EA048482B1 - N-(2-(4-CYANOTHIAZOLIDIN-3-YL)-2-OXOETHYL)QUINOLINE-4-CARBOXAMIDES - Google Patents

Description

Field of technology to which the invention relates

In general, the present invention relates to N-(2-(4-cyanothiazolidin-3-yl)-2-oxoethyl)quinoline-4-carboxamides and pharmaceutically acceptable salts thereof. The disclosure further relates to pharmaceutical compositions containing such compounds and salts; the use of such compounds and salts for the treatment or prevention of conditions mediated by fibroblast prolyl endopeptidase (FAP) activating protein; kits containing such compounds and salts; and methods for making such compounds and salts.

Background of the invention

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

FAP is characterized by a consensus cleavage motif downstream of Gly-Pro and exhibits both endopeptidase and exopeptidase activities. Known enzymatic activities include cleavage of collagens (Hepatology 1999, 29, 1768), α2-antiplasmin (α2AP) (Blood 2004 103, 3783), and fibroblast growth factor 21 (FGF21) (Biochem J 2016, 473, 605). FAP activity on the cell surface of activated fibroblasts (including collagen cleavage) creates a pro-fibrotic environment. FAP cleavage of α2AP allows for more efficient cross-linking of α2AP with fibrin and results in decreased fibrin clearance. FAP cleavage of FGF21 inactivates the metabolic effects of FGF21 (Biochem J 2016, 473, 605). All such actions are associated with worsening NASH disease, and FAP inhibition has potential for the treatment of NASH and other conditions by targeting multiple mechanisms.

Inhibition of FAP activity is a currently unexploited therapeutic approach for the treatment of NASH and other diseases associated with such activity. There are currently no approved pharmacological agents that inhibit FAP activity in general or that specifically inhibit FAP activity. Accordingly, there is a need for FAP inhibitors, in particular FAP inhibitors, that have pharmacologically appropriate selectivity and bioavailability and are therefore suitable for administration to a subject in need of such treatment. The present invention addresses this great unmet need by providing such compounds together with corresponding pharmaceutical compositions and methods for the treatment or prevention of NASH and related conditions.

Brief description

In one aspect, the present invention provides compounds characterized by the structure of formula (I)

R ⁵

^R2 (I).

and their pharmaceutically acceptable salts, where

X ¹ is selected from the group consisting of -S-, -S(O)- and -S(O) ₂ -;

R ¹ is selected from the group consisting of hydrogen, halogen, hydroxy, C _1-3 αalkyl and C _1-6 alkoxy;

R ² is selected from the group consisting of:

(a) a heterocyclyl having a total of 4 to 10 ring atoms, wherein the heterocyclyl ring: (i) is a saturated, partially saturated, or fully unsaturated monocyclic or fused bicyclic ring, (ii) contains one, two, or three nitrogen atoms in the ring, the remaining ring atoms being carbon, and (iii) is optionally substituted with one or more substituents independently selected from the group consisting of halogen, hydroxy, oxo, cyano, C _1-6 αalkyl, C _3-6 cycloalkyl, C _3-6 cycloalkyl-C _1-3 alkyl, C _1-6 αalkoxy, C _3-6 cycloalkoxy, C _1-3 αalkoxy-C _1-3 alkylα, C _1-3 alkoxy-C _2-3 alkoxy, C _1-3 alkoxy-C _2-3 alkoxy-C _1-3 alkyl, C _1-3 alkylcarbonyl, C _3-6 cycloalkylcarbonyl, C _1-3 alkylcarbonylamino-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, azetidinyl, pyrrolidinyl, piperidinyl, morpholinyl, tetrahydrofuranyl, tetrahydropyranyl and tetrahydrooxepanyl, and wherein: (a) C _1-6 αalkyl, C _3-6 cycloalkyl, C _3-6 cycloalkyl-C _1-3 alkyl, C _1-6 alkoxy, C _3-6 cycloalkoxy, C _1-3 alkoxy, C _1-3 αlkyl, C _1-3 alkoxy-C _2-3 alkoxy, C _1-3 alkoxy-C _2-3 alkoxy-C _1-3 alkyl, C _1-3 alkylcarbonyl,

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_C3-6 cycloalkylcarbonyl, _C1-3 alkylcarbonylamino- _C1-3 alkyl, _C1-3 alkylsulfonyl- _C1-3 alkyl, phenyl, tolyl, _C1-3 alkoxyphenyl, phenyl- _C1-3 alkyl, _C1-3 alkoxyphenyl- _C1-3 alkyl, azetidinyl, pyrrolidinyl, piperidinyl, morpholinyl, tetrahydrofuranyl, tetrahydropyranyl and tetrahydrooxepanyl may be further substituted with one or more halogen atoms, and (b) _C1-6 alkyl may be further substituted with one or more hydroxy;

(b) a heterocyclyl having a total of 5 to 10 ring atoms, wherein the heterocyclyl ring: (i) is a saturated, partially saturated, or fully unsaturated monocyclic or fused bicyclic ring, (ii) contains: (a) one ring nitrogen atom and one ring oxygen atom, the remaining ring atoms being carbon, or (b) one ring nitrogen atom and one ring sulfur atom, the remaining ring atoms being carbon, and (iii) is optionally substituted with one or more substituents independently selected from the group consisting of halogen, cyano, oxo, C _1-6 alkyl, C ₃ . _b cycloalkyl, C _1-6 alkoxy, 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 where C _1-6 alkyl, C _3-6 cycloalkyl, C _1-6 alkoxy, C _1-3 alkoxy-C _1-3 alkyl, C _1-3 alkylcarbonyl-C _1-3 alkyl and C _1-3 alkylsulfonylC _1-3 alkyl may be further substituted with one or more halogen atoms; and (c) spiroheterocyclyl having a total of 6 to 11 ring atoms, wherein spiroheterocyclyl: (i) contains two saturated rings, (ii) contains: (a) one or two ring nitrogen atoms, the remaining ring atoms being carbon, (b) one or two ring nitrogen atoms and one or two ring oxygen atoms, the remaining ring atoms being carbon, or (c) one ring nitrogen atom and one ring sulfur atom, the remaining ring atoms being carbon, and (iii) is optionally substituted with 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, C _1-6 haloalkoxy and C _1-6 alkylcarbonyl;

R ³ is selected from the group consisting of hydrogen, halogen and C1-3alkyl; R ⁴ is selected from the group consisting of hydrogen, halogen and C1-3alkyl; R ⁵ is selected from the group consisting of hydrogen, halogen and C1-3αalkyl; and R ⁶ is selected from the group consisting of hydrogen, halogen and C1-3alkyl. In another aspect, the present invention provides compounds characterized by the structure of formulae (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.

In another aspect, the present invention provides pharmaceutical compositions comprising a therapeutically effective amount of a compound characterized by the structure of formulas (I), (II), (III-A), (III-B), (III-C), (III-D), (III-E), (IV), (IV-A), (V), (VI), (VII), (VIII), (IX), (X) or (XI), or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable carrier.

In another aspect, the present invention provides pharmaceutical compositions comprising therapeutically effective amounts of a compound characterized by the structure of formulas (I), (II), (III-A), (III-B), (III-C), (III-D), (III-E), (IV), (IV-A), (V), (VI), (VII), (VIII), (IX), (X) or (XI), or a pharmaceutically acceptable salt thereof; a second pharmacological agent and a pharmaceutically acceptable carrier.

In another aspect, the present invention provides methods for treating or preventing a FAP-mediated condition by administering a therapeutically effective amount of a compound characterized by the structure of formulae (I), (II), (III-A), (III-B), (III-C), (III-D), (III-E), (IV), (IV-A), (V), (VI), (VII), (VIII), (IX), (X) or (XI), or a pharmaceutically acceptable salt thereof, to a subject in need thereof. In a further aspect, the FAP-mediated condition is selected from the group consisting of liver disease, type 2 diabetes mellitus, cardiovascular conditions, obesity, obesity-related conditions, fibrosis, keloid disorder, inflammation and cancer. In yet a further aspect, the FAP-mediated condition is a liver disease, in particular non-alcoholic steatohepatitis (NASH).

In another aspect, the present invention provides compounds 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), or pharmaceutically acceptable salts thereof, for use as medicaments intended for the treatment or prevention of a FAP-mediated condition.

In another aspect, the present invention provides the use of compounds 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), or pharmaceutically acceptable salts thereof, for the manufacture of medicaments intended for the treatment or prevention of a FAP-mediated condition.

In another aspect, the present invention provides kits comprising a compound characterized by the structure of formulas (I), (II), (III-A), (III-B), (III-C), (III-D), (III-E), (IV), (IV-A), (V), (VI), (VII), (VIII), (IX), (X) or (XI), or a pharmaceutically acceptable salt thereof.

In another aspect, the present invention provides methods for preparing compounds characterized by the structure of formulas (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.

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Detailed description

Many embodiments are described in detail in the description and will be apparent to a reader skilled in the art. The description should not be interpreted as limited to any particular embodiment(s) disclosed herein.

I. Definitions

With respect to the embodiments disclosed in this specification, the following terms have the meanings set forth below.

Reference to singular forms means one or more. Throughout the text, plural and singular are to be considered interchangeable except where number is concerned.

Unless the context clearly requires otherwise, the words comprise or contains or containing are used on the basis and clear understanding that they are to be interpreted inclusively and not exclusively, and that the applicant intends that each of these words be so interpreted in interpreting this patent, including the claims below.

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

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

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

The term oxo (alone or in combination with another term(s)) means the oxo radical and can be depicted as =O.

The term alkyl (alone or in combination with another term(s)) means a substituent that is a saturated, non-cyclic, straight- or branched-chain hydrocarbon radical (i.e., a substituent containing only carbon and hydrogen). Alkyl typically contains 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, isoamyl, 2,2-dimethylpropyl, hexyl, heptyl, and octyl.

The term cycloalkyl (alone or in combination with another term(s)) means a saturated carbocyclyl substituent containing from 3 to about 14 ring carbon atoms, more typically from 3 to about 12 ring carbon atoms, and even more typically from 3 to about 8 ring carbon atoms. Cycloalkyl includes a single carbon ring, which typically contains from 3 to 6 ring carbon atoms. Examples of single-ring cycloalkyls include cyclopropyl, cyclobutyl, cyclopentyl, and cyclohexyl.

The term cycloalkylalkyl (alone or in combination with another term(s)) means alkyl substituted with cycloalkyl. Examples of such substituents include cyclopropylmethyl, cyclobutylmethyl, cyclopentylmethyl and cyclohexylmethyl.

The term alkoxy (alone or in combination with another term(s)) means an alkyl ether substituent, i.e., alkyl-O-. Examples of alkoxy include methoxy (CH ₃ -O-), ethoxy, n-propoxy, isopropoxy, n-butoxy, iso-butoxy, sec-butoxy and tert-butoxy. Thus, for example:

(i) the term alkoxyalkyl (alone or in combination with another term(s)) means alkyl substituted with alkoxy, such as methoxymethyl, which may be represented as:

n ₃ s.

(ii) the term cycloalkylalkoxy (alone or in combination with another term(s)) means alkoxy substituted with cycloalkyl, such as cyclopropylmethoxy, which may be represented as:

(iii) the term alkoxyalkoxy (alone or in combination with another term(s)) means an alkoxy substituted by another alkoxy, such as methoxyethoxy, which may be represented as:

(iv) the term alkoxyalkoxyalkyl (alone or in combination with another term(s)) means alkyl substituted with alkoxyalkoxy, such as methoxyethoxymethyl, which may be represented as:

n ₃ s.

' h-;

(v) the term alkoxyphenyl (alone or in combination with another term(s)) means phenyl substituted with alkoxy, such as 4-methoxyphenyl, which may be represented as:

- 3 048482 H ₃ c—o (vi) the term alkoxyphenylalkyl (alone or in combination with another term(s)) means alkyl substituted by alkoxyphenyl, such as 4-methoxyphenylmethyl, which may be represented as:

n ₃ s—o

In some cases, the number of carbon atoms in a substituent (e.g., alkyl, cycloalkyl, etc.) is indicated by the prefix C _x-y- , where x represents the minimum number of carbon atoms in the substituent and y represents the maximum number of carbon atoms in the substituent. Thus, for example, C _1-6 alkyl refers to an alkyl substituent containing from 1 to 6 carbon atoms. Illustrating further, C _3-6 cycloalkyl refers to a cycloalkyl substituent containing from 3 to 6 carbon atoms in the ring.

The prefix halogen indicates that the substituent to which the prefix is attached is substituted by one or more independently selected radicals representing a halogen atom. For example, haloalkyl means an alkyl substituent wherein at least one hydrogen radical is replaced by a radical representing a halogen atom. If more than one hydrogen atom is replaced by halogen atoms, the halogen atoms may be the same or different. Examples of haloalkyls 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 wherein at least one hydrogen radical is replaced by a radical representing a halogen atom. If more than one hydrogen atom is replaced by halogen atoms, the halogen atoms may be identical or different. Examples of haloalkoxy substituents include fluoromethoxy, difluoromethoxy, trifluoromethoxy (also known as perfluoromethyloxy), 1,1,1-trifluoroethoxy, and chloromethoxy.

The term carbonyl (alone or in combination with another term(s)) means -C(O)-, which can also be depicted as:

Thus, for example:

(i) the term alkylcarbonyl (alone or in combination with another term(s)) means alkyl-C(O)-, such as methylcarbonyl (i.e. acetyl), which may be represented as:

other alkylcarbonyl substituents such as ethylcarbonyl, propylcarbonyl, butylcarbonyl, pentylcarbonyl and hexylcarbonyl;

(ii) the term alkylcarbonylalkyl (alone or in combination with another term(s)) means alkyl substituted by alkylcarbonyl, such as methylcarbonylmethyl, which may be represented as:

(iii) the term cycloalkylcarbonyl (alone or in combination with another term(s)) means cycloalkyl-C(O)-, such as cyclopropylcarbonyl, which may be represented as:

(iv) the term cycloalkylcarbonylalkyl (alone or in combination with another term(s)) means alkyl substituted with cycloalkylcarbonyl, such as cyclopropylcarbonylmethyl, which may be represented as:

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The term thio or thia (alone or in combination with another term(s)) means a divalent sulfur atom, which can also be represented as -S-.

The term sulfinyl or sulfoxido (alone or in combination with another term(s)) means -S(O)-, which can also be represented as:

The term sulfonyl (alone or in combination with another term(s)) means -S(O) _2- , which can also be depicted as:

O.,0

Thus, for example, alkylsulfonyl (alone or in combination with another term(s)) means alkyl-S(O) _2- . Examples of alkylsulfonyl substituents include methylsulfonyl, ethylsulfonyl, and propylsulfonyl. Similarly, the term alkylsulfonylalkyl (alone or in combination with another term(s)) means alkyl substituted with alkylsulfonyl, such as methylsulfonylmethyl, which may be depicted as:

°ч z°

Hu n ₃ s

The term alkylcarbonylaminoalkyl (alone or in combination with another term(s)) means alkyl-C(O)-N(H)-alkyl-, such as methylcarbonylaminomethyl, which may also be depicted as:

The term heterocyclyl (alone or in combination with another term(s)) means a saturated, partially saturated, or fully unsaturated (i.e., heteroaryl) ring structure containing a total of from 3 to 14 ring atoms. At least one of the ring atoms is a heteroatom (i.e., oxygen, nitrogen, or sulfur), with the remaining ring atoms independently selected from the group consisting of carbon, oxygen, nitrogen, and sulfur.

Heterocyclyl includes monocyclic saturated, partially unsaturated and fully unsaturated ring structures containing, for example, from 3 to 7 members, such as from 3 to 6 members, from 5 to 7 members, such as from 5 to 6 members, wherein at least one member and not more than 4 members, in particular 1, 2 or 3 members of the ring are heteroatoms selected from N, O and S, and the remaining atoms in the ring are carbon atoms, in stable combinations known to those skilled in the art. Examples of monocyclic heterocyclyls include furanyl, dihydrofuranyl, tetrahydrofuranyl, thiophenyl, dihydrothiophenyl, tetrahydrothiophenyl, pyrrolyl, isopyrrolyl, pyrrolinyl, pyrrolidinyl, imidazolyl, isoimidazolyl, imidazolinyl, imidazolidinyl, pyrazolyl, pyrazolinyl, pyrazolidinyl, triazolyl, tetrazolyl, dithiolyl, oxathiolyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, thiazolinyl, isothiazolinyl, thiazolidinyl, isothiazolidinyl, thiodiazolyl, oxathiazolyl, dioxazolyl, oxathiazolyl, oxathiolyl, oxathiolanyl, pyranyl, dihydropyranyl, pyridinyl, piperidinyl, pyridazinyl, pyrimidinyl, pyrazinyl, piperazinyl, triazinyl, oxazinyl, isoxazinyl, oxazolidinyl, isoxazolidinyl, oxathiazinyl, morpholinyl, azepinil, oxepinyl, thiepinyl and diazepinyl.

Heterocyclyl further includes bicyclic ring structures fused together (i.e., fused bicyclic) or two rings with only one common atom (i.e., spiro), wherein at least one such ring contains a heteroatom as a ring atom (i.e., nitrogen, oxygen, or sulfur). Examples of heterocyclyls containing two ring structures fused together include indolizinyl, pyrindinyl, pyranopyrrolyl, 4H-quinolizinyl, purinyl, naphthyridinyl, pyridopyridinyl, pteridinyl, indolyl, isoindolyl, indolinyl, isoindazolyl, benzazinyl, phthalazinyl, quinoxalinyl, quinazolinyl, benzodiazinyl, benzouranyl, benzothiouranyyl, benzoxazolyl, indoxazinyl, anthranilyl, benzodioxolyl, benzodioxanyl, benzoxadiazolyl, benzofuranyl, isobenzofuranyl, benzothienyl, isobenzothienyl, benzothiazolyl, benzothiadiazolyl, benzimidazolyl, benzotriazolyl, benzoxazinyl, benzisoxazinyl and tetrahydroisoquinolinyl.

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A substituent is substitutable if it contains at least one carbon or nitrogen atom that is bonded to one or more hydrogen atoms. Thus, for example, hydrogen, halogen and cyano are not within the scope of this definition.

When a substituent is described as substituted, a non-hydrogen radical is substituted for a hydrogen radical in place of a carbon or nitrogen atom of the substituent. Thus, for example, a substituted alkyl substituent is an alkyl substituent wherein at least one non-hydrogen radical is substituted for a hydrogen radical in the alkyl substituent. As an example, a monofluoroalkyl is an alkyl substituted with a radical that is fluorine, and a difluoroalkyl is an alkyl substituted with two radicals that are fluorine. It should be recognized that if more than one substitution is present on a substituent, each non-hydrogen radical may be the same or different (unless otherwise specified).

When a substituent is described as optionally substituted, the substituent may be either (1) unsubstituted or (2) substituted. When a carbon of a substituent is described as optionally substituted by one or more substituents from the list, one or more hydrogen atoms on the carbon atom (to the extent that they are present) may be individually and/or collectively replaced with an independently selected optional substituent. When a nitrogen of a substituent is described as optionally substituted by one or more substituents from the list, each of the one or more hydrogen atoms on the nitrogen atom (to the extent that they are present) may be replaced with an independently selected optional substituent.

When substituents are described as being independently selected from a group, each substituent is selected independently of the other substituents. Therefore, each substituent may be identical or different from the other substituent(s).

The term pharmaceutically acceptable is used as an adjective in this specification to indicate that the modified noun is suitable for use as a pharmaceutical product or as part of a pharmaceutical product. For example, pharmaceutically acceptable salts are salts that are suitable for use in mammals, particularly humans, and include salts with an inorganic base, an organic base, an inorganic acid, an organic acid, or a basic or acidic amino acid that are suitable for use in mammals, particularly humans.

A therapeutically effective amount of a pharmacological agent is an amount sufficient to achieve beneficial or desired results, including clinical results, and will essentially depend on the situation in which it is administered. When a pharmacological agent is administered to treat a liver disease, for example, a therapeutically effective amount of the agent is an amount of the agent that is sufficient, either alone or in combination with additional therapies, to achieve an effect on the liver disease in a subject compared to the response obtained without the agent.

The term prevention is one that is readily understood by a physician of ordinary skill and, in relation to the treatment of a specific condition, may be understood to have its usual meaning and include primary prophylaxis to prevent the development of a condition and secondary prophylaxis when the condition has already developed and the patient is temporarily or permanently protected against exacerbation or worsening of the disease or the development of new symptoms associated with the condition.

The term treatment is one that is readily understood by a physician of ordinary skill and, when used to treat a specific condition, may include (1) reducing the extent or cause of the condition being treated and/or (2) alleviating or eliminating one or more symptoms associated with the condition. Treatment of liver disease, for example, may include stabilizing (i.e., not worsening), delaying, or slowing the spread or progression of the liver disease; prolonging survival compared with expected survival without treatment; and/or otherwise eliminating or alleviating the cancer or the severity of the liver disease, in whole or in part.

II . Connections

In one embodiment, the present invention provides compounds characterized by the structure of formula (I),

and their pharmaceutically acceptable salts, where

X ¹ is selected from the group consisting of -S-, -S(O)- and -S(O) ₂ -;

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R ¹ is selected from the group consisting of hydrogen, halogen, hydroxy, C _1-3 alkyl and C _1-6 alkoxy;

R ² is selected from the group consisting of:

(a) a heterocyclyl having a total of 4 to 10 ring atoms, wherein the heterocyclyl ring: (i) is a saturated, partially saturated, or fully unsaturated monocyclic or fused bicyclic ring, (ii) contains one, two, or three nitrogen atoms in the ring, the remaining ring atoms being carbon, and (iii) is optionally substituted with one or more substituents independently selected from the group consisting of halogen, hydroxy, oxo, cyano, C _1-6 alkyl, C _3-6 cycloalkyl, C _3-6 cycloalkyl-C _1-3 alkyl, C _1-6 alkoxy, C _3-6 cycloalkoxy, C _1-3 αlkoxy-C _1-3 alkylα, C _1-3 alkoxy-C _2-3 alkoxy, C _1-3 alkoxy-C _2-3 alkoxy-C _1-3 alkyl, C _1-3 alkylcarbonyl, C _3-6 cycloalkylcarbonyl, C _1-3 alkylcarbonylamino-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, azetidinyl, pyrrolidinyl, piperidinyl, morpholinyl, tetrahydrofuranyl, tetrahydropyranyl and tetrahydrooxepanyl, and wherein: (a) C _1-6 alkyl, C _3-6 cycloalkyl, C _3-6 cycloalkyl-C _1-3 alkyl, C _1-6 alkoxy, C _{3-6 cycloalkoxy} , C _1-3 alkoxy-C _1-3 alkyl, C _1-3 alkoxy-C _{2-3 alkoxy, C 1-3 alkoxy-C 2-3 alkoxy} -C _1-3 alkyl, C _1-3 alkylcarbonyl,

_C3-6 cycloalkylcarbonyl, _C1-3 alkylcarbonylamino- _C1-3 alkyl, _C1-3 alkylsulfonyl- _C1-3 alkyl, phenyl, tolyl, _C1-3 alkoxyphenyl, phenyl- _C1-3 alkyl, _C1-3 alkoxyphenyl- _C1-3 alkyl, azetidinyl, pyrrolidinyl, piperidinyl, morpholinyl, tetrahydrofuranyl, tetrahydropyranyl and tetrahydrooxepanyl may be further substituted with one or more halogen atoms, and (b) _C1-6 alkyl may be further substituted with one or more hydroxy;

(b) a heterocyclyl having a total of 5 to 10 ring atoms, wherein the heterocyclyl ring: (i) is a saturated, partially saturated, or fully unsaturated monocyclic or fused bicyclic ring, (ii) contains: (a) one ring nitrogen atom and one ring oxygen atom, the remaining ring atoms being carbon, or (b) one ring nitrogen atom and one ring sulfur atom, the remaining ring atoms being carbon, and (iii) is optionally substituted with 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, C _1-3 αlkoxy-C _1-3 alkylα, C _1-3 alkylcarbonyl-C _1-3 alkyl, and C _1-3 alkylsulfonyl-C _1-3 alkyl, and where C _1-3 αalkyl, C _3-6 cycloalkyl, C _1-6 alkoxy, C _1-3 alkoxy-C _1-3 alkyl, C _1-3 alkylcarbonyl-C _1-3 alkyl and C _1-3 αalkylsulfonylC _1-3 alkyl may be further substituted with one or more halogen atoms; and (c) spiroheterocyclyl having a total of 6 to 11 ring atoms, wherein spiroheterocyclyl: (i) contains two saturated rings, (ii) contains: (a) one or two ring nitrogen atoms, the remaining ring atoms being carbon, (b) one or two ring nitrogen atoms and one or two ring oxygen atoms, the remaining ring atoms being carbon, or (c) one ring nitrogen atom and one ring sulfur atom, the remaining ring atoms being carbon, and (iii) is optionally substituted with 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, C _1-6 haloalkoxy and C _1-6 alkylcarbonyl;

R ³ is selected from the group consisting of hydrogen, halogen and C _1-3 alkyl;

R ⁴ is selected from the group consisting of hydrogen, halogen and C _1-3 alkyl;

R ⁵ is selected from the group consisting of hydrogen, halogen and C _1-3 αalkyl; and

R ⁶ is selected from the group consisting of hydrogen, halogen and C _1-3 alkyl.

In some embodiments, the present invention provides compounds characterized by the structure of formula (II)

and pharmaceutically acceptable salts thereof, wherein X ¹ , R ¹ , R ² , R ³ , R ⁴ , R ⁵ and R ⁶ are as defined above for compounds of formula (I). In one aspect, X ¹ is -S-. In another aspect, X ¹ is -S(O)-. In another aspect, X ¹ is -S(O) ₂ -.

In some embodiments, R ¹ is selected from the group consisting of hydrogen, halogen, and C _1-3 alkyl. In one aspect, R ¹ is selected from the group consisting of hydrogen, chlorine, fluorine, and methyl. In another aspect, R ¹ is hydrogen. In another aspect, R ¹ is chlorine. In another aspect, R ¹ is fluorine. In another aspect, R ¹ is methyl.

In some embodiments, R ³ is selected from the group consisting of hydrogen, halogen, and C _1-3 alkyl. In one aspect, R ³ is selected from the group consisting of hydrogen, chlorine, fluorine, and methyl. In another aspect, R ³ is hydrogen. In another aspect, R ³ is chlorine. In another ac

- 7 048482 pect R ³ is fluorine. In another aspect R ³ is methyl.

In some embodiments, R ⁴ is selected from the group consisting of hydrogen, halogen, and C _1-3 alkyl. In one aspect, R ⁴ is hydrogen. In another aspect, R ⁴ is chloro. In another aspect, R ⁴ is fluoro. In another aspect, R ⁴ is methyl.

In some embodiments, R ⁵ is selected from the group consisting of hydrogen, halogen, and C _1-3 alkyl. In one aspect, R ⁵ is selected from the group consisting of hydrogen, chlorine, fluorine, and methyl. In another aspect, R ⁵ is hydrogen. In another aspect, R ⁵ is fluorine. In another aspect, R ⁵ is chlorine. In another aspect, R ⁵ is methyl.

In some embodiments, R ⁶ is selected from the group consisting of hydrogen, halogen, and C _1-3 alkyl. In one aspect, R ⁶ is selected from the group consisting of hydrogen, chlorine, fluorine, and methyl. In another aspect, R ⁶ is hydrogen. In another aspect, R ⁶ is chlorine. In another aspect, R ⁶ is fluorine. In another aspect, R ⁶ is methyl.

In some embodiments, one of the substituents R ¹ , R ³ , R ⁴ , R ⁵ and R ⁶ is selected from the group consisting of halogen and C _1-3 alkyl, and all remaining substituents R ¹ , R ³ , R ⁴ , R ⁵ and R ⁶ are hydrogen. In one aspect, one of the substituents R ¹ , R ³ , R ⁴ , R ⁵ and R ⁶ is selected from the group consisting of chloro, fluoro and methyl, and all remaining substituents R ¹ , R ³ , R ⁴ , R ⁵ and R ⁶ are hydrogen. In another aspect, one of the substituents R ¹ , R ³ , R ⁴ , R ⁵ and R ⁶ is selected from the group consisting of chlorine and fluorine, and all of the remaining substituents R ¹ , R ³ , R ⁴ , R ⁵ and R ⁶ are hydrogen. In another aspect, one of the substituents R ¹ , R ³ , R ⁴ , R ⁵ and R ⁶ is chlorine, and all of the remaining substituents R ¹ , R ³ , R ⁴ , R ⁵ and R ⁶ are hydrogen. In another aspect, one of the substituents R ¹ , R ³ , R ⁴ , R ⁵ and R ⁶ is fluorine, and all of the remaining substituents R ¹ , R ³ , R ⁴ , R ⁵ and R ⁶ are hydrogen. In another aspect, one of R ¹ , R ³ , R ⁴ , R ⁵ and R ⁶ is methyl and all remaining R ¹ , R ³ , R ⁴ , R ⁵ and R ⁶ are hydrogen.

In some embodiments, at least two of the substituents R ¹ , R ³ , R ⁴ , R ⁵ and R ⁶ are independently selected from the group consisting of halogen and C _1-3 alkyl, and all remaining substituents R ¹ , R ³ , R ⁴ , R ⁵ and R ⁶ are hydrogen. In one aspect, two of the substituents R ¹ , R ³ , R ⁴ , R ⁵ and R ⁶ are independently selected from the group consisting of chloro, fluoro and methyl, and all remaining substituents R ¹ , R ³ , R ⁴ , R ⁵ and R ⁶ are hydrogen.

In some embodiments, at least one of R ¹ , R ³ , R ⁴ , R ^{5 ,} and R ⁶ is chloro.

In some embodiments, at least one of R ¹ , R ³ , R ⁴ , R ^{5 ,} and R ⁶ is fluoro.

In some embodiments, at least one of R ¹ , R ³ , R ⁴ , R ⁵ , and R ⁶ is methyl.

In some embodiments, the present invention provides compounds characterized by the structure of formula (III-A) and pharmaceutically acceptable salts thereof, wherein R ¹ and R ² are as defined in the various embodiments above.

In some embodiments, the present invention provides compounds characterized by the structure of formula (III-B) and pharmaceutically acceptable salts thereof, wherein R ² and R ³ are as defined in the various embodiments above.

In some embodiments, the present invention provides compounds characterized by the structure of formula (III-C)

- 8 048482

and pharmaceutically acceptable salts thereof, wherein R ² and R ⁴ are as defined in the various embodiments above.

In some embodiments, the present invention provides compounds characterized by the structure of formula (III-D),

and pharmaceutically acceptable salts thereof, wherein R ² and R ⁵ are as defined in the various embodiments above.

In some embodiments, the present invention provides compounds characterized by the structure of formula (III-E),

and pharmaceutically acceptable salts thereof, wherein R ² and R ⁶ are as defined in the various embodiments above.

In some embodiments, the present invention provides compounds characterized by the structure of formula (IV),

and pharmaceutically acceptable salts thereof, wherein R ² is as defined above for compounds of formula (I).

In some embodiments, the present invention provides compounds characterized by the structure of formula (IV-A),

or pharmaceutically acceptable salts thereof, wherein R ² is as defined above for compounds of formula (I).

A. R ² is a monocyclic or fused bicyclic heterocyclyl (nitrogen and carbon atoms in a ring)

In some embodiments, the present invention provides compounds characterized by the structure of formula (I), (II), (III-A), (III-B), (III-C), (III-D), (III-E), (IV) or (IV-A), and their

- 9 048 482 pharmaceutically acceptable salts, wherein R ² is a heterocyclyl having a total of 4 to 10 ring atoms, wherein the heterocyclyl ring: (i) is a saturated, partially saturated or fully unsaturated monocyclic or fused bicyclic ring, (ii) contains one, two or three nitrogen atoms in the ring, wherein the remaining atoms in the ring are carbon, and (iii) is optionally substituted with one or more substituents independently selected from the group consisting of halogen, hydroxy, oxo, cyano, C _1-6 alkyl, C _3-6 cycloalkyl, C _3-6 cycloalkyl-C _1-3 alkyl, C _1-6 alkoxy, C _3-6 cycloalkoxy, C _1-3 alkoxy-C _1-3 alkyl,

C _1-3 alkoxy-C _2-3 alkoxy, C _1-3 alkoxy-C _2-3 alkoxy-C _1-3 alkyl, C _1-3 alkylcarbonyl, C _3-6 cycloalkylcarbonyl, C _1-3 alkylcarbonylamino-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, azetidinyl, pyrrolidinyl, piperidinyl, morpholinyl, tetrahydrofuranyl, tetrahydropyranyl and tetrahydrooxepanyl, and wherein: (a) C _1-6 alkyl, C _3-6 cycloalkyl, C _3-6 cycloalkyl-C _1-3 alkyl, C _1-6 alkoxy, C _3-6 cycloalkoxy, C _{1-3 alkoxy- C 1-3 alkyl ,} C 1-3 alkoxy _- C _2-3 alkoxy, C _1-3 alkoxy-C 2-3 alkoxy-C _1-3 alkyl, C _1-3 alkylcarbonyl, C _3-6 cycloalkylcarbonyl, C _1-3 alkylcarbonylamino-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, azetidinyl, pyrrolidinyl, piperidinyl, morpholinyl, tetrahydrofuranyl, tetrahydropyranyl and tetrahydrooxepanyl may be further substituted with one or more halogen atoms, and (b) C _1-6 alkyl may be further substituted with one or more hydroxy. In one aspect, the heterocyclyl ring R ² is a saturated monocyclic ring. In another aspect, the heterocyclyl ring R ² is a partially saturated monocyclic ring. In another aspect, the heterocyclyl ring R ² is a fully unsaturated monocyclic ring. In another aspect, the heterocyclyl ring R ² is a saturated fused bicyclic ring. In another aspect, the heterocyclyl ring R ² is a partially saturated fused bicyclic ring. In another aspect, the heterocyclyl ring R ^{2 is a fully unsaturated fused bicyclic ring. In another aspect, the heterocyclyl ring R 2 contains} one nitrogen atom in the ring, wherein the remaining atoms in the ring are carbon. In another aspect, the heterocyclyl ring R ² contains two nitrogen atoms in the ring, wherein the remaining atoms in the ring are carbon. In another aspect, the heterocyclyl ring R ² contains three nitrogen atoms in the ring, wherein the remaining atoms in the ring are carbon.

In some embodiments, the heterocyclyl ring R ² is selected from the group consisting of

- 10 048482

wherein the heterocyclyl ring is optionally substituted with one or more substituents independently selected from the group consisting of halogen, hydroxy, oxo, cyano, C _1-6 alkyl, C _3-6 cycloalkyl, C _3-6 cycloalkyl-C _1-3 alkyl, C _1-6 alkoxy, C _3-6 cycloalkoxy, C _1-3 alkoxy-C _1-3 alkyl, C _1-3 alkoxy-C _2-3 alkoxy, C _1-3 alkoxy-C _2-3 alkoxy-C _1-3 alkyl, C _1-3 alkylcarbonyl,

C _3-6 cycloalkylcarbonyl, C _1-3 alkylcarbonylamino-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, azetidinyl, pyrrolidinyl, piperidinyl, morpholinyl, tetrahydrofuranyl, tetrahydropyranyl and tetrahydrooxepanyl, and where: (a) C _1-6 alkyl, C _3-6 cycloalkyl, C _3-6 cycloalkyl-C _1-3 alkyl, C _1-6 alkoxy, C _3-6 cycloalkoxy, C _1-3 alkoxy, C _1-3 alkyl, C _1-3 alkoxy-C _2-3 alkoxy, C _1-3 alkoxy-C _2-3 alkoxy-C _1-3 αlkyl, C _1-3 alkylcarbonyl,

_C3-6 cycloalkylcarbonyl, _C1-3 alkylcarbonylamino- _C1-3 alkyl, _C1-3 alkylsulfonyl- _C1-3 alkyl, phenyl, tolyl, _C1-3 alkoxyphenyl, phenyl- _C1-3 alkyl, _C1-3 alkoxyphenyl- _C1-3 alkyl, azetidinyl, pyrrolidinyl, piperidinyl, morpholinyl, tetrahydrofuranyl, tetrahydropyranyl and tetrahydrooxepanyl may be further substituted with one or more halogen atoms, and (b) _C1-6 alkyl may be further substituted with one or more hydroxy.

In some embodiments, the heterocyclyl ring R ² is selected from the group consisting of

wherein the heterocyclyl ring is optionally substituted with one or more substituents independently selected from the group consisting of halogen, hydroxy, oxo, cyano, C _1-6 alkyl, C _3-6 cycloalkyl, C _3-6 cycloalkyl-C _1-3 alkyl, C _1-6 alkoxy, C _3-6 cycloalkoxy, C _1-3 alkoxy-C _1-3 alkyl, C _1-3 αalkoxy-C _2-3 alkoxy, C _1-3 αalkoxy-C _2-3 αalkoxy-C _1-3 αalkyl, C _1-3 alkylcarbonyl,

C _3-6 cycloalkylcarbonyl, C _1-3 alkylcarbonylamino-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, azetidinyl, pyrrolidinyl, piperidinyl, morpholinyl, tetrahydrofuranyl, tetrahydropyranyl and tetrahydrooxepanyl, and where: (a) C _1-6 alkyl, C _3-6 cycloalkyl, C _3-6 cycloalkyl-C _1-3 αlkyl, C _1-6 alkoxy, C _3-6 cycloalkoxy, C _1-3 alkoxyC _1-3 αlkyl, C _1-3 alkoxy-C _2-3 alkoxy, C _1-3 alkoxy-C _2-3 alkoxy-C _1-3 alkyl, C _1-3 alkylcarbonyl,

_C3-6 cycloalkylcarbonyl, _C1-3 alkylcarbonylamino- _C1-3 alkyl, _C1-3 alkylsulfonyl- _C1-3 αalkyl, phenyl, tolyl, _C1-3 alkoxyphenyl, phenyl- _C1-3 αalkyl, _C1-3 alkoxyphenyl- _C1-3 alkyl, azetidinyl, pyrrolidinyl, piperidinyl, morpholinyl, tetrahydrofuranyl, tetrahydropyranyl and tetrahydrooxepanyl may be further substituted with one or more halogen atoms, and (b) _C1-6 alkyl may be further substituted with one or more hydroxy.

In some embodiments, the heterocyclyl ring R ² is selected from the group consisting of

- 11 048482

wherein the heterocyclyl ring is optionally substituted with one or more substituents independently selected from the group consisting of halogen, hydroxy, oxo, cyano, C1-6alkyl, _{C3-6cycloalkyl} , _{C3-6cycloalkyl} - _C1-3alkyl , _C1-6alkoxy , _{C3-6cycloalkoxy} , _C1-3alkoxy - _C1-3alkyl , _C1-3alkoxy - _C2-3alkoxy , _C1-3alkoxy - _C2-3alkoxy - _C1-3alkyl , _{C1-3alkylcarbonyl} ,

C _3-6 cycloalkylcarbonyl, C _1-3 alkylcarbonylamino-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, azetidinyl, pyrrolidinyl, piperidinyl, morpholinyl, tetrahydrofuranyl, tetrahydropyranyl and tetrahydrooxepanyl, and where: (a) C _1-6 alkyl, C _3-6 cycloalkyl, C _3-6 cycloalkyl-C _1-3 alkyl, C _1-6 alkoxy, C _3-6 cycloalkoxy, C _1-3 alkoxy, C _1-3 alkyl, C _1-3 alkoxy-C _2-3 alkoxy, C _1-3 alkoxy-C _2-3 alkoxy-C _1-3 alkyl, C _1-3 alkylcarbonyl,

_C3-6 cycloalkylcarbonyl, _C1-3 alkylcarbonylamino- _C1-3 alkyl, _C1-3 alkylsulfonyl- _C1-3 alkyl, phenyl, tolyl, _C1-3 alkoxyphenyl, phenyl- _C1-3 alkyl, _C1-3 alkoxyphenyl- _C1-3 alkyl, azetidinyl, pyrrolidinyl, piperidinyl, morpholinyl, tetrahydrofuranyl, tetrahydropyranyl and tetrahydrooxepanyl may be further substituted with one or more halogen atoms, and (b) _C1-6 alkyl may be further substituted with one or more hydroxy.

In some embodiments, the heterocyclyl ring R ² is optionally substituted with one or more substituents independently selected from the group consisting of halogen, hydroxy, oxo, cyano, C _1-3 alkyl, C _3-6 cycloalkyl, C _1-3 alkoxy, C _1-3 alkylcarbonyl, C _3-6 cycloalkylcarbonyl, C _1-3 alkoxy-C _1-3 alkyl, C _1-3 alkoxy-C _2-3 alkoxy, C _1-3 alkoxy-C _2-3 alkoxy-C _1-3 alkyl,

C _1-3 alkylcarbonylamino-C _1-3 alkyl, C _1-3 alkylsulfonyl-C _1-3 alkyl, morpholinyl, tetrahydrofuranyl, tetrahydropyranyl and tetrahydrooxepanyl, where C _1-3 alkyl, C _3-6 cycloalkyl, C _1-3 alkoxy, C _1-3 alkylcarbonyl, C _3-6 cycloalkylcarbonyl, C _1-3 alkoxy-C _1-3 alkyl, C _1-3 alkoxy-C _2-3 alkoxy, C _1-3 alkoxyC _2-3 alkoxy-C _1-3 alkyl, C _1-3 alkylsulfonyl-C _1-3 alkyl, tetrahydrofuranyl, tetrahydropyranyl and tetrahydrooxepanyl may be further substituted with one or more halogen atoms.

In some embodiments, the heterocyclyl ring R ² is optionally substituted with one or more substituents independently selected from the group consisting of halogen, hydroxy, oxo, C _1-3 alkyl, cyclopropyl, C _1-3 alkoxy, and C _1-3 alkoxy-C _1-3 alkyl, wherein C _1-3 alkyl, cyclopropyl, C _1-3 alkoxy, and C _1-3 alkoxy-C _1-3 alkyl may be further substituted with one or more halogen atoms.

In some embodiments, the heterocyclyl ring R ² is optionally substituted with one or more substituents independently selected from the group consisting of azetidinyl, pyrrolidinyl, piperidinyl, and morpholinyl, wherein azetidinyl, pyrrolidinyl, piperidinyl, and morpholinyl may be further substituted with one or more halogen atoms.

In some embodiments, the heterocyclyl ring R ² is optionally substituted with one or more substituents independently selected from the group consisting of tetrahydrofuranyl, tetrahydropyranyl, and tetrahydrooxepanyl, wherein tetrahydrofuranyl, tetrahydropyranyl, and tetrahydrooxepanyl may be further substituted with one or more halogen atoms.

In some embodiments, the heterocyclyl ring R ² is optionally substituted with one or more halogen atoms. In one aspect, the heterocyclyl ring R ² is optionally substituted with one or more chlorine atoms. In another aspect, the heterocyclyl ring R ² is optionally substituted with one or more fluorine atoms.

In some embodiments, the heterocyclyl ring R ² is optionally substituted with one or more hydroxy.

In some embodiments, the heterocyclyl ring R ² is optionally substituted with one or more oxo.

In some embodiments, the heterocyclyl ring R ² is optionally substituted with one or more cyano.

In some embodiments, the heterocyclyl ring R ² is optionally substituted with one or more C _1-3 alkyl, wherein the C _1-3 alkyl may be further substituted with one or more substituents independently selected from halogen and hydroxy.

In some embodiments, the heterocyclyl ring R ² is optionally substituted with one or more C _3-6 cycloalkyl, wherein the C _3-6 cycloalkyl may be further substituted with one or more halogen atoms.

- 12 048482

In some embodiments, the heterocyclyl ring R ² is optionally substituted with one or more C _3-6 cycloalkyl-C _1-3 αalkyl, wherein the C _3-6 cycloalkyl-C _1-3 αalkyl may be further substituted with one or more halogen atoms.

In some embodiments, the heterocyclyl ring R ² is optionally substituted with one or more C _1-3 alkoxy, wherein the C _1-3 alkoxy may be further substituted with one or more halogen atoms.

In some embodiments, the heterocyclyl ring R ² is optionally substituted with one or more C _3-6 cycloalkoxy, wherein the C _3-6 cycloalkoxy may be further substituted with one or more halogen atoms.

In some embodiments, the heterocyclyl ring R ² is optionally substituted with one or more C _1-3 alkoxy-C _1-3 alkyl, wherein the C _1-3 alkoxy-C _1-3 alkyl may be further substituted with one or more halogen atoms.

In some embodiments, the heterocyclyl ring R ² is optionally substituted with one or more C _1-3 alkoxy-C _2-3 alkoxy, wherein the C _{1-3 α} -alkoxy-C _{2-3 α} -alkoxy may be further substituted with one or more halogen atoms.

In some embodiments, the heterocyclyl ring R ² is optionally substituted with one or more C _1-3 alkoxy-C _2-3 alkoxy-C _1-3 alkyl, wherein the C _1-3 alkoxy-C _2-3 alkoxy-C _1-3 alkyl may be further substituted with one or more halogen atoms.

In some embodiments, the heterocyclyl ring R ² is optionally substituted with one or more C _1-3 alkylcarbonyls, wherein the C _1-3 alkylcarbonyl may be further substituted with one or more halogen atoms.

In some embodiments, the heterocyclyl ring R ² is optionally substituted with one or more C _3-6 cycloalkylcarbonyls, wherein the C 3-6 cycloalkylcarbonyl may be further substituted with one or more halogen atoms.

In some embodiments, the heterocyclyl ring R ² is optionally substituted with one or more C _1-3 alkylcarbonylamino-C _1-3 alkyl, wherein the C _1-3 alkylcarbonylamino-C _1-3 alkyl may be further substituted with one or more halogen atoms.

In some embodiments, the heterocyclyl ring R ² is optionally substituted with one or more C _1-3 alkylsulfonyl-C _1-3 alkyl, wherein the C _1-3 alkylsulfonyl-C _1-3 alkyl may be further substituted with one or more halogen atoms.

In some embodiments, the heterocyclyl ring R ² is optionally substituted with one or more substituents independently selected from the group consisting of phenyl, tolyl, C _1-3 α-alkyl, phenyl-C _{1-3 α} -alkyl, and C _1-3 alkoxyphenyl-C _{1-3 α} -alkyl, wherein the phenyl, tolyl, phenyl-C _1-3 alkyl, and C _1-3 alkoxyphenyl-C _1-3 alkyl may be further substituted with one or more halogen atoms.

In some embodiments, the heterocyclyl ring R ² is optionally substituted with one or more substituents independently selected from the group consisting of azetidinyl, pyrrolidinyl, piperidinyl, and morpholinyl, wherein azetidinyl, pyrrolidinyl, piperidinyl, and morpholinyl may be further substituted with one or more halogen atoms.

In some embodiments, the heterocyclyl ring R ² is optionally substituted with one or more substituents independently selected from the group consisting of tetrahydrofuranyl, tetrahydropyranyl, and tetrahydrooxepanyl, wherein tetrahydrofuranyl, tetrahydropyranyl, and tetrahydrooxepanyl may be further substituted with one or more halogen atoms.

In some embodiments, the heterocyclyl ring R ² is optionally substituted with one or more substituents independently selected from the group consisting of fluoro, hydroxy, oxo, methyl, ethyl, propyl, isopropyl, cyclopropyl, fluoromethyl, difluoromethyl, trifluoromethyl, fluoroethyl, difluoroethyl, trifluoroethyl, difluoropropyl, trifluoropropyl, methoxy, ethoxy, isopropoxy, difluoromethoxy, trifluoromethoxy, methoxymethyl, trifluoromethoxymethyl, methylcarbonylaminomethyl, methylsulfonylmethyl, morpholinyl, and tetrahydropyranyl.

In some embodiments, the heterocyclyl ring R ² is optionally substituted with one or more substituents independently selected from the group consisting of fluoro, hydroxy, methyl, fluoromethyl, difluoromethyl, trifluoromethyl, difluoroethyl, difluoropropyl, cyclopropyl, methoxy, trifluoromethoxy, ethoxy, and methoxymethyl.

In some embodiments, the heterocyclyl ring R ² is

wherein the heterocyclyl ring R ² is optionally substituted with one or more substituents independently selected from the group consisting of halogen, hydroxy, C _1-6 alkyl, C _3-6 cycloalkyl, C _1-6 α-alkoxy, C _1-3 alkoxy-C _1-3 alkyl, C _1-3 alkylcarbonylamino-C _1-3 alkyl, C _1-3 alkylsulfonyl-C _1-3 alkyl, phenyl, tolyl, C _1-3 alkoxyphenyl, phenyl-C _1-3 α-alkyl and morpholinyl, and wherein C _1-6 alkyl, C ₃ . ₆ cycloalkyl, C _1-6 alkoxy, C _1-3 alkoxy-C _1-3 alkyl, C _1-3 alkylcarbonylamino-C _1-3 alkyl, C _1-3 alkylsulfonyl-C _1-3 alkyl,

- 13 048482 phenyl, tolyl, C _1-3 alkoxyphenyl, phenyl-C _1-3 alkyl and morpholinyl may be further substituted with one or more halogen atoms. In one aspect, the heterocyclyl ring R ² is optionally substituted with one or more substituents independently selected from the group consisting of fluoro, hydroxy, C _1-3 alkyl, cyclopropyl, C _1-3 alkoxy and C _1-3 alkoxy-C _1-3 alkyl, wherein C _1-3 alkyl, cyclopropyl, C _1-3 alkoxy and C _1-3 alkoxy-C _1-3 alkyl may be further substituted with one or more fluoro atoms. In another aspect, the heterocyclyl ring R ² is optionally substituted with one or more substituents independently selected from the group consisting of fluoro, hydroxy, methyl, ethyl, propyl, isopropyl, fluoromethyl, difluoromethyl, trifluoromethyl, fluoroethyl, difluoroethyl, trifluoroethyl, difluoropropyl, trifluoropropyl, cyclopropyl, methoxy, ethoxy, difluoromethoxy, trifluoromethoxy, trifluoroethoxy, methoxymethyl, trifluoromethoxymethyl, methylamidomethyl, methylsulfonylmethyl, and morpholinyl. In another aspect, the heterocyclyl ring R ² is optionally substituted with one or more substituents independently selected from the group consisting of fluoro, hydroxy, methyl, ethyl, cyclopropyl, fluoromethyl, difluoromethyl, trifluoromethyl, difluoroethyl, trifluoroethyl, difluoropropyl, trifluoropropyl, methoxy, ethoxy, trifluoromethoxy, trifluoromethoxymethyl, methoxymethyl, methylamidomethyl, and morpholinyl.

In some embodiments, the compounds and pharmaceutically acceptable salts are selected from the group consisting of (7?)-7Y-(2-(4-cyanothiazolide yn-3-yl)-2-oxoethyl)-6-(2,2-dimethylazethidin-1-yl)-quinoline-4-carboxamide (Example 20);

(7?)-7U-(2-(4-cyanothiazolidin-3-yl)-2-oxoethyl)-6-(3-fluoroazide-1-yl)quinoline-4-carboxamide (example 21);

(7?)-7U-(2-(4-cyanothiazolidin-3-yl)-2-oxoethyl)-6-(3,3-dimethylazetidin-1-yl)-quinoline4-carboxamide (example 22);

(7?)-7U-(2-(4-cyanothiazolidin-3-yl)-2-oxoethyl)-6-(3,3-difluoroazetidin-1-yl)-quinoline4-carboxamide (example 23);

(7?)-7U-(2-(4-cyanothiazolid in-3-yl)-2-oxoethyl)-6-(3-fluoro-3-methylazetidin-1-yl)quinolin-4-carboxamide (example 24) ;

(7?)-7U-(2-(4-cyanothiazolidin-3-yl)-2-oxoethyl)-6-(3-methylazethidin-1-yl)quinoline-4-carboxamide (example 25);

(7?)-7U-(2-(4-cyanothiazolidin-3-yl)-2-oxoethyl)-6-(3-(trifluoromethyl)az etidin-1-yl)quinolin-4-carboxamide (example 26) ;

(7?)-7U-(2-(4-cyanothiazolid in-3-yl)-2-oxoethyl)-6-(3-(fluoromethyl)-3-methylazetidin-1 yl)quinoline-4-carboxamide (example 27 );

(7?)-7U-(2-(4-cyanothiazolid in-3-yl)-2-oxoethyl)-6-(3-(difluoromethyl)az ethid in-1-yl)quinoline-4-carboxamide (example 28 );

(7?)-7U-(2-(4-cyanothiazolidin-3-yl)-2-oxoethyl)-6-(3-(methoxymethyl)-3-methylase etidin1-yl)quinolin-4-carboxamide (example 29) ;

7U-(2-((7?)-4-cyanothiazolidin-3-yl)-2-oxoethyl)-6-((25.37?)-3-methoxy-2-methylazetidin1-yl)quinoline-4-carboxamide (example 30);

(7?)-7U-(2-(4-cyanothiazolid in-3-yl)-2-oxoethyl)-6-(3-cyclopropyl-3-fluoroazetidin-1 yl)quinoline-4-carboxamide (Example 31);

(7?)-7U-(2-(4-cyanothiazolidin-3-yl)-2-oxoethyl)-6-(3-methoxyazethidin-1-yl)quinoline-4-carboxamide (example 66);

(7?)-7U-(2-(4-cyanothiazolidin-3-yl)-2-oxoethyl)-6-(3-(fluoromethyl)az etidin-1-yl)quinolin-4-carboxamide (example IZ) ;

(7?)-7U-(2-(4-cyanothiazolidin-3-yl)-2-oxoethyl)-6-(3-morpholinoase etidin-1-yl)quinoline-4-carboxamide (Example 122);

- 14 048482 (/?)-LC2-(4-cyanothiazolidin-3-yl)-2-oxoethyl)-6-(3-((trifluoromethoxy)methyl)azetidin-1-yl)quinolin-4-carboxamide a (example 130);

(7?)-7U-(2-(4-cyanothiazolidin-3-yl)-2-oxoethyl)-6-(3-methyl-3-(2,2,2-trifluoroethyl)azetidin-1-yl)quinoline -4-carboxamide a (example 131);

(7?)-7U-(2-(4-cyanothiazolidin-3-yl)-2-oxoethyl)-6-(3-(trifluoro-methoxy)azetidin-1yl)quinoline-4-carboxamide (Example 132);

(7?)-7U-(2-(4-cyanothiazolidin-3-yl)-2-oxoethyl)-6-(3-(2,2-difluoroethyl)-3-methylase etidin 1-yl)quinolin-4 -carboxamide (example 133);

(/?)-L-(2-(4-cyanothiazole idyn-3-yl)-2-oxoethyl)-6-(3-cyclopropyl-3-methylazetidin-1-yl)quinoline-4-carboxamide (Example 134);

(7?)-7U-(2-(4-cyanothiazolid in-3-yl)-2-oxoethyl)-6-(3-(diforomethyl)-3-methylazetidin-1 yl)quinoline-4-carboxamide (example 135);

(7?)-7U-(2-(4-cyanothiazolidin-3-yl)-2-oxoethyl)-6-(3-(difluoromethoxy)azetidin-1yl)quinoline-4-carboxamide (Example 136);

(7?)-7U-(2-(4-cyanothiazolid in-3-yl)-2-oxoethyl)-6-(3-ethyl-3-methylazetidin-1-yl)quinolin-4-carboxamide (Example 137) ;

(7?)-7U-(2-(4-cyanothiazolid in-3-yl)-2-oxoethyl)-6-(3-ethyl-3-fluoroazetidin-1-yl)quinoline-4-carboxamide (Example 138) ;

(7?)-7U-(2-(4-cyanothiazolidin-3-yl)-2-oxoethyl)-6-(3-(2,2-difluoropropyl)azetidin-1yl)quinoline-4-carboxamide (Example 140) ;

(7?)-7U-(2-(4-cyanothiazolidin-3-yl)-2-oxoethyl)-6-(3 -(3,3,3-trifluoropropyl)azetidin-1 yl)quinoline-4-carboxamide (example 142);

(7?)-7U-(2-(4-cyanothiazolidin-3-yl)-2-oxoethyl)-6-(3-fluoro-3-(trifluoromethyl)-azetidin1-yl)quinoline-4-carboxamide (example 143 );

(7?)-7U-(2-(4-cyanothiazolidin-3-yl)-2-oxoethyl)-6-(3-(2,2-difluoroethyl)azetidin-1-yl)quinoline-4-carboxamide (example 144);

(7?)-7U-(2-(4-cyanothiazolidin-3-yl)-2-oxoethyl)-6-(3-cyclopropyl az etidin-1-yl)quinolin-4-carboxamide (Example 145);

(7?)-tU-(2-(4-cyanothiazolidin-3-yl)-2-oxoethyl)-6-(3-(2-fluoroethyl)azetidin-1-yl)quinoline-4-carboxamide (example 146) ;

(7?)-7U-(2-(4-cyanothiazolid in-3 -yl)-2-oxoethyl)-6-(3 -(1,1-d iforoethyl)azetide in-1 -yl)quinoline-4- carboxamide (example 147);

(7?)-7U-(2-(4-cyanothiazolidin-3-yl)-2-oxoethyl)-6-(3-isopropyl ethyl ...

- 15 048482 (/?)-LC2-(4-cyanothiazol id in-3-yl)-2-oxoethyl)-6-(3-methoxy-3-methylazetidin-1-yl)quinolin-4-carboxamide (example 151 );

(7?)-A-(2-(4-cyanothiazolid in-3 -yl)-2-oxoethyl)-6-(3-ethoxy-3-methyl azetide in-1 -yl)quinoline-4-carboxamide (example 152 );

(7?)-A-(2-(4-cyanothiazolidin-3-yl)-2-oxoethyl)-6-(3-ethyl-3-hydroxyazetidin-1-yl)quinolin-4-carboxamide (Example 154);

(7?)-A-(2-(4-cyanothiazolid in-3-yl)-2-oxoethyl)-6-(3-fluoro-3-(fluoromethyl)azetidin-1 yl)quinoline-4-carboxamide (example 157);

(/?)-LC2-(4-n1anothiazolidin-3-yl)-2-oxoethyl)-6-(3-(2,2,2-trifluoroethyl)azetidin-1yl)quinoline-4-carboxamide (example 158);

A-(2-((7?)-4-cyanothiazolidin-3-yl)-2-oxoethyl)-6-(3,3-d-ifluoro-2-methylazetidin-1-yl)quinoline-4-carboxamide (Example 159);

(7?)-A-(2-(4-cyanothiazolide yn-3-yl)-2-oxoethyl)-6-(3-hydroxy-3-methylazetidin-1-yl)quinoline-4-carboxamide (Example 165);

(7?)-6-(3 -(acetamidomethyl)-3-methylazetidin-1-yl)-A-(2-(4-cyanothiazolid in-3-yl)-2oxoethyl)quinoline-4-carboxamide (Example 181) ;

(7?)-A-(2-(4-cyanothiazolidin-3-yl)-2-oxoethyl)-6-(3-fluoro-3-phenylazetidin-1-yl)quinolin-4-carboxamide (Example 182);

(7?)-A-(2-(4-cyanothiazolidin-3-yl)-2-oxoethyl)-6-(3-(i-tolyl)azetidin-1-yl)quinoline-4-carboxamide (example 183);

(7?)-A-(2-(4-cyanothiazolidin-3-yl)-2-oxoethyl)-6-(3-(4-fluorophenyl)azetidin-1-yl)quinolin-4-carboxamide (Example 185) ;

(7?)-A-(2-(4-cyanothiazolidin-3-yl)-2-oxoethyl)-6-(3-(l/-tolyl)azetidin-1-yl)quinolin4-carboxamide (Example 186);

(7?)-6-(3-(4-chlorobenzyl)azetidin-1-yl)-A-(2-(4-cyanothiazolidin-3-yl)-2-oxoethyl)quinoline-4-carboxamide (Example 187) ;

(7?)-A-(2-(4-cyanothiazolidin-3-yl)-2-oxoethyl)-6-(3-methyl-3-((methylsulfonyl)methyl)azetidin-1-yl)quinoline-4-carboxamide (Example 188) and their pharmaceutically acceptable salts.

In some embodiments, the compounds and pharmaceutically acceptable salts are selected from the group consisting of (7?)-A-(2-(4-cyanothiazolidin-3-yl)-2-oxoethyl)-6-(3,3-dimethylazetidin-1-yl)-quinoline-14-carboxamide (Example 22);

(7?)-A-(2-(4-cyanothiazolid in-3-yl)-2-oxoethyl)-6-(3-fluoro-3-methylazetidin-1-yl)quinolin-4-carboxamide (example 24) ;

- 16 048482 (/?)-LC2-(4-cyanothiazolidin-3-yl)-2-oxoethyl)-6-(3-(fluoromethyl)-3-methylase etidin-1yl)quinoline-4-carboxamide (example 27 );

(7?)-7U-(2-(4-cyanothiazolidin-3-yl)-2-oxoethyl)-6-(3-(difluoromethyl)azetidin-1-yl)quinolin-4-carboxamide (Example 28);

(7?)-7U-(2-(4-cyanothiazolidin-3-yl)-2-oxoethyl)-6-(3-(methoxymethyl)-3-methylase etidin1-yl)quinolin-4-carboxamide (example 29) ;

^(2-((7?)-4-cyanothiazolidin-3-yl)-2-oxoethyl)-6-((25.37?)-3-methoxy-2-methylazetidin1-yl)quinoline-4-carboxamide ( example 30);

(7?)-7U-(2-(4-cyanothiazolidin-3-yl)-2-oxoethyl)-6-(3-cyclopropyl-3-fluoraz etidin-1yl)quinoline-4-carboxamide (Example 31);

(7?)-7U-(2-(4-cyanothiazolidin-3-yl)-2-oxoethyl)-6-(3-methoxyazethidin-1-yl)quinoline-4-carboxamide (example 66);

(7?)-7U-(2-(4-cyanothiazolidin-3-yl)-2-oxoethyl)-6-(3-(fluoromethyl)azetidin-1-yl)quinolin-4-carboxamide (example IZ);

(7?)-7U-(2-(4-cyanothiazolid in-3-yl)-2-oxoethyl)-6-(3-(diforomethyl)-3-methylazetidin-1 yl)quinoline-4-carboxamide (example 135);

(7?)-7U-(2-(4-cyanothiazolid in-3-yl)-2-oxoethyl)-6-(3-ethyl-3-fluoroazetidin-1-yl)quinoline-4-carboxamide (Example 138) ;

(7?)-7U-(2-(4-cyanothiazolidin-3-yl)-2-oxoethyl)-6-(3-(2,2-difluoropropyl)azetidin-1yl)quinoline-4-carboxamide (Example 140) ;

(7?)-?/-(2-(4-cyanothiazolidin-3-yl)-2-oxoethyl)-6-(3-fluoro-3-(trifluoromethyl)-azetidin1-yl)quinoline-4-carboxamide (example 143);

(7?)-7U-(2-(4-cyanothiazolidin-3-yl)-2-oxoethyl)-6-(3-(1,1-d iforoethyl)azetide in-1-yl)quinoline-4-carboxamide (example 147);

(/?)-A'-(2-(4-cyanothiazol ide-3-yl)-2-oxoethyl)-6-(3-methoxy-3-methyl azetide-1-yl)quinoline-4-carboxamide (Example 151);

(7?)-3-(2-(4-cyanothiazolid in-3 -yl)-2-oxoethyl)-6-(3-ethoxy-3-methyl azetide in-1 -yl)quinoline-4-carboxamide (example 152 );

(7?)-7U-(2-(4-cyanothiazolid in-3-yl)-2-oxoethyl)-6-(3-fluoro-3-(fluoromethyl)azetidin-1 yl)quinoline-4-carboxamide (example 157);

(7?)-7U-(2-(4-cyanothiazolidin-3-yl)-2-oxoethyl)-6-(3-hydroxy-3-methylazetidin-1-yl)quinoline-4-carboxamide (Example 165) and their pharmaceutically acceptable salts.

In some embodiments, the heterocyclyl ring R ² is

wherein the heterocyclyl ring R ² is optionally substituted with one or more substituents independently selected from the group consisting of halogen, hydroxy, oxo, C1-6alkyl, hydroxy-C1-3alkyl, C3-6cycloalkyl, C1-6alkoxy, and C1-3alkoxy-C1-3alkyl, wherein the C1-6alkyl, hydroxy-C1-3alkyl, C3-6cycloalkyl, C1-6alkoxy, and C1-3alkoxy-C1-3alkyl may be further substituted with one or more halogen atoms. In one aspect, the heterocyclyl ring R ² is optionally substituted with one or more substituents independently selected from the group consisting of fluoro, hydroxy, C1-3alkyl, hydroxy- _C1-3alkyl , cyclopropyl, _C1-3dlkoxy , and

C _1-3 alkoxy-C _1-3 alkyl, where C _1-3 alkyl, hydroxy-C _1-3 alkyl, cyclopropyl, C _1-3 alkoxy and

C _1-3 alkoxy-C _1-3 alkyl may be further substituted with one or more fluorine atoms. In another aspect, the heterocyclyl ring R ² is optionally substituted with one or more substituents independently selected from the group consisting of fluorine, hydroxy, methyl, ethyl, propyl,

- 17 048482 fluoromethyl, difluoromethyl, trifluoromethyl, fluoroethyl, difluoroethyl, trifluoroethyl, difluoropropyl, hydroxymethyl, cyclopropyl, methoxy, ethoxy, trifluoromethoxy, trifluoroethoxy, methoxymethyl and trifluoromethoxymethyl. In another aspect, the heterocyclyl ring R ² is optionally substituted with one or more substituents independently selected from the group consisting of fluoro, hydroxy, methyl, ethyl, fluoromethyl, hydroxymethyl, methoxy and trifluoromethoxy.

In some embodiments, the compounds and pharmaceutically acceptable salts are selected from the group consisting of (7?)-L'-(2-(4-cyanothiazol idyn-3-yl)-2-oxoethyl)-6-(3,3-difluoropyrrolidin-1-yl)quinoline-4-carboxamide (Example 47);

(/?)-A-(2-(4-cyanothiazol idin-3-yl)-2-oxoethyl)-6-(3, 3-d imethyl pyrrol idin-1-yl)quinolin-4-carboxamide (example 48);

A-(2-((A)-4-cyanothiazolid in-3-yl)-2-oxoethyl)-6-((37?, 45)-3,4-difluoropyrrolide in-1yl)-quinoline-4-carboxamide (example 50);

A ^g -(2-((7?)-4-cyanothiazol idin-3-yl)-2-oxoethyl)-6-((5)-3-fluoropyrrole idin-1-yl)quinoline-4-carboxamide ( example 51);

A-(2-((A)-4-cyanothiazole ide-3-yl)-2-oxoethyl)-6-((7?)-3-fluoropyrrolide-1-yl)quinoline-4-carboxamide (Example 52);

A-(2-((/?)-4-cyanothiazol idin-3-yl)-2-oxoethyl)-6-((5)-3-methyl pyrrol idin-1-yl)quinolin-4-carboxamide ( example 54);

7U-(2-((7?)-4-cyanothiazolid in-3 -yl)-2-oxoethyl)-6-((7?)-3-methylpyrrolid in-1 -yl)quinoline-4-carboxamide (example 55);

A-(2-((A)-4-cyanothiazol id in-3-yl)-2-oxoethyl)-6-((5)-2-(trifluoromethyl)pyrrolidin-1 yl)quinoline-4-carboxamide (example 56);

(7?)-7U-(2-(4-cyanothiazolidin-3-yl)-2-oxoethyl)-6-(2,2-dimethylpyrrolidin-1-yl)quinoline-4-carboxamide (Example 57);

7U-(2-((7?)-4-cyanothiazolid in-3 -yl)-2-oxoethyl)-6-((5)-2-methylpyrrolidin-1 -yl)quinoline-4-carboxamide (example 65) ;

7U-(2-((7?)-4-cyanothiazolidin-3-yl)-2-oxoethyl)-6-((7?)-3-methoxypyrrolidin-1 -yl)quinoline-4-carboxamide (example 161) ;

7U-(2-((7?)-4-cyanothiazolide yn-3-yl)-2-oxoethyl)-6-((7?)-3-hydroxy-3-methylpyrrolidin-1-yl)quinoline-4-carboxamide (example 167);

A-(2-((A)-4-cyanothiazole idyn-3-yl)-2-oxoethyl)-6-((5)-3-hydroxy-3-methylpyrrolidin-1-yl)quinoline-4-carboxamide (Example 168);

7U-(2-((7?)-4-cyanothiazolid in-3-yl)-2-oxoethyl)-6-((7?5)-3-fluoro-3-methylpyrrolid in-1 yl)quinoline-4 -carboxamide (example 198);

2U-(2-((7?)-4-cyanothiazolidin-3-yl)-2-oxoethyl)-6-((7?*)-2-cyclopropylpyrrolidin-1yl)quinoline-4-carboxamide, isomer 1 (example 199);

7U-(2-((7?)-4-cyanothiazolidin-3-yl)-2-oxoethyl)-6-((7?*)-2-cyclopropylpyrrolidin-1yl)quinoline-4-carboxamide, isomer 2 (example 200);

- 18 048482

L-(2-0)-4-cyanothiazolidin-3-yl)-2-oxoethyl)-6-((5)-3-methoxypyrrolidin-1-yl)quinoline-4-carboxamide (Example 207);

L ^g -(2-((7?)-4-cyanothiazolidin-3-yl)-2-oxoethyl)-6-((L)-2-methylpyrrolidin-1-yl)quinolin-4-carboxamide (example 211) ;

LC2-((7?)-4-cyanothiazolidin-3-yl)-2-oxoethyl)-6-((5)-2-(methoxymethyl)pyrrolidin-1yl)quinolin-4-carboxamide (Example 212);

2U-(2-((7?)-4-cyanothiazolid in-3-yl)-2-oxoethyl)-6-((35.45)-3,4-difluoropyrrolidin-1yl)quinoline-4-carboxamide (example 213);

2U-(2-((7?)-4-cyanothiazolidin-3-yl)-2-oxoethyl)-6-((37?,47?)-3,4-difluoropyrrolidin-1yl)quinoline-4-carboxamide ( example 214);

7U-(2-((7?)-4-cyanothiazolid in-3-yl)-2-oxoethyl)-b-((7?)-3 -(hydroxymethyl)pyrrolid in-1 yl)quinoline-4-carboxamide (example 220);

2U-(2-((7?)-4-cyanothiazolidin-3-yl)-2-oxoethyl)-6-((5)-3-(hydroxymethyl)pyrrolidin-1yl)quinoline-4-carboxamide (Example 221) ;

7U-(2-((7?)-4-cyanothiazolidin-3-yl)-2-oxoethyl)-6-((7?5)-3,3-difluoro-4hydroxypyrrolidin-1-yl)quinoline-4- carboxamide (example 224);

7U-(2-((7?)-4-cyanothiazolidin-3-yl)-2-oxoethyl)-6-((37?*,4L*)-3,4-dimethylpyrrolidin-1yl)quinoline-4-carboxamide , isomer 1 (example 225);

7U-(2-((7?)-4-cyanothiazolidin-3-yl)-2-oxoethyl)-6-((37?*,4L*)-3,4-dimethylpyrrolidin-1yl)quinoline-4-carboxamide , isomer 2 (example 226);

and their pharmaceutically acceptable salts.

In some embodiments, the heterocyclyl ring R ² is o

wherein the heterocyclyl ring R ² is optionally substituted with one or more substituents independently selected from the group consisting of halogen, hydroxy, C1-6alkyl, C3-6cycloalkyl, C1-6alkoxy and C1-3alkoxy-C1-3alkyl, and wherein C1-6alkyl, C3-6cycloalkyl, C1-6alkoxy and C1-3alkoxy-C1-3alkyl may be further substituted with one or more halogen atoms. In one aspect, the heterocyclyl ring R ² is optionally substituted with one or more substituents independently selected from the group consisting of fluoro, hydroxy, _C1-3alkyl , cyclopropyl, C1-3alkoxy, and _C1-3alkoxy - _C1-3alkyl , wherein the _C1-3alkyl , cyclopropyl, _C1-3alkoxy , and _C1-3alkoxy - _C1-3alkyl may be further substituted with one or more fluoro atoms. In another aspect, the heterocyclyl ring R ² is optionally substituted with one or more substituents independently selected from the group consisting of fluoro, hydroxy, methyl, ethyl, fluoromethyl, difluoromethyl, trifluoromethyl, fluoroethyl, difluoroethyl, trifluoroethyl, difluoropropyl, cyclopropyl, methoxy, ethoxy, trifluoromethoxy, trifluoroethoxy, methoxymethyl, and trifluoromethoxymethyl. In another aspect, the heterocyclyl ring R ² is optionally substituted with one or more substituents independently selected from the group consisting of fluoro, hydroxy, methyl, ethyl, fluoromethyl, methoxy, and trifluoromethoxy.

In some embodiments, the compounds and pharmaceutically acceptable salts are selected from the group consisting of (7?)-L'-(2-(4-cyanothiazol id-3-yl)-2-oxoethyl)-6-(2-oxopyrrolidin-1-yl)quinoline-4-carboxamide (Example I);

(7?)-7U-(2-(4-cyanothiazolidin-3-yl)-2-oxoethyl)-6-(3,3-dimethyl-2-oxopyrrolidin-1 yl)quinoline-4-carboxamide (example 12) ;

7U-(2-((7?)-4-cyanothiazolidin-3-yl)-2-oxoethyl)-6-((7?*)-3-methyl-2-oxopyrrolidin-1yl)quinoline-4-carboxamide, isomer 1 (example 201);

7U-(2-((7?)-4-cyanothiazolidin-3-yl)-2-oxoethyl)-6-((7?*)-3-methyl-2-oxopyrrolidin-1yl)quinoline-4-carboxamide, isomer 2 (example 202);

- 19 048482 and their pharmaceutically acceptable salts.

In some embodiments, the heterocyclyl ring R ² is

wherein the heterocyclyl ring R ² is optionally substituted with one or more substituents independently selected from the group consisting of halogen, hydroxy, 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, C _1-3 alkoxy-C _1-3 alkyl,

C _1-3 αlkoxy-C _2-3 alkoxy, C _1-3 alkoxy-C _2-3 alkoxy-C _1-3 alkyl, C _1-3 alkylcarbonylamino-C _1-3 αlkyl,

C _1-3 alkylsulfonyl-C _1-3 alkyl, phenyl, tetrahydrofuranyl, tetrahydropyranyl and tetrahydrooxepanyl, and wherein 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, C _1-3 alkoxy-C _1-3 alkyl, C _1-3 alkoxy-C _2-3 alkoxy, C _1-3 alkoxy-C _2-3 alkoxy-C _1-3 alkyl, C _1-3 alkylcarbonylamino-C _1-3 alkyl, C _1-3 alkylsulfonyl-C _1-3 alkyl, phenyl, tetrahydrofuranyl, tetrahydropyranyl and tetrahydrooxepanyl may be further substituted with one or more atoms halogen. In one aspect, the heterocyclyl ring R ² is optionally substituted with one or more substituents independently selected from the group consisting of halogen, hydroxy, C _1-3 alkyl, C _3-6 cycloalkyl, cyclopropyl-C _1-3 alkyl, C _1-3 alkoxy, C _1-3 alkoxy-C _1-3 alkyl, tetrahydrofuranyl, tetrahydropyranyl and tetrahydrooxepanyl, wherein the C _1-3 alkyl, C _3-6 cycloalkyl, cyclopropyl-C _1-3 alkyl, C _1-3 alkoxy, C _1-3 alkoxy-C _1-3 alkyl and tetrahydropyranyl may be further substituted with one or more halogen atoms. In another aspect, the heterocyclyl ring R ² is optionally substituted with one or more substituents independently selected from the group consisting of fluoro, methyl, ethyl, propyl, fluoromethyl, difluoromethyl, trifluoromethyl, fluoroethyl, difluoroethyl, trifluoroethyl, difluoropropyl, cyclopropyl, cyclopropylmethyl, methoxy, ethoxy, trifluoromethoxy, trifluoroethoxy, methoxymethyl, trifluoromethoxymethyl, and tetrahydropyranyl. In another aspect, the heterocyclyl ring R ² is optionally substituted with one or more substituents independently selected from the group consisting of methyl, ethyl, propyl, fluoromethyl, difluoromethyl, trifluoromethyl, fluoroethyl, difluoroethyl, trifluoroethyl, difluoropropyl, cyclopropyl, and tetrahydropyranyl.

In some embodiments, the compounds and pharmaceutically acceptable salts are selected from the group consisting of (7?)-7Y-(2-(4-cyanothiazolidin-3-yl)-2-oxoethyl)-6-(1-methyl-1//-pyrazol-4-yl)-quinoline-4-carboxamide (Example 129);

(7?)-U-(2-(4-cyanothiazolidin-3-yl)-2-oxoethyl)-6-(1-cyclopropyl-1R-pyrazol-4-yl)quinolin-4-carboxamide (Example 170);

(7?)-^Y-(2-(4-cyanothiazolidin-3-yl)-2-oxoethyl)-6-(1,3-dimethyl-1//-pyrazol-4-yl)quinolin-4-carboxamide (example 171);

(7?)-7U-(2-(4-cyanothiazolid in-3-yl)-2-oxoethyl)-6-(3,5-dimethyl-1 -(tetrahydro-2//pyran-4-yl)- 1R-pyrazol-4-yl)quinoline-4-carboxamide (example 172);

(7?)-7U-(2-(4-cyanothiazolidin-3-yl)-2-oxoethyl)-6-(1-(tetrahydro-2N-pyran-4-yl)-1N-pyrazol-4-yl)quinoline-4-carboxamide (Example 173) and their pharmaceutically acceptable salts.

In some embodiments, the heterocyclyl ring R ² is

wherein the heterocyclyl ring R ² is optionally substituted with one or more substituents independently selected from the group consisting of halogen, hydroxy, C _1-6 alkyl, C _3-6 cycloalkyl, C _3-6 cycloalkyl-C _1-3 alkyl, C _1-6 alkoxy, C _1-3 alkoxy-C _1-3 alkyl, C _1-3 alkoxy-C _2-3 alkoxy,

C _1-3 alkoxy-C _2-3 alkoxy-C _1-3 alkyl, C _1-3 alkylsulfonyl-C _1-3 alkyl, phenyl, tetrahydrofuranyl, tetrahydropyranyl and tetrahydrooxepanyl, and where C _1-6 alkyl, C _3-6 cycloalkyl, C _3-6 cycloalkyl-C _1-3 alkyl, C _1-6 alkoxy, C _1-3 alkoxy-C _1-3 alkyl, C _1-3 alkoxy-C _2-3 alkoxy, C _1-3 alkoxy-C _2-3 alkoxy-C _1-3 alkyl, C _1-3 alkylsulfonyl-C _1-3 alkyl, phenyl, tetrahydrofuranyl, tetrahydropyranyl and tetrahydrooxepanyl may be further substituted with one or more halogen atoms. In one aspect, the heterocyclyl ring R ² is optionally substituted with one or more substituents independently selected from the group consisting of halogen, hydroxy, C _1-3 alkyl, C _3-6 cycloalkyl, cyclopropyl-C _1-3 alkyl, C _1-3 alkoxy, C _1-3 alkoxy-C _1-3 alkyl, tetrahydrofuranyl, tetrahydropyranyl, and tetrahydrooxepanyl, wherein the C _1-3 alkyl, C _3-6 cycloalkyl, cyclopropyl-C _1-3 alkyl, C _1-3 alkoxy, C _1-3 alkoxyC _1-3 alkyl, and tetrahydropyranyl may be further substituted with one or more halogen atoms. In another aspect, the heterocyclyl ring R ² is optionally substituted with one or more

- 20 048 482 substituents independently selected from the group consisting of fluoro, methyl, ethyl, propyl, isopropyl, fluoromethyl, difluoromethyl, trifluoromethyl, fluoroethyl, difluoroethyl, trifluoroethyl, difluoropropyl, cyclopropyl, methoxy, ethoxy, trifluoromethoxy, trifluoroethoxy, methoxymethyl, trifluoromethoxymethyl and tetrahydropyranyl. In another aspect, the heterocyclyl ring R ² is optionally substituted with 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.

In some embodiments, the compounds and pharmaceutically acceptable salts are selected from the group consisting of (7?)-7Y-(2-(4-cyanothiazolidin-3-yl)-2-oxoethyl)-6-(1-methyl-1//-pyrazol-5-yl)-quinoline-4-carboxamide (Example 174);

7U-(2-((7?)-4-cyanothiazolid in-3 -yl)-2-oxoethyl)-6-( 1 -(tetrahydro-2//-pyran-2-yl)-1Hpyrazol-5-yl )quinoline-4-carboxamide (example 176);

(7?)-7U-(2-(4-cyanothiazolidin-3-yl)-2-oxoethyl)-6-(1//-pyrazol-5-yl)quinoline-4-carboxamide (example 196);

(7?)-7U-(2-(4-cyanothiazolidin-3-yl)-2-oxoethyl)-6-(1-isopropyl-1//-pyrazol-5-yl)quinoline-4-carboxamide (Example 197) and their pharmaceutically acceptable salts.

In some embodiments, the heterocyclyl ring R ² is

wherein the heterocyclyl ring R ² is optionally substituted with one or more substituents independently selected from the group consisting of halogen, hydroxy, oxo, C _1-6 alkyl, C _3-6 cycloalkylα, C _3-6 cycloalkyl-C _1-3 alkyl, C _1-6 alkoxy, C _1-3 alkoxy-C _1-3 alkyl, C _1-3 alkoxy-C _2-3 alkoxy,

C _1-3 alkoxy-C _2-3 alkoxy-C _1-3 alkyl, phenyl, tolyl and C _1-3 alkoxyphenyl, and where C _1-6 alkyl, C _3-6 cycloalkyl, C _3-6 cycloalkyl-C _1-3 alkyl, C _1-6 alkoxy, C _1-3 alkoxy-C _1-3 alkyl, C _1-3 alkoxy-C _2-3 alkoxy,

C _1-3 alkoxy-C _2-3 alkoxy-C _1-3 alkyl, phenyl, tolyl and C _1-3 alkoxyphenyl may be further substituted with one or more halogen atoms. In one aspect, the heterocyclyl ring R ² is optionally substituted with one or more substituents independently selected from the group consisting of fluoro, hydroxy, C _1-3 alkyl, cyclopropyl, cyclopropyl-C _1-3 alkyl, C _1-3 alkoxy and C _1-3 alkoxy-C _1-3 alkyl, wherein C _1-3 alkyl, cyclopropyl, cyclopropyl-C _1-3 alkyl, C _1-3 α alkoxy and C _1-3 alkoxyC _1-3 alkyl may be further substituted with one or more fluoro atoms. In another aspect, the heterocyclyl ring R ² is optionally substituted with one or more substituents independently selected from the group consisting of fluoro, hydroxy, methyl, ethyl, propyl, isopropyl, fluoromethyl, difluoromethyl, trifluoromethyl, fluoroethyl, difluoroethyl, trifluoroethyl, cyclopropyl, cyclopropylmethyl, methoxy, ethoxy, propoxy, isopropoxy, trifluoromethoxy, trifluoroethoxy, methoxymethyl and trifluoromethoxymethyl. In another aspect, the heterocyclyl ring R ² is optionally substituted with one or more substituents independently selected from the group consisting of fluoro, hydroxy, methyl, ethyl, propyl, isopropyl, fluoromethyl, difluoromethyl, trifluoromethyl, fluoroethyl, difluoroethyl, trifluoroethyl, cyclopropyl, methoxy, ethoxy, propoxy, isopropoxy, trifluoromethoxy, and trifluoroethoxy.

In some embodiments, the compounds and pharmaceutically acceptable salts are selected from the group consisting of

- 21 048482

L-(2-((L ^> )-4-cyanothiazole idyn-3-yl)-2-oxoethyl)-6-((35,45,57?)-4-hydroxy-3,5-dimethylpiperidin-1-yl)quinoline-4-carboxamide (example 7);

(R)-N-(2 -(4-cyanothiazolid in-3 -yl)-2-oxoethyl)-6-(4-methoxypiperidin-1 -yl)-quinoline4-carboxamide (Example 8);

(R)-N-(2 -(4-cyanothiazol idin-3 -yl)-2-oxoethyl)-6-(piperidin-1 -yl)quinolin-4carboxamide (Example 32);

(R)-N-(2-(4-cyanothiazolid in-3-yl)-2-oxoethyl)-6-(4,4-dimethylpiperidin-1-yl)quinoline-4-carboxamide (Example 33);

(R)-N-(2-(4-cyanothiazolid in-3-yl)-2-oxoethyl)-6-(4-fluoro-4-methylpiper idin-1 yl)quinoline-4-carboxamide (Example 34);

(R)-N-(2-(4-cyanothiazolid in-3-yl)-2-oxoethyl)-6-(4,4-difluoropiperidin-1-yl)quinoline-4-carboxamide (Example 35);

(R)-N-(2-(4-cyanothiazolid in-3-yl)-2-oxoethyl)-6-(3,3-d iforpiperidin-1-yl)quinoline-4-carboxamide (Example 36);

(R)-N-(2-(4-cyanothiazolid in-3-yl)-2-oxoethyl)-6-(4-(fluoromethyl)-4-methylpiper idin-1 yl)quinoline-4-carboxamide (Example 37 );

(/?)-A-(2-(4-cyanothiazolide in-3-yl)-2-oxoethyl)-6-(4,4-difluoro-3,3-d and methylpiperidin1-yl)quinoline-4-carboxamide (example 38);

(7?)-^(2-(4-cyanothiazolide 3-yl)-2-oxoethyl)-6-(4-(trifluoromethyl)piperidin-1-yl)quinoline-4-carboxamide (Example 39);

A-(2-((A ^> )-4-cyanothiazole idyn-3-yl)-2-oxoethyl)-6-(3-fluoropiperidine-1-yl)quinoline-4-carboxamide (example 40);

A-(2-((A)-4-cyanothiazol id in-3 -yl)-2-oxoethyl)-6-(3-methoxypiperidin-1 -yl)-quinoline 4-carboxamide (Example 41);

(A)-A-(2-(4-cyanothiazolidin-3-yl)-2-oxoethyl)-6-(4-methoxy-4-methylpiperidin-1yl)quinoline-4-carboxamide (Example 42);

(A)-A-(2-(4-cyanothiazolidin-3-yl)-2-oxoethyl)-6-(4-isopropoxypiperidin-1-yl)quinoline-4-carboxamide (Example 43);

A-(2-((A)-4-cyanothiazolid in-3-yl)-2-oxoethyl)-6-(4,4-difluoro-2-methylpiper idin-1 yl)quinoline-4-carboxamide (example 44 );

7U-(2-((7?)-4-cyanothiazolid in-3-yl)-2-oxoethyl)-6-((5)-2-(fluoromethyl)piper idin-1 yl)quinoline-4-carboxamide (example 45);

(/?)-A-(2-(4-cyanothiazolidin-3-yl)-2-oxoethyl)-6-(4-ethyl-4-hydroxypiperidin-1yl)quinoline-4-carboxamide (Example 189);

(Ya)-7Y-(2-(4-cyanothiazolidin-3-yl)-2-oxoethyl)-6-(4-hydroxy-4-methylpiperidin-1 yl)quinoline-4-carboxamide (Example 190);

(A)-A-(2-(4-cyanothiazolid in-3-yl)-2-oxoethyl)-6-(4-ethyl-4-methoxy piperidin-1-yl)quinoline-4-carboxamide (Example 191) ;

(/?)-A-(2-(4-cyanothiazolidin-3-yl)-2-oxoethyl)-6-(4-hydroxy-4-isopropylpiperidin-1-yl)quinoline-4-carboxamide (Example 192);

A-(2-((A)-4-cyanothiazolidin-3-yl)-2-oxoethyl)-6-((3A,4L',5A')-4-hydroxy-3,4,5-trimethylpiperidin-1-yl)quinoline-4-carboxamide (example 193);

(/?)-A-(2-(4-cyanothiazolidin-3-yl)-2-oxoethyl)-6-(4-fluoropiperidin-1-yl)quinoline-4carboxamide (Example 205);

(/?)-A-(2-(4-cyanothiazolid in-3-yl)-2-oxoethyl)-6-(4-fluoro-4-phenylpiper idin-1-yl)quinoline-4-carboxamide (example 223 )

- 22 048482 and their pharmaceutically acceptable salts.

In some embodiments, the heterocyclyl ring R ² is

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

In some embodiments, the heterocyclyl ring R ² is

wherein the heterocyclyl ring R ² is optionally substituted with one or more substituents independently selected from the group consisting of halogen, hydroxy, oxo, C ₁ . ₆ alkyl, C ₃ . ₆ cycloalkyl, C ₃ . ₆ cycloalkyl-C ₁ . 3 alkyl, C ₁ . ₆ alkoxy, C ₁ . ₃ alkoxy-C ₁ . ₃ alkyl, C ₁ . ₃ alkoxy-C ₂ . ₃ alkoxy,

C ₁ . ₃ alkoxy-C ₂ . ₃ alkoxy-C ₁ . ₃ alkyl, C ₁ . ₃ alkylcarbonyl, C ₃ . ₆ cycloalkylcarbonyl and phenyl, and where C ₁ . ₆ alkyl, C ₃ . ₆ cycloalkyl, C ₃ . ₆ cycloalkyl-C ₁ . ₃ alkyl, C ₁ . ₆ alkoxy, C ₁ . ₃ alkoxy-C ₁ . ₃ alkyl,

C ₁ . ₃ alkoxy-C ₂ . ₃ alkoxy, C ₁ . ₃ alkoxy-C ₂ . ₃ alkoxy-C ₁ . ₃ alkyl, C ₁ . ₃ alkylcarbonyl, C ₃ . ₆ cycloalkylcarbonyl and phenyl may be further substituted with one or more halogen atoms. In one aspect, the heterocyclyl ring R ² is optionally substituted with one or more substituents independently selected from the group consisting of fluoro, hydroxy, 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 may be further substituted with one or more fluorine atoms. In another aspect, the heterocyclyl ring R ² is optionally substituted with one or more substituents independently selected from the group consisting of fluoro, hydroxy, oxo, methyl, ethyl, isopropyl, propyl, fluoromethyl, difluoromethyl, trifluoromethyl, fluoroethyl, difluoroethyl, trifluoroethyl, cyclopropyl, cyclopropylmethyl, methoxy, ethoxy, propoxy, trifluoromethoxy, trifluoroethoxy, methoxymethyl and trifluoromethoxymethyl. In another aspect, the heterocyclyl ring R ² is optionally substituted with one or more substituents independently selected from the group consisting of fluoro, hydroxy, oxo, methyl, ethyl, propyl, isopropyl, fluoromethyl, difluoromethyl, trifluoromethyl, fluoroethyl, difluoroethyl, trifluoroethyl, cyclopropyl, methoxy, ethoxy, trifluoromethoxy, trifluoroethoxy, and methoxymethyl.

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

In some embodiments, the heterocyclyl ring R ² is

wherein the heterocyclyl ring R ² is optionally substituted with one or more substituents independently selected from the group consisting of halogen, hydroxy, C1.6 alkyl, C3.6 cycloalkyl, C1.6 alkoxy, C1.3 alkoxy-C1.3 alkyl, C1.3 alkoxy-C2.3 alkoxy and C1.3 alkoxy-C2.3 alkoxy-C1.3 alkyl, and wherein the C1.6 alkyl, C3.6 cycloalkyl, C1.6 alkoxy, C1.3 alkoxy-C1.3 alkyl, C1.3 alkoxy-C2.3 alkoxy and C1.3 alkoxy-C2.3 alkoxy-C1.3 alkyl may be further substituted with one or more halogen atoms. In one aspect, the heterocyclyl ring R ² is optionally substituted with one or more substituents independently selected from the group consisting of fluoro, hydroxy, _C1.3 alkyl, cyclopropyl _{, C1.3 alkoxy , and C1.3 alkoxy-C1.3 alkyl , wherein the C1.3 alkyl} , _cyclopropyl , _C1.3 alkoxy, and _C1.3 alkoxy- _{C1.3 alkyl} may be further substituted with one or more fluoro atoms. In another aspect, the heterocyclyl ring R ² is optionally substituted with one or more substituents independently selected from the group consisting of fluoro, hydroxy, methyl, ethyl, propyl, isopropyl, fluoromethyl, difluoromethyl, trifluoromethyl, fluoroethyl, difluoroethyl, trifluoroethyl, cyclopropyl, methoxy, ethoxy, propoxy, isopropoxy, trifluoromethoxy, trifluoroethoxy, methoxymethyl, and trifluoromethoxymethyl. In another aspect, the heterocyclyl ring R ² is optionally substituted with one or more substituents independently selected from the group consisting of fluoro, hydroxy, methyl, ethyl, propyl, isopropyl, fluoromethyl, difluoromethyl, trifluoromethyl, fluoroethyl, difluoroethyl, trifluoroethyl, cyclopropyl, methoxy, ethoxy, isopropoxy, trifluoromethoxy, trifluoroethoxy, and methoxymethyl.

In some embodiments, the compounds and pharmaceutically acceptable salts are selected from the group consisting of

- 23 048482 (L)-^-(2-(4-cyanothiazolide in-3-yl)-2-oxoethyl)-6-(2-oxopiperidin-1-yl)quinoline-4-carboxamide (example 14);

(7?)-U-(2-(4-cyanothiazolid in-3-yl)-2-oxoethyl)-6-(3,3-dimethyl-2-oxopiper idin-1-yl) quinoline-4-carboxamide (example 15);

^(2-((7?)-4-cyanothiazolidin-3-yl)-2-oxoethyl)-6-((7?*)-3 -methyl-2-oxopiperidin-1yl)quinoline-4-carboxamide, isomer 1 (example 203);

7U-(2-((L)-4-cyanothiazolidin-3-yl)-2-oxoethyl)-6-((7?*)-3-methyl-2-oxopiperidin-1yl)quinoline-4-carboxamide, isomer 2 (example 204);

and their pharmaceutically acceptable salts.

In some embodiments, the heterocyclyl ring R ² is

wherein the heterocyclyl ring R ² is optionally substituted with one or more substituents independently selected from the group consisting of halogen, hydroxy, C _1-6 alkyl, hydroxy-C _1-3 alkyl, C _3-6 cycloalkyl, C _1-6 alkoxy, 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, and where C _1-6 alkyl, C _3-6 cycloalkyl, C _1-6 alkoxy, 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} may be further substituted with one or more halogen _atoms . In one aspect, the heterocyclyl ring R ² is optionally substituted with one or more substituents independently selected from the group consisting of fluoro, hydroxy, C _1-3 alkyl, hydroxy-C _1-3 alkyl, cyclopropyl, C _1-3 alkoxy and C _1-3 alkoxy-C _1-3 alkyl, wherein C _1-3 alkyl, cyclopropyl, C _1-3 alkoxy and C _1-3 alkoxy-C _1-3 alkyl may be further substituted with one or more fluoro atoms. In another aspect, the heterocyclyl ring R ² is optionally substituted with one or more substituents independently selected from the group consisting of fluoro, hydroxy, methyl, ethyl, propyl, fluoromethyl, difluoromethyl, trifluoromethyl, hydroxymethyl, fluoroethyl, difluoroethyl, trifluoroethyl, cyclopropyl, methoxy, ethoxy, propoxy, trifluoromethoxy, trifluoroethoxy, methoxymethyl, and trifluoromethoxymethyl. In another aspect, the heterocyclyl ring R ² is optionally substituted with one or more substituents independently selected from the group consisting of fluoro, hydroxy, methyl, ethyl, propyl, fluoromethyl, difluoromethyl, trifluoromethyl, fluoroethyl, difluoroethyl, trifluoroethyl, cyclopropyl, methoxy, ethoxy, trifluoromethoxy, trifluoroethoxy, and methoxymethyl.

In some embodiments, the compounds and pharmaceutically acceptable salts are selected from the group consisting of (7?)-2Y-(2-(4-cyanothiazolidin-3-yl)-2-oxoethyl)-6-(pyridin-3-yl)quinoline-4-carboxamide (Example 126);

(7?)-2U-(2-(4-cyanothiazolidin-3-yl)-2-oxoethyl)-6-(2-methylpyridin-3-yl)quinolin-4carboxamide (Example 128);

(7?)-2U-(2-(4-cyanothiazolidin-3-yl)-2-oxoethyl)-6-(6-(difluoromethyl)pyridin-3-yl)quinolin-4-carboxamide (Example 169);

(7?)-2U-(2-(4-cyanothiazolidin-3-yl)-2-oxoethyl)-6-(6-methylpyridin-3-yl)quinolin-4carboxamide (Example 177);

(7?)-?/-(2-(4-cyanothiazolidin-3-yl)-2-oxoethyl)-6-(6-methoxypyridin-3-yl)quinoline-4-carboxamide (Example 178) and their pharmaceutically acceptable salts.

In some embodiments, the heterocyclyl ring R ² is

wherein the heterocyclyl ring R ² is optionally substituted with one or more substituents independently selected from the group consisting of halogen, hydroxy, C _1-6 alkyl, hydroxy-C _1-3 alkyl, C _3-6 cycloalkyl, C _1-6 alkoxy, C _1-3 alkoxy-C _1-3 alkyl, C _1-3 alkoxy-C _2-3 alkoxy and C _{1_3} alkoxy-C _{2_3} alkoxyC _1-3 alkyl, and wherein _the C _1-6 alkyl, C _3-6 cycloalkyl, C _1-6 alkoxy, 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 may be further substituted by one or more atoms

- 24 048482 mi halogen. In one aspect, the heterocyclyl ring R ² is optionally substituted with one or more substituents independently selected from the group consisting of fluoro, hydroxy, C _1-3 alkyl, hydroxy-C _1-3 alkyl, cyclopropyl, C _1-3 alkoxy and C _1-3 alkoxy-C _1-3 alkyl, wherein C _1-3 alkyl, cyclopropyl, C _1-3 αalkoxy and C _1-3 alkoxy-C _1-3 alkyl may be further substituted with one or more fluoro atoms. In another aspect, the heterocyclyl ring R ² is optionally substituted with one or more substituents independently selected from the group consisting of fluoro, hydroxy, methyl, ethyl, propyl, fluoromethyl, difluoromethyl, trifluoromethyl, hydroxymethyl, fluoroethyl, difluoroethyl, trifluoroethyl, cyclopropyl, methoxy, ethoxy, propoxy, trifluoromethoxy, trifluoroethoxy, methoxymethyl, and trifluoromethoxymethyl. In another aspect, the heterocyclyl ring R ² is optionally substituted with one or more substituents independently selected from the group consisting of fluoro, hydroxy, methyl, ethyl, propyl, fluoromethyl, difluoromethyl, trifluoromethyl, fluoroethyl, difluoroethyl, trifluoroethyl, cyclopropyl, methoxy, ethoxy, trifluoromethoxy, trifluoroethoxy, and methoxymethyl.

In some embodiments, the compound or pharmaceutically acceptable salt is (R)-N-(2-(4-cyanothiazolidin-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.

In some embodiments, the heterocyclyl ring R ² is

wherein the heterocyclyl ring R ² is optionally substituted with one or more substituents independently selected from the group consisting of halogen, hydroxy, C1-6alkyl, hydroxy-C1-3alkyl, C3-6cycloalkyl, C1-6alkoxy, C1-3alkoxy-C1-3αalkyl, C1-3alkoxy-C2-3alkoxy and C1-3alkoxy-C2-3alkoxyC1-3alkyl, and wherein the C1-6alkyl, C3-6cycloalkyl, C1-6alkoxy, C1-3alkoxy-C1-3alkyl, C1-3alkoxy-C2-3alkoxy and C1-3αalkoxy-C2-3alkoxy-C1-3alkyl may be further substituted with one or more halogen atoms. In one aspect, the heterocyclyl ring R ² is optionally substituted with one or more substituents independently selected from the group consisting of fluoro, hydroxy, _C1-3alkyl , _hydroxy -C1-3alkyl, cyclopropyl, C1-3alkoxy and _C1-3alkoxy - _C1-3alkyl , wherein _C1-3alkyl , cyclopropyl, _C1-3alkoxy and _C1-3alkoxy - _C1-3alkyl may be further substituted with one or more fluoro atoms. In another aspect, the heterocyclyl ring R ² is optionally substituted with one or more substituents independently selected from the group consisting of fluoro, hydroxy, methyl, ethyl, propyl, fluoromethyl, difluoromethyl, trifluoromethyl, hydroxymethyl, fluoroethyl, difluoroethyl, trifluoroethyl, cyclopropyl, methoxy, ethoxy, propoxy, trifluoromethoxy, trifluoroethoxy, methoxymethyl, and trifluoromethoxymethyl. In another aspect, the heterocyclyl ring R ² is optionally substituted with one or more substituents independently selected from the group consisting of fluoro, hydroxy, methyl, ethyl, propyl, fluoromethyl, difluoromethyl, trifluoromethyl, fluoroethyl, difluoroethyl, trifluoroethyl, cyclopropyl, methoxy, ethoxy, trifluoromethoxy, trifluoroethoxy, and methoxymethyl.

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

In some embodiments, the compounds and pharmaceutically acceptable salts are selected from the group consisting of

- 25 048482

7U-(2-((7?)-4-cyanothiazolidin-3-yl)-2-oxoethyl)-6-((35,45,57?)-4-hydroxy-3,5dimethylpiperidin-1-yl)quinoline -4-carboxamide (example 7);

(7?)-^-(2-(4-cyanothiazolidin-3-yl)-2-oxoethyl)-6-(4-methoxypiperidin-1 -yl)-quinoline4-carboxamide (example 8);

(7?)-^-(2-(4-cyanothiazolidin-3-yl)-2-oxoethyl)-6-(2-oxopyrrolidin-1-yl)quinoline-4-carboxamide (example I);

(7?)-7U-(2-(4-cyanothiazolidin-3-yl)-2-oxoethyl)-6-(3,3-dimethyl-2-oxopyrrolidin-1 yl)quinoline-4-carboxamide (example 12) ;

(7?)-7U-(2-(4-cyanothiazolidin-3-yl)-2-oxoethyl)-6-(2-oxopiper idin-1-yl)quinoline-4carboxamide (example 14);

(7?)-?7-(2-(4-cyanothiazolidin-3-yl)-2-oxoethyl)-6-(3,3-dimethyl-2-oxopiperidin-1 -yl)quinolin-4-carboxamide (example 15);

(7?)-7U-(2-(4-cyanothiazolidin-3-yl)-2-oxoethyl)-6-(2,2-dimethylazetidin-1-yl)-quinoline 4-carboxamide (Example 20);

(7?)-7U-(2-(4-cyanothiazolidin-3-yl)-2-oxoethyl)-6-(3-fluoroazide-1-yl)quinoline-4-carboxamide (example 21);

(7?)-7U-(2-(4-cyanothiazolidin-3-yl)-2-oxoethyl)-6-(3,3-dimethylazetidin-1-yl)-quinoline4-carboxamide (example 22);

(7?)-7U-(2-(4-cyanothiazolidin-3-yl)-2-oxoethyl)-6-(3,3-difluoroazetidin-1-yl)-quinoline4-carboxamide (example 23);

(7?)-7U-(2-(4-cyanothiazolid in-3-yl)-2-oxoethyl)-6-(3-fluoro-3-methylazetidin-1-yl)quinolin-4-carboxamide (example 24) ;

(7?)-7U-(2-(4-cyanothiazolidin-3-yl)-2-oxoethyl)-6-(3-methylazethidin-1-yl)quinoline-4-carboxamide (example 25);

(7?)-7U-(2-(4-cyanothiazolidin-3-yl)-2-oxoethyl)-6-(3-(trifluoromethyl)azetidin-1-yl)quinolin-4-carboxamide (Example 26);

- 26 048482 (/?)-LC2-(4-cyanothiazol id in-3-yl)-2-oxoethyl)-6-(3-(fluoromethyl)-3-methylazetidin-1 yl)quinoline-4-carboxamide (example 27);

(7?)-7U-(2-(4-cyanothiazolidin-3-yl)-2-oxoethyl)-6-(3-(difluoromethyl)azetidin-1-yl)quinolin-4-carboxamide (Example 28);

(7?)-7U-(2-(4-cyanothiazolidin-3-yl)-2-oxoethyl)-6-(3-(methoxymethyl)-3-methylase etidin1-yl)quinolin-4-carboxamide (example 29) ;

7U-(2-((7?)-4-cyanothiazolidin-3-yl)-2-oxoethyl)-6-((25.37?)-3-methoxy-2-methylazetidin1-yl)quinoline-4-carboxamide (example 30);

(7?)-7U-(2-(4-cyanothiazolidin-3-yl)-2-oxoethyl)-6-(3-cyclopropyl-3-fluoroazetidin-1 yl)quinoline-4-carboxamide (Example 31);

(7?)-7U-(2-(4-cyanothiazolidin-3-yl)-2-oxoethyl)-6-(piperidin-1-yl)quinoline-4carboxamide (Example 32);

(7?)-7U-(2-(4-cyanothiazolid in-3-yl)-2-oxoethyl)-6-(4,4-dimethylpiperidin-1-yl)quinolin-4-carboxamide (Example 33);

(7?)-7U-(2-(4-cyanothiazolid in-3-yl)-2-oxoethyl)-6-(4-fluoro-4-methylpiper idin-1 yl)quinoline-4-carboxamide (example 34) ;

(7?)-7U-(2-(4-cyanothiazolid in-3-yl)-2-oxoethyl)-6-(4,4-difluoropiperidin-1-yl)quinoline-4-carboxamide (Example 35);

(7?)-7U-(2-(4-cyanothiazolidin-3-yl)-2-oxoethyl)-6-(3,3-difluoropiperidin-1-yl)quinolin-4-carboxamide (Example 36);

(7?)-7U-(2-(4-cyanothiazolid in-3-yl)-2-oxoethyl)-6-(4-(fluoromethyl)-4-methylpiper idin-1 yl)quinoline-4-carboxamide ( example 37);

(7?)-7U-(2-(4-cyanothiazolid in-3-yl)-2-oxoethyl)-6-(4,4-difluoro-3,3-dimethylpiperidin1-yl)quinoline-4-carboxamide ( example 38);

(7?)-7U-(2-(4-cyanothiazolid in-3-yl)-2-oxoethyl)-6-(4-(trifluoromethyl)piperidin-1-yl)quinoline-4-carboxamide (example 39 );

7U-(2-((7?)-4-cyanothiazolide yn-3-yl)-2-oxoethyl)-6-(3-fluoropiperidin-1-yl)quinoline-4-carboxamide (example 40);

L ^g -(2-((7?)-4-cyanothiazolid in-3 -yl)-2-oxoethyl)-6-(3-methoxypiperidin-1 -yl)-quinoline 4-carboxamide (example 41);

(7?)-7U-(2-(4-cyanothiazolidin-3-yl)-2-oxoethyl)-6-(4-methoxy-4-methylpiperidin-1yl)quinoline-4-carboxamide (Example 42);

(7?)-U-(2-(4-cyanothiazolidin-3-yl)-2-oxoethyl)-6-(4-isopropoxypiperidin-1-yl)quinoline-4-carboxamide (Example 43);

- 27 048482

LC2-((/?)-4-cyanothiazolid in-3-yl)-2-oxoethyl)-6-(4,4-difluoro-2-methylpiper idin-1 yl)quinoline-4-carboxamide (example 44);

7U-(2-((7?)-4-cyanothiazolid in-3-yl)-2-oxoethyl)-6-((5)-2-(fluoromethyl)piperidin-1 yl)quinoline-4-carboxamide (example 45);

(7?)-7U-(2-(4-cyanothiazolidin-3-yl)-2-oxoethyl)-6-(3,3-difluoropyrrolidin-1-yl)quinolin-4-carboxamide (Example 47);

(7?)-7U-(2-(4-cyanothiazolidin-3-yl)-2-oxoethyl)-6-(3,3-dimethylpyrrolidin-1-yl)quinolin-4-carboxamide (Example 48);

^-(2-((7?)-4-cyanothiazolidin-3-yl)-2-oxoethyl)-6-((37?, 45)-3,4-difluoropyrrolidin-1yl)quinoline-4-carboxamide (example 50);

^-(2-((7?)-4-cyanothiazolid in-3-yl)-2-oxoethyl)-6-((5)-3-fluoropyrrolide in-1 -yl)quinoline-4-carboxamide (example 51 );

^-(2-((7?)-4-cyanothiazolid in-3 -yl)-2-oxoethyl)-6-((7?)-3-fluoropyrrolide in-1 -yl)quinoline-4-carboxamide (example 52);

7U-(2-((7?)-4-cyanothiazolidin-3-yl)-2-oxoethyl)-6-(hexahydrocyclopenta[c]pyrrol2(1R)-yl)quinolin-4-carboxamide (example 53);

7U-(2-((7?)-4-cyanothiazolid in-3 -yl)-2-oxoethyl)-6-((5)-3 -methylpyrrolidin-1 -yl)quinoline-4-carboxamide (example 54) ;

7U-(2-((7?)-4-cyanothiazolid in-3 -yl)-2-oxoethyl)-6-((7?)-3 -methylpyrrolidin-1 -yl)quinoline-4-carboxamide (example 55 );

7U-(2-((7?)-4-cyanothiazolid in-3-yl)-2-oxoethyl)-6-((5)-2-(trifluoromethyl)pyrrolidin-1 yl)quinoline-4-carboxamide (example 56);

(7?)-7U-(2-(4-cyanothiazolidin-3-yl)-2-oxoethyl)-6-(2,2-dimethylpyrrolidin-1-yl)quinoline-4-carboxamide (Example 57);

7U-(2-((7?)-4-cyanothiazolid in-3 -yl)-2-oxoethyl)-6-((7?)-3-fluoroazepan-1 -yl)quinoline-4carboxamide (example 59);

7U-(2-((7?)-4-cyanothiazolid in-3-yl)-2-oxoethyl)-6-((5)-3-fluoroazepan-1-yl)quinoline-4carboxamide (Example 60);

A-(2-((7?)-4-cyanothiazolid in-3-yl)-2-oxoethyl)-6-((5)-2-methylpyrrolidin-1 -yl)quinoline-4-carboxamide (example 65) ;

(7?)-7U-(2-(4-cyanothiazolidin-3-yl)-2-oxoethyl)-6-(3-methoxyase etidin-1-yl)quinolin-4 carboxamide (Example 66);

(7?)-?/-(2-(4-cyanothiazolidin-3-yl)-2-oxoethyl)-6-(3-(fluoromethyl)azetidin-1-yl)quinolin-4-carboxamide (example IZ);

- 28 048482 (A)-A-(2-(4-cyanothiazolidin-3-yl)-2-oxoethyl)-6-(4,5,6,7-tetrahydro-III-ind azol-1yl)quinoline-4 -carboxamide (example 114);

(7?)-7U-(2-(4-cyanothiazolidin-3-yl)-2-oxoethyl)-6-(4,5,6,7-tetrahydro-2H-indazol-2yl)quinoline-4-carboxamide ( example 115);

(A)-7U-(2-(4-cyanothiazolidin-3-yl)-2-oxoethyl)-6-(5-methyl-3-(trifluoromethyl)-177pyrazol-1-yl)quinoline-4-carboxamide (example 116);

(7?)-7U-(2-(4-cyanothiazolidin-3-yl)-2-oxoethyl)-6-(6,6-dimethyl-5,6dihydrocyclopenta[c]pyrazol-2(477)-yl)quinoline -4-carboxamide (example 117);

(/?)-L-(2-(4-cyanothiazolyl-3-yl)-2-oxoethyl)-6-(3-(trifluoromethyl)-1H-pyrazol-1-yl)quinoline-4-carboxamide (Example 118);

(7?)-7U-(2-(4-cyanothiazolidin-3-yl)-2-oxoethyl)-6-(4,6-difluoro-177-indol-1-yl)-quinoline 4-carboxamide (example 119);

(7?)-7U-(2-(4-cyanothiazolidin-3-yl)-2-oxoethyl)-6-(5-fluoro-177-indol-1-yl)quinoline-4-carboxamide (example 120);

(7?)-A-(2-(4-cyanothiazolidin-3-yl)-2-oxoethyl)-6-(3-methyl-177-pyrrol-1-yl)-quinoline-4-carboxamide (example 121);

(7?)-A-(2-(4-cyanothiazolidin-3-yl)-2-oxoethyl)-6-(3-morpholinoase etidin-1-yl)quinoline-4-carboxamide (Example 122);

(7?)-7U-(2-(4-cyanothiazolidin-3-yl)-2-oxoethyl)-6-(5,5-dimethyl-5,6-dihydro-477pyrrolo[1,2-th]pyrazol- 3-yl)quinoline-4-carboxamide (Example 123);

(7?)-7U-(2-(4-cyanothiazolidin-3-yl)-2-oxoethyl)-6-(2-fluoropyridin-4-yl)quinoline-4carboxamide (Example 124);

(7?)-7U-(2-(4-cyanothiazolidin-3-yl)-2-oxoethyl)-6-(5-fluoropyridin-2-yl)quinoline-4carboxamide (Example 125);

(7?)-7U-(2-(4-cyanothiazolidin-3-yl)-2-oxoethyl)-6-(pyridin-3-yl)quinoline-4carboxamide (Example 126);

(7?)-7U-(2-(4-cyanothiazolidin-3-yl)-2-oxoethyl)-6-(pyrimidin-5-yl)quinoline-4-carboxamide (example 127);

7?)-A-(2-(4-cyanothiazolidin-3-yl)-2-oxoethyl)-6-(2-methylpyridin-3-yl)quinolin-4carboxamide (Example 128);

(7?)-A-(2-(4-cyanothiazolidin-3-yl)-2-oxoethyl)-6-(1-methyl-1R-pyrazol-4-yl)-quinoline4-carboxamide (Example 129);

(7?)-7U-(2-(4-cyanothiazolidin-3-yl)-2-oxoethyl)-6-(3-((trifluoromethoxy)methyl)azetidin-1-yl)quinolin-4-carboxamide (example 130 );

- 29 048482 (/?)-LC2-(4-cyanothiazol ide in-3-yl)-2-oxoethyl)-6-(3-methyl-3-(2,2,2-trifluoroethyl)azetidin-1-yl )quinoline-4-carboxamide (example 131);

(7?)-7U-(2-(4-cyanothiazolidin-3-yl)-2-oxoethyl)-6-(3-(trifluoro-methoxy)azetidin-1yl)quinoline-4-carboxamide (Example 132);

(7?)-7U-(2-(4-cyanothiazolidin-3-yl)-2-oxoethyl)-6-(3-(2,2-difluoroethyl)-3-methylase etidin1-yl)quinoline-4-carboxamide (example 133);

(7?)-7U-(2-(4-cyanothiazolid in-3-yl)-2-oxoethyl)-6-(3-cyclopropyl-3-methylazetidin-1 yl)quinoline-4-carboxamide (Example 134);

(/f-L--(2-(4-cyanothiazolide and n-3-yl)-2-oxoethyl)-6-(3-(difluoromethyl)-3-methylazetidin-1 yl)quinoline-4-carboxamide ( example 135);

(7?)-7U-(2-(4-cyanothiazolidin-3-yl)-2-oxoethyl)-6-(3-(difluoromethoxy)azetidin-1-yl)quinolin-4-carboxamide (Example 136);

(7?)-7U-(2-(4-cyanothiazolid in-3-yl)-2-oxoethyl)-6-(3-ethyl-3-methylazetidin-1-yl)quinolin-4-carboxamide (Example 137) ;

(7?)-7U-(2-(4-cyanothiazolid in-3-yl)-2-oxoethyl)-6-(3-ethyl-3-fluoroazetidin-1-yl)quinoline-4-carboxamide (Example 138) ;

(7?)-7U-(2-(4-cyanothiazolidin-3-yl)-2-oxoethyl)-6-(3-(2,2-difluoropropyl)azetidin-1yl)quinoline-4-carboxamide (Example 140) ;

(7?)-7U-(2-(4-cyanothiazolidin-3-yl)-2-oxoethyl)-6-(3 -(3,3,3-trifluoropropyl)azetidin-1 yl)quinoline-4-carboxamide (example 142);

(7?)-7U-(2-(4-cyanothiazolidin-3-yl)-2-oxoethyl)-6-(3-fluoro-3-(trifluoromethyl)-azetidin1-yl)quinoline-4-carboxamide (example 143 );

(7?)-7U-(2-(4-cyanothiazolidin-3-yl)-2-oxoethyl)-6-(3-(2,2-difluoroethyl)azetidin-1-yl)quinoline-4-carboxamide (example 144);

(7?)-7U-(2-(4-cyanothiazolidin-3-yl)-2-oxoethyl)-6-(3-cyclopropyl az etidin-1-yl)quinolin-4-carboxamide (Example 145);

(7?)-7U-(2-(4-cyanothiazolidin-3-yl)-2-oxoethyl)-6-(3-(2-fluoroethyl)azetidin-1-yl)quinoline-4-carboxamide (Example 146) ;

(7?)-tU-(2-(4-cyanothiazolid in-3 -yl)-2-oxoethyl)-6-(3 -(1,1-d iforoethyl)azetide in-1 -yl)quinoline-4- carboxamide (example 147);

(7?)-7U-(2-(4-cyanothiazolidin-3-yl)-2-oxoethyl)-6-(3-isopropyl ethyl ...

(7?)-7U-(2-(4-cyanothiazolid in-3 -yl)-2-oxoethyl)-6-(3-methoxy-3-methylazetidin-1 -yl)quinolin-4-carboxamide (Example 151) ;

- 30 048482 (A)-A-(2-(4-cyanothiazolidin-3-yl)-2-oxoethyl)-6-(3-ethoxy-3-methylase etidin-1-yl)quinolin-4-carboxamide (example 152);

(A)-A -(2-(4-cyanothiazol id in-3 -yl)-2-oxoethyl)-6-(3-ethyl-3-hydroxyazetidin-1 -yl)quinolin-4-carboxamide (Example 154) ;

6-(6-azabicyclo[3.2.0]heptan-6-yl)-7U-(2-((A)-4-cyanothiazolidin-3-yl)-2-oxoethyl)quinoline-4-carboxamide (Example 156) ;

(A)-A -(2-(4-cyanothiazol id in-3-yl)-2-oxoethyl)-6-(3-fluoro-3-(fluoromethyl)azetidin-1 yl)quinoline-4-carboxamide (example 157);

(A)-A-(2-(4-cyanothiazolidin-3-yl)-2-oxoethyl)-6-(3-(2,2,2-trifluoroethyl)azetidin-1yl)quinoline-4-carboxamide (Example 158 );

7U-(2-((A)-4-cyanothiazolidin-3-yl)-2-oxoethyl)-6-(3,3-d-ifluoro-2-methylazetidin-1-yl)quinoline-4-carboxamide (Example 159);

7U-(2-((A)-4-cyanothiazolidin-3-yl)-2-oxoethyl)-6-(6,6-difluoro-3azabicyclo[3.1.0]hexan-3-yl)quinoline-4-carboxamide (example 160);

7U-(2-((A)-4-cyanothiazolid in-3 -yl)-2-oxoethyl)-6-((A)-3 -methoxypyrrolidin-1 -yl)quinoline-4-carboxamide (Example 161);

(A)-A-(2-(4-cyanothiazol ide-3-yl)-2-oxoethyl)-6-(3-hydroxy-3-methylazetidin-1-yl)quinoline-4-carboxamide (Example 165);

7U-(2-((A)-4-cyanothiazolidin-3-yl)-2-oxoethyl)-6-((A)-3-hydroxy-3-methylpyrrolidin-1-yl)quinoline-4-carboxamide (example 167);

7U-(2-((A)-4-cyanothiazolide yn-3-yl)-2-oxoethyl)-6-((A)-3-hydroxy-3-methylpyrrolidin-1-yl)quinoline-4-carboxamide (example 168);

(A)-7Y-(2-(4-cyanothiazolidin-3-yl)-2-oxoethyl)-6-(6-(difluoromethyl)pyridin-3-yl)quinolin-4-carboxamide (Example 169);

(A)-A-(2-(4-cyanothiazolidin-3-yl)-2-oxoethyl)-6-(1-cyclopropyl-1//-pyrazol-4-yl)quinolin-4-carboxamide (Example 170) ;

(A)-A-(2-(4-cyanothiazolid in-3-yl)-2-oxoethyl)-6-(1,3-dimethyl-1//-pyrazol-4-yl)quinolin-4-carboxamide ( example 171);

(A)-A-(2-(4-cyanothiazolyl-3-yl)-2-oxoethyl)-6-(3,5-dimethyl-1-(tetrahydro-2//pyran-4-yl)-I//-pyrazol-4-yl)quinoline-4-carboxamide (Example 172);

(A)-A -(2-(4-cyanothiazolide in-3-yl)-2-oxoethyl)-6-(1-(tetrahydro-2//-pyran-4-yl)-1//pyrazol- 4-yl)quinoline-4-carboxamide (Example 173);

(A)-A-(2-(4-cyanothiazolidin-3-yl)-2-oxoethyl)-6-(1-methyl-1//-pyrazol-5-yl)-quinoline4-carboxamide (Example 174);

- 31 048482 (7?)-7U-(2-(4-cyanothiazolidin-3-yl)-2-oxoethyl)-6-(5,6,7,8-tetrahydroimidazo[1,2-a]pyridin-3 -yl)quinoline-4-carboxamide (Example 175);

7U-(2-((7?)-4-cyanothiazolidin-3-yl)-2-oxoethyl)-6-(1 -(tetrahydro-2//-pyran-2-yl)-1Hpyrazol-5-yl) quinoline-4-carboxamide (Example 176);

(7?)-7U-(2-(4-cyanothiazolidin-3-yl)-2-oxoethyl)-6-(6-methylpyridin-3-yl)quinolin-4carboxamide (Example 177);

(7?)-7U-(2-(4-cyanothiazolidin-3-yl)-2-oxoethyl)-6-(6-methoxypyridin-3-yl)quinoline-4-carboxamide (example 178);

(7?)-6-(3 -(acetamidomethyl)-3-methylazetidin-1 -yl)-?/-(2-(4-cyanothiazolid in-3 -yl)-2oxoethyl)quinoline-4-carboxamide (example 181 );

(7?)-7U-(2-(4-cyanothiazolidin-3-yl)-2-oxoethyl)-6-(3-fluoro-3-phenylazetidin-1-yl)quinolin-4-carboxamide (Example 182);

(7?)-7U-(2-(4-cyanothiazolidin-3-yl)-2-oxoethyl)-6-(3-(and-tolyl)azetidin-1-yl)quinolin-4 carboxamide (example 183) ;

(/?)-L-(2-(4-cyanothiazolid in-3-yl)-2-oxoethyl)-6-(3-(4-fluorophenyl)az etidin-1-yl)quinolin-4-carboxamide (example 185);

(7?)-7U-(2-(4-cyanothiazolidin-3-yl)-2-oxoethyl)-6-(3-(l/-tolyl)azetidin-1-yl)quinoline4-carboxamide (Example 186);

(/?)-6-(3-(4-chlorobenzyl)azetidin-1-yl)-L-(2-(4-cyanothiazolidin-3-yl)-2-oxoethyl)quinoline-4-carboxamide (Example 187) ;

(7?)-7U-(2-(4-cyanothiazolidin-3-yl)-2-oxoethyl)-6-(3-methyl-3-((methylsulfonyl)methyl)azetidin-1-yl)quinoline-4- carboxamide (example 188);

(7?)-7U-(2-(4-cyanothiazolidin-3-yl)-2-oxoethyl)-6-(4-ethyl-4-hydroxypiperidin-1 -yl)quinolin-4-carboxamide (Example 189);

(/?)-L-(2-(4-cyanothiazolidin-3-yl)-2-oxoethyl)-6-(4-hydroxy-4-methylpiperidin-1 yl)quinoline-4-carboxamide (Example 190);

(7?)-7U-(2-(4-cyanothiazolidin-3-yl)-2-oxoethyl)-6-(4-ethyl-4-methoxypiperidin-1 -yl)quinolin-4-carboxamide (Example 191);

(7?)-?/-(2-(4-cyanothiazolidin-3-yl)-2-oxoethyl)-6-(4-hydroxy-4-isopropylpiperidin1-yl)quinoline-4-carboxamide (Example 192);

7U-(2-((7?)-4-cyanothiazolidin-3-yl)-2-oxoethyl)-6-((37?,45,56)-4-hydroxy-3,4,5-trimethylpiperidin-1-yl)quinoline-4-carboxamide (example 193);

(7?)-7U-(2-(4-cyanothiazolidin-3-yl)-2-oxoethyl)-6-(4-fluoro-1-methylpiperidin-4-yl)quinolin-4-carboxamide (Example 195);

- 32 048482 (L ^> )-L-(2-(4-cyanothiazolidin-3-yl)-2-oxoethyl)-6-(17/-pyrazol-5-yl)quinoline-4-carboxamide (example 196);

(7?)-7U-(2-(4-cyanothiazolidin-3-yl)-2-oxoethyl)-6-(1-isopropyl-3-pyrazol-5-yl)quinoline-4-carboxamide (example 197);

A-(2-((7?)-4-cyanothiazolide yn-3-yl)-2-oxoethyl)-6-((N$)-3-fluoro-3-methylpyrrolide yn-1-yl)quinoline-4-carboxamide (example 198);

7U-(2-((7?)-4-cyanothiazolidin-3-yl)-2-oxoethyl)-6-((7?*)-2-cyclopropylpyrrolidin-1yl)quinoline-4-carboxamide, isomer 1 (example 199);

7U-(2-((7?)-4-cyanothiazolidin-3-yl)-2-oxoethyl)-6-((7?*)-2-cyclopropylpyrrolidin-1yl)quinoline-4-carboxamide, isomer 2 (example 200);

7U-(2-((7?)-4-cyanothiazolidin-3-yl)-2-oxoethyl)-6-((7?*)-3-methyl-2-oxopyrrolidin-1yl)quinoline-4-carboxamide, isomer 1 (example 201);

7U-(2-((7?)-4-cyanothiazolidin-3-yl)-2-oxoethyl)-6-((7?*)-3-methyl-2-oxopyrrolidin-1yl)quinoline-4-carboxamide, isomer 2 (example 202);

7U-(2-((7?)-4-cyanothiazolidin-3-yl)-2-oxoethyl)-6-((7?*)-3-methyl-2-oxopiperidin-1yl)quinoline-4-carboxamide, isomer 1 (example 203);

7U-(2-((7?)-4-cyanothiazolidin-3-yl)-2-oxoethyl)-6-((7?*)-3-methyl-2-oxopiperidin-1yl)quinoline-4-carboxamide, isomer 2 (example 204);

(7?)-A-(2-(4-cyanothiazolidin-3-yl)-2-oxoethyl)-6-(4-fluoropiper idin-1-yl)quinoline-4carboxamide (Example 205);

6-(3-azabicyclo[3.1.0]hexan-3-yl)-A-(2-((7?)-4-cyanothiazolidin-3-yl)-2-oxoethyl)quinoline-4-carboxamide (example 206 );

A-(2-((7?)-4-cyanothiazolid in-3-yl)-2-oxoethyl)-6-((5)-3-methoxypyrrolidin-1-yl)quinoline-4-carboxamide (example 207) ;

A-(2-((7?)-4-cyanothiazolide yn-3-yl)-2-oxoethyl)-6-((17?,55,67?)-6-(trifluoromethyl)-3 azabicyclo[3.1.0]hexan-3-yl)quinoline-4-carboxamide (example 208);

(7?)-6-(7-azabicyclo[2.2.1] heptan-7-yl)-7U-(2-(4-cyanothiazolid in-3 -yl)-2-oxoethyl)quinoline-4-carboxamide (example 209);

6-(2-azabicyclo[2.2.1] heptan-2-yl)-7U-(2-((7?)-4-cyanothiazolid in-3-yl)-2-oxoethyl)quinoline-4-carboxamide (example 210);

7U-(2-((7?)-4-cyanothiazolidin-3-yl)-2-oxoethyl)-6-((7?)-2-methylpyrrolidin-1-yl)quinolin-4-carboxamide (example 211) ;

7U-(2-((7?)-4-cyanothiazolidin-3-yl)-2-oxoethyl)-6-((5)-2-(methoxymethyl)pyrrolidin-1 yl)quinoline-4-carboxamide (example 212 );

- 33 048482

LC2-((/?)-4-cyanothiazolid in-3-yl)-2-oxoethyl)-6-((35.45)-3,4-difluoropyrrolidin-1yl)quinoline-4-carboxamide (Example 213);

7U-(2-((7?)-4-cyanothiazolidin-3-yl)-2-oxoethyl)-6-((37?,47?)-3,4-difluoropyrrolidin-1yl)quinoline-4-carboxamide ( example 214);

(/?)-L-(2-(4-cyanothiazolidin-3-yl)-2-oxoethyl)-6-(2-phenyl-III-imidazol-1-yl)quinoline-4-carboxamide (Example 217);

(7?)-7U-(2-(4-cyanothiazolid in-3-yl)-2-oxoethyl)-6-(3-phenyl-I R-p irrol-1-yl)-quinoline4-carboxamide (example 218 );

(/?)-L-(2-(4-cyanothiazolidin-3-yl)-2-oxoethyl)-6-(4,5,6,7-tetrahydro-III-indol-1yl)quinoline-4-carboxamide ( example 219);

L-(2-((7?)-4-cyanothiazolide in-3 -yl)-2-oxoethyl)-6-((7?)-3 -(hydroxymethyl)pyrrolid in-1 yl)quinoline-4- carboxamide (example 220);

L-(2-((7?)-4-cyanothiazol id in-3-yl)-2-oxoethyl)-6-((5)-3 -(hydroxymethyl)pyrrolidin-1 yl)quinoline-4-carboxamide ( example 221);

(A)-L-(2-(4-cyanothiazolid in-3-yl)-2-oxoethyl)-6-(4-fluoro-4-phenylpiper idin-1-yl)quinoline-4-carboxamide (Example 223) ;

L-(2-((7?)-4-cyanothiazol id in-3 -yl)-2-oxoethyl)-6-((7?5)-3,3-difluoro-4hydroxypyrrolidin-1-yl)quinolin- 4-carboxamide (example 224);

7U-(2-((7?)-4-cyanothiazolidin-3-yl)-2-oxoethyl)-6-((37?*,47?*)-3,4-dimethylpyrrolidin-1yl)quinoline-4- carboxamide, isomer 1 (example 225);

7U-(2-((7?)-4-cyanothiazolidin-3-yl)-2-oxoethyl)-6-((37?*,47?*)-3,4-dimethylpyrrolidin-1yl)quinoline-4- carboxamide, isomer 2 (example 226);

(7?)-7U-(2-(4-cyanothiazolidin-3-yl)-2-oxoethyl)-6-(4-oxopiperidin-1-yl)quinoline-4-carboxamide (Example 230) and their pharmaceutically acceptable salts.

In some embodiments, the compounds and pharmaceutically acceptable salts are selected from the group consisting of

-(2-((5)-4-cyanothiazolide i n-3-yl)-2-oxoethyl)-6-((3 5,45,57?)-4-hydroxy-3,5 dimethylpiperidin-1-yl)quinoline-4-carboxamide (example 7);

(5)-57-(2-(4-cyanothiazolidin-3-yl)-2-oxoethyl)-6-(4-methoxypiperidin-1-yl)-quinoline4-carboxamide (Example 8);

(R)-N-(2-(4-cyanothiazolyl-3-yl)-2-oxoethyl)-6-(3,3-dimethyl-2-oxopyrrolide-1-yl)quinoline-4-carboxamide (Example 12);

(R)-N-(2 -(4-cyanothiazolide in-3-yl)-2-oxoethyl)-6-(3,3-d imethyl-2-oxopiperid in-1 yl)quinoline-4-carboxamide ( example 15);

- 34 048482 (/?)-LC2-(4-cyanothiazol id in-3-yl)-2-oxoethyl)-6-(3,3-dimethylazetidin-1-yl)-quinoline4-carboxamide (example 22);

(7?)-7U-(2-(4-cyanothiazolid in-3-yl)-2-oxoethyl)-6-(3-fluoro-3-methylazetidin-1-yl)quinolin-4-carboxamide (example 24) ;

(7?)-7U-(2-(4-cyanothiazolid in-3-yl)-2-oxoethyl)-6-(3-(fluoromethyl)-3-methylazetidin-1 yl)quinoline-4-carboxamide (example 27 );

(7?)-7U-(2-(4-cyanothiazolidin-3-yl)-2-oxoethyl)-6-(3-(difluoromethyl)azetidin-1yl)quinoline-4-carboxamide (Example 28);

(7?)-7U-(2-(4-cyanothiazolidin-3-yl)-2-oxoethyl)-6-(3-(methoxymethyl)-3-methylase etidin1-yl)quinolin-4-carboxamide (example 29) ;

7U-(2-((7?)-4-cyanothiazolidin-3-yl)-2-oxoethyl)-6-((25.37?)-3-methoxy-2-methylazetidin1-yl)quinoline-4-carboxamide (example 30);

(7?)-7U-(2-(4-cyanothiazolid in-3-yl)-2-oxoethyl)-6-(3-cyclopropyl-3-fluoroazetidin-1 yl)quinoline-4-carboxamide (Example 31);

(7?)-7U-(2-(4-cyanothiazolidin-3-yl)-2-oxoethyl)-6-(piperidin-1-yl)quinoline-4carboxamide (Example 32);

(7?)-7U-(2-(4-cyanothiazolid in-3-yl)-2-oxoethyl)-6-(4-fluoro-4-methylpiper idin-1 yl)quinoline-4-carboxamide (example 34) ;

7U-(2-((7?)-4-cyanothiazolid in-3-yl)-2-oxoethyl)-6-(3-methoxypiperidin-1-yl)-quinoline4-carboxamide (example 41);

(7?)-7U-(2-(4-cyanothiazolidin-3-yl)-2-oxoethyl)-6-(4-methoxy-4-methylpiperidin-1yl)quinoline-4-carboxamide (Example 42);

(/?)-^(2-(4-cyanothiazole idyn-3-yl)-2-oxoethyl)-6-(4-isopropoxypiperidin-1-yl)quinoline-4-carboxamide (Example 43);

7U-(2-((7?)-4-cyanothiazolid in-3-yl)-2-oxoethyl)-6-((37?,45)-3,4-difluoropyrrolide in-1yl)quinoline-4-carboxamide (example 50);

7U-(2-((7?)-4-cyanothiazolid in-3 -yl)-2-oxoethyl)-6-((7?)-3-fluoropyrrolide in-1 -yl)quinoline-4-carboxamide (example 52);

(7?)-?/-(2-(4-cyanothiazolidin-3-yl)-2-oxoethyl)-6-(3-methoxyazethidin-1-yl)quinoline-4-carboxamide (example 66);

(7?)-7U-(2-(4-cyanothiazolidin-3-yl)-2-oxoethyl)-6-(3-(fluoromethyl)azetidin-1-yl)quinolin-4-carboxamide (example IZ);

(7?)-7U-(2-(4-cyanothiazolid in-3-yl)-2-oxoethyl)-6-(3-(diforomethyl)-3-methylazetidin-1 yl)quinoline-4-carboxamide (example 135);

- 35 048482 (/?)-LC2-(4-cyanothiazol id in-3-yl)-2-oxoethyl)-6-(3-ethyl-3-fluoroazetidin-1-yl)quinoline-4-carboxamide (example 138 );

(7?)-7U-(2-(4-cyanothiazolidin-3-yl)-2-oxoethyl)-6-(3-(2,2-difluoropropyl)azetidin-1yl)quinoline-4-carboxamide (Example 140) ;

(7?)-7U-(2-(4-cyanothiazolidin-3-yl)-2-oxoethyl)-6-(3-fluoro-3-(trifluoromethyl)-azetidin1-yl)quinoline-4-carboxamide (example 143 );

(7?)-7U-(2-(4-cyanothiazolid in-3-yl)-2-oxoethyl)-6-(3-(1,1-d iforoethyl)azetide in-1 yl)quinoline-4-carboxamide (example 147);

(7?)-U-(2-(4-cyanothiazolidin-3-yl)-2-oxoethyl)-6-(3-methoxy-3-methylazetidin-1 yl)quinoline-4-carboxamide (Example 151);

(7?)-7U-(2-(4-cyanothiazolid in-3 -yl)-2-oxoethyl)-6-(3-ethoxy-3-methyl azetide in-1 -yl)quinoline-4-carboxamide (example 152 );

(7?)-7U-(2-(4-cyanothiazolidin-3-yl)-2-oxoethyl)-6-(3-fluoro-3-(fluoromethyl)azetidin-1 yl)quinoline-4-carboxamide (example 157 );

7U-(2-((7?)-4-cyanothiazolid in-3-yl)-2-oxoethyl)-6-((7?)-3-methoxypyrrolidin-1-yl)quinoline-4-carboxamide (example 161 );

(7?)-7U-(2-(4-cyanothiazolide yn-3-yl)-2-oxoethyl)-6-(3-hydroxy-3-methylazetidin-1-yl)quinoline-4-carboxamide (Example 165);

(7?)-7U-(2-(4-cyanothiazolidin-3-yl)-2-oxoethyl)-6-(6-(difluoromethyl)pyridin-3-yl)quinolin-4-carboxamide (Example 169);

(7?)-7U-(2-(4-cyanothiazolid in-3-yl)-2-oxoethyl)-6-(3,5-dimethyl-1 -(tetrahydro-2//pyran-4-yl) -I//-pyrazol-4-yl)quinoline-4-carboxamide (Example 172);

(7?)-7U-(2-(4-cyanothiazolidin-3-yl)-2-oxoethyl)-6-(5,6,7,8-tetrahydroimidazo[1,2a]pyridin-3-yl)quinolin- 4-carboxamide (example 175);

(7?)-7U-(2-(4-cyanothiazolidin-3-yl)-2-oxoethyl)-6-(4-ethyl-4-hydroxypiperidin-1 yl)quinoline-4-carboxamide (Example 189);

(/?)-L-(2-(4-cyanothiazolidin-3-yl)-2-oxoethyl)-6-(4-hydroxy-4-methylpiperidin-1 yl)quinoline-4-carboxamide (Example 190);

(L)-(U-(2-(4-cyanothiazolidin-3-yl)-2-oxoethyl)-6-(4-fluoro-1-methylpiperidin-4-yl)quinolin-4-carboxamide (Example 195);

7U-(2-((7?)-4-cyanothiazolid in-3-yl)-2-oxoethyl)-6-((L$)-3-fluoro-3-methylpyrrolid in-1 yl)quinoline-4- carboxamide (example 198);

7U-(2-((7?)-4-cyanothiazolidin-3-yl)-2-oxoethyl)-6-((7?*)-3-methyl-2-oxopyrrolidin-1yl)quinoline-4-carboxamide, isomer 1 (example 201);

- 36 048482

LC2-((/?)-4-cyanothiazolidin-3-yl)-2-oxoethyl)-6-((7?*)-3-methyl-2-oxopyrrolidin-1 yl)quinoline-4-carboxamide, isomer 2 (example 202);

7U-(2-((7?)-4-cyanothiazolidin-3-yl)-2-oxoethyl)-6-((7?*)-3 -methyl-2-oxopiperidin-1 yl)quinoline-4-carboxamide , isomer 1 (example 203);

7U-(2-((7?)-4-cyanothiazolidin-3-yl)-2-oxoethyl)-6-((7?*)-3-methyl-2-oxopiperidin-1yl)quinoline-4-carboxamide, isomer 2 (example 204);

(7?)-7U-(2-(4-cyanothiazolidin-3-yl)-2-oxoethyl)-6-(4-fluoropiperidin-1-yl)quinoline-4carboxamide (Example 205);

7U-(2-((7?)-4-cyanothiazolid in-3 -yl)-2-oxoethyl)-6-((5)-3-methoxypyrrolidin-1 -yl)quinoline-4-carboxamide (example 207) ;

7U-(2-((7?)-4-cyanothiazolid in-3-yl)-2-oxoethyl)-6-((3£.45)-3,4-difluoropyrrolidin-1yl)quinoline-4-carboxamide ( example 213);

7U-(2-((7?)-4-cyanothiazolid in-3 -yl)-2-oxoethyl)-6-((5)-3 -(hydroxymethyl)pyrrolidin-1 yl)quinoline-4-carboxamide (example 221);

?/-(2-((7?)-4-cyanothiazolide in-3-yl)-2-oxoethyl)-6-((7?5)-3,3-difluoro-4-hydroxypyrrolidin-1-yl)quinoline-4-carboxamide (example 224) and their pharmaceutically acceptable salts.

B. R ² is a monocyclic or fused bicyclic heterocyclyl (nitrogen, oxygen (or sulfur), and carbon atoms in a ring)

In some embodiments, the present invention provides compounds characterized by the structure of Formulae (I), (II), (III-A), (III-B), (III-C), (III-D), (III-E), (IV), or (IV-A), and pharmaceutically acceptable salts thereof, wherein R ² is a heterocyclyl having a total of 5 to 10 ring atoms, wherein the heterocyclyl ring: (i) is a saturated, partially saturated, or fully unsaturated monocyclic or fused bicyclic ring, (ii) comprises: (a) one ring nitrogen atom and one ring oxygen atom, wherein the remaining ring atoms are carbon, or (b) one ring nitrogen atom and one ring sulfur atom, wherein the remaining ring atoms are carbon, and (iii) is optionally substituted with one or more substituents independently selected from the group consisting of halogen, cyano, oxo, C _{b 6} alkyl, C _3-6 cycloalkyl, C _1-6 alkoxy, C _1-3 alkoxy-C _1-3 alkyl, C _1-3 alkylcarbonyl-C _1-3 alkyl and C ₁₃ alkylsulfonyl-C _1-3 alkyl, and wherein the C _1-6 alkyl, C _3-6 cycloalkyl, C _1-6 alkoxy, 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 may be further substituted with one or more halogen atoms. In one aspect, the heterocyclyl ring R ² is a saturated monocyclic ring. In another aspect, the heterocyclyl ring R ² is a partially saturated monocyclic ring. In another aspect, the heterocyclyl ring R ² is a fully unsaturated monocyclic ring. In another aspect, the heterocyclyl ring R ² is a saturated fused bicyclic ring. In another aspect, the heterocyclyl ring R ² is a partially saturated fused bicyclic ring. In another aspect, the heterocyclyl ring R ^{2 is a fully unsaturated fused bicyclic ring. In another aspect, the heterocyclyl ring R 2 contains} one nitrogen atom in the ring and one oxygen atom in the ring, wherein the remaining atoms in the ring are carbon. In another aspect, the heterocyclyl ring R ² contains one nitrogen atom in the ring and one sulfur atom in the ring, wherein the remaining atoms in the ring are carbon.

In some embodiments, the heterocyclyl ring R ² contains a total of 6 to 10 ring atoms.

In some embodiments, the heterocyclyl ring R ² is selected from the group consisting of

- 37 048482

wherein the heterocyclyl ring is optionally substituted with one or more substituents independently selected from the group consisting of halogen, cyano, _C1-6 alkyl, _C3-6 cycloalkyl, _C1-6 alkoxy, _C1-3 alkoxy- _C1-3 alkyl, _C1-3 alkylcarbonyl- _C1-3 alkyl and _C1-3 alkylsulfonyl- _C1-3 alkyl, and wherein the _C1-6 alkyl, _C1-6 alkoxy, _C1-3 alkoxy- _C1-3 alkyl, _C3-6 cycloalkyl, _C1-3 alkylcarbonyl- _C1-3 alkyl and _C1-3 alkylsulfonyl- _C1-3 alkyl may be further substituted with one or more halogen atoms.

In some embodiments, the heterocyclyl ring R ² is selected from the group consisting of

wherein the heterocyclyl ring is optionally substituted with one or more substituents independently selected from the group consisting of halogen, cyano, _C1-6 alkyl, _C3-6 cycloalkyl, _C1-6 alkoxy, _{C1-3 α-} alkoxy- _C1-3 alkyl, C1-3 alkylcarbonyl- _C1-3 alkylα and _C1-3 alkylsulfonyl- _C1-3 alkyl, and wherein the _C1-6 alkyl, _C1-6 alkoxy, _C1-3 alkoxy- _C1-3 alkyl, _C3-6 cycloalkyl, _C1-3 alkylcarbonyl- _C1-3 alkyl and _C1-3 alkylsulfonyl- _C1-3 alkyl may be further substituted with one or more halogen atoms.

In some embodiments, the heterocyclyl ring R ² is selected from the group consisting of

wherein the heterocyclyl ring is optionally substituted with one or more substituents independently selected from the group consisting of halogen, cyano, _C1-6 alkyl, _C3-6 cycloalkyl, _C1-6 alkoxy, _C1-3 alkoxy- _C1-3 alkyl, _C1-3 alkylcarbonyl- _C1-3 alkyl and _C1-3 alkylsulfonyl- _C1-3 alkyl, and wherein the _C1-6 alkyl, _C3-6 cycloalkyl, _C1-6 alkoxy, _C1-3 alkoxy- _C1-3 alkyl, _C1-3 alkylcarbonyl- _C1-3 alkyl and _C1-3 alkylsulfonyl- _C1-3 alkyl may be further substituted with one or more halogen atoms.

- 38 048482

In some embodiments, the heterocyclyl ring R ² is optionally substituted with one or more substituents independently selected from the group consisting of _halogen , cyano, C _1-3 αalkylα, C _3-5 cycloalkyl, C _1-3 αalkoxy, C _1-3 alkoxy-C _1-3 alkyl, C _1-3 alkylcarbonyl- _{C 1-3} alkyl, and C _1-3 αalkylsulfonyl-C _1-3 alkyl, wherein C _1-3 alkyl, C _1-3 alkoxy, C _1-3 αalkoxy-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 may be further substituted with one or more halogen atoms.

In some embodiments, the heterocyclyl ring R ² is optionally substituted with 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, C _1-2 alkoxy-C _1-3 alkyl, C _1-2 alkylcarbonyl- _{C 1-2} alkyl, and C _1-2 αalkylsulfonyl-C _1-2 alkyl, wherein the C _1-2 alkyl, C _3-4 cycloalkyl, C _1-2 alkoxy, C _1-2 alkoxy-C _1-2 alkyl, C _1-2 αalkylcarbonyl-C _1-2 alkyl, and C _1-2 alkylsulfonyl-C _1-2 αalkyl may be further substituted with one or more halogen atoms.

In some embodiments, the heterocyclyl ring R ² is optionally substituted with one or more halogen atoms. In one aspect, the heterocyclyl ring R ² is optionally substituted with one or more fluorine atoms.

In some embodiments, the heterocyclyl ring R ² is optionally substituted with one or more C _1-3 alkyl, wherein the C _1-3 alkyl may be further substituted with one or more halogen atoms.

In some embodiments, the heterocyclyl ring R ² is optionally substituted with one or more C _3-6 cycloalkyl, wherein the C _3-6 cycloalkyl may be further substituted with one or more halogen atoms.

In some embodiments, the heterocyclyl ring R ² is optionally substituted with one or more C _1-3 alkoxy-C _1-3 alkyl, wherein the C _1-3 alkoxy-C _1-3 alkyl may be further substituted with one or more halogen atoms.

In some embodiments, the heterocyclyl ring R ² is optionally substituted with one or more C _1-3 alkylsulfonyl-C _1-3 alkyl, wherein the C _1-3 alkylsulfonyl-C _1-3 alkyl may be further substituted with one or more halogen atoms.

In some embodiments, the heterocyclyl ring R ² is optionally substituted with one or more substituents independently selected from the group consisting of cyano, fluoro, methyl, ethyl, propyl, isopropyl, cyclopropyl, fluoromethyl, difluoromethyl, trifluoromethyl, fluoroethyl, difluoroethyl, trifluoroethyl, trifluoropropyl, methoxy, ethoxy, isopropoxy, trifluoromethoxy, trifluoroethoxy, methoxymethyl, methoxyethyl, trifluoromethoxymethyl, and methylsulfonylmethyl.

In some embodiments, the heterocyclyl ring R ² is optionally substituted with one or more substituents independently selected from the group consisting of fluoro, methyl, ethyl, isopropyl, cyclopropyl, fluoromethyl, difluoropropyl, methoxy, and trifluoromethoxy.

In some embodiments, the heterocyclyl ring R ² is

wherein the heterocyclyl ring R ² is optionally substituted with one or more substituents independently selected from the group consisting of halogen, cyano, oxo, C1-6alkyl, C3-6cycloalkyl, C1-6alkoxy, C1-3alkoxy-C1-3alkyl, C1-3alkylcarbonyl-C1-3alkyl and C1-3alkylsulfonyl-C1-3alkyl, and wherein the C1-6alkyl, C3.6cycloalkyl, C1-6alkoxy, C1-3alkoxy-C1-3alkyl, C1-3alkylcarbonyl-C1-3alkyl and C1-3alkylsulfonyl-C1-3alkyl may be further substituted with one or more halogen atoms. In one aspect, the heterocyclyl ring R ² is optionally substituted with 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, C _1-3 alkoxy-C _1-3 αalkyl, C _1-3 alkylcarbonyl-C _1-3 alkyl and

C _1-3 alkylsulfonyl-C _1-3 alkyl, where C _1-3 alkyl, C _3-5 cycloalkyl, C _1-3 alkoxy, 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 may be further substituted with one or more halogen atoms. In another aspect, the heterocyclyl ring R ² is optionally substituted with one or more substituents independently selected from the group consisting of fluoro, 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, the heterocyclyl ring R ² is optionally substituted with one or more substituents independently selected from the group consisting of fluoro, methyl, ethyl, fluoromethyl, trifluoromethyl, difluoropropyl, methoxy, trifluoromethoxy, and methoxymethyl.

In some embodiments, the compounds and pharmaceutically acceptable salts are selected from the group consisting of

- 39 048482 (7?)-U-(2-(4-cyanothiazolidin-3-yl)-2-oxoethyl)-3-fluoro-6-morpholinoquinoline-4carboxamide (example 2);

(7?)-7U-(2-(4-cyanothiazolidin-3-yl)-2-oxoethyl)-6-(2,2-difluoromorpholino)quinoline-4carboxamide (example 4);

(7?)-7U-(2-(4-cyanothiazolidin-3-yl)-2-oxoethyl)-6-(2,2,6,6-tetrafluoromorpholino)quinoline-4-carboxamide (example 5);

(7?)-7U-(2-(4-cyanothiazolidin-3-yl)-2-oxoethyl)-8-methyl-6-morpholinoquinoline-4carboxamide (example 9);

(7?)-7U-(2-(4-cyanothiazolidin-3-yl)-2-oxoethyl)-7-methyl-6-morpholinoquinoline-4carboxamide (example 10);

(7?)-7U-(2-(4-cyanothiazolidin-3-yl)-2-oxoethyl)-6-(2,2-dimethyl-3-oxomorpholino)quinoline-4-carboxamide (Example 16);

(7?)-7U-(2-(4-cyanothiazolidin-3-yl)-2-oxoethyl)-6-morpholinoquinoline-4-carboxamide (Example 67);

7U-(2-((7?)-4-cyanothiazolidin-3-yl)-2-oxoethyl)-6-((27?,65)-2,6-dimethylmorpholino)quinoline-4-carboxamide (example 68) ;

7U-(2-((7?)-4-cyanothiazolidin-3-yl)-2-oxoethyl)-6-((7?)-2-(fluoromethyl)morpholino)quinoline-4-carboxamide (example 69);

M-(2-((K)-4-cyanothiazolidin-3-yl)-2-oxoethyl)-6-((2K,6K)-2,6-dimethylmorpholino)quinoline-4-carboxamide (Example 70);

7U-(2-((7?)-4-cyanothiazolidin-3-yl)-2-oxoethyl)-6-((5)-2-(fluoromethyl)morpholino)quinoline-4-carboxamide (Example 71);

7U-(2-((7?)-4-cyanothiazolidin-3-yl)-2-oxoethyl)-6-((7?)-2-methylmorpholino)-quinoline-4-carboxamide (example 72);

^-(2-((7?)-4-cyanothiazolidin-3-yl)-2-oxoethyl)-6-((7?)-2-(trifluoromethyl)morpholino)quinoline-4-carboxamide (example 73);

^-(2-((7?)-4-cyanothiazolidin-3-yl)-2-oxoethyl)-6-((5)-2-(trifluoromethyl)morpholino)quinoline-4-carboxamide (Example 74);

7U-(2-((7?)-4-cyanothiazolidin-3-yl)-2-oxoethyl)-6-((25.65)-2,6-dimethylmorpholino)quinoline-4-carboxamide (Example 78);

L ^g -(2-((7?)-4-cyanothiazolidin-3-yl)-2-oxoethyl)-6-((5)-2-methylmorpholino)-quinoline-4-carboxamide (example 80);

7U-(2-((7?)-4-cyanothiazolidin-3-yl)-2-oxoethyl)-6-((27?, 35)-2,3dimethylmorpholino)quinoline-4-carboxamide (example 81);

7U-(2-((7?)-4-cyanothiazolidin-3-yl)-2-oxoethyl)-6-((25.35)-2,3dimethylmorpholino)quinoline-4-carboxamide (Example 82);

- 40 048482

L-(2-((5)-4-cyanothiazolide in-3-yl)-2-oxoethyl)-6-((25.35)-2,3dimethylmorpholino)quinoline-4-carboxamide (Example 83);

,U-(2-((5)-4-cyanothiazolidin-3-yl)-2-oxoethyl)-6-((5*)-3-(trifluoromethyl)morpholino)quinoline-4-carboxamide, isomer 1 (example 84);

,U-(2-((5)-4-cyanothiazolidin-3-yl)-2-oxoethyl)-6-((5*)-3-(trifluoromethyl)morpholino)quinoline-4-carboxamide, isomer 2 (example 85);

5-(2-((5)-4-cyanothiazolid in-3-yl)-2-oxoethyl)-6-((25.55)-2,5dimethylmorpholino)quinoline-4-carboxamide (Example 87);

(5)-2Y-(2-(4-cyanothiazolidin-3-yl)-2-oxoethyl)-6-(2,2-dimethylmorpholino)-quinoline-4·carboxamide (Example 88);

5-(2-((5)-4-cyanothiazolidin-3-yl)-2-oxoethyl)-6-((5)-3-(methoxymethyl)morpholino)quinoline-4-carboxamide (Example 89);

5-(2-((5)-4-cyanothiazolid in-3-yl)-2-oxoethyl)-6-((35.55)-3,5 dimethylmorpholino)quinoline-4-carboxamide (Example 90);

7U-(2-((5)-4-cyanothiazolidin-3-yl)-2-oxoethyl)-6-((5)-2-((methylsulfonyl)methyl)morpholino)quinoline-4-carboxamide (Example 92) ;

5-(2-((5)-4-cyanothiazolidin-3-yl)-2-oxoethyl)-6-((5)-2-(methoxymethyl)morpholino)quinoline-4-carboxamide (Example 93);

5-(2-((5)-4-cyanothiazolidin-3-yl)-2-oxoethyl)-6-((5)-2-((methylsulfonyl)methyl)morpholino)quinoline-4-carboxamide (Example 94);

5-(2-((5)-4-cyanothiazolidin-3-yl)-2-oxoethyl)-6-((5)-3-(2-methoxyethyl)morpholino)quinoline-4-carboxamide (Example 95);

5-(2-((5)-4-cyanothiazolidin-3-yl)-2-oxoethyl)-6-((25.35)-3-(methoxymethyl)-2methylmorpholino)quinoline-4-carboxamide (Example 96) ;

5-(2-((5)-4-cyanothiazolide yn-3-yl)-2-oxoethyl)-6-((25,35)-3-(methoxymethyl)-2methylmorpholino)quinoline-4-carboxamide (Example 97);

7-bromo-5-(2-((5)-4-cyanothiazolidin-3-yl)-2-oxoethyl)-6-((35.55)-3,5 dimethylmorpholino)quinoline-4-carboxamide (example 100 );

(5)-5-chloro-tU-(2-(4-cyanothiazolidin-3-yl)-2-oxoethyl)-6-morpholinoquinoline-4carboxamide (Example 101);

7U-(2-((5)-4-cyanothiazolidin-3-yl)-2-oxoethyl)-6-((5)-3-methylmorpholino)-quinoline-4-carboxamide (example 102);

5-(2-((5)-4-cyanothiazolidin-3-yl)-2-oxoethyl)-6-((35.55)-3,5-dimethylmorpholino)quinoline-4-carboxamide (Example 103);

- 41 048482

L-(2-((7?)-4-cyanothiazol id in-3 -yl)-2-oxoethyl)-6-((37?,5R)-3,5-dimethylmorpholino)quinoline-4-carboxamide (example 105);

7U-(2-((7?)-4-cyanothiazolidin-3-yl)-2-oxoethyl)-6-((5)-3-ethylmorpholino)quinoline-4carboxamide (Example 106);

(7?)-7U-(2-(4-cyanothiazolidin-3-yl)-2-oxoethyl)-6-(3,3-dimethylmorpholino)-quinoline-4-carboxamide (example 107);

7U-(2-((7?)-4-cyanothiazolidin-3-yl)-2-oxoethyl)-6-((7?)-3-methylmorpholino)-quinoline-4-carboxamide (example 108);

(7?)-7U-(2-(4-cyanothiazolidin-3-yl)-2-oxoethyl)-2-methyl-6-morpholinoquinoline-4carboxamide (Example 109);

(7?)-7-chloro-L ^g -(2-(4-cyanothiazolidin-3-yl)-2-oxoethyl)-6-morpholinoquinoline-4carboxamide (Example 179);

(7?)-8-chloro-7U-(2-(4-cyanothiazolidin-3-yl)-2-oxoethyl)-6-morpholinoquinoline-4-carboxamide (Example 180) and their pharmaceutically acceptable salts.

In some embodiments, the compounds and pharmaceutically acceptable salts are selected from the group consisting of (7?)-7Y-(2-(4-cyanothiazolidin-3-yl)-2-oxoethyl)-8-methyl-6-morpholinoquinoline-4-carboxamide (Example 9);

(7?)-7U-(2-(4-cyanothiazolidin-3-yl)-2-oxoethyl)-6-morpholinoquinoline-4-carboxamide (Example 67);

7U-(2-((7?)-4-cyanothiazolidin-3-yl)-2-oxoethyl)-6-((27?,65)-2,6-dimethylmorpholino)quinoline-4-carboxamide (example 68) ;

7U-(2-((7?)-4-cyanothiazolidin-3-yl)-2-oxoethyl)-6-((7?)-2-(fluoromethyl)morpholino)quinoline-4-carboxamide (example 69);

7U-(2-((7?)-4-cyanothiazolidin-3-yl)-2-oxoethyl)-6-((27?,67?)-2,6-dimethylmorpholino)quinoline-4-carboxamide (example 70 );

7U-(2-((7?)-4-cyanothiazolidin-3-yl)-2-oxoethyl)-6-((5)-2-(fluoromethyl)morpholino)quinoline-4-carboxamide (Example 71);

7U-(2-((7?)-4-cyanothiazolidin-3-yl)-2-oxoethyl)-6-((7?)-2-methylmorpholino)-quinoline-4-carboxamide (example 72);

7U-(2-((7?)-4-cyanothiazolidin-3-yl)-2-oxoethyl)-6-((7?)-2-(trifluoromethyl)morpholino)quinoline-4-carboxamide (example 73);

L ^g -(2-((7?)-4-cyanothiazolidin-3-yl)-2-oxoethyl)-6-((5)-2-(trifluoromethyl)morpholino)quinoline-4-carboxamide (example 74);

- 42 048482

7U-(2-((7?)-4-cyanothiazolidin-3-yl)-2-oxoethyl)-6-((25.65)-2,6-dimethylmorpholino)quinoline-4-carboxamide (Example 78);

7U-(2-((7?)-4-cyanothiazolidin-3-yl)-2-oxoethyl)-6-((5)-2-methylmorpholino)-quinoline-4-carboxamide (example 80);

7U-(2-((7?)-4-cyanothiazolidin-3-yl)-2-oxoethyl)-6-((27?,35)-2,3-dimethylmorpholino)quinoline-4-carboxamide (example 81) ;

7U-(2-((7?)-4-cyanothiazolidin-3-yl)-2-oxoethyl)-6-((25.35)-2,3-dimethylmorpholino)quinoline-4-carboxamide (Example 82);

(7?)-7U-(2-(4-cyanothiazolidin-3-yl)-2-oxoethyl)-6-(2,2-dimethylmorpholino)-quinoline-4·carboxamide (Example 88);

7U-(2-((7?)-4-cyanothiazolidin-3-yl)-2-oxoethyl)-6-((5)-3-(methoxymethyl)morpholino)quinoline-4-carboxamide (Example 89);

7U-(2-((7?)-4-cyanothiazolidin-3-yl)-2-oxoethyl)-6-((5)-2-(methoxymethyl)morpholino)quinoline-4-carboxamide (Example 93);

7U-(2-((7?)-4-cyanothiazolide yn-3-yl)-2-oxoethyl)-6-((27?, 3R)-3-(methoxymethyl)-2methylmorpholino)quinoline-4-carboxamide (example 97);

?7-(2-((7?)-4-cyanothiazolidin-3-yl)-2-oxoethyl)-6-((5)-3-methylmorpholino)-quinoline-4-carboxamide (example 102);

7U-(2-((7?)-4-cyanothiazolidin-3-yl)-2-oxoethyl)-6-((5)-3-ethylmorpholino)quinoline-4carboxamide (Example 106);

(7?)-U-(2-(4-cyanothiazolidin-3-yl)-2-oxoethyl)-6-(3,3-dimethylmorpholino)-quinoline-4· carboxamide (Example 107) and their pharmaceutically acceptable salts.

In some embodiments, the heterocyclyl ring R ² is

wherein the heterocyclyl ring is optionally substituted with one or more substituents independently selected from the group consisting of halogen, cyano, oxo, _C1-6 alkyl, _C3-6 cycloalkyl, C1-6 alkyloxy, _C1-3 alkoxy- _C1-3 alkyl, _C1-3 alkylcarbonyl- _C1-3 alkyl and _C1-3 alkylsulfonyl- _C1-3 alkyl, and wherein the _C1-6 alkyl, _C3-6 cycloalkyl, C1-6 alkoxy, _C1-3 alkoxy- _C1-3 alkyl, _C1-3 alkylcarbonyl- _C1-3 alkyl and _C1-3 alkylsulfonyl- _C1-3 alkyl may be further substituted _with one _or more halogen atoms. In one aspect, the heterocyclyl ring R ² is optionally substituted with 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, 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 C _1-3 alkyl, C _3-6 cycloalkyl, C _1-3 alkoxy, 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 may be further substituted with one or more halogen atoms. In another aspect, the heterocyclyl ring R ² is optionally substituted with one or more substituents independently selected from the group consisting of halogen, cyano, fluoro, methyl, ethyl, propyl, isopropyl, cyclopropyl, fluoromethyl, difluoromethyl, trifluoromethyl, fluoroethyl, difluoroethyl, trifluoroethyl, trifluoropropyl, methoxy, ethoxy, trifluoromethoxy, trifluoroethoxy, methoxymethyl, trifluoromethoxymethyl, and methylsulfonylmethyl. In another aspect, the heterocyclyl ring R ² is optionally substituted with one or more substituents independently selected from the group consisting of fluoro, methyl, ethyl, isopropyl, cyclopropyl, fluoromethyl, difluoropropyl, methoxy and trifluoromethoxy.

In some embodiments, the compound or pharmaceutically acceptable salt is (R)-N-(2-(4-cyanothiazolidin-3-yl)-2-oxoethyl)-6-thiomorpholinoquinoline-4-carboxamide (Example 3) or a pharmaceutically acceptable salt thereof.

In some embodiments, the heterocyclyl ring R ² is

- 43 048482

wherein the heterocyclyl ring is optionally substituted with one or more substituents independently selected from the group consisting of halogen, cyano, _C1-6 alkyl, _C3-6 cycloalkyl, _C1-6 alkoxy, _C1-3 alkoxy- _C1-3 alkyl, _C1-3 alkylcarbonyl- _C1-3 alkyl and _C1-3 alkylsulfonyl- _C1-3 alkyl, and wherein the _C1-6 alkyl, _C3-6 cycloalkyl, _C1-6 alkoxy, _C1-3 alkoxy- _C1-3 alkyl, _C1-3 alkylcarbonyl- _C1-3 alkyl and _C1-3 alkylsulfonyl- _C1-3 alkyl may be further substituted with one or more halogen atoms. In one aspect, the heterocyclyl ring R ² is optionally substituted with 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, 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 C _1-3 alkyl, C _3-6 cycloalkyl, C _1-3 alkoxy, 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 may be further substituted with one or more halogen atoms. In another aspect, the heterocyclyl ring R ² is optionally substituted with one or more substituents independently selected from the group consisting of cyano, fluoro, methyl, ethyl, propyl, isopropyl, cyclopropyl, fluoromethyl, difluoromethyl, trifluoromethyl, fluoroethyl, difluoroethyl, trifluoroethyl, trifluoropropyl, methoxy, ethoxy, trifluoromethoxy, trifluoroethoxy, methoxymethyl, trifluoromethoxymethyl, and methylsulfonylmethyl. In another aspect, the heterocyclyl ring R ² is optionally substituted with one or more substituents independently selected from the group consisting of fluoro, methyl, ethyl, isopropyl, cyclopropyl, fluoromethyl, difluoropropyl, methoxy and trifluoromethoxy.

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

In some embodiments, the heterocyclyl ring R ² is

wherein the heterocyclyl ring is optionally substituted with one or more substituents independently selected from the group consisting of halogen, cyano, _C1-6 alkyl, _C3-6 cycloalkyl, _C1-6 alkoxy, _C1-3 alkoxy- _C1-3 alkyl, _C1-3 alkylcarbonyl- _C1-3 alkyl and _C1-3 alkylsulfonyl- _C1-3 alkyl, and wherein the _C1-6 alkyl, _C3-6 cycloalkyl, _C1-6 alkoxy, _C1-3 alkoxy- _C1-3 alkyl, _C1-3 alkylcarbonyl- _C1-3 alkyl and _C1-3 alkylsulfonyl- _C1-3 alkyl may be further substituted with one or more halogen atoms. In one aspect, the heterocyclyl ring R ² is optionally substituted with 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, 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 C _1-3 alkyl, C _3-6 cycloalkyl, C _1-3 alkoxy, 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 may be further substituted with one or more halogen atoms. In another aspect, the heterocyclyl ring R ² is optionally substituted with one or more substituents independently selected from the group consisting of cyano, fluoro, methyl, ethyl, propyl, isopropyl, cyclopropyl, fluoromethyl, difluoromethyl, trifluoromethyl, fluoroethyl, difluoroethyl, trifluoroethyl, trifluoropropyl, methoxy, ethoxy, trifluoromethoxy, trifluoroethoxy, methoxymethyl, trifluoromethoxymethyl, and methylsulfonylmethyl. In another aspect, the heterocyclyl ring R ² is optionally substituted with one or more substituents independently selected from the group consisting of fluoro, methyl, ethyl, isopropyl, cyclopropyl, fluoromethyl, difluoropropyl, methoxy and trifluoromethoxy. In another aspect, the heterocyclyl ring R ² is optionally substituted with one or more substituents independently selected from the group consisting of fluoro, methyl, ethyl, fluoromethyl, difluoropropyl, methoxy, and trifluoromethoxy.

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

In some embodiments, the heterocyclyl ring R ² is

wherein the heterocyclyl ring is optionally substituted with one or more substituents independently selected from the group consisting of halogen, cyano, oxo, C _1-6 alkyl, C _3-6 cycloalkyl,

- 44 048482

C1-6alkoxy, _C1-3alkoxy - _C1-3alkyl , _{C1-3alkylcarbonyl} - _C1-3alkyl and _{C1-3alkylsulfonyl} - _C1-3alkyl , and where _C1-6 alkyl, _C3-6 cycloalkyl, _C1-6 alkoxy, _C1-3alkoxy - _C1-3alkyl , _{C1-3alkylcarbonyl} - _C1-3alkyl and _{C1-3alkylsulfonyl} - _C1-3alkyl may be further substituted with one or more halogen atoms. In one aspect, the heterocyclyl ring R ² is optionally substituted with 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, 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, where C _1-3 alkyl, C _3-6 cycloalkyl, C _1-3 alkoxy, 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 may be further substituted with one or more halogen atoms. In another aspect, the heterocyclyl ring R ² is optionally substituted with one or more substituents independently selected from the group consisting of cyano, fluoro, methyl, ethyl, propyl, isopropyl, cyclopropyl, fluoromethyl, difluoromethyl, trifluoromethyl, fluoroethyl, difluoroethyl, trifluoroethyl, trifluoropropyl, methoxy, ethoxy, trifluoromethoxy, trifluoroethoxy, methoxymethyl, trifluoromethoxymethyl, and methylsulfonylmethyl. In another aspect, the heterocyclyl ring R ² is optionally substituted with one or more substituents independently selected from the group consisting of fluoro, methyl, ethyl, isopropyl, fluoromethyl, difluoropropyl, methoxy and trifluoromethoxy.

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

In some embodiments, the heterocyclyl ring R ² is

wherein the heterocyclyl ring is optionally substituted with one or more substituents independently selected from the group consisting of halogen, cyano, oxo, _C1-6 alkyl, C3-6 cycloalkyl, _C1-6 alkoxy, _C1-3 alkoxy- _C1-3 alkyl, _C1-3 alkylcarbonyl- _C1-3 alkyl and _C1-3 alkylsulfonyl- _C1-3 alkyl, and wherein the _C1-6 alkyl, _C3-6 cycloalkyl, _C1-6 alkoxy, _C1-3 alkoxy- _C1-3 alkyl, _C1-3 alkylcarbonyl- _C1-3 alkyl and _C1-3 alkylsulfonyl- _C1-3 alkyl may be further substituted _with one or more halogen atoms. In one aspect, the heterocyclyl ring R ² is optionally substituted with 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, 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 C _1-3 alkyl, C _3-6 cycloalkyl, C _1-3 alkoxy, 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 may be further substituted with one or more halogen atoms. In another aspect, the heterocyclyl ring R ² is optionally substituted with one or more substituents independently selected from the group consisting of cyano, fluoro, methyl, ethyl, propyl, isopropyl, cyclopropyl, fluoromethyl, difluoromethyl, trifluoromethyl, fluoroethyl, difluoroethyl, trifluoroethyl, trifluoropropyl, methoxy, ethoxy, trifluoromethoxy, trifluoroethoxy, methoxymethyl, trifluoromethoxymethyl, and methylsulfonylmethyl. In another aspect, the heterocyclyl ring R ² is optionally substituted with one or more substituents independently selected from the group consisting of fluoro, methyl, ethyl, fluoromethyl, difluoropropyl, methoxy, and trifluoromethoxy.

In some embodiments, the compounds and pharmaceutically acceptable salts are selected from the group consisting of

6-((1S,4S)-2-oxa-5-azabicyclo[2.2.1]heptan-5-yl)-N-(2-((R)-4-cyanothiazolidin-3-yl)-2oxoethyl)quinoline -4-carboxamide (example 75);

6-((1 R,4R)-2-oxa-5-azabicyclo[2.2.1 ]heptan-5-yl)-N-(2-((R)-4-cyanothiazolidin-3-yl)-2oxoethyl)quinoline-4-carboxamide (Example 76) and their pharmaceutically acceptable salts.

In some embodiments, the heterocyclyl ring R ² is

wherein the heterocyclyl ring is optionally substituted with one or more substituents independently selected from the group consisting of halogen, cyano, oxo, _C1-6 alkyl, C3-6 cycloalkyl, _C1-6 alkoxy, _C1-3 alkoxy- _C1-3 alkyl, _C1-3 alkylcarbonyl- _C1-3 alkyl and _C1-3 alkylsulfonyl- _C1-3 alkyl, and wherein the _C1-6 alkyl, _C3-6 cycloalkyl, _C1-6 alkoxy, _C1-3 alkoxy- _C1-3 alkyl, _C1-3 alkylcarbonyl- _C1-3 alkyl and _C1-3 alkylsulfonyl- _C1-3 alkyl may be further substituted _with one or more halogen atoms. In one aspect, the heterocyclyl ring R ² is optionally substituted with 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, 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, where C _1-3 alkyl, C _3-6 cycloalkyl, C _1-3 alkoxy, C _1-3 alkoxy-C _1-3 alkyl,

- 45 048482

C _1-3 alkylcarbonyl-C _1-3 alkyl and C _1-3 alkylsulfonyl-C _1-3 alkyl may be further substituted with one or more halogen atoms. In another aspect, the heterocyclyl ring R ² is optionally substituted with one or more substituents independently selected from the group consisting of cyano, fluoro, methyl, ethyl, propyl, isopropyl, cyclopropyl, fluoromethyl, difluoromethyl, trifluoromethyl, fluoroethyl, difluoroethyl, trifluoroethyl, trifluoropropyl, methoxy, ethoxy, trifluoromethoxy, trifluoroethoxy, methoxymethyl, trifluoromethoxymethyl and methylsulfonylmethyl. In another aspect, the heterocyclyl ring R ² is optionally substituted with one or more substituents independently selected from the group consisting of fluoro, methyl, ethyl, fluoromethyl, difluoropropyl, methoxy, and trifluoromethoxy.

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

In some embodiments, the heterocyclyl ring R ² is wherein the heterocyclyl ring is optionally substituted with 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, 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, 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 may be further substituted with one or more halogen atoms. In one aspect, the heterocyclyl ring R ² is optionally substituted with 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, 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, where C _1-3 alkyl, C _3-6 cycloalkyl, C _1-3 alkoxy, 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 may be further substituted with one or more halogen atoms. In another aspect, the heterocyclyl ring R ² is optionally substituted with one or more substituents independently selected from the group consisting of cyano, fluoro, methyl, ethyl, propyl, isopropyl, cyclopropyl, fluoromethyl, difluoromethyl, trifluoromethyl, fluoroethyl, difluoroethyl, trifluoroethyl, trifluoropropyl, methoxy, ethoxy, trifluoromethoxy, trifluoroethoxy, methoxymethyl, trifluoromethoxymethyl, and methylsulfonylmethyl. In another aspect, the heterocyclyl ring R ² is optionally substituted with one or more substituents independently selected from the group consisting of fluoro, methyl, ethyl, isopropyl, fluoromethyl, difluoropropyl, methoxy and trifluoromethoxy.

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

In some embodiments, the heterocyclyl ring R ² is wherein the heterocyclyl ring is optionally substituted with 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, 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, 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 may be further substituted with one or more halogen atoms. In one aspect, the heterocyclyl ring R ² is optionally substituted with 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, 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 C _1-3 alkyl, C _3-6 cycloalkyl, C _1-3 alkoxy, 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 may be further substituted with one or more halogen atoms. In another aspect, the heterocyclyl ring R ² is optionally substituted with one or more substituents independently selected from the group consisting of cyano, fluoro, methyl, ethyl, propyl, isopropyl, cyclopropyl, fluoromethyl, difluoromethyl, trifluoromethyl, fluoroethyl, difluoroethyl, trifluoroethyl, trifluoropropyl, methoxy, ethoxy, trifluoromethoxy, trifluoroethoxy, methoxymethyl, trifluoromethoxymethyl, and methylsulfonylmethyl. In another aspect, the heterocyclyl ring R ² is optionally substituted with one or more substituents independently selected from the group consisting of fluoro, methyl, ethyl, fluoromethyl, difluoropropyl, methoxy, and trifluoromethoxy.

In some embodiments, the compound or pharmaceutically acceptable salt is

- 46 048482 is (R)-N-(2-(4-cyanothiazolidin-3-yl)-2-oxoethyl)-6-(1,2-oxazinan-2-yl)quinoline-4-carboxamide (example 1) or a pharmaceutically acceptable salt thereof.

In some embodiments, the heterocyclyl ring R ² is

wherein the heterocyclyl ring is optionally substituted with one or more substituents independently selected from the group consisting of halogen, cyano, oxo, _C1-6 alkyl, _C3-6 cycloalkyl, _C1-6 αalkoxy, _C1-3 alkoxy- _C1-3 alkyl, _C1-3 αalkylcarbonyl- _C1-3 alkyl and _C1-3 alkylsulfonyl- _C1-3 alkyl, and wherein the _C1-6 alkyl, _C3-6 cycloalkyl, _C1-6 αalkoxy, _C1-3 alkoxy- _C1-3 alkyl, _C1-3 alkylcarbonyl- _C1-3 alkyl and _C1-3 αalkylsulfonyl- _C1-3 alkyl may be further substituted with one or more halogen atoms. In one aspect, the heterocyclyl ring R ² is optionally substituted with 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, C _1-3 alkoxy-C _1-3 alkyl, C _1-3 alkylcarbonyl-C _1-3 alkyl and

C _1-3 αalkylsulfonyl-C _1-3 alkyl, where C _1-3 alkyl, C _3-6 cycloalkyl, C _1-3 alkoxy, C _1-3 αalkoxy-C _1-3 alkyl, C _1-3 αalkylcarbonyl-C _1-3 alkyl and C _1-3 alkylsulfonyl-C _1-3 alkyl may be further substituted with one or more halogen atoms. In another aspect, the heterocyclyl ring R ² is optionally substituted with one or more substituents independently selected from the group consisting of cyano, fluoro, methyl, ethyl, propyl, isopropyl, cyclopropyl, fluoromethyl, difluoromethyl, trifluoromethyl, fluoroethyl, difluoroethyl, trifluoroethyl, trifluoropropyl, methoxy, ethoxy, trifluoromethoxy, trifluoroethoxy, methoxymethyl, trifluoromethoxymethyl, and methylsulfonylmethyl. In another aspect, the heterocyclyl ring R ² is optionally substituted with one or more substituents independently selected from the group consisting of fluoro, methyl, ethyl, fluoromethyl, difluoropropyl, methoxy, and trifluoromethoxy.

In some embodiments, the compounds and pharmaceutically acceptable salts are selected from the group consisting of

7U-(2-((7?)-4-cyanothiazolidin-3-yl)-2-oxoethyl)-6-((7?)-7-methyl-1,4-oxozepan-4yl)quinoline-4-carboxamide (example 61);

7U-(2-((7?)-4-cyanothiazolidin-3-yl)-2-oxoethyl)-6-((5)-7-methyl-1,4-oxazepan-4yl)quinoline-4-carboxamide ( example 62);

7U-(2-((7?)-4-cyanothiazolid in-3-yl)-2-oxoethyl)-6-((5)-3-methyl-1,4-oxazepan-4yl)quinoline-4-carboxamide (example 63);

2U-(2-((7?)-4-cyanotidzolidin-3-yl)-2-oxoethyl)-6-((7?)-2-methyl-1,4-oxzepan-4yl)quinoline-4-carboxamide (example 64);

(7?)-7U-(2-(4-cyanotidzolidin-3-yl)-2-oxoethyl)-6-(1,4-oxazepan-4-yl)quinoline-4-carboxamide (Example 91) and their pharmaceutically acceptable salts.

In some embodiments, the heterocyclyl ring R ² is

wherein the heterocyclyl ring is optionally substituted with one or more substituents independently selected from the group consisting of halogen, cyano, oxo, _C1-6alkyl , _{C3-6cycloalkyl} , _C1-6αalkoxy , _C1-3alkoxy - _C1-3alkyl , _{C1-3αalkylcarbonyl} - _C1-3alkyl and C1-3alkylsulfonyl- _C1-3alkyl , and wherein the _C1-6alkyl , _{C3-6cycloalkyl} , _C1-6alkoxy , _C1-3alkoxy - _C1-3alkyl , _{C1-3alkylcarbonyl} - _C1-3alkyl and _{C1-3αalkylsulfonyl} - _C1-3alkyl may be further substituted _with one or more halogen atoms. In one aspect, the heterocyclyl ring R ² is optionally substituted with 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, C _1-3 alkoxy-C _1-3 alkyl, C _1-3 alkylcarbonyl-C _1-3 alkyl and

C _1-3 αalkylsulfonyl-C _1-3 alkyl, wherein C _1-3 αalkyl, C _3-6 cycloalkyl, C _1-3 alkoxy, C _1-3 alkoxy-C _1-3 alkyl, C _1-3 alkylcarbonyl-C _1-3 alkyl and C _1-3 αalkylsulfonyl-C _1-3 alkyl may be further substituted with one or more halogen atoms. In another aspect, the heterocyclyl ring R ² is optionally substituted with one or more substituents independently selected from the group consisting of cyano, fluoro, methyl, ethyl, propyl, isopropyl, cyclopropyl, fluoromethyl, difluoromethyl, trifluoro

- 47 048482 methyl, fluoroethyl, difluoroethyl, trifluoroethyl, trifluoropropyl, methoxy, ethoxy, trifluoromethoxy, trifluoroethoxy, methoxymethyl, trifluoromethoxymethyl and methylsulfonylmethyl. In another aspect, the heterocyclyl ring R ² is optionally substituted with one or more substituents independently selected from the group consisting of fluoro, methyl, ethyl, fluoromethyl, difluoropropyl, methoxy and trifluoromethoxy.

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

In some embodiments, the compounds and pharmaceutically acceptable salts are selected from the group consisting of (7?)-LA(2-(4-cyanothiazolidin-3-yl)-2-oxoethyl)-6-(1,2-oxazinan-2-yl)quinoline-4-carboxamide (Example 1);

(7?)-AA(2-(4-cyanothiazolidin-3-yl)-2-oxoethyl)-3-fluoro-6-morpholinoquinoline-4carboxamide (example 2);

(7?)-DA(2-(4-cyanothiazolidin-3-yl)-2-oxoethyl)-6-thiomorpholinoquinoline-4carboxamide (example 3);

(7?)-7U-(2-(4-cyanothiazolidin-3-yl)-2-oxoethyl)-6-(2,2-difluoromorpholino)quinoline-4carboxamide (example 4);

(7?)-7U-(2-(4-cyanothiazolidin-3-yl)-2-oxoethyl)-6-(2,2,6,6-tetrafluoromorpholino)quinoline-4-carboxamide (example 5);

(7?)-DA(2-(4-cyanothiazolidin-3-yl)-2-oxoethyl)-6-(2,3-dihydro-4Rabenzo[0][1,4]oxazin-4-yl)quinolin- 4-carboxamide (example 6);

(7?)-AA(2-(4-cyanothiazolidin-3-yl)-2-oxoethyl)-8-methyl-6-morpholinoquinoline-4carboxamide (example 9);

(7?)-7U-(2-(4-cyanothiazolidin-3-yl)-2-oxoethyl)-7-methyl-6-morpholinoquinoline-4carboxamide (example 10);

(7?)-DA(2-(4-cyanothiazolidin-3-yl)-2-oxoethyl)-6-(5,5-dimethyl-2-oxooxazolidin-3yl)quinolin-4-carboxamide (example 13);

(7?)-LA(2-(4-cyanothiazolidin-3-yl)-2-oxoethyl)-6-(2,2-dimethyl-3-oxomorpholino)quinoline-4-carboxamide (Example 16);

DA(2-((R)-4-cyanothiazolidin-3-yl)-2-oxoethyl)-6-((R)-7-methyl-1,4-oxazepan-4-yl)quinolin-4-carboxamide ( example 61);

7U-(2-((7?)-4-cyanothiazolidin-3-yl)-2-oxoethyl)-6-((5)-7-methyl-1,4-oxazepan-4-yl)quinolin-4- carboxamide (example 62);

A-(2-((7?)-4-cyanothiazol id in-3 -yl)-2-oxoethyl)-6-((5)-3 -methyl-1,4-oxazepan-4-yl)quinolin- 4-carboxamide (example 63);

7U-(2-((7?)-4-cyanothiazolidin-3-yl)-2-oxoethyl)-6-((7?)-2-methyl-1,4-oxazepan-4-yl)quinolin-4 -carboxamide (example 64);

(7?)-7U-(2-(4-cyanothiazolidin-3-yl)-2-oxoethyl)-6-morpholinoquinoline-4-carboxamide (Example 67);

7U-(2-((7?)-4-cyanothiazolidin-3-yl)-2-oxoethyl)-6-((27?,65)-2,6-dimethylmorpholino)quinoline-4-carboxamide (example 68) ;

A-(2-((A)-4-cyanothiazolidin-3-yl)-2-oxoethyl)-6-((A)-2-(fluoromethyl)morpholino)quinoline-4-carboxamide (Example 69);

A-(2-((A)-4-cyanothiazolide in-3-yl)-2-oxoethyl)-6-((2A,6/?)-2,6-dimethyl morpholino)quinoline-4-carboxamide ( example 70);

A-(2-((A)-4-cyanothiazolidin-3-yl)-2-oxoethyl)-6-((A)-2-(fluoromethyl)morpholino)quinoline-4-carboxamide (Example 71);

- 48 048482

LC2-((/?)-4-cyanothiazolidin-3-yl)-2-oxoethyl)-6-((7?)-2-methylmorpholino)-quinoline-4-carboxamide (example 72);

A-(2-((^)-4-cyanothiazolidin-3-yl)-2-oxoethyl)-6-((7?)-2-(trifluoromethyl)morpholino)quinoline-4-carboxamide (example 73);

A-(2-((7?)-4-cyanothiazolidin-3-yl)-2-oxoethyl)-6-((5)-2-(trifluoromethyl)morpholino)quinoline-4-carboxamide (Example 74);

6-(( 15',45)-2-oxa-5 -azabicyclo[2.2.1] heptan-5-yl )-A ^f -(2-((A)-4-cyanothiazolide in-3 -yl) -2 oxoethyl)quinoline-4-carboxamide (example 75);

6-((17?,47?)-2-oxa-5-azabicyclo[2.2.1]heptan-5-yl)-U-(2-((7?)-4-cyanothiazolidin-3-yl)2 -oxoethyl)quinoline-4-carboxamide (example 76);

6-(6-oxa-3-azabicyclo[3.1.1] heptan-3-yl)-A-(2-((7?)-4-cyanothiazolid in-3 -yl)-2oxoethyl)quinoline-4-carboxamide (example 77);

7U-(2-((7?)-4-cyanothiazolidin-3-yl)-2-oxoethyl)-6-((25',65)-2,6-dimethylmorpholino)quinoline-4-carboxamide (example 78) ;

6-(8-oxa-3-azabicyclo[3.2.1]octan-3-yl)-7U-(2-((7?)-4-cyanothiazolidin-3-yl)-2oxoethyl)quinoline-4-carboxamide ( example 79);

A-(2-((7?)-4-cyanothiazolidin-3-yl)-2-oxoethyl)-6-((5)-2-methylmorpholino)-quinoline-4-carboxamide (example 80);

7U-(2-((7?)-4-cyanothiazolidin-3-yl)-2-oxoethyl)-6-((27?,35)-2,3-dimethylmorpholino)quinoline-4-carboxamide (example 81) ;

7U-(2-((7?)-4-cyanothiazolidin-3-yl)-2-oxoethyl)-6-((25',35)-2,3-dimethylmorpholino)quinoline-4-carboxamide (example 82) ;

7U-(2-((7?)-4-cyanothiazolidin-3-yl)-2-oxoethyl)-6-((27?,37?)-2,3-dimethylmorpholino)quinoline-4-carboxamide (example 83 );

7U-(2-((7?)-4-cyanothiazolidin-3-yl)-2-oxoethyl)-6-((7?*)-3-(trifluoromethyl)morpholino)quinoline-4-carboxamide, isomer 1 ( example 84);

A-(2-((L)-4-cyanothiazolidin-3-yl)-2-oxoethyl)-6-((L*)-3-(trifluoromethyl)morpholino)quinoline-4-carboxamide, isomer 2 (example 85 );

6-(3-oxa-9-azabicyclo[3.3.1]nonan-9-yl)-L ^g -(2-((7?)-4-cyanothiazolidin-3-yl)-2oxoethyl)quinoline-4-carboxamide (example 86);

7U-(2-((7?)-4-cyanothiazolidin-3-yl)-2-oxoethyl)-6-((27?,57?)-2,5-dimethylmorpholino)quinoline-4-carboxamide (example 87 );

(7?)-A-(2-(4-cyanothiazolidin-3-yl)-2-oxoethyl)-6-(2,2-dimethylmorpholino)-quinoline-4-carboxamide (example 88);

- 49 048482

A-(2-((7?)-4-cyanothiazolidin-3-yl)-2-oxoethyl)-6-((5)-3-(methoxymethyl)morpholino)quinoline-4-carboxamide (Example 89);

A-(2-((7?)-4-cyanothiazolid in-3-yl)-2-oxoethyl)-6-((35.5R)-3,5 dimethylmorpholino)quinoline-4-carboxamide (Example 90);

(7?)-A-(2-(4-cyanothiazolidin-3-yl)-2-oxoethyl)-6-(1,4-oxazepan-4-yl)quinoline-4carboxamide (Example 91);

A-(2-((7?)-4-cyanothiazolidin-3-yl)-2-oxoethyl)-6-((7?)-2-((methylsulfonyl)methyl)morpholino)quinoline-4-carboxamide (example 92);

A-(2-((7?)-4-cyanothiazolidin-3-yl)-2-oxoethyl)-6-((5)-2-(methoxymethyl)morpholino)quinoline-4-carboxamide (Example 93);

A-(2-((7?)-4-cyanothiazolidin-3-yl)-2-oxoethyl)-6-((5)-2-((methylsulfonyl)methyl)morpholino)quinoline-4-carboxamide (example 94 );

A-(2-((7?)-4-cyanothiazolidin-3-yl)-2-oxoethyl)-6-((7?)-3-(2-methoxyethyl)morpholino)quinoline-4-carboxamide (example 95 );

A-(2-((7?)-4-cyanothiazolidin-3-yl)-2-oxoethyl)-6-((25.35)-3-(methoxymethyl)-2methylmorpholino)quinoline-4-carboxamide (example 96 );

A-(2-((7?)-4-cyanothiazolide yn-3-yl)-2-oxoethyl)-6-((27?, 3R)-3-(methoxymethyl)-2methylmorpholino)quinoline-4-carboxamide (Example 97);

6-(3-oxa-8-azabicyclo[3.2.1]octan-8-yl)-A-(2-((7?)-4-cyanothiazolidin-3-yl)-2oxoethyl)quinoline-4-carboxamide ( example 98);

7-bromo-A-(2-((7?)-4-cyanothiazolidin-3-yl)-2-oxoethyl)-6-((35.5R)-3,5 dimethylmorpholino)quinoline-4-carboxamide (example 100);

(7?)-5-chloro-A-(2-(4-cyanothiazolidin-3-yl)-2-oxoethyl)-6-morpholinoquinoline-4carboxamide (Example 101);

A-(2-((7?)-4-cyanothiazolidin-3-yl)-2-oxoethyl)-6-((5)-3-methylmorpholino)-quinoline-4-carboxamide (example 102);

A-(2-((7?)-4-cyanothiazolidin-3-yl)-2-oxoethyl)-6-((35.55)-3,5-dimethylmorpholino)quinoline-4-carboxamide (Example 103);

?/-(2-((7?)-4-cyanothiazolid in-3-yl)-2-oxoethyl)-6-((37?,5R)-3,5-dimethylmorpholino)quinoline-4-carboxamide (example 105);

7U-(2-((7?)-4-cyanothiazolidin-3-yl)-2-oxoethyl)-6-((5)-3-ethylmorpholino)quinoline-4carboxamide (Example 106);

(7?)-A-(2-(4-cyanothiazolidin-3-yl)-2-oxoethyl)-6-(3,3-dimethylmorpholino)-quinoline-4·carboxamide (Example 107);

- 50 048482

7U-(2-((7?)-4-cyanothiazolidin-3-yl)-2-oxoethyl)-6-((7?)-3-methylmorpholino)-quinoline-4-carboxamide (example 108);

(7?)-7U-(2-(4-cyanothiazolidin-3-yl)-2-oxoethyl)-2-methyl-6-morpholinoquinoline-4carboxamide (Example 109);

(7?)-7U-(2-(4-cyanothiazolidin-3-yl)-2-oxoethyl)-6-(6,6-dimethyl-2-oxo-1,3-oxazinan-3 yl)quinoline-4 -carboxamide (example 112);

(7?)-7-chloro-7U-(2-(4-cyanothiazolidin-3-yl)-2-oxoethyl)-6-morpholinoquinoline-4carboxamide (Example 179);

(7?)-8-chloro-7U-(2-(4-cyanothiazolidin-3-yl)-2-oxoethyl)-6-morpholinoquinoline-4carboxamide (Example 180);

6-(( 17?, 55)-9-oxa-3-azabicyclo[3.3.1]nonan-3-yl)-L-(2-((/?)-4-cyanothiazolide and n-3-yl )-2oxoethyl)quinoline-4-carboxamide (Example 194);

(7?)-7U-(2-(4-cyanothiazolidin-3-yl)-2-oxoethyl)-6-(2,4-dimethyloxazol-5-yl)quinolin-4·carboxamide (Example 215);

(7?)-7U-(2-(4-cyanothiazolidin-3-yl)-2-oxoethyl)-6-(3,5-dimethylisoxazol-4-yl)quinoline-4-carboxamide (Example 216) and their pharmaceutically acceptable salts.

In some embodiments, the compounds and pharmaceutically acceptable salts are selected from the group consisting of (7?)-7Y-(2-(4-cyanothiazolidin-3-yl)-2-oxoethyl)-6-(1,2-oxazinan-2-yl)quinoline-4-carboxamide (Example 1);

(7?)-7U-(2-(4-cyanothiazolidin-3-yl)-2-oxoethyl)-3-fluoro-6-morpholinoquinoline-4carboxamide (example 2);

(7?)-7U-(2-(4-cyanothiazolidin-3-yl)-2-oxoethyl)-6-(2,2-difluoromorpholino)quinoline-4carboxamide (example 4);

(7?)-7U-(2-(4-cyanothiazolidin-3-yl)-2-oxoethyl)-8-methyl-6-morpholinoquinoline-4carboxamide (example 9);

(7?)-7U-(2-(4-cyanothiazolidin-3-yl)-2-oxoethyl)-6-morpholinoquinoline-4-carboxamide (Example 67);

7U-(2-((7?)-4-cyanothiazolidin-3-yl)-2-oxoethyl)-6-((27?,65)-2,6-dimethylmorpholino)quinoline-4-carboxamide (example 68) ;

7U-(2-((7?)-4-cyanothiazolidin-3-yl)-2-oxoethyl)-6-((7?)-2-(fluoromethyl)morpholino)quinoline-4-carboxamide (example 69);

7U-(2-((7?)-4-cyanothiazolidin-3-yl)-2-oxoethyl)-6-((27?,67?)-2,6-dimethylmorpholino)quinoline-4-carboxamide (example 70 );

- 51 048482

LC2-((/?)-4-cyanothiazolidin-3-yl)-2-oxoethyl)-6-((5)-2-(fluoromethyl)morpholino)quinoline-4-carboxamide (Example 71);

^-(2-((7?)-4-cyanothiazolidin-3-yl)-2-oxoethyl)-6-((7?)-2-methylmorpholino)-quinoline-4-carboxamide (example 72);

^-(2-((7?)-4-cyanothiazolidin-3-yl)-2-oxoethyl)-6-((7?)-2-(trifluoromethyl)morpholino)quinoline-4-carboxamide (example 73);

7U-(2-((7?)-4-cyanothiazolidin-3-yl)-2-oxoethyl)-6-((5)-2-(trifluoromethyl)morpholino)quinoline-4-carboxamide (Example 74);

6-(( 15',45)-2-oxa-5 -azabicyclo[2.2.1] heptan-5-yl )-A ^f -(2-((7?)-4-cyanothiazol id in-3 -yl )-2·oxoethyl)quinoline-4-carboxamide (example 75);

6-((17?,47?)-2-oxa-5-azabicyclo[2.2.1]heptan-5-yl)-7U-(2-((7?)-4-cyanothiazolidin-3-yl)2 -oxoethyl)quinoline-4-carboxamide (example 76);

6-(6-oxa-3-azabicyclo[3.1.1] heptan-3 -yl)-A-(2-((/?)-4-cyanothiazol id in-3 -yl)-2oxoethyl)quinoline-4- carboxamide (example 77);

7U-(2-((7?)-4-cyanothiazolidin-3-yl)-2-oxoethyl)-6-((25',65)-2,6-dimethylmorpholino)quinoline-4-carboxamide (example 78) ;

6-(8-oxa-3-azabicyclo[3.2.1]octan-3-yl)-A -(2-((/?)-4-cyanothiazol id in-3 -yl)-2oxoethyl)quinoline-4- carboxamide (example 79);

7U-(2-((7?)-4-cyanothiazolidin-3-yl)-2-oxoethyl)-6-((5)-2-methylmorpholino)-quinoline-4-carboxamide (example 80);

7U-(2-((7?)-4-cyanothiazolidin-3-yl)-2-oxoethyl)-6-((27?,35)-2,3-dimethylmorpholino)quinoline-4-carboxamide (example 81) ;

7U-(2-((7?)-4-cyanothiazolidin-3-yl)-2-oxoethyl)-6-((25',35)-2,3-dimethylmorpholino)quinoline-4-carboxamide (example 82) ;

(7?)-7U-(2-(4-cyanothiazolidin-3-yl)-2-oxoethyl)-6-(2,2-dimethylmorpholino)-quinoline-4-carboxamide (example 88);

7U-(2-((7?)-4-cyanothiazolidin-3-yl)-2-oxoethyl)-6-((5)-3-(methoxymethyl)morpholino)quinoline-4-carboxamide (Example 89);

A7-(2-((7?)-4-cyanothiazolidin-3-yl)-2-oxoethyl)-6-((5)-2-(methoxymethyl)morpholino)quinoline-4-carboxamide (Example 93);

7U-(2-((7?)-4-cyanothiazolide yn-3-yl)-2-oxoethyl)-6-((27?, 3R)-3-(methoxymethyl)-2methylmorpholino)quinoline-4-carboxamide (example 97);

6-(3-oxa-8-azabicyclo[3.2.1]octan-8-yl)-A-(2-((A)-4-cyanothiazolidin-3-yl)-2oxoethyl)quinoline-4-carboxamide (example 98);

- 52 048482

L ^g -(2-((7?)-4-cyanothiazolidin-3-yl)-2-oxoethyl)-6-((5)-3-methylmorpholino)-quinoline-4-carboxamide (example 102);

L ^g -(2-((A)-4-cyanothiazolidin-3-yl)-2-oxoethyl)-6-((5)-3-ethylmorpholino)quinoline-4carboxamide (Example 106);

(A)-/U-(2-(4-cyanothiazolidin-3-yl)-2-oxoethyl)-6-(3,3-dimethylmorpholino)-quinoline-4-carboxamide (Example 107);

(7?)-A-(2-(4-cyanothiazolidin-3-yl)-2-oxoethyl)-2-methyl-6-morpholinoquinoline-4carboxamide (Example 109);

(7?)-A-(2-(4-cyanothiazolid in-3-yl)-2-oxoethyl)-6-(6,6-dimethyl-2-oxo-1,3-oxazinan-3 yl)quinoline- 4-carboxamide (Example 112) and pharmaceutically acceptable salts thereof.

C. R ² is spiroheterocyclyl

In some embodiments, the present invention provides compounds characterized by the structure of Formulae (I), (II), (III-A), (III-B), (III-C), (III-D), (III-E), (IV), or (IV-A), or a pharmaceutically acceptable salt thereof, wherein R ² is spiroheterocyclyl having a total of 6 to 11 ring atoms, wherein the spiroheterocyclyl: (i) comprises two saturated rings, (ii) comprises: (a) one or two ring nitrogen atoms, wherein the remaining ring atoms are carbon, (b) one or two ring nitrogen atoms and one or two ring oxygen atoms, wherein the remaining ring atoms are carbon, or (c) one ring nitrogen atom and one ring sulfur atom, wherein the remaining ring atoms are carbon, and (iii) is optionally substituted with 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, C ₁ . ₆ haloalkoxy and C ₁ . ₆ alkylcarbonyl. In one aspect, spiroheterocyclyl R ² comprises: (a) one or two nitrogen atoms in a ring, wherein the remaining atoms in the ring are carbon, or (b) one or two nitrogen atoms in a ring and one or two oxygen atoms in a ring, wherein the remaining atoms in the ring are carbon. In another aspect, spiroheterocyclyl R ² comprises one or two nitrogen atoms in a ring and optionally one or two oxygen atoms in a ring, wherein the remaining atoms in the ring are carbon. In another aspect, spiroheterocyclyl R ² comprises one nitrogen atom in a ring, wherein the remaining atoms in the ring are carbon. In another aspect, spiroheterocyclyl R ² comprises two nitrogen atoms in the ring, wherein the remaining atoms in the ring are carbon. In another aspect, spiroheterocyclyl R ² comprises one nitrogen atom in the ring and one oxygen atom in the ring, wherein the remaining atoms in the ring are carbon. In another aspect, spiroheterocyclyl R ² comprises one nitrogen atom in the ring and two oxygen atoms in the ring, wherein the remaining atoms in the ring are carbon.

In some embodiments, two saturated spiroheterocyclyl rings R ² are selected from the group consisting of wherein one or both rings are optionally substituted with one or more substituents independently selected from the group consisting of halogen, C1-6 alkyl, C1-6 haloalkyl, C1-6 alkoxy, C1-6 haloalkoxy, and C _1-6 alkylcarbonyl.

In some embodiments, the two saturated spiroheterocyclyl rings R ² are selected from the group consisting of

wherein one or both rings are optionally substituted with one or more substituents independently selected from the group consisting of halogen, C _1-6 alkyl, C _1-6 haloalkyl, C _1-6 alkoxy, C _1-6 haloalkoxy, and C _1-6 alkylcarbonyl.

In some embodiments, the two saturated spiroheterocyclyl rings R ² are selected from the group consisting of

wherein one or both rings are optionally substituted with one or more substituents independently selected from the group consisting of halogen, C _1-6 alkyl, C _1-6 haloalkyl, C _1-6 alkoxy, C _1-6 haloalkoxy, and C _1-6 alkylcarbonyl.

In some embodiments, the two saturated spiroheterocyclyl rings R ² are selected from the group consisting of

- 54 048482 wherein one or both rings are optionally substituted with one or more substituents independently selected from the group consisting of halogen, C _1-6 alkyl, C _1-6 haloalkyl, C _1-6 alkoxy, C _1-6 haloalkoxy and C _1-6 alkylcarbonyl.

In some embodiments, the R ² spiroheterocyclyl ring is optionally substituted with one or more substituents independently selected from the group consisting of halogen, C _1-3 alkyl, C _1-3 haloalkyl, C _1-3 alkoxy, C _1-3 haloalkoxy, and C _1-3 alkylcarbonyl.

In some embodiments, the spiroheterocyclyl ring R ² is optionally substituted with one or more halogen atoms. In one aspect, the spiroheterocyclyl ring R ² is optionally substituted with one or more fluorine atoms.

In some embodiments, the spiroheterocyclyl ring R ² is optionally substituted with one or more C _1-3 alkyl.

In some embodiments, the R ² spiroheterocyclyl ring is optionally substituted with one or more C _1-3 haloalkyl.

In some embodiments, the spiroheterocyclyl ring R ² is optionally substituted with one or more C _1-3 alkoxy.

In some embodiments, the spiroheterocyclyl ring R ² is optionally substituted with one or more C _1-3 haloalkoxy.

In some embodiments, the spiroheterocyclyl ring R ² is optionally substituted with one or more C _1-3 alkylcarbonyls. In one aspect, the spiroheterocyclyl ring R ² is optionally substituted with one or more methylcarbonyls.

In some embodiments, the spiroheterocyclyl ring R ² is optionally substituted with one or more substituents independently selected from the group consisting of fluoro, methyl, ethyl, propyl, isopropyl, fluoromethyl, difluoromethyl, trifluoromethyl, fluoroethyl, difluoroethyl, trifluoroethyl, trifluoropropyl, methoxy, ethoxy, trifluoromethoxy, trifluoroethoxy, methylcarbonyl, ethylcarbonyl, and isopropylcarbonyl.

In some embodiments, the spiroheterocyclyl ring R ² is optionally substituted with one or more substituents independently selected from the group consisting of fluoro, methyl, ethyl, fluoromethyl, difluoromethyl, and trifluoromethyl.

In some embodiments, two saturated spiroheterocyclyl rings R ² are wherein one or both rings are optionally substituted with one or more substituents independently selected from the group consisting of halogen, C _1-6 alkyl, C _1-6 haloalkyl, C _1-6 alkoxy, C _1-6 haloalkoxy, and C _1-6 alkylcarbonyl. In one aspect, the spiroheterocyclyl ring R ² is optionally substituted with one or more substituents independently selected from the group consisting of halogen, C 1-3 alkyl, C 1-3 haloalkyl, C 1-3 alkoxy, C 1-3 haloalkoxy, and C 1-3 alkylcarbonyl. In another aspect, the spiroheterocyclyl ring R ² is optionally substituted with one or more substituents independently selected from the group consisting of halogen, C1-3alkyl, _{C1-3haloalkyl} , _C1-3alkoxy , _{C1-3haloalkoxy} , and _{C1-3alkylcarbonyl} . In another aspect, the spiroheterocyclyl ring R ² is optionally substituted with one or more substituents independently selected from the group consisting of fluoro, methyl, ethyl, propyl, fluoromethyl, difluoromethyl, trifluoromethyl, fluoroethyl, difluoroethyl, trifluoroethyl, trifluoropropyl, methoxy, ethoxy, trifluoromethoxy, and trifluoroethoxy. In another aspect, the spiroheterocyclyl ring R ² is optionally substituted with one or more substituents independently selected from the group consisting of fluoro, methyl, ethyl, fluoromethyl, difluoromethyl, and trifluoromethyl.

- 55 048482

In some embodiments, the compounds and pharmaceutically acceptable salts are selected from the group consisting of (5)-7V-(2-(4-cyanothiazolidin-3-yl)-2-oxoethyl)-6-(2-azaspiro[3.3]heptan-2-yl)quinoline-4-carboxamide (Example 17);

(5)-7U-(2-(4-cyanothiazolidin-3-yl)-2-oxoethyl)-6-(6-fluoro-2-azaspiro[3.3]heptan-2yl)quinoline-4-carboxamide (Example 155) ;

(5)-R-(2-(4-cyanothiazolidin-3-yl)-2-oxoethyl)-6-(6-(trifluoromethyl)-2|azaspiro[3.3]heptan-2-yl)quinoline-4-carboxamide (example 150);

(5)-N-(2-(4-cyanothiazolidin-3-yl)-2-oxoethyl)-6-(6-methyl-2-azaspiro[3.3]heptan-2yl)quinoline-4-carboxamide (Example 149) and pharmaceutically acceptable salts thereof.

In some embodiments, two saturated rings of spiroheterocyclyl R ² are wherein one or both rings are optionally substituted with one or more substituents independently selected from the group consisting of halogen, C _1-6 alkyl, C _1-6 haloalkyl, C _1-6 alkoxy, C _1-6 haloalkoxy, and C _1-6 alkylcarbonyl. In one aspect, the spiroheterocyclyl ring R ² is optionally substituted with one or more substituents independently selected from the group consisting of halogen, C _1-3 alkyl, C _1-3 haloalkyl, C _1-3 alkoxy, C _1-3 haloalkoxy, and C _1-3 alkylcarbonyl. In another aspect, the spiroheterocyclyl ring R ² is optionally substituted with one or more substituents independently selected from the group consisting of fluoro, methyl, ethyl, propyl, fluoromethyl, difluoromethyl, trifluoromethyl, fluoroethyl, difluoroethyl, trifluoroethyl, trifluoropropyl, methoxy, ethoxy, trifluoromethoxy, trifluoroethoxy, and methylcarbonyl. In another aspect, the spiroheterocyclyl ring R ² is optionally substituted with one or more substituents independently selected from the group consisting of fluoro, methyl, ethyl, fluoromethyl, difluoromethyl, trifluoromethyl, and methylcarbonyl.

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

In some embodiments, two saturated rings of spiroheterocyclyl R ² are /\ /XN\ wherein one or both rings are optionally substituted with one or more substituents independently selected from the group consisting of halogen, C _1-6 alkyl, C _1-6 haloalkyl, C _1-6 alkoxy, C _1-6 haloalkoxy, and C _1-6 alkylcarbonyl. In one aspect, the spiroheterocyclyl ring R ² is optionally substituted with one or more substituents independently selected from the group consisting of halogen, C _1-3 alkyl, C _1-3 haloalkyl, C _1-3 alkoxy, C _1-3 haloalkoxy, and C _1-3 alkylcarbonyl. In another aspect, the spiroheterocyclyl ring R ² is optionally substituted with one or more substituents independently selected from the group consisting of fluoro, methyl, ethyl, propyl, fluoromethyl, difluoromethyl, trifluoromethyl, fluoroethyl, difluoroethyl, trifluoroethyl, trifluoropropyl, methoxy, ethoxy, trifluoromethoxy, trifluoroethoxy, methylcarbonyl, and ethylcarbonyl. In another aspect, the spiroheterocyclyl ring R ² is optionally substituted with one or more substituents independently selected from the group consisting of fluoro, methyl, ethyl, fluoromethyl, difluoromethyl, and trifluoromethyl.

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

In some embodiments, the two saturated spiroheterocyclyl rings R ² are

wherein one or both rings are optionally substituted with one or more substituents independently selected from the group consisting of halogen, C _1-6 alkyl, C _1-6 haloalkyl, C _1-6 alkoxy, C _1-6 haloalkoxy, and C _1-6 alkylcarbonyl. In one aspect, the spiroheterocyclyl ring R ² is optionally substituted with one or more substituents independently selected from the group consisting of halogen, C _1-3 alkyl, C _1-3 haloalkyl, C _1-3 alkoxy, C _1-3 haloalkoxy, and C _1-3 alkylcarbonyl. In another

- 56 048482 In one aspect, the spiroheterocyclyl ring R ² is optionally substituted with one or more substituents independently selected from the group consisting of fluoro, methyl, ethyl, propyl, fluoromethyl, difluoromethyl, trifluoromethyl, fluoroethyl, difluoroethyl, trifluoroethyl, trifluoropropyl, methoxy, ethoxy, trifluoromethoxy, trifluoroethoxy, methylcarbonyl, and ethylcarbonyl. In another aspect, the spiroheterocyclyl ring R ² is optionally substituted with one or more substituents independently selected from the group consisting of fluoro, methyl, ethyl, fluoromethyl, difluoromethyl, and trifluoromethyl.

In some embodiments, the compounds and pharmaceutically acceptable salts are selected from the group consisting of (R)-N-(2-(4-cyanothiazolidin-3-yl)-2-oxoethyl)-6-(3,3-dimethyl-1-oxa-6-azaspiro[3.3]heptan-6yl)quinoline-4-carboxamide (Example 18);

(R)-N-(2-(4-cyanothiazolidin-3-yl)-2-oxoethyl)-6-(1-oxa-6-azaspiro[3.3]heptan-6-yl)quinoline-4-carboxamide (Example 153) and pharmaceutically acceptable salts thereof.

In some embodiments, two saturated rings of spiroheterocyclyl R ² are wherein one or both rings are optionally substituted with one or more substituents independently selected from the group consisting of halogen, C _1-6 alkyl, C _1-6 haloalkyl, C _1-6 alkoxy, C _1-6 haloalkoxy, and C _1-6 alkylcarbonyl. In one aspect, the spiroheterocyclyl ring R ² is optionally substituted with one or more substituents independently selected from the group consisting of halogen, C _1-3 alkyl, C _1-3 haloalkyl, C _1-3 alkoxy, C _1-3 haloalkoxy, and C _1-3 alkylcarbonyl. In another aspect, the spiroheterocyclyl ring R ² is optionally substituted with one or more substituents independently selected from the group consisting of fluoro, methyl, ethyl, propyl, fluoromethyl, difluoromethyl, trifluoromethyl, fluoroethyl, difluoroethyl, trifluoroethyl, trifluoropropyl, methoxy, ethoxy, trifluoromethoxy, trifluoroethoxy, methylcarbonyl, and ethylcarbonyl. In another aspect, the spiroheterocyclyl ring R ² is optionally substituted with one or more substituents independently selected from the group consisting of fluoro, methyl, ethyl, fluoromethyl, difluoromethyl, and trifluoromethyl.

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

In some embodiments, two saturated rings of spiroheterocyclyl R ² are wherein one or both rings are optionally substituted with one or more substituents independently selected from the group consisting of halogen, C _1-6 alkyl, C _1-6 haloalkyl, C _1-6 alkoxy, C _1-6 haloalkoxy, and C _1-6 alkylcarbonyl. In one aspect, the spiroheterocyclyl ring R ² is optionally substituted with one or more substituents independently selected from the group consisting of halogen, C _1-3 alkyl, C _1-3 haloalkyl, C _1-3 alkoxy, C _1-3 haloalkoxy, and C _1-3 alkylcarbonyl. In another aspect, the spiroheterocyclyl ring R ² is optionally substituted with one or more substituents independently selected from the group consisting of fluoro, methyl, ethyl, propyl, fluoromethyl, difluoromethyl, trifluoromethyl, fluoroethyl, difluoroethyl, trifluoroethyl, trifluoropropyl, methoxy, ethoxy, trifluoromethoxy, trifluoroethoxy, methylcarbonyl, and ethylcarbonyl. In another aspect, the spiroheterocyclyl ring R ² is optionally substituted with one or more substituents independently selected from the group consisting of fluoro, methyl, ethyl, fluoromethyl, difluoromethyl, and trifluoromethyl.

In some embodiments, the compounds and pharmaceutically acceptable salts are selected from the group consisting of (7?)-7Y-(2-(4-cyanothiazolidin-3-yl)-2-oxoethyl)-6-(2-azaspiro[3.4]octan-2-yl)quinoline-I4-carboxamide (Example 139);

(7?)-7U-(2-(4-cyanothiazolidin-3-yl)-2-oxoethyl)-6-(5,5-difluoro-2-azaspiro[3.4]octan-2yl)quinoline-4-carboxamide (Example 141) and their pharmaceutically acceptable salts.

In some embodiments, the two saturated spiroheterocyclyl rings R ² are

- 57 048482

wherein one or both rings are optionally substituted with one or more substituents independently selected from the group consisting of halogen, _C1-6 alkyl, _C1-6 haloalkyl, _C1-6 alkoxy, _C1-6 haloalkoxy, and _C1-6 alkylcarbonyl. In one aspect, the spiroheterocyclyl ring ^R2 is optionally substituted with one or more substituents independently selected from the group consisting of halogen, _C1-3 alkyl, _C1-3 haloalkyl, _C1-3 alkoxy, _C1-3 haloalkoxy, and _C1-3 alkylcarbonyl. In another aspect, the spiroheterocyclyl ring R ² is optionally substituted with one or more substituents independently selected from the group consisting of fluoro, methyl, ethyl, propyl, fluoromethyl, difluoromethyl, trifluoromethyl, fluoroethyl, difluoroethyl, trifluoroethyl, trifluoropropyl, methoxy, ethoxy, trifluoromethoxy, trifluoroethoxy, methylcarbonyl, and ethylcarbonyl. In another aspect, the spiroheterocyclyl ring R ² is optionally substituted with one or more substituents independently selected from the group consisting of fluoro, methyl, ethyl, fluoromethyl, difluoromethyl, and trifluoromethyl.

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

In some embodiments, two saturated rings of the spiroheterocyclyl R ² are “5 ^N wherein one or both rings are optionally substituted with one or more substituents independently selected from the group consisting of halogen, C _1-6 alkyl, C _1-6 haloalkyl, C _1-6 alkoxy, C _1-6 haloalkoxy, and C _1-6 alkylcarbonyl. In one aspect, the spiroheterocyclyl ring R ² is optionally substituted with one or more substituents independently selected from the group consisting of halogen, C _1-3 alkyl, C _1-3 haloalkyl, C _1-3 alkoxy, C _1-3 haloalkoxy, and C _1-3 alkylcarbonyl. In another aspect, the spiroheterocyclyl ring R ² is optionally substituted with one or more substituents independently selected from the group consisting of fluoro, methyl, ethyl, propyl, fluoromethyl, difluoromethyl, trifluoromethyl, fluoroethyl, difluoroethyl, trifluoroethyl, trifluoropropyl, methoxy, ethoxy, trifluoromethoxy, and trifluoroethoxy. In another aspect, the spiroheterocyclyl ring R ² is optionally substituted with one or more substituents independently selected from the group consisting of fluoro, methyl, ethyl, fluoromethyl, difluoromethyl, and trifluoromethyl.

In some embodiments, two saturated rings of spiroheterocyclyl R ² are —ς—ν o wherein one or both rings are optionally substituted with one or more substituents independently selected from the group consisting of halogen, C _1-6 alkyl, C _1-6 haloalkyl, C _1-6 alkoxy, C _1-6 haloalkoxy, and C _1-6 alkylcarbonyl. In one aspect, the spiroheterocyclyl ring R ² is optionally substituted with one or more substituents independently selected from the group consisting of halogen, C _1-3 alkyl, C _1-3 haloalkyl, C _1-3 alkoxy, C _1-3 haloalkoxy, and C _1-3 alkylcarbonyl. In another aspect, the spiroheterocyclyl ring R ² is optionally substituted with one or more substituents independently selected from the group consisting of fluoro, methyl, ethyl, propyl, fluoromethyl, difluoromethyl, trifluoromethyl, fluoroethyl, difluoroethyl, trifluoroethyl, trifluoropropyl, methoxy, ethoxy, trifluoromethoxy, trifluoroethoxy, methylcarbonyl, and ethylcarbonyl. In another aspect, the spiroheterocyclyl ring R ² is optionally substituted with one or more substituents independently selected from the group consisting of fluoro, methyl, ethyl, fluoromethyl, difluoromethyl, and trifluoromethyl.

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

In some embodiments, the two saturated spiroheterocyclyl rings R ² are

wherein one or both rings are optionally substituted with one or more substituents, regardless

- 58 048 482 independently selected from the group consisting of halogen, C1-6 alkyl, C1-6 haloalkyl, C1-6 alkoxy, C1-6 haloalkoxy and C _1-6 alkylcarbonyl. In one aspect, the spiroheterocyclyl ring R ² is optionally substituted with one or more substituents independently selected from the group consisting of halogen, C _1-3 alkyl, C _1-3 haloalkyl, C _1-3 alkoxy, C _1-3 haloalkoxy and C _1-3 alkylcarbonyl. In another aspect, the spiroheterocyclyl ring R ² is optionally substituted with one or more substituents independently selected from the group consisting of fluoro, methyl, ethyl, propyl, fluoromethyl, difluoromethyl, trifluoromethyl, fluoroethyl, difluoroethyl, trifluoroethyl, trifluoropropyl, methoxy, ethoxy, trifluoromethoxy, trifluoroethoxy, methylcarbonyl, and ethylcarbonyl. In another aspect, the spiroheterocyclyl ring R ² is optionally substituted with one or more substituents independently selected from the group consisting of fluoro, methyl, ethyl, fluoromethyl, difluoromethyl, and trifluoromethyl.

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

In some embodiments, two saturated rings of spiroheterocyclyl R ² are wherein one or both rings are optionally substituted with one or more substituents independently selected from the group consisting of halogen, C _1-6 alkyl, C _1-6 haloalkyl, C _1-6 alkoxy, C _1-6 haloalkoxy, and C _1-6 alkylcarbonyl. In one aspect, the spiroheterocyclyl ring R ² is optionally substituted with one or more substituents independently selected from the group consisting of halogen, C _1-3 alkyl, C _1-3 haloalkyl, C _1-3 alkoxy, C _1-3 haloalkoxy, and C _1-3 alkylcarbonyl. In another aspect, the spiroheterocyclyl ring R ² is optionally substituted with one or more substituents independently selected from the group consisting of fluoro, methyl, ethyl, propyl, fluoromethyl, difluoromethyl, trifluoromethyl, fluoroethyl, difluoroethyl, trifluoroethyl, trifluoropropyl, methoxy, ethoxy, trifluoromethoxy, trifluoroethoxy, methylcarbonyl, and ethylcarbonyl. In another aspect, the spiroheterocyclyl ring R ² is optionally substituted with one or more substituents independently selected from the group consisting of fluoro, methyl, ethyl, fluoromethyl, difluoromethyl, and trifluoromethyl.

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

In some embodiments, two saturated rings of spiroheterocyclyl R ² are wherein one or both rings are optionally substituted with one or more substituents independently selected from the group consisting of halogen, C _1-6 alkyl, C _1-6 haloalkyl, C _1-6 alkoxy, C _1-6 haloalkoxy, and C _1-6 alkylcarbonyl. In one aspect, the spiroheterocyclyl ring R ² is optionally substituted with one or more substituents independently selected from the group consisting of halogen, C _1-3 alkyl, C _1-3 haloalkyl, C _1-3 alkoxy, C _1-3 haloalkoxy, and C _1-3 alkylcarbonyl. In another aspect, the spiroheterocyclyl ring R ² is optionally substituted with one or more substituents independently selected from the group consisting of fluoro, methyl, ethyl, propyl, fluoromethyl, difluoromethyl, trifluoromethyl, fluoroethyl, difluoroethyl, trifluoroethyl, trifluoropropyl, methoxy, ethoxy, trifluoromethoxy, and trifluoroethoxy. In another aspect, the spiroheterocyclyl ring R ² is optionally substituted with one or more substituents independently selected from the group consisting of fluoro, methyl, ethyl, fluoromethyl, difluoromethyl, and trifluoromethyl.

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

In some embodiments, the two saturated spiroheterocyclyl rings R ² are

- 59 048482

wherein one or both rings are optionally substituted with one or more substituents independently selected from the group consisting of halogen, _C1-6 alkyl, _C1-6 haloalkyl, _C1-6 alkoxy, _C1-6 haloalkoxy, and _C1-6 alkylcarbonyl. In one aspect, the spiroheterocyclyl ring ^R2 is optionally substituted with one or more substituents independently selected from the group consisting of halogen, _C1-3 alkyl, _C1-3 haloalkyl, _C1-3 alkoxy, _C1-3 haloalkoxy, and _C1-3 alkylcarbonyl. In another aspect, the spiroheterocyclyl ring R ² is optionally substituted with one or more substituents independently selected from the group consisting of fluoro, methyl, ethyl, propyl, fluoromethyl, difluoromethyl, trifluoromethyl, fluoroethyl, difluoroethyl, trifluoroethyl, trifluoropropyl, methoxy, ethoxy, trifluoromethoxy, and trifluoroethoxy. In another aspect, the spiroheterocyclyl ring R ² is optionally substituted with one or more substituents independently selected from the group consisting of fluoro, methyl, ethyl, fluoromethyl, difluoromethyl, and trifluoromethyl.

In some embodiments, the compound or pharmaceutically acceptable salt is (R)-N-(2-(4-cyanothiazolidin-3-yl)-2-oxoethyl)-6-(2-oxo-1-oxa-3-azaspiro[5.5]undecan3-yl)quinoline-4-carboxamide (Example 110) or a pharmaceutically acceptable salt thereof.

In some embodiments, the two saturated spiroheterocyclyl rings R ² are

wherein one or both rings are optionally substituted with one or more substituents independently selected from the group consisting of halogen, _C1-6 alkyl, _C1-6 haloalkyl, _C1-6 alkoxy, _C1-6 haloalkoxy, and _C1-6 alkylcarbonyl. In one aspect, the spiroheterocyclyl ring ^R2 is optionally substituted with one or more substituents independently selected from the group consisting of halogen, _C1-3 alkyl, _C1-3 haloalkyl, _C1-3 alkoxy, _C1-3 haloalkoxy, and _C1-3 alkylcarbonyl. In another aspect, the spiroheterocyclyl ring R ² is optionally substituted with one or more substituents independently selected from the group consisting of fluoro, methyl, ethyl, propyl, fluoromethyl, difluoromethyl, trifluoromethyl, fluoroethyl, difluoroethyl, trifluoroethyl, trifluoropropyl, methoxy, ethoxy, trifluoromethoxy, trifluoroethoxy, methylcarbonyl, and ethylcarbonyl. In another aspect, the spiroheterocyclyl ring R ² is optionally substituted with one or more substituents independently selected from the group consisting of fluoro, methyl, ethyl, fluoromethyl, difluoromethyl, and trifluoromethyl.

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

In some embodiments, the two saturated spiroheterocyclyl rings R ² are

wherein one or both rings are optionally substituted with one or more substituents independently selected from the group consisting of halogen, C _1-6 alkyl, C _1-6 haloalkyl, C _1-6 alkoxy, C _1-6 haloalkoxy, and C _1-6 alkylcarbonyl. In one aspect, the spiroheterocyclyl ring R ² is optionally substituted with one or more substituents independently selected from the group consisting of halogen, C _1-3 alkyl, C _1-3 haloalkyl, C _1-3 alkoxy, C _1-3 haloalkoxy, and C _1-3 alkylcarbonyl. In another aspect, the spiroheterocyclyl ring R ² is optionally substituted with one or more substituents independently selected from the group consisting of fluoro, methyl, ethyl, propyl, fluoromethyl, difluoromethyl, trifluoromethyl, fluoroethyl, difluoroethyl, trifluoroethyl, trifluoropropyl, methoxy, ethoxy, trifluoromethoxy, trifluoroethoxy, methylcarbonyl, and ethylcarbonyl. In another aspect, the spiroheterocyclyl ring R ² is optionally substituted with one or more substituents independently selected from the group consisting of fluoro, methyl, ethyl, fluoromethyl, difluoromethyl, and trifluoromethyl.

In some embodiments, the compound or pharmaceutically acceptable salt is (R)-N-(2-(4-cyanothiazolidin-3-yl)-2-oxoethyl)-6-(1,4-dioxa-8-azaspiro[4.5]decan-8yl)quinoline-4-carboxamide (Example 228) or a pharmaceutically acceptable salt thereof. In some embodiments, the two saturated spiroheterocyclyl rings R ² are

wherein one or both rings are optionally substituted with one or more substituents, regardless

- 60 048482 independently selected from the group consisting of halogen, C1-6alkyl, C1-6haloalkyl, _C1-6alkoxy , _{C1-6haloalkoxy} and _{C1-6alkylcarbonyl} . In one aspect, the spiroheterocyclyl ring ^R2 is optionally substituted with one or more substituents independently selected from the group consisting of halogen, _C1-3alkyl , _{C1-3haloalkyl} , _C1-3alkoxy , _{C1-3haloalkoxy} and _{C1-3alkylcarbonyl} . In another aspect, the spiroheterocyclyl ring R ² is optionally substituted with one or more substituents independently selected from the group consisting of fluoro, methyl, ethyl, propyl, fluoromethyl, difluoromethyl, trifluoromethyl, fluoroethyl, difluoroethyl, trifluoroethyl, trifluoropropyl, methoxy, ethoxy, trifluoromethoxy, trifluoroethoxy, methylcarbonyl, and ethylcarbonyl. In another aspect, the spiroheterocyclyl ring R ² is optionally substituted with one or more substituents independently selected from the group consisting of fluoro, methyl, ethyl, fluoromethyl, difluoromethyl, and trifluoromethyl.

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

In some embodiments, the compounds and pharmaceutically acceptable salts are selected from the group consisting of (7?)-7Y-(2-(4-cyanothiazolidin-3-yl)-2-oxoethyl)-6-(2-azaspiro[3.3]heptan-2-yl)quinoline-4-carboxamide (Example 17);

(/?)-L-(2-(4-cyanothiazol id in-3-yl)-2-oxoethyl)-6-(3,3-dimethyl-1-oxa-6azaspiro[3.3]heptan-6-yl) quinoline-4-carboxamide (example 18);

(7?)-7U-(2-(4-cyanothiazolidin-3-yl)-2-oxoethyl)-6-(1-azaspiro[3.3]heptan-1-yl)quinoline4-carboxamide (example 19);

(7?)-7U-(2-(4-cyanothiazolid in-3-yl)-2-oxoethyl)-6-(5-azaspiro[2.5] octan-5 -yl)quinoline4-carboxamide (example 46);

(/f-L-^-N-cyanothiazolidin-3-yl^-oxoethylphb-Sb-azaspiroR^heptan-b-yl^inolin4-carboxamide (example 49);

7U-(2-((7?)-4-cyanothiazolidin-3-yl)-2-oxoethyl)-6-((7?)-6-(fluoromethyl)-5azaspiro[2.4]heptan-5-yl)quinoline -4-carboxamide (example 58);

(7?)-7U-(2-(4-cyanothiazolidin-3-yl)-2-oxoethyl)-6-(1,9-dioxa-4-azaspiro[5.5]undecan-4yl)quinoline-4-carboxamide ( example 99);

(7?)-7U-(2-(4-cyanothiazolidin-3-yl)-2-oxoethyl)-6-(8-oxa-5-azaspiro[3.5]nonan-5yl)quinoline-4-carboxamide (example 104 );

(7?)-7U-(2-(4-cyanothiazolid in-3-yl)-2-oxoethyl)-6-(2-oxo-1-oxa-3 azaspiro[5.5]undecan-3-yl)quinolin- 4-carboxamide (example 110);

(7?)-7U-(2-(4-cyanothiazolidin-3-yl)-2-oxoethyl)-6-(7-oxo-6-oxa-8-azaspiro[4.5]decan8-yl)quinoline-4- carboxamide (example 111);

(7?)-7U-(2-(4-cyanothiazolidin-3-yl)-2-oxoethyl)-6-(2-azaspiro[3.4]octan-2-yl)quinoline4-carboxamide (Example 139);

(7?)-?7-(2-(4-cyanothiazolidin-3-yl)-2-oxoethyl)-6-(5,5-difluoro-2-azaspiro[3.4]octan-2yl)quinoline-4-carboxamide (example 141);

(7?)-7U-(2-(4-cyanothiazolidin-3-yl)-2-oxoethyl)-6-(6-methyl-2-azaspiro[3.3]heptan-2yl)quinoline-4-carboxamide (example 149 );

(7?)-7U-(2-(4-cyanothiazolidin-3-yl)-2-oxoethyl)-6-(6-(trifluoromethyl)-2azaspiro[3.3]heptan-2-yl)quinoline-4-carboxamide ( example 150);

- 61 048482 (/?)-LC2-(4-cyanothiazolidin-3-yl)-2-oxoethyl)-6-(1-oxa-6-azaspiro[3.3]heptan-6yl)quinoline-4-carboxamide (example 153);

(7?)-7U-(2-(4-cyanothiazolidin-3-yl)-2-oxoethyl)-6-(6-fluoro-2-azaspiro[3.3]heptan-2yl)quinoline-4-carboxamide (example 155 );

(7?)-7U-(2-(4-cyanothiazolidin-3-yl)-2-oxoethyl)-6-(3-oxa-9-azaspiro[5.5]undecan-9yl)quinoline-4-carboxamide (example 162 );

(7?)-7U-(2-(4-cyanothiazolidin-3-yl)-2-oxoethyl)-6-(5,8-dioxa-2-azaspiro[3.4]octan-2yl)quinoline-4-carboxamide ( example 163);

(7?)-^-(2-(4-cyanothiazolidin-3-yl)-2-oxoethyl)-6-(5-azaspiro[2.3]hexan-5-yl)quinolin4-carboxamide (Example 164);

(7?)-7U-(2-(4-cyanothiazolidin-3-yl)-2-oxoethyl)-6-(2-oxa-6-azaspiro[3.3]heptan-6yl)quinoline-4-carboxamide (example 166 );

(7?)-6-(6-acetyl-2,6-diazaspiro[3.3]heptan-2-yl)-7U-(2-(4-cyanothiazolidin-3-yl)-2oxoethyl)quinoline-4-carboxamide ( example 184);

(7?)-7U-(2-(4-cyanothiazolidin-3-yl)-2-oxoethyl)-6-(1-thia-6-azaspiro[3.3]heptan-6yl)quinoline-4-carboxamide (Example 222 );

(7?)-M-(2-(4-cyanothiazolidin-3-yl)-2-oxoethyl)-6-(1,5-dioxa-9-azaspiro[5.5]undecan9-yl)quinoline-4-carboxamide ( example 227);

(7?)-7U-(2-(4-cyanothiazolidin-3-yl)-2-oxoethyl)-6-(1,4-dioxa-8-azaspiro[4.5]decane-8yl)quinoline-4-carboxamide ( example 228);

(7?)-7U-(2-(4-cyanothiazolide yn-3-yl)-2-oxoethyl)-6-(2-oxa-7-azaspiro[3.5 ]nonan-7-yl)quinoline-4-carboxamide (Example 229) and their pharmaceutically acceptable salts.

In some embodiments, the compounds and pharmaceutically acceptable salts are selected from the group consisting of (7?)-7Y-(2-(4-cyanothiazolidin-3-yl)-2-oxoethyl)-6-(3,3-dimethyl-1-oxa-6azaspiro[3.3]heptan-6-yl)quinoline-4-carboxamide (Example 18);

(7?)-7U-(2-(4-cyanothiazolidin-3-yl)-2-oxoethyl)-6-(1,9-dioxa-4-azaspiro[5.5]undecan-4yl)quinoline-4-carboxamide ( example 99);

(7?)-7U-(2-(4-cyanothiazolid in-3-yl)-2-oxoethyl)-6-(2-oxo-1-oxa-3 azaspiro[5.5]undecan-3-yl)quinolin- 4-carboxamide (example 110);

(7?)-?7-(2-(4-cyanothiazolidin-3-yl)-2-oxoethyl)-6-(6-(trifluoromethyl)-2azaspiro[3.3]heptan-2-yl)quinoline-4-carboxamide (example 150);

(7?)-7U-(2-(4-cyanothiazolidin-3-yl)-2-oxoethyl)-6-(1-oxa-6-azaspiro[3.3]heptan-6yl)quinoline-4-carboxamide (example 153 );

(7?)-7U-(2-(4-cyanothiazolidin-3-yl)-2-oxoethyl)-6-(5,8-dioxa-2-azaspiro[3.4]octan-2yl)quinoline-4-carboxamide ( example 163);

(7?)-7U-(2-(4-cyanothiazolidin-3-yl)-2-oxoethyl)-6-(2-oxa-6-azaspiro[3.3]heptan-6yl)quinoline-4-carboxamide (example 166 );

(7?)-7U-(2-(4-cyanothiazolidin-3-yl)-2-oxoethyl)-6-(1-thia-6-azaspiro[3.3]heptan-6yl)quinoline-4-carboxamide (Example 222) and their pharmaceutically acceptable salts.

D. R ² is azetidinyl

In some embodiments, the present invention provides compounds characterized by the structure of formula (V),

- 62 048482

R ²⁰ L

R ²⁰ ® ^20d r20c and their pharmaceutically acceptable salts, where

R ¹ , R ³ , R ⁴ , R ⁵ and R ⁶ are independently selected from the group consisting of hydrogen, chlorine, fluorine and methyl;

R ^20a and R ^20b are independently selected from the group consisting of hydrogen and C _1-3 alkyl;

R ^20c and R ^20d are independently selected from the group consisting of hydrogen, fluoro, hydroxy, C _1-3 alkyl, C _3-6 cycloalkyl, C _3-6 cycloalkyl-C _1-3 alkyl, C _1-3 ylkoxy, C _3-6 cycloalkoxy, C _1-3 alkoxy-C _1-3 alkyl, phenyl, tolyl, phenyl-C _1-3 alkyl, morpholinyl, C _1-3 alkylsulfonyl-C _1-3 alkyl and

C _1-3 alkylcarbonylamino-C _1-3 alkyl; and wherein C _1-3 alkyl, C _3-6 cycloalkyl, C _3-6 cycloalkyl-C _1-3 alkyl, C _1-3 alkoxy, C _3-6 cycloalkoxy, C _1-3 alkoxy-C _1-3 alkyl, phenyl and phenyl-C _1-3 alkyl may be further substituted with one or more halogen atoms; and

R ^20e and R ^20f are independently selected from the group consisting of hydrogen and C _1-3 alkyl.

In some embodiments of compounds having the structure of formula (V), one of R ¹ , R ³ , R ⁴ , R ⁵ and R ⁶ is selected from the group consisting of chloro, fluoro and methyl, and all remaining substituents R ¹ , R ³ , R ⁴ , R ⁵ and R ⁶ are hydrogen. In one aspect, one of R ¹ , ^{R 3 ,} R 4 , R ⁵ and R ⁶ is chloro, and all remaining substituents R ¹ , R ³ , R ⁴ , R ⁵ and R ⁶ are hydrogen. In another aspect, one of R ¹ , R ³ , R ⁴ , R ⁵ and R ⁶ is fluoro, and all remaining substituents R ¹ , R ³ , R ⁴ , R ⁵ and R ⁶ are hydrogen. In another aspect, one of R ¹ , R ³ , R ⁴ , R ⁵ and R ⁶ is methyl and all remaining R ¹ , R ³ , R ⁴ , R ⁵ and R ⁶ are hydrogen.

In some embodiments of compounds having the structure of formula (V), all of R ¹ , R ³ , R ⁴ , R ⁵ and R ⁶ are hydrogen.

In some embodiments of compounds having the structure of formula (V), R ^20a and R ^20b are independently selected from the group consisting of hydrogen and methyl;

R ^20c and R ^20d are independently selected from the group consisting of hydrogen, fluoro, hydroxy, C _1-3 alkyl, C _3-6 cycloalkyl, C _1-3 alkoxy, C _1-3 alkoxy-C _1-3 alkyl, morpholinyl, C _1-3 alkylsulfonyl-C _1-3 alkyl and C _1-3 alkylcarbonylamino-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 may be further substituted with one or more halogen atoms; and

R ^20e and R ^20f are independently selected from the group consisting of hydrogen and methyl.

In some embodiments of compounds characterized by the structure of formula (V), R ^20c and R ^20d are independently selected from the group consisting of hydrogen, fluoro, C _1-3 alkyl, C _1-3 alkoxy, morpholinyl, and C _1-3 alkylcarbonylamino-C _1-3 alkyl; and wherein the C _1-3 alkyl and C _1-3 alkoxy may be further substituted with one or more halogen atoms.

In some embodiments, the compounds and pharmaceutically acceptable salts are selected from the group consisting of (5)-?/-(2-(4-cyanothiazolide yn-3-yl)-2-oxoethyl)-6-(3-(fluoromethyl)-3-methylazetidin-1-yl)quinoline-4-carboxamide (Example 27);

(5)-7U-(2-(4-cyanothiazolidin-3-yl)-2-oxoethyl)-6-(3-(fluoromethyl)azetidin-1yl)quinoline-4-carboxamide (example IZ);

(5)-?/-(2-(4-cyanothiazolide 3-yl)-2-oxoethyl)-6-(3-methoxy-3-methylazetidin-1-yl)quinoline-4-carboxamide (Example 151) and their pharmaceutically acceptable salts.

E. R ² is morpholinyl

In some embodiments, the present invention provides compounds characterized by the structure of formula (VI),

- 63 048482

and their pharmaceutically acceptable salts, where

R ¹ , R ³ , R ⁴ , R ⁵ and R ⁶ are independently selected from the group consisting of hydrogen, chlorine, fluorine and methyl;

R ^30a and R ^30b are independently selected from the group consisting of hydrogen, C _1-3 alkyl, halo-C _1-3 alkyl and C _1-3 α-alkoxy-C _1-3 alkyl;

R ^30c and R ^30d are independently selected from the group consisting of hydrogen, halogen, C _1-3 alkyl, halogen-C _1-3 alkyl, C _1-3 alkoxy-C _1-3 alkyl, and C _1-3 alkylsulfonyl-C _1-3 alkyl;

R ^30e and R ^30f are independently selected from the group consisting of hydrogen, halogen, 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

R ^30g and R ^30h are independently selected from the group consisting of hydrogen, C _1-3 alkyl, halo-C _1-3 alkyl, and C _1-3 α-alkoxy-C _1-3 alkyl.

In some embodiments of compounds having the structure of formula (VI), one of R ¹ , R ³ , R ⁴ , R ⁵ , and R ⁶ is selected from the group consisting of chloro, fluoro, and methyl, and all remaining substituents R ¹ , R ³ , R ⁴ , R ⁵ , and R ⁶ are hydrogen. In one aspect, one of R ¹ , R ³ , R ⁴ , R ⁵ , and R ⁶ is chloro, and all remaining substituents R ¹ , R ³ , R ⁴ , R ⁵ , and R ⁶ are hydrogen. In another aspect, one of R ¹ , R ³ , R ⁴ , R ⁵ , and R ⁶ is fluoro, and all remaining substituents R ¹ , R ³ , R ⁴ , R ⁵ , and R ⁶ are hydrogen. In another aspect, one of R ¹ , R ³ , R ⁴ , R ⁵ and R ⁶ is methyl and all remaining R ¹ , R ³ , R ⁴ , R ⁵ and R ⁶ are hydrogen.

In some embodiments of compounds having the structure of formula (VI), all of R ¹ , R ³ , R ⁴ , R ⁵ and R ⁶ are hydrogen.

In some embodiments of compounds having a structure of formula (VI),

R ^30a and R ^30b are independently selected from the group consisting of hydrogen, C _1-2 αalkyl, halo-C _1-2 alkyl and C _1-2 αalkoxy-C _1-2 alkyl;

R ^30c and R ^30d are independently selected from the group consisting of hydrogen, halogen, 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;

R ^30e and R ^30f are independently selected from the group consisting of hydrogen, halogen, 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

R ^30g and R ^30h are independently selected from the group consisting of hydrogen, C _1-2 alkyl, halo-C _1-2 alkyl, and C _1-2 α-alkoxy-C _1-2 alkyl.

In some embodiments, the compounds and pharmaceutically acceptable salts are selected from the group consisting of (R)-N-(2-(4-cyanothiazolidin-3-yl)-2-oxoethyl)-8-methyl-6-morpholinoquinoline-4-carboxamide (Example 9);

(R)-N-(2-(4-cyanothiazolidin-3-yl)-2-oxoethyl)-6-morpholinoquinoline-4-carboxamide (Example 67);

N-(2-((R)-4-cyanothiazolidin-3-yl)-2-oxoethyl)-6-((2R,6S)-2,6-dimethylmorpholino)quinoline-4-carboxamide (Example 68);

N-(2-((R)-4-cyanothiazolidin-3-yl)-2-oxoethyl)-6-((R)-2-(fluoromethyl)morpholino)quinoline-4-carboxamide (Example 69);

N-(2-((R)-4-cyanothiazolidin-3-yl)-2-oxoethyl)-6-((2R,6R)-2,6-dimethylmorpholino)quinoline-4-carboxamide (Example 70);

N-(2-((R)-4-cyanothiazolidin-3-yl)-2-oxoethyl)-6-((S)-2-(fluoromethyl)morpholino)quinoline-4-carboxamide (Example 71);

N-(2-((R)-4-cyanothiazolidin-3-yl)-2-oxoethyl)-6-((R)-2-methylmorpholino)quinoline-4-carboxamide (Example 72);

N-(2-((R)-4-cyanothiazolidin-3-yl)-2-oxoethyl)-6-((S)-2-methylmorpholino)quinoline-4-carboxamide (Example 80) and their pharmaceutically acceptable salts.

F. R ² is piperidin-1-yl

In some embodiments, the present invention provides compounds characterized by the structure of formula (VII).

and their pharmaceutically acceptable salts, where

R ¹ , R ³ , R ⁴ , R ⁵ and R ⁶ are independently selected from the group consisting of hydrogen, chlorine, fluorine and methyl;

R ^40a and R ^40b are independently selected from the group consisting of hydrogen, C _1-3 alkyl and halo-C _1-3 alkyl;

R ^40c and R ^40d are independently selected from the group consisting of hydrogen, fluoro, C _1-3 alkyl, halo-C _1-3 alkyl and C _1-3 alkoxy;

R ^40e and R ^40f are independently selected from the group consisting of hydrogen, fluoro, hydroxy, oxo, C _1-3 alkyl, halo-C _1-3 alkyl, cyclopropyl and C _1-3 alkoxy;

R ^40g and R ^40h are independently selected from the group consisting of hydrogen, fluoro, C _1-3 alkyl, halo-C _1-3 alkyl and C _1-3 alkoxy; and

R ⁴⁰ⁱ and R ^40j are independently selected from the group consisting of hydrogen, C _1-3 alkyl and halo-C _1-3 alkyl.

In some embodiments of compounds having the structure of formula (VII), one of R ¹ , R ³ , R ⁴ , R ⁵ , and R ⁶ is selected from the group consisting of chloro, fluoro, and methyl, and all remaining substituents R ¹ , R ³ , R ⁴ , R ⁵ , and R ⁶ are hydrogen. In one aspect, one of R ¹ , R ³ , R ⁴ , R ⁵ , and R ⁶ is chloro, and all remaining substituents R ¹ , R ³ , R ⁴ , R ⁵ , and R ⁶ are hydrogen. In another aspect, one of R ¹ , R ³ , R ⁴ , R ⁵ , and R ⁶ is fluoro, and all remaining substituents R ¹ , R ³ , R ⁴ , R ⁵ , and R ⁶ are hydrogen. In another aspect, one of R ¹ , R ³ , R ⁴ , R ⁵ and R ⁶ is methyl and all remaining R ¹ , R ³ , R ⁴ , R ⁵ and R ⁶ are hydrogen.

In some embodiments of compounds having the structure of formula (VII), all of R ¹ , R ³ , R ⁴ , R ⁵ and R ⁶ are hydrogen.

In some embodiments of compounds having the structure of formula (VII), R ^40a and R ^40b are independently selected from the group consisting of hydrogen, C1-3 alkyl, and halo-C1-3 alkyl; R ^40c and R ^40d are independently selected from the group consisting of hydrogen, fluoro, C1-3 alkyl, halo- _C1-3 alkyl, and _C1-3 alkoxy;

R ^40e and R ^40f are independently selected from the group consisting of hydrogen, fluoro, hydroxy, C _1-3 alkyl, halo-C _1-3 alkyl, cyclopropyl and C _1-3 alkoxy;

R ^40g and R ^40h are independently selected from the group consisting of hydrogen, fluoro, C _1-3 alkyl, halo-C _1-3 alkyl and C _1-3 alkoxy; and _R 40i _{and R} 40j are independently selected from the group consisting of hydrogen, C _1-3 alkyl and halo-C _1-3 alkyl.

In some embodiments of compounds having the structure of formula (VII), R ^40a and R ^40b are independently selected from the group consisting of hydrogen, C1-3 alkyl, and halo-C1-2 alkyl; R ^40c and R ^40d are independently selected from the group consisting of hydrogen, fluoro, C1-2 alkyl, halo- _C1-2 alkyl, and _C1-2 alkoxy;

R ^40e and R ^40f are independently selected from the group consisting of hydrogen, fluoro, hydroxy, C _1-2 alkyl, halo-C _1-2 alkyl and C _1-2 alkoxy;

R ^40g and R ^40h are independently selected from the group consisting of hydrogen, fluoro, C _1-3 alkyl, halo-C _1-2 alkyl and C _1-2 alkoxy; and

R ⁴⁰ⁱ and R ^40j are independently selected from the group consisting of hydrogen, C _1-2 alkyl and halo-C _1-2 alkyl.

In some embodiments, the compounds and pharmaceutically acceptable salts are selected from the group consisting of

- 65 048482 (/?)-LC2-(4-cyanothiazolidin-3-yl)-2-oxoethyl)-6-(4-methoxypiper idin-1-yl)quinoline4-carboxamide (example 8);

(A)-A-(2-(4-cyanothiazolidin-3-yl)-2-oxoethyl)-6-(4-methoxy-4-methylpiperidin-1yl)quinoline-4-carboxamide (Example 42);

(A)-A-(2-(4-cyanothiazolidin-3-yl)-2-oxoethyl)-6-(4-fluoropiperidin-1-yl)quinoline-4carboxamide (Example 205);

(A)-A-(2-(4-cyanothiazolidin-3-yl)-2-oxoethyl)-6-(4-oxopiperidin-1-yl)quinoline-4-carboxamide (Example 230) and pharmaceutically acceptable salts thereof.

G. R ² is piperidin-4-yl

In some embodiments, the present invention provides compounds characterized by the structure of formula (VIII),

and their pharmaceutically acceptable salts, where

R ¹ , R ³ , R ⁴ , R ⁵ and R ⁶ are independently selected from the group consisting of hydrogen, chlorine, fluorine and methyl;

R ^50a and R ^50b are independently selected from the group consisting of hydrogen, fluoro, C _1-3 alkyl, halo-C _1-3 alkyl and C _1-3 alkoxy;

R ^50c and R ^50d are independently selected from the group consisting of hydrogen, C _1-3 alkyl and halo-C _1-3 alkyl, or together are oxo;

R ^50e is selected from the group consisting of hydrogen, C _1-3 alkyl, halo-C _1-3 alkyl,

C _1-3 alkoxy-C _2-3 alkyl, C _1-3 alkylcarbonylα and C _3-6 cycloalkylcarbonyl;

R ^50f and R ^50g are independently selected from the group consisting of hydrogen, C _1-3 alkyl and halo-C _1-3 alkyl, or together are oxo;

R ^50h and R ⁵⁰¹ are independently selected from the group consisting of hydrogen, fluoro, C _1-3 alkyl, halo-C _1-3 alkyl and C _1-3 alkoxy; and

R ^50j is selected from the group consisting of hydrogen and fluorine.

In some embodiments of compounds having a structure of formula (VIII), one of R ¹ , R ³ , R ⁴ , R ⁵ and R ⁶ is selected from the group consisting of chloro, fluoro and methyl, and all remaining substituents R ¹ , R ³ , R ⁴ , R ⁵ and R ⁶ are hydrogen. In one aspect, one of R ¹ , ^{R 3 ,} R 4 , R ⁵ and R ⁶ is chloro, and all remaining substituents R ¹ , R ³ , R ⁴ , R ⁵ and R ⁶ are hydrogen. In another aspect, one of R ¹ , R ³ , R ⁴ , R ⁵ and R ⁶ is fluoro, and all remaining substituents R ¹ , R ³ , R ⁴ , R ⁵ and R ⁶ are hydrogen. In another aspect, one of R ¹ , R ³ , R ⁴ , R ⁵ and R ⁶ is methyl and all remaining R ¹ , R ³ , R ⁴ , R ⁵ and R ⁶ are hydrogen.

In some embodiments of compounds having the structure of formula (VIII), all of R ¹ , R ³ , R ⁴ , R ⁵ , and R ⁶ are hydrogen.

In some embodiments of compounds having a structure of formula (VIII),

R ¹ , R ³ , R ⁴ , R ⁵ and R ⁶ are independently selected from the group consisting of hydrogen, fluoro and methyl;

R ^50a and R ^50b are independently selected from the group consisting of hydrogen, fluoro, C _1-2 alkyl, halo-C _1-2 alkyl and C _1-2 alkoxy;

R ^50c and R ^50d are independently selected from the group consisting of hydrogen, C _1-2 alkyl and halo-C _1-2 alkyl;

R ^50e is selected from the group consisting of hydrogen, C _1-2 alkyl, halo-C _1-2 alkyl and C _1-2 alkoxy-C _2-3 alkyl;

R ^50f and R ^50g are independently selected from the group consisting of hydrogen, C _1-2 alkyl and halo-C _1-2 alkyl;

R ^50h and R ⁵⁰¹ are independently selected from the group consisting of hydrogen, fluoro, C _1-2 alkyl, halo-C _1-2 alkyl and C _1-2 alkoxy; and

- 66 048482

R ^50j ' is selected from the group consisting of hydrogen and fluorine.

In some embodiments of compounds having the structure of formula (VIII), at least one of R ^50a , R ^50b , R ^50h , R ⁵⁰ⁱ and R ^50j is fluoro.

H. R ² is 3-oxomorpholinyl

In some embodiments, the present invention provides compounds characterized by the structure of formula (IX),

and their pharmaceutically acceptable salts, where

R ¹ , R ³ , R ⁴ , R ⁵ and R ⁶ are independently selected from the group consisting of hydrogen, chlorine, fluorine and methyl;

R ^60a and R ^60b are independently selected from the group consisting of hydrogen and C _1-3 alkyl;

R ^60c and R ^60d are independently selected from the group consisting of hydrogen and C _1-3 alkyl; and

R ^60e and R ^60f are independently selected from the group consisting of hydrogen and C _1-3 alkyl.

In some embodiments of compounds having the structure of formula (IX), one of R ¹ , R ³ , R ⁴ , R ⁵ and R ⁶ is selected from the group consisting of chloro, fluoro and methyl, and all remaining substituents R ¹ , R ³ , R ⁴ , R ⁵ and R ⁶ are hydrogen. In one aspect, one of R ¹ , ^{R 3 ,} R 4 , R ⁵ and R ⁶ is chloro, and all remaining substituents R ¹ , R ³ , R ⁴ , R ⁵ and R ⁶ are hydrogen. In another aspect, one of R ¹ , R ³ , R ⁴ , R ⁵ and R ⁶ is fluoro, and all remaining substituents R ¹ , R ³ , R ⁴ , R ⁵ and R ⁶ are hydrogen. In another aspect, one of R ¹ , R ³ , R ⁴ , R ⁵ and R ⁶ is methyl and all remaining R ¹ , R ³ , R ⁴ , R ⁵ and R ⁶ are hydrogen.

In some embodiments of compounds having the structure of formula (IX), all of R ¹ , R ³ , R ⁴ , R ⁵ and R ⁶ are hydrogen.

In some embodiments of compounds having the structure of formula (IX), R ⁴ is methyl; and all of R ¹ , R ³ , R ⁵ , and R ⁶ are hydrogen.

In some embodiments of compounds having the structure of formula (IX), R ¹ , R ³ , R ⁴ , R ⁵ and R ⁶ are independently selected from the group consisting of hydrogen, fluoro and methyl;

R ^60a and R ^60b are independently selected from the group consisting of hydrogen and C _1-2 alkyl;

R ^60c and R ^60d are independently selected from the group consisting of hydrogen and C _1-2 alkyl; and

R ^60e and R ^60f are independently selected from the group consisting of hydrogen and C _1-2 alkyl.

I. R ² is 5,8-dioxa-2-azaspiro[3.4]octan-2-yl

In some embodiments, the present invention provides compounds characterized by the structure of formula (X),

and their pharmaceutically acceptable salts, where

R ¹ , R ³ , R ⁴ , R ⁵ and R ⁶ are independently selected from the group consisting of hydrogen, chlorine, fluorine and methyl;

R ^70a and R ^70b are independently selected from the group consisting of hydrogen and C _1-3 alkyl;

- 67 048482

R ^70c and R ^70d are independently selected from the group consisting of hydrogen and C _1-3 alkyl;

R ^70e and R ^70f are independently selected from the group consisting of hydrogen and C _1-3 alkyl; and

R ^70g and R ^70h are independently selected from the group consisting of hydrogen and C _1-3 alkyl.

In some embodiments of compounds having a structure of formula (X), one of R ¹ , R ³ , R ⁴ , R ⁵ , and R ⁶ is selected from the group consisting of chloro, fluoro, and methyl, and all remaining substituents R ¹ , R ³ , R ⁴ , R ⁵ , and R ⁶ are hydrogen. In one aspect, one of R ¹ , R ³ , R ⁴ , R ⁵ , and R ⁶ is chloro, and all remaining substituents R ¹ , R ³ , R ⁴ , R ⁵ , and R ⁶ are hydrogen. In another aspect, one of R ¹ , R ³ , R ⁴ , R ⁵ , and R ⁶ is fluoro, and all remaining substituents R ¹ , R ³ , R ⁴ , R ⁵ , and R ⁶ are hydrogen. In another aspect, one of R ¹ , R ³ , R ⁴ , R ⁵ and R ⁶ is methyl and all remaining R ¹ , R ³ , R ⁴ , R ⁵ and R ⁶ are hydrogen.

In some embodiments of compounds having the structure of formula (X), all of R ¹ , R ³ , R ⁴ , R ⁵ , and R ⁶ are hydrogen.

In some embodiments of compounds having a structure of formula (X), R ¹ , R ³ , R ⁴ , R ⁵ and R ⁶ are independently selected from the group consisting of hydrogen, fluoro and methyl;

R ^70a and R ^70b are independently selected from the group consisting of hydrogen and C1-2 alkyl; R ^70c and R ^70d are independently selected from the group consisting of hydrogen and C1-2 alkyl; R ^70e and R ^70f are independently selected from the group consisting of hydrogen and C1-2 alkyl; and R ^70g and R ^70h are independently selected from the group consisting of hydrogen and C1-2 alkyl.

J. R ² is pyridin-3-yl

In some embodiments, the present invention provides compounds characterized by the structure of formula (XI),

R ⁵

R ^80b (XI), and their pharmaceutically acceptable salts, where

R ¹ , R ³ , R ⁴ , R ⁵ and R ⁶ are independently selected from the group consisting of hydrogen, chlorine, fluorine and methyl;

R ^80a is selected from the group consisting of hydrogen, fluoro, C _1-3 alkyl, halo-C _1-3 alkyl and C _1-3 alkoxy;

R ^80b is selected from the group consisting of hydrogen, fluoro, C _1-3 alkyl, halo-C _1-3 alkyl and C _1-3 alkoxy;

R ^80c is selected from the group consisting of hydrogen, fluoro, C _1-3 alkyl, halo-C _1-3 alkyl and C _1-3 alkoxy; and

R ^80d is selected from the group consisting of hydrogen, fluoro, C _1-3 alkyl, halo-C _1-3 alkyl and C _1-3 alkoxy.

In some embodiments of compounds having the structure of formula (XI), one of R ¹ , R ³ , R ⁴ , R ⁵ and R ⁶ is selected from the group consisting of chloro, fluoro and methyl, and all remaining substituents R ¹ , R ³ , R ⁴ , R ⁵ and R ⁶ are hydrogen. In one aspect, one of R ¹ , ^{R 3 ,} R 4 , R ⁵ and R ⁶ is chloro, and all remaining substituents R ¹ , R ³ , R ⁴ , R ⁵ and R ⁶ are hydrogen. In another aspect, one of R ¹ , R ³ , R ⁴ , R ⁵ and R ⁶ is fluoro, and all remaining substituents R ¹ , R ³ , R ⁴ , R ⁵ and R ⁶ are hydrogen. In another aspect, one of R ¹ , R ³ , R ⁴ , R ⁵ and R ⁶ is methyl and all remaining R ¹ , R ³ , R ⁴ , R ⁵ and R ⁶ are hydrogen.

In some embodiments of compounds having the structure of formula (XI), all of R ¹ , R ³ , R ⁴ , R ⁵ , and R ⁶ are hydrogen.

In some embodiments of compounds having the structure of formula (XI), R ¹ , R ³ , R ⁴ , R ⁵ and R ⁶ are independently selected from the group consisting of hydrogen, fluoro and methyl;

R ^80a is selected from the group consisting of hydrogen, fluoro, C _1-2 alkyl, halo-C _1-2 alkyl and C _1-2 alkoxy;

R ^80b is selected from the group consisting of hydrogen, fluoro, C _1-2 alkyl, halo-C _1-2 alkyl and C _1-2 alkoxy;

R ^80c is selected from the group consisting of hydrogen, fluoro, C _1-2 alkyl, halo-C _1-2 alkyl and C _1-2 alkoxy; and

R ^80d is selected from the group consisting of hydrogen, fluoro, C _1-2 alkyl, halo-C _1-2 alkyl and C _1-2 alkoxy.

In some embodiments, the compound or pharmaceutically acceptable salt is (R)-N-(2-(4-cyanothiazolidin-3-yl)-2-oxoethyl)-6-(6-(difluoromethyl)pyridin-3yl)quinoline-4-carboxamide (Example 169) or a pharmaceutically acceptable salt thereof.

K. Additional embodiments

Any embodiment of the compounds described in the present invention may be combined with any other suitable embodiment described herein,

- 68 048482 obtaining additional embodiments. For example, if one embodiment separately or together describes possible groups for R ¹ , R ³ , R ⁴ , R ⁵ and/or R ⁶ and a separate embodiment describes possible groups for R ² , it is to be understood that these embodiments can be combined to obtain an additional embodiment describing the possible groups described for R ¹ , R ³ , R ⁴ , R ⁵ and/or R ⁶ together with the possible groups described for R ² . In other words, for any of the embodiments of the compounds described in the present invention, the substituent R ² can be as defined in any of the embodiments of R ² described below.

The compounds of the present invention are characterized by pharmaceutically acceptable FAP inhibitory activity, measured as described for the hFAP (stable binders) inhibition assay provided in the examples below. In one aspect, the compounds are characterized by FAP inhibitory activity at _IC50 values of less than about 100 nM. In another aspect, the compounds are characterized by FAP inhibitory activity at _IC50 values of less than about 50 nM. In another aspect, the compounds are characterized by FAP inhibitory activity at _IC50 values of less than about 10 nM. In another aspect, the compounds are characterized by FAP inhibitory activity at _IC50 values of less than about 1 nM.

In some embodiments, the compounds of the present invention have a pharmaceutically acceptable surface plasmon resonance (SPR) pK _d value, measured as described for the SPR assay provided in the examples below. In one aspect, the compounds have a surface plasmon resonance (SPR) pK _d value of greater than about 7. In another aspect, the compounds have a surface plasmon resonance (SPR) pK _d value of greater than about 8. In another aspect, the compounds have an SPR pK _d value of greater than about 9. In another aspect, the compounds have an SPR pK _d value of greater than about 10.

In some embodiments, the compounds of the present invention have a pharmaceutically acceptable selectivity for FAP over PREP, as measured as described for the hFAP (stable binders) inhibition assay and the hPREP inhibition assay exemplified below. In one aspect, the compounds are at least about 50-fold more selective for FAP over PREP. In another aspect, the compounds are at least about 100-fold more selective for FAP over PREP. In another aspect, the compounds are at least about 1,000-fold more selective for FAP over PREP. In another aspect, the compounds are at least about 10,000-fold more selective for FAP over PREP. In another aspect, the compounds have a PREP IC50 value of greater than about 0.1 μM. In another aspect, the compounds have a PREP IC50 value of greater than about 1.0 μM. In another aspect, the compounds are characterized by a PREP IC50 value of greater than about 10.0 μM.

In some embodiments, the compounds of the present invention have a pharmaceutically acceptable selectivity for FAP over DPP7, as measured as described for the hFAP (stable binders) inhibition assay and the DPP7 selectivity assay examples below. In one aspect, the compounds are at least about 50-fold more selective for FAP over DPP7. In another aspect, the compounds are at least about 100-fold more selective for FAP over DPP7. In another aspect, the compounds are at least about 1,000-fold more selective for FAP over DPP7. In another aspect, the compounds are at least about 10,000-fold more selective for FAP over DPP7. In another aspect, the compounds have an IC50 for DPP7 that is greater than about 0.1 μM. In another aspect, the compounds have an _IC50 for DPP7 that is greater than about 1 μM. In another aspect, the compounds are characterized by an IC ₅₀ value for DPP7 that is greater than about 10 μM.

In some embodiments, the compounds of the present invention have pharmaceutically acceptable selectivity for FAP over DPP8 and/or DPP9, measured as described for the hFAP Inhibition Assay (Stable Binders), the DPP8 Selectivity Assay, and the DPP9 Selectivity Assay exemplified below. In one aspect, the compounds are selective for FAP over DPP8. In another aspect, the compounds are selective for FAP over DPP9. In another aspect, the compounds are selective for FAP over both DPP8 and DPP9. In one aspect, the compounds are at least about 50-fold selective for FAP over DPP8 and/or DPP9. In another aspect, the compounds are at least about 100-fold selective for FAP over DPP8 and/or DPP9. In another aspect, the compounds are at least about 500-fold selective for FAP over DPP8

- 69 048482 and/or DPP9. In another aspect, the compounds are at least about 1000 times more selective for FAP over DPP8 and/or DPP9. In another aspect, the compounds are characterized by an IC ₅₀ value relative to DPP8 and/or DPP9 that is greater than about 0.01 μM. In another aspect, the compounds are characterized by an IC ₅₀ value relative to DPP8 and/or DPP9 that is greater than about 0.1 μM. In another aspect, the compounds are characterized by an IC ₅₀ value relative to DPP8 and/or DPP9 that is greater than about 0.4 μM.

In some embodiments, the compounds of the present invention have pharmaceutically acceptable metabolic stability, as measured as described for the human liver microsome (HLM) assay provided in the examples below. In one aspect, the compounds have an HLM CLint value of less than about 300 μL/min/mg. In another aspect, the compounds have an HLM _CLint value of less than about 100 μL/min/mg. In another aspect, the compounds have an HLM CLint value of less than about 50 μL/min/mg.

In some embodiments, the compounds of the present invention are characterized by pharmaceutically acceptable metabolic stability, as measured as described for the rat hepatocyte assay (rHep) provided in the examples below. In one aspect, the compounds are characterized by an rHep _CLint value of less than about 300 μL/min/10 ⁶ cells. In another aspect, the compounds are characterized by an rHep CLint value of less than about 100 μL/min/10 ⁶ cells. In another aspect, the compounds are characterized by an rHep CLint value of less than about 50 μL/min/10 ⁶ cells.

In some embodiments, the compounds of the present invention are characterized by a pharmaceutically acceptable Caco-2 AB intrinsic permeability, measured as described for the Caco-2 AB intrinsic permeability assay provided in the examples below. In one aspect, the compounds are characterized by an apparent Caco-2 intrinsic permeability of at least about 0.1 x 10 ⁶ cm/s. In another aspect, the compounds are characterized by an apparent Caco-2 intrinsic permeability of at least about 0.5 x 10 ⁶ cm/s. In another aspect, the compounds are characterized by an apparent Caco-2 intrinsic permeability of at least about 1 x 10 ⁶ cm/s.

In some embodiments, the compounds of the present invention are characterized by a pharmaceutically acceptable bidirectional apparent Caco-2 permeability (ABBA) from A to B, measured as described for the bidirectional apparent Caco-2 permeability (ABBA) from A to B assay provided in the examples below. In one aspect, the compounds are characterized by a bidirectional apparent Caco-2 permeability (ABBA) from A to B of at least about 0.1 x 10 ⁶ cm/s. In another aspect, the compounds are characterized by a bidirectional apparent Caco-2 permeability (ABBA) from A to B of at least about 0.25 x 10 ⁶ cm/s. In another aspect, the compounds are characterized by a bidirectional apparent Caco-2 permeability (ABBA) from A to B of at least about 0.5 x 10 ⁶ cm/s.

In some embodiments, the compounds of the present invention have a pharmaceutically acceptable kinetic solubility, measured as described for the kinetic solubility assay provided in the examples below. In one aspect, the compounds have a kinetic solubility of at least about 1 μM. In another aspect, the compounds have a kinetic solubility of at least about 10 μM. In another aspect, the compounds have a kinetic solubility of at least about 25 μM. In another aspect, the compounds have a kinetic solubility of at least about 50 μM.

L. Salts

The compounds of the present invention may be in a salt form or a non-salt form (i.e., as a free base), and the present invention contemplates both the salt and non-salt forms. The compounds may form acid addition salts or base addition salts. In general, an acid addition salt may be prepared using various inorganic or organic acids. Such salts may generally be formed, for example, by mixing the compound with an acid (e.g., a stoichiometric amount of an acid) using various methods known in the art. This mixing may occur in water, an organic solvent (e.g., ether, ethyl acetate, ethanol, methanol, isopropanol, or acetonitrile), or in an aqueous/organic mixture. In another aspect, the acid addition salts are, for example, a trifluoroacetate salt, a formate salt, an acetic acid salt, or a hydrochloride salt. In general, the base addition salt can be prepared using various inorganic or organic bases, for example, an alkali or alkaline earth metal salt, for example, a sodium, calcium or magnesium salt, or salts of other metals, for example, a potassium or zinc salt, or an ammonium salt, or a salt with an organic base, for example, methylamine, dimethylamine, trimethylamine, piperidine or morpholine. Specia

- 70 048482 sheet, the general principles and methods for preparing pharmaceutical salts will be known in the art, such as those described, for example, in J Pharm Sci. 1977 66, 1. Examples of pharmaceutically acceptable salts are also described in Handbook of Pharmaceutical Salts: Properties, Selection, and Use by Stahl and Wermuth (Wiley-VCH, Weinheim, Germany, 2002).

M. Isomers

The compounds and salts of the present invention may exist in one or more geometric, optical, enantiomeric, and diastereomeric forms, including, but not limited to, cis and trans forms, E and Z forms, and R, S and meso forms. Unless otherwise indicated, reference to a particular compound includes all such isomeric forms, including racemic and other mixtures thereof. If desired, such isomers can be isolated from mixtures thereof by the application or adaptation of known methods (e.g., chromatographic techniques and recrystallization techniques). If desired, such isomers can be prepared by the application or adaptation of known methods. In some embodiments, a single stereoisomer is obtained by isolating it from a mixture of isomers (e.g., a racemate) using, for example, chiral chromatographic separation. In other embodiments, a single stereoisomer is obtained by direct synthesis, for example, from a chiral starting material.

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

In another embodiment, the present invention relates to a pharmaceutical composition comprising a compound or a pharmaceutically acceptable salt thereof, which is a single enantiomer present in an enantiomeric excess (%ee) of >90, >95%, >96%, >97, >98% or >99%, or a pharmaceutically acceptable salt thereof, in combination with one or more pharmaceutically acceptable excipients. In one aspect, the single enantiomer is present in an enantiomeric excess (%ee) of >99%.

N. Additional forms

The compounds and salts of the present invention may exist in various tautomeric forms, and the present description covers all such tautomeric forms. Tautomers are structural isomers that are in equilibrium as a result of migration of a hydrogen atom.

The compounds of the present invention and their pharmaceutically acceptable salts may exist in both solvate (such as hydrates) and unsolvated forms, and this disclosure encompasses all such solvates.

The compounds of the present invention and their pharmaceutically acceptable salts may be in crystalline or amorphous form, and all such forms are encompassed by this disclosure.

The compounds and salts of the present invention may be isotopically labeled (or radioisotopically labeled). In such cases, one or more atoms are replaced by an atom of an atomic mass or mass number different from the atomic mass or mass number normally found in nature. This disclosure encompasses isotopically labeled forms of the compounds disclosed herein. Examples of isotopes that may be included include ² H (also designated as D, deuterium), ³ H (also designated as T, tritium), ⁿ C, ¹³ C, ¹⁴ C, ¹³ N, ¹⁵ N, ¹⁵ O, ¹⁷ O, ¹⁸ O, and ³⁶ Cl. The isotope that is used will depend on the particular application of the radioisotopically labeled derivative. For example, ³ H or ¹⁴ C are often useful for receptor labeling and in vitro competition assays. ⁿ C is often useful for radioimaging applications. In some embodiments, the radionuclide is ³ H. In some embodiments, the radionuclide is ¹⁴ C. In some embodiments, the radionuclide is ⁿ C.

O. Intermediate compounds

In some embodiments, the present invention provides additional compounds that are useful as intermediates for preparing the compounds of the present invention and their pharmaceutically acceptable salts.

III. Methods of application

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

FAP is thought to cleave and inactivate human fibroblast growth factor 21 (FGF-21) (Biochem J 2016, 473, 605), a protein involved in the regulation of glucose and lipid metabolism. Inhibition of FAP is thought to increase endogenous FGF-21 levels and signaling and result in, for example, reduced steatosis, improved insulin sensitivity, improved tole

- 71 048482 glucose tolerance, weight loss and/or reduction in cardiovascular mortality.

FAP is also thought to cleave human α2-antiplasmin (α2AP) (Blood 2004 103, 3783), a protein involved in the regulation of fibrosis and fibrinolysis. Tissue repair involves coagulation, which results in fibrin deposition. Thrombus fibrin is normally lysed primarily by plasmin during its conversion from an inactive form (plasminogen) by plasminogen activators. Fibrinolysis is inhibited by plasminogen activator inhibitor-1 (PAI-1), plasminogen activator inhibitor-2 (PAI-2), and α2AP (Experimental & Molecular Medicine 2020, 52, 367), all of which are induced by tissue injury. FAP converts α2AP to a more active form, which decreases plasmin activity and increases fibrin deposition at the injury site. Inhibition of FAP is suggested to enhance fibrinolysis and improve tissue regeneration at the site of injury (J Thromb Haemost 2013, 11, 2029; Proteomics Clin. Appl. 2014, 8, 454).

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

In view of the above, it is proposed that FAP inhibition collectively reduces fibrosis and inflammation by decreasing hepatic stellate cell activity and enhancing fibrinolysis, and additionally provides beneficial metabolic effects by enhancing FGF21 signaling and improving glucose tolerance.

Therefore, in some embodiments, the present invention provides a method of treating or preventing a FAP-mediated condition in a subject in need thereof by administering to the subject a therapeutically effective amount of a compound of Formula I or a pharmaceutically acceptable salt thereof.

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

In some embodiments, the present invention provides a method of treating or preventing a liver disease in a subject in need thereof by administering to the subject a therapeutically effective amount of a compound of the present invention 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 another aspect, NAFLD is selected from the group consisting of isolated steatosis, non-alcoholic steatohepatitis (NASH), liver fibrosis, and liver cirrhosis. In another aspect, the liver disease is end-stage liver disease. In another aspect, the subject also suffers from or is susceptible to one or more conditions selected from the group consisting of obesity, dyslipidemia, insulin resistance, type 2 diabetes, and renal failure.

In some embodiments, the present invention provides a method of treating a liver disease in a subject in need thereof by administering to the subject a therapeutically effective amount of a compound of the present invention or a pharmaceutically acceptable salt thereof, wherein the subject has a body mass index (BMI) of 27 to 40 kg/ ^m2 . In one aspect, the subject has a BMI of 30 to 39.9 kg/ ^m2 . In another aspect, the subject has a BMI of at least 40 kg/ ^m2 . In another aspect, the subject is overweight. In another aspect, the subject is obese. In another aspect, the liver disease is NAFLD. In another aspect, the liver disease is NASH. In another aspect, the liver disease is liver fibrosis. In another aspect, the liver disease is liver cirrhosis.

In some embodiments, the present invention provides a method of treating a liver disease in a subject in need thereof by administering to the subject a therapeutically effective amount of a compound of the present invention 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 liver cirrhosis.

In some embodiments, the present invention provides a method of treating a liver disease in a subject in need thereof by administering to the subject a therapeutically effective amount of a compound of the present invention 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 disease

- 72 048482 liver disease is liver cirrhosis.

In some embodiments, the present invention provides a method of treating a liver disease in a subject in need thereof by administering to the subject a therapeutically effective amount of a compound of the present invention 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 failure. In another aspect, the liver disease is NAFLD. In another aspect, the liver disease is NASH. In another aspect, the liver disease is liver fibrosis. In another aspect, the liver disease is liver cirrhosis.

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

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

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

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

In some embodiments, the present invention provides a method of treating or preventing non-alcoholic steatohepatitis (NASH) in a subject in need thereof by administering to the subject a therapeutically effective amount of a compound of the present invention or a pharmaceutically acceptable salt thereof. In one aspect, the NASH is NASH stage 1. In another aspect, the NASH is NASH stage 2. In another aspect, the NASH is NASH stage 3. In another aspect, the NASH is NASH stage 4. In another aspect, the subject also suffers from or is susceptible to one or more conditions selected from the group consisting of obesity, dyslipidemia, insulin resistance, type 2 diabetes, and renal failure.

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

In some embodiments, the present invention provides a method of treating or preventing cirrhosis in a subject in need thereof by administering to the subject a therapeutically effective amount of a compound of the present invention or a pharmaceutically acceptable salt thereof. In one aspect, the subject suffers from stage F4 liver cirrhosis. In another aspect, the subject

- 73 048482 also suffers from or is susceptible to one or more conditions selected from the group consisting of obesity, dyslipidemia, insulin resistance, type 2 diabetes, and renal failure.

In some embodiments, the present invention provides a method of treating or preventing type 2 diabetes mellitus in a subject in need thereof by administering to the subject a therapeutically effective amount of a compound of the present invention or a pharmaceutically acceptable salt thereof. In one aspect, the subject is a subject suffering from diabetic kidney disease. In another aspect, the subject suffers from renal failure. In another aspect, administering the compound is an adjunct to diet and exercise. In another aspect, administering the compound also reduces body weight and/or treats obesity. In another aspect, the subject has a BMI of 27 to 40 kg/ ^m2 . In another aspect, the subject has a BMI of 30 to 39.9 kg/ ^m2 . In another aspect, the subject has a BMI of at least 40 kg/ ^m2 . In another aspect, the subject is overweight. In another aspect, the subject is obese.

In some embodiments, the present invention provides a method of improving glycemic control in a subject in need thereof by administering to the subject a therapeutically effective amount of a compound of the present invention or a pharmaceutically acceptable salt thereof. In one aspect, the subject is a subject suffering from type 2 diabetes mellitus. In another aspect, the subject is a subject suffering from diabetic kidney disease. In another aspect, the subject suffers from renal failure. In another aspect, administering the compound is an adjunct to diet and exercise. In another aspect, administering the compound also reduces body weight and/or treats obesity. In another aspect, the subject has a BMI of 27 to 40 kg/ ^m2 . In another aspect, the subject has a BMI of 30 to 39.9 kg/ ^m2 . In another aspect, the subject has a BMI of at least 40 kg/ ^m2 . In another aspect, the subject is overweight. In another aspect, the subject is obese.

In some embodiments, the present invention provides a method of improving glycemic control in a subject with type 2 diabetes mellitus and diabetic kidney disease by administering to the subject a therapeutically effective amount of a compound of the present invention or a pharmaceutically acceptable salt thereof. In one aspect, administering the compound is an adjunct to diet and exercise. In another aspect, administering the compound also reduces body weight and/or treats obesity. In another aspect, the subject has a BMI of 27 kg/ ^m2 to 40 kg/ ^m2 . In another aspect, the subject has a BMI of 30 kg/ ^m2 to 39.9 kg/ ^m2 . In another aspect, the subject has a BMI of at least 40 kg/ ^m2 . In another aspect, the subject is overweight. In another aspect, the subject is obese.

In some embodiments, the present invention provides a method of improving glycemic control in a subject with type 2 diabetes mellitus and renal failure by administering to the subject a therapeutically effective amount of a compound of the present invention or a pharmaceutically acceptable salt thereof. In one aspect, administering the compound is an adjunct to a diet and exercise regimen. In another aspect, administering the compound also reduces body weight and/or treats obesity. In another aspect, the subject has a BMI of 27 kg/ ^m2 to 40 kg/ ^m2 . In another aspect, the subject has a BMI of 30 kg/ ^m2 to 39.9 kg/ ^m2 . In another aspect, the subject has a BMI of at least 40 kg/ ^m2 . In another aspect, the subject is overweight. In another aspect, the subject is obese.

In some embodiments, the present invention provides a method of treating or preventing insulin resistance in a subject by administering to the subject a therapeutically effective amount of a compound of the present invention or a pharmaceutically acceptable salt thereof. In another aspect, the subject is a subject suffering from type 2 diabetes mellitus. In another aspect, the subject is a subject suffering from diabetic kidney disease. In another aspect, the subject suffers from renal failure. Insulin resistance can be measured, for example, using the homeostatic model assessment of insulin resistance (HOMA-IR) and/or the MATSUDA index. HOMA-IR is 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.

In some embodiments, the present invention provides a method of treating or preventing impaired glucose tolerance in a subject in need thereof by administering to the subject a therapeutically effective amount of a compound of the present invention or a pharmaceutically acceptable salt thereof. In one aspect, the subject is a subject suffering from type 2 diabetes mellitus. In another aspect, the subject is a subject suffering from diabetic kidney disease. In another aspect, the subject suffers from renal failure.

In some embodiments, the present invention provides a method of treating a cardiovascular condition in a subject in need of treatment by administering to the subject a therapeutically effective amount of a compound of the present invention or a pharmaceutically acceptable amount thereof.

- 74 048482 of an acceptable salt. 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, hypertrophic cardiomyopathy, ischemic cardiomyopathy, ischemic cardiomyopathy, dilated cardiomyopathy, and idiopathic cardiomyopathy. In another aspect, the cardiovascular condition is atherosclerosis. In another aspect, the cardiovascular condition is venous thromboembolism. In another aspect, the cardiovascular condition is atrial fibrillation.

In some embodiments, the present invention provides a method of treating obesity or an obesity-related condition in a subject in need thereof by administering to the subject a therapeutically effective amount of a compound of the present invention or a pharmaceutically acceptable salt thereof. In one aspect, the obesity-related condition is a metabolic condition associated with obesity. In another aspect, the obesity-related condition is selected from the group consisting of insulin resistance, prediabetes, type 2 diabetes mellitus, impaired glucose tolerance, elevated fasting glucose, and types of glucagonoma. In another aspect, the obesity-related condition is dyslipidemia. In another aspect, the obesity-related condition is a cardiovascular condition selected from the group consisting of heart failure, cardiomyopathy, atherosclerosis, venous thromboembolism, and atrial fibrillation. Another aspect of obesity-related condition is kidney disease.

In some embodiments, the present invention provides a method of reducing body weight in a subject in need thereof by administering to the subject a therapeutically effective amount of a compound of the present invention or a pharmaceutically acceptable salt thereof. In one aspect, the subject is a subject suffering from type 2 diabetes mellitus. In another aspect, the subject is a subject suffering from diabetic kidney disease. In another aspect, the subject suffers from renal failure. In another aspect, administering the compound is an adjunct to diet and exercise. In another aspect, administering the compound also reduces body weight and/or treats obesity. In another aspect, the subject has a BMI of 27 kg/ ^m2 to 40 kg/ ^m2 . In another aspect, the subject has a BMI of 30 kg/ ^m2 to 39.9 kg/ ^m2 . In another aspect, the subject has a BMI of at least 40 kg/ ^m2 . In another aspect, the subject is overweight. In another aspect, the subject is characterized by obesity. In another aspect, the subject's weight is reduced, for example, by at least about 5%, 10%, 15%, 20%, 25%, 30%, 35%, or 40%.

In some embodiments, the present invention provides a method of reducing body fat in a subject in need of treatment by administering to the subject a therapeutically effective amount of a compound of the present invention or a pharmaceutically acceptable salt thereof. In another aspect, the subject is a subject suffering from type 2 diabetes mellitus. In another aspect, the subject is a subject suffering from diabetic kidney disease. In another aspect, the subject suffers from renal failure. In another aspect, administering the compound is an adjunct to diet and exercise. In another aspect, administering the compound also reduces body weight and/or treats obesity. In another aspect, the subject has a BMI of 27 kg/ ^m2 to 40 kg/ ^m2 . In another aspect, the subject has a BMI of 30 kg/ ^m2 to 39.9 kg/ ^m2 . In another aspect, the subject has a BMI of at least 40 kg/ ^m2 . In another aspect, the subject is overweight. In another aspect, the subject is characterized by obesity. In another aspect, the fat is liver fat.

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

In some embodiments, the present invention provides a method for promoting tissue remodeling in a subject in need thereof by administering to the subject a therapeutically effective amount of a compound of the present invention or a pharmaceutically acceptable salt thereof. In one aspect, the subject has suffered cardiac tissue damage due to a myocardial infarction.

In some embodiments, the present invention provides a method for stimulating

- 75 048482 improving wound healing and/or reducing adhesion formation in a subject in need thereof by administering to the subject a therapeutically effective amount of a compound of the present invention or a pharmaceutically acceptable salt thereof. In one aspect, administering the compound promotes wound healing and/or reducing adhesion formation by increasing fibrinolysis.

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

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

In some embodiments, the present invention provides a method of treating cancer in a subject in need of treatment by administering to the subject a therapeutically effective amount of a compound of the present invention 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 cancer, laryngeal cancer, myeloma cells, bladder cancer, cholangiocellular carcinoma, clear cell renal carcinoma, neuroendocrine tumor, oncogenic osteomalacia, sarcoma, CUP (carcinoma of unknown primary origin), thyroid carcinoma, desmoid tumors, glioma, astrocytoma, cervical carcinoma, and prostate cancer. In another aspect, the cancer is hepatocellular carcinoma.

The subject to be treated will typically be a human or a non-human mammal, in particular a human. Suitable subjects may also include domestic or wild animals; companion animals (including dogs, cats, etc.); farm animals (including horses, cows and other ruminants, pigs, poultry, rabbits, etc.); primates (including monkeys such as rhesus macaques, cynomolgus macaques (also known as crab-eating or long-tailed macaques), marmosets, tamarins, chimpanzees, macaques, etc.); and rodents (including rats, mice, gerbils, guinea pigs, etc.).

In some embodiments, the present invention provides compounds of the present invention or pharmaceutically acceptable salts thereof for use as medicaments.

As discussed above, in some embodiments, the present invention provides the use of compounds of Formula I or pharmaceutically acceptable salts thereof for the treatment or prevention of a FAP-mediated condition.

As discussed above, in some embodiments, the present invention provides the use of compounds of Formula I or pharmaceutically acceptable salts thereof for the manufacture of medicaments intended for the treatment or prevention of a FAP-mediated condition.

IV. Combination therapy and fixed-dose combinations

The compounds of the present invention may be used in the methods described above either as single pharmacological agents or in combination with other pharmacological agents or procedures. Such combination therapies may be accomplished by simultaneous, sequential, or separate dosing of the individual components of the treatment. Such combination therapies (and corresponding combination products) employ the compounds of the present invention in the dosage range described herein and the other pharmacological agent(s), typically in their approved dosage range(s).

In some embodiments, the present invention provides a combination suitable for use in the treatment of a condition selected from the previously discussed conditions, wherein the combination comprises a compound of the present invention or a pharmaceutically acceptable salt thereof and a sodium-glucose transport protein-2 (SGLT2) inhibitor. In one aspect, the SGLT2 inhibitor is selected from the group consisting of canagliflozin, dapagliflozin, empagliflozin, ertugliflozin, ipragliflozin, luseogliflozin and remogliflozin. In another aspect, the SGLT2 inhibitor is dapagliflozin.

In some embodiments, the present invention provides a combination suitable for use in the treatment of a condition selected from the previously discussed conditions, wherein the combination comprises a compound of the present invention or a pharmaceutically acceptable salt thereof and metformin.

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In some embodiments, the present invention provides a combination suitable for use in the treatment of a condition selected from the previously discussed conditions, wherein the combination comprises a compound of the present invention or a pharmaceutically acceptable salt thereof and a glucagon-like peptide-1 (GLP-1) receptor agonist. In one aspect, the SGLT2 inhibitor is selected from the group consisting of exenatide, liraglutide, lixisenatide, albiglutide, dulaglutide and semaglutide.

In some embodiments, the present invention provides a combination suitable for use in the treatment of a condition selected from the previously discussed conditions, wherein the combination comprises a compound of the present invention or a pharmaceutically acceptable salt thereof and a dipeptidyl peptidase-4 (DPP4) inhibitor. In one aspect, the DPP4 inhibitor is selected from the group consisting of sitagliptin, vildagliptin, saxagliptin, linagliptin, gemigliptin, anagliptin, teneligliptin, alogliptin, trelagliptin, omarigliptin, evogliptin, gosogliptin and dutogliptin.

In some embodiments, the present invention provides a combination suitable for use in treating a condition selected from the previously discussed conditions, wherein the combination comprises a compound of the present invention, or a pharmaceutically acceptable salt thereof, and a peroxisome proliferator-activated receptor (PPAR) agonist. In one aspect, the PPAR agonist is a PPARa agonist. In another aspect, the PPAR agonist is a PPARy agonist. In another aspect, the PPAR agonist is a PPARa/γ agonist. In another aspect, the PPAR agonist is selected from the group consisting of clofibrate, gemfibrozil, ciprofibrate, bezafibrate, and fenofibrate. In another aspect, the PPAR agonist is a thiazolidinedione. In another aspect, the thiazolidinedione is selected from the group consisting of pioglitazone, rosiglitazone, lobeglitazone, and rivoglitazone. In another aspect, a PPAR agonist stimulates FGF21 expression in the liver.

In some embodiments, the present invention provides a pharmaceutical composition comprising a compound of the present invention 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 use in the treatment of 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.

In some embodiments, the present invention provides a combination suitable for use in the treatment of cancer, wherein the combination comprises a compound of the present 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 another aspect, the immune checkpoint inhibitor is an anti-PD-L1 antibody (e.g., atezolizumab (Tecentriq), avelumab (Bavencio), durvalumab (Imfinzi), etc.). In another aspect, the immune checkpoint inhibitor is an anti-CTLA4 antibody (e.g., ipilimumab (Yervoy), tremelimumab, etc.). In another aspect, the cancer is selected from the group consisting of pancreatic cancer, colon cancer, and rectal cancer.

V. Pharmaceutical compositions

The compounds of the present invention and their pharmaceutically acceptable salts can be administered as pharmaceutical compositions containing one or more pharmaceutically acceptable excipients. Accordingly, in some embodiments, the present invention provides pharmaceutical compositions comprising a compound of the present invention or a pharmaceutically acceptable salt thereof and at least one pharmaceutically acceptable excipient.

The choice of excipient(s) to include in a particular composition will depend on such factors as the route of administration and the form of the composition to be provided. Suitable pharmaceutically acceptable excipients are well known to those skilled in the art and are described, for example, in Handbook of Pharmaceutical Excipients, Sixth Edition, Pharmaceutical Press, edited by Rowe, Ray C; Sheskey, Paul J; Quinn, Marian. Pharmaceutically acceptable excipients may function, for example, as adjuvants, diluents, carriers, stabilizers, flavoring agents, coloring agents, fillers, binders, disintegrants, lubricants, glidants, thickeners, and coating agents. As will be appreciated by those skilled in the art, some pharmaceutically acceptable excipients may serve more than one function and may serve alternative

- 77 048482 tive functions depending on the amount of auxiliary substance present in the composition and on what other auxiliary substances are present in the composition.

The compositions may be in a form suitable for oral administration (e.g., as tablets, troches, hard or soft gelatin capsules, aqueous or oily suspensions, emulsions, dispersible powders or granules, syrups or tinctures), for topical administration (e.g., as creams, ointments, gels, or aqueous or oily solutions or suspensions), for administration by inhalation (e.g., as a finely divided powder or a liquid aerosol), for administration by insufflation (e.g., as a finely divided powder), or for parenteral administration (e.g., as a sterile aqueous or oily solution for intravenous, subcutaneous or intramuscular dosing), or as a suppository for rectal dosing. The compositions may be prepared by conventional procedures using conventional pharmaceutical excipients well known in the art. Thus, compositions intended for oral use may contain, for example, one or more coloring agents, sweetening agents, flavoring agents and/or preservatives.

The daily dosage will necessarily vary depending on the subject being treated, the particular route of administration, any co-administered therapeutic agents, and the severity of the disorder being treated, and may comprise single or multiple doses. Specific dosages may be adjusted depending on, for example, the condition being treated; the age, weight, general health, sex, and diet of the subject; the route of administration; the dosage interval; the rate of excretion; and other drugs co-administered to the subject. A physician of ordinary skill in the art, to whom the description of this application is provided, will be able to determine appropriate dosages and regimens for administering the therapeutic agent to a subject and, if necessary, adjust such dosages and regimens during the course of treatment in accordance with methods well known in the art of therapy. The compound of the present invention or a pharmaceutically acceptable salt thereof will generally be administered to a warm-blooded animal in a unit dose within the range of 2.5-5000 mg/ ^m2 of animal body surface area or about 0.05-100 mg/kg, and this amount normally provides a therapeutically effective dose. A unit dosage form such as a tablet or capsule may contain, for example, from 0.1 to 500 mg, from 0.1 to 250 mg, from 0.1 to 100 mg of the active ingredient.

In some embodiments, the present invention provides pharmaceutical compositions for use in therapy comprising a compound of the present invention or a pharmaceutically acceptable salt thereof and at least one pharmaceutically acceptable excipient.

In some embodiments, the present invention provides pharmaceutical compositions for use in treating a FAP-mediated condition comprising a compound of the present invention or a pharmaceutically acceptable salt thereof and at least one pharmaceutically acceptable excipient. In one aspect, the FAP-mediated condition is selected from the group consisting of liver disease, type 2 diabetes mellitus, cardiovascular conditions, obesity, obesity-related conditions, fibrosis, keloid disorder, inflammation, and cancer.

VI. Sets

The present invention further provides kits comprising a unit dosage form comprising a compound of the present invention or a pharmaceutically acceptable salt thereof contained in a packaging material and a label or package insert that indicates that the unit dosage form can be used to treat one or more of the previously described conditions.

In some embodiments, the kit comprises a unit dosage form comprising a compound of the present invention or a pharmaceutically acceptable salt thereof contained in a packaging material and a label or package insert that indicates that the pharmaceutical composition can be used to treat a FAP-mediated condition. In another aspect, the FAP-mediated condition is a liver disease. In another aspect, the liver disease is selected from the group consisting of fatty liver disease, end-stage liver disease, and liver cirrhosis. In another aspect, the liver disease is selected from the group consisting of non-alcoholic steatohepatitis (NASH) and non-alcoholic fatty liver disease (NAFLD).

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

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VII. Methods of obtaining

The present invention further provides methods for preparing compounds of 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 their pharmaceutically acceptable salts.

The following Schemes 1-14 illustrate routes to synthesize compounds of formula (II) wherein R ¹ , R ² , R ³ , R ⁴ , R ⁵ , R ⁶ and X ¹ are as defined in formula (I), R ⁷ is an alkyl group (e.g., methyl, ethyl or t-butyl), and X ² , X ³ and X ⁴ are leaving groups (e.g., Cl, Br, I or OTf). One skilled in the art will appreciate that such routes are illustrative and do not include all possible routes to the compounds of the present invention. The substituents RX in each scheme are as defined for the compounds of the present invention unless otherwise noted. It is known that the methods of preparation described in schemes 1-14 can be carried out starting from any enantiomer or racemic mixture of compounds of formula (2), (4), (6), (8), (9), (10), (11), (12), (13) or (14), to obtain compounds of formula (II) or any stereoisomer of formula (II).

Scheme 1

Scheme 1 illustrates routes to the synthesis of certain compounds of formula (II). A compound of formula (2) can be reacted with a compound of formula (3) to yield a compound of formula (II). The reaction can be carried out using suitable coupling reagents (e.g., HATU, HOBt/EDC, or T3P) in the presence of a base (typically an organic base such as DIPEA or TEA) using a solvent such as DCM, DMF, EtOAc, or MeCN, or mixtures thereof, and at temperatures typically ranging from 0°C to 60°C.

Scheme 2

Scheme 2 illustrates additional routes to the synthesis of certain compounds of formula (II). A compound of formula (4) can be reacted with a compound of formula (5) to yield a compound of formula (II). The reaction can be carried out using suitable coupling reagents (e.g., HATU, HOBt/EDC, or T3P) in the presence of a base (typically an organic base such as DIPEA or TEA) using a solvent such as DCM, DMF, EtOAc, or MeCN, or mixtures thereof, and at temperatures typically ranging from 0°C to 60°C.

Scheme 3

Scheme 3 illustrates additional routes to the synthesis of certain compounds of formula (II). A compound of formula (6) can be converted to a compound of formula (II) by dehydration using a suitable reagent (typically TFAA or T3P) in a solvent such as DCM, DMF, EtOAc or MeCN or mixtures thereof and at a temperature in the range typically from 0°C to 120°C.

- 79 048482

Scheme 4

Scheme 4 illustrates routes to the synthesis of certain compounds of formula (2). A compound of formula (4) can be reacted with (tert-butoxycarbonyl)glycine (7) to give a compound of formula (8). The reaction can be carried out using suitable coupling reagents (e.g., HATU, HOBt/EDC, or T3P) in the presence of a base (typically an organic base such as DIPEA or TEA) using a solvent such as DCM, DMF, EtOAc, or MeCN, or mixtures thereof, and at temperatures typically ranging from 0°C to 120°C.

The compound of formula (2) can be formed by reacting the compound of 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 acids such as TFA, neat or in a solvent such as DCM, at temperatures typically ranging from 0°C to 60°C.

Scheme 5

(9) (U) (11) (4)

Scheme 5 illustrates routes to the synthesis of certain compounds of formula (4). A compound of formula (10) can be formed by reacting a compound of formula (9) with _NH3 either neat or in solution, such as in water or MeOH, or with a synthetic equivalent of ammonia (e.g. NH4Cl). The reaction can be carried out using suitable coupling reagents (e.g. HATU, HOBt/EDC, T3P or _Boc2O ) in the presence of a base (typically an organic base such as DIPEA or TEA) using a solvent such as THF, DMF, EtOAc or MeCN or a mixture thereof, and at temperatures typically ranging from 0°C to 120°C.

The compound of formula (10) can be converted into the compound of formula (11) by dehydration using a suitable reagent (typically TFAA or T3P) in a solvent such as DCM, DMF, EtOAc or MeCN, or a mixture thereof, and at a temperature ranging typically from 0°C to 120°C.

The compound of formula (4) can be formed by reacting the compound of 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 acids such as TFA, neat or in a solvent such as DCM, at temperatures typically ranging from 0°C to 60°C.

Scheme 6

Scheme 6 illustrates routes for the synthesis of certain compounds of formula (6). A compound of formula (12) can be reacted with a compound of formula (3) to yield a compound of formula (6). The reaction can be carried out under the conditions described for the analogous reaction described in Scheme 1.

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Scheme 7

Scheme 7 illustrates routes for the synthesis of certain compounds of formula (12). A compound of formula (12) can be formed from compounds of formula (13) and (7) using a compound of formula (14). The reaction can be carried out under the conditions described for the analogous reactions disclosed in Scheme 4.

Scheme 8

Scheme 8 illustrates routes to the synthesis of certain compounds of formula (5). A compound of formula (3) can be reacted with a compound of formula (15) to yield a compound of formula (16). The reaction can be carried out using suitable coupling reagents (e.g., HATU, HOBt/EDC, or T3P) in the presence of a base (typically an organic base such as DIPEA or TEA) using a solvent such as DCM, DMF, EtOAc, or MeCN, or mixtures thereof, and at temperatures typically ranging from 0°C to 120°C.

A compound of formula (5) can be formed by reacting a compound of 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 at temperatures ranging from 0°C to reflux temperature. Alternatively, for compounds of formula (16) where R7 = tert-butyl, the reaction can be carried out 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 acids such as TFA, neat or in a solvent such as DCM, at temperatures typically ranging from 0°C to 60°C.

Scheme 9

Scheme 9 illustrates routes to the synthesis of certain compounds of formula (3). A compound of formula (18) can be formed by reacting a compound of 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 an alcohol as a solvent. Alternatively, the reaction can be facilitated by reagents such as SOCl2 in a suitable solvent or using an alcohol (e.g., MeOH or EtOH) as a solvent. Alternatively, a compound of formula (18) can be reacted with an alcohol (e.g. MeOH or EtOH) enhanced with coupling reagents (e.g. EDC or TBTU) in the presence of a base (such as DIPEA, TEA or DMAP) using a solvent such as DCM, DMF, EtOAc or MeCN or mixtures thereof and at temperatures typically ranging from 0°C to 120°C.

A compound of formula (19), wherein R ² is as defined in formula (I), and wherein the point of attachment to the quinoline is through the nitrogen atom, can be formed by reacting a compound of formula (18) with an amine HR ² (20), wherein R ² is as defined in formula (I). The reaction can be catalyzed with a suitable Pd reagent, for example Pd ₂ (dba) ₃ , with a suitable phosphine ligand (for example XPhos, CPhos, SPhos, RuPhos, DavePhos or XantPhos) in the presence of a base (such as Cs ₂ CO ₃ ) in a suitable solvent (such as 1,4-dioxane) optionally in the presence of water at temperatures ranging from room temperature to reflux temperature.

- 81 048482

A compound of formula (19), wherein R ² is as defined in formula (I), and wherein the point of attachment to the quinoline passes through the nitrogen atom, can be formed by reacting a compound of formula (18) with an amine HR ² (20), wherein R ² is as defined in formula (I). The reaction can be catalyzed by a suitable Cu reagent (e.g. CuI or Cu ₂ O) in the presence of a base (such as K2CO3 or Cs ₂ CO3) in a suitable solvent (such as DMF) at temperatures ranging from room temperature to 160°C.

A compound of formula (3) can be formed by reacting a compound of 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 at temperatures ranging from 0°C to reflux temperature. Alternatively, for compounds of formula (19) where R7 = tert-butyl, the reaction can be carried out with a suitable acid (e.g. HCl) in a solvent such as 1,4-dioxane, EtOAc, MeOH or water or mixtures thereof. Alternatively, for compounds of formula (19) where R7 = tert-butyl, the reaction can be carried out using acids such as TFA, neat or in a solvent such as DCM, at temperatures typically ranging from 0°C to 60°C.

Alternatively, a compound of formula (3), wherein R ² is as defined in formula (I), and wherein the point of attachment to the quinoline is through the nitrogen atom, can be formed directly from a compound of formula (17) by reaction with an amine HR ² (20), wherein R ² is as defined in formula (I). The reaction can be carried out under the conditions described for the analogous reactions disclosed above in Scheme 9.

Scheme 10

(21)

Scheme 10 illustrates routes to the synthesis of certain compounds of formula (3). A compound of formula (19), wherein R ² is as defined in formula (I), and wherein the point of attachment to the quinoline is through a carbon atom, can be formed by reacting a compound of formula (18) with a compound BR ² (21), wherein B is a boronic acid, a boronate ester, or a trifluoroborate salt, and wherein R ² is as defined in formula (I). The reaction can be catalyzed with a suitable Pd reagent (e.g., Pd(dppf)Cl ₂ ) in the presence of a base (such as Na 2 CO 3 or K 2 CO 3 ) in a suitable solvent (such as 1,4-dioxane), optionally in the presence of water, at temperatures ranging from room temperature to reflux temperature.

A compound of formula (3) can be formed by reacting a compound of formula (19) under the conditions described for the analogous reactions disclosed in Scheme 9. Alternatively, a compound of formula (3), wherein R ² is as defined in formula (I), and wherein the point of attachment to the quinoline is through a carbon atom, can be formed directly from a compound of formula (17) by reaction with a compound BR ² (21), wherein B is a boronic acid, a boronate ester, or a trifluoroborate salt, and wherein R ² is as defined in formula (I). The reaction can be carried out under the conditions described for the analogous reaction disclosed above in Scheme 10.

Scheme 11

(18) (22) (19)

Scheme 11 illustrates routes to the synthesis of certain compounds of formula (19). A compound of formula (22), wherein B is a boronic acid, boronate ester, or trifluoroborate salt, can be formed by reacting a compound of formula (18) with bis-boronic compounds (e.g., B ₂ (OH) ₄ (hypodiboronic acid) or B ₂ pin ₂ (4,4,4',4',5,5,5',5'-octamethyl-2,2'bis(1,3,2-dioxaborolane)). The reaction can be catalyzed with a suitable Pd reagent (e.g., Pd(dppf)Cl2) in the presence of a base (such as Na2CO3 or K2CO3) in a suitable solvent (such as ethanol or 1,4-dioxane), optionally in the presence of water, at temperatures ranging from

- 82 048482 zone from room temperature to the temperature of phlegm formation.

A compound of formula (19), wherein R ² is as defined in formula (I) and wherein the point of attachment to the quinoline is through a carbon atom, can be formed by reacting a compound of formula (22) with an aryl halide or aryl pseudohalide of formula (23), wherein R ² is as defined in formula (I) and X ³ is attached to R ² through a carbon atom. The reaction can be catalyzed with a suitable Pd reagent (e.g. Pd(dppf)Cl ₂ ) in the presence of a base (such as Na ₂ CO ₃ or K ₂ CO ₃ ) in a suitable solvent (such as 1,4-dioxane) optionally in the presence of water at temperatures ranging from room temperature to reflux temperature.

Scheme 12

Scheme 12 illustrates routes to the synthesis of certain compounds of formula (17). A compound of formula (26) can be formed by reacting a compound of formula (24) with a 2-ketocarboxylic acid of formula (25) or a salt thereof (e.g., sodium salt) in the presence of a base (e.g., NaOH) in water at reflux temperature or at elevated temperatures typically in the range of 100 to 160°C in a sealed vessel or in a sealed tube in a microwave reactor. A compound of formula (17) can be formed by heating a compound of formula (26) either neat or in a suitable solvent (e.g., water) at elevated temperatures typically in the range of 150 to 250°C in a sealed vessel or in a sealed tube in a microwave reactor.

Scheme 13

Scheme 13 illustrates routes to the synthesis of certain compounds of formula (19). A compound of formula (28), wherein R ² is as defined in formula (I), and wherein the point of attachment to the quinoline is through a nitrogen atom or a carbon atom, can be formed from a compound of formula (27) using a synthetic procedure carried out under the conditions described for the analogous reactions disclosed in Schemes 9, 10 and 11.

The compound of formula (19) can be formed by reacting the compound of formula (28) with carbon monoxide (1-10 atm), typically at a pressure of 10 atm, at a temperature in the range of typically 80 to 120°C, in a sealed vessel. The reaction can be catalyzed with a suitable Pd reagent (e.g. Pd(dppf) _Cl2 ) 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 using an alcohol as a solvent.

Scheme 14

Scheme 14 illustrates routes to the synthesis of certain compounds of formula (31). A compound of formula (29), wherein R ⁵⁰ is as defined in formula (VIII), can be formed from a compound of formula (27) by metal-halogen exchange using an organometallic reagent (e.g., BuLi) followed by reaction with an electrophile such as a ketone of formula (30). The reaction can be carried out in a solvent such as THF at a temperature typically in the range of -78°C to room temperature.

A compound of formula (31) in which R ⁵⁰ ' is fluorine can be formed by reacting a compound of formula (29) with a fluorinating agent (e.g. DAST) in a solvent such as DCM at a temperature in the range typically from -20°C to reflux temperature.

The compound of formula (31) can be converted to the compound of formula (VIII) using a synthetic procedure similar to that described in Scheme 13, 10 and 1.

It should be understood that: (i) the organic reactions described in the present invention are carried out in accordance with laboratory practice known to those skilled in the art; (ii) some of the reactions described in the present invention may optionally be carried out in orders other than those set forth herein; (iii) chiral isomers of the compounds in the present invention may be separated at any stage of the synthetic 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 described further in the Examples; (iv) additional and/or different protecting groups may optionally be necessary in some of the steps described above, and (v) therefore, a step of deprotection may optionally be carried out using a method described in the literature and known to those skilled in the art. The introduction and removal of protecting groups for functional groups is described in Protective Groups in Organic Synthesis ^3rd Ed, TW Greene and PGM Wutz, Wiley-Interscience (1999), the publication of which is incorporated herein by reference.

VIII. Examples

The following descriptions of experiments, procedures, examples, and intermediates are intended to illustrate embodiments of the invention and are not intended to be limiting in any way. Other compounds of the invention can be prepared using the methods illustrated in such examples, either alone or in combination with techniques well known in the art.

A. General Conditions

Unless otherwise stated:

(i) operations were carried out at room temperature (RT), i.e. in the range from 17 to 25°C, and under an inert gas atmosphere such as N2, unless otherwise stated;

(ii) if the reaction description refers to the use of a microwave reactor, one of the following microwave reactors was used: Biotage Initiator, Personal Chemistry Emrys Optimizer, Personal Chemistry Smith Creator, or CEM Explorer;

(iii) typically, the progress of reactions was monitored using thin layer chromatography (TLC) and/or analytical high performance liquid chromatography (HPLC or UPLC), which is usually coupled with mass spectrometry (LCMS);

(iv) where necessary, organic solutions were dried over anhydrous _MgSO4 or _Na2SO4 or using ISOLUTE® phase _separator and work-up procedures were carried out using conventional phase separation techniques;

(v) evaporation was performed either by rotary evaporation in vacuo or in a Genevac HT-4/EZ-2 or Biotage V10;

(vi) Unless otherwise stated, flash column chromatography was performed on straight-phase silica gel using either Merck silica gel (Art. 9385) or pre-packed cartridges such as Biotage® SNAP cartridges (40-63 μm silica gel, 4-330 g), Biotage® Sfar Silica НС D cartridges (20 μm, 10-100 g), Interchim puriFlash™ cartridges (25 μm, 4-120 g), Interchim puriFlash™ cartridges (50 μm, 25-330 g), Grace™ GraceResolv™ Silica Flash cartridges (4-120 g) or Agela Flash Colum Silica-CS cartridges (80-330 g), or on reversed-phase silica gel using Agela Technologies C-18 spherical cartridges (20-35 μm, 100A, 80-330g), manually or automatically using the Grace Reveleris® X2 Flash system or similar system;

(vii) reversed-phase preparative HPLC and reversed-phase preparative SFC were performed using standard HPLC and SFC instruments, respectively, equipped with either MS and/or UV triggered fraction collection, using either an isocratic or gradient mobile phase as described in the experimental section and one of the following methods as described below;

Preparative HPLC methods: PrepMethod A: The compound was purified by preparative HPLC on a YMC-Actus Triart C18 ExRS column (5 µm, 150x30 mm i.d.) using a gradient

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MeCN in _H2O / _NH4HCO3 (10 mM) as mobile phase; PrepMethod B: The compound was purified by preparative HPLC on an XBridge™ C18 OBD column (5 μm, 150x30 mm i.d.) using a gradient of MeCN in _H2O / _NH4HCO3 (10 mM) _NH3 (0.1%, aq.) buffer as mobile phase; _PrepMethod C: The compound was purified _by preparative HPLC on an XSelect CSH OBD column (5 μm, 150x30 mm i.d.) using a gradient of MeCN in H2O/FA (0.1%) as mobile phase; PrepMethod D: The compound was purified by preparative HPLC on a XSelect CSH C18 OBD column (5 μm, 250x19 mm i.d.) using a gradient of MeCN in H2O/FA (0.1%) as the mobile phase; PrepMethod E: The compound was purified by preparative HPLC on a Kromasil C8 column (10 μm, 250x20 mm i.d.) using a gradient of MeCN in _H2O /MeCN/FA (95/5/0.2) as the mobile phase; PrepMethod F: The compound was purified by preparative HPLC on a Waters™ Sunfire™ C18 OBD column (5 μm, 150x30 mm i.d.) using a gradient of MeCN in H2O/FA (0.1%) as the mobile phase; PrepMethod G: The compound was purified by preparative HPLC on a Kromasil C8 column (10 μm, 250 x 50 mm i.d.) using a gradient of MeCN in H ₂ O/MeCN/FA (95/5/0.2) as the mobile phase; PrepMethod H: The compound was purified by preparative HPLC on an XBridge™ C18 column (10 μm, 250 x 50 mm i.d.) using a gradient of MeCN in H ₂ O/MeCN/NH ₃ (95/5/0.2) as the mobile phase; PrepMethod I: The compound was purified by preparative HPLC on an XBridge™ C18 OBD column (5 μm, 250x19 mm ID) using a gradient of MeCN in H2O/NH4HCO3 (10 mM) as the mobile phase; PrepMethod N: The compound was purified by preparative HPLC on an XBridge™ C18 column (10 μm, 250x19 mm ID) using a gradient of MeCN in H2O/MeCN/NH3 (95/5/0.2) as the mobile phase; PrepMethod O: The compound was purified by preparative HPLC on an XBridge™ C18 column (5 μm, _250x19 mm i.d.) using a gradient of MeOH in _H2O / _NH4HCO3 (10 mM) as the mobile phase; PrepMethod P: The compound was purified by preparative HPLC on an XBridge™ Shield C18 column (5 μm, 150x30 mm i.d.) using a gradient of MeCN in H2O/FA (0.1%) as the mobile phase; PrepMethod Q: The compound was purified by preparative HPLC on an Xbridge™ C18 ODB column (5 μm, 150x19 mm i.d.) using a gradient of MeCN in H2O/NH3 buffer system (0.2%, pH 10) as the mobile phase; PrepMethod R: The compound was purified by preparative HPLC on an XBridge™ C18 OBD column (5 μm, _150x30 mm i.d.) using a gradient of MeCN in _H2O / _NH4HCO3 (10 mM) as the mobile phase; PrepMethod T: The compound was purified by preparative HPLC on an XBridge™ Shield C18 column (5 μm, 150x30 mm i.d.) using a gradient of MeCN in H2O/NH4CO3 (10 mM)/ _NH3 (0.1%, aq.) buffer as the mobile phase; PrepMethod U: The compound was purified by preparative HPLC on an Xselect CSH F-Phenyl OBD column (5 μm, 250 x 19 mm i.d.) using a gradient of MeCN in H2O/FA (0.1%) as the mobile phase; PrepMethod V: The compound was purified by preparative HPLC on a Waters™ Sunfire™ C18 OBD column (5 μm, 150 x 30 mm i.d.) using a gradient of MeCN in _H2O /FA (0.1 M) as the mobile phase; PrepMethod X: The compound was purified by preparative HPLC on an Xselect CSH OBD column (5 μm, 150 x 30 mm i.d.) using a gradient of MeCN in H2O/FA (0.1%) as the mobile phase.

Preparative SFC methods: PrepMethod SFC-A: The compound was purified by preparative SFC on a Phenomenex Luna® HILIC column (5 μm, 250 x 30 mm i.d.) using EtOH/FA (20 mM) in CO ₂ as the mobile phase; PrepMethod SFC-B: The compound was purified by preparative SFC on a DAICEL DCpak® P4VP, (5 μm, 250 x 20 mm i.d.) using MeOH/2 M NH ₃ in MeOH (99.5/0.5) in CO ₂ as the mobile phase; PrepMethod SFC-C: The compound was purified by preparative SFC on a Waters™ BEH (5 µm, 250 x 30 mm i.d.) using MeOH/ _H2O ( _NH3 50 mM) (97/3) in _CO2 as the mobile phase;

PrepMethod SFC-D: Compound was purified by preparative SFC on a Waters™ BEH (5 μm, 30x250 mm i.d.) using EtOH/FA (20 mM) in CO2 as the mobile phase; PrepMethod SFC-E: Compound was purified by preparative SFC on a Waters™ BEH (5 μm, 250x30 mm i.d.) using _MeOH /NH3 (20 mM) in _CO2 as the mobile phase; PrepMethod SFC-G: Compound was purified by preparative SFC on a Waters™ BEH (3.5 μm, 100x3 mm i.d.) using MeOH/ _NH3 (20 mM) in CO2 as the mobile phase; PrepMethod SFC-H: The compound was purified by preparative SFC on a Phenomenex Luna® HILIC column (5 µm, 250x30 mm i.d.) using _MeOH /NH3 (20 mM) in CO2 as the mobile phase.

The appropriate fractions were collected, combined and lyophilized to give the purified compound, or the appropriate fractions were collected, combined and concentrated under reduced pressure, extracted with DCM or EtOAc, and the organic phase was dried either over Na2SO4 or using a phase separator and then concentrated under reduced pressure to give the purified compound;

(viii) Chiral preparative chromatography was performed using HPLC or SFC on standard HPLC or SFC instruments, respectively, and using either isocratic or procratic

- 85 048482 gradient runs with the mobile phase as described in the experimental section;

(x) yield values, if given, are not necessarily the maximum achievable and reactions were repeated if necessary to obtain more product;

(xi) where certain compounds were prepared as an acid addition salt, for example, a monohydrochloride salt or a dihydrochloride salt, the stoichiometric composition of the salt was based on the number and nature of the basic groups in the compound, and the exact stoichiometric composition of the salt was not usually determined, for example, by elemental analysis;

(xii) In general, the structures of the final products of formula (I) were confirmed by nuclear magnetic resonance (NMR) and/or mass spectrometry; proton NMR chemical shift values were measured on the delta scale using Bruker Avance III 300, 400, 500 and 600 spectrometers operating at ¹ H frequencies of 300, 400, 500 and 600 MHz, respectively. Experiments were typically recorded at 25 °C. Chemical shifts are reported in ppm using the solvent as an internal standard. Protons on heteroatoms, such as NH and OH, are reported only when they are detectable by NMR and thus may be missed. In some cases, protons may be masked or partially masked by solvent peaks and will therefore either be absent and not reported or will be reported as multiplets overlapping with the solvent. The following abbreviations (and their derivatives, e.g. dd, doublet of doublets, etc.) have been used: s, singlet; d, doublet; t, triplet; q, quartet; m, multiplet; br, broad; qn, quintet; p, pentet. In some cases, the structures of the final products of formula (I) may appear as rotamers in the NMR spectrum, in which case only the peaks of the major rotamer are reported. Electrospray mass spectral data were obtained using a Waters Acquity UPLC coupled to a Waters single quadrupole mass spectrometer or similar equipment, acquiring both positive and negative ion data, and generally only those ions related to the parent structure are reported; High-resolution electrospray mass spectral data were obtained using a Waters XEVO qToF mass spectrometer or equivalent coupled to a Waters Acquity UPLC, generating positive and negative ion data, and generally only ions related to the parent structure are shown.

(xiii) the intermediates were not necessarily completely purified, but their structures and purity were assessed by TLC, analytical HPLC/UPLC, and/or NMR analysis, and/or mass spectroscopy;

(xiv) unless otherwise stated, compounds containing an asymmetric carbon and/or sulfur atom were not separated;

(xv) In general, examples and intermediates are named using ChemDraw Professional, version 19.0.0.22 from PerkinElmer. ChemDraw Professional, version 19.0.0.22 generates chemical structure names using the Cahn-Ingold-Prelog (CIP) rules for stereochemistry and follows the IUPAC rules for chemical naming as closely as possible. Stereoisomers are distinguished from each other by stereodescriptors specified in the names and assigned according to the CIP rules.

ChemDraw optionally uses labels in graphical representations of stereocenters, such as 'and' and 'or', to describe the configuration of stereochemical centers present in the structure. In general, chemical structures of examples and intermediates that contain an 'and' label at a stereocenter mean that the configuration of such example or intermediate at that stereocenter is a mixture of both (R) and (S); and an 'or' label means that the configuration of such example or intermediate at that stereocenter is either (S) or (R). Absolute, unspecified 'and' and 'or' stereocenters may be present in the same structure.

Typically, for example structures and intermediates where all stereocenters are designated as 'and', the structure is named with the prefix rac-. For example structures and intermediates where all stereocenters are designated as 'or', the structure is named with the prefix rel-.

In general, examples and intermediates are named using the descriptors (RS) and (SR) to denote common 'and' centers for chemical structures with multiple chiral centers, where only some of them are designated as 'and'. The descriptors (R*) and (S*) are used to denote common 'or' centers for chemical structures with multiple chiral centers, where only some are designated as 'or'.

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

In general, the label isomer 1 corresponds to the first eluting isomer and isomer 2 corresponds to the second eluting isomer on a given chiral HPLC column and eluent, and the distinctions between two isomers containing one or more stereocenters with a completely unknown configuration are used;

(xvi) where reactions involve degassing or purging, this may be accomplished, for example, by purging the reaction solvent with a constant flow of nitrogen for a suitable period

- 86 048482 time (e.g. from 5 to 10 min.) (xvii) in addition to those specified above, the following abbreviations were used:

a2AR a2-antiplasmin Me! iodomethane Ala alanine MeOH methanol AMS 7-amino-4-methylcoumarin min minute(s) water. water ml milliliter atm atmosphere MS mass spectrometry BMI body mass index MTBE Othreot-butyl methyl ether VOS2O di-tert-butyl dicarbonate MW molecular weight BSA bovine serum albumin mass/charge mass spectrometric peak(s) n-BuLi n-butyllithium NAFLD non-alcoholic fatty liver disease tert- ViON 2-methylpropan-2-ol NASH non-alcoholic steatohepatitis WITH degrees Celsius NBS A-bromosuccinimide Chaps (3-((3- cholamidopropyl)dimethylammonium onio)-1-propanesulfonate) NCS A-chlorosuccinimide CLint own clearance NHS A-hydroxysuccinimide END. concentration Ni nickel t- SRVA 3-chloroperoxybenzoic acid NiBr ₂ O(CH ₂ CH ₂ OS H3) ₂ complex of nickel(II) bromide and 2-methoxyethyl ether CPhos 2'-(dicyclohexylphosphanyl)A2,A2,A6,A6-tetramethyl-[1,1 'biphenyl]-2,6-diamine NΝΜΡ A-methyl-2-pyrrolidone SRME cyclopentyl methyl ether NMR nuclear magnetic resonance CR concentration-response n.d. not true Yes dalton OTf trifluoromethanesulfonate DAST diethylaminosulfur trifluoride Papp apparent permeability coefficient DavePh os 2'-(dicyclohexylphosphanyl)A,A-d imethyl- [1,1 '-biphenyl] 2-amine PBS phosphate buffered saline solution DCM dichloromethane PCR polymerase chain reaction DEA diethylamine Pd based catalyst [CAS: 1810068-35-9] methanesulfonato(2-bis(3,5 di(trifluoromethyl)phenylphosphino)-3,6-dimethoxy-2',6'bis(dimethylamino)-1, Gbiphenyl)(2'-methylamino1,1'-biphenyl-2yl) palladium(P) DIPEA A-ethyl-A-isopropylpropane-2- Pd(dba) ₂ bis(dibenzylideneacetone)pal

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amine lady DMAP 4-dimethylaminopyridine Pd ₂ (dba) ₃ (tris(dibenzylideneacetone)dipalladium(O) DMF A,A-dimethylformamide Pd(dppf) _Cl2 -DCM dichloromethane complex with [1,1'-bis(diphenylphosphino)ferrocene]- dichloropalladium(II) (1:1) DMPU Ν,Ν'- dimethylpropylene urea Pd(dtbpf) _Cl2 1,1'-bis(di-tert-butylphosphino)ferrocenepalladium dichloride DMSO dimethyl sulfoxide Pd(OAc) ₂ palladium(P) acetate DPP4 dipeptidyl peptide aza-4 PK pharmacokinetics dppf 1,G- bis(diphenylphosphino)ferrocene PPAR peroxisome proliferator-activated receptor EDC hydrochloride 3- (ethyl iminomethyl enamino) - N, N-d imethylpropan-1-amine PREP prolyl endopeptidase EDTA ethylenediaminetetraacetic acid Pro proline %ee enantiomeric excess rHep rat hepatocytes EPhos Pd G4 With AS No. 2132978-44-8 rpm revolutions per minute ESI ionization electrospray k.t. room temperature EtOAc ethyl acetate RU response unit EtOH ethanol RuPhos dicyclohexyl(2',6'diisopropoxy-[1,1'biphenyl]-2-yl)phosphane _Et2Zn diethylzinc RuPhos Pd G2 chloro(2- dicyclohexylphosphino-2', 6 'diisopropoxy-1, Gbiphenyl)[2-(2'-amino-1, Gbiphenyl)]palladium(II) [CAS

- 88 048482

№1375325-68-0] FA formic acid RuPhos Pd G3 dicyclohexyl(2',6'diisopropoxy-[1,1biphenyl]-2-yl)phosphane(2'amino-[1,1'-biphenyl]-2yl)((methylsulfonyl)oxy)p alladium [CAS No. 1445085-777] FAC final concentration for analysis RuPhos Pd G4 dicyclohexyl(2',6'diisopropoxy-[1,1'biphenyl]-2-yl)phosphane(2'(methylamino)-[1,1 '-biphenyl]- 2- yl)((methylsulfonyl)oxy)p alladium [CAS No. 1599466-85- 9] FAP activating protein of fibroblast prolyl endopeptidase saturation saturated FGF21 fibroblast growth factor 21 SD standard deviation G gram SFC supercritical fluid chromatography GLP1 glucagon-like peptide-1 receptor SGLT2 sodium-glucose transport protein 2 gly glycine SPhos dicyclohexyl(2',6'dimethoxy-[1,1'-biphenyl]-2yl)phosphane 4. watch) SPhos Pd G3 (2-dicyclohexylphosphino2', 6'-dimethoxybiphenyl) [2(2'-amino-1, G-

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biphenyl)] palladium (P) methanesulfonate [C AS No. 1445085-82-4] HATU hexafluorophosphate (1[bis(dimethylamino)methylene] -\H-1,2,3 triazolo[4,5-b]pyridinium-3 oxide twti 2-(1R-benzotriazol-1-yl)1,1,3,3-tetramethyl amino tetrafluoroborate hDPP7 human dipeptidyl peptidase VII TCER tris(2-carboxyethyl)phosphine hydrochloride hDPP8 human dipeptidyl peptidase VIII TEA triethylamine hDPP9 human dipeptidyl peptidase IX TFA trifluoroacetic acid HEPES (4-(2-hydroxyethyl)-1 piperazineethanesulfonic acid) TFAA trifluoroacetic anhydride hFAP activating protein of human fibroblast prolyl endopeptidase THF tetrahydrofuran HFIP 1,1,1,3,3,3 -hexafluoropropan2-ol TLC thin layer chromatography HIS histidine TZR propanephosphonic acid anhydride HLM human liver microsomes Triphosgene bis(trichloromethyl)carbonate HOBt hydrate 1- hydroxybenzotriazole; Tris HCl hydrochloride tris(hydroxymethyl)amine ethane HOME -IR homeostatic model of insulin resistance assessment Triton X-100 tert- octyl phenoxypol etoxyeta NOL HPLC high performance liquid chromatography TsOH i-toluenesulfonic acid

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HRMS high resolution mass spectrometry mcl microliter ICso half-maximal inhibitory concentration UPLC ultra high performance liquid chromatography internal diam. inner diameter UV ultraviolet IPA propan-2-ol vol./vol. volume/volume KOtBu potassium otreot-butoxide XantPhos (9,9-dimethyl-9R-xanthene-4,5diyl)bis(diphenylphosphane) LC liquid chromatography XantPhos Pd G4 [CAS No. 1621274-19-8] m molar XPhos dicyclohexyl(2',4',6'triisopropyl-[1,Gbiphenyl]-2-yl)phosphane MeCN acetonitrile XPhos-Pd-G2 chlorine(2- dicyclohexylphosphino2',4',6'-triisopropyl-1,Hbiphenyl)[2-(2'-amino-1,Hbiphenyl)-]palladium(P), precatalyst X-Phos aminobiphenylpalladium chloride [CAS No. 1310584-14- 5] XPhos Pd G3 methanesulfonate (2-dicyclohexylphosphino-2',4',6'-triisopropyl-1,G-biphenyl)[2-(2'-amino-1,1'biphenyl)]palladium(II) [CAS No. 1445085-55-1]

B. Intermediate compounds

Intermediate 1. tert-Butyl (R)-4-cyanothiazolidine-3-carboxylate

Step a) tert-butyl-(R)-4-carbamoylthiazolidine-3-carboxylate

Boc ₂ O (18.6 mL, 80.2 mmol) was added to a stirred solution of (R)-3-(tert-butoxycarbonyl)thiazolidine-4-carboxylic acid (17.0 g, 72.9 mmol) and pyridine (7.07 mL, 87.5 mmol) in EtOAc (170 mL) and the reaction mixture was stirred at rt for 3 h. Then NH ₃ solution (aq, 25%, 6 mL) was added dropwise and the mixture was stirred at rt overnight. The reaction mixture was diluted with EtOAc, the phases were separated and the organic phase was washed with sat. NaCl solution, dried, filtered through a pad of silica gel, washed with EtOAc and evaporated to give the crude title compound (16.9 g, 100%) as a colourless oil, which was used directly in the next step.

Step b) tert-butyl (R)-4-cyanothiazolidine-3-carboxylate

TFAA (12.4 mL, 87.5 mmol) as a solution in EtOAc (20 mL) was added to a solution of crude tert-butyl(R)-4-carbamoylthiazolidine-3-carboxylate (16.9 g, 72.9 mmol) and pyridine (14.7 mL, 182

- 91 048482 mmol) in EtOAc (150 mL) at rt. The mixture was stirred at rt for 4 h and then diluted with EtOAc, washed with aq. HCl (1 M) and sat. NaHCO ₃ . The organic phase was dried, filtered through a pad of silica gel, washed with EtOAc and evaporated to give a light yellow oil that solidified on standing. The crude solid was suspended in heptane:EtOAc (4:1, 50 mL) and stirred at rt overnight. The solids were filtered, washed with heptane:EtOAc (4:1) and dried to give the title compound (12.0 g, 83%) as a colourless solid;

1H NMR (400 MHz, CDCl ₃ ) δ 5.20 - 4.79 (m, 1H), 4.60 - 4.53 (m, 1H), 4.53 - 4.36 (m, 1H), 3 .40-3.18 (m, 2H), 1.51 (s, 9H).

Intermediate 2. (R)-thiazolidine-4-carbonitrile hydrochloride

ΗΝ^θ kg

A solution of aq. HCl (12 M, 11 mL) in MeOH (140 mL) was slowly added to a solution of tert-butyl (R)-4-cyanothiazolidine-3-carboxylate, intermediate 1 (6.0 g, 28 mmol), in MeOH (140 mL) at rt. The clear, colorless solution was stirred at rt for 2 h. The solvents were evaporated to give the title compound (4.22 g, 100%) as a colorless solid;

1H NMR (400 MHz, CD3OD) δ 4.90 (dd, 1H), 4.35 - 4.24 (m, 2H), 3.37 - 3.24 (m, 2H).

Intermediate 3. tert-Butyl (R)-(2-(4-cyanothiazolidin-3-yl)-2-oxoethyl)carbamate

DIPEA (19.6 mL, 112 mmol) was added to a suspension of (R)-thiazolidine-4-carbonitrile hydrochloride, intermediate 2 (4.22 g, 28 mmol), (tert-butoxycarbonyl)glycine (6.13 g, 35.0 mmol), and T3P (41.6 mL, 70.0 mmol, 50% solution in EtOAc) in EtOAc (120 mL). The mixture was heated at 60 °C for 4 h. The mixture was diluted with EtOAc and washed successively with water, aq. HCl (1 M), and saturated NaHCO ₃ . The organic phase was dried, filtered, and evaporated. The residue was filtered through a plug of silica gel, washed with heptane:EtOAc (1:1) and evaporated to give an oil which was triturated with heptane:DCM to give the title compound (7.60 g, 100%) as a nearly colourless solid;

1H NMR (400 MHz, CDCl ₃ ) δ 5.36 - 5.25 (m, 2H), 4.59 - 4.52 (m, 2H), 4.14 - 3.90 (m, 2H), 3 .29 (d, 2H), 1.45 (s, 9H).

Intermediate 4. (R)-3-glycylthiozolidine-4-carbonitrile hydrochloride

A solution of aq. HCl (12 M, 5.6 mL) in MeOH (140 mL) was slowly added to a solution of tert-butyl (R)-(2-(4-cyanothiazolidin-3-yl)-2-oxoethyl)carbamate, intermediate 3 (7.60 g, 28.0 mmol), in MeOH (140 mL), then the solution was stirred at rt overnight. The solvents were evaporated to give the title compound (5.80 g, 100%) as a colorless solid;

1H NMR (400 MHz, CD3OD) δ 5.34 (t, 1H), 4.72 (d, 1H), 4.62 (d, 1H), 4.11 - 3.94 (m, 2H), 3 .41 - 3.36 (m, 2H).

Intermediate 5. Ethyl 6-(1,2-oxazinan-2-yl)quinoline-4-carboxylate

1,2-Oxazinane hydrochloride (37 mg _, 0.30 mmol) was added to a mixture of ethyl 6-bromoquinoline- _{4-carboxylate (56 mg, 0.20 mmol), Cs2CO3 (195 mg, 0.60 mmol), Pd2dba3 ( 9.0} mg, 10 μmol) and XPhos (9.5 mg, 0.02 mmol) in dioxane (1 mL). The flask was sealed, purged with N2 (gas) and the mixture was heated at 90 °C overnight. The mixture was diluted with EtOAc and washed with water. The organic phase was dried, filtered and evaporated. The residue was purified by straight-phase flash chromatography on silica gel (gradient: 20-50% EtOAc in heptane) to give the title compound (50 mg, 87%) as a yellow oil that solidified on standing; MS m/z (ESI) [M+H]+ 287.2.

- 92 048482

Intermediate 6. 6-(1,2-oxazinan-2-yl)quinoline-4-carboxylic acid

Aqueous NaOH (1 M, 0.52 mL) was added to a solution of ethyl 6-(1,2-oxazinan-2-yl)quinoline-4-carboxylate, intermediate 5 (50 mg, 0.17 mmol), in MeOH (2 mL) and water (1 mL). The mixture was stirred at rt for 3 h, then neutralized with aq. HCl (1 M) and evaporated to give the title compound (45 mg, 100%) as a yellow-red semi-solid; MS m/z (ESI)[M+H]+259.1.

Intermediate 7. Ethyl 3-fluoro-6-morpholinoquinoline-4-carboxylate

Morpholine (70 mg, 0.80 mmol) was added to a mixture _{of ethyl 6-chloro-3-fluoroquinoline-4-carboxylate (101 mg, 0.4 mmol), Cs2CO3 (} 0.391 g, 1.20 mmol), _Pd2dba3 ( ₁₈ mg, 0.02 mmol) and XPhos (19 mg, 0.04 mmol) in dioxane (2 mL). The flask was sealed, purged with N2 (g) and the mixture was heated at 90 °C for 1 h. The mixture was diluted with EtOAc and washed with water. The organic phase was dried, filtered and evaporated to give the title compound (122 mg, 100%) as a yellow semi-solid; MS mass/charge (ESI) [M+H]+ 305.2.

Intermediate 8. 3-fluoro-6-morpholinoquinoline-4-carboxylic acid

Aq. NaOH (1 M, 1.25 mL) was added to a solution of ethyl 3-fluoro-6-morpholinoquinoline-4-carboxylate, intermediate 7 (190 mg, 0.62 mmol), in MeOH (6 mL) and water (3 mL). The mixture was stirred at rt for 3 h. The mixture was neutralized with aq. HCl (1 M) and evaporated to give the title compound (172 mg, 100%) as a red-yellow semi-solid; MS m/z (ESI) [M+H]+ 277.3.

Intermediate 9. Ethyl 6-thiomorpholinoquinoline-4-carboxylate

Thiomorpholine (41 mg, 0.40 mmol) was added to a mixture of ethyl 6-bromoquinoline-4-carboxylate (56 mg, 0.2 mmol _{), Cs2CO3 (} 0.130 g, 0.40 mmol), _Pd2dba3 (9.2 mg, 0.01 mmol) and XPhos (9.5 mg, 0.02 mmol) in dioxane (1 mL). The flask was sealed, purged with _N2 (g ₎ and the mixture was heated at 90 °C overnight. The mixture was diluted with EtOAc, washed with water (3x). The organic phase was dried, filtered and evaporated. The residue was purified by straight-phase flash chromatography on silica gel (gradient: 20-50% EtOAc in heptane) to give the title compound (55 mg, 91%) as a yellow oil; MS m/z (ESI) [M+H]+ 303.2.

Intermediate 10. 6-Thiomorpholinoquinoline-4-carboxylic acid

LiOH (22 mg, 0.91 mmol) was added to a solution of ethyl 6-thiomorpholinoquinoline-4-carboxylate, intermediate 9 (55 mg, 0.18 mmol), in MeOH (1 mL) and water (1 mL). The mixture was stirred at rt overnight and then neutralized with aq. HCl (1 M). The solvents were evaporated under reduced pressure to give the title compound (50 mg, 100%) as a yellow-red semi-solid; MS m/z (ESI) [M+H]+ 275.1.

Intermediate 11. Ethyl 6-(2,2-difluoromorpholino)quinoline-4-carboxylate

2,2-Difluoromorpholine hydrochloride (72 mg, _{0.45 mmol) was added to a mixture of ethyl 6-bromoquinoline-4- 93 048482 carboxylate (84 mg, 0.30 mmol), Cs2CO3 (} 0.293 g, 0.90 mmol), _Pd2dba3 ( ₁₄ mg, 0.02 mmol) and XPhos (14 mg, 0.03 mmol) in dioxane (1.5 mL). The flask was sealed, purged with N2 (g) and the mixture was heated at 90 °C overnight. The mixture was diluted with EtOAc and washed with water. The organic phase was dried, filtered and evaporated. The residue was purified by direct phase flash chromatography on silica gel (heptane:EtOAc 1:1) to give the title compound (85 mg, 88%) as a yellow solid; MS m/z (ESI) [M+H]+ 323.4.

Intermediate 12. 6-(2,2-difluoromorpholino)quinoline-4-carboxylic acid

Aqueous NaOH (1 M, 0.5 mL) was added to a solution of ethyl 6-(2,2-difluoromorpholino)quinoline-4-carboxylate, intermediate 11 (80 mg, 0.25 mmol), in MeOH (2.5 mL) and water (1 mL). The mixture was stirred at rt overnight and then neutralized with aq. HCl (1 M). The solvents were evaporated under reduced pressure to give the title compound (73 mg, 100%) as a yellow solid; MS m/z (ESI) [M+H]+ 295.3.

Intermediate 13. Ethyl 6-(2,2,6,6-tetrafluoromorpholino)quinoline-4-carboxylate

2,2,6,6-Tetrafluoromorpholine (64 mg _{, 0.40 mmol) was added to a mixture of ethyl 6-bromoquinoline-4-carboxylate (56 mg, 0.2 mmol), Cs2CO3 (} 0.195 g, 0.60 mmol), _Pd2dba3 (9.2 mg, 0.01 mmol) and XPhos (9.5 mg, 0.02 mmol) in dioxane (1 _mL ). The flask was sealed, purged with N2 (gas) and the mixture was heated at 90 °C overnight. The mixture was diluted with EtOAc and washed with water. The organic phase was dried, filtered and evaporated. The residue was purified by direct phase flash chromatography on silica gel (gradient: 20-50% EtOAc in heptane) to give the title compound (60 mg, 84%) as a nearly colorless solid; MS m/z (ESI) [M+H]+ 359.2.

Intermediate 14. 6-(2,2,6,6-tetrafluoromorpholino)quinoline-4-carboxylic acid

Aqueous NaOH (1 M, 0.5 mL, 0.50 mmol) was added to a solution of ethyl 6-(2,2,6,6-tetrafluoromorpholino)quinoline-4-carboxylate, intermediate 13 (60 mg, 0.17 mmol), in MeOH (2 mL) and water (1 mL). The mixture was stirred at rt for 3 h and then neutralized with aq. HCl (1 M). The solvents were evaporated under reduced pressure to give the title compound (55 mg, 99%) as a light yellow solid; MS m/z (ESI) [M+H]+ 331.1.

Intermediate 15. Ethyl 6-(2,3-dihydro-4H-benzo[b][1,4]oxazin-4-yl)quinoline-4-carboxylate

3,4-Dihydro-2H-benzo[b][1,4]oxazine (54 mg, 0.40 mmol) was added to a mixture of ethyl 6-bromoquinoline-4-carboxylate (56 mg, 0.2 mmol), _Cs2CO3 (0.130 g, 0.40 mmol) and RuPhosPdG2 (16 mg, 0.02 mmol) in dioxane (1 _mL ). The flask was sealed, purged with N2 (gas) and the mixture was heated at 90 °C overnight. The mixture was diluted with EtOAc and washed with water. The organic phase was dried, filtered and evaporated. The residue was purified by straight-phase flash chromatography on silica gel (gradient: 20-50% EtOAc in heptane) to give the title compound (53 mg, 79%) as a yellow semi-solid; MS m/z (ESI) [M+H]+ 335.2.

Intermediate 16. 6-(2,3-dihydro-4H-benzo[b][1,4]oxazin-4-yl)quinoline-4-carboxylic acid

Vodn. NaOH solution (1M, 0.5 ml) was added to ethyl 6-(2,3-dihydro-4H-benzo[b][1,4]oxazine solution

- 94 048482

4-yl)quinoline-4-carboxylate, intermediate 15 (53 mg, 0.16 mmol), in MeOH (1 ml) and water (0.5 ml). The mixture was stirred at rt overnight and then neutralized with aq. HCl (1 M). The solvents were evaporated under reduced pressure to give the title compound (49 mg, 100%) as a yellow-red semi-solid; MS m/z (ESI) [M+H]+ 307.2.

Intermediate 17. Ethyl 6-((3S,4s,5R)-4-hydroxy-3,5-dimethylpiperidin-1yl)quinoline-4-carboxylate

(3R,4s,5S)-3,5-dimethylpiperidin-4-ol hydrochloride (50 mg, 0.30 mmol) was added to a mixture of ethyl 6-bromoquinoline-4-carboxylate (56 mg, 0.2 mmol), _Cs2CO3 ( _0.195 g, 0.60 mmol), _Pd2 (dba) ₃ (9 mg, 0.01 mmol) and XPhos (9.5 mg, 0.02 mmol) in 1,4-dioxane (1 mL). The flask was sealed, purged with N2 (g) and heated at 90 °C overnight. The mixture was diluted with EtOAc and washed with water. The organic phase was dried, filtered and evaporated. The residue was purified by straight-phase flash chromatography on silica gel (gradient: 20-50% EtOAc in heptane) to give the title compound (20 mg, 30%) as a yellow semi-solid; MS m/z (ESI) [M+H]+ 329.2.

Intermediate 18. 6-((3S,4s,5R)-4-hydroxy-3,5-dimethylpiperidin-1-yl)quinoline-4-carboxylic acid

Aqueous NaOH (1 M, 0.18 mL) was added to a solution of ethyl 6-((3S,4s,5R)-4-hydroxy-3,5-dimethylpiperidin-1-yl)quinoline-4-carboxylate, intermediate 17 (20 mg, 0.06 mmol), in MeOH (1 mL) and water (0.5 mL). The mixture was stirred at rt overnight. The mixture was neutralized with aqueous HCl (1 M) and evaporated to give the title compound (18 mg, 98%) as a yellow-red semi-solid; MS m/z (ESI) [M+H]+ 301.2.

Intermediate 19. tert-Butyl 6-(4-methoxypiperidin-1-yl)quinoline-4-carboxylate

4-Methoxypiperidine (179 mg, 1.56 mmol) was added to tert-butyl 6-bromoquinoline-4-carboxylate (WO2019/154886) (400 mg, 1.30 mmol), CS2CO3 (846 mg, 2.60 mmol), XPhos (124 mg, 0.26 mmol) and _Pd2 (dba) ₃ (119 mg, 0.13 mmol) in 1,4-dioxane (15 mL) at 15 °C under N2 (g). The resulting mixture was stirred at 100 °C for 3 h. The reaction mixture was concentrated and the residue was dissolved in EtOAc (125 mL) and washed successively with water (75 mL) and brine (75 mL). _The organic layer was dried over _Na2SO4 , filtered and evaporated. The residue was purified by preparative TLC (petroleum ether:EtOAc, 3:1) to give the title compound (300 mg, 68%) as a yellow solid; MS m/z (ESI) [M+H]+ 343.1.

Intermediate 20. 6-(4-methoxypiperidin-1-yl)quinoline-4-carboxylic acid

HCl (0.025 ml, 4 M in 1,4-dioxane) was added to tert-butyl 6-(4-methoxypiperidin-1-yl)quinoline-4-carboxylate, intermediate 19 (280 mg, 0.82 mmol), in 1,4-dioxane (15 ml) at 20 °C under air. The resulting mixture was stirred at 20 °C for 20 h. The precipitate was collected by filtration, washed with 1,4-dioxane (100 ml) and dried in vacuo to give the title compound (200 mg, 85%) as a yellow solid; MS m/z (ESI) [M+H]+ 287.1.

- 95 048482

Intermediate 21. 6-bromo-8-methylquinoline-2,4-dicarboxylic acid

5-Bromo-7-methylindolin-2,3-dione (500 mg, 2.08 mmol) was added to a solution of sodium 2-oxopropanoate (275 mg, 2.50 mmol) in aq. NaOH (20%, 10 mL) in a microwave digestion tube. The tube was sealed and heated at 110 °C for 1 h in the microwave reactor and then cooled to rt. The reaction mixture was acidified to pH 2 with aq. HCl (2 M). The precipitate was collected by filtration, washed with water (100 mL) and dried in vacuo to give the title compound (550 mg, 85%) as a yellow solid; MS m/z (ESI) [M+H] ⁺ 309.9.

Intermediate 22. 6-bromo-8-methylquinoline-4-carboxylic acid

6-Bromo-8-methylquinoline-2,4-dicarboxylic acid, intermediate 21 (430 mg, 1.39 mmol), was dissolved in water (15 mL) in a steel reactor. The reactor was sealed and heated at 190 °C for 6 h in an oil bath and then cooled to rt. The precipitate was collected by filtration, washed with water (100 mL) and dried in vacuo to give the title compound (233 mg, 63%) as a yellow solid; MS m/z (ESI) [M+H] ⁺ 265.9.

Intermediate 23. Methyl 6-bromo-8-methylquinoline-4-carboxylate

_SOCl2 (0.082 ml, 1.13 mmol) was slowly added to 6-bromo-8-methylquinoline-4-carboxylic acid, intermediate 22 (300 mg, 1.13 mmol), in MeOH (10 ml) at 15 °C under air. The resulting mixture was stirred at 60 °C for 16 h. The reaction mixture was concentrated, the residue was dissolved in DCM (100 ml) and washed successively with water (50 ml) and brine (50 ml). The organic layer was dried over _Na2SO4 , filtered and evaporated. The crude product was purified by preparative TLC (DCM: _MeOH , 40:1) to give the title compound (250 mg, 79%) as a yellow solid; MS mass/charge (ESI) [M+H] ⁺ 279.9.

Intermediate 24. Methyl 8-methyl-6-morpholinoquinoline-4-carboxylate

Morpholine (311 mg, 3.57 mmol) was added to a mixture of methyl 6-bromo-8-methylquinoline-4-carboxylate, intermediate 23 (200 mg, 0.71 mmol), _Cs2CO3 (465 mg, 1.43 mmol), Pd catalyst [CAS: 1810068-35-9] (82 mg, 0.07 mmol) in 1,4-dioxane (15 mL) at 20 _° C under N2 (g). The resulting mixture was heated at 100 °C for 5 h. The reaction mixture was concentrated, diluted with EtOAc (100 mL), and washed successively with water (50 mL) and brine (50 mL). _The organic layer was dried over _Na2SO4 , filtered and evaporated. The residue was purified by preparative TLC (petroleum ether:EtOAc, 5:1) to give the title compound (190 mg, 93%) as a yellow solid; MS m/z (ESI) [M+H]+ 287.0.

Intermediate 25. 8-methyl-6-morpholinoquinoline-4-carboxylic acid

A solution of NaOH (126 mg, 3.14 mmol) in water (3 ml) was added to a stirred solution of methyl 8-methyl-6-morpholinoquinoline-4-carboxylate, intermediate 24 (180 mg, 0.63 mmol), in MeOH (9 ml) at 20 °C. The resulting mixture was stirred at 20 °C for 2 h. The reaction mixture was acidified to pH 5 with aq. HCl (2 M). The reaction mixture was concentrated and diluted with EtOAc (125 ml), and washed successively with water (50 ml) and brine (50 ml). The organic layer was dried over Na2SO4, filtered and evaporated to give the title compound (150 mg, 88%) as a red solid; MS mass/charge (ESI) [M+H] ⁺ 273.0.

Intermediate 26. 6-bromo-7-methylquinoline-2,4-dicarboxylic acid

5-Bromo-6-methylindolin-2,3-dione (800 mg, 3.33 mmol) was added to sodium 2-oxopropanoate (440 mg, 4.00 mmol) in aq. NaOH (20%, 15 mL) in a microwave digestion tube. The tube was sealed and heated at 110 °C for 1 h in the microwave reactor and then cooled to rt. The reaction mixture was acidified to pH 2 with aq. HCl (2 M). The precipitate was collected by filtration, washed with water (50 mL), and dried in vacuo to afford the title compound (540 mg, 52%) as a brown solid; MS m/z (ESI) [M+H] ⁺ 309.9.

Intermediate 27. 6-bromo-7-methylquinoline-4-carboxylic acid

6-Bromo-7-methylquinoline-2,4-dicarboxylic acid, intermediate 26 (400 mg, 1.29 mmol), was dissolved in water (10 mL) in a steel reactor. The reactor was sealed and heated at 190 °C for 6 h in an oil bath and then cooled to rt. The precipitate was collected by filtration, washed with water (125 mL) and dried in vacuo to give the title compound (200 mg, 58%) as a dark solid; MS m/z (ESI) [M+H] ⁺ 265.9.

Intermediate 28. Methyl 6-bromo-7-methylquinoline-4-carboxylate

_SOCl2 (0.34 ml, 4.7 mmol) was slowly added to 6-bromo-7-methylquinoline-4-carboxylic acid, intermediate 27 (250 mg, 0.94 mmol), in MeOH (10 ml) at 15 °C under air. The resulting mixture was heated at 60 °C for 2 h. The reaction mixture was concentrated, the residue was diluted with DCM (75 ml) and washed successively with water (20 ml) and brine (20 ml). _The organic layer was dried over _Na2SO4 , filtered and evaporated. The residue was purified by preparative TLC (DCM:MeOH, 40:1) to give the title compound (215 mg, 82%) as a yellow solid; MS mass/charge (ESI) [M+H]+ 279.9.

Intermediate 29. Methyl 7-methyl-6-morpholinoquinoline-4-carboxylate

Morpholine (112 mg, 1.29 mmol) was added to methyl 6-bromo-7-methylquinoline-4-carboxylate, intermediate 28 (180 mg, 0.64 mmol), Pd catalyst [CAS: 1810068-35-9] (73 mg, 0.06 mmol) and _Cs2CO3 (419 mg, 1.29 mmol) in 1,4-dioxane (10 mL) at 15 _° C under N2 (g). The resulting mixture was heated at 100 °C for 16 h. The reaction mixture was filtered through filter paper and the filtrate was concentrated. The residue was diluted with EtOAc (100 mL) and washed successively with brine (25 mL) and water (25 mL). _The organic layer was dried over _Na2SO4 , filtered and evaporated. The residue was purified by preparative TLC (petroleum ether:EtOAc, 5:1) to give the title compound (138 mg, 75%) as a yellow solid; MS m/z (ESI) [M+H] ⁺ 287.0.

Intermediate 30. 7-methyl-6-morpholinoquinoline-4-carboxylic acid

NaOH (112 mg, 2.79 mmol) in water (3 mL) was added to a stirred solution of methyl 7-methyl-6-morpholinoquinoline-4-carboxylate, intermediate 29 (160 mg, 0.56 mmol), in MeOH (9 mL) at 16 °C under N2 (g). The resulting mixture was stirred at 20 °C for 2 h. The reaction mixture was adjusted to pH 5 with aq. HCl (2 M). The reaction mixture was concentrated, and the residue was dissolved in EtOAc (50 mL), and washed successively with brine (25 mL) and

- 97 048482 with water (25 ml). The organic layer was dried over Na ₂ SO ₄ , filtered and evaporated to give the title compound (120 mg, 79%) as a yellow solid; MS m/z (ESI) [M+H] ⁺ 273.0.

Intermediate 31. tert-Butyl 6-(2-oxopyrrolidin-1-yl)quinoline-4-carboxylate

Pyrrolidin-2-one (57 mg, 0.67 mmol) was added to tert-butyl 6-bromoquinoline-4-carboxylate (160 mg, 0.52 mmol), _Cs2CO3 (254 mg, 0.78 mmol) and XPhosPdG3 ( ₄₄ mg, 0.05 mmol) in 1,4-dioxane (5 mL) at 15 °C. The resulting suspension was stirred at 100 °C for 2 h under N2 (g). The reaction mixture was filtered through Celite®. The filtrate was concentrated under reduced pressure and the residue was purified by preparative TLC (EtOAc:petroleum ether, 2:1) to give the title compound (160 mg, 99%) as a beige oil that solidified on standing; MS mass/charge (ESI) [M+H] ⁺ 313.15.

Intermediate 32. 6-(2-oxopyrrolidin-1-yl)quinoline-4-carboxylic acid

TFA (5 ml, 65 mmol) was added to a stirred solution of tert-butyl 6-(2-oxopyrrolidin-1yl)quinoline-4-carboxylate, intermediate 31 (140 mg, 0.45 mmol), in DCM (5 ml) at 27 °C. The resulting solution was stirred at 27 °C for 7 h. The solvent was removed under reduced pressure to give the title compound (115 mg, 100%) as a yellow solid; MS m/z (ESI) [M+H]+ 257.0.

Intermediate 33. tert-Butyl 6-(3,3-dimethyl-2-oxopyrrolidin-1-yl)quinoline-4-carboxylate

3,3-Dimethylpyrrolidin-2-one (132 mg, 1.17 mmol) was added to a mixture of tert-butyl 6-bromoquinoline-4-carboxylate (300 mg, 0.97 mmol), _Cs2CO3 ( ₆₃₄ mg, 1.95 mmol), _Pd2 (dba) ₃ (89 mg, 0.10 mmol) and XPhos (93 mg, 0.19 mmol) in 1,4-dioxane (15 mL) at 20 °C under _N2 (g). The resulting mixture was heated at 100 °C for 3 h. The reaction mixture was concentrated, diluted with EtOAc (100 mL) and washed successively with water (25 mL) and brine (25 mL). _The organic layer was dried over _Na2SO4 , filtered and evaporated. The residue was purified by preparative TLC (petroleum ether:EtOAc, 5:1) to give the title compound (220 mg, 66%) as a yellow solid; MS m/z (ESI) [M+H] ⁺ 341.0.

Intermediate 34. 6-(3,3-dimethyl-2-oxopyrrolidin-1-yl)quinoline-4-carboxylic acid

TFA (2 ml, 26 mmol) was added to tert-butyl 6-(3,3-dimethyl-2-oxopyrrolidin-1-yl)quinoline-4-carboxylate, intermediate 33 (200 mg, 0.59 mmol), in DCM (10 ml) at 20 °C under air. The resulting mixture was stirred at 20 °C for 3 h. The reaction mixture was concentrated, redissolved in DCM (50 ml) and washed with water (15 ml). The organic layer was dried over Na ₂ SO ₄ , filtered and evaporated to give the crude product. The residue was purified by preparative TLC (DCM:MeOH, 10:1) to give the title compound (120 mg, 72%) as a yellow solid; MS mass/charge (ESI) [M+H] ⁺ 285.0.

Intermediate 35. tert-Butyl 6-(5,5-dimethyl-2-oxooxazolidin-3-yl)quinoline-4-carboxylate

5,5-Dimethyloxazolidin-2-one (134 mg, 1.17 mmol) was added to a mixture of tert-butyl 6-bromoquinoline-4-carboxylate (300 mg, 0.97 mmol), Cs ₂ CO ₃ (634 mg, 1.95 mmol), Pd ₂ (dba) ₃ (89 mg, 0.10 mmol) and XPhos (93

- 98 048482 mg, 0.19 mmol) in 1,4-dioxane (10 mL) at 20 °C under N2 (g). The resulting mixture was stirred at 100 °C for 3 h. The reaction mixture was concentrated and redissolved in EtOAc (100 mL) and washed successively with water (20 mL) and brine (20 mL). _The organic layer was dried over _Na2SO4 , filtered and evaporated to give the crude product. The residue was purified by preparative TLC (EtOAc:petroleum ether, 1:5) to give the title compound (240 mg, 72%) as a yellow solid; MS w/z (ESI) [M+H] ⁺ 343.1.

Intermediate 36. 6-(5,5-dimethyl-2-oxooxazolidin-3-yl)quinoline-4-carboxylic acid

HCl (4 M in 1,4-dioxane) (10 mL) was added to tert-butyl 6-(5,5-dimethyl-2-oxooxazolidin-3-yl)quinoline-4-carboxylate, intermediate 35 (220 mg, 0.64 mmol), at 20 °C under air. The resulting mixture was stirred at 40 °C for 6 h. The reaction mixture was concentrated, the residue was dissolved in EtOAc (50 mL) and washed with water (20 mL). The organic layer was dried over Na ₂ SO ₄ , filtered and evaporated to give the title compound (150 mg, 82%) as a yellow solid; MS m/z (ESI) [M+H] ⁺ 287.0.

Intermediate 37. tert-Butyl 6-(2-oxopiperidin-1-yl)quinoline-4-carboxylate

Piperidin-2-one (575 mg, 5.80 mmol) was added to tert-butyl 6-bromoquinoline-4-carboxylate (500 mg, 1.45 mmol), _Cs2CO3 ( ₉₄₅ mg, 2.90 mmol), _Pd2 (dba) ₃ (13 mg, 0.01 mmol) and XPhos (14 mg, 0.03 mmol) in 1,4-dioxane (20 mL) at 15 °C. The resulting suspension was stirred at 100 °C for 15 h under N2 (g). The reaction mixture was filtered through Celite®. The solvent was removed under reduced pressure. The residue was purified by preparative TLC (petroleum ether:EtOAc, 4:1) to give the title compound (132 mg, 28%) as a brown solid; MS m/z (ESI) [M+H]+ 327.2.

Intermediate 38. 6-(2-oxopiperidin-1-yl)quinoline-4-carboxylic acid

TFA (0.11 ml, 1.5 mmol) was added to a solution of tert-butyl 6-(2-oxopiperidin-1-yl)quinoline-4-carboxylate, intermediate 37 (120 mg, 0.37 mmol), in DCM (2 ml). The resulting solution was stirred at 25 °C for 6 h. The solvent was removed under reduced pressure to give the title compound (130 mg) as a brown solid; MS m/z (ESI) [M+H] ⁺ 271.15.

Intermediate 39. tert-Butyl 6-(3,3-dimethyl-2-oxopiperidin-1-yl)quinoline-4-carboxylate

3,3-Dimethylpiperidin-2-one (825 mg, 6.49 mmol) was added to a mixture of tert-butyl 6-bromoquinoline-4-carboxylate (500 mg, 1.62 mmol), _Cs2CO3 ( ₇₉₃ mg, 2.43 mmol), _Pd2 (dba) ₃ (15 mg, 0.02 mmol) and XPhos (15 mg, 0.03 mmol) in 1,4-dioxane (15 mL) under N2 (g). The resulting suspension was stirred at 100 °C for 24 h. The reaction mixture was filtered through silica gel. The solvent was removed under reduced pressure. The residue was purified by preparative TLC (petroleum ether:EtOAc, 2:1) to give the title compound (80 mg, 14%) as a brown solid. MS m/z (ESI) [M+H] ⁺ 355.2.

Intermediate 40. 6-(3,3-dimethyl-2-oxopiperidin-1-yl)quinoline-4-carboxylic acid

TFA (0.061 mL, 0.79 mmol) was added to the solution of tert-butyl-6-(3,3-dimethyl-2-oxopiperidine-1

- 99 048482 yl)quinoline-4-carboxylate, intermediate 39 (70 mg, 0.20 mmol), in DCM (2 ml). The resulting solution was stirred at 25 °C for 6 h. The solvent was removed under reduced pressure to give the title compound (60 mg, 100%) as a brown solid; MS m/z (ESI) [M+H]+ 299.15.

Intermediate 41. tert-Butyl 6-(2,2-dimethyl-3-oxomorpholino)quinoline-4-carboxylate

2,2-Dimethylmorpholin-3-one (122 mg, 0.94 mmol) was added to a mixture of tert-butyl 6-bromoquinoline-4-carboxylate (291 mg, 0.94 mmol), Cs ₂ CO ₃ (616 mg, 1.89 mmol), Pd ₂ (dba) ₃ (86 mg, 0.09 mmol) and CPhos (82 mg, 0.19 mmol) in 1,4-dioxane (1 ml) at 25°C.

The resulting suspension was stirred at 100 °C for 2 h. The reaction mixture was extracted with DCM (3 x 100 mL). The organic phases were combined and washed with sat. brine (2 x 60 mL). The organic layer was dried over Na ₂ SO ₄ , filtered and concentrated under reduced pressure. The residue was purified by preparative TLC (petroleum ether:EtOAc, 1:2) to give the title compound (299 mg, 89%) as a yellow solid; MS m/z (ESI) [M+H] ⁺ 357.2.

Intermediate 42. 6-(2,2-dimethyl-3-oxomorpholino)quinoline-4-carboxylic acid

HCl (4 M in 1,4-dioxane, 10 ml) was added to tert-butyl 6-(5,5-dimethyl-2-oxooxazolidin-3-yl)quinoline-4-carboxylate, intermediate 41 (289 mg, 0.84 mmol), at 20 °C under air. The resulting mixture was stirred at 40 °C for 12 h. The solvent was removed under reduced pressure to give the title compound (315 mg) as a beige solid; MS m/z (ESI) [M+H] ⁺ 301.1.

Intermediate 43. tert-Butyl 6-(2-azaspiro[3.3]heptan-2-yl)quinoline-4-carboxylate

2-Azaspiro[3.3]heptane hydrochloride (347 mg, 2.60 mmol) was added to tert-butyl 6-bromoquinoline-4-carboxylate (400 mg, 1.30 mmol), _Cs2CO3 ( _1.69 g, 5.19 mmol), _Pd2 (dba) ₃ (119 mg, 0.13 mmol) and XPhos (124 mg, 0.26 mmol) in 1,4-dioxane (10 mL) at 10 °C. The resulting suspension was stirred at 100 °C for 3 h under N2 (g). The solvent was removed under reduced pressure. The residue was purified by preparative TLC (petroleum ether:EtOAc, 2:1) to give the title compound (150 mg, 36%) as a yellow solid. MS m/z (ESI) [M+H] ⁺ 325.3.

Intermediate 44. 6-(2-azaspiro[3.3]heptan-2-yl)quinoline-4-carboxylic acid

TFA (53 mg, 0.46 mmol) was added to a solution of tert-butyl 6-(2-azaspiro[3.3]heptan-2-yl)quinoline-4-carboxylate, intermediate 43 (150 mg, 0.46 mmol), in 1,4-dioxane (3 mL) and stirred at 25 °C overnight. The solvent was removed under reduced pressure to give the title compound; MS m/z (ESI)[M+H] ⁺ 269.1.

Intermediate 45. tert-Butyl 6-(3,3-dimethyl-1-oxa-6-azaspiro[3.3]heptan-6yl)quinoline-4-carboxylate

3,3-Dimethyl-1-oxa-6-azaspiro[3.3]heptane hydrochloride (223 mg, 1.36 mmol) was added to tert-butyl 6-bromoquinoline-4-carboxylate (280 mg, 0.91 mmol), Cs2CO3 (888 mg, 2.73 mmol) and Pd catalyst [CAS: 1810068-35-9] (52 mg, 0.05 mmol) in 1,4-dioxane (15 mL) at 25 °C. The resulting suspension was stirred at 100 °C for 4 h under N2 (g). The solid was filtered off. The filtrate was concentrated under reduced pressure. The residue was purified by preparative TLC (petroleum ether:EtOAc, 2:1) to give the title compound (200 mg, 62%) in

- 100 048482 as a yellow solid; MS mass/charge (ESI) [M+H]+ 355.2.

Intermediate 46. 6-(3,3-dimethyl-1-oxa-6-azaspiro[3.3]heptan-6-yl)quinoline-4-carboxylic acid

TFA (3 mL) was added to a solution of tert-butyl 6-(3,3-dimethyl-1-oxa-6-azaspiro[3.3]heptan-6yl)quinoline-4-carboxylate, intermediate 45 (200 mg, 0.56 mmol), in DCM (6 mL). The reaction mixture was stirred at rt for 15 h. The solvent was removed under reduced pressure and the residue was dried in vacuo to give the title compound (168 mg, 100%) as a yellow solid; MS m/z (ESI) [M+H]+ 299.2.

Intermediate 47. Methyl 6-(1-azaspiro[3.3]heptan-1-yl)quinoline-4-carboxylate

1-Azaspiro[3.3]heptane hydrochloride (301 mg, 2.25 mmol) was added to a mixture of methyl 6-bromoquinoline- ₄ -carboxylate (300 mg, 1.13 mmol), _Pd2 (dba) ₃ (103 mg, 0.11 mmol), XPhos (161 mg, 0.34 mmol) and _Cs2CO3 (1.10 g, 3.38 mmol) in 1,4-dioxane (15 mL) under N2 (g). The reaction mixture was stirred at 100 °C for 15 h. The solid was filtered off. The filtrate was concentrated under reduced pressure. The residue was purified by preparative TLC (petroleum ether:EtOAc, 1:1) to give the title compound (250 mg, 79%) as a yellow solid; MS m/z (ESI) [M+H]+ 283.2.

Intermediate 48. 6-(1-azaspiro[3.3]heptan-1-yl)quinoline-4-carboxylic acid

LiOH (106 mg, 4.43 mmol) was added to a solution of methyl 6-(1-azaspiro[3.3]heptan-1-yl)quinoline-4-carboxylate, intermediate 47 (250 mg, 0.89 mmol), in MeOH (10 mL) and water (2 mL). The reaction mixture was stirred at rt for 5 h. The solvent was removed under reduced pressure. The residue was diluted with water and the pH was adjusted to 6 with citric acid. The reaction mixture was extracted with EtOAc and the organic phases were washed with water. The organic layer was dried over Na ₂ SO ₄ , filtered and evaporated to give the title compound (215 mg, 90%) as an orange solid; MS m/z (ESI) [M+H]+ 269.2.

Intermediate 49. Methyl 6-(2,2-dimethylazetidin-1-yl)quinoline-4-carboxylate

2,2-Dimethylazetidine hydrochloride (147 mg, 1.21 mmol) was added to a mixture of methyl 6-bromoquinoline-4-carboxylate (215 mg, 0.81 mmol), _Cs2CO3 (1.05 g, 3.23 mmol) and RuPhosPdG3 (68 mg, 0.08 mmol) in 1,4-dioxane (5 mL) at 5 _° C. The resulting suspension was stirred at 100 °C for 2 h under N2 (g). The reaction mixture was diluted with EtOAc (10 mL) and filtered through Celite®. The filter pad was washed with EtOAc and the filtrate was concentrated under reduced pressure. The residue was purified by preparative TLC (petroleum ether:EtOAc, 1:1) to give the title compound (196 mg, 90%) as a brown gum; MS m/z (ESI) [M+H]+ 271.2.

Intermediate 50. 6-(2,2-dimethylazetidin-1-yl)quinoline-4-carboxylic acid

NaOH (96 mg, 2.4 mmol) in water (2 ml) was slowly added to a stirred solution of methyl 6-(2,2-dimethylazetidin-1-yl)quinoline-4-carboxylate, intermediate 49 (130 mg, 0.48 mmol), in MeOH (6 ml) cooled to 0 °C. The resulting solution was stirred at 10 °C for 2 h. The reaction mixture was diluted with water (20 ml) and acidified with aq. HCl (1 M). The mixture was extracted with EtOAc (5 x 75 ml). The organic layers were combined and washed with water (4 x 25 ml). The aqueous layers were combined and extracted with EtOAc (4 x 25 ml). All organic layers were combined, dried over Na ₂ SO ₄ , filtered and evaporated to give the title compound.

- 101 048482 compound (120 mg, 97%) as a yellow solid; MS mass/charge (ESI) [M+H]+ 257.2.

Intermediate 51. Methyl 6-(3-fluoroazetidin-1-yl)quinoline-4-carboxylate

3-Fluoroazetidine hydrochloride (252 mg, 2.25 mmol) was added to a mixture of methyl 6-bromoquinoline-4-carboxylate (300 mg, 1.13 mmol ₎ , _Cs2CO3 (1.10 mg, 3.38 mmol), _Pd2 (dba) ₃ (103 mg, 0.11 mmol) and XPhos (161 mg, 0.34 mmol) in 1,4-dioxane (20 mL) and stirred at 100 °C for 2 h. The precipitate was collected by filtration, washed with MeOH and dried in vacuo. The residue was purified by preparative TLC (petroleum ether:EtOAc, 1:1) to give the title compound (180 mg, 61%) as a yellow solid; MS mass/charge (ESI) [M+H]+ 261.0.

Intermediate 52. 6-(3-fluoroazetidin-1-yl)quinoline-4-carboxylic acid O on

LiOH (83 mg, 3.5 mmol) was added to a solution of methyl 6-(3-fluoroazetidin-1-yl)quinoline-4-carboxylate, intermediate 51 (180 mg, 0.69 mmol), in MeOH (10 mL) and water (2 mL). The reaction mixture was stirred at rt for 2 h. The reaction mixture was adjusted to pH 5 with aq. HCl (1 M). The reaction mixture was diluted with water and extracted with EtOAc. The organic layer was dried over Na ₂ SO ₄ , filtered and evaporated to give the title compound (150 mg, 88%) as a yellow solid; MS m/z (ESI) [M+H]+ 247.1.

Intermediate 53. Methyl 6-(3,3-dimethylazetidin-1-yl)quinoline-4-carboxylate \ ⁰ <^ ⁰ \

VJN

3,3-Dimethylazetidine hydrochloride (274 mg, 2.25 mmol) was added to a mixture of methyl 6-bromoquinoline-4-carboxylate (300 mg, 1.13 mmol), Cs2CO3 (1.10 mg, 3.38 mmol), Pd2(dba)3 (103 mg, 0.11 mmol) and XPhos (161 mg, 0.34 mmol) in 1,4-dioxane (20 mL). The mixture was stirred at 100 °C for 4 h under N2 (g). The precipitate was collected by filtration, washed with MeOH and dried under vacuum to give the crude product, which was purified by preparative TLC (petroleum ether:1:1) to give the title compound (200 mg, 66%) as a yellow solid; MS m/z (ESI) [M+H]+ 271.10.

Intermediate 54. 6-(3,3-dimethylazetidin-1-yl)quinoline-4-carboxylic acid

LiOH (89 mg, 3.7 mmol) was added to a solution of methyl 6-(3,3-dimethylazetidin-1-yl)quinoline-4-carboxylate, intermediate 53 (200 mg, 0.74 mmol), in MeOH (10 mL) and water (2 mL). The reaction mixture was stirred at rt for 2 h and then the pH was adjusted to 5 with aq. HCl (1 M). The reaction mixture was diluted with EtOAc and washed with water. The organic layer was dried over Na2SO4, filtered and evaporated to give the title compound (180 mg, 95%) as a yellow solid; MS m/z (ESI) [M+H]+ 257.2.

Intermediate 55. Methyl 6-(3,3-difluoroazetidin-1-yl)quinoline-4-carboxylate

3,3-Difluoroazetidine hydrochloride (294 mg, 2.27 mmol) was added to a mixture of methyl 6-bromoquinoline-4-carboxylate (302 mg, 1.13 mmol), Cs2CO3 (1.11 g, 3.40 mmol), Pd2(dba)3 (104 mg, 0.11 mmol) and XPhos (108 mg, 0.23 mmol) in 1,4-dioxane (3 mL) at 10 °C. The resulting suspension was stirred at 100 °C for 2 h under N ₂ (g). The reaction mixture was diluted with water (50 mL) and extracted with EtOAc (3 x 50 mL). The organic phases were combined and washed with brine (150 mL). _The organic layer was dried over _Na2SO4 , filtered and evaporated. The residue was purified by preparative TLC (petroleum ether:EtOAc, 1:1) to give the title compound (313 mg, 99%) as a brown solid; MS m/z (ESI) [M+H]+ 279.2.

- 102 048482

Intermediate 56. 6-(3,3-difluoroazetidin-1-yl)quinoline-4-carboxylic acid

NaOH (224 mg, 5.61 mmol) was added to methyl 6-(3,3-difluoroazetidin-1-yl)quinoline-4-carboxylate, intermediate 55 (312 mg, 1.12 mmol), in MeOH (3 mL) and water (1 mL) at 10 °C. The resulting solution was stirred at 10 °C for 1 h under N ₂ (g). The solvent was removed under reduced pressure. The reaction mixture was diluted with water (50 mL), adjusted to pH 5 with aq. HCl (1 M) and extracted with EtOAc (6 x 50 mL). The combined organic phases were dried over Na ₂ SO ₄ , filtered and evaporated. The crude product was purified by preparative HPLC, PrepMethod F (gradient: 0-50%), to give the title compound (127 mg, 43%) as a yellow solid; MS m/z (ESI) [M+H]+ 265.2.

Intermediate 57. Methyl 6-(3-fluoro-3-methylazetidin-1-yl)quinoline-4-carboxylate

3-Fluoro-3-methylazetidine hydrochloride (176 mg, 1.40 mmol) was added to a mixture of methyl 6-bromoquinoline-4-carboxylate (212 mg, 0.70 mmol), _Cs2CO3 ( ₆₈₅ mg, 2.10 mmol), _Pd2 (dba) ₃ (64 mg, 0.07 mmol) and XPhos (67 mg, 0.14 mmol) in 1,4-dioxane (3 mL) at 10 °C. The resulting suspension was stirred at 100 °C for 2 h under N2 (g). The reaction mixture was diluted with DCM. The solvents were removed under reduced pressure. The residue was suspended in water (5 mL) and extracted with EtOAc (3 x 20 mL). The organic layers were combined and washed with brine (20 mL). _The organic phase was dried over _Na2SO4 , filtered and evaporated. The residue was purified by preparative TLC (petroleum ether:EtOAc, 1:1) to give the title compound (153 mg, 80%) as a brown gum; MS m/z (ESI) [M+H]+ 275.0.

Intermediate 58. 6-(3-fluoro-3-methylazetidin-1-yl)quinoline-4-carboxylic acid

NaOH (112 mg, 2.79 mmol) was added to methyl 6-(3-fluoro-3-methylazetidin-1-yl)quinoline-4-carboxylate, intermediate 57 (153 mg, 0.56 mmol), in MeOH (3 mL) and water (1 mL) at 5 °C. The resulting solution was stirred at 5 °C for 1 h under N ₂ (g). The solvent was removed under reduced pressure. The reaction mixture was diluted with water and the pH was adjusted to 5 with aq. HCl (1 M). The mixture was diluted with water (10 mL) and extracted with EtOAc (25 mL). The combined organic layers were dried over Na2SO4, filtered and evaporated. The crude product was purified by preparative HPLC, PrepMethod F (gradient: 0-50%), to give the title compound (88 mg, 61%) as an orange solid; MS m/z (ESI) [M+H]+ 261.2.

Intermediate 59. tert-Butyl 6-(3-methylazetidin-1-yl)quinoline-4-carboxylate

3-Methylazetidine (102 mg, 1.43 mmol) was added to a mixture of tert-butyl 6-bromoquinoline-4-carboxylate (400 mg, 1.30 mmol), _Cs2CO3 ( _1.06 g, 3.24 mmol), _Pd2 (dba) ₃ (119 mg, 0.13 mmol) and DavePhos (102 mg, 0.26 mmol) in 1,4-dioxane (2 mL). The resulting mixture was heated at 100 °C for 3 h under N2 (g). The reaction mixture was filtered through Celite® and the filtrate was concentrated under reduced pressure. The residue was purified by preparative TLC (petroleum ether:EtOAc, 3:1) to give the title compound (350 mg, 90%) as a yellow solid; MS m/z (ESI) [M+H]+ 299.3.

Intermediate 60. 6-(3-methylazetidin-1-yl)quinoline-4-carboxylic acid

TFA (4.5 ml) was added to tert-butyl 6-(3-methylazetidin-1-yl)quinoline-4-carboxylate, intermediate 59 (300 mg, 1.01 mmol), in DCM (9 ml). The resulting mixture was stirred at 40 °C for 3 h. The solvents were removed under reduced pressure to give the title compound.

- 103 048482 units (200 mg, 82%) as a violet solid; MS m/z (ESI) [M+H]+ 243.2.

Intermediate 61. tert-Butyl 6-(3-(trifluoromethyl)azetidin-1-yl)quinoline-4-carboxylate

3-(Trifluoromethyl)azetidine (112 mg, 0.89 mmol) was added to a mixture of tert-butyl 6-bromoquinoline-4-carboxylate (250 mg, 0.81 mmol), _Cs2CO3 (661 mg, 2.03 mmol), XPhos (77 mg, 0.16 mmol) and _Pd2 ( _dba ) ₃ (74 mg, 0.08 mmol) in 1,4-dioxane (2 mL). The resulting mixture was heated at 100 °C for 3 h under N2 (g). The reaction mixture was filtered through Celite® and the filtrate was concentrated under reduced pressure. The residue was purified by preparative TLC (petroleum ether:EtOAc, 1:1) to give the title compound (180 mg, 63%) as a yellow oil; MS mass/charge (ESI) [M+H] ⁺ 253.2.

Intermediate 62. 6-(3-(trifluoromethyl)azetidin-1-yl)quinoline-4-carboxylic acid

TFA (42 mg, 0.37 mmol) was added to tert-butyl 6-(3-(trifluoromethyl)azetidin-1-yl)quinoline-4-carboxylate, intermediate 61 (130 mg, 0.37 mmol), in DCM (1.5 ml). The resulting mixture was heated at 60 °C for 5 h. The solvent was removed under reduced pressure to give the title compound (100 mg, 91%) as a violet solid; MS m/z (ESI) [M+H] ⁺ 297.1.

Intermediate 63. tert-Butyl 6-(3-(fluoromethyl)-3-methylazetidin-1-yl)quinoline-4-carboxylate

O^O.

KOtBu (336 mg, 3.00 mmol) was added to tert-butyl 6-bromoquinoline-4-carboxylate (308 mg, 1.00 mmol), 3-(fluoromethyl)-3-methylazetidine (206 mg, 2.00 mmol), Pd(OAc) ₂ (150 mg, 0.67 mmol) and XantPhos (300 mg, 0.52 mmol) in 1,4-dioxane (3 mL) at 10 °C. The resulting suspension was stirred at 100 °C for 2 h under _N2 (g). The reaction mixture was diluted with DCM. The solvent was removed under reduced pressure. The residue was purified by preparative TLC (petroleum ether:EtOAc, 1:1) to give the title compound (147 mg, 44%) as a brown gum; MS m/z (ESI) [M+H] ⁺ 331.3.

Intermediate 64. 6-(3-(fluoromethyl)-3-methylazetidin-1-yl)quinoline-4-carboxylic acid

TFA (3 ml) was added to tert-butyl 6-(3-(fluoromethyl)-3-methylazetidin-1-yl)quinoline-4-carboxylate, intermediate 63 (147 mg, 0.44 mmol), in DCM (3 ml) at 10 °C. The resulting solution was stirred at 10 °C overnight under N ₂ (g). The solvent was removed under reduced pressure to give the title compound (298 mg) as a red gum; MS m/z (ESI) [M+H] ⁺ 275.05.

Intermediate 65. tert-Butyl 6-(3-(difluoromethyl)azetidin-1-yl)quinoline-4-carboxylate

0^0.

Pd ₂ (dba) ₃ (149 mg, 0.16 mmol) was added to 3-(difluoromethyl)azetidine (191 mg, 1.78 mmol), tert-butyl 6-bromoquinoline-4-carboxylate (500 mg, 1.62 mmol), Cs ₂ CO ₃ (1.06 g, 3.24 mmol) and XPhos (155 mg, 0.32 mmol) in 1,4-dioxane (10 mL) at 25 °C under N ₂ (g). The resulting mixture was stirred at 100 °C for 5 h. The reaction mixture was concentrated and the residue was dissolved in EtOAc (125 mL) and washed successively with brine (75 mL) and water (75 mL). The organic layer was dried.

- 104 048482 was suspended over _Na2SO4 , filtered and evaporated. The residue was purified by preparative TLC (petroleum ether:EtOAc, 3:1) to give the title compound (380 mg, 70%) as a yellow solid; _MS m/z (ESI) [M+H]+ 335.05.

Intermediate 66. 6-(3-(difluoromethyl)azetidin-1-yl)quinoline-4-carboxylic acid

F

TFA (0.17 ml, 2.2 mmol) was added to tert-butyl 6-(3-(difluoromethyl)azetidin-1-yl)quinoline-4-carboxylate, intermediate 65 (250 mg, 0.75 mmol), in DCM (5 ml) at 20 °C under air. The resulting mixture was stirred at 25 °C for 16 h. The reaction mixture was concentrated and diluted with DCM (100 ml), and washed successively with sat. NaHCO ₃ solution (25 ml), brine (25 ml) and water (25 ml). The organic layer was dried over Na ₂ SO ₄ , filtered and evaporated. The residue was purified by preparative TLC (DCM:MeOH, 5:1) to give the title compound (150 mg, 72%) as a yellow solid. MS m/z (ESI) [M+H]+ 279.2.

Intermediate 67. Ethyl 6-(3-(methoxymethyl)-3-methylazetidin-1-yl)quinoline-4-carboxylate

3-(Methoxymethyl)-3-methylazetidine hydrochloride (108 mg, 0.71 mmol) was added to a mixture of ethyl 6-bromoquinoline-4-carboxylate (100 mg, 0.36 mmol), _Cs2CO3 ( ₄₆₅ mg, 1.43 mmol), XPhos (34 mg, 0.07 mmol) and _Pd2 (dba) ₃ (33 mg, 0.04 mmol) in 1,4-dioxane (2 mL). The vial was sealed, purged with N2 (g) and the reaction mixture was heated at 100 °C for 2 h. After cooling to rt, water (10 mL) and DCM (10 mL) were added, the mixture was stirred, filtered through a phase separator. The phase separator was rinsed with more DCM and evaporated. The residue was purified by straight-phase flash chromatography on silica gel (gradient: 5-50% EtOAc in heptane) to give the title compound (87 mg, 78%); MS m/z (ESI) [M+H]+ 315.3.

Intermediate 68. 6-(3-(methoxymethyl)-3-methylazetidin-1-yl)quinoline-4-carboxylic acid

Aq. NaOH (1 M, 0.51 ml) was added to ethyl 6-(3-(methoxymethyl)-3-methylazetidin-1yl)quinoline-4-carboxylate, intermediate 67 (80 mg, 0.25 mmol), in MeOH (2 ml). The reaction mixture was stirred at 50 °C for 20 min, then cooled to rt. Aq. HCl (3.8 M, 0.17 ml) was added and the mixture was stirred, then evaporated to give the title compound (73 mg, 100%); MS m/z (ESI) [M+H]+ 287.3.

Intermediate 69. tert-Butyl 6-((2S,3R)-3-methoxy-2-methylazetidin-1-yl)quinoline-4-carboxylate

(2S,3R)-3-methoxy-2-methylazetidine oxalate (285 mg, _1.95 mmol) was added to a mixture of tert-butyl 6-bromoquinoline-4-carboxylate (300 mg, 0.97 mmol), _Cs2CO3 (1.27 mg, 3.89 mmol) and Pd catalyst [CAS: 1810068-35-9] (55 mg, 0.05 mmol) in 1,4-dioxane (20 mL) at 25 °C. The resulting suspension was heated at 100 °C for 48 h under N2 (g). The solid was filtered off and the filtrate was concentrated under reduced pressure. The residue was purified by preparative TLC (petroleum ether:EtOAc, 2:1) to give the title compound (200 mg, 63%) as a yellow solid; MS m/z (ESI) [M+H]+ 329.2.

Intermediate 70. 6-((2S,3R)-3-methoxy-2-methylazetidin-1-yl)quinoline-4-carboxylic acid

TFA (3 ml) was added to the solution of tert-butyl 6-((2S,3R)-3-methoxy-2-methylazetidin-1-yl)quinoline-4

- 105 048482 carboxylate, intermediate 69 (200 mg, 0.61 mmol), in DCM (6 mL). The solution was stirred at rt for 4 h. The solvent was removed under reduced pressure to give the crude title compound (166 mg, 100%); MS m/z (ESI) [M+H] ⁺ 273.2.

Intermediate 71. Methyl 6-(3-cyclopropyl-3-fluoroazetidin-1-yl)quinoline-4-carboxylate

3-Cyclopropyl-3-fluoroazetidine (143 mg, 1.24 mmol) was added to a mixture of methyl 6-bromoquinoline-4-carboxylate (300 mg, 1.13 mmol), Cs ₂ CO ₃ (21 mg, 0.06 mmol), Pd ₂ (dba) ₃ (103 mg, 0.11 mmol) and XPhos (107 mg, 0.23 mmol) in 1,4-dioxane (2 mL) at 20 °C under N2 (g). The mixture was heated at 100 °C for 5 h. The reaction mixture was concentrated and the residue was diluted with EtOAc (75 mL) and washed successively with saturated NH ₄ Cl solution (25 mL), brine (25 mL) and water (25 mL). _The organic layer was dried over _Na2SO4 , filtered and evaporated. The residue was purified by preparative TLC (petroleum ether:EtOAc, 3:1) to give the title compound (180 mg, 53%) as a yellow solid; MS m/z (ESI) [M+H]+ 301.1.

Intermediate 72. 6-(3-cyclopropyl-3-fluoroazetidin-1-yl)quinoline-4-carboxylic acid

A solution of NaOH (113 mg, 2.83 mmol) in water (4 ml) was added to a stirred solution of methyl 6-(3-cyclopropyl-3-fluoroazetidin-1-yl)quinoline-4-carboxylate, intermediate 71 (170 mg, 0.57 mmol), in MeOH (12 ml) at 20 °C. The resulting mixture was stirred at 25 °C for 2 h. The reaction mixture was adjusted to pH 5 with aq. HCl (2 M). The reaction mixture was concentrated and the residue was redissolved in DCM (50 ml) and washed successively with brine (25 ml) and water (25 ml). The organic layer was dried over Na2SO4, filtered and evaporated to give the title compound (130 mg, 80%) as a red solid; MS mass/charge (ESI) [M+H] ⁺ 287.0.

Intermediate 73. Methyl 6-(piperidin-1-yl)quinoline-4-carboxylate

Piperidine (0.061 mL _{, 0.62 mmol) was added to a mixture of methyl 6-bromoquinoline-4-carboxylate (150 mg, 0.56 mmol), Cs2CO3 (} 367 mg, 1.13 mmol), DavePhos (44 mg, 0.11 mmol) and Pd2(dba) ₃ (52 mg, 0.06 mmol) in 1,4-dioxane (2 mL) at 16 °C. The resulting suspension was heated at 100 °C for 2 h under N2 (g). The reaction mixture was diluted with DCM ( ₅ mL). The organic layer was filtered and the solvents were evaporated under reduced pressure. The crude product was purified by preparative TLC (DCM:MeOH, 30:1) to give the title compound (109 mg, 71%) as a yellow oil; MS m/z (ESI) [M+H] ⁺ 271.2.

Intermediate 74. 6-(piperidin-1-yl)quinoline-4-carboxylic acid

A solution of NaOH (81 mg, 2.0 mmol) in water (1 ml) was slowly added to a stirred solution of methyl 6-(piperidin-1-yl)quinoline-4-carboxylate, intermediate 73 (109 mg, 0.40 mmol), in MeOH (4 ml), cooled to 0 °C. The resulting solution was stirred at 16 °C for 1 h. The reaction mixture was diluted with water (20 ml), adjusted to pH 5 with aq. HCl (2 M) and extracted with EtOAc (4 x 50 ml). The organic layers were combined and washed with water (4 x 25 ml), dried over Na2SO4, filtered and evaporated to give the title compound (90 mg, 87%) as a yellow oil; MS m/z (ESI) [M+H] ⁺ 257.1.

Intermediate 75. Methyl 6-(4,4-dimethylpiperidin-1-yl)quinoline-4-carboxylate

4,4-Dimethylpiperidine hydrochloride (93 mg, 0.62 mmol) was added to a mixture of methyl 6-bromoquinoline- 106 048482

4-carboxylate (150 mg, 0.56 mmol), _{Cs2CO3 (} 551 mg, 1.69 mmol), _Pd2 (dba) ₃ (52 mg, 0.06 mmol) and XPhos (54 mg, 0.11 mmol) in 1,4-dioxane (3 mL) at 15 °C. The resulting suspension was heated at 100 °C for 4 h under N2 (g). The reaction mixture was diluted with DCM (5 mL) and filtered. _The filtrate was dried over _Na2SO4 , filtered and evaporated to give the crude product. The residue was purified by preparative TLC (DCM:MeOH, 20:1) to give the title compound (140 mg, 83%) as a yellow oil; MS mass/charge (ESI) [M+H]+ 299.1.

Intermediate 76. 6-(4,4-dimethylpiperidin-1-yl)quinoline-4-carboxylic acid

A solution of NaOH (94 mg, 2.4 mmol) in water (1 ml) was slowly added to a stirred solution of methyl 6-(4,4-dimethylpiperidin-1-yl)quinoline-4-carboxylate, intermediate 75 (140 mg, 0.47 mmol), in MeOH (4 ml), cooled to 0 °C. The resulting solution was stirred at 15 °C for 1 h. The reaction mixture was diluted with water (20 ml), adjusted to pH 5 with aq. HCl (2 M) and extracted with EtOAc (4 x 50 ml). The organic layers were combined and washed with water (4 x 30 ml). The organic layer was dried over Na ₂ SO ₄ , filtered and evaporated to give the title compound (101 mg, 76%) as a yellow solid; MS mass/charge (ESI) [M+H]+ 285.3.

Intermediate 77. Methyl 6-(4-fluoro-4-methylpiperidin-1-yl)quinoline-4-carboxylate

4-Fluoro-4-methylpiperidine hydrochloride (76 mg, 0.50 mmol) was added to a mixture of methyl -6-bromoquinoline-4-carboxylate (120 mg, 0.45 mmol), Cs2CO3 (441 mg, 1.35 mmol), Pd2(dba)3 (41 mg, 0.05 mmol) and DavePhos (36 mg, 0.09 mmol) in 1,4-dioxane (2 mL) at 15 °C. The resulting suspension was heated at 100 °C for 2 h under N ₂ (g). The reaction mixture was diluted with DCM (2 mL), filtered and evaporated under reduced pressure. The residue was purified by preparative TLC (DCM:MeOH, 20:1) to give the title compound (102 mg, 75%) as a yellow oil; MS m/z (ESI) [M+H]+ 303.1.

Intermediate 78. 6-(4-fluoro-4-methylpiperidin-1-yl)quinoline-4-carboxylic acid

A solution of NaOH (67 mg, 1.7 mmol) in water (1 ml) was added to a stirred solution of methyl 6-(4-fluoro-4-methylpiperidin-1-yl)quinoline-4-carboxylate, intermediate 77 (101 mg, 0.33 mmol), in MeOH (4 ml) at 18 °C. The resulting solution was stirred at 18 °C for 1 h. The reaction mixture was diluted with water (20 ml) and the pH was adjusted to 4 with aq. HCl (2 M). The mixture was extracted with EtOAc (4 x 50 ml). The organic layers were combined and washed with water (4 x 25 ml). The organic layer was dried over Na ₂ SO ₄ , filtered and evaporated to give the title compound (65 mg, 68%) as a yellow solid; MS mass/charge (ESI) [M+H]+ 289.2.

Intermediate 79. Methyl 6-(4,4-difluoropiperidin-1-yl)quinoline-4-carboxylate

4,4-Difluoropiperidine (89 mg, 0.73 mmol) was added to a mixture of methyl 6-bromoquinoline-4-carboxylate (150 mg, 0.56 mmol), _Cs2CO3 ( ₅₅₁ mg, 1.69 mmol), _Pd2 (dba) ₃ (52 mg, 0.06 mmol) and XPhos (54 mg, 0.11 mmol) in 1,4-dioxane (15 mL) at 20 °C. The resulting mixture was stirred at 100 °C for 15 h under N2 (g). The solvents were evaporated under reduced pressure and the residue was purified by preparative TLC (petroleum ether:EtOAc, 5:1) to give the title compound (160 mg, 93%) as a pale yellow oil; MS mass/charge (ESI) [M+H]+ 307.2.

Intermediate 80. 6-(4,4-difluoropiperidin-1-yl)quinoline-4-carboxylic acid

- 107 048482

Aqueous NaOH (1 M, 3 mL) was added to methyl 6-(4,4-difluoropiperidin-1-yl)quinoline-4-carboxylate, intermediate 79 (150 mg, 0.49 mmol), in MeOH (10 mL) at 20 °C. The resulting mixture was stirred at 20 °C for 3 h. The reaction mixture was adjusted to pH 5 with aqueous HCl (1 M). The solvents were evaporated to give the title compound (140 mg, 98%) as a yellow solid; MS m/z (ESI) [M+H]+ 293.2.

Intermediate 81. Methyl 6-(3,3-difluoropiperidin-1-yl)quinoline-4-carboxylate

3,3-Difluoropiperidine hydrochloride (98 mg, 0.62 mmol) was added to a mixture of methyl 6-bromoquinoline-4-carboxylate ₍ 150 mg, 0.56 mmol), _Cs2CO3 (551 mg, 1.69 mmol), _Pd2 (dba) ₃ (52 mg, 0.06 mmol) and XPhos (54 mg, 0.11 mmol) in 1,4-dioxane (3 mL) at 15 °C. The resulting suspension was heated at 100 °C for 2 h under _N2 (g). The reaction mixture was diluted with DCM (5 mL) and filtered. _The filtrate was dried over _Na2SO4 , filtered and evaporated. The crude product was purified by preparative TLC (DCM:MeOH, 20:1) to give the title compound (162 mg, 94%) as a yellow gum; MS m/z (ESI) [M+H] ⁺ 307.1.

Intermediate 82. 6-(3,3-difluoropiperidin-1-yl)quinoline-4-carboxylic acid

A solution of NaOH (104 mg, 2.61 mmol) in water (1 ml) was added dropwise to a stirred solution of methyl 6-(3,3-difluoropiperidin-1-yl)quinoline-4-carboxylate, intermediate 81 (160 mg, 0.52 mmol), in MeOH (4 ml) cooled to 0 °C. The resulting solution was stirred at 15 °C for 1 h. The reaction mixture was diluted with water (20 ml) and the pH was adjusted to 4 with aq. HCl (2 M). The mixture was extracted with EtOAc (4 x 50 ml). The organic layers were combined and washed with water (4 x 25 ml). The organic layer was dried over Na ₂ SO ₄ , filtered and evaporated to give the title compound (143 mg, 94%) as a yellow solid; MS mass/charge (ESI) [M+H] ⁺ 293.1.

Intermediate 83. Methyl 6-(4-(fluoromethyl)-4-methylpiperidin-1-yl)quinoline-4-carboxylate

4-(Fluoromethyl)-4-methylpiperidine hydrochloride (162 mg _, 0.97 mmol) was added to a mixture of methyl 6-bromoquinoline-4-carboxylate (266 mg, 0.88 mmol), _Cs2CO3 (859 mg, 2.64 mmol), _Pd2 (dba) ₃ (81 mg, 0.09 mmol) and DavePhos (69 mg, 0.18 mmol) in 1,4-dioxane (5 mL) at 11 °C. The resulting suspension was heated at 100 °C for 2 h under N2 (g). The reaction mixture was diluted with DCM (3 mL) and filtered. The filtrate was concentrated under reduced pressure and the residue was purified by preparative TLC (petroleum ether:EtOAc, 1:1) to give the title compound (170 mg, 61%) as a yellow oil; MS m/z (ESI) [M+H] ⁺ 317.3.

Intermediate 84. 6-(4-(fluoromethyl)-4-methylpiperidin-1-yl)quinoline-4-carboxylic acid

A solution of NaOH (107 mg, 2.69 mmol) in water (1 ml) was slowly added to a stirred solution of methyl 6-(4-(fluoromethyl)-4-methylpiperidin-1-yl)quinoline-4-carboxylate, intermediate 83 (170 mg, 0.54 mmol), in MeOH (3 ml) cooled to 0 °C. The resulting solution was stirred at 10 °C for 1 h. The reaction mixture was diluted with water (20 ml), adjusted to pH 5 with aq. HCl (2 M) and extracted with EtOAc (4 x 50 ml). The organic layers were combined and washed with water (4 x 25 ml). The organic layer was dried over Na2SO4, filtered and evaporated to give the title compound (129 mg, 79%) as a yellow solid; MS mass/charge (ESI) [M+H] ⁺ 303.2.

- 108 048482

Intermediate 85. Methyl 6-(4,4-difluoro-3,3-dimethylpiperidin-1-yl)quinoline-4-carboxylate

4,4-Difluoro-3,3-dimethylpiperidine hydrochloride (230 mg, 1.24 mmol) was added to a mixture of methyl 6-bromoquinoline-4-carboxylate (300 mg, 1.13 mmol), Cs2CO3 (1.10 g, 3.38 mmol), XPhos (107 mg, 0.23 mmol), and _Pd2 (dba) ₃ (103 mg, 0.11 mmol) in 1,4-dioxane (10 mL) at 11 °C. The resulting suspension was heated at 100 °C for 5 h under _N2 (g). The reaction mixture was filtered. The filtrate was concentrated and redissolved in EtOAc (75 mL), and washed successively with brine (25 mL) and water (20 mL). The organic layer was dried over Na2SO4, filtered and evaporated. The residue was purified by preparative TLC (EtOAc:petroleum ether, 1:1) to give the title compound (310 mg, 82%) as a yellow oil; MS m/z (ESI) [M+H] ⁺ 335.1.

Intermediate 86. 6-(4,4-difluoro-3,3-dimethylpiperidin-1-yl)quinoline-4-carboxylic acid

A solution of NaOH (179 mg, 4.49 mmol) in water (4 ml) was added to a stirred solution of methyl (4,4-difluoro-3,3-dimethylpiperidin-1-yl)quinoline-4-carboxylate, intermediate 85 (300 mg, 0.90 mmol), in MeOH (12 ml) at 20 °C. The resulting mixture was stirred at 20 °C for 3 h. The reaction mixture was adjusted to pH 5 with aq. HCl (2 M). The solvents were evaporated under reduced pressure and the residue was dissolved in EtOAc (100 ml) and washed with brine (25 ml). The organic layer was dried over Na2SO4, filtered and evaporated to give the title compound (250 mg, 87%) as a yellow solid; MS mass/charge (ESI) [M+H] ⁺ 321.1.

Intermediate 87. Methyl 6-(4-(trifluoromethyl)piperidin-1-yl)quinoline-4-carboxylate

_4- (Trifluoromethyl)piperidine (169 mg, 1.10 mmol) was added to a mixture of methyl 6-bromoquinoline-4-carboxylate (303 mg, 1.00 mmol), _Cs2CO3 (0.98 g, 3.00 mmol), _Pd2 (dba) ₃ (92 mg, 0.10 mmol) and DavePhos (79 mg, 0.20 mmol) in 1,4-dioxane (1 mL) at 10 °C. The resulting suspension was heated at 100 °C for 2 h under N2 (g). The reaction mixture was diluted with DCM (3 mL) and filtered. The filtrate was concentrated under reduced pressure. The residue was purified by preparative TLC (EtOAc:petroleum ether, 1:1) to give the title compound (243 mg, 72%) as a yellow oil that solidified on standing; MS m/z (ESI) [M+H] ⁺ 339.1.

Intermediate 88. 6-(4-(trifluoromethyl)piperidin-1-yl)quinoline-4-carboxylic acid

A solution of NaOH (142 mg, 3.55 mmol) in water (1 ml) was slowly added to a stirred solution of methyl 6-(4-(trifluoromethyl)piperidin-1-yl)quinoline-4-carboxylate, intermediate 87 (240 mg, 0.71 mmol), in MeOH (4 ml) cooled to 0 °C. The resulting solution was stirred at 12 °C for 1 h. The reaction mixture was diluted with water (20 ml) and the pH was adjusted to 5 with aq. HCl (2 M). The aqueous layer was extracted with EtOAc (4 x 50 ml). The organic layers were combined and washed with water (4 x 25 ml). The organic layer was dried over Na ₂ SO ₄ , filtered and evaporated to give the title compound (190 mg, 83%) as a brown solid; MS mass/charge (ESI) [M+H]+ 325.0.

Intermediate 89. rac-methyl (R)-6-(3-fluoropiperidin-1-yl)quinoline-4-carboxylate

- 109 048482

3-Fluoropiperidine (64 mg _{, 0.62 mmol) was added to a solution of methyl 6-bromoquinoline-4-carboxylate (150 mg, 0.56 mmol), Cs2CO3 (} 367 mg, 1.13 mmol), DavePhos (44 mg, 0.11 mmol) and _Pd2 (dba) ₃ (52 mg, 0.06 mmol) in 1,4-dioxane (20 mL) at 16 °C. The resulting suspension was stirred at 100 °C for 2 h under _N2 (g). The solvent was removed under reduced pressure. The residue was purified by preparative TLC (petroleum ether:ElecOAc, 1:1) to give the title compound (140 mg, 86%) as a yellow gum; MS mass/charge (ESI) [M+H]+ 289.0.

Intermediate 90. rac-(R)-6-(3-fluoropiperidin-1-yl)quinoline-4-carboxylic acid

NaOH (78 mg, 1.9 mmol) in water (3.5 ml) was added to a stirred solution of methyl 6-(3-fluoropiperidin-1-yl)quinoline-4-carboxylate, intermediate 89 (140 mg, 0.49 mmol), in MeOH (14 ml) at 0 °C and then stirred for 1 h at rt. The reaction mixture was diluted with water (15 ml), adjusted to pH 5 with aq. HCl (2 M) and extracted with EtOAc (3 x 25 ml). The combined organic phases were washed with brine (15 ml), the organic layer was dried over Na ₂ SO ₄ , filtered and evaporated to give the title compound (120 mg, 90%) as an orange solid; MS mass/charge (ESI) [M+H]+ 275.2.

Intermediate 91. rac-methyl-(R)-6-(3-methoxypiperidin-1-yl)quinoline-4-carboxylate

3-Methoxypiperidine (71 mg _{, 0.62 mmol) was added to a mixture of methyl 6-bromoquinoline-4-carboxylate (150 mg, 0.56 mmol), Cs2CO3 (} 367 mg, 1.13 mmol), DavePhos (44 mg, 0.11 mmol) and _Pd2 (dba) ₃ (52 mg, 0.06 mmol) in 1,4-dioxane (20 mL) at 16 °C. The resulting suspension was heated at 100 °C for 2 h under N2 (g). The solvent was removed under reduced pressure. The residue was purified by preparative TLC (petroleum ether:EtOAc, 1:2) to give the title compound (150 mg, 89%) as a yellow gum; MS mass/charge (ESI) [M+H]+ 301.1.

Intermediate 92. rac-(R)-6-(3-methoxypiperidin-1-yl)quinoline-4-carboxylic acid

A solution of NaOH (104 mg, 2.59 mmol) in water (3 ml) was slowly added to a stirred solution of methyl 6-(piperidin-1-yl)quinoline-4-carboxylate, intermediate 91 (140 mg, 0.52 mmol), in MeOH (12 ml) cooled to 0 °C. The resulting solution was stirred at 16 °C for 1 h. The reaction mixture was diluted with water (20 ml), and the pH was adjusted to 5 with aq. HCl (2 M), and extracted with EtOAc (4 x 50 ml). The combined organic layers were dried over Na2SO4, filtered and evaporated. The crude product was purified by C18 straight phase flash column chromatography (gradient: 0-50% MeCN in water) to give the title compound (133 mg, 100%) as a yellow gum.

Intermediate 93. tert-Butyl 6-(4-methoxy-4-methylpiperidin-1-yl)quinoline-4-carboxylate

4-Methoxy-4-methylpiperidine hydrochloride (105 mg, _0.63 mmol) was added to a mixture of tert-butyl 6-bromoquinoline-4-carboxylate (150 mg, 0.49 mmol), _Cs2CO3 (206 mg, 0.63 mmol), XPhos (46 mg, 0.10 mmol) and _Pd2 (dba) ₃ (45 mg, 0.05 mmol) in 1,4-dioxane (5 mL) at 25 °C. The resulting suspension was heated at 100 °C for 2 h under N2 (g). The reaction mixture was filtered, the filtrate was concentrated under reduced pressure and purified by preparative TLC (EtOAc:petroleum ether, 3:2) to give the title compound (140 mg, 81%) as a yellow oil that solidified on standing; MS m/z (ESI) [M+H]+ 357.2.

- 110 048482

Intermediate 94. 6-(4-methoxy-4-methylpiperidin-1-yl)quinoline-4-carboxylic acid

HCl in 1,4-dioxane (4 M, 5 mL) was slowly added to a stirred solution of tert-butyl 6-(4-methoxy-4-methylpiperidin-1-yl)quinoline-4-carboxylate, intermediate 93 (110 mg, 0.31 mmol), in 1,4-dioxane (5 mL) at 25 °C. The resulting solution was stirred at 50 °C for 15 h. The solvent was removed under reduced pressure to give the title compound (90 mg, 97%) as a red solid; MS m/z (ESI) [M+H]+ 301.2.

Intermediate 95. tert-Butyl 6-(4-isopropoxypiperidin-1-yl)quinoline-4-carboxylate

4-Isopropoxypiperidine hydrochloride (117 mg, 0.65 mmol) was added to a mixture of tert-butyl 6-bromoquinoline-4-carboxylate (200 mg, 0.65 mmol), Cs ₂ CO ₃ (634 mg, 1.95 mmol), Pd ₂ (dba) ₃ (59 mg, 0.06 mmol) and XPhos (91 mg, 0.19 mmol) in 1,4-dioxane (10 mL) under N2 (g). The reaction mixture was heated at 80 °C for 20 h. The solvent was removed under reduced pressure. The residue was diluted with EtOAc and washed with water. The organic layer was dried over Na ₂ SO ₄ , filtered and evaporated. The residue was purified by preparative TLC (petroleum ether:EtOAc, 5:1) to give the title compound (180 mg, 75%) as a yellow solid; MS m/z (ESI) [M+H]+ 371.1.

Intermediate 96. 6-(4-isopropoxypiperidin-1-yl)quinoline-4-carboxylic acid

TFA (3 mL) was added to a solution of tert-butyl 6-(4-isopropoxypiperidin-1-yl)quinoline-4-carboxylate, intermediate 95 (120 mg, 0.32 mmol), in DCM (6 mL). The reaction mixture was stirred at rt for 2 h. The solvent was removed under reduced pressure to give the title compound (100 mg, 98%) as a yellow solid; MS m/z (ESI) [M+H]+ 315.05.

Intermediate 97. rac-methyl-(R)-6-(4,4-difluoro-2-methylniperidin-1-yl)quinoline-4-carboxylate

4,4-Difluoro-2-methylpiperidine hydrochloride (387 mg, 2.25 mmol) was added to a mixture of methyl 6-bromoquinoline-4-carboxylate (300 mg, 1.13 mmol), _Cs2CO3 (1.10 g, 3.38 mmol) and Pd catalyst [CAS: 1810068-35-9] (64 mg, 0.06 mmol) in 1,4-dioxane (20 mL) at 25 _° C. The resulting suspension was heated at 85 °C for 18 h under N2 (g). The reaction mixture was filtered and the filtrate was concentrated under reduced pressure. The residue was purified by preparative TLC (petroleum ether:EtOAc, 1:1) to give the title compound (170 mg, 47%) as a yellow solid; MS m/z (ESI) [M+H]+ 321.2.

Intermediate 98. rac-(R)-6-(4,4-difluoro-2-methylpiperidin-1-yl)quinoline-4-carboxylic acid

LiOH (64 mg, 2.65 mmol) was added to a solution of methyl 6-(4,4-difluoro-2-methylpiperidin-1yl)quinoline-4-carboxylate, intermediate 97 (170 mg, 0.53 mmol), in MeOH (10 mL) and water (2 mL). The reaction mixture was stirred at rt for 2 h. The solvent was removed under reduced pressure. The reaction mixture was diluted with water, the pH was adjusted to 6 with aq. HCl (2 M) and evaporated under reduced pressure. The residue was dissolved in EtOAc and washed with water. The organic layer was dried over Na ₂ SO ₄ , filtered and evaporated to give the title compound.

- 111 048482 units (150 mg, 92%) as a yellow solid; MS m/z (ESI) [M+H] ⁺ 307.1.

Intermediate 99. Methyl (8)-6-(2-(fluoromethyl)piperidin-1-yl)quinoline-4-carboxylate

(S)-2-(fluoromethyl)piperidine hydrobromide (447 mg, 2.25 mmol) was added to a mixture of methyl 6-bromoquinoline-4-carboxylate (300 mg, 1.13 mmol), Cs2CO3 (1.10 g, 3.38 mmol) and Pd catalyst [CAS: 1810068-35-9] (64 mg, 0.06 mmol) in 1,4-dioxane (20 mL) at 25 °C. The resulting suspension was heated at 100 °C for 18 h under N ₂ (g). The reaction mixture was filtered and the filtrate was concentrated under reduced pressure. The residue was purified by preparative TLC (petroleum ether:EtOAc, 1:1) to give the title compound (110 mg, 32%) as a yellow solid; MS m/z (ESI) [M+H] ⁺ 303.2.

Intermediate 100. (S)-6-(2-(fluoromethyl)piperidin-1-yl)quinoline-4-carboxylic acid

LiOH (44 mg, 1.82 mmol) was added to a solution of methyl (S)-6-(2-(fluoromethyl)piperidin-1-yl)quinoline-4-carboxylate, intermediate 99 (110 mg, 0.36 mmol), in MeOH (5 mL) and water (1 mL). The reaction mixture was stirred at rt for 2 h. The solvent was removed under reduced pressure. The residue was diluted with water, the pH was adjusted to 6 with aq. HCl (2 M), and evaporated under reduced pressure. The residue was dissolved in EtOAc and washed with water. The organic layer was dried over Na ₂ SO ₄ , filtered and evaporated to give the title compound (90 mg, 86%); MS m/z (ESI) [M+H] ⁺ 289.2.

Intermediate 101. Methyl 6-(5-azaspiro[2.5]octan-5-yl)quinoline-4-carboxylate

5-Azaspiro[2.5]octane hydrochloride (325 mg, 2.20 mmol) was added to a mixture of methyl 6-bromoquinoline-4-carboxylate (605 mg, 2.00 mmol), Cs2CO3 (2.60 g, 8.00 mmol), Pd2(dba)3 (183 mg, 0.20 mmol), and DavePhos (157 mg, 0.40 mmol) in 1,4-dioxane (5 mL) at 10 °C. The resulting suspension was heated at 100 °C overnight under N ₂ (g). The reaction mixture was diluted with DCM (3 mL) and filtered. The solvent was removed under reduced pressure. The residue was purified by preparative TLC (petroleum ether:EtOAc, 1:1) to give the title compound (273 mg, 46%) as a yellow oil that solidified on standing; MS m/z (ESI) [M+H]+ 297.05.

Intermediate 102. 6-(5-azaspiro[2.5]octan-5-yl)quinoline-4-carboxylic acid

A solution of NaOH (151 mg, 3.78 mmol) in water (2 ml) was slowly added to a stirred solution of methyl 6-(5-azaspiro[2.5]octan-5-yl)quinoline-4-carboxylate, intermediate 101 (270 mg, 0.76 mmol), in MeOH (6 ml), cooled to 0 °C. The resulting solution was stirred at 10 °C for 1 h. The solvent was removed under reduced pressure. The residue was dissolved in water (5 ml) and the pH was adjusted to 4 with aq. HCl (2 M). The solvent was removed under reduced pressure. The crude product was purified by preparative HPLC, PrepMethod P (gradient: 0-50%), affording the title compound (115 mg, 54%) as an orange solid; MS mass/charge (ESI) [M+H] ⁺ 283.1.

Intermediate 103. Methyl 6-(3,3-difluoropyrrolidin-1-yl)quinoline-4-carboxylate

3,3-Difluoropyrrolidine hydrochloride (324 mg, 2.25 mmol) was added to a mixture of methyl 6-bromoquinoline-4-carboxylate (300 mg, 1.13 mmol), Cs ₂ CO ₃ (1.10 g, 3.38 mmol), Pd ₂ (dba) ₃ (52 mg, 0.06 mmol) and XPhos (161 mg, 0.34 mmol) in 1,4-dioxane (20 mL). The reaction mixture was heated at 100 °C for 4 h. The precipitate was collected by filtration, washed with MeOH and dried.

- 112 048482 under vacuum to give a crude product, which was purified by preparative TLC (petroleum ether:EtOAc, 1:1) to give the title compound (180 mg, 55%) as a yellow solid; MS m/z (ESI) [M+H]+ 293.0.

Intermediate 104. 6-(3,3-difluoropyrrolidin-1-yl)quinoline-4-carboxylic acid

LiOH (74 mg, 3.1 mmol) was added to a solution of methyl 6-(3,3-difluoropyrrolidin-1-yl)quinoline-4-carboxylate, intermediate 103 (180 mg, 0.62 mmol), in MeOH (10 mL) and water (2 mL). The mixture was stirred at rt for 2 h. The reaction mixture was adjusted to pH 5 with aq. HCl (2 M). The reaction mixture was diluted with EtOAc and washed with water. The organic layer was dried over Na ₂ SO ₄ , filtered and evaporated to give the title compound (150 mg, 88%) as a yellow solid; MS m/z (ESI) [M+H] ⁺ 279.1.

Intermediate 105. tert-Butyl 6-(3,3-dimethylpyrrolidin-1-yl)quinoline-4-carboxylate

3,3-Dimethylpyrrolidine hydrochloride (149 mg, 1.10 _mmol ) was added to a mixture of tert-butyl 6-bromoquinoline-4-carboxylate (308 mg, 1.00 mmol), _Cs2CO3 (977 mg, 3.00 mmol), _Pd2 (dba) ₃ (92 mg, 0.10 mmol) and XPhos (95 mg, 0.20 mmol) in 1,4-dioxane (5 mL) at 8 °C. The resulting suspension was heated at 100 °C for 2 h under N2 (g). The reaction mixture was diluted with DCM (3 mL). The reaction mixture was filtered and the filtrate was concentrated under reduced pressure. The residue was purified by preparative TLC (EtOAc:petroleum ether, 1:1) to give the title compound (285 mg, 87%) as a brown solid; MS m/z (ESI) [M+H] ⁺ 327.3.

Intermediate 106. 6-(3,3-dimethylpyrrolidin-1-yl)quinoline-4-carboxylic acid

TFA (2.5 ml, 32 mmol) was added to a stirred solution of tert-butyl 6-(3,3-dimethylpyrrolidin-1-yl)quinoline-4-carboxylate, intermediate 105 (265 mg, 0.81 mmol), in DCM (5 ml) at 8 °C. The resulting solution was stirred at 8 °C overnight. The solvent was removed under reduced pressure to give the title compound (343 mg) as a dark red gum; MS m/z (ESI) [M+H] ⁺ 271.1.

Intermediate 107. tert-Butyl 6-(5-azaspiro[2.4]heptan-5-yl)quinoline-4-carboxylate

5-Azaspiro[2.4]heptane hydrochloride (147 mg, 1.10 mmol) was added to a mixture of tert-butyl 6-bromoquinoline-4-carboxylate (308 mg, 1.00 mmol), _Cs2CO3 (977 mg, 3.00 mmol), _Pd2 ( _dba ) ₃ (92 mg, 0.10 mmol), and XPhos (95 mg, 0.20 mmol) in 1,4-dioxane (5 mL) at 8 °C. The resulting suspension was heated at 100 °C for 2 h under N2 (g). The reaction mixture was diluted with DCM (3 mL) and filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by preparative TLC (EtOAc:petroleum ether, 1:1) to give the title compound (243 mg, 75%) as a brown oil that solidified on standing; MS m/z (ESI) [M+H] ⁺ 325.2.

Intermediate 108. 6-(5-azaspiro[2.4]heptan-5-yl)quinoline-4-carboxylic acid

TFA (5.0 mL, 65 mmol) was added to a stirred solution of tert-butyl 6-(5-azaspiro[2.4]heptan-5-yl)quinoline-4-carboxylate, intermediate 107 (240 mg, 0.74 mmol), in DCM (5 mL) at 8 °C. The resulting solution was stirred at 8 °C overnight. The solvent was removed under reduced pressure to give the title compound (423 mg) as a dark red solid; MS m/z (ESI) [M+H] ⁺ 269.1.

Intermediate 109. tert-Butyl-6-((3R,4S)-3,4-difluoropyrrolidin-1-yl)quinoline-4

- 113 048482 carboxylate

(3R,4S)-3,4-difluoropyrrolidine hydrochloride (158 mg, 1.10 mmol) was added to a mixture of tert-butyl 6-bromoquinoline-4-carboxylate (308 mg, 1.00 mmol), Cs2CO3 (977 mg, 3.00 mmol), Pd2(dba)3 (92 mg, 0.10 mmol) and XPhos (95 mg, 0.20 mmol) in 1,4-dioxane (1 mL) at 5 °C. The resulting suspension was heated at 100 °C for 2 h under N2 (g). The reaction mixture was diluted with DCM (3 mL). The reaction mixture was filtered and the filtrate was concentrated under reduced pressure. The residue was purified by preparative TLC (EtOAc:petroleum ether, 2:1) to give the title compound (263 mg, 79%) as a brown solid; MS m/z (ESI) [M+H]+ 335.2.

Intermediate 110. 6-((3R,4S)-3,4-difluoropyrrolidin-1-yl)quinoline-4-carboxylic acid

TFA (2.5 ml, 32 mmol) was added to a stirred solution of tert-butyl 6-((3S,4R)-3,4-difluoropyrrolidin-1-yl)quinoline-4-carboxylate, intermediate 109 (233 mg, 0.70 mmol), in DCM (5 ml) at 9 °C. The resulting solution was stirred at 9 °C overnight. The solvent was removed under reduced pressure to give the title compound (350 mg) as a dark red solid; MS m/z (ESI) [M+H]+ 279.0.

Intermediate 111. tert-Butyl (S)-6-(3-fluoropyrrolidin-1-yl)quinoline-4-carboxylate

(S)-3-Fluoropyrrolidine hydrochloride (138 mg, 1.10 mmol) was added to a mixture of tert-butyl 6-bromoquinoline-4-carboxylate (308 mg, 1.00 mmol), _Cs2CO3 ( ₉₇₇ mg, 3.00 mmol), _Pd2 (dba) ₃ (92 mg, 0.10 mmol), and XPhos (95 mg, 0.20 mmol) in 1,4-dioxane (5 mL) at 9 °C. The resulting suspension was heated at 100 °C for 2 h under N2 (g). The reaction mixture was diluted with DCM (3 mL) and filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by preparative TLC (EtOAc:petroleum ether, 1:1) to give the title compound (246 mg, 78%) as a brown oil that solidified on standing; MS m/z (ESI) [M+H]+ 317.3.

Intermediate 112. (S)-6-(3-fluoropyrrolidin-1-yl)quinoline-4-carboxylic acid

TFA (4 ml, 52 mmol) was added to a stirred solution of tert-butyl (S)-6-(3-fluoropyrrolidin-1-yl)quinoline-4-carboxylate, intermediate 111 (217 mg, 0.69 mmol), in DCM (5 ml) at 9 °C. The resulting solution was stirred at 9 °C overnight. The solvent was removed under reduced pressure to give the title compound (305 mg) as a dark red oil that solidified on standing; MS m/z (ESI) [M+H]+ 261.2.

Intermediate 113. tert-Butyl (R)-6-(3-fluoropyrrolidin-1-yl)quinoline-4-carboxylate

(R)-3-Fluoropyrrolidine hydrochloride (138 mg, 1.10 mmol) was added to a mixture of tert-butyl 6-bromoquinoline-4-carboxylate (308 mg, 1.00 mmol), _Cs2CO3 ( ₉₇₇ mg, 3.00 mmol), _Pd2 (dba) ₃ (92 mg, 0.10 mmol) and XPhos (95 mg, 0.20 mmol) in 1,4-dioxane (5 mL) at 8 °C. The resulting suspension was stirred at 100 °C for 2 h under N2 (g). The reaction mixture was diluted with DCM (3 mL) and filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by preparative TLC (EtOAc:petroleum ether, 1:1) to give the title compound (245 mg, 77%) as a brown oil that solidified on standing; MS m/z (ESI)

- 114 048482

[M+N]+ 317.3.

Intermediate 114. (R)-6-(3-fluoropyrrolidin-1-yl)quinoline-4-carboxylic acid

TFA (4 ml, 52 mmol) was added to a stirred solution of tert-butyl (R)-6-(3-fluoropyrrolidin-1-yl)quinoline-4-carboxylate, intermediate 113 (230 mg, 0.73 mmol), in DCM (5 ml) at 9 °C. The resulting solution was stirred at 9 °C overnight. The solvent was removed under reduced pressure to give the title compound (447 mg) as a dark red oil that solidified on standing; MS m/z (ESI) [M+H] ⁺ 261.2.

Intermediate 115. Methyl 6-(hexahydrocyclopenta[c]pyrrol-2(1H-yl)quinoline-4-carboxylate

Octahydrocyclopenta[c]pyrrole hydrochloride (333 mg, 2.25 mmol) was added to a mixture of methyl 6-bromoquinoline-4-carboxylate (300 mg, 1.13 mmol), _Cs2CO3 (1.10 g, 3.38 mmol), _Pd2 ( _dba ) ₃ (103 mg, 0.11 mmol), and XPhos (161 mg, 0.34 mmol) in 1,4-dioxane (20 mL). The mixture was heated at 100 °C for 4 h under N2 (g). The precipitate was collected by filtration, washed with MeOH and dried under vacuum to give the crude product, which was purified by preparative TLC (petroleum ether:EtOAc, 1:1) to give the title compound (200 mg, 60%) as a yellow solid; MS m/z (ESI) [M+H] ⁺ 297.1.

Intermediate 116. 6-(hexahydrocyclopenta[c]pyrrol-2(1H)-yl)quinoline-4-carboxylic acid

LiOH (40 mg, 1.69 mmol) was added to a solution of methyl 6-(hexahydrocyclopenta[c]pyrrole-2(1H)yl)quinoline-4-carboxylate, intermediate 115 (100 mg, 0.34 mmol), in MeOH (10 mL) and water (2 mL). The reaction mixture was stirred at rt for 2 h. The reaction mixture was adjusted to pH 5 with aq. HCl (2 M). The reaction mixture was diluted with EtOAc and washed with water. The organic layer was dried over Na ₂ SO ₄ , filtered and evaporated to give the title compound (85 mg, 89%) as a yellow solid; MS m/z (ESI) [M+H] ⁺ 283.2.

Intermediate 117. tert-Butyl (S)-6-(3-methylpyrrolidin-1-yl)quinoline-4-carboxylate

(S)-3-methylpyrrolidine hydrochloride (87 mg _, 0.71 mmol) was added to a mixture of tert-butyl 6-bromoquinoline-4-carboxylate (200 mg, 0.65 mmol), _Cs2CO3 (634 mg, 1.95 mmol), _Pd2 (dba) ₃ (59 mg, 0.06 mmol) and XantPhos (75 mg, 0.13 mmol) in 1,4-dioxane (5 mL) at 20 °C. The resulting suspension was then heated at 100 °C for 2 h under N2 (g). The reaction mixture was filtered through Celite®. The solvent was removed under reduced pressure. The residue was purified by preparative TLC (petroleum ether:EtOAc, 2:1) to give the title compound (125 mg, 61%) as a brown solid; MS m/z (ESI) [M+H] ⁺ 313.3.

Intermediate 118. (S)-6-(3-methylpyrrolidin-1-yl)quinoline-4-carboxylic acid

HCl (4 M in 1,4-dioxane, 0.3 ml) was added to tert-butyl (S)-6-(3-methylpyrrolidin-1-yl)quinoline-4-carboxylate, intermediate 117 (240 mg, 0.77 mmol), in 1,4-dioxane (5 ml) at 0 °C. The reaction mixture was stirred at 25 °C for 19 h. The solvent was removed under reduced pressure to give the title compound (197 mg); MS m/z (ESI) [M+H] ⁺ 257.3.

- 115 048482

Intermediate 119. tert-Butyl (R)-6-(3-methylpyrrolidin-1-yl)quinoline-4-carboxylate

(R)-3-methylpyrrolidine hydrochloride (118 _mg , 0.97 mmol) was added to a mixture of tert-butyl 6-bromoquinoline-4-carboxylate (200 mg, 0.65 mmol), _Cs2CO3 (423 mg, 1.30 mmol), _Pd2 (dba) ₃ (30 mg, 0.03 mmol) and XantPhos (38 mg, 0.06 mmol) in 1,4-dioxane (5 mL) at 20 °C. The resulting suspension was then heated at 100 °C for 2 h under _N2 (g). The reaction mixture was filtered through Celite®. The solvent was removed under reduced pressure. The residue was purified by preparative TLC (petroleum ether:EtOAc, 2:1) to give the title compound (135 mg, 66%) as a brown solid; MS m/z (ESI) [M+H]+ 313.4.

Intermediate 120. (R)-6-(3-methylpyrrolidin-1-yl)quinoline-4-carboxylic acid

HCl (4 M in 1,4-dioxane, 0.65 ml) was added to tert-butyl (R)-6-(3-methylpyrrolidin-1-yl)quinoline-4-carboxylate, intermediate 119 (270 mg, 0.86 mmol), in 1,4-dioxane (5 ml) at 0 °C. The reaction mixture was stirred at 25 °C for 19 h. The solvent was removed under reduced pressure to give the title compound (222 mg); MS m/z (ESI) [M+H]+ 257.2.

Intermediate 121. Methyl (S)-6-(2-(trifluoromethyl)pyrrolidin-1-yl)quinoline-4-carboxylate

(S)-2-(trifluoromethyl)pyrrolidine (314 mg, 2.25 mmol) was added to a mixture of methyl 6-bromoquinoline-4-carboxylate (300 mg, 1.13 mmol), _Cs2CO3 (1.10 g, 3.38 mmol) and Pd catalyst [CAS: 1810068-35-9] (129 mg, 0.11 mmol) in 1,4-dioxane (15 mL) at 25 _° C. The resulting suspension was heated at 100 °C for 18 h under _N2 (g). The solid was filtered off and the filtrate was concentrated under reduced pressure. The residue was purified by preparative TLC (petroleum ether:EtOAc, 1:1) to give the title compound (150 mg, 41%) as a yellow solid; MS m/z (ESI) [M+H]+ 325.1.

Intermediate 122. (S)-6-(2-(trifluoromethyl)pyrrolidin-1-yl)quinoline-4-carboxylic acid

LiOH (55 mg, 2.31 mmol) was added to a solution of methyl (S)-6-(2-(trifluoromethyl)pyrrolidin-1yl)quinoline-4-carboxylate, intermediate 121 (150 mg, 0.46 mmol), in MeOH (5 mL) and water (1 mL). The reaction mixture was stirred at rt for 2 h. The solvent was removed under reduced pressure. The residue was diluted with water, adjusted to pH 6 with aq. HCl (1 M) and extracted with EtOAc. The combined organic phases were washed with water. The organic layer was dried over Na ₂ SO ₄ , filtered and evaporated to give the title compound (130 mg, 91%) as a yellow solid; MS w/z (ESI) [M+H]+ 311.05.

Intermediate 123. tert-Butyl 6-(2,2-dimethylpyrrolidin-1-yl)quinoline-4-carboxylate

2,2-Dimethylpyrrolidine (193 mg, 1.95 mmol) was added to a mixture of tert-butyl 6-bromoquinoline-4-carboxylate (300 mg, 0.97 mmol), _Cs2CO3 (952 mg, 2.92 mmol) and Pd catalyst [CAS: 1810068-35-9] (55 mg, 0.05 mmol) in 1,4-dioxane (15 mL) at 25 _° C. The resulting suspension was stirred at 100 °C for 18 h under N2 (g). The solid was filtered off and the filtrate was concentrated in vacuo. The residue was purified by preparative TLC (petroleum ether:EtOAc, 2:1) to give the title compound (160 mg, 50%) as a yellow solid.

- 116 048482 substance; MS mass/charge (ESI) [M+H]+ 327.3.

Intermediate 124. 6-(2,2-dimethylpyrrolidin-1-yl)quinoline-4-carboxylic acid

TFA (3 mL) was added to a solution of tert-butyl 6-(2,2-dimethylpyrrolidin-1-yl)quinoline-4-carboxylate, intermediate 123 (150 mg, 0.46 mmol), in DCM (6 mL). The reaction mixture was stirred at rt for 4 h. The solvent was removed under reduced pressure to give the title compound (300 mg); MS m/z (ESI) [M+H]+ 271.2.

Intermediate 125. tert-Butyl (R)-6-(6-(fluoromethyl)-5-azaspiro[2.4]heptan-5yl)quinoline-4-carboxylate

(R)-6-(fluoromethyl)-5-azaspiro[2.4]heptane hydrochloride (202 mg, 1.22 mmol) was added to a mixture of tert-butyl 6-bromoquinoline-4-carboxylate (250 mg, 0.81 mmol), _Cs2CO3 (793 _mg , 2.43 mmol) and Pd catalyst [CAS: 1810068-35-9] (46 mg, 0.04 mmol) in 1,4-dioxane (15 mL) at 25 °C. The resulting suspension was stirred at 100 °C for 4 h under _N2 (g). The reaction mixture was filtered and the filtrate was concentrated in vacuo. The residue was purified by preparative TLC (petroleum ether:EtOAc, 2:1) to give the title compound (180 mg, 62%) as a yellow solid; MS m/z (ESI) [M+H]+ 357.3.

Intermediate compound carboxylic acid

TFA (3 ml) was added to

126. (R)-6-(6-(fluoromethyl)-5-azaspiro[2.4]heptan-5-yl)quinoline-4

a solution of tert-butyl (R)-6-(6-(fluoromethyl)-5-azaspiro[2.4]heptan-5-yl)quinoline-4-carboxylate, intermediate 125 (180 mg, 0.50 mmol), in DCM (6 ml). The reaction mixture was stirred at rt for 5 h. The solvent was removed under reduced pressure to give the title compound (152 mg, 100%); MS m/z (ESI) [M+H]+ 301.2.

Carboxylate intermediate

127. tert-Butyl-(S)-6-(2-methylpyrrolidin-1-yl)quinoline-4-

(S)-2-methylpyrrolidine (111 mg,

1.30 mmol) was added to a mixture of tert-butyl 6-bromoquinoline-4 carboxylate (200 mg, 0.65 mmol) _{, Cs2CO3 (} 634 mg, 1.95 mmol) and Pd catalyst [CAS: 1810068-35-9] (37 mg, 0.03 mmol) in 1,4-dioxane (5 mL). The mixture was stirred under _N2 (g) at 100 °C overnight. The solvent was removed under reduced pressure. The residue was purified by preparative TLC (petroleum ether:EtOAc, 3:1) to give the title compound (120 mg, 59%) as a yellow solid; MS w/z (ESI) [M+H]+ 313.3.

Intermediate 128. (S)-6-(2-methylpyrrolidin-1-yl)quinoline-4-carboxylic acid

TFA (44 mg, 0.38 mmol) was added to a solution of tert-butyl (S)-6-(2-methylpyrrolidin-1-yl)quinoline-4-carboxylate, intermediate 127 (120 mg, 0.38 mmol), in DCM (3 ml). The reaction mixture was stirred at 25 °C overnight. The solvent was removed under reduced pressure to give the title compound; MS m/z (ESI) [M+H]+ 257.15.

Intermediate 129. Methyl (R)-6-(3-fluoroazepan-1-yl)quinoline-4-carboxylate

(R)-3-fluoroazepane hydrobromide (395 mg, 2.00 mmol) was added to the methyl-6 hydrochloride mixture

- 117 048482 bromoquinoline-4-carboxylate, intermediate 422 (302 mg, 1.00 mmol), _Cs2CO3 (976 mg, 2.99 mmol), Pd2( _dba )3 (150 mg, 0.16 mmol) and XPhos (150 mg, 0.31 mmol) in 1,4-dioxane (20 mL) at 10 °C. The resulting suspension was stirred at 100 °C for 2 h under _N2 (g). The reaction mixture was diluted with DCM (2 mL) and filtered. The filtrate was concentrated under reduced pressure. The residue was purified by preparative TLC (petroleum ether:EtOAc, 1:1) to give the title compound (195 mg, 65%) as a yellow gum; MS mass/charge (ESI) [M+H]+ 303.1.

Intermediate 130. (R)-6-(3-fluoroazepan-1-yl)quinoline-4-carboxylic acid

NaOH (97 mg, 2.42 mmol) was added to methyl (R)-6-(3-fluoroazepan-1-yl)quinoline-4-carboxylate, intermediate 129 (195 mg, 0.48 mmol), in MeOH (3 mL) and water (1 mL) at 13 °C. The resulting suspension was stirred at 13 °C for 1 h. The reaction mixture was acidified to pH 4 with aq. HCl (1 M). The reaction mixture was diluted with water (20 mL) and extracted with EtOAc (3 x 50 mL). The organic layer was dried over Na ₂ SO ₄ , filtered and evaporated. The crude product was purified by preparative HPLC, PrepMethod P, to give the title compound (20 mg, 14%); MS mass/charge (ESI) [M+H]+ 289.2.

Intermediate 131. Methyl (S)-6-(3-fluoroazepan-1-yl)quinoline-4-carboxylate

(S)-3-fluoroazepane hydrobromide (395 mg, 2.00 mmol) was added to a mixture of methyl 6-bromoquinoline-4-carboxylate hydrochloride, intermediate 422 (302 mg, 1.00 mmol), Cs2CO3 (976 mg, 2.99 mmol), _Pd2 (dba) ₃ (91 mg, 0.10 mmol) and XPhos (95 mg, 0.20 mmol) in 1,4-dioxane (5 mL) at 13 °C. The resulting suspension was stirred at 100 °C overnight under N2 (g). The reaction mixture was diluted with DCM (20 mL) and filtered. The filtrate was concentrated under reduced pressure. The residue was purified by preparative TLC (petroleum ether:EtOAc, 1:1) to give the title compound (173 mg, 57%) as a yellow gum; MS m/z (ESI) [M+H]+ 303.1.

Intermediate 132. (S)-6-(3-fluoroazepan-1-yl)quinoline-4-carboxylic acid

NaOH (80 mg, 2.00 mmol) was added to methyl (S)-6-(3-fluoroazepan-1-yl)quinoline-4-carboxylate, intermediate 131 (173 mg, 0.40 mmol), in MeOH (3 mL) and water (1 mL) at 13 °C. The resulting solution was stirred at 13 °C for 1 h. The reaction mixture was acidified to pH 4 with aq. HCl (1 M). The reaction mixture was diluted with water (20 mL) and extracted with EtOAc (3 x 50 mL). The organic layer was dried over Na ₂ SO ₄ , filtered and evaporated. The crude product was purified by preparative HPLC, PrepMethod P, to give the title compound (84 mg, 73%) as an orange solid; MS mass/charge (ESI) [M+H]+ 289.2.

Intermediate 133. tert-Butyl (R)-6-(7-methyl-1,4-oxazepan-4-yl)quinoline-4-carboxylate

((S)-7-methyl-1,4-oxazepane hydrochloride ( ₁₀₀ mg, 0.66 mmol) was added to a mixture of tert-butyl 6-bromoquinoline-4-carboxylate (185 mg, 0.60 mmol), _Cs2CO3 (587 mg, 1.80 mmol) and RuPhosPdG3 (50 mg, 0.06 mmol) in 1,4-dioxane (3 mL) at 10 °C. The resulting suspension was stirred at 100 °C for 2 h under N2 (g). The reaction mixture was filtered and the filtrate was washed with water (3 mL). The aqueous layer was extracted with EtOAc (3 x 15 mL). The organic layers were combined and washed with water (3 x 5 mL). _The organic layer was dried over _Na2SO4 , filtered and evaporated. The residue was purified by preparative TLC (petroleum ether:EtOAc, 2:1) to give the title compound (155 mg, 75%) as a brown gum; MS m/z (ESI) [M+H]+ 343.15.

- 118 048482

Intermediate 134. (R)-6-(7-methyl-1,4-oxazepan-4-yl)quinoline-4-carboxylic acid

TFA (5 ml, 65 mmol) was added to a stirred solution of tert-butyl ((S)-6-(7-methyl-1,4-oxazepan-4-yl)quinoline-4-carboxylate, intermediate 133 (136 mg, 0.40 mmol), in DCM (5 ml) at 3 °C. The resulting solution was stirred at 3 °C overnight. The solvent was removed under reduced pressure to give the title compound (265 mg) as a dark red gum. MS m/z (ESI) [M+H]+ 287.1.

Intermediate 135. tert-Butyl (S)-6-(7-methyl-1,4-oxazepan-4-yl)quinoline-4-carboxylate

(S)-7-methyl-1,4-oxazepane hydrochloride ( ₁₀₀ mg, 0.66 mmol) was added to a mixture of tert-butyl 6-bromoquinoline-4-carboxylate (185 mg, 0.60 mmol), _Cs2CO3 (587 mg, 1.80 mmol) and RuPhosPdG3 (50 mg, 0.06 mmol) in 1,4-dioxane (3 ml) at 10 °C. The resulting suspension was stirred at 100 °C for 2 h under _N2 (g). The reaction mixture was filtered and the filtrate was washed with water (3 ml). The aqueous layer was extracted with EtOAc (3 x 15 ml). The organic layers were combined and washed with water (3 x 5 ml). _The organic layer was dried over _Na2SO4 , filtered and evaporated. The residue was purified by preparative TLC (petroleum ether:EtOAc, 2:1) to give the title compound (166 mg, 81%) as a brown gum; MS m/z (ESI) [M+H] ⁺ 343.15.

Intermediate 136. (S)-6-(7-methyl-1,4-oxazepan-4-yl)quinoline-4-carboxylic acid

TFA (5 ml, 65 mmol) was slowly added to a stirred solution of tert-butyl (S)-6-(7-methyl-1,4-oxazepan-4-yl)quinoline-4-carboxylate, intermediate 135 (148 mg, 0.43 mmol), in DCM (5 ml) at 3 °C. The resulting solution was stirred at 3 °C overnight. The solvent was removed under reduced pressure to give the title compound (405 mg) as a dark red gum; MS m/z (ESI)[M+H] ⁺ 287.1.

Intermediate 137. Methyl (S)-6-(3-methyl-1,4-oxazepan-4-yl)quinoline-4-carboxylate

(S)-3-methyl-1,4-oxazepane hydrochloride (228 mg, 1.50 mmol) was added to a mixture of methyl 6-bromoquinoline-4-carboxylate (200 mg, 0.75 mmol), Cs2CO3 (1.47 g, 4.51 mmol) and Pd catalyst [CAS: 1810068-35-9] (43 mg, 0.04 mmol) in 1,4-dioxane (3 mL) at 5 °C. The resulting suspension was stirred at 100 °C for 2 days under _N2 (g). The reaction mixture was diluted with EtOAc. The solvent was removed under reduced pressure. The residue was diluted with water (50 mL) and extracted with EtOAc (3x50 mL). The organic layers were combined and washed with brine (200 mL). The organic layer was dried over _Na2SO4 , filtered and evaporated. The residue was purified by preparative TLC (petroleum ether: _EtOAc , 1:1) to give the title compound (147 mg, 65%) as an orange solid; MS m/z (ESI) [M+H] ⁺ 301.0.

Intermediate 138. (S)-6-(3-methyl-1,4-oxazepan-4-yl)quinoline-4-carbonic acid

NaOH (91 mg, 2.3 mmol) was added to methyl (R)-6-(3-methyl-1,4-oxazepan-4-yl)quinoline-4-carboxylate, intermediate 137 (136 mg, 0.45 mmol), in MeOH (3 ml) and water (1 ml) at 10 °C. The resulting solution was stirred at 10 °C for 1 h. The solvent was removed under reduced pressure. The residue was diluted with water (20 ml) and the pH was adjusted to 5 with aq. HCl (1 M). The mixture was diluted with water (10 ml) and extracted with EtOAc (6 x 30 ml). The organic layers were combined, dried over Na ₂ SO ₄ , filtered and evaporated. The crude product was purified by preparative HPLC, PrepMethod F, to give the title compound (80 mg, 62%) as an orange solid; MS m/z (ESI) [M+H] ⁺ 287.0.

- 119 048482

Intermediate 139. tert-Butyl (R)-6-(2-methyl-1,4-oxazepan-4-yl)quinoline-4-carboxylate

(R)-2-methyl-1,4-oxazepane (168 mg, 1.46 mmol) was added to a mixture of tert-butyl 6-bromoquinoline-4-carboxylate (300 mg, 0.97 mmol), _Cs2CO3 (952 mg, 2.92 mmol), _Pd2 (dba) ₃ (89 mg, _0.10 mmol) and XantPhos (113 mg, 0.19 mmol) in 1,4-dioxane (5 mL). The reaction mixture was stirred under N2(g) at 100 °C for 3 h. The solvent was removed under reduced pressure. The residue was purified by preparative TLC (petroleum ether:EtOAc, 2:1) to give the title compound (150 mg, 45%) as a yellow solid; MS mass/charge (ESI) [M+H]+ 343.3.

Intermediate 140. (R)-6-(2-methyl-1,4-oxazenan-4-yl)quinoline-4-carboxylic acid

TFA (50 mg, 0.44 mmol) was added to tert-butyl (R)-6-(2-methyl-1,4-oxazepan-4-yl)quinoline-4-carboxylate, intermediate 139 (150 mg, 0.44 mmol), in DCM (3 ml). The reaction mixture was stirred at 25 °C overnight. The solvent was removed under reduced pressure to give the title compound; MS m/z (ESI) [M+H]+ 287.3.

Intermediate 141. Ethyl 6-(3-methoxyazetidin-1-yl)quinoline-4-carboxylate

A mixture of ethyl 6-bromoquinoline-4-carboxylate (140 mg, 0.50 mmol), Cs ₂ CO ₃ (651 mg, 2.00 mmol), RuPhos Pd G4 (43 mg, 0.05 mmol), 3-methoxyazetidine hydrochloride (80 mg, 0.65 mmol) and dioxane (1.2 mL) under N2 (g) was stirred at 90 °C for 5.5 h. The reaction mixture was diluted with EtOAc (5 mL), SiliaMetS® Thiol (150 mg; loading 1.4 mmol/g) was added and the mixture was stirred for 1 h. The mixture was filtered through a pad of Celite® 521, the filter pad was washed with EtOAc (12 mL) and the filtrate was concentrated. The residue was purified using preparative HPLC, PrepMethod H (gradient: 30-70%) to give the title compound (104 mg, 0.36 mmol); MS (ESI) m/z [M+H]+ 287.3.

Intermediate 142. 6-(3-methoxyazetidin-1-yl)quinoline-4-carboxylic acid

Aq. NaOH (3.8 M, 184 μL, 0.70 mmol) was added to a solution of ethyl 6-(3-methoxyazetidin-1-yl)quinoline-4-carboxylate, intermediate 141 (100 mg, 0.35 mmol), in MeOH (2 mL) and the reaction mixture was stirred at rt overnight. Aq. HCl (3.8 M, 230 μL, 0.87 mmol) was added dropwise and the resulting mixture was concentrated and lyophilized from MeCN/H2O to give the crude title compound (0.102 g); MS m/z (ESI)[M+H]+ 259.1.

Intermediate 143. Ethyl 6-morpholinoquinoline-4-carboxylate

Morpholine (0.22 mL, 2.5 mmol) was added to a mixture of ethyl 6-bromoquinoline-4-carboxylate (0.355 g, 1.27 mmol), Pd(dba) ₂ (36 mg, 0.06 mmol), RuPhos (59 mg, 0.13 mmol) _, and _K3PO4 (0.538 g, 2.53 mmol) in t-BuOH (2.3 mL). The flask was sealed, purged with N2(g), and heated at 90 °C overnight. The reaction mixture was diluted with EtOAc, washed successively with water and brine. The organic layer was dried by passing through a phase separator and concentrated under reduced pressure to give the title compound (110 mg, 30%); MS mass/charge (ESI) [M+H]+ 287.2.

- 120 048482

Intermediate 144. 6-Morpholinoquinoline-4-carboxylic acid

NaOH (31 mg, 0.77 mmol) was added to a solution of ethyl 6-morpholinoquinoline-4-carboxylate, intermediate 143 (110 mg, 0.38 mmol), in MeOH (4 mL) and heated at 60 °C for 2 h. The reaction mixture was cooled to rt and aq. HCl (0.023 mL) was added. The reaction mixture was concentrated under reduced pressure to give the title compound (95 mg, 96%); MS m/z (ESI)[M+H]+ 259.1.

Carboxylate intermediate

145. tert-Butyl-(R)-6-(2-(fluoromethyl)morpholino)quinoline-4-

A mixture of tert-butyl 6-bromoquinoline-4-carboxylate (0.616 g, 2 mmol), (R)-2(fluoromethyl)morpholine hydrochloride (0.405 g, 2.60 mmol), RuPhosPd G4 (0.170 g, _{0.20 mmol), Cs2CO3 (} 1.955 g, 6.00 mmol) and dioxane (5 mL) under N2 (g) was stirred vigorously at 85-90 °C for 19 h. After cooling to rt, the reaction mixture was diluted with EtOAc (8 mL) and stirred with SiliaMetS® Thiol scavenger (0.7 g; 1.4 mmol/g) at rt overnight. The reaction mixture was filtered through Celite® 521. The filter pad was washed with EtOAc and the combined filtrates were concentrated under reduced pressure. The residue was purified by preparative HPLC, PrepMethod H (gradient: 35-75%) to give the title compound (0.62 g, 89%) as a yellow syrup; MS (ESI) m/z [M+H]+ 347.3.

Intermediate 146. (R)-6-(2-(fluoromethyl)morpholino)quinoline-4-carboxylic acid

A solution of tert-butyl (R)-6-(2-(fluoromethyl)morpholino)quinoline-4-carboxylate, intermediate 145 (0.554 g, 1.60 mmol), in 90% TFA (aq, 3 mL) was stirred at 50 °C for 70 min. The volatiles were removed under reduced pressure and the residue was concentrated from heptane twice to give the crude title compound (1.09 g); MS (ESI) m/z [M+H]+ 291.1.

Intermediate 147. Ethyl 6-((2R,6R)-2,6-dimethylmorpholino)quinoline-4-carboxylate

A mixture of ethyl 6-bromoquinoline-4-carboxylate (0.098 g, 0.35 mmol), Cs2CO3 (0.456 g, 1.40 mmol), RuPhosPd G4 (0.030 g, 0.04 mmol), (2R,6R)-2,6-dimethylmorpholine hydrochloride (70 mg, 0.46 mmol) and dioxane (0.9 mL) under _N2 (g) was stirred at 90 °C for 4.5 h. After cooling to rt, SilaMetS® Thiol scavenger (150 mg; loading 1.4 mmol/g) was added and the mixture was stirred overnight, diluted with EtOAc (3 mL) and filtered through a pad of Celite® 521. The filter pad was washed with EtOAc (10 mL) and The filtrate was concentrated. The residue was purified by preparative HPLC, PrepMethod H (gradient: 35-75%), to give the title compound (83 mg, 76%) as a yellow film; MS (ESI) m/z [M+H]+ 315.2.

Intermediate 148. 6-((2R,6R)-2,6-dimethylmorpholino)quinoline-4-carboxylic acid

Aqueous NaOH (3.8 M, 158 μL, 0.60 mmol) was added to a solution of ethyl 6-((2R,6R)-2,6-dimethylmorpholino)quinoline-4-carboxylate, intermediate 147 (81 mg, 0.26 mmol), in MeOH (2 mL) and the reaction mixture was stirred at rt for 2.5 h and then at 50 °C for 30 min, after which time the reaction mixture was allowed to reach rt. Aqueous HCl (3.8 M, 0.12 mL, 0.45 mmol) was added dropwise and the resulting mixture was concentrated under reduced pressure at rt to give the crude title compound (99 mg) as a red solid; MS (ESI) m/z [M+H]+ 287.3.

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Intermediate 149. tert-Butyl 6-((2R,6S)-2,6-dimethylmorpholino)quinoline-4-carboxylate

A mixture of tert-butyl 6-bromoquinoline-4-carboxylate (149 mg, 0.48 mmol), Cs2CO3 (473 mg, 1.45 mmol), RuPhosPd G3 (40 mg, 0.05 mmol), (2R,6S)-2,6-dimethylmorpholine (69 mg, 0.63 mmol) and dioxane (1.2 mL) under N2 (g) was stirred at 85 °C for 22 h. After cooling to rt, the reaction mixture was diluted with EtOAc (2 mL). SiliaMetS® Thiol (ca. 150 mg; loading 1.4 mmol/g) was added and the mixture was stirred for 2 h and filtered through a pad of Celite® 521. The filter pad was washed with EtOAc (9 mL) and the combined filtrate was concentrated. The residue was purified by preparative HPLC, PrepMethod H (gradient: 35-75%) to give the title compound (141 mg, 85%); MS (ESI) m/z [M+H]+ 343.4.

Intermediate 150. tert-Butyl (S)-6-(2-(fluoromethyl)morpholino)quinoline-4-carboxylate

A mixture of tert-butyl 6-bromoquinoline-4-carboxylate (149 mg, 0.48 mmol), _Cs2CO3 (473 mg, 1.45 mmol), RuPhosPd G3 (40 mg, 0.05 mmol), (S)-2-(fluoromethyl)morpholine hydrochloride (98 mg, 0.63 mmol) and dioxane (1.2 mL) under N2 (g) was stirred at 85 °C for 19 h. After cooling to rt, the reaction mixture was diluted with EtOAc (2 mL). SilaMetS® Thiol scavenger (ca. 150 mg; loading 1.4 mmol/g) was added and the mixture was stirred for 2 h and filtered through a pad of Celite® 521. The filter pad was washed with EtOAc (9 mL) and the combined filtrates were concentrated. The residue was purified by preparative HPLC, PrepMethod H (gradient: 35-75%) to give the title compound (137 mg, 82%); MS m/z (ESI) [M+H]+ 347.3.

Intermediate 151. Ethyl (R)-6-(2-methylmorpholino)quinoline-4-carboxylate

A mixture of ethyl 6-bromoquinoline-4-carboxylate (0.280 g, 1.0 mmol), (R)-2-methylmorpholine hydrochloride (0.179 g, 1.30 mmol), RuPhosPd G4 (0.085 g, 0.10 mmol), _Cs2CO3 ( _0.977 g, 3.00 mmol) and dioxane (2.5 mL) under N2 (gas) was stirred vigorously at 85-90°C for 1 h 45 min. After cooling to rt, the reaction mixture was diluted with EtOAc (5 mL) and stirred with SilaMetS® Thiol scavenger (0.5 g; loading: 1.4 mmol/g) at rt for 1.5 h. The reaction mixture was filtered through Celite® 521. The filter was washed with EtOAc and the combined filtrates were concentrated. The residue was purified by preparative HPLC, PrepMethod H (gradient: 30-70%) to afford the title compound (0.248 g, 83%) as a yellow solid; MS (ESI) m/z [M+H]+ 301.3.

Intermediate 152. (R)-6-(2-methylmorpholino)quinoline-4-carboxylic acid

Aqueous NaOH (3.8 M, 0.42 mL, 1.6 mmol) was added to a solution of ethyl (R)-6-(2-methylmorpholino)quinoline-4-carboxylate, intermediate 151 (241 mg, 0.80 mmol), in MeOH (5 mL) and the reaction mixture was stirred at rt overnight and at 50 °C for 1 h. Additional aq. NaOH (3.8 M, 106 μL, 0.40 mmol) was added and heating was continued for 20 min. Aq. HCl (3.8 M, 528 μL, 2.01 mmol) was added dropwise and the resulting mixture was concentrated under reduced pressure. The residue was concentrated from MeCN to give crude (R)-6-(2-methylmorpholino)quinoline-4-carboxylic acid (0.309 g) as a red solid; MS (ESI) m/z [M+H]+ 273.1.

Intermediate 153. Ethyl (R)-6-(2-(trifluoromethyl)morpholino)quinoline-4-carboxylate

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A mixture of ethyl 6-bromoquinoline-4-carboxylate (0.098 g, 0.35 mmol), _Cs2CO3 (0.456 g, 1.40 mmol), RuPhosPdG4 (0.030 g, 0.04 mmol) and (R)-2-(trifluoromethyl)morpholine hydrochloride ₍ 0.088 g, 0.46 mmol) in dioxane (0.9 mL) under N2 (g) was stirred at 90 °C for 4.5 h. After cooling to rt, SilaMetS® Thiol scavenger (0.150 g; loading 1.4 mmol/g) was added and the mixture was stirred overnight at rt. The mixture was diluted with EtOAc (3 mL) and filtered through a pad of Celite® 521. The filter pad was washed with EtOAc (10 mL) and the combined filtrates were concentrated. The residue was purified by preparative HPLC, PrepMethod H (gradient: 35-75%) to give the title compound (0.113 g, 91%) as a yellow film; MS (ESI) m/z [M+H]+ 355.2.

Intermediate 154. (R)-6-(2-(trifluoromethyl)morpholino)quinoline-4-carboxylic acid

Aqueous NaOH (3.8 M, 0.16 mL, 0.60 mmol) was added to a solution of ethyl (R)-6-(2(trifluoromethyl)morpholino)quinoline-4-carboxylate, intermediate 153 (0.106 g, 0.30 mmol), in MeOH (2 mL) and the reaction mixture was stirred at rt for 2.5 h and then at 50 °C for 30 min. The reaction mixture was brought to rt, aqueous HCl (3.8 M, 0.118 mL, 0.45 mmol) was added dropwise and the resulting mixture was concentrated to give the crude title compound (0.121 g) as a red solid; MS (ESI) m/z [M+H] ⁺ 327.1.

Intermediate 155. Ethyl (S)-6-(2-(trifluoromethyl)morpholino)quinoline-4-carboxylate

A mixture of ethyl 6-bromoquinoline-4-carboxylate (0.098 g, 0.35 mmol), Cs2CO3 (0.456 g, 1.40 mmol), RuPhosPd G4 (0.030 g, 0.04 mmol) and (S)-2-(trifluoromethyl)-morpholine hydrochloride (0.088 g, 0.46 mmol) in dioxane (0.9 mL) under _N2 (g) was stirred at 90 °C for 4.5 h. After cooling to rt, SilaMetS® Thiol scavenger (0.150 g; loading 1.4 mmol/g) was added and the mixture was stirred overnight at rt. The mixture was diluted with EtOAc (3 mL) and filtered through a pad of Celite® 521. The filter pad was washed with EtOAc (10 mL) and the combined filtrates were concentrated. The residue was purified by preparative HPLC, PrepMethod H (gradient: 35-75%) to give the title compound (0.114 g, 92%) as a yellow film; MS (ESI) m/z [M+H] ⁺ 355.2.

Intermediate 156. (S)-6-(2-(trifluoromethyl)morpholino)quinoline-4-carboxylic acid

Aqueous NaOH (3.8 M, 159 μL, 0.60 mmol) was added to a solution of ethyl (S)-6-(2(trifluoromethyl)morpholino)quinoline-4-carboxylate, intermediate 155 (0.107 g, 0.30 mmol), in MeOH (2 mL) and the reaction mixture was stirred at rt for 2.5 h and then at 50 °C for 30 min. The reaction mixture was brought to rt, aqueous HCl (3.8 M, 119 μL, 0.45 mmol) was added and the resulting mixture was concentrated to give the crude title compound (0.120 g) as a red solid; MS (ESI) m/z [M+H] ⁺ 327.17.

Intermediate 157. Ethyl 6-((1S,4S)-2-oxa-5-azabicyclo[2.2.1]heptan-5-yl)quinoline-4-carboxylate

A mixture of ethyl 6-bromoquinoline-4-carboxylate (0.098 g, 0.35 mmol), (1S,4S)-2-oxa-5azabicyclo[2.2.1]heptane (0.045 g, 0.46 mmol), RuPhosPd G4 (0.030 g, 0.04 mmol ₎ , _Cs2CO3 (0.342 g, 1.05 mmol) and dioxane (0.9 mL) under _N2 (g) was stirred vigorously at 85-90 °C for 1 h 50 min. After cooling to rt, the reaction mixture was diluted with EtOAc (3 mL) and stirred with SilaMetS® Thiol scavenger (0.15 g; 1.4 mmol/g) at rt overnight. The reaction mixture was filtered through Celite® 521. The filter pad was washed with EtOAc and the combined filtrates

- 123 048482 you concentrated. The residue was purified by preparative HPLC, PrepMethod H (gradient: 2565%) to give the title compound (0.097 g, 93%) as a yellow solid; MS (ESI) m/z [M+H] ⁺ 299.2.

Intermediate 158. 6-((1S,4S)-2-oxa-5-azabicyclo[2.2.1]heptan-5-yl)quinoline-4-carboxylic acid

Aq. NaOH (3.8 M, 0.16 mL, 0.62 mmol) was added to a solution of ethyl 6-((1S,4S)-2-oxa-5azabicyclo[2.2.1]heptan-5-yl)quinoline-4-carboxylate, intermediate 157 (0.092 g, 0.31 mmol), in MeOH (2 mL) and the reaction mixture was stirred at 50 °C for 90 min and then at rt overnight. Aq. HCl (3.8 M, 0.122 mL, 0.46 mmol) was added dropwise and the resulting mixture was concentrated at rt to give the crude title compound (0.110 g) as a red solid; MS (ESI) m/z [M+H] ⁺ 271.1.

Intermediate 159. Ethyl 6-((1R,4R)-2-oxa-5-azabicyclo[2.2.1]heptan-5-yl)quinoline-4-carboxylate

A mixture of ethyl 6-bromoquinoline-4-carboxylate (0.098 g, 0.35 mmol), (1R,4R)-2-oxa-5azabicyclo[2.2.1]heptane hydrochloride (0.062 g, 0.46 mmol), RuPhosPd G4 (0.030 g, 0.04 mmol), _Cs2CO3 (0.342 g, 1.05 mmol) and dioxane (0.9 mL) under _N2 (g) was stirred vigorously at 85-90 °C for 85 min. After cooling to rt, the reaction mixture _was diluted with EtOAc (3 mL) and stirred with SilaMetS® Thiol scavenger (0.15 g; 1.4 mmol/g) at rt overnight. The mixture was filtered through Celite® 521. The filter pad was washed with EtOAc and the combined filtrates were concentrated. The residue was purified by preparative HPLC, PrepMethod H (gradient: 15-55%) to give the title compound (0.087 g, 83%) as a solid; MS (ESI) m/z [M+H] ⁺ 299.3.

Intermediate 160. 6-((1R,4R)-2-oxa-5-azabicyclo[2.2.1]heptan-5-yl)quinoline-4-carboxylic acid

Aq. NaOH (3.8 M, 0.15 mL, 0.56 mmol) was added to a solution of ethyl 6-((1R,4R)-2-oxa-5azabicyclo[2.2.1]heptan-5-yl)quinoline-4-carboxylate, intermediate 159 (0.084 g, 0.28 mmol), in MeOH (2 mL) and the reaction mixture was stirred at 50 °C for 1 h 30 min and then at rt overnight. Aq. HCl (3.8 M, 0.11 mL, 0.42 mmol) was added dropwise and the resulting mixture was concentrated at rt to give the crude title compound (0.099 g) as a red solid; MS (ESI) m/z [M+H] ⁺ 271.2.

Intermediate 161. Ethyl 6-(6-oxa-3-azabicyclo[3.1.1]heptan-3-yl)quinoline-4-carboxylate

A mixture of ethyl 6-bromoquinoline-4-carboxylate (0.098 g, 0.35 mmol), _Cs2CO3 ( _0.456 g, 1.40 mmol), RuPhosPdG4 (0.030 g, 0.04 mmol), 6-oxa-3-azabicyclo[3.1.1]heptane-4-methylbenzenesulfonate (0.125 g, 0.46 mmol) and dioxane (0.9 mL) was stirred at 90°C for 4.5 h under N2 (g). After cooling to rt, SilaMetS® Thiol scavenger (0.15 g; loading 1.4 mmol/g) was added and the mixture was stirred overnight at rt, diluted with EtOAc (3 mL) and filtered through a pad of Celite® 521. The filter pad was washed with EtOAc (10 mL) and the combined filtrate was concentrated. The residue was purified by preparative HPLC, PrepMethod H (gradient: 20-60%), to afford the compound as a yellow film; MS (ESI) m/z [M+H]+ 299.3.

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Intermediate 162. 6-(6-oxa-3-azabicyclo[3.1.1]heptan-3-yl)quinoline-4-carboxylic acid

Aqueous NaOH (3.8 M, 0.16 mL, 0.60 mmol) was added to a solution of ethyl 6-(6-oxa-3azabicyclo[3.1.1]heptan-3-yl)quinoline-4-carboxylate, intermediate 161 (89 mg, 0.30 mmol), in MeOH (2 mL) and the reaction mixture was stirred at rt overnight. 1 M TFA in MeOH (299 μL, 0.30 mmol) was added dropwise and the resulting mixture was concentrated at rt. The residue was suspended in MeCN and concentrated to give the crude title compound (0.123 g) as a red solid; MS (ESI) m/z [M+H]+ 271.2.

Intermediate 163. Ethyl 6-((2S,6S)-2,6-dimethylmorpholino)quinoline-4-carboxylate

A mixture of ethyl 6-bromoquinoline-4-carboxylate (0.098 g, 0.35 mmol), (2S,6S)-2,6-dimethylmorpholine (0.052 g, 0.46 mmol), RuPhosPd G4 (0.030 g, 0.04 mmol), _Cs2CO3 (0.342 _g , 1.05 mmol) and dioxane (0.9 mL) under N2 (g) was stirred vigorously at 85-90 °C for 1.5 h. After cooling to rt, the reaction mixture was diluted with EtOAc (3 mL), stirred with SilaMetS® Thiol (0.15 g; 1.4 mmol/g) at rt overnight and filtered through Celite® 521. The filter pad was washed with EtOAc and the combined filtrates were concentrated. The residue was purified by preparative HPLC, PrepMethod H (gradient: 35-75%) to give the title compound (0.109 g, 99%) as a yellow syrup; MS (ESI) m/z [M+H] ⁺ 315.3.

Intermediate 164. 6-((2S,6S)-2,6-dimethylmorpholino)quinoline-4-carboxylic acid

Aq. NaOH (3.8 M, 149 μL, 0.57 mmol) was added to a solution of ethyl 6-((2S,6S)-2,6-dimethylmorpholino)quinoline-4-carboxylate, intermediate 163 (89 mg, 0.28 mmol), in MeOH (2 mL) and the reaction mixture was stirred at rt overnight. Additional aq. NaOH (3.8 M, 37 μL, 0.14 mmol) was added and the reaction mixture was stirred at 50 °C for 45 min. The reaction mixture was brought to rt, aq. HCl solution (3.8 M, 149 µL, 0.57 mmol) was added and the resulting mixture was concentrated and lyophilized from MeCN/ _H2O to give the crude title compound (0.116 g) as a red solid; m/z (ESI) [M+H] ⁺ 287.2.

Intermediate 165. Ethyl 6-(8-oxa-3-azabicyclo[3.2.1]octan-3-yl)quinoline-4-carboxylate

A mixture of ethyl 6-bromoquinoline-4-carboxylate (0.098 g, 0.35 mmol), 8-oxa-3-azabicyclo[3.2.1]octane (0.051 g, 0.46 mmol), RuPhosPd G4 (0.030 g, 0.04 mmol) _{, Cs2CO3 (} 0.342 g, 1.05 mmol) and dioxane (0.9 mL) under N2 (g) was stirred vigorously at 85-90 °C for 1 h 50 min. After cooling to rt, the reaction mixture was diluted with EtOAc (3 mL) and stirred with SilaMetS® Thiol scavenger (0.15 g, 1.4 mmol/g) at rt overnight. The mixture was filtered through Celite® 521. The filter pad was washed with EtOAc and the combined filtrates were concentrated. The residue was purified by preparative HPLC, PrepMethod H (gradient: 25-65%) to give the title compound (0.099 g, 91%) as a yellow solid; MS (ESI) m/z [M+H] ⁺ 313.2.

Intermediate 166. 6-(8-oxa-3-azabicyclo[3.2.1]octan-3-yl)quinoline-4-carboxylic acid

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Aqueous NaOH (3.8 M, 160 µl, 0.61 mmol) was added to a solution of ethyl 6-(8-oxa-3azabicyclo[3.2.1]octan-3-yl)quinoline-4-carboxylate, intermediate 165 (95 mg, 0.30 mmol), in MeOH (2 ml) and the reaction mixture was stirred at 50 °C for 1 h 30 min and then at rt overnight. Aqueous HCl (3.8 M, 0.12 ml, 0.46 mmol) was added dropwise and the resulting mixture was concentrated at rt to give the crude title compound (0.108 g) as a red solid; MS (ESI) m/z [M+H]+ 285.1.

Intermediate 167. Ethyl (S)-6-(2-methylmorpholino)quinoline-4-carboxylate

UU

A mixture of ethyl 6-bromoquinoline-4-carboxylate (0.098 g, 0.35 mmol), (S)-2-methylmorpholine (0.046 g, 0.46 mmol), RuPhosPd G4 (0.030 g, 0.04 mmol), _Cs2CO3 ( _0.342 g, 1.05 mmol) and dioxane (0.9 mL) under N2 (g) was stirred vigorously at 85-90 °C for 2 h. After cooling to rt, the reaction mixture was diluted with EtOAc (3 mL) and stirred with SilaMetS® Thiol scavenger (0.15 g; 1.4 mmol/g) at rt overnight. The mixture was filtered through Celite® 521, the filter pad was washed with EtOAc and the combined filtrates were concentrated. The residue was purified by preparative HPLC, PrepMethod H (gradient: 20-60%) to give the title compound (0.096 g, 91%) as a yellow solid; MS (ESI) m/z [M+H]+ 301.3.

Intermediate 168. (S)-6-(2-methylmorpholino)quinoline-4-carboxylic acid °уОН

.....

CO

N

Aqueous NaOH (3.8 M, 0.16 mL, 0.61 mmol) was added to a solution of ethyl (S)-6-(2-methylmorpholino)quinoline-4-carboxylate, intermediate 167 (91 mg, 0.30 mmol), in MeOH (2 mL) and stirred at 50 °C for 1 h 30 min and then at rt overnight. Aqueous HCl (3.8 M, 120 μL, 0.45 mmol) was added dropwise and the resulting mixture was concentrated to give the crude title compound (0.108 g) as a red solid; MS (ESI) m/z [M+H]+ 273.1.

Intermediate 169. Ethyl 6-((2R,3S)-2,3-dimethylmorpholino)quinoline-4-carboxylate

A mixture of ethyl 6-bromoquinoline-4-carboxylate (0.140 g, 0.5 mmol), (2R,3S)-2,3-dimethylmorpholine hydrochloride (0.099 g, 0.65 mmol), Pd catalyst [CAS: 1810068-35-9] (0.057 g, 0.05 mmol) _{, Cs2CO3 (} 0.489 g, 1.50 mmol) and anhydrous dioxane (1.3 mL) under N2 (g) was stirred vigorously at 80-85 °C overnight. The reaction mixture was allowed to reach rt and stirred with SilaMetS® Thiol scavenger (0.2 g; 1.4 mmol/g) overnight. The mixture was filtered (Celite® 521) and the filter cake was washed with EtOAc (10 mL). The combined filtrates were concentrated and the residue was purified by preparative HPLC, PrepMethod H (gradient: 35-75%). The compound was dissolved in DCM, washed with H2O and the organic layer was concentrated to give the title compound (0.111 g, 71%) as a yellow solid; MS (ESI) m/z [M+H]+ 315.3.

Intermediate 170. 6-((2R,3S)-2,3-dimethylmorpholino)quinoline-4-carboxylic acid

Aqueous NaOH (3.8 M, 228 μL, 0.87 mmol) was added to a solution of ethyl 6-((2R,3S)-2,3-dimethylmorpholino)quinoline-4-carboxylate, intermediate 169 (109 mg, 0.35 mmol), in MeOH (3 mL) and the reaction mixture was stirred at 50 °C for 70 min. The reaction mixture was cooled to rt, aqueous HCl (3.8 M, 0.18 mL, 0.69 mmol) was added dropwise and the resulting mixture was concentrated and lyophilized from MeCN/H2O to give the crude title compound (0.137 g) as a red solid; MS (ESI) m/z [M+H]+ 287.2.

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Intermediate 171. Ethyl 6-((2S,3S)-2,3-dimethylmorpholino)quinoline-4-carboxylate

A mixture of ethyl 6-bromoquinoline-4-carboxylate (98 mg, 0.35 mmol), (2S,3S)-2,3-dimethylmorpholine hydrobromide (WO2014/016849) (95 mg, 0.48 mmol), Pd catalyst [CAS: 1810068-359] (44 mg, 0.04 mmol), _Cs2CO3 (342 mg, 1.05 mmol) and anhydrous dioxane (0.9 mL) under N2 (g) was stirred vigorously at 80-85 _° C overnight. The reaction mixture was brought to rt, diluted with EtOAc (2 mL) and stirred with SilaMetS® Thiol scavenger (0.15 g; 1.4 mmol/g) at rt. overnight. The mixture was filtered and the filter cake was washed with EtOAc. The combined filtrates were concentrated and the residue was purified by preparative HPLC, PrepMethod H (gradient: 35-65%) to give the title compound (0.088 g, 80%) as a yellow film; m/z (ESI) [M+H]+ 315.3.

Intermediate 172. 6-((2S,3S)-2,3-dimethylmorpholino)quinoline-4-carboxylic acid

Aq. NaOH (3.8 M, 182 μL, 0.69 mmol) was added to a solution of ethyl 6-((2S,3S-2,3-dimethylmorpholino)quinoline-4-carboxylate, intermediate 171 (87 mg, 0.28 mmol), in MeOH (2.3 mL) and stirred at 50 °C for 50 min. The reaction mixture was cooled to rt, aq. HCl (3.8 M, 0.146 mL, 0.55 mmol) was added dropwise and the resulting mixture was concentrated and lyophilized from MeCN/H ₂ O to give the crude title compound (0.107 g) as a dark orange solid; MS (ESI) m/z [M+H]+ 287.2.

Intermediate 173. Ethyl 6-((2R,3R)-2,3-dimethylmorpholino)quinoline-4-carboxylate

A mixture of ethyl 6-bromoquinoline-4-carboxylate (98 dimethylmorpholine (89 mg, 0.45 mmol), catalyst mg, 0.35 mmol), (2R,3R)-2,3-Pd hydrobromide [CAS: 1810068-35-9] (45 mg, 0.04 mmol) _{, Cs2CO3 (} 342 mg, 1.05 mmol) and dioxane (0.9 mL) under N2 (g) was stirred vigorously at 80-85 °C for 17.5 h. The reaction mixture was brought to rt, diluted with EtOAc (2 mL) and stirred with SilaMetS® Thiol scavenger (0.15 g, 1.4 mmol/g) at rt overnight. The mixture was filtered and the filter cake was washed with EtOAc (10 mL). The combined filtrates were concentrated and the residue was purified by preparative HPLC, PrepMethod H (gradient: 35-70%) to give the title compound (0.088 g, 80%) as a yellow film; MS (ESI) m/z [M+H]+ 315.27.

Intermediate 174. 6-(2R,3R)-2,3-dimethylmorpholino)quinoline-4-carboxylic acid

Aqueous NaOH (3.8 M, 178 μL, 0.68 mmol) was added to a solution of ethyl 6-((2R,3R)-2,3-dimethylmorpholino)quinoline-4-carboxylate, intermediate 173 (85 mg, 0.27 mmol), in MeOH (2.3 mL) and the reaction mixture was stirred at 50 °C for 45 min. The reaction mixture was brought to rt, aqueous HCl (3.8 M, 142 μL, 0.54 mmol) was added dropwise and the resulting mixture was concentrated and lyophilized from MeCN/H2O to give the crude title compound (0.111 g) as a dark orange solid; MS (ESI) m/z [M+H]+ 287.3.

Intermediate 175. rac-tert-butyl (R)-6-(3-(trifluoromethyl)morpholino)quinoline-4-carboxylate

A mixture of tert-butyl 6-bromoquinoline-4-carboxylate (298 mg, 0.97 mmol), a Pd-based catalyst

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[CAS: 1810068-35-9] (110 mg, 0.10 mmol), rac-(R)-3-(trifluoromethyl)morpholine hydrochloride (241 mg, 1.26 mmol), _Cs2CO3 (945 mg, 2.90 mmol) and dioxane (2.4 mL) under N2 (g) were stirred vigorously at 80-85 _° C overnight. The reaction mixture was cooled to rt, SilaMetS® Thiol scavenger (360 mg, loading 1.4 mmol/g) was added and the mixture was stirred overnight, diluted with EtOAc and filtered (Celite® 521). The filter cake was washed with EtOAc and the combined filtrates were concentrated. The residue was purified by preparative HPLC, PrepMethod H (gradient: 35-75%), to give the title compound (0.26 g, 70%); MS (ESI) m/z [M+H]+ 383.29.

Intermediate 176. rel-tert-butyl (R)-6-(3-(trifluoromethyl)morpholino)quinoline-4carboxylate, isomer 1

Intermediate 177. rel-tert-butyl (R)-6-(3-(trifluoromethyl)morpholino)quinoline-4carboxylate, isomer 2

isomer 1 isomer 2

The isomers of rac-tert-butyl (R)-6-(3-(trifluoromethyl)morpholino)quinoline-4-carboxylate, intermediate 175 (259 mg, 0.68 mmol), were separated by preparative chiral SFC on a Chiralpak IC (5 μm, 250 x 30 mm i.d.) using 20% IPA/DEA 100/20 mM in CO2 120 bar as mobile phase to give the first eluting compound, rel-tert-butyl (R)-6-(3-(trifluoromethyl)morpholino)quinoline-4-carboxyαlate, isomer 1, intermediate 176 (0.114 g, 44%), and the second eluting compound, rel-tert-butyl (R)6-(3-(trifluoromethyl)morpholino)quinoline-4-carboxylate, isomer 2, intermediate 177 (0.122 g, 47%).

Intermediate 178. rel-(R)-6-(3-(trifluoromethyl)morpholino)quinoline-4-carboxylic acid, isomer 1

V

SK.ON |Or1| F

Qu N isomer 1

A solution of rel-tert-butyl (R)-6-(3-(trifluoromethyl)morpholino)quinoline-4-carboxylate, isomer 1, intermediate 176 (101 mg, 0.26 mmol), in 90% TFA (aq, 0.5 mL) was heated at

50°C for 1 h. The reaction solution was concentrated and the residue was lyophilized from MeCN/H2O to give the crude title compound (0.150 g) as a red viscous oil; MS (ESI) m/z [M+H] ⁺ 327.1.

Intermediate 179. rel-(R)-6-(3-(trifluoromethyl)morpholino)quinoline-4-carboxylic acid, isomer 2

isomer 2

A solution of rel-tert-butyl (R)-6-(3-(trifluoromethyl)morpholino)quinoline-4-carboxylate, isomer 2, intermediate 177 (108 mg, 0.28 mmol), in 90% TFA (aq, 0.5 mL) was heated at 50 °C for 1 h. The reaction solution was concentrated and the residue was lyophilized from MeCN/H ₂ O to give the crude title compound (0.152 g) as a red oil; MS (ESI) m/z [M+H] ⁺ 327.1.

Intermediate 180. tert-Butyl 6-(3-oxa-9-azabicyclo[3.3.1]nonan-9-yl)quinoline-4-carboxylate

A mixture of tert-butyl 6-bromoquinoline-4-carboxylate (82 mg, 0.27 mmol), Pd catalyst [CAS: 1810068-35-9] (30 mg, _0.03 mmol), 3-oxa-9-azabicyclo[3.3.1]nonane hydrochloride (56 mg, 0.34 mmol), _Cs2CO3 (260 mg, 0.80 mmol) and dioxane (0.65 mL) under N2 (gas) was vigorously stirred

- 128 048482 at 80-85 °C overnight. The reaction mixture was brought to rt, diluted with EtOAc (3 mL) and the mixture was stirred with SilaMetS® Thiol (140 mg; 1.4 mmol/g) at rt for 2 h. The mixture was filtered through Celite® 521 and the filtrate was concentrated. The residue was purified by preparative HPLC, PrepMethod H (gradient: 35-80%) to give the title compound (0.065 g, 69%); MS (ESI) m/z [M+H]+ 355.4.

Intermediate 181. 6-(3-oxa-9-azabicyclo[3.3.1]nonan-9-yl)quinoline-4-carboxylic acid

A solution of tert-butyl 6-(3-oxa-9-azabicyclo[3.3.1]nonan-9-yl)quinoline-4-carboxylate, intermediate 180 (56 mg, 0.15 mmol), in 90% TFA (aq, 0.5 mL) was stirred at 50 °C for 1.5 h. The reaction solution was concentrated and lyophilized from MeCN/H ₂ O to give the crude title compound (0.070 g); MS (ESI) m/z [M+H]+ 299.3.

Intermediate 182. tert-Butyl 6-((2R,5R)-2,5-dimethylmorpholino)quinoline-4-carboxylate

A mixture of tert-butyl 6-bromoquinoline-4-carboxylate (149 mg, 0.48 mmol), _Cs2CO3 (473 mg, 1.45 mmol), Pd catalyst [CAS: 1810068-35-9] (55 mg, 0.05 mmol), (2R,5R ₎ -2,5-dimethylmorpholine hydrochloride (96 mg, 0.63 mmol) and dioxane (1.2 mL) under _N2 (g) was stirred at 85 °C for 19 h. After cooling to rt, the reaction mixture was diluted with EtOAc (2 mL) and stirred with SilaMetS® Thiol scavenger (150 mg; loading 1.4 mmol/g) for 2 h. The mixture was filtered through a pad of Celite® 521, filter pad washed with EtOAc (9 mL) and the combined filtrates were concentrated. The residue was purified by preparative HPLC, PrepMethod H (gradient: 35-75%) to give the title compound (0.147 g, 89%); MS (ESI) m/z [M+H]+ 343.3.

Intermediate 183. 6-((2R,5R)-2,5-dimethylmorpholino)quinoline-4-carboxylic acid

A vial was charged with tert-butyl 6-((2R,5R)-2,5-dimethylmorpholino)quinoline-4-carboxylate, intermediate 182 (0.12 g, 0.35 mmol), and 90% TFA (aq, 0.5 mL) and heated at 50 °C for 1 h 40 min. The reaction mixture was concentrated. A mixture of H2O and MeCN was added to the residue and the resulting mixture was concentrated to give the crude title compound (0.158 g); MS (ESI) m/z [M+H]+ 287.2.

Intermediate 184. tert-Butyl 6-(2,2-dimethylmorpholino)quinoline-4-carboxylate

A mixture of tert-butyl 6-bromoquinoline-4-carboxylate (149 mg, _0.48 mmol), _Cs2CO3 (473 mg, 1.45 mmol), RuPhosPd G3 (40 mg, 0.05 mmol), 2,2-dimethylmorpholine (0.069 g, 0.63 mmol) and dioxane (1.2 mL) under _N2 (g) was stirred at 85 °C for 22 h. After cooling to rt, the reaction mixture was diluted with EtOAc (2 mL), SilaMetS® Thiol scavenger (0.150 g; loading 1.4 mmol/g) was added and the mixture was stirred for 2 h. The mixture was filtered through a pad of Celite® 521, the filter pad was washed with EtOAc (9 mL) and the combined filtrates concentrated. The residue was purified by preparative HPLC, PrepMethod H (gradient: 35-75%) to give the title compound (0.136 mg, 82%); MS (ESI) m/z [M+H]+ 343.4.

Intermediate 185. 6-(2,2-dimethylmorpholino)quinoline-4-carboxylic acid

Crude tert-butyl 6-(2,2-dimethylmorpholino)quinoline-4-carboxylate was loaded into the vial,

- 129 048482 intermediate 184 (0.120 g, 0.35 mmol), and 90% TFA (aq, 0.5 mL). The vial was heated at 50 °C for 1 h 40 min. The reaction mixture was concentrated. A mixture of H2O and MeCN was added to the residue and the mixture was concentrated to give the crude title compound (0.145 g); MS (ESI) m/z [M+H]+ 287.2.

Intermediate 186. tert-Butyl (S)-6-(3-(methoxymethyl)morpholino)quinoline-4-carboxylate

A mixture of tert-butyl 6-bromoquinoline-4-carboxylate (150 mg, 0.49 mmol), (S)-3(methoxymethyl)morpholine hydrochloride (106 mg, 0.63 _{mmol), Pd catalyst [CAS: 1810068-35-9] (56 mg, 0.05 mmol), Cs2CO3 (} 476 mg, 1.46 mmol) and dioxane (1.2 mL) was stirred vigorously at 80-85 °C for 15 h. The reaction mixture was diluted with EtOAc and filtered through Celite®. The filter pad was washed with EtOAc and the combined filtrates were concentrated. The residue was purified by straight-phase flash chromatography on silica gel (gradient: 0-75% EtOAc in heptane) to give the title compound (0.146 g, 84%) as a yellow solid; MS (ESI) m/z [M+H]+ 359.3.

Intermediate 187. tert-Butyl 6-((3S,5R)-3,5-dimethylmorpholino)quinoline-4-carboxylate

A mixture of tert-butyl 6-bromoquinoline-4-carboxylate (149 mg, 0.48 mmol), _Cs2CO3 (473 mg, 1.45 mmol), Pd catalyst [CAS: 1810068-35-9] (55 mg, 0.05 mmol), (3S,5R ₎ -3,5-dimethylmorpholine hydrochloride (96 mg, 0.63 mmol) and dioxane (1.2 mL) under _N2 (g) was stirred at 85 °C for 60 h. After cooling to rt, the reaction mixture was diluted to 3.5 mL with EtOAc and filtered through a pad of Celite® 521. The filter pad was washed with EtOAc and the combined filtrates were concentrated. The residue was purified by straight-phase flash chromatography on silica gel (gradient: 0-75% EtOAc in heptane) to give the title compound (73 mg, 41%) as a yellow oil; MS (ESI) m/z [M+H]+ 343.3.

Intermediate 188. 6-((3S,5R)-3,5-dimethylmorpholino)quinoline-4-carboxylic acid

A solution of tert-butyl 6-((3S,5R)-3,5-dimethylmorpholino)quinoline-4-carboxylate, intermediate 187 (67 mg, 0.20 mmol), in 90% TFA (aq, 1 ml) was stirred at 50 °C for 3 h. The reaction mixture was concentrated and the residue was concentrated from a mixture of DCM and heptane and dried in vacuo to give the crude title compound (0.127 g); MS (ESI) m/z [M+H]+ 287.2.

Intermediate 189. tert-Butyl 6-(1,4-oxazepan-4-yl)quinoline-4-carboxylate

A mixture of tert-butyl 6-bromoquinoline _- 4-carboxylate (149 mg, 0.48 mmol), _Cs2CO3 (473 mg, 1.45 mmol), RuPhosPdG3 (40 mg, 0.05 mmol), 1,4-oxazepane hydrochloride (83 mg, 0.6 mmol) and dioxane (1.2 mL) under N2 (g) was stirred at 85 °C for 22 h. After cooling to rt, the reaction mixture was diluted with EtOAc (2 mL). SilaMetS® Thiol scavenger (ca. 150 mg; loading 1.4 mmol/g) was added and the mixture was stirred for 2 h and filtered through a pad of Celite® 521. The filter pad was washed with EtOAc (9 mL) and the filtrate was concentrated. The residue was purified by preparative HPLC, PrepMethod G (gradient: 25-100%). The appropriate fractions were partially concentrated to remove MeCN, and the aqueous mixture was basified with 8% _NaHCO3 (aq) and extracted with DCM. The organic layer was concentrated to give the title compound (0.117 g, 74%); MS (ESI) m/z [M+H]+ 329.3.

Intermediate 190. (R)-4-benzyl-2-((methylthio)methyl)morpholine

KI (7.3 g, 44.5 mmol) was added to a solution of (R)-4-benzyl-2-(chloromethyl)morpholine (200 g, 0.89 mol)

- 130 048482 in DMF (2.0 L), then 18% NaSCH3 (aq, 690 g, 1.78 mol) was added at 0 °C. The mixture was stirred at rt for 12 h. The reaction mixture was poured into ice water and extracted with EtOAc (3 x 500 mL). The combined organic layers were washed with water (500 mL) and brine (500 mL), dried over Na ₂ SO ₄ , filtered and evaporated to dryness to give the title compound (192 g, 91%) as a colourless oil; MS w/z (ESI) [M+H]+ 238.0.

Intermediate 191. (R)-4-benzyl-2-((methylsulfonyl)methyl)morpholine m-CPBA (494 g, 2.435 mol) was added portionwise at 10 °C to a solution of (R)-4-benzyl-2-((methylthio)methyl)morpholine, intermediate 190 (192 g, 0.812 mol), in anhydrous DCM (2 L). After the addition, the mixture was stirred at rt for 16 h. The mixture was filtered and the filtrate was washed with sat. NaHSO3 (2 x 1 L), sat. NaHCO3 (3 x 1 L) and brine (800 mL), dried over Na ₂ SO ₄ , filtered and concentrated in vacuo. The residue was triturated with MTBE/petroleum ether (100 mL/500 mL) and the solids were collected by filtration to give the title compound (130 g, 60%) as a white solid; MS m/z (ESI) [M+H] ⁺ 269.9.

Intermediate 192. (R)-2-((methylsulfonyl)methyl)morpholine ^,Ρ Ό

S.NH d

A mixture of (R)-4-benzyl-2-((methylsulfonyl)methyl)morpholine, intermediate 191 (120 g, 0.44 mol), and Pd(OH) ₂ /C (12 g) in MeOH (1000 mL) was hydrogenated (50 psi _H2 ) at 40 °C for 24 h. The resulting mixture was filtered to remove Pd(OH) ₂ /C and the filtrate was concentrated to give the title compound (68 g, 86%) as a white solid; MS m/z (ESI) [M+H] ⁺ 180.2.

Intermediate 193. tert-Butyl (R)-6-(2((methylsulfonyl)methyl)morpholino)quinoline-4-carboxylate

The title compound was synthesized analogously to the procedure for intermediate 189, starting from tert-butyl 6-bromoquinoline-4-carboxylate (149 mg, 0.48 mmol) and (R)-2((methylsulfonyl)methyl)morpholine, intermediate 192 (0.108 g, 0.6 mmol), to give the title compound (147 mg, 75%); MS (ESI) m/z [M+H] ⁺ 407.2.

Intermediate 194. tert-Butyl (8)-6-(2-(methoxymethyl) morpholino) quinoline-4-carboxylate

The title compound was synthesized and purified analogously to the procedure for intermediate 187, starting from tert-butyl 6-bromoquinoline-4-carboxylate (149 mg, 0.48 mmol) and (S)-2-(methoxymethyl)morpholine hydrochloride (0.106 g, 0.63 mmol), with a reaction time of 20 h, to give the title compound (0.16 g, 88%); MS (ESI) m/z [M+H] ⁺ 359.3.

Intermediate 195. (S)-4-benzyl-2-((methylthio)methyl)morpholine

KI (7.3 g, 0.045 mol) was added to a solution of (S)-4-benzyl-2-(chloromethyl)morpholine (200 g, 0.89 mol) in DMF (2.0 L), then 18% NaSCH3 (aq, 690 g, 1.78 mol) was added at 0 °C and the mixture was stirred at rt for 12 h. The reaction mixture was poured into ice water and extracted with EtOAc (3 x 0.5 L). The combined organic layers were washed with water (0.5 L) and brine (0.5 L), dried over Na ₂ SO ₄ and evaporated to dryness to give the title compound (200 g, 95%) as a colourless oil; MS m/z (ESI) [M+H] ⁺ 238.0.

Intermediate 196. (S)-4-benzyl-2-((methylsulfonyl)methyl)morpholine o

m-CPBA (494 g, 2.44 mol) was added portionwise at a temperature below 10°C to the solution.

- 131 048482 A sol. of (S)-4-benzyl-2-((methylthio)methyl)morpholine, intermediate 195 (192 g, 0.812 mol) was dissolved in anhydrous DCM (2 L) and the mixture was stirred at rt for 16 h. The mixture was filtered and the filtrate was washed with sat. NaHSO3 ( ₂ x 1 L), sat. NaHCO3 ( ₃ x 1 L) and brine (0.8 L), dried over _{Na2SO4 ,} filtered and concentrated under reduced pressure. The residue was triturated with a mixture of MTBE (100 mL) and petroleum ether (500 mL). The solids were collected by filtration to give the title compound (150 g, 68%) as a white solid; MS mass/charge (ESI) [M+H]+ 270.0.

Intermediate 197. (S)-2-((methylsulfonyl)methyl)morpholine

A mixture of (S)-4-benzyl-2-((methylsulfonyl)methyl)morpholine, intermediate 196 (120 g, 0.44 mol), and Pd(OH)2/C (12 g) in MeOH (1 L) was hydrogenated (50 psi _H2 ) at 40 °C for 24 h. The resulting mixture was filtered to remove Pd(OH)2/C and the filtrate was concentrated to give the title compound (49 g, 62%) as a white solid; MS m/z (ESI) [M+H]+ 180.2.

Intermediate 198. tert-Butyl (S)-6-(2-((methylsulfonyl)methyl)morpholino)quinoline-4-carboxylate o^o.

o=s=o

The title compound was synthesized and purified analogously to the procedure for intermediate 187, starting from tert-butyl 6-bromoquinoline-4-carboxylate (149 mg, 0.48 mmol) and (S)-2((methylsulfonyl)methyl)morpholine, intermediate 197 (0.113 g, 0.63 mmol), with a reaction time of 20 h to give the title compound (0.111 g, 50%); MS (ESI) m/z [M+H]+ 407.2.

Intermediate 199. (R)-4-benzyl-3-(2-methoxyethyl)morpholine —O

NaH (24.4 g, 0.61 mol) was added to a solution of (R)-2-(4-benzylmorpholin-3-yl)ethan-1-ol WO 2011111875 (90 g, 0.41 mol) in THF (1.30 L) at 0 °C and the reaction mixture was stirred for 1 h. MeI (63.6 g, 448 mmol) was added at 0 °C and stirred for 6 h. The reaction was quenched with H ₂ O (0.80 L), extracted with EtOAc (2 x 1.50 L). The organic phase was dried over Na ₂ SO ₄ , filtered and concentrated to give the title compound (100 g, 100%); MS m/z (ESI) [M+H]+ 236.1.

Intermediate 200. (R)-3-(2-methoxyethyl)morpholine hydrochloride

Pd(OH) ₂ /C (25 g) was added to a solution of (R)-4-benzyl-3-(2-methoxyethyl)morpholine, intermediate 199 (100 g, 0.425 mol), in MeOH (1.0 L). The mixture was hydrogenated at 50 °C for 16 h. The reaction mixture was filtered and HCl/EtOAc was added to the filtrate. The filtrate was concentrated and the residue was triturated with EtOAc to give the title compound (52 g, 68%); MS m/z (ESI) [M+H]+ 145.9.

Intermediate 201. tert-Butyl (R)-6-(3-(2-methoxyethyl)morpholino)quinoline-4-carboxylate

The title compound was synthesized and purified analogously to the procedure for intermediate 187, starting from tert-butyl 6-bromoquinoline-4-carboxylate (149 mg, 0.48 mmol) and (R)-3-(2-methoxyethyl)morpholine hydrochloride, intermediate 200 (0.114 g, 0.63 mmol), with a reaction time of 20 h, to give the title compound (0.151 g, 79%); MS (ESI) m/z [M+H]+ 373.3.

- 132 048482

Intermediate 202. (2S,3S)-4-benzyl-3-(methoxymethyl)-2-methylmorpholine

NaH (19.5 g, 814 mmol) was added to a solution of ((2S,3S)-4-benzyl-2-methylmorpholin-3-yl)methanol (WO2015/144093) (90 g, 407 mmol) in THF (1.2 L) at 0 °C and the suspension was stirred at 5 °C for 1 h. MeI (63.6 g, 448 mmol) was added at 0 °C and the reaction mixture was stirred for 2 h. The temperature was raised to rt and the reaction mixture was stirred overnight. The reaction was quenched by adding H2O at 0 °C and extracted with DCM (2 x 2 L). The combined organic layers were concentrated to give the title compound (100 g) as an oil; MS w/z (ESI) [M+H]+ 235.9.

Intermediate 203. (2S,3S)-3-(methoxymethyl)-2-methylmorpholine hydrochloride

Pd(OH) ₂ /C (20 g) was added to a solution of (2S,3S)-4-benzyl-3-(methoxymethyl)-2-methylmorpholine, intermediate 202 (100 g, 407 mmol), in MeOH (1 L) under N2(g). The system was evacuated and filled with N2(g) (3x), and hydrogenated (50 psi) at 50 °C for 18 h. The reaction mixture was filtered and the filtrate was concentrated. HCl in EtOAc was added to the residue and the mixture was stirred for 30 min. The solid was collected by filtration, washed with EtOAc, and dried to give the title compound (57 g, 79%) as a solid; MS w/z (ESI) [M+H]+ 146.1.

Intermediate 204. tert-Butyl 6-((2S,3S)-3-(methoxymethyl)-2methylmorpholino)quinoline-4-carboxylate

The title compound was synthesized and purified analogously to the procedure for intermediate 187, starting from tert-butyl 6-bromoquinoline-4-carboxylate (149 mg, 0.48 mmol) and (2S,3S)-3-(methoxymethyl)-2-methylmorpholineα hydrochloride, intermediate 203 (0.114 g, 0.63 mmol), with a reaction time of 20 h to give the title compound (0.155 g, 71%); MS (ESI) m/z [M+H]+ 373.4.

Intermediate 205. (2R,3R)-4-benzyl-3-(methoxymethyl)-2-methylmorpholine

NaH (23.4 g, 584 mmol, 60%) was added to a solution of ((2R,3R)-4-benzyl-2-methylmorpholin-3yl)methanol (86 g, 0.39 mol) in THF (1.5 L) at -5-0 °C and the mixture was stirred at 0 °C for 2 h. MeI (60.7 g, 428 mmol) was added dropwise and the mixture was stirred at rt overnight. The mixture was quenched with H2O and extracted with DCM (3 x 1 L). The combined organic layers were dried over anhydrous _MgSO4 , filtered and concentrated under reduced pressure to give the title compound (88 g, 86%); MS m/z (ESI) [M+H]+ 236.1.

Intermediate 206. (2R,3R)-3-(methoxymethyl)-2-methylmorpholineα hydrochloride

Pd(OH) ₂ (20 g) was added to a solution of (2R,3R)-4-benzyl-3-(methoxymethyl)-2-methylmorpholine, intermediate 205 (86 g, 370 mmol), in MeOH (1 L). The mixture was stirred at 50 °C under _H2 (g) (50 psi) overnight. The mixture was filtered, 4 M HCl in EtOAc (200 mL) was added to the filtrate and the solvent was evaporated to give the title compound (55 g, 82%) as a light yellow solid; MS m/z (ESI) [M+H]+ 146.0.

- 133 048482

Intermediate 207. tert-Butyl 6-((2R,3R)-3-(methoxymethyl)-2methylmorpholino)quinoline-4-carboxylate

The title compound was synthesized analogously to the procedure of intermediate 187, starting from tert-butyl 6-bromoquinoline-4-carboxylate (0.149 g, 0.48 mmol) and (2R,3R)-3-(methoxymethyl)-2-methylmorpholine hydrochloride, intermediate 206 (0.110 g, 0.61 mmol), with a reaction time of 14.5 h. The compound was purified by straight phase flash chromatography on silica gel (0-40% EtOAc in heptane) to give the title compound (0.128 g, 71%); MS (ESI) m/z [M+H]+ 373.4.

Intermediate 208. tert-Butyl 6-(3-oxa-8-azabicyclo[3.2.1]octan-8-yl)quinoline-4-carboxylate

A mixture of tert-butyl 6-bromoquinoline-4-carboxylate (200 mg, 0.65 mmol), 3-oxa-8azabicyclo[3.2.1]octane hydrochloride (126 mg, 0.84 mmol), Pd catalyst [CAS: 1810068-35-9] (74 mg, 0.06 mmol), _Cs2CO3 (634 mg, 1.95 mmol) and dioxane (1.6 mL) under N2 (g) was stirred vigorously at 80-85 _° C for 27 h. After cooling to rt, the reaction mixture was diluted with EtOAc and filtered through Celite® 521. The filter pad was washed with EtOAc and the combined filtrates were concentrated. The compound was purified by straight-phase flash chromatography on silica gel (0-75% EtOAc in heptane) to give the title compound (0.20 g, 90%) as a yellow solid; MS (ESI) m/z [M+H]+ 341.3.

Intermediate 209. tert-Butyl 6-(1,9-dioxa-4-azaspiro[5.5]undecan-4-yl)quinoline-4-carboxylate

The title compound was synthesized analogously to the procedure for intermediate 189, starting from tert-butyl 6-bromoquinoline-4-carboxylate (149 mg, 0.48 mmol) and 1,9-dioxa-4-azaspiro[5.5]undecane hydrochloride (0.116 g, 0.6 mmol) to give the title compound (147 mg, 75%); MS (ESI) m/z [M+H]+ 385.3.

Intermediate 210. Ethyl 6-((3S,5R)-3,5-dimethylmorpholino)quinoline-4-carboxylate

A mixture of ethyl 6-bromoquinoline-4-carboxylate (160 mg, 0.57 mmol) and (3R,5S)-3,5-dimethylmorpholine hydrochloride (106 mg, 0.70 mmol), Pd catalyst [CAS: 1810068-35-9] (49 mg, 0.04 mmol), Cs2CO3 (558 mg, 1.71 mmol) and dioxane (1 mL) under N2 (g) atmosphere was stirred vigorously at 90 °C for 13 h. Another batch of Pd catalyst [CAS: 1810068-35-9] (20 mg, 0.02 mmol) was added and the reaction mixture was stirred vigorously at 90 °C overnight. After cooling to rt, the reaction mixture was diluted with EtOAc and filtered through Celite® 521. The filter pad was washed with EtOAc and the combined filtrates were concentrated. The residue was purified by straight-phase flash chromatography on silica gel (gradient: 0-65% EtOAc in heptane) to give the title compound (0.070 g, 39%) as a yellow film; MS (ESI) m/z [M+H]+ 315.2.

Intermediate 211. Ethyl 7-bromo-6-((3S,5R)-3,5-dimethylmorpholino)quinoline-4-carboxylate

NBS (39 mg, 0.21 mmol) was added to a solution of ethyl 6-((3S,5R)-3,5-dimethylmorpholino)quinoline-4-carboxylate, intermediate 210 (65 mg, 0.21 mmol), in HFIP (2 mL) at 0 °C and the reaction mixture was stirred for 1 h at 0 °C. NBS (8 mg, 0.04 mmol) was added and the reaction mixture was stirred for 10 min at 0 °C. The reaction mixture was concentrated and the compound was purified by straight-phase flash chromatography on silica gel (gradient: 0-65% EtOAc in heptane)

- 134 048482 to give the title compound (0.012 g, 15%); MS (ESI) m/z [M+H]+ 393.1, 395.1.

Intermediate 212. 7-bromo-6-((3S,5R)-3,5-dimethylmorpholino)quinoline-4-carboxylic acid

M NaOH (aq, 75 μL, 0.15 mmol) was added to a suspension of ethyl 7-bromo-6-((3S,5R)-3,5-dimethylmorpholino)quinoline-4-carboxylate, intermediate 211 (12 mg, 0.03 mmol), in MeOH (200 μL). The reaction mixture was heated at 50 °C for 25 min. The solution was cooled to rt, aq. HCl (3.8 M, 39.5 μL, 0.15 mmol) was added and the resulting mixture was concentrated under a stream of N2 (g). The residue was suspended in EtOAc and concentrated (EtOAc) to give the crude title compound (0.020 g) as an orange solid; MS (ESI) mass/charge [M+H]+ 365.1, 367.1.

Intermediate 213. Ethyl 5-chloro-6-morpholinoquinoline-4-carboxylate hydrochloride

NCS (56 mg, 0.42 mmol) was added to a solution of ethyl 6-morpholinoquinoline-4-carboxylate, intermediate 143 (100 mg, 0.35 mmol), in MeCN (1.5 mL) at rt and the reaction mixture was stirred at rt overnight. The reaction mixture was concentrated and the residue was dissolved in EtOAc (2 mL). 4 M HCl in dioxane (87 µL, 0.35 mmol) was added and the mixture was stirred until complete precipitation was observed. The solids were collected by filtration, washed with EtOAc and dried in vacuo to give the title compound (0.103 g, 83%) as a yellow solid; MS (ESI) m/z [M+H]+ 321.2.

Intermediate 214. tert-Butyl (S)-6-(3-methylmorpholino)quinoline-4-carboxylate

A mixture of tert-butyl 6-bromoquinoline-4-carboxylate (104 mg, 0.34 mmol), 2'-(bis(3,5bis(trifluoromethyl)phenyl)phosphanyl)-3',6'-dimethoxy-N ₂ ,N ₂ ,N ⁶ ,N ⁶ -tetramethyl-[1,1'-biphenyl]-2,6-diamine (26 mg, 0.03 mmol), Pd ₂ (dba) ₃ (9 mg, 10 μmol), sodium 2-methylbutan-2-olate (48 mg, 0.44 mmol), and (S)-3-methylmorpholine (41 mg, 0.40 mmol) in CPME (0.7 mL) under argon was heated at 80-85 °C for 3 h. The mixture was diluted with EtOAc and washed with H2O. The aqueous layer was extracted with EtOAc and the combined organic layers were dried over _Na2SO4 , filtered and concentrated. The residue was purified by silica gel flash chromatography (gradient: 0-75% _EtOAc in heptane) to give the title compound (0.052 g, 47%) as a yellow film; MS (ESI) m/z [M+H]+ 329.4.

Intermediate 215. tert-Butyl 6-((3S,5S)-3,5-dimethylmorpholino)quinoline-4-carboxylate

A mixture of tert-butyl 6-bromoquinoline-4-carboxylate (100 mg, 0.32 mmol), 2'-(bis(3,5bis(trifluoromethyl)phenyl)phosphanyl)-3',6'-dimethoxy-N ₂ ,N ₂ ,N ⁶ ,N ⁶ -tetramethyl-[1,T-biphenyl]-2,6-diamine (25 mg, 0.03 mmol), Pd ₂ (dba) ₃ (9 mg, 9.7 μmol), sodium 2-methylbutan-2-olate (39 mg, 0.36 mmol), (3S,5S)-3,5-dimethylmorpholine (59 mg, 0.51 mmol) and CPME (0.7 mL) under argon atmosphere was stirred at 80 °C for 4 h. After cooling to rt. The reaction mixture was diluted with EtOAc and washed with _H2O . The aqueous layer was extracted with EtOAc and the combined organic layers were dried over Na2SO4, filtered and concentrated. The residue was purified by silica gel flash chromatography (gradient: 0-75% EtOAc in heptane) to give the title compound (0.054 g, 48%) as a yellow film; MS (ESI) m/z [M+H]+ 343.4.

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Intermediate 216. tert-Butyl 6-(8-oxa-5-azaspiro[3.5]nonan-5-yl)quinoline-4-carboxylate

A mixture of tert-butyl 6-bromoquinoline-4-carboxylate (150 mg, 0.49 mmol), 8-oxa-5azaspiro[3.5]nonane hydrochloride (104 mg, 0.63 mmol), Pd catalyst [CAS: 1810068-35-9] (56 mg, 0.05 mmol), _Cs2CO3 (476 mg, 1.46 mmol) and dioxane (1.2 mL) under N2 (g) was stirred vigorously at 80-85 _° C for 18 h. After cooling to rt, the reaction mixture was diluted with EtOAc and filtered through Celite® 521. The filter pad was washed with EtOAc and the combined filtrates were concentrated. The residue was purified by straight-phase flash chromatography on silica gel (gradient: 0-65% EtOAc in heptane) to give the title compound (0.103 g, 60%) as a yellow film; MS (ESI) m/z [M+H]+ 355.4.

Intermediate 217. tert-Butyl 6-((3R,5R)-3,5-dimethylmorpholino)quinoline-4 carboxylate

Under N2 (gas) atmosphere, the vial was charged with a stir bar, tert-butyl 6-bromoquinoline-4-carboxylate (40 mg, 0.13 mmol), (3R,5R)-3,5-dimethylmorpholineα hydrochloride (30 mg, 0.19 mmol), Pd catalyst [CAS: 1810068-35-9] (18 mg, 15 μmol), _Cs2CO3 (127 mg, 0.39 mmol), and dioxane (0.6 mL). The vial was stirred vigorously at 80-85 °C for ₁₈ h and then allowed to cool to rt. The reaction was repeated but using (26 mg, 23 μmol) of Pd catalyst [CAS: 1810068-35-9]. The reaction mixtures were diluted with EtOAc and The combined mixtures were filtered through a pad of Celite® 521. The filter pad was washed with EtOAc and the combined filtrates were concentrated. The residue was purified by straight-phase flash chromatography on silica gel (gradient: 0-65% EtOAc in heptane) to give the title compound (48 mg, 54%) as a yellow oil; MS (ESI) m/z [M+H] ⁺ 343.4.

Intermediate 218. tert-Butyl (S)-6-(3-ethylmorpholino)quinoline-4-carboxylate

A mixture of tert-butyl 6-bromoquinoline-4-carboxylate (87 mg, 0.28 mmol), Pd catalyst [CAS: 1810068-35-9] (9 mg, 7.72 μmol), (S)-3-ethylmorpholine hydrochloride (86 mg, 0.56 mmol), _Cs2CO3 (276 mg, 0.85 mmol) and CPME (1.5 mL) was stirred at 80 °C overnight under argon atmosphere. Pd catalyst [CAS: 1810068-35-9] (17 mg, 0.01 mmol) was added and stirring _was continued at 80 °C for 2 days. The reaction mixture was diluted with EtOAc and washed with H2O. The aqueous layer was extracted with EtOAc and _the combined organic layer was dried over _Na2SO4 , filtered and concentrated. The residue was purified by silica gel flash chromatography (gradient: 0-75% EtOAc in heptane) to give the title compound (0.050 g, 51%) as a yellow film; MS (ESI) m/z [M+H] ⁺ 343.4.

Intermediate 219. (S)-6-(3-ethylmorpholino)quinoline-4-carbonic acid

A solution of tert-butyl (S)-6-(3-ethylmorpholino)quinoline-4-carboxylateα, intermediate 218 (32 mg, 0.09 mmol), in 90% TFA (aq, 0.5 mL) was stirred at 25-30 °C for 4 h. The solution was concentrated under reduced pressure and the residue was concentrated from heptane (2x) to give the crude title compound (0.048 g, 99%); MS (ESI) m/z [M+H] ⁺ 287.3.

Intermediate 220. tert-Butyl 6-(3,3-dimethylmorpholino)quinoline-4-carboxylate

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A mixture of tert-butyl 6-bromoquinoline-4-carboxylate (100 mg, 0.32 mmol), Pd catalyst [CAS: 1810068-35-9] (50 mg, 0.04 mmol), 3,3-dimethylmorpholine (75 mg, 0.65 mmol) _{, Cs2CO3 (} 211 mg, 0.65 mmol) and CPME (1.5 mL) was stirred at 80 °C under argon for 2 days. The reaction mixture was diluted with EtOAc and washed with SH2O. The aqueous layer was extracted with EtOAc and _the combined organic layer was dried over _Na2SO4 , filtered and concentrated. The residue was purified by straight-phase flash chromatography on silica gel (gradient: 0-75% EtOAc in heptane) to give the title compound (0.053 g, 48%) as a yellow film; MS (ESI) m/z [M+H]+ 343.3.

Intermediate 221. tert-Butyl (R)-6-(3-methylmorpholino)quinoline-4-carboxylate

A mixture of tert-butyl 6-bromoquinoline-4-carboxylate (83 mg, 0.27 mmol), 2'-(bis(3,5bis(trifluoromethyl)phenyl)phosphanyl)-3',6'-dimethoxy-N ₂ ,N ₂ ,N ⁶ ,N ⁶ -tetramethyl-[1,1'-biphenyl]-2,6-diamine (31 mg, 0.04 mmol), Pd ₂ (dba) ₃ (12 mg, 0.01 mmol), sodium 2-methylbutan-2-olate (39 mg, 0.35 mmol), (R)-3-methylmorpholine (33 mg, 0.32 mmol) and CPME (0.6 mL) was stirred under argon at 80-85 °C for 3 h. After cooling to rt. The reaction mixture was partitioned between EtOAc and _H2O . The mixture was filtered and the layers were allowed to separate. The aqueous layer was extracted with EtOAc (2x) and the combined organic layer was passed through a phase separator and concentrated. The residue was purified by straight-phase flash chromatography on silica gel (gradient: 0-75% EtOAc in heptane) to give the title compound (0.067 g, 76%) as a yellow film; MS (ESI) m/z [M+H] ⁺ 329.3.

Intermediate 222. Ethyl 2-methyl-6-morpholinoquinoline-4-carboxylate

Pd(dba) ₂ (16 mg, 0.03 mmol), RuPhos (25 mg, 0.05 mmol) and K3PO4 (231 mg, 1.09 mmol) were added to ethyl 6-bromo-2-methylquinoline-4-carboxylate (160 mg, 0.54 mmol) in tert-BuOH (3 mL). Morpholine (47 mg, 0.54 mmol) was added and the reaction flask was stoppered with rubber, purged with _N2 (g) and heated at 90 °C overnight. The reaction mixture was diluted with EtOAc and washed with H2O and brine. The organic layer was evaporated and the residue was purified by preparative HPLC, PrepMethod E (gradient: 15-55%), to give the title compound (89 mg, 55%); MS (ESI) m/z (M+H) ⁺ 301.3.

Intermediate 223. tert-Butyl 6-(2-oxo-1-oxa-3-azaspiro[5.5]undecan-3yl)quinoline-4-carboxylate

Step a) tert-butyl 6-((2-(1-hydroxycyclohexyl)ethyl)amino)quinoline-4-carboxylate

A mixture of tert-butyl 6-bromoquinoline-4-carboxylate (0.200 g, 0.65 mmol), XantPhos Pd G4 (0.062 g, 0.06 mmol), Cs2CO3 (0.634 g, 1.95 mmol), 1-(2-aminoethyl)cyclohexan-1-ol hydrochloride (0.152 g, 0.84 mmol) and anhydrous dioxane (3.25 mL) under _N2 (g) was stirred vigorously at 85 °C for 3 h. The vial was brought to rt, SilaMetS® Thiol scavenger (300 mg; loading: 1.4 mmol/g) was added and the mixture was stirred overnight. The mixture was diluted with EtOAc and H2O and the resulting mixture was filtered. The filtrate layers were separated and the organic layer was dried over _Na2SO4 , filtered and concentrated to give crude tert-butyl ₆ -((2-(1-hydroxycyclohexyl)ethyl)amino)quinoline-4-carboxylate.

Step b) tert-butyl 6-(2-oxo-1-oxa-3-azaspiro[5.5]undecan-3-yl)quinoline-4-carboxylate

Triphosgene (0.148 g, 0.5 mmol) was added to a stirred mixture of crude tert-butyl 6-((2(1-hydroxycyclohexyl)ethyl)amino)quinoline-4-carboxylate from step a) and DIPEA (0.453 mL, 2.60 mmol) in EtOAc (12 mL) at rt. The reaction mixture was stirred at rt for 10 min and then heated at 120 °C for 20 min. DIPEA (0.113 mL, 0.65 mmol) was added and the reaction mixture was heated at 120 °C for 5 min. The reaction mixture was diluted with EtOAc and washed with H ₂ O and 8% NaHCO ₃ (aq), passed through a phase separator and concentrated. The residue was purified by preparative HPLC, PrepMethod H (gradient: 35-75%). The purified product was dissolved in DCM, washed with _H2O and concentrated to give the title compound (0.12 g, 47%) as a pale yellow solid; MS (ESI) m/z

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[M+N]+ 397.5.

Intermediate 224. tert-Butyl 6-((2-(1-hydroxycyclopentyl)ethyl)amino)quinoline-4-carboxylate

A mixture of tert-butyl 6-bromoquinoline-4-carboxylate (0.200 g, _{0.65 mmol), XantPhos Pd G4 (0.062 g, 0.06 mmol), Cs2CO3 (} 0.634 g, 1.95 mmol), 1-(2-aminoethyl)cyclopentan-1-ol (170 mg, 1.32 mmol) and anhydrous dioxane (3.25 mL) under N2 (g) was stirred vigorously at 80-85 °C for 75 min and then allowed to reach rt. SilaMetS® Thiol scavenger (300 mg; loading 1.4 mmol/g) was added and the mixture was stirred for 1.5 h, diluted with EtOAc and filtered (Celite® 521). The filter cake was washed with EtOAc and the combined filtrates were concentrated. The residue was purified by preparative HPLC, PrepMethod H (gradient: 35-75%). The pure fractions were partially concentrated to remove most of the MeCN and the resulting aqueous mixture was extracted with DCM and the phases separated using a phase separator. The organic layer was concentrated to give the title compound (0.163 g, 71%) as a yellow viscous oil; MS (ESI) m/z [M+H] ⁺ 357.4.

Intermediate 225. tert-Butyl 6-(7-oxo-6-oxa-8-azaspiro[4.5]decan-8-yl)quinoline-4-carboxylate

Triphosgene (74 mg, 0.25 mmol) was added to a stirred mixture of tert-butyl 6-((2-(1-hydroxycyclopentyl)ethyl)amino)quinoline-4-carboxylate, intermediate 224 (159 mg, 0.41 mmol), and DIPEA (289 μL, 1.66 mmol) in anhydrous DCM (4.5 mL) at rt. The reaction mixture was stirred at rt for 1.5 h and then heated at 120 °C for 15 min. The solution was concentrated and the residue was purified by preparative HPLC, PrepMethod H (gradient: 30-70%). The purified product was dissolved in DCM and washed with H2O. The aqueous layer was extracted with DCM (x4) and the combined organic layers were concentrated to give the title compound (0.106 g, 67%) as a pale yellow foam; MS (ESI) m/z [M+H] ⁺ 383.4.

Intermediate 226. tert-Butyl 6-(6,6-dimethyl-2-oxo-1,3-oxazinan-3-yl)quinoline-4-carboxylate

A mixture of tert-butyl 6-bromoquinoline-4-carboxylate (280 mg, 0.91 mmol), 6,6-dimethyl-1,3-oxazinan2-one (WO2013/050454) (176 mg, 1.36 mmol), Pd ₂ (dba) ₃ (25 mg, 0.03 mmol), XPhos (26 mg, 0.05 mmol) and Cs ₂ CO ₃ (592 mg, 1.82 mmol) in 1,4-dioxane (5 mL) under N ₂ (g) was stirred at 100 °C for 24 h. The solvent was removed under reduced pressure and the residue was purified by preparative TLC (eluent: petroleum ether, EtOAc 1:1) to give the title compound (0.040 g, 12%) as a white solid; MS mass/charge (ESI) [M+H] ⁺ 357.25.

Intermediate 227. tert-Butyl 6-(3-(fluoromethyl)azetidin-1-yl)quinoline-4-carboxylate

_Cs2CO3 (977 mg, 3.00 mmol) was added to tert-butyl 6-bromoquinoline-4-carboxylate (308 mg, 1.00 mmol), 3- ₍ fluoromethyl)azetidine hydrochloride (251 mg, 2.00 mmol), _Pd2 (dba) ₃ (92 mg, 0.10 mmol), and DavePhos (79 mg, 0.20 mmol) in 1,4-dioxane (3 mL) at 13°C.

The resulting suspension was stirred at 100 °C for 2 h under N ₂ (g). The reaction mixture was diluted with DCM. The solvent was removed under reduced pressure and the residue was purified by preparative TLC (petroleum ether:EtOAc, 1:1) to give the title compound (0.282 g, 89%) as a brown gum; MS m/z (ESI) [M+H] ⁺ 317.

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Intermediate 228. 6-(3-(fluoromethyl)azetidin-1-yl)quinoline-4-carboxylic acid

TFA (5 mL) was added to tert-butyl 6-(3-(fluoromethyl)azetidin-1-yl)quinoline-4-carboxylate, intermediate 227 (274 mg, 0.87 mmol), in DCM (5 mL) at 10 °C. The resulting solution was stirred at 10 °C overnight. The solvent was removed under reduced pressure to give the crude title compound (0.466 g); MS m/z (ESI) [M+H]+ 261.

Intermediate 229. tert-Butyl 6-(4,5,6,7-tetrahydro-1H-indazol-1-yl)quinoline-4-carboxylate

Intermediate 230. tert-Butyl 6-(4,5,6,7-tetrahydro-2H-indazol-2-yl)quinoline-4-carboxylate

_Cs2CO3 (1057 mg, 3.24 mmol) was added to tert-butyl 6-bromoquinoline-4-carboxylate ₍ 500 mg, 1.62 mmol), 4,5,6,7-tetrahydro-1H-indazole (297 mg, 2.43 mmol) and EPhosPd G4 (149 mg, 0.16 mmol) in 1,4-dioxane (10 mL) at 15 °C. The resulting suspension was stirred at 100 °C for 16 h under N2 (g). The mixture was filtered through a pad of Celite® and the filtrate was concentrated under reduced pressure. The residue was purified by preparative TLC (EtOAc:petroleum ether, 2:1) followed by preparative HPLC, PrepMethod F (gradient: 70-90%) to give the first eluting compound, tert-butyl 6-(4,5,6,7-tetrahydro-1H-indazol-1-yl)quinoline-4-carboxylate, intermediate 229 (0.040 g, 7%), as a pale yellow solid; MS m/z (ESI) [M+H]+ 350;

1H NMR (300 MHz, CDCl3) δ 9.01 (d, 1H), 8.92 (d, 1H), 8.25 (d, 1H), 8.12 (dd, 1H), 7.91 (d , 1H), 7.57 (s, 1H), 2.92 (t, 2H), 2.65 (t, 2H), 1.89 (t, 4H), 1.70 (s, 9H).

and the second eluting compound, tert-butyl 6-(4,5,6,7-tetrahydro-2-indazol-2-yl)quinoline-4-carboxylate, intermediate 230 (0.245 g, 43%), as a white solid; MS m/z (ESI) [M+H]+ 350;

^1H NMR (300 MHz, CDCl3) δ 9.01 (d, 1H), 8.92 (d, 1H), 8.25 (d, 1H), 8.12 (dd, 1H), 7.91 ( d, 1H), 7.57 (s, 1H), 2.92 (t, 2H), 2.65 (t, 2H), 1.89 (t, 4H), 1.70 (s, 9H).

The configuration of regioisomers was assigned according to NOESY NMR.

Intermediate 231. tert-Butyl 6-(5-methyl-3-(trifluoromethyl)-1H-pyrazol-1yl)quinoline-4-carboxylate

_Cs2CO3 (529 mg, 1.62 mmol) was added to tert-butyl 6-bromoquinoline-4-carboxylate (250 mg, 0.81 mmol), 5-methyl-3-(trifluoromethyl)-1H-pyrazole (183 mg, 1.22 mmol) and _EPhosPdG4 (75 mg, 0.08 mmol) in 1,4-dioxane (5 mL) at 10 °C under N2 (g). The resulting suspension was stirred at 100 °C for 15 h. The reaction mixture was filtered through Celite® and the filtrate was concentrated under reduced pressure. The residue was purified by preparative TLC (EtOAc:petroleum ether, 2:1) followed by preparative HPLC, PrepMethod F (gradient: 60-85%) to give the title compound (0.133 g, 43%) as a white solid; MS m/z (ESI) [M+H]+ 378.

Intermediate 232. 6,6-Dimethyl-2,4,5,6-tetrahydrocyclopenta[c]pyrazole hydrochloride

Hydrazine hydrate (5.3 g, 106 mmol) was added dropwise with stirring at 25 °C over 10 min to stirred (5E)-5-[(dimethylamino)methylidene]-2,2-dimethylcyclopentan-1-one (18 g, 108 mmol) in a 500 mL three-neck round-bottom flask that was purged and maintained under an inert atmosphere of N2 (g). EtOH (180 mL, 3.10 mol) was added and the resulting solution was heated at reflux overnight in an oil bath. The reaction mixture was cooled to 25 °C. The resulting mixture was concentrated in vacuo. The residue was dissolved in 200 mL of ether and the HCl salt of the title compound (12.6 g, 68%) was precipitated as an off-white solid; MS mass/charge (ESI) [M+H]+ 137.1.

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Intermediate 233. tert-Butyl 6-(6,6-dimethyl-5,6-dihydrocyclopenta[c]pyrazol2(4H)-yl)quinoline-4-carboxylate

_Cs2CO3 (793 mg, 2.43 mmol) was added to tert-butyl 6-bromoquinoline-4-carboxylate ₍ 250 mg, 0.81 mmol), 6,6-dimethyl-2,4,5,6-tetrahydrocyclopenta[c]pyrazole hydrochloride, intermediate 232 (210 mg, 1.22 mmol), and EPhosPd G4 (75 mg, 0.08 mmol) in 1,4-dioxane (1 mL) at 15 °C. The resulting suspension was stirred at 100 °C for 16 h under N2 (g). The reaction mixture was filtered through Celite® and the filter cake was washed with DCM (10 mL). The filtrate was concentrated under reduced pressure and the residue was purified by preparative TLC (EtOAc:petroleum ether, 2:1) to give the title compound (0.268 g, 91%) as a yellow solid; MS m/z (ESI) [M+H]+ 364.

Intermediate 234. 6-(3-(trifluoromethyl)-1H-pyrazol-1-yl)quinoline-4-carboxylic acid

_Cs2CO3 (776 _mg , 2.38 mmol) was added to 6-bromoquinoline-4-carboxylic acid (200 mg, 0.79 mmol), 3-(trifluoromethyl)-1H-pyrazole (162 mg, 1.19 mmol) and _Cu2O (11 mg, 0.08 mmol) in DMF (5 mL) at 10 °C. The resulting suspension was stirred at 120 °C for 20 h under _N2 (g). The reaction mixture was filtered through Celite®. The reaction mixture was adjusted to pH ~ 6 with aq. HCl (2 M) and the mixture was filtered again through Celite®. The filtrate was purified by preparative HPLC, PrepMethod C (gradient: 40-60%), to give the title compound (0.088 g, 36%) as a white solid; MS m/z (ESI) [M+H] ⁺ 308.

Intermediate 235. 6-(4,6-difluoro-1H-indol-1-yl)quinoline-4-carboxylic acid

CuI (15 mg, 0.08 mmol) was added to a solution of 6-bromoquinoline-4-carboxylic acid (200 mg, 0.79 mmol), 4,6-difluoro-III-indole (243 mg, 1.59 mmol) and K2CO3 (219 mg, 1.59 mmol) in DMF (10 mL) under N2 (g). The reaction mixture was stirred at 150 °C for 15 h. The solvent was removed under reduced pressure. The reaction mixture was diluted with _H2O (15 mL) and the reaction mixture was adjusted to pH 6 with aq. HCl (1 M). The precipitate was collected by filtration and washed with H2O (30 mL) to give a brown solid. The solid was dissolved in DMF (15 mL) and filtered. The filtrate was concentrated in vacuo to give the crude title compound (0.20 g, 78%) as a brown solid; MS m/z (ESI) [M+H] ⁺ 325.

Intermediate 236. 6-(5-fluoro-1H-indol-1-yl)quinoline-4-carboxylic acid

_Cs2CO3 (238 mg, 0.73 mmol) was added to tert-butyl 6-bromoquinoline-4-carboxylate ₍ 150 mg, 0.49 mmol), 5-Fluoro-7H-indole (99 mg, 0.73 mmol) and _Cu2O (7 mg, 0.05 mmol) in dry DMF (5 mL) at 10 °C. The resulting suspension was stirred at 120 °C for 19 h under N2 (g). The reaction mixture was adjusted to pH ~ 6 with aq. HCl (1 M) and filtered through a pad of Celite®. The filtrate was purified by preparative HPLC, PrepMethod F (gradient: 45-70%) to give the title compound (0.035 g, 23%) as a pale yellow solid; MS m/z (ESI) [M+H] ⁺ 307.

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Intermediate 237. 6-(3-methyl-1H-pyrrol-1-yl)quinoline-4-carboxylic acid

_K2CO3 (123 mg, 0.89 mmol) was added to 6- _{bromoquinoline} -4-carboxylic acid (150 mg, 0.60 mmol), 3-methyl-7H-pyrrole (78 µL, 0.89 mmol) and CuI (11 mg, 0.06 mmol) in dry DMF (3 mL) at 10 °C. The resulting suspension was stirred at 150 °C for 15 h under _N2 (g). The reaction mixture was adjusted to pH ~ 6 with aq. HCl (1 M). The mixture was filtered through a pad of Celite®. The filtrate was purified by preparative HPLC, PrepMethod D (gradient: 50-65%) to give the title compound (0.050 g, 33%) as a grey solid; MS mass/charge (ESI)[M+H]+ 253.

Intermediate 238. Ethyl 6-(3-morpholinoazetidin-1-yl)quinoline-4-carboxylate

A mixture of ethyl 6-bromoquinoline-4-carboxylate (140 mg, 0.50 mmol), _Cs2CO3 (651 mg, 2.00 mmol), RuPhosPdG4 (43 mg, 0.05 mmol) and 4-(azetidin-3-yl)morpholine hydrochloride ₍ 116 mg, 0.65 mmol) and dioxane (1.2 mL) under N2 (g) was stirred at 90 °C for 5.5 h. The reaction mixture was diluted with EtOAc (5 mL). SilaMetS® Thiol scavenger (150 mg; loading 1.4 mmol/g) was added and the mixture was stirred for 1 h and then filtered through a pad of Celite® 521. The filter pad was washed with EtOAc (12 mL) and the combined filtrates were concentrated. The residue was purified by reversed-phase preparative HPLC, PrepMethod H (gradient: 15-65%) to give the title compound (0.141 g, 83%) as a yellow solid; MS (ESI) m/z [M+H] ⁺ 342.3.

Intermediate 239. 6-(3-morpholinoazetidin-1-yl)quinoline-4-carboxylic acid

Aq. NaOH (3.8 M, 0.220 mL, 0.84 mmol) was added to a solution of ethyl 6-(3-morpholinoazetidin-1-yl)quinoline-4-carboxylate, intermediate 238 (143 mg, 0.42 mmol), in MeOH (2 mL) and the reaction mixture was stirred at rt overnight. Aq. HCl (3.8 M, 0.220 mL, 0.84 mmol) was added dropwise and the resulting mixture was concentrated under reduced pressure at rt. The residue was concentrated under reduced pressure from MeCN to give the crude title compound (0.176 g); MS (ESI) m/z [M+H] ⁺ 314.3.

Intermediate 240. 6-(4,5,6,7-tetrahydro-1H-indazol-1-yl)quinoline-4-carboxylic acid

TFA (4 ml) was slowly added to a stirred solution of tert-butyl 6-(4,5,6,7-tetrahydro-1H-indazol-1-yl)quinoline-4-carboxylate, intermediate 229 (36 mg, 0.10 mmol), in DCM (4 ml) at 15 °C. The resulting solution was stirred at 15 °C for 15 h. The solvent was removed under reduced pressure to give the crude title compound (0.063 g) as a beige solid; MS m/z (ESI) [M+H] ⁺ 294.

Intermediate 241. 6-(4,5,6,7-tetrahydro-2H-indazol-2-yl)quinoline-4-carboxylic acid

TFA (5 ml) was slowly added to a stirred solution of tert-butyl 6-(4,5,6,7-tetrahydro-2H-indazol-2-yl)quinoline-4-carboxylate, intermediate 230 (239 mg, 0.68 mmol), in DCM (5 ml) at 15 °C. The resulting solution was stirred at 15 °C for 15 h. The solvent was removed under reduced pressure to give the crude title compound (0.527 g) as a yellow oil that solidified on standing; MS m/z (ESI) [M+H] ⁺ 294.

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Intermediate 242. 6-(5-methyl-3-(trifluoromethyl)-III-pyrazol-1-yl)quinoline-4-carboxylic acid

TFA (5 ml) was added to a stirred solution of tert-butyl 6-(5-methyl-3-(trifluoromethyl)-1H-pyrazol-1-yl)quinoline-4-carboxylate, intermediate 231 (130 mg, 0.34 mmol), in DCM (5 ml) at 15 °C. The resulting solution was stirred at 15 °C for 18 h. The solvent was removed under reduced pressure to give the crude title compound (0.230 g) as a brown gum; MS m/z (ESI) [M+H]+ 322.

Intermediate 243. 6-(6,6-dimethyl-5,6-dihydrocyclopenta[c]pyrazole-2(4H)yl)quinoline-4-carboxylic acid

TFA (5 ml) was added to a stirred solution of tert-butyl 6-(6,6-dimethyl-5,6-dihydrocyclopenta[c]pyrazol-2(4H)-yl)quinoline-4-carboxylate, intermediate 233 (260 mg, 0.72 mmol), in DCM (5 ml) at 15 °C. The resulting solution was stirred at 15 °C for 15 h. The solvent was removed under reduced pressure to give the crude title compound (0.552 g) as a yellow oil; MS m/z (ESI) [M+H]+ 308.

Intermediate 244. 6-(5,5-dimethyl-5,6-dihydro-4H-pyrrolo[1,2-b]pyrazol-3yl)quinoline-4-carboxylic acid

1,4-Dioxane (3 mL) and water (0.75 mL) were added to a mixture of 6-bromoquinoline-4- _carboxylic acid (100 mg, 0.40 mmol), 5,5-dimethyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-5,6-dihydro-4Hpyrrolo[1,2-b]pyrazole (114 mg, 0.44 mmol), _Cs2CO3 (323 mg, 0.99 mmol) and Pd(dtbpf) _Cl2 (26 mg, 0.04 mmol). The reaction mixture was purged with _N2 (g) and then stirred at rt overnight. DMSO (3 mL) was added to the reaction mixture and it was concentrated under reduced pressure. The residue was purified by preparative HPLC, PrepMethod E (gradient: 5-45%) to give the title compound (74 mg, 61%) as a light yellow solid; MS (ESI) m/z [M+H]+ 308.3.

Intermediate 245. 6-(2-fluoropyridin-4-yl)quinoline-4-carboxylic acid

The title compound was prepared as described for intermediate 244 using 6-bromoquinoline-4-carboxylic acid (100 mg, 0.40 mmol) and (2-fluoropyridin-4-yl)boronic acid (61 mg, 0.44 mmol). The crude product was purified by preparative HPLC, PrepMethod E (gradient: 0-40%) to give the title compound (5 mg, 5%) as a white solid; MS (ESI) m/z [M+H]+ 269.2.

Intermediate 246. 6-(5-fluoropyridin-2-yl)quinoline-4-carboxylic acid

1,4-Dioxane (3 mL) and water (0.75 mL) were added to a mixture of 6-bromoquinoline-4-carboxylic acid (100 mg, 0.40 mmol), (5-fluoropyridin-2-yl)boronic acid (67 mg, 0.48 mmol), Cs2CO3 (323 mg, 0.99 mmol), and Pd(dtbpf) _Cl2 (26 mg, 0.04 mmol). The reaction mixture was purged with N2 (g) and then stirred at rt overnight. (5-Fluoropyridin-2-yl)boronic acid (67 mg, 0.48 mmol), Pd(dtbpf) _Cl2 (26 mg, 0.04 mmol) and _Cs2CO3 (323 mg, 0.99 mmol) were added to the reaction mixture and it was purged with N2 (g) and heated at 100 _° C overnight in a microwave reactor. DMSO (2 mL) was added to the reaction mixture and it was concentrated under reduced pressure. The residue was purified by preparative HPLC, PrepMethod E (gradient: 0-40%) to give the title compound (6 mg, 6%) as a white solid; MS (ESI) m/z [M+H]+ 269.2.

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Intermediate 247. Methyl 6-(3-((trifluoromethoxy)methyl)azetidin-1-yl)quinoline-4-carboxylate

_Cs2CO3 (255 mg, 0.78 mmol) was added to a mixture of methyl 6-bromoquinoline-4-carboxylate ₍ 160 mg, 0.60 mmol), 3-((trifluoromethoxy)methyl)azetidine hydrochloride (150 mg, 0.78 mmol), _Pd2 (dba) ₃ (55 mg, 0.06 mmol) and XPhos (57 mg, 0.12 mmol) in 1,4-dioxane (1 mL) at 30 °C and the reaction mixture was stirred at 100 °C for 2 h. The reaction mixture was filtered through Celite® and the filtrate was concentrated under reduced pressure. The residue was purified by preparative TLC (EtOAc:petroleum ether, 3:2) to give the title compound (0.20 g, 98%) as a brown oil that solidified on standing; MS (ESI) m/z [M+H] ⁺ 431.

Intermediate 248. 6-(3-((trifluoromethoxy)methyl)azetidin-1-yl)quinoline-4-carboxylic acid

A solution of NaOH (109 mg, 2.72 mmol) in water (2 ml) was slowly added to a stirred solution of methyl 6-(3-((trifluoromethoxy)methyl)azetidin-1-yl)quinoline-4-carboxylate, intermediate 247 (185 mg, 0.54 mmol), in MeOH (6 ml), cooled to 0 °C, and the resulting mixture was stirred at 30 °C for 1 h. The reaction mixture was diluted with water (20 ml), adjusted to pH 6 with aq. HCl (2 M) and extracted with EtOAc (8 x 75 ml). The combined organic layer was dried over Na ₂ SO ₄ , filtered and evaporated under reduced pressure to give the title compound (0.175 g, 99%) as an orange solid; MS (ESI) mass/charge [M+H] ⁺ 327.

Intermediate 249. Methyl 6-(3-methyl-3-(2,2,2-trifluoroethyl)azetidin-1-yl)quinoline-4-carboxylate

_Cs2CO3 (255 mg, 0.78 mmol) was added to a mixture of methyl 6-bromoquinoline-4-carboxylate (160 _mg , 0.60 mmol), 3-methyl-3-(2,2,2-trifluoroethyl)azetidine hydrochloride (148 mg, 0.78 mmol), _Pd2 (dba) ₃ (55 mg, 0.06 mmol) and XPhos (57 mg, 0.12 mmol) in 1,4-dioxane (1 mL) at 30 °C and the reaction mixture was stirred at 100 °C for 2 h. The reaction mixture was filtered through Celite® and the filtrate was concentrated under reduced pressure. The crude product was purified by preparative TLC (EtOAc:petroleum ether, 3:2) to give the title compound (0.199 g, 98%) as a brown oil that solidified on standing; MS (ESI) m/z [M+H] ⁺ 339.

Intermediate 250. 6-(3-methyl-3-(2,2,2-trifluoroethyl)azetidin-1-yl)quinoline-4-carboxylic acid

A solution of NaOH (109 mg, 2.73 mmol) in water (2 ml) was slowly added to a stirred solution of methyl 6-(3-methyl-3-(2,2,2-trifluoroethyl)azetidin-1-yl)quinoline-4-carboxylate, intermediate 249 (185 mg, 0.55 mmol), in MeOH (6 ml), cooled to 0 °C, and the reaction mixture was stirred at 30 °C for 1 h. The reaction mixture was diluted with water (20 ml), the pH was adjusted to 6 with aq. HCl (2 M) and extracted with EtOAc (8 x 75 ml). The combined organic layer was dried over Na ₂ SO ₄ , filtered and evaporated under reduced pressure to give the title compound (0.173 g, 98%) as a yellow solid; MS (ESI) mass/charge [M+H]+ 325.

- 143 048482

Carboxylate intermediate

251. Methyl-6-(3-(trifluoromethoxy)azetidin-1-yl)quinoline-4-

_Cs2CO3 (478 mg, 1.47 mmol) was added to a mixture of methyl 6-bromoquinoline-4-carboxylate ₍ 300 mg, 1.13 mmol), 3-(trifluoromethoxy)azetidine hydrochloride (260 mg, 1.47 mmol), _Pd2 (dba) ₃ (103 mg, 0.11 mmol) and XPhos (107 mg, 0.23 mmol) in 1,4-dioxane (10 mL) at 35 °C and the reaction mixture was stirred at 100 °C for 2 h. The reaction mixture was filtered through Celite® and the filtrate was concentrated under reduced pressure. The crude product was purified by preparative TLC (EtOAc:petroleum ether, 2:1) to give the title compound (0.354 g, 96%) as a brown oil that solidified on standing; MS (ESI) m/z [M+H]+ 327.

Intermediate 252. 6-(3-(trifluoromethoxy)azetidin-1-yl)quinoline-4-carboxylic acid

A solution of NaOH (201 mg, 5.03 mmol) in water (2 ml) was added to a stirred solution of methyl 6-(3-(trifluoromethoxy)azetidin-1-yl)quinoline-4-carboxylate, intermediate 251 (328 mg, 1.01 mmol), in MeOH (6 ml), cooled to 0 °C, and the reaction mixture was stirred at 37 °C for 1 h. The reaction mixture was diluted with water (20 ml), the pH was adjusted to 6 with aq. HCl (2 M) and extracted with EtOAc (6 x 75 ml). The combined organic layer was dried over Na ₂ SO ₄ , filtered and evaporated under reduced pressure to give the title compound (0.30 g, 96%) as a yellow solid; MS (ESI) mass/charge [M+H] ⁺ 313.

Intermediate 253. Methyl 6-(3-(2,2-difluoroethyl)-3-methylazetidin-1-yl)quinoline-4-carboxylate

_Cs2CO3 (302 mg, 0.93 mmol) was added to a mixture of methyl 6-bromoquinoline-4-carboxylate ₍ 190 mg, 0.71 mmol), 3-(2,2-difluoroethyl)-3-methylazetidine hydrochloride (159 mg, 0.93 mmol), Pd2(dba)3 (65 mg, 0.07 mmol) and XPhos (68 mg, 0.14 mmol) in 1,4-dioxane (10 mL) at 28 °C and the reaction mixture was stirred at 100 °C for 2 h. The reaction mixture was filtered through Celite® and the filtrate was concentrated under reduced pressure. The crude product was purified by preparative TLC (EtOAc:petroleum ether, 3:2) followed by purification by reverse phase flash chromatography on a C18 column (gradient: 0-8% MeCN in water) to give the title compound (0.203 g) as a beige gum; MS (ESI) m/z [M+H] ⁺ 321.

Intermediate 254. 6-(3-(2,2-difluoroethyl)-3-methylazetidin-1-yl)quinoline-4-carboxylic acid

A solution of NaOH (97 mg, 2.4 mmol) in water (2 ml) was slowly added to a stirred solution of methyl 6-(3-(2,2-difluoroethyl)-3-methylazetidin-1-yl)quinoline-4-carboxylate, intermediate 253 (173 mg), in MeOH (6 ml) cooled to 0 °C and the reaction mixture was stirred at 28 °C for 1 h. The reaction mixture was diluted with water (20 ml), the pH was adjusted to 6 with aq. HCl (2 M) and extracted with EtOAc (4 x 100 ml). The combined organic layer was dried over Na ₂ SO ₄ , filtered and evaporated under reduced pressure to give the title compound (0.14 g, 94%) as an orange solid; MS (ESI) mass/charge [M+H] ⁺ 307.

Intermediate 255. Methyl 6-(3-cyclopropyl-3-methylazetidin-1-yl)quinoline-4-carboxylate

Cs ₂ CO ₃ (207 mg, 0.64 mmol) was added to a mixture of methyl 6-bromoquinoline-4-carboxylate (130 mg, 0.49

- 144 048482 mmol), 3-cyclopropyl-3-methylazetidine (71 mg, 0.64 mmol), Pd ₂ (dba) ₃ (45 mg, 0.05 mmol) and XPhos (47 mg, 0.10 mmol) in 1,4-dioxane (10 mL) at 30 °C and the reaction mixture was stirred at 100 °C for 3 h. The reaction mixture was filtered and the filtrate was concentrated under reduced pressure. The crude product was purified by preparative TLC (EtOAc:petroleum ether, 3:2) to give the title compound (0.14 g, 97%) as a brown gum; MS (ESI) m/z [M+H]+ 297.

Intermediate 256. 6-(3-cyclopropyl-3-methylazetidin-1-yl)quinoline-4-carboxylic acid

A solution of NaOH (74 mg, 1.9 mmol) in water (2 ml) was added to a stirred suspension of methyl 6-(3-cyclopropyl-3-methylazetidin-1-yl)quinoline-4-carboxylate, intermediate 255 (110 mg, 0.37 mmol), in MeOH (6 ml) cooled to 0 °C and the reaction mixture was stirred at 23 °C for 1 h. The reaction mixture was diluted with water (15 ml), the pH was adjusted to 6 with aq. HCl (2 M) and extracted with EtOAc (4 x 75 ml). The combined organic layer was dried over Na ₂ SO ₄ , filtered and evaporated under reduced pressure to give the title compound (0.10 g, 95%) as a yellow solid; MS (ESI) mass/charge [M+H] ⁺ 283.

Intermediate 257. Methyl 6-(3-(difluoromethyl)-3-methylazetidin-1-yl)quinoline-4-carboxylate

_Cs2CO3 (207 mg, 0.64 mmol) was added to a mixture of methyl 6-bromoquinoline-4-carboxylate (130 mg, 0.49 mmol), 3-( _{difluoromethyl} )-3-methylazetidine hydrochloride (100 mg, 0.64 mmol), _Pd2 (dba) ₃ (45 mg, 0.05 mmol) and XPhos (47 mg, 0.10 mmol) in 1,4-dioxane (10 mL) at 30 °C and the reaction mixture was stirred at 100 °C for 4 h. The reaction mixture was filtered through Celite® and the filtrate was concentrated under reduced pressure. The crude product was purified by preparative TLC (EtOAc:petroleum ether, 6:5) to give the title compound (0.145 g, 97%) as a brown gum; MS (ESI) m/z [M+H] ⁺ 307.

Intermediate 258. 6-(3-(difluoromethyl)-3-methylazetidin-1-yl)quinoline-4-carboxylic acid

F

NaOH (78 mg, 2.0 mmol) was added to a stirred solution of methyl 6-(3-(difluoromethyl)-3methylazetidin-1-yl)quinoline-4-carboxylate, intermediate 257 (120 mg, 0.39 mmol), in MeOH (8 ml) and water (2 ml) at 0 °C and the reaction mixture was stirred at 23 °C for 1 h. The reaction mixture was diluted with water (15 ml) and the pH was adjusted to 6 with aq. HCl (2 M) and extracted with EtOAc (6 x 75 ml). The combined organic layer was dried over Na ₂ SO ₄ , filtered and evaporated under reduced pressure to give the title compound (0.11 g, 96%) as a yellow solid; MS (ESI) mass/charge [M+H] ⁺ 293.

Intermediate 259. Methyl 6-(3-(difluoromethoxy)azetidin-1-yl)quinoline-4-carboxylate

_Cs2CO3 (398 mg, 1.22 mmol) was added to a mixture of methyl 6-bromoquinoline-4-carboxylate ₍ 250 mg, 0.94 mmol), 3-(difluoromethoxy)azetidine hydrochloride (195 mg, 1.22 mmol), _Pd2 (dba) ₃ (86 mg, 0.09 mmol) and XPhos (90 mg, 0.19 mmol) in 1,4-dioxane (10 mL) at 28 °C and the reaction mixture was stirred at 100 °C for 2 h. The reaction mixture was filtered through Celite® and the filtrate was concentrated under reduced pressure. The crude product was purified by preparative TLC (EtOAc:petroleum ether, 3:2) followed by reverse phase flash chromatography on a C18 column (gradient: 0-4% MeCN in water) to give the title compound (0.281 g) as a brown gum; MS (ESI) m/z [M+H] ⁺ 309.

- 145 048482

Intermediate 260. 6-(3-(difluoromethoxy)azetidin-1-yl)quinoline-4-carboxylic acid

A solution of NaOH (154 mg, 3.85 mmol) in water (3 ml) was slowly added to a stirred solution of crude methyl 6-(3-(difluoromethoxy)azetidin-1-yl)quinoline-4-carboxylate, intermediate 259 (260 mg), in MeOH (9 ml) cooled to 0 °C and the reaction mixture was stirred at 28 °C for 1 h. The reaction mixture was diluted with water (20 ml), the pH was adjusted to 6 with aq. HCl (2 M) and extracted with EtOAc (8 x 100 ml). The combined organic layer was dried over Na ₂ SO ₄ , filtered and evaporated under reduced pressure to give the title compound (0.207 g, 91%) as an orange solid; MS (ESI) mass/charge [M+H] ⁺ 295.

Intermediate 261. Methyl 6-(3-ethyl-3-methylazetidin-1-yl)quinoline-4-carboxylate

_Cs2CO3 (276 mg, 0.85 mmol) was added to a mixture of methyl 6-bromoquinoline-4-carboxylate ₍ 150 mg, 0.56 mmol), 3-ethyl-3-methylazetidine hydrochloride (115 mg, 0.85 mmol), _Pd2 (dba) ₃ (52 mg, 0.06 mmol) and XPhos (54 mg, 0.11 mmol) in 1,4-dioxane (10 mL) at 25 °C and the reaction mixture was stirred at 100 °C for 6 h. The reaction mixture was filtered through Celite® and the filtrate was concentrated under reduced pressure. The crude product was purified by preparative TLC (EtOAc:petrol ether, 1:1) to give the title compound (0.157 g, 98%) as a brown oil that solidified on standing; MS (ESI) m/z [M+H] ⁺ 285.

Intermediate 262. 6-(3-ethyl-3-methylazetidin-1-yl)quinoline-4-carboxylic acid

A solution of NaOH (98 mg, 2.5 mmol) in water (2 ml) was slowly added to a stirred suspension of methyl 6-(3-ethyl-3-methylazetidin-1-yl)quinoline-4-carboxylate, intermediate 261 (140 mg, 0.49 mmol), in MeOH (6 ml) cooled to 0 °C and the reaction mixture was stirred at 30 °C for 1 h. The reaction mixture was diluted with water (15 ml), the pH was adjusted to 6 with aq. HCl (2 M) and extracted with EtOAc (6 x 75 ml). The combined organic layer was dried over Na ₂ SO ₄ , filtered and evaporated under reduced pressure to give the title compound (0.13 g, 98%) as an orange solid; MS (ESI) mass/charge [M+H]+ 271.

Intermediate 263. Methyl 6-(3-ethyl-3-fluoroazetidin-1-yl)quinoline-4-carboxylate

Pd ₂ (dba) ₃ (138 mg, 0.15 mmol) was added to a mixture of methyl 6-bromoquinoline-4-carboxylate (400 mg, 1.50 mmol), 3-ethyl-3-fluoroazetidine (186 mg, 1.80 mmol), Cs ₂ CO ₃ (980 mg, 3.01 mmol) and XPhos (143 mg, 0.30 mmol) in 1,4-dioxane (15 mL) at 25 °C and the reaction mixture was stirred at 100 °C for 3 h. The reaction mixture was concentrated and diluted with EtOAc (125 mL), and washed successively with brine (75 mL) and water (75 mL). The organic layer was dried over Na ₂ SO ₄ , filtered and evaporated under reduced pressure. The crude product was purified by preparative TLC (MeOH:DCM, 1:5) to give the title compound (0.20 g, 46%) as a yellow solid; MS (ESI) m/z [M+H] ⁺ 289.

Intermediate 264. 6-(3-ethyl-3-fluoroazetidin-1-yl)quinoline-4-carboxylic acid

A solution of NaOH (104 mg, 2.60 mmol) in water (4 ml) was added to a stirred solution of methyl 6-(3-ethyl-3-fluoroazetidin-1-yl)quinoline-4-carboxylate, intermediate 263 (150 mg, 0.52 mmol), in MeOH (12 ml) at 20 °C and the reaction mixture was stirred at 25 °C for 2 h. The pH of the reaction

- 146 048482 the reaction mixture was adjusted to 4 using aq. HCl (2 M, 7 mL). The reaction mixture was concentrated under reduced pressure, diluted with EtOAc (100 mL) and washed successively with brine (50 mL) and water (50 mL). The organic layer was dried over Na ₂ SO ₄ , filtered and evaporated under reduced pressure to give the title compound (0.12 g, 84%) as a red solid; MS (ESI) m/z [M+H]+ 275.0.

Intermediate 265. Methyl 6-(2-azaspiro[3.4]octan-2-yl)quinoline-4-carboxylate

Pd ₂ (dba) ₃ (103 mg, 0.11 mmol) was added to a mixture of methyl 6-bromoquinoline-4-carboxylate (300 mg, 1.13 mmol), 2-azaspiro[3.4]octane (150 mg, 1.35 mmol), Cs ₂ CO ₃ (735 mg, 2.25 mmol) and XPhos (107 mg, 0.23 mmol) in 1,4-dioxane (15 mL) at 20 °C and the reaction mixture was stirred at 100 °C for 5 h. The reaction mixture was concentrated under reduced pressure, diluted with EtOAc (125 mL) and washed successively with water (75 mL) and brine (75 mL). _The organic layer was dried over _Na2SO4 , filtered and concentrated under reduced pressure. The crude product was purified by preparative TLC (EtOAc:petroleum ether, 1:2) to give the title compound (0.20 g, 60%) as a yellow solid; MS (ESI) m/z [M+H] ⁺ 397.0.

Intermediate 266. 6-(2-azaspiro[3.4]octan-2-yl)quinoline-4-carboxylic acid

A solution of NaOH (135 mg, 3.37 mmol) in water (3 mL) was added to a stirred solution of methyl 6-(2-azaspiro[3.4]octan-2-yl)quinoline-4-carboxylate, intermediate 265 (200 mg, 0.67 mmol), in MeOH (9 mL) at 20 °C and the reaction mixture was stirred at 25 °C for 2 h. The pH of the reaction mixture was adjusted to 4 with aq. HCl (2 M, 25 mL). The reaction mixture was concentrated under reduced pressure, diluted with EtOAc (100 mL) and washed successively with water (25 mL) and brine (25 mL). The organic layer was dried over Na2SO4, filtered and evaporated under reduced pressure to give the title compound (0.15 g, 79%) as a red solid; MS (ESI) m/z [M+H] ⁺ 283.3.

Intermediate 267. Methyl 6-(3-(2,2-difluoropropyl)azetidin-1-yl)quinoline-4-carboxylate

XPhos (107 mg, 0.23 mmol) was added to a mixture of methyl 6-bromoquinoline-4-carboxylate (300 mg, 1.13 mmol), 3-(2,2-difluoropropyl)azetidine (183 mg, 1.35 mmol), Pd2(dba)3 (103 mg, 0.11 mmol) and Cs2CO3 (735 mg, 2.25 mmol) in 1,4-dioxane (15 mL) at 20 °C and the reaction mixture was stirred at 100 °C for 3 h. The reaction mixture was concentrated under reduced pressure, diluted with EtOAc (100 mL) and washed successively with water (25 mL) and brine (25 mL). The organic layer was dried over Na2SO4, filtered and evaporated under reduced pressure. The crude product was purified by preparative TLC (EtOAc:petroleum ether, 1:3) to give the title compound (0.25 g, 69%) as a yellow oil; MS (ESI) m/z [M+H] ⁺ 321.0.

Intermediate 268. 6-(3-(2,2-difluoropropyl)azetidin-1-yl)quinoline-4-carboxylic acid

A solution of NaOH (181 mg, 4.53 mmol) in water (3 mL) was added to a stirred solution of methyl 6-(3-(2,2-difluoropropyl)azetidin-1-yl)quinoline-4-carboxylate, intermediate 267 (290 mg, 0.91 mmol), in MeOH (9 mL) at 20 °C and the reaction mixture was stirred at 25 °C for 2 h. The pH was adjusted to 5 with aq. HCl (2 M). The reaction mixture was concentrated under reduced pressure, diluted with EtOAc (125 mL) and washed successively with brine (75 mL) and water (75 mL). The organic layer was dried over Na ₂ SO ₄ , filtered and evaporated under reduced pressure to give the title compound (0.20 g, 72%) as

- 147 048482 yellow solid; MS (ESI) m/z [M+H] ⁺ 307.0.

Intermediate 269. Methyl 6-(5,5-difluoro-2-azaspiro[3.4]octan-2-yl)quinoline-4-carboxylate

Pd ₂ (dba) ₃ (55 mg, 0.06 mmol) was added to a mixture of methyl 6-bromoquinoline-4-carboxylate (160 mg, 0.60 mmol), 5,5-difluoro-2-azaspiro[3.4]octane (106 mg, 0.72 mmol), Cs ₂ CO ₃ (24 mg, 0.08 mmol) and XPhos (57 mg, 0.12 mmol) in 1,4-dioxane (15 mL) at 25 °C and the reaction mixture was stirred at 100 °C for 3 h. The reaction mixture was concentrated under reduced pressure, diluted with EtOAc (125 mL) and washed successively with brine (75 mL) and water (75 mL). _The organic layer was dried over _Na2SO4 , filtered and evaporated under reduced pressure. The crude product was purified by preparative TLC (EtOAc:petroleum ether, 1:3) to give the title compound (0.15 g, 75%) as a yellow solid; MS (ESI) m/z [M+H] ⁺ 333.0.

Intermediate 270. 6-(5,5-difluoro-2-azaspiro[3.4]octan-2-yl)quinoline-4-carboxylic acid

A solution of NaOH (120 mg, 3.01 mmol) in water (3 mL) was added to a stirred solution of methyl 6-(5,5-difluoro-2-azaspiro[3.4]octan-2-yl)quinoline-4-carboxylate, intermediate 269 (200 mg, 0.60 mmol), in MeOH (9 mL) at 20 °C and the reaction mixture was stirred at 25 °C for 3 h. The pH of the reaction mixture was adjusted to 5 with aq. HCl (2 M). The reaction mixture was concentrated under reduced pressure, diluted with EtOAc (100 mL) and washed successively with brine (20 mL) and water (20 mL). The organic layer was dried over Na2SO4, filtered and evaporated under reduced pressure to give the title compound (0.15 g, 78%) as a red solid; MS (ESI) m/z [M+H] ⁺ 319.0.

Intermediate 271. Methyl 6-(3-(3,33-trifluoropropyl)azetidin-1-yl)quinoline-4-carboxylate

Pd ₂ (dba) ₃ (43 mg, 0.05 mmol) was added to a mixture of methyl 6-bromoquinoline-4-carboxylate (250 mg, 0.94 mmol), 3-(3,3,3-trifluoropropyl)azetidine hydrochloride (267 mg, 1.41 mmol), XPhos (67 mg, 0.14 mmol) and Cs ₂ CO ₃ (918 mg, 2.82 mmol) in 1,4-dioxane (10 mL) and the reaction mixture was stirred at 100 °C for 2 h. The solid was filtered off and the filtrate was concentrated under reduced pressure. The residue was diluted with EtOAc and washed with water. The organic layer was dried over Na ₂ SO ₄ , filtered and evaporated under reduced pressure. The crude product was purified by preparative TLC (petroleum ether:EtOAc, 2:1) to give the title compound (0.25 g, 79%) as an orange gum; MS (ESI) m/z [M+H]+ 339.

Intermediate 272. 6-(3-(3,3,3-trifluoropropyl)azetidin-1-yl)quinoline-4-carboxylic acid

A solution of methyl 6-(3-(3,3,3-trifluoropropyl)azetidin-1-yl)quinoline-4-carboxylate, intermediate 271 (230 mg, 0.68 mmol), and LiOH (49 mg, 2.0 mmol) in MeOH (10 mL) and water (2 mL) was stirred at rt for 2 h. The solvent was removed under reduced pressure and the reaction mixture was diluted with water. The pH of the reaction mixture was adjusted to 6 with aq. HCl (0.1 M). The precipitate was collected by filtration, washed with water and dried in vacuo to give the title compound (0.20 g, 91%) as an orange solid; MS (ESI) m/z [M+H] ⁺ 325.

- 148 048482

Intermediate 273. Methyl 6-(3-fluoro-3-(trifluoromethyl)azetidin-1-yl)quinoline-4-carboxylate

Pd ₂ (dba) ₃ (34 mg, 0.04 mmol) was added to a mixture of methyl 6-bromoquinoline-4-carboxylate (200 mg, 0.75 mmol), 3-fluoro-3-(trifluoromethyl)azetidine hydrochloride (202 mg, 1.13 mmol), XPhos (54 mg, 0.11 mmol) and Cs ₂ CO ₃ (735 mg, 2.25 mmol) in 1,4-dioxane (10 mL) and the reaction mixture was stirred at 100 °C for 2 h. The solid was filtered off and the filtrate was concentrated under reduced pressure. The residue was diluted with EtOAc and washed with water. The organic layer was dried over Na ₂ SO ₄ , filtered and evaporated under reduced pressure. The crude product was purified by preparative TLC (petroleum ether:EtOAc, 2:1) to give the title compound (0.20 g, 81%) as a yellow solid; MS (ESI) m/z [M+H]+ 329.

Intermediate 274. 6-(3-fluoro-3-(trifluoromethyl)azetidin-1-yl)quinoline-4-carboxylic acid

A solution of methyl 6-(3-fluoro-3-(trifluoromethyl)azetidin-1-yl)quinoline-4-carboxylate, intermediate 273 (200 mg, 0.61 mmol), and LiOH (44 mg, 1.83 mmol) in MeOH (8 mL) and water (2 mL) was stirred at rt for 2 h. The solvent was removed under reduced pressure and the reaction mixture was diluted with water. The pH of the reaction mixture was adjusted to 6 with aq. HCl (1 M). The precipitate was collected by filtration, washed with water and dried in vacuo to give the title compound (0.17 g, 89%) as a yellow solid; MS (ESI) m/z [M+H]+ 315.

Intermediate 275. Methyl 6-(3-(2,2-difluoroethyl)azetidin-1-yl)quinoline-4-carboxylate

Pd ₂ (dba) ₃ (43 mg, 0.05 mmol) was added to a mixture of methyl 6-bromoquinoline-4-carboxylate (250 mg, 0.94 mmol), 3-(2,2-difluoroethyl)azetidine 2,2,2-trifluoroacetate (247 mg, 1.13 mmol), XPhos (67 mg, 0.14 mmol) and Cs ₂ CO ₃ (918 mg, 2.82 mmol) in 1,4-dioxane (10 mL) and the reaction mixture was stirred at 100 °C for 2 h. The solid was filtered off and the filtrate was concentrated under reduced pressure. The residue was diluted with EtOAc and washed successively with water. The organic layer was dried over Na ₂ SO ₄ , filtered and evaporated under reduced pressure. The crude product was purified by preparative TLC (petroleum ether:EtOAc, 2:1) to give the title compound (0.23 g, 80%) as an orange gum; MS (ESI) m/z [M+H]+ 307.

Intermediate 276. 6-(3-(2,2-difluoroethyl)azetidin-1-yl)quinoline-4-carboxylic acid

A solution of methyl 6-(3-(2,2-difluoroethyl)azetidin-1-yl)quinoline-4-carboxylate, intermediate 275 (230 mg, 0.75 mmol), and LiOH (54 mg, 2.3 mmol) in MeOH (10 mL) and water (2 mL) was stirred at rt for 2 h. The solvent was removed under reduced pressure and the reaction mixture was diluted with water. The pH of the reaction mixture was adjusted to 6 with aq. HCl (1 M). The precipitate was collected by filtration, washed with water and dried in vacuo to give the title compound (0.19 g, 87%) as an orange solid; MS (ESI) m/z [M+H]+ 293.

Intermediate 277. Methyl 6-(3-cyclopropylazetidin-1-yl)quinoline-4-carboxylate

- 149 048482

_Pd2 (dba) ₃ (43 mg, 0.05 mmol) was added to a mixture of methyl 6-bromoquinoline-4-carboxylate (250 mg, 0.94 mmol), 3-cyclopropylazetidine hydrochloride (151 mg, 1.13 mmol), XPhos (67 mg, 0.14 mmol) and _Cs2CO3 (918 mg, 2.82 mmol) in 1,4-dioxane (10 mL) and the reaction mixture was stirred at 100 °C for 2 _h . The solid was filtered off and the filtrate was concentrated under reduced pressure. The residue was diluted with EtOAc and washed successively with water. _The organic layer was dried over _Na2SO4 , filtered and evaporated under reduced pressure. The crude product was purified by preparative TLC (petroleum ether:EtOAc, 2:1) to give the title compound (0.20 g, 75%) as an orange solid; MS (ESI) m/z [M+H] ⁺ 283.

Intermediate 278. 6-(3-cyclopropylazetidin-1-yl)quinoline-4-carboxylic acid

A solution of methyl 6-(3-cyclopropylazetidin-1-yl)quinoline-4-carboxylate, intermediate 277 (200 mg, 0.71 mmol), and LiOH (51 mg, 2.1 mmol) in MeOH (10 mL) and water (2 mL) was stirred at rt for 2 h. The solvent was removed under reduced pressure and the reaction mixture was diluted with water. The pH of the reaction mixture was adjusted to 6 with aq. HCl (1 M). The precipitate was collected by filtration, washed with water and dried in vacuo to give the title compound (0.17 g, 89%) as an orange solid; MS (ESI) m/z [M+H] ⁺ 269.

Intermediate 279. Methyl 6-(3-(2-fluoroethyl)azetidin-1-yl)quinoline-4-carboxylate

_Pd2 (dba) ₃ (34 mg, 0.04 mmol) was added to a mixture of methyl 6-bromoquinoline-4-carboxylate (200 mg, 0.75 mmol), 3-(2-fluoroethyl)azetidine 2,2,2-trifluoroacetate (197 mg, 0.98 mmol), XPhos (54 mg, 0.11 mmol) and _Cs2CO3 (735 mg, 2.25 mmol) in 1,4- _dioxane (12 mL) and the reaction mixture was stirred at 100 °C for 2 h. The solid was filtered off and the filtrate was concentrated under reduced pressure. The residue was diluted with EtOAc and washed successively with water. The organic layer was dried over Na2SO4, filtered and evaporated under reduced pressure. The crude product was purified by preparative TLC (petroleum ether:EtOAc, 2:1) to give the title compound (0.17 g, 78%) as a yellow solid; MS (ESI) m/z [M+H] ⁺ 289.

Intermediate 280. 6-(3-(2-fluoroethyl)azetidin-1-yl)quinoline-4-carboxylic acid

A solution of methyl 6-(3-(2-fluoroethyl)azetidin-1-yl)quinoline-4-carboxylate, intermediate 279 (170 mg, 0.59 mmol), and LiOH (42 mg, 1.77 mmol) in MeOH (8 mL) and water (2 mL) was stirred at rt for 2 h. The solvent was removed under reduced pressure and the reaction mixture was diluted with water. The pH of the reaction mixture was adjusted to 6 with aq. HCl (1 M). The precipitate was collected by filtration, washed with water and dried in vacuo to give the title compound (0.145 g, 90%) as a yellow solid; MS (ESI) m/z [M+H] ⁺ 275.

Intermediate 281. Methyl 6-(3-(1,1-difluoroethyl)azetidin-1-yl)quinoline-4-carboxylate

_Pd2 (dba)3 (34 mg, 0.04 mmol) was added to a mixture of methyl 6-bromoquinoline-4-carboxylate (200 mg, 0.75 mmol), 3-(1,1-difluoroethyl)azetidine hydrochloride (142 mg, 0.90 mmol), XPhos (54 mg, 0.11 mmol) and _Cs2CO3 (735 mg, 2.3 mmol) in 1,4-dioxane (10 mL) and the reaction mixture was stirred at 100 °C for ₂ h. The solid was filtered off and the filtrate was concentrated under reduced pressure. The residue was diluted with EtOAc and washed with water. _The organic layer was dried over _Na2SO4 , filtered and evaporated under reduced pressure. The crude product was purified by preparative TLC (petroleum ether:EtOAc, 2:1) to give the title compound (0.18 g, 78%) as a yellow solid; MS (ESI) m/z [M+H]+ 307.

- 150 048482

Intermediate 282. 6-(3-(1,1-difluoroethyl)azetidin-1-yl)quinoline-4-carboxylic acid

A solution of methyl 6-(3-(1,1-difluoroethyl)azetidin-1-yl)quinoline-4-carboxylate, intermediate 281 (180 mg, 0.59 mmol), and LiOH (42 mg, 1.8 mmol) in MeOH (8 mL) and water (2 mL) was stirred at rt for 3 h. The solvent was removed under reduced pressure and the reaction mixture was diluted with water. The pH of the reaction mixture was adjusted to 6 with aq. HCl (1 M). The precipitate was collected by filtration, washed with water and dried in vacuo to give the title compound (0.155 g, 90%) as a yellow solid; MS (ESI) m/z [M+H]+ 293.

Intermediate 283. Methyl 6-(3-isopropylazetidin-1-yl)quinoline-4-carboxylate

_Cs2CO3 (765 mg, 2.35 mmol) was added to a mixture of methyl 6-bromoquinoline-4-carboxylate ₍ 250 mg, 0.94 mmol), 3-isopropylazetidine hydrochloride (255 mg, 1.88 mmol), _Pd2 (dba) ₃ (86 mg, 0.09 mmol) and CPhos (410 mg, 0.94 mmol) in 1,4-dioxane (5.0 mL) at 25 °C and the reaction mixture was stirred at 100 °C for 2 h. The reaction mixture was diluted with DCM (10 mL) and the solvent was removed under reduced pressure. The crude product was purified by preparative TLC (EtOAc:petroleum ether, 1:1) to give the title compound (0.262 g, 98%) as an orange gum; MS (ESI) m/z [M+H] ⁺ 285.

Intermediate 284. 6-(3-isopropylazetidin-1-yl)quinoline-4-carboxylic acid

NaOH (181 mg, 4.52 mmol) was added to methyl 6-(3-isopropylazetidin-1-yl)quinoline-4-carboxylate, intermediate 283 (257 mg, 0.90 mmol), in MeOH (9 ml) and water (3 ml) at 25 °C and the reaction mixture was stirred at 25 °C for 1 h. The solvent was removed under reduced pressure and the residue was diluted with water (50 ml). The reaction mixture was adjusted to pH 3 with aq. HCl (1 M) and extracted with EtOAc (3 x 50 ml). The combined organic layer was dried over Na ₂ SO ₄ , filtered and evaporated under reduced pressure to give the title compound (0.242 g, 99%) as an orange solid; MS (ESI) mass/charge [M+H] ⁺ 271.

Intermediate 285. Methyl 6-(6-methyl-2-azaspiro[3.3]heptan-2-yl)quinoline-4-carboxylate

_Cs2CO3 (612 mg, 1.88 mmol) was added to methyl 6-bromoquinoline-4-carboxylate ₍ 200 mg, 0.75 mmol), 6-methyl-2-azaspiro[3.3]heptane hydrochloride (222 mg, 1.50 mmol), _Pd2 (dba) ₃ (69 mg, 0.08 mmol) and SPhos (62 mg, 0.15 mmol) in 1,4-dioxane (5 mL) at 25 °C and the reaction mixture was stirred at 100 °C for 2 h. The reaction mixture was diluted with DCM (10 mL) and the solvent was removed under reduced pressure. The crude product was purified by preparative TLC (EtOAc:petroleum ether, 1:1) to give the title compound (0.22 g, 99%) as an orange solid; MS (ESI) m/z [M+H] ⁺ 297.

Intermediate 286. 6-(6-methyl-2-azaspiro[3.3]heptan-2-yl)quinoline-4-carboxylic acid

NaOH (145 mg, 3.63 mmol) was added to a solution of methyl 6-(6-methyl-2-azaspiro[3.3]heptan-2yl)quinoline-4-carboxylate, intermediate 285 (215 mg, 0.73 mmol), in MeOH (6 mL) and water (2 mL) at 25 °C and the reaction solution was stirred at 25 °C for 1 h. The solvent was removed under reduced pressure, the residue was diluted with water (50 mL) and the pH was adjusted to 3 with aq.

- 151 048482

HCl (1 M). The aqueous phase was extracted with EtOAc (3x50 mL), the combined organic layer was dried _{over Na2SO4} , filtered and evaporated under reduced pressure to give the title compound (0.20 g, 98%) as an orange solid; MS (ESI) m/z [M+H]+ 283.

Intermediate 287. Methyl 6-(6-(trifluoromethyl)-2-azaspiro[3.3]heptan-2-yl)quinoline-4-carboxylate

Cs2CO3 (612 mg, 1.88 mmol) was added to a mixture of methyl 6-bromoquinoline-4-carboxylate (200 mg, 0.75 mmol), 6-(trifluoromethyl)-2-azaspiro[3.3]heptane hydrochloride (303 mg, 1.50 mmol), _Pd2 (dba) ₃ (69 mg, 0.08 mmol) and SPhos (62 mg, 0.15 mmol) in 1,4-dioxane (5 mL) at 25 °C and the reaction mixture was stirred at 100 °C for 2 h. The reaction mixture was diluted with DCM (10 mL) and the solvent was removed under reduced pressure. The crude product was purified by preparative TLC (EtOAc:petroleum ether, 1:1) to give the title compound (0.26 g, 99%) as a yellow solid; MS (ESI) m/z [M+H]+ 351.

Intermediate 288. 6-(6-(trifluoromethyl)-2-azaspiro[3.3]heptan-2-yl)quinoline-4-carboxylic acid

NaOH (148 mg, 3.70 mmol) was added to a solution of methyl 6-(6-(trifluoromethyl)-2-azaspiro[3.3]heptan2-yl)quinoline-4-carboxylate, intermediate 287 (259 mg, 0.74 mmol), in MeOH (9 mL) and water (3 mL) at 25 °C and the reaction mixture was stirred at 25 °C for 1 h. The solvent was removed under reduced pressure and the reaction mixture was diluted with water (50 mL) and the pH was adjusted to 3 with aq. HCl (1 M). The aqueous phase was extracted with EtOAc (3x50 mL), _the combined organic layer was dried over _Na2SO4 , filtered and evaporated under reduced pressure to give the title compound (0.24 g, 97%) as an orange solid; MS (ESI) m/z [M+H]+ 337.

Intermediate 289. Methyl 6-(3-methoxy-3-methylazetidin-1-yl)quinoline-4-carboxylate

_Cs2CO3 (918 mg, 2.82 mmol) was added to a mixture of methyl 6-bromoquinoline-4-carboxylate (300 mg, 1.13 mmol), 3-methoxy-3-methylazetidine hydrochloride (310 mg, 2.25 mmol), _Pd2 (dba) ₃ (103 mg, 0.11 mmol) and RuPhos (105 mg, 0.23 mmol) in 1,4-dioxane (5 mL) at 25 °C and the reaction mixture was stirred at 100 °C for 2 h under N2 (g). The reaction mixture was diluted with DCM (10 mL) and the solvent was removed under reduced pressure. The crude product was purified by preparative TLC (EtOAc:petroleum ether, 1:1) to give the title compound (0.321 g, 99%) as a brown gum; MS (ESI) m/z [M+H]+ 287.

Intermediate 290. 6-(3-methoxy-3-methylazetidin-1-yl)quinoline-4-carboxylic acid

NaOH (223 mg, 5.59 mmol) was added to a solution of methyl 6-(3-methoxy-3-methylazetidin-1yl)quinoline-4-carboxylate, intermediate 289 (320 mg, 1.12 mmol), in MeOH (6 ml) and water (2 ml) at 25 °C and the reaction mixture was stirred at 25 °C for 1 h. The solvent was removed under reduced pressure, the reaction mixture was diluted with water (50 ml) and the pH was adjusted to 3 with aq. HCl (1 M). The aqueous phase was extracted with EtOAc (3 x 50 ml), the combined organic layer was dried over Na ₂ SO ₄ , filtered and evaporated under reduced pressure to give the title compound (0.296 g, 97%) as an orange solid; MS (ESI) mass/charge [M+H]+ 273.

- 152 048482

Intermediate 291. Methyl 6-(3-ethoxy-3-methylazetidin-1-yl)quinoline-4-carboxylate

_Cs2CO3 (918 mg, 2.82 mmol) was added to a mixture of methyl 6-bromoquinoline-4-carboxylate ₍ 300 mg, 1.13 mmol), 3-ethoxy-3-methylazetidine hydrochloride (342 mg, 2.25 mmol), _Pd2 (dba) ₃ (103 mg, 0.11 mmol) and RuPhos (105 mg, 0.23 mmol) in 1,4-dioxane (5 mL) at 25 °C and the reaction mixture was stirred at 100 °C for 2 h. The reaction mixture was diluted with DCM (10 mL) and the solvent was removed under reduced pressure. The crude product was purified by preparative TLC (petroleum ether:EtOAc, 1:1) to give the title compound (0.33 g, 97%) as a red gum; MS (ESI) m/z [M+H]+ 301.

Intermediate 292. 6-(3-ethoxy-3-methylazetidin-1-yl)quinoline-4-carboxylic acid

NaOH (216 mg, 5.41 mmol) was added to a solution of methyl 6-(3-ethoxy-3-methylazetidin-1-yl)quinoline-4-carboxylate, intermediate 291 (325 mg, 1.08 mmol), in MeOH (9 ml) and water (3 ml) at 25 °C and the reaction mixture was stirred at 25 °C for 1 h. The solvent was removed under reduced pressure, the reaction mixture was diluted with water (50 ml) and the pH was adjusted to 3 with aq. HCl (1 M). The aqueous phase was extracted with EtOAc (3 x 50 ml) and the combined organic layer was dried over Na ₂ SO ₄ , filtered and evaporated under reduced pressure to give the title compound (0.305 g, 98%) as an orange solid; MS (ESI) mass/charge [M+H]+ 287.

Intermediate 293. Methyl 6-(1-oxa-6-azaspiro[3.3]heptan-6-yl)quinoline-4-carboxylate

_Cs2CO3 (430 mg, 1.32 mmol) was added to a mixture of methyl 6-bromoquinoline-4-carboxylate ₍ 270 mg, 1.01 mmol), 1-oxa-6-azaspiro[3.3]heptane oxalate (250 mg, 1.32 mmol) and RuPhosPd G3 (85 mg, 0.10 mmol) in 1,4-dioxane (5 mL) at 35 °C and the reaction mixture was stirred at 100 °C for 2 h. The reaction mixture was filtered through Celite® and the filtrate was concentrated under reduced pressure. The crude product was purified by preparative TLC (MeOH:DCM, 1:10) to give the title compound (0.283 g, 98%) as a yellow solid; MS (ESI) mass/charge [M+H]+ 285.

Intermediate 294. 6-(1-oxa-6-azaspiro[3.3]heptan-6-yl)quinoline-4-carboxylic acid

A solution of NaOH (177 mg, 4.43 mmol) in water (2 ml) was added to a stirred solution of methyl 6-(1-oxa-6-azaspiro[3.3]heptan-6-yl)quinoline-4-carboxylate, intermediate 293 (252 mg, 0.89 mmol), in MeOH (6 ml) at 0 °C and the reaction mixture was stirred at 37 °C for 1 h. The reaction mixture was diluted with water (20 ml) and the pH was adjusted to 6 with aq. HCl (2 M). The reaction mixture was extracted with EtOAc (8 x 75 ml), the combined organic layer was dried over Na ₂ SO ₄ , filtered and evaporated under reduced pressure to give the title compound (0.214 g, 89%) as an orange solid; MS (ESI) mass/charge [M+H]+ 271.

Intermediate 295. Methyl 6-(3-ethyl-3-hydroxyazetidin-1-yl)quinoline-4-carboxylate

_Pd2 (dba) ₃ (103 mg, 0.11 mmol) was added to a mixture of methyl 6-bromoquinoline-4-carboxylate (300 mg, 1.13 mmol), 3-ethylazetidin-3-ol (137 mg, 1.35 mmol), _Cs2CO3 ( ₇₃₅ mg, 2.25 mmol) and DavePhos (89 mg, 0.23 mmol) in 1,4-dioxane (15 mL) at 20 °C and the reaction mixture was stirred at 100 °C for 3 h. The reaction mixture was concentrated under reduced pressure and the residue was diluted with EtOAc (75 mL). The mixture was washed successively with water (20 mL) and sat. brine (20 ml) and the organic layer was dried over Na ₂ SO ₄ , filtered and evaporated under reduced pressure. The crude

- 153 048482 The product was purified by preparative TLC (EtOAc:petroleum ether, 1:5) to give the title compound (0.20 g, 62%) as a yellow solid; MS (ESI) m/z [M+H]+ 287.0.

Intermediate 296. 6-(3-ethyl-3-hydroxyazetidin-1-yl)quinoline-4-carboxylic acid

A solution of NaOH (140 mg, 3.49 mmol) in water (3 mL) was added to a stirred solution of methyl 6-(3-ethyl-3-hydroxyazetidin-1-yl)quinoline-4-carboxylate, intermediate 295 (200 mg, 0.70 mmol), in MeOH (9 mL) at 25 °C and the reaction mixture was stirred at 25 °C for 3 h. The pH of the reaction mixture was adjusted to 4 with aq. HCl (2 M) and the reaction mixture was concentrated under reduced pressure. The residue was diluted with EtOAc (75 mL) and the organic layer was washed successively with water (25 mL) and sat. brine (25 ml), dried over _{Na2SO4 ,} filtered and evaporated under reduced pressure to give the title compound (0.15 g, 79%) as a red solid; MS (ESI) m/z [M+H]+ 273.0.

Intermediate 297. Methyl 6-(6-fluoro-2-azaspiro[3.3]heptan-2-yl)quinoline-4-carboxylate

_Cs2CO3 (612 mg, 1.88 mmol) was added to a mixture of methyl 6-bromoquinoline-4-carboxylate (200 mg, 0.75 mmol), 6-fluoro-2-azaspiro[3.3]heptane trifluoroacetate (344 mg, 1.50 mmol), _Pd2 (dba) ₃ (69 mg, 0.08 mmol) and DavePhos (59 mg, 0.15 mmol) in 1,4-dioxane (5 mL) at 25 °C and the reaction mixture was stirred at 100 °C for 2 h. The reaction mixture was diluted with DCM (10 mL) and the solvent was removed under reduced pressure. The crude product was purified by preparative TLC (EtOAc:petroleum ether, 1:1) to give the title compound (0.22 g, 97%) as an orange gum; MS (ESI) m/z [M+H]+ 301.

Intermediate 298. 6-(6-fluoro-2-azaspiro[3.3]heptan-2-yl)quinoline-4-carboxylic acid

NaOH (146 mg, 3.65 mmol) was added to a solution of methyl 6-(6-fluoro-2-azaspiro[3.3]heptan-2yl)quinoline-4-carboxylate, intermediate 297 (219 mg, 0.73 mmol), in MeOH (6 ml) and water (2 ml) at 25 °C and the reaction mixture was stirred at 25 °C for 1 h. The solvent was removed under reduced pressure and the residue was diluted with water (50 ml) and the pH was adjusted to 3 with aq. HCl (1 M). The aqueous phase was extracted with EtOAc (3 x 50 ml), the combined organic layer was dried over Na ₂ SO ₄ , filtered and evaporated under reduced pressure to give the title compound (0.205 g, 98%) as an orange solid; MS (ESI) mass/charge [M+H]+ 287.

Intermediate 299. rac-methyl 6-((1R,5R)-6-azabicyclo[3.2.0]heptan-6-yl)quinoline-4-carboxylate

A solution of methyl 6-bromoquinoline-4-carboxylate (400 mg, 1.50 mmol) in 1,4-dioxane (10 mL) was added to a mixture of 6-azabicyclo[3.2.0]heptane (146 mg, 1.50 mmol), Pd ₂ (dba) ₃ (14 mg, 0.02 mmol), XPhos (14 mg, 0.03 mmol) and Cs ₂ CO ₃ (980 mg, 3.01 mmol), and the reaction mixture was stirred at 100 °C for 3 h. The reaction mixture was filtered through silica gel and the filtrate was concentrated under reduced pressure. The crude product was purified by preparative TLC (petroleum ether:EtOAc, 2:1) to give the title compound (0.17 g, 40%) as a yellow solid; MS (ESI) m/z [M+H]+ 382.2.

- 154 048482

Intermediate 300. rac-6-((1R,5R)-6-azabicyclo[3.2.0]heptan-6-yl)quinoline-4-carboxylic acid

LiOH (25 mg, 1.1 mmol) was added to a stirred solution of methyl 6-(6azabicyclo[3.2.0]heptan-6-yl)quinoline-4-carboxylate, intermediate 299 (150 mg, 0.53 mmol), in THF (3 mL) and water (3 mL) and the reaction mixture was stirred at 25 °C for 4 h. The pH of the reaction mixture was adjusted to 5 with aq. HCl (2 M) and the reaction mixture was concentrated under reduced pressure to give the title compound (0.13 g, 91%) as a red solid; MS (ESI) m/z [M+H]+ 269.2.

Intermediate 301. Methyl 6-(3-hydroxy-3-(hydroxymethyl)azetidin-1-yl)quinoline-4-carboxylate

BUT °-^°\

N

_Cs2CO3 (814 mg, 2.50 mmol) was added to methyl 6-bromoquinoline-4-carboxylate (266 mg, 1.00 mmol), 3- ₍ hydroxymethyl)azetidin-3-ol oxalate (193 mg, 1.30 mmol), _Pd2 (dba) ₃ (92 mg, 0.10 mmol) and XPhos (95 mg, 0.20 mmol) in 1,4-dioxane (5 mL) at 12 °C and the reaction mixture was stirred at 100 °C for 15 h. The reaction mixture was filtered through Celite® and the filtrate was concentrated under reduced pressure. The crude product was purified by preparative TLC (DCM:MeOH, 10:1) to give the title compound (0.134 g, 46%) as a brown solid; MS (ESI) m/z [M+H]+ 289.

Intermediate 302. Methyl 6-(3-fluoro-3-(fluoromethyl)azetidin-1-yl)quinoline-4-carboxylate

F 0^.0^

N

A solution of DAST (972 μl, 7.35 mmol) in anhydrous DCM (5 ml) was added dropwise to a stirred solution of methyl 6-(3-hydroxy-3-(hydroxymethyl)azetidin-1-yl)quinoline-4-carboxylate, intermediate 301 (212 mg, 0.74 mmol), in anhydrous DCM (25 ml) cooled to -60 °C over a period of 10 min. The reaction mixture was warmed to 25 °C and stirred for 8 h. The reaction mixture was poured into saturated NaHCO ₃ solution (25 ml, aq.) and extracted with DCM (5 x 75 ml). The combined organic layer was washed with water (3 x 50 ml), dried over Na ₂ SO ₄ , filtered and evaporated under reduced pressure. The crude product was purified by preparative TLC (DCM:MeOH, 10:1) to give the title compound (0.12 g, 56%) as a brown oil; MS (ESI) m/z [M+H]+ 293.

Intermediate 303. 6-(3-fluoro-3-(fluoromethyl)azetidin-1-yl)quinoline-4-carboxylic acid

A solution of NaOH (45 mg, 1.13 mmol) in water (1 ml) was slowly added to a stirred solution of methyl 6-(3-fluoro-3-(fluoromethyl)azetidin-1-yl)quinoline-4-carboxylate, intermediate 302 (110 mg, 0.38 mmol), in MeOH (3 ml), cooled to 0 °C, and the reaction mixture was stirred at 28 °C for 1.5 h. The reaction mixture was acidified with aq. HCl (2 M) and extracted with EtOAc (5 x 100 ml). The combined organic layer was dried over Na ₂ SO ₄ , filtered and evaporated under reduced pressure to give the title compound (0.10 g, 95%) as a beige solid; MS (ESI) mass/charge [M+H]+ 279.

Intermediate 304. Methyl 6-(3-(2,2,2-trifluoroethyl)azetidin-1-yl)quinoline-4-carboxylate

_Cs2CO3 (563 mg, 1.73 mmol) was added to methyl 6-bromoquinoline-4 _- carboxylate (200 mg, 0.75 mmol),

- 155 048482 3-(2,2,2-trifluoroethyl)azetidine hydrochloride (172 mg, 0.98 mmol), Pd ₂ (dba) ₃ (69 mg, 0.08 mmol) and XPhos (72 mg, 0.15 mmol) in 1,4-dioxane (20 mL) at 28 °C and the reaction mixture was stirred at 100 °C for 2 h. The reaction mixture was filtered through Celite® and the filtrate was concentrated under reduced pressure. The crude product was purified by preparative TLC (DCM:MeOH, 10:1) to give the title compound (0.415 g) as a crude product; MS (ESI) m/z [M+H]+ 325.

Intermediate 305. 6-(3-(2,2,2-trifluoroethyl)azetidin-1-yl)quinoline-4-carboxylic acid

A solution of NaOH (134 mg, 3.36 mmol) in water (2 ml) was added to a stirred solution of methyl 6-(3-(2,2,2-trifluoroethyl)azetidin-1-yl)quinoline-4-carboxylate, intermediate 304 (363 mg, 1.12 mmol), in MeOH (6 ml), cooled to 0 °C, and the reaction mixture was stirred at 20 °C for 2 h. The reaction mixture was acidified to pH 6 with aq. HCl (2 M, aq.) and extracted with EtOAc (10 x 100 ml). The combined organic layer was dried over Na2SO4, filtered and evaporated under reduced pressure to give the title compound (0.333 g, 96%) as an orange solid; MS (ESI) mass/charge [M+H]+ 311.

Intermediate 306. rac-methyl (R)-6-(3,3-difluoro-2-methylazetidin-1-yl)quinoline-4-carboxylate

_Cs2CO3 (735 mg, 2.25 mmol) was added to a mixture of methyl 6-bromoquinoline-4-carboxylate ₍ 200 mg, 0.75 mmol), 3,3-difluoro-2-methylazetidine hydrochloride (216 mg, 1.50 mmol) and RuPhosPd G3 (63 mg, 0.08 mmol) in 1,4-dioxane (4 mL) at 20 °C and the reaction mixture was stirred at 100 °C for 4 h. The reaction mixture was diluted with DCM and filtered through silica gel, and the filter cake was washed with DCM. The filtrate was concentrated under reduced pressure and the crude product was purified by preparative TLC (petroleum ether:EtOAc, 1:1) to give the title compound (0.215 g, 98%) as a brown gum; MS (ESI) m/z [M+H]+ 293.

Intermediate carboxylic acid compound

307. rac-(R)-6-(3,3-difluoro-2-methylazetidin-1-yl)quinoline-4NaOH (146 mg,

3.66 mmol)

was added to a solution of methyl 6-(3,3-difluoro-2-methylazetidin-1yl)quinoline-4-carboxylate, intermediate 306 (214 mg, 0.73 mmol), in MeOH (1.5 ml) and water (0.5 ml) at 20 °C and the reaction mixture was stirred at 20 °C for 1 h. The reaction mixture was concentrated under reduced pressure, diluted with water and the pH was adjusted to 3 with HCl solution (1 M). The reaction mixture was diluted with water (50 ml) and washed with EtOAc (10 ml). The combined organic layer was dried over Na ₂ SO ₄ , filtered and evaporated at 20 °C. (5x50 under reduced pressure to give the title compound (0.198 g, 97%) as a yellow solid; MS (ESI) m/z [M+H]+ 279.

Intermediate 308. tert-Butyl 6-(6,6-difluoro-3-azabicyclo[3.1.0]hexan-3yl)quinoline-4-carboxylate

_Cs2CO3 (132 mg, 0.41 mmol) was added to a mixture of tert-butyl 6-bromoquinoline-4-carboxylate ₍ 50 mg, 0.16 mmol), 6,6-difluoro-3-azabicyclo[3.1.0]hexane hydrochloride (28 mg, 0.18 mmol), _Pd2 (dba) ₃ (15 mg, 0.02 mmol) and XPhos (15 mg, 0.03 mmol) in 1,4-dioxane (5 mL) at 20 °C and the reaction mixture was stirred at 100 °C for 5 h. The reaction mixture was filtered through Celite® and the filtrate was concentrated under reduced pressure. The crude product was purified by preparative TLC (EtOAc:petroleum ether, 2:1) followed by reverse phase flash chromatography on a C18 column (gradient: 0-75% MeCN in water) to give the title compound (0.137 g) as a crude product.

- 156 048482 yellow solid; MS (ESI) m/z [M+H]+ 347.

Intermediate 309. 6-(6,6-difluoro-3-azabicyclo[3.1.0]hexan-3-yl)quinoline-4-carboxylic acid

TFA (5 mL) was added to a stirred solution of tert-butyl 6-(6,6-difluoro-3azabicyclo[3.1.0]hexan-3-yl)quinoline-4-carboxylate, intermediate 308 (123 mg, 0.36 mmol), in DCM (5 mL) at 15 °C and the reaction mixture was stirred at 15 °C for 15 h. The solvent was removed under reduced pressure to give the title compound (0.198 g, 97%) as a crude, dark red solid; MS (ESI) m/z [M+H] ⁺ 291.

Intermediate 310. Methyl (R)-6-(3-methoxypyrrolidin-1-yl)quinoline-4-carboxylate —o

_Cs2CO3 (735 mg, 2.25 mmol), _Pd2 ( _dba ) ₃ (10 mg, 0.01 mmol) and XPhos (11 mg, 0.02 mmol) were added to a solution of methyl 6-bromoquinoline-4-carboxylate (300 mg, 1.13 mmol) and (R)-3-methoxypyrrolidine (228 mg, 2.25 mmol) in 1,4-dioxane (10 mL) and the reaction mixture was stirred at 100 °C for 2 h. The solvent was removed under reduced pressure and the crude product was purified by preparative TLC (petroleum ether:EtOAc, 2:1) to give the title compound (0.30 g, 93%) as a red oil that solidified on standing; MS (ESI) mass/charge [M+H] ⁺ 287.1.

Intermediate 311. (R)-6-(3-methoxypyrrolidin-1-yl)quinoline-4-carboxylic acid

LiOH (90 mg, 3.8 mmol) was added to a solution of methyl (N)-6-(3-methoxypyrrolidin-1-yl)quinoline-4-carboxylate, intermediate 310 (270 mg, 0.94 mmol), in THF (0.5 ml) and water (0.5 ml) and the reaction mixture was stirred at 25 °C for 3 h. The pH of the reaction mixture was adjusted to 5 with aq. HCl (2 M) and the reaction mixture was concentrated under reduced pressure to give the title compound (0.20 g, 78%) as a red solid; MS (ESI) m/z [M+H] ⁺ 273.

Intermediate 312. Methyl 6-(3-oxa-9-azaspiro[5.5]undecan-9-yl)quinoline-4-carboxylate

Pd ₂ (dba) ₃ (52 mg, 0.06 mmol) was added to a mixture of methyl 6-bromoquinoline-4-carboxylate (300 mg, 1.13 mmol), 3-oxa-9-azaspiro[5.5]undecane (263 mg, 1.69 mmol), Cs ₂ CO ₃ (735 mg, 2.25 mmol) and XantPhos (98 mg, 0.17 mmol) in 1,4-dioxane (15 mL) and the reaction mixture was stirred at 80 °C for 2 h. The reaction mixture was concentrated under reduced pressure, diluted with EtOAc and washed with water. The organic layer was dried over Na ₂ SO ₄ , filtered and evaporated under reduced pressure. The crude product was purified by preparative TLC (petroleum ether:EtOAc, 2:1) to give the title compound (0.24 g, 62%) as a yellow gum; MS (ESI) m/z [M+H] ⁺ 341.

Intermediate 313. 6-(3-oxa-9-azaspiro[5.5]undecan-9-yl)quinoline-4-carboxylic acid

A solution of methyl 6-(3-oxa-9-azaspiro[5.5]undecan-9-yl)quinoline-4-carboxylate, intermediate 312 (230 mg, 0.68 mmol), and LiOH (81 mg, 3.4 mmol) in MeOH (10 mL) and water (2 mL) was stirred at rt for 3 h. The solvent was removed under reduced pressure and the reaction mixture was diluted with water and the pH was adjusted to 6 with aq. HCl (1 M). The precipitate was collected by filtration, washed with water and dried in vacuo to give the title compound

- 157 048482 units (0.20 g, 91%) as a yellow solid; MS (ESI) m/z [M+H]+ 327.

Intermediate 314. Methyl 6-(5,8-dioxa-2-azaspiro[3.4]octan-2-yl)quinoline-4-carboxylate

A solution of methyl 6-bromoquinoline-4-carboxylate (400 mg, 1.50 mmol) in 1,4-dioxane (15 mL) was added to a mixture of 5,8-dioxa-2-azaspiro[3.4]octane (260 mg, 2.25 mmol), Pd ₂ (dba) ₃ (14 mg, 0.02 mmol), XPhos (14 mg, 0.03 mmol) and Cs ₂ CO ₃ (980 mg, 3.01 mmol), and the reaction mixture was stirred at 100 °C for 3 h. The reaction mixture was filtered through silica gel and the filtrate was concentrated under reduced pressure. The crude product was purified by preparative TLC (petroleum ether:EtOAc, 2:1) to give the title compound (0.35 g, 78%) as a yellow solid; MS (ESI) m/z [M+H]+ 301.1.

Intermediate 315. 6-(5,8-dioxa-2-azaspiro[3.4]octan-2-yl)quinoline-4-carboxylic acid

LiOH (115 mg, 4.79 mmol) was added to a stirred solution of methyl 6-(5,8-dioxa-2-azaspiro[3.4]octan-2-yl)quinoline-4-carboxylate, intermediate 314 (360 mg, 1.20 mmol), in THF (5 mL) and water (5 mL) and the reaction mixture was stirred at 25 °C for 4 h. The pH of the reaction mixture was adjusted to 5 with aq. HCl (2 M) and the reaction mixture was concentrated under reduced pressure to give the title compound (0.30 g, 87%) as a red solid; MS (ESI) m/z [M+H]+ 287.1.

Intermediate 316. Methyl 6-(5-azaspiro[2.3]hexan-5-yl)quinoline-4-carboxylate

_Cs2CO3 (612 mg, 1.88 mmol) was added to a mixture of methyl 6-bromoquinoline-4-carboxylate (200 mg, 0.75 mmol), 5-azaspiro _[ 2.3]hexane hydrochloride (135 mg, 1.13 mmol), _Pd2 (dba) ₃ (69 mg, 0.08 mmol) and XPhos (72 mg, 0.15 mmol) in 1,4-dioxane (4 mL) at 15 °C and the reaction mixture was stirred at 100 °C for 2 h. The reaction mixture was diluted with DCM and the solvent was removed under reduced pressure. The crude product was purified by preparative TLC (petroleum ether:EtOAc, 1:1) to give the title compound (0.189 g, 94%) as a yellow solid; MS (ESI) m/z [M+H]+ 269.

Intermediate 317. 6-(5-azaspiro[2.3]hexan-5-yl)quinoline-4-carboxylic acid l O^OH

NaOH (140 mg, 3.50 mmol) was added to a solution of methyl 6-(5-azaspiro[2.3]hexan-5-yl)quinoline-4-carboxylate, intermediate 316 (188 mg, 0.70 mmol), in MeOH (1.5 ml) and water (0.5 ml) at 15 °C and the reaction mixture was stirred at 15 °C for 1 h. The reaction mixture was concentrated under reduced pressure, diluted with water and the pH was adjusted to 3 with aq. HCl (1 M). The reaction mixture was diluted with EtOAc (50 ml) and washed with water (10 x 50 ml). The organic layer was dried over Na ₂ SO ₄ , filtered and evaporated under reduced pressure to give the title compound (0.327 g) as an orange solid; MS (ESI) mass/charge [M+H]+ 255.

Intermediate 318. Methyl 6-(3-hydroxy-3-methylazetidin-1-yl)quinoline-4-carboxylate

Cs ₂ CO ₃ (1.30 g, 4.01 mmol) was added to a mixture of methyl 6-bromoquinoline-4-carboxylate hydrochloride, intermediate 422 (303 mg, 1.00 mmol), 3-methylazetidin-3-ol hydrochloride (155 mg, 1.25

- 158 048482 mmol), Pd ₂ (dba) ₃ (92 mg, 0.10 mmol) and XPhos (95 mg, 0.20 mmol) in 1,4-dioxane (7 mL) at 20 °C and the reaction mixture was stirred at 100 °C for 2 h. The reaction mixture was filtered and the filtrate was concentrated under reduced pressure. The crude product was purified by preparative TLC (EtOAc:petroleum ether, 10:1) to give the title compound (0.193 g, 71%) as a yellow solid; MS (ESI) m/z [M+H]+ 273.

Intermediate 319. 6-(3-hydroxy-3-methylazetidin-1-yl)quinoline-4-carboxylic acid

A solution of NaOH (110 mg, 2.75 mmol) in water (4 ml) was slowly added to a stirred solution of methyl 6-(3-hydroxy-3-methylazetidin-1-yl)quinoline-4-carboxylate, intermediate 318 (150 mg, 0.55 mmol), in MeOH (12 ml), cooled to 0 °C, and the reaction mixture was stirred at 20 °C for 1 h. The pH of the reaction mixture was adjusted to 6 with aq. HCl (2 M) and the mixture was extracted with EtOAc (5 x 75 ml). The combined organic layer was washed with water (3 x 50 ml), dried over Na ₂ SO ₄ , filtered and evaporated under reduced pressure to give the title compound (0.095 g, 67%) as a yellow oil which solidified on standing; MS (ESI) mass/charge [M+H]+ 259.

Intermediate 320. Methyl 6-(2-oxa-6-azaspiro[3.3]heptan-6-yl)quinoline-4-carboxylate

_Cs2CO3 (1.53 g, 4.70 mmol) was added to a mixture of methyl 6-bromoquinoline-4-carboxylate ₍ 500 mg, 1.88 mmol), 2-oxa-6-azaspiro[3.3]heptane oxalate (462 mg, 2.44 mmol) and RuPhosPd G3 (157 mg, 0.19 mmol) in 1,4-dioxane (15 mL) at 28 °C and the reaction mixture was stirred at 100 °C for 4 h. The reaction mixture was filtered through Celite® and the filtrate was concentrated under reduced pressure. The crude product was purified by preparative TLC (DCM:MeOH, 10:1) to give the title compound (0.254 g, 48%) as a yellow solid; MS (ESI) mass/charge [M+H]+ 285.

Intermediate 321. 6-(2-oxa-6-azaspiro[3.3]heptan-6-yl)quinoline-4-carboxylic acid

A solution of NaOH (196 mg, 4.90 mmol) in water (3 ml) was slowly added to a stirred suspension of methyl 6-(2-oxa-6-azaspiro[3.3]heptan-6-yl)quinoline-4-carboxylate, intermediate 320 (232 mg, 0.82 mmol), in MeOH (12 ml) cooled to 0 °C and the reaction mixture was stirred at 25 °C for 1 h. The reaction mixture was diluted with water (20 ml), the pH was adjusted to 6 with aq. HCl (2 M) and the reaction mixture was extracted with EtOAc (6 x 100 ml). The combined organic layer was dried over Na2SO4, filtered and evaporated under reduced pressure to give the title compound (0.19 g, 86%) as a red solid; MS (ESI) mass/charge [M+H]+ 271.

Intermediate 322. Methyl (R)-6-(3-hydroxy-3-methylpyrrolidin-1-yl)quinoline-4-carboxylate

Pd2(dba)3 (52 mg, 0.06 mmol) was added to a mixture of methyl 6-bromoquinoline-4-carboxylate (300 mg, 1.13 mmol), (K)-3-methylpyrrolidin-3-ol (228 mg, 2.25 mmol), XPhos (81 mg, 0.17 mmol) and _Cs2CO3 ( ₇₃₅ mg, 2.25 mmol) in 1,4-dioxane (15 mL) and the reaction mixture was stirred at 100 °C for 3 h. The residue was diluted with _EtOAc and washed with water. The organic layer was dried over _Na2SO4 , filtered and evaporated under reduced pressure. The crude product was purified by preparative TLC (petroleum ether:EtOAc, 1:3) to give the title compound (0.28 g, 87%) as a yellow solid; MS (ESI) m/z [M+H]+ 287.

- 159 048482

Intermediate 323. (R)-6-(3-hydroxy-3-methylpyrrolidin-1-yl)quinoline-4-carboxylic acid

A solution of methyl (R)-6-(3-hydroxy-3-methylpyrrolidin-1-yl)quinoline-4-carboxylate, intermediate 322 (280 mg, 0.98 mmol), and LiOH (94 mg, 3.91 mmol) in MeOH (10 mL) and water (2 mL) was stirred at rt for 1 h. The solvent was removed under reduced pressure. The residue was diluted with water and the pH was adjusted to 6 with aq. HCl (1 M). The precipitate was collected by filtration, washed with water and dried in vacuo to give the title compound (0.22 g, 83%) as an orange solid; MS (ESI) m/z [M+H]+ 273.

Intermediate 324. Methyl (S)-6-(3-hydroxy-3-methylpyrrolidin-1-yl)quinoline-4-carboxylate

Pd ₂ (dba) ₃ (52 mg, 0.06 mmol) was added to a mixture of methyl 6-bromoquinoline-4-carboxylate (300 mg, 1.13 mmol), (S)-3-methylpyrrolidin-3-ol hydrochloride (233 mg, 1.69 mmol), XPhos (81 mg, 0.17 mmol) and Cs ₂ CO ₃ (1.10 g, 3.38 mmol) in 1,4-dioxane (10 mL) and the reaction mixture was stirred at 100 °C for 2 h. The reaction mixture was filtered and the filtrate was concentrated under reduced pressure. The reaction mixture was diluted with EtOAc and washed with water. The organic layer was dried over Na ₂ SO ₄ , filtered and evaporated under reduced pressure. The crude product was purified by preparative TLC (petroleum ether:EtOAc, 1:3) to give the title compound (0.26 g, 81%) as a yellow solid; MS (ESI) m/z [M+H] ⁺ 287.

Intermediate 325. (S)-6-(3-hydroxy-3-methylpyrrolidin-1-yl)quinoline-4-carboxylic acid

A solution of methyl (S)-6-(3-hydroxy-3-methylpyrrolidin-1-yl)quinoline-4-carboxylate, intermediate 324 (250 mg, 0.87 mmol), and LiOH (63 mg, 2.6 mmol) in MeOH (10 mL) and water (2 mL) was stirred at rt for 2 h. The solvent was removed under reduced pressure. The reaction mixture was diluted with water and the pH was adjusted to 6 with aq. HCl (1 M). The precipitate was collected by filtration, washed with water and dried in vacuo to give the title compound (0.21 g, 88%) as an orange solid; MS (ESI) m/z [M+H] ⁺ 273.

Intermediate 326. 6-(6-(difluoromethyl)pyridin-3-yl)quinoline-4-carboxylic acid

A mixture of (6-(difluoromethyl)pyridin-3-yl)boronic acid (103 mg, 0.60 mmol), 6-bromoquinoline-4-carboxylic acid (150 mg, 0.60 mmol), _Cs2CO3 ( ₃₈₈ mg, 1.19 mmol) and Pd(dtbpf) _Cl2 (58 mg, 0.09 mmol) in 1,4-dioxane (4.8 mL) and water (1.2 mL) was stirred at rt for 2 h. The reaction mixture was concentrated under reduced pressure, diluted with water and the pH was adjusted to 2 with aq. HCl (1 M). The precipitate was filtered, washed with diethyl ether and dried in vacuo to give the title compound (143 mg, 80%); MS (ESI) mass/charge [M+H] ⁺ 301.1.

Intermediate 327. 6-(1-cyclopropyl-1H-pyrazol-4-yl)quinoline-4-carboxylic acid

A mixture of 6-bromoquinoline-4-carboxylic acid (150 mg, 0.60 mmol), (1-cyclopropyl-1H-pyrazol-4yl)boronic acid (136 mg, 0.89 mmol), Cs ₂ CO ₃ (388 mg, 1.19 mmol) and Pd(dtbpf)Cl ₂ (58 mg, 0.09

- 160 048482 mmol) in 1,4-dioxane (4.8 mL) and water (1.2 mL) was stirred at rt for 2 h. The reaction mixture was concentrated under reduced pressure, diluted with water and the pH was adjusted to 2 with aq. HCl (1 M). The precipitate was filtered, washed with diethyl ether and dried in vacuo to give the title compound (0.124 g, 75%); MS (ESI) m/z [M+H]+ 280.1.

Intermediate 328. 6-(1,3-dimethyl-1H-pyrazol-4-yl)quinoline-4-carboxylic acid

A mixture of 1,3-dimethyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (0.448 g, 2.02 mmol), 6-bromoquinoline-4-carboxylic acid (0.508 g, 2.02 mmol), _{Cs2CO3 (} 1.31 g, 4.03 mmol) and Pd(dtbpf) _Cl2 (0.131 g, 0.20 mmol) in 1,4-dioxane (10 mL) and water (2.5 mL) was stirred overnight. Pd(dtbpf) _Cl2 (25 mg, 0.04 mmol) was added and the reaction mixture was stirred for 6 h. Pd(dtbpf) _Cl2 (25 mg, 0.04 mmol) was added and the reaction mixture was stirred for 4 days. The reaction mixture was diluted with a few ml of DMSO and evaporated under reduced pressure and the crude product was purified by preparative HPLC, PrepMethod E (gradient: 0-30%) to give the title compound (0.314 g, 58%); MS (ESI) m/z [M+H] ⁺ 268.

Intermediate 329. 6-(3,5-dimethyl-1-(tetrahydro-2H-pyran-4-yl)-1H-pyrazol-4yl)quinoline-4-carboxylic acid

A mixture of 3,5-dimethyl-1-(tetrahydro-2H-pyran-4-yl)-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)1H-pyrazole (68 mg, 0.22 mmol), 6-bromoquinoline-4- _{carboxylic acid (56 mg, 0.22 mmol), Cs2CO3 (} 145 mg, 0.44 mmol) and Pd(dtbpf)Cl2 (14 mg, 0.02 mmol) in 1,4-dioxane (1 mL) and water (0.25 mL) was stirred overnight. The reaction mixture was diluted with a few ml of DMSO and evaporated under reduced pressure, and the crude product was purified by preparative HPLC, PrepMethod E (gradient: 5-45%), to give the title compound (40 mg, 51%); MS (ESI) m/z [M+H] ⁺ 352.

Intermediate 330. 6-(1-(tetrahydro-2H-pyran-4-yl)-1H-nirazol-4-yl)quinoline-4-carboxylic acid

A mixture of (1-(tetrahydro-2H-pyran-4-yl)-1H _{-pyrazol-4-yl)boronic acid (40 mg, 0.21 mmol), 6-bromoquinoline-4-carboxylic acid (52 mg, 0.21 mmol), Cs2CO3 (} 134 mg, 0.41 mmol) and Pd(dtbpf) _Cl2 (13 mg, 0.02 mmol) in 1,4-dioxane (1 ml) and water (0.25 ml) was stirred overnight. The reaction mixture was diluted with a few ml of DMSO and evaporated under reduced pressure, and the crude product was purified by preparative HPLC, PrepMethod E (gradient: 5-45%), to give the title compound (26 mg, 39%); MS (ESI) mass/charge [M+H] ⁺ 324.

Intermediate 331. 6-(1-methyl-1H-pyrazol-5-yl)quinoline-4-carboxylic acid

A mixture of 1-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (41 mg, 0.20 mmol), 6-bromoquinoline-4-carboxylic acid (50 mg, 0.20 mmol), _{Cs2CO3 (} 194 mg, 0.60 mmol) and Pd(dtbpf) _Cl2 (22 mg, 0.03 mmol) in 1,4-dioxane (1 ml) and water (0.25 ml) was stirred overnight. The reaction mixture was diluted with a few ml of DMSO and evaporated under reduced pressure, and the crude product was purified by preparative HPLC, PrepMethod E (gradient: 0-30%), to give the title compound (29 mg, 58%); MS (ESI) mass/charge [M+H] ⁺ 254.

Intermediate 332. (5,6,7,8-tetrahydroimidazo[1,2-a]pyridin-3-yl)boronic acid

\ / ¹ \' HE

A solution of n-BuLi (280 mL, 0.69 mol, 2.5 M in hexane) was added via cannula to a solution of 5,6,7,8-tetrahydroimidazo[1,2-a]pyridine in THF at -60 °C over 20 min. The reaction mixture was stirred at rt for 30 min and then cooled to -60 °C and added dropwise to a solution of B(C ₃ H ₇ O) ₃ (150 g, 0.7 mol). The reaction mixture was stirred at rt for 6 h and then quenched with

- 161 048482 addition of aq. HCl (1 M). The reaction mixture was concentrated under reduced pressure and the pH was adjusted to 2 with aq. HCl (1 M). The reaction mixture was filtered and the filter cake was washed with EtOAc and dried under vacuum to give the title compound (54 g, 57%); MS (ESI) m/z [M+H]+ 167.1.

Intermediate 333. 6-(5,6,7,8-tetrahydroimidazo[1,2-a]pyridin-3-yl)quinoline-4-carboxylic acid

A mixture of (5,6,7,8-tetrahydroimidazo[1,2-a]pyridin-3-yl)boronic acid, intermediate 332 (37 mg, 0.22 mmol), 6-bromoquinoline-4-carboxylic acid (56 mg, 0.22 mmol), _Cs2CO3 (145 _mg , 0.44 mmol) and Pd(dtbpf) _Cl2 (14 mg, 0.02 mmol) in 1,4-dioxane (1 ml) and water (0.25 ml) was stirred overnight. The reaction mixture was diluted with a few ml of DMSO and evaporated under reduced pressure, and the crude compound was purified by preparative HPLC, PrepMethod E (gradient: 0-45%), to give the title compound (25 mg, 38%); MS (ESI) mass/charge [M+H]+ 294.

Intermediate 334. Methyl 6-bromo-7-chloroquinoline-4-carboxylate

SOCl2 (410 µL, 5.62 mmol) was slowly added to a solution of 6-bromo-7-chloroquinoline-4-carboxylic acid (322 mg, 1.12 mmol) in MeOH (10 mL) at 20 °C and the reaction mixture was stirred at 60 °C for 4 h. _The reaction mixture was diluted with DCM (75 mL) and washed successively with water (20 mL) and brine (20 mL, aq). The organic layer was dried over _Na2SO4 , filtered and evaporated under reduced pressure. The crude product was purified by preparative TLC (DCM:MeOH, 40:1) to give the title compound (0.188 g, 56%) as a yellow solid; MS (ESI) m/z [M+H]+ 301.9.

Intermediate 335. Methyl 7-chloro-6-morpholinoquinoline-4-carboxylate

Pd ₂ (dba) ₃ (46 mg, 0.05 mmol) was added to a suspension of methyl 6-bromo-7-chloroquinoline-4-carboxylate, intermediate 334 (150 mg, 0.50 mmol), morpholine (217 mg, 2.50 mmol), Cs ₂ CO ₃ (22 mg, 0.07 mmol) and XantPhos (58 mg, 0.10 mmol) in 1,4-dioxane (15 mL) at 20 °C and the reaction mixture was stirred at 100 °C for 5 h. The reaction mixture was concentrated under reduced pressure, diluted with EtOAc (75 mL) and washed successively with water (15 mL) and brine (15 mL, aq.). _The organic layer was dried over _Na2SO4 , filtered and evaporated under reduced pressure. The crude product was purified by preparative TLC (DCM:MeOH, 40:1) to give the title compound (0.074 g, 48%) as a yellow solid; MS (ESI) m/z [M+H]+ 307.0.

Intermediate 336. 7-Chloro-6-morpholinoquinoline-4-carboxylic acid

NaOH (46 mg, 1.1 mmol) was added to a solution of methyl 7-chloro-6-morpholinoquinoline-4-carboxylate, intermediate 335 (70 mg, 0.23 mmol), in MeOH (9 mL) and water (1 mL) at 20 °C and the reaction mixture was stirred at 25 °C for 3 h. The pH of the reaction mixture was adjusted to 3 using aq. HCl (2 M, 15 mL). The reaction mixture was concentrated under reduced pressure, diluted with EtOAc (20 mL) and washed with water (10 mL). The organic layer was dried over Na ₂ SO ₄ , filtered and evaporated under reduced pressure to give the title compound (0.060 g, 90%) as a yellow solid; MS (ESI) m/z [M+H]+ 292.9.

Intermediate 337. Methyl 6-bromo-8-chloroquinoline-4-carboxylate

SOC12 (159 µL, 2.18 mmol) was slowly added to the solution of 6-bromo-8-chloroquinoline-4-carboxylic acid

- 162 048482 acid (125 mg, 0.44 mmol) in MeOH (10 mL) at 20 °C and the reaction mixture was stirred at 60 °C for 3 h. The reaction mixture was concentrated under reduced pressure, diluted with EtOAc (50 mL) and washed successively with water (15 mL) and brine (15 mL). The organic layer was dried over Na ₂ SO ₄ , filtered and evaporated under reduced pressure. The crude product was purified by preparative TLC (EtOAc:petroleum ether, 1:5) to give the title compound (0.10 g, 76%) as a yellow solid; MS (ESI) m/z [M+H]+ 301.9.

Intermediate 338. Methyl 8-chloro-6-morpholinoquinoline-4-carboxylate

Pd ₂ (dba) ₃ (30 mg, 0.03 mmol) was added to a suspension of methyl 6-bromo-8-chloroquinoline-4-carboxylate, intermediate 337 (100 mg, 0.33 mmol), morpholine (145 mg, 1.66 mmol), XantPhos (38 mg, 0.07 mmol) and Cs ₂ CO ₃ (217 mg, 0.67 mmol) in 1,4-dioxane (15 mL) at 20 °C and the reaction mixture was stirred at 100 °C for 2 h. The reaction mixture was concentrated under reduced pressure, diluted with EtOAc (50 mL) and washed successively with brine (15 mL) and water (15 mL). _The organic layer was dried over _Na2SO4 , filtered and evaporated under reduced pressure. The crude product was purified by preparative TLC (EtOAc:petroleum ether, 1:5) to give the title compound (0.082 g, 80%) as a yellow solid; MS (ESI) m/z [M+H]+ 307.

Intermediate 339. 8-Chloro-6-morpholinoquinoline-4-carboxylic acid θγθΗ io ν ci

A solution of NaOH (52 mg, 1.3 mmol) in water (3 ml) was added to a stirred solution of methyl 8-chloro-6-morpholinoquinoline-4-carboxylate, intermediate 338 (80 mg, 0.26 mmol), in MeOH (9 ml) at 20 °C and the reaction mixture was stirred at 25 °C for 2 h. The pH of the reaction mixture was adjusted to 4 with aq. HCl (2 M). The reaction mixture was concentrated under reduced pressure, diluted with EtOAc (50 ml) and washed successively with brine (20 ml) and water (15 ml). The organic layer was dried over Na ₂ SO ₄ , filtered and evaporated under reduced pressure to give the title compound (0.070 g, 92%) as a red solid; MS (ESI) mass/charge [M+H]+ 293.0.

Intermediate 340. Ethyl 6-(3-(acetamidomethyl)-3-methylazetidin-1-yl)quinoline-4-carboxylate

A 5 mL vial was charged with ethyl 6-bromoquinoline-4-carboxylate (100 mg, 0.36 mmol), N-((3-methylazetidin-3-yl)methyl)acetamide hydrochloride (128 mg, 0.71 mmol), _Cs2CO3 ( ₄₆₅ mg, 1.43 mmol), XPhos (34 mg, 0.07 mmol), and _Pd2 (dba) ₃ (33 mg, 0.04 mmol). Dioxane (2 mL) was added and the reaction mixture was purged with N2 (gas) for 10 min. The vial was sealed and the reaction mixture was stirred at 100 °C for 2 h. After cooling to rt. Water (10 mL) and DCM (10 mL) were added and the reaction mixture was stirred, filtered through a phase separator and evaporated. The residue was purified by straight-phase flash chromatography on silica gel (gradient: 20-100% EtOAc (containing 5% 2 M NH3 in MeOH) in heptane) to give the title compound (47 mg, 39%); MS (ESI) m/z [M+H]+ 342.3.

Intermediate 341. 6-(3-(acetamidomethyl)-3-methylazetidin-1-yl)quinoline-4-carboxylic acid

Aq. NaOH (1 M, 264 μL, 0.26 mmol, 1 M) was added to a solution of ethyl 6-(3-acetamidomethyl)-3-methylazetidin-1-yl)quinoline-4-carboxylate, intermediate 340 (45 mg, 0.13 mmol), in MeOH (1.5 mL). The reaction mixture was stirred at 50 °C for 20 min, then cooled to rt. Aq. HCl (3.8 M, 87 μL, 0.33 mmol, 3.8 M) was added, and the reaction mixture was evaporated under reduced pressure and co-evaporated under reduced pressure with

- 163 048482

EtOH (2x) and MeCN (1x) to give the crude title compound; MS (ESI) m/z [M+H]+ 314.2.

Intermediate 342. Ethyl 6-(3-fluoro-3-phenylazetidin-1-yl)quinoline-4-carboxylate

A 5 mL vial was charged with ethyl 6-bromoquinoline-4-carboxylate (120 mg, 0.43 mmol), 3-fluoro-3-phenylazetidine hydrochloride (161 mg, 0.86 mmol), _Cs2CO3 (558 mg, 1.71 mmol), XPhos ₍ 41 mg, 0.09 mmol), and _Pd2 (dba) ₃ (39 mg, 0.04 mmol). Dioxane (2 mL) was added and the reaction mixture was purged with N2 (gas) for 10 min. The vial was sealed and the reaction mixture was stirred at 100 °C for 2 h. After cooling to rt, water (10 mL) and DCM (10 mL) were added and the reaction mixture was stirred, filtered through a phase separator, and evaporated under reduced pressure. The residue was purified by straight-phase flash chromatography on silica gel (gradient: 5-50% EtOAc in heptane) to give the title compound (26 mg, 17%); MS (ESI) m/z [M+H]+ 351.3.

Intermediate 343. 6-(3-fluoro-3-phenylazetidin-1-yl)quinoline-4-carboxylic acid

Aq. NaOH (1 M, 143 μL, 0.14 mmol) was added to a solution of ethyl 6-(3-fluoro-3-phenylazetidin-1-yl)quinoline-4-carboxylate, intermediate 342 (25 mg, 0.07 mmol), in MeOH (1 mL), and the reaction mixture was stirred at 50 °C for 20 min and then cooled to rt. Aq. HCl (3.8 M, 47 μL, 0.18 mmol) was added and the reaction mixture was evaporated under reduced pressure and co-evaporated under reduced pressure with EtOH (2x) and MeCN (1x) to give the crude title compound; MS (ESI) m/z [M+H]: 323.2.

Intermediate 344. Ethyl 6-(3-(p-tolyl)azetidin-1-yl)quinoline-4-carboxylate

A 5 mL vial was charged with ethyl 6-bromoquinoline-4-carboxylate (150 mg, 0.54 mmol), 3-(p-tolyl)azetidine hydrochloride (148 mg, 0.80 mmol), Cs ₂ CO ₃ (698 mg, 2.14 mmol), XPhos (51 mg, 0.11 mmol), and Pd ₂ (dba) ₃ (49 mg, 0.05 mmol). Dioxane (2 mL) was added and the reaction mixture was purged with N ₂ (gas) for 10 min. The vial was sealed and the reaction mixture was stirred at 100 °C for 3 h. After cooling to rt, water (10 mL) and DCM (15 mL) were added and the reaction mixture was stirred, filtered through a phase separator, and evaporated under reduced pressure. The residue was purified by straight-phase flash chromatography on silica gel (gradient: 5-50% EtOAc in heptane) to give the title compound (22 mg, 12%); MS (ESI) m/z [M+H]+ 347.3.

Intermediate 345. 6-(3-(p-tolyl)azetidin-1-yl)quinoline-4-carboxylic acid

Aq. NaOH (1 M, 115 μL, 0.12 mmol) was added to a solution of ethyl 6-(3-(p-tolyl)azetidin-1yl)quinoline-4-carboxylate, intermediate 344 (20 mg, 0.06 mmol), in MeOH (1 mL). The reaction mixture was stirred at 50 °C for 20 min, then cooled to rt. Aq. HCl (1 M, 144 μL, 0.14 mmol) was added and the reaction mixture was stirred, evaporated under reduced pressure and co-evaporated under reduced pressure with EtOH (2x) and MeCN (1x) to give the crude title compound; MS (ESI) m/z [M+H]+ 319.2.

- 164 048482

Intermediate 346. Ethyl 6-(6-acetyl-2,6-diazaspiro[3.3]heptan-2-yl)quinoline-4-carboxylate

A 5 mL vial was charged with ethyl 6-bromoquinoline-4-carboxylate (120 mg, 0.43 mmol), 1-(2,6-diazaspiro[3.3]heptan-2-yl)ethan-1-one _{oxalate (148 mg, 0.64 mmol), Cs2CO3 (} 558 mg, 1.71 mmol), XPhos (41 mg, 0.09 mmol), and _Pd2 (dba) ₃ (39 mg, 0.04 mmol). Dioxane (2.5 mL) was added and the reaction mixture was purged with N2 (gas) for 10 min. The vial was sealed and the reaction mixture was stirred at 100 °C for 3 h. After cooling to rt. Water (10 mL) and DCM (15 mL) were added and the reaction mixture was stirred, filtered through a phase separator and evaporated under reduced pressure. The residue was purified by straight-phase flash chromatography on silica gel (gradient: 25-100% EtOAc (containing 5% 2 M NH3 in MeOH) in heptane) to give the title compound (120 mg, 83%); MS (ESI) m/z [M+H] ⁺ 340.29.

Intermediate 347. 6-(6-acetyl-2,6-diazaspiro[3.3]heptan-2-yl)quinoline-4-carboxylic acid

Aq. NaOH (1 M, 707 μL, 0.71 mmol) was added to a solution of ethyl 6-(6-acetyl-2,6-diazaspiro[3.3]heptan-2-yl)quinoline-4-carboxylate, intermediate 346 (120 mg, 0.35 mmol), in MeOH (4 mL). The reaction mixture was stirred at 50 °C for 20 min and then cooled to rt. Aq. HCl (1 M, 884 μL, 0.88 mmol) was added and the reaction mixture was stirred, evaporated under reduced pressure and co-evaporated under reduced pressure with EtOH (2x) and MeCN (1x) to give the crude title compound; MS (ESI) m/z [M+H]+ 312.2.

Intermediate 348. Ethyl 6-(3-(4-fluorophenyl)azetidin-1-yl)quinoline-4-carboxylate

A 5 mL vial was charged with ethyl 6-bromoquinoline-4-carboxylate (120 mg, 0.43 mmol), 3-(4-fluorophenyl)-azetidine hydrochloride (121 mg, 0.64 mmol), _Cs2CO3 (558 mg, 1.71 mmol), _XPhos (41 mg, 0.09 mmol), and _Pd2 (dba) ₃ (39 mg, 0.04 mmol). Toluene (2.5 mL) was added and the reaction mixture was purged with N2 (gas) for 10 min. The vial was sealed and the reaction mixture was stirred at 110 °C for 2 h. After cooling to rt, water (10 mL) and DCM (15 mL) were added and the reaction mixture was stirred, filtered through a phase separator, and evaporated under reduced pressure. The residue was purified by straight-phase flash chromatography on silica gel (gradient: 5-50% EtOAc in heptane) to give the title compound (130 mg, 87%); MS (ESI) m/z [M+H] ⁺ 351.2.

Intermediate 349. 6-(3-(4-fluorophenyl)azetidin-1-yl)quinoline-4-carboxylic acid

Aq. NaOH (1 M, 685 μL, 0.68 mmol) was added to a solution of ethyl 6-(3-(4-fluorophenyl)azetidin-1-yl)quinoline-4-carboxylate, intermediate 348 (120 mg, 0.34 mmol), in MeOH (4 mL). The reaction mixture was stirred at 50 °C for 20 min, then cooled to rt. Aq. HCl (1 M, 856 μL, 0.86 mmol) was added and the reaction mixture was stirred, evaporated under reduced pressure and co-evaporated under reduced pressure with EtOH (2x) and MeCN (1x) to give the crude title compound; MS (ESI) m/z [M+H] ⁺ 323.19.

- 165 048482

Intermediate 350. Ethyl 6-(3-(m-tolyl)azetidin-1-yl)quinoline-4-carboxylate

A 5 mL vial was charged with ethyl 6-bromoquinoline-4-carboxylate (120 mg, 0.43 mmol), 3-(m-tolyl)azetidine hydrochloride (118 mg, 0.64 mmol), _Cs2CO3 (558 mg, 1.71 mmol), _XPhos (41 mg, 0.09 mmol), and _Pd2 (dba) ₃ (39 mg, 0.04 mmol). Toluene (2.5 mL) was added and the reaction mixture was purged with N2 (gas) for 10 min. The vial was sealed and the reaction mixture was stirred at 100 °C for 3 h. After cooling to rt, water (10 mL) and DCM (15 mL) were added and the reaction mixture was stirred, filtered through a phase separator, and evaporated under reduced pressure. The residue was purified by straight-phase flash chromatography on silica gel (gradient: 5-50% EtOAc in heptane) to give the title compound (128 mg, 86%); MS (ESI) m/z [M+H] ⁺ 347.36.

Intermediate 351. 6-(3-(m-tolyl)azetidin-1-yl)quinoline-4-carboxylic acid

Aq. NaOH (1 M, 687 μL, 0.69 mmol) was added to a solution of ethyl 6-(3-(m-tolyl)azetidin-1yl)quinoline-4-carboxylate, intermediate 350 (119 mg, 0.34 mmol), in MeOH (4 mL). The reaction mixture was stirred at 50 °C for 20 min, then cooled to rt. Aq. HCl (1 M, 859 μL, 0.86 mmol) was added and the reaction mixture was stirred, evaporated under reduced pressure and co-evaporated under reduced pressure with EtOH (2x), MeCN (1x) to give the crude title compound; MS (ESI) m/z [M+H]+ 319.2.

Intermediate 352. Ethyl 6-(3-(4-chlorobenzyl)azetidin-1-yl)quinoline-4-carboxylate

A 5 mL vial was charged with ethyl 6-bromoquinoline-4-carboxylate (100 mg, 0.36 mmol), 3-(4-chlorobenzyl)azetidine hydrochloride (117 mg, 0.54 mmol), _Cs2CO3 (465 mg, 1.43 mmol), _XPhos (34 mg, 0.07 mmol), and _Pd2 (dba) ₃ (33 mg, 0.04 mmol). Toluene (2 mL) was added and the reaction mixture was purged with N2 (gas) for 10 min. The vial was sealed and the reaction mixture was stirred at 110 °C for 1 h. After cooling to rt, water (10 mL) and DCM (15 mL) were added and the reaction mixture was stirred, filtered through a phase separator, and evaporated under reduced pressure. The residue was purified by straight-phase flash chromatography on silica gel (gradient: 5-50% EtOAc in heptane) to give the title compound (110 mg, 81%); MS (ESI) m/z [M+H] ⁺ 381.22.

Intermediate 353. 6-(3-(4-chlorobenzyl)azetidin-1-yl)quinoline-4-carboxylic acid

Aq. NaOH (1 M, 525 μL, 0.53 mmol) was added to a solution of ethyl 6-(3-(4-chlorobenzyl)azetidin-1-yl)quinoline-4-carboxylate, intermediate 352 (100 mg, 0.26 mmol), in MeOH (3 mL). The reaction mixture was stirred at 50 °C for 20 min, then cooled to rt. Aq. HCl (1 M, 656 μL, 0.66 mmol) was added and the reaction mixture was stirred, evaporated under reduced pressure and co-evaporated under reduced pressure with EtOH (2x) and MeCN (1x) to give the crude title compound; MS (ESI) m/z [M+H] ⁺ 353.2.

Intermediate 354. Ethyl 6-(3-methyl-3-((methylsulfonyl)methyl)azetidin-1yl)quinoline-4-carboxylate

A sample of ethyl 6-bromoquinoline-4-carboxylate (100 mg, 0.36

- 166 048 482 mmol), 3-methyl-3-((methylsulfonyl)methyl) _{azetidine hydrochloride (143 mg, 0.71 mmol), Cs2CO3 (} 465 mg, 1.43 mmol), XPhos (34 mg, 0.07 mmol) and _Pd2 (dba) ₃ (33 mg, 0.04 mmol). Dioxane (2 mL) was added and the reaction mixture was purged with N2 (g) for 10 min. The vial was sealed and the reaction mixture was stirred at 100 °C for 2 h. After cooling to rt, water (10 mL) and DCM (10 mL) were added and the reaction mixture was stirred, filtered through a phase separator and evaporated under reduced pressure. The residue was purified by straight-phase flash chromatography on silica gel (gradient: 10-100% EtOAc in heptane) to give the title compound (77 mg, 60%); MS (ESI) m/z [M+H]+ 363.21.

Intermediate 355. 6-(3-methyl-3-((methylsulfonyl)methyl)azetidin-1-yl)quinoline-4-carboxylic acid

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Aq. NaOH (1 M, 386 μL, 0.39 mmol) was added to a solution of ethyl 6-(3-methyl-3((methylsulfonyl)methyl)azetidin-1-yl)quinoline-4-carboxylate, intermediate 354 (70 mg, 0.19 mmol), in MeOH (2 mL). The reaction mixture was stirred at 50 °C for 20 min, then cooled to rt. Aq. HCl (3.8 M, 127 μL, 0.48 mmol) was added and the reaction mixture was stirred, evaporated under reduced pressure and co-evaporated under reduced pressure with EtOH (2x) and MeCN (1x) to give the crude title compound, MS (ESI) m/z [M+H] ⁺ 335.1.

Intermediate 356. tert-Butyl 6-(4-ethyl-4-hydroxypiperidin-1-yl)quinoline-4-carboxylate

Cs2CO3 (206 mg, 0.63 mmol) was added to a mixture of tert-butyl 6-bromoquinoline-4-carboxylate (150 mg, 0.49 mmol), 4-ethylpiperidin-4-ol hydrochloride (105 mg, 0.63 mmol), XPhos (46 mg, 0.10 mmol) and Pd ₂ (dba) ₃ (45 mg, 0.05 mmol) in 1,4-dioxane (10 mL) and the reaction mixture was stirred at 100 °C for 15 h. 4-Ethylpiperidin-4-ol hydrochloride (105 mg, 0.63 mmol), Cs ₂ CO ₃ (206 mg, 0.63 mmol), XPhos (46 mg, 0.10 mmol) and Pd ₂ (dba) ₃ (45 mg, 0.05 mmol) and the reaction mixture was stirred at 100 °C for an additional 24 h. The reaction mixture was filtered and the filtrate was concentrated under reduced pressure. The residue was purified by preparative TLC (EtOAc:petroleum ether; 3:2) to give the title compound (0.147 g, 85%) as a brown gum; MS (ESI) m/z [M+H] ⁺ 357.

Intermediate 357. 6-(4-ethyl-4-hydroxypiperidin-1-yl)quinoline-4-carboxylic acid

HCl in 1,4-dioxane (4 M, 5 mL) was added to a stirred solution of tert-butyl 6-(4-ethyl-4-hydroxypiperidin-1-yl)quinoline-4-carboxylate, intermediate 356 (130 mg, 0.36 mmol), in 1,4-dioxane (5 mL) and the reaction mixture was stirred at 50 °C for 15 h. The volatiles were removed under reduced pressure to give the title compound (0.105 g, 96%) as a red solid; MS (ESI) m/z [M+H] ⁺ 301.

Intermediate 358. tert-Butyl 6-(4-hydroxy-4-methylpiperidin-1-yl)quinoline-4-carboxylate

_Cs2CO3 (793 mg, 2.43 mmol) was added to a stirred solution of tert-butyl 6-bromoquinoline-4-carboxylate (250 mg, 0.81 mmol) _, 4-methylpiperidin-4-ol (140 mg, 1.22 mmol), XPhos (58 mg, 0.12 mmol) and Pd2(dba)3 (74 mg, 0.08 mmol) in 1,4-dioxane (10 mL) and stirred at 80 °C for 2 h. The volatiles were removed under reduced pressure, diluted with _EtOAc and washed with H2O. The organic layer was dried over _Na2SO4 , filtered and evaporated. The residue was purified by preparative TLC (EtOAc:petroleum ether; 1:1) to give the title compound.

- 167 048482 compounds (0.20 g, 72%) as a yellow solid; MS (ESI) m/z [M+H]+ 343.

Intermediate 359. 6-(4-hydroxy-4-methylpiperidin-1-yl)quinoline-4-carboxylic acid

A solution of DCM (6 mL) and TFA (3 mL) was added to tert-butyl 6-(4-hydroxy-4-methylpiperidin-1yl)quinoline-4-carboxylate, intermediate 358 (100 mg, 0.29 mmol), and stirred at rt for 2 h. The volatiles were removed under reduced pressure to give the title compound (0.084 g, 100%) as a yellow solid; MS (ESI) m/z [M+H]+ 287.

Intermediate 360. tert-Butyl 6-(4-ethyl-4-methoxypiperidin-1-yl)quinoline-4-carboxylate

_Cs2CO3 (634 mg, 1.95 mmol) was added to a mixture of tert-butyl 6-bromoquinoline-4-carboxylate (200 mg, 0.65 mmol) _, 4-ethyl-4-methoxypiperidine hydrochloride (128 mg, 0.71 mmol), XPhos (93 mg, 0.19 mmol) and _Pd2 (dba) ₃ (59 mg, 0.06 mmol) in 1,4-dioxane (10 mL) and stirred at 80 °C for 20 h. The volatiles were removed under reduced pressure, diluted with EtOAc (20 mL) and washed with H2O (20 mL). _The organic layer was dried over _Na2SO4 , filtered and evaporated. The residue was purified by preparative TLC (EtOAc:petroleum ether; 1:1) to give the title compound (0.20 g, 83%) as a yellow solid; MS (ESI) m/z [M+H]+ 371.

Intermediate 361. 6-(4-ethyl-4-methoxypiperidin-1-yl)quinoline-4-carboxylic acid

A solution of DCM (10 mL) and TFA (3 mL) was added to tert-butyl 6-(4-ethyl-4-methoxypiperidin-1yl)quinoline-4-carboxylate, intermediate 360 (100 mg, 0.29 mmol), and stirred at rt for 5 h. The solvent was removed under reduced pressure and the solid was further dried under vacuum to give the title compound (0.085 g, 100%) as a solid; MS (ESI) m/z [M+H]+ 315.

Intermediate 362. tert-Butyl 6-(4-hydroxy-4-isopropylpiperidin-1-yl)quinoline-4-carboxylate

_Cs2CO3 (275 mg, 0.84 mmol) was added to a mixture of tert-butyl 6-bromoquinoline-4-carboxylate (200 mg, 0.65 mmol) _, 4-isopropylpiperidin-4-ol (121 mg, 0.84 mmol), XPhos (62 mg, 0.13 mmol) and _Pd2 (dba) ₃ (59 mg, 0.06 mmol) in 1,4-dioxane (10 mL) and stirred at 100 °C for 15 h. The reaction mixture was filtered and the filtrate was concentrated under reduced pressure. The residue was purified by preparative TLC (EtOAc:petroleum ether; 3:2) to give the title compound (0.209 g, 87%) as a brown gum; MS (ESI) mass/charge [M+H]+ 371.

Intermediate 363. 6-(4-hydroxy-4-isopropylpiperidin-1-yl)quinoline-4-carboxylic acid

HCl in 1,4-dioxane (4 M, 5 ml) was slowly added to a stirred solution of tert-butyl 6-(4-hydroxy-4-isopropylpiperidin-1-yl)quinoline-4-carboxylate, intermediate 362 (185 mg, 0.50 mmol), in 1,4-dioxane (5 ml) at 28 °C and the reaction mixture was stirred at 50 °C for 15 h. The volatiles were removed under reduced pressure to give the title compound.

- 168 048482 niya (0.155 g, 91%) as a red solid; MS (ESI) m/z [M+H]+ 315.

Intermediate 364. tert-Butyl (3R,4s,5S)-4-hydroxy-3,4,5-trimethylpiperidine-1carboxylate

MeMgBr (120 mL, 360 mmol) was slowly added to a stirred solution of tert-butyl (3R,5S)-3,5-dimethyl-4-oxopiperidine-1-carboxylate (30.8 g, 136 mmol) in THF (500 mL) at 0 °C. The reaction mixture was allowed to slowly return to rt and stirred overnight. The reaction was quenched with saturated NH4Cl (aq) and extracted with EtOAc (3 x 400 mL). The combined organic layers were concentrated to give the title compound (33 g, 100%) as a white solid;

1H NMR (300 MHz, CDCl3) δ 3.95-3.55 (m, 2H), 2.80 - 2.55 (m, 2H), 1.58-1.50 (m, 2H), 1 .50 (s, 9H), 1.18 (s, 3H), 0.92-0.90 (m, 6H).

Intermediate 365. (3R,4s,5S)-3,4,5-trimethylpiperidin-4-ol

Methanolic HCl (400 mL) was added to a solution of tert-butyl (3R,4s,5S)-4-hydroxy-3,4,5-trimethylpiperidine-1-carboxylate, intermediate 364 (33 g, 0.23 mol), in MeOH (100 mL). The reaction mixture was stirred at rt for 5 h and then concentrated to give the title compound (24.5 g, 100%) as a white solid; MS (ESI) m/z [M+H] ⁺ 144.1.

Intermediate 366. tert-Butyl 6-((3R,4s,5S)-4-hydroxy-3,4,5-trimethylpiperidin-1yl)quinoline-4-carboxylate

_Cs2CO3 (137 mg, 0.42 mmol) was added to a mixture of tert-butyl 6-bromoquinoline-4-carboxylate ₍ 100 mg, 0.32 mmol), (3R,4s,5S)-3,4,5-trimethylpiperidin-4-ol, intermediate 365 (76 mg, 0.42 mmol), XPhos (30 mg, 0.06 mmol) and _Pd2 (dba) ₃ (30 mg, 0.03 mmol) in 1,4-dioxane (5 ml) at 25 °C. The resulting suspension was stirred at 100 °C for 23 h. The reaction mixture was filtered and the filtrate was concentrated under reduced pressure. The residue was purified by preparative TLC (EtOAc:petroleum ether; 1:1) to give the title compound (0.118 g, 98%) as an orange solid; MS (ESI) m/z [M+H] ⁺ 371.

Intermediate 367. 6-((3R,4s,5S)-4-hydroxy-3,4,5-trimethylpiperidin-1-yl)quinoline-4-carboxylic acid

HCl in dioxane (4 M, 5 mL) was slowly added to a stirred solution of tert-butyl 6((3R,4s,5S)-4-hydroxy-3,4,5-trimethylpiperidin-1-yl)quinoline-4-carboxylate, intermediate 366 (105 mg, 0.28 mmol), in 1,4-dioxane (5 mL) at 20 °C and the reaction mixture was stirred at 50 °C for 3 h. The volatiles were removed under reduced pressure to give the title compound (0.85 g, 95%) as a dark red solid; MS (ESI) m/z [M+H] ⁺ 315.

Intermediate 368. Ethyl 6-((1R,5S)-9-oxa-3-azabicyclo[3.3.1]nonan-3-yl)quinoline-4-carboxylate

A mixture of ethyl 6-bromoquinoline-4-carboxylate (0.098 g, 0.35 mmol), 9-oxa-3azabicyclo[3.3.1]nonane hydrochloride (0.074 g, 0.46 mmol), RuPhos Pd G4 (30 mg, 0.04 mmol), Cs ₂ CO ₃ (0.342 g, 1.05

- 169 048 482 mmol) and dioxane (0.9 mL) were degassed with 5 vacuum/N(gas) cycles and stirred vigorously at 90 °C for 17 h. The reaction mixture was allowed to return to rt and diluted with EtOAc (3 mL) and stirred with SilaMet S-thiol scavenger (0.15 g, 1.4 mmol/g) at rt for 7 h. The mixture was filtered through Celite® 521. The filter was washed with EtOAc and the combined filtrates were concentrated. The residue was purified by preparative HPLC, PrepMethod G (gradient: 35-75%) to give the title compound (0.085 g, 75%) as a yellow syrup; MS (ESI) mass/charge [M+H]+ 327.3.

Intermediate 369. 6-((1R,5S)-9-oxa-3-azabicyclo[3.3.1]nonan-3-yl)quinoline-4-carboxylic acid

NaOH (3.8 M, 156 μL, aq) was added to a solution of ethyl 6-((1R,5S)-9-oxa-3azabicyclo[3.3.1]nonan-3-yl)quinoline-4-carboxylate, intermediate 368 (77 mg, 0.24 mmol), in MeOH (2 mL) and the reaction mixture was stirred at 50 °C for 1 h. Aq. HCl (3 M, 125 μL) was added dropwise and the resulting mixture was concentrated and lyophilized from MeCN/H ₂ O to give the title compound (0.097 g) as a red solid; MS (ESI) m/z [M+H]+ 299.22.

Intermediate 370. 4-(4-chloroquinolin-6-yl)-1-methylpiperidin-4-ol

6-Bromo-4-chloroquinoline (1 g, 4 mmol) was dissolved in THF (25 mL) in a dried two-necked flask under argon, cooled to -70 °C, and n-BuLi (2.47 mL, 6.19 mmol) was slowly added dropwise such that the internal temperature did not exceed -65 °C. The reaction mixture was stirred for 1 h at -70 °C. 1-Methylpiperidin-4-one (0.70 g, 6.2 mmol) in THF (3 mL) was slowly added dropwise such that the internal temperature did not exceed -65 °C. The reaction mixture was stirred for 1 h at -70 °C and then allowed to return to rt and stirred for 3 h. The reaction mixture was diluted with EtOAc and washed with H2O. _The organic layer was dried over _Na2SO4 , filtered and concentrated. The residue was purified by preparative TLC (DCM:MeOH; 10:1) to give the title compound (0.30 g, 26%) as a pale yellow solid; MS (ESI) m/z [M+H]+ 277.

Intermediate 371. Methyl 6-(4-hydroxy-1-methylpiperidin-4-yl)quinoline-4-carboxylate

TEA (0.45 ml, 3.3 mmol) was added to a stirred solution of 4-(4-chloroquinolin-6-yl)-1-methylpiperidin-4-ol, intermediate 370 (300 mg, 1.08 mmol), Pd(OAc) ₂ (24 mg, 0.11 mmol), _PdCl2 (dppf) (40 mg, 0.05 mmol) and dppf (90 mg, 0.16 mmol) in MeOH (15 ml). The resulting mixture was stirred under CO(g) at 10 atm and 100°C for 12 h. The reaction mixture was filtered and the filtrate was concentrated in vacuo. The residue was purified by preparative TLC (DCM:MeOH; 10:1) to give the title compound (0.25 g, 77%) as a pale yellow solid; MS (ESI) m/z [M+H]+ 301.

Intermediate 372. Methyl 6-(4-fluoro-1-methylpiperidin-4-yl)quinoline-4-carboxylate

DAST (0.22 ml, 1.7 mmol) in DCM (2 ml) was added dropwise to a solution of methyl 6-(4-hydroxy-1-methylpiperidin-4-yl)quinoline-4-carboxylate, intermediate 371 (250 mg, 0.83 mmol), in DCM (10 ml) at 0 °C. The reaction mixture was allowed to return to rt and stirred for 2 h. The solvent was removed under reduced pressure and the reaction mixture was diluted with EtOAc and washed with H2O. The organic layer was dried over _Na2SO4 , filtered and evaporated. The residue was purified by preparative TLC (DCM: _MeOH ; 10:1) to give the title compound (0.25 g, 53%) as a white solid; MS (ESI) mass/charge [M+H]+ 303.

- 170 048482

Intermediate 373. 6-(4-fluoro-1-methylpiperidin-4-yl)quinoline-4-carboxylic acid

Methyl 6-(4-fluoro-1-methylpiperidin-4-yl)quinoline-4-carboxylate, intermediate 372 (230 mg, 0.55 mmol), and LiOH (132 mg, 5.52 mmol) were dissolved in a mixture of MeOH (8 mL) and H2O (2 mL). The reaction mixture was stirred at rt for 2 h and the volatiles were removed under reduced pressure. The reaction mixture was diluted with H2O and the pH was adjusted to ₆ with aq. HCl (0.1 M). EtOAc was added and the mixture was washed with H2O. The organic layer was dried over _Na2SO4 , filtered and evaporated to give the title compound (0.145 g, 91%) as a white solid; MS (ESI) mass/charge [M+H] ⁺ 289.

Intermediate 374. 6-(1H-pyrazol-5-yl)quinoline-4-carboxylic acid

A mixture of 1-(tetrahydro-2H-pyran-2-yl)-5-(4,4,5,5-tetramethyl-1,3,2-dioxαborolan-2-yl)-1H-pyrazole (59 mg, 0.21 mmol), 6-bromoquinoline-4-carboxylic acid (53 mg, 0.21 mmol) _{, Cs2CO3 (} 137 mg, 0.42 mmol) and Pd(dtbpf) _Cl2 (14 mg, 0.02 mmol) in 1,4-dioxane (1 mL) and H2O (0.250 mL) was stirred at rt overnight. The reaction mixture was diluted with DMSO and concentrated under reduced pressure. The compound was purified by preparative HPLC, PrepMethod E (gradient: 5-45%), to give the title compound (32 mg, 64%); MS (ESI) m/z [M+H] ⁺ 240.2.

Intermediate 375. 6-(1-isopropyl-1H-pyrazol-5-yl)quinoline-4-carboxylic acid

A mixture of 1-isopropyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrαzole (48 mg, 0.20 mmol), 6-bromoquinoline-4-carboxylic acid (51 mg, 0.20 mmol), _{Cs2CO3 (} 198 mg, 0.61 mmol) and Pd(dtbpf) _Cl2 (13 mg, 0.02 mmol) in 1,4-dioxane (1 mL) and H2O (0.25 mL) was stirred at rt overnight. The reaction mixture was concentrated under reduced pressure to give the title compound (56 mg); MS (ESI) m/z [M+H] ⁺ 282.2.

Intermediate 376. rac-tert-butyl (R)-6-(3-fluoro-3-methylpyrrolidin-1-yl)quinoline-4-carboxylate

_Cs2CO3 (587 mg, 1.80 mmol) was added to a mixture of tert-butyl 6-bromoquinoline-4-carboxylate ₍ 185 mg, 0.60 mmol), 3-fluoro-3-methylpyrrolidine hydrochloride (168 mg, 1.20 mmol) and _Pd2 (dba) ₃ (55 mg, 0.06 mmol), XPhos (57 mg, 0.12 mmol) in 1,4-dioxane (4 mL). The resulting suspension was stirred at 100 °C for 2 h. The reaction mixture was diluted with EtOAc and H2O (50 mL) and extracted with EtOAc (3 x 50 mL). The organic layers were combined and washed with brine (150 mL). _The organic layer was dried over _Na2SO4 , filtered and evaporated. The residue was purified by preparative TLC (EtOAc:petroleum ether; 1:1) to give the title compound (0.188 g, 95%) as a brown gum; MS (ESI) m/z [M+H] ⁺ 331.

Intermediate 377. rac-(R)-6-(3-fluoro-3-methylpyrrolidin-1-yl)quinoline-4-carbonic acid

TFA (2 ml) was added to rac-tert-butyl (R)-6-(3-fluoro-3-methylpyrrolidin-1-yl)quinoline-4-carboxylate, intermediate 376 (187 mg, 0.57 mmol), in DCM (2 ml) at 10 °C and stirred overnight. The volatiles were removed under reduced pressure to give the title compound (0.494 g) as a red gum; MS (ESI) m/z [M+H]+ 275.

- 171 048482

Intermediate 378. rac-(R)-6-(3-methyl-2-oxopyrrolidin-1-yl)quinoline-4-carboxylate

_Cs2CO3 (244 mg, 0.75 mmol) was added to a mixture of methyl 6-bromoquinoline-4-carboxylate ₍ 133 mg, 0.50 mmol), 3-methylpyrrolidin-2-one (64 mg, 0.65 mmol) and XPhosPd G3 (42 mg, 0.05 mmol) in 1,4-dioxane (7 mL) at 20 °C. The resulting suspension was stirred at 100 °C for 2 h and filtered through a pad of Celite®. The filtrate was concentrated under reduced pressure and the resulting residue was purified by preparative TLC (EtOAc:petroleum ether; 3:1) to give the title compound (0.55 g) as a beige solid; MS (ESI) m/z [M+H]+ 285.

Intermediate 379. rac-(R)-6-(3-methyl-2-oxopyrrolidin-1-yl)quinoline-4-carboxylic acid

NaOH (366 mg, 9.14 mmol) was added to a stirred solution of rac-(R)-6-(3-methyl-2-oxopyrrolidin-1-yl)quinoline-4-carboxylate, intermediate 378 (520 mg, 1.83 mmol), in MeOH (9 ml) and H2O (3 ml) at 20 °C and stirred for 1 h. The reaction mixture was acidified with aq. HCl (2 M). The aq. layer was extracted with EtOAc (6 x 50 ml), the combined organic layers were washed with H2O (3 x 25 ml) and _the organic layer was dried over _Na2SO4 , filtered and evaporated to give the title compound (0.31 g, 63%) as a beige oil; MS (ESI) mass/charge [M+H]+ 271.

Intermediate 380. rac-mert-butyl (R)-6-(3-methyl-2-oxopiperidin-1-yl)quinoline-4-carboxylate

_Cs2CO3 (634 mg, 1.95 mmol) was added to a mixture of tert-butyl 6-bromoquinoline-4-carboxylate ₍ 400 mg, 1.30 mmol), 3-methylpiperidin-2-one (588 mg, 5.19 mmol) and _Pd2 (dba) ₃ (12 mg, 0.01 mmol), XPhos (12 mg, 0.03 mmol) in 1,4-dioxane (20 mL). The resulting suspension was stirred at 100 °C for 24 h. The reaction mixture was filtered through silica gel and the volatiles were removed under reduced pressure.

The residue was purified by preparative TLC (EtOAc:petroleum ether; 4:1) to give the title compound (0.33 g, 75%) as a brown solid; MS (ESI) m/z [M+H]+ 341.20.

Intermediate 381. rac-(R)-6-(3-methyl-2-oxopiperidin-1-yl)quinoline-4-carboxylic acid

TFA (0.27 ml, 3.5 mmol) was added to a solution of rac-tert-butyl (R)-6-(3-methyl-2-oxopiperidin-1yl)quinoline-4-carboxylate, intermediate 380 (300 mg, 0.88 mmol), in DCM (5 ml) and stirred at 25 °C for 6 h. The volatiles were removed under reduced pressure and the solid was further dried under vacuum to give the title compound (0.33 g) as a brown solid; MS (ESI) m/z [M+H]+ 285.1.

Intermediate 382. tert-Butyl 6-(4-fluoropiperidin-1-yl)quinoline-4-carboxylate

_Cs2CO3 (977 mg, 3.00 mmol) was added to a mixture of tert-butyl 6-bromoquinoline-4-carboxylate ₍ 308 mg, 1.00 mmol), 4-fluoropiperidine hydrochloride (153 mg, 1.10 mmol), _Pd2 (dba) ₃ (92 mg, 0.10 mmol), XPhos (95 mg, 0.20 mmol) in 1,4-dioxane (1 mL). The resulting suspension was stirred at 100 °C for 2 h and filtered through Celite®. The solvent was removed under reduced pressure and the residue was purified by preparative TLC (EtOAc:petroleum ether; 2:1) to give the title compound (0.33 g, 100%) as a yellow gum; MS (ESI) m/z [M+H]+ 331.

Intermediate 383. 6-(4-fluoropiperidin-1-yl)quinoline-4-carboxylic acid

tert-Butyl 6-(4-fluoropiperidin-1-yl)quinoline-4-carboxylate, intermediate 382 (320 mg, 0.97 mmol), was added to a mixture of TFA (4.5 ml) in DCM (4.5 ml) and stirred at 20 °C for 15 h. The volatiles were removed under reduced pressure and the solid was further dried under vacuum to give the title compound (0.674 g) as a dark red gum; MS (ESI) m/z [M+H]+ 275.

Intermediate 384. tert-Butyl 6-(3-azabicyclo[3.1.0]hexan-3-yl)quinoline-4-carboxylate

_Cs2CO3 (977 mg, 3.00 mmol) was added to a mixture of tert-butyl 6-bromoquinoline-4-carboxylate ₍ 308 mg, 1.00 mmol), 3-azabicyclo[3.1.0]hexane hydrochloride (239 mg, 2.00 mmol), _Pd2 (dba) ₃ (92 mg, 0.10 mmol), XPhos (95 mg, 0.20 mmol) in 1,4-dioxane (3 mL). The resulting suspension was stirred at 100 °C for 2 h. The reaction mixture was diluted with DCM and concentrated under reduced pressure. The reaction mixture was partitioned between H2O and EtOAc, extracted with EtOAc (3 x 20 mL), and the organic phases were washed with brine (20 mL). _The organic phases were dried over _Na2SO4 , filtered and concentrated. The residue was purified by preparative TLC (EtOAc:petroleum ether; 1:1) to give the title compound (0.281 g, 91%) as a yellow solid; MS (ESI) m/z [M+H]+ 311.

Intermediate 385. 6-(3-azabicyclo[3.1.0]hexan-3-yl)quinoline-4-carboxylic acid

tert-Butyl 6-(3-azabicyclo[3.1.0]hexan-3-yl)quinoline-4-carboxylate, intermediate 384 (320 mg, 0.97 mmol), was added to a mixture of TFA (3 mL) in DCM (3 mL) and stirred at 10 °C overnight. The solvent was removed under reduced pressure and the solid was further dried under vacuum to give the title compound (0.435 g) as a red gum; MS (ESI) m/z [M+H]+ 255.

Intermediate 386. Methyl (S)-6-(3-methoxypyrrolidin-1-yl)quinoline-4-carboxylate

_Cs2CO3 (735 mg, 2.25 mmol) was added to a mixture of methyl 6-bromoquinoline-4-carboxylate ₍ 300 mg, 1.13 mmol), (S)-3-methoxypyrrolidine (171 mg, 1.69 mmol) and _Pd2 (dba) ₃ (10 mg, 0.01 mmol), XPhos (11 mg, 0.02 mmol) in 1,4-dioxane (10 mL). The resulting suspension was stirred at 100 °C for 2 h. The reaction mixture was concentrated under reduced pressure. The residue was purified by preparative TLC (EtOAc:petroleum ether; 1:1) to give the title compound (0.298 g, 92%) as a yellow solid; MS (ESI) mass/charge [M+H]+ 287.

Intermediate 387. (S)-6-(3-methoxypyrrolidin-1-yl)quinoline-4-carboxylic acid

Methyl (S)-6-(3-methoxypyrrolidin-1-yl)quinoline-4-carboxylate, intermediate 386 (270 mg, 0.94 mmol) and LiOH (132 mg, 5.52 mmol) were dissolved in a mixture of THF (5 mL) and H2O (5 mL) under air. The reaction mixture was stirred at 25 °C for 3 h. The solvent was removed under reduced pressure and the reaction mixture was diluted with _H2O and pH 5 was adjusted with aq. HCl (2 M). The reaction mixture was concentrated in vacuo to give the title compound (0.20 g, 78%) as a red solid; MS (ESI) m/z [M+H]+ 273.1.

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Intermediate 388. tert-Butyl 6-((1R,5S,6r)-6-(trifluoromethyl)-3azabicyclo[3.1.0]hexan-3-yl)quinoline-4-carboxylate

_Cs2CO3 (977 mg, 3.00 mmol) was added to a stirred suspension of tert-butyl 6-bromoquinoline-4-carboxylate ₍ 308 mg, 1.00 mmol), (1R,5S,6r)-6-(Ίfluoromethyl)-3azabicyclo[3.1.0]hexane hydrochloride (375 mg, 2.00 mmol), _Pd2 (dba) ₃ (92 mg, 0.10 mmol), XPhos (95 mg, 0.20 mmol) in 1,4-dioxane (3 mL). The resulting suspension was stirred at 100 °C for 2 h. The reaction mixture was diluted with DCM and concentrated under reduced pressure. The reaction mixture was diluted with EtOAc (50 mL) and washed with H2O (3x50 mL), _the organic layer was dried over _Na2SO4 , filtered and evaporated. The residue was purified by preparative TLC (EtOAc:petroleum ether; 1:1) to give the title compound (0.455 g, 92%) as a brown solid; MS (ESI) m/z [M+H]+ 379.

Intermediate 389. 6-((1R,5S,6r)-6-(trifluoromethyl)-3-azabicyclo[3.1.0]hexan-3yl)quinoline-4-carboxylic acid

tert-Butyl 6-((1R,5S,6r)-6-(trifluoromethyl)-3-azabicyclo[3.1.0]hexan-3-yl)quinoline-4-carboxylate, intermediate 388 (454 mg, 1.20 mmol), was added to a mixture of TFA (5 mL) in DCM (5 mL) and stirred at 13 °C overnight under air. The solvent was removed under reduced pressure and the solid was further dried under vacuum to give the title compound (0.728 g) as a red gum; MS (ESI) m/z [M+H]+ 323.

Intermediate 390. Methyl 6-(7-azabicyclo[2.2.1]heptan-7-yl)quinoline-4-carboxylate

_Cs2CO3 (1.47 g, 4.51 mmol) was added to a mixture of methyl 6-bromoquinoline-4-carboxylate ₍ 200 mg, 0.75 mmol), 7-azabicyclo[2.2.1]heptane hydrochloride (201 mg, 1.50 mmol) and Pd catalyst [CAS: 1810068-35-9] (43 mg, 0.04 mmol) in 1,4-dioxane (3 mL). The resulting suspension was stirred at 100 °C for 2 days. The reaction mixture was diluted with _H2O (50 mL), extracted with EtOAc (3x50 mL), the organic layers were washed with brine (200 mL), dried over _Na2SO4 , _filtered and concentrated under reduced pressure. The residue was purified by preparative TLC (EtOAc:petroleum ether; 1:1) to give the title compound (0.039 g, 18%) as a yellow solid; MS (ESI) m/z [M+H]+ 283.

Intermediate 391. 6-(7-azabicyclo[2.2.1]heptan-7-yl)quinoline-4-carboxylic acid

Methyl 6-(7-azabicyclo[2.2.1]heptan-7-yl)quinoline-4-carboxylate, intermediate 390 (36 mg, 0.13 mmol), and NaOH (25 mg, 0.63 mmol) were dissolved in a mixture of MeOH (3 mL) and H2O (1 mL) under air. The reaction mixture was stirred at 10 °C for 1 h. The solvent was removed under reduced pressure. The reaction mixture was diluted with H2O (20 mL) and pH 3 was adjusted with aq. HCl (1 M). The reaction mixture was diluted with H2O (10 mL) and extracted with EtOAc (6 x 30 mL), dried over Na2SO4, filtered and concentrated in vacuo. The material was purified by preparative HPLC, PrepMethod P (gradient: 5-17%), to give the title compound (0.030 g, 89%) as a yellow solid; MS (ESI) m/z [M+H]+ 269.

Intermediate 392. rac-tert-butyl 6-((1R,4S)-2-azabicyclo[2.2.1]heptan-2yl)quinoline-4-carboxylate

- 174 048482

_Cs2CO3 (651 mg, 2.00 mmol) was added to a mixture of tert-butyl 6-bromoquinoline-4-carboxylate (154 mg, 0.50 mmol) _, 2-azabicyclo[2.2.1]heptane (97 mg, 1.0 mmol) and Pd catalyst [CAS: 181006835-9] (29 mg, 0.02 mmol) in 1,4-dioxane (5 mL). The resulting suspension was stirred at 100 _° C for 24 h. 2-Azabicyclo[2.2.1]heptane (97 mg, 1.00 mmol) and _Cs2CO3 (651 mg, 2.00 mmol) were added and the suspension was stirred at 100 °C for an additional 18 h. The reaction mixture was diluted with EtOAc (10 mL) and filtered through Celite®, the filter pad was washed with EtOAc (3 x 2 mL) and the combined filtrate was concentrated in vacuo. The residue was purified by preparative TLC (EtOAc:petroleum ether; 2:1) to give the title compound (0.059 g, 36%) as a yellow gum; MS (ESI) m/z [M+H] ⁺ 325.

Intermediate 393. rac-6-((1R,4S)-2-azabicyclo[2.2.1]heptan-2-yl)quinoline-4-carboxylic acid tert-butyl 6-(2-azabicyclo[2.2.1]heptan-2-yl)quinoline-4-carboxylate, intermediate 392 (50 mg, 0.15 mmol), was added to a mixture of TFA (3 mL) in DCM (5 mL) and stirred at 10 °C overnight under air. The volatiles were removed under reduced pressure and the solid was further dried under vacuum to give the title compound (0.11 g) as a dark purple gum; MS (ESI) m/z [M+H] ⁺ 269.

Intermediate 394. tert-Butyl (R)-6-(2-methylpyrrolidin-1-yl)quinoline-4-carboxylate

_Cs2CO3 (634 mg, 1.95 mmol) was added to a mixture of tert-butyl 6-bromoquinoline-4-carboxylate ₍ 200 mg, 0.65 mmol), (R)-2-methylpyrrolidine (111 mg, 1.30 mmol) and Pd catalyst [CAS: 181006835-9] (37 mg, 0.03 mmol) in 1,4-dioxane (5 mL). The resulting suspension was stirred at 100 °C overnight. The solvent was removed under reduced pressure. The residue was purified by preparative TLC (EtOAc:petroleum ether; 3:1) to give the title compound (0.19 g, 94%) as a yellow gum; MS (ESI) mass/charge [M+H] ⁺ 313.3.

Intermediate 395. (R)-6-(2-methylpyrrolidin-1-yl)quinoline-4-carboxylic acid

O^/OH tert-Butyl (R)-6-(2-methylpyrrolidin-1-yl)quinoline-4-carboxylate, intermediate 394 (190 mg, 0.61 mmol), was added to a mixture of TFA (69 mg, 0.61 mmol) in DCM (5 mL) and stirred at 25 °C overnight under air. The solvent was removed under reduced pressure and the solid was further dried under vacuum to give the title compound (0.18 g) as a brown solid; MS (ESI) m/z [M+H] ⁺ 257.

Intermediate 396. tert-Butyl (S)-6-(2-(methoxymethyl)pyrrolidin-1-yl)quinoline-4-carboxylate

_Cs2CO3 (952 mg, 2.92 mmol) was added to a mixture of tert-butyl 6-bromoquinoline-4-carboxylate (300 mg, 0.97 mmol), (S)-2-(methoxymethyl)pyrrolidine (224 mg, 1.95 mmol) and _Pd catalyst [CAS: 1810068-35-9] (56 mg, 0.05 mmol) in 1,4-dioxane (15 mL). The resulting suspension was stirred at 100 °C for 8 h. The reaction mixture was filtered and the filtrate was concentrated under reduced pressure. The residue was purified by preparative TLC (EtOAc:petroleum ether; 2:1) to give the title compound (0.18 g, 54%) as a yellow solid; MS (ESI) mass/charge [M+H] ⁺ 343.

Intermediate 397. (S)-6-(2-(methoxymethyl)pyrrolidin-1-yl)quinoline-4-carboxylic acid o^one tert-butyl (S)-6-(2-(methoxymethyl)pyrrolidin-1-yl)quinoline-4-carboxylate, intermediate

- 175 048482 compound 396 (180 mg, 0.53 mmol) was added to a mixture of TFA (5 mL) in DCM (10 mL) and stirred at rt.

for 6 h under air. The solvent was removed under reduced pressure and the solid was further dried under vacuum to give the title compound (0.15 g, 100%) as a dark yellow solid; MS (ESI) m/z [M+H]+ 287.

Intermediate 398. tert-Butyl 6-((3S,4S)-3,4-difluoropyrrolidin-1-yl)quinoline-4-carboxylate

_Cs2CO3 (952 mg, 2.92 mmol) was added to a mixture of tert-butyl 6-bromoquinoline-4-carboxylate ₍ 300 mg, 0.97 mmol), (3S,4S)-3,4-difluoropyrrolidine (115 mg, 1.07 mmol) and _Pd2 (dba) ₃ (89 mg, 0.10 mmol), XantPhos (113 mg, 0.19 mmol) in 1,4-dioxane (6 mL). The resulting suspension was stirred at 100 °C for 2 h. The reaction mixture was concentrated under reduced pressure. The residue was purified by preparative TLC (EtOAc:petroleum ether; 1:1) to give the title compound (0.30 g, 92%) as a red solid; MS (ESI) mass/charge [M+H]+335.3.

Intermediate 399. 6-((3S,4S)-3,4-difluoropyrrolidin-1-yl)quinoline-4-carboxylic acid

tert-Butyl 6-((3S,4S)-3,4-difluoropyrrolidin-1-yl)quinoline-4-carboxylate, intermediate 398 (300 mg, 0.90 mmol), was added to a mixture of TFA (512 mg, 4.49 mmol) in DCM (5 mL) and stirred at 25 °C overnight under air. The solvent was removed under reduced pressure and the solid was further dried under vacuum to give the title compound (0.3 g) as a solid; MS (ESI) m/z [M+H]+ 279.2.

Intermediate 400. rac-tert-butyl 6-((3R,4R)-3,4-difluoropyrrolidin-1-yl)quinoline-4-carboxylate

_Cs2CO3 (952 mg, 2.92 mmol) was added to a mixture of tert-butyl 6-bromoquinoline-4-carboxylate ₍ 300 mg, 0.97 mmol), rac-(3R,4R)-3,4-difluoropyrrolidine (115 mg, 1.07 mmol) and _Pd2 (dba) ₃ (89 mg, 0.10 mmol), XantPhos (113 mg, 0.19 mmol) in 1,4-dioxane (8 mL). The resulting suspension was stirred at 100 °C for 2 h. The reaction mixture was concentrated under reduced pressure. The residue was purified by preparative TLC (EtOAc:petroleum ether; 2:1) to give the title compound (0.27 g, 83%) as a yellow solid; MS (ESI) mass/charge [M+H]+ 335.3.

Intermediate 401. rac-6-((3R,4R)-3,4-difluoropyrrolidin-1-yl)quinoline-4-carboxylic acid

rac-tert-butyl 6-((3R,4R)-3,4-difluoropyrrolidin-1-yl)quinoline-4-carboxylate, intermediate 400 (260 mg, 0.78 mmol), was added to a mixture of TFA (443 mg, 3.89 mmol) in DCM (5 mL) and stirred at 25 °C for 5 h under air. The solvent was removed under reduced pressure and the solid was further dried under vacuum to give the title compound (0.23 g, 100%) as a solid; MS (ESI) m/z [M+H]+ 279.2.

Intermediate 402. 6-(2,4-dimethyloxazol-5-yl)quinoline-4-carboxylic acid

A mixture of 2,4-dimethyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)oxazole (54 mg, 0.24 mmol), 6-bromoquinoline-4-carboxylic acid (61 mg, 0.24 mmol), _Cs2CO3 (237 mg, 0.73 mmol) and Pd(dtbpf) _Cl2 (13 mg, 0.02 mmol) in 1,4-dioxane (2 _mL ) and _H2O (0.5 mL) was stirred at rt overnight. The reaction mixture was concentrated under reduced pressure and purified by preparative HPLC, Prep

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Method E (gradient: 5-45%) to give the title compound (18 mg, 28%); MS (ESI) m/z [M+H]+ 269.

Intermediate 403. 6-(3,5-dimethylisoxazol-4-yl)quinoline-4-carboxylic acid

A mixture of (3,5-dimethylisoxazol-4-yl)boronic acid (37 mg, _0.26 mmol), 6-bromoquinoline-4-carboxylic acid (60 mg, 0.24 mmol), _Cs2CO3 (194 mg, 0.60 mmol) and Pd(dtbpf) _Cl2 (16 mg, 0.02 mmol) in 1,4-dioxane (2 mL) and H2O (0.5 mL) was stirred under argon at rt overnight. H2O was added to the reaction mixture and the aq. layer was extracted with EtOAc. The aq. layer was acidified with aq. HCl (2 M) to pH 3 and concentrated under reduced pressure to give the title compound, which was used in the next step without further purification; MS (ESI) mass/charge [M+H] ⁺ 269.2.

Intermediate 404. 6-(2-phenyl-1H-imidazol-1-yl)quinoline-4-carbonic acid

A mixture of 2-phenyl-1H-imidazole (86 mg, _{0.60 mmol), 6-bromoquinoline-4-carboxylic acid (100 mg, 0.40 mmol), Cs2CO3 (} 194 mg, 0.60 mmol) and _Cu2O (6 mg, 0.04 mmol) in DMF (3 mL) was stirred at 150 °C for 14 h. The reaction mixture was adjusted to pH 6 with aq. HCl (1 M) and filtered through a pad of Celite®. The reaction mixture was concentrated under reduced pressure and purified by preparative HPLC, PrepMethod B (gradient: 2-30%), to give the title compound (0.033 g, 26%) as a yellow solid; MS (ESI) m/z [M+H] ⁺ 316.

Intermediate 405. 6-(3-phenyl-1H-pyrrol-1-yl)quinoline-4-carboxylic acid

_K2CO3 (208 mg, 1.50 mmol) was added to a mixture of methyl 6-bromoquinoline-4-carboxylate ₍ 200 mg, 0.75 mmol), 3-phenyl-1H-pyrrole (161 mg, 1.13 mmol) and CuI (14 mg, 0.08 mmol) in DMF (10 mL). The resulting suspension was stirred at 150 °C for 15 h. The reaction mixture was concentrated under reduced pressure and diluted with _H2O , and the pH was adjusted to 6 with aq. HCl (1 M). The formed precipitate was collected by filtration, washed with H2O (30 mL) and the collected brown solid was dissolved in DMF (15 mL), the solids were filtered and the filtrate was concentrated under reduced pressure to give the title compound (0.15 g, 64%) as a brown solid; MS (ESI) m/z [M+H] ⁺ 315.

Intermediate 406. 6-(4,5,6,7-tetrahydro-1H-indol-1-yl)quinoline-4-carboxylic acid

A mixture of 4,5,6,7-tetrahydro-1H-indole (216 mg, 1.79 mmol), 6-bromoquinoline-4-carboxylic acid (300 mg, 1.19 mmol), _Cs2CO3 (1.16 g, 3.57 mmol) and EPhosPdG4 (109 mg, 0.12 mmol) in 1,4-dioxane (4 mL) was stirred at 100 _° C overnight. A second reaction batch was set up. A mixture of 4,5,6,7-tetrahydro-1H-indole (144 mg, 1.19 mmol), 6-bromoquinoline-4-carboxylic acid (200 mg, 0.79 mmol), Cs2CO3 (776 mg, 2.38 mmol) and EPhosPd G4 (73 mg, 0.08 mmol) in 1,4-dioxane (3 mL) was stirred at 100 °C overnight. The reaction mixture of the two batches was combined and filtered through Celite®, the pH was adjusted to 6 with aq. HCl (2 M) and the filtrate was filtered through Celite® and concentrated. The residue was purified by preparative TLC (DCM:MeOH; 5:1) to give the title compound (0.055 g, 14%) as a yellow solid; MS (ESI) mass/charge [M+H] ⁺ 293.

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Intermediate 407. tert-Butyl (R)-6-(3-(hydroxymethyl)pyrrolidin-1-yl)quinoline-4-carboxylate

_Cs2CO3 (634 mg, 1.95 mmol) was added to a mixture of tert-butyl 6-bromoquinoline-4-carboxylate ₍ 300 mg, 0.97 mmol), (R)-pyrrolidin-3-ylmethanol (118 mg, 1.17 mmol) and _Pd2 (dba) ₃ (89 mg, 0.10 mmol), XantPhos (77 mg, 0.19 mmol) in 1,4-dioxane (15 mL). The resulting suspension was stirred at 100 °C for 5 h. The reaction mixture was concentrated under reduced pressure and diluted with EtOAc (125 mL). The organic layer was washed with H2O (2x75 mL), sat. _NH4Cl solution (75 mL, aq), dried over _{Na2SO4 ,} filtered and concentrated under reduced pressure. The residue was purified by preparative TLC (DCM:MeOH; 10:1) to give the title compound (0.28 g, 88%) as a yellow oil; MS (ESI) m/z [M+H]+ 329.1.

Intermediate 408. (R)-6-(3-(hydroxymethyl)pyrrolidin-1-yl)quinoline-4-carboxylic acid

BUT Ογ°Η

Taj

HCl in 1,4-dioxane (4 M, 8 mL) was added slowly to tert-butyl (R)-6-(3(hydroxymethyl)pyrrolidin-1-yl)quinoline-4-carboxylate, intermediate 407 (200 mg, 0.61 mmol), and the reaction mixture was stirred at 20 °C for 12 h. The volatiles were removed under reduced pressure and the reaction mixture was diluted with EtOAc (75 mL). The organic layer was washed with H2O (15 mL), brine (20 _mL ), dried over _Na2SO4 , filtered and concentrated to give the title compound (0.10 g, 60%) as a red solid; MS (ESI) m/z [M+H]+ 273.

Intermediate 409. tert-Butyl (S)-6-(3-(hydroxymethyl)pyrrolidin-1-yl)quinoline-4-carboxylate

_Cs2CO3 (846 mg, 2.60 mmol) was added to a mixture of tert-butyl 6-bromoquinoline-4-carboxylate ₍ 400 mg, 1.30 mmol), (S)-pyrrolidin-3-ylmethanol (158 mg, 1.56 mmol) and _Pd2 (dba) ₃ (119 mg, 0.13 mmol), XantPhos (102 mg, 0.26 mmol) in 1,4-dioxane (3 mL). The resulting suspension was stirred at 100 °C for 5 h. The reaction mixture was concentrated under reduced pressure and diluted with EtOAc (125 mL). The organic layer was washed with H2O (50 mL), brine (75 _mL ), dried over _Na2SO4 , filtered and concentrated under reduced pressure. The residue was purified by preparative TLC (DCM:MeOH; 10:1) to give the title compound (0.357 g, 84%) as a yellow solid; MS (ESI) m/z [M+H]+ 329.1.

Intermediate 410. (S)-6-(3-(hydroxymethyl)pyrrolidin-1-yl)quinoline-4-carboxylic acid

HCl in 1,4-dioxane (4 M, 5 ml)

was slowly added to tert-butyl (S)-6-(3-hydroxymethyl)pyrrolidin-1-yl)quinoline-4-carboxylate, intermediate 409 (200 mg, 0.61 mmol), and the reaction mixture was stirred at 20 °C for 12 h. The volatiles were removed under reduced pressure and the reaction mixture was diluted with EtOAc (75 mL). The organic layer was washed with H2O (25 mL), brine (25 mL), dried over Na2SO4, filtered and concentrated to give the title compound (0.12 g, 72%) as a red solid; MS (ESI) m/z [M+H]+ 273.05.

Intermediate 411. Methyl 6-(1-thia-6-azaspiro[3.3]heptan-6-yl)quinoline-4-carboxylate

Cs ₂ CO ₃ (367 mg, 1.13 mmol) was added to a mixture of methyl 6-bromoquinoline-4-carboxylate (150 mg, 0.56

- 178 048482 mmol), 1-thia-6-azaspiro[3.3]heptane hydrochloride (171 mg, 1.13 mmol) and RuPhosPd G3 (94 mg, 0.11 mmol) in 1,4-dioxane (10 mL) at 35 °C. The resulting suspension was stirred at 100 °C for 15 h. Cs ₂ CO ₃ (367 mg, 1.13 mmol), 1-thia-6-azaspiro[3.3]heptane hydrochloride (171 mg, 1.13 mmol) and RuPhosPd G3 (94 mg, 0.11 mmol) were added and the reaction mixture was stirred at 100 °C for 20 h. The reaction mixture was filtered and the filtrate was concentrated under reduced pressure. The residue was purified by preparative TLC (EtOAc:petroleum ether; 6:5) to give the title compound (0.098 g, 58%) as a brown gum; MS (ESI) m/z [M+H]+ 301.

Intermediate 412. 6-(1-thia-6-azaspiro[3.3]heptan-6-yl)quinoline-4-carboxylic acid

To a solution of methyl 6-(1-thia-6-azaspiro[3.3]heptan-6-yl)quinoline-4-carboxylate, intermediate 411 (84 mg, 0.28 mmol), dissolved in MeOH (6 mL), was added a solution of NaOH (56 mg, 1.4 mmol) in _H2O (2 mL) under air at 0°C. The reaction mixture was stirred at 30°C for 1 h. The reaction mixture was diluted with H2O (10 mL) and the pH was adjusted to 6 with aq. HCl (2 M). The reaction mixture was diluted with H2O (10 mL) and extracted with EtOAc ( _6x75 mL), dried over _Na2SO4 , filtered and concentrated under reduced pressure to give the title compound (0.075 g, 94%) as an orange solid; MS (ESI) m/z [M+H]+ 287.

Intermediate 413. carboxylate

Methyl-6-(4-hydroxy-4-phenylpiperidin-1-yl)quinoline-4-

_Cs2CO3 (490 mg, 1.50 mmol) was added to a mixture of methyl 6-bromoquinoline-4-carboxylate (200 mg, 0.75 mmol) _, 4-phenylpiperidin-4-ol (266 mg, 1.50 mmol), XPhos (72 mg, 0.15 mmol) and _Pd2 (dba) ₃ (34 mg, 0.04 mmol) in 1,4-dioxane (8 mL). The resulting suspension was stirred at 90 °C for 2 h and filtered. The filtrate was concentrated under reduced pressure. EtOAc (25 mL) was added and the mixture was washed with water (2 x 15 mL), dried over _Na2SO4 , _filtered and concentrated under reduced pressure. The residue was purified by preparative TLC (EtOAc:petroleum ether; 2:1) to give the title compound (0.20 g, 73%) as a yellow solid; MS (ESI) m/z [M+H]+ 285.

Intermediate 414. Methyl 6-(4-fluoro-4-phenylpiperidin-1-yl)quinoline-4-carboxylate

DAST (146 µl, 1.10 mmol) was added dropwise to a solution of methyl 6-(4-hydroxy-4-phenylpiperidin-1-yl)quinoline-4-carboxylate, intermediate 413 (200 mg, 0.55 mmol), in DCM (10 ml) at -50 °C and stirred for 3 h. The residue was purified by preparative TLC (EtOAc:petroleum ether; 1:2) to give the title compound (0.15 g, 75%) as a yellow solid; MS (ESI) m/z [M+H]+ 365.

Intermediate 415. 6-(4-fluoro-4-phenylpiperidin-1-yl)quinoline-4-carboxylic acid

Methyl 6-(4-fluoro-4-phenylpiperidin-1-yl)quinoline-4-carboxylate, intermediate 414 (140 mg, 0.38 mmol), and LiOH (18 mg, 0.77 mmol) were dissolved in a mixture of MeOH (10 mL) and H2O (1 mL). The reaction mixture was stirred at 30 °C for 2 h and the volatiles were removed under reduced pressure. The reaction mixture was diluted with _H2O (15 mL) and the pH was adjusted to 6 with aq. HCl (1 M). The precipitate was collected by filtration, washed with H2O and dried in vacuo to give the title compound (0.115 g, 85%) as a yellow solid; MS (ESI) m/z [M+H]+ 351.

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Intermediate 416. rac-tert-butyl (R)-6-(3,3-difluoro-4-hydroxypyrrolidin-1yl)quinoline-4-carboxylate

_Cs2CO3 (634 mg, 1.95 mmol) was added to a mixture of tert-butyl 6-bromoquinoline-4-carboxylate (300 mg, 0.97 mmol) _, 4,4-difluoropyrrolidin-3-ol (144 mg, 1.17 mmol), DavePhos (77 mg, 0.19 mmol) and _Pd2 (dba) ₃ (89 mg, 0.10 mmol) in 1,4-dioxane (15 mL). The resulting suspension was stirred at 100 °C for 2 h and filtered. The reaction mixture was diluted with EtOAc (125 mL) and washed with water (75 mL), brine (75 mL), dried over _{Na2SO4 ,} filtered and concentrated under reduced pressure. The residue was purified by preparative TLC (DCM:MeOH; 5:1) to give the title compound (0.28 g, 82%) as a yellow solid; MS (ESI) m/z [M+H]+ 351.15.

Intermediate 417. rac-(R)-6-(3,3-difluoro-4-hydroxypyrrolidin-1-yl)quinoline-4-carboxylic acid

A solution of DCM (5 mL) and TFA (1.5 mL) was added to rac-tert-butyl (R)-6-(3,3-difluoro-4-hydroxypyrrolidin-1-yl)quinoline-4-carboxylate, intermediate 416 (160 mg, 0.46 mmol), and stirred at 20 °C for 16 h. The volatiles were removed under reduced pressure and the reaction mixture was diluted with DCM (75 mL), washed with H2O (25 mL), brine (25 _mL ), dried over _Na2SO4 , filtered and evaporated to give the title compound (0.12 g, 89%) as a red solid; MS (ESI) m/z [M+H]+ 295.0.

Intermediate 418. rac-tert-butyl 6-((3R,4R)-3,4-dimethylpyrrolidin-1-yl)quinoline-4-carboxylate

_Cs2CO3 (977 mg, 3.00 mmol) was added to a stirred solution of tert-butyl 6-bromoquinoline-4-carboxylate ₍ 308 mg, 1.00 mmol), rac-(3R,4R)-3,4-dimethylpyrrolidine hydrochloride (149 mg, 1.10 mmol), XPhos (95 mg, 0.20 mmol) and _Pd2 (dba) ₃ (92 mg, 0.10 mmol) in 1,4-dioxane (5 mL) and stirred at 100 °C for 2 h. The reaction mixture was filtered and the filtrate was washed with H2O (3 mL). The aq. layer was extracted with EtOAc (4 x 20 mL), the combined organic layers were washed with H2O (3 x 10 mL). _The organic layers were dried over _Na2SO4 , filtered and concentrated under reduced pressure. The residue was purified by preparative TLC (EtOAc:petroleum ether; 1:1) to give the title compound (0.307 g, 94%) as a yellow solid; MS (ESI) m/z [M+H]+ 327.

Intermediate 419. rac-6-((3R,4R)-3,4-dimethylpyrrolidin-1-yl)quinoline-4-carboxylic acid

TFA (5 ml) was added to a solution of rac-tert-butyl 6-((3R,4R)-3,4-dimethylpyrrolidin-1-yl)quinoline-4-carboxylate, intermediate 418 (270 mg, 0.83 mmol), in DCM (5 ml) and stirred at 6 °C for 15 h. The volatiles were removed under reduced pressure to give the title compound (0.493 g, 97%) as a dark red gum; MS (ESI) m/z [M+H]+ 271.

Intermediate 420. rac-tert-butyl (R)-6-(2-cyclopropylpyrrolidin-1-yl)quinoline-4-carboxylate

_Cs2CO3 (977 mg, 3.00 mmol) was added to a mixture of tert-butyl 6-bromoquinoline-4-carboxylate (308 mg, 1.00 mmol), rac-(R)-2-cyclopropylpyrrolidine hydrochloride (162 mg, 1.10 mmol), and Pd catalyst [CAS: 1810068-35-9] (57 mg, 0.05 mmol) in 1,4-dioxane (5 mL). The resulting suspension was

- 180 048482 was stirred at 100 °C for 48 h. The reaction mixture was diluted with EtOAc (10 mL) and filtered through Celite®, the filter pad was washed with EtOAc (3 x 2 mL) and the combined filtrates were concentrated under reduced pressure. The residue was purified by preparative TLC (EtOAc:petroleum ether; 1:1) to give the title compound (0.192 g, 57%) as a yellow solid; MS (ESI) m/z [M+H] ⁺ 339.

Intermediate 421. rac-(R)-6-(2-cyclopropylpyrrolidin-1-yl)quinoline-4-carboxylic acid

rac-tert-butyl (R)-6-(2-cyclopropylpyrrolidin-1-yl)quinoline-4-carboxylate, intermediate 420 (180 mg, 0.53 mmol), was added to a mixture of TFA (5 mL) in DCM (5 mL) and stirred at 10 °C for 15 h. The volatiles were removed under reduced pressure and the solid was further dried under vacuum to give the title compound (0.37 g, 100%) as a red gum; MS (ESI) m/z [M+H] ⁺ 283.

Intermediate 422. Methyl 6-bromoquinoline-4-carboxylate hydrochloride

A solution of 6-bromoquinoline-4-carboxylic acid (3.0 g, 12 mmol) in MeOH (70 mL) was added dropwise to stirred _SOCl2 (7.08 g, 59.5 mmol) over a period of 25 min. The reaction mixture was heated at 60 °C for 13 h. The reaction mixture was concentrated under reduced pressure to give the title compound (3.50 g, 97%) as a yellow solid; MS (ESI) m/z [M+H] ⁺ 266.

Intermediate 423. Methyl 6-(1,5-dioxa-9-azaspiro[5.5]undecan-9-yl)quinoline-4-carboxylate

_Cs2CO3 (490 mg, 1.50 mmol) was added to a mixture of methyl 6-bromoquinoline-4-carboxylate ₍ 200 mg, 0.75 mmol), 1,5-dioxa-9-azaspiro[5.5]undecane (236 mg, 1.50 mmol), _Pd2 (dba) ₃ (69 mg, 0.08 mmol) and SPhos (62 mg, 0.15 mmol) in 1,4-dioxane (4.0 mL) at 15 °C and the reaction mixture was stirred at 100 °C for 2 h under N2 (g). The solvent was removed under reduced pressure. The residue was diluted with water (30 mL) and the aqueous phase was extracted with EtOAc (3x50 mL). _The combined organic layer was dried over _Na2SO4 , filtered and evaporated under reduced pressure. The crude product was purified by preparative TLC (EtOAc:petroleum ether, 1:1) to give the title compound (0.25 g, 97%) as an orange gum; MS (ESI) m/z [M+H] ⁺ 343.1.

Intermediate 424. 6-(1,5-dioxa-9-azaspiro[5.5]undecan-9-yl)quinoline-4-carboxylic acid

NaOH (146 mg, 3.65 mmol) was added to a solution of methyl 6-(1,5-dioxa-9-azaspiro[5.5]undecan-9-yl)quinoline-4-carboxylate, intermediate 423 (250 mg, 0.73 mmol), in MeOH (9.0 mL) and water (3.0 mL) at 15 °C and the reaction mixture was stirred at 15 °C for 1 h. The solvent was removed under reduced pressure. The residue was diluted with water (10 mL) and the pH was adjusted to 3 with aq. HCl (1 M). The aqueous phase was extracted with EtOAc (3x50 mL) and _the combined organic layer was dried over _Na2SO4 , filtered and evaporated to give the title compound (0.221 g, 92%) as an orange solid; MS (ESI) m/z [M+H] ⁺ 329.0.

Intermediate 425. Methyl 6-(1,4-dioxa-8-azaspiro[4.5]decan-8-yl)quinoline-4-carboxylate

Cs ₂ CO ₃ (490 mg, 1.50 mmol) was added to a mixture of methyl 6-bromoquinoline-4-carboxylate (200 mg, 0.75

- 181 048482 mmol), 1,4-dioxa-8-azaspiro[4.5]decane (215 mg, 1.50 mmol), Pd ₂ (dba) ₃ (69 mg, 0.08 mmol) and SPhos (62 mg, 0.15 mmol) in 1,4-dioxane (5.0 mL) at 25 °C and the reaction mixture was stirred at 100 °C for 2 h under N2 (g). The solvent was removed under reduced pressure. The residue was diluted with water (50 mL) and the aqueous phase was extracted with EtOAc (3x50 mL). The combined organic layer was dried over Na ₂ SO ₄ , filtered and evaporated under reduced pressure. The residue was purified by preparative TLC (EtOAc:petroleum ether, 1:1) to give the title compound (0.104 g, 42%) as a brown gum; MS (ESI) m/z [M+H]+ 329.0.

Intermediate 426. 6-(1,4-dioxa-8-azaspiro[4.5]decan-8-yl)quinoline-4-carboxylic acid

NaOH (60 mg, 1.50 mmol) was added to a solution of methyl 6-(1,4-dioxa-8-azaspiro[4.5]decan-8-yl)quinoline-4-carboxylate, intermediate 425 (99 mg, 0.30 mmol), in MeOH (9.0 ml) and water (3.0 ml) at 15 °C and the reaction mixture was stirred at 15 °C for 1 h. The solvent was removed under reduced pressure. The residue was diluted with water (20 ml) and the pH was adjusted to 3 with aq. HCl (1 M). The aqueous phase was extracted with EtOAc (3 x 50 ml) and the combined organic layer was dried over Na ₂ SO ₄ , filtered and evaporated to give the crude title compound (0.137 g) as an orange solid; MS (ESI) mass/charge [M+H] ⁺ 315.

Intermediate 427. Methyl 6-(2-oxa-7-azaspiro[3.5]nonan-7-yl)quinoline-4-carboxylate

_Cs2CO3 (918 mg, 2.82 mmol) was added to methyl 6-bromoquinoline-4-carboxylate ₍ 300 mg, 1.13 mmol), 2-oxa-7-azaspiro[3.5]nonane oxalate (490 mg, 2.25 mmol) and SPhosPdG3 (98 mg, 0.11 mmol) in 1,4-dioxane (5 mL) at 15 _° C and the reaction mixture was stirred at 100 °C for 16 h under _N2 (g). _Cs2CO3 (367 mg, 1.13 mmol) and SPhosPdG3 (98 mg, 0.11 mmol) were added and the reaction mixture was stirred at 100 °C for additional 5 h. The solvent was removed under reduced pressure. The residue was diluted with water (50 mL) and extracted with EtOAc (3 x 50 mL). The combined organic layer was dried over Na2SO4, filtered and evaporated. The residue was purified by preparative TLC (EtOAc:petroleum ether, 2:1) to give the title compound (0.142 g, 40%) as a brown gum; MS (ESI) m/z [M+H] ⁺ 313.1.

C. End connections

Example 1. (R)-N-(2-(4-cyanothiazolidin-3-yl)-2-oxoethyl)-6-(1,2-oxazinan-2-yl)quinoline-4-carboxamide

DIPEA (0.15 mL, 0.87 mmol) was added to a mixture of 6-(1,2-oxazinan-2-yl)quinoline-4-carboxylic acid, intermediate 6 (45 mg, 0.17 mmol), (R)-3-glycylthiazolidine-4-carbonitrile hydrochloride, intermediate 4 (54 mg, 0.26 mmol), and HATU (79 mg, 0.21 mmol) in EtOAc (1.5 mL) and MeCN (1.5 mL). The mixture was stirred at rt for 4 h. The mixture was diluted with EtOAc, washed successively with water and saturated NaHCO ₃ solution. The organic phase was dried, filtered and evaporated. The residue was purified by straight phase flash chromatography on silica gel (gradient: 0-10% MeOH in EtOAc). The appropriate fractions were combined and evaporated to give a yellow oil. The oil was dissolved in MeCN:water and lyophilized overnight to give the title compound ( ₆₅ mg, 91%) as a loose yellow powder; HRMS (ESI) m/z _[ M+ _H ] ⁺ calcd for _C20H22N5O3S : 412.1438 found: 412.1438;

^1H NMR (500 MHz, DMSO- _d6 ) δ 9.02 (brs, 1H), 8.78 (d, 1H), 7.95 (d, 1H), 7.85 (d, 1H), 7 .62 (dd, 1H), 7.48 (d, 1H), 5.34 - 5.31 (m, 1H), 4.88 (d, 1H), 4.71 (d, 1H), 4.31 (d, 2H), 4.09 (t, 2H), 3.55 (t, 2H), 3.46 - 3 .35 (m, 2H), 1.91 - 1.83 (m, 2H), 1.72 - 1.65 (m, 2H).

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Example 2. (R)-N-(2-(4-cyanothiazolidin-3-yl)-2-oxoethyl)-3-fluoro-6-morpholino-quinoline-4-carboxamide

H?

O^, I I J—/

N

DIPEA (0.33 mL, 1.9 mmol) was added to a mixture of 3-fluoro-6-morpholinoquinoline-4-carboxylic acid, intermediate 8 (172 mg, 0.62 mmol), ((S)-3-glycylthiazolidine-4-carbonitrile hydrochloride, intermediate 4 (129 mg, 0.62 mmol), and HATU (308 mg, 0.81 mmol) in EtOAc (3 mL) and MeCN (3 mL). The mixture was stirred at rt for 3 h. The mixture was diluted with EtOAc, washed successively with water and saturated NaHCO ₃ solution. The organic phase was dried, filtered and evaporated. The residue was purified by silica gel straight phase flash chromatography (gradient: 75-100% EtOAc in heptane) and then further purified using preparative HPLC, PrepMethod SFC-D, to give the title compound (60 mg, 22%); HRMS (ESI) m/z [M+H]+ calcd for C ₂₀ H ₂₁ FN ₅ O ₃ S: 430.1344 found: 430.1318;

1H NMR (600 MHz, DMSO- _d6 ) δ 9.28 (t, 1H), 8.70 (s, 1H), 7.93 (d, 1H), 7.65 (dd, 2H), 5, 33 (dd, 1H), 4.90 (d, 1H), 4.71 (d, 1H), 4.41 (dd, 1H), 4.32 (dd, 1H), 3.80 (t, 4H), 3.44 - 3.36 (m, 6H).

Example 3: (R)-N-(2-(4-cyanothiazolidin-3-yl)-2-oxoethyl)-6-thiomorpholinoquinoline-4-carboxamide

DIPEA (0.16 mL, 0.91 mmol) was added to a mixture of 6-thiomorpholinoquinoline-4-carboxylic acid, intermediate 10 (50 mg, 0.18 mmol), (R)-3-glycylthiazolidine-4-carbonitrile hydrochloride, intermediate 4 (38 mg, 0.18 mmol), and HATU (83 mg, 0.22 mmol) in EtOAc (1.5 mL) and MeCN (1.5 mL). The mixture was stirred at rt overnight. The mixture was diluted with EtOAc, washed successively with water and saturated _NaHCO3 solution. The organic phase was dried, filtered and evaporated. The residue was purified by straight-phase flash chromatography on silica gel (gradient: 0-10% MeOH in EtOAc). The appropriate fractions were combined and evaporated to give a yellow oil. The oil was dissolved in MeCN/water and lyophilized overnight to give the title compound (55 mg, 71%) as a loose yellow powder; HRMS (ESI) m/z [ _M + _H ] ⁺ calcd for _C20H22N5O2S2 : _428.1210 found: _428.1210 ;

1H NMR (500 MHz, DMSO-d6) δ 9.01 (t, 1H), 8.67 (d, 1H), 7.89 (d, 1H), 7.73 (d, 1H), 7.64 (dd, 1H), 7.39 (d, 1H), 5.33 (dd, 1H), 4.89 (d, 1H), 4.71 (d, 1H), 4.37 - 4.25 (m, 2H), 3.79 (t, 4H), 3.44 - 3.35 (m, 2H), 2.71 (ddt, 4H).

Example 4. (R)-N-(2-(4-cyanothiazolidin-3-yl)-2-oxoethyl)-6-(2,2-difluoromorpholino)quinoline-4-carboxamide

DIPEA (0.13 mL, 0.75 mmol) was added to a mixture of 6-(2,2-difluoromorpholino)quinoline-4-carboxylic acid, intermediate 12 (74 mg, 0.25 mmol), (R)-3-glycylthiazolidine-4-carbonitrile hydrochloride, intermediate 4 (52 mg, 0.25 mmol), and HATU (124 mg, 0.33 mmol) in EtOAc (2 mL) and MeCN (2 mL). The mixture was stirred at rt for 3 h. The mixture was diluted with EtOAc, washed successively with water and saturated NaHCO3 solution. The organic phase was dried, filtered and evaporated. The residue was purified by silica gel flash chromatography (gradient: 0-10% MeOH in EtOAc) and then further purified using preparative HPLC, PrepMethod SFC-D, to give the title compound (40 mg, 36%); HRMS (ESI) m/z [M+H] ⁺ calcd for C ₂₀ H ₂₀ F ₂ N ₅ O ₃ S: 448.1250 found: 448.1252;

1H NMR (600 MHz, DMSO- _d6 ) δ 9.08 (t, 1H), 8.76 (d, 1H), 7.97 (d, 1H), 7.84 (d, 1H), 7. 75 (dd, 1H), 7.47 (d, 1H), 5.32 (dd, 1H), 4.91 (d, 1H), 4.73 (d, 1H), 4.38 - 4.29 (m, 2H), 4.29 - 4.23 (m, 2H), 3.89 - 3.80 (m , 2H), 3.61 -3.54 (m, 2H), 3.45 - 3.35 (m, 2H).

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Example 5. (R)-N-(2-(4-cyanothiazolidin-3-ul)-2-oxoethyl)-6-(2,2,6,6-tetrafluoromorpholino)quinolin4-carboxamide

DIPEA (0.14 mL, 0.83 mmol) was added to a mixture of 6-(2,2,6,6-tetrafluoromorpholino)quinoline-4-carboxylic acid, intermediate 14 (55 mg, 0.17 mmol), (R)-3-glycylthiazolidine-4-carbonitrile hydrochloride, intermediate 4 (52 mg, 0.25 mmol), and HATU (76 mg, 0.20 mmol) in EtOAc (1.5 mL) and MeCN (1.5 mL). The mixture was stirred at rt overnight. The mixture was diluted with EtOAc and washed successively with water and saturated NaHCO ₃ solution. The organic phase was dried, filtered and evaporated. The residue was purified by direct phase flash chromatography on silica gel (gradient: 0-10% MeOH in EtOAc) and then further purified using preparative HPLC, PrepMethod SFC-D, to give the title compound (20 mg, 25%); HRMS (ESI) m/z [M+H]+ calcd for C ₂₀ H ₁₈ F ₄ N ₅ O ₃ S: 484.1060 found: 484.1052;

Ή NMR (600 MHz, DMSO-d ₆ ) δ 9.11 (t, 1H), 8.80 (d, 1H), 8.01 (d, 1H), 7.98 (d, 1H), 7.81 (dd, 1H), 7.48 (d, 1H), 5.28 (dd, 1H), 4.92 (d, 1H), 4.73 (d, 1H), 4.40 - 4.30 (m, 2H), 4.29 -4.21 (m, 4H), 3.47 - 3.36 (m, 2H, overlaps with solvent peak).

Example 6. (R)-N-(2-(4-cyanothiazolidin-3-yl)-2-oxoethyl)-6-(2,3-dihydro-4H-benzo[b][1,4]oxazin4-yl)quinoline-4-carboxamide

DIPEA (0.14 ml, 0.80 mmol) was added to a mixture of 6-(2,3-dihydro-4H-benzo[b][1,4]oxazin-4-yl)quinoline-4-carboxylic acid, intermediate 16 (49 mg, 0.16 mmol), (R)-3-glycylthiazolidine-4-carbonitrile hydrochloride, intermediate 4 (50 mg, 0.24 mmol), and HATU (73 mg, 0.19 mmol) in EtOAc (1.5 ml) and MeCN (1.5 ml). The mixture was stirred at rt overnight. The mixture was diluted with EtOAc and washed successively with water and saturated NaHCO ₃ solution. The organic phase was dried, filtered and evaporated. The residue was purified by straight phase flash chromatography on silica gel (gradient: 0-10% MeOH in EtOAc). The appropriate fractions were combined and evaporated to give a yellow oil. The oil was dissolved in MeCN/water and lyophilized overnight to give the title compound (59 mg, 80%) as a loose yellow powder; HRMS (ESI) m/z [M+H]+ calcd for C ₂₄ H22N ₅ O ₃ S: 460.1438 found: 460.1428;

^1H NMR (500 MHz, DMSO- _d6 ) δ 9.06 (t, 1H), 8.84 (d, 1H), 8.11 (d, 1H), 8.02 (d, 1H), 7 .81 (dd, 1H), 7.53 (d, 1H), 7.05 (dd, 1H), 6.88 (dd, 1H), 6.85 - 6.72 (m, 2H), 5.32 (dd, 1H), 4.87 (d, 1H), 4.70 (d, 1H), 4.30 ( t, 4H), 3.86 (q, 2H), 3.39 (dd, 2H).

Example 7. N-(2-((R)-4-cyanothiazolidin-3-yl)-2-oxoethyl)-6-((3S,4S,5R)-4-hydroxy-3,5-dimethylpiperidin-1-yl)quinoline-4-carboxamide

DIPEA (0.052 ml, 0.30 mmol) was added to a mixture of 6-((3S,4s,5R)-4-hydroxy-3,5-dimethylpiperidin-1yl)quinoline-4-carboxylic acid, intermediate 18 (18 mg, 0.06 mmol), (R)-3-glycylthiazolidine-4-carbonitrile hydrochloride, intermediate 4 (19 mg, 0.09 mmol), and HATU (27 mg, 0.07 mmol) in EtOAc (1.5 ml) and MeCN (1.5 ml). The mixture was stirred at rt overnight and then diluted with EtOAc, washed successively with water and saturated NaHCO ₃ solution. The organic phase was dried, filtered and evaporated. The residue was purified by silica gel straight phase flash chromatography (gradient: 0-10% MeOH in EtOAc) and then further purified by preparative HPLC, PrepMethod SFC-A, to give the title compound (5 mg, 18%); HRMS (ESI) m/z [M+H]+ calcd for C ₂₃ H ₂₈ N ₅ O ₃ S: 454.1908 found: 454.1886;

1H NMR (600 MHz, DMSO- _d6 ) δ 8.98 (t, 1H), 8.63 (d, 1H), 7.86 (d, 1H), 7.70 - 7.60 (m, 2H ), 7.37 (d, 1H), 5.30 (dd, 1H), 4.89 (d, 1H), 4.73 (d, 1H), 4.48 (brs, 1H), 4.35 - 4.25 (m, 2H), 3.60 -3.50 (m, 3H), 2.74 (t, 4H),

- 184 048482

1.85 - 1.75 (m, 2H), 0.98 (dd, 6H).

Example 8. (R)-N-(2-(4-cyanothiazolidin-3-yl)-2-oxoethyl)-6-(4-methoxypiperidin-1-yl)quinoline-4-carboxamide

DIPEA (0.24 ml, 1.4 mmol) was added to 6-(4-methoxypiperidin-1-yl)quinoline-4-carboxylic acid, intermediate 20 (200 mg, 0.70 mmol), (R)-3-glycylthiazolidine-4-carbonitrile hydrochloride, intermediate 4 (179 mg, 1.05 mmol), and HATU (266 mg, 0.70 mmol) in MeCN (5 ml) and EtOAc (5 ml) at 20 °C under air. The resulting mixture was stirred at 20 °C for 4 h. The reaction mixture was concentrated and the residue was dissolved in EtOAc (100 ml) and washed successively with saturated NaHCO ₃ solution (25 ml), brine (50 ml), and water (25 ml). _The organic layer was dried over _Na2SO4 , filtered and evaporated. The crude product was purified by preparative HPLC, PrepMethod F (gradient: 12-37%) to afford the title compound (70 mg, 23%) as a red solid; HRMS (ESI) m/z [M ₊ H]+ calcd for _C22H26N5O3S : 440.1750 found: _{440.1744 ;}

1H NMR (500 MHz, DMSO-d6) δ 9.14 (t, 1H), 8.78 (d, 1H), 7.95 (d, 1H), 7.84 - 7.71 (m, 2H), 7.57 (d, 1H), 5.33 (dd, 1H), 4.91 (d, 1H), 4.72 (d, 1H), 4.40 - 4.27 (m, 2H), 3.79 - 3.71 (m, overlaps with solvent peak), 3.47 - 3.33 (m, 3H), 3.29 (s, 3H), 3.22 - 3.07 (m, 2H), 2.03 - 1.94 (m, 2H), 1.60-1.50 (m, 2H).

Example 9

DIPEA (0.205 mL, 1.18 mmol) was added to 8-methyl-6-morpholinoquinoline-4-carboxylic acid, intermediate 25 (160 mg, 0.59 mmol), (R)-3-glycylthiazolidine-4-carbonitrile hydrochloride, intermediate 4 (151 mg, 0.88 mmol), and HATU (223 mg, 0.59 mmol) in MeCN (5 mL) and EtOAc (5 mL) at 20 °C. The resulting mixture was stirred at 20 °C for 3 h. The reaction mixture was concentrated, diluted with EtOAc (75 mL), and washed successively with sat. NaHCO3 solution (20 mL), water (15 mL), and brine (20 mL). _The organic layer was dried over _Na2SO4 , filtered and evaporated to give the crude product. The crude product was purified by preparative _{HPLC, PrepMethod F (gradient: 12-35%) to give the title compound (50 mg, 20%) as a red solid; HRMS (ESI) m/z [M+H]+ calcd for C21H24N5O3S : 426.1594} found: 426.1600 _;

1H NMR (400 MHz, DMSO-d6) δ 9.17 (t, 1H), 8.81 (d, 1H), 7.77 (s, 1H), 7.68 - 7.62 (m, 2H), 5.32 (dd, 1H), 4.90 (d, 1H), 4.71 (d, 1H), 4.42 - 4.25 (m, 2H), 3.79 (t, 4H), 3.46 - 3.32 (m, overlaps with solvent peak), 2.73 (s, 3H).

Example 10. (R)-N-(2-(4-cyanothiazolidin-3-yl)-2-oxoethyl)-7-methyl-6-morpholino-quinoline-4-carboxamide

DIPEA (0.31 mL, 1.8 mmol) was added to 7-methyl-6-morpholinoquinoline-4-carboxylic acid, intermediate 30 (160 mg, 0.59 mmol), (R)-3-glycylthiazolidine-4-carbonitrile hydrochloride, intermediate 4 (151 mg, 0.88 mmol), and T3P (50% solution in EtOAc, 712 mg, 2.24 mmol) in EtOAc (1 mL) and MeCN (1 mL) at 20 °C under N2 (g). The resulting mixture was stirred at 20 °C for 4 h. The reaction mixture was concentrated, and the residue was dissolved in EtOAc (75 mL) and washed successively with brine (25 mL) and water (25 mL). The organic layer was dried over Na2SO4, filtered and evaporated. The crude product was purified by preparative HPLC, PrepMethod F (gradient: _12-35 %) to afford the title compound (50 mg, 20%) as a yellow solid; HRMS (ESI) m/z [M _{+H]+ calcd for C21H24N5O3S :} 426.1594 found: _426.1582 ;

1H NMR (400 MHz, DMSO-d ₆ ) δ 9.05 (t, 1H), 8.80 (d, 1H), 7.91 (s, 1H), 7.88 (s, 1H), 7.45 (d, 1H), 5.35 (dd, 1H), 4.90 (d, 1H), 4.72 (d, 1H), 4.32 (t, 2H), 3.79 (t, 4H), 3.45 - 3.35 (m, overlaps with solvent peak), 3.10 - 2.90 (m, 4H), 2.54 - 2.46 (m, overlaps with solvent peak).

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Example 11. (R)-N-(2-(4-cyanothiazolidin-3-yl)-2-oxoethyl)-6-(2-oxopyrrolidin-1-yl)quinoline-4-carboxamide

DIPEA (1.8 ml, 10 mmol) was added to a stirred suspension of 6-(2-oxopyrrolidin-1yl)quinoline-4-carboxylic acid, intermediate 32 (224 mg, 0.52 mmol), (R)-3-glycylthiazolidine-4-carbonitrile hydrochloride, intermediate 4 (214 mg, 1.03 mmol), HOBt (395 mg, 2.58 mmol) and EDC (494 mg, 2.58 mmol) in MeCN (5 ml) and EtOAc (5 ml) at 29 °C. The resulting solution was stirred at 50 °C for 2 h. The solvent was removed under reduced pressure. The residue was dissolved in a mixture of NaHCO ₃ (aq, 40 ml) and EtOAc (80 ml). The phases were separated and the aqueous layer was extracted with EtOAc (5x75 mL). _The organic layers were combined and washed with water (3x50 mL). The organic layer was dried over _Na2SO4 , filtered and evaporated to give the crude product. The crude product was purified by preparative HPLC, PrepMethod F (gradient: 15-30%) to give the title compound ( ₉₀ mg, _{43%) as a white solid; HRMS (ESI) m/z [M+H] + calcd for C20H20N5O3S :} ^410.1282 _found : 410.1288;

1H NMR (300 MHz, DMSO-d6) δ 9.10 (t, 1H), 8.90 (d, 1H), 8.55 (dd, 1H), 8.31-8.16 (m, 1H), 8.07 (d, 1H), 7.56 (d, 1H), 5.43 - 5.24 (m, 1H), 4.90 (m, 1H), 4.77 (d, 1H), 4.50 - 4.16 (m, 2H), 4.07 - 3.89 (m, 2H), 3.70 - 3.20 (m, overlaps with solvent peak) 2.57 (t, 2H), 2.22 - 2.02 (m, 2H).

Example 12 (R)-N-(2-(4-cyanothiazolidin-3-yl)-2-oxoethyl)-6-(3,3-dimethyl-2-oxopyrrolidin-1 yl)quinoline-4-carboxamide

DIPEA (0.22 mL, 1.3 mmol) was added to a mixture of 6-(3,3-dimethyl-2-oxopyrrolidin-1-yl)quinoline-4-carboxylic acid, intermediate 34 (120 mg, 0.42 mmol), (R)-3-glycylthiazolidine-4-carbonitrile hydrochloride, intermediate 4 (108 mg, 0.63 mmol), and T3P (50% solution in EtOAc, 1.07 g, 1.69 mmol) in MeCN (5 mL) and EtOAc (5 mL) at 20 °C under _N2 (g). The resulting mixture was stirred at 20 °C for 3 h. The reaction mixture was concentrated and diluted with EtOAc (100 mL), and washed successively with water (20 mL) and sat. brine (20 mL). _The organic layer was dried over _Na2SO4 , filtered and evaporated to give the crude product. The crude product was purified by preparative HPLC, PrepMethod F (gradient: 25-40%) to give the title compound ( ₁₀₀ mg, 54%) as a yellow solid; HRMS (ESI) m/z [M+H] ⁺ calcd for _C22H24N5O3S : 438.1594 found: _{438.1616 ;}

1H NMR (400 MHz, CD3OD) δ 8.93 - 8.85 (m, 1H), 8.66 - 8.59 (m, 1H), 8.45 (d, 1H), 8.10 (d, 1H), 7.68 (d, 1H), 5.35 (dd, 1H), 4.95 - 4.83 (m, overlaps with solvent peak), 4.79 (d, 1H), 4.43 (s, 2H), 4.17-4.00 (m, 2H), 3.60 - 3.35 (m, 2H), 2.12 (t, 2H), 1.27 (s, 3H), 1.26 (s, 3H).

Example 13

DIPEA (0.37 mL, 2.10 mmol) was added to a mixture of 6-(5,5-dimethyl-2-oxooxazolidin-3-yl)quinoline-4-carboxylic acid, intermediate 36 (200 mg, 0.70 mmol), (R)-3-glycylthiazolidine-4-carbonitrile hydrochloride, intermediate 4 (179 mg, 1.05 mmol), and T3P (50% solution in EtOAc, 1.78 g, 2.79 mmol) in EtOAc (8 mL) and MeCN (8 mL) at 20 °C under air. The resulting mixture was stirred at 25 °C for 3 h. The reaction mixture was concentrated and diluted with EtOAc (75 mL), and washed successively with water (20 mL) and sat. brine (25 mL). The organic layer was dried over Na2SO4, filtered and evaporated to give the crude product. The crude product was purified by preparative HPLC, PrepMethod B (gradient: 20-40%) to give the title compound ( ₇₀ mg, 23%) as a white solid; HRMS (ESI) m/z [M _{+H] + calcd for C21H22N5O4S :} ^440.1388 _found : 440.1380;

1H NMR (400 MHz, DMSO-d6) δ 9.12 (t, 1H), 8.90 (d, 1H), 8.57 (dd, 1H), 8.21 (d, 1H), 8.10 (d, 1H), 7.55 (d, 1H), 5.33 (dd, 1H), 4.91 (d, 1H), 4.72 (d, 1H), 4.37 - 4.31 (m, 2H), 4.10 - 3.99 (m, 2H), 3.50 -3.33 (m, re

- 186 048482 overlaps with the solvent peak), 1.55 (s, 3H), 1.52 (s, 3H).

Example 14. (R)-N-(2-(4-cyanothiazolidin-3-yl)-2-oxoethyl)-6-(2-oxopiperidin-1-yl)quinoline-4-carboxamide

DIPEA (230 mg, 1.78 mmol) was added to a stirred mixture of 6-(2-oxopiperidin-1yl)quinoline-4-carboxylic acid, intermediate 38 (120 mg, 0.44 mmol), (R)-3-glycylthiazolidine-4-carbonitrile hydrochloride, intermediate 4 (152 mg, 0.89 mmol), and T3P (1.13 mL, 50% in EtOAc) in DMF (5 mL). The resulting solution was stirred at 25 °C for 6 h. The solvent was removed under reduced pressure. The residue was purified by preparative TLC (DCM:MeOH, 19:1) followed by further purification by preparative HPLC, PrepMethod B (gradient 13-33%) to afford the title compound (48 mg, 26%) as a white solid; HRMS (ESI) m/z [M+H]+ calcd for C ₂₁ H ₂₂ N ₅ O ₃ S: 424.1438 found: 424.1444;

1H NMR (300 MHz, DMSO-d ₆ ) δ 9.12 (t, 1H), 8.95 (d, 1H), 8.28 (d, 1H), 8.02 (d, 1H), 7.78 (dd, 1H), 7.56 (d, 1H), 5.33 (dd, 1H), 4.88 (d, 1H), 4.70 (d, 1H), 4.31 (d, 2H), 3.85 - 3.65 (m, 2H), 3.43 - 3.34 (m, overlaps with solvent peak), 2.46 - 2.35 (m, overlaps with solvent peak), 2.00 - 1.78 (m, 4H).

Example 15

DIPEA (104 mg, 0.80 mmol) was added to a mixture of 6-(3,3-dimethyl-2-oxopiperidin-1-yl)quinoline-4-carboxylic acid, intermediate 40 (60 mg, 0.20 mmol), (R)-3-glycylthiazolidine-4-carbonitrile hydrochloride, intermediate 4 (69 mg, 0.40 mmol), and T3P (0.51 mL, 50% in EtOAc) in DMF (2 mL). The resulting solution was stirred at 25 °C for 6 h. The solvent was removed under reduced pressure. The residue was purified by preparative TLC (DCM:MeOH, 18:1) followed by further purification by preparative HPLC, PrepMethod B (gradient 22-42%) to afford the title compound (25 mg, 28%) as a white solid; HRMS (ESI) m/z [M+H] ⁺ calcd for C ₂₃ H ₂₆ N ₅ O ₃ S: 452.1750 found: 452.1752;

1H NMR (300 MHz, DMSO-d ₆ ) δ 9.12 (t, 1H), 8.94 (d, 1H), 8.29 (d, 1H), 8.01 (d, 1H), 7.69 (dd, 1H), 7.55 (d, 1H), 5.32 (dd, 1H), 4.88 (d, 1H), 4.70 (d, 1H), 4.31 (d, 2H), 3.77 (t, 2H), 3.43 - 3.34 (m, overlaps with solvent peak), 2.04 - 1.91 (m, 2H), 1.88 - 1.75 (m, 2H), 1.24 (s, 3H), 1.24 (s, 3H).

Example 16 (R)-N-(2-(4-cyanothiazolidin-3-yl)-2-oxoethyl)-6-(2,2-dimethyl-3oxomorpholino)quinoline-4-carboxamide

DIPEA (0.88 ml, 5.1 mmol) was added to a mixture of 6-(2,2-dimethyl-3-oxomorpholino)quinoline-4-carboxylic acid, intermediate 42 (304 mg, 1.01 mmol), (R)-3-glycylthiazolidine-4-carbonitrile hydrochloride, intermediate 4 (260 mg, 1.52 mmol), and HATU (1.15 g, 3.04 mmol) in EtOAc (10 ml) and MeCN (10 ml) at 20 °C. The resulting mixture was stirred at 25 °C for 6 h. The reaction mixture was diluted with saturated NaHCO ₃ solution. The phases were separated and the aqueous layer was extracted with DCM (3 x 100 ml). _The combined organic phases were dried over _Na2SO4 , filtered and evaporated. The residue was purified by preparative TLC (DCM:MeOH, 17:1) followed by further purification by preparative HPLC, PrepMethod C (gradient 17-27% ₎ to afford the title compound ( ₂₀₀ mg, 44%) as a white solid; HRMS (ESI) m/z [M+ _H ] ⁺ calcd for C22H24N5O4S: 454.1544 found: _454.1542 ;

1H NMR (300 MHz, DMSO-d6) δ 9.16 (t, 1H), 8.99 (d, 1H), 8.42 (d, 1H), 8.08 (d, 1H), 7.86 (dd, 1H), 7.60 (d, 1H), 5.45 - 5.25 (m, 1H), 4.90 (d, 1H), 4.71 (d, 1H), 4.34 (d, 2H), 4.11 - 3.96 (m, 2H), 3.94 - 3.80 (m, 2H), 3.59 - 3.35 (m, overlaps with solvent peak), 1.47 (s, 6H).

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Example 17 (R)-N-(2-(4-cyanothiazolidin-3-yl)-2-oxoethyl)-6-(2-azaspiro[3.3]heptan-2-yl)quinoline4-carboxamide

DIPEA (289 mg, 2.24 mmol) was added to a mixture of 6-(2-azaspiro[3.3]heptan-2-yl)quinoline-4-carboxylic acid, intermediate 44 (100 mg, 0.37 mmol), (K)-3-glycylthiazolidine-4-carbonitrile hydrochloride, intermediate 4 (96 mg, 0.56 mmol), and HATU (283 mg, 0.75 mmol) in MeCN (5 mL) and EtOAc (5 mL). The reaction mixture was stirred under air at 25 °C for 3 h. The solvent was removed under reduced pressure. The crude product was purified by preparative HPLC, PrepMethod F (20-40% gradient) to give the title compound ( ₄₄ mg, 28%) as a red solid; HRMS (ESI) m/z [M+ _H ]+ calcd for _C22H24N5O2S : _422.1646 found: 422.1650;

^1H NMR (300 MHz, DMSO- _d6 ) δ 9.20 - 9.05 (m, 1H), 8.75 (d, 1H), 7.96 (d, 1H), 7.61 (d, 1H), 7.30 - 7.15 (m, 2H), 5.40 - 5.30 (m, 1H), 4.91 (d, 1H), 4.73 (d, 1H), 4.34 (d, 2H), 3.99 (s, 4H), 3.48 - 3.32 (m, 2H), 2 .21 (t, 4H), 1.95 - 1.75 (m, 2H).

Example 18 (R)-N-(2-(4-cyanothiazolidin-3-yl)-2-oxoethyl)-6-(3,3-dimethyl-1-oxa-6azaspiro[3.3]heptan-6-yl) quinoline-4-carboxamide

DIPEA (0.50 ml, 2.9 mmol) was added to a mixture of 6-(3,3-dimethyl-1-oxa-6-azaspiro[3.3]heptan-6-yl)quinoline-4-carboxylic acid, intermediate 46 (170 mg, 0.57 mmol), (K)-3-glycylthiazolidine-4-carbonitrile hydrochloride, intermediate 4 (178 mg, 0.85 mmol), EDC (218 mg, 1.14 mmol), and HOBt (175 mg, 1.14 mmol) in MeCN (5 ml) and EtOAc (5 ml). The reaction mixture was stirred at 50 °C for 3 h. The solvent was removed under reduced pressure. The residue was diluted with EtOAc and washed with water. _The organic layer was dried over _Na2SO4 , filtered and evaporated. The crude product was purified by preparative HPLC, PrepMethod P ( _15-25 % gradient) to give the title compound (160 mg, 62%) as a yellow solid; HRMS (ESI) m/z [M ₊ H] ⁺ calcd for _C23H26N5O3S : 452.1750 found: _452.1748 ;

1H NMR (300 MHz, DMSO-d6) δ 8.95 (t, 1H), 8.62 (d, 1H), 7.87 (d, 1H), 7.38 (d, 1H), 7.28 (d, 1H), 7.13 (dd, 1H), 5.35 - 5.25 (m, 1H), 4.88 (d, 1H), 4.70 (d, 1H), 4.35 - 4.20 (m, 4H), 4.16 (s, 2H), 3.94 - 3.83 (m, 2H), 3.42 - 3.34 (m, 2H), 1.22 (s, 6H).

Example 19

DIPEA (0.65 ml, 3.7 mmol) was added to a mixture of 6-(1-azaspiro[3.3]heptan-1-yl)quinoline-4-carboxylic acid, intermediate 48 (200 mg, 0.75 mmol), (R)-3-glycylthiazolidine-4-carbonitrile hydrochloride, intermediate 4 (232 mg, 1.12 mmol), EDC (286 mg, 1.49 mmol) and HOBt (228 mg, 1.49 mmol) in EtOAc (6 ml) and MeCN (6 ml). The mixture was stirred at 45 °C for 5 h. The solvent was removed under reduced pressure. The residue was dissolved in EtOAc and washed with water. The organic layer was dried over Na ₂ SO ₄ , filtered and evaporated. The crude product was purified by preparative HPLC, PrepMethod B (gradient: 28-48%) to give the title compound (220 mg, 70%) as a yellow solid; HRMS (ESI) m/z [M+H] ⁺ calcd for C22H24N5O2S: 422.1646 found: 422.1626;

1H NMR (300 MHz, CD3OD) δ 8.55 (d, 1H), 7.89 (d, 1H), 7.49 (d, 1H), 7.37 (dd, 1H), 7.28 (d , 1H), 5.40 5.25 (m, 1H), 4.85 - 4.63 (m, 2H), 4.37 (d, 2H), 3.87 (t, 2H), 3.51 - 3.34 (m, 2H), 3.04 - 2.88 (m, 2H), 2.51 (t, 2H), 2.17 - 2.03 (m, 2H), 2.02 - 1.70 (m, 2H).

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Example 20. (R)-N-(2-(4-cyanothiazolidin-3-yl)-2-oxoethyl)-6-(2,2-dimethylazetidin-1-yl)quinoline4-carboxamide

TEA (0.62 ml, 4.5 mmol) was added to a stirred suspension of 6-(2,2-dimethylazetidin-1yl)quinoline-4-carboxylic acid, intermediate 50 (114 mg, 0.44 mmol), (E)-3-glycylthiazolidine-4-carbonitrile hydrochloride, intermediate 4 (185 mg, 0.89 mmol), HOBt (341 mg, 2.22 mmol) and EDC (426 mg, 2.22 mmol) in EtOAc (13 ml) and MeCN (13 ml) at 10 °C. The resulting suspension was stirred at 10 °C overnight. The solvent was removed under reduced pressure. The residue was dissolved with a mixture of NaHCO ₃ solution (50 ml) and EtOAc (100 ml). The aqueous layer was extracted with EtOAc (4x100 mL). The organic layers were combined and washed with water (2x50 mL). The aqueous layers were combined and extracted with EtOAc (2x25 mL). _The organic layers were combined, dried over _Na2SO4 , filtered and evaporated. The crude product was purified by preparative HPLC, PrepMethod B (gradient: 34-48%), to give the title compound (82 mg, 45 _% ) as a yellow solid; HRMS (ESI) m/z [M+ _H ]+ calcd for _C21H24N5O2S : 410.1646 found: _410.1640 ;

¹ H NMR (300 MHz, DMSO-d ₆ ) δ 9.00 - 8.89 (m, 1H), 8.58 (d, 1H), 7.83 (d, 1H), 7.37 (d, 1H), 7.14 (dd, 1H), 7.09 (d, 1H), 5.30 (dd, 1H), 4.88 (d, 1H), 4.71 (d, 1H), 4.28 (d, 2H), 3.75 (t, 2H), 3.35 (m, overlaps with solvent peak), 2.18-2.03 (m, 1H), 1.49 (s, 3H), 1.48 (s, 3H).

Example 21. (R)-N-(2-(4-cyanothiazolidin-3-yl)-2-oxoethyl)-6-(3-fluoroazetidin-1-yl)quinoline-4-carboxamide

DIPEA (0.53 mL, 3.1 mmol) was added to a mixture of 6-(3-fluoroazetidin-1-yl)quinoline-4-carboxylic acid, intermediate 52 (150 mg, 0.61 mmol), (R)-3-glycylthiazolidine-4-carbonitrile hydrochloride, intermediate 4 (253 mg, 1.22 mmol), EDC (234 mg, 1.22 mmol) and HOBt (187 mg, 1.22 mmol) in EtOAc (5 mL) and MeCN (5 mL). The mixture was stirred at rt for 10 h. The solvent was removed under reduced pressure. The residue was dissolved in EtOAc and washed with water. The organic layer was dried over Na ₂ SO ₄ , filtered and evaporated. The crude product was purified by preparative HPLC, PrepMethod C (gradient: 17-29%) to afford the title compound (110 mg, 45%) as a yellow solid; HRMS (ESI) m/z [M+H]+ calcd for C ₁₉ H ₁₉ FN ₅ O ₂ S: 400.1238 found: 400.1246;

¹ H NMR (300 MHz, CD3OD) δ 8.60 (d, 1H), 7.91 (d, 1H), 7.50 (d, 1H), 7.32 (d, 1H), 7.18 (dd, 1H), 5.64-5.32 (m, 2H), 4.83-4.69 (m, overlaps with solvent peak), 4.50-4.25 (m, 4H), 4.20-4.00 (m, 2H), 3.52-3.34 (m, overlaps with solvent peak).

Example 22

DIPEA (0.58 ml, 3.3 mmol) was added to a suspension of 6-(3,3-dimethylazetidin-1-yl)quinoline-4-carboxylic acid, intermediate 54 (170 mg, 0.66 mmol), (R)-3-glycylthiazolidine-4-carbonitrile hydrochloride, intermediate 4 (344 mg, 1.66 mmol), EDC (254 mg, 1.33 mmol) and HOBt (203 mg, 1.33 mmol) in MeCN (10 ml) and EtOAc (10 ml). The mixture was stirred at rt for 20 h. The solvent was removed under reduced pressure. The residue was dissolved in EtOAc and washed with water. The organic layer was dried over Na2SO4, filtered and evaporated. The crude product was purified by preparative HPLC, PrepMethod C (gradient: 19-30%) to afford the title compound (90 mg, 33%) as a yellow solid; HRMS (ESI) m/z [M+H]+ calcd for C ₂₁ H ₂₄ N ₅ O ₂ S: 410.1646 found: 410.1642;

^1H NMR (300 MHz, CD3OD) δ 8.54 (d, 1H), 7.87 (d, 1H), 7.48 (d, 1H), 7.21 - 7.07 (m, 2H), 5.40 - 5.28 (m, 1H), 4.82 - 4.59 (m, 2H), 4.38 (d, 2H), 3.74 (s, 4H), 3.53 -3.35 (m, 2H), 1.35 (s, 6H).

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Example 23. (R)-N-(2-(4-cyanothiazolidin-3-yl)-2-oxoethyl)-6-(3,3-difluoroazetidin-1-yl)quinoline-4-carboxamide

DIPEA (1.38 mL, 7.87 mmol) was added to 6-(3,3-difluoroazetidin-1-yl)quinoline-4-carboxylic acid, intermediate 56 (104 mg, 0.39 mmol), (R)-3-glycylthiazolidine-4-carbonitrile hydrochloride, intermediate 4 (123 mg, 0.59 mmol), HOBt (603 mg, 3.94 mmol), and EDC (755 mg, 3.94 mmol) in EtOAc (5 mL) and MeCN (5 mL) at 10 °C. The resulting solution was stirred at 10 °C overnight under N ₂ (g). The solvent was removed under reduced pressure. The residue was diluted with sat. NaHCO ₃ solution (50 mL) and extracted with EtOAc (6 x 50 mL). The organic layers were combined and washed with sat. brine (5 x 200 mL). The organic layer was dried over Na ₂ SO ₄ , filtered and evaporated. The crude product was purified by preparative HPLC, PrepMethod P (gradient: 18-45%), to give the title compound (116 mg, 70%) as a yellow solid; HRMS (ESI) m/z [M+H]+ calcd for C ₁₉ H ₁₈ F ₂ N ₅ O ₂ S: 418.1144 found: 418.1158;

¹ H NMR (300 MHz, DMSO-d ₆ ) δ 9.05 - 8.95 (m, 1H), 8.72 (d, 1H), 7.96 (d, 1H), 7.55 -7.38 (m, 2H), 7.25 (dd, 1H), 5.45 - 5.30 (m, 1H), 4.90 (d, 1H), 4.72 (d, 1H), 4.44 (t, 4H), 4.32 (d, 2H), 3.42 - 3.35 (m, overlaps with solvent peak).

Example 24

DIPEA (0.43 ml, 2.5 mmol) was added to 6-(3-fluoro-3-methylazetidin-1-yl)quinoline-4-carboxylic acid, intermediate 58 (65 mg, 0.25 mmol), (R)-3-glycylthiazolidine-4-carbonitrile hydrochloride, intermediate 4 (103 mg, 0.50 mmol), and TBTU (282 mg, 0.74 mmol) in MeCN (6 ml) and EtOAc (6 ml) at 10 °C. The resulting solution was stirred at 40 °C for 4 h under N ₂ (g). The solvent was removed under reduced pressure. The reaction mixture was diluted with saturated NaHCO ₃ solution (50 ml) and extracted with EtOAc (6 x 50 ml). The organic layers were combined and washed with brine (5 x 50 mL). The organic layer was dried over Na ₂ SO ₄ , filtered and evaporated. The crude product was purified by preparative HPLC, PrepMethod D (gradient: 20-45%) to give the title compound (57 mg, 56%) as an orange solid; HRMS (ESI) m/z [M+H]+ calcd for C ₂₀ H ₂₁ FN ₅ O ₂ S: 414.1394 found: 414.1394;

¹ H NMR (300 MHz, DMSO-d ₆ ) δ 9.05 - 8.96 (m, 1H), 8.66 (d, 1H), 7.91 (d, 1H), 7.42 (d, 1H), 7.31 (d, 1H), 7.17 (dd, 1H), 5.40 - 5.25 (m, 1H), 4.90 (d, 1H), 4.72 (d, 1H), 4.31 (d, 2H), 4.20 - 4.00 (m, 4H), 3.45 - 3.34 (m, overlaps with solvent peak), 1.66 (d, 3H).

Example 25. (R)-N-(2-(4-cyanothiazolidin-3-yl)-2-oxoethyl)-6-(3-methylazetidin-1-yl)quinoline-4-carboxamide

TEA (0.83 g, 8.3 mmol) was added to a mixture of 6-(3-methylazetidin-1-yl)quinoline-4-carboxylic acid, intermediate 60 (200 mg, 0.83 mmol), (R)-3-glycylthiazolidine-4-carbonitrile hydrochloride, intermediate 4 (141 mg, 0.83 mmol), EDC (317 mg, 1.65 mmol) and HOBt (253 mg, 1.65 mmol) in EtOAc (2.5 mL) and MeCN (2.5 mL). The resulting mixture was stirred at 25 °C for 3 h. The reaction mixture was diluted with EtOAc (20 mL) and washed with brine (3 x 50 mL). _The organic layer was dried over _Na2SO4 , filtered and evaporated. The crude product was purified by preparative HPLC, PrepMethod F (gradient: 15-30%) to afford the title compound (190 mg, 58%) as a red solid; HRMS (ESI) m/z [M ₊ H]+ calcd for _C20H22N5O2S : _396.1488 found: _396.1490 ;

1H NMR (300 MHz, CD3OD) δ 8.69 (d, 1H), 7.99 (d, 1H), 7.80 (d, 1H), 7.37 (dd, 1H), 7.34 - 7.27 (m, 1H), 5.40 - 5.25 (m, 1H), 4.83 - 4.65 (m, overlaps with solvent peak), 4.44 (s, 2H), 4.35 - 4.18 (m, 3H),

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3.77 - 3.67 (m, 2H), 3.36 (m, overlaps with solvent peak), 3.00 - 2.85 (m, 1H), 1.35 (d, 3H).

Example 26

DIPEA (0.59 mL, 3.4 mmol) was added to a mixture of 6-(3-(trifluoromethyl)azetidin-1-yl)quinoline-4-carboxylic acid, intermediate 62 (100 mg, 0.34 mmol), (R)-3-glycylthiazolidine-4-carbonitrile hydrochloride, intermediate 4 (116 mg, 0.68 mmol), and HATU (261 mg, 0.68 mmol) in EtOAc (2 mL) and MeCN (2 mL). The resulting mixture was stirred at 25 °C for 4 h. The solvent was removed under reduced pressure. The crude product was purified by preparative HPLC, PrepMethod F (gradient: 19-30%), affording the title compound (60 mg, 40%) as a red solid; HRMS (ESI) mass/charge [M+H]+ calcd for C ₂₀ H ₁₉ F ₃ N ₅ O ₂ S: 450.1206 found value: 450.1194;

1H NMR (400 MHz, CD3OD) δ 8.79 (brs, 1H), 8.07 (d, 1H), 7.85 (d, 1H), 7.60 - 7.40 (m, 2H), 5.45 - 5.25 (m, 1H), 4.79 (d, overlaps with solvent peak), 4.52 - 4.35 (m, 4H), 4.28 - 4.15 (m, 2H), 3.80 - 3.60 (m, 1H), 3.45 - 3.34 (m, 2H).

Example 27

DIPEA (0.25 mL, 1.4 mmol) was added to a mixture of 6-(3-(fluoromethyl)-3-methylazetidin-1-yl)quinoline-4-carboxylic acid, intermediate 64 (268 mg, 0.28 mmol), (R)-3-glycylthiazolidine-4-carbonitrile hydrochloride, intermediate 4 (118 mg, 0.57 mmol), HOBt (192 mg, 1.42 mmol), and EDC (333 mg, 1.74 mmol) in MeCN (3 mL) and EtOAc (3 mL) at 13 °C. The resulting solution was stirred at 13 °C overnight under N2 (g). The solvent was removed under reduced pressure. The residue was diluted with sat. NaHCO ₃ solution (100 mL) and extracted with EtOAc (5x100 mL). The organic layers were combined and washed with brine (3x50 mL). The organic layer was dried over Na ₂ SO ₄ , filtered and evaporated. The crude product was purified by preparative HPLC, PrepMethod C (17-30% gradient) to give the title compound (66 mg, 54%) as an orange solid; HRMS (ESI) m/z [M+H]+ calcd for C ₂₁ H ₂₃ FN ₅ O ₂ S: 428.1550 found: 428.1538;

1H NMR (400 MHz, DMSO-d6) δ 8.94 (t, 1H), 8.63 (d, 1H), 7.89 (d, 1H), 7.41 (d, 1H), 7.23 - 7.16 (m, 1H), 7.12 (dd, 1H), 5.40 - 5.25 (m, 1H), 4.89 (d, 1H), 4.72 (d, 1H), 4.50 (d, 2H), 4.30 (d, 2H), 3.88 (d, 2H), 3.68 (dd, 2H), 3.44 - 3.34 (m, overlaps with solvent peak), 1.35 (s, 3H).

Example 28

DIPEA (0.19 mL, 1.1 mmol) was added to a mixture of 6-(3-(difluoromethyl)azetidin-1-yl)quinoline-4-carboxylic acid, intermediate 66 (120 mg, 0.43 mmol), (R)-3-glycylthiazolidine-4-carbonitrile hydrochloride, intermediate 4 (90 mg, 0.43 mmol), HOBt (99 mg, 0.65 mmol), and EDC (124 mg, 0.65 mmol) in MeCN (5 mL) and EtOAc (5 mL) at 20 °C under N ₂ (g). The resulting mixture was stirred at 25 °C for 3 h. The reaction mixture was concentrated and diluted with DCM (100 mL), and washed successively with sat. _NH4Cl solution (50 mL), brine (50 mL) and water (50 mL). The organic layer was dried over Na2SO4, filtered and evaporated. The crude product was purified by preparative HPLC, PrepMethod C ( _12-23 % gradient) to give the title compound ( ₇₁ mg, 38%) as a yellow solid; HRMS (ESI) m/z [M+ _{H]+ calcd for C20H20F2N5O2S : 432.1300} found: 432.1292;

1H NMR (400 MHz, DMSO-d6) δ 8.97 (t, 1H), 8.64 (d, 1H), 7.90 (d, 1H), 7.41 (d, 1H), 7.22 (d, 1H), 7.15 (dd, 1H), 6.39 (td, 1H), 5.33 (dd, 1H), 4.89 (d, 1H), 4.71 (d, 1H), 4.29 (d, 2H), 4.15 - 4.05 (m, 2H), 3.95- 3.85 (m, 2H), 3.44 - 3.30 (m, overlaps with solvent peak).

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Example 29

DIPEA (0.16 ml, 0.91 mmol) was added to a mixture of 6-(3-(methoxymethyl)-3-methylazetidin-1yl)quinoline-4-carboxylic acid, intermediate 68 (65 mg, 0.23 mmol), (R)-3-glycylthiazolidine-4-carbonitrileα hydrochloride, intermediate 4 (57 mg, 0.27 mmol), and HATU (129 mg, 0.34 mmol) in MeCN (2 ml) and EtOAc (2 ml). The mixture was stirred at rt overnight. DCM (10 ml) and sat. _NaHCO3 (aq., 7 ml) were added to the reaction mixture and the mixture was stirred and filtered through a phase separator. The phase separator was washed with DCM and the combined organic layer was evaporated. The crude product was purified by preparative HPLC, PrepMethod SFC-D (2-94% gradient), to afford the title compound (38 mg, 38%); HRMS (ESI) m/z [M+H]+ calcd for C ₂₂ H ₂₆ N ₅ O ₃ S: 440.1750 found: 440.1748;

¹ H NMR (600 MHz, DMSO-d6) δ 8.93 (t, 1H), 8.60 (d, 1H), 7.86 (d, 1H), 7.39 (d, 1H), 7.12 (d, 1H), 7.09 (dd, 1H), 5.32 (dd, 1H), 4.87 (d, 1H), 4.71 (d, 1H), 4.28 (d, 2H), 3.80 (dd, 2H), 3.60 (dd, 2H), 3.32 - 3.41 (m, overlaps with solvent peak), 3.31 (s, 3H), 1.30 (s, 3H).

Example 30 carboxamide

DIPEA (0.51 ml, 2.9 mmol) was added to a mixture of 6-((2S,3R)-3-methoxy-2-methylαzetidin-1-yl)quinoline-4-carboxylic acid, intermediate 70 (160 mg, 0.59 mmol), (R)-3-glycylthiazolidine-4-carbonitrile hydrochloride, intermediate 4 (183 mg, 0.88 mmol), EDC (225 mg, 1.18 mmol) and HOBt (180 mg, 1.18 mmol) in EtOAc (5 ml) and MeCN (5 ml). The mixture was stirred at 50 °C for 3 h. The solvent was removed under reduced pressure. The residue was diluted with EtOAc and washed with water. The organic layer was dried over Na ₂ SO ₄ , filtered and evaporated. The crude product was purified by preparative HPLC, PrepMethod P (13-23% gradient) to give the title compound (220 mg, 88%) as a yellow solid; HRMS (ESI) m/z [M+H]+ calcd for C ₂₁ H ₂₄ N ₅ O ₃ S: 426.1594 found: 426.1576;

¹ H NMR (300 MHz, DMSO-d6) δ 9.01 - 8.91 (m, 1H), 8.62 (d, 1H), 7.87 (d, 1H), 7.38 (d, 1H), 7.29 (d, 1H), 7.16 (dd, 1H), 5.31 (dd, 1H), 4.88 (d, 1H), 4.71 (d, 1H), 4.35 - 4.20 (m, 3H), 4.10 - 3.85 (m, 2H), 3.50 3.29 (m, overlaps with solvent peak), 3.27 (s, 3H), 1.50 (d, 3H).

Example 31

DIPEA (0.15 ml, 0.87 mmol) was added to a mixture of 6-(3-cyclopropyl-3-fluoroazetidin-1-yl)quinoline-4-carboxylic acid, intermediate 72 (100 mg, 0.35 mmol), (R)-3-glycylthiazolidine-4-carbonitrile hydrochloride, intermediate 4 (73 mg, 0.35 mmol), EDC (100 mg, 0.52 mmol) and HOBt (71 mg, 0.52 mmol) in EtOAc (8 ml) and MeCN (8 ml) at 20 °C under N ₂ (g). The resulting mixture was stirred at 25 °C for 12 h. The reaction mixture was concentrated and diluted with EtOAc (100 mL) and washed successively with brine (50 mL) and water (50 mL). The organic layer was dried over Na ₂ SO ₄ , filtered and evaporated. The crude product was purified by preparative HPLC, PrepMethod C (12-23% gradient) to give the title compound (68 mg, 34%) as a yellow solid; HRMS (ESI) m/z [M+H]+ calcd for C ₂₂ H ₂₃ FN ₅ O ₂ S: 440.1550 found: 440.1546;

1H NMR (400 MHz, DMSO-d6) δ 9.11 (t, 1H), 8.78 (d, 1H), 7.99 (d, 1H), 7.60 (d, 1H), 7.40 (d, 1H), 7.29 (dd, 1H), 5.34 (dd, 1H), 4.90 (d, 1H), 4.71 (d, 1H), 4.41-4.25 (m, 2H), 4.10 - 3.95 (m, 2H), 3.46 - 3.32 (m, 2H) , 1.50 - 1.35 (m, 1H), 0.67 - 0.61 (2H, m), 0.49 (d, 2H),

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Example 32. (R)-N-(2-(4-cyanothiazolidin-3-yl)-2-oxoethyl)-6-(piperidin-1-yl)quinoline-4-carboxamide

TEA (0.81 ml, 5.9 mmol) was slowly added to a mixture of 6-(piperidin-1-yl)quinoline-4-carboxylic acid, intermediate 74 (60 mg, 0.23 mmol), (R)-3-glycylthiazolidine-4-carbonitrile hydrochloride, intermediate 4 (194 mg, 0.94 mmol), and T3P (0.57 ml, 50% in EtOAc) in EtOAc (4 ml) at 15 °C under N2(g). The resulting mixture was stirred at 15 °C overnight under N2(g). The reaction mixture was filtered and the filtrate was washed successively with brine (3x10 ml) and water (2x10 ml). _The organic layer was dried over _Na2SO4 , filtered and evaporated. The crude product was purified by preparative HPLC, PrepMethod F (gradient: 15-30%) to afford the title compound (12 mg, 12%) as a yellow solid; HRMS (ESI) m/z [M+H]+ calcd for C ₂₁ H ₂₄ N ₅ O ₂ S: 410.1646 found: 410.1648;

¹ H NMR (400 MHz, DMSO-d ₆ ) δ 9.10 - 8.90 (m, 1H), 8.66 (d, 1H), 7.86 (d, 1H), 7.72 - 7.53 (m, 2H), 7.39 (d, 1H), 5.50 - 5.20 (m, 1H), 4.89 (d, 1H), 4.71 (d, 1H), 4.36 - 4.22 (m, 2H), 3.40 - 3.34 (m, overlaps with solvent peak), 1.75 - 1.50 (m, 6H).

Example 33

TEA (0.34 ml, 2.5 mmol) was slowly added to a mixture of 6-(4,4-dimethylpiperidin-1-yl)quinoline-4-carboxylic acid, intermediate 76 (70 mg, 0.25 mmol), (R)-3-glycylthiazolidine-4-carbonitrile hydrochloride, intermediate 4 (102 mg, 0.49 mmol), EDC (142 mg, 0.74 mmol) and HOBt (113 mg, 0.74 mmol) in DMF (5 ml) at 10 °C under N2 (g). The resulting suspension was stirred at 10 °C overnight. The reaction mixture was diluted with _saturated NaHCO3 (25 ml) and extracted with EtOAc (4 x 20 ml). The organic layers were combined and washed with brine (3 x 10 mL). The organic layer was dried over Na ₂ SO ₄ , filtered and evaporated. The crude product was purified by preparative HPLC, PrepMethod P (10-25% gradient) to give the title compound (12 mg, 11%) as a yellow solid; HRMS (ESI) m/z [M+H]+ calcd for C ₂₃ H ₂₈ N ₅ O ₂ S: 438.1958 found: 438.1946;

1H NMR (300 MHz, DMSO-d ₆ ) δ 8.97 (t, 1H), 8.63 (d, 1H), 7.84 (d, 1H), 7.74 - 7.50 (m, 2H), 7.37 (d, 1H), 5.40 - 5.20 (m, 1H), 4.87 (d, 1H), 4.69 (d, 1H), 4.27 (d, 2H), 3.37 - 3.32 (m, overlaps with solvent peak), 1.65 - 1.35 (m, 4H), 0.96 (s, 6H).

Example 34

DIPEA (0.30 ml, 1.7 mmol) was slowly added to a mixture of 6-(4-fluoro-4-methylpiperidin-1yl)quinoline-4-carboxylic acid, intermediate 78 (50 mg, 0.17 mmol), (R)-3-glycylthiazolidine-4-carbonitrile hydrochloride, intermediate 4 (72 mg, 0.35 mmol), and HATU (198 mg, 0.52 mmol) in DMF (5 ml) at 10 °C under N2 (g). The resulting mixture was stirred at 10 °C overnight. The reaction mixture was diluted with water (10 ml) and extracted with EtOAc (3 x 25 ml). The organic layers were combined and washed with brine (3 x 20 ml).

The organic layer was dried over Na2SO4, filtered and evaporated. The crude product was purified by preparative HPLC, PrepMethod P (10-25% gradient) to give the title compound ( ₁₃ mg, 17%) as a yellow solid; HRMS (ESI) m/z [M _{+H]+ calcd for C22H25FN5O2S : 442.1708} found: 442.1726;

1H NMR (300 MHz, DMSO-d ₆ ) δ 9.05 - 8.91 (m, 1H), 8.65 (d, 1H), 7.87 (d, 1H), 7.74 - 7.62 (m, 2H), 7.37 (d, 1H), 5.40 - 5.20 (m, 1H), 4.87 (d, 1H), 4.69 (d, 1H), 4.32 -4.24 (m, 2H), 3.82 - 3.60 (m, 2H), 3.55 -3.07 (m, overlaps with solvent peak), 1.94 - 1.62 (m, 4H), 1.35 (d, 3H).

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Example 3 5. (R)-N-(2-(4-cyanothiazolidin-3 -yl)-2-oxoethyl)-6-(4,4-difluoropiperidin-1 -yl)quinoline4-carboxamide

DIPEA (0.84 ml, 4.8 mmol) was added to 6-(4,4-difluoropiperidin-1-yl)quinoline-4-carboxylic acid, intermediate 80 (140 mg, 0.48 mmol), (R)-3-glycylthiazolidine-4-carbonitrile hydrochloride, intermediate 4 (98 mg, 0.57 mmol), and T3P (0.91 ml, 50% in EtOAc) in DMF (8 ml) at 20 °C. The resulting mixture was stirred at 50 °C for 35 h. The reaction mixture was diluted with EtOAc (50 ml) and washed with water (3 x 50 ml), filtered and evaporated. The crude product was purified by preparative HPLC, PrepMethod C (25-55% gradient) to give the title compound (28 _mg , 13%) as a _pale yellow solid; HRMS (ESI) m/z [ _{M +H]+ calcd for C21H22F2N5O2S :} 446.1456 found: 446.1452;

1H NMR (300 MHz, DMSO-d ₆ ) δ 9.01 (t, 1H), 8.68 (d, 1H), 7.90 (d, 1H), 7.83 (d, 1H), 7.70 (dd, 1H), 7.39 (d, 1H), 5.37 - 5.20 (m, 1H), 4.88 (d, 1H), 4.69 (d, 1H), 4.40 - 4.20 (m, 2H), 3.65 - 3.45 (m, 4H), 3.42 - 3.33 (m, overlaps with solvent peak), 2.16 - 1.94 (m, 4H).

Example 36

TEA (1.05 ml, 7.53 mmol) was added to 6-(3,3-difluoropiperidin-1-yl)quinoline-4-carboxylic acid, intermediate 82 (110 mg, 0.38 mmol), (R)-3-glycylthiazolidine-4-carbonitrile hydrochloride, intermediate 4 (782 mg, 3.78 mmol), and T3P (2.4 ml, 50% in EtOAc) in DMF (5 ml) at 10 °C under N2(g). The resulting mixture was stirred at 10 °C overnight under N2(g). The reaction mixture was diluted with saturated _NaHCO3 (25 ml) and extracted with EtOAc (4 x 25 ml). The organic layers were combined and washed with brine (5 x 20 ml). _The organic layer was dried over _Na2SO4 , filtered and evaporated. The crude product was purified by preparative HPLC, PrepMethod P ( _10-25 % gradient) to give the title compound (28 mg, 17%) as a yellow solid; _HRMS (ESI) m/z [M ₊ H]+ _calcd for _{C21H22F2N5O2S} : 446.1456 found: 446.1460;

¹ H NMR (300 MHz, DMSO-d ₆ ) δ 9.10 - 8.90 (m, 1H), 8.70 (d, 1H), 8.19 - 7.86 (m, 1H), 7.84 - 7.60 (m, 2H), 7.42 (d, 1H), 5.36 -5.26 (m, 1H), 4.89 (d, 1H), 4.72 (d, 1H), 4.30 (d, 2H), 3.70 (t, 2H), 3.55 - 3.30 (m, overlaps with solvent peak), 2.18 - 1.99 (m, 2H), 1.98 - 1.80 (m, 2H).

Example 37

TEA (1.10 mL, 7.87 mmol) was added to 6-(4-(fluoromethyl)-4-methylpiperidin-1-yl)quinoline-4-carboxylic acid, intermediate 84 (119 mg, 0.39 mmol), (R)-3-glycylthiazolidine-4-carbonitrile hydrochloride, intermediate 4 (327 mg, 1.57 mmol), HOBt (532 mg, 3.94 mmol) and EDC (755 mg, 3.94 mmol) in DMF (5 mL) at 10 °C under N2(g). The resulting suspension was stirred at 10 °C overnight under N2(g). The reaction mixture was diluted with water (50 mL) and extracted with EtOAc (4x50 mL). The organic layers were combined and washed with brine (5 x 25 mL). The organic layer was dried over Na ₂ SO ₄ , filtered and evaporated. The crude product was purified by preparative HPLC, PrepMethod P (10-25% gradient) to give the title compound (16 mg, 9%) as a yellow solid; HRMS (ESI) m/z [M+H]+ calcd for C ₂₃ H ₂₇ FN ₅ O ₂ S: 456.1864 found: 456.1850;

¹ H NMR (300 MHz, DMSO-d ₆ ) δ 8.97 (t, 1H), 8.64 (d, 1H), 7.93 - 7.80 (m, 1H), 7.65 (m, 2H), 7.38 (d, 1H), 5.82 - 5.23 (m, 1H), 4.89 (d, 1H), 4.71 (d, 1H), 4.35 - 4.07 (m, 4H), 3.70 - 3.00 (m, overlaps with solvent peak), 1.75 - 1.55 (m, 2H), 1.53 - 1.34 (m, 2H), 1.01 (d, 3H).

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Example 3 8. (R)-N-(2-(4-cyanothiazolidin-3-yl)-2-oxoethyl)-6-(4,4-difluoro-3,3-dimethylpiperidin-1 yl)quinoline-4- carboxamide

DIPEA (0.22 mL, 1.3 mmol) was added to 6-(4,4-difluoro-3,3-dimethylpiperidin-1-yl)quinoline-4-carboxylic acid, intermediate 86 (200 mg, 0.62 mmol), (R)-3-glycylthiazolidine-4-carbonitrile hydrochloride, intermediate 4 (194 mg, 0.94 mmol), and HATU (237 mg, 0.62 mmol) in MeCN (10 mL) and EtOAc (10 mL) at 15 °C under N2 (g). The resulting mixture was stirred at 20 °C for 3 h. The reaction mixture was filtered through silica gel. The filtrate was concentrated and re-dissolved in DCM (100 mL), and washed successively with brine (50 mL) and water (50 mL). _The organic layer was dried over _Na2SO4 , filtered and evaporated. The crude product was purified by preparative HPLC, _PrepMethod F ( _30-40 % gradient) to give the title compound (75 mg, ₂₅ %) as a yellow solid; HRMS (ESI) m/z [M ₊ H]+ calcd for _{C23H26F2N5O2S} : 474.1770 found: 474.1760;

1H NMR (300 MHz, DMSO-d6) δ 9.03 (t, 1H), 8.68 (d, 1H), 7.90 (d, 1H), 7.80 (d, 1H), 7.71 (dd, 1H), 7.39 (d, 1H), 5.37 - 5.29 (m, 1H), 4.91 (d, 1H), 4.72 (d, 1H), 4.31 (d, 2H), 3.62 - 3.35 (m, overlaps with solvent peak), 2.28 - 2.12 (m, 2H), 1.12 (s, 6H).

Example 39

DIPEA (0.83 mL, 4.8 mmol) was added to 6-(4-(trifluoromethyl)piperidin-1-yl)quinoline-4-carboxylic acid, intermediate 88 (154 mg, 0.47 mmol), (R)-3-glycylthiazolidine-4-carbonitrile hydrochloride, intermediate 4 (197 mg, 0.95 mmol), and TBTU (540 mg, 1.42 mmol) in DMF (5 mL) at 10 °C under N2(g). The resulting solution was stirred at 10 °C overnight under _N2 (g).

The reaction mixture was diluted with water (30 mL). The aqueous layer was extracted with EtOAc (4 x 50 mL). The organic layers were combined and washed with water (4 x 25 mL). The organic layer was dried over Na2SO4, filtered and evaporated. The residue was purified by preparative TLC (DCM:MeOH, 10:1) and further purified by preparative _HPLC , PrepMethod D ( _10-40 % gradient) to give the title compound ( ₂₇ mg, 12%) as an orange solid; HRMS (ESI) m/z [M+ _H ] ⁺ calcd for _{C22H23F3N5O2S} : 478.1518 found: 478.1514;

1H NMR (300 MHz, DMSO-d6) δ 9.05 (t, 1H), 8.72 (d, 1H), 7.92 (d, 1H), 7.81 - 7.63 (m, 2H), 7.46 (d, 1H), 5.40 - 5.20 (m, 1H), 4.90 (d, 1H), 4.71 (m, 1H), 4.40 - 4.20 (m, 2H), 4.09 (d, 2H), 3.70 - 3.34 (m, overlaps with solvent peak), 2.91 (t, 2H), 1.94 (d, 2H), 1.70 - 1.45 (m, 2H).

Example 40 N-(2-((R)-4-cyanothiazolidin-3-yl)-2-oxoethyl)-6-((RS)-3-fluoropiperidin-1yl)quinoline-4-carboxamide

TEA (0.51 ml, 3.7 mmol) was added to a mixture of 6-(3-fluoropiperidin-1-yl)quinoline-4-carboxylic acid, intermediate 90 (100 mg, 0.36 mmol), (R)-3-glycylthiazolidine-4-carbonitrile hydrochloride, intermediate 4 (125 mg, 0.73 mmol), HOBt (279 mg, 1.82 mmol) and EDC (349 mg, 1.82 mmol) in DMF (15 ml) at rt. The mixture was stirred for 15 h at rt under N2(g). The reaction mixture was diluted with water (25 ml) and extracted with EtOAc (3x25 ml). The combined organic layers were dried over Na2SO4, filtered and evaporated. The residue was purified by preparative TLC (DCM:MeOH, 12:1) and further purified by preparative HPLC, PrepMethod C (gradient 14-25%) to give the title compound (28 mg, 18%) as a yellow solid; HRMS (ESI) m/z [M+H] ⁺ calcd for C ₂₁ H ₂₃ FN ₅ O ₂ S: 428.1550 found: 428.1514;

1H NMR (300 MHz, DMSO- _d6 ) δ 8.99 (t, 1H), 8.66 (d, 1H), 7.87 (d, 1H), 7.75 - 7.55 (m, 2H ), 7.39 (d, 1H),

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4.87 (d, 1H), 4.72 (d, 1H), 5.40 - 5.20 (m, 1H), 5.00 - 4.50 (m, 3H), 4.30 (d, 1H), 3.66 - 3.20 (m, overlaps with solvent peak), 2.06 - 1.47 (4H, m).

Example 41 N-(2-((R)-4-cyanothiazolidin-3-yl)-2-oxoethyl)-6-((RS)-3-methoxypiperidin-1yl)quinoline-4-carboxamide

DIPEA (0.73 mL, 4.2 mmol) was added to a mixture of 6-(3-methoxypiperidin-1-yl)quinoline-4-carboxylic acid, intermediate 92 (120 mg, 0.42 mmol), (R)-3-glycylthiazolidine-4-carbonitrile hydrochloride, intermediate 4 (144 mg, 0.84 mmol), and HATU (478 mg, 1.26 mmol) in DMF (15 mL) at rt. The mixture was stirred for 15 h at rt under N2(g). The reaction mixture was diluted with water (20 mL) and extracted with EtOAc (3x25 mL). The combined organic phases were washed with brine (20 mL). _The organic layer was dried over _Na2SO4 , filtered and evaporated to give a yellow oil which was purified by preparative TLC (DCM:MeOH, 10:1) and then further purified by preparative HPLC, PrepMethod P (57-67% gradient) to give the title compound ( ₁₁ mg, 6%) as a yellow solid; HRMS (ESI) m/z [M _{+H]+ calcd for C22H26N5O3S : 440.1750} , found: 440.1722;

Ή NMR (300 MHz, DMSO-d ₆ ) δ 9.10 - 8.90 (m, 1H), 8.64 (d, 1H), 7.86 (d, 1H), 7.77 - 7.56 (m, 2H), 7.38 (d, 1H), 5.40 - 5.20 (m, 1H), 4.87 (d, 1H), 4.70 (d, 1H), 4.28 (d, 2H), 3.85 -3.70 (m, 1H), 3.66 - 3.33 (m, overlaps with solvent peak), 3.10 - 2.80 (m, 2H), 2.10 - 1.72 (2H, d), 1.65-1.30 (m, 2H).

Example 42

DIPEA (0.22 ml, 1.3 mmol) was added to a stirred suspension of 6-(4-methoxy-4-methylpiperidin-1-yl)quinoline-4-carboxylic acid, intermediate 94 (75 mg, 0.25 mmol), (R)-3-glycylthiazolidine-4-carbonitrile hydrochloride, intermediate 4 (104 mg, 0.50 mmol), HOBt (101 mg, 0.75 mmol), and EDC (144 mg, 0.75 mmol) in MeCN (5 ml) and EtOAc (5 ml) at 25 °C. The resulting solution was stirred at 50 °C for 2 h. The solvent was removed under reduced pressure. The residue was redissolved in a mixture of sat. NaHCO ₃ solution (aq, 25 ml) and EtOAc (100 ml). The phases were separated, the aqueous layer was extracted with EtOAc (4x50 ml).

The organic layers were combined and washed with water (3x25 mL). _The organic layer was dried over _Na2SO4 , filtered and evaporated. The crude product was purified by preparative HPLC, PrepMethod C (16-26% gradient) to give the title compound (70 mg, 61%) as a yellow solid; HRMS (ESI) m/z [ _{M +} H]+ calcd for _C23H28N5O3S : _454.1908 found: 454.1918;

¹ H NMR (300 MHz, DMSO-d6) δ 8.99 (t, 1H), 8.64 (d, 1H), 7.85 (d, 1H), 7.75 - 7.55 (m, 2H), 7.38 (d, 1H), 5.40 - 5.20 (m, 1H), 4.88 (d, 1H), 4.69 (d, 1H), 4.32 - 4.22 (m, 2H), 3.55 - 3.33 (m, overlaps with solvent peak), 3.25 - 3.13 (m, overlaps with solvent peak), 1.90 - 1.68 (m, 2H), 1.66 - 1.49 (m, 2H), 1.12 (s, 3H).

Example 43. (R)-N-(2-(4-cyanothiazolidin-3-yl)-2-oxoethyl)-6-(4-isopropoxypiperidin-1yl)quinoline-4-carboxamide

DIPEA (0.17 ml, 0.95 mmol) was added to a mixture of 6-(4-isopropoxypiperidin-1-yl)quinoline-4-carboxylic acid, intermediate 96 (100 mg, 0.32 mmol), (R)-3-glycylthiazolidine-4-carbonitrile hydrochloride, intermediate 4 (99 mg, 0.48 mmol), EDC (91 mg, 0.48 mmol) and HOBt (73 mg, 0.48 mmol) in MeCN (5 ml) and EtOAc (5 ml). The reaction mixture was stirred at 50 °C for 2 h. The solvent was removed under reduced pressure. The residue was diluted with EtOAc and washed with water. The organic layer was dried over Na ₂ SO ₄ , filtered and evaporated. The crude product was purified by preparative HPLC, PrepMethod C (20-30% gradient), to give the title compound (105 mg, 71%) as a yellow solid; HRMS

- 196 048482 (ESI) mass/charge [M+H]+ calc. for C24H30N5O3S: 468.2064 found value: 468.2062;

1H NMR (300 MHz, CD3OD) δ 8.62 (d, 1H), 7.90 (d, 1H), 7.75 (s, 1H), 7.67 (dd, 1H), 7.49 (d, 1H), 5.43-5.23 (m, 1H), 4.90-4.65 (m, overlaps with solvent peak), 4.38 (s, 2H), 3.93-3.75 (m, 3H), 3.74-3.55 (m, 1H), 3.52-3.35 (m, 2H), 3.20-3.05 (m, 2H), 2.13-1.93 (m, 2H), 1.79-1.55 (m, 2H), 1.16 (d, 6H).

Example 44 carboxamide

DIPEA (0.43 ml, 2.5 mmol) was added to a mixture of 6-(4,4-difluoro-2-methylpiperidin-1-yl)quinoline-4-carboxylic acid, intermediate 98 (150 mg, 0.49 mmol), (R)-3-glycylthiazolidine-4-carbonitrile hydrochloride, intermediate 4 (153 mg, 0.73 mmol), EDC (141 mg, 0.73 mmol) and HOBt (112 mg, 0.73 mmol) in EtOAc (3 ml) and MeCN (3 ml). The reaction mixture was stirred at 40 °C for 4 h. The solvent was removed under reduced pressure. The residue was redissolved in EtOAc and washed with water. The organic layer was dried over Na ₂ SO ₄ , filtered and evaporated. The crude product was purified by preparative HPLC, PrepMethod P (22-33% gradient) to give the title compound (120 mg, 53%) as a yellow solid; HRMS (ESI) m/z [M _{+ H} ]+ calcd for _{C22H24F2N5O2S} : _460.1614 found: _460.1608 ;

1H NMR (400 MHz, CD3OD) δ 8.68 (d, 1H), 7.96 (d, 1H), 7.86 (dd, 1H), 7.71 (dd, 1H), 7.52 (dd, 1H), 5.38 - 5.32 (m, 1H), 4.83 - 4.73 (m, overlaps with solvent peak), 4.59 - 4.44 (m, 1H), 4.42 - 4.31 (m, 2H), 3.93 - 3.69 (m, 1H), 3.50 - 3.33 (m, overlaps with solvent peak), 2.38 - 1.96 (m, 4H), 1.23 (td, 3H).

Example 45

DIPEA (0.27 ml, 1.6 mmol) was added to a solution of (S)-6-(2-(fluoromethyl)niperidin-1-yl)quinoline-4-carboxylic acid, intermediate 100 (90 mg, 0.31 mmol), (R)-3-glycylthiazolidine-4-carbonitrile hydrochloride, intermediate 4 (97 mg, 0.47 mmol), EDC (90 mg, 0.47 mmol) and HOBt (72 mg, 0.47 mmol) in EtOAc (4 ml) and MeCN (4 ml). The reaction mixture was stirred at 40 °C for 3 h. The solvent was removed under reduced pressure. The residue was diluted with EtOAc and washed with water. The organic layer was dried over Na2SO4, filtered and evaporated. The crude product was purified by preparative HPLC, PrepMethod P (17-27% gradient) to give the title compound ( ₄₅ mg, 33%) as a yellow solid; HRMS (ESI) m/z [ _{M+H]+ calcd for C22H25FN5O2S : 442.1708} found: 442.1708;

1H NMR (300 MHz, CD3OD) δ 8.59 (d, 1H), 7.89 (d, 1H), 7.75 - 7.55 (m, 2H), 7.47 (d, 1H), 5.40 - 5.27 (m, 1H), 4.87 - 4.65 (m, overlaps with solvent peak), 4.58 - 4.43 (m, 2H), 4.37 (s, 2H), 3.86 - 3.66 (m, 1H), 3.54 - 3.34 (m, overlaps with solvent peak), 3.25 - 3.13 (m, 1H), 2.03 - 1.60 (m, 6H).

Example 46

DIPEA (0.54 ml, 3.1 mmol) was added to a stirred suspension of 6-(5-azaspiro[2.5]octan-5-yl)quinoline-4-carboxylic acid, intermediate 102 (107 mg, 0.31 mmol), (R)-3-glycylthiazolidine-4-carbonitrile hydrochloride, intermediate 4 (129 mg, 0.62 mmol), and TBTU (354 mg, 0.93 mmol) in MeCN (5 ml) and EtOAc (5 ml) at 9 °C. The resulting solution was stirred at 9 °C overnight. The solvent was removed under reduced pressure. The residue was dissolved in a mixture of sat. NaHCO ₃ (aq., 60 ml) and EtOAc (80 ml). The aqueous layer was extracted with EtOAc (4x75 mL). The organic layers were combined and washed with water (4x50 mL). The aqueous layers were combined and extracted with EtOAc (3x25 mL). _The organic layers were combined and dried over _Na2SO4 , filtered and evaporated. The crude product was purified by preparative HPLC, PrepMethod P (16-26% gradient) to give the title compound (45 mg, 32%) as an orange solid; HRMS (ESI) m/z [ _{M+H]+ calcd for C23H26N5O2S : 436.1802 ,} found value

- 197 048482 number: 436.1784;

1H NMR (300 MHz, DMSO-d6) δ 8.99 (t, 1H), 8.64 (d, 1H), 7.85 (d, 1H), 7.70 - 7.50 (m, 2H), 7.38 (d, 1H), 5.31 (dd, 1H), 4.89 (d, 1H), 4.71 (d, 1H), 4.37 - 4.20 (m, 2H), 3.50 - 3.20 (m, overlaps with solvent peak), 3.16 (s, 2H), 1.89 - 1.69 (m, 2H), 1.53 - 1.35 (m, 2H), 0.63 - 0.39 (m, 2H), 0.38 - 0.20 (m, 2H).

Example 47. (R)-N-(2-(4-cyanothiazolidin-3-yl)-2-oxoethyl)-6-(3,3-difluoropyrrolidin-1yl)quinoline-4-carboxamide

DIPEA (0.63 ml, 3.6 mmol) was added to a mixture of 6-(3,3-difluoropyrrolidin-1-yl)quinoline-4-carboxylic acid, intermediate 104 (200 mg, 0.72 mmol), (R)-3-glycylthiazolidine-4-carbonitrile hydrochloride, intermediate 4 (299 mg, 1.44 mmol), EDC (276 mg, 1.44 mmol), HOBt (194 mg, 1.44 mmol) in EtOAc (6 ml) and MeCN (6 ml). The reaction was heated at 25 °C for 10 h. The solvent was removed under reduced pressure. The reaction mixture was diluted with EtOAc (25 ml) and washed with water (3 x 10 ml). _The organic layer was dried over _Na2SO4 , filtered and evaporated. The crude product was purified by preparative HPLC, PrepMethod C ( _17-29 % gradient) to give the title compound (120 mg, 38%) as a yellow solid; HRMS (ESI) m/z [M ₊ H]+ calcd for _{C20H20F2N5O2S} : 432.1300, found: _{432.1310 ;}

1H NMR (300 MHz, DMSO-d6) δ 8.97 (t, 1H), 8.63 (d, 1H), 7.93 (d, 1H), 7.43 - 7.30 (m, 3H), 5.40 - 5.20 (m, 1H), 4.88 (d, 1H), 4.70 (d, 1H), 4.29 (d2H), 3.85 (t, 2H), 3.63 (t, 2H), 3.44 - 3.32 (m, overlaps with solvent peak), 2.70 -2.50 (m, overlaps with solvent peak).

Example 48

TEA (2.07 mL, 14.8 mmol) was added to a stirred suspension of 6-(3,3-dimethylpyrrolidin-1yl)quinoline-4-carboxylic acid, intermediate 106 (347 mg, 0.74 mmol), (R)-3-glycylthiazolidine-4-carbonitrile hydrochloride, intermediate 4 (385 mg, 1.86 mmol), HOBt (568 mg, 3.71 mmol), and EDC (711 mg, 3.71 mmol) in MeCN (7 mL) and EtOAc (7 mL) at 7 °C. The resulting suspension was stirred at 7 °C overnight. The solvent was removed under reduced pressure. The residue was suspended in EtOAc and washed with a solution of sat. NaHCO ₃ (50 mL). The aqueous layer was extracted with EtOAc (4 x 50 mL). The organic layers were combined and washed with water (4 x 20 mL) and concentrated under reduced pressure. The crude product was purified by preparative HPLC, PrepMethod P, to give the title compound (174 mg, 55%) as an orange solid; HRMS (ESI) m/z [M+H]+ calcd for C ₂₂ H ₂₆ N ₅ O ₂ S: 424.1802 found: 424.1806;

1H NMR (300 MHz, DMSO-d6) δ 8.91 (t, 1H), 8.53 (d, 1H), 7.84 (d, 1H), 7.34 (d, 1H), 7.29 - 7.15 (m, 2H), 5.30 (dd, 1H), 4.89 (d, 1H), 4.71 (d, 1H), 4.27 (d, 2H), 3.51 - 3.33 (m, overlaps with solvent peak), 3.15 (s, 2H), 1.80 (t, 2H), 1.14 (s, 3H), 1.13 (s, H).

Example 49

DIPEA (2.12 ml, 12.2 mmol) was added to a mixture of 6-(5-azaspiro[2.4]heptan-5-yl)quinoline-4-carboxylic acid, intermediate 108 (346 mg, 0.61 mmol), (R)-3-glycylthiazolidine-4-carbonitrile hydrochloride, intermediate 4 (253 mg, 1.22 mmol), HOBt (465 mg, 3.04 mmol), and EDC (583 mg, 3.04 mmol) in EtOAc (8 ml) and MeCN (8 ml) at 5 °C. The resulting solution was stirred at 5 °C overnight. The solvent was removed under reduced pressure. The residue was dissolved in a mixture of sat. NaHCO ₃ (aq., 80 ml) and EtOAc (100 ml). The phases were separated and the aqueous layer was extracted with EtOAc (4x100 mL). The organic layers were combined and washed with water (4x25 mL). The aqueous layers were combined and extracted with EtOAc (3x20 mL). _The organic layers were combined, dried over _Na2SO4 , filtered and evaporated. The crude product was purified by preparative HPLC, PrepMethod P, to give the title compound (120 mg, 47%).

- 198 048482 as an _orange solid; HRMS (ESI) m/z [M+H]+ calcd for _C22H24N5O2S : _422.1646 , found: 422.1654;

¹ H NMR (300 MHz, DMSO-d6) δ 8.91 (t, 1H), 8.54 (d, 1H), 7.85 (d, 1H), 7.34 (d, 1H), 7.30 - 7.14 (m, 2H), 5.29 (dd, 1H), 4.88 (d, 1H), 4.70 (d, 1H), 4.27 (d, 2H), 3.54 (t, 2H), 3.40 - 3.25 (m, overlaps with solvent peak), 1.94 (t, 2H), 0.75 - 0.57 (m, 4H).

Example 50. N-(2-((R)-4-cyanothiazolidin-3-yl)-2-oxoethyl)-6-((3R,4S)-3,4-difluoropyrrolidin-1yl)quinoline-4-carboxamide

TEA (1.86 mL, 13.4 mmol) was added to a stirred suspension of 6-((3S,4R)-3,4-difluoropyrrolidin-1-yl)quinoline-4-carboxylic acid, intermediate 110 (335 mg, 0.67 mmol), (R)-3-glycylthiozolidine-4-carbonitrileα hydrochloride, intermediate 4 (347 mg, 1.67 mmol), HOBt (511 mg, 3.34 mmol), and EDC (640 mg, 3.34 mmol) in EtOAc (9 mL) and MeCN (9 mL) at 5 °C. The resulting suspension was stirred at 5 °C overnight. The solvent was removed under reduced pressure. The residue was suspended in sat. NaHCO ₃ solution (50 ml) and extracted with EtOAc (4x50 ml). The organic layers were combined and washed with water (4x25 ml). The aqueous layers were combined and extracted with EtOAc (3x25 ml). The organic layers were combined and dried over Na ₂ SO ₄ , filtered and evaporated. The crude product was purified by preparative HPLC, PrepMethod P, to give the title compound (128 mg, 44%) as a yellow solid; HRMS (ESI) m/z [M+H]+ calcd for C ₂₀ H ₂₀ N ₅ O ₂ S: 432.1300, found: 432.1294;

¹ H NMR (300 MHz, DMSO-d ₆ ) δ 9.06 - 8.89 (m, 1H), 8.62 (d, 1H), 7.93 (d, 1H), 7.40 (d, 1H), 7.38 - 7.30 (m, 2H), 5.65 - 5.25 (m, 3H), 4.89 (d, 1H), 4.72 (d, 1H), 4.34 - 4.15 (m, 2H), 3.92 - 3.75 (m, 2H), 3.71 - 3.53 (m, 2H), 3.41 - 3.34 (m, overlaps with solvent peak).

Example 51

DIPEA (2.64 mL, 15.1 mmol) was added to a stirred solution of (S)-6-(3-fluoropyrrolidin-1yl)quinoline-4-carboxylic acid, intermediate 112 (282 mg, 0.76 mmol), (R)-3-glycylthiazolidine-4-carbonitrile hydrochloride, intermediate 4 (392 mg, 1.89 mmol), and TBTU (860 mg, 2.27 mmol) in EtOAc (7 mL) and MeCN (7 mL) at 6 °C. The resulting solution was stirred at 5 °C overnight. The solvent was removed under reduced pressure. The residue was dissolved in a mixture of sat. NaHCO ₃ (aq., 70 mL) and EtOAc (100 mL). The phases were separated and the aqueous layer was extracted with EtOAc (4 x 100 mL). The organic layers were combined and washed with water (4 x 25 mL). The aqueous layers were combined and extracted with EtOAc (4 x 20 mL). The organic layers were combined, dried over Na ₂ SO ₄ , filtered and evaporated. The crude product was purified by preparative HPLC, PrepMethod P, to give the title compound (120 mg, 38%) as an orange solid; HRMS (ESI) m/z [M+H]+ calcd for C ₂₀ H ₂₁ FN ₅ O ₂ S: 414.1394, found: 414.1384;

¹ H NMR (300 MHz, DMSO-d ₆ ) δ 8.95 (t, 1H), 8.60 (d, 1H), 7.90 (d, 1H), 7.45 - 7.30 (m, 3H), 5.49 (d, 1H), 5.36 - 5.25 (m, 1H), 4.89 (d, 1H), 4.72 (d, 1H), 4.30 (d, 2H), 3.80 - 3.34 (m, overlaps with solvent peak), 2.43 - 2.01 (m, 2H).

Example 52 N-(2-((R)-4-cyanothiazolidin-3-yl)-2-oxoethyl)-6-((R)-3-fluoropyrrolidin-1yl)quinoline-4-carboxamide

DIPEA (1.39 mL, 7.96 mmol) was added to a stirred solution of (R)-6-(3-fluoropyrrolidin-1yl)quinoline-4-carboxylic acid, intermediate 114 (297 mg, 0.80 mmol), (R)-3-glycylthiazolidine-4-carbonitrile hydrochloride, intermediate 4 (248 mg, 1.19 mmol), and TBTU (905 mg, 2.39 mmol) in MeCN (7 mL) and EtOAc (7 mL) at 6 °C. The resulting solution was stirred at 6 °C overnight. The solvent was removed under reduced pressure. The residue was dissolved with a mixture of

- 199 048482 saturated NaHCO ₃ solution (70 mL) and EtOAc (100 mL). The phases were separated and the aqueous layer was extracted with EtOAc (4x100 mL). The organic layers were combined and washed with water (4x50 mL). The aqueous layers were combined and extracted with EtOAc (4x20 mL). The organic layers were combined and dried over Na ₂ SO ₄ , filtered and evaporated. The crude product was purified by preparative HPLC, PrepMethod P, to give the title compound (113 mg, 34%) as an orange solid; HRMS (ESI) m/z [M+H]+ calcd. for C ₂₀ H ₂₁ FN ₅ O ₂ S: 414.1394, found value: 414.1406;

1H NMR (300 MHz, DMSO-d6) δ 8.93 (t, 1H), 8.59 (d, 1H), 7.90 (d, 1H), 7.48 - 7.22 (m, 3H), 5.49 (d, 1H), 5.32 (dd, 1H), 4.89 (d, 1H), 4.72 (d, 1H), 4.35 - 4.24 (m, 2H), 3.74 - 3.68 (m, 1H), 3.64 - 3.37 (m, overlaps with solvent peak), 2.38-2.17 (m, 2H).

Example 53. N-(2-((R)-4-cyanotiazolidin-3-yl)-2-oxoethyl)-6-(hexαhydrocyclopenmα[c]pyrrol2( 1 H)-yl)quinolin-4-carboxamide

DIPEA (0.26 ml, 1.5 mmol) was added to a mixture of 6-(hexahydrocyclopenta[c]pyrrol-2(1H)yl)quinoline-4-carboxylic acid, intermediate 116 (85 mg, 0.30 mmol), (R)-3-glycylthiazolidine-4-carbonitrile hydrochloride, intermediate 4 (94 mg, 0.45 mmol), EDC (87 mg, 0.45 mmol) and HOBt (69 mg, 0.45 mmol) in EtOAc (5 ml) and MeCN (5 ml). The reaction mixture was stirred at 40 °C for 3 h. The solvent was removed under reduced pressure. The residue was diluted with EtOAc and washed with water. The organic layer was dried over Na ₂ SO ₄ , filtered and evaporated. The crude product was purified by preparative HPLC, PrepMethod P (2333% gradient) to give the title compound (40 mg, 30%) as a yellow solid; HRMS (ESI) m/z [M _{+H]+ calcd for C23H26N5O2S : 436.1802} , found: 436.1808 _;

1H NMR (300 MHz, DMSO-d ₆ ) δ 8.93 (t, 1H), 8.58 (d, 1H), 7.86 (d, 1H), 7.40 - 7.26 (m, 3H), 5.32 (dd, 1H), 4.89 (d, 1H), 4.71 (d, 1H), 4.29 (d, 2H), 3.62 - 3.50 (m, 2H), 3.45 - 3.33 (m, overlaps with solvent peak), 3.19 - 3.10 (m, 2H), 2.83 - 2.77 (m, 3H), 1.92 - 1.43 (m, 5H).

Example 54 N-(2-((R)-4-cyanothiazolidin-3-yl)-2-oxoethyl)-6-((S)-3-methylpyrrolidin-1yl)quinoline-4-carboxamide

DIPEA (0.20 ml, 1.2 mmol) was added to a mixture of (S)-6-(3-methylpyrrolidin-1-yl)quinoline-4-carboxylic acid, intermediate 118 (100 mg, 0.39 mmol), (R)-3-glycylthiazolidine-4-carbonitrile hydrochloride, intermediate 4 (100 mg, 0.59 mmol), and HATU (297 mg, 0.78 mmol) in MeCN (10 ml) and EtOAc (10 ml). The reaction mixture was stirred at 25 °C for 2 h. The solvent was removed under reduced pressure. The residue was purified by preparative TLC (DCM:MeOH, 8:1) and then further purified by preparative HPLC, PrepMethod F (20-30% gradient) to give the title compound (56 mg, 35%) as a red solid; HRMS (ESI) m/z [M+H]+ calcd for C ₂₁ H ₂₄ N ₅ O ₂ S: 410.1646, found: 410.1634;

1H NMR (400 MHz, DMSO-d ₆ ) δ 9.12 (t, 1H), 8.71 (d, 1H), 7.97 (d, 1H), 7.60 (d, 1H), 7.47 (dd, 1H), 7.30 (d, 1H), 5.31 (dd, 1H), 4.90 (d, 1H), 4.72 (d, 1H), 4.49 - 4.17 (m, 2H), 3.66 - 3.30 (m, overlaps with solvent peak), 3.06 -2.92 (m, 1H), 2.47-2.30 (m, 1H), 2.22-2.10 (m, 1H), 1.75 - 1.57 (m, 1H), 1.13 (d, 3H).

Example 55 N-(2-((R)-4-cyanothiazolidin-3-yl)-2-oxoethyl)-6-((R)-3-methylpyrrolidin-1yl)quinoline-4-carboxamide

DIPEA (0.36 ml, 2.1 mmol) was added to a mixture of (R)-6-(3-methylpyrrolidin-1-yl)quinoline-4-carboxylic acid, intermediate 120 (175 mg, 0.68 mmol), (R)-3-glycylthiazolidine-4-carbonitrile hydrochloride, intermediate 4 (175 mg, 1.02 mmol), and HATU (519 mg, 1.37 mmol) in MeCN (10 ml) and EtOAc (10 ml). The reaction mixture was stirred at 25 °C for 2 h. The solvent was removed under reduced pressure. The residue was purified by preparative TLC (DCM:MeOH, 8:1) and then further purified by preparative HPLC, PrepMethod F

- 200 048482 (gradient 17-36%) to give the title compound (80 mg, 29%) as a red solid; HRMS (ESI) m/z [M _{+H]+ calcd for C21H24N5O2S :} 410.1646, found _{: 410.1650} ;

1H NMR (400 MHz, DMSO-d ₆ ) δ 9.11 (t, 1H), 8.71 (d, 1H), 7.97 (d, 1H), 7.60 (d, 1H), 7.47 (dd, 1H), 7.30 (d, 1H), 5.32 (dd, 1H), 4.90 (d, 1H), 4.73 (d, 1H), 4.45 - 4.20 (m, 2H), 3.66 - 3.57 (m, 1H), 3.56 - 3.33 (m, overlaps with solvent peak), 3.04 - 2.93 (m, 1H), 2.47 - 2.30 (m, 1H), 2.25 - 2.05 (m, 1H), 1.76 -1.56 (m, 1H), 1.13 (d, 3H).

Example 56

DIPEA (0.37 ml, 2.1 mmol) was added to a mixture of (S)-6-(2-(trifluoromethyl)pyrrolidin-1-yl)quinoline-4-carboxylic acid, intermediate 122 (130 mg, 0.42 mmol), (R)-3-glycylthiazolidine-4-carbonitrile hydrochloride, intermediate 4 (131 mg, 0.63 mmol), EDC (161 mg, 0.84 mmol) and HOBt (128 mg, 0.84 mmol) in EtOAc (5 ml) and MeCN (5 ml). The reaction mixture was stirred at 50 °C for 4 h. The solvent was removed under reduced pressure. The residue was redissolved in EtOAc and washed with water. The organic layer was dried over Na ₂ SO ₄ , filtered and evaporated. The crude product was purified by preparative HPLC, PrepMethod P (25-35% gradient) to give the title compound (110 mg, 57%) as a yellow solid; HRMS (ESI) m/z [M+H]+ calcd for C ₂₁ H ₂₁ F ₃ N ₅ O ₂ S: 464.1362, found: 464.1366;

1H NMR (400 MHz, CD3OD) δ 8.61 (d, 1H), 7.94 (d, 1H), 7.75 - 7.61 (m, 1H), 7.60 - 7.40 (m, 2H), 5.32 (dd, 1H), 4.84 - 4.66 (m, overlaps with solvent peak), 4.47 (d, 1H), 4.31 (d, H), 3.91 - 3.74 (m, 1H), 3.50 - 3.34 (m, overlaps with solvent peak), 2.38 - 2.06 (m, 4H).

Example 57

DIPEA (0.40 ml, 2.3 mmol) was added to a mixture of 6-(2,2-dimethylpyrrolidin-1-yl)quinoline-4-carboxylic acid, intermediate 124 (125 mg, 0.46 mmol), (R)-3-glycylthiazolidine-4-carbonitrile hydrochloride, intermediate 4 (144 mg, 0.69 mmol), EDC (133 mg, 0.69 mmol) and HOBt (106 mg, 0.69 mmol) in EtOAc (5 ml) and MeCN (5 ml). The reaction mixture was stirred at 40 °C for 4 h. The solvent was removed under reduced pressure. The residue was dissolved in EtOAc and washed with water. The organic layer was dried over Na ₂ SO ₄ , filtered and evaporated. The crude product was purified by preparative HPLC, PrepMethod P (15-25% gradient) to give the title compound (110 mg, 56%) as a yellow solid; HRMS (ESI) _m /z [M+H]+ calcd for _C22H26N5O2S : _424.1802 , found: _424.1810 ;

1H NMR (300 MHz, CD3OD) δ 8.49 (d, 1H), 7.83 (d, 1H), 7.54 (dd, 1H), 7.46 (d, 1H), 7.36 (d, 1H), 5.40-5.20 (m, 1H), 4.84-4.65 (m, overlaps with solvent peak), 4.37 (s, 2H), 3.58-3.48 (m, 2H), 3.47-3.33 (m overlaps with solvent peak), 2.10-1.90 (m, 4H), 1.53 (s, 6H).

Example 58 quinoline-4-carboxamide

DIPEA (0.47 ml, 2.7 mmol) was added to a mixture of (R)-6-(6-(fluoromethyl)-5-azaspiro[2.4]heptan-5yl)quinoline-4-carboxylic acid, intermediate 126 (160 mg, 0.53 mmol), (R)-3-glycylthiazolidine-4-carbonitrile hydrochloride, intermediate 4 (166 mg, 0.80 mmol), EDC (204 mg, 1.07 mmol) and HOBt (163 mg, 1.07 mmol) in EtOAc (6 ml) and MeCN (6 ml). The reaction mixture was stirred at 50 °C for 5 h. The solvent was removed under reduced pressure. The residue was redissolved in EtOAc and washed with water. The organic layer was dried over Na2SO4, filtered and evaporated. The crude product was purified by preparative HPLC, PrepMethod P (18-28% gradient) to give the title compound (145 mg, 60%) as a yellow solid; HRMS (ESI) m/ _z [M _{+H]+ calcd for C23H25FN5O2S : 454.1708} , found: 454.1712;

- 201 048482

Ή NMR (300 MHz, DMSO-d6) δ 8.94 (t, 1H), 8.57 (d, 1H), 7.87 (d, 1H), 7.44 - 7.31 (m, 3H), 5.27 (dd, 1H), 4.87 (d, 1H), 4.73 - 4.12 (m, 6H), 3.51-3.15 (m, overlaps with solvent peak), 2.35 (dd, 1H), 1.64 (d, 1H), 0.75 - 0.52 (m, 4H).

Example 59. N-(2-((R)-4-cyanothiazolidin-3-yl)-2-oxoethyl)-6-((R)-3-fluoroazepan-1-yl)quinoline-4-carboxamide

TEA (0.50 ml, 3.6 mmol) was added to (R)-6-(3-fluoroazepan-1-yl)quinoline-4-carboxylic acid, intermediate 130 (52 mg, 0.18 mmol), (R)-3-glycylthiazolidine-4-carbonitrile hydrochloride, intermediate 4 (150 mg, 0.72 mmol), HOBt (276 mg, 1.80 mmol) and EDC (346 mg, 1.80 mmol) in DMF (5 ml) at 15 °C. The resulting solution was stirred at 40 °C overnight under N2 (g). The reaction mixture was diluted with sat. _NaHCO3 (30 ml) and extracted with EtOAc (9 x 50 ml). The organic layers were combined and washed with brine (5 x 200 mL). The organic layer was dried over Na ₂ SO ₄ , filtered and evaporated to give the crude product. The crude product was purified by preparative HPLC, PrepMethod F, to give the title compound (39 mg, 49%) as an orange solid; HRMS (ESI) m/z [M+H]+ calcd for C ₂₂ H ₂₅ FN ₅ O ₂ S: 442.1708, found: 442.1702;

1H NMR (300 MHz, DMSO-d6) δ 9.05 - 8.80 (m, 1H), 8.57 (d, 1H), 7.85 (d, 1H), 7.59 - 7.41 (m, 2H), 7.35 (d, 1H), 5.40 - 5.20 (m, 1H), 5.18 - 4.92 (m, 1H), 4.88 (d, 1H), 4.72 (d, 1H), 4.28 (d, 2H), 3.96 -3.81 (m, 1H), 3.63 - 3.34 (m, overlaps with solvent peak), 2.00 - 1.58 (m, 5H), 1.52 - 1.28 (m, 1H).

Example 60. N-(2-((R)-4-cyanothiazolidin-3-yl)-2-oxoethyl)-6-((S)-3-fluoroazepan-1-yl)quinoline-4-carboxamide

TEA (0.68 ml, 4.9 mmol) was added to (S)-6-(3-fluoroazepan-1-yl)quinoline-4-carboxylic acid, intermediate 132 (70 mg, 0.24 mmol), (R)-3-glycylthiazolidine-4-carbonitrile hydrochloride, intermediate 4 (202 mg, 0.97 mmol), HOBt (372 mg, 2.43 mmol) and EDC (465 mg, 2.43 mmol) in DMF (10 ml) at 13 °C. The resulting suspension was stirred at 30 °C for 5 h under N ₂ (g). The reaction mixture was diluted with saturated NaHCO ₃ (50 ml) and extracted with EtOAc (9 x 50 ml). The organic layers were combined and washed with brine (5 x 200 mL). The organic layer was dried over Na ₂ SO ₄ , filtered and evaporated to give the crude product. The crude product was purified by preparative HPLC, PrepMethod P, to give the title compound (58 mg, 54%) as an orange solid; HRMS (ESI) m/z [M+H]+ calcd for C ₂₂ H ₂₅ FN ₅ O ₂ S: 442.1708, found: 442.1698;

1H NMR (300 MHz, DMSO-d6) δ 8.93 (t, 1H), 8.56 (d, 1H), 7.83 (d, 1H), 7.58 - 7.41 (m, 2H), 7.34 (d, 1H), 5.33 - 4.80 (m, 3H), 4.76 - 4.50 (m, 1H), 4.36 - 4.15 (m, 2H), 4.07 - 3.73 (m, 2H), 3.70 - 3.30 (m, overlaps with solvent peak), 1.89 - 1.32 (m, 6H).

Example 61 carboxamide

DIPEA (0.54 ml, 3.1 mmol) was added to a stirred suspension of (R)-6-(7-methyl-1,4-oxazepan4-yl)quinoline-4-carboxylic acid, intermediate 134 (205 mg, 0.31 mmol), (R)-3-glycylthiazolidine-4-carbonitrile hydrochloride, intermediate 4 (96 mg, 0.46 mmol), and TBTU (350 mg, 0.92 mmol) in EtOAc (5 ml) and MeCN (5 ml) at 4 °C. The resulting solution was stirred at 4 °C overnight. The solvent was removed under reduced pressure. The residue was dissolved in a mixture of saturated NaHCO ₃ solution (70 ml) and EtOAc (100 ml). The phases were separated and the aqueous layer was extracted with EtOAc (3x100 mL). The organic layers were combined and washed with water (4x25 mL). The aqueous layers were combined and extracted with EtOAc (4x50 mL). All organic layers were combined, dried, and refluxed.

- 202 048482 _was washed over _Na2SO4 , filtered and evaporated. The crude product was purified by preparative HPLC, PrepMethod F, to give the title compound (90 mg, 66%) as a yellow solid; HRMS (ESI) m/z [M _{+ H} ]+ calcd for _C22H26N5O3S : 440.1750, found: _440.1746 ;

¹ H NMR (300 MHz, DMSO-d6) δ 8.96 (t, 1H), 8.55 (d, 1H), 7.84 (d1H), 7.55 - 7.40 (m, 2H), 7.32 (d, 1H), 5.39 - 5.19 (m, 1H), 4.89 (d, 1H), 4.70 (d, 1H), 4.37 - 4.16 (m, 2H), 4.01 - 3.81 (m, 2H), 3.79 - 3.34 (m, overlaps with solvent peak), 2.16 - 1.95 (m, 1H), 1.74 - 1.51 (m, 1H), 1.05 (d, 3H).

Example 62 carboxamide

DIPEA (1.14 mL, 6.51 mmol) was added to a stirred suspension of (S)-6-(7-methyl-1,4-oxazenα-4-yl)quinoline-4-carboxylic acid, intermediate 136 (305 mg, 0.33 mmol), (R)-3-glycylthiazolidine-4-carbonitrile hydrochloride, intermediate 4 (135 mg, 0.65 mmol), HOBt (249 mg, 1.63 mmol), and EDC (312 mg, 1.63 mmol) in EtOAc (5 mL) and MeCN (5 mL) at 6 °C. The resulting solution was stirred at 4 °C overnight and then at 40 °C for an additional 4 h. The solvent was removed under reduced pressure. The residue was dissolved in a mixture of sat. _NaHCO3 solution (50 ml) and EtOAc (100 ml). The phases were separated and the aqueous layer was extracted with EtOAc (3x100 ml). The organic layers were combined and washed with water (4x25 ml). All organic layers were combined, dried over Na2SO4, filtered and evaporated. The crude product was purified by preparative HPLC, PrepMethod F, to give the title compound ( ₁₀₀ mg, 70%) as a yellow solid; HRMS (ESI) m/z [M+H] ⁺ _calcd for _C22H26N5O3S : 440.1750, found: _440.1746 ;

¹ H NMR (300 MHz, DMSO-d ₆ ) δ 8.95 (t, 1H), 8.56 (d, 1H), 7.85 (d, 1H), 7.59 - 7.43 (m, 2H), 7.33 (d, 1H), 5.40 - 5.20 (m, 1H), 4.89 (d, 1H), 4.71 (d, 1H), 4.33 - 4.19 (m, 2H), 4.05 - 3.80 (m, 2H), 3.78 -3.23 (m, overlaps with solvent peak), 2.17 - 1.98 (m, 1H), 1.75 - 1.50 (m, 1H), 1.07 (d, 3H).

Example 63 carboxamide

DIPEA (0.79 mL, 4.5 mmol) was added dropwise to a mixture of (R)-6-(3-methyl-1,4-oxazepan-4-yl)quinoline-4-carboxylic acid, intermediate 138 (65 mg, 0.23 mmol), (R)-3-glycylthiazolidine-4-carbonitrile hydrochloride, intermediate 4 (94 mg, 0.45 mmol), HOBt (348 mg, 2.27 mmol), and EDC (435 mg, 2.27 mmol) in MeCN (3 mL) and EtOAc (3 mL) at 10 °C. The resulting solution was stirred at 10 °C overnight under N ₂ (g). The solvent was removed under reduced pressure. The residue was diluted with sat. NaHCO ₃ solution (100 mL) and extracted with EtOAc (6 x 100 mL). The organic layers were combined and washed with brine (5 x 200 mL). The organic layer was dried over Na ₂ SO ₄ , filtered and evaporated. The crude product was purified by preparative HPLC, PrepMethod C, to give the title compound (45 mg, 45%) as an orange solid; HRMS (ESI) m/z [M+H] ⁺ calcd for C ₂₂ H ₂₆ N ₅ O ₃ S: 440.1750, found: 440.1742;

¹ H NMR (300 MHz, DMSO-d6) δ 8.94 (brs, 0.5H), 8.52 (d, 1H), 8.32 (brs, 0.5H), 7.84 (d, 1H), 7.54 - 7.35 (m, 2H), 7.31 (d, 1H), 5.31 (dd, 1H), 4.87 (d, 1H), 4.68 (d, 1H), 4.37 - 4.10 (m, 3H), 4.00 (dd, 1H), 3.97 - 3.72 (m, 2H), 3.61 -3.30 (m, overlaps with solvent peak), 1.93 - 1.64 (m, 2H), 1.07 (d, 3H).

Example 64 carboxamide

DIPEA (0.37 ml, 2.1 mmol) was added to a mixture of (R)-6-(2-methyl-1,4-oxazepan-4-yl)quinoline-4-carboxylic acid, intermediate 140 (100 mg, 0.35 mmol), (R)-3-glycylthiazolidine-4-carbonitrile hydrochloride, intermediate 4 (90 mg, 0.52 mmol), and HATU (266 mg, 0.70 mmol) in MeCN (5 ml) and EtOAc (5 ml). The mixture was stirred under air at 25 °C for

- 203 048482

h. The solvent was removed under reduced pressure. The residue was purified by preparative TLC (DCM:MeOH, 19: ₁ ) then preparative HPLC, PrepMethod F (gradient 15-25%) to give the title compound (30 mg, 20%) as a red solid; HRMS (ESI) m/z [M _{+H]+ calcd for C22H26N5O3S :} 440.1750, found: _440.1724 ;

1H NMR (400 MHz, DMSO-d6) δ 9.18 (t, 1H), 8.74 (d, 1H), 7.98 (d, 1H), 7.74 (dd, 1H), 7.67 - 7.50 (m, 2H), 5.38 - 5.18 (m, 1H), 4.90 (d, 1H), 4.72 (d, 1H), 4.39 - 4.25 (m, 2H), 4.23 - 4.01 (m, 2H), 3.93 - 3.75 (m, 2H), 3.60 - 3.31 (m, overlaps with solvent peak), 3.29 - 3.06 (m, 2H), 2.19 - 1.98 (m, 1H), 1.95 1.80 (m, 1H), 1.20 (d, 3H).

Example 65

DIPEA (0.41 ml, 2.3 mmol) was added to a mixture of (S)-6-(2-methylpyrrolidin-1-yl)quinoline-4-carboxylic acid, intermediate 128 (100 mg, 0.39 mmol), (R)-3-glycylthiazolidine-4-carbonitrile hydrochloride, intermediate 4 (122 mg, 0.59 mmol), and HATU (297 mg, 0.78 mmol) in MeCN (5 ml) and EtOAc (5 ml). The mixture was stirred at 25 °C for 3 h. The solvent was removed under reduced pressure. The residue was purified by preparative TLC (DCM:MeOH, 19:1) and further purified by preparative HPLC, PrepMethod F (20-30% gradient) to give the title compound (35 mg, 22%) as an orange solid; HRMS (ESI) m/z [M+H]+ calcd for C ₂₁ H ₂₄ N ₅ O ₂ S: 410.1646, found: 410.1636;

1H NMR (400 MHz, DMSO-d6) δ 8.93 (t, 1H), 8.55 (d, 1H), 7.86 (d, 1H), 7.39 - 7.18 (m, 3H), 5.40 - 5.25 (m, 1H), 4.90 (d, 1H), 4.72 (d, 1H), 4.37 - 4.19 (m, 2H), 4.15 -4.00 (m, 1H), 3.57 - 3.18 (m, overlaps with solvent peak), 2.16 - 1.94 (m, 3H), 1.80 -1.60 (m, 1H), 1.17 (d, 3H).

Example 66. (R)-N-(2-(4-cyanothiazolidin-3-yl)-2-oxoethyl)-6-(3-methoxyazetidin-1-yl)quinoline-4-carboxamide

HATU (159 mg, 0.42 mmol) was added to a stirred mixture of crude 6-(3-methoxyazetidin-1-yl)quinoline-4-carboxylic acid, intermediate 142 (102 mg, 0.35 mmol), and DIPEA (0.303 mL, 1.74 mmol) in a mixture of MeCN (1.5 mL) and EtOAc (1.5 mL) at rt. The reaction mixture was stirred for 1 min, after which (R)-3-glycylthiazolidine-4-carbonitrile hydrochloride, intermediate 4 (87 mg, 0.42 mmol) was added and the reaction mixture was stirred for 1.5 h at rt. The reaction mixture was diluted with EtOAc (8 mL) and washed with 8% NaHCO ₃ (aq, 6 mL). The aqueous layer was extracted with EtOAc and the combined organic layers were dried over Na ₂ SO ₄ , filtered and concentrated. The residue was purified by preparative HPLC, PrepMethod G (gradient: 5-45%) to give the title compound (0.071 g, 49%) as an orange solid; HRMS (ESI) m/z [M+H]+ calcd for C ₂₀ H ₂₂ N ₅ O ₃ S: 412.1438 found: 412.1442;

^1H NMR (500 MHz, DMSO-d6) δ 9.14 (t, 1H). 8.79 (d, 1H), 7.98 (d, 1H), 7.65 (d, 1H), 7.33 - 7.27 (m, 2H), 5.34 (dd, 1H), 4 .90 (d, 1H), 4.72 (d, 1H), 4.42 - 4.29 (m, 3H), 4.27 - 4.18 (m, 2H), 3.83 (dd, 2H), 3.41 (dd, 1H), 3.36 (dd, 1H), 3.27 (s, 3H).

Example 67 (R)-N-(2-(4-cyanothiazolidin-3-yl)-2-oxoethyl)-6-morpholinoquinoline-4-carboxamide

DIPEA (0.15 mL, 0.87 mmol) was added to a suspension of 6-morpholinoquinoline-4-carboxylic acid, intermediate 144 (75 mg, 0.29 mmol), (R)-3-glycylthiazolidine-4-carbonitrile hydrochloride, intermediate 4 (121 mg, 0.58 mmol), HOBt (53 mg, 0.35 mmol) and EDC (84 mg, 0.44 mmol) in EtOAc (1 mL) and MeCN (1 mL). A clear yellow solution was obtained, which was stirred at rt overnight. The mixture was diluted with EtOAc, washed with sat. _NaHCO3 and brine. The organic phase was dried, filtered and evaporated. The residue was purified by preparative HPLC, PrepMethod E (5-65% gradient) to give the title compound (26 mg, 21%); HRMS (ESI) m/z [M+H]+ calcd for

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C ₂₀ H ₂₂ N ₅ O ₃ S: 412.1438 found value: 412.1437;

1H NMR (400 MHz, CD ₃ CN) δ 8.71 (d, 1H), 8.05 (s, 1H), 7.96 (d, 1H), 7.69 (d, 1H), 7.60 (dd, 1H), 7.43 (d, 1H), 5.24 (dd, 1H), 4.79 - 4.60 (m, 2H), 4.30 (d, 2H), 3.88 - 3.79 (m, 4H), 3.35 - 3.28 (m, 6H).

Example 68. N-(2-((R)-4-cyanothiazolidin-3-yl)-2-oxoethyl)-6-((2R,6S)-2,6-dimethylmorpholino)quinoline-4-carboxamide

A vial was charged with tert-butyl 6-((2R,6S)-2,6-dimethylmorpholino)quinoline-4-carboxylate, intermediate 149 (121 mg, 0.35 mmol), and 90% TFA (aq, 0.5 mL). The vial was heated at 50 °C for 1 h 40 min. The reaction mixture was concentrated and coevaporated from a mixture of H2O and MeCN. MeCN (1.5 mL), EtOAc (1.5 mL) and DIPEA (0.305 mL, 1.75 mmol) were added to the residue, then HATU (0.16 g, 0.42 mmol) was added and the mixture was stirred at 1 min, after which (R)-3-glycylthiazolidine-4-carbonitrile hydrochloride, intermediate 4 (0.087 g, 0.42 mmol) was added. The mixture was stirred at rt for 3 h. The reaction mixture was partitioned between EtOAc (25 mL) and 8% _NaHCO3 (aq, 10 mL). The aqueous layer was extracted with EtOAc (10 mL) and the combined organic layers were concentrated. The residue was purified by preparative HPLC, PrepMethod G (5-45% gradient) to give the title compound (85 mg, 55 _% ) as an orange solid; HRMS (ESI) m/z [M+ _H ]+ calcd for _C22H26N5O3S : _440.1750 found: 440.1756;

^1H NMR (500 MHz, DMSO- _d6 ) δ 9.08 (t, 1H), 8.72 (d, 1H), 7.93 (d, 1H), 7.77 - 7.71 (m, 2H), 7.45 (d, 1H), 5.31 (dd, 1H), 4.90 (d, 1H), 4.71 (d, 1H), 4.36 - 4.27 (m, 2H), 3.89 (dd, 2H), 3.79 - 3.69 (m, 2H), 3.42 (dd, 1H), 3.36 (dd, 1H), 2.42 (t, 2H), 1.25-1.17 (m, 6H).

Example 69. N-(2-((R)-4-cyanothiazolidin-3-yl)-2-oxoethyl)-6-((R)-2-(fluoromethyl)morpholino)quinoline-4-carboxamide

HATU (0.730 g, 1.92 mmol) was added to a stirred mixture of crude (R)-6-(2(fluoromethyl)morpholino)quinoline-4-carboxylic acid, intermediate 146 (1.60 mmol), and DIPEA (1.68 mL, 9.60 mmol) in a mixture of MeCN (7 mL) and EtOAc (7 mL) at rt. The reaction mixture was stirred for 1 min, after which (R)-3-glycylthiazolidine-4-carbonitrileα hydrochloride, intermediate 4 (0.399 g, 1.92 mmol) was added and the reaction mixture was stirred for 1 h at rt. The reaction mixture was diluted with EtOAc (100 mL) and washed successively with 8% _NaHCO3 (aq, 2x20 mL) and H2O (2x10 mL). The organic layer was dried over _Na2SO4 , filtered and concentrated. The residue was purified by silica _gel flash chromatography (EtOAc then EtOAc:MeOH 20:1). The product was further purified twice by preparative HPLC, PrepMethod G (gradients: 0-30% and 5-35%). The product was further purified by silica gel flash chromatography (EtOAc then EtOAc:MeOH, 20:1) to give the title compound (0.314 g, 44%) as a yellow solid; HRMS (ESI) mass/charge [M+H]+ calcd for C ₂₁ H ₂₃ FN ₅ O ₃ S: 444.1500 found value: 444.1506;

1H NMR (500 MHz, DMSO- _d6 ) δ 9.05 (t, 1H), 8.71 (d, 1H), 7.93 (d, 1H), 7.76 (d, 1H), 7. 70 (dd, 1H), 7.42 (d, 1H), 5.32 (dd, 1H), 4.90 (d, 1H), 4.71 (d, 1H), 4.68 - 4.48 (m, 2H), 4.37 - 4.25 (m, 2H), 4.08 - 4.01 (m , 1H), 3.95 - 3.82 (m, 2H), 3.82 - 3.68 (m, 2H), 3.43 (dd, 1H), 3.36 (dd, 1H), 2.82 (td, 1H), 2.68 (t, 1H).

Example 70. N-2-((R)-4-cyanothiazolidin-3-yl)-2-oxoethyl)-6-((2R,6R)-2,6-dimethylmorpholino)quinoline-4-carboxamide

HATU (0.119 g, 0.31 mmol) was added to a stirred mixture of crude 6-((2R,6R)-2,6-dimethylmorpholino)quinoline-4-carboxylic acid, intermediate 148 (0.26 mmol), and DIPEA (0.227 mL, 1.30 mmol) in a mixture of MeCN (1.2 mL) and EtOAc (1.2 mL) at rt. The reaction mixture was stirred for 1 min, after which (R)-3-glycylthiazolidine-4-carbonitrileα hydrochloride, intermediate 4 (0.065 g, 0.31 mmol) was added. The reaction mixture was stirred for 4.5 h.

- 205 048482 at rt. The reaction mixture was diluted with EtOAc (5 mL) and washed with 8% NaHCO3 (aq, 5 mL). The aqueous layer was extracted with EtOAc (3 mL) and _the combined organic layers were dried over _Na2SO4 , filtered and concentrated. The residue was purified by preparative HPLC, PrepMethod G (gradient: 15-55%). The compound was dissolved in EtOAc and the organic layer was washed twice with H2O, concentrated and lyophilized to give the title compound (0.042 g, 37%) as an orange solid; HRMS (ESI) m/z [M+H]+ calcd. for C ₂₂ H ₂₆ N ₅ O ₃ S: 440.1750 found value: 440.1746;

1H NMR (500 MHz, DMSO-d6) δ 9.10 (t, 1H), 8.73 (d, 1H), 7.93 (d, 1H), 7.7 - 7.8 (m, 2H) , 7.49 (d, 1H), 5.31 (dd, 1H), 4.90 (d, 1H), 4.71 (d, 1H), 4.25 - 4.39 (m, 2H), 4.07 - 4.16 (m, 2H), 3.43 (td, 3H), 3.36 (dd, 1H), 3.12 (dd, 2H), 1.24 (d, 6H).

Example 71

A vial was charged with tert-butyl (S)-6-(2-(fluoromethyl)morpholino)quinoline-4-carboxylate, intermediate 150 (121 mg, 0.35 mmol), and 90% TFA (aq, 0.5 mL) and the reaction mixture was heated at 50 °C for 1 h 40 min. The reaction mixture was concentrated and the residue was co-evaporated from a mixture of H2O and MeCN. MeCN (1.5 mL), EtOAc (1.5 mL), and DIPEA (0.305 mL, 1.75 mmol) were added to the residue, followed by HATU (0.160 g, 0.42 mmol). The mixture was stirred for 1 min, after which (R)-3-glycylthiazolidine-4-carbonitrile hydrochloride, intermediate 4 (0.087 g, 0.42 mmol) was added. The mixture was stirred at rt for 3 h. The reaction mixture was partitioned between EtOAc (25 mL) and 8% _NaHCO3 (aq, 10 mL). The aqueous layer was extracted with EtOAc (10 mL) and the combined organic layers were concentrated. The residue was purified by preparative HPLC, PrepMethod G (5-45% gradient), to give the title compound (65 mg, 42%) as an orange solid; HRMS (ESI) m/z [M+H]+ calcd. for C ₂₁ H ₂₃ FN ₅ O ₃ S: 444.1500 found value: 444.1496;

1H NMR (500 MHz, DMSO-d6) δ 9.06 (t, 1H), 8.72 (d, 1H), 7.94 (d, 1H), 7.78 (d, 1H), 7.71 (dd, 1H), 7.44 (d, 1H), 5.34 (dd, 1H), 4.90 (d, 1H), 4.71 (d, 1H), 4.68 - 4.47 (m, 2H), 4.37 - 4.25 (m, 2H), 4.08 - 4.01 (m, 1H) , 3.93 - 3.82 (m, 2H), 3.82 - 3.68 (m, 2H), 3.42 (dd, 1H), 3.36 (dd, 1H), 2.85 (td, 1H), 2.68 (t, 1H).

Example 72. N-(2-((R)-4-cyanothiazolidin-3-yl)-2-oxoethyl)-6-((R)-2-methylmorpholino)quinoline-4-carboxamide

HATU (0.160 g, 0.42 mmol) was added to a stirred mixture of crude (R)-6-(2-methylmorpholino)quinoline-4-carboxylic acid, intermediate 152 (0.134 g), and DIPEA (0.306 mL, 1.75 mmol) in MeCN/EtOAc (3 mL, 1:1) at rt. The reaction mixture was stirred for 1 min, after which (R)-3-glycylthiazolidine-4-carbonitrile hydrochloride, intermediate 4 (0.087 g, 0.42 mmol) was added. The reaction mixture was stirred for 45 min at rt. The reaction mixture was diluted with EtOAc (6 mL) and washed with 8% NaHCO3 (aq, 6 mL). The aqueous layer was extracted with EtOAc (2x3 mL) and _the combined organic layers were dried over _Na2SO4 , filtered and concentrated. The residue was purified by preparative HPLC, PrepMethod G (5-55% gradient) to give the title compound ( ₅₆ mg, 38%) as a red/orange solid; HRMS (ESI) m/z [M+ _H ]+ calcd for _C21H24N5O3S : _426.1594 found: 426.1582;

1H NMR (500 MHz, DMSO-d6) δ 9.10 (t, 1H), 8.75 (d, 1H), 7.95 (d, 1H), 7.79 - 7.73 (m, 2H) , 7.50 (d, 1H), 5.32 (dd, 1H), 4.90 (d, 1H), 4.71 (d, 1H), 4.39 -4.25 (m, 2H), 4.01 - 3.94 (m, 1H), 3.88 (d, 1H), 3.78 (d, 1H), 3.74 - 3.62 (m, 3H), 3.42 (dd, 1H), 3.36 (dd, 1H), 2.83 (td, 1H), 1.22 (d, 3H).

Example 73 N-(2-((R)-4-cyanothiazolidin-3-yl)-2-oxoethyl)-6-((R)-2-(trifluoromethyl)morpholino)quinoline-4-carboxamide

HATU (0.137 g, 0.36 mmol) was added to the stirred mixture of crude (R)-6-(2

- 206 048482 (trifluoromethyl)morpholino)quinoline-4-carboxylic acid, intermediate 154 (0.30 mmol), and DIPEA (0.262 mL, 1.50 mmol) in MeCN/EtOAc (2.8 mL, 1:1) at rt. The reaction mixture was stirred for ~1 min, after which (R)-3-glycylthiazolidine-4-carbonitrile hydrochloride, intermediate 4 (0.075 g, 0.36 mmol) was added. The reaction mixture was stirred for 4.5 h at rt, diluted with EtOAc (5 mL) and washed with 8% NaHCO ₃ (aq, 5 mL). The aqueous layer was extracted with EtOAc (3 mL) and _the combined organic layers were dried over _Na2SO4 , filtered and concentrated. The residue was purified by preparative HPLC, PrepMethod G (gradient: 5-55%). The purified compound was dissolved in EtOAc and washed successively with 8% _NaHCO3 (aq) and H2O (2x). The organic layer was concentrated and lyophilized from MeCN/H2O to give the title compound ( _0.066 g, 46%) as a solid; HRMS (ESI) m/z [M ₊ H]+ calcd for _{C21H21F3N5O3S} : 480.1312 found: _{480.1308 ;}

1H NMR (500 MHz, DMSO-d6) δ 9.06 (t, 1H), 8.74 (d, 1H), 7.95 (d, 1H), 7.82 (d, 1H), 7.76 (dd, 1H), 7.44 (d, 1H), 5.26 (dd, 1H), 4.90 (d, 1H), 4.71 (d, 1H), 4.45 - 4.39 (m, 1H), 4.37 - 4.25 (m, 2H), 4.14 (d, 1H), 3.99 (d, 1H), 3.89 - 3.8 (m, 2H), 3.43 (dd, 1H), 3.37 (dd, 1H), 2.96 - 2.84 (m, 2H).

Example 74 N-(2-((R)-4-cyanothiazolidin-3-yl)-2-oxoethyl)-6-((S)-2-(trifluoromethyl)morpholino)quinoline-4-carboxamide

HATU (0.137 g, 0.36 mmol) was added to a stirred mixture of crude (S)-6-(2(trifluoromethyl)morpholino)quinoline-4-carboxylic acid, intermediate 156 (0.30 mmol), and DIPEA (0.262 mL, 1.50 mmol) in MeCN (1.4 mL) and EtOAc (1.4 mL) at rt. The reaction mixture was stirred for 1 min, after which (R)-3-glycylthiazolidine-4-carbonitrile hydrochloride, intermediate 4 (0.075 g, 0.36 mmol) was added and the mixture was stirred for 4.5 h at rt. The reaction mixture was diluted with EtOAc (5 mL) and washed with 8% _NaHCO3 (aq, 5 mL). The aqueous layer was extracted with EtOAc (3 mL) and _the combined organic layers were dried over _Na2SO4 , filtered and concentrated. The residue was purified by preparative HPLC, PrepMethod G (gradient: 5-55%). The product was partitioned between EtOAc and 8% _NaHCO3 (aq). The organic layer was washed with small portions of H2O (3x), concentrated and lyophilized from MeCN/ _H2O to give the title compound (0.043 g, 30 _% ); HRMS (ESI) m/z [M+ _H ] ⁺ calcd for _{C21H21F3N5O3S} : 480.1312, found: _{480.1302 ;}

1H NMR (500 MHz, DMSO-d6) δ 9.04 (t, 1H), 8.74 (d, 1H), 7.95 (d, 1H), 7.84 (d, 1H), 7.76 (dd, 1H), 7.44 (d, 1H), 5.29 - 5.24 (m, 1H), 4.89 (d, 1H), 4.72 (d, 1H), 4.44-4.38 (m, 1H), 4.31 (dd, 2H), 4.15 (d, 1H), 3 .96 (d, 1H), 3.89 - 3.79 (m, 2H), 3.43 (d, 1H), 3.37 (dd, 1H), 2.99 - 2.88 (m, 2H).

Example 75. 6-((1S,4S)-2-oxa-5-azabicyclo[2.2.1]hentan-5-yl)-N-(2-((R)-4-cyanothiazolidin-3-yl)-2oxoethyl)quinoline-4-carboxamide

.. O

N^s

HATU (0.141 g, 0.37 mmol) was added to a stirred mixture of crude 6-((1S,4S)-2-oxa-5azabicyclo[2.2.1]heptan-5-yl)quinoline-4-carboxylic acid, intermediate 158 (0.31 mmol), and DIPEA (0.271 mL, 1.55 mmol) in MeCN/EtOAc (2.8 mL, 1:1) at rt and the reaction mixture was stirred for 1 min. (R)-3-Glycylthiazolidine-4-carbonitrile hydrochloride, intermediate 4 (0.077 g, 0.37 mmol) was added and the reaction mixture was stirred for 45 min at rt. The reaction mixture was diluted with EtOAc (5 mL) and washed with 8% NaHCO3 (aq, 5 mL). The aqueous layer was extracted with EtOAc (3 mL) and the combined organic layers were dried over Na2SO4, filtered and concentrated. The residue was purified by preparative HPLC, PrepMethod G (5-45% gradient) to give an orange solid which was dissolved in EtOAc. The organic layer was washed with 8% _NaHCO3 (aq, 2x) and H2O (2x). The organic layer was concentrated and lyophilized from a mixture of MeCN and H2O to give the title compound (0.035 g, 27%) as a yellow solid; HRMS (ESI) m/z [M+H] ⁺ calcd. for C ₂₁ H ₂₂ N ₅ O ₃ S: 424.1438 found value: 424.1442;

^1H NMR (500 MHz, DMSO- _d6 ) δ 8.96 (t, 1H), 8.59 (d, 1H), 7.87 (d, 1H), 7.45 (d, 1H), 7 .36 (dd, 2H), 5.31 (dd, 1H), 4.89 (d, 1H), 4.77 (brs, 1H), 4.70 (d, 1H), 4.66 (brs, 1H), 4.36 - 4.23 (m, 2H), 3.84 (d, 1H), 3.74 ( d, 1H), 3.62 (d, 1H), 3.42 - 3.34 (m, 2H), 3.14 (d, 1H), 1.98 (dd, 1H), 1.89 (d, 1H).

- 207 048482

Example 76 -oxoethyl)quinoline-4-carboxamide

HATU (0.128 g, 0.34 mmol) was added to a stirred mixture of crude 6-((1R,4R)-2-oxa-5azabicyclo[2.2.1]heptan-5-yl)quinoline-4-carboxylic acid, intermediate 160 (0.28 mmol), and DIPEA (0.245 mL, 1.40 mmol) in MeCN/EtOAc (2.6 mL, 1:1) at rt. The reaction mixture was stirred for 1 min, after which (R)-3-glycylthiazolidine-4-carbonitrile hydrochloride, intermediate 4 (0.070 g, 0.34 mmol) was added. The reaction mixture was stirred for 3 h at rt. The reaction mixture was diluted with EtOAc (5 mL) and washed with 8% NaHCO ₃ (aq, 5 mL). The aqueous layer was extracted with EtOAc (3 mL) and the combined organic layers were dried over Na ₂ SO ₄ , filtered and concentrated. The residue was purified by direct phase flash chromatography on silica gel (EtOAc then EtOAc:MeOH, 6:1). The compound was further purified by preparative HPLC, PrepMethod G (gradient 5-45%). The compound was partitioned between EtOAc and 8% NaHCO ₃ (aq). The organic layer was washed with 8% NaHCO ₃ (aq) then H2O (2x). The organic layer was concentrated and the washing sequence was repeated. The crude compound was purified by straight phase flash chromatography (EtOAc:MeOH, 6:1) and lyophilized from MeCN/ _H2O to give the title compound ( _0.026 g, 22%) as a yellow solid; HRMS ( _{ESI) m/z [M+H]+ calcd for C21H22N5O3S : 424.1438} found: 424.1430;

1H NMR (500 MHz, DMSO-d6) δ 8.97 (t, 1H), 8.59 (d, 1H), 7.87 (d, 1H), 7.47 (d, 1H), 7.38 - 7.32 (m, 2H), 5.32 (dd, 1H), 4.89 (d, 1H), 4.79 (brs, 1H), 4.70 (d, 1H), 4.68 - 4.64 (m, 1H), 4.29 (d, 2H), 3.82 (d, 1H), 3 .75 (d, 1H), 3.62 (d, 1H), 3.41 (dd, 1H), 3.38 - 3.36 (m, 1H), 2.02 - 1.96 (m, 1H), 3.14 (d, 1H), 1.88 (m, 1H).

Example 77 carboxamide

HATU (0.137 g, 0.36 mmol) was added to a stirred mixture of crude 6-(6-oxa-3azabicyclo[3.1.1]heptan-3-yl)quinoline-4-carboxylic acid, intermediate 162 (0.30 mmol), and DIPEA (0.262 mL, 1.50 mmol) in MeCN/EtOAc (2.8 mL, 1:1) at rt. The reaction mixture was stirred for 5 min, after which (R)-3-glycylthiazolidine-4-carbonitrile hydrochloride, intermediate 4 (0.075 g, 0.36 mmol) was added. The reaction mixture was stirred for 4.5 h at rt, diluted with EtOAc (5 mL) and washed with 5 mL 8% NaHCO3 (aq). The aqueous layer was extracted with EtOAc (3 mL) and _the combined organic layers were dried over _Na2SO4 , filtered and concentrated. The residue was purified by preparative HPLC, PrepMethod G (gradient: 5-45%) followed by straight-phase flash chromatography on silica gel (EtOAc:MeOH, 9:1). The appropriate fractions were combined, concentrated and the residue was partitioned between EtOAc and _NaHCO3 (aq). The organic layer was washed with _H2O (3x), concentrated and lyophilized from MeCN/H2O to give _the title compound (0.028 g, 22%) as a solid; HRMS (ESI) _m /z [M+H] ⁺ calcd for C21H22N5O3S: 424.1438 found: _424.1454 ;

^1H NMR (500 MHz, DMSO-d6) δ 8.99 (t, 1H), 8.62 (d, 1H), 7.95 (d, 1H), 7.55 - 7.48 (m, 2H ), 7.40 (d, 1H), 5.31 (dd, 1H), 4.89 (d, 1H), 4.76 (d, 2H), 4.71 (d, 1H), 4.37 - 4.23 (m, 2H), 3.71 (t, 2H), 3.56 (t, 2H), 3 .43 - 3.34 (m, 2H), 3.16 (q, 1H), 1.94 (d, 1H).

Example 78

HATU (0.114 g, 0.30 mmol) was added to a stirred mixture of crude 6-((2S,6S)-2,6-dimethylmorpholino)quinoline-4-carboxylic acid, intermediate 164 (0.25 mmol), and DIPEA (0.218 mL, 1.25 mmol) in MeCN/EtOAc (2.2 mL, 1:1) at rt. The reaction mixture was stirred

- 208 048482 was stirred for 1 min, after which (R)-3-glycylthiazolidine-4-carbonitrile hydrochloride, intermediate 4 (0.062 g, 0.30 mmol) was added and the reaction mixture was stirred for 2 h 45 min at rt. The reaction mixture was diluted with EtOAc (5 mL) and washed twice with 8% _NaHCO3 (aq, 5 + 3 mL), then H2O (2x5 mL). _The organic layer was dried over _Na2SO4 , filtered and concentrated. The residue was purified by normal phase flash chromatography on silica gel (EtOAc, then EtOAc:MeOH, 10:1). The compound was further purified twice by preparative HPLC, PrepMethod G (gradients: 15-55% and 5-45%) to afford the title compound (0.041 g, 38%) as a yellow solid; HRMS (ESI) m/z [M+H] ⁺ calcd for C ₂₂ H ₂₆ N ₅ O ₃ S: 440.1750 found: 440.1754;

¹ H NMR (500 MHz, DMSO-d ₆ ) δ 9.03 (t, 1H), 8.67 (d, 1H), 7.90 (d, 1H), 7.70 (d, 1H), 7.65 (dd, 1H), 7.39 (d, 1H), 5.30 (dd, 1H), 4.90 (d, 1H), 4.71 (d, 1H), 4.31 (d, 2H), 4.15-4.06 (m, 2H), 3.44 - 3.37 (m, overlaps with solvent peak), 3.08 (dd, 2H), 1.25 (d, 6H).

Example 79 carboxamide

HATU (0.137 g, 0.36 mmol) was added to a stirred mixture of crude 6-(8-oxa-3azabicyclo[3.2.1]octan-3-yl)quinoline-4-carboxylic acid, intermediate 166 (0.30 mmol), and DIPEA (0.262 mL, 1.50 mmol) in MeCN/EtOAc (2.8 mL, 1:1) at rt. The reaction mixture was stirred for 1 min, after which (R)-3-glycylthiazolidine-4-carbonitrile hydrochloride, intermediate 4 (0.075 g, 0.36 mmol) was added and the reaction mixture was stirred for 3 h at rt. The reaction mixture was diluted with EtOAc (5 mL) and washed with 8% NaHCO ₃ (aq, 5 mL). The aqueous layer was extracted with EtOAc (3 mL) and the combined organic layers were dried over Na ₂ SO ₄ , filtered and concentrated. The crude compound was purified by silica gel flash chromatography (EtOAc then EtOAc:MeOH, 6:1) and further purified by preparative HPLC, PrepMethod G (gradient: 5-50%). The compound was dissolved in EtOAc and the organic layer was washed with 8% NaHCO ₃ (aq, 2x) and H ₂ O (2x), concentrated and lyophilized to give the title compound (0.051 g, 39%) as a yellow solid; HRMS (ESI) mass/charge [M+H] ⁺ calc. for C22H24N5O3S: 438.1594 found value: 438.1608;

1H NMR (500 MHz, DMSO-d6) δ 9.00 (t, 1H), 8.66 (d, 1H), 7.89 (d, 1H), 7.64 - 7.58 (m, 2H) , 7.39 (d, 1H), 5.32 (dd, 1H), 4.90 (d, 1H), 4.71 (d, 1H), 4.48 (s, 2H), 4.36 - 4.23 (m, 2H), 3.61 (d, 2H), 3.41 (dd, 1H), 3 .36 (dd, 1H), 2.95 (ddd, 2H), 1.86 (s, 4H).

Example 80. N-(2-((R)-4-cyanothiazolidin-3-yl)-2-oxoethyl)-6-((S)-2-methylmorpholino)quinoline-4-carboxamide

HATU (0.137 g, 0.36 mmol) was added to a stirred mixture of crude (S)-6-(2-methylmorpholino)quinoline-4-carboxylic acid, intermediate 168 (0.30 mmol), and DIPEA (0.262 mL, 1.50 mmol) in MeCN/EtOAc (2.8 mL, 1:1) at rt. The reaction mixture was stirred for 1 min, after which (R)-3-glycylthiazolidine-4-carbonitrile hydrochloride, intermediate 4 (0.075 g, 0.36 mmol) was added and the reaction mixture was stirred for 45 min at rt. The reaction mixture was diluted with EtOAc (5 mL) and washed with 8% NaHCO3 (aq, 5 mL). The aqueous layer was extracted with EtOAc (3 mL) and the combined organic layers were dried over Na2SO4, filtered and concentrated. The residue was purified by preparative HPLC, PrepMethod G (5-45% gradient). The compound was dissolved in EtOAc and the organic layer was washed with 8% _NaHCO3 (aq) and _H2O (3x), concentrated and lyophilized. The compound was further purified by normal phase flash chromatography on silica gel (EtOAc then EtOAc:MeOH, 20:1) and lyophilized from MeCN/ _H2O to give the title compound (0.041 g, 32%) as a yellow solid; HRMS (ESI) m/z [M+H] ⁺ calcd. for C ₂₁ H ₂₄ N ₅ O ₃ S: 426.1594 found value: 426.1588;

1H NMR (500 MHz, DMSO-d6) δ 9.04 (t, 1H), 8.69 (d, 1H), 7.91 (d, 1H), 7.74 - 7.66 (m, 2H) , 7.40 (d, 1H), 5.30 (dd, 1H), 4.90 (d, 1H), 4.71 (d, 1H), 4.31 (d, 2H), 3.96 (dd, 1H), 3.87 (d, 1H), 3.75 (d, 1H), 3.72 - 3 .63 (m, 2H), 3.44 - 3.34 (m, 2H), 2.78 (td, 1H), 2.47 (d, 1H), 1.22(d, 3H).

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Example 81

HATU (0.160 g, 0.42 mmol) was added to a stirred mixture of crude 6-((2R,3S)-2,3-dimethylmorpholino)quinoline-4-carboxylic acid, intermediate 170 (0.35 mmol), and DIPEA (0.306 mL, 1.75 mmol) in MeCN/EtOAc (3.2 mL, 1:1) at rt. The reaction mixture was stirred for 1 min, after which (R)-3-glycylthiazolidine-4-carbonitrile hydrochloride, intermediate 4 (0.087 g, 0.42 mmol) was added and the reaction mixture was stirred for 2.5 h at rt. The reaction mixture was diluted with EtOAc (20 mL) and washed with 8% _NaHCO3 (aq, 10 mL) then H2O (2 mL). The organic layer was dried over _Na2SO4 , filtered and concentrated. The residue was purified by silica _gel flash chromatography (EtOAc then EtOAc:MeOH, 20:1). The compound was further purified by preparative HPLC, PrepMethod G (gradient: 0-30% over 30 min) then silica gel flash chromatography (EtOAc then EtOAc:MeOH, 20:1). The compound was lyophilized from MeCN/ _H2O to give the title compound (0.073 g, 47%) as a yellow solid; HRMS (ESI) mass/charge [M+H]+ calcd for C ₂₂ H ₂₆ N ₅ O ₃ S: 440.1750, found value: 440.1752;

1H NMR (500 MHz, DMSO-de) δ 9.01 (t, 1H), 8.65 (d, 1H), 7.90 (d, 1H), 7.68 - 7.60 (m, 2H) , 7.38 (d, 1H), 5.32 (dd, 1H), 4.89 (d, 1H), 4.70 (d, 1H), 4.29 (d, 2H), 4.14 - 4.08 (dd, 1H), 3.98 (dd, 1H), 3.86 - 3.78 (m, 1H), 3.63 (td, 1H), 3.47 - 3.34 (m, 3H), 3.06 (td, 1H), 1.14 (d, 3H), 0.93 (d, 3H).

Example 82

HATU (0.114 g, 0.30 mmol) was added to a stirred mixture of crude 6-((2S,3S)-2,3-dimethylmorpholino)quinoline-4-carboxylic acid, intermediate 172 (0.25 mmol), and DIPEA (0.218 mL, 1.25 mmol) in MeCN/EtOAc (2.2 mL, 1:1) at rt. The reaction mixture was stirred for 1 min, after which (R)-3-glycylthiazolidine-4-carbonitrile hydrochloride, intermediate 4 (0.062 g, 0.30 mmol) was added and the reaction mixture was stirred for 1.5 h at rt. The reaction mixture was diluted with EtOAc (15 mL) and washed with 8% _NaHCO3 (aq, 6+3 mL) and H2O (2x2 mL). _The organic layer was dried over _Na2SO4 , filtered and concentrated. The residue was purified by direct phase flash chromatography on silica gel (EtOAc then EtOAc/MeOH, 20:1). The compound was further purified by preparative HPLC, PrepMethod G (gradient: 0-30% in 30 min) to give the title compound (0.056 g, 51%) as a yellow solid; HRMS (ESI) m/z [M+H] ⁺ calcd. for C ₂₂ H ₂₆ N ₅ O ₃ S: 440.1750 found value: 440.1750;

1H NMR (500 MHz, DMSO- _d6 ) δ 9.03 (t, 1H), 8.71 (d, 1H), 7.92 (d, 1H), 7.77 (d, 1H), 7. 63 (dd, 1H), 7.41 (d, 1H), 5.32 (dd, 1H), 4.89 (d, 1H), 4.71 (d, 1H), 4.30 (d, 2H), 3.92 - 3.84 (m, 1H), 3.75 - 3.64 (m, 3H), 3.45 3.35 (m, 2H), 3.27 - 3.18 (m, 2H), 1.34 (d, 3H), 1.06 (d, 3H).

Example 83. N-(2-((R)-4-cyanothiazolidin-3-yl)-2-oxoethyl)-6-((2R,3R)-2,3-dimethylmorpholino)quinoline-4-carboxamide

HATU (0.110 g, 0.29 mmol) was added to a stirred mixture of crude 6-((2R,3R)-2,3-dimethylmorpholino)quinoline-4-carboxylic acid, intermediate 174 (0.24 mmol), and DIPEA (0.210 mL, 1.20 mmol) in MeCN/EtOAc (2.2 mL, 1:1) at rt. The reaction mixture was stirred for 1 min, after which (R)-3-glycylthiazolidine-4-carbonitrile hydrochloride, intermediate 4 (0.060 g, 0.29 mmol) was added and the reaction mixture was stirred for 1.5 h at rt. The reaction mixture was diluted with EtOAc (15 mL) and washed with 8% _NaHCO3 (aq, 6+3 mL) then H2O (2x2 mL). The organic layer was dried over Na2SO4, filtered and concentrated. The residue was purified by silica gel flash chromatography (EtOAc then EtOAc:MeOH, 10:1). The compound was further purified by preparative

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HPLC, PrepMethod G (gradient: 5-35%) to give the title compound ₍ 0.048 g, 46%) as an orange solid; HRMS (ESI) m/z [M _{+H]+ calcd for C22H26N5O3S :} 440.1750 found: _440.1756 ;

¹ H NMR (500 MHz, DMSO-d ₆ ) δ 9.03 (t, 1H); 8.71 (d, 1H), 7.92 (d, 1H), 7.73 (d, 1H), 7.63 (dd, 1H), 7.42 (d, 1H), 5.30 (dd, 1H), 4.90 (d, 1H), 4.70 (d, 1H), 4.34 (dd, 1H), 4.26 (dd, 1H), 3.93 - 3.84 (m, 1H), 3.75 - 3.65 (m, 3H), 3.43 - 3.34 (m, 2H), 3.30 - 3.17 (m, 2H), 1.34 (d, 3H), 1.07 (d, 3H).

Example 84. N-(2-((R)-4-cyanothiazolidin-3-yl)-2-oxoethyl)-6-((R*)-3-(trifluoromethyl)morpholino)quinoline-4-carboxamide, isomer 1

isomer 1

HATU (0.119 g, 0.31 mmol) was added to a stirred solution of crude rel-(R)-6-(3(trifluoromethyl)morpholino)quinoline-4-carboxylic acid, isomer 1, intermediate 178 (0.26 mmol), and DIPEA (0.227 mL, 1.30 mmol) in MeCN/EtOAc (2.4 mL, 1:1) at rt. The reaction mixture was stirred for 1 min, after which (R)-3-glycylthiazolidine-4-carbonitrile hydrochloride, intermediate 4 (0.065 g, 0.31 mmol) was added and the reaction mixture was stirred for 45 min at rt. The reaction mixture was diluted with EtOAc (8 mL) and washed with 8% NaHCO ₃ (aq, 5 mL). The aqueous layer was extracted with EtOAc and the combined organic layers were dried over Na ₂ SO ₄ , filtered and concentrated. The residue was purified by preparative HPLC, PrepMethod G (gradient: 5-55%) to give the title compound (0.082 g, 66%) as an orange solid; HRMS (ESI) m/z [M+H] ⁺ calcd for C ₂₁ H ₂₁ F ₃ N ₅ O ₃ S: 480.1312, found: 480.1308;

¹ H NMR (500 MHz, DMSO-d ₆ ) δ 9.07 (t, 1H), 8.74 (d, 1H), 7.94 (d, 1H), 7.85 - 7.78 (m, 2H), 7.45 (d, 1H), 5.34 (dd, 1H), 5.11 - 5.01 (m, 1H), 4.89 (d, 1H), 4.71 (d, 1H), 4.38-4.27 (m, 2H), 4.24 (d, 1H), 4.06 (dd, 1H), 3.89 - 3.82 (m, 1H), 3.64 (td, 1H), 3.55 - 3.33 (m, overlaps with solvent peak).

Example 85. N-(2-((R)-4-cyanothiazolidin-3-yl)-2-oxoethyl)-6-((R*)-3-(trifluoromethyl)morpholino)quinoline-4-carboxamide, isomer 2

Isomer 2

HATU (0.128 g, 0.34 mmol) was added to a stirred solution of crude rel-(R)-6-(3(trifluoromethyl)morpholino)quinoline-4-carboxylic acid, isomer 2, intermediate 179 (0.150 g, 0.28 mmol), and DIPEA (0.245 mL, 1.40 mmol) in MeCN/EtOAc (2.4 mL, 1:1) at rt. The reaction mixture was stirred for 1 min, after which (R)-3-glycylthiazolidine-4-carbonitrile hydrochloride, intermediate 4 (0.070 g, 0.34 mmol) was added and the reaction mixture was stirred for 1.5 h at rt. The reaction mixture was diluted with EtOAc (8 mL) and washed with 8% NaHCO ₃ (aq, 5 mL). The aqueous layer was extracted with EtOAc and the combined organic layers were dried over Na ₂ SO ₄ , filtered and concentrated. The residue was purified by preparative HPLC, PrepMethod G (gradient: 5-55%) to give the title compound (0.085 g, 63%) as a yellow solid; HRMS (ESI) m/z [M+H] ⁺ calcd for C ₂₁ H ₂₁ F ₃ N ₅ O ₃ S: 480.1312, found: 480.1308;

Ή NMR (500 MHz, DMSO-d ₆ ) δ 9.07 (t, 1H), 8.73 (d, 1H), 7.94 (d, 1H), 7.83 - 7.76 (m, 2H), 7.45 (d, 1H), 5.29 (dd, 1H), 5.11 -5.03 (dd, 1H), 4.90 (d, 1H), 4.70 (d, 1H), 4.37 (dd, 1H), 4.30 - 4.20 (m, 2H), 4.06 (dd, 1H), 3.89 - 3.81 (m, 1H), 3.64 (td, 1H), 3.56-3.32 (m, overlaps with solvent peak).

Example 86 carboxamide

HATU (0.068 g, 0.18 mmol) was added to a stirred solution of crude 6-(3-oxa-9azabicyclo[3.3.1]nonan-9-yl)quinoline-4-carboxylic acid, intermediate 181 (0.070 g,

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0.15 mmol), and DIPEA (0.131 mL, 0.75 mmol) in MeCN/EtOAc (1.2 mL, 1:1) at rt and the reaction mixture was stirred for 1 min. (R)-3-Glycylthiozolidine-4-carbonitrileα hydrochloride, Intermediate 4 (0.037 g, 0.18 mmol) was added and the reaction mixture was stirred for 2 h at rt. The reaction mixture was diluted with EtOAc (8 mL) and washed with 8% NaHCO ₃ (aq, 5 mL). The aqueous layer was extracted with EtOAc and the combined organic layers were dried over Na ₂ SO ₄ , filtered and concentrated. The residue was purified by preparative HPLC, PrepMethod G (gradient: 5-55%) to give the title compound (0.040 g, 60%) as an orange solid; HRMS (ESI) m/z [ _{M +H]+ calcd for C23H26N5O3S :} 452.1750, found: _452.1756 ;

¹ H NMR (500 MHz, DMSO-d ₆ ) δ 9.01 (t, 1H), 8.62 (d, 1H), 7.89 (d, 1H), 7.73 (d, 1H), 7.61 (dd, 1H), 7.37 (d, 1H), 5.29 (dd, 1H), 4.89 (d, 1H), 4.69 (d, 1H), 4.35 - 4.22 (m, 2H), 4.11 (s, 2H), 3.99 (d, 2H), 3.85 (d, 2H), 3.44 - 3.35 (m, overlaps with solvent peak), 2.55 - 2.52 (m, overlaps with solvent peak), 1.98 - 1.83 (m, 2H), 1.83 - 1.70 (m, 2H), 1.58-1.48 (m, 1H).

Example 87

HATU (0.160 g, 0.42 mmol) was added to a stirred mixture of crude 6-((2R,5R)-2,5-dimethylmorpholino)quinoline-4-carboxylic acid, intermediate 183 (0.35 mmol), and DIPEA (0.305 mL, 1.75 mmol) in MeCN/EtOAc (3 mL, 1:1) and the mixture was stirred for 1 min. (R)-3-Glycylthiazolidine-4-carbonitrile hydrochloride, intermediate 4 (0.087 g, 0.42 mmol) was added and the mixture was stirred at rt for 3 h. The reaction mixture was partitioned between EtOAc (25 mL) and 8% _NaHCO3 (aq, 10 mL). The aqueous layer was extracted with EtOAc (10 mL) and the combined organic layers were concentrated. The residue was purified by preparative _HPLC , PrepMethod G (gradient: 5-45%) to give the title compound (0.072 g, 47%) as an orange solid; HRMS (ESI) m/z [M ₊ H] ⁺ calcd for _C22H26N5O3S : 440.1750, found: _440.1748 ;

1H NMR (500 MHz, DMSO-d ₆ ) δ 9.03 (t, 1H), 8.66 (d, 1H), 7.91 (d, 1H), 7.70 - 7.64 (m, 2H), 7.39 (d, 1H), 5.31 (dd, 1H), 4.89 (d, 1H), 4.71 (d, 1H), 4.34 (dd, 1H), 4.26 (dd, 1H), 4.20 - 4.14 (m, 1H), 3.85 - 3.73 (m, 2H), 3.69 - 3.53 (m, 2H), 3.45 - 3.33 (m, overlaps with solvent peak), 2.75 (dd, 1H), 1.27 (d, 3H), 1.05 (d, 3H).

Example 88. (R)-N-(2-(4-cyanothiazolidin-3-yl)-2-oxoethyl)-6-(2,2-dimethylmorpholino)quinoline-4-carboxamide

HATU (0.160 g, 0.42 mmol) was added to a stirred mixture of crude 6-(2,2-dimethylmorpholino)quinoline-4-carboxylic acid, intermediate 185 (0.35 mmol), and DIPEA (0.305 ml, 1.75 mmol) in MeCN/EtOAc (3 ml, 1:1) and the mixture was stirred for 1 min. (R)-3-Glycylthiazolidine-4-carbonitrile hydrochloride, intermediate 4 (0.087 g, 0.42 mmol) was added and the mixture was stirred at rt for 3 h. The reaction mixture was partitioned between EtOAc (25 ml) and 8% NaHCO ₃ (aq, 10 ml). The aqueous layer was extracted with EtOAc (10 mL) and the combined organic layers were concentrated. The residue was purified by preparative _HPLC , PrepMethod G (gradient: 5-55%) to give the title compound (0.076 g, 49%) as an orange solid; HRMS (ESI) m/z [M ₊ H] ⁺ calcd for _C22H26N5O3S : 440.1750, found: _440.1768 ;

¹ H NMR (500 MHz, DMSO-d ₆ ) δ 9.05 (t, 1H), 8.69 (d, 1H), 7.91 (d, 1H), 7.74 (d, 1H), 7.68 (dd, 1H), 7.41 (d, 1H), 5.30 (dd, 1H), 4.90 (d, 1H), 4.71 (d, 1H), 4.36 - 4.26 (m, 2H), 3.81 (t, 2H), 3.47 - 3.15 (m, overlaps with solvent peak), 1.28 (s, 6H).

Example 89

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To a vial containing tert-butyl (S)-6-(3-(methoxymethyl)morpholino)quinoline-4-carboxylate, intermediate 186 (146 mg, 0.41 mmol), was added 4 M HCl in dioxane (2 mL, 8 mmol). The reaction mixture was heated at 60 °C for 1 h. The volatiles were removed under reduced pressure and the residue was suspended in EtOAc and concentrated (x2). MeCN/EtOAc (4.8 mL, 1:1) was added to the residue at rt, followed by DIPEA (0.430 mL, 2.46 mmol) and HATU (0.187 g, 0.49 mmol). The mixture was stirred for 1 min, after which (R)-3-glycylthiazolidine-4-carbonitrile hydrochloride, intermediate 4 (0.102 g, 0.49 mmol) was added and the reaction mixture was stirred for 1.5 h at rt. The reaction mixture was diluted with EtOAc and washed with 8% NaHCO ₃ (aq). The aqueous layer was extracted with EtOAc and the combined organic layers were dried over Na ₂ SO ₄ , filtered and concentrated. The residue was purified by preparative SFC, PrepMethod SFC-D, to give the title compound (0.062 g, 33%); HRMS (ESI) m/z [M+H]+ calcd. for C ₂₂ H ₂₆ N ₅ O ₄ S: 456.1700, found value: 456.1698;

1H NMR (500 MHz, DMSO-d6) δ 9.00 (t, 1H), 8.67 (d, 1H), 7.91 (d, 1H), 7.69 (dd, 1H), 7.64 (d, 1H), 7.40 (d, 1H), 5.31 (dd, 1H), 4.88 (d, 1H), 4.70 (d, 1H), 4.35 - 4.23 (m, 2H), 4.12 (s, 1H), 4.02 - 3.95 (m, 2H), 3.70 - 3.64 (m, 2H), 3.58 (td, 1H), 3.45 -3.42 (m, overlaps with solvent peak), 3.24 - 3.13 (m, overlaps with the solvent peak).

Example 90

HATU (0.091 g, 0.24 mmol) was added to a stirred solution of crude 6-((3S,5R)-3,5-dimethylmorpholino)quinoline-4-carboxylic acid, intermediate 188 (0.2 mmol), and DIPEA (0.210 mL, 1.20 mmol) in MeCN/ _H2O (2.4 mL, 1:1) at rt. The reaction mixture was stirred for 1 min, after which (R)-3-glycylthiazolidine-4-carbonitrile hydrochloride, intermediate 4 (0.050 g, 0.24 mmol) was added. The reaction mixture was stirred for 3 h at rt, diluted with EtOAc and washed with 0.4 M NaOH (aq, 4.5 mL). The aqueous layer was extracted with EtOAc and the combined organic layers were dried over Na2SO4, filtered and concentrated. The residue _was purified by preparative SFC, PrepMethod SFC-D, to give the title compound (0.039 g, 44%); FIRMS (ESI) m/z [M ₊ H] ⁺ calcd for _C22H26N5O3S : 440.1750, found: _440.1744 ;

1H NMR (500 MHz, DMSO- _d6 ) δ 9.01 (t, 1H), 8.69 (d, 1H), 7.95 (d, 1H), 7.72 (d, 1H), 7. 59 (dd, 1H), 7.41 (d, 1H), 5.31 (dd, 1H), 4.89 (d, 1H), 4.71 (d, 1H), 4.36 - 4.23 (m, 2H), 3.87 - 3.81 (m, 2H), 3.75 - 3.66 (m , 4H), 1.09 (d, 6H).

Example 91

A vial was charged with tert-butyl 6-(1,4-oxazepan-4-yl)quinoline-4-carboxylate, intermediate 189 (0.085 g, 0.25 mmol), and 90% TFA (aq, 0.5 mL) and the reaction mixture was heated at 50 °C for 3 h. The reaction mixture was concentrated, a mixture of heptane and DCM (3 mL, 2:1) was added to the residue and the mixture was concentrated. A mixture of MeCN/EtOAc (3 mL, 1:1) and DIPEA (0.261 mL, 1.50 mmol) was added to the residue, then HATU (0.114 g, 0.30 mmol) was added. The mixture was stirred for 1 min, after which (R)-3-glycylthiazolidine-4-carbonitrile hydrochloride, intermediate 4 (0.062 g, 0.30 mmol) was added. The mixture was stirred at rt for 4 h and then partitioned between EtOAc (4 mL) and 8% _NaHCO3 (aq, 5 mL). The aqueous layer was extracted with EtOAc (2 x 1 mL) and the combined organic layers were dried over Na2SO4, filtered and concentrated. The residue was purified by prep SFC, PrepMethod SFC-A, then prep HPLC, PrepMethod V (gradient: 5-95%) to give the title compound (30 mg, 27%); HRMS (ESI) m/z [M+H] ⁺ calcd. for C ₂₁ H ₂₄ N ₅ O ₃ S: 426.1594 found value: 426.1576;

1H NMR (600 MHz, DMSO-d6) δ 8.93 (t, 1H), 8.53 (d, 1H), 7.82 (d, 1H), 7.50 - 7.45 (m, 2H), 7.30 (d, 1H), 5.26 (dd, 1H), 4.84 (d, 1H), 4.66 (d, 1H), 4.30 -4.18 (m, 2H), 3.76 - 3.66 (m, overlaps with solvent peak), 3.57 - 3.51 (m, overlaps with solvent peak), 3.38 - 3.29 (m, overlaps with solvent peak), 1.95 - 1.88 (m, 2H).

- 213 048482

Example 92. N-(2-((R)-4-cyanothiazolidin-3-yl)-2-oxoethyl)-6-((R)-2-((methylsulfonyl)methyl)morpholino)quinoline-4-carboxamide

The compound was synthesized and purified analogously to the procedure of Example 91, starting from tert-butyl (R)6-(2-((methylsulfonyl)methyl)morpholino)quinoline-4-carboxylate, intermediate 193 (0.102 g, 0.25 mmol), and (R)-3-glycylthiazolidine-4-carbonitrile hydrochloride, intermediate 4 (0.062 g, _0.30 mmol), to give the title compound ( ₂₆ mg, 20%); FIRMS (ESI) m/z [M+H]+ calcd for _C22H26N5O5S2 : _504.1370 found: _504.1372 ;

1H NMR (600 MHz, DMSO-d ₆ ) δ 9.00 (m, 1H), 8.68 (d, 1H), 7.91 (d, 1H), 7.68 (d, 1H), 7.62 (dd, 1H), 7.40 (d, 1H), 5.31 - 5.27 (m, 1H), 4.86 (d, 1H), 4.67 (d, 1H), 4.31 (dd, 1H), 4.23 (dd, 1H), 4.10 - 3.99 (m, 2H), 3.88 - 3.81 (m, 1H), 3.75 - 3.65 (m, 2H), 3.53 (dd, overlaps with solvent peak), 3.37-3.27 (m, overlaps with solvent peak), 3.01 (s, 3H), 2.91 -2.82 (m, 1H), 2.73 - 2.68 (m, 1H).

Example 93

N P

N

The compound was synthesized and purified analogously to the procedure of Example 91, starting from tert-butyl (S)6-(2-(methoxymethyl)morpholino)quinoline-4-carboxylate, intermediate 194 (76 mg, 0.25 mmol), and (R)-3-glycylthiazolidine-4-carbonitrile hydrochloride, intermediate 4 (0.062 _g , 0.30 mmol), to give the title compound (0.026 g, 22%); HRMS (ESI) m/z _[ M+H] ⁺ calcd for _C22H26N5O4S : 456.1700 found: _456.1712 ;

¹ H NMR (600 MHz, DMSO-d6) δ 8.99 (t, 1H), 8.66 (d, 1H), 7.88 (d, 1H), 7.69 (d, 1H), 7.64 (dd, 1H), 7.38 (d, 1H), 5.29 (dd, 1H), 4.85 (d, 1H), 4.68 (d, 1H), 4.32 - 4.22 (m, 2H), 3.99 - 3.93 (m, 1H), 3.78 -3.68 (m, 3H), 3.64 (td, 1H), 3.48 - 3.42 (m, overlaps with solvent peak), 3.35 - 3.31 (m, overlaps with solvent peak), 3.27 (s, 3H), 2.80 (td, 1H), 2.61 - 2.56 (m, overlaps with the solvent peak).

Example 94. N-(2-((R)-4-cyanothiazolidin-3-yl)-2-oxoethyl)-6-((S)-2-((methylsulfonyl)methyl)morpholino)quinoline-4-carboxamide

The compound was synthesized analogously to the procedure of Example 91, starting from tert-butyl (S)-6-(2((methylsulfonyl)methyl)morpholino)quinoline-4-carboxylate, intermediate 198 (0.102 g, 0.25 mmol), and (R)-3-glycylthiazolidine-4-carbonitrile hydrochloride, intermediate 4 (0.062 g, 0.30 mmol). The compound was purified by preparative SFC, PrepMethod SFC-A followed by PrepMethod SFC-D, to afford the title compound (0.023 g, 18%); FIRMS (ESI) m/z [M+H] ⁺ calcd. for C ₂₂ H ₂₆ N ₅ O ₅ S ₂ : 504.1370, found value: 504.1364;

1H NMR (600 MHz, DMSO-d6) δ 9.00 (t, 1H), 8.68 (d, 1H), 7.91 (d, 1H), 7.71 (d, 1H), 7.62 (dd, 1H), 7.39 (d, 1H), 5.31 - 5.26 (m, 1H), 4.85 (d, 1H), 4.67 (d, 1H), 4.32 - 4.22 (m, 2H), 4.09 - 3.98 (m, 2H), 3.86 (d, 1H), 3.70 (t, 2H), 3.52 (dd, overlaps with solvent peak), 3.34 - 3.27 (m, overlaps with solvent peak), 3.01 (s, 3H), 2.93 - 2.84 (m, 1H), 2.74 - 2.67 (m, 1H).

Example 95

The compound was synthesized analogously to the procedure of Example 91, starting from tert-butyl (R)-6-(3-(2-methoxyethyl)morpholino)quinoline-4-carboxylate, intermediate 201 (0.093 g, 0.25 mmol), and (R)-3-glycylthiazolidine-4-carbonitrile hydrochloride, intermediate 4 (0.062 g, 0.30 mmol). The compound was purified by preparative SFC, PrepMethod SFC-A, then preparative HPLC, PrepMethod F, to afford the title compound (0.031 g, 25%); FIRMS

- 214 048482 (ESI) mass/charge [M+H]+ calc. for C ₂₃ H ₂₈ N5O ₄ S: 470.1856, found value: 470.1846;

1H NMR (600 MHz, DMSC-06) δ 8.95 (t, 1H), 8.62 (d, 1H), 7.87 (d, 1H), 7.59 - 7.56 (m, 2H), 7.36 (d, 1H), 5.26 (dd, 1H), 4.85 (d, 1H), 4.67 (d, 1H), 4.30 (dd, 1H), 4.22 (dd, 1H), 4.05 - 4.00 (m, 1H), 3.93 (dd, 1H), 3.84 (d, 1H), 3.66 - 3.63 (m, 2H), 3.58 - 3.48 (m, overlaps with solvent peak), 3.46 - 3.42 (m, overlaps with solvent peak), 3.39 - 3.29 (m, overlaps with solvent peak), 3.28 - 3.21 (m, 1H), 3.17 - 3.10 (m, overlaps with solvent peak), 3.09 (s, 3H), 1.97 - 1.88 (m, 1H), 1.65 - 1.57 (m, 1H).

Example 96

The compound was synthesized and purified analogously to the procedure of Example 91, starting from tert-butyl 6-((2S,3S)-3-(methoxymethyl)-2-methylmorpholino)quinoline-4-carboxylate, intermediate 204 (0.093 g, 0.25 mmol), and (R)-3-glycylthiazolidine-4-carbonitrile hydrochloride, intermediate 4 (0.062 g, _0.30 mmol), to give the title compound ( _0.030 g, 25%); FIRMS ( _ESI ) m/z [M+H]+ calcd for C23H28N5O4S: 470.1856 found: _470.1848 ;

1H NMR (600 MHz, DMSO-d ₆ ) δ 8.96 (t, 1H), 8.63 (d, 1H), 7.87 (d, 1H), 7.63 - 7.58 (m, 2H), 7.36 (d, 1H), 5.26 (dd, 1H), 4.85 (d, 1H), 4.67 (d, 1H), 4.29 (dd, 1H), 4.22 (dd, 1H), 4.05 - 3.98 (m, 1H), 3.88 (td, 1H), 3.83-3.80 (m, 1H), 3.67 - 3.61 (m, overlaps with solvent peak), 3.42 -3.28 (m, overlaps with solvent peak), 3.17 (dd, 1H), 3.15 - 3.12 (m, 5H), 1.35 (d, 3H).

Example 97. N-(2-((R)-4-cyanothiazolidin-3-yl)-2-oxoethyl)-6-((2R,3R)-3-(methoxymethyl)-2methylmorpholino)quinoline-4-carboxamide

The compound was synthesized analogously to the procedure of Example 91, starting from tert-butyl 6-((2R,3R)-3(methoxymethyl)-2-methylmorpholino)quinoline-4-carboxylate, intermediate 207 (0.093 g, 0.25 mmol), and (R)-3-glycylthiazolidine-4-carbonitrile hydrochloride, intermediate 4 (0.062 g, 0.30 mmol). The compound was purified by preparative SFC, PrepMethod SFC-A then PrepMethod SFC-D, to give the title compound (0.045 g, 36%); FIRMS (ESI) m/z [M+H]+ calcd. for C ₂₃ H ₂₈ N ₅ O ₄ S: 470.1856 found value: 470.1856;

1H NMR (600 MHz, DMSO-d ₆ ) δ 8.96 (t, 1H), 8.63 (d, 1H), 7.87 (d, 1H), 7.65 (d, 1H), 7.61 (dd, 1H), 7.37 (d, 1H), 5.27 (dd, 1H), 4.85 (d, 1H), 4.67 (d, 1H), 4.26 (d, 2H), 4.05 - 3.98 (m, 1H), 3.87 (td, 1H), 3.84 - 3.78 (m, 1H), 3.69 - 3.61 (m, 2H), 3.43 - 3.27 (m, overlaps with solvent peak), 3.19 (td, 1H), 3.15 (s, 3H), 1.35 (d, 3H).

Example 98 carboxamide

The compound was synthesized and purified analogously to the procedure of Example 91, starting from tert-butyl 6-(3-oxa-8-azabicyclo[3.2.1]octan-8-yl)quinoline-4-carboxylate, intermediate 208 (0.085 g, 0.25 mmol), and (R)-3-glycylthiazolidine-4-carbonitrile hydrochloride, intermediate 4 ( _0.062 g, 0.30 mmol), to give the title compound ( _0.054 g, 49 _% ); HRMS (ESI) m/z [M+H]+ calcd for _C22H24N5O3S : 438.1594, found: 438.1606;

1H NMR (500 MHz, DMSO-d6) δ 8.99 (t, 1H), 8.62 (d, 1H), 7.88 (d, 1H), 7.71 (d, 1H), 7.57 (dd, 1H), 7.35 (d, 1H), 5.29 (dd, 1H), 4.89 (d, 1H), 4.69 (d, 1H), 4.43 - 4.36 (m, 2H), 4.29 (d, 2H), 3.78 (dd, 2H), 3.50 (dd, 2H), 3.43 - 3.34 (m, overlaps with solvent peak), 2.04 - 1.93 (m, 4H).

Example 99 carboxamide

The compound was synthesized and purified analogously to the procedure of Example 91, starting from tert-butyl-6

- 215 048482 (1,9-dioxa-4-azaspiro[5.5]undecan-4-yl)quinoline-4-carboxylate, intermediate 209 (0.096 g, 0.25 mmol), and (R)-3-glycylthiazolidine-4-carbonitrile hydrochloride, intermediate 4 (0.062 g, 0.30 mmol) to give the title compound (0.029 g, 24%); HRMS (ESI) m/z [M+H]+ calcd for C ₂₄ H ₂₈ N ₅ O ₄ S: 482.1856, found: 482.1846;

¹ H NMR (600 MHz, DMSO-d ₆ ) δ 8.99 (t, 1H), 8.64 (d, 1H), 7.87 (d, 1H), 7.70 (d, 1H), 7.64 (dd, 1H), 7.36 (d, 1H), 5.26 (dd, 1H), 4.85 (d, 1H), 4.67 (d, 1H), 4.32 - 4.22 (m, 2H), 3.80 (t, overlaps with solvent peak), 3.62 - 3.54 (m, overlaps with solvent peak), 3.39 - 3.31 (m, overlaps with solvent peak), 3.28 - 3.18 (m, overlaps with solvent peak), 1.81- 1.72 (m, 2H), 1.71-1.62 (m, 2H).

Example 100

HATU (13.5 mg, 0.04 mmol) was added to a solution of crude 7-6pom-6-((3R,5S)-3,5-dimethylmorpholino)quinoline-4-carboxylic acid, intermediate 212 (0.020 g, 0.03 mmol), and DIPEA (25.9 μL, 0.15 mmol) in MeCN/EtOAc (1 mL, 1:1) at rt. The reaction mixture was stirred for 1.5 min, after which (R)-3-glycylthiazolidine-4-carbonitrile hydrochloride, intermediate 4 (7 mg, 0.04 mmol) was added and the reaction mixture was stirred for 2 h at rt. The reaction mixture was diluted with EtOAc and washed with 8% NaHCO3 (aq). The aqueous layer was extracted with EtOAc and _the combined organic layers were dried over _Na2SO4 , filtered and concentrated. The residue was purified by preparative _{SFC, PrepMethod SFC-A, to give the title compound (5.7 mg, 37%); HRMS (ESI) m/z [M+H]+ calcd for C22H25BrN5O3S : 518.0856 ,} found: 518.0858;

1H NMR (600 MHz, DMSO-d ₆ ) δ 9.14 (t, 1H), 8.96 (d, 1H), 8.41 (s, 1H), 8.38 (s, 1H), 7.59 (d, 1H), 5.30 (dd, 1H), 4.85 (d, 1H), 4.69 (d, 1H), 4.31 (d, 2H), 3.80 (d, overlaps with solvent peak), 3.37 - 3.31 (m, 2H), 3.17 - 3.08 (m, overlaps with solvent peak), 0.58 (d, 6H).

Example 101 (R)-5-chloro-N-(2-(4-cyanothiazolidin-3-yl)-2-oxoethyl)-6-morpholinoquinoline-4carboxamide

Step a) 2 M NaOH (aq, 1.025 mL, 2.05 mmol) was added to a suspension of ethyl 5-chloro-6-morpholinoquinoline-4-carboxylate hydrochloride, intermediate 213 (8 mg, 0.23 mmol), in MeOH (1.4 mL) and the reaction mixture was heated at 80 °C for 20 min. Aq. NaOH (3.8 M, 0.54 mL, 2.1 mmol) was added and the reaction mixture was heated at 120 °C for 50 min. After cooling to rt, aq. HCl (3.8 M, 1.2 mL, 4.6 mmol) was added dropwise and the resulting mixture was concentrated. The residue was co-evaporated once from _H2O and twice from EtOAc to give crude 5-chloro-6-morpholinoquinoline-4-carboxylic acid as a solid; MS (ESI) m/z [M+H]+ 293.1.

Step b) A mixture of MeCN/EtOAc (3 mL, 1:1) and DIPEA was added to the crude 5-chloro-6-morpholinoquinoline-4-carboxylic acid, then HATU (96 mg, 0.25 mmol) was added. The reaction mixture was stirred for 2 min at rt, after which (R)-3-glycylthiazolidine-4-carbonitrile hydrochloride, intermediate 4 (52 mg, 0.25 mmol) was added and the reaction mixture was stirred for 4.5 h at rt. The reaction mixture was diluted with EtOAc and washed with 8% NaHCO ₃ (aq). The aqueous layer was extracted with EtOAc and the combined organic layers were dried over Na ₂ SO ₄ , filtered and concentrated. The residue _was purified by preparative SFC, PrepMethod SFC-D, to give the title compound (0.042 g, 41%); HRMS (ESI) m/z [M+H]+ calcd for _{C20H21ClN5O3S} : _446.1048 , found: _446.1044 ;

1H NMR (600 MHz, DMSO- _d6 ) δ 8.91 (t, 1H), 8.85 (d, 1H), 8.03 (d, 1H), 7.73 (d, 1H), 7. 46 (d, 1H), 5.30 (dd, 1H), 4.85 (d, 1H), 4.68 (d, 1H), 4.45 - 4.05 (m, 2H), 3.75 (t, 4H), 3.36 (dd, 1H), 3.30 (dd, 1H), 3.09 ( brs, 4H).

- 216 048482

Example 102. N-(2-((R)-4-cyanothiazolidin-3-yl)-2-oxoethyl)-6-((S)-3-methylmorpholino)quinoline-4-carboxamide

A solution of tert-butyl ((3-methylmorpholino)quinoline-4-carboxylate, intermediate 214 (48 mg, 0.15 mmol), in 90% TFA (aq, 0.5 mL) was stirred at rt for 5 h. The volatiles were removed under reduced pressure and the residue was suspended in heptane/DCM, concentrated (2x) and dried in vacuo. HATU (0.068 g, 0.18 mmol) was added to a solution of the residue in MeCN/EtOAc (2 mL, 1:1) and DIPEA (0.131 mL, 0.75 mmol). The reaction mixture was stirred for 1 min, after which (R)-3-glycylthiazolidine-4-carbonitrile hydrochloride, intermediate 4 (0.037 g, 0.18 mmol) was added. The resulting solution was stirred for 1 h at rt, diluted with EtOAc and washed with 8% NaHCO ₃ (aq). The aqueous layer was extracted with EtOAc and the combined organic layers were dried over Na ₂ SO ₄ , filtered and concentrated. The residue was purified by preparative SFC, PrepMethod SFC-C, to give the title compound (0.026 g, 41%); FIRMS (ESI) m/z [M+H]+ calcd. for C ₂₁ H ₂₄ N ₅ O ₃ S: 426.1594, found value: 426.1594;

¹ H NMR (600 MHz, DMSO-d6) δ 8.99 (t, 1H), 8.66 (d, 1H), 7.89 (d, 1H), 7.63 (dd, 2H), 7.40 (d, 1H), 5.28 (dd, 1H), 4.86 (d, 1H), 4.68 (d, 1H), 4.27 (d, 2H), 4.16 -4.11 (m, 1H), 3.96 (dd, 1H), 3.72 (d, 2H), 3.54 (dd, 1H), 3.43 - 3.35 (m, overlaps with solvent peak), 3.33 (dd, 1H), 3.16 - 3.12 (m, 1H), 1.04 (d, 3H).

Example 103 N-(2-((R)-4-cyanothiazolidin-3-yl)-2-oxoethyl)-6-((3S,5S)-3,5-dimethylmorpholino)quinoline-4-carboxamide

A solution of tert-butyl 6-((3S,5S)-3,5-dimethylmorpholino)quinoline-4-carboxylate, intermediate 215 (54 mg, 0.16 mmol), in 90% TFA (aq, 0.5 mL) was stirred at rt for 5 h. The volatiles were removed under reduced pressure and the residue was suspended in heptane/DCM, concentrated (2x) and dried in vacuo. HATU (0.073 g, 0.19 mmol) was added to a stirred solution of the residue in MeCN/EtOAc (2 mL, 1:1) at rt. The reaction mixture was stirred for 1 min. and (R)-3-glycylthiazolidine-4-carbonitrile hydrochloride, intermediate 4 (0.040 g, 0.19 mmol) was added. The resulting solution was stirred for 45 min at rt, diluted with EtOAc and washed with 8% NaHCO ₃ (aq). The aqueous layer was extracted with EtOAc and the combined organic layers were dried over Na ₂ SO ₄ , filtered and concentrated. The residue was purified by preparative SFC, PrepMethod SFC-D, to give the title compound (0.029 g, 41%); HRMS (ESI) m/z [M+H]+ calcd for C ₂₂ H ₂₆ N ₅ O ₃ S: 440.1750, found: 440.1738;

1H NMR (600 MHz, DMSO-d6) δ 9.02 (t, 1H), 8.76 (d, 1H), 7.91 (d, 1H), 7.79 (d, 1H), 7.58 (dd, 1H), 7.44 (d, 1H), 5.29 (dd, 1H), 4.85 (d, 1H), 4.68 (d, 1H), 4.31 - 4.24 (m, 2H), 3.84 (dd, overlaps with solvent peak), 3.72 - 3.67 (m, overlaps with solvent peak), 3.42 (dd, 2H), 3.38 - 3.31 (m, 2H), 0.87 (d, 6H).

Example 104

A solution of tert-butyl 6-(8-oxa-5-azaspiro[3.5]nonan-5-yl)quinoline-4-carboxylate, intermediate 216 (103 mg, 0.29 mmol), in 90% TFA (aq, 1 mL) was stirred at 50 °C for 20 min. After cooling to rt, the solution was concentrated under reduced pressure and the residue was suspended in heptane/DCM and concentrated. This was repeated 3x and the residue was dried under vacuum overnight. HATU (0.132 g, 0.35 mmol) was added to a stirred solution of the residue (0.153 g, 0.29 mmol) and DIPEA (0.253 mL, 1.45 mmol) in MeCN/EtOAc (3 mL, 1:1) at rt. The reaction mixture was stirred for 1 min and (R)-3-glycylthiazolidine-4-carbonitrile hydrochloride, intermediate 4 (0.072 g, 0.35 mmol) was added. The resulting solution was stirred at rt for 80 min, diluted with EtOAc and washed with 8% _NaHCO3 (aq.

- 217 048482 solution). The aqueous layer was extracted with EtOAc and _the combined organic layers were dried over _Na2SO4 , filtered and concentrated. The residue was purified by preparative SFC, PrepMethod SFC-C, to give the title compound (0.042 _g , 32%); HRMS (ESI) m/z [M+H]+ _{calcd for C23H26N5O3S :} 452.1750, found: 452.1754;

¹ H NMR (600 MHz, DMSO-d6) δ 9.00 (t, 1H), 8.73 (d, 1H), 7.88 (d, 1H), 7.56 (d, 1H), 7.48 - 7.41 (m, 2H), 5.28 (dd, 1H), 4.86 (d, 1H), 4.68 (d, 1H), 4.31 (dd, 1H), 4.21 (dd, 1H), 3.84 - 3.76 (m, 2H), 3.54 - 3.47 (m, overlaps with solvent peak), 3.37 - 3.29 (m, overlaps with solvent peak), 2.16 - 2.07 (m, 2H), 2.05 - 1.96 (m, 2H), 1.70 - 1.62 (m, 1H), 1.54 - 1.46 (m, 1H).

Example 105. N-(2-((R)-4-cyanothiazolidin-3-yl)-2-oxoethyl)-6-((3R,5R)-3,5-dimethylmorpholino)quinoline-4-carboxamide

A solution of tert-butyl 6-((3R,5R)-3,5-dimethylmorpholino)quinoline-4-carboxylate, intermediate 217 (84 mg, 0.25 mmol), in 90% TFA (aq, 2 mL) was stirred at rt for 5 h. After cooling to rt, the solution was concentrated under reduced pressure and the residue was co-evaporated with heptane/DCM (×2) and dried under vacuum overnight. HATU (132 mg, 0.35 mmol) was added to a stirred solution of the residue in MeCN/EtOAc (3 mL, 1:1) and DIPEA (253 µL, 1.45 mmol) at rt. The reaction mixture was stirred for 1 min, after which (E)-3-glycylthiazolidine-4-carbonitrile hydrochloride, intermediate 4 (72 mg, 0.35 mmol) was added. The resulting solution was stirred for 1 h at rt, diluted with EtOAc and washed with 8% NaHCO ₃ (aq). The aqueous layer was extracted with EtOAc and the combined organic layers were dried over Na ₂ SO ₄ , filtered and concentrated. The residue was purified by preparative SFC, PrepMethod SFC-D, to give the title compound (0.043 g, 39%); HRMS (ESI) m/z [M+H] ⁺ calcd. for C ₂₂ H ₂₆ N ₅ O ₃ S: 440.1750, found value: 440.1746;

1H NMR (600 MHz, DMSO- _d6 ) δ 9.02 (t, 1H), 8.77 (d, 1H), 7.92 (d, 1H), 7.72 (d, 1H), 7. 58 (dd, 1H), 7.46 (d, 1H), 5.29 (dd, 1H), 4.86 (d, 1H), 4.69 (d, 1H), 4.33 (dd, 1H), 4.23 (dd, 1H), 3.84 (dd, 2H), 3.70 - 3.62 ( m, 2H), 3.43 (dd, 2H), 3.40 - 3.29 (m, 2H), 0.87 (d, 6H).

Example 106. N-(2-((R)-4-cyanothiazolidin-3-yl)-2-oxoethyl)-6-((S)-3-ethylmorpholino)quinoline-4-carboxamide

HATU (103 mg, 0.27 mmol) was added to a stirred solution of crude (S)-6-(3-ethylmorpholino)quinoline-4-carboxylic acid, intermediate 219 (116 mg), and DIPEA (197 µL, 1.13 mmol) in DMF (2 mL) at rt. The reaction mixture was stirred for ~1 min, after which (E)-3-glycylthiazolidine-4-carbonitrile hydrochloride, intermediate 4 (56.2 mg, 0.27 mmol) was added. The resulting solution was stirred for 2 h at rt. The reaction mixture was diluted with DCM and washed with 8% _NaHCO3 (aq). The organic layer was concentrated and co-evaporated with heptane (x4) until most of the DMF was removed. The residue was purified by preparative SFC, PrepMethod SFC-D, to give the title compound (0.046 g, 47%); FIRMS (ESI) m/z [M ₊ H] ⁺ calcd for _C22H26N5O3S : 440.1750, found _{: 440.1748} ;

1H NMR (600 MHz, DMSO-d ₆ ) δ 8.96 (t, 1H), 8.63 (d, 1H), 7.87 (d, 1H), 7.64 - 7.58 (m, 2H), 7.37 (d, 1H), 5.28 (dd, 1H), 4.85 (d, 1H), 4.67 (d, 1H), 4.26 (dd, 2H), 3.93 (dd, 1H), 3.87 (d, 1H), 3.85 - 3.79 (m, 1H), 3.61 (dd, 1H), 3.56 - 3.51 (m, 1H), 3.44 (d, overlaps with solvent peak), 3.38 - 3.30 (m, overlaps with solvent peak), 3.18-3.12 (m, 1H), 1.77 - 1.66 (m, 1H), 1.36 (m, 1H), 0.82 (t, 3H).

Example 107. (R)-N-(2-(4-cyanothiazolidin-3-yl)-2-oxoethyl)-6-(3,3-dimethylmorpholino)quinoline-4-carboxamide

A solution of tert-butyl 6-(3,3-dimethylmorpholino)quinoline-4-carboxylate, intermediate 220 (51 mg, 0.15 mmol), in 90% TFA (aq, 1 mL) was stirred at rt for 5 h. The solution was concentrated under reduced pressure and the residue was suspended in DCM/heptane and then concentrated (×2). The residue was dissolved in DMF (1 mL) and DIPEA (0.13 mL, 0.76 mmol), and

- 218 048482

HATU (69 mg, 0.18 mmol) at rt and the reaction mixture was stirred for 1 min, after which (R)-3-glycylthiazolidine-4-carbonitrile hydrochloride, intermediate 4 (38 mg, 0.18 mmol) was added. The resulting solution was stirred for 3 h at rt, diluted with DCM and washed with 8% _NaHCO3 (aq). The organic layer was concentrated and the residue was co-evaporated with heptane (x4) until most of the DMF was removed. The residue was purified by preparative SFC, PrepMethod SFC-A, to give the title compound (0.027 g, 41%); FIRMS (ESI) m/z [M+H]+ calcd. for C ₂₂ H ₂₆ N5O ₃ S: 440.1750, found value: 440.1748;

^1H NMR (600 MHz, DMSO-d6) δ 9.01 (t, 1H), 8.81 (d, 1H), 7.98 (d, 1H), 7.90 (d, 1H), 7. 58 (dd, 1H), 7.47 (d, 1H), 5.30 (dd, 1H), 4.85 (d, 1H), 4.69 (d, 1H), 4.32 - 4.24 (m, 2H), 3.72 (t, 2H), 3.40 (s, 2H), 3.36 (dd, 1H ), 3.32 (dd, 1H), 3.20 - 3.14 (m, 2H), 1.05 (s, 3H), 1.04 (s, 3H).

Example 108. N-(2-((R)-4-cyanothiazolidin-3-yl)-2-oxoethyl)-6-((R)-3-methylmorpholino)quinoline-4-carboxamide

A solution of tert-butyl (R)-6-(3-methylmorpholino)quinoline-4-carboxylate, intermediate 221 (67 mg, 0.20 mmol), in 90% TFA (aq, 3 mL) was stirred at rt for 5 h. The solution was concentrated under reduced pressure and the residue was co-evaporated twice with heptane. The residue was dissolved in DMF (1 mL) and DIPEA (157 μL, 0.90 mmol) and HATU (82 mg, 0.22 mmol) was added at rt. The reaction mixture was stirred for 1 min, after which (R)-3-glycylthiazolidine-4-carbonitrile hydrochloride, intermediate 4 (45 mg, 0.22 mmol) was added. The resulting solution was stirred for 2 h at rt, diluted with DCM and washed with 8% NaHCO ₃ (aq). The organic layer was concentrated and the residue was co-evaporated with heptane (4x) to remove most of the DMF. The residue was purified by preparative SFC, PrepMethod SFC-C, to give the title compound (0.028 g, 37%); HRMS (ESI) m/z [M+H]+ calcd for C ₂₁ H ₂₄ N ₅ O ₃ S: 426.1594, found: 426.1602;

1H NMR (600 MHz, DMSO-d ₆ ) δ 8.96 (t, 1H), 8.63 (d, 1H), 7.88 (d, 1H), 7.63 - 7.58 (m, 2H), 7.36 (d, 1H), 5.27 (dd, 1H), 4.86 (d, 1H), 4.67 (d, 1H), 4.30 (dd, 1H), 4.22 (dd, 1H), 4.16 - 4.09 (m, 1H), 3.95 (dd, 1H), 3.71 (d, 2H), 3.55 (td, 1H), 3.42 - 3.30 (m, overlaps with solvent peak), 3.09 (td, 1H), 1.04 (d, 3H).

Example 109. (R)-N-(2-(4-cyanothiazolidin-3-yl)-2-oxoethyl)-2-methyl-6-morpholinoquinoline-4-carboxamide

Ethyl 2-methyl-6-morpholinoquinoline-4-carboxylate, intermediate 222 (89 mg, 0.30 mmol), was dissolved in MeOH (1 mL). 2 M NaOH (aq., 0.148 mL, 0.30 mmol) was added and the reaction mixture was stirred at rt for 2 h and then evaporated to dryness. HATU (141 mg, 0.37 mmol) and DIPEA (0.155 mL, 0.89 mmol) were added to a suspension of the residue and (R)3-glycylthiazolidine-4-carbonitrile hydrochloride, intermediate 4 (61 mg, 0.30 mmol), in EtOAc (1 mL), MeCN (1.0 mL), and DMF (1.0 mL). The solution was stirred at rt overnight. The reaction mixture was evaporated and the residue was purified by preparative HPLC, PrepMethod Q, to give the title compound (0.6 g, 0.5%); HRMS (ESI) m/z [M+H]+ calcd for C ₂₁ H ₂₄ N ₅ O ₃ S: 426.1594, found: 426.1594.

Example 110 4-carboxamide

A solution of tert-butyl 6-(2-oxo-1-oxa-3-azaspiro[5.5]undecan-3-yl)quinoline-4-carboxylate, intermediate 223 (115 mg, 0.29 mmol), in 90% TFA (2 ml) was stirred at 50 °C for 15 min. The reaction solution was concentrated and the residue was co-evaporated twice from water. A mixture of MeCN/EtOAc (2.6 ml, 1:1) and DIPEA (0.253 ml, 1.45 mmol) was added to the residue, then HATU (0.132 g, 0.35 mmol) was added. The reaction mixture was stirred for 1 min, after which (R)-3-glycylthiazolidine-4-carbonitrile hydrochloride, intermediate 4 (0.072 g, 0.35 mmol) was added. The reaction mixture was stirred for 1 h 15 min, diluted with EtOAc (20 mL) and washed with

- 219 048482 with 8% _NaHCO3 (aq, 10 mL) then H2O (2 mL). _The organic layer was dried over _Na2SO4 , filtered and concentrated. The residue was purified by direct phase flash chromatography on silica gel (EtOAc then EtOAc:MeOH, 20:1). The compound was further purified by preparative HPLC, PrepMethod G (gradient: 10-50%), and preparative SFC, PrepMethod SFC-D, to give the title compound (0.046 g, 32%);

HRMS (ESI) mass/charge [M+H]+ calcd for C ₂₅ H ₂₈ N ₅ O ₄ S: 494.1856, found value: 494.1838;

1H NMR (500 MHz, DMSO-d6) δ 9.17 (t, 1H), 8.96 (d, 1H), 8.49 (d, 1H), 8.05 (d, 1H), 7.88 (dd, 1H), 7.56 (d, 1H), 5.32 (dd, 1H), 4.90 (d, 1H), 4.71 (d, 1H), 4.34 (d, 2H), 3.93 - 3.79 (m, 2H), 3.43 (dd, 1H), 3.36 (dd, 1H ), 2.09 (t, 2H), 1.91 - 1.82 (m, 2H), 1.72 - 1.60 (m, 4H), 1.58 - 1.50 (m, 3H), 1.45 - 1.32 (m, 1H).

Example 111 4-carboxamide

A solution of tert-butyl 6-(7-oxo-6-oxa-8-azaspiro[4.5]decan-8-yl)quinoline-4-carboxylate, intermediate 225 (105 mg, 0.27 mmol), in 90% TFA (aq, 1 mL) was stirred at 50 °C for 15 min. The reaction solution was concentrated and the residue was dissolved in water/MeCN and lyophilized. MeCN/EtOAc (2.4 mL, 1:1) was added to the residue, then DIPEA (0.236 mL, 1.35 mmol) and HATU (0.123 g, 0.32 mmol) were added. The reaction mixture was stirred at rt. for 1 min, after which (R)-3-glycylthiazolidine-4-carbonitrile hydrochloride, intermediate 4 (0.067 g, 0.32 mmol) was added. The reaction mixture was stirred for 2 h, diluted with EtOAc (20 mL) and washed with 8% NaHCO ₃ (aq, 10 mL) then water (2 mL). The organic layer was dried over Na ₂ SO ₄ , filtered and concentrated. The residue was purified by straight-phase flash chromatography on silica gel (EtOAc then EtOAc/MeOH 10:1). The compound was further purified by preparative HPLC, PrepMethod G (gradients: 0-30% and 0-45%), and preparative SFC to afford the title compound (0.031 g, 24%) as an off-white solid; HRMS (ESI) m/z [M+H] ⁺ calcd for C ₂₄ H ₂₆ N ₅ O ₄ S: 480.1700, found: 480.1718;

1H NMR (500 MHz, DMSO-d6) δ 9.17 (t, 1H), 8.96 (d, 1H), 8.49 (d, 1H), 8.05 (d, 1H), 7.89 (dd, 1H), 7.57 (d, 1H), 5.33 (dd, 1H), 4.90 (d, 1H), 4.71 (d, 1H), 4.34 (d, 2H), 3.93 - 3.82 (m, 2H), 3.46 - 3.36 (m, 2H), 2.18 (t, 2H), 2.03 - 1.95 (m, 2H), 1.87 - 1.66 (m, 6H).

Example 112 4-carboxamide

TFA (35 μl, 0.45 mmol) was added to a solution of tert-butyl 6-(6,6-dimethyl-2-oxo-1,3-oxazinan-3-yl)quinoline-4-carboxylate, intermediate 226 (40 mg, 0.11 mmol), in DCM (2 ml). The resulting solution was stirred at 25 °C for 6 h. The solvent was removed by distillation under vacuum. The residue was dissolved in DMF (2 ml) and (R)-3-glycylthiazolidine-4-carbonitrile hydrochloride, intermediate 4 (55 mg, 0.27 mmol), T3P (170 mg, 0.53 mmol) and DIPEA (69 mg, 0.53 mmol) were added. The resulting solution was stirred at 25 °C for 6 h. The solvent was removed under reduced pressure and the residue was purified by preparative TLC (DCM:MeOH 18:1) followed by preparative HPLC, PrepMethod B (gradient: 11-41%) to give the title compound (0.028 g, 46%) as a white solid; HRMS (ESI) m/z [M+H] ⁺ calcd for C22H24N5O4S: 454.1544, found: 454.1554;

1H NMR (300 MHz, DMSO-d6) δ 9.16 (t, 1H), 8.95 (d, 1H), 8.49 (d, 1H), 8.04 (d, 1H), 7.86 (dd, 1H), 7.55 (d, 1H), 5.31 (dd, 1H), 4.88 (d, 1H), 4.69 (d, 1H), 4.33 (d, 2H), 3.86 (t, 2H), 3.46 - 3.32 (m, overlaps with solvent peak), 2.07 (t, 2H), 1.44 (s, 6H).

Example 113

DIPEA (1.37 mL, 7.81 mmol) was added to the mixture of crude 6-(3-(fluoromethyl)-azetidine-1

- 220 048482 yl)quinoline-4-carboxylic acid, intermediate 228 (0.436 g, 0.724 mmol), (R)-3-glycylthiazolidine-4-carbonitrile hydrochloride, intermediate 4 (263 mg, 1.27 mmol), HOBt (428 mg, 3.16 mmol) and EDC (607 mg, 3.16 mmol) in EtOAc (5 mL) and MeCN (5 mL) at 13 °C. The resulting solution was stirred at 13 °C overnight under N2 (g). The solvent was removed under reduced pressure. The reaction mixture was diluted with _saturated NaHCO3 (aq, 100 mL) and extracted with EtOAc (5 x 100 mL). The organic layers _were combined and washed with saturated NaCl solution (aq, 3x50 mL), dried over _Na2SO4 , filtered and evaporated. The residue was purified by preparative HPLC, PrepMethod C (gradient: 10-30%) and further purified by straight phase flash chromatography on silica gel (EtOAc:MeOH, 9:1) to give the title compound ( _0.103 g, 34 _{%) as a yellow solid; HRMS (ESI) m/z [M+H]+ calcd for C20H21FN5O2S :} 414.1394, found: _414.1412 ;

1H NMR (500 MHz, DMSO- _d6 ) δ 8.97 (t, 1H), 8.63 (d, 1H), 7.89 (d, 1H), 7.41 (d, 1H), 7. 19 (d, 1H), 7.13 (dd, 1H), 5.34 (dd, 1H), 4.89 (d, 1H), 4.72 (d, 1H), 4.70 (d, 1H), 4.60 (d, 1H), 4.30 (d, 2H), 4.07 (t, 2H) , 3.78 (dd, 2H), 3.44 - 3.36 (m, 2H), 3.20 - 3.06 (m, 1H).

Example 114 carboxamide

DIPEA (0.429 ml, 2.45 mmol) was added to a stirred suspension of crude 6-(4,5,6,7-tetrahydro-1H-indazol-1-yl)quinoline-4-carboxylic acid, intermediate 240 (50 mg, 0.08 mmol), (R)-3-glycylthiazolidine-4-carbonitrile hydrochloride, intermediate 4 (26 mg, 0.12 mmol), HOBt (55 mg, 0.41 mmol), and EDC (78 mg, 0.41 mmol) in MeCN (3 ml) and EtOAc (3 ml) at 18 °C. The resulting solution was stirred at 50 °C for 2 h. The solvent was removed under reduced pressure. The residue was partitioned between sat. _NaHCO3 solution (20 ml) and EtOAc (50 ml). The aqueous layer was extracted with EtOAc (5x50 ml). The organic layers were combined and washed with H2O (3x20 ml). The aqueous layers were combined and extracted with EtOAc (3x15 ml). All organic layers were combined and dried over Na2SO4, filtered and evaporated. The residue was purified by preparative HPLC, PrepMethod C (gradient: 35-50%), affording the title compound (0.035 g, 96%) as a white solid; HRMS (ESI) m/z [M _{+H]+ calcd for C23H23N6O2S : 447.1598} , found: 447.1618 _;

1H NMR (300 MHz, DMSO-d6) δ 9.30 - 9.10 (m, 1H), 9.01 (d, 1H), 8.42 (d, 1H), 8.28 - 8.04 (m, 2H), 7.72 - 7.50 (m, 2H), 5.33 (dd, 1H), 4.91 (d, 1H), 4.72 (d, 1H), 4.48 - 4.23 (m, 2H), 3.48 -3.34 (m, overlaps with solvent peak), 2.99 - 2.79 (m, 2H), 2.65 - 2.50 (m, overlaps with solvent peak), 1.89 1.63 (m, 4H).

Example 115 carboxamide

DIPEA (4.21 mL, 24.1 mmol) was added to a stirred suspension of crude 6-(4,5,6,7-tetrahydro-2H-indazol-2-yl)quinoline-4-carboxylic acid, intermediate 241 (465 mg, 0.59 mmol), (R)-3-glycylthiazolidine-4-carbonitrile hydrochloride, intermediate 4 (185 mg, 0.89 mmol), HOBt (401 mg, 2.97 mmol), and EDC (569 mg, 2.97 mmol) in MeCN (5 mL) and EtOAc (5 mL) at 18 °C. The resulting solution was stirred at 50 °C for 2 h. The solvent was removed under reduced pressure. The residue was partitioned between sat. _NaHCO3 solution (aq, 50 mL) and EtOAc (100 mL). The aqueous layer was extracted with EtOAc (5x100 mL). The organic layers were combined and washed with _H2O (3x50 mL). _The organic layer was dried over _Na2SO4 , filtered and evaporated. The residue was purified by preparative HPLC, PrepMethod C (gradient: 35-45%) _, to give the title compound (0.122 g, 46%) as a white solid; HRMS (ESI) m/z [ _M + _H ]+ calcd for _C23H23N6O2S : 447.1598, found: 447.1594;

1H NMR (300 MHz, DMSO-d6) δ 9.28 - 9.08 (m, 1H), 8.94 (d, 1H), 8.77 (s, 1H), 8.43 - 8.30 (m, 2H), 8.16 (d, 1H), 7.60 (d, 1H), 5.45 - 5.28 (m, 1H), 4.93 (d, 1H), 4.74 (d, 1H), 4.39 (d, 2H), 3.50 - 3.34 (m, overlaps with solvent peak), 2.80 - 2.52 (m, overlaps with solvent peak), 1.77 (m, 4H).

- 221 048482

Example 116 carboxamide

DIPEA (1.56 mL, 8.92 mmol) was added to a stirred suspension of crude 6-(5-methyl-3(trifluoromethyl)-1H-pyrazol-1-yl)quinoline-4-carboxylic acid, intermediate 242 (199 mg, 0.29 mmol), (R)-3-glycylthiazolidine-4-carbonitrile hydrochloride, intermediate 4 (90 mg, 0.44 mmol), HOBt (196 mg, 1.45 mmol), and EDC (278 mg, 1.45 mmol) in MeCN (5 mL) and EtOAc (5 mL) at 15 °C. The resulting solution was stirred at 50 °C for 2 h. The solvent was removed under reduced pressure and the residue was partitioned between sat. NaHCO ₃ solution (aq, 50 ml) and EtOAc (100 ml). The aqueous layer was extracted with EtOAc (4x100 ml).

The organic layers were combined and washed with H2O (3x50 mL). _The organic layer was dried over _Na2SO4 , filtered and evaporated. The residue was purified by preparative HPLC, PrepMethod C (gradient: 40-52%) to _afford the title _compound (0.090 g, 65%) as a white solid; HRMS ( _ESI ) m/z [M+ _H ]+ calcd for C21H18F3N6O2S: 475.1158, found: _475.1138 ;

Ή NMR (300 MHz, DMSO-d6) δ 9.23 (t, 1H), 9.09 (d, 1H), 8.54 (d, 1H), 8.26 (d, 1H), 8.04 (dd, 1H), 7.71 (d, 1H), 6.83 (s, 1H), 5.40 - 5.20 (m, 1H), 4.87 (d, 1H), 4.69 (d, 1H), 4.36 - 4.28 (m, 2H), 3.42 - 3.32 (m, overlaps with solvent peak), 2.46 (s, overlaps with solvent peak).

Example 117. (R)-N-(2-(4-cyanothiazolidin-3-yl)-2-oxoethyl)-6-(6,6-dimethyl-5,6-dihydrocyclopenta[c]pyrazol-2(4H)-yl)quinoline-4-carboxamide

DIPEA (3.29 mL, 18.8 mmol) was added to a stirred suspension of crude 6-(6,6-dimethyl-5,6-dihydrocyclopenta[c]pyrazol-2(4H)-yl)quinoline-4-carboxylic acid, intermediate 243 (482 mg, 0.62 mmol), (R)-3-glycylthiazolidine-4-carbonitrile hydrochloride, intermediate 4 (194 mg, 0.94 mmol), HOBt (420 mg, 3.14 mmol), and EDC (596 mg, 3.14 mmol) in MeCN (7 mL) and EtOAc (7 mL) at 15 °C. The resulting solution was stirred at 50 °C for 2 h. The solvent was removed under reduced pressure and the residue was partitioned between sat. _NaHCO3 solution (aq, 60 mL) and EtOAc (100 mL). The aqueous layer was extracted with EtOAc (5x100 mL). The organic layers were combined and washed with H2O (3x50 mL). _The organic layer was dried over _Na2SO4 , filtered and evaporated. The residue was purified by preparative HPLC, PrepMethod F (42-52% _gradient ) to give the title compound ( _0.14 g, 49%) as a white solid; HRMS (ESI) m/z [M+ _H ]+ calcd for C24H25N6O2S: 461.1754, found: _461.1742 ;

1H NMR (300 MHz, DMSO-d6) δ 9.14 (t, 1H), 8.92 (d, 1H), 8.70 (d, 1H), 8.31 (dd, 1H), 8.22 (s, 1H), 8.13 (d, 1H), 7.58 (d, 1H), 5.44 - 5.24 (m, 1H), 4.90 (d, 1H), 4.72 (d, 1H), 4.36 (d, 2H), 3.46 - 3.30 (m, overlaps with solvent peak), 2.66 (t, 2H), 2.19 (t, 2H), 1.30 (s, 6H).

Example 118

DIPEA (0.443 ml, 2.54 mmol) was added to a stirred suspension of 6-(3-(trifluoromethyl)-1H-pyrazol-1-yl)quinoline-4-carboxylic acid, intermediate 234 (78 mg, 0.25 mmol), (R)-3-glycylthiazolidine-4-carbonitrile hydrochloride, intermediate 4 (79 mg, 0.38 mmol), HOBt (172 mg, 1.27 mmol), and EDC (243 mg, 1.27 mmol) in MeCN (5 ml) and EtOAc (5 ml) at 10 °C. The resulting suspension was stirred at 50 °C for 2 h. The solvent was removed under reduced pressure and the residue was partitioned between saturated NaHCO ₃ solution (30 ml) and EtOAc (60 ml). The aqueous layer was extracted with EtOAc (4x75 mL). _The organic layers were combined and washed with _H2O (3x20 mL). The organic layer was dried over _Na2SO4 , filtered and evaporated. The residue was purified by preparative HPLC, PrepMethod F (gradient: 40-50%) to give the title compound.

- 222 048482 units (0.052 g, 43%) as a white solid; HRMS (ESI) m/z [M+ _H ]+ _{calcd for C2oH16F3N6O2S :} 461.1002, found: 461.1018;

1H NMR (300 MHz, DMSO-d6) δ 9.22 (t, 1H), 9.04 (d, 1H), 8.94 (d, 1H), 8.88 (d, 1H), 8.38 (dd, 1H), 8.26 (d, 1H), 7.69 (d, 1H), 7.15 - 7.00 (m, 1H), 5.35 (dd, 1H), 4.91 (d, 1H) 4.73 (d, 1H), 4.44 - 4.25 (m, 2H), 3.70 3.34 (m, overlaps with solvent peak).

Example 119. (R)-N-(2-(4-cyanothiazolidin-3-yl)-2-oxoethyl)-6-(4,6-difluoro-1H-indol-1yl)quinoline-4-carboxamide

A solution of 6-(4,6-difluoro-1H-indol-1-yl)quinoline-4-carboxylic acid, intermediate 235 (180 mg, 0.56 mmol), (R)-3-glycylthiozolidine-4-carbonitrile hydrochloride, intermediate 4 (173 mg, 0.83 mmol), EDC (213 mg, 1.11 mmol), HOBt (150 mg, 1.11 mmol) and DIPEA (485 μl, 2.78 mmol) in EtOAc (6 ml) and MeCN (6 ml) was stirred at 50 °C for 2 h. The solvent was removed under reduced pressure. The reaction mixture was diluted with EtOAc (25 ml) and washed with H2O (3x10 ml). _The organic layer was dried over _Na2SO4 , filtered and evaporated. The residue was purified by preparative TLC (DCM: _MeOH 10: ₁ ) followed by preparative HPLC, PrepMethod U (40-50% gradient) to give the title compound (0.105 g, 40%); HRMS (ESI) m/z _[ M ₊ H]+ calcd for _{C24H18F2N5O2S} : 478.1144, found: 478.1134;

1H NMR (300 MHz, DMSO-d ₆ ) δ 9.22 (t, 1H), 9.06 (d, 1H), 8.57 (d, 1H), 8.29 (d, 1H), 8.10 (dd, 1H), 7.86 (d, 1H), 7.71 (d, 1H), 7.42 - 7.32 (m, 1H), 7.03 (td, 1H), 6.85 (d, 1H), 5.81 - 5.20 (m, 1H), 4.86 (d, 1H), 4.69 (d, 1H), 4.55 - 4.26 (m, 2H), 3.36 - 3.25 (m, overlaps with solvent peak).

Example 120. (R)-N-(2-(4-cyanothiazolidin-3-yl)-2-oxoethyl)-6-(5-fluoro-1H-indol-1-yl)quinoline-4-carboxamide

TEA (137 μL, 0.98 mmol) was added to a stirred suspension of 6-(5-Fluoro-1H-indol-1yl)quinoline-4-carboxylic acid, intermediate 236 (30 mg, 0.10 mmol), (R)-3-glycylthiazolidine-4-carbonitrile hydrochloride, intermediate 4 (31 mg, 0.15 mmol), HOBt (66 mg, 0.49 mmol) and EDC (94 mg, 0.49 mmol) in MeCN (3 mL) and EtOAc (3 mL) at 10 °C. The resulting suspension was stirred at 50 °C for 2 h. The solvent was removed under reduced pressure. The residue was dissolved in a mixture of NaHCO ₃ (aq, 30 mL) and EtOAc (60 mL). The aqueous layer was extracted with EtOAc (4x75 mL). The organic layers were combined and washed with water (3x25 mL). The aqueous layers were combined and extracted with EtOAc (3x25 mL). All organic layers were combined, dried over _Na2SO4 , filtered and evaporated. The residue was purified by preparative HPLC, PrepMethod F (gradient: 40-50%) to give the title compound (0.018 _g , 40%) as a grey solid; HRMS (ESI) m/z [M+H]+ calcd for _C24H19FN5O2S : 460.1238, found: _460.1236 ;

¹ H NMR (300 MHz, DMSO-d ₆ ) δ 9.19 (t, 1H), 9.03 (d, 1H), 8.54 (d, 1H), 8.28 (d, 1H), 8.10 (dd, 1H), 7.89 (d, 1H), 7.75 (dd, 1H), 7.68 (d, 1H), 7.47 (dd, 1H), 7.16 - 7.05 (m, 1H), 6.77 (d, 1H), 5.39 - 5.19 (m, 1h), 4.88 (d, 1H), 4.71 (d, 1H), 4.32 (d, 2H), 3.38 - 3.34 (m, overlaps with solvent peak).

Example 121

TEA (249 μL, 1.78 mmol) was added to a stirred suspension of 6-(3-methyl-1H-pyrrol-1yl)quinoline-4-carboxylic acid, intermediate 237 (45 mg, 0.18 mmol), (B)-3-glycylthiazolidine-4-carbonitrile hydrochloride, intermediate 4 (56 mg, 0.27 mmol), HOBt (121 mg, 0.89 mmol), and EDC (171 mg, 0.89 mmol) in MeCN (5 mL) and EtOAc (5 mL) at 10 °C. The resulting suspension was stirred at 50 °C for 2 h. The solvent was removed under reduced pressure. The residue was partitioned between saturated NaHCO ₃ (30 mL) and EtOAc (60 mL). The aqueous layer was extracted with EtOAc (4x60 mL). The organic layers were combined and washed with water (3x30 mL). The aqueous layers

- 223 048482 were combined and extracted with EtOAc (2x20 mL). All organic layers were combined, dried _{over Na2SO4} , filtered and evaporated. The residue was purified by preparative HPLC, PrepMethod F (gradient: 35-47%) _, affording the title compound ( _0.021 g, 29%) as a pale yellow solid; HRMS (ESI) m/z [M+H]+ calcd for _C21H20N5O2S : 406.1332, found: _406.1326 ;

1H NMR (300 MHz, DMSO-d6) δ 9.16 (t, 1H), 8.89 (d, 1H), 8.60 - 8.40 (m, 1H), 8.17 - 8.01 (m, 2H), 7.55 (d, 1H), 7.53 - 7.30 (m, 1H), 6.21 - 6.12 (m, 1H), 5.36 (dd, 1H), 4.90 (d, 1H), 4.72 (d, 1H), 4.35 (d, 2H), 3.41-3.37 (m, overlaps with solvent peak), 2.11 (s, 3H).

Example 122

HATU (114 mg, 0.30 mmol) was added to a stirred mixture of crude 6-(3-morpholinoazetidin-1-yl)quinoline-4-carboxylic acid, intermediate 239 (104 mg), and DIPEA (0.217 mL, 1.24 mmol) in MeCN/EtOAc (2.4 mL, 1:1) at rt. The reaction mixture was stirred for 1 min, after which (R)-3-glycylthiazolidine-4-carbonitrile hydrochloride, intermediate 4 (62 mg, 0.30 mmol) was added and the reaction mixture was stirred for 2 h at rt. The reaction mixture was diluted with EtOAc (8 mL) and washed with 8% _NaHCO3 (aq, 6 mL). The aqueous layer was extracted with EtOAc and _the combined organic layers were dried over _Na2SO4 , filtered and concentrated. The residue was purified by preparative HPLC, PrepMethod G (0-30% gradient) followed by silica gel flash chromatography (EtOAc:MeOH, 6:1) to give the title compound (0.037 g, 32%) as a yellow solid;

HRMS (ESI) mass/charge [M+H] ⁺ calc. for C ₂₃ H ₂₇ N ₆ O ₃ S: 467.1860, found value: 467.1860;

^1H NMR (500 MHz, DMSO- _d6 ) δ 8.96 (t, 1H), 8.62 (d, 1H), 7.88 (d, 1H), 7.39 (d, 1H), 7 .23 (d, 1H), 7.12 (dd, 1H), 5.31 (dd, 1H), 4.89 (d, 1H), 4.70 (d, 1H), 4.29 (d, 2H), 4.06 (t, 2H), 3.81 - 3.72 (m, 2H), 3.62 - 3.56 (m, 4H), 3.40 (dd, 1H), 3.36 (d, 1H), 3.32 - 3.26 (m, 1H), 2.41 -2.30 (m, 4H).

Example 123. (R)-N-(2-(4-cyanothiazolidin-3-yl)-2-oxoethyl)-6-(5,5-dimethyl-5,6-dihydro-4Hpyrrolo[1,2-b] pyrazol-3-yl)quinoline-4-carboxamide

(R)-3-Glycylthiazolidine-4-carbonitrile hydrochloride, intermediate 4 (57 mg, 0.27 mmol), was added to a mixture of 6-(5,5-dimethyl-5,6-dihydro-4H-nupropyl[1,2-b]pyrazole-3-yl)quinoline-4-carboxylic acid, intermediate 244 (70 mg, 0.23 mmol), HATU (130 mg, 0.34 mmol) and DIPEA (119 μl, 0.68 mmol) in DMF (2 ml) and the reaction mixture was stirred at rt overnight. EtOAc (10 ml) and _NaHCO3 (5 ml, aq) were added and the reaction mixture was stirred and the phases were separated. The organic layer was washed with water and brine and the combined aqueous phase was extracted with EtOAc. The combined organic layer was dried over _MgSO4 , filtered and evaporated under reduced pressure. The crude product was purified by preparative SFC, PrepMethod SFC-A (gradient: _27-32 %) to give the title compound ( ₃₉ mg, 37%); HRMS (ESI) m/z [M+ _H ] ⁺ calcd for _C24H25N6O2S : 461.1754 found: 461.1748;

1H NMR (600 MHz, DMSO-d6) δ 9.09 (t, 1H), 8.84 (d, 1H), 8.37 (d, 1H), 8.19 (s, 1H), 8.03 (d, 1H), 7.96 (dd, 1H), 7.48 (d, 1H), 5.31 (d, 1H), 4.79 (dd, 2H), 4.30 (qd, 2H), 3.87 (s, 2H), 3.49 - 3.31 (m, 2H), 3.13 (s, 2H ), 1.18-1.13 (m, 6H).

Example 124. (R)-N(2-(4-cyanothiazolidin-3-yl)-2-oxoethyl)-6-(2-fluoropyridin-4-yl)quinoline-4-carboxamide

(R)-3-Glycylthiazolidine-4-carbonitrile hydrochloride, intermediate 4 (5 mg, 0.02 mmol), was added to a mixture of 6-(2-fluoropyridin-4-yl)quinoline-4-carboxylic acid, intermediate 245 (5 mg, 0.02 mmol), HATU (11 mg, 0.03 mmol) and DIPEA (9.8 μL, 0.06 mmol) in DMF (0.2 mL) and the reaction mixture was stirred at rt overnight. DCM (5 mL) and _NaHCO3 (aq) were added and the reaction mixture was stirred, filtered through a phase separator and the filtrate was evaporated under reduced pressure. The crude product was purified by preparative SFC, PrepMethod SFC-A (gradient: 27-32%) to afford the title compound (2 mg, 29%); HRMS (ESI) m/z [M+H]+ calcd for C ₂₁ H ₁₇ FN ₅ O ₂ S: 422.1082, found: 422.1082.

Example 125. (R)-N-(2-(4-cyanothiazolidin-3-yl)-2-oxoethyl)-6-(5-fluoropyridin-2-yl)quinoline-4-carboxamide

(R)-3-Glycylthiazolidine-4-carbonitrile hydrochloride, Intermediate 4 (6 mg, 0.03 mmol), was added to a mixture of 6-(5-fluoropyridin-2-yl)quinoline-4-carboxylic acid, Intermediate 246 (6 mg, 0.02 mmol), HATU (13 mg, 0.03 mmol) and DIPEA (12 μl, 0.07 mmol) in MeCN (0.2 ml) and EtOAc (0.2 ml) and the reaction mixture was stirred at rt overnight. EtOAc (3 ml) and _NaHCO3 (3 ml, aq) were added and the reaction mixture was stirred and the phases were separated. The organic layer was filtered through a phase separator and the filtrate was evaporated under reduced pressure. The crude product was purified by preparative SFC, PrepMethod SFC-A (gradient: 27-32%) to afford the title compound (2.5 mg, 26%); HRMS (ESI) m/z [M+H]+ calcd for C ₂₁ H ₁₇ FN ₅ O ₂ S: 422.1082, found: 422.1092.

Example 126. (R)-N-(2-(4-cyanothiazolidin-3-yl)-2-oxoethyl)-6-(pyridin-3-yl)quinoline-4-carboxamide

Step a) 6-(pyridin-3-yl)quinoline-4-carboxylic acid

A mixture of 6-bromoquinoline-4-carboxylic acid (60 mg, 0.24 mmol), pyridin-3-ylboronic acid (32 mg, 0.26 mmol), _Cs2CO3 ( ₁₉₄ mg, 0.60 mmol) and Pd(dtbpf) _Cl2 (16 mg, 0.02 mmol) in 1,4-dioxane (2 mL) and water (0.5 mL) was stirred at rt under argon overnight. Water was added to the reaction mixture and the aqueous phase was washed with EtOAc. The aqueous phase was concentrated under reduced pressure to give the title compound.

Step b) (R)-N-(2-(4-cyanothiazolidin-3-yl)-2-oxoethyl)-6-(pyridin-3-yl)quinoline-4-carboxamide

A mixture of crude 6-(pyridin-3-yl)quinoline-4-carboxylic acid, (R)-3-glycylthiazolidine-4-carbonitrile hydrochloride, intermediate 4 (60 mg, 0.29 mmol), HATU (109 mg, 0.29 mmol) and DIPEA (0.167 mL, 0.96 mmol) in DMF (2 mL) was stirred at rt overnight. The reaction mixture was diluted with DCM (15 mL) and washed with sat. _NaHCO3 (8 mL, aq). The organic phase was filtered through a phase separator and the filtrate was evaporated under reduced pressure. The crude product was purified by preparative HPLC, PrepMethod V (0-50% gradient), to give the title compound (28 mg, 29%); HRMS (ESI) mass/charge [M+H]+ calcd for C ₂₁ H ₁₈ N ₅ O ₂ S: 404.1176 found value: 404.1140;

1H NMR (600 MHz, DMSO-d6) δ 9.20 (t, 1H), 9.09 (d, 1H), 9.02 (d, 1H), 8.82 (d, 1H), 8.65 (dd, 1H), 8.36 - 8.19 (m, 3H), 7.62 (d, 1H), 7.57 (dd, 1H), 5.37 (dd, 1H), 4.82 (dd, 2H), 4.37 (d, 2H), 3.44 - 3.36 (m, overlaps with solvent peak).

Example 127. (R)-N-(2-(4-cyanothiazolidin-3-yl)-2-oxoethyl)-6-(pyrimidin-5-yl)quinoline-4-carboxamide

- 225 048482

Step a) 6-(pyrimidin-5-yl)quinoline-4-carboxylic acid

A mixture of 6-bromoquinoline-4-carboxylic acid (60 mg _{, 0.24 mmol), pyrimidin-5-ylboronic acid (32 mg, 0.26 mmol), Cs2CO3 (} 194 mg, 0.60 mmol) and Pd(dtbpf) _Cl2 (16 mg, 0.02 mmol) in 1,4-dioxane (2 mL) and water (0.5 mL) was stirred at rt under argon overnight. Water was added to the reaction mixture and the aqueous phase was washed with EtOAc. The aqueous phase was acidified to pH 3 with aq. HCl (2 M), washed with DCM and concentrated under reduced pressure to give the title compound.

Step b) (R)-N-(2-(4-cyanothiazolidin-3-yl)-2-oxoethyl)-6-(pyrimidin-5-yl)quinoline-4-carboxamide

A mixture of crude 6-(pyrimidin-5-yl)quinoline-4-carboxylic acid, (R)-3-glycylthiazolidine-4-carbonitrile hydrochloride, intermediate 4 (60 mg, 0.29 mmol), HATU (109 mg, 0.29 mmol) and DIPEA (1.04 mL, 5.97 mmol) in DMF (2 mL) was stirred at rt overnight. The reaction mixture was diluted with DCM (15 mL) and washed with sat. _NaHCO3 solution (8 mL, aq.). The organic phase was filtered through a phase separator and the filtrate was evaporated under reduced pressure. The crude product was purified by preparative HPLC, PrepMethod V (gradient: 0-50%), to give the title compound (40 mg, 42%); HRMS (ESI) mass/charge [M+H] ⁺ calc. for C ₂₀ H ₁₇ N ₆ O ₂ S: 405.1128 found value: 405.1136;

1H NMR (600 MHz, DMSO-d6) δ 9.33 (s, 2H), 9.26 (s, 1H), 9.23 (t, 1H) 9.05 (d, 1H), 8.87 (d, 1H), 8.33 8.23 (m, 2H), 7.65 (d, 1H), 5.36 (dd, 1H), 4.82 (dd, 2H), 4.37 (dd, 2H), 3.44 - 3.36 (m, overlaps with solvent peak).

Example 128. (R)-N-(2-(4-cyanothiazolidin-3-yl)-2-oxoethyl)-6-(2-methylpyridin-3-yl)quinoline-4-carboxamide

Step a) 6-(2-methylpyridin-3-yl)quinoline-4-carboxylic acid

The title compound was prepared as described in Example 127, step a) from 6-bromoquinoline-4-carboxylic acid (60 mg, 0.24 mmol) and (2-methylpyridin-3-yl)boronic acid (36 mg, 0.26 mmol) to give the title compound as a crude product.

Step b) (R)-N-(2-(4-cyanothiazolidin-3-yl)-2-oxoethyl)-6-(2-methylpyridin-3-yl)quinoline-4-carboxamide

The title compound was prepared as described for Example 127, step b) from (R)-3-glycylthiazolidine-4-carbonitrile hydrochloride, intermediate 4 (57 mg, 0.27 mmol), and crude 6-(2- _{methylpyridin} -3-yl)quinoline-4-carboxylic acid to give the title compound (38 mg, 40%); HRMS (ESI) m/z [M _{+H]+ calcd for C22H20N5O2S :} 418.1332 found: _418.1350 ;

1H NMR (600 MHz, DMSO-d ₆ ) δ 9.16 (t, 1H), 9.04 (d, 1H), 8.55 (dd, 1H), 8.37 (d, 1H), 8.19 (d, 1H), 7.90 (dd, 1H), 7.80 (d, 1H), 7.64 (d, 1H), 7.41 (dd, 1H), 5.31 (dd, 1H), 4.77 (dd, 2H), 4.31 (d, 2H), 3.40 - 3.35 (m, overlaps with solvent peak), 2.52 (s, 3H).

Example 129

Step a) 6-(1-methyl-1H-pyrazol-4-yl)quinoline-4-carboxylic acid

- 226 048482

The title compound was prepared as described in Example 127, step a) from 6-bromoquinoline-4-carboxylic acid (60 mg, 0.24 mmol) and (1-methyl-1H-pyrazol-4-yl)boronic acid (33 mg, 0.26 mmol) to give the title compound as a crude product.

Step b) (R)-N-(2-(4-cyanothiazolidin-3-yl)-2-oxoethyl)-6-(1-methyl-1H-pyrazol-4-yl)quinoline-4-carboxamide

The title compound was prepared as described for Example 127, step b) from (R)-3-glycylthiazolidine-4-carbonitrile hydrochloride, intermediate 4 (59 mg, 0.28 mmol), and crude 6-(1-methyl-1H-pyrazol-4-yl)quinoline-4-carboxylic _acid to give the title compound (39 mg, 41%); HRMS (ESI) m/z [M _{+H]+ calcd for C20H19N6O2S :} 407.1284 found: _407.1286 ;

^1H NMR (600 MHz, DMSO- _d6 ) δ 9.14 (t, 1H), 8.88 (d, 1H), 8.74 (d, 1H), 8.37 (s, 1H), 8 .11 - 8.03 (m, 3H), 7.50 (d, 1H), 5.42 (dd, 1H), 4.83 (dd, 2H), 4.37 (d, 2H), 3.92 (s, 3H), 3.51 - 3.37 (m, 2H).

Example 130

DIPEA (415 μL, 2.38 mmol) was added to a stirred suspension of 6-(3((trifluoromethoxy)methyl)azetidin-1-yl)quinoline-4-carboxylic acid, intermediate 248 (155 mg, 0.48 mmol), (R)-3-glycylthiazolidine-4-carbonitrile hydrochloride, intermediate 4 (197 mg, 0.95 mmol), HOBt (193 mg, 1.43 mmol) and EDC (273 mg, 1.43 mmol) in MeCN (10 mL) and EtOAc (10 mL) at 20 °C and the reaction mixture was stirred at 50 °C for 2 h. The solvent was removed under reduced pressure and the residue was dissolved in NaHCO ₃ (40 mL, aq.) and EtOAc (100 ml).

The phases were separated and the aqueous layer was extracted with EtOAc (4x75 mL). _The combined organic layer was washed with water (3x50 mL), dried over _Na2SO4 , filtered and evaporated under reduced pressure. The crude product was purified by preparative HPLC, PrepMethod R (gradient: 32-52%), to give the title compound (0.090 g, 39%) as _a yellow solid; HRMS (ESI) m/z [ _{M+H]+ calcd for C21H21F3N5O3S : 480.1312} found: _480.1292 ;

¹ H NMR (300 MHz, DMSO-d ₆ ) δ 8.95 (t, 1H), 8.62 (d, 1H), 7.87 (d, 1H), 7.40 (d, 1H), 7.18 - 7.07 (m, 2H), 5.35 - 5.26 (m, 1H), 4.87 (d, 1H), 4.69 (d, 1H), 4.34 (d, 2H), 4.29 (d, 2H), 4.06 (t, 2H), 3.79 - 3.69 (m, 2H), 3.39 - 3.35 (m, overlaps with solvent peak), 3.21 - 3.04 (m, 2H).

Example 131 )quinoline-4-carboxamide

DIPEA (404 µl, 2.31 mmol) was added to a stirred suspension of 6-(3-methyl-3-(2,2,2-trifluoroethyl)azetidin-1-yl)quinoline-4-carboxylic acid, intermediate 250 (150 mg, 0.46 mmol), (R)-3-glycylthiazolidine-4-carbonitrile hydrochloride, intermediate 4 (192 mg, 0.93 mmol), HOBt (187 mg, 1.39 mmol) and EDC (266 mg, 1.39 mmol) in MeCN (10 ml) and EtOAc (10 ml) at 20 °C and the reaction mixture was stirred at 50 °C for 2 h. The solvent was removed under reduced pressure and the residue was dissolved in NaHCO ₃ (40 ml, aq.) and EtOAc (100 ml). The phases were separated and the aqueous layer was extracted with EtOAc (4x75 ml). _The combined organic layer was washed with water (3x50 ml), dried over _Na2SO4 , filtered and evaporated under reduced pressure. _The crude product was purified by preparative HPLC, PrepMethod R (gradient: 33-55%), to give the title compound (0.080 g, 36%) as _a yellow solid; HRMS (ESI) m/z [M ₊ H]+ calcd for _{C22H23F3N5O2S} : 478.1518 found: _478.1524 .

¹ H NMR (300 MHz, DMSO-d ₆ ) δ 8.93 (t, 1H), 8.61 (d, 1H), 7.86 (d, 1H), 7.39 (d, 1H), 7.18 - 7.07 (m, 2H), 5.29 (dd, 1H), 4.87 (d, 1H), 4.69 (d, 1H), 4.28 (d, 2H), 3.84 (d, 2H), 3.72 (d, 2H), 3.45 - 3.34 (m, overlaps with solvent peak), 2.72 (q, 2H), 1.46 (s, 3H).

- 227 048482

Example 132

DIPEA (783 μL, 4.48 mmol) was added to a stirred suspension of 6-(3(trifluoromethoxy)azetidin-1-yl)quinoline-4-carboxylic acid, intermediate 252 (280 mg, 0.90 mmol), (R)-3-glycylthiazolidine-4-carbonitrile hydrochloride, intermediate 4 (372 mg, 1.79 mmol), HOBt (364 mg, 2.69 mmol) and EDC (516 mg, 2.69 mmol) in MeCN (10 mL) and EtOAc (10 mL) at 25 °C and the reaction mixture was stirred at 50 °C for 2 h. The solvent was removed under reduced pressure and the residue was dissolved in NaHCO ₃ (50 mL, aq.) and EtOAc (100 mL). The phases were separated and the aqueous layer was extracted with EtOAc (4x75 mL). _The combined organic layer was washed with water (3x50 mL), dried over _Na2SO4 , filtered and evaporated under reduced pressure. The crude product was purified by preparative _HPLC , PrepMethod R (gradient: 3151%), to give the title compound (0.27 g, 65%) as _a yellow solid; HRMS (ESI) m/z [M _{+H]+ calcd for C20H19F3N5O3S :} 466.1156 found: _466.1152 .

1H NMR (300 MHz, DMSO-d6) δ 9.00 (t, 1H), 8.68 (d, 1H), 7.92 (d, 1H), 7.43 (d, 1H), 7.33 (d, 1H), 7.19 (dd, 1H), 5.45 - 5.29 (m, 2H), 4.89 (d, 1H), 4.71 (d, 1H), 4.40 (dd, 2H), 4.31 (d, 2H), 4.05 (dd, 2H), 3.46 - 3.34 (m, overlaps with solvent peak).

Example 133 carboxamide

DIPEA (356 μL, 2.04 mmol) was added to a stirred suspension of 6-(3-(2,2-difluoroethyl)-3methylazetidin-1-yl)quinoline-4-carboxylic acid, intermediate 254 (125 mg, 0.41 mmol), (R)-3-glycylthiazolidine-4-carbonitrile hydrochloride, intermediate 4 (127 mg, 0.61 mmol), HOBt (165 mg, 1.22 mmol) and EDC (235 mg, 1.22 mmol) in MeCN (5 mL) and EtOAc (5 mL) at 25 °C and the reaction mixture was stirred at 50 °C for 2 h. The solvent was removed under reduced pressure and the residue was dissolved in NaHCO ₃ (40 mL, aq.) and EtOAc ₍ 100 ml). The phases were separated and the aqueous layer was extracted with EtOAc (4x100 ml). The combined organic layer was washed with water (3x50 ml), dried over _Na2SO4 , filtered and evaporated under reduced _pressure . The crude product was purified by preparative HPLC, PrepMethod R (gradient: 29-49 _% ), to give the title compound (0.11 g, 59 _% ) as a yellow solid; HRMS ( _ESI ) m/z [M+H] ⁺ calcd for _{C22H24F2N5O2S} : 460.1614 found: 460.1582.

1H NMR (300 MHz, DMSO-d6) δ 8.95 (brs, 1H), 8.64 (d, 1H), 7.89 (d, 1H), 7.42 (d, 1H), 7.26 - 7.00 (m, 2H), 6.25 (t, 1H), 5.45 - 5.27 (m, 1H), 4.90 (d, 1H), 4.72 (d, 1H), 4.31 (d, 2H), 3.84 (d, 2H), 3.69 (d, 2H), 3.40 - 3.34 (m, overlaps with solvent peak), 2.24 (td, 2H), 1.43 (s, 3H).

Example 134. (R)-N-(2-(4-cyanothiazolidin-3-yl)-2-oxoethyl)-6-(3-cyclopropyl-3-methylazetidin-1yl)quinoline-4-carboxamide

DIPEA (247 μl, 1.42 mmol) was added to a stirred suspension of 6-(3-cyclopropyl-3-methylazetidin-1-yl)quinoline-4-carboxylic acid, intermediate 256 (80 mg, 0.28 mmol), (P)-3-glycylthiazolidine-4-carbonitrile hydrochloride, intermediate 4 (118 mg, 0.57 mmol), HOBt (115 mg, 0.85 mmol) and EDC (163 mg, 0.85 mmol) in MeCN (10 ml) and EtOAc (10 ml) at 20 °C and the reaction mixture was stirred at 50 °C for 2 h. The solvent was removed under reduced pressure and the residue was dissolved in NaHCO ₃ (40 ml, aq.) and EtOAc (100 ml). The phases were separated and the aqueous layer was extracted with EtOAc (4x50 ml). _The combined organic layer was washed with water (3x25 ml), dried over _Na2SO4 , filtered and evaporated under reduced pressure. The crude product was purified by preparative HPLC, _PrepMethod I (gradient: 55-65%), to give the title compound (0.050 g, 40%) as a yellow solid; HRMS (ESI) m/z [M+H] ⁺ calcd for _C23H26N5O2S : _436.1802 found: 436.1806 _;

1H NMR (400 MHz, DMSO-d6) δ 8.96 (t, 1H), 8.62 (d, 1H), 7.88 (d, 1H), 7.40 (d, 1H), 7.18 (d, 1H), 7.09

- 228 048482 (dd, 1H), 5.83 - 5.30 (m, 1H), 4.90 (d, 1H), 4.72 (d, 1H), 4.31 (d, 2H), 3.57 (s, 4H), 3.42 - 3.33 (m, overlaps with solvent peak), 1.33 (s, 3H), 1.10 - 0.98 (m, 1H), 0.49 - 0.39 (m, 2H), 0.35 - 0.20 (m, 2H).

Example 135

DIPEA (284 μL, 1.63 mmol) was added to a stirred suspension of 6-(3-(difluoromethyl)-3methylazetidin-1-yl)quinoline-4-carboxylic acid, intermediate 258 (95 mg, 0.33 mmol), (R)-3-glycylthiazolidine-4-carbonitrile hydrochloride, intermediate 4 (135 mg, 0.65 mmol), HOBt (132 mg, 0.98 mmol) and EDC (187 mg, 0.98 mmol) in MeCN (10 mL) and EtOAc (10 mL) at 20 °C and the reaction mixture was stirred at 50 °C for 2 h. The solvent was removed under reduced pressure and the residue was dissolved in NaHCO ₃ (40 mL, aq.) and EtOAc (100 ml). The phases were separated and the aqueous layer was extracted with EtOAc (4x75 ml). _The combined organic layer was washed with water (3x25 ml), dried over _Na2SO4 , filtered and evaporated under reduced pressure. The crude product was purified by preparative HPLC, PrepMethod A (gradient: 32-62%), to give the title compound (0.083 _g , 57%) as _a yellow solid; HRMS (ESI) m/z [M+ _H ]+ calcd for _{C21H22F2N5O2S} : 446.1456 found: _446.1438 ;

^1H NMR (300 MHz, DMSO- _d6 ) δ 8.98 (t, 1H), 8.65 (d, 1H), 7.90 (d, 1H), 7.42 (d, 1H), 7 .26 - 7.10 (m, 2H), 6.29 (t, 1H), 5.33 (dd, 1H), 4.90 (d, 1H), 4.72 (d, 1H), 4.30 (d, 2H), 4.01 (d, 2H), 3.73 (d, 2H), 3.45 - 3 .35 (m, 2H), 1.41 (s, 3H).

Example 136

DIPEA (564 μL, 3.23 mmol) was added to a stirred suspension of 6-(3(difluoromethoxy)azetidin-1-yl)quinoline-4-carboxylic acid, intermediate 260 (190 mg, 0.65 mmol), (R)-3-glycylthiazolidine-4-carbonitrile hydrochloride, intermediate 4 (201 mg, 0.97 mmol), HOBt (262 mg, 1.94 mmol) and EDC (371 mg, 1.94 mmol) in MeCN (5 mL) and EtOAc (5 mL) at 30 °C and the reaction mixture was stirred at 50 °C for 2 h. The solvent was removed under reduced pressure and the residue was dissolved in NaHCO ₃ (40 mL, aq.) and EtOAc (100 mL). The phases were separated and the aqueous layer was extracted with EtOAc (5x75 mL). _The combined organic layer was washed with water (3x50 mL), dried over _Na2SO4 , filtered and evaporated under reduced pressure. The crude product was purified by preparative HPLC, PrepMethod R (gradient: 24-44%), to give the title compound (0.242 g, 84%) as _a yellow solid; HRMS (ESI) m/z [ _{M+H]+ calcd for C20H20F2N5O3S : 448.1250} found: _448.1246 ;

1H NMR (300 MHz, DMSO-d ₆ ) δ 8.98 (t, 1H), 8.66 (d, 1H), 7.91 (d, 1H), 7.43 (d, 1H), 7.27 (d, 1H), 7.17 (dd, 1H), 6.81 (t, 1H), 5.34 (dd, 1H), 5.20 - 5.07 (m, 1H), 4.90 (d, 1H), 4.72 (d, 1H), 4.46 - 4.16 (m, 4H), 3.93 (dd, 2H), 3.45 - 3.36 (m, overlaps with solvent peak).

Example 137

DIPEA (372 μL, 2.13 mmol) was added to a stirred suspension of 6-(3-ethyl-3-methylazetidin-1yl)quinoline-4-carboxylic acid, intermediate 262 (115 mg, 0.43 mmol), (R)-3-glycylthiazolidine-4-carbonitrile hydrochloride, intermediate 4 (177 mg, 0.85 mmol), HOBt (172 mg, 1.28 mmol) and EDC (245 mg, 1.28 mmol) in MeCN (6 mL) and EtOAc (6 mL) at 20 °C and the reaction mixture was stirred at 50 °C for 2 h. The solvent was removed under reduced pressure and the residue was dissolved in NaHCO ₃ (30 mL, aq.) and EtOAc (80 mL). The phases were separated and the aqueous layer was extracted with EtOAc (4x75 mL). The combined organic layer was washed with water (3x50 mL), dried over _Na2SO4 , filtered and evaporated under reduced pressure. The crude product was purified by preparative HPLC, PrepMethod I (gradient: 60-78%), to give the title compound _.

_{- 229 048482 title compound (0.110 g, 61%) as a yellow solid; HRMS (ESI) m/z [M+H]+ calcd for C22H26N5O2S : 424.1802 found} : 424.1802;

¹ H NMR (400 MHz, DMSO-d6) δ 9.02 - 8.90 (m, 1H), 8.61 (d, 1H), 7.87 (d, 1H), 7.39 (d, 1H), 7.17 (d, 1H), 7.10 (dd, 1H), 5.32 (dd, 1H), 4.89 (d, 1H), 4.71 (d, 1H), 4.30 (d, 2H), 3.70 (dd, 2H), 3.62 (d, 2H), 3.43 - 3.34 (m, overlaps with solvent peak), 1.63 (q, 2H), 1.27 (s, 3H), 0.90 (t, 3H).

Example 138

A solution of T3P (1.48 g, 2.33 mmol, 50% in EtOAc) in MeCN (8 mL) was added to a stirred solution of 6-(3-ethyl-3-fluoroazetidin-1-yl)quinoline-4-carboxylic acid, intermediate 264 (160 mg, 0.58 mmol), (R)-3-glycylthiazolidine-4-carbonitrile hydrochloride, intermediate 4 (121 mg, 0.87 mmol), and DIPEA (306 µL, 1.75 mmol) in EtOAc (8 mL) at 20 °C, and the reaction mixture was stirred at 25 °C for 3 h. The reaction mixture was concentrated under reduced pressure, diluted with EtOAc (75 mL), and washed successively with water (25 mL) and sat. brine (25 ml). _The organic layer was dried over _Na2SO4 , filtered and evaporated under reduced pressure. The crude product was purified by preparative HPLC, PrepMethod R (gradient: 28-48%), to give the title compound (0.050 g, 20 _{%) as a yellow solid; HRMS (ESI) m/z [M+H]+ calcd for C21H23FN5O2S : 428.1550} found: _428.1550 ;

1H NMR (400 MHz, DMSO-d6) δ 8.98 (t, 1H), 8.65 (d, 1H), 7.91 (d, 1H), 7.41 (d, 1H), 7.33 (d, 1H), 7.17 (dd, 1H), 5.34 (dd, 1H), 4.90 (d, 1H), 4.71 (d, 1H), 4.30 (d, 2H), 4.15 - 3.97 (m, 4H), 3.45 - 3.34 (m, 2H), 2.05 1.80 (m, 2H), 0.98 (t, 3H).

Example 139

A solution of T3P (1.35 g, 2.13 mmol, 50% in EtOAc) in EtOAc (8 mL) was added to a stirred solution of 6-(2-azaspiro[3.4]octan-2-yl)quinoline-4-carboxylic acid, intermediate 266 (150 mg, 0.53 mmol), (R)-3-glycylthiazolidine-4-carbonitrile hydrochloride, intermediate 4 (110 mg, 0.53 mmol), and DIPEA (278 μL, 1.59 mmol) in MeCN (8 mL) at 25 °C, and the reaction mixture was stirred at 25 °C for 2 h. The reaction mixture was concentrated under reduced pressure, diluted with EtOAc (75 mL), and washed successively with sat. brine (25 ml) and water (25 ml). The organic layer was dried over Na2SO4, filtered and evaporated under reduced pressure. The crude product was purified by preparative HPLC, PrepMethod O (gradient: 57-67%) _, to give the title _compound (0.050 g, 22%) as a yellow solid; HRMS ( _ESI ) m/z [M+H]+ calcd for C23H26N5O2S: 436.1802, found: _436.1826 ;

Ή NMR (400 MHz, DMSO-d6) δ 8.93 (t, 1H), 8.61 (d, 1H), 7.86 (d, 1H), 7.39 (d, 1H), 7.18 (d, 1H), 7.10 (dd, 1H), 5.32 (dd, 1H), 4.89 (d, 1H), 4.71 (d, 1H), 4.29 (d, 2H), 3.81 (s, 4H), 3.44 - 3.34 (m, overlaps with solvent peak), 1.89 - 1.71 (m, 4H), 1.69 - 1.50 (m, 4H).

Example 140

A solution of T3P (831 mg, 1.31 mmol, 50% in EtOAc) in EtOAc (8 mL) was added to a stirred solution of 6-(3-(2,2-difluoropropyl)azetidin-1-yl)quinoline-4-carboxylic acid, intermediate 268 (100 mg, 0.33 mmol), (R)-3-glycylthiazolidine-4-carbonitrile hydrochloride, intermediate 4 (68 mg, 0.49 mmol), and DIPEA (171 μL, 0.98 mmol) in MeCN (8 mL) at 25 °C, and the reaction mixture was stirred at 25 °C for 3 h. The reaction mixture was concentrated under reduced pressure, diluted with EtOAc (100 mL), and washed successively with water (25 mL) and saturated with brine (25 ml). The organic layer was dried over Na ₂ SO ₄ , filtered and evaporated at

- 230 048482 low pressure.

The crude product was purified by preparative HPLC, PrepMethod R (gradient: 2949%) to give the title compound (0.050 g, 33%) as a yellow solid; HRMS (ESI) m/z [M+H] ⁺ calcd for C22H24F2N5O2S: 460.1614, found: 460.1600;

1H NMR (400 MHz, DMSO-d6) δ 8.95 (t, 1H), 8.62 (d, 1H), 7.87 (d, 1H), 7.41 (d, 1H), 7.17 - 7.07 (m, 2H), 5.31 (dd, 1H), 4.88 (d, 1H), 4.71 (d, 1H), 4.29 (d, 2H), 4.16 (t, 2H), 3.66 (t, 2H), 3.44 - 3.34 (m, overlaps with solvent peak), 3.12 - 2.95 (m, 1H), 2.28 (td, 2H), 1.63 (t, 3H).

Example 141 carboxamide

A solution of T3P (639 mg, 2.01 mmol, 50% in EtOAc) in EtOAc (8 mL) was added to a stirred solution of 6-(5,5-difluoro-2-azaspiro[3.4]octan-2-yl)quinoline-4-carboxylic acid, intermediate 270 (160 mg, 0.50 mmol), (R)-3-glycylthiazolidine-4-carbonitrile hydrochloride, intermediate 4 (104 mg, 0.75 mmol), and DIPEA (263 μL, 1.51 mmol) in MeCN (8.0 mL) at 20 °C, and the reaction mixture was stirred at 25 °C for 3 h. The reaction mixture was concentrated under reduced pressure, diluted with EtOAc (125 mL), and washed successively with water. (75 mL) and brine (75 mL). _The organic layer was dried over _Na2SO4 , filtered and evaporated under reduced pressure. The crude product was purified by preparative HPLC, PrepMethod R (gradient: 31-51% ₎ to give the title compound ( _0.050 g, 21%) as _a yellow solid; _HRMS (ESI) m/z [M+H]+ calcd for _{C23H24F2N5O2S} : 472.1614, found: 472.1612;

¹ H NMR (400 MHz, DMSO-d6) δ 8.97 (t, 1H), 8.64 (d, 1H), 7.90 (d, 1H), 7.40 (d, 1H), 7.31 (d, 1H), 7.16 (dd, 1H), 5.32 (dd, 1H), 4.89 (d, 1H), 4.71 (d, 1H), 4.30 (d, 2H), 4.12 - 4.00 (m, 2H), 3.84 (d, 2H), 3.48 - 3.34 (m, overlaps with solvent peak), 2.22 - 2.02 (m, 4H), 1.83 - 1.65 (m, 2H).

Example 142

A solution of 6-(3-(3,3,3-trifluoropropyl)azetidin-1-yl)quinoline-4-carboxylic acid, intermediate 272 (110 mg, 0.34 mmol), (R)-3-glycylthiazolidine-4-carbonitrile hydrochloride, intermediate 4 (106 mg, 0.51 mmol), EDC (98 mg, 0.51 mmol), HOBt (78 mg, 0.51 mmol) and DIPEA (178 μl, 1.02 mmol) in MeCN (4 ml) and EtOAc (4 ml) was stirred at 50 °C for 2 h. The solvent was removed under reduced pressure and the residue was diluted with EtOAc and washed with water. The organic layer was dried over Na ₂ SO ₄ , filtered and evaporated under reduced pressure. The crude product was purified by preparative HPLC, PrepMethod F (gradient: 28-38%) to afford the title compound (0.110 g, 68%) as a yellow solid; HRMS (ESI) m/z [M+H] ⁺ calcd for C ₂₂ H ₂₃ F ₃ N ₅ O ₂ S: 478.1518, found: 478.1520;

1H NMR (300 MHz, CD3OD) δ 8.56 (d, 1H), 7.88 (d, 1H), 7.48 (d, 1H), 7.24 (s, 1H), 7.15 (dd, 1H), 5.33 (dd, 1H), 4.85-4.70 (m, overlaps with solvent peak), 4.38 (s, 2H), 4.25 - 4.10 (m, 2H), 3.70 (dd, 2H), 3.49 - 3.34 (m, 2H), 2.90 - 2.75 (m, 1H), 2.31 - 2.12 (m, 2H), 1.94 (q, 2H).

Example 143

A solution of 6-(3-fluoro-3-(trifluoromethyl)azetidin-1-yl)quinoline-4-carboxylic acid, intermediate 274 (100 mg, 0.32 mmol), (R)-3-glycylthiazolidine-4-carbonitrile hydrochloride, intermediate 4 (99 mg, 0.48 mmol), EDC (92 mg, 0.48 mmol), HOBt (73 mg, 0.48 mmol) and DIPEA (167 μl, 0.95 mmol) in MeCN (6 ml) and EtOAc (6 ml) was stirred at 50 °C for 2 h. The solvent was removed under reduced pressure and the residue was diluted with EtOAc and washed successively with water. The organic layer was dried over Na ₂ SO ₄ , filtered and evaporated under reduced pressure. The crude product was purified by preparative HPLC, PrepMethod F (gradient:

- 231 048482

31-41%) to give the title compound (110 mg, 74%) as a yellow solid; HRMS (ESI) m/z [ _{M +} H]+ calcd for _{C20H18F4N5O2S} : 468.1112, found: _468.1124 ;

1H NMR (300 MHz, CD3OD) δ 8.66 (d, 1H), 7.97 (d, 1H), 7.56 - 7.49 (m, 2H), 7.26 (dd, 1H), 5.34 (dd, 1H), 4.85 - 4.66 (m, overlaps with solvent peak), 4.61 - 4.46 (m, 2H), 4.44 -4.25 (m, 4H), 3.52 - 3.33 (m, 2H).

Example 144

A solution of 6-(3-(2,2-difluoroethyl)azetidin-1-yl)quinoline-4-carboxylic acid, intermediate 276 (110 mg, 0.38 mmol), (R)-3-glycylthiazolidine-4-carbonitrile hydrochloride, intermediate 4 (117 mg, 0.56 mmol), EDC (108 mg, 0.56 mmol), HOBt (76 mg, 0.56 mmol) and DIPEA (197 μl, 1.13 mmol) in MeCN (4 ml) and EtOAc (4 ml) was stirred at 50 °C for 2 h. The solvent was removed under reduced pressure and the residue was diluted with EtOAc and washed successively with water. The organic layer was dried over Na ₂ SO ₄ , filtered and evaporated under reduced pressure. The crude product was purified by preparative HPLC, PrepMethod F (gradient: 2131%) to give the title compound (128 mg, 76%) as a yellow solid; HRMS (ESI) m/z [M+H]+ calcd for C ₂₁ H ₂₂ F ₂ N ₅ O ₂ S: 446.1456, found: 446.1442;

1H NMR (300 MHz, CD3OD) δ 8.57 (d, 1H), 7.88 (d, 1H), 7.49 (d, 1H), 7.30 - 7.10 (m, 2H), 5 .98 (tt, 1H), 5.40 - 5.25 (m, 1H), 4.85 - 4.70 (m, 2H), 4.45 - 4.30 (m, 2H), 4.22 (t, 2H), 3.82 - 3.72 (m, 2H), 3.51-3.34 (m , 2H), 3.08-2.95 (m, 1H), 2.35-2.12 (m, 2H).

Example 145

A solution of 6-(3-cyclopropylazetidin-1-yl)quinoline-4-carboxylic acid, intermediate 278 (110 mg, 0.41 mmol), (R)-3-glycylthiazolidine-4-carbonitrile hydrochloride, intermediate 4 (128 mg, 0.61 mmol), EDC (118 mg, 0.61 mmol), HOBt (83 mg, 0.61 mmol) and DIPEA (215 μl, 1.23 mmol) in MeCN (6 ml) and EtOAc (6 ml) was stirred at 50 °C for 2 h. The solvent was removed under reduced pressure, the residue was diluted with EtOAc and washed successively with water. The organic layer was dried over Na ₂ SO ₄ , filtered and evaporated under reduced pressure. The crude product was purified by preparative HPLC, PrepMethod C (gradient: 1940%) to afford the title compound (130 mg, 75%) as a yellow solid; HRMS (ESI) m/z [ _{M+H]+ calcd for C22H24N5O2S : 422.1646} , found: _422.1638 ;

1H NMR (300 MHz, CD3OD) δ 8.55 (d, 1H), 7.87 (d, 1H), 7.49 (d, 1H), 7.22 - 7.09 (m, 2H), 5 .39 -5.31 (m, 1H), 4.85 - 4.70 (m, 2H), 4.38 (d, 2H), 4.12 (t, 2H), 3.72 (dd, 2H), 3.45 - 3.34 (m, 2H), 2.48 - 2.35 (m, 1H), 1.18 - 0.99 (m, 1H), 0.59 - 0.46 (m, 2H), 0.28 - 0.17 (m, 2H).

Example 146

A solution of 6-(3-(2-fluoroethyl)azetidin-1-yl)quinoline-4-carboxylic acid, intermediate 280 (100 mg, 0.36 mmol), (R)-3-glycylthiazolidine-4-carbonitrile hydrochloride, intermediate 4 (114 mg, 0.55 mmol), EDC (105 mg, 0.55 mmol), HOBt (84 mg, 0.55 mmol) and DIPEA (191 μl, 1.09 mmol) in MeCN (8 ml) and EtOAc (8 ml) was stirred at 50 °C for 2 h. The solvent was removed under reduced pressure and the residue was diluted with EtOAc and washed successively with water. The organic layer was dried over Na ₂ SO ₄ , filtered and evaporated under reduced pressure. The crude product was purified by preparative HPLC, PrepMethod F (gradient: 1828%) to afford the title compound (120 mg, 77%) as a yellow solid; HRMS (ESI) m/z [M+H]+ calcd for C ₂₁ H ₂₃ FN ₅ O ₂ S: 428.1550, found: 428.1558;

1H NMR (300 MHz, CD3OD) δ 8.56 (d, 1H), 7.88 (d, 1H), 7.49 (d, 1H), 7.25 - 7.10 (m, 2H), 5 .37 -5.29 (m,

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1H), 4.86 - 4.73 (m, 2H), 4.60 (t, 1H), 4.49 - 4.35 (m, 3H), 4.20 (t, 2H), 3.74 (t, 2H), 3.55 - 3.36 (m, 2H), 3.00 2.85 (m, 1H), 2.11 (q, 1H), 2.03 (q, 1H).

Example 147

A solution of 6-(3-(1,1-difluoroethyl)azetidin-1-yl)quinoline-4-carboxylic acid, intermediate 282 (100 mg, 0.34 mmol), (R)-3-glycylthiazolidine-4-carbonitrile hydrochloride, intermediate 4 (107 mg, 0.51 mmol), EDC (98 mg, 0.51 mmol), HOBt (79 mg, 0.51 mmol) and DIPEA (179 μl, 1.03 mmol) in MeCN (8 ml) and EtOAc (8 ml) was stirred at 50 °C for 2 h. The solvent was removed under reduced pressure and the residue was diluted with EtOAc and washed with water (3 x 10 ml). _The organic layer was dried over _Na2SO4 , filtered and evaporated under reduced pressure. The crude product was triturated with MeOH (20 _mL ), the precipitate was collected by filtration and dried under vacuum to give the title compound (115 _mg , 75%) as a yellow solid; HRMS (ESI) m/z [M+ _H ]+ calcd for _{C21H22F2N5O2S} : 446.1456, found: _446.1448 ;

1H NMR (300 MHz, DMSO-d ₆ ) δ 8.97 (t, 1H), 8.62 (d, 1H), 7.88 (d, 1H), 7.39 (d, 1H), 7.24 (d, 1H), 7.12 (dd, 1H), 5.35 - 5.25 (m, 1H), 4.88 (d, 1H), 4.69 (d, 1H), 4.28 (d, 2H), 4.15 -4.00 (m, 2H), 3.98 - 3.80 (m, 2H), 3.41 - 3.33 (m, overlaps with solvent peak), 1.66 (t, 3H).

Example 148. (R)-N-(2-(4-cyanothiazolidin-3-yl)-2-oxoethyl)-6-(3-isopropylazetidin-1yl)quinoline-4-carboxamide

DIPEA (3.1 ml, 18 mmol) was added to a solution of 6-(3-isopropylazetidin-1-yl)quinoline-4-carboxylic acid, intermediate 284 (237 mg, 0.88 mmol), (R)-3-glycylthiazolidine-4-carbonitrile hydrochloride, intermediate 4 (273 mg, 1.31 mmol), HOBt (1.18 g, 8.75 mmol), and EDC (1.68 mg, 8.75 mmol) in MeCN (6 ml) and EtOAc (6 ml) at 25 °C, and the reaction mixture was stirred at 50 °C for 2 h. The solvent was removed under reduced pressure and the residue was diluted with sat. _NaHCO3 solution (200 mL, aq) and extracted with EtOAc (3x200 mL). _The combined organic layer was washed with water (3x50 mL), dried over _Na2SO4 , filtered and evaporated under reduced pressure. The crude product was purified by preparative HPLC, PrepMethod C (gradient: 22-38%), to give the title compound ( ₁₈₃ mg, 49%) as an orange solid; HRMS (ESI) m/z [M _{+H]+ calcd for C22H26N5O2S :} ^424.1802 _, found: 424.1798;

1H NMR (300 MHz, DMSO-d ₆ ) δ 8.95 (t, 1H), 8.61 (d, 1H), 7.87 (d, 1H), 7.40 (d, 1H), 7.18 (d, 1H), 7.10 (dd, 1H), 5.33 (dd, 1H), 4.90 (d, 1H), 4.72 (d, 1H), 4.30 (d, 2H), 4.10 - 3.98 (m, 2H), 3.70 - 3.52 (m, 2H), 3.48 - 3.38 (m, overlaps with solvent peak), 2.48 -2.30 (m, 1H), 1.82 - 1.60 (m, 1H), 0.89 (d, 6H).

Example 149

DIPEA (4.2 ml, 24 mmol) was added to a solution of 6-(6-methyl-2-azaspiro[3.3]heptan-2-yl)quinoline-4-carboxylic acid, intermediate 286 (337 mg, 1.19 mmol), (R)-3-glycylthiazolidine-4-carbonitrile hydrochloride, intermediate 4 (372 mg, 1.79 mmol), HOBt (1.61 g, 11.9 mmol), and EDC (2.29 g, 11.9 mmol) in MeCN (5 ml) and EtOAc (5 ml) at 25 °C, and the reaction mixture was stirred at 50 °C for 2 h. The solvent was removed under reduced pressure and the residue was diluted with sat. NaHCO ₃ solution (250 mL, aq) and extracted with EtOAc (3 x 250 mL). The combined organic layer was washed with water (3 x 50 mL), dried over Na ₂ SO ₄ , filtered and evaporated under reduced pressure. The crude product was purified by preparative HPLC, PrepMethod C (gradient: 27-39%), to give the title compound (81 mg, 15%) as an orange solid; HRMS (ESI) m/z [M+H] ⁺ calcd for C23H26N5O2S: 436.1802, found: 436.1808;

- 233 048482

1H NMR (400 MHz, DMSO-d ₆ ) δ 8.92 (t, 1H), 8.61 (d, 1H), 7.86 (d, 1H), 7.39 (d, 1H), 7.16 (d, 1H), 7.07 (dd, 1H), 5.33 (dd, 1H), 4.89 (d, 1H), 4.72 (d, 1H), 4.29 (d, 2H), 3.96 (s, 2H), 3.87 (s, 2H), 3.45 - 3.37 (m, overlaps with solvent peak), 2.41 - 2.19 (m, 3H), 1.86 - 1.70 (m, 2H), 1.05 (d, 3H).

Example 150 carboxamide

DIPEA (2.39 ml, 13.7 mmol) was added to 6-(6-(trifluoromethyl)-2-azaspiro[3.3]heptan-2-yl)quinoline-4-carboxylic acid, intermediate 288 (230 mg, 0.68 mmol), (R)-3-glycylthiazolidine-4-carbonitrile hydrochloride, intermediate 4 (213 mg, 1.03 mmol), HOBt (924 mg, 6.84 mmol), and EDC (1.31 g, 6.84 mmol) in MeCN (6 ml) and EtOAc (6 ml) at 25 °C and the reaction mixture was stirred at 50 °C for 2 h. The solvent was removed under reduced pressure and the residue was diluted with sat. NaHCO ₃ solution (300 mL, aq.) and extracted with EtOAc (3x300 mL). The combined organic layer was washed with water (3x50 mL), dried over Na ₂ SO ₄ , filtered and evaporated under reduced pressure. The crude product was purified by preparative HPLC, PrepMethod C (gradient: 26-40%), to give the title compound (185 mg, 55%) as an orange solid; HRMS (ESI) m/z [M+H]+ calcd for C ₂₃ H ₂₃ F ₃ N ₅ O ₂ S: 490.1518, found: 490.1510;

1H NMR (300 MHz, DMSO-d ₆ ) δ 8.96 (t, 1H), 8.63 (d, 1H), 7.88 (d, 1H), 7.41 (d, 1H), 7.22 - 7.13 (m, 1H), 7.09 (dd, 1H), 5.34 (dd, 1H), 4.90 (d, 1H), 4.72 (d, 1H), 4.31 (d, 2H), 4.00 (s, 2H), 3.94 (s, 2H), 3.55 - 3.34 (m, overlaps with solvent peak), 3.21 - 3.05 (m, 1H), 2.60 - 2.40 (m, overlaps with solvent peak), 2.34 - 2.24 (m, 2H).

Example 151

TEA (3.13 ml, 22.5 mmol) was added to a solution of 6-(3-methoxy-3-methylazetidin-1-yl)quinoline-4-carboxylic acid, intermediate 290 (306 mg, 1.12 mmol), (R)-3-glycylthiazolidine-4-carbonitrile hydrochloride, intermediate 4 (350 mg, 1.69 mmol), HOBt (1.52 g, 11.2 mmol) and EDC (2.15 g, 11.2 mmol) in EtOAc (6 ml) and MeCN (6 ml) at 25 °C and the reaction mixture was stirred at 25 °C for 16 h. The solvent was removed under reduced pressure and the residue was diluted with sat. NaHCO ₃ solution (250 mL, aq) and extracted with EtOAc (3x250 mL). The combined organic layer was washed with water (3x50 mL), dried over Na ₂ SO ₄ , filtered and evaporated under reduced pressure. The crude product was purified by preparative HPLC, PrepMethod C (gradient: 13-23%), to give the title compound (126 mg, 26%) as an orange solid; HRMS (ESI) m/z [M+H] ⁺ calcd for C ₂ iH ₂₄ N ₅ O ₃ S: 426.1594, found: 426.1596;

1H NMR (300 MHz, DMSO-d ₆ ) δ 8.97 (t, 1H), 8.63 (d, 1H), 7.89 (d, 1H), 7.41 (d, 1H), 7.25 (d, 1H), 7.14 (dd, 1H), 5.34 (dd, 1H), 4.89 (d, 1H), 4.71 (d, 1H), 4.30 (d, 2H), 3.93 - 3.78 (m, 4H), 3.45 - 3.34 (m, overlaps with solvent peak), 3.22 (s, 3H), 1.51 (s, 3H).

Example 152

DIPEA (3.98 ml, 22.8 mmol) was added to a solution of 6-(3-ethoxy-3-methylazetidin-1-yl)quinoline-4-carboxylic acid, intermediate 292 (326 mg, 1.14 mmol), (R)-3-glycylthiazolidine-4-carbonitrile hydrochloride, intermediate 4 (355 mg, 1.71 mmol), HOBt (1.54 g, 11.4 mmol), and EDC (2.19 g, 11.4 mmol) in MeCN (5 ml) and EtOAc (5 ml) at 25 °C, and the reaction mixture was stirred at 50 °C for 2 h. The solvent was removed under reduced pressure and the residue was diluted with sat. NaHCO ₃ solution (250 mL, aq.) and extracted with EtOAc (3x250 mL). The combined organic layer was washed with water (3x50 mL), dried over Na ₂ SO ₄ ,

- 234 048482 was filtered and evaporated under reduced pressure. The crude product was purified by preparative HPLC, PrepMethod C (gradient: _13-28 %) to give the title compound (251 mg, 49%) as an orange solid; HRMS (ESI) m/z [M ₊ H] ⁺ calcd for _C22H26N5O3S : 440.1750, found: _440.1754 ;

¹ H NMR (400 MHz, DMSO-d ₆ ) δ 8.95 (t, 1H), 8.63 (d, 1H), 7.88 (d, 1H), 7.40 (d, 1H), 7.24 (d, 1H), 7.13 (dd, 1H), 5.33 (dd, 1H), 4.89 (d, 1H), 4.72 (d, 1H), 4.30 (d, 2H), 3.90 - 3.80 (m, 4H), 3.50 - 3.33 (m, overlaps with solvent peak), 1.51 (s, 3H), 1.13 (t, 3H).

Example 153

DIPEA (620 μL, 3.55 mmol) was added to a stirred suspension of 6-(1-oxa-6-azaspiro[3.3]heptan-6-yl)quinoline-4-carboxylic acid, intermediate 294 (192 mg, 0.71 mmol), (R)-3-glycylthiazolidine-4-carbonitrile hydrochloride, intermediate 4 (251 mg, 1.21 mmol), HOBt (288 mg, 2.13 mmol), and EDC (409 mg, 2.13 mmol) in MeCN (10 mL) and EtOAc (10 mL) at 30 °C and the reaction mixture was stirred at 50 °C for 2 h. The solvent was removed under reduced pressure and the residue was dissolved in a mixture of NaHCO ₃ (40 mL, aq.) and EtOAc (100 mL). The aqueous layer was extracted with EtOAc (4x75 mL). _The combined organic layer was washed with water (3x50 mL), dried over _Na2SO4 , filtered and evaporated under reduced pressure. The crude product _was purified by preparative HPLC, PrepMethod R (gradient: 15-35%) to give the title compound (90 mg, 30%) as _a yellow solid; HRMS (ESI) m/z [M+H] ⁺ _{calcd for C21H22N5O3S :} 424.1438, found: 424.1448;

1H NMR (400 MHz, DMSO-d6) δ 9.10 - 8.90 (m, 1H), 8.65 (d, 1H), 7.89 (d, 1H), 7.42 (d, 1H) , 7.24 (d, 1H), 7.13 (dd, 1H), 5.45 - 5.33 (m, 1H), 4.91 (d, 1H), 4.73 (d, 1H), 4.47 (t, 2H), 4.31 (d, 2H), 4.24 (d, 2H), 4. 03 (d, 2H), 3.60 - 3.37 (m, 2H), 2.90 (t, 2H).

Example 154

T3P (1.40 g, 2.20 mmol, 50% in EtOAc) was added to a solution of 6-(3-ethyl-3-hydroxyazetidin-1yl)quinoline-4-carboxylic acid, intermediate 296 (150 mg, 0.55 mmol), (R)-3-glycylthiazolidine-4-carbonitrile hydrochloride, intermediate 4 (114 mg, 0.55 mmol), and DIPEA (289 μL, 1.65 mmol) in MeCN (8 mL) and EtOAc (8 mL) at 25 °C and the reaction mixture was stirred at 25 °C for 3 h. The reaction mixture was concentrated under reduced pressure, diluted with EtOAc (75 mL), and washed successively with brine (15 mL) and water (15 mL). _The organic layer was dried over _Na2SO4 , filtered and evaporated under reduced pressure. The crude product was purified by preparative HPLC, _PrepMethod R (gradient: 15-35%) to give the title compound (50 mg, 21%) as a yellow solid; HRMS (ESI) m/z [M+H]+ calcd for _C21H24N5O3S : _426.1594 , found: 426.1586 _;

1H NMR (400 MHz, DMSO-d ₆ ) δ 8.95 (t, 1H), 8.61 (d, 1H), 7.87 (d, 1H), 7.39 (d, 1H), 7.17 (d, 1H), 7.12 (dd, 1H), 5.33 (dd, 1H), 4.89 (d, 1H), 4.71 (d, 1H), 4.29 (d, 2H), 4.00 - 3.85 (m, 2H), 3.71 (d, 2H), 3.50 - 3.34 (m, overlaps with solvent peak), 1.74 (q, 2H), 0.94 (t, 3H).

Example 155

DIPEA (3.36 mL, 19.2 mmol) was added to a solution of 6-(6-fluoro-2-azaspiro[3.3]heptan-2-yl)quinoline-4-carboxylic acid, intermediate 298 (275 mg, 0.96 mmol), (R)-3-glycylthiazolidine-4-carbonitrile hydrochloride, intermediate 4 (299 mg, 1.44 mmol), HOBt (1.30 g, 9.61 mmol), and EDC (1.84 g, 9.61 mmol) in MeCN (6 mL) and EtOAc (6 mL) at 25 °C and the reaction mixture was stirred at 50 °C for 2 h. The reaction mixture was concentrated under reduced pressure, diluted with sat. NaHCO ₃ solution (250 mL, aq.) and extracted with EtOAc

- 235 048482 (3x250 ml). The combined organic layer was washed _with water (3x50 ml), dried over _Na2SO4 , filtered and evaporated under reduced pressure. The crude product was purified by preparative HPLC, PrepMethod C (gradient: 16-30%), to give the title compound ( ₁₄₂ mg, 34%) as an orange solid; HRMS (ESI) m/z [M _{+H]+ calcd for C22H23FN5O2S : 440.1550} , found: 440.1556;

^1H NMR (300 MHz, DMSO- _d6 ) δ 8.94 (t, 1H), 8.63 (d, 1H), 7.88 (d, 1H), 7.41 (d, 1H), 7 .23 - 7.02 (m, 2H), 5.34 (dd, 1H), 5.20 -4.80 (m, 2H), 4.75 - 4.59 (m, 1H), 4.30 (d, 2H), 3.96 (d, 4H), 3.46 - 3.39 (m, 2H), 2.73 2.58 (m, 2H), 2.45 - 2.25 (m, 2H).

Example 156 4-carboxamide

A solution of 6-(6-azabicyclo[3.2.0]heptan-6-yl)quinoline-4-carboxylic acid, intermediate 300 (100 mg, 0.37 mmol), in DMF (5 mL) was added to a mixture of (R)-3-glycylthiazolidine-4-carbonitrile hydrochloride, intermediate 4 (155 mg, 0.75 mmol), HATU (283 mg, 0.75 mmol) and DIPEA (193 mg, 1.49 mmol) and the reaction mixture was stirred at 25 °C for 6 h. The solvent was removed under reduced pressure and the crude product was purified by preparative TLC (DCM:MeOH, 18:1) followed by preparative HPLC, PrepMethod T (gradient: 30-50%), to yield the title compound (86 mg, 55%) as a yellow solid; HRMS (ESI) m/z [ _{M +H] + calcd for C22H24N5O2S :} ^422.1646 _, found: 422.1640;

¹ H NMR (300 MHz, DMSO-d6) δ 8.91 (t, 1H), 8.54 (d, 1H), 7.82 (d, 1H), 7.35 (d, 1H), 7.12 - 6.99 (m, 2H), 5.40 - 5.25 (m, 1H), 4.87 (d, 1H), 4.77 - 4.47 (m, 2H), 4.27 (d, 2H), 3.95 (t, 1H), 3.50 (dd, 1H), 3.41 - 3.33 (m, overlaps with solvent peak), 3.15-2.95 (m, 1H), 2.14 - 1.97 (m, 1H), 1.91 - 1.68 (m, 3H), 1.62-1.33 (m, 2H).

Example 157

DIPEA (565 μL, 3.23 mmol) was added to a stirred suspension of 6-(3-fluoro-3(fluoromethyl)azetidin-1-yl)quinoline-4-carboxylic acid, intermediate 303 (90 mg, 0.32 mmol), (K)-3-glycylthiazolidine-4-carbonitrile hydrochloride, intermediate 4 (101 mg, 0.49 mmol), HOBt (248 mg, 1.62 mmol) and EDC (310 mg, 1.62 mmol) in MeCN (5 mL) and EtOAc (5 mL) and the reaction mixture was stirred at 18 °C for 15 h. The solvent was removed under reduced pressure and the residue was dissolved in NaHCO ₃ (30 mL, aq.) and EtOAc (80 mL). The aqueous layer was extracted with EtOAc (5x75 mL) and _the combined organic layer was washed with water (3x50 mL), dried over _Na2SO4 , filtered and evaporated under reduced pressure. The crude product was purified by preparative HPLC, PrepMethod R (gradient: _22-42 %) to give the title compound ( ₃₅ mg, 25%) as a yellow solid; HRMS (ESI) m/z [M ₊ H] ⁺ calcd for _{C20H20F2N5O2S} : 432.1300, found: _432.1294 ;

¹ H NMR (300 MHz, DMSO-d ₆ ) δ 9.10 - 8.90 (m, 1H), 8.68 (d, 1H), 7.94 (d, 1H), 7.44 (d, 1H), 7.35 (d, 1H), 7.22 (dd, 1H), 5.40 - 5.24 (m, 1H), 5.03 - 4.68 (m, 4H), 4.35 - 3.98 (m, 6H), 3.41 (m, overlaps with solvent peak).

Example 158 carboxamide

DIPEA (1.80 ml, 10.3 mmol) was added to a stirred suspension of 6-(3-(2,2,2-trifluoroethyl)azetidin-1-yl)quinoline-4-carboxylic acid, intermediate 305 (320 mg, 1.03 mmol), (R)-3-glycylthiazolidine-4-carbonitrile hydrochloride, intermediate 4 (321 mg, 1.55 mmol), HOBt (790 mg, 5.16 mmol) and EDC (989 mg, 5.16 mmol) in MeCN (8 ml) and EtOAc (8 ml) at 28 °C and the reaction mixture was stirred at 50 °C for 2 h. The solvent was removed under reduced pressure and the residue was dissolved in NaHCO ₃ (60 ml, aq.) and EtOAc (100 ml). The aqueous layer ex

- 236 048482 was extracted with EtOAc (6x100 mL). _The combined organic layer was washed with water (3x50 mL), dried over _Na2SO4 , filtered and evaporated under reduced pressure. The crude product was purified by preparative HPLC, PrepMethod R (gradient: 32-45%), to give the title compound ( ₂₅₀ mg, 52%) as a yellow solid; HRMS (ESI) m/z [M _{+ H} ]+ calcd for _{C21H21F3N5O2S} : 464.1362, found: _464.1360 ;

1H NMR (300 MHz, DMSO- _d6 ) δ 8.94 (t, 1H), 8.62 (d, 1H), 7.87 (d, 1H), 7.40 (d, 1H), 7. 18 - 7.07 (m, 2H), 5.30 (dd, 1H), 4.87 (d, 1H), 4.70 (d, 1H), 4.28 (d, 2H), 4.15 (t, 2H), 3.71 (t, 2H), 3.43 -3.33 (m, 2H), 3 .15 - 2.95 (m, 1H), 2.80 - 2.58 (m, 2H).

Example 159 carboxamide

DIPEA (2.36 ml, 13.5 mmol) was added to a mixture of 6-(3,3-difluoro-2-methylazetidin-1-yl)quinoline-4-carboxylic acid, intermediate 307 (188 mg, 0.68 mmol), (R)-3-glycylthiazolidine-4-carbonitrile hydrochloride, intermediate 4 (210 mg, 1.01 mmol), HOBt (1.04 g, 6.76 mmol), and EDC (1.30 g, 6.76 mmol) in MeCN (5 ml) and EtOAc (5 ml) at 20 °C and the reaction mixture was stirred at 50 °C for 2 h. The solvent was removed under reduced pressure and the reaction mixture was diluted with sat. _NaHCO3 solution (250 mL, aq) and extracted with EtOAc (4 x 250 mL). _The combined organic layer was dried over _Na2SO4 , filtered and evaporated under reduced pressure. The crude product was purified by preparative _HPLC , PrepMethod C (gradient _25-50 %) to give the title compound (169 mg, 58%) as an orange solid; HRMS (ESI) m/z [M ₊ H] ⁺ calcd for _{C20H20F2N5O2S} : 432.1300, found: _432.1306 ;

1H NMR (300 MHz, DMSO-d ₆ ) δ 9.04 (brs, 1H), 8.72 (d, 1H), 7.96 (d, 1H), 7.56 -7.50 (m, 1H), 7.45 (d, 1H), 7.27 (dd, 1H), 5.45 - 5.25 (m, 1H), 4.91 (d, 1H), 4.78 - 4.49 (m, 3H), 4.37 - 4.15 (m, 3H), 3.42 - 3.32 (m, overlaps with solvent peak), 1.52 (d, 3H).

Example 160. N-(2-((R)-4-cyanothiazolidin-3-yl)-2-oxoethyl)-6-(6,6-difluoro-3-azabicyclo[3.1.0]hexan-3-yl)quinoline-4-carboxamide

DIPEA (957 μL, 5.48 mmol) was added to a stirred suspension of 6-(6,6-difluoro-3azabicyclo[3.1.0]hexan-3-yl)quinoline-4-carboxylic acid, intermediate 309 (153 mg, 0.27 mmol), (R)-3-glycylthiazolidine-4-carbonitrile hydrochloride, intermediate 4 (114 mg, 0.55 mmol), HOBt (210 mg, 1.37 mmol) and EDC (263 mg, 1.37 mmol) in MeCN (5 mL) and EtOAc (5 mL) at 12 °C and the reaction mixture was stirred at 50 °C for 2 h. The solvent was removed under reduced pressure and the residue was dissolved in NaHCO ₃ (30 mL, aq.) and EtOAc (80 mL). The aqueous layer was extracted with EtOAc (5x75 mL). _The combined organic layer was washed with water (3x50 mL), dried over _Na2SO4 , filtered and evaporated under reduced pressure. The crude product _was purified by preparative HPLC, PrepMethod F (gradient: 10-40%) to give the title compound (150 mg, 86%) as a yellow solid; HRMS (ESI) m/z [M ₊ H] ⁺ calcd for _{C21H20F2N5O2S} : _444.1300 , found: _444.1282 ;

1H NMR (300 MHz, DMSO-d6) δ 8.97 (t, 1H), 8.59 (d, 1H), 7.88 (d, 1H), 7.37 (d, 1H), 7.33 - 7.20 (m, 2H), 5.36 - 5.22 (m, 1H), 4.90 (d, 1H), 4.72 (d, 1H), 4.31 - 4.24 (m, 2H), 3.85 - 3.58 (m, 4H), 3.42 - 3.34 (m, overlaps with solvent peak), 2.80 - 2.60 (m, 2H).

Example 161

HATU (348 mg, 0.88 mmol), DIPEA (411 μl, 2.35 mmol) were added to a stirred solution of (R)-6-(3-methoxypyrrolidin-1-yl)quinoline-4-carboxylic acid, intermediate 311 (160 mg, 0.59 mmol), and (R)-3-glycylthiazolidine-4-carbonitrile hydrochloride, intermediate 4 (122 mg, 0.59 mmol), in DMF (5 ml) and the reaction mixture was stirred at 25 °C for 2 h.

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The solvent was removed under reduced pressure and the crude product was purified by preparative TLC (DCM:MeOH, 18:1) followed by preparative HPLC, PrepMethod F (gradient: 1-35%) to give the title compound (108 mg, 42%) as a yellow solid; FIRMS (ESI) m/z [M+H]+ calcd for C ₂₁ H ₂₄ N ₅ O ₃ S: 426.1594, found: 426.1584;

1H NMR (300 MHz, DMSO-d6) δ 8.92 (t, 1H), 8.55 (d, 1H), 7.86 (d, 1H), 7.44 - 7.19 (m, 3H), 5.30 (dd, 1H), 4.88 (d, 1H), 4.70 (d, 1H), 4.38 - 4.23 (m, 2H), 4.18 - 4.01 (m, 1H), 3.60 - 3.18 (m, overlaps with solvent peak), 2.20 - 2.00 (m, 2H).

Example 162

A solution of 6-(3-oxa-9-azaspiro[5.5]undecan-9-yl)quinoline-4-carboxylic acid, intermediate 313 (100 mg, 0.31 mmol), (R)-3-glycylthiozolidine-4-carbonitrile hydrochloride, intermediate 4 (95 mg, 0.46 mmol), EDC (88 mg, 0.46 mmol), HOBt (70 mg, 0.46 mmol) and DIPEA (161 μl, 0.92 mmol) in MeCN (6 ml) and EtOAc (6 ml) was stirred at 50 °C for 2 h. The solvent was removed under reduced pressure and the residue was diluted with EtOAc and washed with water. _The organic layer was dried over _Na2SO4 , filtered and evaporated under reduced pressure. The crude product was purified by preparative HPLC, PrepMethod F (gradient: 30-40%) to give the title compound (75 mg, 51%) as a yellow solid; HRMS (ESI) m/z [M ₊ H] ⁺ calcd for _C25H30N5O3S : _480.2064 , found: 480.2057 _;

¹ H NMR (300 MHz, CD3OD) δ 8.62 (d, 1H), 7.90 (d, Hz, 1H), 7.78 - 7.62 (m, 2H), 7.48 (d, 1H), 5.35 - 5.27 (m, 1H), 4.90 -4.80 (m, overlaps with solvent peak), 4.77 (d, 1H), 4.38 (s, 2h), 3.71 (t, 4H), 3.54 -3.35 (m, 6H), 1.75 (t, 4H), 1.58 (t, 4H).

Example 163 carboxamide

(R)-3-Glycylthiazolidine-4-carbonitrile hydrochloride, intermediate 4 (290 mg, 1.40 mmol), was added to a solution of 6-(5,8-dioxa-2-azaspiro[3.4]octan-2-yl)quinoline-4-carboxylic acid, intermediate 315 (200 mg, 0.70 mmol), HATU (531 mg, 1.40 mmol) and DIPEA (361 mg, 2.79 mmol) in DMF (5 mL) and the reaction mixture was stirred at 25 °C for 4 h. The solvent was evaporated under reduced pressure and the residue was purified by preparative TLC (DCM:MeOH, 18:1) followed by preparative HPLC, PrepMethod B (gradient: 18-38%), to yield the title compound (50 mg, 16%) as a yellow solid; HRMS (ESI) m/z [M+H] ⁺ calcd for C ₂₁ H ₂₂ N ₅ O ₄ S: 440.1388, found: 440.1394;

1H NMR (300 MHz, DMSO- _d6 ) δ 8.95 (t, 1H), 8.63 (d, 1H), 7.89 (d, 1H), 7.39 (d, 1H), 7. 30 (d, 1H), 7.14 (dd, 1H), 5.32 (dd, 1H), 4.88 (d, 1H), 4.70 (d, 1H), 4.28 (d, 2H), 4.09 (s, 4H), 3.95 (s, 4H), 3.43-3.33 ( m, 2H).

Example 164

DIPEA (3.98 ml, 22.8 mmol) was added to a mixture of 6-(5-azaspiro[2.3]hexan-5-yl)quinoline-4-carboxylic acid, intermediate 317 (290 mg, 1.14 mmol), (R)-3-glycylthiazolidine-4-carbonitrile hydrochloride, intermediate 4 (474 mg, 2.28 mmol), HOBt (1746 mg, 11.40 mmol) and EDC (2186 mg, 11.40 mmol) in MeCN (3 ml) and EtOAc (3 ml) at 15 °C and the reaction mixture was stirred at 15 °C overnight. The solvent was removed under reduced pressure. The residue was diluted with _NaHCO3 (100 mL, aq) and extracted with EtOAc (5x100 mL). _The combined organic layer was dried over _Na2SO4 , filtered and evaporated under reduced pressure. The crude product was purified by preparative HPLC, PrepMethod C (gradient: 20-35%) to give the title compound (92 mg, 20%) as an orange solid; HRMS (ESI) m/z [M ₊ H] ⁺ calcd for _C21H22N5O2S : _408.1488 , found: 408.1500 _;

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1H NMR (300 MHz, DMSO-d6) δ 9.05 - 8.90 (m, 1H), 8.63 (d, 1H), 7.89 (d, 1H), 7.41 (d, 1H), 7.25 - 7.16 (m, 1H), 7.12 (dd, 1H), 5.32 (dd, 1H), 4.88 (d, 2H), 4.70 (d, 1H), 4.29 (d, 2H), 4.06 (s, 4H), 3.41 -3.35 (m, overlaps with solvent peak), 1.27 - 1.21 (m, 1H), 0.69 (s, 4H).

Example 165. (R)-N-(2-(4-cyanothiazolidin-3-yl)-2-oxoethyl)-6-(3-hydroxy-3-methylazetidin-1 yl)quinoline-4-carboxamide

DIPEA (575 μL, 3.29 mmol) was added to a stirred suspension of 6-(3-hydroxy-3-methylazetidin-1-yl)quinoline-4-carboxylic acid, intermediate 319 (85 mg, 0.33 mmol), (R)-3-glycylthiazolidine-4-carbonitrile hydrochloride, intermediate 4 (137 mg, 0.66 mmol), HOBt (252 mg, 1.65 mmol) and EDC (315 mg, 1.65 mmol) in MeCN (3 mL) and EtOAc (3 mL) at 15 °C and the reaction mixture was stirred at 50 °C for 2 h. The solvent was removed under reduced pressure and the residue was dissolved in NaHCO ₃ (20 mL, aq.) and EtOAc (60 mL). The aqueous layer was extracted with EtOAc (5x75 mL) and the combined organic layer was washed with water (3x25 mL). The combined aqueous layer was extracted with EtOAc (3x20 mL). _The combined organic layer was dried over _Na2SO4 , filtered and evaporated under reduced pressure. The crude product was purified by preparative HPLC, PrepMethod R (gradient: 15-35%) to give the title compound ( ₂₀ mg, 15%) as a yellow solid; HRMS (ESI) _m /z [M _{+H]+ calcd for C20H22N5O3S :} 412.1438, found: 412.1428;

1H NMR (300 MHz, DMSO-d ₆ ) δ 8.95 (t, 1H), 8.61 (d, 1H), 7.87 (d, 1H), 7.39 (d, 1H), 7.22 - 7.06 (m, 2H), 5.60 (s, 1H), 5.39 - 5.24 (m, 1H), 4.89 (d, 1H), 4.72 (d, 1H), 4.29 (d, 2H), 3.89 (d, 2H), 3.76 (d, 2H), 3.48 - 3.33 (d, overlaps with solvent peak), 1.48 (s, 3H).

Example 166

DIPEA (746 μL, 4.27 mmol) was added to a stirred suspension of 6-(2-oxa-6-azaspiro[3.3]heptan-6-yl)quinoline-4-carboxylic acid, intermediate 321 (231 mg, 0.85 mmol), (R)-3-glycylthiazolidine-4-carbonitrile hydrochloride, intermediate 4 (266 mg, 1.28 mmol), HOBt (346 mg, 2.56 mmol) and EDC (492 mg, 2.56 mmol) in MeCN (5 mL) and EtOAc (5 mL) at 25 °C and the reaction mixture was stirred at 50 °C for 2 h. The solvent was removed under reduced pressure. The residue was dissolved in _NaHCO3 (40 mL, aq) and EtOAc (100 mL). The aqueous layer was extracted with EtOAc (6x75 mL) and _the combined organic layer was washed with water (3x50 mL), dried over _Na2SO4 , filtered and evaporated under reduced pressure. The crude product was purified by preparative HPLC, PrepMethod R (gradient: 20-45%) to give the title compound ( ₈₀ mg, 22%) as a yellow solid; HRMS (ESI) m/z [M+ _H ]+ _{calcd for C21H22N5O3S :} 424.1438, found: 424.1428;

1H NMR (300 MHz, DMSO-d6) δ 8.94 (t, 1H), 8.63 (d, 1H), 7.88 (d, 1H), 7.40 (d, 1H), 7.20 (d, 1H), 7.11 (dd, 1H), 5.36 (dd, 1H), 4.89 (d, 1H), 4.84 - 4.64 (m, 5H), 4.30 (d, 2H), 4.13 (s, 4H), 3.41 - 3.36 (m, overlaps with solvent peak).

Example 167. N-(2-((R)-4-cyanothiazolidin-3-yl)-2-oxoethyl)-6-((R)-3-hydroxy-3methylpyrrolidin-1-yl)quinoline-4-carboxamide

A solution of (E)-6-(3-hydroxy-3-methylpyrrolidin-1-yl)quinoline-4-carboxylic acid, intermediate 323 (150 mg, 0.55 mmol), (R)-3-glycylthiazolidine-4-carbonitrile hydrochloride, intermediate 4 (149 mg, 0.72 mmol), EDC (211 mg, 1.10 mmol), HOBt (169 mg, 1.10 mmol) and DIPEA (481 μl, 2.75 mmol) in EtOAc (5 ml) and MeCN (5 ml) was stirred at 50 °C for 2 h. The solvent was removed under reduced pressure and the residue was diluted with EtOAc and washed with water. The organic layer was dried over Na ₂ SO ₄ , filtered and evaporated under reduced pressure. The crude product was purified by preparative HPLC, PrepMethod C (gradient: 9

- 239 048482

19%) to give the title compound (120 mg, 50%) as an orange solid; HRMS (ESI) m/z [M+H]+ calcd for C ₂₁ H ₂₄ N ₅ O ₃ S: 426.1594, found: 426.1604;

¹ H NMR (300 MHz, CD3OD) δ 8.49 (d, 1H), 7.87 (d, 1H), 7.46 (d, 1H), 7.31 (dd, 1H), 7.24 (d, 1H), 5.44-5.24 (m, 1H), 4.87-4.67 (m, overlaps with solvent peak), 4.38 (d, 2H), 3.72-3.51 (m, 2H), 3.49-3.33 (m, 4H), 2.12-1.97 (m, 2H), 1.48 (s, 3H).

Example 168. N-(2-((R)-4-cyanothiazolidin-3-yl)-2-oxoethyl)-6-((S)-3-hydroxy-3-methylpyrrolidin-1-yl)quinoline-4-carboxamide

A solution of (S)-6-(3-hydroxy-3-methylpyrrolidin-1-yl)quinoline-4-carboxylic acid, intermediate 325 (150 mg, 0.55 mmol), (R)-3-glycylthiazolidine-4-carbonitrile hydrochloride, intermediate 4 (149 mg, 0.72 mmol), EDC (211 mg, 1.10 mmol), HOBt (169 mg, 1.10 mmol) and DIPEA (481 μl, 2.75 mmol) in EtOAc (5 ml) and MeCN (5 ml) was stirred at 50 °C for 2 h. The solvent was removed under reduced pressure and the residue was diluted with EtOAc and washed with water. The organic layer was dried over Na ₂ SO ₄ , filtered and evaporated under reduced pressure. The crude product was purified by preparative HPLC, PrepMethod C (gradient (920%)), to give the title compound (125 mg, 52%) as an orange solid; HRMS (ESI) m/z [M+H] ⁺ calcd for C ₂₁ H ₂₄ N ₅ O ₃ S: 426.1594, found: 426.1581;

¹ H NMR (300 MHz, CD ₃ OD) δ 8.49 (d, 1H), 7.87 (d, 1H), 7.46 (d, 1H), 7.31 (dd, 1H), 7.24 (d, 1H), 5.44-5.24 (m, 1H), 4.87-4.67 (m, overlaps with solvent peak), 4.38 (d, 2H), 3.72-3.51 (m, 2H), 3.49-3.33 (m, 4H), 2.12-1.97 (m, 2H), 1.48 (s, 3H).

Example 169

(R)-3-Glycylthiazolidine-4-carbonitrile hydrochloride, intermediate 4 (104 mg, 0.50 mmol), and DIPEA (0.13 mL, 0.75 mmol) were added to a suspension of 6-(6-(difluoromethyl)pyridin-3-yl)quinoline-4-carboxylic acid, intermediate 32b (75 mg, 0.25 mmol), HOBT (46 mg, 0.30 mmol), and EDC (0.072 g, 0.37 mmol) in EtOAc (1.18 mL) and MeCN (1.18 mL), and the reaction mixture was stirred at rt overnight. The reaction mixture was diluted with EtOAc and washed successively with sat. _NaHCO3 (aq) and brine. The organic phase was dried using a phase separator, filtered and evaporated under reduced pressure. The crude product was purified by preparative SFC, PrepMethod SFC-G (gradient: 20-25%) to give the title compound (17 mg, 15%); HRMS (ESI) m/z [M+H] ⁺ calcd for C ₂₂ H ₁₈ F ₂ N ₅ O ₂ S: 454.1144, found: 454.1140;

^1H NMR (600 MHz, DMSO- _d6 ) δ 9.29 - 9.17 (m, 2H), 9.05 (d, 1H), 8.92 (d, 1H), 8.56 (dd, 1H), 8.33 (dd, 1H), 8.25 (d, 1H), 7.88 (d, 1H), 7.65 (d, 1H), 7.05 (t, 1H), 5.39 (dd, 1H), 4.91 (d, 1H), 4.74 (d, 1H), 4.38 (t , 2H).

Example 170. (R)-N-(2-(4-cyanothiazolidin-3-yl)-2-oxoethyl)-6-(1-cyclopropyl-1H-pyrazol-4yl)quinoline-4-carboxamide

DIPEA (1.42 mL, 8.13 mmol) was added to a suspension of 6-(1-cyclopropyl-1H-pyrazol-4-yl)quinoline-4-carboxylic acid, intermediate 327 (0.568 g, 2.03 mmol), (R)-3-glycylthiazolidine-4-carbonitrile hydrochloride, intermediate 4 (0.422 g, 2.03 mmol), and HATU (0.773 g, 2.03 mmol) in DCM (16 mL) and MeCN (4 mL), and the reaction mixture was stirred at rt overnight. The reaction mixture was diluted with EtOAc and washed successively with sat. _NaHCO3 (aq) and brine. The organic phase was dried, filtered and evaporated under reduced pressure and the crude product was purified by preparative SFC, PrepMethod SFC-H (gradient: 25-30%) to give the title compound (220 mg, 25%); HRMS (ESI) m/z [M+H] ⁺ calcd for C ₂₂ H ₂₁ N ₆ O ₂ S: 433.1442, found: 433.1454;

^1H NMR (600 MHz, DMSO- _d6 ) δ 9.10 (t, 1H), 8.95 (d, 1H), 8.53 (s, 1H), 8.36 (d, 1H), 8 .27 (d, 1H), 8.13 (d, 1H), 7.98 (dd, 1H), 7.48 (d, 1H), 5.38 (dd, 1H), 4.90 (d, 1H), 4.73 (d, 1H), 4.33 (d, 2H), 3.79 (tt, 1H) , 3.45 -

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3.36 (m, overlaps with solvent peak), 1.15-1.11 (m, 2H), 1.05 - 0.99 (m, 2H).

Example 171

HATU (267 mg, 0.70 mmol) and DIPEA (0.294 mL, 1.68 mmol) were added to a suspension of 6-(1,3-dimethyl-1H-pyrazol-4-yl)quinoline-4-carboxylic acid, intermediate 328 (150 mg, 0.56 mmol), and (R)-3-glycylthiazolidine-4-carbonitrile hydrochloride, intermediate 4 (117 mg, 0.56 mmol), in EtOAc (3 mL) and MeCN (3 mL) and the reaction mixture was stirred at rt overnight. The reaction mixture was concentrated under reduced pressure and the crude product was purified by preparative HPLC, PrepMethod V (gradient: 0-50%), to give the title compound (90 mg, 38%); HRMS (ESI) mass/charge [M+H]+ calcd for C ₂₁ H ₂₁ N ₆ O ₂ S: 421.1442, found value: 421.1456;

1H NMR (600 MHz, DMSO-d6) δ 9.12 (t, 1H), 8.92 (d, 1H), 8.45 (d, 1H), 8.14 - 8.06 (m, 2H), 7.94 (dd, 1H), 7.55 (d, 1H), 5.36 (dd, 1H), 4.91 (d, 1H), 4.73 (d, 1H), 4.34 (qd, 2H), 3.84 (s, 3H), 3.45 - 3.36 (m, overlaps with solvent peak), 2.40 (s, 3H).

Example 172 (R)-N-(2-(4-cyanothiazolidin-3-yl)-2-oxoethyl)-6-(3,5-dimethyl-1-(tetrahydro-2Hpyran-4-yl)-1 H -pyrazol-4-yl)quinoline-4-carboxamide

HATU (54 mg, 0.14 mmol) and DIPEA (60 µl, 0.34 mmol) were added to a suspension of 6-(3,5-dimethyl-1(tetrahydro-2H-pyran-4-yl)-1H-pyrazol-4-yl)quinoline-4-carboxylic acid, intermediate 329 (40 mg, 0.11 mmol), and (R)-3-glycylthiazolidine-4-carbonitrile hydrochloride, intermediate 4 (24 mg, 0.11 mmol), in EtOAc (0.75 ml) and MeCN (0.75 ml) and the reaction mixture was stirred at rt overnight. The reaction mixture was concentrated under reduced pressure and the residue was purified by preparative HPLC, PrepMethod F (gradient: 5-95%) to give the title compound (15 mg, 26%); HRMS (ESI) m/z [M+H]+ calcd for C ₂₆ H ₂₉ N ₆ O ₃ S: 505.2016, found: 505.2020;

1H NMR (600 MHz, DMSO-d6) δ 9.12 (t, 1H), 8.96 (d, 1H), 8.27 (d, 1H), 8.11 (d, 1H), 7.78 (dd, 1H), 7.56 (d, 1H), 5.31 (dd, 1H), 4.89 (d, 1H), 4.71 (d, 1H), 4.51 - 4.26 (m, 3H), 3.99 (dd, 2H), 3.49 (tt, 2H), 3.44 - 3.39 (m, overlaps with solvent peak), 2.35 (s, 3H), 2.23 (s, 3H), 2.08 (qt, 2H), 1.83 (tdd, 2H).

Example 173. (R)-N-(2-(4-cyanothiazolidin-3-yl)-2-oxoethyl)-6-(1-(tetrahydro-2H-pyran-4-yl)-1Hpyrazol-4-yl) quinoline-4-carboxamide

HATU (35 mg, 0.09 mmol) and DIPEA (0.039 ml, 0.22 mmol) were added to a suspension of 6-(1-(tetrahydro2H-pyran-4-yl)-1H-pyrazol-4-yl)quinoline-4-carboxylic acid, intermediate 330 (24 mg, 0.07 mmol), and (R)-3-glycylthiazolidine-4-carbonitrile hydrochloride, intermediate 4 (15 mg, 0.07 mmol), in EtOAc (0.75 ml) and MeCN (0.75 ml) and the reaction mixture was stirred at rt overnight. The reaction mixture was concentrated under reduced pressure and the residue was purified by preparative SFC, PrepMethod SFC-G (gradient: 0-50%) to give the title compound (11 mg, 31%); HRMS (ESI) m/z [M+H]+ calcd for C ₂₄ H ₂₅ N ₆ O ₃ S: 477.1704, found: 477.1706;

1H NMR (600 MHz, DMSO-d6) δ 9.17 (t, 1H), 8.88 (d, 1H), 8.77 (d, 1H), 8.53 (s, 1H), 8.15 - 8.10 (m, 2H), 8.06 (d, 1H), 7.50 (d, 1H), 5.44 (dd, 1H), 4.94 (d, 1H), 4.75 (d, 1H), 4.52 - 4.44 (m, 1H), 4.38 (d, 2H), 4.05 3.95 (m, 2H), 3.54 - 3.39 (m, overlaps with solvent peak), 2.12 - 1.94 (m, 4H).

Example 174

HATU (52 mg, 0.14 mmol) and DIPEA (0.058 ml, 0.33 mmol) were added to a suspension of 6-(1-methyl-1H- 241 048482 pyrazol-5-yl)quinoline-4-carboxylic acid, intermediate 331 (28 mg, 0.11 mmol), and (R)-3-glycylthiazolidine-4-carbonitrile hydrochloride, intermediate 4 (23 mg, 0.11 mmol), in EtOAc (0.7 ml) and MeCN (0.7 ml) and the reaction mixture was stirred at rt. for 36 h. The reaction mixture was concentrated under reduced pressure and the crude product was purified by preparative SFC, PrepMethod SFC-H (gradient: 22-27%) to give the title compound (16 mg, 36%); FIRMS (ESI) m/z [M+H] ⁺ calcd for C ₂₀ H ₁₉ N ₆ O ₂ S: 407.1284, found: 407.1278;

1H NMR (600 MHz, DMSO-d ₆ ) δ 9.21 (t, 1H), 9.04 (d, 1H), 8.54 (brs, 1H), 8.20 (d, 1H), 8.00 (d, 1H), 7.64 (d, 1H), 7.54 (brs, 1H), 6.61 (brs, 1H), 5.36 (d, 1H), 4.90 (d, 1H), 4.72 (d, 1H), 4.34 (qd, 2H), 3.99 (s, 3H), 3.43–3.35 (m, overlaps with solvent peak).

Example 175 quinoline-4-carboxamide

HATU (40 mg, 0.11 mmol) and DIPEA (0.045 ml, 0.26 mmol) were added to a suspension of 6-(5,6,7,8-tetrahydroimidazo[1,2-a]pyridin-3-yl)quinoline-4-carboxylic acid, intermediate 333 (25 mg, 0.09 mmol), and (R)-3-glycylthiazolidine-4-carbonitrile hydrochloride, intermediate 4 (18 mg, 0.09 mmol), in EtOAc (0.5 ml) and MeCN (0.5 ml), and the reaction mixture was stirred at rt overnight. The reaction mixture was concentrated under reduced pressure and the residue was purified by preparative SFC, PrepMethod SFC-H (gradient: 27-32%), then preparative HPLC, PrepMethod N (gradient: 5-45%) to give the title compound (5 mg, 13%): HRMS (ESI) m/z [M+H] ⁺ calc for C ₂₃ H ₂₃ N ₆ O ₂ S: 447.1598, found: 447.1619;

1H NMR (500 MHz, CD3OD) δ 9.00 (d, 1H), 8.65 (s, 1H), 8.26 (s, 1H), 8.21 (d, 1H), 7.99 (d, 1H), 7.70 (d, 1H), 7.55 (s, 1H), 5.34 -5.29 (m, 1H), 4.80 - 4.74 (m, overlaps with solvent peak), 4.51 - 4.21 (m, 4H), 3.52 - 3.33 (m, 2H), 3.07 (d, 2H), 2.18 - 2.02 (m, 4H).

Example 176. N-(2-((R)-4-cyanothiazolidin-3-yl)-2-oxoethyl)-6-(1-((RS)-tetrahydro-2H-pyran-2-yl)1H-pyrazol-5-yl)quinoline-4-carboxamide

Step a) rac-(R)-6-(1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-5-yl)quinoline-4-carboxylic acid

A mixture of 1-(tetrahydro-2H-pyran-2-yl)-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (77 mg, 0.28 mmol), 6-bromoquinoline-4-carboxylic acid (70 mg, 0.28 mmol) _{, Cs2CO3 (} 181 mg, 0.56 mmol) and Pd(dtbpf) _Cl2 (18 mg, 0.03 mmol) in 1,4-dioxane (1.5 mL) and water (0.37 mL) was stirred overnight. The reaction mixture was concentrated under reduced pressure to give the title compound (90 mg); MS (ESI) m/z [M+H]+ 324.

Step b) N-(2-((R)-4-cyanothiazolidin-3-yl)-2-oxoethyl)-6-(1-(tetrahydro-2H-pyran-2-yl)-1Hpyrazol-5-yl)quinoline-4-carboxamide HATU (132 mg, 0.35 mmol) and DIPEA (0.146 mL, 0.84 mmol) were added to a suspension of crude 6-(1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-5-yl)quinoline-4-carboxylic acid (90 mg) and (R)-3-glycylthiazolidine-4-carbonitrile hydrochloride, intermediate 4 (58 mg, 0.28 mmol), in EtOAc (1 mL) and MeCN (1 mL) and the reaction mixture was stirred at rt. overnight. The reaction mixture was concentrated under reduced pressure and the crude compound was purified by preparative SFC, PrepMethod _SFC -C (gradient: 27-32%) to give the title compound ( ₇₄ mg, 56%); HRMS (ESI) m/z [M ₊ H] ⁺ calcd for _C24H25N6O3S : 477.1704, found: 477.1722;

1H NMR (600 MHz, DMSO-d6) δ 9.17 (t, 1H), 9.06 (d, 1H), 8.49 (s, 1H), 8.22 (d, 1H), 8.00 - 7.95 (m, 1H), 7.68 - 7.63 (m, 2H), 6.64 (dd, 1H), 5.35 - 5.32 (m, 1H), 4.89 (dd, 1H), 4.72 (d, 1H), 4.40 - 4.27 (m, 2H), 4.04 3.97 (m, 1H), 3.58 (dt, 1H), 3.47 - 3.36 (m, overlaps with solvent peak), 2.48 - 2.37 (m, 1H), 1.94 (s, 1H), 1.85 (t, 1H), 1.63 - 1.47 (m, 3H).

- 242 048482

Example 177. (R)-N-(2-(4-cyanothiazolidin-3-yl)-2-oxoethyl)-6-(6-methylpyridin-3-yl)quinoline-4-carboxamide

Step a) 6-(6-methylpyridin-3-yl)quinoline-4-carboxylic acid

A mixture of 2-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine (47 mg, 0.21 mmol), 6-bromoquinoline-4-carboxylic acid (54 mg, 0.21 mmol), _Cs2CO3 (209 mg, 0.64 mmol) and Pd(dtbpf) _Cl2 (21 mg, 0.03 mmol) in 1,4-dioxane (1 _mL ) and water (0.25 mL) was stirred overnight. The reaction mixture was concentrated under reduced pressure to give the title compound (56 mg) as a crude product; MS (ESI) m/z [M+H]+ 263.

Step b) (R)-N-(2-(4-cyanothiazolidin-3-yl)-2-oxoethyl)-6-(6-methylpyridin-3-yl)quinoline-4-carboxamide

HATU (101 mg, 0.26 mmol) and DIPEA (0.111 mL, 0.64 mmol) were added to a suspension of crude 6-(6-methylpyridin-3-yl)quinoline-4-carboxylic acid (56 mg) and (R)-3-glycylthiazolidine-4-carbonitrile hydrochloride, intermediate 4 (44 mg, 0. mmol), in EtOAc (1 mL) and MeCN (1 mL) and the solution was stirred at rt overnight. The reaction mixture was concentrated under reduced pressure and the crude product was purified by preparative HPLC, PrepMethod F (gradient: 0-30%), to give the title compound (30 mg, 34%); FIRMS (ESI) m/z [M+H] ⁺ calc. for C ₂₂ H ₂₀ N ₅ O ₂ S: 418.1332, found value: 418.1328;

¹ H NMR (600 MHz, DMSO-d6) δ 9.20 (t, 1H), 9.01 (d, 1H), 8.96 (d, 1H), 8.78 (d, 1H), 8.26 - 8.17 (m, 3H), 7.62 (d, 1H), 7.42 (d, 1H), 5.38 (dd, 1H), 4.91 (d, 1H), 4.74 (d, 1H), 4.37 (d, 2H), 3.49 - 3.38 (m, overlaps with solvent peak), 2.55 (s, 3H).

Example 178. (R)-N-(2-(4-cyanothiazolidin-3-yl)-2-oxoethyl)-6-(6-methoxypyridin-3-yl)quinoline-4-carboxamide

Step a) 6-(6-methoxypyridin-3-yl)quinoline-4-carboxylic acid

A mixture of 2-methoxy-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine (49 mg, 0.0 mmol), 6-bromoquinoline-4-carboxylic acid (53 mg, 0.21 mmol), _Cs2CO3 (206 mg, 0.63 mmol) and Pd(dtbpf) _Cl2 (21 mg, 0.03 mmol) in 1,4-dioxane (2 _mL ) and water (0.5 mL) was stirred overnight. The reaction mixture was evaporated under reduced pressure to give the crude title compound (58 mg); MS (ESI) m/z [M+H] ⁺ 281.

Step b) (R)-N-(2-(4-cyanothiazolidin-3-yl)-2-oxoethyl)-6-(6-methoxypyridin-3-yl)quinoline-4-carboxamide

HATU (98 mg, 0.26 mmol) and DIPEA (0.108 mL, 0.62 mmol) were added to a suspension of crude 6-(6-methoxypyridin-3-yl)quinoline-4-carboxylic acid (58 mg) and (R)-3-glycylthiazolidine-4-carbonitrile hydrochloride, intermediate 4 (43 mg, 0.21 mmol), in EtOAc (1 mL) and MeCN (1 mL) and the reaction mixture was stirred at rt overnight. The reaction mixture was concentrated under reduced pressure and the crude product was purified by preparative SFC, PrepMethod SFC-C (gradient: 25-30%) followed by PrepMethod SFC-E (gradient: 20-25%), to afford the title compound (23 mg, 25%); FIRMS (ESI) mass/charge [M+H] ⁺ calc. for C ₂₂ H ₂₀ N ₅ O ₃ S: 434.1282, found value: 434.1268;

1H NMR (600 MHz, DMSO-d ₆ ) δ 9.18 (t, 1H), 8.99 (d, 1H), 8.76 (d, 1H), 8.69 (d, 1H), 8.30 (dd, 1H), 8.26 - 8.15 (m, 2H), 7.60 (d, 1H), 7.00 (d, 1H), 5.38 (dd, 1H), 4.91 (d, 1H), 4.74 (d, 1H), 4.41 - 4.33 (m, 2H), 3.94 (s, 3H), 3.48 - 3.39 (m, overlaps with solvent peak).

- 243 048482

Example 179

DIPEA (107 µL, 0.61 mmol) was added to

7-Chloro-6-morpholinoquinoline-4-carboxylic acid, intermediate 336 (60 mg, 0.20 mmol), (R)-3-glycylthiazolidine-4-carbonitrile hydrochloride, intermediate 4 (43 mg, 0.20 mmol), and T3P (521 mg, 0.82 mmol, 50% in EtOAc) in MeCN (5 mL) and EtOAc (5 mL) and the reaction mixture was stirred at 20 °C for 3 h. The reaction mixture was concentrated under reduced pressure, diluted with EtOAc (50 mL), and washed successively with water (15 mL) and brine (15 mL). The organic layer was dried over Na ₂ SO ₄ , filtered, and evaporated under reduced pressure. The crude product was purified by preparative HPLC, PrepMethod F (gradient: 29-39%) to afford the _title compound (0.050 g, 55%) as a yellow solid; HRMS (ESI) m/z [ _{M+H]+ calcd for C20H21ClN5O3S :} 446.1048, found: _446.1046 ;

1H NMR (400 MHz, DMSO-d ₆ ) δ 9.23 - 9.05 (m, 1H), 8.88 (d, 1H), 8.16 (s, 1H), 8.09 (s, 1H), 7.55 (d, 1H), 5.34 (dd, 1H), 4.90 (d, 1H), 4.72 (d, 1H), 4.41 - 4.27 (m, 2H), 3.81 (t, 4H), 3.45 - 3.34 (m, overlaps with people solvent peak), 3.20 - 3.05 (m, 4H).

Example 180

A solution of T3P (608 mg, 0.96 mmol, 50% in EtOAc) in EtOAc (10 mL) was added to a stirred mixture of 8-chloro-6-morpholinoquinoline-4-carboxylic acid, intermediate 339 (70 mg, 0.24 mmol), and (R)-3-glycylthiazolidine-4-carbonitrile hydrochloride, intermediate 4 (50 mg, 0.24 mmol), in MeCN (10 mL) at 20 °C and the reaction mixture was stirred at 25 °C for 3 h. The reaction mixture was concentrated under reduced pressure, diluted with EtOAc (50 mL), and washed successively with brine (20 mL) and water (15 mL). _The organic layer was dried over _Na2SO4 , filtered and evaporated under reduced pressure. The crude product was purified by preparative _HPLC , _{PrepMethod R (gradient: 19-39%) to give the title compound (0.060 g, 56%) as a yellow solid; HRMS (ESI) m/z [M+H]+ calcd for C20H21ClN5O3S : 446.1048} , found: 446.1026;

¹ H NMR (400 MHz, DMSO-d6) δ 9.07 (t, 1H), 8.79 (d, 1H), 7.91 (d, 1H), 7.71 (d, 1H), 7.50 (d, 1H), 5.31 (dd, 1H), 4.89 (d, 1H), 4.70 (d, 1H), 4.39 - 4.22 (m, 2H), 3.78 (t, 4H), 3.45 - 3.34 (m, overlaps with solvent peak).

Example 181

(R)-3-Glycylthiazolidine-4-carbonitrile hydrochloride, intermediate 4 (32 mg, 0.15 mmol), was added to a mixture of 6-(3-(acetamidomethyl)-3-methylazetidin-1-yl)quinoline-4-carboxylic acid, intermediate 341 (40 mg), HATU (73 mg, 0.19 mmol) and DIPEA (89 μL, 0.51 mmol) in MeCN (1.5 mL) and EtOAc (1.5 mL) and the reaction mixture was stirred at rt overnight. DCM (10 mL) and _NaHCO3 (7 mL, aq.) were added and the reaction mixture was filtered through a phase separator and evaporated under reduced pressure. The crude compound was purified by preparative HPLC, PrepMethod F (5-95% gradient), to give the title compound (3 mg, 6%); HRMS (ESI) m/z [M+H]+ calcd for C ₂₃ H ₂₇ N ₆ O ₃ S: 467.1860, found: 467.1818;

1H NMR (600 MHz, DMSO-d6) δ 8.89 (t, 1H), 8.57 (d, 1H), 7.98 (t, 1H), 7.83 (d, 1H), 7.37 (d, 1H), 7.07-7.01 (m, 2H), 5.33 - 5.25 (m, 1H), 4.84 (d, 1H), 4.68 (d, 1H), 4.31 - 4.21 (m, 2H), 3.74 (dd, 2H), 3.52 (d, 2H), 3.45 - 3.30 (m, overlaps with solvent peak), 3.25 (d, 2H), 1.79 (s, 3H), 1.23 (s, 3H).

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Example 182

6-(3-Fluoro-3-phenylazetidin-1-yl)quinoline-4-carboxylic acid, intermediate 343 (22 mg, 0.07 mmol), HATU (39 mg, 0.10 mmol) and DIPEA (48 μl, 0.27 mmol) were mixed in MeCN (1 ml) and EtOAc (1 ml). (R)-3-Glycylthiazolidine-4-carbonitrile hydrochloride, intermediate 4 (17 mg, 0.08 mmol) was added and the reaction mixture was stirred at rt for 1 h. DCM (8 ml) and _NaHCO3 (5 ml, aq) were added and the reaction mixture was stirred, filtered through a phase separator and evaporated under reduced pressure. The crude compound was purified by preparative SFC, PrepMethod SFC-E (gradient: 30-35%) to give the title compound (2.4 mg, 7%); HRMS (ESI) m/z [M+H]+ calcd for C ₂₅ H ₂₃ FN ₅ O ₂ S: 476.1550, found: 476.1560.

Example 183

6-(3-(p-tolyl)azetidin-1-yl)quinoline-4-carboxylic acid, intermediate 345 (18 mg, 0.06 mmol), HATU (32 mg, 0.08 mmol) and DIPEA (40 µl, 0.23 mmol) were mixed in MeCN (0.5 ml) and EtOAc (0.5 ml). (R)-3-Glycylthiazolidine-4-carbonitrile hydrochloride, intermediate 4 (14 mg, 0.07 mmol) was added and the reaction mixture was stirred at rt for 1 h. DCM (5 ml) and _NaHCO3 (5 ml, aq) were added and the reaction mixture was stirred, filtered through a phase separator and evaporated under reduced pressure. The compound was purified by preparative HPLC, PrepMethod F (5-95% gradient) to afford the title compound (85 mg, 32%); FIRMS (ESI) m/z [M+H] ⁺ calcd for C ₂₆ H ₂₆ N ₅ O ₂ S: 472.1802, found: 472.1800;

1H NMR (600 MHz, DMSO-d6) δ 8.93 (t, 1H), 8.60 (d, 1H), 7.87 (d, 1H), 7.37 (d, 1H), 7.27 - 7.22 (m, 3H), 7.16 - 7.11 (m, 3H), 5.28 (dd, 1H), 4.84 (d, 1H), 4.67 (d, 1H), 4.37 (t, 2H), 4.25 (d, 2H), 3.99 - 3.85 (m, 3H ), 3.35 -3.25 (m, overlapping with water), 2.25 (s, 3H).

Example 184 carboxamide

6-(6-Acetyl-2,6-diazaspiro[3.3]heptan-2-yl)quinoline-4-carboxylic acid, intermediate 347 (90 mg, 0.29 mmol), HATU (165 mg, 0.43 mmol) and DIPEA (202 μl, 1.16 mmol) were mixed in MeCN (2 ml) and EtOAc (2 ml). (R)-3-Glycylthiazolidine-4-carbonitrile hydrochloride, intermediate 4 (72 mg, 0.35 mmol) was added and the reaction mixture was stirred at rt for 3 h. DCM (15 ml) and NaHCO3 (15 ml, aq) were added and the reaction mixture was stirred, filtered through a phase separator and evaporated under reduced pressure. The crude compound was purified by preparative HPLC, PrepMethod F (5-95% gradient) to afford the title compound (37 mg, 28%); HRMS (ESI) m/z [M+H] ⁺ calcd for C ₂₃ H ₂₅ N ₆ O ₃ S: 465.1704, found: 465.1692;

1H NMR (600 MHz, DMSO-d6) δ 8.90 (t, 1H), 8.60 (d, 1H), 7.85 (d, 1H), 7.38 (d, 1H), 7.16 (d, 1H), 7.08 (dd, 1H), 5.31 (dd, 1H), 4.85 (d, 1H), 4.68 (d, 1H), 4.27 (s, 4H), 4.06 (s, 4H), 4.00 (s, 2H), 3.39 - 3.30 (m, 2H ), 5 1.72 (s, 3H).

Example 185

6-(3-(4-fluorophenyl)azetidin-1-yl)quinoline-4-carboxylic acid, intermediate 349

- 245 048482 (80 mg, 0.25 mmol), HATU (142 mg, 0.37 mmol) and DIPEA (173 µl, 0.99 mmol) were mixed in MeCN (2 ml) and EtOAc (2 ml). (R)-3-Glycylthiazolidine-4-carbonitrile hydrochloride, intermediate 4 (62 mg, 0.30 mmol) was added and the reaction mixture was stirred at rt for 3 h. DCM (15 ml) and _NaHCO3 (15 ml, aq) were added and the reaction mixture was stirred, filtered through a phase separator and evaporated under reduced pressure. The crude compound was purified by preparative HPLC, PrepMethod F (5-95% gradient), to give the title compound (60 mg, 51%); HRMS (ESI) mass/charge [M+H]+ calcd for C ₂₅ H ₂₃ FN ₅ O ₂ S: 476.1550, found value: 476.1550;

1H NMR (600 MHz, DMSO-d6) δ 8.97 (t, 1H), 8.64 (d, 1H), 7.90 (d, 1H), 7.46 - 7.38 (m, 3H) , 7.28 (d, 1H), 7.20 - 7.11 (m, 3H), 5.28 (dd, 1H), 4.84 (d, 1H), 4.67 (d, 1H), 4.39 (t, 2H), 4.27 (d, 2H), 4.00 (p, 1H), 3. 91 (dq, 2H), 3.37 - 3.27 (m, 2H).

Example 186

6-(3-(m-tolyl)azetidin-1-yl)quinoline-4-carboxylic acid, intermediate 351 (90 mg, 0.28 mmol), HATU (161 mg, 0.42 mmol) and DIPEA (197 μl, 1.13 mmol) were mixed in MeCN (2 ml) and EtOAc (2 ml). (R)-3-Glycylthiazolidine-4-carbonitrile hydrochloride, intermediate 4 (70 mg, 0.34 mmol) was added and the reaction mixture was stirred at rt for 3 h. DCM (15 ml) and NaHCO3 (15 ml, aq) were added and the reaction mixture was stirred, filtered through a phase separator and evaporated under reduced pressure. The compound was purified by preparative HPLC, PrepMethod F (5-95% gradient) to afford the title compound (58 mg, 51%); HRMS (ESI) m/z [M+H] ⁺ calcd for C ₂₆ H ₂₆ N ₅ O ₂ S: 472.1802, found: 472.1792: 471.18;

^1H NMR (600 MHz, DMSO- _d6 ) δ 8.97 (t, 1H), 8.64 (d, 1H), 7.89 (d, 1H), 7.43 (d, 1H), 7 .27 (d, 1H), 7.23 7.12 (m, 4H), 7.03 (d, 1H), 5.28 (dd, 1H), 4.84 (d, 1H), 4.67 (d, 1H), 4.38 (t, 2H), 4.27 (d, 2H), 3.99 -3 .88 (m, 3H), 3.37 - 3.26 (m, 2H), 2.27 (s, 3H).

Example 187

6-(3-(4-Chlorobenzyl)azetidin-1-yl)quinoline-4-carboxylic acid, intermediate 353 (80 mg, 0.23 mmol), HATU (129 mg, 0.34 mmol) and DIPEA (158 μl, 0.91 mmol) were mixed in MeCN (2 ml) and EtOAc (2 ml). (R)-3-Glycylthiazolidine-4-carbonitrile hydrochloride, intermediate 4 (56 mg, 0.27 mmol) was added and the reaction mixture was stirred at rt for 3 h. DCM (15 ml) and _NaHCO3 (15 ml, aq) were added and the reaction mixture was stirred, filtered through a phase separator and evaporated under reduced pressure. The crude compound was purified by preparative HPLC, PrepMethod F (5-95% gradient) to afford the title compound (18 mg, 16%); HRMS (ESI) m/z [M+H] ⁺ calcd for C ₂₆ H ₂₅ ClN ₅ O ₂ S: 506.1412, found: 506.1428;

1H NMR (600 MHz, DMSO-d6) δ 8.89 (t, 1H), 8.57 (d, 1H), 7.82 (d, 1H), 7.36 (d, 1H), 7.33 - 7.29 (m, 2H), 7.25 (d, 2H), 7.11 - 7.03 (m, 2H), 5.27 - 5.21 (m, 1H), 4.82 (d, 1H), 4.66 (d, 1H), 4.24 (d, 2H), 3.99 (q, 2H ), 3.66 - 3.59 (m, 2H), 3.35 - 3.28 (m, 2H), 2.99 (dt, 1H), 2.90(d, 2H).

Example 188. (R)-N-(2-(4-cyanothiazolidin-3-yl)-2-oxoethyl)-6-(3-methyl-3-((methylsulfonyl)methyl)azetidin-1-yl)quinoline-4-carboxamide

6-(3-Methyl-3-((methylsulfonyl)methyl)azetidin-1-yl)quinoline-4-carboxylic acid, intermediate 355 (55 mg, 0.16 mmol), HATU (94 mg, 0.25 mmol) and DIPEA (115 µl, 0.66 mmol) were mixed in MeCN (1.5 ml) and EtOAc (1.5 ml). (R)-3-Glycylthiazolidine-4-carbonitrile hydrochloride, intermediate 4 (41 mg, 0.20 mmol) was added and the reaction mixture was stirred at rt overnight. DCM (10 ml) and NaHCO3 (7 ml, aq) were added and the reaction mixture was stirred, filtered through a phase separator and evaporated under reduced pressure. The crude

- 246 048482 The resulting compound was purified by preparative SFC, PrepMethod SFC-E (35-40% gradient), to give the title compound ( ₁₉ mg _, 24%); HRMS (ESI) m/z [M+H]+ calcd for _{C22H26N5O4S2 :} 488.1420, found: _488.1442 ;

¹ H NMR (600 MHz, DMSO-d ₆ ) δ 8.89 (t, 1H), 8.59 (d, 1H), 7.84 (d, 1H), 7.38 (d, 1H), 7.08 (dd, 2H), 5.28 (dd, 1H), 4.83 (d, 1H), 4.67 (d, 1H), 4.29 - 4.21 (m, 2H), 3.94 (d, 2H), 3.71 (d, 2H), 3.59 (s, 2H), 2.98 (s, 3H), 3.35 - 3.25 (m, overlaps with solvent peak), 1.56 (s, 3H).

Example 189

DIPEA (262 μL, 1.50 mmol) was added to a stirred suspension of 6-(4-ethyl-4-hydroxypiperidin-1-yl)quinoline-4-carboxylic acid, intermediate 357 (90 mg, 0.30 mmol), (R)-3-glycylthiazolidine-4-carbonitrile hydrochloride, intermediate 4 (124 mg, 0.60 mmol), HOBt (121 mg, 0.90 mmol), and EDC (172 mg, 0.90 mmol) in MeCN (5 mL) and EtOAc (5 mL) at 28 °C and the reaction mixture was stirred at 50 °C for 2 h. The reaction mixture was concentrated under reduced pressure and further diluted with sat. _NaHCO3 solution (30 mL, aq.) and EtOAc (100 mL). The aq. layer was extracted with EtOAc (4x50 mL) and _the combined organic layers were dried over _Na2SO4 , filtered and evaporated. The crude product was purified by preparative HPLC, PrepMethod F (gradient: 13-23%), to give the title compound (0.089 g, 64%) as a yellow solid; HRMS (ESI) m/z [M _{+H]+ calcd for C23H28N5O3S : 454.1908} , found: _454.1926 ;

¹ H NMR (300 MHz, DMSO-d ₆ ) δ 8.99 (t, 1H), 8.64 (d, 1H), 7.86 (d, 1H), 7.70 - 7.60 (m, 2H), 7.39 (d, 1H), 5.40 - 5.23 (m, 1H), 4.89 (d, 1H), 4.71 (d, 1H), 4.29 (d, 2H), 4.13 (brs, 1H), 3.67 - 3.51 (m, 2H), 3.50 - 3.15 (m, overlaps with solvent peak), 1.63 - 1.54 (m, 4H), 1.41 (q, 2H), 0.86 (t, 3H).

Example 190. (R)-N-(2-(4-cyanothiazolidin-3-yl)-2-oxoethyl)-6-(4-hydroxy-4-methylpiperidin-1yl)quinoline-4-carboxamide

DIPEA (183 μL, 1.05 mmol) was added to a stirred suspension of 6-(4-hydroxy-4-methylpiperidin-1-yl)quinoline-4-carboxylic acid, intermediate 359 (90 mg, 0.30 mmol), (K)-3-glycylthiazolidine-4-carbonitrile hydrochloride, intermediate 4 (109 mg, 0.52 mmol), HOBt (80 mg, 0.52 mmol), and EDC (100 mg, 0.52 mmol) in MeCN (5 mL) and EtOAc (5 mL) at 28 °C, and the reaction mixture was stirred at 50 °C for 2 h. The reaction mixture was concentrated under reduced pressure, further diluted with EtOAc, and washed successively with H2O. _The organic layer was dried over _Na2SO4 , filtered and evaporated. The residue was purified by preparative HPLC, PrepMethod C (gradient: 10-16%) to give the title compound (0.075 g, 44%) as a yellow solid; HRMS (ESI) m/z [M _{+H]+ calcd for C22H26N5O3S :} 440.1750, found: _{440.1760 ;}

¹ H NMR (300 MHz, CD3OD) δ 8.61 (d, 1H), 7.90 (d, 1H), 7.75 - 7.63 (m, 2H), 7.50 (d, 1H), 5.34 (dd, 1H), 4.86 - 4.73 (m, 2H), 4.38 (d, 2H), 3.68 - 3.56 (m, 2H), 3.52 - 3.34 (m, overlaps with solvent peak), 1.85 - 1.65 (m, 4H), 1.26 (s, 3H).

Example 191

DIPEA (142 μL, 0.81 mmol) was added to a stirred suspension of 6-(4-ethyl-4-methoxypiperidin-1-yl)quinoline-4-carboxylic acid, intermediate 361 (85 mg, 0.27 mmol), (K)-3-glycylthiazolidine-4-carbonitrile hydrochloride, intermediate 4 (84 mg, 0.41 mmol), HOBt (62 mg, 0.41 mmol), and EDC (78 mg, 0.41 mmol) in MeCN (5 mL) and EtOAc (5 mL) at 28 °C, and the reaction mixture was stirred at 50 °C for 2 h. The reaction mixture was concentrated under reduced pressure and further diluted with EtOAc (20 mL), and successively

- 247 048482 was washed with H2O (2x15 mL). _The organic layer was dried over _Na2SO4 , filtered and evaporated. The residue was purified by preparative HPLC, PrepMethod C (20-31% gradient) to give the title compound (0.075 g, 59%) as a yellow solid; HRMS (ESI) m/z [M+H]+ calcd for C24H30N5O3S: 468.2064, found: 468.2066;

1H NMR (400 MHz, CD3OD) δ 8.62 (d, 1H), 7.90 (d, 1H), 7.75 (d, 1H), 7.68 (dd, 1H), 7.49 (d, 1H), 5.33 (dd, 1H), 4.85 (d, 1H), 4.77 (d, 1H), 4.39 (d, 2H), 3.75 - 3.63 (m, 2H), 3.51 - 3.32 (m, overlaps with solvent peak), 3.25 - 3.10 (m, 4H), 1.98 - 1.88 (m, 2H), 1.70 - 1.50 (m, 4H), 0.88 (t, 3H).

Example 192. (R)-N-(2-(4-cyanothiazolidin-3-yl)-2-oxoethyl)-6-(4-hydroxy-4-isopropylpiperidin-1-yl)quinoline-4-carboxamide

DIPEA (389 µL, 2.23 mmol) was added to a stirred suspension of 6-(4-hydroxy-4-isopropylpiperidin-1-yl)quinoline-4-carboxylic acid, intermediate 363 (140 mg, 0.45 mmol), (R)-3-glycylthiazolidine-4-carbonitrile hydrochloride, intermediate 4 (185 mg, 0.89 mmol), HOBt (181 mg, 1.34 mmol), and EDC (256 mg, 1.34 mmol) in MeCN (5 mL) and EtOAc (5 mL) at 28 °C and the reaction mixture was stirred at 50 °C for 2 h. The reaction mixture was concentrated under reduced pressure and further diluted with EtOAc (100 mL) and sat. NaHCO ₃ solution (30 mL, aq.). The aq. layer was extracted with EtOAc (4x50 mL). The organic layers were combined and washed with H ₂ O (3x25 mL). The organic layer was dried over Na ₂ SO ₄ , filtered and evaporated. The residue was purified by preparative HPLC, PrepMethod F (18-28% gradient) to give the title compound (0.12 g, 58%) as a yellow solid; HRMS (ESI) m/z [M+H]+ calcd for C ₂₄ H ₃₀ N ₅ O ₃ S: 468.2064, found: 468.2068;

1H NMR (300 MHz, DMSO-d ₆ ) δ 8.99 (t, 1H), 8.65 (d, 1H), 7.86 (d, 1H), 7.70 - 7.59 (m, 2H), 7.39 (d, 1H), 5.40 - 5.25 (m, 1H), 4.89 (d, 1H), 4.71 (d, 1H), 4.30 (d, 2H), 4.00 (brs, 1H), 3.80 - 3.60 (m, 2H), 3.50 - 3.34 (m, overlaps with solvent peak), 3.21 - 3.08 (m, 2H), 1.68 -1.45 (m, 5H), 0.86 (d, 6H).

Example 193. N-(2-((R)-4-cyanothiazolidin-3-yl)-2-oxoethyl)-6-(3R,4S,5S)-4-hydroxy-3,4,5-trimethylpiperidin-1-yl)quinoline-4-carboxamide

DIPEA (194 μL, 1.11 mmol) was added to a stirred suspension of 6-((3R,4s,5S)-4-hydroxy-3,4,5-trimethylpiperidin-1-yl)quinoline-4-carboxylic acid, intermediate 367 (70 mg, 0.22 mmol), (R)-3-glycylthiazolidine-4-carbonitrile hydrochloride, intermediate 4 (92 mg, 0.45 mmol), HOBt (90 mg, 0.67 mmol), and EDC (128 mg, 0.67 mmol) in MeCN (5 mL) and EtOAc (5 mL) at 25 °C and the reaction mixture was stirred at 25 °C for 15 h. The reaction mixture was concentrated under reduced pressure and further diluted with EtOAc (100 mL) and saturated _NaHCO3 solution (20 mL, aq). The aq. layer was extracted with EtOAc (4x75 mL). The organic layers were combined and washed with H2O (3x25 mL). The organic layer was dried over Na2SO4, filtered and evaporated. The residue was purified by preparative HPLC, PrepMethod C (15-25% gradient) to give the title compound ( _0.078 g, 75%) as a yellow solid; HRMS (ESI) m/z [M+H]+ _calcd for _C24H30N5O3S : 468.2064, found: _468.2072 ;

1H NMR (300 MHz, DMSO-d ₆ ) δ 8.98 (t, 1H), 8.61 (d, 1H), 7.83 (d, 1H), 7.68 - 7.58 (m, 2H), 7.34 (d, 1H), 5.80 - 5.22 (m, 1H), 4.87 (d, 1H), 4.70 (d, 1H), 4.27 (d, 2H), 4.00 (s, 1H), 3.65 - 3.45 (m, 2H), 3.44 - 3.34 (m, overlaps with solvent peak), 2.79 (t, 2H), 1.74 - 1.50 (m, 2H), 1.07 (s, 3H), 1.00 - 0.85 (m, 6H).

Example 194 -4-carboxamide

HATU (0.110 g, 0.29 mmol) was added to a stirred mixture of 6-((1R,5S)-9-oxa-3azabicyclo[3.3.1]nonan-3-yl)quinoline-4-carboxylic acid, intermediate 369 (0.098 g, 0.24 mmol), and DIPEA (0.210 mL, 1.20 mmol) in a mixture of MeCN (1.1 mL) and EtOAc (1.1 mL) at rt. The reaction mixture was stirred for 1 min, after which intermediate 4, hydro

- 248 048482 (R)-3-glycylthiazolidine-4-carbonitrile chloride (0.060 g, 0.29 mmol). The reaction mixture was stirred for 1 h at rt. The reaction mixture was diluted with EtOAc (15 mL) and washed with sat. _NaHCO3 (8 mL, aq.) then _H2O (2x2 mL). _The organic layer was dried over _Na2SO4 , filtered and concentrated. The residue was purified by flash chromatography (EtOAc:MeOH, gradient: 0% then 10%). The residue was further purified by preparative HPLC, PrepMethod G (gradient 5-35%) to give the title compound (0.053 g, 49%) as an orange solid; HRMS (ESI) mass/charge [M+H]+ calcd for C ₂₃ H ₂₆ N ₅ O ₃ S: 452.1750 found value: 452.1746;

^1H NMR (500 MHz, DMSO- _d6 ) δ 9.03 (t, 1H), 8.66 (d, 1H), 7.91 (d, 1H), 7.73 - 7.65 (m, 2H), 7.39 (d, 1H), 5.28 - 5.32 (m, 1H), 4.90 (d, 1H), 4.70 (d, 1H), 4.37 - 4.25 (m, 2H), 4.08 - 4.02 (m, 2H), 3.89 (d, 2H), 3.44 - 3.37 (m, 2H), 3.18 - 3.10 (m, 2H), 2.37 - 2.23 (m, 1H), 2.00 - 1.89 (m, 2H), 1.84 - 1.75 (m, 2H), 1.58 - 1.44 (m, 1H).

Example 195

DIPEA (200 μl, 1.14 mmol) was added to a stirred suspension of 6-(4-fluoro-1-methylpiperidin-4-yl)quinoline-4-carboxylic acid, intermediate 373 (110 mg, 0.38 mmol), (R)-3-glycylthiozolidine-4-carbonitrile hydrochloride, intermediate 4 (119 mg, 0.57 mmol), HOBt (88 mg, 0.57 mmol) and EDC (110 mg, 0.57 mmol) in MeCN (6 ml) and EtOAc (6 ml) at 25 °C and the reaction mixture was stirred at 50 °C for 2 h. The solvent was removed under reduced pressure. The reaction mixture was diluted with EtOAc and washed successively with _H2O . _The organic layer was dried over _Na2SO4 , filtered and evaporated. The residue was purified by preparative HPLC, PrepMethod I (24-33% gradient). The residue was further purified by preparative SFC, PrepMethod SFC-B, to give the title compound ( _0.025 g, 15%) as a white solid; HRMS (ESI) m/z [M _{+H]+ calcd for C22H25FN5O2S : 442.1708} found: 442.1698;

1H NMR (400 MHz, CD3OD) δ 8.97 (d, 1H), 8.52 (s, 1H), 8.15 (d, 1H), 7.95 (dd, 1H), 7.71 (d , 1H), 5.68 5.38 (m, 1H), 4.87 - 4.72 (m, 2H), 4.52 - 4.36 (m, 2H), 3.57 - 3.35 (m, 2H), 3.00 - 2.83 (m, 2H), 2.65 -2.50 (t, 2H ), 2.49 - 2.36 (m, 5H), 2.25 - 2.06 (m, 2H).

Example 196. (R)-N-(2-(4-cyanothiazolidin-3-yl)-2-oxoethyl)-6-(1H-pyrazol-5-yl)quinoline-4-carboxamide

To a suspension of 6-(1H-pyrazol-5-yl)quinoline-4-carboxylic acid, intermediate 374 (32 mg, 0.13 mmol), and (R)-3-glycylthiazolidine-4-carbonitrile hydrochloride, intermediate 4 (28 mg, 0.13 mmol), in EtOAc (0.7 mL) and MeCN (0.7 mL) were added HATU (64 mg, 0.17 mmol) and DIPEA (0.070 mL, 0.40 mmol). The solution was stirred at rt overnight and stirred for an additional 24 h. The reaction mixture was evaporated and the residue was purified by preparative SFC, PrepMethod SFC-C (27-32% gradient), to give the title compound (8.9 mg, 17%); HRMS (ESI) mass/charge [M+H]+ calcd for C ₁₉ H ₁₇ N ₆ O ₂ S: 393.1128 found value: 393.1130;

1H NMR (500 MHz, CD3OD) δ 8.91 (d, 1H), 8.87 (s, 1H), 8.34 (d, 1H), 8.13 (d, 1H), 7.72 (d, 1H), 7.66 (d, 1H), 7.06 - 7.02 (m, 1H), 5.43 - 5.38 (m, 1H), 4.89 - 4.70 (m, overlaps with solvent peak), 4.52 4.39 (m, 2H), 3.47 - 3.35 (m, 2H).

Example 197. (R)-N-(2-(4-cyanothiazolidin-3-yl)-2-oxoethyl)-6-(1-isopropyl-1H-pyrazol-5yl)quinoline-4-carboxamide

To a suspension of 6-(1-isopropyl-1H-pyrazol-5-yl)quinoline-4-carboxylic acid, intermediate 375 (56 mg, 0.20 mmol), and (R)-3-glycylthiazolidine-4-carbonitrile hydrochloride, intermediate 4 (41 mg, 0.20 mmol), in EtOAc (0.7 mL) and MeCN (0.7 mL) were added HATU (95 mg, 0.25 mmol) and DIPEA (0.104 mL, 0.60 mmol). The solution was stirred at rt overnight and stirred for an additional 24 h. The reaction mixture was evaporated and the residue was purified by

- 249 048482 preparative SFC, PrepMethod SFC-C (27-32 _% gradient), to give the title compound (29 mg, 33%); HRMS (ESI) m/z [M _{+H]+ calcd for C22H23N6O2S : 435.1598} found: 435.1590;

¹ H NMR (600 MHz, DMSO-d ₆ ) δ 9.15 (t, 1H), 8.87 (d, 1H), 8.73 (d, 1H), 8.46 (s, 1H), 8.13 - 8.08 (m, 2H), 8.05 (d, 1H), 7.49 (d, 1H), 5.42 (dd, 1H), 4.93 (d, 1H), 4.74 (d, 1H), 4.62 - 4.52 (m, 1H), 4.37 (d, 2H), 3.45 - 3.32 (m, overlaps with solvent peak), 1.52 - 1.46 (m, 6H).

Example 198

DIPEA (614 μL, 3.51 mmol) was added to a solution of rac-(R)-6-(3-fluoro-3-methylpyrrolidin-1yl)quinoline-4-carboxylic acid, intermediate 377 (439 mg, 0.35 mmol), (R)-3-glycylthiazolidine-4-carbonitrile hydrochloride, intermediate 4 (146 mg, 0.70 mmol), and HATU (401 mg, 1.05 mmol) in MeCN (5 mL) and EtOAc (5 mL). The reaction mixture was stirred at 10 °C overnight and then concentrated under reduced pressure. The reaction mixture was diluted with _saturated NaHCO3 (50 mL, aq.) and extracted with EtOAc (6 x 50 mL). The organic layers were combined and washed with brine (5 x 200 mL). The combined organic layers were dried over Na ₂ SO ₄ , filtered and evaporated. The crude product was purified by preparative HPLC, PrepMethod F (gradient: 15-25%) to give the title compound (0.064 g, 42%) as a yellow solid; FIRMS (ESI) m/z [M+H]+ calcd for C ₂₁ H ₂₃ FN ₅ O ₂ S: 428.1550 found: 428.1538;

¹ H NMR (300 MHz, DMSO-d ₆ ) δ 8.99 (t, 1H), 8.61 (d, 1H), 7.91 (d, 1H), 7.40 (d, 1H), 7.36 - 7.24 (m, 2H), 5.33 (dd, 1H), 4.89 (d, 1H), 4.71 (d, 1H), 4.37 - 4.26 (m, 2H), 3.68 - 3.34 (m, overlaps with solvent peak), 2.34 - 2.02 (m, 2H), 1.70 - 1.57 (m, 3H).

Example 199 N-(2-((R)-4-cyanothiazolidin-3-yl)-2-oxoethyl)-6-((R*)-2-cyclopropylpyrrolidin-1yl)quinoline-4-carboxamide, isomer 1

isomer 1

Example 200

isomer 2

DIPEA (1.54 ml, 8.81 mmol) was added to a stirred suspension of rac-(R)-6-(2-cyclopropylpyrrolidin-1-yl)quinoline-4-carboxylic acid, intermediate 421 (335 mg, 0.44 mmol), (R)-3-glycylthiazolidine-4-carbonitrile hydrochloride, intermediate 4 (275 mg, 1.32 mmol), HOBt (472 mg, 3.08 mmol), and EDC (591 mg, 3.08 mmol) in MeCN (5 ml) and EtOAc (5 ml). The reaction mixture was stirred at 10 °C overnight and then concentrated under reduced pressure. The residue was dissolved in a mixture of sat. NaHCO ₃ (80 ml, aq.) and EtOAc (100 ml). The aq. layer was extracted with EtOAc (4x100 ml). The organic layers were combined and washed with H2O (3x75 ml). The aq. layers _were combined and extracted with EtOAc (3x25 ml). All organic layers were combined, dried over _Na2SO4 , filtered and evaporated. The residue was purified by preparative HPLC, PrepMethod C (gradient: 23-35%). The isomers were separated by preparative chiral HPLC on a CHIRALPAK® IA column (5 μm, 250x20 mm i.d.) using an isocratic run of 30% MeOH in hexane/DCM (0.5% 2 M NH3 in MeOH) 3/1 as mobile phase and a flow rate of 20 ml/min; the first eluting compound to give the title compound, isomer 1, Example 199 (0.030 g, 44%), as a yellow solid; HRMS (ESI) m/z [M _{+H]+ calcd for C23H26N5O2S : 436.1802} found: _436.1798 ;

^1H NMR (300 MHz, DMSO-d6) δ 8.89 (t, 1H), 8.54 (d, 1H), 7.83 (d, 1H), 7.43 - 7.24 (m, 3H ), 5.40 - 5.25 (m, 1H), 4.90 (d, 1H), 4.72 (d, 1H), 4.27 (qd, 2H), 3.90 - 3.70 (m, 1H), 3.62 3.45 (m, 1H), 3.43 - 3.10 (m, re

- 250 048482 overlaps with the solvent peak), 2.19 - 1.80 (m, 4H), 1.02 - 0.87 (m, 1H), 0.60 - 0.41 (m, 2H), 0.40 - 0.24 (m, 1H), 0.22 - 0.08 (m, 1H);

and the second eluting compound to give the title compound, isomer 2, Example 200 (0.025 g, 37%), as a yellow solid; HRMS (ESI) m/z [M _{+H]+ calcd for C23H26N5O2S : 436.1802} found: 436.1796 _;

1H NMR (300 MHz, DMSO-d6) δ 8.90 (t, 1H), 8.54 (d, 1H), 7.83 (d, 1H), 7.50 - 7.20 (m, 3H), 5.82 - 5.25 (m, 1H), 4.89 (d, 1H), 4.72 (d, 1H), 4.35 - 4.19 (m, 2H), 3.90 - 3.74 (m, 1H), 3.53 (t, 1H), 3.45 -3.10 (m, overlaps with solvent peak), 2.17 - 1.71 (m, 4H), 1.05 - 0.85 (m, 1H), 0.58 - 0.40 (m, 2H), 0.40 - 0.27 (m, 1H), 0.23 - 0.08 (m, 1H).

Example 201 , isomer 1 isomer 1

Example 202 carboxamide, isomer 2

DIPEA (1874 μL, 10.73 mmol) was added to a stirred suspension of rac-(R)-6-(3-methyl-2-oxopyrrolidin-1-yl)quinoline-4-carboxylic acid, intermediate 379 (290 mg, 1.07 mmol), (R)-3-glycylthiazolidine-4-carbonitrile hydrochloride, intermediate 4 (446 mg, 2.15 mmol), HOBt (822 mg, 5.36 mmol), and EDC (1028 mg, 5.36 mmol) in MeCN (10 mL) and EtOAc (10 mL) at 15 °C. The reaction mixture was stirred at 50 °C for 2 h and then concentrated under reduced pressure. The residue was dissolved with a mixture of sat. NaHCO ₃ solution (60 mL, aq.) and EtOAc (100 mL). The aq. layer was extracted with EtOAc (5x100 mL). The organic layers were combined and washed with H ₂ O (3x50 mL). The aq. layers were combined and extracted with EtOAc (4x25 mL). All organic layers were combined, dried over Na ₂ SO ₄ , filtered and evaporated. The residue was purified by preparative HPLC, PrepMethod F (gradient: 15-35%). The isomers were separated by preparative chiral HPLC on a CHIRALPAK® IE column (5 μm, 250 x 20 mm i.d.) using an isocratic run of 50% MeOH in hexane/DCM (0.5% 2 M NH3 in MeOH) 3/1 as the mobile phase and a flow rate of 20 ml/min;

the first eluting compound to give the title compound, isomer 1, example 201 (0.052 g, 49%) _, as a white solid; HRMS (ESI) m/z [M ₊ H] ⁺ calcd for _C21H22N5O3S : 424.1438 found: 424.1438 _;

1H NMR (400 MHz, DMSO-d ₆ ) δ 9.10 (t, 1H), 8.90 (d, 1H), 8.55 (dd, 1H), 8.30 (d, 1H), 8.08 (d, 1H), 7.56 (d, 1H), 5.40 - 5.30 (m, 1H), 4.90 (d, 1H), 4.72 (d, 1H), 4.33 (d, 2H), 3.98 - 3.74 (m, 2H), 3.44 - 3.35 (m, overlaps with solvent peak), 2.78 - 2.65 (m, 1H), 2.42 - 2.31 (m, 1H), 1.85 - 1.65 (m, 1H), 1.20 (d, 3H);

and the second eluting compound to give the title compound, isomer 2, Example 202 (0.048 g, 45%), as a white solid; HRMS (ESI) m/z [M ₊ H] ⁺ calcd for _C21H22N5O3S : _424.1438 found: _424.1418 ;

1H NMR (400 MHz, DMSO-d6) δ 9.10 (t, 1H), 8.90 (d, 1H), 8.55 (dd, 1H), 8.32 (d, 1H), 8.08 (d, 1H), 7.56 (d, 1H), 5.42 - 5.29 (m, 1H), 4.90 (d, 1H), 4.72 (d, 1H), 4.54 - 4.17 (m, 2H), 3.99 -3.82 (m, 2H), 3.51 - 3.34 (m, overlaps with solvent peak), 2.78 - 2.61 (m, 1H), 2.43 - 2 25 (m, 1H), 1.85 - 1.65 (m, 1H), 1.20 (d, 3H).

Example 203 , isomer 1 isomer 1

Example 204 , isomer 2

- 251 048482

isomer 2

DIPEA (509 mg, 3.94 mmol) was added to a stirred suspension of rac-(R)-6-(3-methyl-2-oxopiperidin-1-yl)quinoline-4-carboxylic acid, intermediate 381 (280 mg, 0.98 mmol), (R)-3-glycylthiazolidine-4-carbonitrile hydrochloride, intermediate 4 (337 mg, 1.97 mmol), T3P (50% in EtOAc, 1253 mg, 3.94 mmol) in DMF (5 mL) under air. The reaction mixture was stirred at 25 °C for 6 h. The solvent was removed under reduced pressure. The residue was purified by preparative TLC (DCM:MeOH; 18:1). The residue was further purified by preparative HPLC, PrepMethod B (gradient: 18-38%). The isomers were separated by preparative chiral HPLC on a CHIRALPAK® IE column (5 μm, 250x20 mm i.d.) using an isocratic run of 50% MeOH in hexane/DCM (0.5% 2 M NH3 in MeOH) 3/1 as the mobile phase and a flow rate of 20 ml/min;

the first eluting compound to give the title compound, isomer 1, example 203 (0.025 g, 25%), as a white solid; HRMS (ESI) m/z [M _{+H]+ calcd for C22H24N5O3S : 438.1594} found: 438.1592 _;

1H NMR (300 MHz, DMSO-d ₆ ) δ 9.11 (t, 1H), 8.94 (d, 1H), 8.35 - 8.20 (m, 1H), 8.01 (d, 1H), 7.75 (dd, 1H), 7.55 (d, 1H), 5.42 - 5.22 (m, 1H), 4.88 (d, 1H), 4.70 (d, 1H), 4.31 (d, 2H), 3.88 - 3.68 (m, 2H), 3.44 - 3.34 (m, overlaps with solvent peak), 2.63-2.53 (m, overlaps with solvent peak), 2.06 - 1.89 (m, 3H), 1.71 - 1.51 (m, 1H), 1.18 (d, 3H);

and the second eluting compound to give the title compound, isomer 2, Example 204 (0.071 g, 71%), as a white solid; HRMS (ESI) m/z [M ₊ H] ⁺ calcd for _C22H24N5O3S : _438.1594 found: 438.1588 _;

1H NMR (300 MHz, DMSO-d6) δ 9.12 (t, 1H), 8.94 (d, 1H), 8.40 - 8.20 (m, 1H), 8.01 (d, 1H), 7.75 (dd, 1H), 7.55 (d, 1H), 5.45 - 5.25 (m, 1H), 4.88 (d, 1H), 4.70 (d, 1H), 4.31 (d, 2H), 3.94 - 3.63 (m, 2H), 3.44 - 3.33 (m, overlaps with solvent peak), 2.61 - 2.52 (m, overlaps with solvent peak), 2.15 1.80 (m, 3H), 1.71 - 1.53 (m, 1H), 1.18 (d, 3H).

Example 205. (R)-N-(2-(4-cyanothiazolidin-3-yl)-2-oxoethyl)-6-(4-fluoropiperidin-1-yl)quinoline-4-carboxamide

DIPEA (6.11 mL, 35.0 mmol) was added to a solution of 6-(4-fluoropiperidin-1-yl)quinoline-4-carboxylic acid, intermediate 383 (600 mg, 0.87 mmol), (R)-3-glycylthiazolidine-4-carbonitrile hydrochloride, intermediate 4 (363 mg, 1.75 mmol), EDC (839 mg, 4.37 mmol), and HOBt (670 mg, 4.37 mmol) in MeCN (10 mL) and EtOAc (10 mL). The reaction mixture was stirred at 15 °C for 15 h and then concentrated under reduced pressure. The reaction mixture was diluted with EtOAc (100 mL) and sat. _NaHCO3 solution (60 mL, aq.) and extracted with EtOAc (5x100 mL). _The organic layer was dried over _Na2SO4 , filtered and evaporated. The crude product was purified by preparative HPLC, PrepMethod I (gradient: 40-52%), to give the title compound ( _0.21 g, 56%) as a yellow solid; HRMS (ESI) m/z [M ₊ H] ⁺ calcd for _C21H23FN5O2S : _428.1550 , found: 428.1548;

1H NMR (300 MHz, DMSO- _d6 ) δ 9.00 (t, 1H), 8.66 (d, 1H), 7.88 (d, 1H), 7.77 - 7.62 (m, 2H ), 7.38 (d, 1H), 5.31 (dd, 1H), 5.01 -4.54 (m, 3H), 4.43 - 4.16 (m, 2H), 3.70 - 3.33 (m, overlapping solvent), 2.13 - 1.90 (m, 2H), 1.89-1.71 (m, 2H).

Example 206. 6-(3-azabicyclo[3.1.0]hexan-3-yl)-N-(2-((R)-4-cyanothiazolidin-3-yl)-2oxoethyl)quinoline-4-carboxamide

DIPEA (927 µL, 5.31 mmol) was added to a solution of 6-(3-azabicyclo[3.1.0]hexan-3-yl)quinoline-4-carboxylic acid, intermediate 385 (368 mg, 0.53 mmol), (R)-3-glycylthiazolidine-4-carbonitrile hydrochloride, intermediate 4 (221 mg, 1.06 mmol), and HATU (604 mg, 1.59 mmol) in MeCN (5 mL) and EtOAc (5 mL). The reaction mixture was stirred at 10 °C overnight and

- 252 048482 was then concentrated under reduced pressure. The reaction mixture was diluted with sat. NaHCO3 solution (50 mL, aq.) and extracted with EtOAc (6 x 50 mL). The organic layers were combined and washed with brine (5 x 200 mL). The combined organic layers were dried over Na ₂ SO ₄ , filtered and evaporated. The crude product was purified by preparative HPLC, PrepMethod P (gradient: 15-25%), affording the title compound (0.132 g, 61%) as an orange solid; HRMS (ESI) m/z [M+H]+ calcd for C ₂₁ H ₂₂ N ₅ O ₂ S: 408.1488, found: 408.1486;

¹ H NMR (300 MHz, DMSO-d ₆ ) δ 8.92 (t, 1H), 8.56 (d, 1H), 7.83 (d, 1H), 7.35 (d, 1H), 7.29 (dd, 1H), 7.23 (d, 1H), 5.74 - 5.31 (m, 1H), 4.89 (d, 1H), 4.72 (d, 1H), 4.27 (d, 2H), 3.75 - 3.55 (m, 2H), 3.39 - 3.32 (m, overlaps with solvent peak), 1.82 - 1.60 (m, 2H), 0.85 - 0.65 (m, 1H), 0.35 - 0.15 (m, 1H).

Example 207 N-(2-((R)-4-cyanothiazolidin-3-yl)-2-oxoethyl)-6-((S)-3-methoxypyrrolidin-1yl)quinoline-4-carboxamide

DIPEA (411 μL, 2.35 mmol) was added to a solution of (S)-6-(3-methoxypyrrolidin-1-yl)quinoline-4-carboxylic acid, intermediate 387 (160 mg, 0.59 mmol), (R)-3-glycylthiazolidine-4-carbonitrile hydrochloride, intermediate 4 (101 mg, 0.59 mmol), and HATU (335 mg, 0.88 mmol) in DMF (5 mL). The reaction mixture was stirred at 25 °C for 2 h and then concentrated under reduced pressure. The crude product was purified by preparative TLC (DCM:MeOH; 18:1) and further purified by preparative HPLC, PrepMethod D (gradient: 25-33%) to give the title compound (0.049 g, 19%) as a yellow solid; HRMS (ESI) m/z [M+H] ⁺ calcd for C ₂₁ H ₂₄ N ₅ O ₃ S: 426.1594, found: 426.1584;

¹ H NMR (300 MHz, DMSO-d6) δ 8.93 (t, 1H), 8.56 (d, 1H), 7.86 (d, 1H), 7.39 - 7.19 (m, 3H), 5.31 (dd, 1H), 4.88 (d, 1H), 4.70 (d, 1H), 4.28 (d, 2H), 4.21 - 4.01 (m, 1H), 3.60 - 3.34 (m, overlaps with solvent peak), 2.20-1.99 (m, 2H).

Example 208. N-(2-((R)-4-cyanothiazolidin-3-yl)-2-oxoethyl)-6-((1R,5S,6R)-6-(trifluoromethyl)-3azabicyclo[3.1.0]hexan-3-yl)quinoline-4-carboxamide

DIPEA (742 μL, 4.25 mmol) was added to a solution of 6-((1R,5S,6r)-6-(trifluoromethyl)-3azabicyclo[3.1.0]hexan-3-yl)quinoline-4-carboxylic acid, intermediate 389 (349 mg, 0.42 mmol), (R)-3-glycylthiazolidine-4-carbonitrile hydrochloride, intermediate 4 (176 mg, 0.85 mmol), EDC (407 mg, 2.12 mmol), and HOBt (325 mg, 2.12 mmol) in MeCN (9 mL) and EtOAc (9 mL). The reaction mixture was stirred at 40 °C for 3 h and then concentrated under reduced pressure. The reaction mixture was diluted with EtOAc (100 mL) and washed with sat. _NaHCO3 (3x200 mL, aq.) and brine (3x200 mL). The organic layer was dried over Na2SO4, filtered and evaporated. The crude product was purified by preparative _HPLC , PrepMethod C (gradient: 20-55%), to give the title compound (0.201 g, 99%) as _a yellow solid; HRMS (ESI) m/z [M ₊ H] ⁺ calcd for _{C22H21F3N5O2S} : 476.1362, found: _476.1356 ;

¹ H NMR (300 MHz, DMSO-d6) δ 8.92 (t, 1H), 8.60 (d, 1H), 7.88 (m, 1H), 7.40 - 7.28 (m, 3H), 5.40 - 5.20 (m, 1H), 4.89 (d, 1H), 4.72 (d, 1H), 4.28 (d, 2H), 3.79 (d, 2H), 3.43 - 3.34 (m, overlaps with solvent peak), 2.33 - 2.10 (m, 2H), 1.98 - 1.73 (m, 1H).

Example 209

DIPEA (560 µL, 3.21 mmol) was added to a suspension of 6-(7-azabicyclo[2.2.1]heptan-7-yl)quinoline-4-carboxylic acid, intermediate 391 (43 mg, 0.16 mmol), (R)-3-glycylthiazolidine-4-carbonitrile hydrochloride, intermediate 4 (67 mg, 0.32 mmol), EDC (307 mg, 1.60 mmol), and HOBt (245 mg, 1.60 mmol) in MeCN (3 mL) and EtOAc (3 mL). The reaction mixture was stirred

- 253 048482 at 10 °C overnight and then concentrated under reduced pressure. The reaction mixture was diluted with sat. NaHCO3 solution (100 mL, aq.), and extracted with EtOAc (6 x 100 mL), and washed with brine (5 x 200 mL). The organic layer was dried over Na ₂ SO ₄ , filtered and evaporated. The crude product was purified by preparative HPLC, PrepMethod C (gradient: 10-35%), to give the title compound (0.025 g, 37%) as a yellow solid; HRMS (ESI) m/z [M+H]+ calcd for C ₂₂ H ₂₄ N ₅ O ₂ S: 422.1646, found: 422.1658;

1H NMR (300 MHz, DMSO-d6) δ 9.10 - 8.90 (m, 1H), 8.64 (d, 1H), 7.84 (d, 1H), 7.75 - 7.60 (m, 1H), 7.56 (dd, 1H), 7.36 (d, 1H), 5.34 - 5.28 (m, 1H), 4.88 (d, 1H), 4.70 (d, 1H), 4.43 (brs, 2H), 4.28 (d, 2H), 3.41 - 3.36 (m, overlaps with solvent peak), 1.85 - 1.64 (m, 4H), 1.58 - 1.35 (m, 4H).

Example 210 4-carboxamide

TEA (291 μL, 2.08 mmol) was added to a suspension of 6-(2-azabicyclo[2.2.1]heptan-2-yl)quinoline-4-carboxylic acid, intermediate 393 (75 mg, 0.10 mmol), (R)-3-glycylthiazolidine-4-carbonitrile hydrochloride, intermediate 4 (43 mg, 0.21 mmol), EDC (100 mg, 0.52 mmol), and HOBt (80 mg, 0.52 mmol) in MeCN (5 mL) and EtOAc (5 mL). The reaction mixture was stirred at 10 °C overnight and then concentrated under reduced pressure. The reaction mixture was partitioned between sat. _NaHCO3 solution (50 mL, aq.) and EtOAc (100 mL), extracted with EtOAc (4x100 mL) and washed with brine (5x200 mL). _The organic layer was dried over _Na2SO4 , filtered and evaporated. The crude _product was purified by preparative HPLC, PrepMethod C (gradient: 10-40%), to give the title compound (0.13 g) as a yellow solid; HRMS (ESI) m/z [M _{+H] + calcd for C22H24N5O2S :} ^422.1646 _, found: 422.1658;

¹ H NMR (300 MHz, DMSO-d ₆ ) δ 8.89 (t, 1H), 8.51 (d, 1H), 7.81 (d, 1H), 7.40 - 7.10 (m, 3H), 5.40 - 5.20 (m, 1H), 4.87 (d, 1H), 4.70 (d, 1H), 4.45 - 4.15 (m, 3H), 3.60 - 3.34 (m, overlaps with solvent peak), 2.85 (d, 1H), 2.61 (s, 1H), 1.80 - 1.42 (m, 5H), 1.40 -1.15 (m, 1H).

Example 211 N-(2-((R)-4-cyanothiazolidin-3-yl)-2-oxoethyl)-6-((R)-2-methylpyrrolidin-1 yl)quinoline-4-carboxamide

DIPEA (454 mg, 3.51 mmol) was added to a solution of (R)-6-(2-methylpyrrolidin-1-yl)quinoline-4-carboxylic acid, intermediate 395 (150 mg, 0.59 mmol), (R)-3-glycylthiazolidine-4-carbonitrile hydrochloride, intermediate 4 (150 mg, 0.88 mmol), and HATU (445 mg, 1.17 mmol) in MeCN (5 mL) and EtOAc (5 mL). The reaction mixture was stirred at 25 °C for 3 h and then concentrated under reduced pressure. The crude product was purified by preparative TLC (DCM:MeOH; 19:1) and further purified by preparative HPLC, PrepMethod F (gradient: 15-32%) to give the title compound (0.050 g, 21%) as an orange solid; HRMS (ESI) m/z [M+H] ⁺ calcd for C ₂₁ H ₂₄ N ₅ O ₂ S: 410.1646, found: 410.1634;

1H NMR (400 MHz, DMSO-d6) δ 8.92 (t, 1H), 8.55 (d, 1H), 7.86 (d, 1H), 7.39 - 7.29 (m, 2H), 7.25 (d, 1H), 5.40 - 5.20 (m, 1H), 4.89 (d, 1H), 4.73 (d, 1H), 4.29 (d, 2H), 4.15 - 4.00 (m, 1H), 3.55 -3.20 (m, overlaps with solvent peak), 2.16 - 1.90 (m, 3H), 1.82 -1.65 (m, 1H), 1.17 (d, 3H).

Example 212

DIPEA (549 μL, 3.14 mmol) was added to a suspension of (S)-6-(2-(methoxymethyl)pyrrolidin-1yl)quinoline-4-carboxylic acid, intermediate 397 (150 mg, 0.52 mmol), (R)-3-glycylthiazolidine-4-carbonitrile hydrochloride, intermediate 4 (163 mg, 0.79 mmol), EDC (201 mg, 1.05 mmol), and HOBt (160 mg, 1.05 mmol) in MeCN (4 mL) and EtOAc (4 mL). The reaction mixture was stirred

- 254 048482 was stirred at 50 °C for 3 h and then concentrated under reduced pressure. The reaction mixture was diluted with EtOAc and washed with H2O. _The organic layer was dried over _Na2SO4 , filtered and evaporated. The crude product was purified by preparative HPLC, PrepMethod P (gradient: 15-25%), to give the title compound ( _0.205 g, 89%) as a yellow solid; HRMS (ESI) m/z [M+ _H ]+ calcd for _C22H26N5O3S : 440.1750, found: _440.1772 ;

1H NMR (300 MHz, DMSO-d6) δ 8.91 (t, 1H), 8.55 (d, 1H), 7.85 (d, 1H), 7.41 - 7.31 (m, 2H), 7.27 (d, 1H), 5.30 (dd, 1H), 4.87 (d, 1H), 4.70 (d, 1H), 4.27 (d, 2H), 4.06 (brs, 1H), 3.54 - 3.10 (m, overlaps with solvent peak), 2.13 - 1.93 (m, 4H).

Example 213

DIPEA (279 mg, 2.16 mmol) was added to a solution of 6-((3S,4S)-3,4-difluoropyrrolidine-1-yl)quinoline-4-carboxylic acid, intermediate 399 (100 mg, 0.36 mmol), (R)-3-glycylthiazolidine-4-carbonitrile hydrochloride, intermediate 4 (92 mg, 0.54 mmol), and HATU (273 mg, 0.72 mmol) in MeCN (2 mL) and EtOAc (2 mL). The reaction mixture was stirred at 25 °C for 3 h and then concentrated under reduced pressure. The crude product was purified by preparative TLC (DCM:MeOH; 20:1) and further purified by preparative HPLC, PrepMethod F (gradient: 17-35%) to give the title compound (0.063 g, 40%) as a red solid;

HRMS (ESI) mass/charge [M+H]+ calcd for C ₂₀ H ₂₀ F ₂ N ₅ O ₂ S: 432.1300, found value: 432.1310;

¹ H NMR (400 MHz, DMSO-d6) δ 9.10 (t, 1H), 8.75 (d, 1H), 8.00 (d, 1H), 7.50 - 7.25 (m, 3H), 5.70 - 5.25 (m, 3H), 4.91 (d, 1H), 4.72 (d, 1H), 4.45 - 4.25 (m, 2H), 3.95 - 3.65 (m, 4H), 3.47 - 3.33 (m, overlaps with solvent peak).

Example 214

DIPEA (557 mg, 4.31 mmol) was added to a solution of rac-6-((3R,4R)-3,4-difluoropyrrolidin-1yl)quinoline-4-carboxylic acid, intermediate 401 (200 mg, 0.72 mmol), (R)-3-glycylthiazolidine-4-carbonitrile hydrochloride, intermediate 4 (185 mg, 1.08 mmol), and HATU (547 mg, 1.44 mmol) in MeCN (4 mL) and EtOAc (4 mL). The reaction mixture was stirred at 25 °C for 3 h and then concentrated under reduced pressure. The crude product was purified by preparative TLC (DCM:MeOH; 20:1) and the isomers were separated by preparative chiral HPLC on a CHIRAL ART Cellulose-SB column (5 μm, 250x20 mm i.d.) using an isocratic run of 30% MeOH in hexane/DCM (0.5% 2 M _NH3 in MeOH) 3/1 as the mobile phase and a flow rate of 20 ml/min;

the first eluting compound to give the title compound, Example 214 (0.080 g, 26%), as a yellow solid; HRMS (ESI) m/z [M+H]+ calcd for C20H20F2N5O2S: 432.1300, found: 432.1286;

1H NMR (400 MHz, DMSO-d6) δ 8.97 (t, 1H), 8.63 (d, 1H), 7.93 (d, 1H), 7.50 - 7.28 (m, 3H), 5.65 - 5.38 (m, 2H), 5.34 (dd, 1H), 4.90 (d, 1H), 4.72 (d, 1H), 4.37 - 4.27 (m, 2H), 3.92 - 3.68 (m, 4H), 3.49 -3.34 (m, overlaps with solvent peak).

Example 215

Ω

DIPEA (0.078 mL, 0.45 mmol) was added to a solution of 6-(2,4-dimethyloxazol-5-yl)quinoline-4-carboxylic acid, intermediate 402 (30 mg, 0.11 mmol), (R)-3-glycylthiazolidine-4-carbonitrile hydrochloride, intermediate 4 (23 mg, 0.11 mmol), and HATU (47 mg, 0.12 mmol) in DCM (4 mL). The reaction mixture was stirred at rt overnight. Hydro

- 255 048482 (R)-3-glycylthiazolidine-4-carbonitrileα chloride, intermediate 4 (23.22 mg, 0.11 mmol), HATU (14 mg, 0.04 mmol) and DIPEA (0.025 mL, 0.15 mmol). The reaction mixture was stirred for 2 h and diluted with DMSO. The residue was purified by preparative HPLC, PrepMethod SFC-C (gradient: 20-25%), to give the title compound (37 mg, 79%). HRMS (ESI) m/z [M+H]+ calcd for C ₂₁ H ₂₀ N ₅ O ₃ S: 422.1282, found: 422.1286;

1H NMR (600 MHz, DMSO-d ₆ ) δ 9.17 (t, 1H), 8.98 (d, 1H), 8.57 (d, 1H), 8.16 (d, 1H), 8.04 (dd, 1H), 7.62 (d, 1H), 5.33 (dd, 1H), 4.90 (d, 1H), 4.72 (d, 1H), 4.41 - 4.26 (m, 2H), 3.46 - 3.32 (m, overlaps with solvent peak), 2.48 (s, 3H), 2.40 (s, 3H).

Example 216

DIPEA (0.98 mL, 5.6 mmol) was added to a solution of 6-(3,5-dimethylisoxazol-4-yl)quinoline-4-carboxylic acid, intermediate 403 (60 mg, 0.22 mmol), (R)-3-glycylthiazolidine-4-carbonitrile hydrochloride, intermediate 4 (56 mg, 0.27 mmol), and HATU (102 mg, 0.27 mmol) in DMF (2 mL). The reaction mixture was stirred at rt overnight. The reaction mixture was diluted with DCM (15 mL) and washed with sat. _NaHCO3 (8 mL, aq.), passed through a phase separator and concentrated. The residue was purified by preparative HPLC, PrepMethod F (gradient: 5-95%) to afford the title compound (57 mg, 60% over two steps). FIRMS (ESI) m/z [M+H] ⁺ calcd for C ₂₁ H ₂₀ N ₅ O ₃ S: 422.1282, found: 422.1298;

1H NMR (600 MHz, DMSO-d ₆ ) δ 9.17 (t, 1H), 9.01 (d, 1H), 8.43 (d, 1H), 8.17 (d, 1H), 7.87 (dd, 1H), 7.60 (d, 1H), 5.33 (dd, 1H), 4.89 (d, 1H), 4.71 (d, 1H), 4.32 (qd, 2H), 3.42 - 3.34 (m, overlaps with solvent peak), 2.54 (s, 6H).

Example 217

TEA (133 μL, 0.95 mmol) was added to a suspension of 6-(2-phenyl-1H-imidazol-1-yl)quinoline-4-carboxylic acid, intermediate 404 (30 mg, 0.10 mmol), (R)-3-glycylthiazolidine-4-carbonitrile hydrochloride, intermediate 4 (30 mg, 0.14 mmol), EDC (91 mg, 0.48 mmol), and HOBt (64 mg, 0.48 mmol) in MeCN (3 mL) and EtOAc (3 mL). The reaction mixture was stirred at 50 °C for 2 h and then concentrated under reduced pressure. The reaction mixture was diluted with EtOAc (60 mL) and sat. _NaHCO3 solution (30 ml, aq) was extracted with EtOAc (5x75 ml). _The combined organic layers were washed with H2O (3x25 ml), dried over _Na2SO4 , filtered and evaporated. The crude product was purified by preparative HPLC, PrepMethod C (gradient: 5-35%), to give the title compound (0.023 g, 52%) as a grey solid; HRMS (ESI) m/z [M _{+H]+ calcd for C25H21N6O2S :} ^469.1442 _, found: 469.1450 _;

¹ H NMR (300 MHz, DMSO-d6) δ 9.20 - 9.00 (m, 2H), 8.41 (d, 1H), 8.14 -8.04 (m, 1H), 7.68 (d, 1H), 7.61 - 7.51 (m, 2H), 7.38 - 7.20 (m, 6H), 5.32 (dd, 1H), 4.85 (d, 1H), 4.68 (d, 1H), 4.28 (d, 2H), 3.37 - 3.33 (m, overlaps with solvent peak).

Example 218

DIPEA (417 μL, 2.39 mmol) was added to a suspension of 6-(3-phenyl-1H-pyrrol-1-yl)quinoline-4-carboxylic acid, intermediate 405 (150 mg, 0.48 mmol), (R)-3-glycylthiazolidine-4-carbonitrile hydrochloride, intermediate 4 (149 mg, 0.72 mmol), EDC (183 mg, 0.95 mmol), and HOBt (129 mg, 0.95 mmol) in MeCN (5 mL) and EtOAc (5 mL). The reaction mixture was stirred at 50 °C for 2 h and then concentrated under reduced pressure. The reaction mixture

- 256 048482 was diluted with EtOAc (25 mL) and washed with H2O (3x10 mL). _The organic layer was dried over _Na2SO4 , filtered and evaporated. The crude product was purified by preparative TLC (DCM:MeOH; 10:1) and further purified by preparative HPLC, PrepMethod C (gradient: 40-60%), to _give the title compound (0.105 g, 47%) as _a grey solid; HRMS (ESI) _m /z [M+H] ⁺ calcd for _C26H22N5O2S : 468.1488, found: 468.1496;

1H NMR (300 MHz, DMSO-d ₆ ) δ 9.24 (t, 1H), 8.93 (d, 1H), 8.77 - 8.65 (m, 1H), 8.31 - 8.14 (m, 3H), 7.76 7.68 (m, 3H), 7.58 (d, 1H), 7.49 - 7.25 (m, 2H), 7.19 (t, 1H), 6.84 - 6.76 (m, 1H), 5.40 (dd, 1H), 4.94 (d, 1H), 4.74 (d, 1H), 4.55 - 4.23 (m, 2H), 3.52 - 3.37 (m, overlaps with solvent peak).

Example 219. (R)-N-(2-(4-cyanothiazolidin-3-yl)-2-oxoethyl)-6-(4,5,6,7-tetrahydro-1H-indol-1yl)quinoline-4-carboxamide

DIPEA (394 μL, 2.26 mmol) was added to a suspension of 6-(4,5,6,7-tetrahydro-1H-indol-1-yl)quinoline-4-carboxylic acid, intermediate 406 (50 mg, 0.15 mmol), (R)-3-glycylthiazolidine-4-carbonitrile hydrochloride, intermediate 4 (47 mg, 0.23 mmol), EDC (144 mg, 0.75 mmol), and HOBt (102 mg, 0.75 mmol) in MeCN (4 mL) and EtOAc (4 mL). The reaction mixture was stirred at 50 °C for 2 h and then concentrated under reduced pressure. The reaction mixture was diluted with EtOAc (60 mL) and sat. _NaHCO3 solution (30 ml, aq) was extracted with EtOAc (5x50 ml). The combined organic layers were washed with H2O (3x20 ml), the aqueous layers were combined and extracted with EtOAc (3x20 ml) and all organic layers were combined, dried over Na2SO4, filtered and evaporated. The crude product was purified by preparative HPLC, PrepMethod C (gradient: 40-60%), to give the title compound ( _0.020 g, 30%) as a white solid; HRMS (ESI) m/z [M ₊ H] ⁺ calcd for _C24H24N5O2S : 446.1646, found: _446.1636 ;

1H NMR (300 MHz, DMSO-d ₆ ) δ 9.25 - 9.10 (m, 1H), 8.97 (d, 1H), 8.25 (d, 1H), 8.15 (d, 1H), 7.87 (dd, 1H), 7.61 (d, 1H), 6.99 (d, 1H), 6.04 (d, 1H), 5.30 (dd, 1H), 4.87 (d, 1H), 4.71 (d, 1H), 4.40 - 4.20 (m, 2H), 3.38 - 3.35 (m, overlaps with solvent peak), 2.80 -2.52 (m, overlaps with solvent peak), 1.78 - 1.66 (m, 4H).

Example 220

DIPEA (192 μL, 1.10 mmol) was added to a suspension of (R)-6-(3-(hydroxymethyl)pyrrolidin-1yl)quinoline-4-carboxylic acid, intermediate 408 (100 mg, 0.37 mmol), (R)-3-glycylthiazolidine-4-carbonitrile hydrochloride, intermediate 4 (76 mg, 0.37 mmol), T3P (50% in EtOAc, 934 mg, 1.47 mmol) in MeCN (5 mL) and EtOAc (5 mL). The reaction mixture was stirred at 20 °C for 5 h and then concentrated under reduced pressure. The reaction mixture was diluted with EtOAc (100 mL), washed with H2O (50 mL) and brine (50 mL). _The organic layer was dried over _Na2SO4 , filtered and evaporated. The crude product was purified by preparative HPLC, PrepMethod C (gradient: 1-25%) to give the title compound (0.027 g, 17%) as a yellow solid; HRMS (ESI) m/z [M ₊ H]+ calcd for _C21H24N5O3S : 426.1594, found: _{426.1580 ;}

1H NMR (400 MHz, DMSO-d ₆ ) δ 8.92 (t, 1H), 8.56 (d, 1H), 7.86 (d, 1H), 7.37 (d, 1H), 7.29 (dd, 1H), 7.20 (d, 1H), 5.32 (dd, 1H), 4.89 (d, 1H), 4.77 - 4.68 (m, 2H), 4.30 (d, 2H), 3.53 - 3.32 (m, overlaps with solvent peak), 3.15 (dd, 1H), 2.50 - 2.42 (m, overlaps with solvent peak), 2.14 -2.02 (m, 1H), 1.86 - 1.73 (m, 1H).

Example 221

DIPEA (231 μL, 1.32 mmol) was added to a suspension of (S)-6-(3-(hydroxymethyl)pyrrolidin-1yl)quinoline-4-carboxylic acid, intermediate 410 (120 mg, 0.44 mmol), hydrochloride

- 257 048482 (R)-3-glycylthiazolidine-4-carbonitrile, intermediate 4 (92 mg, 0.44 mmol), T3P (50% in EtOAc, 1.12 g, 1.76 mmol) in MeCN (5 mL) and EtOAc (5 mL). The reaction mixture was stirred at 20 °C for 5 h and then concentrated under reduced pressure. The reaction mixture was diluted with EtOAc (100 mL), washed with H ₂ O (25 mL) and brine (25 mL). The organic layer was dried over Na ₂ SO ₄ , filtered and evaporated. The crude product was purified by preparative HPLC, PrepMethod C (gradient: 5-23%) to give the title compound (0.032 g, 17%) as a yellow solid; HRMS (ESI) m/z [ _M + _H ]+ calcd for _C21H24N5O3S : 426.1594, found: _426.1596 ;

1H NMR (400 MHz, DMSO-d ₆ ) δ 8.92 (t, 1H), 8.56 (d, 1H), 7.86 (d, 1H), 7.37 (d, 1H), 7.29 (dd, 1H), 7.20 (d, 1H), 5.32 (dd, 1H), 4.89 (d, 1H), 4.80 - 4.65 (m, 2H), 4.30 (d, 2H), 3.50 - 3.32 (m, overlaps with solvent peak), 3.15 (dd, 1H), 2.50 - 2.42 (m, overlaps with solvent peak), 2.14 -2.02 (m, 1H), 1.86 - 1.73 (m, 1H).

Example 222

DIPEA (198 µl, 1.13 mmol) was added to a suspension of 6-(1-thia-6-azaspiro[3.3]heptan-6-yl)quinoline-4-carboxylic acid, intermediate 412 (65 mg, 0.23 mmol), (R)-3-glycylthiazolidine-4-carbonitrile hydrochloride, intermediate 4 (94 mg, 0.45 mmol), EDC (131 mg, 0.68 mmol), and HOBt (92 mg, 0.68 mmol) in MeCN (5 ml) and EtOAc (5 ml). The reaction mixture was stirred at 50 °C for 2 h and then concentrated under reduced pressure. The reaction mixture was diluted with EtOAc (80 ml) and sat. _NaHCO3 solution (30 ml, aq) was extracted with EtOAc (5x75 ml). _The combined organic layers were washed with _H2O (3x50 ml), dried over _Na2SO4 , filtered and evaporated. The crude product was purified by preparative HPLC, PrepMethod B (gradient: 26-46%), to give the title compound (0.055 _{g, 55%) as a yellow solid; HRMS (ESI) m/z [M+H]+ calcd for C21H22N5O2S2 : 440.1210 ,} found: _440.1218 ;

1H NMR (300 MHz, DMSO-d ₆ ) δ 8.94 (t, 1H), 8.62 (d, 1H), 7.86 (d, 1H), 7.39 (d, 1H), 7.20 (d, 1H), 7.09 (dd, 1H), 5.51 - 5.29 (m, 1H), 4.88 (d, 1H), 4.71 (d, 1H), 4.33 -4.18 (m, 4H), 4.08 (d, 2H), 3.41 - 3.36 (m, overlaps with solvent peak), 3.22 - 3.00 (m, 4H).

Example 223

DIPEA (274 μL, 1.57 mmol) was added to a suspension of 6-(4-fluoro-4-phenylpiperidin-1-yl)quinoline-4-carboxylic acid, intermediate 415 (110 mg, 0.31 mmol), (R)-3-glycylthiazolidine-4-carbonitrile hydrochloride, intermediate 4 (98 mg, 0.47 mmol), EDC (120 mg, 0.63 mmol), and HOBt (85 mg, 0.63 mmol) in MeCN (5 mL) and EtOAc (5 mL). The reaction mixture was stirred at 50 °C for 2 h and then concentrated under reduced pressure. The reaction mixture was diluted with EtOAc (25 mL), washed with _H2O (2x15 mL), dried over _Na2SO4 , filtered and evaporated. _The crude product was purified by preparative HPLC, PrepMethod B (gradient: 59-66%), to give the title compound ( _0.060 g, 38%) as a yellow solid; HRMS (ESI) m/z [M _{+H]+ calcd for C27H27FN5O2S : 504.1864} , found: 504.1872;

1H NMR (300 MHz, CD3OD) δ 8.67 (d, 1H), 7.97 (d, 1H), 7.88 (d, 1H), 7.78 (dd, 1H), 7.53 (d, 1H), 7.50-7.25 (m, 5H), 5.33 (dd, 1H), 4.88 - 4.68 (m, overlaps with solvent peak), 4.41 (d, 2H), 4.17 - 3.99 (m, 2H), 3.58 - 3.33 (m, overlaps with solvent peak), 2.48 - 2.03 (m, 4H).

Example 224 carboxamide

TEA (142 μL, 1.02 mmol) was added to the suspension of rac-(R)-6-(3,3-difluoro-4-hydroxypyrrolidine-1

- 258 048482 yl)quinoline-4-carboxylic acid, intermediate 417 (100 mg, 0.34 mmol), (R)-3-glycylthiazolidine-4-carbonitrile hydrochloride, intermediate 4 (71 mg, 0.34 mmol), EDC (98 mg, 0.51 mmol) and HOBt (69 mg, 0.51 mmol) in MeCN (5 mL) and EtOAc (5 mL). The reaction mixture was stirred at 20 °C for 16 h, diluted with EtOAc (75 mL), washed with sat. NaHCO ₃ solution (3x25 mL, aq.), H ₂ O (20 mL), brine (20 mL), dried over Na ₂ SO ₄ , filtered and concentrated under reduced pressure. The crude product was purified by preparative HPLC, PrepMethod C (gradient: 5-30%) to give the _title compound (0.055 _g , 35%) as a yellow solid; HRMS (ESI) m/z [ _M + _H ]+ calcd for C20H20F2N5O3S: 448.1250, found: _448.1242 ;

1H NMR (400 MHz, DMSO-d ₆ ) δ 9.00 (t, 1H), 8.64 (d, 1H), 7.93 (d, 1H), 7.40 (d, 1H), 7.38 - 7.30 (m, 2H), 6.17 (d, 1H), 5.33 (dd, 1H), 4.90 (d, 1H), 4.72 (d, 1H), 4.40 (brs, 1H), 4.34 - 4.27 (d, 2H), 3.98 - 3.75 (m, 3H), 3.49 - 3.33 (m, overlaps with solvent peak).

Example 225 carboxamide, isomer 1

isomer 1

Example 226 carboxamide, isomer 2

isomer 2

DIPEA (1.17 mL, 6.70 mmol) was added to a stirred suspension of rac-6-((3R,4R)-3,4-dimethylpyrrolidin-1-yl)quinoline-4-carboxylic acid, intermediate 419 (410 mg, 0.67 mmol), (R)-3-glycylthiazolidine-4-carbonitrile hydrochloride, intermediate 4 (209 mg, 1.00 mmol), and HATU (762 mg, 2.01 mmol) in MeCN (5 mL) and EtOAc (5 mL). The reaction mixture was stirred at 4 °C for 15 h and then concentrated under reduced pressure. The residue was dissolved in a mixture of sat. NaHCO ₃ (50 mL, aq.) and EtOAc (100 mL). Aq. layer was extracted with EtOAc (3x100 ml). The organic layers were combined and washed with H2O (3x75 ml). The aq. layers were combined and extracted with EtOAc (4x25 ml). All organic layers were combined, dried _{over Na2SO4} , filtered and evaporated. The residue was purified by preparative HPLC, PrepMethod F (gradient: 25-40%). The isomers were separated by preparative chiral HPLC on a CHIRAL ART Cellulose-SB column (5 μm, 250x20 mm i.d.) using an isocratic run of 50% MeOH in MTBE (0.5% 2 M NH3 in MeOH) as mobile phase and a flow rate of 20 ml/min;

the first eluting compound to give the title compound, isomer 1, example 225 (0.088 g, 37%), as a yellow solid; HRMS (ESI) m/z [M+H] ⁺ calcd for C22H26N5O2S: 424.1802, found: 424.1798;

¹ H NMR (300 MHz, DMSO-d6) δ 8.90 (t, 1H), 8.53 (d, 1H), 7.83 (d, 1H), 7.34 (d, 1H), 7.30 - 7.06 (m, 2H), 5.40 - 5.22 (m, 1H), 4.89 (d, 1H), 4.71 (d, 1H), 4.28 (d, 2H), 3.62 (dd, 2H), 3.42 - 3.33 (m, overlaps with solvent peak), 2.98 (t, 2H), 2.00 - 1.78 (m, 2H), 1.08 (d, 6H);

and the second eluting compound to give the title compound, isomer 2, example 226 (0.088 g, 37%), as a yellow solid; HRMS (ESI) m/z [M ₊ H] ⁺ calcd for _C22H26N5O2S : _424.1802 , found: _424.1808 ;

1H NMR (300 MHz, DMSO-d6) δ 8.91 (t, 1H), 8.53 (d, 1H), 7.83 (d, 1H), 7.34 (d, 1H), 7.29 - 7.09 (m, 2H), 5.40 - 5.27 (m, 1H), 4.89 (d, 1H), 4.71 (d, 1H), 4.40 - 4.20 (m, 2H), 3.70 - 3.53 (m, 2H), 3.45 - 3.34 (m, overlaps with solvent peak), 2.98 (t, 2H), 2.00 - 1.78 (m, 2H), 1.08 (d, 6H).

Example 227 carboxamide

DIPEA (586 µL, 3.36 mmol) was added to a solution of 6-(1,5-dioxa-9-azaspiro[5.5]undecan-9yl)quinoline-4-carboxylic acid, intermediate 424 (220 mg, 0.67 mmol), hydrochloride

- 259 048482 (R)-3-glycylthiazolidine-4-carbonitrile, intermediate 4 (209 mg, 1.01 mmol), HOBt (272 mg, 2.01 mmol) and EDC (386 mg, 2.01 mmol) in MeCN (10 mL) and EtOAc (10 mL) at 15 °C. The reaction mixture was stirred at 40 °C for 3 h. The solvent was removed under reduced pressure and the residue was diluted with sat. NaHCO ₃ solution (aq, 200 mL). The aqueous phase was extracted with EtOAc (3x200 mL) and the combined organic layer was washed with water (3x50 mL), dried over Na ₂ SO ₄ , filtered and evaporated under reduced pressure. The crude product was purified by preparative HPLC, PrepMethod T (gradient: 14-47%) to give the title compound (0.157 g, 49%) as a yellow solid; HRMS (ESI) m/z [M+H]+ calcd for C ₂₄ H ₂₈ N ₅ O ₄ S: 482.1856 found: 482.1854;

1H NMR (400 MHz, DMSO-d ₆ ) δ 8.99 (t, 1H), 8.66 (d, 1H), 7.87 (d, 1H), 7.74 - 7.63 (m, 2H), 7.39 (d, 1H), 5.33 (dd, 1H), 4.90 (d, 1H), 4.72 (d, 1H), 4.30 (dd, 2H), 3.87 (t, 4H), 3.45 - 3.34 (m overlaps with solvent peak), 1.98 - 1.90 (m, 4H), 1.63 (p, 2H).

Example 228 carboxamide

DIPEA (351 μL, 2.01 mmol) was added to a solution of 6-(1,4-dioxa-8-azaspiro[4.5]-decan-8-yl)quinoline-4-carboxylic acid, intermediate 426 (126 mg, 0.40 mmol), (R)-3-glycylthiazolidine-4-carbonitrile hydrochloride, intermediate 4 (125 mg, 0.60 mmol), HOBt (544 mg, 4.02 mmol), and EDC (771 mg, 4.02 mmol) in MeCN (6.0 mL) and EtOAc (6.0 mL) at 15 °C. The reaction mixture was stirred at 15 °C for 16 h under N2 (g). The solvent was removed under reduced pressure and the residue was diluted with sat. NaHCO ₃ solution (aq, 250 mL). The aqueous phase was extracted with EtOAc (3x250 mL) and the combined organic layer was washed with water (3x50 mL), dried over Na ₂ SO ₄ , filtered and evaporated under reduced pressure. The crude product was purified by preparative HPLC, PrepMethod C (gradient 12-22%), to give the title compound (0.065 g, 34%) as a yellow solid; HRMS (ESI) m/z [M+H]+ calcd for C23H26N5O4S: 468.1705 found: 468.1723;

1H NMR (300 MHz, DMSO-d6) δ 9.03 (t, 1H), 8.67 (d, 1H), 7.89 (d, 1H), 7.78 - 7.64 (m, 2H), 7.40 (d, 1H), 5.33 (dd, 1H), 4.90 (d, 1H), 4.71 (d, 1H), 4.30 (d, 2H), 3.92 (s, 4H), 3.56 - 3.45 (m, 4H), 3.41 - 3.25 (m, overlaps with solvent peak), 1.76 (dd, 4H).

Example 229 carboxamide

Step a) 6-(2-oxa-7-azaspiro[3.5]nonan-7-yl)quinoline-4-carboxylic acid

NaOH (88 mg, 2.19 mmol) was added to a solution of methyl 6-(2-oxa-7-azaspiro[3.5]nonan-7-yl)quinoline-4-carboxylate, intermediate 427 (137 mg, 0.44 mmol), in MeOH (9.0 ml) and water (3.0 ml) and the reaction mixture was stirred at 15 °C for 2 h. The solvent was removed under reduced pressure. The residue was diluted with water (20 ml) and the pH was adjusted to 3 with aq. HCl (1 M). The aqueous phase was extracted with EtOAc (10 x 50 ml) and the combined organic layer was dried over Na ₂ SO ₄ , filtered and evaporated to give the title compound (0.55 g) as a crude orange solid; MS (ESI) mass/charge [M+H]+ 299.05.

Step b) (R)-N-(2-(4-cyanothiazolidin-3-yl)-2-oxoethyl)-6-(2-oxa-7-azaspiro[3.5]nonan-7yl)quinoline-4-carboxamide DIPEA (754 µL, 4.32 mmol) was added to 6-(2-oxa-7-azaspiro[3.5]nonan-7yl)quinoline-4-carboxylic acid from step a) (541 mg, 0.43 mmol), (R)-3-glycylthiazolidine-4-carbonitrile hydrochloride, intermediate 4 (134 mg, 0.65 mmol), HOBt (583 mg, 4.32 mmol), and EDC (827 mg, 4.32 mmol) in MeCN (5 mL) and EtOAc (5 ml) at 15 °C. The reaction mixture was stirred at 15 °C for 16 h. The solvent was removed under reduced pressure and the residue was diluted with sat. _NaHCO3 solution (aq, 250 ml). The aqueous phase was extracted with EtOAc (3x250 ml) and the combined organic layer was washed with water (3x50 ml), dried over Na2SO4, filtered and evaporated. The crude product was purified by preparative HPLC, PrepMethod R (gradient: 15-35%), to give the title compound (0.171 g, 88%) as

- 260 048482 yellow solid; HRMS (ESI) m/z [M+H]+ calcd for C ₂₃ H ₂₆ N ₅ O ₃ S: 452.1750, found: 452.1724;

¹ H NMR (400 MHz, DMSO-d ₆ ) δ 8.99 (t, 1H), 8.67 (d, 1H), 7.87 (d, 1H), 7.71 - 7.62 (m, 2H), 7.39 (d, 1H), 5.33 (dd, 1H), 4.90 (d, 1H), 4.71 (d, 1H), 4.31 (s, 4H), 4.30 (dd, 2H), 3.40 - 3.27 (m, overlaps with solvent peak), 1.96 - 1.89 (m, 4H).

Example 230. (R)-N-(2-(4-cyanothiazolidin-3-yl)-2-oxoethyl)-6-(4-oxoniperidin-1-yl)quinoline-4-carboxamide

DIPEA (189 μL, 1.08 mmol) was added to a solution of 6-(1,5-dioxa-9-azaspiro[5.5]undecan-9-yl)quinoline-4-carboxylic acid, intermediate 424 (71 mg, 0.22 mmol), (R)-3-glycylthiazolidine-4-carbonitrile hydrochloride, intermediate 4 (67 mg, 0.32 mmol), HOBt (292 mg, 2.16 mmol) and EDC (415 mg, 2.16 mmol) in MeCN (5 mL) and EtOAc (5 mL) at 15 °C. The reaction mixture was stirred at 50 °C for 2 h. The solvent was removed under reduced pressure and the residue was diluted with saturated NaHCO ₃ (aq., 200 mL). The aqueous phase was extracted with EtOAc (3x200 mL) and _the combined organic layer was washed with water (3x50 mL), dried over _Na2SO4 , filtered and evaporated under reduced pressure. The crude product was purified by preparative HPLC, PrepMethod X (gradient: 14-24%). The product containing fractions were collected and evaporated and the residue was lyophilized from water _/ MeCN ( _x3 ) to give the title compound ( ₅₇ mg, 61%) as a yellow solid; HRMS (ESI) m/z [M+H] ⁺ calcd for C21H22N5O3S: 424.1438 found _: 424.1450;

1H NMR (500 MHz, DMSO-d ₆ ) δ 9.02 (t, 1H), 8.68 (d, 1H), 7.94 (d, 1H), 7.85 (d, 1H), 7.75 (dd, 1H), 7.40 (d, 1H), 5.32 (dd, 1H), 4.89 (d, 1H), 4.71 (d, 1H), 4.37 - 4.24 (m, 2H), 3.82 (t, 4H), 3.50 - 3.34 (m, overlaps with solvent peak), 2.49 - 2.46 (m, overlaps with solvent peak).

D. Biological data

The hFAP protein used in the examples was either obtained from commercial sources or produced in insect cells as recombinant hFAP (Gp67-6HN-TEV-FAP(M39-A757) with a MW of 89,086.7 Da or cd33-FAP(27-757)-6His with a MW of 85,926 Da). Recombinant hFAP protein was secreted from Sf21 cells in medium, purified by affinity (batch mode, Ni excel resin, AKTA, GE Healthcare) and size exclusion chromatography (Superdex200, AKTA, GE Healthcare), concentrated to 19.5 mg/mL, immediately frozen in liquid N2 and stored at -80°C.

Example 231. FAP Inhibition and Binding Assays

A. hFAP inhibition assay

Compounds were tested in an inhibition assay using the hFAP enzyme at a FAC of 0.24 nM (Proteros, 38-760 (PR-0071)) and the Ala-Pro-AMC substrate (ARI-3144) at a FAC of 20 μM. Low volume black 384-well plates (Greiner #784076) were used. 4 μL of enzyme solution (100 mM Tris HCl, 100 mM NaCl, 0.05% Chaps, pH 7.4) at a concentration of 0.48 nM were added to 40 nL of compounds (in DMSO) at a CR of 10, a 3-fold dilution series from a FAC of 50 μM. Plates were incubated for 15 min at RT in the dark. To each well, 4 μl of substrate solution (100 mM Tris HCl, 100 mM NaCl, 0.05% Chaps, pH 7.4) at a concentration of 40 μM were added. Plates were centrifuged at 1000 rpm and incubated for 30 min at RT in the dark. Plates were read on a PHERAstar® reader with excitation at 340 nm and emission at 460 nm. Data were analyzed in the Genedata Screener®. _IC50 values were determined by plotting % inhibition versus log compound concentration and using a single site dose response model. Raw data signals were normalized using 0.5% DMSO as 0% control and reference compound A (i.e., (S)-N-(2-(2-cyano-4,4-difluoropyrrolidin-1-yl)-2oxoethyl)quinoline-4-carboxamide as described in J. Med. Chem. 2014, 57, 3053) at 50 μM as 100% inhibitor control. Data for test compounds are shown in Table 1.

B. hFAP (stable binders) inhibition assay

Compounds were tested in an inhibition assay using human fibroblast activating protein, alpha (hFAP) enzyme at a FAC of 2.4 pM (Proteros, 38-760 (PR-0071)) and Ala-Pro-AMC substrate (ARI-3144) at a FAC of 20 μM. Low volume black 384-well plates (Greiner #784076) were used. Four μL of enzyme solution (100 mM Tris HCl, 100 mM NaCl, 0.05% Chaps, pH 7.4) at a concentration of 4.8 pM were added to 40 nL of compounds (in DMSO) at a CR of 10, a 3-fold dilution series from a FAC of 50 nM. The plates were incubated for 15 min at RT in the dark. Each

- 4 μl of substrate solution (100 mM Tris-HCl, 100 mM NaCl, 0.05% Chaps, pH 7.4) at a concentration of 40 μM were added to well 261 048482. The plates were centrifuged at 1000 rpm and incubated for 2.5 h at RT in the dark. The plates were read on a PHERAstar® plate reader with excitation at 340 nm and emission at 460 nm. Data were analyzed in the Genedata Screener®. _IC50 values were determined by plotting % inhibition versus log compound concentration and using a single site dose response model. Raw data signals were normalized using 0.5% DMSO as 0% control and reference compound A (i.e., (S)-N-(2-(2-cyano-4,4-difluoropyrrolidin-1-yl)-2-oxoethyl)quinoline-4-carboxamide as described in J. Med. Chem. 2014, 57, 3053) at 50 μM as 100% inhibitor control. Data for the test compounds are shown in Table 1.

C. hFAP binding assay

Compounds were tested in a direct binding assay using an 8K surface plasmon resonance biosensor (GE Healthcare) at 20°C. Immobilization of hFAP (M39A757) on a CMD200M sensor chip (Xantec) was performed using a standard amine coupling procedure in immobilization buffer (10 mM HEPES, 150 mM NaCl, 0.05% Tween 20, pH 7.4). The surface was washed with 10 mM NaOH, 1 M NaCl before activation with EDC/NHS (GE Healthcare) followed by immobilization of hFAP (in 10 mM acetate, pH 5.0). Finally, the surface was deactivated with ethanolamine. hFAP immobilization levels were around 4000-6000 RU. The reference point was processed as described, excluding the injection of hFAP. Compound concentration series were introduced into the immobilized protein at increasing concentrations (2-500 nM) using single cycle kinetics in running buffer (20 mM Tris, 150 mM NaCl, 0.05% Tween 20, 1% DMSO, pH 7.4). Interaction models were globally fitted to experimental trace amounts, providing k _on , k _off , and K _d . Data for the test compounds are summarized in Table 1.

Table 1

Example hFAP Inhibition Assay IC50 (nM) ¹ hFAP inhibition assay (stable binders) 1C ₅ o (nM) ² hFAP binding assay K _l (nM) ³ hFAP k(on) (M'V ¹ ) ³ binding assay hFAP binding assay k(off) (1/s) ³ 1 0,099 0.18 730000 0,00014 2 0.52 9.5 410000 0,0038 3 0.24 0.13 0,095 4100000 0,00040 4 0,058 0,079 1200000 0,000094 5 0,060 0,049 n.d. n.d. 6 0.51 0.38 40000000000 18 7 0.16 0,10 740000 0,000075 8 0,063 0,032 1300000 0,000034 9 0.25 0.66 1200000 0,00076 10 0,054 0,15 370000 0,000056 AND 0,057 0,044 N. d. n.d. 12 0,065 0,038 1900000 0,000064 13 0,041 0,014 9200000 0,000076 14 0,080 0,050 1300000 0,000064 15 0,12 oh, and 490000 0,000046

- 262 048482

16 0D1 0,054 740000 0,000041 17 0.22 0,085 0,015 8300000 0,00012 18 0.19 0,047 0,068 1400000 0,000059 19 0.66 0.38 0,15 430000 0,000066 20 0.74 0.43 0,030 4200000 0,00012 21 0.29 ο,ιι 0,066 3000000 0,00020 22 0.34 0,12 0,050 940000 0,000047 23 0.31 0,20 0,085 2100000 0,00018 24 0.27 0,20 0,0094 25000000 0,00048 25 0.41 0,30 0,076 1400000 0,00011 26 0.31 0,10 0,056 1300000 0,000065 27 0.29 ο,ιι 0,024 1100000 0,000026 28 0.26 0,10 ο,ιι 1100000 0,00011 29 0.13 0,055 0,057 1100000 0,000061 30 0.28 0,12 0,042 5200000 0,00022 31 0.22 0,10 0,031 9700000 0,00024 32 0,30 0.16 0,022 1300000 0,000029 33 0.34 0.27 0,059 1100000 0,000052 34 0.27 0.22 0,057 2200000 0,000082 35 0.47 0.17 0,10 900000 0,00010 36 0.24 0,084 0,053 3000000 0,000090 37 0.22 0.19 0,028 1000000 0,000030 38 0,10 ο,ιι 520000 0,000078 39 0.28 0,10 0,040 4900000 0,00016 40 0.24 0,065 0,043 1300000 0,000046 41 0.33 0.16 0,093 680000 0,000064 42 0,053 0,030 1800000 0,000054 43 0,045 0,0061 3200000 0,000019 44 0.22 0,074 0,042 1700000 0,000072 45 0,20 0.14 0,048 5400000 0,00018 46 0.29 0,082 0,020 3000000 0,000062 47 0.22 0,20 0,031 5600000 0,00016 48 0.29 ο,ιι 0,067 1400000 0,000089 49 0.19 0,041 0,020 8800000 0,00017 50 0.34 0,069 0,071 n.d. N. d. 51 0.21 0,064 0,021 5600000 0,00011 52 0,20 0,045 0,044 6800000 0,00019 53 0.27 0.18 0,074 680000 0,000050 54 0.22 0,062 0,045 6200000 0,00023 55 0.25 0,083 0,036 6700000 0,00025 56 0.44 0.19 0.14 540000 0,00011 57 0.26 0,098 0,022 8000000 0,00018 58 0.23 0,076 0,016 8800000000 0,091 59 0.27 0,061 0,087 2600000 0,00019 60 0.22 0.14 0,099 1700000 0,00017 61 0.21 0,060 0,062 N. d. N. d. 62 0.25 0,058 0,12 710000 0,000085 63 0.33 0.19 0,030 4100000 0,000059

- 263 048482

64 0.28 0,085 0,12 1300000 0,00015 65 0.28 0.17 0,055 6700000 0,00047 66 0,077 0,035 26000000 0,00022 67 0.37 0,084 0,012 4900000 0,000046 68 0.37 0,10 ο,ιι 1000000 0,00011 69 0.29 0,070 0,070 1400000 0,000093 70 0,12 0,022 5400000 0,00014 71 0.22 0,068 0,050 n.d. n.d. 72 0,079 0,026 5200000 0,00016 73 0.13 0,066 2400000 0,00016 74 0,094 0.14 1100000 0,00016 75 0,050 0,0063 2300000 0,000024 76 0,080 0,051 1000000 0,000052 77 0,051 0,014 4800000 0,000066 78 0,097 0,12 880000 0,00010 79 0,043 0,018 16000000 0,00012 80 0,10 0,036 2400000 0,000088 81 0.13 0,044 1400000 0,000063 82 0D1 0,052 1400000 0,000071 83 0,082 0,039 1700000 0,000064 84 0,074 0,12 1200000 0,00011 85 0,087 0,032 4000000 0,00011 86 0,074 0,081 730000 0,000058 87 0,40 ο,ιι 0,039 2800000 0,00011 88 0.31 0,074 0,082 4200000 0,00034 89 0,096 0,053 3600000 0,00015 90 0.75 0.35 0.38 480000 0,00010 91 0,088 0,072 3200000 0,00021 92 0,074 0,047 2200000 0,00011 93 0,091 0,047 1800000 0,000080 94 0,071 0,074 1900000 0,000099 95 0.16 0,024 2900000 0,000056 96 0.17 0,067 4000000 0,00022 97 0.23 ο,ιι 690000 0,000076 98 0.27 ο,ιι 0,0088 1600000 0,000015 99 0,12 ο,ιι 2100000 0,00020 100 0,50 0.27 0.73 3000000 0,0022 101 0.38 0.35 0,034 740000 0,000025 102 0.21 0,066 0,046 2000000 0,000080 103 0.31 ο,ιι 0,033 3000000 0,00010 104 0.21 0,081 0,020 3000000 0,000061 105 0.37 0,088 0,082 890000 0,000068 106 0.23 0,080 0,075 1800000 0,00014 107 0.64 0.21 0,083 1900000 0,00016 108 0.28 0,12 0,038 1400000 0,000050 109 1,2 8.5 1200000 0,0099 110 0,054 0,019 2200000 0,000050 111 0,064 0,055 1800000 0,000096

- 264 048482

112 0,20 0.31 440000 0,00014 FROM 0.25 0,12 0,031 1500000 0,000045 114 0,072 0,062 n.d.,n.d. n.d.,n.d. 115 0,040 ο,ιι N. d.,N. d. N. d.,N. d. 116 0.16 0,15 7900000 0,0012 117 0,061 0,060 n.d.,n.d. n.d.,n.d. 118 0,10 0.17 N.D. N.D. 119 0.16 0.39 610000 0,00031 120 0,15 0.13 n.d. n.d. 121 0,15 0,012 1100000 0,000016 122 0,049 0,033 1300000 0,000043 123 0.25 0,083 0.14 3000000 0,00042 124 0.24 0,055 0,094 3000000 0,00028 125 0.21 0,046 0,048 3000000 0,00014 126 0.32 0,081 ο,ιι 1800000 0,00021 127 0.38 0.16 0.34 6000000 0,0020 128 0.45 0.24 0,15 5400000 0,00066 129 0,20 0,041 0,087 1400000 0,00012 130 0.19 0.18 440000 0,000078 131 0,12 0,033 1800000 0,00014 132 0.41 0.52 270000 0,00014 133 0,10 0,066 1200000 0,000073 134 0.13 0.13 620000 0,000080 135 0D1 0,013 1700000 0,000023 136 0,061 0,036 2000000 0,000050 137 ο,ιι 0,013 9500000 0,000098 138 0,047 0,028 2500000 0,000075 139 0.32 0,015 n.d. n.d. 140 0,10 0,064 2600000 0,00016 141 0,059 0,062 1400000 0,000078 142 0,088 0,028 1800000 0,000055 143 0,069 0,036 1600000 0,000057 144 0,081 0,049 9100000 0,00051 145 0,070 0,029 4500000 0,00013 146 0,15 0,12 1400000 0,00017 147 0,067 0,045 2800000 0,00012 148 0,059 0,031 6600000 0,00020 149 0,097 0,0087 4800000 0,000039 150 0,50 0.16 280000 0,000043 151 0.13 0,039 1500000 0,000053 152 0,062 0,013 1000000 0,000014 153 ο,ιι 0,015 5300000 0,000085 154 0,092 0,059 910000 0,000054 155 0,086 0,016 3100000 0,000050 156 0.22 0,056 1200000 0,000066 157 0.37 0,065 1900000 0,00012 158 0,10 0,10 3100000 0,00029 159 0,073 0,039 2100000 0,000092

- 265 048482

160 0,050 0,068 1100000 0,000074 161 0,052 0,022 14000000 0,00028 162 0,053 0,018 1900000 0,000028 163 0,079 0,034 n.d. N. d. 164 0,081 0,027 1400000 0,000036 165 0.32 0,051 1200000 0,000063 166 0.34 0.22 0,030 2200000 0,000049 167 0,091 168 0.16 0,032 1600000 0,000048 169 0.22 0,057 0.16 6200000 0,00096 170 0.24 0,063 0,017 10000000 0,00018 171 0.28 0.13 0,086 1000000 0,000092 172 0.55 0.26 0,036 2400000 0,000076 173 0.27 0,078 0.51 110000 0,000054 174 0.44 0.26 0.13 1900000 0,00024 175 0.34 0,12 0,086 1400000 0,00012 176 0.54 0,087 1,9 120000 0,00022 177 0.29 0D1 0.56 100000 0,000058 178 0,20 0,042 0,053 3100000 0,00017 179 0,048 0,052 3200000 0,00016 180 0,20 1,3 560000 0,00095 181 0.94 0.38 0.16 180000 0,000027 182 0.41 0.19 0,093 250000 0,000042 183 0.33 0.19 0,086 N. d. N. d. 184 0,40 0.22 0,015 950000 0,000014 185 0.23 0,12 0,043 N. d. N. d. 186 0.27 0,10 0,045 N. d. N. d. 187 0,098 0,072 0,070 3100000 0,00022 188 0.28 0.19 0,011 2600000 0,000022 189 0,056 0,020 2600000 0,000051 190 0,069 0,020 1800000 0,000036 191 0,038 0,022 1500000 0,000033 192 0,051 0,0077 1300000 0,000014 193 0.24 0.16 740000 0,00012 194 0,046 0,066 1100000 0,000068 195 0.39 0.33 190000 0,000061 196 0.19 0,066 0,080 3200000 0,00026 197 0.72 0.42 0.75 88000 0,000066 198 0,056 0,038 2900000 0,00011 199 0,30 0,10 2300000 0,00026 200 0.24 0,090 2500000 0,00023 201 <0.025 0,059 1800000 0,00010 202 0,044 0,043 1600000 0,000070 203 0.26 0,15 440000 0,000063 204 0,067 0,068 850000 0,000058 205 0.27 0,067 0,026 2100000 0,000046 206 0.22 0,065 0,033 N. d. N. d. 207 0.17 0,011 4600000 0,000053

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208 0.22 0.11 0,046 5600000 0,00026 209 0.44 0,15 0,020 3200000 0,000042 210 0.44 0.18 0,026 3800000 0,000098 211 0,20 0,10 0,049 5900000 0,00020 212 0.29 0.26 0,10 3300000 0,00034 213 0.18 0,039 0,039 4400000 0,00017 214 0,20 0,079 0,043 2900000 0,000092 215 0.41 0,12 0,095 1800000 0,00017 216 2,4 1,7 0.27 5200000 0,00090 217 0.67 0.71 1800000 0,0013 218 0,068 0.48 670000 0,00032 219 oh, and 0,083 2400000 0,00020 220 0,091 0,038 1600000 0,000050 221 0.17 0,0048 8500000 0,000046 222 0,087 0,022 n.d. n.d. 223 0,076 0,010 2500000 0,000026 224 0,073 0,023 3000000 0,000068 225 oh, and 0,077 n.d. n.d. 226 0,20 0,044 N.D. N.D. 228 0,087 229 0,091 0,010 2400000 0,000026 230 0,078

¹ The IC ₅₀ value is given after a single measurement (n=1) or as the geometric mean of several measurements (n=2-3).

² The IC ₅₀ value is given after a single measurement (n=1) or as the geometric mean of several measurements (n=2-6).

³ Kd is given after a single measurement (n=1) or as the geometric mean of several measurements (n=2-4). k( _on) and k( _off ) are given after a single measurement (n=1) or as the geometric mean of several measurements (n=2-4). NV is invalid.

D. FAP inhibition assay in plasma

This assay was adapted from the method described in Example 237 to detect the activity of the target-binding enzyme FAP in plasma. Plasma (anticoagulant K2EDTA) was used as the enzyme source: human plasma (pooled from AZ Biobank), mouse plasma (AZ AST Biobank), and cynomolgus monkey plasma (BioIVT, #NHP00PLK2FNN, lot CYN222 895). Fluotrack PS 384-well black plates (Greiner 781076) were used. 20 μl of diluted plasma (human and cynomolgus monkey plasma 1:40, mouse plasma 1:67) in buffer (PBS, 0.1% BSA) in 0.6 μl of compounds (in DMSO) were added. Compounds were tested using a CR value of 10, a 3-fold dilution series from a 500 nM FAC. Duplicate assays were performed on the same plate for each assay point. A blank fluorescence reading was obtained before adding substrate. The substrate, a stock solution of Ala-Pro-AMC (ARI-3144) (20 mM in DMSO), was diluted in buffer (PBS, 0.1% BSA) to a concentration of 150 μM and 20 μl was added to give a FAC of 75 μM. Plates were incubated for 40 min at RT in the dark. Plates were read on a Beckman Paradigm® reader with excitation at 360 nm and emission at 465 nm. Data were analyzed in Excel (IDBS XLfit Add-In) using a single-site dose-response model (4-parameter logistic model). _IC50 values were determined by plotting % inhibition versus log compound concentration. Raw data signals were normalized using 1.5% DMSO in diluted plasma as a 0% control and 1.5% DMSO in buffer (no plasma) as a 100% inhibitor control. Data for the test compounds are summarized in Table 2.

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Table 2

Example Human blood plasma containing FAP 1C ₅ o (nM) ¹ Mouse blood plasma containing FAP 1C ₅ o (nM) ² Cynomolgus macaque blood plasma containing FAP 1C ₅ o (nM) ³ 2 8.1 7.3 9.2 8 0,10 0,20 0,20 9 0,60 0,60 0,60 16 0,20 0,40 0,20 24 27 28 50 67 68 69 70 71 72 74 82 88 98 102 112 OF 147 151 157 163 166 170 171 172 173 174 175 178 181 184 195 196 203 0.20 0.20 0.20 0.30 0.36 0.30 0.20 0.20 0.20 0.20 0.20 0.30 0.20 0.20 0.20 0.60 0.20 0.10 0.20 0.30 0.10 0.30 0.30 0.20 0.20 0.10 0.20 0.20 0.10 0.30 0.20 0.90 0.10 0.40 0.40 0.50 0.50 0.50 0.52 0.50 0.30 0.30 0.20 0.20 0.30 0.40 0.30 0.40 0.20 0.80 0.50 0.20 0.40 0.60 0.20 0.60 0.50 0.30 0.60 0.20 0.40 0.40 0.10 0.90 0.60 1.4 0.20 0.50 0.30 0.30 0.30 0.30 0.40 0.30 0.20 0.20 0.20 0.20 0.20 0.30 0.20 0.30 0.20 0.50 0.40 0.10 0.30 0.40 0.20 0.30 0.50 0.30 1 0.40 204 0,20 0,30 0,20 205 0,30 0,30 0,30

¹ The IC50 value is given after a single measurement (n=1) or as the geometric mean of several measurements (n=4).

The IC ₅₀ value is given after a single measurement (n=1) or as the geometric mean of several measurements (n=4).

³ IC50 value is given after a single measurement (n=1).

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Example 232. hPrep Inhibition Assay

Compounds were tested in a biochemical inhibition assay using the enzyme prolyl endopeptidase, prolyl oligopeptidase (hPREP) at an FAC of 0.6 nM (R&D Systems, 4308-SE) and the substrate Z-Gly-Pro-amino-methylcoumarin (Bachem, I-1145) at an FAC of 50 μM. 384-well black low-well volume plates (Greiner #784076) were used. Four microliters of enzyme solution (25 mM Tris HCl, 250 mM NaCl, 0.01% Triton X-100, 5 mM glutathione, pH 7.5) at a concentration of 1.2 nM were added to 40 nl of compounds (in DMSO) at a CR of 10, a 3-fold dilution series from 50 μM FAC. The plates were incubated for 15 min at RT in the dark. Four microliters of substrate solution (25 mM Tris HCl, 250 mM NaCl, 0.01% Triton X-100, 5 mM glutathione, pH 7.5) at a concentration of 100 μM were added to each well. The plates were centrifuged at 1000 rpm and incubated for 20 min at RT in the dark. The plates were read on a PHERAstar® reader with excitation at 340 nm and emission at 460 nm. Data were analyzed in the Genedata Screener®. _IC50 values were determined by plotting % inhibition versus log compound concentration and using a single site dose response model. Raw data signals were normalized using 0.5% DMSO as the 0% control and reference compound B (i.e., (R)-N-(2-(4-cyanothiazolidin-3-yl)-2 oxoethyl)-7-methylquinoline-4-carboxamide) at 50 μM as the 100% inhibitor control. Data for the test compounds are summarized in Table 3.

Table 3

Example PREP IC50 (nM) ¹ 1 410 2 1700 3 690 4 1100 5 220 6 200 7 510 8 1400 9 980 10 940 AND 140 12 510 13 380 14 1200 15 2100 16 1600 17 160 18 570 19 160 20 430 21 93 22 470 23 160 24 510 25 370 26 580 27 660 28 580 29 500 30 510 31 760 32 450 33 220 34 430

Example PREP IC50 (nM) ¹ 77 470 78 890 79 630 80 1500 81 1700 82 930 83 640 84 710 85 720 86 360 87 760 88 1200 89 1300 90 1100 91 260 92 2400 93 1900 94 1800 95 740 96 880 97 890 98 790 99 1100 100 170 101 380 102 680 103 580 104 650 105 590 106 520 107 1100 108 1000 109 4400 110 1100

Example PREP IC50 (nM) ¹ 153 540 154 590 155 380 156 310 157 1200 158 560 159 280 160 210 161 470 162 280 163 980 164 240 165 670 166 1700 167 1000 168 630 169 440 170 260 171 270 172 540 173 940 174 87 175 760 176 560 177 360 178 120 179 470 180 590 181 1600 182 210 183 140 184 1100 185 130 186 150

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35 1700 111 1200 36 400 112 3600 37 270 FROM 490 38 480 114 230 39 500 115 130 40 280 116 230 41 640 117 170 42 880 118 360 43 1000 119 76 44 540 120 25 45 190 121 88 46 110 122 840 47 270 123 740 48 170 124 220 49 340 125 120 50 540 126 260 51 130 127 130 52 400 128 110 53 170 129 330 54 300 130 540 55 440 131 360 56 220 132 3700 57 160 133 370 58 180 134 620 59 30 135 500 60 86 136 300 61 390 137 340 62 280 138 470 63 400 139 1000 64 610 140 840 65 100 141 460 66 490 142 530 67 1200 143 460 68 1700 144 460 69 2000 145 250 70 1100 146 450 71 1400 147 570 72 1900 148 420 73 1800 149 470 74 2300 150 2000 75 490 151 1000 76 510 152 690

187 38 188 430 189 440 190 690 191 550 192 200 193 360 194 460 195 1200 196 84 197 1900 198 410 199 170 200 130 201 610 202 550 203 3500 204 920 205 640 206 330 207 430 208 210 209 540 210 220 211 BY 212 330 213 470 214 280 215 250 216 190 217 310 218 390 219 230 220 390 221 410 222 490 223 86 224 670 225 470 226 660 227 600 228 1200 229 320 230 600 In ² 5.2 From ³ 7.1

¹ The IC ₅₀ value is given after a single measurement (n=1) or as the geometric mean of several measurements (n=2-9).

² Reference compound B: (R)-N-(2-(4-cyanothiazolidin-3-yl)-2-oxoethyl)-7-methylquinoline-4-carboxamide ³ Reference compound C: (R)-N-(2-(4-cyanothiazolidin-3-yl)-2-oxoethyl)quinoline-4-carboxamide

Example 233. hDPP Inhibition Assays

A. hDPP7 inhibition assay

Compounds were tested in an inhibition assay using human dipeptidyl peptidase-7 (hDPP7) enzyme at an FAC of 15 nM (BPS Bioscience, #80070) and the substrate A1a-Pro-amino-methylcoumarin (BPS Bioscience, #80305) at an FAC of 5 μM. Enzyme reactions were performed in duplicate at RT for 30 min in 50 μL DPP assay buffer (BPS Bioscience, #80300). Compound solutions (in DMSO) at a CR of 10, 3-fold dilution series, were prepared in assay buffer at ten times the final concentration and 5 µl of the dilutions were added to 50 µl of the reaction mixture such that the highest compound concentration corresponded to a FAC of 100 µM and the DMSO concentration was 1% in all wells. Plates were read on a Tecan Infinite M1000 microplate reader with excitation at 340 nm and emission at 460 nm. Data were analyzed in a Graph Pad Prism. IC ₅₀ values were determined by plotting % inhibition versus log compound concentration and using a single site dose response model. Raw data signals were normalized using 1% DMSO as a 0% control and no enzyme as a 100% inhibitor control. Data on the tested compounds are presented in Table 4.

B. hDPP8 inhibition assay

Compounds were tested in an inhibition assay using the human dipeptidyl peptidase-8 (hDPP8) enzyme at an FAC of 1.5 nM (BPS Bioscience, #80080) and the substrate A1a-Pro-amino-methylcoumarin (BPS Bioscience #80305) at an FAC of 5 μM. Enzyme reactions were performed in duplicate at RT for 30 min in 50 μl DPP assay buffer (BPS Bioscience, #80300). Compound solutions (in DMSO) at a CR of 10, 3-fold dilution series, were prepared in assay buffer at ten times the final concentration and 5 µl of the dilutions were added to 50 µl of the reaction mixture such that the highest compound concentration corresponded to a FAC of 100 µM and the DMSO concentration was 1% in all wells. Plates were read on a Tecan Infinite M1000 microplate reader with excitation at 340 nm and emission at 460 nm. Data were analyzed in a Graph Pad Prism. IC ₅₀ values were determined by plotting % inhibition versus log compound concentration and using a single site dose response model. Raw data signals were normalized using 1% DMSO as a 0% control and no enzyme as a 100% inhibitor control. Data on the tested compounds are presented in Table 4.

C. hDPP9 inhibition assay

Compounds were tested in an inhibition assay using the human dipeptidyl peptidase-9 (hDPP9) enzyme at an FAC of 0.4 nM (BPS Bioscience, #80090) and the substrate A1a-Pro-amino-methylcoumarin (BPS Bioscience #80305) at an FAC of 5 μM. Enzyme reactions were performed in duplicate at RT for 30 min in 50 μl DPP assay buffer (BPS Bioscience, #80300). Compound solutions (in DMSO) at a CR of 10, 3-fold dilution series, were prepared in assay buffer at ten times the final concentration and 5 µl of the dilutions were added to 50 µl of the reaction mixture such that the highest compound concentration corresponded to a FAC of 100 µM and the DMSO concentration was 1% in all wells. Plates were read on a Tecan Infinite M1000 microplate reader with excitation at 340 nm and emission at 460 nm. Data were analyzed in a Graph Pad Prism. IC ₅₀ values were determined by plotting % inhibition versus log compound concentration and using a single site dose response model. Raw data signals were normalized using 1% DMSO as a 0% control and no enzyme as a 100% inhibitor control. Data on the tested compounds are presented in Table 4.

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Table 4

Example hDPP7 IC50 (nM) ¹ hDPP8 ICso (nM) ¹ hDPP9 ICso (nM) ¹ 8 >100000 3300 400 9 >100000 5100 640 27 >100000 4300 1100 67 33000 13000 1900 68 >100000 6600 1500 69 >100000 7500 950 70 >100000 4700 1400 71 >100000 5900 1900 72 >100000 6600 2500 80 >100000 3500 1400 110 >100000 430 250 111 >100000 950 410 151 >100000 3800 2000 163 >100000 3900 1500 171 >100000 3000 630

¹ IC50 value is given after a single measurement (n=1).

Example 234. Metabolic stability assays

A. Analysis of aldehyde oxidase-1 (AO) metabolism

AO-mediated metabolism was measured essentially as described in Drug Metab. Disp. 2010, 38,1322. Human liver cytosol (Corning life sciences, UltraPool Human Cytosol 150, product 452115) in phosphate buffer, pH 7.4, was pre-incubated for 5 min at 37°C with shaking at 900 rpm. Reactions were initiated by adding pre-diluted test compounds, including the positive control, zaleplon, and incubated at 37°C with final conditions: 2.5 mg/mL human liver cytosol fraction, 1 μM test compound, 0.01% DMSO, and 0.09% MeCN. Samples were incubated for 120 min. with time points of 0, 10, 30, 60, 90 and 120 min. Aliquots (25 μl) were precipitated with 100 μl MeCN containing an internal standard of (4-((2'-(1H-tetrazol-5-yl)-[1,1'-biphenyl]-4-yl)methoxy)-2-ethylquinoline (J Med Chem 1992, 35, 4027), centrifuged at 3500 rpm for 10 min, and the supernatant was diluted 1 to 7 (v/v) with HPLC-grade water before analysis by LC-MS/MS. All incubations were performed in duplicate. The in vitro elimination rate constant, corresponding to the decrease in the level of the parent compound, was determined for each reaction using the ^11th order decay calculator in a Microsoft Excel Sheet. In some cases, the experiment was additionally performed in the presence of an aldehyde oxidase inhibitor: the cytosol mixture was preincubated with 3 μM raloxifene, shaking at 900 rpm for 5 min at 37°C before adding the test compound. Data for the test compounds are given in Table 5.

B. Analysis of aldehyde oxidase-2 (AO) metabolism

AO-mediated metabolism was measured essentially as described in Drug Metab. Disp. 2010, 38,1322. Human liver cytosol (BioreclamationIVT, stored at -80°C prior to use, protein concentration was 2.5 mg/mL) and 0.1 M phosphate buffer (with 0.1 mM EDTA) pH 7.4 were pre-incubated at 37°C. The reaction was initiated by adding the test compound (final substrate concentration was 1 μM, final DMSO concentration was 0.3%, and final incubation volume was 500 μL). Phthalazine (known to be metabolized by AO) was used as a control compound. Test compounds were incubated for 0, 5, 15, 30, 60, and 120 min. Reactions were stopped by removing an aliquot of the incubation into an organic solvent containing the internal standard at appropriate time points. Termination plates were centrifuged at 2500 rpm for 30 min at 4°C to precipitate the protein. Sample supernatants were pooled into cassettes containing up to four compounds and analyzed using general LC MS/MS conditions. The gradient of the line was determined from a plot of the peak area ratio of In (compound peak area/internal standard peak area) versus time. The half-life and intrinsic clearance were subsequently calculated using the following equations:

Elimination rate constant (k) = (- gradient)

Half-life (t _1/2 )(min) = 0.693/k

Intrinsic clearance (CL _int (µl/min/mg protein) = V x 0.693/t _1/2 , where V = incubation volume (µl)/protein (mg)

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The percentage of parent compound remaining at each time point was reported along with the intrinsic clearance (CL _int ), half-life, and standard error of CL _int . Data for the test compounds are presented in Table 5.

Table 5

Example AO-1 CLint assay (µl/min/mg) ¹ AO-2 CLint assay (µl/min/mg) ¹ 8 0,50 9 <0.50 22 0,07 27 0,12 40 1,1 47 1,3 67 <0.50 0.25 68 <0.50 69 <0.50 71 0.56 107 0 129 0.76 151 0.32 163 0,30 170 <0.50 0.18 171 <0.50 172 <0.50 173 0.58 175 0,60 196 <0.50 205 0.68 Compound A ² 3.8 Connection C ³ 5.3

¹ CL _int is given after a single measurement (n=1).

² Compound A, which is ((S)-N-(2-(2-cyano-4,4-difluoropyrrolidin-1-yl)-2-oxoethyl)quinoline-4-carboxamide, J Med Chem 2014, 57, 3053) ³ Compound C, which is (R)-N-(2-(4-cyanothiazolidin-3-yl)-2-oxoethyl)quinoline-4-carboxamide

C. Human liver microsomes (HLM)

Metabolic stability in HLM was measured as described in J Comput Aided Mol Des 2015, 29, 795. Data for the tested compounds are presented in Table 6.

D. Rat hepatocytes (rHep)

Metabolic stability in rat hepatocytes was measured as described in J Comput Aided Mol Des 2015, 29, 795. Data for the test compounds are shown in Table 6.

E. Human hepatocytes (hHep)

Metabolic stability in human hepatocytes was measured as described in Xenobiotica 2010, 40, 637. Data for the test compounds are shown in Table 6.

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Table 6

Example HLM CLmt ¹ (µl/min./mg) gNer CLint ² (µl/min/1E6) hHep CLint ³ (µl/min./1E6) 1 14 4.9 <1 2 22 3 <1 3 75 28 4 50 14 5 93 32 6 N.D. 100 7 31 2.6 8 <3 2.7 <1 9 21 4.3 <1 10 130 41 AND <3 2,5 12 6.4 <1 13 12 5.4 14 <3 <1 15 43 AND 16 <3 <1 17 48 16 18 22 6 3.7 19 190 63 20 290 120 21 15 17 <1 22 21 14 2.9 23 25 27 24 14 20 <1 25 23 14 26 31 7.6 27 16 8.3 <1.4 28 <3 13 2.6 29 18 4,5 <1 30 <3 7.2 <1 31 45 14 32 40 19 4.1 33 92 44 34 38 33 35 63 64

Example NEM CLint ¹ (µl/min/mg) gNer CLint ² (µl/min/1E6) hHep CLint ³ (µl/min./1E 6) 114 170 36 115 120 20 116 98 15 117 170 29 118 41 21 119 68 27 120 100 27 121 43 13 122 <3 <1 123 32 7.1 1,6 124 12 14 125 14 7.4 126 16 10 127 AND 8.2 128 27 AND 129 <3 1,4 130 54 AND 131 97 16 132 38 8.5 133 40 8,8 134 210 74 135 23 6.8 136 <3 4.8 137 70 17 138 20 33 139 72 13 140 32 7,7 141 54 AND 142 43 6,7 143 40 13 144 14 7 145 40 10 146 AND 4.3 147 17 2.9 148 53 12

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36 48 19 37 66 30 38 >300 >300 39 120 31 40 23 15 <1 41 30 12 42 21 7.6 2.7 43 36 9.1 44 220 160 45 260 160 46 190 72 47 32 33 48 89 51 49 58 48 50 13 20 1,7 51 14 24 52 22 21 53 120 71 54 57 49 55 55 63 56 >300 160 57 >300 >300 58 140 72 59 >300 91 60 210 120 61 47 26 62 31 46 63 180 30 64 56 29 65 150 110 66 <3 <1 67 <5.2 3,4 <1 68 12 5.2 <1 69 5,6 2.6 <1 70 18 5.9 2 71 7 4 <1 72 9.7 2.7 <1 73 32 AND 74 28 13 <1 75 9 6,7 76 4.2 3.5 77 7.1 5.4 78 23 12 1,2 79 21 6.2 80 7.5 2 <1 81 17 8.1 82 39 AND 83 70 9.2 84 64 26 85 260 35 86 160 44 87 52 12 88 22 8.6 <1 89 16 7.1 <1

149 56 7 150 49 5 151 10 4,5 <1 152 23 8.2 153 <3 <1 154 <3 2.7 155 19 3.2 156 140 120 157 7.3 <1 <1 158 17 4.7 159 61 47 160 45 33 161 6,7 8.5 162 44 3,4 163 5,6 <1 <1 164 22 8.1 165 <3 <1 166 <3 <1 <1 167 <3 <1 168 169 18 8,8 170 4.9 4.2 1,3 171 7 3.1 <1 172 22 3.7 <1 173 12 2,2 174 12 7.2 175 10 9.7 176 92 15 177 13 7.4 178 16 7.2 179 140 47 180 110 3 181 <3 2 <1 182 100 26 183 49 19 184 <3 <1 <1 185 58 15 186 70 24 187 190 140 188 3.1 1,8 <1 189 AND <1 190 <3 <1 191 94 5.3 192 28 2.9 193 53 AND 194 78 44 195 <3 1,8 196 <3 4.7 197 15 5.3 198 20 22 199 >300 250 200 >300 >300 201 <3 <1 202 7,7 <1

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90 100 20 4.6 91 <3 8 92 14 1,7 <1 93 <3 2.6 94 7.1 2,2 <1 95 63 13 96 71 15 97 32 19 98 26 13 1,8 99 16 8.1 1,9 100 N.D. 280 101 8.6 2,3 102 12 10 1,2 103 54 23 104 130 28 105 180 18 106 47 21 107 42 8.1 2.8 108 53 12 109 110 39 3,3 111 20 <1 112 <3 <1 <1 FROM <3 And <1.5

203 12 2.9 204 8 1,8 205 26 17 <1.1 206 46 130 207 <3 1,4 208 72 12 209 170 52 210 220 250 211 200 190 212 110 57 213 31 19 214 27 15 215 8 3.9 216 58 17 217 >300 37 218 37 18 219 160 75 220 <3 4,4 221 <3 3.8 222 40 4.2 223 57 51 224 <3 <1 225 110 37 226 94 44 227 17 2.8 228 <3 9 <1 229 <3 15 230 <3 2.8

¹ CLi _nt is given after a single measurement (n=1) or as the average value of several measurements (n=2-3).

² CLint is given after a single measurement (n=1) or as the geometric mean of several measurements (n=2-3).

³ CLint is given after a single measurement (n=1) or as the geometric mean of several measurements (n=2).

Example 235. Permeability of Caco-2 cells

Caco-2 cell permeability was measured as described in Mol Pharm 2017, 14, 1601. Data for the test compounds are presented in Table 7.

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Table 7

Example Saso2 AB Own NY Parr ¹ (1Eb.cm/s) Caco2 Bidirectional (ABBA) from A to B Papp ¹ (1E-6.cm/s) Caco2 Bidirectional (ABBA) from B to A Pap ¹ (IE-b.cm/s) Saco2 Bidirectional (ABBA) Efflux Ratio 1 4.7 29 6.1 2 23 0.98 31 32 4 1,6 28 18 5 1,9 32 17 7 0.34 20 59 8 17 1,8 28 16 9 18 1,9 23 12 AND 0.34 9.8 29 12 0.29 19 65 14 0,15 2,4 16 15 0,30 13 45 16 0.16 4.2 26 18 13 0.90 31 34 21 3.7 23 6.2 22 41 6.9 26 3.8 24 3.5 33 9.3 27 30 4.9 29 5.9 28 21 1,6 20 12 29 26 3.7 37 10 30 15 3.1 30 9.6 32 8.7 28 3,3 33 7.5 19 2,5 40 20 3 28 9.3 41 16 42 2.8 33 12 50 0.83 27 32 67 6 1 19 19 68 16 2,5 21 8.3 69 7.6 0.79 22 28 70 1,4 26 18 71 0.78 23 30 72 1,3 24 19 74 1,8 53 29 75 0.77 17 21 76 0.64 20 31 77 0.57 16 29 78 1,2 27 21 79 1,1 33 29 80 0.81 25 31 81 1 25 24 87 1,4 29 21 88 13 1,3 29 23 89 5.4 0.38 18 47 90 1,2 19 16

Example Caco2 from A to B Own PApp ¹ (1Eb.cm/s) Caco2 Bidirectional (ABBA) from A to B Papp ¹ (IE-b.cm/s) Caco2 Bidirectional (ABBA) from B to A Pap ¹ (IE-b.cm/s) Caco2 Bidirectional (ABBA) Efflux Ratio 102 9 0.97 21 22 107 0.78 25 32 108 1,4 22 16 111 0.17 10 61 112 <0.24 0.51 3 6 FROM 20 1,9 23 12 122 0,20 10 50 123 14 0.17 29 170 124 0.65 39 59 128 0.57 26 45 129 0.39 21 54 135 4,4 29 6.5 138 5.5 32 5.8 147 2.7 40 15 151 9.5 2.6 30 AND 152 3.2 25 7,8 153 0.82 23 28 154 0.32 12 37 155 4.2 27 6.5 157 2 29 15 163 8.7 0.99 22 22 165 0.51 166 2 0.56 13 24 167 0.13 9.5 74 170 10 1,4 24 17 171 3.8 0.27 22 81 172 0.26 21 84 173 0.18 24 130 174 0.54 25 46 175 0.52 6.4 12 177 1,3 22 17 181 <0.20 0.24 z,z 13 184 0,10 0.25 0.78 3.1 188 0.28 0.18 3.7 21 189 0.29 13 46 190 0.32 7.6 24 192 0.51 39 76 195 0,40 4.8 12 196 0.63 10 17 198 3,4 36 AND 201 4.8 202 5.2 203 0,40 8 20 204 0.44 8.5 19

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91 0.90 30 33 92 0,12 4.2 35 93 0.33 17 50 94 0,15 4,4 29 97 0.52 23 45 98 8.6 0.71 18 25 99 0.46 21 46

205 25 3,4 23 6.9 207 2,3 30 13 215 0.48 29 59 216 0.62 40 65 220 0.29 16 56 224 1,2 228 0.9 25 27 0.9 229 0,7 22 32 0,7 230 2 34 17 2

¹ Papp is given after a single measurement (n=1) or as the average value of several measurements (n=2-4).

Example 236. Kinetic solubility

Kinetic solubility was measured as described in Comput Aided Mol Des 2015, 29, 795. Data for the test compounds are presented in Table 8.

Example R Soluble (μM) ¹ 1 >1000 2 83 3 700 4 55 5 11 6 120 7 >1000 8 680 9 310 10 270 11 170 12 830 13 27 14 830 15 890 16 170 17 250 18 93 19 480 20 900 21 390 22 460 23 63 24 500 25 130 26 15 27 720

Table 8

Example R Soluble (μM) ¹ 77 850 78 190 79 610 80 980 81 900 82 970 83 840 84 940 85 800 86 640 87 910 88 >980 89 910 90 >1000 91 >1000 92 810 93 300 94 920 95 960 96 >1000 97 950 98 >1000 99 800 100 36 101 >1000 102 >1000 103 >1000

Example Soluble (μM) ¹ 153 930 154 850 155 400 156 100 157 62 158 8.9 159 550 160 1,8 161 84 162 140 163 160 164 64 165 >1000 166 >910 167 240 168 169 26 170 11 171 320 172 100 173 32 174 800 175 640 176 800 177 40 178 6 179 BY

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28 73 29 560 30 >1000 31 180 32 240 55 85 34 770 35 600 36 <98 37 210 38 33 39 22 40 290 41 620 42 850 43 52 44 140 45 340 46 190 47 57 48 18 49 13 50 33 51 56 52 57 53 2.6 54 13 55 AND 56 5.9 57 150 58 5.8 59 40 60 160 61 670 62 640 63 690 64 130 65 49 66 210 67 >860 68 180 69 >1000

104 930 105 >1000 106 700 107 >1000 108 880 109 110 950 111 330 112 670 FROM 71 114 4,5 115 0.59 116 490 117 25 118 20 119 1 120 0.92 121 44 122 >1000 123 280 124 38 125 38 126 400 127 120 128 960 129 58 130 16 131 140 132 13 133 <380 134 71 135 310 136 21 137 74 138 260 139 50 140 39 141 140 142 1,8 143 33 144 18 145 5.3

180 170 181 >1000 182 230 183 19 184 930 185 7 186 130 187 19 188 990 189 840 190 >1000 191 400 192 530 193 940 194 480 195 830 196 700 197 6 198 38 199 85 200 81 201 90 202 140 203 540 204 480 205 270 206 26 207 280 208 1,6 209 970 210 150 211 110 212 16 213 100 214 230 215 350 216 710 217 410 218 <0.16 219 2,5 220 460 221 360

- 279 048482

¹ Solubility is given after a single measurement (n=1) or as the average value of several measurements (n=2-3).

Example 237. Activity of the target-binding enzyme FAP in mouse plasma

The effect of the test compound on FAP enzyme activity in mouse plasma was assessed in an enzymatic assay using the fibroblast activating protein alpha (FAP)-specific fluorogenic dipeptide-coumarin substrate, Ala-Pro-AMC, (ARI-3144). In this assay, FAP cleaves Ala-Pro-AMC to release free AMC, which is measured as a fluorescent signal that correlates with enzymatic activity.

Male C57B1/6 mice (Charles River, Germany), 8 weeks old, were housed individually in a temperature-controlled room under a 12-hour light/dark cycle (lights on 06:00-18:00). Mice had ad libitum access to water and rodent chow (R70, Lactamine, Kimstad, Sweden) and were acclimatized for 5 days upon arrival. After acclimatization, all mice received a single oral dose of test compound (3 or 10 mg/kg). Blood samples were collected to measure whole blood exposure to the compounds at 0.25, 0.5, 1, 2, 4, 8, and 24 h after oral dosing. Samples were collected into EDTA-containing capillary tubes (20 µl, K2E, REF 19.447) and transferred to a 96-well deepwell plate (NUNC, Thermo Discher Scientific) and stored at -20°C until further analysis. Blood samples for plasma FAP enzyme activity measurement were collected at 0, 0.25, 0.5, 1, 2, 8 and 24 h post-dose. 25 µl of whole blood were collected into Microvette® CB 300 tubes (K2E, REF 16.444.100) with EDTA and centrifuged at 4,000 x g for 5 min. 10 µl of plasma were then transferred to PCR tubes and stored at -20°C until further analysis. All blood samples were collected by saphenous vein puncture.

Recombinant human FAP (PB-17-1837, construct PL-17-0278, cd33-FAP(27-757)-6His with a MW of 85,926 Da) was used as a standard for this assay. The protein was secreted from Sf21 cells (insect cells) in medium, purified by affinity (batch mode, Ni excel resin) and size exclusion chromatography (Superdex200), concentrated and aliquoted for freezing in liquid _N2 for storage at -80°C. Recombinant FAP was diluted in protein buffer (25 mM Tris/HCl, pH 7.6, 150 mM NaCl, 5% glycerol, 1 mM EDTA, 0.25 mM TCEP) and 5 µl aliquots (0.1 mg/ml, 1.15 µM) were stored at -80°C. Standards were prepared using 2-fold dilution steps, 8 concentrations, 4 replicates (FAC: 1.2 nM, 0.6 nM, 0.3 nM ...). Plates were read on a Beckman Paradigm plate reader with excitation at 360 nm and emission at 465 nm. Fluorescence measurements were performed with kinetic readings every 5 min for 60 min at room temperature. Data were analyzed in Excel (IDBS XLfit Add-In) using a linear regression model (y=k*x+m) to generate a standard curve of recombinant human FAP.

On the day of analysis, blood plasma was diluted (1:2) to a volume of 20 μl in buffer (PBS, 0.1% BSA) and 7.5 μl was transferred to an assay plate (black 384-well, fluotrack PS, Greiner 781076). Ala-Pro-AMS (stock solution in 10 mM DMSO) was diluted in buffer (PBS, 0.1% BSA) to a concentration of 150 μM (180 μl of stock solution per 12 ml of buffer) and 7.5 μl was added to the assay plate, followed by pipetting of the mixture. Plates were read on a Beckman Paradigm reader with excitation at 360 nm and emission at 465 nm. Fluorescence measurements were performed with kinetic readings every 5 minutes for 60 minutes at room temperature. As noted above, FAP cleaves Ala-Pro-AMC to release free AMC, which is measured as a fluorescent signal.

The in vivo IC ₅₀ potency of each test compound was then estimated by relating the compound's plasma exposure C to its plasma target binding ^E using the following equation:

where E ₀ represents the baseline plasma FAP level before dosing and I _max represents the maximal effect of the compound. Data from each binding experiment were

- 280 048482 targets were analyzed separately and hence slightly different estimates of baseline FAP were obtained for each compound. Complete inhibition was achieved for all test compounds at earlier time points and hence the I _max parameter was fixed at 1 for all compounds. Parameter estimation was performed in Phoenix WinNonlin Certara, build 8.1.0.3530 with the 'Naive pooled' algorithm as the parameter estimation method. Estimated in vivo IC ₅₀ values for the test compounds are listed in Table 9.

Table 9

Example IC50 mouse in vivo (nM) ¹ 27 1,4 67 0.18 68 19 69 2,1 71 2.8 72 7.2 80 9.0 FROM 2.0 151 z,z 163 3.0 169 1,4 170 8.7 171 2,5 205 1,2

Although specific embodiments and examples have been described above, such embodiments and examples are illustrative only and do not limit the scope of the invention. Changes and modifications can be made by a person of ordinary skill in the art without departing from the scope of the invention in its broader aspects, as defined in the following claims. For example, any embodiment described herein can be combined with any other suitable embodiment described herein to produce additional embodiments.

As will be understood by those skilled in the art, all numbers, including numbers expressing quantities of ingredients, properties such as molecular weight, reaction conditions, etc., are approximate and are understood in all cases as modified by the term approximately. Such values may vary depending on the desired properties to be obtained by those skilled in the art using the present teachings of the present invention. It is also understood that such values by their nature contain variability necessarily arising from standard deviations found in their respective test measurements.

One skilled in the art will also readily appreciate that when members are grouped together in a conventional manner, such as in a Markush group, the present invention encompasses not only the entire group as recited, but also each individual member of the group and all possible subgroups of the main group. Additionally, for all purposes, the present invention encompasses not only the main group, but also a main group from which one or more members of the group are missing. The present invention also contemplates an express exclusion or qualification for one or more members of a group in the claimed invention.

As will be understood by one skilled in the art, for any and all purposes, particularly in terms of providing a written description, all ranges disclosed herein also encompass any and all possible subranges and combinations of subranges thereof, as well as individual values comprising the range, particularly integer values. Any range listed can be readily recognized as being sufficiently descriptive and allowing the same range to be subdivided into at least equal halves, thirds, quarters, fifths, tenths, etc. As a non-limiting example, each range discussed herein can readily be subdivided into a lower third, a middle third, and an upper third, etc. For example, the range C( _1-6 ) includes the subranges C( _{2_6} ), C( _3-6 ), C( _3-5 ), _C (4-6), etc., as well as C1 (methyl), C2 (ethyl), _C3 (propyl), _C4 (butyl), _C5 (pentyl), and _C6 (hexyl) individually. As will be understood by one skilled in the art, all phrases such as up to, at least, greater than, less than, more than, or more, etc., include the stated number and refer to ranges that can be successively subdivided into subranges as discussed above. Likewise, all ratios disclosed in

- 281 048482 in this document also include all sub-ratios falling under the broader ratio.

Reference to a step in the present invention is for convenience only and does not classify, define or limit the invention as set forth herein.

Claims (11)

CLAUSE OF INVENTION E A compound which is (K)-N-(2-(4-cyanothiazolidin-3-yl)-2-oxoethyl)-6-morpholinoquinoline-4-carboxamide, having the structure: or a pharmaceutically acceptable salt thereof. 2. The compound according to claim 1, which is a non-salt form of (R)-N-(2-(4-cyanothiazolidin-3-yl)-2-oxoethyl)-6-morpholinoquinoline-4-carboxamide having the structure 3. The compound of claim 1, which is a pharmaceutically acceptable salt of (R)-N-(2-(4-cyanothiazolidin-3-yl)-2-oxoethyl)-6-morpholinoquinoline-4-carboxamide, having the structure 4. A pharmaceutical composition comprising a compound according to any one of claims 1-3 and one or more pharmaceutically acceptable excipients. 5. Use of a compound according to any one of claims 1-3 as a medicinal product. 6. Use of a compound according to any one of claims 1 to 3 for the treatment of liver disease. 7. A method for treating or preventing liver disease in a subject suffering from or susceptible to liver disease, the method comprising administering to the subject a therapeutically effective amount of a compound according to any one of claims 1-3. 8. Use of the pharmaceutical composition according to item 4 as a medicinal product. 9. Use of the pharmaceutical composition according to item 4 for the treatment of liver disease. 10. A method for treating or preventing liver disease in a subject suffering from or susceptible to liver disease, the method comprising administering to the subject a therapeutically effective amount of the pharmaceutical composition of claim 4. I. Use according to claim 6 or 9, wherein the liver disease is non-alcoholic steatohepatitis. 12. The method according to claim 7 or 10, wherein the liver disease is non-alcoholic steatohepatitis.