N-(2-(3-cyano-2-azabicyclo [3.1. 0] hex-2-yl)-2-oxoethyl)-quinoline-4-carboxamides

Abstract

The present invention provides compounds having the structure of formula (I) and pharmaceutically acceptable salts thereof, wherein R2, R3, R5, R6, R7 and R8 are as defined in the specification; pharmaceutical compositions comprising such compounds and salts; the use of such compounds and salts for the treatment or prevention of prolyl endopeptidase fibroblast activation protein (FAP) mediated disorders; comprising such compounds and salts; and processes for preparing such compounds and salts. # imgabs0 #

Description

[0001] Cross-references to related patent applications

[0002] This specification claims the benefit of priority to U.S. Provisional Patent Application No. 63 / 366,700 (filed on June 21, 2022). The entire text of the above patent application is incorporated into this specification by reference. Technical Field

[0003] The present disclosure as a whole relates to N-(2-(3-cyano-2-azabicyclo-[3.1.0]hex-2-yl)-2-oxoethyl)quinoline-4-carboxamide and pharmaceutically acceptable salts thereof. The present specification also 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 disorders; kits comprising such compounds and salts; and methods for preparing such compounds and salts. Background Art

[0004] FAP (type II transmembrane serine protease) is expressed by fibroblast-like cells involved in tissue remodeling and healing. In non-alcoholic steatohepatitis (NASH), FAP is upregulated on the cell surface of activated hepatic stellate cells involved in fibrosis formation (Hepatology 1999, 29, 1768), which is a major aspect of NASH for predicting disease outcomes (Gastroenterology 2020, 158, 1611). FAP can also exist as a shed plasma protease. Increased levels of circulating FAP are associated with NASH disease severity (Diabetes Res Clin Pract 2015, 108, 466).

[0005] FAP has a common cleavage motif after Gly-Pro and exhibits endopeptidase activity and exopeptidase activity. Known enzyme activities include the cutting 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 the cutting of collagen) on the cell surface of activated fibroblasts creates a pro-fibrotic environment. FAP cleavage of α2AP can make α2AP more effectively cross-linked to fibrin, thereby reducing fibrin clearance. FAP cleavage of FGF21 can inactivate FGF21 metabolism (Biochem J 2016, 473, 605). All of these activities are associated with the exacerbation of NASH disease, and inhibition of FAP has the potential to treat NASH and other conditions by affecting multiple mechanisms.

[0006] Inhibition of FAP activity is currently an undeveloped therapeutic approach for treating NASH and other diseases associated with FAP activity. There are currently no approved pharmacological agents that inhibit FAP activity generally or specifically. Therefore, there is a need for FAP inhibitors, particularly FAP inhibitors with pharmacologically appropriate selectivity and bioavailability, suitable for administration to subjects in need of such treatment. The present disclosure addresses this large unmet need by providing such compounds and their corresponding pharmaceutical compositions and methods for treating or preventing NASH and related conditions. Summary of the invention

[0007] In one aspect, the present disclosure provides compounds having the structure of Formula (I):

[0008]

[0009] and pharmaceutically acceptable salts thereof, wherein:

[0010] R 2 is selected from hydrogen, halogen and methyl;

[0011] R 3 is hydrogen or halogen;

[0012] R 5 is selected from hydrogen, hydroxy, halogen, methyl and methoxy;

[0013] R 6 and R 7 One of them is hydrogen, and R 6 and R 7 The other one is selected from:

[0014] (a) halogen;

[0015] (b)C 1-6 -alkyl, wherein the C 1-6 -alkyl is optionally substituted by one or more independently selected from halogen, hydroxy, C 1-6 -alkoxy, halo-C 1-6 -alkoxy, C 3-6 -cycloalkyl and C 3-6 - Substitution of cycloalkoxy groups;

[0016] (c) cyclopropyl, wherein the cyclopropyl is optionally substituted by one or more independently selected from cyano, fluoro, C 1-6 -alkyl, halo-C 1-6 -alkyl and C 1-6 - Substitution of alkoxy groups;

[0017] (d)C 1-6 -alkoxy, wherein the C 1-6- alkoxy is optionally substituted with one or more substituents independently selected from halogen and cyclopropyl; and

[0018] (e)C 3-6 -cycloalkoxy, wherein the C 3-6 -cycloalkoxy is optionally substituted by one or more independently selected from halogen and C 1-3 - alkyl is substituted with a substituent; and

[0019] R 8 is selected from hydrogen, halogen and methyl.

[0020] In another aspect, the present 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.

[0021] In another aspect, the present disclosure provides pharmaceutical compositions comprising a therapeutically effective amount of a compound having a 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, and a pharmaceutically acceptable carrier.

[0022] In another aspect, the present disclosure provides pharmaceutical compositions comprising a therapeutically effective amount of a compound having a structure of Formula (I), (II-A), (II-B), (II-C), (III-A), (III-B) or (III-C), or a pharmaceutically acceptable salt thereof, as further defined herein; a second pharmacological agent; and a pharmaceutically acceptable carrier.

[0023] In another aspect, the present disclosure provides methods of treating or preventing a FAP-mediated disorder by administering to a subject in need thereof 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 herein, or a pharmaceutically acceptable salt thereof. In one aspect, the FAP-mediated disorder is selected from liver disease, type 2 diabetes, a cardiovascular disorder, obesity, an obesity-related disorder, fibrosis, a keloid disorder, inflammation and cancer. In another aspect, the FAP-mediated disorder is a liver disease, in particular non-alcoholic steatohepatitis (NASH).

[0024] In another aspect, the present disclosure provides a compound having a 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 disorder.

[0025] In another aspect, the present disclosure provides the use of a compound having a 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 disorder.

[0026] In another aspect, the present disclosure provides kits comprising a compound having a 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.

[0027] In another aspect, the present disclosure provides methods for preparing compounds having a 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

[0028] Numerous embodiments are described in detail throughout the specification and will be apparent to those skilled in the art. This specification should not be construed as limited to any specific embodiment described herein.

[0029] I. Definitions

[0030] With respect to the embodiments disclosed in this specification, the following terms have the following meanings:

[0031] References to "a" or "an" mean "one or more." Throughout the text, except where quantities are indicated, plural and singular are to be regarded as interchangeable.

[0032] Unless the context requires otherwise, the words "comprise," "comprises," or "comprising" are used with the basis and express understanding that such words are to be interpreted inclusively and not exclusively, and applicants intend that each of such words be so interpreted when interpreting this patent, including the claims below.

[0033] The term "halogen" (alone or in combination with other terms) refers to a fluoro (which may be depicted as -F), chloro (which may be depicted as -Cl), bromo (which may be depicted as -Br) or iodo (which may be depicted as -I).

[0034] The term "hydroxy" (alone or in combination with another term(s)) means -OH.

[0035] The term "cyano" (alone or in combination with other terms) means -CN.

[0036] The term "alkyl" (alone or in combination with other terms) refers to a straight-chain or branched-chain saturated hydrocarbon substituent (i.e., a substituent containing only carbon and hydrogen). Alkyl groups typically contain 1 to about 20 carbon atoms, more typically 1 to about 12 carbon atoms, even more typically 1 to about 8 carbon atoms, and even more typically 1 to about 6 carbon atoms. Examples of such substituents include methyl, ethyl, propyl (including n-propyl and isopropyl), butyl (including n-butyl, isobutyl, sec-butyl and tert-butyl), pentyl (including n-pentyl, iso-pentyl and 2,2-dimethylpropyl) and hexyl.

[0037] The term "cycloalkyl" (alone or in combination with other terms) refers to 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. Cycloalkyl includes a single carbocyclic ring, which typically contains 3 to 6 carbon ring atoms. Examples of mono-cyclic cycloalkyls include cyclopropyl, cyclobutyl, cyclopentyl, and cyclohexyl.

[0038] The term "alkoxy" (alone or in combination with other terms) refers to an alkyl ether substituent (ie, alkyl-O-). Examples of alkoxy include methoxy (CH 3 -O-), ethoxy, n-propoxy, isopropoxy, n-butoxy, isobutoxy, sec-butoxy and tert-butoxy. Thus, for example:

[0039] (i) The term "alkoxyalkyl" (alone or in combination with other terms) means an alkyl group substituted by an alkoxy group, such as "methoxymethyl", which may be described as:

[0040]

[0041] (ii) The term "cycloalkylalkoxy" (alone or in combination with another term(s)) means an alkoxy group substituted by a cycloalkyl group, such as "cyclopropylmethoxy", which may be depicted as:

[0042]

[0043] The term "cycloalkoxy" (alone or in combination with other terms) refers to a cycloalkyl ether substituent (i.e., cycloalkyl-O-). Examples of cycloalkoxy include cyclopropyloxy, cyclobutyloxy, cyclopentyloxy, and cyclohexyloxy. Thus, for example, the term "alkylcycloalkoxy" (alone or in combination with other terms) refers to a cycloalkoxy group substituted with an alkyl group, such as "methylcyclopropyloxy", which can be described as:

[0044]

[0045] In some cases, the number of carbon atoms in a substituent (e.g., alkyl, cycloalkyl, etc.) is indicated by the prefix "C x-y -". In the substituent, x is the minimum number of carbon atoms and y is the maximum number of carbon atoms. Thus, for example, "C 1-6 -alkyl" refers to an alkyl substituent containing 1 to 6 carbon atoms. Further, C 3-6 -Cycloalkyl refers to a cycloalkyl substituent containing 3 to 6 carbon ring atoms.

[0046] The prefix "halo" indicates that the substituent to which the prefix is ​​attached is substituted by one or more independently selected halogen groups. For example, a haloalkyl group refers to an alkyl substituent in which at least one hydrogen group is replaced by a halogen group. When more than one hydrogen is replaced by a halogen, the halogens may be the same or different. Examples of haloalkyl groups include fluoromethyl, difluoromethyl, trifluoromethyl, difluoroethyl, 1,1,1-trifluoroethyl, pentafluoroethyl, difluoropropyl, heptafluoropropyl, chloromethyl, dichloromethyl, trichloromethyl, difluorochloromethyl, dichlorofluoromethyl, and dichloropropyl. Similarly, a "haloalkoxy" group refers to an alkoxy substituent in which at least one hydrogen group is replaced by a halogen group. When more than one hydrogen is replaced by a halogen, the halogens may be the same or different. Examples of haloalkoxy substituents include fluoromethoxy, difluoromethoxy, trifluoromethoxy (also known as "perfluoromethoxy"), 1,1,1-trifluoroethoxy, and chloromethoxy.

[0047] A substituent is "substitutable" if it contains at least one carbon or nitrogen atom bonded to one or more hydrogen atoms. Thus, for example, hydrogen, halogen, and cyano do not fall within this definition.

[0048] If a substituent is described as "substituted," a non-hydrogen group is substituted for a hydrogen group on a carbon or nitrogen on the substituent. Thus, for example, a substituted alkyl substituent is an alkyl substituent in which at least one non-hydrogen group is substituted for a hydrogen group on the alkyl substituent. For example, a monofluoroalkyl is an alkyl substituted with one fluoro group, and a difluoroalkyl is an alkyl substituted with two fluoro groups. It should be recognized that if there is more than one substitution on a substituent, each non-hydrogen group may be the same or different (unless otherwise specified).

[0049] If a substituent is described as "optionally substituted," the substituent may be any of the following: (1) unsubstituted or (2) substituted. If a carbon of a substituent is described as optionally substituted with one or more of a list of substituents, then one or more hydrogens on the carbon (if any) may be substituted individually and / or together with independently selected optional substituents. If a nitrogen of a substituent is described as optionally substituted with one or more of a list of substituents, then one or more hydrogens on the nitrogen (if any) may each be substituted with an independently selected optional substituent.

[0050] If substituents are described as being "independently selected" from a group, each substituent is selected independently of the others. Thus, each substituent may be the same as or different from the other substituents.

[0051] The term "pharmaceutically acceptable" is used as an adjective in this specification, meaning that the modified noun is suitable for use as a pharmaceutical product or a part of a pharmaceutical product. For example, "pharmaceutically acceptable salts" are salts suitable for mammals (especially humans), and include salts suitable for mammals (especially humans) and inorganic bases, organic bases, inorganic acids, organic acids or basic amino acids or acidic amino acids.

[0052] A "therapeutically effective amount" of a pharmacological agent is an amount sufficient to achieve a beneficial or desired effect, including a clinical effect, and will therefore depend on the context in which it is administered. For example, in the case of administering a pharmacological agent to treat liver disease, a therapeutically effective amount of the agent refers to an amount of the agent, alone or in combination with an additional therapy, sufficient to provide an anti-liver disease effect in a subject as compared to the response obtained without administration of the agent.

[0053] The term "prevention" will be readily understood by a physician of ordinary skill and, with respect to the treatment of a particular condition, is intended to include its ordinary meaning and includes primary prevention, which is intended to prevent the development of that condition, and secondary prevention, which is intended to temporarily or permanently protect the patient from worsening or worsening of the disease, or the development of new symptoms associated with the condition, if the condition has already developed.

[0054] The term "treat" is readily understood by a physician of ordinary skill and, with respect to treatment of a particular condition, may 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. For example, treatment of liver disease may include stabilizing (i.e., not worsening), delaying or slowing the spread or progression of liver disease; prolonging survival compared to expected survival without treatment; and / or otherwise ameliorating or alleviating the severity of the cancer or liver disease, in whole or in part.

[0055] II.Compounds

[0056] A. Compounds of formula (I)

[0057] In one embodiment, the present disclosure provides a compound having the structure of Formula (I):

[0058]

[0059] and pharmaceutically acceptable salts thereof, wherein:

[0060] R 2 is selected from hydrogen, halogen and methyl;

[0061] R 3 is hydrogen or halogen;

[0062] R 5 is selected from hydrogen, hydroxy, halogen, methyl and methoxy;

[0063] R 6 and R 7 One of them is hydrogen, and R 6 and R 7 The other one is selected from:

[0064] (a) halogen;

[0065] (b)C 1-6 -alkyl, wherein the C 1-6 -alkyl is optionally substituted by one or more independently selected from halogen, hydroxy, C 1-6 -alkoxy, halo-C 1-6 -alkoxy, C 3-6 -cycloalkyl and C 3-6 - Substitution of cycloalkoxy groups;

[0066] (c) cyclopropyl, wherein the cyclopropyl is optionally substituted by one or more independently selected from cyano, fluoro, C 1-6 -alkyl, halo-C 1-6 -alkyl and C 1-6 - Substitution of alkoxy groups;

[0067] (d)C 1-6 -alkoxy, wherein the C 1-6 - alkoxy is optionally substituted with one or more substituents independently selected from halogen and cyclopropyl; and

[0068] (e)C 3-6 -cycloalkoxy, wherein the C 3-6 -cycloalkoxy is optionally substituted by one or more independently selected from halogen and C 1-3 - alkyl is substituted with a substituent; and

[0069] R 8 is selected from hydrogen, halogen and methyl.

[0070] In some embodiments, R 2 is selected from hydrogen, chlorine, fluorine and methyl. 2 In another aspect, R 2 is selected from hydrogen, fluorine and methyl. 2 is hydrogen or halogen. 2 is hydrogen or chlorine. 2 is hydrogen or fluorine.2 is hydrogen or methyl. 2 is hydrogen. On the other hand, R 2 is halogen. On the other hand, R 2 On the other hand, R 2 is fluorine. On the other hand, R 2 It is methyl.

[0071] In some embodiments, R 3 is selected from hydrogen, chlorine and fluorine. 3 is hydrogen or chlorine. 3 is hydrogen or fluorine. 3 is hydrogen. On the other hand, R 3 is halogen. On the other hand, R 3 On the other hand, R 3 For fluorine.

[0072] In some embodiments, R 5 is selected from the group consisting of hydrogen, hydroxy, chloro, fluoro, methyl and methoxy. 5 In another aspect, R 5 is selected from hydrogen, fluorine and methyl. 5 is hydrogen or halogen. 5 is hydrogen or chlorine. 5 is hydrogen or fluorine. 5 is hydrogen or methyl. 5 is hydrogen. On the other hand, R 5 On the other hand, R 5 is halogen. On the other hand, R 5 On the other hand, R 5 is fluorine. On the other hand, R 5 On the other hand, R 5 It is a methoxy group.

[0073] In some embodiments, R 8 is selected from hydrogen, chlorine, fluorine and methyl. 8 is hydrogen or chlorine. 8 is hydrogen or fluorine. 8 is hydrogen or methyl. 8 is hydrogen. On the other hand, R 8 is halogen. On the other hand, R 8 On the other hand, R 8 is fluorine. On the other hand, R 8 It is methyl.

[0074] In some embodiments, R 2 is selected from hydrogen, chlorine, fluorine and methyl; R 3 is selected from hydrogen, chlorine and fluorine; R 5 is selected from hydrogen, hydroxy, chloro, fluoro, methyl and methoxy; and R 8 is selected from the group consisting of hydrogen, chlorine, fluorine and methyl.

[0075] In some embodiments, R 2 is selected from hydrogen, chlorine, fluorine and methyl; R 3 is selected from hydrogen, chlorine and fluorine; R 5 is selected from hydrogen, chlorine and fluorine; and R 8 Selected from hydrogen, chlorine and fluorine.

[0076] In some embodiments, R 2 is selected from hydrogen, fluorine and methyl; R 3 is hydrogen or fluorine; R 5 is hydrogen or fluorine; and R 8 is hydrogen or fluorine.

[0077] In some embodiments, R 2 is hydrogen or methyl; R 3 is selected from hydrogen, chlorine and fluorine; R 5 is selected from hydrogen, chlorine and fluorine; and R 8 Selected from hydrogen, chlorine and fluorine.

[0078] In some embodiments, R 2 , R 3 , R 5 and R 8 are independently selected from hydrogen and fluorine.

[0079] In some embodiments, R 2 , R 3 , R 5 and R 8 Two of the substituents are not hydrogen, and the remaining R 2 , R 3 , R 5 and R 8 All substituents are hydrogen.

[0080] In some embodiments, R 2 , R 3 , R 5 and R 8 One of the substituents is not hydrogen, and the remaining R 2 , R 3 , R 5 and R 8 All substituents are hydrogen.

[0081] In some embodiments, R 2, R 3 , R 5 and R 8 All substituents are hydrogen.

[0082] In some embodiments, R 6 and R 7 One of is not hydrogen, and R 6 and R 7 The other of is hydrogen. In one aspect, R 6 is not hydrogen, and R 7 is hydrogen. On the other hand, R 6 is hydrogen, and R 7 Not hydrogen.

[0083] In some embodiments, R 6 and R 7 One of is hydrogen and the other is halogen. In one aspect, R 6 and R 7 One of is hydrogen and the other is chlorine. On the other hand, R 6 and R 7 One of is hydrogen and the other is fluorine. 6 and R 7 One of is hydrogen and the other is bromine. On the other hand, R 6 and R 7 One of them is hydrogen and the other is iodine.

[0084] In some embodiments, R 6 and R 7 One of them is hydrogen and the other is C 1-6 -alkyl, wherein the C 1-6 -alkyl is optionally substituted by one or more independently selected from halogen, hydroxy, C 1-6 -alkoxy, halo-C 1-6 -alkoxy, C 3-6 Cycloalkyl and C 3-6 -cycloalkyloxy is substituted with a substituent. 6 and R 7 One of them is hydrogen and the other is C 1-3 -alkyl, wherein the C 1-3 -alkyl is optionally substituted by one or more independently selected from halogen, hydroxy, C 1-3 -alkoxy, halo-C 1-3 -alkoxy, C 3-6 -cycloalkyl and C 3-6 -cycloalkyloxy is substituted with a substituent. 6 and R 7 One of them is hydrogen and the other is C1-3 -alkyl, wherein the C 1-3 -alkyl is optionally substituted with one or more substituents independently selected from halogen, hydroxy, methoxy and halomethoxy. 6 and R 7 One of them is hydrogen and the other is C 1-3 -alkyl, wherein the C 1-3 -alkyl is optionally substituted with one or more substituents independently selected from fluoro, hydroxy, methoxy and fluoromethoxy. 6 and R 7 One of them is hydrogen and the other is C 1-3 -alkyl, wherein the C 1-3 -alkyl is optionally substituted with one or more substituents independently selected from fluoro and methoxy. 6 and R 7 One of them is hydrogen and the other is C 1-6 -alkyl, wherein the C 1-6 -alkyl is optionally substituted by one or more independently selected from halogen and C 1-6 -alkoxy is substituted with a substituent. 6 and R 7 One of them is hydrogen and the other is C 1-3 -alkyl, wherein the C 1-3 -alkyl is optionally substituted by one or more independently selected from halogen and C 1-3 -substituted by a substituent of the alkoxy group.

[0085] 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 -alkyl. On the other hand, R 6 and R 7 One of them is hydrogen and the other is methyl.

[0086] In some embodiments, R 6 and R 7 One of them is hydrogen and the other is C 1-6 -alkyl, wherein the 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, wherein the C 1-3 -Alkyl is optionally substituted by one or more fluorine.

[0087] In some embodiments, R 6 and R 7 One of them is hydrogen and the other is C 1-6 -alkyl, wherein the C 1-6 -alkyl is optionally substituted with one or more hydroxyl groups. 6 and R 7 One of them is hydrogen and the other is C 1-3 -alkyl, wherein the C 1-3 The -alkyl group is optionally substituted with one or more hydroxy groups.

[0088] In some embodiments, R 6 and R 7 One of them is hydrogen and the other is C 1-6 -alkyl, wherein the C 1-6 -alkyl is optionally substituted with one or more C 1-6 -alkoxy substituted. In one aspect, R 6 and R 7 One of them is hydrogen and the other is C 1-3 -alkyl, wherein the C 1-3 -alkyl is optionally substituted with one or more C 1-3 -Alkoxy substitution.

[0089] In some embodiments, R 6 and R 7 One of them is hydrogen and the other is C 1-6 -alkyl, wherein the C 1-6 -alkyl is optionally substituted with one or more halo-C 1-6 -alkoxy substituted. In one aspect, R 6 and R 7 One of them is hydrogen and the other is C 1-3 -alkyl, wherein the C 1-3 -alkyl is optionally substituted with one or more halo-C 1-3 -alkoxy substituted. On the other hand, R 6 and R 7 One of them is hydrogen and the other is C 1-3 -alkyl, wherein the C 1-3 -alkyl is optionally substituted with one or more fluoro-C 1-3 -Alkoxy substitution.

[0090] In some embodiments, R 6 and R 7 One of them is hydrogen and the other is C 1-6 -alkyl, wherein the C 1-6 -alkyl is optionally substituted with one or more C3-6 -cycloalkyl substituted. In one aspect, R 6 and R 7 One of them is hydrogen and the other is C 1-3 -alkyl, wherein the C 1-3 -alkyl is optionally substituted with one or more C 3-6 -cycloalkyl substitution.

[0091] In some embodiments, R 6 and R 7 One of them is hydrogen and the other is C 1-6 -alkyl, wherein the C 1-6 -alkyl is optionally substituted with one or more C 3-6 -cycloalkyloxy substituted. In one aspect, R 6 and R 7 One of them is hydrogen and the other is C 1-3 -alkyl, wherein the C 1-3 -alkyl is optionally substituted with one or more C 3-6 -cycloalkoxy substitution.

[0092] In some embodiments, R 6 and R 7 One of R is hydrogen and the other is selected from methyl, ethyl, fluoromethyl, difluoromethyl, trifluoromethyl, fluoropropyl, hydroxyethyl, hydroxypropyl, methoxyethyl, methoxypropyl, trifluoromethoxymethyl and trifluoromethoxyethyl. 6 and R 7 One of the groups is hydrogen, and the other is selected from the group consisting of methyl, ethyl, fluoromethyl, difluoromethyl, trifluoromethyl, fluoropropyl, methoxyethyl and methoxypropyl.

[0093] In some embodiments, R 6 and R 7 One of them is hydrogen and the other is cyclopropyl, wherein the cyclopropyl is optionally substituted by one or more independently selected from cyano, fluoro, C 1-6 -alkyl, halo-C 1-6 -alkyl and C 1-6 -alkoxy is substituted with a substituent. 6 and R 7 One of them is hydrogen and the other is cyclopropyl, wherein the cyclopropyl is optionally substituted by one or more independently selected from cyano, fluoro, C 1-3 -alkyl, halo-C 1-3 -alkyl and C 1-3 -alkoxy is substituted with a substituent. 6 and R 7One of them is hydrogen and the other is cyclopropyl, wherein the cyclopropyl is optionally substituted by one or more independently selected from cyano, C 1-3 -alkyl, fluoro-C 1-3 -alkyl and C 1-3 -substituted by a substituent of the alkoxy group.

[0094] In some embodiments, R 6 and R 7 One of them is hydrogen and the other is cyclopropyl.

[0095] In some embodiments, R 6 and R 7 One of the is hydrogen and the other is cyclopropyl, wherein the cyclopropyl is optionally substituted with one or more cyano groups.

[0096] In some embodiments, R 6 and R 7 One of the is hydrogen and the other is cyclopropyl, wherein the cyclopropyl is optionally substituted with one or more fluorines.

[0097] In some embodiments, R 6 and R 7 One of them is hydrogen and the other is cyclopropyl, wherein the cyclopropyl is optionally substituted with one or C 1-6 -alkyl substituted. In one aspect, R 6 and R 7 One of them is hydrogen and the other is cyclopropyl, wherein the cyclopropyl is optionally substituted with one or more C 1-3 -alkyl substitution.

[0098] In some embodiments, R 6 and R 7 One of them is hydrogen and the other is cyclopropyl, wherein the cyclopropyl is optionally substituted with one or more halo-C 1-6 -alkyl substituted. In one aspect, R 6 and R 7 One of them is hydrogen and the other is cyclopropyl, wherein the cyclopropyl is optionally substituted with one or more halo-C 1-3 -alkyl substitution. On the other hand, R 6 and R 7 One of the cyclopropyl radicals is hydrogen and the other is cyclopropyl, wherein the cyclopropyl radical is optionally substituted with one or more fluoro-C 1-3 -alkyl substitution.

[0099] In some embodiments, R 6 and R 7 One of them is hydrogen and the other is cyclopropyl, wherein the cyclopropyl is optionally substituted with one or more C 1-6-alkoxy substituted. On the other hand, R 6 and R 7 One of them is hydrogen and the other is cyclopropyl, wherein the cyclopropyl is optionally substituted with one or more C 1-3 -Alkoxy substitution.

[0100] In some embodiments, R 6 and R 7 One of the is hydrogen and the other is cyclopropyl, wherein the cyclopropyl is optionally substituted with one or more substituents independently selected from cyano, methyl, trifluoromethyl and ethoxy.

[0101] In some embodiments, R 6 and R 7 One of them is hydrogen and the other is C 1-6 -alkoxy, wherein the C 1-6 -alkoxy is optionally substituted with one or more substituents independently selected from halogen and cyclopropyl. 6 and R 7 One of them is hydrogen and the other is C 1-3 -alkoxy, wherein the C 1-3 -alkoxy is optionally substituted with one or more substituents independently selected from halogen and cyclopropyl.

[0102] In some embodiments, R 6 and R 7 One of them is hydrogen and the other is C 1-6 -alkoxy. In one aspect, R 6 and R 7 One of them is hydrogen and the other is C 1-3 -alkoxy.

[0103] In some embodiments, R 6 and R 7 One of them is hydrogen and the other is C 1-6 -alkoxy, wherein the 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, wherein the C 1-3 -alkoxy is optionally substituted by one or more halogens. 6 and R 7 One of them is hydrogen and the other is C 1-3 -alkoxy, wherein the C 1-3 The -alkoxy group is optionally substituted by one or more fluorine groups.

[0104] In some embodiments, R 6 and R 7 One of them is hydrogen and the other is C 1-6 -alkoxy, wherein the C 1-6 -alkoxy is optionally substituted with one or more cyclopropyl groups. In one aspect, R 6 and R 7 One of them is hydrogen and the other is C 1-3 -alkoxy, wherein the C 1-3 The -alkoxy group is optionally substituted by one or more cyclopropyl groups.

[0105] In some embodiments, R 6 and R 7 One of the groups is hydrogen, and the other is selected from methoxy, propoxy, trifluoroethoxy and cyclopropylmethoxy.

[0106] In some embodiments, R 6 and R 7 One of them is hydrogen and the other is C 3-6 -cycloalkoxy, wherein the C 3-6 -cycloalkoxy is optionally substituted with one or more C 1-3 -alkyl substitution.

[0107] In some embodiments, R 6 and R 7 One of them is hydrogen and the other is C 3-6 -cycloalkoxy, wherein the 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, wherein the C 3-6 -cycloalkoxy is optionally substituted with one or more fluorine. 6 and R 7 One of R is hydrogen, and the other is cyclohexyloxy, wherein the cyclohexyloxy is optionally substituted with one or more halogens. 6 and R 7 One of R is hydrogen, and the other is cyclohexyloxy, wherein the cyclohexyloxy is optionally substituted with one or more fluorine. 6 and R 7 In one embodiment, R is hydrogen, and the other is cyclopropyloxy, wherein the cyclopropyloxy is optionally substituted with one or more halogens. 6 and R 7 One of the is hydrogen and the other is cyclopropyloxy, wherein the cyclopropyloxy is optionally substituted by one or more fluorines.

[0108] In some embodiments, R 6 and R 7 One of them is hydrogen and the other is C 3-6 -cycloalkyloxy. In one aspect, R 6 and R 7 One of is hydrogen and the other is cyclopropyloxy. 6 and R 7 One of them is hydrogen and the other is cyclohexyloxy.

[0109] In some embodiments, the compound and its pharmaceutically acceptable salts have the structure of Formula (II-A):

[0110]

[0111] Where R 6 and R 7 As defined in the various embodiments of this specification.

[0112] In some embodiments, the compound and its pharmaceutically acceptable salts have the structure of Formula (II-B):

[0113]

[0114] Where R 7 As defined in the various embodiments of this specification.

[0115] In some embodiments, the compound and its pharmaceutically acceptable salts have the structure of Formula (II-C):

[0116]

[0117] Where R 6 As defined in the various embodiments of this specification.

[0118] In some embodiments, the compound and its pharmaceutically acceptable salts have the structure of Formula (III-A):

[0119]

[0120] Where R 6 and R 7 As defined in the various embodiments of this specification.

[0121] In some embodiments, the compound and its pharmaceutically acceptable salts have the structure of Formula (III-B):

[0122]

[0123] Where R 7As defined in the various embodiments of this specification.

[0124] In some embodiments, the compound and its pharmaceutically acceptable salts have the structure of Formula (III-C):

[0125]

[0126] Where R 6 As defined in the various embodiments of this specification.

[0127] B. Implementation Plan

[0128] Embodiment 1: A compound having a structure of formula (I) or a pharmaceutically acceptable salt thereof, wherein R 6 and R 7 One of them is hydrogen, and R 6 and R 7 The other one is selected from:

[0129] (a) halogen;

[0130] (b)C 1-6 -alkyl, wherein the C 1-6 -alkyl is optionally substituted by one or more independently selected from halogen, hydroxy, C 1-6 -alkoxy, halo-C 1-6 -alkoxy, C 3-6 -cycloalkyl and C 3-6 - substitution of the cycloalkoxy group with a substituent; and

[0131] (c) cyclopropyl, wherein the cyclopropyl is optionally substituted by one or more independently selected from cyano, fluoro, C 1-6 -alkyl, halo-C 1-6 -alkyl and C 1-6 -substituted by a substituent of the alkoxy group.

[0132] Embodiment 2: A compound having a structure of formula (I) or a pharmaceutically acceptable salt thereof, wherein:

[0133] R 2 is selected from hydrogen, halogen and methyl;

[0134] R 3 is hydrogen or halogen;

[0135] R 5 is selected from hydrogen, hydroxy, halogen, methyl and methoxy;

[0136] R 6 and R 7 One of them is hydrogen, and R 6 and R 7 The other one is selected from:

[0137] (a) halogen;

[0138] (b)C 1-6 -alkyl, wherein the C 1-6 -alkyl is optionally substituted by one or more independently selected from halogen, hydroxy, C 1-6 -alkoxy and halo-C 1-6 - substitution of the alkoxy group with a substituent; and

[0139] (c) cyclopropyl, wherein the cyclopropyl is optionally substituted by one or more independently selected from cyano, C 1-6 -alkyl, halo-C 1-6 -alkyl and C 1-6 - substituted with a substituent of the alkoxy group; and

[0140] R 8 is hydrogen or halogen.

[0141] Embodiment 3: A compound having a structure of formula (I) or a pharmaceutically acceptable salt thereof, wherein:

[0142] R 2 is selected from the group consisting of hydrogen, chlorine, fluorine and methyl;

[0143] R 3 is selected from the group consisting of hydrogen, chlorine and fluorine;

[0144] R 5 is selected from the group consisting of hydrogen, hydroxy, chlorine, fluorine, methyl and methoxy;

[0145] R 6 and R 7 One of them is hydrogen, and R 6 and R 7 The other one is selected from:

[0146] (a) halogen;

[0147] (b)C 1-6 -alkyl, wherein the C 1-6 -alkyl is optionally substituted by one or more independently selected from halogen, hydroxy, C 1-6 -alkoxy and halo-C 1-6 - substitution of the alkoxy group with a substituent; and

[0148] (c) cyclopropyl, wherein the cyclopropyl is optionally substituted by one or more independently selected from cyano, C 1-6 -alkyl, halo-C 1-6 -alkyl and C 1-6 - substituted with a substituent of the alkoxy group; and

[0149] R 8 Selected from hydrogen, chlorine and fluorine.

[0150] Embodiment 4: A compound having a structure of formula (I) or a pharmaceutically acceptable salt thereof, wherein:

[0151] R 2 is selected from the group consisting of hydrogen, chlorine and methyl;

[0152] R 3 is hydrogen or chlorine;

[0153] R 5 is hydrogen or chlorine;

[0154] R 6 and R 7 One of them is hydrogen, and R 6 and R 7 The other one is selected from:

[0155] (a) halogen;

[0156] (b)C 1-6 -alkyl, wherein the C 1-6 -alkyl is optionally substituted by one or more independently selected from halogen, hydroxy, C 1-6 -alkoxy and halo-C 1-6 - substitution of the alkoxy group with a substituent; and

[0157] (c) cyclopropyl, wherein the cyclopropyl is optionally substituted by one or more independently selected from cyano, C 1-6 -alkyl, halo-C 1-6 -alkyl and C 1-6 - substituted with a substituent of the alkoxy group; and

[0158] R 8 is hydrogen or chlorine.

[0159] Embodiment 5: A compound having a structure of formula (I) or a pharmaceutically acceptable salt thereof, wherein:

[0160] R 2 is selected from hydrogen, fluorine and methyl;

[0161] R 3 is hydrogen or fluorine;

[0162] R 5 is hydrogen or fluorine;

[0163] R 6 and R 7 One of them is hydrogen, and R 6 and R 7 The other one is selected from:

[0164] (a) halogen;

[0165] (b)C 1-6 -alkyl, wherein the C 1-6-alkyl is optionally substituted by one or more independently selected from halogen, hydroxy, C 1-6 -alkoxy and halo-C 1-6 - substitution of the alkoxy group with a substituent; and

[0166] (c) cyclopropyl, wherein the cyclopropyl is optionally substituted by one or more independently selected from cyano, C 1-6 -alkyl, halo-C 1-6 -alkyl and C 1-6 - substituted with a substituent of the alkoxy group; and

[0167] R 8 is hydrogen or fluorine.

[0168] Embodiment 6: A compound having a structure of formula (I) or a pharmaceutically acceptable salt thereof, wherein R 6 and R 7 One of them is hydrogen, and R 6 and R 7 The other one is selected from:

[0169] (a) halogen;

[0170] (b)C 1-3 -alkyl, wherein the C 1-3 -alkyl is optionally substituted by one or more independently selected from halogen, hydroxy, C 1-3 -alkoxy and halo-C 1-3 - substitution of the alkoxy group with a substituent; and

[0171] (c) cyclopropyl, wherein the cyclopropyl is optionally substituted by one or more independently selected from cyano, C 1-3 -alkyl, halo-C 1-3 -alkyl and C 1-3 -substituted by a substituent of the alkoxy group.

[0172] Embodiment 7: A compound according to any one of Embodiments 1 to 6 or a pharmaceutically acceptable salt thereof, wherein R 6 and R 7 One of them is hydrogen and the other is halogen.

[0173] Embodiment 8: A compound according to any one of Embodiments 1 to 6 or a pharmaceutically acceptable salt thereof, wherein R 6 and R 7 One of them is hydrogen and the other is chlorine.

[0174] Embodiment 9: A compound according to any one of Embodiments 1 to 6 or a pharmaceutically acceptable salt thereof, wherein R 6 and R 7 One of them is hydrogen and the other is fluorine.

[0175] Embodiment 10: A compound according to any one of Embodiments 1 to 6 or a pharmaceutically acceptable salt thereof, wherein R 6 and R 7 One of them is hydrogen and the other is bromine.

[0176] Embodiment 11: A compound according to any one of Embodiments 1 to 6 or a pharmaceutically acceptable salt thereof,

[0177] Where R 6 and R 7 One of them is hydrogen and the other is iodine.

[0178] Embodiment 12: A compound according to any one of Embodiments 1 to 5, or a pharmaceutically acceptable salt thereof, wherein R 6 and R 7 One of them is hydrogen and the other is C 1-6 -alkyl, wherein the C 1-6 -alkyl is optionally substituted by one or more independently selected from halogen, hydroxy, C 1-6 -alkoxy and halo-C 1-6 -substituted by a substituent of the alkoxy group.

[0179] Embodiment 13: A compound according to any one of Embodiments 1 to 6 or a pharmaceutically acceptable salt thereof, wherein R 6 and R 7 One of them is hydrogen and the other is C 1-3 -alkyl, wherein the C 1-3 -alkyl is optionally substituted by one or more independently selected from halogen, hydroxy, C 1-3 -alkoxy and halo-C 1-3 -substituted by a substituent of the alkoxy group.

[0180] Embodiment 14: A compound according to any one of Embodiments 1 to 6 or a pharmaceutically acceptable salt thereof, wherein R 6 and R 7 One of them is hydrogen and the other is C 1-3 -alkyl, wherein the C 1-3 -Alkyl is optionally substituted with one or more substituents independently selected from halogen, hydroxy, methoxy and halomethoxy.

[0181] Embodiment 15: A compound according to any one of Embodiments 1 to 6, or a pharmaceutically acceptable salt thereof, wherein R 6 and R 7 One of them is hydrogen and the other is C 1-3 -alkyl, wherein the C 1-3-alkyl is optionally substituted with one or more substituents independently selected from fluoro, hydroxy, methoxy and fluoromethoxy.

[0182] Embodiment 16: A compound according to any one of Embodiments 1 to 6, or a pharmaceutically acceptable salt thereof, wherein R 6 and R 7 One of them is hydrogen and the other is C 1-3 -alkyl, wherein the C 1-3 -alkyl is optionally substituted with one or more substituents independently selected from fluoro and methoxy.

[0183] Embodiment 17: A compound according to any one of Embodiments 1 to 5, or a pharmaceutically acceptable salt thereof, wherein R 6 and R 7 One of them is hydrogen and the other is C 1-6 -alkyl, wherein the C 1-6 -alkyl is optionally substituted by one or more independently selected from halogen and C 1-6 -substituted by a substituent of the alkoxy group.

[0184] Embodiment 18: A compound according to any one of Embodiments 1 to 6, or a pharmaceutically acceptable salt thereof, wherein R 6 and R 7 One of them is hydrogen and the other is C 1-3 -alkyl, wherein the C 1-3 -alkyl is optionally substituted by one or more independently selected from halogen and C 1-3 -substituted by a substituent of the alkoxy group.

[0185] Embodiment 19: A compound according to any one of Embodiments 1 to 5, or a pharmaceutically acceptable salt thereof, wherein R 6 and R 7 One of them is hydrogen and the other is C 1-6 -alkyl.

[0186] Embodiment 20: A compound according to any one of Embodiments 1 to 6 or a pharmaceutically acceptable salt thereof, wherein R 6 and R 7 One of them is hydrogen and the other is C 1-3 -alkyl.

[0187] Embodiment 21: A compound according to any one of Embodiments 1 to 6, or a pharmaceutically acceptable salt thereof, wherein R 6 and R 7 One of them is hydrogen and the other is methyl.

[0188] Embodiment 22: A compound according to any one of Embodiments 1 to 5, or a pharmaceutically acceptable salt thereof, wherein R 6 and R 7 One of them is hydrogen and the other is C 1-6 -alkyl, wherein the C 1-6 -Alkyl is optionally substituted with one or more halogens.

[0189] Embodiment 23: A compound according to any one of Embodiments 1 to 6, or a pharmaceutically acceptable salt thereof, wherein R 6 and R 7 One of them is hydrogen and the other is C 1-3 -alkyl, wherein the C 1-3 -Alkyl is optionally substituted by one or more fluorine.

[0190] Embodiment 24: A compound according to any one of Embodiments 1 to 5, or a pharmaceutically acceptable salt thereof, wherein R 6 and R 7 One of them is hydrogen and the other is C 1-6 -alkyl, wherein the C 1-6 The -alkyl group is optionally substituted with one or more hydroxy groups.

[0191] Embodiment 25: A compound according to any one of Embodiments 1 to 6, or a pharmaceutically acceptable salt thereof, wherein R 6 and R 7 One of them is hydrogen and the other is C 1-3 -alkyl, wherein the C 1-3 The -alkyl group is optionally substituted with one or more hydroxy groups.

[0192] Embodiment 26: A compound according to any one of Embodiments 1 to 5, or a pharmaceutically acceptable salt thereof, wherein R 6 and R 7 One of them is hydrogen and the other is C 1-6 -alkyl, wherein the C 1-6 -alkyl is optionally substituted with one or more C 1-6 -Alkoxy substitution.

[0193] Embodiment 27: A compound according to any one of Embodiments 1 to 6, or a pharmaceutically acceptable salt thereof, wherein R 6 and R 7 One of them is hydrogen and the other is C 1-3 -alkyl, wherein the C 1-3 -alkyl is optionally substituted with one or more C 1-3 -Alkoxy substitution.

[0194] Embodiment 28: A compound according to any one of Embodiments 1 to 5, or a pharmaceutically acceptable salt thereof, wherein R 6 and R 7 One of them is hydrogen and the other is C 1-6 -alkyl, wherein the C 1-6 -alkyl is optionally substituted with one or more halo-C 1-6 -Alkoxy substitution.

[0195] Embodiment 29: A compound according to any one of Embodiments 1 to 6, or a pharmaceutically acceptable salt thereof, wherein R 6 and R 7 One of them is hydrogen and the other is C 1-3 -alkyl, wherein the C 1-3 -alkyl is optionally substituted with one or more halo-C 1-3 -Alkoxy substitution.

[0196] Embodiment 30: A compound according to any one of Embodiments 1 to 6, or a pharmaceutically acceptable salt thereof, wherein R 6 and R 7 One of them is hydrogen and the other is C 1-3 -alkyl, wherein the C 1-3 -alkyl is optionally substituted with one or more fluoro-C 1-3 -Alkoxy substitution.

[0197] Embodiment 31: A compound according to any one of Embodiments 1 to 6, or a pharmaceutically acceptable salt thereof, wherein R 6 and R 7 One of them is hydrogen and the other is selected from methyl, ethyl, fluoromethyl, difluoromethyl, trifluoromethyl, fluoropropyl, hydroxyethyl, hydroxypropyl, methoxyethyl, methoxypropyl, trifluoromethoxymethyl and trifluoromethoxyethyl.

[0198] Embodiment 32: A compound according to any one of Embodiments 1 to 6, or a pharmaceutically acceptable salt thereof, wherein R 6 and R 7 One of the groups is hydrogen, and the other is selected from the group consisting of methyl, ethyl, fluoromethyl, difluoromethyl, trifluoromethyl, fluoropropyl, methoxyethyl and methoxypropyl.

[0199] Embodiment 33: A compound according to any one of Embodiments 1 to 5, or a pharmaceutically acceptable salt thereof, wherein R 6 and R 7 One of them is hydrogen and the other is cyclopropyl, wherein the cyclopropyl is optionally substituted by one or more independently selected from cyano, C 1-6 -alkyl, halo-C 1-6 -alkyl and C1-6 -substituted by a substituent of the alkoxy group.

[0200] Embodiment 34: A compound according to any one of Embodiments 1 to 6, or a pharmaceutically acceptable salt thereof, wherein R 6 and R 7 One of them is hydrogen and the other is cyclopropyl, wherein the cyclopropyl is optionally substituted by one or more independently selected from cyano, C 1-3 -alkyl, halo-C 1-3 -alkyl and C 1-3 -substituted by a substituent of the alkoxy group.

[0201] Embodiment 35: A compound according to any one of Embodiments 1 to 6, or a pharmaceutically acceptable salt thereof, wherein R 6 and R 7 One of them is hydrogen and the other is cyclopropyl, wherein the cyclopropyl is optionally substituted by one or more independently selected from cyano, C 1-3 -alkyl, fluoro-C 1-3 -alkyl and C 1-3 -substituted by a substituent of the alkoxy group.

[0202] Embodiment 36: A compound according to any one of Embodiments 1 to 6, or a pharmaceutically acceptable salt thereof, wherein R 6 and R 7 One of them is hydrogen and the other is cyclopropyl.

[0203] Embodiment 37: A compound according to any one of Embodiments 1 to 6, or a pharmaceutically acceptable salt thereof, wherein R 6 and R 7 One of the is hydrogen and the other is cyclopropyl, wherein the cyclopropyl is optionally substituted with one or more cyano groups.

[0204] Embodiment 38: A compound according to any one of Embodiments 1 to 5, or a pharmaceutically acceptable salt thereof, wherein R 6 and R 7 One of them is hydrogen and the other is cyclopropyl, wherein the cyclopropyl is optionally substituted with one or C 1-6 -alkyl substitution.

[0205] Embodiment 39: A compound according to any one of Embodiments 1 to 6, or a pharmaceutically acceptable salt thereof, wherein R 6 and R 7 One of them is hydrogen and the other is cyclopropyl, wherein the cyclopropyl is optionally substituted with one or more C 1-3 -alkyl substitution.

[0206] Embodiment 40: A compound according to any one of Embodiments 1 to 5, or a pharmaceutically acceptable salt thereof, wherein R 6 and R 7 One of them is hydrogen and the other is cyclopropyl, wherein the cyclopropyl is optionally substituted with one or more halo-C 1-6 -alkyl substitution.

[0207] Embodiment 41: A compound according to any one of Embodiments 1 to 6, or a pharmaceutically acceptable salt thereof, wherein R 6 and R 7 One of them is hydrogen and the other is cyclopropyl, wherein the cyclopropyl is optionally substituted with one or more halo-C 1-3 -alkyl substitution.

[0208] Embodiment 42: A compound according to any one of Embodiments 1 to 6, or a pharmaceutically acceptable salt thereof, wherein R 6 and R 7 One of the cyclopropyl radicals is hydrogen and the other is cyclopropyl, wherein the cyclopropyl radical is optionally substituted with one or more fluoro-C 1-3 -alkyl substitution.

[0209] Embodiment 43: A compound according to any one of Embodiments 1 to 5, or a pharmaceutically acceptable salt thereof, wherein R 6 and R 7 One of them is hydrogen and the other is cyclopropyl, wherein the cyclopropyl is optionally substituted with one or more C 1-6 -Alkoxy substitution.

[0210] Embodiment 44: A compound according to any one of Embodiments 1 to 6, or a pharmaceutically acceptable salt thereof, wherein R 6 and R 7 One of them is hydrogen and the other is cyclopropyl, wherein the cyclopropyl is optionally substituted with one or more C 1-3 -Alkoxy substitution.

[0211] Embodiment 45: A compound according to any one of Embodiments 1 to 6, or a pharmaceutically acceptable salt thereof, wherein R 6 and R 7 One of the is hydrogen and the other is cyclopropyl, wherein the cyclopropyl is optionally substituted with one or more substituents independently selected from cyano, methyl, trifluoromethyl and ethoxy.

[0212] Embodiment 46: A compound according to any one of Embodiments 1 to 6, or a pharmaceutically acceptable salt thereof, wherein R 6 and R 7 One of them is hydrogen, and R 6 and R 7The other one is selected from:

[0213] (a) Chlorine, fluorine, bromine and iodine;

[0214] (b)C 1-3 -alkyl, wherein the C 1-3 -alkyl is optionally substituted by one or more independently selected from halogen, hydroxy, C 1-3 -alkoxy and halo-C 1-3 - substitution of the alkoxy group with a substituent; and

[0215] (c) cyclopropyl, wherein the cyclopropyl is optionally substituted by one or more independently selected from cyano, C 1-3 -alkyl, halo-C 1-3 -alkyl and C 1-3 -substituted by a substituent of the alkoxy group.

[0216] Embodiment 47: A compound according to any one of Embodiments 1 to 6, or a pharmaceutically acceptable salt thereof, wherein R 6 and R 7 One of them is hydrogen, and R 6 and R 7 The other one is selected from:

[0217] (a) Chlorine, fluorine, bromine and iodine;

[0218] (b)C 1-3 -alkyl, wherein the C 1-3 - alkyl is optionally substituted with one or more substituents independently selected from halogen, hydroxy, methoxy and halomethoxy; and

[0219] (c) cyclopropyl, wherein the cyclopropyl is optionally substituted by one or more independently selected from cyano, C 1-3 -alkyl, halo-C 1-3 -alkyl and C 1-3 -substituted by a substituent of the alkoxy group.

[0220] Embodiment 48: A compound according to any one of Embodiments 1 to 5, or a pharmaceutically acceptable salt thereof, wherein R 6 and R 7 One of them is hydrogen, and R 6 and R 7 The other one is selected from:

[0221] (a) Chlorine, fluorine, bromine and iodine;

[0222] (b)C 1-6 -alkyl, wherein the C 1-6 -alkyl is optionally substituted by one or more independently selected from halogen and C 1-6 - substitution of the alkoxy group with a substituent; and

[0223] (c) cyclopropyl, wherein the cyclopropyl is optionally substituted by one or more independently selected from cyano, C 1-3 -alkyl, halo-C 1-3 -alkyl and C 1-3 -substituted by a substituent of the alkoxy group.

[0224] Embodiment 49: A compound according to any one of Embodiments 1 to 6, or a pharmaceutically acceptable salt thereof, wherein R 6 and R 7 One of them is hydrogen, and R 6 and R 7 The other one is selected from:

[0225] (a) Chlorine, fluorine, bromine and iodine;

[0226] (b)C 1-3 -alkyl, wherein the C 1-3 -alkyl is optionally substituted by one or more independently selected from halogen and C 1-3 - substitution of the alkoxy group with a substituent; and

[0227] (c) cyclopropyl, wherein the cyclopropyl is optionally substituted by one or more independently selected from cyano, C 1-3 -alkyl, halo-C 1-3 -alkyl and C 1-3 -substituted by a substituent of the alkoxy group.

[0228] Embodiment 50: A compound according to any one of Embodiments 1 to 6, or a pharmaceutically acceptable salt thereof, wherein R 6 and R 7 One of them is hydrogen, and R 6 and R 7 The other one is selected from:

[0229] (a) Chlorine, fluorine, bromine and iodine;

[0230] (b)C 1-3 -alkyl, wherein the C 1-3 -alkyl is optionally substituted by one or more independently selected from halogen, hydroxy, C 1-3 -alkoxy and halo-C 1-3 - substitution of the alkoxy group with a substituent; and

[0231] (c) cyclopropyl, wherein the cyclopropyl is optionally substituted with one or more substituents independently selected from cyano, methyl, trifluoromethyl and ethoxy.

[0232] Embodiment 51: A compound according to any one of Embodiments 1 to 6, or a pharmaceutically acceptable salt thereof, wherein R 6 and R 7One of them is hydrogen, and R 6 and R 7 The other one is selected from:

[0233] (a) Chlorine, fluorine, bromine and iodine;

[0234] (b)C 1-3 -alkyl, wherein the C 1-3 -alkyl is optionally substituted by one or more independently selected from halogen and C 1-3 - substitution of the alkoxy group with a substituent; and

[0235] (c) cyclopropyl, wherein the cyclopropyl is optionally substituted with one or more substituents independently selected from cyano, methyl, trifluoromethyl and ethoxy.

[0236] Embodiment 52: A compound according to any one of Embodiments 1 to 6, or a pharmaceutically acceptable salt thereof, wherein R 6 and R 7 One of them is hydrogen, and R 6 and R 7 The other one is selected from:

[0237] (a) Chlorine and fluorine;

[0238] (b)C 1-3 -alkyl, wherein the C 1-3 - alkyl is optionally substituted with one or more substituents independently selected from halogen, hydroxy, methoxy and halomethoxy; and

[0239] (c) cyclopropyl, wherein the cyclopropyl is optionally substituted with one or more substituents independently selected from cyano, methyl, trifluoromethyl and ethoxy.

[0240] Embodiment 53: A compound according to any one of Embodiments 1 to 6, or a pharmaceutically acceptable salt thereof, wherein R 6 and R 7 One of them is hydrogen, and R 6 and R 7 The other one is selected from:

[0241] (a) Chlorine and fluorine;

[0242] (b)C 1-3 -alkyl, wherein the C 1-3 -alkyl is optionally substituted with one or more substituents independently selected from fluoro, hydroxy, methoxy and fluoromethoxy; and

[0243] (c) cyclopropyl, wherein the cyclopropyl is optionally substituted with one or more substituents independently selected from cyano, methyl, trifluoromethyl and ethoxy.

[0244] Embodiment 54: A compound according to any one of Embodiments 1 to 6, or a pharmaceutically acceptable salt thereof, wherein R 6 and R 7 One of them is hydrogen, and R 6 and R 7 The other one is selected from:

[0245] (a) Chlorine and fluorine;

[0246] (b)C 1-3 -alkyl, wherein the C 1-3 -alkyl is optionally substituted with one or more substituents independently selected from methyl, ethyl, propyl, fluoromethyl, difluoromethyl, trifluoromethyl, fluoropropyl, hydroxyethyl, hydroxypropyl, methoxyethyl, methoxypropyl, trifluoromethoxymethyl and trifluoromethoxyethyl; and

[0247] (c) cyclopropyl, wherein the cyclopropyl is optionally substituted with one or more substituents independently selected from cyano, methyl, trifluoromethyl and ethoxy.

[0248] Embodiment 55: A compound according to any one of Embodiments 1 to 6, or a pharmaceutically acceptable salt thereof, wherein R 6 and R 7 One of them is hydrogen, and R 6 and R 7 The other one is selected from:

[0249] (a) Chlorine and fluorine;

[0250] (b)C 1-3 -alkyl, wherein the C 1-3 -alkyl is optionally substituted with one or more substituents independently selected from methyl, ethyl, propyl, fluoromethyl, difluoromethyl, trifluoromethyl, fluoropropyl, methoxyethyl and methoxypropyl; and

[0251] (c) cyclopropyl, wherein the cyclopropyl is optionally substituted with one or more substituents independently selected from cyano, methyl, trifluoromethyl and ethoxy.

[0252] Embodiment 56: A compound according to any one of Embodiments 1 to 5, or a pharmaceutically acceptable salt thereof, wherein R 6 and R 7 One of them is hydrogen, and R 6 and R 7 The other one is selected from:

[0253] (a) Chlorine and fluorine;

[0254] (b)C 1-6 -alkyl, wherein the C 1-6- alkyl is optionally substituted with one or more substituents independently selected from chloro, fluoro and methoxy; and

[0255] (c) cyclopropyl, wherein the cyclopropyl is optionally substituted with one or more cyano groups.

[0256] Embodiment 57: A compound according to any one of Embodiments 1 to 56, or a pharmaceutically acceptable salt thereof, wherein R 6 For hydrogen.

[0257] Embodiment 58: A compound according to any one of Embodiments 1 to 56, or a pharmaceutically acceptable salt thereof, wherein R 7 For hydrogen.

[0258] Embodiment 59: A compound according to any one of Embodiments 1 to 6 or a pharmaceutically acceptable salt thereof, wherein the compound has the structure of Formula (II-A).

[0259] Embodiment 60: A compound according to any one of Embodiments 1 to 6 or a pharmaceutically acceptable salt thereof, wherein the compound has the structure of Formula (II-B).

[0260] Embodiment 61: A compound according to any one of Embodiments 1 to 6 or a pharmaceutically acceptable salt thereof, wherein the compound has the structure of Formula (II-C).

[0261] Embodiment 62: A compound according to any one of Embodiments 1 to 6 or a pharmaceutically acceptable salt thereof, wherein the compound has the structure of Formula (III-A).

[0262] Embodiment 63: A compound according to any one of Embodiments 1 to 6 or a pharmaceutically acceptable salt thereof, wherein the compound has the structure of Formula (III-B).

[0263] Embodiment 64: A compound according to any one of Embodiments 1 to 6, or a pharmaceutically acceptable salt thereof, wherein the compound has the structure of Formula (III-C) as further defined herein and a pharmaceutically acceptable salt thereof.

[0264] Embodiment 65: A compound of formula (I) or a pharmaceutically acceptable salt thereof, wherein the compound is selected from:

[0265] 6-Bromo-N-(2-((1S,3S,5S)-3-cyano-2-azabicyclo[3.1.0]hex-2-yl)-2-oxoethyl)quinoline-4-carboxamide (Example 1);

[0266] 7-Chloro-N-(2-((1S,3S,5S)-3-cyano-2-azabicyclo[3.1.0]hex-2-yl)-2-oxoethyl)quinoline-4-carboxamide (Example 2);

[0267] 7-Bromo-N-(2-((1S,3S,5S)-3-cyano-2-azabicyclo[3.1.0]hex-2-yl)-2-oxoethyl)quinoline-4-carboxamide (Example 3);

[0268] N-(2-((1S,3S,5S)-3-cyano-2-azabicyclo[3.1.0]hex-2-yl)-2-oxoethyl)-6-fluoro-2-methylquinoline-4-carboxamide (Example 4);

[0269] 6-Chloro-N-(2-((1S,3S,5S)-3-cyano-2-azabicyclo[3.1.0]hex-2-yl)-2-oxoethyl)-2-methylquinoline-4-carboxamide (Example 5);

[0270] 6-Bromo-N-(2-((1S,3S,5S)-3-cyano-2-azabicyclo[3.1.0]hex-2-yl)-2-oxoethyl)-2-methylquinoline-4-carboxamide (Example 6);

[0271] N-(2-((1S,3S,5S)-3-cyano-2-azabicyclo[3.1.0]hex-2-yl)-2-oxoethyl)-6-iodo-2-methylquinoline-4-carboxamide (Example 7); and

[0272] N-(2-((1S,3S,5S)-3-cyano-2-azabicyclo[3.1.0]hex-2-yl)-2-oxoethyl)-7-fluoro-2-methylquinoline-4-carboxamide (Example 8).

[0273] Embodiment 66: A compound of formula (I) or a pharmaceutically acceptable salt thereof, wherein the compound is selected from:

[0274] 6-Bromo-N-(2-((1S,3S,5S)-3-cyano-2-azabicyclo[3.1.0]hex-2-yl)-2-oxoethyl)quinoline-4-carboxamide (Example 1);

[0275] N-(2-((1S,3S,5S)-3-cyano-2-azabicyclo[3.1.0]hex-2-yl)-2-oxoethyl)-6-fluoro-2-methylquinoline-4-carboxamide (Example 4);

[0276] 6-Chloro-N-(2-((1S,3S,5S)-3-cyano-2-azabicyclo[3.1.0]hex-2-yl)-2-oxoethyl)-2-methylquinoline-4-carboxamide (Example 5);

[0277] 6-bromo-N-(2-((1S,3S,5S)-3-cyano-2-azabicyclo[3.1.0]hex-2-yl)-2-oxoethyl)-2-methylquinoline-4-carboxamide (Example 6); and

[0278] N-(2-((1S,3S,5S)-3-cyano-2-azabicyclo[3.1.0]hex-2-yl)-2-oxoethyl)-6-iodo-2-methylquinoline-4-carboxamide (Example 7).

[0279] Embodiment 67: A compound of formula (I) or a pharmaceutically acceptable salt thereof, wherein the compound is selected from:

[0280] 7-Chloro-N-(2-((1S,3S,5S)-3-cyano-2-azabicyclo[3.1.0]hex-2-yl)-2-oxoethyl)quinoline-4-carboxamide (Example 2);

[0281] 7-bromo-N-(2-((1S,3S,5S)-3-cyano-2-azabicyclo[3.1.0]hex-2-yl)-2-oxoethyl)quinoline-4-carboxamide (Example 3); and

[0282] N-(2-((1S,3S,5S)-3-cyano-2-azabicyclo[3.1.0]hex-2-yl)-2-oxoethyl)-7-fluoro-2-methylquinoline-4-carboxamide (Example 8).

[0283] Embodiment 68: A compound of formula (I) or a pharmaceutically acceptable salt thereof, wherein the compound is selected from:

[0284] N-(2-((1S,3S,5S)-3-cyano-2-azabicyclo[3.1.0]hex-2-yl)-2-oxoethyl)-6-methylquinoline-4-carboxamide (Example 9);

[0285] N-(2-((1S,3S,5S)-3-cyano-2-azabicyclo[3.1.0]hex-2-yl)-2-oxoethyl)-6-(trifluoromethyl)quinoline-4-carboxamide (Example 10);

[0286] N-(2-((1S,3S,5S)-3-cyano-2-azabicyclo[3.1.0]hex-2-yl)-2-oxoethyl)-6-(fluoromethyl)quinoline-4-carboxamide (Example 11);

[0287] N-(2-((1S,3S,5S)-3-cyano-2-azabicyclo[3.1.0]hex-2-yl)-2-oxoethyl)-6-(2-fluoroprop-2-yl)quinoline-4-carboxamide (Example 12);

[0288] N-(2-((1S,3S,5S)-3-cyano-2-azabicyclo[3.1.0]hex-2-yl)-2-oxoethyl)-6-(2-hydroxypropan-2-yl)quinoline-4-carboxamide (Example 13);

[0289] N-(2-((1S,3S,5S)-3-cyano-2-azabicyclo[3.1.0]hex-2-yl)-2-oxoethyl)-6-(1-hydroxyethyl)quinoline-4-carboxamide (Example 14);

[0290] N-(2-((1S,3S,5S)-3-cyano-2-azabicyclo[3.1.0]hex-2-yl)-2-oxoethyl)-6-(1-methoxyethyl)quinoline-4-carboxamide (Example 15);

[0291] N-(2-((1S,3S,5S)-3-cyano-2-azabicyclo[3.1.0]hex-2-yl)-2-oxoethyl)-6-(2-methoxyprop-2-yl)quinoline-4-carboxamide (Example 16);

[0292] N-(2-((1S,3S,5S)-3-cyano-2-azabicyclo[3.1.0]hex-2-yl)-2-oxoethyl)-6-((trifluoromethoxy)methyl)quinoline-4-carboxamide (Example 17);

[0293] N-(2-((1S,3S,5S)-3-cyano-2-azabicyclo[3.1.0]hex-2-yl)-2-oxoethyl)-6-ethyl-2-methylquinoline-4-carboxamide (Example 18);

[0294] N-(2-((1S,3S,5S)-3-cyano-2-azabicyclo[3.1.0]hex-2-yl)-2-oxoethyl)-2,6-dimethylquinoline-4-carboxamide (Example 19);

[0295] N-(2-((1S,3S,5S)-3-cyano-2-azabicyclo[3.1.0]hex-2-yl)-2-oxoethyl)-7-methylquinoline-4-carboxamide (Example 20);

[0296] N-(2-((1S,3S,5S)-3-cyano-2-azabicyclo[3.1.0]hex-2-yl)-2-oxoethyl)-7-(2-fluoroprop-2-yl)quinoline-4-carboxamide (Example 21);

[0297] N-(2-((1S,3S,5S)-3-cyano-2-azabicyclo[3.1.0]hex-2-yl)-2-oxoethyl)-7-(difluoromethyl)quinoline-4-carboxamide (Example 22);

[0298] N-(2-((1S,3S,5S)-3-cyano-2-azabicyclo[3.1.0]hex-2-yl)-2-oxoethyl)-7-(trifluoromethyl)quinoline-4-carboxamide (Example 23);

[0299] N-(2-((1S,3S,5S)-3-cyano-2-azabicyclo[3.1.0]hex-2-yl)-2-oxoethyl)-7-(fluoromethyl)quinoline-4-carboxamide (Example 24);

[0300] N-(2-((1S,3S,5S)-3-cyano-2-azabicyclo[3.1.0]hex-2-yl)-2-oxoethyl)-7-(1-hydroxyethyl)quinoline-4-carboxamide (Example 25);

[0301] N-(2-((1S,3S,5S)-3-cyano-2-azabicyclo[3.1.0]hex-2-yl)-2-oxoethyl)-7-(2-hydroxypropan-2-yl)quinoline-4-carboxamide (Example 26);

[0302] N-(2-((1S,3S,5S)-3-cyano-2-azabicyclo[3.1.0]hex-2-yl)-2-oxoethyl)-7-(1-methoxyethyl)quinoline-4-carboxamide (Example 27);

[0303] N-(2-((1S,3S,5S)-3-cyano-2-azabicyclo[3.1.0]hex-2-yl)-2-oxoethyl)-7-(2-methoxyprop-2-yl)quinoline-4-carboxamide (Example 28);

[0304] N-(2-((1S,3S,5S)-3-cyano-2-azabicyclo[3.1.0]hex-2-yl)-2-oxoethyl)-7-((trifluoromethoxy)methyl)quinoline-4-carboxamide (Example 29);

[0305] N-(2-((1S,3S,5S)-3-cyano-2-azabicyclo[3.1.0]hex-2-yl)-2-oxoethyl)-7-(1-(trifluoromethoxy)ethyl)quinoline-4-carboxamide (Example 30); and

[0306] N-(2-((1S,3S,5S)-3-cyano-2-azabicyclo[3.1.0]hex-2-yl)-2-oxoethyl)-2,7-dimethylquinoline-4-carboxamide (Example 31).

[0307] Embodiment 69: A compound of formula (I) or a pharmaceutically acceptable salt thereof, wherein the compound is selected from:

[0308] N-(2-((1S,3S,5S)-3-cyano-2-azabicyclo[3.1.0]hex-2-yl)-2-oxoethyl)-6-methylquinoline-4-carboxamide (Example 9);

[0309] N-(2-((1S,3S,5S)-3-cyano-2-azabicyclo[3.1.0]hex-2-yl)-2-oxoethyl)-6-(trifluoromethyl)quinoline-4-carboxamide (Example 10);

[0310] N-(2-((1S,3S,5S)-3-cyano-2-azabicyclo[3.1.0]hex-2-yl)-2-oxoethyl)-6-(fluoromethyl)quinoline-4-carboxamide (Example 11);

[0311] N-(2-((1S,3S,5S)-3-cyano-2-azabicyclo[3.1.0]hex-2-yl)-2-oxoethyl)-6-(2-fluoroprop-2-yl)quinoline-4-carboxamide (Example 12);

[0312] N-(2-((1S,3S,5S)-3-cyano-2-azabicyclo[3.1.0]hex-2-yl)-2-oxoethyl)-6-(2-hydroxypropan-2-yl)quinoline-4-carboxamide (Example 13);

[0313] N-(2-((1S,3S,5S)-3-cyano-2-azabicyclo[3.1.0]hex-2-yl)-2-oxoethyl)-6-(1-hydroxyethyl)quinoline-4-carboxamide (Example 14);

[0314] N-(2-((1S,3S,5S)-3-cyano-2-azabicyclo[3.1.0]hex-2-yl)-2-oxoethyl)-6-(1-methoxyethyl)quinoline-4-carboxamide (Example 15);

[0315] N-(2-((1S,3S,5S)-3-cyano-2-azabicyclo[3.1.0]hex-2-yl)-2-oxoethyl)-6-(2-methoxyprop-2-yl)quinoline-4-carboxamide (Example 16);

[0316] N-(2-((1S,3S,5S)-3-cyano-2-azabicyclo[3.1.0]hex-2-yl)-2-oxoethyl)-6-((trifluoromethoxy)methyl)quinoline-4-carboxamide (Example 17);

[0317] N-(2-((1S,3S,5S)-3-cyano-2-azabicyclo[3.1.0]hex-2-yl)-2-oxoethyl)-6-ethyl-2-methylquinoline-4-carboxamide (Example 18); and

[0318] N-(2-((1S,3S,5S)-3-cyano-2-azabicyclo[3.1.0]hexan-2-yl)-2-oxoethyl)-2,6-dimethylquinoline-4-carboxamide (Example 19).

[0319] Embodiment 70: A compound of formula (I) or a pharmaceutically acceptable salt thereof, wherein the compound is selected from:

[0320] N-(2-((1S,3S,5S)-3-cyano-2-azabicyclo[3.1.0]hex-2-yl)-2-oxoethyl)-7-methylquinoline-4-carboxamide (Example 20);

[0321] N-(2-((1S,3S,5S)-3-cyano-2-azabicyclo[3.1.0]hex-2-yl)-2-oxoethyl)-7-(2-fluoroprop-2-yl)quinoline-4-carboxamide (Example 21);

[0322] N-(2-((1S,3S,5S)-3-cyano-2-azabicyclo[3.1.0]hex-2-yl)-2-oxoethyl)-7-(difluoromethyl)quinoline-4-carboxamide (Example 22);

[0323] N-(2-((1S,3S,5S)-3-cyano-2-azabicyclo[3.1.0]hex-2-yl)-2-oxoethyl)-7-(trifluoromethyl)quinoline-4-carboxamide (Example 23);

[0324] N-(2-((1S,3S,5S)-3-cyano-2-azabicyclo[3.1.0]hex-2-yl)-2-oxoethyl)-7-(fluoromethyl)quinoline-4-carboxamide (Example 24);

[0325] N-(2-((1S,3S,5S)-3-cyano-2-azabicyclo[3.1.0]hex-2-yl)-2-oxoethyl)-7-(1-hydroxyethyl)quinoline-4-carboxamide (Example 25);

[0326] N-(2-((1S,3S,5S)-3-cyano-2-azabicyclo[3.1.0]hex-2-yl)-2-oxoethyl)-7-(2-hydroxypropan-2-yl)quinoline-4-carboxamide (Example 26);

[0327] N-(2-((1S,3S,5S)-3-cyano-2-azabicyclo[3.1.0]hex-2-yl)-2-oxoethyl)-7-(1-methoxyethyl)quinoline-4-carboxamide (Example 27);

[0328] N-(2-((1S,3S,5S)-3-cyano-2-azabicyclo[3.1.0]hex-2-yl)-2-oxoethyl)-7-(2-methoxyprop-2-yl)quinoline-4-carboxamide (Example 28);

[0329] N-(2-((1S,3S,5S)-3-cyano-2-azabicyclo[3.1.0]hex-2-yl)-2-oxoethyl)-7-((trifluoromethoxy)methyl)quinoline-4-carboxamide (Example 29);

[0330] N-(2-((1S,3S,5S)-3-cyano-2-azabicyclo[3.1.0]hex-2-yl)-2-oxoethyl)-7-(1-(trifluoromethoxy)ethyl)quinoline-4-carboxamide (Example 30); and

[0331] N-(2-((1S,3S,5S)-3-cyano-2-azabicyclo[3.1.0]hex-2-yl)-2-oxoethyl)-2,7-dimethylquinoline-4-carboxamide (Example 31).

[0332] Embodiment 71: A compound of formula (I) or a pharmaceutically acceptable salt thereof, wherein the compound is selected from:

[0333] N-(2-((1S,3S,5S)-3-cyano-2-azabicyclo[3.1.0]hex-2-yl)-2-oxoethyl)-7-(1-cyanocyclopropyl)quinoline-4-carboxamide (Example 40);

[0334] N-(2-((1S,3S,5S)-3-cyano-2-azabicyclo[3.1.0]hex-2-yl)-2-oxoethyl)-6-cyclopropylquinoline-4-carboxamide (Example 42);

[0335] N-(2-((1S,3S,5S)-3-cyano-2-azabicyclo[3.1.0]hex-2-yl)-2-oxoethyl)-6-(1-methylcyclopropyl)quinoline-4-carboxamide (Example 43);

[0336] N-(2-((1S,3S,5S)-3-cyano-2-azabicyclo[3.1.0]hex-2-yl)-2-oxoethyl)-6-(1-(trifluoromethyl)cyclopropyl)quinoline-4-carboxamide (Example 44);

[0337] N-(2-((1S,3S,5S)-3-cyano-2-azabicyclo[3.1.0]hex-2-yl)-2-oxoethyl)-6-(1-ethoxycyclopropyl)quinoline-4-carboxamide (Example 45);

[0338] N-(2-((1S,3S,5S)-3-cyano-2-azabicyclo[3.1.0]hex-2-yl)-2-oxoethyl)-6-(1-cyanocyclopropyl)quinoline-4-carboxamide (Example 46);

[0339] N-(2-((1S,3S,5S)-3-cyano-2-azabicyclo[3.1.0]hex-2-yl)-2-oxoethyl)-7-cyclopropylquinoline-4-carboxamide (Example 47);

[0340] N-(2-((1S,3S,5S)-3-cyano-2-azabicyclo[3.1.0]hex-2-yl)-2-oxoethyl)-7-(1-methylcyclopropyl)quinoline-4-carboxamide (Example 32);

[0341] N-(2-((1S,3S,5S)-3-cyano-2-azabicyclo[3.1.0]hex-2-yl)-2-oxoethyl)-7-(1-(trifluoromethyl)cyclopropyl)quinoline-4-carboxamide (Example 36); and

[0342] N-(2-((1S,3S,5S)-3-cyano-2-azabicyclo[3.1.0]hex-2-yl)-2-oxoethyl)-7-(1-ethoxycyclopropyl)quinoline-4-carboxamide (Example 39).

[0343] Embodiment 72: A compound of formula (I) or a pharmaceutically acceptable salt thereof, wherein the compound is selected from:

[0344] N-(2-((1S,3S,5S)-3-cyano-2-azabicyclo[3.1.0]hex-2-yl)-2-oxoethyl)-6-cyclopropylquinoline-4-carboxamide (Example 42);

[0345] N-(2-((1S,3S,5S)-3-cyano-2-azabicyclo[3.1.0]hex-2-yl)-2-oxoethyl)-6-(1-methylcyclopropyl)quinoline-4-carboxamide (Example 43);

[0346] N-(2-((1S,3S,5S)-3-cyano-2-azabicyclo[3.1.0]hex-2-yl)-2-oxoethyl)-6-(1-(trifluoromethyl)cyclopropyl)quinoline-4-carboxamide (Example 44);

[0347] N-(2-((1S,3S,5S)-3-cyano-2-azabicyclo[3.1.0]hex-2-yl)-2-oxoethyl)-6-(1-ethoxycyclopropyl)quinoline-4-carboxamide (Example 45); and

[0348] N-(2-((1S,3S,5S)-3-cyano-2-azabicyclo[3.1.0]hex-2-yl)-2-oxoethyl)-6-(1-cyanocyclopropyl)quinoline-4-carboxamide (Example 46).

[0349] Embodiment 73: A compound of formula (I) or a pharmaceutically acceptable salt thereof, wherein the compound is selected from:

[0350] N-(2-((1S,3S,5S)-3-cyano-2-azabicyclo[3.1.0]hex-2-yl)-2-oxoethyl)-7-(1-cyanocyclopropyl)quinoline-4-carboxamide (Example 40);

[0351] N-(2-((1S,3S,5S)-3-cyano-2-azabicyclo[3.1.0]hex-2-yl)-2-oxoethyl)-7-cyclopropylquinoline-4-carboxamide (Example 47);

[0352] N-(2-((1S,3S,5S)-3-cyano-2-azabicyclo[3.1.0]hex-2-yl)-2-oxoethyl)-7-(1-methylcyclopropyl)quinoline-4-carboxamide (Example 32);

[0353] N-(2-((1S,3S,5S)-3-cyano-2-azabicyclo[3.1.0]hex-2-yl)-2-oxoethyl)-7-(1-(trifluoromethyl)cyclopropyl)quinoline-4-carboxamide (Example 36); and

[0354] N-(2-((1S,3S,5S)-3-cyano-2-azabicyclo[3.1.0]hex-2-yl)-2-oxoethyl)-7-(1-ethoxycyclopropyl)quinoline-4-carboxamide (Example 39).

[0355] Embodiment 74: A compound of formula (I) or a pharmaceutically acceptable salt thereof, wherein the compound is selected from:

[0356] N-(2-((1S,3S,5S)-3-cyano-2-azabicyclo[3.1.0]hex-2-yl)-2-oxoethyl)-6-(2,2,2-trifluoroethoxy)quinoline-4-carboxamide (Example 33);

[0357] N-(2-((1S,3S,5S)-3-cyano-2-azabicyclo[3.1.0]hex-2-yl)-2-oxoethyl)-6-isopropoxyquinoline-4-carboxamide (Example 34);

[0358] N-(2-((1S,3S,5S)-3-cyano-2-azabicyclo[3.1.0]hex-2-yl)-2-oxoethyl)-6-(cyclopropylmethoxy)quinoline-4-carboxamide (Example 35); and

[0359] N-(2-((1S,3S,5S)-3-cyano-2-azabicyclo[3.1.0]hex-2-yl)-2-oxoethyl)-7-methoxy-2-methylquinoline-4-carboxamide (Example 41).

[0360] Embodiment 75: A compound of formula (I) or a pharmaceutically acceptable salt thereof, wherein the compound is selected from:

[0361] N-(2-((1S,3S,5S)-3-cyano-2-azabicyclo[3.1.0]hex-2-yl)-2-oxoethyl)-6-(2,2,2-trifluoroethoxy)quinoline-4-carboxamide (Example 33);

[0362] N-(2-((1S,3S,5S)-3-cyano-2-azabicyclo[3.1.0]hex-2-yl)-2-oxoethyl)-6-isopropoxyquinoline-4-carboxamide (Example 34); and

[0363] N-(2-((1S,3S,5S)-3-cyano-2-azabicyclo[3.1.0]hex-2-yl)-2-oxoethyl)-6-(cyclopropylmethoxy)quinoline-4-carboxamide (Example 35).

[0364] 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).

[0365] Embodiment 77: A compound of formula (I) or a pharmaceutically acceptable salt thereof, wherein the compound is selected from:

[0366] N-(2-((1S,3S,5S)-3-cyano-2-azabicyclo[3.1.0]hex-2-yl)-2-oxoethyl)-6-cyclopropyloxyquinoline-4-carboxamide (Example 37); and

[0367] N-(2-((1S,3S,5S)-3-cyano-2-azabicyclo[3.1.0]hex-2-yl)-2-oxoethyl)-6-((4,4-difluorocyclohexyl)oxy)quinoline-4-carboxamide (Example 38).

[0368] Embodiment 78: A compound of formula (I) or a pharmaceutically acceptable salt thereof, wherein the compound is selected from:

[0369] N-(2-((1S,3S,5S)-3-cyano-2-azabicyclo[3.1.0]hex-2-yl)-2-oxoethyl)-2,7-dimethylquinoline-4-carboxamide (Example 31);

[0370] 6-Bromo-N-(2-((1S,3S,5S)-3-cyano-2-azabicyclo[3.1.0]hex-2-yl)-2-oxoethyl)-2-methylquinoline-4-carboxamide (Example 6);

[0371] N-(2-((1S,3S,5S)-3-cyano-2-azabicyclo[3.1.0]hex-2-yl)-2-oxoethyl)-7-fluoro-2-methylquinoline-4-carboxamide (Example 8);

[0372] N-(2-((1S,3S,5S)-3-cyano-2-azabicyclo[3.1.0]hex-2-yl)-2-oxoethyl)-7-methoxy-2-methylquinoline-4-carboxamide (Example 41);

[0373] N-(2-((1S,3S,5S)-3-cyano-2-azabicyclo[3.1.0]hex-2-yl)-2-oxoethyl)-6-ethyl-2-methylquinoline-4-carboxamide (Example 18);

[0374] N-(2-((1S,3S,5S)-3-cyano-2-azabicyclo[3.1.0]hex-2-yl)-2-oxoethyl)-6-iodo-2-methylquinoline-4-carboxamide (Example 7);

[0375] N-(2-((1S,3S,5S)-3-cyano-2-azabicyclo[3.1.0]hex-2-yl)-2-oxoethyl)-2,6-dimethylquinoline-4-carboxamide (Example 19);

[0376] 6-chloro-N-(2-((1S,3S,5S)-3-cyano-2-azabicyclo[3.1.0]hex-2-yl)-2-oxoethyl)-2-methylquinoline-4-carboxamide (Example 5); and

[0377] N-(2-((1S,3S,5S)-3-cyano-2-azabicyclo[3.1.0]hex-2-yl)-2-oxoethyl)-6-fluoro-2-methylquinoline-4-carboxamide (Example 4).

[0378] Embodiment A-1: ​​A compound or a pharmaceutically acceptable salt thereof, wherein the compound has the structure of formula (I):

[0379]

[0380] in:

[0381] R 2 is selected from hydrogen, halogen and methyl;

[0382] R 3 is hydrogen or halogen;

[0383] R 5 is selected from hydrogen, hydroxy, halogen, methyl and methoxy;

[0384] R 6 and R 7 One of them is hydrogen, and R 6 and R 7 The other one is selected from:

[0385] (a) halogen;

[0386] (b)C 1-6 -alkyl, wherein the C 1-6 -alkyl is optionally substituted by one or more independently selected from halogen, hydroxy, C 1-6 -alkoxy, halo-C 1-6 -alkoxy, C 3-6 -cycloalkyl and C 3-6 - Substitution of cycloalkoxy groups;

[0387] (c) cyclopropyl, wherein the cyclopropyl is optionally substituted by one or more independently selected from cyano, fluoro, C 1-6 -alkyl, halo-C 1-6 -alkyl and C 1-6 - Substitution of alkoxy groups;

[0388] (d)C 1-6 -alkoxy, wherein the C 1-6 - alkoxy is optionally substituted with one or more substituents independently selected from halogen and cyclopropyl; and

[0389] (e)C 3-6 -cycloalkoxy, wherein the C 3-6 -cycloalkoxy is optionally substituted by one or more independently selected from halogen and C 1-3 - alkyl is substituted with a substituent; and

[0390] R 8 is selected from hydrogen, halogen and methyl.

[0391] Embodiment A-2: A compound according to Embodiment A-1 or a pharmaceutically acceptable salt thereof, wherein R 2 is selected from the group consisting of hydrogen, chlorine, fluorine and methyl.

[0392] Embodiment A-3: A compound according to Embodiment A-1 or a pharmaceutically acceptable salt thereof, wherein R 2 is selected from hydrogen, chlorine and methyl.

[0393] Embodiment A-4: A compound according to Embodiment A-1 or a pharmaceutically acceptable salt thereof, wherein R 2 is selected from hydrogen, fluorine and methyl.

[0394] Embodiment A-5: A compound according to Embodiment A-1 or a pharmaceutically acceptable salt thereof, wherein R 2 is hydrogen or halogen.

[0395] Embodiment A-6: A compound according to Embodiment A-1 or a pharmaceutically acceptable salt thereof, wherein R 2 is hydrogen or chlorine.

[0396] Embodiment A-7: A compound according to Embodiment A-1 or a pharmaceutically acceptable salt thereof, wherein R 2 is hydrogen or fluorine.

[0397] Embodiment A-8: A compound according to Embodiment A-1 or a pharmaceutically acceptable salt thereof, wherein R 2 It is hydrogen or methyl.

[0398] Embodiment A-9: A compound according to Embodiment A-1 or a pharmaceutically acceptable salt thereof, wherein R 2 For hydrogen.

[0399] Embodiment A-10: A compound according to Embodiment A-1 or a pharmaceutically acceptable salt thereof, wherein R 2 It is a halogen.

[0400] Embodiment A-11: A compound according to Embodiment A-1 or a pharmaceutically acceptable salt thereof, wherein R 2 For chlorine.

[0401] Embodiment A-12: A compound according to Embodiment A-1 or a pharmaceutically acceptable salt thereof, wherein R 2 For fluorine.

[0402] Embodiment A-13: A compound according to Embodiment A-1 or a pharmaceutically acceptable salt thereof, wherein R 2 It is methyl.

[0403] Embodiment A-14: A compound according to any one of Embodiments A-1 to A-13, or a pharmaceutically acceptable salt thereof, wherein R 3 Selected from hydrogen, chlorine and fluorine.

[0404] Embodiment A-15: A compound according to any one of Embodiments A-1 to A-13, or a pharmaceutically acceptable salt thereof, wherein R 3 is hydrogen or chlorine.

[0405] Embodiment A-16: A compound according to any one of Embodiments A-1 to A-13, or a pharmaceutically acceptable salt thereof, wherein R 3 is hydrogen or fluorine.

[0406] Embodiment A-17: A compound according to any one of Embodiments A-1 to A-13, or a pharmaceutically acceptable salt thereof, wherein R 3 For hydrogen.

[0407] Embodiment A-18: A compound according to any one of Embodiments A-1 to A-13, or a pharmaceutically acceptable salt thereof, wherein R 3 It is a halogen.

[0408] Embodiment A-19: A compound according to any one of Embodiments A-1 to A-13, or a pharmaceutically acceptable salt thereof, wherein R 3 For chlorine.

[0409] Embodiment A-20: A compound according to any one of Embodiments A-1 to A-13, or a pharmaceutically acceptable salt thereof, wherein R 3 For fluorine.

[0410] Embodiment A-21: A compound according to any one of Embodiments A-1 to A-20, or a pharmaceutically acceptable salt thereof, wherein R 5 is selected from the group consisting of hydrogen, hydroxy, chlorine, fluorine, methyl and methoxy.

[0411] Embodiment A-22: A compound according to any one of Embodiments A-1 to A-20, or a pharmaceutically acceptable salt thereof, wherein R 5 is selected from hydrogen, chlorine and methyl.

[0412] Embodiment A-23: A compound according to any one of Embodiments A-1 to A-20, or a pharmaceutically acceptable salt thereof, wherein R 5 is selected from hydrogen, fluorine and methyl.

[0413] Embodiment A-24: A compound according to any one of Embodiments A-1 to A-20, or a pharmaceutically acceptable salt thereof, wherein R 5 is hydrogen or halogen.

[0414] Embodiment A-25: A compound according to any one of Embodiments A-1 to A-20, or a pharmaceutically acceptable salt thereof, wherein R 5 is hydrogen or chlorine.

[0415] Embodiment A-26: A compound according to any one of Embodiments A-1 to A-20, or a pharmaceutically acceptable salt thereof, wherein R 5 is hydrogen or fluorine.

[0416] Embodiment A-27: A compound according to any one of Embodiments A-1 to A-20, or a pharmaceutically acceptable salt thereof, wherein R 5 It is hydrogen or methyl.

[0417] Embodiment A-28: A compound according to any one of Embodiments A-1 to A-20, or a pharmaceutically acceptable salt thereof, wherein R 5 For hydrogen.

[0418] Embodiment A-29: A compound according to any one of Embodiments A-1 to A-20, or a pharmaceutically acceptable salt thereof, wherein R 5 It is hydroxyl.

[0419] Embodiment A-30: A compound according to any one of Embodiments A-1 to A-20, or a pharmaceutically acceptable salt thereof, wherein R 5 It is a halogen.

[0420] Embodiment A-31: A compound according to any one of Embodiments A-1 to A-20, or a pharmaceutically acceptable salt thereof, wherein R 5 For chlorine.

[0421] Embodiment A-32: A compound according to any one of Embodiments A-1 to A-20, or a pharmaceutically acceptable salt thereof, wherein R 5 For fluorine.

[0422] Embodiment A-33: A compound according to any one of Embodiments A-1 to A-20, or a pharmaceutically acceptable salt thereof, wherein R 5 It is methyl.

[0423] Embodiment A-34: A compound according to any one of Embodiments A-1 to A-20, or a pharmaceutically acceptable salt thereof, wherein R 5 It is a methoxy group.

[0424] Embodiment A-35: A compound according to any one of Embodiments A-1 to A-34, or a pharmaceutically acceptable salt thereof, wherein R 8 is selected from the group consisting of hydrogen, chlorine, fluorine and methyl.

[0425] Embodiment A-36: A compound according to any one of Embodiments A-1 to A-34, or a pharmaceutically acceptable salt thereof, wherein R 8 is hydrogen or chlorine.

[0426] Embodiment A-37: A compound according to any one of Embodiments A-1 to A-34, or a pharmaceutically acceptable salt thereof, wherein R 8 is hydrogen or fluorine.

[0427] Embodiment A-38: A compound according to any one of Embodiments A-1 to A-34, or a pharmaceutically acceptable salt thereof, wherein R 8 It is hydrogen or methyl.

[0428] Embodiment A-39: A compound according to any one of Embodiments A-1 to A-34, or a pharmaceutically acceptable salt thereof, wherein R 8 For hydrogen.

[0429] Embodiment A-40: A compound according to any one of Embodiments A-1 to A-34, or a pharmaceutically acceptable salt thereof, wherein R 8 It is a halogen.

[0430] Embodiment A-41: A compound according to any one of Embodiments A-1 to A-34, or a pharmaceutically acceptable salt thereof, wherein R 8 For chlorine.

[0431] Embodiment A-42: A compound according to any one of Embodiments A-1 to A-34, or a pharmaceutically acceptable salt thereof, wherein R 8 For fluorine.

[0432] Embodiment A-43: A compound according to any one of Embodiments A-1 to A-34, or a pharmaceutically acceptable salt thereof, wherein R 8 It is methyl.

[0433] Embodiment A-44: A compound according to Embodiment A-1 or a pharmaceutically acceptable salt thereof, wherein:

[0434] R 2 is selected from the group consisting of hydrogen, chlorine, fluorine and methyl;

[0435] R 3 is selected from the group consisting of hydrogen, chlorine and fluorine;

[0436] R 5 is selected from the group consisting of hydrogen, hydroxy, chloro, fluoro, methyl and methoxy; and

[0437] R 8 is selected from the group consisting of hydrogen, chlorine, fluorine and methyl.

[0438] Embodiment A-45: A compound according to Embodiment A-1 or a pharmaceutically acceptable salt thereof, wherein:

[0439] R 2 is selected from the group consisting of hydrogen, chlorine, fluorine and methyl;

[0440] R 3 is selected from the group consisting of hydrogen, chlorine and fluorine;

[0441] R 5 is selected from the group consisting of hydrogen, chlorine and fluorine; and

[0442] R 8 Selected from hydrogen, chlorine and fluorine.

[0443] Embodiment A-46: A compound according to Embodiment A-1 or a pharmaceutically acceptable salt thereof, wherein:

[0444] R 2 is selected from hydrogen, fluorine and methyl;

[0445] R 3 is hydrogen or fluorine;

[0446] R 5 is hydrogen or fluorine; and

[0447] R 8 is hydrogen or fluorine.

[0448] Embodiment A-47: A compound according to Embodiment A-1 or a pharmaceutically acceptable salt thereof, wherein:

[0449] R 2 is hydrogen or methyl;

[0450] R 3 is selected from the group consisting of hydrogen, chlorine and fluorine;

[0451] R 5 is selected from the group consisting of hydrogen, chlorine and fluorine; and

[0452] R 8 Selected from hydrogen, chlorine and fluorine.

[0453] Embodiment A-48: A compound according to Embodiment A-1 or a pharmaceutically acceptable salt thereof, wherein R 2, R 3 , R 5 and R 8 are independently selected from hydrogen and fluorine.

[0454] Embodiment A-49: A compound according to any one of Embodiments A-1 to A-48, or a pharmaceutically acceptable salt thereof, wherein R 2 , R 3 , R 5 and R 8 One of the substituents is not hydrogen, and the remaining R 2 , R 3 , R 5 and R 8 All substituents are hydrogen.

[0455] Embodiment A-50: A compound according to any one of Embodiments A-1 to A-49, or a pharmaceutically acceptable salt thereof, wherein R 6 and R 7 One of them is hydrogen and the other is chlorine.

[0456] Embodiment A-51: A compound according to any one of Embodiments A-1 to A-49, or a pharmaceutically acceptable salt thereof, wherein R 6 and R 7 One of them is hydrogen and the other is fluorine.

[0457] Embodiment A-52: A compound according to any one of Embodiments A-1 to A-49, or a pharmaceutically acceptable salt thereof, wherein R 6 and R 7 One of them is hydrogen and the other is bromine.

[0458] Embodiment A-53: A compound according to any one of Embodiments A-1 to A-49, or a pharmaceutically acceptable salt thereof, wherein R 6 and R 7 One of them is hydrogen and the other is iodine.

[0459] Embodiment A-54: A compound according to any one of Embodiments A-1 to A-49, or a pharmaceutically acceptable salt thereof, wherein R 6 and R 7 One of them is hydrogen and the other is C 1-6 -alkyl, wherein the C 1-6 -alkyl is optionally substituted by one or more independently selected from halogen, hydroxy, C 1-6 -alkoxy, halo-C 1-6 -alkoxy, C 3-6 -cycloalkyl and C 3-6 -cycloalkyloxy is substituted with a substituent.

[0460] Embodiment A-55: A compound according to any one of Embodiments A-1 to A-49, or a pharmaceutically acceptable salt thereof, wherein R 6 and R 7 One of them is hydrogen and the other is C 1-3 -alkyl, wherein the C 1-3 -alkyl is optionally substituted by one or more independently selected from halogen, hydroxy, C 1-3 -alkoxy, halo-C 1-3 -alkoxy, C 3-6 -cycloalkyl and C 3-6 -cycloalkyloxy is substituted with a substituent.

[0461] Embodiment A-56: A compound according to any one of Embodiments A-1 to A-49, or a pharmaceutically acceptable salt thereof, wherein R 6 and R 7 One of them is hydrogen and the other is C 1-3 -alkyl, wherein the C 1-3 -Alkyl is optionally substituted with one or more substituents independently selected from halogen, hydroxy, methoxy and halomethoxy.

[0462] Embodiment A-57: A compound according to any one of Embodiments A-1 to A-49, or a pharmaceutically acceptable salt thereof, wherein R 6 and R 7 One of them is hydrogen and the other is C 1-3 -alkyl, wherein the C 1-3 -alkyl is optionally substituted with one or more substituents independently selected from fluoro, hydroxy, methoxy and fluoromethoxy.

[0463] Embodiment A-58: A compound according to any one of Embodiments A-1 to A-49, or a pharmaceutically acceptable salt thereof, wherein R 6 and R 7 One of them is hydrogen and the other is C 1-3 -alkyl, wherein the C 1-3 -alkyl is optionally substituted with one or more substituents independently selected from fluoro and methoxy.

[0464] Embodiment A-59: A compound according to any one of Embodiments A-1 to A-49, or a pharmaceutically acceptable salt thereof, wherein R 6 and R 7 One of them is hydrogen and the other is C 1-6 -alkyl, wherein the C 1-6 -alkyl is optionally substituted by one or more independently selected from halogen and C 1-6 -substituted by a substituent of the alkoxy group.

[0465] Embodiment A-60: A compound according to any one of Embodiments A-1 to A-49, or a pharmaceutically acceptable salt thereof, wherein R 6 and R 7 One of them is hydrogen and the other is C 1-3 -alkyl, wherein the C 1-3 -alkyl is optionally substituted by one or more independently selected from halogen and C 1-3 -substituted by a substituent of the alkoxy group.

[0466] Embodiment A-61: A compound according to any one of Embodiments A-1 to A-49, or a pharmaceutically acceptable salt thereof, wherein R 6 and R 7 One of them is hydrogen and the other is C 1-6 -alkyl.

[0467] Embodiment A-62: A compound according to any one of Embodiments A-1 to A-49, or a pharmaceutically acceptable salt thereof, wherein R 6 and R 7 One of them is hydrogen and the other is C 1-3 -alkyl.

[0468] Embodiment A-63: A compound according to any one of Embodiments A-1 to A-49, or a pharmaceutically acceptable salt thereof, wherein R 6 and R 7 One of them is hydrogen and the other is methyl.

[0469] Embodiment A-64: A compound according to any one of Embodiments A-1 to A-49, or a pharmaceutically acceptable salt thereof, wherein R 6 and R 7 One of them is hydrogen and the other is C 1-6 -alkyl, wherein the C 1-6 -Alkyl is optionally substituted with one or more halogens.

[0470] Embodiment A-65: A compound according to any one of Embodiments A-1 to A-49, or a pharmaceutically acceptable salt thereof, wherein R 6 and R 7 One of them is hydrogen and the other is C 1-3 -alkyl, wherein the C 1-3 -Alkyl is optionally substituted by one or more fluorine.

[0471] Embodiment A-66: A compound according to any one of Embodiments A-1 to A-49, or a pharmaceutically acceptable salt thereof, wherein R 6 and R7 One of them is hydrogen and the other is C 1-6 -alkyl, wherein the C 1-6 The -alkyl group is optionally substituted with one or more hydroxy groups.

[0472] Embodiment A-67: A compound according to any one of Embodiments A-1 to A-49, or a pharmaceutically acceptable salt thereof, wherein R 6 and R 7 One of them is hydrogen and the other is C 1-3 -alkyl, wherein the C 1-3 The -alkyl group is optionally substituted with one or more hydroxy groups.

[0473] Embodiment A-68: A compound according to any one of Embodiments A-1 to A-49, or a pharmaceutically acceptable salt thereof, wherein R 6 and R 7 One of them is hydrogen and the other is C 1-6 -alkyl, wherein the C 1-6 -alkyl is optionally substituted with one or more C 1-6 -Alkoxy substitution.

[0474] Embodiment A-69: A compound according to any one of Embodiments A-1 to A-49, or a pharmaceutically acceptable salt thereof, wherein R 6 and R 7 One of them is hydrogen and the other is C 1-3 -alkyl, wherein the C 1-6 -alkyl is optionally substituted with one or more C 1-3 -Alkoxy substitution.

[0475] Embodiment A-70: A compound according to any one of Embodiments A-1 to A-49, or a pharmaceutically acceptable salt thereof, wherein R 6 and R 7 One of them is hydrogen and the other is C 1-6 -alkyl, wherein the C 1-6 -alkyl is optionally substituted with one or more halo-C 1-6 -Alkoxy substitution.

[0476] Embodiment A-71: A compound according to any one of Embodiments A-1 to A-49, or a pharmaceutically acceptable salt thereof, wherein R 6 and R 7 One of them is hydrogen and the other is C 1-3 -alkyl, wherein the C 1-3 -alkyl is optionally substituted with one or more halo-C 1-3 -Alkoxy substitution.

[0477] Embodiment A-72: A compound according to any one of Embodiments A-1 to A-49, or a pharmaceutically acceptable salt thereof, wherein R 6 and R 7 One of them is hydrogen and the other is C 1-3 -alkyl, wherein the C 1-3 -alkyl is optionally substituted with one or more fluoro-C 1-3 -Alkoxy substitution.

[0478] Embodiment A-73: A compound according to any one of Embodiments A-1 to A-49, or a pharmaceutically acceptable salt thereof, wherein R 6 and R 7 One of them is hydrogen and the other is C 1-6 -alkyl, wherein the C 1-6 -alkyl is optionally substituted with one or more C 3-6 -cycloalkyl substitution.

[0479] Embodiment A-74: A compound according to any one of Embodiments A-1 to A-49, or a pharmaceutically acceptable salt thereof, wherein R 6 and R 7 One of them is hydrogen and the other is C 1-3 -alkyl, wherein the C 1-3 -alkyl is optionally substituted with one or more C 3-6 -cycloalkyl substitution.

[0480] Embodiment A-75: A compound according to any one of Embodiments A-1 to A-49, or a pharmaceutically acceptable salt thereof, wherein R 6 and R 7 One of them is hydrogen and the other is C 1-6 -alkyl, wherein the C 1-6 -alkyl is optionally substituted with one or more C 3-6 -cycloalkoxy substitution.

[0481] Embodiment A-76: A compound according to any one of Embodiments A-1 to A-49, or a pharmaceutically acceptable salt thereof, wherein R 6 and R 7 One of them is hydrogen and the other is C 1-3 -alkyl, wherein the C 1-3 -alkyl is optionally substituted with one or more C 3-6 -cycloalkoxy substitution.

[0482] Embodiment A-77: A compound according to any one of Embodiments A-1 to A-49, or a pharmaceutically acceptable salt thereof, wherein R 6 and R 7One of them is hydrogen and the other is selected from methyl, ethyl, fluoromethyl, difluoromethyl, trifluoromethyl, fluoropropyl, hydroxyethyl, hydroxypropyl, methoxyethyl, methoxypropyl, trifluoromethoxymethyl and trifluoromethoxyethyl.

[0483] Embodiment A-78: A compound according to any one of Embodiments A-1 to A-49, or a pharmaceutically acceptable salt thereof, wherein R 6 and R 7 One of the groups is hydrogen, and the other is selected from the group consisting of methyl, ethyl, fluoromethyl, difluoromethyl, trifluoromethyl, fluoropropyl, methoxyethyl and methoxypropyl.

[0484] Embodiment A-79: A compound according to any one of Embodiments A-1 to A-49, or a pharmaceutically acceptable salt thereof, wherein R 6 and R 7 One of them is hydrogen and the other is cyclopropyl, wherein the cyclopropyl is optionally substituted by one or more independently selected from cyano, fluoro, C 1-6 -alkyl, halo-C 1-6 -alkyl and C 1-6 -substituted by a substituent of the alkoxy group.

[0485] Embodiment A-80: A compound according to any one of Embodiments A-1 to A-49, or a pharmaceutically acceptable salt thereof, wherein R 6 and R 7 One of them is hydrogen and the other is cyclopropyl, wherein the cyclopropyl is optionally substituted by one or more independently selected from cyano, fluoro, C 1-3 -alkyl, halo-C 1-3 -alkyl and C 1-3 -substituted by a substituent of the alkoxy group.

[0486] Embodiment A-81: A compound according to any one of Embodiments A-1 to A-49, or a pharmaceutically acceptable salt thereof, wherein R 6 and R 7 One of them is hydrogen and the other is cyclopropyl, wherein the cyclopropyl is optionally substituted by one or more independently selected from cyano, C 1-3 -alkyl, fluoro-C 1-3 -alkyl and C 1-3 -substituted by a substituent of the alkoxy group.

[0487] Embodiment A-82: A compound according to any one of Embodiments A-1 to A-49, or a pharmaceutically acceptable salt thereof, wherein R 6 and R 7 One of them is hydrogen and the other is cyclopropyl.

[0488] Embodiment A-83: A compound according to any one of Embodiments A-1 to A-49, or a pharmaceutically acceptable salt thereof, wherein R 6 and R 7 One of the is hydrogen and the other is cyclopropyl, wherein the cyclopropyl is optionally substituted with one or more cyano groups.

[0489] Embodiment A-84: A compound according to any one of Embodiments A-1 to A-49, or a pharmaceutically acceptable salt thereof, wherein R 6 and R 7 One of the is hydrogen and the other is cyclopropyl, wherein the cyclopropyl is optionally substituted with one or more fluorines.

[0490] Embodiment A-85: A compound according to any one of Embodiments A-1 to A-49, or a pharmaceutically acceptable salt thereof, wherein R 6 and R 7 One of them is hydrogen and the other is cyclopropyl, wherein the cyclopropyl is optionally substituted with one or C 1-6 -alkyl substitution.

[0491] Embodiment A-86: A compound according to any one of Embodiments A-1 to A-49, or a pharmaceutically acceptable salt thereof, wherein R 6 and R 7 One of them is hydrogen and the other is cyclopropyl, wherein the cyclopropyl is optionally substituted with one or more C 1-3 -alkyl substitution.

[0492] Embodiment A-87: A compound according to any one of Embodiments A-1 to A-49, or a pharmaceutically acceptable salt thereof, wherein R 6 and R 7 One of them is hydrogen and the other is cyclopropyl, wherein the cyclopropyl is optionally substituted with one or more halo-C 1-6 -alkyl substitution.

[0493] Embodiment A-88: ​​A compound according to any one of Embodiments A-1 to A-49, or a pharmaceutically acceptable salt thereof, wherein R 6 and R 7 One of them is hydrogen and the other is cyclopropyl, wherein the cyclopropyl is optionally substituted with one or more halo-C 1-3 -alkyl substitution.

[0494] Embodiment A-89: A compound according to any one of Embodiments A-1 to A-49, or a pharmaceutically acceptable salt thereof, wherein R 6 and R 7 One of the cyclopropyl radicals is hydrogen and the other is cyclopropyl, wherein the cyclopropyl radical is optionally substituted with one or more fluoro-C1-3 -alkyl substitution.

[0495] Embodiment A-90: A compound according to any one of Embodiments A-1 to A-49, or a pharmaceutically acceptable salt thereof, wherein R 6 and R 7 One of them is hydrogen and the other is cyclopropyl, wherein the cyclopropyl is optionally substituted with one or more C 1-6 -Alkoxy substitution.

[0496] Embodiment A-91: A compound according to any one of Embodiments A-1 to A-49, or a pharmaceutically acceptable salt thereof, wherein R 6 and R 7 One of them is hydrogen and the other is cyclopropyl, wherein the cyclopropyl is optionally substituted with one or more C 1-3 -Alkoxy substitution.

[0497] Embodiment A-92: A compound according to any one of Embodiments A-1 to A-49, or a pharmaceutically acceptable salt thereof, wherein R 6 and R 7 One of the is hydrogen and the other is cyclopropyl, wherein the cyclopropyl is optionally substituted with one or more substituents independently selected from cyano, methyl, trifluoromethyl and ethoxy.

[0498] Embodiment A-93: A compound according to any one of Embodiments A-1 to A-49, or a pharmaceutically acceptable salt thereof, wherein R 6 and R 7 One of them is hydrogen and the other is C 1-6 -alkoxy, wherein the C 1-6 -alkoxy is optionally substituted with one or more substituents independently selected from halogen and cyclopropyl.

[0499] Embodiment A-94: A compound according to any one of Embodiments A-1 to A-49, or a pharmaceutically acceptable salt thereof, wherein R 6 and R 7 One of them is hydrogen and the other is C 1-3 -alkoxy, wherein the C 1-3 -alkoxy is optionally substituted with one or more substituents independently selected from halogen and cyclopropyl.

[0500] Embodiment A-95: A compound according to any one of Embodiments A-1 to A-49, or a pharmaceutically acceptable salt thereof, wherein R 6 and R 7 One of them is hydrogen and the other is C 1-6 -alkoxy.

[0501] Embodiment A-96: A compound according to any one of Embodiments A-1 to A-49, or a pharmaceutically acceptable salt thereof, wherein R 6 and R 7 One of them is hydrogen and the other is C 1-3 -alkoxy.

[0502] Embodiment A-97: A compound according to any one of Embodiments A-1 to A-49, or a pharmaceutically acceptable salt thereof, wherein R 6 and R 7 One of them is hydrogen and the other is C 1-6 -alkoxy, wherein the C 1-6 -Alkoxy is optionally substituted by one or more halogens.

[0503] Embodiment A-98: A compound according to any one of Embodiments A-1 to A-49, or a pharmaceutically acceptable salt thereof, wherein R 6 and R 7 One of them is hydrogen and the other is C 1-3 -alkoxy, wherein the C 1-3 -Alkoxy is optionally substituted by one or more halogens.

[0504] Embodiment A-99: A compound according to any one of Embodiments A-1 to A-49, or a pharmaceutically acceptable salt thereof, wherein R 6 and R 7 One of them is hydrogen and the other is C 1-3 -alkoxy, wherein the C 1-3 The -alkoxy group is optionally substituted by one or more fluorine groups.

[0505] Embodiment A-100: A compound according to any one of Embodiments A-1 to A-49, or a pharmaceutically acceptable salt thereof, wherein R 6 and R 7 One of them is hydrogen and the other is C 1-6 -alkoxy, wherein the C 1-6 The -alkoxy group is optionally substituted by one or more cyclopropyl groups.

[0506] Embodiment A-101: A compound according to any one of Embodiments A-1 to A-49, or a pharmaceutically acceptable salt thereof, wherein R 6 and R 7 One of them is hydrogen and the other is C 1-3 -alkoxy, wherein the C 1-3 The -alkoxy group is optionally substituted by one or more cyclopropyl groups.

[0507] Embodiment A-102: A compound according to any one of Embodiments A-1 to A-49, or a pharmaceutically acceptable salt thereof, wherein R 6 and R 7 One of the groups is hydrogen, and the other is selected from methoxy, propoxy, trifluoroethoxy and cyclopropylmethoxy.

[0508] Embodiment A-103: A compound according to any one of Embodiments A-1 to A-49, or a pharmaceutically acceptable salt thereof, wherein R 6 and R 7 One of them is hydrogen and the other is C 3-6 -cycloalkoxy, wherein the C 3-6 -Cycloalkoxy is optionally substituted by one or more halogens.

[0509] Embodiment A-104: A compound according to any one of Embodiments A-1 to A-49, or a pharmaceutically acceptable salt thereof, wherein R 6 and R 7 One of them is hydrogen and the other is C 3-6 -cycloalkoxy, wherein the C 3-6 -cycloalkoxy is optionally substituted with one or more C 1-3 -alkyl substitution.

[0510] Embodiment A-105: A compound according to any one of Embodiments A-1 to A-49, or a pharmaceutically acceptable salt thereof, wherein R 6 and R 7 One of them is hydrogen and the other is C 3-6 -cycloalkoxy.

[0511] Embodiment A-106: A compound according to any one of Embodiments A-1 to A-49, or a pharmaceutically acceptable salt thereof, wherein R 6 and R 7 One of them is hydrogen and the other is cyclopropyloxy.

[0512] Embodiment A-107: A compound according to any one of Embodiments A-1 to A-49, or a pharmaceutically acceptable salt thereof, wherein R 6 and R 7 One of them is hydrogen and the other is cyclohexyloxy.

[0513] Embodiment A-108: A compound according to any one of Embodiments A-1 to A-49, or a pharmaceutically acceptable salt thereof, wherein R 6 and R 7 One of them is hydrogen and the other is C 3-6 -cycloalkoxy, wherein the C 3-6-Cycloalkoxy is optionally substituted by one or more fluorine.

[0514] Embodiment A-109: A compound according to any one of Embodiments A-1 to A-49, or a pharmaceutically acceptable salt thereof, wherein R 6 and R 7 One of the is hydrogen and the other is cyclohexyloxy, wherein the cyclohexyloxy is optionally substituted by one or more halogens.

[0515] Embodiment A-110: A compound according to any one of Embodiments A-1 to A-49, or a pharmaceutically acceptable salt thereof, wherein R 6 and R 7 One of the is hydrogen and the other is cyclohexyloxy, wherein the cyclohexyloxy is optionally substituted by one or more fluorines.

[0516] Embodiment A-111: A compound according to any one of Embodiments A-1 to A-49, or a pharmaceutically acceptable salt thereof, wherein R 6 and R 7 One of the is hydrogen and the other is cyclopropyloxy, wherein the cyclopropyloxy is optionally substituted with one or more halogens.

[0517] Embodiment A-112: A compound according to Embodiment 1 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.

[0518] Embodiment B-1: A compound according to any one of Embodiments 1 to 78 or A-1 to A-112, or a pharmaceutically acceptable salt thereof, wherein R 6 and R 7 One of the is hydrogen and the other is cyclopropyloxy, wherein the cyclopropyloxy is optionally substituted by one or more fluorines.

[0519] Embodiment C-1: A pharmaceutical composition comprising a compound according to any one of Embodiments 1 to 78 or A-1 to A-112 or a pharmaceutically acceptable salt thereof, and one or more pharmaceutically acceptable excipients.

[0520] Embodiment C-2: A method for treating or preventing a FAP-mediated disorder in a subject suffering from or susceptible to a FAP-mediated disorder, the method comprising administering to the subject a therapeutically effective amount of a compound of any one of Embodiments 1 to 78 or A-1 to A-112, or a pharmaceutically acceptable salt thereof.

[0521] Embodiment C-3: The method according to embodiment C-2, wherein the FAP-mediated disorder is selected from liver disease, type 2 diabetes, cardiovascular disorders, obesity, obesity-related disorders, fibrosis, keloid disorders, inflammation and cancer.

[0522] Embodiment C-4: The method according to embodiment C-3, wherein the FAP-mediated disorder is liver disease.

[0523] Embodiment C-5: The method according to embodiment C-4, wherein the liver disease is non-alcoholic steatohepatitis.

[0524] Embodiment C-6: Use of a compound according to any one of Embodiments 1 to 78 or A-1 to A-112, or a pharmaceutically acceptable salt thereof, for the preparation of a medicament for the treatment or prevention of a FAP-mediated disorder.

[0525] C. Combination of Implementation Schemes

[0526] Any embodiment of the compounds described in the present disclosure can be combined with any other appropriate embodiment described herein to provide additional embodiments. For example, in one embodiment, R is described alone or together. 2 , R 3 , R 5 , R 6 , R 7 and / or R 8 A possible group, while another embodiment describes R 7 In the case of possible groups, it should be understood that these embodiments can be combined together to provide additional embodiments, which describe the 2 , R 3 , R 5 , R 6 , R 7 and / or R 8 The possible groups mentioned together with the 7 In other words, for any embodiment of the compounds described in the present disclosure, R 7 The substituents may be as described in the specification. 7 as defined in any embodiment of .

[0527] D. Other implementation plans

[0528] The compounds of the present disclosure have pharmaceutically acceptable FAP inhibitory activity as measured as described in the hFAP inhibition assay (tight binders) reported in the Examples below. In one aspect, the compounds have an IC of less than about 100 nM. 50In another aspect, the compound has FAP inhibitory activity at an IC of less than about 50 nM. 50 In another aspect, the compound has FAP inhibitory activity at an IC of less than about 10 nM. 50 In another aspect, the compound has FAP inhibitory activity at an IC of less than about 1 nM. 50 It has FAP inhibitory activity at concentrations of 1.

[0529] In some embodiments, the compounds of the present disclosure have a pharmaceutically acceptable surface plasmon resonance (SPR) pK d Value, which is measured as described in the SPR assay reported in the Examples below. In one aspect, the compound has a surface plasmon resonance (SPR) pK greater than about 6. d In another aspect, the compound has a surface plasmon resonance (SPR) pK greater than about 7. d In another aspect, the compound has an SPR pK greater than about 8. d In another aspect, the compound has an SPR pK greater than about 9. d value.

[0530] In some embodiments, the compounds of the present disclosure have a pharmaceutically acceptable selectivity for FAP relative to PREP as measured in the hFAP inhibition assay (tight binders) and hPREP inhibition assay reported in the Examples below. In one aspect, the compound has a selectivity of at least up to about 50-fold for FAP relative to PREP. In another aspect, the compound has a selectivity of at least up to about 100-fold for FAP relative to PREP. In another aspect, the compound has a selectivity of at least up to about 1,000-fold for FAP relative to PREP. In another aspect, the compound has a selectivity of at least up to about 10,000-fold for FAP relative to PREP. In another aspect, the compound has a PREP IC greater than about 0.1 μM. 50 In another aspect, the compound has a PREP IC greater than about 1.0 μM. 50 In another aspect, the compound has a PREP IC greater than about 10.0 μM. 50 value.

[0531] In some embodiments, the compounds of the present disclosure have a pharmaceutically acceptable selectivity for FAP relative to DPP7 as measured in the hFAP inhibition assay (tight binders) and DPP7 selectivity assay reported in the Examples below. In one aspect, the compound has a selectivity for FAP relative to DPP7 of at least up to about 50-fold. In another aspect, the compound has a selectivity for FAP relative to DPP7 of at least up to about 100-fold. In another aspect, the compound has a selectivity for FAP relative to DPP7 of at least up to about 1,000-fold. In another aspect, the compound has a selectivity for FAP relative to DPP7 of at least up to about 10,000-fold. In another aspect, the compound has a DPP7 IC greater than about 0.1 μM. 50 In another aspect, the compound has a DPP7 IC greater than about 1 μM. 50 In another aspect, the compound has a DPP7 IC greater than about 10 μM. 50 value.

[0532] In some embodiments, the compounds of the present disclosure have pharmaceutically acceptable selectivity for FAP relative to DPP8 and / or DPP9, as measured in the hFAP inhibition assay (tight binders), DPP8 selectivity assay, and DPP9 selectivity assay reported in the Examples below. In one aspect, the compound has selectivity for FAP relative to DPP8. In another aspect, the compound has selectivity for FAP relative to DPP9. In another aspect, the compound has selectivity for FAP relative to both DPP8 and DPP9. In one aspect, the compound has selectivity for FAP relative to DPP8 and / or DPP9 of at least up to about 50 times. In another aspect, the compound has selectivity for FAP relative to DPP8 and / or DPP9 of at least up to about 100 times. In another aspect, the compound has selectivity for FAP relative to DPP8 and / or DPP9 of at least up to about 500 times. In another aspect, the compound has selectivity for FAP relative to DPP8 and / or DPP9 of at least up to about 1,000 times. In another aspect, the compound has an IC of DPP8 and / or DPP9 greater than about 0.01 μM. 50 In another aspect, the compound has a DPP8 and / or DPP9 IC greater than about 0.1 μM. 50 In another aspect, the compound has a DPP8 and / or DPP9 IC greater than about 0.4 μM. 50 value.

[0533] In some embodiments, the compounds of the present disclosure have a pharmaceutically acceptable metabolic stability as measured in the human liver microsome (HLM) assay reported in the Examples below. In one aspect, the compounds have an HLM CL of less than about 300 μL / min / mg. int In another aspect, the compound has an HLMCL of less than about 100 μL / min / mg. int In another aspect, the compound has an HLM CL of less than about 50 μL / min / mg. int value.

[0534] In some embodiments, the compounds of the present disclosure have a pharmaceutically acceptable metabolic stability as measured in the rat hepatocyte (rHep) assay reported in the Examples below. In one aspect, the compounds have a metabolic stability of less than about 300 μL / min / 10 6 rHep CL int In another aspect, the compound has a flow rate of less than about 100 μL / min / 10 6 rHep CL int In another aspect, the compound has a concentration of less than about 50 μL / min / 10 6 rHepCL int value.

[0535] In some embodiments, the compounds of the present disclosure have a pharmaceutically acceptable Caco-2 AB intrinsic permeability as measured in the Caco-2 AB intrinsic permeability assay reported in the Examples below. In one aspect, the compounds have a Caco-2 AB intrinsic permeability of at least about 0.1×10 6 In another aspect, the compound has a Caco-2 intrinsic permeability of at least about 0.5×10 6 cm / s. In another aspect, the compound has a Caco-2 intrinsic permeability of at least about 1×10 6 Intrinsic apparent permeability of Caco-2 in cm / s.

[0536] In some embodiments, the compounds of the present disclosure have a pharmaceutically acceptable Caco-2 bidirectional (ABBA) A to B apparent permeability as measured as described in the Caco-2 bidirectional (ABBA) A to B apparent permeability assay reported in the Examples below. In one aspect, the compounds have a permeability of at least about 0.1×10 6 In another aspect, the compound has an apparent permeability of at least about 0.25×10 6cm / s Caco-2 bidirectional (ABBA) A to B apparent permeability. In another aspect, the compound has an apparent permeability of at least about 0.5×10 6 Apparent permeability of Caco-2 bidirectional (ABBA) A to B in cm / s.

[0537] In some embodiments, the compounds of the present disclosure have a pharmaceutically acceptable kinetic solubility, which is measured as described in the kinetic solubility assay reported in the following examples. In one aspect, the compound has a kinetic solubility of at least about 1 μM. In another aspect, the compound has a kinetic solubility of at least about 10 μM. In another aspect, the compound has a kinetic solubility of at least about 25 μM. In another aspect, the compound has a kinetic solubility of at least about 50 μM.

[0538] E. Salt

[0539] The compounds of the present disclosure may exist in salt form or non-salt form (i.e., as free alkali), and the present disclosure encompasses both salt form and non-salt form. The compound may form an acid addition salt or a base addition salt. Typically, various inorganic acids or organic acids may be used to prepare acid addition salts. For example, such salts may be formed by mixing compounds with acids (e.g., stoichiometric amounts of acid) using various methods known in the art. The mixing may be carried out in water, an organic solvent (e.g., ether, ethyl acetate, ethanol, methanol, isopropanol or acetonitrile) or a water / organic mixture. On the other hand, acid addition salts are, for example, trifluoroacetate, formate, acetate or hydrochloride. Typically, base addition salts may be prepared using various inorganic bases or organic bases, such as alkali metal salts or alkaline earth metal salts (such as sodium salts, calcium salts or magnesium salts), or other metal salts (such as potassium salts or zinc salts), or ammonium salts, or salts formed with organic bases (such as methylamine, dimethylamine, trimethylamine, piperidine or morpholine). The skilled artisan will be aware of the general principles and techniques for preparing pharmaceutically acceptable salts, such as those described in J. Pharm. Sci. 1977 66, 1. Examples of pharmaceutically acceptable salts are also described in Stahl and Wermuth, "Handbook of Pharmaceutical Salts: Properties, Selection, and Use" (Wiley-VCH, Weinheim, Germany, 2002).

[0540] F. Isomers

[0541] Compounds and salts of the present disclosure can exist in one or more geometric, optical, enantiomeric and diastereomeric forms, including but not limited to cis and trans, E and Z, and R, S and meso forms. Unless otherwise indicated, the specific compound referred to includes all such isomeric forms, including racemates and other mixtures thereof. Where appropriate, such isomers can be separated from their mixtures by applying or adjusting known methods (e.g., chromatography techniques and recrystallization techniques). Where appropriate, such isomers can be prepared by applying or adjusting known methods. In some embodiments, a single stereoisomer is obtained by separating a single stereoisomer from an isomer mixture (e.g., racemate) using, for example, chiral chromatography. In other embodiments, a single stereoisomer is obtained by direct synthesis by, for example, chiral raw materials.

[0542] A specific 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, a single enantiomer is present in an enantiomeric excess (%ee) of ≥99%.

[0543] In another embodiment, the present disclosure relates to a pharmaceutical composition comprising a compound or a pharmaceutically acceptable salt thereof, and one or more pharmaceutically acceptable excipients, wherein the compound or a pharmaceutically acceptable salt thereof is a single enantiomer with an enantiomeric excess (%ee) ≥90%, ≥95%, ≥96%, ≥97%, ≥98%, or ≥99%. In one aspect, the single enantiomer is present in an enantiomeric excess (%ee) of ≥99%.

[0544] G. Additional forms

[0545] The compounds and salts of the present disclosure may exist in various tautomeric forms, and the present specification encompasses all such tautomeric forms. "Tautomers" are structural isomers that exist in equilibrium due to the migration of a hydrogen atom.

[0546] The compounds of the present disclosure and pharmaceutically acceptable salts thereof may exist as solvates (such as hydrates) as well as unsolvated forms, and the present specification encompasses all such solvates.

[0547] The compounds of the present disclosure and pharmaceutically acceptable salts thereof may exist in crystalline or amorphous forms, and the present specification encompasses all such forms.

[0548] The compounds and salts of the present disclosure may be isotopically labeled (or "radiolabeled"). In this 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 normally found in nature. This specification encompasses isotopically labeled forms of the compounds disclosed herein. Examples of isotopes that may be incorporated include 2 H (deuterium is also written as "D"), 3 H (tritium is also written as "T"), 11 C. 13 C. 14 C. 13 N. 15 N. 15 O. 17 O. 18 O and 36 The isotope used will depend on the specific application of the radiolabeled derivative. For example, for in vitro receptor labeling and competition assays, 3 H or 14 C is often useful. For radiographic applications, 11 C is often useful. In some embodiments, the radionuclide is 3 H. In some embodiments, the radionuclide is 14 C. In some embodiments, the radionuclide is 11 C.

[0549] H.Intermediates

[0550] In some embodiments, the present disclosure provides additional compounds and pharmaceutically acceptable salts thereof that are useful as intermediates in preparing the compounds of the present disclosure.

[0551] III. How to use

[0552] The compounds disclosed in the present invention and their pharmaceutically acceptable salts are inhibitors of the activity of prolyl endopeptidase fibroblast activation protein (FAP). FAP is an endopeptidase that enzymatically cleaves substrates involved in glucose and lipid metabolism, fibrinolysis and collagen production.

[0553] It is believed that FAP can cleave and inactivate human fibroblast growth factor 21 (FGF-21), a protein involved in regulating glucose and lipid metabolism (Biochem. J. 2016, 473, 605). It is speculated that inhibition of FAP can increase endogenous FGF-21 levels and signal transduction, thereby, for example, reducing steatosis, improving insulin sensitivity, improving glucose tolerance, reducing body weight and / or reducing cardiovascular disease mortality.

[0554] FAP is also believed to be able to cleave human α2-antiplasmin (α2AP), a protein involved in regulating fibrosis and fibrinolysis (Blood 2004 103, 3783). Tissue repair involves coagulation, which leads to fibrin deposition. Fibrin in blood clots is usually mainly dissolved by plasmin, which is converted from its inactive form (plasminogen) under the action of 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 can convert α2AP into a form that binds to fibrin more effectively, thereby reducing plasmin degradation of fibrin at the site of injury. It is speculated that inhibiting FAP can increase fibrinolysis and improve tissue regeneration at the site of injury (J. Thromb. Haemost. 2013, 11, 2029; Proteomics Clin. Appl. 2014, 8, 454).

[0555] It is believed that FAP also promotes the production and deposition of collagen and plays a role in the exacerbation of fibrosis by changing the turnover of the extracellular matrix (ECM) (J Biol Chem 2016, 8, 291). It is speculated that inhibiting FAP will reduce collagen deposition and reduce inflammation (Inflamm. Bowel Dis. 2018, 18, 332).

[0556] In view of the above, it is hypothesized that inhibition of FAP could jointly reduce fibrosis and inflammation by decreasing hepatic stellate cell activity and increasing fibrinolysis, and further provide positive metabolic effects by increasing FGF21 signaling and improving glucose tolerance.

[0557] Thus, in some embodiments, the present disclosure provides a method of treating or preventing a FAP-mediated disorder in a subject by administering to the subject in need of such treatment a therapeutically effective amount of a compound of Formula I or a pharmaceutically acceptable salt thereof.

[0558] In some embodiments, the present disclosure provides a method of treating or preventing a disorder characterized by overexpression of FAP in a subject in need thereof by administering to the subject a therapeutically effective amount of a compound of the present disclosure or a pharmaceutically acceptable salt thereof.

[0559] In some embodiments, the present disclosure provides a method of treating or preventing liver disease in a subject by administering a therapeutically effective amount of a compound of the present disclosure or a pharmaceutically acceptable salt thereof to a subject in need of treatment. In one aspect, the liver disease is fatty liver disease. On the other hand, the liver disease is non-alcoholic fatty liver disease (NAFLD). On the other hand, NAFLD is selected from isolated steatosis, non-alcoholic steatohepatitis (NASH), liver fibrosis and cirrhosis. On the other hand, the liver disease is end-stage liver disease. On the other hand, the subject also suffers from or is susceptible to one or more conditions selected from obesity, dyslipidemia, insulin resistance, type 2 diabetes and renal insufficiency.

[0560] In some embodiments, the present disclosure provides a method of treating liver disease in a subject by administering to the subject a therapeutically effective amount of a compound of the present disclosure or a pharmaceutically acceptable salt thereof, wherein the subject has a 27 kg / m 2 Up to 40kg / m 2 In one aspect, the subject has a body mass index (BMI) of 30 kg / m 2 Up to 39.9kg / m 2 In another aspect, the subject has a BMI of at least 40 kg / m 2 In another aspect, the subject is overweight. In another aspect, the subject is obese. In another aspect, the liver disease is NAFLD. In another aspect, the liver disease is NASH. In another aspect, the liver disease is liver fibrosis. In another aspect, the liver disease is cirrhosis.

[0561] In some embodiments, the present disclosure provides a method of treating a subject's liver disease by administering a therapeutically effective amount of a compound of the present disclosure or a pharmaceutically acceptable salt thereof to a subject in need of treatment, wherein the subject also suffers from or is susceptible to dyslipidemia. In another aspect, the liver disease is NAFLD. In another aspect, the liver disease is NASH. In another aspect, the liver disease is liver fibrosis. In another aspect, the liver disease is cirrhosis.

[0562] In some embodiments, the present disclosure provides a method of treating a subject's liver disease by administering a therapeutically effective amount of a compound of the present disclosure or a pharmaceutically acceptable salt thereof to a subject in need of treatment, wherein the subject also suffers from or is susceptible to insulin resistance. In another aspect, the liver disease is NAFLD. In another aspect, the liver disease is NASH. In another aspect, the liver disease is liver fibrosis. In another aspect, the liver disease is cirrhosis.

[0563] In some embodiments, the present disclosure provides a method of treating a subject's liver disease by administering a therapeutically effective amount of a compound of the present disclosure or a pharmaceutically acceptable salt thereof to a subject in need of treatment, wherein the subject also suffers from or is susceptible to at least one of type 2 diabetes and renal insufficiency. In another aspect, the liver disease is NAFLD. In another aspect, the liver disease is NASH. In another aspect, the liver disease is liver fibrosis. In another aspect, the liver disease is cirrhosis.

[0564] In some embodiments, the present disclosure provides a method of treating a subject's liver disease by administering a therapeutically effective amount of a compound of the present disclosure or a pharmaceutically acceptable salt thereof to a subject in need of treatment, wherein the subject also suffers from or is susceptible to type 2 diabetes. In another aspect, the liver disease is NAFLD. In another aspect, the liver disease is NASH. In another aspect, the liver disease is liver fibrosis. In another aspect, the liver disease is cirrhosis.

[0565] In some embodiments, the present disclosure provides a method of treating a subject's liver disease by administering a therapeutically effective amount of a compound of the present disclosure or a pharmaceutically acceptable salt thereof to a subject in need of treatment, wherein the subject also suffers from or is susceptible to renal insufficiency. In another aspect, the liver disease is NAFLD. In another aspect, the liver disease is NASH. In another aspect, the liver disease is liver fibrosis. In another aspect, the liver disease is cirrhosis.

[0566] In some embodiments, the present disclosure provides a method of reducing liver fat in a subject by administering a therapeutically effective amount of a compound of the present disclosure or a pharmaceutically acceptable salt thereof to a subject in need of treatment. In one aspect, the subject suffers from or is susceptible to NAFLD. In another aspect, the subject suffers from or is susceptible to NASH. In another aspect, the subject suffers from or is susceptible to liver fibrosis. In another aspect, the subject suffers from or is susceptible to cirrhosis. In another aspect, the subject also suffers from or is susceptible to one or more conditions selected from obesity, dyslipidemia, insulin resistance, type 2 diabetes, and renal insufficiency.

[0567] In some embodiments, the present disclosure provides a method of treating or preventing nonalcoholic fatty liver disease (NAFLD) of a subject by administering a therapeutically effective amount of a compound of the present disclosure or a pharmaceutically acceptable salt thereof to a subject in need of treatment. In one aspect, NAFLD is stage 1 NAFLD. On the other hand, NAFLD is stage 2 NAFLD. On the other hand, NAFLD is stage 3 NAFLD. On the other hand, NAFLD is stage 4 NAFLD. See, for example, "The Diagnosis and Management of Nonalcoholic Fatty Liver Disease: Practice Guidance From the American Association for the Study of Liver Diseases," Hepatology, 2018, Vol. 67, No. 1. On the other hand, the subject also suffers from or is susceptible to one or more conditions selected from obesity, dyslipidemia, insulin resistance, type 2 diabetes, and renal insufficiency.

[0568] In some embodiments, the present disclosure provides a method of treating or preventing non-alcoholic steatohepatitis (NASH) in a subject by administering a therapeutically effective amount of a compound of the present disclosure or a pharmaceutically acceptable salt thereof to a subject in need of treatment. 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 obesity, dyslipidemia, insulin resistance, type 2 diabetes, and renal insufficiency.

[0569] In some embodiments, the present disclosure provides a method of treating or preventing liver fibrosis 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. In one aspect, the subject suffers from stage 3 liver fibrosis. In another aspect, the subject also suffers from or is susceptible to one or more conditions selected from obesity, dyslipidemia, insulin resistance, type 2 diabetes, and renal insufficiency.

[0570] In some embodiments, the present disclosure provides a method of treating or preventing cirrhosis of the subject by administering a therapeutically effective amount of a compound of the present disclosure or a pharmaceutically acceptable salt thereof to a subject in need of treatment. In one aspect, the subject suffers from stage F4 cirrhosis. In another aspect, the subject also suffers from or is susceptible to one or more conditions selected from obesity, dyslipidemia, insulin resistance, type 2 diabetes, and renal insufficiency.

[0571] In some embodiments, the present disclosure provides a method of treating or preventing type 2 diabetes in a subject by administering a therapeutically effective amount of a compound of the present disclosure or a pharmaceutically acceptable salt thereof to a subject in need of treatment. In one aspect, the subject is a subject with diabetic nephropathy. In another aspect, the subject suffers from renal insufficiency. In another aspect, administration of the compound is an adjunct to diet and exercise. In another aspect, administration of the compound also reduces weight and / or treats obesity. In another aspect, the subject has a 27 kg / m 2 Up to 40kg / m 2 On the other hand, the subject has a BMI of 30 kg / m 2 Up to 39.9kg / m 2 In another aspect, the subject has a BMI of at least 40 kg / m 2 In another aspect, the subject is overweight. In another aspect, the subject is obese.

[0572] In some embodiments, the present disclosure provides a method of improving glycemic control of a subject by administering a therapeutically effective amount of a compound of the present disclosure or a pharmaceutically acceptable salt thereof to a subject in need of treatment. In one aspect, the subject is a subject with type 2 diabetes. In another aspect, the subject is a subject with diabetic nephropathy. In another aspect, the subject suffers from renal insufficiency. In another aspect, administration of the compound is an adjunct to diet and exercise. In another aspect, administration of the compound also reduces weight and / or treats obesity. In another aspect, the subject has 27 kg / m 2 Up to 40kg / m 2 On the other hand, the subject has a BMI of 30 kg / m 2 Up to 39.9kg / m 2 In another aspect, the subject has a BMI of at least 40 kg / m 2 In another aspect, the subject is overweight. In another aspect, the subject is obese.

[0573] In some embodiments, the present disclosure provides a method of improving glycemic control in a subject by administering a therapeutically effective amount of a compound of the present disclosure or a pharmaceutically acceptable salt thereof to a subject suffering from type 2 diabetes and diabetic nephropathy. In one aspect, administration of the compound is an adjunct to diet and exercise. In another aspect, administration of the compound also reduces weight and / or treats obesity. In another aspect, the subject has a 27 kg / m 2 Up to 40kg / m 2 On the other hand, the subject has a BMI of 30 kg / m 2 Up to 39.9kg / m 2In another aspect, the subject has a BMI of at least 40 kg / m 2 In another aspect, the subject is overweight. In another aspect, the subject is obese.

[0574] In some embodiments, the present disclosure provides a method of improving glycemic control in a subject by administering a therapeutically effective amount of a compound of the present disclosure or a pharmaceutically acceptable salt thereof to a subject suffering from type 2 diabetes and renal insufficiency. In one aspect, administration of the compound is an adjunct to diet and exercise. In another aspect, administration of the compound also reduces weight and / or treats obesity. In another aspect, the subject has a 27 kg / m 2 Up to 40kg / m 2 On the other hand, the subject has a BMI of 30 kg / m 2 Up to 39.9kg / m 2 In another aspect, the subject has a BMI of at least 40 kg / m 2 In another aspect, the subject is overweight. In another aspect, the subject is obese.

[0575] In some embodiments, the present disclosure provides a method for treating or preventing insulin resistance of a subject by administering a therapeutically effective amount of a compound of the present disclosure or a pharmaceutically acceptable salt thereof to a subject in need of treatment. On the other hand, the subject is a subject with type 2 diabetes. On the other hand, the subject is a subject with diabetic nephropathy. On the other hand, the subject suffers from renal insufficiency. For example, insulin resistance can be measured using the homeostatic model assessment method (HOMA-IR) and / or the Matsuda index of insulin resistance. For example, HOMA-IR is explained in Diabetologia 1985, 28, 412, which is incorporated herein by reference in its entirety. For example, the Matsuda index is explained in Diabetes Care 1999, 22, 1462, which is incorporated herein by reference in its entirety.

[0576] In some embodiments, the present disclosure provides a method of treating or preventing glucose intolerance in a subject by administering a therapeutically effective amount of a compound of the present disclosure or a pharmaceutically acceptable salt thereof to a subject in need of treatment. In one aspect, the subject is a subject with type 2 diabetes. In another aspect, the subject is a subject with diabetic nephropathy. In another aspect, the subject suffers from renal insufficiency.

[0577] In some embodiments, the present disclosure provides a method of treating a cardiovascular disorder of a subject by administering a therapeutically effective amount of a compound of the present disclosure or a pharmaceutically acceptable salt thereof to a subject in need of treatment. In one aspect, the cardiovascular disorder is selected from heart failure, cardiomyopathy, atherosclerosis, venous thromboembolism, and atrial fibrillation. In one aspect, the cardiovascular disorder is heart failure. On the other hand, the cardiovascular disorder is heart failure with preserved ejection fraction (HFpEF). On the other hand, the cardiovascular disorder is cardiomyopathy. On the other hand, the cardiomyopathy is selected from hypertrophic cardiomyopathy, dilated cardiomyopathy, restrictive cardiomyopathy, hypertrophic cardiomyopathy, ischemic cardiomyopathy, ischemic cardiomyopathy, dilated cardiomyopathy, and idiopathic cardiomyopathy. On the other hand, the cardiovascular disorder is atherosclerosis. On the other hand, the cardiovascular disorder is venous thromboembolism. On the other hand, the cardiovascular disorder is atrial fibrillation.

[0578] In some embodiments, the present disclosure provides a method of treating obesity or obesity-related conditions 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. In one aspect, obesity-related conditions are obesity-related metabolic conditions. On the other hand, obesity-related conditions are selected from insulin resistance, prediabetes, type 2 diabetes, glucose intolerance, elevated fasting blood sugar, and glucagonoma. On the other hand, obesity-related conditions are dyslipidemia. On the other hand, obesity-related conditions are cardiovascular conditions selected from heart failure, cardiomyopathy, atherosclerosis, venous thromboembolism, and atrial fibrillation. On the other hand, obesity-related conditions are nephropathy.

[0579] In some embodiments, the present disclosure provides a method of reducing the weight of a subject by administering a therapeutically effective amount of a compound of the present disclosure or a pharmaceutically acceptable salt thereof to a subject in need of treatment. In one aspect, the subject is a subject with type 2 diabetes. In another aspect, the subject is a subject with diabetic nephropathy. In another aspect, the subject suffers from renal insufficiency. In another aspect, administration of the compound is an adjunct to diet and exercise. In another aspect, administration of the compound also reduces weight and / or treats obesity. In another aspect, the subject has a 27 kg / m 2 Up to 40kg / m 2 On the other hand, the subject has a BMI of 30 kg / m 2 Up to 39.9kg / m 2 In another aspect, the subject has a BMI of at least 40 kg / m 2 In another aspect, the subject is overweight. In another aspect, the subject is obese. In another aspect, the subject loses weight, for example, by at least about 5%, 10%, 15%, 20%, 25%, 30%, 35%, or 40%.

[0580] In some embodiments, the present disclosure provides a method of reducing body fat in a subject by administering a therapeutically effective amount of a compound of the present disclosure or a pharmaceutically acceptable salt thereof to a subject in need of treatment. In another aspect, the subject is a subject with type 2 diabetes. In another aspect, the subject is a subject with diabetic nephropathy. In another aspect, the subject suffers from renal insufficiency. In another aspect, administration of the compound is an adjunct to diet and exercise. In another aspect, administration of the compound also reduces weight and / or treats obesity. In another aspect, the subject has 27 kg / m 2 Up to 40kg / m 2 On the other hand, the subject has a BMI of 30 kg / m 2 Up to 39.9kg / m 2 In another aspect, the subject has a BMI of at least 40 kg / m 2 In another aspect, the subject is overweight. In another aspect, the subject is obese. In another aspect, the fat is liver fat.

[0581] In some embodiments, the present disclosure provides a method of treating or preventing fibrosis in a subject by administering a therapeutically effective amount of a compound of the present disclosure or a pharmaceutically acceptable salt thereof to a subject in need of treatment. In one aspect, fibrosis is interstitial lung disease. In another aspect, fibrosis is interstitial lung disease with progressive fibrosis. In another aspect, interstitial lung disease is pulmonary fibrosis. In another aspect, interstitial lung disease is idiopathic pulmonary fibrosis (IPF).

[0582] In some embodiments, the present disclosure provides a method of promoting tissue remodeling in a subject by administering a therapeutically effective amount of a compound of the present disclosure or a pharmaceutically acceptable salt thereof to a subject in need of treatment. In one aspect, the subject suffers from cardiac tissue damage caused by myocardial infarction.

[0583] In some embodiments, the present disclosure provides a method of promoting wound healing and / or reducing adhesions 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. In one aspect, administering a compound promotes wound healing and / or reduces adhesions by increasing fibrinolysis.

[0584] In some embodiments, the present disclosure provides a method of treating or preventing a keloid 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 keloid condition is selected from scar formation, keloid tumor, and keloid scar.

[0585] In some embodiments, the present disclosure provides a method of treating or preventing inflammation in a subject by administering a therapeutically effective amount of a compound of the present disclosure or a pharmaceutically acceptable salt thereof to a subject in need of treatment. In one aspect, the inflammation is a chronic inflammation. In one aspect, the chronic inflammation is selected from rheumatoid arthritis, osteoarthritis, and Crohn's disease. In another aspect, the chronic inflammation is rheumatoid arthritis.

[0586] In some embodiments, the disclosure provides a method of treating cancer of a subject by administering a therapeutically effective amount of a compound of the disclosure or a pharmaceutically acceptable salt thereof to a subject in need of treatment. In one aspect, the cancer is selected from breast cancer, pancreatic cancer, small intestine cancer, colon cancer, rectal cancer, lung cancer, head and neck cancer, ovarian cancer, hepatocellular carcinoma, esophageal cancer, laryngopharyngeal cancer, nasopharyngeal cancer, laryngeal cancer, myeloma cells, bladder cancer, cholangiocarcinoma, renal clear cell carcinoma, neuroendocrine tumors, carcinogenic osteomalacia, sarcoma, CUP (metastatic cancer of unknown primary focus), thymic carcinoma, desmoid tumor, glioma, astrocytoma, cervical cancer and prostate cancer. On the other hand, the cancer is hepatocellular carcinoma.

[0587] The subject of treatment is usually a human or non-human mammal, particularly a human. Suitable subjects may also include domestic or wild animals; companion animals (including dogs, cats, etc.); livestock (including horses, cattle and other ruminants, pigs, poultry, rabbits, etc.); primates (including monkeys (such as rhesus monkeys), cynomolgus monkeys (also known as cynomolgus monkeys or long-tailed monkeys), marmosets, silk monkeys, chimpanzees, macaques, etc.); and rodents (including rats, mice, gerbils, guinea pigs, etc.).

[0588] In some embodiments, the present disclosure provides a compound of the present disclosure, or a pharmaceutically acceptable salt thereof, for use as a medicament.

[0589] In some embodiments, the present disclosure provides for the use of a compound of Formula I or a pharmaceutically acceptable salt thereof for treating or preventing a FAP-mediated disorder as described above.

[0590] In some embodiments, the present disclosure provides the use of a compound of Formula I or a pharmaceutically acceptable salt thereof for the preparation of a medicament for treating or preventing a FAP-mediated disorder as described above.

[0591] IV. Combination Therapies and Fixed-Dose Combinations

[0592] In the above method, the compounds of the present invention can be used as a single pharmacological agent or in combination with other pharmacological agents or technologies. Such combination therapies can be achieved by administering the components of the treatment simultaneously, successively or separately. These combination therapies (and corresponding combination products) use the compounds of the present invention within the dosage range described in the application and other pharmacological agents generally within the dosage range approved by them.

[0593] In some embodiments, the present disclosure provides a combination suitable for treating a disorder selected from those disorders previously discussed, wherein the combination comprises a compound of the present disclosure or a pharmaceutically acceptable salt thereof and a sodium-glucose transporter 2 (SGLT2) inhibitor. In one aspect, the SGLT2 inhibitor is selected from canagliflozin, dapagliflozin, empagliflozin, erpagliflozin, ipagliptin, rupagliflozin and repagliflozin. On the other hand, the SGLT2 inhibitor is dapagliflozin.

[0594] In some embodiments, the present disclosure provides a combination suitable for treating a condition selected from those previously discussed, wherein the combination comprises a compound of the present disclosure, or a pharmaceutically acceptable salt thereof, and metformin.

[0595] In some embodiments, the present disclosure provides a combination suitable for treating a condition selected from those previously discussed, wherein the combination comprises 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 exenatide, liraglutide, lixisenatide, albiglutide, dulaglutide and semaglutide.

[0596] In some embodiments, the present disclosure provides a combination suitable for treating a condition selected from those previously discussed, wherein the combination comprises 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 sitagliptin, vildagliptin, saxagliptin, linagliptin, gemagliptin, aragliliptin, teneligliptin, alogliptin, trelagliptin, ogliptin, emlagliptin, golagliptin and dulagliptin.

[0597] In some embodiments, the present disclosure provides a combination suitable for treating a condition selected from those previously discussed, wherein the combination comprises 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. On the other hand, the PPAR agonist is a PPARγ agonist. On the other hand, the PPAR agonist is a PPARα / γ agonist. On the other hand, the PPAR agonist is selected from clofibrate, gemfibrozil, ciprofibrate, bezafibrate and fenofibrate. On the other hand, the PPAR agonist is a thiazolidinedione. On the other hand, the thiazolidinedione is selected from pioglitazone, rosiglitazone, lobeglitazone and rivoglitazone. On the other hand, the PPAR agonist stimulates FGF21 expression in the liver.

[0598] In some embodiments, the present disclosure provides a pharmaceutical composition comprising a compound of the present disclosure or a pharmaceutically acceptable salt thereof; one or more pharmacological agents selected from SGLT2 inhibitors, metformin, GLP1 agonists, DPP4 inhibitors and PPAR agonists; and a pharmaceutically acceptable diluent or carrier. This combination can be used to prepare a medicament for treating a condition selected from those conditions previously discussed. In one aspect, the pharmaceutical composition comprises an SGLT2 inhibitor. In another aspect, the pharmaceutical composition comprises metformin. In another aspect, the pharmaceutical composition comprises a GLP1 agonist. In another aspect, the pharmaceutical composition comprises a DPP4 inhibitor. In another aspect, the pharmaceutical composition comprises a PPAR agonist.

[0599] In some embodiments, the present disclosure provides a combination suitable for treating cancer, wherein the combination comprises 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 anti-PD-1 antibodies, anti-PD-L1 antibodies, anti-CTLA4 antibodies, TLR7 agonists, CD40 agonists, Lag-3 antagonists and OX40 agonists. On the other hand, the immune checkpoint inhibitor is an anti-PD-1 antibody (e.g., pembrolizumab (Keytruda), nivolumab (Opdivo), simiprilimumab (Libtayo), etc.). On the other hand, the immune checkpoint inhibitor is an anti-PD-L1 antibody (e.g., atezolizumab (Tecentriq), avelumab (Bavencio), durvalumab (Imfinzi), etc.). On the other hand, the immune checkpoint inhibitor is an anti-CTLA4 antibody (e.g., ipilimumab (Yervoy), tesimumab, etc.). On the other hand, cancer is selected from pancreatic cancer, colon cancer and rectal cancer.

[0600] V. Pharmaceutical Compositions

[0601] The compounds of the present disclosure and their pharmaceutically acceptable salts can be administered as a pharmaceutical composition comprising one or more pharmaceutically acceptable excipients. Therefore, in some embodiments, the present disclosure provides a pharmaceutical composition comprising a compound of the present disclosure or its pharmaceutically acceptable salt and at least one pharmaceutically acceptable excipient.

[0602] The excipients selected for inclusion in a particular composition will depend on factors such as the mode of administration and the form in which the composition is 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, by Rowe, Ray C; Sheskey, Paul J; Quinn, Marian. Pharmaceutically acceptable excipients may function, for example, as adjuvants, diluents, carriers, stabilizers, flavoring agents, colorants, fillers, binders, disintegrants, lubricants, glidants, thickeners, and coating agents. As will be appreciated by those skilled in the art, certain pharmaceutically acceptable excipients may serve more than one function and may serve other functions, depending on how much excipient is present in the composition and what other excipients are also present in the composition.

[0603] The composition 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), in a form suitable for topical use (e.g., as creams, ointments, gels, or aqueous or oily solutions or suspensions), in a form suitable for administration by inhalation (e.g., as finely divided powders or liquid aerosols), in a form suitable for administration by insufflation (e.g., as finely divided powders) or in a form suitable for parenteral administration (e.g., as sterile aqueous or oily solutions for intravenous, subcutaneous or intramuscular administration) or in a suppository suitable for rectal administration. The composition may be obtained by conventional procedures using conventional pharmaceutical excipients well known in the art. Thus, a composition intended for oral use may contain, for example, one or more coloring agents, sweeteners, flavoring agents and / or preservatives.

[0604] The total daily dose must be varied depending on the subject being treated, the particular route of administration, any co-administered therapy, and the severity of the disease being treated, and may include single or multiple doses. For example, the specific dose may be adjusted based on the following aspects, including: the condition being treated; the age, weight, general health, sex, and diet of the subject; the route of administration; the dose interval; the excretion rate; and other drugs co-administered to the subject. A physician with ordinary skills who understands the disclosure of this application will be able to determine the appropriate dose and regimen for administering the therapeutic agent to the subject according to methods well known in the therapeutic field, and adjust these doses and regimens as needed during the course of treatment. The compounds of the present disclosure, or pharmaceutically acceptable salts thereof, are generally administered to warm-blooded animals in a unit dose range of 2.5 mg / m 2 Animal body surface area up to 5000mg / m 2 About 0.05 mg / kg to 100 mg / kg of animal body surface area generally provides a therapeutically effective dose.

[0605] In some embodiments, the present disclosure provides a pharmaceutical composition for use in treatment, the pharmaceutical composition comprising a compound of the present disclosure or a pharmaceutically acceptable salt thereof and at least one pharmaceutically acceptable excipient.

[0606] In some embodiments, the present disclosure provides a pharmaceutical composition for treating a FAP-mediated disorder, the pharmaceutical composition 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 disorder is selected from liver disease, type 2 diabetes, cardiovascular disorders, obesity, obesity-related disorders, fibrosis, keloid disorders, inflammation, and cancer.

[0607] VI. Kit

[0608] The present disclosure also provides a kit comprising a unit dosage form comprising a compound of the present disclosure or a pharmaceutically acceptable salt thereof, enclosed in packaging material and accompanied by a label or package insert indicating that the unit dosage form can be used to treat one or more of the conditions previously described.

[0609] In some embodiments, the kit includes a unit dosage form comprising a compound of the present disclosure or a pharmaceutically acceptable salt thereof, the unit dosage form being contained in packaging material and accompanied by 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 fatty liver disease, end-stage liver disease, and cirrhosis. In another aspect, the liver disease is selected from non-alcoholic steatohepatitis (NASH) and non-alcoholic fatty liver disease (NAFLD).

[0610] In some embodiments, the kit includes: (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 an SGLT2 inhibitor, metformin, a GLP1 agonist, a DPP4 inhibitor, and a PPAR agonist; (c) a container device for containing the first dosage form and the second dosage form; and (d) a label or package insert indicating that the first unit dosage form and the second unit dosage form can be used to treat a FAP-mediated disorder.

[0611] VII. Preparation method

[0612] The present disclosure also provides methods for preparing 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 to 30 show the synthetic routes of these compounds, wherein unless otherwise indicated, R 2 , R 3 , R 5 , R 6 , R 7 and R 8 As defined in formula (I); R 9 is an alkyl group (eg, methyl, ethyl, tert-butyl, etc.); R 10 and R 11 is hydrogen or alkyl; and X 1 , X 2 and X 3 is a leaving group (eg, Cl, Br, I, OTf, etc.) One skilled in the art will appreciate that these methods are representative and do not include all possible methods for preparing the compounds of the present disclosure.

[0613] Solution 1

[0614]

[0615] Scheme 1 shows a synthetic route for certain compounds of formula (I). A compound of formula (2) can be reacted with a compound of formula (3) or a salt thereof to give a compound of formula (I). The reaction can be carried out using a suitable coupling agent (such as HATU, HOBt / EDC, T3P, etc.) in the presence of a base (usually an organic base (such as DIPEA, TEA, etc.) at a temperature ranging from typically 0°C to 60°C using a solvent (such as DCM, DMF, EtOAc, MeCN, or a mixture thereof).

[0616] Solution 2

[0617]

[0618] Scheme 2 shows a synthetic route for certain compounds of formula (2). Compounds of formula (2) can be formed by reacting a compound of formula (4) with a base (such as NaOH, LiOH, etc.) in an organic solvent (such as 1,4-dioxane, THF, MeOH or a mixture thereof) and optionally in the presence of water. The reaction can be carried out at a temperature ranging from 0°C to reflux. Alternatively, for compounds wherein R 9 = tert-butyl compound of formula (4), the reaction can be carried out in a solvent such as 1,4-dioxane, EtOAc, MeOH, water or a mixture thereof with a suitable acid such as HCl, etc. Alternatively, the reaction can be carried out at a temperature ranging from typically 0°C to 60°C, using neat carboxylic acid such as TFA or in a solvent such as DCM.

[0619] Solution 3

[0620]

[0621] Scheme 3 shows a synthetic route for certain compounds of formula (I). A compound of formula (5) can be reacted with a compound of formula (6) to give a compound of formula (I). The reaction can be carried out using a suitable coupling agent (such as HATU, HOBt / EDC, T3P, etc.) in the presence of a base (usually an organic base (such as DIPEA, TEA, etc.) at a temperature ranging from typically 0°C to 60°C using a solvent (such as DCM, DMF, EtOAc, MeCN or a mixture thereof).

[0622] Solution 4

[0623]

[0624] Scheme 4 shows a synthetic route for certain compounds of formula (5). Compounds of formula (2) can be reacted with compounds of formula (7) to give compounds of formula (8). The reaction can be carried out using a suitable coupling agent (such as HATU, HOBt / EDC, T3P, etc.) in the presence of a base (usually an organic base (such as DIPEA, TEA, etc.)) at a temperature ranging from typically 0°C to 120°C using a solvent (such as DCM, DMF, EtOAc, MeCN or a mixture thereof).

[0625] The compound of formula (5) can be formed by reacting the compound of formula (8) with a base (such as NaOH, LiOH, etc.) in an organic solvent (such as 1,4-dioxane, THF, MeOH or a mixture thereof) and optionally in the presence of water. The reaction can be carried out at a temperature ranging from 0°C to reflux. Alternatively, for the compound wherein R 9= tert-butyl compound of formula (8), the reaction can be carried out in a solvent such as 1,4-dioxane, EtOAc, MeOH, water or a mixture thereof with a suitable acid such as HCl, etc. Alternatively, the reaction can be carried out at a temperature ranging from typically 0°C to 60°C, using neat carboxylic acid such as TFA or in a solvent such as DCM.

[0626] Solution 5

[0627]

[0628] Scheme 5 shows a synthetic route for certain compounds of formula (I). Compounds of formula (9) can be converted to compounds of formula (I) by reaction with an alkyl zinc reagent of formula (10), wherein R 6 As defined in groups (b) and (c) of formula (I), and Y 1 is a monoalkyl or halide derivative of zinc (such as diethylzinc). The reaction can be carried out by a Pd catalyst (such as PdCl 2 (dppf)·DCM etc.) is catalyzed in a suitable solvent such as 1,4-dioxane, THF etc. at a temperature ranging from typically 20°C to reflux.

[0629] Alternatively, the compound of formula (9) can be converted to the compound of formula (I) by reaction with an alkyl boron reagent of formula (10), wherein R 6 As defined in groups (b) and (c) of formula (I), and Y 1 is boron or its derivatives (such as trimethylcyclotriboroxane, etc.). The reaction can be carried out by a Pd catalyst (such as PdCl 2 (dppf)·DCM, etc.) in a base (such as K 2 CO 3 、Na 2 CO 3 The method is catalyzed in the presence of 2,4-dioxane, THF, etc., at a temperature ranging from typically 20°C to reflux.

[0630] Alternatively, the compound of formula (9) can be converted to the compound of formula (I) by reaction with an alkyl halide of formula (10), wherein R 6 As defined in groups (b) and (c) of formula (I), and Y 1 is a halogen, usually an alkyl bromide. The reaction can be carried out using a Ni catalyst (such as NiCl 2 DCM, etc.) and a suitable ligand (such as bbbpy, etc.) and a suitable photoredox catalyst (such as Ir[dF(CF 3 )ppy] 2 (dtbbpy)PF 6 etc.), in HSi(SiMe3 ) 3 and bases (such as Na 2 CO 3 The method is catalyzed in the presence of , etc., at typically 20°C, in a suitable solvent (such as DME, etc.), while irradiating with a blue LED.

[0631] Alternatively, the compound of formula (9) can be converted to the compound of formula (I) by reaction with an alcohol of formula (10), wherein R 6 As defined in groups (d) and (e) of formula (I), and Y 1 This reaction can be carried out with a suitable Pd reagent (such as Pd(OAc) 2 etc.) with a suitable phosphine ligand (such as XPhos, t-BuXPhos, etc.) in the presence of a base (such as K 3 PO 4 The reaction is carried out in the presence of , in a suitable solvent (such as toluene, 1,4-dioxane, etc.), catalyzed, and at high temperature.

[0632] Alternatively, the compound of formula (9) can be converted to the compound of formula (I) by reaction with an alcohol of formula (10), wherein R 6 As defined in groups (d) and (e) of formula (I), and Y 1 This reaction can be carried out with a suitable Cu reagent (such as CuBr, etc.) in the presence of a base (such as K 2 CO 3 , Cs 2 CO 3 The reaction is carried out in the presence of a free radical initiator (such as AIBN, etc.), in a suitable solvent (such as DMF), and at an elevated temperature.

[0633] Alternatively, the compound of formula (9) can be converted to the compound of formula (I) by reaction with an alcohol of formula (10), wherein R 6 As defined in groups (d) and (e) of formula (I), and Y 1 This reaction can be carried out using a Ni catalyst (such as NiCl 2 DCM, etc.) and a suitable ligand (such as bbbpy, etc.) and a suitable photoredox catalyst (such as Ir[dF(CF 3 )ppy] 2 (dtbbpy)PF 6 etc.), in quinuclidine and bases (such as K 2 CO 3 The method is catalyzed in the presence of , etc., at typically 20°C, in a suitable solvent (such as acetonitrile), while irradiating with a blue LED.

[0634] Solution 6

[0635]

[0636] Scheme 6 shows a synthetic route for certain compounds of formula (9). Compounds of formula (11) can be reacted with compounds of formula (3) to give compounds of formula (9). The reaction can be carried out under the conditions described for the similar reaction described in Scheme 1.

[0637] Solution 7

[0638]

[0639] Scheme 7 shows a synthetic route for certain compounds of formula (9). Compounds of formula (12) can be reacted with compounds of formula (6) to give compounds of formula (9). The reaction can be carried out under the conditions described for the similar reaction described in Scheme 3.

[0640] Solution 8

[0641]

[0642] Scheme 8 shows a synthetic route for certain compounds of formula (12). Compounds of formula (11) can be reacted with compounds of formula (7) to give compounds of formula (13). Compounds of formula (12) can be formed from compounds of formula (13). These reactions can be carried out under the conditions described for similar reactions described in Scheme 4.

[0643] Solution 9

[0644]

[0645] Scheme 9 shows a synthetic route for certain compounds of formula (I). Compounds of formula (14) can be converted to compounds of formula (I) by reaction with an alkyl zinc reagent of formula (15), wherein R 7 As defined in groups (b) and (c) of formula (I), and Y 1 is a monoalkyl or halide derivative of zinc (such as diethylzinc). The reaction can be carried out by a Pd catalyst (such as PdCl 2 (dppf)·DCM etc.) is catalyzed in a suitable solvent such as 1,4-dioxane, THF etc. at a temperature ranging from typically 20°C to reflux.

[0646] Alternatively, the compound of formula (14) can be converted to the compound of formula (I) by reaction with an alkyl boron reagent of formula (15), wherein R 7 As defined in groups (b) and (c) of formula (I), and Y 1 is boron or its derivatives (such as trimethylcyclotriboroxane, etc.). The reaction can be carried out by a Pd catalyst (such as PdCl 2 (dppf)·DCM, etc.) in a base (such as K2 CO 3 、Na 2 CO 3 The method is catalyzed in the presence of 2,4-dioxane, THF, etc., at a temperature ranging from typically 20°C to reflux.

[0647] Alternatively, the compound of formula (14) can be converted to the compound of formula (I) by reaction with an alkyl halide of formula (15), wherein R 7 As defined in groups (b) and (c) of formula (I), and Y 1 is a halogen, usually an alkyl bromide. The reaction can be carried out using a Ni catalyst (such as NiCl 2 DCM, etc.) and a suitable ligand (such as bbbpy, etc.) and a suitable photoredox catalyst (such as Ir[dF(CF 3 )ppy] 2 (dtbbpy)PF 6 etc.), in HSi(SiMe 3 ) 3 and bases (such as Na 2 CO 3 The method is catalyzed in the presence of , etc., at typically 20°C, in a suitable solvent (such as DME, etc.), while irradiating with a blue LED.

[0648] Alternatively, the compound of formula (14) can be converted to the compound of formula (I) by reaction with an alcohol of formula (15), wherein R 7 As defined in groups (d) and (e) of formula (I), and Y 1 This reaction can be carried out with a suitable Pd reagent (such as Pd(OAc) 2 etc.) with a suitable phosphine ligand (such as XPhos, t-BuXPhos, etc.) in the presence of a base (such as K 3 PO 4 The reaction is carried out in the presence of , in a suitable solvent (such as toluene, 1,4-dioxane, etc.), catalyzed, and at high temperature.

[0649] Alternatively, the compound of formula (14) can be converted to the compound of formula (I) by reaction with an alcohol of formula (15), wherein R 7 As defined in groups (d) and (e) of formula (I), and Y 1 This reaction can be carried out with a suitable Cu reagent (such as CuBr, etc.) in the presence of a base (such as K 2 CO 3 , Cs 2 CO 3 The reaction is carried out in the presence of a free radical initiator (such as AIBN), in a suitable solvent (such as DMF), and at an elevated temperature.

[0650] Alternatively, the compound of formula (14) can be converted to the compound of formula (I) by reaction with an alcohol of formula (15), wherein R 7 As defined in groups (d) and (e) of formula (I), and Y 1 This reaction can be carried out using a Ni catalyst (such as NiCl 2 DCM, etc.) and a suitable ligand (such as bbbpy, etc.) and a suitable photoredox catalyst (such as Ir[dF(CF 3 )ppy] 2 (dtbbpy)PF 6 etc.), in quinuclidine and bases (such as K 2 CO 3 The method is catalyzed in the presence of , etc., at typically 20°C, in a suitable solvent (such as acetonitrile), while irradiating with a blue LED.

[0651] Solution 10

[0652]

[0653] Scheme 10 shows a synthetic route for certain compounds of formula (14). Compounds of formula (14) can be formed from compounds of formula (16) and compounds of formula (3). The reaction can be carried out under the conditions described for the similar reaction described in Scheme 1.

[0654] Solution 11

[0655]

[0656] Scheme 11 shows a synthetic route for certain compounds of formula (14). Compounds of formula (14) can be formed from compounds of formula (17) and compounds of formula (6). The reaction can be carried out under the conditions described for the similar reaction described in Scheme 3.

[0657] Solution 12

[0658]

[0659] Scheme 12 shows a synthetic route for certain compounds of formula (17). Compounds of formula (16) can be reacted with compounds of formula (7) to give compounds of formula (18). Compounds of formula (17) can be formed from compounds of formula (18). These reactions can be carried out under the conditions described for similar reactions described in Scheme 4.

[0660] Solution 13

[0661]

[0662] Scheme 13 shows a synthetic route for certain compounds of formula (8). Compounds of formula (13) can be converted to compounds of formula (8) by reaction with compounds of formula (10), wherein R 6 As defined in groups (b), (c), (d) and (e) of formula (I), and Y 1 As defined in Scheme 5. These reactions can be carried out under the conditions described for the analogous reactions described in Scheme 5.

[0663] Solution 14

[0664]

[0665] Scheme 14 shows a synthetic route for certain compounds of formula (4). Compounds of formula (19) can be converted to compounds of formula (4) by reaction with compounds of formula (10), wherein R 6 As defined in groups (b), (c), (d) and (e) of formula (I), and Y 1 As defined in Scheme 5. These reactions can be carried out under the conditions described for the analogous reactions described in Scheme 5.

[0666] Solution 15

[0667]

[0668] Scheme 15 shows a synthetic route for certain compounds of formula (8). Compounds of formula (18) can be converted to compounds of formula (8) by reaction with compounds of formula (15), wherein R 7 As defined in groups (b), (c), (d) and (e) of formula (I), and Y 1 As defined in Scheme 9. These reactions can be carried out under the conditions described for the analogous reactions described in Scheme 9.

[0669] Scheme 16

[0670]

[0671] Scheme 16 shows a synthetic route for certain compounds of formula (4). Compounds of formula (20) can be converted to compounds of formula (4) by reaction with compounds of formula (15), wherein R 7 As defined in groups (b), (c), (d) and (e) of formula (I), and Y 1 As defined in Scheme 9. These reactions can be carried out under the conditions described for the analogous reactions described in Scheme 9.

[0672] Solution 17

[0673]

[0674] Scheme 17 shows the synthetic route for certain compounds of formula (8). 10 The compound of formula (22) wherein R is hydrogen or alkyl can be 10 is hydrogen or alkyl and R 11 The compound of formula (21) which is hydrogen is formed by reaction with an oxidizing agent such as Dess-Martin periodinane, etc. The reaction can be carried out at a temperature ranging from typically 0°C to 40°C in a suitable solvent such as DCM, etc.

[0675] Where R 6 Compounds of formula (8) as defined in group (b) of formula (I) can be formed by reacting a compound of formula (22) with a fluorinating agent (such as DAST, etc.) at a temperature ranging typically from 0°C to 60°C in a suitable solvent (such as DCM, THF, etc.).

[0676] Alternatively, where R 6 The compound of formula (8) as defined in group (b) of formula (I) can be formed from the compound of formula (22) by reduction with a reducing agent such as sodium borohydride, etc. The reaction can be carried out at a temperature ranging from typically 0°C to 40°C in a solvent such as methanol, etc.

[0677] Alternatively, where R 6 Compounds of formula (8) as defined in group (b) of formula (I) can be prepared from compounds of formula (22) by reacting with a Grignard reagent such as CH 3 MgCl, CH 3 The reaction can be carried out at a temperature ranging generally from -78°C to 40°C in a suitable solvent such as diethyl ether, THF, etc.

[0678] Alternatively, where R 6 Compounds of formula (8) as defined in group (b) of formula (I) can be formed by reacting a compound of formula (21) with a fluorinating agent (such as DAST, etc.) at a temperature ranging typically from 0°C to 60°C in a suitable solvent (such as DCM, THF, etc.).

[0679] Alternatively, where R 6 Compounds of formula (8) 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 at a temperature ranging from typically 0° C. to 25° C. in a suitable solvent such as EtOAc.

[0680] Alternatively, where R 6The compound of formula (8) as defined in group (b) of formula (I) can be formed by reacting the compound of formula (21) with an alkyl halide (such as MeI, etc.) or another alkylating agent (such as alkyl sulfonate, alkyl trifluoromethanesulfonate, etc.). The reaction can be carried out at a temperature ranging from usually 0° C. to 25° C. using a base (such as NaH, etc.) in a suitable solvent (such as THF, DMF, etc.).

[0681] Scheme 18

[0682]

[0683] Scheme 18 shows the synthetic route for certain compounds of formula (21). 10 The compound of formula (22) which is an alkyl group (such as methyl) can be formed by reacting the compound of formula (13) with a trialkyl (1-alkoxyvinyl) tin reagent (such as tributyl (1-ethoxyvinyl) tin). The reaction can be carried out by a Pd reagent (such as PdCl 2 (dppf)·DCM, Pd(PPh 3 ) 4 etc.) at a temperature ranging typically from 80° C. to reflux in a suitable solvent such as toluene, 1,4-dioxane, etc.

[0684] Alternatively, where R 10 The compound of formula (22) which is hydrogen can be formed by reacting the compound of formula (13) with formic acid and acetic anhydride. This reaction can be carried out using a Pd reagent such as Pd(OAc) 2 etc.) with a suitable ligand (such as butyl-1-adamantylphosphine) and NaHCO 3 and TEA at a temperature ranging typically from 80°C to 120°C in a suitable solvent such as DMF and the like.

[0685] Where R 10 and R 11 Compounds of formula (21) that are hydrogen can be formed by reacting compounds of formula (13) with a (trialkylstannyl)methanol reagent such as (tributylstannyl)methanol. This reaction can be carried out by a Pd reagent such as PdCl 2 (dppf)·DCM, Pd(PPh 3 ) 4 etc.) at a temperature ranging typically from 80° C. to reflux in a suitable solvent such as toluene, 1,4-dioxane, etc.

[0686] Alternatively, where R 10 is an alkyl group and R 11The compound of formula (21) which is hydrogen can be formed from the compound of formula (22) by reduction with a reducing agent such as sodium borohydride, etc. The reaction can be carried out at a temperature ranging generally from 0°C to 40°C in a solvent such as methanol, etc.

[0687] Alternatively, where R 10 and R 11 The compound of formula (21) which is an alkyl group can be prepared from the compound of formula (22) by reacting with a Grignard reagent (such as CH 3 MgCl, CH 3 The reaction can be carried out at a temperature ranging generally from -78°C to 40°C in a suitable solvent such as diethyl ether, THF, etc.

[0688] Solution 19

[0689]

[0690] Scheme 19 shows the synthetic route for certain compounds of formula (4). 6 The compound of formula (4) as defined in group (b) of formula (I) may be composed of 10 and R 11 Compounds of formula (23) or formula (24) are formed as defined in Scheme 17. These reactions can be carried out under the conditions described for the analogous reactions described in Scheme 17.

[0691] Solution 20

[0692]

[0693] Scheme 20 shows the synthesis route of some compounds of formula (23). Compounds of formula (23) can be prepared from 10 and R 11 Compounds of formula (19) or formula (24) are formed as defined in Scheme 18. These reactions can be carried out under the conditions described for the analogous reactions described in Scheme 18.

[0694] Solution 21

[0695]

[0696] Scheme 21 shows the synthetic route for certain compounds of formula (8). 7 The compound of formula (8) as defined in group (b) of formula (I) may be composed of 10 and R 11 Compounds of formula (25) or formula (26) are formed as defined in Scheme 17. These reactions can be carried out under the conditions described for the similar reactions described in Scheme 17.

[0697] Solution 22

[0698]

[0699] Scheme 22 shows the synthesis route of certain compounds of formula (25). Compounds of formula (25) can be prepared from 10 and R 11 Compounds of formula (18) or formula (26) are formed as defined in Scheme 18. These reactions can be carried out under the conditions described for the similar reactions described in Scheme 18.

[0700] Solution 23

[0701]

[0702] Scheme 23 shows the synthetic route for certain compounds of formula (4). 7 The compound of formula (4) as defined in group (b) of formula (I) may be composed of 10 and R 11 Compounds of formula (27) or formula (28) are formed as defined in Scheme 17. These reactions can be carried out under the conditions described for the analogous reactions described in Scheme 17.

[0703] Solution 24

[0704]

[0705] Scheme 24 shows the synthesis route of some compounds of formula (27). Compounds of formula (27) can be prepared from 10 and R 11 Compounds of formula (20) or formula (28) are formed as defined in Scheme 18. These reactions can be carried out under the conditions described for the analogous reactions described in Scheme 18.

[0706] Solution 25

[0707]

[0708] Scheme 25 shows a synthetic route for certain compounds of formula (8). Compounds of formula (29) can be converted to compounds wherein R 6 Compounds of formula (8) as defined in groups (d) and (e) of formula (I). The reaction can be carried out by a base (such as NaOH, K 2 CO 3 etc.) at a temperature ranging typically from 20°C to reflux in a suitable solvent such as DMF etc.

[0709] Scheme 26

[0710]

[0711] Scheme 26 shows the synthetic route for certain compounds of formula (4). 6 Compounds of formula (4) as defined in groups (d) and (e) of formula (I) may be formed from compounds of formula (30). These reactions may be carried out under the conditions described for the analogous reactions described in Scheme 25.

[0712] Scheme 27

[0713]

[0714] Scheme 27 shows the synthetic route for certain compounds of formula (8). 7 Compounds of formula (8) as defined in groups (d) and (e) of formula (I) may be formed from compounds of formula (31). These reactions may be carried out under the conditions described for the analogous reactions described in Scheme 25.

[0715] Scheme 28

[0716]

[0717] Scheme 28 shows the synthetic route for certain compounds of formula (4). 7 Compounds of formula (4) as defined in groups (d) and (e) of formula (I) may be formed from compounds of formula (32). These reactions may be carried out under the conditions described for the analogous reactions described in Scheme 25.

[0718] Scheme 29

[0719]

[0720] Scheme 29 shows the synthetic route for certain compounds of formula (4). 6 and R 7 Compounds of formula (35) as defined in formula (I) can be formed from compounds of formula (33) or compounds of formula (34) using synthetic methods performed under conditions similar to those described for reactions described in Schemes 5, 9, 17 and 18.

[0721] The compound of formula (4) can be formed by reacting the compound of formula (35) with carbon monoxide at a pressure of typically 10 atm and at a temperature ranging typically from 80° C. to 120° C. in a sealed container. The reaction can be carried out in the presence of a base such as TEA, in the presence of a suitable alcohol such as MeOH, EtOH, etc., in a suitable solvent or using an alcohol as a solvent, with a suitable Pd reagent such as Pd(dppf)Cl 2 DCM, etc.) catalyzed.

[0722] Scheme 30

[0723]

[0724] Scheme 30 shows a synthetic route for certain compounds of formula (2). Compounds of formula (38) can be formed by reacting a compound of formula (36) with a 2-ketocarboxylic acid of formula (37) or a salt thereof (such as a sodium salt, etc.) in the presence of an aqueous base (such as NaOH, etc.) at reflux temperature or at an elevated temperature ranging from typically 100° C. to 160° C. in a sealed container or in a sealed tube in a microwave reactor.

[0725] Compounds of formula (2) can be formed by heating compounds of formula (38) neat or in a suitable solvent such as water in a microwave oven and in a sealed container or sealed tube at elevated temperatures ranging typically 150°C to 250°C.

[0726] It should be understood that: (i) the organic reactions described in the present disclosure are performed according to laboratory practices known to those skilled in the art; (ii) some of the reactions described in the present disclosure may optionally be performed in an order different from that described herein; (iii) chiral isomers of the compounds in the present disclosure may be resolved at any stage during the synthesis 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 (v) deprotection steps may therefore optionally be performed using methods described in the literature and known to those skilled in the art. Protection and deprotection of functional groups are described, for example, in "Protective Groups in Organic Synthesis", 3rd edition, TW Greene and PGM Wutz, Wiley-Interscience (1999), the disclosure of which is incorporated herein by reference.

[0727] VIII. Examples

[0728] The following descriptions of experiments, steps, examples and intermediates are intended to illustrate embodiments of the present disclosure. They are by no means limiting. Other compounds of the present disclosure can be prepared using the methods shown in these examples alone or in combination with techniques generally known in the art.

[0729] A. General conditions

[0730] Unless otherwise stated:

[0731] (i) at room temperature (rt) (i.e., in the range of 17°C to 25°C) and under an inert gas such as N 2 Operate in an atmosphere of

[0732] (ii) when the reaction involves the use of a microwave reactor, one of the following microwave reactors is used: BiotageInitiator, Personal Chemistry Emrys Optimizer, Personal Chemistry Smith Creator or CEM Explorer;

[0733] (iii) When the reaction involved irradiation with LED, a commercial standardized EvoluChem from HepatoChem equipped with a Kessil H150 blue LED (456 nm, 34 W) was used. TM PhotoRedOx Box photoreactor or commercial standardized photoreactor m2 from Penn Photon Devices equipped with LED modules (365 nm);

[0734] (iv) Generally, the progress of the reaction is followed by thin layer chromatography (TLC) and / or analytical high performance liquid chromatography (HPLC or UPLC) usually coupled with mass spectrometry (LCMS);

[0735] (v) If necessary, the organic solution was purified by anhydrous MgSO 4 Or Na 2 SO 4 Dry or use Phase separator drying and post-processing procedures using conventional phase separation techniques;

[0736] (vi) by vacuum rotary evaporation or evaporation in a Genevac HT-4 / EZ-2 or Biotage V10;

[0737] (vii) Unless otherwise stated, flash column chromatography was performed on normal phase silica using Merck silica gel (Cat. No. 9385) or prepacked columns such as SNAP column (40μm-63μm silica, 4g-330g), Silica HC D column (20μm, 10g-100g), Interchim puriFlash TM Column (25μm, 4g-120g), InterchimpuriFlash TM Column (50 μm, 25 g-330 g), Grace TM GraceResolv TMSilica Flash columns (4 g-120 g) or AgelaFlash Colum Silica-CS columns (80 g-330 g), or AgelaTechnologies C-18 spherical columns (20 μm-35 μm, 100A, 80 g-330 g) on ​​reversed phase silica and using Grace Manually or automatically by X2Flash system or similar system;

[0738] (viii) Preparative reverse phase HPLC and preparative reverse phase SFC were performed using standard HPLC and SFC instruments, respectively, equipped with MS and / or UV triggered fraction collection instruments, using isocratic or gradient mobile phases as described in the experimental section and one of the following methods as described below:

[0739] HPLC preparation method: Preparation method A: The compound was purified by preparative HPLC on a Kromasil C8 column (10 μm, 250×50 mm ID) using MeCN in H 2 A gradient of O / MeCN / FA (95 / 5 / 0.2) was used as the mobile phase; Preparation Method B: The compound was purified by preparative HPLC on an XSelect CSH OBD column (5 μm, 150×30 mm ID) using MeCN in H 2 O / TFA (0.05%) gradient as mobile phase; Preparation Method C: The compound was purified by preparative HPLC on an XSelect CSH OBD column (5 μm, 150×30 mm ID) using MeCN in H 2 O / FA (0.1%) gradient as mobile phase; Preparation method D: Compounds were purified by preparative SFC on Waters TM The product was purified on a BEH 2-EP column (5 μm, 250 × 30 mm ID) using CO 2 MeOH / H 2 O(NH 3 20 mM) as the mobile phase; Preparation Method E: The compound was purified by preparative SFC on a Phenomenex LunaHilic column (5 μm, 250×30 mm ID) using CO 2 MeOH / H 2 O(NH 3 20mM) as mobile phase; Preparation method F: Compounds were purified by preparative HPLC on XBridge TM The product was purified on an OBD C18 column (5 μm, 150 × 30 mm ID) using MeCN in H 2 O / NH 3Preparation method G: The compound was purified by preparative HPLC on an AtlantisPrep T3 OBD column (10 μm, 250×19 mm ID) using MeCN in H 2 O / TFA (0.05%) gradient as mobile phase; Preparation method H: Compounds were purified by preparative HPLC on XBridge TM The product was purified on an OBD C18 column (5 μm, 250 × 19 mm ID) using MeCN in H 2 O / FA (0.1%) gradient as mobile phase; Preparation method I: Compounds were purified by preparative HPLC on XBridge TM The product was purified on an OBD C18 column (5 μm, 150 × 30 mm ID) using MeCN in H 2 O / FA (0.1%) gradient as mobile phase; Preparation method J: Compounds were purified by preparative HPLC on XBridge TM The product was purified on an OBD C18 column (5 μm, 250 × 19 mm ID) using MeCN in H 2 O / NH 3 (0.05%) as the mobile phase; Preparation Method K: Compounds were analyzed by preparative HPLC on XBridge TM The product was purified on a C18 OBD column (5 μm, 150 × 19 mm ID) using MeCN in H 2 O / NH 4 HCO 3 (10mM) / NH 3 (0.1%, aqueous solution) in a buffer system as the mobile phase; Preparation method L: Compounds were analyzed by preparative HPLC on XBridge TM The product was purified on a C18 OBD column (5 μm, 150 × 30 mm ID) using MeCN in H 2 O / NH 4 HCO 3 (10 mM) as the mobile phase; Preparation Method M: Compounds were analyzed by preparative HPLC on XBridge TM The product was purified on a C18 OBD column (5 μm, 250 × 19 mm ID) using MeCN in H 2 O / NH 4 HCO 3 (10mM) / NH 3 (0.1%, aqueous solution) in a buffer system as the mobile phase; Preparation method N: Compounds were analyzed by preparative HPLC on XBridge TMThe product was purified on a C18 OBD column (5 μm, 150 × 30 mm ID) using MeCN in H 2 O / NH 4 HCO 3 (10mM) / NH 3 (0.1%, aqueous solution) in a buffer system as the mobile phase; Preparation Method O: Compounds were prepared by preparative SFC on Waters TM The product was purified on an Acquity UPC2 BEH 2-EP column (3.5 μm, 100 × 3 mm ID) using CO 2 MeOH / H 2 O(NH 3 20 mM) as mobile phase; Preparation method P: Compounds were prepared by preparative SFC on Waters TM The product was purified on a BEH column (5 μm, 250 × 30 mm ID) using CO 2 MeOH / H 2 O(NH 3 20mM) as mobile phase; Preparation method R: Compounds were prepared by preparative HPLC on Waters TM Sunfire TM The product was purified on a C18 OBD column (5 μm, 150 × 30 mm ID) using MeCN in H 2 O / FA (0.1 M) gradient was used as mobile phase; Preparation Method S: Compounds were purified by preparative HPLC on XBridge TM The product was purified on an OBD C18 column (5 μm, 150 × 30 mm ID) using MeCN in H 2 O (pH 10) as the mobile phase; and Preparative Method T: The compound was purified by preparative SFC on a CHIRAL ART amylose-SA column (5 μm, 250×20 mm ID) using CO 2 MeOH / H 2 O as the mobile phase;

[0740] The relevant fractions were collected, combined, and freeze-dried to obtain a purified compound, or the relevant fractions were collected, combined, concentrated under reduced pressure, extracted with DCM or EtOAc, and the organic phase was purified by Na 2 SO 4 Drying or drying using a phase separator and then concentrating under reduced pressure to obtain a purified compound;

[0741] (ix) chiral preparative chromatography was performed using HPLC or SFC on standard HPLC or SFC instruments, respectively, and using isocratic or gradient runs of the mobile phase as described in the experimental section;

[0742] (x) the yield, if any, is not necessarily the maximum achievable and, if necessary, the reaction is repeated if a larger amount of the reaction product is desired;

[0743] (xi) When certain compounds are obtained as acid addition salts (e.g., monohydrochloride or dihydrochloride salts), the stoichiometry of the salt is based on the number and nature of the basic groups in the compound, and the precise stoichiometry of the salt is generally not determinable, for example, from elemental analysis data;

[0744] (xii) In general, the structure of the final product of formula (I) is confirmed by nuclear magnetic resonance (NMR) and / or mass spectrometry techniques; using Bruker Avance III 300, 400, 500 and 600 spectrometers at 300 MHz, 400 MHz, 500 MHz and 600 MHz, respectively. 1 H frequency, and proton NMR chemical shift values ​​are measured on the δ scale. Experiments are typically recorded at 25°C. Chemical shifts are given in ppm with the solvent as an internal standard. Protons on heteroatoms (such as NH protons and OH protons) are reported only when detected in the NMR and may therefore be missing. In some cases, protons may be masked or partially masked by solvent peaks and are therefore either missing, not reported, or reported as multiplets overlapping with the solvent. The following abbreviations (and their derivatives, such as dd, doublets, etc.) have been used: s, singlet; d, doublet; t, triplet; q, quartet; m, multiplet; br, broad; qn, quintet; and p, pentad. 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 peaks of the major rotamers are reported. Electrospray mass spectral data were obtained using a Waters Acquity UPLC coupled to a Waters single quadrupole mass spectrometer or similar device, collecting both positive and negative ion data, and generally reporting only ions associated with the parent structure; High resolution electrospray mass spectral data were obtained using a Waters XEVO qToF mass spectrometer coupled to a Waters Acquity UPLC or similar device, collecting both positive and negative ion data, and generally reporting only ions associated with the parent structure;

[0745] (xiii) Intermediates do not have to be completely purified, but their structure and purity are assessed by TLC, analytical HPLC / UPLC and / or NMR analysis and / or mass spectrometry;

[0746] (xiv) Unless otherwise stated, compounds containing asymmetric carbon and / or sulfur atoms are not resolved;

[0747] (xv) In general, the examples and intermediate compounds were named using ChemDraw Professional 19.0.0.22 or 20.0.2.51 from PerkinElmer. ChemDraw Professional 19.0.0.22 and 20.0.2.51 used the Cahn-Ingold-Prelog (CIP) rules for stereochemistry to generate names for chemical structures and followed the IUPAC rules as closely as possible when generating chemical names. Stereoisomers are distinguished from each other by stereodescriptors cited in the names and are designated according to the CIP rules.

[0748] ---ChemDraw optionally uses markers such as "&" and "or" in the graphical representation of stereocenters to describe the configuration of stereochemical centers present in the structure. In general, chemical structures containing the marker "&" at a stereocenter for embodiments and intermediates refer to the configuration of such embodiments or intermediates at that stereocenter as a mixture of both (R) and (S); while the marker "or" refers to the configuration of such embodiments or intermediates at that stereocenter as either (S) or (R). Absolute, unspecified, "&" and "or" stereocenters can all be present in a single structure.

[0749] --- In general, for structures of embodiments and intermediates where all stereocenters are designated as "&", the structure is named with a "rac-" prefix. For structures of embodiments and intermediates where all stereocenters are designated as "or", the structure is named with a "rel-" prefix.

[0750] --- In general, the examples and intermediate compounds are named using the descriptors (RS) and (SR) to denote the general "&" center of a chemical structure having multiple chiral centers, only some of which are designated as "&". The descriptors (R*) and (S*) are used to denote the general "or" center of a chemical structure having multiple chiral centers, only some of which are designated as "or".

[0751] --- 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.

[0752] ---Usually, on a given chiral HPLC column and eluent, the label "Isomer 1" corresponds to the first eluting isomer and "Isomer 2" corresponds to the second eluting isomer, and is used to distinguish between two isomers containing one or more stereocenters and having absolutely unknown configuration at one or more stereocenters;

[0753] (xvi) when the reaction involves degassing or purging, this can be carried out, for example, by purging the reaction solvent with a constant stream of nitrogen for a suitable period of time (e.g., 5 to 10 minutes);

[0754] (xvii) When the reaction involves the application of an evacuation-refill cycle, this may be accomplished by evacuating the reaction vessel by applying a vacuum to the reaction vessel and then refilling with an inert gas, typically N 2 or argon. Generally, the process is repeated, usually three times; and

[0755] (xvii) In addition to the abbreviations mentioned above, the following abbreviations are used:

[0756]

[0757]

[0758]

[0759]

[0760] B. Intermediate Compounds

[0761] Intermediate 1: (2-((1S,3S,5S)-3-cyano-2-azabicyclo[3.1.0]hexan-2-yl)-2-oxoethyl)amine tert-Butyl formate

[0762]

[0763] 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 minutes. 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 with 1 M citric acid (aqueous solution, containing 0.5 mL of brine) and 1 M citric acid (aqueous solution), followed by saturated NaHCO 3 The crude product was purified by normal phase flash chromatography on silica (gradient: 10%-100% EtOAc in heptane). The fractions containing the compound were collected, concentrated in vacuo and purified by normal phase flash chromatography on silica (gradient: 0%-100% EtOAc in heptane) to give the title compound (1.24 g, 82%): 1 H NMR (400MHz, CD 3OD)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).

[0764] Intermediate 2: (1S,3S,5S)-2-glycyl-2-azabicyclo[3.1.0]hexane-3-carbonitrile 4-methylbenzenesulfonic acid ester

[0765]

[0766] Tert-butyl (2-((1S, 3S, 5S)-3-cyano-2-azabicyclo [3.1.0] hex-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 in DCM twice and evaporated to obtain a beige protein cream (meringue). The residue was suspended in cold EtOAc while remaining on an ice bath. The solid was settled and the EtOAc was removed using a Pasteur pipette. The solid was suspended in cold EtOAc again, settled, 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.

[0767] Intermediate 3: (1S,3S,5S)-2-glycyl-2-azabicyclo[3.1.0]hexane-3-carbonitrile hydrochloride

[0768]

[0769] 12M HCl (aqueous solution, 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]hex-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, CD 3OD)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).

[0770] Intermediate 4: (1S,3S,5S)-2-glycyl-2-azabicyclo[3.1.0]hexane-3-carbonitrile

[0771]

[0772] Tert-butyl (2-((1S,3S,5S)-3-cyano-2-azabicyclo[3.1.0]hex-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 hours. 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 HNMR (300MHz, CD 3 OD)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).

[0773] Intermediate 5: (6-bromoquinoline-4-carbonyl)glycine tert-butyl ester

[0774]

[0775] DIPEA (2.08 mL, 11.9 mmol) was added to a mixture of 6-bromoquinoline-4-carboxylic acid (1.0 g, 4.0 mmol), glycine tert-butyl ester 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 washed with saturated NaHCO 3 (aqueous solution, 20 mL) and water (20 mL) were quenched, and the suspension was filtered. The solid was washed with water and dried in vacuo to give the title compound (1.40 g, 97%); MS (ESI) m / z [M+H] + 365 / 367.

[0776] Intermediate 6: (6-bromoquinoline-4-carbonyl)glycine

[0777]

[0778] TFA (1.0 mL, 13 mmol) was added to a solution of (6-bromoquinoline-4-carbonyl)glycine tert-butyl ester 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 hours. The solvent was removed under reduced pressure. The residue was dissolved in water and washed with saturated NaHCO 3 (aqueous solution) was basified to pH = 5-6. The reaction mixture was filtered, the solid was washed with water, and dried in vacuo to give the title compound (0.130 g, 61%); MS (ESI) m / z [M+H] + 309 / 311.

[0779] Intermediate 7: (7-bromoquinoline-4-carbonyl)glycine tert-butyl ester

[0780]

[0781] A solution of 7-bromoquinoline-4-carboxylic acid (4.50 g, 17.9 mmol), glycine tert-butyl ester 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 hours. The solvent was removed under reduced pressure and the reaction mixture was diluted with EtOAc (80 mL). The organic phase was washed with saturated NaHCO 3 (aqueous solution, 2×35 mL) and water (35 mL). The organic layer was washed with Na 2 SO 4 Dry, filter and evaporate. The crude product was purified by normal phase flash chromatography on silica (gradient: 5%-55% EtOAc in heptane) to give the title compound (6.0 g, 92%). MS (ESI) m / z [M+H] + 365.

[0782] Intermediate 8: (7-bromoquinoline-4-carbonyl)glycine

[0783]

[0784] TFA (40.5 mL, 526 mmol) was added to a solution of (7-bromoquinoline-4-carbonyl)glycine tert-butyl ester 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.

[0785] Intermediate 9: (6-(trifluoromethyl)quinoline-4-carbonyl)glycine tert-butyl ester

[0786]

[0787] 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), glycine tert-butyl ester 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 washed with saturated NaHCO 3 (aqueous solution, 20 mL) and filtered the reaction mixture. The solid was dried in vacuo to give the title compound (0.220 g, 83%); MS (ESI) m / z [M+H] + 335.

[0788] Intermediate 10: (6-(trifluoromethyl)quinoline-4-carbonyl)glycine

[0789]

[0790] TFA (0.478 mL, 6.21 mmol) was added to a solution of (6-(trifluoromethyl)quinoline-4-carbonyl)glycine tert-butyl ester 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 hours. The solvent was removed under reduced pressure to give the crude title compound (120 mg); MS (ESI) m / z [M+H] + 299.

[0791] Intermediate 11: (6-(Hydroxymethyl)quinoline-4-carbonyl)glycine tert-butyl ester

[0792]

[0793] At 20 °C and N 2 (g) (tributylstannyl)methanol (0.527 g, 1.64 mmol) was added to (6-bromoquinoline-4-carbonyl)glycine tert-butyl ester intermediate 5 (0.50 g, 1.4 mmol) and Pd(PPh 3 ) 4 (0.158 g, 0.14 mmol) in degassed 1,4-dioxane (5 mL), and the reaction mixture was stirred at 80 °C for 18 hours. The reaction was quenched with water (20 mL), and the mixture was extracted with EtOAc (3 x 20 mL). The combined organic layers were purified by Na 2 SO4 Dry, filter and evaporate 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 light yellow oil; MS (ESI) m / z [M+H] + 317.

[0794] Intermediate 12: (6-(Fluoromethyl)quinoline-4-carbonyl)glycine tert-butyl ester

[0795]

[0796] DAST (0.125 mL, 0.95 mmol) was added to a solution of (6-(hydroxymethyl)quinoline-4-carbonyl)glycine tert-butyl ester intermediate 11 (0.15 g, 0.47 mmol) in DCM (3 mL), and the reaction mixture was stirred at 18 °C for 4 hours. 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.

[0797] Intermediate 13: (6-(Fluoromethyl)quinoline-4-carbonyl)glycine

[0798]

[0799] At 20 °C and N 2 (g) A 4M HCl solution in 1,4-dioxane (1.20 mL, 4.84 mmol) was added dropwise to (6-(fluoromethyl)quinoline-4-carbonyl)glycine tert-butyl ester intermediate 12 (77 mg, 0.24 mmol) under a (g) atmosphere, and the reaction mixture was stirred at 20°C for 20 hours. 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 and stirred at 20°C for 4 hours. The solvent was removed under reduced pressure, and 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.

[0800] Intermediate 14: (6-acetylquinoline-4-carbonyl)glycine tert-butyl ester

[0801]

[0802] At 20 °C and N 2(g) Tributyl(1-ethoxyvinyl)stannane (0.593 g, 1.64 mmol) was added to (6-bromoquinoline-4-carbonyl)glycine tert-butyl ester intermediate 5 (0.50 g, 1.4 mmol) and Pd(dppf)Cl under atmospheric pressure. 2 ·DCM (0.112 g, 0.14 mmol) in degassed toluene (5 mL) was added and the reaction mixture was stirred at 100 ° C for 18 hours. The reaction mixture was diluted with MeCN (5 mL). 6M HCl (aqueous solution, 0.1 mL) was added and the reaction mixture was stirred for 20 minutes. The reaction was quenched with water (15 mL) and extracted with EtOAc (3×15 mL). The combined organic layers were purified by Na 2 SO 4 Dry, filter and evaporate 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.

[0803] Intermediate 15: (6-(2-hydroxypropan-2-yl)quinoline-4-carbonyl)glycine tert-butyl ester

[0804]

[0805] At 0°C and N 2 (g) Under the atmosphere, CH 3 MgCl in THF (3M in THF, 0.51 mL, 1.5 mmol) was added to a solution of (6-acetylquinoline-4-carbonyl)glycine tert-butyl ester intermediate 14 (0.20 g, 0.61 mmol) in THF (5 mL), and the reaction mixture was stirred at 0 °C for 3 h. 4 The reaction was quenched with Cl (aqueous solution, 20 mL) and extracted with DCM (3×20 mL). The combined organic layers were purified by Na 2 SO 4 Dry, filter and evaporate 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.

[0806] Intermediate 16: (6-(2-fluoropropan-2-yl)quinoline-4-carbonyl)glycine tert-butyl ester

[0807]

[0808] DAST (0.153 mL, 1.16 mmol) was added to a solution of (7-(2-hydroxypropan-2-yl)quinoline-4-carbonyl)glycine tert-butyl ester 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 hours. 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 product) as a light yellow gum; MS (ESI) m / z [M+H] + 347.

[0809] Intermediate 17: (6-(2-fluoropropan-2-yl)quinoline-4-carbonyl)glycine

[0810]

[0811] TFA (0.267 mL, 3.46 mmol) was added to a solution of crude (6-(2-fluoropropan-2-yl)quinoline-4-carbonyl)glycine tert-butyl ester intermediate 16 (30 mg) in DCM (0.5 mL) at 20°C, and the reaction mixture was stirred at 20°C for 4 hours. The solvent was removed under reduced pressure and the residue was dried in vacuo to give the crude title compound (30 mg) as an orange gum; MS (ESI) m / z [M+H] + 291.

[0812] Intermediate 18: (6-(2-hydroxypropan-2-yl)quinoline-4-carbonyl)glycine

[0813]

[0814] TFA (0.215 mL, 2.79 mmol) was added to a solution of (7-(2-hydroxypropan-2-yl)quinoline-4-carbonyl)glycine tert-butyl ester 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 hours. The solvent was removed under reduced pressure, and the residue was dried in vacuo to give the crude title compound (50 mg, 89%) as a light orange gum; 1 H NMR (400MHz, CD 3 OD)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).

[0815] Intermediate 19: (6-(1-hydroxyethyl)quinoline-4-carbonyl)glycine tert-butyl ester

[0816]

[0817] NaBH4 (42 mg, 1.1 mmol) was added to a solution of (6-acetylquinoline-4-carbonyl)glycine tert-butyl ester intermediate 14 (120 mg, 0.37 mmol) in THF (1 mL), and the reaction mixture was stirred at 20 °C for 4 hours. The reaction was quenched with water (10 mL) and extracted with EtOAc (3×10 mL). The combined organic layers were purified by Na 2 SO 4 Dry, filter and concentrate in vacuo, and the residue is purified by preparative TLC (DCM:MeOH, 10:1) to give the title compound (90 mg, 74%); MS (ESI) m / z [M+H] + 331.

[0818] Intermediate 20: (6-(1-hydroxyethyl)quinoline-4-carbonyl)glycine

[0819]

[0820] TFA (0.117 mL, 1.51 mmol) was added to a solution of (6-(1-hydroxyethyl)quinoline-4-carbonyl)glycine tert-butyl ester intermediate 19 (100 mg, 0.30 mmol) in DCM (1 mL), and the reaction mixture was stirred at 20° C. for 4 hours. The solvent was removed under reduced pressure to give the crude title compound (100 mg); MS (ESI) m / z [M+H] + 289.1.

[0821] Intermediate 21: 6-acetylquinoline-4-carboxylic acid methyl ester

[0822]

[0823] At 20 °C and N 2 (g) Tributyl (1-ethoxyvinyl) stannane (1.63 g, 4.51 mmol) was added to 6-bromoquinoline-4-carboxylic acid methyl ester (0.80 g, 3.0 mmol) and Pd(dppf)Cl at once under atmosphere. 2 · DCM (0.22 g, 0.30 mmol) in toluene (10 mL) was added and the reaction mixture was stirred at 100 °C for 4 hours. The reaction mixture was diluted with 4M HCl in 1,4-dioxane and stirred at 20 °C for 30 minutes. 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.

[0824] Intermediate 22: 6-(1-hydroxyethyl)quinoline-4-carboxylic acid methyl ester

[0825]

[0826] NaBH 4 (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 hours. 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.

[0827] Intermediate 23: 6-(1-methoxyethyl)quinoline-4-carboxylic acid methyl ester

[0828]

[0829] 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 minutes. 3 I (110 mg, 0.78 mmol) was added to the reaction mixture and stirred at 0°C for 1 hour. 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.

[0830] Intermediate 24: 6-(1-methoxyethyl)quinoline-4-carboxylic acid

[0831]

[0832] 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 hours. The solvent was removed under reduced pressure, and the residue was acidified to pH ~6-7 with 2M HCl (aq). 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.

[0833] Intermediate 25: 6-(2-hydroxypropan-2-yl)quinoline-4-carboxylic acid methyl ester

[0834]

[0835] At 0°C and N2 (g) Under the atmosphere, CH 3 MgCl (3M 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), and the reaction mixture was stirred at 0°C for 3 hours. 4 The reaction was quenched with Cl (aqueous solution, 20 mL), and the mixture was extracted with DCM (3×20 mL). The combined organic layers were purified by Na 2 SO 4 Dry, filter and evaporate 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.

[0836] Intermediate 26: 6-(2-methoxyprop-2-yl)quinoline-4-carboxylic acid methyl ester

[0837]

[0838] 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. 3 I (0.051 mL, 0.82 mmol) was added to the reaction mixture and stirred at room temperature for 16 hours. Another batch was prepared as described above using intermediate 25 (70 mg, 0.29 mmol). The reaction mixtures from these two batches were combined, quenched with water (10 mL), and extracted with EtOAc (3×10 mL). The combined organic layers were purified by Na 2 SO 4 Dry, filter and evaporate. 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.

[0839] Intermediate 27: 6-(2-methoxyprop-2-yl)quinoline-4-carboxylic acid

[0840]

[0841] 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 hours. The reaction mixture was acidified to pH 5-6 with 2M HCl (aq), and the reaction mixture was concentrated to dryness to give the crude title compound (60 mg); MS (ESI) m / z [M+H] + 246.

[0842] Intermediate 28: 6-(Hydroxymethyl)quinoline-4-carboxylic acid methyl ester

[0843]

[0844] At 20 °C and N 2 (g) (tributylstannyl)methanol (1.45 g, 4.51 mmol) was added to 6-bromoquinoline-4-carboxylic acid methyl ester (1.0 g, 3.8 mmol) and Pd(PPh 3 ) 4 (0.43 g, 0.38 mmol) was suspended in degassed toluene (25 mL), and the reaction mixture was stirred at 80 ° C for 18 hours. 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.

[0845] Intermediate 29: 6-((trifluoromethoxy)methyl)quinoline-4-carboxylic acid methyl ester

[0846]

[0847] At 25°C and N 2 (g) 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 6-(hydroxymethyl)-quinoline-4-carboxylic acid methyl ester intermediate 28 (440 mg, 2.03 mmol), (CH 3 ) 3 SiC 3 (576 mg, 4.05 mmol) and KF (353 mg, 6.08 mmol) in EtOAc (9.4 mL), and the reaction mixture was stirred at 25 ° C for 12 hours. 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.

[0848] Intermediate 30: 6-((trifluoromethoxy)methyl)quinoline-4-carboxylic acid

[0849]

[0850] NaOH (194 mg, 4.84 mmol) was added to a solution of 6-((trifluoromethoxy)methyl)-quinoline-4-carboxylic acid methyl ester 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 hours. 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.

[0851] Intermediate 31: 7-acetylquinoline-4-carboxylic acid methyl ester

[0852]

[0853] In N 2 (g) Pd(PPh 3)4 (1.18 g, 1.02 mmol) was added to a solution of methyl 7-bromoquinoline-4-carboxylate (2.72 g, 10.2 mmol) and tributyl (1-ethoxyvinyl) stannane (4.81 g, 13.3 mmol) in 1,4-dioxane (50 mL), and the reaction mixture was stirred at 80 ° C for 16 hours. The reaction mixture was cooled and diluted with MeCN (20 mL). 2M HCl (aqueous solution, 10 mL) was added, and the reaction mixture was stirred for 30 minutes. The reaction mixture was poured into water (50 mL), and the mixture was extracted with EtOAc (3×60 mL). The combined organic phases were purified by Na 2 SO 4 Dry, filter and concentrate 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.

[0854] Intermediate 32: 7-(2-hydroxypropan-2-yl)quinoline-4-carboxylic acid methyl ester

[0855]

[0856] 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 h. The reaction was heated with saturated NH 4 Cl (aqueous solution, 5 mL) was quenched, and the mixture was extracted with EtOAc (3×20 mL). The combined organic layers were purified by Na 2 SO 4 Dry, filter and evaporate 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, CD 3 OD)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).

[0857] Intermediate 33: 7-(2-fluoropropan-2-yl)quinoline-4-carboxylic acid methyl ester

[0858]

[0859] 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 hours. The mixture was quenched with water (20 mL), and the mixture was extracted with EtOAc (2 x 50 mL). The combined organic layers were purified by Na 2 SO 4 Dry, filter and concentrate in vacuo, and the crude product is purified by preparative TLC (DCM:MeOH, 20:1) to give the title compound (60 mg, 40%); MS (ESI) m / z [M+H] + 248.

[0860] Intermediate 34: 7-(2-fluoropropan-2-yl)quinoline-4-carboxylic acid

[0861]

[0862] 7-(2-fluoropropane-2-yl)quinoline-4-carboxylic acid methyl ester 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 hours. The pH of the reaction mixture was adjusted to 5 using 2M HCl (aqueous solution, 1 mL). The mixture was diluted with EtOAc (20 mL) and washed successively with saturated brine (2×10 mL). The organic layer was purified by Na 2 SO 4 Dry, filter and evaporate in vacuo to give the crude title compound (30 mg); MS (ESI) m / z [M+H] + 234.

[0863] Intermediate 35: (7-(Hydroxymethyl)quinoline-4-carbonyl)glycine tert-butyl ester

[0864]

[0865] At 20 °C and N 2 (g) Pd(dppf)Cl 2 DCM (112 mg, 0.14 mmol) was added in one portion to a solution of (7-bromoquinoline-4-carbonyl)glycine tert-butyl ester intermediate 7 (500 mg, 1.37 mmol) and (tributylstannyl)methanol (484 mg, 1.51 mmol) in 1,4-dioxane (5 mL), and the reaction mixture was stirred at 80 ° C for 16 hours. 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 (400MHz, CD 3 OD)δ8.93(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,overlapping with solvent),1.56(s,9H).

[0866] Intermediate 36: (7-(difluoromethyl)quinoline-4-carbonyl)glycine tert-butyl ester

[0867]

[0868] Step a) (7-Formylquinoline-4-carbonyl)glycine tert-butyl ester

[0869]

[0870] Dess-Martin periodinane (1488 mg, 3.51 mmol) was added portionwise to a solution of (7-(hydroxymethyl)quinoline-4-carbonyl)glycine tert-butyl ester intermediate 35 (370 mg, 1.17 mmol) in DCM (6 mL), and the reaction mixture was stirred at 35 °C for 5 hours. The reaction mixture was diluted with EtOAc (100 mL) and washed with water (2 x 100 mL). The organic layer was purified by Na 2 SO 4 Dry, filter and evaporate in vacuo and the residue purified by preparative TLC (EtOAc: petroleum ether, 1:1) to give the subtitle compound of step a) (250 mg, crude).

[0871] Step b) (7-(difluoromethyl)quinoline-4-carbonyl)glycine tert-butyl ester

[0872] DAST (0.841 mL, 6.36 mmol) was added dropwise to a solution of (7-formylquinoline-4-carbonyl)glycine tert-butyl ester step a) intermediate (250 mg, 0.80 mmol) in DCM (5 mL), and the reaction mixture was stirred at 0°C for 16 hours. The reaction mixture was diluted with EtOAc (20 mL) and washed with saturated brine (2×20 mL). The organic layer was purified by Na 2 SO 4 Dry, filter and evaporate in vacuo, and the crude product is purified by preparative TLC (EtOAc: petroleum ether, 1:1) to give the title compound as a yellow liquid (100 mg, 37%); MS (ESI) m / z [M+H] + 337.

[0873] Intermediate 37: (7-(difluoromethyl)quinoline-4-carbonyl)glycine

[0874]

[0875] 4M HCl in 1,4-dioxane (0.037 mL, 1.5 mmol) was added dropwise to a solution of (7-(difluoromethyl)quinoline-4-carbonyl)glycine tert-butyl ester 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.

[0876] Intermediate 38: (7-(Trifluoromethyl)quinoline-4-carbonyl)glycine tert-butyl ester

[0877]

[0878] 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), glycine tert-butyl ester 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 heated with saturated NaHCO 3 (aqueous solution, 20 mL) and extracted with EtOAc (3×20 mL). The combined organic layers were purified by Na 2 SO 4 Dry, filter and evaporate 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.

[0879] Intermediate 39: (7-(Trifluoromethyl)quinoline-4-carbonyl)glycine

[0880]

[0881] 4M HCl in 1.4-dioxane (1.06 mL, 4.23 mmol) was added to a solution of (7-(trifluoromethyl)quinoline-4-carbonyl)glycine tert-butyl ester 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 hours. The solvent was removed under reduced pressure to give the crude title compound (0.180 g); MS (ESI) m / z [M+H] + 299.

[0882] Intermediate 40: (7-(Fluoromethyl)quinoline-4-carbonyl)glycine tert-butyl ester

[0883]

[0884] DAST (550 mg, 3.41 mmol) was added to a solution of (7-(hydroxymethyl)quinoline-4-carbonyl)glycine tert-butyl ester 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 hours. The reaction mixture was poured into saturated NaHCO 3 (aqueous solution, 100 mL), and the mixture was extracted with DCM (3×50 mL). The combined organic layers were purified by Na 2 SO 4 Dry, filter and evaporate in vacuo, and the residue is purified by preparative TLC (EtOAc: petroleum ether, 1:1) to give the title compound (250 mg, 46%); MS (ESI) m / z [M+H]+ 318.

[0885] Intermediate 41: (7-(Fluoromethyl)quinoline-4-carbonyl)glycine

[0886]

[0887] 4M HCl in 1,4-dioxane (2.0 mL, 2.5 mmol) was added to a solution of (7-(fluoromethyl)quinoline-4-carbonyl)glycine tert-butyl ester 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.

[0888] Intermediate 42: (7-acetylquinoline-4-carbonyl)glycine tert-butyl ester

[0889]

[0890] In N 2 (g) Under atmosphere, (7-bromoquinoline-4-carbonyl)glycine tert-butyl ester intermediate 7 (800 mg, 2.19 mmol), tributyl(1-ethoxyvinyl)stannane (949 mg, 2.63 mmol) and Pd(dppf)Cl 2 DCM (160 mg, 0.22 mmol) was suspended in toluene (10 mL), and the reaction mixture was stirred at 100 ° C for 12 hours. The reaction mixture was acidified to pH 6 with 2M HCl (aqueous solution), 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.

[0891] Intermediate 43: (7-(1-hydroxyethyl)quinoline-4-carbonyl)glycine tert-butyl ester

[0892]

[0893] NaBH 4 (28 mg, 0.73 mmol) was added to a solution of (7-acetylquinoline-4-carbonyl)glycine tert-butyl ester intermediate 42 (120 mg, 0.37 mmol) in THF (1 mL), and the reaction mixture was stirred at 20 °C for 2 hours. The reaction mixture was diluted with EtOAc (10 mL) and then washed with saturated NaHCO 3 (aqueous solution), saturated NaCl (aqueous solution) and water. The organic layer was washed with Na 2 SO 4Dry, filter and concentrate 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.

[0894] Intermediate 44: (7-(1-hydroxyethyl)quinoline-4-carbonyl)glycine

[0895]

[0896] TFA (0.069 mL, 0.89 mmol) was added to a solution of (7-(1-hydroxyethyl)quinoline-4-carbonyl)glycine tert-butyl ester intermediate 43 (98 mg, 0.30 mmol) in DCM (1 mL), and the reaction mixture was stirred at 20°C for 4 hours. The solvent was removed under reduced pressure to give the crude title compound (100 mg); MS (ESI) m / z [M+H] + 275.

[0897] Intermediate 45: (7-(2-hydroxypropan-2-yl)quinoline-4-carbonyl)glycine tert-butyl ester

[0898]

[0899] At 0°C and N 2 (g) MeMgCl (3 M in THF, 0.25 mL, 0.76 mmol) was added to a solution of (6-acetylquinoline-4-carbonyl)glycine tert-butyl ester intermediate 42 (100 mg, 0.30 mmol) in THF (1 mL) under an atmosphere, and the reaction mixture was stirred at 0°C for 3 h. 4 The reaction was quenched with Cl (aqueous solution, 10 mL), and the mixture was extracted with EtOAc (3×10 mL). The combined organic layers were purified by Na 2 SO 4 Dry, filter and evaporate 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.

[0900] Intermediate 46: (7-(2-hydroxypropan-2-yl)quinoline-4-carbonyl)glycine

[0901]

[0902] TFA (5.0 mL, 65 mmol) was slowly added to a solution of (7-(2-hydroxypropan-2-yl)quinoline-4-carbonyl)glycine tert-butyl ester 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.

[0903] Intermediate 47: 7-(1-Hydroxyethyl)quinoline-4-carboxylic acid methyl ester

[0904]

[0905] NaBH 4 (136 mg, 3.60 mmol) was added to a solution of 7-acetylquinoline-4-carboxylic acid methyl ester intermediate 31 (550 mg, 2.40 mmol) in MeOH (10 mL), and the reaction mixture was stirred at room temperature for 2 hours. The reaction mixture was diluted with water (50 mL) and extracted with EtOAc (3×50 mL). The organic layer was purified by Na 2 SO 4 Dry, filter and evaporate 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.

[0906] Intermediate 48: 7-(1-methoxyethyl)quinoline-4-carboxylic acid methyl ester

[0907]

[0908] At 0°C and N 2 (g) 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, and the reaction mixture was stirred at 20° C. for 30 min. The reaction mixture was cooled to 0° C. and CH 3 I (0.054 mL, 0.86 mmol), the reaction mixture was slowly warmed to room temperature and then stirred at room temperature for 2 hours. The reaction was quenched with water (10 mL), and the mixture was extracted with EtOAc (3×10 mL). The combined organic layers were purified by Na 2 SO 4 Dry, filter and evaporate under reduced pressure. The residue was purified by preparative TLC (DCM:MeOH, 10:1) to give the title compound (60 mg, 57%) as a light yellow gum; MS (ESI) m / z [M+H]+ 246.

[0909] Intermediate 49: 7-(1-methoxyethyl)quinoline-4-carboxylic acid

[0910]

[0911] In N 2 (g) 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 atmosphere, 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 2M 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.

[0912] Intermediate 50: 7-(2-methoxyprop-2-yl)quinoline-4-carboxylic acid methyl ester

[0913]

[0914] 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 min. CH 3 I (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 NH 4 The organic layer was washed with Na 2 SO 4 Dry, filter and evaporate under reduced pressure to give the title compound (80 mg, 58%); 1 H NMR (400MHz, CD 3 OD)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).

[0915] Intermediate 51: 7-(2-methoxyprop-2-yl)quinoline-4-carboxylic acid

[0916]

[0917] 7-(2-methoxypropan-2-yl)quinoline-4-carboxylic acid methyl ester 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 hour. The mixture was concentrated in vacuo to give the crude title compound (60 mg); MS (ESI) m / z [M+H] + 246.

[0918] Intermediate 52: 7-(Hydroxymethyl)quinoline-4-carboxylic acid methyl ester

[0919]

[0920] 7-Bromoquinoline-4-carboxylic acid methyl ester (600 mg, 2.25 mmol), (tributylstannyl)-methanol (1.08 g, 3.38 mmol) and Pd(PPh 3 ) 4 (261 mg, 0.23 mmol) was suspended in 1,4-dioxane (10 mL), and the reaction mixture was stirred at 80 ° C for 16 hours. 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.

[0921] Intermediate 53: 7-((trifluoromethoxy)methyl)quinoline-4-carboxylic acid methyl ester

[0922]

[0923] In N 2 (g) 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 a 4% CO atmosphere, and the reaction mixture was stirred at room temperature for 2 minutes. 2-Fluoropyridine (268 mg, 2.76 mmol) and (CH 3 ) 3 SiC 3 (393 mg, 2.76 mmol), and the reaction mixture was stirred at 20 ° C for 12 hours. 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.

[0924] Intermediate 54: 7-(1-(trifluoromethoxy)ethyl)quinoline-4-carboxylic acid methyl ester

[0925]

[0926] At 20 °C and N 2 (g) atmosphere, (CH 3 ) 3 SiC 3 (1.48 g, 10.4 mmol) was added to a solution of 7-(1-hydroxyethyl)quinoline-4-carboxylic acid methyl ester 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), and the reaction mixture was stirred at 20 ° C for 96 hours. The reaction mixture was filtered through diatomaceous earth. The filtrate was washed with water (2×60 mL), and the organic layer was purified by Na 2 SO 4 Dry and concentrate 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.

[0927] Intermediate 55: 7-(1-(trifluoromethoxy)ethyl)quinoline-4-carboxylic acid

[0928]

[0929] 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 hours. The solvent was removed in vacuo to give the crude title compound (150 mg); MS (ESI) m / z [M+H] + 286.

[0930] Intermediate 56: (7-(1-ethoxyvinyl)quinoline-4-carbonyl)glycine tert-butyl ester

[0931]

[0932] At 19°C and N 2 (g) Pd(dppf)Cl 2DCM (112 mg, 0.14 mmol) was added in one portion to a solution of (7-bromoquinoline-4-carbonyl)glycine tert-butyl ester intermediate 7 (500 mg, 1.37 mmol) and tributyl (1-ethoxyvinyl) stannane (593 mg, 1.64 mmol) in toluene (8 mL), and the reaction mixture was stirred at 100 ° C for 8 hours. 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) and purified by Na 2 SO 4 Dry, filter and concentrate under reduced pressure.The crude product was purified by preparative TLC (EtOAc: petroleum ether, 1:1) to give the title compound (350 mg, 72%). 1 H NMR (400MHz, CD 3 OD)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).

[0933] Intermediate 57: (7-(1-ethoxycyclopropyl)quinoline-4-carbonyl)glycine tert-butyl ester

[0934]

[0935] at -78 °C and N 2 (g) Under the atmosphere, CH 2 I 2 A solution of (451 mg, 1.68 mmol) in DCM (1 mL) was added to Et 2 Zn (15 wt% hexane solution, 693 mg, 0.84 mmol) in DCM (4 mL) was added, and the reaction mixture was stirred at -15 ° C for 30 minutes. TFA (65 μL, 0.84 mmol) in DCM (1 mL) was added, and the reaction mixture was stirred at -15 ° C for 30 minutes. (7- (1-ethoxyvinyl) quinoline-4-carbonyl) glycine tert-butyl ester 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 hours. The reaction mixture was diluted with DCM (50 mL) and washed with saturated NH 4 The organic layer was washed with Na 2 SO 4 Dry, filter and evaporate under reduced pressure to give the crude title product (200 mg): MS (ESI) m / z [M+H] + 371.

[0936] Intermediate 58: (7-(1-ethoxycyclopropyl)quinoline-4-carbonyl)glycine

[0937]

[0938] 4M HCl in 1,4-dioxane (4.0 mL, 16 mmol) was added to (7-(1-ethoxycyclopropyl)quinoline-4-carbonyl)glycine tert-butyl ester 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.

[0939] Intermediate 59: (6-(1-methylcyclopropyl)quinoline-4-carbonyl)glycine tert-butyl ester

[0940]

[0941] At 20 °C and N 2 (g) Under atmosphere, Dtbbpy (0.022 g, 0.08 mmol) was added to NiCl 2 DME (0.012 g, 0.05 mmol) in degassed DME (12 mL) was added and the resulting mixture was stirred at 20°C for 30 minutes. Tris(trimethylsilyl)silane (0.272 g, 1.10 mmol), (6-bromoquinoline-4-carbonyl)glycine tert-butyl ester intermediate 5 (0.20 g, 0.55 mmol), 1-bromo-1-methylcyclopropane (0.148 g, 1.10 mmol), Na 2 CO 3 (0.174 g, 1.64 mmol) and [Ir{dF(CF 3 )ppy} 2 (dtbbpy)]PF 6 (0.012 g, 11 μmol), and the reaction mixture was heated under N 2 (g) The mixture was stirred for 20 hours under 34W blue LED light irradiation at room temperature under atmosphere. The reaction was quenched with water (20 mL), and the mixture was extracted with EtOAc (3×20 mL). The organic layer was purified by Na 2 SO 4 Dried, 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.

[0942] Intermediate 60: (6-(1-methylcyclopropyl)quinoline-4-carbonyl)glycine

[0943]

[0944] TFA (0.905 mL, 11.8 mmol) was added to a solution of (6-(1-methylcyclopropyl)quinoline-4-carbonyl)glycine tert-butyl ester 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 hours. The solvent was removed under reduced pressure, and the crude product was purified by preparative HPLC, Preparative Method B (gradient: 13%-23%) to give the title compound (0.045 g, 27%): MS (ESI) m / z [M+H] + 285.

[0945] Intermediate 61: 6-Formylquinoline-4-carboxylic acid methyl ester

[0946]

[0947] 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 at 25° C. for 2 hours. 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.

[0948] Intermediate 62: 6-(3-(trimethylsilyl)propionyl)quinoline-4-carboxylic acid methyl ester

[0949]

[0950] At 25°C and N 2 (g) Under the atmosphere, RhCl(PPh 3 ) 3 (344 mg, 0.37 mmol) and benzoic acid (91 mg, 0.74 mmol) were added to a toluene (10 mL) 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), and the reaction mixture was heated at 150° C. for 2 hours. 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.

[0951] Intermediate 63: 6-(1,1,1-trifluoro-2-hydroxy-4-(trimethylsilyl)butan-2-yl)quinoline-4-carboxylic acid ester

[0952]

[0953] (CH 3 ) 3 SiC 3 The mixture was stirred at 25 °C for 4 hours. 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 hours. The reaction mixture was poured into saturated brine (50 mL), extracted with EtOAc (3×50 mL), and the combined organic layers were purified by Na 2 O 4 . 2 SO 4 Dry, filter and evaporate 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.

[0954] Intermediate 64: 6-(1,1,1-trifluoro-2-((methylsulfonyl)oxy)-4-(trimethylsilyl)butan-2-yl) Quinoline-4-carboxylic acid methyl ester

[0955]

[0956] 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 minutes and then at 25°C for 2 hours. 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.

[0957] Intermediate 65: 6-(1-(trifluoromethyl)cyclopropyl)quinoline-4-carboxylic acid

[0958]

[0959] Step a) 6-(1-(trifluoromethyl)cyclopropyl)quinoline-4-carboxylic acid methyl ester

[0960]

[0961] Pyridine (61 mg, 0.78 mmol) was added to a solution of 6-(1,1,1-trifluoro-2-((methylsulfonyl)oxy)-4-(trimethylsilyl)butan-2-yl)quinoline-4-carboxylic acid methyl ester intermediate 64 (180 mg, 0.39 mmol) in HFIP (2 mL), and the reaction mixture was stirred at 25 °C for 2 hours. The reaction mixture was poured into 0.5 M citric acid (aqueous solution, 50 mL) and extracted with EtOAc (3×50 mL). The combined organic layers were purified by Na 2 SO 4 Drying, filtration and evaporation gave the title compound as a yellow oil (100 mg, 87%). MS (ESI) m / z [M+H] + 296.1.

[0962] Step b) 6-(1-(trifluoromethyl)cyclopropyl)quinoline-4-carboxylic acid

[0963] 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 hours. The reaction mixture was poured into water (50 mL), the pH was adjusted to pH 3 with 2M HCl (aq), and the mixture was extracted with EtOAc (3 x 50 mL). The combined organic layers were purified by Na 2 SO 4 Drying, filtration and evaporation gave the title compound as a yellow oil (80 mg, 93%); MS (ESI) m / z [M+H] + 282.0.

[0964] Intermediate 66: 6-(1-ethoxyvinyl)quinoline-4-carboxylic acid methyl ester

[0965]

[0966] 6-Bromoquinoline-4-carboxylic acid methyl ester (400 mg, 1.50 mmol), tributyl(1-ethoxyvinyl)stannane (651 mg, 1.80 mmol) and Pd(dppf) were added. 2 A solution of DCM (123 mg, 0.15 mmol) in 1,4-dioxane (15 mL) was stirred at 80 °C for 15 hours. The solvent was removed under reduced pressure and the residue was dried in vacuo. 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.

[0967] Intermediate 67: 6-(1-ethoxycyclopropyl)quinoline-4-carboxylic acid methyl ester

[0968]

[0969] at -78 °C and N 2 (g) Under the atmosphere, CH 2 I 2 A solution of (1.25 g, 4.66 mmol) in DCM (1 mL) was added to Et 2 Zn (15 wt % hexane solution, 288 mg, 2.33 mmol) in DCM (4 mL) solution. After the addition was completed, the reaction mixture was stirred at -15 ° C for 30 minutes. TFA (0.180 mL, 2.33 mmol) in DCM (1 mL) solution was added at -15 ° C, and the reaction mixture was stirred at -15 ° C for 30 minutes. 6- (1-ethoxyvinyl) -quinoline-4-carboxylic acid methyl ester intermediate 66 (300 mg, 1.17 mmol) in DCM (0.5 mL) solution was added at -5 ° C, and the reaction mixture was stirred at 20 ° C for 3 hours. The reaction mixture was poured into water (50 mL), extracted with DCM (2 × 100 mL), and the combined organic layer was purified by Na 2 SO 4 Dry, filter and evaporate 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.

[0970] Intermediate 68: 6-(1-ethoxycyclopropyl)quinoline-4-carboxylic acid

[0971]

[0972] 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 using 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.

[0973] Intermediate 69: 6-(Cyanomethyl)quinoline-4-carboxylic acid methyl ester

[0974]

[0975] At 20 °C and N 2 (g) Under the atmosphere, Pd 2 (dba)3 ·CHCl 3 (194 mg, 0.19 mmol) was added to 6-bromoquinoline-4-carboxylic acid methyl ester (500 mg, 1.88 mmol), 2-(trimethylsilyl)acetonitrile (277 mg, 2.44 mmol), ZnF 2 (136 mg, 1.32 mmol) and XantPhos (109 mg, 0.19 mmol) were suspended in DMF (8 mL), and the reaction mixture was stirred at 105 ° C for 10 hours. The reaction mixture was diluted with EtOAc (100 mL) and washed with saturated brine (3×50 mL). The organic layer was purified by Na 2 SO 4 Dry, filter and evaporate in vacuo, and the residue is purified by preparative TLC (EtOAc: petroleum ether, 1:2) to give the title compound (340 mg, 80%): MS (ESI) m / z [M+H] + 227.

[0976] Intermediate 70: 6-(1-cyanocyclopropyl)quinoline-4-carboxylic acid methyl ester

[0977]

[0978] 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 hour. 1,2-Dibromoethane (249 mg, 1.33 mmol) was added and the reaction mixture was stirred at 20 °C for 2 hours. The reaction mixture was diluted with EtOAc (50 mL) and washed with water (2×20 mL). The organic layer was purified by Na 2 SO 4 Dry, filter and evaporate, and the residue is purified by preparative TLC (EtOAc: petroleum ether, 1:2) to give the title compound (200 mg, 60%): MS (ESI) m / z [M+H] + 253.

[0979] Intermediate 71: 6-(1-Cyanocyclopropyl)quinoline-4-carboxylic acid

[0980]

[0981] A solution of 6-(1-cyanocyclopropyl)quinoline-4-carboxylic acid methyl ester 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 2M HCl (aqueous solution), 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.

[0982] Intermediate 72: (7-(1-methylcyclopropyl)quinoline-4-carbonyl)glycine tert-butyl ester

[0983]

[0984] At 20 °C and N 2 (g) Under atmosphere, Dtbbpy (0.022 g, 0.08 mmol) was added to NiCl 2 DME (0.012 g, 0.05 mmol) in degassed DME (12 mL) was added, and the resulting mixture was stirred at 20°C for 30 minutes. Tris(trimethylsilyl)silane (0.272 g, 1.10 mmol), (7-bromoquinoline-4-carbonyl)glycine tert-butyl ester intermediate 7 (0.20 g, 0.55 mmol), 1-bromo-1-methylcyclopropane (0.148 g, 1.10 mmol), Na 2 CO 3 (0.174 g, 1.64 mmol) and [Ir{dF(CF 3 )ppy} 2 (dtbbpy)]PF 6 (0.012 g, 11 μmol), and the reaction mixture was heated at room temperature under N 2 (g) The mixture was stirred for 20 hours under 34 W blue LED light irradiation under atmosphere. The reaction was quenched with water (20 mL), extracted with DCM (3×20 mL), and the organic layer was purified by Na 2 SO 4 Dry, filter and evaporate 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 light yellow gum: MS (ESI) m / z [M+H] + 341.

[0985] Intermediate 73: (7-(1-methylcyclopropyl)quinoline-4-carbonyl)glycine

[0986]

[0987] TFA (0.362 mL, 4.70 mmol) was added to a solution of (7-(1-methylcyclopropyl)-quinoline-4-carbonyl)glycine tert-butyl ester 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 hours. The solvent was removed under reduced pressure and the residue was dried in vacuo to give the crude title compound (40 mg) as a light orange gum; MS (ESI) m / z [M+H] + 285.

[0988] Intermediate 74: 7-Formylquinoline-4-carboxylic acid methyl ester

[0989]

[0990] 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 at 25°C for 3 hours. 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.

[0991] Intermediate 75: 7-(3-(trimethylsilyl)propionyl)quinoline-4-carboxylic acid methyl ester

[0992]

[0993] At 25℃, N 2 (g) Under the atmosphere, RhCl(PPh 3 ) 3 (365 mg, 0.39 mmol) and trimethyl(vinyl)silane (3.96 g, 39.5 mmol) were added to a toluene (10 mL) solution of benzoic acid (96 mg, 0.79 mmol), 7-formylquinoline-4-carboxylic acid methyl ester intermediate 74 (850 mg, 3.95 mmol) and 3-methylpyridin-2-amine (427 mg, 3.95 mmol), and the reaction mixture was stirred at 150° C. for 2 hours. 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.

[0994] Intermediate 76: 7-(1,1,1-trifluoro-2-hydroxy-4-(trimethylsilyl)butan-2-yl)quinoline-4-carboxylic acid ester

[0995]

[0996] At 25°C and N 2 (g) atmosphere, (CH 3 )3SiCF3 (176 mg, 1.24 mmol) and CsF (7 mg, 0.05 mmol) were added to a mixture of methyl 7-(3-(trimethylsilyl)propionyl)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). The reaction mixture was stirred at 25 ° C for 12 hours 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.

[0997] Intermediate 77: 7-(1,1,1-trifluoro-2-((methylsulfonyl)oxy)-4-(trimethylsilyl)butan-2-yl) Quinoline-4-carboxylic acid methyl ester

[0998]

[0999] 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 3 (aqueous solution, 50 mL) and extracted with DCM (3×50 mL). The combined organic layers were purified by Na 2 SO 4 Drying, filtration and evaporation under reduced pressure gave the title product as a yellow oil (300 mg, 92%); MS (ESI) m / z [M+H] + 464.1.

[1000] Intermediate 78: 7-(1-(trifluoromethyl)cyclopropyl)quinoline-4-carboxylic acid methyl ester

[1001]

[1002] Pyridine (63 mg, 0.80 mmol) was added to a solution of 7-(1,1,1-trifluoro-2-((methylsulfonyl)oxy)-4-(trimethylsilyl)butan-2-yl)quinoline-4-carboxylic acid methyl ester intermediate 77 (185 mg, 0.40 mmol) in HFIP (2 mL), and the reaction mixture was stirred at 25 °C for 2 hours. The reaction mixture was poured into 0.5 M citric acid (aqueous solution, 50 mL) and extracted with EtOAc (3×50 mL). The combined organic layers were purified by Na 2 SO 4 Drying, filtration and evaporation under reduced pressure gave the title compound in crude form (170 mg); MS (ESI) m / z [M+H] + 296.1.

[1003] Intermediate 79: 7-(1-(trifluoromethyl)cyclopropyl)quinoline-4-carboxylic acid

[1004]

[1005] 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 hours. The reaction mixture was poured into water (50 mL) and the pH was adjusted to 3 with 2M HCl (aq). The mixture was extracted with EtOAc (3×50 mL), and the combined organic layers were purified by Na 2 SO 4 Dry, filter and evaporate under reduced pressure to give the title compound (150 mg, 95%); MS (ESI) m / z [M+H] + 282.0.

[1006] Intermediate 80: 7-(1-cyanocyclopropyl)quinoline-4-carboxylic acid methyl ester

[1007]

[1008] In N 2 (g) Under atmosphere, 7-bromoquinoline-4-carboxylic acid methyl ester (500 mg, 1.88 mmol), bis(pinacolato)diboron (716 mg, 2.82 mmol), Pd(dppf)Cl 2 A solution of 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 hours. 1-Bromocyclopropane-1-carbonitrile (549 mg, 3.76 mmol), K 2 CO 3(519 mg, 3.76 mmol) and water (2 mL) and heated under N 2 (g) The reaction mixture was stirred at 80°C overnight under an atmosphere of 40 °C. The solid was 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.

[1009] Intermediate 81: 7-(1-Cyanocyclopropyl)quinoline-4-carboxylic acid

[1010]

[1011] A solution of 7-(1-cyanocyclopropyl)quinoline-4-carboxylic acid methyl ester 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 hours. 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 2M HCl (aqueous solution). 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.

[1012] C. Final Compound

[1013] Example 1: 6-bromo-N-(2-((1S,3S,5S)-3-cyano-2-azabicyclo[3.1.0]hex-2-yl)-2-oxo Ethyl)quinoline-4-carboxamide

[1014]

[1015] 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 heated with saturated NaHCO 3 (aqueous solution, 10 mL) and extracted with EtOAc (3×15 mL). The combined organic layers were purified by Na 2 SO 4 Dry, filter and evaporate. The crude product was purified by preparative HPLC, Preparation Method C (gradient: 28%-38%) to give the title compound (38 mg, 42%); HRMS (ESI) m / z [M+H] + C18 H 16 Bn 4 O 2 Calculated value: 399.0452, measured value: 399.0454; 1 H NMR (400 MHz, DMSO-d 6 )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(dd,1H),4.2 3(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).

[1016] Example 2: 7-chloro-N-(2-((1S,3S,5S)-3-cyano-2-azabicyclo[3.1.0]hex-2-yl)-2-oxo Ethyl)quinoline-4-carboxamide

[1017]

[1018] 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 NaHCO 3 (aqueous solution). 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, Preparation Method D (gradient: 15%-20%) to give the title compound (20 mg, 38%); HRMS (ESI) m / z [M+H] + C 18 H 16 C1N 4 O 2 Calculated value: 355.0956, measured value: 355.0934; 1 H NMR (600 MHz, DMSO-d 6)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(dd,1H),4.2 3(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).

[1019] Example 3: 7-bromo-N-(2-((1S,3S,5S)-3-cyano-2-azabicyclo[3.1.0]hex-2-yl)-2-oxo Ethyl)quinoline-4-carboxamide

[1020]

[1021] 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 heated with saturated NaHCO 3 (aqueous solution, 10 mL) and extracted with EtOAc (3×15 mL). The organic layer was purified by Na 2 SO 4 Dry, filter and evaporate. The crude product was purified by preparative HPLC, Preparation Method C (gradient: 25%-36%) to give the title compound (74 mg, 57%); HRMS (ESI) m / z [M+H] + C 18 H 16 Bn 4 O 2 Calculated value: 399.0452, measured value: 399.0454; 1 H NMR (400 MHz, DMSO-d 6)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,1H),4.23(d d,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).

[1022] Example 4: N-(2-((1S,3S,5S)-3-cyano-2-azabicyclo[3.1.0]hex-2-yl)-2-oxoethyl 6-Fluoro-2-methylquinoline-4-carboxamide

[1023]

[1024] 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 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, followed by MeCN (0.2 mL), and the reaction mixture was stirred at room temperature overnight. The mixture was diluted with DCM and saturated with NaHCO 3 (aqueous solution) and washed. The organic phase was dried using a phase separator and evaporated in vacuo. The crude product was purified by preparative SFC, Preparation D (gradient: 12%-17%) to give the title compound (25 mg, 51%); HRMS (ESI) m / z [M+H] + C 19 H 18 FN 4 O 2 Calculated value: 353.1408, measured value: 353.1402; 1 H NMR (600 MHz, DMSO-d 6 )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).

[1025] Example 5: 6-chloro-N-(2-((1S,3S,5S)-3-cyano-2-azabicyclo[3.1.0]hex-2-yl)-2-oxo ethyl)-2-methylquinoline-4-carboxamide

[1026]

[1027] 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 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, 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 saturated with NaHCO 3 (aqueous solution) was washed. The organic phase was dried using a phase separator and evaporated in vacuo. The crude product was purified by preparative SFC, Preparation D (gradient: 15%-20%) to give the title compound (29 mg, 57%); HRMS (ESI) m / z [M+H] + C 19 H 18 C1N 4 O 2 Calculated value: 369.1112, measured value: 369.1118; 1 H NMR (600 MHz, DMSO-d 6 )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).

[1028] Example 6: 6-bromo-N-(2-((1S,3S,5S)-3-cyano-2-azabicyclo[3.1.0]hex-2-yl)-2-oxo ethyl)-2-methylquinoline-4-carboxamide

[1029]

[1030] 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 minutes. 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 the addition of MeCN (0.2 mL), and the reaction mixture was stirred at room temperature for 2 hours. The reaction mixture was diluted with DCM and saturated with NaHCO 3 (aqueous solution). The organic phase was dried using a phase separator and evaporated in vacuo. The crude product was purified by preparative SFC, Preparation Method E (gradient: 15%-20%) to give the title compound (15 mg, 26%); HRMS (ESI) m / z [M+H] + C 19 H 18 Bn 4 O 2 Calculated value: 413.0608, measured value: 413.0630; 1 H NMR (600 MHz, DMSO-d 6 )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).

[1031] Example 7: N-(2-((1S,3S,5S)-3-cyano-2-azabicyclo[3.1.0]hex-2-yl)-2-oxoethyl 6-iodo-2-methylquinoline-4-carboxamide

[1032]

[1033] HATU (59mg, 0.15mmol) is added to a suspension of 6-iodo-2-methylquinoline-4-carboxylic acid (44mg, 0.14mmol) in DCM (1mL), and the reaction mixture is stirred at room temperature for 15 minutes. (1S, 3S, 5S) -2-glycyl -2- azabicyclo [3.1.0] hexane -3-carbonitrile hydrochloride intermediate 3 (28mg, 0.14mmol) and DIPEA (0.073mL, 0.42mmol) are added to the reaction mixture, followed by DCM (0.5mL) and MeCN (0.2mL). The reaction mixture is stirred at room temperature overnight. The reaction mixture is diluted with DCM, and saturated NaHCO 3 (aqueous solution) and the organic phase was dried using a phase separator and evaporated in vacuo. The crude product was purified by preparative SFC, preparation method D (gradient: 15%-20%) to give the title compound (33 mg, 52%); HRMS (ESI) m / z [M+H] + C 19 H 18 IN 4 O 2 Calculated value: 461.0468, measured value: 461.0460; 1 H NMR (600 MHz, DMSO-d 6 )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).

[1034] Example 8: N-(2-((1S,3S,5S)-3-cyano-2-azabicyclo[3.1.0]hex-2-yl)-2-oxoethyl 7-Fluoro-2-methylquinoline-4-carboxamide

[1035]

[1036] 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 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, 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 saturated with NaHCO 3 (aqueous solution) and the organic phase was dried using a phase separator and evaporated in vacuo. The crude product was purified by preparative SFC, preparation method D (gradient: 12%-17%) to give the title compound (29 mg, 58%); HRMS (ESI) m / z [M+H] + C 19 H 18 FN 4 O 2 Calculated value: 353.1408, measured value: 353.1406; 1 H NMR (600 MHz, DMSO-d 6 )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).

[1037] Example 9: N-(2-((1S,3S,5S)-3-cyano-2-azabicyclo[3.1.0]hex-2-yl)-2-oxoethyl 6-Methylquinoline-4-carboxamide

[1038]

[1039] Pd(dppf) 2 DCM (12 mg, 0.02 mmol) was added to 6-bromo-N-(2-((1S,3S,5S)-3-cyano-2-azabicyclo[3.1.0]hex-2-yl)-2-oxoethyl)quinoline-4-carboxamide Example 1 (120 mg, 0.30 mmol), TMB (113 mg, 0.90 mmol) and K 2 CO 3(125 mg, 0.90 mmol) was suspended in 1,4-dioxane (2 mL), and the reaction mixture was stirred at 80 °C for 4 hours. The reaction mixture was diluted with EtOAc (10 mL), and the mixture was washed with saturated NaHCO 3 (aqueous solution), saturated NaCl (aqueous solution), and H 2 O. The organic layer was washed with Na 2 SO 4 Dry, filter and concentrate in vacuo, and the residue is purified by preparative TLC (MeOH:DCM, 1:10). The crude product is purified by preparative HPLC, Preparation Method F (gradient: 15%-40%) to give the title compound (50 mg, 50%); HRMS (ESI) m / z [M+H] + C 19 H 19 N 4 O 2 Calculated value: 335.1502, measured value: 335.1506; 1 H NMR (400MHz, CD 3 OD)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).

[1040] Example 10: N-(2-((1S,3S,5S)-3-cyano-2-azabicyclo[3.1.0]hex-2-yl)-2-oxoethyl 6-(Trifluoromethyl)quinoline-4-carboxamide

[1041]

[1042] At 0°C, EDC (85 mg, 0.44 mmol) and DIPEA (0.14 mL, 0.80 mmol) were added to a DMF (2 mL) 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), and the reaction mixture was stirred at 20°C for 4 hours. The reaction mixture was diluted with EtOAc (10 mL) and washed with saturated NaHCO 3(aqueous solution), saturated NaCl (aqueous solution) and water. The organic layer was washed with Na 2 SO 4 Dry, filter and concentrate in vacuo. The crude product was purified by preparative HPLC, Preparation Method F (gradient: 15%-40%) to give the title compound (50 mg, 32%); HRMS (ESI) m / z [M+H] + C 19 H 16 F 3 N 4 O 2 Calculated value: 389.1220, measured value: 389.1224; 1 HNMR (300MHz, CD 3 OD)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).

[1043] Example 11: N-(2-((1S,3S,5S)-3-cyano-2-azabicyclo[3.1.0]hex-2-yl)-2-oxoethyl 6-(Fluoromethyl)quinoline-4-carboxamide

[1044]

[1045] 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 hours. The reaction mixture was washed with saturated NaHCO 3 (aqueous solution, 15 mL) and extracted with DCM (3×15 mL). The combined organic layers were purified by Na 2 SO 4 Dry, filter and evaporate under reduced pressure. The crude product was purified by preparative HPLC, Preparation F (isocratic 34%) to give the title compound (6.5 mg, 5%); HRMS (ESI) m / z [M+H] + C 19 H 18 FN 4 O2 Calculated value: 353.1408, measured value: 353.1388; 1 H NMR (400MHz, CD 3 OD)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).

[1046] Example 12: N-(2-((1S,3S,5S)-3-cyano-2-azabicyclo[3.1.0]hex-2-yl)-2-oxoethyl 6-(2-fluoropropan-2-yl)quinoline-4-carboxamide

[1047]

[1048] 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 heated to 40 ℃ with saturated NaHCO 3 (aqueous solution, 10 mL), extracted with DCM (3 x 10 mL), and the combined organic layers were purified by Na 2 SO 4 Dry, filter and evaporate under reduced pressure. The crude product was purified by preparative HPLC, Preparation Method H (gradient 45%-47%), then by preparative HPLC, Preparation Method I (gradient 10%-50%) to give the title compound (8 mg, 20%); HRMS (ESI) m / z [M+H] + C 21 H 22 FN 4 O 2 Calculated value: 381.1722, measured value: 381.1722; 1 H NMR (400MHz, CD 3OD)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).

[1049] Example 13: N-(2-((1S,3S,5S)-3-cyano-2-azabicyclo[3.1.0]hex-2-yl)-2-oxoethyl 6-(2-hydroxypropan-2-yl)quinoline-4-carboxamide

[1050]

[1051] 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 washed with saturated NaHCO 3 (aqueous solution, 20 mL), extracted with DCM (3 x 20 mL), and the combined organic layers were purified by Na 2 SO 4 Dry, filter and evaporate under reduced pressure. The crude product was purified by preparative HPLC, Preparation Method B (gradient: 13%-23%), then by preparative HPLC, Preparation Method B (gradient: 10%-21%) to give the title compound (6 mg, 9%); HRMS (ESI) m / z [M+H] + C 21 H 23 N 4 O 3 Calculated value: 379.1764, measured value: 379.1760; 1 H NMR (300MHz, CD 3OD)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).

[1052] Example 14: N-(2-((1S,3S,5S)-3-cyano-2-azabicyclo[3.1.0]hex-2-yl)-2-oxoethyl 6-(1-hydroxyethyl)quinoline-4-carboxamide

[1053]

[1054] 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 NaHCO 3 (aqueous solution), saturated NaCl (aqueous solution) and water. The organic layer was washed with Na 2 SO 4 Dry, filter and concentrate under reduced pressure. The crude product was purified by preparative HPLC, preparation method B (gradient: 8%-18%) to give the title compound (10 mg, 8%); HRMS (ESI) m / z [M+H] + C 20 H 21 N 4 O 3 Calculated value: 365.1608, measured value: 365.1596; 1 HNMR (300MHz, CD 3OD)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).

[1055] Example 15: N-(2-((1S,3S,5S)-3-cyano-2-azabicyclo[3.1.0]hex-2-yl)-2-oxoethyl 6-(1-methoxyethyl)quinoline-4-carboxamide

[1056]

[1057] 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 heated to 40 °C with saturated NaHCO 3 (aqueous solution, 10 mL) and extracted with DCM (3×10 mL). The combined organic layers were purified by Na 2 SO 4 Dry, filter and concentrate in vacuo. The crude product was purified by preparative HPLC, Preparation Method B (gradient: 17%-27%) to give the title compound (33 mg, 67%); HRMS (ESI) m / z [M+H] + C 21 H 23 N 4 O 3 Calculated value: 379.1764, measured value: 379.1764; 1 H NMR (300MHz, CD 3OD)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),3.8 0(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).

[1058] Example 16: N-(2-((1S,3S,5S)-3-cyano-2-azabicyclo[3.1.0]hex-2-yl)-2-oxoethyl 6-(2-methoxypropan-2-yl)quinoline-4-carboxamide

[1059]

[1060] 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 heated to 40 °C with saturated NaHCO 3 (aqueous solution, 10 mL) and extracted with DCM (3×10 mL). The combined organic layers were purified by Na 2 SO 4 Dry, filter and evaporate under reduced pressure. The crude product was purified by preparative HPLC, Preparation Method I (gradient: 18%-28%) to give the title compound (37 mg, 58%); HRMS (ESI) m / z [M+H] + C 22 H 25 N 4 O 3 Calculated value: 393.1922, measured value: 393.1934; 1 H NMR (400MHz, CD 3OD)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).

[1061] Example 17: N-(2-((1S,3S,5S)-3-cyano-2-azabicyclo[3.1.0]hex-2-yl)-2-oxoethyl 6-((trifluoromethoxy)methyl)quinoline-4-carboxamide

[1062]

[1063] In N 2 (g) (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 and the reaction mixture was stirred at 38° C. for 2 hours. The reaction mixture was concentrated in vacuo and the residue was purified by preparative HPLC, Preparation Method J (gradient: 30%-60%) to give the title compound (33 mg, 14%); HRMS (ESI) m / z [M+H] + C 20 H 18 F 3 N 4 O 3 Calculated value: 419.1326, measured value: 419.1326; 1 H NMR (400MHz, CD 3 OD)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).

[1064] Example 18: N-(2-((1S,3S,5S)-3-cyano-2-azabicyclo[3.1.0]hex-2-yl)-2-oxoethyl 6-ethyl-2-methylquinoline-4-carboxamide

[1065]

[1066] 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 saturated with NaHCO 3 (aqueous solution). 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, Preparation Method D (gradient: 12%-17%) to give the title compound (25 mg, 49%); HRMS (ESI) m / z [M+H] + C 21 H 23 N 4 O 2 Calculated value: 363.1816, measured value: 363.1814; 1 H NMR (600 MHz, DMSO-d 6 )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).

[1067] Example 19: N-(2-((1S,3S,5S)-3-cyano-2-azabicyclo[3.1.0]hex-2-yl)-2-oxoethyl 2,6-Dimethylquinoline-4-carboxamide

[1068]

[1069] 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 saturated with NaHCO 3 (aqueous solution). 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, Preparation Method D (gradient: 12%-17%) to give the title compound (25 mg, 52%); HRMS (ESI) m / z [M+H] + C 20 H 21 N 4 O 2 Calculated value: 349.1658, measured value: 349.1650; 1 H NMR (600 MHz, DMSO-d 6 )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).

[1070] Example 20: N-(2-((1S,3S,5S)-3-cyano-2-azabicyclo[3.1.0]hex-2-yl)-2-oxoethyl 4-Methylquinoline-7-carboxamide

[1071]

[1072] In N 2 (g) Under the atmosphere, Pd(dppf)Cl 2 DCM (15 mg, 0.02 mmol) was added to 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), K 2CO 3 (156 mg, 1.13 mmol) and TMB (141 mg, 1.13 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 then washed with saturated NaHCO 3 (aqueous solution), saturated NaCl (aqueous solution) and water. The organic layer was washed with Na 2 SO 4 Dry, filter and concentrate under reduced pressure. The residue was purified by preparative TLC (MeOH:DCM, 1:10). The crude product was purified by preparative HPLC, preparation method B (gradient: 11%-21%) to give the title compound (80 mg, 64%); HRMS (ESI) m / z [M+H] + C 19 H 19 N 4 O 2 Calculated value: 335.1508, measured value: 335.1507; 1 H NMR (400MHz, CD 3 OD)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).

[1073] Example 21: N-(2-((1S,3S,5S)-3-cyano-2-azabicyclo[3.1.0]hex-2-yl)-2-oxoethyl 7-(2-fluoropropan-2-yl)quinoline-4-carboxamide

[1074]

[1075] 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 hours. The reaction mixture was concentrated in vacuo, and the residue was purified by preparative HPLC, Preparative Method K (gradient: 29%-30%) to give the title compound (5 mg, 15%); HRMS (ESI) m / z [M+H] + C 21 H 22 FN 4 O 2 Calculated value: 381.1722, measured value: 381.1724; 1 H NMR (400MHz, CD 3 OD)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).

[1076] Example 22: N-(2-((1S,3S,5S)-3-cyano-2-azabicyclo[3.1.0]hex-2-yl)-2-oxoethyl 4-(difluoromethyl)quinolinecarboxamide

[1077]

[1078] 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 hours. The reaction mixture was concentrated in vacuo and the crude product was purified by preparative HPLC, Preparation Method K (isocratic: 27%) to give the title compound (15 mg, 23%); HRMS (ESI) m / z [M+H] + C 19 H 17 F 2 N 4 O 2 Calculated value: 371.1320, measured value: 371.1304; 1 H NMR (400MHz, CD 3 OD)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).

[1079] Example 23: N-(2-((1S,3S,5S)-3-cyano-2-azabicyclo[3.1.0]hex-2-yl)-2-oxoethyl 4-(Trifluoromethyl)quinolinecarboxamide

[1080]

[1081] 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 NaHCO 3(aqueous solution), saturated NaCl (aqueous solution) and water. The organic layer was washed with Na 2 SO 4 Dry, filter and concentrate under reduced pressure. The crude product was purified by preparative HPLC, Preparation Method L (isocratic: 35%) to give the title compound (80 mg, 34%); HRMS (ESI) m / z [M+H] + C 19 H 16 F 3 N 4 O 2 Calculated value: 389.1220, measured value: 389.1224; 1 H NMR (300MHz, CD 3 OD)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).

[1082] Example 24: N-(2-((1S,3S,5S)-3-cyano-2-azabicyclo[3.1.0]hex-2-yl)-2-oxoethyl 4-(Fluoromethyl)quinolinecarboxamide

[1083]

[1084] 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 hours. The reaction mixture was concentrated in vacuo, and the residue was purified by preparative HPLC, Preparation Method F (gradient: 23%-30%) to give the title compound (21 mg, 15%); HRMS (ESI) m / z [M+H] + C 19 H 18 FN 4 O 2 Calculated value: 353.1408, measured value: 353.1400; 1 H NMR (400MHz, CD 3OD)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),4.4 2(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).

[1085] Example 25: N-(2-((1S,3S,5S)-3-cyano-2-azabicyclo[3.1.0]hex-2-yl)-2-oxoethyl 4-(1-hydroxyethyl)quinolinecarboxamide

[1086]

[1087] DIPEA (0.172 mL, 0.98 mmol) and EDC (69 mg, 0.36 mmol) were added to a DMF (1 mL) 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), and the reaction mixture was stirred at 20°C for 6 hours. The reaction mixture was diluted with EtOAc (10 mL) and washed with saturated NaHCO 3 (aqueous solution), saturated NaCl (aqueous solution) and water. The organic layer was washed with Na 2 SO 4 Dry, filter and concentrate in vacuo. The crude product was purified by preparative HPLC, Preparation Method M (isocratic 20%) to give the title compound (10 mg, 8%); HRMS (ESI) m / z [M+H] + C 20 H 21 N 4 O 3 Calculated value: 365.1608, measured value: 365.1610; 1 H NMR (400MHz, CD 3OD)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).

[1088] Example 26: N-(2-((1S,3S,5S)-3-cyano-2-azabicyclo[3.1.0]hex-2-yl)-2-oxoethyl 2-(2-Hydroxypropyl)-7-(2-hydroxypropan-2-yl)quinoline-4-carboxamide

[1089]

[1090] 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 hours. 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, Prep N (gradient: 18%-35%) to give the title compound (25 mg, 29%); HRMS (ESI) m / z [M+H] + C 21 H 23 N 4 O 3 Calculated value: 377.1608, measured value: 377.1620; 1 H NMR (400MHz, CD 3 OD)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).

[1091] Example 27: N-(2-((1S,3S,5S)-3-cyano-2-azabicyclo[3.1.0]hex-2-yl)-2-oxoethyl 1-Methoxyethyl)quinoline-4-carboxamide

[1092]

[1093] 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 heated to 40°C with saturated NaHCO 3 (aqueous solution, 10 mL) and extracted with DCM (3×10 mL). The organic layer was washed with Na 2 SO 4 Dry, filter and evaporate under reduced pressure, and the crude product is purified by preparative HPLC, preparation method B (gradient: 16%-26%) to give the title compound (25 mg, 31%); HRMS (ESI) m / z [M+H] + C 21 H 23 N 4 O 3 Calculated value: 379.1764, measured value: 379.1748; 1 H NMR (300MHz, CD 3 OD)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).

[1094] Example 28: N-(2-((1S,3S,5S)-3-cyano-2-azabicyclo[3.1.0]hex-2-yl)-2-oxoethyl 2-(2-methoxypropan-2-yl)quinoline-4-carboxamide

[1095]

[1096] 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 hours. The reaction mixture was concentrated in vacuo, and the residue was purified by preparative HPLC, Prep N (gradient: 20%-38%) to give the title compound (30 mg, 19%); HRMS (ESI) m / z [M+H] + C 22 H 25 N 4 O 3 Calculated value: 393.1922, measured value: 393.1928; 1 H NMR (300MHz, CD 3 OD)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).

[1097] Example 29: N-(2-((1S,3S,5S)-3-cyano-2-azabicyclo[3.1.0]hex-2-yl)-2-oxoethyl 4-((trifluoromethoxy)methyl)quinolinecarboxamide

[1098]

[1099] Step a) 7-((trifluoromethoxy)methyl)quinoline-4-carboxylic acid

[1100]

[1101] 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 subtitle compound as a crude product.

[1102] Step b) N-(2-((1S,3S,5S)-3-cyano-2-azabicyclo[3.1.0]hex-2-yl)-2-oxoethyl)- 7-((Trifluoromethoxy)methyl)quinoline-4-carboxamide

[1103] 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 hours. The reaction mixture was concentrated in vacuo and the residue was purified by preparative HPLC, Preparation Method F (Gradient: 34%-39%) to give the title compound (50 mg, 26%); HRMS (ESI) m / z [M+H] + C 20 H 18 F 3 N 4 O 3 Calculated value: 419.1326, measured value: 419.1308; 1 H NMR (400MHz, CD 3 OD)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).

[1104] Example 30: N-(2-((1S,3S,5S)-3-cyano-2-azabicyclo[3.1.0]hex-2-yl)-2-oxoethyl 1-(trifluoromethoxy)ethyl)quinoline-4-carboxamide

[1105]

[1106] (1S,3S,5S)-2-glycyl-2-azabicyclo[3.1.0]hexane-3-carbonitrile intermediate 4 (87 mg, 0.53 mmol) was added to 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 hours. The solvent was removed in vacuo and the residue was purified by preparative TLC (MeOH:DCM, 1:10) and then by preparative HPLC, Preparative Method F (gradient: 33%-45%) to give the title compound (16 mg, 7%); HRMS (ESI) m / z [M+H] + C 21 H 20 F 3 N 4 O 3 Calculated value: 433.1482, measured value: 433.1488; 1 HNMR (400 MHz, DMSO-d 6 )δ9.14(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, overlapped 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).

[1107] Example 31: N-(2-((1S,3S,5S)-3-cyano-2-azabicyclo[3.1.0]hex-2-yl)-2-oxoethyl 2,7-Dimethylquinoline-4-carboxamide

[1108]

[1109] 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 minutes. 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 the addition of MeCN (0.2 mL), and the reaction mixture was stirred at room temperature overnight. The reaction mixture was diluted with DCM and saturated with NaHCO 3 (aqueous solution) was washed. 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, Preparation Method O (gradient: 12%-17%), then by preparative SFC, Preparation Method P (gradient: 15%-20%) to give the title compound (32 mg, 60%); HRMS (ESI) m / z [M+H] + C 20 H 21 N 4 O 2 Calculated value: 349.1664, measured value: 349.1658; 1 H NMR (600 MHz, DMSO-d 6 )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).

[1110] Example 32: N-(2-((1S,3S,5S)-3-cyano-2-azabicyclo[3.1.0]hex-2-yl)-2-oxoethyl 4-(1-Methylcyclopropyl)quinolinecarboxamide

[1111]

[1112] 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 washed with saturated NaHCO 3 (10 mL), extracted with DCM (3 x 10 mL), and the organic layer was purified by Na 2 SO 4 Dry, filter and evaporate under reduced pressure. The crude product was purified by preparative HPLC, preparation method B (gradient: 21%-32%) to give the title compound (15 mg, 28%); HRMS (ESI) m / z [M+H] + C 22 H 23 N 4 O 2 Calculated value: 375.1816, measured value: 375.1814; 1 H NMR (300MHz, CD 3 OD)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).

[1113] Example 33: N-(2-((1S,3S,5S)-3-cyano-2-azabicyclo[3.1.0]hex-2-yl)-2-oxoethyl 6-(2,2,2-trifluoroethoxy)quinoline-4-carboxamide

[1114]

[1115] Stock solution A was prepared by mixing NiCl 2DME (4 mg, 18 μmol) and dtbbpy (5 mg, 0.02 mmol) were prepared by dissolving 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 6-bromo-N-(2-((1S,3S,5S)-3-cyano-2-azabicyclo[3.1.0]hex-2-yl)-2-oxoethyl)quinoline-4-carboxamide Example 1 (0.015 g, 0.04 mmol), Ir[dF(CF 3 )ppy] 2 (dtbbpy)PF 6 (2.1 mg, 1.8 μmol) and K 2 CO 3 (5.2 mg, 0.04 mmol) and N was applied to the reaction vessel. 2 (g) Atmosphere. 2,2,2-Trifluoroethane-1-ol (0.011 g, 0.11 mmol) was added and the mixture was stirred for 2 h using N 2 (g) The reaction mixture was degassed three times using an evacuation-refill cycle as an inert gas. The reaction vessel was capped and sealed with parafilm, and the reaction mixture was irradiated with a blue LED (34 W, 456 nm) for 24 hours at room temperature in a fan-cooled room. 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, preparation method E (gradient: 15%-20%) to give the title compound (1.5 mg, 10%); HRMS (ESI) m / z[M+H] + C 20 H 18 F 3 N 4 O 3 Calculated value: 419.1326, measured value: 419.1338.

[1116] Example 34: N-(2-((1S,3S,5S)-3-cyano-2-azabicyclo[3.1.0]hex-2-yl)-2-oxoethyl 6-isopropoxyquinoline-4-carboxamide

[1117]

[1118] Stock solution A was prepared by mixing NiCl 2DME (4.2 mg, 19 μmol) and dtbbpy (5 mg, 0.02 mmol) were prepared by dissolving 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 6-bromo-N-(2-((1S,3S,5S)-3-cyano-2-azabicyclo[3.1.0]hex-2-yl)-2-oxoethyl)quinoline-4-carboxamide Example 1 (0.015 g, 0.04 mmol), Ir[dF(CF 3 )ppy] 2 (dtbbpy)PF 6 (2.1 mg, 1.9 μmol) and K 2 CO 3 (5.2 mg, 0.04 mmol) and N was applied to the reaction vessel. 2 (g) Atmosphere. Propan-2-ol (8.7 μL, 0.11 mmol) was added and the reaction vessel was capped and heated to 40 ℃ under N 2 (g) The reaction mixture was degassed three times using an evacuation-refill cycle as an inert gas. The reaction vessel was sealed with paraffin film and the reaction mixture was irradiated with a blue LED (34 W, 456 nm) at room temperature in a fan-cooled room for 24 hours. The reaction mixture was distributed 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, preparation method A (gradient: 5%-55%) to give the title compound (3.0 mg, 21%); HRMS (ESI) m / z[M+H]+C 21 H 23 N 4 O 3 Calculated value: 379.1764, measured value: 379.1772; 1 H NMR (500MHz, CD 3 OD)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),3.7 9(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).

[1119] Example 35: N-(2-((1S,3S,5S)-3-cyano-2-azabicyclo[3.1.0]hex-2-yl)-2-oxoethyl 6-(cyclopropylmethoxy)quinoline-4-carboxamide

[1120]

[1121] Stock solution A was prepared by mixing NiCl 2 DME (14 mg, 63 μmol) and dtbbpy (17 mg, 63 μmol) were prepared by dissolving in MeCN (2.5 mL). Stock solution B was prepared by dissolving quinuclidine (14 mg, 0.13 mmol) in MeCN (2 mL). Stock solution B (0.2 mL) and stock solution A (0.25 mL) were added to 6-bromo-N-(2-((1S,3S,5S)-3-cyano-2-azabicyclo[3.1.0]hex-2-yl)-2-oxoethyl)quinoline-4-carboxamide Example 1 (50 mg, 0.13 mmol), Ir[dF(CF 3 )ppy] 2 (dtbbpy)PF 6 (7.0 mg, 6.3 μmol) and K 2 CO 3 (17 mg, 0.13 mmol) and N 2 (g) Atmosphere. Cyclopropyl-methanol (15 μL, 0.19 mmol) was added and the reaction vessel was capped and heated to 40 ℃ under N 2 (g) The reaction mixture was degassed three times using an evacuation-refill cycle as an inert gas. The reaction vessel was sealed with paraffin film and the reaction mixture was irradiated with a blue LED (34 W, 456 nm) at room temperature in a fan-cooled room 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, Preparation Method S (gradient: 5%-90%) to give the title compound (7 mg, 14%); HRMS (ESI) m / z[M+H] + C 22 H 23 N 4 O 3 Calculated value: 391.1764, measured value: 391.1772; 1 H NMR (600 MHz, DMSO-d 6)δ9.07(t,1H),8.80(d,1H),7.98(d,1H),7.86(d,1H),7.48(d,1H),7.47(dd,1 H),5.14(dd,1H),4.54(dd,1H),4.23(dd,1H),4.03(dd,1H),3.96(dd,1H),3.8 6(td,1H),2.65–2.57(m,1H),2.26(dd,1H),1.94–1.86(m,1H),1.34–1.25(m,1 H),1.04–0.95(m,1H),0.82–0.77(m,1H),0.63–0.55(m,2H),0.45–0.36(m,2H).

[1122] Example 36: N-(2-((1S,3S,5S)-3-cyano-2-azabicyclo[3.1.0]hex-2-yl)-2-oxoethyl 1-(trifluoromethyl)cyclopropyl)quinoline-4-carboxamide

[1123]

[1124] At 25°C, (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), and the mixture was stirred at 40°C for 2 hours. The reaction mixture was concentrated in vacuo and the residue was purified by preparative HPLC, Preparative Method F (gradient: 22%-37%) to give the title compound (19 mg, 16%); HRMS (ESI) m / z [M+H] + C 22 H 20 F 3 N 4 O 2 Calculated value: 429.1532, measured value: 429.1544; 1 H NMR (400MHz, CD 3OD)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(td,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).

[1125] Example 37: N-(2-((1S,3S,5S)-3-cyano-2-azabicyclo[3.1.0]hex-2-yl)-2-oxoethyl 4-(2-(2-(4 ...nitrophenyl)quinoline)-4-carboxamide)

[1126]

[1127] The pre-catalyst solution was prepared as follows. NiCl 2 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 quenched with N 2 (g) Purge. DME (2 mL) was added and the solution was stirred for 5 minutes. 3 Si) 3 SiH (93 mg, 0.38 mmol) and Na 2 CO 3 (60 mg, 0.56 mmol) was added to 7-bromo-N-(2-((1S,3S,5S)-3-cyano-2-azabicyclo[3.1.0]hex-2-yl)-2-oxoethyl)-quinoline-4-carboxamide (150 mg, 0.38 mmol) Example 3 (150 mg, 0.38 mmol), [Ir{dF(CF 3 )ppy} 2 (dtbbpy)]PF 6 (4.2 mg, 3.8 μmol) and bromocyclopropane (91 mg, 0.75 mmol) in DME (1 mL). The precatalyst solution (1 mL, 0.5 mol% catalyst, 2.5 μmol) was injected into the reaction mixture and the mixture was heated to 40 ℃ for 2 h. 2 (g) The solution was degassed by bubbling while stirring for 10 minutes. The reaction mixture was sealed with parafilm, stirred and cooled with a fan at 25°C and irradiated with a 34W blue LED for 16 hours. The reaction mixture was diluted with EtOAc (30 mL) and washed with saturated NaHCO 3 (aqueous solution), saturated NaCl (aqueous solution) and water. The organic layer was washed with Na 2 SO4 Dry, filter and concentrate under reduced pressure. The residue was purified by preparative HPLC, preparation method B (gradient: 13%-23%) to give the title compound (8 mg, 6%); HRMS (ESI) m / z [M+H] + C 21 H 21 N 4 O 2 Calculated value: 361.1658, measured value: 361.1660; 1 H NMR (400 MHz, DMSO-d 6 )δ9.09(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, overlapped 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).

[1128] Example 38: N-(2-((1S,3S,5S)-3-cyano-2-azabicyclo[3.1.0]hex-2-yl)-2-oxoethyl 4-((4,4-difluorocyclohexyl)oxy)quinolinecarboxamide

[1129]

[1130] Stock solution A was prepared by mixing NiCl 2 DME (5.5 mg, 25 μmol) and dtbbpy (6.7 mg, 25 μmol) were prepared by dissolving 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 6-bromo-N-(2-((1S,3S,5S)-3-cyano-2-azabicyclo[3.1.0]hex-2-yl)-2-oxoethyl)quinoline-4-carboxamide Example 1 (0.020 g, 0.05 mmol), Ir[dF(CF 3 )ppy] 2 (dtbbpy)PF 6 (2.8 mg, 2.5 μmol) and K 2 CO 3 (28 mg, 0.20 mmol) and N 2 (g) Atmosphere. 4,4-difluorocyclohexan-1-ol (20 mg, 0.15 mmol) was added and the reaction vessel was capped and heated to 40 ℃ under N 2(g) The reaction mixture was degassed three times using an evacuation-refill cycle as an inert gas. The reaction vessel was sealed with paraffin film and the reaction mixture was irradiated with a blue LED (34 W, 456 nm) at room temperature in a fan-cooled room 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 preparativ...

Claims

1. A compound or a pharmaceutically acceptable salt thereof, wherein the compound has the structure of formula (I): in: R 2 is selected from hydrogen, halogen and methyl; R 3 is hydrogen or halogen; R 5 is selected from hydrogen, hydroxy, halogen, methyl and methoxy; R 6 and R 7 One of them is hydrogen, and R 6 and R 7 The other one is selected from: (a) halogen; (b)C 1-6 -alkyl, wherein the C 1-6 -alkyl is optionally substituted by one or more independently selected from halogen, hydroxy, C 1-6 -alkoxy, halo-C 1-6 -alkoxy, C 3-6 -Cycloalkyl and C 3-6 - Substitution of cycloalkoxy groups; (c) cyclopropyl, wherein the cyclopropyl is optionally substituted by one or more independently selected from cyano, fluoro, C 1-6 -alkyl, halo-C 1-6 -alkyl and C 1-6 - Substitution of alkoxy groups; (d)C 1-6 -alkoxy, wherein the C 1-6 - alkoxy is optionally substituted with one or more substituents independently selected from halogen and cyclopropyl; and (e)C 3-6 -cycloalkoxy, wherein the C 3-6 -cycloalkoxy is optionally substituted by one or more independently selected from halogen and C 1-3 - substituted with a substituent of the alkyl group; and R 8 is selected from hydrogen, halogen and methyl.

2. The compound according to claim 1 or a pharmaceutically acceptable salt thereof, wherein the compound has the structure of formula (II-A): And R 6 and R 7 As defined in claim 1.

3. The compound according to claim 1 or a pharmaceutically acceptable salt thereof, wherein the compound has a structure of formula (III-A): And R 6 and R 7 As defined in claim 1.

4. The compound according to any one of claims 1 to 3 or a pharmaceutically acceptable salt thereof, wherein R 6 and R 7 One of them is hydrogen and the other is halogen.

5. The compound according to any one of claims 1 to 3 or a pharmaceutically acceptable salt thereof, wherein R 6 and R 7 One of them is hydrogen and the other is C 1-6 -alkyl, wherein the C 1-6 -alkyl is optionally substituted by one or more independently selected from halogen, hydroxy, C 1-6 -alkoxy, halo-C 1-6 -alkoxy, C 3-6 -Cycloalkyl and C 3-6 -cycloalkyloxy is substituted with a substituent.

6. The compound according to any one of claims 1 to 3 or a pharmaceutically acceptable salt thereof, wherein R 6 and R 7 One of them is hydrogen and the other is selected from methyl, ethyl, fluoromethyl, difluoromethyl, trifluoromethyl, fluoropropyl, hydroxyethyl, hydroxypropyl, methoxyethyl, methoxypropyl, trifluoromethoxymethyl and trifluoromethoxyethyl.

7. A compound according to any one of claims 1 to 3 or a pharmaceutically acceptable salt thereof, wherein R 6 and R 7 One of them is hydrogen and the other is methyl.

8. A compound according to any one of claims 1 to 3 or a pharmaceutically acceptable salt thereof, wherein R 6 and R 7 One of them is hydrogen and the other is cyclopropyl, wherein the cyclopropyl is optionally substituted by one or more independently selected from cyano, fluoro, C 1-6 -alkyl, halo-C 1-6 -alkyl and C 1-6 -substituted by a substituent of the alkoxy group.

9. The compound according to any one of claims 1 to 3 or a pharmaceutically acceptable salt thereof, wherein R 6 and R 7 One of the is hydrogen and the other is cyclopropyl, wherein the cyclopropyl is optionally substituted with one or more substituents independently selected from cyano, methyl, trifluoromethyl and ethoxy.

10. The compound according to any one of claims 1 to 3 or a pharmaceutically acceptable salt thereof, wherein R 6 and R 7 One of them is hydrogen and the other is C 1-6 -alkoxy, wherein the C 1-6 -alkoxy is optionally substituted with one or more substituents independently selected from halogen and cyclopropyl.

11. A compound according to any one of claims 1 to 3 or a pharmaceutically acceptable salt thereof, wherein R 6 and R 7 One of the groups is hydrogen, and the other is selected from methoxy, propoxy, trifluoroethoxy and cyclopropylmethoxy.

12. A compound according to any one of claims 1 to 3 or a pharmaceutically acceptable salt thereof, wherein R 6 and R 7 One of them is hydrogen and the other is C 3-6 -cycloalkoxy, wherein the C 3-6 -Cycloalkoxy is optionally substituted by one or more halogens.

13. The compound according to any one of claims 1 to 3 or a pharmaceutically acceptable salt thereof, wherein: R 6 and R 7 One of them is hydrogen, and R 6 and R 7 The other one is selected from: (a) halogen; (b)C 1-6 -alkyl, wherein the C 1-6 -alkyl is optionally substituted by one or more independently selected from halogen, hydroxy, C 1-6 -alkoxy, halo-C 1-6 -alkoxy, C 3-6 -Cycloalkyl and C 3-6 - substitution of the cycloalkoxy group with a substituent; and (c) cyclopropyl, wherein the cyclopropyl is optionally substituted by one or more independently selected from cyano, fluoro, C 1-6 -alkyl, halo-C 1-6 -alkyl and C 1-6 -substituted by a substituent of the alkoxy group.

14. A compound according to any one of claims 1 to 3 or a pharmaceutically acceptable salt thereof, Where R 6 and R 7 One of them is hydrogen, and R 6 and R 7 The other one is selected from: (a) Chlorine, fluorine, bromine and iodine; (b)C 1-3 -alkyl, wherein the C 1-3 -alkyl is optionally substituted by one or more independently selected from halogen, hydroxy, C 1-3 -alkoxy and halo-C 1-3 - substitution of the alkoxy group with a substituent; and (c) cyclopropyl, wherein the cyclopropyl is optionally substituted by one or more independently selected from cyano, C 1-3 -alkyl, halo-C 1-3 -alkyl and C 1-3 -substituted by a substituent of the alkoxy group.

15. A compound according to any one of claims 1 to 3 or a pharmaceutically acceptable salt thereof, Where R 6 and R 7 One of them is hydrogen, and R 6 and R 7 The other one is selected from: (a) Chlorine and fluorine; (b)C 1-3 -alkyl, wherein the C 1-3 - alkyl is optionally substituted with one or more substituents independently selected from halogen, hydroxy, methoxy and halomethoxy; and (c) cyclopropyl, wherein the cyclopropyl is optionally substituted with one or more substituents independently selected from cyano, methyl, trifluoromethyl and ethoxy.

16. A compound according to any one of claims 1 to 3 or a pharmaceutically acceptable salt thereof, Where R 6 and R 7 One of them is hydrogen, and R 6 and R 7 The other one is selected from: (a) Chlorine and fluorine; (b)C 1-3 -alkyl, wherein the C 1-3 -alkyl is optionally substituted with one or more substituents independently selected from methyl, ethyl, propyl, fluoromethyl, difluoromethyl, trifluoromethyl, fluoropropyl, hydroxyethyl, hydroxypropyl, methoxyethyl, methoxypropyl, trifluoromethoxymethyl and trifluoromethoxyethyl; and (c) cyclopropyl, wherein the cyclopropyl is optionally substituted with one or more substituents independently selected from cyano, methyl, trifluoromethyl and ethoxy.

17. A compound according to any one of claims 1 to 16 or a pharmaceutically acceptable salt thereof, wherein R 6 For hydrogen.

18. A compound according to any one of claims 1 to 16 or a pharmaceutically acceptable salt thereof, wherein R 7 For hydrogen.

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

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

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

22. The compound according to claim 1 or a pharmaceutically acceptable salt thereof, wherein the compound is selected from: N-(2-((1S,3S,5S)-3-cyano-2-azabicyclo[3.1.0]hex-2-yl)-2-oxoethyl)-6-(2,2,2-trifluoroethoxy)quinoline-4-carboxamide; N-(2-((1S,3S,5S)-3-cyano-2-azabicyclo[3.1.0]hexan-2-yl)-2-oxoethyl)-6-isopropoxyquinoline-4-carboxamide; and N-(2-((1S,3S,5S)-3-cyano-2-azabicyclo[3.1.0]hex-2-yl)-2-oxoethyl)-6-(cyclopropylmethoxy)quinoline-4-carboxamide.

23. The compound according to claim 1 or a pharmaceutically acceptable salt thereof, wherein the compound is N-(2-((1S,3S,5S)-3-cyano-2-azabicyclo[3.1.0]hex-2-yl)-2-oxoethyl)-7-methoxy-2-methylquinoline-4-carboxamide.

24. The compound according to claim 1 or a pharmaceutically acceptable salt thereof, wherein the compound is selected from: N-(2-((1S,3S,5S)-3-cyano-2-azabicyclo[3.1.0]hexan-2-yl)-2-oxoethyl)-6-cyclopropyloxyquinoline-4-carboxamide; and N-(2-((1S,3S,5S)-3-cyano-2-azabicyclo[3.1.0]hex-2-yl)-2-oxoethyl)-6-((4,4-difluorocyclohexyl)oxy)quinoline-4-carboxamide.

25. The compound according to claim 1 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.

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. Use of a compound according to any one of claims 1 to 25, or a pharmaceutically acceptable salt thereof, for the preparation of a medicament for the treatment or prevention of a FAP-mediated disorder.

Images