-2-yl)quinoline-4-carboxamide

[0743] [ka]

[0744] DIPEA (0.072 mL, 0.41 mmol) was added to a solution of (6-(2-fluoropropan-2-yl)quinoline-4-carbonyl)glycine intermediate 17 (30 mg, 0.10 mmol), (1S,3S,5S)-2-azabicyclo[3.1.0]hexane-3-carbonitrile 4-methylbenzenesulfonate WO2007029086 (43 mg, 0.16 mmol), EDC (40 mg, 0.21 mmol), and HOBt (32 mg, 0.21 mmol) in DMF (1 mL) at 20 °C, and the reaction mixture was stirred at 30 °C for 20 h. The reaction was quenched with saturated NaHCO (aq, 10 mL), extracted with DCM (3 × 10 mL), and the combined organic layers were dried over NaSO, filtered, and evaporated under reduced pressure. The crude product was purified by preparative HPLC, preparative method H (gradient 45-47%), followed by preparative HPLC, preparative method I (gradient 10-50%) to give the title compound (8 mg, 20%); HRMS (ESI) m / z [M+H] + C 21 H 22 Calculated value for FN4O2: 381.1722, Measured value: 381.1722; 1 H NMR(400MHz,CD3OD)δ8.94(d,1H),8.51-8.45(m,1H),8.10(d,1H),7.94(dd,1H),7.69(d,1H),5.12(dd,1H),4.64(d,1H),4.43 (d,1H),3.80(td,1H),2.78-2.64(m,1H),2.36(dd,1H),2.03-1.92(m,1H),1.79(d,6H),1.15-1.05(m,1H),1.05-0.97(m,1H).

[0745] Example 13: N-(2-((1S,3S,5S)-3-cyano-2-azabicyclo[3.1.0]hexan-2-yl)-2-oxoethyl)-6-(2-hydroxypropan-2-yl)quinoline-4-carboxamide

[0746] [ka]

[0747] DIPEA (0.091 mL, 0.52 mmol) was added to a solution of (6-(2-hydroxypropan-2-yl)quinoline-4-carbonyl)glycine intermediate 18 (50 mg, 0.17 mmol), (1S,3S,5S)-2-azabicyclo[3.1.0]hexane-3-carbonitrile 4-methylbenzenesulfonate WO2007029086 (53 mg, 0.19 mmol), EDC (50 mg, 0.26 mmol), and HOBt (40 mg, 0.26 mmol) in DMF (1 mL) at 20 °C, and the reaction mixture was stirred at 20 °C for 20 h. The reaction mixture was quenched with saturated aqueous NaHCO (20 mL) and extracted with DCM (3 × 20 mL), and the combined organic layers were dried over NaSO, filtered, and evaporated under reduced pressure. The crude product was purified by preparative HPLC, Preparative Method B (gradient: 13-23%), followed by preparative HPLC, Preparative Method B (gradient: 10-21%) to give the title compound (6 mg, 9%); HRMS (ESI) m / z [M+H] + C 21 H 23 Calculated value for N4O3: 379.1764, Measured value: 379.1760; 1 H NMR(300MHz,CD3OD)δ9.04(d,1H),8.59(d,1H),8.19(dd,1H),8.13(d,1H),7.86(d,1H),5.12(dd,1H),4.67(d,1H),4.46(d ,1H),3.81(td,1H),2.83-2.64(m,1H),2.37(dd,1H),2.08-1.92(m,1H),1.66(s,6H),1.20-1.06(m,1H),1.05-0.94(m,1H).

[0748] Example 14: N-(2-((1S,3S,5S)-3-cyano-2-azabicyclo[3.1.0]hexan-2-yl)-2-oxoethyl)-6-(1-hydroxyethyl)quinoline-4-carboxamide

[0749] [ka]

[0750] EDC (77 mg, 0.40 mmol) and DIPEA (0.191 mL, 1.09 mmol) were added to a solution of (1S,3S,5S)-2-azabicyclo[3.1.0]hexane-3-carbonitrile 4-methylbenzenesulfonate WO2007029086 (112 mg, 0.40 mmol), (6-(1-hydroxyethyl)quinoline-4-carbonyl)glycine intermediate 20 (100 mg, 0.36 mmol), and HOBt (61 mg, 0.40 mmol) in DMF (1 mL), and the reaction mixture was stirred at 20 °C for 16 h. The reaction mixture was diluted with EtOAc (10 mL) and washed with saturated aqueous NaHCO, saturated aqueous NaCl, and water. The organic layer was dried over NaSO, filtered, and concentrated under reduced pressure. The crude product was purified by preparative HPLC, Prep Method B (gradient: 8-18%) to give the title compound (10 mg, 8%); HRMS (ESI) m / z [M+H] + C 20 H 21 Calculated value for N4O3: 365.1608, Measured value: 365.1596; 1 H NMR(300MHz,CD3OD)δ9.03(d,1H),8.43(d,1H),8.15(d,1H),8.04(dd,1H),7.86(d,1H),5.21-5.03(m,2H),4.66(d,1H),4.46 (d,1H),3.80(td,1H),2.79-2.59(m,1H),2.36(dd,1H),2.09-1.86(m,1H),1.54(d,3H),1.17-1.06(m,1H),1.06-0.95(m,1H).

[0751] Example 15: N-(2-((1S,3S,5S)-3-cyano-2-azabicyclo[3.1.0]hexan-2-yl)-2-oxoethyl)-6-(1-methoxyethyl)quinoline-4-carboxamide

[0752] [ka]

[0753] DIPEA (0.068 mL, 0.39 mmol) was added to a solution of 6-(1-methoxyethyl)quinoline-4-carboxylic acid intermediate 24 (30 mg, 0.13 mmol), (1S,3S,5S)-2-glycyl-2-azabicyclo[3.1.0]hexane-3-carbonitrile intermediate 4 (26 mg, 0.16 mmol), EDC (37 mg, 0.19 mmol), and HOBt (30 mg, 0.19 mmol) in DMF (2 mL), and the reaction mixture was stirred at 20 °C for 18 h. The reaction was quenched with saturated NaHCO (aq, 10 mL) and extracted with DCM (3 × 10 mL). The combined organic layers were dried over NaSO, filtered, and concentrated in vacuo. The crude product was purified by preparative HPLC, Prep Method B (gradient: 17-27%) to give the title compound (33 mg, 67%); HRMS (ESI) m / z [M+H] + C 21 H 23 Calculated value for N4O3: 379.1764, Measured value: 379.1764; 1 H NMR(300MHz,CD3OD)δ9.07(d,1H),8.48-8.42(m,1H),8.18(d,1H),8.00(dd,1H),7.90(d,1H),5.13(dd,1H),4.72-4.56(m,2H),4.47(dd, 1H),3.80(td,1H),3.28(d,3H),2.78-2.62(m,1H),2.37(dd,1H),2.06-1.90(m,1H),1.50(dd,3H),1.18-1.07(m,1H),1.06-0.96(m,1H).

[0754] Example 16: N-(2-((1S,3S,5S)-3-cyano-2-azabicyclo[3.1.0]hexan-2-yl)-2-oxoethyl)-6-(2-methoxypropan-2-yl)quinoline-4-carboxamide

[0755] [ka]

[0756] DIPEA (0.085 mL, 0.49 mmol) was added to a solution of 6-(2-methoxypropan-2-yl)quinoline-4-carboxylic acid intermediate 27 (40 mg, 0.16 mmol), (1S,3S,5S)-2-glycyl-2-azabicyclo[3.1.0]hexane-3-carbonitrile intermediate 4 (27 mg, 0.16 mmol), EDC (47 mg, 0.24 mmol), and HOBt (38 mg, 0.24 mmol) in DMF (1 mL), and the reaction mixture was stirred at 30 °C for 20 h. The reaction was quenched with saturated NaHCO (aq, 10 mL) and extracted with DCM (3 × 10 mL). The combined organic layers were dried over NaSO, filtered, and evaporated under reduced pressure. The crude product was purified by preparative HPLC, Prep Method I (gradient: 18-28%) to give the title compound (37 mg, 58%); HRMS (ESI) m / z [M+H] + C 22 H 25 Calculated value for N4O3: 393.1922, Measured value: 393.1934; 1 H NMR(400MHz,CD3OD)δ8.92(d,1H),8.42(d,1H),8.09(d,1H),7.97(dd,1H),7.68(d,1H),5.11(dd,1H),4.64(d,1H),4.43(d,1H),3 .80(td,1H),3.11(s,3H),2.78-2.64(m,1H),2.36(dd,1H),2.03-1.92(m,1H),1.64(s,6H),1.17-1.06(m,1H),1.05-0.97(m,1H).

[0757] Example 17: N-(2-((1S,3S,5S)-3-cyano-2-azabicyclo[3.1.0]hexan-2-yl)-2-oxoethyl)-6-((trifluoromethoxy)methyl)quinoline-4-carboxamide

[0758] [ka]

[0759] (1S,3S,5S)-2-Glycyl-2-azabicyclo[3.1.0]hexane-3-carbonitrile intermediate 4 (97 mg, 0.59 mmol), EDC (226 mg, 1.18 mmol), and HOBt (159 mg, 1.18 mmol) were added to a solution of 6-((trifluoromethoxy)methyl)quinoline-4-carboxylic acid intermediate 30 (160 mg, 0.59 mmol) and DIPEA (305 mg, 2.36 mmol) in DMF (4 mL) under an atmosphere of N2 (g), and the reaction mixture was stirred at 38 °C for 2 h. The reaction mixture was concentrated in vacuo, and the residue was purified by preparative HPLC, Prep Method J (gradient: 30-60%) to give the title compound (33 mg, 14%); HRMS (ESI) m / z [M+H] + C 20 H 18 Calculated value for F3N4O3: 419.1326, Found value: 419.1326; 1 H NMR(400MHz,CD3OD)δ9.00(d,1H),8.48-8.42(m,1H),8.15(d,1H),7.88(dd,1H),7.73(d,1H),5.31(s,2H),5.12(dd,1H),4.64 (d,1H),4.44(d,1H),3.81(td,1H),2.76-2.63(m,1H),2.37(dd,1H),2.04-1.92(m,1H),1.16-1.06(m,1H),1.05-0.97(m,1H).

[0760] Example 18: N-(2-((1S,3S,5S)-3-cyano-2-azabicyclo[3.1.0]hexan-2-yl)-2-oxoethyl)-6-ethyl-2-methylquinoline-4-carboxamide

[0761] [ka]

[0762] HATU (59 mg, 0.15 mmol) was added to a suspension of 6-ethyl-2-methylquinoline-4-carboxylic acid (30 mg, 0.14 mmol) in DCM (1 mL), and the reaction mixture was stirred at room temperature for 15 minutes. (1S,3S,5S)-2-Glycyl-2-azabicyclo[3.1.0]hexane-3-carbonitrile hydrochloride intermediate 3 (28 mg, 0.14 mmol) and DIPEA (0.073 mL, 0.42 mmol) were added to the reaction mixture, followed by DCM (0.5 mL) and MeCN (0.2 mL), and the reaction mixture was stirred at room temperature overnight. The reaction mixture was diluted with DCM and washed with saturated aqueous NaHCO3. The organic layer was dried using a phase separator and evaporated under reduced pressure to give a yellow oil. The residue was dissolved in MeCN, filtered through a syringe filter, and purified by preparative SFC, preparative method D (gradient: 12-17%) to give the title compound (25 mg, 49%); HRMS (ESI) m / z [M+H] + C 21 H 23 Calculated value for N4O2: 363.1816, Measured value: 363.1814; 1 H NMR(600MHz,DMSO-d6)δ9.03(t,1H),8.07(d,1H),7.89(d,1H),7.64(dd,1H),7.43(s,1H),5.15(dd,1H),4.52(dd,1H),4.23(dd,1H),3.85 (td,1H),2.78(q,2H),2.67(s,3H),2.62-2.56(m,1H),2.24(dd,1H),1.93-1.86(m,1H),1.27(t,3H),1.04-0.98(m,1H),0.83-0.73(m,1H).

[0763] Example 19: N-(2-((1S,3S,5S)-3-cyano-2-azabicyclo[3.1.0]hexan-2-yl)-2-oxoethyl)-2,6-dimethylquinoline-4-carboxamide

[0764] [ka]

[0765] HATU (59 mg, 0.15 mmol) was added to a suspension of 2,6-dimethylquinoline-4-carboxylic acid (28 mg, 0.14 mmol) in DCM (1 mL), and the reaction mixture was stirred at room temperature for 15 minutes. (1S,3S,5S)-2-Glycyl-2-azabicyclo[3.1.0]hexane-3-carbonitrile hydrochloride intermediate 3 (28 mg, 0.14 mmol) and DIPEA (0.073 mL, 0.42 mmol) were added to the reaction mixture, followed by DCM (0.5 mL) and MeCN (0.2 mL), and the reaction mixture was stirred at room temperature overnight. The reaction mixture was diluted with DCM and washed with saturated aqueous NaHCO3. The organic layer was dried using a phase separator and evaporated under reduced pressure. The residue was dissolved in MeCN, filtered through a syringe filter, and purified by preparative SFC, preparative method D (gradient; 12-17%) to give the title compound (25 mg, 52%); HRMS (ESI) m / z [M+H] + C 20 H 21 Calculated value for N4O2: 349.1658, Measured value: 349.1650; 1 H NMR(600MHz,DMSO-d6)δ9.03(t,1H),8.06-8.02(m,1H),7.87(d,1H),7.60(dd,1H),7.43(s,1H),5.15(dd,1H),4.52(dd,1H),4.22(dd, 1H),3.85(td,1H),2.67(s,3H),2.63-2.55(m,1H),2.48(s,3H),2.24(dd,1H),1.94-1.86(m,1H),1.07-0.91(m,1H),0.85-0.68(m,1H).

[0766] Example 20: N-(2-((1S,3S,5S)-3-cyano-2-azabicyclo[3.1.0]hexan-2-yl)-2-oxoethyl)-7-methylquinoline-4-carboxamide

[0767] [ka]

[0768] Pd(dppf)Cl·DCM (15 mg, 0.02 mmol) was added to a suspension of 7-bromo-N-(2-((1S,3S,5S)-3-cyano-2-azabicyclo[3.1.0]hexan-2-yl)-2-oxoethyl)quinoline-4-carboxamide Example 3 (150 mg, 0.38 mmol), KCO (156 mg, 1.13 mmol), and TMB (141 mg, 1.13 mmol) in 1,4-dioxane (2 mL) under a N(g) atmosphere, and the reaction mixture was stirred at 80 °C for 4 h. The reaction mixture was diluted with EtOAc (10 mL) and washed sequentially with saturated aqueous NaHCO, saturated aqueous NaCl, and water. The organic layer was dried over NaSO, filtered, and concentrated under reduced pressure. The residue was purified by preparative TLC (MeOH:DCM, 1:10). The crude product was purified by preparative HPLC, Prep Method B (gradient: 11-21%) to give the title compound (80 mg, 64%); HRMS (ESI) m / z [M+H] + C 19 H 19 Calculated value for N4O2: 335.1508, Measured value: 335.1507; 1 H NMR(400MHz,CD3OD)δ9.09(d,1H),8.48(d,1H),8.01-7.96(m,1H),7.89(d,1H),7.76(dd,1H),5.13(dd,1H),4.67(d,1H) ),4.47(d,1H),3.81(td,1H),2.78-2.66(m,4H),2.38(dd,1H),2.07-1.94(m,1H),1.16-1.08(m,1H),1.07-0.99(m,1H).

[0769] Example 21: N-(2-((1S,3S,5S)-3-cyano-2-azabicyclo[3.1.0]hexan-2-yl)-2-oxoethyl)-7-(2-fluoropropan-2-yl)quinoline-4-carboxamide

[0770] [ka]

[0771] DIPEA (0.060 mL, 0.34 mmol) was added dropwise to a solution of 7-(2-fluoropropan-2-yl)quinoline-4-carboxylic acid intermediate 34 (20 mg, 0.09 mmol), (1S,3S,5S)-2-glycyl-2-azabicyclo[3.1.0]hexane-3-carbonitrile intermediate 4 (17 mg, 0.10 mmol), EDC (33 mg, 0.17 mmol), and HOBt (26 mg, 0.17 mmol) in DMF (2 mL), and the reaction mixture was stirred at 35 °C for 4 h. The reaction mixture was concentrated in vacuo, and the residue was purified by preparative HPLC, Prep Method K (gradient: 29-30%) to give the title compound (5 mg, 15%); HRMS (ESI) m / z [M+H] + C 21 H 22 Calculated value for FN4O2: 381.1722, Measured value: 381.1724; 1 H NMR(400MHz,CD3OD)δ8.97(d,1H),8.44(d,1H),8.13(d,1H),7.75(dd,1H),7.69(d,1H),5.13(dd,1H),4.65(d,1H),4.44(d ,1H),3.82(td,1H),2.75-2.64(m,1H),2.38(dd,1H),2.05-1.93(m,1H),1.79(d,6H),1.17-1.06(m,1H),1.05-0.98(m,1H).

[0772] Example 22: N-(2-((1S,3S,5S)-3-cyano-2-azabicyclo[3.1.0]hexan-2-yl)-2-oxoethyl)-7-(difluoromethyl)quinoline-4-carboxamide

[0773] [ka]

[0774] DIPEA (0.125 mL, 0.71 mmol) was added dropwise to a solution of (7-(difluoromethyl)quinoline-4-carbonyl)glycine intermediate 37 (50 mg, 0.18 mmol), (1S,3S,5S)-2-azabicyclo[3.1.0]hexane-3-carbonitrile 4-methylbenzenesulfonate WO2007029086 (75 mg, 0.27 mmol), EDC (68 mg, 0.36 mmol), and HOBt (55 mg, 0.36 mmol) in DMF (2 mL), and the reaction mixture was stirred at 35° C. for 4 h. The reaction mixture was concentrated in vacuo, and the crude product was purified by preparative HPLC, Prep Method K (isocratic: 27%) to give the title compound (15 mg, 23%); HRMS (ESI) m / z [M+H] + C 19 H 17 Calculated value for F2N4O2: 371.1320, Measured value: 371.1304; 1 H NMR(400MHz,CD3OD)δ9.04(d,1H),8.55(d,1H),8.26(d,1H),7.83(dd,1H),7.78(d,1H),7.04(t,1H),5.12(dd,1H),4.64(d ,1H),4.43(d,1H),3.81(td,1H),2.77-2.62(m,1H),2.37(dd,1H),2.04-1.89(m,1H),1.17-1.06(m,1H),1.05-0.97(m,1H).

[0775] Example 23: N-(2-((1S,3S,5S)-3-cyano-2-azabicyclo[3.1.0]hexan-2-yl)-2-oxoethyl)-7-(trifluoromethyl)quinoline-4-carboxamide

[0776] [ka]

[0777] EDC (139 mg, 0.72 mmol) and DIPEA (0.316 mL, 1.81 mmol) were added to a solution of (1S,3S,5S)-2-azabicyclo[3.1.0]hexane-3-carbonitrile 4-methylbenzenesulfonate WO2007029086 (203 mg, 0.72 mmol), (7-(trifluoromethyl)quinoline-4-carbonyl)glycine intermediate 39 (180 mg, 0.60 mmol), and HOBt (98 mg, 0.72 mmol) in DMF (1 mL), and the reaction mixture was stirred at 20 °C for 4 h. The reaction mixture was diluted with EtOAc (20 mL) and washed with saturated aqueous NaHCO, saturated aqueous NaCl, and water. The organic layer was dried over NaSO, filtered, and concentrated under reduced pressure. The crude product was purified by preparative HPLC, Prep Method L (isocratic: 35%) to give the title compound (80 mg, 34%); HRMS (ESI) m / z [M+H] + C 19 H 16 Calculated value for F3N4O2: 389.1220, Measured value: 389.1224; 1 H NMR(300MHz,CD3OD)δ9.10(d,1H),8.68-8.58(m,1H),8.44-8.37(m,1H),7.90(dd,1H),7.83(d,1H),5.12(dd,1H) ,4.64(d,1H),4.45(d,1H),3.80(td,1H),2.78-2.62(m,1H),2.37(dd,1H),2.05-1.90(m,1H),1.22-0.96(m,2H).

[0778] Example 24: N-(2-((1S,3S,5S)-3-cyano-2-azabicyclo[3.1.0]hexan-2-yl)-2-oxoethyl)-7-(fluoromethyl)quinoline-4-carboxamide

[0779] [ka]

[0780] HOBt (129 mg, 0.95 mmol) and EDC (146 mg, 0.76 mmol) were added to a solution of (7-(fluoromethyl)quinoline-4-carbonyl)glycine intermediate 41 (100 mg, 0.38 mmol), (1S,3S,5S)-2-azabicyclo[3.1.0]hexane-3-carbonitrile 4-methylbenzenesulfonate WO2007029086 (128 mg, 0.46 mmol), and DIPEA (197 mg, 1.53 mmol) in DMF (5 mL), and the reaction mixture was stirred at 80 °C for 24 h. The reaction mixture was concentrated in vacuo, and the residue was purified by preparative HPLC, Prep Method F (gradient: 23-30%) to give the title compound (21 mg, 15%); HRMS (ESI) m / z [M+H] + C 19 H 18 Calculated value for FN4O2: 353.1408, Measured value: 353.1400; 1 H NMR(400MHz,CD3OD)δ8.97(d,1H),8.45(d,1H),8.14-8.05(m,1H),7.76-7.66(m,2H),5.64(d,2H),5.12(dd,1H),4.63(d, 1H),4.42(d,1H),3.80(td,1H),2.77-2.62(m,1H),2.37(dd,1H),2.03-1.91(m,1H),1.16-1.05(m,1H),1.05-0.96(m,1H).

[0781] Example 25: N-(2-((1S,3S,5S)-3-cyano-2-azabicyclo[3.1.0]hexan-2-yl)-2-oxoethyl)-7-(1-hydroxyethyl)quinoline-4-carboxamide

[0782] [ka]

[0783] DIPEA (0.172 mL, 0.98 mmol) and EDC (69 mg, 0.36 mmol) were added to a solution of (1S,3S,5S)-2-azabicyclo[3.1.0]hexane-3-carbonitrile 4-methylbenzenesulfonate WO2007029086 (101 mg, 0.36 mmol), HOBt (55 mg, 0.36 mmol), and (7-(1-hydroxyethyl)-quinoline-4-carbonyl)glycine intermediate 44 (90 mg, 0.33 mmol) in DMF (1 mL), and the reaction mixture was stirred at 20 °C for 6 h. The reaction mixture was diluted with EtOAc (10 mL) and washed sequentially with saturated aqueous NaHCO, saturated aqueous NaCl, and water. The organic layer was dried over NaSO, filtered, and concentrated in vacuo. The crude product was purified by preparative HPLC, Prep Method M (20% isocratic) to give the title compound (10 mg, 8%); HRMS (ESI) m / z [M+H] + C 20 H 21 Calculated value for N4O3: 365.1608, Measured value: 365.1610; 1 H NMR(400MHz,CD3OD)δ8.93(d,1H),8.38(d,1H),8.11-8.06(m,1H),7.73(dd,1H),7.66(d,1H),5.24-5.02(m,2H),4.63(d,1H),4. 42(d,1H),3.81(td,1H),2.75-2.64(m,1H),2.37(dd,1H),2.04-1.92(m,1H),1.55(d,3H),1.15-1.05(m,1H),1.05-0.97(m,1H).

[0784] Example 26: N-(2-((1S,3S,5S)-3-cyano-2-azabicyclo[3.1.0]hexan-2-yl)-2-oxoethyl)-7-(2-hydroxypropan-2-yl)quinoline-4-carboxamide

[0785] [ka]

[0786] DIPEA (0.197 mL, 1.13 mmol) was added dropwise to a solution of (7-(2-hydroxypropan-2-yl)quinoline-4-carbonyl)glycine intermediate 46 (65 mg, 0.23 mmol), (1S,3S,5S)-2-azabicyclo[3.1.0]hexane-3-carbonitrile (37 mg, 0.34 mmol), EDC (86 mg, 0.45 mmol), and HOBt (69 mg, 0.45 mmol) in DMF (2 mL), and the reaction mixture was stirred at 25 °C for 4 h. The reaction mixture was concentrated in vacuo, and the residue was purified by preparative TLC (DCM:MeOH, 10:1). The crude product was purified by preparative HPLC, preparative method N (gradient 18-35%) to give the title compound (25 mg, 29%); HRMS (ESI) m / z [M+H] + C 21 H 23 Calculated value for N4O3: 377.1608, Measured value: 377.1620; 1 H NMR(400MHz,CD3OD)δ8.93(d,1H),8.38(d,1H),8.22(d,1H),7.87(dd,1H),7.67(d,1H),5.13(dd,1H),4.64(d,1H),4.43(d ,1H),3.82(td,1H),2.76-2.64(m,1H),2.38(dd,1H),2.07-1.93(m,1H),1.66(s,6H),1.17-1.06(m,1H),1.05-0.97(m,1H).

[0787] Example 27: N-(2-((1S,3S,5S)-3-cyano-2-azabicyclo[3.1.0]hexan-2-yl)-2-oxoethyl)-7-(1-methoxyethyl)quinoline-4-carboxamide

[0788] [ka]

[0789] DIPEA (0.038 mL, 0.22 mmol) was added to a solution of 7-(1-methoxyethyl)quinoline-4-carboxylic acid intermediate 49 (50 mg, 0.22 mmol), (1S,3S,5S)-2-glycyl-2-azabicyclo[3.1.0]hexane-3-carbonitrile intermediate 4 (36 mg, 0.22 mmol), EDC (41 mg, 0.22 mmol), and HOBt (33 mg, 0.22 mmol) in DMF (1 mL) at 20 °C, and the reaction mixture was stirred at 40 °C for 18 h. The reaction was quenched with saturated NaHCO (aq, 10 mL) and extracted with DCM (3 × 10 mL). The organic layer was dried over Na2SO4, filtered, evaporated under reduced pressure and the crude product was purified by preparative HPLC, Prep Method B (gradient: 16-26%) to give the title compound (25 mg, 31%); HRMS (ESI) m / z [M+H] + C 21 H 23 Calculated value for N4O3: 379.1764, Measured value: 379.1748; 1 H NMR(300MHz,CD3OD)δ9.09(d,1H),8.55(d,1H),8.13-8.06(m,1H),7.92-7.86(m,1H),7.83(dd,1H),5.17-5.07(m,1H),4.73-4.58(m,2H) ,4.53-4.38(m,1H),3.88-3.73(m,1H),3.33(s,3H),2.78-2.65(m,1H),2.37(dd,1H),2.07-1.88(m,1H),1.51(d,3H),1.20-0.92(m,2H).

[0790] Example 28: N-(2-((1S,3S,5S)-3-cyano-2-azabicyclo[3.1.0]hexan-2-yl)-2-oxoethyl)-7-(2-methoxypropan-2-yl)quinoline-4-carboxamide

[0791] [ka]

[0792] DIPEA (0.285 mL, 1.63 mmol) was added in one portion to a solution of 7-(2-methoxypropan-2-yl)quinoline-4-carboxylic acid intermediate 51 (100 mg, 0.41 mmol), (1S,3S,5S)-2-glycyl-2-azabicyclo[3.1.0]hexane-3-carbonitrile intermediate 4 (101 mg, 0.61 mmol), EDC (156 mg, 0.82 mmol), and HOBt (125 mg, 0.82 mmol) in DMF (1 mL), and the reaction mixture was stirred at 35 °C for 3 h. The reaction mixture was concentrated in vacuo, and the residue was purified by preparative HPLC, Prep Method N (gradient: 20-38%) to give the title compound (30 mg, 19%); HRMS (ESI) m / z [M+H] + C 22 H 25 Calculated value for N4O3: 393.1922, Measured value: 393.1928; 1 H NMR(300MHz,CD3OD)δ8.94(d,1H),8.40(d,1H),8.09(d,1H),7.82(dd,1H),7.68(d,1H),5.12(dd,1H),4.64(d,1H),4.42 (d,1H),3.81(td,1H),3.14(s,3H),2.78-2.62(m,1H),2.37(dd,1H),2.05-1.90(m,1H),1.65(s,6H),1.19-0.96(m,2H).

[0793] Example 29: N-(2-((1S,3S,5S)-3-cyano-2-azabicyclo[3.1.0]hexan-2-yl)-2-oxoethyl)-7-((trifluoromethoxy)methyl)quinoline-4-carboxamide

[0794] [ka]

[0795] Step a) 7-((trifluoromethoxy)methyl)quinoline-4-carboxylic acid

[0796] [ka]

[0797] Methyl 7-((trifluoromethoxy)methyl)quinoline-4-carboxylate intermediate 53 (220 mg, 0.77 mmol) and NaOH (30.9 mg, 0.77 mmol) were dissolved in MeOH (4 mL) and water (1 mL), and the reaction mixture was stirred for 2 h at 20° C. The mixture was concentrated in vacuo to give the subtitled compound as a crude product.

[0798] Step b) N-(2-((1S,3S,5S)-3-cyano-2-azabicyclo[3.1.0]hexan-2-yl)-2-oxoethyl)-7-((trifluoromethoxy)methyl)quinoline-4-carboxamide DIPEA (0.322 mL, 1.84 mmol) was added dropwise to a solution of 7-((trifluoromethoxy)methyl)quinoline-4-carboxylic acid Example 29, step a) (150 mg, 0.55 mmol), (1S,3S,5S)-2-glycyl-2-azabicyclo[3.1.0]hexane-3-carbonitrile intermediate 4 (76 mg, 0.46 mmol), EDC (177 mg, 0.92 mmol), and HOBt (141 mg, 0.92 mmol) in DMF (5 mL), and the reaction mixture was stirred at 38 °C for 3 h. The reaction mixture was concentrated in vacuo, and the residue was purified by preparative HPLC, Prep Method F (gradient: 34-39%) to give the title compound (50 mg, 26%); HRMS (ESI) m / z [M+H] + C 20 H 18 Calculated value for F3N4O3: 419.1326, Found value: 419.1308; 1 H NMR(400MHz,CD3OD)δ9.00(d,1H),8.48(d,1H),8.14(d,1H),7.77-7.68(m,2H),5.36(s,2H),5.13(dd,1H),4.65(d,1H) ,4.44(d,1H),3.82(td,1H),2.77-2.64(m,1H),2.38(dd,1H),2.05-1.92(m,1H),1.16-1.06(m,1H),1.05-0.97(m,1H).

[0799] Example 30: N-(2-((1S,3S,5S)-3-cyano-2-azabicyclo[3.1.0]hexan-2-yl)-2-oxoethyl)-7-(1-(trifluoromethoxy)ethyl)quinoline-4-carboxamide

[0800] [ka]

[0801] (1S,3S,5S)-2-Glycyl-2-azabicyclo[3.1.0]hexane-3-carbonitrile intermediate 4 (87 mg, 0.53 mmol) was added to a solution of 7-(1-(trifluoromethoxy)ethyl)quinoline-4-carboxylic acid intermediate 55 (150 mg, 0.53 mmol), T3P (50% in EtOAc, 335 mg, 1.05 mmol) in DMF (2.0 mL), and TEA (0.147 mL, 1.05 mmol) in EtOAc (8 mL), and the reaction mixture was stirred at 20 °C for 48 h. The solvent was removed in vacuo, and the residue was purified by preparative TLC (MeOH:DCM, 1:10) followed by preparative HPLC, Prep Method F (gradient: 33-45%) to give the title compound (16 mg, 7%); HRMS (ESI) m / z [M+H] + C 21 H 20 Calculated value for F3N4O3: 433.1482, Found value: 433.1488; 1 H NMR (400 MHz, DMSO-d₆) δ 9.14 (t, 1H), 9.03 (d, 1H), 8.43 (d, 1H), 8.15-8.10 (m, 1H), 7.76 (dd, 1H), 7.61 (d, 1H), 5.86 (q, 1H), 5.17 (dd, 1H), 4.57 (dd, 1H), 4.23 (dd, 1H), 3.91-3.83 (m, 1H), 2.70-2.55 (m, overlapping with solvent peak), 2.26 (dd, 1H), 1.97-1.84 (m, 1H), 1.70 (d, 3H), 1.07-0.94 (m, 1H), 0.85-0.72 (m, 1H).

[0802] Example 31: N-(2-((1S,3S,5S)-3-cyano-2-azabicyclo[3.1.0]hexan-2-yl)-2-oxoethyl)-2,7-dimethylquinoline-4-carboxamide

[0803] [ka]

[0804] DIPEA (0.085 mL, 0.48 mmol) and HATU (0.068 g, 0.18 mmol) were added to a suspension of 2,7-dimethylquinoline-4-carboxylic acid (0.032 g, 0.16 mmol) in DCM (1 mL), and the reaction mixture was stirred at room temperature for 15 min. A solution of (1S,3S,5S)-2-glycyl-2-azabicyclo[3.1.0]hexane-3-carbonitrile 4-methylbenzenesulfonate intermediate 2 (0.071 g, 0.16 mmol) in DCM (1 mL) was added, followed by MeCN (0.2 mL), and the reaction mixture was stirred at room temperature overnight. The reaction mixture was diluted with DCM and washed with saturated aqueous NaHCO. The organic layer was dried using a phase separator and evaporated under reduced pressure. The residue was dissolved in MeCN, filtered through a syringe filter, and purified by preparative SFC, preparative method O (gradient: 12-17%), followed by preparative SFC, preparative method P (gradient: 15-20%) to give the title compound (32 mg, 60%); HRMS (ESI) m / z [M+H] + C 20 H 21 Calculated value for N4O2: 349.1664, Measured value: 349.1658; 1 H NMR(600MHz,DMSO-d6)δ9.03(t,1H),8.16(d,1H),7.79-7.73(m,1H),7.43(dd,1H),7.39(s,1H),5.14(dd,1H),4.51(dd,1H),4.20(dd ,1H),3.84(td,1H),2.66(s,3H),2.62-2.55(m,1H),2.54(s,3H),2.24(dd,1H),1.93-1.86(m,1H),1.04-0.98(m,1H),0.78(ddd,1H).

[0805] Example 32: N-(2-((1S,3S,5S)-3-cyano-2-azabicyclo[3.1.0]hexan-2-yl)-2-oxoethyl)-7-(1-methylcyclopropyl)quinoline-4-carboxamide

[0806] [ka]

[0807] DIPEA (0.074 mL, 0.42 mmol) was added to a solution of (7-(1-methylcyclopropyl)-quinoline-4-carbonyl)glycine intermediate 73 (40 mg, 0.14 mmol), (1S,3S,5S)-2-azabicyclo[3.1.0]hexane-3-carbonitrile 4-methylbenzenesulfonate WO2007029086 (47 mg, 0.17 mmol), EDC (40 mg, 0.21 mmol), and HOBt (32 mg, 0.21 mmol) in DMF (1 mL) at 20 °C, and the reaction mixture was stirred at 20 °C for 18 h. The reaction mixture was quenched with saturated NaHCO (10 mL), extracted with DCM (3 × 10 mL), and the organic layer was dried over NaSO, filtered, and evaporated under reduced pressure. The crude product was purified by preparative HPLC, Prep Method B (gradient: 21-32%) to give the title compound (15 mg, 28%); HRMS (ESI) m / z [M+H] + C 22 H 23 Calculated value for N4O2: 375.1816, Measured value: 375.1814; 1 H NMR(300MHz,CD3OD)δ9.09(d,1H),8.49(d,1H),8.02(d,1H),7.89(d,1H),7.70(dd,1H),5.11(dd,1H),4.65(d,1H) ),4.45(d,1H),3.80(td,1H),2.77-2.60(m,1H),2.37(dd,1H),2.04-1.91(m,1H),1.59(s,3H),1.22-0.95(m,6H).

[0808] Example 33: N-(2-((1S,3S,5S)-3-cyano-2-azabicyclo[3.1.0]hexan-2-yl)-2-oxoethyl)-6-(2,2,2-trifluoroethoxy)quinoline-4-carboxamide

[0809] [ka]

[0810] Stock solution A was prepared by dissolving NiCl DME (4 mg, 18 μmol) and dtbbpy (5 mg, 0.02 mmol) in MeCN (1 mL). Stock solution B was prepared by dissolving quinuclidine (4.2 mg, 38 μmol) in MeCN (1 mL). Stock solution B (0.1 mL) and stock solution A (0.1 mL) were added to a mixture of 6-bromo-N-(2-((1S,3S,5S)-3-cyano-2-azabicyclo[3.1.0]hexan-2-yl)-2-oxoethyl)quinoline-4-carboxamide Example 1 (0.015 g, 0.04 mmol), Ir[dF(CF)ppy](dtbbpy)PF (2.1 mg, 1.8 μmol), and KCO (5.2 mg, 0.04 mmol), and a N(g) atmosphere was applied to the reaction vessel. 2,2,2-Trifluoroethan-1-ol (0.011 g, 0.11 mmol) was added, and the reaction mixture was degassed three times by applying evacuation-refill cycles using N(g) as the inert gas. The reaction vessel was capped and sealed using parafilm, and the reaction mixture was irradiated with a blue LED (34 W, 456 nm) in a fan-cooled chamber at room temperature for 24 h. The reaction mixture was partitioned between EtOAc (2 mL) and water (2 mL). The aqueous phase was extracted with EtOAc (2 × 2 mL). The combined organic layers were washed with brine, dried using a phase separator, and then concentrated in vacuo. The residue was purified by preparative SFC, preparative method E (gradient: 15-20%) to give the title compound (1.5 mg, 10%); HRMS (ESI) m / z [M+H] + C 20 H 18Calculated value for F3N4O3: 419.1326, Found value: 419.1338.

[0811] Example 34: N-(2-((1S,3S,5S)-3-cyano-2-azabicyclo[3.1.0]hexan-2-yl)-2-oxoethyl)-6-isopropoxyquinoline-4-carboxamide

[0812] [ka]

[0813] Stock solution A was prepared by dissolving NiCl DME (4.2 mg, 19 μmol) and dtbbpy (5 mg, 0.02 mmol) in MeCN (1 mL). Stock solution B was prepared by dissolving quinuclidine (4.1 mg, 37 μmol) in MeCN (1 mL). Stock solution B (0.1 mL) and stock solution A (0.1 mL) were added to a mixture of 6-bromo-N-(2-((1S,3S,5S)-3-cyano-2-azabicyclo[3.1.0]hexan-2-yl)-2-oxoethyl)quinoline-4-carboxamide Example 1 (0.015 g, 0.04 mmol), Ir[dF(CF)ppy](dtbbpy)PF (2.1 mg, 1.9 μmol), and KCO (5.2 mg, 0.04 mmol), and a N(g) atmosphere was applied to the reaction vessel. Propan-2-ol (8.7 μL, 0.11 mmol) was added, the reaction vessel was capped, and the reaction mixture was degassed three times by applying evacuation-refill cycles using N(g) as the inert gas. The reaction vessel was sealed using parafilm, and the reaction mixture was irradiated with a blue LED (34 W, 456 nm) in a fan-cooled chamber at room temperature for 24 hours. The reaction mixture was partitioned between EtOAc (5 mL) and water (5 mL). The aqueous phase was extracted with EtOAc. The combined organic layers were washed with brine, dried using a phase separator, and then concentrated in vacuo. The residue was purified by preparative HPLC, Preparative Method A (gradient: 5-55%) to give the title compound (3.0 mg, 21%); HRMS (ESI) m / z [M+H]+ C 21 H23 Calculated value for N4O3: 379.1764, Measured value: 379.1772; 1 H NMR(500MHz,CD3OD)δ8.74(d,1H),8.01-7.92(m,2H),7.58(d,1H),7.41(dd,1H),5.10(dd,1H),4.67-4.57(m,2H),4.41(d, 1H),3.79(td,1H),2.78-2.62(m,1H),2.36(dd,1H),2.02-1.93(m,1H),1.40(t,6H),1.14-1.06(m,1H),1.04-0.96(m,1H).

[0814] Example 35: N-(2-((1S,3S,5S)-3-cyano-2-azabicyclo[3.1.0]hexan-2-yl)-2-oxoethyl)-6-(cyclopropylmethoxy)quinoline-4-carboxamide

[0815] [ka]

[0816] Stock solution A was prepared by dissolving NiCl·DME (14 mg, 63 μmol) and dtbbpy (17 mg, 63 μmol) in MeCN (2.5 mL). Stock solution B was prepared by dissolving quinuclidine (14 mg, 0.13 mmol) in MeCN (2 mL). Stock solution A (0.2 mL) and stock solution B (0.25 mL) were added to a mixture of 6-bromo-N-(2-((1S,3S,5S-3-cyano-2-azabicyclo[3.1.0]hexan-2-yl)-2-oxoethyl)quinoline-4-carboxamide Example 1 (50 mg, 0.13 mmol), Ir[dF(CF)ppy](dtbbpy)PF (7.0 mg, 6.3 μmol), and KCO (17 mg, 0.13 mmol), and an atmosphere of N(g) was applied to the reaction vessel. Cyclopropyl-methanol (15 μL, 0.19 mmol) was added, the reaction vessel was capped, and the reaction mixture was The mixture was degassed three times by applying evacuation-refill cycles using N2(g) as the inert gas. The reaction vessel was sealed using parafilm, and the reaction mixture was irradiated with a blue LED (34 W, 456 nm) in a fan-cooled chamber at room temperature for 24 h. The reaction mixture was partitioned between EtOAc and water. The aqueous phase was extracted with EtOAc. The combined organic layers were washed with brine, dried using a phase separator, and then concentrated in vacuo. The residue was purified by preparative HPLC, Prep Method S, (gradient: 5-90%) to give the title compound (7 mg, 14%); HRMS (ESI) m / z [M+H] + C 22 H 23 Calculated value for N4O3: 391.1764, Measured value: 391.1772; 1H NMR(600MHz,DMSO-d6)δ9.07(t,1H),8.80(d,1H),7.98(d,1H),7.86(d,1H),7.48(d ,1H),7.47(dd,1H),5.14(dd,1H),4.54(dd,1H),4.23(dd,1H),4.03(dd,1H),3.96(d d,1H),3.86(td,1H),2.65-2.57(m,1H),2.26(dd,1H),1.94-1.86(m,1H),1.34-1.25 (m,1H),1.04-0.95(m,1H),0.82-0.77(m,1H),0.63-0.55(m,2H),0.45-0.36(m,2H).

[0817] Example 36: N-(2-((1S,3S,5S)-3-cyano-2-azabicyclo[3.1.0]hexan-2-yl)-2-oxoethyl)-7-(1-(trifluoromethyl)cyclopropyl)quinoline-4-carboxamide

[0818] [ka]

[0819] (1S,3S,5S)-2-Glycyl-2-azabicyclo[3.1.0]hexane-3-carbonitrile intermediate 4 (56 mg, 0.34 mmol) and EDC (109 mg, 0.57 mmol) were added to a solution of 7-(1-(trifluoromethyl)cyclopropyl)quinoline-4-carboxylic acid intermediate 79 (80 mg, 0.28 mmol), HOBt (87 mg, 0.57 mmol), and DIPEA (199 μL, 1.14 mmol) in DMF (2 mL) at 25 °C, and the reaction mixture was stirred at 40 °C for 2 h. The reaction mixture was concentrated in vacuo, and the residue was purified by preparative HPLC, Prep Method F (gradient: 22-37%) to give the title compound (19 mg, 16%); HRMS (ESI) m / z [M+H] + C 22 H 20 Calculated value for F3N4O2: 429.1532, Measured value: 429.1544; 1H NMR(400MHz,CD3OD)δ8.98(d,1H),8.42(d,1H),8.19(d,1H),7.80(dd,1H),7.71(d,1H),5.12(dd,1H),4.63(d,1H),4.42(d,1H),3.80(t d,1H),2.75-2.63(m,1H),2.37(dd,1H),2.03-1.92(m,1H),1.56-1.47(m,2H),1.35-1.23(m,2H),1.16-1.06(m,1H),1.05-0.94(m,1H).

[0820] Example 37: N-(2-((1S,3S,5S)-3-cyano-2-azabicyclo[3.1.0]hexan-2-yl)-2-oxoethyl)-7-cyclopropylquinoline-4-carboxamide

[0821] [ka]

[0822] A pre-catalyst solution was prepared as follows: NiCl DME (4.1 mg, 0.02 mmol) and dtbbpy (4.2 mg, 0.02 mmol) were suspended in DME (1 mL), and the catalyst mixture was sealed and purged with N (g). DME (2 mL) was added, and the solution was stirred for 5 min. (CHSi)SiH (93 mg, 0.38 mmol) and NaCO (60 mg, 0.56 mmol) were added to a solution of 7-bromo-N-(2-((1S,3S,5S)-3-cyano-2-azabicyclo[3.1.0]hexan-2-yl)-2-oxoethyl)-quinoline-4-carboxamide (150 mg, 0.38 mmol) Example 3 (150 mg, 0.38 mmol), [Ir{dF(CF)ppy}(dtbbpy)]PF (4.2 mg, 3.8 μmol), and bromocyclopropane (91 mg, 0.75 mmol) in DME (1 mL). Precatalyst solution (1 mL, 0.5 mol% catalyst, 2.5 μmol) was injected into the reaction mixture, and the solution was degassed by sparging with N(g) for 10 min while stirring. The reaction mixture was sealed with parafilm, and the reaction was stirred and irradiated with a 34 W blue LED at 25 °C with fan cooling for 16 h. The reaction mixture was diluted with EtOAc (30 mL) and washed with saturated aqueous NaHCO3, saturated aqueous NaCl, and water. The organic layer was dried over Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by preparative HPLC, Prep Method B (gradient: 13-23%) to give the title compound (8 mg, 6%); HRMS (ESI) m / z [M+H]+ C 21 H 21 Calculated value for N4O2: 361.1658, Measured value: 361.1660; 1 H NMR (400 MHz, DMSO-d₆) δ 9.09 (t, 1H), 8.95 (d, 1H), 8.27 (d, 1H), 7.79 (d, 1H), 7.51 (d, 1H), 7.41 (dd, 1H), 5.16 (dd, 1H), 4.55 (dd, 1H), 4.21 (dd, 1H), 3.86 (td, 1H), 2.69-2.53 (m, overlapping with solvent peak), 2.30-2.16 (m, 2H), 1.99-1.81 (m, 1H), 1.17-0.96 (m, 3H), 0.95-0.72 (m, 3H).

[0823] Example 38: N-(2-((1S,3S,5S)-3-cyano-2-azabicyclo[3.1.0]hexan-2-yl)-2-oxoethyl)-6-((4,4-difluorocyclohexyl)oxy)quinoline-4-carboxamide

[0824] [ka]

[0825] Stock solution A was prepared by dissolving NiCl₂·DME (5.5 mg, 25 μmol) and dtbbpy (6.7 mg, 25 μmol) in MeCN (1 mL). Stock solution B was prepared by dissolving quinuclidine (5.6 mg, 50 μmol) in MeCN (1 mL). Stock solution B (0.1 mL) and stock solution A (0.1 mL) were added to a mixture of 6-bromo-N-(2-((1S,3S,5S)-3-cyano-2-azabicyclo[3.1.0]hexan-2-yl)-2-oxoethyl)quinoline-4-carboxamide Example 1 (0.020 g, 0.05 mmol), Ir[dF(CF)ppy](dtbbpy)PF (2.8 mg, 2.5 μmol), and KCO (28 mg, 0.20 mmol), and a N(g) atmosphere was applied to the reaction vessel. 4,4-Difluorocyclohexan-1-ol (20 mg, 0.15 mmol) was added, the reaction vessel was capped, and the reaction mixture was degassed three times by applying evacuation-refill cycles using N(g) as the inert gas. The reaction vessel was sealed using parafilm, and the reaction mixture was irradiated with a blue LED (34 W, 456 nm) in a fan-cooled chamber at room temperature for 24 hours. The reaction mixture was partitioned between EtOAc and water. The aqueous phase was extracted with EtOAc. The combined organic layers were washed with brine, dried using a phase separator, and then concentrated in vacuo. The residue was purified by preparative HPLC, Preparative Method A (gradient: 5-60%) to give the title compound (7.3 mg, 32%); HRMS (ESI) m / z [M+H]+ C 24 H 25 Calculated value for F2N4O3: 455.1890, Found value: 455.1888;1 H NMR(500MHz,CD3OD)8.76(d,1H),8.08(d,1H),7.99(d,1H),7.57(d,1H),7.48(dd,1H),5.08(dd,1H),4.95-4.85(m,1H),4.61 (d,1H),4.39(d,1H),3.78(td,1H),2.75-2.66(m,1H),2.37(dd,1H),2.26-1.93(m,9H),1.14-1.06(m,1H),1.03-0.97(m,1H).

[0826] Example 39: N-(2-((1S,3S,5S)-3-cyano-2-azabicyclo[3.1.0]hexan-2-yl)-2-oxoethyl)-7-(1-ethoxycyclopropyl)quinoline-4-carboxamide

[0827] [ka]

[0828] DIPEA (0.089 mL, 0.51 mmol) was added dropwise to a solution of (7-(1-ethoxy-cyclopropyl)quinoline-4-carbonyl)glycine intermediate 58 (40 mg, 0.13 mmol), (1S,3S,5S)-2-azabicyclo[3.1.0]hexane-3-carbonitrile 4-methylbenzenesulfonate WO2007029086 (53 mg, 0.19 mmol), EDC (49 mg, 0.25 mmol), and HOBt (39 mg, 0.25 mmol) in DMF (5 mL), and the reaction mixture was stirred at 35° C. for 3 h. The reaction mixture was diluted with EtOAc (20 mL) and washed with saturated brine (3×20 mL). The organic layer was dried over Na2SO4, filtered, evaporated and the crude product was purified by preparative HPLC, Prep Method K (gradient: 29-30%) to give the title compound (10 mg, 19%); HRMS (ESI) m / z [M+H] + C 23 H 25 Calculated value for N4O3: 405.1922, Measured value: 405.1912; 1H NMR(400MHz,CD3OD)δ8.92(d,1H),8.38(d,1H),8.01(d,1H),7.65(d,1H),7.59(dd,1H),5.11(dd,1H),4.63(d,1H),4.42(d,1H),3.80(td,1H) ,3.55(q,2H),2.79-2.62(m,1H),2.37(dd,1H),2.05-1.93(m,1H),1.44 -1.32(m,2H),1.29-1.15(m,5H),1.14-1.06(m,1H),1.05-0.96(m,1H).

[0829] Example 40: N-(2-((1S,3S,5S)-3-cyano-2-azabicyclo[3.1.0]hexan-2-yl)-2-oxoethyl)-7-(1-cyanocyclopropyl)quinoline-4-carboxamide

[0830] [ka]

[0831] A solution of 7-(1-cyanocyclopropyl)quinoline-4-carboxylic acid intermediate 81 (150 mg, 0.63 mmol), (1S,3S,5S)-2-glycyl-2-azabicyclo[3.1.0]hexane-3-carbonitrile intermediate 4 (312 mg, 1.89 mmol), EDC (181 mg, 0.94 mmol), HOBt (145 mg, 0.94 mmol), and DIPEA (0.550 mL, 3.15 mmol) in DMF (8 mL) was stirred at room temperature for 3 h. The reaction mixture was concentrated under reduced pressure, and the residue was purified by preparative TLC (DCM:MeOH, 20:1). The crude product was purified by preparative HPLC, Prep Method L (gradient: 28-38%) followed by preparative SFC, Prep Method T (isocratic 50%) to give the title compound (55 mg, 23%); HRMS (ESI) m / z [M+H] + C 22 H 20 Calculated value for N5O2: 386.1612, Measured value: 386.1612; 1H NMR(400MHz,CD3OD)δ8.98(d,1H),8.46(d,1H),8.11(d,1H),7.70(d,1H),7.57(dd,1H),5.12(dd,1H),4.64(d,1H),4.43(d,1H),3.81(t d,1H),2.75-2.63(m,1H),2.36(dd,1H),2.05-1.93(m,1H),1.93-1.84(m,2H),1.80-1.67(m,2H),1.16-1.05(m,1H),1.05-0.97(m,1H).

[0832] Example 41: N-(2-((1S,3S,5S)-3-cyano-2-azabicyclo[3.1.0]hexan-2-yl)-2-oxoethyl)-7-methoxy-2-methylquinoline-4-carboxamide

[0833] [ka]

[0834] HATU (59 mg, 0.15 mmol) was added to a suspension of 7-methoxy-2-methylquinoline-4-carboxylic acid (30 mg, 0.14 mmol) in DCM (1 mL), and the reaction mixture was stirred at room temperature for 15 min. (1S,3S,5S)-2-Glycyl-2-azabicyclo[3.1.0]hexane-3-carbonitrile hydrochloride intermediate 3 (28 mg, 0.14 mmol) and DIPEA (0.073 mL, 0.42 mmol), followed by DCM (0.5 mL) and MeCN (0.2 mL) were added, and the reaction mixture was stirred at room temperature overnight. The reaction mixture was diluted with DCM and washed with saturated aqueous NaHCO3. The organic layer was dried using a phase separator and evaporated under reduced pressure. The crude product was dissolved in MeCN, filtered through a syringe filter, and purified by preparative SFC, preparative method D (gradient: 15-20%) to give the title compound (26 mg, 51%); HRMS (ESI) m / z [M+H] + C 20 H 21 Calculated value for N4O3: 365.1608, Measured value: 365.1620; 1H NMR(600MHz,DMSO-d6)δ9.02(t,1H),8.19(d,1H),7.37(d,1H),7.31(s,1H),7.23(dd,1H),5.14(dd,1H),4.52(dd,1H),4.19(dd,1H) ,3.91(s,3H),3.85(td,1H),2.66(s,3H),2.63-2.55(m,1H),2.24(dd,1H),1.93-1.86(m,1H),1.03-0.98(m,1H),0.82-0.73(m,1H).

[0835] Example 42: N-(2-((1S,3S,5S)-3-cyano-2-azabicyclo[3.1.0]hexan-2-yl)-2-oxoethyl)-6-cyclopropylquinoline-4-carboxamide

[0836] [ka]

[0837] A pre-catalyst solution was prepared as follows: NiCl DME (2.7 mg, 0.01 mmol) and dtbbpy (3.4 mg, 0.02 mmol) were suspended in DME (1 mL), and the catalyst mixture was sealed and purged with N (g). DME (2 mL) was added, and the solution was stirred for 5 min.

[0838] (CHSi)SiH (93 mg, 0.38 mmol) and NaCO (53 mg, 0.50 mmol) were added to a solution of 6-bromo-N-(2-((1S,3S,5S)-3-cyano-2-azabicyclo[3.1.0]hexan-2-yl)-2-oxoethyl)quinoline-4-carboxamide Example 1 (150 mg, 0.38 mmol), [Ir{dF(CF)ppy}(dtbbpy)]PF (2.8 mg, 2.5 μmol), and bromocyclopropane (45 mg, 0.38 mmol) in DME (1 mL). Precatalyst solution (1 mL, 0.5 mol% catalyst, 2.5 μmol) was injected into the reaction mixture, and the solution was degassed by sparging with N(g) for 10 min while stirring. The reaction mixture was sealed with parafilm, and the reaction was stirred and irradiated with a 34 W blue LED at 25 °C with fan cooling for 16 h. The reaction mixture was diluted with EtOAc (10 mL) and washed with saturated aqueous NaHCO3, saturated aqueous NaCl, and water. The organic layer was dried over Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by preparative TLC (EtOAc:petroleum ether, 1:1). The crude product was purified by preparative HPLC, Prep Method B (gradient: 10-40%) to give the title compound (8.0 mg, 9%); HRMS (ESI) m / z [M+H] + C 21 H 21 Calculated value for N4O2: 361.1658, Measured value: 361.1668; 1 H NMR(300MHz,DMSO-d6)δ9.21(t,1H),8.98(d,1H),8.14(d,1H),8.04(d,1H),7.73-7.62(m,2H),5.13(dd,1H),4.52(d,1H),4.28(d,1H),3.8 6-3.75 (m, overlap peak with solvent), 2.67-2.52 (m, overlap peak with solvent), 2.24 (dd, 1H), 2.19-2.03 (m, 1H), 1.96-1.82 (m, 1H), 1.14-0.96 (m, 3H), 0.93-0.71 (m, 3H).

[0839] Example 43: N-(2-((1S,3S,5S)-3-cyano-2-azabicyclo[3.1.0]hexan-2-yl)-2-oxoethyl)-6-(1-methylcyclopropyl)quinoline-4-carboxamide

[0840] [ka]

[0841] DIPEA (0.056 mL, 0.32 mmol) was added to a solution of (6-(1-methylcyclopropyl)quinoline-4-carbonyl)glycine intermediate 60 (46 mg, 0.16 mmol), (1S,3S,5S)-2-azabicyclo[3.1.0]hexane-3-carbonitrile 4-methylbenzenesulfonate WO2007029086 (30 mg, 0.11 mmol), EDC (31 mg, 0.16 mmol), and HOBt (25 mg, 0.16 mmol) in DMF (0.5 mL) at 20 °C, and the reaction mixture was stirred at 20 °C for 18 h. Saturated NaHCO3 (15 mL) was added to the reaction mixture, and the mixture was extracted with DCM (3 × 15 mL). The organic layer was dried over Na2SO4, filtered, and evaporated. The crude product was purified by preparative HPLC, Prep Method B (gradient: 22-32%) to give the title compound (16 mg, 40%); HRMS (ESI) m / z [M+H] + C 22 H 23 Calculated value for N4O2: 375.1816, Measured value: 375.1830; 1 H NMR(300MHz,CD3OD)δ9.04(d,1H),8.43(d,1H),8.10(d,1H),7.97-7.86(m,2H),5.12(dd,1H),4.66(d,1H),4.46(d,1H) ,3.80(td,1H),2.78-2.62(m,1H),2.37(dd,1H),2.03-1.92(dd,1H),1.56(s,3H),1.17-0.97(m,4H),0.97-0.89(m,2H).

[0842] Example 44: N-(2-((1S,3S,5S)-3-cyano-2-azabicyclo[3.1.0]hexan-2-yl)-2-oxoethyl)-6-(1-(trifluoromethyl)cyclopropyl)quinoline-4-carboxamide

[0843] [ka]

[0844] (1S,3S,5S)-2-Glycyl-2-azabicyclo[3.1.0]hexane-3-carbonitrile intermediate 4 (49 mg, 0.30 mmol) and EDC (95 mg, 0.50 mmol) were added to a solution of HOBt (67 mg, 0.50 mmol), 6-(1-(trifluoromethyl)cyclopropyl)quinoline-4-carboxylic acid intermediate 65 (70 mg, 0.25 mmol), and DIPEA (129 mg, 1.00 mmol) in DMF (2 mL) at 25 °C, and the reaction mixture was stirred at 40 °C for 2 h. The reaction mixture was concentrated in vacuo, and the residue was purified by preparative HPLC, Prep Method C (gradient: 35-47%) to give the title compound (11 mg, 10%); HRMS (ESI) m / z [M+H] + C 22 H 20 Calculated value for F3N4O2: 429.1532, Measured value: 429.1518; 1 H NMR(400MHz,CD3OD)δ8.97(d,1H),8.53(d,1H),8.10(d,1H),8.01-7.93(m,1H),7.72(d,1H),5.13(dd,1H),4.65(d,1H),4.43(d,1H),3.80 (td,1H),2.76-2.64(m,1H),2.37(dd,1H),2.03-1.92(m,1H),1.50-1.42(m,2H),1.37-1.24(m,2H),1.17-1.05(m,1H),1.05-0.98(m,1H).

[0845] Example 45: N-(2-((1S,3S,5S)-3-cyano-2-azabicyclo[3.1.0]hexan-2-yl)-2-oxoethyl)-6-(1-ethoxycyclopropyl)quinoline-4-carboxamide

[0846] [ka]

[0847] DIPEA (50 mg, 0.39 mmol) was added dropwise to a solutio...

Claims

1. Equation (I): 【Chemistry 1】 Compounds having the structure or a pharmaceutically acceptable salt thereof R ２ It is selected from the group consisting of hydrogen, halogens, and methyl; R ３ is hydrogen or halogen; R ５ is selected from the group consisting of hydrogen, hydroxyl, halogen, methyl, and methoxy; R ６ and R ７ One of them is hydrogen, and R ６ and R ７ The other side is, (a) Halogen; (b) halogen, hydroxy, C １～６ -alkoxy, halo-C １～６ -alkoxy, C ３～６ -cycloalkyl, and C ３～６ -cycloalkoxy, optionally substituted with one or more substituents independently selected from the group consisting of: C １～６ -alkyl; (c) Cyano, Fluoro, C １～６ -Alkyl, Halo-C １～６ - Alkyl and C １～６ - Cyclopropyl, optionally substituted with one or more substituents independently selected from the group consisting of alkoxys; (d) C, which is optionally substituted with one or more substituents independently selected from the group consisting of halogens and cyclopropyls. １～６ -alkoxy; and (e) Halogens and C １～３ - Optionally substituted with one or more substituents independently selected from the group consisting of alkyl groups, C ３～６ - Selected from the group consisting of cycloalkoxys, R ８ This refers to a compound or a pharmaceutically acceptable salt thereof, selected from the group consisting of hydrogen, halogens, and methyl.

2. The aforementioned compound is of formula (II-A): 【Chemistry 2】 Having a structure, R ６ and R ７ However, the compound according to claim 1 or a pharmaceutically acceptable salt thereof, as defined in claim 1.

3. The aforementioned compound is of formula (III-A): 【Transformation 3】 Having a structure, R ６ and R ７ However, the compound according to claim 1 or a pharmaceutically acceptable salt thereof, as defined in claim 1.

4. R ６ and R ７ The compound according to claim 1 or a pharmaceutically acceptable salt thereof, wherein one of the atoms is hydrogen and the other is a halogen.

5. R ６ and R ７ One of them is hydrogen, and the other is C １～６ - Alkyl, and the C １～６ - Alkyl, halogen, hydroxy, C １～６ - Alkoxy, Halo-C １～６ - Alkoxy, C ３～６ -Cycloalkyl and C ３～６ - The compound according to claim 1 or a pharmaceutically acceptable salt thereof, optionally substituted with one or more substituents independently selected from the group consisting of cycloalkoxys.

6. R ６ and R ７ The compound according to claim 1 or a pharmaceutically acceptable salt thereof, wherein one of the atoms is hydrogen and the other is selected from the group consisting of methyl, ethyl, fluoromethyl, difluoromethyl, trifluoromethyl, fluoropropyl, hydroxyethyl, hydroxypropyl, methoxyethyl, methoxypropyl, trifluoromethoxymethyl, and trifluoromethoxyethyl.

7. R ６ and R ７ The compound according to claim 1 or a pharmaceutically acceptable salt thereof, wherein one of the atoms is hydrogen and the other is methyl.

8. R ６ and R ７ One of them is hydrogen, and the other is cyclopropyl, and the cyclopropyl is cyano, fluoro, C １～６ -Alkyl, Halo-C １～６ - Alkyl and C １～６ - The compound according to claim 1 or a pharmaceutically acceptable salt thereof, optionally substituted with one or more substituents independently selected from the group consisting of alkoxys.

9. R ６ and R ７ The compound according to claim 1 or a pharmaceutically acceptable salt thereof, wherein one of the atoms is hydrogen and the other is cyclopropyl, and the cyclopropyl is optionally substituted with one or more substituents independently selected from the group consisting of cyano, methyl, trifluoromethyl, and ethoxy.

10. R ６ and R ７ One of them is hydrogen, and the other is C １～６ - is an alkoxy, and the C １～６ - The compound according to claim 1 or a pharmaceutically acceptable salt thereof, wherein the alkoxy is optionally substituted with one or more substituents independently selected from the group consisting of halogens and cyclopropyls.

11. R ６ and R ７ The compound according to claim 1 or a pharmaceutically acceptable salt thereof, wherein one of the atoms is hydrogen and the other is selected from the group consisting of methoxy, propoxy, trifluoroethoxy, and cyclopropylmethoxy.

12. R ６ and R ７ One of them is hydrogen, and the other is C ３～６ - It is a cycloalkoxy, and the C ３～６ - The compound according to claim 1 or a pharmaceutically acceptable salt thereof, wherein the cycloalkoxy is optionally substituted with one or more halogens.

13. R ６ and R ７ One of them is hydrogen, and R ６ and R ７ The other side is, (a) Halogen; (b) Halogen, hydroxyl, C １～６ - Alkoxy, Halo-C １～６ - Alkoxy, C ３～６ -Cycloalkyl and C ３～６ - Optionally substituted with one or more substituents independently selected from the group consisting of cycloalkoxys, C １～６ - Alkyl; and (c) Cyano, Fluoro, C １～６ -Alkyl, Halo-C １～６ - Alkyl and C １～６ - A compound according to claim 1 or a pharmaceutically acceptable salt thereof, selected from the group consisting of cyclopropyls, which is optionally substituted with one or more substituents independently selected from the group consisting of alkoxys.

14. R ６ and R ７ One of them is hydrogen, and R ６ and R ７ The other side is, (a) The group consisting of chloro, fluoro, bromo, and iodine; (b) Halogen, hydroxyl, C １～３ - Alkoxy and halo-C １～３ - Optionally substituted with one or more substituents independently selected from the group consisting of alkoxys, C １～３ - Alkyl; and (c) Cyano, C １～３ -Alkyl, Halo-C １～３ - Alkyl and C １～３ - A compound according to claim 1 or a pharmaceutically acceptable salt thereof, selected from the group consisting of cyclopropyls, which is optionally substituted with one or more substituents independently selected from the group consisting of alkoxys.

15. R ６ and R ７ One of them is hydrogen, and R ６ and R ７ The other side is, (a) A group consisting of chloro and fluoro; (b) C, which is optionally substituted with one or more substituents independently selected from the group consisting of halogens, hydroxy, methoxy, and halomethoxy. １～３ - Alkyl; and (c) The compound according to claim 1 or a pharmaceutically acceptable salt thereof, selected from the group consisting of cyclopropyl, which is optionally substituted with one or more substituents independently selected from the group consisting of cyano, methyl, trifluoromethyl, and ethoxy.

16. R ６ and R ７ One of them is hydrogen, and R ６ and R ７ The other side is, (a) A group consisting of chloro and fluoro; (b) C, which is optionally substituted with one or more substituents independently selected from the group consisting of methyl, ethyl, propyl, fluoromethyl, difluoromethyl, trifluoromethyl, fluoropropyl, hydroxyethyl, hydroxypropyl, methoxyethyl, methoxypropyl, trifluoromethoxymethyl, and trifluoromethoxyethyl. １～３ - Alkyl; and (c) The compound according to claim 1 or a pharmaceutically acceptable salt thereof, selected from the group consisting of cyclopropyl, which is optionally substituted with one or more substituents independently selected from the group consisting of cyano, methyl, trifluoromethyl, and ethoxy.

17. R ６ The compound according to claim 1 or a pharmaceutically acceptable salt thereof, wherein the compound is hydrogen.

18. R ７ The compound according to claim 1 or a pharmaceutically acceptable salt thereof, wherein the compound is hydrogen.

19. The aforementioned compound, 7-Chloro-N-(2-((1S,3S,5S)-3-cyano-2-azabicyclo[3.1.0]hexane-2-yl)-2-oxoethyl)-quinoline-4-carboxamide; 6-Bromo-N-(2-((1S,3S,5S)-3-cyano-2-azabicyclo[3.1.0]hexane-2-yl)-2-oxoethyl)-quinoline-4-carboxamide; 7-Bromo-N-(2-((1S,3S,5S)-3-cyano-2-azabicyclo[3.1.0]hexane-2-yl)-2-oxoethyl)-quinoline-4-carboxamide; N-(2-((1S,3S,5S)-3-cyano-2-azabicyclo[3.1.0]hexane-2-yl)-2-oxoethyl)-6-fluoro-2-methylquinoline-4-carboxamide; 6-Chloro-N-(2-((1S,3S,5S)-3-cyano-2-azabicyclo[3.1.0]hexane-2-yl)-2-oxoethyl)-2-methylquinoline-4-carboxamide; 6-Bromo-N-(2-((1S,3S,5S)-3-cyano-2-azabicyclo[3.1.0]hexane-2-yl)-2-oxoethyl)-2-methylquinoline-4-carboxamide; N-(2-((1S,3S,5S)-3-cyano-2-azabicyclo[3.1.0]hexane-2-yl)-2-oxoethyl)-6-iodo-2-methylquinoline-4-carboxamide; and A compound according to claim 1, or a pharmaceutically acceptable salt thereof, selected from the group consisting of N-(2-((1S,3S,5S)-3-cyano-2-azabicyclo[3.1.0]hexane-2-yl)-2-oxoethyl)-7-fluoro-2-methylquinoline-4-carboxamide.

20. The aforementioned compound, N-(2-((1S,3S,5S)-3-cyano-2-azabicyclo[3.1.0]hexane-2-yl)-2-oxoethyl)-7-methyl-quinoline-4-carboxamide; N-(2-((1S,3S,5S)-3-cyano-2-azabicyclo[3.1.0]hexane-2-yl)-2-oxoethyl)-6-methyl-quinoline-4-carboxamide; N-(2-((1S,3S,5S)-3-cyano-2-azabicyclo[3.1.0]hexane-2-yl)-2-oxoethyl)-6-(trifluoromethyl)quinoline-4-carboxamide; N-(2-((1S,3S,5S)-3-cyano-2-azabicyclo[3.1.0]hexane-2-yl)-2-oxoethyl)-6-(fluoromethyl)quinoline-4-carboxamide; N-(2-((1S,3S,5S)-3-cyano-2-azabicyclo[3.1.0]hexane-2-yl)-2-oxoethyl)-6-(2-fluoropropan-2-yl)quinoline-4-carboxamide; N-(2-((1S,3S,5S)-3-cyano-2-azabicyclo[3.1.0]hexane-2-yl)-2-oxoethyl)-6-(2-hydroxypropan-2-yl)quinoline-4-carboxamide; N-(2-((1S,3S,5S)-3-cyano-2-azabicyclo[3.1.0]hexane-2-yl)-2-oxoethyl)-6-(1-hydroxyethyl)quinoline-4-carboxamide; N-(2-((1S,3S,5S)-3-cyano-2-azabicyclo[3.1.0]hexane-2-yl)-2-oxoethyl)-6-(1-methoxyethyl)quinoline-4-carboxamide; N-(2-((1S,3S,5S)-3-cyano-2-azabicyclo[3.1.0]hexane-2-yl)-2-oxoethyl)-6-(2-methoxypropan-2-yl)quinoline-4-carboxamide; N-(2-((1S,3S,5S)-3-cyano-2-azabicyclo[3.1.0]hexane-2-yl)-2-oxoethyl)-6-((trifluoromethoxy)methyl)-quinoline-4-carboxamide; N-(2-((1S,3S,5S)-3-cyano-2-azabicyclo[3.1.0]hexane-2-yl)-2-oxoethyl)-6-ethyl-2-methylquinoline-4-carboxamide; N-(2-((1S,3S,5S)-3-cyano-2-azabicyclo[3.1.0]hexane-2-yl)-2-oxoethyl)-2,6-dimethylquinoline-4-carboxamide; N-(2-((1S,3S,5S)-3-cyano-2-azabicyclo[3.1.0]hexane-2-yl)-2-oxoethyl)-7-(2-fluoropropan-2-yl)quinoline-4-carboxamide; N-(2-((1S,3S,5S)-3-cyano-2-azabicyclo[3.1.0]hexane-2-yl)-2-oxoethyl)-7-(difluoromethyl)quinoline-4-carboxamide; N-(2-((1S,3S,5S)-3-cyano-2-azabicyclo[3.1.0]hexane-2-yl)-2-oxoethyl)-7-(trifluoromethyl)quinoline-4-carboxamide; N-(2-((1S,3S,5S)-3-cyano-2-azabicyclo[3.1.0]hexane-2-yl)-2-oxoethyl)-7-(fluoromethyl)quinoline-4-carboxamide; N-(2-((1S,3S,5S)-3-cyano-2-azabicyclo[3.1.0]hexane-2-yl)-2-oxoethyl)-7-(1-hydroxyethyl)quinoline-4-carboxamide; N-(2-((1S,3S,5S)-3-cyano-2-azabicyclo[3.1.0]hexane-2-yl)-2-oxoethyl)-7-(2-hydroxypropan-2-yl)quinoline-4-carboxamide; N-(2-((1S,3S,5S)-3-cyano-2-azabicyclo[3.1.0]hexane-2-yl)-2-oxoethyl)-7-(1-methoxyethyl)quinoline-4-carboxamide; N-(2-((1S,3S,5S)-3-cyano-2-azabicyclo[3.1.0]hexane-2-yl)-2-oxoethyl)-7-(2-methoxypropan-2-yl)quinoline-4-carboxamide; N-(2-((1S,3S,5S)-3-cyano-2-azabicyclo[3.1.0]hexane-2-yl)-2-oxoethyl)-7-((trifluoromethoxy)methyl)quinoline-4-carboxamide; N-(2-((1S,3S,5S)-3-cyano-2-azabicyclo[3.1.0]hexane-2-yl)-2-oxoethyl)-7-(1-(trifluoromethoxy)ethyl)quinoline-4-carboxamide; and A compound according to claim 1, selected from the group consisting of N-(2-((1S,3S,5S)-3-cyano-2-azabicyclo[3.1.0]hexane-2-yl)-2-oxoethyl)-2,7-dimethylquinoline-4-carboxamide, or a pharmaceutically acceptable salt thereof.

21. The aforementioned compound, N-(2-((1S,3S,5S)-3-cyano-2-azabicyclo[3.1.0]hexane-2-yl)-2-oxoethyl)-7-(1-cyanocyclopropyl)quinoline-4-carboxamide; N-(2-((1S,3S,5S)-3-cyano-2-azabicyclo[3.1.0]hexane-2-yl)-2-oxoethyl)-6-cyclopropylquinoline-4-carboxamide; N-(2-((1S,3S,5S)-3-cyano-2-azabicyclo[3.1.0]hexane-2-yl)-2-oxoethyl)-6-(1-methylcyclopropyl)quinoline-4-carboxamide; N-(2-((1S,3S,5S)-3-cyano-2-azabicyclo[3.1.0]hexane-2-yl)-2-oxoethyl)-6-(1-(trifluoromethyl)cyclopropyl)quinoline-4-carboxamide; N-(2-((1S,3S,5S)-3-cyano-2-azabicyclo[3.1.0]hexane-2-yl)-2-oxoethyl)-6-(1-ethoxycyclopropyl)quinoline-4-carboxamide; N-(2-((1S,3S,5S)-3-cyano-2-azabicyclo[3.1.0]hexane-2-yl)-2-oxoethyl)-6-(1-cyanocyclopropyl)quinoline-4-carboxamide; N-(2-((1S,3S,5S)-3-cyano-2-azabicyclo[3.1.0]hexane-2-yl)-2-oxoethyl)-7-cyclopropylquinoline-4-carboxamide; N-(2-((1S,3S,5S)-3-cyano-2-azabicyclo[3.1.0]hexane-2-yl)-2-oxoethyl)-7-(1-methylcyclopropyl)quinoline-4-carboxamide; N-(2-((1S,3S,5S)-3-cyano-2-azabicyclo[3.1.0]hexane-2-yl)-2-oxoethyl)-7-(1-(trifluoromethyl)cyclopropyl)quinoline-4-carboxamide; and A compound according to claim 1, or a pharmaceutically acceptable salt thereof, selected from the group consisting of N-(2-((1S,3S,5S)-3-cyano-2-azabicyclo[3.1.0]hexane-2-yl)-2-oxoethyl)-7-(1-ethoxycyclopropyl)quinoline-4-carboxamide.

22. The aforementioned compound, N-(2-((1S,3S,5S)-3-cyano-2-azabicyclo[3.1.0]hexane-2-yl)-2-oxoethyl)-6-(2,2,2-trifluoroethoxy)quinoline-4-carboxamide; N-(2-((1S,3S,5S)-3-cyano-2-azabicyclo[3.1.0]hexane-2-yl)-2-oxoethyl)-6-isopropoxyquinoline-4-carboxamide; and A compound according to claim 1, or a pharmaceutically acceptable salt thereof, selected from the group consisting of N-(2-((1S,3S,5S)-3-cyano-2-azabicyclo[3.1.0]hexane-2-yl)-2-oxoethyl)-6-(cyclopropylmethoxy)quinoline-4-carboxamide.

23. The aforementioned compound has the following structure: The compound according to claim 1 or a pharmaceutically acceptable salt thereof, having N-(2-((1S,3S,5S)-3-cyano-2-azabicyclo[3.1.0]hexane-2-yl)-2-oxoethyl)-7-methoxy-2-methylquinoline-4-carboxamide.

24. The aforementioned compound has the following structure: A compound according to claim 1 or a pharmaceutically acceptable salt thereof, selected from the group consisting of N-(2-((1S,3S,5S)-3-cyano-2-azabicyclo[3.1.0]hexane-2-yl)-2-oxoethyl)-6-((4,4-difluorocyclohexyl)oxy)quinoline-4-carboxamide having the above.

25. The aforementioned compound has the following structure: The compound according to claim 1 or a pharmaceutically acceptable salt thereof, having N-(2-((1S,3S,5S)-3-cyano-2-azabicyclo[3.1.0]hexane-2-yl)-2-oxoethyl)-7-methylquinoline-4-carboxamide.

26. A pharmaceutical composition comprising a compound according to any one of claims 1 to 25 or a pharmaceutically acceptable salt thereof, and one or more pharmaceutically acceptable excipients.

27. A pharmaceutical agent for treating or preventing a FAP-mediated condition, comprising a compound described in any one of claims 1 to 25 or a pharmaceutically acceptable salt thereof.

28. The pharmaceutical product according to claim 27, wherein the FAP-mediated condition is selected from the group consisting of liver disease, type 2 diabetes mellitus, cardiovascular condition, obesity, obesity-related condition, fibrosis, keloid disorder, inflammation, and cancer.

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