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

Abstract

Compounds having the structure of formula (I) and their pharmaceutically acceptable salts are disclosed, wherein X 1 R 1 R 2 R 3 R 4 R 5 and R 6 This refers to: pharmaceutical compositions comprising such compounds and salts as defined in the specification; the use of such compounds and salts for the treatment or prevention of prolyl endopeptidase fibroblast activation protein (FAP)-mediated diseases; kits comprising such compounds and salts; and methods for manufacturing such compounds and salts. Formula (I):

Description

Technical Field

[0001] This disclosure generally relates to N-(2-(4-cyanothiazolidine-3-yl)-2-oxoethyl)-quinoline-4-carboxamide and pharmaceutically acceptable salts thereof. This specification further 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 manufacturing such compounds and salts. Background Technology

[0002] FAP (type II transmembrane serine protease) is expressed by fibroblast-like cells involved in tissue remodeling and healing. In the case 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 Research & Clin Pract 2015, 108, 466).

[0003] FAP shares a common cleavage motif after Gly-Pro and exhibits both endopeptidase and exopeptidase activities. Known enzymatic activities include collagen cleavage (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) on the cell surface of activated fibroblasts creates a pro-fibrotic environment. FAP cleavage of α2AP provides for more efficient cross-linking of α2AP to fibrin and leads to reduced fibrin clearance. FAP cleavage of FGF21 inhibits the metabolic effects of FGF21 (Biochem J 2016, 473, 605). All of these activities are associated with the exacerbation of NASH disease, and FAP inhibition may treat NASH and other conditions by influencing multiple mechanisms.

[0004] Inhibition of FAP activity is an untapped treatment method currently used to treat NASH and other diseases associated with this activity. Currently, approved pharmacological agents that generally or specifically inhibit FAP activity are not available. Therefore, there is a need for FAP inhibitors, particularly FAP inhibitors with suitable 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 for the treatment or prevention of NASH and related conditions, along with corresponding pharmaceutical compositions and methods. Summary of the Invention

[0005] In one aspect, this disclosure provides compounds having the structure of formula (I):

[0006]

[0007] and its pharmaceutically acceptable salts, of which:

[0008] X 1 Choose from the following groups: -S-, -S(O)-, and -S(O)2-;

[0009] R 1 Choose from the following groups: hydrogen, halogen, hydroxyl, C 1-3 -alkyl and C 1-6 -alkoxy group;

[0010] R 2 Choose from the following groups:

[0011] (a) A heterocyclic group containing a total of 4 to 10 ring atoms, wherein the heterocyclic ring: (i) is a saturated, partially saturated, or fully unsaturated monocyclic or fused bicyclic ring, (ii) has one, two, or three nitrogen 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, oxo, cyano, C 1-6 -alkyl, C 3-6 -cycloalkyl, C 3-6 -cycloalkyl-C 1-3 -alkyl, C 1-6 -alkoxy group, C 3-6 -cycloalkoxy, C 1-3 -alkoxy-C 1-3 -alkyl, C 1-3 -alkoxy-C 2-3 -alkoxy group, C 1-3 -alkoxy-C 2-3 -alkoxy-C 1-3 -alkyl, C 1-3 -alkyl carbonyl, C 3-6-cycloalkylcarbonyl, C 1-3 -alkyl-carbonylamino-C 1-3 -alkyl, C 1-3 -alkylsulfonyl-C 1-3 -alkyl, phenyl, tolyl, C 1-3 -alkoxyphenyl, phenyl-C 1-3 -alkyl, C 1-3 -alkoxyphenyl-C 1-3 -alkyl, azacyclic butyl, pyrrolidinyl, piperidinyl, morpholinyl, tetrahydrofuranyl, tetrahydropyranyl and tetrahydrooxocyclic heptyl, wherein: (a) the C 1-6 -alkyl, C 3-6 -cycloalkyl, C 3-6 -cycloalkyl-C 1-3 -alkyl, C 1-6 -alkoxy group, C 3-6 -cycloalkoxy, C 1-3 -alkoxy-C 1-3 -alkyl, C 1-3 -alkoxy-C 2-3 -alkoxy group, C 1-3 -alkoxy-C 2-3 -alkoxy-C 1-3 -alkyl, C 1-3 -alkyl carbonyl, C 3-6 -cycloalkylcarbonyl, C 1-3 -alkyl-carbonylamino-C 1-3 -alkyl, C 1-3 -alkylsulfonyl-C 1-3 -alkyl, phenyl, tolyl, C 1-3 -alkoxyphenyl, phenyl-C 1-3 -alkyl, C 1-3 -alkoxyphenyl-C 1-3 -Alkyl, azacyclic butyl, pyrrolidinyl, piperidinyl, morpholinyl, tetrahydrofuranyl, tetrahydropyranyl, and tetrahydrooxocyclic heptyl can be further substituted with one or more halogens, and (b) the C 1-6 -Alkyl groups can be further substituted with one or more hydroxyl groups;

[0012] (b) A heterocyclic group containing a total of 5 to 10 ring atoms, wherein the heterocyclic ring: (i) is a saturated, partially saturated, or fully unsaturated monocyclic or fused bicyclic ring, (ii) has: (a) a nitrogen ring atom and an oxygen ring atom with the remaining ring atom being carbon, or (b) a nitrogen ring atom and a sulfur ring atom with the remaining ring atom being carbon, and (iii) optionally substituted by one or more substituents independently selected from the group consisting of: halogen, cyano, oxo, C 1-6 -alkyl, C 3-6 -cycloalkyl, C1-6 -alkoxy group, C 1-3 -alkoxy-C 1-3 -alkyl, C 1-3 -alkylcarbonyl-C 1-3 -alkyl, and C 1-3 -alkylsulfonyl-C 1-3 -alkyl, and wherein the C 1-6 -alkyl, C 3-6 -cycloalkyl, C 1-6 -alkoxy group, C 1-3 -alkoxy-C 1-3 -alkyl, C 1-3 -alkylcarbonyl-C 1-3 -alkyl and C 1-3 -alkylsulfonyl-C 1-3 -The alkyl group can be further substituted with one or more halogens; and

[0013] (c) A spiroheterocyclic group containing a total of 6 to 11 ring atoms, wherein the spiroheterocyclic group: (i) comprises two saturated rings, (ii) has: (a) one or two nitrogen ring atoms and the remaining ring atoms are carbon, (b) one or two nitrogen ring atoms and one or two oxygen ring atoms and the remaining ring atoms are carbon, or (c) one nitrogen ring atom and one sulfur ring atom and the remaining ring atoms are carbon, and (iii) optionally substituted by one or more substituents independently selected from the group consisting of: halogen, oxo, C 1-6 -alkyl, C 1-6 - Haloalkyl, C 1-6 -alkoxy group, C 1-6 - Haloalkoxy groups and C 1-6 -alkyl carbonyl;

[0014] R 3 Choose from the following groups: hydrogen, halogens, and carbon. 1-3 -alkyl;

[0015] R 4 Choose from the following groups: hydrogen, halogens, and carbon. 1-3 -alkyl;

[0016] R 5 Choose from the following groups: hydrogen, halogens, and carbon. 1-3 -alkyl; and

[0017] R 6 Choose from the following groups: hydrogen, halogens, and carbon. 1-3 -alkyl.

[0018] In another respect, this disclosure provides compounds having the structure of formula (II), (III-A), (III-B), (III-C), (III-D), (III-E), (IV), (IV-A), (V), (VI), (VII), (VIII), (IX), (X), or (XI) as further defined herein, and pharmaceutically acceptable salts thereof.

[0019] In another aspect, this disclosure provides a pharmaceutical composition comprising a therapeutically effective amount of the compound or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier, the compound having a structure of formula (I), (II), (III-A), (III-B), (III-C), (III-D), (III-E), (IV), (IV-A), (V), (VI), (VII), (VIII), (IX), (X), or (XI).

[0020] In another aspect, this disclosure provides a pharmaceutical composition comprising a therapeutically effective amount of a compound or a pharmaceutically acceptable salt thereof, a second pharmacological agent, and a pharmaceutically acceptable carrier, the compound having a structure of formula (I), (II), (III-A), (III-B), (III-C), (III-D), (III-E), (IV), (IV-A), (V), (VI), (VII), (VIII), (IX), (X), or (XI).

[0021] In another aspect, this disclosure provides a method for treating or preventing FAP-mediated conditions by administering a therapeutically effective amount of a compound or a pharmaceutically acceptable salt thereof to a subject in need, the compound having a structure of formula (I), (II), (III-A), (III-B), (III-C), (III-D), (III-E), (IV), (IV-A), (V), (VI), (VII), (VIII), (IX), (X), or (XI). In another aspect, FAP-mediated conditions are selected from the group consisting of: liver disease, type 2 diabetes, cardiovascular disease, obesity, obesity-related conditions, fibrosis, keloid disorder, inflammation, and cancer. In yet another aspect, FAP-mediated conditions are liver diseases, particularly non-alcoholic steatohepatitis (NASH).

[0022] In another aspect, this disclosure provides compounds having the structure of formula (I), (II), (III-A), (III-B), (III-C), (III-D), (III-E), (IV), (IV-A), (V), (VI), (VII), (VIII), (IX), (X), or (XI), or pharmaceutically acceptable salts thereof, for use as medicaments for the treatment or prevention of FAP-mediated conditions.

[0023] In another aspect, this disclosure provides the use of compounds having the structure of formula (I), (II), (III-A), (III-B), (III-C), (III-D), (III-E), (IV), (IV-A), (V), (VI), (VII), (VIII), (IX), (X), or (XI) or pharmaceutically acceptable salts thereof in the preparation of medicaments for the treatment or prevention of FAP-mediated conditions.

[0024] In another aspect, this disclosure provides a kit comprising a compound or a pharmaceutically acceptable salt thereof having the structure of formula (I), (II), (III-A), (III-B), (III-C), (III-D), (III-E), (IV), (IV-A), (V), (VI), (VII), (VIII), (IX), (X), or (XI).

[0025] In another aspect, this disclosure provides methods for preparing compounds having the structure of formula (I), (II), (III-A), (III-B), (III-C), (III-D), (III-E), (IV), (IV-A), (V), (VI), (VII), (VIII), (IX), (X), or (XI), or pharmaceutically acceptable salts thereof. Detailed Implementation

[0026] Numerous embodiments are described in detail throughout this specification and will be apparent to readers skilled in the art. This specification is not to be construed as being limited to any specific one or more embodiments described herein.

[0027] I. definition

[0028] For the embodiments disclosed in this specification, the following terms have the meanings described below:

[0029] The phrase "a / kind (a or an)" means "one / kind or more / kinds". Throughout the text, the plural and singular forms should be considered interchangeable, except when indicating quantity.

[0030] Unless the context otherwise requires, the words “comprise” or “comprises” are used on the basis of explicit understanding, that is, they are interpreted inclusively rather than exclusively, and the applicant wishes that each of those words be interpreted in this way when interpreting this patent (including the following claims).

[0031] The term "halogen" (alone or in combination with one or more other terms) refers to a fluorine group (which can be described as -F), a chlorine group (which can be described as -Cl), a bromine group (which can be described as -Br), or an iodine group (which can be described as -I).

[0032] The term "hydroxyl" (alone or in combination with one or more other terms) means -OH.

[0033] The term "cyano" (alone or in combination with one or more other terms) means -CN.

[0034] The term “oxo” (alone or in combination with one or more other terms) refers to an oxo group and can be described as =O.

[0035] The term "alkyl" (alone or in combination with one or more 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 from 1 to about 20 carbon atoms, more typically from 1 to about 12 carbon atoms, even more typically from 1 to about 8 carbon atoms, and even more typically from 1 to about 6 carbon atoms. Examples of such substituents include methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, pentyl, isopentyl, 2,2-dimethylpropyl, hexyl, heptyl, and octyl.

[0036] The term "cycloalkyl" (alone or in combination with one or more other terms) refers to a saturated carbocyclic substituent containing from 3 to about 14 carbon ring atoms, more typically from 3 to about 12 carbon ring atoms, and even more typically from 3 to about 8 carbon ring atoms. Cycloalkyl groups include a single carbon ring, which typically contains from 3 to 6 carbon ring atoms. Examples of monocyclic cycloalkyl groups include cyclopropyl, cyclobutyl, cyclopentyl, and cyclohexyl.

[0037] The term "cycloalkylalkyl" (alone or in combination with one or more other terms) refers to an alkyl group that has been substituted with a cycloalkyl group. Examples of such substituents include cyclopropylmethyl, cyclobutylmethyl, cyclopentylmethyl, and cyclohexylmethyl.

[0038] The term "alkoxy" (alone or in combination with one or more 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:

[0039] (i) The term “alkoxyalkyl” (alone or in combination with one or more other terms) means an alkyl group substituted with an alkoxy group, such as “methoxymethyl”, which can be described as:

[0040]

[0041] (ii) The term “cycloalkylalkoxy” (alone or in combination with one or more other terms) means an alkoxy group substituted with a cycloalkyl group, such as “cyclopropylmethoxy”, which can be described as:

[0042]

[0043] (iii) The term “alkoxyalkoxy” (alone or in combination with one or more other terms) means an alkoxy group substituted with another alkoxy group, such as “methoxyethoxy”, which can be described as:

[0044]

[0045] (iv) The term “alkoxyalkoxyalkyl” (alone or in combination with one or more other terms) means an alkyl group substituted with an alkoxyalkoxy group, such as “methoxyethoxymethyl”, which can be described as:

[0046]

[0047] (v) The term "alkoxyphenyl" (alone or in combination with one or more other terms) refers to a phenyl group substituted with an alkoxy group, such as "4-methoxyphenyl," which can be described as:

[0048] and

[0049] (vi) The term “alkoxyphenylalkyl” (alone or in combination with one or more other terms) means an alkyl group substituted with an alkoxyphenyl, such as “4-methoxyphenylmethyl”, which can be described as:

[0050]

[0051] In some cases, the number of carbon atoms in a substituent (e.g., alkyl, cycloalkyl, etc.) is determined by the prefix "C". x-y The "-" indicates that x is the minimum number of carbon atoms in the substituent and y is the maximum number. Therefore, for example, "C 1-6"-alkyl" refers to an alkyl substituent containing 1 to 6 carbon atoms. Further explanation is needed: C 3-6 -Cycloalkyl refers to cycloalkyl substituents containing 3 to 6 carbon ring atoms.

[0052] The prefix "halogenated" indicates that the substituent attached to the prefix is ​​replaced by one or more independently chosen halogen groups. For example, haloalkyl means an alkyl substituent in which at least one hydrogen group is replaced by a halogen group. When more than one hydrogen is replaced by a halogen, these 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 group is replaced by a halogen group. When more than one hydrogen is replaced by a halogen, these 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.

[0053] The term "carbonyl" (alone or in combination with one or more other terms) refers to -C(O)-, which can also be described as:

[0054]

[0055] Therefore, for example:

[0056] (i) The term “alkyl carbonyl” (alone or in combination with one or more other terms) means alkyl-C(O)-, such as “methyl carbonyl” (i.e., acetyl), which can be described as:

[0057] as well as

[0058] Other alkyl carbonyl substituents, such as ethyl carbonyl, propyl carbonyl, butyl carbonyl, pentyl carbonyl, and hexyl carbonyl;

[0059] (ii) The term “alkylcarbonylalkyl” (alone or in combination with one or more other terms) means an alkyl group substituted with an alkyl carbonyl group, such as “methylcarbonylmethyl”, which can be described as:

[0060]

[0061] (iii) The term “cycloalkyl carbonyl” (alone or in combination with one or more other terms) means cycloalkyl-C(O)-, such as “cyclopropyl carbonyl”, which can be described as:

[0062] and

[0063] (iv) The term “cycloalkylcarbonylalkyl” (alone or in combination with one or more other terms) means an alkyl group substituted with a cycloalkylcarbonyl group, such as “cyclopropylcarbonylmethyl”, which can be described as:

[0064]

[0065] The term "thio" or "thia" (alone or in combination with one or more other terms) refers to a divalent sulfur atom, which can also be described as -S-.

[0066] The term "sulfinyl" (or "sulfoxido") (alone or in combination with one or more other terms) means -S(O)-, and can also be described as:

[0067]

[0068] The term "sulfonyl" (alone or in combination with one or more other terms) refers to -S(O)2-, which can also be described as:

[0069]

[0070] Therefore, for example, "alkylsulfonyl" (alone or in combination with one or more other terms) means alkyl-S(O)2-. Examples of alkylsulfonyl substituents include methylsulfonyl, ethylsulfonyl, and propylsulfonyl. Similarly, the term "alkylsulfonylalkyl" (alone or in combination with one or more other terms) means an alkyl group substituted with an alkylsulfonyl group, such as "methylsulfonylmethyl," which can be described as:

[0071]

[0072] The term "alkylcarbonylaminoalkyl" (alone or in combination with one or more other terms) means alkyl-C(O)-N(H)-alkyl-, such as "methylcarbonylaminomethyl", which can also be described as:

[0073]

[0074] The term "heterocyclic" (alone or in combination with one or more other terms) refers to a saturated, partially saturated, or fully unsaturated (i.e., heteroaryl) ring structure containing a total of 3 to 14 ring atoms. At least one of the ring atoms is a heteroatom (i.e., oxygen, nitrogen, or sulfur), and the remaining ring atoms are independently selected from the group consisting of carbon, oxygen, nitrogen, and sulfur.

[0075] Heterocyclic groups include monocyclic saturated, partially unsaturated, and fully unsaturated ring structures having, for example, 3 to 7 members (e.g., 3 to 6 members), 5 to 7 members (e.g., 5 or 6 members), wherein at least one and up to 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. Examples of monocyclic heterocyclic groups include furanyl, dihydrofuranyl, tetrahydrofuranyl, thienyl, dihydrothienyl, tetrahydrothienyl, pyrroleyl, isopyrroleyl, pyrrolinyl, pyrrolidinyl, imidazolyl, isopyrazoleyl, imidazolinyl, imidazolinyl, pyrazolyl, pyrazololinyl, pyrazolyl, triazolyl, tetraazolyl, dithiolyl, oxathiolyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, thiazolinyl, thiazolinyl, iso... Thiazolinyl, thiazolinyl, isothiazolinyl, thiadiazolyl, oxthiazolinyl, dioxazolinyl, oxthiazolinyl, oxthiocyclopentenyl, oxathiolanyl, pyranyl, dihydropyranyl, pyridinyl, piperidinyl, pyridinyl, pyrazinyl, piperazinyl, triazinyl, oxazinyl, isoxazinyl, oxazolyl, isoxazolyl, oxthiazolinyl, morpholinyl, azirheptatrienyl, oxacycloheptatrienyl, thioheptatrienyl, and diazirheptatrienyl.

[0076] Heterocyclic groups further include fused bicyclic structures (i.e., fused bicycles) or two rings having only one common atom (i.e., spiro), wherein at least one such ring contains a heteroatom (i.e., nitrogen, oxygen, or sulfur) as a ring atom. Examples of heterocyclic groups having a fused two-ring structure include indoleazinyl, pyrindinyl, pyranopyrroleyl, 4H-quinazinyl, purinyl, naphthidyl, pyridopyridyl, pteridylyl, indole, isoindole, indoleninyl, isoindazoleyl, benzo[azinyl], phthalazinyl, quinoxalinyl, quinazolinyl, benzo[azinyl] Diazinyl, benzopyranyl, benzothiaranyl, benzooxazolyl, indoleoxazinyl, anthranilyl, benzo-m-dioxacyclopentenyl, benzodioxalkyl, benzooxadiazolyl, benzofuranyl, isobenzofuranyl, benzothiophenyl, isobenzothiophenyl, benzothiazolyl, benzothiadiazolyl, benzoimidazolyl, benzotriazolyl, benzooxazinyl, benzoisooxazinyl, and tetrahydroisoquinolinyl.

[0077] 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 within this definition.

[0078] If a substituent is described as “substituted,” then a non-hydrogen group replaces a hydrogen group on the carbon or nitrogen of that substituent. Thus, for example, a substituted alkyl substituent is an alkyl substituent in which at least one non-hydrogen group replaces a hydrogen group on the alkyl substituent. For illustration, a monofluoroalkyl group is an alkyl group substituted with one fluorine group, and a difluoroalkyl group is an alkyl group substituted with two fluorine groups. It should be recognized that if more than one substituent is present on a substituent, each non-hydrogen group may be the same or different (unless otherwise stated).

[0079] 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 the substituents in the list, then one or more hydrogens on the carbon (if present) 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 the substituents in the list, then one or more hydrogens on the nitrogen (if present) may each be substituted by independently selected optional substituents.

[0080] If a substituent is described as being "independently selected" from the group, then each substituent is selected independently of the others. Therefore, each substituent may be the same as or different from one or more other substituents.

[0081] The term "pharmaceutically acceptable" is used as an adjective in this specification to mean a noun that is suitable for use as a pharmaceutical product or 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, with inorganic bases, organic bases, inorganic acids, organic acids, or basic or acidic amino acids.

[0082] The "therapeutic effective amount" of a pharmacological agent is the amount sufficient to produce a beneficial or desired outcome (including clinical outcomes), and therefore will depend on the circumstances of its administration. When a pharmacological agent is administered to treat liver disease, for example, the therapeutic effective amount of the agent is the amount sufficient, alone or in combination with other therapies, to provide an anti-hepatic effect to the subject, compared to the response obtained without the administration of the agent.

[0083] The term “prevention” is easily understood by physicians with general skills and is intended to have its normal meaning in the treatment of specific conditions, including primary prevention and secondary prevention of the development of the condition, where the condition has already developed and the patient is temporarily or permanently protected against the aggravation or worsening of the disease or against the development of new symptoms related to the condition.

[0084] The term “treatment” is readily understood by physicians of general medical skill and, in the context of treating a specific condition, can include (1) reducing the severity or cause of the condition being treated, and / or (2) alleviating or reducing 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 when compared to expected survival without treatment; and / or otherwise reducing or mitigating the severity of cancer or liver disease, either wholly or partially.

[0085] II. compound

[0086] In one embodiment, this disclosure provides a compound having the structure of formula (I):

[0087]

[0088] and its pharmaceutically acceptable salts, of which:

[0089] X 1 Choose from the following groups: -S-, -S(O)-, and -S(O)2-;

[0090] R 1 Choose from the following groups: hydrogen, halogen, hydroxyl, C 1-3 -alkyl and C 1-6 -alkoxy group;

[0091] R 2 Choose from the following groups:

[0092] (a) A heterocyclic group containing a total of 4 to 10 ring atoms, wherein the heterocyclic ring: (i) is a saturated, partially saturated, or fully unsaturated monocyclic or fused bicyclic ring, (ii) has one, two, or three nitrogen 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, oxo, cyano, C 1-6 -alkyl, C 3-6 -cycloalkyl, C 3-6 -cycloalkyl-C 1-3 -alkyl, C 1-6 -alkoxy group, C 3-6 -cycloalkoxy, C 1-3 -alkoxy-C 1-3 -alkyl, C 1-3 -alkoxy-C 2-3 -alkoxy group, C 1-3 -alkoxy-C 2-3 -alkoxy-C 1-3 -alkyl, C 1-3 -alkyl carbonyl, C 3-6 -cycloalkylcarbonyl, C1-3 -alkyl-carbonylamino-C 1-3 -alkyl, C 1-3 -alkylsulfonyl-C 1-3 -alkyl, phenyl, tolyl, C 1-3 -alkoxyphenyl, phenyl-C 1-3 -alkyl, C 1-3 -alkoxyphenyl-C 1-3 -alkyl, azacyclic butyl, pyrrolidinyl, piperidinyl, morpholinyl, tetrahydrofuranyl, tetrahydropyranyl and tetrahydrooxocyclic heptyl, wherein: (a) the C 1-6 -alkyl, C 3-6 -cycloalkyl, C 3-6 -cycloalkyl-C 1-3 -alkyl, C 1-6 -alkoxy group, C 3-6 -cycloalkoxy, C 1-3 -alkoxy-C 1-3 -alkyl, C 1-3 -alkoxy-C 2-3 -alkoxy group, C 1-3 -alkoxy-C 2-3 -alkoxy-C 1-3 -alkyl, C 1-3 -alkyl carbonyl, C 3-6 -cycloalkylcarbonyl, C 1-3 -alkyl-carbonylamino-C 1-3 -alkyl, C 1-3 -alkylsulfonyl-C 1-3 -alkyl, phenyl, tolyl, C 1-3 -alkoxyphenyl, phenyl-C 1-3 -alkyl, C 1-3 -alkoxyphenyl-C 1-3 -Alkyl, azacyclic butyl, pyrrolidinyl, piperidinyl, morpholinyl, tetrahydrofuranyl, tetrahydropyranyl, and tetrahydrooxocyclic heptyl can be further substituted with one or more halogens, and (b) the C 1-6 -Alkyl groups can be further substituted with one or more hydroxyl groups;

[0093] (b) A heterocyclic group containing a total of 5 to 10 ring atoms, wherein the heterocyclic ring: (i) is a saturated, partially saturated, or fully unsaturated monocyclic or fused bicyclic ring, (ii) has: (a) a nitrogen ring atom and an oxygen ring atom with the remaining ring atom being carbon, or (b) a nitrogen ring atom and a sulfur ring atom with the remaining ring atom being carbon, and (iii) optionally substituted by one or more substituents independently selected from the group consisting of: halogen, cyano, oxo, C 1-6 -alkyl, C 3-6 -cycloalkyl, C 1-6-alkoxy group, C 1-3 -alkoxy-C 1-3 -alkyl, C 1-3 -alkylcarbonyl-C 1-3 -alkyl, and C 1-3 -alkylsulfonyl-C 1-3 -alkyl, and wherein the C 1-6 -alkyl, C 3-6 -cycloalkyl, C 1-6 -alkoxy group, C 1-3 -alkoxy-C 1-3 -alkyl, C 1-3 -alkylcarbonyl-C 1-3 -alkyl and C 1-3 -alkylsulfonyl-C 1-3 -The alkyl group can be further substituted with one or more halogens; and

[0094] (c) A spiroheterocyclic group containing a total of 6 to 11 ring atoms, wherein the spiroheterocyclic group: (i) comprises two saturated rings, (ii) has: (a) one or two nitrogen ring atoms and the remaining ring atoms are carbon, (b) one or two nitrogen ring atoms and one or two oxygen ring atoms and the remaining ring atoms are carbon, or (c) one nitrogen ring atom and one sulfur ring atom and the remaining ring atoms are carbon, and (iii) optionally substituted by one or more substituents independently selected from the group consisting of: halogen, oxo, C 1-6 -alkyl, C 1-6 - Haloalkyl, C 1-6 -alkoxy group, C 1-6 - Haloalkoxy groups and C 1-6 -alkyl carbonyl;

[0095] R 3 Choose from the following groups: hydrogen, halogens, and carbon. 1-3 -alkyl;

[0096] R 4 Choose from the following groups: hydrogen, halogens, and carbon. 1-3 -alkyl;

[0097] R 5 Choose from the following groups: hydrogen, halogens, and carbon. 1-3 -alkyl; and

[0098] R 6 Choose from the following groups: hydrogen, halogens, and carbon. 1-3 -alkyl.

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

[0100]

[0101] and its pharmaceutically acceptable salts, of which X 1 R 1 R 2 R 3 R 4 R 5 and R 6 This is as defined above for compounds having 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-.

[0102] In some embodiments, R 1 Choose from the following groups: hydrogen, halogens, and C. 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 is chlorine. On the other hand, R 1 It's fluorine. In another respect, R... 1 It is a methyl group.

[0103] In some embodiments, R 3 Choose from the following groups: hydrogen, halogens, and C. 1-3 -alkyl. In one respect, R 3 Choose from the following groups: hydrogen, chlorine, fluorine, and methyl. In another aspect, R... 3 It's hydrogen. In another respect, R... 3 It is chlorine. On the other hand, R 3 It's fluorine. In another respect, R... 3 It is a methyl group.

[0104] In some embodiments, R 4 Choose from the following groups: hydrogen, halogens, and C. 1-3 -alkyl. In one respect, 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.

[0105] In some embodiments, R 5 Choose from the following groups: hydrogen, halogens, and C. 1-3 -alkyl. In one respect, R 5 Choose from the following groups: hydrogen, chlorine, fluorine, and methyl. In another aspect, 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.

[0106] In some embodiments, R 6 Choose from the following groups: hydrogen, halogens, and C. 1-3 -alkyl. In one respect, R 6 Choose from the following groups: hydrogen, chlorine, fluorine, and methyl. In another aspect, 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.

[0107] In some embodiments, 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 The substituents are all 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 The substituents are all hydrogen. In another aspect, R... 1 R 3 R 4 R 5 and R 6One of the substituents is chlorine, and the remaining R 1 R 3 R 4 R 5 and R 6 The substituents are all hydrogen. In another aspect, R... 1 R 3 R 4 R 5 and R 6 One of the substituents is fluorine, and the remaining R 1 R 3 R 4 R 5 and R 6 The substituents are all hydrogen. In another aspect, R... 1 R 3 R 4 R 5 and R 6 One of the substituents is a methyl group, and the remaining R 1 R 3 R 4 R 5 and R 6 All the substituents are hydrogen.

[0108] In some embodiments, 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 substituents are hydrogen. In one respect, R... 1 R 3 R 4 R 5 and R 6 The two 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.

[0109] In some embodiments, R 1 R 3 R 4 R 5 and R 6 At least one of the substituents is chlorine.

[0110] In some embodiments, R 1 R 3 R 4 R 5 and R 6 At least one of the substituents is fluorine.

[0111] In some embodiments, R 1 R 3 R 4 R 5 and R 6 At least one of the substituents is a methyl group.

[0112] In some embodiments, this disclosure provides compounds having the structure of formula (III-A):

[0113]

[0114] and its pharmaceutically acceptable salts, of which R 1 and R 2 It is as defined in the above embodiments.

[0115] In some embodiments, this disclosure provides compounds having the structure of formula (III-B):

[0116]

[0117] and its pharmaceutically acceptable salts, of which R 2 and R 3 It is as defined in the above embodiments.

[0118] In some embodiments, this disclosure provides compounds having the structure of formula (III-C):

[0119]

[0120] and its pharmaceutically acceptable salts, of which R 2 and R 4 It is as defined in the above embodiments.

[0121] In some embodiments, this disclosure provides compounds having the structure of formula (III-D):

[0122]

[0123] and its pharmaceutically acceptable salts, of which R 2 and R 5 It is as defined in the above embodiments.

[0124] In some embodiments, this disclosure provides compounds having the structure of formula (III-E):

[0125]

[0126] and its pharmaceutically acceptable salts, of which R 2 and R 6 It is as defined in the above embodiments.

[0127] In some embodiments, this disclosure provides compounds having the structure of formula (IV):

[0128]

[0129] and its pharmaceutically acceptable salts, of which R 2 It is as defined above for compounds having formula (I).

[0130] In some embodiments, this disclosure provides compounds having the structure of formula (IV-A):

[0131]

[0132] Or a pharmaceutically acceptable salt thereof, wherein R 2 It is as defined above for compounds having formula (I).

[0133] A. R 2 It is a monocyclic or fused bicyclic heterocyclic group (nitrogen and carbon ring atoms).

[0134] 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), and pharmaceutically acceptable salts thereof, wherein R 2 It is a heterocyclic group containing a total of 4 to 10 ring atoms, wherein the heterocyclic ring: (i) is a saturated, partially saturated, or fully unsaturated monocyclic or fused bicyclic ring, (ii) has one, two, or three nitrogen 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, oxo, cyano, C 1-6 -alkyl, C 3-6 -cycloalkyl, C 3-6 -cycloalkyl-C 1-3 -alkyl, C 1-6 -alkoxy group, C 3-6 -cycloalkoxy, C 1-3 -alkoxy-C 1-3 -alkyl, C 1-3 -alkoxy-C 2-3 -alkoxy group, C 1-3-alkoxy-C 2-3 -alkoxy-C 1-3 -alkyl, C 1-3 -alkyl carbonyl, C 3-6 -cycloalkylcarbonyl, C 1-3 -alkyl-carbonylamino-C 1-3 -alkyl, C 1-3 -alkylsulfonyl-C 1-3 -alkyl, phenyl, tolyl, C 1-3 -alkoxyphenyl, phenyl-C 1-3 -alkyl, C 1-3 -alkoxyphenyl-C 1-3 -alkyl, azacyclic butyl, pyrrolidinyl, piperidinyl, morpholinyl, tetrahydrofuranyl, tetrahydropyranyl and tetrahydrooxocyclic heptyl, wherein: (a) the C 1-6 -alkyl, C 3-6 -cycloalkyl, C 3-6 -cycloalkyl-C 1-3 -alkyl, C 1-6 -alkoxy group, C 3-6 -cycloalkoxy, C 1-3 -alkoxy-C 1-3 -alkyl, C 1-3 -alkoxy-C 2-3 -alkoxy group, C 1-3 -alkoxy-C 2-3 -alkoxy-C 1-3 -alkyl, C 1-3 -alkyl carbonyl, C 3-6 -cycloalkylcarbonyl, C 1-3 -alkyl-carbonylamino-C 1-3 -alkyl, C 1-3 -alkylsulfonyl-C 1-3 -alkyl, phenyl, tolyl, C 1-3 -alkoxyphenyl, phenyl-C 1-3 -alkyl, C 1-3 -alkoxyphenyl-C 1-3 -Alkyl, azacyclic butyl, pyrrolidinyl, piperidinyl, morpholinyl, tetrahydrofuranyl, tetrahydropyranyl, and tetrahydrooxocyclic heptyl can be further substituted with one or more halogens, and (b) the C 1-6 -Alkyl groups can be further substituted with one or more hydroxyl groups. In one aspect, R 2 The heterocyclic group ring is a saturated monocyclic ring. In another aspect, R... 2 The heterocyclic base ring is a partially saturated monocyclic ring. In another aspect, R... 2 The heterocyclic group ring is a completely unsaturated monocyclic ring. In another aspect, R... 2 The heterocyclic group ring is a saturated, fused bicyclic ring. In another aspect, R...2 The heterocyclic ring is a partially saturated, fused bicyclic ring. In another aspect, R... 2 The heterocyclic group ring is a fully unsaturated fused bicyclic ring. In another aspect, R... 2 The heterocyclic base ring has one nitrogen ring atom and the remaining ring atoms are carbon. In another aspect, R... 2 The heterocyclic base ring has two nitrogen ring atoms and the remaining ring atoms are carbon. In another aspect, R... 2 The heterocyclic base ring has three nitrogen ring atoms and the remaining ring atoms are carbon.

[0135] In some embodiments, R 2 Heterocyclic rings are selected from the following groups:

[0136]

[0137]

[0138] The heterocyclic ring is optionally substituted by one or more substituents independently selected from the group consisting of: halogen, hydroxyl, oxo, cyano, C. 1-6 -alkyl, C 3-6 -cycloalkyl, C 3-6 -cycloalkyl-C 1-3 -alkyl, C 1-6 -alkoxy group, C 3-6 -cycloalkoxy, C 1-3 -alkoxy-C 1-3 -alkyl, C 1-3 -alkoxy-C 2-3 -alkoxy group, C 1-3 -alkoxy-C 2-3 -alkoxy-C 1-3 -alkyl, C 1-3 -alkyl carbonyl, C 3-6 -cycloalkylcarbonyl, C 1-3 -alkyl-carbonylamino-C 1-3 -alkyl, C 1-3 -alkylsulfonyl-C 1-3 -alkyl, phenyl, tolyl, C 1-3 -alkoxyphenyl, phenyl-C 1-3 -alkyl, C 1-3 -alkoxyphenyl-C 1-3 -alkyl, azacyclic butyl, pyrrolidinyl, piperidinyl, morpholinyl, tetrahydrofuranyl, tetrahydropyranyl and tetrahydrooxocyclic heptyl, wherein: (a) the C 1-6 -alkyl, C 3-6 -cycloalkyl, C 3-6 -cycloalkyl-C 1-3 -alkyl, C 1-6-alkoxy group, C 3-6 -cycloalkoxy, C 1-3 -alkoxy-C 1-3 -alkyl, C 1-3 -alkoxy-C 2-3 -alkoxy group, C 1-3 -alkoxy-C 2-3 -alkoxy-C 1-3 -alkyl, C 1-3 -alkyl carbonyl, C 3-6 -cycloalkylcarbonyl, C 1-3 -alkyl-carbonylamino-C 1-3 -alkyl, C 1-3 -alkylsulfonyl-C 1-3 -alkyl, phenyl, tolyl, C 1-3 -alkoxyphenyl, phenyl-C 1-3 -alkyl, C 1-3 -alkoxyphenyl-C 1-3 -Alkyl, azacyclic butyl, pyrrolidinyl, piperidinyl, morpholinyl, tetrahydrofuranyl, tetrahydropyranyl, and tetrahydrooxocyclic heptyl can be further substituted with one or more halogens, and (b) the C 1-6 -Alkyl groups can be further substituted with one or more hydroxyl groups.

[0139] In some embodiments, R 2 Heterocyclic rings are selected from the following groups:

[0140]

[0141]

[0142] The heterocyclic ring is optionally substituted by one or more substituents independently selected from the group consisting of: halogen, hydroxyl, oxo, cyano, C. 1-6 -alkyl, C 3-6 -cycloalkyl, C 3-6 -cycloalkyl-C 1-3 -alkyl, C 1-6 -alkoxy group, C 3-6 -cycloalkoxy, C 1-3 -alkoxy-C 1-3 -alkyl, C 1-3 -alkoxy-C 2-3 -alkoxy group, C 1-3 -alkoxy-C 2-3 -alkoxy-C 1-3 -alkyl, C 1-3 -alkyl carbonyl, C 3-6 -cycloalkylcarbonyl, C 1-3 -alkyl-carbonylamino-C 1-3 -alkyl, C1-3 -alkylsulfonyl-C 1-3 -alkyl, phenyl, tolyl, C 1-3 -alkoxyphenyl, phenyl-C 1-3 -alkyl, C 1-3 -alkoxyphenyl-C 1-3 -alkyl, azacyclic butyl, pyrrolidinyl, piperidinyl, morpholinyl, tetrahydrofuranyl, tetrahydropyranyl and tetrahydrooxocyclic heptyl, wherein: (a) the C 1-6 -alkyl, C 3-6 -cycloalkyl, C 3-6 -cycloalkyl-C 1-3 -alkyl, C 1-6 -alkoxy group, C 3-6 -cycloalkoxy, C 1-3 -alkoxy-C 1-3 -alkyl, C 1-3 -alkoxy-C 2-3 -alkoxy group, C 1-3 -alkoxy-C 2-3 -alkoxy-C 1-3 -alkyl, C 1-3 -alkyl carbonyl, C 3-6 -cycloalkylcarbonyl, C 1-3 -alkyl-carbonylamino-C 1-3 -alkyl, C 1-3 -alkylsulfonyl-C 1-3 -alkyl, phenyl, tolyl, C 1-3 -alkoxyphenyl, phenyl-C 1-3 -alkyl, C 1-3 -alkoxyphenyl-C 1-3 -Alkyl, azacyclic butyl, pyrrolidinyl, piperidinyl, morpholinyl, tetrahydrofuranyl, tetrahydropyranyl, and tetrahydrooxocyclic heptyl can be further substituted with one or more halogens, and (b) the C 1-6 -Alkyl groups can be further substituted with one or more hydroxyl groups.

[0143] In some embodiments, R 2 Heterocyclic rings are selected from the following groups:

[0144]

[0145]

[0146] The heterocyclic ring is optionally substituted by one or more substituents independently selected from the group consisting of: halogen, hydroxyl, oxo, cyano, C. 1-6 -alkyl, C 3-6 -cycloalkyl, C 3-6 -cycloalkyl-C1-3 -alkyl, C 1-6 -alkoxy group, C 3-6 -cycloalkoxy, C 1-3 -alkoxy-C 1-3 -alkyl, C 1-3 -alkoxy-C 2-3 -alkoxy group, C 1-3 -alkoxy-C 2-3 -alkoxy-C 1-3 -alkyl, C 1-3 -alkyl carbonyl, C 3-6 -cycloalkylcarbonyl, C 1-3 -alkyl-carbonylamino-C 1-3 -alkyl, C 1-3 -alkylsulfonyl-C 1-3 -alkyl, phenyl, tolyl, C 1-3 -alkoxyphenyl, phenyl-C 1-3 -alkyl, C 1-3 -alkoxyphenyl-C 1-3 -alkyl, azacyclic butyl, pyrrolidinyl, piperidinyl, morpholinyl, tetrahydrofuranyl, tetrahydropyranyl and tetrahydrooxocyclic heptyl, wherein: (a) the C 1-6 -alkyl, C 3-6 -cycloalkyl, C 3-6 -cycloalkyl-C 1-3 -alkyl, C 1-6 -alkoxy group, C 3-6 -cycloalkoxy, C 1-3 -alkoxy-C 1-3 -alkyl, C 1-3 -alkoxy-C 2-3 -alkoxy group, C 1-3 -alkoxy-C 2-3 -alkoxy-C 1-3 -alkyl, C 1-3 -alkyl carbonyl, C 3-6 -cycloalkylcarbonyl, C 1-3 -alkyl-carbonylamino-C 1-3 -alkyl, C 1-3 -alkylsulfonyl-C 1-3 -alkyl, phenyl, tolyl, C 1-3 -alkoxyphenyl, phenyl-C 1-3 -alkyl, C 1-3 -alkoxyphenyl-C 1-3 -Alkyl, azacyclic butyl, pyrrolidinyl, piperidinyl, morpholinyl, tetrahydrofuranyl, tetrahydropyranyl, and tetrahydrooxocyclic heptyl can be further substituted with one or more halogens, and (b) the C 1-6 -Alkyl groups can be further substituted with one or more hydroxyl groups.

[0147] In some embodiments, R 2 The heterocyclic ring may optionally be substituted by one or more substituents independently selected from the group consisting of: halogen, hydroxyl, oxo, cyano, C. 1-3 -alkyl, C 3-6 -cycloalkyl, C 1-3 -alkoxy group, C 1-3 -alkyl carbonyl, C 3-6 -cycloalkylcarbonyl, C 1-3 -alkoxy-C 1-3 -alkyl, C 1-3 -alkoxy-C 2-3 -alkoxy group, C 1-3 -alkoxy-C 2-3 -alkoxy-C 1-3 -alkyl, C 1-3 -alkyl-carbonylamino-C 1-3 -alkyl, C 1-3 -alkylsulfonyl-C 1-3 -alkyl, morpholinyl, tetrahydrofuranyl, tetrahydropyranyl, and tetrahydrooxocyclic heptyl, wherein the C 1-3 -alkyl, C 3-6 -cycloalkyl, C 1-3 -alkoxy group, C 1-3 -alkyl carbonyl, C 3-6 -cycloalkylcarbonyl, C 1-3 -alkoxy-C 1-3 -alkyl, C 1-3 -alkoxy-C 2-3 -alkoxy group, C 1-3 -alkoxy-C 2-3 -alkoxy-C 1-3 -alkyl, C 1-3 -alkylsulfonyl-C 1-3 -Alkyl, tetrahydrofuranyl, tetrahydropyranyl, and tetrahydrooxoheptanyl can be further substituted with one or more halogens.

[0148] In some embodiments, R 2 The heterocyclic ring may optionally be substituted by one or more substituents independently selected from the group consisting of: halogen, hydroxyl, oxo, C. 1-3 -alkyl, cyclopropyl, C 1-3 -alkoxy groups, and C 1-3 -alkoxy-C 1-3 -alkyl, wherein the C 1-3 -alkyl, cyclopropyl, C 1-3 -alkoxy groups, and C 1-3 -alkoxy-C 1-3 -Alkyl groups can be further substituted with one or more halogens.

[0149] In some embodiments, R 2 The heterocyclic ring is optionally substituted by one or more substituents independently selected from the group consisting of: aziridine, pyrrolidinyl, piperidinyl, and morpholinyl, wherein the aziridine, pyrrolidinyl, piperidinyl, and morpholinyl may be further substituted by one or more halogens.

[0150] In some embodiments, R 2 The heterocyclic ring is optionally substituted by one or more substituents independently selected from the group consisting of tetrahydrofuranyl, tetrahydropyranyl, and tetrahydrooxoheptanyl, wherein the tetrahydrofuranyl, tetrahydropyranyl, and tetrahydrooxoheptanyl may be further substituted by one or more halogens.

[0151] In some embodiments, R 2 The heterocyclic ring is optionally substituted with one or more halogens. In one aspect, R 2 The heterocyclic ring is optionally substituted with one or more chlorine compounds. In another aspect, R 2 The heterocyclic ring may optionally be substituted with one or more fluorine molecules.

[0152] In some embodiments, R 2 The heterocyclic ring may optionally be replaced by one or more hydroxyl groups.

[0153] In some embodiments, R 2 The heterocyclic ring may optionally be substituted with one or more oxo groups.

[0154] In some embodiments, R 2 The heterocyclic ring may optionally be substituted with one or more cyano groups.

[0155] In some embodiments, R 2 The heterocyclic base ring is optionally separated by one or more C 1-3 -alkyl substitution, wherein the C 1-3 -Alkyl groups can be further substituted by one or more substituents independently selected from halogens and hydroxyl groups.

[0156] In some embodiments, R 2 The heterocyclic base ring is optionally separated by one or more C 3-6 - Cycloalkyl substitution, wherein the C 3-6 -Cycloalkyl groups can be further substituted with one or more halogens.

[0157] In some embodiments, R 2 The heterocyclic base ring is optionally separated by one or more C 3-6 -cycloalkyl-C 1-3 -alkyl substitution, wherein the C 3-6 -cycloalkyl-C 1-3-Alkyl groups can be further substituted with one or more halogens.

[0158] In some embodiments, R 2 The heterocyclic base ring is optionally separated by one or more C 1-3 -alkoxy substitution, wherein the C 1-3 -Alkoxy groups can be further substituted by one or more halogens.

[0159] In some embodiments, R 2 The heterocyclic base ring is optionally separated by one or more C 3-6 - Cycloalkoxy substitution, wherein the C 3-6 -Cycloalkoxy groups can be further substituted by one or more halogens.

[0160] In some embodiments, R 2 The heterocyclic base ring is optionally separated by one or more C 1-3 -alkoxy-C 1-3 -alkyl substitution, wherein the C 1-3 -alkoxy-C 1-3 -Alkyl groups can be further substituted with one or more halogens.

[0161] In some embodiments, R 2 The heterocyclic base ring is optionally separated by one or more C 1-3 -alkoxy-C 2-3 -alkoxy substitution, wherein the C 1-3 -alkoxy-C 2-3 -Alkoxy groups can be further substituted by one or more halogens.

[0162] In some embodiments, R 2 The heterocyclic base ring is optionally separated by one or more C 1-3 -alkoxy-C 2-3 -alkoxy-C 1-3 -alkyl substitution, wherein the C 1-3 -alkoxy-C 2-3 -alkoxy-C 1-3 -Alkyl groups can be further substituted with one or more halogens.

[0163] In some embodiments, R 2 The heterocyclic base ring is optionally separated by one or more C 1-3 -alkyl carbonyl substitution, where C 1-3 -The alkyl carbonyl group can be further replaced by one or more halogens.

[0164] In some embodiments, R 2 The heterocyclic base ring is optionally separated by one or more C 3-6 - Cycloalkyl carbonyl substitution, wherein the C 3-6-The cycloalkyl carbonyl group can be further replaced by one or more halogens.

[0165] In some embodiments, R 2 The heterocyclic base ring is optionally separated by one or more C 1-3 -alkyl-carbonylamino-C 1-3 -alkyl substitution, wherein the C 1-3 -alkyl-carbonylamino-C 1-3 -Alkyl groups can be further substituted with one or more halogens.

[0166] In some embodiments, R 2 The heterocyclic base ring is optionally separated by one or more C 1-3 -alkylsulfonyl-C 1-3 -alkyl substitution, wherein the C 1-3 -alkylsulfonyl-C 1-3 -Alkyl groups can be further substituted with one or more halogens.

[0167] In some embodiments, R 2 The heterocyclic ring is optionally substituted by one or more substituents independently selected from the group consisting of: phenyl, tolyl, C 1-3 -alkoxyphenyl, phenyl-C 1-3 -alkyl and C 1-3 -alkoxyphenyl-C 1-3 -alkyl, wherein the phenyl, tolyl, phenyl-C 1-3 -alkyl and C 1-3 -alkoxyphenyl-C 1-3 -Alkyl groups can be further substituted with one or more halogens.

[0168] In some embodiments, R 2 The heterocyclic ring is optionally substituted by one or more substituents independently selected from the group consisting of: aziridine, pyrrolidinyl, piperidinyl, and morpholinyl, wherein the aziridine, pyrrolidinyl, piperidinyl, and morpholinyl may be further substituted by one or more halogens.

[0169] In some embodiments, R 2 The heterocyclic ring is optionally substituted by one or more substituents independently selected from the group consisting of tetrahydrofuranyl, tetrahydropyranyl, and tetrahydrooxoheptanyl, wherein the tetrahydrofuranyl, tetrahydropyranyl, and tetrahydrooxoheptanyl may be further substituted by one or more halogens.

[0170] In some embodiments, R 2The heterocyclic ring may optionally be substituted by one or more substituents independently selected from the group consisting of: fluorine, hydroxyl, oxo, methyl, ethyl, propyl, isopropyl, cyclopropyl, fluoromethyl, difluoromethyl, trifluoromethyl, fluoroethyl, difluoroethyl, trifluoroethyl, difluoropropyl, trifluoropropyl, methoxy, ethoxy, isopropoxy, difluoromethoxy, trifluoromethoxy, methoxymethyl, trifluoromethoxymethyl, methylcarbonylaminomethyl, methylsulfonylmethyl, morpholino, and tetrahydropyranyl.

[0171] In some embodiments, R 2 The heterocyclic ring may optionally be substituted by one or more substituents independently selected from the group consisting of: fluorine, hydroxyl, methyl, fluoromethyl, difluoromethyl, trifluoromethyl, difluoroethyl, difluoropropyl, cyclopropyl, methoxy, trifluoromethoxy, ethoxy, and methoxymethyl.

[0172] In some embodiments, R 2 The heterocyclic base ring is:

[0173]

[0174] Where R 2 The heterocyclic ring is optionally substituted by one or more substituents independently selected from the group consisting of: halogen, hydroxyl, C. 1-6 -alkyl, C 3-6 -cycloalkyl, C 1-6 -alkoxy group, C 1-3 -alkoxy-C 1-3 -alkyl, C 1-3 -alkyl-carbonylamino-C 1-3 -alkyl, C 1-3 -alkylsulfonyl-C 1-3 -alkyl, phenyl, tolyl, C 1-3 -alkoxyphenyl, phenyl-C 1-3 -alkyl and morpholino, and wherein the C 1-6 -alkyl, C 3-6 -cycloalkyl, C 1-6 -alkoxy group, C 1-3 -alkoxy-C 1-3 -alkyl, C 1-3 -alkyl-carbonylamino-C 1-3 -alkyl, C 1-3 -alkylsulfonyl-C 1-3 -alkyl, phenyl, tolyl, C 1-3 -alkoxyphenyl, phenyl-C 1-3 -The alkyl and morpholino groups can be further substituted with one or more halogens. In one aspect, R 2 The heterocyclic ring is optionally substituted by one or more substituents independently selected from the group consisting of: fluorine, hydroxyl, C.1-3 -alkyl, cyclopropyl, C 1-3 -alkoxy and C 1-3 -alkoxy-C 1-3 -alkyl, wherein the C 1-3 -alkyl, cyclopropyl, C 1-3 -alkoxy and C 1-3 -alkoxy-C 1-3 -alkyl groups can be further substituted with one or more fluorine molecules. In another aspect, R 2 The heterocyclic ring is optionally substituted by one or more substituents independently selected from the group consisting of: fluorine, hydroxyl, methyl, ethyl, propyl, isopropyl, fluoromethyl, difluoromethyl, trifluoromethyl, fluoroethyl, difluoroethyl, trifluoroethyl, difluoropropyl, trifluoropropyl, cyclopropyl, methoxy, ethoxy, difluoromethoxy, trifluoromethoxy, trifluoroethoxy, methoxymethyl, trifluoromethoxymethyl, methylamidomethyl, methanesulfonylmethyl, and morpholino. In another aspect, R 2 The heterocyclic ring is optionally substituted by one or more substituents independently selected from the group consisting of: fluorine, hydroxyl, methyl, ethyl, cyclopropyl, fluoromethyl, difluoromethyl, trifluoromethyl, difluoroethyl, trifluoroethyl, difluoropropyl, trifluoropropyl, methoxy, ethoxy, trifluoromethoxy, trifluoromethoxymethyl, methoxymethyl, methylamidomethyl, and morpholino.

[0175] In some embodiments, the compound and pharmaceutically acceptable salt are selected from the group consisting of:

[0176] (R)-N-(2-(4-cyanothiazolidine-3-yl)-2-oxoethyl)-6-(2,2-dimethylazacyclobutane-1-yl)-quinoline-4-carboxamide (Example 20);

[0177] (R)-N-(2-(4-cyanothiazolidine-3-yl)-2-oxoethyl)-6-(3-fluorozahexacyclobutan-1-yl)quinoline-4-carboxamide (Example 21);

[0178] (R)-N-(2-(4-cyanothiazolidine-3-yl)-2-oxoethyl)-6-(3,3-dimethylazacyclobutane-1-yl)-quinoline-4-carboxamide (Example 22);

[0179] (R)-N-(2-(4-cyanothiazolidine-3-yl)-2-oxoethyl)-6-(3,3-difluorozahexacyclobutane-1-yl)-quinoline-4-carboxamide (Example 23);

[0180] (R)-N-(2-(4-cyanothiazolidine-3-yl)-2-oxoethyl)-6-(3-fluoro-3-methylazacyclobutane-1-yl)-quinoline-4-carboxamide (Example 24);

[0181] (R)-N-(2-(4-cyanothiazolidine-3-yl)-2-oxoethyl)-6-(3-methylazacyclobutane-1-yl)quinoline-4-carboxamide (Example 25);

[0182] (R)-N-(2-(4-cyanothiazolidine-3-yl)-2-oxoethyl)-6-(3-(trifluoromethyl)azacyclobutane-1-yl)-quinoline-4-carboxamide (Example 26);

[0183] (R)-N-(2-(4-cyanothiazolidine-3-yl)-2-oxoethyl)-6-(3-(fluoromethyl)-3-methylazacyclobutane-1-yl)quinoline-4-carboxamide (Example 27);

[0184] (R)-N-(2-(4-cyanothiazolidine-3-yl)-2-oxoethyl)-6-(3-(difluoromethyl)azacyclobutane-1-yl)-quinoline-4-carboxamide (Example 28);

[0185] (R)-N-(2-(4-cyanothiazolidine-3-yl)-2-oxoethyl)-6-(3-(methoxymethyl)-3-methyl-azacyclobutane-1-yl)quinoline-4-carboxamide (Example 29);

[0186] N-(2-((R)-4-cyanothiazolidine-3-yl)-2-oxoethyl)-6-((2S,3R)-3-methoxy-2-methyl-azacyclobutane-1-yl)quinoline-4-carboxamide (Example 30);

[0187] (R)-N-(2-(4-cyanothiazolidine-3-yl)-2-oxoethyl)-6-(3-cyclopropyl-3-fluorozahexacyclobutane-1-yl)quinoline-4-carboxamide (Example 31);

[0188] (R)-N-(2-(4-cyanothiazolidine-3-yl)-2-oxoethyl)-6-(3-methoxyazacyclobutane-1-yl)quinoline-4-carboxamide (Example 66);

[0189] (R)-N-(2-(4-cyanothiazolidine-3-yl)-2-oxoethyl)-6-(3-(fluoromethyl)azacyclobutane-1-yl)-quinoline-4-carboxamide (Example 113);

[0190] (R)-N-(2-(4-cyanothiazolidine-3-yl)-2-oxoethyl)-6-(3-morpholinoazonicyclobutane-1-yl)-quinoline-4-carboxamide (Example 122);

[0191] (R)-N-(2-(4-cyanothiazolidine-3-yl)-2-oxoethyl)-6-(3-((trifluoromethoxy)methyl)-azacyclobutane-1-yl)quinoline-4-carboxamide (Example 130);

[0192] (R)-N-(2-(4-cyanothiazolidine-3-yl)-2-oxoethyl)-6-(3-methyl-3-(2,2,2-trifluoroethyl)-azacyclobutane-1-yl)quinoline-4-carboxamide (Example 131);

[0193] (R)-N-(2-(4-cyanothiazolidine-3-yl)-2-oxoethyl)-6-(3-(trifluoromethoxy)azacyclobutane-1-yl)quinoline-4-carboxamide (Example 132);

[0194] (R)-N-(2-(4-cyanothiazolidine-3-yl)-2-oxoethyl)-6-(3-(2,2-difluoroethyl)-3-methyl-azacyclobutane-1-yl)quinoline-4-carboxamide (Example 133);

[0195] (R)-N-(2-(4-cyanothiazolidine-3-yl)-2-oxoethyl)-6-(3-cyclopropyl-3-methylazacyclobutane-1-yl)quinoline-4-carboxamide (Example 134);

[0196] (R)-N-(2-(4-cyanothiazolidine-3-yl)-2-oxoethyl)-6-(3-(difluoromethyl)-3-methyl-azacyclobutane-1-yl)quinoline-4-carboxamide (Example 135);

[0197] (R)-N-(2-(4-cyanothiazolidine-3-yl)-2-oxoethyl)-6-(3-(difluoromethoxy)azacyclobutane-1-yl)quinoline-4-carboxamide (Example 136);

[0198] (R)-N-(2-(4-cyanothiazolidine-3-yl)-2-oxoethyl)-6-(3-ethyl-3-methylazacyclobutane-1-yl)-quinoline-4-carboxamide (Example 137);

[0199] (R)-N-(2-(4-cyanothiazolidine-3-yl)-2-oxoethyl)-6-(3-ethyl-3-fluorozahexacyclobutane-1-yl)-quinoline-4-carboxamide (Example 138);

[0200] (R)-N-(2-(4-cyanothiazolidine-3-yl)-2-oxoethyl)-6-(3-(2,2-difluoropropyl)azacyclobutane-1-yl)quinoline-4-carboxamide (Example 140);

[0201] (R)-N-(2-(4-cyanothiazolidine-3-yl)-2-oxoethyl)-6-(3-(3,3,3-trifluoropropyl)azacyclobutane-1-yl)quinoline-4-carboxamide (Example 142);

[0202] (R)-N-(2-(4-cyanothiazolidine-3-yl)-2-oxoethyl)-6-(3-fluoro-3-(trifluoromethyl)-azacyclobutane-1-yl)quinoline-4-carboxamide (Example 143);

[0203] (R)-N-(2-(4-cyanothiazolidine-3-yl)-2-oxoethyl)-6-(3-(2,2-difluoroethyl)azacyclobutane-1-yl]-quinoline-4-carboxamide (Example 144);

[0204] (R)-N-(2-(4-cyanothiazolidine-3-yl)-2-oxoethyl)-6-(3-cyclopropylazacyclobutane-1-yl)-quinoline-4-carboxamide (Example 145);

[0205] (R)-N-(2-(4-cyanothiazolidine-3-yl)-2-oxoethyl)-6-(3-(2-fluoroethyl)azacyclobutane-1-yl)-quinoline-4-carboxamide (Example 146);

[0206] (R)-N-(2-(4-cyanothiazolidine-3-yl)-2-oxoethyl)-6-(3-(1,1-difluoroethyl)azacyclobutane-1-yl)-quinoline-4-carboxamide (Example 147);

[0207] (R)-N-(2-(4-cyanothiazolidine-3-yl)-2-oxoethyl)-6-(3-isopropylazacyclobutane-1-yl)quinoline-4-carboxamide (Example 148);

[0208] (R)-N-(2-(4-cyanothiazolidine-3-yl)-2-oxoethyl)-6-(3-methoxy-3-methylazacyclobutane-1-yl)-quinoline-4-carboxamide (Example 151);

[0209] (R)-N-(2-(4-cyanothiazolidine-3-yl)-2-oxoethyl)-6-(3-ethoxy-3-methylazacyclobutane-1-yl)-quinoline-4-carboxamide (Example 152);

[0210] (R)-N-(2-(4-cyanothiazolidine-3-yl)-2-oxoethyl)-6-(3-ethyl-3-hydroxyazacyclobutane-1-yl)-quinoline-4-carboxamide (Example 154);

[0211] (R)-N-(2-(4-cyanothiazolidine-3-yl)-2-oxoethyl)-6-(3-fluoro-3-(fluoromethyl)azacyclobutane-1-yl)quinoline-4-carboxamide (Example 157);

[0212] (R)-N-(2-(4-cyanothiazolidine-3-yl)-2-oxoethyl)-6-(3-(2,2,2-trifluoroethyl)azacyclobutane-1-yl)quinoline-4-carboxamide (Example 158);

[0213] N-(2-((R)-4-cyanothiazolidine-3-yl)-2-oxoethyl)-6-(3,3-difluoro-2-methylazacyclobutane-1-yl)quinoline-4-carboxamide (Example 159);

[0214] (R)-N-(2-(4-cyanothiazolidine-3-yl)-2-oxoethyl)-6-(3-hydroxy-3-methylazacyclobutane-1-yl)-quinoline-4-carboxamide (Example 165);

[0215] (R)-6-(3-(acetamidomethyl)-3-methylazacyclobutane-1-yl)-N-(2-(4-cyanothiazolidine-3-yl)-2-oxoethyl)quinoline-4-carboxamide (Example 181);

[0216] (R)-N-(2-(4-cyanothiazolidine-3-yl)-2-oxoethyl)-6-(3-fluoro-3-phenylazacyclobutane-1-yl)-quinoline-4-carboxamide (Example 182);

[0217] (R)-N-(2-(4-cyanothiazolidine-3-yl)-2-oxoethyl)-6-(3-(p-tolyl)azacyclobutane-1-yl)quinoline-4-carboxamide (Example 183);

[0218] (R)-N-(2-(4-cyanothiazolidine-3-yl)-2-oxoethyl)-6-(3-(4-fluorophenyl)azacyclobutane-1-yl)-quinoline-4-carboxamide (Example 185);

[0219] (R)-N-(2-(4-cyanothiazolidine-3-yl)-2-oxoethyl)-6-(3-(m-tolyl)azacyclobutane-1-yl)quinoline-4-carboxamide (Example 186);

[0220] (R)-6-(3-(4-chlorobenzyl)azacyclobutane-1-yl)-N-(2-(4-cyanothiazolidine-3-yl)-2-oxoethyl)-quinoline-4-carboxamide (Example 187);

[0221] (R)-N-(2-(4-cyanothiazolidine-3-yl)-2-oxoethyl)-6-(3-methyl-3-((methanesulfonyl)-methyl)azacyclobutane-1-yl)quinoline-4-carboxamide (Example 188);

[0222] And its pharmaceutically acceptable salts.

[0223] In some embodiments, the compound and pharmaceutically acceptable salt are selected from the group consisting of:

[0224] (R)-N-(2-(4-cyanothiazolidine-3-yl)-2-oxoethyl)-6-(3,3-dimethylazacyclobutane-1-yl-1-quinoline-4-carboxamide (Example 22);

[0225] (R)-N-(2-(4-cyanothiazolidine-3-yl)-2-oxoethyl)-6-(3-fluoro-3-methylazacyclobutane-1-yl)-quinoline-4-carboxamide (Example 24);

[0226] (R)-N-(2-(4-cyanothiazolidine-3-yl)-2-oxoethyl)-6-(3-(fluoromethyl)-3-methylazacyclobutane-1-yl)quinoline-4-carboxamide (Example 27);

[0227] (R)-N-(2-(4-cyanothiazolidine-3-yl)-2-oxoethyl)-6-(3-(difluoromethyl)azacyclobutane-1-yl)-quinoline-4-carboxamide (Example 28);

[0228] (R)-N-(2-(4-cyanothiazolidine-3-yl)-2-oxoethyl)-6-(3-(methoxymethyl)-3-methyl-azacyclobutane-1-yl)quinoline-4-carboxamide (Example 29);

[0229] N-(2-((R)-4-cyanothiazolidine-3-yl)-2-oxoethyl)-6-((2S,3R)-3-methoxy-2-methyl-azacyclobutane-1-yl)quinoline-4-carboxamide (Example 30);

[0230] (R)-N-(2-(4-cyanothiazolidine-3-yl)-2-oxoethyl)-6-(3-cyclopropyl-3-fluorozahexacyclobutane-1-yl)quinoline-4-carboxamide (Example 31);

[0231] (R)-N-(2-(4-cyanothiazolidine-3-yl)-2-oxoethyl)-6-(3-methoxyazacyclobutane-1-yl)quinoline-4-carboxamide (Example 66);

[0232] (R)-N-(2-(4-cyanothiazolidine-3-yl)-2-oxoethyl)-6-(3-(fluoromethyl)azacyclobutane-1-yl)-quinoline-4-carboxamide (Example 113);

[0233] (R)-N-(2-(4-cyanothiazolidine-3-yl)-2-oxoethyl)-6-(3-(difluoromethyl)-3-methyl-azacyclobutane-1-yl)quinoline-4-carboxamide (Example 135);

[0234] (R)-N-(2-(4-cyanothiazolidine-3-yl)-2-oxoethyl)-6-(3-ethyl-3-fluorozahexacyclobutane-1-yl)-quinoline-4-carboxamide (Example 138);

[0235] (R)-N-(2-(4-cyanothiazolidine-3-yl)-2-oxoethyl)-6-(3-(2,2-difluoropropyl)azacyclobutane-1-yl)quinoline-4-carboxamide (Example 140);

[0236] (R)-N-(2-(4-cyanothiazolidine-3-yl)-2-oxoethyl)-6-(3-fluoro-3-(trifluoromethyl)-azacyclobutane-1-yl)quinoline-4-carboxamide (Example 143);

[0237] (R)-N-(2-(4-cyanothiazolidine-3-yl)-2-oxoethyl)-6-(3-(1,1-difluoroethyl)azacyclobutane-1-yl)-quinoline-4-carboxamide (Example 147);

[0238] (R)-N-(2-(4-cyanothiazolidine-3-yl)-2-oxoethyl)-6-(3-methoxy-3-methylazacyclobutane-1-yl)-quinoline-4-carboxamide (Example 151);

[0239] (R)-N-(2-(4-cyanothiazolidine-3-yl)-2-oxoethyl)-6-(3-ethoxy-3-methylazacyclobutane-1-yl)-quinoline-4-carboxamide (Example 152);

[0240] (R)-N-(2-(4-cyanothiazolidine-3-yl)-2-oxoethyl)-6-(3-fluoro-3-(fluoromethyl)azacyclobutane-1-yl)quinoline-4-carboxamide (Example 157);

[0241] (R)-N-(2-(4-cyanothiazolidine-3-yl)-2-oxoethyl)-6-(3-hydroxy-3-methylazacyclobutane-1-yl)-quinoline-4-carboxamide (Example 165);

[0242] And its pharmaceutically acceptable salts.

[0243] In some embodiments, R 2 The heterocyclic base ring is:

[0244]

[0245] Where R 2 The heterocyclic ring may optionally be substituted by one or more substituents independently selected from the group consisting of: halogen, hydroxyl, oxo, C. 1-6 -alkyl, hydroxy-C 1-3 -alkyl, C 3-6 -cycloalkyl, C 1-6 -alkoxy and C 1-3 -alkoxy-C 1-3 -alkyl, wherein the C 1-6 -alkyl, hydroxy-C 1-3 -alkyl, C 3-6 -cycloalkyl, C 1-6 -alkoxy and C 1-3 -alkoxy-C 1-3 -Alkyl groups can be further substituted with one or more halogens. In one aspect, R 2 The heterocyclic ring is optionally substituted by one or more substituents independently selected from the group consisting of: fluorine, hydroxyl, C. 1-3 -alkyl, hydroxy-C 1-3 -alkyl, cyclopropyl, C 1-3 -alkoxy and C 1-3 -alkoxy-C 1-3 -alkyl, wherein the C 1-3 -alkyl, hydroxy-C 1-3 -alkyl, cyclopropyl, C 1-3 -alkoxy and C 1-3 -alkoxy-C 1-3 -alkyl groups can be further substituted with one or more fluorine molecules. In another aspect, R 2 The heterocyclic ring is optionally substituted by one or more substituents independently selected from the group consisting of: fluorine, hydroxyl, methyl, ethyl, propyl, fluoromethyl, difluoromethyl, trifluoromethyl, fluoroethyl, difluoroethyl, trifluoroethyl, difluoropropyl, hydroxymethyl, cyclopropyl, methoxy, ethoxy, trifluoromethoxy, trifluoroethoxy, methoxymethyl, and trifluoromethoxymethyl. In another aspect, R 2 The heterocyclic ring may optionally be substituted by one or more substituents independently selected from the group consisting of: fluorine, hydroxyl, methyl, ethyl, fluoromethyl, hydroxymethyl, methoxy, and trifluoromethoxy.

[0246] In some embodiments, the compound and pharmaceutically acceptable salt are selected from the group consisting of:

[0247] (R)-N-(2-(4-cyanothiazolidine-3-yl)-2-oxoethyl)-6-(3,3-difluoropyrrolidine-1-yl)-quinoline-4-carboxamide (Example 47);

[0248] (R)-N-(2-(4-cyanothiazolidine-3-yl)-2-oxoethyl)-6-(3,3-dimethylpyrrolidine-1-yl)-quinoline-4-carboxamide (Example 48);

[0249] N-(2-((R)-4-cyanothiazolidine-3-yl)-2-oxoethyl)-6-((3R,4S)-3,4-difluoropyrrolidine-1-yl)-quinoline-4-carboxamide (Example 50);

[0250] N-(2-((R)-4-cyanothiazolidine-3-yl)-2-oxoethyl)-6-((S)-3-fluoropyrrolidine-1-yl)-quinoline-4-carboxamide (Example 51);

[0251] N-(2-((R)-4-cyanothiazolidine-3-yl)-2-oxoethyl)-6-((R)-3-fluoropyrrolidine-1-yl)-quinoline-4-carboxamide (Example 52);

[0252] N-(2-((R)-4-cyanothiazolidine-3-yl)-2-oxoethyl)-6-((S)-3-methylpyrrolidine-1-yl)-quinoline-4-carboxamide (Example 54);

[0253] N-(2-((R)-4-cyanothiazolidine-3-yl)-2-oxoethyl)-6-((R)-3-methylpyrrolidine-1-yl)-quinoline-4-carboxamide (Example 55);

[0254] N-(2-((R)-4-cyanothiazolidine-3-yl)-2-oxoethyl)-6-((S)-2-(trifluoromethyl)pyrrolidine-1-yl)quinoline-4-carboxamide (Example 56);

[0255] (R)-N-(2-(4-cyanothiazolidine-3-yl)-2-oxoethyl)-6-(2,2-dimethylpyrrolidine-1-yl)-quinoline-4-carboxamide (Example 57);

[0256] N-(2-((R)-4-cyanothiazolidine-3-yl)-2-oxoethyl)-6-((S)-2-methylpyrrolidine-1-yl)-quinoline-4-carboxamide (Example 65);

[0257] N-(2-((R)-4-cyanothiazolidine-3-yl)-2-oxoethyl)-6-((R)-3-methoxypyrrolidine-1-yl)-quinoline-4-carboxamide (Example 161);

[0258] N-(2-((R)-4-cyanothiazolidine-3-yl)-2-oxoethyl)-6-((R)-3-hydroxy-3-methylpyrrolidine-1-yl)quinoline-4-carboxamide (Example 167);

[0259] N-(2-((R)-4-cyanothiazolidine-3-yl)-2-oxoethyl)-6-((S)-3-hydroxy-3-methylpyrrolidine-1-yl)quinoline-4-carboxamide (Example 168);

[0260] N-(2-((R)-4-cyanothiazolidine-3-yl)-2-oxoethyl)-6-((RS)-3-fluoro-3-methylpyrrolidine-1-yl)quinoline-4-carboxamide (Example 198);

[0261] N-(2-((R)-4-cyanothiazolidine-3-yl)-2-oxoethyl)-6-((R*)-2-cyclopropylpyrrolidine-1-yl)quinoline-4-carboxamide isomer 1 (Example 199);

[0262] N-(2-((R)-4-cyanothiazolidine-3-yl)-2-oxoethyl)-6-((R*)-2-cyclopropylpyrrolidine-1-yl)quinoline-4-carboxamide isomer 2 (Example 200);

[0263] N-(2-((R)-4-cyanothiazolidine-3-yl)-2-oxoethyl)-6-((S)-3-methoxypyrrolidine-1-yl)-quinoline-4-carboxamide (Example 207);

[0264] N-(2-((R)-4-cyanothiazolidine-3-yl)-2-oxoethyl)-6-((R)-2-methylpyrrolidine-1-yl)-quinoline-4-carboxamide (Example 211);

[0265] N-(2-((R)-4-cyanothiazolidine-3-yl)-2-oxoethyl)-6-((S)-2-(methoxymethyl)pyrrolidine-1-yl)quinoline-4-carboxamide (Example 212);

[0266] N-(2-((R)-4-cyanothiazolidine-3-yl)-2-oxoethyl)-6-((3S,4S)-3,4-difluoropyrrolidine-1-yl)quinoline-4-carboxamide (Example 213):

[0267] N-(2-((R)-4-cyanothiazolidine-3-yl)-2-oxoethyl)-6-((3R,4R)-3,4-difluoropyrrolidine-1-yl)quinoline-4-carboxamide (Example 214);

[0268] N-(2-((R)-4-cyanothiazolidine-3-yl)-2-oxoethyl)-6-((R)-3-(hydroxymethyl)pyrrolidine-1-yl)quinoline-4-carboxamide (Example 220);

[0269] N-(2-((R)-4-cyanothiazolidine-3-yl)-2-oxoethyl)-6-((S)-3-(hydroxymethyl)pyrrolidine-1-yl)quinoline-4-carboxamide (Example 221):

[0270] N-(2-((R)-4-cyanothiazolidine-3-yl)-2-oxoethyl)-6-((RS)-3,3-difluoro-4-hydroxy-pyrrolidine-1-yl)quinoline-4-carboxamide (Example 224);

[0271] N-(2-((R)-4-cyanothiazolidine-3-yl)-2-oxoethyl)-6-((3R*,4R*)-3,4-dimethylpyrrolidine-1-yl)quinoline-4-carboxamide isomer 1 (Example 225);

[0272] N-(2-((R)-4-cyanothiazolidine-3-yl)-2-oxoethyl)-6-((3R*,4R*)-3,4-dimethylpyrrolidine-1-yl)quinoline-4-carboxamide isomer 2 (Example 226);

[0273] And its pharmaceutically acceptable salts.

[0274] In some embodiments, R 2 The heterocyclic base ring is:

[0275]

[0276] Where R 2 The heterocyclic ring is optionally substituted by one or more substituents independently selected from the group consisting of: halogen, hydroxyl, C. 1-6 -alkyl, C 3-6 -cycloalkyl, C 1-6 -alkoxy and C 1-3 -alkoxy-C 1-3 -alkyl, and wherein the C 1-6 -alkyl, C 3-6 -cycloalkyl, C 1-6 -alkoxy and C 1-3 -alkoxy-C 1-3 -Alkyl groups can be further substituted with one or more halogens. In one aspect, R 2 The heterocyclic ring is optionally substituted by one or more substituents independently selected from the group consisting of: fluorine, hydroxyl, C. 1-3 -alkyl, cyclopropyl, C 1-3 -alkoxy and C1-3 -alkoxy-C 1-3 -alkyl, wherein the C 1-3 -alkyl, cyclopropyl, C 1-3 -alkoxy and C 1-3 -alkoxy-C 1-3 -alkyl groups can be further substituted with one or more fluorine molecules. In another aspect, R 2 The heterocyclic ring is optionally substituted by one or more substituents independently selected from the group consisting of: fluorine, hydroxyl, methyl, ethyl, fluoromethyl, difluoromethyl, trifluoromethyl, fluoroethyl, difluoroethyl, trifluoroethyl, difluoropropyl, cyclopropyl, methoxy, ethoxy, trifluoromethoxy, trifluoroethoxy, methoxymethyl, and trifluoromethoxymethyl. In another aspect, R 2 The heterocyclic ring may optionally be substituted by one or more substituents independently selected from the group consisting of: fluorine, hydroxyl, methyl, ethyl, fluoromethyl, methoxy, and trifluoromethoxy.

[0277] In some embodiments, the compound and pharmaceutically acceptable salt are selected from the group consisting of:

[0278] (R)-N-(2-(4-cyanothiazolidine-3-yl)-2-oxoethyl)-6-(2-oxopyrrolidine-1-yl)quinoline-4-carboxamide (Example 11);

[0279] (R)-N-(2-(4-cyanothiazolidine-3-yl)-2-oxoethyl)-6-(3,3-dimethyl-2-oxopyrrolidine-1-yl)quinoline-4-carboxamide (Example 12);

[0280] N-(2-((R)-4-cyanothiazolidine-3-yl)-2-oxoethyl)-6-((R*)-3-methyl-2-oxopyrrolidine-1-yl)quinoline-4-carboxamide isomer 1 (Example 201);

[0281] N-(2-((R)-4-cyanothiazolidine-3-yl)-2-oxoethyl)-6-((R*)-3-methyl-2-oxopyrrolidine-1-yl)quinoline-4-carboxamide isomer 2 (Example 202);

[0282] And its pharmaceutically acceptable salts.

[0283] In some embodiments, R 2 The heterocyclic base ring is:

[0284]

[0285] Where R 2 The heterocyclic ring is optionally substituted by one or more substituents independently selected from the group consisting of: halogen, hydroxyl, C.1-6 -alkyl, hydroxy-C 1-3 -alkyl, C 3-6 -cycloalkyl, C 3-6 -cycloalkyl-C 1-3 -alkyl, C 1-6 -alkoxy group, C 1-3 -alkoxy-C 1-3 -alkyl, C 1-3 -alkoxy-C 2-3 -alkoxy group, C 1-3 -alkoxy-C 2-3 -alkoxy-C 1-3 -alkyl, C 1-3 -alkyl-carbonylamino-C 1-3 -alkyl, C 1-3 -alkylsulfonyl-C 1-3 -alkyl, phenyl, tetrahydrofuranyl, tetrahydropyranyl and tetrahydrooxetaneheptyl, wherein the C 1-6 -alkyl, hydroxy-C 1-3 -alkyl, C 3-6 -cycloalkyl, C 3-6 -cycloalkyl-C 1-3 -alkyl, C 1-6 -alkoxy group, C 1-3 -alkoxy-C 1-3 -alkyl, C 1-3 -alkoxy-C 2-3 -alkoxy group, C 1-3 -alkoxy-C 2-3 -alkoxy-C 1-3 -alkyl, C 1-3 -alkyl-carbonylamino-C 1-3 -alkyl, C 1-3 -alkylsulfonyl-C 1-3 -alkyl, phenyl, tetrahydrofuranyl, tetrahydropyranyl, and tetrahydrooxetaneheptyl groups can be further substituted with one or more halogens. In one aspect, R 2 The heterocyclic ring is optionally substituted by one or more substituents independently selected from the group consisting of: halogen, hydroxyl, C. 1-3 -alkyl, C 3-6 -cycloalkyl, cyclopropyl-C 1-3 -alkyl, C 1-3 -alkoxy group, C 1-3 -alkoxy-C 1-3 -alkyl, tetrahydrofuranyl, tetrahydropyranyl, and tetrahydrooxocyclic heptyl, wherein the C 1-3 -alkyl, C 3-6 -cycloalkyl, cyclopropyl-C 1-3 -alkyl, C 1-3 -alkoxy group, C1-3 -alkoxy-C 1-3 -alkyl and tetrahydropyranyl groups can be further substituted with one or more halogens. In another aspect, R 2 The heterocyclic ring is optionally substituted by one or more substituents independently selected from the group consisting of: fluorine, methyl, ethyl, propyl, fluoromethyl, difluoromethyl, trifluoromethyl, fluoroethyl, difluoroethyl, trifluoroethyl, difluoropropyl, cyclopropyl, cyclopropylmethyl, methoxy, ethoxy, trifluoromethoxy, trifluoroethoxy, methoxymethyl, trifluoromethoxymethyl, and tetrahydropyranyl. In another aspect, R 2 The heterocyclic ring may optionally be substituted by one or more substituents independently selected from the group consisting of: methyl, ethyl, propyl, fluoromethyl, difluoromethyl, trifluoromethyl, fluoroethyl, difluoroethyl, trifluoroethyl, difluoropropyl, cyclopropyl, and tetrahydropyranyl.

[0286] In some embodiments, the compound and pharmaceutically acceptable salt are selected from the group consisting of:

[0287] (R)-N-(2-(4-cyanothiazolidine-3-yl)-2-oxoethyl)-6-(1-methyl-1H-pyrazol-4-yl)-quinoline-4-carboxamide (Example 129);

[0288] (R)-N-(2-(4-cyanothiazolidine-3-yl)-2-oxoethyl)-6-(1-cyclopropyl-1H-pyrazol-4-yl)-quinoline-4-carboxamide (Example 170);

[0289] (R)-N-(2-(4-cyanothiazolidine-3-yl)-2-oxoethyl)-6-(1,3-dimethyl-1H-pyrazol-4-yl)-quinoline-4-carboxamide (Example 171);

[0290] (R)-N-(2-(4-cyanothiazolidine-3-yl)-2-oxoethyl)-6-(3,5-dimethyl-1-(tetrahydro-2H-pyran-4-yl)-1H-pyrazol-4-yl)quinoline-4-carboxamide (Example 172);

[0291] (R)-N-(2-(4-cyanothiazolidine-3-yl)-2-oxoethyl)-6-(1-(tetrahydro-2H-pyran-4-yl)-1H-pyrazol-4-yl)quinoline-4-carboxamide (Example 173);

[0292] And its pharmaceutically acceptable salts.

[0293] In some embodiments, R 2 The heterocyclic base ring is:

[0294]

[0295] Where R 2 The heterocyclic ring is optionally substituted by one or more substituents independently selected from the group consisting of: halogen, hydroxyl, C. 1-6 -alkyl, C 3-6 -cycloalkyl, C 3-6 -cycloalkyl C 1-3 -alkyl, C 1-6 -alkoxy group, C 1-3 -alkoxy-C 1-3 -alkyl, C 1-3 -alkoxy-C 2-3 -alkoxy group, C 1-3 -alkoxy-C 2-3 -alkoxy-C 1-3 -alkyl, C 1-3 -alkylsulfonyl-C 1-3 -alkyl, phenyl, tetrahydrofuranyl, tetrahydropyranyl and tetrahydrooxetaneheptyl, wherein the C 1-6 -alkyl, C 3-6 -cycloalkyl, C 3-6 -cycloalkyl C 1-3 -alkyl, C 1-6 -alkoxy group, C 1-3 -alkoxy-C 1-3 -alkyl, C 1-3 -alkoxy-C 2-3 -alkoxy group, C 1-3 -alkoxy-C 2-3 -alkoxy-C 1-3 -alkyl, C 1-3 -alkylsulfonyl-C 1-3 -alkyl, phenyl, tetrahydrofuranyl, tetrahydropyranyl, and tetrahydrooxetaneheptyl groups can be further substituted with one or more halogens. In one aspect, R 2 The heterocyclic ring is optionally substituted by one or more substituents independently selected from the group consisting of: halogen, hydroxyl, C. 1-3 -alkyl, C 3-6 -cycloalkyl, cyclopropyl-C 1-3 -alkyl, C 1-3 -alkoxy group, C 1-3 -alkoxy-C 1-3 -alkyl, tetrahydrofuranyl, tetrahydropyranyl, and tetrahydrooxocyclic heptyl, wherein the C 1-3 -alkyl, C 3-6 -cycloalkyl, cyclopropyl-C 1-3 -alkyl, C 1-3 -alkoxy group, C 1-3 -alkoxy-C 1-3 -alkyl and tetrahydropyranyl groups can be further substituted with one or more halogens. In another aspect, R2 The heterocyclic ring is optionally substituted by one or more substituents independently selected from the group consisting of: fluorine, methyl, ethyl, propyl, isopropyl, fluoromethyl, difluoromethyl, trifluoromethyl, fluoroethyl, difluoroethyl, trifluoroethyl, difluoropropyl, cyclopropyl, methoxy, ethoxy, trifluoromethoxy, trifluoroethoxy, methoxymethyl, trifluoromethoxymethyl, and tetrahydropyranyl. In another aspect, R 2 The heterocyclic ring may optionally be substituted by one or more substituents independently selected from the group consisting of: methyl, ethyl, propyl, isopropyl, fluoromethyl, difluoromethyl, trifluoromethyl, fluoroethyl, difluoroethyl, trifluoroethyl, difluoropropyl, cyclopropyl, and tetrahydropyranyl.

[0296] In some embodiments, the compound and pharmaceutically acceptable salt are selected from the group consisting of:

[0297] (R)-N-(2-(4-cyanothiazolidine-3-yl)-2-oxoethyl)-6-(1-methyl-1H-pyrazol-5-yl)-quinoline-4-carboxamide (Example 174);

[0298] N-(2-((R)-4-cyanothiazolidine-3-yl)-2-oxoethyl)-6-(1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-5-yl)quinoline-4-carboxamide (Example 176);

[0299] (R)-N-(2-(4-cyanothiazolidine-3-yl)-2-oxoethyl)-6-(1H-pyrazol-5-yl)quinoline-4-carboxamide (Example 196);

[0300] (R)-N-(2-(4-cyanothiazolidine-3-yl)-2-oxoethyl)-6-(1-isopropyl-1H-pyrazol-5-yl)-quinoline-4-carboxamide (Example 197);

[0301] And its pharmaceutically acceptable salts.

[0302] In some embodiments, R 2 The heterocyclic base ring is:

[0303]

[0304] Where R 2 The heterocyclic ring may optionally be substituted by one or more substituents independently selected from the group consisting of: halogen, hydroxyl, oxo, C. 1-6 -alkyl, C 3-6 -cycloalkyl, C 3-6 -cycloalkyl-C 1-3 -alkyl, C 1-6 -alkoxy group, C 1-3 -alkoxy-C1-3 -alkyl, C 1-3 -alkoxy-C 2-3 -alkoxy group, C 1-3 -alkoxy-C 2-3 -alkoxy-C 1-3 -alkyl, phenyl, tolyl and C 1-3 -alkoxyphenyl, and wherein the C 1-6 -alkyl, C 3-6 -cycloalkyl, C 3-6 -cycloalkyl-C 1-3 -alkyl, C 1-6 -alkoxy group, C 1-3 -alkoxy-C 1-3 -alkyl, C 1-3 -alkoxy-C 2-3 -alkoxy group, C 1-3 -alkoxy-C 2-3 -alkoxy-C 1-3 -alkyl, phenyl, tolyl and C 1-3 -Alkoxyphenyl can be further substituted with one or more halogens. In one aspect, R 2 The heterocyclic ring is optionally substituted by one or more substituents independently selected from the group consisting of: fluorine, hydroxyl, C. 1-3 -alkyl, cyclopropyl, cyclopropyl-C 1-3 -alkyl, C 1-3 -alkoxy and C 1-3 -alkoxy-C 1-3 -alkyl, wherein the C 1-3 -alkyl, cyclopropyl, cyclopropyl-C 1-3 -alkyl, C 1-3 -alkoxy and C 1-3 -alkoxy-C 1-3 -alkyl groups can be further substituted with one or more fluorine molecules. In another aspect, R 2 The heterocyclic ring is optionally substituted by one or more substituents independently selected from the group consisting of: fluorine, hydroxyl, methyl, ethyl, propyl, isopropyl, fluoromethyl, difluoromethyl, trifluoromethyl, fluoroethyl, difluoroethyl, trifluoroethyl, cyclopropyl, cyclopropylmethyl, methoxy, ethoxy, propoxy, isopropoxy, trifluoromethoxy, trifluoroethoxy, methoxymethyl, and trifluoromethoxymethyl. In another aspect, R 2 The heterocyclic ring may optionally be substituted by one or more substituents independently selected from the group consisting of: fluorine, hydroxyl, methyl, ethyl, propyl, isopropyl, fluoromethyl, difluoromethyl, trifluoromethyl, fluoroethyl, difluoroethyl, trifluoroethyl, cyclopropyl, methoxy, ethoxy, propoxy, isopropoxy, trifluoromethoxy, and trifluoroethoxy.

[0305] In some embodiments, the compound and pharmaceutically acceptable salt are selected from the group consisting of:

[0306] N-(2-((R)-4-cyanothiazolidine-3-yl)-2-oxoethyl)-6-((3S,4S,5R)-4-hydroxy-3,5-dimethylpiperidin-1-yl)quinoline-4-carboxamide (Example 7);

[0307] (R)-N-(2-(4-cyanothiazolidine-3-yl)-2-oxoethyl)-6-(4-methoxypiperidin-1-yl)-quinoline-4-carboxamide (Example 8);

[0308] (R)-N-(2-(4-cyanothiazolidine-3-yl)-2-oxoethyl)-6-(piperidin-1-yl)quinoline-4-carboxamide (Example 32);

[0309] (R)-N-(2-(4-cyanothiazolidine-3-yl)-2-oxoethyl)-6-(4,4-dimethylpiperidin-1-yl)-quinoline-4-carboxamide (Example 33);

[0310] (R)-N-(2-(4-cyanothiazolidine-3-yl)-2-oxoethyl)-6-(4-fluoro-4-methylpiperidin-1-yl)quinoline-4-carboxamide (Example 34);

[0311] (R)-N-(2-(4-cyanothiazolidine-3-yl)-2-oxoethyl)-6-(4,4-difluoropiperidin-1-yl)-quinoline-4-carboxamide (Example 35);

[0312] (R)-N-(2-(4-cyanothiazolidine-3-yl)-2-oxoethyl)-6-(3,3-difluoropiperidin-1-yl)-quinoline-4-carboxamide (Example 36);

[0313] (R)-N-(2-(4-cyanothiazolidine-3-yl)-2-oxoethyl)-6-(4-(fluoromethyl)-4-methyl-piperidin-1-yl)quinoline-4-carboxamide (Example 37);

[0314] (R)-N-(2-(4-cyanothiazolidine-3-yl)-2-oxoethyl)-6-(4,4-difluoro-3,3-dimethyl-piperidin-1-yl)quinoline-4-carboxamide (Example 38);

[0315] (R)-N-(2-(4-cyanothiazolidine-3-yl)-2-oxoethyl)-6-(4-(trifluoromethyl)piperidin-1-yl)-quinoline-4-carboxamide (Example 39);

[0316] N-(2-((R)-4-cyanothiazolidine-3-yl)-2-oxoethyl)-6-(3-fluoropiperidin-1-yl)quinoline-4-carboxamide (Example 40);

[0317] N-(2-((R)-4-cyanothiazolidine-3-yl)-2-oxoethyl)-6-(3-methoxypiperidin-1-yl)-quinoline-4-carboxamide (Example 41);

[0318] (R)-N-(2-(4-cyanothiazolidine-3-yl)-2-oxoethyl)-6-(4-methoxy-4-methylpiperidin-1-yl)quinoline-4-carboxamide (Example 42);

[0319] (R)-N-(2-(4-cyanothiazolidine-3-yl)-2-oxoethyl)-6-(4-isopropoxypiperidin-1-yl)-quinoline-4-carboxamide (Example 43);

[0320] N-(2-((R)-4-cyanothiazolidine-3-yl)-2-oxoethyl)-6-(4,4-difluoro-2-methylpiperidin-1-yl)quinoline-4-carboxamide (Example 44);

[0321] N-(2-((R)-4-cyanothiazolidine-3-yl)-2-oxoethyl)-6-((S)-2-(fluoromethyl)piperidin-1-yl)quinoline-4-carboxamide (Example 45);

[0322] (R)-N-(2-(4-cyanothiazolidine-3-yl)-2-oxoethyl)-6-(4-ethyl-4-hydroxypiperidin-1-yl)quinoline-4-carboxamide (Example 189);

[0323] (R)-N-(2-(4-cyanothiazolidine-3-yl)-2-oxoethyl)-6-(4-hydroxy-4-methylpiperidin-1-yl)quinoline-4-carboxamide (Example 190);

[0324] (R)-N-(2-(4-cyanothiazolidine-3-yl)-2-oxoethyl)-6-(4-ethyl-4-methoxypiperidin-1-yl)-quinoline-4-carboxamide (Example 191);

[0325] (R)-N-(2-(4-cyanothiazolidine-3-yl)-2-oxoethyl)-6-(4-hydroxy-4-isopropylpiperidin-1-yl)quinoline-4-carboxamide (Example 192);

[0326] N-(2-((R)-4-cyanothiazolidine-3-yl)-2-oxoethyl)-6-((3R,4S,5S)-4-hydroxy-3,4,5-trimethylpiperidin-1-yl)quinoline-4-carboxamide (Example 193);

[0327] (R)-N-(2-(4-cyanothiazolidine-3-yl)-2-oxoethyl)-6-(4-fluoropiperidin-1-yl)quinoline-4-carboxamide (Example 205);

[0328] (R)-N-(2-(4-cyanothiazolidine-3-yl)-2-oxoethyl)-6-(4-fluoro-4-phenylpiperidin-1-yl)-quinoline-4-carboxamide (Example 223);

[0329] And its pharmaceutically acceptable salts.

[0330] In some embodiments, R 2 The heterocyclic base ring is:

[0331]

[0332] In some embodiments, the compound or pharmaceutically acceptable salt is (R)-N-(2-(4-cyanothiazolidine-3-yl)-2-oxoethyl)-6-(4-oxopiperidin-1-yl)quinoline-4-carboxamide (Example 230), or a pharmaceutically acceptable salt thereof.

[0333] In some embodiments, R 2 The heterocyclic base ring is:

[0334]

[0335] Where R 2 The heterocyclic ring may optionally be substituted by one or more substituents independently selected from the group consisting of: halogen, hydroxyl, oxo, C. 1-6 -alkyl, C 3-6 -cycloalkyl, C 3-6 -cycloalkyl-C 1-3 -alkyl, C 1-6 -alkoxy group, C 1-3 -alkoxy-C 1-3 -alkyl, C 1-3 -alkoxy-C 2-3 -alkoxy group, C 1-3 -alkoxy-C 2-3 -alkoxy-C 1-3 -alkyl, C 1-3 -alkyl carbonyl, C 3-6 -cycloalkyl carbonyl and phenyl, and wherein the C 1-6 -alkyl, C 3-6 -cycloalkyl, C 3-6 -cycloalkyl-C 1-3 -alkyl, C 1-6 -alkoxy group, C 1-3 -alkoxy-C 1-3-alkyl, C 1-3 -alkoxy-C 2-3 -alkoxy group, C 1-3 -alkoxy-C 2-3 -alkoxy-C 1-3 -alkyl, C 1-3 -alkyl carbonyl, C 3-6 -The cycloalkyl carbonyl group and phenyl group can be further substituted with one or more halogens. In one aspect, R 2 The heterocyclic ring is optionally substituted by one or more substituents independently selected from the group consisting of: fluorine, hydroxyl, oxo, C. 1-3 -alkyl, cyclopropyl, cyclopropyl-C 1-3 -alkyl, C 1-3 -alkoxy and C 1-3 -alkoxy-C 1-3 -alkyl, wherein the C 1-3 -alkyl, cyclopropyl, cyclopropyl-C 1-3 -alkyl, C 1-3 -alkoxy and C 1-3 -alkoxy-C 1-3 -alkyl groups can be further substituted with one or more fluorine molecules. In another aspect, R 2 The heterocyclic ring is optionally substituted by one or more substituents independently selected from the group consisting of: fluorine, hydroxyl, oxo, methyl, ethyl, isopropyl, propyl, fluoromethyl, difluoromethyl, trifluoromethyl, fluoroethyl, difluoroethyl, trifluoroethyl, cyclopropyl, cyclopropylmethyl, methoxy, ethoxy, propoxy, trifluoromethoxy, trifluoroethoxy, methoxymethyl, and trifluoromethoxymethyl. In another aspect, R 2 The heterocyclic ring may optionally be substituted by one or more substituents independently selected from the group consisting of: fluorine, hydroxyl, oxo, methyl, ethyl, propyl, isopropyl, fluoromethyl, difluoromethyl, trifluoromethyl, fluoroethyl, difluoroethyl, trifluoroethyl, cyclopropyl, methoxy, ethoxy, trifluoromethoxy, trifluoroethoxy, and methoxymethyl.

[0336] In some embodiments, the compound or pharmaceutically acceptable salt is (R)-N-(2-(4-cyanothiazolidine-3-yl)-2-oxoethyl)-6-(4-fluoro-1-methylpiperidin-4-yl)quinoline-4-carboxamide (Example 195), or a pharmaceutically acceptable salt thereof.

[0337] In some embodiments, R 2 The heterocyclic base ring is:

[0338]

[0339] Where R 2The heterocyclic ring is optionally substituted by one or more substituents independently selected from the group consisting of: halogen, hydroxyl, C. 1-6 -alkyl, C 3-6 -cycloalkyl, C 1-6 -alkoxy group, C 1-3 -alkoxy-C 1-3 -alkyl, C 1-3 -alkoxy-C 2-3 -alkoxy and C 1-3 -alkoxy-C 2-3 -alkoxy-C 1-3 -alkyl, and wherein the C 1-6 -alkyl, C 3-6 -cycloalkyl, C 1-6 -alkoxy group, C 1-3 -alkoxy-C 1-3 -alkyl, C 1-3 -alkoxy-C 2-3 -alkoxy and C 1-3 -alkoxy-C 2-3 -alkoxy-C 1-3 -Alkyl groups can be further substituted with one or more halogens. In one aspect, R 2 The heterocyclic ring is optionally substituted by one or more substituents independently selected from the group consisting of: fluorine, hydroxyl, C. 1-3 -alkyl, cyclopropyl, C 1-3 -alkoxy and C 1-3 -alkoxy-C 1-3 -alkyl, wherein the C 1-3 -alkyl, cyclopropyl, C 1-3 -alkoxy and C 1-3 -alkoxy-C 1-3 -alkyl groups can be further substituted with one or more fluorine molecules. In another aspect, R 2 The heterocyclic ring is optionally substituted by one or more substituents independently selected from the group consisting of: fluorine, hydroxyl, methyl, ethyl, propyl, isopropyl, fluoromethyl, difluoromethyl, trifluoromethyl, fluoroethyl, difluoroethyl, trifluoroethyl, cyclopropyl, methoxy, ethoxy, propoxy, isopropoxy, trifluoromethoxy, trifluoroethoxy, methoxymethyl, and trifluoromethoxymethyl. In another aspect, R 2 The heterocyclic ring may optionally be substituted by one or more substituents independently selected from the group consisting of: fluorine, hydroxyl, methyl, ethyl, propyl, isopropyl, fluoromethyl, difluoromethyl, trifluoromethyl, fluoroethyl, difluoroethyl, trifluoroethyl, cyclopropyl, methoxy, ethoxy, isopropyl, trifluoromethoxy, trifluoroethoxy, and methoxymethyl.

[0340] In some embodiments, the compound and pharmaceutically acceptable salt are selected from the group consisting of:

[0341] (R)-N-(2-(4-cyanothiazolidine-3-yl)-2-oxoethyl)-6-(2-oxopiperidin-1-yl)quinoline-4-carboxamide (Example 14);

[0342] (R)-N-(2-(4-cyanothiazolidine-3-yl)-2-oxoethyl)-6-(3,3-dimethyl-2-oxopiperidin-1-yl)-quinoline-4-carboxamide (Example 15);

[0343] N-(2-((R)-4-cyanothiazolidine-3-yl)-2-oxoethyl)-6-((R*)-3-methyl-2-oxopiperidin-1-yl)quinoline-4-carboxamide isomer 1 (Example 203);

[0344] N-(2-((R)-4-cyanothiazolidine-3-yl)-2-oxoethyl)-6-((R*)-3-methyl-2-oxopiperidin-1-yl)quinoline-4-carboxamide isomer 2 (Example 204);

[0345] And its pharmaceutically acceptable salts.

[0346] In some embodiments, R 2 The heterocyclic base ring is:

[0347]

[0348] Where R 2 The heterocyclic ring is optionally substituted by one or more substituents independently selected from the group consisting of: halogen, hydroxyl, C. 1-6 -alkyl, hydroxy-C 1-3 -alkyl, C 3-6 -cycloalkyl, C 1-6 -alkoxy group, C 1-3 -alkoxy-C 1-3 -alkyl, C 1-3 -alkoxy-C 2-3 -alkyloxy and C 1-3 -alkoxy-C 2-3 -alkyloxy-C 1-3 Alkyl group, and wherein the C 1-6 -alkyl, C 3-6 -cycloalkyl, C 1-6 -alkoxy group, C 1-3 -alkoxy-C 1-3 -alkyl, C 1-3 -alkoxy-C 2-3 -alkyloxy and C 1-3 -alkoxy-C 2-3 -alkyloxy-C 1-3Alkyl groups can be further substituted with one or more halogens. In one aspect, R 2 The heterocyclic ring is optionally substituted by one or more substituents independently selected from the group consisting of: fluorine, hydroxyl, C. 1-3 -alkyl, hydroxy-C 1-3 -alkyl, cyclopropyl, C 1-3 -alkoxy and C 1-3 -alkoxy-C 1-3 -alkyl, wherein the C 1-3 -alkyl, cyclopropyl, C 1-3 -alkoxy and C 1-3 -alkoxy-C 1-3 -alkyl groups can be further substituted with one or more fluorine molecules. In another aspect, R 2 The heterocyclic ring is optionally substituted by one or more substituents independently selected from the group consisting of: fluorine, hydroxyl, methyl, ethyl, propyl, fluoromethyl, difluoromethyl, trifluoromethyl, hydroxymethyl, fluoroethyl, difluoroethyl, trifluoroethyl, cyclopropyl, methoxy, ethoxy, propoxy, trifluoromethoxy, trifluoroethoxy, methoxymethyl, and trifluoromethoxymethyl. In another aspect, R 2 The heterocyclic ring may optionally be substituted by one or more substituents independently selected from the group consisting of: fluorine, hydroxyl, methyl, ethyl, propyl, fluoromethyl, difluoromethyl, trifluoromethyl, fluoroethyl, difluoroethyl, trifluoroethyl, cyclopropyl, methoxy, ethoxy, trifluoromethoxy, trifluoroethoxy, and methoxymethyl.

[0349] In some embodiments, the compound and pharmaceutically acceptable salt are selected from the group consisting of:

[0350] (R)-N-(2-(4-cyanothiazolidine-3-yl)-2-oxoethyl)-6-(pyridin-3-yl)quinoline-4-carboxamide (Example 126);

[0351] (R)-N-(2-(4-cyanothiazolidine-3-yl)-2-oxoethyl)-6-(2-methylpyridin-3-yl)quinoline-4-carboxamide (Example 128);

[0352] (R)-N-(2-(4-cyanothiazolidine-3-yl)-2-oxoethyl)-6-(6-(difluoromethyl)pyridin-3-yl)-quinoline-4-carboxamide (Example 169);

[0353] (R)-N-(2-(4-cyanothiazolidine-3-yl)-2-oxoethyl)-6-(6-methylpyridin-3-yl)quinoline-4-carboxamide (Example 177);

[0354] (R)-N-(2-(4-cyanothiazolidine-3-yl)-2-oxoethyl)-6-(6-methoxypyridin-3-yl)quinoline-4-carboxamide (Example 178);

[0355] And its pharmaceutically acceptable salts.

[0356] In some embodiments, R 2 The heterocyclic base ring is:

[0357]

[0358] Where R 2 The heterocyclic ring is optionally substituted by one or more substituents independently selected from the group consisting of: halogen, hydroxyl, C. 1-6 -alkyl, hydroxy-C 1-3 -alkyl, C 3-6 -cycloalkyl, C 1-6 -alkoxy group, C 1-3 -alkoxy-C 1-3 -alkyl, C 1-3 -alkoxy-C 2-3 -alkoxy and C 1-3 -alkoxy-C 2-3 -alkoxy-C 1-3 -alkyl, and wherein the C 1-6 -alkyl, C 3-6 -cycloalkyl, C 1-6 -alkoxy group, C 1-3 -alkoxy-C 1-3 -alkyl, C 1-3 -alkoxy-C 2-3 -alkoxy and C 1-3 -alkoxy-C 2-3 -alkoxy-C 1-3 -Alkyl groups can be further substituted with one or more halogens. In one aspect, R 2 The heterocyclic ring is optionally substituted by one or more substituents independently selected from the group consisting of: fluorine, hydroxyl, C. 1-3 -alkyl, hydroxy-C 1-3 -alkyl, cyclopropyl, C 1-3 -alkoxy and C 1-3 -alkoxy-C 1-3 -alkyl, wherein the C 1-3 -alkyl, cyclopropyl, C 1-3 -alkoxy and C 1-3 -alkoxy-C 1-3 -alkyl groups can be further substituted with one or more fluorine molecules. In another aspect, R 2The heterocyclic ring is optionally substituted by one or more substituents independently selected from the group consisting of: fluorine, hydroxyl, methyl, ethyl, propyl, fluoromethyl, difluoromethyl, trifluoromethyl, hydroxymethyl, fluoroethyl, difluoroethyl, trifluoroethyl, cyclopropyl, methoxy, ethoxy, propoxy, trifluoromethoxy, trifluoroethoxy, methoxymethyl, and trifluoromethoxymethyl. In another aspect, R 2 The heterocyclic ring may optionally be substituted by one or more substituents independently selected from the group consisting of: fluorine, hydroxyl, methyl, ethyl, propyl, fluoromethyl, difluoromethyl, trifluoromethyl, fluoroethyl, difluoroethyl, trifluoroethyl, cyclopropyl, methoxy, ethoxy, trifluoromethoxy, trifluoroethoxy, and methoxymethyl.

[0359] In some embodiments, the compound or pharmaceutically acceptable salt is (R)-N-(2-(4-cyanothiazolidine-3-yl)-2-oxoethyl)-6-(5,5-dimethyl-5,6-dihydro-4H-pyrrolo[1,2-b]pyrazol-3-yl)quinoline-4-carboxamide (Example 123), or a pharmaceutically acceptable salt thereof.

[0360] In some embodiments, R 2 The heterocyclic base ring is:

[0361]

[0362] Where R 2 The heterocyclic ring is optionally substituted by one or more substituents independently selected from the group consisting of: halogen, hydroxyl, C. 1-6 -alkyl, hydroxy-C 1-3 -alkyl, C 3-6 -cycloalkyl, C 1-6 -alkoxy group, C 1-3 -alkoxy-C 1-3 -alkyl, C 1-3 -alkoxy-C 2-3 -alkoxy and C 1-3 -alkoxy-C 2-3 -alkoxy-C 1-3 -alkyl, and wherein the C 1-6 -alkyl, C 3-6 -cycloalkyl, C 1-6 -alkoxy group, C 1-3 -alkoxy-C 1-3 -alkyl, C 1-3 -alkoxy-C 2-3 -alkoxy and C 1-3 -alkoxy-C 2-3 -alkoxy-C 1-3 -Alkyl groups can be further substituted with one or more halogens. In one aspect, R 2The heterocyclic ring is optionally substituted by one or more substituents independently selected from the group consisting of: fluorine, hydroxyl, C. 1-3 -alkyl, hydroxy-C 1-3 -alkyl, cyclopropyl, C 1-3 -alkoxy and C 1-3 -alkoxy-C 1-3 -alkyl, wherein the C 1-3 -alkyl, cyclopropyl, C 1-3 -alkoxy and C 1-3 -alkoxy-C 1-3 -alkyl groups can be further substituted with one or more fluorine molecules. In another aspect, R 2 The heterocyclic ring is optionally substituted by one or more substituents independently selected from the group consisting of: fluorine, hydroxyl, methyl, ethyl, propyl, fluoromethyl, difluoromethyl, trifluoromethyl, hydroxymethyl, fluoroethyl, difluoroethyl, trifluoroethyl, cyclopropyl, methoxy, ethoxy, propoxy, trifluoromethoxy, trifluoroethoxy, methoxymethyl, and trifluoromethoxymethyl. In another aspect, R 2 The heterocyclic ring may optionally be substituted by one or more substituents independently selected from the group consisting of: fluorine, hydroxyl, methyl, ethyl, propyl, fluoromethyl, difluoromethyl, trifluoromethyl, fluoroethyl, difluoroethyl, trifluoroethyl, cyclopropyl, methoxy, ethoxy, trifluoromethoxy, trifluoroethoxy, and methoxymethyl.

[0363] In some embodiments, the compound or pharmaceutically acceptable salt is (R)-N-(2-(4-cyanothiazolidine-3-yl)-2-oxoethyl)-6-(5,6,7,8-tetrahydroimidazo[1,2-a]pyridin-3-yl)quinoline-4-carboxamide (Example 175), or a pharmaceutically acceptable salt thereof.

[0364] In some embodiments, the compound and pharmaceutically acceptable salt are selected from the group consisting of:

[0365] N-(2-((R)-4-cyanothiazolidine-3-yl)-2-oxoethyl)-6-((3S,4S,5R)-4-hydroxy-3,5-dimethylpiperidin-1-yl)quinoline-4-carboxamide (Example 7);

[0366] (R)-N-(2-(4-cyanothiazolidine-3-yl)-2-oxoethyl)-6-(4-methoxypiperidin-1-yl)-quinoline-4-carboxamide (Example 8);

[0367] (R)-N-(2-(4-cyanothiazolidine-3-yl)-2-oxoethyl)-6-(2-oxopyrrolidine-1-yl)quinoline-4-carboxamide (Example 11);

[0368] (R)-N-(2-(4-cyanothiazolidine-3-yl)-2-oxoethyl)-6-(3,3-dimethyl-2-oxopyrrolidine-1-yl)quinoline-4-carboxamide (Example 12);

[0369] (R)-N-(2-(4-cyanothiazolidine-3-yl)-2-oxoethyl)-6-(2-oxopiperidin-1-yl)quinoline-4-carboxamide (Example 14);

[0370] (R)-N-(2-(4-cyanothiazolidine-3-yl)-2-oxoethyl)-6-(3,3-dimethyl-2-oxopiperidin-1-yl)-quinoline-4-carboxamide (Example 15);

[0371] (R)-N-(2-(4-cyanothiazolidine-3-yl)-2-oxoethyl)-6-(2,2-dimethylazacyclobutane-1-yl)-quinoline-4-carboxamide (Example 20);

[0372] (R)-N-(2-(4-cyanothiazolidine-3-yl)-2-oxoethyl)-6-(3-fluorozahexacyclobutan-1-yl)quinoline-4-carboxamide (Example 21);

[0373] (R)-N-(2-(4-cyanothiazolidine-3-yl)-2-oxoethyl)-6-(3,3-dimethylazacyclobutane-1-yl)-quinoline-4-carboxamide (Example 22);

[0374] (R)-N-(2-(4-cyanothiazolidine-3-yl)-2-oxoethyl)-6-(3,3-difluorozahexacyclobutane-1-yl)-quinoline-4-carboxamide (Example 23);

[0375] (R)-N-(2-(4-cyanothiazolidine-3-yl)-2-oxoethyl)-6-(3-fluoro-3-methylazacyclobutane-1-yl)-quinoline-4-carboxamide (Example 24);

[0376] (R)-N-(2-(4-cyanothiazolidine-3-yl)-2-oxoethyl)-6-(3-methylazacyclobutane-1-yl)quinoline-4-carboxamide (Example 25);

[0377] (R)-N-(2-(4-cyanothiazolidine-3-yl)-2-oxoethyl)-6-(3-(trifluoromethyl)azacyclobutane-1-yl)-quinoline-4-carboxamide (Example 26);

[0378] (R)-N-(2-(4-cyanothiazolidine-3-yl)-2-oxoethyl)-6-(3-(fluoromethyl)-3-methylazacyclobutane-1-yl)quinoline-4-carboxamide (Example 27);

[0379] (R)-N-(2-(4-cyanothiazolidine-3-yl)-2-oxoethyl)-6-(3-(difluoromethyl)azacyclobutane-1-yl)-quinoline-4-carboxamide (Example 28);

[0380] (R)-N-(2-(4-cyanothiazolidine-3-yl)-2-oxoethyl)-6-(3-(methoxymethyl)-3-methyl-azacyclobutane-1-yl)quinoline-4-carboxamide (Example 29);

[0381] N-(2-((R)-4-cyanothiazolidine-3-yl)-2-oxoethyl)-6-((2S,3R)-3-methoxy-2-methyl-azacyclobutane-1-yl)quinoline-4-carboxamide (Example 30);

[0382] (R)-N-(2-(4-cyanothiazolidine-3-yl)-2-oxoethyl)-6-(3-cyclopropyl-3-fluorozahexacyclobutane-1-yl)quinoline-4-carboxamide (Example 31);

[0383] (R)-N-(2-(4-cyanothiazolidine-3-yl)-2-oxoethyl)-6-(piperidin-1-yl)quinoline-4-carboxamide (Example 32);

[0384] (R)-N-(2-(4-cyanothiazolidine-3-yl)-2-oxoethyl)-6-(4,4-dimethylpiperidin-1-yl)-quinoline-4-carboxamide (Example 33);

[0385] (R)-N-(2-(4-cyanothiazolidine-3-yl)-2-oxoethyl)-6-(4-fluoro-4-methylpiperidin-1-yl)quinoline-4-carboxamide (Example 34);

[0386] (R)-N-(2-(4-cyanothiazolidine-3-yl)-2-oxoethyl)-6-(4,4-difluoropiperidin-1-yl)-quinoline-4-carboxamide (Example 35);

[0387] (R)-N-(2-(4-cyanothiazolidine-3-yl)-2-oxoethyl)-6-(3,3-difluoropiperidin-1-yl)-quinoline-4-carboxamide (Example 36);

[0388] (R)-N-(2-(4-cyanothiazolidine-3-yl)-2-oxoethyl)-6-(4-(fluoromethyl)-4-methyl-piperidin-1-yl)quinoline-4-carboxamide (Example 37);

[0389] (R)-N-(2-(4-cyanothiazolidine-3-yl)-2-oxoethyl)-6-(4,4-difluoro-3,3-dimethyl-piperidin-1-yl)quinoline-4-carboxamide (Example 38);

[0390] (R)-N-(2-(4-cyanothiazolidine-3-yl)-2-oxoethyl)-6-(4-(trifluoromethyl)piperidin-1-yl)-quinoline-4-carboxamide (Example 39);

[0391] N-(2-((R)-4-cyanothiazolidine-3-yl)-2-oxoethyl)-6-(3-fluoropiperidin-1-yl)quinoline-4-carboxamide (Example 40);

[0392] N-(2-((R)-4-cyanothiazolidine-3-yl)-2-oxoethyl)-6-(3-methoxypiperidin-1-yl)-quinoline-4-carboxamide (Example 41);

[0393] (R)-N-(2-(4-cyanothiazolidine-3-yl)-2-oxoethyl)-6-(4-methoxy-4-methylpiperidin-1-yl)quinoline-4-carboxamide (Example 42);

[0394] (R)-N-(2-(4-cyanothiazolidine-3-yl)-2-oxoethyl)-6-(4-isopropoxypiperidin-1-yl)-quinoline-4-carboxamide (Example 43);

[0395] N-(2-((R)-4-cyanothiazolidine-3-yl)-2-oxoethyl)-6-(4,4-difluoro-2-methylpiperidin-1-yl)quinoline-4-carboxamide (Example 44);

[0396] N-(2-((R)-4-cyanothiazolidine-3-yl)-2-oxoethyl)-6-((S)-2-(fluoromethyl)piperidin-1-yl)quinoline-4-carboxamide (Example 45);

[0397] (R)-N-(2-(4-cyanothiazolidine-3-yl)-2-oxoethyl)-6-(3,3-difluoropyrrolidine-1-yl)-quinoline-4-carboxamide (Example 47);

[0398] (R)-N-(2-(4-cyanothiazolidine-3-yl)-2-oxoethyl)-6-(3,3-dimethylpyrrolidine-1-yl)-quinoline-4-carboxamide (Example 48);

[0399] N-(2-((R)-4-cyanothiazolidine-3-yl)-2-oxoethyl)-6-((3R,4S)-3,4-difluoropyrrolidine-1-yl)quinoline-4-carboxamide (Example 50);

[0400] N-(2-((R)-4-cyanothiazolidine-3-yl)-2-oxoethyl)-6-((S)-3-fluoropyrrolidine-1-yl)-quinoline-4-carboxamide (Example 51);

[0401] N-(2-((R)-4-cyanothiazolidine-3-yl)-2-oxoethyl)-6-((R)-3-fluoropyrrolidine-1-yl)-quinoline-4-carboxamide (Example 52);

[0402] N-(2-((R)-4-cyanothiazolidine-3-yl)-2-oxoethyl)-6-(hexahydrocyclopenteno[c]pyrrolo-2(1H)-yl)quinoline-4-carboxamide (Example 53);

[0403] N-(2-((R)-4-cyanothiazolidine-3-yl)-2-oxoethyl)-6-((S)-3-methylpyrrolidine-1-yl)-quinoline-4-carboxamide (Example 54);

[0404] N-(2-((R)-4-cyanothiazolidine-3-yl)-2-oxoethyl)-6-((R)-3-methylpyrrolidine-1-yl)-quinoline-4-carboxamide (Example 55);

[0405] N-(2-((R)-4-cyanothiazolidine-3-yl)-2-oxoethyl)-6-((S)-2-(trifluoromethyl)pyrrolidine-1-yl)quinoline-4-carboxamide (Example 56);

[0406] (R)-N-(2-(4-cyanothiazolidine-3-yl)-2-oxoethyl)-6-(2,2-dimethylpyrrolidine-1-yl)-quinoline-4-carboxamide (Example 57);

[0407] N-(2-((R)-4-cyanothiazolidine-3-yl)-2-oxoethyl)-6-((R)-3-fluorozaheptan-1-yl)quinoline-4-carboxamide (Example 59);

[0408] N-(2-((R)-4-cyanothiazolidine-3-yl)-2-oxoethyl)-6-((S)-3-fluorozaheptan-1-yl)quinoline-4-carboxamide (Example 60);

[0409] N-(2-((R)-4-cyanothiazolidine-3-yl)-2-oxoethyl)-6-((S)-2-methylpyrrolidine-1-yl)-quinoline-4-carboxamide (Example 65);

[0410] (R)-N-(2-(4-cyanothiazolidine-3-yl)-2-oxoethyl)-6-(3-methoxyazacyclobutane-1-yl)quinoline-4-carboxamide (Example 66);

[0411] (R)-N-(2-(4-cyanothiazolidine-3-yl)-2-oxoethyl)-6-(3-(fluoromethyl)azacyclobutane-1-yl)-quinoline-4-carboxamide (Example 113);

[0412] (R)-N-(2-(4-cyanothiazolidine-3-yl)-2-oxoethyl)-6-(4,5,6,7-tetrahydro-1H-indazol-1-yl)quinoline-4-carboxamide (Example 114);

[0413] (R)-N-(2-(4-cyanothiazolidine-3-yl)-2-oxoethyl)-6-(4,5,6,7-tetrahydro-2H-indazol-2-yl)quinoline-4-carboxamide (Example 115);

[0414] (R)-N-(2-(4-cyanothiazolidine-3-yl)-2-oxoethyl)-6-(5-methyl-3-(trifluoromethyl)-1H-pyrazol-1-yl)quinoline-4-carboxamide (Example 116);

[0415] (R)-N-(2-(4-cyanothiazolidine-3-yl)-2-oxoethyl)-6-(6,6-dimethyl-5,6-dihydrocyclopenteno[c]pyrazol-2(4H)-yl)quinoline-4-carboxamide (Example 1l7);

[0416] (R)-N-(2-(4-cyanothiazolidine-3-yl)-2-oxoethyl)-6-(3-(trifluoromethyl)-1H-pyrazol-1-yl)quinoline-4-carboxamide (Example 118);

[0417] (R)-N-(2-(4-cyanothiazolidine-3-yl)-2-oxoethyl)-6-(4,6-difluoro-1H-indol-1-yl)-quinoline-4-carboxamide (Example 119);

[0418] (R)-N-(2-(4-cyanothiazolidine-3-yl)-2-oxoethyl)-6-(5-fluoro-1H-indol-1-yl)quinoline-4-carboxamide (Example 120):

[0419] (R)-N-(2-(4-cyanothiazolidine-3-yl)-2-oxoethyl)-6-(3-methyl-1H-pyrrolo-1-yl)-quinoline-4-carboxamide (Example 121);

[0420] (R)-N-(2-(4-cyanothiazolidine-3-yl)-2-oxoethyl)-6-(3-morpholinoazonicyclobutane-1-yl)-quinoline-4-carboxamide (Example 122);

[0421] (R)-N-(2-(4-cyanothiazolidine-3-yl)-2-oxoethyl)-6-(5,5-dimethyl-5,6-dihydro-4H-pyrrolo[1,2-b]pyrazol-3-yl)quinoline-4-carboxamide (Example 123);

[0422] (R)-N-(2-(4-cyanothiazolidine-3-yl)-2-oxoethyl)-6-(2-fluoropyridin-4-yl)quinoline-4-carboxamide (Example 124);

[0423] (R)-N-(2-(4-cyanothiazolidine-3-yl)-2-oxoethyl)-6-(5-fluoropyridin-2-yl)quinoline-4-carboxamide (Example 125);

[0424] (R)-N-(2-(4-cyanothiazolidine-3-yl)-2-oxoethyl)-6-(pyridin-3-yl)quinoline-4-carboxamide (Example 126);

[0425] (R)-N-(2-(4-cyanothiazolidine-3-yl)-2-oxoethyl)-6-(pyrimidin-5-yl)quinoline-4-carboxamide (Example 127);

[0426] (R)-N-(2-(4-cyanothiazolidine-3-yl)-2-oxoethyl)-6-(2-methylpyridin-3-yl)quinoline-4-carboxamide (Example 128);

[0427] (R)-N-(2-(4-cyanothiazolidine-3-yl)-2-oxoethyl)-6-(1-methyl-1H-pyrazol-4-yl)-quinoline-4-carboxamide (Example 129);

[0428] (R)-N-(2-(4-cyanothiazolidine-3-yl)-2-oxoethyl)-6-(3-((trifluoromethoxy)methyl)-azacyclobutane-1-yl)quinoline-4-carboxamide (Example 130);

[0429] (R)-N-(2-(4-cyanothiazolidine-3-yl)-2-oxoethyl)-6-(3-methyl-3-(2,2,2-trifluoroethyl)-azacyclobutane-1-yl)quinoline-4-carboxamide (Example 131);

[0430] (R)-N-(2-(4-cyanothiazolidine-3-yl)-2-oxoethyl)-6-(3-(trifluoromethoxy)azacyclobutane-1-yl)quinoline-4-carboxamide (Example 132);

[0431] (R)-N-(2-(4-cyanothiazolidine-3-yl)-2-oxoethyl)-6-(3-(2,2-difluoroethyl)-3-methyl-azacyclobutane-1-yl)quinoline-4-carboxamide (Example 133);

[0432] (R)-N-(2-(4-cyanothiazolidine-3-yl)-2-oxoethyl)-6-(3-cyclopropyl-3-methylazacyclobutane-1-yl)quinoline-4-carboxamide (Example 134);

[0433] (R)-N-(2-(4-cyanothiazolidine-3-yl)-2-oxoethyl)-6-(3-(difluoromethyl)-3-methyl-azacyclobutane-1-yl)quinoline-4-carboxamide (Example 135);

[0434] (R)-N-(2-(4-cyanothiazolidine-3-yl)-2-oxoethyl)-6-(3-(difluoromethoxy)azacyclobutane-1-yl)-quinoline-4-carboxamide (Example 136);

[0435] (R)-N-(2-(4-cyanothiazolidine-3-yl)-2-oxoethyl)-6-(3-ethyl-3-methylazacyclobutane-1-yl)-quinoline-4-carboxamide (Example 137);

[0436] (R)-N-(2-(4-cyanothiazolidine-3-yl)-2-oxoethyl)-6-(3-ethyl-3-fluorozahexacyclobutane-1-yl)-quinoline-4-carboxamide (Example 138);

[0437] (R)-N-(2-(4-cyanothiazolidine-3-yl)-2-oxoethyl)-6-(3-(2,2-difluoropropyl)azacyclobutane-1-yl)quinoline-4-carboxamide (Example 140);

[0438] (R)-N-(2-(4-cyanothiazolidine-3-yl)-2-oxoethyl)-6-(3-(3,3,3-trifluoropropyl)azacyclobutane-1-yl)quinoline-4-carboxamide (Example 142);

[0439] (R)-N-(2-(4-cyanothiazolidine-3-yl)-2-oxoethyl)-6-(3-fluoro-3-(trifluoromethyl)-azacyclobutane-1-yl)quinoline-4-carboxamide (Example 143);

[0440] (R)-N-(2-(4-cyanothiazolidine-3-yl)-2-oxoethyl)-6-(3-(2,2-difluoroethyl)azacyclobutane-1-yl)-quinoline-4-carboxamide (Example 144);

[0441] (R)-N-(2-(4-cyanothiazolidine-3-yl)-2-oxoethyl)-6-(3-cyclopropylazacyclobutane-1-yl)-quinoline-4-carboxamide (Example 145);

[0442] (R)-N-(2-(4-cyanothiazolidine-3-yl)-2-oxoethyl)-6-(3-(2-fluoroethyl)azacyclobutane-1-yl)-quinoline-4-carboxamide (Example 146);

[0443] (R)-N-(2-(4-cyanothiazolidine-3-yl)-2-oxoethyl)-6-(3-(1,1-difluoroethyl)azacyclobutane-1-yl)-quinoline-4-carboxamide (Example 147);

[0444] (R)-N-(2-(4-cyanothiazolidine-3-yl)-2-oxoethyl)-6-(3-isopropylazacyclobutane-1-yl)quinoline-4-carboxamide (Example 148);

[0445] (R)-N-(2-(4-cyanothiazolidine-3-yl)-2-oxoethyl)-6-(3-methoxy-3-methylazacyclobutane-1-yl)-quinoline-4-carboxamide (Example 151);

[0446] (R)-N-(2-(4-cyanothiazolidine-3-yl)-2-oxoethyl)-6-(3-ethoxy-3-methylazacyclobutane-1-yl)-quinoline-4-carboxamide (Example 152);

[0447] (R)-N-(2-(4-cyanothiazolidine-3-yl)-2-oxoethyl)-6-(3-ethyl-3-hydroxyazacyclobutane-1-yl)-quinoline-4-carboxamide (Example 154);

[0448] 6-(6-azabicyclo[3.2.0]heptane-6-yl)-N-(2-((R)-4-cyanothiazolidine-3-yl)-2-oxoethyl)-quinoline-4-carboxamide (Example 156);

[0449] (R)-N-(2-(4-cyanothiazolidine-3-yl)-2-oxoethyl)-6-(3-fluoro-3-(fluoromethyl)azacyclobutane-1-yl)quinoline-4-carboxamide (Example 157);

[0450] (R)-N-(2-(4-cyanothiazolidine-3-yl)-2-oxoethyl)-6-(3-(2,2,2-trifluoroethyl)azacyclobutane-1-yl)quinoline-4-carboxamide (Example 158);

[0451] N-(2-((R)-4-cyanothiazolidine-3-yl)-2-oxoethyl)-6-(3,3-difluoro-2-methylazacyclobutane-1-yl)quinoline-4-carboxamide (Example 159);

[0452] N-(2-((R)-4-cyanothiazolidine-3-yl)-2-oxoethyl)-6-(6,6-difluoro-3-azabicyclo[3.1.0]hexane-3-yl)quinoline-4-carboxamide (Example 160);

[0453] N-(2-((R)-4-cyanothiazolidine-3-yl)-2-oxoethyl)-6-((R)-3-methoxypyrrolidine-1-yl)-quinoline-4-carboxamide (Example 161);

[0454] (R)-N-(2-(4-cyanothiazolidine-3-yl)-2-oxoethyl)-6-(3-hydroxy-3-methylazacyclobutane-1-yl)-quinoline-4-carboxamide (Example 165);

[0455] N-(2-((R)-4-cyanothiazolidine-3-yl)-2-oxoethyl)-6-((R)-3-hydroxy-3-methylpyrrolidine-1-yl)quinoline-4-carboxamide (Example 167);

[0456] N-(2-((R)-4-cyanothiazolidine-3-yl)-2-oxoethyl)-6-((S)-3-hydroxy-3-methylpyrrolidine-1-yl)quinoline-4-carboxamide (Example 168);

[0457] (R)-N-(2-(4-cyanothiazolidine-3-yl)-2-oxoethyl)-6-(6-(difluoromethyl)pyridin-3-yl)-quinoline-4-carboxamide (Example 169);

[0458] (R)-N-(2-(4-cyanothiazolidine-3-yl)-2-oxoethyl)-6-(1-cyclopropyl-1H-pyrazol-4-yl)-quinoline-4-carboxamide (Example 170);

[0459] (R)-N-(2-(4-cyanothiazolidine-3-yl)-2-oxoethyl)-6-(1,3-dimethyl-1H-pyrazol-4-yl)-quinoline-4-carboxamide (Example 171);

[0460] (R)-N-(2-(4-cyanothiazolidine-3-yl)-2-oxoethyl)-6-(3,5-dimethyl-1-(tetrahydro-2H-pyran-4-yl)-1H-pyrazol-4-yl)quinoline-4-carboxamide (Example 172);

[0461] (R)-N-(2-(4-cyanothiazolidine-3-yl)-2-oxoethyl)-6-(1-(tetrahydro-2H-pyran-4-yl)-1H-pyrazol-4-yl)quinoline-4-carboxamide (Example 173);

[0462] (R)-N-(2-(4-cyanothiazolidine-3-yl)-2-oxoethyl)-6-(1-methyl-1H-pyrazol-5-yl)-quinoline-4-carboxamide (Example 174);

[0463] (R)-N-(2-(4-cyanothiazolidine-3-yl)-2-oxoethyl)-6-(5,6,7,8-tetrahydroimidazo[1,2-a]pyridin-3-yl)quinoline-4-carboxamide (Example 175);

[0464] N-(2-((R)-4-cyanothiazolidine-3-yl)-2-oxoethyl)-6-(1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-5-yl)quinoline-4-carboxamide (Example 176);

[0465] (R)-N-(2-(4-cyanothiazolidine-3-yl)-2-oxoethyl)-6-(6-methylpyridin-3-yl)quinoline-4-carboxamide (Example 177);

[0466] (R)-N-(2-(4-cyanothiazolidine-3-yl)-2-oxoethyl)-6-(6-methoxypyridin-3-yl)quinoline-4-carboxamide (Example 178);

[0467] (R)-6-(3-(acetamidomethyl)-3-methylazacyclobutane-1-yl)-N-(2-(4-cyanothiazolidine-3-yl)-2-oxoethyl)quinoline-4-carboxamide (Example 181);

[0468] (R)-N-(2-(4-cyanothiazolidine-3-yl)-2-oxoethyl)-6-(3-fluoro-3-phenylazacyclobutane-1-yl)-quinoline-4-carboxamide (Example 182);

[0469] (R)-N-(2-(4-cyanothiazolidine-3-yl)-2-oxoethyl)-6-(3-(p-tolyl)azacyclobutane-1-yl)quinoline-4-carboxamide (Example 183);

[0470] (R)-N-(2-(4-cyanothiazolidine-3-yl)-2-oxoethyl)-6-(3-(4-fluorophenyl)azacyclobutane-1-yl)-quinoline-4-carboxamide (Example 185);

[0471] (R)-N-(2-(4-cyanothiazolidine-3-yl)-2-oxoethyl)-6-(3-(m-tolyl)azacyclobutane-1-yl)quinoline-4-carboxamide (Example 186);

[0472] (R)-6-(3-(4-chlorobenzyl)azacyclobutane-1-yl)-N-(2-(4-cyanothiazolidine-3-yl)-2-oxoethyl)-quinoline-4-carboxamide (Example 187);

[0473] (R)-N-(2-(4-cyanothiazolidine-3-yl)-2-oxoethyl)-6-(3-methyl-3-((methanesulfonyl)-methyl)azacyclobutane-1-yl)quinoline-4-carboxamide (Example 188);

[0474] (R)-N-(2-(4-cyanothiazolidine-3-yl)-2-oxoethyl)-6-(4-ethyl-4-hydroxypiperidin-1-yl)-quinoline-4-carboxamide (Example 189);

[0475] (R)-N-(2-(4-cyanothiazolidine-3-yl)-2-oxoethyl)-6-(4-hydroxy-4-methylpiperidin-1-yl)quinoline-4-carboxamide (Example 190);

[0476] (R)-N-(2-(4-cyanothiazolidine-3-yl)-2-oxoethyl)-6-(4-ethyl-4-methoxypiperidin-1-yl)-quinoline-4-carboxamide (Example 191);

[0477] (R)-N-(2-(4-cyanothiazolidine-3-yl)-2-oxoethyl)-6-(4-hydroxy-4-isopropylpiperidin-1-yl)quinoline-4-carboxamide (Example 192);

[0478] N-(2-((R)-4-cyanothiazolidine-3-yl)-2-oxoethyl)-6-((3R,4S,5S)-4-hydroxy-3,4,5-trimethylpiperidin-1-yl)quinoline-4-carboxamide (Example 193);

[0479] (R)-N-(2-(4-cyanothiazolidine-3-yl)-2-oxoethyl)-6-(4-fluoro-1-methylpiperidin-4-yl)-quinoline-4-carboxamide (Example 195);

[0480] (R)-N-(2-(4-cyanothiazolidine-3-yl)-2-oxoethyl)-6-(1H-pyrazol-5-yl)quinoline-4-carboxamide (Example 196);

[0481] (R)-N-(2-(4-cyanothiazolidine-3-yl)-2-oxoethyl)-6-(1-isopropyl-1H-pyrazol-5-yl)-quinoline-4-carboxamide (Example 197);

[0482] N-(2-((R)-4-cyanothiazolidine-3-yl)-2-oxoethyl)-6-((RS)-3-fluoro-3-methylpyrrolidine-1-yl)quinoline-4-carboxamide (Example 198);

[0483] N-(2-((R)-4-cyanothiazolidine-3-yl)-2-oxoethyl)-6-((R*)-2-cyclopropylpyrrolidine-1-yl)quinoline-4-carboxamide isomer 1 (Example 199);

[0484] N-(2-((R)-4-cyanothiazolidine-3-yl)-2-oxoethyl)-6-((R*)-2-cyclopropylpyrrolidine-1-yl)quinoline-4-carboxamide isomer 2 (Example 200);

[0485] N-(2-((R)-4-cyanothiazolidine-3-yl)-2-oxoethyl)-6-((R*)-3-methyl-2-oxopyrrolidine-1-yl)quinoline-4-carboxamide isomer 1 (Example 201);

[0486] N-(2-((R)-4-cyanothiazolidine-3-yl)-2-oxoethyl)-6-((R*)-3-methyl-2-oxopyrrolidine-1-yl)quinoline-4-carboxamide isomer 2 (Example 202);

[0487] N-(2-((R)-4-cyanothiazolidine-3-yl)-2-oxoethyl)-6-((R*)-3-methyl-2-oxopiperidin-1-yl)quinoline-4-carboxamide isomer 1 (Example 203);

[0488] N-(2-((R)-4-cyanothiazolidine-3-yl)-2-oxoethyl)-6-((R*)-3-methyl-2-oxopiperidin-1-yl)quinoline-4-carboxamide isomer 2 (Example 204);

[0489] (R)-N-(2-(4-cyanothiazolidine-3-yl)-2-oxoethyl)-6-(4-fluoropiperidin-1-yl)quinoline-4-carboxamide (Example 205);

[0490] 6-(3-azabicyclo[3.1.0]hexane-3-yl)-N-(2-((R)-4-cyanothiazolidine-3-yl)-2-oxoethyl)-quinoline-4-carboxamide (Example 206);

[0491] N-(2-((R)-4-cyanothiazolidine-3-yl)-2-oxoethyl)-6-((S)-3-methoxypyrrolidine-1-yl)-quinoline-4-carboxamide (Example 207);

[0492] N-(2-((R)-4-cyanothiazolidine-3-yl)-2-oxoethyl)-6-((1R,5S,6R)-6-(trifluoromethyl)-3-azabicyclo[3.1.0]hexane-3-yl)quinoline-4-carboxamide (Example 208);

[0493] (R)-6-(7-azabicyclo[2.2.1]heptane-7-yl)-N-(2-(4-cyanothiazolidine-3-yl)-2-oxoethyl)-quinoline-4-carboxamide (Example 209);

[0494] 6-(2-azabicyclo[2.2.1]heptane-2-yl)-N-(2-((R)-4-cyanothiazolidine-3-yl)-2-oxoethyl)-quinoline-4-carboxamide (Example 210);

[0495] N-(2-((R)-4-cyanothiazolidine-3-yl)-2-oxoethyl)-6-((R)-2-methylpyrrolidine-1-yl)-quinoline-4-carboxamide (Example 211);

[0496] N-(2-((R)-4-cyanothiazolidine-3-yl)-2-oxoethyl)-6-((S)-2-(methoxymethyl)pyrrolidine-1-yl)quinoline-4-carboxamide (Example 212);

[0497] N-(2-((R)-4-cyanothiazolidine-3-yl)-2-oxoethyl)-6-((3S,4S)-3,4-difluoropyrrolidine-1-yl)quinoline-4-carboxamide (Example 213);

[0498] N-(2-((R)-4-cyanothiazolidine-3-yl)-2-oxoethyl)-6-((3R,4R)-3,4-difluoropyrrolidine-1-yl)quinoline-4-carboxamide (Example 214);

[0499] (R)-N-(2-(4-cyanothiazolidine-3-yl)-2-oxoethyl)-6-(2-phenyl-1H-imidazol-1-yl)-quinoline-4-carboxamide (Example 217);

[0500] (R)-N-(2-(4-cyanothiazolidine-3-yl)-2-oxoethyl)-6-(3-phenyl-1H-pyrrolo-1-yl)-quinoline-4-carboxamide (Example 218);

[0501] (R)-N-(2-(4-cyanothiazolidine-3-yl)-2-oxoethyl)-6-(4,5,6,7-tetrahydro-1H-indol-1-yl)quinoline-4-carboxamide (Example 219);

[0502] N-(2-((R)-4-cyanothiazolidine-3-yl)-2-oxoethyl)-6-((R)-3-(hydroxymethyl)pyrrolidine-1-yl)quinoline-4-carboxamide (Example 220);

[0503] N-(2-((R)-4-cyanothiazolidine-3-yl)-2-oxoethyl)-6-((S)-3-(hydroxymethyl)pyrrolidine-1-yl)quinoline-4-carboxamide (Example 221);

[0504] (R)-N-(2-(4-cyanothiazolidine-3-yl)-2-oxoethyl)-6-(4-fluoro-4-phenylpiperidin-1-yl)-quinoline-4-carboxamide (Example 223);

[0505] N-(2-((R)-4-cyanothiazolidine-3-yl)-2-oxoethyl)-6-((RS)-3,3-difluoro-4-hydroxy-pyrrolidine-1-yl)quinoline-4-carboxamide (Example 224);

[0506] N-(2-((R)-4-cyanothiazolidine-3-yl)-2-oxoethyl)-6-((3R*,4R*)-3,4-dimethylpyrrolidine-1-yl)quinoline-4-carboxamide isomer 1 (Example 225);

[0507] N-(2-((R)-4-cyanothiazolidine-3-yl)-2-oxoethyl)-6-((3R*,4R*)-3,4-dimethylpyrrolidine-1-yl)quinoline-4-carboxamide isomer 2 (Example 226);

[0508] (R)-N-(2-(4-cyanothiazolidine-3-yl)-2-oxoethyl)-6-(4-oxopiperidin-1-yl)quinoline-4-carboxamide (Example 230);

[0509] And its pharmaceutically acceptable salts.

[0510] In some embodiments, the compound and pharmaceutically acceptable salt are selected from the group consisting of:

[0511] N-(2-((R)-4-cyanothiazolidine-3-yl)-2-oxoethyl)-6-((3S,4S,5R)-4-hydroxy-3,5-dimethylpiperidin-1-yl)quinoline-4-carboxamide (Example 7);

[0512] (R)-N-(2-(4-cyanothiazolidine-3-yl)-2-oxoethyl)-6-(4-methoxypiperidin-1-yl)-quinoline-4-carboxamide (Example 8);

[0513] (R)-N-(2-(4-cyanothiazolidine-3-yl)-2-oxoethyl)-6-(3,3-dimethyl-2-oxopyrrolidine-1-yl)quinoline-4-carboxamide (Example 12);

[0514] (R)-N-(2-(4-cyanothiazolidine-3-yl)-2-oxoethyl)-6-(3,3-dimethyl-2-oxopiperidin-1-yl)quinoline-4-carboxamide (Example 15);

[0515] (R)-N-(2-(4-cyanothiazolidine-3-yl)-2-oxoethyl)-6-(3,3-dimethylazacyclobutane-1-yl)-quinoline-4-carboxamide (Example 22);

[0516] (R)-N-(2-(4-cyanothiazolidine-3-yl)-2-oxoethyl)-6-(3-fluoro-3-methylazacyclobutane-1-yl)-quinoline-4-carboxamide (Example 24);

[0517] (R)-N-(2-(4-cyanothiazolidine-3-yl)-2-oxoethyl)-6-(3-(fluoromethyl)-3-methylazacyclobutane-1-yl)quinoline-4-carboxamide (Example 27);

[0518] (R)-N-(2-(4-cyanothiazolidine-3-yl)-2-oxoethyl)-6-(3-(difluoromethyl)azacyclobutane-1-yl)quinoline-4-carboxamide (Example 28);

[0519] (R)-N-(2-(4-cyanothiazolidine-3-yl)-2-oxoethyl)-6-(3-(methoxymethyl)-3-methyl-azacyclobutane-1-yl)quinoline-4-carboxamide (Example 29);

[0520] N-(2-((R)-4-cyanothiazolidine-3-yl)-2-oxoethyl)-6-((2S,3R)-3-methoxy-2-methyl-azacyclobutane-1-yl)quinoline-4-carboxamide (Example 30);

[0521] (R)-N-(2-(4-cyanothiazolidine-3-yl)-2-oxoethyl)-6-(3-cyclopropyl-3-fluorozahexacyclobutane-1-yl)quinoline-4-carboxamide (Example 31);

[0522] (R)-N-(2-(4-cyanothiazolidine-3-yl)-2-oxoethyl)-6-(piperidin-1-yl)quinoline-4-carboxamide (Example 32);

[0523] (R)-N-(2-(4-cyanothiazolidine-3-yl)-2-oxoethyl)-6-(4-fluoro-4-methylpiperidin-1-yl)quinoline-4-carboxamide (Example 34);

[0524] N-(2-((R)-4-cyanothiazolidine-3-yl)-2-oxoethyl)-6-(3-methoxypiperidin-1-yl)-quinoline-4-carboxamide (Example 41);

[0525] (R)-N-(2-(4-cyanothiazolidine-3-yl)-2-oxoethyl)-6-(4-methoxy-4-methylpiperidin-1-yl)quinoline-4-carboxamide (Example 42);

[0526] (R)-N-(2-(4-cyanothiazolidine-3-yl)-2-oxoethyl)-6-(4-isopropoxypiperidin-1-yl)-quinoline-4-carboxamide (Example 43);

[0527] N-(2-((R)-4-cyanothiazolidine-3-yl)-2-oxoethyl)-6-((3R,4S)-3,4-difluoropyrrolidine-1-yl)quinoline-4-carboxamide (Example 50);

[0528] N-(2-((R)-4-cyanothiazolidine-3-yl)-2-oxoethyl)-6-((R)-3-fluoropyrrolidine-1-yl)-quinoline-4-carboxamide (Example 52);

[0529] (R)-N-(2-(4-cyanothiazolidine-3-yl)-2-oxoethyl)-6-(3-methoxyazacyclobutane-1-yl)quinoline-4-carboxamide (Example 66);

[0530] (R)-N-(2-(4-cyanothiazolidine-3-yl)-2-oxoethyl)-6-(3-(fluoromethyl)azacyclobutane-1-yl)-quinoline-4-carboxamide (Example 113);

[0531] (R)-N-(2-(4-cyanothiazolidine-3-yl)-2-oxoethyl)-6-(3-(difluoromethyl)-3-methyl-azacyclobutane-1-yl)quinoline-4-carboxamide (Example 135);

[0532] (R)-N-(2-(4-cyanothiazolidine-3-yl)-2-oxoethyl)-6-(3-ethyl-3-fluorozahexacyclobutane-1-yl)-quinoline-4-carboxamide (Example 138);

[0533] (R)-N-(2-(4-cyanothiazolidine-3-yl)-2-oxoethyl)-6-(3-(2,2-difluoropropyl)azacyclobutane-1-yl)quinoline-4-carboxamide (Example 140);

[0534] (R)-N-(2-(4-cyanothiazolidine-3-yl)-2-oxoethyl)-6-(3-fluoro-3-(trifluoromethyl)-azacyclobutane-1-yl)quinoline-4-carboxamide (Example 143);

[0535] (R)-N-(2-(4-cyanothiazolidine-3-yl)-2-oxoethyl)-6-(3-(1,1-difluoroethyl)azacyclobutane-1-yl)quinoline-4-carboxamide (Example 147);

[0536] (R)-N-(2-(4-cyanothiazolidine-3-yl)-2-oxoethyl)-6-(3-methoxy-3-methylazacyclobutane-1-yl)quinoline-4-carboxamide (Example 151);

[0537] (R)-N-(2-(4-cyanothiazolidine-3-yl)-2-oxoethyl)-6-(3-ethoxy-3-methylazacyclobutane-1-yl)-quinoline-4-carboxamide (Example 152);

[0538] (R)-N-(2-(4-cyanothiazolidine-3-yl)-2-oxoethyl)-6-(3-fluoro-3-(fluoromethyl)azacyclobutane-1-yl)quinoline-4-carboxamide (Example 157);

[0539] N-(2-((R)-4-cyanothiazolidine-3-yl)-2-oxoethyl)-6-((R)-3-methoxypyrrolidine-1-yl)-quinoline-4-carboxamide (Example 161);

[0540] (R)-N-(2-(4-cyanothiazolidine-3-yl)-2-oxoethyl)-6-(3-hydroxy-3-methylazacyclobutane-1-yl)-quinoline-4-carboxamide (Example 165);

[0541] (R)-N-(2-(4-cyanothiazolidine-3-yl)-2-oxoethyl)-6-(6-(difluoromethyl)pyridin-3-yl)-quinoline-4-carboxamide (Example 169);

[0542] (R)-N-(2-(4-cyanothiazolidine-3-yl)-2-oxoethyl)-6-(3,5-dimethyl-1-(tetrahydro-2H-pyran-4-yl)-1H-pyrazol-4-yl)quinoline-4-carboxamide (Example 172);

[0543] (R)-N-(2-(4-cyanothiazolidine-3-yl)-2-oxoethyl)-6-(5,6,7,8-tetrahydroimidazo[1,2-a]pyridin-3-yl)quinoline-4-carboxamide (Example 175);

[0544] (R)-N-(2-(4-cyanothiazolidine-3-yl)-2-oxoethyl)-6-(4-ethyl-4-hydroxypiperidin-1-yl)quinoline-4-carboxamide (Example 189);

[0545] (R)-N-(2-(4-cyanothiazolidine-3-yl)-2-oxoethyl)-6-(4-hydroxy-4-methylpiperidin-1-yl)quinoline-4-carboxamide (Example 190);

[0546] (R)-N-(2-(4-cyanothiazolidine-3-yl)-2-oxoethyl)-6-(4-fluoro-1-methylpiperidin-4-yl)-quinoline-4-carboxamide (Example 195);

[0547] N-(2-((R)-4-cyanothiazolidine-3-yl)-2-oxoethyl)-6-((RS)-3-fluoro-3-methylpyrrolidine-1-yl)quinoline-4-carboxamide (Example 198);

[0548] N-(2-((R)-4-cyanothiazolidine-3-yl)-2-oxoethyl)-6-((R*)-3-methyl-2-oxopyrrolidine-1-yl)quinoline-4-carboxamide isomer 1 (Example 201);

[0549] N-(2-((R)-4-cyanothiazolidine-3-yl)-2-oxoethyl)-6-((R*)-3-methyl-2-oxopyrrolidine-1-yl)quinoline-4-carboxamide isomer 2 (Example 202);

[0550] N-(2-((R)-4-cyanothiazolidine-3-yl)-2-oxoethyl)-6-((R*)-3-methyl-2-oxopiperidin-1-yl)quinoline-4-carboxamide isomer 1 (Example 203);

[0551] N-(2-((R)-4-cyanothiazolidine-3-yl)-2-oxoethyl)-6-((R*)-3-methyl-2-oxopiperidin-1-yl)quinoline-4-carboxamide isomer 2 (Example 204);

[0552] (R)-N-(2-(4-cyanothiazolidine-3-yl)-2-oxoethyl)-6-(4-fluoropiperidin-1-yl)quinoline-4-carboxamide (Example 205);

[0553] N-(2-((R)-4-cyanothiazolidine-3-yl)-2-oxoethyl)-6-((S)-3-methoxypyrrolidine-1-yl)-quinoline-4-carboxamide (Example 207);

[0554] N-(2-((R)-4-cyanothiazolidine-3-yl)-2-oxoethyl)-6-((3S,4S)-3,4-difluoropyrrolidine-1-yl)quinoline-4-carboxamide (Example 213);

[0555] N-(2-((R)-4-cyanothiazolidine-3-yl)-2-oxoethyl)-6-((S)-3-(hydroxymethyl)pyrrolidine-1-yl)quinoline-4-carboxamide (Example 221):

[0556] N-(2-((R)-4-cyanothiazolidine-3-yl)-2-oxoethyl)-6-((RS)-3,3-difluoro-4-hydroxy-pyrrolidine-1-yl)quinoline-4-carboxamide (Example 224);

[0557] And its pharmaceutically acceptable salts.

[0558] B. R 2 It is a monocyclic or fused bicyclic heterocyclic group (nitrogen, oxygen (or sulfur) and a carbide ring atom).

[0559] 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), and pharmaceutically acceptable salts thereof, wherein R 2 It is a heterocyclic group containing a total of 5 to 10 ring atoms, wherein the heterocyclic ring: (i) is a saturated, partially saturated, or fully unsaturated monocyclic or fused bicyclic ring, (ii) has: (a) a nitrogen ring atom and an oxygen ring atom and the remaining ring atom is carbon, or (b) a nitrogen ring atom and a sulfur ring atom and the remaining ring atom is carbon, and (iii) optionally is substituted by one or more substituents independently selected from the group consisting of: halogen, cyano, oxo, C 1-6 -alkyl, C 3-6 -cycloalkyl, C 1-6 -alkoxy group, C 1-3 -alkoxy-C 1-3 -alkyl, C 1-3 -alkylcarbonyl-C 1-3 -alkyl, and C 1-3 -alkylsulfonyl-C 1-3 -alkyl, and wherein the C 1-6 -alkyl, C 3-6 -cycloalkyl, C 1-6 -alkoxy group, C 1-3 -alkoxy-C 1-3-alkyl, C 1-3 -alkylcarbonyl-C 1-3 -alkyl and C 1-3 -alkylsulfonyl-C 1-3 -Alkyl groups can be further substituted with one or more halogens. In one aspect, R 2 The heterocyclic group ring is a saturated monocyclic ring. In another aspect, R... 2 The heterocyclic base ring is a partially saturated monocyclic ring. In another aspect, R... 2 The heterocyclic group ring is a completely unsaturated monocyclic ring. In another aspect, R... 2 The heterocyclic group ring is a saturated, fused bicyclic ring. In another aspect, R... 2 The heterocyclic ring is a partially saturated, fused bicyclic ring. In another aspect, R... 2 The heterocyclic group ring is a fully unsaturated fused bicyclic ring. In another aspect, R... 2 The heterocyclic base ring has one nitrogen ring atom and one oxygen ring atom, with the remaining ring atoms being carbon. In another aspect, R... 2 The heterocyclic base ring has one nitrogen ring atom and one sulfur ring atom, and the remaining ring atoms are carbon.

[0560] In some embodiments, R 2 Heterocyclic base rings contain a total of 6 to 10 ring atoms.

[0561] In some embodiments, R 2 Heterocyclic rings are selected from the following groups:

[0562]

[0563] The heterocyclic ring is optionally substituted by one or more substituents independently selected from the group consisting of: halogen, cyano, C 1-6 -alkyl, C 3-6 -cycloalkyl, C 1-6 -alkoxy group, C 1-3 -alkoxy-C 1-3 -alkyl, C 1-3 -alkylcarbonyl-C 1-3 -alkyl and C 1-3 -alkylsulfonyl-C 1-3 -alkyl, and wherein the C 1-6 -alkyl, C 1-6 -alkoxy group, C 1-3 -alkoxy-C 1-3 -alkyl, C 3-6 -cycloalkyl, C 1-3 -alkylcarbonyl-C 1-3 -alkyl and C 1-3 -alkylsulfonyl-C 1-3 -Alkyl groups can be further substituted with one or more halogens.

[0564] In some embodiments, R 2 Heterocyclic rings are selected from the following groups:

[0565]

[0566] The heterocyclic ring is optionally substituted by one or more substituents independently selected from the group consisting of: halogen, cyano, C 1-6 -alkyl, C 3-6 -cycloalkyl, C 1-6 -alkoxy group, C 1-3 -alkoxy-C 1-3 -alkyl, C 1-3 -alkylcarbonyl-C 1-3 -alkyl and C 1-3 -alkylsulfonyl-C 1-3 -alkyl, and wherein the C 1-6 -alkyl, C 1-6 -alkoxy group, C 1-3 -alkoxy-C 1-3 -alkyl, C 3-6 -cycloalkyl, C 1-3 -alkylcarbonyl-C 1-3 -alkyl and C 1-3 -alkylsulfonyl-C 1-3 -Alkyl groups can be further substituted with one or more halogens.

[0567] In some embodiments, R 2 Heterocyclic rings are selected from the following groups:

[0568]

[0569] The heterocyclic ring is optionally substituted by one or more substituents independently selected from the group consisting of: halogen, cyano, C. 1-6 -alkyl, C 3-6 -cycloalkyl, C 1-6 -alkoxy group, C 1-3 -alkoxy-C 1-3 -alkyl, C 1-3 -alkylcarbonyl-C 1-3 -alkyl, and C 1-3 -alkylsulfonyl-C 1-3 -alkyl, and wherein the C 1-6 -alkyl, C 3-6 -cycloalkyl, C 1-6 -alkoxy group, C 1-3 -alkoxy-C 1-3 -alkyl, C 1-3 -alkylcarbonyl-C 1-3-alkyl, and C 1-3 -alkylsulfonyl-C 1-3 -Alkyl groups can be further substituted with one or more halogens.

[0570] In some embodiments, R 2 The heterocyclic ring may optionally be substituted by one or more substituents independently selected from the group consisting of: halogen, cyano, C. 1-3 -alkyl, C 3-5 -cycloalkyl, C 1-3 -alkoxy group, C 1-3 -alkoxy-C 1-3 -alkyl, C 1-3 -alkylcarbonyl-C 1-3 -alkyl and C 1-3 -alkylsulfonyl-C 1-3 -alkyl, wherein the C 1-3 -alkyl, C 1-3 -alkoxy group, C 1-3 -alkoxy-C 1-3 -alkyl, C 1-3 -alkylcarbonyl-C 1-3 -alkyl, C 3-5 -Cycloalkyl and C 1-3 -alkylsulfonyl-C 1-3 -Alkyl groups can be further substituted with one or more halogens.

[0571] In some embodiments, R 2 The heterocyclic ring may optionally be substituted by one or more substituents independently selected from the group consisting of: halogen, cyano, C. 1-2 -alkyl, C 3-4 -cycloalkyl, C 1-2 -alkoxy group, C 1-2 -alkoxy-C 1-3 -alkyl, C 1-2 -alkylcarbonyl-C 1-2 -alkyl and C 1-2 -alkylsulfonyl-C 1-2 -alkyl, wherein the C 1-2 -alkyl, C 3-4 -cycloalkyl, C 1-2 -alkoxy group, C 1-2 -alkoxy-C 1-2 -alkyl, C 1-2 -alkylcarbonyl-C 1-2 -alkyl and C 1-2 -alkylsulfonyl-C 1-2 -Alkyl groups can be further substituted with one or more halogens.

[0572] In some embodiments, R 2The heterocyclic ring is optionally substituted with one or more halogens. In one aspect, R 2 The heterocyclic ring may optionally be substituted with one or more fluorine molecules.

[0573] In some embodiments, R 2 The heterocyclic base ring is optionally separated by one or more C 1-3 -alkyl substitution, wherein the C 1-3 -Alkyl groups can be further substituted with one or more halogens.

[0574] In some embodiments, R 2 The heterocyclic base ring is optionally separated by one or more C 3-6 - Cycloalkyl substitution, wherein the C 3-6 -Cycloalkyl groups can be further substituted with one or more halogens.

[0575] In some embodiments, R 2 The heterocyclic base ring is optionally separated by one or more C 1-3 -alkoxy-C 1-3 -alkyl substitution, wherein the C 1-3 -alkoxy-C 1-3 -Alkyl groups can be further substituted with one or more halogens.

[0576] In some embodiments, R 2 The heterocyclic base ring is optionally separated by one or more C 1-3 -alkylsulfonyl-C 1-3 -alkyl substitution, wherein the C 1-3 -alkylsulfonyl-C 1-3 -Alkyl groups can be further substituted with one or more halogens.

[0577] In some embodiments, R 2 The heterocyclic ring may optionally be substituted by one or more substituents independently selected from the group consisting of: cyano, fluorine, methyl, ethyl, propyl, isopropyl, cyclopropyl, fluoromethyl, difluoromethyl, trifluoromethyl, fluoroethyl, difluoroethyl, trifluoroethyl, trifluoropropyl, methoxy, ethoxy, isopropoxy, trifluoromethoxy, trifluoroethoxy, methoxymethyl, methoxyethyl, trifluoromethoxymethyl, and methylsulfonylmethyl.

[0578] In some embodiments, R 2 The heterocyclic ring may optionally be substituted by one or more substituents independently selected from the group consisting of: fluorine, methyl, ethyl, isopropyl, cyclopropyl, fluoromethyl, difluoropropyl, methoxy, and trifluoromethoxy.

[0579] In some embodiments, R 2 The heterocyclic base ring is:

[0580]

[0581] Where R 2 The heterocyclic ring may optionally be substituted by one or more substituents independently selected from the group consisting of: halogen, cyano, oxo, C. 1-6 -alkyl, C 3-6 -cycloalkyl, C 1-6 -alkoxy group, C 1-3 -alkoxy-C 1-3 -alkyl, C 1-3 -alkylcarbonyl-C 1-3 -alkyl and C 1-3 -alkylsulfonyl-C 1-3 -alkyl, and wherein the C 1-6 -alkyl, C 3-6 -cycloalkyl, C 1-6 -alkoxy group, C 1-3 -alkoxy-C 1-3 -alkyl, C 1-3 -alkylcarbonyl-C 1-3 -alkyl and C 1-3 -alkylsulfonyl-C 1-3 -Alkyl groups can be further substituted with one or more halogens. In one aspect, R 2 The heterocyclic ring may optionally be substituted by one or more substituents independently selected from the group consisting of: halogen, cyano, C. 1-3 -alkyl, C 3-5 -cycloalkyl, C 1-3 -alkoxy group, C 1-3 -alkoxy-C 1-3 -alkyl, C 1-3 -alkylcarbonyl-C 1-3 -alkyl, and C 1-3 -alkylsulfonyl-C 1-3 -alkyl, wherein the C 1-3 -alkyl, C 3-5 -cycloalkyl, C 1-3 -alkoxy group, C 1-3 -alkoxy-C 1-3 -alkyl, C 1-3 -alkylcarbonyl-C 1-3 -alkyl, and C 1-3 -alkylsulfonyl-C 1-3 -alkyl groups can be further substituted with one or more halogens. In another aspect, R 2The heterocyclic ring is optionally substituted by one or more substituents independently selected from the group consisting of: fluorine, cyano, methyl, ethyl, propyl, isopropyl, cyclopropyl, fluoromethyl, difluoromethyl, trifluoromethyl, fluoroethyl, difluoroethyl, trifluoroethyl, trifluoropropyl, methoxy, ethoxy, trifluoromethoxy, trifluoroethoxy, methoxymethyl, methoxyethyl, trifluoromethoxymethyl, and methylsulfonylmethyl. In another aspect, R 2 The heterocyclic ring may optionally be substituted by one or more substituents independently selected from the group consisting of: fluorine, methyl, ethyl, fluoromethyl, trifluoromethyl, difluoropropyl, methoxy, trifluoromethoxy, and methoxymethyl.

[0582] In some embodiments, the compound and pharmaceutically acceptable salt are selected from the group consisting of:

[0583] (R)-N-(2-(4-cyanothiazolidine-3-yl)-2-oxoethyl)-3-fluoro-6-morpholinoquinoline-4-carboxamide (Example 2);

[0584] (R)-N-(2-(4-cyanothiazolidine-3-yl)-2-oxoethyl)-6-(2,2-difluoromorpholino)quinoline-4-carboxamide (Example 4);

[0585] (R)-N-(2-(4-cyanothiazolidine-3-yl)-2-oxoethyl)-6-(2,2,6,6-tetrafluoromorpholino)-quinoline-4-carboxamide (Example 5);

[0586] (R)-N-(2-(4-cyanothiazolidine-3-yl)-2-oxoethyl)-8-methyl-6-morpholinoquinoline-4-carboxamide (Example 9);

[0587] (R)-N-(2-(4-cyanothiazolidine-3-yl)-2-oxoethyl)-7-methyl-6-morpholinoquinoline-4-carboxamide (Example 10);

[0588] (R)-N-(2-(4-cyanothiazolidine-3-yl)-2-oxoethyl)-6-(2,2-dimethyl-3-oxomorpholino)-quinoline-4-carboxamide (Example 16);

[0589] (R)-N-(2-(4-cyanothiazolidine-3-yl)-2-oxoethyl)-6-morpholinoquinoline-4-carboxamide (Example 67);

[0590] N-(2-((R)-4-cyanothiazolidine-3-yl)-2-oxoethyl)-6-((2R,6S)-2,6-dimethylmorpholino)-quinoline-4-carboxamide (Example 68);

[0591] N-(2-((R)-4-cyanothiazolidine-3-yl)-2-oxoethyl)-6-((R)-2-(fluoromethyl)morpholino)-quinoline-4-carboxamide (Example 69);

[0592] N-(2-((R)-4-cyanothiazolidine-3-yl)-2-oxoethyl)-6-((2R,6R)-2,6-dimethylmorpholino)-quinoline-4-carboxamide (Example 70);

[0593] N-(2-((R)-4-cyanothiazolidine-3-yl)-2-oxoethyl)-6-((S)-2-(fluoromethyl)morpholino)-quinoline-4-carboxamide (Example 71);

[0594] N-(2-((R)-4-cyanothiazolidine-3-yl)-2-oxoethyl)-6-((R)-2-methylmorpholino)-quinoline-4-carboxamide (Example 72);

[0595] N-(2-((R)-4-cyanothiazolidine-3-yl)-2-oxoethyl)-6-((R)-2-(trifluoromethyl)-morpholino)quinoline-4-carboxamide (Example 73);

[0596] N-(2-((R)-4-cyanothiazolidine-3-yl)-2-oxoethyl)-6-((S)-2-(trifluoromethyl)-morpholino)quinoline-4-carboxamide (Example 74);

[0597] N-(2-((R)-4-cyanothiazolidine-3-yl)-2-oxoethyl)-6-((2S,6S)-2,6-dimethylmorpholino)-quinoline-4-carboxamide (Example 78);

[0598] N-(2-((R)-4-cyanothiazolidine-3-yl)-2-oxoethyl)-6-((S)-2-methylmorpholino)-quinoline-4-carboxamide (Example 80):

[0599] N-(2-((R)-4-cyanothiazolidine-3-yl)-2-oxoethyl)-6-((2R,3S)-2,3-dimethyl-morpholino)quinoline-4-carboxamide (Example 81);

[0600] N-(2-((R)-4-cyanothiazolidine-3-yl)-2-oxoethyl)-6-((2S,3S)-2,3-dimethylmorpholino)quinoline-4-carboxamide (Example 82);

[0601] N-(2-((R)-4-cyanothiazolidine-3-yl)-2-oxoethyl)-6-((2R,3R)-2,3-dimethyl-morpholino)quinoline-4-carboxamide (Example 83);

[0602] N-(2-((R)-4-cyanothiazolidine-3-yl)-2-oxoethyl)-6-((R*)-3-(trifluoromethyl)-morpholino)quinoline-4-carboxamide isomer 1 (Example 84);

[0603] N-(2-((R)-4-cyanothiazolidine-3-yl)-2-oxoethyl)-6-((R*)-3-(trifluoromethyl)-morpholino)quinoline-4-carboxamide isomer 2 (Example 85);

[0604] N-(2-((R)-4-cyanothiazolidine-3-yl)-2-oxoethyl)-6-((2R,5R)-2,5-dimethylmorpholino)quinoline-4-carboxamide (Example 87);

[0605] (R)-N-(2-(4-cyanothiazolidine-3-yl)-2-oxoethyl)-6-(2,2-dimethylmorpholino)-quinoline-4-carboxamide (Example 88);

[0606] N-(2-((R)-4-cyanothiazolidine-3-yl)-2-oxoethyl)-6-((S)-3-(methoxymethyl)-morpholino)quinoline-4-carboxamide (Example 89);

[0607] N-(2-((R)-4-cyanothiazolidine-3-yl)-2-oxoethyl)-6-((3S,5R)-3,5-dimethyl-morpholino)quinoline-4-carboxamide (Example 90);

[0608] N-(2-((R)-4-cyanothiazolidine-3-yl)-2-oxoethyl)-6-((R)-2-((methanesulfonyl)-methyl)morpholino)quinoline-4-carboxamide (Example 92);

[0609] N-(2-((R)-4-cyanothiazolidine-3-yl)-2-oxoethyl)-6-((S)-2-(methoxymethyl)-morpholino)quinoline-4-carboxamide (Example 93);

[0610] N-(2-((R)-4-cyanothiazolidine-3-yl)-2-oxoethyl)-6-((S)-2-((methanesulfonyl)-methyl)morpholino)quinoline-4-carboxamide (Example 94);

[0611] N-(2-((R)-4-cyanothiazolidine-3-yl)-2-oxoethyl)-6-((R)-3-(2-methoxyethyl)-morpholino)quinoline-4-carboxamide (Example 95);

[0612] N-(2-((R)-4-cyanothiazolidine-3-yl)-2-oxoethyl)-6-((2S,3S)-3-(methoxymethyl)-2-methylmorpholino)quinoline-4-carboxamide (Example 96);

[0613] N-(2-((R)-4-cyanothiazolidine-3-yl)-2-oxoethyl)-6-((2R,3R)-3-(methoxymethyl)-2-methylmorpholino)quinoline-4-carboxamide (Example 97);

[0614] 7-Bromo-N-(2-((R)-4-cyanothiazolidine-3-yl)-2-oxoethyl)-6-((3S,5R)-3,5-dimethylmorpholino)quinoline-4-carboxamide (Example 100);

[0615] (R)-5-chloro-N-(2-(4-cyanothiazolidine-3-yl)-2-oxoethyl)-6-morpholinoquinoline-4-carboxamide (Example 101);

[0616] N-(2-((R)-4-cyanothiazolidine-3-yl)-2-oxoethyl)-6-((S)-3-methylmorpholino)-quinoline-4-carboxamide (Example 102);

[0617] N-(2-((R)-4-cyanothiazolidine-3-yl)-2-oxoethyl)-6-((3S,5S)-3,5-dimethylmorpholino)-quinoline-4-carboxamide (Example 103);

[0618] N-(2-((R)-4-cyanothiazolidine-3-yl)-2-oxoethyl)-6-((3R,5R)-3,5-dimethylmorpholino)-quinoline-4-carboxamide (Example 105);

[0619] N-(2-((R)-4-cyanothiazolidine-3-yl)-2-oxoethyl)-6-((S)-3-ethylmorpholino)quinoline-4-carboxamide (Example 106);

[0620] (R)-N-(2-(4-cyanothiazolidine-3-yl)-2-oxoethyl)-6-(3,3-dimethylmorpholino)-quinoline-4-carboxamide (Example 107);

[0621] N-(2-((R)-4-cyanothiazolidine-3-yl)-2-oxoethyl)-6-((R)-3-methylmorpholino)-quinoline-4-carboxamide (Example 108);

[0622] (R)-N-(2-(4-cyanothiazolidine-3-yl)-2-oxoethyl)-2-methyl-6-morpholinoquinoline-4-carboxamide (Example 109);

[0623] (R)-7-chloro-N-(2-(4-cyanothiazolidine-3-yl)-2-oxoethyl)-6-morpholinoquinoline-4-carboxamide (Example 179);

[0624] (R)-8-chloro-N-(2-(4-cyanothiazolidine-3-yl)-2-oxoethyl)-6-morpholinoquinoline-4-carboxamide (Example 180);

[0625] And its pharmaceutically acceptable salts.

[0626] In some embodiments, the compound and pharmaceutically acceptable salt are selected from the group consisting of:

[0627] (R)-N-(2-(4-cyanothiazolidine-3-yl)-2-oxoethyl)-8-methyl-6-morpholinoquinoline-4-carboxamide (Example 9);

[0628] (R)-N-(2-(4-cyanothiazolidine-3-yl)-2-oxoethyl)-6-morpholinoquinoline-4-carboxamide (Example 67);

[0629] N-(2-((R)-4-cyanothiazolidine-3-yl)-2-oxoethyl)-6-((2R,6S)-2,6-dimethylmorpholino)-quinoline-4-carboxamide (Example 68);

[0630] N-(2-((R)-4-cyanothiazolidine-3-yl)-2-oxoethyl)-6-((R)-2-(fluoromethyl)morpholino)-quinoline-4-carboxamide (Example 69);

[0631] N-(2-((R)-4-cyanothiazolidine-3-yl)-2-oxoethyl)-6-((2R,6R)-2,6-dimethylmorpholino)-quinoline-4-carboxamide (Example 70);

[0632] N-(2-((R)-4-cyanothiazolidine-3-yl)-2-oxoethyl)-6-((S)-2-(fluoromethyl)morpholino)-quinoline-4-carboxamide (Example 71);

[0633] N-(2-((R)-4-cyanothiazolidine-3-yl)-2-oxoethyl)-6-((R)-2-methylmorpholino)-quinoline-4-carboxamide (Example 72);

[0634] N-(2-((R)-4-cyanothiazolidine-3-yl)-2-oxoethyl)-6-((R)-2-(trifluoromethyl)-morpholino)quinoline-4-carboxamide (Example 73);

[0635] N-(2-((R)-4-cyanothiazolidine-3-yl)-2-oxoethyl)-6-((S)-2-(trifluoromethyl)-morpholino)quinoline-4-carboxamide (Example 74);

[0636] N-(2-((R)-4-cyanothiazolidine-3-yl)-2-oxoethyl)-6-((2S,6S)-2,6-dimethylmorpholino)-quinoline-4-carboxamide (Example 78);

[0637] N-(2-((R)-4-cyanothiazolidine-3-yl)-2-oxoethyl)-6-((S)-2-methylmorpholino)-quinoline-4-carboxamide (Example 80);

[0638] N-(2-((R)-4-cyanothiazolidine-3-yl)-2-oxoethyl)-6-((2R,3S)-2,3-dimethylmorpholino)-quinoline-4-carboxamide (Example 81);

[0639] N-(2-((R)-4-cyanothiazolidine-3-yl)-2-oxoethyl)-6-((2S,3S)-2,3-dimethylmorpholino)-quinoline-4-carboxamide (Example 82);

[0640] (R)-N-(2-(4-cyanothiazolidine-3-yl)-2-oxoethyl)-6-(2,2-dimethylmorpholino)-quinoline-4-carboxamide (Example 88);

[0641] N-(2-((R)-4-cyanothiazolidine-3-yl)-2-oxoethyl)-6-((S)-3-(methoxymethyl)-morpholino)quinoline-4-carboxamide (Example 89);

[0642] N-(2-((R)-4-cyanothiazolidine-3-yl)-2-oxoethyl)-6-((S)-2-(methoxymethyl)-morpholino)quinoline-4-carboxamide (Example 93);

[0643] N-(2-((R)-4-cyanothiazolidine-3-yl)-2-oxoethyl)-6-((2R,3R)-3-(methoxymethyl)-2-methylmorpholino)-quinoline-4-carboxamide (Example 97);

[0644] N-(2-((R)-4-cyanothiazolidine-3-yl)-2-oxoethyl)-6-((S)-3-methylmorpholino)-quinoline-4-carboxamide (Example 102);

[0645] N-(2-((R)-4-cyanothiazolidine-3-yl)-2-oxoethyl)-6-((S)-3-ethylmorpholino)quinoline-4-carboxamide (Example 106);

[0646] (R)-N-(2-(4-cyanothiazolidine-3-yl)-2-oxoethyl)-6-(3,3-dimethylmorpholino)-quinoline-4-carboxamide (Example 107);

[0647] And its pharmaceutically acceptable salts.

[0648] In some embodiments, R 2 The heterocyclic base ring is:

[0649]

[0650] The heterocyclic ring is optionally substituted by one or more substituents independently selected from the group consisting of: halogen, cyano, oxo, C 1-6 -alkyl, C 3-6 -cycloalkyl, C 1-6 -alkoxy group, C 1-3 -alkoxy-C 1-3 -alkyl, C 1-3 -alkylcarbonyl-C 1-3 -alkyl, and C 1-3 -alkylsulfonyl-C 1-3 -alkyl, and wherein the C 1-6 -alkyl, C 3-6 -cycloalkyl, C 1-6 -alkoxy group, C 1-3 -alkoxy-C 1-3 -alkyl, C 1-3 -alkylcarbonyl-C 1-3 -alkyl, and C 1-3 -alkylsulfonyl-C 1-3 -Alkyl groups can be further substituted with one or more halogens. In one aspect, R 2 The heterocyclic ring may optionally be substituted by one or more substituents independently selected from the group consisting of: halogen, cyano, C. 1-3 -alkyl, C 3-6 -cycloalkyl, C 1-3 -alkoxy group, C 1-3 -alkoxy-C 1-3 -alkyl, C 1-3 -alkylcarbonyl-C 1-3 -alkyl, and C 1-3 -alkylsulfonyl-C 1-3 -alkyl, wherein the C 1-3 -alkyl, C 3-6 -cycloalkyl, C 1-3 -alkoxy group, C 1-3 -alkoxy-C 1-3 -alkyl, C 1-3 -alkylcarbonyl-C1-3 -alkyl, and C 1-3 -alkylsulfonyl-C 1-3 -alkyl groups can be further substituted with one or more halogens. In another aspect, R 2 The heterocyclic ring is optionally substituted by one or more substituents independently selected from the group consisting of: halogen, cyano, fluorine, methyl, ethyl, propyl, isopropyl, cyclopropyl, fluoromethyl, difluoromethyl, trifluoromethyl, fluoroethyl, difluoroethyl, trifluoroethyl, trifluoropropyl, methoxy, ethoxy, trifluoromethoxy, trifluoroethoxy, methoxymethyl, trifluoromethoxymethyl, and methanesulfonylmethyl. In another aspect, R 2 The heterocyclic ring may optionally be substituted by one or more substituents independently selected from the group consisting of: fluorine, methyl, ethyl, isopropyl, cyclopropyl, fluoromethyl, difluoropropyl, methoxy, and trifluoromethoxy.

[0651] In some embodiments, the compound or pharmaceutically acceptable salt is (R)-N-(2-(4-cyanothiazolidine-3-yl)-2-oxoethyl)-6-thiomorpholine-quinoline-4-carboxamide (Example 3), or a pharmaceutically acceptable salt thereof.

[0652] In some embodiments, R 2 The heterocyclic base ring is:

[0653]

[0654] The heterocyclic ring is optionally substituted by one or more substituents independently selected from the group consisting of: halogen, cyano, C. 1-6 -alkyl, C 3-6 -cycloalkyl, C 1-6 -alkoxy group, C 1-3 -alkoxy-C 1-3 -alkyl, C 1-3 -alkylcarbonyl-C 1-3 -alkyl, and C 1-3 -alkylsulfonyl-C 1-3 -alkyl, and wherein the C 1-6 -alkyl, C 3-6 -cycloalkyl, C 1-6 -alkoxy group, C 1-3 -alkoxy-C 1-3 -alkyl, C 1-3 -alkylcarbonyl-C 1-3 -alkyl, and C 1-3 -alkylsulfonyl-C 1-3 -Alkyl groups can be further substituted with one or more halogens. In one aspect, R 2The heterocyclic ring may optionally be substituted by one or more substituents independently selected from the group consisting of: halogen, cyano, C. 1-3 -alkyl, C 3-6 -cycloalkyl, C 1-3 -alkoxy group, C 1-3 -alkoxy-C 1-3 -alkyl, C 1-3 -alkylcarbonyl-C 1-3 -alkyl, and C 1-3 -alkylsulfonyl-C 1-3 -alkyl, wherein the C 1-3 -alkyl, C 3-6 -cycloalkyl, C 1-3 -alkoxy group, C 1-3 -alkoxy-C 1-3 -alkyl, C 1-3 -alkylcarbonyl-C 1-3 -alkyl, and C 1-3 -alkylsulfonyl-C 1-3 -alkyl groups can be further substituted with one or more halogens. In another aspect, R 2 The heterocyclic ring is optionally substituted by one or more substituents independently selected from the group consisting of: cyano, fluorine, methyl, ethyl, propyl, isopropyl, cyclopropyl, fluoromethyl, difluoromethyl, trifluoromethyl, fluoroethyl, difluoroethyl, trifluoroethyl, trifluoropropyl, methoxy, ethoxy, trifluoromethoxy, trifluoroethoxy, methoxymethyl, trifluoromethoxymethyl, and methanesulfonylmethyl. In another aspect, R 2 The heterocyclic ring may optionally be substituted by one or more substituents independently selected from the group consisting of: fluorine, methyl, ethyl, isopropyl, cyclopropyl, fluoromethyl, difluoropropyl, methoxy, and trifluoromethoxy.

[0655] In some embodiments, the compound or pharmaceutically acceptable salt is (R)-N-(2-(4-cyanothiazolidine-3-yl)-2-oxoethyl)-6-(2,2-dimethyl-3-oxomorpholino)quinoline-4-carboxamide (Example 16), or a pharmaceutically acceptable salt thereof.

[0656] In some embodiments, R 2 The heterocyclic base ring is:

[0657]

[0658] The heterocyclic ring is optionally substituted by one or more substituents independently selected from the group consisting of: halogen, cyano, C. 1-6 -alkyl, C 3-6 -cycloalkyl, C 1-6 -alkoxy group, C 1-3 -alkoxy-C1-3 -alkyl, C 1-3 -alkylcarbonyl-C 1-3 -alkyl, and C 1-3 -alkylsulfonyl-C 1-3 -alkyl, and wherein the C 1-6 -alkyl, C 3-6 -cycloalkyl, C 1-6 -alkoxy group, C 1-3 -alkoxy-C 1-3 -alkyl, C 1-3 -alkylcarbonyl-C 1-3 -alkyl, and C 1-3 -alkylsulfonyl-C 1-3 -Alkyl groups can be further substituted with one or more halogens. In one aspect, R 2 The heterocyclic ring may optionally be substituted by one or more substituents independently selected from the group consisting of: halogen, cyano, C. 1-3 -alkyl, C 3-6 -cycloalkyl, C 1-3 -alkoxy group, C 1-3 -alkoxy-C 1-3 -alkyl, C 1-3 -alkylcarbonyl-C 1-3 -alkyl, and C 1-3 -alkylsulfonyl-C 1-3 -alkyl, wherein the C 1-3 -alkyl, C 3-6 -cycloalkyl, C 1-3 -alkoxy group, C 1-3 -alkoxy-C 1-3 -alkyl, C 1-3 -alkylcarbonyl-C 1-3 -alkyl, and C 1-3 -alkylsulfonyl-C 1-3 -alkyl groups can be further substituted with one or more halogens. In another aspect, R 2 The heterocyclic ring is optionally substituted by one or more substituents independently selected from the group consisting of: cyano, fluorine, methyl, ethyl, propyl, isopropyl, cyclopropyl, fluoromethyl, difluoromethyl, trifluoromethyl, fluoroethyl, difluoroethyl, trifluoroethyl, trifluoropropyl, methoxy, ethoxy, trifluoromethoxy, trifluoroethoxy, methoxymethyl, trifluoromethoxymethyl, and methanesulfonylmethyl. In another aspect, R 2 The heterocyclic ring is optionally substituted by one or more substituents independently selected from the group consisting of: fluorine, methyl, ethyl, isopropyl, cyclopropyl, fluoromethyl, difluoropropyl, methoxy, and trifluoromethoxy. In another aspect, R 2The heterocyclic ring may optionally be substituted by one or more substituents independently selected from the group consisting of: fluorine, methyl, ethyl, fluoromethyl, difluoropropyl, methoxy, and trifluoromethoxy.

[0659] In some embodiments, the compound or pharmaceutically acceptable salt is (R)-N-(2-(4-cyanothiazolidine-3-yl)-2-oxoethyl)-6-(6,6-dimethyl-2-oxo-1,3-oxazinidine-3-yl)quinoline-4-carboxamide (Example 112), or a pharmaceutically acceptable salt thereof.

[0660] In some embodiments, R 2 The heterocyclic base ring is:

[0661]

[0662] The heterocyclic ring is optionally substituted by one or more substituents independently selected from the group consisting of: halogen, cyano, oxo, C 1-6 -alkyl, C 3-6 -cycloalkyl, C 1-6 -alkoxy group, C 1-3 -alkoxy-C 1-3 -alkyl, C 1-3 -alkylcarbonyl-C 1-3 -alkyl, and C 1-3 -alkylsulfonyl-C 1-3 -alkyl, and wherein the C 1-6 -alkyl, C 3-6 -cycloalkyl, C 1-6 -alkoxy group, C 1-3 -alkoxy-C 1-3 -alkyl, C 1-3 -alkylcarbonyl-C 1-3 -alkyl, and C 1-3 -alkylsulfonyl-C 1-3 -Alkyl groups can be further substituted with one or more halogens. In one aspect, R 2 The heterocyclic ring may optionally be substituted by one or more substituents independently selected from the group consisting of: halogen, cyano, C. 1-3 -alkyl, C 3-6 -cycloalkyl, C 1-3 -alkoxy group, C 1-3 -alkoxy-C 1-3 -alkyl, C 1-3 -alkylcarbonyl-C 1-3 -alkyl, and C 1-3 -alkylsulfonyl-C 1-3 -alkyl, wherein the C 1-3 -alkyl, C 3-6 -cycloalkyl, C 1-3-alkoxy group, C 1-3 -alkoxy-C 1-3 -alkyl, C 1-3 -alkylcarbonyl-C 1-3 -alkyl, and C 1-3 -alkylsulfonyl-C 1-3 -alkyl groups can be further substituted with one or more halogens. In another aspect, R 2 The heterocyclic ring is optionally substituted by one or more substituents independently selected from the group consisting of: cyano, fluorine, methyl, ethyl, propyl, isopropyl, cyclopropyl, fluoromethyl, difluoromethyl, trifluoromethyl, fluoroethyl, difluoroethyl, trifluoroethyl, trifluoropropyl, methoxy, ethoxy, trifluoromethoxy, trifluoroethoxy, methoxymethyl, trifluoromethoxymethyl, and methanesulfonylmethyl. In another aspect, R 2 The heterocyclic ring may optionally be substituted by one or more substituents independently selected from the group consisting of: fluorine, methyl, ethyl, isopropyl, fluoromethyl, difluoropropyl, methoxy, and trifluoromethoxy.

[0663] In some embodiments, the compound or pharmaceutically acceptable salt is 6-(6-oxa-3-azabicyclo[3.1.1]heptane-3-yl)-N-(2-((R)-4-cyanothiazolidine-3-yl)-2-oxoethyl)quinoline-4-carboxamide (Example 77), or a pharmaceutically acceptable salt thereof.

[0664] In some embodiments, R 2 The heterocyclic base ring is:

[0665]

[0666] The heterocyclic ring is optionally substituted by one or more substituents independently selected from the group consisting of: halogen, cyano, oxo, C 1-6 -alkyl, C 3-6 -cycloalkyl, C 1-6 -alkoxy group, C 1-3 -alkoxy-C 1-3 -alkyl, C 1-3 -alkylcarbonyl-C 1-3 -alkyl, and C 1-3 -alkylsulfonyl-C 1-3 -alkyl, and wherein the C 1-6 -alkyl, C 3-6 -cycloalkyl, C 1-6 -alkoxy group, C 1-3 -alkoxy-C 1-3 -alkyl, C 1-3 -alkylcarbonyl-C 1-3 -alkyl, and C 1-3 -alkylsulfonyl-C1-3 -Alkyl groups can be further substituted with one or more halogens. In one aspect, R 2 The heterocyclic ring may optionally be substituted by one or more substituents independently selected from the group consisting of: halogen, cyano, C. 1-3 -alkyl, C 3-6 -cycloalkyl, C 1-3 -alkoxy group, C 1-3 -alkoxy-C 1-3 -alkyl, C 1-3 -alkylcarbonyl-C 1-3 -alkyl, and C 1-3 -alkylsulfonyl-C 1-3 -alkyl, wherein the C 1-3 -alkyl, C 3-6 -cycloalkyl, C 1-3 -alkoxy group, C 1-3 -alkoxy-C 1-3 -alkyl, C 1-3 -alkylcarbonyl-C 1-3 -alkyl, and C 1-3 -alkylsulfonyl-C 1-3 -alkyl groups can be further substituted with one or more halogens. In another aspect, R 2 The heterocyclic ring is optionally substituted by one or more substituents independently selected from the group consisting of: cyano, fluorine, methyl, ethyl, propyl, isopropyl, cyclopropyl, fluoromethyl, difluoromethyl, trifluoromethyl, fluoroethyl, difluoroethyl, trifluoroethyl, trifluoropropyl, methoxy, ethoxy, trifluoromethoxy, trifluoroethoxy, methoxymethyl, trifluoromethoxymethyl, and methanesulfonylmethyl. In another aspect, R 2 The heterocyclic ring may optionally be substituted by one or more substituents independently selected from the group consisting of: fluorine, methyl, ethyl, fluoromethyl, difluoropropyl, methoxy, and trifluoromethoxy.

[0667] In some embodiments, the compound and pharmaceutically acceptable salt are selected from the group consisting of:

[0668] 6-((1S,4S)-2-oxa-5-azabicyclo[2.2.1]heptane-5-yl)-N-(2-((R)-4-cyanothiazolidine-3-yl)-2-oxoethyl)quinoline-4-carboxamide (Example 75);

[0669] 6-((1R,4R)-2-oxa-5-azabicyclo[2.2.1]heptane-5-yl)-N-(2-((R)-4-cyanothiazolidine-3-yl)-2-oxoethyl)quinoline-4-carboxamide (Example 76);

[0670] And its pharmaceutically acceptable salts.

[0671] In some embodiments, R 2 The heterocyclic base ring is:

[0672]

[0673] The heterocyclic ring is optionally substituted by one or more substituents independently selected from the group consisting of: halogen, cyano, oxo, C 1-6 -alkyl, C 3-6 -cycloalkyl, C 1-6 -alkoxy group, C 1-3 -alkoxy-C 1-3 -alkyl, C 1-3 -alkylcarbonyl-C 1-3 -alkyl, and C 1-3 -alkylsulfonyl-C 1-3 -alkyl, and wherein the C 1-6 -alkyl, C 3-6 -cycloalkyl, C 1-6 -alkoxy group, C 1-3 -alkoxy-C 1-3 -alkyl, C 1-3 -alkylcarbonyl-C 1-3 -alkyl, and C 1-3 -alkylsulfonyl-C 1-3 -Alkyl groups can be further substituted with one or more halogens. In one aspect, R 2 The heterocyclic ring may optionally be substituted by one or more substituents independently selected from the group consisting of: halogen, cyano, C. 1-3 -alkyl, C 3-6 -cycloalkyl, C 1-3 -alkoxy group, C 1-3 -alkoxy-C 1-3 -alkyl, C 1-3 -alkylcarbonyl-C 1-3 -alkyl, and C 1-3 -alkylsulfonyl-C 1-3 -alkyl, wherein the C 1-3 -alkyl, C 3-6 -cycloalkyl, C 1-3 -alkoxy group, C 1-3 -alkoxy-C 1-3 -alkyl, C 1-3 -alkylcarbonyl-C 1-3 -alkyl, and C 1-3 -alkylsulfonyl-C 1-3 -alkyl groups can be further substituted with one or more halogens. In another aspect, R 2The heterocyclic ring is optionally substituted by one or more substituents independently selected from the group consisting of: cyano, fluorine, methyl, ethyl, propyl, isopropyl, cyclopropyl, fluoromethyl, difluoromethyl, trifluoromethyl, fluoroethyl, difluoroethyl, trifluoroethyl, trifluoropropyl, methoxy, ethoxy, trifluoromethoxy, trifluoroethoxy, methoxymethyl, trifluoromethoxymethyl, and methanesulfonylmethyl. In another aspect, R 2 The heterocyclic ring may optionally be substituted by one or more substituents independently selected from the group consisting of: fluorine, methyl, ethyl, fluoromethyl, difluoropropyl, methoxy, and trifluoromethoxy.

[0674] In some embodiments, the compound or pharmaceutically acceptable salt is 6-(3-oxa-8-azabicyclo[3.2.1]octane-8-yl)-N-(2-((R)-4-cyanothiazolidine-3-yl)-2-oxoethyl)quinoline-4-carboxamide (Example 98), or a pharmaceutically acceptable salt thereof.

[0675] In some embodiments, R 2 The heterocyclic base ring is:

[0676]

[0677] The heterocyclic ring is optionally substituted by one or more substituents independently selected from the group consisting of: halogen, cyano, oxo, C 1-6 -alkyl, C 3-6 -cycloalkyl, C 1-6 -alkoxy group, C 1-3 -alkoxy-C 1-3 -alkyl, C 1-3 -alkylcarbonyl-C 1-3 -alkyl, and C 1-3 -alkylsulfonyl-C 1-3 -alkyl, and wherein the C 1-6 -alkyl, C 3-6 -cycloalkyl, C 1-6 -alkoxy group, C 1-3 -alkoxy-C 1-3 -alkyl, C 1-3 -alkylcarbonyl-C 1-3 -alkyl, and C 1-3 -alkylsulfonyl-C 1-3 -Alkyl groups can be further substituted with one or more halogens. In one aspect, R 2 The heterocyclic ring may optionally be substituted by one or more substituents independently selected from the group consisting of: halogen, cyano, C. 1-3 -alkyl, C 3-6 -cycloalkyl, C 1-3 -alkoxy group, C 1-3-alkoxy-C 1-3 -alkyl, C 1-3 -alkylcarbonyl-C 1-3 -alkyl, and C 1-3 -alkylsulfonyl-C 1-3 -alkyl, wherein the C 1-3 -alkyl, C 3-6 -cycloalkyl, C 1-3 -alkoxy group, C 1-3 -alkoxy-C 1-3 -alkyl, C 1-3 -alkylcarbonyl-C 1-3 -alkyl, and C 1-3 -alkylsulfonyl-C 1-3 -alkyl groups can be further substituted with one or more halogens. In another aspect, R 2 The heterocyclic ring is optionally substituted by one or more substituents independently selected from the group consisting of: cyano, fluorine, methyl, ethyl, propyl, isopropyl, cyclopropyl, fluoromethyl, difluoromethyl, trifluoromethyl, fluoroethyl, difluoroethyl, trifluoroethyl, trifluoropropyl, methoxy, ethoxy, trifluoromethoxy, trifluoroethoxy, methoxymethyl, trifluoromethoxymethyl, and methanesulfonylmethyl. In another aspect, R 2 The heterocyclic ring may optionally be substituted by one or more substituents independently selected from the group consisting of: fluorine, methyl, ethyl, isopropyl, fluoromethyl, difluoropropyl, methoxy, and trifluoromethoxy.

[0678] In some embodiments, the compound or pharmaceutically acceptable salt is 6-((1R,5S)-9-oxa-3-azabicyclo[3.3.1]nonane-3-yl)-N-(2-((R)-4-cyanothiazolidine-3-yl)-2-oxoethyl)quinoline-4-carboxamide (Example 194), or a pharmaceutically acceptable salt thereof.

[0679] In some embodiments, R 2 The heterocyclic base ring is:

[0680]

[0681] The heterocyclic ring is optionally substituted by one or more substituents independently selected from the group consisting of: halogen, cyano, oxo, C 1-6 -alkyl, C 3-6 -cycloalkyl, C 1-6 -alkoxy group, C 1-3 -alkoxy-C 1-3 -alkyl, C 1-3 -alkylcarbonyl-C 1-3 -alkyl, and C 1-3 -alkylsulfonyl-C 1-3-alkyl, and wherein the C 1-6 -alkyl, C 3-6 -cycloalkyl, C 1-6 -alkoxy group, C 1-3 -alkoxy-C 1-3 -alkyl, C 1-3 -alkylcarbonyl-C 1-3 -alkyl, and C 1-3 -alkylsulfonyl-C 1-3 -Alkyl groups can be further substituted with one or more halogens. In one aspect, R 2 The heterocyclic ring may optionally be substituted by one or more substituents independently selected from the group consisting of: halogen, cyano, C. 1-3 -alkyl, C 3-6 -cycloalkyl, C 1-3 -alkoxy group, C 1-3 -alkoxy-C 1-3 -alkyl, C 1-3 -alkylcarbonyl-C 1-3 -alkyl, and C 1-3 -alkylsulfonyl-C 1-3 -alkyl, wherein the C 1-3 -alkyl, C 3-6 -cycloalkyl, C 1-3 -alkoxy group, C 1-3 -alkoxy-C 1-3 -alkyl, C 1-3 -alkylcarbonyl-C 1-3 -alkyl, and C 1-3 -alkylsulfonyl-C 1-3 -alkyl groups can be further substituted with one or more halogens. In another aspect, R 2 The heterocyclic ring is optionally substituted by one or more substituents independently selected from the group consisting of: cyano, fluorine, methyl, ethyl, propyl, isopropyl, cyclopropyl, fluoromethyl, difluoromethyl, trifluoromethyl, fluoroethyl, difluoroethyl, trifluoroethyl, trifluoropropyl, methoxy, ethoxy, trifluoromethoxy, trifluoroethoxy, methoxymethyl, trifluoromethoxymethyl, and methanesulfonylmethyl. In another aspect, R 2 The heterocyclic ring may optionally be substituted by one or more substituents independently selected from the group consisting of: fluorine, methyl, ethyl, fluoromethyl, difluoropropyl, methoxy, and trifluoromethoxy.

[0682] In some embodiments, the compound or pharmaceutically acceptable salt is (R)-N-(2-(4-cyanothiazolidine-3-yl)-2-oxoethyl)-6-(1,2-oxazinidine-2-yl)quinoline-4-carboxamide (Example 1), or a pharmaceutically acceptable salt thereof.

[0683] In some embodiments, R2 The heterocyclic base ring is:

[0684]

[0685] The heterocyclic ring is optionally substituted by one or more substituents independently selected from the group consisting of: halogen, cyano, oxo, C 1-6 -alkyl, C 3-6 -cycloalkyl, C 1-6 -alkoxy group, C 1-3 -alkoxy-C 1-3 -alkyl, C 1-3 -alkylcarbonyl-C 1-3 -alkyl, and C 1-3 -alkylsulfonyl-C 1-3 -alkyl, and wherein the C 1-6 -alkyl, C 3-6 -cycloalkyl, C 1-6 -alkoxy group, C 1-3 -alkoxy-C 1-3 -alkyl, C 1-3 -alkylcarbonyl-C 1-3 -alkyl, and C 1-3 -alkylsulfonyl-C 1-3 -Alkyl groups can be further substituted with one or more halogens. In one aspect, R 2 The heterocyclic ring may optionally be substituted by one or more substituents independently selected from the group consisting of: halogen, cyano, C. 1-3 -alkyl, C 3-6 -cycloalkyl, C 1-3 -alkoxy group, C 1-3 -alkoxy-C 1-3 -alkyl, C 1-3 -alkylcarbonyl-C 1-3 -alkyl, and C 1-3 -alkylsulfonyl-C 1-3 -alkyl, wherein the C 1-3 -alkyl, C 3-6 -cycloalkyl, C 1-3 -alkoxy group, C 1-3 -alkoxy-C 1-3 -alkyl, C 1-3 -alkylcarbonyl-C 1-3 -alkyl, and C 1-3 -alkylsulfonyl-C 1-3 -alkyl groups can be further substituted with one or more halogens. In another aspect, R 2The heterocyclic ring is optionally substituted by one or more substituents independently selected from the group consisting of: cyano, fluorine, methyl, ethyl, propyl, isopropyl, cyclopropyl, fluoromethyl, difluoromethyl, trifluoromethyl, fluoroethyl, difluoroethyl, trifluoroethyl, trifluoropropyl, methoxy, ethoxy, trifluoromethoxy, trifluoroethoxy, methoxymethyl, trifluoromethoxymethyl, and methanesulfonylmethyl. In another aspect, R 2 The heterocyclic ring may optionally be substituted by one or more substituents independently selected from the group consisting of: fluorine, methyl, ethyl, fluoromethyl, difluoropropyl, methoxy, and trifluoromethoxy.

[0686] In some embodiments, the compound and pharmaceutically acceptable salt are selected from the group consisting of:

[0687] N-(2-((R)-4-cyanothiazolidine-3-yl)-2-oxoethyl)-6-((R)-7-methyl-1,4-oxazetane-4-yl)quinoline-4-carboxamide (Example 61);

[0688] N-(2-((R)-4-cyanothiazolidine-3-yl)-2-oxoethyl)-6-((S)-7-methyl-1,4-oxazetane-4-yl)quinoline-4-carboxamide (Example 62);

[0689] N-(2-((R)-4-cyanothiazolidine-3-yl)-2-oxoethyl)-6-((S)-3-methyl-1,4-oxazetane-4-yl)quinoline-4-carboxamide (Example 63);

[0690] N-(2-((R)-4-cyanothiazolidine-3-yl)-2-oxoethyl)-6-((R)-2-methyl-1,4-oxazetane-4-yl)quinoline-4-carboxamide (Example 64);

[0691] (R)-N-(2-(4-cyanothiazolidine-3-yl)-2-oxoethyl)-6-(1,4-oxazetane-4-yl)quinoline-4-carboxamide (Example 91);

[0692] And its pharmaceutically acceptable salts.

[0693] In some embodiments, R 2 The heterocyclic base ring is:

[0694]

[0695] The heterocyclic ring is optionally substituted by one or more substituents independently selected from the group consisting of: halogen, cyano, oxo, C 1-6 -alkyl, C 3-6 -cycloalkyl, C1-6 -alkoxy group, C 1-3 -alkoxy-C 1-3 -alkyl, C 1-3 -alkylcarbonyl-C 1-3 -alkyl, and C 1-3 -alkylsulfonyl-C 1-3 -alkyl, and wherein the C 1-6 -alkyl, C 3-6 -cycloalkyl, C 1-6 -alkoxy group, C 1-3 -alkoxy-C 1-3 -alkyl, C 1-3 -alkylcarbonyl-C 1-3 -alkyl, and C 1-3 -alkylsulfonyl-C 1-3 -Alkyl groups can be further substituted with one or more halogens. In one aspect, R 2 The heterocyclic ring may optionally be substituted by one or more substituents independently selected from the group consisting of: halogen, cyano, C. 1-3 -alkyl, C 3-6 -cycloalkyl, C 1-3 -alkoxy group, C 1-3 -alkoxy-C 1-3 -alkyl, C 1-3 -alkylcarbonyl-C 1-3 -alkyl, and C 1-3 -alkylsulfonyl-C 1-3 -alkyl, wherein the C 1-3 -alkyl, C 3-6 -cycloalkyl, C 1-3 -alkoxy group, C 1-3 -alkoxy-C 1-3 -alkyl, C 1-3 -alkylcarbonyl-C 1-3 -alkyl, and C 1-3 -alkylsulfonyl-C 1-3 -alkyl groups can be further substituted with one or more halogens. In another aspect, R 2 The heterocyclic ring is optionally substituted by one or more substituents independently selected from the group consisting of: cyano, fluorine, methyl, ethyl, propyl, isopropyl, cyclopropyl, fluoromethyl, difluoromethyl, trifluoromethyl, fluoroethyl, difluoroethyl, trifluoroethyl, trifluoropropyl, methoxy, ethoxy, trifluoromethoxy, trifluoroethoxy, methoxymethyl, trifluoromethoxymethyl, and methanesulfonylmethyl. In another aspect, R 2 The heterocyclic ring may optionally be substituted by one or more substituents independently selected from the group consisting of: fluorine, methyl, ethyl, fluoromethyl, difluoropropyl, methoxy, and trifluoromethoxy.

[0696] In some embodiments, the compound or pharmaceutically acceptable salt is 6-(8-oxa-3-azabicyclo[3.2.1]octane-3-yl)-N-(2-((R)-4-cyanothiazolidine-3-yl)-2-oxoethyl)quinoline-4-carboxamide (Example 79), or a pharmaceutically acceptable salt thereof.

[0697] In some embodiments, the compound and pharmaceutically acceptable salt are selected from the group consisting of:

[0698] (R)-N-(2-(4-cyanothiazolidine-3-yl)-2-oxoethyl)-6-(1,2-oxazinidine-2-yl)quinoline-4-carboxamide (Example 1);

[0699] (R)-N-(2-(4-cyanothiazolidine-3-yl)-2-oxoethyl)-3-fluoro-6-morpholinoquinoline-4-carboxamide (Example 2);

[0700] (R)-N-(2-(4-cyanothiazolidine-3-yl)-2-oxoethyl)-6-thiomorpholine-quinoline-4-carboxamide (Example 3);

[0701] (R)-N-(2-(4-cyanothiazolidine-3-yl)-2-oxoethyl)-6-(2,2-difluoromorpholino)quinoline-4-carboxamide (Example 4);

[0702] (R)-N-(2-(4-cyanothiazolidine-3-yl)-2-oxoethyl)-6-(2,2,6,6-tetrafluoromorpholino)-quinoline-4-carboxamide (Example 5);

[0703] (R)-N-(2-(4-cyanothiazolidine-3-yl)-2-oxoethyl)-6-(2,3-dihydro-4H-benzo[b][1,4]oxazin-4-yl)quinoline-4-carboxamide (Example 6);

[0704] (R)-N-(2-(4-cyanothiazolidine-3-yl)-2-oxoethyl)-8-methyl-6-morpholinoquinoline-4-carboxamide (Example 9);

[0705] (R)-N-(2-(4-cyanothiazolidine-3-yl)-2-oxoethyl)-7-methyl-6-morpholinoquinoline-4-carboxamide (Example 10);

[0706] (R)-N-(2-(4-cyanothiazolidine-3-yl)-2-oxoethyl)-6-(5,5-dimethyl-2-oxooxazolidine-3-yl)quinoline-4-carboxamide (Example 13);

[0707] (R)-N-(2-(4-cyanothiazolidine-3-yl)-2-oxoethyl)-6-(2,2-dimethyl-3-oxomorpholino)-quinoline-4-carboxamide (Example 16);

[0708] N-(2-((R)-4-cyanothiazolidine-3-yl)-2-oxoethyl)-6-((R)-7-methyl-1,4-oxazetane-4-yl)-quinoline-4-carboxamide (Example 61);

[0709] N-(2-((R)-4-cyanothiazolidine-3-yl)-2-oxoethyl)-6-((S)-7-methyl-1,4-oxazetane-4-yl)-quinoline-4-carboxamide (Example 62);

[0710] N-(2-((R)-4-cyanothiazolidine-3-yl)-2-oxoethyl)-6-((S)-3-methyl-1,4-oxazetane-4-yl)-quinoline-4-carboxamide (Example 63);

[0711] N-(2-((R)-4-cyanothiazolidine-3-yl)-2-oxoethyl)-6-((R)-2-methyl-1,4-oxazetane-4-yl)-quinoline-4-carboxamide (Example 64);

[0712] (R)-N-(2-(4-cyanothiazolidine-3-yl)-2-oxoethyl)-6-morpholinoquinoline-4-carboxamide (Example 67);

[0713] N-(2-((R)-4-cyanothiazolidine-3-yl)-2-oxoethyl)-6-((2R,6S)-2,6-dimethylmorpholino)-quinoline-4-carboxamide (Example 68);

[0714] N-(2-((R)-4-cyanothiazolidine-3-yl)-2-oxoethyl)-6-((R)-2-(fluoromethyl)-morpholino)quinoline-4-carboxamide (Example 69);

[0715] N-(2-((R)-4-cyanothiazolidine-3-yl)-2-oxoethyl)-6-((2R,6R)-2,6-dimethylmorpholino)-quinoline-4-carboxamide (Example 70);

[0716] N-(2-((R)-4-cyanothiazolidine-3-yl)-2-oxoethyl)-6-((S)-2-(fluoromethyl)-morpholino)quinoline-4-carboxamide (Example 71);

[0717] N-(2-((R)-4-cyanothiazolidine-3-yl)-2-oxoethyl)-6-((R)-2-methylmorpholino)-quinoline-4-carboxamide (Example 72);

[0718] N-(2-((R)-4-cyanothiazolidine-3-yl)-2-oxoethyl)-6-((R)-2-(trifluoromethyl)-morpholino)quinoline-4-carboxamide (Example 73);

[0719] N-(2-((R)-4-cyanothiazolidine-3-yl)-2-oxoethyl)-6-((S)-2-(trifluoromethyl)-morpholino)quinoline-4-carboxamide (Example 74);

[0720] 6-((1S,4S)-2-oxa-5-azabicyclo[2.2.1]heptane-5-yl)-N-(2-((R)-4-cyanothiazolidine-3-yl)-2-oxoethyl)quinoline-4-carboxamide (Example 75);

[0721] 6-((1R,4R)-2-oxa-5-azabicyclo[2.2.1]heptane-5-yl)-N-(2-((R)-4-cyanothiazolidine-3-yl)-2-oxoethyl)quinoline-4-carboxamide (Example 76);

[0722] 6-(6-oxa-3-azabicyclo[3.1.1]heptane-3-yl)-N-(2-((R)-4-cyanothiazolidine-3-yl)-2-oxoethyl)quinoline-4-carboxamide (Example 77);

[0723] N-(2-((R)-4-cyanothiazolidine-3-yl)-2-oxoethyl)-6-((2S,6S)-2,6-dimethylmorpholino)-quinoline-4-carboxamide (Example 78);

[0724] 6-(8-oxa-3-azabicyclo[3.2.1]octane-3-yl)-N-(2-((R)-4-cyanothiazolidine-3-yl)-2-oxoethyl)quinoline-4-carboxamide (Example 79);

[0725] N-(2-((R)-4-cyanothiazolidine-3-yl)-2-oxoethyl)-6-((S)-2-methylmorpholino)-quinoline-4-carboxamide (Example 80);

[0726] N-(2-((R)-4-cyanothiazolidine-3-yl)-2-oxoethyl)-6-((2R,3S)-2,3-dimethylmorpholino)-quinoline-4-carboxamide (Example 81);

[0727] N-(2-((R)-4-cyanothiazolidine-3-yl)-2-oxoethyl)-6-((2S,3S)-2,3-dimethylmorpholino)-quinoline-4-carboxamide (Example 82);

[0728] N-(2-((R)-4-cyanothiazolidine-3-yl)-2-oxoethyl)-6-((2R,3R)-2,3-dimethylmorpholino)-quinoline-4-carboxamide (Example 83);

[0729] N-(2-((R)-4-cyanothiazolidine-3-yl)-2-oxoethyl)-6-((R*)-3-(trifluoromethyl)-morpholino)quinoline-4-carboxamide isomer 1 (Example 84);

[0730] N-(2-((R)-4-cyanothiazolidine-3-yl)-2-oxoethyl)-6-((R*)-3-(trifluoromethyl)-morpholino)quinoline-4-carboxamide isomer 2 (Example 85);

[0731] 6-(3-oxa-9-azabicyclo[3.3.1]nonane-9-yl)-N-(2-((R)-4-cyanothiazolidine-3-yl)-2-oxoethyl)quinoline-4-carboxamide (Example 86);

[0732] N-(2-((R)-4-cyanothiazolidine-3-yl)-2-oxoethyl)-6-((2R,5R)-2,5-dimethylmorpholino)-quinoline-4-carboxamide (Example 87);

[0733] (R)-N-(2-(4-cyanothiazolidine-3-yl)-2-oxoethyl)-6-(2,2-dimethylmorpholino)-quinoline-4-carboxamide (Example 88);

[0734] N-(2-((R)-4-cyanothiazolidine-3-yl)-2-oxoethyl)-6-((S)-3-(methoxymethyl)-morpholino)quinoline-4-carboxamide (Example 89);

[0735] N-(2-((R)-4-cyanothiazolidine-3-yl)-2-oxoethyl)-6-((3S,5R)-3,5-dimethyl-morpholino)quinoline-4-carboxamide (Example 90);

[0736] (R)-N-(2-(4-cyanothiazolidine-3-yl)-2-oxoethyl)-6-(1,4-oxazetane-4-yl)quinoline-4-carboxamide (Example 91);

[0737] N-(2-((R)-4-cyanothiazolidine-3-yl)-2-oxoethyl)-6-((R)-2-((methanesulfonyl)-methyl)morpholino)quinoline-4-carboxamide (Example 92);

[0738] N-(2-((R)-4-cyanothiazolidine-3-yl)-2-oxoethyl)-6-((S)-2-(methoxymethyl)-morpholino)quinoline-4-carboxamide (Example 93);

[0739] N-(2-((R)-4-cyanothiazolidine-3-yl)-2-oxoethyl)-6-((S)-2-((methanesulfonyl)-methyl)morpholino)quinoline-4-carboxamide (Example 94);

[0740] N-(2-((R)-4-cyanothiazolidine-3-yl)-2-oxoethyl)-6-((R)-3-(2-methoxyethyl)-morpholino)quinoline-4-carboxamide (Example 95);

[0741] N-(2-((R)-4-cyanothiazolidine-3-yl)-2-oxoethyl)-6-((2S,3S)-3-(methoxymethyl)-2-methylmorpholino)quinoline-4-carboxamide (Example 96);

[0742] N-(2-((R)-4-cyanothiazolidine-3-yl)-2-oxoethyl)-6-((2R,3R)-3-(methoxymethyl)-2-methylmorpholino)quinoline-4-carboxamide (Example 97);

[0743] 6-(3-oxa-8-azabicyclo[3.2.1]octane-8-yl)-N-(2-((R)-4-cyanothiazolidine-3-yl)-2-oxoethyl)quinoline-4-carboxamide (Example 98);

[0744] 7-Bromo-N-(2-((R)-4-cyanothiazolidine-3-yl)-2-oxoethyl)-6-((3S,5R)-3,5-dimethyl-morpholino)quinoline-4-carboxamide (Example 100);

[0745] (R)-5-chloro-N-(2-(4-cyanothiazolidine-3-yl)-2-oxoethyl)-6-morpholinoquinoline-4-carboxamide (Example 101);

[0746] N-(2-((R)-4-cyanothiazolidine-3-yl)-2-oxoethyl)-6-((S)-3-methylmorpholino)-quinoline-4-carboxamide (Example 102):

[0747] N-(2-((R)-4-cyanothiazolidine-3-yl)-2-oxoethyl)-6-((3S,5S)-3,5-dimethylmorpholino)-quinoline-4-carboxamide (Example 103);

[0748] N-(2-((R)-4-cyanothiazolidine-3-yl)-2-oxoethyl)-6-((3R,5R)-3,5-dimethylmorpholino)-quinoline-4-carboxamide (Example 105);

[0749] N-(2-((R)-4-cyanothiazolidine-3-yl)-2-oxoethyl)-6-((S)-3-ethylmorpholino)quinoline-4-carboxamide (Example 106):

[0750] (R)-N-(2-(4-cyanothiazolidine-3-yl)-2-oxoethyl)-6-(3,3-dimethylmorpholino)-quinoline-4-carboxamide (Example 107);

[0751] N-(2-((R)-4-cyanothiazolidine-3-yl)-2-oxoethyl)-6-((R)-3-methylmorpholino)-quinoline-4-carboxamide (Example 108);

[0752] (R)-N-(2-(4-cyanothiazolidine-3-yl)-2-oxoethyl)-2-methyl-6-morpholinoquinoline-4-carboxamide (Example 109);

[0753] (R)-N-(2-(4-cyanothiazolidine-3-yl)-2-oxoethyl)-6-(6,6-dimethyl-2-oxo-1,3-oxazinidine-3-yl)quinoline-4-carboxamide (Example 112);

[0754] (R)-7-chloro-N-(2-(4-cyanothiazolidine-3-yl)-2-oxoethyl)-6-morpholinoquinoline-4-carboxamide (Example 179);

[0755] (R)-8-chloro-N-(2-(4-cyanothiazolidine-3-yl)-2-oxoethyl)-6-morpholinoquinoline-4-carboxamide (Example 180);

[0756] 6-((1R,5S)-9-oxa-3-azabicyclo[3.3.1]nonane-3-yl)-N-(2-((R)-4-cyanothiazolidine-3-yl)-2-oxoethyl)quinoline-4-carboxamide (Example 194);

[0757] (R)-N-(2-(4-cyanothiazolidine-3-yl)-2-oxoethyl)-6-(2,4-dimethyloxazol-5-yl)quinoline-4-carboxamide (Example 215);

[0758] (R)-N-(2-(4-cyanothiazolidine-3-yl)-2-oxoethyl)-6-(3,5-dimethylisoxazol-4-yl)-quinoline-4-carboxamide (Example 216);

[0759] And its pharmaceutically acceptable salts.

[0760] In some embodiments, the compound and pharmaceutically acceptable salt are selected from the group consisting of:

[0761] (R)-N-(2-(4-cyanothiazolidine-3-yl)-2-oxoethyl)-6-(1,2-oxazinidine-2-yl)quinoline-4-carboxamide (Example 1);

[0762] (R)-N-(2-(4-cyanothiazolidine-3-yl)-2-oxoethyl)-3-fluoro-6-morpholinoquinoline-4-carboxamide (Example 2);

[0763] (R)-N-(2-(4-cyanothiazolidine-3-yl)-2-oxoethyl)-6-(2,2-difluoromorpholino)quinoline-4-carboxamide (Example 4);

[0764] (R)-N-(2-(4-cyanothiazolidine-3-yl)-2-oxoethyl)-8-methyl-6-morpholinoquinoline-4-carboxamide (Example 9);

[0765] (R)-N-(2-(4-cyanothiazolidine-3-yl)-2-oxoethyl)-6-morpholinoquinoline-4-carboxamide (Example 67);

[0766] N-(2-((R)-4-cyanothiazolidine-3-yl)-2-oxoethyl)-6-((2R,6S)-2,6-dimethylmorpholino)-quinoline-4-carboxamide (Example 68);

[0767] N-(2-((R)-4-cyanothiazolidine-3-yl)-2-oxoethyl)-6-((R)-2-(fluoromethyl)morpholino)-quinoline-4-carboxamide (Example 69);

[0768] N-(2-((R)-4-cyanothiazolidine-3-yl)-2-oxoethyl)-6-((2R,6R)-2,6-dimethylmorpholino)-quinoline-4-carboxamide (Example 70);

[0769] N-(2-((R)-4-cyanothiazolidine-3-yl)-2-oxoethyl)-6-((S)-2-(fluoromethyl)morpholino)-quinoline-4-carboxamide (Example 71);

[0770] N-(2-((R)-4-cyanothiazolidine-3-yl)-2-oxoethyl)-6-((R)-2-methylmorpholino)-quinoline-4-carboxamide (Example 72);

[0771] N-(2-((R)-4-cyanothiazolidine-3-yl)-2-oxoethyl)-6-((R)-2-(trifluoromethyl)-morpholino)quinoline-4-carboxamide (Example 73);

[0772] N-(2-((R)-4-cyanothiazolidine-3-yl)-2-oxoethyl)-6-((S)-2-(trifluoromethyl)-morpholino)quinoline-4-carboxamide (Example 74);

[0773] 6-((1S,4S)-2-oxa-5-azabicyclo[2.2.1]heptane-5-yl)-N-(2-((R)-4-cyanothiazolidine-3-yl)-2-oxoethyl)quinoline-4-carboxamide (Example 75);

[0774] 6-((1R,4R)-2-oxa-5-azabicyclo[2.2.1]heptane-5-yl)-N-(2-((R)-4-cyanothiazolidine-3-yl)-2-oxoethyl)quinoline-4-carboxamide (Example 76);

[0775] 6-(6-oxa-3-azabicyclo[3.1.1]heptane-3-yl)-N-(2-((R)-4-cyanothiazolidine-3-yl)-2-oxoethyl)quinoline-4-carboxamide (Example 77);

[0776] N-(2-((R)-4-cyanothiazolidine-3-yl)-2-oxoethyl)-6-((2S,6S)-2,6-dimethylmorpholino)-quinoline-4-carboxamide (Example 78);

[0777] 6-(8-oxa-3-azabicyclo[3.2.1]octane-3-yl)-N-(2-((R)-4-cyanothiazolidine-3-yl)-2-oxoethyl)quinoline-4-carboxamide (Example 79);

[0778] N-(2-((R)-4-cyanothiazolidine-3-yl)-2-oxoethyl)-6-((S)-2-methylmorpholino)-quinoline-4-carboxamide (Example 80);

[0779] N-(2-((R)-4-cyanothiazolidine-3-yl)-2-oxoethyl)-6-((2R,3S)-2,3-dimethylmorpholino)-quinoline-4-carboxamide (Example 81);

[0780] N-(2-((R)-4-cyanothiazolidine-3-yl)-2-oxoethyl)-6-((2S,3S)-2,3-dimethylmorpholino)-quinoline-4-carboxamide (Example 82);

[0781] (R)-N-(2-(4-cyanothiazolidine-3-yl)-2-oxoethyl)-6-(2,2-dimethylmorpholino)-quinoline-4-carboxamide (Example 88);

[0782] N-(2-((R)-4-cyanothiazolidine-3-yl)-2-oxoethyl)-6-((S)-3-(methoxymethyl)-morpholino)quinoline-4-carboxamide (Example 89);

[0783] N-(2-((R)-4-cyanothiazolidine-3-yl)-2-oxoethyl)-6-((S)-2-(methoxymethyl)-morpholino)quinoline-4-carboxamide (Example 93);

[0784] N-(2-((R)-4-cyanothiazolidine-3-yl)-2-oxoethyl)-6-((2R,3R)-3-(methoxymethyl)-2-methylmorpholino)quinoline-4-carboxamide (Example 97);

[0785] 6-(3-oxa-8-azabicyclo[3.2.1]octane-8-yl)-N-(2-((R)-4-cyanothiazolidine-3-yl)-2-oxoethyl)quinoline-4-carboxamide (Example 98);

[0786] N-(2-((R)-4-cyanothiazolidine-3-yl)-2-oxoethyl)-6-((S)-3-methylmorpholino)-quinoline-4-carboxamide (Example 102);

[0787] N-(2-((R)-4-cyanothiazolidine-3-yl)-2-oxoethyl)-6-((S)-3-ethylmorpholino)quinoline-4-carboxamide (Example 106);

[0788] (R)-N-(2-(4-cyanothiazolidine-3-yl)-2-oxoethyl)-6-(3,3-dimethylmorpholino)-quinoline-4-carboxamide (Example 107);

[0789] (R)-N-(2-(4-cyanothiazolidine-3-yl)-2-oxoethyl)-2-methyl-6-morpholinoquinoline-4-carboxamide (Example 109);

[0790] (R)-N-(2-(4-cyanothiazolidine-3-yl)-2-oxoethyl)-6-(6,6-dimethyl-2-oxo-1,3-oxazinidine-3-yl)quinoline-4-carboxamide (Example 112);

[0791] And its pharmaceutically acceptable salts.

[0792] C. R 2 It is a spiroheterocyclic group

[0793] 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 spiroheterocyclic group containing a total of 6 to 11 ring atoms, wherein the spiroheterocyclic group: (i) comprises two saturated rings, (ii) has: (a) one or two nitrogen ring atoms and the remaining ring atoms are carbon, (b) one or two nitrogen ring atoms and one or two oxygen ring atoms and the remaining ring atoms are carbon, or (c) one nitrogen ring atom and one sulfur ring atom and the remaining ring atoms are carbon, and (iii) optionally substituted by one or more substituents independently selected from the group consisting of: halogen, oxo, C 1-6 -alkyl, C 1-6 - Haloalkyl, C 1-6 -alkoxy group, C 1-6 - Haloalkoxy groups and C 1-6 -alkyl carbonyl. In one respect, R 2 Spiroheterocyclic groups have: (a) one or two nitrogen ring atoms and the remaining ring atoms are carbon, or (b) one or two nitrogen ring atoms and one or two oxygen ring atoms and the remaining ring atoms are carbon. In another aspect, R... 2 Spiroheterocyclic groups have one or two nitrogen ring atoms and optionally one or two oxygen ring atoms, with the remaining ring atoms being carbon. In another aspect, R... 2 Spiroheterocyclic groups have one nitrogen ring atom and the remaining ring atoms are carbon. In another aspect, R... 2 Spiroheterocyclic groups have two nitrogen ring atoms and the remaining ring atom is carbon. In another aspect, R... 2 Spirocyclic groups have one nitrogen ring atom and one oxygen ring atom, with the remaining ring atoms being carbon. In another aspect, R... 2 Spiroheterocyclic groups have one nitrogen ring atom and two oxygen ring atoms, with the remaining ring atoms being carbon.

[0794] In some embodiments, R 2 The two saturated rings of the spiroheterocyclic group are selected from the following group:

[0795]

[0796]

[0797] One or two of these rings may optionally be substituted by one or more substituents independently selected from the group consisting of: halogens, C 1-6 -alkyl, C 1-6 - Haloalkyl, C 1-6 -alkoxy group, C 1-6 - Haloalkoxy groups and C 1-6 -alkyl carbonyl.

[0798] In some embodiments, R 2 The two saturated rings of the spiroheterocyclic group are selected from the following group:

[0799]

[0800] One or two of these rings may optionally be substituted by one or more substituents independently selected from the group consisting of: halogens, C 1-6 -alkyl, C 1-6 - Haloalkyl, C 1-6 -alkoxy group, C 1-6 - Haloalkoxy groups and C 1-6 -alkyl carbonyl.

[0801] In some embodiments, R 2 The two saturated rings of the spiroheterocyclic group are selected from the following group:

[0802]

[0803] One or two of these rings may optionally be substituted by one or more substituents independently selected from the group consisting of: halogens, C 1-6 -alkyl, C 1-6 - Haloalkyl, C 1-6 -alkoxy group, C 1-6 - Haloalkoxy groups and C 1-6 -alkyl carbonyl.

[0804] In some embodiments, R 2 The two saturated rings of the spiroheterocyclic group are selected from the following group:

[0805]

[0806]

[0807] One or two of these rings may optionally be substituted by one or more substituents independently selected from the group consisting of: halogens, C 1-6 -alkyl, C 1-6 - Haloalkyl, C 1-6 -alkoxy group, C 1-6 - Haloalkoxy groups and C 1-6-alkyl carbonyl.

[0808] In some embodiments, R 2 The spiroheterocyclic ring is optionally substituted by one or more substituents independently selected from the group consisting of: halogens, C 1-3 -alkyl, C 1-3 - Haloalkyl, C 1-3 -alkoxy group, C 1-3 - Haloalkoxy groups and C 1-3 -alkyl carbonyl.

[0809] In some embodiments, R 2 The spiroheterocyclic base ring is optionally replaced by one or more halogens. In one aspect, R 2 The spirocyclic base ring is optionally substituted with one or more fluorine molecules.

[0810] In some embodiments, R 2 Spiroherocyclic base rings are optionally surrounded by one or more C 1-3 -Alkyl substitution.

[0811] In some embodiments, R 2 Spiroherocyclic base rings are optionally surrounded by one or more C 1-3 - Haloalkyl substitution.

[0812] In some embodiments, R 2 Spiroherocyclic base rings are optionally surrounded by one or more C 1-3 -Alkyl substitution.

[0813] In some embodiments, R 2 Spiroherocyclic base rings are optionally surrounded by one or more C 1-3 - Haloalkoxy substitution.

[0814] In some embodiments, R 2 Spiroherocyclic base rings are optionally surrounded by one or more C 1-3 -alkyl carbonyl substitution. In one aspect, R 2 The spiroheterocyclic ring is optionally substituted with one or more methyl carbonyl groups.

[0815] In some embodiments, R 2 The spirocyclic ring may optionally be substituted by one or more substituents independently selected from the group consisting of: fluorine, methyl, ethyl, propyl, isopropyl, fluoromethyl, difluoromethyl, trifluoromethyl, fluoroethyl, difluoroethyl, trifluoroethyl, trifluoropropyl, methoxy, ethoxy, trifluoromethoxy, trifluoroethoxy, methyl carbonyl, ethyl carbonyl, and isopropyl carbonyl.

[0816] In some embodiments, R 2The spirocyclic ring may optionally be substituted by one or more substituents independently selected from the group consisting of: fluorine, methyl, ethyl, fluoromethyl, difluoromethyl, and trifluoromethyl.

[0817] In some embodiments, R 2 The two saturated rings of the spiroheterocyclic group are:

[0818]

[0819] One or two of these rings may optionally be substituted by one or more substituents independently selected from the group consisting of: halogens, C 1-6 -alkyl, C 1-6 - Haloalkyl, C 1-6 -alkoxy group, C 1-6 - Haloalkoxy groups and C 1-6 -alkyl carbonyl. In one respect, R 2 The spiroheterocyclic ring is optionally substituted by one or more substituents independently selected from the group consisting of: halogens, C 1-3 -alkyl, C 1-3 - Haloalkyl, C 1-3 -alkoxy group, C 1-3 - Haloalkoxy groups and C 1-3 -alkyl carbonyl. In another aspect, R 2 The spiroheterocyclic ring is optionally substituted by one or more substituents independently selected from the group consisting of: halogens, C 1-3 -alkyl, C 1-3 - Haloalkyl, C 1-3 -alkoxy group, C 1-3 - Haloalkoxy groups and C 1-3 -alkyl carbonyl. In another aspect, R 2 The spiroheterocyclic ring is optionally substituted by one or more substituents independently selected from the group consisting of: fluorine, methyl, ethyl, propyl, fluoromethyl, difluoromethyl, trifluoromethyl, fluoroethyl, difluoroethyl, trifluoroethyl, trifluoropropyl, methoxy, ethoxy, trifluoromethoxy, and trifluoroethoxy. In another aspect, R 2 The spirocyclic ring may optionally be substituted by one or more substituents independently selected from the group consisting of: fluorine, methyl, ethyl, fluoromethyl, difluoromethyl, and trifluoromethyl.

[0820] In some embodiments, the compound and pharmaceutically acceptable salt are selected from the group consisting of:

[0821] (R)-N-(2-(4-cyanothiazolidine-3-yl)-2-oxoethyl)-6-(2-azaspiro[3.3]heptane-2-yl)-quinoline-4-carboxamide (Example 17);

[0822] (R)-N-(2-(4-cyanothiazolidine-3-yl)-2-oxoethyl)-6-(6-fluoro-2-azaspiro[3.3]heptane-2-yl)quinoline-4-carboxamide (Example 155);

[0823] (R)-N-(2-(4-cyanothiazolidine-3-yl)-2-oxoethyl)-6-(6-(trifluoromethyl)-2-azaspiro[3.3]heptane-2-yl)quinoline-4-carboxamide (Example 150);

[0824] (R)-N-(2-(4-cyanothiazolidine-3-yl)-2-oxoethyl)-6-(6-methyl-2-azaspiro[3.3]heptane-2-yl)quinoline-4-carboxamide (Example 149);

[0825] And its pharmaceutically acceptable salts.

[0826] In some embodiments, R 2 The two saturated rings of the spiroheterocyclic group are:

[0827]

[0828] One or two of these rings may optionally be substituted by one or more substituents independently selected from the group consisting of: halogens, C 1-6 -alkyl, C 1-6 - Haloalkyl, C 1-6 -alkoxy group, C 1-6 - Haloalkoxy groups and C 1-6 -alkyl carbonyl. In one respect, R 2 The spiroheterocyclic ring is optionally substituted by one or more substituents independently selected from the group consisting of: halogens, C 1-3 -alkyl, C 1-3 - Haloalkyl, C 1-3 -alkoxy group, C 1-3 - Haloalkoxy groups and C 1-3 -alkyl carbonyl. In another aspect, R 2 The spiroheterocyclic ring is optionally substituted by one or more substituents independently selected from the group consisting of: fluorine, methyl, ethyl, propyl, fluoromethyl, difluoromethyl, trifluoromethyl, fluoroethyl, difluoroethyl, trifluoroethyl, trifluoropropyl, methoxy, ethoxy, trifluoromethoxy, trifluoroethoxy, and methyl carbonyl. In another aspect, R 2 The spirocyclic ring may optionally be substituted by one or more substituents independently selected from the group consisting of: fluorine, methyl, ethyl, fluoromethyl, difluoromethyl, trifluoromethyl, and methyl carbonyl.

[0829] In some embodiments, the compound or pharmaceutically acceptable salt is (R)-6-(6-acetyl-2,6-diazaspiro[3.3]heptane-2-yl)-N-(2-(4-cyanothiazolidine-3-yl)-2-oxoethyl)quinoline-4-carboxamide (Example 184), or a pharmaceutically acceptable salt thereof.

[0830] In some embodiments, R 2 The two saturated rings of the spiroheterocyclic group are:

[0831]

[0832] One or two of these rings may optionally be substituted by one or more substituents independently selected from the group consisting of: halogens, C 1-6 -alkyl, C 1-6 - Haloalkyl, C 1-6 -alkoxy group, C 1-6 - Haloalkoxy groups and C 1-6 -alkyl carbonyl. In one respect, R 2 The spiroheterocyclic ring is optionally substituted by one or more substituents independently selected from the group consisting of: halogens, C 1-3 -alkyl, C 1-3 - Haloalkyl, C 1-3 -alkoxy group, C 1-3 - Haloalkoxy groups and C 1-3 -alkyl carbonyl. In another aspect, R 2 The spiroheterocyclic ring is optionally substituted by one or more substituents independently selected from the group consisting of: fluorine, methyl, ethyl, propyl, fluoromethyl, difluoromethyl, trifluoromethyl, fluoroethyl, difluoroethyl, trifluoroethyl, trifluoropropyl, methoxy, ethoxy, trifluoromethoxy, trifluoroethoxy, methyl carbonyl, and ethyl carbonyl. In another aspect, R 2 The spirocyclic ring may optionally be substituted by one or more substituents independently selected from the group consisting of: fluorine, methyl, ethyl, fluoromethyl, difluoromethyl, and trifluoromethyl.

[0833] In some embodiments, the compound or pharmaceutically acceptable salt is (R)-N-(2-(4-cyanothiazolidine-3-yl)-2-oxoethyl)-6-(1-thia-6-azaspiro[3.3]heptane-6-yl)quinoline-4-carboxamide (Example 222), or a pharmaceutically acceptable salt thereof.

[0834] In some embodiments, R 2 The two saturated rings of the spiroheterocyclic group are:

[0835]

[0836] One or two of these rings may optionally be substituted by one or more substituents independently selected from the group consisting of: halogens, C 1-6 -alkyl, C 1-6 - Haloalkyl, C 1-6 -alkoxy group, C 1-6 - Haloalkoxy groups and C 1-6 -alkyl carbonyl. In one respect, R 2 The spiroheterocyclic ring is optionally substituted by one or more substituents independently selected from the group consisting of: halogens, C 1-3 -alkyl, C 1-3 - Haloalkyl, C 1-3 -alkoxy group, C 1-3 - Haloalkoxy groups and C 1-3 -alkyl carbonyl. In another aspect, R 2 The spiroheterocyclic ring is optionally substituted by one or more substituents independently selected from the group consisting of: fluorine, methyl, ethyl, propyl, fluoromethyl, difluoromethyl, trifluoromethyl, fluoroethyl, difluoroethyl, trifluoroethyl, trifluoropropyl, methoxy, ethoxy, trifluoromethoxy, trifluoroethoxy, methyl carbonyl, and ethyl carbonyl. In another aspect, R 2 The spirocyclic ring may optionally be substituted by one or more substituents independently selected from the group consisting of: fluorine, methyl, ethyl, fluoromethyl, difluoromethyl, and trifluoromethyl.

[0837] In some embodiments, the compound and pharmaceutically acceptable salt are selected from the group consisting of:

[0838] (R)-N-(2-(4-cyanothiazolidine-3-yl)-2-oxoethyl)-6-(3,3-dimethyl-1-oxa-6-azaspiro[3.3]heptane-6-yl)quinoline-4-carboxamide (Example 18);

[0839] (R)-N-(2-(4-cyanothiazolidine-3-yl)-2-oxoethyl)-6-(1-oxa-6-azaspiro[3.3]heptane-6-yl)quinoline-4-carboxamide (Example 153);

[0840] And its pharmaceutically acceptable salts.

[0841] In some embodiments, R 2 The two saturated rings of the spiroheterocyclic group are:

[0842]

[0843] One or two of these rings may optionally be substituted by one or more substituents independently selected from the group consisting of: halogens, C 1-6 -alkyl, C 1-6- Haloalkyl, C 1-6 -alkoxy group, C 1-6 - Haloalkoxy groups and C 1-6 -alkyl carbonyl. In one respect, R 2 The spiroheterocyclic ring is optionally substituted by one or more substituents independently selected from the group consisting of: halogens, C 1-3 -alkyl, C 1-3 - Haloalkyl, C 1-3 -alkoxy group, C 1-3 - Haloalkoxy groups and C 1-3 -alkyl carbonyl. In another aspect, R 2 The spiroheterocyclic ring is optionally substituted by one or more substituents independently selected from the group consisting of: fluorine, methyl, ethyl, propyl, fluoromethyl, difluoromethyl, trifluoromethyl, fluoroethyl, difluoroethyl, trifluoroethyl, trifluoropropyl, methoxy, ethoxy, trifluoromethoxy, trifluoroethoxy, methyl carbonyl, and ethyl carbonyl. In another aspect, R 2 The spirocyclic ring may optionally be substituted by one or more substituents independently selected from the group consisting of: fluorine, methyl, ethyl, fluoromethyl, difluoromethyl, and trifluoromethyl.

[0844] In some embodiments, the compound or pharmaceutically acceptable salt is (R)-N-(2-(4-cyanothiazolidine-3-yl)-2-oxoethyl)-6-(2-oxa-6-azaspiro[3.3]heptane-6-yl)quinoline-4-carboxamide (Example 166), or a pharmaceutically acceptable salt thereof.

[0845] In some embodiments, R 2 The two saturated rings of the spiroheterocyclic group are:

[0846]

[0847] One or two of these rings may optionally be substituted by one or more substituents independently selected from the group consisting of: halogens, C 1-6 -alkyl, C 1-6 - Haloalkyl, C 1-6 -alkoxy group, C 1-6 - Haloalkoxy groups and C 1-6 -alkyl carbonyl. In one respect, R 2 The spiroheterocyclic ring is optionally substituted by one or more substituents independently selected from the group consisting of: halogens, C 1-3 -alkyl, C 1-3 - Haloalkyl, C 1-3 -alkoxy group, C 1-3 - Haloalkoxy groups and C 1-3 -alkyl carbonyl. In another aspect, R 2The spiroheterocyclic ring is optionally substituted by one or more substituents independently selected from the group consisting of: fluorine, methyl, ethyl, propyl, fluoromethyl, difluoromethyl, trifluoromethyl, fluoroethyl, difluoroethyl, trifluoroethyl, trifluoropropyl, methoxy, ethoxy, trifluoromethoxy, trifluoroethoxy, methyl carbonyl, and ethyl carbonyl. In another aspect, R 2 The spirocyclic ring may optionally be substituted by one or more substituents independently selected from the group consisting of: fluorine, methyl, ethyl, fluoromethyl, difluoromethyl, and trifluoromethyl.

[0848] In some embodiments, the compound and pharmaceutically acceptable salt are selected from the group consisting of:

[0849] (R)-N-(2-(4-cyanothiazolidine-3-yl)-2-oxoethyl)-6-(2-azaspiro[3.4]octane-2-yl)quinoline-4-carboxamide (Example 139);

[0850] (R)-N-(2-(4-cyanothiazolidine-3-yl)-2-oxoethyl)-6-(5,5-difluoro-2-azaspiro[3.4]octane-2-yl)quinoline-4-carboxamide (Example 141);

[0851] And its pharmaceutically acceptable salts.

[0852] In some embodiments, R 2 The two saturated rings of the spiroheterocyclic group are:

[0853]

[0854] One or two of these rings may optionally be substituted by one or more substituents independently selected from the group consisting of: halogens, C 1-6 -alkyl, C 1-6 - Haloalkyl, C 1-6 -alkoxy group, C 1-6 - Haloalkoxy groups and C 1-6 -alkyl carbonyl. In one respect, R 2 The spiroheterocyclic ring is optionally substituted by one or more substituents independently selected from the group consisting of: halogens, C 1-3 -alkyl, C 1-3 - Haloalkyl, C 1-3 -alkoxy group, C 1-3 - Haloalkoxy groups and C 1-3 -alkyl carbonyl. In another aspect, R 2The spiroheterocyclic ring is optionally substituted by one or more substituents independently selected from the group consisting of: fluorine, methyl, ethyl, propyl, fluoromethyl, difluoromethyl, trifluoromethyl, fluoroethyl, difluoroethyl, trifluoroethyl, trifluoropropyl, methoxy, ethoxy, trifluoromethoxy, trifluoroethoxy, methyl carbonyl, and ethyl carbonyl. In another aspect, R 2 The spirocyclic ring may optionally be substituted by one or more substituents independently selected from the group consisting of: fluorine, methyl, ethyl, fluoromethyl, difluoromethyl, and trifluoromethyl.

[0855] In some embodiments, the compound or pharmaceutically acceptable salt is (R)-N-(2-(4-cyanothiazolidine-3-yl)-2-oxoethyl)-6-(5,8-dioxa-2-azaspiro[3.4]octane-2-yl)quinoline-4-carboxamide (Example 163), or a pharmaceutically acceptable salt thereof.

[0856] In some embodiments, R 2 The two saturated rings of the spiroheterocyclic group are:

[0857]

[0858] One or two of these rings may optionally be substituted by one or more substituents independently selected from the group consisting of: halogens, C 1-6 -alkyl, C 1-6 - Haloalkyl, C 1-6 -alkoxy group, C 1-6 - Haloalkoxy groups and C 1-6 -alkyl carbonyl. In one respect, R 2 The spiroheterocyclic ring is optionally substituted by one or more substituents independently selected from the group consisting of: halogens, C 1-3 -alkyl, C 1-3 - Haloalkyl, C 1-3 -alkoxy group, C 1-3 - Haloalkoxy groups and C 1-3 -alkyl carbonyl. In another aspect, R 2 The spiroheterocyclic ring is optionally substituted by one or more substituents independently selected from the group consisting of: fluorine, methyl, ethyl, propyl, fluoromethyl, difluoromethyl, trifluoromethyl, fluoroethyl, difluoroethyl, trifluoroethyl, trifluoropropyl, methoxy, ethoxy, trifluoromethoxy, and trifluoroethoxy. In another aspect, R 2 The spirocyclic ring may optionally be substituted by one or more substituents independently selected from the group consisting of: fluorine, methyl, ethyl, fluoromethyl, difluoromethyl, and trifluoromethyl.

[0859] In some embodiments, R 2 The two saturated rings of the spiroheterocyclic group are:

[0860]

[0861] One or two of these rings may optionally be substituted by one or more substituents independently selected from the group consisting of: halogens, C 1-6 -alkyl, C 1-6 - Haloalkyl, C 1-6 -alkoxy group, C 1-6 - Haloalkoxy groups and C 1-6 -alkyl carbonyl. In one respect, R 2 The spiroheterocyclic ring is optionally substituted by one or more substituents independently selected from the group consisting of: halogens, C 1-3 -alkyl, C 1-3 - Haloalkyl, C 1-3 -alkoxy group, C 1-3 - Haloalkoxy groups and C 1-3 -alkyl carbonyl. In another aspect, R 2 The spiroheterocyclic ring is optionally substituted by one or more substituents independently selected from the group consisting of: fluorine, methyl, ethyl, propyl, fluoromethyl, difluoromethyl, trifluoromethyl, fluoroethyl, difluoroethyl, trifluoroethyl, trifluoropropyl, methoxy, ethoxy, trifluoromethoxy, trifluoroethoxy, methyl carbonyl, and ethyl carbonyl. In another aspect, R 2 The spirocyclic ring may optionally be substituted by one or more substituents independently selected from the group consisting of: fluorine, methyl, ethyl, fluoromethyl, difluoromethyl, and trifluoromethyl.

[0862] In some embodiments, the compound or pharmaceutically acceptable salt is (R)-N-(2-(4-cyanothiazolidine-3-yl)-2-oxoethyl)-6-(8-oxa-5-azaspiro[3.5]nonane-5-yl)quinoline-4-carboxamide (Example 104), or a pharmaceutically acceptable salt thereof.

[0863] In some embodiments, R 2 The two saturated rings of the spiroheterocyclic group are:

[0864]

[0865] One or two of these rings may optionally be substituted by one or more substituents independently selected from the group consisting of: halogens, C 1-6 -alkyl, C 1-6 - Haloalkyl, C 1-6 -alkoxy group, C 1-6 - Haloalkoxy groups and C 1-6 -alkyl carbonyl. In one respect, R 2The spiroheterocyclic ring is optionally substituted by one or more substituents independently selected from the group consisting of: halogens, C 1-3 -alkyl, C 1-3 - Haloalkyl, C 1-3 -alkoxy group, C 1-3 - Haloalkoxy groups and C 1-3 -alkyl carbonyl. In another aspect, R 2 The spiroheterocyclic ring is optionally substituted by one or more substituents independently selected from the group consisting of: fluorine, methyl, ethyl, propyl, fluoromethyl, difluoromethyl, trifluoromethyl, fluoroethyl, difluoroethyl, trifluoroethyl, trifluoropropyl, methoxy, ethoxy, trifluoromethoxy, trifluoroethoxy, methyl carbonyl, and ethyl carbonyl. In another aspect, R 2 The spirocyclic ring may optionally be substituted by one or more substituents independently selected from the group consisting of: fluorine, methyl, ethyl, fluoromethyl, difluoromethyl, and trifluoromethyl.

[0866] In some embodiments, the compound or pharmaceutically acceptable salt is (R)-N-(2-(4-cyanothiazolidine-3-yl)-2-oxoethyl)-6-(3-oxa-9-azaspiro[5.5]deca-alkyl-9-yl)quinoline-4-carboxamide (Example 162), or a pharmaceutically acceptable salt thereof.

[0867] In some embodiments, R 2 The two saturated rings of the spiroheterocyclic group are:

[0868]

[0869] One or two of these rings may optionally be substituted by one or more substituents independently selected from the group consisting of: halogens, C 1-6 -alkyl, C 1-6 - Haloalkyl, C 1-6 -alkoxy group, C 1-6 - Haloalkoxy groups and C 1-6 -alkyl carbonyl. In one respect, R 2 The spiroheterocyclic ring is optionally substituted by one or more substituents independently selected from the group consisting of: halogens, C 1-3 -alkyl, C 1-3 - Haloalkyl, C 1-3 -alkoxy group, C 1-3 - Haloalkoxy groups and C 1-3 -alkyl carbonyl. In another aspect, R 2The spiroheterocyclic ring is optionally substituted by one or more substituents independently selected from the group consisting of: fluorine, methyl, ethyl, propyl, fluoromethyl, difluoromethyl, trifluoromethyl, fluoroethyl, difluoroethyl, trifluoroethyl, trifluoropropyl, methoxy, ethoxy, trifluoromethoxy, trifluoroethoxy, methyl carbonyl, and ethyl carbonyl. In another aspect, R 2 The spirocyclic ring may optionally be substituted by one or more substituents independently selected from the group consisting of: fluorine, methyl, ethyl, fluoromethyl, difluoromethyl, and trifluoromethyl.

[0870] In some embodiments, the compound or pharmaceutically acceptable salt is (R)-N-(2-(4-cyanothiazolidine-3-yl)-2-oxoethyl)-6-(1,9-dioxa-4-azaspiro[5.5]undecane-4-yl)quinoline-4-carboxamide (Example 99), or a pharmaceutically acceptable salt thereof.

[0871] In some embodiments, R 2 The two saturated rings of the spiroheterocyclic group are:

[0872]

[0873] One or two of these rings may optionally be substituted by one or more substituents independently selected from the group consisting of: halogens, C 1-6 -alkyl, C 1-6 - Haloalkyl, C 1-6 -alkoxy group, C 1-6 - Haloalkoxy groups and C 1-6 -alkyl carbonyl. In one respect, R 2 The spiroheterocyclic ring is optionally substituted by one or more substituents independently selected from the group consisting of: halogens, C 1-3 -alkyl, C 1-3 - Haloalkyl, C 1-3 -alkoxy group, C 1-3 - Haloalkoxy groups and C 1-3 -alkyl carbonyl. In another aspect, R 2 The spiroheterocyclic ring is optionally substituted by one or more substituents independently selected from the group consisting of: fluorine, methyl, ethyl, propyl, fluoromethyl, difluoromethyl, trifluoromethyl, fluoroethyl, difluoroethyl, trifluoroethyl, trifluoropropyl, methoxy, ethoxy, trifluoromethoxy, and trifluoroethoxy. In another aspect, R 2 The spirocyclic ring may optionally be substituted by one or more substituents independently selected from the group consisting of: fluorine, methyl, ethyl, fluoromethyl, difluoromethyl, and trifluoromethyl.

[0874] In some embodiments, the compound or pharmaceutically acceptable salt is (R)-N-(2-(4-cyanothiazolidine-3-yl)-2-oxoethyl)-6-(7-oxo-6-oxa-8-azaspiro[4.5]decane-8-yl)quinoline-4-carboxamide (Example 111), or a pharmaceutically acceptable salt thereof.

[0875] In some embodiments, R 2 The two saturated rings of the spiroheterocyclic group are:

[0876]

[0877] One or two of these rings may optionally be substituted by one or more substituents independently selected from the group consisting of: halogens, C 1-6 -alkyl, C 1-6 - Haloalkyl, C 1-6 -alkoxy group, C 1-6 - Haloalkoxy groups and C 1-6 -alkyl carbonyl. In one respect, R 2 The spiroheterocyclic ring is optionally substituted by one or more substituents independently selected from the group consisting of: halogens, C 1-3 -alkyl, C 1-3 - Haloalkyl, C 1-3 -alkoxy group, C 1-3 - Haloalkoxy groups and C 1-3 -alkyl carbonyl. In another aspect, R 2 The spiroheterocyclic ring is optionally substituted by one or more substituents independently selected from the group consisting of: fluorine, methyl, ethyl, propyl, fluoromethyl, difluoromethyl, trifluoromethyl, fluoroethyl, difluoroethyl, trifluoroethyl, trifluoropropyl, methoxy, ethoxy, trifluoromethoxy, and trifluoroethoxy. In another aspect, R 2 The spirocyclic ring may optionally be substituted by one or more substituents independently selected from the group consisting of: fluorine, methyl, ethyl, fluoromethyl, difluoromethyl, and trifluoromethyl.

[0878] In some embodiments, the compound or pharmaceutically acceptable salt is (R)-N-(2-(4-cyanothiazolidine-3-yl)-2-oxoethyl)-6-(2-oxo-1-oxa-3-azaspiro[5.5]undecane-3-yl)quinoline-4-carboxamide (Example 110), or a pharmaceutically acceptable salt thereof.

[0879] In some embodiments, R 2 The two saturated rings of the spiroheterocyclic group are:

[0880]

[0881] One or two of these rings may optionally be substituted by one or more substituents independently selected from the group consisting of: halogens, C 1-6 -alkyl, C 1-6 - Haloalkyl, C 1-6 -alkoxy group, C 1-6 - Haloalkoxy groups and C 1-6 -alkyl carbonyl. In one respect, R 2 The spiroheterocyclic ring is optionally substituted by one or more substituents independently selected from the group consisting of: halogens, C 1-3 -alkyl, C 1-3 - Haloalkyl, C 1-3 -alkoxy group, C 1-3 - Haloalkoxy groups and C 1-3 -alkyl carbonyl. In another aspect, R 2 The spiroheterocyclic ring is optionally substituted by one or more substituents independently selected from the group consisting of: fluorine, methyl, ethyl, propyl, fluoromethyl, difluoromethyl, trifluoromethyl, fluoroethyl, difluoroethyl, trifluoroethyl, trifluoropropyl, methoxy, ethoxy, trifluoromethoxy, trifluoroethoxy, methyl carbonyl, and ethyl carbonyl. In another aspect, R 2 The spirocyclic ring may optionally be substituted by one or more substituents independently selected from the group consisting of: fluorine, methyl, ethyl, fluoromethyl, difluoromethyl, and trifluoromethyl.

[0882] In some embodiments, the compound or pharmaceutically acceptable salt is (R)-N-(2-(4-cyanothiazolidine-3-yl)-2-oxoethyl)-6-(2-oxa-7-azaspiro[3.5]nonane-7-yl)quinoline-4-carboxamide (Example 229), or a pharmaceutically acceptable salt thereof.

[0883] In some embodiments, R 2 The two saturated rings of the spiroheterocyclic group are:

[0884]

[0885] One or two of these rings may optionally be substituted by one or more substituents independently selected from the group consisting of: halogens, C 1-6 -alkyl, C 1-6 - Haloalkyl, C 1-6 -alkoxy group, C 1-6 - Haloalkoxy groups and C 1-6 -alkyl carbonyl. In one respect, R 2 The spiroheterocyclic ring is optionally substituted by one or more substituents independently selected from the group consisting of: halogens, C 1-3 -alkyl, C 1-3 - Haloalkyl, C1-3 -alkoxy group, C 1-3 - Haloalkoxy groups and C 1-3 -alkyl carbonyl. In another aspect, R 2 The spiroheterocyclic ring is optionally substituted by one or more substituents independently selected from the group consisting of: fluorine, methyl, ethyl, propyl, fluoromethyl, difluoromethyl, trifluoromethyl, fluoroethyl, difluoroethyl, trifluoroethyl, trifluoropropyl, methoxy, ethoxy, trifluoromethoxy, trifluoroethoxy, methyl carbonyl, and ethyl carbonyl. In another aspect, R 2 The spirocyclic ring may optionally be substituted by one or more substituents independently selected from the group consisting of: fluorine, methyl, ethyl, fluoromethyl, difluoromethyl, and trifluoromethyl.

[0886] In some embodiments, the compound or pharmaceutically acceptable salt is (R)-N-(2-(4-cyanothiazolidine-3-yl)-2-oxoethyl)-6-(1,4-dioxa-8-azaspiro[4.5]decane-8-yl)quinoline-4-carboxamide (Example 228), or a pharmaceutically acceptable salt thereof. In some embodiments, R 2 The two saturated rings of the spiroheterocyclic group are:

[0887]

[0888] One or two of these rings may optionally be substituted by one or more substituents independently selected from the group consisting of: halogens, C 1-6 -alkyl, C 1-6 - Haloalkyl, C 1-6 -alkoxy group, C 1-6 - Haloalkoxy groups and C 1-6 -alkyl carbonyl. In one respect, R 2 The spiroheterocyclic ring is optionally substituted by one or more substituents independently selected from the group consisting of: halogens, C 1-3 -alkyl, C 1-3 - Haloalkyl, C 1-3 -alkoxy group, C 1-3 - Haloalkoxy groups and C 1-3 -alkyl carbonyl. In another aspect, R 2 The spiroheterocyclic ring is optionally substituted by one or more substituents independently selected from the group consisting of: fluorine, methyl, ethyl, propyl, fluoromethyl, difluoromethyl, trifluoromethyl, fluoroethyl, difluoroethyl, trifluoroethyl, trifluoropropyl, methoxy, ethoxy, trifluoromethoxy, trifluoroethoxy, methyl carbonyl, and ethyl carbonyl. In another aspect, R 2 The spirocyclic ring may optionally be substituted by one or more substituents independently selected from the group consisting of: fluorine, methyl, ethyl, fluoromethyl, difluoromethyl, and trifluoromethyl.

[0889] In some embodiments, the compound or pharmaceutically acceptable salt is (R)-N-(2-(4-cyanothiazolidine-3-yl)-2-oxoethyl)-6-(1,5-dioxa-9-azaspiro[5.5]undecane-9-yl)quinoline-4-carboxamide (Example 227), or a pharmaceutically acceptable salt thereof.

[0890] In some embodiments, the compound and pharmaceutically acceptable salt are selected from the group consisting of:

[0891] (R)-N-(2-(4-cyanothiazolidine-3-yl)-2-oxoethyl)-6-(2-azaspiro[3.3]heptane-2-yl)quinoline-4-carboxamide (Example 17);

[0892] (R)-N-(2-(4-cyanothiazolidine-3-yl)-2-oxoethyl)-6-(3,3-dimethyl-1-oxa-6-azaspiro[3.3]heptane-6-yl)quinoline-4-carboxamide (Example 18);

[0893] (R)-N-(2-(4-cyanothiazolidine-3-yl)-2-oxoethyl)-6-(1-azaspiro[3.3]heptane-1-yl)quinoline-4-carboxamide (Example 19);

[0894] (R)-N-(2-(4-cyanothiazolidine-3-yl)-2-oxoethyl)-6-(5-azaspiro[2.5]octane-5-yl)quinoline-4-carboxamide (Example 46);

[0895] (R)-N-(2-(4-cyanothiazolidine-3-yl)-2-oxoethyl)-6-(5-azaspiro[2.4]heptane-5-yl)quinoline-4-carboxamide (Example 49);

[0896] N-(2-((R)-4-cyanothiazolidine-3-yl)-2-oxoethyl)-6-((R)-6-(fluoromethyl)-5-azaspiro[2.4]heptane-5-yl)quinoline-4-carboxamide (Example 58);

[0897] (R)-N-(2-(4-cyanothiazolidine-3-yl)-2-oxoethyl)-6-(1,9-dioxa-4-azaspiro[5.5]undecane-4-yl)quinoline-4-carboxamide (Example 99);

[0898] (R)-N-(2-(4-cyanothiazolidine-3-yl)-2-oxoethyl)-6-(8-oxa-5-azaspiro[3.5]nonane-5-yl)quinoline-4-carboxamide (Example 104);

[0899] (R)-N-(2-(4-cyanothiazolidine-3-yl)-2-oxoethyl)-6-(2-oxo-1-oxa-3-azaspiro[5.5]undecane-3-yl)quinoline-4-carboxamide (Example 110);

[0900] (R)-N-(2-(4-cyanothiazolidine-3-yl)-2-oxoethyl)-6-(7-oxo-6-oxa-8-azaspiro[4.5]decane-8-yl)quinoline-4-carboxamide (Example 111);

[0901] (R)-N-(2-(4-cyanothiazolidine-3-yl)-2-oxoethyl)-6-(2-azaspiro[3.4]octane-2-yl)quinoline-4-carboxamide (Example 139);

[0902] (R)-N-(2-(4-cyanothiazolidine-3-yl)-2-oxoethyl)-6-(5,5-difluoro-2-azaspiro[3.4]octane-2-yl)quinoline-4-carboxamide (Example 141);

[0903] (R)-N-(2-(4-cyanothiazolidine-3-yl)-2-oxoethyl)-6-(6-methyl-2-azaspiro[3.3]heptane-2-yl)quinoline-4-carboxamide (Example 149);

[0904] (R)-N-(2-(4-cyanothiazolidine-3-yl)-2-oxoethyl)-6-(6-(trifluoromethyl)-2-azaspiro[3.3]heptane-2-yl)quinoline-4-carboxamide (Example 150);

[0905] (R)-N-(2-(4-cyanothiazolidine-3-yl)-2-oxoethyl)-6-(1-oxa-6-azaspiro[3.3]heptane-6-yl)quinoline-4-carboxamide (Example 153);

[0906] (R)-N-(2-(4-cyanothiazolidine-3-yl)-2-oxoethyl)-6-(6-fluoro-2-azaspiro[3.3]heptane-2-yl)quinoline-4-carboxamide (Example 155);

[0907] (R)-N-(2-(4-cyanothiazolidine-3-yl)-2-oxoethyl)-6-(3-oxa-9-azaspiro[5.5]undecane-9-yl)quinoline-4-carboxamide (Example 162);

[0908] (R)-N-(2-(4-cyanothiazolidine-3-yl)-2-oxoethyl)-6-(5,8-dioxa-2-azaspiro[3.4]octane-2-yl)quinoline-4-carboxamide (Example 163);

[0909] (R)-N-(2-(4-cyanothiazolidine-3-yl)-2-oxoethyl)-6-(5-azaspiro[2.3]hexane-5-yl)quinoline-4-carboxamide (Example 164);

[0910] (R)-N-(2-(4-cyanothiazolidine-3-yl)-2-oxoethyl)-6-(2-oxa-6-azaspiro[3.3]heptane-6-yl)quinoline-4-carboxamide (Example 166);

[0911] (R)-6-(6-acetyl-2,6-diazaspiro[3.3]heptane-2-yl)-N-(2-(4-cyanothiazolidine-3-yl)-2-oxoethyl)quinoline-4-carboxamide (Example 184);

[0912] (R)-N-(2-(4-cyanothiazolidine-3-yl)-2-oxoethyl)-6-(1-thia-6-azaspiro[3.3]heptane-6-yl)quinoline-4-carboxamide (Example 222);

[0913] (R)-N-(2-(4-cyanothiazolidine-3-yl)-2-oxoethyl)-6-(1,5-dioxa-9-azaspiro[5.5]undecane-9-yl)quinoline-4-carboxamide (Example 227);

[0914] (R)-N-(2-(4-cyanothiazolidine-3-yl)-2-oxoethyl)-6-(1,4-dioxa-8-azaspiro[4.5]decane-8-yl)quinoline-4-carboxamide (Example 228);

[0915] (R)-N-(2-(4-cyanothiazolidine-3-yl)-2-oxoethyl)-6-(2-oxa-7-azaspiro[3.5]nonane-7-yl)quinoline-4-carboxamide (Example 229);

[0916] And its pharmaceutically acceptable salts.

[0917] In some embodiments, the compound and pharmaceutically acceptable salt are selected from the group consisting of:

[0918] (R)-N-(2-(4-cyanothiazolidine-3-yl)-2-oxoethyl)-6-(3,3-dimethyl-1-oxa-6-azaspiro[3.3]heptane-6-yl)quinoline-4-carboxamide (Example 18);

[0919] (R)-N-(2-(4-cyanothiazolidine-3-yl)-2-oxoethyl)-6-(1,9-dioxa-4-azaspiro[5.5]undecane-4-yl)quinoline-4-carboxamide (Example 99);

[0920] (R)-N-(2-(4-cyanothiazolidine-3-yl)-2-oxoethyl)-6-(2-oxo-1-oxa-3-azaspiro[5.5]undecane-3-yl)quinoline-4-carboxamide (Example 110);

[0921] (R)-N-(2-(4-cyanothiazolidine-3-yl)-2-oxoethyl)-6-(6-(trifluoromethyl)-2-azaspiro[3.3]heptane-2-yl)quinoline-4-carboxamide (Example 150);

[0922] (R)-N-(2-(4-cyanothiazolidine-3-yl)-2-oxoethyl)-6-(1-oxa-6-azaspiro[3.3]heptane-6-yl)quinoline-4-carboxamide (Example 153);

[0923] (R)-N-(2-(4-cyanothiazolidine-3-yl)-2-oxoethyl)-6-(5,8-dioxa-2-azaspiro[3.4]octane-2-yl)quinoline-4-carboxamide (Example 163);

[0924] (R)-N-(2-(4-cyanothiazolidine-3-yl)-2-oxoethyl)-6-(2-oxa-6-azaspiro[3.3]heptane-6-yl)quinoline-4-carboxamide (Example 166);

[0925] (R)-N-(2-(4-cyanothiazolidine-3-yl)-2-oxoethyl)-6-(1-thia-6-azaspiro[3.3]heptane-6-yl)quinoline-4-carboxamide (Example 222);

[0926] And its pharmaceutically acceptable salts.

[0927] D. R 2 It is a nitrogen-containing heterocyclic butyl group

[0928] In some embodiments, this disclosure provides compounds having the structure of formula (V):

[0929]

[0930] and its pharmaceutically acceptable salts, of which:

[0931] R 1 R 3 R 4 R 5 and R 6 Independently selected from the following groups: hydrogen, chlorine, fluorine, and methyl;

[0932] R 20a and R 20b Choose independently the following groups: hydrogen and C 1-3 -alkyl;

[0933] R 20c and R 20d Independently select from the following groups: hydrogen, fluorine, hydroxyl, C 1-3 -alkyl, C 3-6 -cycloalkyl, C 3-6 -cycloalkyl-C 1-3 -alkyl, C 1-3 -alkoxy group, C 3-6 -cycloalkoxy, C 1-3 -alkoxy-C 1-3 -alkyl, phenyl, tolyl, phenyl-C 1-3 -alkyl, morpholino, C 1-3 -alkylsulfonyl-C 1-3 -alkyl and C 1-3 -alkyl-carbonylamino-C 1-3 -alkyl; and wherein the C 1-3 -alkyl, C 3-6 -cycloalkyl, C 3-6 -cycloalkyl-C 1-3 -alkyl, C 1-3 -alkoxy group, C 3-6 -cycloalkoxy, C 1-3 -alkoxy-C 1-3 -alkyl, phenyl and phenyl-C 1-3 -alkyl groups can be further substituted with one or more halogens; and

[0934] R 20e and R 20f Choose independently the following groups: hydrogen and C 1-3 -alkyl.

[0935] In some embodiments of compounds having the structure of formula (V), 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 one respect, R... 1 R 3 R 4 R 5 and R 6 One of the substituents is chlorine, and the remaining R 1 R 3 R 4 R5 and R 6 The substituents are all hydrogen. In another aspect, R... 1 R 3 R 4 R 5 and R 6 One of the substituents is fluorine, and the remaining R 1 R 3 R 4 R 5 and R 6 The substituents are all hydrogen. In another aspect, R... 1 R 3 R 4 R 5 and R 6 One of the substituents is a methyl group, and the remaining R 1 R 3 R 4 R 5 and R 6 All the substituents are hydrogen.

[0936] In some embodiments of compounds having the structure of formula (V), R 1 R 3 R 4 R 5 and R 6 They're all hydrogen.

[0937] In some embodiments of compounds having the structure of formula (V):

[0938] R 20a and R 20b Independently selected from the group consisting of: hydrogen and methyl;

[0939] R 20c and R 20d Independently select from the following groups: hydrogen, fluorine, hydroxyl, C 1-3 -alkyl, C 3-6 -cycloalkyl, C 1-3 -alkoxy group, C 1-3 -alkoxy-C 1-3 -alkyl, morpholino, C 1-3 -alkylsulfonyl-C 1-3 -alkyl and C 1-3 -alkyl-carbonylamino-C 1-3 -alkyl; and wherein the C 1-3 -alkyl, C 3-6 -cycloalkyl, C 1-3 -alkoxy and C 1-3 -alkoxy-C 1-3-alkyl groups can be further substituted with one or more halogens; and

[0940] R 20e and R 20f Choose independently from the following groups: hydrogen and methyl.

[0941] In some embodiments of compounds having the structure of formula (V): R 20c and R 20d Choose independently from the following groups: hydrogen, fluorine, C 1-3 -alkyl, C 1-3 -alkoxy, morpholino and C 1-3 -alkyl-carbonylamino-C 1-3 -alkyl; and wherein the C 1-3 -alkyl and C 1-3 -Alkoxy groups can be further substituted by one or more halogens.

[0942] In some embodiments, the compound and pharmaceutically acceptable salt are selected from the group consisting of:

[0943] (R)-N-(2-(4-cyanothiazolidine-3-yl)-2-oxoethyl)-6-(3-(fluoromethyl)-3-methylazacyclobutane-1-yl)quinoline-4-carboxamide (Example 27);

[0944] (R)-N-(2-(4-cyanothiazolidine-3-yl)-2-oxoethyl)-6-(3-(fluoromethyl)azacyclobutane-1-yl)quinoline-4-carboxamide (Example 113);

[0945] (R)-N-(2-(4-cyanothiazolidine-3-yl)-2-oxoethyl)-6-(3-methoxy-3-methylazacyclobutane-1-yl)quinoline-4-carboxamide (Example 151);

[0946] And its pharmaceutically acceptable salts.

[0947] E. R 2 Is it morpholino?

[0948] In some embodiments, this disclosure provides compounds having the structure of formula (VI):

[0949]

[0950] and its pharmaceutically acceptable salts, of which:

[0951] R 1 R 3 R 4 R 5 and R 6Independently selected from the following groups: hydrogen, chlorine, fluorine, and methyl;

[0952] R 30a and R 30b Choose independently from the following groups: hydrogen, C 1-3 -alkyl, halo-C 1-3 -alkyl and C 1-3 -alkoxy-C 1-3 -alkyl;

[0953] R 30c and R 30d Independently select from the following groups: hydrogen, halogens, C 1-3 -alkyl, halo-C 1-3 -alkyl, C 1-3 -alkoxy-C 1-3 -alkyl and C 1-3 -alkylsulfonyl-C 1-3 -alkyl;

[0954] R 30e and R 30f Independently select from the following groups: hydrogen, halogens, C 1-3 -alkyl, halo-C 1-3 -alkyl, C 1-3 -alkoxy-C 1-3 -alkyl and C 1-3 -alkylsulfonyl-C 1-3 -alkyl; and

[0955] R 30g and R 30h Choose independently from the following groups: hydrogen, C 1-3 -alkyl, halo-C 1-3 -alkyl and C 1-3 -alkoxy-C 1-3 -alkyl.

[0956] In some embodiments of compounds having the structure of formula (VI), R 1 R 3 R 4 R 3 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 one respect, R... 1 R 3 R 4 R 5 and R6 One of the substituents is chlorine, and the remaining R 1 R 3 R 4 R 5 and R 6 The substituents are all hydrogen. In another aspect, R... 1 R 3 R 4 R 5 and R 6 One of the substituents is fluorine, and the remaining R 1 R 3 R 4 R 5 and R 6 The substituents are all hydrogen. In another aspect, R... 1 R 3 R 4 R 5 and R 6 One of the substituents is a methyl group, and the remaining R 1 R 3 R 4 R 5 and R 6 All the substituents are hydrogen.

[0957] In some embodiments of compounds having the structure of formula (VI), R 1 R 3 R 4 R 3 and R 6 They're all hydrogen.

[0958] In some embodiments of compounds having the structure of formula (VI):

[0959] R 30a and R 30b Choose independently from the following groups: hydrogen, C 1-2 -alkyl, halo-C 1-2 -alkyl and C 1-2 -alkoxy-C 1-2 -alkyl;

[0960] R 30c and R 30d Independently select from the following groups: hydrogen, halogens, C 1-2 -alkyl, halo-C 1-2 -alkyl, C 1-2 -alkoxy-C 1-2 -alkyl and C 1-2 -alkylsulfonyl-C 1-2 -alkyl;

[0961] R30e and R 30f Independently select from the following groups: hydrogen, halogens, C 1-2 -alkyl, halo-C 1-2 -alkyl, C 1-2 -alkoxy-C 1-2 -alkyl and C 1-2 -alkylsulfonyl-C 1-2 -alkyl; and

[0962] R 30g and R 30h Choose independently from the following groups: hydrogen, C 1-2 -alkyl, halo-C 1-2 -alkyl and C 1-2 -alkoxy-C 1-2 -alkyl.

[0963] In some embodiments, the compound and pharmaceutically acceptable salt are selected from the group consisting of:

[0964] (R)-N-(2-(4-cyanothiazolidine-3-yl)-2-oxoethyl)-8-methyl-6-morpholinoquinoline-4-carboxamide (Example 9);

[0965] (R)-N-(2-(4-cyanothiazolidine-3-yl)-2-oxoethyl)-6-morpholinoquinoline-4-carboxamide (Example 67);

[0966] N-(2-((R)-4-cyanothiazolidine-3-yl)-2-oxoethyl)-6-((2R,6S)-2,6-dimethylmorpholino)-quinoline-4-carboxamide (Example 68);

[0967] N-(2-((R)-4-cyanothiazolidine-3-yl)-2-oxoethyl)-6-((R)-2-(fluoromethyl)morpholino)-quinoline-4-carboxamide (Example 69);

[0968] N-(2-((R)-4-cyanothiazolidine-3-yl)-2-oxoethyl)-6-((2R,6R)-2,6-dimethylmorpholino)-quinoline-4-carboxamide (Example 70);

[0969] N-(2-((R)-4-cyanothiazolidine-3-yl)-2-oxoethyl)-6-((S)-2-(fluoromethyl)morpholino)-quinoline-4-carboxamide (Example 71);

[0970] N-(2-((R)-4-cyanothiazolidine-3-yl)-2-oxoethyl)-6-((R)-2-methylmorpholino)-quinoline-4-carboxamide (Example 72);

[0971] N-(2-((R)-4-cyanothiazolidine-3-yl)-2-oxoethyl)-6-((S)-2-methylmorpholino)-quinoline-4-carboxamide (Example 80);

[0972] And its pharmaceutically acceptable salts.

[0973] F. R 2 It is piperidine-1-yl

[0974] In some embodiments, this disclosure provides compounds having the structure of formula (VII):

[0975]

[0976] and its pharmaceutically acceptable salts, of which:

[0977] R 1 R 3 R 4 R 5 and R 6 Independently selected from the following groups: hydrogen, chlorine, fluorine, and methyl;

[0978] R 40a and R 40b Choose independently from the following groups: hydrogen, C 1-3 -alkyl and halogenated-C 1-3 -alkyl;

[0979] R 40c and R 40d Choose independently from the following groups: hydrogen, fluorine, C 1-3 -alkyl, halo-C 1-3 -alkyl and C 1-3 -alkoxy group;

[0980] R 40e and R 40f Independently select from the following groups: hydrogen, fluorine, hydroxyl, oxo group, C 1-3 -alkyl, halo-C 1-3 -alkyl, cyclopropyl and C 1-3 -alkoxy group;

[0981] R 40g and R 40h Choose independently from the following groups: hydrogen, fluorine, C 1-3 -alkyl, halo-C 1-3 -alkyl and C 1-3 -alkoxy group; and

[0982] R 40i and R 40j Choose independently from the following groups: hydrogen, C1-3 -alkyl and halogenated-C 1-3 -alkyl.

[0983] In some embodiments of compounds having the structure of formula (VII), 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 one respect, R... 1 R 3 R 4 R 5 and R 6 One of the substituents is chlorine, and the remaining R 1 R 3 R 4 R 5 and R 6 The substituents are all hydrogen. In another aspect, R... 1 R 3 R 4 R 5 and R 6 One of the substituents is fluorine, and the remaining R 1 R 3 R 4 R 5 and R 6 The substituents are all hydrogen. In another aspect, R... 1 R 3 R 4 R 5 and R 6 One of the substituents is a methyl group, and the remaining R 1 R 3 R 4 R 5 and R 6 All the substituents are hydrogen.

[0984] In some embodiments of compounds having the structure of formula (VII), R 1 R 3 R 4 R 3 and R 6 They're all hydrogen.

[0985] In some embodiments of compounds having the structure of formula (VII):

[0986] R 40a and R 40b Choose independently from the following groups: hydrogen, C 1-3 -alkyl and halogenated-C 1-3 -alkyl;

[0987] R 40c and R 40d Choose independently from the following groups: hydrogen, fluorine, C 1-3 -alkyl, halo-C 1-3 -alkyl and C 1-3 -alkoxy group;

[0988] R 40e and R 40f Independently select from the following groups: hydrogen, fluorine, hydroxyl, C 1-3 -alkyl, halo-C 1-3 -alkyl, cyclopropyl and C 1-3 -alkoxy group;

[0989] R 40g and R 40h Choose independently from the following groups: hydrogen, fluorine, C 1-3 -alkyl, halo-C 1-3 -alkyl and C 1-3 -alkoxy group; and

[0990] R 40i and R 40j Choose independently from the following groups: hydrogen, C 1-3 -alkyl and halogenated-C 1-3 -alkyl.

[0991] In some embodiments of compounds having the structure of formula (VII):

[0992] R 40a and R 40b Choose independently from the following groups: hydrogen, C 1-2 -alkyl and halogenated-C 1-2 -alkyl;

[0993] R 40c and R 40d Choose independently from the following groups: hydrogen, fluorine, C 1-2 -alkyl, halo-C 1-2 -alkyl and C 1-2 -alkoxy group;

[0994] R 40e and R 40f Independently select from the following groups: hydrogen, fluorine, hydroxyl, C 1-2 -alkyl, halo-C 1-2-alkyl and C 1-2 -alkoxy group;

[0995] R 40g and R 40h Choose independently from the following groups: hydrogen, fluorine, C 1-2 -alkyl, halo-C 1-2 -alkyl and C 1-2 -alkoxy group; and

[0996] R 40i and R 40j Choose independently from the following groups: hydrogen, C 1-2 -alkyl and halogenated-C 1-2 -alkyl.

[0997] In some embodiments, the compound and pharmaceutically acceptable salt are selected from the group consisting of:

[0998] (R)-N-(2-(4-cyanothiazolidine-3-yl)-2-oxoethyl)-6-(4-methoxypiperidin-1-yl)quinoline-4-carboxamide (Example 8);

[0999] (R)-N-(2-(4-cyanothiazolidine-3-yl)-2-oxoethyl)-6-(4-methoxy-4-methylpiperidin-1-yl)quinoline-4-carboxamide (Example 42);

[1000] (R)-N-(2-(4-cyanothiazolidine-3-yl)-2-oxoethyl)-6-(4-fluoropiperidin-1-yl)quinoline-4-carboxamide (Example 205);

[1001] (R)-N-(2-(4-cyanothiazolidine-3-yl)-2-oxoethyl)-6-(4-oxopiperidin-1-yl)quinoline-4-carboxamide (Example 230)

[1002] And its pharmaceutically acceptable salts.

[1003] G. R 2 It is piperidine-4-yl

[1004] In some embodiments, this disclosure provides compounds having the structure of formula (VIII):

[1005]

[1006] and its pharmaceutically acceptable salts, of which:

[1007] R 1 R 3 R 4 R 5 and R 6Independently selected from the following groups: hydrogen, chlorine, fluorine, and methyl;

[1008] R 50a and R 50b Choose independently from the following groups: hydrogen, fluorine, C 1-3 -alkyl, halo-C 1-3 -alkyl and C 1-3 -alkoxy group;

[1009] R 50c and R 50d Choose independently from the following groups: hydrogen, C 1-3 -alkyl and halogenated-C 1-3 -alkyl, or combined to form an oxo group;

[1010] R 50e Choose from the following groups: hydrogen, C 1-3 -alkyl, halo-C 1-3 -alkyl, C 1-3 -alkoxy-C 2-3 -alkyl, C 1-3 -alkyl-carbonyl and C 3-6 -cycloalkyl-carbonyl;

[1011] R 50f and R 50g Choose independently from the following groups: hydrogen, C 1-3 -alkyl and halogenated-C 1-3 -alkyl, or combined to form an oxo group;

[1012] R 50h and R 50i Choose independently from the following groups: hydrogen, fluorine, C 1-3 -alkyl, halo-C 1-3 -alkyl and C 1-3 -alkoxy group; and

[1013] R 50j Choose the group consisting of: hydrogen and fluorine.

[1014] In some embodiments of compounds having the structure of formula (VIII), 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 one respect, R... 1R 3 R 4 R 5 and R 6 One of the substituents is chlorine, and the remaining R 1 R 3 R 4 R 5 and R 6 The substituents are all hydrogen. In another aspect, R... 1 R 3 R 4 R 5 and R 6 One of the substituents is fluorine, and the remaining R 1 R 3 R 4 R 5 and R 6 The substituents are all hydrogen. In another aspect, R... 1 R 3 R 4 R 5 and R 6 One of the substituents is a methyl group, and the remaining R 1 R 3 R 4 R 5 and R 6 All the substituents are hydrogen.

[1015] In some embodiments of compounds having the structure of formula (VIII), R 1 R 3 R 4 R 3 and R 6 They're all hydrogen.

[1016] In some embodiments of compounds having the structure of formula (VIII):

[1017] R 1 R 3 R 4 R 5 and R 6 Independently selected from the following groups: hydrogen, fluorine, and methyl;

[1018] R 50a and R 50b Choose independently from the following groups: hydrogen, fluorine, C 1-2 -alkyl, halo-C 1-2 -alkyl and C 1-2 -alkoxy group;

[1019] R 50c and R 50dChoose independently from the following groups: hydrogen, C 1-2 -alkyl and halogenated-C 1-2 -alkyl;

[1020] R 50e Choose from the following groups: hydrogen, C 1-2 -alkyl, halo-C 1-2 -alkyl and C 1-2 -alkoxy-C 2-3 -alkyl;

[1021] R 50f and R 50g Choose independently from the following groups: hydrogen, C 1-2 -alkyl and halogenated-C 1-2 -alkyl;

[1022] R 50h and R 50i Choose independently from the following groups: hydrogen, fluorine, C 1-2 -alkyl, halo-C 1-2 -alkyl and C 1-2 -alkoxy group; and

[1023] R 50j Choose the group consisting of: hydrogen and fluorine.

[1024] In some embodiments of compounds having the structure of formula (VIII), R 50a R 50b R 50h R 50i and R 50j At least one of them is fluorine.

[1025] H. R 2 It is 3-oxomorpholino

[1026] In some embodiments, this disclosure provides compounds having the structure of formula (IX):

[1027]

[1028] and its pharmaceutically acceptable salts, of which:

[1029] R 1 R 3 R 4 R 5 and R 6 Independently selected from the following groups: hydrogen, chlorine, fluorine, and methyl;

[1030] R 60a and R 60b Choose independently the following groups: hydrogen and C 1-3 -alkyl;

[1031] R 60c and R 60d Choose independently the following groups: hydrogen and C 1-3 -alkyl; and

[1032] R 60e and R 60f Choose independently the following groups: hydrogen and C 1-3 -alkyl.

[1033] In some embodiments of compounds having the structure of formula (IX), R 1 R 3 R 4 R 5 and R 6 One of the substituents is selected from the group consisting of chlorine, fluorine, and methyl, 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 chlorine, and the remaining R 1 R 3 R 4 R 5 and R 6 The substituents are all hydrogen. In another aspect, R... 1 R 3 R 4 R 5 and R 6 One of the substituents is fluorine, and the remaining R 1 R 3 R 4 R 5 and R 6 The substituents are all hydrogen. In another aspect, R... 1 R 3 R 4 R 5 and R 6 One of the substituents is a methyl group, and the remaining R 1 R 3 R 4 R 5 and R 6 All the substituents are hydrogen.

[1034] In some embodiments of compounds having the structure of formula (IX), R 1R 3 R 4 R 5 and R 6 They're all hydrogen.

[1035] In some embodiments of compounds having the structure of formula (IX):

[1036] R 4 It is methyl; and

[1037] R 1 R 3 R 5 and R 6 They're all hydrogen.

[1038] In some embodiments of compounds having the structure of formula (IX):

[1039] R 1 R 3 R 4 R 5 and R 6 Independently selected from the following groups: hydrogen, fluorine, and methyl;

[1040] R 60a and R 60b Choose independently the following groups: hydrogen and C 1-2 -alkyl;

[1041] R 60c and R 60d Choose independently the following groups: hydrogen and C 1-2 -alkyl; and

[1042] R 60e and R 60f Choose independently the following groups: hydrogen and C 1-2 -alkyl.

[1043] I. R 2 It is 5,8-dioxa-2-azaspiro[3,4]octane-2-yl

[1044] In some embodiments, this disclosure provides compounds having the structure of formula (X):

[1045]

[1046] and its pharmaceutically acceptable salts, of which:

[1047] R 1 R 3 R 4 R 5 and R 6 Independently selected from the following groups: hydrogen, chlorine, fluorine, and methyl;

[1048] R 70a and R 70b Choose independently the following groups: hydrogen and C 1-3 -alkyl;

[1049] R 70c and R 70d Choose independently the following groups: hydrogen and C 1-3 -alkyl;

[1050] R 70e and R 70f Choose independently the following groups: hydrogen and C 1-3 -alkyl; and

[1051] R 70g and R 70h Choose independently the following groups: hydrogen and C 1-3 -alkyl.

[1052] In some embodiments of compounds having the structure of formula (X), R 1 R 3 R 4 R 3 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 one respect, R... 1 R 3 R 4 R 5 and R 6 One of the substituents is chlorine, and the remaining R 1 R 3 R 4 R 5 and R 6 The substituents are all hydrogen. In another aspect, R... 1 R 3 R 4 R 5 and R 6 One of the substituents is fluorine, and the remaining R 1 R 3 R 4 R 5 and R 6 The substituents are all hydrogen. In another aspect, R... 1 R 3 R 4 R 5 and R6 One of the substituents is a methyl group, and the remaining R 1 R 3 R 4 R 5 and R 6 All the substituents are hydrogen.

[1053] In some embodiments of compounds having the structure of formula (X), R 1 R 3 R 4 R 3 and R 6 They're all hydrogen.

[1054] In some embodiments of compounds having the structure of formula (X):

[1055] R 1 R 3 R 4 R 5 and R 6 Independently selected from the following groups: hydrogen, fluorine, and methyl;

[1056] R 70a and R 70b Choose independently the following groups: hydrogen and C 1-2 -alkyl;

[1057] R 70c and R 70d Choose independently the following groups: hydrogen and C 1-2 -alkyl;

[1058] R 70e and R 70f Choose independently the following groups: hydrogen and C 1-2 -alkyl; and

[1059] R 70g and R 70h Choose independently the following groups: hydrogen and C 1-2 -alkyl.

[1060] J. R 2 It is pyridin-3-yl

[1061] In some embodiments, this disclosure provides compounds having the structure of formula (XI):

[1062]

[1063] and its pharmaceutically acceptable salts, of which:

[1064] R 1 R 3 R 4R 5 and R 6 Independently selected from the following groups: hydrogen, chlorine, fluorine, and methyl;

[1065] R 80a Choose from the following groups: hydrogen, fluorine, C 1-3 -alkyl, halo-C 1-3 -alkyl and C 1-3 -alkoxy group;

[1066] R 80b Choose from the following groups: hydrogen, fluorine, C 1-3 -alkyl, halo-C 1-3 -alkyl and C 1-3 -alkoxy group;

[1067] R 80c Choose from the following groups: hydrogen, fluorine, C 1-3 -alkyl, halo-C 1-3 -alkyl and C 1-3 -alkoxy group; and

[1068] R 80d Choose from the following groups: hydrogen, fluorine, C 1-3 -alkyl, halo-C 1-3 -alkyl and C 1-3 -alkoxy group.

[1069] In some embodiments of compounds having the structure of formula (XI), R 1 R 3 R 4 R 5 and R 6 One of the substituents is selected from the group consisting of chlorine, fluorine, and methyl, 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 chlorine, and the remaining R 1 R 3 R 4 R 5 and R 6 The substituents are all hydrogen. In another aspect, R... 1 R 3 R 4 R 5 and R 6One of the substituents is fluorine, and the remaining R 1 R 3 R 4 R 5 and R 6 The substituents are all hydrogen. In another aspect, R... 1 R 3 R 4 R 5 and R 6 One of the substituents is a methyl group, and the remaining R 1 R 3 R 4 R 5 and R 6 All the substituents are hydrogen.

[1070] In some embodiments of compounds having the structure of formula (XI), R 1 R 3 R 4 R 5 and R 6 They're all hydrogen.

[1071] In some embodiments of compounds having the structure of formula (XI):

[1072] R 1 R 3 R 4 R 5 and R 6 Independently selected from the following groups: hydrogen, fluorine, and methyl;

[1073] R 80a Choose from the following groups: hydrogen, fluorine, C 1-2 -alkyl, halo-C 1-2 -alkyl and C 1-2 -alkoxy group;

[1074] R 80b Choose from the following groups: hydrogen, fluorine, C 1-2 -alkyl, halo-C 1-2 -alkyl and C 1-2 -alkoxy group;

[1075] R 80c Choose from the following groups: hydrogen, fluorine, C 1-2 -alkyl, halo-C 1-2 -alkyl and C 1-2 -alkoxy group; and

[1076] R 80d Choose from the following groups: hydrogen, fluorine, C 1-2 -alkyl, halo-C 1-2-alkyl and C 1-2 -alkoxy group.

[1077] In some embodiments, the compound or pharmaceutically acceptable salt is (R)-N-(2-(4-cyanothiazolidine-3-yl)-2-oxoethyl)-6-(6-(difluoromethyl)pyridin-3-yl)quinoline-4-carboxamide (Example 169), or a pharmaceutically acceptable salt thereof.

[1078] K. Other embodiments

[1079] Any embodiment of the compound described in this disclosure may be combined with any other suitable embodiment described herein to provide additional embodiments. For example, when an embodiment is described alone or in conjunction with other embodiments for R 1 R 3 R 4 R 5 and / or R 6 Possible groups and different embodiments are described for R 2 When considering possible functional groups, it should be understood that these embodiments can be combined to provide other embodiments, which describe the application of R. 1 R 3 R 4 R 5 and / or R 6 The possible groups and for R 2 The possible functional groups mentioned. In other words, for any of the embodiments of the compounds described in this disclosure, R 2 Substituents can be as follows: R 2 As defined in any of the embodiments.

[1080] The disclosed compounds have pharmaceutically acceptable FAP inhibitory activity as measured by the hFAP inhibition assay (tight binder) as 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.

[1081] In some embodiments, the compounds disclosed herein have a pharmaceutically acceptable surface plasmon resonance (SPR) pK value as reported in the examples below. dValue. 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.

[1082] In some embodiments, the compounds disclosed herein have pharmaceutically acceptable selectivity relative to PREEP for FAP in the hFAP inhibition assay (tight binder) and hPREP inhibition assay, as reported in the examples below. In one aspect, the compound has a selectivity for FAP relative to PREEP that is at least about 50-fold greater. In another aspect, the compound has a selectivity for FAP relative to PREEP that is at least about 100-fold greater. In another aspect, the compound has a selectivity for FAP relative to PREEP that is at least about 1,000-fold greater. In another aspect, the compound has a selectivity for FAP relative to PREEP that is at least about 10,000-fold greater. In another aspect, the compound has a PREPIC concentration 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.

[1083] In some embodiments, the compounds disclosed herein have pharmaceutically acceptable selectivity relative to DPP7 for FAP in the hFAP inhibition assay (tight binder) and DPP7 selectivity assay, as reported in the examples below. In one aspect, the compound has a selectivity for DPP7 relative to FAP that is at least about 50-fold greater. In another aspect, the compound has a selectivity for DPP7 relative to FAP that is at least about 100-fold greater. In another aspect, the compound has a selectivity for DPP7 relative to FAP that is at least about 1,000-fold greater. In another aspect, the compound has a selectivity for DPP7 relative to FAP that is at least about 10,000-fold greater. In yet another aspect, the compound has an IC50 greater than about 0.1 μM for DPP7. 50 Value. On another note, the compound has an IC50 value greater than approximately 1 μM for DPP7. 50 Value. On another note, the compound has an IC50 value greater than approximately 10 μM for DPP7. 50 value.

[1084] In some embodiments, the compounds disclosed herein have pharmaceutically acceptable selectivity relative to DPP8 and / or DPP9 for FAP as measured in the hFAP inhibition assay (tight binder), DPP8 selectivity assay, and DPP9 selectivity assay, as 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's selectivity for FAP relative to DPP8 and / or DPP9 is at least about 50 times greater. In another aspect, the compound's selectivity for FAP relative to DPP8 and / or DPP9 is at least about 100 times greater. In yet another aspect, the compound's selectivity for FAP relative to DPP8 and / or DPP9 is at least about 500 times greater. In yet another aspect, the compound's selectivity for FAP relative to DPP8 and / or DPP9 is at least about 1,000 times greater. In another aspect, the compound has an IC50 greater than about 0.01 μM for DPP8 and / or DPP9. 50 Value. On another note, the compound has an IC50 value greater than about 0.1 μM for DPP8 and / or DPP9. 50 Value. On the other hand, the compounds have IC50 values ​​greater than about 0.4 μM for DPP8 and / or DPP9. 50 value.

[1085] In some embodiments, the compounds disclosed herein have pharmaceutically acceptable metabolic stability for human liver microsome (HLM) assays, as 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.

[1086] In some embodiments, the compounds disclosed herein have pharmaceutically acceptable metabolic stability for the measurements performed on rat hepatocytes (rHep), as reported in the examples below. In one aspect, the compounds have a stability of less than about 300 μL / min / 10 6 rHep CL of cells int Value. In one respect, the compound has a flow rate of less than about 100 μL / min / 10 6 rHepCL cells int Value. In one respect, the compound has a flow rate of less than about 50 μL / min / 106 rHep CL of cells int value.

[1087] In some embodiments, the compounds disclosed herein have a pharmaceutically acceptable Caco-2 AB intrinsic permeability as reported in the examples below for the determination of the intrinsic permeability of Caco-2 AB. In one aspect, the compound has 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.

[1088] In some embodiments, the compounds disclosed herein have a pharmaceutically acceptable apparent permeability of Caco-2 bidirectional (ABBA)A to B as measured in the Caco-2 bidirectional (ABBA)A to B apparent permeability determination, as 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.

[1089] In some embodiments, the compounds disclosed herein have pharmaceutically acceptable dynamic solubility for the measurements described in the examples below. In one aspect, the compound has a dynamic solubility of at least about 1 μM. In another aspect, the compound has a dynamic solubility of at least about 10 μM. In another aspect, the compound has a dynamic solubility of at least about 25 μM. In yet another aspect, the compound has a dynamic solubility of at least about 50 μM.

[1090] L. Salt

[1091] The compounds disclosed herein can exist in either salt or non-salt form (i.e., as free bases), and this disclosure covers both salt and non-salt forms. The compounds can form acid addition salts or base addition salts. Generally, acid addition salts can be prepared using various inorganic or organic acids. Typically, such salts are formed by mixing the compound with an acid (e.g., a stoichiometric amount of an acid) using various methods known in the art, for example. This mixing can occur in water, an organic solvent (e.g., ether, ethyl acetate, ethanol, methanol, isopropanol, or acetonitrile), or an aqueous / organic mixture. On the other hand, acid addition salts are, for example, trifluoroacetates, formates, acetates, or hydrochlorides. In general, base addition salts can be prepared using various inorganic or organic bases, such as alkali metal or alkaline earth metal salts (e.g., sodium, calcium, or magnesium salts), or other metal salts (e.g., potassium or zinc salts, or ammonium salts) or salts with organic bases (e.g., methylamine, dimethylamine, trimethylamine, piperidine, or morpholine). Technicians are familiar with the general principles and techniques for preparing pharmaceutical salts, such as those described in, for example, 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).

[1092] M. Isomers

[1093] 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, E- and Z-forms, and R-, S-, and mesoforms. Unless otherwise stated, references to a particular compound include all such isomer forms, including their racemic and other mixtures. Where appropriate, such isomers can be separated from their mixtures by applying or modifying known methods (e.g., chromatographic techniques and recrystallization techniques). Where appropriate, such isomers can be prepared by applying or modifying known methods. In some embodiments, a single stereoisomer is obtained by separating it from a mixture of isomers (e.g., racemic mixtures) using, for example, chiral chromatographic separation. In other embodiments, a single stereoisomer is obtained by direct synthesis from, for example, chiral starting materials.

[1094] The activity of a particular enantiomer of the compound described herein may be higher than that of 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%.

[1095] In another embodiment, this disclosure relates to a pharmaceutical composition comprising a compound or a pharmaceutically acceptable salt thereof (a single enantiomer or a pharmaceutically acceptable salt thereof in an enantiomer excess (%ee) of ≥90%, ≥95%, ≥96%, ≥97%, ≥98%, or ≥99%) in combination with one or more pharmaceutically acceptable excipients. In one aspect, the single enantiomer is present in an enantiomer excess (%ee) of ≥99%.

[1096] N. Other forms

[1097] The compounds and salts disclosed herein can exist in a variety of tautomeric forms, and all such tautomeric forms are covered in this specification. A “tautomer” is a structural isomer that exists in equilibrium arising from the migration of hydrogen atoms.

[1098] 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.

[1099] The compounds disclosed herein and their pharmaceutically acceptable salts may exist in crystalline or amorphous forms, and this specification covers all such forms.

[1100] 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 typically 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" for deuterium) 3 H (also written as "T" for tritium) 11 C 13 C 14 C 13 N、 15 N、 15 O、 17 O、 18 O and 36Cl. 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 or 14 C is often useful. For radiographic imaging applications, 11 C is often useful. In some embodiments, the radionuclide is 3 H. In some embodiments, the radionuclide is 14 C. In some embodiments, the radionuclide is 11 C.

[1101] O. intermediate

[1102] In some embodiments, this disclosure provides additional compounds that can be used as intermediates for the preparation of the compounds disclosed herein and their pharmaceutically acceptable salts.

[1103] III. How to use

[1104] The compounds disclosed in this disclosure, and their pharmaceutically acceptable salts, are inhibitors of prolyl endopeptidase fibroblast activating protein (FAP) activity. FAP is an endopeptidase involved in the enzymatic cleavage of substrates in glucose and lipid metabolism, fibrinolysis, and collagen production.

[1105] FAP is believed to cleave and inhibit human fibroblast growth factor 21 (FGF-21) protein involved in the regulation of glucose and lipid metabolism (Biochem J [Journal of Biochemistry] 2016, 473, 605). It is speculated that inhibition of FAP increases endogenous FGF-21 levels and signaling, and leads to, for example, reduced steatosis, improved insulin sensitivity, improved glucose tolerance, reduced body weight, and / or reduced cardiovascular mortality.

[1106] It is also believed that human α2-anti-plasmin (α2AP) protein is involved in the regulation of fibrinolysis and fibrosis by FAP (Blood 2004, 103, 3783). Tissue repair involves coagulation that leads to fibrin deposition. Fibrin in clots is typically lysed primarily by plasminogen activator when it is converted from its inactive form (plasminogen) by plasminogen activator. Fibrinolysis is inhibited by plasminogen activator inhibitor-1 (PAI-1), plasminogen activator inhibitor-2 (PAI-2), and α2AP (Experimental & Molecular Medicine 2020, 52, 367), all of which are induced by tissue damage. FAP converts α2AP into a more active form that reduces plasmin activity and increases fibrin deposition at the site of injury. It is speculated that inhibiting FAP increases fibrinolysis and improves tissue regeneration at the site of injury (J Thromb Haemost, 2013, 11, 2029; Proteomics Clin. Appl., 2014, 8, 454).

[1107] FAP is further believed to promote collagen production and deposition and play a role in increasing fibrosis by altering extracellular matrix (ECM) transformation (J Biol Chem, 2016, 8, 291). It is speculated that inhibition of FAP leads to a reduction in collagen deposition and inflammation (Inflamm Bowel Dis., 2018, 18, 332).

[1108] Based on the above, it is hypothesized that inhibiting FAP reduces fibrosis and inflammation by decreasing hepatic stellate cell activity and increasing fibrinolysis, and further provides positive metabolic effects by increasing FGF21 signaling and improving glucose tolerance.

[1109] Therefore, in some embodiments, this disclosure provides a method for treating or preventing FAP-mediated conditions in a subject of need by administering to the subject a therapeutically effective amount of a compound having Formula I or a pharmaceutically acceptable salt thereof.

[1110] In some embodiments, this disclosure provides a method for treating or preventing a condition characterized by FAP overexpression in a subject of need, the method being to administer to the subject a therapeutically effective amount of the compound of this disclosure or a pharmaceutically acceptable salt thereof.

[1111] In some embodiments, this disclosure provides a method for treating or preventing liver disease in a subject of need, the method being by administering to the subject a therapeutically effective amount of a compound of this disclosure or a pharmaceutically acceptable salt thereof. In one aspect, the liver disease is fatty liver disease. In another aspect, the liver disease is non-alcoholic fatty liver disease (NAFLD). In 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.

[1112] In some embodiments, this disclosure provides a method for treating liver disease in a subject in need, the method comprising administering to the subject a therapeutically effective amount of the compound of this disclosure or a pharmaceutically acceptable salt thereof, wherein the subject has a liver condition of 27 kg / m². 2 Up to 40kg / m 2 Body Mass Index (BMI). In one aspect, 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 In one aspect, the subject's BMI was [not specified]. 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.

[1113] In some embodiments, this disclosure provides a method for treating liver disease in a subject of need by administering to the subject a therapeutically effective amount of the disclosed compound or a pharmaceutically acceptable salt thereof, wherein the subject also suffers from or is susceptible to dyslipidemia. In another aspect, the liver disease is NAFLD. In another aspect, the liver disease is NASH. In another aspect, the liver disease is liver fibrosis. In another aspect, the liver disease is cirrhosis.

[1114] In some embodiments, this disclosure provides a method for treating liver disease in a subject of need by administering to the subject a therapeutically effective amount of a compound of this disclosure or a pharmaceutically acceptable salt thereof, wherein the subject also suffers from or is susceptible to insulin resistance. In another aspect, the liver disease is NAFLD. In another aspect, the liver disease is NASH. In another aspect, the liver disease is liver fibrosis. In another aspect, the liver disease is cirrhosis.

[1115] In some embodiments, this disclosure provides a method for treating liver disease in a subject of need by administering to the subject a therapeutically effective amount of the disclosed compound or a pharmaceutically acceptable salt thereof, wherein the subject also suffers from or is susceptible to at least one of type 2 diabetes and renal insufficiency. In another aspect, the liver disease is NAFLD. In another aspect, the liver disease is NASH. In another aspect, the liver disease is liver fibrosis. In another aspect, the liver disease is cirrhosis.

[1116] In some embodiments, this disclosure provides a method for treating liver disease in a subject of need by administering to the subject a therapeutically effective amount of the disclosed compound or a pharmaceutically acceptable salt thereof, 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.

[1117] In some embodiments, this disclosure provides a method for treating liver disease in a subject of need by administering to the subject a therapeutically effective amount of a compound of this disclosure or a pharmaceutically acceptable salt thereof, 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.

[1118] In some embodiments, this disclosure provides a method for reducing liver fat in a subject of need by administering to the subject a therapeutically effective amount of a compound of this disclosure or a pharmaceutically acceptable salt thereof. 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.

[1119] In some embodiments, this disclosure provides a method for treating or preventing nonalcoholic fatty liver disease (NAFLD) in a subject of need by administering to the subject a therapeutically effective amount of a compound of this disclosure or a pharmaceutically acceptable salt thereof. In one aspect, NAFLD is stage 1 NAFLD. In another aspect, NAFLD is stage 2 NAFLD. In another aspect, NAFLD is stage 3 NAFLD. In another aspect, 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.

[1120] In some embodiments, this disclosure provides a method for treating or preventing non-alcoholic steatohepatitis (NASH) in a subject of need by administering to the subject a therapeutically effective amount of a compound of this disclosure or a pharmaceutically acceptable salt thereof. In one aspect, the NASH is stage 1 NASH. In another aspect, the NASH is stage 2 NASH. In another aspect, the NASH is stage 3 NASH. In another aspect, the NASH is stage 4 NASH. In 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.

[1121] In some embodiments, this disclosure provides a method for treating or preventing liver fibrosis in a subject of need, the method being by administering to the subject a therapeutically effective amount of a compound of this disclosure or a pharmaceutically acceptable salt thereof. 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.

[1122] In some embodiments, this disclosure provides a method for treating or preventing cirrhosis in a subject of need by administering to the subject a therapeutically effective amount of a compound of this disclosure or a pharmaceutically acceptable salt thereof. 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.

[1123] In some embodiments, this disclosure provides a method for treating or preventing type 2 diabetes in a subject of need, the method being by administering to the subject a therapeutically effective amount of the compound of this disclosure or a pharmaceutically acceptable salt thereof. In one aspect, the subject is a subject suffering from diabetic nephropathy. In another aspect, the subject suffers from 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.

[1124] In some embodiments, this disclosure provides a method for improving glycemic control in a subject of need, the method being by administering to the subject a therapeutically effective amount of the compound of this disclosure or a pharmaceutically acceptable salt thereof. 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.

[1125] In some embodiments, this disclosure provides a method for improving glycemic control in subjects suffering from type 2 diabetes and diabetic nephropathy, the method being by administering to the subject a therapeutically effective amount of the compound of this 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.

[1126] In some embodiments, this disclosure provides a method for improving glycemic control in a subject with type 2 diabetes and renal insufficiency, the method being by administering to the subject a therapeutically effective amount of the compound of this 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.

[1127] In some embodiments, this disclosure provides a method for treating or preventing insulin resistance in a subject of need by administering to the subject a therapeutically effective amount of a compound of this disclosure or a pharmaceutically acceptable salt thereof. In another 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. 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 (which is incorporated herein by reference in its entirety). The MATSUDA index is explained, for example, in Diabetes Care 1999, 22, 1462 (which is incorporated herein by reference in its entirety).

[1128] In some embodiments, this disclosure provides a method for treating or preventing glucose intolerance in a subject of need by administering to the subject a therapeutically effective amount of the disclosed compound or a pharmaceutically acceptable salt thereof. 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.

[1129] In some embodiments, this disclosure provides a method for treating a cardiovascular condition in a subject requiring treatment, the method being by administering to the subject a therapeutically effective amount of the disclosed compound or a pharmaceutically acceptable salt thereof. In one aspect, the cardiovascular condition is selected from the group consisting of: heart failure, cardiomyopathy, atherosclerosis, venous thromboembolism, and atrial fibrillation. In one aspect, the cardiovascular condition is heart failure. In another aspect, the cardiovascular condition is heart failure with preserved ejection fraction (HFpEF). In another aspect, the cardiovascular condition 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 condition is atherosclerosis. In another aspect, the cardiovascular condition is venous thromboembolism. In another aspect, the cardiovascular condition is atrial fibrillation.

[1130] In some embodiments, this disclosure provides a method for treating obesity or obesity-related conditions in a subject of need by administering to the subject a therapeutically effective amount of the disclosed compound or a pharmaceutically acceptable salt thereof. 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, impaired glucose tolerance, increased fasting glucose, and glucagonoma. In another aspect, obesity-related conditions are dyslipidemia. In another aspect, obesity-related conditions are cardiovascular diseases selected from the group consisting of: heart failure, cardiomyopathy, atherosclerosis, venous thromboembolism, and atrial fibrillation. In another aspect, obesity-related conditions are kidney disease.

[1131] In some embodiments, this disclosure provides a method for reducing the weight of a subject in need by administering to the subject a therapeutically effective amount of the compound of this disclosure or a pharmaceutically acceptable salt thereof. 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 approximately 5%, 10%, 15%, 20%, 25%, 30%, 35%, or 40%.

[1132] In some embodiments, this disclosure provides a method for reducing body fat in a subject requiring treatment, the method being performed by administering to the subject a therapeutically effective amount of the compound of this disclosure or a pharmaceutically acceptable salt thereof. 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, one subject was overweight. In another respect, another subject was obese. In another respect, the fat was liver fat.

[1133] In some embodiments, this disclosure provides a method for treating or preventing fibrosis in a subject of need, the method being performed by administering to the subject a therapeutically effective amount of a compound of this disclosure or a pharmaceutically acceptable salt thereof. 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).

[1134] In some embodiments, this disclosure provides a method for promoting tissue remodeling in a subject in need, the method being by administering to the subject a therapeutically effective amount of the disclosed compound or a pharmaceutically acceptable salt thereof. In one aspect, the subject has suffered cardiac tissue damage due to myocardial infarction.

[1135] In some embodiments, this disclosure provides a method for promoting wound healing and / or reducing adhesions in a subject in need, the method being performed by administering to the subject a therapeutically effective amount of a compound of this disclosure or a pharmaceutically acceptable salt thereof. In one aspect, the application of the compound promotes wound healing and / or reduces adhesions by increasing fibrinolysis.

[1136] In some embodiments, this disclosure provides a method for treating or preventing keloid disorder in a subject of need, the method being performed by administering to the subject a therapeutically effective amount of a compound of this disclosure or a pharmaceutically acceptable salt thereof. In one aspect, keloid disorder is selected from the group consisting of scar formation, keloid tumors, and keloids.

[1137] In some embodiments, this disclosure provides a method for treating or preventing inflammation in a subject of need, the method being by administering to the subject a therapeutically effective amount of a compound of this disclosure or a pharmaceutically acceptable salt thereof. 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.

[1138] In some embodiments, this disclosure provides a method for treating a subject with cancer in need of treatment by administering to the subject a therapeutically effective amount of the disclosed compound or a pharmaceutically acceptable salt thereof. 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 carcinoma, neuroendocrine tumors, carcinogenic rickets, sarcoma, CUP (metastatic cancer of unknown primary origin), thymic carcinoma, desmoidoma, glioma, astrocytoma, cervical cancer, and prostate cancer. In another aspect, the cancer is hepatocellular carcinoma.

[1139] Subjects for treatment will typically be human or non-human mammals, especially humans. Suitable subjects may also include domestic or wild animals; pets (including dogs, cats, etc.); livestock (including horses, cattle and other ruminants, pigs, poultry, rabbits, etc.); primates (including monkeys such as macaques, cynomolgus monkeys, marmosets, tamarins, chimpanzees, rhesus monkeys, etc.); and rodents (including rats, mice, gerbils, guinea pigs, etc.).

[1140] In some embodiments, this disclosure provides compounds of this disclosure or pharmaceutically acceptable salts thereof for use as medicaments.

[1141] In some embodiments, this disclosure provides the use of compounds having Formula I or pharmaceutically acceptable salts thereof for the treatment or prevention of FAP-mediated conditions as discussed above.

[1142] In some embodiments, this disclosure provides the use of a compound having Formula I or a pharmaceutically acceptable salt thereof for the manufacture of a medicament for the treatment or prevention of FAP-mediated conditions as discussed above.

[1143] IV. Combination therapy and fixed-dose combination

[1144] The compounds disclosed herein can be used in the methods described above, either as a single pharmacological agent or in combination with other pharmacological agents or techniques. Such combination therapies can be achieved by administering single components simultaneously, sequentially, or individually. These combination therapies (and corresponding combination products) use the compounds disclosed herein within the dosage range described in this application and typically use other pharmacological agents within the approved dosage ranges.

[1145] In some embodiments, this disclosure provides a combination suitable for use in treating conditions selected from those previously discussed, wherein the combination comprises a compound of the disclosure or a pharmaceutically acceptable salt thereof, and a sodium-glucose transporter 2 (SGLT2) inhibitor. In one aspect, the SGLT2 inhibitor is selected from the group consisting of canagliflozin, dapagliflozin, empagliflozin, ertugliflozin, ipagliflozin, luseogliflozin, and remogliflozin. In another aspect, the SGLT2 inhibitor is dapagliflozin.

[1146] In some embodiments, this disclosure provides a combination suitable for use in treating a condition selected from those previously discussed, wherein the combination comprises a compound of the disclosure or a pharmaceutically acceptable salt thereof, and metformin.

[1147] In some embodiments, this disclosure provides combinations suitable for use in 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 SGLT2 inhibitor is selected from the group consisting of exenatide, liraglutide, lixisenatide, albiglutide, dulaglutide, and semaglutide.

[1148] In some embodiments, this disclosure provides a combination suitable for use in 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, vedagliptin, saxagliptin, liraliptin, giglitin, alagliptin, terliliptin, alogliptin, treagliptin, oxagliptin, evogliptin, gogliptin, and dutogliptin.

[1149] In some embodiments, this disclosure provides a combination suitable for use in treating conditions selected from those previously discussed, wherein the combination comprises a compound of the 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 letoglitazone. In yet another aspect, the PPAR agonist stimulates hepatic expression of FGF21.

[1150] 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. Such a combination can be used to manufacture a medicament for treating a condition selected from the previously discussed conditions. 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.

[1151] In some embodiments, this disclosure provides a combination suitable for treating cancer, wherein the combination comprises a compound of the disclosed invention 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), cemiplimab (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.). On another front, the immune checkpoint inhibitor is an anti-CTLA4 antibody (e.g., ipilimumab (Yervoy), tremelimumab, etc.). On yet another front, the cancers selected are grouped into: pancreatic cancer, colon cancer, and rectal cancer.

[1152] V. Pharmaceutical Composition

[1153] 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.

[1154] The selection of one or more excipients for inclusion in a particular composition will depend on factors such as the method 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 the Handbook of Pharmaceutical Excipients (6th edition, Pharmaceutical Press; edited by Rowe, Ray C; Sheskey, Paul J; Quinn, Marian). Pharmaceutically acceptable excipients can be used as, for example, adjuvants, diluents, carriers, stabilizers, flavoring agents, coloring agents, fillers, binders, disintegrants, lubricants, flow aids, thickeners, and coating agents. As will be understood by those skilled in the art, some pharmaceutically acceptable excipients can be used for more than one function and can be used for alternative effects, depending on how much of the excipient is present in the composition and what other excipients are present in the composition.

[1155] These compositions may be available in forms 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), topical application (e.g., as creams, ointments, gels, or aqueous or oily solutions or suspensions), inhalation (e.g., as fine powders or liquid aerosols), inhalation (e.g., as fine powders), or parenteral administration (e.g., as sterile aqueous or oily solutions for intravenous, subcutaneous, or intramuscular administration), or as suppositories for rectal administration. The compositions can be obtained using conventional pharmaceutical excipients known in the art through routine procedures. Therefore, compositions intended for oral use may contain, for example, one or more colorants, sweeteners, flavoring agents, and / or preservatives.

[1156] The total daily dose will necessarily 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 single or multiple doses. Specific doses may be adjusted, for example, based on: the disease being treated; the subject's age, weight, general health status, sex, and diet; the route of administration; the dosing interval; the excretion rate; and any other drugs co-administered to the subject. A physician with the ordinary skills disclosed in this application will be able to determine the appropriate dose and regimen for administering the therapeutic agent to the subject, and, if necessary, adjust such doses and regimens during treatment according to methods well known in the field of medicine. The compounds disclosed herein, or pharmaceutically acceptable salts thereof, will typically be administered at doses ranging from 2.5 to 5000 mg / m². 2Administered to warm-blooded animals at a unit dose of approximately 0.05 to 100 mg / kg of the animal's body surface area, and this typically provides a therapeutically effective dose. Unit dosage forms such as tablets or capsules may contain, for example, 0.1 to 500 mg, 0.1 to 250 mg, or 0.1 to 100 mg of the active ingredient.

[1157] In some embodiments, this disclosure provides a pharmaceutical composition for a therapy comprising a compound of the disclosure or a pharmaceutically acceptable salt thereof, and at least one pharmaceutically acceptable excipient.

[1158] In some embodiments, this disclosure provides pharmaceutical compositions for treating FAP-mediated conditions, the compositions 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.

[1159] VI. Reagent test kit

[1160] This disclosure further provides kits comprising unit dosage forms including the disclosed compound or a pharmaceutically acceptable salt thereof contained in packaging material, and a label or package insert indicating that the unit dosage form can be used to treat one or more of the previously described conditions.

[1161] In some embodiments, the kit comprises a unit dosage form including a compound disclosed herein or a pharmaceutically acceptable salt thereof contained within packaging material, and a label or package insert indicating that the pharmaceutical composition may be used to treat FAP-mediated conditions. In another aspect, the FAP-mediated condition is liver disease. In yet another aspect, the liver disease is selected from the group consisting of: fatty liver disease, end-stage liver disease, and cirrhosis. In yet another aspect, the liver disease is selected from the group consisting of: non-alcoholic steatohepatitis (NASH) and non-alcoholic fatty liver disease (NAFLD).

[1162] In some embodiments, the kit comprises: (a) a first unit dosage form containing a compound disclosed herein or a pharmaceutically acceptable salt thereof; (b) a second unit dosage form containing 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.

[1163] VII. Preparation method

[1164] This disclosure further provides methods for preparing compounds having formulas (I), (II), (III-A), (III-B), (III-C), (III-D), (III-E), (IV), (IV-A), (V), (VI), (VII), (VIII), (IX), (X), and (XI), and pharmaceutically acceptable salts thereof.

[1165] Schemes 1 to 14 below illustrate synthetic routes for compounds having formula (II), where R 1 R 2 R 3 R 4 R 5 R 6 and X 1 As defined in equation (I), R 7 It is an alkyl group (e.g., methyl, ethyl, or tert-butyl), and X 2 X 3 and X 4 It is a leaving group (e.g., Cl, Br, I, or OTf). Those skilled in the art will understand that these methods are representative and do not encompass all possible methods for preparing the compounds disclosed herein. Unless otherwise stated, R in each scheme... X Substituents are as defined for the compounds disclosed herein. It should be understood that the preparation methods described in schemes 1 to 14 may be carried out from any enantiomer or racemic mixture of compounds having formula (2), (4), (6), (8), (9), (10), (11), (12), (13) or (14) to give a compound having formula (II) or any stereoisomer having formula (II).

[1166] Option 1

[1167]

[1168] Scheme 1 illustrates a synthetic route for certain compounds having formula (II). A compound having formula (2) can be reacted with a compound having formula (3) to give a compound having formula (II). The reaction can be carried out using suitable coupling agents (e.g., HATU, HOBt / EDC, or T3P) in the presence of a base (typically an organic base such as DIPEA or TEA) using solvents such as DCM, DMF, EtOAc, or MeCN, or mixtures thereof, and at temperatures typically ranging from 0°C to 60°C.

[1169] Option 2

[1170]

[1171] Scheme 2 illustrates an alternative synthetic route for certain compounds having formula (II). A compound having formula (4) can be reacted with a compound having formula (5) to give a compound having formula (II). The reaction can be carried out using suitable coupling agents (e.g., HATU, HOBt / EDC, or T3P) in the presence of a base (typically an organic base such as DIPEA or TEA) using solvents such as DCM, DMF, EtOAc, or MeCN, or mixtures thereof, and at temperatures typically ranging from 0°C to 60°C.

[1172] Option 3

[1173]

[1174] Scheme 3 illustrates an alternative synthetic route for certain compounds having formula (II). Compounds having formula (6) can be converted to compounds having formula (II) by dehydration using suitable reagents (typically TFAA or T3P) in solvents such as DCM, DMF, EtOAc or MeCN, or mixtures thereof, at temperatures ranging from typically 0°C to 120°C.

[1175] Option 4

[1176]

[1177] Scheme 4 illustrates a synthetic route for certain compounds having formula (2). Compounds having formula (4) can be reacted with (tert-butoxycarbonyl)-glycine (7) to give compounds having formula (8). The reaction can be carried out using suitable coupling agents (e.g., HATU, HOBt / EDC, or T3P) in the presence of a base (typically an organic base such as DIPEA or TEA) using solvents such as DCM, DMF, EtOAc, or MeCN, or mixtures thereof, and at temperatures typically ranging from 0°C to 120°C.

[1178] Compounds having formula (2) can be formed by reacting a compound having formula (8) with a suitable acid (e.g., HCl) in a solvent such as 1,4-dioxane, EtOAc, MeOH, or water, or mixtures thereof. Alternatively, the reaction can be carried out using a pure acid, such as TFA, or in a solvent such as DCM, at a temperature typically ranging from 0°C to 60°C.

[1179] Option 5

[1180]

[1181] Scheme 5 illustrates a synthetic route for certain compounds having formula (4). Compounds having formula (10) can be formed by reacting a compound having formula (9) with NH3 (pure or as a solution, e.g., in water or MeOH), or with an ammonia synthesis equivalent (e.g., NH4Cl). The reaction can be carried out using suitable coupling agents (e.g., HATU, HOBt / EDC, T3P, or Boc2O) in the presence of a base (typically an organic base such as DIPEA or TEA) using solvents such as THF, DMF, EtOAc, or MeCN, or mixtures thereof, and at temperatures typically ranging from 0°C to 120°C.

[1182] Compounds having formula (10) can be converted into compounds having formula (11) by using a suitable reagent (typically TFAA or T3P) in a solvent such as DCM, DMF, EtOAc or MeCN, or mixtures thereof, and by dehydration at a temperature typically from 0°C to 120°C.

[1183] Compounds having formula (4) can be formed by reacting a compound having formula (11) with a suitable acid (e.g., HCl or TsOH) in a solvent such as MeCN, 1,4-dioxane, EtOAc, MeOH, or water, or mixtures thereof. Alternatively, the reaction can be carried out using a pure acid, such as TFA, or in a solvent such as DCM, at a temperature typically ranging from 0°C to 60°C.

[1184] Option 6

[1185]

[1186] Scheme 6 illustrates a synthetic route for certain compounds having formula (6). A compound having formula (12) can react with a compound having formula (3) to give a compound having formula (6). The reaction can be carried out under the conditions described for a similar reaction as described in Scheme 1.

[1187] Option 7

[1188]

[1189] Scheme 7 illustrates a synthetic route for certain compounds having formula (12). Compounds having formula (12) can be formed from compounds having formulas (13) and (7) via compounds having formula (14). The reaction can be carried out under the conditions described for a similar reaction as described in Scheme 4.

[1190] Option 8

[1191]

[1192] Scheme 8 illustrates a synthetic route for certain compounds having formula (5). A compound having formula (3) can be reacted with a compound having formula (15) to give a compound having formula (16). The reaction can be carried out using suitable coupling agents (e.g., HATU, HOBt / EDC, or T3P) in the presence of a base (typically an organic base such as DIPEA or TEA) using solvents such as DCM, DMF, EtOAc, or MeCN, or mixtures thereof, and at temperatures typically ranging from 0°C to 120°C.

[1193] Compounds having formula (5) can be formed by reacting a compound having formula (16) with a base (e.g., NaOH or LiOH) in an organic solvent (e.g., dioxane, THF, or MeOH, or mixtures thereof), and optionally in the presence of water. The reaction can be carried out in a temperature range from 0°C to reflux. Alternatively, for compounds having formula (16), where R... 7 =tert-Butyl, the reaction can be carried out in solvents such as 1,4-dioxane, EtOAc, MeOH, or water, or mixtures thereof, with a suitable acid (e.g., HCl). Alternatively, the reaction can be carried out with pure acid, such as TFA, or in solvents such as DCM, at temperatures typically ranging from 0°C to 60°C.

[1194] Option 9

[1195]

[1196] Scheme 9 illustrates a synthetic route for certain compounds having formula (3). Compounds having formula (18) can be formed by reacting a compound having formula (17) with an alcohol (e.g., MeOH or EtOH) in the presence of an acid (e.g., HCl or H₂SO₄) in a suitable solvent or using the alcohol as a solvent. Alternatively, the reaction can be promoted by a reagent such as SOCl₂ in a suitable solvent or by using an alcohol (e.g., MeOH or EtOH) as a solvent. Alternatively, compounds having formula (18) can be reacted with an alcohol (e.g., MeOH or EtOH) (promoted by a coupling agent (e.g., EDC or TBTU)) in the presence of a base (e.g., DIPEA, TEA, or DMAP) using a solvent such as DCM, DMF, EtOAc, or MeCN, or mixtures thereof, and at a temperature typically ranging from 0°C to 120°C.

[1197] Compounds having formula (19) (where R) 2 As defined in formula (I), and wherein the attachment point with quinoline is via a nitrogen atom, can be achieved by reacting a compound having formula (18) with an amine HR. 2 (20)(where R) 2It is formed by a reaction as defined in formula (I). The reaction can be catalyzed in the presence of a base (such as Cs2Co3) in a suitable solvent (such as 1,4-dioxane), optionally in the presence of water, at temperatures ranging from room temperature to reflux, using a suitable Pd reagent such as Pd2(dba)3 with a suitable phosphine ligand (e.g., XPhos, CPhos, SPhos, RuPhos, DavePhos, or XantPhos).

[1198] Compounds having formula (19) (where R) 2 As defined in formula (I), and wherein the attachment point with quinoline is via a nitrogen atom, can be achieved by reacting a compound having formula (18) with an amine HR. 2 (20)(where R) 2 It is formed by a reaction as defined in formula (I). The reaction can be catalyzed by a suitable Cu reagent (e.g., CuI or Cu2O) in the presence of a base (e.g., K2CO3 or Cs2CO3) in a suitable solvent (e.g., DMF) at a temperature ranging from room temperature to 160°C.

[1199] Compounds having formula (3) can be formed by reacting a compound having formula (19) with a base (e.g., NaOH or LiOH) in an organic solvent (e.g., 1,4-dioxane, THF, or MeOH, or mixtures thereof), and optionally in the presence of water. The reaction can be carried out in a temperature range from 0°C to reflux. Alternatively, for compounds having formula (19), where R... 7 =tert-butyl, the reaction can be carried out in a solvent such as 1,4-dioxane, EtOAc, MeOH or water, or mixtures thereof, with a suitable acid (e.g., HCl). Alternatively, for compounds having formula (19), where R 7 = tert-butyl, the reaction can be carried out using pure acid or acid such as TFA in solvent such as DCM, at temperatures typically ranging from 0°C to 60°C.

[1200] Alternatively, compounds having formula (3) (where R) 2 As defined in formula (I), and wherein the attachment site with quinoline (via nitrogen atom) can be directly obtained from a compound having formula (17) via amine HR 2 (20)(where R) 2 It is formed by a reaction as defined in formula (I). The reaction can be carried out under the conditions described for a similar reaction as described in scheme 9 above.

[1201] Option 10

[1202]

[1203] Scheme 10 illustrates the synthetic routes for certain compounds having formula (3). Compounds having formula (19) (where R...) 2 As defined in formula (I), and wherein the attachment point with quinoline is via a carbon atom, can be made by reacting a compound having formula (18) with compound BR. 2 (21) (where B is boric acid, borate ester or trifluoroborate, and where R) 2 It is formed by a reaction as defined in formula (I). The reaction can be catalyzed by a suitable Pd reagent (e.g., Pd(dppf)Cl2) in the presence of a base (e.g., Na2CO3 or K2CO3) in a suitable solvent (e.g., 1,4-dioxane), optionally in the presence of water, at temperatures ranging from room temperature to reflux.

[1204] Compounds having formula (3) can be formed by reacting a compound having formula (19) under conditions similar to those described in scheme 9. Alternatively, compounds having formula (3) (wherein R) 2 As defined in formula (I), and wherein the attachment point with quinoline (through a carbon atom) can be directly obtained from a compound having formula (17) via a compound BR. 2 (21) (where B is boric acid, borate ester or trifluoroborate, and where R) 2 It is formed by a reaction as defined in formula (I). The reaction can be carried out under the conditions described above for a similar reaction as described in scheme 10.

[1205] Option 11

[1206]

[1207] Scheme 11 illustrates a synthetic route for certain compounds having formula (19). Compounds having formula (22) (where B is boric acid, borate ester, or trifluoroborate) can be formed by reacting a compound having formula (18) with a bis-boronic acid (e.g., B2(OH)4 (diboronic acid) or B2pin2 (4,4,4′,4′,5,5,5′,5′-octamethyl-2,2′-bis(1,3,2-dioxacyclopentaborane)). This reaction can be catalyzed by a suitable Pd reagent (e.g., Pd(dppf)Cl2) in the presence of a base (e.g., Na2CO3 or K2CO3) in a suitable solvent (e.g., ethanol or 1,4-dioxane), optionally in the presence of water, at temperatures ranging from room temperature to reflux.

[1208] Compounds having formula (19) (where R) 2As defined in formula (I), and wherein the attachment point with quinoline is via a carbon atom) can be achieved by reacting a compound having formula (22) with an aryl halide or aryl pseudohalide having formula (23) (where R 2 It is as defined in equation (I) and X 3 By attaching carbon atoms to R 2 The reaction is formed by the reaction described above. This reaction can be carried out in the presence of a base (such as Na2CO3 or K2CO3) in a suitable solvent (such as 1,4-dioxane), optionally in the presence of water, and catalyzed by a suitable Pd reagent (e.g., Pd(dppf)Cl2) at temperatures ranging from room temperature to reflux.

[1209] Option 12

[1210]

[1211] Scheme 12 illustrates a synthetic route for certain compounds having formula (17). Compounds having formula (26) can be formed by reacting a compound having formula (24) with a 2-ketocarboxylic acid having formula (25) or a salt thereof (e.g., sodium salt) in water in the presence of an alkali (e.g., NaOH), at reflux temperature or at a high temperature ranging from typically 100°C to 160°C. Compounds having formula (17) can be formed by heating a pure compound having formula (26) in a suitable solvent (e.g., water) in a sealed container or at a high temperature ranging from typically 150°C to 250°C in a sealed tube of a microwave reactor.

[1212] Option 13

[1213]

[1214] Scheme 13 illustrates the synthetic routes for certain compounds having formula (19). Compounds having formula (28) (where R...) 2 It is as defined in formula (I), and wherein the attachment point with quinoline (via nitrogen or carbon atom) can be formed by a synthetic method using a compound having formula (27) under conditions similar to those described in schemes 9, 10 and 11.

[1215] Compounds having formula (19) can be formed by reacting compounds having formula (28) with carbon monoxide (1-10 atm), typically at a pressure of 10 atm, in a sealed container at a temperature typically ranging from 80°C to 120°C. The reaction can be carried out in the presence of a base (e.g., TEA), in the presence of a suitable alcohol (such as MeOH or EtOH), in a suitable solvent, or catalyzed using an alcohol as a solvent with a suitable Pd reagent (e.g., Pd(dppf)Cl2).

[1216] Option 14

[1217]

[1218] Scheme 14 illustrates the synthetic routes for certain compounds having formula (31). Compounds having formula (29) (where R...) 50 (As defined in formula (VIII)) can be formed from a compound having formula (27) by metal halide exchange using an organometallic reagent (e.g., BuLi), followed by reaction with an electrophilic reagent such as a ketone having formula (30). The reaction can be carried out in a solvent such as THF at temperatures ranging from typically -78°C to room temperature.

[1219] Compounds having formula (31) (where R) 50j Fluorine can be formed by reacting a compound having formula (29) with a fluorinating agent (e.g., DAST) in a solvent such as DCM at a temperature ranging from typically -20°C to reflux.

[1220] Compounds having formula (31) can be converted into compounds having formula (VIII) using synthetic methods similar to those described in schemes 13, 10 and 1.

[1221] It should be understood that: (i) the organic reactions described in this disclosure are carried out based on laboratory practices known to those skilled in the art; (ii) some of the reactions described in this disclosure may optionally be carried out in a different order than those listed herein; (iii) the chiral isomers of the compounds in this disclosure may be resolved at any stage of the synthesis process using chiral resolving agents described in the literature and known to those skilled in the art, or using chiral chromatographic methods described in the literature and known to those skilled in the art, or as further described in the examples; (iv) additional and / or other protecting groups may optionally be required in some of the foregoing steps; and (v) therefore the deprotection step may optionally be carried out using methods described in the literature and known to those skilled in the art. Protection and deprotection of functional groups are described in “Protective Groups in Organic Synthesis”, 3rd edition, TW Greene and PGM Utz, Wiley-Interscience (1999), which is incorporated herein by reference.

[1222] VIII. Example

[1223] The following descriptions of experiments, procedures, examples, and intermediates are intended to illustrate embodiments of this disclosure and are in no way intended to be limiting. Other compounds disclosed may be prepared using the methods shown in these examples (alone or in combination with techniques generally known in the art).

[1224] A. General conditions

[1225] Unless otherwise stated,

[1226] (i) Unless otherwise stated, the operation shall be 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);

[1227] (ii) When 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 detector.

[1228] (iii) Generally, the reaction process is followed by thin-layer chromatography (TLC) and / or analytical high-performance liquid chromatography (HPLC or UPLC), which are usually coupled with a mass spectrometer (LCMS).

[1229] (iv) If necessary, the organic solution is passed through anhydrous MgSO4 or Na2SO4, or by using... The phase separator is dried, and the post-processing procedure is carried out using conventional phase separation techniques.

[1230] (v) Evaporation by vacuum rotary evaporation or by evaporation in Genevac HT-4 / EZ-2 or Biotage V10;

[1231] (vi) Unless otherwise specified, rapid column chromatography uses Grace chromatography. The X2 fast system or similar systems use Merck silicone (Art. 9385) or pre-filled cartridges on normal silica. SNAP cartridge (40-63μm silica, 4-330g) Silica HCD tube (20μm, 10-100g), Interchim puriFlash TM Cylinder (25μm, 4-120g), Interchim puriFlash TM Cylinder (50μm, 25-330g), Grace TM GraceResolv TM The process can be performed manually or automatically using a silica rapid cylinder (4-120g) or an Agela rapid column silica-CS cylinder (80-330g), or using Agela Technologies' C-18 spherical cylinder (20-35μm, 100A, 80-330g) on ​​reverse silica.

[1232] (vii) Preparative reversed-phase HPLC and preparative reversed-phase SFC were performed using standard HPLC and SFC instruments equipped with MS and / or UV-triggered fraction collection instruments, respectively, using isocratic or gradient mobile phases as described in the Experimental Section and one of the following methods as described below;

[1233] HPLC Preparation Methods: Method A: The compound was purified by preparative HPLC on a YMC-Actus Triart C18 ExRS column (5 μm, 150 × 30 mm ID) using a gradient of MeCN in H2O / NH4HCO3 (10 mM) as the mobile phase; Method B: The compound was purified by preparative HPLC on an XBridge column. TMPreparation Method C: The compound was purified by preparative HPLC on an XSelect CSHC18 OBD column (5 μm, 150 × 30 mm ID) using a gradient of MeCN in H2O / NH4HCO3 (10 mM) / NH3 (0.1%, aqueous) buffer as the mobile phase; Preparation Method D: The compound was purified by preparative HPLC on an XSelect CSHC18 OBD column (5 μm, 150 × 30 mm ID) using a gradient of MeCN in H2O / FA ​​(0.1%) as the mobile phase; Preparation Method E: The compound was purified by preparative HPLC on an XSelect CSHC18 OBD column (5 μm, 250 × 19 mm ID) using a gradient of MeCN in H2O / FA ​​(0.1%) as the mobile phase; Preparation Method F: The compound was purified by preparative HPLC on a Kromasil C8 column (10 μm, 250 × 20 mm ID) using a gradie...

Claims

1. A compound having the following structure ( R )- N -(2-(4-cyanothiazolidine-3-yl)-2-oxoethyl)-6-morpholinoquinoline-4-carboxamide: ， Its pharmaceutically acceptable salt.

2. The compound of claim 1, wherein the compound has the following structure ( R )- N The non-salt form of -(2-(4-cyanothiazolidine-3-yl)-2-oxoethyl)-6-morpholinoquinoline-4-carboxamide: 。 3. The compound of claim 1, wherein the compound has the following structure ( R )- N Pharmaceutically acceptable salts of -(2-(4-cyanothiazolidine-3-yl)-2-oxoethyl)-6-morpholinoquinoline-4-carboxamide: 。 4. A pharmaceutical composition comprising a compound as described in any one of claims 1 to 3 or a pharmaceutically acceptable salt thereof, and one or more pharmaceutically acceptable excipients.

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