Compounds for use in treating neurological disorders

Abstract

To provide methods for treating neurological disorders.SOLUTION: The present invention provides methods including administration of compounds of Formula (I) or pharmaceutically acceptable salts thereof.SELECTED DRAWING: None

Description

[Technical Field]

[0001] Related Applications This application claims priority to U.S. Provisional Application No. 62 / 879,870, filed July 29, 2019, the entire contents of which are incorporated herein by reference. [Background technology]

[0002] Neurological disorders affect the central, peripheral, or autonomic nervous system. The specific causes of neurological problems vary but can include genetic disorders, congenital abnormalities or disorders, infections, lifestyle or environmental health issues including malnutrition, and brain injury, spinal cord injury, nerve injury, and gluten sensitivity (with or without intestinal disorders or digestive symptoms).

[0003] According to the World Health Organization (WHO), neurological disorders are one of the greatest threats to public health. In 2006 alone, the WHO estimated that neurological disorders and their direct consequences affect as many as 1 billion people worldwide. Furthermore, according to the Interfederal Forum on Aging-Related Statistics, 35.8% of people aged 85 years and older have moderate or severe memory impairment, and more than 16% of U.S. households contain an individual with a brain disorder. Despite current research, the prevalence of neurological disorders remains high. Therefore, there is a continuing need for new, effective therapeutic agents for neurological disorders. Summary of the Invention

[0004] Provided herein are compounds that are useful for treating neurological disorders. Such compounds include compounds having formula I: [ka] and pharmaceutically acceptable salts and compositions thereof, wherein B, R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , and R 7is as described herein. DETAILED DESCRIPTION OF THE INVENTION

[0005] 1. Overview of the compound The compounds described in the methods herein include both the neutral form and pharmaceutically acceptable salts thereof.

[0006] In a first embodiment, the present invention provides a method of treating a neurological disorder, comprising administering to a subject an effective amount of a compound of formula I: [ka] or a pharmaceutically acceptable salt thereof, wherein: Ring B is aryl, heterocyclyl, or heteroaryl, each of which is R b and optionally substituted with 1 to 4 groups selected from R 6 is hydrogen or C 1-6 is alkyl, R 7 is aryl or heteroaryl, each of which is R f Selected from is substituted with one group, R 7 The aryl and heteroaryl for a or R 6 and R 7 together with the nitrogen ring to which they are attached, optionally R a forming a fused bicyclic heterocyclyl substituted with 1 to 4 groups selected from R 1 is C 1-6 Alkyl, C 1-6 Haloalkyl, C 2-6 Alkenyl, -C 1-6 Alkyl OR c , -C 1-6 AlkylN(R d )2, -C 1-6 AlkylC(O)OR d , -C1-6 Alkyl OC 1-6 AlkylN(R d )2, -C 1-6 Alkyl SOR d , -C 1-6 AlkylS(O)R d , -C 1-6 Alkyl SON(R d )2, -C 1-6 Alkyl SO2N(R d ) 2、 -C 1-6 Alkylcycloalkyl, -C 1-6 Alkylheterocyclyl, -C 1-6 Alkylheteroaryl, -C 1-6 alkylaryl, cycloalkyl, aryl, heteroaryl, or heterocyclyl, each of which is independently as well as -C 1-6 Alkylcycloalkyl, -C 1-6 Alkylaryl, -C 1-6 alkylheteroaryl, and -C 1-6 At the bond to the alkylheterocyclyl, optionally R c and is substituted with 1 to 3 groups selected from R 2 , R 3 , R 4 , and R 5 each independently represents hydrogen or C 1-6 alkyl, and the C 1-6 The alkyl is optionally selected from halo, -C(O)OR d , -OC 1-6 AlkylN(R d )2, -C 1-6 AlkylN(R d )2, -N(R d )2, -NR d C 1-6 Alkyl OR d , -SOR d , -S(O)2R d , -SON(R d )2, -SO2N(R d )2, C 3-10 Cycloalkyl, C 5-10Heterocyclyl, C 5-10 Heteroaryl, and C 6-10 substituted with one or two groups selected from aryl; R a , R b , and R c each independently selected from halo, CN, oxo, NO2, C 1-6 Alkyl, C 2-6 Alkenyl, C 1-6 Alkoxy, C 1-6 Haloalkoxy, C 1-6 Haloalkyl, -C 1-6 Alkyl OR d , -C(O)R d , -C(O)OR d , -C 1-6 AlkylC(O)OR d , -C(O)N(R d )2, -C(O)NR d C 1-6 Alkyl OR d , -OC 1-6 AlkylN(R d )2, -C 1-6 AlkylC(O)N(R d )2, -C 1-6 AlkylN(R d )2, -N(R d )2, -C(O)NR d C 1-6 AlkylN(R d )2, -NR d C 1-6 AlkylN(R d )2, -NR d C 1-6 Alkyl OR d , -SOR d , -S(O)2R d , -SON(R d )2, -SO2N(R d )2, SF5, -Ocycloalkyl, -OC 1-4 Alkylaryl, -C 1-6 Alkylcycloalkyl, -C 1-6 Alkylaryl, -C 1-6 Alkylheteroaryl, -C 1-6alkylheterocyclyl, cycloalkyl, heterocyclyl, heteroaryl, or aryl, each of which is independently cycloalkyl, heterocyclyl, aryl, and heteroaryl; and -Ocycloalkyl, -C 1-6 Alkylcycloalkyl, -C 1-6 Alkylaryl, -C 1-6 alkylheteroaryl, and -C 1-6 At the bond to the alkylheterocyclyl, optionally halo, C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 1-6 Haloalkoxy, -N(R d )2, -C(O)R d , and -C 1-6 Alkyl OR d and substituted with 1 to 3 groups selected from Each R d are independently hydrogen, C 1-6 Haloalkyl, or C 1-6 is alkyl, Each R f is independently cycloalkyl, heterocyclyl, heteroaryl, or aryl, each of which is optionally selected from halo, CN, oxo, NO, C 1-6 Alkyl, C 2-6 Alkenyl, C 1-6 Alkoxy, C 1-6 Haloalkoxy, C 1-6 Haloalkyl, -C 1-6 Alkyl OR d , -C(O)R d , -C(O)OR d , -C 1-6 AlkylC(O)OR d , -C(O)N(R d )2, -C(O)NR d C 1-6 Alkyl OR d , -OC 1-6 AlkylN(R d )2, -C 1-6 AlkylC(O)N(R d)2, -C 1-6 AlkylN(R d )2, -N(R d )2, -C(O)NR d C 1-6 AlkylN(R d )2, -NR d C 1-6 AlkylN(R d )2, -NR d C 1-6 Alkyl OR d , -SOR d , -S(O)2R d , -SON(R d )2, -SO2N(R d )2, SF5, -Ocycloalkyl. Also provided as part of the first embodiment is the use of an effective amount of a compound of Formula I, or a pharmaceutically acceptable salt thereof, for the treatment of a neurological disorder, wherein the variables of Formula I are as described above in this paragraph. Also provided as part of the first embodiment is the use of a compound of Formula I, or a pharmaceutically acceptable salt thereof, for the manufacture of a medicament for treating a neurological disorder, wherein the variables of Formula I are as described above in this paragraph. Additionally provided is a pharmaceutical composition comprising a compound of Formula I, or a pharmaceutically acceptable salt thereof, for the treatment of a neurological disorder, wherein the variables of Formula I are as described above in this paragraph.

[0007] 2.Definition When used in conjunction to describe a chemical group that may have multiple points of attachment, the hyphen (-) designates the point of attachment of that group to the variable for which it is defined. For example, -N(R d )2 and -NR d C 1-6 Alkyl OR d means that the point of attachment of this group occurs on the nitrogen atom.

[0008] The terms "halo" and "halogen" refer to an atom selected from fluorine (fluoro, -F), chlorine (chloro, -Cl), bromine (bromo, -Br), and iodine (iodo, -I).

[0009] The term "alkyl" can be used alone or in the form of "haloalkyl", "alkyl C 5-10 When used as part of a larger moiety, such as "heterocyclyl," means a saturated straight-chain or branched monovalent hydrocarbon radical. Unless otherwise specified, an alkyl group typically has 1 to 6 carbon atoms, i.e., (C1-C6) alkyl.

[0010] "Alkoxy" refers to an alkyl radical attached through an oxygen linking atom, represented by -O-alkyl. For example, "(C1-C4)alkoxy" includes methoxy, ethoxy, butoxy, and butoxy.

[0011] The term "haloalkyl" includes mono-, poly-, and perhaloalkyl groups, where the halogens are independently selected from fluorine, chlorine, bromine, and iodine.

[0012] A "haloalkoxy" is a haloalkyl group attached to another moiety via an oxygen atom, such as, but not limited to, -OCHCF2 or -OCF3.

[0013] The term "oxo" refers to the diradical =O.

[0014] The term "aryl" refers to an aromatic carbocyclic single ring or two fused ring systems containing 6 to 10 carbon atoms. Examples include phenyl, indanyl, tetrahydronaphthalene, and naphthyl.

[0015] The term "carbocyclyl" refers to a monocyclic, bicyclic (e.g., bridged or spiro bicyclic ring), polycyclic (e.g., tricyclic), or fused hydrocarbon ring system that is fully saturated or contains one or more units of unsaturation, but no aromatic rings are present. A cycloalkyl is a fully saturated carbocycle. Monocyclic cycloalkyl groups include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, and cyclooctyl. Bridged bicyclic cycloalkyl groups include, but are not limited to, bicyclo[3.2.1]octane, bicyclo[2.2.1]heptane, bicyclo[3.1.0]hexane, bicyclo[1.1.1]pentane, and the like. Spiro bicyclic cycloalkyl groups include, for example, spiro[3.6]decane, spiro[4.5]decane, and the like. ]decane, etc. Fused cycloalkyl rings include, for example, decahydronaphthalene, octahydropentalene, etc. It will be understood that when specified, any substituent on a carbocyclyl (e.g., in the case of an optionally substituted cycloalkyl) can be located at any substitutable position, including, for example, the position at which the carbocyclyl group is attached.

[0016] The term "heteroaryl," used alone or as part of a larger moiety, refers to a 5- to 12-membered aromatic radical containing 1 to 4 heteroatoms selected from N, O, and S. Heteroaryl groups can be monocyclic or bicyclic. Monocyclic heteroaryls include, for example, thienyl, furanyl, pyrrolyl, imidazolyl, pyrazolyl, triazolyl, tetrazolyl, oxazolyl, isoxazolyl, oxadiazolyl, thiazolyl, isothiazolyl, thiadiazolyl, pyridyl, pyridazinyl, pyrimidinyl, pyrazinyl, and the like. Bicyclic heteroaryls include groups in which a monocyclic heteroaryl ring is fused to one or more aryl or heteroaryl rings. Non-limiting examples include indolyl, imidazopyridinyl, benzoxazolyl, benzoxodiazolyl, indazolyl, benzimidazolyl, benzthiazolyl, quinolyl, quinazolinyl, quinoxalinyl, pyrrolopyridinyl, pyrrolopyrimidinyl, pyrazolopyridinyl, thienopyridinyl, thienopyrimidinyl, indolizinyl, purinyl, naphthyridinyl, and pteridinyl. When specified, it will be understood that any substituent on a heteroaryl group may be present at any substitutable position, including, for example, the position at which the heteroaryl is attached.

[0017] The term "heterocyclyl" refers to a 5- to 12-membered saturated or partially unsaturated heterocycle containing 1 to 4 heteroatoms independently selected from N, O, and S. It can be monocyclic, bicyclic (e.g., bridged, fused, or spiro bicyclic rings), or tricyclic. The heterocyclyl ring can be attached to its pendant group at any heteroatom or carbon atom that results in a stable structure. Examples of such saturated or partially unsaturated heterocyclic radicals include, but are not limited to, tetrahydrofuranyl, tetrahydrothienyl, tetrahydropyranyl, pyrrolidinyl, pyridinonyl, pyrrolidonyl, piperidinyl, oxazolidinyl, piperazinyl, dioxanyl, dioxolanyl, morpholinyl, dihydrofuranyl, dihydropyranyl, dihydropyridinyl, tetrahydropyridinyl, dihydropyrimidinyl, oxetanyl, azetidinyl, and tetrahydropyrimidinyl. The heterocyclyl group can be monocyclic or bicyclic. The term "heterocyclyl" also includes another unsaturated heterocyclic radical or an unsaturated heterocyclic radical fused to an aryl or heteroaryl ring, such as, for example, tetrahydronaphthyridine, indolinone, dihydropyrotriazole, imidazopyrimidine, quinolinone, dioxaspirodecane, etc. It will also be understood that, when specified, any substituent on a heterocyclyl group may be located at any substitutable position, including, for example, the position at which the heterocyclyl is attached (e.g., optionally substituted heterocyclyl or optionally substituted in the case of heterocyclyl).

[0018] The term "spiro" refers to two rings that share one ring atom (eg, carbon).

[0019] The term "fused" refers to two rings that share two adjacent ring atoms with each other.

[0020] The term "bridged" refers to two rings which share three ring atoms with one another.

[0021] The disclosed compounds exist in various stereoisomeric forms. Stereoisomers are compounds that differ only in their spatial configuration. Enantiomers are pairs of stereoisomers whose mirror images are not superimposable, most commonly consisting of an asymmetrically substituted carbon atom that serves as a chiral center. atoms. "Enantiomer" means one of a pair of molecules that are mirror images of each other and are not superimposable. Diastereomers are stereoisomers that contain two or more asymmetrically substituted carbon atoms. The symbol "*" in a structural formula denotes the presence of a chiral carbon center. "R" and "S" represent the configuration of substituents around one or more chiral carbon atoms. Thus, "R*" and "S*" indicate the relative configuration of substituents around one or more chiral carbon atoms.

[0022] A "racemate" or "racemic mixture" means a compound of equimolar amounts of two enantiomers; such a mixture exhibits no optical activity, i.e., does not rotate the plane of polarized light.

[0023] The compounds of the methods herein can be prepared as individual enantiomers by enantiospecific synthesis or resolved from enantiomerically enriched mixtures. Traditional resolution techniques include using optically active acids to form salts of the free bases of each isomer of the enantiomeric pair (followed by fractional crystallization and regeneration of the free bases), using optically active amines to form salts of the acid forms of each enantiomer of the enantiomeric pair (followed by fractional crystallization and regeneration of the free acids), using optically pure acids, amines, or alcohols to form esters or amides of each enantiomer of the enantiomeric pair (followed by chromatographic separation and removal of the chiral auxiliary), or resolving enantiomeric mixtures of either the starting material or the final product using a variety of well-known chromatographic methods. Additionally, compounds can be prepared as individual enantiomers by separating racemic mixtures using conventional chiral chromatographic techniques.

[0024] When the stereochemistry of a disclosed compound is named or depicted by structure, the named or depicted stereoisomer is at least 60%, 70%, 80%, 90%, 99%, or 99.9% pure by weight relative to all other stereoisomers. Percent pure by weight relative to all other stereoisomers is the ratio of the weight of one stereoisomer to the weight of the other stereoisomer. When a single enantiomer is named or depicted by structure, the depicted or named enantiomer is at least 60%, 70%, 80%, 90%, 99%, or 99.9% optically pure by weight. Percent optical purity by weight refers to the ratio of the weight of an enantiomer to the weight of the enantiomer plus the weight of its optical isomer.

[0025] When the stereochemistry of a disclosed compound is named or depicted by structure, and the named or depicted structure encompasses more than one stereoisomer (e.g., as in a diastereomeric pair), it is to be understood that one of the encompassed stereoisomers or any mixture of the encompassed stereoisomers is included. It is further understood that the stereoisomeric purity of the named or depicted stereoisomer is at least 60%, 70%, 80%, 90%, 99%, or 99.9% pure by weight relative to all other stereoisomers. Stereoisomeric purity in this case is determined by dividing the total weight in the mixture of the stereoisomers encompassed by the name or structure by the total weight in the mixture of all stereoisomers.

[0026] When a disclosed compound is named or depicted by structure without indicating stereochemistry, and the compound has one chiral center, it is understood that the name or structure encompasses one enantiomer of the compound free of the corresponding optical isomer, a racemic mixture of the compound, or a mixture enriched in one enantiomer relative to its corresponding optical isomer.

[0027] The disclosed compounds are named or depicted by structure without indicating stereochemistry, e.g., where a compound has more than one chiral center (e.g., at least two chiral centers), In this case, it is understood that the name or structure encompasses a single stereoisomer free of other stereoisomers, a mixture of stereoisomers, or a mixture of stereoisomers enriched in one or more stereoisomers relative to the other stereoisomers. For example, a name or structure may encompass a single stereoisomer free of other diastereomers, a mixture of stereoisomers, or a mixture of stereoisomers enriched in one or more diastereomers relative to the other diastereomers.

[0028] Unless otherwise specified, when only some of the stereochemical centers in a disclosed compound are depicted or named by structure, the named or depicted configurations are enriched relative to the remaining configurations, e.g., by at least a 60%, 70%, 80%, 90%, 99%, or 99.9% molar excess. For example, the following structure: [ka] This means that the configuration about the chiral carbon for which stereochemistry is depicted is stereochemically enriched as S (e.g., by at least 60%, 70%, 80%, 90%, 99%, or 99.9% molar excess), and the stereochemistry at the other chiral center for which stereochemistry is not specified can be R or S, or a mixture thereof.

[0029] The terms "subject" and "patient" may be used interchangeably and refer to a mammal in need of treatment, such as companion animals (e.g., dogs, cats, etc.), livestock (e.g., cows, pigs, horses, sheep, goats, etc.), and laboratory animals (e.g., rats, mice, guinea pigs, etc.). Typically, the subject is a human in need of treatment.

[0030] The terms "inhibit," "inhibition," or "inhibiting" include a decrease in the baseline activity of a biological activity or process.

[0031] As used herein, the terms "treatment," "treat," and "treating" refer to reversing, alleviating, delaying the onset of, or inhibiting the progression of a neurological disorder described herein, or one or more symptoms thereof. In some embodiments, treatment may be administered after one or more symptoms have developed, i.e., therapeutic treatment. In other embodiments, treatment may be administered in the absence of symptoms. For example, treatment may be administered to a susceptible individual prior to the onset of symptoms (e.g., in light of a history of symptoms and / or exposure to a particular organism or other susceptibility factor), i.e., prophylactic treatment. Treatment may also be continued after symptoms have resolved, e.g., to delay recurrence.

[0032] The term "pharmaceutically acceptable carrier" refers to a non-toxic carrier, adjuvant, or vehicle that does not destroy the pharmacological activity of the compound in which it is formulated. Pharmaceutically acceptable carriers, adjuvants, or vehicles that can be used in the compositions described herein include, but are not limited to, ion exchangers, alumina, aluminum stearate, lecithin, serum proteins such as human serum albumin, buffer substances such as phosphates, partial glyceride mixtures of saturated vegetable fatty acids, water, salts, or electrolytes such as glycine, sorbic acid, potassium sorbate, and protamine sulfate, disodium hydrogen phosphate, potassium hydrogen phosphate, sodium chloride, zinc salts, colloidal silica, magnesium trisilicate, polyvinylpyrrolidone, cellulose-based substances, polyethylene glycol, sodium carboxymethylcellulose, polyacrylates, waxes, polyethylene-polyoxypropylene-block polymers, polyethylene glycol, and wool fat.

[0033] The term "effective amount" or "therapeutically effective amount" refers to an amount of a compound described herein that elicits a biological or medical response in a subject, e.g., a dosage of 0.01 to 100 mg / kg body weight / day.

[0034] 3.Compound In a second embodiment of the methods described herein, a compound of formula I: [ka] or a pharmaceutically acceptable salt thereof, in which the variables are as described above, with the proviso that the compound is not N-[1,1'-biphenyl]-2-yl-2-[[2-(3,4-dimethoxyphenyl)ethyl]amino]-propanamide, or 2-[(2-phenylpropyl)amino]-N-[4-(1H-1,2,4-triazol-1-yl)phenyl]-propanamide, and salts thereof.

[0035] In a third embodiment of the methods described herein, the compound of formula I is of formula II or III: [ka] or a pharmaceutically acceptable salt thereof, wherein the remainder of the variables are as described for Formula I or the second embodiment.

[0036] In a fourth embodiment of the methods described herein, R in a compound of formula I, II, or III 6 is hydrogen and R 7 is aryl or heteroaryl, each of which is R f and R 7 The aryl and heteroaryl for a or R 6 and R 7 together with the nitrogen ring to which they are attached, optionally R a and the remainder of the variables are as described above with respect to Formula I or the second embodiment. Alternatively, R in compounds of Formula I, II, or III forms a fused bicyclic heterocyclyl substituted with 1 to 4 groups selected from 6 is hydrogen and R 7 is phenyl, pyridyl, pyrimidinyl, or quinolinyl, each of which is R f and R 7The phenyl, pyridyl, pyrimidinyl, and quinolinyl groups may also optionally be R a or R 6 and R 7 together with the nitrogen ring to which they are attached, optionally R a and the remaining variables are as described above with respect to Formula I or the second embodiment. As another alternative, R in a compound of Formula I, II, or III forms a 5,6- or 6,6-fused bicyclic heterocyclyl substituted with 1 to 4 groups selected from 6 is hydrogen and R 7 is selected from phenyl, 2-pyridinyl, 3-pyridinyl, pyrimidin-5-yl, and quinolin-6-yl, each of which is selected from R f and R 7 The phenyl, 2-pyridinyl, 3-pyridinyl, pyrimidin-5-yl, and quinolin-6-yl for a or R 6 and R 7 together with the nitrogen ring to which they are attached form indolin-1-yl or dihydroquinolin-1(2H)-yl, each of which optionally contains R a and the remaining variables are as defined for Formula I or the second embodiment. As described above.

[0037] In a fifth embodiment of the methods described herein, ring B of the compound of formula I, II, or III is R b and the remainder of the variables are as described above with respect to Formula I or the second or fourth embodiment.

[0038] In a sixth embodiment of the methods described herein, R in a compound of formula I, II, or III 1 is R cand the remainder of the variables are as described above with respect to Formula I or the second, fourth, or fifth embodiment.

[0039] In a seventh embodiment of the methods described herein, R in the compound of formula I, II, or III 3 is hydrogen, and the remainder of the variables are as described above with respect to Formula I or the second, fourth, fifth, or sixth embodiment.

[0040] In an eighth embodiment of the methods described herein, R in the compound of formula I, II, or III 5 is hydrogen, and the remainder of the variables are as described above with respect to Formula I or the second, fourth, fifth, sixth, or seventh embodiment.

[0041] In a ninth embodiment of the methods described herein, R in a compound of formula I, II, or III 2 is hydrogen or C 1-4 is alkyl, and the remainder of the variables are as described above with respect to Formula I or the second, fourth, fifth, sixth, seventh, or eighth embodiment. Alternatively, R of a compound of Formula I, II, or III is 2 is hydrogen or methyl, and the remaining variables are as described above with respect to Formula I, or the second, fourth, fifth, sixth, seventh, or eighth embodiment. As another alternative, R in a compound of Formula I, II, or III 2 is hydrogen, and the remainder of the variables are as described above with respect to Formula I or the second, fourth, fifth, sixth, seventh, or eighth embodiment.

[0042] In a tenth embodiment of the methods described herein, R in a compound of formula I, II, or III 4 is hydrogen or C 1-4 alkyl, and the remainder of the variables are as described above with respect to Formula I or the second, fourth, fifth, sixth, seventh, eighth, or ninth embodiment. Alternatively, R in a compound of Formula I, II, or III 4is hydrogen, methyl, or ethyl, and the remaining variables are as described above with respect to Formula I or the second, fourth, fifth, sixth, seventh, eighth, or ninth embodiment. As another alternative, R in a compound of Formula I, II, or III 4 is hydrogen, and the remainder of the variables are as described above with respect to Formula I or the second, fourth, fifth, sixth, seventh, eighth, or ninth embodiment.

[0043] In an eleventh embodiment of the methods described herein, the compound of formula I is of formula IV or V: [ka] or a pharmaceutically acceptable salt thereof, wherein w, q, and t are each independently 0, 1, or 2, and the remaining variables are as described above with respect to Formula I or the second, fourth, fifth, sixth, seventh, eighth, ninth, or tenth embodiment. Alternatively, the compound of Formula I can be one of Formula VI or VII: [ka] or a pharmaceutically acceptable salt thereof, wherein w, q, and t are each independently 0, 1, or 2, and the remaining variables are as described above with respect to Formula I or the second, fourth, fifth, sixth, seventh, eighth, ninth, or tenth embodiment. In another alternative, the compound of Formula I is of Formula VIII or IX: [ka] or a pharmaceutically acceptable salt thereof, wherein w, q, and t are each independently 0, 1, or 2, and the remaining variables are as described above with respect to Formula I or the second, fourth, fifth, sixth, seventh, eighth, ninth, or tenth embodiment.

[0044] In a twelfth embodiment of the methods described herein, in the compound of formula I, II, III, IV, V, VI, VII, VIII, or IX, R c If present, C 1-6Alkyl, C 1-6 Alkoxy, C 1-6 Haloalkoxy, or C 1-6 haloalkyl, and the remainder of the variables are as described above with respect to Formula I or the second, fourth, fifth, sixth, seventh, eighth, ninth, tenth, or eleventh embodiment.

[0045] In a thirteenth embodiment of the methods described herein, the compound of formula I is of formula X or XI: [ka] or a pharmaceutically acceptable salt thereof, and the remainder of the variables are as described above with respect to Formula I or the second, fourth, fifth, sixth, seventh, eighth, ninth, tenth, eleventh, or twelfth embodiment.

[0046] In a fourteenth embodiment of the methods described herein, q in the compound of Formula IV, V, VI, VII, VIII, or IX is 0 or 1, and the remaining variables are as described above with respect to Formula I or the second, fourth, fifth, sixth, seventh, eighth, ninth, tenth, eleventh, twelfth, or thirteenth embodiments.

[0047] In a fifteenth embodiment of the methods described herein, R in compounds of formula I, II, III, IV, V, VI, VII, VIII, IX, X, and XI a is C 1-4 alkoxy or halo, and the remainder of the variables are described above with respect to Formula I or the second, fourth, fifth, sixth, seventh, eighth, ninth, tenth, eleventh, twelfth, thirteenth, or fourteenth embodiment. That's right.

[0048] In a sixteenth embodiment of the methods described herein, R in compounds of formula I, II, III, IV, V, VI, VII, VIII, IX, X, and XI f is heteroaryl or heterocyclyl, each of which is optionally selected from halo, CN, oxo, NO, C 1-6 Alkyl, C 2-6 Alkenyl, C1-6 Alkoxy, C 1-6 Haloalkoxy, C 1-6 Haloalkyl, -C 1-6 Alkyl OR d , -C(O)R d , -C(O)OR d , -C 1-6 AlkylC(O)OR d , -C(O)N(R d )2, -C(O)NR d C 1-6 Alkyl OR d , -OC 1-6 AlkylN(R d )2, -C 1-6 AlkylC(O)N(R d )2, -C 1-6 AlkylN(R d )2, -N(R d )2, -C(O)NR d C 1-6 AlkylN(R d )2, -NR d C 1-6 AlkylN(R d )2, -NR d C 1-6 Alkyl OR d , -SOR d , -S(O)2R d , -SON(R d )2, -SO2N(R d )2, SF5, —Ocycloalkyl, and the remainder of the variables are as described above with respect to Formula I, or the second, fourth, fifth, sixth, seventh, eighth, ninth, tenth, eleventh, twelfth, thirteenth, fourteenth, or fifteenth embodiment. Alternatively, R in compounds of Formula I, II, III, IV, V, VI, VII, VIII, IX, X, and XI f is pyrazolyl, imidazolyl, pyridazinyl, piperazinyl, or piperidinyl, each of which is optionally selected from halo, CN, oxo, NO, C 1-6 Alkyl, C 2-6 Alkenyl, C 1-6 Alkoxy, C 1-6 Haloalkoxy, C 1-6 Haloalkyl, -C 1-6Alkyl OR d , -C(O)R d , -C(O)OR d , -C 1-6 AlkylC(O)OR d , -C(O)N(R d )2, -C(O)NR d C 1-6 Alkyl OR d , -OC 1-6 AlkylN(R d )2, -C 1-6 AlkylC(O)N(R d )2, -C 1-6 AlkylN(R d )2, -N(R d )2, -C(O)NR d C 1-6 AlkylN(R d )2, -NR d C 1-6 AlkylN(R d )2, -NR d C 1-6 Alkyl OR d , -SOR d , -S(O)2R d , -SON(R d )2, -SO2N(R d )2, SF5, —Ocycloalkyl, and the remainder of the variables are as described above for Formula I, or the second, fourth, fifth, sixth, seventh, eighth, ninth, tenth, eleventh, twelfth, thirteenth, fourteenth, or fifteenth embodiment.

[0049] In a seventeenth embodiment of the methods described herein, R in compounds of formula I, II, III, IV, V, VI, VII, VIII, IX, X, and XI f is pyrazolyl, imidazolyl, pyridazinyl, piperazinyl, or piperidinyl, each of which is C 1-4 Alkyl and -C(O)R d and R d is C 1-4is alkyl, and the remainder of the variables are as described above with respect to Formula I or the second, fourth, fifth, sixth, seventh, eighth, ninth, tenth, eleventh, twelfth, thirteenth, fourteenth, fifteenth, or sixteenth embodiment.

[0050] In an eighteenth embodiment of the methods described herein, R in compounds of formula I, II, III, IV, V, VI, VII, VIII, IX, X, and XI b is halo, and the remainder of the variables are as described above for Formula I or the second, fourth, fifth, sixth, seventh, eighth, ninth, tenth, eleventh, twelfth, thirteenth, fourteenth, fifteenth, sixteenth, or seventeenth embodiment.

[0051] In a nineteenth embodiment of the methods described herein, the compound of formula I is of formula XII or XIII: [ka] or a pharmaceutically acceptable salt thereof, wherein w, q, and t are each independently 0, 1, or 2, and the remaining variables are as described above with respect to Formula I or the second, fourth, fifth, sixth, seventh, eighth, ninth, or tenth embodiment. Alternatively, the compound of Formula I can be of Formula XIV or XV: [ka] or a pharmaceutically acceptable salt thereof, wherein w, q, and t are each independently 0, 1, or 2, and the remaining variables are as described above with respect to Formula I or the second, fourth, fifth, sixth, seventh, eighth, ninth, or tenth embodiment. In another alternative, the compound of Formula I is of Formula XVI or XVII: [ka] or a pharmaceutically acceptable salt thereof, wherein w, q, and t are each independently 0, 1, or 2, and the remaining variables are as described above with respect to Formula I or the second, fourth, fifth, sixth, seventh, eighth, ninth, or tenth embodiment. In another alternative, the compound of Formula I is of Formula XVIII or XIX: [ka] or a pharmaceutically acceptable salt thereof, wherein w, q, and t are each independently 0, 1, or 2, and the remaining variables are as described above with respect to Formula I or the second, fourth, fifth, sixth, seventh, eighth, ninth, or tenth embodiment. In another alternative, the compound of Formula I is of Formula XX or XXI: [ka] or a pharmaceutically acceptable salt thereof, wherein w, q, and t are each independently 0, 1, or 2, and the remaining variables are as described above with respect to Formula I or the second, fourth, fifth, sixth, seventh, eighth, ninth, or tenth embodiment. In another alternative, the compound of Formula I is of Formula XXII or XXIII: [ka] or a pharmaceutically acceptable salt thereof, wherein w, q, and t are each independently 0, 1, or 2, and the remaining variables are as described above with respect to Formula I or the second, fourth, fifth, sixth, seventh, eighth, ninth, or tenth embodiment.

[0052] In a twentieth embodiment of the methods described herein, R in compounds of formula XII, XIII, XIV, XV, XVI, XVII, XVIII, XIX, XX, XXI, XXII, and XXIII c If present, independently, C 1-6alkyl, halo, or CN, and the remainder of the variables are as described above with respect to Formula I or the second, fourth, fifth, sixth, seventh, eighth, ninth, tenth, or nineteenth embodiment. Alternatively, R in compounds of Formulas XII, XIII, XIV, XV, XVI, XVII, XVIII, XIX, XX, XXI, XXII, and XXIII is c If present, C 1-4 is alkyl, and the remainder of the variables are as described above with respect to Formula I or the second, fourth, fifth, sixth, seventh, eighth, ninth, tenth, or nineteenth embodiment.

[0053] In a twenty-first embodiment of the methods described herein, w in the compounds of Formula XII, XIII, XIV, XV, XVI, XVII, XVIII, XIX, XX, XXI, XXII, and XXIII is 0 or 1, and the remaining variables are as described above with respect to Formula I or the second, fourth, fifth, sixth, seventh, eighth, ninth, tenth, nineteenth, or twentieth embodiment.

[0054] In a twenty-second embodiment of the methods described herein, R in compounds of formula XII, XIII, XIV, XV, XVI, XVII, XVIII, XIX, XX, XXI, XXII, and XXIII b is cyano, and the remainder of the variables are as described above with respect to Formula I, or the second, fourth, fifth, sixth, seventh, eighth, ninth, tenth, nineteenth, twentieth, or twenty-first embodiment.

[0055] In a 23rd embodiment of the methods described herein, t in the compounds of Formula XII, XIII, XIV, XV, XVI, XVII, XVIII, XIX, XX, XXI, XXII, and XXIII is 1, and the remaining variables are as described above for Formula I or the second, fourth, fifth, sixth, seventh, eighth, ninth, tenth, nineteenth, twentieth, twenty-first, or twenty-second embodiment.

[0056] In a 24th embodiment of the methods described herein, q in compounds of Formula XII, XIII, XIV, XV, XVI, XVII, XVIII, XIX, XX, XXI, XXII, and XXIII is 1, and the remaining variables are as described above for Formula I or the second, fourth, fifth, sixth, seventh, eighth, ninth, tenth, nineteenth, twentieth, twenty-first, twenty-second, or twenty-third embodiment.

[0057] In a twenty-fifth embodiment of the methods described herein, R in compounds of formula XII, XIII, XIV, XV, XVI, XVII, XVIII, XIX, XX, XXI, XXII, and XXIII f is cycloalkyl, phenyl, heteroaryl, or heterocyclyl, each of which is optionally selected from halo, CN, oxo, NO, C 1-6 Alkyl, C 2-6 Alkenyl, C 1-6 Alkoxy, C 1-6 Haloalkoxy, C 1-6 Haloalkyl, -C 1-6 Alkyl OR d , -C(O)R d , -C(O)OR d , -C 1-6 AlkylC(O)OR d , -C(O)N(R d )2, -C(O)NR d C 1-6 Alkyl OR d , -OC 1-6 AlkylN(R d )2, -C 1-6 AlkylC(O)N(R d )2, -C 1-6 AlkylN(R d )2, -N(R d )2, -C(O)NR d C 1-6 AlkylN(R d )2, -NR d C 1-6 AlkylN(R d )2, -NR d C 1-6 Alkyl OR d , -SOR d , -S(O)2Rd , -SON(R d )2, -SO2N(R d )2, SF5, —Ocycloalkyl, and the remainder of the variables are as described above with respect to Formula I, or the second, fourth, fifth, sixth, seventh, eighth, ninth, tenth, nineteenth, twentieth, twenty-first, twenty-second, twenty-third, or twenty-fourth embodiment. Alternatively, R in compounds of Formulas XII, XIII, XIV, XV, XVI, XVII, XVIII, XIX, XX, XXI, XXII, and XXIII is substituted with 1 to 3 groups selected from 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 19, 20, 21, 22, 23, or 24 ... f is pyrimidinyl, phenyl, cyclobutanyl, cyclopropyl, pyrazolyl, imidazolyl, azetidinyl, piperidinyl, pyrrolidinyl, piperazinyl, triazolopyrazinyl, triazolyl, imidazolidinyl, thiadiazolidinyl, morpholinyl, oxaazaspiroheptanyl, oxaazaspirooctanyl, dihydropyrimidinyl, oxadiazolyl, isoxazolyl, or dihydropyridazinyl, each of which is optionally selected from halo, CN, oxo, NO, C 1-6 Alkyl, C 2-6 Alkenyl, C 1-6 Alkoxy, C 1-6 Haloalkoxy, C 1-6 Haloalkyl, -C 1-6 Alkyl OR d , -C(O)R d , -C(O)OR d , -C 1-6 AlkylC(O)OR d , -C(O)N(R d )2, -C(O)NR d C 1-6 Alkyl OR d , -OC 1-6 AlkylN(R d )2, -C 1-6 AlkylC(O)N(R d )2, -C 1-6 AlkylN(R d )2, -N(R d )2, -C(O)NR d C 1-6 AlkylN(R d )2, -NR d C 1-6AlkylN(R d )2, -NR d C 1-6 Alkyl OR d , -SOR d , -S(O)2R d , -SON(R d )2, -SO2N(R d )2, SF5, —Ocycloalkyl, and the remaining variables are as described above with respect to Formula I or the second, fourth, fifth, sixth, seventh, eighth, ninth, tenth, nineteenth, twentieth, twenty-first, twenty-second, twenty-third, or twenty-fourth embodiment. As another alternative, R in compounds of Formulas XII, XIII, XIV, XV, XVI, XVII, XVIII, XIX, XX, XXI, XXII, and XXIII is substituted with 1 to 3 groups selected from 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 19, 20, 21, 22, 23, or 24. f is pyrimidinyl, phenyl, pyrazolyl, imidazolyl, azetidinyl, piperidinyl, pyrrolidinyl, piperazinyl, triazolopyrazinyl, triazolyl, imidazolidinyl, thiadiazolidinyl, morpholinyl, oxaazaspiroheptanyl, oxaazaspirooctanyl, dihydropyrimidinyl, oxadiazolyl, isoxazolyl, or dihydropyridazinyl, each of which is optionally selected from halo, oxo, C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Haloalkyl, -C 1 6 Alkyl OR d , -C(O)R d , -C(O)N(R d )2, -C 1-6 AlkylC(O)N(R d )2, and -S(O)2R d and the remainder of the variables are as described above with respect to Formula I or the second, fourth, fifth, sixth, seventh, eighth, ninth, tenth, nineteenth, twentieth, twenty-first, twenty-second, twenty-third, or twenty-fourth embodiment. R in compounds II, XIX, XX, XXI, XXII, and XXIII f is pyrazolyl or triazolyl, each of which is optionally C1-3 Alkyl or -C(O)N(R d )2, and the remainder of the variables are as described above with respect to Formula I or the second, fourth, fifth, sixth, seventh, eighth, ninth, tenth, nineteenth, twentieth, twenty-first, twenty-second, twenty-third, or twenty-fourth embodiment.

[0058] In a twenty-sixth embodiment of the methods described herein, R in compounds of formula XII, XIII, XIV, XV, XVI, XVII, XVIII, XIX, XX, XXI, XXII, and XXIII d is hydrogen or C 1-3 alkyl, and the remainder of the variables are as described above with respect to Formula I or the second, fourth, fifth, sixth, seventh, eighth, ninth, tenth, nineteenth, twentieth, twenty-first, twenty-second, twenty-third, twenty-fourth, or twenty-fifth embodiment. Alternatively, R in compounds of Formulas XII, XIII, XIV, XV, XVI, XVII, XVIII, XIX, XX, XXI, XXII, and XXIII is d is C 1-3 is alkyl, and the remainder of the variables are as described above for Formula I, or the second, fourth, fifth, sixth, seventh, eighth, ninth, tenth, nineteenth, twentieth, twenty-first, twenty-second, twenty-third, twenty-fourth, or twenty-fifth embodiment.

[0059] In a twenty-seventh embodiment of the methods described herein, the compound of formula XX or XXI has the formula: [ka] or a pharmaceutically acceptable salt thereof, wherein the remaining variables are as described above with respect to Formula I, or the second, fourth, fifth, sixth, seventh, eighth, ninth, tenth, nineteenth, twentieth, twenty-first, twenty-second, twenty-third, twenty-fourth, twenty-fifth, or twenty-sixth embodiment, excluding those

[0060] In a twenty-eighth embodiment of the methods described herein, the compound of formula I is selected from the following formulae: [ka] [ka] [ka] or a pharmaceutically acceptable salt thereof of any of the above.

[0061] In a twenty-ninth embodiment of the methods described herein, the compound of formula I is selected from the following formulae: [ka] [ka] [ka] [ka] [ka] [ka] [ka] [ka] [ka] [ka] [ka] [ka] [ka] [ka] [ka] [ka] [ka] [ka] [ka] [ka] [ka] or any of the above pharmaceutically acceptable salts thereof.

[0062] Specific examples of compounds are provided in the Exemplification section and are included herein. Neutral forms of these compounds as well as pharmaceutically acceptable salts are also included.

[0063] 4. Use, Formulation, and Administration The compounds and compositions described herein are useful for treating neurological disorders.

[0064] Examples of neurological disorders include: (i) frontotemporal lobar degeneration (frontotemporal dementia, FTD), FTD-GRN, familial and sporadic amyotrophic lateral sclerosis (FALS and ALS, respectively), familial and sporadic Parkinson's disease, Parkinson's disease dementia, Huntington's disease, familial and sporadic Alzheimer's disease, multiple sclerosis, muscular dystrophy, cumulus cerebellar atrophy, multiple system atrophy, Wilson's disease, progressive supranuclear palsy, diffuse Lewy body disease, cortical dentonigral degeneration, progressive familial myoclonic epilepsy, striatal degeneration, torsion dystonia, familial tremor, Down syndrome, Gilles-de-la-Tourette syndrome, Halford-Shepat disease, peripheral neuropathy, diabetic peripheral neuropathy, and boxer syndrome. (ii) chronic neurodegenerative disorders such as dementia, AIDS dementia, age-related dementia, age-related memory impairment, and amyloidosis-related neurodegenerative diseases, e.g., those caused by prion protein (PrP) associated with transmissible spongiform encephalopathies (Creutzfeldt-Jakob disease, Gerstmann-Straussler-Scheinker syndrome, scrapie, and kuru), and those caused by excessive cystatin C accumulation (hereditary cystatin C angiopathy); and (iii) acute neurodegenerative disorders such as traumatic brain injury (e.g., surgery-related brain injury), cerebral edema, peripheral nerve injury, spinal cord injury, lysosomal storage disorders such as Leigh disease, Guillain-Barré syndrome, lipofuscinosis, and Alper's disease; Conditions resulting from alcohol or drug abuse, such as degeneration of neurons in the locus of the coelum and cerebellum, drug-induced movement disorders, age-related conditions including degeneration of cerebellar and cortical neurons resulting in cognitive and motor impairments, and conditions resulting from chronic amphetamine abuse, including degeneration of basal ganglia neurons resulting in movement disorders; pathological changes resulting from focal trauma such as stroke, focal ischemia, vascular insufficiency, hypoxic-ischemic encephalopathy, hyperglycemia, hypoglycemia, or direct trauma; conditions arising as negative side effects of therapeutic drugs and therapeutic agents (e.g., degeneration of glomerular and endocortical neurons in response to anticonvulsant drug administration of NMDA class antagonists of glutamate receptors) and dementia associated with Wernicke-Korsakoff syndrome.

[0065] Other neurological disorders include trauma associated with nerve injury or spinal cord injury. Neurological disorders of the limbic and cortical systems include, for example, cerebral amyloidosis, Pick's atrophy, and Rett syndrome. In another embodiment, neurological disorders include mood disorders such as affective disorders and anxiety, disorders of social behavior such as character deficits and personality disorders, and disorders of learning, memory, and intelligence such as mental retardation and dementia. Thus, in one embodiment, the disclosed compounds and compositions may be useful in treating schizophrenia, delirium, attention-deficit hyperactivity disorder (ADHD), schizoaffective disorder, Alzheimer's disease, vascular dementia, Rubinstein-Taybi syndrome, depression, mania, attention-deficit disorder, drug addiction, dementia, and dementia, including symptoms of BPSD.

[0066] Additional neurological conditions include, for example, tauopathies, spinal and bulbar muscular atrophies, spinocerebellar ataxia type 3, pain (including, for example, acute and chronic pain, somatic pain, visceral pain, neuropathic pain, peripheral neuropathy, nociceptive pain, central pain syndromes, muscle or joint pain), and neuroinflammation.

[0067] In one aspect, the compounds and compositions described herein are useful for treating a neurological disorder selected from frontotemporal dementia, Alzheimer's disease, tauopathy, vascular dementia, Parkinson's disease, and dementia with Lewy bodies.

[0068] In certain aspects, the compositions described herein are formulated for administration to patients in need of such compositions. The compositions disclosed herein can be administered orally, parenterally, by inhalation spray, topically, rectally, nasally, orally, vaginally, or via an implanted reservoir. As used herein, the term "parenteral" includes subcutaneous, intravenous, intramuscular, intra-articular, intrasynovial, intrasternal, intrathecal, intrahepatic, intralesional, and intracranial injection or infusion techniques. In some embodiments, the compositions are administered orally, intraperitoneally, or intravenously. Sterile injectable forms of the compositions described herein can be aqueous or oily suspensions. These suspensions can be formulated using suitable dispersing or wetting agents and suspending agents according to techniques known in the art.

[0069] In some embodiments, the composition is administered orally.

[0070] The specific dosage and treatment regimen for any particular patient will depend on a variety of factors, including the activity of the specific compound used, age, body weight, general health, sex, diet, time of administration, rate of excretion, drug combination, and the judgment of the treating physician, as well as the severity of the particular disease being treated. The amount of a compound described herein in a composition will also depend on the specific compound in the composition.

[0071] The compounds described herein can exist in the form of pharmaceutically acceptable salts.For use in medicine, the salts of the compounds described herein refer to non-toxic "pharmaceutically acceptable salts".As pharmaceutically acceptable salt forms, pharmaceutically acceptable acidic / anionic or basic / cationic salts. Suitable pharmaceutically acceptable acid addition salts of the compounds described herein include, for example, salts with inorganic acids (e.g., hydrochloric acid, hydrobromic acid, phosphoric acid, nitric acid, and sulfuric acid) and organic acids (e.g., acetic acid, benzenesulfonic acid, benzoic acid, methanesulfonic acid, and p-toluenesulfonic acid). Compounds of the present teachings, with acidic groups such as carboxylic acids, can form pharmaceutically acceptable salts with pharmaceutically acceptable bases. Suitable pharmaceutically acceptable base salts include, for example, ammonium salts, alkali metal salts (e.g., sodium salts and potassium salts), alkaline earth metal salts (e.g., magnesium salts and calcium salts). Compounds with quaternary ammonium groups also include counter anions such as chloride, bromide, iodide, acetate, and perchlorate. Other examples of such salts include hydrochlorides, hydrobromides, sulfates, methanesulfonates, nitrates, benzoates, and salts with amino acids such as glutamic acid.

[0072] Also included herein is a combination therapy using a therapeutically effective amount of the compound of Formula I or its pharmaceutically acceptable salt and an effective amount of one or more additional pharmaceutically active agents.The additional active agents that can be combined with the compound of Formula I or its pharmaceutically acceptable salt include, for example, those that target estrogen receptor (ER).These include, but are not limited to, selective estrogen receptor degraders (SERDs), ER antagonists, selective estrogen receptor modulators (SERMs), and aromatase inhibitors (AIs).Examples of SERD and ER antagonists include fulvestrant, RAD-1901 (elastrant), GDC-0927 ((2S)-2-(4-2-[3-(fluoromethyl)-1-azetidinyl])ethoxy}phenyl)-3-(3-hydroxyphenyl)-4-methyl-2H-chromen-6-ol), GDC-0810 (brillanestran), AZD-9496 ((2E)-3-[3,5-difluoro-4-[(1R , 3R)-2-(2-fluoro-2-methylpropyl)-2,3,4,9-tetrahydro-3-methyl-1H-pyrido[3,4-b]indol-1-yl]phenyl]-2-propanoic acid), OP-1250 (a prodrug of (S)-3-(4-hydroxyphenyl)-4-methyl-2-(4-(2-((R)-3-methylpyrrolidin-1-yl)ethoxy)phenyl)-2H-chromen-7-ol, U.S. Pat. No. 9,018,244 (S)-3-(4-hydroxyphenyl)-4-methyl-2-(4-(2-((R)-3-methylpyrrolidin-1-yl)ethoxy)phenyl)-2H-chromen-7-ol, also found in U.S. Pat. No. 9,018,244, the contents of which are incorporated herein by reference), LSZ102 ((E)-3-(4-((2-(2-(1,1-difluoroethyl)-4-fluoro ... Examples of SERMs include, but are not limited to, tamoxifen, toremifene, raloxifene, bazedoxifene, ospemifene, and nafoxidene. Examples of AIs include, but are not limited to, anastrozole, letrozole, exemestane, vorozole, formstane, and fadrozole.In one embodiment, a compound of Formula I or a pharmaceutically acceptable salt thereof is provided, together with an additional therapeutic agent selected from fulvestrant, RAD-1901, GDC-0927, GDC-0810, AZD-9496, OP-1250, LSZ102, H3B-6545, tamoxifen, toremifene, raloxifene, bazedoxifene, ospemifene, nafoxidene, anastrozole, letrozole, exemestane, vorozole, formestane, and fadrozole. In one embodiment, the additional therapeutic agent is fulvestrant. The use of one or more of the above-mentioned combination therapies for treating the conditions listed herein is also within the scope of the present disclosure. [Example]

[0073] Representative examples of the disclosed compounds are illustrated in the following non-limiting methods, schemes, and examples.

[0074] Typical starting materials used were obtained from commercial sources or prepared in other examples unless otherwise noted.

[0075] The following abbreviations have the indicated meanings: Ac = acetyl, ACN = acetonitrile, AcO acetate, BOC = t-butyloxycarbonyl, CBZ = carbobenzoxy, CDI = carbonyldiimidazole, DBU = 1,8-diazabicycloundec-7-ene, DCC = 1,3-dicyclohexylcarbodiimide, DCE = 1,2-dichloroethane, DI = deionized water, DIAD = diisopropyl azodicarboxylate, DIBAL = diisobutylaluminum hydride, DIPA = diisopropylamine, DIPEA or DIEA = N,N-diisopropylethylamine, also known as Hunig's base, DMA = dimethylacetamide, DMAP = 4-(dimethylamino)pyridine, DMF = dimethylformamide, DMP = Dess-Martin periodinus azinan, DPPA = diphenylphosphoric azide, DPPP = 1,3-bis(diphenylphosphino)propane, Dtbbpy = 4,4'-di- / e / 7-butyl-2,2'-dipyridyl, EDC or EDCI = 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride, EDTA = ethylenediaminetetraacetic acid, tetrasodium salt, EtOAc = ethyl acetate, FAB = fast atom bombardment, FMOC = 9-fluorenylmethoxycarbonyl, HMPA = hexamethylphosphoramide, HATU = (9-(7-azabenzotriazol-1-yl)-N,N,N,N-tetramethyluronium hexafluorophosphate), HOAt = 1-hydroxy-7-azabenzotriazole or 3H-[1,2,3]triazolo[4,5-b]pyridin-3-ol, HOBt = 1-hydroxybenzotriazole, HRMS = high-resolution mass spectrometry, KHMDS = potassium hexamethyldisilazane, LC-MS = liquid chromatography-mass spectrometry, LDA = lithium diisopropylamide, LiHMDS = lithium hexamethyldisilazane, MCPBA = metachloroperbenzoic acid, MMPP = magnesium monoperoxyfuran hexahydrate, Ms = methanesulfonyl mesylate, MsO = methanesulfonate mesylate, MTBE = methyl t-butyl ether, NBS = N-bromosuccinimide, NMM = 4-methylmorpholine, NMP = N-methylpyroidinone, NMR = nuclear magnetic resonance, PCC = pyridinium chlorochromate, PDC = pyridinium dichromate, Ph = phenyl, PPTS = pyridinium p-toluenesulfonate, pTSA = p-toluenesulfonic acid, rt / RT = room temperature, rac. = racemic, T3P = 2,4,6-tripropyl-1,3,5,2,4,6-trioxatriphosphinane 2,4,6-trioxide, TEA = triethylamine, TFA = trifluoroacetic acid, TfO = trifluoromethanesulfonate, THF = tetrahydrofuran, TLC = thin layer chromatography, TMSCl = trimethylsilyl chloride.

[0076] Unless otherwise specified, the absolute configuration of each eluting stereoisomer in the following examples was not specified.

[0077] Reaction progress was often monitored by TLC or LC-MS, which was recorded using one of the following methods: [Table 1] [Table 2] [Table 3] [Table 4] [Table 5]

[0078] Unless otherwise noted, NMR was recorded at room temperature on a Varian Inova 400 or 500 MHz spectrometer with the solvent peak used as the reference or on a Bruker 300 or 400 MHz spectrometer with the TMS peak used as the internal reference.

[0079] The compounds described herein can be prepared using the following methods and schemes: Unless otherwise specified, all starting materials used are commercially available.

[0080] Method 1 [ka] Method 1 is a two-step protocol consisting of an acylation reaction with 2-bromoacyl chloride followed by an alkylation reaction with a substituted ethylamine for the preparation of N-(haloaryl)-2-(arylethylamino)-2-substituted acetamides or N-(haloheteroaryl)-2-(arylethylamino)-2-substituted acetamides, which are useful for the synthesis of intermediates en route to the compounds described herein.

[0081] Method 2 [ka] Method 2 is a two-step protocol consisting of a Suzuki cross-coupling reaction and a palladium-catalyzed hydrogenation reaction for the preparation of methyl 4-alkylanilines starting from haloanilines and alkenylboronic esters, which is useful for the synthesis of intermediates en route to the compounds described herein.

[0082] Method 3 [ka] Method 3 is a two-step protocol consisting of a Suzuki cross-coupling reaction and an amide coupling for the preparation of 2-bromo-N-(4-heteroaryl)-2-substituted acetamides starting from haloanilines and heteroarylboronic esters, which is useful for the synthesis of intermediates en route to the compounds described herein.

[0083] Methods 4, 5, and 6 [ka] Methods 4, 5, and 6 are protocols for the coupling of substituted nitropyridines or aminopyridines with aliphatic and heteroaromatic amines for the preparation of substituted pyridines, which are useful for the synthesis of intermediates en route to the compounds described herein.

[0084] Method 7 [ka] Method 7 describes the preparation of substituted pyridines, pyridine boronic acids and esters with aryl and hydroxyl groups. Protocols for Suzuki cross-coupling reactions with heteroaryl halides or halopyridines with aryl or heteroaryl boronic acids and esters, which are useful for the synthesis of intermediates en route to the compounds described herein.

[0085] Method 8 [ka] Method 8 is a protocol for preparing substituted 2-aminopyridines from 2-nitropyridines via palladium-catalyzed hydrogenation, which is useful for the synthesis of intermediates en route to the compounds described herein.

[0086] Method 9 [ka] Method 9 is a five-step protocol for the preparation of substituted 2-arylethylamines and 2-heteroarylethylamines using substituted benzaldehydes or ketones, which are useful for the synthesis of intermediates en route to the compounds described herein.

[0087] Method 10 [ka] Method 10 is a protocol for the preparation of 2-substituted nitropyridines from 2-halonitropyridines and amines, which is useful for the synthesis of intermediates en route to the compounds described herein.

[0088] Method 11 [ka] Method 11 is a two-step protocol for the preparation of substituted ethyl 2-bromo-2-phenylacetates from substituted phenylacetic acid derivatives, which provides access to the compounds described herein. It is useful for synthesizing intermediates along the way.

[0089] Method 12 [ka] Method 12 is a three-step protocol for the synthesis of methyl 2-(4-bromo-1H-pyrazol-1-yl)-2-methylpropanenitrile from 4-bromo-1H-pyrazole, which is useful for the synthesis of intermediates en route to the compounds described herein.

[0090] Method 13 [ka] Method 13 is a protocol for the preparation of 5-(4-methyl-1H-1,2,3-triazol-1-yl)pyridin-2-amine from 5-iodopyridin-2-amine, which is useful for the synthesis of intermediates en route to the compounds described herein.

[0091] Method 14 [ka] Method 14 is a three-step protocol used for the preparation of substituted ethylphenethylamino-2-phenylacetates starting from substituted benzaldehydes, which are useful for the synthesis of intermediates en route to the compounds described herein.

[0092] Method 15 [ka] Method 15 is a two-step protocol used for the preparation of substituted acetophenones starting from substituted benzoic acids, which is useful for the synthesis of intermediates en route to the compounds described herein.

[0093] Method 16 [ka] Method 16 is a four-step protocol used for the preparation of 5-(5-methyl-1,2,4-oxadiazol-3-yl)pyridin-2-amine starting from substituted 6-aminonicotinonitrile, which is useful for the synthesis of intermediates en route to the compounds described herein.

[0094] Method 17 [ka] Method 17 is a seven-step protocol used for the preparation of 4-(6-aminopyridin-3-yl)-1-methylpyrrolidin-2-one starting from 2,2-dimethyl-1,3-dioxane-4,6-dione, which is useful for the synthesis of intermediates en route to the compounds described herein.

[0095] Method 18 [ka] Method 18 is a two-step protocol used for the preparation of substituted ethyl 2-(arylethylamino)-2-(1-substituted-1H-pyrazol-4-yl)acetates starting from arylethylamines and substituted boronic acid (or boronate) pyrazoles, which is useful for the synthesis of intermediates en route to the compounds described herein.

[0096] Method 19 [ka] Method 19 is a two-step protocol used for the preparation of substituted 1-(amino)-2-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazol-1-yl)ethan-1-ones starting from amines, which are useful for the synthesis of intermediates en route to the compounds described herein.

[0097] method 20 [ka] Method 20 is a protocol used for the preparation of 5-(3,5-dimethyl-1H-pyrazol-4-yl)pyridin-2-amine starting from tert-butyl 4-(6-aminopyridin-3-yl)-3,5-dimethyl-1H-pyrazole-1-carboxylate, which is useful for the synthesis of intermediates en route to the compounds described herein.

[0098] Method 21 [ka] Method 21 is a seven-step protocol for the preparation of ethyl trifluoromethyl phenethyl alanine derivatives from methyl benzoate derivatives, which is useful for the synthesis of intermediates en route to the compounds described herein.

[0099] Method 22 [ka] Method 22 provides the synthesis of ethylaryls (heteroaryls) from aryl and heteroaryl bromides. A six-step protocol for the synthesis of (aryl)propylalanine derivatives, which are useful for the synthesis of intermediates en route to the compounds described herein.

[0100] Method 23 [ka] Method 23 is a protocol for the synthesis of ethyl 2-((2-(1H-pyrazol-1-yl)ethyl)amino)-2-acetate derivatives from ethyl 2-((2-chloroethyl)amino)-acetate, which is useful for the synthesis of intermediates en route to the compounds described herein.

[0101] Method 24 [ka] Method 24 is a two-step protocol for the synthesis of ethyl 2-((2-(5-cyanopyridin-2-yl)ethyl)amino)-2-acetate derivatives from 2-bromo-5-cyanopyridine, which is useful for the synthesis of intermediates en route to the compounds described herein.

[0102] Method 25 [ka] Method 25 is a four-step protocol for the synthesis of ethylaryl(heteroaryl)propylalanine derivatives from aryl or heteroaryl bromides, which is useful for the synthesis of intermediates en route to the compounds described herein.

[0103] Scheme 1 [ka] Scheme 1 shows a general method for the synthesis of compounds of the invention via alkylation of an amine with an α-bromoketone or α-bromoamide,1 , R 2 , R 3 , R 4 , R 5 , R 6 , and R 7 is as described herein.

[0104] Scheme 2 [ka] Scheme 2 shows a general method for synthesizing a subset of the compounds described herein via Suzuki reactions of various aryl esters or heteroaryl boronic acids with substituted compounds of Formula I, where B, R 1 , R 2 , R 3 , R 4 , and R 5 as described herein.

[0105] Scheme 3 [ka] Scheme 3 shows a two-step sequence useful for the synthesis of a subset of compounds described herein, consisting of a palladium-catalyzed borylation reaction of a compound of formula I, B, R 1 , R 2 , R 3 , R 4 , and R 5 is as described herein.

[0106] Scheme 4 [ka] Scheme 4 shows a general method for synthesizing a subset of the compounds described herein via copper-catalyzed coupling reactions of various azoles with a family of substituted compounds of formula I, where B, R a , R 1 , R 2 , R 3 , R 4 , and R 5 is as described herein.

[0107] Scheme 5 [ka] Scheme 5 shows the palladium-catalyzed CN coupling of amines with the substituted compound family of Formula I. 1 illustrates a method for synthesizing a subset of compounds of the present invention via a ring reaction, a , R 1 , R 2 , R 3 , R 4 , and R 5 is as described herein.

[0108] Scheme 6 [ka] Scheme 6 shows a two-step synthetic sequence for converting α-bromoesters to N-aryl-2-(alkylamino)acetamides. This method is useful for the synthesis of a subset of compounds of Formula I, where R 1 is a substituted phenyl, and B, R a , R 2 , R 3 , R 4 , and R 5 is as described herein.

[0109] Scheme 7 [ka] Scheme 7 shows the synthetic sequence used to convert halogenated amines, such as bromotetrahydroquinolines (n=1) or bromoindolines (n=0), to a subset of compounds of Formula I, where R 1 is a substituted phenyl, and B, R 2 , R 3 , R 4 , and R 5 is as described herein.

[0110] Method 1 [ka] N-(4-bromophenyl)-2-((4-chlorophenethyl)amino)-2-phenylacetamide Method 1, Step 1. 2-Bromo-N-(4-bromophenyl)-2-phenylacetamide: To a stirred solution of 2-bromo-2-phenylacetic acid (1 g, 2.32 mmol) in dry DCM (10 ml) was added dropwise thionyl chloride (1.1 ml, 3.95 mmol) at 0° C., and the reaction mixture was stirred at 40° C. overnight. After completion of the reaction, excess thionyl chloride and DCM were evaporated under reduced pressure. To this was then added THF (10 ml) and 4-bromoaniline (0.79 g, 4.64 mmol), and the resulting reaction mixture was stirred at room temperature for 4 hours. After completion of the reaction, 1N aqueous HCl was slowly added and the DCM layer was separated. The aqueous layer was extracted with DCM (2×30 ml), and the combined organic layers were washed with 2N aqueous NaOH, dried over anhydrous NaSO, and concentrated under reduced pressure to give the title compound (1 g, 65%). LCMS: m / z=367.98 [M+1].

[0111] Method 1, Step 2. N-(4-bromophenyl)-2-((4-chlorophenethyl)amino)-2-phenylacetamide: A mixture of 2-bromo-N-(4-bromophenyl)-2-phenylacetamide (0.8 g, 2.17 mmol), 2-(4-chlorophenyl)ethan-1-amine (0.680 g, 4.35 mmol), and TEA (0.7 ml, 4.35 mmol) in DMF (15 ml) was heated at 60 °C for 2 hours. After completion of the reaction, the reaction mixture was poured into ice-cold water (10 ml) and extracted with ethyl acetate (2 × 30 ml). The combined organic layers were washed with brine (10 ml), dried over anhydrous NaSO, and concentrated under reduced pressure. The resulting residue was purified by silica gel chromatography to give the title compound (0.7 g, 67%) as an off-white solid. LCMS: m / z = 443.5 [M+1] and 445.5 [M+2].

[0112] Method 2 [ka] 1-(4-(4-aminophenyl)piperidin-1-yl)ethan-1-one Method 2, Step 1. 1-(4-(4-aminophenyl)-3,6-dihydropyridin-1(2H)-yl)ethan-1-one: A mixture of 4-bromoaniline (0.3 g, 1.74 mmol), 1-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3,6-dihydropyridin-1(2H)-yl)ethan-1-one (0.525 g, 2.09 mmol) and cesium carbonate (1.70 g, 5.23 mmol) in 4:1 dioxane:water (15 ml) was purged with argon for 20 minutes. S-Phos Pd-precatalyst G3 (0.066 g, 0.087 mmol) was then added and argon purging continued for another 10 minutes. The reaction mixture was heated at 90° C. overnight. After completion of the reaction (monitored by TLC), the reaction mixture was treated with water (6 ml) and extracted with ethyl acetate (2×15 ml). The combined organic layers were washed with brine (10 ml), dried over anhydrous NaSO, and concentrated under reduced pressure. The resulting residue was purified by silica gel chromatography to give the title compound (0.35 g, 92%) as a solid. LCMS: m / z=217.32 [M+1].

[0113] Method 2, Step 2. 1-(4-(4-aminophenyl)piperidin-1-yl)ethan-1-one: 1-(4-(4-aminophenyl)-3,6-dihydropyridin-1(2H)-yl)ethan-1-one (350 mg, 1.62 mmol) was dissolved in 1:1 MeOH:ethyl acetate (3.5 ml) in an autoclave, and 10% Pd / C (35 mg, 50% water) was added. The reaction was heated at 50° C. under 100 PSI of hydrogen gas pressure for 2 hours. After completion of the reaction (monitored by TLC), the reaction mixture was filtered through a celite pad, and the filtrate was concentrated to give the title compound (300 mg, 85%). LCMS: m / z=219.3 [M+1].

[0114] Method 3 [ka] 2-Bromo-N-(4-(1-methyl-1H-pyrazol-4-yl)phenyl)-2-phenylacetamide Method 3, Step 1. 4-(1-methyl-1H-pyrazol-4-yl)aniline: A mixture of 4-bromoaniline (1.0 g, 5.81 mmol), 1-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (1.3 g, 6.39 mmol), and cesium carbonate (5.68 g, 17.43 mmol) in 4:1 dioxane:water (20 mL) was purged with argon for 20 minutes. S-Phos Pd-precatalyst G3 (0.213 g, 0.29 mmol) was added, and purging continued for an additional 10 minutes. The reaction mixture was heated at 100° C. for 2 hours. The reaction mixture was poured into water (15 mL) and extracted with ethyl acetate (2×20 mL). The combined organic layers were washed with brine (10 mL), dried over anhydrous NaSO, and concentrated under reduced pressure. The resulting residue was purified by silica gel chromatography to give the title compound (0.965 g, 95%) as a solid. 1 H NMR(400MHz,DMSO-d6):3.81(s,3H),5.01(s,2H,-NH2),6.54(d,J=8.0Hz,2H),7.20(d,J=8.4Hz,2H),7.63(s,1H),7.86(s,1H).LCMS:m / z=174.2[M+1].

[0115] Method 3, Step 2. 2-Bromo-N-(4-(1-methyl-1H-pyrazol-4-yl)phenyl)-2-phenylacetamide: To a stirred solution of 4-(1-methyl-1H-pyrazol-4-yl)aniline (0.95 g, 5.48 mmol) and 2-bromo-2-phenylacetic acid (1.3 g, 6.03 mmol) in ethyl acetate (10 ml) was added T3P (5.22 g, 8.22 mmol; 50% in ethyl acetate). The reaction mixture was stirred at room temperature for 30 minutes. After 30 minutes, DIPEA (1.41 g, 10.96 mmol) was added, and the reaction mixture was heated at 60° C. for 3 hours. The reaction mixture was poured into water (15 ml) and extracted with ethyl acetate (2×10 ml). The combined organic layers were washed with brine (10 ml), dried over anhydrous Na2SO4, and concentrated under reduced pressure. The resulting residue was purified by silica gel chromatography to give the title compound (1.2 g, 59%) as a solid. 1 H NMR(400MHz,DMSO-d6):3.85(s,3H),5.79(s,1H),7.38-7.44(m,3H),7.52-7.59(m,4H),7.65(d,J =6.8Hz,2H),7.82(s,1H),8.09(s,1H),10.54(s,1H,-NH).LCMS:m / z=370.1[M+1] and 372.4[M+2].

[0116] Method 4 [ka] 1-methyl-4-(6-nitropyridin-3-yl)piperazine Method 4, Step 1. 1-Methyl-4-(6-nitropyridin-3-yl)piperazine: To a stirred solution of 5-bromo-2-nitropyridine (0.5 g, 2.46 mmol) in DMSO (5 ml) was added 1-methylpiperazine (0.369 g, 3.69 mmol), K2CO3 (0.679 g, 4.92 mmol), and TBAB (0.079 g, 0.0246 mmol) at room temperature. The reaction mixture was stirred at 100 °C for 6 hours. After completion of the reaction (monitored by TLC), the reaction was quenched with 1 N HCl (15 ml) and extracted with ethyl acetate (2 × 15 ml). The aqueous layer was treated with 1 N NaOH solution and ethyl acetate (2 × 15 ml) was added. 25 ml), the combined organic layers were dried over anhydrous Na2SO4 and concentrated under reduced pressure to give the title compound (0.5 g, 91%). 1 H NMR(400MHz,DMSO-d6):2.39(s,3H),2.61(t,J=5.2Hz,4H),3.50(t,J=5.2Hz,4H),7.22(dd,J=8.8Hz,2.8Hz,1H),8.15-8.20(m,2H).

[0117] Method 5 [ka] 5-(4-methyl-1H-imidazol-1-yl)pyridin-2-amine Method 5, Step 1. 5-(4-methyl-1H-imidazol-1-yl)pyridin-2-amine: To a stirred solution of 5-bromopyridin-2-amine (0.5 g, 2.89 mmol) in DMF (10 ml) was added 4-methyl-1H-imidazole (1.19 g, 14.45 mmol), CsCO (0.94 g, 2.89 mmol), CuI (0.276 g, 1.45 mmol), and 1-(5,6,7,8-tetrahydroquinolin-8-yl)ethanone (0.11 g, 0.58 mmol) at room temperature. The reaction mixture was purged with argon gas for 30 minutes and heated at 135 °C overnight. After completion of the reaction, water (15 ml) was added, and the mixture was extracted with ethyl acetate (2 × 25 ml). The combined organic layers were dried over anhydrous NaSO and concentrated under reduced pressure. The resulting residue was purified by silica gel chromatography to give the title compound (0.23 g, 46%). LCMS: m / z=175.3[M+1].

[0118] Method 6 [ka] 5-(3-Methoxyazetidin-1-yl)-2-nitropyridine Method 6, Step 1. 5-(3-Methoxyazetidin-1-yl)-2-nitropyridine: To a stirred solution of 5-bromo-2-nitropyridine (0.55 g, 4.44 mmol) in 1,4-dioxane (2.5 ml), 3-methoxyazetidine (1.08 g, 5.33 mmol), CsCO (4.38 g, 13.49 mmol), Pd(dba) (0.162 g, 0.17 mmol), and Xantphos (0.257 g, 0.44 mmol) were added at room temperature. The reaction mixture was purged with argon gas for 30 minutes and heated at 100 °C for 3 hours. After completion of the reaction, water (15 ml) was added, and the aqueous layer was extracted with ethyl acetate (2 × 25 ml). The combined organic layers were dried over anhydrous NaSO and concentrated under reduced pressure. The resulting residue was purified by silica gel chromatography to give the title compound (0.77 g, 74%). LCMS: m / z=210.1[M+1].

[0119] Method 7 [ka] 5-(1-methyl-1H-pyrazol-4-yl)pyridin-2-amine Method 7 5-(1-methyl-1H-pyrazol-4-yl)pyridin-2-amine: A mixture of 5-bromopyridin-2-amine (18.0 g, 104.04 mmol), 1-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (32.47 g, 156.06 mmol), and cesium carbonate (101.75 g, 312.12 mmol) in dioxane:water (4:1, 360 ml) was purged with argon gas for 20 minutes. To this mixture, Pd(dppf)Cl (7.61 g, 10.40 mmol) was added, and purging was continued for another 10 minutes. The reaction mixture was heated at 80 °C for 1.5 hours. The reaction mixture was poured into water (200 ml) and extracted with ethyl acetate (2 × 200 ml). The combined organic layers were washed with brine (150 ml), dried over anhydrous NaSO, and concentrated under reduced pressure. The crude product was purified by column chromatography to give the title compound (15 g, 82%) as a solid. 1H NMR(400MHz,DMSO-d6):3.83(s,3H),5.86(s,2H,-NH2),6.44(d,J=8.4Hz,1H),7.20(dd,J=8 .4Hz,2.4Hz,1H),7.70(s,1H),7.95(s,1H),8.14(d,J=2.09Hz,1H).LCMS:m / z=175.1[M+1].

[0120] [ka] 5-Cyclopropylpyridin-2-amine Method 7 5-Cyclopropylpyridin-2-amine: 5-Bromopyridin-2-amine (0.5 g, 2.89 mmol), cyclopropylboronic acid (0.49 g, 5.78 mmol), and KPO (1.84 g, 8.67 mmol) were combined in a mixture of toluene:water (4:1, 10 ml), and the mixture was degassed with argon gas for 20 minutes. Palladium acetate (0.032 g, 0.144 mmol) and tricyclohexylphosphine (0.081 g, 0.289 mmol) were added to the reaction mixture, and degassing was continued for an additional 10 minutes. The reaction mixture was heated in a sealed tube at 100 °C for 16 hours. The reaction mixture was diluted with water (15 ml) and extracted with ethyl acetate (2 × 15 ml). The combined organic layers were washed with brine (15 ml), dried over anhydrous NaSO, and concentrated under reduced pressure. The residue was purified by silica gel chromatography to give the title compound (0.3 g, 77%) as a solid. 1 H NMR(400MHz,DMSO-d6):δ 0.49-0.56(m,2H),0.75-0.83(m,2H),1.70-1.77(m,1H),5.65(s,2H,-NH2),6.36(d,J=8 .4Hz,1H),7.04(dd,J=8.4Hz,2.0Hz,1H),7.74(d,J=1.6Hz,1H).LCMS:m / z=135.2[M+1].

[0121] Method 8 [ka] Method 8. 5-(3-Methoxyazetidin-1-yl)pyridin-2-amine: To a stirred solution of 5-((1-methylpiperidin-4-yl)oxy)-2-nitropyridine (1.0 g, 4.78 mmol) in a mixture of methanol (10 ml) was added 10% Pd / C (0.10 g, 10% w / w, 50% water). The reaction mixture was then stirred at room temperature under an atmosphere of H gas for 3 hours. After completion of the reaction (monitored by TLC), the reaction mixture was diluted with ethyl acetate and filtered through a Celite pad. The Celite pad was washed with ethyl acetate (2 x 25 ml). The combined filtrate was concentrated under reduced pressure to give the title compound (0.22 g, 44%) as a solid. LCMS: m / z = 180.3 [M+1].

[0122] Method 9 [ka] (S)-4-(1-aminopropan-2-yl)benzonitrile hydrochloride Method 9, Step 1. Ethyl (E,Z)-3-(4-cyanophenyl)but-2-enoate: To a stirred solution of potassium tert-butoxide (10.09 g, 89.7 mmol) in dry THF (90 ml) was added triethyl phosphonoacetate (20.08 g, 89.7 mmol) at 0°C under a nitrogen atmosphere. The reaction mixture was then stirred at the same temperature for 15 minutes. The reaction was then warmed to room temperature and stirred for 1 hour. 4-Acetylbenzonitrile (10.0 g, 69.0 mmol) was then added as a THF solution (50 ml), and the reaction was heated to 70°C for 3 hours. After completion of the reaction (monitored by TLC), the pH of the reaction mixture was adjusted to 3-4 with 1N HCl. The THF was removed under reduced pressure, and the aqueous layer was extracted with ethyl acetate (2 x 50 ml). The combined organic layers were washed with brine (50 ml), dried over anhydrous NaSO, and concentrated under reduced pressure. The residue was purified by silica gel chromatography to give the title compound (8.5 g, 58%). 1H NMR(400MHz,DMSO-d6):1.15(t,J=6.8Hz,1.5H),1.36(t,J=6.8Hz,3H),2.21(s,1.5H),2.60(s,3 H),4.05(q,J=7.1Hz,1H),4.27(q,J=7.2Hz,2H),6.01(s,0.5H),6.19(s,1H),7.30-7.71(m,6H).

[0123] Method 9, Step 2. Ethyl 3-(4-cyanophenyl)butanoate: To a stirred solution of ethyl (E,Z)3-(4-cyanophenyl)but-2-enoate (8.0 g, 37.2 mmol) in methanol:ethyl acetate (1:4, 140 ml) was added Pd / C (0.8 g, 10% w / w, 50% water). The reaction was stirred at room temperature under an atmosphere of hydrogen gas for 3 hours. The reaction mixture was diluted with ethyl acetate and filtered through a pad of Celite. The combined organic layers were concentrated under reduced pressure to give the title compound (4.5 g, 56%). 1 H NMR(400MHz,CDCl3):1.23(t,J=7.2Hz,3H),1.33(d,J=6.8Hz,3H),2.62(dd,J=7.6Hz,1.2Hz ,2H),3.70(q,J=7.2Hz,1H),4.07-4.15(m,2H),7.37(d,J=8.0Hz,2H),7.37(d,J=8.4Hz,2H).

[0124] Method 9, Step 3. 3-(4-cyanophenyl)butanoic acid: To a stirred solution of 3-(4-cyanophenyl)butanoate (4.5 g, 20.71 mmol) in a mixture of MeOH:THF:HO (4:2:1, 100 ml) was added LiOH (3.48 g, 82.95 mmol) at 5°C-10°C. The resulting reaction was stirred at room temperature for 1.5 hours. After completion of the reaction (monitored by TLC), the reaction solvent was evaporated. The residue was dissolved in water (10 ml) and extracted with ethyl acetate (2 x 15 ml). The pH of the aqueous layer was adjusted to 3-4 with concentrated HCl. The formed precipitate was filtered off to give the title compound (3.8 g, 97%) as a white solid. 1H NMR(400MHz,DMSO-d6):1.23(d,J=6.8,3H),2.58(d,J=7.6Hz,2H),3.24(q,J=7.2,1H),7.49(d,J=8.4Hz,2H),7.77(d,J=8.4Hz,2H),12.15(s,1H).

[0125] Method 9, Step 4. tert-Butyl (2-(4-cyanophenyl)propyl)carbamate: 3-(4-cyanophenyl)butanoic acid (5.0 ml) in tert-butanol (65 ml) To a stirred solution of 1,2-dimethyl-3,4-dichloro-2 ... 1 H NMR(400MHz,DMSO-d6):1.17(d,J=6.8Hz,2H),1.33(s,9H),2.90-3.00(m,1H),3.04- 3.15(m,2H),6.91(t,J=5.2Hz,1H,-NH),7.42(d,J=8.4Hz,2H),7.77(d,J=7.2Hz,2H).

[0126] Method 9, Step 5. 4-(1-aminopropan-2-yl)benzonitrile hydrochloride: To a stirred solution of tert-butyl-(2-(4-cyanophenyl)propyl)carbamate (4.5 g, 17.29 mmol) in methanol (9 ml) was added dropwise a solution of 4 M HCl in dioxane (10.8 ml, 2.4 vol) at 0° C. The resulting mixture was stirred at room temperature for 2 hours. The reaction mixture was concentrated under reduced pressure to give the title compound (2.81 g, 83%) as a solid. 1H NMR(400MHz,DMSO-d6):1.28(d,J=6.8Hz,2H),3.03(d,J=5.6Hz,2H),3.15-3.26(m,1 H),7.55(d,J=8.0Hz,2H),7.83(d,J=8.0Hz,2H),8.21(s,3H).LCMS:m / z=161.6[M+1].

[0127] Method 9, Step 6. 4-(1-aminopropan-2-yl)benzonitrile: 4-(1-aminopropan-2-yl)benzonitrile hydrochloride was treated with saturated aqueous sodium bicarbonate and extracted with ethyl acetate (3 x 30 ml) to give the crude compound as a liquid, which was purified by silica gel chromatography (DCM:MeOH = 90:10) to give the racemic title compound as a thick oil (2.29 g, 83%). 1 H NMR (400 MHz, CDCl): 1.28 (d, J = 6.8 Hz, 3H), 2.85 (d, J = 5.6 Hz, 3H), 7.34 (d, J = 7.2 Hz, 2H), 7.63 (d, J = 7.2 Hz, 2H). LCMS: m / z = 161.5 [M + 1]. The racemic amine can be resolved in enantiopure title compounds by preparative chiral SFC using a CHIRALPAK AD-H column (250 mm, 50 mm, 5 micron; mobile phase 25% acetonitrile:methanol:dimethylamine (80:20:0.1) in 75% CO). The early-eluting isomer has been unambiguously assigned as (S)-4-(1-aminopropan-2-yl)benzonitrile by obtaining X-ray co-crystal structures of truncated p300 with both Example 22 (Isomer 1; (S)-2-((4-cyanophenethyl)amino)-N-(5-(1-methyl-1H-pyrazol-4-yl)pyridin-2-yl)-2-phenylacetamide) and Example 33 (Isomer 4; (R,S)-2-((2-(4-cyanophenyl)-propyl)amino)-N-(5-(1-methyl-1H-pyrazol-4-yl)pyridin-2-yl)-2-phenylacetamide).

[0128] Method 10 [ka] 5-nitro-2-(pyrrolidin-1-yl)pyridine Method 10. 5-Nitro-2-(pyrrolidin-1-yl)pyridine: To a stirred solution of 2-bromo-5-nitropyridine (0.5 g, 2.46 mmol) in DMSO (2 ml) was added pyrrolidine (0.262 g, 3.69 mmol) at room temperature. The reaction mixture was heated in a microwave at 120° C. for 1 hour. After completion of the reaction, ice-cold water was added (15 ml) and the resulting precipitate was filtered through a Buchner funnel to obtain the crude compound. The crude compound obtained was purified by trituration with n-hexane (10 ml) to obtain the title compound (0.370 g, 77%). LCMS: m / z=194.01 [M+1].

[0129] Method 11 [ka] Ethyl 2-bromo-2-(3-methoxyphenyl)acetate Method 11, Step 1. Ethyl 2-(3-methoxyphenyl)acetate: To a stirred solution of 3-methoxy-2-phenylacetic acid (5 g, 30 mmol) in absolute ethanol (50 ml) was added sulfuric acid (0.3 ml) at 0° C., and the reaction mixture was refluxed at 70° C. for 2 hours. The progress of the reaction was monitored by TLC. After completion of the reaction, ethanol was removed by evaporation under reduced pressure. The reaction mixture was then neutralized with a saturated solution of sodium bicarbonate, extracted with DCM (2×15 ml), dried over anhydrous NaSO, and concentrated under reduced pressure to give the title compound (3.82 g, 81%) as a colorless liquid. LCMS: m / z=195.26 [M+1].

[0130] Method 11, Step 2. Ethyl 2-bromo-2-(3-methoxyphenyl)acetate: A mixture of ethyl 2-(3-methoxyphenyl)acetate (0.5 g, 2.5 mmol), N-bromosuccinamide (0.50 g, 2.80 mmol), and 2,2'-azobis(2-methylpropionitrile) (0.02, 0.12 mmol) in CCl4 (10 ml) was refluxed for 2 hours. After completion of the reaction (monitored by TLC), the reaction mixture was diluted with n-hexane and filtered through a Celite pad. The filtrate was dried over anhydrous Na2SO4 and concentrated under reduced pressure. The resulting compound was purified by silica gel chromatography to give the title compound (0.8 g, 99%) as a yellow liquid. LCMS: m / z = 273.2 [M+1].

[0131] Method 12 [ka] 2-(4-Bromo-1H-pyrazol-1-yl)-2-methylpropanenitrile Method 12, Step 1. Methyl 2-(4-bromo-1H-pyrazol-1-yl)-2-methylpropanoate: To a stirred solution of 4-bromo-1H-pyrazole (3.0 g, 20.41 mmol) in dry DMF (30 ml), CsCO (19.95 g, 61.23 mmol) and methyl 2-bromo-2-methylpropanoate (3.96 ml, 30.61 mmol) were added at room temperature under a nitrogen atmosphere. The reaction mixture was then stirred at 80° C. for 18 hours. After completion of the reaction (monitored by TLC), the reaction mixture was diluted with ice-cold water (30 ml) and extracted with ethyl acetate (2×50 ml). The combined organic layer was washed with brine (50 ml), dried over anhydrous NaSO, and concentrated under reduced pressure. The resulting residue was purified by silica gel chromatography to give the title compound (3.0 g, 60%). 1 H NMR (40 0MHz,DMSO-d6):1.76(s,6H),4.63(s,3H),7.61(s,1H),8.21(s,1H).

[0132] Method 12, Step 2. 2-(4-Bromo-1H-pyrazol-1-yl)-2-methylpropanamide: An oven-dried autoclave was charged with methyl 2-(4-bromo-1H-pyrazol-1-yl)-2-methylpropanoate (1.0 g, 4.05 mmol) and CaCl (0.5 g, 4.46 mmol) in methanol (10 ml). The reaction mixture was cooled to -78 °C, and NH gas was purged into it. The reaction was then stirred at room temperature for 20 hours. After completion of the reaction (monitored by TLC), the reaction mixture was diluted with water and extracted with ethyl acetate (2 × 30 ml). The combined organic layer was concentrated under reduced pressure and purified by silica gel chromatography to give the title compound (0.55 g, 59%). 1 H NMR (400MHz, DMSO-d6): 1.70 (s, 6H), 6.96 (s, NH, 1H), 7.22 (s, NH, 1H), 7.60 (s, 1H), 8.09 (s, 1H).

[0133] Method 12, Step 3. 2-(4-Bromo-1H-pyrazol-1-yl)-2-methylpropanenitrile: A solution of 2-(4-bromo-1H-pyrazol-1-yl)-2-methylpropanamide (0.5 g, 2.16 mmol) in POCl (5 ml) was heated to 90° C. for 1.5 hours. After completion of the reaction (confirmed by TLC), the reaction was quenched with saturated aqueous NaHCO solution. The resulting mixture was extracted with ethyl acetate (2×20 ml). The combined organic layers were washed with water (2×20 ml), washed with brine (20 ml), dried over anhydrous NaSO, and concentrated under reduced pressure to give the title compound (0.35 g, 75%) as a solid. 1 H NMR (400MHz, DMSO-d6): 1.98 (s, 6H), 7.78 (s, 1H), 8.34 (s, 1H).

[0134] Method 13 [ka] 5-(4-methyl-1H-1,2,3-triazol-1-yl)pyridin-2-amine Method 13. 5-(4-methyl-1H-1,2,3-triazol-1-yl)pyridin-2-amine: 5-Iodo-2-aminopyridine (0.5 g, 2.28 mmol), NaN (0.22 g, 3.41 mmol), KCO (0.38 g, 2.76 mmol), CuSO.5HO (0.06 g, 0.23 mmol), sodium ascorbate (0.09 g, 0.46 mmol), L-proline (0.06 g, 0.46 mmol), and 2-butynoic acid (0.28 g, 3.41 mmol) were combined in DMSO (6 ml) at room temperature. The reaction mixture was then heated at 65 °C for 6 hours. After completion of the reaction (monitored by TLC), the reaction mixture was diluted with water (20 ml) and extracted with ethyl acetate (4 × 25 ml). The combined organic layers were dried over anhydrous NaSO and concentrated under reduced pressure to give a residue that was purified by silica gel chromatography to give the title compound (0.25 g, 71%). LCMS: m / z=176.1[M+1].

[0135] Method 14 [ka] 2-((4-cyano-2,6-difluorophenethyl)amino)-2-phenylacetic acid ethyl ester Method 14, Step 1. (E)-3,5-Difluoro-4-(2-methoxyvinyl)benzonitrile: To a stirred solution of methoxymethyltriphenylphosphonium chloride (1.47 g, 4.31 mmol) in THF (6 ml) was added potassium carbonate (0.594 g, 4.31 mmol) at 0° C. and stirred at room temperature for 30 minutes. To this was added 3,5-difluoro-4-formylbenzonitrile (0.6 g, 3.59 mmol) at room temperature and heated to reflux at 60° C. for 16 hours. The reaction mixture was quenched with water (30 ml) and extracted with ethyl acetate (2×30 ml). The organic layer was dried over sodium sulfate and concentrated under reduced pressure. The crude product was purified by silica gel chromatography to give the title compound (0.24 g, 34%). 1 H NMR(400MHz,DMSO-d6):δ 7.72-7.72(m,2H),6.65(d,J=6.4Hz,1H),5.20(d,J=6.4Hz,1H),3.74(s,3H).

[0136] Method 14, Step 2. 3,5-Difluoro-4-(2-oxoethyl)benzonitrile: (E)-3,5-Difluoro-4-(2-methoxyvinyl)benzonitrile (0.120 g, 0.614 mmol) was dissolved in THF (3 ml) and 6N HCl (0.6 ml) was added. The reaction mixture was heated at 60° C. for 2 hours. The reaction mixture was neutralized with saturated sodium bicarbonate solution (10 ml) and extracted with ethyl acetate (2×20 ml). The organic layer was dried over sodium sulfate and concentrated under reduced pressure to give the crude title compound, which was used in the next step without further purification (0.120 g). 1 H NMR (400MHz, DMSO-d6): δ 9.71(s,1H),7.84-7.86(m,2H),4.10(s,2H).

[0137] Method 14, Step 3. Ethyl 2-((4-cyano-2,6-difluorophenethyl)amino)-2-phenylacetate To a solution of 3,5-difluoro-4-(2-oxoethyl)benzonitrile (0.120 g, 0.66 mmol) and ethyl 2-amino-2-phenylacetate (0.171 g, 0.79 mmol) in a 1:1 mixture of methanol:DCE (4 ml), acetic acid (4 drops) was added, followed by powdered molecular sieves (0.1 g). The reaction mixture was stirred at room temperature for 1 hour. To this was added sodium cyanoborohydride (0.061 g, 0.99 mmol), and the reaction mixture was stirred at room temperature for 16 hours. The reaction mixture was quenched with sodium bicarbonate solution (5 ml) and extracted with ethyl acetate (3 × 10 ml). The organic layer was dried over sodium sulfate and concentrated under reduced pressure. The residue was purified by silica gel chromatography to give the title compound (0.1 g, 44%). LCMS: m / z = 345.5 [M+1].

[0138] Method 15 [ka] 4-Acetyl-3-fluorobenzonitrile Method 15, Step 1. 4-cyano-2-fluoro-N-methoxy-N-methylbenzamide: To a stirred solution of 4-cyano-2-fluorobenzoic acid (15 g, 90.84 mmol) in DMF (100 ml), HATU (51.81 g, 136.36 mmol) and DIPEA (58.70 g, 454.21 mmol) were added, and the reaction mixture was stirred at room temperature for 1 hour. N,O-Dimethylhydroxylamine hydrochloride (26.60 g, 272.7 mmol) was added at 0° C., and the reaction mixture was stirred at room temperature for 5 hours. The reaction mixture was diluted with cold water (200 ml) and extracted with ethyl acetate (2×250 ml). The combined organic layers were washed with brine (100 ml), dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel chromatography to give the title compound (12.5 g, 66%). LCMS: m / z=209.1 [M+1].

[0139] Method 15, Step 2. 4-Acetyl-3-fluorobenzonitrile: To a stirred solution of 4-cyano-2-fluoro-N-methoxy-N-methylbenzamide (15 g, 72.11 mmol) in THF (150 ml), methylmagnesium bromide (154.53 ml, 1.4 M in 3:1 THF:toluene, 216.34 mmol) was added dropwise at 0° C. and stirred for 30 minutes. The reaction mixture was quenched with ice-cold water (150 ml) and extracted with ethyl acetate (2×250 ml). The combined organic layers were washed with brine (100 ml), dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel chromatography to give the title compound (8.1 g, 69%). 1 H NMR (400MHz, DMSO-d6): δ 8.05-8.07(m,1H),7.94-7.96(m,1H),7.82-7.84(m,1H),2.62(s,3H).

[0140] Method 16 [ka] 5-(5-methyl-1,2,4-oxadiazol-3-yl)pyridin-2-amine Method 16, Step 1. N-(5-cyanopyridin-2-yl)-4-methylbenzenesulfonamide: To a stirred solution of 6-aminonicotinonitrile (1 g, 8.39 mmol) in dry pyridine (30 ml) at 0° C. was added para-tosyl chloride (3.2 g, 16.7 mmol). The reaction mixture was stirred at room temperature for 30 minutes. After 30 minutes, the reaction mixture was heated to 90° C. overnight. The solvent was removed and the residue was treated with water (25 ml). The resulting precipitate was collected by filtration and washed with water (25 ml) to give the pure title compound (1.1 g, 50%). 1 H NMR(400MHz,DMSO-d6):δ 2.36(s,3H),7.11(d,J=8.8Hz,1H),7.39(d,J=8Hz,2H),7.78-7.88(m,2H),8.10 (dd,J=8.8Hz,J=6.8Hz,1H),8.62(s,1H),11.89(s,1H).LCMS:m / z=274.26[M+1].

[0141] Method 16, Step 2. (Z)-N'-Hydroxy-6-((4-methylphenyl)sulfonamido)-nicotinimidamide: A mixture of hydroxylamine hydrochloride (0.106 g, 1.53 mmol) and potassium carbonate (0.11 g, 0.80 mmol) in water (2 ml) was added to a solution of N-(5-cyanopyridin-2-yl)-4-methylbenzenesulfonamide (0.2 g, 0.732 mmol) in ethanol (8 ml). The reaction mixture was heated to reflux overnight. The reaction mixture was concentrated, and the residue was treated with water (10 ml). The precipitated solid was collected by filtration and washed with water to give the pure title compound (0.14 g, 62%). LCMS: m / z=307.61 [M+1].

[0142] Method 16, Step 3. 4-Methyl-N-(5-(5-methyl-1,2,4-oxadiazol-3-yl)pyridin-2-yl)benzenesulfonamide: To a stirred solution of (Z)-N'-hydroxy-6-((4-methylphenyl)sulfonamido)-nicotinimidamide (0.72 g, 2.35 mmol) in DMSO (15 ml) was added ethyl acetate (0.35 ml, 3.52 mmol) and the reaction mixture was stirred for 15 minutes. To this was added NaOH (0.141 g, 3.52 mmol) powder in one portion. After completion of the reaction, the reaction was quenched with ice-cold water (20 ml) and the aqueous layer was extracted with ethyl acetate (2 x 50 ml). The combined organic layers were washed with brine (25 ml), dried over anhydrous sodium sulfate and concentrated under reduced pressure to give the title compound (0.25 g, 33%). 1 H NMR(400MHz,DMSO-d6):δ 2.36(s,3H),2.65(s,3H),7.24(d,J=8.8Hz,1H),7.39(d,J=8Hz,2H),7.85(d,J=8Hz,2H ),8.21(dd,J=8.8Hz,J=6.4Hz,1H),8.67(s,1H),11.74(s,1H).LCMS:m / z=331.66[M+1].

[0143] Method 16, Step 4. 5-(5-methyl-1,2,4-oxadiazol-3-yl)pyridin-2-amine: 4-Methyl-N-(5-(5-methyl-1,2,4-oxadiazol-3-yl)pyridin-2-yl)benzenesulfonamide (0.25 g, 0.75 mmol) was taken in a vial and concentrated H2SO4 (2.5 ml) was added at 0 °C. After completion of the reaction, the reaction mass was poured into a cooled solution of 50% NaOH (aq). The resulting precipitate was filtered and washed with cold water (20 ml). The solid was dried under high vacuum to give the title compound (0.12 g, 90%). 1 H NMR(400MHz,DMSO-d6):δ 2.60(s,3H),6.53(d,J=8.8Hz,1H),6.62(s,2H),7.86(dd,J=8.4Hz,6.4Hz,1H),8.50(d,J=2Hz,1H).LCMS:m / z=177.51[M+1].

[0144] Method 17 [ka] 4-(6-fluoropyridin-3-yl)-1-methylpyrrolidin-2-one Method 17, Step 1. tert-Butyl 4-hydroxy-2-oxo-2,5-dihydro-1H-pyrrole-1-carboxylate: To a stirred solution of (tert-butoxycarbonyl)glycine (0.5 g, 2.85 mmol) in DCM was added 2,2-dimethyl-1,3-dioxane-4,6-dione (0.62 g, 4.28 mmol) and DMAP (0.52 g, 4.28 mmol) at room temperature. The reaction mixture was stirred for 15 minutes and then cooled to room temperature. . HCl (0.82 g, 4.28 mmol) was added at 0° C. The reaction mixture was further stirred at room temperature for 5 hours. After the reaction was completed, the reaction mixture was The mixture was diluted with ethyl acetate (100 ml) and the organic layer was washed with brine (50 ml), 20% aqueous citric acid (50 ml), and brine (50 ml). The organic layer was dried over sodium sulfate and evaporated to give the crude product. The crude product was refluxed in ethyl acetate (50 ml) for 1 hour. After 1 hour, the reaction mixture was concentrated to give the pure desired compound (0.5 g, 88%). 1 H NMR(400MHz,DMSO-d6):δ 1.45-1.47(m,9H),4.16(s,2H),4.89(s,1H),12.17(s,1H).LCMS:m / z=144.25[M-56].

[0145] Method 17, Step 2. tert-Butyl 2-oxo-4-(tosyloxy)-2,5-dihydro-1H-pyrrole-1-carboxylate: To a stirred solution of tert-butyl 4-hydroxy-2-oxo-2,5-dihydro-1H-pyrrole-1-carboxylate (0.5 g, 2.51 mmol) in DCM (25 ml) was added DIPEA (0.86 ml, 5.02 mmol) at room temperature. The reaction mixture was stirred for 15 minutes and cooled to 0° C. Then, para-tosyl chloride (0.47 g, 2.51 mmol) was added portionwise to the reaction mixture, and the mixture was stirred at room temperature overnight. After completion of the reaction, the reaction mixture was diluted with saturated sodium bicarbonate (50 ml), and the product was extracted with ethyl acetate (2×50 ml). The combined organic layers were washed with brine (50 ml), dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel chromatography to give the title compound (0.42 g, 48%). 1 H NMR(400MHz,DMSO-d6):δ 1.44(s,9H),2.46(s,3H),4.36(s,2H),5.80(s,1H),7.56-7.58(m,2H),8.01-8.03(m,2H).LCMS:m / z=298.36[M-56].

[0146] Method 17, Step 3. tert-Butyl 4-(6-fluoropyridin-3-yl)-2-oxo-2,5-dihydro-1H-pyrrole-1-carboxylate: To a mixture of tert-butyl 2-oxo-4-(tosyloxy)-2,5-dihydro-1H-pyrrole-1-carboxylate (1.0 g, 2.83 mmol) and (6-fluoropyridin-3-yl)boronic acid (0.598 g, 4.24 mmol) in 1,2-dimethoxyethane (30 ml), Pd(dppf)Cl2-DCM complex (0.41 g, 0.56 mmol) was added at room temperature. 2 M sodium carbonate solution (10 ml) was added, and the reaction mixture was purged with argon gas for 30 minutes. The reaction mixture was heated to 90 °C and stirred for 3 hours. The reaction mixture was diluted with water (50 ml) and extracted with ethyl acetate (2 × 50 ml). The combined organic layer was washed with brine (50 ml), dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by column chromatography to give the title compound (0.36 g, 57%). 1H NMR(400MHz,DMSO-d6):δ 1.52(s,9H),4.84(s,2H),6.82(s,1H),7.37(dd,J=8.4Hz,6.0Hz,1H),8.37-8.42(m,1H),8.67(s,1H).LCMS:m / z=223.07[M-56].

[0147] Method 17, Step 4. 4-(6-Fluoropyridin-3-yl)-1,5-dihydro-2H-pyrrol-2-one: To a stirred solution of tert-butyl 4-(6-fluoropyridin-3-yl)-2-oxo-2,5-dihydro-1H-pyrrole-1-carboxylate (1.5 g, 5.39 mmol) in DCM (25 ml) was added dropwise TFA (5 ml) at room temperature. The reaction mixture was further stirred at room temperature for 3 hours. The mixture was concentrated and the residue was co-distilled twice with toluene to give the title compound, which was used directly in the next step without further purification. LCMS: m / z=179.16 [M+1].

[0148] Method 17, Step 5. 4-(6-Fluoropyridin-3-yl)pyrrolidin-2-one: To a stirred solution of 4-(6-fluoropyridin-3-yl)-1,5-dihydro-2H-pyrrol-2-one (0.25 g, 1.40 mmol) in methanol (2.5 ml) was added 10% Pd / C (0.25 g, 50% water). The reaction was then stirred at room temperature under a hydrogen gas atmosphere for 3 hours. The reaction mixture was diluted with methanol and filtered through a pad of Celite. The eluate was concentrated under reduced pressure to give the title compound (0.16 g, 44%). 1 H NMR(400MHz,DMSO-d6):2.33-2.40(m,1H),3.18-3.27(m,2H),3.60-3.74(m,2H),7.17(dd,J =8.4Hz,J=6.0Hz,1H),7.78(s,1H),7.98-8.02(m,1H),8.19(s,1H).LCMS:m / z=181.16[M+1].

[0149] Method 17, Step 6. 4-(6-Fluoropyridin-3-yl)-1-methylpyrrolidin-2-one: To a stirred solution of 4-(6-fluoropyridin-3-yl)pyrrolidin-2-one (0.16 g, 0.88 mmol) in DMF (3 ml) was added 60% NaH (0.053 g, 1.32 mmol) at 0 ° C. The reaction mixture was stirred at the same temperature for 30 minutes, and iodomethane (0.25 g, 1.77 mmol) was added. The reaction mixture was stirred at room temperature for another 2 hours. The reaction was quenched with cold water (30 ml) and extracted with ethyl acetate (2 × 50 ml). The combined organic layers were washed with brine (30 ml), dried over sodium sulfate, and concentrated. The residue was purified by silica gel chromatography to give the title compound (0.12 g, 70%). 1 H NMR(400MHz,DMSO-d6):δ 2.38-2.44(m,1H),2.63-2.70(m,1H),2.78(s,3H),3.33-3.37(m,1H),3.61-3.7 4(m,2H),7.17-7.19(m,1H),7.96-8.01(m,1H),8.19(s,1H).LCMS:m / z=195.56[M + +1].

[0150] Method 17, Step 7. 4-(6-aminopyridin-3-yl)-1-methylpyrrolidin-2-one: A solution of 4-(6-fluoropyridin-3-yl)-1-methylpyrrolidin-2-one (0.30 g, 1.54 mmol) in ammonium hydroxide solution (3 ml) was stirred for 48 hours at 140° C. The reaction mixture was concentrated under reduced pressure, and the residue was purified by reverse-phase HPLC to give the title compound (0.10 g, 34%). 1 H NMR(400MHz,DMSO-d6):δ 2.23-2.29(m,1H),2.54-2.56(m,1H),2.74(s,3H),3.19-3.24(m,1H),3.36-3.41(m,1H),3.58-3.62(m,1H),5.79(s ,2H,-NH2),6.40(d,J=8.4Hz,1H),7.33(dd,J=8.8Hz,J=2.4Hz,1H),7.79(d,J=2.4Hz,1H).LCMS:m / z=192.20[M+1].

[0151] Method 18 [ka] 2-((2-(4-cyanophenyl)propyl)amino)-2-(1-methyl-1H-pyrazol-4-yl)acetic acid ethyl ester Method 18, Step 1. 2-((2-(4-cyanophenyl)propyl)amino)-2-(1-methyl-1H-pyrazol-4-yl)acetic acid: To a stirred solution of 4-(1-aminopropan-2-yl)benzonitrile hydrochloride (5 g, 30.86 mmol) in DCM (75 ml) was added TEA (3.12 g, 30.86 mmol) at room temperature. mol), 2-oxoacetic acid (2.28 g, 30.86 mmol), and (1-methyl-1H-pyrazol-4-yl)boronic acid (3.80 g, 30.86 mmol) were added. The reaction mixture was stirred at the same temperature for 15 minutes. Then, HFIP (13.48 g, 80.24 mmol) was added, and the reaction mixture was stirred at room temperature for 16 hours. The reaction mixture was concentrated, and the residue was stirred with DCM:pentane (3:7; 150 ml) for 30 minutes. The solid precipitate was filtered through a Buchner funnel and washed with n-pentane to give the title compound (5.5 g, 59%). LCMS: m / z=299 [M+1].

[0152] Method 18, Step 2. Ethyl 2-((2-(4-cyanophenyl)propyl)amino)-2-(1-methyl-1H-pyrazol-4-yl)acetate: A mixture of 2-((2-(4-cyanophenyl)propyl)amino)-2-(1-methyl-1H-pyrazol-4-yl)acetic acid (5 g, 16.77 mmol) in DMF (100 ml) was heated at 80 °C until the reaction mixture became a clear solution. K2CO3 (5.79 g, 41.94 mmol) and ethyl iodide (2.61 g, 16.77 mmol) were added at the same temperature, and the mixture was stirred for 30 minutes. The reaction mixture was then stirred at room temperature for 16 hours. The reaction was quenched with ice-cold water (200 ml) and extracted with ethyl acetate (2 × 75 ml). The combined organic layers were washed with brine (100 ml), dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel chromatography to give the title compound (2.5 g, 45%) as a thick liquid. LCMS: m / z = 327.7 [M + 1].

[0153] Method 19 [ka] 1-(pyrrolidin-1-yl)-2-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazol-1-yl)ethan-1-one Method 19, Step 1. 2-Chloro-1-(pyrrolidin-1-yl)ethan-1-one: To a stirred solution of pyrrolidine (2 g, 28.12 mmol) and triethylamine (11.7 ml, 84.36 mmol) in DCM (20 ml), chloroacetyl chloride (3.4 ml, 42.18 mmol) was added dropwise and cooled to 0° C. The reaction mixture was stirred at room temperature for 2 hours. The reaction mixture was poured into cold 1N HCl solution (20 ml) and extracted with DCM (2×30 ml). The combined organic layers were washed with brine (20 ml), dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel chromatography to give the title compound (1.1 g, 26%). 1H NMR(400MHz,DMSO-d6):δ 4.30(s,2H),3.44-3.47(m,2H),3.30-3.35(m,2H),1.86-1.93(m,2H),1.77-1.82(m,2H).LCMS:m / z=148.05[M+1].

[0154] Method 19, Step 2. 1-(pyrrolidin-1-yl)-2-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazol-1-yl)ethan-1-one: To a stirred solution of 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (0.943 g, 4.86 mmol) in dry DMF (10 ml) was added NaH (0.213 g, 60%, 5.34 mmol) at 0° C. The reaction mixture was stirred at room temperature for 15 minutes. To this was added 2-chloro-1-(pyrrolidin-1-yl)ethan-1-one (1.0 g, 7.29 mmol) at 0° C. and stirred at the same temperature for 30 minutes. The reaction mixture was then stirred at room temperature for another hour. The reaction mixture was then washed with ice-cold water (20 The resulting mixture was poured into 100 ml of ethyl acetate and extracted with DCM (2 x 30 ml). The combined organic layers were washed with brine (20 ml), dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The crude product was purified by silica gel chromatography to give the title compound (0.81 g, 58%). LCMS: m / z = 306.28 [M+1].

[0155] method 20 [ka] 5-(3,5-dimethyl-1H-pyrazol-4-yl)pyridin-2-amine Method 24, Step 1. 5-(3,5-dimethyl-1H-pyrazol-4-yl)pyridin-2-amine: A stirred solution of tert-butyl 4-(6-aminopyridin-3-yl)-3,5-dimethyl-1H-pyrazole-1-carboxylate (0.3 g, 1.04 mmol) in DCM (3 ml) was cooled to 0° C. and HCl (2.2 ml, 8.79 mmol; 4 M in 1,4-dioxane) was added dropwise. The reaction mixture was allowed to warm to room temperature and stirred for 3.5 hours. The reaction mixture was concentrated under reduced pressure to give the crude product. The crude product was triturated with n-pentane (3×5 ml) and the solid was filtered off to give the title compound (175 mg, 75%). LCMS: m / z=189.21 [M+1].

[0156] Method 21 [ka] 2-((2-(4-cyanophenyl)-3,3,3-trifluoropropyl)amino)-2-phenylacetic acid ethyl ester Method 21, Step 1. 4-(2,2,2-trifluoroacetyl)benzonitrile: To a stirred solution of methyl 4-cyanobenzoate (1.5 g, 9.31 mmol) in dry THF (30 ml) was added trifluoromethyltrimethylsilane (1.98 g, 13.97 mmol) and cesium fluoride (0.14 g, 0.93 mmol) at room temperature, and the reaction mixture was stirred for 1 hour. The pH of the reaction mixture was adjusted to 5-6 with 1 N HCl, and the aqueous layer was extracted with ethyl acetate (2 × 50 ml). The combined organic layers were washed with brine (50 ml), dried over anhydrous sodium sulfate, and concentrated under reduced pressure. To the resulting residue was added TBAF (9.31 ml, 1 M in THF, 9.31 mmol) and water (10 ml) at room temperature. The reaction mixture was stirred for 1 hour. Water (50 ml) was added, and the mixture was extracted with ethyl acetate (2 × 50 ml). The combined organic layers were washed with brine (50 ml), dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel chromatography to give the title compound (1 g, 51%). 1 H NMR(400MHz,DMSO-d6):δ 7.77(d,J=8.4Hz,2H),7.90(d,J=8.0Hz,2H).

[0157] Method 21, Step 2. Ethyl (Z)-3-(4-cyanophenyl)-4,4,4-trifluorobut-2-enoate: Potassium tert-butoxide (0.12 g, 1.1 mmol) in dry THF (4 ml) To a stirred solution of HCl (III), triethylphosphonoacetate (0.27 g, 1.1 mmol) was added at -5 to 0°C under a nitrogen atmosphere. The reaction mixture was then stirred at the same temperature for 15 minutes. The reaction mixture was then warmed to room temperature and stirred for an additional hour. 4-(2,2,2-trifluoroacetyl)benzonitrile (0.2 g, 0.92 mmol) in THF (2 ml) was added to the reaction mixture, and the reaction mixture was heated to 70°C for 2 hours. The pH of the reaction mixture was adjusted to 3-4 with 1N HCl, and then the THF was removed under reduced pressure. The aqueous layer was extracted with ethyl acetate (2 x 50 ml), and the combined organic layers were washed with brine (50 ml), dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The resulting residue was purified by silica gel chromatography to give the title compound (0.1 g, 37%). 1 H NMR(400MHz, CDCl3): δ 1.16(t,J=7.2Hz,3H),4.08-4.14(m,2H),6.71(s,1H),7.45(d,J=7.6Hz,2H),7.76(d,J=8.0Hz,2H).

[0158] Method 21, Step 3. Ethyl 3-(4-cyanophenyl)-4,4,4-trifluorobutanoate: To a stirred solution of ethyl (Z)-3-(4-cyanophenyl)-4,4,4-trifluorobut-2-enoate (0.1 g, 0.37 mmol) in 1:4 methanol:ethyl acetate (1.5 ml) was carefully added Pd / C (0.02 g, 20% w / w, 50% water). The reaction mixture was stirred under a hydrogen atmosphere at room temperature for 3 hours. The reaction mixture was then diluted with ethyl acetate (5 ml) and filtered through a Celite pad. The Celite pad was washed with ethyl acetate (2 × 10 ml). The combined filtrate was concentrated under reduced pressure to give the title compound (0.1 g, quantitative). 1H NMR(400MHz,CDCl3):δ 1.07(t,J=6.8Hz,3H),3.13-3.15(m,2H),3.95-4.04(m,2H),4.27-4.33(m,1H),7.71(d,J=8.0Hz,2H),7.89(d,J=8.4Hz,2H).

[0159] Method 21, Step 4. 3-(4-cyanophenyl)-4,4,4-trifluorobutanoic acid: A stirred solution of ethyl 3-(4-cyanophenyl)-4,4,4-trifluorobutanoate (0.28 g, 1.03 mmol) in a mixture of MeOH:THF:HO (4:2:1, 10 ml) was treated with LiOH at 5-10 °C. . HO (0.08 g, 1.93 mmol) was added. The resulting reaction was stirred at room temperature for 1.5 hours. The organic solvent was then removed by evaporation. The crude material was dissolved in water (10 ml) and extracted with ethyl acetate (2 x 15 ml). The pH of the aqueous layer was adjusted to 3-4 with concentrated HCl. The desired compound precipitated during this process, and the solid product was filtered off to give the title compound (0.2 g, 74%) as a white solid. 1 H NMR(400MHz,DMSO-d6):δ 3.02(d,J=7.6Hz,2H),4.21-4.25(m,1H),7.68(d,J=8.4,2H),7.87(d,J=8.0Hz,2H),12.52(s,1H).

[0160] Method 21, Step 5. tert-Butyl (2-(4-cyanophenyl)-3,3.3-trifluoropropyl)carbamate: To a stirred solution of 3-(4-cyanophenyl)-4,4,4-trifluorobutanoic acid (0.5 g, 2.05 mmol) in tert-butanol (5 mL) was added triethylamine (0.86 mL, 5.96 mmol) at room temperature. The reaction mixture was then cooled to 5-10 °C, and DPPA (0.96 g, 3.49 mmol) was added dropwise. After the formation of the acyl azide, confirmed by TLC (1 h), the reaction was stirred at 90 °C overnight. The reaction mixture was diluted with water (30 mL) and extracted with ethyl acetate (2 × 30 mL). The combined organic layers were washed with brine (25 mL), dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The resulting residue was purified by silica gel chromatography to afford the title compound (0.3 g, 46%) as a solid. 1 H NMR(400MHz,DMSO-d6):δ 1.33( s,9H),2.90-3.00(m,1H),3.04-3.15(m,2H),6.91(t,J=5.2Hz,1H,-NH),7.42(d,J=8.4Hz,2H),7.77(d,J=7.2Hz,2H).

[0161] Method 21, Step 6. 4-(3-amino-1,1,1-trifluoropropan-2-yl)benzonitrile hydrochloride: To a stirred solution of tert-butyl (2-(4-cyanophenyl)-3,3,3-trifluoropropyl)carbamate (0.1 g, 0.31 mmol) in methanol (1 ml) at 0° C. was added dropwise a solution of 4 M HCl in dioxane (0.24 ml, 2.4 volumes). The resulting mixture was stirred at room temperature for 2 hours. The reaction mixture was concentrated under reduced pressure to give the title compound (0.05 g, 63%) as a solid. 1 H NMR(400MHz,DMSO-d6):δ 3.52-3.57(m,2H),4.33-4.41(m,1H),7.73(d,J=8.0Hz,2H),7.97(d,J=8.4Hz,2H),8.36(s,3H,-HCl).LCMS:m / z=215.1[M+1].

[0162] Method 21, Step 7. Ethyl 2-((2-(4-cyanophenyl)-3,3,3-trifluoropropyl)amino)-2-phenylacetate: A mixture of ethyl 2-bromo-2-phenylacetate (0.40 g, 1.44 mmol), 4-(3-amino-1,1,1-trifluoropropan-2-yl)benzonitrile hydrochloride (0.3 g, 1.20 mmol), and triethylamine (0.58 ml, 4.20 mmol) in DMF (3 ml) was heated at 60° C. for 3 hours. The reaction mixture was poured into ice-cold water (50 ml) and extracted with ethyl acetate (2×50 ml). The combined organic layers were washed with brine (25 ml), dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The resulting residue was purified by silica gel chromatography to give the title compound (0.40 g, 76%) as a thick yellow oil. 1 H NMR(400MHz,DMSO-d6):δ 1.08-1.11(m,3H),2.59-2.61(m,2H),2.99-3.10(m,3H),4.01-4.11(m,3H),4.40-4.47(m ,1H),7.23-7.36(m,5H),7.55-7.61(m,2H),7.88(t,J=8Hz,2H).LCMS:m / z=377.62[M+1].

[0163] Method 22 [ka] 2-((2-(2-methylpyrimidin-5-yl)propyl)amino)-2-phenylacetic acid ethyl ester Method 22, Step 1. Methyl (Z)-3-(2-methylpyrimidin-5-yl)but-2-enoate: To a stirred solution of 5-bromo-2-methylpyrimidine (5 g, 28.9 mmol) in dry DMF (3 ml) was added methyl crotonate (3.75 g, 37.57 mmol) at room temperature. To this mixture was added Pd(OAc) (0.64 g, 2.89 mmol), tri(o-tolyl)phosphine (0.88 g, 2.89 mmol), and triethylamine (4.80 ml, 34.68 mmol) at room temperature. The reaction mixture was then purged with argon for 20 minutes. The mixture was then heated to 100° C. overnight. The reaction mixture was then poured into ice-cold water (50 ml) and extracted with ethyl acetate (3×50 ml). The combined organic layers were washed with brine (50 ml), dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The resulting residue was purified by silica gel chromatography to give the title compound (1.8 g, 32%). 1 H NMR(400MHz,DMSO-d6):δ 2.61(s,3H),2.80(s,3H),3.82(s,3H),6.20(s,1H),8.77(s,2H).LCMS:m / z=193.3[M+1].

[0164] Method 22, Step 2. Methyl 3-(2-methylpyrimidin-5-yl)butanoate: To a stirred solution of methyl (Z)-3-(2-methylpyrimidin-5-yl)but-2-enoate (1.8 g, 9.37 mmol) in 1:1 methanol:ethyl acetate (20 ml) at room temperature was added 10% Pd / C (0.18 g, 10% w / w, 50% water). The reaction mixture was stirred overnight under hydrogen gas pressure (100 psi). The reaction mixture was then filtered through a pad of Celite and washed with 1:1 methanol:ethyl acetate (50 ml). The filtrate was concentrated under reduced pressure to give the title compound (1.2 g, 66%). LCMS: m / z=195.5 [M+1].

[0165] Method 22, Step 3. 3-(2-methylpyrimidin-5-yl)butanoic acid: A stirred solution of methyl 3-(2-methylpyrimidin-5-yl)butanoate (1.2 g, 6.18 mmol) in a mixture of MeOH:THF:HO (4:2:1, 10 ml) was treated with LiOH at 5-10 °C. . HO (0.38 g, 9.23 mmol) was added. The resulting reaction was stirred at room temperature for 2 hours. The reaction solvent was then evaporated, and the resulting residue was dissolved in water (10 ml) and extracted with ethyl acetate (2 x 15 ml). The pH of the aqueous layer was adjusted to 3-4 with concentrated HCl. The desired compound precipitated during this process, and the solid was filtered off to give the title compound (0.6 g, 54%) as a white solid. LCMS: m / z = 181.2 [M+1].

[0166] Method 22, Step 4. tert-Butyl (2-(2-methylpyrimidin-5-yl)propyl)carbamate: To a stirred solution of 3-(2-methylpyrimidin-5-yl)butanoic acid (0.6 g, 3.33 mmol) in tert-butanol (6 mL) was added triethylamine (1.37 mL, 9.99 mmol) at room temperature. The reaction mixture was then cooled to 5-10 °C, and DPPA (1.5 g, 5.45 mmol) was added dropwise. After the formation of the acyl azide was confirmed by TLC, the reaction mixture was stirred at 90 °C overnight. The reaction mixture was diluted with water (30 mL) and extracted with ethyl acetate (2 × 30 mL). The combined organic layers were washed with brine (25 mL), dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The resulting residue was purified by silica gel chromatography to give the title compound (0.4 g, 47%) as a thick oil. LCMS: m / z = 252.2 [M+1].

[0167] Method 22, Step 5. 2-(2-methylpyrimidin-5-yl)propan-1-amine hydrochloride: To a stirred solution of tert-butyl (2-(2-methylpyrimidin-5-yl)propyl)carbamate (0.4 g, 1.59 mmol) in methanol (4 ml) was added dropwise a solution of 4 M HCl in dioxane (0.96 ml, 2.4 vol) at 0° C. The resulting mixture was stirred at room temperature for 2 hours. The reaction mixture was concentrated under reduced pressure to give the title compound (0.26 g) as a solid. LCMS: m / z=152.1 [M+1].

[0168] Method 22, Step 6. Ethyl 2-((2-(2-methylpyrimidin-5-yl)propyl)amino)-2-phenylacetate: A mixture of ethyl 2-bromo-2-phenylacetate (0.37 g, 1.52 mmol), 2-(2-methylpyrimidin-5-yl)propan-1-amine hydrochloride (0.26 g, 1.38 mmol), and triethylamine (0.41 ml, 3.04 mmol) in DMF (3 ml) was heated at 60° C. for 3 hours. The reaction mixture was poured into ice-cold water (50 ml) and extracted with ethyl acetate (2×50 ml). The combined organic layers were washed with brine (25 ml) and Drying over anhydrous sodium sulfate and concentration under reduced pressure gave the crude product (0.32 g). LCMS: m / z=314.6 [M+1].

[0169] Method 23 [ka] 2-((2-(4-cyano-1H-pyrazol-1-yl)ethyl)amino)-2-phenylacetic acid ethyl ester Method 23. Ethyl 2-((2-(4-cyano-1H-pyrazol-1-yl)ethyl)amino)-2-phenylacetate: To a stirred solution of ethyl 2-((2-chloroethyl)amino)-2-phenylacetate (0.10 g, 0.413 mmol) in DMF (1 ml) was added K2CO3 (0.114 g, 0.827 mmol) at 25 °C. After stirring for 15 minutes, 1H-pyrazole-4-carbonitrile (0.046 g, 0.496 mmol) was added at 25 °C. The reaction mixture was heated at 60 °C for 3 hours. The reaction mixture was poured into ice water (15 ml), and the product was extracted with ethyl acetate (2 × 30 ml). The combined organic layers were washed with brine (20 ml), dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel chromatography to give the title compound (0.050 g, 40%). LCMS: m / z = 299.76 [M + 1].

[0170] Method 24 [ka] 2-((2-(5-cyanopyridin-2-yl)ethyl)amino)-2-phenylacetic acid ethyl ester Method 24, Step 1. 6-Vinylnicotinonitrile: A mixture of 6-bromonicotinonitrile (2.0 g, 10.92 mmol), 4,4,5,5-tetramethyl-2-vinyl-1,3,2-dioxaborolane (2.5 g, 16.39 mmol), and sodium carbonate (1.4 g, 13.50 mmol) in 4:1 dioxane:water (25 ml) was purged with argon for 20 minutes. Pd(PPh3)4 (0.63 g, 0.54 mmol) was added to the reaction mixture, and purging with argon continued for an additional 10 minutes. The reaction mixture was heated at 90 °C for 12 hours. The reaction mixture was poured into water (50 ml) and extracted with ethyl acetate (2 × 100 ml). The combined organic layers were washed with brine (50 ml), dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The crude product was purified by silica gel chromatography to give the title compound (0.7 g, 49%) as a solid. 1H NMR(400MHz,DMSO-d6):δ 5.72(d,J=10.8Hz,1H),6.42(d,J=17.2Hz,1H),6.82-6.89(m,1H),7.44(d,J=8 .0Hz,1H),7.93(dd,J=8.0Hz,2.0Hz,1H),8.85(s,1H).LCMS:m / z=131.3[M+1].

[0171] Method 24, Step 2. Ethyl 2-((2-(5-cyanopyridin-2-yl)ethyl)amino)-2-phenylacetate: 6-vinylnicotinonitrile (0.20 g, 15.0 mmol) in ethanol (2 ml) To a stirred solution of 2-amino-2-phenylacetate (1.1g, 16.7mmol) was added triethylamine (2.0ml, 15.0mmol) and ethyl 2-amino-2-phenylacetate (0.30g, 16.7mmol) at 25°C. The reaction mixture was heated at 90°C for 5 hours. The reaction mixture was concentrated under reduced pressure, and water (25ml) was added to the residue. The aqueous layer was extracted with ethyl acetate (2x30ml). The combined organic layers were washed with brine (20ml), dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The crude product was purified by silica gel chromatography to give the title compound (0.3g, 40%). 1 H NMR(400MHz,DMSO-d6):δ 1.23(t,J=7.2Hz,3H),2.93-2.98(m,1H),3.03-3.11(m,3H),4.12-4.26(m,2H),4.4 0(s,1H),7.30-7.43(m,7H),7.89(dd,J=8.0Hz,2.0Hz,1H),LCMS:m / z=310.36[M+1].

[0172] Method 25 [ka] 2-((2-(6-methylpyridin-3-yl)propyl)amino)-2-phenylacetic acid ethyl ester Method 25, Step 1. 2-Methyl-5-(prop-1-en-2-yl)pyridine: A mixture of 5-bromo-2-methylpyridine (2.0 g, 11.62 mmol), potassium isopropenyltrifluoroborate (2.5 g, 17.43 mmol), and cesium carbonate (11.3 g, 34.88 mmol) in 4:1 isopropanol:water (50 mL) was purged with argon for 20 minutes. The reaction mixture was charged with Pd(dppf)Cl2 . DCM (0.84 g, 1.16 mmol) was added and purging with argon continued for another 10 minutes. The reaction mixture was heated at 100° C. for 2-3 hours. The reaction mixture was poured into water (50 ml) and extracted with ethyl acetate (2×100 ml). The combined organic layers were washed with brine (50 ml), dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel chromatography to give the title compound (1.03 g, 49%) as a solid. LCMS: m / z=134.5 [M+1].

[0173] Method 25, Step 2. (E)-2-Methyl-5-(1-nitroprop-1-en-2-yl)pyridine: To a stirred solution of 1-chloro-4-(prop-1-en-2-yl)benzene (0.5 g, 3.73 mmol) in dry DCE (5.0 ml) under a nitrogen atmosphere was added AgNO (1.72 g, 11.19 mmol), TEMPO (0.23 g, 1.49 mmol), and 4 Å molecular sieves (1.5 g) at room temperature. The resulting reaction mixture was stirred at room temperature for 10 minutes and then heated to 70 °C overnight. The reaction mixture was cooled to room temperature and diluted with dichloromethane (50 ml). The mixture was then filtered through a pad of Celite, and the pad was washed with dichloromethane (50 ml). The eluate was then concentrated under reduced pressure. The residue was purified by silica gel column chromatography to give the title compound (0.4 g, 30%) as a pale yellow solid. LCMS: m / z = 179.5 [M+1].

[0174] Method 25, Step 3. 2-(6-methylpyridin-3-yl)propan-1-amine: Under a nitrogen atmosphere, LAH (5.0 ml, 1 M in THF, 5.05 mmol) was added dropwise to a solution of (E)-1-chloro-4-(1-nitroprop-1-en-2-yl)benzene (0.45 g, 2.52 mmol) in dry THF (5 ml) at 0° C. The reaction mixture was stirred at room temperature overnight. Saturated aqueous sodium bicarbonate solution (50 ml) was added, and the reaction mixture was cooled to room temperature. Extraction with ethyl acetate (3 x 50 ml) was performed. The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to give the title compound (0.35 g) as a yellow oil, which was used in the next step without further purification.

[0175] Method 25, Step 4. Ethyl 2-((2-(6-methylpyridin-3-yl)propyl)amino)-2-phenylacetate: A mixture of ethyl 2-bromo-2-phenylacetate (0.37 g, 1.55 mmol), 2-(6-methylpyridin-3-yl)propan-1-amine (0.35 g, 2.32 mmol), and triethylamine (0.58 ml, 3.10 mmol) in DMF (5 ml) was heated at 60° C. for 3 hours. The reaction mixture was poured into ice-cold water (50 ml) and extracted with ethyl acetate (2×50 ml). The combined organic layers were washed with brine (25 ml), dried over anhydrous sodium sulfate, and concentrated under reduced pressure to give the crude product, which was purified by silica gel column chromatography to give the title compound (0.15 g, 20%). LCMS: m / z=313.1 [M+1].

[0176] Scheme 1 The starting materials required for the synthesis of examples prepared using Scheme 1 were either commercially available or prepared using Methods 1-3.

[0177] Example 1 [ka] (S)- and (R)-2-((4-cyanophenethyl)amino)-N-(4-(1-methyl-1H-pyrazol-4-yl)phenyl)-2-phenylacetamide Scheme 1. (S)- and (R)-2-((4-cyanophenethyl)amino)-N-(4-(1-methyl-1H-pyrazol-4-yl)phenyl)-2-phenylacetamide: A mixture of 2-bromo-N-(4-(1-methyl-1H-pyrazol-4-yl)phenyl)-2-phenylacetamide (0.5 g, 1.35 mmol), 4-(2-aminoethyl)benzonitrile hydrochloride (0.296 g, 2.7 mmol), and TEA (0.6 ml, 4.05 mmol) in DMF (5 ml) was heated at 60° C. for 2 hours. After completion of the reaction, the reaction mixture was poured into ice-cold water (15 ml) and extracted with ethyl acetate (2×30 ml). The combined organic layers were washed with brine (15 ml), dried over anhydrous NaSO, and concentrated under reduced pressure. The resulting residue was purified by silica gel chromatography to afford the title compound (0.35 g, 59%) as a solid in racemic form.

[0178] The racemic title compound was resolved by chiral HPLC (CHIRALPAK AD-H; 30% (50:50 ACN:IPA) + 0.1% DEA in liquid CO to give the enantiopure compound. The faster eluting enantiomer of the title compound was obtained as a solid (Isomer 1). 1 H NMR (400 MHz, DMSO-d6): δ 2.76-2.78 (m, 2H), 2.86-2.88 (m, 2H), 3.85 (s, 3H), 4.38 (s, 1H), 7.28-7.37 (m, 3H), 7.45-7.49 (m, 6H), 7.53 (d, J = 8.8 Hz, 2H), 7.75 (d, J = 8.4 Hz, 2H), 7.79 (s, 1H), 8.06 (s, 1H), 10.04 (s, 1H). LCMS: m / z = 436.5 [M+1]. The slower eluting enantiomer of the title compound was obtained as a solid (isomer 2: 1 H NMR(400MHz,DMSO-d6):δ 2.76-2.79(m,2H),2 .86-2.89(m,2H),3.85(s,3H),4.38(s,1H),7.28-7.37(m,3H),7.44-7.49(m,6H),7.53(d,J=8.8Hz,2H),7.75(d,J=8.0Hz,2H),7.79(s,1H),8.06(s,1H),10.03(s,1H).LCMS:m / z=436.5[M+1].

[0179] The following compounds were prepared using the appropriate starting materials and procedures similar to those described for Example 1. The separated isomers of each compound are listed in the order in which they elute. For example, if two isomers are present, isomer 1 is the faster-eluting isomer and isomer 2 is the slower-eluting isomer. If four isomers are present, isomer 1 is the fastest-eluting isomer, followed by isomer 2, then isomer 3, and then isomer 4. Furthermore, when more than one chiral series is listed, the series are used in the order listed. For example, if three columns are listed for the purification of a compound with two stereocenters, the first column was used to separate the mixture into two stereoisomers, 1 and 2, and a mixture of stereoisomers 3 and 4. The mixture of stereoisomers 1 and 2 was then further separated into pure stereoisomers by the second column listed, and the mixture of stereoisomers 3 and 4 was separated into pure stereoisomers by the third column listed. In some cases, a single chiral column can resolve all four stereoisomers. Additionally, one column may resolve a mixture into pure stereoisomer 1, pure stereoisomer 2, a mixture of stereoisomers 3 and 4, and a second chiral column is used to resolve the mixture. The stereochemical designation (i.e., R or S) of each isomer of the compound is not depicted in the table, but rather is named to clarify that support for both is intended. Chiral carbon atoms are designated with an asterisk (*). In some cases, chiral building blocks are used to prepare compounds with multiple stereocenters, and specific stereoisomers have not been prepared. If the stereochemistry of one stereocenter is known, it is depicted as such, and the other stereocenter that has not been specifically assigned is designated with an asterisk (*). In instances where the compound is racemic, it is so indicated. In one aspect, the present disclosure relates to the racemic form of any compound described herein. These rules are adhered to throughout the application. [Table 6]

[0180] Scheme 2 The starting materials required for the synthesis of examples prepared using Scheme 2 were either commercially available or prepared using Methods 1-3.

[0181] Example 5 [ka] (S)- and (R)-2-((4-chlorophenethyl)amino)-N-(4-(1-methyl-1H-pyrazol-4-yl)phenyl)-2-phenylacetamide Scheme 2. (S)- and (R)-2-((4-chlorophenethyl)amino)-N-(4-(1-methyl-1H-pyrazol-4-yl)phenyl)-2-phenylacetamide: A mixture of N-(4-bromophenyl)-2-((4-chlorophenethyl)amino)-2-phenylacetamide (0.2 g, 0.90 mmol), 1-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (0.205 g, 0.99 mmol), and cesium carbonate (0.9 g, 2.69 mmol) in 4:1 dioxane:water (5 mL) was purged with argon for 20 minutes. S-Phos Pd-precatalyst G3 (0.070 g, 0.089 mmol) was added, and purging continued for an additional 10 minutes. The reaction mixture was heated in a sealed tube at 100° C. for 2 hours. After completion of the reaction (monitored by TLC), the reaction mixture was treated with water (10 mL) and extracted with ethyl acetate (2×15 mL). The combined organic layers were washed with brine (20 ml), dried over anhydrous NaSO, and concentrated under reduced pressure. The resulting residue was purified by silica gel chromatography to give the title compound as a solid in racemic form (0.090 g, 55%).

[0182] The racemic title compound was resolved by chiral HPLC (CHIRALPAK IB; 30% (50:50 MeOH:IPA) + 0.1% DEA in hexanes) to give the enantiopure compound. The faster eluting enantiomer of the title compound was obtained as a solid (Isomer 1). 1H NMR (400 MHz, DMSO-d6): δ 2.68-2.78 (m, 4H), 3.85 (s, 3H), 4.37 (s, 1H), 7.25-7.30 (m, 3H), 7.33-7.37 (m, 4H), 7.44-7.49 (m, 4H), 7.53 (d, J = 8.4 Hz, 2H), 7.80 (s, 1H), 8.06 (s, 1H), 10.01 (s, 1H). LCMS: m / z = 445.57 [M+1]. The slower eluting enantiomer of the title compound was obtained as a solid (isomer 2): 1 H NMR(400MHz,DMSO-d6):δ 2.72-2.78(m,4H),3.85(s,3H),4.37(s,1H),7.25-7.30(m,3H),7.33-7.37(m,4H), 7.44-7.54(m,6H),7.80(s,1H),8.06(s,1H),10.01(s,1H).LCMS:m / z=445.62[M+1].

[0183] Example 6 [ka] (S,S)-, (R,R)-, (S,R)-, and (R,S)-2-((2-(4-cyanophenyl)propyl)amino)-N-(5-(2-methylpyrimidin-5-yl)pyridin-2-yl)-2-phenylacetamide Scheme 3, Step 1. 2-((2-(4-cyanophenyl)propyl)amino)-N-(5-(2-methylpyrimidin-5-yl)pyridin-2-yl)-2-phenylacetamide: A mixture of N-(5-bromopyridin-2-yl)-2-((2-(4-cyanophenyl)propyl)amino)-2-phenylacetamide (0.300 g, 0.66 mmol), 2-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyrimidine (0.293 g, 1.33 mmol), and cesium carbonate (0.650 g, 2.0 mmol) in dioxane:water (4:1, 7.5 mL) was degassed with argon gas for 20 minutes. PdCl(dppf) (0.049 g, 0.066 mmol) was added, and degassing was continued for another 10 minutes. The reaction mixture was heated at 100° C. for 1 hour. After completion of the reaction (monitored by TLC), the reaction mixture was diluted with water (20 ml) and extracted with ethyl acetate (2×30 ml). The combined organic layers were washed with brine, dried over anhydrous Na SO and concentrated under reduced pressure. The crude product was purified by silica gel chromatography to give the title compound (0.270 g, 78%) as an off-white solid in racemic form.

[0184] The racemic title compound was resolved by chiral HPLC (CHIRALCEL OX-H; 30% (30:70 ACN:IPA) + 0.1% DEA in hexanes) followed by (CHIRALCEL OJ-H; 25% (MeOH) + 0.1% DEA in liquid CO) to give the enantiopure compound. The first eluting enantiomer of the title compound was obtained as a solid (Isomer 1). 1 H NMR (400 MHz, DMSO-d) δ 1.21 (d, J = 7.2 Hz, 3H), 2.66 (s, 3H), 2.69-2.71 (m, 3H), 3.03-3.05 (m, 1H), 4.50 (d, J = 7.6 Hz, 1H), 7.25-7.41 (m, 7H), 7.76 (d, J = 8 Hz, 2H), 8.12-8.30 (m, 2H), 8.74 (d, J = 2 Hz 1H), 9.05 (s, 2H), 10.52 (s, 1H). LCMS: m / z = 463.4 [M+1]; the second eluting enantiomer of the title compound was obtained as a solid (isomer 2).1 H NMR (400 MHz, DMSO-d6) δ 1.22 (d, J = 6.8 Hz, 3H), 2.68 (s, 3H), 2.69-2.73 (m, 3H), 3.04-3.06 (m, 1H), 4.52 (d, J = 6.0 Hz, 1H), 7.25-7.49 (m, 7H), 7.77 (d, J = 8 Hz, 2H), 8.12-8.30 (m, 2H), 8.74 (s, 1H), 9.06 (s, 2H), 10.54 (s, 1H). LCMS: m / z = 463.6 [M+1]. The third eluting enantiomer of the title compound was obtained as a solid (isomer 3). 1 H NMR(400MHz,DMSO-d6)δ 1.23(d,J=6.8Hz,3H),2.68(s,3H),2.70-2. 72 (m, 2H), 3.04-3.06 (m, 1H), 4.51 (d, J = 6.0 Hz, 1H), 7.25-7.49 (m, 7H), 7.77 (d, J = 8 Hz, 2H), 8.12-8.30 (m, 2H), 8.74 (s, 1H), 9.06 (s, 2H), 10.55 (s, 1H). LCMS: m / z = 463.5 [M+1]; the fourth eluting enantiomer of the title compound was obtained as a solid (isomer 4). 1 H NMR(400MHz,DMSO-d6)δ 1.23(d,J=6.8Hz,3H),2.68(s,3H),2.70-2.72(m,2H),3.04-3.06(m,1H),4.51(d,J=6.4Hz,1H),7.25-7.49(m, 7H),7.77(d,J=8.4Hz,2H),8.14-8.24(m,2H),8.76(s,1H),9.07(s,2H),10.55(s,1H).LCMS:m / z=463.4[M+1].

[0185] The compounds in Table 2 were prepared using procedures similar to those described for Examples 5 and 6, using the appropriate starting materials. [Table 7]

[0186] Scheme 3 The starting materials required for the synthesis of examples prepared using Scheme 3 were either commercially available or prepared using Methods 1-3.

[0187] Example 9 [ka] (S)- and (R)-2-((4-chlorophenethyl)amino)-N-(4-(5-methyl-1H-imidazol-2-yl)phenyl)-2-phenylacetamide Scheme 3, Step 1. 2-((4-chlorophenethyl)amino)-2-phenyl-N-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)acetamide: A mixture of N-(4-bromophenyl)-2-((4-chlorophenethyl)amino)-2-phenylacetamide (1.5 g, 3.39 mmol), bis(pinacolato)diborane (1.2 g, 5.09 mmol), and KOAc (0.83 g, 8.47 mmol) in 1,4-dioxane (30 mL) was purged with argon for 20 minutes. To this mixture was added 1,1'-bis(diphenylphosphino)ferrocene-palladium(II) dichloride (0.248 g, 0.33 mmol), and the mixture was stirred for an additional 10 minutes. Purging was continued for 6 hours. The reaction mixture was heated in a sealed tube at 90° C. for 6 hours. After completion of the reaction (monitored by TLC), the reaction mixture was treated with water (20 ml) and extracted with ethyl acetate (3×20 ml). The combined organic layers were washed with brine (20 ml), dried over anhydrous NaSO, and concentrated under reduced pressure. The crude residue was purified by silica gel chromatography to give the title compound (1.2 g, 72%) as a solid. 1 H NMR(400MHz,DMSO-d6):δ 1.28(s,12H),2.69-2.76(m,4H),4.38(s,1H),7.25-7.30(m,3H),7.33-7.36(m,4H),7.44(d,J= 6.8Hz,2H),7.54(d,J=8.4Hz,2H),7.60(d,J=8.4Hz,2H),10.09(s,-NH).LCMS:m / z=491.5[M+1].

[0188] Scheme 3, Step 2. (S)- and (R)-2-((4-chlorophenethyl)amino)-N-(4-(5-methyl-1H-imidazol-2-yl)phenyl)-2-phenylacetamide: A mixture of 2-((4-chlorophenyl)amino)-2-phenyl-N-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)acetamide (0.2 g, 0.40 mmol), 2-bromo-5-methyl-1H-imidazole (0.131 g, 0.81 mmol), and cesium carbonate (0.332 g, 1.02 mmol) in 4:1 dioxane:water (10 ml) was purged with argon for 20 minutes. 1,1′-Bis(diphenylphosphino)-ferrocene-palladium(II) dichloride (0.029 g, 0.04 mmol) was added, and purging continued for an additional 10 minutes. The reaction mixture was heated in a sealed tube with microwave irradiation at 135° C. for 2 hours. After completion of the reaction (monitored by TLC), the reaction mixture was treated with water (20 ml) and extracted with ethyl acetate (2 x 20 ml). The combined organic layers were washed with brine (20 ml), dried over anhydrous NaSO, and concentrated under reduced pressure. The crude residue was purified by silica gel chromatography to obtain the title compound as a solid (0.080 g, 44%) in racemic form.

[0189] The racemic title compound was resolved by chiral HPLC (CHIRALPAK AD-H; (50:50 ACN:IPA) + 0.1% DEA in liquid CO) to give the enantiopure compound. The faster eluting enantiomer of the title compound was obtained as a solid (Isomer 1). 1H NMR (400 MHz, DMSO-d6): δ 2.13-2.21 (m, 3H), 2.67-2.77 (m, 4H), 4.37 (s, 1H), 6.64-6.88 (m, 1H), 7.25-7.29 (m, 3H), 7.33-7.36 (m, 4H), 7.44 (d, J = 7.6 Hz, 2H), 7.55 (d, J = 8.4 Hz, 2H), 7.78 (t, J = 5.6 Hz, 2H), 10.08 (s, 1H, -NH), 12.06-12.12 (m, 1H, -NH). LCMS: m / z = 445.4 [M+1]. The slower eluting enantiomer of the title compound was obtained as a solid (isomer 2): 1 H NMR(400MHz,DMSO-d6):δ 2.13-2.21(m,3H),2.73-2.77(m,4H),4.37(s,1H),6.64-6.88(m,1H),7.25-7.29(m,3H),7.33-7.36(m,4H),7.44(d,J=7 .2Hz,2H),7.55(d,J=8.4Hz,2H),7.78-7.80(m,2H),10.08(s,1H,-NH),12.06-12.13(m,1H,-NH).LCMS:m / z=445.5[M+1].

[0190] The following compounds were prepared using procedures similar to those described for Example 9, using the appropriate starting materials. [Table 8]

[0191] Scheme 4 The starting materials required for the synthesis of examples prepared using Scheme 4 were either commercially available or prepared using Methods 1-3.

[0192] Example 16 [ka] (S)- and (R)-2-((4-chlorophenethyl)amino)-N-(4-(4-methyl-1H-imidazol-1-yl)phenyl)-2-phenylacetamide Scheme 4. (S)- and (R)-2-((4-chlorophenethyl)amino)-N-(4-(4-methyl-1H-imidazol-1-yl)phenyl)-2-phenylacetamide: N-(4-bromophenyl)-2-((4-chlorophenethyl)amino)-2-phenylacetamide (0.15 g, 0.33 mmol), 4-methyl-1H-imidazole (0.14 g, 1.69 mmol), CuI (0.032 g, 0.1 A mixture of 1-(5,6,7,8-tetrahydroquinolin-8-yl)ethanone (0.011 g, 0.06 mmol) and cesium carbonate (0.11 g, 0.33 mmol) was purged with argon for 20 minutes. 1-(5,6,7,8-tetrahydroquinolin-8-yl)ethanone (0.011 g, 0.06 mmol) was added, and purging was continued for another 10 minutes. The reaction mixture was heated in a sealed tube at 135° C. for 16 hours. After completion of the reaction (monitored by TLC), the mixture was treated with water (10 ml) and extracted with ethyl acetate (2×10 ml). The combined organic layers were washed with brine (10 ml), dried over anhydrous NaSO, and concentrated under reduced pressure. The resulting residue was purified by silica gel chromatography to give the title compound as a solid (0.1 g, 66%) in racemic form.

[0193] The racemic title compound was resolved by chiral HPLC (CHIRALPAK OJ-H; 20% MeOH + 0.1% DEA in liquid CO2) to give the enantiopure compound. The faster eluting enantiomer of the title compound was obtained as a solid (Isomer 1). 1 H NMR (400 MHz, DMSO-d6): δ 2.15 (s, 3H), 2.68-2.78 (m, 4H), 4.39 (d, J = 7.6 Hz, 1H), 7.25-7.31 (m, 3H), 7.33-7.37 (m, 4H), 7.45-7.47 (m, 2H), 7.52 (d, J = 8.0 Hz, 2H), 7.66-7.77 (m, 3H), 8.05 (s, 1H), 10.21 (s, -NH). LCMS: m / z = 445.4 [M+1]. The slower eluting enantiomer of the title compound was obtained as a solid (isomer 2): 1H NMR(400MHz,DMSO-d6):2.15(s,3H),2.72-2.82(m,4H),4.40(s,1H),7.25-7.30(m,3H),7.33-7.37(m,4H),7.46 (d,J=7.2Hz,2H),7.52(d,J=8.8Hz,2H),7.66-7.70(m,3H),8.05(s,1H),10.26(s,-NH).LCMS:m / z=445.4[M+1].

[0194] Scheme 5 The starting materials required for the synthesis of examples prepared using Scheme 5 were either commercially available or prepared using Methods 1-3.

[0195] Example 17 [ka] (S)- and (R)-2-((4-chlorophenethyl)amino)-N-(4-(4-methylpiperazin-1-yl)phenyl)-2-phenylacetamide Scheme 6. (S)- and (R)-2-((4-chlorophenethyl)amino)-N-(4-(4-methylpiperazin-1-yl)phenyl)-2-phenylacetamide: A mixture of N-(4-bromophenyl)-2-((4-chlorophenethyl)amino)-2-phenylacetamide (0.4 g, 0.79 mmol), 1-methylpiprazine (0.1 g, 1.01 mmol), and cesium carbonate (0.55 g, 1.69 mmol) in dioxane (4 ml) was purged with argon for 20 minutes. Brett-Phos Pd-precatalyst G3 (0.061 g, 0.067 mmol) was added, and purging continued for another 10 minutes. The reaction mixture was heated in a sealed tube under microwave irradiation at 135 °C for 2 hours. After completion of the reaction (monitored by TLC), the mixture was treated with water (15 ml) and extracted with ethyl acetate (2 × 15 ml). The combined organic layers were washed with brine (15 ml), dried over anhydrous NaSO, and concentrated under reduced pressure. The resulting residue was purified by silica gel chromatography to give the title compound as a solid in racemic form (0.08 g, 25%).

[0196] The racemic title compound was resolved by chiral HPLC (CHIRALCEL OX-H; 35% (50:50 MeOH:IPA) + 0.1% DEA in hexanes) to give the enantiopure compound. The faster eluting enantiomer of the title compound was obtained as a solid (Isomer 1). 1 H NMR (400 MHz, DMSO-d6): δ 2.21 (s, 3H), 2.42-2.45 (m, 4H), 2.68-2.77 (m, 5H), 3.04-3.06 (m, 4H), 4.32 (d, J = 7.2 Hz, 1H), 6.86 (d, J = 8.8 Hz, 2H), 7.24-7.44 (m, 11H), 9.83 (s, 1H). LCMS: m / z = 463.1 [M+1]. The slower eluting enantiomer of the title compound was obtained as a solid (isomer 2): 1 H NMR(400MHz,DMSO-d6):δ 2.23(s,3H),2.46-2.51(m,4H),2.69-2.77(m,5H),3.04-3.06(m,4H),4.33(s,1H) ),6.86(d,J=8.8Hz,2H),7.24-7.44(m,11H),9.83(s,1H).LCMS:m / z=463.5[M+1].

[0197] The following compounds were prepared using procedures similar to those described for Example 17, using the appropriate starting materials. [Table 9]

[0198] Scheme 6 The starting materials required for the synthesis of examples prepared using Scheme 7 were generally prepared using Methods 1-3 or are commercially available.

[0199] Example 19 [ka] (S)- and (R)-2-((4-cyanophenethyl)amino)-N-(6-(1-methyl-1H-pyrazol-4-yl)pyridin-3-yl)-2-phenylacetamide. Scheme 6, Step 1. Ethyl 2-((4-cyanophenethyl)amino)-2-phenylacetate: A mixture of ethyl 2-bromo-2-phenylacetate (2.0 g, 8.22 mmol), 4-(2-aminoethyl)benzonitrile hydrochloride (2.25 g, 12.33 mmol), and TEA (2.50 g, 24.66 mmol) in DMF (20 ml) was heated at 60° C. for 3 hours. The reaction mixture was poured into ice-cold water (50 ml) and extracted with ethyl acetate (2×50 ml). The combined organic layers were washed with brine (25 ml), dried over anhydrous NaSO, and concentrated under reduced pressure. The residue was purified by silica gel chromatography to give the title compound (2.2 g, 86%) as a thick liquid. 1 H NMR(400MHz,DMSO-d6):δ 1.10(t,J=7.2Hz,3H),2.62-2.82(m,4 H),4.02-4.09(m,2H),4.39(d,J=8.4Hz,1H),7.28-7.35(m,5H),7.40(d,J=8.4Hz,2H),7.72(d,J=8.4Hz,2H).LCMS:m / z=309.28[M+1].

[0200] Scheme 6, Step 2, Procedure 1. (S)- and (R)-2-((4-cyanophenethyl)amino)-N-(6-(1-methyl-1H-pyrazol-4-yl)pyridin-3-yl)-2-phenylacetamide: To a mixture of 6-(1-methyl-1H-pyrazol-4-yl)pyridin-3-amine (250 mg, 1.44 mmol) and ethyl 2-((4-cyanophenethyl)amino)-2-phenylacetate (531 mg, 1.72 mmol) in toluene, trimethylaluminum (2.9 ml, 2.870 mmol; 1 M in toluene) was added at room temperature under a nitrogen atmosphere. The resulting reaction mixture was heated to 100° C. for 2 hours. After completion of the reaction (monitored by TLC), the mixture was diluted with ethyl acetate (20 ml) and slowly quenched with water (20 ml) at room temperature. The aqueous layer was extracted with ethyl acetate (2×20 ml). The combined organic layers were washed with brine (20 ml), dried over anhydrous NaSO, and concentrated under reduced pressure. The resulting residue was purified by silica gel chromatography to give the title compound (150 mg, 30%) in racemic form.

[0201] The racemic title compound was resolved by chiral HPLC (CHIRALPAK IB; 55% (50:50 MeOH:IPA) + 0.1% DEA in hexanes) to give the enantiopure compound. The faster eluting enantiomer of the title compound was obtained as a solid (Isomer 1). 1 H NMR(400MHz,DMSO-d6):δ 2.61-2.82(m,2H),2.87-2.89(m,2H),3.87(s,3H),4.43(s,1H),7.27-7.31(m,1H),7. 34-7.39(m,2H),7.44-7.48(m,4H),7.57-7.59(d,J=8.8Hz,1H),7.74-7.76(d,J=8.0H z, 2H), 7.92 (s, 1H), 8.01 (dd, J = 8.8 Hz, 2.4 Hz, 1H), 8.20 (s, 1H), 8.66 (d, J = 2.4 Hz, 1H), 10.34 (s, 1H, -NH). LCMS: m / z = 437.24 [M+1]. The slower eluting enantiomer of the title compound was obtained as a solid (isomer 2): 1H NMR(400MHz,DMSO-d6):δ 2.77-2.78(m,2H),2.87-2.89(m,2H),3.87(s,3H),4.42(s,1H),7.27-7. 31(m,1H),7.34-7.39(m,2H),7.44-7.48(m,4H),7.59(d,J=8.4Hz,1H),7 .75(d,J=8.0Hz,2H),7.92(s,1H),8.01(dd,J=8.4Hz,2.4Hz,1H),8.20(s,1H),8.66(d,J=2.0Hz,1H),10.34(s,1H,-NH).LCMS:m / z=437.24[M+1].

[0202] Example 22 [ka] (S)- and (R)-2-((4-cyanophenethyl)amino)-N-(5-(1-methyl-1H-pyrazol-4-yl)pyridin-2-yl)-2-phenylacetamide Scheme 6, Step 2, Procedure 1. (S)- and (R)-2-((4-cyanophenethyl)amino)-N-(5-(1-methyl-1H-pyrazol-4-yl)pyridin-2-yl)-2-phenylacetamide: 5-(1-methyl-1H-pyrazol-4-yl)pyrazole in dry toluene (10 ml) To a stirred solution of zinzin-2-amine (1.0 g, 5.74 mmol), ethyl 2-((4-cyanophenethyl)amino)-2-phenylacetate (2.12 g, 6.88 mmol), trimethylaluminum (5.8 ml, 2 M in toluene, 11.48 mmol) was added at 0° C. The reaction mixture was stirred at 100° C. for 2 hours. After completion of the reaction, the reaction mixture was poured into ice-cold water (50 ml) and extracted with ethyl acetate (2×100 ml). The combined organic layers were washed with brine (50 ml), dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The resulting residue was purified by silica gel chromatography to give the title compound (0.30 g, 12%) as a racemic mixture.

[0203] The racemic title compound was resolved by chiral HPLC (CHIRALCEL OJ-H; 14% MeOH + 0.1% DEA in liquid CO) to give the enantiopure compound. The faster eluting enantiomer of the title compound (Example 22, Isomer 1 in Tables 5 and 8 below) was obtained as a solid. 1 H NMR(400MHz,DMSO-d6):δ 2.73-2.80(m,2H),2.85-2.88(m,3H),3.86(s,3H),4.53(d,J=8.8Hz,1H ),7.25-7.29(m,1H),7.32-7.35(m,2H),7.44(d,J=8.0Hz,4H),7.73(d, LCMS:m / z=437.22[M+1].

[0204] Example 100 [ka] Scheme 6, Step 2, Procedure 1. (R,S)-,(S,S)-2-((2-(4-cyanophenyl)propyl)amino)-N-(5-(1-methyl-1H-1,2,3-triazol-4-yl)pyridin-2-yl)-2-phenylacetamide: To a 1:1 mixture of 5-(1-methyl-1H-1,2,3-triazol-4-yl)pyridin-2-amine (0.1 g, 0.56 mmol), (S,R)- and (S,S)-ethyl 2-((4-cyanophenethyl)amino)-2-phenylacetate (0.27 g, 0.85 mmol) in dry toluene (2 ml), trimethylaluminum (0.6 ml, 2 M in toluene, 1.13 mmol) was added at 0° C. The reaction mixture was stirred at 100° C. for 2 hours. After completion of the reaction, the reaction mixture was poured into ice-cold water (25 ml) and extracted with ethyl acetate (2×50 ml). The combined organic layers were washed with brine (25 ml), dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The resulting residue was purified by silica gel chromatography to give the title compounds (0.078 g, 31%) as a mixture.

[0205] The title compound was resolved by chiral HPLC (CHIRALPAK IC; 10% (70:30 IPA:ACN) + 0.1% DEA in hexanes). The slower eluting enantiomer of the title compound (Example 100, Isomer 2 in Tables 5 and 8 below) was obtained as a solid. 1 H NMR(400MHz,DMSO-d6):δ 1.24(d,J=5.6Hz,1H),2.51-2.66(m,3H),3.04(d,J=7.2Hz,1H),4.10(s,3H),4.50(d,J=7.6Hz,1H),7.28-7.47(m ,7H),7.76(d,J=7.2Hz,2H),8.12-8.18(m,2H),8.57(s,1H),8.79(s,1H),10.64(s,1H).LCMS:m / z=452.52=[M+1].

[0206] Example 20 [ka] (S,R)-, (R,S)-, (S,S)-, (R,R)-(2-((2-(4-cyanophenyl)propyl)amino)-N-(5-(1-(difluoromethyl)-1H-pyrazol-4-yl)pyridin-2-yl)-2-phenylacetamide Scheme 6, Step 2, Procedure 2. (S,R)-, (R,S)-, (S,S)-, (R,R)-(2-((2-(4-cyanophenyl)propyl)amino)-N-(5-(1-(difluoromethyl)-1H-pyrazol-4-yl)pyridin-2-yl)-2-phenylacetamide: To a stirred solution of 5-(1-(difluoromethyl)-1H-pyrazol-4-yl)pyridin-2-amine (0.35 g, 1.67 mmol), ethyl 2-((4-cyanophenethyl)amino)-2-phenylacetate (0.59 g, 1.83 mmol) in dry THF (4 ml), LiHMDS (2 ml, 1 M in THF, 3.34 mmol) was added at 0° C. The reaction mixture was stirred at room temperature for 1 hour. After completion of the reaction (monitored by TLC), the reaction mixture was poured into ice-cold water (15 ml) and extracted with ethyl acetate (2×25 ml). The combined organic layer was washed with brine (15 ml), dried over anhydrous NaSO, and concentrated under reduced pressure. The resulting residue was purified by silica gel chromatography to give a mixture of the title compounds (0.5 g, 61%).

[0207] The mixture was resolved by chiral HPLC (CHIRALCEL OX-H; 45% (50:50 MeOH:IPA) + 0.1% DEA in hexanes) followed by (CHIRALPAK IC; 30% (50:50 MeOH:IPA) + 0.1% DEA in hexanes) to give the enantiopure compound. The first eluting enantiomer of the title compound was obtained as a solid (Isomer 1). 1 H NMR (400 MHz, DMSO-d) δ 1.22 (d, J = 6.8 Hz, 3H), 2.69-2.71 (m, 3H), 3.03-3.07 (m, 1H), 4.49 (d, J = 6.8 Hz, 1H), 7.26-7.49 (m, 7H), 7.72-7.78 (m, 2H), 7.87 (s, 1H), 8.02-8.12 (m, 2H), 8.33 (s, 1H), 8.71 (d, J = 1.2 Hz, 1H), 8.79 (s, 1H), 10.46 (s, 1H). LCMS: m / z = 487.7 [M+1]; the second eluting enantiomer of the title compound was obtained as a solid (isomer 2). 1H NMR (400 MHz, DMSO-d) δ 1.24 (d, J = 6.8 Hz, 3H), 2.60-2.71 (m, 3H), 3.01-3.07 (m, 1H), 4.50 (d, J = 8.4 Hz, 1H), 7.21-7.49 (m, 7H), 7.72-7.80 (m, 2H), 7.87 (s, 1H), 8.02-8.12 (m, 2H), 8.33 (s, 1H), 8.72 (s, 1H), 8.79 (s, 1H), 10.61 (s, 1H). LCMS: m / z = 487.7 [M+1]; the third eluting enantiomer of the title compound was obtained as a solid (isomer 3). 1 H NMR(400MHz,DMSO-d6)δ 1.22(d,J=6.8Hz,3H),2.69-2.71(m,3H),3.04-3.07(m,1H),4.49(d,J=7.6Hz,, 1H),7.26-7.49(m,7H),7.72-7.78(m,2H),7.87(s,1H),8.02-8.12(m,2H),8.33 (s,1H), 8.71 (s,1H), 8.79 (s,1H), 10.46 (s,1H). LCMS: m / z=487.7 [M+1]; the fourth eluting enantiomer of the title compound was obtained as a solid (isomer 4). 1 H NMR(400MHz,DMSO-d6)δ 1.24(d,J=6.4Hz,3H),2.62-2.70(m,3H),3.01-3.07(m,1H),4.50(d,J=8.8Hz,,1H),7.22-7.49(m,7H),7.72-7.78( m,2H),7.87(s,1H),8.02-8.13(m,2H),8.33(s,1H),8.72(s,1H),8.79(s,1H),10.61(s,1H).LCMS:m / z=487.7[M+1].

[0208] Example 33 [ka] (R,S)-,(S,S)-2-(4-cyanophenyl)propyl)amino)-N-(5-(1-methyl-1H-pyrazol-4-yl)pyridin-2-yl)-2-phenylacetamide Scheme 6, Step 1. (R,S)-,(S,S)-2-((2-(4-cyanophenyl)propyl)amino)-2-phenylethyl acetate: A mixture of 2-bromo-2-phenylethyl acetate (9.11 g, 37.5 mmol), (S)-4-(1-aminopropan-2-yl)benzonitrile (5.0 g, 31.2 mmol), and TEA (13.1 ml, 93.7 mmol) in DMF (50 ml) was heated at 60 °C for 3 h. The reaction mixture was poured into ice-cold water (150 ml) and extracted with ethyl acetate (2 × 150 ml). The combined organic layers were washed with brine (150 ml), dried over anhydrous NaSO, and concentrated under reduced pressure. The resulting residue was purified by silica gel chromatography to give a mixture of the title compounds (7.0 g, 70%) as a thick liquid. 1 H NMR(400MHz,DMSO-d6):1.08(t,J=6.8Hz,3H),1.16(d,J=6.8Hz,3H),2.35-2.44(m,1H),2.49-2.66(m,1H),2.96( q,J=6.8Hz,1H),3.96-4.06(m,2H),4.32(s,1H),7.26-7.42(m,7H),7.74(t,J=7.6Hz,2H).LCMS:m / z=323.6[M+1].

[0209] Scheme 6, Step 2, Procedure 2. (R,S)-,(S,S)-2-(4-cyanophenyl)propyl)amino)-N-(5-(1-methyl-1H-pyrazol-4-yl)pyridin-2-yl)-2-phenylacetamide: To a stirred solution of 5-(1-methyl-1H-pyrazol-4-yl)pyridin-2-amine (2.5 g, 14.4 mmol), a 1:1 mixture of (S,R)- and (S,S)-ethyl 2-((2-(4-cyanophenyl)propyl)amino)-2-phenylacetate (7.0 g, 21.7 mmol) in dry THF (50 ml) was added LiHMDS (37 ml, 1 M in THF, 36.2 mmol) at 0° C. The reaction mixture was stirred at room temperature for 1 hour. After completion of the reaction, the reaction mixture was poured into ice-cold water (100 ml) and extracted with ethyl acetate (2×75 ml). The combined organic layers were washed with brine (100 ml), dried over anhydrous NaSO, and concentrated under reduced pressure. The resulting residue was purified by silica gel chromatography to give a mixture of the title compounds (5.0 g, 51%).

[0210] The title compound was resolved by chiral HPLC (CHIRALCEL OJ-H; 15% MeOH+0.1% DEA in liquid CO 2 ) to give the slower eluting isomer (Example 33, Isomer 4 in Tables 5 and 8 below). 1 H NMR (400MHz, DMSO-d): 1.23(d,J=6.8Hz,3H),2.64-2.69(m,3H),3.02 (q,J=6.8Hz,1H),3.86(s,3H),4.47(d,J=7.6Hz,1H),7.24-7.45(m,7H),7.75(d,J=8.4Hz,2H);7.90(s ,1H),7.92-8.03(m,2H),8.18(s,1H),8.56(d,J=1.6Hz,1H),10.52(s,-NH,1H).LCMS:m / z=451.5[M+1].

[0211] Example 84 [ka] (S,S)-,(R,S)-2-((2-(4-cyanophenyl)propyl)amino)-N-(5-(1-(2-(dimethylamino)-2-oxoethyl)-1H-pyrazol-4-yl)pyridin-2-yl)-2-phenylacetamide Scheme 6, Step 2, Procedure 2. (S,S)-,(R,S)-2-((2-(4-cyanophenyl)propyl)amino)-N-(5-(1-(2-(dimethylamino)-2-oxoethyl)-1H-pyrazol-4-yl)pyridin-2-yl)-2-phenylacetamide: To a stirred solution of 2-(4-(6-aminopyridin-3-yl)-1H-pyrazol-1-yl)-N,N-dimethylacetamide (2.0 g, 8.15 mmol), a 1:1 mixture of (S,R)- and (S,S)-ethyl 2-((2-(4-cyanophenyl)propyl)amino)-2-phenylacetate (3.94 g, 12.23 mmol) in dry THF (30 ml), LiHMDS (16.3 ml, 1 M in THF, 16.30 mmol) was added at 0° C. The reaction mixture was stirred at room temperature for 1 hour. After completion of the reaction, the reaction mixture was poured into ice-cold water (50 ml) and extracted with ethyl acetate (2×100 ml). The combined organic layers were washed with brine (50 ml), dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The resulting residue was purified by silica gel chromatography to give a mixture of the title compounds (2.5 g, 59%).

[0212] The mixture was resolved by chiral HPLC (CHIRALCEL OJ-H; 15% MeOH in liquid CO + 0.1% DEA) to give the enantiopure compound. The slower eluting enantiomer of the title compound (Example 84, Isomer 2 in Tables 5 and 8 below) was obtained as a solid. 1H NMR(400MHz,DMSO-d6)δ 1.24(d,J=6.8Hz,3H),2.67(d,J=6.4Hz,3H),2.87(s,3H),3.01-3.05(m,4H),4.48(d,J=7.2Hz,1H),5.14(s,2H),7.25-7.46 (m,7H),7.76(d,J=8.0Hz,2H),7.93-8.05(m,3H),8.12(s,1H),8.59(d,J=1.6Hz,1H),10.50(s,1H).LCMS:m / z=522.61[M+1].

[0213] Example 104 [ka] (R,S)-, (S,S)-N-(5-(1H-pyrazol-4-yl)pyridine-2- yl)-2-((2-(4-cyanophenyl)propyl)amino)-2-phenylacetamide Scheme 6, Step 2, Procedure 2. (R,S)-,(S,S)—N-(5-(1H-pyrazol-4-yl)pyridin-2-yl)-2-((2-(4-cyanophenyl)propyl)amino)-2-phenylacetamide: To a stirred solution of tert-butyl 4-(6-aminopyridin-3-yl)-1H-pyrazole-1-carboxylate (0.8 g, 3.07 mmol), a 1:1 mixture of (S,R)- and (S,S)-ethyl 2-((4-cyanophenyl)amino)-2-phenylacetate (1.38 g, 4.30 mmol) in dry THF (20 ml) was added LiHMDS (7.6 ml, 1 M in THF, 7.69 mmol) at 0° C. The reaction mixture was stirred at room temperature for 1 hour. After completion of the reaction, the reaction mixture was poured into ice-cold water (50 ml) and extracted with ethyl acetate (2×50 ml). The combined organic layers were washed with brine (50 ml), dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The resulting residue was purified by silica gel chromatography to give a mixture of the title compounds (0.52 g, 40%).

[0214] The mixture was resolved by chiral HPLC (CHIRALPAK IG; 100% (70:30 MeOH:ACN)) to give the enantiopure compound. The slower eluting enantiomer of the title compound (Example 104, Isomer 2 in Tables 5 and 8 below) was obtained as a solid. 1 H NMR(400MHz,DMSO-d6)δ 1.24(d,J=8.0Hz,3H),2.66(s,3H),3.01-3.06(s,1H),4.49(s,1H),7.25-7.46(m,7H),7.76(d,J=8.0Hz ,2H),7.97-8.04(m,3H),8.25(s,1H),8.62(s,1H),10.51(s,1H),13.02(s,1H).LCMS:m / z=437.46[M+1].

[0215] Example 127 [ka] (R,S)-,(S,S)-2-((2-(4-cyanophenyl)propyl)amino)-2-(1-methyl-1H-pyrazol-4-yl)-N-(5-(1-methyl-1H-pyrazol-4-yl)pyridin-2-yl)acetamide: Scheme 6, Step 2, Procedure 2. (R,S)-,(S,S)-((2-(4-cyanophenyl)propyl)amino)-2-(1-methyl-1H-pyrazol-4-yl)-N-(5-(1-methyl-1H-pyrazol-4-yl)pyridin-2-yl)acetamide: To a stirred solution of 5-(1-methyl-1H-pyrazol-4-yl)pyridin-2-amine (1.5 g, 8.61 mmol), a 1:1 mixture of (S,R)- and (S,S)-ethyl 2-((2-(4-cyanophenyl)propyl)amino)-2-(1-methyl-1H-pyrazol-4-yl)acetate (3.37 g, 10.33 mmol) in dry THF (30 ml), LiHMDS (22.0 ml, 1 M in THF, 21.52 mmol) was added at 0° C. The reaction mixture was stirred at room temperature for 1 hour. After completion of the reaction, the reaction mixture was poured into ice-cold water (50 ml) and extracted with ethyl acetate (2×100 ml). The combined organic layer was washed with brine (50 ml), dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The resulting residue was purified by silica gel chromatography to give a mixture of the title compounds (2.9 g, 74%).

[0216] The mixture was analyzed by chiral HPLC (CHIRALCEL OJ-H; 10% Me in liquid CO The enantiopure compound was obtained by resolution with HCl (HCOOH + 0.1% DEA). The slower eluting enantiomer of the title compound (Example 127, Isomer 4 in Tables 5 and 8 below) was obtained as a solid. 1 H NMR(400MHz,DMSO-d6)δ 1.24(d,J=6.8Hz,3H),2.68(s,2H),2.97-3.03(s,1H),3.57(s,1H),3.77( s,3H),3.87(s,3H),4.36(s,1H),7.34(s,1H),7.45(d,J=8.4Hz,2H),7.59( s,1H),7.75(d,J=8.4Hz,2H),7.91(s,1H),7.95(dd,J=2.0Hz,8.4Hz,2H), 8.18(s,1H),8.57(d,J=1.6Hz,1H),10.36(s,1H).LCMS:m / z=455.51[M+1].

[0217] The following compounds were prepared using procedures similar to those described for Examples 19, 22, 100, 20, 33, 84, 104, and 127 using the appropriate starting materials. [Table 10-1] [Table 10-2] [Table 10-3] [Table 10-4] [Table 10-5] [Table 10-6] [Table 10-7] [Table 10-8] [Table 10-9] [Table 10-10] [Table 10-11] [Table 10-12] [Table 10-13] [Table 10-14]

[0218] Scheme 7 Starting materials required for the synthesis of examples prepared using Scheme 8. Examples were generally prepared using methods 1-16 or are commercially available.

[0219] Example 151 [ka] (S)- and (R)-4-(2-(2-(6-(1-methyl-1H-pyrazol-4-yl)-3,4-dihydroquinolin-1(2H)-yl)-2-oxo-1-phenylethyl)amino)ethyl)benzonitrile Scheme 7, Step 1. tert-Butyl 6-(1-methyl-1H-pyrazol-4-yl)-3,4-dihydroquinoline-1(2H)-carboxylate: A mixture of tert-butyl 6-bromo-3,4-dihydroquinoline-1(2H)-carboxylate (0.55 g, 1.76 mmol), 1-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (0.439 g, 2.11 mmol), and cesium carbonate (1.43 g, 4.40 mmol) in a 4:1 mixture of dioxane:water (10 ml) was purged with argon gas for 20 minutes. S-Phos Pd-G3-precatalyst (0.066 g, 0.08 mmol) was added, and the purging was continued for an additional 10 minutes. The reaction mixture was heated at 100° C. for 2 hours. The residue was purified by silica gel chromatography to give the title compound (0.55 g, 99%) as a solid. 1 H NMR(400MHz,DMSO-d6):1.08(s,9H),1.81-1.87(m,2H),2.74(t,J=6.4Hz,2H),3.63(t,J=6.0Hz,2H),3 .85(s,3H),7.29-7.31(m,2H),7.54(d,J=9.2Hz,1H),7.80(s,1H),8.07(s,1H);LCMS:m / z=314.2[M+1].

[0220] Scheme 7, Step 2. 6-(1-methyl-1H-pyrazol-4-yl)-1,2,3,4-tetrahydroquinoline: To a stirred solution of tert-butyl 6-(1-methyl-1H-pyrazol-4-yl)-3,4-dihydroquinoline-1(2H)-carboxylate (0.1 g, 0.31 mmol) in dry 1,4-dioxane (1 ml) was added 4 M HCl in dioxane (1 ml) dropwise at 0 °C. The reaction mixture was stirred at room temperature for 2 hours. The reaction mixture was concentrated, neutralized with saturated sodium bicarbonate, and extracted with ethyl acetate (3 × 10 ml). The combined organic layers were washed with brine (10 ml), dried over anhydrous NaSO, and concentrated under reduced pressure to give the title compound (0.050 g, 73%). LCMS: m / z = 214.2 [M+1].

[0221] Method 7, Step 3. (S)- and (R)-4-(2-(2-(6-(1-methyl-1H-pyrazol-4-yl)-3,4-dihydroquinolin-1(2H)-yl)-2-oxo-1-phenylethyl)amino)ethyl)benzonitrile: To a mixture of 6-(1-methyl-1H-pyrazol-4-yl)-1,2,3,4-tetrahydroquinoline (0.05 g, 0.23 mmol) and ethyl 2-((4-cyanophenyl)amino)-2-phenylacetate (0.060 g, 0.19 mmol) in toluene (0.6 ml) was added TMA (0.19 ml, 2 M in toluene, 0.39 mmol) at 0° C. under a nitrogen atmosphere. The resulting reaction mixture was heated at 100° C. for 2 hours. After completion of the reaction (monitored by TLC), the mixture was slowly quenched with saturated sodium bicarbonate (10 ml), and the aqueous layer was extracted with ethyl acetate (2×10 ml). The combined organic layers were washed with brine (10 ml), dried over anhydrous NaSO, and concentrated under reduced pressure. The resulting residue was purified by silica gel chromatography to give the title compound (0.03 g, 32%) as a racemic mixture. The racemate was resolved by chiral HPLC (CHIRALCEL OJ-H; 15% (50:50 ACN:IPA) + 0.1% DEA in liquid CO) to give the enantiopure compound. The faster eluting enantiomer of the title compound was obtained as a solid (Isomer 1). 1H NMR (400 MHz, DMSO-d6): δ 1.71-1.77 (m, 2H), 2.58-2.79 (m, 6H), 3.36-3.52 (m, 1H), 3.79-3.85 (m, 1H), 3.86 (s, 3H), 4.86 (s, 1H), 6.85-7.19 (m, 2H), 7.25-7.35 (m, 6H), 7.41 (d, J = 7.6 Hz, 2H), 7.75 (d, J = 8.0 Hz, 2H), 7.85 (s, 1H), 8.12 (s, 1H). LCMS: m / z = 476.3 [M+1]. The slower eluting enantiomer of the title compound was obtained as a solid (isomer 2): 1 H NMR(400MHz,DMSO-d6):δ 1.71-1.77(m,2H),2.65-2.79(m,6H),3.36-3.46(m,1H),3.79-3.81(m,1H),3.86(s,3H),4.86(s,1H),6.85-7.15(m,2 H),7.25-7.35(m,6H),7.41(d,,J=8.0Hz,2H),7.75(d,J=8.0Hz,2H),7.85(s,1H),8.12(s,1H).LCMS:m / z=476.3[M+1].

[0222] The following compounds were prepared using procedures similar to those described for Example 151, using the appropriate starting materials. [Table 11]

[0223] Example 153 [ka] (S)- and (R)-4-(2-(2-(indolin-1-yl)-2-oxo-1-phenylethyl)amino)ethyl)benzenesulfonamide To a solution of indoline (0.5 g, 4.19 mmol) and TEA (0.849 g, 8.39 mmol) in DMF (10 ml) was added 2-chloro-2-phenylacetyl chloride (0.79 g, 4.19 mmol) dropwise at 0° C., and the reaction mixture was stirred at room temperature for 2 hours. The above reaction mixture was added dropwise to a stirred solution of 4-(2-aminoethyl)benzenesulfonamide (1.67 g, 8.38 mmol) in DMF (5 ml) at room temperature over 10 minutes. The resulting reaction mixture was stirred at room temperature for 2 hours. The reaction mixture was poured into ice-cold water (15 ml) and extracted with ethyl acetate (2×15 ml). The combined organic layers were washed with brine (15 ml), dried over anhydrous NaSO, and concentrated under reduced pressure. The resulting product was purified by silica gel chromatography to give the title compound as a racemic solid (0.25 g, 14%).

[0224] The racemic title compound was resolved by chiral HPLC (CHIRALPAK IB; 40% (50:50 MeOH:IPA in hexanes) + 0.1% DEA) to give the enantiopure compound. The faster eluting enantiomer of the title compound was obtained as a solid (Isomer 1). 1 H NMR(400MHz,DMSO-d6):δ 2.61-2.84(m,4H),2.99-3.15(m,2H),3.68-3.75(m,1H),4.31-4.38(m,1H),4.69(s,1H),7.01(t,J=8.0Hz ,1H),7.12-7.25(m,2H),7.28-7.44(m,8H),7.73(d,J=8.0Hz,2H),8.15(d,J=8.0Hz,1H).LCMS:(Method C-3):R T 1.54 min; m / z 436.5 [M+1]. The slower eluting enantiomer of the title compound was obtained as a solid (isomer 2). 1H NMR(400MHz,DMSO-d6):δ 2.64-2.83(m,4H),2.99-3.18(m,2H),3.68-3.75(m,1H),4.31-4.38(m,1H),4.69(s,1H),7.01(t,J=8.0Hz,1H ),7.14-7.22(m,2H),7.28-7.41(m,8H),7.73(d,J=8.0Hz,2H),8.15(d,J=8.0Hz,1H).LCMS:m / z=436.5[M+1].

[0225] The following compounds were prepared using procedures similar to those described for Example 153, using the appropriate starting materials. [Table 12]

[0226] While several embodiments have been described, it will be apparent that our basic examples can be modified to provide other embodiments that utilize the compounds and methods of the present invention. It will therefore be understood that the scope of this invention is to be defined by the appended claims rather than by the specific embodiments that have been represented by way of example.

[0227] All references (including literature references, issued patents, published patent applications, and co-pending patent applications) cited throughout this application are expressly incorporated herein by reference in their entirety. Unless otherwise defined, all technical and scientific terms used herein accord with the meaning commonly known to those skilled in the art.

Claims

1. 1. A method of treating a neuropathy in a subject in need thereof, comprising administering to said subject an effective amount of a compound having formula I: 【Chemical 1】 or a pharmaceutically acceptable salt thereof, wherein: Ring B is aryl, heterocyclyl, or heteroaryl, each of which is R ｂ and optionally substituted with 1 to 4 groups selected from R ６ is hydrogen or C １－６ is alkyl, R ７ is aryl or heteroaryl, each of which is R ｆ and R ７ The aryl and heteroaryl for ａ or R ６ and R ７ together with the nitrogen ring to which they are attached, optionally R ａ forming a fused bicyclic heterocyclyl substituted with 1 to 4 groups selected from R １ But C １－６ Alkyl, C １－６ Haloalkyl, C ２－６ Alkenyl, -C １－６ Alkyl OR ｃ , -C １－６ AlkylN(R ｄ ) ２ , -C １－６ AlkylC(O)OR ｄ , -C １－６ Alkyl OC １－６ AlkylN(R ｄ ) ２ , -C １－６ Alkyl SOR ｄ , -C １－６ AlkylS(O) ２ R ｄ , -C １－６ Alkyl SON (R ｄ ) ２ , -C １－６ Alkyl SO ２ N (R ｄ ) ２ , -C １－６ Alkylcycloalkyl, —C １－６ alkylheterocyclyl, —C １－６ alkylheteroaryl, —C １－６ alkylaryl, cycloalkyl, aryl, heteroaryl, or heterocyclyl, wherein each of said cycloalkyl, heterocyclyl, aryl, and heteroaryl may be independently selected from the group consisting of -C １－６ Alkylcycloalkyl, —C １－６ Alkylaryl, —C １－６ alkylheteroaryl, and —C １－６ At the bond to the alkylheterocyclyl, optionally, R ｃ and is substituted with 1 to 3 groups selected from R ２ , R ３ , R ４ , and R ５ each independently represents hydrogen or C １－６ alkyl, １－６ The alkyl is optionally selected from halo, —C(O)OR ｄ , -OC １－６ AlkylN(R ｄ ) ２ , -C １－６ AlkylN(R ｄ ) ２ , -N(R ｄ ) ２、 -NR ｄ C １－６ Alkyl OR ｄ , -SOR ｄ , -S(O) ２ R ｄ , -SON(R ｄ ) ２ , -SO ２ N (R ｄ ) ２ , C ３－１０ Cycloalkyl, C ５－１０ Heterocyclyl, C ５－１０ Heteroaryl, and C ６－１０ substituted with one or two groups selected from aryl; R ａ , R ｂ , and R ｃ each independently represents halo, CN, oxo, NO ２ , C １－６ Alkyl, C ２－６ Alkenyl, C １－６ Alkoxy, C １－６ Haloalkoxy, C １－６ Haloalkyl, —C １－６ Alkyl OR ｄ , -C(O)R ｄ , -C(O)OR ｄ , -C １－６ AlkylC(O)OR ｄ , -C(O)N(R ｄ ) ２ , —C(O)NR ｄ C １－６ Alkyl OR ｄ , -OC １－６ AlkylN(R ｄ ) ２ , -C １－６ AlkylC(O)N(R ｄ ) ２、 -C １－６ AlkylN(R ｄ ) ２ , -N(R ｄ ) ２ , —C(O)NR ｄ C １－６ AlkylN(R ｄ ) ２ , -NR ｄ C １－６ AlkylN(R ｄ ) ２ , -NR ｄ C １－６ Alkyl OR ｄ , -SOR ｄ , -S(O) ２ R ｄ , -SON(R ｄ ) ２ , -SO ２ N (R ｄ ) ２ , SF ５ , —Ocycloalkyl, —O—C １－４ Alkylaryl, —C １－６ Alkylcycloalkyl, —C １－６ Alkylaryl, —C １－６ alkylheteroaryl, —C １－６ alkylheterocyclyl, cycloalkyl, heterocyclyl, heteroaryl, or aryl, each of said cycloalkyl, heterocyclyl, aryl, and heteroaryl independently; and —Ocycloalkyl, —C １－６ Alkylcycloalkyl, —C １－６ Alkylaryl, —C １－６ Alkylheteroary -C １－６ At the bond to the alkylheterocyclyl, optionally halo, C １－６ Alkyl, C １－６ Haloalkyl, C １－６ Alkoxy, C １－６ haloalkoxy, —N(R ｄ ) ２ , -C(O)R ｄ , and -C １－６ Alkyl OR ｄ is substituted with 1 to 3 groups selected from Each R ｄ are independently hydrogen, C １－６ haloalkyl, or C １－６ is alkyl, Each R ｆ is independently cycloalkyl, heterocyclyl, heteroaryl, or aryl, each of said cycloalkyl, heterocyclyl, aryl, and heteroaryl optionally selected from halo, CN, oxo, NO ２ , C １－６ Alkyl, C ２－６ Alkenyl, C １－６ Alkoxy, C １－６ Haloalkoxy, C １－６ Haloalkyl, —C １－６ Alkyl OR ｄ , -C(O)R ｄ , -C(O)OR ｄ , -C １－６ AlkylC(O)OR ｄ , -C(O)N(R ｄ ) ２ , —C(O)NR ｄ C １－６ Alkyl OR ｄ , -OC １－６ AlkylN(R ｄ ) ２ , -C １－６ AlkylC(O)N(R ｄ ) ２ , -C １－６ AlkylN(R ｄ ) ２ , -N(R ｄ ) ２ , —C(O)NR ｄ C １－６ AlkylN(R ｄ ) ２ , -NR ｄ C １－６ AlkylN(R ｄ ) ２ , -NR ｄ C １－６ Alkyl OR ｄ , -SOR ｄ , -S(O) ２ R ｄ , -SON(R ｄ ) ２ , -SO ２ N (R ｄ ) ２ , SF ５ , —Ocycloalkyl; However, the compound is not N-[1,1'-biphenyl]-2-yl-2-[[2-(3,4-dimethoxyphenyl)ethyl]amino]-propanamide, or 2-[(2-phenylpropyl)amino]-N-[4-(1H-1,2,4-triazol-1-yl)phenyl]-propanamide, or a salt thereof.

2. The compound is of formula II or III: 【Chemistry 2】 or a pharmaceutically acceptable salt thereof.

3. R ６ is hydrogen, and R ７ is aryl or heteroaryl, each of which is R ｆ and R ７ The aryl and heteroaryl for ａ or R ６ and R ７ together with the nitrogen ring to which they are attached, optionally R ａ The method according to claim 1 or 2, wherein the fused bicyclic heterocyclyl is formed substituted with 1 to 4 groups selected from:

4. R ６ is hydrogen, and R ７ is phenyl, pyridyl, pyrimidinyl, or quinolinyl, each of which is R ｆ and R ７ The phenyl, pyridyl, pyrimidinyl, and quinolinyl for ａ or R ６ and R ７ together with the nitrogen ring to which they are attached, optionally R ａ The method according to any one of claims 1 to 3, wherein a 5,6- or 6,6-fused bicyclic heterocyclyl is formed which is substituted with 1 to 4 groups selected from:

5. R ６ is hydrogen, and R ７ is selected from phenyl, 2-pyridinyl, 3-pyridinyl, pyrimidin-5-yl, and quinolin-6-yl, each of which is R ｆ and R ７ The phenyl, 2-pyridinyl, 3-pyridinyl pyrimidin-5-yl, and quinolin-6-yl are also optionally represented by R ａ or R ６ and R ７ together with the nitrogen ring to which they are attached form indolin-1-yl or dihydroquinolin-1(2H)-yl, each of which optionally contains R ａ The method according to any one of claims 1 to 4, wherein the aryl group is optionally substituted with 1 to 4 groups selected from the group consisting of:

6. Ring B is optionally R ｂ The method according to any one of claims 1 to 5, wherein the phenyl is phenyl substituted with 1 to 3 groups selected from the group consisting of:

7. R １ Optionally, R ｃ The method according to any one of claims 1 to 6, wherein the phenyl is phenyl substituted with 1 to 3 groups selected from the group consisting of:

8. R ３ The method of any one of claims 1 to 7, wherein is hydrogen.

9. R ５ The method of any one of claims 1 to 8, wherein is hydrogen.

10. R ２ is hydrogen or C １－４ The method of any one of claims 1 to 9, wherein the alkyl is alkyl.

11. R ２ The method of any one of claims 1 to 10, wherein is hydrogen or methyl.

12. R ２ The method of any one of claims 1 to 11, wherein is hydrogen.

13. R ４ is hydrogen or C １－４ The method of any one of claims 1 to 12, wherein the alkyl is alkyl.

14. R ４ The method of any one of claims 1 to 13, wherein is hydrogen or methyl.

15. R ４ The method of any one of claims 1 to 14, wherein is hydrogen.

16. The compound is of formula IV or V: 【Chemistry 3】 or a pharmaceutically acceptable salt thereof, wherein w, q, and t are each independently 0, 1, or 2.

17. The compound is of formula VI or VII: 【Chemistry 4】 or a pharmaceutically acceptable salt thereof, wherein w, q, and t are each independently 0, 1, or 2.

18. The compound is of formula VIII or IX: 【Chemistry 5】 or a pharmaceutically acceptable salt thereof, wherein w, q, and t are each independently 0, 1, or 2.

19. R ｃ If C exists, １－６ Alkyl, C １－６ Alkoxy, C １－６ haloalkoxy, or C １－６ The method of any one of claims 1 to 18, wherein the alkyl is haloalkyl.

20. The compound is of formula X or XI, 【Chemistry 6】 or a pharmaceutically acceptable salt thereof.

21. 21. The method of any one of claims 1 to 20, wherein q is 0 or 1.

22. R ａ But C １－４ The method of any one of claims 1 to 21, wherein the aryl group is alkoxy or halo.

23. R ｆ is heteroaryl or heterocyclyl, each of which is optionally selected from halo, CN, oxo, NO ２ , C １－６ Alkyl, C ２－６ Alkenyl, C １－６ Alkoxy, C １－６ Haloalkoxy, C １－６ Haloalkyl, —C １－６ Alkyl OR ｄ , -C(O)R ｄ , -C(O)OR ｄ , -C １－６ AlkylC(O)OR ｄ , -C(O)N(R ｄ ) ２ , —C(O)NR ｄ C １－６ Alkyl OR ｄ , -OC １－６ AlkylN(R ｄ ) ２ , -C １－６ AlkylC(O)N(R ｄ ) ２ , -C １－６ AlkylN(R ｄ ) ２ , -N(R ｄ ) ２ , —C(O)NR ｄ C １－６ AlkylN(R ｄ ) ２ , -NR ｄ C １－６ AlkylN(R ｄ ) ２ , -NR ｄ C １－６ Alkyl OR ｄ , -SOR ｄ , -S(O) ２ R ｄ , -SON(R ｄ ) ２ , -SO ２ N (R ｄ ) ２ , SF ５ 23. The method of any one of claims 1 to 22, wherein the alkyl group is substituted with 1 to 3 groups selected from -Ocycloalkyl.

24. R ｆ is pyrazolyl, imidazolyl, pyridazinyl, piperazinyl, or piperidinyl, each of which is optionally selected from halo, CN, oxo, NO ２ , C １－６ Alkyl, C ２－６ Alkenyl, C １－６ Alkoxy, C １－６ Haloalkoxy, C １－６ Haloalkyl, —C １－６ Alkyl OR ｄ , -C(O)R ｄ , -C(O)OR ｄ , -C １－６ AlkylC(O)OR ｄ , -C(O)N(R ｄ ) ２ , —C(O)NR ｄ C １－６ Alkyl OR ｄ , -OC １－６ AlkylN(R ｄ ) ２ , -C １－６ AlkylC(O)N(R ｄ ) ２ , -C １－６ AlkylN(R ｄ ) ２ , -N(R ｄ ) ２ , —C(O)NR ｄ C １－６ Archi LuN (R ｄ ) ２ , -NR ｄ C １－６ AlkylN(R ｄ ) ２ , -NR ｄ C １－６ Alkyl OR ｄ , -SOR ｄ , -S(O) ２ R ｄ , -SON(R ｄ ) ２ , -SO ２ N (R ｄ ) ２ , SF ５ 24. The method of any one of claims 1 to 23, wherein the alkyl group is substituted with 1 to 3 groups selected from -Ocycloalkyl.

25. R ｆ is pyrazolyl, imidazolyl, pyridazinyl, piperazinyl, or piperidinyl, each of which is optionally １－４ Alkyl and —C(O)R ｄ and R ｄ is C １－４ The method of any one of claims 1 to 24, wherein the alkyl is alkyl.

26. R ｂ is halo, cyano, or -SO ２ NH ２ The method according to any one of claims 1 to 25, wherein

27. The compound is of formula XII or XIII: 【Chemistry 7】 or a pharmaceutically acceptable salt thereof, wherein w, q, and t are each independently 0, 1, or 2.

28. The compound is of formula XIV or XV: 【Chemistry 8】 or a pharmaceutically acceptable salt thereof, wherein w, q, and t are each independently 0, 1, or 2.

29. The compound is of formula XVI or XVII: 【Chemistry 9】 or a pharmaceutically acceptable salt thereof, wherein w, q, and t are each independently 0, 1, or 2.

30. The compound is of formula XVIII or XIX: 【Chemistry 10】 or a pharmaceutically acceptable salt thereof, wherein w, q, and t are each independently 0, 1, or 2.

31. The compound is of formula XX or XXI, 【Chemistry 11】 or a pharmaceutically acceptable salt thereof, wherein w, q, and t are each independently 0, 1, or 2.

32. The compound is of formula XXII or XXIII: 【Chemistry 12】 or a pharmaceutically acceptable salt thereof, wherein w, q, and t are each independently 0, 1, or 2.

33. R ｃ If present, independently, C １－６ The method of any one of claims 27 to 32, wherein the alkyl, halo, or CN.

34. R ｃ If C exists, １－４ The method of any one of claims 27 to 33, wherein the alkyl is alkyl.

35. 35. The method of any one of claims 27 to 34, wherein w is 0 or 1.

36. R ｂ is halo, cyano, or -SO ２ NH ２ The method according to any one of claims 27 to 35, wherein

37. R ｂ The method of any one of claims 27 to 36, wherein is cyano.

38. 38. The method of any one of claims 27 to 37, wherein t is 1.

39. 39. The method of any one of claims 27 to 38, wherein q is 1.

40. R ｆ is cycloalkyl, phenyl, heteroaryl or heterocyclyl, each of which is optionally selected from halo, CN, oxo, NO ２ , C １－６ Alkyl, C ２－６ Alkenyl, C １－６ Alkoxy, C １－６ Haloalkoxy, C １－６ Haloalkyl, —C １－６ Alkyl OR ｄ , -C(O)R ｄ , -C(O)OR ｄ , -C １－６ AlkylC(O)OR ｄ , -C(O)N(R ｄ ) ２ , —C(O)NR ｄ C １－６ Alkyl OR ｄ , -OC １－６ AlkylN(R ｄ ) ２ , -C １－６ AlkylC(O)N(R ｄ ) ２ , -C １－６ AlkylN(R ｄ ) ２ , -N(R ｄ ) ２ , —C(O)NR ｄ C １－６ AlkylN(R ｄ ) ２ , -NR ｄ C １－６ AlkylN(R ｄ ) ２ , -NR ｄ C １－６ Alkyl OR ｄ , -SOR ｄ , -S(O) ２ R ｄ , -SON(R ｄ ) ２ , -SO ２ N (R ｄ ) ２ , SF ５ 40. The method of any one of claims 27 to 39, wherein the alkyl group is substituted with 1 to 3 groups selected from -Ocycloalkyl.

41. R ｆ is pyrimidinyl, phenyl, cyclobutanyl, cyclopropyl, pyrazolyl, imidazolyl, azetidinyl, piperidinyl, pyrrolidinyl, piperazinyl, triazolopyrazinyl, triazolyl, imidazolidinyl, thiadiazolidinyl, morpholinyl, oxaazaspiroheptanyl, oxaazaspirooctanyl, dihydropyrimidinyl, oxadiazolyl, isoxazolyl, or dihydropyridazinyl, each of which is optionally selected from halo, CN, oxo, NO, ２ , C １－６ Alkyl, C ２－６ Alkenyl, C １－６ Alkoxy, C １－６ Haloalkoxy, C １－６ Haloalkyl, —C １－６ Alkyl OR ｄ , -C(O)R ｄ , -C(O)OR ｄ , -C １－６ AlkylC(O)OR ｄ , -C(O)N(R ｄ ) ２ , —C(O)NR ｄ C １－６ Alkyl OR ｄ , -OC １－６ AlkylN(R ｄ ) ２ , -C １－６ AlkylC(O)N(R ｄ ) ２ , -C １－６ AlkylN(R ｄ ) ２ , -N(R ｄ ) ２ , —C(O)NR ｄ C １－６ AlkylN(R ｄ ) ２ , -NR ｄ C １－６ AlkylN(R ｄ ) ２ , -NR ｄ C １－６ Alkyl OR ｄ , -SOR ｄ , -S(O) ２ R ｄ , -SON(R ｄ ) ２ , -SO ２ N (R ｄ ) ２ , SF ５ 41. The method of any one of claims 27 to 40, wherein the alkyl group is substituted with 1 to 3 groups selected from -Ocycloalkyl.

42. R ｆ is pyrimidinyl, phenyl, pyrazolyl, imidazolyl, azetidinyl, piperidinyl, pyrrolidinyl, piperazinyl, triazolopyrazinyl, triazolyl, imidazolidinyl, thiadiazolidinyl, morpholinyl, oxaazaspiroheptanyl, oxaazaspirooctanyl, dihydropyrimidinyl, oxadiazolyl, isoxazolyl, or dihydropyridazinyl, each of which is optionally selected from halo, oxo, C １－６ Alkyl, C １－６ Alkoxy, C １－６ Haloalkyl, —C １－６ Alkyl OR ｄ , -C(O)R ｄ , -C(O)N(R ｄ ) ２ , -C １－６ AlkylC(O)N(R ｄ ) ２ , and -S(O) ２ R ｄ The method of any one of claims 27 to 41, wherein the compound is optionally substituted with 1 to 3 groups selected from the group consisting of:

43. R ｆ is pyrazolyl or triazolyl, each of which is optionally １－３ Alkyl or —C(O)N(R ｄ ) ２ 43. The method of any one of claims 27 to 42, wherein the substituted

44. R ｄ is hydrogen or C １－３ The method of any one of claims 27 to 43, wherein the alkyl is alkyl.

45. R ｄ But C １－３ The method of any one of claims 27 to 44, wherein the alkyl is alkyl.

46. 46. ​​The method of any one of claims 1 to 45, wherein the neurological disorder is selected from frontotemporal dementia, Alzheimer's disease, tauopathy, vascular dementia, Parkinson's disease, and dementia with Lewy bodies.

Images