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

Abstract

The present disclosure provides compounds having the structure of Formula (I) and pharmaceutically acceptable salts thereof, wherein X1, R1, R2, R3, R4, R5 and R6 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; kits comprising such compounds and salts; and processes for preparing such compounds and salts. # imgabs0 #

Description

[0001] Cross-referencing of related patent applications

[0002] This specification claims priority to U.S. Provisional Patent Application No. 63 / 366,699 (filed June 21, 2022). The entire text of the aforementioned patent application is incorporated herein by reference. Technical Field

[0003] This disclosure generally relates to N-(2-(4-cyanothiazolidine-3-yl)-2-oxoethyl)-quinoline-4-carboxamide and pharmaceutically acceptable salts thereof. This specification also relates to 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 conditions; kits comprising such compounds and salts; and methods for preparing such compounds and salts. Background Technology

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

[0005] FAP shares a common cleavage motif following Gly-Pro and exhibits both endopeptidase and exopeptidase activities. Known enzymatic activities include cleavage of collagen (Hepatology 1999, 29, 1768), α2-antifibrinolytic enzyme (α2AP) (Blood 2004 103, 3783), and fibroblast growth factor 21 (FGF21) (Biochem J 2016, 473, 605). FAP activity (including collagen cleavage) at the cell surface of activated fibroblasts creates a pro-fibrotic environment. FAP cleavage of α2AP allows α2AP to crosslink more effectively to fibrin, leading to reduced fibrin clearance. FAP cleavage of FGF21 inactivates FGF21 metabolism (Biochem J 2016, 473, 605). All these activities are associated with the worsening of NASH disease, and inhibiting FAP has the potential to treat NASH and other conditions by influencing multiple mechanisms.

[0006] Inhibition of FAP activity is a currently undeveloped treatment for NASH and other conditions associated with this activity. There are currently no approved pharmacological agents that can universally or specifically inhibit FAP activity. Therefore, there is a need for FAP inhibitors, particularly FAP inhibitors with appropriate pharmacological selectivity and bioavailability, and thus suitable for administration to subjects requiring such treatment. This disclosure addresses this significant unmet need by providing such compounds, along with corresponding pharmaceutical compositions and methods for treating or preventing NASH and related conditions. Summary of the Invention

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

[0008]

[0009] Or its pharmaceutically acceptable salt, wherein:

[0010] X 1 Choose from the following groups: -S-, -S(O)-, and -S(O)2-;

[0011] R 1 Choose from the following groups: hydrogen, halogen, hydroxyl, C 1-3 -alkyl and C 1-6 -alkoxy group;

[0012] R 2 Choose from the following groups:

[0013] (a)C 1-6 -alkyl, wherein the C 1-6 -The alkyl group is optionally substituted with one or more substituents, which are independently selected from the group consisting of: halogen, hydroxyl, cyano, C 3-6 -Cycloalkyl, halogenated-C 3-6 -cycloalkyl, C 1-6 -alkoxy, halogenated-C 1-6 -alkoxy group, C 3-6 -cycloalkoxy, halogenated-C 3-6 -cycloalkoxy, C 1-6 -alkoxy-C 1-6 -alkoxy, oxetane, tetrahydrofuranyl, tetrahydrofuranyloxy, tetrahydropyranyl, morpholinyl, pyrazolyl, iso Azolyl, triazolyl, and pyridyl; wherein the oxetane is butyl, tetrahydrofuranyl, tetrahydrofuranyloxy, tetrahydropyranyl, morpholinyl, pyrazolyl, or iso The azole, triazole, and pyridyl groups may optionally be substituted by one or more substituents, which are independently selected from the group consisting of: halogen, cyano, C. 1-6 -alkyl and halogenated-C 1-6 -alkyl;

[0014] (b)C 3-6 -cycloalkyl, wherein the C 3-6 -The cycloalkyl group is optionally substituted by one or more substituents, which are independently selected from the group consisting of: halogen, hydroxyl, cyano, C 1-6 -alkyl, halo-C 1-6 -alkyl, C 1-6 -alkoxy, halogenated-C 1-6 -alkoxy, isoalkoxy azole group and pyridinyl group; wherein the isopropyl group The azole and pyridyl groups are optionally substituted by one or more substituents, which are independently selected from the group consisting of halogens, C... 1-6 -alkyl and halogenated-C 1-6 -alkyl;

[0015] (c) Phenyl, wherein the phenyl group is optionally substituted with one or more substituents, the one or more substituents being independently selected from the group consisting of: halogen, cyano, C 1-6 -alkyl, halo-C 1-6 -alkyl, C 1-6 -alkoxy, halogenated-C 1-6 -alkoxy and C 1-6 -alkoxy-C 1-6 -alkoxy group; and

[0016] (d) A 4-, 5-, 6-, or 7-membered heterocyclic group, wherein the heterocyclic ring: (i) is a saturated, partially saturated, or fully unsaturated monocyclic or fused bicyclic ring, (ii) has one or two oxygen ring atoms and the remaining ring atoms are carbon, and (iii) is optionally substituted by one or more substituents, which are independently selected from the group consisting of: halogen, hydroxyl, cyano, C 1-6 -alkyl, halo-C 1-6 -alkyl, C 2-6 -Alynyl group, C 1-6 -alkoxy and halogenated-C 1-6 -alkoxy group; and

[0017] (e)-OR 7 , where R 7 Choose from the following groups: C 1-6 -alkyl, phenyl and tetrahydropyranyl; wherein:

[0018] (i) The C 1-6 -The alkyl group is optionally substituted with one or more substituents, which are independently selected from the group consisting of: halogen, cyano, C 3-6 -Cycloalkyl, halogenated-C 3-6 -cycloalkyl, C 1-6 -alkoxy and halogenated-C 1-6 -alkoxy group;

[0019] (ii) The phenyl group is optionally substituted with one or more substituents, which are independently selected from the group consisting of: halogens, C 1-6 -alkyl, halo-C 1-6 -alkyl, C 1-6 -alkoxy and halogenated-C 1-6 -alkoxy group; and

[0020] (iii) The tetrahydropyranyl group is optionally substituted with one or more substituents, which are independently selected from the group consisting of: halogens, C 1-6 -alkyl, halo-C 1-6 -alkyl, C 1-6 -alkoxy and halogenated-C 1-6 -alkoxy group;

[0021] R 3 Choose from the following groups: hydrogen, halogens, and carbon. 1-3 -alkyl;

[0022] R 4 Choose from the following groups: hydrogen, halogens, and carbon. 1-3 -alkyl;

[0023] R 5 Choose from the following groups: hydrogen, halogens, and carbon. 1-3 -alkyl; and

[0024] R 6 Choose from the following groups: hydrogen, halogens, and carbon. 1-3 -alkyl.

[0025] In another aspect, this disclosure provides compounds having structures of formula (II), (III-A), (III-B), (III-C), (III-D), (III-E), (IV) or (IV-A) as further defined herein, and pharmaceutically acceptable salts thereof.

[0026] In another aspect, this disclosure provides pharmaceutical compositions comprising a therapeutically effective amount of a compound having a structure of formula (I), (II), (III-A), (III-B), (III-C), (III-D), (III-E), (IV), or (IV-A) as further defined herein, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.

[0027] In another aspect, this disclosure provides pharmaceutical compositions comprising a therapeutically effective amount of a compound having a structure of formula (I), (II), (III-A), (III-B), (III-C), (III-D), (III-E), (IV), or (IV-A) as further defined herein, or a pharmaceutically acceptable salt thereof; a second pharmacological agent; and a pharmaceutically acceptable carrier.

[0028] In another aspect, this disclosure provides a method for treating or preventing FAP-mediated conditions by administering to a subject in need a therapeutically effective amount of a compound having a structure of formula (I), (II), (III-A), (III-B), (III-C), (III-D), (III-E), (IV), or (IV-A) as further defined herein. In one aspect, FAP-mediated conditions are selected from the group consisting of: liver disease, type 2 diabetes, cardiovascular disease, obesity, obesity-related conditions, fibrosis, keloid disorders, inflammation, and cancer. In another aspect, FAP-mediated conditions are liver diseases, particularly non-alcoholic steatohepatitis (NASH).

[0029] In another aspect, this disclosure provides compounds having structures of formula (I), (II), (III-A), (III-B), (III-C), (III-D), (III-E), (IV) or (IV-A) as further defined herein, for use as medicaments for treating or preventing FAP-mediated conditions.

[0030] In another aspect, this disclosure provides the use of compounds having structures of formula (I), (II), (III-A), (III-B), (III-C), (III-D), (III-E), (IV), or (IV-A) as further defined herein, or pharmaceutically acceptable salts thereof, for the preparation of medicaments for the treatment or prevention of FAP-mediated conditions.

[0031] In another aspect, this disclosure provides kits comprising compounds having a structure of formula (I), (II), (III-A), (III-B), (III-C), (III-D), (III-E), (IV), or (IV-A) as further defined herein, or pharmaceutically acceptable salts thereof.

[0032] In another aspect, this disclosure provides methods for preparing compounds having structures of formula (I), (II), (III-A), (III-B), (III-C), (III-D), (III-E), (IV), or (IV-A) as further defined herein, or pharmaceutically acceptable salts thereof. Detailed Implementation

[0033] Numerous embodiments are described in detail throughout this specification, and these embodiments will be apparent to those skilled in the art. This specification should not be construed as limiting oneself to any particular embodiment described herein.

[0034] I. Definition

[0035] Regarding the embodiments disclosed in this specification, the following terms have the meanings described below:

[0036] The reference to “a” or “an” means “one or more” or “one or more types of”. Throughout the text, the plural and singular forms should be considered interchangeable, except for indications of quantity.

[0037] Unless the context otherwise requires, the words “comprising,” “including,” or “containing” are used on the basis and clearly understood that they will be interpreted as inclusive rather than exclusive, and that the applicant intends each of these words to be interpreted in the interpretation of this patent (including the claims below).

[0038] The term "halogen" (alone or in combination with other terms) refers to a fluorine radical (which can be described as -F), a chlorine radical (which can be described as -Cl), a bromine radical (which can be described as -Br), or an iodine radical (which can be described as -I).

[0039] The term "hydroxyl" (alone or in combination with other terms) refers to -OH.

[0040] The term "cyano" (alone or in combination with other terms) refers to -CN.

[0041] The term "alkyl" (alone or in combination with other terms) refers to a straight-chain or branched 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, isopentyl, and 2,2-dimethylpropyl), and hexyl.

[0042] The term "cycloalkyl" (alone or in combination with other terms) refers to a saturated carbocyclic substituent containing 3 to 14 carbon ring atoms, more typically 3 to 12 carbon ring atoms, and even more typically 3 to 8 carbon ring atoms. Cycloalkyl groups include a single carbon ring, typically containing 3 to 6 carbon ring atoms. Examples of monocyclic cycloalkyl groups include cyclopropyl, cyclobutyl, cyclopentyl, and cyclohexyl.

[0043] The term "alkoxy" (alone or in combination with other terms) refers to an alkyl ether substituent, i.e., alkyl-O-. Examples of alkoxy groups include methoxy (CH3-O-), ethoxy, n-propoxy, isopropoxy, n-butoxy, isobutoxy, sec-butoxy, and tert-butoxy. Therefore, for example:

[0044] (i) The term “alkoxyalkyl” (alone or in combination with other terms) means an alkyl group substituted with an alkoxy group, such as “methoxymethyl”, which can be described as:

[0045]

[0046] (ii) The term “cycloalkylalkoxy” (alone or in combination with other terms) means an alkoxy group substituted with a cycloalkyl group, such as “cyclopropylmethoxy”, which can be described as:

[0047]

[0048] The term "cycloalkoxy" (alone or in combination with other terms) refers to a cycloalkyl ether substituent, i.e., cycloalkyl-O-. Examples of cycloalkoxy groups include cyclopropoxy, cyclobutoxy, cyclopentoxy, and cyclohexoxy. Therefore, for example, the term "alkylcycloalkoxy" (alone or in combination with other terms) refers to an alkyl-substituted cycloalkoxy group, such as "methylcyclopropoxy," which can be described as:

[0049]

[0050] In some cases, the number of carbon atoms in a substituent (e.g., alkyl, cycloalkyl, etc.) is indicated by the prefix "Cx–y-", where x is the minimum number of carbon atoms in the substituent and y is the maximum number of carbon atoms. Thus, for example, "C1–6-alkyl" refers to an alkyl substituent containing 1 to 6 carbon atoms. Further, C3–6-cycloalkyl refers to a cycloalkyl substituent containing 3 to 6 carbon ring atoms.

[0051] The prefix "halogenated" indicates that the substituent attached to the prefix is ​​replaced by one or more independently selected halogen radicals. For example, haloalkyl means an alkyl substituent in which at least one hydrogen radical is replaced by a halogen radical. In cases where more than one hydrogen is replaced by a halogen, the halogens can be the same or different. Examples of haloalkyl include fluoromethyl, difluoromethyl, trifluoromethyl, difluoroethyl, 1,1,1-trifluoroethyl, pentafluoroethyl, difluoropropyl, heptafluoropropyl, chloromethyl, dichloromethyl, trichloromethyl, difluorochloromethyl, dichlorofluoromethyl, and dichloropropyl. Similarly, "haloalkoxy" means an alkoxy substituent in which at least one hydrogen radical is replaced by a halogen radical. In cases where more than one hydrogen is replaced by a halogen, the halogens can be the same or different. Examples of haloalkoxy substituents include fluoromethoxy, difluoromethoxy, trifluoromethoxy (also known as "perfluoromethoxy"), 1,1,1-trifluoroethoxy, and chloromethoxy.

[0052] The term "heterocyclic group" (alone or in combination with other terms) refers to a saturated, partially saturated, and or fully unsaturated (i.e., "heteroaryl") ring structure containing a total of 3 to 14 ring atoms. At least one ring atom is a heteroatom (i.e., oxygen, nitrogen, or sulfur), and the remaining ring atoms are independently selected from the group consisting of carbon, oxygen, nitrogen, and sulfur. Heterocyclic groups include monocyclic saturated, partially unsaturated, and fully unsaturated ring structures having, for example, 4 to 7 members (such as 4 to 6 members, 5 to 7 members, or 5 or 6 members), wherein at least one and at most four members (particularly 1, 2, or 3 members) are heteroatoms selected from N, O, and S, and the remaining ring atoms are carbon atoms in a stable combination known to those skilled in the art. Heterocyclic groups also include fused bicyclic structures (i.e., fused bicycles) in which at least one such ring contains a heteroatom as a ring atom (i.e., nitrogen, oxygen, or sulfur).

[0053] A substituent is "substitutable" if it contains at least one carbon or nitrogen atom bonded to one or more hydrogen atoms. Therefore, hydrogen, halogens, and cyano groups, for example, do not fall into this definition.

[0054] If a substituent is described as “substituted,” then a non-hydrogen radical replaces a hydrogen radical on the carbon or nitrogen of the substituent. Thus, for example, a substituted alkyl substituent is an alkyl substituent in which at least one non-hydrogen radical replaces a hydrogen radical on the alkyl substituent. For example, a monofluoroalkyl group is an alkyl group substituted with one fluorine radical, and a difluoroalkyl group is an alkyl group substituted with two fluorine radicals. It should be recognized that if more than one substitution is present on the substituent, each non-hydrogen radical can be the same or different (unless otherwise stated).

[0055] If a substituent is described as “optionally substituted,” then the substituent may be (1) unsubstituted or (2) substituted. If the carbon of the substituent is described as being optionally substituted by one or more of a series of substituents, then one or more hydrogens on the carbon (in the presence of any hydrogens) may be substituted individually and / or together by independently selected optional substituents. If the nitrogen of the substituent is described as being optionally substituted by one or more of a series of substituents, then one or more hydrogens on the nitrogen (in the presence of any hydrogens) may each be substituted by independently selected optional substituents.

[0056] If a substituent is described as being “independently selected” from a set, then each substituent is selected independently of the others. Therefore, each substituent can be the same as or different from the other substituents.

[0057] The term "pharmaceutically acceptable" is used as an adjective in this specification, meaning that the noun it modifies is suitable for use as a pharmaceutical product or as part of a pharmaceutical product. For example, "pharmaceutically acceptable salt" is a salt suitable for mammals (especially humans), and includes salts suitable for mammals (especially humans) formed with inorganic bases, organic bases, inorganic acids, organic acids, or basic or acidic amino acids.

[0058] The "therapeutic effective amount" of a pharmacological agent is the amount sufficient to achieve a beneficial or desired outcome (including clinical outcomes), and therefore will depend on the circumstances under which it is administered. For example, in the case of a pharmacological agent being administered to treat liver disease, the therapeutic effective amount of the agent is the amount, alone or in combination with an adjunct therapy, sufficient to provide an anti-liver disease effect in a subject compared to the response obtained without the administration of the agent.

[0059] The term “prevention” is easily understood by a general practitioner and, in relation to the treatment of a particular condition, can include the intention to have its normal meaning, and includes primary prevention to prevent the development of the condition as well as secondary prevention where the condition has already developed and which temporarily or permanently protects the patient against the aggravation or worsening of the condition or the development of new symptoms associated with the condition.

[0060] The term "treatment" is easily understood by a general practitioner, and treatment of a specific condition can include (1) reducing the severity or cause of the condition being treated, and / or (2) alleviating or improving one or more symptoms associated with the condition. Treatment of liver disease, for example, can 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 wholly or partially improving or mitigating the severity of cancer or liver disease.

[0061] II.Compounds

[0062] A. Compounds of formula (I)

[0063] In one embodiment, this disclosure provides compounds having the structure of formula (I):

[0064]

[0065] Or its pharmaceutically acceptable salt, wherein:

[0066] X 1 Choose from the following groups: -S-, -S(O)-, and -S(O)2-;

[0067] R 1 Choose from the following groups: hydrogen, halogen, hydroxyl, C 1-3 -alkyl and C 1-6 -alkoxy group;

[0068] R 2 Choose from the following groups:

[0069] (a)C 1-6 -alkyl, wherein the C 1-6 -The alkyl group is optionally substituted with one or more substituents, which are independently selected from the group consisting of: halogen, hydroxyl, cyano, C 3-6 -Cycloalkyl, halogenated-C 3-6 -cycloalkyl, C 1-6 -alkoxy, halogenated-C 1-6 -alkoxy group, C 3-6 -cycloalkoxy, halogenated-C 3-6 -cycloalkoxy, C 1-6 -alkoxy-C 1-6 -alkoxy, oxetane, tetrahydrofuranyl, tetrahydrofuranyloxy, tetrahydropyranyl, morpholinyl, pyrazolyl, iso Azolyl, triazolyl, and pyridyl; wherein the oxetane is butyl, tetrahydrofuranyl, tetrahydrofuranyloxy, tetrahydropyranyl, morpholinyl, pyrazolyl, or iso The azole, triazole, and pyridyl groups may optionally be substituted by one or more substituents, which are independently selected from the group consisting of: halogen, cyano, C. 1-6 -alkyl and halogenated-C 1-6 -alkyl;

[0070] (b)C 3-6 -cycloalkyl, wherein the C 3-6 -The cycloalkyl group is optionally substituted by one or more substituents, which are independently selected from the group consisting of: halogen, hydroxyl, cyano, C 1-6 -alkyl, halo-C 1-6 -alkyl, C 1-6 -alkoxy, halogenated-C 1-6 -alkoxy, isoalkoxy azole group and pyridinyl group; wherein the iso The azole and pyridyl groups are optionally substituted by one or more substituents, which are independently selected from the group consisting of halogens, C... 1-6 -alkyl and halogenated-C 1-6 -alkyl;

[0071] (c) Phenyl, wherein the phenyl group is optionally substituted with one or more substituents, the one or more substituents being independently selected from the group consisting of: halogen, cyano, C 1-6 -alkyl, halo-C 1-6 -alkyl, C 1-6 -alkoxy, halogenated-C 1-6 -alkoxy and C 1-6 -alkoxy-C 1-6 -alkoxy group; and

[0072] (d) A 4-, 5-, 6-, or 7-membered heterocyclic group, wherein the heterocyclic ring: (i) is a saturated, partially saturated, or fully unsaturated monocyclic or fused bicyclic ring, (ii) has one or two oxygen ring atoms and the remaining ring atoms are carbon, and (iii) is optionally substituted by one or more substituents, which are independently selected from the group consisting of: halogen, hydroxyl, cyano, C 1-6 -alkyl, halo-C 1-6 -alkyl, C 2-6 -Alynyl group, C 1-6 -alkoxy and halogenated-C 1-6 -alkoxy group; and

[0073] (e)-OR 7 , where R 7 Choose from the following groups: C 1-6 -alkyl, phenyl and tetrahydropyranyl; wherein:

[0074] (i) The C 1-6 -The alkyl group is optionally substituted with one or more substituents, which are independently selected from the group consisting of: halogen, cyano, C 3-6 -Cycloalkyl, halogenated-C 3-6 -cycloalkyl, C 1-6 -alkoxy and halogenated-C 1-6 -alkoxy group;

[0075] (ii) The phenyl group is optionally substituted with one or more substituents, which are independently selected from the group consisting of: halogens, C 1-6 -alkyl, halo-C 1-6 -alkyl, C 1-6 -alkoxy and halogenated-C 1-6 -alkoxy group; and

[0076] (iii) The tetrahydropyranyl group is optionally substituted with one or more substituents, which are independently selected from the group consisting of: halogens, C 1-6 -alkyl, halo-C 1-6 -alkyl, C 1-6 -alkoxy and halogenated-C 1-6 -alkoxy group;

[0077] R 3 Choose from the following groups: hydrogen, halogens, and carbon. 1-3 -alkyl;

[0078] R 4 Choose from the following groups: hydrogen, halogens, and carbon. 1-3 -alkyl;

[0079] R 5 Choose from the following groups: hydrogen, halogens, and carbon. 1-3 -alkyl; and

[0080] R 6 Choose from the following groups: hydrogen, halogens, and carbon. 1-3 -alkyl.

[0081] In some embodiments, this disclosure provides compounds having the structure of formula (II):

[0082]

[0083] and its pharmaceutically acceptable salts, of which X 1 R 1 R 2 R 3 R 4 R 5 and R 6As defined above for compounds of formula (I). In one aspect, X 1 It's -S-. On the other hand, X 1 It is -S(O)-. In another aspect, X 1 It is -S(O)2-.

[0084] In some implementation schemes, R 1 Choose from the following groups: hydrogen, halogens, and carbon. 1-3 -alkyl. In one respect, R 1 Choose from the following groups: hydrogen, chlorine, fluorine, and methyl. In another aspect, R... 1 It's hydrogen. In another respect, R... 1 It's chlorine. On the other hand, R 1 It's fluorine. In another respect, R... 1 It is a methyl group.

[0085] In some implementation schemes, R 3 Choose from the following groups: hydrogen, chlorine, fluorine, and methyl. In one respect, R 3 It's hydrogen. In another respect, R... 3 It's chlorine. On the other hand, R 3 It's fluorine. In another respect, R... 3 It is a methyl group.

[0086] In some implementation schemes, R 4 Choose from the following groups: hydrogen, halogens, and methyl groups. In one aspect, R... 4 It's hydrogen. In another respect, R... 4 It's chlorine. On the other hand, R 4 It's fluorine. In another respect, R... 4 It is a methyl group.

[0087] In some implementation schemes, R 5 Choose from the following groups: hydrogen, chlorine, fluorine, and methyl. In one respect, R 5 It's hydrogen. In another respect, R... 5 It's fluorine. In another respect, R... 5 It's chlorine. On the other hand, R 5 It is a methyl group.

[0088] In some implementation schemes, R 6 Choose from the following groups: hydrogen, chlorine, fluorine, and methyl. In one respect, R 6 It's hydrogen. In another respect, R... 6 It's chlorine. On the other hand, R 6 It's fluorine. In another respect, R... 6 It is a methyl group.

[0089] In some implementation schemes, R 1 R 3 R 4 R 5 and R 6 One of the substituents is selected from the group consisting of: halogens and C. 1-3 -alkyl, and the remaining R 1 R 3 R 4 R 5 and R 6 All substituents are hydrogen. In one respect, R 1 R 3 R 4 R 5 and R 6 One of the substituents is selected from the group consisting of chlorine, fluorine, and methyl, and the remaining R... 1 R 3 R 4 R 5 and R 6 All substituents are hydrogen. In another aspect, R... 1 R 3 R 4 R 5 and R 6 One of the substituents is selected from the group consisting of chlorine and fluorine, and the remaining R... 1 R 3 R 4 R 5 and R 6 All substituents are hydrogen. In another aspect, R... 1 R 3 R 4 R 5 and R 6 One of the substituents is methyl, and the remaining R 1 R 3 R 4 R 5 and R 6 All the substituents are hydrogen.

[0090] In some implementation schemes, R 1 R 3 R 4 R 5 and R 6 At least two of the substituents are independently selected from the group consisting of halogens and C. 1-3 -alkyl, and the remaining R 1 R 3 R 4 R 5 and R6 All the substituents are hydrogen.

[0091] In some implementation schemes, R 1 R 3 R 4 R 5 and R 6 The two substituents in the substituents are independently selected from the group consisting of chlorine, fluorine, and methyl, and the remaining R... 1 R 3 R 4 R 5 and R 6 All the substituents are hydrogen.

[0092] In some implementation schemes, R 1 R 3 R 4 R 5 and R 6 At least one of the substituents is chlorine.

[0093] In some implementation schemes, R 1 R 3 R 4 R 5 and R 6 At least one of the substituents is fluorine.

[0094] In some implementation schemes, R 1 R 3 R 4 R 5 and R 6 At least one of the substituents is methyl.

[0095] In some implementation schemes, R 1 R 3 R 4 R 5 and R 6 The substituent is hydrogen, and X 1 Choose from the following groups: -S-, -S(O)-, and -S(O)2-.

[0096] In some embodiments, this disclosure provides compounds having the structure of formula (III-A):

[0097]

[0098] and its pharmaceutically acceptable salts, of which R 1 and R 2 As defined in the various implementation schemes described above.

[0099] In some embodiments, this disclosure provides compounds having the structure of formula (III-B):

[0100]

[0101] and its pharmaceutically acceptable salts, of which R 2 and R 3 As defined in the various implementation schemes described above.

[0102] In some embodiments, this disclosure provides compounds having the structure of formula (III-C):

[0103]

[0104] and its pharmaceutically acceptable salts, of which R 2 and R 4 As defined in the various implementation schemes described above.

[0105] In some embodiments, this disclosure provides compounds having the structure of formula (III-D):

[0106]

[0107] and its pharmaceutically acceptable salts, of which R 2 and R 5 As defined in the various implementation schemes described above.

[0108] In some embodiments, this disclosure provides compounds having the structure of formula (III-E):

[0109]

[0110] and its pharmaceutically acceptable salts, of which R 2 and R 6 As defined in the various implementation schemes described above.

[0111] In some embodiments, this disclosure provides compounds having the structure of formula (IV):

[0112]

[0113] and its pharmaceutically acceptable salts, of which R 2 As defined in the various implementation schemes described above.

[0114] In some embodiments, this disclosure provides compounds having the structure of formula (IV-A):

[0115]

[0116] and its pharmaceutically acceptable salts, of which R 2 As defined in the various implementation schemes described above.

[0117] BR 2 It is C 1-6 -alkyl

[0118] In some embodiments, this disclosure provides compounds having the structure of formula (I), (II), (III-A), (III-B), (III-C), (III-D), (III-E), (IV), or (IV-A), or pharmaceutically acceptable salts thereof, wherein R 2 It is C 1-6 -alkyl, wherein the C 1-6 -The alkyl group is optionally substituted with one or more substituents, which are independently selected from the group consisting of: halogen, hydroxyl, cyano, C 3-6 -Cycloalkyl, halogenated-C 3-6 -cycloalkyl, C 1-6 -alkoxy, halogenated-C 1-6 -alkoxy group, C 3-6 -cycloalkoxy, halogenated-C 3-6 -cycloalkoxy, C 1-6 -alkoxy-C 1-6 -alkoxy, oxetane, tetrahydrofuranyl, tetrahydrofuranyloxy, tetrahydropyranyl, morpholinyl, pyrazolyl, iso Azolyl, triazolyl, and pyridyl; wherein the oxetane is butyl, tetrahydrofuranyl, tetrahydrofuranyloxy, tetrahydropyranyl, morpholinyl, pyrazolyl, or iso The azole, triazole, and pyridyl groups are optionally substituted by one or more substituents, which are independently selected from the group consisting of halogens, C... 1-6 -alkyl and halogenated-C 1-6 -alkyl. In one respect, R 2 It is C 1-3 -alkyl, wherein the C 1-3 -The alkyl group is optionally substituted with one or more substituents, which are independently selected from the group consisting of: halogen, hydroxyl, cyano, C 3-6 -Cycloalkyl, halogenated-C 3-6 -cycloalkyl, C 1-3 -alkoxy, halogenated-C 1-3 -alkoxy group, C 3-6 -cycloalkoxy, halogenated-C 3-6 -cycloalkoxy, C 1-3 -alkoxy-C 1-3 -alkoxy, oxetane, tetrahydrofuranyl, tetrahydrofuranyloxy, tetrahydropyranyl, morpholinyl, pyrazolyl, iso Azolyl, triazolyl, and pyridyl; wherein the oxetane is butyl, tetrahydrofuranyl, tetrahydrofuranyloxy, tetrahydropyranyl, morpholinyl, pyrazolyl, or iso The azole, triazole, and pyridyl groups are optionally substituted by one or more substituents, which are independently selected from the group consisting of halogens, C... 1-3 -alkyl and halogenated-C 1-3 -alkyl. In another respect, R 2 It is C 1-6 -alkyl, wherein the C 1-6 -The alkyl group is optionally substituted with one or more substituents, which are independently selected from the group consisting of: halogens, hydroxyl groups, C... 1-6 -alkoxy, halogenated-C 1-6 -alkoxy group, C 3-6 -cycloalkoxy, C 1-6 -alkoxy-C 1-6 -alkoxy, tetrahydrofuranyl, tetrahydrofuranyloxy, tetrahydropyranyl, morpholinyl, pyrazolyl, iso Azolyl, triazolyl, and pyridyl; wherein the tetrahydrofuranyl, tetrahydrofuranyloxy, tetrahydropyranyl, morpholinyl, pyrazolyl, iso The azole, triazole, and pyridyl groups are optionally substituted by one or more substituents, which are independently selected from the group consisting of halogens, C... 1-6 -alkyl and halogenated-C 1-6 -alkyl. In another respect, R 2 It is C 1-3 -alkyl, wherein the C 1-3 -The alkyl group is optionally substituted with one or more substituents, which are independently selected from the group consisting of: halogens, hydroxyl groups, C... 1-3 -alkoxy, halogenated-C 1-3 -alkoxy group, C 3-6 -cycloalkoxy, C 1-3 -alkoxy-C 1-3 -alkoxy, tetrahydrofuranyl, tetrahydrofuranyloxy, tetrahydropyranyl, morpholinyl, pyrazolyl, iso Azolyl, triazolyl, and pyridyl; wherein the tetrahydrofuranyl, tetrahydrofuranyloxy, tetrahydropyranyl, morpholinyl, pyrazolyl, iso The azole, triazole, and pyridyl groups are optionally substituted by one or more substituents, which are independently selected from the group consisting of halogens, C... 1-3 -alkyl and halogenated-C 1-6 -alkyl.

[0119] In some implementation schemes, R 2 It is C 1-6-alkyl. In one respect, R 2 It is C 1-3 -alkyl. In one respect, R 2 It is a methyl group.

[0120] In some implementation schemes, R 2 It is C 1-6 -alkyl, wherein the C 1-6 -The alkyl group is optionally substituted with one or more halogens. In one aspect, R 2 It is C 1-6 -alkyl, wherein the C 1-6 -The alkyl group is optionally substituted with one or more fluorine molecules.

[0121] In some implementation schemes, R 2 It is C 1-6 -alkyl, wherein the C 1-6 -The alkyl group is optionally replaced by one or more hydroxyl groups.

[0122] In some implementation schemes, R 2 It is C 1-6 -alkyl, wherein the C 1-6 -Alkyl groups are optionally separated by one or more C groups. 1-6 -Alkyl substitution.

[0123] In some implementation schemes, R 2 It is C 1-6 -alkyl, wherein the C 1-6 -Alkyl groups are optionally halogenated by one or more -C 1-6 -Alkyl substitution.

[0124] In some implementation schemes, R 2 It is C 1-6 -alkyl, wherein the C 1-6 -Alkyl groups are optionally separated by one or more C groups. 3-6 - Cycloalkoxy substitution.

[0125] In some implementation schemes, R 2 It is C 1-6 -alkyl, wherein the C 1-6 -Alkyl groups are optionally separated by one or more C groups. 1-6 -alkoxy-C 1-6 -Alkyl substitution.

[0126] In some implementation schemes, R 2 It is C 1-6 -alkyl, wherein the C 1-6 The alkyl group is optionally substituted with one or more tetrahydrofuranyl groups, wherein the tetrahydrofuranyl group is optionally substituted with one or more substituents, which are independently selected from the group consisting of halogens, C...1-6 -alkyl and halogenated-C 1-6 -alkyl.

[0127] In some implementation schemes, R 2 It is C 1-6 -alkyl, wherein the C 1-6 The alkyl group is optionally substituted with one or more tetrahydrofuranyloxy groups, wherein the tetrahydrofuranyloxy group is optionally substituted with one or more substituents, which are independently selected from the group consisting of halogens, C 1-6 -alkyl and halogenated-C 1-6 -alkyl.

[0128] In some implementation schemes, R 2 It is C 1-6 -alkyl, wherein the C 1-6 The alkyl group is optionally substituted with one or more tetrahydropyranyl groups, wherein the tetrahydropyranyl group is optionally substituted with one or more substituents, which are independently selected from the group consisting of halogens, C 1-6 -alkyl and halogenated-C 1-6 -alkyl.

[0129] In some implementation schemes, R 2 It is C 1-6 -alkyl, wherein the C 1-6 The alkyl group is optionally substituted with one or more morpholino groups, wherein the morpholino group is optionally substituted with one or more substituents, which are independently selected from the group consisting of halogens, C... 1-6 -alkyl and halogenated-C 1-6 -alkyl.

[0130] In some implementation schemes, R 2 It is C 1-6 -alkyl, wherein the C 1-6 The alkyl group is optionally substituted with one or more pyrazolyl groups, wherein the pyrazolyl group is optionally substituted with one or more substituents, which are independently selected from the group consisting of halogens, C 1-6 -alkyl and halogenated-C 1-6 -alkyl.

[0131] In some implementation schemes, R 2 It is C 1-6 -alkyl, wherein the C 1-6 -Alkyl groups are optionally separated by one or more isocyanates. Azolium substitution, wherein the isopropyl group is substituted. The azole group may optionally be substituted by one or more substituents, which are independently selected from the group consisting of: halogens, C 1-6 -alkyl and halogenated-C1-6 -alkyl.

[0132] In some implementation schemes, R 2 It is C 1-6 -alkyl, wherein the C 1-6 The -alkyl group is optionally substituted with one or more triazole groups, wherein the triazole group is optionally substituted with one or more substituents, the one or more substituents being independently selected from the group consisting of: halogens, C 1-6 -alkyl and halogenated-C 1-6 -alkyl.

[0133] In some implementation schemes, R 2 It is C 1-6 -alkyl, wherein the C 1-6 The -alkyl group is optionally substituted with one or more pyridyl groups, wherein the pyridyl group is optionally substituted with one or more substituents, which are independently selected from the group consisting of: halogens, C 1-6 -alkyl and halogenated-C 1-6 -alkyl.

[0134] In some implementation schemes, R 2 Choose from the group consisting of: methyl, fluoromethyl, difluoromethyl, trifluoromethyl, hydroxyethyl, hydroxypropyl, ethoxymethyl, difluoroethoxymethyl, methoxyethyl, dimethoxyethyl, difluoropropyl, trifluoropropyl, methoxypropyl, methoxyethoxymethyl, cyclopropoxymethyl, morpholinomethyl, tetrahydrofuranylmethyl, tetrahydrofuranyloxymethyl, tetrahydropyranylmethyl, pyrazolylmethyl, dimethylpyrazolylmethyl, methyl isomethyl azole methyl, methyl iso Azolylethyl, methyltriazolylmethyl, dimethyltriazolylmethyl, dimethylpyridylmethyl, methylpyridylethyl, fluoropyridylethyl, chloropyridylethyl, and trifluoromethylpyridylethyl.

[0135] In some implementations, the compound and pharmaceutically acceptable salt are selected from the group consisting of:

[0136] N-(2-((R)-4-cyanothiazolidine-3-yl)-2-oxoethyl)-6-((RS)-1-(3-fluoropyridin-2-yl)-ethyl)quinoline-4-carboxamide (Example 12);

[0137] (R)-N-(2-(4-cyanothiazolidine-3-yl)-2-oxoethyl)-6-(2-hydroxypropyl-2-yl)quinoline-4-carboxamide (Example 16);

[0138] (R)-N-(2-(4-cyanothiazolidine-3-yl)-2-oxoethyl)-6-(trifluoromethyl)-quinoline-4-carboxamide (Example 17);

[0139] (R)-N-(2-(4-cyanothiazolidine-3-yl)-2-oxoethyl)-6-(2-methoxypropyl-2-yl)quinoline-4-carboxamide (Example 18);

[0140] (R)-N-(2-(4-cyanothiazolidine-3-yl)-2-oxoethyl)-6-((2,5-dimethyl-2H-1,2,3-triazol-4-yl)-methyl)quinoline-4-carboxamide (Example 19);

[0141] (R)-N-(2-(4-cyanothiazolidine-3-yl)-2-oxoethyl)-6-(morpholinomethyl)quinoline-4-carboxamide (Example 24);

[0142] N-(2-((R)-4-cyanothiazolidine-3-yl)-2-oxoethyl)-6-((RS)-1-hydroxyethyl)quinoline-4-carboxamide (Example 25);

[0143] N-(2-((R)-4-cyanothiazolidine-3-yl)-2-oxoethyl)-6-((RS)-1-methoxyethyl)quinoline-4-carboxamide (Example 26);

[0144] (R)-N-(2-(4-cyanothiazolidine-3-yl)-2-oxoethyl)-6-(ethoxymethyl)-quinoline-4-carboxamide (Example 27);

[0145] (R)-N-(2-(4-cyanothiazolidine-3-yl)-2-oxoethyl)-6-methylquinoline-4-carboxamide (Example 28);

[0146] (R)-N-(2-(4-cyanothiazolidine-3-yl)-2-oxoethyl)-6-(fluoromethyl)-quinoline-4-carboxamide (Example 29);

[0147] N-(2-((R)-4-cyanothiazolidine-3-yl)-2-oxoethyl)-6-((RS)-1,2-dimethoxyethyl)quinoline-4-carboxamide (Example 30);

[0148] (R)-N-(2-(4-cyanothiazolidine-3-yl)-2-oxoethyl)-6-((2-methoxyethoxy)-methyl)quinoline-4-carboxamide (Example 31);

[0149] N-(2-((R)-4-cyanothiazolidin-3-yl)-2-oxoethyl)-6-((((RS)-tetrahydrofuran-3-yl)oxy)-methyl)quinoline-4-carboxamide (Example 35);

[0150] (R)-N-(2-(4-cyanothiazolidine-3-yl)-2-oxoethyl)-6-((2,2-difluoroethoxy)methyl)quinoline-4-carboxamide (Example 36);

[0151] (R)-N-(2-(4-cyanothiazolidine-3-yl)-2-oxoethyl)-6-(cyclopropoxymethyl)quinoline-4-carboxamide (Example 37);

[0152] (R)-N-(2-(4-cyanothiazolidine-3-yl)-2-oxoethyl)-6-((4-methylisocyano) (3-yl)-methyl)-quinoline-4-carboxamide (Example 38);

[0153] (R)-N-(2-(4-cyanothiazolidine-3-yl)-2-oxoethyl)-6-((4,6-dimethylpyridin-3-yl)methyl)-quinoline-4-carboxamide (Example 39);

[0154] (R)-N-(2-(4-cyanothiazolidine-3-yl)-2-oxoethyl)-6-((1,3-dimethyl-1H-pyrazol-5-yl)-methyl)quinoline-4-carboxamide (Example 40);

[0155] (R)-N-(2-(4-cyanothiazolidine-3-yl)-2-oxoethyl)-6-((2-methyl-2H-1,2,3-triazol-4-yl)-methyl)quinoline-4-carboxamide (Example 41);

[0156] (R)-N-(2-(4-cyanothiazolidine-3-yl)-2-oxoethyl)-6-((5-methylisocyano) (Azol-3-yl)-methyl)quinoline-4-carboxamide (Example 42);

[0157] N-(2-((R)-4-cyanothiazolidine-3-yl)-2-oxoethyl)-6-((RS)-1-(5-methylisocyano) (Azazole-3-yl)-ethyl)quinoline-4-carboxamide (Example 46);

[0158] 6-((RS)-1-(5-chloropyridin-2-yl)ethyl)-N-(2-((R)-4-cyanothiazolidine-3-yl)-2-oxoethyl)quinoline-4-carboxamide (Example 48);

[0159] N-(2-((R)-4-cyanothiazolidine-3-yl)-2-oxoethyl)-6-((RS)-1-(3-methylisocyano) (Azolium-5-yl)-ethyl)quinoline-4-carboxamide (Example 49);

[0160] N-(2-((R)-4-cyanothiazolidine-3-yl)-2-oxoethyl)-6-((RS)-1-(6-methylpyridin-3-yl)-ethyl)quinoline-4-carboxamide (Example 51);

[0161] N-(2-((R)-4-cyanothiazolidine-3-yl)-2-oxoethyl)-6-((RS)-1-(2-(trifluoromethyl)pyridin-4-yl)-ethyl)quinoline-4-carboxamide (Example 52);

[0162] (R)-N-(2-(4-cyanothiazolidine-3-yl)-2-oxoethyl)-6-(2,2-difluoropropyl)quinoline-4-carboxamide (Example 53);

[0163] (R)-N-(2-(4-cyanothiazolidine-3-yl)-2-oxoethyl)-6-((tetrahydro-2H-pyran-4-yl)-methyl)quinoline-4-carboxamide (Example 56);

[0164] (R)-N-(2-(4-cyanothiazolidine-3-yl)-2-oxoethyl)-6-(3,3,3-trifluoropropyl)quinoline-4-carboxamide (Example 58);

[0165] N-(2-((R)-4-cyanothiazolidine-3-yl)-2-oxoethyl)-6-(((RS)-tetrahydrofuran-3-yl)-methyl)quinoline-4-carboxamide (Example 65);

[0166] (R)-N-(2-(4-cyanothiazolidine-3-yl)-2-oxoethyl)-6-(difluoromethyl)-quinoline-4-carboxamide (Example 71);

[0167] (R)-6-((1H-pyrazol-1-yl)methyl)-N-(2-(4-cyanothiazolidine-3-yl)-2-oxoethyl)quinoline-4-carboxamide (Example 80);

[0168] (R)-N-(2-(4-cyanothiazolidine-3-yl)-2-oxoethyl)-6-(3-methoxypropyl)quinoline-4-carboxamide (Example 81);

[0169] (R)-N-(2-(4-cyanothiazolidine-3-yl)-2-oxoethyl)-6-(2-methoxyethyl)quinoline-4-carboxamide (Example 82);

[0170] And its pharmaceutically acceptable salts.

[0171] CR 2 It is C 3-6 -cycloalkyl

[0172] In some embodiments, this disclosure provides compounds having the structure of formula (I), (II), (III-A), (III-B), (III-C), (III-D), (III-E), (IV), or (IV-A), or pharmaceutically acceptable salts thereof, wherein R 2 It is C 3-6 -cycloalkyl, wherein the C 3-6 -The cycloalkyl group is optionally substituted by one or more substituents, which are independently selected from the group consisting of: halogen, hydroxyl, cyano, C 1-6 -alkyl, halo-C 1-6 -alkyl, C 1-6 -alkoxy, halogenated-C 1-6 -alkoxy, isoalkoxy azole group and pyridinyl group; wherein the isopropyl group The azole and pyridyl groups are optionally substituted by one or more substituents, which are independently selected from the group consisting of halogens, C... 1-6 -alkyl and halogenated-C 1-6 -alkyl. In one respect, R 2 It is C 3-6 -cycloalkyl, wherein the C 3-6 -The cycloalkyl group is optionally substituted by one or more substituents, which are independently selected from the group consisting of: halogen, hydroxyl, cyano, C 1-3 -alkyl, halo-C 1-3 -alkyl, C 1-3 -alkoxy, halogenated-C 1-3 -alkoxy, isoalkoxy azole group and pyridinyl group; wherein the isopropyl group The azole and pyridyl groups are optionally substituted by one or more substituents, which are independently selected from the group consisting of halogens, C... 1-3 -alkyl and halogenated-C 1-3 -alkyl. In another respect, R 2 It is C 3-6 -cycloalkyl, wherein the C 3-6 -The cycloalkyl group is optionally substituted by one or more substituents, which are independently selected from the group consisting of: halogen, cyano, C 1-6 -alkoxy, isoalkoxy azole group and pyridinyl group; wherein the isopropyl group The azole and pyridyl groups are optionally substituted by one or more substituents, which are independently selected from the group consisting of halogens, C... 1-6 -alkyl and halogenated-C 1-6 -alkyl. In another respect, R 2 It is C 3-6 -cycloalkyl, wherein the C 3-6 -The cycloalkyl group is optionally substituted by one or more substituents, which are independently selected from the group consisting of: halogen, cyano, C 1-3 -alkoxy, isoalkoxy azole group and pyridinyl group; wherein the iso The azole and pyridyl groups are optionally substituted by one or more substituents, which are independently selected from the group consisting of halogens, C... 1-3 -alkyl and halogenated-C 1-3 -alkyl.

[0173] In some implementation schemes, R 2 It is an optionally substituted cyclopropyl group.

[0174] In some implementation schemes, R 2 It is an optional substituted cyclobutyl group.

[0175] In some implementation schemes, R 2 It is an optional substituted cyclopentyl group.

[0176] In some implementation schemes, R 2 It is an substituted cyclohexyl group.

[0177] In some implementation schemes, R 2 It is unreplaced C 3-6 -Cycloalkyl.

[0178] In some implementation schemes, R 2 It is C 3-6 -cycloalkyl, wherein the C 3-6 -The cycloalkyl group is optionally replaced by one or more halogens.

[0179] In some implementation schemes, R 2 It is C 3-6 -cycloalkyl, wherein the C 3-6 -The cycloalkyl group is optionally replaced by one or more cyano groups.

[0180] In some implementation schemes, R 2 It is C 3-6 -cycloalkyl, wherein the C 3-6 -Cycloalkyl groups are optionally separated by one or more C groups. 1-6 -Alkyl substitution.

[0181] In some implementation schemes, R 2 It is C 3-6 -cycloalkyl, wherein the C 3-6 -The cycloalkyl group is optionally separated by one or more isocyanates. Azolium substitution, wherein the isopropyl group is substituted. The azole group may optionally be substituted by one or more substituents, which are independently selected from the group consisting of: halogens, C 1-6 -alkyl and halogenated-C 1-6 -alkyl.

[0182] In some implementation schemes, R 2 It is C 3-6 -cycloalkyl, wherein the C 3-6 -The cycloalkyl group is optionally substituted with one or more pyridyl groups, wherein the pyridyl group is optionally substituted with one or more substituents, which are independently selected from the group consisting of: halogens, C 1-6 -alkyl and halogenated-C 1-6 -alkyl.

[0183] In some implementation schemes, R 2 Choose from the group consisting of: cyclopropyl, cyanocyclopropyl, ethoxycyclopropyl, methylisopropyl Azolylcyclopropyl, methylpyridylcyclopropyl, chloropyridylcyclopropyl, fluoropyridylcyclopropyl, trifluoropyridylcyclopropyl, fluorocyclobutyl, (fluoro)(methoxy)cyclobutyl, methoxycyclohexyl and cyanocyclohexyl.

[0184] In some implementations, the compound and pharmaceutically acceptable salt are selected from the group consisting of:

[0185] (R)-N-(2-(4-cyanothiazolidine-3-yl)-2-oxoethyl)-6-(1-(2-(trifluoromethyl)pyridin-4-yl)cyclopropyl)quinoline-4-carboxamide (Example 13);

[0186] (R)-N-(2-(4-cyanothiazolidine-3-yl)-2-oxoethyl)-6-(1-(6-methylpyridin-3-yl)cyclopropyl)quinoline-4-carboxamide (Example 43);

[0187] (R)-N-(2-(4-cyanothiazolidine-3-yl)-2-oxoethyl)-6-(1-(3-fluoropyridin-2-yl)-cyclopropyl)quinoline-4-carboxamide (Example 44);

[0188] (R)-N-(2-(4-cyanothiazolidine-3-yl)-2-oxoethyl)-6-(1-(5-methylisocyano) (Azol-3-yl)-cyclopropyl)quinoline-4-carboxamide (Example 45);

[0189] (R)-6-(1-(5-chloropyridin-2-yl)cyclopropyl)-N-(2-(4-cyanothiazolidine-3-yl)-2-oxoethyl)quinoline-4-carboxamide (Example 47);

[0190] (R)-N-(2-(4-cyanothiazolidine-3-yl)-2-oxoethyl)-6-(1-(3-methylisocyano) (Azol-5-yl)-cyclopropyl)quinoline-4-carboxamide (Example 50);

[0191] 6-((1r,4R*)-4-cyanocyclohexyl)-N-(2-((R)-4-cyanothiazolidin-3-yl)-2-oxoethyl)-quinoline-4-carboxamide isomer 1 (Example 54);

[0192] 6-((1r,4R*)-4-cyanocyclohexyl)-N-(2-((R)-4-cyanothiazolidin-3-yl)-2-oxoethyl)-quinoline-4-carboxamide isomer 2 (Example 55);

[0193] (R)-6-(1-cyanocyclohexyl)-N-(2-(4-cyanothiazolidin-3-yl)-2-oxoethyl)quinoline-4-carboxamide (Example 60);

[0194] N-(2-((R)-4-cyanothiazolidine-3-yl)-2-oxoethyl)-6-((1r,3R*)-1-fluoro-3-methoxycyclobutyl)quinoline-4-carboxamide isomer 1 (Example 62);

[0195] N-(2-((R)-4-cyanothiazolidine-3-yl)-2-oxoethyl)-6-((1r,3R*)-1-fluoro-3-methoxycyclobutyl)quinoline-4-carboxamide isomer 2 (Example 63);

[0196] (R)-6-(1-cyanocyclopropyl)-N-(2-(4-cyanothiazolidin-3-yl)-2-oxoethyl)quinoline-4-carboxamide (Example 70);

[0197] (R)-N-(2-(4-cyanothiazolidine-3-yl)-2-oxoethyl)-6-(1-fluorocyclobutyl)quinoline-4-carboxamide (Example 75);

[0198] (R)-N-(2-(4-cyanothiazolidine-3-yl)-2-oxoethyl)-6-(1-ethoxycyclopropyl)quinoline-4-carboxamide (Example 76);

[0199] (R)-N-(2-(4-cyanothiazolidine-3-yl)-2-oxoethyl)-6-cyclopropylquinoline-4-carboxamide (Example 77);

[0200] N-(2-((R)-4-cyanothiazolidine-3-yl)-2-oxoethyl)-6-((1r,4R*)-4-methoxycyclohexyl)-quinoline-4-carboxamide isomer 1 (Example 78);

[0201] N-(2-((R)-4-cyanothiazolidine-3-yl)-2-oxoethyl)-6-((1r,4R*)-4-methoxycyclohexyl)-quinoline-4-carboxamide isomer 2 (Example 79);

[0202] And its pharmaceutically acceptable salts.

[0203] DR 2 It is phenyl

[0204] In some embodiments, this disclosure provides compounds having the structure of formula (I), (II), (III-A), (III-B), (III-C), (III-D), (III-E), (IV), or (IV-A), or pharmaceutically acceptable salts thereof, wherein R 2 It is a phenyl group, wherein the phenyl group is optionally substituted with one or more substituents, which are independently selected from the group consisting of: halogen, cyano, C 1-6 -alkyl, halo-C 1-6 -alkyl, C 1-6 -alkoxy, halogenated-C 1-6 -alkoxy and C 1-6 -alkoxy-C 1-6 -alkoxy group. In one respect, R 2 It is a phenyl group, wherein the phenyl group is optionally substituted with one or more substituents, which are independently selected from the group consisting of: halogen, cyano, C 1-3 -alkyl, halo-C 1-3 -alkyl, C 1-3 -alkoxy, halogenated-C 1-3 -alkoxy and C 1-3 -alkoxy-C 1-3 -alkoxy group.

[0205] In some implementation schemes, R 2 It is a phenyl group, wherein the phenyl group is optionally substituted with one or more halogens.

[0206] In some implementation schemes, R 2 It is a phenyl group, wherein the phenyl group is optionally bonded by one or more C atoms. 1-6 -Alkyl substitution.

[0207] In some implementation schemes, R 2 It is a phenyl group, wherein the phenyl group is optionally halogenated by one or more halogenated-C groups. 1-6 -Alkyl substitution.

[0208] In some implementation schemes, R 2 It is a phenyl group, wherein the phenyl group is optionally bonded by one or more C atoms. 1-6 -Alkyl substitution.

[0209] In some implementation schemes, R 2 It is a phenyl group, wherein the phenyl group is optionally halogenated by one or more halogenated-C groups. 1-6 -Alkyl substitution.

[0210] In some implementation schemes, R 2 It is a phenyl group, wherein the phenyl group is optionally bonded by one or more C atoms. 1-6 -alkoxy-C 1-6 -Alkyl substitution.

[0211] In some embodiments, the compound is (R)-N-(2-(4-cyanothiazolidine-3-yl)-2-oxoethyl)-6-(4-(3-methoxy-propoxy)phenyl)quinoline-4-carboxamide or a pharmaceutically acceptable salt thereof (Example 72).

[0212] ER 2 It is a 5-, 6-, or 7-membered heterocyclic group.

[0213] In some embodiments, this disclosure provides compounds having the structure of formula (I), (II), (III-A), (III-B), (III-C), (III-D), (III-E), (IV), or (IV-A), or pharmaceutically acceptable salts thereof, wherein R 2 It is a 4-, 5-, 6-, or 7-membered heterocyclic group, wherein the heterocyclic ring: (i) is a saturated, partially saturated, or fully unsaturated monocyclic or fused bicyclic ring, (ii) has one or two oxygen ring atoms and the remaining ring atoms are carbon, and (iii) is optionally substituted by one or more substituents, which are independently selected from the group consisting of: halogen, hydroxyl, cyano, C 1-6 -alkyl, halo-C 1-6 -alkyl, C 2-6 -Alynyl group, C 1-6 -alkoxy and halogenated-C 1-6 -alkoxy group. In one respect, R 2It is a 4-, 5-, 6-, or 7-membered heterocyclic group, wherein the heterocyclic ring: (i) is a saturated, partially saturated, or fully unsaturated monocyclic or fused bicyclic ring, (ii) has one or two oxygen ring atoms and the remaining ring atoms are carbon, and (iii) is optionally substituted by one or more substituents, which are independently selected from the group consisting of: halogen, hydroxyl, cyano, C 1-3 -alkyl, halo-C 1-3 -alkyl, C 2-3 -Alynyl group, C 1-3 -alkoxy and halogenated-C 1-3 -alkoxy group.

[0214] In some implementation schemes, R 2 It is a 5- or 6-membered heterocyclic group, wherein the heterocyclic ring: (i) is a saturated, partially saturated, or fully unsaturated monocyclic or fused bicyclic ring, (ii) has one or two oxygen ring atoms and the remaining ring atoms are carbon, and (iii) is optionally substituted by one or more substituents, which are independently selected from the group consisting of: halogen, hydroxyl, cyano, C 1-3 -alkyl, C 2-3 -Alynyl group and C 1-3 -alkoxy group.

[0215] In some implementation schemes, R 2 It is a 4-membered ring heterocyclic group, wherein the heterocyclic ring: (i) is a saturated or partially saturated monocyclic ring, (ii) has one oxygen ring atom and the remaining ring atom is carbon, and (iii) is optionally substituted by one or more substituents, which are independently selected from the group consisting of: halogen, hydroxyl, cyano, C 1-6 -alkyl, halo-C 1-6 -alkyl, C 2-6 -Alynyl group, C 1-6 -alkoxy and halogenated-C 1-6 -alkoxy group. In one respect, R 2 It is a 4-membered ring heterocyclic group, wherein the heterocyclic ring: (i) is a saturated or partially saturated monocyclic ring, (ii) has one oxygen ring atom and the remaining ring atom is carbon, and (iii) is optionally substituted by one or more substituents, which are independently selected from the group consisting of: halogen, hydroxyl, cyano, C 1-3 -alkyl, halo-C 1-3 -alkyl, C 2-3 -Alynyl group, C 1-3 -alkoxy and halogenated-C 1-3 -alkoxy group.

[0216] In some implementation schemes, R 2It is a 5-membered ring heterocyclic group, wherein the heterocyclic ring: (i) is a saturated, partially saturated, or fully unsaturated monocyclic ring, (ii) has one or two oxygen ring atoms and the remaining ring atoms are carbon, and (iii) is optionally substituted by one or more substituents, which are independently selected from the group consisting of: halogen, hydroxyl, cyano, C 1-6 -alkyl, halo-C 1-6 -alkyl, C 2-6 -Alynyl group, C 1-6 -alkoxy and halogenated-C 1-6 -alkoxy group. In one respect, R 2 It is a 5-membered ring heterocyclic group, wherein the heterocyclic ring: (i) is a saturated, partially saturated, or fully unsaturated monocyclic ring, (ii) has one or two oxygen ring atoms and the remaining ring atoms are carbon, and (iii) is optionally substituted by one or more substituents, which are independently selected from the group consisting of: halogen, hydroxyl, cyano, C 1-3 -alkyl, halo-C 1-3 -alkyl, C 2-3 -Alynyl group, C 1-3 -alkoxy and halogenated-C 1-3 -alkoxy group.

[0217] In some implementation schemes, R 2 It is a 6-membered ring heterocyclic group, wherein the heterocyclic ring: (i) is a saturated, partially saturated, or fully unsaturated monocyclic ring, (ii) has one or two oxygen ring atoms and the remaining ring atoms are carbon, and (iii) is optionally substituted by one or more substituents, which are independently selected from the group consisting of: halogen, hydroxyl, cyano, C 1-6 -alkyl, halo-C 1-6 -alkyl, C 2-6 -Alynyl group, C 1-6 -alkoxy and halogenated-C 1-6 -alkoxy group. In one respect, R 2 It is a 6-membered ring heterocyclic group, wherein the heterocyclic ring: (i) is a saturated, partially saturated, or fully unsaturated monocyclic ring, (ii) has one or two oxygen ring atoms and the remaining ring atoms are carbon, and (iii) is optionally substituted by one or more substituents, which are independently selected from the group consisting of: halogen, hydroxyl, cyano, C 1-3 -alkyl, halo-C 1-3 -alkyl, C 2-3 -Alynyl group, C 1-3 -alkoxy and halogenated-C 1-3 -alkoxy group.

[0218] In some implementation schemes, R 2It is a 7-membered ring heterocyclic group, wherein the heterocyclic ring: (i) is a saturated, partially saturated, or fully unsaturated monocyclic or fused bicyclic ring, (ii) has one or two oxygen ring atoms and the remaining ring atoms are carbon, and (iii) is optionally substituted by one or more substituents, which are independently selected from the group consisting of: halogen, hydroxyl, cyano, C 1-6 -alkyl, halo-C 1-6 -alkyl, C 2-6 -Alynyl group, C 1-6 -alkoxy and halogenated-C 1-6 -alkoxy group. In one respect, R 2 It is a 7-membered ring heterocyclic group, wherein the heterocyclic ring: (i) is a saturated, partially saturated, or fully unsaturated monocyclic or fused bicyclic ring, (ii) has one or two oxygen ring atoms and the remaining ring atoms are carbon, and (iii) is optionally substituted by one or more substituents, which are independently selected from the group consisting of: halogen, hydroxyl, cyano, C 1-3 -alkyl, halo-C 1-3 -alkyl, C 2-3 -Alynyl group, C 1-3 -alkoxy and halogenated-C 1-3 -alkoxy group.

[0219] In some implementation schemes, R 2 Choose from the group consisting of: tetrahydrofuranyl, furanyl, dihydropyranyl, tetrahydropyranyl, 1,4-dihydrofuranyl, furanyl, di ... Alkyl and 3-oxabicyclo[4.1.0]heptane, wherein the tetrahydrofuranyl, dihydropyranyl, tetrahydropyranyl, 1,4-dihydrofuranyl, di ...pyranyl, dihydropy The alkyl group and 3-oxabicyclo[4.1.0]heptane are optionally substituted with one or more substituents, which are independently selected from the group consisting of: halogen, hydroxyl, cyano, C 1-6 -alkyl, halo-C 1-6 -alkyl, C 2-6 -Alynyl group, C 1-6 -alkoxy and halogenated-C 1-6 -alkoxy group. In one respect, R 2 Choose from the group consisting of: tetrahydrofuranyl, furanyl, dihydropyranyl, tetrahydropyranyl, 1,4-dihydrofuranyl, furanyl, di ... Alkyl and 3-oxabicyclo[4.1.0]heptane, wherein the tetrahydrofuranyl, dihydropyranyl, tetrahydropyranyl, 1,4-dihydrofuranyl, di ...pyranyl, dihydropy The alkyl group and 3-oxabicyclo[4.1.0]heptane are optionally substituted with one or more substituents, which are independently selected from the group consisting of: halogen, hydroxyl, cyano, C 1-3 -alkyl, halo-C1-3 -alkyl, C 2-3 -Alynyl group, C 1-3 -alkoxy and halogenated-C 1-3 -alkoxy group.

[0220] In some implementation schemes, R 2 It is a tetrahydrofuranyl group, wherein the tetrahydrofuranyl group is optionally substituted by one or more substituents, which are independently selected from the group consisting of: halogen, hydroxyl, cyano, C. 1-6 -alkyl, halo-C 1-6 -alkyl, C 2-6 -Alynyl group, C 1-6 -alkoxy and halogenated-C 1-6 -alkoxy group.

[0221] In some implementation schemes, R 2 It is a tetrahydropyranyl group, wherein the tetrahydropyranyl group is optionally substituted by one or more substituents, which are independently selected from the group consisting of: halogen, hydroxyl, cyano, C 1-6 -alkyl, halo-C 1-6 -alkyl, C 2-6 -Alynyl group, C 1-6 -alkoxy and halogenated-C 1-6 -alkoxy group.

[0222] In some implementation schemes, R 2 It is a dihydropyranyl group, wherein the dihydropyranyl group is optionally substituted by one or more substituents, which are independently selected from the group consisting of: halogen, hydroxyl, cyano, C 1-6 -alkyl, halo-C 1-6 -alkyl, C 2-6 -Alynyl group, C 1-6 -alkoxy and halogenated-C 1-6 -alkoxy group.

[0223] In some implementation schemes, R 2 It is 1,4-two Alkyl group, wherein the 1,4-di The alkyl group is optionally substituted with one or more substituents, which are independently selected from the group consisting of: halogen, hydroxyl, cyano, C. 1-6 -alkyl, halo-C 1-6 -alkyl, C 2-6 -Alynyl group, C 1-6 -alkoxy and halogenated-C 1-6 -alkoxy group.

[0224] In some implementation schemes, R 2It is 3-oxabicyclo[4.1.0]heptane, wherein the 3-oxabicyclo[4.1.0]heptane is optionally substituted with one or more substituents, which are independently selected from the group consisting of: halogen, hydroxyl, cyano, C 1-6 -alkyl, halo-C 1-6 -alkyl, C 2-6 -Alynyl group, C 1-6 -alkoxy and halogenated-C 1-6 -alkoxy group.

[0225] In some implementation schemes, R 2 Select from the group consisting of: tetrahydrofuranyl, furanyl, dimethyltetrahydrofuranyl, dihydropyranyl, tetrahydropyranyl, hydroxytetrahydropyranyl, fluorotetrahydropyranyl, cyanotetrahydropyranyl, methyltetrahydropyranyl, dimethyltetrahydropyranyl, methoxytetrahydropyranyl, ethoxytetrahydropyranyl, 1,4-di Alkyl and 3-oxabicyclo[4.1.0]heptane.

[0226] In some implementations, the compound and pharmaceutically acceptable salt are selected from the group consisting of:

[0227] (R)-N-(2-(4-cyanothiazolidine-3-yl)-2-oxoethyl)-6-(furan-3-yl)quinoline-4-carboxamide (Example 14);

[0228] (R)-N-(2-(4-cyanothiazolidine-3-yl)-2-oxoethyl)-6-(4-hydroxytetrahydro-2H-pyran-4-yl)-quinoline-4-carboxamide (Example 15);

[0229] (R)-N-(2-(4-cyanothiazolidine-3-yl)-2-oxoethyl)-6-(tetrahydro-2H-pyran-4-yl)quinoline-4-carboxamide (Example 20);

[0230] (R)-N-(2-(4-cyanothiazolidine-3-yl)-2-oxoethyl)-6-(4-methyltetrahydro-2H-pyran-4-yl)-quinoline-4-carboxamide (Example 21);

[0231] (R)-N-(2-(4-cyanothiazolidine-3-yl)-2-oxoethyl)-6-(3,6-dihydro-2H-pyran-4-yl)quinoline-4-carboxamide (Example 22);

[0232] (R)-N-(2-(4-cyanothiazolidine-3-yl)-2-oxoethyl)-6-(4-ethoxytetrahydro-2H-pyran-4-yl)-quinoline-4-carboxamide (Example 23);

[0233] N-(2-((R)-4-cyanothiazolidine-3-yl)-2-oxoethyl)-6-((RS)-tetrahydro-2H-pyran-2-yl)-quinoline-4-carboxamide (Example 32);

[0234] N-(2-((R)-4-cyanothiazolidine-3-yl)-2-oxoethyl)-6-((RS)-1,4-di- Alkyl-2-yl)quinoline-4-carboxamide (Example 33);

[0235] N-(2-((R)-4-cyanothiazolidine-3-yl)-2-oxoethyl)-6-((RS)-tetrahydrofuran-2-yl)quinoline-4-carboxamide (Example 34);

[0236] (R)-N-(2-(4-cyanothiazolidine-3-yl)-2-oxoethyl)-6-(4-ethynyltetrahydro-2H-pyran-4-yl)-quinoline-4-carboxamide (Example 57);

[0237] (R)-6-(4-cyanotetrahydro-2H-pyran-4-yl)-N-(2-(4-cyanothiazolidin-3-yl)-2-oxoethyl)-quinoline-4-carboxamide (Example 59);

[0238] N-(2-((R)-4-cyanothiazolidine-3-yl)-2-oxoethyl)-6-(5,5-dimethyltetrahydrofuran-3-yl)-quinoline-4-carboxamide (Example 61);

[0239] (R)-N-(2-(4-cyanothiazolidine-3-yl)-2-oxoethyl)-6-(4-fluorotetrahydro-2H-pyran-4-yl)-quinoline-4-carboxamide (Example 64);

[0240] (R)-N-(2-(4-cyanothiazolidine-3-yl)-2-oxoethyl)-6-(4-methoxytetrahydro-2H-pyran-4-yl)quinoline-4-carboxamide (Example 66);

[0241] N-(2-((R)-4-cyanothiazolidine-3-yl)-2-oxoethyl)-6-((RS)-tetrahydrofuran-3-yl)quinoline-4-carboxamide (Example 67);

[0242] N-(2-((R)-4-cyanothiazolidine-3-yl)-2-oxoethyl)-6-((RS)-2,2-dimethyltetrahydro-2H-pyran-4-yl)quinoline-4-carboxamide (Example 68);

[0243] 6-((1RS,6SR)-3-oxabicyclo[4.1.0]hept-6-yl)-N-(2-((R)-4-cyanothiazolidine-3-yl)-2-oxoethyl)quinoline-4-carboxamide (Example 69);

[0244] And its pharmaceutically acceptable salts.

[0245] F.R 2 is - OR 7

[0246] In some embodiments, this disclosure provides compounds having the structure of formula (I), (II), (III-A), (III-B), (III-C), (III-D), (III-E), (IV), or (IV-A), or pharmaceutically acceptable salts thereof, wherein R 2 Yes - OR 7 , where R 7 Choose from the following groups: C 1-6 -alkyl, phenyl and tetrahydropyranyl; wherein:

[0247] (i) The C 1-6 -The alkyl group is optionally substituted with one or more substituents, which are independently selected from the group consisting of: halogen, cyano, C 3-6 -Cycloalkyl, halogenated-C 3-6 -cycloalkyl, C 1-6 -alkoxy and halogenated-C 1-6 -alkoxy group;

[0248] (ii) The phenyl group is optionally substituted with one or more substituents, which are independently selected from the group consisting of: halogens, C 1-6 -alkyl, halo-C 1-6 -alkyl, C 1-6 -alkoxy and halogenated-C 1-6 -alkoxy group; and

[0249] (iii) The tetrahydropyranyl group is optionally substituted with one or more substituents, which are independently selected from the group consisting of: halogens, C 1-6 -alkyl, halo-C 1-6 -alkyl, C 1-6 -alkoxy and halogenated-C 1-6 -alkoxy group.

[0250] In some implementation schemes, R 2 Yes - OR 7 , where R 7 Choose from the following groups: C 1-4 -alkyl, phenyl and tetrahydropyranyl; wherein:

[0251] (i) The C 1-4 -The alkyl group is optionally substituted with one or more substituents, which are independently selected from the group consisting of: halogen, cyano, C 3-6 -Cycloalkyl, halogenated-C 3-6 -cycloalkyl, C 1-3 -alkoxy and halogenated-C 1-3 -alkoxy group;

[0252] (ii) The phenyl group is optionally substituted with one or more substituents, which are independently selected from the group consisting of: halogens, C 1-3 -alkyl, halo-C 1-3 -alkyl, C 1-3 -alkoxy and halogenated-C 1-3 -alkoxy group; and

[0253] (iii) The tetrahydropyranyl group is optionally substituted with one or more substituents, which are independently selected from the group consisting of: halogens, C 1-3 -alkyl, halo-C 1-3 -alkyl, C 1-3 -alkoxy and halogenated-C 1-3 -alkoxy group.

[0254] In some implementation schemes, R 2 Yes - OR 7 , where R 7 Choose from the following groups: C 1-6 -alkyl, phenyl and tetrahydropyranyl; wherein:

[0255] (i) The C 1-6 -The alkyl group is optionally substituted with one or more substituents, which are independently selected from the group consisting of: halogen, cyano, C 3-6 -Cycloalkyl, halogenated-C 3-6 -Cycloalkyl and C 1-6 -alkoxy group; and

[0256] (ii) The tetrahydropyranyl group is optionally surrounded by one or C 1-6 -Alkyl substitution.

[0257] In some implementation schemes, R 2 Yes - OR 7 , where R 7 Choose from the following groups: C 1-4 -alkyl, phenyl and tetrahydropyranyl; wherein:

[0258] (i) The C 1-4-The alkyl group is optionally substituted with one or more substituents, which are independently selected from the group consisting of: halogen, cyano, C 3-6 -Cycloalkyl, halogenated-C 3-6 -Cycloalkyl and C 1-3 -alkoxy group; and

[0259] (ii) The tetrahydropyranyl group is optionally surrounded by one or C 1-3 -Alkyl substitution.

[0260] In some implementation schemes, R 2 Yes - OR 7 , where R 7 It is C 1-6 -alkyl, wherein the C 1-6 -The alkyl group is optionally substituted with one or more substituents, which are independently selected from the group consisting of: halogen, cyano, C 3-6 -Cycloalkyl, halogenated-C 3-6 -cycloalkyl, C 1-6 -alkoxy and halogenated-C 1-6 -alkoxy group.

[0261] In some implementation schemes, R 2 Yes - OR 7 , where R 7 It is C 1-4 -alkyl, wherein the C 1-4 -The alkyl group is optionally substituted with one or more substituents, which are independently selected from the group consisting of: halogen, cyano, C 3-6 -Cycloalkyl, halogenated-C 3-6 -Cycloalkyl and C 1-3 -alkoxy group.

[0262] In some implementation schemes, R 2 Yes - OR 7 , where R 7 It is C 1-4 -alkyl, wherein the C 1-4 -The alkyl group is optionally substituted by one or more substituents, which are independently selected from the group consisting of fluorine.

[0263] In some implementation schemes, R 2 Yes - OR 7 , where R 7 It is a phenyl group, wherein the phenyl group is optionally substituted with one or more substituents, which are independently selected from the group consisting of: halogens, C 1-6 -alkyl, halo-C 1-6 -alkyl, C 1-6 -alkoxy and halogenated-C1-6 -alkoxy group.

[0264] In some implementation schemes, R 2 Yes - OR 7 , where R 7 Phenyl.

[0265] In some implementation schemes, R 2 Yes - OR 7 , where R 7 It is a tetrahydropyranyl group; wherein the tetrahydropyranyl group is optionally substituted by one or more substituents, which are independently selected from the group consisting of: halogens, C 1-6 -alkyl, halo-C 1-6 -alkyl, C 1-6 -alkoxy and halogenated-C 1-6 -alkoxy group.

[0266] In some implementation schemes, R 2 Yes - OR 7 , where R 7 It is a tetrahydropyranyl group; wherein the tetrahydropyranyl group is optionally surrounded by one or more C groups. 1-3 -Alkyl substitution.

[0267] In some implementation schemes, R 2 Yes - OR 7 , where R 7 Tetrahydropyranyl;

[0268] In some implementation schemes, R 2 Yes - OR 7 , where R 7 Choose from the group consisting of: cyanomethyl, fluoroethyl, difluoroethyl, propyl, difluoropropyl, fluorobutyl, methoxyethyl, cyclopropylmethyl, difluorocyclobutylmethyl, phenyl, tetrahydropyranyl, and dimethyltetrahydropyranyl.

[0269] In some implementations, the compound and pharmaceutically acceptable salt are selected from the group consisting of:

[0270] (R)-N-(2-(4-cyanothiazolidine-3-yl)-2-oxoethyl)-6-phenoxyquinoline-4-carboxamide (Example 1);

[0271] (R)-N-(2-(4-cyanothiazolidine-3-yl)-2-oxoethyl)-6-(2,2-difluoroethoxy)quinoline-4-carboxamide (Example 2);

[0272] (R)-N-(2-(4-cyanothiazolidine-3-yl)-2-oxoethyl)-6-(2-fluoro-2-methylpropoxy)quinoline-4-carboxamide (Example 3);

[0273] (R)-N-(2-(4-cyanothiazolidine-3-yl)-2-oxoethyl)-6-(2-methoxyethoxy)quinoline-4-carboxamide (Example 4);

[0274] (R)-N-(2-(4-cyanothiazolidine-3-yl)-2-oxoethyl)-6-(cyclopropylmethoxy)quinoline-4-carboxamide (Example 5);

[0275] (R)-N-(2-(4-cyanothiazolidine-3-yl)-2-oxoethyl)-6-((tetrahydro-2H-pyran-4-yl)oxy)-quinoline-4-carboxamide (Example 6);

[0276] (R)-N-(2-(4-cyanothiazolidine-3-yl)-2-oxoethyl)-6-((1,3-difluoroprop-2-yl)oxy)-quinoline-4-carboxamide (Example 7);

[0277] (R)-N-(2-(4-cyanothiazolidine-3-yl)-2-oxoethyl)-6-((3,3-difluorocyclobutyl)-methoxy)quinoline-4-carboxamide (Example 8);

[0278] N-(2-((R)-4-cyanothiazolidine-3-yl)-2-oxoethyl)-6-(((RS)-2,2-dimethyltetrahydro-2H-pyran-4-yl)oxy)quinoline-4-carboxamide (Example 9);

[0279] (R)-6-(cyanomethoxy)-N-(2-(4-cyanothiazolidine-3-yl)-2-oxoethyl)quinoline-4-carboxamide (Example 10);

[0280] (R)-N-(2-(4-cyanothiazolidine-3-yl)-2-oxoethyl)-6-(2,2-difluoropropoxy)quinoline-4-carboxamide (Example 11);

[0281] (R)-N-(2-(4-cyanothiazolidine-3-yl)-2-oxoethyl)-6-propoxyquinoline-4-carboxamide (Example 73);

[0282] (R)-N-(2-(4-cyanothiazolidine-3-yl)-2-oxoethyl)-6-(2-fluoroethoxy)-quinoline-4-carboxamide (Example 74);

[0283] And its pharmaceutically acceptable salts.

[0284] G. Additional Implementation Plan

[0285] In some embodiments, this disclosure provides compounds having the structure of formula (I), (II), (III-A), (III-B), (III-C), (III-D), (III-E), (IV), or (IV-A), or pharmaceutically acceptable salts thereof, wherein R 2 Choose from the following groups:

[0286] (a)C 1-3 -alkyl, wherein the C 1-3 -The alkyl group is optionally substituted with one or more substituents, which are independently selected from the group consisting of: halogen, hydroxyl, cyano, C 3-6 -Cycloalkyl, halogenated-C 3-6 -cycloalkyl, C 1-3 -alkoxy, halogenated-C 1-3 -alkoxy group, C 3-6 -cycloalkoxy, halogenated-C 3-6 -cycloalkoxy, C 1-3 -alkoxy-C 1-3 -alkoxy, oxetane, tetrahydrofuranyl, tetrahydrofuranyloxy, tetrahydropyranyl, morpholinyl, pyrazolyl, iso Azolyl, triazolyl, and pyridyl; wherein the oxetane is butyl, tetrahydrofuranyl, tetrahydrofuranyloxy, tetrahydropyranyl, morpholinyl, pyrazolyl, or iso The azole, triazole, and pyridyl groups are optionally substituted by one or more substituents, which are independently selected from the group consisting of halogens, C... 1-3 -alkyl and halogenated-C 1-3 -alkyl;

[0287] (b)C 3-6 -cycloalkyl, wherein the C 3-6 -The cycloalkyl group is optionally substituted by one or more substituents, which are independently selected from the group consisting of: halogen, cyano, C 1-3 -alkyl, halo-C 1-3 -alkyl, C 1-3 -alkoxy, halogenated-C 1-3 -alkoxy, isoalkoxy azole group and pyridinyl group; wherein the isopropyl group The azole and pyridyl groups are optionally substituted by one or more substituents, which are independently selected from the group consisting of halogens, C... 1-3 -alkyl and halogenated-C 1-3 -alkyl;

[0288] (c) Phenyl, wherein the phenyl group is optionally substituted with one or more substituents, the one or more substituents being independently selected from the group consisting of: halogens, C1-3 -alkyl, halo-C 1-3 -alkyl, C 1-3 -alkoxy, halogenated-C 1-3 -alkoxy and C 1-3 -alkoxy-C 1-3 -alkoxy group;

[0289] (d) A 4-, 5-, 6-, or 7-membered heterocyclic group, wherein the heterocyclic ring: (i) is a saturated or partially saturated monocyclic or fused bicyclic ring, (ii) has one or two oxygen ring atoms and the remaining ring atoms are carbon, and (iii) is optionally substituted with one or more substituents, said one or more substituents being independently selected from the group consisting of: halogen, hydroxyl, cyano, C 1-3 -alkyl, halo-C 1-3 -alkyl, C 2-3 -Alynyl group, C 1-3 -alkoxy and halogenated-C 1-3 -alkoxy group; and

[0290] (e)-OR 7 , where R 7 Choose from the following groups: C 1-4 -alkyl, phenyl and tetrahydropyranyl; wherein:

[0291] (i) The C 1-4 -The alkyl group is optionally substituted with one or more substituents, which are independently selected from the group consisting of: halogen, cyano, C 3-6 -Cycloalkyl, halogenated-C 3-6 -cycloalkyl, C 1-3 -alkoxy and halogenated-C 1-3 -alkoxy group;

[0292] (ii) The phenyl group is optionally substituted with one or more substituents, which are independently selected from the group consisting of: halogens, C 1-3 -alkyl, halo-C 1-3 -alkyl, C 1-3 -alkoxy and halogenated-C 1-3 -alkoxy group; and

[0293] (iii) The tetrahydropyranyl group is optionally substituted with one or more substituents, which are independently selected from the group consisting of: halogens, C 1-3 -alkyl, halo-C 1-3 -alkyl, C 1-3 -alkoxy and halogenated-C 1-3 -alkoxy group.

[0294] In some embodiments, this disclosure provides compounds having the structure of formula (I), (II), (III-A), (III-B), (III-C), (III-D), (III-E), (IV), or (IV-A), or pharmaceutically acceptable salts thereof, wherein R 2 Choose from the following groups:

[0295] (a)C 3-6 -cycloalkyl, wherein the C 3-6 -The cycloalkyl group is optionally substituted by one or more substituents, which are independently selected from the group consisting of: halogen, cyano, C 1-3 -alkyl, halo-C 1-3 -alkyl, C 1-3 -alkoxy, halogenated-C 1-3 -alkoxy, isoalkoxy azole group and pyridinyl group; wherein the isopropyl group The azole and pyridyl groups are optionally substituted by one or more substituents, which are independently selected from the group consisting of halogens, C... 1-3 -alkyl and halogenated-C 1-3 -alkyl; and

[0296] (b) A 4-, 5-, 6-, or 7-membered heterocyclic group, wherein the heterocyclic ring: (i) is a saturated or partially saturated monocyclic or fused bicyclic ring, (ii) has one or two oxygen ring atoms and the remaining ring atoms are carbon, and (iii) is optionally substituted by one or more substituents independently selected from the group consisting of: halogen, hydroxyl, cyano, C 1-3 -alkyl, halo-C 1-3 -alkyl, C 2-3 -Alynyl group, C 1-3 -alkoxy and halogenated-C 1-3 -alkoxy group; and

[0297] (c)-OR 7 , where R 7 Choose from the following groups: C 1-4 -alkyl, phenyl and tetrahydropyranyl; wherein:

[0298] (i) The C 1-4 -The alkyl group is optionally substituted with one or more substituents, which are independently selected from the group consisting of: halogen, cyano, C 3-6 -Cycloalkyl, halogenated-C 3-6 -cycloalkyl, C 1-3 -alkoxy and halogenated-C 1-3 -alkoxy group;

[0299] (ii) The phenyl group is optionally substituted with one or more substituents, which are independently selected from the group consisting of: halogens, C 1-3 -alkyl, halo-C 1-3 -alkyl, C 1-3 -alkoxy and halogenated-C 1-3 -alkoxy group; and

[0300] (iii) The tetrahydropyranyl group is optionally substituted with one or more substituents, which are independently selected from the group consisting of: halogens, C 1-3 -alkyl, halo-C 1-3 -alkyl, C 1-3 -alkoxy and halogenated-C 1-3 -alkoxy group.

[0301] In some embodiments, this disclosure provides compounds having the structure of formula (I), (II), (III-A), (III-B), (III-C), (III-D), (III-E), (IV), or (IV-A), or pharmaceutically acceptable salts thereof, wherein R 2 Choose from the following groups:

[0302] (a)C 1-6 -alkyl, wherein the C 1-6 -The alkyl group is optionally substituted with one or more substituents, which are independently selected from the group consisting of: halogens, hydroxyl groups, C... 1-6 -alkoxy, halogenated-C 1-6 -alkoxy group, C 3-6 -cycloalkoxy, C 1-6 -alkoxy-C 1-6 -alkoxy, tetrahydrofuranyl, tetrahydrofuranyloxy, tetrahydropyranyl, morpholinyl, pyrazolyl, iso Azolyl, triazolyl, and pyridyl; wherein the tetrahydrofuranyl, tetrahydrofuranyloxy, tetrahydropyranyl, morpholinyl, pyrazolyl, iso The azole, triazole, and pyridyl groups are optionally substituted by one or more substituents, which are independently selected from the group consisting of halogens, C... 1-6 -alkyl and halogenated-C 1-6 -alkyl;

[0303] (b)C 3-6 -cycloalkyl, wherein the C 3-6 -The cycloalkyl group is optionally substituted by one or more substituents, which are independently selected from the group consisting of: halogen, cyano, C 1-6 -alkoxy, isoalkoxy azole group and pyridinyl group; wherein the iso The azole and pyridyl groups are optionally substituted by one or more substituents, which are independently selected from the group consisting of halogens, C... 1-6 -alkyl and halogenated-C 1-6 -alkyl;

[0304] (c) Phenyl, wherein the phenyl group is optionally substituted with one or more substituents, the one or more substituents being independently selected from the group consisting of: halogens, C 1-3 -alkyl, halo-C 1-3 -alkyl, C 1-3 -alkoxy, halogenated-C 1-3 -alkoxy and C 1-3 -alkoxy-C 1-3 -alkoxy group;

[0305] (d) A 5-, 6-, or 7-membered heterocyclic group, wherein the heterocyclic ring: (i) is a saturated or partially saturated monocyclic or fused bicyclic ring, (ii) has one or two oxygen ring atoms and the remaining ring atoms are carbon, and (iii) is optionally substituted by one or more substituents independently selected from the group consisting of: halogen, hydroxyl, cyano, C 1-3 -alkyl, C 2-3 -Alynyl group and C 1-3 -alkoxy group; and

[0306] (e)-OR 7 , where R 7 Choose from the following groups: C 1-6 -alkyl, phenyl and tetrahydropyranyl; wherein:

[0307] (i) The C 1-6 -The alkyl group is optionally substituted with one or more substituents, which are independently selected from the group consisting of: halogen, cyano, C 3-6 -Cycloalkyl, halogenated-C 3-6 -Cycloalkyl and C 1-6 -alkoxy group; and

[0308] (ii) The tetrahydropyranyl group is optionally surrounded by one or C 1-6 -Alkyl substitution.

[0309] In some embodiments, this disclosure provides compounds having the structure of formula (I), (II), (III-A), (III-B), (III-C), (III-D), (III-E), (IV), or (IV-A), or pharmaceutically acceptable salts thereof, wherein R 2 Choose from the following groups:

[0310] (a)C 3-6-cycloalkyl, wherein the C 3-6 -The cycloalkyl group is optionally substituted by one or more substituents, which are independently selected from the group consisting of: halogen, cyano, C 1-6 -alkoxy, isoalkoxy azole group and pyridinyl group; wherein the iso The azole and pyridyl groups are optionally substituted by one or more substituents, which are independently selected from the group consisting of halogens, C... 1-6 -alkyl and halogenated-C 1-6 -alkyl;

[0311] (b) A 5-, 6-, or 7-membered heterocyclic group, wherein the heterocyclic ring: (i) is a saturated or partially saturated monocyclic or fused bicyclic ring, (ii) has one or two oxygen ring atoms and the remaining ring atoms are carbon, and (iii) is optionally substituted with one or more substituents independently selected from the group consisting of: halogen, hydroxyl, cyano, C 1-3 -alkyl, C 2-3 -Alynyl group and C 1-3 -alkoxy group; and

[0312] (c)-OR 7 , where R 7 Choose from the following groups: C 1-6 -alkyl, phenyl and tetrahydropyranyl; wherein:

[0313] (i) The C 1-6 -The alkyl group is optionally substituted with one or more substituents, which are independently selected from the group consisting of: halogen, cyano, C 3-6 -Cycloalkyl, halogenated-C 3-6 -Cycloalkyl and C 1-6 -alkoxy group; and

[0314] (ii) The tetrahydropyranyl group is optionally surrounded by one or C 1-6 -Alkyl substitution.

[0315] In one respect, R 2 It is a 4-membered ring heterocyclic group, wherein the heterocyclic ring: (i) is a saturated or partially saturated monocyclic ring, (ii) has one oxygen ring atom and the remaining ring atom is carbon, and (iii) is optionally substituted by one or more substituents, which are independently selected from the group consisting of: halogen, hydroxyl, cyano, C 1-3 -alkyl, C 2-3 -Alynyl group and C 1-3 -alkoxy group. In another respect, R 2It is a 5-membered ring heterocyclic group, wherein the heterocyclic ring: (i) is a saturated or partially saturated monocyclic ring, (ii) has one or two oxygen ring atoms and the remaining ring atoms are carbon, and (iii) is optionally substituted by one or more substituents, which are independently selected from the group consisting of: halogen, hydroxyl, cyano, C 1-3 -alkyl and C 2-3 -Alynyl group, C 1-3 -alkoxy group. In another respect, R 2 It is a 6-membered ring heterocyclic group, wherein the heterocyclic ring: (i) is a saturated or partially saturated monocyclic ring, (ii) has one or two oxygen ring atoms and the remaining ring atoms are carbon, and (iii) is optionally substituted by one or more substituents, which are independently selected from the group consisting of: halogen, hydroxyl, cyano, C 1-3 -alkyl, C 2-3 -Alynyl group and C 1-3 -alkoxy group. In another respect, R 2 It is a 7-membered ring heterocyclic group, wherein the heterocyclic ring: (i) is a saturated or partially saturated monocyclic or fused bicyclic ring, (ii) has one or two oxygen ring atoms and the remaining ring atoms are carbon, and (iii) is optionally substituted by one or more substituents, which are independently selected from the group consisting of: halogen, hydroxyl, cyano, C 1-3 -alkyl, C 2-3 -Alynyl group and C 1-3 -alkoxy group.

[0316] In some embodiments, this disclosure provides compounds having the structure of formula (I), (II), (III-A), (III-B), (III-C), (III-D), (III-E), (IV), or (IV-A), or pharmaceutically acceptable salts thereof, wherein R 2 Choose from the following groups:

[0317] (a)C 1-3 -alkyl, wherein the C 1-3 -The alkyl group is optionally substituted with one or more substituents, which are independently selected from the group consisting of: halogens, hydroxyl groups, C... 1-3 -alkoxy, halogenated-C 1-3 -alkoxy group, C 3-6 -cycloalkoxy, C 1-3 -alkoxy-C 1-3 -alkoxy, tetrahydrofuranyl, tetrahydrofuranyloxy, tetrahydropyranyl, morpholinyl, pyrazolyl, iso Azolyl, triazolyl, and pyridyl; wherein the tetrahydrofuranyl, tetrahydrofuranyloxy, tetrahydropyranyl, morpholinyl, pyrazolyl, iso The azole, triazole, and pyridyl groups are optionally substituted by one or more substituents, which are independently selected from the group consisting of halogens, C... 1-3 -alkyl and halogenated-C 1-6 -alkyl;

[0318] (b)C 3-6 -cycloalkyl, wherein the C 3-6 -The cycloalkyl group is optionally substituted by one or more substituents, which are independently selected from the group consisting of: halogen, cyano, C 1-3 -alkoxy, isoalkoxy azole group and pyridinyl group; wherein the iso The azole and pyridyl groups are optionally substituted by one or more substituents, which are independently selected from the group consisting of halogens, C... 1-3 -alkyl and halogenated-C 1-3 -alkyl;

[0319] (c) Phenyl, wherein the phenyl group is optionally substituted with one or more substituents, the one or more substituents being independently selected from the group consisting of: halogens, C 1-3 -alkyl, halo-C 1-3 -alkyl, C 1-3 -alkoxy, halogenated-C 1-3 -alkoxy and C 1-3 -alkoxy-C 1-3 -alkoxy group;

[0320] (d) A 5-, 6-, or 7-membered heterocyclic group selected from the group consisting of: tetrahydrofuranyl, dihydropyranyl, tetrahydropyranyl, 1,4-dihydrofuranyl, etc. Alkyl and 3-oxabicyclo[4.1.0]heptane, wherein the tetrahydrofuranyl, dihydropyranyl, tetrahydropyranyl, 1,4-dihydrofuranyl, di ...pyranyl, dihydropy The alkyl group and 3-oxabicyclo[4.1.0]heptane are optionally substituted with one or more substituents, which are independently selected from the group consisting of: halogen, hydroxyl, cyano, C 1-6 -alkyl, halo-C 1-6 -alkyl, C 2-6 -Alynyl group, C 1-6 -alkoxy and halogenated-C 1-6 -alkoxy group; and

[0321] (e)-OR 7 , where R 7 Choose from the following groups: C 1-4 -alkyl, phenyl and tetrahydropyranyl; wherein:

[0322] (i) The C 1-4-The alkyl group is optionally substituted with one or more substituents, which are independently selected from the group consisting of: halogen, cyano, C 3-6 -Cycloalkyl, halogenated-C 3-6 -Cycloalkyl and C 1-3 -alkoxy group; and

[0323] (ii) The tetrahydropyranyl group is optionally surrounded by one or C 1-3 -Alkyl substitution.

[0324] In some embodiments, this disclosure provides compounds having the structure of formula (I), (II), (III-A), (III-B), (III-C), (III-D), (III-E), (IV), or (IV-A), or pharmaceutically acceptable salts thereof, wherein R 2 Choose from the following groups:

[0325] (a)C 3-6 -cycloalkyl, wherein the C 3-6 -The cycloalkyl group is optionally substituted by one or more substituents, which are independently selected from the group consisting of: halogen, cyano, C 1-3 -alkoxy, isoalkoxy azole group and pyridinyl group; wherein the isopropyl group The azole and pyridyl groups are optionally substituted by one or more substituents, which are independently selected from the group consisting of halogens, C... 1-3 -alkyl and halogenated-C 1-3 -alkyl;

[0326] (b) A 5-, 6-, or 7-membered heterocyclic group selected from the group consisting of: tetrahydrofuranyl, dihydropyranyl, tetrahydropyranyl, 1,4-dihydrofuranyl, etc. Alkyl and 3-oxabicyclo[4.1.0]heptane, wherein the tetrahydrofuranyl, dihydropyranyl, tetrahydropyranyl, 1,4-dihydrofuranyl, di ...pyranyl, dihydropy The alkyl group and 3-oxabicyclo[4.1.0]heptane are optionally substituted with one or more substituents, which are independently selected from the group consisting of: halogen, hydroxyl, cyano, C 1-6 -alkyl, halo-C 1-6 -alkyl, C 2-6 -Alynyl group, C 1-6 -alkoxy and halogenated-C 1-6 -alkoxy group; and

[0327] (c)-OR 7 , where R 7 Choose from the following groups: C 1-4 -alkyl, phenyl and tetrahydropyranyl; wherein:

[0328] (i) The C 1-4 -The alkyl group is optionally substituted with one or more substituents, which are independently selected from the group consisting of: halogen, cyano, C 3-6 -Cycloalkyl, halogenated-C 3-6 -Cycloalkyl and C 1-3 -alkoxy group; and

[0329] (ii) The tetrahydropyranyl group is optionally surrounded by one or C 1-3 -Alkyl substitution.

[0330] In one respect, R 2 It is an optionally substituted cyclopropyl group. In another aspect, R... 2 It is an optionally substituted cyclobutyl group. In another aspect, R 2 It is an optionally substituted cyclopentyl group. In another aspect, R... 2 It is an substituted cyclohexyl group.

[0331] In some embodiments, this disclosure provides compounds having the structure of formula (I), (II), (III-A), (III-B), (III-C), (III-D), (III-E), (IV), or (IV-A), or pharmaceutically acceptable salts thereof, wherein R 2 Choose from the following groups:

[0332] (a) C with optional substitution 1-3 -alkyl groups, selected from the group consisting of: methyl, fluoromethyl, difluoromethyl, trifluoromethyl, hydroxyethyl, hydroxypropyl, ethoxymethyl, difluoroethoxymethyl, methoxyethyl, dimethoxyethyl, difluoropropyl, trifluoropropyl, methoxypropyl, methoxyethoxymethyl, cyclopropoxymethyl, morpholinylmethyl, tetrahydrofuranylmethyl, tetrahydrofuranyloxymethyl, tetrahydropyranylmethyl, pyrazolylmethyl, dimethylpyrazolylmethyl, methyl isomethyl azole methyl, methyl iso Azolylethyl, methyltriazolylmethyl, dimethyltriazolylmethyl, dimethylpyridylmethyl, methylpyridylethyl, fluoropyridylethyl, chloropyridylethyl, and trifluoromethylpyridylethyl.

[0333] (b) C with optional substitution 3-6 -Cycloalkyl groups, selected from the group consisting of: cyclopropyl, cyanocyclopropyl, ethoxycyclopropyl, methylisopropyl Azolylcyclopropyl, methylpyridylcyclopropyl, chloropyridylcyclopropyl, fluoropyridylcyclopropyl, trifluoropyridylcyclopropyl, fluorocyclobutyl, (fluoro)(methoxy)cyclobutyl, methoxycyclohexyl and cyanocyclohexyl;

[0334] (c) Optionally substituted 5-, 6-, or 7-membered heterocyclic groups selected from the group consisting of: tetrahydrofuranyl, dimethyltetrahydrofuranyl, dihydropyranyl, tetrahydropyranyl, hydroxytetrahydropyranyl, fluorotetrahydropyranyl, cyanotetrahydropyranyl, methyltetrahydropyranyl, dimethyltetrahydropyranyl, methoxytetrahydropyranyl, ethoxytetrahydropyranyl, 1,4-di- Alkyl groups and 3-oxabicyclo[4.1.0]heptane; and

[0335] (d)-OR 7 , where R 7 Choose from the group consisting of: cyanomethyl, fluoroethyl, difluoroethyl, propyl, difluoropropyl, fluorobutyl, methoxyethyl, cyclopropylmethyl, difluorocyclobutylmethyl, phenyl, tetrahydropyranyl, and dimethyltetrahydropyranyl.

[0336] In some embodiments, this disclosure provides compounds having the structure of formula (I), (II), (III-A), (III-B), (III-C), (III-D), (III-E), (IV), or (IV-A), or pharmaceutically acceptable salts thereof, wherein R 2 Choose from the following groups:

[0337] (a) C with optional substitution 3-6 -Cycloalkyl groups, selected from the group consisting of: cyclopropyl, cyanocyclopropyl, ethoxycyclopropyl, methylisopropyl Azolylcyclopropyl, methylpyridylcyclopropyl, chloropyridylcyclopropyl, fluoropyridylcyclopropyl, trifluoropyridylcyclopropyl, fluorocyclobutyl, (fluoro)(methoxy)cyclobutyl, methoxycyclohexyl and cyanocyclohexyl;

[0338] (b) Optionally substituted 5-, 6-, or 7-membered heterocyclic groups selected from the group consisting of: tetrahydrofuranyl, dimethyltetrahydrofuranyl, dihydropyranyl, tetrahydropyranyl, hydroxytetrahydropyranyl, fluorotetrahydropyranyl, cyanotetrahydropyranyl, methyltetrahydropyranyl, dimethyltetrahydropyranyl, methoxytetrahydropyranyl, ethoxytetrahydropyranyl, 1,4-di... Alkyl groups and 3-oxabicyclo[4.1.0]heptane; and

[0339] (c)-OR 7 , where R 7 Choose from the group consisting of: cyanomethyl, fluoroethyl, difluoroethyl, propyl, difluoropropyl, fluorobutyl, methoxyethyl, cyclopropylmethyl, difluorocyclobutylmethyl, phenyl, tetrahydropyranyl, and dimethyltetrahydropyranyl.

[0340] In some embodiments, this disclosure provides compounds having the structure of formula (I), (II), (III-A), (III-B), (III-C), (III-D), (III-E), (IV), or (IV-A), or pharmaceutically acceptable salts thereof, wherein R 2 Choose from the group consisting of: methoxycyclohexyl, tetrahydropyranyl, fluorobutoxy, and tetrahydropyranyloxy.

[0341] H. Combination of Implementation Schemes

[0342] Any embodiment of the compounds described in this disclosure may be combined with any other suitable embodiments described herein to provide additional embodiments. For example, R may be described alone or together with other embodiments. 1 R 2 R 3 R 4 R 5 and / or R 6 Possible functional groups and a separate embodiment of R are described. 2 In the case of possible functional groups, it should be understood that these embodiments can be combined to provide a description for R. 1 R 2 R 3 R 4 R 5 and / or R 6 The described possible groups, along with those for R 2 Additional embodiments of the described possible groups. In other words, for any embodiment of the compound described in this disclosure, R 2 Substituents can be R as described in this specification. 2 As defined in any implementation scheme.

[0343] I. Alternative Implementation Plan

[0344] The compounds disclosed herein possess pharmaceutically acceptable FAP inhibitory activity as measured for the hFAP inhibition assay (tightly bound) reported in the examples below. In one aspect, the compounds exhibit FAP inhibitory activity at IC50 values ​​below about 100 nM. 50 It exhibits FAP inhibitory activity at certain concentrations. In another aspect, the compound shows IC50 activity below approximately 50 nM. 50 It exhibits FAP inhibitory activity at concentrations below approximately 10 nM. In another aspect, the compound shows IC50 activity at concentrations below approximately 10 nM. 50 It exhibits FAP inhibitory activity at concentrations below approximately 1 nM. In another aspect, the compound shows IC50 activity at concentrations below approximately 1 nM. 50 It exhibits FAP inhibitory activity at certain concentrations.

[0345] In some embodiments, the compounds of this disclosure have a pharmaceutically acceptable SPR pK as reported for the surface plasmon resonance (SPR) determinations in the examples below. d Value. In one respect, the compound has a surface plasmon resonance (SPR) pK greater than about 7. d Value. On another front, the compound exhibits a surface plasmon resonance (SPR) pK greater than approximately 8. d Value. On the other hand, the compound has a SPR pK greater than approximately 9. d Value. On the other hand, the compound has a SPR pK greater than about 10. d value.

[0346] In some embodiments, the compounds of this disclosure have pharmaceutically acceptable selectivity for FAP relative to PREP, as measured for the hFAP inhibition assay (tight binder) and hPREP inhibition assay reported in the examples below. In one aspect, the compounds exhibit at least about 50-fold higher selectivity for FAP relative to PREP. In another aspect, the compounds exhibit at least about 100-fold higher selectivity for FAP relative to PREP. In yet another aspect, the compounds exhibit at least about 1,000-fold higher selectivity for FAP relative to PREP. In yet another aspect, the compounds exhibit at least about 10,000-fold higher selectivity for FAP relative to PREP. In yet another aspect, the compounds have a PREP IC50 greater than about 0.1 μM. 50 Value. On another front, the compound has a PREP IC greater than approximately 1.0 μM. 50 Value. On another front, the compound has a PREP IC greater than approximately 10.0 μM. 50 value.

[0347] In some embodiments, the compounds of this disclosure have pharmaceutically acceptable selectivity for FAP relative to DPP7, as measured for the hFAP inhibition assay (tight binder) and DPP7 selectivity assay reported in the examples below. In one aspect, the compounds exhibit at least about 50-fold higher selectivity for FAP relative to DPP7. In another aspect, the compounds exhibit at least about 100-fold higher selectivity for FAP relative to DPP7. In yet another aspect, the compounds exhibit at least about 1,000-fold higher selectivity for FAP relative to DPP7. In yet another aspect, the compounds exhibit at least about 10,000-fold higher selectivity for FAP relative to DPP7. In yet another aspect, the compounds exhibit an IC50 value for DPP7... 50 The value is greater than approximately 0.1 μM. In another aspect, the compound's IC50 value for DPP7... 50 The value is greater than approximately 1 μM. In another aspect, the compound's IC50 value for DPP7... 50The value is greater than approximately 10 μM.

[0348] In some embodiments, the compounds of this disclosure have pharmaceutically acceptable selectivity for FAP relative to DPP8 and / or DPP9, as measured for the hFAP inhibition assay (tight binder), DPP8 selectivity assay, and DPP9 selectivity assay reported in the examples below. In one aspect, the compound is selective for FAP relative to DPP8. In another aspect, the compound is selective for FAP relative to DPP9. In yet another aspect, the compound is selective for FAP relative to both DPP8 and DPP9. In one aspect, the compound has at least about 50-fold higher selectivity for FAP relative to DPP8 and / or DPP9. In another aspect, the compound has at least about 100-fold higher selectivity for FAP relative to DPP8 and / or DPP9. In yet another aspect, the compound has at least about 500-fold higher selectivity for FAP relative to DPP8 and / or DPP9. In yet another aspect, the compound has at least about 1,000-fold higher selectivity for FAP relative to DPP8 and / or DPP9. In another aspect, the compound exhibits IC50 susceptibility to DPP8 and / or DPP9. 50 The value is greater than approximately 0.01 μM. In another aspect, the compound exhibits IC50 values ​​for DPP8 and / or DPP9. 50 The value is greater than approximately 0.1 μM. In another aspect, the compound exhibits IC50 values ​​for DPP8 and / or DPP9. 50 The value is greater than approximately 0.4 μM.

[0349] In some embodiments, the compounds of this disclosure have pharmaceutically acceptable metabolic stability, as measured in the human liver microsome (HLM) assays 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 respect, the compound has an HLM CL of less than about 100 μL / min / mg. int In another respect, the compound has an HLM CL of less than about 50 μL / min / mg. int value.

[0350] In some embodiments, the compounds of this disclosure have pharmaceutically acceptable metabolic stability, as measured for rat hepatocyte (rHep) assays reported in the examples below. In one aspect, the compounds have a stability of less than about 300 μL / min / 10 6 rHep CL per cell int Value. On another front, the compound exhibits a flow rate of less than approximately 100 μL / min / 10 6 rHep CL per cell intValue. On another front, the compound exhibits a flow rate of less than approximately 50 μL / min / 10 6 rHep CL per cell int value.

[0351] In some embodiments, the compounds of this disclosure have a pharmaceutically acceptable inherent permeability to Caco-2 AB, as measured for the Caco-2 AB inherent permeability determination reported in the examples below. In one aspect, the compounds have at least about 0.1 × 10⁻⁶. 6 The inherent apparent permeability of Caco-2 is cm / s. In another aspect, the compound has at least about 0.5 × 10⁻⁶ cm / s. 6 The inherent apparent permeability of Caco-2 is cm / s. In another aspect, the compound has at least about 1 × 10⁻⁶ cm / s. 6 The inherent apparent permeability of Caco-2 is cm / s.

[0352] In some embodiments, the compounds of this disclosure have pharmaceutically acceptable Caco-2 bidirectional (ABBA) A-to-B apparent permeability, as measured for the Caco-2 bidirectional (ABBA) A-to-B apparent permeability determination reported in the examples below. In one aspect, the compound has at least about 0.1 × 10⁻⁶. 6 The apparent permeability of Caco-2 bidirectional (ABBA)A to B is cm / s. In another aspect, the compound has at least about 0.25 × 10⁻⁶ cm / s. 6 The apparent permeability of Caco-2 bidirectional (ABBA)A to B is cm / s. In another aspect, the compound has at least about 0.5 × 10⁻⁶ cm / s. 6 Apparent permeability of Caco-2 bidirectional (ABBA) A to B at cm / s.

[0353] In some embodiments, the compounds of this disclosure have pharmaceutically acceptable kinetic solubility, as measured as in the kinetic solubility determination reported in the examples below. In one aspect, the compound has a kinetic solubility of at least about 1 μM. In another aspect, the compound has a kinetic solubility of at least about 10 μM. In yet another aspect, the compound has a kinetic solubility of at least about 25 μM. In yet another aspect, the compound has a kinetic solubility of at least about 50 μM.

[0354] J. Salt

[0355] The compounds disclosed herein may exist in salt form or in non-salt form (i.e., as free bases), and this disclosure covers both salt and non-salt forms. The compounds may form acid addition salts or base addition salts. Generally, acid addition salts can be prepared using a variety of inorganic or organic acids. Such salts are typically formed by mixing the compound with an acid (e.g., a stoichiometric amount of acid) using various methods known in the art, for example. This mixing can occur in water, organic solvents (e.g., ether, ethyl acetate, ethanol, methanol, isopropanol, or acetonitrile), or aqueous / organic mixtures. In another aspect, acid addition salts are, for example, trifluoroacetate, formate, acetate, or hydrochloride salts. Generally, base addition salts can be prepared using a variety of inorganic or organic bases, such as alkali metal or alkaline earth metal salts, such as sodium, calcium, or magnesium salts; or other metal salts, such as potassium or zinc; or ammonium salts; or salts formed with organic bases (such as methylamine, dimethylamine, trimethylamine, piperidine, or morpholine). Technicians will be aware of the general principles and techniques for preparing pharmaceutical salts, such as those described, for example, in J. Pharm. Sci. 1977 66, 1. Examples of pharmaceutically acceptable salts are also described in Stahl and Wermuth's "Handbook of Pharmaceutical Salts: Properties, Selection, and Use" (Wiley-VCH, Weinheim, Germany, 2002).

[0356] K isomer

[0357] The compounds and salts disclosed herein may exist in one or more geometric, optical, enantiomeric, and diastereomeric forms, including but not limited to cis and trans forms, E and Z forms, and R, S, and meso forms. Unless otherwise stated, references to a particular compound include all such isomeric forms, including their racemic and other mixtures. Where appropriate, such isomers can be separated from mixtures thereof by applying or adapting known methods (e.g., chromatographic techniques and recrystallization techniques). Where appropriate, such isomers can be prepared by applying or adapting known methods. In some embodiments, a single stereoisomer is obtained by separating it from a mixture of isomers (e.g., racemates) using, for example, chiral chromatographic separation. In other embodiments, a single stereoisomer is obtained by direct synthesis from, for example, chiral starting materials.

[0358] A particular enantiomer of the compound described herein may be more active than other enantiomers of the same compound. In one embodiment, the compound or a pharmaceutically acceptable salt thereof is a single enantiomer with an enantiomer excess (%ee) of ≥90%, ≥95%, ≥96%, ≥97%, ≥98%, or ≥99%. In one aspect, the single enantiomer is present with an enantiomer excess (%ee) of ≥99%.

[0359] In another embodiment, this disclosure relates to a pharmaceutical composition comprising a compound or a pharmaceutically acceptable salt thereof together with one or more pharmaceutically acceptable excipients, wherein the compound or a pharmaceutically acceptable salt thereof is a single enantiomer with an enantiomer excess (%ee) of ≥90%, ≥95%, ≥96%, ≥97%, ≥98%, or ≥99%. In one aspect, the single enantiomer is present with an enantiomer excess (%ee) of ≥99%.

[0360] L. Additional Form

[0361] The compounds and salts disclosed herein can exist in various tautomeric forms, and this specification covers all such tautomeric forms. A “tautomer” is a structural isomer that exists in equilibrium due to the migration of hydrogen atoms.

[0362] The compounds disclosed herein and their pharmaceutically acceptable salts may exist as solvates (such as hydrates) as well as in non-solvated forms, and this specification covers all such solvates.

[0363] The compounds disclosed herein and their pharmaceutically acceptable salts may exist in crystalline or amorphous forms, and all such forms are covered in this specification.

[0364] The compounds and salts disclosed herein may be isotopically labeled (or “radiolabeled”). In this case, one or more atoms are replaced by atoms having an atomic mass or mass number different from those commonly found in nature. This specification covers isotopically labeled forms of the compounds disclosed herein. Examples of isotopes that may be incorporated include… 2 H (also written as "D", representing deuterium) 3 H (also written as "T", representing tritium) 11 C 13 C 14 C 13 N、 15 N、 15 O、 17 O、 18 O and 36 Cl. The isotope used will depend on the specific application of the radiolabeled derivative. For example, for in vitro receptor labeling and competitive assays, 3 H or14 C is often useful. For radiographic imaging applications, 11 C is often useful. In some implementations, the radionuclide is... 3 H. In some implementations, the radionuclide is 14 C. In some implementations, the radionuclide is 11 C.

[0365] M. Intermediate

[0366] In some embodiments, this disclosure provides additional compounds that can be used as intermediates for the preparation of the compounds of this disclosure and their pharmaceutically acceptable salts.

[0367] III. How to Use

[0368] The disclosed compounds and their pharmaceutically acceptable salts are inhibitors of prolyl endopeptidase fibroblast activating protein (FAP) activity. FAP is an endopeptidase that enzymatically cleaves substrates involved in glucose and lipid metabolism, fibrinolysis, and collagen production.

[0369] FAP is thought to cleave and inactivate human fibroblast growth factor 21 (FGF-21) (Biochem.J. 2016, 473, 605), a protein involved in the regulation of glucose and lipid metabolism. It is hypothesized that inhibition of FAP increases endogenous FGF-21 levels and signaling, leading to effects such as reduced steatosis, improved insulin sensitivity, improved glucose tolerance, weight loss, and / or reduced cardiovascular mortality.

[0370] FAP is also thought to cleave human α2-antifibrinolytic enzyme (α2AP) (Blood 2004103, 3783), a protein involved in the regulation of fibrosis and fibrinolysis. Tissue repair involves coagulation, which leads to fibrin deposition. Fibrin in clots is typically cleaved primarily by plasminogen activator when converted from its inactive form (plasminogen). 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 caused by tissue trauma. FAP converts α2AP into a form that binds more effectively to fibrin, which reduces plasminogenic degradation of fibrin at the site of injury. It is speculated that inhibition of FAP increases fibrinolysis and improves tissue regeneration at the site of injury (J.Thromb.Haemost.2013,11,2029;Proteomics Clin.Appl.2014,8,454).

[0371] FAP is further thought to promote collagen production and deposition, and to play a role in increasing fibrosis by altering extracellular matrix (ECM) turnover (J Biol Chem 2016, 8, 291). It is speculated that inhibition of FAP will reduce collagen deposition and alleviate inflammation (Inflamm.Bowel Dis. 2018, 18, 332).

[0372] Given the above, it is speculated that FAP inhibition reduces fibrosis and inflammation by decreasing hepatic stellate cell activity and increasing fibrinolysis, and further provides a positive metabolic effect by increasing FGF21 signaling and improving glucose tolerance.

[0373] Therefore, in some embodiments, this disclosure provides a method for treating or preventing FAP-mediated conditions in a subject by administering a therapeutically effective amount of a compound of formula I or a pharmaceutically acceptable salt thereof to that subject in need.

[0374] In some embodiments, this disclosure provides a method for treating or preventing a condition characterized by FAP overexpression in 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.

[0375] In some embodiments, this disclosure provides a method for treating or preventing liver disease in a subject by administering a therapeutically effective amount of a compound of the disclosure or a pharmaceutically acceptable salt thereof to the subject in need. In one aspect, the liver disease is fatty liver disease. In another aspect, the liver disease is non-alcoholic fatty liver disease (NAFLD). In yet another aspect, NAFLD is selected from the group consisting of: isolated steatosis, non-alcoholic steatohepatitis (NASH), liver fibrosis, and cirrhosis. In yet another aspect, the liver disease is end-stage liver disease. In yet another aspect, the subject also has or is susceptible to one or more conditions selected from the group consisting of: obesity, dyslipidemia, insulin resistance, type 2 diabetes, and renal insufficiency.

[0376] In some embodiments, this disclosure provides a method for treating a subject with liver disease by administering a therapeutically effective amount of a compound of this disclosure or a pharmaceutically acceptable salt thereof to a subject in need, wherein the subject has a liver condition of 27 kg / m². 2 Up to 40kg / m 2 Body Mass Index (BMI). In one respect, the subject had a body mass index (BMI) of 30 kg / m². 2 Up to 39.9 kg / m 2 BMI. On the other hand, the subject had a BMI of at least 40 kg / m². 2 The subject's BMI. In another aspect, the subject was overweight. In another aspect, the subject was obese. In another aspect, the liver disease was NAFLD. In another aspect, the liver disease was NASH. In another aspect, the liver disease was liver fibrosis. In another aspect, the liver disease was cirrhosis.

[0377] In some embodiments, this disclosure provides a method for treating a subject with liver disease by administering a therapeutically effective amount of a compound of this disclosure or a pharmaceutically acceptable salt thereof to a subject in need, wherein the subject also has or is susceptible to dyslipidemia. In another aspect, the liver disease is NAFLD. In another aspect, the liver disease is NASH. In another aspect, the liver disease is liver fibrosis. In another aspect, the liver disease is cirrhosis.

[0378] In some embodiments, this disclosure provides a method for treating a subject with liver disease by administering a therapeutically effective amount of a compound of this disclosure or a pharmaceutically acceptable salt thereof to a subject in need, wherein the subject also has or is susceptible to insulin resistance. In another aspect, the liver disease is NAFLD. In another aspect, the liver disease is NASH. In another aspect, the liver disease is liver fibrosis. In another aspect, the liver disease is cirrhosis.

[0379] In some embodiments, this disclosure provides a method for treating a subject with liver disease by administering a therapeutically effective amount of a compound of the disclosure or a pharmaceutically acceptable salt thereof to a subject in need, wherein the subject also has or is susceptible to at least one of type 2 diabetes and renal insufficiency. In another aspect, the liver disease is NAFLD. In another aspect, the liver disease is NASH. In another aspect, the liver disease is liver fibrosis. In another aspect, the liver disease is cirrhosis.

[0380] In some embodiments, this disclosure provides a method for treating a subject with liver disease by administering a therapeutically effective amount of a compound of the disclosure or a pharmaceutically acceptable salt thereof to a subject in need, wherein the subject also has or is susceptible to type 2 diabetes. In another aspect, the liver disease is NAFLD. In another aspect, the liver disease is NASH. In another aspect, the liver disease is liver fibrosis. In another aspect, the liver disease is cirrhosis.

[0381] In some embodiments, this disclosure provides a method for treating a subject with liver disease by administering a therapeutically effective amount of a compound of this disclosure or a pharmaceutically acceptable salt thereof to a subject in need, wherein the subject also has 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.

[0382] In some embodiments, this disclosure provides a method for reducing liver fat in a subject by administering a therapeutically effective amount of a compound of this disclosure or a pharmaceutically acceptable salt thereof to a subject in need. In one aspect, the subject has or is susceptible to NAFLD. In another aspect, the subject has or is susceptible to NASH. In another aspect, the subject has or is susceptible to liver fibrosis. In another aspect, the subject has or is susceptible to cirrhosis. In yet another aspect, the subject also has or is susceptible to one or more conditions selected from the group consisting of: obesity, dyslipidemia, insulin resistance, type 2 diabetes, and renal insufficiency.

[0383] In some embodiments, this disclosure provides a method for treating or preventing nonalcoholic fatty liver disease (NAFLD) in a subject by administering a therapeutically effective amount of a compound of the disclosure or a pharmaceutically acceptable salt thereof to the subject in need. In one aspect, the NAFLD is stage 1 NAFLD. In another aspect, the NAFLD is stage 2 NAFLD. In another aspect, the NAFLD is stage 3 NAFLD. In another aspect, the NAFLD is stage 4 NAFLD. See, for example, “The Diagnosis and Management of Nonalcoholic Fatty Liver Disease: Practice Guidance From the American Association for the Study of Liver Diseases,” Hepatology, 2018, Vol. 67, No. 1. In another aspect, the subject also has or is susceptible to one or more conditions selected from the group consisting of: obesity, dyslipidemia, insulin resistance, type 2 diabetes, and renal insufficiency.

[0384] In some embodiments, this disclosure provides a method for treating or preventing nonalcoholic steatohepatitis (NASH) in a subject by administering a therapeutically effective amount of a compound of the disclosure or a pharmaceutically acceptable salt thereof to the subject in need. 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 yet another aspect, the subject also has or is susceptible to one or more conditions selected from the group consisting of: obesity, dyslipidemia, insulin resistance, type 2 diabetes, and renal insufficiency.

[0385] In some embodiments, this disclosure provides a method for treating or preventing liver fibrosis in 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. In one aspect, the subject has stage 3 liver fibrosis. In another aspect, the subject also has or is susceptible to one or more conditions selected from the group consisting of: obesity, dyslipidemia, insulin resistance, type 2 diabetes, and renal insufficiency.

[0386] In some embodiments, this disclosure provides a method for treating or preventing cirrhosis in 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. In one aspect, the subject has stage F4 cirrhosis. In another aspect, the subject also has or is susceptible to one or more conditions selected from the group consisting of: obesity, dyslipidemia, insulin resistance, type 2 diabetes, and renal insufficiency.

[0387] In some embodiments, this disclosure provides a method for treating or preventing type 2 diabetes in 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. In one aspect, the subject is a subject with diabetic nephropathy. In another aspect, the subject has renal insufficiency. In yet another aspect, the administration of the compound is an adjunct to diet and exercise. In yet another aspect, the administration of the compound also reduces weight and / or treats obesity. In yet another aspect, the subject has a weight of 27 kg / m². 2 Up to 40kg / m 2 BMI. On another note, the subject had a BMI of 30 kg / m². 2 Up to 39.9 kg / m 2 BMI. On the other hand, the subject had a BMI of at least 40 kg / m². 2 The subjects had different BMIs. On one hand, the subjects were overweight. On the other hand, the subjects were obese.

[0388] In some embodiments, this disclosure provides a method for improving glycemic control in 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. 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 has renal insufficiency. In another aspect, the administration of the compound is an adjunct to diet and exercise. In another aspect, the administration of the compound also reduces weight and / or treats obesity. In another aspect, the subject has a weight of 27 kg / m². 2 Up to 40kg / m 2 BMI. On another note, the subject had a BMI of 30 kg / m². 2 Up to 39.9 kg / m 2 BMI. On the other hand, the subject had a BMI of at least 40 kg / m². 2 The subjects had different BMIs. On one hand, the subjects were overweight. On the other hand, the subjects were obese.

[0389] In some embodiments, this disclosure provides a method for improving glycemic control in a subject suffering from type 2 diabetes and diabetic nephropathy by administering a therapeutically effective amount of a compound of the disclosure or a pharmaceutically acceptable salt thereof. In one aspect, the administration of the compound is an adjunct to diet and exercise. In another aspect, the administration of the compound also reduces weight and / or treats obesity. In yet another aspect, the subject has a weight of 27 kg / m². 2 Up to 40kg / m 2 BMI. On another note, the subject had a BMI of 30 kg / m². 2 Up to 39.9 kg / m 2 BMI. On the other hand, the subject had a BMI of at least 40 kg / m². 2 The subjects had different BMIs. On one hand, the subjects were overweight. On the other hand, the subjects were obese.

[0390] In some embodiments, this disclosure provides a method for improving glycemic control in a subject suffering from type 2 diabetes and renal insufficiency by administering a therapeutically effective amount of a compound of the disclosure or a pharmaceutically acceptable salt thereof. In one aspect, the administration of the compound is an adjunct to diet and exercise. In another aspect, the administration of the compound also reduces weight and / or treats obesity. In yet another aspect, the subject has a weight of 27 kg / m². 2 Up to 40kg / m 2 BMI. On another note, the subject had a BMI of 30 kg / m². 2 Up to 39.9 kg / m 2 BMI. On the other hand, the subject had a BMI of at least 40 kg / m². 2 The subjects had different BMIs. On one hand, the subjects were overweight. On the other hand, the subjects were obese.

[0391] In some embodiments, this disclosure provides a method for treating or preventing insulin resistance in 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. 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 has renal insufficiency. Insulin resistance can be measured, for example, using the Homeostasis Model Assessment of Insulin Resistance (HOMA-IR) and / or the Matsuda index. HOMA-IR is explained, for example, in Diabetologia 1985, 28, 412, the full text of which is incorporated herein by reference. The Matsuda index is explained, for example, in Diabetes Care 1999, 22, 1462, the full text of which is incorporated herein by reference.

[0392] In some embodiments, this disclosure provides a method of treating or preventing glucose intolerance in 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. In one aspect, the subject is a subject with type 2 diabetes. In another aspect, the subject is a subject with diabetic nephropathy. In yet another aspect, the subject has renal insufficiency.

[0393] In some embodiments, this disclosure provides a method of treating or preventing cardiovascular disease in a subject by administering a therapeutically effective amount of a compound of the disclosure or a pharmaceutically acceptable salt thereof to the subject requiring treatment. In one aspect, the cardiovascular disease is selected from the group consisting of: heart failure, cardiomyopathy, atherosclerosis, venous thromboembolism, and atrial fibrillation. In one aspect, the cardiovascular disease is heart failure. In another aspect, the cardiovascular disease is heart failure with preserved ejection fraction (HFpEF). In another aspect, the cardiovascular disease is cardiomyopathy. In another aspect, the cardiomyopathy is selected from the group consisting of: hypertrophic cardiomyopathy, dilated cardiomyopathy, restrictive cardiomyopathy, ischemic cardiomyopathy, dilated cardiomyopathy, and idiopathic cardiomyopathy. In another aspect, the cardiovascular disease is atherosclerosis. In another aspect, the cardiovascular disease is venous thromboembolism. In another aspect, the cardiovascular disease is atrial fibrillation.

[0394] In some embodiments, this disclosure provides a method of treating or preventing obesity or obesity-related conditions in a subject by administering a therapeutically effective amount of a compound of the disclosure or a pharmaceutically acceptable salt thereof to that subject in need. In one aspect, obesity-related conditions are obesity-related metabolic disorders. In another aspect, obesity-related conditions are selected from the group consisting of insulin resistance, prediabetes, type 2 diabetes, glucose intolerance, increased fasting glucose, and glucagonoma. In another aspect, obesity-related conditions are dyslipidemia. In another aspect, obesity-related conditions are cardiovascular conditions selected from the group consisting of heart failure, cardiomyopathy, atherosclerosis, venous thromboembolism, and atrial fibrillation. In another aspect, obesity-related conditions are kidney disease.

[0395] In some embodiments, this disclosure provides a method for reducing the weight 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. 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 has renal insufficiency. In another aspect, the administration of the compound is an adjunct to diet and exercise. In another aspect, the administration of the compound also reduces weight and / or treats obesity. In another aspect, the subject has a weight of 27 kg / m². 2 Up to 40kg / m 2 BMI. On another note, the subject had a BMI of 30 kg / m². 2 Up to 39.9 kg / m 2 BMI. On the other hand, the subject had a BMI of at least 40 kg / m². 2 The subjects' BMI. In another respect, the subjects were overweight. In another respect, the subjects were obese. In another respect, the subjects' weight had decreased by, for example, at least about 5%, 10%, 15%, 20%, 25%, 30%, 35%, or 40%.

[0396] In some embodiments, this disclosure provides a method for reducing body fat in a subject by administering a therapeutically effective amount of a compound of the disclosure or a pharmaceutically acceptable salt thereof to a subject requiring 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 has renal insufficiency. In another aspect, the administration of the compound is an adjunct to diet and exercise. In another aspect, the administration of the compound also reduces weight and / or treats obesity. In another aspect, the subject has a body fat percentage of 27 kg / m². 2 Up to 40kg / m 2 BMI. On another note, the subject had a BMI of 30 kg / m². 2 Up to 39.9 kg / m 2 BMI. On the other hand, the subject had a BMI of at least 40 kg / m². 2 The subjects had different BMIs. In another respect, they were overweight. In another respect, they were obese. In another respect, the fat was liver fat.

[0397] In some embodiments, this disclosure provides a method for treating or preventing fibrosis in a subject by administering a therapeutically effective amount of a compound of the disclosure or a pharmaceutically acceptable salt thereof to the subject in need. In one aspect, fibrosis is interstitial lung disease. In another aspect, fibrosis is interstitial lung disease with progressive fibrosis. In yet another aspect, interstitial lung disease is pulmonary fibrosis. In yet another aspect, interstitial lung disease is idiopathic pulmonary fibrosis (IPF).

[0398] In some embodiments, this disclosure provides a method for promoting tissue remodeling in 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. In one aspect, the subject suffers from cardiac tissue damage due to myocardial infarction.

[0399] In some embodiments, this disclosure provides a method for promoting wound healing and / or reducing adhesions in a subject by administering a therapeutically effective amount of a compound of the disclosure or a pharmaceutically acceptable salt thereof to that subject in need. In one aspect, the administration of the compound promotes wound healing and / or reduces adhesions by increasing fibrinolysis.

[0400] In some embodiments, this disclosure provides a method for treating or preventing keloid disorder in a subject by administering a therapeutically effective amount of a compound of the disclosure or a pharmaceutically acceptable salt thereof to the subject in need. In one aspect, the keloid disorder is selected from the group consisting of: scar formation, keloid tumors, and keloid scars.

[0401] In some embodiments, this disclosure provides a method for treating or preventing inflammation in a subject by administering a therapeutically effective amount of a compound of the disclosure or a pharmaceutically acceptable salt thereof to that subject in need. In one aspect, the inflammation is chronic inflammation. In another aspect, chronic inflammation is selected from the group consisting of rheumatoid arthritis, osteoarthritis, and Crohn's disease. In yet another aspect, chronic inflammation is rheumatoid arthritis.

[0402] In some embodiments, this disclosure provides a method of treating or preventing cancer in a subject by administering a therapeutically effective amount of a compound of the disclosure or a pharmaceutically acceptable salt thereof to the subject in need of treatment. In one aspect, the cancer is selected from the group consisting of: breast cancer, pancreatic cancer, small bowel cancer, colon cancer, rectal cancer, lung cancer, head and neck cancer, ovarian cancer, hepatocellular carcinoma, esophageal cancer, hypopharyngeal cancer, nasopharyngeal carcinoma, laryngeal cancer, myeloma cells, bladder cancer, cholangiocarcinoma, clear cell renal cell carcinoma, neuroendocrine tumors, carcinogenic osteomalacia, sarcoma, CUP (unknown primary cancer), thymic carcinoma, desmoid tumor, glioma, astrocytic tumor, cervical cancer, and prostate cancer. In another aspect, the cancer is hepatocellular carcinoma.

[0403] The subjects treated are typically human or non-human mammals, especially humans. 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 crab-eating macaques or long-tailed macaques), marmosets, tamarins, chimpanzees, macaques, etc.); and rodents (including rats, mice, gerbils, guinea pigs, etc.).

[0404] In some embodiments, this disclosure provides compounds of this disclosure or pharmaceutically acceptable salts thereof for use as medicaments.

[0405] In some embodiments, this disclosure provides the use of compounds of Formula I or pharmaceutically acceptable salts thereof for the treatment or prevention of FAP-mediated conditions as discussed above.

[0406] In some embodiments, this disclosure provides the use of compounds of Formula I or pharmaceutically acceptable salts thereof in the preparation of medicaments for treating or preventing FAP-mediated conditions as discussed above.

[0407] IV. Combination therapy and fixed-dose combination

[0408] The compounds disclosed herein can be used as a single pharmacological agent or in combination with other pharmacological agents or technologies in the methods described above. Such combination therapies can be achieved by administering the individual components simultaneously, sequentially, or separately. These combination therapies (and corresponding combination products) use the compounds of this disclosure within the dose range described in this application and other pharmacological agents typically within their approved dose ranges.

[0409] In some embodiments, this disclosure provides combinations suitable for treating conditions selected from those previously discussed, wherein the combination comprises a compound of this disclosure or a pharmaceutically acceptable salt thereof, and a sodium-glucose transporter 2 (SGLT2) inhibitor. In one aspect, the SGLT2 inhibitor is selected from the group consisting of canagliflozin, dapagliflozin, empagliflozin, eleggliflozin, ilagliflozin, lupugliflozin, and repaggliflozin. In another aspect, the SGLT2 inhibitor is dapagliflozin.

[0410] In some embodiments, this disclosure provides a combination suitable for treating conditions selected from those previously discussed, wherein the combination comprises a compound of this disclosure or a pharmaceutically acceptable salt thereof, and metformin.

[0411] In some embodiments, this disclosure provides combinations suitable for treating conditions selected from those previously discussed, wherein the combination comprises a compound of the disclosure or a pharmaceutically acceptable salt thereof, and a glucagon-like peptide-1 receptor (GLP1) agonist. In one aspect, the GLP1 agonist is selected from the group consisting of exenatide, liraglutide, lixinatide, abiglutide, dulaglutide, and semaglutide.

[0412] In some embodiments, this disclosure provides combinations suitable for treating conditions selected from those previously discussed, wherein the combination comprises a compound of the disclosure or a pharmaceutically acceptable salt thereof, and a dipeptidyl peptidase 4 (DPP4) inhibitor. In one aspect, the DPP4 inhibitor is selected from the group consisting of: sitagliptin, vendalliptin, saxagliptin, linagliptin, giglitazone, angliptin, terliliptin, alogliptin, treagliptin, ocagliptin, elegliptin, gogliptin, and dugliptin.

[0413] In some embodiments, this disclosure provides combinations suitable for treating conditions selected from those previously discussed, wherein the combination comprises a compound of this disclosure or a pharmaceutically acceptable salt thereof, and a peroxisome proliferator-activated receptor (PPAR) agonist. In one aspect, the PPAR agonist is a PPARα agonist. In another aspect, the PPAR agonist is a PPARγ agonist. In yet another aspect, the PPAR agonist is a PPARα / γ agonist. In yet another aspect, the PPAR agonist is selected from the group consisting of: clofibrate, gemfibrozil, ciprofibrate, bezafibrate, and fenofibrate. In yet another aspect, the PPAR agonist is a thiazolidinedione. In yet another aspect, the thiazolidinedione is selected from the group consisting of: pioglitazone, rosiglitazone, lobeglitazone, and linaglitazone. In yet another aspect, the PPAR agonist stimulates hepatic expression of FGF21.

[0414] In some embodiments, this disclosure provides a pharmaceutical composition comprising a compound of the 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 conditions selected from those previously discussed. In one aspect, the pharmaceutical composition comprises an SGLT2 inhibitor. In another aspect, the pharmaceutical composition comprises metformin. In another aspect, the pharmaceutical composition comprises a GLP1 agonist. In another aspect, the pharmaceutical composition comprises a DPP4 inhibitor. In another aspect, the pharmaceutical composition comprises a PPAR agonist.

[0415] In some embodiments, this disclosure provides combinations suitable for treating cancer, wherein the combination comprises a compound of the disclosure or a pharmaceutically acceptable salt thereof, and an immune checkpoint inhibitor. In one aspect, the immune checkpoint inhibitor is selected from the group consisting of: anti-PD-1 antibodies, anti-PD-L1 antibodies, anti-CTLA4 antibodies, TLR7 agonists, CD40 agonists, Lag-3 antagonists, and OX40 agonists. In another aspect, the immune checkpoint inhibitor is an anti-PD-1 antibody (e.g., pembrolizumab (Keytruda), nivolumab (Opdivo), cimipril (Libtayo), etc.). In yet another aspect, the immune checkpoint inhibitor is an anti-PD-L1 antibody (e.g., atezolizumab (Tecentriq), avelumab (Bavencio), durvalumab (Imfinzi), etc.). In yet another aspect, the immune checkpoint inhibitor is an anti-CTLA4 antibody (e.g., iplimumab (Yervoy), trimemumab, etc.). On the other hand, cancers are selected from the following groups: pancreatic cancer, colon cancer, and rectal cancer.

[0416] V. Pharmaceutical Composition

[0417] The compounds disclosed herein and their pharmaceutically acceptable salts can be administered as pharmaceutical compositions comprising one or more pharmaceutically acceptable excipients. Therefore, in some embodiments, this disclosure provides pharmaceutical compositions comprising the compounds disclosed herein or their pharmaceutically acceptable salts, and at least one pharmaceutically acceptable excipient.

[0418] 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, 6th Edition, Pharmaceutical Press, edited by Ray C. Rowe, Paul J. Sheskey, and Marian Quinn. Pharmaceutically acceptable excipients can function as, for example, adjuvants, diluents, carriers, stabilizers, flavoring agents, coloring agents, fillers, binders, disintegrants, lubricants, flow aids, thickeners, and coating agents. As those skilled in the art will understand, some pharmaceutically acceptable excipients can perform more than one function and can perform alternative functions, depending on the amount of excipient present in the composition and what other excipients are present in the composition.

[0419] The composition may be in the form suitable for oral administration (e.g., as tablets, lozenges, hard or soft capsules, aqueous or oily suspensions, emulsions, dispersible powders or granules, syrups or elixirs), suitable for topical administration (e.g., as creams, ointments, gels, or aqueous or oily solutions or suspensions), suitable for inhalation administration (e.g., as fine powders or liquid aerosols), suitable for inhalation administration (e.g., as fine powders), or suitable for parenteral administration (e.g., as sterile aqueous or oily solutions for intravenous, subcutaneous, or intramuscular administration), or suitable for rectal administration as a suppository. The composition can be obtained using conventional pharmaceutical excipients known in the art through conventional processes. Therefore, compositions intended for oral use may contain, for example, one or more colorants, sweeteners, flavoring agents, and / or preservatives.

[0420] The total daily dose will have to vary depending on the subject being treated, the specific route of administration, any co-administered therapies, and the severity of the disease being treated, and may include a single dose or multiple doses. Specific doses may be adjusted, for example, based on factors such as: the condition being treated; the subject's age, weight, general health condition, sex, and diet; the route of administration; the dosing interval; the excretion rate; and any other drugs co-administered to the subject. Those skilled in the art who understand the disclosure of this application will be able to determine appropriate doses and regimens for administering the therapeutic agent to a subject using methods well known in the therapeutic field, and to adjust such doses and regimens as needed during treatment. The compounds disclosed herein, or pharmaceutically acceptable salts thereof, will generally be administered at a dose of 2.5 mg / m². 2 Up to 5000 mg / m 2 Administer a unit dose to warm-blooded animals at a dose that is approximately 0.05 mg / kg to 100 mg / kg of animal body area, and this usually provides a therapeutically effective dose.

[0421] In some embodiments, this disclosure provides pharmaceutical compositions for use in a therapy, the pharmaceutical composition comprising a compound of the disclosure or a pharmaceutically acceptable salt thereof and at least one pharmaceutically acceptable excipient.

[0422] In some embodiments, this disclosure provides pharmaceutical compositions for use in treating FAP-mediated conditions, the pharmaceutical composition comprising a compound of the disclosure or a pharmaceutically acceptable salt thereof and at least one pharmaceutically acceptable excipient. In one aspect, FAP-mediated conditions are selected from the group consisting of: liver disease, type 2 diabetes, cardiovascular disease, obesity, obesity-related conditions, fibrosis, keloid disorders, inflammation, and cancer.

[0423] VI. Reagent Kit

[0424] This disclosure also provides a kit containing a unit dosage form and a label or package insert, the unit dosage form containing a compound of the disclosure or a pharmaceutically acceptable salt thereof contained in packaging material, the label or package insert indicating that the unit dosage form can be used to treat one or more of the previously described conditions.

[0425] In some embodiments, the kit comprises a unit dosage form and a label or package insert containing a compound of the present disclosure or a pharmaceutically acceptable salt thereof contained within packaging material, the label or package insert indicating that the pharmaceutical composition can be used to treat FAP-mediated conditions. In another aspect, FAP-mediated conditions are liver diseases. In another aspect, liver diseases are selected from the group consisting of: fatty liver disease, end-stage liver disease, and cirrhosis. In another aspect, liver diseases are selected from the group consisting of: non-alcoholic steatohepatitis (NASH) and non-alcoholic fatty liver disease (NAFLD).

[0426] In some embodiments, the kit comprises: (a) a first unit dosage form comprising a compound of the present disclosure or a pharmaceutically acceptable salt thereof; (b) a second unit dosage form comprising a pharmacological agent selected from the group consisting of SGLT2 inhibitors, metformin, GLP1 agonists, DPP4 inhibitors, and PPAR agonists; (c) a container device for containing the first and second dosage forms; and (d) a label or package insert indicating that the first and second unit dosage forms can be used to treat FAP-mediated conditions.

[0427] VII. Preparation Method

[0428] This disclosure also provides methods for preparing compounds of formulas (I), (II), (III-A), (III-B), (III-C), (III-D), (III-E), (IV), and (IV-A), and their pharmaceutically acceptable salts. Reaction schemes 1 to 10 illustrate synthetic routes for these compounds, wherein, unless otherwise stated, R... 1 R 2 R 3 R 5 and R 6 As defined in equation (I); R 7 It is an alkyl group (e.g., methyl, ethyl, tert-butyl, etc.); R 8 and R 9 It is an alkyl group, an aryl group, or hydrogen; X 1 It is S, S(O) or S(O)2; X 2 and X 3It is a leaving group (e.g., Cl, Br, I, OM, OT, OTf, etc.); and PG 1 These are protecting groups. Those skilled in the art will understand that these methods are representative and do not include all possible methods for preparing the compounds of this disclosure.

[0429] Option 1

[0430]

[0431] Scheme 1 illustrates the synthetic route for certain compounds of formula (I). Compounds of formula (2) can react with compounds of formula (3) to yield compounds of formula (I). This reaction can be carried out using suitable coupling agents (e.g., HATU, HOBt / EDC, T3P, etc.) in the presence of a base (usually an organic base such as DIPEA or TEA) and a solvent (such as DCM, DMF, EtOAc, MeCN, or mixtures thereof) at temperatures typically ranging from 0°C to 60°C.

[0432] Option 2

[0433]

[0434] Scheme 2 illustrates the synthetic route for certain compounds of formula (2). Compounds of formula (2) can be synthesized by reacting compounds of formula (4) with a base (e.g., NaOH, LiOH, etc.) in an organic solvent (e.g., 1,4-dioxanone). It is formed by reacting alkane, THF, MeOH, or mixtures thereof, and optionally in the presence of water. The reaction can be carried out over a temperature interval from 0°C to reflux. Alternatively, for alkane, THF, MeOH, or mixtures thereof, R... 7 = tert-butyl compounds of formula (4), the reaction can be carried out in solvents (such as 1,4-dimethylbutylene oxide) The reaction can be carried out in alkanes, EtOAc, MeOH, water, or mixtures thereof with a suitable acid (e.g., HCl). Alternatively, the reaction can be carried out in pure carboxylic acids (such as TFA) or in solvents (such as DCM) at a temperature typically in the range of 0°C to 60°C.

[0435] Option 3

[0436]

[0437] Scheme 3 illustrates the synthetic routes for certain compounds of formula (4). Compounds of formula (5) can be synthesized by reacting with alkyl halides (typically alkyl bromides) of formula (6) (where R...). 2 As defined in equation (I) and Y 1As defined above, the reaction transforms the compound into the compound of formula (4). This reaction can be carried out under blue LED illumination, typically at 20°C, in a suitable solvent (such as DME) in the presence of HSi(SiMe3)3 and a base (such as Na2CO3), using a Ni catalyst (such as NiBr2, DME, etc.) and a suitable ligand (such as dtbbpy, etc.) and a suitable photo-redox catalyst (such as Ir[dF(CF3)ppy]2(dtbbpy)PF6, etc.).

[0438] Alternatively, the compound of formula (4) can be formed by reacting the compound of formula (5) with the alkyl halide of formula (6) using the methods and conditions described in the following publications: MacMillan DWC et al. J. Am. Chem. Soc. 2020, 142, 11691-11697; Weix DJ et al. J. Am. Chem. Soc. 2010, 132, 920–921; Weix DJ et al. Nat. Chem. 2016, 8, 1126–1130; Gong H. et al. J. Am. Chem. Soc. 2015, 137, 11562-11565; and Gong H. et al. J. Am. Chem. Soc. 2018, 140, 14490-14497.

[0439] Alternatively, the compound of formula (4) can be obtained by reacting the compound of formula (5) with an alkyl ether of formula (6) (where R... 2 As defined in equation (I) and Y 1 It is formed by the reaction of hydrogen. This reaction can be carried out under blue LED illumination, typically at 20°C, in a suitable solvent (such as MeCN), in the presence of a base (such as K3PO4), with a Ni catalyst (such as NiBr2 dtbbpy) and a suitable photo-redox catalyst (such as TBADT).

[0440] Alternatively, the compound of formula (4) can be obtained by reacting the compound of formula (5) with an aryl or alkylboron reagent of formula (6) (where R... 2 As defined in equation (I) and Y 1 It is formed by the reaction of boron derivatives (such as boric acid, trifluoroborate, etc.). This reaction can typically be carried out at temperatures ranging from 20°C to reflux in a suitable solvent (such as 1,4-dioxanone). In alkanes, THF, etc., catalysis is carried out in the presence of bases (such as K2CO3, Na2CO3, etc.) via Pd catalysts (such as PdCl2(dppf)DCM, etc.).

[0441] Alternatively, the compound of formula (4) can be reacted with the alkylboron reagent of formula (6) using the methods and conditions described in the following publications (where R... 2 As defined in equation (I) and Y 1 It is formed by the reaction of boron derivatives (such as boric acid, trifluoroborate, etc.): Org. Lett. 2018, 20, 2867-2871.

[0442] Alternatively, the compound of formula (4) can be obtained from the compound of formula (5) by reacting it with an alcohol or phenol of formula (6) (where R... 2 As defined in equation (I) and Y 1 It is formed by hydrogen. This reaction can be carried out in suitable solvents (such as toluene, 1,4-dihydrogen). Catalysis is carried out in alkanes, etc., in the presence of a base (such as K3PO4, etc.) with a suitable Pd reagent (e.g., Pd(OAc)2, etc.) and a suitable phosphine ligand (e.g., XPhos, t-BuXPhos, etc.), and at elevated temperatures.

[0443] Alternatively, the compound of formula (4) can be obtained from the compound of formula (5) by reacting it with an alcohol or phenol of formula (6) (where R... 2 As defined in equation (I) and Y 1 It is formed by hydrogen. The reaction can be promoted at elevated temperatures in a suitable solvent (such as DMF) in the presence of a base (such as K2CO3, Cs2CO3) and a free radical initiator (such as AIBN) with a suitable Cu reagent (e.g., CuBr).

[0444] Alternatively, the compound of formula (4) can be obtained by reacting the compound of formula (5) with the compound of formula (6) (where R... 2 As defined in equation (I) and Y 1 It is formed by the reaction of hydrogen (which is hydrogen). This reaction can occur in suitable solvents (such as 1,4-dihydrogen). Catalysis is carried out in alkanes, etc., in the presence of a base (such as NaHMDS, Cs2CO3, etc.) with a suitable Pd reagent (e.g., Pd(OAc)2, etc.) and a suitable phosphine ligand (e.g., BINAP, SPhos, etc.), and at elevated temperatures.

[0445] Option 4

[0446]

[0447] Scheme 4 illustrates the synthetic routes for certain compounds of formula (4). Compounds of formula (8) can be synthesized from compounds of formula (7) (where R...). 8 It is a hydrogen or alkyl group and R 9It is formed by the reaction of hydrogen with an oxidizing agent (such as Dess-Martin periodinane). This reaction can usually be carried out at a temperature in the range of 0°C to 40°C in a suitable solvent (such as DCM).

[0448] Compound of formula (4) (where R) 2 As defined in formula (I), it can be formed by reacting the compound of formula (8) with a fluorinating agent (such as DAST) in a suitable solvent (such as DCM, THF, etc.) at a temperature typically in the range of 0°C to 60°C.

[0449] Alternatively, the compound of formula (4) can be formed by reducing the compound of formula (8) with a reducing agent (such as sodium borohydride). The reaction can be carried out in a solvent (such as methanol) at a temperature typically in the range of 0°C to 40°C.

[0450] Alternatively, the compound of formula (4) can be formed by reacting the compound of formula (8) with a Grignard reagent (such as MeMgCl, MeMgBr, etc.). This reaction can be carried out in a suitable solvent (such as diethyl ether, THF, etc.) at a temperature typically in the range of -78°C to 40°C.

[0451] Alternatively, the compound of formula (4) can be obtained by reacting the compound of formula (8) with a sulfonyl hydrazine such as 4-methylbenzenesulfonyl hydrazine in a suitable solvent (such as 1,4-dimethylbenzenesulfonyl hydrazine). It is formed by condensation in alkanes, etc. The intermediate hydrazone can then be reacted with boric acid. This reaction can be carried out according to the procedure described in the following literature, typically at reflux temperature in the presence of an alkali (such as K₂CO₃ or Na₂CO₃) and in a suitable solvent (such as 1,4-dioxane). (Alkane, etc.) were used in: Barluenga J. et al. Nat. Chem. 2009, 1, 494-499.

[0452] Alternatively, compounds of formula (4) (where R) 2 As defined in formula (I), it can be formed by reacting the compound of formula (7) with a fluorinating agent (such as DAST) in a suitable solvent (such as DCM, THF, etc.) at a temperature typically in the range of 0°C to 60°C.

[0453] Alternatively, the compound of formula (4) can be formed from the compound of formula (7) by reacting it with an alkyl halide (such as MeI) or another alkylating agent (such as an alkyl sulfonate, alkyl trifluoromethanesulfonate, etc.). This reaction can be carried out using a base (such as NaH) in a solvent (such as THF, 1,4-dimethylamine). (e.g., alkyl)

[0454] Option 5

[0455]

[0456] Scheme 5 illustrates the synthetic routes for certain compounds of formula (7). Compounds of formula (8) (where R...) 8 Alkyl groups (such as methyl groups, etc.) can be formed by reacting a compound of formula (5) with a trialkyl(1-alkoxyvinyl)tin reagent (such as tributyl(1-ethoxyvinyl)tin, etc.). This reaction can be carried out in a suitable solvent (such as toluene, 1,4-dimethylsiloxane, etc.). Catalysis can be carried out in alkanes and at temperatures typically from 80°C to reflux using Pd reagents such as PdCl2(dppf)DCM, Pd(PPh3)4, etc.

[0457] Alternatively, compounds of formula (8) (where R) 8 (Is hydrogen) can be formed by reacting the compound of formula (5) with formic acid and acetic anhydride. The reaction can be carried out in a suitable solvent (such as DMF) and at a temperature typically in the range of 80°C to 120°C with a Pd reagent (such as PdOAc2) and a suitable ligand (such as butyl-1-adamantylphosphine) with NaHCO3 and TEA.

[0458] Compound of formula (7) (where R) 8 and R 9 (Is hydrogen) can be formed by reacting a compound of formula (5) with a (trialkyltinyl)methanol reagent (such as (tributyltinyl)methanol, etc.). This reaction can be carried out in a suitable solvent (such as toluene, 1,4-dimethylsilane, etc.). Catalysis can be carried out in alkanes and at temperatures typically from 80°C to reflux using Pd reagents such as PdCl2(dppf)DCM, Pd(PPh3)4, etc.

[0459] Alternatively, compounds of formula (7) (where R) 9 (Is hydrogen) can be formed by reducing the compound of formula (8) with a reducing agent (such as sodium borohydride). The reaction can be carried out in a solvent (such as methanol) at a temperature typically in the range of 0°C to 40°C.

[0460] Alternatively, compounds of formula (7) (where R) 9 (where alkyl groups are present) can be formed from compounds of formula (8) by reacting with Grignard reagents (such as MeMgCl, MeMgBr, etc.). This reaction can typically be carried out at temperatures ranging from -78°C to 40°C in a suitable solvent (such as diethyl ether, THF, etc.).

[0461] Option 6

[0462]

[0463] Scheme 6 illustrates the synthetic routes for certain compounds of formula (4). Compounds of formula (9) can be synthesized from compounds of formula (7) (where R...). 8 and R 9 It is formed by reacting hydrogen or alkyl groups with a suitable reagent (such as thionyl chloride, MsCl, etc.). The reaction can usually be carried out at a temperature in the range of 0°C to 40°C in a suitable solvent (such as DCM, etc.).

[0464] The compound of formula (4) can be derived from the compound of formula (9) (where R) 8 and R 9 It is formed by the reaction of hydrogen or alkyl groups with alcohols. This reaction can usually be carried out at 0°C to 40°C in the presence of a base (such as NaH) and a suitable solvent (such as THF, DMF, etc.).

[0465] Alternatively, the compound of formula (4) can be derived from the compound of formula (9) (where R... 8 and R 9 It is formed by the reaction of hydrogen or alkyl groups with amines. The reaction can be carried out at temperatures typically from 0°C to 80°C in the presence of a base (such as TEA, Cs2CO3, etc.) and a suitable solvent (such as MeCN, DMF, etc.) with or without additives (such as KI).

[0466] Option 7

[0467]

[0468] Scheme 7 illustrates the synthetic routes for certain compounds of formula (4). Compounds of formula (4) can be synthesized from compounds of formula (10) (where Y...). 2 Boron derivatives (such as boric acid, borate esters, trifluoroborate esters, etc.) are reacted with a reagent of formula (11) (where R 2 As defined in equation (I) and X 2 It is formed by the reaction of a leaving group as defined above. This reaction can be carried out in suitable solvents (such as toluene, 1,4-dimethylbenzene, ... In alkanes, etc., with or without anhydrous conditions and at temperatures typically in the range of 80°C to 120°C, catalyzed by Pd reagents (such as PdCl2(dppf)DCM, trans-bromo(N-succinimide)-bis(diphenylphosphine)palladium(II), etc.).

[0469] Alternatively, the compound of formula (4) can be derived from the compound of formula (10) (where Y... 2Boric acid is formed by reacting with a sulfonylhydrazone (usually toluenesulfonylhydrazone) of an aldehyde or ketone. This reaction can be performed according to the procedures described in the following literature, typically at reflux temperature in the presence of a base (such as K₂CO₃, Na₂CO₃, etc.) and in a suitable solvent (such as 1,4-dioxanone). (Alkane, etc.) were used in: Barluenga J. et al. Nat. Chem. 2009, 1, 494-499.

[0470] Option 8

[0471]

[0472] Scheme 8 illustrates the synthetic routes for certain compounds of formula (4). Compounds of formula (4) (where R...) 2 As defined in formula (I), it can be formed by reacting a compound of formula (12) with an alkyl halide, alkyl sulfonate or alkyl trifluoromethanesulfonate of formula (11). The reaction can be promoted in a suitable solvent (such as DMF) and at a temperature typically in the range of 20°C to 100°C by a base (such as Cs2CO3, K2CO3, etc.).

[0473] Alternatively, the compound of formula (4) can be obtained from the compound of formula (12) by reacting with an alcohol of formula (11) (where R... 2 As defined in equation (I) and X 2 It is formed by the reaction of hydroxyl groups. This reaction can be carried out in a suitable solvent (such as THF) and at a temperature typically in the range of 20°C to 60°C in the presence of phosphine (such as Ph3P) and azodicarboxylic acid esters (such as DIAD).

[0474] Option 9

[0475]

[0476] Scheme 9 illustrates the synthetic routes for certain compounds of formula (12). Compounds of formula (10) (where Y...) 2 Boron derivatives (such as boric acid, borate esters, trifluoroborate esters, etc.) can be derived from compounds of formula (5) (where X... 2 It is formed by the leaving group (as defined above) and a boron reagent (such as B2(OH)4 or B2pin2). This reaction can typically be carried out at temperatures ranging from 80°C to 120°C in a suitable solvent (such as toluene, 1,4-dioxane). Catalysis in alkanes, EtOH, etc. is achieved through Pd reagents (such as PdCl2(dppf)DCM, etc.) and bases (such as KOAc, etc.).

[0477] The compound of formula (12) can be derived from the compound of formula (10) (where Y) 2It is formed from boron derivatives (such as boric acid, borate esters, etc.). The reaction can be promoted at room temperature in a suitable solvent (such as a THF / water mixture) by a suitable reagent (such as NaBO3).

[0478] Option 10

[0479]

[0480] Scheme 10 illustrates the synthetic routes for certain compounds of formula (7). Compounds of formula (14) can be synthesized from compounds of formula (13) (where X...). 2 and X 3 As defined above, and selected in the following manner: X 2 It can selectively react with organometallic reagents (such as BuLi, etc.) and then with an aldehyde or ketone of formula (15) (where R 8 and R 9 As defined above, the reaction is formed. This reaction can be carried out in a suitable solvent (such as THF) and is typically conducted at low temperatures ranging from -78°C to 0°C.

[0481] The compound of formula (7) can be formed by reacting the compound of formula (14) with carbon monoxide at a pressure typically between 1 atmosphere and 10 atmospheres and a temperature typically between 80°C and 120°C in a sealed container. This reaction can be carried out in a suitable solvent or using an alcohol as a solvent in the presence of a suitable alcohol (such as MeOH, EtOH, etc.) and catalyzed by a suitable Pd reagent (such as Pd(dppf)Cl2, etc.) in the presence of a base (such as TEA, etc.).

[0482] It should be understood that the organic reactions described herein were performed based on laboratory practice known to those skilled in the art. It should be understood that some of the reactions described herein may optionally be performed in a different order than those listed herein. It should be understood that the chiral isomers of the compounds described herein can be separated using chiral resolving agents described in the literature and known to those skilled in the art, or chiral chromatographic methods described in the literature and known to those skilled in the art, or as further described in the examples.

[0483] It should also be understood that additional protecting groups may optionally be required in some of the steps described above, and it should also be understood that 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 in “Protective Groups in Organic Synthesis”, 3rd edition, TW Greene and PGM Utz, Wiley-Interscience (1999), the disclosure of which is incorporated herein by reference.

[0484] VIII. Numbering Implementation Scheme

[0485] Implementation Scheme 1. A compound having the structure of formula (I):

[0486]

[0487] Or its pharmaceutically acceptable salt, wherein:

[0488] X 1 Choose from the following groups: -S-, -S(O)-, and -S(O)2-;

[0489] R 1 Choose from the following groups: hydrogen, halogen, hydroxyl, C 1-3 -alkyl and C 1-6 -alkoxy group;

[0490] R 2 Choose from the following groups:

[0491] (a)C 1-6 -alkyl, wherein the C 1-6 The alkyl group is optionally substituted with one or more substituents, said one or more substituents being independently selected from the group consisting of: halogen, hydroxyl, cyano, C 3-6 -Cycloalkyl, halogenated-C 3-6 -cycloalkyl, C 1-6 -alkoxy, halogenated-C 1-6 -alkoxy group, C 3-6 -cycloalkoxy, halogenated-C 3-6 -cycloalkoxy, C 1-6 -alkoxy-C 1-6 -alkoxy, oxetane, tetrahydrofuranyl, tetrahydrofuranyloxy, tetrahydropyranyl, morpholinyl, pyrazolyl, iso Azolyl, triazolyl, and pyridyl; and wherein said oxetyl, tetrahydrofuranyl, tetrahydrofuranyloxy, tetrahydropyranyl, morpholinyl, pyrazolyl, iso The azole, triazole, and pyridyl groups are optionally substituted by one or more substituents, said one or more substituents being independently selected from the group consisting of: halogen, cyano, C 1-6 -alkyl and halogenated-C 1-6 -alkyl;

[0492] (b)C 3-6 -cycloalkyl, wherein the C 3-6 -The cycloalkyl group is optionally substituted by one or more substituents, said one or more substituents being independently selected from the group consisting of: halogen, hydroxyl, cyano, C 1-6 -alkyl, halo-C 1-6-alkyl, C 1-6 -alkoxy, halogenated-C 1-6 -alkoxy, isoalkoxy azole group and pyridinyl group; wherein the iso The azole and pyridyl groups are optionally substituted by one or more substituents, said one or more substituents being independently selected from the group consisting of: halogens, C 1-6 -alkyl and halogenated-C 1-6 -alkyl;

[0493] (c) Phenyl, wherein the phenyl group is optionally substituted with one or more substituents, the one or more substituents being independently selected from the group consisting of: halogen, cyano, C 1-6 -alkyl, halo-C 1-6 -alkyl, C 1-6 -alkoxy, halogenated-C 1-6 -alkoxy and C 1-6 -alkoxy-C 1-6 -alkoxy group; and

[0494] (d) A 4-, 5-, 6-, or 7-membered heterocyclic group, wherein the heterocyclic ring: (i) is a saturated, partially saturated, or fully unsaturated monocyclic or fused bicyclic ring, (ii) has one or two oxygen ring atoms and the remaining ring atoms are carbon, and (iii) is optionally substituted with one or more substituents, said one or more substituents being independently selected from the group consisting of: halogen, hydroxyl, cyano, C 1-6 -alkyl, halo-C 1-6 -alkyl, C 2-6 -Alynyl group, C 1-6 -alkoxy and halogenated-C 1-6 -alkoxy group; and

[0495] (e)-OR 7 , where R 7 Choose from the following groups: C 1-6 -alkyl, phenyl and tetrahydropyranyl; wherein:

[0496] (i) The C 1-6 The alkyl group is optionally substituted with one or more substituents, said one or more substituents being independently selected from the group consisting of: halogen, cyano, C 3-6 -Cycloalkyl, halogenated-C 3-6 -cycloalkyl, C 1-6 -alkoxy and halogenated-C 1-6 -alkoxy group;

[0497] (ii) The phenyl group is optionally substituted with one or more substituents, which are independently selected from the group consisting of: halogens, C 1-6-alkyl, halo-C 1-6 -alkyl, C 1-6 -alkoxy and halogenated-C 1-6 -alkoxy group; and

[0498] (iii) The tetrahydropyranyl group is optionally substituted with one or more substituents, said one or more substituents being independently selected from the group consisting of: halogens, C 1-6 -alkyl, halo-C 1-6 -alkyl, C 1-6 -alkoxy and halogenated-C 1-6 -alkoxy group;

[0499] R 3 Choose from the following groups: hydrogen, halogens, and carbon. 1-3 -alkyl;

[0500] R 4 Choose from the following groups: hydrogen, halogens, and carbon. 1-3 -alkyl;

[0501] R 5 Choose from the following groups: hydrogen, halogens, and carbon. 1-3 -alkyl; and

[0502] R 6 Choose from the following groups: hydrogen, halogens, and carbon. 1-3 -alkyl.

[0503] Implementation Scheme 2. The compound or a pharmaceutically acceptable salt thereof according to Implementation Scheme 1, wherein the compound has the structure of formula (II):

[0504]

[0505] Where X 1 R 1 R 2 R 3 R 4 R 5 and R 6 As defined in Implementation Scheme 1.

[0506] Implementation Scheme 3. The compound or a pharmaceutically acceptable salt thereof as described in Implementation Scheme 1 or 2, wherein X 1 Yes -S-.

[0507] Implementation Scheme 4. The compound or a pharmaceutically acceptable salt thereof as described in Implementation Scheme 1 or 2, wherein X 1 It is -S(O)-.

[0508] Implementation Scheme 5. The compound or a pharmaceutically acceptable salt thereof according to Implementation Scheme 1 or 2, wherein X1 It is -S(O)2-.

[0509] Implementation Scheme 6. The compound or a pharmaceutically acceptable salt thereof according to any one of Implementation Schemes 1 to 5, wherein R 1 Choose from the following groups: hydrogen, halogens, and carbon. 1-3 -alkyl.

[0510] Implementation Scheme 7. The compound or a pharmaceutically acceptable salt thereof according to any one of Implementation Schemes 1 to 5, wherein R 1 Choose from the following groups: hydrogen, chlorine, fluorine, and methyl.

[0511] Implementation Scheme 8. The compound or a pharmaceutically acceptable salt thereof according to any one of Implementation Schemes 1 to 5, wherein R 1 It is hydrogen.

[0512] Implementation Scheme 9. The compound or a pharmaceutically acceptable salt thereof according to any one of Implementation Schemes 1 to 5, wherein R 1 It is chlorine.

[0513] Implementation Scheme 10. The compound or a pharmaceutically acceptable salt thereof according to any one of Implementation Schemes 1 to 5, wherein R 1 It's fluorine.

[0514] Implementation Scheme 11. The compound or a pharmaceutically acceptable salt thereof according to any one of Implementation Schemes 1 to 5, wherein R 1 It is a methyl group.

[0515] Implementation Scheme 12. The compound or a pharmaceutically acceptable salt thereof according to any one of Implementation Schemes 1 to 11, wherein R 3 Choose from the following groups: hydrogen, chlorine, fluorine, and methyl.

[0516] Implementation Scheme 13. The compound or a pharmaceutically acceptable salt thereof according to any one of Implementation Schemes 1 to 11, wherein R 3 It is hydrogen.

[0517] Implementation Scheme 14. The compound or a pharmaceutically acceptable salt thereof according to any one of Implementation Schemes 1 to 11, wherein R 3 It is chlorine.

[0518] Implementation Scheme 15. The compound or a pharmaceutically acceptable salt thereof according to any one of Implementation Schemes 1 to 11, wherein R 3 It's fluorine.

[0519] Implementation Scheme 16. The compound or a pharmaceutically acceptable salt thereof according to any one of Implementation Schemes 1 to 11, wherein R 3 It is a methyl group.

[0520] Implementation Scheme 17. The compound or a pharmaceutically acceptable salt thereof according to any one of Implementation Schemes 1 to 16, wherein R 4 Choose from the following groups: hydrogen, halogens, and methyl.

[0521] Implementation Scheme 18. The compound or a pharmaceutically acceptable salt thereof according to any one of Implementation Schemes 1 to 16, wherein R 4 It is hydrogen.

[0522] Implementation Scheme 19. The compound or a pharmaceutically acceptable salt thereof according to any one of Implementation Schemes 1 to 16, wherein R 4 It is chlorine.

[0523] Implementation Scheme 20. The compound or a pharmaceutically acceptable salt thereof according to any one of Implementation Schemes 1 to 16, wherein R 4 It's fluorine.

[0524] Implementation Scheme 21. The compound or a pharmaceutically acceptable salt thereof according to any one of Implementation Schemes 1 to 16, wherein R 4 It is a methyl group.

[0525] Implementation Scheme 22. The compound or a pharmaceutically acceptable salt thereof according to any one of Implementation Schemes 1 to 21, wherein R 5 Choose from the following groups: hydrogen, chlorine, fluorine, and methyl.

[0526] Implementation Scheme 23. The compound or a pharmaceutically acceptable salt thereof according to any one of Implementation Schemes 1 to 21, wherein R 5 It is hydrogen.

[0527] Implementation Scheme 24. The compound or a pharmaceutically acceptable salt thereof according to any one of Implementation Schemes 1 to 21, wherein R 5 It's fluorine.

[0528] Implementation Scheme 25. The compound or a pharmaceutically acceptable salt thereof according to any one of Implementation Schemes 1 to 21, wherein R 5 It is chlorine.

[0529] Implementation Scheme 26. The compound or a pharmaceutically acceptable salt thereof according to any one of Implementation Schemes 1 to 21, wherein R 5 It is a methyl group.

[0530] Implementation Scheme 27. The compound or a pharmaceutically acceptable salt thereof according to any one of Implementation Schemes 1 to 26, wherein R 6 Choose from the following groups: hydrogen, chlorine, fluorine, and methyl.

[0531] Implementation Scheme 28. The compound or a pharmaceutically acceptable salt thereof according to any one of Implementation Schemes 1 to 26, wherein R 6 It is hydrogen.

[0532] Implementation Scheme 29. The compound or a pharmaceutically acceptable salt thereof according to any one of Implementation Schemes 1 to 26, wherein R 6 It is chlorine.

[0533] Implementation Scheme 30. The compound or a pharmaceutically acceptable salt thereof according to any one of Implementation Schemes 1 to 26, wherein R 6 It's fluorine.

[0534] Implementation Scheme 31. The compound or a pharmaceutically acceptable salt thereof according to any one of Implementation Schemes 1 to 26, wherein R 6 It is a methyl group.

[0535] Implementation Scheme 32. The compound or a pharmaceutically acceptable salt thereof according to any one of Implementation Schemes 1 to 5, wherein R 1 R 3 R 4 R 5 and R 6 One of the substituents is selected from the group consisting of: halogens and C. 1-3 -alkyl, and the remaining R 1 R 3 R 4 R 5 and R 6 All the substituents are hydrogen.

[0536] Implementation Scheme 33. The compound or a pharmaceutically acceptable salt thereof according to Implementation Scheme 32, wherein R 1 R 3 R 4 R 5 and R 6 One of the substituents is selected from the group consisting of chlorine, fluorine, and methyl, and the remaining R... 1 R 3 R 4 R 5 and R 6 All the substituents are hydrogen.

[0537] Implementation Scheme 34. The compound or a pharmaceutically acceptable salt thereof according to Implementation Scheme 32, wherein R 1 R 3 R 4 R 5 and R 6 One of the substituents is selected from the group consisting of chlorine and fluorine, and the remaining R...1 R 3 R 4 R 5 and R 6 All the substituents are hydrogen.

[0538] Implementation Scheme 35. The compound or a pharmaceutically acceptable salt thereof according to Implementation Scheme 32, wherein R 1 R 3 R 4 R 5 and R 6 One of the substituents is methyl, and the remaining R 1 R 3 R 4 R 5 and R 6 All the substituents are hydrogen.

[0539] Implementation Scheme 36. A compound or a pharmaceutically acceptable salt thereof according to any one of Implementation Schemes 32 to 35, wherein the compound has the structure of formula (III-A):

[0540]

[0541] Where R 1 and R 2 As defined in Implementation Scheme 1.

[0542] Implementation Scheme 37. A compound or a pharmaceutically acceptable salt thereof according to any one of Implementation Schemes 32 to 35, wherein the compound has the structure of formula (III-B):

[0543]

[0544] Where R 2 and R 3 As defined in Implementation Scheme 1.

[0545] Implementation Scheme 38. A compound or a pharmaceutically acceptable salt thereof according to any one of Implementation Schemes 32 to 35, wherein the compound has the structure of formula (III-C):

[0546]

[0547] Where R 2 and R 4 As defined in Implementation Scheme 1.

[0548] Implementation Scheme 39. A compound or a pharmaceutically acceptable salt thereof according to any one of Implementation Schemes 32 to 35, wherein the compound has a structure of formula (III-D):

[0549]

[0550] Where R 2 and R 5 As defined in Implementation Scheme 1.

[0551] Implementation Scheme 40. A compound or a pharmaceutically acceptable salt thereof according to any one of Implementation Schemes 32 to 35, wherein the compound has the structure of formula (III-E):

[0552]

[0553] Where R 2 and R 6 As defined in Implementation Scheme 1.

[0554] Implementation Scheme 41. The compound or a pharmaceutically acceptable salt thereof according to any one of Implementation Schemes 1 to 5, wherein R 1 R 3 R 4 R 5 and R 6 At least two of the substituents are independently selected from the group consisting of halogens and C. 1-3 -alkyl, and the remaining R 1 R 3 R 4 R 5 and R 6 All the substituents are hydrogen.

[0555] Implementation Scheme 42. The compound or a pharmaceutically acceptable salt thereof according to Implementation Scheme 41, wherein R 1 R 3 R 4 R 5 and R 6 The two substituents in the substituents are independently selected from the group consisting of chlorine, fluorine, and methyl, and the remaining R... 1 R 3 R 4 R 5 and R 6 All the substituents are hydrogen.

[0556] Implementation Scheme 43. The compound or a pharmaceutically acceptable salt thereof according to Implementation Scheme 42, wherein R 1 R 3 R 4 R 5 and R 6 At least one of the substituents is chlorine.

[0557] Implementation Scheme 44. The compound or a pharmaceutically acceptable salt thereof according to Implementation Scheme 42, wherein R 1 R 3 R 4 R 5 and R 6 At least one of the substituents is fluorine.

[0558] Implementation Scheme 45. The compound or a pharmaceutically acceptable salt thereof according to Implementation Scheme 42, wherein R 1 R 3 R 4 R 5 and R 6 At least one of the substituents is methyl.

[0559] Implementation Scheme 46. The compound or a pharmaceutically acceptable salt thereof according to Implementation Scheme 1, wherein the compound has the structure of formula (IV):

[0560]

[0561] Where R 2 As defined in Implementation Scheme 1.

[0562] Implementation Scheme 47. The compound or a pharmaceutically acceptable salt thereof according to Implementation Scheme 1, wherein the compound has the structure of formula (IV-A):

[0563]

[0564] Where R 2 As defined in Implementation Scheme 1.

[0565] Implementation Scheme 48. The compound or a pharmaceutically acceptable salt thereof according to any one of Implementation Schemes 1 to 47, wherein R 2 It is C 1-6 -alkyl, wherein the C 1-6 The alkyl group is optionally substituted with one or more substituents, said one or more substituents being independently selected from the group consisting of: halogen, hydroxyl, cyano, C 3-6 -Cycloalkyl, halogenated-C 3-6 -cycloalkyl, C 1-6 -alkoxy, halogenated-C 1-6 -alkoxy group, C 3-6 -cycloalkoxy, halogenated-C 3-6 -cycloalkoxy, C 1-6 -alkoxy-C 1-6 -alkoxy, oxetane, tetrahydrofuranyl, tetrahydrofuranyloxy, tetrahydropyranyl, morpholinyl, pyrazolyl, iso Azolyl, triazolyl, and pyridyl; and wherein said oxetyl, tetrahydrofuranyl, tetrahydrofuranyloxy, tetrahydropyranyl, morpholinyl, pyrazolyl, iso The azole, triazole, and pyridyl groups are optionally substituted by one or more substituents, said one or more substituents being independently selected from the group consisting of: halogens, C 1-6 -alkyl and halogenated-C 1-6 -alkyl.

[0566] Implementation Scheme 49. The compound or a pharmaceutically acceptable salt thereof according to any one of Implementation Schemes 1 to 47, wherein R 2 It is C 1-3 -alkyl, wherein the C 1-3 The alkyl group is optionally substituted with one or more substituents, said one or more substituents being independently selected from the group consisting of: halogen, hydroxyl, cyano, C 3-6 -Cycloalkyl, halogenated-C 3-6 -cycloalkyl, C 1-3 -alkoxy group, halogenated-C 1-3 -alkoxy group, C 3-6 -cycloalkoxy, halogenated-C 3-6 -cycloalkoxy, C 1-3 -alkoxy-C 1-3 -alkoxy, oxetane, tetrahydrofuranyl, tetrahydrofuranyloxy, tetrahydropyranyl, morpholinyl, pyrazolyl, iso Azolyl, triazolyl, and pyridyl; and wherein said oxetyl, tetrahydrofuranyl, tetrahydrofuranyloxy, tetrahydropyranyl, morpholinyl, pyrazolyl, iso The azole, triazole, and pyridyl groups are optionally substituted by one or more substituents, said one or more substituents being independently selected from the group consisting of: halogens, C 1-3 -alkyl and halogenated-C 1-3 -alkyl.

[0567] Implementation Scheme 50. The compound or a pharmaceutically acceptable salt thereof according to any one of Implementation Schemes 1 to 47, wherein R 2 It is C 1-6 -alkyl, wherein the C 1-6 -The alkyl group is optionally substituted with one or more substituents, said one or more substituents being independently selected from the group consisting of: halogens, hydroxyl groups, C 1-6 -alkoxy group, halogenated-C 1-6 -alkoxy group, C 3-6 -cycloalkoxy, C 1-6 -alkoxy-C 1-6 -alkoxy, tetrahydrofuranyl, tetrahydrofuranyloxy, tetrahydropyranyl, morpholinyl, pyrazolyl, iso Azolyl, triazolyl, and pyridyl; and wherein said tetrahydrofuranyl, tetrahydrofuranyloxy, tetrahydropyranyl, morpholinyl, pyrazolyl, iso The azole, triazole, and pyridyl groups are optionally substituted by one or more substituents, said one or more substituents being independently selected from the group consisting of: halogens, C 1-6 -alkyl and halogenated-C 1-6 -alkyl.

[0568] Implementation Scheme 51. The compound or a pharmaceutically acceptable salt thereof according to any one of Implementation Schemes 1 to 47, wherein R 2 It is C 1-3 -alkyl, wherein the C 1-3 -The alkyl group is optionally substituted with one or more substituents, said one or more substituents being independently selected from the group consisting of: halogens, hydroxyl groups, C 1-3 -alkoxy, halogenated-C 1-3 -alkoxy group, C 3-6 -cycloalkoxy, C 1-3 -alkoxy-C 1-3 -alkoxy, tetrahydrofuranyl, tetrahydrofuranyloxy, tetrahydropyranyl, morpholinyl, pyrazolyl, iso Azolyl, triazolyl, and pyridyl; and wherein said tetrahydrofuranyl, tetrahydrofuranyloxy, tetrahydropyranyl, morpholinyl, pyrazolyl, iso The azole, triazole, and pyridyl groups are optionally substituted by one or more substituents, said one or more substituents being independently selected from the group consisting of: halogens, C 1-3 -alkyl and halogenated-C 1-6 -alkyl.

[0569] Implementation Scheme 52. The compound or a pharmaceutically acceptable salt thereof according to any one of Implementation Schemes 1 to 47, wherein R 2 It is C 1-6 -alkyl.

[0570] Implementation Scheme 53. The compound or a pharmaceutically acceptable salt thereof according to any one of Implementation Schemes 1 to 47, wherein R 2 It is C 1-6 -alkyl, wherein the C 1-6 -The alkyl group is optionally replaced by one or more halogens.

[0571] Implementation Scheme 54. The compound or a pharmaceutically acceptable salt thereof according to any one of Implementation Schemes 1 to 47, wherein R 2 It is C 1-6 -alkyl, wherein the C 1-6 -The alkyl group is optionally substituted with one or more fluorine molecules.

[0572] Implementation Scheme 55. The compound or a pharmaceutically acceptable salt thereof according to any one of Implementation Schemes 1 to 47, wherein R 2 It is C 1-6 -alkyl, wherein the C 1-6 -The alkyl group is optionally replaced by one or more hydroxyl groups.

[0573] Implementation Scheme 56. The compound or a pharmaceutically acceptable salt thereof according to any one of Implementation Schemes 1 to 47, wherein R 2 It is C 1-6 -alkyl, wherein the C 1-6 -Alkyl groups are optionally separated by one or more C groups. 1-6 -Alkyl substitution.

[0574] Implementation Scheme 57. The compound or a pharmaceutically acceptable salt thereof according to any one of Implementation Schemes 1 to 47, wherein R 2 It is C 1-6 -alkyl, wherein the C 1-6 -Alkyl groups are optionally halogenated by one or more -C 1-6 -Alkyl substitution.

[0575] Implementation Scheme 58. The compound or a pharmaceutically acceptable salt thereof according to any one of Implementation Schemes 1 to 47, wherein R 2 It is C 1-6 -alkyl, wherein the C 1-6 -Alkyl groups are optionally separated by one or more C groups. 3-6 - Cycloalkoxy substitution.

[0576] Implementation Scheme 59. The compound or a pharmaceutically acceptable salt thereof according to any one of Implementation Schemes 1 to 47, wherein R 2 It is C 1-6 -alkyl, wherein the C 1-6 -Alkyl groups are optionally separated by one or more C groups. 1-6 -alkoxy-C 1-6 -Alkyl substitution.

[0577] Implementation Scheme 60. The compound or a pharmaceutically acceptable salt thereof according to any one of Implementation Schemes 1 to 47, wherein R 2 It is C 1-6 -alkyl, wherein the C 1-6 The alkyl group is optionally substituted with one or more tetrahydrofuranyl groups, wherein the tetrahydrofuranyl group is optionally substituted with one or more substituents, the one or more substituents being independently selected from the group consisting of: halogens, C 1-6 -alkyl and halogenated-C 1-6 -alkyl.

[0578] Implementation Scheme 61. The compound or a pharmaceutically acceptable salt thereof according to any one of Implementation Schemes 1 to 47, wherein R 2 It is C 1-6 -alkyl, wherein the C 1-6 The alkyl group is optionally substituted with one or more tetrahydrofuranyloxy groups, wherein the tetrahydrofuranyloxy group is optionally substituted with one or more substituents, the one or more substituents being independently selected from the group consisting of: halogens, C 1-6 -alkyl and halogenated-C 1-6 -alkyl.

[0579] Implementation Scheme 62. The compound or a pharmaceutically acceptable salt thereof according to any one of Implementation Schemes 1 to 47, wherein R 2 It is C 1-6 -alkyl, wherein the C 1-6 The alkyl group is optionally substituted with one or more tetrahydropyranyl groups, wherein the tetrahydropyranyl groups are optionally substituted with one or more substituents, the one or more substituents being independently selected from the group consisting of: halogens, C 1-6 -alkyl and halogenated-C 1-6 -alkyl.

[0580] Implementation Scheme 63. The compound or a pharmaceutically acceptable salt thereof according to any one of Implementation Schemes 1 to 47, wherein R 2 It is C 1-6 -alkyl, wherein the C 1-6 The alkyl group is optionally substituted with one or more morpholino groups, wherein the morpholino groups are optionally substituted with one or more substituents, the one or more substituents being independently selected from the group consisting of: halogens, C 1-6 -alkyl and halogenated-C 1-6 -alkyl.

[0581] Implementation Scheme 64. The compound or a pharmaceutically acceptable salt thereof according to any one of Implementation Schemes 1 to 47, wherein R 2 It is C 1-6 -alkyl, wherein the C 1-6 The alkyl group is optionally substituted with one or more pyrazolyl groups, wherein the pyrazolyl group is optionally substituted with one or more substituents, the one or more substituents being independently selected from the group consisting of: halogens, C 1-6 -alkyl and halogenated-C 1-6 -alkyl.

[0582] Implementation Scheme 65. The compound or a pharmaceutically acceptable salt thereof according to any one of Implementation Schemes 1 to 47, wherein R 2 It is C 1-6 -alkyl, wherein the C 1-6-Alkyl groups are optionally separated by one or more isocyanates. Azolium substitution, wherein the iso The azole group may optionally be substituted by one or more substituents, said one or more substituents being independently selected from the group consisting of: halogens, C 1-6 -alkyl and halogenated-C 1-6 -alkyl.

[0583] Implementation Scheme 66. The compound or a pharmaceutically acceptable salt thereof according to any one of Implementation Schemes 1 to 47, wherein R 2 It is C 1-6 -alkyl, wherein the C 1-6 The alkyl group is optionally substituted with one or more triazole groups, wherein the triazole groups are optionally substituted with one or more substituents, the one or more substituents being independently selected from the group consisting of: halogens, C 1-6 -alkyl and halogenated-C 1-6 -alkyl.

[0584] Implementation Scheme 67. The compound or a pharmaceutically acceptable salt thereof according to any one of Implementation Schemes 1 to 47, wherein R 2 It is C 1-6 -alkyl, wherein the C 1-6 The alkyl group is optionally substituted with one or more pyridyl groups, wherein the pyridyl group is optionally substituted with one or more substituents, the one or more substituents being independently selected from the group consisting of: halogens, C 1-6 -alkyl and halogenated-C 1-6 -alkyl.

[0585] Implementation Scheme 68. The compound or a pharmaceutically acceptable salt thereof according to any one of Implementation Schemes 1 to 47, wherein R 2 Choose from the group consisting of: methyl, fluoromethyl, difluoromethyl, trifluoromethyl, hydroxyethyl, hydroxypropyl, ethoxymethyl, difluoroethoxymethyl, methoxyethyl, dimethoxyethyl, difluoropropyl, trifluoropropyl, methoxypropyl, methoxyethoxymethyl, cyclopropoxymethyl, morpholinomethyl, tetrahydrofuranylmethyl, tetrahydrofuranyloxymethyl, tetrahydropyranylmethyl, pyrazolylmethyl, dimethylpyrazolylmethyl, methyl isomethyl azole methyl, methyl iso Azolylethyl, methyltriazolylmethyl, dimethyltriazolylmethyl, dimethylpyridylmethyl, methylpyridylethyl, fluoropyridylethyl, chloropyridylethyl, and trifluoromethylpyridylethyl.

[0586] Implementation Scheme 69. The compound or a pharmaceutically acceptable salt thereof according to Implementation Scheme 1, wherein the compound is selected from the group consisting of:

[0587] N-(2-((R)-4-cyanothiazolidine-3-yl)-2-oxoethyl)-6-((RS)-1-(3-fluoropyridin-2-yl)-ethyl)quinoline-4-carboxamide;

[0588] (R)-N-(2-(4-cyanothiazolidine-3-yl)-2-oxoethyl)-6-(2-hydroxypropyl-2-yl)quinoline-4-carboxamide;

[0589] (R)-N-(2-(4-cyanothiazolidine-3-yl)-2-oxoethyl)-6-(trifluoromethyl)-quinoline-4-carboxamide;

[0590] (R)-N-(2-(4-cyanothiazolidine-3-yl)-2-oxoethyl)-6-(2-methoxypropyl-2-yl)quinoline-4-carboxamide;

[0591] (R)-N-(2-(4-cyanothiazolidine-3-yl)-2-oxoethyl)-6-((2,5-dimethyl-2H-1,2,3-triazol-4-yl)-methyl)quinoline-4-carboxamide;

[0592] (R)-N-(2-(4-cyanothiazolidine-3-yl)-2-oxoethyl)-6-(morpholinomethyl)quinoline-4-carboxamide;

[0593] N-(2-((R)-4-cyanothiazolidine-3-yl)-2-oxoethyl)-6-((RS)-1-hydroxyethyl)quinoline-4-carboxamide;

[0594] N-(2-((R)-4-cyanothiazolidine-3-yl)-2-oxoethyl)-6-((RS)-1-methoxyethyl)quinoline-4-carboxamide;

[0595] (R)-N-(2-(4-cyanothiazolidine-3-yl)-2-oxoethyl)-6-(ethoxymethyl)-quinoline-4-carboxamide;

[0596] (R)-N-(2-(4-cyanothiazolidine-3-yl)-2-oxoethyl)-6-methylquinoline-4-carboxamide;

[0597] (R)-N-(2-(4-cyanothiazolidine-3-yl)-2-oxoethyl)-6-(fluoromethyl)-quinoline-4-carboxamide;

[0598] N-(2-((R)-4-cyanothiazolidine-3-yl)-2-oxoethyl)-6-((RS)-1,2-dimethoxyethyl)quinoline-4-carboxamide;

[0599] (R)-N-(2-(4-cyanothiazolidine-3-yl)-2-oxoethyl)-6-((2-methoxyethoxy)-methyl)quinoline-4-carboxamide;

[0600] N-(2-((R)-4-cyanothiazolidine-3-yl)-2-oxoethyl)-6-((((RS)-tetrahydrofuran-3-yl)oxy)-methyl)quinoline-4-carboxamide;

[0601] (R)-N-(2-(4-cyanothiazolidine-3-yl)-2-oxoethyl)-6-((2,2-difluoroethoxy)methyl)quinoline-4-carboxamide;

[0602] (R)-N-(2-(4-cyanothiazolidine-3-yl)-2-oxoethyl)-6-(cyclopropoxymethyl)quinoline-4-carboxamide;

[0603] (R)-N-(2-(4-cyanothiazolidine-3-yl)-2-oxoethyl)-6-((4-methylisocyano) (3-yl)-methyl)-quinoline-4-carboxamide;

[0604] (R)-N-(2-(4-cyanothiazolidine-3-yl)-2-oxoethyl)-6-((4,6-dimethylpyridin-3-yl)-methyl)quinoline-4-carboxamide;

[0605] (R)-N-(2-(4-cyanothiazolidine-3-yl)-2-oxoethyl)-6-((1,3-dimethyl-1H-pyrazol-5-yl)-methyl)quinoline-4-carboxamide;

[0606] (R)-N-(2-(4-cyanothiazolidine-3-yl)-2-oxoethyl)-6-((2-methyl-2H-1,2,3-triazol-4-yl)-methyl)quinoline-4-carboxamide;

[0607] (R)-N-(2-(4-cyanothiazolidine-3-yl)-2-oxoethyl)-6-((5-methylisocyano) (-3-yl)-methyl)quinoline-4-carboxamide;

[0608] N-(2-((R)-4-cyanothiazolidine-3-yl)-2-oxoethyl)-6-((RS)-1-(5-methylisocyano) (3-yl)-ethyl)quinoline-4-carboxamide;

[0609] 6-((RS)-1-(5-chloropyridin-2-yl)ethyl)-N-(2-((R)-4-cyanothiazolidin-3-yl)-2-oxoethyl)quinoline-4-carboxamide;

[0610] N-(2-((R)-4-cyanothiazolidine-3-yl)-2-oxoethyl)-6-((RS)-1-(3-methylisocyano) (Azol-5-yl)-ethyl)quinoline-4-carboxamide;

[0611] N-(2-((R)-4-cyanothiazolidine-3-yl)-2-oxoethyl)-6-((RS)-1-(6-methylpyridin-3-yl)-ethyl)quinoline-4-carboxamide;

[0612] N-(2-((R)-4-cyanothiazolidine-3-yl)-2-oxoethyl)-6-((RS)-1-(2-(trifluoromethyl)pyridin-4-yl)ethyl)quinoline-4-carboxamide;

[0613] (R)-N-(2-(4-cyanothiazolidine-3-yl)-2-oxoethyl)-6-(2,2-difluoropropyl)quinoline-4-carboxamide;

[0614] (R)-N-(2-(4-cyanothiazolidine-3-yl)-2-oxoethyl)-6-((tetrahydro-2H-pyran-4-yl)-methyl)quinoline-4-carboxamide;

[0615] (R)-N-(2-(4-cyanothiazolidine-3-yl)-2-oxoethyl)-6-(3,3,3-trifluoropropyl)quinoline-4-carboxamide;

[0616] N-(2-((R)-4-cyanothiazolidine-3-yl)-2-oxoethyl)-6-(((RS)-tetrahydrofuran-3-yl)-methyl)quinoline-4-carboxamide;

[0617] (R)-N-(2-(4-cyanothiazolidine-3-yl)-2-oxoethyl)-6-(difluoromethyl)-quinoline-4-carboxamide;

[0618] (R)-6-((1H-pyrazol-1-yl)methyl)-N-(2-(4-cyanothiazolidine-3-yl)-2-oxoethyl)quinoline-4-carboxamide;

[0619] (R)-N-(2-(4-cyanothiazolidine-3-yl)-2-oxoethyl)-6-(3-methoxypropyl)quinoline-4-carboxamide; and

[0620] (R)-N-(2-(4-cyanothiazolidine-3-yl)-2-oxoethyl)-6-(2-methoxyethyl)quinoline-4-carboxamide.

[0621] Implementation Scheme 70. The compound or a pharmaceutically acceptable salt thereof according to any one of Implementation Schemes 1 to 47, wherein R 2 It is C3-6 -cycloalkyl, wherein the C 3-6 -The cycloalkyl group is optionally substituted by one or more substituents, said one or more substituents being independently selected from the group consisting of: halogen, hydroxyl, cyano, C 1-6 -alkyl, halo-C 1-6 -alkyl, C 1-6 -alkoxy group, halogenated-C 1-6 -alkoxy, isoalkoxy azole group and pyridinyl group; wherein the iso The azole and pyridyl groups are optionally substituted by one or more substituents, said one or more substituents being independently selected from the group consisting of: halogens, C 1-6 -alkyl and halogenated-C 1-6 -alkyl.

[0622] Implementation Scheme 71. The compound or a pharmaceutically acceptable salt thereof according to any one of Implementation Schemes 1 to 47, wherein R 2 It is C 3-6 -cycloalkyl, wherein the C 3-6 -The cycloalkyl group is optionally substituted by one or more substituents, said one or more substituents being independently selected from the group consisting of: halogen, hydroxyl, cyano, C 1-3 -alkyl, halo-C 1-3 -alkyl, C 1-3 -alkoxy group, halogenated-C 1-3 -alkoxy, isoalkoxy azole group and pyridinyl group; wherein the iso The azole and pyridyl groups are optionally substituted by one or more substituents, said one or more substituents being independently selected from the group consisting of: halogens, C 1-3 -alkyl and halogenated-C 1-3 -alkyl.

[0623] Implementation Scheme 72. The compound or a pharmaceutically acceptable salt thereof according to any one of Implementation Schemes 1 to 47, wherein R 2 It is C 3-6 -cycloalkyl, wherein the C 3-6 -The cycloalkyl group is optionally substituted with one or more substituents, said one or more substituents being independently selected from the group consisting of: halogen, cyano, C 1-6 -alkoxy, isoalkoxy azole group and pyridinyl group; wherein the iso The azole and pyridyl groups are optionally substituted by one or more substituents, said one or more substituents being independently selected from the group consisting of: halogens, C 1-6 -alkyl and halogenated-C 1-6 -alkyl.

[0624] Implementation Scheme 73. The compound or a pharmaceutically acceptable salt thereof according to any one of Implementation Schemes 1 to 47, wherein R 2 It is C 3-6 -cycloalkyl, wherein the C 3-6 -The cycloalkyl group is optionally substituted with one or more substituents, said one or more substituents being independently selected from the group consisting of: halogen, cyano, C 1-3 -alkoxy, isoalkoxy azole group and pyridinyl group; wherein the iso The azole and pyridyl groups are optionally substituted by one or more substituents, said one or more substituents being independently selected from the group consisting of: halogens, C 1-3 -alkyl and halogenated-C 1-3 -alkyl.

[0625] Implementation Scheme 74. The compound or a pharmaceutically acceptable salt thereof according to any one of Implementation Schemes 1 to 47, wherein R 2 It is C 3-6 -Cycloalkyl.

[0626] Implementation Scheme 75. The compound or a pharmaceutically acceptable salt thereof according to any one of Implementation Schemes 1 to 47, wherein R 2 It is C 3-6 -cycloalkyl, wherein the C 3-6 -The cycloalkyl group is optionally replaced by one or more halogens.

[0627] Implementation Scheme 76. The compound or a pharmaceutically acceptable salt thereof according to any one of Implementation Schemes 1 to 47, wherein R 2 It is C 3-6 -cycloalkyl, wherein the C 3-6 -The cycloalkyl group is optionally replaced by one or more cyano groups.

[0628] Implementation Scheme 77. The compound or a pharmaceutically acceptable salt thereof according to any one of Implementation Schemes 1 to 47, wherein R 2 It is C 3-6 -cycloalkyl, wherein the C 3-6 -Cycloalkyl groups are optionally separated by one or more C groups. 1-6 -Alkyl substitution.

[0629] Implementation Scheme 78. The compound or a pharmaceutically acceptable salt thereof according to any one of Implementation Schemes 1 to 47, wherein R 2 It is C 3-6 -cycloalkyl, wherein the C 3-6 -The cycloalkyl group is optionally separated by one or more isocyanates. Azolium substitution, wherein the iso The azole group may optionally be substituted by one or more substituents, said one or more substituents being independently selected from the group consisting of: halogens, C 1-6 -alkyl and halogenated-C 1-6 -alkyl.

[0630] Implementation Scheme 79. The compound or a pharmaceutically acceptable salt thereof according to any one of Implementation Schemes 1 to 47, wherein R 2 It is C 3-6 -cycloalkyl, wherein the C 3-6 -The cycloalkyl group is optionally substituted with one or more pyridyl groups, wherein the pyridyl group is optionally substituted with one or more substituents, wherein the one or more substituents are independently selected from the group consisting of: halogens, C 1-6 -alkyl and halogenated-C 1-6 -alkyl.

[0631] Implementation Scheme 80. The compound or a pharmaceutically acceptable salt thereof according to any one of Implementation Schemes 70 to 79, wherein R 2 It is an optionally substituted cyclopropyl group.

[0632] Implementation Scheme 81. The compound or a pharmaceutically acceptable salt thereof according to any one of Implementation Schemes 70 to 79, wherein R 2 It is an optional substituted cyclobutyl group.

[0633] Implementation Scheme 82. The compound or a pharmaceutically acceptable salt thereof according to any one of Implementation Schemes 70 to 79, wherein R 2 It is an optional substituted cyclopentyl group.

[0634] Implementation Scheme 83. The compound or a pharmaceutically acceptable salt thereof according to any one of Implementation Schemes 70 to 79, wherein R 2 It is an substituted cyclohexyl group.

[0635] Implementation Scheme 84. The compound or a pharmaceutically acceptable salt thereof according to any one of Implementation Schemes 1 to 47, wherein R 2 Choose from the group consisting of: cyclopropyl, cyanocyclopropyl, ethoxycyclopropyl, methylisopropyl Azolylcyclopropyl, methylpyridylcyclopropyl, chloropyridylcyclopropyl, fluoropyridylcyclopropyl, trifluoropyridylcyclopropyl, fluorocyclobutyl, (fluoro)(methoxy)cyclobutyl, methoxycyclohexyl and cyanocyclohexyl.

[0636] Implementation Scheme 85. The compound or a pharmaceutically acceptable salt thereof according to Implementation Scheme 1, wherein the compound is selected from the group consisting of:

[0637] (R)-N-(2-(4-cyanothiazolidine-3-yl)-2-oxoethyl)-6-(1-(2-(trifluoromethyl)pyridin-4-yl)cyclopropyl)quinoline-4-carboxamide;

[0638] (R)-N-(2-(4-cyanothiazolidine-3-yl)-2-oxoethyl)-6-(1-(6-methylpyridin-3-yl)-cyclopropyl)quinoline-4-carboxamide;

[0639] (R)-N-(2-(4-cyanothiazolidine-3-yl)-2-oxoethyl)-6-(1-(3-fluoropyridin-2-yl)-cyclopropyl)quinoline-4-carboxamide;

[0640] (R)-N-(2-(4-cyanothiazolidine-3-yl)-2-oxoethyl)-6-(1-(5-methylisocyano) (Zol-3-yl)-cyclopropyl)quinoline-4-carboxamide;

[0641] (R)-6-(1-(5-chloropyridin-2-yl)cyclopropyl)-N-(2-(4-cyanothiazolidine-3-yl)-2-oxoethyl)quinoline-4-carboxamide;

[0642] (R)-N-(2-(4-cyanothiazolidine-3-yl)-2-oxoethyl)-6-(1-(3-methylisocyano) (Zol-5-yl)-cyclopropyl)quinoline-4-carboxamide;

[0643] 6-((1r,4R*)-4-cyanocyclohexyl)-N-(2-((R)-4-cyanothiazolidin-3-yl)-2-oxoethyl)-quinoline-4-carboxamide;

[0644] 6-((1r,4R*)-4-cyanocyclohexyl)-N-(2-((R)-4-cyanothiazolidin-3-yl)-2-oxoethyl)-quinoline-4-carboxamide;

[0645] (R)-6-(1-cyanocyclohexyl)-N-(2-(4-cyanothiazolidin-3-yl)-2-oxoethyl)quinoline-4-carboxamide;

[0646] N-(2-((R)-4-cyanothiazolidine-3-yl)-2-oxoethyl)-6-((1r,3R*)-1-fluoro-3-methoxycyclobutyl)quinoline-4-carboxamide isomer 1;

[0647] N-(2-((R)-4-cyanothiazolidine-3-yl)-2-oxoethyl)-6-((1r,3R*)-1-fluoro-3-methoxycyclobutyl)quinoline-4-carboxamide isomer 2;

[0648] (R)-6-(1-cyanocyclopropyl)-N-(2-(4-cyanothiazolidin-3-yl)-2-oxoethyl)quinoline-4-carboxamide;

[0649] (R)-N-(2-(4-cyanothiazolidine-3-yl)-2-oxoethyl)-6-(1-fluorocyclobutyl)quinoline-4-carboxamide;

[0650] (R)-N-(2-(4-cyanothiazolidine-3-yl)-2-oxoethyl)-6-(1-ethoxycyclopropyl)quinoline-4-carboxamide;

[0651] (R)-N-(2-(4-cyanothiazolidine-3-yl)-2-oxoethyl)-6-cyclopropylquinoline-4-carboxamide;

[0652] N-(2-((R)-4-cyanothiazolidine-3-yl)-2-oxoethyl)-6-((1r,4R*)-4-methoxycyclohexyl)-quinoline-4-carboxamide isomer 1; and

[0653] N-(2-((R)-4-cyanothiazolidine-3-yl)-2-oxoethyl)-6-((1r,4R*)-4-methoxycyclohexyl)-quinoline-4-carboxamide isomer 2.

[0654] Implementation Scheme 86. The compound or a pharmaceutically acceptable salt thereof according to any one of Implementation Schemes 1 to 47, wherein R 2 It is a phenyl group, wherein the phenyl group is optionally substituted with one or more substituents, the one or more substituents being independently selected from the group consisting of: halogen, cyano, C 1-6 -alkyl, halo-C 1-6 -alkyl, C 1-6 -alkoxy group, halogenated-C 1-6 -alkoxy and C 1-6 -alkoxy-C 1-6 -alkoxy group.

[0655] Implementation Scheme 87. The compound or a pharmaceutically acceptable salt thereof according to any one of Implementation Schemes 1 to 47, wherein R 2 It is a phenyl group, wherein the phenyl group is optionally substituted with one or more substituents, the one or more substituents being independently selected from the group consisting of: halogen, cyano, C 1-3 -alkyl, halo-C 1-3 -alkyl, C 1-3 -alkoxy group, halogenated-C 1-3 -alkoxy and C 1-3 -alkoxy-C 1-3 -alkoxy group.

[0656] Implementation Scheme 88. The compound or a pharmaceutically acceptable salt thereof according to any one of Implementation Schemes 1 to 47, wherein R 2 It is a phenyl group, wherein the phenyl group is optionally substituted with one or more halogens.

[0657] Implementation Scheme 89. The compound or a pharmaceutically acceptable salt thereof according to any one of Implementation Schemes 1 to 47, wherein R 2 It is a phenyl group, wherein the phenyl group is optionally oxidized by one or more C atoms. 1-6 -Alkyl substitution.

[0658] Implementation Scheme 90. The compound or a pharmaceutically acceptable salt thereof according to any one of Implementation Schemes 1 to 47, wherein R 2 It is a phenyl group, wherein the phenyl group is optionally halogenated by one or more -C groups. 1-6 -Alkyl substitution.

[0659] Implementation Scheme 91. The compound or a pharmaceutically acceptable salt thereof according to any one of Implementation Schemes 1 to 47, wherein R 2 It is a phenyl group, wherein the phenyl group is optionally oxidized by one or more C atoms. 1-6 -Alkyl substitution.

[0660] Implementation Scheme 92. The compound or a pharmaceutically acceptable salt thereof according to any one of Implementation Schemes 1 to 47, wherein R 2 It is a phenyl group, wherein the phenyl group is optionally halogenated by one or more -C groups. 1-6 -Alkyl substitution.

[0661] Implementation Scheme 93. The compound or a pharmaceutically acceptable salt thereof according to any one of Implementation Schemes 1 to 47, wherein R 2 It is a phenyl group, wherein the phenyl group is optionally oxidized by one or more C atoms. 1-6 -alkoxy-C 1-6 -Alkyl substitution.

[0662] Implementation Scheme 94. The compound according to Implementation Scheme 1 or a pharmaceutically acceptable salt thereof, wherein the compound is (R)-N-(2-(4-cyanothiazolidine-3-yl)-2-oxoethyl)-6-(4-(3-methoxy-propoxy)-phenyl)quinoline-4-carboxamide.

[0663] Implementation Scheme 95. The compound or a pharmaceutically acceptable salt thereof according to any one of Implementation Schemes 1 to 47, wherein R 2It is a 4-, 5-, 6-, or 7-membered heterocyclic group, wherein the heterocyclic ring: (i) is a saturated, partially saturated, or fully unsaturated monocyclic or fused bicyclic ring, (ii) has one or two oxygen ring atoms and the remaining ring atoms are carbon, and (iii) is optionally substituted by one or more substituents, said one or more substituents being independently selected from the group consisting of: halogen, hydroxyl, cyano, C 1-6 -alkyl, halo-C 1-6 -alkyl, C 2-6 -Alynyl group, C 1-6 -alkoxy and halogenated-C 1-6 -alkoxy group.

[0664] Implementation Scheme 96. The compound or a pharmaceutically acceptable salt thereof according to any one of Implementation Schemes 1 to 47, wherein R 2 It is a 4-, 5-, 6-, or 7-membered heterocyclic group, wherein the heterocyclic ring: (i) is a saturated, partially saturated, or fully unsaturated monocyclic or fused bicyclic ring, (ii) has one or two oxygen ring atoms and the remaining ring atoms are carbon, and (iii) is optionally substituted by one or more substituents, said one or more substituents being independently selected from the group consisting of: halogen, hydroxyl, cyano, C 1-3 -alkyl, halo-C 1-3 -alkyl, C 2-3 -Alynyl group, C 1-3 -alkoxy and halogenated-C 1-3 -alkoxy group.

[0665] Implementation Scheme 97. The compound or a pharmaceutically acceptable salt thereof according to any one of Implementation Schemes 1 to 47, wherein R 2 It is a 5- or 6-membered heterocyclic group, wherein the heterocyclic ring: (i) is a saturated, partially saturated, or fully unsaturated monocyclic or fused bicyclic ring, (ii) has one or two oxygen ring atoms and the remaining ring atoms are carbon, and (iii) is optionally substituted by one or more substituents, said one or more substituents being independently selected from the group consisting of: halogen, hydroxyl, cyano, C 1-3 -alkyl, C 2-3 -Alynyl group and C 1-3 -alkoxy group.

[0666] Implementation Scheme 98. The compound or a pharmaceutically acceptable salt thereof according to any one of Implementation Schemes 1 to 47, wherein R 2 It is a 4-membered ring heterocyclic group, wherein the heterocyclic ring: (i) is a saturated or partially saturated monocyclic ring, (ii) has one oxygen ring atom and the remaining ring atom is carbon, and (iii) is optionally substituted by one or more substituents, said one or more substituents being independently selected from the group consisting of: halogen, hydroxyl, cyano, C1-6 -alkyl, halo-C 1-6 -alkyl, C 2-6 -Alynyl group, C 1-6 -alkoxy and halogenated-C 1-6 -alkoxy group.

[0667] Implementation Scheme 99. The compound or a pharmaceutically acceptable salt thereof according to any one of Implementation Schemes 1 to 47, wherein R 2 It is a 4-membered ring heterocyclic group, wherein the heterocyclic ring: (i) is a saturated or partially saturated monocyclic ring, (ii) has one oxygen ring atom and the remaining ring atom is carbon, and (iii) is optionally substituted by one or more substituents, said one or more substituents being independently selected from the group consisting of: halogen, hydroxyl, cyano, C 1-3 -alkyl, halo-C 1-3 -alkyl, C 2-3 -Alynyl group, C 1-3 -alkoxy and halogenated-C 1-3 -alkoxy group.

[0668] Implementation Scheme 100. The compound or a pharmaceutically acceptable salt thereof according to any one of Implementation Schemes 1 to 47, wherein R 2 It is a 5-membered ring heterocyclic group, wherein the heterocyclic ring: (i) is a saturated, partially saturated, or fully unsaturated monocyclic ring, (ii) has one or two oxygen ring atoms and the remaining ring atoms are carbon, and (iii) is optionally substituted by one or more substituents, said one or more substituents being independently selected from the group consisting of: halogen, hydroxyl, cyano, C 1-6 -alkyl, halo-C 1-6 -alkyl, C 2-6 -Alynyl group, C 1-6 -alkoxy and halogenated-C 1-6 -alkoxy group.

[0669] Implementation Scheme 101. The compound or a pharmaceutically acceptable salt thereof according to any one of Implementation Schemes 1 to 47, wherein R 2 It is a 5-membered ring heterocyclic group, wherein the heterocyclic ring: (i) is a saturated, partially saturated, or fully unsaturated monocyclic ring, (ii) has one or two oxygen ring atoms and the remaining ring atoms are carbon, and (iii) is optionally substituted by one or more substituents, said one or more substituents being independently selected from the group consisting of: halogen, hydroxyl, cyano, C 1-3 -alkyl, halo-C 1-3 -alkyl, C 2-3 -Alynyl group, C 1-3 -alkoxy and halogenated-C 1-3 -alkoxy group.

[0670] Implementation Scheme 102. The compound or a pharmaceutically acceptable salt thereof according to any one of Implementation Schemes 1 to 47, wherein R 2 It is a 6-membered ring heterocyclic group, wherein the heterocyclic ring: (i) is a saturated, partially saturated, or fully unsaturated monocyclic ring, (ii) has one or two oxygen ring atoms and the remaining ring atoms are carbon, and (iii) is optionally substituted by one or more substituents, said one or more substituents being independently selected from the group consisting of: halogen, hydroxyl, cyano, C 1-6 -alkyl, halo-C 1-6 -alkyl, C 2-6 -Alynyl group, C 1-6 -alkoxy and halogenated-C 1-6 -alkoxy group.

[0671] Implementation Scheme 103. The compound or a pharmaceutically acceptable salt thereof according to any one of Implementation Schemes 1 to 47, wherein R 2 It is a 6-membered ring heterocyclic group, wherein the heterocyclic ring: (i) is a saturated, partially saturated, or fully unsaturated monocyclic ring, (ii) has one or two oxygen ring atoms and the remaining ring atoms are carbon, and (iii) is optionally substituted by one or more substituents, said one or more substituents being independently selected from the group consisting of: halogen, hydroxyl, cyano, C 1-3 -alkyl, halo-C 1-3 -alkyl, C 2-3 -Alynyl group, C 1-3 -alkoxy and halogenated-C 1-3 -alkoxy group.

[0672] Implementation Scheme 104. The compound or a pharmaceutically acceptable salt thereof according to any one of Implementation Schemes 1 to 47, wherein R 2 It is a 7-membered ring heterocyclic group, wherein the heterocyclic ring: (i) is a saturated, partially saturated, or fully unsaturated monocyclic or fused bicyclic ring, (ii) has one or two oxygen ring atoms and the remaining ring atoms are carbon, and (iii) is optionally substituted by one or more substituents, said one or more substituents being independently selected from the group consisting of: halogen, hydroxyl, cyano, C 1-6 -alkyl, halo-C 1-6 -alkyl, C 2-6 -Alynyl group, C 1-6 -alkoxy and halogenated-C 1-6 -alkoxy group.

[0673] Implementation Scheme 105. The compound or a pharmaceutically acceptable salt thereof according to any one of Implementation Schemes 1 to 47, wherein R 2It is a 7-membered ring heterocyclic group, wherein the heterocyclic ring: (i) is a saturated, partially saturated, or fully unsaturated monocyclic or fused bicyclic ring, (ii) has one or two oxygen ring atoms and the remaining ring atoms are carbon, and (iii) is optionally substituted by one or more substituents, said one or more substituents being independently selected from the group consisting of: halogen, hydroxyl, cyano, C 1-3 -alkyl, halo-C 1-3 -alkyl, C 2-3 -Alynyl group, C 1-3 -alkoxy and halogenated-C 1-3 -alkoxy group.

[0674] Implementation Scheme 106. The compound or a pharmaceutically acceptable salt thereof according to any one of Implementation Schemes 1 to 47, wherein R 2 Choose from the group consisting of: tetrahydrofuranyl, furanyl, dihydropyranyl, tetrahydropyranyl, 1,4-dihydrofuranyl, furanyl, di ... Alkyl and 3-oxabicyclo[4.1.0]heptane, wherein the tetrahydrofuranyl, dihydropyranyl, tetrahydropyranyl, 1,4-dihydrofuranyl, di ...pyranyl, dihydropyranyl, dihydropy The alkyl group and 3-oxabicyclo[4.1.0]heptane are optionally substituted with one or more substituents, said one or more substituents being independently selected from the group consisting of: halogen, hydroxyl, cyano, C 1-6 -alkyl, halo-C 1-6 -alkyl, C 2-6 -Alynyl group, C 1-6 -alkoxy and halogenated-C 1-6 -alkoxy group.

[0675] Implementation Scheme 107. The compound or a pharmaceutically acceptable salt thereof according to any one of Implementation Schemes 1 to 47, wherein R 2 Choose from the group consisting of: tetrahydrofuranyl, furanyl, dihydropyranyl, tetrahydropyranyl, 1,4-dihydrofuranyl, furanyl, di ... Alkyl and 3-oxabicyclo[4.1.0]heptane, wherein the tetrahydrofuranyl, dihydropyranyl, tetrahydropyranyl, 1,4-dihydrofuranyl, di ...pyranyl, dihydropyranyl, dihydropy The alkyl group and 3-oxabicyclo[4.1.0]heptane are optionally substituted with one or more substituents, said one or more substituents being independently selected from the group consisting of: halogen, hydroxyl, cyano, C 1-3 -alkyl, halo-C 1-3 -alkyl, C 2-3 -Alynyl group, C 1-3 -alkoxy and halogenated-C 1-3 -alkoxy group.

[0676] Implementation Scheme 108. The compound or a pharmaceutically acceptable salt thereof according to any one of Implementation Schemes 1 to 47, wherein R2 It is a tetrahydrofuranyl group, wherein the tetrahydrofuranyl group is optionally substituted with one or more substituents, the one or more substituents being independently selected from the group consisting of: halogen, hydroxyl, cyano, C 1-6 -alkyl, halo-C 1-6 -alkyl, C 2-6 -Alynyl group, C 1-6 -alkoxy and halogenated-C 1-6 -alkoxy group.

[0677] Implementation Scheme 109. The compound or a pharmaceutically acceptable salt thereof according to any one of Implementation Schemes 1 to 47, wherein R 2 It is a tetrahydropyranyl group, wherein the tetrahydropyranyl group is optionally substituted by one or more substituents, the one or more substituents being independently selected from the group consisting of: halogen, hydroxyl, cyano, C 1-6 -alkyl, halo-C 1-6 -alkyl, C 2-6 -Alynyl group, C 1-6 -alkoxy and halogenated-C 1-6 -alkoxy group.

[0678] Implementation Scheme 110. The compound or a pharmaceutically acceptable salt thereof according to any one of Implementation Schemes 1 to 47, wherein R 2 It is a dihydropyranyl group, wherein the dihydropyranyl group is optionally substituted by one or more substituents, the one or more substituents being independently selected from the group consisting of: halogen, hydroxyl, cyano, C 1-6 -alkyl, halo-C 1-6 -alkyl, C 2-6 -Alynyl group, C 1-6 -alkoxy and halogenated-C 1-6 -alkoxy group.

[0679] Implementation Scheme 111. The compound or a pharmaceutically acceptable salt thereof according to any one of Implementation Schemes 1 to 47, wherein R 2 It is 1,4-two Alkyl groups, wherein the 1,4-dialkyl group is... The alkyl group is optionally substituted with one or more substituents, said one or more substituents being independently selected from the group consisting of: halogen, hydroxyl, cyano, C 1-6 -alkyl, halo-C 1-6 -alkyl, C 2-6 -Alynyl group, C 1-6 -alkoxy and halogenated-C 1-6 -alkoxy group.

[0680] Implementation Scheme 112. The compound or a pharmaceutically acceptable salt thereof according to any one of Implementation Schemes 1 to 47, wherein R2 It is 3-oxabicyclo[4.1.0]heptane, wherein the 3-oxabicyclo[4.1.0]heptane is optionally substituted with one or more substituents, the one or more substituents being independently selected from the group consisting of: halogen, hydroxyl, cyano, C 1-6 -alkyl, halo-C 1-6 -alkyl, C 2-6 -Alynyl group, C 1-6 -alkoxy and halogenated-C 1-6 -alkoxy group.

[0681] Implementation Scheme 113. The compound or a pharmaceutically acceptable salt thereof according to any one of Implementation Schemes 1 to 47, wherein R 2 Select from the group consisting of: tetrahydrofuranyl, furanyl, dimethyltetrahydrofuranyl, dihydropyranyl, tetrahydropyranyl, hydroxytetrahydropyranyl, fluorotetrahydropyranyl, cyanotetrahydropyranyl, methyltetrahydropyranyl, dimethyltetrahydropyranyl, methoxytetrahydropyranyl, ethoxytetrahydropyranyl, 1,4-di Alkyl and 3-oxabicyclo[4.1.0]heptane.

[0682] Implementation Scheme 114. The compound or a pharmaceutically acceptable salt thereof according to Implementation Scheme 1, wherein the compound is selected from the group consisting of:

[0683] (R)-N-(2-(4-cyanothiazolidine-3-yl)-2-oxoethyl)-6-(furan-3-yl)quinoline-4-carboxamide;

[0684] (R)-N-(2-(4-cyanothiazolidine-3-yl)-2-oxoethyl)-6-(4-hydroxytetrahydro-2H-pyran-4-yl)-quinoline-4-carboxamide;

[0685] (R)-N-(2-(4-cyanothiazolidine-3-yl)-2-oxoethyl)-6-(tetrahydro-2H-pyran-4-yl)quinoline-4-carboxamide;

[0686] (R)-N-(2-(4-cyanothiazolidine-3-yl)-2-oxoethyl)-6-(4-methyltetrahydro-2H-pyran-4-yl)-quinoline-4-carboxamide;

[0687] (R)-N-(2-(4-cyanothiazolidine-3-yl)-2-oxoethyl)-6-(3,6-dihydro-2H-pyran-4-yl)quinoline-4-carboxamide;

[0688] (R)-N-(2-(4-cyanothiazolidine-3-yl)-2-oxoethyl)-6-(4-ethoxytetrahydro-2H-pyran-4-yl)-quinoline-4-carboxamide;

[0689] N-(2-((R)-4-cyanothiazolidine-3-yl)-2-oxoethyl)-6-((RS)-tetrahydro-2H-pyran-2-yl)-quinoline-4-carboxamide;

[0690] N-(2-((R)-4-cyanothiazolidine-3-yl)-2-oxoethyl)-6-((RS)-1,4-di- Alkyl-2-yl)quinoline-4-carboxamide;

[0691] N-(2-((R)-4-cyanothiazolidine-3-yl)-2-oxoethyl)-6-((RS)-tetrahydrofuran-2-yl)quinoline-4-carboxamide;

[0692] (R)-N-(2-(4-cyanothiazolidine-3-yl)-2-oxoethyl)-6-(4-ethynyltetrahydro-2H-pyran-4-yl)-quinoline-4-carboxamide;

[0693] (R)-6-(4-cyanotetrahydro-2H-pyran-4-yl)-N-(2-(4-cyanothiazolidin-3-yl)-2-oxoethyl)-quinoline-4-carboxamide;

[0694] N-(2-((R)-4-cyanothiazolidine-3-yl)-2-oxoethyl)-6-(5,5-dimethyltetrahydrofuran-3-yl)-quinoline-4-carboxamide;

[0695] (R)-N-(2-(4-cyanothiazolidine-3-yl)-2-oxoethyl)-6-(4-fluorotetrahydro-2H-pyran-4-yl)-quinoline-4-carboxamide;

[0696] (R)-N-(2-(4-cyanothiazolidine-3-yl)-2-oxoethyl)-6-(4-methoxytetrahydro-2H-pyran-4-yl)quinoline-4-carboxamide;

[0697] N-(2-((R)-4-cyanothiazolidine-3-yl)-2-oxoethyl)-6-((RS)-tetrahydrofuran-3-yl)quinoline-4-carboxamide;

[0698] N-(2-((R)-4-cyanothiazolidine-3-yl)-2-oxoethyl)-6-((RS)-2,2-dimethyltetrahydro-2H-pyran-4-yl)quinoline-4-carboxamide; and

[0699] 6-((1RS,6SR)-3-oxabicyclo[4.1.0]hept-6-yl)-N-(2-((R)-4-cyanothiazolidine-3-yl)-2-oxoethyl)quinoline-4-carboxamide.

[0700] Implementation Scheme 115. The compound or a pharmaceutically acceptable salt thereof according to any one of Implementation Schemes 1 to 47, wherein R 2 Yes - OR 7 , where R 7 Choose from the following groups: C 1-6 -alkyl, phenyl and tetrahydropyranyl; wherein:

[0701] (i) The C 1-6 The alkyl group is optionally substituted with one or more substituents, said one or more substituents being independently selected from the group consisting of: halogen, cyano, C 3-6 -Cycloalkyl, halogenated-C 3-6 -cycloalkyl, C 1-6 -alkoxy and halogenated-C 1-6 -alkoxy group;

[0702] (ii) The phenyl group is optionally substituted with one or more substituents, which are independently selected from the group consisting of: halogens, C 1-6 -alkyl, halo-C 1-6 -alkyl, C 1-6 -alkoxy and halogenated-C 1-6 -alkoxy group; and

[0703] (iii) The tetrahydropyranyl group is optionally substituted with one or more substituents, which are independently selected from the group consisting of: halogens, C 1-6 -alkyl, halo-C 1-6 -alkyl, C 1-6 -alkoxy and halogenated-C 1-6 -alkoxy group.

[0704] Implementation Scheme 116. The compound or a pharmaceutically acceptable salt thereof according to any one of Implementation Schemes 1 to 47, wherein R 2 Yes - OR 7 , where R 7 Choose from the following groups: C 1-4 -alkyl, phenyl and tetrahydropyranyl; wherein:

[0705] (i) The C 1-4 The alkyl group is optionally substituted with one or more substituents, said one or more substituents being independently selected from the group consisting of: halogen, cyano, C 3-6 -Cycloalkyl, halogenated-C 3-6 -cycloalkyl, C 1-3 -alkoxy and halogenated-C 1-3 -alkoxy group;

[0706] (ii) The phenyl group is optionally substituted with one or more substituents, which are independently selected from the group consisting of: halogens, C 1-3 -alkyl, halo-C 1-3 -alkyl, C 1-3 -alkoxy and halogenated-C 1-3 -alkoxy group; and

[0707] (iii) The tetrahydropyranyl group is optionally substituted with one or more substituents, which are independently selected from the group consisting of: halogens, C 1-3 -alkyl, halo-C 1-3 -alkyl, C 1-3 -alkoxy and halogenated-C 1-3 -alkoxy group.

[0708] Implementation Scheme 117. The compound or a pharmaceutically acceptable salt thereof according to any one of Implementation Schemes 1 to 47, wherein R 2 Yes - OR 7 , where R 7 Choose from the following groups: C 1-6 -alkyl, phenyl and tetrahydropyranyl; wherein:

[0709] (i) The C 1-6 The alkyl group is optionally substituted with one or more substituents, said one or more substituents being independently selected from the group consisting of: halogen, cyano, C 3-6 -Cycloalkyl, halogenated-C 3-6 -Cycloalkyl and C 1-6 -alkoxy group; and

[0710] (ii) The tetrahydropyranyl group is optionally surrounded by one or C 1-6 -Alkyl substitution.

[0711] Implementation Scheme 118. The compound or a pharmaceutically acceptable salt thereof according to any one of Implementation Schemes 1 to 47, wherein R 2 Yes - OR 7 , where R 7 Choose from the following groups: C 1-4 -alkyl, phenyl and tetrahydropyranyl; wherein:

[0712] (i) The C 1-4 The alkyl group is optionally substituted with one or more substituents, said one or more substituents being independently selected from the group consisting of: halogen, cyano, C 3-6 -Cycloalkyl, halogenated-C 3-6 -Cycloalkyl and C 1-3 -alkoxy group; and

[0713] (ii) The tetrahydropyranyl group is optionally surrounded by one or C 1-3 -Alkyl substitution.

[0714] Implementation Scheme 119. The compound or a pharmaceutically acceptable salt thereof according to any one of Implementation Schemes 1 to 47, wherein R 2 Yes - OR 7 , where R 7 It is C 1-6 -alkyl, wherein the C 1-6 The alkyl group is optionally substituted with one or more substituents, said one or more substituents being independently selected from the group consisting of: halogen, cyano, C 3-6 -Cycloalkyl, halogenated-C 3-6 -cycloalkyl, C 1-6 -alkoxy and halogenated-C 1-6 -alkoxy group.

[0715] Implementation Scheme 120. The compound or a pharmaceutically acceptable salt thereof according to any one of Implementation Schemes 1 to 47, wherein R 2 Yes - OR 7 , where R 7 It is C 1-4 -alkyl, wherein the C 1-4 The alkyl group is optionally substituted with one or more substituents, said one or more substituents being independently selected from the group consisting of: halogen, cyano, C 3-6 -Cycloalkyl, halogenated-C 3-6 -Cycloalkyl and C 1-3 -alkoxy group.

[0716] Implementation Scheme 121. The compound or a pharmaceutically acceptable salt thereof according to any one of Implementation Schemes 1 to 47, wherein R 2 Yes - OR 7 , where R 7 It is C 1-4 -alkyl, wherein the C 1-4 -The alkyl group is optionally substituted with one or more substituents, which are independently selected from the group consisting of fluorine.

[0717] Implementation Scheme 122. The compound or a pharmaceutically acceptable salt thereof according to any one of Implementation Schemes 1 to 47, wherein R 2 Yes - OR 7 , where R 7 It is a phenyl group, wherein the phenyl group is optionally substituted with one or more substituents, the one or more substituents being independently selected from the group consisting of: halogens, C 1-6 -alkyl, halo-C 1-6 -alkyl, C 1-6 -alkoxy and halogenated-C1-6 -alkoxy group.

[0718] Implementation Scheme 123. The compound or a pharmaceutically acceptable salt thereof according to any one of Implementation Schemes 1 to 47, wherein R 2 Yes - OR 7 , where R 7 It is a phenyl group.

[0719] Implementation Scheme 124. The compound or a pharmaceutically acceptable salt thereof according to any one of Implementation Schemes 1 to 47, wherein R 2 Yes - OR 7 , where R 7 It is a tetrahydropyranyl group; wherein the tetrahydropyranyl group is optionally substituted by one or more substituents, the one or more substituents being independently selected from the group consisting of: halogens, C 1-6 -alkyl, halo-C 1-6 -alkyl, C 1-6 -alkoxy and halogenated-C 1-6 -alkoxy group.

[0720] Implementation Scheme 125. The compound or a pharmaceutically acceptable salt thereof according to any one of Implementation Schemes 1 to 47, wherein R 2 Yes - OR 7 , where R 7 It is a tetrahydropyranyl group; wherein the tetrahydropyranyl group is optionally surrounded by one or more C... 1-3 -Alkyl substitution.

[0721] Implementation Scheme 126. The compound or a pharmaceutically acceptable salt thereof according to any one of Implementation Schemes 1 to 47, wherein R 2 Yes - OR 7 , where R 7 It is tetrahydropyranyl.

[0722] Implementation Scheme 127. The compound or a pharmaceutically acceptable salt thereof according to any one of Implementation Schemes 1 to 47, wherein R 2 Yes - OR 7 , where R 7 Choose from the group consisting of: cyanomethyl, fluoroethyl, difluoroethyl, propyl, difluoropropyl, fluorobutyl, methoxyethyl, cyclopropylmethyl, difluorocyclobutylmethyl, phenyl, tetrahydropyranyl, and dimethyltetrahydropyranyl.

[0723] Implementation Scheme 128. The compound or a pharmaceutically acceptable salt thereof according to Implementation Scheme 1, wherein the compound is selected from the group consisting of:

[0724] (R)-N-(2-(4-cyanothiazolidine-3-yl)-2-oxoethyl)-6-phenoxyquinoline-4-carboxamide;

[0725] (R)-N-(2-(4-cyanothiazolidine-3-yl)-2-oxoethyl)-6-(2,2-difluoroethoxy)quinoline-4-carboxamide;

[0726] (R)-N-(2-(4-cyanothiazolidine-3-yl)-2-oxoethyl)-6-(2-fluoro-2-methylpropoxy)quinoline-4-carboxamide;

[0727] (R)-N-(2-(4-cyanothiazolidine-3-yl)-2-oxoethyl)-6-(2-methoxyethoxy)quinoline-4-carboxamide;

[0728] (R)-N-(2-(4-cyanothiazolidine-3-yl)-2-oxoethyl)-6-(cyclopropylmethoxy)quinoline-4-carboxamide;

[0729] (R)-N-(2-(4-cyanothiazolidine-3-yl)-2-oxoethyl)-6-((tetrahydro-2H-pyran-4-yl)oxy)-quinoline-4-carboxamide;

[0730] (R)-N-(2-(4-cyanothiazolidine-3-yl)-2-oxoethyl)-6-((1,3-difluoroprop-2-yl)oxy)-quinoline-4-carboxamide;

[0731] (R)-N-(2-(4-cyanothiazolidine-3-yl)-2-oxoethyl)-6-((3,3-difluorocyclobutyl)-methoxy)quinoline-4-carboxamide;

[0732] N-(2-((R)-4-cyanothiazolidine-3-yl)-2-oxoethyl)-6-(((RS)-2,2-dimethyltetrahydro-2H-pyran-4-yl)oxy)quinoline-4-carboxamide;

[0733] (R)-6-(cyanomethoxy)-N-(2-(4-cyanothiazolidin-3-yl)-2-oxoethyl)quinoline-4-carboxamide;

[0734] (R)-N-(2-(4-cyanothiazolidine-3-yl)-2-oxoethyl)-6-(2,2-difluoropropoxy)quinoline-4-carboxamide;

[0735] (R)-N-(2-(4-cyanothiazolidine-3-yl)-2-oxoethyl)-6-propoxyquinoline-4-carboxamide; and

[0736] (R)-N-(2-(4-cyanothiazolidine-3-yl)-2-oxoethyl)-6-(2-fluoroethoxy)-quinoline-4-carboxamide.

[0737] Implementation Scheme 129. The compound or a pharmaceutically acceptable salt thereof according to any one of Implementation Schemes 1 to 47, wherein R 2 Choose from the following groups:

[0738] (a)C 1-3 -alkyl, wherein the C 1-3 The alkyl group is optionally substituted with one or more substituents, said one or more substituents being independently selected from the group consisting of: halogen, hydroxyl, cyano, C 3-6 -Cycloalkyl, halogenated-C 3-6 -cycloalkyl, C 1-3 -alkoxy group, halogenated-C 1-3 -alkoxy group, C 3-6 -cycloalkoxy, halogenated-C 3-6 -cycloalkoxy, C 1-3 -alkoxy-C 1-3 -alkoxy, oxetane, tetrahydrofuranyl, tetrahydrofuranyloxy, tetrahydropyranyl, morpholinyl, pyrazolyl, iso Azolyl, triazolyl, and pyridyl; and wherein said oxetyl, tetrahydrofuranyl, tetrahydrofuranyloxy, tetrahydropyranyl, morpholinyl, pyrazolyl, iso The azole, triazole, and pyridyl groups are optionally substituted by one or more substituents, said one or more substituents being independently selected from the group consisting of: halogens, C 1-3 -alkyl and halogenated-C 1-3 -alkyl;

[0739] (b)C 3-6 -cycloalkyl, wherein the C 3-6 -The cycloalkyl group is optionally substituted with one or more substituents, said one or more substituents being independently selected from the group consisting of: halogen, cyano, C 1-3 -alkyl, halo-C 1-3 -alkyl, C 1-3 -alkoxy group, halogenated-C 1-3 -alkoxy, isoalkoxy azole group and pyridinyl group; wherein the iso The azole and pyridyl groups are optionally substituted by one or more substituents, said one or more substituents being independently selected from the group consisting of: halogens, C 1-3 -alkyl and halogenated-C 1-3 -alkyl;

[0740] (c) Phenyl, wherein the phenyl group is optionally substituted with one or more substituents, the one or more substituents being independently selected from the group consisting of: halogens, C 1-3 -alkyl, halo-C 1-3 -alkyl, C 1-3 -alkoxy group, halogenated-C 1-3 -alkoxy and C 1-3 -alkoxy-C 1-3 -alkoxy group;

[0741] (d) A 4-, 5-, 6-, or 7-membered heterocyclic group, wherein the heterocyclic ring: (i) is a saturated or partially saturated monocyclic or fused bicyclic ring, (ii) has one or two oxygen ring atoms and the remaining ring atoms are carbon, and (iii) is optionally substituted with one or more substituents, said one or more substituents being independently selected from the group consisting of: halogen, hydroxyl, cyano, C 1-3 -alkyl, halo-C 1-3 -alkyl, C 2-3 -Alynyl group, C 1-3 -alkoxy and halogenated-C 1-3 -alkoxy group; and

[0742] (e)-OR 7 , where R 7 Choose from the following groups: C 1-4 -alkyl, phenyl and tetrahydropyranyl; wherein:

[0743] (i) The C 1-4 The alkyl group is optionally substituted with one or more substituents, said one or more substituents being independently selected from the group consisting of: halogen, cyano, C 3-6 -Cycloalkyl, halogenated-C 3-6 -cycloalkyl, C 1-3 -alkoxy and halogenated-C 1-3 -alkoxy group;

[0744] (ii) The phenyl group is optionally substituted with one or more substituents, which are independently selected from the group consisting of: halogens, C 1-3 -alkyl, halo-C 1-3 -alkyl, C 1-3 -alkoxy and halogenated-C 1-3 -alkoxy group; and

[0745] (iii) The tetrahydropyranyl group is optionally substituted with one or more substituents, which are independently selected from the group consisting of: halogens, C 1-3 -alkyl, halo-C 1-3 -alkyl, C 1-3 -alkoxy and halogenated-C1-3 -alkoxy group.

[0746] Implementation Scheme 130. The compound or a pharmaceutically acceptable salt thereof according to any one of Implementation Schemes 1 to 47, wherein R 2 Choose from the following groups:

[0747] (a)C 3-6 -cycloalkyl, wherein the C 3-6 -The cycloalkyl group is optionally substituted with one or more substituents, said one or more substituents being independently selected from the group consisting of: halogen, cyano, C 1-3 -alkyl, halo-C 1-3 -alkyl, C 1-3 -alkoxy, halogenated-C 1-3 -alkoxy, isoalkoxy azole group and pyridinyl group; wherein the iso The azole and pyridyl groups are optionally substituted by one or more substituents, said one or more substituents being independently selected from the group consisting of: halogens, C 1-3 -alkyl and halogenated-C 1-3 -alkyl; and

[0748] (b) A 4-, 5-, 6-, or 7-membered heterocyclic group, wherein the heterocyclic ring: (i) is a saturated or partially saturated monocyclic or fused bicyclic ring, (ii) has one or two oxygen ring atoms and the remaining ring atoms are carbon, and (iii) is optionally substituted with one or more substituents, said one or more substituents being independently selected from the group consisting of: halogen, hydroxyl, cyano, C 1-3 -alkyl, halo-C 1-3 -alkyl, C 2-3 -Alynyl group, C 1-3 -alkoxy and halogenated-C 1-3 -alkoxy group; and

[0749] (c)-OR 7 , where R 7 Choose from the following groups: C 1-4 -alkyl, phenyl and tetrahydropyranyl; wherein:

[0750] (i) The C 1-4 The alkyl group is optionally substituted with one or more substituents, said one or more substituents being independently selected from the group consisting of: halogen, cyano, C 3-6 -Cycloalkyl, halogenated-C 3-6 -cycloalkyl, C 1-3 -alkoxy and halogenated-C 1-3 -alkoxy group;

[0751] (ii) The phenyl group is optionally substituted with one or more substituents, which are independently selected from the group consisting of: halogens, C 1-3 -alkyl, halo-C 1-3 -alkyl, C 1-3 -alkoxy and halogenated-C 1-3 -alkoxy group; and

[0752] (iii) The tetrahydropyranyl group is optionally substituted with one or more substituents, which are independently selected from the group consisting of: halogens, C 1-3 -alkyl, halo-C 1-3 -alkyl, C 1-3 -alkoxy and halogenated-C 1-3 -alkoxy group.

[0753] Implementation Scheme 131. The compound or a pharmaceutically acceptable salt thereof according to any one of Implementation Schemes 1 to 47, wherein R 2 Choose from the following groups:

[0754] (a)C 1-6 -alkyl, wherein the C 1-6 -The alkyl group is optionally substituted with one or more substituents, said one or more substituents being independently selected from the group consisting of: halogens, hydroxyl groups, C 1-6 -alkoxy group, halogenated-C 1-6 -alkoxy group, C 3-6 -cycloalkoxy, C 1-6 -alkoxy-C 1-6 -alkoxy, tetrahydrofuranyl, tetrahydrofuranyloxy, tetrahydropyranyl, morpholinyl, pyrazolyl, iso Azolyl, triazolyl, and pyridyl; and wherein said tetrahydrofuranyl, tetrahydrofuranyloxy, tetrahydropyranyl, morpholinyl, pyrazolyl, iso The azole, triazole, and pyridyl groups are optionally substituted by one or more substituents, said one or more substituents being independently selected from the group consisting of: halogens, C 1-6 -alkyl and halogenated-C 1-6 -alkyl;

[0755] (b)C 3-6 -cycloalkyl, wherein the C 3-6 -The cycloalkyl group is optionally substituted with one or more substituents, said one or more substituents being independently selected from the group consisting of: halogen, cyano, C 1-6 -alkoxy, isoalkoxy azole group and pyridinyl group; wherein the iso The azole and pyridyl groups are optionally substituted by one or more substituents, said one or more substituents being independently selected from the group consisting of: halogens, C 1-6 -alkyl and halogenated-C 1-6 -alkyl;

[0756] (c) Phenyl, wherein the phenyl group is optionally substituted with one or more substituents, the one or more substituents being independently selected from the group consisting of: halogens, C 1-3 -alkyl, halo-C 1-3 -alkyl, C 1-3 -alkoxy group, halogenated-C 1-3 -alkoxy and C 1-3 -alkoxy-C 1-3 -alkoxy group;

[0757] (d) A 5-, 6-, or 7-membered heterocyclic group, wherein the heterocyclic ring: (i) is a saturated or partially saturated monocyclic or fused bicyclic ring, (ii) has one or two oxygen ring atoms and the remaining ring atoms are carbon, and (iii) is optionally substituted with one or more substituents, said one or more substituents being independently selected from the group consisting of: halogen, hydroxyl, cyano, C 1-3 -alkyl, C 2-3 -Alynyl group and C 1-3 -alkoxy group; and

[0758] (e)-OR 7 , where R 7 Choose from the following groups: C 1-6 -alkyl, phenyl and tetrahydropyranyl; wherein:

[0759] (i) The C 1-6 The alkyl group is optionally substituted with one or more substituents, said one or more substituents being independently selected from the group consisting of: halogen, cyano, C 3-6 -Cycloalkyl, halogenated-C 3-6 -Cycloalkyl and C 1-6 -alkoxy group; and

[0760] (ii) The tetrahydropyranyl group is optionally surrounded by one or C 1-6 -Alkyl substitution.

[0761] Implementation Scheme 132. The compound or a pharmaceutically acceptable salt thereof according to any one of Implementation Schemes 1 to 47, wherein R 2 Choose from the following groups:

[0762] (a)C 3-6 -cycloalkyl, wherein the C 3-6-The cycloalkyl group is optionally substituted with one or more substituents, said one or more substituents being independently selected from the group consisting of: halogen, cyano, C 1-6 -alkoxy, isoalkoxy azole group and pyridinyl group; wherein the iso The azole and pyridyl groups are optionally substituted by one or more substituents, said one or more substituents being independently selected from the group consisting of: halogens, C 1-6 -alkyl and halogenated-C 1-6 -alkyl;

[0763] (b) A 5-, 6-, or 7-membered heterocyclic group, wherein the heterocyclic ring: (i) is a saturated or partially saturated monocyclic or fused bicyclic ring, (ii) has one or two oxygen ring atoms and the remaining ring atoms are carbon, and (iii) is optionally substituted with one or more substituents, said one or more substituents being independently selected from the group consisting of: halogen, hydroxyl, cyano, C 1-3 -alkyl, C 2-3 -Alynyl group and C 1-3 -alkoxy group; and

[0764] (c)-OR 7 , where R 7 Choose from the following groups: C 1-6 -alkyl, phenyl and tetrahydropyranyl; wherein:

[0765] (i) The C 1-6 The alkyl group is optionally substituted with one or more substituents, said one or more substituents being independently selected from the group consisting of: halogen, cyano, C 3-6 -Cycloalkyl, halogenated-C 3-6 -Cycloalkyl and C 1-6 -alkoxy group; and

[0766] (ii) The tetrahydropyranyl group is optionally surrounded by one or C 1-6 -Alkyl substitution.

[0767] Implementation Scheme 133. The compound or a pharmaceutically acceptable salt thereof according to any one of Implementation Schemes 129 to 132, wherein R 2 It is a 4-membered ring heterocyclic group, wherein the heterocyclic ring: (i) is a saturated or partially saturated monocyclic ring, (ii) has one oxygen ring atom and the remaining ring atom is carbon, and (iii) is optionally substituted by one or more substituents, said one or more substituents being independently selected from the group consisting of: halogen, hydroxyl, cyano, C 1-3 -alkyl, C 2-3 -Alynyl group and C 1-3 -alkoxy group.

[0768] Implementation Scheme 134. The compound or a pharmaceutically acceptable salt thereof according to any one of Implementation Schemes 129 to 132, wherein R 2 It is a 5-membered ring heterocyclic group, wherein the heterocyclic ring: (i) is a saturated or partially saturated monocyclic ring, (ii) has one or two oxygen ring atoms and the remaining ring atoms are carbon, and (iii) is optionally substituted by one or more substituents, said one or more substituents being independently selected from the group consisting of: halogen, hydroxyl, cyano, C 1-3 -alkyl and C 2-3 -Alynyl group, C 1-3 -alkoxy group.

[0769] Implementation Scheme 135. The compound or a pharmaceutically acceptable salt thereof according to any one of Implementation Schemes 129 to 132, wherein R 2 It is a 6-membered ring heterocyclic group, wherein the heterocyclic ring: (i) is a saturated or partially saturated monocyclic ring, (ii) has one or two oxygen ring atoms and the remaining ring atoms are carbon, and (iii) is optionally substituted by one or more substituents, said one or more substituents being independently selected from the group consisting of: halogen, hydroxyl, cyano, C 1-3 -alkyl, C 2-3 -Alynyl group and C 1-3 -alkoxy group.

[0770] Implementation Scheme 136. The compound or a pharmaceutically acceptable salt thereof according to any one of Implementation Schemes 129 to 132, wherein R 2 It is a 7-membered ring heterocyclic group, wherein the heterocyclic ring: (i) is a saturated or partially saturated monocyclic or fused bicyclic ring, (ii) has one or two oxygen ring atoms and the remaining ring atoms are carbon, and (iii) is optionally substituted by one or more substituents, said one or more substituents being independently selected from the group consisting of: halogen, hydroxyl, cyano, C 1-3 -alkyl, C 2-3 -Alynyl group and C 1-3 -alkoxy group.

[0771] Implementation Scheme 137. The compound or a pharmaceutically acceptable salt thereof according to any one of Implementation Schemes 1 to 47, wherein R 2 Choose from the following groups:

[0772] (a)C 1-3 -alkyl, wherein the C 1-3 -The alkyl group is optionally substituted with one or more substituents, said one or more substituents being independently selected from the group consisting of: halogens, hydroxyl groups, C 1-3 -alkoxy group, halogenated-C 1-3 -alkoxy group, C 3-6 -cycloalkoxy, C1-3 -alkoxy-C 1-3 -alkoxy, tetrahydrofuranyl, tetrahydrofuranyloxy, tetrahydropyranyl, morpholinyl, pyrazolyl, iso Azolyl, triazolyl, and pyridyl; and wherein said tetrahydrofuranyl, tetrahydrofuranyloxy, tetrahydropyranyl, morpholinyl, pyrazolyl, iso The azole, triazole, and pyridyl groups are optionally substituted by one or more substituents, said one or more substituents being independently selected from the group consisting of: halogens, C 1-3 -alkyl and halogenated-C 1-6 -alkyl;

[0773] (b)C 3-6 -cycloalkyl, wherein the C 3-6 -The cycloalkyl group is optionally substituted with one or more substituents, said one or more substituents being independently selected from the group consisting of: halogen, cyano, C 1-3 -alkoxy, isoalkoxy azole group and pyridinyl group; wherein the iso The azole and pyridyl groups are optionally substituted by one or more substituents, said one or more substituents being independently selected from the group consisting of: halogens, C 1-3 -alkyl and halogenated-C 1-3 -alkyl;

[0774] (c) Phenyl, wherein the phenyl group is optionally substituted with one or more substituents, the one or more substituents being independently selected from the group consisting of: halogens, C 1-3 -alkyl, halo-C 1-3 -alkyl, C 1-3 -alkoxy group, halogenated-C 1-3 -alkoxy and C 1-3 -alkoxy-C 1-3 -alkoxy group;

[0775] (d) A 5-, 6-, or 7-membered cyclic heterocyclic group selected from the group consisting of: tetrahydrofuranyl, dihydropyranyl, tetrahydropyranyl, 1,4-dihydrofuranyl, etc. Alkyl and 3-oxabicyclo[4.1.0]heptane, wherein the tetrahydrofuranyl, dihydropyranyl, tetrahydropyranyl, 1,4-dihydrofuranyl, di ...pyranyl, dihydropyranyl, dihydropy The alkyl group and 3-oxabicyclo[4.1.0]heptane are optionally substituted with one or more substituents, said one or more substituents being independently selected from the group consisting of: halogen, hydroxyl, cyano, C 1-6 -alkyl, halo-C 1-6 -alkyl, C 2-6 -Alynyl group, C 1-6 -alkoxy and halogenated-C 1-6 -alkoxy group;

[0776] (e)-OR 7 , where R 7 Choose from the following groups: C 1-4 -alkyl, phenyl and tetrahydropyranyl; wherein:

[0777] (i) The C 1-4 The alkyl group is optionally substituted with one or more substituents, said one or more substituents being independently selected from the group consisting of: halogen, cyano, C 3-6 -Cycloalkyl, halogenated-C 3-6 -Cycloalkyl and C 1-3 -alkoxy group; and

[0778] (ii) The tetrahydropyranyl group is optionally surrounded by one or C 1-3 -Alkyl substitution.

[0779] Implementation Scheme 138. The compound or a pharmaceutically acceptable salt thereof according to any one of Implementation Schemes 1 to 47, wherein R 2 Choose from the following groups:

[0780] (a)C 3-6 -cycloalkyl, wherein the C 3-6 -The cycloalkyl group is optionally substituted with one or more substituents, said one or more substituents being independently selected from the group consisting of: halogen, cyano, C 1-3 -alkoxy, isoalkoxy azole group and pyridinyl group; wherein the iso The azole and pyridyl groups are optionally substituted by one or more substituents, said one or more substituents being independently selected from the group consisting of: halogens, C 1-3 -alkyl and halogenated-C 1-3 -alkyl;

[0781] (b) A 5-, 6-, or 7-membered heterocyclic group selected from the group consisting of: tetrahydrofuranyl, dihydropyranyl, tetrahydropyranyl, 1,4-dihydrofuranyl, etc. Alkyl and 3-oxabicyclo[4.1.0]heptane, wherein the tetrahydrofuranyl, dihydropyranyl, tetrahydropyranyl, 1,4-dihydrofuranyl, di ...pyranyl, dihydropyranyl, dihydropy The alkyl group and 3-oxabicyclo[4.1.0]heptane are optionally substituted with one or more substituents, said one or more substituents being independently selected from the group consisting of: halogen, hydroxyl, cyano, C 1-6 -alkyl, halo-C 1-6 -alkyl, C 2-6 -Alynyl group, C 1-6 -alkoxy and halogenated-C 1-6 -alkoxy group; and

[0782] (c)-OR 7 , where R 7 Choose from the following groups: C 1-4 -alkyl, phenyl and tetrahydropyranyl; wherein:

[0783] (i) The C 1-4 The alkyl group is optionally substituted with one or more substituents, said one or more substituents being independently selected from the group consisting of: halogen, cyano, C 3-6 -Cycloalkyl, halogenated-C 3-6 -Cycloalkyl and C 1-3 -alkoxy group; and

[0784] (ii) The tetrahydropyranyl group is optionally surrounded by one or C 1-3 -Alkyl substitution.

[0785] Implementation Scheme 139. The compound or a pharmaceutically acceptable salt thereof according to any one of Implementation Schemes 129 to 138, wherein R 2 It is an optionally substituted cyclopropyl group.

[0786] Implementation Scheme 140. The compound or a pharmaceutically acceptable salt thereof according to any one of Implementation Schemes 129 to 138, wherein R 2 It is an optional substituted cyclobutyl group.

[0787] Implementation Scheme 141. The compound or a pharmaceutically acceptable salt thereof according to any one of Implementation Schemes 129 to 138, wherein R 2 It is an optional substituted cyclopentyl group.

[0788] Implementation Scheme 142. The compound or a pharmaceutically acceptable salt thereof according to any one of Implementation Schemes 129 to 138, wherein R 2 It is an substituted cyclohexyl group.

[0789] Implementation Scheme 143. The compound or a pharmaceutically acceptable salt thereof according to any one of Implementation Schemes 1 to 47, wherein R 2 Choose from the following groups:

[0790] (a) C with optional substitution 1-3 -alkyl groups, selected from the group consisting of: methyl, fluoromethyl, difluoromethyl, trifluoromethyl, hydroxyethyl, hydroxypropyl, ethoxymethyl, difluoroethoxymethyl, methoxyethyl, dimethoxyethyl, difluoropropyl, trifluoropropyl, methoxypropyl, methoxyethoxymethyl, cyclopropoxymethyl, morpholinylmethyl, tetrahydrofuranylmethyl, tetrahydrofuranyloxymethyl, tetrahydropyranylmethyl, pyrazolylmethyl, dimethylpyrazolylmethyl, methyl isomethyl azole methyl, methyl iso Azolylethyl, methyltriazolylmethyl, dimethyltriazolylmethyl, dimethylpyridylmethyl, methylpyridylethyl, fluoropyridylethyl, chloropyridylethyl, and trifluoromethylpyridylethyl.

[0791] (b) C with optional substitution 3-6 -Cycloalkyl groups, selected from the group consisting of: cyclopropyl, cyanocyclopropyl, ethoxycyclopropyl, methylisopropyl Azolylcyclopropyl, methylpyridylcyclopropyl, chloropyridylcyclopropyl, fluoropyridylcyclopropyl, trifluoropyridylcyclopropyl, fluorocyclobutyl, (fluoro)(methoxy)cyclobutyl, methoxycyclohexyl and cyanocyclohexyl;

[0792] (c) Optionally substituted 5-, 6-, or 7-membered heterocyclic groups selected from the group consisting of: tetrahydrofuranyl, dimethyltetrahydrofuranyl, dihydropyranyl, tetrahydropyranyl, hydroxytetrahydropyranyl, fluorotetrahydropyranyl, cyanotetrahydropyranyl, methyltetrahydropyranyl, dimethyltetrahydropyranyl, methoxytetrahydropyranyl, ethoxytetrahydropyranyl, 1,4-di- Alkyl groups and 3-oxabicyclo[4.1.0]heptane; and

[0793] (d)-OR 7 , where R 7 Choose from the group consisting of: cyanomethyl, fluoroethyl, difluoroethyl, propyl, difluoropropyl, fluorobutyl, methoxyethyl, cyclopropylmethyl, difluorocyclobutylmethyl, phenyl, tetrahydropyranyl, and dimethyltetrahydropyranyl.

[0794] Implementation Scheme 144. The compound or a pharmaceutically acceptable salt thereof according to any one of Implementation Schemes 1 to 47, wherein R 2 Choose from the following groups:

[0795] (a) C with optional substitution 3-6 -Cycloalkyl groups, selected from the group consisting of: cyclopropyl, cyanocyclopropyl, ethoxycyclopropyl, methylisopropyl Azolylcyclopropyl, methylpyridylcyclopropyl, chloropyridylcyclopropyl, fluoropyridylcyclopropyl, trifluoropyridylcyclopropyl, fluorocyclobutyl, (fluoro)(methoxy)cyclobutyl, methoxycyclohexyl and cyanocyclohexyl;

[0796] (b) Optionally substituted 5-, 6-, or 7-membered heterocyclic groups selected from the group consisting of: tetrahydrofuranyl, dimethyltetrahydrofuranyl, dihydropyranyl, tetrahydropyranyl, hydroxytetrahydropyranyl, fluorotetrahydropyranyl, cyanotetrahydropyranyl, methyltetrahydropyranyl, dimethyltetrahydropyranyl, methoxytetrahydropyranyl, ethoxytetrahydropyranyl, 1,4-di... Alkyl groups and 3-oxabicyclo[4.1.0]heptane; and

[0797] (c)-OR 7 , where R 7 Choose from the group consisting of: cyanomethyl, fluoroethyl, difluoroethyl, propyl, difluoropropyl, fluorobutyl, methoxyethyl, cyclopropylmethyl, difluorocyclobutylmethyl, phenyl, tetrahydropyranyl, and dimethyltetrahydropyranyl.

[0798] Implementation Scheme 145. The compound or a pharmaceutically acceptable salt thereof according to any one of Implementation Schemes 1 to 47, wherein R 2 Choose from the group consisting of: methoxycyclohexyl, tetrahydropyranyl, fluorobutoxy, and tetrahydropyranyloxy.

[0799] Implementation Scheme 146. A pharmaceutical composition comprising a compound or a pharmaceutically acceptable salt thereof according to any one of Implementation Schemes 1 to 145 and one or more pharmaceutically acceptable excipients.

[0800] Implementation Scheme 147. A method for treating or preventing FAP-mediated disease in a subject who has or is susceptible to FAP-mediated disease, the method comprising administering to the subject a therapeutically effective amount of a compound or a pharmaceutically acceptable salt thereof according to any one of Implementation Schemes 1 to 145.

[0801] Implementation Scheme 148. The method according to Implementation Scheme 147, wherein the FAP-mediated condition is selected from the group consisting of: liver disease, type 2 diabetes, cardiovascular disease, obesity, obesity-related conditions, fibrosis, keloid conditions, inflammation, and cancer.

[0802] Implementation Scheme 149. The method according to Implementation Scheme 148, wherein the FAP-mediated condition is liver disease.

[0803] Implementation Scheme 150. The method according to Implementation Scheme 149, wherein the liver disease is non-alcoholic steatohepatitis.

[0804] Implementation Scheme 151. Use of the compound or a pharmaceutically acceptable salt thereof according to any one of Implementation Schemes 1 to 145 for the preparation of a medicament for the treatment or prevention of FAP-mediated conditions.

[0805] VIX. Implementation

[0806] The following descriptions of experiments, procedures, examples, and intermediates are intended to illustrate embodiments of this disclosure. They are in no way intended to be limiting. Other compounds of this disclosure can be prepared using the methods shown in these examples, alone or in combination with techniques generally known in the art.

[0807] A. General conditions

[0808] Unless otherwise stated:

[0809] (i) Operation is carried out at room temperature (rt) (i.e., in the range of 17°C to 25°C) and in an inert gas atmosphere such as N2;

[0810] (ii) In cases where the reaction involves the use of a microwave reactor, use one of the following microwave reactors: Biotage Initiator, Personal Chemistry Emrys Optimizer, Personal Chemistry Smith Creator, or CEM Explorer;

[0811] (iii) In cases where the reaction involves the use of LED irradiation, commercially standardized EvoluChem LEDs from HepatoChem equipped with Kessil H150 blue LEDs (456nm, 34W) are used. TM PhotoRedOx Box photoreactor or a commercially standardized photoreactor m2 from PennPhoton Devices equipped with an LED module (365nm);

[0812] (iv) Generally, the reaction process is tracked by thin-layer chromatography (TLC) and / or analytical high-performance liquid chromatography (HPLC or UPLC) usually coupled with mass spectrometry (LCMS);

[0813] (v) If necessary, dry the organic solution with anhydrous MgSO4 or Na2SO4, or by using... The phase separator is dried, and post-processing is performed using conventional phase separation technology;

[0814] (vi) Evaporation by rotary evaporation in a vacuum or by evaporation in Genevac HT-4 / EZ-2 or Biotage V10;

[0815] (vii) Unless otherwise specified, rapid column chromatography uses Merck silica gel (Art. 9385) or pre-packed small columns such as those on straight-phase silica. SNAP columns (40μm-63μm silica, 4g-330g) Silica HCD column (20μm, 10g-100g), Interchim PuriFlash TM Small column (25μm, 4g-120g), Interchim puriFlash TMSmall column (50μm, 25g-330g), Grace TM GraceResolv TM The procedure can be performed using rapid silica columnar ingots (4g-120g) or Agela rapid columnar silica-CS columnar ingots (80g-330g), or using Agela Technologies C-18 spherical columnar ingots (20μm-35μm, 100A, 80g–330g) on ​​reversed silica using Grace. The X2 Fast System or similar systems can be operated manually or automatically.

[0816] (viii) Preparative reversed-phase HPLC and preparative reversed-phase SFC were performed using a mobile phase of isocratic or gradient as described in the Experimental Section and one of the following methods described below, respectively, using standard HPLC and SFC instruments equipped with MS and / or UV-triggered fractionation collection instruments:

[0817] (vii) Using isocratic or gradient mobile phases as described in the Experimental Section and one of the following methods described below, preparative reversed-phase HPLC and preparative reversed-phase SFC were performed using standard HPLC and SFC instruments equipped with MS and / or UV-triggered fractionation collection instruments, respectively.

[0818] HPLC preparation methods: Method A: The compound was purified by preparative HPLC on a Kromasil C8 column (10 μm, 250 × 50 mm ID) using a gradient of MeCN in H2O / MeCN / FA (95 / 5 / 0.2) as the mobile phase; Method B: The compound was purified by preparative HPLC on an XSelect CSH C18 OBD column (5 μm, 150 × 30 mm ID) using a gradient of MeCN in H2O / TFA (0.05%) as the mobile phase; Method C: The compound was purified by preparative HPLC on a Kromasil C8 column (10 μm, 250 × 20 mm ID) using a gradient of MeCN in H2O / MeCN / FA (95 / 5 / 0.2) as the mobile phase; Method D: The compound was purified by preparative HPLC on an XSelect CSH OBD column (5 μm, 150 × 30 mm ID). Preparation Method E: The compound was purified by preparative HPLC on an XBridge C18 column (10 μm, 250 × 19 mm ID) using a gradient of MeCN in H2O / MeCN / NH3 (95 / 5 / 0.2) as the mobile phase; Preparation Method F: The compound was purified by preparative HPLC on a Sunfire prep C18 column (5 μm, 150 × 30 mm ID) using a gradient of MeCN in H2O / FA ​​(0.1%) as the mobile phase; Preparation Method G: The compound was purified by preparative HPLC on a Waters Sunfire C18 ODB column (5 μm, 150 × 30 mm ID) using a gradient of MeCN in H2O / FA ​​(0.1 M) as the mobile phase; Preparation Method H: The compound was purified by preparative HPLC on an XBridge Prep OBD C18 column (5 μm, 150 × 30 mm ID) using a gradient of MeCN in H2O / FA ​​(0.1 M) as the mobile phase; Preparation Method H: The compound was purified by preparative HPLC on an XBridge Prep OBD C18 column (5 μm, 150 × 30 mm ID) using a gradient of MeCN in H2O / FA ​​(0.1 M) as the mobile phase. The compound was purified by using a gradient of MeCN in H2O / NH4HCO3 (10 mM) + NH3 (0.1%) as the mobile phase on an XBridge Prep OBD C18 column (5 μm, 150 × 30 mm ID) as the mobile phase; Preparation method I: The compound was purified by preparative HPLC using a gradient of MeCN in H2O / NH4HCO3 (10 mM) + NH3 (0.1%) as the mobile phase on an XSelect CSH Prep C18 OBD column (5 μm, 250 × 19 mm ID) as the mobile phase on an XSelect CSH Prep C18 OBD column (5 μm, 250 × 19 mm ID) as the mobile phase on an XSelect CSH Prep C18 OBD column (0.1%) ...The compound was purified by preparative HPLC using a gradient of MeCN in H2O / NH4HCO3 (10 mM) as the mobile phase on a Sunfire C18 OBD Prep column (5 μm, 250 × 19 mm ID). Preparation method K: The compound was purified by preparative HPLC using a gradient of MeCN in H2O / NH4HCO3 (10 mM) as the mobile phase on a Kinetex EVO C18 column (5 μm, 150 × 30 mm ID). Preparation method L: The compound was purified by preparative HPLC using a gradient of MeCN in H2O / NH4HCO3 (10 mM) as the mobile phase on a Kinetex EVO C18 column (5 μm, 150 × 30 mm ID). Preparation method M: The compound was purified by preparative HPLC using a gradient of MeCN in H2O / NH3 (0.2%) as the mobile phase on an XBridge C18 ODB column (5 μm, 150 × 30 mm ID). Preparation method N: The compound was purified by preparative HPLC using a gradient of MeCN in H2O / NH3 (0.2%) as the mobile phase on an XSelect CSH fluorophenyl column (5 μm, 150 × 30 mm ID). The compound was purified by preparative HPLC on an XSelect CSH fluorophenyl OBD column (5 μm, 250 × 19 mm ID) using a gradient of MeCN in H2O / TFA (0.05%) as the mobile phase; Method O: The compound was purified by preparative HPLC on an XSelect CSHPrep C18 OBD column (5 μm, 250 × 19 mm ID) using a gradient of MeCN in H2O / TFA (0.1%) as the mobile phase; Method P: The compound was purified by preparative HPLC on an XSelect CSHPrep C18 OBD column (5 μm, 250 × 19 mm ID) using a gradient of MeCN in H2O / TFA (0.1%) as the mobile phase; Method Q: The compound was purified by preparative HPLC on a CHIRALPAK IA column (5 μm, 250 × 50 mm ID) using a gradient of EtOH in MTBE / NH3-MeOH (0.5%, 2 M) as the mobile phase; Method R: The compound was purified by preparative HPLC on an XSelect CSH OBD column (5 μm, 150 × 30 mm ID) using a gradient of EtOH in MTBE / NH3-MeOH (0.5%, 2 M) as the mobile phase; The compound was purified by preparative HPLC on an XBridge Prep OBD C18 column (5 μm, 150 × 30 mm ID) using a gradient of MeCN in H2O / FA ​​(0.1%) as the mobile phase; Preparation method S: The compound was purified by preparative HPLC on an XSelect CSH C18 OBD column (5 μm, 150 × 30 mm ID) using a gradient of MeCN in H2O / FA ​​(0.1%) as the mobile phase; Preparation method T: The compound was purified by preparative HPLC on an XSelect CSH C18 OBD column (5 μm, 150 × 30 mm ID) using a gradient of MeCN in H2O / FA ​​(0.1%) as the mobile phase; Preparation method U: The compound was purified by preparative HPLC on a CHIRALPAK IA-3 column (3 μm, 50 × 4.6 mm ID) using EtOH in hexane / DCM (3:1, 0).The compound was purified by a gradient of MeCN in H2O / FA ​​(0.1%) as the mobile phase; Preparation method V: The compound was purified by preparative HPLC on an XSelect CSH Prep C18 OBD column (5 μm, 250 × 19 mm ID) using a gradient of MeCN in H2O / FA ​​(0.1%) as the mobile phase.

[0819] SFC preparation methods: Preparation method SFC-A: The compound was purified by preparative SFC using a Waters BEH column (5 μm, 250 × 30 mm ID) with EtOH / FA (20 mM) in CO2 as the mobile phase; Preparation method SFC-B: The compound was purified by preparative SFC using a Phenomenex Luna Hilic column (5 μm, 250 × 30 mm ID) with EtOH / FA (20 mM) in CO2 as the mobile phase; Preparation method SFC-C: The compound was purified by preparative SFC using a Phenomenex Luna Hilic column (5 μm, 250 × 30 mm ID) with MeOH / NH3 (20 mM) in CO2 as the mobile phase.

[0820] Collect the relevant fractions, combine them, and freeze-dry to obtain the purified compound, or

[0821] Collect the relevant fractions, combine and concentrate under reduced pressure, extract with DCM or EtOAc, and dry the organic phase with Na2SO4 or by using a phase separator, then concentrate under reduced pressure to obtain the purified compound;

[0822] (ix) Chiral preparative chromatography was performed using HPLC or SFC on a standard HPLC or SFC instrument and with isocratic or gradient runs using the mobile phase as described in the experimental section.

[0823] (x) The yield (in the presence of the product) is not necessarily the maximum obtainable, and the reaction is repeated if a larger amount of reaction product is required.

[0824] (xi) In cases where certain compounds are obtained as acid addition salts (e.g., monohydrochloride or dihydrochloride), 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 cannot usually be determined, for example, by elemental analysis data;

[0825] (xii) Generally, the structure of the final product of formula (I) is confirmed by nuclear magnetic resonance (NMR) and / or mass spectrometry; Bruker Avance III 300, 400, 500 and 600 spectrometers (at 300 MHz, 400 MHz, 500 MHz and 600 MHz respectively) are used. 1(Operated at H frequency) Proton NMR chemical shift values ​​are measured on the delta scale. Experiments are typically recorded at 25 °C. Chemical shifts are given in ppm, with the solvent used as an internal standard. Protons on heteroatoms, such as NH and OH protons, are only reported if detected in the NMR and may therefore be lost. In some cases, protons may be masked or partially masked by solvent peaks, and thus either lost and not reported, or reported as multiplets overlapping with the solvent. The following abbreviations (and their derivatives, such as dd, doublet, etc.) have been used: s, singlet; d, doublet; t, triplet; q, quartet; m, multiplet; br, broad peak; qn, quintet; and p, pentet. In some cases, the structure of the final product of formula (I) may appear as a rotational isomer in the NMR spectrum; in such cases, only the peak of the dominant rotational isomer is reported. Electrospray ionization mass spectrometry data were acquired using a Waters AcquityUPLC coupled to a Waters single quadrupole mass spectrometer or similar equipment, acquiring both cation and anion data, and typically only reporting ions relevant to the parent structure; high-resolution electrospray ionization mass spectrometry data were acquired using a Waters XEVO qToF mass spectrometer coupled to a Waters AcquityUPLC or similar equipment, acquiring both cation and anion data, and typically only reporting ions relevant to the parent structure.

[0826] (xiii) Intermediates may not be completely purified, but their structure and purity are assessed by TLC, analytical HPLC / UPLC and / or NMR analysis and / or mass spectrometry;

[0827] (xiv) Unless otherwise stated, compounds containing asymmetric carbon and / or sulfur atoms are not resolved;

[0828] (xv) Generally, examples and intermediate compounds are named using ChemDraw Professional versions 19.0.0.22 or 20.0.2.51 from PerkinElmer. ChemDraw Professional versions 19.0.0.22 and 20.0.2.51 use the Cahn-Ingold-Prelog (CIP) rules for stereochemistry to generate names of chemical structures, and adhere to the IUPAC rules as strictly as possible when generating chemical names. Stereoisomers are distinguished from each other by the stereo descriptors referenced in their names and are assigned according to the CIP rules.

[0829] ---ChemDraw optionally uses notations such as "&" and "or" in the illustration of stereocenters to describe the configuration of the stereochemical center present in the structure. Generally, a chemical structure containing the notation "&" at the stereocenter indicates that the configuration of such an example or intermediate at the stereocenter is a mixture of both (R) and (S); and the notation "or" indicates that the configuration of such an example or intermediate at the stereocenter is (S) or (R). Absolute, unspecified, "&", and "or" stereocenters can all exist in a single structure.

[0830] Generally, for embodiments and intermediates where all stereocenters are designated as "&", the structure is named with the prefix "exogenous-". For embodiments and intermediates where all stereocenters are designated as "or", the structure is named with the prefix "rel-".

[0831] ---Generally, the examples and intermediate compounds are named using descriptors (RS) and (SR) to represent the general "&" center of a chemical structure having multiple chiral centers, where only some are specified as "&". Descriptors (R*) and (S*) are used to represent the general "or" center of a chemical structure having multiple chiral centers, where only some are specified as "or".

[0832] ---Generally speaking, descriptors (r) and (s) are used to describe the absolute configuration of any pseudo-asymmetric centers in the structure of embodiments and intermediates.

[0833] ---Generally speaking, on a given chiral HPLC column and eluent, "Isomer 1" corresponds to the first eluting isomer and "Isomer 2" corresponds to the second eluting isomer, and is used to distinguish two isomers that contain one or more stereocenters and have an absolutely unknown configuration at one or more stereocenters;

[0834] (xvi) In cases where the reaction involves degassing or purging, this can be done, 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).

[0835] (xvii) In reactions involving a evacuation-refill cycle, this can be achieved by evacuating the reaction vessel by applying a vacuum and then refilling it with an inert gas (typically N2 or argon). This process is typically repeated, usually three times; and

[0836] (xvii) In addition to those mentioned above, the following abbreviations are also used:

[0837] (xvii) In addition to those mentioned above, the following abbreviations are also used:

[0838]

[0839]

[0840]

[0841]

[0842] B. Intermediate compounds

[0843] Intermediate 1: (R)-4-cyanothiazolidine-3-carboxylic acid tert-butyl ester

[0844]

[0845] Step a)(R)-4-carbamoylthiazolidin-3-carboxylic acid tert-butyl ester

[0846]

[0847] Boc₂O (18.6 mL, 80.2 mmol) was added to a stirred solution of (R)-4-carbamoylthiazoline-3-carboxylic acid tert-butyl ester (17.0 g, 72.9 mmol) and pyridine (7.07 mL, 87.5 mmol) in EtOAc (170 mL), and the reaction mixture was stirred at room temperature for 3 hours. Then, NH₃ solution (25% aqueous solution, 6 mL) was added dropwise, and the mixture was stirred at room temperature overnight. The reaction mixture was diluted with EtOAc, the phases were separated, and the organic phase was washed with saturated NaCl, dried, filtered through a silica gel pad, washed with EtOAc, and evaporated to give a crude title compound (16.9 g, 100%) as a colorless oil, which was used directly in the next step.

[0848] Step b)(R)-4-cyanothiazolidine-3-carboxylic acid tert-butyl ester

[0849] At room temperature, TFAA (12.4 mL, 87.5 mmol) in solution in EtOAc (20 mL) was added to a solution of crude (R)-4-carbamoylthiazolyl-3-carboxylic acid tert-butyl ester (16.9 g, 72.9 mmol) and pyridine (14.7 mL, 182 mmol) in EtOAc (150 mL). The mixture was stirred at room temperature for 4 hours, then diluted with EtOAc and washed with HCl (1 M, aqueous solution) and saturated NaHCO3 (aqueous solution). The organic phase was dried, filtered through a silica gel pad, washed with EtOAc and evaporated to give a pale yellow oil that solidified upon standing. The crude solid material was suspended in heptane:EtOAc (4:1, 50 mL) and stirred overnight at room temperature. The solid was filtered off, washed with heptane:EtOAc (4:1) and dried to give the title compound (12.0 g, 83%) as a colorless solid. 1H NMR (400MHz, CDCl3) δ5.20–4.79(m,1H),4.60–4.53(m,1H),4.53–4.36(m,1H),3.40-3.18(m,2H),1.51(s,9H).

[0850] Intermediate 2: (R)-Thiazolidin-4-carboxynitrile hydrochloride

[0851]

[0852] At room temperature, a solution of concentrated HCl (11 mL) in MeOH (140 mL) was slowly added to a solution of (R)-4-cyanothiazolidine-3-carboxylic acid tert-butyl ester intermediate 1 (6.0 g, 28 mmol) in MeOH (140 mL). The clear, colorless solution was stirred at room temperature for 2 hours. The solvent was evaporated to give the title compound (4.22 g, 100%) as a colorless solid. 1 H NMR (400MHz, CD3OD) δ4.90(dd,1H), 4.35–4.24(m,2H), 3.37–3.24(m,2H).

[0853] Intermediate 3: (R)-(2-(4-cyanothiazolidine-3-yl)-2-oxoethyl)tert-butyl carbamate

[0854]

[0855] DIPEA (19.6 mL, 112 mmol) was added to a suspension of (R)-thiazolidin-4-carboxynitrile hydrochloride intermediate 2 (4.22 g, 28 mmol), (tert-butoxycarbonyl)glycine (6.13 g, 35.0 mmol), and T3P (42 mL, 70 mmol, a 50% solution in EtOAc) in EtOAc (120 mL). The mixture was heated at 60 °C for 4 hours. The mixture was diluted with EtOAc and washed successively with water, HCl (1 M, aqueous solution), and saturated NaHCO3 (aqueous solution). The organic phase was dried, filtered, and evaporated. The residue was filtered through a silica gel pad, washed with heptane:EtOAc (1:1), and evaporated to give an oily substance, which was ground with heptane:DCM to give the title compound (7.6 g, 100%) as an almost colorless solid. 1 H NMR (400MHz, CDCl3) δ5.36–5.25(m,2H),4.59–4.52(m,2H),4.14–3.90(m,2H),3.29(d,2H),1.45(s,9H).

[0856] Intermediate 4: (R)-3-glycylthiazolidin-4-carboxynitrile hydrochloride

[0857]

[0858] A solution of concentrated HCl (5.6 mL) in MeOH (140 mL) was slowly added to a solution of (R)-(2-(4-cyanothiazolidine-3-yl)-2-oxoethyl)carbamate intermediate 3 (7.6 g, 28 mmol) in MeOH (140 mL), and the solution was stirred overnight at room temperature. The solvent was evaporated to give the title compound (5.8 g, 100%) as a colorless solid. 1 HNMR (400MHz, CD3OD) δ5.34(t,1H),4.72(d,1H),4.62(d,1H),4.11–3.94(m,2H),3.41–3.36(m,2H).

[0859] Intermediate 5: Methyl 6-acetylquinoline-4-carboxylate

[0860]

[0861] Tributyl(1-ethoxyvinyl)stanane (1.63 g, 4.51 mmol) was added to a degassed 1,4-di(2,4-di) atmosphere under N2(g) at 20 °C. The mixture was prepared in 25 mL of pentane (1.0 g, 3.8 mmol) and Pd(dppf)Cl2·DCM (0.307 g, 0.38 mmol). The resulting mixture was stirred at 80 °C for 18 hours. The mixture was diluted with MeCN (3 mL), ten drops of 3N HCl (aqueous solution) were added, and stirring was continued for 30 minutes. The reaction mixture was diluted with water (10 mL) and extracted with EtOAc (3 × 10 mL). The organic layer was dried over Na2SO4, filtered, and concentrated. The residue was purified by preparative TLC (pentane:EtOAc 1:1) to give the title compound (0.70 g, 81%) as a white solid; MS (ESI) m / z [M+H] + 230.

[0862] Intermediate 6: Methyl 6-(2-hydroxypropyl-2-yl)quinoline-4-carboxylate

[0863]

[0864] Under a nitrogen atmosphere (N2(g) atmosphere), CH3MgCl (3M THF solution, 0.87 mL, 2.6 mmol) was added dropwise to a solution of methyl 6-acetylquinoline-4-carboxylate intermediate 5 (0.30 g, 1.3 mmol) in THF (3 mL), and the reaction mixture was stirred at 0 °C for 3 h. The reaction was quenched with saturated NH4Cl (water solution, 20 mL), and the mixture was extracted with DCM (3 × 20 mL). The combined organic layers were dried over Na2SO4, filtered, and evaporated under reduced pressure. The residue was purified by preparative TLC (DCM:MeOH, 10:1) to give the title compound (0.20 g, 62%) as an orange gel; MS (ESI) m / z [M+H] + 246.

[0865] Intermediate 7: Methyl 6-(hydroxymethyl)quinoline-4-carboxylate

[0866]

[0867] (Tributyltinyl)methanol (1.45 g, 4.51 mmol) was added to a suspension of methyl 6-bromoquinoline-4-carboxylate (1.0 g, 3.8 mmol) and Pd(PPh3)4 (0.43 g, 0.38 mmol) in degassed toluene (25 mL) under a N2(g) atmosphere at 20 °C, and the reaction mixture was stirred at 80 °C for 18 h. The solvent was removed under reduced pressure, and the residue was purified by preparative TLC (EtOAc:pentane 3:2) to give the title compound (0.62 g, 76%) as a pale yellow solid; MS (ESI) m / z [M+H] + 218.

[0868] Intermediate 8: Methyl 6-formylquinoline-4-carboxylate

[0869]

[0870] Des-Martin periodide (4.64 g, 10.9 mmol) was added to a solution of methyl 6-(hydroxymethyl)quinoline-4-carboxylate intermediate 7 (950 mg, 4.37 mmol) in DCM (20 mL), and the reaction mixture was stirred at 25 °C for 2 hours. The reaction mixture was concentrated under vacuum, and the crude product was purified by preparative TLC (EtOAc: petroleum ether, 1:1) to give the title compound (850 mg, 90%) as a yellow solid: MS (ESI) m / z [M+H] + 215.

[0871] Intermediate 9: Methyl 6-(chloromethyl)quinoline-4-carboxylate

[0872]

[0873] At 20 °C, intermediate 7 (0.37 g, 1.7 mmol) of methyl 6-(hydroxymethyl)quinoline-4-carboxylate was added to a solution of SOCl2 (0.26 mL, 3.6 mmol) in DCM (18 mL). The resulting mixture was stirred at 20 °C for 16 hours. The substance was diluted with EtOAc and filtered through silica. The solvent was removed under reduced pressure to give the title compound (0.44 g) as a pale yellow solid: MS(ESI) m / z [M+H] + 236.

[0874] Intermediate 10: 6-((1H-pyrazol-1-yl)methyl)quinoline-4-carboxylic acid

[0875]

[0876] Intermediate 9 (220 mg, 0.93 mmol) was added at 20 °C to a mixture of 1H-pyrazole (76 mg, 1.1 mmol), Cs₂CO₃ (1.52 g, 4.67 mmol), and KI (465 mg, 2.80 mmol) in MeCN (25 mL). The resulting mixture was stirred at 80 °C for 16 hours. The reaction mixture was acidified with HCl (0.1 M) and volatiles were removed under reduced pressure. The dried solid was ground with DCM (2 × 50 mL), filtered, and concentrated under reduced pressure. The residue was purified by preparative HPLC method F (gradient: 1%–21%) to give the title compound (40 mg, 17%) as a white solid: MS (ESI) m / z [M+H] + 254.

[0877] Intermediate 11: tert-butyl 6-(3-methoxypropyl)quinoline-4-carboxylate

[0878]

[0879] NiBr₂O(CH₂CH₂OCH₃)₂ (30 mg, 0.10 mmol) was added to a mixture of tert-butyl 6-bromoquinoline-4-carboxylate (WO₂019154886) (300 mg, 0.97 mmol), 1-bromo-3-methoxypropane (298 mg, 1.95 mmol), Zn (127 mg, 1.95 mmol), 4,4'-dimethoxy-2,2'-bipyridine (21 mg, 0.10 mmol), and NaI (146 mg, 0.97 mmol) in DMPU (8 mL). The reaction was stirred at 80 °C for 2 hours, diluted with EtOAc, and washed with water. The organic layer was dried over Na₂SO₄, filtered, and evaporated under reduced pressure. The residue was purified by preparative TLC (EtOAc: petroleum ether; 1:5) to give the title compound (0.12 g, 41%) as a pale yellow gel: MS (ESI) m / z [M+H]+ 302.

[0880] Intermediate 12: 6-(3-methoxypropyl)quinoline-4-carboxylic acid

[0881]

[0882] Intermediate 11 (160 mg, 0.53 mmol) of 6-(3-methoxypropyl)quinoline-4-carboxylic acid tert-butyl ester was added to a mixture of TFA (4 mL) and DCM (10 mL), and stirred at room temperature for 2 hours. Volatiles were removed under reduced pressure, and the solid was further dried under vacuum to give the title compound (0.13 g) as a pale yellow gel: MS(ESI) m / z [M+H] + 246.

[0883] Intermediate 13: tert-butyl 6-(2-methoxyethyl)quinoline-4-carboxylate

[0884]

[0885] NiBr₂O(CH₂CH₂OCH₃)₂ (45 mg, 0.15 mmol) was added to a mixture of tert-butyl 6-bromoquinoline-4-carboxylate (WO₂019154886) (300 mg, 0.97 mmol), 1-bromo-2-methoxyethane (271 mg, 1.95 mmol), Zn (127 mg, 1.95 mmol), 4,4'-dimethoxy-2,2'-bipyridine (21 mg, 0.10 mmol), and NaI (146 mg, 0.97 mmol) in DMPU (10 mL). The reaction was stirred at 80 °C for 2 h, diluted with EtOAc, and washed with water. The organic layer was dried over Na₂SO₄, filtered, and evaporated. The residue was purified by preparative TLC (EtOAc: petroleum ether; 1:4) to give the title compound (80 mg, 29%) as a pale yellow solid: MS (ESI) m / z [M+H] + 288.

[0886] Intermediate 14: 6-(2-methoxyethyl)quinoline-4-carboxylic acid

[0887]

[0888] Intermediate 13 (80 mg, 0.28 mmol) of 6-(2-methoxyethyl)quinoline-4-carboxylic acid tert-butyl ester was added to a mixture of TFA (2 mL) and DCM (5 mL), and stirred at room temperature for 2 hours. Volatiles were removed under reduced pressure, and the solid was further dried under vacuum to give the title compound (64 mg, 99%) as a pale yellow gel: MS (ESI) m / z [M+H] + 232.

[0889] Intermediate 15: Methyl 6-(cyanomethyl)quinoline-4-carboxylate

[0890]

[0891] Pd₂(dba)₃·CHCl₃ (194 mg, 0.19 mmol) was added in a single step to a suspension of methyl 6-bromoquinoline-4-carboxylate (500 mg, 1.88 mmol), 2-(trimethylsilyl)acetonitrile (277 mg, 2.44 mmol), ZnF₂ (136 mg, 1.32 mmol), and XantPhos (109 mg, 0.19 mmol) in DMF (8 mL) under a N₂(g) atmosphere at 20 °C, and the reaction mixture was stirred at 105 °C for 10 h. The reaction mixture was diluted with EtOAc (100 mL) and washed with saturated brine (3 × 50 mL). The organic layer was dried over Na₂SO₄, filtered, and evaporated under vacuum. The residue was purified by preparative TLC (EtOAc: petroleum ether, 1:2) to give the title compound (340 mg, 80%) as a yellow solid: MS(ESI) m / z [M+H] + 227.

[0892] Intermediate 16: Methyl 6-(1-cyanocyclopropyl)quinoline-4-carboxylate

[0893]

[0894] NaH (32 mg, 1.3 mmol) was added in portions to a solution of methyl 6-(cyanomethyl)quinoline-4-carboxylate intermediate 15 (300 mg, 1.33 mmol) in DMF (2 mL), and the reaction mixture was stirred at room temperature for 1 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 dried over Na₂SO₄, filtered, and evaporated. The residue was purified by preparative TLC (EtOAc: petroleum ether, 1:2) to give the title compound (200 mg, 60%) as a yellow solid: MS (ESI) m / z [M+H]. + 253.

[0895] Intermediate 17: 6-(1-cyanocyclopropyl)quinoline-4-carboxylic acid

[0896]

[0897] A solution of methyl 6-(1-cyanocyclopropyl)quinoline-4-carboxylate intermediate 16 (130 mg, 0.52 mmol) and LiOH (25 mg, 1.0 mmol) in THF (6 mL) and water (1 mL) was stirred at room temperature for 2 hours. The solvent was removed under reduced pressure. The reaction mixture was acidified with 2 M HCl (aqueous solution), and the precipitate was collected by filtration and washed with water to give a crude title compound (70 mg, 57%) as a white solid. MS (ESI) m / z [M+H] + 239.

[0898] Intermediate 18: Methyl 6-(2-methoxyethoxy)quinoline-4-carboxylate

[0899]

[0900] Add 1-bromo-2-methoxyethane (137 mg, 0.98 mmol) and Cs₂CO₃ (802 mg, 2.46 mmol) to a stirred solution of methyl 6-hydroxyquinoline-4-carboxylate (200 mg, 0.98 mmol) in DMF (5 mL). Stir the resulting mixture at 25 °C for 2 hours. The reaction mixture was filtered. The solvent was removed under reduced pressure. The residue was purified by preparative TLC (petroleum ether:EtOAc, 2:1) to give the title compound (0.19 g, 73%) as a colorless oil; MS m / z (ESI), [M+H) + 262.0.

[0901] Intermediate 19: 6-(2-methoxyethoxy)quinoline-4-carboxylic acid

[0902]

[0903] LiOH (55 mg, 2.3 mmol) was added to methyl 6-(2-methoxyethoxy)quinoline-4-carboxylate intermediate 18 (150 mg, 0.57 mmol) in THF (2 mL) and water (2 mL) at 25 °C. The resulting suspension was stirred at 25 °C for 3 hours. The reaction mixture was adjusted to pH 5 with 2 M HCl (aqueous solution). The solvent was removed under reduced pressure to give a crude product as a pale yellow solid; MS m / z (ESI), [M+H] + 248.0.

[0904] Intermediate 20: Methyl 6-(cyclopropylmethoxy)quinoline-4-carboxylate

[0905]

[0906] K₂CO₃ (340 mg, 2.46 mmol) was added to a solution of methyl 6-hydroxyquinoline-4-carboxylate (200 mg, 0.98 mmol) and (bromomethyl)cyclopropane (199 mg, 1.48 mmol) in DMF (3 mL) at 30 °C. The resulting suspension was stirred at 60 °C under N₂ (g) for 3 h. The solvent was removed under reduced pressure. The residue was purified by preparative TLC (EtOAc: petroleum ether, 1:1) to give the title compound (197 mg, 78%) as a yellow solid; MS m / z (ESI), [M+H] + 258.2.

[0907] Intermediate 21: 6-(cyclopropylmethoxy)quinoline-4-carboxylic acid

[0908]

[0909] NaOH (148 mg, 3.7 mmol) was added to methyl 6-(cyclopropylmethoxy)quinoline-4-carboxylate intermediate 20 (191 mg, 0.74 mmol) in MeOH (9 mL) and water (3 mL) at 25 °C. The resulting solution was stirred at 25 °C for 1 hour. The solvent was removed under reduced pressure. The residue was diluted with water (50 mL) and adjusted to pH 3 with 1 M HCl (aqueous solution). The aqueous phase was extracted with EtOAc (3 × 50 mL), and the organic layer was dried over Na2SO4, filtered, and evaporated to give the title compound (173 mg, 96%) as a white solid, which was used directly for the next step without further purification; MS m / z (ESI), [M+H + 244.0.

[0910] Intermediate 22: Methyl 6-((tetrahydro-2H-pyran-4-yl)oxy)quinoline-4-carboxylate

[0911]

[0912] DIAD (574 μL, 2.95 mmol) was slowly added at 60 °C to a solution of methyl 6-hydroxyquinoline-4-carboxylate (120 mg, 0.59 mmol), tetrahydro-2H-pyran-4-ol (302 mg, 2.95 mmol), and triphenylphosphine (774 mg, 2.95 mmol) in THF (5 mL). The resulting suspension was stirred at 60 °C for 15 min. The solvent was removed under reduced pressure. The residue was purified by preparative TLC (EtOAc: petroleum ether, 1:2) to give a crude title compound (1.1 g) as a yellow solid; MS m / z (ESI), [M+H + 288.2.

[0913] Intermediate 23: 6-((tetrahydro-2H-pyran-4-yl)oxy)quinoline-4-carboxylic acid

[0914]

[0915] NaOH (762 mg, 19.1 mmol) was added to methyl 6-((tetrahydro-2H-pyran-4-yl)oxy)quinoline-4-carboxylate intermediate 22 (1.10 g, 3.81 mmol) in MeOH (9 mL) and water (3 mL). The resulting solution was stirred at 25 °C for 1 hour. The solvent was removed under reduced pressure. The residue was diluted with saturated NaHCO3 (50 mL aqueous solution) and extracted with EtOAc (3 × 50 mL). The aqueous layer was adjusted to pH 3 with 1 M HCl (aqueous solution) and then extracted with EtOAc (3 × 100 mL). The combined organic layers were dried over Na2SO4, filtered, and evaporated to give the title compound (161 mg, 15%) as a white solid. The product was used directly for the next step without further purification; MS m / z (ESI), [M+H] + 274.1.

[0916] Intermediate 24: Methyl 6-((1,3-difluoroprop-2-yl)oxy)quinoline-4-carboxylate

[0917]

[0918] DIAD (0.896 g, 4.43 mmol) was added dropwise at 60 °C to a solution of methyl 6-hydroxyquinoline-4-carboxylate (0.15 g, 0.74 mmol), 1,3-difluoroprop-2-ol (0.426 g, 4.43 mmol), and triphenylphosphine (1.16 g, 4.43 mmol) in THF (15 mL). The resulting solution was stirred at 60 °C for 15 min. The solvent was removed under reduced pressure. The crude product was purified by rapid silica chromatography (gradient: 1%–50% EtOAc in petroleum ether solution) to give a crude title compound (1 g) as a pale yellow solid, which was used for the next step; MS m / z (ESI), [M+H] + 282.1.

[0919] Intermediate 25: 6-((1,3-difluoroprop-2-yl)oxy)quinoline-4-carboxylic acid

[0920]

[0921] NaOH (722 mg, 18.0 mmol) was added to methyl 6-((1,3-difluoroprop-2-yl)oxy)quinoline-4-carboxylate intermediate 24 (1015 mg, 3.61 mmol) in MeOH (9 mL) and water (3 mL) at 25 °C. The resulting solution was stirred in air at 25 °C for 1 hour. The solvent was removed under reduced pressure. The residue was diluted with saturated NaHCO3 (50 mL aqueous solution) and extracted with EtOAc (3 × 50 mL). The aqueous layer was adjusted to pH 3 with 1 M HCl (aqueous solution) and extracted with EtOAc (3 × 50 mL). The organic layer was dried over Na2SO4, filtered, and evaporated to give the title compound (174 mg, 18%) as a pale yellow solid, which was used directly for the next step without further purification; MS m / z (ESI), [M+H + 268.0.

[0922] Intermediate 26: Methyl 6-((3,3-difluorocyclobutyl)methoxy)quinoline-4-carboxylate

[0923]

[0924] Cs₂CO₃ (802 mg, 2.46 mmol) was added at 25 °C to a solution of methyl 6-hydroxyquinoline-4-carboxylate (200 mg, 0.98 mmol) and 3-(bromomethyl)-1,1-difluorocyclobutane (273 mg, 1.48 mmol) in DMF (3 mL). The resulting suspension was stirred at 55 °C for 3 hours under N₂ (g). The solvent was removed under reduced pressure. The residue was diluted with water (50 mL) and extracted with EtOAc (3 × 50 mL). The organic layer was dried over Na₂SO₄, filtered, and evaporated. The residue was purified by preparative TLC (EtOAc: petroleum ether, 1:2) to give the title compound (132 mg, 43%) as a brown gel; MS m / z (ESI), [M+H) + 308.0.

[0925] Intermediate 27: 6-((3,3-difluorocyclobutyl)methoxy)quinoline-4-carboxylic acid

[0926]

[0927] NaOH (83 mg, 2.1 mmol) was added to methyl 6-((3,3-difluorocyclobutyl)methoxy)quinoline-4-carboxylate intermediate 26 (127 mg, 0.41 mmol) in MeOH (9 mL) and water (3 mL) at 25 °C. The resulting solution was stirred at 25 °C for 1 hour. The solvent was removed under reduced pressure, and the mixture was diluted with water (50 mL). The pH was adjusted to pH 3 with 1 M HCl (aqueous solution). The aqueous phase was extracted with EtOAc (3 × 50 mL). The organic phase was dried over Na₂SO₄, filtered, and evaporated to give the title compound (120 mg, 99%) as a white solid, which was used directly for the next step without further purification; MS m / z (ESI), [M+H + 294.0.

[0928] Intermediate 28: Racemic-(R)-6-((2,2-dimethyltetrahydro-2H-pyran-4-yl)oxy)quinoline-4-carboxylic acid Methyl ester

[0929]

[0930] DIAD (718 μL, 3.69 mmol) was slowly added at 60 °C to a solution of methyl 6-hydroxyquinoline-4-carboxylate (150 mg, 0.74 mmol), racemic (R)-2,2-dimethyltetrahydro-2H-pyran-4-ol (WO 2012021591) (481 mg, 3.69 mmol), and triphenylphosphine (968 mg, 3.69 mmol) in THF (10 mL). The resulting suspension was stirred at 60 °C for 15 min. The solvent was removed under reduced pressure. The residue was ground with Et2O (2 × 15 mL) and filtered. The residue was purified by preparative TLC (EtOAc: petroleum ether, 1:2) to give a crude title compound (365 mg) as a yellow gel, which was used for the next step; MS m / z (ESI), [M+H + 316.0.

[0931] Intermediate 29: Racemic-(R)-6-((2,2-dimethyltetrahydro-2H-pyran-4-yl)oxy)quinoline-4-carboxylic acid

[0932]

[0933] NaOH (224 mg, 5.60 mmol) was added to racemic (R)-6-((2,2-dimethyltetrahydro-2H-pyran-4-yl)oxy)quinoline-4-carboxylate intermediate 28 (353 mg, 1.12 mmol) in MeOH (9 mL) and water (3 mL). The resulting solution was stirred at 25 °C for 1 hour. The solvent was removed under reduced pressure. The residue was diluted with saturated NaHCO3 (50 mL aqueous solution) and extracted with EtOAc (3 × 50 mL). The pH of the aqueous layer was adjusted to pH 3 with 1 M HCl (aqueous solution) and then extracted with EtOAc (3 × 50 mL). The organic layer was dried over Na2SO4, filtered, and evaporated to give the title compound (194 mg, 57%) as a white solid, which was used directly for the next step without further purification; MS m / z (ESI), [M+H + 302.2.

[0934] Intermediate 30: tert-butyl 6-(4,4,5,5-tetramethyl-1,3,2-dioxoboronyl-2-yl)quinoline-4-carboxylate

[0935]

[0936] Pd(dppf)Cl2 (137 mg, 0.19 mmol) was added to 1,4-didi The solution was prepared in 10 mL of alkyl 6-bromoquinoline-4-carboxylic acid tert-butyl ester (WO 2019154886) (640 mg, 2.08 mmol), KOAc (549 mg, 5.59 mmol), and bis(pinacol)diboron (711 mg, 2.80 mmol). The resulting solution was stirred at 80 °C for 3 hours under N2 (g). The solvent was removed under reduced pressure. The mixture was diluted with EtOAc (50 mL) and washed successively with water (3 × 25 mL). The organic layer was dried over Na2SO4, filtered, and evaporated. The residue was purified by preparative TLC (EtOAc: petroleum ether, 2:1) to give the title compound (540 mg, 73%) as a yellow solid; MS m / z (ESI), [M+H] + 356.1.

[0937] Intermediate 31: tert-butyl 6-hydroxyquinoline-4-carboxylate

[0938]

[0939] Sodium perborate tetrahydrate (458 mg, 2.98 mmol) was added to tert-butyl 6-(4,4,5,5-tetramethyl-1,3,2-dioxoboropentane-2-yl)quinoline-4-carboxylate intermediate 30 (580 mg, 1.63 mmol) in THF (8 mL) and water (4 mL). The resulting solution was stirred at 20 °C for 6 hours. The solvent was removed under reduced pressure. The residue was purified by preparative TLC (EtOAc: petroleum ether, 1:2) to give the title compound (350 mg, 87%) as a yellow solid; MS m / z (ESI), [M+H) + 246.0.

[0940] Intermediate 32: tert-butyl 6-(cyanomethoxy)quinoline-4-carboxylate

[0941]

[0942] Bromoacetonitrile (257 mg, 2.14 mmol) was added to intermediate 31 of 6-hydroxyquinoline-4-carboxylic acid tert-butyl ester (350 mg, 1.43 mmol) and K₂CO₃ (493 mg, 3.57 mmol) in DMF (20 mL). The resulting solution was stirred at 60 °C for 6 hours under N₂ (g). The solvent was removed under reduced pressure. The residue was purified by preparative TLC (EtOAc: petroleum ether, 1:1) to give the title compound (320 mg, 79%) as a yellow solid. MS m / z (ESI), [M+H) + 285.1.

[0943] Intermediate 33: 6-(cyanomethoxy)quinoline-4-carboxylic acid

[0944]

[0945] TFA (650 μL, 8.44 mmol) was slowly added to a solution of tert-butyl 6-(cyanomethoxy)quinoline-4-carboxylate intermediate 32 (300 mg, 1.06 mmol) in DCM (3 mL). The resulting solution was stirred at 20 °C for 18 hours. The solvent was removed under reduced pressure to give the crude title compound (300 mg, 83%); MS m / z (ESI), [M+H) + 229.1.

[0946] Intermediate 34: Methyl 6-(2-oxopropoxy)quinoline-4-carboxylate

[0947]

[0948] A solution of methyl 6-hydroxyquinoline-4-carboxylate (200 mg, 0.98 mmol), 1-bromoprop-2-one (270 mg, 1.97 mmol), and Cs₂CO₃ (641 mg, 1.97 mmol) in THF (8 mL) was stirred at 50 °C for 20 h. The solvent was removed under reduced pressure. The reaction mixture was diluted with EtOAc (25 mL) and washed with water (3 × 10 mL). The organic layer was dried over Na₂SO₄, filtered, and evaporated. The crude extract was purified by preparative TLC (petroleum ether:EtOAc, 3:2) to give the title compound (220 mg, 86%) as a white solid; MS m / z (ESI), [M+H + 260.0.

[0949] Intermediate 35: Methyl 6-(2,2-difluoropropoxy)quinoline-4-carboxylate

[0950]

[0951] DAST (561 μL, 4.24 mmol) was added to a solution of methyl 6-(2-oxopropoxy)quinoline-4-carboxylate intermediate 34 (220 mg, 0.85 mmol) in DCM (10 mL) at 0 °C. The reaction was stirred at 25 °C for 20 h. The solvent was removed under reduced pressure. The residue was purified by preparative TLC (petroleum ether:EtOAc, 3:2) to give the title compound (180 mg, 75%) as a white solid; MS m / z (ESI), [M+H) + 282.1.

[0952] Intermediate 36: 6-(2,2-difluoropropoxy)quinoline-4-carboxylic acid

[0953]

[0954] A solution of methyl 6-(2,2-difluoropropoxy)quinoline-4-carboxylate intermediate 35 (170 mg, 0.60 mmol) and LiOH (29 mg, 1.2 mmol) in MeOH (6 mL) and water (1 mL) was stirred at 25 °C for 3 hours. The solvent was removed under reduced pressure. The mixture was diluted with water (10 mL) and the pH was adjusted to pH 6 with 1 M HCl (aqueous solution). The precipitate was collected by filtration, washed with water (25 mL), and dried under vacuum to give the title compound (150 mg, 93%) as a white solid, which was ready for use without further purification; MS m / z (ESI), [M+H] + 268.0.

[0955] Intermediate 37: Racemic-(R)-1-(4-chloroquinolin-6-yl)-1-(3-fluoropyridin-2-yl)ethanol-1-ol

[0956]

[0957] n-BuLi (4.95 mL, 12.4 mmol, 2.5 M in hexane) was slowly added to a solution of 6-bromo-4-chloroquinoline (2.0 g, 8.3 mmol) in THF (20 mL) under N2 (g) at -78 °C. The resulting solution was stirred under N2 (g) at -78 °C for 3 hours. 1-(3-fluoropyridin-2-yl)ethyl-1-one (1.15 g, 8.25 mmol) was slowly added to the stirred mixture heated to -40 °C over a 15-minute period. The resulting solution was stirred under N2 (g) at -40 °C for 2 hours. The reaction mixture was quenched with saturated NH4Cl (20 mL aqueous solution) and extracted with EtOAc (3 × 50 mL). The organic layer was dried over Na2SO4, filtered, and evaporated. The crude product was purified by C18 rapid chromatography (gradient: 40%–45% aqueous MeCN), and the title compound (687 mg, 27%) was obtained as a brown gel after evaporation of the pure fraction; MS m / z (ESI), [M+H) + 303.2.

[0958] Intermediate 38: Racemic-(R)-6-(1-(3-fluoropyridin-2-yl)-1-hydroxyethyl)quinoline-4-carboxylic acid methyl ester

[0959]

[0960] Under N2(g) atmosphere, Pd(OAc)2 (54 mg, 0.24 mmol) and Pd(dppf)Cl2 (88 mg, 0.12 mmol) were added to a mixture of racemic-(R)-1-(4-chloroquinoline-6-yl)-1-(3-fluoropyridin-2-yl)ethanol-1-ol intermediate 37 (727 mg, 2.40 mmol), TEA (1.0 mL, 7.2 mmol), and dppf (200 mg, 0.36 mmol) in MeOH (5 mL). The resulting mixture was stirred at 100 °C for 12 hours under a CO(g) atmosphere (20 atm). The solvent was removed under reduced pressure. The residue was diluted with water (50 mL) and extracted with EtOAc (3 × 50 mL). The organic layer was dried over Na2SO4, filtered, and evaporated. The crude product was purified by rapid silica gel chromatography (gradient: 50%-80% EtOAc in petroleum ether solution), and the title compound (537 mg, 68%) was obtained as a brown gel after evaporation of the pure fraction; MS m / z (ESI), [M+H) + 327.2.

[0961] Intermediate 39: Racemic-(R)-6-(1-(3-fluoropyridin-2-yl)ethyl)quinoline-4-carboxylic acid methyl ester

[0962]

[0963] Racemic (R)-6-(1-(3-fluoropyridin-2-yl)-1-hydroxyethyl)quinoline-4-carboxylate intermediate 38 (120 mg, 0.37 mmol) was added to triethylsilane (5 mL) and TFA (5 mL) at 13 °C. The resulting solution was stirred at 100 °C for 2 days under N2 (g). Additional triethylsilane (1 mL) and TFA (1 mL) were added, and the reaction was stirred at 100 °C for 1 day. The solvent was removed under reduced pressure. The residue was diluted with saturated NaHCO3 (50 mL aqueous solution) and extracted with EtOAc (3 × 100 mL). The organic layer was dried over Na2SO4, filtered, and evaporated. The crude product was purified by C18 rapid chromatography (gradient: 40%-60% aqueous MeCN), and the title compound (12 mg, 10%) was obtained as a yellow gel after evaporation of the pure fraction; MS m / z (ESI), [M+H) + 311.1.

[0964] Intermediate 40: Racemic-(R)-6-(1-(3-fluoropyridin-2-yl)ethyl)quinoline-4-carboxylic acid

[0965]

[0966] NaOH (32 mg, 0.79 mmol) was added to racemic (R)-6-(1-(3-fluoropyridin-2-yl)ethyl)quinoline-4-carboxylate intermediate 39 (49 mg, 0.16 mmol) in MeOH (3 mL) and water (1 mL) at 15 °C. The resulting solution was stirred at 15 °C under N2 (g) for 1 hour. The solvent was removed under reduced pressure. The mixture was diluted with water (10 mL) and the pH was adjusted to pH 3 with 1 M HCl (aqueous solution). The aqueous phase was extracted with EtOAc (3 × 50 mL). The organic layer was dried over Na2SO4, filtered, and evaporated to give crude title compound (100 mg) as a colorless gel, which was used directly in the next step; MS m / z (ESI), [M+H] + 297.2.

[0967] Intermediate 41: 2,2'-(cyclopropane-1,1-diyl)bis(4,4,5,5-tetramethyl-1,3,2-dioxoboronyl)

[0968]

[0969] Under N2(g) conditions, bromocyclopropane (7.0 g, 58 mmol) in THF (50 mL) and 4,4,4',4',5,5,5',5'-octamethyl-2,2'-bis(1,3,2-dioxoboronylcyclopropane) (14.1 g, 55.6 mmol) were added dropwise over a 30-minute period to 2,2,6,6-tetramethylpiperidine-1-lithium (11.9 g, 81.0 mmol) in THF (100 mL) and the mixture was cooled to -78 °C. The resulting solution was stirred at -80 °C for 1 hour. The reaction mixture was poured into saturated NaHCO3 (aqueous solution, 300 mL) and extracted with EtOAc (3 × 200 mL). The organic layer was dried over Na2SO4, filtered, and evaporated. The crude product was purified by silica gel rapid chromatography (gradient: 0%-2% petroleum ether solution of EtOAc), and the title compound (7.2 g, 42%) was obtained as a white solid after evaporation of the pure fraction. 1 H NMR (300MHz, CDCl3): δ1.20 (s, 24H), 0.78 (s, 4H).

[0970] Intermediate 42: 4-chloro-6-(1-(4,4,5,5-tetramethyl-1,3,2-dioxoboron-2-yl)cyclopropyl)quinoline

[0971]

[0972] At 20℃ A Pd G3 (0.557 g, 0.77 mmol) was added to 1,4-diphenyl ether. The mixture was prepared in alkyl (20 mL) and water (2 mL) containing 2,2'-(cyclopropane-1,1-diyl)bis(4,4,5,5-tetramethyl-1,3,2-dioxoboronyl) intermediate 41 (5.0 g, 17 mmol) and 6-bromo-4-chloroquinoline (5.36 g, 22.1 mmol) and Cs₂CO₃ (11.1 g, 34.0 mmol). The resulting solution was stirred at 100 °C for 20 hours under N₂ (g). The reaction mixture was diluted with EtOAc, dried over Na₂SO₄, filtered, and evaporated to give a brown gel. The crude product was purified by rapid silica gel chromatography (gradient 2%–20% petroleum ether solution of EtOAc) to give the title compound (3.8 g, 67%) as a pale yellow oil, which solidified upon standing; MS m / z (ESI), [M+H] + 330.3.

[0973] Intermediate 43: Potassium (1-(4-chloroquinoline-6-yl)cyclopropyl)-trifluoroborate

[0974]

[0975] KHF2 (5.40 g, 69.2 mmol) was added to 4-chloro-6-(1-(4,4,5,5-tetramethyl-1,3,2-dioxoboronyl-2-yl)cyclopropyl)quinoline intermediate 42 (3.8 g, 12 mmol) in MeOH (20 mL) at 20 °C. The resulting solution was stirred at 80 °C under N2 (g) for 14 hours. The reaction mixture was evaporated. The crude white solid was ground with petroleum ether:TBME (1:1) to give a solid. The precipitate was collected by filtration and washed with hot MeCN (100 mL). The filtrate was concentrated to give the title compound (2.3 g, 64%) as a yellow solid, which was ready for use without further purification; MS m / z (ESI), [M+H] + 269.9.

[0976] Intermediate 44: 4-chloro-6-(1-(2-(trifluoromethyl)pyridin-4-yl)cyclopropyl)-quinoline

[0977]

[0978] At 20℃ A Pd G3 (57 mg, 0.08 mmol) was added to 1,4-diphenyl ether. The mixture was prepared in alkyl (10 mL) and water (1 mL) containing 4-bromo-2-(trifluoromethyl)pyridine (263 mg, 1.16 mmol), potassium intermediate 43 (1-(4-chloroquinoline-6-yl)cyclopropyl)trifluoroborate (300 mg, 0.97 mmol), and Cs₂CO₃ (632 mg, 1.94 mmol). The resulting solution was stirred at 100 °C for 14 hours under N₂ (g). The reaction mixture was dried over Na₂SO₄ and subjected to... Filtration. Wash the filter cake with DCM (20 mL). Remove solvent under reduced pressure. Purify the residue by preparative TLC (EtOAc: petroleum ether, 1:1) to give the title compound (256 mg, 76%) as a pale yellow gel. MS m / z (ESI), [M+H) + 349.0.

[0979] Intermediate 45: Methyl 6-(1-(2-(trifluoromethyl)pyridin-4-yl)cyclopropyl)-quinoline-4-carboxylate

[0980]

[0981] At 13 °C, TEA (318 μL, 2.28 mmol) was added to 4-chloro-6-(1-(2-(trifluoromethyl)pyridin-4-yl)cyclopropyl)quinoline intermediate 44 (265 mg, 0.76 mmol), Pd(OAc)2 (17 mg, 0.08 mmol), Pd(dppf)Cl2 (28 mg, 0.04 mmol), and dppf (63 mg, 0.11 mmol) in MeOH (5 mL). The resulting solution was stirred at 100 °C for 12 hours under a CO(g) atmosphere (20 atm). The solvent was removed under reduced pressure. The residue was diluted with water (50 mL) and extracted with EtOAc (3 × 50 mL). The organic layer was dried over Na2SO4, filtered, and evaporated. The residue was purified by preparative TLC (EtOAc: petroleum ether, 1:1) to give the title compound (161 mg, 56%) as a brown gel; MS m / z (ESI), [M+H) + 373.1.

[0982] Intermediate 46: 6-(1-(2-(trifluoromethyl)pyridin-4-yl)cyclopropyl)quinoline-4-carboxylic acid

[0983]

[0984] NaOH (86 mg, 2.2 mmol) was added to methyl 6-(1-(2-(trifluoromethyl)pyridin-4-yl)cyclopropyl)quinoline-4-carboxylate intermediate 45 (160 mg, 0.43 mmol) in MeOH (6 mL) and water (2 mL) at 15 °C. The resulting solution was stirred at 15 °C for 1 hour. The solvent was removed under reduced pressure. The residue was diluted with water (10 mL) and the pH was adjusted to pH 3 with 1 M HCl (aqueous solution). The aqueous phase was extracted with EtOAc (3 × 50 mL), and the organic layer was dried over Na2SO4, filtered, and evaporated to give a crude title compound (158 mg) as an orange solid, which was used directly in the next step without further purification; MS m / z (ESI), [M+H + 359.0.

[0985] Intermediate 47: 6-(furan-3-yl)quinoline-4-carboxylic acid

[0986]

[0987] 6-Bromoquinoline-4-carboxylic acid (250 mg, 0.99 mmol), furan-3-ylboronic acid (111 mg, 0.99 mmol), Pd(dppf)Cl2 (65 mg, 0.10 mmol), and Cs2CO3 (969 mg, 2.98 mmol) were prepared in a 1,4-dioxanone atmosphere. The mixture was prepared in alkyl (6 mL) and water (1.5 mL). The mixture was bubbled with N2 (g) for 10 minutes, then stirred at room temperature under N2 (g) for 19 hours. HCl (3.8 M, 783 μL, 2.98 mmol) and DMSO (5 mL) were added, and 1,4-dialkyl ... Alkane. The mixture was filtered through a syringe filter and purified by preparative HPLC method A (gradient 5%–40%), followed by solvent evaporation and co-evaporation with EtOH (1×) to give the title compound as a solid (137 mg, 58%); MS m / z (ESI), [M+H). + 240.0.

[0988] Intermediate 48: 4-(4-chloroquinoline-6-yl)tetrahydro-2H-pyran-4-ol

[0989]

[0990] Under an argon atmosphere, 10 g (41 mmol) of 6-bromo-4-chloroquinoline was dissolved in 200 mL of THF in a dry two-necked flask and cooled to -70 °C. n-BuLi (24.7 mL, 61.9 mmol, in 2.5 M hexane solution) was slowly added dropwise, keeping the internal temperature below -65 °C. The reaction mixture was stirred at -70 °C for 1 hour. 6.19 g (61.9 mmol) of tetrahydro-4H-pyran-4-one was slowly added dropwise to 10 mL of THF, keeping the internal temperature below -65 °C. The reaction mixture was stirred at -70 °C for 1 hour, then heated to room temperature and stirred for 3 hours. The reaction mixture was poured into 100 mL of saturated NH4Cl and extracted with EtOAc (4 × 100 mL). The organic layer was dried over Na2SO4, filtered, and evaporated. The crude product was purified by silica gel rapid chromatography (gradient: 10%-50% EtOAc in petroleum ether solution) to give the title compound (3.5 g, 32%) as a pale yellow solid; MS m / z (ESI), [M+H) + 264.0.

[0991] Intermediate 49: Methyl 6-(4-hydroxytetrahydro-2H-pyran-4-yl)quinoline-4-carboxylate

[0992]

[0993] Under N2(g) atmosphere, Pd(OAc)2 (0.17 g, 0.76 mmol) and Pd(dppf)Cl2·DCM (0.31 g, 0.38 mmol) were added to a mixture of 4-(4-chloroquinoline-6-yl)tetrahydro-2H-pyran-4-ol intermediate 48 (2.0 g, 7.6 mmol), dppf (0.63 g, 1.1 mmol), and TEA (3.2 mL, 23 mmol) in MeOH (20 mL). The resulting mixture was stirred at 100 °C for 12 hours under a CO(g) atmosphere (10 atm). The solvent was removed under reduced pressure. The reaction mixture was diluted with EtOAc (50 mL) and washed successively with water (3 ...

Claims

1. A compound having a structure of formula (I): or a pharmaceutically acceptable salt thereof, wherein: X 1 Selected from the group consisting of: -S-, -S(O)- and -S(O)2-; R 1 Selected from the group consisting of: hydrogen, halogen, hydroxyl, C 1-3 -alkyl and C 1-6 - alkoxy; R 2 Selected from the group consisting of: (a)C 1-6 -alkyl, wherein the C 1-6 -alkyl is optionally substituted with one or more substituents independently selected from the group consisting of halogen, hydroxy, cyano, C 3-6 -cycloalkyl, halo-C 3-6 -Cycloalkyl, C 1-6 -alkoxy, halo-C 1-6 -alkoxy, C 3-6 -cycloalkoxy, halo-C 3-6 -cycloalkoxy, C 1-6 -alkoxy-C 1-6 -alkoxy, oxetanyl, tetrahydrofuranyl, tetrahydrofuranyloxy, tetrahydropyranyl, morpholinyl, pyrazolyl, isocyanate, oxetane, tetrahydrofuranyl, tetrahydrofuranyloxy, tetrahydropyranyl, morpholinyl, pyrazolyl, isocyanate, Oxylidene, triazolyl and pyridinyl are optionally substituted with one or more substituents independently selected from the group consisting of halogen, cyano, C 1-6 -alkyl and halo-C 1-6 -alkyl; (b)C 3-6 -cycloalkyl, wherein the C 3-6 -cycloalkyl is optionally substituted with one or more substituents independently selected from the group consisting of halogen, hydroxy, cyano, C 1-6 -alkyl, halo-C 1-6 -alkyl, C 1-6 -alkoxy, halo-C 1-6 -Alkoxy, Isopropyl Azolyl and pyridinyl; wherein the iso Oxylidene and pyridinyl are optionally substituted with one or more substituents independently selected from the group consisting of halogen, C 1-6 -alkyl and halo-C 1-6 -alkyl; (c) phenyl, wherein the phenyl is optionally substituted with one or more substituents independently selected from the group consisting of halogen, cyano, C 1-6 -alkyl, halo-C 1-6- Alkyl, C 1-6 -alkoxy, halo-C 1-6 -alkoxy and C 1-6 -alkoxy-C 1-6 - alkoxy; and (d) a 4-, 5-, 6- or 7-membered heterocyclyl ring, wherein the heterocyclyl ring: (i) is a saturated, partially saturated or fully unsaturated monocyclic or fused bicyclic ring, (ii) has one or two oxygen ring atoms and the remaining ring atoms are carbon, and (iii) is optionally substituted with one or more substituents independently selected from the group consisting of halogen, hydroxy, cyano, C 1-6 -alkyl, halo-C 1-6- Alkyl, C 2-6 -Alkynyl, C 1-6 -alkoxy and halo-C 1-6 - alkoxy; and (e)-OR 7 , where R 7 Selected from the group consisting of: C 1-6 -alkyl, phenyl and tetrahydropyranyl; wherein: (i) C 1-6 -alkyl is optionally substituted with one or more substituents independently selected from the group consisting of halogen, cyano, C 3-6 -cycloalkyl, halo-C 3-6 -Cycloalkyl, C 1-6 -alkoxy and halo-C 1-6 - alkoxy; (ii) the phenyl group is optionally substituted by one or more substituents, the one or more substituents being independently selected from the group consisting of halogen, C 1-6 -alkyl, halo-C 1-6 -alkyl, C 1-6 -alkoxy and halo-C 1-6 - alkoxy; and (iii) the tetrahydropyranyl group is optionally substituted by one or more substituents, the one or more substituents being independently selected from the group consisting of halogen, C 1-6 -alkyl, halo-C 1-6 -alkyl, C 1-6 -alkoxy and halo-C 1-6 - alkoxy; R 3 Selected from the group consisting of hydrogen, halogen and C 1-3 -alkyl; R 4 Selected from the group consisting of hydrogen, halogen and C 1-3 -alkyl; R 5 Selected from the group consisting of hydrogen, halogen and C 1-3 -alkyl; and R 6 Selected from the group consisting of hydrogen, halogen and C 1-3 -alkyl.

2. The compound according to claim 1 or a pharmaceutically acceptable salt thereof, wherein the compound has a structure of formula (II): Where X 1 , R 1 , R 2 , R 3 , R 4 , R 5 and R 6 As defined in claim 1.

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

4. The compound according to claim 1 or a pharmaceutically acceptable salt thereof, wherein the compound has a structure of formula (IV-A): Where R 2 As defined in claim 1.

5. The compound according to any one of claims 1 to 4 or a pharmaceutically acceptable salt thereof, wherein R 2 It is C 1-6 -alkyl, wherein the C 1-6 -alkyl is optionally substituted with one or more substituents independently selected from the group consisting of halogen, hydroxy, cyano, C 3-6 -cycloalkyl, halo-C 3-6 -Cycloalkyl, C 1-6 -alkoxy, halo-C 1-6 -alkoxy, C 3-6 -cycloalkoxy, halo-C 3-6 -cycloalkoxy, C 1-6 -alkoxy-C 1-6 -alkoxy, oxetanyl, tetrahydrofuranyl, tetrahydrofuranyloxy, tetrahydropyranyl, morpholinyl, pyrazolyl, isocyanate, oxetane, tetrahydrofuranyl, tetrahydrofuranyloxy, tetrahydropyranyl, morpholinyl, pyrazolyl, isocyanate, Oxylidene, triazolyl and pyridinyl are optionally substituted with one or more substituents independently selected from the group consisting of halogen, C 1-6 -alkyl and halo-C 1-6 -alkyl.

6. The compound according to claim 1 or a pharmaceutically acceptable salt thereof, wherein the compound is selected from the group consisting of: N-(2-((R)-4-cyanothiazolidin-3-yl)-2-oxoethyl)-6-((RS)-1-(3-fluoropyridin-2-yl)-ethyl)quinoline-4-carboxamide; (R)-N-(2-(4-cyanothiazolidin-3-yl)-2-oxoethyl)-6-(2-hydroxypropan-2-yl)quinoline-4-carboxamide; (R)-N-(2-(4-cyanothiazolidin-3-yl)-2-oxoethyl)-6-(trifluoromethyl)-quinoline-4-carboxamide; (R)-N-(2-(4-cyanothiazolidin-3-yl)-2-oxoethyl)-6-(2-methoxypropan-2-yl)quinoline-4-carboxamide; (R)-N-(2-(4-cyanothiazolidin-3-yl)-2-oxoethyl)-6-((2,5-dimethyl-2H-1,2,3-triazol-4-yl)-methyl)quinoline-4-carboxamide; (R)-N-(2-(4-cyanothiazolidin-3-yl)-2-oxoethyl)-6-(morpholinomethyl)quinoline-4-carboxamide; N-(2-((R)-4-cyanothiazolidin-3-yl)-2-oxoethyl)-6-((RS)-1-hydroxyethyl)quinoline-4-carboxamide; N-(2-((R)-4-cyanothiazolidin-3-yl)-2-oxoethyl)-6-((RS)-1-methoxyethyl)quinoline-4-carboxamide; (R)-N-(2-(4-cyanothiazolidin-3-yl)-2-oxoethyl)-6-(ethoxymethyl)-quinoline-4-carboxamide; (R)-N-(2-(4-cyanothiazolidin-3-yl)-2-oxoethyl)-6-methylquinoline-4-carboxamide; (R)-N-(2-(4-cyanothiazolidin-3-yl)-2-oxoethyl)-6-(fluoromethyl)-quinoline-4-carboxamide; N-(2-((R)-4-cyanothiazolidin-3-yl)-2-oxoethyl)-6-((RS)-1,2-dimethoxyethyl)quinoline-4-carboxamide; (R)-N-(2-(4-cyanothiazolidin-3-yl)-2-oxoethyl)-6-((2-methoxyethoxy)-methyl)quinoline-4-carboxamide; N-(2-((R)-4-cyanothiazolidin-3-yl)-2-oxoethyl)-6-((((RS)-tetrahydrofuran-3-yl)oxy)-methyl)quinoline-4-carboxamide; (R)-N-(2-(4-cyanothiazolidin-3-yl)-2-oxoethyl)-6-((2,2-difluoroethoxy)methyl)quinoline-4-carboxamide; (R)-N-(2-(4-cyanothiazolidin-3-yl)-2-oxoethyl)-6-(cyclopropyloxymethyl)quinoline-4-carboxamide; (R)-N-(2-(4-cyanothiazolidin-3-yl)-2-oxoethyl)-6-((4-methylisothiazolidin-3-yl)-2-oxoethyl)- oxazol-3-yl)methyl)-quinoline-4-carboxamide; (R)-N-(2-(4-cyanothiazolidin-3-yl)-2-oxoethyl)-6-((4,6-dimethylpyridin-3-yl)-methyl)quinoline-4-carboxamide; (R)-N-(2-(4-cyanothiazolidin-3-yl)-2-oxoethyl)-6-((1,3-dimethyl-1H-pyrazol-5-yl)-methyl)quinoline-4-carboxamide; (R)-N-(2-(4-cyanothiazolidin-3-yl)-2-oxoethyl)-6-((2-methyl-2H-1,2,3-triazol-4-yl)-methyl)quinoline-4-carboxamide; (R)-N-(2-(4-cyanothiazolidin-3-yl)-2-oxoethyl)-6-((5-methylisothiazolidine-3-yl)-2-oxoethyl)- oxazol-3-yl)-methyl)quinoline-4-carboxamide; N-(2-((R)-4-cyanothiazolidin-3-yl)-2-oxoethyl)-6-((RS)-1-(5-methylisothiazolidin-3-yl)-2-oxoethyl)- oxazol-3-yl)-ethyl)quinoline-4-carboxamide; 6-((RS)-1-(5-chloropyridin-2-yl)ethyl)-N-(2-((R)-4-cyanothiazolidin-3-yl)-2-oxoethyl)quinoline-4-carboxamide; N-(2-((R)-4-cyanothiazolidin-3-yl)-2-oxoethyl)-6-((RS)-1-(3-methylisothiazolidin-3-yl)-2-oxoethyl)- oxazol-5-yl)-ethyl)quinoline-4-carboxamide; N-(2-((R)-4-cyanothiazolidin-3-yl)-2-oxoethyl)-6-((RS)-1-(6-methylpyridin-3-yl)-ethyl)quinoline-4-carboxamide; N-(2-((R)-4-cyanothiazolidin-3-yl)-2-oxoethyl)-6-((RS)-1-(2-(trifluoromethyl)pyridin-4-yl)ethyl)quinoline-4-carboxamide; (R)-N-(2-(4-cyanothiazolidin-3-yl)-2-oxoethyl)-6-(2,2-difluoropropyl)quinoline-4-carboxamide; (R)-N-(2-(4-cyanothiazolidin-3-yl)-2-oxoethyl)-6-((tetrahydro-2H-pyran-4-yl)-methyl)quinoline-4-carboxamide; (R)-N-(2-(4-cyanothiazolidin-3-yl)-2-oxoethyl)-6-(3,3,3-trifluoropropyl)quinoline-4-carboxamide; N-(2-((R)-4-cyanothiazolidin-3-yl)-2-oxoethyl)-6-(((RS)-tetrahydrofuran-3-yl)-methyl)quinoline-4-carboxamide; (R)-N-(2-(4-cyanothiazolidin-3-yl)-2-oxoethyl)-6-(difluoromethyl)-quinoline-4-carboxamide; (R)-6-((1H-pyrazol-1-yl)methyl)-N-(2-(4-cyanothiazolidin-3-yl)-2-oxoethyl)quinoline-4-carboxamide; (R)-N-(2-(4-cyanothiazolidin-3-yl)-2-oxoethyl)-6-(3-methoxypropyl)quinoline-4-carboxamide; and (R)-N-(2-(4-cyanothiazolidin-3-yl)-2-oxoethyl)-6-(2-methoxyethyl)quinoline-4-carboxamide.

7. A compound according to any one of claims 1 to 4 or a pharmaceutically acceptable salt thereof, wherein R 2 It is C 3-6 -cycloalkyl, wherein the C 3-6 -cycloalkyl is optionally substituted with one or more substituents independently selected from the group consisting of halogen, hydroxy, cyano, C 1-6 -alkyl, halo-C 1-6 -alkyl, C 1-6 -alkoxy, halo-C 1-6 -Alkoxy, Isopropyl Azolyl and pyridinyl; wherein the iso Oxylidene and pyridinyl are optionally substituted with one or more substituents independently selected from the group consisting of halogen, C 1-6 -alkyl and halo-C 1-6 -alkyl.

8. The compound according to claim 1 or a pharmaceutically acceptable salt thereof, wherein the compound is selected from the group consisting of: (R)-N-(2-(4-cyanothiazolidin-3-yl)-2-oxoethyl)-6-(1-(2-(trifluoromethyl)pyridin-4-yl)-cyclopropyl)quinoline-4-carboxamide; (R)-N-(2-(4-cyanothiazolidin-3-yl)-2-oxoethyl)-6-(1-(6-methylpyridin-3-yl)-cyclopropyl)quinoline-4-carboxamide; (R)-N-(2-(4-cyanothiazolidin-3-yl)-2-oxoethyl)-6-(1-(3-fluoropyridin-2-yl)-cyclopropyl)quinoline-4-carboxamide; (R)-N-(2-(4-cyanothiazolidin-3-yl)-2-oxoethyl)-6-(1-(5-methylisothiazolidine-3-yl)-2-oxoethyl)- oxazol-3-yl)-cyclopropyl)quinoline-4-carboxamide; (R)-6-(1-(5-chloropyridin-2-yl)cyclopropyl)-N-(2-(4-cyanothiazolidin-3-yl)-2-oxoethyl)quinoline-4-carboxamide; (R)-N-(2-(4-cyanothiazolidin-3-yl)-2-oxoethyl)-6-(1-(3-methylisothiazolidin-3-yl)-2-oxoethyl)- oxazol-5-yl)-cyclopropyl)quinoline-4-carboxamide; 6-((1r,4R*)-4-cyanocyclohexyl)-N-(2-((R)-4-cyanothiazolidin-3-yl)-2-oxoethyl)-quinoline-4-carboxamide; 6-((1r,4R*)-4-cyanocyclohexyl)-N-(2-((R)-4-cyanothiazolidin-3-yl)-2-oxoethyl)-quinoline-4-carboxamide; (R)-6-(1-cyanocyclohexyl)-N-(2-(4-cyanothiazolidin-3-yl)-2-oxoethyl)quinoline-4-carboxamide; N-(2-((R)-4-cyanothiazolidin-3-yl)-2-oxoethyl)-6-((1r,3R*)-1-fluoro-3-methoxycyclobutyl)quinoline-4-carboxamide isomer 1; N-(2-((R)-4-cyanothiazolidin-3-yl)-2-oxoethyl)-6-((1r,3R*)-1-fluoro-3-methoxycyclobutyl)quinoline-4-carboxamide isomer 2; (R)-6-(1-cyanocyclopropyl)-N-(2-(4-cyanothiazolidin-3-yl)-2-oxoethyl)quinoline-4-carboxamide; (R)-N-(2-(4-cyanothiazolidin-3-yl)-2-oxoethyl)-6-(1-fluorocyclobutyl)quinoline-4-carboxamide; (R)-N-(2-(4-cyanothiazolidin-3-yl)-2-oxoethyl)-6-(1-ethoxycyclopropyl)quinoline-4-carboxamide; (R)-N-(2-(4-cyanothiazolidin-3-yl)-2-oxoethyl)-6-cyclopropylquinoline-4-carboxamide; N-(2-((R)-4-cyanothiazolidin-3-yl)-2-oxoethyl)-6-((1r,4R*)-4-methoxycyclohexyl)-quinoline-4-carboxamide Isomer 1; and N-(2-((R)-4-cyanothiazolidin-3-yl)-2-oxoethyl)-6-((1r,4R*)-4-methoxycyclohexyl)-quinoline-4-carboxamide Isomer 2.

9. The compound according to any one of claims 1 to 4 or a pharmaceutically acceptable salt thereof, wherein R 2 is phenyl, wherein the phenyl is optionally substituted with one or more substituents independently selected from the group consisting of halogen, cyano, C 1-6 -alkyl, halo-C 1-6 -alkyl, C 1-6 -alkoxy, halo-C 1-6 -alkoxy and C 1-6 -alkoxy-C 1-6 -alkoxy.

10. The compound according to any one of claims 1 to 4 or a pharmaceutically acceptable salt thereof, wherein R 2 is a 4-, 5-, 6- or 7-membered heterocyclyl ring, wherein the heterocyclyl ring: (i) is a saturated, partially saturated or fully unsaturated monocyclic or fused bicyclic ring, (ii) has one or two oxygen ring atoms and the remaining ring atoms are carbon, and (iii) is optionally substituted with one or more substituents independently selected from the group consisting of halogen, hydroxy, cyano, C 1-6 -alkyl, halo-C 1-6 -alkyl, C 2-6 -Alkynyl, C 1-6 -alkoxy and halo-C 1-6 -alkoxy.

11. A compound according to any one of claims 1 to 4 or a pharmaceutically acceptable salt thereof, wherein R 2 Selected from the group consisting of tetrahydrofuranyl, furanyl, dimethyltetrahydrofuranyl, dihydropyranyl, tetrahydropyranyl, hydroxytetrahydropyranyl, fluorotetrahydropyranyl, cyanotetrahydropyranyl, methyltetrahydropyranyl, dimethyltetrahydropyranyl, methoxytetrahydropyranyl, ethoxytetrahydropyranyl, 1,4-dihydropyranyl, alkyl and 3-oxabicyclo[4.1.0]heptane.

12. The compound according to claim 1 or a pharmaceutically acceptable salt thereof, wherein the compound is selected from the group consisting of: (R)-N-(2-(4-cyanothiazolidin-3-yl)-2-oxoethyl)-6-(furan-3-yl)quinoline-4-carboxamide; (R)-N-(2-(4-cyanothiazolidin-3-yl)-2-oxoethyl)-6-(4-hydroxytetrahydro-2H-pyran-4-yl)-quinoline-4-carboxamide; (R)-N-(2-(4-cyanothiazolidin-3-yl)-2-oxoethyl)-6-(tetrahydro-2H-pyran-4-yl)quinoline-4-carboxamide; (R)-N-(2-(4-cyanothiazolidin-3-yl)-2-oxoethyl)-6-(4-methyltetrahydro-2H-pyran-4-yl)-quinoline-4-carboxamide; (R)-N-(2-(4-cyanothiazolidin-3-yl)-2-oxoethyl)-6-(3,6-dihydro-2H-pyran-4-yl)quinoline-4-carboxamide; (R)-N-(2-(4-cyanothiazolidin-3-yl)-2-oxoethyl)-6-(4-ethoxytetrahydro-2H-pyran-4-yl)-quinoline-4-carboxamide; N-(2-((R)-4-cyanothiazolidin-3-yl)-2-oxoethyl)-6-((RS)-tetrahydro-2H-pyran-2-yl)-quinoline-4-carboxamide; N-(2-((R)-4-cyanothiazolidin-3-yl)-2-oxoethyl)-6-((RS)-1,4-dimethoxythiazolidine-3-yl)- 4-(2-(2-(2-nitro-1-ol)quinolinecarboxamide; N-(2-((R)-4-cyanothiazolidin-3-yl)-2-oxoethyl)-6-((RS)-tetrahydrofuran-2-yl)quinoline-4-carboxamide; (R)-N-(2-(4-cyanothiazolidin-3-yl)-2-oxoethyl)-6-(4-ethynyltetrahydro-2H-pyran-4-yl)-quinoline-4-carboxamide; (R)-6-(4-cyanotetrahydro-2H-pyran-4-yl)-N-(2-(4-cyanothiazolidin-3-yl)-2-oxoethyl)-quinoline-4-carboxamide; N-(2-((R)-4-cyanothiazolidin-3-yl)-2-oxoethyl)-6-(5,5-dimethyltetrahydrofuran-3-yl)-quinoline-4-carboxamide; (R)-N-(2-(4-cyanothiazolidin-3-yl)-2-oxoethyl)-6-(4-fluorotetrahydro-2H-pyran-4-yl)-quinoline-4-carboxamide; (R)-N-(2-(4-cyanothiazolidin-3-yl)-2-oxoethyl)-6-(4-methoxytetrahydro-2H-pyran-4-yl)quinoline-4-carboxamide; N-(2-((R)-4-cyanothiazolidin-3-yl)-2-oxoethyl)-6-((RS)-tetrahydrofuran-3-yl)quinoline-4-carboxamide; N-(2-((R)-4-cyanothiazolidin-3-yl)-2-oxoethyl)-6-((RS)-2,2-dimethyltetrahydro-2H-pyran-4-yl)quinoline-4-carboxamide; and 6-((1RS,6SR)-3-oxabicyclo[4.1.0]hept-6-yl)-N-(2-((R)-4-cyanothiazolidin-3-yl)-2-oxoethyl)quinoline-4-carboxamide.

13. A compound according to any one of claims 1 to 4 or a pharmaceutically acceptable salt thereof, wherein R 2 Yes-OR 7 , where R 7 Selected from the group consisting of: C 1-6 -alkyl, phenyl and tetrahydropyranyl; wherein: (i) C 1-6 -alkyl is optionally substituted with one or more substituents independently selected from the group consisting of halogen, cyano, C 3-6 -cycloalkyl, halo-C 3-6 -Cycloalkyl, C 1-6 -alkoxy and halo-C 1-6 - alkoxy; (ii) the phenyl group is optionally substituted by one or more substituents, the one or more substituents being independently selected from the group consisting of halogen, C 1-6 -alkyl, halo-C 1-6 -alkyl, C 1-6 -alkoxy and halo-C 1-6 - alkoxy; and (iii) the tetrahydropyranyl group is optionally substituted by one or more substituents, the one or more substituents being independently selected from the group consisting of halogen, C 1-6 -alkyl, halo-C 1-6- Alkyl, C 1-6 -alkoxy and halo-C 1-6- Alkoxy.

14. A compound according to any one of claims 1 to 4 or a pharmaceutically acceptable salt thereof, wherein R 2 Yes-OR 7 , where R 7 Selected from the group consisting of cyanomethyl, fluoroethyl, difluoroethyl, propyl, difluoropropyl, fluorobutyl, methoxyethyl, cyclopropylmethyl, difluorocyclobutylmethyl, phenyl, tetrahydropyranyl and dimethyltetrahydropyranyl.

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

16. A compound according to any one of claims 1 to 4 or a pharmaceutically acceptable salt thereof, wherein R 2 Selected from the group consisting of: (a)C 1-3 -alkyl, wherein the C 1-3 -alkyl is optionally substituted with one or more substituents independently selected from the group consisting of halogen, hydroxy, cyano, C 3-6 -cycloalkyl, halo-C 3-6 -Cycloalkyl, C 1-3 -alkoxy, halo-C 1-3 -alkoxy, C 3-6 -cycloalkoxy, halo-C 3-6 -cycloalkoxy, C 1-3 -alkoxy-C 1-3 -alkoxy, oxetanyl, tetrahydrofuranyl, tetrahydrofuranyloxy, tetrahydropyranyl, morpholinyl, pyrazolyl, isocyanate, oxetane, tetrahydrofuranyl, tetrahydrofuranyloxy, tetrahydropyranyl, morpholinyl, pyrazolyl, isocyanate, Oxylidene, triazolyl and pyridinyl are optionally substituted with one or more substituents independently selected from the group consisting of halogen, C 1-3 -alkyl and halo-C 1-3 -alkyl; (b)C 3-6 -cycloalkyl, wherein the C 3-6 -cycloalkyl is optionally substituted with one or more substituents independently selected from the group consisting of halogen, cyano, C 1-3 -alkyl, halo-C 1-3 -alkyl, C 1-3 -alkoxy, halo-C 1-3 -Alkoxy, Isopropyl Azolyl and pyridinyl; wherein the iso Oxylidene and pyridinyl are optionally substituted with one or more substituents independently selected from the group consisting of halogen, C 1-3 -alkyl and halo-C 1-3 -alkyl; (c) phenyl, wherein the phenyl is optionally substituted with one or more substituents independently selected from the group consisting of halogen, C 1-3 -alkyl, halo-C 1-3- Alkyl, C 1-3 -alkoxy, halo-C 1-3 -alkoxy and C 1-3 -alkoxy-C 1-3 - alkoxy; (d) a 4-, 5-, 6-, or 7-membered heterocyclyl ring, wherein the heterocyclyl ring: (i) is a saturated or partially saturated monocyclic or fused bicyclic ring, (ii) has one or two oxygen ring atoms and the remaining ring atoms are carbon, and (iii) is optionally substituted with one or more substituents independently selected from the group consisting of halogen, hydroxy, cyano, C 1-3 -alkyl, halo-C 1-3 -alkyl, C 2-3 -Alkynyl, C 1-3 -alkoxy and halo-C 1-3 - alkoxy; and (e)-OR 7 , where R 7 Selected from the group consisting of: C 1-4 -alkyl, phenyl and tetrahydropyranyl; wherein: (i) C 1-4 -alkyl is optionally substituted with one or more substituents independently selected from the group consisting of halogen, cyano, C 3-6 -cycloalkyl, halo-C 3-6 -Cycloalkyl, C 1-3 -alkoxy and halo-C 1-3 - alkoxy; (ii) the phenyl group is optionally substituted by one or more substituents, the one or more substituents being independently selected from the group consisting of halogen, C 1-3 -alkyl, halo-C 1-3 -alkyl, C 1-3 -alkoxy and halo-C 1-3 - alkoxy; and (iii) the tetrahydropyranyl group is optionally substituted by one or more substituents, the one or more substituents being independently selected from the group consisting of halogen, C 1-3 -alkyl, halo-C 1-3- Alkyl, C 1-3 -alkoxy and halo-C 1-3 -alkoxy.

17. A compound according to any one of claims 1 to 4 or a pharmaceutically acceptable salt thereof, wherein R 2 Selected from the group consisting of: (a)C 3-6 -cycloalkyl, wherein the C 3-6 -cycloalkyl is optionally substituted with one or more substituents independently selected from the group consisting of halogen, cyano, C 1-3 -alkyl, halo-C 1-3 -alkyl, C 1-3 -alkoxy, halo-C 1-3 -Alkoxy, Isopropyl Azolyl and pyridinyl; wherein the iso Oxylidene and pyridinyl are optionally substituted with one or more substituents independently selected from the group consisting of halogen, C 1-3 -alkyl and halo-C 1-3 -alkyl; and (b) a 4-, 5-, 6-, or 7-membered heterocyclyl ring, wherein the heterocyclyl ring: (i) is a saturated or partially saturated monocyclic or fused bicyclic ring, (ii) has one or two oxygen ring atoms and the remaining ring atoms are carbon, and (iii) is optionally substituted with one or more substituents independently selected from the group consisting of halogen, hydroxy, cyano, C 1-3 -alkyl, halo-C 1-3 -alkyl, C 2-3 -Alkynyl, C 1-3 -alkoxy and halo-C 1-3 - alkoxy; and (c)-OR 7 , where R 7 Selected from the group consisting of: C 1-4 -alkyl, phenyl and tetrahydropyranyl; wherein: (i) C 1-4 -alkyl is optionally substituted with one or more substituents independently selected from the group consisting of halogen, cyano, C 3-6 -cycloalkyl, halo-C 3-6 -Cycloalkyl, C 1-3 -alkoxy and halo-C 1-3 - alkoxy; (ii) the phenyl group is optionally substituted by one or more substituents, the one or more substituents being independently selected from the group consisting of halogen, C 1-3 -alkyl, halo-C 1-3 -alkyl, C 1-3 -alkoxy and halo-C 1-3 - alkoxy; and (iii) the tetrahydropyranyl group is optionally substituted by one or more substituents, the one or more substituents being independently selected from the group consisting of halogen, C 1-3 -alkyl, halo-C 1-3 -alkyl, C 1-3 -alkoxy and halo-C 1-3 -alkoxy.

18. A compound according to any one of claims 1 to 4 or a pharmaceutically acceptable salt thereof, wherein R 2 Selected from the group consisting of: (a)C 3-6 -cycloalkyl, wherein the C 3-6 -cycloalkyl is optionally substituted with one or more substituents independently selected from the group consisting of halogen, cyano, C 1-6 -Alkoxy, Isopropyl Azolyl and pyridinyl; wherein the iso Oxylidene and pyridinyl are optionally substituted with one or more substituents independently selected from the group consisting of halogen, C 1-6 -alkyl and halo-C 1-6 -alkyl; (b) a 5-, 6-, or 7-membered heterocyclyl ring, wherein the heterocyclyl ring: (i) is a saturated or partially saturated monocyclic or fused bicyclic ring, (ii) has one or two oxygen ring atoms and the remaining ring atoms are carbon, and (iii) is optionally substituted with one or more substituents independently selected from the group consisting of halogen, hydroxy, cyano, C 1-3 -alkyl, C 2-3 -Alkynyl and C 1-3 - alkoxy; and (c)-OR 7 , where R 7 Selected from the group consisting of: C 1-6 -alkyl, phenyl and tetrahydropyranyl; wherein: (i) C 1-6 -alkyl is optionally substituted with one or more substituents independently selected from the group consisting of halogen, cyano, C 3-6 -cycloalkyl, halo-C 3-6 -cycloalkyl and C 1-6 - alkoxy; and (ii) the tetrahydropyranyl group is optionally substituted by one or C 1-6 -alkyl substitution.

19. A compound according to any one of claims 1 to 4 or a pharmaceutically acceptable salt thereof, wherein R 2 Selected from the group consisting of: (a)C 3-6 -cycloalkyl, wherein the C 3-6 -cycloalkyl is optionally substituted with one or more substituents independently selected from the group consisting of halogen, cyano, C 1-3 -Alkoxy, Isopropyl Azolyl and pyridinyl; wherein the iso Oxylidene and pyridinyl are optionally substituted with one or more substituents independently selected from the group consisting of halogen, C 1-3 -alkyl and halo-C 1-3 -alkyl; (b) a 5-, 6- or 7-membered heterocyclic group selected from the group consisting of tetrahydrofuranyl, dihydropyranyl, tetrahydropyranyl, 1,4-dihydropyranyl, alkyl and 3-oxabicyclo[4.1.0]heptane, wherein the tetrahydrofuranyl, dihydropyranyl, tetrahydropyranyl, 1,4-dihydropyranyl The alkyl and 3-oxabicyclo[4.1.0]heptane are optionally substituted with one or more substituents independently selected from the group consisting of halogen, hydroxy, cyano, C 1-6 -alkyl, halo-C 1-6 -alkyl, C 2-6 -Alkynyl, C 1-6 -alkoxy and halo-C 1-6 - alkoxy; and (c)-OR 7 , where R 7 Selected from the group consisting of: C 1-4 -alkyl, phenyl and tetrahydropyranyl; wherein: (i) C 1-4 -alkyl is optionally substituted with one or more substituents independently selected from the group consisting of halogen, cyano, C 3-6 -cycloalkyl, halo-C 3-6 -cycloalkyl and C 1-3 - alkoxy; and (ii) the tetrahydropyranyl group is optionally substituted by one or C 1-3 -alkyl substitution.

20. A compound according to any one of claims 1 to 4 or a pharmaceutically acceptable salt thereof, wherein R 2 Selected from the group consisting of: (a) optionally substituted C 3-6 - cycloalkyl, which is selected from the group consisting of cyclopropyl, cyanocyclopropyl, ethoxycyclopropyl, methylisothiocyano oxazolylcyclopropyl, methylpyridylcyclopropyl, chloropyridylcyclopropyl, fluoropyridylcyclopropyl, trifluoropyridylcyclopropyl, fluorocyclobutyl, (fluoro)(methoxy)cyclobutyl, methoxycyclohexyl and cyanocyclohexyl; (b) an optionally substituted 5-, 6- or 7-membered heterocyclic group selected from the group consisting of tetrahydrofuranyl, dimethyltetrahydrofuranyl, dihydropyranyl, tetrahydropyranyl, hydroxytetrahydropyranyl, fluorotetrahydropyranyl, cyanotetrahydropyranyl, methyltetrahydropyranyl, dimethyltetrahydropyranyl, methoxytetrahydropyranyl, ethoxytetrahydropyranyl, 1,4-dihydrotetrahydropyranyl, alkyl and 3-oxabicyclo[4.1.0]heptane; and (c) -OR7, wherein R7 is selected from the group consisting of cyanomethyl, fluoroethyl, difluoroethyl, propyl, difluoropropyl, fluorobutyl, methoxyethyl, cyclopropylmethyl, difluorocyclobutylmethyl, phenyl, tetrahydropyranyl and dimethyltetrahydropyranyl.

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

22. Use of a compound according to any one of claims 1 to 21 or a pharmaceutically acceptable salt thereof for the preparation of a medicament for the treatment or prevention of a FAP-mediated disorder.

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